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21st October 2016 @ 10:54

AT-1-012

Synthesis of 4-(Pyrrolidin-1-yl)benzaldehyde from 4-Bromobenzaldehyde and Pyrrolidine via Buchwald-Hartwig Coupling #2

 

 

 

 

Reagent

Eq

Mw

mmol

w/vol

4-Bromobenzaldehyde

1

185.02

2.70

0.50g

Pyrrolidine

1

71.12

2.30

0.19ml

BINAP

0.04

622.67

0.109

0.068g

Na-t-Bu

1.5

96.10

4.06

0.39g

Pd(dba)2

0.03

575.00

0.087

0.05g

Toluene

-

92.14

-

5ml

 

Experimental Procedure

 

4-Bromobenzaldehyde (0.50 g, 2.7 mmol) was added to toluene (5 mL) in a round bottom flask which was then sealed with a septum. Then pyrrolidine (0.19ml, 2.3 mmol), NaO-t-Bu (0.39 g, 4.06 mmol), BINAP (0.068 g, 0.109 mmol) and Pd(dba)2 (0.05 g, 0.087 mmol) were sequentially added to the flask which flushed with N2, and a N2 atmosphere maintained. The mixture was brown/yellow.

 

image1.png
 

 

The reaction was stirred at 70 °C for 2.5 hours, over which time the reaction changed from brown/yellow to green/brown.

 

image2.png

Upon completion, as determined by TLC analysis (85:15 Pet. Ether: Diethyl Ether) the solvent was removed under reduced pressure, EtOAC was added to the oily residue, and the solvent removed again.

 

image6.png
 
image4.png
 
image5.png

 

The crude product was purified by flash chromatography (silica gel; 85:15 Pet. Ether: Diethyl Ether).

image3.png

This produced the product as an orange oil (139mg, 0.195mmol, 29%). 1H NMR showed that the material isolated contained many impurities, which were mainly solvents. The product was washed with chloroform-d and rotor evaporated off, then another NMR sample was taken which proved to be pure apart from what appears to be BINAP between 7.2-8.2ppm. Yield and purity increased but not by enough, SNAr route alternative to be tried.

A-1-012.

crude nmr.png
 
final nmr.png
 
carbon.png
 
carbon2.png
IR_1.png
 
image4_.png
 
HSQC.png
 
HMBC.png

Reference:

1.C. Fattorusso, G. Campiani, G. Kukreja, M. Persico, S. Butini, M. Romano, M. Altarelli, S. Ros, M. Brindisi, L. Savini, E. Novellino, V. Nacci, E. Fattorusso, S. Parapini, N. Basilico, D. Taramelli, V. Yardley, S. Croft, M. Borriello and S. Gemma, J. Med. Chem., 2008, 51, 1333-1343.

Attached Files
17th October 2016 @ 13:04

AT-1-012

Synthesis of 4-(Pyrrolidin-1-yl)benzaldehyde from 4-Bromobenzaldehyde and Pyrrolidine via Buchwald-Hartwig Coupling

 

 

 

Reagent

Eq

Mw

mmol

w/vol

4-Bromobenzaldehyde

1

185.02

1.08

0.20g

Pyrrolidine

1

71.12

1.08

90µL

BINAP

0.04

622.67

0.04

0.027g

Na-t-Bu

1.5

96.10

1.62

0.16g

Pd(dba)2

0.03

575.00

0.03

0.02g

Toluene

-

92.14

-

4ml

 

Experimental Procedure

 

4-Bromobenzaldehyde (0.20 g, 1.08 mmol) was added to toluene (2 mL) in a round bottom flask which was then sealed with a septum. Then pyrrolidine (90 µL, 1.08 mmol), NaOt-Bu (0.16 g, 1.62 mmol), BINAP (0.027 g, 0.04 mmol) and Pd(dba)2 (0.02 g, 0.03 mmol) were sequentially added to the flask which flushed with N2, and a N2 atmosphere maintained. The mixture was brown/yellow.

 

Reaction.png

 

The reaction was stirred at 70 °C for 2.5 hours, over which time the reaction changed from brown/yellow to brown/red.

 

Reaction Colour Change.png

After an additional 30 minutes, further toluene (2 mL) was added. Upon completion, as determined by TLC analysis (60% EtOAc/Pet. Ether) the solvent was removed under reduced pressure, EtOAC was added to the oily residue, and the solvent removed again.

 

TLC.png
 
TLC.1.png

 

The crude product was purified by flash chromatography (silica gel; 85:15 pet. ether: diethyl ether) to furnish the product as an orange oil (33mg, 0.19 mmol, 17%). 1H NMR showed that the material isolated contained many impurities.

 

It was decided to repeat the reaction on larger scale, as it was thought that this would facilitate product isolation. See AT-1-012.

CRUDE NMR.png

3&4 NMR.png

5&6 NMR.png

 

 References:

1. C. Fattorusso, G. Campiani, G. Kukreja, M. Persico, S. Butini, M. Romano, M. Altarelli, S. Ros, M. Brindisi, L. Savini, E. Novellino, V. Nacci, E. Fattorusso, S. Parapini, N. Basilico, D. Taramelli, V. Yardley, S. Croft, M. Borriello and S. Gemma, J. Med. Chem., 2008, 51, 1333-1343.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Attached Files