A novel, general method for the synthesis of nitrile oxides: Dehydration of O-silylated hydroxamic acids

Article abstract of DOI:10.1021/ol991396q

(Formula presented) O-Silylated hydroxamic acids serve as stable, readily accessible, crystalline precursors to nitrile oxides when treated with trifluoromethanesulfonic anhydride and triethylamine. Under these mild conditions in the presence of olefins O

Full text of DOI:10.1021/ol991396q

ORGANIC
LETTERS
2000
Vol. 2, No. 4
539-541
A Novel, General Method for the
Synthesis of Nitrile Oxides: Dehydration
of O-Silylated Hydroxamic Acids
Dieter Muri, Jeffrey W. Bode, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Zentrum, CH-8092 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received December 23, 1999
ABSTRACT
O-Silylated hydroxamic acids serve as stable, readily accessible, crystalline precursors to nitrile oxides when treated with trifluoromethanesulfonic
anhydride and triethylamine. Under these mild conditions in the presence of olefins O-silylated hydroxamic acids afford isoxazoline cycloadducts.
This procedure represents a novel, general method for the one-step generation of nitrile oxides, which complements existing protocols.
The [3 + 2] dipolar cycloaddition reaction of olefins and
nitrile oxides to give isoxazolines has long been valued as
an important transformation for chemical synthesis. These
heterocyclic products are not only themselves of interest but
are also valuable because they may be readily elaborated to
a variety of highly functionalized compounds.1 Thus, for
example, as elegantly exemplified by the recent synthesis
of amphotericin,2 the isoxazoline adducts of a nitrile oxide/
olefin cycloaddition reaction can be utilized as masked
â-hydroxy carbonyl aldolate equivalents. We have previously
reported the dipolar cycloaddition of Me3SiCHN2 with chiral
acrylates to give optically active pyrazolines, which in turn
serve as useful starting materials for the rapid assembly of
building blocks for asymmetric synthesis.3 In our continuing
interest in this area, we have sought to develop new methods
for the generation and elaboration of similarly functionalized
heterocycles. In this regard, although nitrile oxides represent
a highly valuable class of dipoles for dipolar cycloaddition
reactions, methods for their in situ generation are limited.
Thus, there has been interest in the discovery and develop-
ment of alternative methods for their formation from stable,
readily accessible precursors.4 In this letter, we now report
the use of O-tert-butyldiphenylsilyl hydroxamates as stable,
crystalline precursors to nitrile oxides, which in the presence
of triflic anhydride and base (Tf2O, Et3N, 0 °C, CH2Cl2) lead
to the formation of nitrile oxides that participate in dipolar
cycloaddition reactions with olefins.
There are currently two well-established, widely used
methods for the in situ formation of nitrile oxides. The most
common approach, base-induced elimination of HCl from
hydroximinoyl chlorides, has seen numerous applications in
a vast range of cycloadditions.5 The requisite hydroximinoyl
chlorides are prepared from the corresponding oxime, derived
from an aldehyde, and an electrophilic chlorine source (NCS,
NaOCl, Cl2). This method is not amenable, however, for
substrates highly sensitive to oxidation or halogenation,
including electron-rich aromatics, olefins, and sulfides.6 The
second approach, known as the Mukaiyama method, involves
the dehydration of nitroalkanes by the action of phenyl
isocyanate, DCC, or similar reagents in the presence of base.7
(4) For examples, see: (a) Curran, D. P.; Fenk, C. J. J. Am. Chem. Soc.
1985, 107, 5310. (b) Nishiwaki, N.; Uehara, T.; Asaka, N.; Tohda, Y.; Ariga,
M.; Kanemasa, S. Tetrahedron Lett. 1998, 39, 4851.
(5) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: New York, 1988. (b) Werner, A.; Buss, H. Chem.
Ber. 1894, 27, 2193. (c) Larsen, K. E.; Torssell, K. B. G. Tetrahedron 1984,
40, 2985.
(1) (a) Easton, C.; Huges, C. M. M.; Savage, G. P.; Simpson, G. W.
AdV. Heterocycl. Chem. 1994, 60, 261. (b) Torssell, K. B. G. Nitrile Oxides,
Nitrones, and Nitronates in Organic Synthesis; VCH: New York, 1988.
(2) McGarvery, G. J.; Mathys, J. A. Wilson, K. J. J. Org. Chem. 1996,
61, 5704.
(3) (a) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc.
1997, 119, 8379. (b) Whitlock, G. A.; Carreira, E. M. J. Org. Chem. 1997,
62, 7916. (c) Sasaki, H.; Carreira, E. M. Synthesis, in press.
(6) (a) Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916. (b) Wiley: R. H.; Wakefield, B. J. J. Org. Chem. 1959, 25, 546.
(7) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
10.1021/ol991396q CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/02/2000

This procedure has been widely utilized and is limited only
by the occasional difficulty in obtaining the necessary nitro
precursors. Moreover, as a functional group nitroalkanes can
display relatively high reactivity toward commonly employed
organic and inorganic reagents in a multistep synthesis.
In principle, in the presence of an activating agent, suitably
O-substituted hydroxamic acids should be amenable to a
dehydration reaction to yield the corresponding nitrile oxides
(Scheme 1). Surprisingly, this sequence has not been
desilylation agent was unnecessary for nitrile oxide formation
(Scheme 2). This observation led to the development of an
Scheme 2. Conversion of Silyl Hydroxamates to Nitrile
Oxides
Scheme 1. Conversion of Hydroxamates to Nitrile Oxides
experimentally straightforward procedure for the generation
of nitrile oxides: treatment of the O-SitBuPh2-protected
hydroxamate with 1.1 equiv of triflic anhydride in the
presence of 3 equiv of triethylamine at -40 °C, followed
by warming to room temperature.
As shown in Table 1, the use of O-SitBuPh2-protected
hydroxamates as precursors permits the preparation of a wide
range of nitrile oxides. In particular, aromatic (entries 1-3),
unsaturated (entry 4), and saturated hydroxamates (entries 5
and 6) all participated in the dipolar cycloaddition reaction
with the range of alkenes representative of those normally
employed.
previously exploited for the preparation of nitrile oxides.8
Likely precluding its development is the tendency of hy-
droxamates to form isocynates, via the Lossen rearrangement,
under the conditions that would be required for their
dehydration.9 We speculated, however, that proper selection
of the hydroxamate protecting group (Z) and activating agent
(Y) would lead to cleavage of the C-O bond, via dehydra-
tion, in preference to the N-O bond (Lossen rearrangement).
In preliminary studies, treatment of O-protected benzhy-
t
droxamic acids (Scheme 1, Z ) SiR3, Boc, or Bu) with
Intramolecular nitrile oxides cycloadditions are also readily
achieved with this method.11 The cycloadduct yields are
comparable to those previously reported employing existing,
complementary methods.
acylating or sulfonylating reagents (MsCl, Tf2O, perfluoro-
butanesulfonyl fluoride, oxalyl chloride) occurred predomi-
nantly at the carbonyl oxygen, as expected from the literature
precedent with amides and O-alkyl hydroxamates.10 Treat-
ment of these intermediates with various deprotection
reagents (TBAT ([Bu4N]Ph3SiF2), pyridinium acetate, NEt3,
Hu¨nig’s base) resulted in either formation of a nitrile oxide,
as detected by trapping with norbornene, or decomposition.
The O-Boc and O-tert-butyl derivatives gave primarily the
products of Lossen rearrangement; however, O-silyl deriva-
tives proved successful. In particular, the O-tert-butyldi-
phenylsilylated hydroxamate was identified as optimal in
terms of ease of preparation, reactivity, stability of the
precursor, and crystallinity. In contrast, the O-SiMe3 and
O-SitBuMe2 hydroxamates proved too labile for general use.
In comparison to procedures employing other activating
agents such as mesic anhydride, the use of triflic anhydride
offers distinct advantages. Thus, when triflic anhydride was
employed in the activation step we noted that use of a
Although the requisite hydroxamates may be prepared
simply by the silylation of the corresponding hydroxamic
acid (NaH, ClSitBuPh2),12 they are also conveniently syn-
thesized by the coupling of carboxylic acids and O-SitBuPh2
hydroxylamine, a stable, crystalline, and easily prepared
reagent.13 In contrast to chlorinated aldoxamines and some
nitroalkanes, we have found these precursors amenable to a
number of synthetic transformations and common chromato-
graphic techniques, while still allowing for a single step
generation of the nitrile oxide.
The following reaction of O-tert-butyldiphenylsilyl ben-
hydroxamate with norbornene is representative for the
conversion of hydroxamates to nitrile oxides and their
susequent cycloaddition with alkenes. To a stirred solution
of O-SitBuPh2 benzhydoxamate (50 mg, 0.13 mmol, 1.0
equiv) and NEt3 (540 uL, 0.39 mmol, 3.0 equiv) in 2.0 mL
of CH2Cl2 at -40 °C was added triflic anhydride (0.63 M
solution in CH2Cl2, 0.24 mL, 0.15 mmol, 1.1 equiv)
(8) (a) To our knowledge, there has been only one report of a similar
transformation, namely, the thermolysis of 1,3,2,4-dioxathiazole 2-oxides
to give apparent generation of nitrile oxides, albeit with competing
isocyanate formation. In contrast, cyclic hydroxamate esters give exclusively
isocynates via Lossen rearrangement; see: Frantz, J. E.; Pearl, H. K. J.
Org. Chem. 1975, 41, 1296. (b) O-Trimethylsilyl hydroximinoyl chlorides
have been used to prepare nitrile oxides. However, the necessary intermedi-
ates must be prepared from nitrile oxides themselves, and the method is
therefore not, in itself, a preparative method for nitrile oxides. Cunico, R.
F.; Bedell, L. J. Org. Chem. 1983, 48, 2780.
(9) (a) Kind, F. D.; Pike, S.; Walton, D. R. M. J. Chem. Soc., Chem.
Commun. 1978, 351. (b) Pihuleac, J.; Bauer, L. Synthesis 1989, 61-64.
(10) (a) Sharma, N.; Misra, B. N. Collect. Czech. Chem. Commun. 1989,
54, 2738. (b) Charette, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908.
(11) In preliminary work, we have documented that 3a, 6-dihydro-3H-
cyclopenta[c]isoxazoline can be prepared by intramolecular nitrile oxide
cycloaddition reaction of the corresponding silylated hydroxamic acid. This
result along with an accompanying study of intramolecular cycloadditions
utilizing the method described herein is part of ongoing investigations in
our group and will be reported as results become available.
(12) Papaioannou, D.; Barlos, K.; Francis, G. W.; Brekke, T.; Aksnes,
D. W.; Maartmann-Moe, K. Acta Chem. Scand. 1990, 44, 189.
(13) (a) Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T. J.
Am. Chem. Soc. 1990, 112, 3466. (b) Bottaro, J. C.; Bedford, C. D.; Dodge,
A. Synth. Comm. 1985, 15, 1333.
540
Org. Lett., Vol. 2, No. 4, 2000

Table 1. Dipolar Cycloaddition Reactions of Alkenes and Nitrile Oxides Generated from O-SitBuPh2Si Hydroxamatesa
a Conditions: Tf2O, NEt3, CH2Cl2, -40 to 0 °C, then olefin, rt or 40 °C. b A ) norbornene, B ) styrene, C ) methyl cinnamate.
dropwise. After the addition was complete, the solution was
allowed to warm to 0 °C for 1 h before norbenene (0.025 g,
0.27 mmol, 2.0 equiv) was added. The reaction was warmed
to room temperature and stirred for 5 h. Aqueous workup
and purification by flash chromatography (silica gel, hexane/
EtOAc 20:1) provided the isoxazoline 3a as a white solid
(24 mg, 86% yield). This material was identical spectro-
scopically (1H and 13C NMR) and by melting point (mp 99-
100 °C) to an authentic sample prepared as previously
described.14
nitrile oxides, which in a single step under mild conditions
lead to cycloadducts.
Acknowledgment. Support has been provided by gener-
ous funds from the ETH, the Kontaktgruppe fu¨r Forschungs-
fragen (KGF), and Hoffman-La Roche. J.W.B. thanks the
NSF for a predoctoral fellowship.
Supporting Information Available: Full characterization
and experimental procedures for the synthesis of the silylated
hydroxaminates. This material is available free of charge via
the Internet at http://pubs.acs.org.
In summary, we have found O-SitBuPh2-protected hy-
droxamates to be stable, readily accessible precursors to
(14) Kanemasa, S.; Nishiuchi, M. Tetrahedron Lett. 1993, 34, 4011.
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