Oxidation of α-oxo-oximes to nitrile oxides with hypervalent iodine reagents

Article abstract of DOI:10.1021/jo102241s

Upon reaction with PhI(OAc)₂, α-oxo-aldoximes are oxidized to α-oxo-nitrile oxides, while α-oxo-ketoximes are converted into nitrile oxides via the oxidative cleavage of the carbonyl-imino σ bond. The nitrile oxides thus formed were trapped wit

Full text of DOI:10.1021/jo102241s

pubs.acs.org/joc
SCHEME 1. Predicted Course of the DIB Oxidation of r-Oxo-
Oximes
Oxidation of r-Oxo-Oximes to Nitrile Oxides with
Hypervalent Iodine Reagents
Tim Jen, Brian A. Mendelsohn, and Marco A. Ciufolini*
Department of Chemistry, The University of British
Columbia, 2036 Main Mall, Vancouver,
BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received November 11, 2010
technique was initially developed with the aim of achieving
a tandem phenolic oxidative amidation4-intramolecular
nitrile oxide cycloaddition5 sequence,6 a wider range of
applications may be envisioned. For instance, the oxidation
of R-oxo-aldoxime 1 (Scheme 1), R = OEt, could lead to
carbethoxyformonitrile oxide (CEFNO).7 Alternatively,
oxidative attack of R-oxo-ketoximes 4 in, e.g., MeOH could
proceed with solvolytic fragmentation of the carbonyl-imino
C-C bond, leading to the formation of nitrile oxides such as
7. Products 3 and 8 ensuing from the reaction of such reactive
1,3-dipoles with appropriate dipolarophiles (cf. the generic
species X = Y in Scheme 1), e.g., olefins, are generally useful
in synthetic8 and medicinal9 chemistry.
A screen of suitable conditions for the conduct of the
desired transformation was carried out with oxime 910 as a
test substrate and norbornene as a trap for the nascent nitrile
oxide. This exercise ascertained that, much as in the original
case,1 the reaction was best carried out in MeOH, at room
temperature, in the presence of TFA (0.1-1% v/v; Table 1).
Upon reaction with PhI(OAc)2, R-oxo-aldoximes are
oxidized to R-oxo-nitrile oxides, while R-oxo-ketoximes
are converted into nitrile oxides via the oxidative cleavage
of the carbonyl-imino σ bond. The nitrile oxides thus
formed were trapped with norbornene or styrene in good
yield. R,R0-Dioxo-ketoximes react less efficiently.
A recent contribution from our laboratory1 describes the
oxidation of aldoximes to nitrile oxides with hypervalent
iodine reagents2 such as PhI(OAc)2 (“DIB”).3 While the
(1) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539.
(2) Reviews: (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(b) Zhdankin, V. V.; 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, CA, 1997.
(3) Other methods for the oxidation of oximes to nitrile oxides with
hypervalent iodine reagents: (a) Radhakrishna, A. S.; Sivaprakash, K.;
Singh, B. B. Synth. Commun. 1991, 21, 1625 (PhICl2). (b) Tanaka, S.; Ito, M.;
Kishikawa, K.; Kohmoto, S.; Yamamoto, M. Nippon Kagaku Kaishi 2002, 3,
471 (PhIO). (c) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Ravinder
Reddy, M. Tetrahedron Lett. 2004, 45, 7347 (DIB). (d) Das, B.; Holla, H.;
Maheder, G.; Venkateswarlu, K.; Bangdar, B. P. Synthesis 2005, 1572 (DIB).
(e) Chatterjee, N.; Pandit, P.; Halder, S.; Patra, A.; Maiti, D. K. J. Org.
Chem. 2008, 73, 7775 (PhIO). (f) Raihan, M. J.; Kavala, V.; Kuo, C.-W.;
Rama Raju, B.; Yao, C. F. Green Chem. 2010, 12, 1090 (PhI(OH)OTs). These
techniques, however, are unsuitable for the conduct of tandem oxidative
amidation/intramolecular nitrile oxide cycloaddition sequences (see text and
ref 6).
(4) Reviews: (a) Ciufolini, M. A.; Canesi, S.; Ousmer, M.; Braun, N. A.
Tetrahedron 2006, 62, 5318. (b) Ciufolini, M. A.; Braun, N. A.; Canesi, S.;
Ousmer, M.; Chang, J.; Chai, D. Synthesis 2007, 3759. Recent developments:
(c) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299. (d) Liang, H.;
Ciufolini, M. A. Org. Lett. 2010, 12, 1760. (e) Liang, H.; Ciufolini, M. A.
Tetrahedron 2010, 66, 5884. (f) Liang, H.; Ciufolini, M. A. Chem.;Eur. J.
2010, 16, 13262. See also: (g) Braun, N. A.; Ciufolini, M. A.; Peters, K.;
Peters, E.-M. Tetrahedron Lett. 1998, 39, 4667. (h) Braun, N. A.; Bray, J.;
Ciufolini, M. A. Tetrahedron Lett. 1999, 40, 4985. (i) Braun, N. A.; Bray, J.;
Ousmer, M.; Peters, K.; Peters, E.-M.; Bouchu, D.; Ciufolini, M. A. J. Org.
Chem. 2000, 65, 4397. (j) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.;
Ciufolini, M. A. Tetrahedron Lett. 2002, 43, 5193. (k) Canesi, S.; Bouchu, D.;
Ciufolini, M. A. Org. Lett. 2005, 7, 175.
(5) Reviews on intramolecular nitrile oxide cycloadditions: (a) Mulzer, J.
In Organic Synthesis Highlights; Mulzer, J., Altenbach, H. J., Braun, M.,
Krohn, K., Reissig, H. U., Eds.; VCH: Weinheim, Germany, 1990; Vol. I,
p 77. (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247. See especially
pp 12255-12259.
(6) (a) Mendelsohn, B. A.; Ciufolini, M. A. Org. Lett. 2009, 11, 4736. The
methodology also enables the conduct of oxidative phenolic alkoxylation/
INOC sequences: (b) Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009,
11, 5394.
(7) Key references: (a) Skinner, G. S. J. Am. Chem. Soc. 1924, 46, 731. (b)
Panizzi, L. Gazz. Chim. Ital. 1939, 69, 332. (c) Vaughan, W. R.; Spencer, J. L.
J. Org. Chem. 1960, 25, 1160. (d) Kozikowski, A. P.; Adamczyk, M. J. Org.
Chem. 1983, 48, 366.
(8) Reviews on bimolecular nitrile oxide cycloadditions and synthetic
applications thereof: (a) Grundmann, C. Synthesis 1970, 344. (b) Kozikowski,
A. P. Acc. Chem. Res. 1984, 17, 410. (c) Padwa, A. In1,3-DipolarCycloaddition
Chemistry; John Wiley & Sons: New York, 1984; Vols. 1 and 2. (d) Torssell,
K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH
Publishers: New York. 1988. (e) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863. (f) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719. (g)
Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (h) Belen’kii, L. I. In
Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis: Novel Strategies
in Synthesis, 2nd ed.; Feuer, H., Ed.; John Wiley & Sons: Hoboken, NJ, 2008;
pp 1-128. See also ref 5.
(9) Bondar, N. F.; Isaenya, L. P.; Skupskaya, R. V.; Lakhvich, F. A. Russ.
J. Org. Chem. 2003, 39, 1089.
(10) Commercially available.
728 J. Org. Chem. 2011, 76, 728–731
Published on Web 12/22/2010
DOI: 10.1021/jo102241s
r
2010 American Chemical Society

Jen et al.
JOCNote
TABLE 1. Effect of Solvent, Temperature, and Reaction Time on the
TABLE 3. Oxidation of r-Oxo-Ketoximesa
DIB Oxidation of r-Oximinoacetonea
entry
solvent
CH3CN
CH3CN/TFA(1%)
MeOH
MeOH/TFA(0.1%)
MeOH/TFA (1%)
MeOH/TFA(10%)
MeOH/TFA (1%)
MeOH/TFA (1%)
MeOH/TFA (1%)
MeOH/TFA (1%)
time
temp
yieldb
a
b
c
d
e
f
g
h
i
overnight
overnight
overnight
overnight
overnight
overnight
overnight
4.5 h
rt
rt
rt
rt
rt
rt
40 °C
rt
rt
30
26
74
76
75
0
52
67
69
74c
2 h
30 min
j
rt
aTypical procedure: a solution of 9 (130 mg, 1.5 mmol) in a solvent
(3 mL) was added slowly to a stirred solution of DIB (580 mg, 1.8 mmol,
1.2 equiv), TFA (table body), and norbornene (151 mg, 1.8 mmol,
1.2 equiv) in the same solvent (2 mL). Another 0.5 mL of solvent was
used to transfer any remaining oxime into the solution. After the stated
time, the mixture was evaporated in vacuo and the residue was purified
by flash chromatography. We note that 10 is slightly volatile: to
minimize loss of material, it should not be allowed to stand under
vacuum (removal of traces of chromatographic eluants) for longer than
necessary. bYields of chromatographically purified product. cSuch a
short reaction time may be insufficient to promote complete oxidation of
other oximes.
TABLE 2. DIB Oxidation of r-Oxo-Aldoximes 9 and 12a
aAll reactions run under the conditions of Table 2. bN = norbornene;
S = styrene. cYields of chromatographically purified product. dThe
yield of this reaction was unchanged when the amount of TFA was
reduced to 0.1% (v/v). eThe product was obtained as a 1:1 mixture of exo
diastereomers arising from the two possible topologies of the cycloaddi-
tion step. fThe product was obtained as a 1:0.8 mixture of unassigned Ph
epimers.
The DIB oxidation of R-oxo-aldoximes 910 and 12 under
the foregoing conditions, and in the presence of norbornene
or styrene as the olefinic trap, proceeded to afford products
10-11 and 13-14 in good yield (Table 2). Furthermore, the
oxidative attack of R-oxo-ketoximes 15,11 18,12 and 2113 with
DIB in MeOH promoted nitrile oxide formation in concert
with the anticipated C-C bond fragmentation. The expected
norbornene-derived isoxazolines were isolated in good yield
(Table 3). It should be noted that compounds of the type 16
have been used as building blocks for the synthesis of
prostaglandin analogues.9 Of special note is the conversion
of (D)-camphor-derived 21 into a nearly 1:1 mixture of
diastereomers of exo-adducts 22, which clearly arose from
the two possible exo topologies of the cycloaddition step.
However, the reaction consistently afforded poorer yields
when styrene was used as the trap. The reasons for this
remain unclear at this time.
aTypical procedure: a solution of oxime (1.5 mmol) in MeOH (3.5 mL
total) was added slowly to a stirred solution of DIB (580 mg, 1.8 mmol,
1.2 equiv), TFA (55 μL, 1% v/v), and norbornene (151 mg, 1.8 mmol, 1.2
equiv) in the same solvent (2 mL). After the stated time, the mixture was
evaporated in vacuo and the residue was purified by flash chromatog-
raphy (see the Experimental Section for details). bN = norbornene; S =
styrene. cYields of chromatographically purified product. dThis reaction
was run with 0.1% v/v of TFA. A reaction run with the customary 1%
TFA afforded 11 in only 59% yield.
(11) Prepared according to: Cope, A. C.; Estes, L. L., Jr.; Emery, J. R.;
Haven, A. C., Jr. J. Am. Chem. Soc. 1951, 73, 1199.
(12) Prepared according to: Werber, F. X. US 19610919 (CAS No.
61:83839). Details are provided as Supporting Information.
(13) Prepared according to: Chen, Y. K.; Jeon, S.-J.; Walsh, P. J.;
Nugent, W. A. Org. Synth. 2005, 82, 87.
In particular, higher temperatures or larger amounts of TFA
(cf. entries f and g) had an adverse effect on the reaction.
J. Org. Chem. Vol. 76, No. 2, 2011 729

Jen et al.
JOCNote
TABLE 4. Oxidation of r,r0-Dioxo-Ketoximes in MeOHa
SCHEME 2. Poor Substrates for the Reaction
SCHEME 3. Problematic Steps in the Reaction of Substrates
26-28
aThe same procedure detailed in Table 2 was utilized in the present
c
case. bN = norbornene; S = styrene. Yields of chromatographically
purified product. dReaction run with 0.1% TFA. eChromatography
permitted the recovery of 29% of the starting oxime 25. Also, the yield of
13 dropped to 19% with 0.1% TFA. fThe yield of 14 dropped to 24%
with 0.1% TFA.
Contrary to the foregoing oximes, R,R0-dioxo-ketoximes
proved to be generally unsatisfactory substrates. As seen in
Table 4, the DIB oxidation of 2414 proceeded as well as that
of 9, but the reaction of 2515 was less efficient than that of 12.
It should also be noted that when the oxidation of 25 was
carried out in the less nucleophilic EtOH as the solvent,
product 13 was isolated in 32% yield together with 30%
recovered 25, and 14 was obtained in 47% yield with 37%
recovered 25. By contrast, the reaction of oxime 12 to furnish
14, a process that does not require a solvolytic step, pro-
ceeded equally well in EtOH (86% yield) and in MeOH (82%
yield, Table 2), consistent with the assumption (Scheme 1)
that nitrile oxide formation depends on the rate of solvolytic
fragmentation of an intermediate such as 5.
oxidative polymerization in the presence of DIB. This could
possibly account for the low yield.
At this time, however, we believe that the main factor
responsible for the generally disappointing behavior of R,R0-
dioxo-ketoximes is a severely retarded rate of formation and/
or of nucleophilic cleavage of presumed intermediate of the
type 5 (cf. 32-33, Scheme 3). It seems likely that the pair of
flanking carbonyls diminish the nucleophilicity of the OH
group of the oxime by a combination of inductive, reso-
nance, and steric effects. Steric barriers and mesomeric
abatement of nucleophilicity may be especially pronounced
in 33, wherein conformational rigidity and near planarity of
the dioxoketoxime system enhance resonance interactions
and compress the OH group against a carbonyl system. On
the other hand, the diminished electrophilic character of
ester groups, relative to ketones, is likely to retard the
solvolysis of species 32, compounding the difficulty of con-
verting ester substrates into a nitrile oxide. Such an explana-
tion is consistent with the increasingly poorer yields of
cycloadducts observed as the keto groups in oxime 24 are
replaced with ester groups (cf. 25 vs 26).
Substrates 26,16 27,17 and 2817 (Scheme 2) were even more
problematic. Thus, compound 13a emerged in only 9% yield
upon treatment of 26 with methanolic DIB/TFA and nor-
bonene, while 29 was obtained in 10% yield from the
reaction of 27 under similar conditions, but with no added
TFA. Finally, DIB oxidation of compound 28 provided 30 in
a meager 4% yield.18 While the substrate clearly existed as
the diketo-oxime tautomer (1H and 13C NMR), we cannot
exclude formation of the aromatic tautomer 31 under the
acidic conditions of the reaction. In all likelihood, such a
highly electron-rich aromatic compound would be lost to
(14) Obtained as per: Cai, X.-H.; Yang, H.-J.; Zhang, G. L. Synthesis
2005, 1569.
(15) Prepared according to: Rodionov, V. M.; Machinskaya, I. V.;
Belikov, V. M. Zh. Obshch. Khim. 1948, 18, 917.
(16) Obtained as per: Hellmann, H.; Lingens, F. Z. Phys. Chem. 1954,
297, 283.
(17) Prepared according to: Zolfigol, M. A. Molecules 2001, 6, 694.
(18) Because of such poor yields, compounds 29 and 30 were not fully
characterized.
In summary, hypervalent iodine reagents such as DIB
mediate the oxidative conversion of R-oxo-oximes into nitrile
730 J. Org. Chem. Vol. 76, No. 2, 2011

Jen et al.
JOCNote
oxides in a generally satisfactory manner, while R,R0-dioxo-
oximes are generally poor substrates for the reaction. The method
complements existing avenues to analogous nitrile oxides,19 the
usefulness of which is likely to make this chemistry of interest to a
broad cross section of synthetic and medicinal chemists.
39.4, 32.3, 27.2, 22.7, 14.2. ESI-MS [M þ Na]þ 232.3. HRMS
calcd for C11H15NO3Na 232.0950, found 232.0948.
General Procedure for the Oxidation of r-Oxo-Ketoximes:
Preparation of Compound 16. A solution of oxime 15 (50 mg,
0.44 mmol) in MeOH (3 mL) was added dropwise at rt to a
solution of norbornene (50 mg, 1.2 equiv), PhI(OAc)2 (170 mg,
1.2 equiv), TFA (1% v/v, 55 μL), and MeOH (2 mL) with
stirring. Another 0.5 mL of MeOH was used to transfer any
remaining oxime into the solution. The reaction was complete in
30 min. The crude product was purified by flash column
chromatography by using a step-gradient (5%, 10%, 15%,
and 20% ethyl acetate/hexane), and pure fractions were col-
lected and concentrated in vacuo, yielding 74 mg (70%) of 16 as
a colorless viscous oil. 1H NMR 4.34 (d, 1H, J = 8.2 Hz), 3.61 (s,
3H), 2.95 (d, 1H, J = 8.2 Hz), 2.44 (br s, 1H), 2.40-2.12 (m, 5H),
Experimental Section20
General Procedure for the Oxidation of r-Oxo-Aldoximes:
Preparation of Compound 13. A solution of oxime 12 (158 mg,
77% w/w in toluene, 1.04 mmol) in MeOH (2 mL) was added
over 20 min to a well-stirred solution of DIB (402 mg, 1.25
mmol, 1.2 equiv), TFA (70 μL, 1% v/v), and norbornene (117
mg, 1.25 mmol, 1.2 equiv) in MeOH (4.5 mL) at rt (the solution
became homogeneous after addition of TFA). An additional
0.5 mL of MeOH was used to transfer residual oxime into the
reaction mixture. A series of color changes, from colorless
to light yellow, occurred. After stirring for 30 min at rt, the
mixture was evaporated in vacuo and the residue was purified by
flash chromatography (step gradient 5%, 10%, 15%, and 20%
EtOAc/hexane) to afford 194 mg (90% yield) of the known 1319
as a clear, viscous oil. 1H NMR 4.65 (br d, 1H, J = 8.5 Hz), 4.31
(m, 2H), 3.27 (br d, 1H, J = 8.5 Hz), 2.57 (br d, 2H, J = 10.0
Hz), 1.54 (m, 2H), 1.37 (m, 1H), 1.34 (t, 3H, J = 7.1 Hz), 1.23 (m,
2H), 1.11 (m, 1H). 13C NMR 160.9, 152.3, 90.3, 61.9, 55.7, 43.0,
2.00-1.76 (m, 2H), 1.56-1.29 (m, 3H), 1.22-0.96 (m, 3H). 13
C
NMR 173.5, 157.9, 86.1, 59.3, 51.5, 42.8, 38.2, 33.2, 32.1, 27.2,
26.0, 22.7, 21.4. IR 1732. ESI-MS [M þ Na]þ 260.4. HRMS
calcd for C13H19NO3Na 260.1263, found 260.1265.
Acknowledgment. Financial support by the University of
British Columbia, the Canada Research Chair Program,
CFI, BCKDF, NSERC, CIHR, and MerckFrosst Canada,
Ltd., is gratefully acknowledged. We also thank Mr. Kam Ho
for technical assistance.
(19) E.g.: (a) Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem.
2006, 4852. (b) Machetti, F.; Cecchi, L.; Trogu, E.; De Sarlo, F. Eur. J. Org.
Chem. 2007, 4352 and references cited therein.
Supporting Information Available: experimental protocols,
characterization data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Experimental protocols are provided as Supporting Information.
J. Org. Chem. Vol. 76, No. 2, 2011 731