Angewandte
Chemie
(1.0 mL) and Cu2(OTf)2·C6H6 (0.1 mmol). The vial was degassed
predominate. Deprotection of the methoxycarbonyl vinyl
(MocVinyl) group of 12 with pyrrolidine (4–6 equiv, 208C,
6 h)[12] gave 13 in practically quantitative yield. Desulfonyla-
tion of 13 with NaBH4/MeOH (4 mmol of NaBH4 per mmol
of 13, added in portions, 208C, 1 h) took place with
concomitant deacetylation to afford in excellent yield the
desired tetrazole derivative 14, the structure of which was
confirmed byNMR spectroscopy. [13] We attribute the absence
of the 1,4-disubstituted isomer in the present case to a steric
effect, that is, to low percentages of [NNN(CuX)R] (see
Scheme 2, bottom right, coordination to the internal N atom)
in the medium when R is a branched chain.
with Ar, sealed, and irradiated at 808C for 2 h. Once cooled, the
reaction mixture was diluted with CH2Cl2/Et2O (9:1, 20 mL) and
treated with aqueous NaHS (1.5m, 5 mL). Isolation of the desired
products was carried out as indicated above.
Received: December 18, 2006
Published online: April 10, 2007
Keywords: azides · copper · cycloaddition ·
.
homogeneous catalysis · tetrazoles
[1] a) C. Meadows, J. Harvey-Hague, ChemMedChem 2006, 1, 16;
b) P. Cotelle, Recent Pat. Anti-Infect. Drug Discovery 2006, 1, 1;
c) X. Li, R. Vince, Bioorg. Med. Chem. 2006, 14, 5742; d) R.
Di Santo, R. Costi, A. Roux, M. Artico, A. Lavecchia, L.
Marinelli, E. Novellino, L. Palmisano, M. Andreotti, R. Amici,
C. M. Galluzzo, L. Nencioni, A. T. Palamara, Y. Pommier, C.
Marchand, J. Med. Chem. 2006, 49, 1939; e) M. Sato, T.
Motomura, H. Aramaki, T. Matsuda, M. Yamashita, Y. Ito, K.
Kawakami, Y. Matsuzaki, W. Watanabe, K. Yamataka, S. Ikeda,
E. Kodama, M. Matusuoka, H. Shinkai, J. Med. Chem. 2006, 49,
1506; f) V. Nair, G. Chi, R. Ptak, N. Neamati, J. Med. Chem.
2006, 49, 445; g) M. Fardis, H. Jin, S. Jabri, R. Z. Cai, M. Mish, M.
Tsiang, C. U. Kim, Bioorg. Med. Chem. Lett. 2006, 16, 4031;
h) M. L. Barreca, S. Ferro, A. Rao, L. D. Luca, M. Zappalꢀ, A.-
M. Monforte, Z. Debyser, M. Witvrouw, A. Chimirri, J. Med.
Chem. 2005, 48, 7084.
In conclusion, we have discovered a click reaction,
parallel to the well-known one between organoazides and
terminal alkynes, which in many cases affords excellent yields
of 1,5-disubstituted tetrazoles 5–11 in CH2Cl2 at ambient
temperature with 1–10 mol% of soluble Cu2(OTf)2·C6H6 as
the catalyst. Under heterogeneous conditions with 50–
100 mol% of the same catalyst, the reaction yields mainly
1,4-disubstituted tetrazoles 5a–11a. Onlywith a reluctant
secondaryazide (an AZT derivative) did the reaction have to
be carried out at 808C in a MW reactor; in the other
examples, this activation was not strictlynecessary, though the
reaction times were then shortened to 2 h. For the tetrazoles
À
prepared from PMB-N3, the cleavage of the PMB N bond is
feasible in almost quantitative yields with standard reagents,
[2] Reviews: a) R. J. Herr, Bioorg. Med. Chem. 2002, 10, 3379;
b) R. N. Butler in Comprehensive Heterocyclic Chemistry, Vol. 4
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon,
Oxford, 1996, p. 621. c) The direct reaction of organic nitriles
with the azide ion, when N-unsubstituted tetrazoles are aimed
for, is much more common and easier to accomplish but poses
other well-known safetyrequirements or handicaps (including
the explosive nature of manytransition-metal azides in catalytic
reactions). For an additional review, see: V. Y. Zubarev, V. A.
Ostrovskii, Chem. Heterocycl. Compd. 2000, 36, 759. d) For the
reaction of nitriles with NaN3/ZnBr2 in water at only80 8C, see:
Z. P. Demko, K. B. Sharpless, Org. Lett. 2002, 4, 2525. e) For the
reaction of nitriles with an in situ generated allylpalladium azide,
see: S. Kamijo, T. Jin, Y. Yamamoto, J. Org. Chem. 2002, 67,
7413. f) For a veryrecent review on the chemistryof azides, see:
S. Brꢁse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem.
2005, 117, 5320; Angew. Chem. Int. Ed. 2005, 44, 5188.
À
as it is the cleavage of several EWG C bonds (or, depending
on the EWG, the elongation of this side chain, as will be
reported elsewhere in connection with the development of
new HIV integrase inhibitors). In other words, PMB-N3, a
synthetic equivalent of the toxic and explosive HN3, can be
made to react with EWG-CN, that is, with synthetic equiv-
alents of the toxic HCN, under verymild, nonhazardous
conditions. Overall, we have established the safest procedure
reported to date for the installation of tetrazole rings directly
from organic azides and nitriles.
Experimental Section
Caution: Polynitrogenated compounds may behave as explosives. We
have not had anyadverse reactions with the compounds reported
here under the conditions of reference [3] (1308C, solvent-free
conditions, preparation of a sample of 5 as a blank) or, obviously,
under our verymild conditions (20–80 8C), which were designed for
working safelyon a large scale. [14]
General procedure at room temperature: Cu2(OTf)2·C6H6
(0.10 mmol) was added to a stirred mixture of the azide (1.0 mmol)
and acyl cyanide (1.1 mmol) in anhydrous CH2Cl2 (1.0 mL), and the
mixture was stirred in a water bath at 208C for 2 days or, for the most
reactive samples, until no starting azide was observed bythin layer
chromatography(TLC). The reaction mixture was then diluted with
CH2Cl2/Et2O (9:1, 20 mL) and aqueous NaHS (1.5m, 5 mL) was
added. The layers were separated and the aqueous one was extracted
twice with CH2Cl2/Et2O (9:1, 15 mL). The combined organic phases
were washed with water (10 mL) and brine (10 mL), dried over
anhydrous Na2SO4, and filtered. The solvent was evaporated and the
crude product was purified, when necessary, by flash chromatography
with CH2Cl2 as the eluent.
[3] D. H. Klaubert, J. H. Sellstedt, C. J. Guinosso, S. C. Bell, R. J.
Capetola, J. Med. Chem. 1981, 24, 748.
[4] a) Z. P. Demko, K. B. Sharpless, Angew. Chem. 2002, 114, 2217;
Angew. Chem. Int. Ed. 2002, 41, 2113; b) Z. P. Demko, K. B.
Sharpless, Angew. Chem. 2002, 114, 2214; Angew. Chem. Int. Ed.
2002, 41, 2110, and references therein.
[5] a) For the “click chemistry” concept, see: H. C. Kolb, M. G.
Finn, K. B. Sharpless, Angew. Chem. 2001, 113, 2056; Angew.
Chem. Int. Ed. 2001, 40, 2004. b) For pioneering reports of the
CuI-catalyzed reaction of terminal alkynes with organoazides,
see: C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057; c) V. V. Rostovtsev, L. K. Green, V. V. Fokin,
K. B. Sharpless, Angew. Chem. 2002, 114, 2708; Angew. Chem.
Int. Ed. 2002, 41, 2596. d) For reviews, see: V. D. Bock, H.
Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2005, 51;
e) Q. Wang, S. Chittaboina, H. N. Barnhill, Lett. Org. Chem.
2005, 2, 293; f) H. C. Kolb, K. B. Sharpless, Drug Discovery
Today 2003, 8, 1128. A search through SciFinder in December
2006 indicates the growing number of articles that are being
published on click chemistryapplications (126 in 2006, 59 in
2005, 26 in 2004, 5 in 2003).
General procedure under MW irradiation (Biotage Initiator Exp
MW Synthesizer): A Biotage vial of 0.5–2.0 mL was filled with the
azide (1.0 mmol), acyl cyanide (1.1 mmol), anhydrous CH2Cl2
Angew. Chem. Int. Ed. 2007, 46, 3926 –3930
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