Exp189scheme-i.jpg

Objective

To optimize the reaction from Exp099 to make this Ugi product using Mettler Toledo's automated Minimapper. Forty eight reactions are run in parallel using four reactant (2.0M in methanol) in different solvents / concentration.

Procedure

Make up 2M methanol solutions (50mL each) of starting materials - Benzaldehyde (10.550mL), Furfurylamine (8.837mL), Boc-glycine (17.518g) and tert-butyl isocyanide (11.310mL).
The following are added in this order in a reaction tube equipped with a filtration frit
1) The additional solvent (200uL methanol)
2) The benzaldehyde solution
3) The Furfurylamine solution
4) The Boc-Glycine solution
5) The tert-butyl isocycanide solution

Parameters to modify:
concentration - 0.5M, 0.25M and 0.1M
reagent excess - 1.0 and 1.2 equivalents
solvent (for 0.25 and 0.1 conc only): ethanol, acetonitrile, THF

This is 48 experiments total and they are listed in this spreadsheet

Map file ;

Results

Job file.

HNMR

G10run41 Acetonitrile/Methanol
G2run37 Acetonitrile/Methanol
G4run38 Acetonitrile/Methanol
D7run22 Ethanol /Methanol
D1run19 Ethanol /Methanol
A12run6 Methanol
A4run2 Methanol
H1run43 THF/Methanol
H3run44 THF/Methanol
189D-1
HNMR
Labile H-Exchange



BlueminiblockNumbering.jpg
Numbering
Exp189day1-1.JPG
Day-1
(6/5/08-19:37)
Exp189day2-13.JPG
Day-2
(6/6/08-11:40)
Exp189day3-3.JPG
189C (Day-3)
(6/7/08-14:44)
Exp189D-Crystals-5.JPG
189D
if you have other pics - put them here - just make sure they are defined and named in the log

Discussion

  1. looking at UID59 from the job file it looks like the values in the spreadsheet are incorrect for t-butylisonitrile. For example the last value for run 48 should be 0.25 ml, which is correct in the job file but incorrect (0.3 ml) in the spreadsheet. Those incorrect cells are highlighted in red.
  2. The positive control - run one with 0.5M final concentration of all components in methanol has the absolute worst yeild of 1.4%. This makes the rest of these results suspect.
  3. Yield Report : Acetonitrile : 24-61%; Ethanol : 6-35%; Methanol : 1-39%; THF : 7-19%
  4. Best yield (61.4%) was obtained when the reaction was performed with equimolar reagents (0.2mmol) and acetonitrile:methanol (1.6mL:0.2mL)
  5. Not withstanding the ambiguity of the data obtained, effect of acetonitrile as solvent is overwhelming, other solvents seem to have either similar or lesser effect than methanol on precipitation of the Ugi product [product yield 24-61%]. This effect could either be due the enhanced rate of Ugi reaction itself in acetonitrile compared to other solvents or it may just be that acetonitrile is more suited for product precipitation.
  6. D:1; D:7, A:4; H:1 and H:3 traces of Boc-Glycine still visible (eg:in D:7 Boc t-butyl group of the product 1.45 ppm and the acid 1.43 ppm). It appears that the starting materials survived methanol wash in the mentioned reaction tubes. However no such impurities are observed in the products which came from reactions run in acetonitrile-methanol solvent system (G sequence).

Conclusion

Acetonitrile-methanol mixture serves as a good solvent system for the reaction being performed.

Log

Log file1 ; Log file 2

2008-06-05
18:11 Minimapper stopped abruptly at E8 while dispensing component 4, it had to be modified, the run was continued further without changes. It is not very clear if vessel E8 had received component 4 (isocyanide).
19:00 Removed the reaction rack from the docking station, obtained a picture and placed it on an auto shaker set to 600 rpm.
21:00 Autoshaker stopped shaking
2008-06-06
11:40 Obtained a picture of the miniblock
12:00 Turned on the autoshaker- timer not set-
It is hard to tell from the pic if there is a precipitate - do you see any looking at the side of the tubes? There is solid in a few of them.
2008-06-07
14:25 Turned off autoshaker.
14:30 Vacuumed off the solvent from the reaction tubes. Obtained a pic of the rack (189C). The excess solvents /reagents were collected in a beaker and left in the hood. (189D)
17:00 Removed from vacuum, pipetted methanol (1ml) into each reaction tube and set it on the shaker (600rpm)
19:20 Stopped autoshaker and vacuumed off the solvent from the tubes.
19:25 Left the miniblock connected to vacuum in order to dry the product.
20:27 Obtained a picture of the crystals that have develped in 189D.
21:20 Obtained a movie of the miniblock after drying under vacuum.
2008-06-12
14:00 Added dichloromethane (3mL) to each reaction tube and set it on the autoshaker.
15:00 Removed from the autoshaker and drained the DCM solution containing the ugi product to clean, dry and preweighed tubes. These tubes were left under vacuum to evaporate DCM and obtain dry product which could be accurately weighed.
2008-06-14
15:00 Removed the tubes from vacuum and obtained dry ugi products which were weighed..(weights recorded in google spreadsheet).
2008-06-15
12:00 Decanted excess solvent from the beaker containing the crystals (189D), washed the crystals with methanol (3x3mL) each time decanted the solvent, and finally dried the crystals under vacuum.
2008-06-16
14:30 Obtained 189D-1 (467.8mg) dry crystals.

Tags

Furfurylamine: InChI=1/C5H7NO/c6-4-5-2-1-3-7-5/h1-3H,4,6H2
Benzaldehyde InChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
tert-butyl isocyanide InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
Boc-Gly-OH InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)
189Ugiproduct:InChI=1/C24H33N3O5/c1-23(2,3)26-21(29)20(17-11-8-7-9-12-17)27(16- ​18-13-10-14-31-18)19(28)15-25-22(30)32-24(4,5)6/h7-14,20H,15-16H2​ ,1-6H3,(H,25,30)(H,26,29) InChIKey:BXAOUWIVXLQYOZ-UHFFFAOYAZ