A Weinreb nitrile oxide and nitrone for cycloaddition

Article abstract of DOI:10.1021/ol0489752

(Chemical Equation Presented) The cycloaddition of Weinreb amide functionalized nitrile oxide/nitrones with a range of dipolarophiles has been explored.

Full text of DOI:10.1021/ol0489752

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3063-3065
A Weinreb Nitrile Oxide and Nitrone for
Cycloaddition
Ajit K. Parhi and Richard W. Franck*
Department of Chemistry, Hunter College of CUNY, 695 Park AVenue,
New York, New York 10021
rfranck@hunter.cuny.edu
Received June 3, 2004
ABSTRACT
The cycloaddition of Weinreb amide functionalized nitrile oxide/nitrones with a range of dipolarophiles has been explored.
This Letter describes the simple preparations and cyclo-
addition reactions of a new nitrile oxide and nitrone. Our
reagent design stemmed from the consideration of three well-
known concepts. One idea is the use of heterocycles as
peptidomimetics.1 A second precedent is the preparation of
five-membered heterocycles via 1,3-dipolar addition.2 The
third component of our design is the popularity of the
N-methyl-N-methoxyamide (Weinreb amide) as a stable
control element for nucleophilic additions to carboxyl
derivatives.3 As a versatile synthon for peptidomimetics to
be developed within our neoglycopeptide program,4 the
Weinreb amide isoxazole of generic structure 1 was envi-
sioned. There are two obvious synthetic options for the
preparation of 1, summarized in eqs 1 and 2. Thus, the known
ester nitrile oxide 2 could be used to prepare isoxazole 3,
which would then be converted to 1 (eq 1),5 or the unknown
nitrile oxide 4 could be used to produce 1 directly (eq 2).
Preliminary studies of the route shown in eq 1 led us to
develop the alternate route of eq 2.
(1) (a) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Webber, S. E.; Marakovits,
J. T.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Ford, C.
E. Burke, B. J.; Rejto, P. A.; Hendrickson, T. F.; Tuntland, T.; Brown, E.
L.; Meador, J. W., III.; Ferre, R. A.; Harr, J. E. V.; Kosa, M. B.; Worland,
S. T. J. Med. Chem. 1999, 42, 1213-1224. (b) Groutas W. C.; Kuang, R.;
Venkataraman, R.; Epp, J. B.; Ruan, S.; Prakash, O. Biochemistry 1997,
36 4739-4750. (c) Bondebjerg, J.; Xiang, Z.; Bauzo, R. M.; Haskell-
Luevano, C.; Meldal, M. J. Am. Chem. Soc. 2002, 124, 11046-11055. (d)
Hoesl, C. E.; Nefzi, A.; Ostresh, J. M.; Yu, Y.; Houghten, R. A. Methods
Enzymol. 2003, 369, 496-517. (e) Lewis, J. G.; Bartlett, P. A. J. Comb.
Chem. 2003, 5, 278-284. (f) Baldwin, S. W.; Long, A. Org. Lett. 2004, 6,
1653-1656.
(2) (a) Torsell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: Weinheim, 1988. (b) Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W. H., Eds; Wiley: Chichester, 2002. (c)
Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 164, 5366-
5367. (d) See ref 1f.
The required starting material for both dipolar reactants
is the Weinreb aldehyde 8 prepared from commercially
(4) (a) Li, B.; Franck, R. W.; Capozzi, G.; Menichetti, S.; Nativi, C.
Org. Lett. 1999, 1, 111-113. (b) Bartolozzi, A.; Li, B.; Franck, R. W.
Bioorg. Med. Chem. 2003, 11, 3021-3027.
(3) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
10.1021/ol0489752 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/03/2004

available trans-cinnamic acid 6 in two steps. Cinnamic acid
derivative 76 is subjected to ozonolysis to produce the desired
material isolated as the mixture of aldehyde 8 and its
hemiacetal, with methanol used as a cosolvent for the
ozonolysis. This inseparable mixture of the desired products,
however, was easily separated from benzaldehyde by silica
gel chromatography. Treatment of 8 with hydroxylamine
hydrochloride produced the crude Weinreb amide-oxime 9
in quantitative yield. The crude oxime 9 can be converted
to 4 via the conventional method:7 chlorination with N-
chlorosuccinimide followed by removal of HCl by triethyl-
amine (Scheme 1).
Table 1. [3 + 2] Cycloaddition of Weinreb Amide-Nitrile
Oxide
Scheme 1. Preparation of Weinreb Amide-Nitrile Oxidea
Similarly the Weinreb amide-nitrone 5 was synthesized
by treating 8 with N-benzyl hydroxylamine hydrochloride
(Scheme 2).8 The crude nitrone was used for cycloadditions
Scheme 2. Preparation of Weinreb Amide-Nitrone and
Cycloaddition
a Reagents and conditions: (a) 2-chloro-4,6-dimethoxy-1,3,5-
triazine, NMM, Me(MeO)NH‚HCl, THF, 10 h, 90%; (b) O3,
CH2Cl2/MeOH, Me2S, 78%; (c) H2NOH‚HCl, NaHCO3, ether/H2O,
1 h, 91%; (d) NDS, Pyr, CHCl3; (e) NEt3, CH2Cl2.
The labile Weinreb amide functionalized nitrile oxide
generated in situ was allowed to react with different alkynes
(entries 1-4) and alkenes (entries 5 and 6) at room
temperature to give substituted isoxazoles and isoxazolines
in moderate yield based on oxime. In all cases the reactions
are regioselective and give only one product.
without further purification (Table 2). In both cases cis and
trans stereoisomers were obtained in a 1:20 ratio favoring
the trans isomer. The stereochemistry was tentatively as-
signed from the coupling constant (4 Hz) of the hydrogen at
Table 1 records our results from reacting 4 with a range
of dipolarophiles.
Table 2. [3 + 2] Cycloaddition of Weinreb Amide-Nitrone
(5) Micetich, R. G.; Shaw, C. C.; Hall, T. W.; Spevak, P.; Fortier, R.
A.; Wolfert, P.; Foster, B. C.; Bains, B. K. Heterocycles 1985, 23, 571-
583.
(6) Luca, L. D.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
2534-2537.
(7) (a) Yin, H.; Franck, R. W.; Chen, S. L.; Quigley, G. J.; Todaro, L.
J. Org. Chem. 1992, 57, 644-651. (b) Jeger, V.; Schohe, R. Tetrahedron
1984, 40, 2199-2210. (c) Houk, K. N.; Caramella, P.; Cellerinn, G.; Coda,
A. C.; Invernizzi, A. G.; Grunanger, P.; Albini, F. M. J. Org. Chem. 1976,
41, 3349-3357. (d) Jager, V.; Muller, I. Tetrahedron 1985, 41, 3519-
3528. (e) Grunanger, P.; Coda, A. C.; Vernesi, G. Tetrahedron Lett. 1966,
2911-2912.
(8) Deshong, P.; Dicken, C. M. J. Org. Chem. 1982, 47, 2047-
2051.
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Org. Lett., Vol. 6, No. 18, 2004

carbon 5 of the compound 17. This assignment is based on
the work of Deshong8 and Go´mez-Guille´n,9 who had similar
isoxazolidines and similar coupling constants at the C-5
hydrogen.
Equations 3 and 4 show that a Weinreb-functionalized
isoxazole undergoes reactions with an organolithium and
LiAlH4 in the expected manner.3,10
Acknowledgment. We dedicate this report to Professor
Steven M. Weinreb in recognition of the significance of his
amide concept for organic synthesis. This research was
supported by NIH grants GM 60271 (R.W.F.), RCMI RR
03037 (Hunter College science infrastructure), and RR
017818 (500 MHz NMR spectrometer).
Note Added after ASAP Posting. The footnote for
Scheme 1 was missing in the version posted ASAP
July 27, 2004; the corrected version was posted August 6,
2004.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 8, 11-14,
and 16-20; copies of the 300 or 500 MHz 1H NMR and 75
MHz 13C NMR spectra of compounds 8, 12, 14, 16, and
18-20; and (ESI) mass spectra of compounds 18 and 19.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, two versatile N-methyl-O-methyl hydrox-
amate cycloaddition reagents are available for the synthetic
community.
(9) Borrachero, P.; Cabrera-Escribano, F.; Go´mez-Guille´n, M.; Torres,
M. I. Tetrahedron Lett. 2004, 45, 4835-4839.
(10) Fehrentz, J. A.; Castro, B. Synthesis 1983, 676.
OL0489752
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