Alexander Stadler and C. Oliver Kappe*

7th Annual High-Throughput Organic Synthesis Meeting, February 13-15, 2002, San Diego, California

Institute of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austriaemail: alexander.stadler@uni-graz.at website: http://www-ang.uni-graz.at/~kappeco

Software Aided Library Generation

Microwave Equipment

Automated Generation of a Dihydropyrimidine Library Using Sequential Microwave-Assisted Synthesis

http://www.personalchemistry.com

Single-mode microwave cavity, 2.45 GHz Continuous MW irradiation power 0-300W Automated liquid handling & vial transfer Temperature measurement by IR sensor Built-in magnetic stirring Teflon-sealed reaction vials Reactions up to 20 bar and 250°C Rapid gas jet cooling

SmithSynthesizer

48 member DHPM library generated within 12h (52% average yield)

DHPMs produced in 200-1000 mg quantities

Reaction times reduced from hours to minutes

Reaction optimization within hours

Establishing of library production protocol within days

Sequential treatment allows for individuality optimized conditions

Stadler A., Kappe C.O., J. Comb. Chem., 2001, 3, 624-

530

GrazGrazMicrowave & Combichem

Results and Conclusions

Step 1: Choose Solvent

best solvent: AcOH/EtOH 3:1 • effectively couples with microwaves• dissolves building blocks under reaction conditions• DHPM products sparingly soluble at rt

Optimization of Reaction Conditions using Microwaves

N

N

R1

ZR2

E H

R3

NH2

ZN

R3

H

R1

HO

OR2

E+

(17)

(25)

(8)(3400 DHPMs)

MW, 120°C

10 min

This work was supported by the Austrian Science Fund.

We thank PersonalChemistry AB (Uppsala, Sweden) for the use of their instument.

Acknowledgements

Smith Workflow Manager

solventcatalyst

Conventional Conditions: EtOH, cat. HCl, reflux, 3h, 78% yield K. Folkers et al., J. Am. Chem. Soc., 1932, 54, 3751-3758

Step 3: Optimize Temperature & Time

5 min10 min

15 min0

20

40

60

80

100

120°C100°C130°C 140°C

Iso

late

d Y

ield

(%

)

AcOH/EtOH 3:1, 10 mol% Yb(OTf)3

Step 4: Reoptimization for Troublesome Building Block Combinations

N

N

S

H

H

EtO

O

N

N

S

H

Me

EtO

O

N

N

O

H

H

EtO

OO

N

N

O

H

H

H2N

O

NO2

AcOH/EtOH 3:110 mol% LaCl3120°C, 10 min

56% yield

EtOH 10 mol% LaCl3120°C, 10 min

41% yield

EtOH 10 mol% HCl120°C, 15 min

59% yield

EtOH10 mol% Yb(OTf)3

100°C, 20 min50% yield

Introduction: The Biginelli MCR (1893)

C.O. Kappe, Acc. Chem. Res., 2000, 33, 879-888C.O. Kappe, Eur. J. Med. Chem., 2000, 35, 1042-1053

For reviews see:

Aim: Generate a Library of Dihydropyrimidines Utilizing Rapid Automated Sequential Microwave-Assisted Chemistry

• Prepare stock solutions of aldehydes (AcOH) and CH-acidic carbonyls (EtOH)• Enter building blocks & reaction conditions into the software• Generate dispensing strategy• Run the automated protocol (unattended)

• Work up (filter products directly or add H2O)

experimentalprogress

sample order

dispensing strategy&

protocol generation

ISIS Draw surface

creating tools

General MW Protocol: 4 mmol building blocks, 2 ml AcOH/EtOH 3:110mol% Yb(OTf)3, 10 min, 120°C

Step 2: Select Catalyst

• HCl causes decomposition of urea and leads

to unwanted byproducts at higher temperatures• Lewis acids are more tolerable and have been

reported to be effective catalysts

Yb(OTf)3

FeCl3

LaCl3

InCl3

0 20 40 60 80 100

Isolated Yield (%)

5 mol%10 mol%

AcOH/EtOH 3:1, 120°C, 10 min

Heating Profile

0

20

40

60

80

100

120

140

0 60 120 180 240 300 360 420 480 540 600 660

Time (sec)

Tem

per

atu

re (

°C)

0

1

2

3

4

5

6

Pre

ssu

re (

bar

)

T

p

Model Reaction:

MW

OMe

O

EtO

Ph

HO

NH2

OH2NN

N

Ph

OMe

H

H

EtO

O

+

Institutfür Chemie