Copper-Catalyzed Synthesis of Azoles
A R T I C L E S
Scheme 1. Copper-Catalyzed Synthesis of 1,2,3-Triazoles and
Isoxazoles
dissolved in 6 mL of a 1:1 tert-BuOH/H2O mixture. While the mix-
ture was being stirred, sodium ascorbate (1 M solution in water, 100
µL, 10 mol %) was added, followed by copper(II) sulfate pentahydrate
(2.7 mg in 100 µL of H2O, 2 mol %). The reaction mixture was then
treated with KHCO3 (4.33 mmol, 433 mg) and left stirring for 1 h at
ambient temperature, after which time it was diluted with water, and
the solid off-white isoxazole product was filtered off (231 mg, 92%).
1H NMR (CDCl3): δ ) 3.89 (s, 3H), 6.78 (s, 1H), 7.00 (m, 2H), 7.47
(m, 3H), 7.82 (m, 4H). 13C NMR (CDCl3): δ ) 55.4, 97.3, 114.5,
120.7, 125.8, 127.3, 128.2, 129.0, 130.2, 157.3, 159. 2, 160.6. mp
122 °C.
Computational Details
All geometries and energies presented in this study were computed
using the B3LYP9 density functional theory method as implemented
in the Gaussian 98 program package.10 Geometry optimizations were
performed using the triple-ú plus polarization basis set 6-311G(d,p),
followed by single-point energy calculation using the larger basis set
6-311+G(2d,2p). Hessians were calculated at the B3LYP/6-311G(d,p)
level of theory.
130.4, 126.0, 123.3, 114.9, 112.7, 81.1, 70.6, 70.4, 63.2, 52.6, 47.5,
46.7, 43.2, 37.2, 32.6, 29.3, 27.2, 26.1, 23.6, 14.4.
General Procedure B, with Copper Metal as a Source of Catalytic
Species, As Exemplified for 2,2-Bis((4-phenyl-1H-1,2,3-triazol-1-
yl)methyl)propane-1,3-diol. Phenylacetylene (2.04 g, 20 mmol) and
2,2-bis(azidomethyl)propane-1,3-diol (1.86 g, 10 mmol) were dissolved
in a 1:2 tert-butyl alcohol/water mixture (50 mL). About 1 g of copper
metal turnings was added, and the reaction mixture was stirred for 24
h, after which time TLC analysis indicated complete consumption of
starting materials. Copper was removed, and the white product was
filtered off, washed with water, and dried to yield 3.85 g (98%) of
pure bis-triazole product. 1H NMR (399 MHz, [d6]DMSO): δ ) 3.24
(d, 3JHH ) 4.8 Hz, 4H, -CH2OH), 4.50 (s, 4H, -CH2-triazole), 5.09
Solvation energies were added as single-point calculations using the
conductor-like solvation model COSMO11 at the B3LYP/6-311G(d,p)
level. In this model, a cavity around the system is surrounded by a
polarizable dielectric continuum. The dielectric constant was chosen
as the standard value for water, ꢀ ) 80. Some experiments were
performed in acetonitrile, which has a dielectric constant of ꢀ ) 35.
As the solvation energy to a first approximation is proportional to (1
3/2ꢀ) for large ꢀ,12 the water and acetonitrile values give almost
3
-
(t, JHH ) 4.8 Hz, 2H, -CH2OH), 7.33 (pseudo t, Japp ) 7.6 Hz,
identical solvation energies. Because we are mainly interested in relative
activation barriers (reactant f transition state), the differences are not
significant. All energies presented herein are enthalpies to which
solvation energies are added. Zero-point energy (ZPE) effects are
included.
The initial computational studies were performed with the simplest
reactants, methyl azide (CH3N3) (or acetonitrile oxide) and propyne
(CH3CtCH). The results should, however, be directly applicable to
other azides, nitrile oxides, and alkynes.
2H, p-H in triazole-C6H5), 7.44 (pseudo t, Japp ) 7.6 Hz, 4H, m-H
in triazole-C6H5), 7.86 (pseudo d, Japp ) 7.6 Hz, 4H, o-H in tri-
azole-C6H5), 8.51 (s, 2H, triazole H). 13C NMR (99.75 MHz,
[δ6]DMSO): δ ) 45.45, 49.76, 59.96, 123.25, 125.23, 127.89, 128.91,
130.67, 146.04. ES-MS m/z (ion): 391.2 (M + H+), 413.2 (M + Na+).
mp 211-212 °C.
Copper(I)-Catalyzed Synthesis of 3,5-Disubstituted Isoxazoles.
General Procedure for Preparation of Imidoyl Chlorides. To a
suspension of 10 mmol of aldehyde in a 1:1:2 mixture of H2O/EtOH/
ice (10 mL) was added 10 mmol of hydroxylamine hydrochloride,
followed by 25 mmol of NaOH (as a 50% solution in water), while
keeping the temperature below 30 °C. After being stirred at room
temperature for 1 h, the solution was extracted with diethyl ether. The
aqueous phase was acidified to pH 6 by adding concentrated HCl while
keeping the temperature below 30 °C and extracted with Et2O. The
organic phase was dried over MgSO4, and the solvent was evaporated
to give the oxime products in 85-95% yield, which were used directly
in the next reaction.
To a solution of 10 mmol of oxime in DMF (10 mL) was added 1.8
mmol of N-chlorosuccinimide (NCS) in one portion. (The beginning
of the reaction can be detected by a slight increase of the reaction
temperature. If the reaction does not start, a small amount of HCl gas
can be bubbled through the solution. With the electron-deficient oximes,
the reaction mixture is heated to 45 °C.) The remaining 8.2 mmol of
NCS was added in small portions while keeping the temperature below
35 °C (below 60 °C for electron-deficient oximes). The mixture was
stirred at room temperature for 1 h, poured into water, and extracted
with diethyl ether. The organic phase was washed with brine and dried
over MgSO4, and the solvent was removed to give the imidoyl chloride
products in 70-90% yield. They were used directly without further
purification in the next reaction. Aromatic imidoyl chlorides can be
stored over a long time without noticeable decomposition. However,
most aliphatic imidoyl chlorides should be used soon after preparation
to avoid decomposition.
Results and Discussion
(A) Experimental Evidence. Synthesis of 1,4-Disubstituted
1,2,3-Triazoles. Terminal alkynes and organic azides containing
a wide range of functional groups are regiospecifically united
to form the corresponding triazole products in excellent yields.
Several key features set this transformation apart from most
other catalytic processes: (1) it exhibits enormous scope
regarding both alkynes and azides, and most functional groups
do not need to be protected, (2) it proceeds well in a variety of
solvent systems (while water without an organic cosolvent or
water/alcohol mixtures have been used most commonly, such
solvents as dimethyl sulfoxide, tetrahydrofuran, acetone, di-
methylformamide, and acetonitrile have all been used success-
(9) (a) Becke, A. D. Phys. ReV. 1988, A38, 3098. (b) Becke, A. D. J. Chem.
Phys. 1993, 98, 1372. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9;
Gaussian, Inc.: Pittsburgh, PA, 1998.
General Procedure for the Synthesis of Isoxazoles from Nitrile
Oxides and Alkynes, As Exemplified for 3-(4-Methoxyphenyl)-5-
phenylisoxazole. N-Hydroxy-4-methoxy-benzenecarboximidoyl chlo-
ride (186 mg, 1 mmol) and phenylacetylene (102 mg, 1 mmol) were
(11) (a) Barone, V.; Cossi, M. J. Phys. Chem. 1998, 102, 1995. (b) Barone, B.;
Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404.
(12) Orozco, M.; Luque, F. J. Chem. ReV. 2000, 100, 4187.
9
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