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 (25mL each) of starting materials - Furfurylamine (4.418mL), Boc-glycine (8.759g) and tert-butyl isocyanide (5.655mL) and 2.077M Benzaldehyde (5.275mL ) in methanol. Were these made up fresh or used from a previous experiment?
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
Limiting reagent conc : 0.2mmol

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

Map file ;

Results

Job file.
The yields are listed in this spreadsheet

Discussion

  1. Taking the average of 6 runs in a given solvent and concentration we obtain:
    1. 0.2M acetonitrile/methanol 60/40: 49.2%
    2. 0.2M ethanol/methanol 60/40 42.3%
    3. 0.4M methanol 33.0%
    4. 0.2M methanol 30.5%
    5. 0.2M THF/methanol 60/40 15.1%
    6. 0.07M ethanol/methanol 87/13 10.8%
    7. 0.07M acetonitrile/methanol 87/13 7.2%
    8. 0.07M methanol 0.1%
  2. In most cases the excess of isonitrile gave the best result within each solvent/concentration set.

Conclusion

The results are not meaningful because the liquid handler was not properly programmed. In this case it appears that the line was not flushed sufficiently when changing solvents.

Log

Log file1 ;

2008-07-10
10:00 Weighed each empty reaction tube (wts in the spreadsheet)
11:00 Made-up 2M (25mL) solutions of the starting materials)
13:04 The minimapper started working on the addition of solvents and chemicals for this run.
14:13 Minimapper completed the run
14:23 Placed the miniblock on the shaker and started shaking at 400rpm.
2008-07-11
10:25 Removed the miniblock from the shaker and vacuumed off excess solvent.
10:35 Set the miniblock on the minimapper and programmed it to deliver methanol (1mL) to each reaction tube.
10:50 Minimapper completed adding methanol to the reaction tubes.
10:55 Placed the miniblock on the shaker and started shaking at 400 rpm for 15 min.
11:10 Removed from the shaker and vacuumed off the solvent from the reaction tubes.
11:20 Set the miniblock on the minimapper and programmed it to deliver methanol (1mL) to each reaction tube for washing a second time.
11:55 Minimapper completed adding methanol to the reaction tubes.
12:30 Placed the miniblock on the shaker and started shaking at 400 rpm for 15 min.
12:50 Removed from the shaker and vacuumed off the solvent from the reaction tubes. The miniblock is let connected to the house vac for 30min.
13:25 The miniblock was disconnected from the house vac and placed in a desiccator connected to a high-vac.
16:05 Removed the miniblock from desiccator and weighed the filter tubes...the weights of the tubes/products were recorded into the spreadsheet.

Tags


Compound
Inchi Key
Inchi
Furfurylamine
DDRPCXLAQZKBJP-UHFFFAOYAX
InChI=1/C5H7NO/c6-4-5-2-1-3-7-5/h1-3H,4,6H2
Benzaldehyde
HUMNYLRZRPPJDN-UHFFFAOYAE
InChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
tert-butylisocynide
FAGLEPBREOXSAC-UHFFFAOYAL
InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
Boc-Glycine
VRPJIFMKZZEXLR-UHFFFAOYAN
InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(​H,9,10)
Ugi Product
BXAOUWIVXLQYOZ-UHFFFAOYAZ
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)