Oana Genoveva Schramm

Organisch-Chemisches Institut, Heidelberg, Germany

Chalcones via Coupling-Isomerization Reaction (CIR) as An Entry to Multicomponent Heterocycle Syntheses

Oana Genoveva Schramm

10.10.2006

Outline

Introduction to Coupling-Isomerization Reaction (CIR) Microwave Assisted CIR (MACIR) Towards a General CIR

One-Pot Quinolines Synthesis A direct Application of MACIR

One-Pot Synthesis Based upon CIR under Conventional Heating One-Pot Synthesis Based upon CIR under Microwave Irradiation One-Pot Synthesis of Fluorescent Annelated Pyridines Conclusion

Introduction to Coupling-Isomerization Reaction (CIR)

EWG-Ar

OH

2 % (Ph3P)2PdCl2 1 % CuI, base

EWG-Ar

OH
1

Hal

+ R
2

Sonogashira Coupling

Optimization of CIR under Microwave Irradiation. General Idea Goals:

Drawbacks of the CIR conditions:
long reaction time (16-24 h) reduce the reaction time large excess of base reduce the amount of base Heterocycles demand for a reactive, generalize the coupling partner to electron deficient aryl halide - electron deficient aryl halides - electron neutral aryl halides - electron rich aryl halides

Isomerization

base

O EWG-Ar
1

Chalcone

Michael acceptor

T. J. J. Mller, M. Ansorge, D. Aktah, Angew. Chem. Int. Ed. 2000, 39, 1253.
For microwave assisted Sonogashira coupling, see e. g. M. Erdelyi, A. Gogoll, J. Org. Chem. 2001, 66, 4165.

Microwave Assisted CIR (MACIR) Towards a General CIR

Electron deficient aryl halydes as coupling partner
2 % (Ph3P)2PdCl2 1 % CuI NC Ph Ph O OH + NC Ph

OH NC Br +

oil bath, 80 C, NEt , 16 h

3

0%

95 %

microwave, 150 C, THF 5 equiv of NEt3 , 15 min

0%

96 %

oil bath, 150 C, THF 5 equiv of NEt3 , 15 min

12 %

61 %

Oana G. Schramm ne Dediu, Thomas J. J. Mller Adv. Synth. Catal. 2006, accepted.

Microwave Assisted CIR (MACIR) Towards a General CIR

Electron neutral aryl halydes as coupling partner
OH 2 % (Ph3P)2PdCl2 1 % CuI OH O

Entry 5

+Base Ph

Conditions
THF, Base conditions

Propargyl + Ph alcohol 0% Propargyl alcohol 0% 80 % 9% Propargyl alcohol 70 % 0% 0% 0%

Chalcone
Ph

DBU (2 equiv)

microwave, 100 C, 30 min

92 %

Entry
1 2

Base
NEt3 (5 equiv)

Conditions
microwave, 100 C, 30 min microwave, 100 C, 30 min microwave, 150 C, 30 min Conditions microwave, 100 C, 60 min microwave, 120 C, 30 min microwave, 100 C, 30 min oil bath, 100 C, 30 min

Chalcone
35 % 0% 0% Chalcone 8% 73-92 % 92 % 71 %

Electron rich aryl halydes as coupling partner

piperidine (5 equiv) piperidine (5 equiv) Base DBU (1.05 equiv) DBU (2 equiv) DBU (2 equiv) DBU (2 equiv) 3 Entry 4 1-3 5 6

Microwave Assisted CIR (MACIR) Towards a General CIR

Electron deficient aryl halydes as coupling partner
O N NC N
96 %
N F3 C

Electron neutral aryl halydes as coupling partner

Electron rich aryl halydes as coupling partner

O
O

95 % O

84 % 91 %

92 % (microwave) 0 % (oil bath, 80 C, 16 h)

78 %
EtO2C

92 %

0%

79 %

O H2NO2S

75 % 65 %

H2N

62 %

59 %

62 % 31 %

O NC S NC

S
87 % O 70 % -

reduced reaction times 15-30 minutes reduced amount of base 2-5 equiv

73 %

0%

O O

O
85 % 0%

N NC S
77 % 62 % -

Oana G. Schramm ne Dediu, Thomas J. J. Mller Adv. Synth. Catal. 2006, accepted.

One-Pot Quinolines Synthesis A direct Application of MACIR

O R OH R R NH2
microwave, 120-150 C, 30 minutes
2

R NH2

Hal R NH2
+

OH R
2

2 % (Ph3P)2PdCl2 1 % CuI, 2 equiv of DBU

R O NH2

naturally occuring quinolines

NC N N N NC N
57 %

- H2O

I H2N

81 %

I +
F3C

S OH 80 % 2 % (Ph3P)2PdCl2% 70 1 % CuI, 3 equiv of DBU N N

microwave, N N N120-150 C, 30 minutes 92 % 79 %

N
40 %

NH2

N
N
64 % 78 %

R N R
2

One-Pot Synthesis Based upon CIR under conductive Heating

Four-Component, One-Pot Synthesis of Pyridines N N
N

CN

EtO2C
N
N 65 %

N N
EtO2C N N Ar61 %
CF3

N 64 % 1

OH Hal + Ar
2

1. 2% PdCl2(Ph3P)2, 57 % 1% CuI, NEt3, O

O

R R

Ar

Ar

69 %

CN

(Het)Aryl OH (Het)Aryl EWG 2. + Hal O O EWG EWGO + NH4N Cl, N O CH (Het)Aryl [(Ph3P)2PdCl2, CuI] COOH + H (Het)Aryl (Het)Aryl R' EWG EWG N H O N 3O R' R NEt3, THF, R R' R 1

EtO 39 - 69 % 2C

N N 58 %

R
N N

2
CN
N EtO2C N N 41 %

N MeO 49 %
MeO 39 % N

3. NH4Cl acetic acid,

N S 40 %

O. G. Dediu, N. A. M. Yehia, K. Polborn, T. Oeser, T. J. J. Mller, Eur. J. Org. Chem. 2005, 1834.

One-Pot Synthesis Based upon CIR

Mechanistic rationale
O N

(Het)Aryl EWG O

n =1,2

hydrolytic work-up
n

EWG O (Het)Aryl O

O N

path a)
n

EWG O
n

H2O/H+ (Het)Aryl

n =1,2 Michael

addition or [4+2] path b)

N O (Het)Aryl EWG H O N
n

O. G. Dediu, N. A. M. Yehia, K. Polborn, T. Oeser, T. J. J. Mller, Eur. J. Org. Chem. 2005, 1834.

One-Pot Synthesis Based upon CIR under conductive Heating

Three-Component, One-Pot Synthesis of Dihydroyridines
EtO2C N H
EtO2C H 2% PdCl2(Ph3P)2, 1% CuI 1. 37 NEt3 or HNEt2, % N

CN

CF3

CN

EtO2C

Ar EtO2C N

N 40 %

Ar

45 % OH

Ar

Hal

+ Ar

OH O H + NH2 O EWG Hal OEt O 2. (Het)Aryl - 45 % (Het)Aryl EWG 37 [(Ph3P) PdCl2, CuI] (Het)Aryl EWG , 2 R H3C acetic acid, NEtunder 2 N 3, THF, CH3CO2H

NH2 O

EtO2C or Cyclocondensation Ph under aerobic N conditions

Ph

26 - 50 %

N EtO2C N
EtO2C
50 % EtO2C

N
N

26 %

26 %

O. G. Dediu, N. A. M. Yehia, K. Polborn, T. Oeser, T. J. J. Mller, Eur. J. Org. Chem. 2005, 1834.

One-Pot Synthesis Based upon CIR under Microwave Irradiation

Three-Component, One-Pot Syntheses
Ar
2

O R
1

NHR

Ar

R =Alkyl Ar
1

NHR

Hal PdCl2(PPh3)2, CuI O Ar

1

MW, 10 min. CH3COOH

2

12 examples 30-74 %

+ OH Ar
2

MW, 15 min.

Ar

MW, 10 min. CH3COOH O R

1

NHR

Ar Ar
1

hydrolysis R =NMe 2
1

Ar Ar
1

NHR

9 examples 48-70 %

O. G. Schramm ne Dediu, T. J. J. Mller, Synlett. 2006, 1841.

One-Pot Synthesis Based upon CIR

under Microwave Irradiation
Mechanistic rationale
(Het)Aryl EWG O

R' H3C

NH

O R R

EWG

CH3CO2H Microwave (150 C, 10 min)

R' N H

(Het)Aryl

R' H 3C

NH

O R

Acid catalyzed Aldol condensation -H2O

(Het)Aryl EWG O O N R' H3C H R

[H+]

(Het)Aryl EWG O R O CH2 N H R'

O. G. Schramm ne Dediu, T. J. J. Mller, Synlett. 2006, 1841.

One-Pot Synthesis of Fluorescent Annelated Pyridines under Conventional Heating

n = 1, 2, 3
Tos
2

HN Ar
1

2 % PdCl2(PPh3)2, 1 % CuI

H3CS
N Tos Ar
2

N CH3

Ar

Hal

+ Ar

THF/NEt3,

Ar

Ar

N n CH3

CN N N N

CN n = 1, 2, 3

CN

H3CS
N CH3 N CH3

N CH3

aromatization by twofold elimination

Ar
1

H
N O N CH3

N MeO

64 %

N CH3 MeO

N MeO

Ar

66 %

49 %

MeO [4+2]-Cycloaddition CN

31

N n N N CH3 % SMe CH3 Ts

43 %
CN

N MeO

N CH3

N MeO

N CH3 O

N CH3

N MeO

N CH3 MeO

N CH3

48 %

56 %

43 %

52 %

52 %

O. G. Schramm ne Dediu, T. Oeser, T. J. J. Mller, J. Org.Chem. 2006, 71 (9), 1841.

One-Pot Synthesis of Fluorescent Annelated Pyridines under Conventional Heating

Absorption 338- 392 nm

Emission 438-518 nm

Quantum yield 12-63 %

4200- 9600 cm-1

Fluorescence color green to blue

CN N N

CN

CN

N MeO

N CH3

N MeO

N CH3 O

N CH3

N O

N CH3

Conclusions

new efficient one-pot synthese of various heterocycles - quinolines (naturally occuring quinolines) - tri- and tetrasubstituted pyridines - 2-amino annelated pyridines

generalized CIR by the use of microwave irradiation

Acknowledgments

Prof. Thomas J. J. Mller

Research Assistants: Anette Loos and Birgit Thaler

X-Ray: Dr. Frank Rominger and Dr. Thomas Oeser Financial Support: The Morphochem AG and Deutsche Forschung Gesellschaft