Radical Fragmentation of β-Hydroxy Azides. Synthesis of Chiral Nitriles

Full text of DOI:10.1021/jo971836w

8974
J . Org. Chem. 1997, 62, 8974-8975
Sch em e 1
Ra d ica l F r a gm en ta tion of â-Hyd r oxy
Azid es. Syn th esis of Ch ir a l Nitr iles
Rosendo Herna´ndez, Elisa I. Leo´n, Pilar Moreno, and
Ernesto Sua´rez*
Instituto de Productos Naturales y Agrobiologı´a del CSIC,
Carretera de La Esperanza 3, 38206-La Laguna, Tenerife,
Spain
Received October 6, 1997
In previous papers, we have described the preparation
of chiral building blocks by fragmentation of anomeric
alkoxy radicals of carbohydrates.1 Moreover, nitriles
have proven to be extremely versatile functional groups.2
They may undergo a variety of reactions, especially
reduction, alkylation of their enolates, enzymatic hy-
drolysis to acids and amides by nitrile hydratase,3 Ritter
reaction,4 and many other synthetically useful transfor-
mations.
Ta ble 1. Nitr iles by â-F r a gm en ta tion of â-Hyd r oxy
Azid esa
In this paper, we develop a new protocol for the
synthesis of nitriles by â-fragmentation of alkoxy radicals
by reaction of â-hydroxy azides with (diacetoxyiodo)ben-
zene (DIB) and iodine. In particular, this reaction has
been applied to the synthesis of chiral nitriles by â-frag-
mentation of anomeric alkoxy radicals from 2-azido-2-
deoxy sugars, as shown in Scheme 1.
Related methodologies for the synthesis of cyano
ketones by cleavage of trisubstituted cyclic olefins with
DIB-trimethylsilyl azide, LTA-trimethylsilyl azide,5 or
photooxygenation in the presence of NaN3/Cu(OTf)2 have
been described.6 Moreover, an interesting synthesis of
aldononitriles by reaction of N-bromoglycoxylimines with
Zn/Ag-graphite or C8K has been reported.7
Several excellent methods exist in the literature for
the synthesis of â-hydroxy azides in general by electro-
philic or radical addition reactions to olefins.8 We have
prepared 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-glucose9 (1)
by reaction of 3,4,6-tri-O-acetyl-D-glucal with sodium
azide/ceric ammonium nitrate10 and subsequent anomeric
denitration11 with hydrazine acetate of the â-nitro azide
obtained. Reaction of this compound with DIB and iodine
(1) (a) Armas, P.; Francisco, C. G.; Sua´rez, E. Angew. Chem., Int.
Ed. Engl. 1992, 31, 772-774. (b) Armas, P.; Francisco, C. G.; Sua´rez,
E J . Am. Chem. Soc. 1993, 115, 8865-8866. (c) Armas, P.; Francisco,
C. G.; Sua´rez, E. Tetrahedron Lett. 1993, 34, 7331-7334. (d) Francisco,
C. G.; Gonza´lez, C. C.; Sua´rez, E. Tetrahedron Lett. 1996, 37, 1687-
1690. (e) Francisco, C. G.; Freire, R.; Gonza´lez, C. C.; Sua´rez, E.
Tetrahedron: Asymmetry 1997, 8, 1971-1974.
(2) (a) The Chemistry of the Cyano Group; Rappoport, Z., Ed.;
Interscience: New York, 1970. (b) Arseniyadis, S.; Kyler, K. S.; Watt,
D. S. In Organic Reactions; Dauben, W. G., Ed.; J ohn Wiley: New York,
1984; Vol. 31, pp 1-374.
a
All reactions were performed in dry dichloromethane with
(3) (a) Brennam, B. A.; Alms, G.; Nelson, M. J .; Durney, L. T.;
Scarrow, R. C. J . Am. Chem. Soc. 1996, 118, 9194-9195. (b) Taylor,
S. K.; Chmiel, H. H.; Simons, L. J .; Vyvyan, J . R. J . Org. Chem. 1996,
61, 9084-9085. (c) Maddrell, S. J .; Turner, N. J .; Kerridge, A.; Willetts,
A. J .; Crosby, J . Tetrahedron Lett. 1996, 37, 6001-6004.
(4) Bishop, R. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I.; Eds.; Pergamon Press: Oxford, 1991; Vol. 6, pp 261-300.
(5) Zbiral, E.; Nestler, G.; Kischa, K. Tetrahedron 1970, 26, 1427-
1434. (b) Zbiral, E.; Nestler, G. Tetrahedron 1970, 26, 2945-2951. (c)
Ehrenfreund, J .; Zbiral, E. Tetrahedron 1972, 28, 1697-1704.
(6) Shimizu, I.; Fujita, M.; Nakajima, T.; Sato, T. Synlett 1997, 887-
888.
(diacetoxyiodo)benzene (1.2 mmol) and iodine (1 mmol) per mmol
of substrate. The monoterpene substrates 7 and 9 were irradiated
with 2 × 80W tungsten-filament lamps.
under the conditions shown in Table 1 (entry 1) gave the
arabinonitrile derivative 2.
In a typical procedure, a solution of â-hydroxy azide 1
(102 mg, 0.31 mmol) in CH2Cl2 (20 mL) containing DIB
(120 mg, 0.37 mmol) and iodine (79 mg, 0.31 mmol) was
stirred at 20 °C for 2 h. The reaction mixture was then
(7) Fu¨rstner, A.; Praly, J .-P. Angew. Chem., Int. Ed. Engl. 1994, 33,
751-753.
(8) Boche, G. In Stereoselective Synthesis, Methods of Organic
Chemistry (Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer,
J ., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E 21-9; pp
5190-5221.
(9) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826-
1847.
(10) (a) Lemieux, R. U.; Ratcliffe, R. M. Can. J . Chem. 1979, 57,
1244-1251. (b) Lin, C.-H.; Sugai, T.; Halcomb, R. L.; Ichikawa, Y.;
Wong, C.-H. J . Am. Chem. Soc. 1992, 114, 10138-10145. (c) Bemiller,
J . N.; Blazis, V. J .; Myers, R. W. J . Carbohydr. Chem. 1990, 9, 39-57.
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S0022-3263(97)01836-7 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 26, 1997 8975
Sch em e 2
poured into a 10% aqueous sodium thiosulfate solution
and extracted with CH2Cl2, dried (Na2SO4), and concen-
trated in vacuo. Chromatotron chromatography of the
residue (hexanes-EtOAc, 70:30) yielded 2 (82.3 mg,
88%).
The reaction can also be performed with carbohydrates
in furanose form as can be observed from Table 1 (entry
2). The 2-azide-2-deoxy-5,6-O-isopropylidene-3-O-meth-
yl-D-mannofuranose (3) obtained starting from 1,4-an-
hydro-2-deoxy-5,6-O-isopropylidene-D-arabino-hex-1-en-
itol12 by azidophenylselenation with N-(phenylseleno)-
phthalimide and trimethylsilyl azide followed by ano-
meric dephenylselenation with N-iodosuccinimide13 gave
the arabinonitrile derivative 4. The arabinonitrile de-
rivatives 2 and 4 possess very different patterns of
protection and have been synthesized in order to explore
the utility of this methodology for the synthesis of chiral
synthons.
As can be seen in Table 1 (entry 3), the reaction was
also applied to carbohydrates of the threose series, so the
2-azido-2-deoxy-galactose derivative 5, obtained from the
commercially available 3,4,6-tri-O-acetyl-D-galactal by an
analogous azidophenylselenation-hydrolysis,13 gave the
lyxonitrile derivative 6.
The reaction can be extended to noncarbohydrate
compounds such as the monoterpenes 7 and 9. Both
â-hydroxy azides were prepared by photooxygenation in
the presence of sodium azide of the corresponding olefins,
(+)-limonene and (-)-R-pinene, and subsequent reduc-
tion, with sodium sulfite, of the azidohydroperoxides
formed.14 The radical fragmentation reaction gave 1,5-
cyano ketones 8 and 10 in similar yields (entries 4 and
5). Although, in both cases, the reaction may proceed
under natural light conditions, assisted irradiation with
2 × 80W tungsten-filament lamps reduced reaction times.
The reaction mechanism deserves special comment. As
shown in Scheme 2, the C2 radical initially formed must
be oxidized by the reagent to a carbocation in order for
the nitrile group to be formed after loss of a molecule of
nitrogen. Another transformation of azides into nitriles
can be observed during the thermal or photochemical
decomposition of vinyl azides.15
As may be inferred from Table 1, the reaction proceeds
under similar conditions to other anomeric alkoxy radical
fragmentations.1 These conditions are mild enough to
be compatible with the protective groups most widely
used in carbohydrate chemistry. The obtained products
possess an easily hydrolyzable formate group at a posi-
tion that only depends on the pyranose or furanose form
of the starting carbohydrate. This may be of interest
when products are to be employed as chiral templates or
chiral auxiliaries and further chemical transformations
are required.
Ack n ow led gm en t. This work was supported by the
Investigation Program no. PB96-1461 of the Direccio´n
General de Investigacio´n Cient´ıfica y Te´cnica, Spain.
P.M. thanks the Ministerio de Educacio´n y Cultura,
Spain, for a fellowship.
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J O971836W
(14) Griesbeck, A. G.; Hundertmark, T.; Steinwascher, J . Tetrahe-
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(15) The Chemistry of the Azido Group; Patai, S., Ed.; Interscience:
New York, 1971; pp 348, 441.