Objective

To synthesize a 16 Ugi adducts using Ugi 4CR following Explan005 .The target compound were ranked 13-30 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 sixteen vials, labeled 13-29) (except 23) and charged with methanol, four reactants [aldehyde, amine, acid and isocyanide] (1mmol each) were added to each in that order. After each addition, the resulting solution was vortexed for 15s (or more) and confirmed that a homogeneous solution had been obtained. The vials were capped tight and left at room temperature. After crystallization, the solution was decanted and the solid was washed with methanol (3x 500uL, and dried under vacuum to obtain corresponding di-amides
173B/14 N-[2-(tert-butylamino)-2-oxo-1-(p-tolyl)ethyl]-N-methyl-4-pyren-1​-yl-butanamide: C34H36N2O2; White solid; M.Pt- 140-142C; 1H NMR (external image delta.gif ppm, 500MHz, CDCl3) 1.35 (s, 9H), 2.16-2.28 (m, 2H), 2.30 (s, 3H), 2.36-2.45 (m, 1H), (2.46-2.60 (m, 1H), 2.76 (s, 3H), 3.38 (ddd, 2H J=9.3, 6.5, 7.5Hz), 5.71 (bs, 1H), 6.24 (s, 1H), 7.14 (d, 2H, J=8.0Hz), 7.21 (d, 2H, J=8.0Hz), 7.82 (d, 1H, J=7.7Hz), 7.90-8.20 (m, 7H), 8.30 (d, 1H, J=9.3Hz); 13C NMR (external image delta.gif ppm, CDCl3) 20.8, 26.5, 28.5, 32.2, 32.5, 32.8, 51.3, 60.1, 123.2, 124.4, 124.5, 124.7, 124.8, 125.5, 126.3, 127.0, 127.1, 127.2, 128.5, 128.9, 129,2, 129.6, 130.6, 131.1, 132.7, 136.0, 137.7, 169.3, 173.2; HRMS (FAB,m-nitrobenzyl alcohol): m/z calcd for C34H36N2O2Na (M+Na) 527.2674 Da, found 527.2667 Da; yield 46%
173G19-4 N-benzyl-N-[2-butylamino-1-(3,5-dimethoxyphenyl)-2-oxo-ethyl]-3-p​henyl-prop-2-ynamide: C30H32N2O4; White solid; M.Pt-137-139C; 1H NMR (external image delta.gif ppm, 500MHz, CDCl3); listed NMR peaks are common to both rotamers (E, Z) unless otherwise stated; rotamers are denoted by major and minor and are present in a 3:1 ratio at rt) 0.79 (t, 3H, J=7.3 Hz, minor), 0.88 (t, 3H, J= 7.3Hz, major), 1.13-1.23 (m, 2H, minor), 1.24-1.33 (m, 2H, major), 1.37-1.50 (m, 2H), 3.12-1.24 (m, 1H), 3.23-3.34 (m, 1H), 3.65 (s, 6H, major), 3.66 (s, 6H, minor), 4.59 (d, 1H, J= 15.1Hz, minor), 4.66 (d, 1H, J= 15.1Hz, minor), 4.78 (d, 1H, J= 16.6 Hz, major), 5.14 (d, 1H, J= 16.6 Hz, major), 5.68 (s, 1H, major), 5.97 (t, 1H, J= 5.8Hz, minor), 6.04 (t, 1H, J= 5.8Hz, major), 6.12 (s, 1H, minor), 6.29-6.34 (m, 1H, major), 6.35-6.37 (m, 1H, minor), 6.40 (d, 1H, J=2.4Hz), minor),6.43 (d, 1H, J=2.4Hz, major), 7.09 (dd, 1H, J= 7.8, 1.4Hz), 7.14-7.23 (m, 5H), 7.24-7.31 (m, 2H), 7.32-7.48 (m, 2H), 7.56 (d,H, J= 7.8Hz); 13C NMR (external image delta.gif ppm, CDCl3 / CD3OD) 13.11(minor), 13.17(major), 19.60, 30.79(major), 30.85(minor), 39.01(major), 39.06(minor), 47.26, 51.45, 54.87(major), 54.91(minor), 62.25(major), 66.32(minor), 80.80(minor), 81.39(major), 91.40(major), 92.70(minor), 100.50(minor), 100.55(major), 107.54(major), 107.60(minor), 119.50(minor), 119.53(major), 126.55(major), 126.65(minor), 127.34, 127.71(minor), 127.78(major), 128.16(major), 128.27(minor), 130.06(major), 130.25(minor), 132.08(major), 132.23(minor), 135.50(major), 135.54(minor), 137.10(major), 137.50(minor), 156.16(minor), 156.29(major), 160.44(major), 160.56(minor) 168.78(major), 168.95(minor). HRMS (FAB,m-nitrobenzyl alcohol): m/z calcd for C30H32N2O4Na (M+Na) 507.2259 Da, found 507.2247 Da; yield 44%


ExpID/
VB2Rank
Solvent Methanol
Aldehyde
Amine
Acid
Isocyanide
Ppt(Y/N) & Yield
173A/13
Methanol
2-hydroxybenzaldehyde
(1mmol,106.6uL)
Aniline
(1mmol,91.1uL)
4-chlorophenylacetic acid (1mmol,170.6mg)
Tosylmethylisocyanide
(1mmol, 195.24mg)
N
173B/14
Methanol
4-methylbenzaldehyde
(1mol,118uL)
Methylamine
(1mmol,500uL)
1-Pyrenebutanoic acid
(1mmol,288.3mg)
t-butylisocyanide
(1mmol,113.1uL)
Y
Yield 46%
173C/15
Methanol
4-(trifluoromethyl)benzaldehyde
(1mmol,136.5uL)
Methylamine
(1mmol,500uL)
1-Pyrenebutanoic acid
(1mmol, 288.3mg)
t-butylisocyanide
(1mmol, 113.1uL)
Reactants insoluble under the conditions
173D/16
Methanol
2-hydroxybenzaldehyde
(1mmol, 106.5uL)
Methylamine
(1mmol, 500uL)
1-Pyrenebutanoic acid
(1mmol, 288.3mg)
n-Butylisocyanide
(1mmol,104.5uL)
Reactants insoluble under the conditions
173E/17
Methanol
3,4-dihydroxybenzaldehyde
(1mmol, 138.1mg)
Methylamine
(1mmol, 500uL)
Boc-tryptophan
(1mmol, 304.3mg)
t-butylisocyanide
(1mmol, 113.1uL)
N
173F/18
Methanol
Phenanthrene-9-carbaldehyde
(1mmol, 206.2mg)
Furfurylamine
(1mmol, 88.3uL)
2,3-dihydroxybenzoic acid
(1mmol, 1)154.1mg
t-butylisocyanide
(1mmol, 113.1uL)
N
173G/19
Methanol
3,5-dimethoxybenzaldehyde
(1mmol, 166.2mg)
Benzylamine
(1mmol,109.2uL)
Phenylpropynoic acid
(1mmol, 146.1mg)
n-Butylisocyanide
(1mmol, 104.5uL)
Y
Yield 44%
173H/20
Methanol
2-Naphthaldehyde
(1mmol, 156.2mg)
5-Methyl furfurylamine
(1mmol,111.5uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
N
173I/21
Methanol
3-hydroxybenzaldehyde
(1mmol, 122.1mg)
Methylamine
(1mmol, 500uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
N
173J/22
Methanol
3,4-dihydroxybenzaldehyde
(1mmol, 138.1mg)
Methylamine
(1mmol, 500uL)
1-Pyrenebutanoic acid
(1mmol,288.3mg)
t-butylisocyanide
(1mmol, 113.1uL)
Reactants insoluble under the conditions
173L24
Methanol
3-hydroxybenzaldehyde
(1mmol, 122.1mg)
Furfurylamine
(1mmol, 88.4uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
N
173M/25
Methanol
4-chlorobenzaldehyde
(1mmol, 140.5mg)
Furfurylamine
(1mmol, 88.4uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
N
173N/26
Methanol
2-hydroxy-3-methoxy benzaldehyde (o-vanillin)
(1mmol, 152.1mg)
2-Chloroaniline
(1mmol,105.2uL)
decanoic acid
(1mmol, 192.9mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
Waiting Analysis
173O/27
Methanol
Benzaldehyde
(1mmol, 101.5uL)
Furfurylamine
(1mmol, 88.4uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
Y
173P/28
Methanol
3-methoxy benzaldehyde
(1mmol, 121.9uL)
Methylamine
(1mmol, 500uL)
1-Pyrenebutanoic acid
(1mmol,288.3mg)
t-butylisocyanide
(1mmol, 113.1uL)
Reactants insoluble under the conditions
173Q/29
Methanol
4-methylbenzaldehyde
(1mmol, 118uL)
Furfurylamine
(1mmol, 88.4uL)
3,4-dihydroxy phenylacetic acid
(1mmol, 168.1mg)
Tosylmethylisocyanide
(1mmol, 195.2mg)
N
Compounds ranked 23 and 30 will be synthesized at a later date - 4-hydroxybenzaldehyde is not available at this time.

Results


Pictures taken soon after the addition of all reactants.
173A/13
173B/14
173C/15
173D/16
173E/17
173F/18
173G/19
173H/20
173I/21
173J/22
173L/24
173M/25
17N/26
173O/27
173P/28
173Q/29
173A-13.JPG
173B-14.JPG
173C-15.JPG
173D-16.JPG
173E-17.JPG
173F-18.JPG
173G-19.JPG
173H-20.JPG
173I-21.JPG
173J-22.JPG
173L-24.JPG
173M-25.JPG
173N-26.JPG
173O-27.JPG
173P-28.JPG
173Q-29.JPG
Pictures taken on the fifth day after the addition of all reactants
173A/13-2
173B/14-2
173C/15-2
173D/16-2
173E/17-2
173F/18-2
173G/19-2
173H/20-2
173I/21-2
173J/22-2
173L/24-2
173M/25-2
17N/26-2
173O/27-2
173P/28-2
173Q/29-2
173A-13.JPG
173B-2.JPG
173C-2.JPG
173D-2.JPG
173E-2.JPG
173F-2.JPG
173G-2.JPG
173H-2.JPG
173I-2.JPG
173J-2.JPG
173L-2.JPG
173M-2.JPG
173N-2.JPG
173O-2.JPG
173P-2.JPG
173Q-2.JPG

Pictures taken if any significant changes were observed
173A/13-3
173B/14-3
173C/15-3
173D/16-3
173E/17-3
173F/18-3
173G/19-3
173H/20-3
173I/21-3
173J/22-3
173L/24-3
173M/25-3
17N/26-3
173O/27-3
173P/28-3
173Q/29-3
No Ppt
173B14-7thday.JPG
Reactants
insoluble
Reactants
insoluble
No Ppt
No Ppt
Crystals reported
Deep green coating on walls
No Ppt
Reactants
insoluble
No Ppt
No Ppt
Ppt isolated
173O-9thday.JPG
Reactants
insoluble
No Ppt
Aborted
7th day
ISOLATED
Aborted
Aborted
Aborted
Aborted
5th day
ISOLATED
Aborted
Aborted
Aborted
Aborted
Aborted
5th day
ISOLATED
9th day
ISOLATED
Aborted
Aborted

Characterization of 173B14-4
amount: 232 mg ; Yield- 46 %
  1. Melting Point :140-142C
  2. IR
  3. HNMR(300MHz)
  4. HNMR(500MHz)
  5. HNMR [H-Exchange with methanol-d4]
  6. Overlay [with labile H Vs Exchanged]
  7. CNMR
  8. FAB-MS (Nominal Mass)
  9. FAB-MS (HRMS)
Characterization of 173G19-4
amount: 213 mg; Yield- 43.9 %
  1. Melting Point :137-139C
  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)

Characterization of 173O27-4
amount: 035 mg (Yield %)
  1. Melting Point :176-178 C
  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)

Discussion

Based on the images of 173B, it appears that all the undissolved starting material went into solution by day 5 then a precipitate formed on day 7 without any vortexing. This suggests that it is worth taking pictures every day to observe exactly how long the dissolution process took.
IR - Shows the presence of carbonyl at 1624 cm-1, amide NH at 3318cm-1, etc.
NMR - Proton NMR : A siglet corresponding to t-butyl (9H) is seen at 1.34 ppm, the region between 1.56 - 2.0 ppm is populated with a lot of signals, which may be attributed to the diastereotopic protons (from pyrene-butyric acid precursor) and one of the methyl groups (most likely one on benzene ring). This region some how integrates for more than 7 protons (expected)..this may either be due to instrument malfunction or impurities in the sample. A nice doublet of doublet of doublet integrating for 2H is seen at 3.31 ppm the coupling constants (9.3, 6.5 7.5Hz) and the location of the peak suggests that it corresponds to the diasterotopic CH2 connected to the pyrene ring...(see SDBS # 6700). The chiral proton appears at 6.3 ppm and the amide NH at 5.94ppm.Yield 46%

IR - Shows the presence of carbonyls at 1600 and 1632 cm-1, amide at 3274 cm-1 and C≡C stretch at 2222 cm-1.
NMR - Proton NMR : Most peaks are duplicated, indicating the presence of (E/Z) rotamers. This can be a result of rotation along a double bond formed by resonance between N- and the carbon of the carbonyl group.
Diasterotopic methylenes: The spectrum is further complicated by the diastereotopic nature of the CH2 groups of the n-butyl side chain and the benzylic CH2. Each proton of the diastereotopic CH2 next to the methyl group could in theory be a dddq (total 32 peaks), each proton of the following CH2 could be ddddd (total 32 peaks) and similarly a ddddd for each proton of the next CH2. Each proton of the benzylic methylene of each rotamer appears as dd (J=xxHz) . However, since the n-butyl side chain is not very close to the chiral center, the splitting effect (magnetic non-equivalence) is not as pronounced consequently, a less complex spectrum. The enantiomeric (chiral) proton is seen as a singlet at 5.68 ppm.
Rotamers : The two rotamers are in a ~3:1 ratio, a NOE experiment may be able to tell which of the two rotamers (E or Z) is more favored. The n-butyl side chain is seen for both the rotamers; for instance the terminal methyl group of the favored rotamer is seen at 0.88 ppm and for the other is seen at 0.79 ppm (in a ~ 3:1) ratio).. A similar duplication is seen for the benzylic CH2 groups. Yield 44%


Conclusion

Only two Ugi products were obtained.


Log

2008-02-24

13:00 Weighed all the solid aldehydes (1mmol).
14:00 Made up a solutions of all aldehydes (1mmol) in methanol. Vials requiring methylamine solution in methanol were added only 3500uL methanol (to make it even 4mL after the amine (500uL) addition) All other vials which use different amines were added 4mL of methanol. Vortexed each to make a homogenous solution, all aldehydes except phanthrene-9-carboxaldehyde dissolved in methanol.
15:35: Added respective amines to each aldehyde solution. Vortexed each solution to homogenize it. Obtained a picture after amine addition .
18:50 It was noticed that vial 173N/26 (-o-vanillin, o-chloroaniline in methanol), previously clear, now formed crystals..(maybe the imine); even after vortexing for 3min the crystals did not dissolve..
19:20 Weighed out all the acids and tosylmethyl isocyanide (1mmol,195.2mg x 8).
20:00 Started adding respective acids to the previously made aldehyde/amine solutions.Vortexed each solution.
21:26 Obtained a picture of the vials after acid addition. The previously insoluble reactants from vial 173F/18 with Phenanthrene-9-carboxaldehyde and furfurylamine dissolved after the addition of 2,3-dihydroxybenzoic acid..ofcourse a little extra vortexing (4min) was required. Solutions to which 1-Pyrenebutanoic acid was added remained undissolved (173B/14, 173C/15, 173D/16, 173J/22, 173P/28). Apart from these, contents of vial 173N/26 remained undissolved after the addition of decanoic acid.
21:28 Started adding respective isocyanides to the vials. Vortexed for 15s...all the clear dissolved the isocyanides without any problem...the ones which had solid, still remained so...(previously mentioned six)
21:53 Obtained a picture of the vials after isocyanide additions.

2008-02-29

17:30 Obtained a picture of the vials (all series -2 pics) remember to vortex before taking pic in case solution supersaturated
missing log entry for day 7 pics and observations

2008-03-04

13:30 Observed crystals in 173O/27, obtained a picture.

2008-03-20

16:00 The methanolic solution from the crystalline products 173B/14, 173G/19 and 173O/27 was decanted. To the solid in the vials, methanol (1ml) was added, vortexed, transferred to a pre-weighed small vial and centrifuged. The supernatant was decanted. The solid was washed with methanol (2 x 1ml). A total of three methanol washes were performed.
19:40 The solid obtained after the decanting the supernatant was set under a high vac.
22:30 Removed the products from the high vac and stored them uncapped in a desiccator set under house vac. The products are now renamed as 173B/14-4, 173G/19-4, 173O/27-4.

2008-03-21

14:30 Obtained
  • 173B/14-4 -- 232 mg
  • 173G/19-4 -- 213 mg
  • 173O/27-4 -- 035 mg

2008-03-23

14:52 Obtained HNMR of 173B/14-4 after dissolving it in CDCl3 (1ml)
18:00 Obtained CNMR of 17B/14-4.

2008-03-25

16:00 Obtained CNMR of 173G/19-4
18:00 Obtained CNMR of 173O/27-4
19:00 Decanted the solutions from the NMR tubes after adding methanol (1ml) to the NMR tubes (173B/14-4, 173G/19-4, 173O/27-4) in to a vial, evaporated the solvent and set them in a desiccator under a high vac.
21:00 Turned off the high vac and connected the high vac to house vac.

2008-03-26

11:00 The dry compounds were capped and stored back under vacuum.

2008-03-29

14:00 Tried to dissolve 173N in DMSO-d6..no success...IRof 173N (130mg)

Tags

Compound
Inchi
InchiKey
2-hydroxybenzaldehyde
InChI=1/C7H6O2/c8-5-6-3-1-2-4-7(6)9/h1-5,9H
SMQUZDBALVYZAC-UHFFFAOYAD
4-methylbenzaldehyde


4-(trifluoromethyl)benzaldehyde


3,4-dihydroxybenzaldehyde


Phenanthrene-9-carbaldehyde


3,5-dimethoxybenzaldehyde


2-Naphthaldehyde


3-hydroxybenzaldehyde


3,4-dihydroxybenzaldehyde


4-chlorobenzaldehyde


2-hydroxy-3-methoxy benzaldehyde (o-vanillin)


Benzaldehyde


3-methoxy benzaldehyde


Aniline


Methylamine


Furfurylamine


5-Methyl furfurylamine


2-Chloroaniline


Benzylamine


173B14-4
InChI=1/C34H36N2O2/c1-22-12-14-27(15-13-22)32(33(38)35-34(2,3)4)3 ​6(5)29(37)11-7-8-23-16-17-26-19-18-24-9-6-10-25-20-21-28(23)31(26​ )30(24)25/h6,9-10,12-21,32H,7-8,11H2,1-5H3,(H,35,38
KNHNINYGWDFMQZ-UHFFFAOYAI
173G19-4
InChI=1/C30H32N2O4/c1-4-5-18-31-30(34)29(25-19-26(35-2)21-27(20-2 ​5)36-3)32(22-24-14-10-7-11-15-24)28(33)17-16-23-12-8-6-9-13-23/h6​ -15,19-21,29H,4-5,18,22H2,1-3H3,(H,31,34)
VOGZWAORWZGOTE-UHFFFAOYAY
173N26-4
InChI=1/C33H41ClN2O6S/c1-4-5-6-7-8-9-10-18-30(37)36(28-16-12-11-1 ​5-27(28)34)31(26-14-13-17-29(42-3)32(26)38)33(39)35-23-43(40,41)2​ 5-21-19-24(2)20-22-25/h11-17,19-22,31,38H,4-10,18,23H2,1-3H3,(H,3​5,39)
KYIHNAOLRBXNCE-UHFFFAOYAO
173O27-4**
InChI=1/C29H28N2O7S/c1-20-9-12-24(13-10-20)39(36,37)19-30-29(35)2 ​8(22-6-3-2-4-7-22)31(18-23-8-5-15-38-23)27(34)17-21-11-14-25(32)2​ 6(33)16-21/h2-16,28,32-33H,17-19H2,1H3,(H,30,35)
UBEBESNSOHELHI-UHFFFAOYAZ