Oxidation of oximes to nitrile oxides with hypervalent iodine reagents

Article abstract of DOI:10.1021/ol900194v

Iodobenzene diacetate in MeOH containing a catalytic amount of TFA efficiently oxidizes aldoximes to nitrile oxides. The latter may be trapped in situ with olefins in a bimolecular or an intramolecular mode. The new method enables the execution of tandem oxidative dearomatization of phenols/intramolecular nitrile oxide cycloaddition sequences leading to useful synthetic intermediates.

Full text of DOI:10.1021/ol900194v

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1539-1542
Oxidation of Oximes to Nitrile Oxides
with Hypervalent Iodine Reagents
Brian A. Mendelsohn, Shelley Lee, Simon Kim, Florian Teyssier,
Virender S. Aulakh, and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received January 29, 2009
ABSTRACT
Iodobenzene diacetate in MeOH containing a catalytic amount of TFA efficiently oxidizes aldoximes to nitrile oxides. The latter may be trapped in situ
with olefins in a bimolecular or an intramolecular mode. The new method enables the execution of tandem oxidative dearomatization of phenols/
intramolecular nitrile oxide cycloaddition sequences leading to useful synthetic intermediates.
Hypervalent iodine reagents1 such as PhI(OAc)2 (“DIB”) and
PhI(OCOCF3)2 (“PIFA”) react with 4-substituted phenols 1 in
the presence of MeCN to furnish compounds 2 (Scheme 1),
phenols.3 Ongoing work unveiled the desirability of executing
the oxidative amidation of a phenol in tandem with an
intramolecular nitrile oxide cycloaddition (INOC),4 leading to
tricyclic intermediates 4. That dienones arising through oxidative
dearomatization of phenols are capable of participating in
tandem reactions, especially 1,4-addition processes, leading to
densely functionalized, synthetically valuable, intermediates is
well established. For instance, a tandem oxidative hydroxylation/
Michael cyclization5 of tyrosine derivatives has been used as a
key step in the synthesis of Stemona alkaloids6 and of
hydroxylated aminoacids related to parkacine, aeruginosine, and
castanospermine,7 while an oxidative amidation/conjugate ad-
dition sequence was central to a synthesis of cylindricine C.8
Scheme 1. Hypothetical Tandem Oxidative
Amidation-Intramolecular Nitrile Oxide Cycloaddition
(2) (a) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299. (b)
Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175.
(3) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M; Chang, J;
Chai, D. Synthesis 2007, 3759.
(4) Reviews: (a) Mulzer, J. In Organic Synthesis Highlights; Mulzer,
J., Altenbach, H. J., Braun, M., Krohn, K., Reissig, H. U., Eds.; VCH:
Weinheim, 1990; Vol. I, p 77. (b) Nair, V.; Suja, T. D. Tetrahedron 2007,
63, 12247. See especially pp 12255-12259.
which are useful building blocks for the synthesis of nitrogenous
substances.2 This is an example of oxidative amidation of
(5) Reviews: (a) Wipf, P.; Jung, J.-K. Chem. ReV. 1999, 99, 1469. (b)
Rodr´ıguez, S.; Wipf, P. Synthesis 2004, 2767.
(1) Reviews: (a) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96,
1123. (b) Stang, P. J. Chem. ReV. 2002, 102, 2523. (c) Moriarty, R. M. J.
Org. Chem. 2005, 70, 2893. (d) Kita, Y. Yakugaku Zasshi 2002, 122, 1011.
(e) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. Monograph: (f)
Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic Press:
San Diego, 1997.
(6) Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225, and
references cited therein.
(7) Pierce, J. G; Dhanalakshmi, K.; Fushimi, M.; Cuzzuppe, A.; Wipf,
P. J. Org. Chem. 2008, 73, 7807.
(8) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed.
2004, 43, 4336.
10.1021/ol900194v CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

However, the precise transformation depicted in Scheme 1
appears to be undocumented.
insignificant effect on yields. An important finding is that
MeOH is nearly as good a solvent as the more costly fluoro
alcohols. Furthermore, the yields of reactions run in MeOH
improve appreciably upon addition of a small catalytic
quantity of TFA, typically 15 µL for a reaction run with
about 0.5 mmol of substrate (cf. entry k). However, larger
amounts of TFA should be avoided (entry l). Best results
were obtained when the oxime was added to a solution of
1.1 equiv of DIB and 1.1 equiv of olefin at rt.
An especially direct approach to 4 would materialize if
group Z in 1 could be oxidatively converted into a nitrile
oxide with the same hypervalent iodine reagent utilized in
the oxidative amidation step, but at a slower rate relative to
the oxidative amidation reaction proper. This rate difference
is essential to ensure efficient intramolecular capture of the
nascent nitrile oxide. An attractive solution envisioned that
Z should be an aldoxime group. Aldoximes are established
precursors of nitrile oxides;4 moreover, their conversion
thereto with PhIdO in CHCl3 is documented.9 However,
such conditions would not permit the occurrence of a
simultaneous oxidative amidation step, which requires DIB
in fluoro alcohol solvents3,10 or in MeCN containing a
catalytic amount of TFA.2a Thus, an initial phase of this work
aimed to establish whether aldoximes may be converted into
nitrile oxides under conditions that would also promote the
oxidative amidation of phenols.
Table 2 provides representative examples of nitrile oxide
generation/trapping in MeOH/cat. TFA in the bimolecular
Table 2. DIB Oxidation of Aldoximes to Nitrile Oxides in
MeOH Containing Catalytic TFA
The feasibility of such a transformation was uncertain,
because hypervalent iodine reagents could induce oxidative
deoximation of the substrates,11 thereby suppressing nitrile
oxide formation. Fortunately, such concerns proved to be
unfounded. As shown in Table 1 for the test oxidation of 5
Table 1. Solvent Effect in the DIB Oxidation of Aldoximes to
Nitrile Oxides
a Representative procedure: a solution of oxime (1 mmol) in MeOH (1
mL) was added slowly (syringe pump, 1 h) at rt to a stirred solution of
DIB (1.1 equiv) and an olefin (1.1 equiv) in MeOH (2 mL) containing TFA
(15 µL). A white precipitate formed immediately and then slowly dissolved
as the reaction progressed. Upon consumption of the oxime (TLC, ca. 1 h),
the mixture was concentrated in vacuo and the residue was purified by flash
chromatography (step gradient 5-10% to 20% EtOAc/hexanes in each case).
b After column chromatography. c Variable quantities of 3,5-diphenyl-1,2,4-
oxadiazole 4-oxide (dimer of benzonitrile oxide) were recovered from this
reaction.
a Typical procedure: a solution of oxime (1.5 mmol) in an appropriate
solvent (3 mL) was added slowly at rt to a stirred solution of DIB and
styrene in the same solvent (3 mL). After the stated time, the mixture was
evaporated in vacuo and the residue was purified by flash chromatography
(step gradient 5-10% to 15-20% EtOAc/hexanes). b After column
chromatography. c Reactions run with 0.5 mmol of oxime dissolved in 1
mL of solvent and added slowly at rt to a stirred solution of DIB, styrene,
and TFA (15 µL) in the same solvent (1 mL).
regime. Yields of chromatographically purified isoxazoline
are uniformly good to excellent. Replacing the olefinic trap
with a terminal alkyne resulted in formation of a fully
aromatic isoxazole, but in lower yields and with variable
with DIB in the presence of styrene, fluoroalcohols such as
trifluoroethanol (TFE) and hexafluoro-2-propanol (HFIP)
were superior to CHCl3. An excess of DIB or of trap had an
1540
Org. Lett., Vol. 11, No. 7, 2009

efficiency. It seems likely that this was due to a competing
in situ formation of alkynyliodonium species12 and ensuing
degradation thereof in the presence of nucleophilic MeOH.
Thus, DIB oxidation of benzaldoxime in the presence of
phenylacetylene furnished 3,5-diphenylisoxazole in 50%
yield (Table 2, entry I), together with a significant amount
of benzonitrile oxide dimer (3,5-diphenyl-1,2,4-oxadiazole-
4-oxide). By contrast, an analogous reaction with 1-hexyne
as the trap provided the isoxazole in only 16% yield.
Intramolecular variants of the reaction were examined
using substrates 9,13 11,14 and 13, which cyclized in 60-70%
yield under the influence of DIB in MeOH/cat. TFA (Scheme
2).15 Citronellal-derived isoxazoline 14 was obtained as
mixture of two diastereomers in a 3.8:1 ratio.
cordingly, the reaction yield was calculated to be 85% by
integration of an NMR spectrum obtained from a solution
of crude 14 containing a known amount of 1,3,5-trimethoxy-
benzene as an internal standard. Only a portion of crude
material was purified for the purpose of characterization. A
pure sample of the major isomer thus obtained had [R]20
)
D
-87.0 (CH2Cl2, c ) 0.01). However, the configuration of
this substance remains undetermined.16
The foregoing experiments indicated that the rate of DIB
oxidation of aldoximes to nitrile oxides (45-60 min for
complete conversion) was significantly slower than that of
oxidative dearomatization of a typical phenol (a virtually
instantaneous reaction). This boded well for the feasibility
of the sequence depicted in Scheme 1.
Oxime 15 (Scheme 3) served to explore the tandem
oxidative methoxylation of the phenol/INOC reaction. Pleas-
Scheme 2. Intramolecular Variants of the Reaction
Scheme 3. Tandem Oxidative Methoxylation-INOC
ingly, compound 16 was isolated in 51% yield after chro-
matography upon treatment of 15 with 2.2 equiv of DIB in
MeOH/catalytic TFA. The substance was quite polar, and it
seemed to adsorb strongly onto silica gel, causing substantial
losses upon chromatography. The NMR yield of 16, recorded
as detailed above for 14 (1,3,5,-trimethoxybenzene as the
internal standard), was 65%. With these encouraging results
in hand, we turned our attention to the chemistry of Scheme
4. Reaction of 15 with DIB in MeCN in the presence of
This material appeared to be volatile, and it was lost during
vacuum concentration of chromatographic fractions. Ac-
(9) Tanaka, S.; Ito, M.; Kishikawa, K.; Kohmoto, S.; Yamamoto, M.
Nippon Kagaku Kaishi 2002, 3, 471.
Scheme 4. Tandem Oxidative Amidation-INOC
(10) Fluoroalcohol solvents are particularly efficacious in DIB-mediated
oxidations: Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.;
Eichhorn, J. J. Org. Chem. 1996, 61, 5857. See also refs 1d and 3.
(11) (a) De, S. K.; Mallik, A. K. Tetrahedron Lett. 1998, 39, 2389. (b)
Bose, D. S.; Srinivas, P. Synlett 1998, 977. (c) Chaudhari, S. S.; Akamanchi,
K. G. Tetrahedron Lett. 1998, 39, 3209. (d) Chaudhari, S. S.; Akamanchi,
K. G. Synthesis 1999, 760. (e) Corsaro, A.; Chiacchio, U.; Librando, V.;
Pistara, V.; Rescifina, A. Synthesis 2000, 1469. (f) Bose, D. S.; Narsaiah,
A. V. Synth. Commun. 1999, 29, 937. See also refs 1a and 1b.
(12) (a) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 4700. (b)
Margida, A. J.; Koser, G. F. J. Org. Chem. 1984, 49, 4703. (c) Lodaya,
J. S.; Koser, G. F. J. Org. Chem. 1990, 55, 1513. (d) Stang, P. J.; Zhdankin,
V. V. Chem. ReV. 1996, 96, 1123. (e) Zhdankin, V. V.; Stang, P. J. Chem.
ReV. 2002, 102, 2523.
(13) Prepared from 1-[2-(1,3-dioxolan-2-yl)ethyl]- 2,5-cyclohexadiene-
1-carboxylic acid [ (a) Chuang, C. P.; Gallucci, J. C.; Hart, D. J. J. Org.
Chem. 1988, 53, 3218. (b) Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem.
Soc. 1986, 108, 5893]starting with reaction with TMSCHdN2. Interestingly,
the TMS group remained in place throughout the sequence. For details,
see the Supporting Information.
(14) Prepared from ethyl 1-[2-(1,3-dioxolan-2-yl)ethyl]-2-oxocyclohex-
anecarboxylate ( Singh, K. P.; Mandell, L. Chem. Ber. 1963, 96, 2485. ) as
described in the Supporting Information.
TFA afforded 17 in 71% yield after chromatography. The
structure of this product was ascertained by X-ray diffrac-
tometry.17 It is recognized that the INOC step induces
(15) The oxidative cyclization of 9 was more efficient when run in the
significantly costlier HFIP as the solvent (85% chromatographed yield).
Details are provided as Supporting Information.
Org. Lett., Vol. 11, No. 7, 2009
1541

desymmetrization of the dienone; in particular, it causes the
NHAc-bearing carbon to become stereogenic. The config-
uration of this emerging stereocenter could be controlled if
the intermediate nitrile oxide were to add selectively to one
of the two enantiotopic π bonds of the dienone. Such a theme
is apparent fron this laboratory’s past efforts on the total
synthesis of FR-90148318 and cylindricine C.8
ering that the presumed nitrile oxide 20 arising upon
oxidation of 18 can undergo cyclization via transition state
A, which leads to the observed product 19, or B, which
would furnish the diastereomeric product 21. Transition state
B appears to be disfavored relative to A, because the bulky
N-benzyl tosylamido group (represented as L in Scheme 5)
is oriented inside the concavity of the developing tricyclic
system. This engenders an unfavorable steric compression
that is absent in A, wherein L resides on the convex face of
the incipient product. Thus, the reaction forms 19selectively.
In summary, this work has determined that PhI(OAc)2 is
a good oxidant for the conversion of aldoximes into nitrile
oxides, and that such a transformation may be carried out in
tandem with the oxidative dearomatization (methoxylation
or amidation) of a phenol. The value of the resulting
intermediates as educts for the synthesis of nitrogenous
substances is currently being evaluated and pertinent results
will be detailed in due course.
The search for an artifice that might attain such a goal in
the present case led us to oxime (()-18 (Scheme 4).19
Scheme 5
.
Presumed Course of the Tandem Oxidative
Amidation-INOC of Oxime 18
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, NSERC,
CIHR, CFI, and MerckFrosst Canada for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds,
hardcopy NMR (1H and 13C) spectra of several molecules,
and details of the X-ray diffractometric study of 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900194V
(16) The resonances of the axial proton on the methylene adjacent to
the oximino group (ca. 1.8 ppm) and of the methyl-bearing methine (ca.
1.50 ppm) overlap with those of other ring protons, preventing the accurate
determination of coupling constants and, hence, of the configuration.
(17) Relevant data are provided as Supporting Information.
Exposure of this material to DIB/TFA in MeCN resulted in
formation of (()-19 as the sole identifiable product in 44%
chromatographed yield. The configuration of 19 was assigned
on the basis of the indicated nuclear Overhauser enhance-
ments (NOE; 2D NOESY spectroscopy). The observed
stereoselectivity may be rationalized (Scheme 5) by consid-
(18) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A.
J. Am. Chem. Soc. 2001, 123, 7534. Ousmer, M.; Braun, N. A.; Ciufolini,
M. A. Org. Lett. 2001, 3, 765.
(19) The preparation of 18 is detailed in the Supporting Information.
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Org. Lett., Vol. 11, No. 7, 2009