Cu2(OTf)2-catalyzed and microwave-controlled preparation of tetrazoles from nitriles and organic azides under mild, safe conditions

Article abstract of DOI:10.1002/anie.200605095

Avoiding hazards: Cu₂(OTf)₂·C ₆H₆ (OTf = O₃SCF₃) is the catalyst of choice for the [3+2] cycloaddition of organic azides and ethyl cyanoformate or related nitriles (see scheme; PG = protect

Full text of DOI:10.1002/anie.200605095

Communications
DOI: 10.1002/anie.200605095
CuI-Catalyzed Cycloadditions
Cu2(OTf)2-Catalyzed and Microwave-Controlled Preparation of
Tetrazoles from Nitriles and Organic Azides under Mild,Safe
Conditions**
Lluís Bosch and Jaume Vilarrasa*
Dedicated to Professor Rolf Huisgen and Professor K. Barry Sharpless
In connection with a project aimed at preparing new series of
diketotetrazoles (see compound 1 in Scheme 1, for which two
representative tautomers are shown) and pharmacophor-
60–70% yields, at best. To reduce the hazards inherent to
heating these polynitrogenated starting materials and prod-
ucts, Demko and Sharpless investigated a “click chemistry”
approach[4,5] by using mainly acyl cyanides (RCO-CN) and
organic azides, which allowed them to obtain compounds of
type 3 (1,5-disubstituted) under solvent-free conditions, with-
out catalysts, at 1208C.[4a] From the more reactive p-toluene-
sulfonyl cyanide, excellent yields of 1,5-disubstituted tetra-
zoles were similarlyobtained at 80–100 8C.[4b]
These outstanding results encouraged us to investigate a
series of potential catalysts for these [3+2]-cycloaddition
reactions, aimed at achieving even safer conditions. The
copper(I) complexes Cu2(OTf)2·tol and Cu2(OTf)2·C6H6
(OTf = O3SCF3, tol = toluene) allow one to carryout most
of the above reactions at room temperature, with or without
solvent. This catalytic activity was not observed for other CuI
salts nor for a number of other transition-metal cations tested
in these reactions.
Scheme 1. Diketotetrazoles and putative precursors; PG=protecting
group, EWG=electron-withdrawinggroup.
related quinolinocarbonyltetrazoles, as further candidates for
HIV-1 integrase inhibitors,[1] we sought a rapid entryinto the
synthesis of tetrazole esters 2 and/or 5-acetyltetrazoles 3
(Scheme 1). Formation of tetrazole rings byccyloaddition
between nitriles and organic azides is in principle the most
direct method,[2] but it usuallyrequires veryharsh conditions.
Moreover, since N-unsubstituted tetrazole rings are well-
recognized bioisosters of the carboxyl groups,[2a] the develop-
ment of anysafe approach to tetrazoles of type 2 and 3, as well
as to derivatives of general formula 4 (Scheme 1), would be of
great use in the pharmaceutical industry.
As we planned to activate CN groups linked to EWGs,
which lower the basicityof the CN nitrogen atoms, mainly
cyanophilic cations were investigated.[6] Ethyl cyanoformate
and p-methoxybenzyl azide (PMB-N3) were mixed without
solvent and, as summarized in Table 1, potential catalysts
were added.
Besides the additives shown in Table 1, manyothers (that
is, Cu powder, AgSbF6, AgBF4, AgF, AgOAc, AuCl3, Au-
(OTf)3, Ru/C, RuCl3, [RuCp*(PPh3)2]Cl2 (Cp* = C5Me5),[7]
[Pd2(dba)3]·CHCl3 (dba = dibenzylideneacetone), PdCl2,
Pt/C, PtCl2, PtCl4, Sc(OTf)3, and LaCl3) were tested, but are
not included in Table 1, as theyturned out to be inactive.
Table 1 shows that cycloaddition was only catalyzed by
some copper salts (entries 4, 7–11, 13, and 14). These salts
appear to be those more soluble copper derivatives that, in
blank experiments, do not cause a premature decomposition
of the reactants. In fact, the results from the two commercially
Most recent studies on the subject relyon a classical paper
in which benzyl azide derivatives and alkyl cyanoformates
(ROCO-CN) were heated without solvent at 1308C in a
sealed tube;[3] tetrazoles of type 2 can be achieved in roughly
[*] L. Bosch, Prof. Dr. J. Vilarrasa
Departament de Química Orgànica
Universitat de Barcelona
[8]
available or easilyprepared copper(I) triflates are remark-
able, as no reduction or Lewis acid mediated decomposition
of the azide was observed. The same reaction without catalyst
requires heating at 1308C to reach an acceptable yield,[3] as we
have mentioned and confirmed. Trace amounts of trifluor-
omethanesulfonic acid (triflic acid, TfOH), which might be
contained in these reagents or produced in the reaction
medium, are not responsible for their activity, since TfOH
does not catalyze the reaction (see entry 12 in Table 1).
For safetypurposes, as mixing of pure liquids without a
solvent to dissipate anyexothermic decomposition of the
Av. Diagonal 647, 08028 Barcelona (Spain)
Fax: (+34)933-397-878
E-mail: jvilarrasa@ub.edu
[**] We thank the FP6 of the European Union for a grant (IP Targeting
Replication and Integration of HIV, TRIoH) including a studentship
to L.B. (2004–2007). R. Huisgen was a Barcelona visiting professor
in the early 1980s, K. B. Sharpless in 1997 (Confer›ncia F›lix
Serratosa). OTf=O3SCF3.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
3926
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 3926 –3930

Angewandte
Chemie
Table 1: Evaluation of the catalytic effect of different additives.[a]
Table 2: Reaction of aliphatic azides with EWG-linked nitriles in CH2Cl2,
catalyzed by Cu2(OTf)2·C6H6.[a]
Entry Reactants[a] Conditions
Product(s)
Yield
[%][b]
Entry
Catalyst (mol%)
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
none
CuCN (20)
Cu2Cl2 (10)
Cu2Cl2 (10)
CuBr·SMe2 (20)
CuI (10)
Cu2(OTf)2·tol (5)
Cu2(OTf)2·tol (10)
Cu2(OTf)2·tol (10)
Cu2(OTf)2·C6H6 (10)
Cu2(OTf)2·C6H6 (10)
TfOH (10)
60
20
20
60
20
60
20
20
60
20
60
20
20
20
20
60
20
20
20
20
20
24
24
72
12
24
6
24
24
6
5
0
30
50
6
10
60
75
80
93
95
0[b]
60[b]
50[c]
0
1
2
PMB-N3
EtOCO-CN
PMB-N3
208C, 48h
808C, 2h,
5
5
90
94
EtOCO-CN MW
PhCH2N3
3
4
208C, 48h
808C, 2h,
95
88
EtOCO-CN
PhCH2N3
24
6
6
7
EtOCO-CN MW
72
24
72
24
24
24
24
24
48
48
Ph(CH2)3N3
EtOCO-CN
Cu(OTf)2 (10)
Cu(OTf)2 (20)[c]
CuCl2 (10)
5
6
208C, 48h
90
97
Ph(CH2)3N3 808C, 2h,
CuSO4 (10)[d]
ZnCl2 (10)
0
0
0
EtOCO-CN MW
Zn(OTf)2 (10)
AgOTf (10)
AuOTf (10)
0[b]
0[b]
0[b]
PMB-N3
7
8
208C, 48h
MeCOCN[c]
9:1 81
[Au(PPh3)]OTf (10)
PMB-N3
808C, 2h,
8/8a
9/9a
9:1 37[d]
[a] Reactions were carried out under solvent-free conditions with PMB-N3
(1.0 mmol) and EtOCO-CN (1.1 mmol). The potential catalyst was
added, and stirringwas maintained under Ar. Except for entries 10 and
11, conversion was incomplete. [b] Partial decomposition of the organic
azide was observed (5–20% of 4-methoxybenzaldehyde was formed).
[c] With larger amounts of catalyst, decomposition of the reactants
increased. [d] Anhydrous and pentahydrate, with identical results.
Addition of sodium ascorbate (aqueous solution or in tBuOH/
H2O)[4a,b,5e] is not recommended, as partial hydrolysis of EtOCO-CN
(EWG-CN) takes place.
MeCOCN[c] MW
PMB-N3
PhCO-CN
9
208C, 48h
92:8 74
95:5 77
10 PMB-N3
PhCO-CN
808C, 2h,
MW
PMB-N3
11
208C, 4h
208C, 4h
7:3 99
8:2 99
Bs-CN
PMB-N3
12
reagents or products maybe dangerous on a large scale, we
next investigated the most appropriate solvent for the above
cycloaddition reaction. At 208C and approximately1 m
concentration, stirring for 24 h with 10 mol% of Cu2-
(OTf)2·C6H6, dichloromethane turned out to be the most
appropriate among the solvents evaluated, according to the
yields of the isolated tetrazole derivative. In fact, the order
was as follows (yields in parenthesis): CH2Cl2 (85%), toluene
(76%), THF (56%), CH3CN (0%; the solvent itself does not
react, see below), DMF (0%), and absolute EtOH (0%).
Thus, the best coordinating solvents are not useful, probably
due to the preferential solvation of the CuI ions; hydroxylic
solvents partiallyreact with EtOCO-CN (or, more generally,
with EWG-CN), as was expected, and this process could be
monitored byNMR spectroscopy.
Having optimized the catalyst and solvent, we applied the
procedure to various organoazides and organocyanides. As
shown in Table 2 (entries 1, 3, 5, 7, and 9), most reactions
could be carried out at room temperature (or at 408C, data
not shown) to afford mainly 5–9, but to shorten the reaction
times to 1–2 h, the samples were heated at approximately
808C in sealed vials. This procedure was carried out in a
Ts-CN
[a] Organic azide/nitrile/catalyst in a 1.0:1.1:0.1 molar ratio in CH2Cl2 (1m
solutions) unless otherwise indicated. [b] Overall yield of tetrazoles.
[c] This nitrile decomposes under the reaction conditions, so that
1.5 equiv were added.[4a] [d] Heatingis not recommended (compare with
entry 7).
microwave (MW) synthesizer, with safe control of the
temperature and pressure. With benzenesulfonyl cyanide
(PhSO2-CN, Bs-CN) and tosyl cyanide (TolSO2-CN, Ts-CN),
the conversion was complete within a few hours without
heating (Table 2, entries 11 and 12), to give mainly 10 and 11,
respectively. It is remarkable that in this process Bs-CN and
Ts-CN playthe role of synthetic equivalents of HCN, the
direct addition of which to organic azides is not feasible.
It is known that bythermal activation only1,5-disubsti-
tuted tetrazoles are formed.[4] However, under our catalytic
conditions (Table 2), minor amounts of several 1,4-regioisom-
ers (8a–11a) were also obtained. These isomers were
separated bychromatography(lower Rf value). The struc-
Angew. Chem. Int. Ed. 2007, 46, 3926 –3930
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3927

Communications
tures of both series of tetrazoles were confirmed by
1
comparison of the H and 13C NMR spectra with the
other compounds in the respective series and with
known data.[2b,4] The chemical shifts of the methylene
groups of p-methoxybenzyl (PMB) and PhCH2 (Bn)
groups of 5–6 and 8–11 are characteristic (d(H) =
5.89–5.82, d(C) = 52.7–52.2 ppm), whereas those of
8a–11a lie at d(H) = 5.80–5.68, d(C) = 57.5–
56.9 ppm). Both the decarboxylation of 5 (byhydrol-
ysis)[3] and deacetylation of 8 (with NaOEt) gave 1-
PMB-tetrazole.[9]
The 10/10a and 11/11a ratios were increased by
carrying out the cycloaddition with only 1–2 mol% of
Cu2(OTf)2·C6H6. The reactions were slower, but
tetrazoles 10 and 11 were formed exclusively. On the
other hand, with much larger amounts of Cu2-
(OTf)2·C6H6, the ratios were inverted. Thus, by
Scheme 2. A mechanism for the CuI-catalyzed cycloadditions. See text for
details.
mixing nitriles and organoazides in CH2Cl2 at À308C,
adding 50–100 mol% of the catalyst, and stirring the resulting
dark slurry(heterogeneous conditions) at 20 8C, the 1,4-
isomers predominated. For example, 11a was the major
compound with 50 mol% of the copper salt (11/11a ratio of
1:10). With 100 mol% of the copper salt, only 11a was
obtained (together with 4-methoxybenzaldehyde and other
decomposition products of PMB-N3 because of such a large
excess of the copper salt). In this way, even the previously
unknown 1,4-disubstituted isomer 5a (d(H) = 5.77 and d(C) =
57.2 ppm for the PMB methylene group) could be obtained
(40:60 5/5a).
For the removal of the PMB protecting group of 5, 5a, 8,
8a, 9, 9a, 10, 10a, 11, and 11a to prepare tetrazole derivatives
of formula 4, we tried several known methods.[10] Using 2,3-
dichloro-5,6-dicyano-1,4-quinone (DDQ) did not work, but
oxidation with ammonium cerium(IV) nitrate (CAN) was
veryefficient (e.g. 1 mmol of 8, 2.5 mmol of CAN, CH3CN/
H2O, 3 h, 20 8C, 100%).[9a] Heating 5,11 , and 11a as
representative samples with 1:1 TFA/CH2Cl2 (TFA = tri-
fluoroacetic acid) and an excess of methoxybenzene (to trap
the released 4-methoxybenzyl cation) also gave clear final
solutions and practicallyquantitative iyelds of the depro-
tected products.
catalyzed addition that gives 5–12, in which the azido group
adds to the CuI-complexed nitrile (as simplified in Scheme 2,
top right). On the other hand, with an excess of CuI in the
medium with regard to the organoazide, both the true
I
reactants maybe Cu -complexed species (as simplified in
Scheme 2, bottom right), which might explain the reversal in
regioselectivity, that is, the formation of larger amounts of5a–
11a.
As an application of the procedures discussed above to
more stericallyhindered aliphatic azides, we studied the 3 ’-
azido-3’-deoxythymidine (AZT/zidovudine) derivative shown
in Scheme 3.[11] Conversion percentages of approximately
15% with EtOCO-CN and 25% with Ts-CN were achieved at
208C within 48 h, using 10 mol% of the catalyst. Thus, heating
was necessaryin this case. For safetypurposes and to avoid
the decomposition of the substrate at higher temperatures, we
carried out the reaction at 808C in a MW synthesizer, as
described above. This procedure afforded 12 in 80% yield
within 12 h with 10 mol% of catalyst (i.e. under homogeneous
conditions). With 50 mol% and even with 200 mol% of
Cu2(OTf)2·C6H6, only 12 was also obtained, to our surprise. In
light of the previous results with the 10/10a and 11/11a pairs,
we had expected that the 1,4-disubtituted isomer 12a would
Treatment of 11 with an excess of magnesium or
NaBH4 in MeOH led to complete removal of the Ts
group to afford excellent yields of 1-PMB-tetrazo-
le,[9a,b] the same product we obtained bydecarbox-
ylation of 5 and deacetylation of 8. Removal of the
Ts group of 11a gave 2-PMB-tetrazole.[9c,d]
Standard aliphatic azides (e.g. PMB-N3) do not
react at all with CH3CN or PhCN (i.e. with common
nitriles) under anyof the conditions mentioned here,
which means that highlyelectrophilic nitrile carbon
atoms are required for a successful addition. Orga-
noazides polarized in the reverse sense (e.g. Ts-N3,
where an azido group is linked to an EWG), do not
react at all with either CH3CN or Ts-CN, even when
forcing the conditions. We therefore suggest a
mechanism (Scheme 2, where X = Cu(OTf)2 or
TfO, depending on the real ratio between the
dimeric and monomeric copper species) for the Scheme 3. Preparation of tetrazole analogues of AZT. See text for details.
3928
www.angewandte.org ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 3926 –3930

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
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 3929

Communications
[6] a) For the coordination of nitriles with transition-metal ions and
[12] At concentrations of 0.1m. Either at higher concentrations, by
concentrating the final mixture in the rotaryevaporator, or when
larger amounts of pyrrolidine are used, deacetylation also occurs
during this step.
its applications, see: V. Y. Kukushkin, A. J. L. Pombeiro, Chem.
Rev. 2002, 102, 1771. b) See also, for representative studies on
CuI acetonitrile complexes: J. K. Irangu, R. B. Jordan, Inorg.
Chem. 2003, 42, 3934; c) A. Lewandowski, J. Malinska, Electro-
chim. Acta 1989, 34, 333. CuI nitrile complexes, for example,
[Cu(NCCH3)4]BF4, are stable and do not disproportionate to Cu0
and CuII.
[13] In [D6]DMSO, H5’’ (tetrazole ring) at d = 9.56 ppm and C5’’ at
d = 143.6 ppm. See the Supporting Information for the full
spectra. This compound (14) and related derivatives (not
substituted at C5’’) had not been reported, to our knowledge.
By opening anhydrothymidine with the tetrazolate anion, on
heating at 1208C, onlyits 1,4-disubstituted isomer (the 2-
tetrazolyl derivative) was obtained, as we have confirmed; See:
A. A. Malin, V. A. Ostrovskii, Russ. J. Org. Chem. 2001, 37, 759.
[14] Throughout the more than thirtyyears in which organic azides
have been used in our lab from time to time [see, e.g.: M. Rull, J.
Vilarrasa, Tetrahedron Lett. 1976, 17, 4175; M. Bartra, V. Bou, J.
Garcia, F. Urpꢃ, J. Vilarrasa, J. Chem. Soc. Chem. Commun. 1988,
270; M. Bartra, P. Romea, F. Urpꢃ, J. Vilarrasa, Tetrahedron 1990,
46, 587; A. M. Costa, M. Faja, J. Farrꢀs, J. Vilarrasa, Tetrahedron
Lett. 1998, 39, 1835], onlytwo explosions have ever taken place;
in one case NaN3 and in the other one Bu4N+N3À had previously
been in contact with CH2Cl2. For information about CH2(N3)2,
see: N. P. Peet, P. M. Weintraub, Chem. Eng. News 1994, 72(11),
4, and references therein; A. Hassner, M. Stern, H. E. Gottlieb,
F. Frolow, J. Org. Chem. 1990, 55, 2304.
[7] L. Zhang, X. Chen, P. Xue, H. H. Sun, I. D. Williams, K. B.
Sharpless, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127,
15998.
[8] R. G. Salomon, J. K. Kochi, J. Am. Chem. Soc. 1973, 95, 3300.
[9] a) Y. Satoh, N. Marcopulos, Tetrahedron Lett. 1995, 36, 1759;
b) characteristic NMR signals for 1-PMB-1H-1,2,3,4-tetrazole:
1H NMR (CDCl3, 400 MHz): d = 8.52 (H5; 9.46 in [D6]DMSO),
5.62 ppm (CH2); 13C NMR (CDCl3, 100.6 MHz): d = 142.2 (C5),
51.8 ppm (CH2); c) characteristic NMR signals in CDCl3 for 2-
PMB-2H-1,2,3,4-tetrazole
(i.e.
1-PMB-1,2,3,5-tetrazole):
1H NMR (CDCl3, 400 MHz): d = 8.60 (H5; 8.95 in
[D6]DMSO), 5.72 ppm (CH2). d) For spectra of the two corre-
sponding N-benzyl tetrazoles, see: W. Holzer, C. Jꢁger, Monatsh.
Chem. 1992, 123, 1027.
[10] Cf. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley-Interscience, New York, 1999, p. 86.
[11] a) M. Faja, X. Ariza, C. Gꢂlvez, J. Vilarrasa, Tetrahedron Lett.
1995, 36, 3261; b) X. Ariza, A. M. Costa, M. Faja, O. Pineda, J.
Vilarrasa, Org. Lett. 2000, 2, 2809, and references therein.
3930
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 3926 –3930