Objective

To synthesize 26 Ugi adducts using Ugi 4CR following Explan005. The target compounds were ranked 31-54 (except 32,37 and 48, pyrene derivatives) in the DEXP014-V2B file from D-EXP014 . The purpose of this experiment is to synthesize an anti-malarial compound based on the inhibition of falcipain-2, as described in this summary post .

Procedure

To twentyone vials, labeled 174# (31-54 sans 32,37,48) and charged with methanol, four reactants [aldehyde, amine, acid and isocyanide] (0.5mmol each) were added to each in that order. After each addition, the resulting solution was vortexed for 30s (or more). The vials were capped tight and left at room temperature. The vials which formed solid precipitates or crystals were decanted, the solid was washed with methanol (3x 500uL) and dried under vacuum to obtain corresponding Ugi products.


ExpID/
VB2Rank
Solvent
Aldehyde
Amine
Acid
Isocyanide
Ppt(Y/N) & Yield
174A/31
Methanol
benzaldehyde
-0.5mmol-50.8uL
5-methylfurfurylamine
-0.5mmol-55.7uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174B/33
Methanol
3-methoxybenzaldehyde
-0.5mmol-61uL
furfurylamine
-0.5mmol-44.2uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174C/34
Methanol
Phenanthrene-9-carboxaldehyde
-0.5mmol-103.12mg
methylamine
(2M in methanol)
-0.5mmol-250uL
5-nitrosalicylic acid
-0.5mmol-91.56mg
n-butylisocyanide
-0.5mmol-52.3uL
YES
174D/35
Methanol
Salicylaldehyde
-0.5mmol-53uL
furfurylamine
-0.5mmol-44.2uL
benzoic acid
-0.5mmol- 122.12mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174E/36
Methanol
Salicylaldehyde
-0.5mmol-53uL
methylamine
(2M in methanol) -0.5mmol-250uL
Boc-L-tryptophan
-0.5mmol-152.17mg
n-butylisocyanide
-0.5mmol-52.3uL
No Ppt
174F/38
Methanol
3,4-dimethoxybenzaldehyde
-0.5mmol-83.1mg
methylamine
(2M in methanol)
-0.5mmol-250uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174G/39
Methanol
4-methylbenzaldehyde
-0.5mmol-59uL
n-propylamine
-0.5mmol-41.1uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174H/40
Methanol
2-naphthaldehyde
-0.5mmol-78.09mg
methylamine
(2M in methanol)
-0.5mmol-250uL
2,4,6-trihydroxybenzoicacid.H2O
-0.5mmol-94.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174I/41
Methanol
3,4-dihydroxybenzaldehyde
-0.5mmol- 69.06mg
aniline
-0.5mmol-45.5uL
2-methylpropeneoicacid
-0.5mmol-42.4uL
TOSMIC
-0.5mmol-97.62mg
No Ppt
174J/42
Methanol
4-chlorobenzaldehyde
-0.5mmol-70.3mg
5-methylfurfurylamine
-0.5mmol-55.7uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174K/43
Methanol
Phenanthrene-9-carboxaldehyde
-0.5mmol-103.12mg
5-methylfurfurylamine
-0.5mmol-55.7uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
t-butylisocyanide
-0.5mmol-56.5uL
YES
174L/44
Methanol
4-methoxybenzaldehyde
-0.5mmol- 61uL
methylamine
(2M in methanol)
-0.5mmol-250uL
2,4,6-trihydroxybenzoicacid.H2O
-0.5mmol-94.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174M/45
Methanol
3,4-dihydroxybenzaldehyde
-0.5mmol-69.06mg
3-chloroaniline
-0.5mmol-53uL
(±)-2-Phenylbutanoic acid
-0.5mmol-82.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174N/46
Methanol
3-hydroxybenzaldehyde
-0.5mmol-61.06mg
methylamine
(2M in methanol)
-0.5mmol-250uL
Boc-L-tryptophan
-0.5mmol-152.17mg
n-butylisocyanide
-0.5mmol-52.3uL
No Ppt
174O/47
Methanol
3,5-dimethoxybenzaldehyde
-0.5mmol-83.1mg
5-methylfurfurylamine
-0.5mmol-55.7uL
D-(−)-Quinic acid
-0.5mmol-96.1mg
t-butylisocyanide
-0.5mmol-56.5uL
No Ppt
174P/49
Methanol
3-methoxybenzaldehyde
-0.5mmol-61uL
5-methylfurfurylamine
-0.5mmol-55.7uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174Q/50
Methanol
Salicylaldehyde
-0.5mmol-53uL
3-chloroaniline
-0.5mmol-53uL
butyric acid
-0.5mmol-45.7uL
TOSMIC
-0.5mmol-97.62mg
No Ppt
174R/51
Methanol
Salicylaldehyde
-0.5mmol-53uL
3-chloroaniline
-0.5mmol-53uL
Mandelic acid
-0.5mmol- 76.075mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174S/52
Methanol
4,7-Dimethoxy-1-naphthaldehyde
-0.5mmol-108.1mg
methylamine
(2M in methanol)
-0.5mmol-250uL
5-nitrosalicylic acid
-0.5mmol-91.56mg
n-butylisocyanide
-0.5mmol-52.3uL
No Ppt
174T/53
Methanol
Salicylaldehyde
-0.5mmol-53uL
aniline
-0.5mmol-45.5uL
(2,5-Dimethoxyphenyl)acetic acid
-0.5mmol-98.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt
174U/54
Methanol
4-methoxybenzaldehyde
-0.5mmol-61uL
furfurylamine
-0.5mmol-44.2uL
3,4-dihydroxyphenylacetic acid
-0.5mmol-84.1mg
TOSMIC
-0.5mmol-97.62mg
No Ppt


Results

ExpID
Day 1
Day 2
Day-12
Characterization
174A
174Aday1.JPG
174Aday2.JPG
No Ppt

174B
174Bday1.JPG
174Bday2.JPG
No Ppt

174C
174Cday1.JPG
174Cday2.JPG
174Cday12.JPG
Amount: 33 mg; Yield -
  1. Melting Point :171-173C
  2. IR
  3. HNMR
  4. HNMR [H-Exchange with methanol-d4]
  5. Overlay [with labile H Vs Exchanged]
  6. CNMR
  7. FAB-MS
174D
174Dday1.JPG
174Dday2.JPG
No Ppt

174E
174Eday1.JPG
174Eday2.JPG
No Ppt

174F
174Fday1.JPG
174Fday2.JPG
No Ppt

174G
174Gday1.JPG
174Gday2.JPG
No Ppt

174H
174Hday1.JPG
174Hday2.JPG
No Ppt

174I
174Iday1.JPG
174Iday2.JPG
No Ppt

174J
174Jday1.JPG
174Jday2.JPG
No Ppt

174K
174Kday1.JPG
174Kday2.JPG
174Kday12.JPG
Amount: 27 mg; Yield -
  1. Melting Point : 143-145C
  2. IR
  3. HNMR
  4. HNMR[H-Exchange with methanol-d4]
  5. Overlay [with labile H Vs Exchanged]
  6. CNMR
  7. FAB-MS (Nominal Mass)
  8. FAB-MS (HRMS)
174L
174Lday1.JPG
174Lday2.JPG
No Ppt

174M
174Mday1.JPG
174Mday2.JPG
No Ppt

174N
174Nday1.JPG
174Nday2.JPG
No Ppt

174O
174Oday1.JPG
174Oday2.JPG
No Ppt

174P
174Pday1.JPG
174Pday2.JPG
No Ppt

174Q
174Qday1.JPG
174Qday2.JPG
No Ppt

174R
174Rday1.JPG
174Rday2.JPG
No Ppt

174S
174Sday1.JPG
174Sday2.JPG
No Ppt

| 174T
174Tday1.JPG
174Tday2.JPG
No Ppt

174U
174Uday1.JPG
174Uday2.JPG
No Ppt


Discussion

From the proton NMR few peaks which may correspond to a ugi product are seen, but the chiral proton which was expected to appear between 5.5-6.0 ppm is missing. Also the FAB-MS rejects the idea of a ugi product. However CNMR shows all the 26 carbons which could correspond to a ugi product.
Therefore in view of the ambiguity of the spectral results, a crystal analysis of the sample maybe useful.
A lot of solvent has evaporated by day12 and so the experiment would have to be repeated making sure the vessel is tightly closed.

Conclusion

A Ugi product could not be isolated from the reactions performed.

Log

2008-04-02

14:50 Pipetted out methanol (2mL) in 14 one dram vials. Also pipetted out methanol (1850uL) in 7 other vials (these will accommodate 2.0 M methyl amine (250uL) as the amine component). The vials with 2ml methanol are labelled 174-A, B, D, G, I, J, K, M, O, P, Q, R, T, and U. The remaining 7 are named 174- C, E, F, H, L, N and S, like listed in the table above.
15:30 Dissolved respective aldehydes in each vial by vortexing them for 30s each. Phenanthrene-9- carboxaldehyde in vials (174C and 174K) did not make a homogenous solution. Similarly vial 174S with 4,7-Dimethoxy-1-naphthaldehyde did not make a homogenous solution even after vortexing for 3min.
19:00 Added respective amines to the vials, vortexed each for 30s.

2008-04-03

13:00 Completed addition of respective acids to each vial, vortexed for 30s each. it was noted that upon acid addition. vials containing salicylaldehyde and 3-chloroaniline (174Q, 174R) as the aldehydes and amine components instantaneously precipitated out from the solution There was no dramatic change in the solubility of 174C, however after the addition of acid to 174K, the insoluble components started to dissolve. Vial 174S containing 4,7-Dimethoxy-1-naphthaldehyde and methylamine formed a yellow precipitate upon the addition of 5-nitrosilcylic acid.
20:00 Completed addition of respective isocyanide to each vial, vortexed for 15s each. Interestingly ppts in vials 174Q, 174R turned more fluid upon the isocyanide addition. 174S showed no change.
20:40 Obtained a picture of each vial (Day 1 series)
21:00 Left the vials tightly capped at room temperature.

2008-04-04

11:30 Samples which remained undissolved last evening have now tuned in to homogeneous solutions. None of the solutions have formed any ppt / crystals yet.
16:45 Obtained pictures of the vial. (Day 2 series)

2008-04-06

15:00 Vortexed the vials for 30s each, none of the solutions have formed any precipitates.

2008-04-09

15:00 Vortexed the vials for 30s each. 174C- has formed solid

2008-04-15

20:30 Solid has appeared in 174C and 174K, no solid in other vials.

2008-04-19

18:00 Vortexed samples vials 174C & 174K for 30s each, centrifuged them for 2m and decanted the supernatant. The residue in each vial was washed with methanol (3x1ml) and set under a high vacuum pump for drying.
22:00 Removed from high vac and obtained 174C (33mg) and 174K (27mg)

2008-05-01

10:00 Obtained HNMR and CNMR

Tags

Chemical
Inchi
InchiKey
benzaldehyde
InChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
HUMNYLRZRPPJDN-UHFFFAOYAE
3-methoxybenzaldehyde
InChI=1/C8H8O2/c1-10-8-4-2-3-7(5-8)6-9/h2-6H,1H3/i1-12,2-12,3-12,4-12,5-12,6-12,7-12,8-12,9-16,10-16
WMPDAIZRQDCGFH-UHFFFAOYAC
Phenanthrene-9-carboxaldehyde
InChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H
QECIGCMPORCORE-UHFFFAOYAE
Salicylaldehyde
InChI=1/C7H6O2/c8-5-6-3-1-2-4-7(6)9/h1-5,9H
SMQUZDBALVYZAC-UHFFFAOYAD
3,4-dimethoxybenzaldehyde
InChI=1/C9H10O3/c1-11-8-4-3-7(6-10)5-9(8)12-2/h3-6H,1-2H3
WJUFSDZVCOTFON-UHFFFAOYAT
4-methylbenzaldehyde
InChI=1/C8H8O/c1-7-2-4-8(6-9)5-3-7/h2-6H,1H3/i1-12,2-12,3-12,4-12,5-12,6-12,7-12,8-12,9-16

2-naphthaldehyde
InChI=1/C11H8O/c12-8-9-5-6-10-3-1-2-4-11(10)7-9/h1-8H
PJKVFARRVXDXAD-UHFFFAOYAM
2,3-dihydroxybenzaldehyde
InChI=1/C7H6O3/c8-4-5-2-1-3-6(9)7(5)10/h1-4,9-10H
IXWOUPGDGMCKGT-UHFFFAOYAD
4-chlorobenzaldehyde
InChI=1/C7H5ClO/c8-7-3-1-6(5-9)2-4-7/h1-5H
AVPYQKSLYISFPO-UHFFFAOYAQ
4-methoxybenzaldehyde
InChI=1/C8H8O2/c1-10-8-4-2-7(6-9)3-5-8/h2-6H,1H3
ZRSNZINYAWTAHE-UHFFFAOYAA
3,4-dihydroxybenzaldehyde
nChI=1/C7H6O3/c8-4-5-1-2-6(9)7(10)3-5/h1-4,9-10H
IBGBGRVKPALMCQ-UHFFFAOYAN
3-hydoxybenzaldehyde
InChI=1/C7H6O2/c8-5-6-2-1-3-7(9)4-6/h1-5,9H
IAVREABSGIHHMO-UHFFFAOYAC
3,5-dimethoxybenzaldehyde
InChI=1/C9H10O3/c1-11-8-3-7(6-10)4-9(5-8)12-2/h3-6H,1-2H3
VFZRZRDOXPRTSC-UHFFFAOYAG
4,7-Dimethoxy-1-naphthaldehyde
InChI=1/C13H12O3/c1-15-10-4-5-11-12(7-10)9(8-14)3-6-13(11)16-2/h3-8H,1-2H3
FFAODEUKHYBIKI-UHFFFAOYAI
5-methylfurfurylamine
InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
YSEAGSCGERFGBL-UHFFFAOYAH
furfurylamine
InChI=1/C5H7NO/c6-4-5-2-1-3-fu7-5/h1-3H,4,6H2c
DDRPCXLAQZKBJP-UHFFFAOYAX
methylamine
InChI=1/CH5N/c1-2/h2H2,1H3
BAVYZALUXZFZLV-UHFFFAOYAN
n-propylamine
InChI=1/C3H9N/c1-2-3-4/h2-4H2,1H3
WGYKZJWCGVVSQN-UHFFFAOYAG
aniline
InChI=1/C6H7N/c7-6-4-2-1-3-5-6/h1-5H,7H2
PAYRUJLWNCNPSJ-UHFFFAOYAP
3-chloroaniline
InChI=1/C6H6ClN/c7-5-2-1-3-6(8)4-5/h1-4H,8H2/i1-12,2-12,3-12,4-12,5-12,6-12,7-35,8-14

3,4-dihydroxyphenylacetiacid
InChI=1/C8H8O4/c9-6-2-1-5(3-7(6)10)4-8(11)12/h1-3,9-10H,4H2,(H,11,12)
CFFZDZCDUFSOFZ-UHFFFAOYAU
5-nitrosalicylic acid
InChI=1/C7H5NO5/c9-6-2-1-4(8(12)13)3-5(6)7(10)11/h1-3,9H,(H,10,11)
PPDRLQLKHRZIJC-UHFFFAOYAT
benzoic acid
InChI=1/C7H6O2/c8-7(9)6-4-2-1-3-5-6/h1-5H,(H,8,9)
WPYMKLBDIGXBTP-UHFFFAOYAD
Boc-L-tryptophan
InChI=1/C1 ​6H20N2O4/c​1-16(2,3)2​2-15(21)18​-13(14(19)​20)8-10-9-​17-12-7-5-​ 4-6-11(10)​12/h4-7,9,​13,17H,8H2​,1-3H3,(H,​18,21)(H,1​9,20)
NFVNYBJCJGKVQK-UHFFFAOYAR
2,4,6-trihydroxybenzoicacid
InChI=1/C7H6O5/c8-3-1-4(9)6(7(11)12)5(10)2-3/h1-2,8-10H,(H,11,12)
IBHWREHFNDMRPR-UHFFFAOYAP
2-methylpropeneoicacid
InChI=1/C4H6O2/c1-3(2)4(5)6/h1H2,2H3,(H,5,6)
CERQOIWHTDAKMF-UHFFFAOYAE
(±)-2-Phenylbutanoic acid
InChI=1/C10H12O2/c1-2-9(10(11)12)8-6-4-3-5-7-8/h3-7,9H,2H2,1H3,(H,11,12)
OFJWFSNDPCAWDK-UHFFFAOYAE
D-(−)-Quinic acid
InChI=1/C7H12O6/c8-3-1-7(13,6(11)12)2-4(9)5(3)10/h3-5,8-10,13H,1-2H2,(H,11,12)/t3-,4-,5?,7?/m1/s1
AAWZDTNXLSGCEK-LNVDRNJUBH
n-butanoic acid
InChI=1/C4H8O2/c1-2-3-4(5)6/h2-3H2,1H3,(H,5,6)
FERIUCNNQQJTOY-UHFFFAOYAP
Mandelic acid
InChI=1/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11)/t7-/m0/s1
IWYDHOAUDWTVEP-ZETCQYMHBP
2-Hydroxy-5-nitrobenzoicacid
InChI=1/C7H5NO5/c9-6-2-1-4(8(12)13)3-5(6)7(10)11/h1-3,9H,(H,10,11)
PPDRLQLKHRZIJC-UHFFFAOYAT
(2,5-Dimethoxyphenyl)acetic acid
InChI=1/C10H12O4/c1-13-8-3-4-9(14-2)7(5-8)6-10(11)12/h3-5H,6H2,1-2H3,(H,11,12)
BBZDYQUXRFATHZ-UHFFFAOYAX
TOSMIC
InChI=1/C9H9NO2S/c1-8-3-5-9(6-4-8)13(11,12)7-10-2/h3-6H,7H2,1H3
CFOAUYCPAUGDFF-UHFFFAOYAC
n-butylisocyanide
InChI=1/C5H9N/c1-3-4-5-6-2/h3-5H2,1H3
FSBLVBBRXSCOKU-UHFFFAOYAR
t-butylisocyanide
InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
FAGLEPBREOXSAC-UHFFFAOYAL
174C
InChI=1/C28H27N3O5/c1-3-4-15-29-27(33)26(30(2)28(34)24-17-19(31(3 ​5)36)13-14-25(24)32)23-16-18-9-5-6-10-20(18)21-11-7-8-12-22(21)23​ /h5-14,16-17,26,32H,3-4,15H2,1-2H3,(H,29,33)
RPZJNWDWTWXITK-UHFFFAOYAS
174K
InChI=1/C34H34N2O5/c1-21-13-15-24(41-21)20-36(31(39)18-22-14-16-2 ​9(37)30(38)17-22)32(33(40)35-34(2,3)4)28-19-23-9-5-6-10-25(23)26-​ 11-7-8-12-27(26)28/h5-17,19,32,37-38H,18,20H2,1-4H3,(H,35,40)
GIXHXKYXADBHHL-UHFFFAOYAS