39
Amination: An Overview Roxanne Atienza Long Literature Presentation September 22, 2008
Amination: An Overview
Roxanne AtienzaLong Literature Presentation
September 22, 2008
The definition of amination
- The process by which an amine group is introduced into an organic molecule through the formation of a new C-N bond.
NH
O
O
R2
R1
X
1) KOH
2) H2NNH2R2
R1
NH2
Gabriel Amine Synthesis
Buchwald-Hartwig Reaction
X
R
+ H2NR'
Pd0 catalyst
NaOt-Bu
dioxane
100oC
NHR'
R
Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224.
Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5969-5970.
Importance of Nitrogen
- Nitrogen is a constituent element in amino acids, proteins, and nucleic acids.
- Carbon-nitrogen bonds are found in the majority of organic molecules, especially biologically active molecules.
- Nitrogen containing compounds are valuable and commercially important bulk chemicals and pharmaceuticals.
- Nitrogen is involved in important biological linkers such as peptide linkers.
- The lone pair on nitrogen allows for hydrogen bonding which is key in the 3D structures adopted by DNA and proteins.
F
F
F
NH2
N
O
NN
N
CF3H3PO4 H2O
Januvia (Merck)inhibitor of DPP-4
for treatment of type 2 diabetes
O
O
HNCO2H
OMe
Me
O
Dynemycinpromising anti-cancer drug
Types of Amination- Electrophilic Amination Combination of nucleophilic carbon and an electrophilic aminating agent
- Reductive Amination Conversion of a carbonyl group to an amine via an intermediate imine and its subsequent
reduction
- Hydroamination Addition of an N-H bond over an alkene or alkyne
- Nucleophilic Amination Introduction of an amino group via a nucleophilic aminating agent
Example: Gabriel amine synthesis
R2N
R1
Z+ Nuc
R2N
R1
Nuc+ Z
R1 NH2 +O
R3R2
-H2O NR1
R3R2
NHR1
R3R2
Rcatalyst MeR
NR2or R
NR2
H
HNR2
Electrophilic AminationCombination of nucleophilic carbon and an electrophilic aminating agent
- This can be accomplished through the use of various aminating agents such as:
- hydroxylamines - oxaziridines
- oximes - azido compounds
- azo compounds - nitroso compounds
R2N
R1
Z+ Nuc
R2N
R1
Nuc+ Z
H2NO
SO2
Me
N
R1 R2
OH
N
N
CO2Et
EtO2C
Ar
N NEt2
O
O
ArSO2
N3
O
NR
Electrophilic Amination with hydroxylamines
t-BuO NH
O
OSO2
Me
n-BuLi
THF
–78 oC
t-BuO N
O
OSO2
Me
Li
n-BuLi
PhCu
t-BuO NH
O
t-BuO NH
O
Ph
n-BuLi 71%
40%
- O-sulfonylhydroxylamines: synthesis of N-protected amines
Asymmetric synthesis of !-amino acid derivatives
Ph
O
N O 1) n-BuLi, –78 oC
2) CuCN,
–78 oC to 0 oCPh
O
Li
Ph
O
CuCN
1
Ph
O
NHBocXc Xc Xc
LiBocNOTs 1
77%, >99% de
Genet, J.P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett. 2008, 32, 2359-2362.
Zheng, N.; Armstrong III, J. D.; McWilliams, J. C.; Volante, R. P. Tetrahedron Lett. 1997, 38, 2817-2820.
Electrophilic Amination
- O-acylhydroxylamines: synthesis of secondary and tertiary amines
O
NHPh O
O
O
O
Ph
KH2PO4
DMF
O
NO
O
PhR2Zn
[CuOTf]2·C6H5
O
NR
Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680-5681.
- O-phosphinylhydroxylamine
O
OEt1) KOt-Bu, THF, –78 oC
2) ArPO2NH2 2, –78 oC ~ 23 oC
3) Ac2O, Et3N O
OEt
NHAc
OP
ONH2
MeO
MeO 2
67%
Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187-4190.
O
NPh
O
N
CO2Et
O
NBn
80% 91% 77%
Electrophilic Amination
- O-trimethylsilylhydroxylamine
N OMe3Si
H
SiMe3+ R2Cu(CN)Li2 N O
Me3Si
Li
SiMe3+ RCu(CN)Li + R-H
Cu
R
Li CN Cu
R
LiNC
N
O
SiMe3
SiMe3R
NH
SiMe3
Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58, 5620-5623.
Electrophilic Amination with oximes
N
R2R1
OR3
+ R4 MN
R2R1
R4
(+ MOR3)
H3OR4 NH2
Competing side reactions- Neber rearrangement - Beckmann rearrangement
N
R2R1
OR3
N
R1
R2
(+ –OR3)
H2O
R2
O
NH
R1N
R2
OR3
(+ HOR3)
H2O
R2
O
R1
H
R1
NH2
N
R2R1
NR1
R2base
General scheme
Electrophilic AminationO-tosyloximes- tetraphenylcyclopentadienone O-tosyloxime
- bis[3,5-bis(trifluoromethyl)phenyl]ketone O-tosyloxime
N
Ph
Ph
Ph
Ph
OSO2p-Tol
+O
LiTHF
–78 oC
N
Ph
Ph
Ph
Ph
OSO2p-TolO
N
Ph
Ph
Ph
Ph
ONH2OH
aq. pyridine N
Ph
Ph
Ph
Ph
OH
O
NH2
+
90%95%
Hagopian, R. A.; Therian, M. J.; Murdoch, J. R. J. Am. Chem. Soc. 1984, 106, 5753-5754.
R-MgBr+
NOSO2p-Tol
F3C
CF3 CF3
CF3
3
toluenert N
Ar Ar
R 1) H3O2) BzCl, Et3N R-NHBz
R= Ph, 96% Et, 87% t-Bu, 35%
98%
Me
Me
Ph Me
MgCl
ca. 91% eetoluene
–70 oC
Ph Me
N Ar
Ar
1) HCl aq.2) AcCl, Et3N Ph Me
NHAc
Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869-1878.
Hoffman, R. W.; Holzer, B.; Konpff. Org. Lett. 2001, 3, 1945-1948.
25%, 90% ee
N
Ar Ar
OTs
Electrophilic Amination
- O-(phenylsulfonyl)oximes
O O
NOSO2Ph
MeMe Me
Me
+ R-MgBr
PhCl
or CH2Cl2
0 oC ~ rtO O
NR
MeMe Me
Me
R NH3 Cl
R= alkyl and aryl substituents, 89-94% 7 examples
4
R MgBr
CuCN·2LiCl P(OMe)3, THF, rt
R CuCN(MgBr)4, THF, rt
O O
N
R
1 M HCl in Et2O
MeOH, rtNH3 ClR
R= CO2Et, 87% CN, 91%
Kitamura, M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004, 6, 4619-4621.
Ricci, Alfredo. Amino Group Chemistry; Wiley-VCH: Weinheim, 2008.
H
N
R'O OR'
OSO2Ph
Electrophilic Amination with azo compounds
O
Me
Me
R
O
+N
N
EtO2C
CO2Et ClCH2CH2Cl
50 oC, 20h
O
MeMe
R
O
N
NHEtO2C
CO2Et
R= Me, 96% OEt, 73%
NiO
O O
O
H
H- Azodicarboxylates
Clariana, J.; Galvez, N.; Marchi, C.; Moreno-Marias, M.; Vallribera, A.; Molins, E. Tetrahedron 1999, 55, 7331-7344.
Me
(2 mol)
+N
N
EtO2C
CO2Et
1 mol SnCl4, CH2Cl2, –60 oC
Li
liquid NH3.
-60 oC
MeN
NHCO2Et
CO2Et87% (E : Z = 11:1)
86%
Brimble, M. A.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5261-5263.
Me
HN
CO2Et
2H2O
Electrophilic Amination
- Arylazo sulfones
NH2
NaNO2
HBF4, rtN2 BF4
TsNaCH2Cl2, rt N N
Ts
1) Ar2MgBr
–20 oC
2) C3H7I, NMP
20 oC
N NTs
ZnAcOH/TFA
(5:1)
X= Br, OMe, I, CN
Y= CO2Et, OTf, Me, OMe64-86%
Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 897-900.
X X
X
N NTs
XX
NH
Y
X
Y
64-95%
X= Br, 80%
Electrophilic Amination with oxaziridines
CN
NO
NEt2
O1) LDA
2)
THF, –78 oC
t-BuO Me
O
Ph
O
Me NC Me
O
PMeEtO
EtOt-BuO
O
Ph
O HN
Me
HN NEt2
O
NEt2
O
NC
O
PEtO
EtOHN
HN
Me
NEt2
O
NEt2
O
substrate substrateproduct product
55%
60%
51%
56%
Me R2
R1SC6H13
O NBoc
EtO2C CO2Et
CH2Cl2, –78 oC - rt Me R2
R1SC6H13
N
Boc
Me R2
R1[2,3] NBocC6H13S
R1 R2 % %ee
H Me 69 >95
H CO2Et 72 >95
Me CO2Et 77 >94
Armstrong, A.; Challinor, L.; Cooke, R. S.; Moir, J. H.; Treweeke, N. R. J. Org. Chem. 2006, 71, 4028-4030.
R
H
EWGHN
R
EWG
O
NH2
Armstrong, A.; Atkin, M. A.; Swallow, S. Tetrahedron Lett. 2000, 41, 2247-2251.Armstrong, A.; Edmonds, I. D.; Swarbrick, M. E.; Treweeke, N. R. Tetrahedron, 2005, 61, 8423-8442.
Electrophilic Amination with azides
SPhN3MgBr
Ph1)
2) (MeCO)2O
THF, –78 oC
NPh N
OMe
N SPhn-Bu4N+HCO2
–
DMF, 45 oCNH
PhMe
O
- with Grignard reagents
86%
- with enolates
Ph
O
N O
O
Ph
1) KN[Si(NMe2)3]
2) trisN3, THF, –78 oC
3) CH3CO2H, THF
rt
Ph
O
N O
O
Ph
N3
91% (97:3)
Trost, B. M.; Pearson, W. J. Am. Chem. Soc. 1981, 103, 2483-2485.
Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030.
Electrophilic Amination with nitroso compounds
Me
Me NO2
Cl+ N
Me
Me Cl
NOH OHMe
Me
Cl
HN OHH2O
Ricci, A. Modern Amination Methods; Wiley-VCH: Weinheim, 2000.
Me
+
N
O
Me
Me
O
Metoluene, reflux
Me
N
OH
O
Me
Keck, G. E.; Yates, J. B. Tetrahedron Lett. 1979, 20, 4627-4631.
Reductive Amination
Conversion of a carbonyl group to an amine via an intermediate imine and its subsquent reduction
R1 NH2 +O
R3R2
-H2O NR1
R3R2
NHR1
R3R2
O
HH+
HCOOH+ H2O
RN
H
RO
H
H
RNR
HO
NOH
R
RN
R
R H
H
O
OHN CH3
R
R-H2O -CO2
Eschweiler-Clarke reaction
H
+ CO2R2N-H R2N-CH3
Reductive Amination with NaBH(OAc)3
O
OO + HN N Ph
O
ON N Ph 78%
NaBH(OAc)3AcOH
DCE, rt
Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849-3862.
- Sodium triacetoxyborohydride
OBnN
Y
CHO MeO
O
NH2
R1
R2+
NaBH(OAc)3
AcOH
CH3CN
0 oC, then refluxBnN N
O
Y
O
R1
R2
Y= alkyl, Ph, OBn
27-99%
OBnN
Y
HNCO2Me
R1R2
BnHN NCO2Me
R1R2
OY
Beshore, D. C.; Dinsmore, C. J. Org. Lett. 2002, 4, 1201-1204.
Y
NH2
ClR1 +
O
R2 R3
Y
HN
ClR2
R3NaBH(OAc)3TFA
i-PrOH, rt R1 72-97%
McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett., 2006, 8, 3307-3310.
Reductive Amination with NaBH4
- Sodium Borohydride
O
R2R1+ H2N-R3
R2R1
OHN R3(i-PrO)3Ti
Ti(i-PrO)4THF, rt
NaBH4
THF/EtOH(3:1), rt
R2R1
HNR3
72-88%
Kumpaty, H. J.; Bhattacharyya, S.; Rehr, E. W.; Gonzalez, A. M. Synthesis, 2003, 2206-2210.
O
R2R1
1) Ti(i-PrO)4
NH3 (5 M in EtOH)
2) NaBH4R2R1
NH2
O
HR
1) Ti(i-PrO)4, NH4Cl, NEt3, EtOH, rt
2) NaBH4
R NH
R
65-96%
Miriyala, B.; Bhattacharyya, S.;Williamson, J. S. Tetrahedron, 2004, 60, 1463-1471.
62-78%
Reductive Amination with B10H14
- Decaborane
OMe
Me+ H2N NO2 HN NO2
MeMe
96%
30 mol% B10H14
MeOH
Bae, J. W.; Lee, S. H.;Cho, Y. J.;Yoon, C. M. J. Chem. Soc., Perkin Trans. 1 2000, 145-146.Bae, J. W.;Cho, Y. J.;Lee, S. H.; Yoon, C.-O. M.;Yoon, C. M. Chem. Commun. 2000, 1857-1858.
MeO
ONH
MeO
ONO2
O+
1) 10 mol% Pd/C, 30 mol% B10H14
MeOH, 40 oC
2) 20 mol% B10H14, rt
Me NHNO2
1) 10 mol% Pd/C, 30 mol% B10H14
AcOH, MeOH, reflux
2) aldehyde, 20 mol% B10H14, rt OH
93%
90%Me
Reductive Amination with Hantzsch ester- Hantzsch ester
NH
EtO2C CO2Et
MeMe
O
CO2EtMeH2N-PMP+
Hantzsch ester
5 mol% (S)-VAPOL-PA
toluene
50 oC
HN
CO2EtMe
PMP
*88%, 99% ee
Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830-5831.
Ph Ph
O OP
OHO
(S)-VAPOL-PA
Me
OY
O
R1+
NH2
OR2
Y
HN
R1
OR2
Hantzsch ester
(R)-TRIP
cyclohexane
5 Å MS
50 oC
Ar
Ar
O
OP
O
OH
(R)-TRIP
O
O
n-Bu
HN
O
n-Bu
OEt
HN
n-Bu
OEt
HN
n-Bu
OEt
HN
n-Bu
OEt
Ar=
Zhou, J.; List, B. J. Am. Chem. Soc., 2007, 129, 7498-7499.
Y= C, O, S
72-78%, 86-96% ee
Reductive Amination
- !-picoline-borane
O
H + H2N
pic-BH3
solvent/ AcOH(10:1)
rt
HN
H
In MeOH: 95%In water: 91%neat: 99%
Sato, S.;Sakamoto, T.;Miyazawa, E.;Kikugawa, Y. Tetrahedron. 2004, 60, 7899-7906.
- polymethylhydrosiloxane
Ph NH
PhMe
O
H+
5 mol% PMHS
0.5 mol% [IrCl(cod)]2THF, 50 oC
Ph N Ph
Me
93%
Mizuta, T.;Sakaguchi, S.;Ishii, Y. J. Org. Chem., 2005, 70, 2195-2199.
N CH3
BH3
Si O Si
H
O Si
n
Hydroamination
The addition of an N-H bond over an alkene or alkyne
Rcatalyst R
NR2or R
NR2
Methods include
- BrØnsted Acid Catalysis
- Base Catalysis
- Metal Catalysis
- Microwave Irradiation
HNR2
Hydroamination - BrØnsted acid catalysis
-Bronsted Acid Catalyzed Intermolecular hydroamination
R1 R2
+
NH2
X
Et2O 5 mol%
R1 R2
HX R1 R2
H HNX
R1 R2
HNH2
X
Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542-14543.
R1 R2 + TsNH2
5% TfOHtoluene
R1 R2
H NHTs
Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175-4178. Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179-4182.
NH3 B(C6F5)4
alkene X A:B norbornene H 84% 1:1 4-Cl 56% A only 4-OMe 32% 1:2 3,5-CF3 80% A onlycyclohexadiene 3,5-CF3 20% A only
A
B
Hydroamination
-Brønsted Acid Catalyzed Intramolecular hydroamination
R
X X
NH
PG
20 mol% TfOH
toluene, 100 oC
NRX
X
PG
( )n
Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471-1474.
R1
R1
NHR2
20 mol% R3NHX1,4 dioxane NR1
R1Me
R2
20 mol% TfOH
toluene, 100 oC
Me
MeMe
NHTsMeCO2Me
TsN
Me Me
Me
CO2MeH
Me
Haskins, C. M.; Knight, D. W. Chem. Commun. 2002, 2724-2725.
Hydroamination - base catalysis
- Base catalyzed intermolecular hydroamination
+N
HN
Bn
n-BuLiTHF R1
N
NBn
N
N
R2
O
N
R3
Kumar, K.; Michalik, D.; Garcia Castro, I.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.;Bottcher, H.;Beller, M. Chem. Eur. J. 2004,10, 746-757.
R1
O
Ot-Bu
NLi
R3R2
toluene, -78 oCPh Ph
MeO OMe
R1
O
Ot-Bu
NR3R2
Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2003, 125, 2886-2887.
R1 R1
65-99%
64-95%68-99% ee
Hydroamination
- Base catalyzed intramolecular hydroamination
NHMe
Ph
NMe
Ph
NMe
Ph
NMe
Ph
+
99%, 91% ee
94% 5%
10 mol% BOX
5 mol% n-BuLi
5 mol% HNi-Pr2toluene, -60 oC
10 mol% n-BuLi
15 mol% HNi-Pr2THF
-78 oC to rt
Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.; Tomioka, K. Tetrahedron Lett. 2007, 48, 6648-6650.
Hydroamination
Co
HN
N
O
O
OMe
Me
Me
Me
O
O
Br + N
N
CO2t-Bu
t-BuO2C
5 mol% Co(III) cat.PhSiH3, EtOH
Br Me
NBoc 90%
PhMe
EtO2CMe
Ph
NBoc
EtO2C
NBoc
Me
BocHN
BocHN
BocHN
Me
88%
66%
Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676-5677.
- hydrohydrazination
MeOH
substrate product
Hydroamination- microwave irradiation
Ph
HN
O
NHTs
O2S
Me
NHTs
+ TsNH2
1-5 mol% (PR3)AuOTfDCE, mw irradiation
TsN
CH2
O2S
Me
NTs
CH2
N
O
Ph
H2C
NHTs
Liu, X.Y.; Li, C. H.; Che, C. M. Org. Lett. 2006, 8, 2707-2710.
H
H
H
H
Hydroamination - metal catalysis
Ph
NH2
1) 5 mol % cat.2) NaBH3CN/ZnCl2
HN
Ph
NTi
NEt2
NEt2
N
Ar= Ph, C6F5
Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun. 2003, 2462-2463.
NH2
R1R2 5 mol % cat A or B
NR2 R1 H
N
R2
R1
+
R1, R2= H; cat A
94:6
94%
R1= 4-MeC6H4, R2= Et; cat B
100:0
93%
HN
TiNEt2
NEt2
OAr
2
SO2
SO2
NZr
NEt2
NEt2
N
SO2
SO2
A B
Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-11963.
97-98%
Hydroamination of aminoallenes- Two-pathway mechanism of the hydroamination of aminoallenes
L2M(NMe2)2
- 2HNMe2
+ RNH2
N
R
ML2
N ML2
N
R
ML2
RHN
R
RNH2
HN
R
RNH2
N ML2
R
NML2
NHR
RNH
R
N
R
Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-11963.
Hydroamination
NH2
MeO
MeO
+ R
5 mol% cat.
benzene, 65 oCN
MeO
MeO
R
TFA, heatNH
MeO
MeO
R
R =Me
X
X
NTi
NEt2
NEt2Ph
2
MeMe
Me
Me
catalyst
Zhang, Z.; Schafer, L. L.; Org. Lett. 2003, 5, 4733-4736.Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick, B. O.; Schafer, L. L. Chem. Eur. J. 2007, 13, 2012-2022.
Metal-catalyzed Amination
X
R
+ H2NR'
Pd0 catalyst
NaOt-Bu
dioxane
100oC
NHR'
R
Buchwald-Hartwig Reaction
Pd0(dppf)X
Ph2P
PdII
Ph2P
Ar
X
Ph2P
PdII
Ph2P
Ar
NHR'
Ph2P
PdII
Ph2P
Ar
Ot-Bu
NaOt-Bu
NaXH2NR'
HOt-Bu
HNR'
Metal-catalyzed Amination
+ H2N
10 mol% Cp*2LaCH(SiMe3)290 oC, C7D8, TOF 11h
HN N
+ H2N
10 mol% Cp*2LaCH(SiMe3)290 oC, C7D8, TOF 6h
HNN
Cp2*La
H
H
NH
Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605.
Nonmetal-catalyzed Amination
Ph H
O+
20 mol% cat.
20 mol% DBU
CH2Cl2, 0 oCN
N
Ph
O
PhN
N
O
O
Ph
PhPh
N
N
NMe
Me
Mes H
O
Ph
Ph
O
HN
NN
Me
Mes
Me
Ph
OH
NN
N
Me
Mes
Me
N
N
Ph
O
Ph
Ph
O
NN
N
Me
Mes
Me
N
N Ph
Ph
O
N
N
O
O
Ph
Ph Ph
HN
NH
Ph
O
Ph
Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740-2741.
N
N
Ph
O
Ph
Nonmetal-catalyzed Amination
MeO2C
CN
Et N
N
Boc
Boc
10 mol %(DHQ)2PYR
CH2Cl2, -24 oC+
MeO2C
CN
Et
NNHBoc
Boc
84%, 98% ee
EWG
EWG
RB*
EWG
EWG
R
B*H
ElectrophileEWG
EWG
R
EH
*
Poulsen, T. B.; Alemparte, C.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614-11615.
(DHQ)2PYR
N N
OO
N N
MeO OMe
N
Me
N
Me
Nonmetal-catalyzed amination
Bertelson, S.; Marigo, M.; Brandes, S.; Diner, P.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973-12980.
O
Me
N
N
CO2Et
EtO2C
10 mol% cat.PhCO2Htoluene
+
NH
OTMS
ArAr
Ar= 3,5-(CF3)2C6H3
O
Me
N
HNCO2Et
CO2Et
56%, 89% ee
O
R
HH
HN
R
TMSO
ArAr
N
R
TMSO
ArAr
E*R
E*
O
cat Elec
Nonmetal-catalyzed Amination
O
HR+ H2N-Ar
0.1 equiv. thiourea
Hantzch ester
toluene, 5 Å MS
70 oC
R NH
Ar
NH
CO2EtEtO2C
Me Me
Hantzch ester
S
H2N NH2
thiourea
O2N
O
H
H2N
OMe
O
HMe
Me
O
HH2N
O
Me
O2N
NH
OMe
Me
MeNH
OMe
NH
O
Me
aldehyde amine product
93%
83%
72%
Menche, D.; Arikan, F. Synlett. 2006, 841-844.
Conclusion
• Nitrogen containing compounds are present in a majority of organicmolecules spanning from synthetic reagents to pharmaceuticals.
• There are many methods available when there is a need to introduce anitrogen to an organic molecule.
+N
HN
Bn
20 mol % n-BuLiTHF, 24h, rt N
NBn
Kumar, K.; Michalik, D.; Garcia Castro, I.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.;Bottcher, H.;Beller, M. Chem. Eur. J. 2004,10, 746-757.
FF
2 equiv. 1 equiv.
10 mol % Pd(OH)2/C
H2, 40oC
10 mol % Et3N, EtOH
7h
N
NH
F
[Pd(PhCN)2Cl2]
dppf, Et3N, CO,
130oC, tolueneNH
Br
N
N
F
ONH
83%
In three catalytic steps, different 5-HT2A receptor antagonists have been
synthesized in good yields.
