General Microwave-assisted Procedures for the …...1 General Microwave-assisted Procedures for the Expedient Synthesis of Substituted Heterocycles M. Brad Nolt Technology Enabled

1

General Microwave-assisted Procedures for the Expedient

Synthesis of Substituted Heterocycles

M. Brad Nolt

Technology Enabled Synthesis Group, Department of Medicinal Chemistry, Merck Research Laboratories

(West Point), Merck & Co., Inc.

October 19, 2006

2

•Merck’s Technology Enabled Synthesis (TES) Group and Microwave Reactors in Organic Synthesis

•Triazines

•Canthines

•Imidazoles

•Quinoxalines and Fused Heterocyclic Pyrazines

•Quinoxalones

•5-Aminooxazoles

Contents

3

•The TES group specializes in rapid lead discovery

•Focus is on analog library synthesis

•Rapidly developing programs and external competition are challenges that drive our efforts to maximize efficiency

•Assisted by four single-mode microwave reactors and automated mass-guided purification

Technology Enabled Synthesis Group

4

•Approximately 96% of all reactions requiring heating are conducted in the microwave reactor

•Advantages of microwave heating are shorter reaction times, diminution of side products, and increased yields

•Organic synthesis procedures using microwave heating are often scaleable

TES and Microwave Reactors

5

Heterocycle Formation

HN

N

O

R1

R2

R1

O

O

R2

N

NNR1

R2 R3

N

HNR1

R2

R3

N

N

N

N

R1

R2

R1

R2

Het

R3

O

OR1

EtO

triazines

imidazoles

quinoxalines

pyrazines

quinoxalinones

N

O OR1

OOH

R2

N

O NR3R4

O

OR1

R2

aminooxazoles

(1)

(2)

(3)HN

RO2C CO2R

O

R

6

Triazines

N

NN

N

NNR1

R2 Het (R3)

1

26

5 3

4

•The triazine ring system is a key component in commercial dyes, herbicides, insecticides and pharmaceutical compositions

•The 1,2,4-triazine core structure is valuable for accessing a variety of ring systems via an intramolecular Diels-Alder reaction

Generic and target 3-heterocyclic-1,2,4-triazines

Shipe, W. D.; Yang, F.; Zhao, Z.; Wolkenberg, S. E.; Nolt, M. B.; Lindsley, C. W. Heterocycles, in press.

7

Triazine Synthesis

O

NH

+ N

NNPh

Ph

HN

N

NH4OAc(10 equiv.)

AcOH

180°C, MWI5 min

N

HN

1

2

385% yield

H2N

Ph

O

O

Ph

R3O

NH

+ N

NNR1

R2 R3

NH4OAc(excess)

AcOHreflux, 6-24 hH2N

R1

O

O

R2

(1)

(2)

• Conventional heating with heterocyclic diketones or heterocyclic acylhydrazides produced the target material in <30% yield with multiple side products

• Optimization of microwave heating conditions led to the synthesis of previously unknown 3

Zhao, Z.; Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.; Lindsley, C. W. Tetrahedron Lett. 2003, 44, 1123-1127.

8

Triazine Synthesis – Scope of acyl hydrazides

aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.

PhPh

O

OR N

HNH2

O

+

NH4OAc (10 equiv.)AcOH

180°C, MWI5 min

N

NNPh

Ph R

entry RCONHNH2 product yield (%)a

1

2

3

4

5

84

80

92

90

81

NH

NH2

O

O

NN

NNPh

PhN

O

NH

NH2

O

NN N

NNPh

Ph NN

NH

NH2

O

S

NN

NNPh

Ph

N

S

NH

NH2

O

N

NNPh

Ph

NH

NH2

O

N

NNPh

Ph

NN

N N

O O

1

9

Triazines – Scope of diketones

R1R2

O

ONH

NH2

O

+


180°C, 5 min N

NNR1

R2

entry R1COCOR2 product yield (%)a

1

2

3

4

92

N

NN

N

O

O

NN

O

N

NN

N

O

N

NNPh

N

O

N

NNPh

N

O

NN

O

O

O

O

O

O

O

OPh

O

OPh

NN

O

O

64 (75)b,c

69 (80)b,c

90

MWI

aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS. bYields when reaction times extended to 10 min. c1:1 mixture of regioisomers

10

Canthines

NN

12

A B C

D46

8

11

Canthine Tetracyclic Skeleton

• First isolated from Pentaceras australis in 1952

• Canthines are a tetracyclic subclass of β-carboline alkaloids that possess an additional D-ring

• Members of this family have exhibited a wide range of pharmacological activities including antifungal, antiviral, and antitumor properties

Ohmoto, T.; Koike, K. The Alkaloids; Brossi, A. Ed; Academic Press: New York, NY, 1989, Vol. 63, pp 135-170.

11

Conventional Canthine Preparation

Benson, S. C.; Li, J.-H.; Snyder, J. K. J. Org. Chem. 1992, 57, 5285-5287.

• Despite the development of this straightforward protocol, limited diversity has existed at the C1 and C2 positions of synthethetic canthines

N

R1R2

O

O

NH4OAc (excess)AcOH, reflux

6-24 h

CONHNH2

N

(55-62%)4 6

5

triisopropylbenzene

reflux, 1.5 to 20 hN

N

R1

R2

7(72-93%)

R1, R2 = H, CH3, CO2Et

R1 = Ph, R2 = H

NN

N

R1

R2

12

Microwave-assisted Canthine Synthesis

Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron Lett. 2003, 44, 4495-4498.

Lindsley, C. W.; Bogusky, M. J.; Leister, W. H.; McClain, R. T.; Robinson, R. G.; Barnett, S. F.; Defeo-Jones, D.; Ross, C. W.; Hartman, G. D. Tetrahedron Lett. 2005, 46, 2779-2782.

entry time (min) temp (°C) 6 : 7a

1

2

3

4

5

6

7

5

10

20

40

60

40

40

180

180

180

180

180

200

220

9 : 1

7 : 3

2 : 1

1 : 1

1 : 2

1 : 5

1 : 19

PhPh

O

O

NH4OAc (excess)AcOH

temp, time

NN

PhPhN

NN

N

PhPh

:N CONHNH2

Optimization of Microwave Procedure

Ratios determined by analytical LCMS.

• 10 to 700-fold reduction in reaction times

• This procedure lead to the synthesis of unnatural canthines that inhibit Akt

13

Canthines

NN

NN N

N

N

N

CO2Et

CO2Et

F

F

NN

NN

NN

O

O

Me

Me

NN

Ph

NN

PhMe

Me

8 (81%) 9 (83%) 10 (59%) 11 (62%)

12 (34%) 13 (26%) 14a 14b

(1:1)

(62%)

Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron Lett. 2003, 44, 4495-4498.

14

Imidazoles

N

HN1

2

3

4

5

N

HN

R1

R3

R2

Generic and target imidazoles

• Imidazoles are components of many natural products, dyes, herbicides, fungicides, catalysts, and pharmaceutical compounds

• Synthetic route via the formamidesynthesis uses glyoxal, formaldehyde and ammonia, and heating for four to six hours

(a) Grimmett, M. R. Comprehensive Heterocyclic Chemistry; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, pp 457-498. (b) Grimmett, M. R. Comprehensive Heterocyclic Chemistry II; Katrizky, A. R.; Rees, C. W.; Scriven , W. F. V., Eds.; Pergamon: New York, 1996; Vol. 3, p 77.

15

Imidazoles

O

O

Ph

Ph

O

H Ph N

HNPh

Ph

Phconditions

entry temp (°C) conversion (%)a

1 242 513 6145 87

98

time (min)6080

100120140160

555555

68

67 718 829 95

160160160

0.513

1 17 18

Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.


• Ultimately, heating at 180°C for five minutes provided nearly complete conversion to 18

Reactions run in acetic acid with 0.2 mmol each of 1, 17 and 10 equiv. of NH4OAc.aRatios determined by analytical LCMS, isolated yield for entry 6, 88%

16Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.

Imidazoles – aldehyde variations

O

O

Ph

Ph

O

H R N

HNPh

Ph

R


180 °C, 5 min

entry product yield (%)a

N

HNPh

Ph

F1 97

N

HNPh

Ph

CN2 88

N

HNPh

Ph

OMe3 87

4N

HNPh

Ph

93O

MWI1

• The procedure is successful with electron withdrawing and donating substitution on the aldehyde

aIsolated yields for analytically pure compounds after neutralization andfiltration

17Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.

Imidazoles – diketone variations

O

O

R1

R2

O

H Ph N

HNR1

R2

Ph


180 °C, 5 minMWI17


N

HN

1 89

O

O

N

HN

2 95

MeO2C

MeO2C

N

HN

3 99

MeO

MeO

N

HN

4 94

Me

Me

N

HN

5 94

Me

Me

N

HN

Me6 93

Me


aIsolated yields for analytically pure compounds obtained after neutralization of the reaction mixture then filtration

18

O

O

Me

Me

O

H Me N

HNMe

Me

MeAcOH

180 °C, 5 min

NH4OAc

76%

N

NMe

Me

Me

Ph

Ph

Cl-

BnCl,CH3CN

5 minMWI

lepidiline B

MWI

+

N

HNPh

Ph

AcOH

180 °C, 5 min

NH4OAc

99%O NMe2

OHC

O NMe2

Ph

Ph

O

O

trifenagrel

MWI

+

Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.

Cui, B.; Zheng, B. L.; He, K.; Zheng, Q. Y. J. Nat. Prod. 2003, 66, 1101.

Abrahams, S. L.; Hazen, R. J.; Batson, A. G.; Phillips, A. P. J. Pharmacol. Exp. Ther. 1989, 249, 359.

Imidazoles

•Natural product isolated from the roots of L. meyenii

•Micromolar cyctotoxicity against several human cancer cell lines

•Potent 2,4,5-triaryl imidazolearachidonate cyclooxygenaseinhibitor

•Existing procedure requires two hours of reflux

19

Quinoxaline and Fused HeterocyclicPyrazines

N

N

N

NR1

R2

R3

1

3

7

6

2N

NR1

R2

Het

Generic and target quinoxaline and fused heterocyclic pyrazines

•Quinoxalines have demonstrated pharmaceutical value as antiviral agents, antibiotics, and kinase inhibitors

•The most common synthetic route requires the condensation of an aryl 1,2-diamine with a 1,2-dicarbonyl compound by refluxing in ethanol or acetic acid for two to 12 hours

20

Quinoxaline

Ph

Ph O

O

H2N

H2N+

N

NPh

Ph

1 19 20

entry conditions yield

1

2

EtOH/AcOH, reflux, 2-12 hr

9:1 MeOH/AcOH, 160 °C (MWI), 5 min

34-85

99

conditions

•Optimal conditions give nearly complete conversion to product 20

•This general procedure gives quinoxalines in high yields with tolerance for variations of the 1,2-diketone and 1,2-diamine

Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.

21

Quinoxaline – 1,2-diamine variations

Ph

Ph O

O

H2N

H2NR+

9:1 MeOH/AcOHR

N

NPh

Ph


1

2

3

4

N

NPh

Ph

N

NPh

Ph

N

NPh

Ph

N

NPh

Ph

NH2

OMe

Cl

CO2CH3

99

97

96

98

160 °C, 5 minMWI

1

N

NPh

Ph

N

NPh

Ph

N

NPh

Ph

N

NPh

Ph

N

NH

F

NH

N

CN

5

6

7

8


99

99

95

95



22

Quinoxaline – 1,2-diketone variations


9:1 MeOH/AcOH

160 °C, 5 minMWIR2

R1 O

O

H2N

H2NR3+ R3

N

NR1

R2


1

2

3

N

N

N

N

N

N

Ph

N

N

NH2

Cl

N

NH

NNH

NN

O

O

NN

N

N CO2CH3O

O

98

95

99

N

NPhN

NH

N

N

96

95

83

4

5

6



23

R2

R1 O

O

H2N

H2N+

N

NR1

R2


1

2

3

97

94

92

NN

N

NN

NNN

NN

NO

O

N N

9:1 MeOH/AcOH

160 °C, 5 minMWI21

Pyrido[2,3-b]pyrazines



24

R2

R1 O

O

H2N

H2N

+N

NR1

R2


1

2

3

74

77

69

N

N

N

NNN

N

NO

O

S S

S

S

S

F

F

9:1 MeOH/AcOH

60 °C, 5 minMWI

22

Thieno[3,4-b]pyrazines



25

Quinoxalinones

HN

N

O

R1

R2

HN

N

O

3 6

71

Generic and target quinoxalinones

•Although infrequently found in nature, the core structure of quinoxalinones is contained in biologically active structures with antifungal, antimicrobial, and analgesic activities

•Fernández et al. have carried out aqueous cyclocondensations of ethyl pyruvate and 1,2-diaminobenzene catalyzed by strong acids, classically called the Hinsberg reaction

Carta, A.; Sanna, P.; Loriga, M.; Setzu, M. G.; La Colla, P.; Savelli, F. Farmaco 2002, 57, 19-25.

Abasolo, M. I.; Gaozza, C. H.; Fernández, B. M. J. Heterocyclic Chem. 1987, 29, 129-133.

26

Quinoxalinones

O OEt

O+

H2N

H2N

10% aq. HClHN

N

O

5 min, MWI

23 19 24

entry temperature conversion (%)a

1

2

3

84

90

97

60

100

125


aConversion determined by LCMS

•With prototypical substrate 23, conversion to product was nearly quantitative with heating at 125°C for five minutes

Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work

27

Quinoxalinones

aDetermined by LCMS. bIsolated as a 3:1 mixture of regioisomers (major isomer shown)

O OEt

O+

H2N

H2N

10% aq. HClHN

N

O

5 min, 125 °CMWI

23

entry product conversion (%)a

1

2

3

4

87

96

100

90

R R

HN

N

O

HN

N

O

HN

N

O

Cl

HN

N

O OMe

HN

N

O F

HN

N

O NO2

b

HN

N

O COOMe

5

6

7

91

51

26


b


28

entry time temperature conversion (%)a

DMF, cat. AcOH

MWI

O OEt

O+

H2N

H2N

HN

N

O

23 19 24

1

2

3

4

5

6

7

5

10

20

5

5

15

5

160

160

160

170

180

180

190

1

2

2

100

100

100

100

Quinoxalinones

Re-optimization of Microwave Procedure

•The re-optimized procedure improved the conversion to target material and also proved to be general with electron-deficient aryl 1,2-diamines



29

Quinoxalinones – scope of 1,2-diamine


1

2

3

4

82

80

100

89

O OEt

O

+H2N

H2N

DMF, cat. AcOH

5 min, 180 °CMWI

R

HN

NR

O

25

HN

N

O

HN

N

O

HN

N

O Cl

Cl

HN

N

O

Cl

HN

N

O

COOMe

HN

N

O

NO2


91

89

5

6



30

Quinoxalinones – scope of α-ketoester

aDetermined by LCMS.



1

2

3

82

100

95

O OEt

OR

+H2N

H2N

DMF, cat. AcOH

5 min, 180 °CMWI

HN

N

O

R19

HN

N

O

HN

N

O

F3C

HN

N

O

HN

N

O

HN

N

O

4

5

100

93


31

entry product isolated yield (%)a

1

2

3

4

69

74

60

59

O OEt

OR

+H2N

H2N

DMF, cat. AcOH

5 min, 180 °CMWI

HN

N

O

R19

HN

N

O

F3C

HN

N

O

HN

N

O

HN

N

O

Quinoxalinones

• Products are insoluble in solvents suitable for chromatographic separation

• Precipitation in methanol gives analytically pure quinoxzalinones



32

O OEt

O +H2N

H2N

HN

N

O

10% aq. HCl

5 min, 125 °CMWI N

NH

27 (97%)

28 (2%)

1926

Quinoxalinones

Unexpected side product

•While the appearance of side products was rare, 28 is presumable formed from the reaction with the carbonyl group of 26, followed by oxidative decarboxylation


33

5-Aminooxazoles

O

OHHO

OHO

N

ON

29

N

NHN

O

O

NH2

30

N

O

OMe

CbzHN

Ph

31

N O

HN

O

HN

MeOO

32

OOMe

O

HN

MeO2C

N

O OR1

N

O NR3R4R2 R2

NR2

R1O

R4R3N

O

O

3433 35

O

NR3R4 OR1

O

• The 5-aminooxazole moiety exists in antibiotics, inhibitors of ricin and shiga toxins, peptidomimetics, and a Rafkinase inhibitor

Biologically active 5-aminooxazoles

Cornforth rearrangement

• We have accessed these structures via a microwave Cornforth rearrangement, to give the thermodynamically stable product 35

34

5-Aminooxazoles

NH2

OEtO

OEt

O Cl

O

NH

EtO

O

OEt

OO

Ph

N

OPh OEt

OEt

O

TFAA aq. KOH N

OPh OEt

OH

O

R1R2NH,PS-DCC,HOBt

N

OPh OEt

NR1R2

O

N

OPh NR1R2

OEt

O

100°C

180°C

DIEA

MWI

MWI MWI

+

36 37

• Using a procedure borrowed from Dewar, we have incorporated microwave heating into a dramatically faster reaction sequence

• The result is a 200-fold reduction in reaction time while generating 5-aminooxazoles in good yield

Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698-4704.

35

5-Aminooxazoles

Optimization of Microwave-assisted Cornforth rearrangement

• We determined that microwave heating at 180°C for five minutes gave the most favorable results

• Trifluorotoluene is a high boiling solvent with sufficient dipole for rapid microwave heating

aDetermined by LCMS. R1R2= piperidine

entry solvent temperature time product:starting materiala

1

2

3

4

5 PhCF3

CH3CN 150 °C

160 °C

170 °C

180 °C

180 °C

10 min

10 min

10 min

10 min

5 min

1:99

31:69

42:58

99:1

99:1

CH3CN

CH3CN

CH3CN

N

OPh OEt

NR1R2

O

N

OPh NR1R2

OEt

Oconditions

MWI

36 37


36

5-Aminooxazoles

HN

HN

F

NH2

H2NS

H2NO

O5

HN

H2N NHBoc5

H2N

N

1

2

3

4

5

6

7

8

100 °C, 5 min

100 °C, 5 minPS-DIEA (1 eq.)

100 °C, 5 min



100 °C, 5 min

100 °C, 5 min

100 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

180 °C, 5 min

98

47

99

51

76

85

99

82

N

OPh OEt

OH

O

N

OPh OEt

NR1R2

O

N

OPh NR1R2

OEt

37

O

MWI MWI

36

entry amine coupling cond rearrang cond yield (%) entry amine coupling cond rearrang cond yield (%)


37

5-Aminooxazoles

NH2

OMeO

OMe

OCl

O

NH

MeO

O

OMe

OO

N

O OMe

OMe

O

aq. KOH N

O OMe

OH

O

N

O OMe

N

O

N

O N

OMe

38

OBn OBn

OBn OBn

O

OBn

80 °C

180 °C

CCl3COCl

OBn

piperidine,PS-DCC,HOBt

MWI MWI

MWI

+

O

OHHO

OHO

N

ON

29 OOMe

• We have demonstrated the utility of this procedure in the formal synthesis of 4-(methoxycarbonyl)-2-(1-normon-2-yl)-5-piperidin-1-yloxazole (29)

• Intermediate 38 was obtained in 29% overall yield

• Deprotection followed by halogenation and olefinationwould provide 29


38

Conclusion

• Microwave heating can significantly shorten reaction times and increase efficiency

• We have demonstrated the effectiveness of microwave-assisted heating in the formation of heterocyclic targets

• Microwave reactors have become an integral part ofmethod development in TES

Products Reaction Development

Microwave as enabling technology

Microwave as driving force

39

Acknowledgements

Technology Enabled Synthesis Group Former Members

James BarrowJaime BundaApril CoxChristopher DenicolaRay McClainJames MulhearnSteven SharikWilliam ShipeCorey ThebergeScott WolkenbergF. Vivien YangZhijian Zhao

Todd AndersonWilliam LeisterCraig LindsleyDavid D. Wisnoski

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General Microwave-assisted Procedures for the …...1 General Microwave-assisted Procedures for the Expedient Synthesis of Substituted Heterocycles M. Brad Nolt Technology Enabled