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1H NMR (500 MHz, CDCl3): d=7.56–7.54 (m, 6H), 7.32–
7.29 (m, 6H), 7.26–7.20 (m, 3H), 3.73 (dd, J=7.3, 2H),
1.66 (d, J=1.4 Hz, 2H), 1.60 (d, J=1.4 Hz, 6H), 0.65 ppm
(d, J=1.5 Hz, 9H); 13C NMR (126 MHz, CDCl3): d=153.8,
145.1, 128.8, 128.3, 127.0, 71.4, 64.3, 53.0, 40.3, 31.7,
30.7, 30.1 ppm; MS (ESI) m/z calculated [M+Na]+:
476.28; found [M+Na]+: 476.38.
Synthetic procedure following Ugi reaction of
benzyl/benzyl strategy
Aldehyde (1 mmol) and benzylamine (1 mmol) were
mixed in MeOH (1 mL) in a vial with a magnetic stirring
bar. The reaction mixture stirred for 5 min at room tem-
perature. Isocyanide (1 mmol) and azidotrimethylsilane
(1 mmol) were then added to the reaction mixture and
it was stirred overnight at room temperature. The sol-
vent was removed under reduced pressure and the resi-
due was purified by using flash column chromatogra-
phy to obtain the desired product.
Scheme 8. Synthesis of aldehydes 27, 30, and 35 for Ugi products 5n, 5s and 5u and
preparation of di-tert-butyl sulfinyldicarbamate 32.
1-Benzyl-5-(1-benzyl-1H-tetrazol-5-yl)pyrrolidin-2-one
(5m’’): The product was obtained as a colorless solid
(60 mg, 18%). Rf =0.49 (Petroleum ether:EtOAc=2:1); 1H NMR
(500 MHz, CDCl3): d=7.38–7.24 (m, 6H), 6.97–6.95 (m, 4H), 5.40 (d,
J=15.5 Hz, 1H), 5.04 (d, J=14.9 Hz, 1H), 4.78 (d, J=15.6 Hz, 1H),
4.62 (dd, J=8.6, 5.0 Hz, 1H), 3.72–3.61 (m, 1H), 2.68–2.58 (m, 1H),
2.47–2.41 (m, 1H), 2.07–1.97 (m, 1H), 1.74–1.67 ppm (m, 1H);
13C NMR (126 MHz, CDCl3): d=174.6, 154.5, 135.1, 133.0, 129.5,
129.4, 129.2, 128.5, 128.3, 127.4, 51.1, 50.9, 45.3, 29.5, 24.4 ppm;
MS (ESI) m/z calculated [M+Na]+: 356.15; found [M+Na]+: 356.30.
Synthetic procedure following Ugi reaction of mixed strat-
egy
Scheme 9. Synthesis of Schiff bases 37 and 40 for Ugi products 6v and 6w.
Methyl
4-(1-benzyl-1H-tetrazol-5-yl)-4-(tritylamino)butanoate
vent peak. Mass spectra (HRMS) were recorded on an Orbitrap XL
(Thermo Fisher Scientific; ESI pos. mode, resolution of 60000 m/z
400). Electrospray ionization mass spectra (ESI-MS) were recorded
on a Waters Investigator Semi-prep 15 SFC-MS instrument. Mass
spectra for deprotected a-amino acid-isosteric a-amino tetrazoles
were measured on an API 3000 triple-quadrupole mass spectrome-
ter (Applied Biosystems/MDS Sciex) via a TurboIonSpray source.
Thin-layer chromatography was performed on precoated silica gel
plates (TLC Silica gel 60 F254). Flash chromatography was performed
on a Teledyne ISCO Combiflash Rf, using RediSep Rf Normal-phase
Silica Flash Columns (Silica Gel 60 , 230–400 mesh). Reagents
were available from commercial suppliers and used without any
purification unless otherwise noted.
(5m): The product was obtained as a light yellow or colorless solid
(239 mg, 45%). Rf =0.32 (Petroleum ether:EtOAc 3:1); 1H NMR
(500 MHz, CDCl3): d=7.38–7.23 (m, 10H), 7.22–7.10 (m, 8H), 7.08–
7.01 (m, 2H), 5.21 (d, J=15.3 Hz, 1H), 4.78 (d, J=15.3 Hz, 1H), 4.18
(d, J=5.6 Hz, 1H), 3.58 (s, 3H), 2.23–2.17 (m, 1H), 2.04–1.98 (m,
1H), 1.92–1.87 (m, 1H), 1.59–1.52 ppm (m, 1H); 13C NMR (126 MHz,
CDCl3): d=173.4, 157.1, 145.2, 133.2, 129.2, 129.0, 128.9, 128.5,
128.1, 127.9, 126.8, 71.4, 51.8, 50.9, 47.0, 31.5, 28.9 ppm; MS (ESI)
m/z calculated [M+Na]+: 540.24; found [M+Na]+: 540.21.
4-(1-Benzyl-1H-tetrazol-5-yl)-4-(tritylamino)butanamide
(5m’):
Methyl 4-(1-benzyl-1H-tetrazol-5-yl)-4-(tritylamino)butanoate (5m;
0.2 g, 0.5 mmol) was dissolved in THF/H2O=1/1 (2 mL) containing
lithium hydroxide (48 mg, 1 mmol). The reaction mixture was
stirred overnight at room temperature. The solvent was removed
and the reaction mixture was acidified to pH 3 with 2 M HCl aque-
ous solution. Then it was extracted with CH2Cl2 (10 mL 3). The or-
ganic layer was collected and concentrated to give the product as
a white solid with a quantitative yield. It was used directly in the
next step without further purification. 4-(1-benzyl-1H-tetrazol-5-yl)-
4-(tritylamino)butanoic acid (0.2 g, 0.5 mmol) was dissolved in THF
(4 mL) and the resultant solution was degassed with N2. Then DIEA
(0.3 mL, 2.3 mmol), HOBt (67 mg, 0.55 mmol), and EDCI (88 mL,
0.055 mmol) were added. The reaction mixture was stirred for
10 min at room temperature. Ammonium carbonate (173 mg,
1.8 mmol) was added. The reaction mixture was further stirred
overnight at room temperature. The solvent was removed and
CH2Cl2 (7 mL) and water (7 mL) were added. The aqueous phase
was separated and extracted with CH2Cl2 (20 mL 3). The organic
Synthetic procedure following Ugi reaction of trityl/tert-
octyl and trityl/benzyl strategy
Aldehyde (1 mmol) and tritylamine (1 mmol) were suspended in
MeOH (1 mL) in a sealed vial with a magnetic stirring bar. The reac-
tion was heated at 1008C for 15 min by using microwave irradia-
tion. Isocyanide (1 mmol) and azidotrimethylsilane (1 mmol) were
then added into the reaction mixture and further heated at 1008C
for 15 min by using microwave irradiation. The solvent was re-
moved under reduced pressure and the residue was purified by
using flash column chromatography.
1,1,1-Triphenyl-N-((1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-
yl)methyl)methanamine (5a): The product was obtained as
a white solid (254 mg, 56%). Rf =0.43 (Petroleum ether:EtOAc 3:1);
Chem. Eur. J. 2016, 22, 3009 – 3018
3015
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