Metal triflate catalyzed reactions of alkenes, NBS, nitriles, and TMSN 3: Synthesis of 1,5-disubstituted tetrazoles

Article abstract of DOI:10.1021/jo062432j

A versatile and highly efficient protocol for the synthesis of 1,5-disubstituted tetrazoles has been developed by metal triflate catalyzed one-pot reaction of alkenes, NBS, nitriles, and TMSN₃. Among the metal triflates, Zn(OTf)₂ was found to be the best catalyst. Use of different combinations of alkenes and nitriles generate a variety of 1,5-disubstituted tetrazoles containing an additional α-bromo functionality of the N1-alkyl substituent.

Full text of DOI:10.1021/jo062432j

Recently, 1-benzyl-5-aryltetrazoles were found to be novel
antagonists for the P2X7 receptor.7
Metal Triflate Catalyzed Reactions of Alkenes,
NBS, Nitriles, and TMSN3: Synthesis of
1,5-Disubstituted Tetrazoles
Intheliterature,1H-tetrazoles8 andpolycyclicfusedtetrazoles6b,9
are mostly prepared by inter- and intramolecular [3 + 2]-cy-
cloaddition, respectively, of azides and nitriles. 1,5-Disubstituted
tetrazoles are usually obtained from secondary amides or
thioamides on reaction with PCl5/HN3,3 TMSN3/Ph3P/DEAD,10
and TMSN3/Et3N/Hg(II),11 mostly under noncatalytic conditions.
Hassner reported AgClO4-promoted reaction of alkenes, halo-
gens (Br2 or I2), nitriles, and NaN3, noting the ability to produce
the 1,5-disubstituted tetrazoles.12 Many methods for the synthesis
of tetrazoles are known, but due to their importance, the
development of new synthetic approaches using mild reaction
conditions remains an active research area. In this paper, we
describe a metal triflate catalyzed one-pot reaction of alkenes,
N-bromosuccinimide (NBS), nitriles, and trimethylsilyl azide
(TMSN3) for the expedient synthesis of 1,5-disubstituted tet-
razoles containing an additional R-bromo functionality of the
N1-alkyl substituent that might provide a further avenue for
structural elaboration.
Saumen Hajra,* Debarshi Sinha, and
Manishabrata Bhowmick
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721 302, India
shajra@chem.iitkgp.ernet.in
ReceiVed NoVember 27, 2006
We are involved in stereoselective 1,2-halo functionalization
of alkenes and recently found that Lewis acids, in particular,
metal triflates, activate NBS to facilitate the formation of
halonium ions from alkenes.13 Accordingly, we anticipated that
a suitable metal triflate might catalyze the reaction of alkenes,
NBS, nitriles, and TMSN3 and that would produce the 1,5-
A versatile and highly efficient protocol for the synthesis of
1,5-disubstituted tetrazoles has been developed by metal
triflate catalyzed one-pot reaction of alkenes, NBS, nitriles,
and TMSN3. Among the metal triflates, Zn(OTf)2 was found
to be the best catalyst. Use of different combinations of
alkenes and nitriles generate a variety of 1,5-disubstituted
tetrazoles containing an additional R-bromo functionality of
the N1-alkyl substituent.
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respectively.2-4 An enormous number of tetrazole-containing
biologically active compounds are known in the literature.5,6
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10.1021/jo062432j CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/01/2007
1852
J. Org. Chem. 2007, 72, 1852-1855

TABLE 1. Screening of Metal Triflates as Catalysts for the
Reaction of 1a with NBS, Acetonitrile, and TMSN3
TABLE 2. Synthesis of 5-Methyltetrazoles via Zn(OTf)2-Catalyzed
Reaction of Alkenes, NBS, CH3CN, and TMSN3
entry
MLn
none
La(OTf)3
Yb(OTf)3
Y(OTf)3
Sm(OTf)3
In(OTf)3
Zn(OTf)2
t (h)
12
10
5
1
1
1
2a/3aa
yield of 2ab (%)
1
2
3
4
5
6
7
50:50c
78:22
80:20
>95:05
>95:05
>95:05
>95:05
20
70
73
82
84
70
87
10 min
a Determined from 1H NMR analysis of the crude reaction mixture.
b Isolated yield of pure 2a after column chromatography. c Along with an
equal amount of 4a.
disubstituted tetrazoles along the lines of the Hassner method.12
In searching for an effective catalyst, we initiated the reaction
of styrene with NBS, acetonitrile, and TMSN3 in the presence
of different Lewis acids, in particular, metal triflates (Table 1).
Among the metal triflates studied, Zn(OTf)2 was found to be
the best catalyst. It should be noted that in the absence of Lewis
acid, 1a reacts very slowly with NBS, CH3CN, and TMSN3,
and after 12 h, a mixture of 1,2-bromotetrazole 2a, bromoazide
3a, and dibromide 4a (1:1:1) was obtained (Table 1, entry 1).
When substrate 1a was treated with 0.05 equiv of Zn(OTf)2,
1.2 equiv of NBS, 1.5 equiv of TMSN3, and 4 Å MS in CH3-
CN at rt (25 °C), within 10 min, tetrazole 2a was selectively
obtained in 87% yield (entry 7). It is worth mentioning that
presence of 4 Å MS in the reaction medium inhibits the
formation of undesired halohydrin compounds.
This method could produce an enormous number of 1,5-
disubstituted tetrazoles, if different combinations of alkenes and
nitriles are reacted. Initially, a variety of alkenes were subjected
to the catalytic reaction in CH3CN and selectively produced
tetrazoles 2 (R3 ) CH3; Table 2) with anti-stereochemistry as
a Isolated yields of tetrazoles 2 after column chromatography. b Obtained
along with 60% of bromoazide 3g.
proceed via nucleophilic14 opening of halonium ion 10 with R3-
CN followed by reaction of the generated nitrilium ion 11 with
azide to produce the tetrazole 2 (route a; Scheme 2).12 Tetrazole
2 might have been produced via nucleophilic ring opening of
the bromonium ion 10 by pregenerated tetrazole15 (route b).
However, no tetrazole was produced in the absence of either
alkene or NBS or both under the same reaction conditions.
1
revealed by the H NMR of the crude products. Reaction of
R,â-unsaturated carbonyl compound methyl p-methoxycin-
namate 1g under the same reaction conditions also afforded
tetrazole 2g in 12% yield along with the bromoazide 3g as a
major product (entry 6).
Similarly, reactions of different alkenes independently with
benzonitrile and benzylcyanide under the same reaction condi-
tions (i.e., using nitrile as a solvent) gave tetrazoles in moderate
to good yields (Table 3). Use of excess nitriles could be avoided
when TMSN3 in CH2Cl2 was slowly added over 1-2 h to the
solution of Zn(OTf)2 (0.05 equiv), alkene (1.0 equiv), NBS (1.2
equiv), nitrile (5 equiv), and 4 Å MS in CH2Cl2 and afforded
the tetrazoles in comparable yields.
We also investigated the intramolecular reaction of substrate
5. When 5 was subjected to the Zn(OTf)2 catalyzed reaction
with NBS, TMSN3 and 4 Å MS in CH2Cl2, it produced
exclusively bromoazide 8, no cyclic fused tetrazole 6 or 7 was
obtained (Scheme 1). The reaction of 5 was also carried out in
CH3CN instead of CH2Cl2 under the same reaction conditions
and afforded the tetrazole 9; here also, no cyclic fused tetrazole
6 or 7 was obtained (Scheme 1).
(14) Three-membered halonium ions are also easily opened by a variety
of nucleophiles. (a) House, H.O. Modern Synthetic Reaction, 2nd ed.;
W. A. Benjamin, Inc.: Menlo Park, 1972; pp 422-446. (b) March, J.
AdVanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 812-
819. (c) Carey, F.; Sundberg, R. AdVanced Organic Chemistry, 4th ed.;
Plenum Press: New York, 2001; Part B, pp 200-216. (d) Larock, R. C.
ComprehensiVe Organic Transformations, 2nd ed.; Wiley-VCH: New York,
2001; pp 629-633, 638-646. Some selected references: (e) Raghavan,
S.; Tony, K. A. Tetrahedron Lett. 2004, 45, 2639-2641. (f) Raghavan, S.;
Tony, K. A. J. Org. Chem. 2003, 68, 5002-5004. (g) Cardillo, G.;
Gentilucci, L.; Mohr, G. P. Eur. J. Org. Chem. 2001, 3545-3551. (h)
Quaglia, W.; Pigini, M.; Tayebati, S. K.; Piergentili, A.; Giannella, M.;
Marucci, G.; Melchiorre, C. J. Med. Chem. 1993, 36, 1520-1528. (i) Kumar,
R.; Wiebe, L. I.; Hall, T. W.; Knaus, E. E.; Tovell, D. R.; Tyrrell, D. L.;
Allen, T. M.; Fathi-Afshar, R. J. Med. Chem. 1989, 32, 941-944. (j)
Hudlicky, T.; Radesca, L.; Rigby, H. L. J. Org. Chem. 1987, 52, 4397-
4399. (k) Karl, Pfister, K.; C. A. Robinson, C. A.; Shabica, A. C.; Tishler,
M. J. Am. Chem. Soc. 1949, 71, 1096-1101. (l) Reference 13 and references
therein.
The synthesis of 1,5-disubstituted tetrazoles via halogen-
promoted reaction of alkenes, nitriles, and azide is thought to
(15) Ek, F.; Wistrand, L.-G.; Frejd, T. Tetrahedron 2003, 59, 6759-
6769.
J. Org. Chem, Vol. 72, No. 5, 2007 1853

TABLE 3. Synthesis of 5-Phenyl- and 5-Benzyltetrazoles via
Zn(OTf)2-Catalyzed Reaction of Alkenes with NBS, R3CN (R3 ) Ph,
PhCH2), and TMSN3
SCHEME 1
SCHEME 2
SCHEME 3
concluded that the reaction might proceed via nitrilium ion 11
followed by reaction with azide as proposed by Hassner12
(Scheme 2). The failure of the intramolecular reaction of 5 that
may be due to excessive strain in the required six/seven-
membered cyclic nitrilium ion intermediate also supports to the
likelihood of a nitrilium ion intermediate 11.
For further structural elaboration, tetrazoles 2a and 2d were
separately treated with NaN3 in DMF and R′SNa (R′ ) Et, Ph)
in MeOH (Scheme 3). However, it produced exclusively
eliminated product 13 in high yield, no nucleophilic substituted
product 12 was obtained. Eliminated product 13 was also
obtained (92%) on reaction with NaOH in MeOH. n-Bu3SnH
mediated reduction of tetrazoles 2a and 2d smoothly provided
compounds 14a and 14b in 89% and 75% yields, respectively
(Scheme 3).
In summary, we have developed an efficient one-pot stereo-
selective method for the synthesis of 1,5-disubstituted tetrazoles
by metal triflate catalyzed one-pot reaction of alkenes, NBS,
nitriles, and TMSN3. Among the metal triflates, Zn(OTf)2 was
a Isolated yields of tetrazoles 2 after column chromatography. Obtained
along with 10-20% of bromoazide 3.
Alternatively, initial formation of intermediate compound bro-
moazide 3 followed by [3 + 2] cycloaddition reaction with
nitriles might produce the tetrazole 2 (route c). When a solution
of pure bromoazide 3a in CH3CN was stirred in the presence
of Zn(OTf)2 catalyst under the same reaction conditions, even
after 10 h it did not yield any tetrazole 2a. Thus, it can be
1854 J. Org. Chem., Vol. 72, No. 5, 2007

1-(2-Bromo-1,2-diphenylethyl)-5-phenyl-1H-tetrazole ((()-
2k): white solid; mp 160-162 °C; FTIR (KBr) 3062, 1611, 1493,
1468, 1454, 1391, 1119, 1101, 1075, 774, 742, 721, 698, 668, 579,
found to be the best catalyst. Use of different combinations of
alkenes and nitriles produces a variety of 1,5-disubstituted
tetrazoles containing an additional R-bromo functionality on the
N1-substituent.
1
520 cm-1; H NMR (200 MHz, CDCl3) δ 7.77-7.82 (m, 2H),
7.45-7.63 (m, 6H), 7.10-7.26 (m, 7H), 5.80 (s, 2H); 13C NMR
(50 MHz, CDCl3) δ 154.6, 137.0, 135.5, 131.4, 129.7, 129.1 (4C),
129.0 (3C), 128.8 (2C), 128.6 (2C), 127.6 (2C), 123.5, 68.1, 53.8.
Anal. Calcd for C21H17BrN4: C, 62.23; H, 4.23; N, 13.82. Found:
C, 62.18; H, 4.21; N, 13.63.
5-Benzyl-1-(2-bromo-1,2-diphenylethyl)-1H-tetrazole ((()-
2o): white solid; mp 177-178 °C; FTIR (KBr), 3068, 3033, 2929,
1509, 1494, 1455, 1431, 1417, 1233, 1110, 1078, 773, 732, 723,
706, 697, 658, 636, 619, 584, 564, 528 cm-1; 1H NMR (200 MHz,
CDCl3) δ 7.26-7.37 (m, 8H), 7.15-7.25 (m, 5H), 6.96-7.05 (m,
2H), 5.80 (d, J ) 11.1 Hz, 1H), 5.55 (d, J ) 11.1 Hz, 1H), 4.04
(d, J ) 16.2 Hz, 1H), 3.82 (d, J ) 16.2 Hz, 1H); 13C NMR (50
MHz, CDCl3) δ 153.0, 137.4, 135.2, 133.5, 129.5, 129.4 (2C),
129.1, 128.9 (2C), 128.8 (2C), 128.7 (2C), 128.3 (2C), 127.8, 127.6
(2C), 68.0, 53.2, 29.3. Anal. Calcd for C22H19BrN4: C, 63.02; H,
4.57; N, 13.36. Found: C, 63.29; H, 4.64; N, 13.29.
Experimental Section
General Procedure for the Synthesis of 1,5-Disubstituted
Tetrazoles 2. To a well-stirred suspension of MS 4 Å (0.100 g)
and Zn(OTf)2 (0.009 g, 0.025 mmol) in dry R3CN (1.0 mL) were
successively added alkene 1 (0.50 mmol), TMSN3 (0.1 mL, 0.75
mmol), and NBS (0.107 g, 0.60 mmol) under argon atmosphere at
rt (25 °C). The reaction was monitored by TLC. On completion, it
was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with water (25 mL) and brine (25 mL), dried over Na2SO4, and
concentrated under vacuum. Flash column chromatography puri-
fication of the crude material using petroleum ether (60-80 °C)/
ethyl acetate as an eluent afforded the pure tetrazole 2. It is to be
noted that quenching the reaction with aqueous solution is to be
taken care as TMSN3 is unstable near moisture with the generation
of hydrazoic acid, an extremely dangerous product.
Acknowledgment. We thank DST (SR/S1/OC-13/2004),
New Delhi, for providing financial support and Professor D.
Mal for the helpful discussions. D.S. and M.B. thank CSIR,
New Delhi, and IIT, Kharagpur, respectively, for their fellow-
ships.
1-(2-Bromo-1,2-diphenylethyl)-5-methyl-1H-tetrazole ((()-
2d): white solid; mp 185-186 °C; FTIR (KBr) 3034, 2969, 2923,
2361, 2343, 1630, 1525, 1494, 1455, 1391, 1117, 1093, 773, 723,
1
705, 658, 569, 529 cm-1; H NMR (200 MHz, CDCl3) δ 7.65-
7.74 (m, 2H), 7.36-7.52 (m, 4H), 7.21-7.34 (m, 4H), 5.87 (d,
J ) 11.1 Hz, 1H), 5.66 (d, J ) 11.1 Hz, 1H), 2.28 (s, 3H); 13C
NMR (50 MHz, CDCl3/DMSO-d6 ) 10:1) δ 150.7, 137.3, 135.2,
129.5, 129.2, 128.9 (2C), 128.8 (2C), 128.2 (2C), 127.4 (2C), 67.9,
52.8, 8.5. Anal. Calcd for C16H15BrN4: C, 55.99; H, 4.41; N, 16.32.
Found: C, 55.78; H, 4.28; N, 16.35.
Supporting Information Available: Spectral data and 1H NMR,
13C NMR, and DEPT spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062432J
J. Org. Chem, Vol. 72, No. 5, 2007 1855