ACHTUNGTRENNUNG[3+2] Dipolar Cycloadditions
FULL PAPER
7.24 (m, 5H), 5.97 (d, J=3.0 Hz, 1H), 4.97 (d, J=2.9 Hz, 1H), 2.81 ppm
(s, 3H); 13C NMR (125 MHz, [D6] DMSO, 258C): d=160.0, 144.8, 140.7,
128.4, 127.6, 126.7, 109.8, 74.8, 46.6 ppm; IR (microscope): n˜ =3400–2100
reactions, under milder conditions, with much improved
product yields and regioselectivities. In some instances, such
as triazole formation from azides and 2-alkynoic acids, catal-
ysis with ortho-nitrophenylboronic acid circumvents the un-
desirable product decarboxylation observed when only using
thermal activation. By using NMR spectroscopic studies, the
boronic acid catalyst was shown to provide activation by
lowering the LUMO of the unsaturated carboxylic acid
likely via a monoacylated hemiboronic ester intermediate.
(br), 1714, 1642, 1555 cmÀ1
; HRMS (ESI): calcd for C11H9NO3:
204.06662; found: 204.06635. Without 2-nitrophenylboronic acid as the
catalyst, this reaction gave N-methylbenzamide (10a) in 41% yield.
Products 8a and 8c, 9d and 9e, 11a and 11b, and 12c and 12d were pre-
pared using a similar procedure and then characterized (see the Support-
ing Information).
Acknowledgements
Experimental Section
This research was generously funded by the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada (E. W. R. Steacie Memo-
rial Fellowship to D.G.H.) and the University of Alberta. H.Z. thanks the
Alberta Ingenuity Foundation for a Graduate Scholarship. The authors
thank Dr. Michael Ferguson for help with X-ray crystallographic analysis.
Typical procedure for the boronic acid catalyzed cycloaddition of azides
to unsaturated carboxylic acids: benzyl-1H-1,2,3-triazole-4-carboxylic
acid (1a; Table 2, entry 1): ortho-Nitrophenylboronic acid (8 mg,
0.05 mmol) was added to a solution of propiolic acid (70 mg, 1 mmol) in
1,2-dichloroethane (2 mL), and the resulting solution was stirred at room
temperature (258C) for 10 min. Benzyl azide (146 mg, 1.1 mmol) was
then added and the resulting mixture was stirred at room temperature
for 4 h. The solvent was then removed under vacuum, at room tempera-
ture. The residue was washed with Et2O (3ꢂ5 mL) and filtered to give
pure triazole 1a (195 mg, 96%) as a white solid. The characterization
data for this compound matched that of previous reports.[15] Products 1b–
r were prepared using a similar procedure and then fully characterized
(see the Supporting Information).
Diez-Gonzalez, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612–
Typical procedure for the boronic acid catalyzed cycloaddition of nitrile
oxides to unsaturated carboxylic acids: 3-phenylisoxazole-5-carboxylic
acid (4a; Table 3, entry 1): Triethylamine (111 mg, 1.1 mmol) was added
to an ice-cooled (08C), stirred solution of phenylhydroximic acid chloride
(171 mg, 1.1 mmol) in 1,2-dichloroethane (2 mL); after 3 min, the mixture
was washed with water (2ꢂ4 mL) and dried over Na2SO4. The resulting
solution was filtered to remove the Na2SO4 and give a solution of benzo-
nitrile oxide (around 4 mL). A solution of propiolic acid (70 mg, 1 mmol)
and ortho-nitrophenylboronic acid (8 mg, 0.05 mmol) in 1,2-dichloro-
ethane (4 mL) was added to the benzonitrile oxide solution prepared in
this way. After stirring for 2 h at room temperature (258C), the solvent
was removed under vacuum, at room temperature. Then, NaOH (1m,
5 mL) was added to the residue and this mixture was washed with Et2O
(3ꢂ5 mL). The aqueous layer was adjusted to pH 4 by adding HCl (6m),
dropwise. The resulting aqueous layer was extracted with EtOAc (3ꢂ
10 mL) and the organic layer was dried over Na2SO4. Filtering off the
Na2SO4 and removing the solvent gave pure isoxazole product 4a
(165 mg, 87%) as a white solid. The regiochemistry was assessed by
using 2D NMR experiments (HMBC and HSQC, see the Supporting In-
formation). 1H NMR (400 MHz, [D6] DMSO, 258C): d=14.30 (brs, 1H),
7.97–7.92 (m, 2H), 7.77 (s, 1H), 7.55–7.49 ppm (m, 3H); 13C NMR
(100 MHz, [D6] DMSO, 258C): d=162.7, 161.7, 157.6, 130.6, 129.1, 127.6,
126.7, 107.5 ppm; IR (microscope): n˜ =3400–2100 (br), 1705, 1595,
1579 cmÀ1; HRMS (ESI): m/z calcd for C10H6NO3: 188.03532; found:
188.03545. Products 4a–c, 5d and 5e, 6a–c, and 7d and 7e were prepared
by using a similar procedure and then characterized (see the Supporting
Information).
[3] a) E. Jimenez-Nunez, A. M. Echavarren, Chem. Commun. 2007,
3325; e) E. Jimenez-Nunez, A. M. Echavarren, Chem. Rev. 2008,
[7] a) R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. De Clercq,
C.-F. Perno, A. Karlsson, J. Balzarini, M. J. Camarasa, J. Med.
[8] CCDC-750311 (1r), 750312 (5e), and 756956 (11a) contain the crys-
tallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
b) B. J. Wakefield, Science of Synthesis: Houben–Weyl Methods of
Molecular Transformations, Vol. 11 (Ed.: E. Shaumann), Thieme,
Stuttgart, 2001, pp. 229–288.
[10] V. Jager, P. A. Colinas, Synthetic Applications of 1,3-Dipolar Cyclo-
addition Chemistry Toward Heterocycles and Natural Products,
Vol. 59 (Ed.: A. Padwa), Wiley, New York, 2002, pp. 361–472.
Typical procedure for the boronic acid catalyzed cycloaddition of nitro-
nes to unsaturated carboxylic acids: 2-methyl-3-phenyl-2,3-dihydroisoxa-
zole-5-carboxylic acid (8a; Table 5, entry 1): A solution of propiolic acid
(70 mg, 1 mmol) and ortho-nitrophenylboronic acid (33 mg, 0.2 mmol) in
1,2-dichloroethane (4 mL) was slowly added by syringe pump, over 6 h,
to a stirred solution of (Z)-N-benzylidenemethanamine oxide (135 mg,
1 mmol) in 1,2-dichloroethane (4 mL) maintained at 408C. After the mix-
ture was stirred at 408C for 48 h, the solvent was removed under vacuum
and the crude product was purified by flash column chromatography
(EtOAc/hexanes=1:2) to give pure isoxazolecarboxylic acid 8a (146 mg,
71%) as
a white solid. The regiochemistry was assessed by using
2D NMR experiments (HMBC and HSQC, see the Supporting Informa-
tion). 1H NMR (400 MHz, [D6] DMSO, 258C): d=13.36 (brs, 1H), 7.38–
Chem. Eur. J. 2010, 16, 5454 – 5460
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