real_ugi1.JPG

Objective

To convert adrenaline to DOPAL by acid catalysis and to accomplish the Ugi reaction and cyclization to a diketopiperazine using the obtained DOPAL and 5-methylfurfurylamine, N-(tert)-butoxycarbonyl)-L-methionine, and benzylisocyanide following the protocol described here.

Procedure

Step1:
A solution of adrenaline (1.0 g 5.5 mmol) in 85% phosphoric acid (15mL; 0.37M) was heated in a 125 ml erlenmeyer flask (for 3 mins) in a glycerol bath then removed from heat and allowed to cool . The solution was added to distilled water and then saturated with NaCl. It was taken up in ethyl ether, and dried over anhydrous MgSO4.The ether extract was then evaporated to obtain DOPAL in about 20% yield.
In the second step of the reaction, the obtained DOPAL was directly used in the Ugi diketopiperazine synthesis without any purification. DOPAL was added to equi-molar amounts of 5-methylfurfurylamine benzylisocyanide,and N-(tert)-butoxycarbonyl)-L-methionine in methanol and stirred at room temperature for 24 hours and then evaporated. A solution of 10% Acetyl chloride in Methanol was added to the product and set aside. It was then rotovaped and set on high vac. The product was taken up in dichloromethane, washed with water, dried over anhydrous MgSO4 and evaporated again.

Results

Characterization

1. TLC of 3:1 methylene chloride-methanol with and without CAM (Cerium Ammonium Molybdate) stain (Under UV light, stained1 (before heating), stined2 (after heating).
2.A H NMR of 23Ain acetone-d6 was obtained on a 500 MHz Varian Inova.

Discussion

1. A rearrangement of adrenaline to DOPAL possibly proceeds through simple a dehydration mechanism (unlike a pinacol type rearrangement suggested by Robbins)
2. It may be problematic to use the crude DOPAL 23A. Based on the integration of the aldehyde peak relative to the aromatic protons, there is a substantial impurity. This may be the carboxylic acid, which will compete with the BOC-amino acid in the UGI reaction.
3. H NMR of 23A shows a substantial loss of the furan system from the product.

Conclusion


Dopal was obtained in 20% yield; however a Ugi product could not be synthesized in the second step. (No furan ring protons, eg. 5.9ppm)


Log

fix time format
STEP 1

2006-08-25

1. 08:35 A glycerin bath was heated to 175C.

2006-08-25

2. 08:45 Placed 1.00 g on Epinephrine in an Erlenmeyer flask, added 15 mls of 85% Phosphoric acid to it.
3. Immersed the Erlenmeyer flask in the glycerin bath, allowed it to reach 120C (took only about 3mins), solid epinephrine completely dissolved in the acid solution.

2006-08-25

4. 08:50 Removed the Erlenmeyer flask from the bath. let it stand for 20 seconds at room temperature.
5. Poured the hot acid solution in 180mls of distilled water (at room temperature), let it stand for 90mins.

2006-08-25

6. 10:25 Saturated the solution with Sodium Chloride (table salt without Iodine).

2006-08-25

7. 10:30 Extracted successively with 120-,70-, and 50 ml portions of ethyl ether

2006-08-25

8. 10:50 The extract was stirred for 10 mins with 20 mls of phosphate buffer solution (pH 7.0), then saturated the solution with sodium chloride (table salt) again.
9. Separated the ether layer, dried it over anhydrous MgSO4, and filtered through a sintered glass funnel, rotovaped and set on high vacuum for 1 1/2 hours.

2006-08-25

10. 10:00 Obtained 23A (164.1 mgs 1.08 mmol)) a yield of 19.6%.

2006-08-27

11. 11:00 A TLC of 23Awas obtained in 3:1 methylene chloride and methanol. (posted in results section)
12. Also a H NMR of 23Awas obtained in acetone-d6.
STEP 2
13. 23A will be directly used in the ugi diketopiperazine synthesis without further purification.

2006-08-28

14. 11:38 73 µl (0.6 mmol)of Benzylisocyanide, 67 µl (0.6 mmol) of 5-methyl furfuryl amine and 149.6 mgs (0.6 mmol) of BOC-Met-OH was added to a round bottom flask containing 90 mgs (0.6 mmol) of Dopal in 24mls of methanol. The reaction mixture was pale yellow in color.
15. The reaction will be stirred for 24 hours.

2006-08-28

16. 17:35 The reaction changed colors from yellow to greenish, after 6 hours, after 8 1/2 hours, and after 24 hours

2006-08-29

17. 11:38 Stopped stirring, evaporated methanol.

2006-08-29

18. 11:45 Made a 10% (50 ml) solution of acetyl chloride(5 ml) in methanol(45 ml).

2006-08-29

19. 11:55 Added 50 ml of 10% acetyl chloride / methanol solution to the Ugi reaction flask and started stirring.

2006-08-29

20. 12:55 Stopped stirring, rotovaped the solution.

2006-08-29

21. 13:30 Added 50 ml of methylene chloride, washed 3 times with water (50 ml each), accumulated the bottom layers, saturated with anhydrous Magnesium Sulfate (the residue turned pink), filtered, rotovaped and then set on high vacuum for half an hour, obtained 23B (22.5 mg) of the product.
22. A TLC of 23B was obtained in 3:1 MeCl2/ MeOH and 1:1 MeCl2:Hexanes.
23. A H NMR for 23B was obtained in acetone-d6..(23B-1, 23B-2, 23B-3, 23B-4, 23B-5, 23B-6, 23B-7) (300 MHz Varian Inova)


Tags

adrenaline InChI=1/C9H13NO3/c1-10-5-9(13)6-2-3-7(11)8(12)4-6/h2-4,9-13H,5H2,1H3
DOPAL InChI=1/C8H8O3/c9-4-3-6-1-2-7(10)8(11)5-6/h1-2,4-5,10-11H,3H2
5-methylfurfurylamine InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
benzylisocyanide, InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2
N-(tert)-butoxycarbonyl)-L-methionineInChI=1/C10H19NO4S/c1-10(2,3)15-9(14)11-7(8(12)13)5-6-16-4/h7H,5-6H2,1-4H3,(H,11,14)(H,12,13)