Exp132-ii.JPG

Objective

To synthesize N-benzyl-N-[(5-methyl-2-furyl)methyl]acetamide from benzaldehyde, 5-methyl furfurylamine, and acetyl chloride, in two steps
a) Reductive amination using Sodium triacetoxyborohydride made in situ from Sodium borohydride and glacial acetic acid;
b) N-acetylation with acetyl chloride in dichloromethane.
This will serve as a model compound to help explain the loss of the methyl furfuryl group upon treating the Ugi products containing the group with 50% TFA in CDCl3 for 2 days or longer, as experienced in Exp098, Exp091, Exp070, EXP067, EXP065., also summarized in the UsefulChem blog.

Procedure

Step1: To a 10% solution of benzaldehyde (20mmol, 2.03ml) in glacial acetic acid (18.3ml) were added 5-methyl furfurylamine (20mol, 2.23ml) with stirring. Sodiumborohydride pellets (0.02mol, 756.6mg) were added to it. The reaction mixture was left at room temperature with constant stirring for 2h. Then a 5% NaOH solution was added to the reaction mixture until the solution turned basic (pH ~ 9). The product was then extracted with two successive 15ml portions of dichloromethane. The combined extracts were dried over anhydrous Calcium Chloride. The solvent was evaporated under vacuum. The product was characterized by NMR.
Step2: A solution of N-benzyl-1-(5-methyl-2-furyl)methanamine (crude) (2.816g, ~14mmol) and triethylamine (6mL, 4.34 g, 42.0 mmol) was stirred in CH2Cl2 (15 mL) at room temperature for 10 min. A solution of acetyl chloride (944uL, 1.05g, 16.1mmol) in CH2Cl2 (10 mL) was added slowly into the above solution maintained between 0- 5 ÂșC for 15 min. The mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with CH2Cl2. The combined organic layers were then washed with 1N HCl (20ml) solution and the separated organic layer was then dried over anhydrous Magnesium Sulfate. The solvent was removed under vacuum to give N-benzyl-N-[(5-methyl-2-furyl)methyl]acetamide, which was characterized by NMR and FAB.

Results

132A
HNMR
CNMR
132B
HNMR
TLC-I TLC-II TLCIII TLCIV
132B Flash Chromatography
Frac-1-13
132B-F9
HNMR

Discussion

132B
HNMR :

Conclusion

Experiment aborted.

Log

2007-09-13

10:20 Measured out glacial acetic acid (18.3ml) in a clean, dry 125ml erlenmeyer flask. Placed a clean magnetic stir bar in it and started stirring it on a stir plate.
10:40 Weighed NaBH4 (756.6mg).
11:25 Added benzaldehyde (2.03ml) to glacial acetic acid.
11:35 Added 5-methyl furfurylamine (2.23ml) to the reaction mixture.
11:45 Added NaBH4 (756.6mg) to the reaction flask.
13:45 Started adding a 10% NaOH solution to the reaction mass until pH 9-10 was reached.
14:30 Transferred the solution into a separatory funnel and extracted the product with dichloromethane (40ml x2), the extract was dried over anhydrous calcium chloride.
15:00 Dichloromethane was evaporated on a rotovap and the brown oil was set on a high vacuum pump to remove any traces of the solvent.
16:05 Removed from high vac and obtained 132A (3.1585g) a brown oil (crude product).
17:06 Obtained HNMR
1758 Obtained CNMR

2007-09-16

14:45 Made-up a solution of the 132A (the crude secondary amine) and triethylamine in methylene chloride in a round bottom flask, started stirring it on a stir plate.
14:50 Cooled the above solution to 3C (in an ice bath).
14:55 Made-up a solution of acetyl chloride in methylene chloride, cooled it down 3C.
15:05 Started adding acetyl chloride to the amine solution in dichloromethane.
15:22 Completed the addition of acetyl chloride solution. At certain point during the addition, temperature of the amine/acetylchloride mix went up to 12C.
15:25 The solution was left to stir.
15:40 Removed the reaction mass from the ice bath, the solution had turned into a yellow precipitate.
16:40 Stopped stirring the solution, transferred the yellow ppt to a separatory funnel, added 50ml distilled water, extracted the bottom layer, washed the top aqueous layers with 15ml CH2Cl2, combined the organic layers.
16:55 Washed the combined organic layers with another 50ml distilled water, separated the layers.
17:10 Finally washed the bottom DCM layer with 1N HCl (20ml), again separated the layers, dried the organic layer over anhydrous MgSO4, filtered off the supernatant, evaporated on a rotovap.
17:30 Set the small amount of deep yellow oil on a high vac.
17:55 Removed from the high vac.

2007-09-17

10:05 Set the round bottom flask back on the vacuum pump.
13:00 Removed the round bottom flask from the high vac and obtained 132B (2.8006g); 82.2%
13:55 Obtained HNMR of 132B
15:51 Obtained TLC of 132B and 133B in diethyl ether.
16:38 Obtained TLC of 132B and 133B in Ether / Hexane (1:1, 2:1, 3:1)

2007-09-18

16:28 Obtained TLC of 132B and 133B in Ether / Pentane (10%, 30%, 50%) and dichloromethane.
16:57 Obtained TLC of 132B and 133B in Ether / Hexane ( 30%).

2007-09-19

16:00 Made-up a flash-column with 50g Silica gel (60-200 mesh) in hexane. Ran 100 ml of hexane through the column. The column will be left overnight to equilibrate.

2007-09-20



References

1.REACTIONS OF SODIUM BOROHYDRIDE IN ACETIC ACID:REDUCTIVE AMINATION OF CARBONYL COMPOUNDS - Panfilov, Markovich, et.al;Pharm Chem J; 34 (7) 371-373.
2.Hao Song et.al. Org Lett.; 2006; 8(26) 6011 - 6014 Exp & Supproting info.

Tags

Benzaldehyde: InChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
5-Methyl fufurylamine: InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
N-benzyl-1-(5-methyl-2-furyl)methanamine:InChI=1/C13H15NO/c1-11-7-8-13(15-11)10-14-9-12-5-3-2-4-6-12/h2-8,14H,9-10H2,1H3
Triethylamine: InChI=1/C6H15N/c1-4-7(5-2)6-3/h4-6H2,1-3H3
Acetyl chloride: InChI=1/C2H3ClO/c1-2(3)4/h1H3
N-benzyl-N-[(5-methyl-2-furyl)methyl]acetamide:InChI=1/C15H17NO2/c1-12-8-9-15(18-12)11-16(13(2)17)10-14-6-4-3-5-7-14/h3-9H,10-11H2,1-2H3