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36, 7507; (c) Moreaux, V.; Warren, H.; Williams, J. M.
Tetrahedron Lett. 1997, 38, 4566; (d) Vonhoff, S.; Vasella,
A. Synth. Commun. 1999, 29, 551.
extracted with EtOAc (3 · 300 mL). The organic fractions
were combined, washed with saturated aqueous NaCl
solution (200 mL), dried over MgSO4, filtered, and con-
centrated to afford the crude product. Recrystallization
from EtOAc/hexanes afforded 20 g (99% yield) of 3a as a
10. (a) EI-AhI, A. S.; Elmorsy, S. S.; Soliman, H.; Amer, F. A.
Tetrahedron Lett. 1995, 36, 7337; (b) Eshghi, H.; Has-
sankhani, A. Synth. Commun. 2005, 35, 115; (c) Suzuki,
H.; Hwang, Y. S.; Nakaya, C.; Matano, Y. Synthesis 1993,
1218.
11. (a) Banik, B. K.; Venkatraman, M. S.; Mukhopadhyay,
C.; Becker, F. F. Tetrahedron Lett. 1998, 39, 7247; (b)
Murahashi, S.-I.; Komiya, N.; Oda, Y.; Kuwabara, T.;
Naota, T. J. Org. Chem. 2000, 65, 9186; (c) Harvey, R. G.;
Abu-shqara, E.; Yang, C.-X. J. Org. Chem. 1992, 57,
6313.
1
white solid. Spectral data for the major isomer: H NMR
(500 MHz, methanol-d4): d 7.39 (d, 2H, J = 7.2 Hz), 7.35
(d, 2H, J = 7.3 Hz), 7.29 (t, 1H, J = 7.2 Hz), 5.13 (d, 1H,
J = 8.8 Hz), 4.69 (ddd, 1H, J = 14.3, 8.3, 2.2 Hz), 4.59
(ddd, 1H, J = 13.7, 7.2, 2.7 Hz), 3.56 (dt, 1H, J = 7.9
2.7 Hz), 2.13–2.06 (m, 1H), 1.88–1.71 (m, 2H), 1.60 (m,
1H), 1.49 (m, 1H) ppm; 13C NMR (500 MHz, methanol-
d4): d 158.36, 142.52, 129.24 (2C), 128.87, 127.52 (2C),
74.68, 49.87, 43.86, 28.39, 27.50, 26.86 ppm; HRMS for
C13H14N4, Calcd for (M+H)+: 227.1297, Found:
227.1296.
7,8-Dihydro-5H-tetrazolo[1,5-a]azepin-9(6H)-one (4a):
A solution of compound 3a (24 g, 106 mmol) in MeOH
(500 mL) and CH2Cl2 (400 mL) was cooled ꢀ78 ꢁC.
Ozone was passed through until a blue-purple color
persisted. Nitrogen was then passed through the reaction
mixture to remove the excess ozone. Dimethyl sulfide
(5 mL) was added and the reaction was warmed to room
temperature and stirred overnight. The mixture was
concentrated and chromatographed on a silica gel column
with 50–80% of EtOAc/hexanes as the eluant to afford
13 g (81% yield) of compound 4a as a white solid. 1H
NMR (500 MHz, methanol-d4): d 4.75 (dd, 1H, J = 13.8,
4.4 Hz), 4.30 (dd, 1H, J = 13.8, 1.1 Hz), 2.17 (dt, 1H,
J = 11.6, 2.8 Hz), 2.07–1.84 (m, 4H), 1.65 (m, 1H) ppm;
13C NMR (500 MHz, methanol-d4): d 157.26, 95.21, 49.83,
37.88, 27.34, 23.84 ppm; HRMS for C6H8N4O, Calcd for
(M+H)+: 153.0776, Found: 153.0775; Anal. Calcd for
C6H8N4O: C, 47.36; H, 5.30; N, 36.82. Found: C, 47.30;
H, 5.25; N, 36.81.
12. The addition of a-lithio-1-methyl-5-ethyltetrazole to 4,40-
difluorobenzophenone and subsequent dehydration to
generate an a-olefinic tetrazole has been previously
reported, see: Sit, S. Y.; Parker, R. A.; Motoc, I.; Han,
W.; Balasubramanian, N.; Catt, J. D.; Brown, P. J.; Harte,
W. E.; Thompson, M. D.; Wright, J. J. J. Med. Chem.
1990, 33, 2982.
13. Phenyl(6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a]azepin-9-yl)-
methyl acetate (2a): A solution of 6,7,8,9-tetrahydro-5H-
tetrazolo[1,5-a]azepine 1a (30 g, 217 mmol) in dry THF
(800 mL) was cooled to ꢀ78 ꢁC. A 2.5 M solution of
n-BuLi in hexanes (88 mL, 220 mmol) was added dropwise
over 20 min and the resulting orange-reddish solution was
stirred for 30 min. Freshly distilled benzaldehyde
(22.2 mL, 218 mmol) was added dropwise over 20 min
and the resulting colorless solution was stirred for
additional 20 min at ꢀ78 ꢁC. Freshly distilled acetyl
chloride (15.7 mL, 220 mmol) was added over a 15 min
period. The reaction was warmed to room temperature
within 30 min and diluted with saturated aqueous NH4Cl
solution (200 mL) and extracted with ethyl acetate
(3 · 200 mL). The organic fractions were combined,
washed with saturated aqueous NaCl solution (100 mL),
dried over MgSO4, filtered, and concentrated to give the
crude product as an off white solid. Recrystallization from
EtOAc/hexanes afforded 25.4 g of 2a. The mother liquor
was concentrated and chromatographed to give additional
25 g 2a (81% yield). Spectral data for the major isomer: 1H
NMR (500 MHz, CDCl3): d 7.46 (d, 2H, J = 6.6 Hz),
7.40–7.33 (m, 3H), 6.24 (d, 1H, J = 11.0 Hz), 4.71 (dd, 1H,
J = 14.5, 6.6 Hz), 4.54 (dd, 1H, J = 12.6, 10.4 Hz), 3.85
(m, 1H), 2.01–1.95 (m, 2H), 1.82 (s, 3H), 1.80–1.69 (m,
2H), 1.57 (m, 1H), 1.46 (m, 1H) ppm; 13C NMR
(500 MHz, CDCl3): d 169.71, 155.82, 136.73, 129.01,
128.83 (2C), 127.47 (2C), 73.30, 49.05, 40.34, 26.65,
26.31, 25.15, 20.62 ppm, HRMS for C15H18N4O2, Calcd
for (M+H)+: 287.1508, Found: 287.1504.
14. It has been demonstrated that 5-substituted-1-alkyltetra-
zoles can be lithiated at the alkyl carbon attached to the
nitrogen and react with electrophiles, see: (a) Moody, C.
J.; Rees, C. W.; Young, R. G. J. Chem. Soc., Perkin Trans.
1 1991, 323; (b) Thomas, E. W.; Cudahy, M. M. J. Org.
Chem. 1993, 58, 1623.
15. For 4a, colorless intergrown plates from EtOAc/hexanes:
T = ꢀ50 ꢁC, a = 12.737(9), b = 6.988(5), c = 8.103(6),
V = 721(1), orthorhombic space group, Pca21, Z = 4,
R = 0.074, Rw = 0.11 for 552 observed intensities at with
I > 3r(I), mp 99–108 ꢁC; refinement of the isomeric struc-
ture with N4 and C5 interchanged gave a significantly
higher R factor (R = 0.10, Rw = 0.20). For 4b: colorless
intergrown plates from EtOAc/hexanes: T = ꢀ50 ꢁC,
a = 14.883(1), b = 6.741(4), c = 6.236(2), V = 625.6(7),
orthorhombic space group, Pna21, Z = 4, R = 0.07,
Rw = 0.12 for 432 observed intensities at with I > 3r(I),
mp 99–112 ꢁC; refinement of the isomeric structure with N4
and C5 interchanged gave a significantly higher R factor
(R = 0.09, Rw = 0.14). CCDC 627731 and CCDC 627732
contain the supplementary crystallographic data (excluding
structure factors) for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
9-Benzylidene-6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a]aze-
pine (3a): To a solution of compound 2a (25.4 g,
88.8 mmol) in dry THF (800 mL) at 0 ꢁC was added
1.0 M potassium t-butoxide in THF (98 mL, 98 mmol)
over 30 min. The reaction was stirred at 0 ꢁC for
additional 30 min and then at room temperature for
30 min. The resulting yellowish solution was quenched
with saturated aqueous NaHCO3 solution (100 mL) and