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10th November 2016 @ 13:48

AT-1-012

Synthesis of 4-(Pyrrolidin-1-yl)benzaldehyde from 4-Fluorobenzaldehyde and Pyrrolidine via SNAr

 

 

 

 

Reagent

Eq

Mw

mmol

w/vol

4-Fluorobenzaldehyde

1

185.02

8

0.9ml

Pyrrolidine

3

71.12

24

1.8ml

DMF

-

73.09

-

15ml

K2CO3

1.5

138.21

12

1.65g

CHCl3

-

119.38

-

5ml

 

Experimental Procedure

Pyrrolidine (1.8ml, 24mmol) was added to dry DMF (15ml), in a round bottom flask and then anhydrous K2CO3 (1.65g, 12mmol) were added sequentially. The reaction was stirred for 15 minutes at room temperature. 4-Fluorobenzaldehyde (0.9ml, 8mmol) was then added and the reaction continued to stir and was heated to 80°C. The reaction started off a pale yellow at the beginning of the reaction.

Reaction.png

The reaction was stirred at 80°C for 11 hours, over which time the reaction changed from pale yellow to orange.

Beginning of reaction.png
 
End of reaction.png
 

Upon completion of the reaction, which was determined by TLC analysis, 5:3 Pet. Ether: Diethyl ether. The TLC’s needed a mini work up due to the DMF disrupting the accuracy of the TLC’s.

TLC to show reaction completed.png

The solution was left to cool for 30 minutes, deionised water (30ml) was then added along with DMF (25ml) and then the solution was added to a separating funnel. The solution was then washed with EtOAc 3x, and then the non-organic layer (bottom layer) was taken off.

Before Separation of organic layer.png
 
Separation of organic and inorganic layer.png

The remaining crude product was then washed with brine 3x to remove the DMF. This crude product was then rotor evaporated down. Silica and EtOAc were added, rotor evaporated down and then Flash columned, to purify the product.

Flash column.png

Solvent system for the column started at 80/20 Pet. Ether/ Diethyl ether, but was changed to 70/30 Pet. Ether/ Diethyl ether to increase the mobile phase. 109 Test tubes were taken, with the product being present between 40-100.

Flash column TLC\'s.png

The Final product was given as an orange solid (1.19g, 6.76 mmol, 84%). 1H NMR showed that the material had petroleum ether impurities, very small amount of starting material and a peak at 3.093ppm which I determined to be Chloromethane. The product was washed again in d-Chloroform 3x and another 1H NMR was taken again and which showed the petroleum ether peaks had decreased, as had the starting material. The peak at 3.093ppm remained however, but this should not affect my next experiment of the condensation reaction to join my product to the pyrazine core.

Product.png

A-1-012.

nmr final.png
 
nmr final 2.png
 
carbon.png
 
carbon2.png
 
image4_.png
 
HMBC.png
 
HSQC.png
 
mass spec.png

 

Reference:

1. D. Kumar, K. Raj, M. Bailey, T. Alling, T. Parish and D. Rawat, Bioorganic & Medicinal Chemistry Letters, 2013, 23, 1365-1369.

Attached Files
End of reaction.png
Flash column TLC\'s.png
Flash column.png
Product.png
Reaction.png
sNAR reaction.png
TLC to show reaction completed.png
Before Separation of organic layer.png
Beginning of reaction.png
Separation of organic and inorganic layer.png
image4_.png
carbon.png
carbon2.png
HMBC.png
HSQC.png
nmr final 2.png
nmr final.png
mass spec.png