Generation of nitrile oxides from oximes using t -BuOI and their cycloaddition

Article abstract of DOI:10.1021/ol2010616

tert-Butyl hypoiodite (t-BuOI) was found to be a powerful reagent for the cycloaddition of oximes and alkenes/alkynes, leading to the formation of a variety of isoxazolines or isoxazoles under mild conditions.

Full text of DOI:10.1021/ol2010616

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2966–2969
Generation of Nitrile Oxides from Oximes
Using t-BuOI and Their Cycloaddition
Satoshi Minakata,*,† Sota Okumura,† Toshiki Nagamachi,† and Youhei Takeda‡
Department of Applied Chemistry and Frontier Research Base for Global Young
Researchers, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita,
Osaka 565-0871, Japan
minakata@chem.eng.osaka-u.ac.jp
Received April 22, 2011
ABSTRACT
tert-Butyl hypoiodite (t-BuOI) was found to be a powerful reagent for the cycloaddition of oximes and alkenes/alkynes, leading to the formation of a
variety of isoxazolines or isoxazoles under mild conditions.
The 1,3-dipolar cycloaddition of nitrile oxides to CÀC
unsaturated bonds has proven to be very useful for the
synthesis of isoxazolines and isoxazoles.1 These frame-
works are found in a wide variety of nitrogen heterocycles
that are molecular components of a large number of
natural products and biologically active compounds.2
Isoxazoline adducts that are produced in nitrile oxide/
alkene cycloaddition reactions can be used as masked
β-hydroxy carbonyl aldolate3 and β-amino alcohol4
equivalents. Nitrile oxides are commonly generated by
the elimination of HCl from hydroximinoyl chlorides in
the presence of a base.5 Hydroximinoyl chlorides can be
prepared from the corresponding oximes, derived from
aldehydes, and electrophilic chlorine-containing sources,
such as N-chlorosuccinimide (NCS), NaOCl, Cl2, etc.6
Although there are a few reports on the use of an electro-
philic bromine reagent, specifically N-bromosuccinimide
(NBS), for generating nitrile oxides from oximes,7 the use
of an electrophilic iodine reagent has not been reported to
date. As an alternate approach, dehydrative8 and oxidative9
processes were developed, and these methods have been
applied to the synthesis of complex molecules. In our
continuing interest in the area of monovalent iodine-con-
taining compounds, tert-butyl hypoiodite (t-BuOI) was
† Department of Applied Chemistry.
(6) (a) Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916–3918. (b) Katritzky, A. R.; Button, M. A. C.; Denisenko, S. N. J.
Heterocycl. Chem. 2000, 37, 1505–1510. (c) Lee, G. A. Synthesis 1982,
508–509. (d) Baruah, A. K.; Prajapati, O.; Sandhu, J. S. Tetrahedron
1988, 44, 1241–1246. (e) Ye, Y.; Zheng, Y.; Xu, G. Y.; Liu, L. Z.
Heteroatom Chem. 2003, 14, 254–257. (f) Kanemasa, S.; Matsuda, H.;
Kamimura, A.; Kakinami, T. Tetrahedron 2000, 56, 1057–1064. (g)
Kumar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 1457–1460. (h)
Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180–1183.
(7) (a) Grundmann, C.; Richter, R. J. Org. Chem. 1968, 33, 476–478.
(b) Tsuge, O.; Kanemasa, S.; Suga, H. Chem. Lett. 1986, 183–186. (c)
Armstrong, S. K.; Collington, E. W.; Knight, J. G.; Naylor, A.; Warren,
S. J. Chem. Soc., Perkin Trans. 1 1993, 1433–1447.
(8) (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339–5342. (b) Shimizu, T.; Hayashi, Y.; Teramura, K. Bull. Chem. Soc.
Jpn. 1984, 57, 2531–2534. (c) Shimizu, T.; Hayashi, Y.; Shibafuchi, H.;
Teramura, K. Bull. Chem. Soc. Jpn. 1986, 59, 2827–2831. (d) Muri, D.;
Bode, J. W.; Carreira, E. M. Org. Lett. 2000, 2, 539–541.
(9) (a) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh,
V. S.; Ciufolini, M. A. Org. Lett. 2009, 11, 1539–1542. (b) Jawalekar,
A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Commun.
2011, 47, 3198–3200.
‡ Frontier Research Base for Global Young Researchers.
(1) (a) 1,3-Dipolar Cycloaddition Chemictry; Padwa, A., Ed.; Wiley:
New York, 1984; Vols. 1 and 2. (b) Torssell, K. B. G. Nitrile Oxides,
Nitrones, and Nitronates in Organic Synthesis; VCH: New York, 1988. (c)
Werner, A.; Buss, H. Chem. Ber. 1894, 27, 2193–2201. (d) Grundmann, C.
Synthesis 1970, 344–359. (e) Larsen, K. E.; Torssell, K. B. G. Tetra-
hedron 1984, 40, 2985–2988.
(2) (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416. (b)
Mousa, S. A.; Bozarth, J. M.; Naik, U. P.; Slee, A. Br. J. Pharmacol.
2001, 133, 311–336. (c) Park, K. K.; Ko, D. H.; You, Z.; Khan, M. O. F.;
Lee, H. J. Steroids 2006, 71, 183–188. (d) Leppik, I. E. Seizure 2004, 13S,
S5–S9. (e) Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.;
Johnson, M.; Lee, F.; Nilakantan, R.; Petersen, R.; Svenson, K.;
Chopra, R.; Tam, M. S.; Wen, Y.; Ellingboe, J.; Arndt, K.; Boschelli,
F. J. Med. Chem. 2008, 51, 373–375. (f) Lamani, R. S.; Shetty, N. S.;
Kamble, R. R.; Khazi, I. A. M. Eur. J. Med. Chem. 2009, 44, 2828–2833.
(3) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
(4) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gilardi, A.; Restelli, A.
J. Chem. Soc., Perkin Trans. 1 1985, 2289–2292.
(5) (a) Liu, K. C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916. (b) Larsen, K. E.; Torssel, K. B. G. Tetrahedron 1984, 40, 2985.
r
10.1021/ol2010616
Published on Web 05/11/2011
2011 American Chemical Society

found to be a versatile reagent for the synthesis of nitrogen-
containing heterocycles from simple amides and alkenes10
and for CO2 fixation by allyl alcohols.11 From these points
of view, herein we report an in situ generation method for
nitrile oxides from oximes using t-BuOI.
with the regioselective formation of the adduct (entry 5).
Although the reaction of aldoxime 1a with methyl propio-
late gave a mixture of regioisomers, the reaction with
phenylacetylene yielded a sole regioisomer (entries 6 and 7).
The reagent t-BuOI can be readily prepared in situ from
commercially available tert-butyl hypochlorite (t-BuOCl)
and sodium iodide (NaI).12 Initially, we examined a
cycloaddition reaction involving benzaldoxime and styr-
ene in the presence of an equimolar amount of t-BuOI.
When benzaldoxime (1a) and styrene were treated with
t-BuOI (1 equiv) in acetonitrile at room temperature for
24 h, isoxazoline 2a was produced in 45% yield. To
improve the efficiency of the reaction, a variety of sol-
vents and temperatures were screened. When dioxane was
used as a solvent, the desired isoxazoline was produced in
54% yield. Since HI is liberated during the reaction, bases
were added to the system. As a result of the screening of
bases, 2,6-lutidine was found to be a suitable base for the
cycloaddition to afford 2a in 88% yield (eq 1). To confirm
the superiority of the system, t-BuOCl and N-iodosucci-
nimide (NIS) were employed separately to the reaction, in
the presence of 2,6-lutidine, and both reagents failed to
provide the desired product 2a in sufficient chemical yield
(with t-BuOCl: 44% yield; with NIS: 25% yield).
Table 1. Cycloaddition of Benzaldoxime Using t-BuOIa
Having optimized the reaction conditions and reagents,
we explored the scope of the reaction with respect to
substrates (dipolarophiles, Table 1). A terminal electron-
deficient olefin was transformed into the corresponding
isoxazoline 2b in excellent yield with complete regioselec-
tivity (entry 1). When geometric isomers (ethyl maleate
and fumarate) were used, diastereomers 2c and 2d were
obtained in both cases (entries 2 and 3). The stereochem-
istry of the major adducts was reflected by the geometry
of the dipolarophiles. In order to clarify the origin of the
production of the minor adducts, each single stereo-
isomer 2c or 2d was treated separately with 2,6-lutidine,
and partial cisÀtrans isomerization of the stereoisomers
was observed in both cases. This result indicates that the
reaction proceeds in a concerted manner and that the
resulting adducts were successively isomerized by the base.
N-Phenylmaleimide functioned as a dipolarophile to af-
ford the adduct in good yield (entry 4). An aliphatic
terminal olefin, 1-octene, was applicable to the reaction,
a Reaction conditions: benzaldoxime (0.25 mmol), dipolarophile
(0.25 mmol), t-BuOCl (0.25 mmol), NaI (0.25 mmol), 2,6-lutidine
(0.25 mmol), dioxane (5 mL). b Determined by 1H NMR.
As shown in Table 2, the reaction tolerates a wide
diversity of substituents at the para position of benzal-
doxime. Benzaldoximes containing both electron-donat-
ing and -withdrawing groups reacted readily with styrene,
selectively leading to the corresponding isoxazolines in
good yields.
The scope of the reaction was also extended to various
aldoximes (Table 3). Aldoximes substituted with alkyl
groups derived from acetaldehyde, butanal, and cyclo-
hexyl carbaldehyde were converted into the corresponding
(10) (a) Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M.
Chem. Commun. 2006, 3337–3339. (b) Minakata, S.; Morino, Y.;
Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2006, 8, 3335–3337. (c)
Minakata, S.; Morino, Y.; Ide, T.; Oderaotoshi, Y.; Komatsu, M. Chem.
Commun. 2007, 3279–3281. (d) Minakata, S. Acc. Chem. Res. 2009, 42,
1172–1182.
(11) Minakata, S.; Sasaki, I.; Ide, T. Angew. Chem., Int. Ed. 2010, 49,
1309–1311.
(12) Tanner, D. D.; Gidley, G. C.; Das, N.; Rowe, J. E.; Potter, A. J.
Am. Chem. Soc. 1984, 106, 5261–5267.
Org. Lett., Vol. 13, No. 11, 2011
2967

temperature for 30 min, isoxazoline-fused C60 derivatives
3a and 3b were obtained in good isolation yield along with
excellent conversion yield.13
Table 2. Cycloaddition of p-Substituted Benzaldoximes Using
t-BuOIa
entry
R
yield (%)
1
2
3
4
5
6
7
OMe (1b)
Me (1c)
NO2 (1d)
CF3 (1e)
CN (1f)
Br (1g)
71 (2j)
76 (2k)
83 (2l)
98 (2m)
84 (2n)
84 (2o)
86 (2p)
Although the precise reaction mechanism is unclear at
present, the proposed mechanism shown in Scheme 1 is
supported by the experimental findings. Since it is known
that t-BuOCl reacts rapidly with NaI,10a the reaction of
1
benzaldoxime and t-BuOI was monitored by H NMR
Cl (1h)
spectroscopy. When t-BuOI was added to a dioxane-d8
solution of benzaldoxime, the signals corresponding to
hydrogens attached to the imine carbon (δ 8.06 ppm) and
the oxygen (δ 9.79 ppm) on benzaldoxime disappeared,
and a broad singlet at δ 10.8 ppm was observed, which
disappeared when one drop of D2O was added to the
solution.14 These results indicate the formation of an
imidoyl iodide intermediate C by the reaction of benzal-
doxime and t-BuOI. Thus, the most likely pathway for the
cycloaddition is proposed to be as follows: (1) R-iodoni-
troso intermediate B is generated through iodination and
deprotonation of aldoxime with t-BuOI; (2) the resulting
intermediate B smoothly tautomerizes to the oxime deri-
vative C, followed by the elimination of HI in the presence
of a base to generate the nitrile oxide D, which then
participates in a cycloaddition to an unsaturated bond,
giving an isoxazoline or isoxazole.
a Reaction conditions: aldoxime (0.25 mmol), styrene (0.25 mmol),
t-BuOCl (0.25 mmol), NaI (0.25 mmol), 2,6-lutidine (0.25 mmol),
dioxane (5 mL).
nitrile oxides, followed by cycloaddition with styrene or
N-phenylmaleimide, giving a variety of isoxazoline deri-
vatives 2qÀv in moderate to good yields (entries 1À6).
The reactions of aldoximes derived from alkanals having
a phenyl group with N-phenylmaleimide proceeded with
good yields (entries 7 and 8).
Table 3. Cycloaddition of Aldoximes Using t-BuOIa
Scheme 1. Plausible Reaction Pathway
entry
R
dipolarophile
styrene
yield (%)
1
2
3
4
5
6
7
8
Me (1i)
65 (2q)
67 (2r)
82 (2s)
85 (2t)
81 (2u)
92 (2v)
80 (2w)
80 (2x)
n-Pr (1j)
styrene
Me (1i)
N-phenylmaleimide
N-phenylmaleimide
styrene
n-Pr (1j)
c-hex (1k)
c-hex (1k)
PhCH2 (1l)
PhCH2CH2 (1m)
N-phenylmaleimide
N-phenylmaleimide
N-phenylmaleimide
a Reaction conditions: aldoxime (0.25 mmol), dipolarophile (0.25
mmol), t-BuOCl (0.25 mmol), NaI (0.25 mmol), 2,6-lutidine (0.25
mmol), dioxane (5 mL).
In summary, an efficient, simple, and general method
for the synthesis of a variety of isoxazolines and iso-
xazoles by the reaction of oximes and alkenes/alkynes
in the presence of t-BuOI and a base is described. This is
The present cycloaddition was also found to be applic-
able to C60 (eq 2). When C60 was treated with benzaldox-
ime (1a) or acetaldoxime (1i) in the presence of t-BuOCl,
NaI, and 2,6-lutidine in o-dichlorobenzene, which is a
commonly used solvent for dissolving C60, at room
(13) When dioxane was used as a solvent, the reaction did not
proceed at all, probably due to the extremely poor solubility of C60 in
dioxane.
(14) See the Supporting Information.
2968
Org. Lett., Vol. 13, No. 11, 2011

the first report of a method for the generation of nitrile
oxides using an electrophilic iodine compound, and
t-BuOI is a versatile reagent for the synthesis of hetero-
cyclic compounds. The application of the potential
reagent, t-BuOI, to other organic reactions is currently
in progress.
Supporting Information Available. General procedures,
spectral data for compounds, verification experiment for
isomerization of isoxazolines 2c and 2d in the presence of
2,6-lutidine, and monitoring of the reaction of benzaldox-
ime and t-BuOI by H NMR. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
Org. Lett., Vol. 13, No. 11, 2011
2969