PRESENTED BY PHILIPPE BOLDUC COLLINS GROUP UNIVERSITÉ DE MONTREAL FEBRUARY 2 ND 2010 The Synthesis...

PRESENTED BYPHILIPPE BOLDUC

COLLINS GROUP

UNIVERSITÉ DE MONTREALFEBRUARY 2ND 2010

The Synthesis of Pyridine; Over a Century of Research

1

History of Pyridine

1846: FIRST ISOLATION BY ANDERSON

1869 AND 1871: KÖRNER AND DEWAR PROPOSED CORRECT STRUCTURE.

1876: FIRST SYNTHETIC ROUTE BY RAMSAY.

1930’S: DECADE WHERE NIACIN WAS RECOGNISED AS IMPORTANT FOR THE PREVENTION OF DERMATITIS AND DEMENTIA.

1940’S : 2-VINYLPYRIDINE AND 2-PICOLINE WERE NOW A CONSTITUENT OF LATEX AND DEMAND OUTSTRETCHED AVAILABILITY FROM COAL TAR. THIS PUSHED CHEMISTS TO DEVELOP INDUSTRIAL PROCESSES TOWARDS PYRIDINES.

FOR THE LAST 60 YEARS MEDICINAL CHEMISTRY INCREASED THE DEMAND FURTHER WITH THE FINDING OF MANY BIOACTIVE MOLECULES.

N

2-picoline

N

2-vinylpyridine

2

Example of Bioactive Pyridines

G. D., Henry. Tetrahedron. 60 (2004) 60643-6061

3

N

Cl

SO2

Cl

ClCl

Me

N

OH

ClCl

N CNNC

Cl

Cl

Cl

N

NC

Cl Cl

CN

N OMeCl

CCl3

NCl CCl3

N O

NH

O

F3C

N N MeMe

davicil(Fugicide)

parinol 3-hydroxy-bis-(4-chlorophenyl)methyl pyridine

(Fungicide)

Dowco 263(fungicide)

pyridinenitrile(fungicide)

pyroxychlor(fungicide)

nitrapyrin(bactericide)

phenoxynicotinamide(herbicide)

paraquat(herbicide)

2Cl-

NN

HN

N

F O Cl

F5-HT receptor agonist

(antidepresant)

NBu

CO2H

O

O

CO2H

endothelin receptor agonist(heart failure, hyertension)

Pyridine Synthesis

Many methods of making pyridine were developed. The methods are usually arranged according to the disconnection;

[2+2+1+1] : .........................

[3+2+1] : .............................

[3+3] : .................................

[2+2+2] : ............................

[4+2] : .................................

[5+1] would refer to: ..........

[6+0] : ……………………………

N

N

N

N

N

N

N

4

Pyridine Synthesis: [2+2+1+1] approach

The Classic Hantzsch disconnection allows, and is limited, to make symetrical pyridines.

1,4-Dihydropyridinesare usually isolated prior to oxidation. Pyridines issued from this route have interesting activity as calcium channel

blocker used in heart conditions. This route sets severe constraints on the substitution patterns of the

pyridines.

J.-J. Xia, G.-W. Wang. Synthesis 2005, 2379–2383.

N

5

N

EtO

O

OEt

OAr

RR

Me

O

Me O

H O

Me

Me

O

MeO

NH3rt, 4 days

pH 8.551% N

H

Me

O

MeMe

Me

O HMe NaNO2AcOH, rt

83% N

Me

O

Me

OMe

MeMeNH3

Me

O

Me O

H O

Me

Me

O

MeO

NH3rt, 4 days

pH 8.551% N

H

Me

O

MeMe

Me

O HMe NaNO2AcOH, rt

83% N

Me

O

Me

OMe

MeMe

Me O OMe

Me H

Me Me

OO

+NH3-2H2O

NH3


Research for one pot ‘greener’ approach; Wang’s work on the synthesis of various pyridines using the Hantzsch approach.

J.-J. Xia, G.-W. Wang. Synthesis 2005, 2379–2383.

N

6

RCHO CH3COCH2COOC2H5

1eq 3 eq 4eq

NH4OAc

Oxidantreflux

N

EtO

O

OEt

OR

MeMe

OrganicSolvant

HNO3 NO CrO2 CrO3

PCC

MnO2 DDQ NaNO2

NH4Ce(NO3)6 Cu(NO3)2 Bi(NO3)3 5H2O

Mn(OAc)3 RuCl3/O2 Activated carbon/O2

Zn(NO3)4

RCHO CH3COCH2COOC2H5

1eq 3 eq 4eq

NH4OAc

KMnO4

H2O

refluxN

EtO

O

OEt

OR

MeMeFeCl3N

EtO

O

OEt

OH

MeMe

N

EtO

O

OEt

OnPr

MeMe N

EtO

O

OEt

O

MeMe

N

EtO

O

OEt

O

MeMe

N

EtO

O

OEt

O

MeMe

N

EtO

O

OEt

O

MeMe

EWG

N

EtO

O

OEt

O

MeMe

EDG

t1; 40mint2; 1h93%

t1; 90mint2; 5h0%

(72%of 1)

t1; 90mint2; 5h75%

t1; 60mint2; 3h74%

t1; 40mint2; 2-3h80-91%

t1; 60mint2; 3h

76-87%

t1; 40mint2; 1h0%

(82%of 1)


In spite of many years of research, the synthesis of 3,5-dicyano pyridines was still defective. Korienko and his team used the Hantzsch approach in order to achieve this pattern

N. M. Evdokimov,I. V. Magedov, A. S. Kireev, A. Kornienko Org. Lett.2006 (8), 5, 899-902

N

7

R H

O CN

CN

R CN

CNR'SH

baseR

NC

N

CN

N SR'

baseH

baseH

N

R

CNNC

HN SR'NH

CNNC

H2N SR'

R

N

CNNC

H2N SR'

R[O]

R H

O CN

CN

CN

CNR'SH

N SR'H2N

NC CN

R

NH

SR'H2N

NC CN

R

or

R=1,6-DisubstitutedAr or HetAr

baseEtOH, reflux

2h


Although the synthesis of these compounds went very well, never did they obtain a yield over 50% of pyridine. ..


N

8


In an attempt to improve the reaction, they tested various other oxidant than air without any improvement.

Then they got a clue from these results.


N

9

•The steric hindrance caused by the o-substituents prevented the aromatisation.


This led to the conclusion that an NADH-like mechanism occurred, where a single-hydride transfer route occurred instead of a regular oxidation.


N

10

R H

O CN

CN

R CN

CNR'SH

baseR

NC

N

CN

N SR'

baseH

baseH

N

R

CNNC

HN SR'NH

CNNC

H2N SR'

R

N

CNNC

H2N SR'

R[O]

R H

O CN

CN

R CN

CNR'SH

baseR

NC

N

CN

N SR'

baseH

baseH

N

R

CNNC

HN SR'N

CNNC

H2N SR'

R

N

CNNC

H2N SR'

R

R CN

CN

H

base

H

R

CN

CN

R'SH

base

NHR'S

NC R

NH2R'S

NC R

Pyridine Synthesis: [3+2+1] approach

Common method used for the [3+2+1] disconnection approach is the base-promoted Michael addition which forms a 1,5-dicarbonyl intermediate.

When x is a pyridinium, quinolinium or picolinium salt the reaction is called a Kröhnke synthesis.

O

X

O O O

X NH3

NH

X

H

N

General scheme

N

11


Katritzky’s synthesis of pyridines via a [3+2+1] approach

Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

N

12

O

R1

R2

Bt

O

R2

OR1 O

R3

Bt

N

R2

R1 R3

NR1

R2

18a, b15

16a-j

CH3COONH4

O

R1

R2

Bt

O

O

R2

R1

O

Bt

NR1

R2

21a-c

NN

N

benzotriazole


Kröhnke, F. Synthesis 1976, 1.Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

N

13

Katritzky’s synthesis of pyridines via a [3+2+1] approach is not revolutionary. The yields are generally a little lower than Krohnke but the scope is greater.

Krohnke’s review is from 1976.

Ph Ph

O

Ph

O

N

Br-

NH4OAc/AcOH20-120oC

NPh

OPh

OPh

Br-

N H Br-

-2H2O

NPh Ph

Ph

92%

Ph Ph

O

Ph

O

NnBuLi THF

-78-0oc

NPh

OPh

OPh

-2H2O

NPh Ph

Ph

81%

NN

NN

-Bt

Krohnke synthesis

Katritzky's improvement


Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999, 12, 2114.

NR1

R2

21a-c

N

R2

R1 R3

16a-j

NR1

R2

18a, b

N

14


Another interesting approach to the [3+2+1] route is the acid catalyzed condensation of the ketone onto the alkynone. Bagley and coworker developed these conditions for a 3+3 approach.

C. Glover, E. A. Merritt, M. C. Bagley Synlett 2007 (16), 2459–2482

O

EtO2C

ON

EtO2CNH4OAc, PhMeacid catalyst

reflux, 20h(67-96%)

5a 2e4c

N

15



O

EtO2C

ON

EtO2CNH4OAc, PhMeacid catalyst

reflux, 20h(67-96%)

5a 2e4c

N

16

Me

O O

OEtEt

O

Me

Ph

O O

OEtPh

O

Me

Me

O O

OtBu TMSO

Me

O O

OEtN

SBocHN

O

Me

NH4OAcPhMe, refluxacid catalyst

50-96%

5a 2e

5b 2g

5c 2d

5d 2b

N N N

N N N

N

MeMe

EtO2C

MeMe

EtO2C

Ph

MeMe

EtO2C

Ph

TMS

EtO2C

Me Me Me

tBuO2C

Ph

Me Me

tBuO2C

Et

Me

Me

EtO2C

N

SBocHN

4i 4n 4a

4b 4j 4d

6


Reissig and coworker published this approach towards 4-hydroxypyridines.

C. Eidamshaus, H.-A. Reissig. Adv. Synth. Catal. 2009, 351, 1162-1166.

N

17

• Few groups focus on the synthesis of chiral pyridines.

COR1

H

1) n-BuLi, Et2O

2) R2-CN, -40oC

3) R3CO2H, -78oC

4) TMSOTf, Et3N

CH2Cl2, reflux 3d

N

OH

OR1

R2R3 NH

O

OR1

R2R3

CO2H

CO2H

Ph

OMeF3C

Ph CO2H

OTBS

CO2HPh

PhCO2H

NBn2

CO2H

CO2H

NHCbz

N

OH

OMe

tBu

N

OH

OMe

tBuPh

Ph

MeO CF3

NH

O

OMe

tBuNH

O

OMe

tBu

NH

O

OMe

tBu

24

45

30

51

45

Carboxilic acid Product Yield % Carboxilic acid Product Yield %

OTBS

NBn2

Ph

OTBS

Ph


Example showing that it is possible to use chiral nitriles as well.


N

CO2H

NH

O

OMe85

Carboxilic acid Product Yield %

OTBS

CO2HPh

Nitrile

CN

PhCN

NH

O

OMe

PhPh

OTBS

24

18

Pyridine Synthesis: [3+3] approach


The [3+3] approach is well known as the Bohlmann-Rahtz pyridine synthesis.

The original Bolmann-Rahtz pyridine synthesis (1957) R1 R2 R3

Me CO2Et H 77

Me CO2Et Me 81Me COMe H 72Me COMe Me 90Me CN Me 72Me CN H 80Ph CN Me 77

Me CO2Et Ph 81

Me CO2Et C7H15 87

R2

R1H2N O R3

R2

R1H2N

R3

O

EtOH, 50oC

120-170oCvacuum

N

R2

R1 R3

N

19

NH2

CO2Et

Z

O

EtOH

50oC

EtO2CH

C O

NH

H

H+

EtO2C

H2N

O

Z98%

140-150oC EtO2C

E

O

NH2

E

Z

NH

OH

N

EtO2C

Proposed mechanism for the two-step Bohlmann-Ratz Synthesis of pyridine

EtO2C



In order to improve the method, Bagley and his team made a number of different experiments. They first investigated the solvent effect.

N

20



Maybe an acid could both catalyse the addition step and the isomerisation.

N

21

R3

R2H2N

R4

O R6

PhMe, AcOH (5:1)

50oC, 5-6h

(65-95%)N R6

R4

R3

R2

N R6

R4

R3

R2



Following this succes in the Brontred acid-catalyzed conditions, they investigated the Lewis acid-catalyzed route.

N

22

H2N

EtO2C

O

3a

N

EtO2C

4a

PhMe, ZnBr2(15mol%)reflux; 5h

(59%)



Zinc(II) and Ytterbium(III) gave the best results.

N

23

R3

R2H2N

R4

O R6

N R6

R4

R3

R2

PhMe, ZnBr2(15mol%)reflux; 5h

(59%)

N R6

R4

R3

R2



To conclude their method, they show small table of comparison between Bronstead and Lewis acid-catalized routes and the traditional reaction conditions.EtO2C

R2H2N O R N R

EtO2CA, B, C

A; initial condition of Bohlmann-RahtzB; Bronstead acid catalyzed routeC; lewis acid catalyzed route

N

24


S. A. Belyakov, A. E. Sorochinsky, S. A. Henderson, J. Chen, A. R. Katritzky. J. Org. Chem. 1997, 62, 6210-6214

N

25

N

Bt R

O Ph N

R

PhEt2N

R1R2NHEthanolReflux

Further innovation with the [3+3] disconnection strategy came from Katritzky and co-workers in 1997, who employed a-benzotriazole nitriles as nucleophiles for Michael addition onto ,-unsaturated carbonyls, as shown here.

N

Bt R

O Ph

HNR1R2

R

Bt

NPh O

R

Bt

NPh O

HNR1R2

N

R

Ph

OHEt2N

Bt-BtH-H2O64%N

R

PhEt2N

N

R

PhN

R2

R1


N.A. Nedolya, N. I. Schlyakhtina,.L. V. Klyba, I. A. Ushakov, S. V. Fedorova, L. Brandsma Tetrahedron Letters. 2002 (43) 9679–9681

Very good yield all around 90%, but limited scope

If R= O O H+, H2O

KOH N SMe

OH

N

26

The last 3+3 shown today was developped by Brandsma and coworkers in 2002. It uses

the reaction of lithiated allenes and alkynes with methoxymethyl isocyanate.

R

N SMe

Rn-BuLiTHF-hexane

MeOCH2N=C=SC

HR

orR Li

C

R

C

R

SLi

N

O

MeI

C

R

SMe

N

O

N

O

SMe

RN

SMe

R

ON SMe

R

n-BuLiTHF-hexane

MeOCH2N=C=S

rearr.heatH+ or heat

R= OMe, OCH(Me)OEt, SMe or Me

-MeOH

C

HR

or


Original laboratory preparation of pyridine by Ramsey in 1876 used this disconnection.

Passing acetylene gas along with hydrogen cyanide thru a red-hot tube afforded some pyridine.

Cobalt-catalysed [2+2+2] replaced this method.

G. D., Henry. Tetrahedron. 60 (2004) 60643-6061

HCN

N

red hot tube

N

27


H. Bonnemann. Angew. Chem. Int. Ed. Engl. 1985 (24) . 248-262

YCoL

+L -L

Y-Co

Y-Co

Y-Co

CoY

NRC

CR N

N R

Synthesis of substituted pyridines with complexes of type[YCoL]Y is the controling ligand, L is the neutral ligand.

N

28

Cobalt catalysed [2+2+2] have been extensively studied by Helmut Bonnemann.


The exchange of 65% of the L ligand for propyne was investigated versus the temperature. Modifying on the left the L ligand and on the right the Y ligand

H. Bonnemann. Angew. Chem. Int. Ed. Enyl. 1985 (24) . 248-262

N

29

YCoL2

YCo



YCoL

+L -L

Y-Co

Y-Co

Y-Co

CoY

NRC

CR N

N R

Synthesis of substituted pyridines with complexes of type[YCoL]Y is the controling ligand, L is the neutral ligand.

N

30

The alkynes seems to be attaching to the Cobalt faster than the nitrile.



This preference for the alkyne brings the problem of chemoselectivity.

Starting material readily available (two-atom fragment) Allows for large numbers of differentially substituted pyridines Atom economy Hard to separate large number of very similar molecules.

A solution is to take non-substituted alkynes like acetylene.

N

N

2

Et

YCoL

NN

N

2

Me

Me Et

Me

Me Et

Me

MeMe

Me

MeMe

YCoL

2,4,6-substitutedpyridine

2,3,6-substitutedpyridine

Benzene derivatives

N

31


C. Brandli ,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47

R1N XCoI catalyst

heat

R1

R1

[Co] R1 [Co]

R1

[Co]

R1

R1

N NR1

R1

X

R1

R1

X

3,5,6 3,4,6

N N

R1

R1 X

R1

R1 X2,4,6 2,5,6

only 2,4,6- and 2,5,6- isomers are observed

2R1

R2

CoI catalystheat

8 different products

N

R1

R1 X

N

R1

R1 X

N

R2

R2 X

N

R2

R2 X

N

R1

R2 X

N

R1

R2 X

N

R2

R1 X

N

R2

R1 X

4-homopyridines 4-heteropyridines

N

32

Addition of a Nitrile to the Three Possible Cobaltacyclopentadiene Intermediates Could Yield Four PyridineRegioisomers; Only the 2,4,6- and 2,5,6-Isomers Are Formed

Two Different Terminal Alkynes React with One Nitrile in the Presence of a Cobalt Catalyst To Afford EightDifferent Pyridine Derivatives



N

33

•2-vinylpyridine is an important constituent of latex.

•The 2+2+2 cobalt-catalyzed cycloaddition is a very effective route to it.

•The 2-vinylpyridine synthesis must be carried out below 130- 140"C, since acrylonitrile and 2-vinylpyridine undergo thermalpolymerisation.

N

acrylonitrileN

Heat

YCo(cod)



N

34

•The search for the best catalyst was then important.• The best results to date were obtained with the complex 30.

B

Co

Complex 30



N

35

•The outstanding position of this catalyst is apparently due to the fact that the catalytic vinylation reactions (32) and (33) are largely suppressed by it.• All other catalyst systems named in Table 9 cause the reactions of acrylonitrile and 2-vinylpyridine to give appreciable amounts of 55 and 56 or 57. •These activated olefins can compete with acetylene for cobalt coordination sites and they therefore act as catalyst poisons.

N N

57

(eq.33)

N

acrylonitrile

2

CNCN

55 56

(eq.32)

•Cobalt-catalysed sythesis of pyridine is very sensitive to conditions.•Once optimized, it is extremelly effective.

B

Co

Complex 30


C. Brandli ,T. R. Ward. J. Comb. Chem. 2000, 2, 42-47

N

36

•Medicinal chemistry still uses this method to screen great library of produts.

•In this image, Ward explains that 3920 pyridines were synthetized from these 14 alkynes mixed with these 10 nitriles.


Clearly, to overcome the problem of selectivity, the best approach is to fuse two of the reacting species together.

In this example from Carlos Saa some cyclo-fused pyridines are synthesised with good regio chemistry

J. A., Varela, C., Saa. Synlett. 2008(17). 2571-2578.

N

37

S C N

OC N

N C N

NC N

n

Bn

Bn

CO2Me

CO2Me

CpCo(CO)2 (15mol%)

Toluene, heat, hv28%

N

N

N

N

S

O

N

NBn

Bn

n

CpCo(CO)2 (15mol%)

Toluene, heat, hvn=1 24%n=2 48%

CpCo(CO)2 (15mol%)


CpCo(CO)2 (15mol%)


CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me


The team of Heller focuses on making different axially chiral pyridines using enantio-selective catalysts.

H.-J. Drexler, A. Spannenberg, B. Sundermann, C. Sundermann, A. Gutnov, B. Heller, C. Fischer. Angew. Chem. Int. Ed. 2004, 43, 3795 –3797

N

38


The best catalyst they investigated were the enantiomers 4 and 5


N

39


They believe that the enantio-selectivity comes from the intermediate cobaltacyclopentadiene shown on the bottom right that will then be attacked by the nitrile to form the pyridine ring.


N

40


The next disconnection is the [4+2].

The 4+2 disconnection have evolved greatly in recent years.

It includes Hetero Diels-Alder type of cyclisation

N

41


Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.

Boger and coworkers investigated in 1981 the use of 4+2 cycloadditions . They used triazine as the diene and a ketone transformed into an enamine as the

dienophile.

N

42

O

NR2

R3

N

R1

N

N

R2

R3

R1NH

N

NR2

R3

N

R1

NN

NN N

R2R3

R1

N

N

R1

R2

R3

-N2

O

NR2

R3

N

R1

N

NH

CHCl3N

R2

R3

R1


Boger, D. L.; Panek, J. s. J. Org. Chem. 1981, 46, 2179.

The scope of the reaction

N

43

O

O

O

O

O

O

O

O

O

HO

NN

N

NN

N

NN

N

NN

N

NN

N

N

NN

C2H5O2C

N

NN

N

NN

CO2C2H5

N

NN

CO2C2H5

N

N

N

N

N

N

N

N

N

CO2C2H5

CO2C2H5

CO2C2H5HO

52

86

93

66

36

19

43

CO2C2H5CO2C2H5

34

50

Yield%productdienedienophile Yield%productdienedienophile


Bondock, S. Heteroatom Chemistry. 2005 (16), 1, 49-55.

N

More recently, Bondock developed a new Diels-alder approach with 2,4-dimethyl-5-methoxyoxazole as the electron rich diene.

44

NO

MeOMe

Me

X

BenzeneN

O Me

X

N

XOMeO

Me

HN

MeOMeHO

Me XH

-MeOH N

Me

Me

OH

X



N

In this example he shows the Diels-Alder on acyclic dienophiles

N

O

Me

Me OMe

N

Me

Me CN

OHN

Me

Me CHO

OH

N

Me

Me CO2H

OH

N

Me

Me CO2Me

OHN

Me

Me

OH

N

Me

Me CHO

OH

N

Me

Me CO2Me

OH

N

Me

Me

OH

quant

quant

quant

quant

84%

65%

70%

65%

CO2tBu

Me

CO2Me

OH

OH

CH2OH

CH2OH

CN

CHO

CO2Me

CO2H

CO2tBu

CHO

CO2Me

CO2Me

45



N

Other cyclic pyridine derivatives.

46

N

O

Me

Me OMe

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

N

Me

Me

OH

92%

90%

92%

quant

85%

87%

N

N

O

N

N

N

quant

70%

O

OO

O

O

O

O

OO

O

O

O

O

O

O

O

Me

CO2H

CHO2H

Me

Me

HO2C N

O

O

HO2C

N

O

O Me

O

O

O

O

N

O

O

CO2H

Me

N

O

O

CO2H

N

O

O

Me

O

O

OMaleicanhydride

Maleimide


An other [4+2]; Involving a hetero-Diels-Alder reaction using isotellurazoles with acetylenic dienophiles has been investigated by Thompson.

Guo. K, M. J. Thompson, B. Chen. J. Org. Chem. 2009, 74, 6999-7006

NX

R2

R1

EWG

R3

-X N R3R1

EWG

R2

NTe

R2

R1

Path A

[4+2]N

R2X

R3R1

EWG

NTe

R2

R1R3

EWG

NTe

R2

R3

EWG

R1

-Te

Path B

NR1 R3

R2

EWGR3

EWG

Plausible pathways for the formation of polysubstituted pyridines involving a concerted or stepwise isotellurazole with acetylenic dienophiles

N

47


Scope of the reaction

Yukichi, T. Yu, O. Akiko, M.-O., Hisashi, K., Maiko, S., Shigenobu, A., Yuji, T., Satoshi, O. Tetrahedron letters 2009 (50), 6651-6653.

NR1 R3

R2

EWG

N

48


Hill, D. M., Ahmad, O. K. Movassaghi, M. J. Am. Chem. Soc. 2007, 129, 10096-10097.

N

Mohammad Movassaghi published his findings in the synthesis of pyridines in 2007 using also a [4+2] type of disconnection.

‘The recognition of the unique electrophilic activation of amides with trifluoromethanesulfonic anhydride (Tf2O) in the presence of 2-chloropyridine (2-ClPyr) as the base additive made possible the development of this methodology’

Rb

HNRc

ORc

1

Rd

Re

2

or

OR

Rd

Re

3

Tf2O

2-ClPyr

N

Rb

Rc

Rd

ReRa

49



N

Based on mechanistic findings in previous research, they proposed this single step pyridine synthesis mechanism for the alkyne nucephile.

next they examined the direct condensation of enol ethers withv N-vinyl and N-aryl amides

Rb

HNRc

ORc

1

N

NRa

Cl

RcRb

H

TfO-

TfO-

-2ClPyr-TfOH

N

Ra

RcRb

Re

CRd

TfO- -TfOHN

Rb

Rc

Rd

ReRa

5

2

64

Tf2O

2-ClPyr

50

Rb

HNRc

ORc

1

N

NRa

Cl

RcRb

H

TfO-

TfO-

-2ClPyr-TfOH

N

Ra

RcRb

Re

TfO-

N

Rb

Rc

Rd

ReRa

5

3

74

Tf2O

2-ClPyr

OR

Rd

HN

Ra

RcRb

Re

TfO-

OR

Rd

N

Rb

Rc

Rd

ReRa

OR-ROH-TfOH



N

The example shown below highlights the greater efficiency of this chemistry when nucleophilic acetylenes are employed in place of enol derivatives.

51

Ph

HN

OS

N

S

OSiPh3

91%

N

Ph

OO

57%

Ph

N

S

Ph

N O

O

HN

O

Me

Me Ph

N

O

N

N

PhMe

Me

OTf2O, 2-Clpyr

CH2Cl2-78-23oC

67%94%ee 94%ee


Hill, D. M., Ahmad, O. J. Am. Chem. Soc. 2007, 129, 10096-10097.

N

The scope of the reaction....

52

Rb

HNRc

ORc

1

Rd

Re

2

or

OR

Rd

Re

3

Tf2O (1.1 equiv)2-ClPyr (1.2 equiv)

CH2Cl2 -78-0oC

N

Rb

Rc

Rd

ReRa

1 equiv 1.1 equiv 2.0 equiv4

Amide:

1b, Ra = cHx, Rb=Me, Rc=Me

1f, Ra = cN(CH2CH2)2O, Rb=CCH, Rc=Ph

1j, Ra =Ph, Rb=CCH, Rc=Ph

1c, Ra = cHx, Rb=CCH, Rc=3,5-(OMe)2Ph

1g, Ra = cHx, Rb=CCH, Rc=4-CO2MePh

1k, Ra =Ph, Rb=(CH2)4, Rc=(CH2)4

1d, Ra = Ph, Rb=CCH, Rc=3-DHP

1h, Ra = Ph, Rb=CCH, Rc=3-thienyl

1l, Ra = 2-thienyl, Rb=CCH, Rc=3-Thienyl

1e, Ra = sBu, Rb=(CH2)4, Rc=(CH2)4

1i, Ra = cHx, Rb=CCH, Rc=4-NO2Ph

OEt OSiiPr3

nBu

OSiiPr3

PhN

Ph

N

Me3SiRe

OO O OMe

2f, R=H2g,R=Me

OR OSiMe3

Rd

3a, R=Et3d, R=SiPh3

3c, Rd=Me3d, Rd=Ph

OR

n

3e, R=SiMe3, n= 13f, R=SiMe3, n= 23g R= SitBuMe2 n= 1

R

R1

3h, R=OSitBuMe2, R1=H

3i R=H, R1=OSitBuMe2

2a 2b 2c 2d 2e

Ncleophile:


Hill, D. M., Ahmad, O. J. Am. Chem. Soc. 2007, 129, 10096-10097.

N

The scope of the reaction....

53

N

Me

Me

OEtH

4a, 83%, A(1b+2a)

N

Rd

ReH

4

NO

OSiiPr3nBu

Ph

4

N

OSiiPr3nBu

BuS

4

N

OSiPr3

Ph

H

4

N

Me

Me

N

Ph

H

4

N

N

Ph

sBu

4

OMe

OMe

O O

O O

4b,68%, A(1c+2a) 4c,61%, A(1d+2b) 4d, 73%, A(1e+2b) 4e, 74%, A(1c+2c) 4f, 80%, A(1b+2d) 4g, 77%, A(1e+2d)

N

N

Ph

N O

O

O

N

N

Ph

H

4O

O

N

N

Ph

H

4O

O

N

Me

Me

N

SiMe3

H

4

N

N

SiMe3

Ph

4

N

Ph

4

N

ReH

4

OMe

OMe

CO2Me

O

S

O

S

OMe

NO2

OMe

4h, 68%, A(1f+2d) 4i, 79%, A(1c+2d) 4j, 86%, A(1g+2d) 4k, 84%, A(1b+2e) 4l, 70%, A(1h+2e) 4m, 62%, A(1h+2f) 4n,Re= 84%, A(1i+2g)4o,Re=H, 42%, A(1i+2f)

N

Rd

ReH

OMe

OMe 4p, Rd=H, Re=H, 97%, A(1c+3a)g

4q, Rd=Me, Re=H, 55%, A(1c+3c)4r, Rd=Ph, Re=H, 61%, B(1c+3e)4s, Rd=Re=(CH2)3, 50%, B(1c+3e)4s, Rd=Re=(CH2)4, 61%, B(1c+3f)c

N

Ph

4u, 74%, A(1j+3a) 62%, A(1j+3a)g N

Ph

4v, 69%, C(1k+3b)c

N

H

N

H

4bb, 66%, C(1a+3i)h 4cc, 78%, C(1a+3i)h

N

Ra

S 4w, Ra=Ph, 75%, C(1h+3b)i

4x, Ra= 71%, C(1l+3b)cSN

H

R

4y, R=OMe, 77%, C(1a+3g)h

4z, =CO2Me, 47%, C(1g+3g)c,h

4aa, R=NO2, 30%, C(1i+3g)c,h

Product


This 4+2 approach was developed by Lenoir.

Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641.

This disconnection, was Reported By Smith and Lenoir in 2000 and is an innovative radical annulation reaction of vinyl isonitriles and iodoalkynes to give the cyclopenta-fused pyridines

N

54

INC

R

R1

NR

R1 N R

R1

N

R1

R N

R

R1Bu3SnSnBu3

hv, tBuC6H5

a b


Lenoir, I.; Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641.

Other types of heterocycles may be achieve.

N

55

NC I

N

NC

Ph

2aN

Ph

NC

2a

N

NC

I

N

N

Ph

1a

1b

1a

2b

I

N N

N

iIsonitrile Alkyne or nitrile Pyrine Yield (%)

1a

1b

1c

1d

2a 2b

2c

6g = 7g

6f

6e

6c = 7c

N

6d

6b

6a

66%

20%

23%

46%

35%

66%

72%


NH3-2H2O

ORR'

ONH

R' RN

[-2H]

R' R

N

Analogous to Hantzsch’s synthesis. Pros The [5+1] approach is a simple and reliable route to 2,6-

disubstituted pyridines when the starting material is available.

Cons 1,4-dihydropyridine intermediate isolated. Method depends on the availability of 1,5 di-carbonyl compounds

56


Chubb, R. W. J.; Bryce, M. R.; Tarbit, B. J. Chem. Soc., Perkin Trans. 1 2001, 16, 1853.

R = H 18%R = Me 25%

R = H 37%R = Me 27%

R = H 35%R = Me 21%

27%

N

OH

R

N

N

OH

R

N

N

OH

R

N

N

OH

NN

OH

N

Br

26%

N

OH

N

OH

O

NN

OH

NH

N

OH

N

N

17%

26% 12%

20%

OR

O

Het

NR Het

OHNH3 liq110-150oCsealed tube5h

N

57


Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem. 1999, 64, 6076.

NH2NC

N

CN

NMe2

N

N N

NH2

NMe2

NC

Cl-

Cl-

NH2NC

NMe2

NN

N

Cl-

NH

NMe2

NC

Cl-

NH2

NMe2

NC

Cl-

N

NMe2

NCNaOH

H

R1

O

R2

NC

NH2

TiCl4, NEt3CH2Cl2, rt. 24h NH2

R1

NC

R2

N

N

N NCH2Cl2, rt. 24h

2N NaOH

N

CNR1

R2

N

58


Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem. 1999, 64, 6076.

N

CN

N

CN

N

CN

N

CN

N

CN

N

CN

N

CN

68 74 687260

75 57

N

CN

N

CN

N

CN

N

CN

N

CN

N

CN

O

56 50 60

55

70

50

R1

O

R2

NC

NH2

TiCl4, NEt3CH2Cl2, rt. 24h NH2

R1

NC

R2

N

N

N NCH2Cl2, rt. 24h

2N NaOH

N

CNR1

R2

N

59


The next and last method seen today is the new 6+0 disconnection by Beauchemin, last July.

T. Rizk, E. J.-F. Bilodeau,A.M. Beauchemin.Angew. Chem. Int. Ed. 2009, 48, 8325 –8327

N

60

N

OH

acid (equiv)

iPrOHtemp, 5h (MW)

N2a

1a

N

O

3

N

OH

N

O

N

OH

H

N2a

base

Proposed mechanism:


Once the optimal conditions established they did a screening to establish a scope


N

61

N

OH

acid (equiv)

iPrOHtemp, 5h (MW)

N2a

1a

N

O

3


Once the optimal conditions established they did a screening to establish a scope


N

62

N

OH

TsOH (2mol%)

iPrOH160-180oC, 5-8h (MW)

N

2a-m1a-o

R2

R1

R2

R1

R3

Conclusion63

N

R

O

R

OR

Me Me

Hantzsch

N

NC CN

SRH2N

R

Hantzsch

NR R

3+2+1

NR

R

R

3+2+1

2+2+2

N

R

R

3+2+1

N

R

R Me

EtO2C

3+2+1

N

OH

OMe

R*R*

3+2+1N R

R

R

R3+3

NNR

R

R

Ph

3+3

N SR

OR

3+3

N RR

R

2+2+2N R

2+2+2 NR

R

2+2+2

N

O

2+2+2

N

R

4+2

N

R

R

4+2N Me

CO2R

OHR

R

4+2NR

R

R

R

R4+2

4+2

N

OH

Ar5+1

N

CN

R

R

5+1R

6+0

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PRESENTED BY PHILIPPE BOLDUC COLLINS GROUP UNIVERSITÉ DE MONTREAL FEBRUARY 2 ND 2010 The Synthesis...

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