To limit potential redox processes that would form
reduced metal-isocyanide complexes, we decided to perform
the organometallic coupling as the last step of the whole
sequence.7 To test the feasibility of such cascades, azide was
selected as the first nucleophile as it is known to react with
imidoyl halides to form tetrazoles (Scheme 2).8 Furthermore,
the outcome of such an intermediate cyclization would be
an increased stability of the final three component adduct
toward water, making the process even more appealing.9
time and the need of a Lewis acid as catalyst, we investigated
other azide sources. Quantitative results were also obtained
using sodium azide in acetonitrile in only 1 h (Scheme 3).
Scheme 3. Optimization of the Tetrazole Formation
Scheme 2. 3-Component Tetrazole Formation
Next we examined the final Suzuki coupling. Unfortu-
nately, it failed in acetonitrile, which leds us to change the
solvent of the last reaction step. After completion of the
reaction, the acetonitrile was removed and toluene was
added to adjust the concentration to 0.5 M concentration.
The boronic acid (3 equiv), potassium carbonate (3 equiv)
and a catalytic amount of tetrakis(triphenylphosphine) pal-
ladium (5 mol %) were added and the resulting mixture was
refluxed for 18 h to give the desired aryl tetrazole in 90%
yield. The amount of boronic acid could be decreased to 1.5
equiv without any change. Finally, the desired aryl tetrazole
was obtained in three steps in a 90% overall yield. We sur-
mised that considering the efficiency of each step, the whole
sequence could be performed in the same pot with an inter-
mediate change of solvent. Thus, we performed the bromi-
nation-addition of the azide-electrocylization in acetonitrile
as solvent. The resulting mixture was then evaporated and
diluted with toluene to perform the pallado-catalyzed cou-
pling. Under these conditions, the desired aryl tetrazole was
isolated in an optimized 97% yield (Scheme 4).
The optimization of each step of the sequence was done
separately. The cyclohexyl isocyanide was chosen as a model
input for starting material. When treated with 1 equivalent of
bromine in dichloromethane at room temperature, the cy-
clohexyl isocyanide was totally transformed to the corre-
sponding dibromide. We examined next various conditions
for the tetrazole formation. First trials were performed using
trimethylsilyl azide. The addition of a slight excess of TMSN3
to the former solution failed to give any coupling adduct.
Various acid catalysts were then tested. The addition of a few
drops of methanol did not give desired products although the
use of a catalytic amount of silver salts resulted in isolation of
the bromo tetrazole. Indeed, the addition of silver perchlo-
rate (40 mol %) gave about 50% of the product while the use
of silver acetate (10 mol %) afforded the bromo tetrazole in
quantitative yield after 3 days. Considering this long reaction
Scheme 4. One-Pot Tetrazole Formation
(6) An isocyanide dihalogenide conversion to chloropyridines followed
by a palladium coupling has been reported in a synthesis of variolin
analogues. However, with the low yields obtained in the first step, a one-
pot multicomponent strategy may be very difficult to settle: Baeza, A.;
Burgos, C.; Alvarez-Builla, J.; Vaquero, J. J. Tetrahedron Lett. 2007, 48,
2597–2601. For an additional cascade involving the cyclization of an
isocyanide followed by a Suzuki coupling see:Liu, L.; Wang, Y.; Wang,
H.; Peng, C.; Zhao, J.; Zhu, Q. Tetrahedron Lett. 2009, 50, 6715–6719.
(7) For reduction of isocyanide dichloride under pallado-catalyzed
Grignard addition see: Ito, Y.; Inouye, M.; Murakami, M. Tetrahedron.
Lett. 1988, 29, 181–192.
(8) For tetrazole formation from isocyanide dichlorides see: (a) Cristiano,
M.; Lurdes, S.; Johnstone, R. A. W. J. Chem. Research, Synopses 1997, 3,
164–165. (b) Alves, J. A.; Johnstone, R. A. W. Synth. Commun. 1997, 27,
2645–2650. (c) Mloston, G.; Galindo, A.; Bartnik, R.; Marchand, A. P.;
Rajagopal, D. J. Het. Chem. 1996, 33, 93–96. (d) Quast, H.; Bieber, L. Chem.
Ber. 1981, 114, 3253–3272. For an alternative three-component palladium
catalyzed preparation of tetrazole using a Tsuji-Trost reaction see:Kamijo,
S.; Jin, T.; Huo, Z.; Young Soo, G.; Shim, J-G; Yamamoto, Y. Mol. Div.
2003, 6, 181–192. For tetrazole formation from isocyanide and X-N3, see:
Fowler, F. W.; Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1967, 89, 2077–
2082. Collibee, W. L.; Nakajima, M.; Anselme, J. -P. J. Org. Chem. 1995,
60, 468–469.
The scope of such a sequence was next examined varying
the isocyanide and the boronic acid partners as depicted in
Table 1. When varying the isocyanide, the electrocyclization
step turned out to be poorly efficient unless increasing the
temperature up to 65 °C. In all the cases, the corresponding
aryl tetrazoles were obtained according to a sequential one-
pot procedure in moderate to good yields. This method
constitutes a straightforward and convenient access to aryl
tetrazoles.
To extend the scope even more of this synthetic path, we
further examined other nucleophiles in the second step.
Indeed, as part of our ongoing interest in 1,2,4-triazoles
(9) Without such a cyclization, sequential nucleophilic additions lead to
imines prone to hydrolytic cleavage unless engaged in further reactions.
1262
Org. Lett., Vol. 13, No. 5, 2011