NHAc
R2 O
R1
SPh
C
R2
SPh
NHAcR1
∆
O
NAcR1
R2
CH2
Section 1-Chemistry of Heteroaromatics
SPh
O2,3-shift
BF3.OEt2
NEt3O
O O
HHO
OCH2Ph PhCH2O
NN
N
X
CN
Ph
Ph N
N
X
Ph
Ph
Literature of Heterocyclic Chemistry
1. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1984, Pergamon, Vol. 1-8
2. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1996, Pergamon, Vol. 1-11
3. "The Chemistry of Heterocyclic Compounds," Weissberger/Taylor, >50 volumes.
4. "Advances in Heterocyclic Chemistry," Katritzky/Boulton, (Vol. 40, p. 1 has review by Katritzky which lists heterocyclic reviews)._____________________________________________________________
Nomenclature of Heterocycles
1. "Nomenclature of Heterocycles" by McNaught/Smith in "Comprehensive Heterocyclic Chem." 1984, Vol. 1, Chap. 2.
2. "Revision of the Extended Hantzsch-Widman System of Nomenclature for Heteromonocycles," Pure Appl. Chem. 1983, 55, 409 [IUPAC].
3. McNaught, in Adv. Heterocycl. Chem. 1976, 20, 175.
4. "Nomenclature of Organic Chemistry" (IUPAC) (The "Blue Book") Pergamon, 1979. Has heterocyclic section.
5. Chemical Abstract Service, "Index Guide" 1982-1986; Appendix IV "Chemical Substance Index Names" •includes heterocycles • generally same as IUPAC, but many exceptions
6. Chemical Abstract service, "Ring Index"
Section one - Chemistry of Heteroaromatics
1
HN
N
N N
N
N
N
NN
O
HN
S
ON
N
N
N
N
N NN
N
N
O
SN
HN
O
N N N
1
3
Pyrazole Pyridine Pyrazine Pyrimidine
O
Pyridazine
O
S
Pyrrole
Furan
N
Thiophene
Isoxazole
HN
N
Quinoline
N
Quinoxaline
Quinazoline
NHN
Cinnoline
Phthalazine
HN
N
Isobenzofuran
Isothiazole
HN
NN
N
Indole
Accepted Trivial Names (partial list)
Pyran(2H-shown)
N
Chromene(2H-shown)
Xanthene
N
N N
N
Phenoxathiin
2H-Pyrrole Imidazole
N
Indolizine
NN
3H-Indole
N
1H-IndazoleIsoindole Purine
N
4H-Quinolizine
NN
N
Isoquinoline Naphthyridine (1,8-shown)
NN
4aH-carbazole CarbazolePteridine
N
N
β-Carboline
S
N
Phenanthridine Acridine Perimidine
ONN
Phenanthroline (1,7-shown)
Phenazine
O
Furazan
H
1
2
8
2
1
27 1
2
H
1
2
1
9 1 9810 11
2
12
12
1
2
1
2
H
1
2
3
1 1 1 1 1 11
22
22 2 2
3
8
4 3
7
3 3 34
7
4
56
7
8
9
1
4
9
5
8 12
3
8 1
2
8 1
2
3
8 1 8 1
4
8 8 1
2
8 1
35
8 9 1
4a
89
1
89
1
4
10
1
4
56
8 9 1
5
10
4
1 3
4
6
7
9
1
104
5
6
7
9 10 1
45
1
2
1
4
10
5
1
2
1
62
Phenothiazine
12
5
Section one - Chemistry of Heteroaromatics
2
Eproxindine--Antiarrhythmic agent
S
Manazodil--Vasodilator
NH
N
Vibunazole--Antiviral agent
Methdilazine--Antihistamine
Clopidogrel--Antithrombotic agent
C
N
N
N
NHNH2
NHNH2
N
NN
Me
MeO
N CONHCH2CH(OH)CH2NEt2
Ph
OMe
S
N
Me
MeNHCH2
S
NH2C
Dihydralazine--Antihypertensive agent
N
H
H
NCH2CH=CHPh
Elks, J.; Ganellin, C. R. Dictionary of Drugs, Chapman and Hall, 1990, N.Y.
Cinprazole--Antiulcerogenic agent
N
NN
CH2 C
tBu
OH
CH2 ClO
Epirizole--Antiflammatory agent
Dictionary of Drugs
Me
OMe
CO2Me
Cl
NMe
Section one - Chemistry of Heteroaromatics
3
Lednicer, D.; Mitscher, L. A.; The Organic Chemistry of Drug Synthesis Wiley-Interscience: New York; Vols 1-4, 1990
S
Cl
F
NH2 Cl
F
N
CO2EtEtO2C
Cl
F
N
OHCO2Et
Cl
F
N
OCO2Et
Et
N
F
N
OCO2H
Me2NCH2CNH2
Et
+
N
BrCH2COCO2Et
Me
Pefloxacin--antimicrobial agent with oral activity
NBr Br NBr
O
MeNBr
Me
N
NCHO
Me
N
N
Me
N
HO2C
Nizatidine--antagonist of histamine at H-2 receptors
Acrivastine--a nonsedating H-1 antihistamine
N
SMe2NCH2
CO2Et
N
SMe2NCH2
CH2S(CH2)2NH2N
SMe2NCH2
CH2S(CH2)2
MeHN
HN H
NO2
Section one - Chemistry of Heteroaromatics
4
CH3
N
ONH
SThiophene
2. Extended Hantzsch-Widman Nomenclature
FuranPyrrole
1. Trivial Names
No structural information, often based on origin.
3-Picoline (from coal tar) Latin picatas = tarry
(systematic name = 3-methylpyridine)
Currently over 60 trivial names accepted by IUPAC for use as "parents" in systematic nomenclature. (See McNaught/Smith for full list.)
Examples:
use for less than10-membered rings
stem and prefix
N = aza-
P = phospha-
O = oxa-indicates ringsize and degreeof unsaturation. S = thia-
indicates which heteroatoms are present
B C N O
drop "a" ending whenfollowed by a vowel.
P S
F
Cl
Br
highest
lowest
Priority of heteroatomsfor numbering purposes:
Se(i.e., O > S > N > P)
Section one - Chemistry of Heteroaromatics
5
OO H
NHN
NH
HN
N
HN
3
NH
HN
3 3
Isochroman
H
These compounds remain as trivial names but are not recommended for use in fusion.
HN
NH
PyrrolidineChroman Pyrroline
Imidazolidine
HN
Imidazoline (∆2 shown)
Pyrazolidine
NH
HN
Pyrazoline(∆3 shown)
Piperidine Piperazine Indoline
HN
Isoindoline
Quinuclidine
NH
Morpholine
O
NNH
8 1
2
4
8 1
4
51
21
2
3
2
1 1
2
12
3
12
3
1
4
71
3
7 1
8
43
216
5
7 1
4
2
2
1
Section one - Chemistry of Heteroaromatics
6
NHN
O O
Ring Size Maximum Unsaturation
HN
(e.g.) Fully Saturated
(e.g.)
O
3 -irine(N only)
-iridine(N only)
Aziridine
N
Stems: (see McNaught/Smith for full discussion)
Azirine
-irene(O,S,...)
-irane(O,S,...)
4 -ete
Azete
Oxirene Oxirane
Azetidine
-etane(O,S,...)
Oxetane
5
NH
-ole*
Oxazole
-olidine*(N only)
N
N
N
Thiazolidine
-olane*(O,S,...)
1,3-dioxolane
O
N
-etidine(N only)
6
SHN
OO
-ine*
*Exception
HN NH
HN
1,2,3-Triazine
Does notoverrideacceptedtrivialnames
Pyrrole,not "azole"
-ane(N only)
1,2,3-Triazane
-inane(O,S,...)
-epineHN
Azepine
7O-epane
Oxepane
8 910
-ocine-onine-ecine
-ocane-onane-ecane
Section one - Chemistry of Heteroaromatics
7
N
Indicated Hydrogen
HN
-- To locate hydrogen (or a substituent) when fullyunsaturated but a "saturated" atom present
O
•Use H prefix (pronounce the letter "H")
italicized
N
•The saturated position takes priority in numbering
e.g.
HN
2H-azirine (not 3H )
1H-azirine
4H-pyran2H-pyrrole (not 5H )
NHN S
1H-pyrrole(often leave out the 1H-)
Partial Unsaturation
•Use fully unsaturated name with dihydro, tetrahydro, etc.
•Alternative: Trivial names are sometimes still used.
N
2,3-dihydro-1,2,5-thiadiazole(Note numbering toward saturated atom)
"1-pyrroline", "∆1-pyrroline"(Better: 3,4-dihydro-2H-pyrrole)
1
23
1
2
3
4 1
2
34
5
1
34 2
5
Section one - Chemistry of Heteroaromatics
8
N
NN
N N
N
Fused Rings ("Fusion names")•CAS Ring Index useful
•If there is an accepted trivial name for a fused compound, you should use it.
HNN
Quinoline
e.g.Otherwise, use fusion name.
•Regard common atoms as belonging to both systems:
regard
as
Pyrimidine
and
Imidazole
Step 1. Choose one component as "base component."
pyrrole
imidazole
pyrrolo-
imidazo - (not imidazolo-)
Step 3. Label "faces" of base component
see "HeterocyclicChemistry" 2nd ed.by T. L. Gilchrist forgood flowchart -pp 376-377
a. N-rings have priorityb. If no N, choose ring with highest priority atomc. Choose system with greatest # of ringsd. Start with larger ring sizee. Choose ring with most heteroatoms
HNN
In our example, pyrimidine is base component.
Step 2. Other component named as prefix by changing ending:
1 2
3
N
N
4
5Step 4. Number second component
a
fe
d
c
b
Step 5. Combine: NN
Nimidazo[1,5-a]pyrimidine
italics
Step 6. Number the new ring system (not easy)
Section one - Chemistry of Heteroaromatics
9
As
Replacement Nomenclature
•Use carbocyclic nomenclature with hetero prefixes.•Most systematic, but not widely used except for (a) heterocycles containing unusual atoms (b) >10-membered rings, and (c) bridged- and spirocyclic systems.
arsabenzene
7-oxabicyclo[2.2.1]hepta-2,5-diene
1 2
O
3
O
5
O
4
6
7
1,6-dioxaspiro[4.5]decane1
2
34
567
8 9 10
(von Baeyer names used for bridged-bicyclics)
AROMATIC HETEROCYCLES
"π-Excessive"
X
"π-Deficient"
X
X=N, P, As, Sb, O , SX=NH, PH, AsH, SbH, O, S, etc;
General Aspects
Section one - Chemistry of Heteroaromatics
10
N
N N H
NR H
RR
Basic lone pair in plane of ring
Perpendicular toπ-system, not involvedin aromaticity
H+
pKa = 5.2
still aromatic (about like an imine)
N N H
c.f. Me3N_H
9.8 ( sp3)
~5(sp2)
~0(sp)
R_C≡N_H
>1 heteroatom: Greatly decreased basicity due to electronegativity
N
pKa = 0.4
π-Nucleophilicity decreased vs
slower than
El
π-Electrophilicity increased vs
El
NNuc much faster than
π-Deficient Heteroaromatics
Nuc
H
Basic compounds
..
Section one - Chemistry of Heteroaromatics
11
N
N
CH3
N
CH3
HH
N
CH3
N
CH3
H
H
H
H
N
N
OCH3
Si(iPr)3
Ph
O Cl
O
N
OCH3
Si(iPr)3
OR*O
OEE
MgBr
CH3I
N
OR*O
HO
NaBH4
H2O, 15oC pH >7
NaBH4
Si(iPr)3
No reaction
N
1-methylpyridinium
H
OH
NaBH4pH 2-5
H+
Cl
1.
2. H3O
(-)-elaeokanine C
OO
CominsJACS, 1991, 113, 6672
CH3
Section one - Chemistry of Heteroaromatics
12
N O
N
N O
N
Li
N N
El
Electrophilic attack at N much faster than attack at carbon
El
13
Deprotonation at ring C-H generally requires activating group
nBuLi
H , Lewis acids (e.g., BF3),alkyl halides (primary iodidesand triflates), and acylating agents
N H N
H H
HH
Electrophiles:
N
H
HH
π-Excessive Heteroaromatics
Basicity
N
1 heteroatom: Poor base - no basic lone pair
HH
1 heteroatom: May be basic - has basic lone pair
N
H
lone pair used in aromaticity, not available for protonation
C-3
H
H
C-2
Nonaromaticpka ~ -5.9
N-protonation
Nonaromaticpka ~ -3.8
Nonaromaticpka ~ -10
Pyrrole is a verypoor base. Whenprotonation isforced, C-2 ispreferred.
H
Section one - Chemistry of Heteroaromatics
:
>
..
NH
O
XX
H
El
X
HEl
X
El
X XEl
H
El
H
Calculated π-electron densities:
1.2
X
1.067
H
El
1.078
1.710
X
1.090
1.647
El
1.087
X
1.000
Regioselectivity
X
El
El
H
C-3
-H+
minor
major
X
Preferred for X=NH, NR, S
Preferred for X=O
H
El
Still aromatic
vs.
Aromaticity disrupted
-
ElC-2
Section one - Chemistry of Heteroaromatics
14
N N O
NR
NH O
H
R
HHOO
RNH2
N NH2
H
OHH
OO
O
XX
O
OMeMeO
O
ClClN
NN
N
O
XR
Cl
O
XX
O
O
RR
O
R R
O O
Synthesis of Heteroaromatics
General
Look for these fragments in target heterocycle
R R
O
Section one - Chemistry of Heteroaromatics
15
O
R
O
R
RHN NHR
X
enamine
enamine
R NHR
X
;
imine
;
O
•Typically, condense bis-nucleophile with bis-electrophile
RNH E X E
1,5-dicarbonylcompound
bis-nucleophiles
1,1:
1,2:
1,3:
1,1: H2O, NH3, H2S
1,2: RNH-NH2, RNH-OH
1,3:
enamine1,4-dicarbonyl
compound
;
;
;
;
;
;
;
;
;
NH3
bis-electrophiles
•Many methods rely on carbonyl chemistry
•Analogies: We know how to make:
XY
XY
XY
X Y X Y
A Classical Method to Prepare Heteroaromatic Ring Systems1Electrophile-Nucleophile Interactions
X
A
O O
A
B
Cyclization Reactions for Heterocyclic Synthesis
O
O
X
OX
XA
Y
HO
X
B
Z
sp3 X: exo-tet
Z
XH
HO O
sp2 X: exo-trig
Z
sp2 Y: endo-trig
X
HO
H
OH
H
Z
X
H H
X
Y
HH
Y
A
H H
Y
X
H H
Z
sp X: exo-dig
H H
sp Y: endo-dig
Aldol-Type Condensations
Synthesis of Five Ring Heteroaromatics Using General Routes
XH2H2
H
H
- 2 H2O
Types of nucleophile-electrophile cyclizations
or B
Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734
Section one - Chemistry of Heteroaromatics
16
O R4
R3
R1
R2
R3R2
R1 R4
OO
R1
O
ClR2
O
OR1R2
COOR3
CH2COOR3
OR1
R2CH2Br
Br COOEt R1
O
R2
CH2COOEt
Ten Top Methods to Synthesize Furans
N
O
1. Cyclization of 1,4-Diketones and Related Compounds (Paal Knorr Reaction)
O
+
O
Base
H+
R2
Obrecht, D. Helvetica Chimica Acta 1989, 72, 447.
+ R4 R5
To a stirred solution of sodium ethoxide, prepared from sodium (2.1 g, 0.092 mol) metal in ethanol (150 mL) isadded the methylene compound (1.0 mol) at –5 °C. The solution turns yellow and, after several min, a solution ofthe chloroketone (10 g, 0.037 mol) in ethanol (15 mL) is added. Stirring is continued for 24 h at 25 °C. The mixture is neutralized by addition of 10% aqueous HCl, the solvent is removed under reduced pressure, water (50 mL) isadded to the residue, the mixture is extracted with ether, and the product is purified by column chromatographyon silica gel.
3. Ring Transformation of Oxazoles
R5 R4
Feist, F. Ber. 1902, 35, 1545. Benary, E. ibid. 1911, 44, 493.
Base
R3R1 R1R3
2. Base Catalyzed Reaction of ββββ-Ketoesters with αααα-Haloketones
To a stirred solution of 10.0 mmol of the acetylenic acetal in toluene (30 mL) was added a 2 N aqueous HClsolution (10 mL) at room temperature. The mixture was stirred at room temperature, diluted with Et2O (100 mL)and poured onto ice (50 g). The aqueous phase was extracted with Et2O (100 mL), the combined organic fractions were washed with brine (50 mL) and the solvent was removed. The residue was chromatographed on SiO2 (80g)and distilled under reduced pressure.
+
Moubarak, I.; Vessiere, R. Synthesis 1980, 52-53.
∆
Hutton, J.; Potts, B. and Southern, P.F. Synth. Commun. 1979, 9, 789-797.
A mixture of oxazole (14.5 g, 10 mmol) and bis-trimethylsilylbuta-1,3-diyne (19.4 g, 10 mmol) was heated in asealed tube at 210°C for 16 h. The crude reaction mixture was distilled and then chromatographed on silica gel using hexane as the eluent to give 22.6 g of the product in 95% yield.
Section one - Chemistry of Heteroaromatics
17
(Feist Benary Reaction)
OR1
R4R5
CSMe2
R2R4CH2COR1
H
R3
R1
R2
R3
O
O
R1
R2
R3
O
O
CH2
R1
R2
R3
O
O
CH3
OO O
A solution of the allene (10 mmol) in ethanol (110 mL) was treated with the ketone (10 mmol) and sodium ethoxide (10 mmol) in ethanol (100 mL). The mixture was heated at reflux for 4 h and the ethanol was distilled and etherwas added to the residue. Filtration and distillation of the filtrate gave the desired product.
5. Direct and Indirect Alkylation of Furan
+NaOEtEtOH
1/ 1 eq base
2/ E1+
E1E2
Batty, J.W.; Howes, P.D. and Stirling, C.J.M. J.Chem.Soc. Perkin1 1973, 65-68.Aso, M.; Ojida, A.; Yang, G.; Cha, O.J.; Osawa, E. and Kanematsu, K. J.Org.Chem. 1993, 58, 3960-3968.
(1) base
(2) E2+
E1+, E2
+ = Aryl, Alkyl, Acyl
Wong, M., K.; Leung, C., Y. and Wong, H., N., C. Tetrahedron Lett. 1997, 53, 3497.Song, Z., Z.; Ho, M., S. and Wong, H., N., C. J.Org.Chem. 1994, 59, 3917.Wong, H.,N.,C. Pure and Appl. Chem. 1996, 68, 2, 335.
H2C CSMe2
To a stirred solution of the silyl furan (1.3 g, 6 mmol) in anhydrous THF (24 mL) was added 6.5 ml of n-BuLi (1M solution in hexane) through a syringe under nitrogen. The mixture was stirred for 30 min and then benzylbromide (1.1 g, 6 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting solution wasstirred for another 30 min and was poured into Et2O (40 mL) and washed with water. The crude productobtained after evaporation of the solvent was purified by chromatography on a silica gel column (50 g, hexane) to give the desired product as a colorless oil (1.5 g, 82%).
+
4. Reaction of Allenic Sulfonium Salts and Enolate Anions of 1,3-Dicarbonyl Compounds
H
NaOEtEtOH
p-TsOH
OE1
Section one - Chemistry of Heteroaromatics
18
Section one - Chemistry of Heteroaromatics
19
Davies, H.M.L., Cantrell, W.R., Romines, K.R., Baum, J.S. Org. Synth. CV 9, 422.
Me OEt
N2
O OPh H
OPh Me
COOEt
6. Diazo-Promoted Furan Cyclization
A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, an addition funnel, and a refluxcondenser is flushed with argon. The reaction vessel is charged with 44 g of phenylacetylene (0.44 mol), 0.38 g ofrhodium(II) acetate dimer, and 100 mL of dichloromethane and the mixture is heated at reflux under an argonatmosphere. The addition funnel is charged with 13.5 g of ethyl diazoacetoacetate (0.087 mol) and 200 mL ofdichloromethane, and this solution is added dropwise over 1.5 h to the reaction mixture. After the reaction mixture is heated under reflux for an additional 12 h, it is cooled and the solvent is removed under reduced pressure. Thecrude product is purified by chromatography on silica gel, followed by vacuum distillation to yield 10 g (50%) of thefuran as a pale yellow liquid.
Rh(II)
R4
CR2
R1O
OH
R1
R2H R2
O
R1
O
R1
R2
7. Pd(0) Catalyzed Formation of Polysubstituted Furans
Ma, S., Zhang, J. Chem. Commun. 2000, 117.
The reaction was carried out using 1.5 equiv of the 1,2-allenyl ketone, 1.0 equiv of R3X, 5 mol % of Pd(PPh3)4, 2.0 equiv of NEt3, and 10 mol % of Ag2CO3. The reaction was heated at reflux in toluene for 13 h.
8. Furans from Acetylenes and Allyl Alcohols
Trost, B.M. and Flygare, J.A. J. Org. Chem. 1994 59 1078.
NMO (1.00 mmol) followed by osmium tetraoxide (0.008 mmol) were added to a solution of 0.84 mmol of the ketone in 4 mL of THF, 1 mL of tBuOH, and 1 mL of water at rt. After stirring for 12 h, 2.5 mmol of p-toluenesulfonyl hydratewas added and stirring was continued for 10 additional h. The reaction was quenched with 100 mg of sodium sulfiteand ether. The ether layer was washed with saturated sodium carbonate, 10% sodium bisulfate, and brine. After drying (Na2SO4) and evacuation in vacuo, the compound was chromatographed on silica gel (hexane) to give the desired product in 88% yield.
R3X
Ag2CO3, Et3N
Pd(PPh3)4
OR1
R4
R3
+R2
OsO4
CpRu(Ph3P)2Cl
20
10. New Advances in Oxo- and Thio-substituted Furans
Section One- Chemistry of Heteroaromatics
Rubin, M., Sromek, A.W., Gevorgyan, V. Synlett 2003, 15, 2265
Greico, P.A., Pogonowski, C.S., Burke, S., J. Org. Chem. 1975, 40, 543.
X = OAc, OTs, OPO(OEt)2, SAr, SR, RCOO, RO, ArO
9. Organoselenium as a Route to Furans via Butenolide Formation
A solution of DIBAL (0.5 M in THF) was added to 1.5 equiv of butenolide (0.3 M in THF). After 3 h of stirring at -20 oC, the reaction was quenched by addition of 10 % sulfuric acid and the reaction mixture was warmed to rt. Water and brineworkup followed by drying with MgSO4 yielded the desired furan in 99% yield.
X
R2R3
R1O
OR1
R2 X
R3
O
O
R1 R2
R3
SePh O
O
R1 R2
R3
O R1
R2R3
H
Copper chloride (0.05 mmol, 5 mg) was loaded into an oven-dried 3 mL microreactor in a glovebox. Anhydrous DMA (1 mL), triethylamine (0.2 mmol, 28 mL), and acyloxy alkynyl ketone (1 mmol) were successively added. The reactor was capped with a Mininert valve and then placed in a preheated aluminum block (130oC), shielded from light, and stirred from 2 to 24 h. After the reaction was complete, the microreactor was allowed to cool and the mixture was poured into 10 mL of water and thoroughly extracted with hexane. The organic layer was dried over anhydrous Na2CO3, concentrated, and chromatographed over silica gel using hexane-ethyl acetate as the eluent.
Rashatasakhon, P. Padwa, A. Org. Lett. 2003, 5 189.
Synthesis of 2-Amido Substituted Furans
To a solution of the lactam (0.5 mmol) in 5 mL of DCM at -78 oC, was added pyridine, (2.7 mmol) and then triflicanhydride. The crude reaction mixture was allowed to warm to rt over 30 min and was stirred at 25oC for an additional 10 min. Water was added and the organic layer was separated. The aqueous layer was extracted with chloroform and theorganic phase was washed with water, brine and then dried over MgSO4. The crude mixture was purified by flashchromatography on silica gel using 20% Et2O in hexane to give the desired furan in 90% yield.
Padwa, A., Crawford, K.R., Rashatasakhon, P., Rose, M. J. Org. Chem. 2003, 68, 2609.
N
O
Me
OH
R Tf2O N
TfO
MeOH
RN
TfO
Me
O
R
O NHRMe
DIBAL
+
5% AgBF4
O
Br
ORO
CH2
OR
Me
OR OOH
PTSAnBu3SnH
AIBN
NBS
Radical cyclization for furan synthesis
45 %
Section one - Chemistry of Heteroaromatics
Srikrishna, A.; Pullaiah, K. C. Tetrahedron Lett. 1987, 5203
OOH
R1R3 R3R1
R2
R3
R1
H
H
O
OR2
R3
H
R1C
R1
HC C
R3
O
OMe
OMe
C
O
O
OMe
OMeO
OMeH
N2
PO(OEt)2
-40 °C
70-86 %
H+
-
tBuOK
-
-
Buxton, S. R.; Holm, K. H.; Skattebol, L. Tetrahedron Lett. 1987, 2167
67 %
R2
R2R2
tBuOK
Marshall, J. A.; Dubay, W. J. J. Org. Chem. 1991, 56, 1685
Isomerization of alkynyl oxiranes
21
ClC
TBDMSO O
TBDMSC
OTBDMS
TBDMS
OO
TBDMSTBDMS
O
H
I
O O
PdI
O
PdI
O O
Et PdI Et
O
BrBr
SO2Ph
O ONa
SO2Ph
BrO
H
O
PhSO2 PhSO2
O O
H
+
+
+AlCl3.
+
Pd (0)
HPdI
2) deformylation
MeONa1) addition/elimination+
Regiocontroled [3+2] annulation reactions of allenylsilanes with acylium ions
Palladium-catalyzed coupling of aryl iodides
General method for the synthesis of 2 and 3 substituted furans
-20 °C
76 %
83 %-HPdI
85 %
New Syntheses of Substituted Furans
available from propargyl alcohol
Na-Hg
Padwa, A.; Murphree, S. S. Org. Prep. and Procedures, 1991, 23, 545. Padwa, A.; Murphree, S. S.; Yeske P. E. J. Org. Chem. 1990, 55, 4241. Padwa, A.; Austin, D. J.; Ishida, M.; Muller, C. L.; Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1992, 57, 1161. Padwa, A.; Ishida, M.; Muller, C.L.; Murphree, S. S. J. Org. Chem. 1992,57, 1170
Larock, R. C.; Stinn, D. E.Tetrahedron Lett. 1988, 4687
Danheiser, R. L.; Stoner, E.; Koyama, H.; Yamashita, D;. Klade, C. A. J. Am. Chem. Soc. 1989,111, 4407
Section one - Chemistry of Heteroaromatics
22
NR1 R2
R3
R1 R2O O
R2 CH2X
O
R3 R4
O O R3 R4
R2
OO
N R2R4
R3
O
R1O
R2 H
O
R4
OR3
2. n-BuLi
R2
O
O
R4
R3
N
R3
R4R2
R1
+
N
R2
R3EtOOC
R1
I. Paal-Knorr Method
Ten Top Methods to Synthesize Pyrroles
R1NH2
EtO
ONO2
R3
O
R2
•••• Reaction of αααα-Haloketones with the Anion of ββββ–Dicarbonyl Compounds
A mixture consisting of a 40% solution of methylamine in 100 mL of water, 2,5-hexanedione (114 g), andbenzene (150 ml) was slowly heated to reflux in a flask fitted with a Dean-Stark trap. After the water wascollected, the reaction mixture became clear and homogeneous. On distillation, the fraction boiling at 60oC (11 mm) was collected to give 82 g (75%) of the product.
Grayson, Martin; Eckroth, David Kirk-Othmer Encycl. Chem. Technol., 3rd Ed. 1982, 19, 499-520Bean, Gerritt P. Chem. Heterocycl. Compd. 1990, 48 (Pyrroles, Pt.(1), 105-294Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33, 2057
EtOOCR3
NO2
R2 O
•••• Cyanide or Thiazolium-ion-Catalyzed Michael Addition of a Vinyl Ketone
Lyer, R. N.; Gopalachari, R. Ind. J. Chem. 1973, 11, 1260
EtOOCR3
O
R2 O
• Michael Addition of Ethyl Nitroacetate to a Vinyl Ketone
Stetter, H.; Krasselt, J. J. Heterocycl. Chem. 1977, 14, 573Jones, R. A. Tetrahedron. 1986, 42, 3753
O3
Thompson, W. J.; Buhr, C. A. J. Org. Chem. 1983, 48, 2769
R1NH2
1. NaCN
3.
R1NH2
-+
+ R3NH2+acid 2H2O
Section one - Chemistry of Heteroaromatics
23
R1
NH2
O
O R2
Z
NH
Z
R2
OR1
NH
Z
R2
HOR1
NH
Z
R2
R1
R R
O O
NEWG R
R
R1
R3EtO
CHOR1NHCH2CO2R2
NCOOR2
R3
O
H
N
R3
COOEt
2. Knorr Pyrrole Synthesis
R1
Condensation of an α-Aminoketone with a Carbonyl Compound.
+
A solution of 7.2 g of sodium nitrite in 25 mL of water was slowly added to a stirred mixture of 19.2 g of benzyl acetoacetate in 30 mL of acetic acid at 5 °C. The mixture was kept at 5 °C for 15 h and was then slowlyadded to a mixture of 13 g of ethyl acetoacetate in 70 mL of glacial acetic acid. Simultaneously, a mixture of18.5 g of Zn and 18.5 g of anhydrous sodium acetate was added in small portions. When the addition wascompleted, the mixture was heated for a further 1.5 h at 75 °C. The mixture was poured over ice-water,filtered, and the residue was crystallized from methanol to give the product (21 g, 70%).
R1
Rezzano, I.; Buldain, G.; Fryman, B. J. Org. Chem. 1982, 47, 3059
3. Condensation of αααα-Aminoketone with 1,3-Dicarbonyl Compounds
NH
EWG-CH2NHR1
+R1 X
O
A mixture of dibenzoylmethane (500 mg) and ethyl glycinate hydrochloride (3.3 g) in dimethylformamide (50mL) was heated at reflux for 24 h. The solution was poured into water (200 mL) and the resultant mixture wasallowed to stand overnight. The precipitated product was isolated by filtration and recrystallized from hexane to give colorless prisms (yield, 74%).
Walizei, G. H.; Breitmaier, E. Synthesis, 1989, 337
+
R1
OR2
Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis, 1982, 157
EWG=electron-withdrawing group
+
Cohnen, E.; Dewald, R. Synthesis, 1987, 566
H2NCH2COR2
Section one - Chemistry of Heteroaromatics
24
TMS N CN
Ph
F-H2C N
Ph
HC CCOOMeN
COOMe
Ph
NCOOMe
Ph
DDQ
N
R1
R1 R4
COOR3
R
R1
O
XR4 OR3
O ORNH2
CH2
4. Formation of Pyrroles via 1,3-Dipolar Cycloaddition Reaction
A. Padwa, Y. Y. Chen, W. Dent, and H. Nimmessgern, J. Org. Chem., 1985, 50, 4006
To a solution of the nitroolefin (200 mg) and isocyanide (169 mg) in a 1:1 mixture of THF and isopropanol (5 mL) was added the guanidine base (180 mg). The resulting solution was heated to 50 °C for 3 h,poured into water, and extracted with CH2Cl2. The organic layer was dried over sodium sulphate andfiltered through a short column of silica gel. Evaporation of the solvent gave the desired pyrrole as apale crystalline solid (272 mg, 90%).
5. αααα-Haloketone-ββββ-Ketoester-Amines Synthesis of Pyrroles
R2 +
Aqueous ammonia was added to the acyl acetate and the halo-compound (0.1 mole) and the mixturewas stirred for 2 h while the temperature rose to 60 °C. After stirring for 24 h, the product was extracted into ether and the extracts were washed with 10% NaOH, water, 5% HCl, and again with water. Theether was removed under reduced pressure and the product crystallized from the residue.
+-
Section one - Chemistry of Heteroaromatics
25
N
HN
H
N
H
62 %CO2Me
heatCO2Me
N3
Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474Roomi, M.W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689
X=halo
6. Rhodium Mediated Masked 1,4-Dicarbonyl Compounds
Cunha, A. C.; Pereira, L. O. R.; de Souza, R. O. P.; Ferreira, V. F. Synthetic Commun. 2000, 30, 3215.Deng, G.; Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 11, 1913.
R1
O
MeN2
O
OBuOBuO Me
O
R1
N
O
R1
Me
R2
Rh2(OAc)4 R2NH2
Section one - Chemistry of Heteroaromatics
+
7. Formation of Pyrroles via the Hantzch Reaction
Condensation of an α-haloketones or aldehydes with β-ketoesters in the presence of an amine.
Grigg, R.; Savic, V. J. Chem. Soc., Chem. Commun. 2000, 873.
DMF, rtBr
NH2
CO2Et
Ph
Br
N
H
Ph
CO2Et
N
H
CO2Et
Ph
Me
Pd(OAc)2, PPh3,+
A solution of starting materials was stirred in DMF at rt until TLC showed complettion of the reaction. The product obtained was subjected to 10 mol % Pd(OAc)2, 20 mol % PPH3, and 2 equiv K2CO3 in DMF at85oC. The product was poured into a saturated NaHCO3 solution, extracted with EtOAc, washed withbrine, dried, filtered and concentrated. The crude product was chromatographed over silica gel usingEtOAc/petroleum ether as the eluent.
To a solution of sulfone and ethyl isocyano acetate (2 equiv) in anhydrous THF was added DBU at rt.After the mixture was stirred for 3 h, aqueous 1 M HCl was added and the mixture was extracted withEtOAc. The organic phase was washed with H2O, brine, dried, filtered, and concentrated. The residue was chromatographed on silica gel with EtOAc and hexane as the eluent.
26
Uno, G.; Tanaka, M.; Inoue, T.; Ono, N. Synthesis 1999, 3, 471.Abel, Y.; Haake, E.; Schmidt, W.; Struve, D.; Walter, A., Montforts, F. Helv. Chim. Acta. 1998, 81, 1978.
R2 R1
SO2R3
N
R1R2
EtO2C
H
CNCH2CO2Et
Base, THF
8. Barton-Zard Synthesis of Pyrroles
Condensation of electron-deficient alkenes with isocyanomethylide anions.
9. Synthesis of Pyrroles from Alkenyl ββββ-Dicarbonyl Compounds
Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M.; Payret, M. E. Tetrahedron 1999, 55, 10915.
Al2O3, CH2Cl2, rt reflux
NHBn
CO2Et
NICH2
CO2Et
N
CO2Et
Section one - Chemistry of Heteroaromatics
Bn Bn
10. Route to Pyrroles via an Intramolecular Wittig Reaction
Burley, I.; Bilic, B.; Hewson, A. T.; Newton, J. R. A. Tetrahedron Lett. 2000, 41, 8969.
OMe
NHCOPhMe
SPh
PPh3NMe
Me SO2Ph
COPh
NMe
Me
COPh
KOt-Bum-CPBA
NaH+
t-BuOH
27
Condensation of ketones and acetylenes (or synthetic equivalents) with oximes
Pyrrole Formation via the Trofimov Reaction
100-110oC
Mikhaleva, A. I.; Sigalov, M. V.; Kalabin, G. A. Tetrahedron Lett. 1982, 23, 5063.
A mixture of the oxime (88 mmol), KOH (53 mmol), water (10 mmol), and DMSO (100 mL) was autoclaved with acetylene at 100oC for 1 h (initial pressure 50 psig). Aqueous workup followed by extraction and vacuum distillation afforded the product.
NOHN
Trofimov, B. A.; Mikhaleva, A. I. Heterocycles 1994, 37, 1193.Brandsma, L.; Nedolya, N. A.; Trofimov, B. A. Eur. J. Org. Chem. 1999, 2663.
KOH, DMSONOH
HH
NH
H
KOH/DMSOHH+
To a solution of the appropriate acyclic β-enamino ester (1 mmol) in anhydrous CH2Cl2 (15 mL) were added solidNaHCO3 (1.1 mmol), Al2O3 (1 g), and I2 (1.1 mmol). After stirring at rt for 24 h, the reaction mixture was extracted with ethyl acetate, washed with NaHSO3, NaHCO3, brine, dried, filtered, and concentrated. The crude productwas either recystallized from cold ethanol (solid) or chromatographed over silica gel utilizing hexane:ethyl acetateas the eluent.
The sulfone (1.5 mmol) was dissolved in dry THF (20 mL) and 1 M potassium t-butoxide in t-butanol (1.5 mmol) was added. The solution was heated at reflux for 2 h. The THF was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. Flash chromatography with ethyl acetate/hexane as the eluent gave the pyrrole (93%).
NaHCO3, I2, DBU, toluene
R2 X
CNR1
NC CN
SKMeS O
R1
X
S-
S-CN
Y
R2R1
O
R1
R2O
O
R3HSCH2CO2H
DMSO
S
YNH2
RNHCO SMe
S
XR2
R1NH2
S
OH
R1CO2R3
S
NH2CN
MeS
R1
O
S
OHR2
R1 CO2R4
To a mixture of phenacyl bromide (2.0 g, 10 mmol) and acetic acid (4 mL), a solution of the sulfur salt (1.9 g, 10 mmol) in dimethyl sulfoxide (20 ml) was added dropwise at 60 oC. After complete addition, the mixture was stirred for 30 min and then poured into water (200 mL). After stirring for 2 h the crude product was collected by filtration andrecrystallized from ethanol (66 %).
1. Gewald Synthesis
Gewald, K. Angew. Chem., 1961, 73, 114.Rehwald, M.; Gewald, K.; Battcher, G. Heterocycles 1997, 45, 493.
Chloracetamide (5 mmol) followed by methyl iodide (5 mmol) were added to the sulfur salt (5 mmol) in dimethylformamide (5 mmL). The mixture was stirred for 5 min, diluted with water (100 mL) and heated 70 oC. Potassiumcarbonate (5 mmol) was added to induce the cyclization and the solution was left to cool. The product was filtered from the cold solution and recrystallized from 1-propanol.
2. Gomper Synthesis
3. Fiesselman Synthesis
A mixture of the 3-alkyl-alkoxyacrylonitrile (10 mmol) and the mercaptoacetic ester (10 mmol) in a suitable alcohol (10 mL) containing potassium acetate (15 mmol) is heated at reflux for 0.5-2 h. The crystals which precipitate during the reaction are collected by filtration.
Woodward, R. B.; Eastman, R. H. J. Am. Chem. Soc., 1946, 68, 2229.Fiesselman, H. Schippark, P. Chem. Ber. 1954, 87, 835.Saito, K.; Kambe, S.; Sakurai, A.; Midorikawa, H. Synthesis, 1982, 12, 1056.
Section one - Chemistry of Heteroaromatics
+
S/Morpholino
EtOH/60 oC
+60 oC
1) ClCH2CONHR2) NaOH3) MeI
Henriksen, L.; Autrup, H. Acta Chem. Scand., 1972, 26, 3342.
Y = -CO2Et, -CN, -CONHMe, -CONH2
HSCH2CO2R3
+1) H+, R4OH
2) NaOR5
Note: Acetylenes, β-ketoesters, α,β-dihalocarboxylates, α-haloarylates, α,β-dihalonitriles, β-chloro acrylonitriles, 1,3-dicarbonyl have been used
2
Top Ten Methods to Synthesize Thiophenes
28
R1 O
XR2
S
R1
R1
NaSH
O R2
R3O
R1 O
SHR2
O R3
R4X
DDQ
S
R3R1
R4R2
S
R3R2
R1R1
S R4
R2
O
O R3
R1
S
R3R1
R4R2
S
OHOHR1 R3
R2 R4
H+
To a stirred solution of t-BuOK ( 310 mg, 2.7 mmol) in THF (5 mL) was added a solution of the diol (300 mg, 0.9 mmol)in THF (2 mL) over a period of 30 min at -18 oC under argon. After 1 h the reaction was quenched by adding ice-water (30 mL) and then pentane (50 mL). The organic layer was washed with water, dried over MgSO4, concentrated, andchromatographed on a column of silica. The column was eluted with pentane, and the pentane was evaporated slowlyunder reduced pressure (86 %).
4. Nakayama Synthesis
Nakayama, J.; Kurado, K. J. Am. Chem. Soc., 1993, 115, 4612.
5. Hinsberg Synthesis and Modifications
To a stirred solution of the diketone (2.7 g, 10 mmol) and biacetyl (1.0 g, 11.6 mmol) in 40 mL of methanol was added0.5 mL of a solution of sodium methoxide (0.5 g of sodium dissolved in 100 mL of methanol) at 40 oC. Theprecipitation of crystals occurred immediately with the evolution of heat. After stirring for 1 h, the product was collected by filtration and washed with methanol. To the filtrate, biacetyl (0.5 g) and the base solution (0.5 mL) were added togive an additional amount of product. The overall yield was 92 %.
Hinsberg, O. Ber., 1910, 43, 901.Miyahara, Y.; Inazu, T.; Yoshiro, T. Bull. Chem. Soc. Jpn., 1980, 53, 1187.
Section one - Chemistry of Heteroaromatics
+Base
TiCl4/ZnTiCl4/Zn
+NaOEt, EtOH R1 = ester, cyano, ketone
rt 0oC
29
H2NOC CN
NMe2Me
R3R2
OR1
OR4
HS CO2Et
∆
P4S10
EtONa
O
Ar
MeSOR
O
R1 R2
SMeMeS
S
Ar
OR
O
ZnCH2
SI
R1 R2
Me
SMe
I
H2NOC CN
SMe CO2Et
S
R3R2
R1 R4
I-
R2
SMeH
H
IZnOR1
Me
S
S
R2R1
SMe
S
NH2H2NOC
Me CO2Et
To a solution of the diketone (0.5 g, 0.002 mol) in CH2Cl2 (10-15 mL), was added phosphorous pentasulfide (2.2 g, 0.05mol) with stirring. Solid sodium bicarbonate (0.84 g, 0.01 mol) was added in 5-6 portions during 5 min. After stirring the reaction mixture overnight at rt, water (50 mL) was added and the mixture was transferred to a separatory funnel and theaqueous layer was extracted with CH2Cl2 and the combined organic extracts were washed with water. Concentration ofthe dried CH2Cl2 extracts gave a crystalline product (75%).
6. Paal-Knorr Reaction
Volz,W.; Vob, J. Synthesis, 1990, 25, 670.Moriarty, R.; Prakash, O.; Duncan, M. Syn. Commun. 1985, 15, 789.
The ester (120 mmol) and K2CO3 (1 g, 7 mmol) were added to a suspension of the enamine (100 mmol) in 100 mL of anyhydrous EtOH. The reaction mixture was refluxed for 16 h, diluted with water, and cooled. The precipitate that formed was filtered off and washed with water to give the aminothiophene.
Ryndina, S. A.; Kadushkin, A. V.; Solov'eva, N. P.; Granik, V. G. Russ. Chem. Bull. 2002, 51, 854.
Et2O/THF
7. Thorpe-Ziegler Cyclization
8. Simmons-Smith Conditions
To a well stirred suspension of zinc-copper couple (4.0 g) in dry ether (25 mL) under nitrogen atmosphere, was addeda small crystal of iodine and CH2I2 (6.7 g, 25 mmol). The reaction mixture is heated at reflux for 45 min. A solution ofthe enone (2.4 g, 10 mmol) in dry THF (15 mL) is added and the reaction mixture was heated at reflux with stirring for8 h. The solvent is removed under reduced pressure and the residue is diluted in water (200 mL) followed by theaddition of CHCl3 (150 mL). The reaction mixture is filtered, the residue washed with CHCl3 and the combined oragnic layer is washed with NHCl4 solution and water, dried (Na2SO4) and evaporated to give the crude product.
Thomas, A.; Singh, G.; Ila, H. Tet. Lett., 1989, 30, 3093.
Section one - Chemistry of Heteroaromatics
R1= aryl, hetaryl, alkylR2= H, alkyl, allyl, Ph, Bn
CH2I2/Zn-Cu
Et2O/THF
CH2I2/Zn-Cu
+
30
O
R3
R1R3
O
R1R2
R3R4 H2S
∆
S
R1R3
R3
S
R3R2
R1 R4
Benzene (10 mL) and Lawesson's reagent (6 mmol) was added to the epoxide (5 mmol) and the mixture heated to reflux. After 5 min., p-toluenesulfonic acid (10 mg) was added, and the mixture was further heated for 1 h. Thereaction was partitioned between sat. NaHCO3 and ether. The aqueous layer was extracted with ether. Thecombined organic layers were washed with water and dried over Na2SO4. Purification by chromatography onsilica gel gave the thiophene derivative.
9. From ββββ,γγγγ-Epoxy Carbonyl Compounds
Kang, K.; J. S. Syn. Commun. 1995, 25, 2647.
Commonly used industrial procedure. However, the yields of the reaction are poor and it is difficult to perform experimentally. In general, alkenes give better yields than alkanes.
For a review: Gronowitz, S. Thiophenes and Its Derivatives; Interscience Publisher: New York, vol. 44, pt. 1, pp. 4-11.
10. Thermally From Alkanes and Alkenes
Section one - Chemistry of Heteroaromatics
+Al-Cr catalyst
Lawesson's Reagent
p-TsOH (cat.)Benzene/∆
S
O
CHO
CO2Et
O
EtO2C O
SCH2CO2SEtO2C CO2H
CHOCHOEtO2CCHSCH2CO2Et H
EtO2CS
CO2Et
O O
-H+ -H2O
H+
H
Hinsberg αααα-Diketone-thiodiacetate Thiophene Synthesis
-EtO
Wynberg, H.; Kooreman, H. J. J. Amer. Chem. Soc. 1965, 87, 1739
31
A sample of DAST (0.24 mmol) is added dropwise at -78°C to a solution of the hydroxy amide in CH2Cl2 (2 mL). After 30 min, the reaction mixture is warmed to -40°C and bromotrichloromethane (0.8 mmol) is added dropwise, followed bywarming to 0°C and addition of DBU (0.8 mmol). The reaction mixture is stirred for 8 h while warming to 20 °C, thenquenched with a saturated NaHCO3 solution. The solution is extracted with EtOAc and the organic layer was dried overMgSO4, filtered, and concentrated.
1. Cyclizations of ββββ-Hydroxy Amides
Ten Top Methods to Synthesize Oxazoles
The carboxylic acid (10 mmol) and DCC (10.5 mmol) is added to a stirred solution of the aminomalononitrilep-toluenesulfonate (10.5 mmol) in pyridine (50 mL) and the mixture is stirred overnight. After removal of the white precipitate by filtration, the filtrate is concentrated to give the oxazole, which is purified by flash chromatography.
2. 2-Substituted 5-Amino-4-cyano-1,3-oxazoles
pyridine 76%
Freeman, F.; Chen, T.; van der Linden, J.B., Synthesis 1997, 861.
+
68%
Phillips, A.J.; Uto, Y.; Wipf, P.; Reno, M.J.; Williams, D.R., Org. Lett. 2000, 2, 1165.
3. 2,5-Disubstituted Oxazoles from N-Propargyl Amides
Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F., Org. Lett. 2001, 3 , 2501.
Pd2(dba)3, P(2-furyl)3
+
75%
A sample of P(2-furyl)3 (0.06 mmol) is added to a solution of Pd2(dba)3 (0.016 mmol) in anhydrous MeCN (3.5 mL)under argon and the solution is stirred at rt for 15 min. The N-propargylamide (0.63 mmol), iodobenzene (0.75 mmol),and NaOtBu (1.2 mmol) is added and the mixture stirred at 40°C for 4 h. The reaction mixture is diluted with EtOAc,washed with 0.1 N HCl and saturated NaHCO3, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified with an axially compressed silica gel column using hexane/EtOAc as the eluent.
2. DBU, BrCCl3
H
CN
CN
NH3•OTs
O
NH
NH
CO2CH3
OH
O
OH
NH
OI
NHO
NCO2CH3
N
O
CN
NH2
N O
1. DAST
DCC
NaOtBu
Section one - Chemistry of Heteroaromatics
32
4. Substituted Oxazoles from Ketoximes
Bhatt, M.V.; Reddy, G.S., Tet. Lett. 1980, 21, 2359.
80%
pyridine
Acetyl chloride+
Ph
N OH
O
O O N O
Ph
Section one - Chemistry of Heteroaromatics
Benzylmethylketoxime (20 mmol) is dissolved in dry pyridine (20 mmol) and acetic anhydride (20 mmol). Themixture is cooled to 0°C and acetyl chloride (26 mmol) is added, then heated over a boiling water bath for 4 h.Dry HCl gas is passed for 3 h (at 100°C). The reaction mixture is cooled, poured into crushed ice, extracted with CH2Cl2, then dried, filtered, and concentrated. The residue is purified by column chromatography to afford theoxazole.
Trifluoromethanesulfonic acid (4.5 mmol) is added to a solution of acetonitrile (10 mL) and iodobenzene diacetate (1.2mmol) and the reaction mixture is stirred at rt for 20 min. Acetophenone (1.0 mmol) is added and the mixture is heated at reflux for 2 h, then concentrated to remove excess acetonitrile. The residue is extracted into CH2Cl2 and the organiclayer washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. Theproduct is purified by elution through a short pad of silica gel.
5. 2,5-Disubstituted Oxazoles from Iodobenzene Diacetate
Varma, R.S.; Kumar, D., J. Heterocyclic Chem. 1998, 35, 1533.
94%
6. Ethyl 5-Oxazole Acetate
Dow, R.L., J. Org. Chem., 1990, 55 (1), 386.
88%
+IOAc
OAcPh
O
NH
O
O
OEt
O
Ph
N
O
H
Ph
NO
OEt
O
Ph
CF3SO3H
MeCN
POCl3
Phosphorus oxychloride (18 mmol) is added to a stirred solution of the keto ester (6 mmol) in DMF (10 mL) andthe reaction mixture is heated at 90°C for 20 min. The mixture is cooled, poured onto ice, and the resulting slurry was stirred for 30 min. The solution is added to a saturated NaHCO3 solution and extracted with EtOAc. Theorganic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reducedpressure. The resulting residue is purified by flash chromatography (silica, EtOAc/hexane).
33
To a solution of the sulfone (0.6 mmol) in dry THF (4 mL) and DMSO (0.5 mL) at 0°C is added lithiumbis(trimethylsilyl)amide (0.7 mmol) under argon. After 40 min, the mixture is diluted with ether and quenched with 1 N HCl. The organic layer is washed with saturated NaHCO3 and brine, then dried with MgSO4, filtered, and concentrated to a residue which is purified by chromatography to afford the oxazole.
7. Synthesis of Oxazoles from Sulfones
Short, K.M.; Ziegler, Jr., C.B., Tetrahedron Lett. 1993, 34, 71.
95%
To an ice-cooled solution of the substituted 2-bromoacetophenone (5 mmol) in DMF (10 mL) was added NaN3 (5.5 mmol) in one portion. After approximately 20 min, POCl3 (30 mmol) was added dropwise. The mixture is warmed to rt and heated at 90°C for 4.5 h to provide the oxazole in good yield.
8. Vilsmeier Cyclizations for the Synthesis of Oxazoles
Majo, V.J.; Paramasivan, T.P., Tetrahedron Lett. 1997, 38, 6889.
56%
9. Synthesis of Oxazoles from Ketones
Lee, J.C.; Kim, S.; Lee, Y.C., Syn. Commun. 2003, 33 , 1611.
To a solution of ethyl pyruvate (1.0 mmol) in acetonitrile (40 mL) is added [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]-benzene (HDNIB) (1.2 mmol) and the mixture is refluxed for 2 h. After cooling to rt, benzamide (3.0 mmol) is added andthe mixture is refluxed for an additional 10 h. The solvent is removed and the residue extracted with CH2Cl2, followed by washing with saturated NaHCO3 and H2O. The organic layer is dried with MgSO4 and the solvent was evaporated underreduced pressure. The resulting product is purified by flash chromatography.
71%
2. PhCONH2
-ODNs =
EtO2C
O
O
BrBr
N
SO2Ph
I
N
OPh
EtO2C
N
O SO2Ph
ON
CHOBr
O S
O
O
NO2
NO2
1. PhI(OH)ODNs
LiN(TMS)2
1. NaN3
2. POCl3
Section one - Chemistry of Heteroaromatics
OHC
H
34
3. Gold(III) Catalyzed One Pot Synthesis of Isooxazoles from Terminal Alkyne
RC CH +N
OR
O
+
Gasparrini, F.; Giovannoli, M.; Misiti, D.; Natile, G.; Palmieri, G.; Maresca, L. J.Am.Chem.Soc, 1993, 115, 4401-4402.
In a typical experiment, the alkyne (5.0 mmol) was dissolved in nitromethane (8 mL) and treated with aqueous HNO3, (16 mL, 25.0 mmol,1.5 M) in the presence of tetrabutylammonium tetrachloroaurate (0.25 mmol) and sodium nitrite (1.0 mmol). The mixture was stirred at 50 oC until complete disappearance of the alkyne and then was extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of Na2S2O3 which removed the catalyst and was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel to give the isoxazole in 35-50% yield.
Ten Top Methods to Synthesize Isoxazoles
Oximation of 1,3-Dicarbonyl Compounds1.
O
O O
Me NH2OH
ON
MeHO
NaOH
H2O/MeOH
Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920.
A solution of nitroethane (2.5 g, 33 mmol) and triethylamine (15 drops) in dry benzene (15 mL) was added dropwise to a solution of 4-chlorophenyl isocyanate (8.6 g, 56 mmol) and trans-4-methoxy-3-buten-2-one (3.0 g, 30 mmol) in dry benzene (25 mL). The reaction mixture was stirred for 1 h, then refluxed for an additional hour. 4-Chlorophenyl isocyanate (6.2 g, 41 mmol), nitroethane (1 mL, 9.8 mmol), and 5 drops of triethylamine were added to the reaction mixture. The solid was filtered and the filtrate was concentrated to give a yellow oil, which was distilled to give the isoxazole (3.3 g, 88% yield).
To a solution of sodium hydroxide (5.2 g, 130 mmol) in a mixture of water (5 cm) and methanol (100 cm) was added, the oxoester (23 g, 125 mmol). To this solution at -70 °C was added a filtered solution of sodium hydroxide (10.3 g, 260 mmol) and hydroxylamine hydrochloride (17 g, 240 mmol) in a mixture of water (10 cm) and MeOH (100 cm). The reaction mixture was stirred for 2 h, and during this period the temperature was raised to 10 °C. Upon addition of acetone (9 cm, 125 mmol), the reaction mixture was poured into hydrochloric acid at 80 °C, and this mixture was stirred for 30 min. The volume was reduced to 100 mL by evaporation and left at 5 °C overnight. The product (16.9 g) was filtered, and the mother liquor was extracted with dichloromethane. The filtrate was dried (magnesium sulfate), the organic phases were evaporated and the residue was subjected to column chromatography to give 17.4 g of 5-tert-butyl-4-methylisoxazol-3-ol (91%).
2. Cycloaddition of Nitrile Oxides to Unsaturated Compounds
R N O+ - OCH3
CH3
O+O
N
R CH3
O
benzene
Brehm, L.; Johansen, J.S.; Krogsgaard-Larsen, P.; J.Chem. Soc., Perkin Trans I, 1992, 16, 2059-2063.
Me
Section one - Chemistry of Heteroaromatics
35
+
TBA+AuCl4-HNO3
and Nitric Acid
H2O
4. Synthesis of Isoxazoles from αααα-Halo Ketone and Isocyanide
R1X
NOH
base
R2NC
Buron, C.; Kaim, L. El.; Uslu, A. Tetrahedron Lett. 1997, 38, 8027-8030
To a solution of the α-halo ketone oxime (2 mmol) in dry dichloromethane (10 mL) is added the isocyanide (8 mmol) and sodium carbonate (850 mg, 8 mmol).
5. Condensation of Aromatic Aldehyde and Nitroethane or Nitropropane
Ar O EtNO2 / NaOH ON
ArMe
A mixture of nitroethane or nitropropane (9.3 mmol), the aldehyde (4.41 mmol) and ethanol (7 mL) was stirredrapidly at rt. A solution of NaOH (6.4 M, 2 mL) was added dropwise and the mixture was heated at reflux for 5 to 18 h. The cooled reaction mixture was extracted with ether and the organic layer was washed with brine anddried over MgSO4. The residue remaining after evaporation of the ether was purifed either by columnchromatography (silica) or by distillation.
6. Condensation of Carboxylic Acid Derivatives with 1,4-Dilithium Oxime Salts
NOMe
Me
NOH
+O
N
Me
n-BuLi
THF
Me
ON
ArR1
NHR2
Nitz, T.J.; Volkots, D.L.; Aldous, D.J.; Oglesby, R.C. J. Org. Chem., 1994, 59, 5828-5832
To a chilled (0 °C) solution of acetone oxime (1.1 g, 15 mmol) in THF (30 mL) was added dropwise 2.5 M n-BuLi in hexane (12 mL, 30 mmol). The initially formed white suspension gave a colorless solution after all of the n-BuLihad been added. After an additional 30 min, N-methoxy-N-methylisobutylamide (2.6 g, 18 mmol) in THF (120 mL)was added dropwise over 20 min. After 30 min, the pale yellow solution was poured into a solution of concentratedH2SO4 (2.5 mL) in THF/water and refluxed for 1 h. The chilled reaction mixture was neutralized with NaHCO3.Sufficient water was added to dissolve the salts, and the mixture was extracted with ether. The combined etherealextracts were washed with brine, dried, and concentrated in vacuo to give a yellow oil which was purified by silicagel chromatography to give 1.5 g (72%) of a colorless oil.
Best, W.M.; Ghisalberti, E. L. ; Powell, M. J. Chem. Res. (S)., 1998, 7, 388-389
Section one - Chemistry of Heteroaromatics
36
H
7. Synthesis of Isoxazoles from ββββ,,,,γγγγ-Acetylenic Oximes
R2NOH
MeOH
ON
R1
R2
Short, K. M.; Ziegler, C. B.Jr. Tetrahedron Lett., 1993, 34, 75-78.
The alkyne(0.6g) was reacted with potassium carbonate (1.5 g) in methanol (15 mL) for 12 h, then the solution was concentrated in vacuo. The residue was treated with water and ethyl acetate. The organic phase was washed with 5% HCl, brine, filtered and the residue was chromatographed on silica gel to give the isoxazole.
8. Synthesis from Benzyl Propargyl Ether and Methyl Nitroacetate
OBnO2NCH2CO2Me
OCNC6H4NCO, Et3N
ON
R
OBn
Alkyne 1 (3.3 g, 22.7 mmol) and methyl nitroacetate (2.7 g, 22.7 mmol) were combined in THF (100 mL), and 1,4-phenylene diisocyanate (9.1 g, 56 mmol) was added in one portion. Thereaction was initiated by the addition of a catalytic amount of triethylamine. When the reaction had gone to completion, 2-3 drops of water were added to quench any excess isocyanate. The polymerized urea by-product was removed by filtration through a plug of Celite, and the filtrate was concentrated to give the isoxazole (4.2 g, 76%) as a light yellow solid.
Sammelson, R. E.;Miller, R.; Kurth, M. J. J. Org. Chem., 2000, 65, 2225-2228
9. Cyclization of N,O-Boc αααα-Keto Hydroxamic Acids Synthesized via Acyl
N
O O
Boc
Boc
The starting ketoamide (450 mg, 1.4 mmol) was dissolved in MeOH (3 mL) and this solution was added toconcentrated HCl (10 mL) at 50 °C. The mixture was stirred for 1 h, cooled to rt, and concentrated in vacuo. Theresidue was dissolved in water (10 mL) and the pH adjusted to 3-4 with 2 M aqueous NaOH followed byextraction with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the final product in high yield.
Conc. HCl ON
HO
Me
Sorensen, U. S.;Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem., 65, 2000, 1003-1007
Section one - Chemistry of Heteroaromatics
Meldrum’s Acids
K2CO3
37
Otting, C.; Messerle, B. A.; Soler, P. L. J. Am. Chem. Soc. 1996, 118, 5096
An Interesting Variation
90%
+
+
O
Br NN
R
Ar1
O O
NN
Ar2
+
Neidlein, R.; Schroeder, G. Helv. Chim Acta 1992, 75, 825.
CO2HAr1
CO2H
A mixture of the 6-aryl-4,6-dioxohexanoic acid (20 mmol), the aryl hydrazine hydrochloride (20 mmol) andtriethylamine (20 mmol) in methanol (150 mL) was stirred at rt for 6 h. The mixture is concentrated in vacuo and the residue is taken up in ether, washed with 5% HCl, and brine (40 mL), dried (Na2SO4), filtered, andconcentrated to an oil. The residue is crystallized from ether/ acetone to afford the product in 94% yield.
Ten Top Methods to Synthesize Pyrazoles
H
1. Reaction of ββββ-Bifunctional Compounds with Hydrazines
94%
69%
Murray, W.; Wachter, M; Barton, D.; Forero-Kelly, Y. Synthesis 1991, 18.
•HCl
Section one - Chemistry of Heteroaromatics
38
o
o
o
o
N
HN
Ethanol (35 mL ) and water (55 mL) were added to hydrazine sulfate (2.1 g, 16 mmol) and the solution was stirredand heated at 75oC for 1.5 h until the hydrazine fully dissolved. Malonaldehyde bis(dimethylacetal) (2.7 g, 16mmol) was added dropwise and the solution was stirred and heated at 75 oC for 2 h. The mixture was then stirred for 24 h at room temperature. The ethanol was removed under reduced pressure and the solution was neutralizedwith CaCO3. After addition of water the solution was filtered through celite. The eluent was extracted with etherthe ether solution was dried over K2CO3 and filtered again through celite. The volume of ether was reduced bydistillation to give the product.
NH2NH2 . H2SO4
Ar2NHNH2
RNHNH2
DMF
MeOH
K2CO3
Et3N
O NH2
NN
R1
CH3
R1N
N
R1
CH3
CNHN
NH2CN
HN
CNN
Ph
NNBn
NH2
80-95%
+
4. Synthesis of 3-Amino Pyrazoles
Me
N
O
A mixture of the β-amino enone (2.8 mmol) and the hydrazine derivative (3.4 mmol) in 5 mL of ethanol were stirred at20oC-80oC with 1 mL AcOH as the catalyst. The solution was poured into water (20 mL) and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Theresidue was purified by recrystallization or chromatography on silica gel.
Alberola, A.; Bleye, L. C.; Gonzalez-Ortega, A.; Sadaba, M. L.; Sanudo, M. C. Heterocycles, 2001, 55, 331.
NN
Me
RH2N
Section one - Chemistry of Heteroaromatics
39
heat
2. ββββ-Substituted Enones and Alkyl Hydrazines
85% total yield
Holschbach, M.H.; Wutz, W.; Olsson, R. A. Tetrahedron Lett. 2003, 44, 41.
+ conc. HCl
Butler, D.; Alexander, S.M. J. Hetereocyclic Chem. 1982, 19, 1173.
95%
+
3. One-pot Synthesis of 3-Amino Pyrazoles
RNH2 R
R
HOAc
N2H4.H2O C6H5CHO
NaOH
RNHNH2
EtOH
NH2
OEt
NHONO2
Cl
ONHN
HN
ONO2
5. Synthesis of 3-Acylaminopyrazoles Starting from Acylated ββββ-Keto Imino Ethers
+
A 5.0 g (0.024 mol) sample ofthe imino ether was added to 4.2 mL (0.05 mol) of pyridine in 25 mL of methylenechloride and cooled in an ice bath. The suspension was stirred for 5 min and 2.9 mL (0.025 mol) of benzoyl chloride was added dropwise over 3 min. The reaction was stirred 5 min at ice bath temperatures and the bath removed andthe reaction stirred at ambient temperatures for 1 h. The reaction was poured into 100 mL of water and 100 mL ofethyl acetate added. After shaking, the aqueous layer was removed, the organic layer washed with water, driedover magnesium sulfate and concentrated to yield 7.0 g (100%) of acylated β-ketone imino ether as a clear oil.Without purification, 5.0 g (0.018 mol) of this compound was dissolved in 50 mL ethanol at room temperature and0.64 mL (0.02 mol) hydrazine added dropwise over 1 min. After 30 min the reaction was poured into water, ethylacetate added and after shaking, the organic layer was washed once with dilute hydrochloric acid and then withwater. The organic layer was dried over magnesium sulfate and concentrated to give 4.1 g (93%) of a white solid.
1. Pyridine, CH2Cl2
2. NH2NH2
U.S., 6593477, 15 Jul 2003.Robert, F.; Susan M.93%
Section one - Chemistry of Heteroaromatics
R SiR1R2
CF2-CF2-RF
R
O
F
F
R
OSiR1R2
CF2-RF
F
NNMe
F R
RF
CH2Cl
ArN
N
6. Synthesis of Fluoro-pyrazoles from Organofluorosilicon Building Blocks
Ar
(CF2)n-1CF3
To a solution of the starting material (0.6 mmol) in ether (5 mL) was added methylhydrazine (2 equiv., 1.2mmol). The mixture was stirred at room temperature for 5 h and filtered. After solvent removal, the pyrazole was purified by silica gel chromatography.
Bouillon, J.- P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J. Org. Chem. 2001, 187-192.
95%
An interesting Variation
Ohkoshi, M.; Yoshida, M.; Matsuyama, H.; Iyoda., M. Tetrahedron Lett. 2001, 42, 33-36.
40
Me-NH-NH2
OH
RFMe-NH-NH2
H
Et2O, rtRF=C4F9 R=alkyl, aryl
- HF,- H2O
CF3(CF2)nI +1. (Bu3Sn)2, hv, O2, benzene
2. NH2NH2.AcOH, EtOH 69%
Cl
Ph
Cl
Ph
Padwa, A.; MacDonald, J. G. J. Heterocyclic Chem. 1987, 24 (4) 1225-1227
R2 R3
O ON
NH
NN
Ar
Ar
BrR1
R1
R2O
R3
O NO
OMe
ArHNN
Br
OEtO
NN
OMe
O
O OEt
Ar
Section one - Chemistry of Heteroaromatics
7. Nitrile Imines as Precursors for Pyrazoles
An Interesting Variation
Shawali, A.S.; Parkanyi, C. J. Hetereocyclic Chem. 1980, 17, 833.
The appropriate 1,3-dicarbonyl compound (0.01 mol) was added to an ethanolic sodium ethoxide solution.After stirring for 10 min, the hydrazonyl bromide (0.01 mol) was added and stirring was continued overnight. The product was collected by filtration or by dilution with water and filtration. Purification by recrystallizationfrom ethanol gave the product in 78-84% yield.
8. Hydrazonyl Bromides and ββββ-Dicarbonyl Anions
Shawali, A.S.; Abdelhamid, A.O. J. Hetereocyclic Chem. 1976, 13, 989.
To a stirred solution containing 1.5 mmol of diphenyl hydrazonyl chloride and 1.5 mmole of carboxymethylenetriphenyl phosphorane in 30 mL benzene at 250 oC was added 1mL of triethylamine. The solution was allowed to stir for 6 h and was filtered. The residue obtained upon removal of the solvent was subjected to silica gelchromatograhy.
41
PhNHN (Ph)3PNEt3
NaOEt
Et3N
+
90%
78-84%
+
+
72%
NN
Ph
EtO
Ph Ph
NH
N
O
CH2
CF3 Br
NH
N
CO2Et
CF3
+
O
An Interesting Variation
Et2O0°C to reflux
2 hr
Ethyl diazoacetate (11 mmol) in ether (3 mL) was added dropwise to a solution of bromopropene (7.6 mmol) in ether (2 mL) at 0°C. The temperature was allowed to rise to 20°C, and was then heated at reflux for 2 h . The productwas distilled using a Kugelrohr apparatus and recrystallized from hexane to give 86% of the desired pyrazole.
H
10. Alkyl Diazo Compounds and Multiple Bonds
85%
42
Plancquaert, M.; Redon, M; Janousek, Z.; Viehe, H. Tetrahedron 1996, 52, 4383.
86%
Section one - Chemistry of Heteroaromatics
Bowden, K.; Jones, E.R.H. J. Chem. Soc. 1946, 953.
+
NHR1
Ar
R2
R3 NH NN
R1
9. Sulfur Monoxide Extrusion from 1,2,6-Thiadiazine S-Oxides
Ar
R2 R3
NS
NPyridine
O
R1Ar
R2
R3
Thionyl chloride (0.012 mol) was added to the starting diimine (0.01 mol) in pyridine (50 mL) at 0 °C. The stirredmixture was warmed to rt and after 2 h, 4N H2SO4 was added. The intermediate thiadiazine S-oxide was extractedinto ether and purified by recrystallization from hexane. Heating this intermediate in toluene at 90 °C for 8 h, followed by concentration in vacuo and recrystallization from hexane gave the desired pyrazole in 80% yield.
toluene+
Barluenga, J.; Lopez-Ortiz, J.F.; Gotor, V. J. Chem. Soc., Chem. Commun. 1979, 891.Barluenga, J.; Lopez-Ortiz, J.F.; Tomas, M.; Gotor, V. J. Chem. Soc., Perkin. Trans. 1 1981, 1891.
90°C
CH2N2Et2O
EtO2CCHN2
SOCl2
-60 ˚C, 0.5 h
(Method B)
R2
Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Prigden, L. N. J. Org Chem. 1997, 62, 8449.
2. TOSMIC Reagent for Synthesis of 4,5-Disubstituted Imidazoles
K2CO3
CHCl3/H2O
A solution of amidine (30 mmol) and 2-bromo-3-(1-methylethoxy)-2-propenal (45 mmol) in chloroform (60 mL) andwater (7.5 mL) was treated with solid potassium carbonate (45 mmol) and stirred at ambient temperature for 18 h.After cooling, the reaction mixture was partitioned between methylene chloride and water. The organic phase waswashed with water and brine and dried (MgSO4). The product was isolated by flash chromatography on silica with 5% (v/v) acetonitrile/methylene chloride as eluent in 83% yield.
1R
N
NHR2Br X
Oi-PrH
1. Synthesis of 1,2,5-Trisubstituted Imidazoles
Method A (Preparation of 5-benzyl-4-butylimidazole). To a cold (-78 ˚C) solution ofN,N-bis(trimethylsilyl)formamide (1.6 mL, 7.5 mmol) in anhydrous THF (10 mL) was added slowly a solution ofn-butyl lithium in hexane (4.7 mL, 1.6 N, 7.5 mmol). After the mixture was stirred at -78 ˚C for 30 min, a solution of the anion of tosylbenzylmethyl isocyanate [prepared by addition of a solution of lithium bis(trimethylsilyl)amide(7.15 mL, 1 N, 7.16 mmol) to a cold (-55 ˚C) solution of tosylbenzylmethyl isocyanate (2.0 g, 7.16 mmol) inanhydrous THF (5 mL) followed by stirring for 30 min at -50 to -60˚C] was added by cannula. The resultantsolution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h) and was then stirred at room temperature for16 h. The reaction mixture was concentrated, the residue was diluted with 30 mL distilled water, and the solutionwas adjusted to pH = 10 by the addition of 1 N HCl. Sodium chloride was added to saturate the aqueous solutionand this solution was extracted with ethyl acetate/ methylene chloride (4 : 1). The combined organic extracts weredried over anhydrous sodium sulfate and potassium carbonate, concentrated, and purified by flash chromatographyon silica gel to give 5-benzyl-4-butylimidazole (1.0 g, 66%).
Method B. (General procedure). To a solution of an aldehyde (1.5 mmol) in anhydrous THF (2 mL) at -60 ˚C wasadded dropwise a solution of lithium bis(trimethylsilyl)amide (1.5 mmol). The resulting solution was warmed to -30˚C (20 min), and then a solution of the anion of tosylmethylisocyanate (1.4 mmol) was added (prepared asdescribed in Method A). The resultant solution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h), andthen stirred at room temperature for 16 h. The reaction mixture was worked up as described in Method A.
-78 ˚C, 0.5 h
(Method A)
N
N1R
X
4R-Li OCHN(SiMe3)2
4R-CHO
4R NSiMe3
Li-N(SiMe3)2HN N
Ten Top Methods to Synthesize Imidazoles
4R = CH3, n-C4H9, C6H5 5R = H, CH3, C6H5CH2
R4
Shih, N. Y. Tetrahedron Letters 1993, 34, 595.
5R
Section one - Chemistry of Heteroaromatics
TosCR5LiNC
1R = n-C4H9, C6H5 2R = C6H5, CH2Ph-4-CO2H, CH2-1-naphthyl
X = CHO, CN
43
1R
EtON CH2CO2R2
1R
EtO N
H
H
N
N
H
OEtR1
1R
EtO CO2R2
2RO2CCH2
H
1R = CH3, C4H9, (CH3)2CHCH2, (CH3)3C, C6H11
N
NR1
R1 CONHCH2CO2R2
2RO2CCH2
N
NR1
R1 CO2R2
R2O2CCH2
- 2EtOH
H
Morel, F.; Lerestif, J. M.; Bazureau, J. P.; Hamelin, J.; Tonnard, F. Heteroatom Chemistry 1996, 7, 187.
Section one - Chemistry of Heteroaromatics
CO2R2
1R = CH3, (CH3)2CH, C6H5CH2, C6H52R = CH3, (CH3CH2)2, CH2CCH
4. Historic Method Improved by Acidic Conditions To Furnish 1-Alkylimidazoles
Gridnev, A. A.; Mihaltseva, I. M. Synthetic Communications 1994, 24, 1547.
3. Acid Induced Synthesis of 1,2,5-Trisubstituted-4-Imidazoyl Glycinates
AcOH
70 ˚C -1RCO2Et- 2ROH
A freshly distilled imidate (40 mmol) and glacial acetic acid (13.2 mmol, 0.79 g) were heated to 70 ˚C under drynitrogen with vigorous stirring for an appropriate reaction time as monitored by tlc. After elimination of thecorresponding alcohols and ester under reduced pressure, the crude reaction mixture was titurated with dry ethylether. After standing 24 hours at 4 ˚C, the precipitated product was filtered, washed with ether, dried in a desicator over CaCl2, and recrystallized from a mixture of Et2O/CH2Cl2 to yield the purified product in 96 % yield.
A 100 mL flask equipped with a mechanical stirrer dropping funnel and reflux condenser was loaded with glyoxal (0.1mol, 11.5 mL of 40% aqueous solution), formaldehyde (0.1 mol, 15 mL of 20% aqueous solution) and thealkylammonium salt (0.1 mol), which had been obtained by acidification of the appropriate alkylamine solution in 8-15 mL of water with phosphoric acid until the pH = 2. The reaction mixture was warmed to 90-95 ˚C and a saturatedaqueous solution of 0.1 mol ammonium chloride was added to the stirred reaction mixture over a period of 60-75min. After an additional 10 min of stirring at 95 oC, the crimson reaction mixture was chilled, solid KOH was addedand the mixture was extracted with ethyl acetate. The combined extract was evaporated and distilled under vacuumto provide the product in 50% yield.
O O
[RNH3]XH H
O
H H N
N
R+
44
+ -
N
N
1R
X(CH3)n
Ph
R
N
N
1R
X(CH3)n
Ph
R
CH2
I
Zn CH2IN
R
N
H
X(CH3)n1R
Ph
N
R
N
HPh
R1
1R N CO2CH3
2RX NXR2
CO2CH3
R1
(CH3)2N
NXR2
CO2CH3
R1
RNH N
1R
R
CO2CH3
5. Simmons Smith Reagent for Imidazole Synthesis
Jayakumar, S.; Ishar, M. P. S.; Mahajan, P. Tetrahedron Letters 1998, 39, 6557.
(CH3)2N OEt
H OEt
To a well stirred solution of zinc-copper couple (0.1 mmol) in dry ether (20 mL), under a nitrogen atmosphere, asmall crystal of iodine and diiodomethane (0.25 mmol) are added, and the reaction mixture is heated to reflux with stirring for 10 min. A solution of 1,3-diazabuta-1,3-diene (0.1 mmol) in dry THF (25 mL) is added slowly and thereaction mixture is again heated to reflux for 3-4 h and monitored by tlc. The solvent is removed under reducedpressure and the residue is treated with water (100 mL) and CHCl3 (75 mL). The reaction mixture is filtered, theresidue is washed with CHCl3 (30 mL) and the combined organic extract is washed with water, dried over Na2SO4and evaporated to give the crude product which is purified by column chromatography on silica gel using hexane-ethyl acetate mixture (10:1) as eluent.
Section one - Chemistry of Heteroaromatics
1R = CH3 , CH3S2RX = OEt, SCH3
R = N(CH3)2, NH(CO2CH3), PhCH2NH2
R = H, CH3 1R = N(CH3)2, N(CH2)5, N(CH2)4O
X = S, n = 1
X = N, n = 2
- 2RXH
CH2I2,Zn(Cu)
Et2O/THF
A solution of imidate (1.0 mmol) and N,N-dimethylformamide diethylacetal (1.1 mmol) in acetonitrile was heated to reflux for 72 h. Removal of solvent under reduced pressure was followed by addition of amine (1.1 mmol) andheating to 70 ˚C for 3 days. The crude product was purified by column chromatography to provide the imidazolecarboxylate in 70 % yield.
Acetonitrile RNH2
-(CH3)2NH
Jouneau, S.; Bazureau, J. P. Tetrahedron Letters 1999, 40, 8097.
HN
6. Aza-Annulation Provides Imidazole-4-Carboxylates
45
Acetonitrile
reflux
R = CH3, C6H5, C6H5CH2NH, C2H5O
Allylamine (5.05 mmol) is added to a solution of 3-hydroximino-2,4-pentadione (5 mmol) in anhydrous acetonitrile(5 mL). The violet solution is stirred at room temperature for 12 h and then heated at reflux for 2 h. The mixture is concentrated and purified by column chromatography on silica gel using ethyl acetate as eluent. Recrystallizationfrom ethyl ether-hexane provided the pure product in 65 % yield.
1RCH2
2R N OH
Veronese, A. C; Vecchiati, G.; Sferra, S.; Orlandini, P. Synthesis 1984, 300.
8. Imidazoles via Hetero-Cope Rearrangement
Cl Ph
NR3
N Ph
3R
2R N
NHR3Ph
O
7. Synthesis of 2-Vinylimidazole Derivatives
1R
N
N
1R
2R
Ph
R3p-TsOH
NEt3
1R = 2R = (CH2)43R = CH3
Lantos, I.; Zhang, W.; Shui, X.; Eggleston, D.S. J. Org. Chem. 1993, 58, 7092.
To a cooled solution of N-methylbenzenecarboximidoyl chloride (R3 = Me) (3.1 g, 20 mmol) in dry THF (50 mL) at-78°C was added a 3.5 molar excess of triethylamine. The mixture was stirred for 0.5 h, and a solution of cyclo-hexanone oxime (1.1 g, 10 mmol) was added. The solution was heated at reflux for 12 h. Water was added andthe mixture was extracted with CH2Cl2. The combined organic layer was washed with saturated NaCl and dried.The solvent was removed under reduced pressure and the crude product was purified by column chromatography. N-Methyl-N-[2-[[(methylamino)phenylmethylene]amino]-1-cyclohexen-1-yl]benzamide was obtained as an oil in52% yield. The amidine (1 g, 2.8 mmol) was heated with p-toluenesulfonic acid (2.5 molar equiv) in toluene atreflux in a Dean-Stark apparatus for 12 h. The solution was cooled to ambient temperature and was washed with 1N NaOH solution. The mixture was concentrated under reduced pressure and purified by chromatography. Theproduct was obtained as white crystals in 97% yield.
Section one - Chemistry of Heteroaromatics
R CH3
O O
N
OH
H2NN
N
H
RO
46
4RBr
O
4RNHR1
O N
N
NO
NH
R5
NR2
O
H2N R5
O
ONHN
R5
O
N N
R5
O
2R
9. 1,4-Disubstituted Imidazoles
1RNH2
ether, -78°
HCONH2
∆1R = t-Bu4R = benzyl
82% yield
Under an argon atmosphere, a pressure-equalizing dropping funnel charged with the α-bromo ketone (10.0 g) indiethyl ether (20 mL) was attached to a 300-ml round-bottomed flask, containing a magnetic stir bar and asolution of the primary amine (3 equiv) in diethyl ether (70 mL). The solution was stirred while cooling in a dryice-acetone bath to -78°C. The solution of the bromide was added dropwise over 15 min, and the mixture wasstirred for an additional 1 h at -78°C . The cooling bath was removed and the mixture allowed to warm to roomtemperature and to stir for several hours, until precipitation of the HBr salts appeared complete. The contents ofthe flask were poured into a separatory funnel and shaken with a small amount of 15% aqueous NaOH until thewhite solids dissolved. The ether layer was washed with water and brine and dried over MgSO4. Filtration andconcentration of the solution afforded the crude amino ketone as a light yellow oil. This material could be isolated by vacuum distillation or flash chromatography, but typically was used immediately in its crude form.
Sorrel, T.N.; Allen, W.E. J. Org. Chem. 1994, 59, 1589
R2
R1
10. Imidazoles From 4-Aminoisoxazoles
R1
Reiter, L. J. Org. Chem. 1987, 52, 2714.
R1
A 300-mL two necked flask with an attached air-cooled condenser was charged with formamide (35 mL), whichwas heated to 180°C under argon with stirring. A pressure-equalizing dropping funnel containing the amino ketone was fitted to the reaction vessel, and the amino ketone was added dropwise over 1 h. The mixture was allowed toreact for an additional 2-3 h at 180°C. After cooling, the dark reaction mixture was treated with an equal volume ofwater and 20 mL of 15% aqueous NaOH. The mixture was extracted twice with 200-mL portions of toluene, whichwere combined, washed with water and brine, and dried over Na2SO4. The drying agent was removed by filtration,and the toluene was evaporated at reduced pressure to yield a yellow-brown oil which was purified by flashchromatography with ethyl acetate as the eluent. Short-path distillation under reduced pressure with use of aKugelrohr apparatus afforded the colorless, hygroscopic 1,4-disubstituted imidazole.
R1
Section one - Chemistry of Heteroaromatics
4R
NO
N
R5
R2
OR1
4R 4R
4R4R
After acylation by standard procedures, 4-(acylamino)isoxazole was hydrogenated at 40 psi over 10 % palladium on carbon in ethanol (ca. 10 mL/mmol of reactant). After 1 h, the reaction was usually complete by tlc. The catalyst isremoved by filtration and washed with ethanol. The filtrate containing the intermediate β-amino-α,β-unsaturatedketone was treated with NaOH (pellets, 1.1 equiv) at reflux for 1 h. Solid NH4Cl (1.2 equiv) was then added, thereaction allowed to cool to r t, and the ethanol removed in vacuo . The residue was slurried in acetone and themixture filtered. Concentration of the filtrate gave the crude product which is purified by column chromatography orrecrystallization to give pure imidazole in 80 % yield.
R1
4R
H2, Pd/C
EtOH, RT
AcylatingReagent
NaOH
EtOH
R1 = CH3, Ph, PhCH2
R2 = H, CH3, CH2CH3, Ph, CF3, C(CH3)3
R4 = H, CH3
R5 = H, CH3
-H2O-
47
SO2CH2
Me
N C N
OPh
N
NH
Ph
NH
CO2MeMe
N
S
Ts
-
Et2OCCH2COMe
van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337
+
NH
NO2Ph
NH
CNPh
NH
CO2EtPh
Ts
Ts
van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337
MeNO2
tBuOK
S
tBuOK92 %
99 %
94 %
van Leusen, D.; Flentge, E.; van Leusen, A. M. Tetrahedron 1991, 47, 4639 van Leusen, D.; van Echten E.; van Leusen, A. M. J. Org. Chem. 1992, 57, 2245
PhCN
1) PhCHO/nBuOK
64 %
NaH
MeCH=CHCO2Me
KOH
70 %
60 %
53 % Ph
N
TsH
Ph CN CH2Ts C
Use of Tosmic Reagent for Heterocyclic Synthesis
n-BuLi (2 eq.)
PhCOOEt
2) POCl3/Et3N
PhCSCH2CO2H+
Me SO2
Et2OCCH2CN
n-BuLi (2 eq.)
tBuOK
Ts =
SO2CH2
Me
N C
SO2CH2
Me
+
N C
-
+ -
SO2CH2
Me
N C+ -
+ -+ -
Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1972, 5777
Section one - Chemistry of Heteroaromatics
van Nispen, S. P.J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 3723
van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S111. Zwanenburg, B.; Klunder, A. J. H. in Perspectives in the Organic Chemistry of Sulfur.; Elsevier Science Publishers: Amsterdam, 1987, pp 119-144 van Leusen, A. M.; Schut, H. Tetrahedron Lett. 1976, 285
48
TsCH2N C
O
MeO
t-BuOK
CN
MeO
Br
OTHP
TsCH2N CNaOH
OTHP
Ts
NC NaOH
Br
OTHP
C
OTHP Ts NC OTHP(NH4)2SO4
O
O
CHO
MeO
MeOTsCH2N C
MeO
MeO
Ts
NC
NH
OMe
OMe
MeO
MeO
Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. J. Org. Chem. 1977, 42, 3114.
49
Applications of Tosmic for Complex Molecule Synthesis
1. Reductive Cyanation
+
2. Use as a Connective Reagent
69%
+
Yadav, J. S.; Gadgil, V. R. Tetrahedron Lett. 1990, 31, 6217.
3. Knoevenagel-type Condensation
+
1) t-BuOK
2) POCl3, i-Pr2NH
64%
papaverine
Barrett, A. G.; Barton, D. H.; Falk, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1979, 652.
van Leusen, D.; van Leusen, A. M. In Organic Reactions; Overman, L. E., Eds.; Wiley & Sons: New York, 2001, 57, 417; Tandon, V. K.; Rai, S. Sulfur Reports 2003, 24, 307.
82%
75%
H
Section one - Chemistry of Heteroaromatics
t-BuOK
t-BuOK
TsCH2N CN
NO
H
NaOMeN
NN
O
TsCN
MeO
O
MeO
MeO
ON
CH2O
Na2CO3
TsCH2N C
Van Leusen, D.; Batist, J. N.; Lei, J.; Van Echten, E.; Brouwer, A. C.; Van Leusen, A. M. J. Org. Chem. 1994, 59, 5650.
50
4. Synthesis of Oxazoles
+
5. Synthesis of Oxazoles
35%
Dopamine D4 Receptor Ligands
Haubmann, C.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 3143.
+
96%
+
O
SH
TsCH2N Cn-BuLi
H
OH
SN
Tos
6. Synthesis of Thiazoles
+79%
Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.
Section one - Chemistry of Heteroaromatics
TsCH2N C NH
OMe
MeO
Ph
O
Ph
NaHNH
OMe
MeO
Ph
OHN
Ph
CN
NH2
CN
N
N
CO2Me
NH2
NH
N
N HN
O
SO2NH2
MeO
O
CHO
51
7. Synthesis of Pyrroles
+55%
Black, D. S.; Bowyer, M. C.; Kumar, N. Tetrahedron 1997, 53, 8565.
8. Synthesis of Imidazoles
Fevig, J. M.; Pinto, D. L.; Han, Q.; Quan, M. L.; Pruitt, I. C.; Jacobson, I. C.; Galemmo, R. A.; Wang, S.; Orwat, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Lam, P. Y.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2001, 11, 641.
1)
2) TOSMIC, K2CO3
Benzamidine Factor Xa Inhibitors
N
N
NH CHO
N
N
N
NTs
N
N
N
N
TsCH2N CDBU
Na2HPO4
9. Synthesis of Pyrimidines
Minguez, J. M.; Vaquero, J. J.; Alvarez-Builla, J.; Castano, O.; Andres, J. L. J. Org. Chem. 1999, 64, 7788.
+Na/Hg
80%55%
Section one - Chemistry of Heteroaromatics
+TsCH2N CN CHO
N
ON
N
S
Ts
S
N
SMeS
Ts
K2CO3
82%
+N CHO
H
van Leusen, A.M.; Wildeman, J. Synthesis 1979, 501.
+ CS2BuN+Br-, 10% NaOH
Bu4N
90%
To a mixture of 2-pyridinecarboxaldehyde (0.01 mol) and tosylmethyl isocyanide (1.9 g, 0.01 mol) in 30 mL ofMeOH was added K2CO3 (1.4 g, 0.01 mol). The solution was refluxed for 2 h and the solvent was removedunder reduced pressure. The residue was poured into ice water and extracted with ether. The organic layer was washed with 2% HCl and water and dried over Na2SO4. After filtration and evaporation of the solvent, the cruderesidue was distilled (95-98°C/0.15 torr) to give an 82% yield of the desired oxazole.
To a solution of tosylmethyl isocyanide (1.9 g, 10 mmol), carbon disulfide (5 mL) and chloroform (10 mL) wasadded tetrabutylammonium bromide (3.5 g, 11 mmol) and 10% NaOH (10 mL). The mixture was stirred for 1.5 hat rt and the layers were separated. The aqueous layer was extracted with chloroform and the combined organic layers were washed with water and dried over MgSO4. After filtration and removal of the solvent, the cruderesidue was taken up in chloroform (20 mL), methyl iodide (2.8 g, 20 mmol) was added, and the mixture wasstirred for 3 h at rt. The solvent was removed and the crude solid was washed with methanol, ether, and dried.Recrystallization from chloroform/methanol gave 2.6 g (90%) of the desired thiazole.
N N
Ts
Reaction with Carbon Disulfide to Form Thiazoles
Tosmic Reagent and Its Use in Heterocyclic Synthesis
Reaction with Aldehydes to Form Oxazoles
R1
R2
R3R3R2
R1
Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A.M. Chem. Pharm. Bull. 1979, 27, 793.
Formation of Pyrrolo[1,2-c]pyrimidines
DBU, THF
61-82%
Minguez, J.M.; Vaquero, J.J.; Garcia-Navio, J.L.; Alvarez-Builla, J. Tetrahedron Lett. 1996, 37, 4263.
To a mixture of 214 mg (1.1 mmol) of tosylmethyl isocyanide and 167 mg (1.1 mmol) of DBU in 2 mL of THF was added 95 mg (1 mmol) of pyrrole-2-carboxaldehyde in 2 mL of THF. The mixture was stirred at rt for 2 h andthen neutralized with acetic acid. The solvent was removed under reduced pressure and the residue waschromatographed on silica gel and recrystallized from CH3CN to give the desired product in 82% yield.
MeITsCH2N C
TsCH2N C
52
Section one - Chemistry of Heteroaromatics
TOSMIC
NPh
Cl
N
N
Ph
Ts
Ph
N
NC
TsH
Ph
Ph
Ph
CN
N
Ph CN
H
N CTs
CH3
A solution of tosylmethyl isocyanide (390 mg, 2.0 mmol) and N-phenylbenzimidoyl chloride (430 mg, 2.0 mmol) in 5 mL of DME was added over 15 min to a suspension of NaH (50 mg, 2.0 mmol) in 5 mL of DME at rt. The mixturewas stirred for 45 min and then slowly poured into water. The precipitate was collected and recrystallized frombenzene/hexane to give 450 mg (60%) of the desired imidazole.
CO2tBu
van Leusen, A.M.; Wildeman, J.; Oldenziel, O.H. J. Org. Chem. 1977, 42, 1153.
NaH
60%
N
CO2tBu
SO2Ph
Reaction with Imidoyl Chlorides to Form Imidazoles
+tBuOK (2 eq.)
CH3
88%
To a stirred solution of t-BuOK (1.0 g, 13 mmol) in THF (30 mL) at -30 °C was added a solution of tosylmethylisocyanide (1.2 g, 6.0 mmol) in THF (10 mL). The mixture was stirred for 4 min and a solution of cinnamonitrile (0.77 g, 6.0 mmol) in THF (10 mL) was added over 4 min. After stirring for 15 min at -10 °C, the mixture was poured onto50 g of ice. The THF was removed under reduced pressure and the precipitate was filtered, washed with water,and dried under vacuum to give 0.89 g (88%) of the desired pyrrole.
Reaction with Olefins to Form 3,4-Disubstituted Pyrroles
N
SO2Ph
van Leusen, D.; van Echten, E.; van Leusen, A.M. J. Org. Chem. 1992, 57, 2245.
CH3
NtBuO2C
SO2PhN
N
H
HO2C
OMe
OH
Ac
Sequential Tosmic Reactions in the Synthesis of PDE II
+1) NaH, HMDS
2) PhSO2Cl, NaH HMDS, Imidazole
TosMICNaH, HMDS
PDE II
H+
Ph+TsCH2N C
TsCH2N C
Section one - Chemistry of Heteroaromatics
53
:
N
S R1
R
N
S
n-C8H17
NH2
Top Ten Methods to Synthesize Thiazoles
1. Modified Hantzsch Type Synthesis
Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-W.; J. Org. Chem., 2003; 68(20); 7887-7888.
To a stirred solution of (Z)-(2-acetoxy-1-decenyl)-iodane (25 mg, 0.05 mmol) and thiourea (5 mg, 0.06 mmol)in dry methanol (1.5 mL) was added triethylamine (6 mg, 0.06 mmol) under nitrogen at room temperature andthe mixture was stirred for 5 h. After removal of the solvent under reduced pressure, the residue was dissolved in a mixture of ether (30 mL) and water (10 mL). The organic layer was washed with water and brine, driedover Na2SO4, and concentrated. Purification by preparative TLC (hexane-ethyl acetate) gave the thiazole(91%) as colorless plates.
2. The Charette Synthesis
DeRoy, P. L.; Charette, A. B.; Org. Lett. 2003; 5, 4163-4165.
Section one - Chemistry of Heteroaromatics
54
R
AcO IPh
BF4 MeOH
S
CNH2R1 , Et3N
n-C8H17
AcO IPh
BF4MeOH
S
CNH2 , Et3N
MeHN
O1. Tf2O, pyr, CH2Cl2
2. L-Cysteine HCl, pyr
90%
N
SO
EtO N
SO
EtO
BrCCl3, DBU
99%
H2N
To a solution of diispropylamine (5 mL, 51 mmol) in anhydrous THF (80 mL) at -20 oC was added a solution of butyllithium (1.6 M in THF), stirred for 15 min, and cooled to -78 oC. A solution of the thioester (6 g, 51 mmol)in THF (20 mL) was cannulated slowly into the yellow solution and stirred for an additional 15 min.Chlorotrimethylsilane (6.4 mL, 51 mmol) was added, and the solution was stirred for an additional 1 h at-78oC. The solution was warmed to rt over a 1 h period before being diluted with pentane (150 mL) andwashed with phosphate buffer pH 7 (100 mL). The organic layer was dried over Na2SO4, concentrated, anddistilled under vacuum to furnish the (Z) silylketene thioacetal. To a solution of thiazoline (4.8 g, 24 mmol) inCH2Cl2 (90 mL) at 0 oC was added DBU (7.2 mL, 48 mmol) and the resulting mixture was stirred for 10 min.Bromotrichloromethane (2.4 mL, 24.1 mmol) was added dropwise and the reaction was then warm up to rt.After 1 h, the reaction was quenched with a saturated aqueous solution of NaHCO3 and transferred in aseparatory funnel and the aqueous phase was discarded. The organic phase was dried over anhydrousMgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by columnchromatography on silica gel (20% EtOAc/hexane) to afford the thiazole (4.8 g, 99%) as a colorless oil.
.
Synthesis of 2,4-Disubstituted Thiazoles from (Z)-(2-Acetoxyvinyl) phenyl-iodanes
Synthesis of Thiazole from Thiazoline
R2 NH2
C
N
SH
S R1
NH
S R1
R2N
S R1
R2
H2N
NH2
C
N
N
S SHH2N
EWGCH2N C-R OEt
S+N
S
EWG
REWG
N
S
R OEt
-
+
3. Cook-Heilbron Type Synthesis
+
α-Aminobenzyl cyanide (13.5 g) was refluxed in ether (250 mL) with carbon disulphide (10 g) for 8 h. Upon cooling, large yellow crystals were deposited. The yield of yellow crystals (12.8 g) was augmented byallowing the filtrate to stand in carbon disulphide overnight. The total yield of5-amino-2-mercapto-4-phenylthiazole was 19.6 g (93%).
CS2
Et2O
Cook, A. H.; Heilbron, I.; Levy, A. L.; J. Chem. Soc. 1947, 1598.
4. Isocyanide Synthesis
Reaction of α-Metallated Isocyanides with Thiono Esters
+
+
H OEt
SN
S
EtO2C
+
base
EtOH
Hartman, G. D.; Weinstock, L. M. Synthesis, 1976, 6, 681.
NaCN
N
EWGCH2N C-
A solution of ethyl isocyanoacetate (4.5 g, 40 mmol) and O-ethyl thioformate (3.6 g, 40 mmol) in dry ethanol(15 mL) was added dropwise with vigorous stirring to a suspension of sodium cyanide (0.25 g) in ethanol (10mL). An exotherm developed during the addition and the reaction mixture was heated at 50 oC for 0.5 h.The solvent was removed under reduced pressure and the resulting dark oil was extracted several times with hot hexane to give 5.8 g (92%) of the product.
C
+
Section one - Chemistry of Heteroaromatics
55
Reaction of α-Aminonitriles with Dithioacids and their Derivatives
-
N
SNHR
5. One-pot Synthesis of 2-Aminothiazoles using Supported Reagents
A mixture of α-bromo ketone (1 mmol), KSCN/SiO2 (5 mmol) and NH4OAc/Al2O3 (6 mmol) was stirred in benzene at 80oC for 6 h, and then the used solid reagents were removed by filtration. The filtrate wasevaporated to leave a crude product, which was purified by column chromatography over silica gel.
6. Synthesis of 2-Acylaminomethylthiazoles
Henkel, B.; Sax, M.; Domling, A. Tetrahedron Letters 2003, 44, 3679-3682.
Section one - Chemistry of Heteroaromatics
56
Kodomari, M.; Aoyama, T.; Suzuki, Y.Tetrahedron Letters 2002, 43, 1717-1720.
R1R2
O
Br
R1R2
O
SCN
R1
R2
KSCN/SiO2 NH4OAc/Al2O3
PhBr
O
Ph
N
S
HN
Ph
Ph
KSCN/SiO2- NH3OAc/Al2O3
Deprotected Rink resin (purchased from Pepchem, Tubingen) (200 mg, 0.21 mmol) was washed with 3 mL oftrimethylorthoformate. Isobutyraldehyde (0.19 mL, 2.1 mmol) was dissolved in 3 mL of trimethylorthoformateand added to the resin which was agitated for 16 h. The resin was filtered and washed withtrimethylorthoformate, a 1:1 mixture of dichloromethane and methanol and finally with methanol. Subsequently, 0.19 g of 3-(N,N-dimethylamino)-2-isocyanoacrylate (1.3 mmol) and 0.15 ml of thiobenzoic acid (1.3 mmol)dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1) was added to the resin and the mixturewas allowed to react for 16 h. The resin was filtered and washed twice with dichloromethane and methanol andagain three times with dichloromethane. The resin was treated with 3 mL of 50% trifluoroacetic acid indichloromethane for 2 h. The cleavage mixture was filtered and the resin washed twice with dichloromethane.The combined solution was evaporated to dryness. The crude product was obtained in 71% yield and waspurified via preparative HPLC using a methanol/water gradient.
97%
NH2 CHOR1
MeOOC
O
R2 SH 16h, 20oC
N
SMeOOC R1
N R2
O
16h, 20oCN
S
MeOOC
R1
NH
O
R2 31~96%
Reaction of α-bromo ketone with KSCN/SiO2 and NH4OAc/Al2O3
Multicomponent solid-phase synthesis
N
S
Ph
7. Synthesis of 4-Substituted 2-Phenylaminothiazoles from Amidines
Romero-Ortega, M.; Aviles, A.; Cruz, R.; Fuentes, A.; Gomez, R. M.; Plata, A.; J. Org. Chem. 2000, 65, 7244.
+
Section one - Chemistry of Heteroaromatics
57
NH
Ph NH2
HX Et N C SNaOH/H2O
THF / 0oC CN N
H
S
EtPh
NH2
Et3N
C6H5COCH2Br
Ph
O
NH
Et
A suspension of amidine salt (1 equiv) in THF (2-5 mL/mmol amidine) was added at 0 oC to aqueous sodium hydroxide (1equiv) and phenyl isothiocyanate (1 equiv), and the reaction mixture was stirred for 1-2 h at this temperature. The mixture was then diluted with ethyl acetate (20 mL), and the organic phase was washed with saturated sodium chloride solution and dried (Na2SO4 ). Evaporation of the solvent in vacuo gave the crude products as a solid. The pure material was obtained after crystallization from hexane-dichloromethane.
The R-bromo carbonyl compound (1 equiv) was added slowly at room temperature to a stirred solution of the N-phenylthiocarbamoylamidine (1 equiv) in anhydrous THF (2 mL) containing anhydrous triethylamine (1 equiv) maintained under a nitrogen atmosphere. The reaction mixture was stirred for an additional 2-3 h, diluted with ethyl acetate (20 mL), the mixture was washed with saturated NH4Cl solution (30 mL). The organic phase was separated, dried (Na2SO4),and evaporated in vacuo.
85%
CN N
S
EtPh
NH2
Ph O
CN N
S
EtPh
NH2
Ph OH
-NH3
68%
R1 O
R2 X
NH2
S R3
R1 O
R2 S R3
NH2+ N
S R3
R1
R2
CH2Br
EtO2C O
S
NH2 HN Ph
O
N
S
MeO2CHN Ph
O
8. Hantzsch Type Synthesis
X-
+
+MeOH
Li, G.; Warner, P. M.; Jebaratnam, D. J. J. Org. Chem., 1996, 61, 778.
Ethyl bromopyruvate (11.6 g, 60 mmol) was added dropwise, over a 0.5 h period, to a 50 oC solution of thethioamide (11.5 g, 59 mmol) in methanol (100 mL) after which time the reaction was refluxed for an additional 2 h. Most of the product crystallized when the solution was set aside at room temperature overnight. The filtratewas evaporated, redissolved in benzene, washed successively with a saturated aqueous sodium bicarbonateand water, dried over anhydrous sodium sulfate, and evaporated. Recystallization of this residue frommethanol provided 12 g (74%) of the product.
Reaction of amidine salt with phenyl isothiocyanate
Condensation of α-Halocarbonyl Compounds with Thioamides
NHR2
OO
R1R3
N
S OH
R1
R2
NH
HN CO2Me
OO
NH
S
N
9. Gabriel Type Synthesis
CO2Me
heat
P2S5
P2Cl5
Uchikawa, O.; Fukatsu, K.; Aono, T. J. Heterocyclic Chem. 1994, 31, 877.
pyridine
To a solution of the diamide (5.2 g) in pyridine (50 mL) was added phosphorous pentasulfide (5.4 g) and themixture was heated at 100 oC for 5 h. After being cooled to room temperature, a saturated aqueous sodiumhydrogen carbonate solution was added to the reaction mixture, and the product was extracted with chloroform.The organic layer was washed with water and dried over magnesium sulfate. The filtrate was concentrated andthe residue was purified by column chromatography. The residue was recrystallized from ethyl acetate to yield 2.8 g (54%) of the product.
Section one - Chemistry of Heteroaromatics
R1 Br
R2 O
HS CH3
O
S
OOR2
CH3R1
N
S CH3
R2
R1
R1 Br
R2O
HS R3
O N
S R3
R2
R1
Et3N
HOAc
NH4OAc
10. Dubs Type Synthesis
+
2-Bromo-butanone (15 g, 0.1 mol) was added to a solution of thioacetic acid (7.6 g, 0.1 mol) in glacial aceticacid (84 mL), combined with ammonium acetate (27 g, 0.35 mol), and kept at reflux for 4 h. Afterneutralization with a saturated sodium hydroxide solution and extraction with pentane, the combined extractswere dried and concentrated. The residue was distilled through a Vigreux column to afford 9.1 g (72%) of the product .
Dubs, P.; Stuessi, R. Synthesis, 1976, 6, 696.
+NH4OAc
HOAc
58
Reaction of α-Acylaminoketones with Phosphorous Pentachloride
Condensation of α-Acylthioketones with Ammonia
Dry methylene chloride (25 mL) was cooled to 0-5oC with an ice/water bath under nitrogen. Thionyl chloride (5 mmol) was added dropwise and the solution was stirred for 10 min. Pyridine (5 mmol) was added and the mixture was allowed to stir for another 15 min at 0oC. The oxime in dry methylene chloride was added dropwise to the solution over a period of 15 min. The solution was stirred for 1 h at 0oC, warmed to room temp, and was then stirred for another 8-10 h. The reaction mixture was diluted with 60 mL diethyl ether, washed with 10% HCl, saturated sodium bicarbonate, distilled water, and brine. The organic phase was dried over MgSO4. Filtration, followed by removal of the solvent and silica gel column chromatography gave the isothiazole in 75-90% yield.
1. From αααα-Oxo Ketene Dithioacetals
2. Conversion of 2,5-Disubstituted Furans into Isothiazoles
A solution of ethyl carbamate (4.3 mmol), SOCl2 (4.3 mmol), and pyridine (2.0 mL) in benzene (20 mL) was stirred under nitrogen at ambient temperature for 30 min. The appropriate furan (1 mmol) was added and the mixture was heated at reflux until the starting material was consumed. The solvent was removed under reduced pressure and the the resulting residue was dissolved in CH2Cl2 (15 mL), washed with HCl, H2O and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography giving the isothiazole in 56-100% yield.
R. Karl Dieter and Hsiu Ju Chang; J. Org. Chem. 1989, 54, 1088-1092
Laaman, S.M.; Meth-Cohn, O.; Rees, C.W.; Synthesis 1999, 5, 757-759
R SCH3
SCH3N
R1
HO
NS
R R1
SCH3
SOCl2, Pyridine
O R1R SN
R1
R
O
ethyl carbamate, SOCl2, pyridine in refluxing benzene
Top Ten Methods to Synthesize Isothiazoles
3. Oxidative Cyclization of Imino Thioamides
R1
NH
NH2
S
R2
NS
R1 R2
NH2
Goerdeler, J.; Pohland, H.; Angew. Chem. , Int. Ed. Engl. 1961, 2950
A 1.9 g sample of the β-iminothioamide was taken up in 80 mL of CHCl3 in an ice bath. A mixture of 1.6 g of bromine in a small amount of CHCl3 was added dropwise. After a short period, the hydrobromide salt precipitated out of solution. The mixture was stirred for 5 min and the salt was filtered. Recrystallization from ethanol/ether gave the isothiazole in 85% yield.
Section one - Chemistry of Heteroaromatics
oxidation
59
4. Cyclization of ββββ-Thioacrolein with Liquid Ammonia
NS
O
H SRliq. NH3
Wille, F.; Capeller, L.; Steiner, A. Angew. Chem. , Int. Ed. Engl. 1962, 335
Wille, F.; Schwab, W.; Schmitzer, J.; Jochum, C. Chem. Ber. 1997, 110, 264
A 67 g sample of the acrolein derivative was taken up in 70 mL of liquid ammonia at -78 oC. The mixture was stirred until a bright yellow solution had formed. The ammonia solution was left to evaporate at roomtemperature and the residue was steam distilled and this was followed by extraction of the distillate with etherand drying over KOH to give 17.7g of the isothiazole (60% yield).
5. Use of Diene Derivatives for Isothiazole Formation
Cl
ClCl
Cl
ClNO2
SN
Cl
Cl CCl3S8
heat
Kaberdin, R.V.; Potkin, V. I.; Oldekop, Yu. A.; Zh. Org. Khim. 1990, 26(7), 1560-166
The polychloro nitrodiene was heated with neat sulfur to give the isothiazole in 52% yield.
Section one - Chemistry of Heteroaromatics
NH2
RX
+S
SN
ClCl
ClS
NNC
RX
6. Use of Primary Enamines for Isothiazole Formation
Clarke, D,; Emayan K.; Rees C.W.; J. Chem. Soc., Perkins Trans. 1, 1998, 77
A mixture of the enamine (3 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (3 mmol) indichloromethane (25 mL) was stirred at room temperature for 1 h. Pyridine was added to the mixturewhich was allowed to stir for an additional 30 min. The product was separated by flash chromatography on silica gel eluting with 1:3 dichloromethane/pentane to give the isothiazole in 40-78% yield.
+
-
60
7. From Nitrile Sulfide Cycloaddition Chemistry
R NH2
O SN
O ORC NR S
SOCl2 heat
-CO2
NS
NS
R R1
R2
R R1
R2
CC
R1
R2
CHCH
R1
R2
Oxathiazolone in xylene was heated (5 h) under reflux with 10 equiv of diethyl furmarate until thestarting material was consumed. After the evaporation of solvent and dipolarophile, by-products were removed by distillation and/or recrystallization (40-80% yield). The resulting isothiazolone (1.4 mmol)in dichloromethane (20 mL) was stirred vigorously with 8% aqueous NaOCl (40 mL) andbenzyltriethylammonium chloride (0.2 mmol) until no starting material remained (5 h). The organiclayer was separated, washed with water, dried over MgSO4, and concentrated under vaccum. Thecrude isothiazole was purified by recrystallization and/or distillation in 86-92% yield.
Crosby, J.; McKie, M. C.; Paton, M. R.;Ross, J. F. ARKIVOC 2000, 1(5), 720-734
Section one - Chemistry of Heteroaromatics
8. From Allylic Derivatives using Trithiazyl Trichloride
R4 R1
R2
R3
SN
R4R3
R2
(NSCl)3
Duan, X-G.; Duan, X-L.; Rees, C.W.; J. Chem. Soc., Perkins Trans. 1, 1997, 127
Either procedure A or B was used depending on the isothiazole. In procedure A, a mixture of the allylicderivative (1 mmol) and the trithiazyl trichloride (1 mmol) in 20 mL tetrachloromethane was heated atreflux overnight. The solvent was evaporated and the residue was purified by flash chromatograhy onsilica using dicloromethane and light petroleum. Procedure B differs only in the use of 4 Ao molecularsieves (2 g) and 25 mL tetrachloromethane. The sieves were filtered and washed with dichloromethane to give the isothiazole in good yield.
9. From 1,2,4-Dithiazane Derivatives
SN
SCH3
CH3
R
SN
CH3 R
CH3
heat
Bryce, M. R. et. al, J. Chem. Soc., Perkin Trans. 1, 1992, 2295
Bryce, M. R.; Davison, G. R.; Gough, S.; J. Chem. Soc., Perkin Trans. 1, 1994, 2571
A solution of the 1,2,4-dithiazane (1 mmol) in dry toluene ( 5 mL) was heated at reflux for 18 h. The solvent was removed under reduced pressure and the mixture was chromatographed on silica gel to give the isothiazole in 55-100% yield.
+ -
oxid
Bryce, M. R. et. al., J. Chem. Soc., Chem. Comm., 1992, 478
61
NO2
CH3
NO2
NMe2
NH
O2N NH NCH3
COOC2H5
O2N
NCOOC2H5
PPA (4 eq)
Top Methods to Synthesize Indoles
1. The Leimgruber-Batcho Indole Synthesis
H
NHCl NR
R1CH3S
NH
R1
R
R.D. Clark, D. Repke, Heterocycles, 1984, 22, 195
A solution of methyl 2-methyl-3-nitrobenzoate (9.8 g, 0.05 mol) and DMFDMA (17.8 g, 0.15 mol) in 50 ml ofDMF was heated at 130 oC for 6 h. The DMF was removed under reduced pressure, and the residue wasdistilled at 120 oC (0.2 mm) to give 10.7 g (86%) of 6-carbomethoxy-β-dimethylamino-2-nitrostyrene. A mixtureof 7.0 g (28 mmol) of 6-carbomethoxy-β-dimethyl- amino-2-nitrostyrene in 140 ml of dry benzene containing 1.4 g of 10% Pd/C was shaken in a Parr apparatus under a hydrogen atmosphere of 50 psi for 1.5 h. The catalystwas removed by filtration and the benzene solution was washed with 5% HCl and brine, dried (MgSO4) andconcentrated. Chromatography of the residue on silica gel afforded 6.9 g (82%) of methylindole-4-carboxylate.
2. Fischer Indole Synthesis
Hughes, D. Organic Preparations and Procedures, 1993, 609Guy, A.; Guette, J-P. Synthesis, 1980, 222
Ethyl 2-(4-nitrophenylhydrozono)-propanoate (3,4-nitophenylhydrazone of ethyl pyruvate (1.5 g, 7 mmol) was added to a stirred suspension of PPA (6 g) in xylene (15 ml) at 80 oC. The mixture is heated at 110 oC for 1h, then washed with water, dried over magnesium sulfate and evaporated to dryness. The product isrecrystallized from diisopropyl ether to give the product in 83% yield.
3. The Gassman 2,3-Sigmatropic Shift Protocol
R1
To a vigorously stirred solution of 0.044 mol of aniline in 150 mL of CH2Cl2 at -65 oC was added dropwise asolution of 0.044 mol of t-butyl hypochlorite in 20 mL of CH2Cl2. After 5-10 min, 0.044 mol of the sulfidedissolved in 20 mL of CH2Cl2 was added causing an isotherm. Stirring was continued at -65 oC for 1 h. To this mixture was added 0.044 mol of triethylamine in 20 mL of CH2Cl2. After the addition was complete, the coolingbath was removed and the solution was allowed to warm to 25 oC. A 50 mL portion of water was added and theorganic layer was separated, dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using CH2Cl2 as the eluent. Recrystallization gave the pure indole. A solution of0.022 mol of the thioindole in absolute ethanol was stirred with an excess of Ra/Ni for 30 min. The organic layerwas decanted from the catalyst and the catalyst was washed thoroughly with ethanol, and the solvent wasremoved under reduced pressure to give the indole.
Gassman, P.G.; Cue, B.W. J. Am. Chem. Soc. 1974, 20, 5495 Gassman, P.G.;Gilbert, D. P. J. Chem. Soc. Chem. Commun. 1974, 201 Hamel, P.; Girard, Y. J. Org. Chem. 1994, 59, 6372 Ishikawa, H.; Uno, T. Chem. Pharm. Bull. 1990, 38, 2459 Gassman, P.G.; Gruetzmacher, G. J. Am. Chem. Soc. 1974, 96, 5512
Me2NCH(OMe)2
DMF, 130o
H2
Pd-C
97% 80%
LiAlH4CH3SCHCOR
NEt3
110 oC, 90 min83%
Section one - Chemistry of Heteroaromatics
62
NRCON
OO
H
R OH Ts
N
R TsTs
H2SO4
n-Bu3SnH (1.1 equiv)AlBN (5%), CH3CN, 100 °C
4. Preparation of Indoles by Annelation of Pyrroles
Muratake, H.; Natsume, M. Heterocycles, 1989, 29, 783Muratake, H.; Natsume, M. Heterocycles, 1990, 31, 683
NC
R
NH
R1
R
To a solution of 3-cyclohexanoyl-1-(4-methylphenylsulfonyl)pyrrole (85 mg) in THF (3 mL) at -20 oC under Ar was added the Grignard reagent prepared from 2-(1,3-dioxan-2-yl) ethyl bromide (0.6 mL) and Mg (90mg) in THF (3.4 mL). After 15 min, the reaction was quenched with aqueous NH4Cl and extracted withCH2Cl2. After washing, the intermediate carbinol was obtained in 97 % yield. A portion of this productwas dissolved in 6% H2SO4 in isopropanol (4.5 mL). The solution was heated at reflux for 30 min. Aftercooling and dilution with water, the solution was extracted with CH2Cl2 and chromatographed to give theindole in 82% yield.
5. Tin-Mediated Indole Synthesis
Fukuyama, T.; Chen, X; J. Am. Chem. Soc, 1994, 116, 3127
A solution of 0.85 mmol ofthe isonitrile, 0.93 mmol of n-Bu3SnH, and 0.04 mol of AIBN in 5 mL of dryacetonitrile was heated to 100 oC for 1 h in a tightly capped culture under an Ar atmosphere. The reactionwas cooled to room temperature and 1.02 mol of triethylamine, 0.04 mmol of Pd(PPh3)4, and 1.02 mmol of bromobenzene was added. The mixture was heated for additional 5 h under Ar. The reaction mixture waspartioned between hexane and CH3CN. Ether was added to the combined hexane layer and the organiclayer was washed with a 1:1 mixture of 3N HCl and brine. The extracts were washed with brine, driedover sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by flash silicagel chromatography to give desired indole.
R1X, Pd(PPh3)4 (5%), NEt3 (1 equiv), 100 °C
63
Section one - Chemistry of Heteroaromatics
NC N
R
H
R
NC
R1
N
R1
CSnBu3
N SnBu3
R1
N SnBu3
R1
N
R1
N R2
R1
H
HH
NC N
CO2Me
H
1) n-Bu3SnH (1.1 equiv) AIBN (5%), CH3CN, 100oC
NC N
H
H+
R2X, Pd(0)
Bu3SnH
CO2Me
OTHP
Synthesis of 3-Substituted Indoles via a Tin Mediated Cyclization
OTHP
2) H3O+
Section one - Chemistry of Heteroaromatics
Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127
64
Synthesis of (+) Vinblastine via Radical Indole Cyclizations
Section one - Chemistry of Heteroaromatics
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137
65
NH
NOH
MeO2CN
N
HOAc
OH
CO2MeMeMeO
N
N
HOAc
OH
CO2MeMeMeO
N
MeO2C
Et
OTFA
OTs
Ns
NH CO2Me
MeO
OH
MeO NH
S
OR
NH
RO
S
OREt
OR
MeO2COR
NR
OREt
OR
MeO2C OR
RO
NH
CO2Bn
CO2Me
Plausible Mechanism
R NH
NH
RR
OR
RS
R NH
NH R
R
OR
SSnBu3R
SSnBu3
H
N RR
RO RO
RO
-HSSnBu3
SnBu3
(+) Vinblastine
+
Additional Methods to Synthesize Indoles
Section one - Chemistry of Heteroaromatics
66
NH
SiEt3
Ma, C.; Cook, J.M.; et. al. J. Org. Chem. 2001, 66, 4525Wu, T.H.Y.; Ding, S.; Gray, N.S.; Schultz, P.S. Org. Lett. 2001, 3, 3827Roesch, K.R.; Larock, R.C. J. Org. Chem. 2001, 66, 412Larock, R.C.; Yum, E.K.; Refvik, M.D. J. Org. Chem. 1998, 63, 7652Larock, R.C.; Yum, E.K. J. Am. Chem. Soc. 1991, 113, 6689
To a three-neck flask (3 L) equipped with an overhead stir were charged 2-iodo-5-methoxyaniline (150 g, 0.6 mol) and the Schöllkopf derivative (265 g, 0.7 mol), as well as lithium chloride (2.5 g, 0.06 mol), sodiumcarbonate (160 g, 1.5 mol), palladium(II) acetate (1.7 g, 1 mol%), and dry DMF (2 L). The mixture wasdegassed with a vacuum pump at room temperature. The suspension that resulted was heated for 36 h at100˚C under an atmosphere of Ar. The reaction mixture was cooled to room temperature and the DMF wasremoved under vacuum. Methylene chloride (2L) was added to the residue, and the suspension that resultedwas filtered to remove unwanted salts. After removal of the CH2Cl2, the crude product was purified by flashchromatography to give 77% (223 g, 0.46 mol) of the desired 6-methoxy substituted indole.
I
NH2
CH2R
MeO MeO
CH2REt3Si
1% Pd(OAc)2, Na2CO3, LiClDMF, 100˚C, 77%
Titanium Catalyzed Indole Synthesis
Fürstner, A.; Hupperts, A.; Seidel, G. Org. Synth. 1999, 76, 142Fürstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron, 1996, 52, 7329
NH
OCl
OEt
O
A flask charged with N-(2-benzoyl-4-chlorophenyl)oxanilic acid ethyl ester (13 g, 40 mmol), titanium(III)chloride (TiCl3) (12.3 g, 80 mmol), zinc dust (10.4 g, 160 mmol) and DME (250 mL) was heated at reflux for 2 hrs with stirring. The mixture was allowed to cool to ambient temperature and then slowly filtered through ashort pad of silica washed with ethyl acetate (5 x 50 ml). The product was recrystallized from ethyl acetate /hexane to afford ethyl 5-chloro-3-phenylindole-2 carboxylate in 85% yield.
TiCl3, Zn, DME
NH
PhCl
O
OEt>85%
N
O
R3
R1
R2
O
Reductive Coupling of Oxo Amides to Indole Derivatives
[Ti]
N
R1
R2
R3
Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215
Palladium Based Strategy for Indole Synthesis
Section one - Chemistry of Heteroaromatics
Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem. Int. Ed. 2003, 42, 4257 (& refs. therein)Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671 (refs. 2-8)Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc . 2000, 122, 5662 (refs. 2 & 3)
67
NH
R3Y
R2
YN
R2
R3
R1
NH
R3Y
R2
X
N
R3Y
NY
R
R2
R1X
X
R1
+
R
N
R3Y
XR1
X
YN
R2R1
R3
c
b,e a
a,e
a,d f
Synthesis of Carbazole Intermediate by Domino Palladium ReactionSaulnier, M.G.; Frennesson, M.S.; Deshpande, M.S.; Vyas, D.M. Tetrahedron Lett. 1995, 36, 7841
NH HN
COCF3 COCF3 Pd(PPh3)4,K2CO3
MeCN, 50oC, 19h, 52%
N
NH
NH
Bn
O O
+
N
Bn
O O
BrBr
f
c
de
ba
N N
CP2Zr
N
El El
R
Cp2Zr
R R
N
Br
RN
CP2Zr
R
N
I I
R
NH2
MeOOMe
NH2
Br
OMeMeO
OMeMeO
BrHN
OMeMeO
BrN N
I
IOMe
MeO
Me
N
INBn
N
N
N
N
Me
MeO
OMeH
Me
MeOOMe
MeOOMe
Me
Me
Bn
2 El+
Regiospecific Synthesis of Polysubstituted Indoles by Means of Zirconocene Stabilized Benzyne Complexes
Cp2Zr(CH3)Cl
Br
2 t-BuLi, THF-78oC to RT
I2, CH2Cl2
OoC
R=Bn; allyl65-70%
H
Bu4NBr3
MeCHCH2Cl2
65%
K2CO3 NaI
74%
Mol
K2CO3
96%
1. Cp2Zr(Me)Cl t-BuLi THF -78oC - RT
2. I2 CH2Cl2
BnNH2
THF
78%
2.5 mol%Pd2(dba)3P(o-tolyl)3
NaO tBu, tol 80oC 72%
10 mol% Pd/C HCO2NH4
MeOH, reflux
80%
Alkaloid Synthesis using the Buchwald Zirconium Benzyne Complex
Section one - Chemistry of Heteroaromatics
Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797
Peat , A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028
68
NO2
R2R1
N
H
R2
R1
CH
NO2
NR
NN
R
NO2
XR
N
XR
N
R
R
N
HR
NN R
N
R
R
N
RH
RN
HR
R
+ 2CO
PdCl2(PPh3)2 SnCl2
+ 2CO
PdCl2(PPh3)2 SnCl2
+ 2CO2 (1)
+ 2CO2 (2)
Palladium Catalyzed Reductive N-Heterocyclization of Nitroarenes
[Pd], 2CO
-2CO2
[Pd]
X = CH
-[Pd]
-[Pd]X = N
[1,5] shift
Section one - Chemistry of Heteroaromatics
Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375
69
N
Me
MeO
HN
Me
H OMe
O
ON
Me
H O
O
N
H
Me
Me
N
ON3
CO2Et
N
OOEt
OH
N
HOOEt
OH
N
H Me
N
N
O
H
Me
Me
ON
Me
N
H
N
N
O
H
H
ellipticinemurrayaquinone B murrayafoline A
N
O
H
NOH
O Ar
murrayaquinone A
PhBrreflux78%
toluene
reflux 87%
ellipticine
PhBr reflux 71%
Synthesis of Carbazole Alkaloids using the Diels-Alder Reaction of Pyranoindolones with Alkynes
ellipticine
N
H
N
N
OH
+
staurosporinine
BA
D
C
E F
from N3 or NO2
N
O
H
NOH
Ar
CO2R
Section one - Chemistry of Heteroaromatics
Moody, C. J. Synlett 1994, 681
70
N
COOH
NN
NMe2NH
O
CH3
CH3
O
NH
CH3
CH3
N
N
ClI
N
ClLi
O
N
OCH3
O
May, C.; Moody, C. J. I. Chem. Soc. Perkin Trans. 1 1988, 247.
To a magnetically stirred solution of 3-chloro-4-iodopyridine (1.3 g, 5.4 mmol) in dry THF (25 mL) under N2 at -95 °C was added tert-BuLi (2.0 M in pentane, 5.5 mL, 11.0 mmol). There immediately resulted abright red color and after 20 min at -95 °C, furan (4.0 mL, 55 mmol) was added via syringe. The reactionmixture was allowed to warm to -25 °C over 2 h, maintaining at this temperature for 1 h, and then allowedto warm to rt overnight. The dark polymeric material was filtered and washed well with Et2O. The organicportions (300 mL) were washed with saturated aqueous NaHCO3 and the aqueous phase was extractedfurther with CH2Cl2. The combined organic portions were washed with brine, dried (K2CO3), andconcentrated in vacuo to afford 0.58 g of a dark oil. Distillation gave 0.26 g (33%) of the cycloadduct as alight amber liquid: bp 92 - 100 °C / 0.25 mm.
Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151.
A solution of pyranoindolone (76 mg, 0.36 mmol) and the triazene (180 mg, 0.93 mmol) in dry acetonitrile (15mL) was heated under reflux for 36 h. The solvent was evaporated and the residue chromatographed onsilica gel eluting with chloroform, slowly increasing to 5 % methanol in chloroform to give ellipticine (18 mg, 20 %), mp 312 - 314 °C and isoellipticine (18 mg, 20 %), mp 244 - 247 °C.
N
OTfTMS
Cl
NPhO2S
CH3
CH3
NO
Cl
NPhO2S
CH3
CH3
NO
Cl
NPhO2S
O
CH3
CH3
O
DÍaz, M. T.; Cobas, A.; Cuitián, E.; Castedo, L. Synlett 1998, 157.
2-Chloro-3-trifluoromethanesulfonyloxy-4-trimethylsilylpyridine (2.07 g, 6.2 mmol) was added portionwiseto a suspension of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole (200 mg, 0.62 mmol) and CsF (1 g, 6.2 mmol) in acetonitrile (8 mL). The mixture was stirred at rt until the mesylate was consumed, and thenthe solvent was removed and the residue was dissolved in CH2Cl2. The solution was washed with water,dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed to affordthe major isomer (170 mg, 63 %) (mp 81 °C) in addition to the minor isomer (70 mg, 26 %), mp 185 °C.
+
+
n-BuLi-78 °C, 2 h
Use Of Pyridynes for Heterocyclic Synthesis
heat
TBAFand
71
Section one - Chemistry of Heteroaromatics
XH
E XH
E XH
E
Electrophilic substitution
Intermediates formed by electrophilic attack at C-2 and at C-3
++
X
+
X
Reaction of indoles with electrophile-preferred site is C-3
HE E
H
H+H+ H2O H+, H2O
NH
O Te Se S
+
Ring-opening reactions of furans - electrophilic substitution reactions
>> > > >
+
+
+
+
+
NH
NH
NH
NH
H
E
H E H E
O
H
H O O
HH
O
H
OH O O+
Chemical Behavior of Five-Membered π-Excessive Heterocycles
Order of Reactivity
.. ..
..
H H
.. ..
E+ E+
Section one - Chemistry of Heteroaromatics
72
O CN
ON2
CO2EtO
CO2EtO
CO2Et
NH
OOH
NH O
(CH2)3Me
O
O O
HHO
OCH2Ph PhCH2OH
OO
SS
O O
H
SS O
O
H
HO
BF3.OEt2
hν
BF3.OEt2
HCO2H
-N2
Examples of ring-opening reactions
NEt3
Furan cationic cyclization reactions
72%
72%
(10 equiv)64%
∆
O O
Hoffman, R. V.; Shechter, H. J. Am. Chem. Soc. 1978, 100, 7934
100%
MeOH
NH
O
O
O O
O
O
CN
CHO CHO
MeO CN
R = H
R R R
Section one - Chemistry of Heteroaromatics
Tanis, S. P.; Chuang, Y. H.; Head, D. B. J. Org. Chem., 1988, 53, 4929. Tanis, S. P.; Dixon, L. Tetrahedron Lett., 1987, 2495 Tanis, S. P.; Johnson, G. M.; McMills, M. C. Tetrahedron Lett., 1988, 4521
Hiraoka, H. Tetrahedron 1973, 29, 2955
73
N
SO2PhN Li
SO2Ph
NO
O
O
N
PhO2S O
N
CO2H
NH
O
N
CO2H
N
N
O
O
Li
Heteroaromatic lithiates - An alternative route for electrophilic substitution
NH
N
Me
Me
ERLiE
LDA
THF - 100 oC83 %
K2CO3
∆
NH
100 %
90 oC84 %
NLi
OO
NH
EI
1) 2 eq MeLi - 100 oC to rt
2) NaBH4 96 %
Indole lithiates for alkaloid synthesis
Indole lithiation at C-2 position
nBuLi
CO2
X EX Li X EX
MeOH-H2O
Ac2O
nBuLi
EI
H
El = D, Me, COPh, CO2H 59-86 %
Section one - Chemistry of Heteroaromatics
Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 5935
Gribble, G. W. In Adv. in Heterocyclic Natural Product Synthesis; Pearson, W. H., Ed.; JAI Press: Greenwich: 1990 Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48, 607 Gribble, G. W., Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. J. Org. Chem. 1989, 54, 3264
74
SCO2Me
O
OS O
OO
New tactics for effecting Diels-Alder reactions
O
OMe
1) liq HCN
O
H
H
2) H3PO4
3) HCl, AcOH-H2O4) SOCl2, ∆
50 %
+
OMe
O
H
H
O
7 kbar, rt, 24 h
(10 g scale)
Ra-Ni, EtOAc∆, 3 h
51 % overall(+8 % epimer)
OH
CH2
H
H
Cantharidin
5 kbar, 72 h
80%
O
+
6 steps
Jatropholone A
Cycloadditions at high pressure
S
OO
Smith and Uchida
O O
OO
O
O
Section one - Chemistry of Heteroaromatics
Smith, A. B.; Liverton, N. J.; Hrib, H.; Sivaramakrishnan, H.; Winzenberg, K. J. Am. Chem. Soc. 1986, 108, 3040
Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 999
Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 7126
Dauben, W. G.; Gerdes, J. M.; Smith, D. B. J. Org. Chem. 1985, 50, 2576
75
CO2Me
OBnO
CH2 CO2Me
CH2OBn
O
Me
CH2OBn
CO2Me
O
Me
CH2OBn
CN
OAcO
CH2OBn
MeAcO
CN
O
Me
CH2OBn
H+
O
MeO2C
LiOHMeOH
175,000 psi
O
MeO2C
KOH
O
MeO2C
290 oC
O
MeO2C
Vinyl furan Diels-Alder reactions
oxygenated targetsFuranoheliangolides
290 oC
100 %
97 %
High pressure furan cycloaddition
CH2Cl298 %
H2O91 % O
O
HC CCH2SMe2+ Br
Section one - Chemistry of Heteroaromatics
Cooper, J. A.; Cornwall, P.; Dell C. P.; Knight, D. W. Tetrahedron Lett. 1988, 29, 2107
Paquette, L. A.; Brown, D. S. J. Org. Chem. 1992, 57, 4512
76
NN
NNN
NNH2
NH2
O CO2Me
CO2Me
OOO
CO2Me
CO2Me
N SiMe3
F Br
Cl
F
HN
NO
Ph NN
N
NH2
N
Ph
O
O
NMe
O
O
2 equiv.
+Pb(OAc)4
N Me
O
O
O
rt 47 %
+
1) n-BuLi2) H2O
49 %
+
Pb(OAc)4
0 oC, 0.5 h
~ 100 % -PhCN
benzene80 oC, 3 h
rt78 %
[4+2]-Cycloaddition of Five-Ring Heterocycles with Benzyne
Double cycloaddition of benzyne with furan
Cycloaddition with oxazole
Cycloaddition with pyrrole
Section one - Chemistry of Heteroaromatics
Hart, H.; Ok, D. J. Org. Chem. 1986, 51, 979
Witney, S. E.; Rickson, B. J. Org. Chem. 1988, 53, 5595
Anderson, P. S.; Christy, M. E.; Engelhardt, E. L.; Lundell, G. F.; Ponticello, G. S. J. Hetereocyclic Chem. 1977, 14, 213
77
NR2 R1
CO2Me
C
C
CO2Me
CO2Me
NR1
CO2Me
CO2Me
NH CO2Me
R2R2
CO2Me
CO2MeR1
CO2Me
N
O
C
CO2Et
CO2Et
N
O
CO2Et
CO2Et
N
O
CO2Et
CO2Et
CO2Et
N
O
CO2Et
NH
O
CO2Et
O
Br
BrO
Br
Br
OO O
OH
O+
Fe2(CO)9
Zn-Cu
H2, Pd (C)
+AlCl3
CH2Cl2
AlCl3
OR
O
R1
R2O
R
R2 R1
O
+KH
BF3-OEt2
NBSLiCl, DMF
2 M KOH
NH2NH2H2O
Diels-Alder reactions of pyrroles
[4+3]-Cycloadditons of furans
Diels-Alder reaction of pyrrole with allene
12 kbar
25 oC
R, R1, R2 = H, Me 43-65 %
70 %
NO
CO2Et
O
High pressure intramolecular Diels-Alder reaction of furan as a diene
75 %
R1 = H; R2 = Me
75 %85 %
Section one - Chemistry of Heteroaromatics
Keay, B. A.; Dibble, P. W. Tetrahedron Lett. 1989, 30, 1045
Bansal, R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1970, 48, 1472
Kozikowski, A. P.; Kuniak, M. P. J. Org. Chem. 1978, 43, 2083
Noyori, R.; Makino, S.; Okita, T.; Hayakawa, Y. J. Org. Chem. 1975, 40, 806
78
Section one - Chemistry of Heteroaromatics
Lee, J. C.; Jin, S.-J.; Cha, J. k. J. Org Chem. 1998, 63, 2804Lee, J. C.; Cha, J. k. Tetrahedron 2000, 56, 10175
Synthesis of (-) -colchicine
O
MeO
MeO
N
OMe
H
OAc +
OTMS
OMe
OMe
TMSOTf
MeO
MeO
N HOAc
OMe OO
O
MeO
MeO
N
OMe
H
Boc+
OTMS
OMe
OMe
TMSOTf
MeO
MeO
NH
Boc
OMe OO
OMe
OMe
Halogen-substituted oxyallyl cations
O
CO2Me
OTBS
+Cl Cl
Cl
O1. Et3N, CF3CH2OH
2. Zn, MeOH
CO2Me
OTBS
OO
Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523
Harmata, M. Acc. Cham. Res. 2001, 34, 595
O
SPhOH
CH2TMS
Tf2O, CH2Cl2
2, 6-lutidine, -78 oC 50%
O
H SPh
79
Me Me
O
Br Br
N MeN
OMe
N
Me
CH2
SCH2Ph
N
SCH2Ph
Me
N
O
Me
N
NMe
N
N NMeMeO
NN
Me O
Me
Me
Me MeN
OHMe
Me
N
Me
Me
S
LAH
O O
89 %
+
O
O
NaH
BnCl
Pyrrole [4+3 ]-cycloaddition
Vinyl pyrroles as dienes for Diels-Alder reactions
NO
∆
Ph
- HCN
OAc
NaI, Cu
N
Ph
OAc
MeCN
THF
1)
2) DDQ
220 oC70 %
OOAc
21% overall
PhC NO
1 : 1
Intramolecular [4+2]-cycloaddition of imidazoles
+180 oC
Tandem Diels-Alder/Retro Diels-Alder reaction of oxazoles
+16 h90 %
Section one - Chemistry of Heteroaromatics
Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1974, 13, 410
Murase, M.; Yoshida, S.; Hosaka, T.; Tobinaga, S. Chem. Pharm. Bull. 1991, 39, 489
Wuonala, M. A.; Smallheer, J. M. Tetrahedron Lett. 1992, 34, 5697
Liotta, D.; Saindane, M.; Ott, W. Tetrahedron Lett. 1983, 24, 2473
80
O
OMe
OMe
NO
O
O
O
Me
O
Me
O
Me
O
O
OMe
N
O
O
OOMe
OH
OH
N
OMe
OTBDMSOTBDMS
TMS
O
NO
N
O
O
TMS O
N
H+
> 50 %
∆
Intramolecular Cycloadditions with Oxazoles
∆
60 %
Gnididione
98 %
Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859
94 %
Paniculide-A
Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859
∆
(-) Norsecurinine
O
O
OOMe
NO
Me
OMeSO2
NO
MeSO2Me
NO
Me
OH
+130 oC
O- MeSO2H
Oxazole cycloadditions - Synthetic equivalent of 2-aza-1,3-dienes
Böll, W.; König, H. Ann. 1979, 1657. Firestone, R. A.; Harris, E. E.; Reuter, W. Tetrahedron 1967, 23, 943
75 %
Section one - Chemistry of Heteroaromatics
Jacobi, P. A. In Advances in Heterocyclic Natural Product Synthesis, Pearson, W. H., Ed.; JAI Press: Greenwich, 1992.Jacobi, P. A.; Walker, D. G.; Odeh, I. M. A. J. Org. Chem. 1981, 46, 2065. Jacobi, P. A.; Craig, T. J. Am. Chem. Soc. 1978, 100, 7748.Jacobi, P. A.; Selnick, H. G. J. Org. Chem. 1990, 55, 202
81
O
N
O OMeN
O
OMe
O
OOMe
O
O
OH
O
N S
OEtMe
S
O
R
OEt
OMe
Me
MeS
N
PhEt
S
O MeMeMe
MeMe
reflux
- MeCN
O
Me
Me
1) NaBH4
2) pH5O
O
OH
H
Retro Diels-Alder of Oxazoles
H H H
Synthesis of furans or functionality derived from a substituted furan
R = CH2OMe
Diels-Alder of Thiazole Derivatives
Formation of fused ring thiophenes
∆ HRa-Ni
H
Paniculide A
O
R - MeCN
1 : 1
94 %
57 %
O
74 % 85 %
Jacobi, P. A.; Weiss, K.; Egbertson, M. Heterocycles 1984, 22, 281.Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.Jacobi, P. A.; Frechette, R. F. Tetrahedron Lett. 1987, 2937
Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron 1987, 43, 5475
Section one - Chemistry of Heteroaromatics
82
N
R2
R4
R4
R1
R3
N
OH
R4
R4
R1
R3
NO
R2
R1
R3
R4
R4
N
R4
R4
R1
R3
N
OH
R4
R1
R3
N
OH
R4
R4
R1
R3
OHR2
NAc
O
N
NAc
N
O
NAc
N
+
-H2O
-R2H
-R4H
N
O
R2 = H
[O], -H2
R2
R1R4
R4R3
R2 = H
4+2 Cycloaddition of oxazole derivatives
Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 38
Intramolecular Kondrat'eva Pyridine Synthesis
∆
o-DCBDBN
∆
-H2O
OTBS OTBS OTBS
H
H
Addition of DBN is helpful to intramolecular cycloadditions.
Section one - Chemistry of Heteroaromatics
Kondrat'eva, G. Y. Khim. Prom. (Moscow) 1957, 2, 666Kondrat'eva, G. Y. Izv. Akad. Nauk. SSSR, Ser. Khim. 1959, 484
Bubramanyam, C.; Noguchi, M.; Weinreb, S. M. J. Org. Chem. 1989, 54, 5580
83
N NH
O O O O
N N O
NH2
O
..
Monocyclic 6-membered heteroaromatics
XH2
O O
O
A
Analysis of Two Methods of Constructing Pyridines
NH3
B
+ NH3
+
Route A
+
Hantzch Synthesis
X
X
H
OHHOX
H
Route B Guareschi-Thorpe Synthesis
NH2
O
+
OO
H
XO
H
H
HO.. ....
Section one - Chemistry of Heteroaromatics
84
R2 H
O
OR3
O
R2O
NH3
NH
R2 R2
R
R3O
O
OR3
O
NR2 R2
R
R3O
O
OR3
O
RO O
RO
OR
Top Ten Methods to Synthesize Pyridines
RO O
N
1. Hantzsch Pyridine Synthesis
Watanabe, Y.; Shiota, K.; Hoshiko, T.; Ozaki, S. Synthesis 1983 761; Pfister, J. R.Synthesis 1990, 689;Singer, A; McElvain, S.M. Org. Synth., Coll. Vol. II 1943, 214-216.
A mixture of aldehyde, β-ketoester, 60 mL of ethanol, and 10 mL of concentrated aqueous ammonia was heatedfor 3 h on a steam bath. To a solution of the above compound in 15 mL of acetone is added a solution of cericammonium nitrate in 3.5 mL water. The orange color of the reagent disappears immediately on addition of eachdrop. After stirring for 10 min, the resulting solution is concentrated to a small volume under reduced pressure.To this mixture is added 20 mL of water and the mixture is extracted with methylene chloride. The organic phase is washed with brine, dried over MgSO4, and evaporated under reduced pressure.
2. Guareschi-Thorpe Condensation
NH3
Section one - Chemistry of Heteroaromatics
N
85
HO OH
RN
+
Holder, R.W.; Daub, J.P.; Baker, W.E.; Gilbert, R.H.; Graf, N.A. J. Org. Chem. 1982, 47, 1445-1450.I. Guareschi, Mem. Reale Accad. Sci. Torino II 1898, 46, 7, 11, 25.
+or NH4OAc,AcOH
In a round-bottom flask were combined the diester (0.4 mol), the cyanoester ((0.6 mol), ammonium acetate (0.1 mol), glacial acetic acid (0.5 mol), and benzene (100 mL). The flask was equipped with a Dean-Stark tube fitted to acondenser attached to a CaCl2 drying tube. The solution was heated at reflux for 45 h. The cooled benzene solutionwas washed with with 75 mL portions of water, dried over CaCl2, and concentrated. Distillation through a 10 cm Vigreaux column afforded the product.
oxid
N R6R2
R3R4
R2
O
R3
R4
R6
OH
R1
O
BrN
R1
O
NR3 R2
O
MnO2, NH4OAcPhMe-AcOH
reflux(60-96%)
Br
4. Modified Bohlmann-Ratz Reaction
N
Bagley, M.C; Hughes, D.D.; Sabo, H.M.;Taylor, P.H.; Xong, X. Synlett 2003,10, 1443-1446.Bagley, M.C.; Lunn, R.; Xiong, X. Tetrahedron Lett. 2001, 43, 8331-8334.
R1
Section one - Chemistry of Heteroaromatics
R3
86
R2
A solution of ester (0.3 mmol), propargylic alcohol (0.6 mmol), ammonium acetate (6 mmol), and activatedMnO2 (6.0 mmol) in toluene-glacial acetic acid was heated at reflux overnight. The mixture was allowed tocool, filtered through Celite, partitioned between a sat. aq. NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic layers were sequentiallywashed with aq. NaHCO3 solution (20 mL) and brine (20 mL), dried (Na2SO4) and evaporated in vacuo.Further purification was accomplished by flash chromatography on silica gel.
3. Krohnke Pyridine Synthesis
The pyridinium bromide 2 (6 mmol) and the α,β−unsaturated ketone 3 (6 mmol) are heated with ammonium acetate (4g) in glacial acetic acid (6 mL) at 80oC for 2 h. The mixture is treated with water (40 mL), theprecipitate is filtered off, dissolved in boiling pyridine (20 mL), and reprecipitated with water.
Krohnke, F. Synthesis 1976, 1-24.
NH4OAc, AcOH
R2 = Me, PhR3 = CO2-alkylR4 = H, EtR5 = alkyl, Ar
40-97%
R1, R2, R3 many functional groups
+ -
Section one - Chemistry of Heteroaromatics
N
R2
R1
N N
N
CHCl3 R2 N
R1
5. Inverse Electron Demand Diels-Alder with 1,2,4-Triazine
+45 oC
A solution of enamine (0.8 mmol) in 0.5 mL CHCl3 was added to a stirred solution of 1,2,4-triazene (1.2mmol) in 0.5 mL CHCl3 under nitrogen at 25oC. The resulting dark orange solution was warmed to 45 oC for 20 h. Chromatography afforded the pure product.
Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179-2182
N
Ar
N
H2N
CN
N
CN
MeArNaH, DMF15 hr rt, 4 hr 100oC
6. Reaction with Vinylogous Iminium Salts
A 100 mL three-neck round-bottom flask was equipped with a stir bar, condenser and placed under a nitrogenatmosphere. Into the flask was placed 0.3g (7.5 mmoles) of a 60% mineral oil dispersion of sodium hydride.The sodium hydride dispersion was washed twice with dry hexane, and the hexane was removed via cannula.Part of a 40 mL portion of dry DMF was added to the sodium hydride, and 0.79 g (9.6 mmol) of3-aminocrotonitrile were subsequently added. The solution was allowed to stir for 15 min. Finally, 1.0 g (2.8mmol) of vinamidinium salt and the remaining DMF was added, and the reaction was allowed to proceed atroom temperature overnight followed by heating at 100oC for 4 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned several times between water andchloroform. The combined chloroform extracts were dried and concentrated. The crude product was passedthrough a short pack of silica gel and purified by radial chromatography using a gradient solution of hexane:ethyl acetate.
Petrich, S.A.; Hicks, F.A.; Wilkinson, D.R.; Tarrant, J.G.; Bruno, S.M.; Vargas, M.; Hosein, K.N.; Gupton, J.T.;Sikorski, J.A. Tetrahedron 1995, 51(6), 1575-1584
87
+
N
N
O
CO2Me
Ac
∆
N
N
Ac
8. Kondrat'eva Pyridine Synthesis
A solution of oxazole (0.4 mmol) and DBN (0.4 mmol) in anhydrous o-dichlorobenzene (60 mL) wasdeoxygenated with argon for 45 min. The mixture was heated at 150o C under argon for 1.5 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flashchromatography.
Subramanyam, C.; Noguchi, M.; Weinreb, S.M. J. Org. Chem. 1989, 54, 5580-5585
Section one - Chemistry of Heteroaromatics
o-DCB, DBN
AcOH
OH
R1
OR2
R2 O
R1
R3
O
R3
R2 O
O
R1
NH4OAc
NR2 R3
7. Sequential Solventless Aldol Condensation and Michael Addition
NaOH(s)grind
grind
Aldehyde (9.7 mmol) ,ketone (9.7 mmol), and NaOH (9.7 mmol) were combined using a mortar and pestle, and the yellow medium was aggregated until a yellow powder formed (~10 min). The second ketone (9.7mmol) was added with stirring (~10 min). The powder was tranferred to a suspension of ammonium acetate(5g, excess) in glacial acetic acid (25 mL) and heated at reflux for 2 h. The crude product was precipitatedout of solution by the addition of water, collected and washed with water and ethanol.
Cave, G.W.V.; Raston, C.L. J. Chem. Soc., Perkin Trans. 1 2001, 24, 3258-3264
64-92%
88
R1
C(O)NEt2
R2
CO2Et
N
Ph
PPh3
R1CHO
Ti(O-i-Pr)2
C(O)NEt2
R2
R1
N
Ph
R3 CO2Et
Ts C N
N
C(O)NEt2R1
R2H
10. Tandem Aza-Wittig/Electrocyclization
The aldehyde or isocyanate (5 mmol) was added to a stirred solution of the phosphazene (5 mmol) in dry acetonitrile (20 mL) or toluene (20 mL) and the mixture was heated at reflux for 12-28 h. Thesolvent was evaporated and the residue was purified by column chromatography.
Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans. 1 1990, 2193-2197Molina, P.; Arques, A.; Fresneda, P.M.; Vinader, M.V.;Foces, M.C.F.; Cano, F.H. Chem. Ber. 1989, 122, 307-313
9. Metal-Mediated [2+2+2] Cycloaddition
Suzuki, D.; Tanaka, R.; Urabe, H Sato, F. J. Am. Chem. Soc. 2002, 124, 3518-3519Varela, J.A.; Saa Chem. Rev. 2003, 103, 3787-3801
Section one - Chemistry of Heteroaromatics
To a stirred solution of N,N-diethyl-2-nonynamide (25 mg, 1.2 mmol) and Ti(O-i-Pr)4 (0.44 mL, 1.5mmol) in 10 mL of Et2O was added i-PrMgCl (1.40 M in Et2O, 2.1 mL, 3.0 mmol) at -78 °C underargon to give a yellow homogeneous solution. The solution was warmed to -50 °C over 30 min,during which period its color turned red. After stirring at -50 °C for an additional 5 h, 1-octyne (0.14mL, 0.9 mmol) was introduced to the reaction mixture at -50 °C and the solution was stirred foranother 3 h. Then, pulverized p-toluenesulfonylnitrile (260 mg,1.4 mmol) was added and the reaction mixture was stirred for 3 h at -50 °C. The reaction wasterminated by the addition of water (0.5 mL)and quickly warmed to room temperature. The resulting heterogeneous mixture was dried overanhydrous sodium sulfate and filtered through a short pad of Celite. The filtrate was concentrated invacuo to give a crude oil, which was chromatographed on a silica gel column.
+
Ti(O-i-Pr)4/2 i-prMgCl
1.25 eq.-50o C
orR2NCO
∆R3 = R1 or R2NH-
68-86%
1.
2. H+ (or I2)
¢
55-70%(or I)
89
PPA, arsenic acid
Can replace glycerol with pre-formed α,β-unsaturated compounds. However, this increases risk of carbonyl polymerization.
NC
CC
C
N
C
C
HO
HO
HO CH2 CH CHONH
C
NH
HO H
N
SkraupDoebner-von MillerCombesConrad-LimpachKnorr
MeO
NO2
NH2
FriedlanderPfitzinger
Arylamine-Glycerol Quinoline Synthesis
H2SO4
CH2 CHCHO
C6H5NH2
H2SO4
N
H2SO4
MeO
oxidation
- H2O
60 %
O
H
Quinoline Synthesis
Skraup, Z. H. Monatsh. 1880, 1, 316. Skraup, Z. H. Ber. 1880, 13, 2086Manske, R. H. F.; Kulka, M. Organic Reactions 1953, 7, 59.Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1
Section one - Chemistry of Heteroaromatics
Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1948, 70, 254
90
NHAc N N
CH2
POCl3
CH3
Cl ClH H
N Cl
Me2N NMe2
N ClN
CHO
Cl
NMe2
To the Vilsmeier complex prepared from DMF (20 mmol) and POCl3 (60 mmol) in 1,2-dichloroethane (150 mL) at 0 °C, was added acylanilide (20 mmol) with stirring. The solution was heated to reflux for 5 h, cooled, pouredinto ice water, made alkaline (pH 9) with 40% aqueous NaOH, and stirred for 30 min. The aqueous phase wasextracted with CH2Cl2, the combined organic layer was dried (MgSO4) and evaporated. The residue waspurified by chromatography on alumina to give 2-chloro-quinoline-3-carbaldehyde.
1. Vilsmeier Approach to Quinolines
Meth-Cohn, O.; Narine, B. Tetrahedron Lett., 1978, 19, 2045.Meth-Cohn, O. Heterocycles, 1993, 35, 539.
N RN R
RXRX
N R
RXH
N
R
RX
OH
RXN RCF3SO3H
2. Synthesis of Quinolines via Intramolecular Cyclization of Oxime Derivatives
Kusama, H.; Yamashita, Y.; Narasaka, K. Chem. Lett., 1995, 5.
Top Methods to Synthesize Quinolines
To a 1,2-dichloroethane suspension (6 mL) of 4-(3,4-methylenedioxyphenyl)butan-2-one oxime (0.98 mmol),4-chloranil (0.51 mmol), and Molecular Sieves 5 Å (100 mg), was added a solution of trifluoromethanesulfonic acid (1.0 mmol) in 1,2-dichloroethane (4 mL) and the mixture was immediately heated at reflux. After 1 h, thereaction was quenched with a saturated aqueous sodium hydrogen carbonate solution and the resultinginorganic materials were filtered through Celite. The organic layer was extracted with CH2Cl2. Afterevaporation of the solvent, the crude product was purified by chromatography to afford the quinoline.
ClH2O
Bu4NReO4
DMF
X = O, N; R = Me, Et
[oxid]
Section one - Chemistry of Heteroaromatics
91
NHCOR1
RI CH(OH)R2
NHCOR1
RCH(OH)R2
RN R2
N
N
Mahanty, J.; De, M.; Das, P.; Kundu, N. G. Tetrahedron, 1997, 53, 13397.
4. Fischer Carbene Benannulation Approach
Me
BocMe N
Me
BocMe
OMe
Cr(CO)5
R
Me
Me
A mixture of o-iodoaniline (1.0 mmol), (Ph3P)2PdCl2 (0.014 mmol) in Et3N (15 mL) was stirred under N2 at rt for 15 min. Freshly distilled propargyl alcohol (2.5 - 3.0 mmol) was added and the mixture was further stirred at rtfor 24 h. The solvent was removed under reduced pressure and the residue was purified by columnchromatography to give the substituted hydroxyalkynyl anilide. To the freshly prepared sodium ethoxide(1.3 mmol) in ethanol (3 mL) was added the above hydroxy-alkynyl anilide (0.28 mmol). The reaction mixturewas refluxed under N2 for 5 h. The mixture was cooled, poured into H2O and extracted with CHCl3. Thecombined organic layer was washed with saturated brine, H2O and dried (Na2SO4). The solvent wasremoved and the resulting residue upon chromatography gave the quinoline as a light yellow solid.
Boc
OHR
OMe
3. Palladium Catalyzed Annulation Approach
Peterson, G. A.; Wulff, W. D. Tetrahedron Lett., 1997, 38, 5587.
A THF solution of α-lithio-1,4-dihydropyridine was transferred to a slurry of chromium hexacarbonyl in THF at-45 °C. The reaction mixture was allowed to warm to rt overnight and then was methylated by the addition of 1 equiv of methyl fluorosulfonate. The reaction was quenched after 30 min with sodium bicarbonate, andpurification by silica gel chromatography gave the carbene complex as a red oil. The benzannulation wascarried out under argon in THF at 0.04 M with the carbene complex together with 1.5 equiv of alkyne at 60 °Cfor 42 h. The dihydroquinoline product was isolated as yellow oil.
NaOEt in EtOH
(Ph3)2PdCl2,Et3N, DMF, rt
R1 = CH3, CF3
1) s-BuLi,2) Cr(CO)6,
3) MeSO3F
Section one - Chemistry of Heteroaromatics
92
NAr
NO2
O
O
NAr
NH2
O
O
N
O
O
OMe
NH
O
OO
CO2
NH2 O R1
R2
N
R2
R1
CO2
N
R2
R1
Na2S
p-CH3OC6H4COCH3, HO
Pfitzinger, W. J. Prakt. Chem. 1886, 33 (2), 100
NaOH+
N
N
NaOH
H , Cu powder+ CO2
Isoquinoline Synthesis
Bischler - NapieralskiPictet - GamsPictet - Spengler
H
Pomeranz - Fritsch
H
Difference in isoquinoline ring structure necessitates different starting materials to those used in quinoline synthesis.
Section one - Chemistry of Heteroaromatics
Borsche, W.; Sell, F. Chem. Ber. 1950, 83, 78(164) Borsche, W.; Barthenheier, J. Annalen 1941, 548, 50
93
MeO
N
OBr
OMeOMe
MeON
Br
MeOOMe
HO2C
CO2Me
BnOOH
NH2
BnOOH
NHO
CO2Me
BnO
N
CO2Me
POCl3MeCN
POCl3
Ten Top Methods to Synthesize Isoquinolines
1. The Bischler-Napieralski Method
Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 142.Jones, G. Compr. Heterocycl. Chem. II, 1996, 179, 182.Zhou, D. -M.; Yue, B. -Z.; Cui, J. -Q.; Cai, M. -S.; Zhang, L. -H. Heterocycles 1997, 45, 439.Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30, 1581.
Pictet-Gams Modification of the Bischler-Napieralski Reaction
Section one - Chemistry of Heteroaromatics
A solution of the amide (1.2 mmol) and phosphorus oxychloride (1.3 g, 8.5 mmol) in dry acetronitrile (20 mL) was heated at reflux for 2-5 h. The excess reagent and solvent were removed under vacuum and theresidue was poured into 5% sodium hydroxide and then extracted with CH2Cl2. The extracts were dried overmagnesium sulfate and evaporated to give a white solid in 91% yield. The solution was dissolved in CH2Cl2and HCl gas was bubbled through to give the hydrochloride salt.
A solution of 2.2 g (10 mmol) of the acid and 1.5 mL (20 mmol) of thionyl chloride in 20 mL of benzene washeated at reflux for 1.5 h. After cooling, the solution was evaporated. The residue contained 2.4 g (100%) of the corresponding acetyl chloride as an orange solid which was used in the next reaction without any furtherpurification. To a solution of 2.4 g (10 mmol) of the amino alcohol in 11 mL of 1 N (11 mmol) NaOH and 20 mLof dioxane was added a solution of 2.4 g of the acid chloride in 15 mL of ether and 3 mL of dioxane. Afterstirring for 1.5 h, the mixture was filtered, the solid was washed with water and dried to give 3.6 g (80%) of theamide as a white solid. To a stirred and boiling solution of 2.7g (6 mmol) of the amide in 50 mL of acetonitrilewas added dropwise 5.6 mL (60 mmol) of phosphorus oxychloride. After 1.5 h at reflux, the solution was cooledand aqueous 5% sodium hydrogen carbonate was added carefully until pH 8.0 was reached. The mixture wasextracted with ethyl acetate. The organic phase was dried and the solvent evaporated. The residue waspurified by silica gel chromatography to give 2.1 g (85%) of the isoquinoline as a white solid.
+
H
94
HO
NH2.HCl
O
HOBn HO
N
BnO
2. The Pictet-Spengler Method
Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 170. Jones, G. Compr. Heterocycl. Chem. II, 1996, 170.Hom, R. K.; Katzellenbogen, J. A. J. Org. Chem. 1997, 62, 6290.
MeOH, reflux
The amine salt, which was synthesized from norphenylephrine hydrochloride according to literatureprocedures, was dissolved in methanol (30 mL) and to this solution was added the (benzyloxy)- acetaldehyde (3.5 g , 1.1 equiv.) with stirring at rt. This mixture was heated at reflux for 18 h. Concentration and flashchromatography of the residue yielded 4.2 g (73%) of the product.
NH
OPh
NHPh
OPOCl2
NH
Ph OPOCl2
N
Ph
N
Ph
Bischler - Napieralski-Synthesis
P2O5, POCl3
xylene - H+
- POCl2(OH) Pd / C 160oC
- Reagents used for ring-closure include P2O5, PCl5, POCl3, and PPA.- Electron-donating substituents improve yield and rate of reaction by enhancing the electrophilic ring-closure step.- Isoquinolines unsubstituted at 1-position require N-formylamines as precursors. This results in poor yields unless the benzene ring contains e- releasing groups.
Section one - Chemistry of Heteroaromatics
+
95
MeO
MeON
O O
O
SMe
MeO
MeON
O O
O
SMe
MeO
MeON
O O
O
SMeH
MeO
MeON
X
HSMe
OMeO
MeON
O
O
Ac2O
Modified Pictet-Spengler Initiated by Pummerer Reaction for Alkaloid Synthesis
Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 27.
N
MeMe
NOEt
OEtconc. H2SO4
3. Pomeranz-Fritsch Method
MeOH, 2 h
Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 218.Chelucci, G.; Cabras, M. A.; Saba, A.; Sechi, A. Tetrahedron: Asymmetry 1996, 7, 1027.Jones, G. Compr. Heterocycl. Chem. II, 1996, 190.
A solution of o-methylbenzylideaminoethanaldiethoxyacetal (2.0 g, 10 mmol) in MeOH (5 mL) under a nitrogen atmosphere was slowly added to concentrated H2SO4 (50 mL) and heated at 160oC. The mixture was madebasic with 50% NaOH solution and the product was removed from the resulting black solution by steamdistillation. The distillate was extracted with ether, the organic phase separated, dried over anhydrous Na2SO4and the solvent was evaporated. The residue was purified by Kougelrohr distillation to give 0.36 g (25%) of8-methylisoquinoline.
Section one - Chemistry of Heteroaromatics
72 %
+ +
-
+
96
NCOR2
SOPh
R1
R1
NCOR2
SPh
R1
R1
NCOR2
R1
R1
Pummerer reaction
5. Intramolecular Pummerer Reaction
Suhinohara, T.; Toda, J.; Sano, T. Chem. & Pharm. Bull. 1997, 45(5), 813-819.Toda, J.; Sakagami, M; Sano, T. Chem & Pharm. Bull. 1999, 47(9). 1269-1275.Padwa, A; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175-203.
97%-98%
TFAA (5 equiv.) was added to 500 mg of the sulfoxide in 40 mL of the appropriate solvent at room temperature andthe mixture was stirred for several hours. The reaction mixture was concentrated under reduced pressure and theproduct was purified by column chromatography. NaBH4 (10 equiv.) was then added in small portions to a stirredsolution of the product with NiCl26H20 in MeOH-THF (3:1)(40 mL) under ice cooling. After the addition, stirring wascontinued at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was suspended in water, acidified with 5% HCl-H20, and extracted with CHCl3. The product was isolated by column chromatography and was purified by recrystallization.
6. One-Pot Synthesis of Ethyl Isoquinoline-3-Carboxylate by Domino Reaction
OO
H2NCO2Et
CO2EtON CO2Et
CO2Et
N
OH
CO2Et
CO2EtN
CO2EtO O
N
CO2Et
+
EtONa, dry EtOH∆, MgSO4, 4h.
-H2O
-EtOH-CO2
80%
Meziane, M.A.; Sylvain, R.; Bazureau, J.P. Tet. Lett. 2001, 42, 1017-1020.
......................................................................................................................................
Section one - Chemistry of Heteroaromatics
97
R
R
Br
NO R1
N
R
R
R1
HN
R
R
R1
HO
2. Et2AlCl -90oC to rt 77-83%
1. PCC, NaOAc mol. sieves, CH2Cl22. KOH, MeOH/THF
7. Tetrahydroisoquinolines from Perhydrobenzoxazines
- Creates stereogenic carbon at C-1 simultaneously with ring closure.- The perhydrobenzoxazine starting material is obtained in high yield in three steps.
Pedrosa, R.; Andres, C.; Iglesias, J.M. J. Org. Chem, 2001, 66, 243-250.
A solution of the substrate in dry ether was treated with t-BuLi (2.2 equiv) at -90oC, and after 5 min, 2 equiv of Et2AlCl was added. The mixture was allowed to reach room temperature and was stirred 16 h. Isolationand purification by flash chromatography, after hydrolysis afforded the tertrahydroisoquinoline derivative.
Section one - Chemistry of Heteroaromatics
1. t-BuLi Et2O, -90oC
8. Benzal Aminoacetal Isoquinoline Synthesis
HO
Cl
CHON
HO
Cl
N
OEtEtO
H2NCH2CH(OEt)2
Gensler, W. J. Organic Reactions, 1951, 6, 191
- Intially for aldimine which is recycled to isoquinoline- Acetal group prevents amonialdehyde self-condensation.- 3-Substituted aldehyde give 7-substituted isoquinolines- these are difficult to prepare by other methods.
98
NR1
COCF3
CHO
RO
RO
S
O:
Ar
HC
Li
(MeO)2P
Ar= C6H5, CH3C6H4, 2,4,6-(iC3H7)3C6H2
NR1
COCF3
RO
RO
STol
O
..
NR1
COCF3
RO
RO
S
O
Tol ..
9. Chiral Vinyl Sulfoxide Cyclization
N
RO
ROR1
SO
Tol
.. ..
N
RO
ROR1
SO
Tol
..
+
Pyne,S.G., J. Chem. Soc., Chem. Commun., 1986, 1688.Pyne, S. G., Chapman, S.L., J . Chem. Soc., Chem. Commum., 1986, 1688.Pyne, S.G., Bloem, P., Chapman, S.L., Dixon, C.E., Griffith, R., J.Org. Chem., 1990, 55, 1086.Pyne, S.G., Tetrahedron Lett., 1979, 28, 4737.
PhCH2NEt3OH-OH
+
Section one - Chemistry of Heteroaromatics
O
OMeN
Me
CO2Et
O
NMe
CO2EtO
NMe
NaOEt OH-
H+
10. Dieckmann Type Condensation
Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 215.Grethe, G.; Lee. H. L.’ Uskokovic, M.; Brossi, A. J. Org. Chem. 1968, 33, 494.Klein, J. T.; Davis, L.; Effland, R. C. J. Heterocycl. Chem. 24, 1987, 725.
A 16.3 g (0.7 mol) portion of sodium metal was added to absolute ethanol (150 mL) and after the reaction wascomplete, the excess ethanol was removed by distillation. A solution of N-(2-carboxmethoxybenzyl)-sarcosineethyl ester (150 g, 0.57 mol) in benzene (200 mL) was added, and slow azeotropic distillation was carried out.The solvent was removed, the resultant yellow solid was dissolved in ethanol (200 mL) and 2N sodiumhydroxide (600 mL)was added and the mixture was heated at reflux for 2 h. The mixture was cooled slowly toroom temperature, then acidified with 6N hydrocloric acid, and refluxed for 3 h. The reaction mixture was cooled, was made basic with 6 N sodium hydroxide, and was extracted with chloroform. The chloroform extracts werewashed with water, brine, dried over MgSO4, and evaporated to give 84 g (92%) of the product.
99
NH2
N
H
NH2
MeCHO
MeCHO
N
Me
N
H
N
Me
H2SO4
H2SO4
NH
Me
H
N
H
N
Me
40 %
tetrahydro-β-carboline
86 %
tetrahydroisoquinoline
Pictet-Spengler Cyclization in Heterocyclic Synthesis
Section one - Chemistry of Heteroaromatics
Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030 Decker, H.; Becker, P. Liebigs Ann. Chem. 1913, 395, 342 Whaley, W. M.; Govindachari, T. R. Org. React. (N. Y.) 1951, 6, 151 Ungemach, F.; Cook, J. M. Heterocycles, 1978, 9, 1089
NHCOR
MeO
MeO CAN
RN
R
SiR3
TMSCH2I
RN
R
SiR3
NCOR
MeO
MeO
-SiR3
NCOR
MeO
MeO
TMS
RN
R RN
R
CH2
Oxidative Pictet Spengler Cyclizations
R=Ph, OBn
Single Electron Transfer Mechanism:
SET+
.
SET +
Mariano, P.; Kim, H. J.; Yoon, U. C.; Jung, Y.; Park, N. S.; Cederstrom, E.; J.. Org. Chem. 1998, 63, 860.
Used for the synthesis of indolopiperidines, pyroglutamic acid derived pyrrolidinones, and phenanthreneindolizidines
CAN CH2
.
100
Section one - Chemistry of Heteroaromatics
NSO2R5
SR6
HNSO2R5
(R6S)3CH
TMS
NSO2R5
SR6
NSO2R5
Thio-orthoEsters in Pictet Spengler Cyclizations
Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett 2003, 44, 6137.
dichloromethane, reflux
R5= Ts, R6= Ph
ZnCl2, dichloromethane
NHR
OMe
R=SiMe3
N
OMe
Regiospecific Silyl Directed Pictet Spengler Cyclization
Miller, R.; Cutter, P.; Schore, N.; Tetrahedron 2002, 58 , 1471. Miller, R.; Tsang, T.; Tet. Lett. 1988, 51, 6715.
HCHO, pH=6
98%
Used for the synthesis of tetrahydropalmatine, canadine, sinactine, corypalmine and isocorypalmine
NH
N CO2Me
NH
N CO2Me
H
Mercuric Acetate Catalysed Pictet Spengler Reaction
Hg(OAc)2 / 10% AcOH / 50% EtOH
101
HNTs
R1
R2
R3
R
O
SPh
ClN
Ts
O R
R1
R2
R3
Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett. 2001, 42, 8947.
Section one - Chemistry of Heteroaromatics
R1= H, OMe, R2= OMe, HR3= OMe, H, R= Ph, tBu
SnCl4 / ZnBr2, dichloromethane,-78oC
O-methyl velucryptine and other benzoyl isoquinoline alkaloids
α-Chloro α-Phenylthio Ketones in the Pictet Spengler Reaction
NH2
MeO
MeOR1
O
R2
N
MeO
MeO
R1 R2
CHO
CF3COOH
N
MeO
MeO
Me Ph
N
MeO
MeOR1 R2
CHO
Pictet Spengler Cyclization using Titanium Isopropoxide as an Imination Reagent
Horiguchi, Y..; Nakamura, M.; Kida, A.; Kodama, H.; Saitoh, T.; Sano, T.: Heterocycles. 2002, 59, 691.
Ti (O-iPr)4
HCOOH / Ac2O +
R1= Me, Ph, R2= Ph, Me, Et, CH2SPh
102
NN
H
CO2H
CO2Me
N
NN
N N
N
N N
H
CN
MeO2C CO2Me
H
H H
CO2Me
H
MeO2C CO2Me
H H
N
CO2Me
HO2C
N CO2Me
H
NN
HEt
MeO2C CO2Me
NN
HEt
MeO2C CO2Me
NN
HEt
MeO2C CO2Me
PhPOCl2
HCl (aq)
83 %
1) AgBF4, THF
2) MeOH, HCl
Hβ = 75 %Hα = 25 %
PhPOCl2
HCl (aq)
Hβ = 75 % Hα = 25 %
MeOH
HClHH
+
Various methods used to generate iminium ion precursors
69 % 10 %
70 %
60 %
Hβ = 80 %Hα = 20 %
Section one - Chemistry of Heteroaromatics
Grierson, D. S. Org. React. (N. Y.) 1990, 39, 85 Grierson, D. S.; Vuilhorgne, M.; Husson, H. P. J. Org. Chem. 1982, 47, 4439 Kametani, T.; Suzuki, T.; Kamada, S.; Unno, K. Heterocycles 1982, 19, 815
103
N
MeEtO2C
Me
H
N
MeEtO2C
Me
HH
NN
MeEtO2C
Me
H N
OH
NN
MeEtO2C
Me
OHN OMe
Me
CO2Me OMe
NHCO2Me
N
CO2Me
MeO
O
N
Me
CO2Me
O
O
NO
OHMeO2C
N
NBr
OSiMe3
NN
H
H
CHO
NN
H
MeO2C
HO
CH2O CH2O
C6H11NH2
-H2O
Amidoalkylation reaction of furan ring
+
H2RSO3H
PhH, 80 oC70 %
DMF, Pri2NEt
70 oC
74 % Vincamine
Bimolecular Mannich reaction using pyrroles
Mannich type cyclization from pyridinium ion precursors
Oppolzer, W., Hauth, H., Pfaeffli, P., Wenger, R. Helv. Chim. Acta. 1977, 60, 180
+
H
75%
68%
Section one - Chemistry of Heteroaromatics
Wenkert, E. Acct. Chem. Res. 1968, 1, 78. Wenkert, E.; Dave, K. G.; Stevens, R. V. J. Am. Chem. Soc. 1968, 90, 6177
Shono, T.; Matsumura, K.; Tsubata, K.; Takata, J. Chem. Lett. 1981, 1121
Burke, W. J.; Hammer, G. N. J. Am. Chem. Soc. 1954, 76, 1294
104
O
N N
N
N
N N
R R
R
R
R
R
EDG
N
N R
R
N
R
R
R
N
N N
N
R
R
N
N
R
R
N
N
RNO
R2
N NN
OR2
N NN
R2
R
R
R1
NO
R2
O
R1
R1
NH
CO2CH3
CO2CH3 R1
N N
N
R2
R1
N N
N
N N
N
R2
R1
N
NR2
R1
N
O R1
R2
N R1
N
R2
R = HR = CO2Et
R = CO2CH3
R = CO2CH3R = SCH3
N
R1
R2
N
N
N
R2
R1
N
Heteroaromatic azadiene Diels-Alder reactions
R = SO2CH3
+
- pyrrolidine
-N2
+ pyrrolidine
+
R = HR = CO2EtR = SCH3
R = CO2CH3R = H, Cl
R = CO2CH3R = SCH3
R = CO2CH3R = SCH3
+
Catalytic Diels-Alder Reaction
NH
1,2,4-Triazine - enamine [4 + 2] cycloaddition
Section one - Chemistry of Heteroaromatics
Boger, D. L. Chem. Rev. 1986, 86, 781
105
N
N
N
CO2Et
CO2EtEtO2CNH2
R
NH-HClN N
CO2Et
CO2EtH2N
R
N
N
N
CO2Et
CO2EtEtO2CN
NHN NH
HN
CO2Et
CO2Et
N
N
N
CO2Et
CO2EtEtO2CN
N
CO2Et
CO2EtHN NH
HN
N
N
N
CO2Et
CO2EtEtO2C
N
N
N N
N
N
SMe
SMeMeS
NH2R
NH-HCl
NH2R
NH2-HCl
SMeR
NH-HI
R = H, 90 oC, 24 h, 85 %
+
+
SMeR
NH2-HI
R = SMe, 90 oC, 48 h, 90 %
100 oC, 24 h, 75 %
+
OMeR
NH-HCl
R = Ph, 100 oC, 24 h, 82 %
R = Me, 100 oC, 72 h, 80 %
Representative 1,3,5-triazine - amidine Diels-Alder reactions
OMeR
NH2-HCl
100 oC, 36 h, 52 %
Diene and dienophile substituent effects
Dienophile Reactivity
Diene Reactivity
Section one - Chemistry of Heteroaromatics
106
NN N
NN
SCH3
SCH3
CH3
CH3
NN
CH3
CH3
SCH3
SCH3
N
CH3
HCH3
CH3
NN N
N
CO2CH3
CO2CH3
H COCH3
CH3O OCH3
NN
CO2CH3
CO2CH3
OCH3
COCH3
HONH
NOH
OCH3
O
NN N
N
CO2CH3
CO2CH3
cis-Trikentin A
A solution of 3,6-bis(methylthio)-1,2,4,5-tetrazine (5.6 g, 32 mmol) in benzene (25 mL) at 0 °C was treated withthe pyrrolidine enamine of 2,4-dimethylcyclopentanone (11.3 g, 2.1 equiv), and the resulting solution was allowed to warm to room temperature and stirred for 1 h. Glacial acetic acid (25 mL) was added, and the resultingreaction mixture was stirred for 10 h at room temperature before the solvent was removed in vacuo.Chromatography followed by recrystallization afforded 6.6 g (85%) of the product as a white crystalline solid.
PDE-I
N
NMe2
[4+2]-Cycloaddition of 1,2,4,5-Tetrazines
Boger, D. L., Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230
NN N
CO2CH3
CO2CH3
NMe2
A mixture of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (14.6 g, 74 mmol) and 4,4-dimethoxybut-3-en-2-one (14.4 g, 110 mmol) in 250 mL of dry dioxane was warmed with stirring at 60 °C under N2. The solvent wasremoved in vacuo, and the residue was dissolved in CH2Cl2 and filtered through a short column of silica gel.Flash chromatography afforded the product (13.9 g, 70%) as a yellow, crystalline solid.
Boger, D. L., Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717
Benson, S. C., Gross, J. L., Snyder, J. K. J. Org. Chem. 1990, 55, 3257
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1.0 g, 5.0 mmol) and dimethylcyanamide (0.4 mL, 0.35 g, 5 mmol) were dissolved in anhydrous o-xylene (10 mL) under argon and refluxed for 12 h. After cooling to roomtemperature, the crude reaction mixture was subjected to flash chromatography on silica gel to give the pureproduct (0.71 g, 59% yield).
+
CONH2
+
+
107
Section one - Chemistry of Heteroaromatics
N
NN
N
CH3
CH3
NN
CH3O2C
CO2CH3 Et3SiO
CO2CH3
CH3
CH3
HNR R
CH3CH3CH3O2C
NH
HN
N N
N
NN
N
OCH3
NN
CH3O2C
CO2CH3 CH3O
CO2CH3
OCH3
CH3O2C
NH
NH
CH3O N
C5H11
CH3
HN
CH3O
CH3O2C R
N
N N
N N
N
SCH3
SCH3
SO2CH3
SO2CH3
N
N
N
NR
SO2CH3
R = CO2CH3R = H
25 oC
N
N
NR
SO2CH3
87 %
+
Zn/HOAc
NCOCH3
SO2CH3
Preparation of OMP
NaOH;-CO2
NCOCH3
68 %
N
N
SO2CH3
NAc
PRODIGIOSIN
SO2CH3 SO2CH3
Key steps of the prodigiosin total synthesis
Intramolecular 1,2-diazine - allene Diels-Alder reaction
N
OMP
N
R = CO2CH3R = H
N
93 %
NH2
NH2
Zn/HOAc
Ac
77 %
Ac
+
Ac
25 oC
ii) m-CPBA97 % x 95 %
235 oC, 22 h
68 %
-N2 -CH3SO2H
120-160 oC
70 %
i)
76 %
27 h, 87 %
R = COCH3
25 oC, 63 %
Section one - Chemistry of Heteroaromatics
108
CH3O
H2N
O
O
NN COOH
CH3H2N
OH
OCH3
OCH3
CH3O
N
NO2
NH
SCH3
N
CH3O
NO2
NN
N
CH3O2C
CO2CH3
N
NN
N
CH3O2C
CO2CH3
N
CH3O
NO2
N CO2CH3
CH3CH3O2C
OCH3
NCH3
OCH2Ph
OCH3
OCH3
OCH3
OCH2Ph
N
NN
N
NN
N
NN
NN
HN
CO2CH3
CH3O2C
CO2CH3Ar
CH3O2C
ArX
CO2CH3
CH3O2C
NH
X NN
N CO2CH3
CH3O2C
N
NN
N CO2CH3
CH3O2C
STREPTONIGRIN
C
B
80 oC
+
X
Ar NH
1,2,4,5-Tetrazine - thioimidate Diels-Alder reaction
Key steps of the streptonigrin total synthesis
25 oC, 50 %
A
N
NHN
CO2CH3
CH3O2C Ar
X
D
82 %
N
N
6.2 kbar
X = SCH3X = OEtX = NH2, NEt2
80 oC, 4 h, 70 %
-N2
-HX
+
80 oC, 20 h, 33 %25 oC, 1 h, 0 %
Diels-Alder Reactivity: NH2, NR2 > OEt = SCH3Elimination (Aromatization): SCH3 > OEt >> NH2, NR2
Section one - Chemistry of Heteroaromatics
109
N N
N
CO2Me
NN
CO2Me
NNO2
MeO
CN
NNO2
MeO
NH
SMe
N N
NN
CO2Me
MeO2C
N
NO2
MeO
NN
N
MeO2C
CO2Me OBn
MeR2N
OMe
OMe
NN CO2Me
MeMeO2C
OBn
OMe
OMe
NO2
MeO
Hetero Diels-Alder Reactions
Cycloadditions involving heteroaromatic azadienes
+ rt
1) H2S, Et2NHdioxane
2) MeI, MeCN
dioxane80 °C, 22 h
82 %
CH2Cl2, 6.2 Kbarrt, 120 h
65 %(2.8 : 1)
+
NN CO2H
MeNH2
OH
OMe
OMe
O
MeO
NH2
O
+
-N2
49 % -pyrrolidineN
NN
NR2
CO2Me
4 eq
42 %
10 steps
Streptonigrin
Section one - Chemistry of Heteroaromatics
Boger, D. L. Chem. Rev. 1986, 86, 781Dittmar, W.; Sauer, J.; Steigel. A. Tetrahedron Lett. 1969, 5171
Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717
110
N
N N
N
CO2Me
CO2Me
NR
N
N
CO2Me
CO2MeN
R
N
N
R1
R2
R3
R4
CH2
OMeMe2N
R1
R2
R3
R4
X
N
N
NN
NN
RH
R1
R1R
NN
Me
- H2
N
N
R
R1
R1
R
+X = NMe2, OMe
57-93 %
Inverse electron demand 4+2 reactions of pyridazines
Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 1955
Indole as a dienophile in inverse electron demand Diels-Alder reaction
-N2
-H2
+
-N2
- N2
CO2Me
CO2Me
NEt2MeO2C
CO2Me
NEt2
Me
MeO2C
MeO2C
N N
NN
MeC≡CNEt2
R1CH=CHR1R
R
Neunhoeffer, H.; Werner, G. Tetrahedron Lett. 1972, 1517Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 437
H
R = Bz
Inverse electron demand 4+2 reactions of 1,2,4,5-tetrazinesNeunhoeffer, H. Comprehensive Heterocyclic Chemistry; Pergamon: London, 1984; Vol. 3, p 550Neunhoffer, H. Chemistry of Heterocyclic Compounds, Wiley: New York, 1978, Vol. 33, pp. 1095-1097
NOTE: Dimethyl aniline derivative formed predominately.
74 %
Section one - Chemistry of Heteroaromatics
Benson, S. C.; Palabrica, C. A.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257
Sauer, J.; Heinrichs, G. Tetrahedron Lett. 1966, 4979
111
N N
NN
CO2Me
CO2Me
NNMe2
H R
NH
EtO Ph
N
NN
N
N
MeO2C H
RNMe2
CO2Me
NN
NN
N
MeO2C Ph
OEtH
CO2Me
N
N
N
NN
N
CO2Me
Ph
CO2Me
CO2Me
NMe2
R
CO2Me
N
NN
N
CO2Me
CO2Me
N
C
NMe2N
NN
N
N
MeO2C
CO2MeNN
N
CO2Me
CO2Me
NMe2NMe2
NN
N
X
CN
Ph
Ph N
N
X
Ph
Ph
R = alkyl, Ph
27 %
-N2
+PhCl, ∆ -N2
78 %
X = O, NCOCF3
225-235 oC
Diels-Alder reactions of electron deficient heteroaromatic dienes
Route to condensed pyrazines via internal cycloadditions using nitriles as dienophiles
-N2
EtOH
56-81%
Taylor, E. C.; French, L. G. J. Org. Chem. 1989, 54, 1245Taylor, E. C.; French, L. G. J. Org. Chem. 1986, 51, 1967
71 %
Section one - Chemistry of Heteroaromatics
Roffey, P.; Verge, J. P. J. Heterocycl. Chem. 1969, 6, 497Seitz, G.; Overheu, W. Arch. Pharm. 1979, 312, 452Müller, K.; Sauer, J. Tetrahedron Lett. 1984, 2541Balcar, J.; Chrismam, G.; Huber, F. X.; Sauer, J. Tetrahedron Lett. 1983, 1481Burg, B.; Dittmar, W.; Reim, H.; Steigel, A.; Sauer, J. Tetrahedron Lett. 1975, 2897
Seitz, G.; Overheu, W. Chem. Zeit. 1979, 103, 230
112
NN
N NCO2MeMeO2C
N
N
MeO2C
CO2Me
OMeO
MeO
OMe
O
NNNAc
MeO O
RO
NAc
OR
O
MeO
NAcHN
MeO2C
MeO OH
N
N
NN
CO2Me
MeO2C OMe
OMeO
dioxane - N2
several230 oC
R = t-BuMe2Si
N
N N
Ph
Ph
R1HN
N
N
N
N
N
N
OR1
N
K
PhPh
N
O N
N
N
N
Ph
Ph
CH3
+
BC
Diels-Alder Reaction of 1,2,4,5-tetrazine-3,6-dicarboxylate
Boger, D. L.; Wysocki, R. J. J. Org. Chem. 1989, 54, 714
70 %
87 %
reflux - MeOH
NN
NO
steps
(Im)2CO
CH3
CH2Cl2
(50%)(R1 = CH3)
Ph
Ph
Inverse Electron Demand Diels-Alder Reaction of Triazines with Indole
∆
Section one - Chemistry of Heteroaromatics
Fan, W. -H.; Parikh, M.; Snyder, J. K. Tetrahedron Lett. 1995, 36, 6591
113
NH
EN
H
E NH
E
N N N
N N N
H
E
H
E
H
E
H EH EH E
NX
YN
X
YN
X
Y
N N N
N N N
Intermediates in the Electrophilic Substitution of Pyridine
X
Y
X
Y
X
Y
X YX YX Y
Intermediates in the Nucleophilic Displacement of X- by Y- in X-Substituted
Pyridines
+ +
+
++
+
+
+
+
--
-
-
- -
-
-
-
Section one - Chemistry of Heteroaromatics
114
Br
NO2
O
H N
S
S
N
73 %
R'-Pd-OR"
90 %
R'-X
Pd(PPh3)4
Pd(PPh3)4
FeSO4
FeSO4
Synthesis of Thieno Fused Quinoline Derivatives
Proposed Catalytic Cycle for the Suzuki Reaction
Pd (0)
R'-Pd-XR'-Pd
R"O-Na
NaXRB
OR
ROB
RO
R'
H
O
B(OH)2
H
OH
O
O2N
S S
SS
B(OH)2Br
NO2
Oxidative Addition
transmetallation
R
R
Reductive Elimination
+
+
Section one - Chemistry of Heteroaromatics
Gronowitz, S.; Lawitz, K. Chemica Scripta 1983, 22, 265 Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1986, 26, 383 Gronowitz, S. Chemica Scripta 1987, 27, 535 Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 383 Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 311 Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1984, 23, 120 Gronowitz, S.; Peters, D. Heterocycles 1990, 30(1), 645
Suzuki, A. Acc. Chem. Res. 1982, 15, 178 Suzuki, A.; Yanagai, T.; Miyaura, N. Synth. Commun. 1981, 11, 513 Suzuki, A.; Suginome, H.; Yamada, K.; Miyaura, N. J. Am. Chem. Soc. 1985, 107, 972 Suzuki, A.; Makoto, S.; Norio, M. Tetrahedron Lett. 1986, 27, 3754 Suzuki, A.; Satoh, M.; Miyaura, N. Tetrahedron Lett. 1984, 23, 120
115
NO2
S B(OH)2
CHO
S Br
NHBoc
S
N
S
S
NHBocBrS
N
S
S CHO
B(OH)2
N
H2N NN
S
Malm, J.; Rehn, B.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 11
67 %
90 %
+
Pd (0)NaHCO3
1. Pd (0)NaHCO3
2. HCl
2. TsONH2HClO4
81 %
60 %
1. Pd (0)NaHCO3
2. HCl
B(OH)2
CHOS Br
NHBoc N
S
Gonowitz, S. J. Heterocyclic Chem. 1992, 29, 1049
Yang, Y.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1989, 26, 865
I
Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 641
S CHO
B(OH)2
NBr
N+
N
S
55 %
ClO4-
+
1. Pd (0)NaHCO3
Suzuki Coupling of Polycondensed Thiophenes
+
+Pd (0)Na2CO3
S
S N
N
OtBu
Peters, D.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1990, 27, 2165
OtBu
Pd (0)NaHCO3
(OH)2B+
Br
55 %
N
N
OtBu
OtBu
S
S
116
Section one - Chemistry of Heteroaromatics
B(OH)2
CON(i-Pr)2N
Br
Et2NOCON
Et2NOCO
CON(i-Pr)2
Pd (0)
NHt-BOC O
H
N
O
O
O
O
NHt-BOC
Br
Br
O
HN
NHt-BOC
B(OH)2
O
H
Br
N
B(OH)2
B(OH)2
Pd(0)
Synthesis of 6H-[2]benzopyrano[4,5-c]pyridin-6-one
Benzo(j)phenanthridine
Benzo(c)phenanthridine
Pd (0)
+
+
+
Benzo(k)phenanthridine
+
Synthesis of Benzophenanthridines
Pd (0)
Et2NOCO
N
CON(i-Pr)2O
N
O
H3O+
92 %
47%
18%
30%
80%
Section one - Chemistry of Heteroaromatics
Snieckus, V. Chem. Rev. 1990, 90, 879 Snieckus, V. Pure Appl. Chem. 1990, 62, 671 Snieckus, V.; Siddiqui, M. A. Tetrahedron Lett. 1988, 29, 5463 Snieckus, V. Siddiqui, M. A. Tetrahedron Lett. 1990, 31, 1523 Snieckus, V.; Alo, B. I.; Kandil, A.; Patil, A.; Sharp, M.; Siddiqui, M. J. Org. Chem. 1991, 56, 3763
Sharp, M. J., Snieckus, V. Tetrahedron Lett. 1985, 26, 5997
117
R'-Pd-R
Pd(0) Cross Coupling for Heteroaromatic Synthesis
General Pd(0) Cross Coupling Catalytic Cycle
Pd (0)
R-Pd-R'
Oxidative Addition
Transmetallation
Reductive Elimination
Section one - Chemistry of Heteroaromatics
118
R-X + R'-M R-R'Pd(0) Cat.
R = (het)aryl, alkynyl, vinyl, benzyl X = I,Br,Cl,OTf, SR"
R' = (het)aryl, alkynyl, vinyl, alkyl, benzylM = B, Sn, Zn, Si, In
General Reaction Scheme
R-Pd-X
R-X
R'-MM-X
R-R'
Cross Coupling Example
N
F
I
+OEt
Sia2B
O O OAlllyl)2Pd2Cl2NaOEt, CH3CN
N
F
OEt
O O O
99% yield
HMG-CoA Reductase InhibitorNK-104
Miyachi, N.; Yanagawa, Y.; Iwasaki, H.; Ohara, Y.; Hiyama, T. Tetrahedron Lett. 1993, 43, 8267-8270
Pd(0) Cross Coupling for Heteroaromatic Synthesis
Section one - Chemistry of Heteroaromatics
119
Wellmar, U.; Hornfeldt, A.; Gronowitz, S. J. Heterocyclic Chem. 1995, 32, 1159
CON(iPr)2
B(OH)2
CON(iPr)2
N
Et2NOCO
BrN
Et2NOCO
To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixturewas stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in aminimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv). The mixture was refluxed for 18 h, cooled, and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated with asaturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product(81%).
81%Tol / aq. Na2CO3
N
N
OAc
AcO
B(OH)2 +OBr
Br DMENaHCO3
N
N
OAc
AcO
OBr
2.5 M HClHN
NH
O
O
OBr
86%
De, D.; Krogstad, J. Org. Lett, 2000, 7, 879-882
N
Br
Cl
+
N
BEt2
NCl
N
+
70%THF, K2CO3
Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
The Suzuki-Miyaura Coupling
Pd(PPh3)4
Pd(DIPHOS)2
Pd(PPh3)4
Pd(0) Cross Coupling for Heteroaromatic Synthesis
Section one - Chemistry of Heteroaromatics
120
Yang, Y.; Wong, H. N. C. J. Chem. Soc., Chem. Commun. 1992, 656.Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583.
A mixture of dichloropurine (126 mg, 0.45 mmol), stannylfuran (0.17 mL, 0.54 mmol), Pd2dba3 (13 mg, 0.013 mmol) and tri(2-furyl)phosphine (23 mg, 0.10 mmol) was added to dry DMF (3 mL) and heated under N2 at50 oC for 22 h. The reaction mixture was evaporated in vacuo and a saturated solution of KF in methanol(20 mL) was added. The resulting mixture was stirred at ambient temperature overnight and evaporated invacuo. Flash chromatography gave 123 mg of the product (88%yield).
Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Queguiner, G.; Siddiqui, M.A..; Snieckus, V. J. Org. Chem. 1995,60, 292.
O
SnBu3Bu3Sn
PdCl2(PPh3)2 THF O
COPhBu3Sn
Pd(PPh3)4 HMPA O
COPh
O2N
81%82%
N OMe
CON(i-Pr)2
B
Pd(PPh3)4/NaOH
NH2
I
N OMe
CON(i-Pr)2
NH2
N
N
OTf
OMe
+N
Bu3Sn
dioxane 79%
N
N
OMeN N
N
NMe
O
O
Amphimedine
Langli, G.; Gundersen, L.; Rise, F. Tetrahedron, 1996, 15, 5625-5638.
N
N
N
Cl
Cl
Ph
+ OSnBu3
Pd[P(2-furyl)3]2 THF N
N
N
Cl
Ph
O
88%
The Stille Coupling
THF,61%
Pd(PPh3)4/LiCl
p-NO2PhBrPhCOCl,
Pd(0) Cross Coupling for Heteroaromatic SynthesisSection one - Chemistry of Heteroaromatics
121
The Negishi Coupling
Cesnek, M.; Hocek, M.; Holy, A. Coll. Czech. Chem. Commun. 2000, 65, 1357.
tBuLi (1.9 mL, 2.8 mmol) was added to THF (8 mL) at -78o C. A solution of 2-bromo-methylpyridine (500 mg, 2.9mmol) in THF (2 mL) was added dropwise. After the mixture had been stirred at -78o C for 30-45 min, a solution ofanhydrous ZnCl2 (490 mg, 3.6 mmol) in THF (5 mL) was added slowly and the reaction mixture was stirred for 2-3 h atroom temperature. Next a solution of Pd(PtBu3)2 (19 mg, 0.038 mmol, 3% Pd) and 2-chloro-6-methoxypyridine (380 mg,2.6 mmol) in THF (5 mL) was added and the reaction heated at reflux until no further consumption was observed byTLC. After cooling to room temperature, a suspension of EDTA (3 g, 10.3 mmol) in water (60 mL) was added and stirred for 15 min then brought to pH 8 with saturated Na2CO3. The mixture was extracted several times with CH2Cl2 and thesolvent was removed in vacuo. The pure product (447 mg, 85%) was obtained after column chromatography.
Dobler, M. R. Tetrahedron Lett. 2003, 44, 7115-7117.
p38MAP kinase inhibitor
Lutzen, A,; Hapke, M,; Staats, H.; Bunzen, J. Eur. J. Org Chem. 2003, 3948-3957.
N
N N
N
I
H2N OP(O)(Oi-Pr)2
Pd(PPh3)4N
N N
N
H2N OP(O)(Oi-Pr)2
N
NClZnMe
+
NNMeNucleotideAnalogue
O
N
N
O
OO
Bn
(i) tBuLi, THF, -78o C(ii) ZnCl2, -78o C to rt(iii) Pd(OAc)2
NI O
N
N
O
OO
Bn
N82% yield
N Br
N ClMeO
(i) tBuLi, THF, -78o C(ii) ZnCl2, -78o C to rt(iii) Pd(PtBu3)2
N
NOMe
85%
83%
Pd(0) Cross Coupling for Heteroaromatic Synthesis
Section one - Chemistry of Heteroaromatics
122
The Liebeskind-Srogl Coupling
Liebeskind, L.S.; Srogl, J. Org. Lett. 2002, 4, 979-981.Egi, M.; Liebeskind, L.S. Org. Lett. 2003, 5, 801-802.
Novak, Z.; Kotschy, A. Org. Lett. 2003, 5, 3495-3497.
SSMe
OEtO2C +
(HO)2B
CO2Me4% Pd2dba316% TFP1.3 equiv. CuTC
CO2MeS
O
EtO2C
82%
TFP = P(2-furyl)3CuTC = copper (I) thiophene-2-carboxylateCuMeSal = copper (I) 3-methylsalicylate
N
SSPh +
OBu3Sn 5% Pd(PPh3)42.2 equiv. CuMeSal
O
N
S96%
The Sonogashira Coupling
N
N N
N
NEt2
Cl
BuH+
5% Pd(PPh3)2Cl25% CuI
N N
NNEt2N Bu 65%
I
NHCOPh
BuH+
5% Pd(PPh3)2Cl210% CuI
HN
Bu 96%
Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51, 1170-1173.
2 equiv. TEADMA
TBAF,THF
NBr
Me
NCl2(Et)Si
Me
Br
CN
CNN
Me
SBr
S
Ph
O
S
Br
(i) BuLi, THF, -78o C
92%
S
Ph
5% Pd(PPh3)2Cl2
+
+ 1/3InPh3
OOHC
Br
4% Pd(PPh3)4 61%
Indium Cross Coupling
OOHC
Me
Pd(0) Cross Coupling for Heteroaromatic Synthesis
Section one - Chemistry of Heteroaromatics
123
The Hiyama Coupling
Hiyama, T. J. Organometallic Chem. 2002, 653, 58-61.
N
In
Lee, P.H.; Lee, S.W.; Lee, K. Org. Lett. 2003, 5, 1103-1106.
MeMe
10% Pd(OAc)220% PPh32 equiv. PhSi(OCH3)3
MeMe
Mowery, M.E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
95%4% Pd(PPh3)2Cl2
+
Jaber, N.; Schumann, H.; Blum, J. J. Heterocyclic Chem. 2003, 4, 565-567.
(ii) EtSiCl3 -78o C to rt
KF, DMF
2 equiv TBAFDMF
1 atm COTHF
Benzene
CON(iPr)2
B(OH)2
CON(iPr)2
N
Et2NOCOBr
N
Et2NOCO
O
N
O
OMeMeO
MeOBr
CHOB(OH)2
CONiPr2
OMeOMe
OMeMeO
MeO
CHO
CONiPr2
OMeOMeOMe
MeO
MeOCONiPr2
OMeOMe
NH2
OMeMeO
MeO
Metallation/Cross Coupling for Polycondensed Heteroaromatics
N
OMe
OMe
Suzuki Coupling
Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
Aryl Lithiation Followed by Suzuki Coupling
Fu, J.-M.; Zhao, B. -P; Sharp, M.J.; Snieckus, V. Can. J. Chem. 1994, 72, 227.
To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixture was stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in aminimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv), and the mixture was refluxed for 18 h,cooled, and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated witha saturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product(81%). A solution of the biaryl compound (0.30 g, 0.75 mmol) was refluxed in 2 M HCl (10 mL) for 24 h.Normal workup followed by chromatography afforded 0.14 g (92%) of the cyclized product.
A mixture of Pd(PPh3)4 (0.44 g, 0.40 mmol) and 5-bromo-2,3,4-trimethoxybenzaldehyde (2.2 g, 8.0 mmol) in DME was stirred at room temperature for 5 min. To this mixture was added dropwise a solution of2-N,N-diisopropylcarboxamido-3,4-dimethoxyphenylboronic acid (3.2 g, 10.4 mmol) dissolved in aminimum amount of EtOH and an aqueous solution of 2 M Na2CO3. The resulting mixture was heated atreflux for 12 h, cooled, and the solid was removed by filtration. The filtrate was evaporated to drynessand the residue was washed with ether. Standard workup followed by flash chromatography afforded thebiaryl product (93%). To a solution of LDA (2.2 mmol) in THF (5 mL) was added a solution of amine (0.28g, 0.6 mmol) in THF (1 mL) at 0 °C. The mixture was stirred for 10 h. Standard workup followed by flashchromatography afforded 0.076 g (36%) of the cyclized product.
81%
reflux
2N HCl
92%
Pd(PPh3)4Tol / aq. Na2CO3
+
Pd(PPh3)4/DMF2M aq Na2CO3
reflux 93%
LDATHF
36%
Section one - Chemistry of Heteroaromatics
124
CONEt2
Br
CONEt2
NH
MacNeil, S.L.; Gray, M.; Briggs, L.E.; Li, J.J.; Snieckus, V. Synlett 1998, 419.
O
O
N
BrO
O
N
HO
O
N
NMe
O
Commercial Merrifield resin (1% cross linked, 1 mequiv Cl/g, 0.15 g) was swollen in anhydrous DMF (5 mL) and thesystem was flushed with argon (30 min). A sample of Pd(PPh3)4 (0.05 equiv) was added and the reaction mixture wasstirred (10 min). The stannane (3 equiv) was added and the mixture was stirred at 60 °C (24 h), cooled to rt, andtreated with NH4Cl solution (5 mL) and stirred (10 min). The resin was removed by filtration (fritted glass funnel) andthe filtrate was washed successively with DMF (5 mL), H2O (15 mL), EtOAc (10 mL), MeOH (15 mL), and dried invacuo (12 h). To cleave the product from the solid support, the resin was swollen in THF (2.5 mL) for 30 min.,LiOH•H2O (5 equiv) dissolved in MeOH:H2O (2:1, 1.5 mL) was added, and the mixture was refluxed for 18-42 h.After cooling to rt, a solution of 1M HCl (3 mL) was added and the whole was stirred (10 min) and subjected tofiltration (fritted glass funnel). The resin was successively washed with THF (30 mL), and Et2O (30 mL) and the filtrate was repeatedly extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4) andevaporated to dryness to give the acid (96%).
A thick-walled screw cap glass tube was charged with a mixture of N,N-diethyl 2-bromobenzamide, aniline (0.2 mL, 2.3mmol), NaOt-Bu (0.27 g, 2.8 mmol), Pd2(dba)3 (5 mg, 0.006 mmol), BINAP (10 mg, 0.017 mmol) and toluene (5 mL)under a N2 atmosphere. The tube was sealed and heated (90-100 °C) with stirring for 21 h, and cooled to rt. Additionof aqueous NH4Cl and standard workup, followed by flash column chromatography afforded N,N-diethylN-phenylanthranilamide (430 mg, 81%). A solution of N,N-diethyl N-phenylanthranilamide (0.11 g, 0.40 mmol) in THF (3 mL) was cooled to 0 °C under argon atmosphere and treated with a solution of LDA (1.4 mmol) in THF (2 mL)precooled to 0 °C for 1.5 h and warmed to rt. Addition of aqueous NH4Cl and standard workup, followed by silica gelflash column chromatography afforded N-methylacridone (0.07 g, 79%).
Stille Coupling on the Merrifield Resin
Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4175.
Application of the Buchwald-Hartwig Amination Protocol
PhSnBu3
Pd(0)
96%
1. LiOH/H2O
2. 1M HCl
AnilinePd2(dba)3, BINAPNaOtBu
90 - 100 °C
1. N-Methylation 98%
2. LDA 79%
81%
Section one - Chemistry of Heteroaromatics
125
N3Me
N
O
Me
O
N
N
O
Me
Me
N3
ONR
CORN
ONR
PPh3
CORN
ONR
R
A Route to Quinazolinones via Intramolecular Aza-Wittig Reaction
PPh3
25 oC, 2 h
N
O
O N3
99 %
Intramolecular aza-Wittig reaction forisoxazolo[4,3-c]quinoline formation
N
O
N
Efficient route to iminolactam derivatives via intramolecular aza-Wittig reaction
(CH2)n(CH2)n
PPh3
toluene, 25 oC 94 %
1) PPh3, xylene rt, 1 h
2) reflux, 2h
b. n = 2; 92 %
R = Me
a. n = 1; 92 %
Section one - Chemistry of Heteroaromatics
Takeuchi, H.; Eguchi, S. Tetrahedron Lett. 1989, 30, 3313Lambert, P. H.; Vautier, M.; Carrie J. Chem. Soc., Chem. Commun. 1982, 1224Lambert, P. H.; Carrie, R. J. Org. Chem. 1985, 50, 5352Molina, P.; Alajarin, M.; Ferao, A. Synthesis 1986, 843 Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1988, 3849
Purwono, B.; Smalley, R. K.; Porter, T. C. Synlett. 1992, 231.
Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun. 1989, 602
126
NAr PPh3Ar N3
C
Ph
N
Ar
NH
Ar
Ph
R1
R2
N3
O
R1
R2
N
O
PPh3
R1
R2
NPPh3
O
R1
R2
N OPPh3
Conversion of Butenyl Azides into Benz[f]indoles by Aza-Wittig reaction
R1
R2
N
reflux
Epoxidation - Staudinger Reaction of o-Allylphenyl Azides
Ph2C C O
toluene, rt
45 %
50 %
PPh3
Et2O
PPh3
N
Ar
Ph
R1 = OCH2PhR2 = OMe
Mn2O2toluene
CHCl3
Section one - Chemistry of Heteroaromatics
Molina, P.; Leonardo, C. L. Tetrahedron Lett. 1993, 34, 2809
Molina, P.; Alajarin, M.; Lazaro, A. L. Tetrahedron Lett. 1992, 33, 2387For a review of the Staudinger reaction see: Gololobov, Y. G.; Zhmurova, I. N.; Kasushim, L. F. Tetrahedron 1981, 37, 437
127
N
O R2
RN3
O
O
R2
R
R1R1
NH
R = p-MeC6H4
R1 = HR2 = Me
N3R
R2
O
R1
O R2
R1
R
O
(EtO)3P, CyH, 90 °C, sealed tube, 24 h
93%
N
N
R2
96%
Ph3P, PhH, rt, 2 h
99%
R
Ph3P, Et2O, rt, 24 h
To a solution of 10 mmol of the azide in 20 mL of anhydrous ether was added 2.6 g (10 mmol) oftriphenylphosphine, with stirring, until all the phosphine had dissolved. Nitrogen evolution started after a few seconds. The reaction mixture was kept at room temperature for 24 h. The solvent was removed in vacuo,and the residue triturated with 40 mL of a 1:1-mixture of ether and petroleum ether. Triphenylphosphineoxide was collected by filtration, and the crystals were thoroughly washed with cold ether. After removal ofthe solvent, the product was purified by Kugelrohr distillation.
3. Imidazolinones via an Intramolecular Aza-Wittig Reaction
R =
RN3
O
R1
O
R2
1. Oxazoles via an Intramolecular Aza-Wittig Reaction
Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J. Org. Chem. 1989, 54, 431
To a stirred solution of the vinyl azide (1 mmol) in dry cyclohexane (5 mL) in a sealed tube was added triethylphosphite (10 mmol). Nitrogen gas evolution started immediately and ceased after 1 h. The mixture washeated at 90 °C for 24 h with continued stirring. The cooled mixture was chromatographed on a short silica gel column, eluting with ethyl acetate-hexane to give the oxazole.
Use of the Aza-Wittig Reaction for Heterocyclic Synthesis
nn
R = OEtR1 = R2 = H
O
2. Vinylogous Urethanes via an Intramolecular Aza-Wittig Reaction
Lambert, P.H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352
R1
OTakeuchi, T.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375
To a stirred solution of the imide (1 mmol) in benzene (10 mL) was added triphenylphosphine (1.1 mmol).The mixture was stirred for 2 h at room temperature and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column to give the imidazolinone.
R1 = MeR2 = H
Section one - Chemistry of Heteroaromatics
128
NH2
N
O
O
N
N
O
N3
N
O
O
CO2Me
4. 2,3-Dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-one via an
1. Ph3PBr22. Et3N
60%
Al-Khathlan, H.; Zimmer, H. J. Heterocyclic Chem. 1988, 25, 1047
A solution of dibromotriphenylphosphorane prepared from 1.4 g of triphenylphosphine and 0.84 g ofbromine in CH2Cl2 was added dropwise to a solution of 1 g of the amine in 150 mL of CH2Cl2. To thismixture was added triethylamine (1.0 g, 10.5 mmol) and the solution was refluxed for 12 h. The resulting solution was extracted with water, dried over anhydrous magnesium sulfate, the solvent was distilled toafford the product.
5. Pyrrolo[2,1-b]quinazolines via an Intramolecular Aza-Wittig Reaction
Ph3P, rt, 4 h, then 80 °C, 9 h
HCl/THFN
N
O CO2Me
Okawa, T.; Sugimori, T.; Eguchi, S.; Kakehi, A. Heterocycles, 1998, 47, 375.
To a solution of the azide (0.144 g, 0.5 mmol) in dry benzene (25 mL) was added triphenylphosphine (0.14 g, 0.55 mmol) under a nitrogen atmosphere at rt. The reaction mixture was stirred for 4 h thenheated to 80 °C for 9 h. After the solvent was evaporated, flash chromatography of the residue gavethe quinazolinyl carboxylate.
Section one - Chemistry of Heteroaromatics
129
Intramolecular Aza-Wittig Reaction
Tandem aza-Wittig / electrocyclization reaction
Bonini, C.; Funicello, M.; Scialpi, R. Spagnolo, P. Tetrahedron 2003, 59, 7515.
S
OMe
N PPh3S N
OMe CO2Me
MeCHCl3, 34 h, 45 oC
CH3COCH=CHCO2Me
Synthesis of Vasicinone Based on Intramolecular aza-Wittig Reaction with Imide
(1) PBu3, toluene, rt 1 h, reflux, 2 h, 76%
Synthesis of Benzodiazepines and Benzothiadiazepines via aza-Wittig Reaction with Ketone
Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou, C. Tetrahedron Lett. 2000, 41, 10107.
(1) PhMgBr, THF
-40 oC
X = SO2 or COR = n-Bu, Ph or polymer supportR1 = H, Me
(2) P(OMe)3, MeOH
60 oC
83% 2 steps
Dess-Martin Toluene, reflux
Section one - Chemistry of Heteroaromatics
(2) TBAF, THF, 0 oC rt
15 h, 82%
l-Vasicinone
Synthesis of 2, 4-Disubstituted Thiazoline via aza-Wittig Reaction with Thioester
Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281.Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125, 8734.
PPh3, THF, 50 oC
67%
Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J. Org. Chem. 1996, 61, 7316.
N3
N
O O
OTBDMS
N
N
O
OH
XN
NS
O
R1
R1PR3
XNH
N
R1
PR3
R1
OH
N
NHX
R1
R1
TESO Me
Me
OTBS
N
S
CO2Me
Me
S
TESO Me
Me
O O
CO2Me
MeN3
TBS
XNH
N
R1
PR3
R1
O
130
Key step in the Synthesis of the Indole Alkaloid Hamacanthin B via an Aza-Witig Reaction with Ketone
PBu3, toluene, reflux
12 h, 82%
R = TsR = H, (Hamacanthin B)L-Selectride
Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1396.
Section one - Chemistry of Heteroaromatics
5
10
Synthesis of Phloeodictine A1 via aza-Wittig with an Imide
Neubert, B. J.; Snider, B. B. Org. Lett. 2003, 5, 765.
PPh3, toluene, 25 oC, 30 min
reflux, 4 h
retro Diels-Alder
Phloeodictine A1
NTsBr
NH
N3
O
O
NH
Br
NRBr
N
NH
NH
Br
O
O
N
O
O
N3
N
N
O N
N
OH
NH
H2N NH2
O
N
N
O
131
Section one - Chemistry of Heteroaromatics
Synthesis of the marine alkaloid variolin B via aza-Wittig reaction
Molina, P.; Fresneda, P. M.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2002, 43, 1005.Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2000, 41, 4777.
Variolin B
Preparation of 2-amino-1,4-disubstituted imidazoles via aza-Wittig reaction
Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999, 64, 2540.
PPh3 / Et2O, rt Ts-NCO, Et2O, rt
R-NH2, Et2O, 0 oC
PhCO2Et
N3
PhCO2Et
N PPh3
PhCO2Et
N C N Ts
PhCO2Et
N C NHTs
HN R
N
NPh
OR
NHTsN
NPh
R
NH2
N
N
OCH3
NH
CO2Et
NPPh3
N
OH
N
NNH2
N
N
NH2
N
OCH3
NH
CO2Et
NCNCH(CH3)Ph
OCH3
N
NN
CO2Et
H
PhCH(CH3)NCO
THF, rt, 100%
Ph
CH3
132
1. Pd Catalyzed Amination of Five-membered Heterocyclic Halides
Hartwig, J. F.; Utsunomiya, M.; Hooper, M. W. J. Org. Chem. 2003, 68, 2861.
Section one - Chemistry of Heteroaromatics
133
O Br
S
NCl
O
Br
S Br
S
Br
N
NCl
Me
O
NCl
O NMePh
O
NMePh
S
NMePh
S NMePh
S
NNnBu2
N
NN
Me
O
O
NN O
S
NBr
S
NNnBu2
OHN
2% Pd(dba)2, PtBu3
PhNHMe
56%
82%
85%
93%
PtBu3, HNnBu2
71%
77%
5% Pd(O2CCF3)2, PtBu3
1.1 eq. base, tol,
74%
51%
In a dry box, aryl bromide (0.5-2.5 mmol), amine (0.5-2.5 mmol), and NaOtBu (0.55 - 2.75 mmol) were weighed directlyinto a screw capped vial. A stir bar and 0.5-2.5 mL of toluene were added. Pd(dba)2 (2 mol %, 0.01-0.05 mmol) andPtBu3 (2 mol %, 0.01-0.05 mmol) were weighed directly into a small vial and suspended in 0.5-2.5 mL of toluene. Thecatalyst suspension was then added to the reactants to give a purple mixture. The mixture was allowed to stir for 16 h atroom temperature in the drybox or at 100 °C for 16 h outside the drybox. After this time, the mixture was poured intopentane (15 mL), filtered, and concentrated in vacuo. The crude product was adsorbed onto neutral alumina and purified by flash chromatography.
In a drybox, aryl halide (1.0 mmol), NaOtBu or K3PO4 (1.10 mmol), and amine (1.0-4.0 mmol) were added to asuspension of Pd(O2CCF3)2 and PtBu3 (0.02-0.05 mmol) in 1.0-2.0 mL of toluene in a screw capped vial. A small stirbarwas added, and the vial was sealed with a cap containing a PTFE septum. The mixture was allowed to stir at roomtemperature in the drybox or at elevated temperature outside of the drybox. After the reaction, the mixture was adsorbed onto neutral alumina and purified by flash chromatography.
1.1 eq. NaOtBu, tol
1.1 eq. base, tol
5% Pd(O2CCF3)2,
2. Pd Catalyzed Amination of Chloropyridines
Buchwald, S. L.; Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J. Org. Chem. 2000, 65, 1158.
Pd(0) catalyzed amination of heteroaromatics - Section one - Chemistry of Heteroaromatics
134
N Cl
N
Cl
N
Cl
O
HN
PhP(R)2
N NO
N
NO
.HCl
H2NBnN
N(H)Bn
N
NBn
N
L Pd0 L
L Pd0
Ar-X
PdIIAr
LX
PdIIL Ar
X NHRR'
PdIILAr
NRR'
70% (27:1)
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with palladiumacetate (0.5 mol %), 1 (1.0 mol %), and NaOt-Bu (1.4 equiv) and evacuated and backfilled with argon. The flask wascapped with a rubber septum, and toluene (2 mL/mmol halide), the aryl chloride (1.0 equiv), and the amine (1.2 equiv)were added through the septum (aryl chlorides or amines that were solids at room temperature were added as solidsfollowing the addition of NaOt-Bu). The septum was replaced with a Teflon screwcap, the flask was sealed, and themixture was heated to 80 °C with stirring until the starting aryl halide had been completely consumed as judged by GCanalysis. The mixture was cooled to room temperature, diluted with ether (30 mL), filtered through Celite, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. N-(2-Pyridyl)morpholine: conducted on a2 mmol scale using a reaction temperature of 100 °C and ligand 2. N-(3-Pyridyl)morpholine: 1 mol % Pd(OAc)2 and areaction temperature of 110 °C gave. N-Benzyl-4-aminopyridine: 1 mol % Pd(OAc)2, 2 mol % 2, 2.8 equiv of NaOt-Bu,dioxane solvent, and a reaction temperature of 100 °C, determined to contain 3.6% of bis(4-pyridyl)benzylamine by 1HNMR analysis.
Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.
General Catalytic Cycle for Buchwald-Hartwig Amination
-LLoxidative addition
NHRR'
amine coordination
NaOtBu
NaX + tBuOH
deprotonation
Ar-NRR'
reductive elimination
+
5 mol % Pd(OAc)2, tBuONa, DMF, 80oC
cat.
+
95%
70%
+ 1 - R=tBu
2 - R=Cy
Section one - Chemistry of Heteroaromatics
135
N Cl
+
N N
Me
N
Br
O
HN
HNPh
Me
N
N
Cl
+N Br
N
N
N
Me
Me
N
NPh
Cy2P
P NNi-Bu
i-Bui-BuN
Me
O
NNcat. Pd(OAc)2,1.5 eq. NaOtBu, tol,
cat.
4. Pd Catalyzed Amination of Pyrazine and Quinoline
Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.; Dommisse, R. A. Synlett. 2003, 12, 1822.
cat. Pd(OAc)2,1.4 eq. NaOtBu, tol,
80%
A pressure vial of 10 mL was charged with (azahetero)aryl chloride (1 mmol), amine (1.2 mmol or 1.5 mmol) andt-BuONa (0.13 g, 1.4 mmol) in air. Subsequently the vial as flushed with Ar for 1 min. Then, 1 mL of a stock solution ofprecatalyst [Pd/2L: Pd(OAc)2 and DCPB [DCPB = 2-(dicyclohexylphosphanyl)biphenyl] in anhydrous toluene was added via a syringe and the resulting mixture was flushed with Ar for an additional 2 min under magnetic stirring. Next, the vialwas sealed with an Al crimp top with septum and heated at 150 °C or 200 °C in a CEM Discover microwave apparatus.The initial power supplied was 300 W. Once the temperature was reached (IR measurement), the power dropped andfluctuated to maintain the temperature at the desired value. The total heating time of all reactions was 10 min. After thereaction vials were cooled down to rt. using a propelled air flow, they were opened and filtered over Celite and rinsedwell with 100 mL CH2Cl2 or Et2O. The filtrate was subsequently evaporated under reduced pressure and the residuepurified by flash column chromatography on silica gel.
microwave, 10 min
83%
3. Pd Catalyzed Amination of Bromopyridines
Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.
93%
84%
An oven dried Schlenk flask equipped with a magnetic stirring bar was charged with Pd(OAc)2 or Pd(dba)2 and CS2CO3(1.5 mmol). Amine (1.2 mmol) and aryl bromide (1.0 mmol) were also added at this time. The flask was capped with arubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. The ligand was then added via syringe from a stock solution. Aryl bromide (if a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol), and toluene (3 mL)were then successively added by syringe. The reaction mixture was heated to 80oC until the starting material had beencompletely consumed as judged by TLC (15-20 h). The mixture was cooled to room temperature, adsorbed onto silicagel, and then purified by column chromatography using a mixture of hexane and ethyl acetate as the eluent.
A flame-dried 10 mL round bottom flask was charged with tris(dibenzylideneacetone), dipalladium(0) (4.0 mg, 0.005mmol, 2.5 mol %), Xantphos (10 mg, 0.02 mmol, 10 mol %), pyridone (0.05 g, 0.18 mmol), and Cs2CO3 (0.09 g, 0.27mmol). The solid reactants were dissolved in 5 mL of dioxane and the appropriate aniline derivative (25 uL, 0.27 mmol)was added to the flask. The flask was capped with a condensor and kept under an atmosphere of argon. The reactionwas heated at 100oC for 1-2 h or until the starting triflate had been completely consumed as judged by TLC. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through a pad of celite and concentratedunder reduced pressure. The crude material was purified by flash column chromatography on silica gel or florisil to givethe 2,3-dihydro-1H-indolizin-5-one.
5. ββββ-Carbolinone Synthesis
1.5 eq. Cs2CO3, tol.
10 mol % Pd(PPh3)2
1.2 eq. Cs2CO3, dioxane, 110oC
Padwa, A.; Harris, J. M. J. Org. Chem. 2003, 5, 4195.
Section one - Chemistry of Heteroaromatics
136
NCO2Et
I
MeO NHMe
NCO2Et
N
MeO
Me
NH
N
HO
Me
Me
N
O O
N2
SO2Ph
N
O
TfO
CO2MeCO2Me
NH2
Br
N
O
NH
CO2Me
Br
N
O
NH
CO2Me
Pd(PPh3)4 (92 mg, 0.08 mmol) was added to a mixture of the indole (0.32 g, 0.80 mmol), NEt3 (4 mL), and K2CO3 (0.33 g, 2.4 mmol) in toluene (10 mL). The yellow mixture was heated to 200 °C for 15 h, cooled to rt, and poured into aseparatory funnel containing Et2O (15 mL) and water (15 mL). The organic layer was washed with water (10 mL) andbrine (10 mL), dried over MgSO4, and filtered, and the solvents were removed using a rotary evaporator. The productwas purified by flash chromatography (4:1 hexane/ethyl acetate) to give 0.18 g (82%) of the product as a white powder.
6. Tetrahydopyrroloquinolines - Dehydrobufotenine
10 mol %Pd(PPh3)4K2CO3, NEt3
81%
1. BBr3
2. MeI
Buchwald, S. L.; Peat, A. J. J. Am. Chem. Soc. 1996, 118, 1028.
50% - 6 steps; 17% overall yield
1. , Rh(II)
2. Tf2O
80% 65%
+
5 mol %Pd(OAc)210% Xantphos
7. Functionalized Pyrido[2,3-b]indoles
cat. Pd2(dba)3
Dodd, R. H.; Abouabdellah, A. Tetrahedron Lett. 1998, 39, 2119.For procedure see: Buchwald, S. L.; Marcoux, J.; Wagaw, S. J. Org. Chem. 1997, 62, 1568.
8. Pd Catalyzed Coupling of Glycosylamines and 6-Chloropurines
Chida, N., Suzuki; T.; Tanaka, S.; Yamada, I. Tetrahedron Lett. 1999, 40, 2573.
1. BBr3, CH2Cl2, -78oC
74%
Section one - Chemistry of Heteroaromatics
137
N
N
N
N
Cl
SEM
N Br
O
H
Me
N Br
HO
Me
O
O
NHBoc
N Br
Me
O
O
NH2
TFA, Me2SLiHMDS SnCl4, -78oC
O
OBocHN
N
Me
N
O
O
O
NH2
OBn
BnO
BnO
OBn
O
NH
OBn
BnO
BnO
OBn
N N
NN MPM
+
O
NH
OH
HO
HO
OH
N N
NNH
5 mol % Pd2(dba)3, 10 mol %BINAP
51%90%
57%
SEM= Me3SiCH2CH2OCH2-
81%
To a mixture of mannopyranosylamine (32 mg, 60 umol) and 6-chloropurine (33 mg, 120 umol), in toluene (2.5 ml) wasbubbled a stream of Ar for 15 min. The reaction mixture was then heated at 140oC in a sealed tube for 9 hr. After cooling, the mixture was diluted with ether and washed with brine, and dried. Removal of the solvent left a syrup, which waschromatographed on a column of silica gel (4 g), with EtOAc-toluene (1:3) to give the product as an anomeric mixture.
tBuONa, DMF, 80oC
(-) BINAP, NaOtBu, tol.
2. recrystallization (H2O)
A round bottom flask was flushed with nitrogen and charged with Pd(OAc)2 (13 mg, 0.06 mmol, 2%), (±)-BINAP (37 mg, 0.06 mmol, 2%) and toluene (10ml). The mixture was stirred under nitrogen for 10 min. In another round bottom flask,dichloropyridine (0.44 g, 3 mmol), amine (3.6 mmol, 1.2 equiv.) and K2CO3 (8.3 g, 60 mmol) were weighed. Then, thePd(OAc)2/BINAP solution was added, and the flask was rinsed with an additional 17 mol toluene. The resulting mixturewas subsequently refluxed in an oil bath under N2 with vigorous stirring until the starting dichloropyridine haddisappeared as judged by TCL and DCI-MS. After cooling down, the solid material was filtered off and washed with 100ml CH2Cl2. The solvent was evaporated and the resulting crude product was purified by flash column chromatography.
10. Selective Pd Catalyzed Aminations of Dichloropyridines
2% Pd(OAc)2, 2% BINAP
83%
Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027.
Section one - Chemistry of Heteroaromatics
138
N
N
F
Cl N
N
F
NH
HN (CH2)CH3
H2N
HN
(CH2)CH3
N
Cl
Cl N
Cl
NH
R
N
NN
O
N
N CH3
CH3
N
N
2 mol% Pd2(dba)3,
9. Multiamino Based Structures
Senanayake, C. H.; Hong, Y.; Xiang, T.; Vandenbossche, C.P.; Tanoury, G. J.; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998, 39, 3121.
77%
+
Anhydrous toluene was degassed with argon for 20 min. prior to use. A dry 25 mL 2-neck flask was charged withN-propylethylenediamine (0.43 mL, 3.5 mmol), tris(dibenzylideneacetone)-dipalladium(0) [Pd2(dba)3] (40 mg, 0.044mmol), 2,2'-Bis(diphenylphosphino)- 1-1 '-binaphthyl (81 mg, 0.13 mmol) [BINAP], sodium tert-butoxide (300 mg, 3.2mmol), and aryl halide (500 mg, 2.9 mmol). The resulting mixture was evacuated and purged with argon, followed by theaddition of anhydrous toluene (10 mL). The solution was degassed with argon for 5 min, at which time it was heated to85°C for 2 h. The reaction was cooled to room temperature, quenched with 0.1N NaOH and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. Silica gelcolumn chromatography was performed using EtOAc:MeOH.
60%
90%
91%
R=
H2N-Ar, 20 eq. K2CO3
BINAP, NaOtBu