Facile nucleophilic substitution of sulfonyl oxime ethers: An easy access to oxime ethers, carbonyl compounds and amines

Article abstract of DOI:10.1039/c0cc02081h

Sulfonyl oxime ethers undergo facile nucleophilic substitutions with various nucleophiles to yield the corresponding oxime ethers which provide an easy access to amines and carbonyl compounds. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc02081h

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Facile nucleophilic substitution of sulfonyl oxime ethers: an easy access
to oxime ethers, carbonyl compounds and aminesw
Sundae Kim,a Nurul Ain Bte Kamaldin,a Sol Kangb and Sunggak Kim*ab
Received 25th June 2010, Accepted 7th September 2010
DOI: 10.1039/c0cc02081h
Sulfonyl oxime ethers undergo facile nucleophilic substitutions
with various nucleophiles to yield the corresponding oxime ethers
which provide an easy access to amines and carbonyl compounds.
alkyl radicals has been well demonstrated,8 their reactivities
toward various nucleophiles have not been investigated. Although
3-sulfonyl isoxazolines, cyclic versions of sulfonyl oxime ethers,
were known to undergo a variety of substitution reactions,9 we
have been interested in the feasibility of bis-methanesulfonyl
oxime ether as a phosgene surrogate along with the reaction
mode of sulfonyl oxime ethers 1 toward nucleophiles.
Organosulfones are very useful functional groups and
important intermediates in organic synthesis and have been
utilized as a source of generating carbanions for carbon–carbon
bond formation.1 However, they have limited use as leaving
groups despite some useful applications as chemical chameleons.2
The synthetic utility of alkyl, allyl, alkenyl, and alkynyl sulfones
has been investigated extensively1 but that of acyl sulfones3 was
not studied in detail. It is well known that various nucleophiles
undergo conjugate additions to alkenyl sulfones (a),4 whereas
nucleophiles should undergo nucleophilic substitutions onto acyl
sulfones (b) (Scheme 1).3 Furthermore, alkenyl sulfones are very
stable but acyl sulfones are extremely unstable and difficult to
prepare. In terms of stability, sulfonyl oxime ethers are very stable
and are inclined to alkenyl sulfones rather than acyl sulfones.
Scheme 3 Cobalt-catalyzed functionalization of alkenes.
We began our studies with an organocuprate using sulfonyl
oxime ether 4 as a model compound. When 4 was treated with
lithium di-n-butylcuprate in THF at À78 1C, the substitution
reaction occurred to yield oxime ether 5a in 42% yield without
any conjugate addition product. When the reactions were
repeated with n-butyllithium and phenyllithium, the reactions
proceeded cleanly and much better results were obtained
(Scheme 4). To determine the scope of the present reaction,
various nucleophiles were reacted with 4 and the experimental
results are summarized in Table 1. Reaction of 4 with
n-butyl- and phenylmagnesium bromide in THF at À78 1C
for 2 h afforded 5a and 5b in 96% and 99% yield, respectively
(entries 1 and 2). Although nucleophiles such as alkyllithium
and alkyl Grignard reagents are very strong, they did not
undergo further additions to the oxime ethers. Much less
nucleophilic lithium phenyl acetylide (entry 3) and lithium
enolates (entries 4 and 5) worked well to afford the desired
substitution products in high yields. Similarly, the reaction of
sodium diethylphosphite with 4 was quite efficient to give 5f in
85% yield (entry 6). However, the reaction of 4 with potassium
cyanide in THF at room temperature did not occur but
proceeded smoothly by performing it in DMF at 60 1C for
2 h (entry 7). Furthermore, when the reaction was carried out
in THF using benzylamine and methanol, no reaction took
place upon prolonged heating. This problem was solved by
employing stronger nucleophiles, lithium benzyl amide,
sodium methoxide, and lithium thiophenoxide (entries 8–10).
Scheme 1 Reaction of alkenyl and acyl sulfones with nucleophiles.
Phenylsulfonyl oxime ether 1 was introduced as a carbonyl
equivalent radical acceptor in radical chemistry (Scheme 2).5
According to kinetic studies, addition of an alkyl radical onto
phenylsulfonyl oxime ether (R = H) is very fast and highly
efficient, thereby achieving radical acylation in an indirect
manner.6 Thus, radical reaction of 1 with an alkyl radical afforded
oxime ether 2 which was readily hydrolyzed to the corresponding
ketone 3. Recently, phenylsulfonyl oxime ethers were effectively
utilized as oxime ether transfer agents in cobalt-catalyzed
functionalization of unactivated alkenes (Scheme 3).7 Although
the efficiency of sulfonyl oxime ethers as radical acceptors toward
Scheme 2 Radical reaction of sulfonyl oxime ether 1.
a Division of Chemistry and Biological Chemistry, School of Physical
& Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore. E-mail: sgkim@ntu.edu.sg;
Fax: +65 6791 1961; Tel: +65 6592 7765
b Department of Chemistry, Korea Advanced Institute of Science and
Technology, Daejeon 305-701, Korea
w Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/c0cc02081h
Scheme 4 Reaction of sulfonyl oxime ether 4 with nucleophiles.
c
7822 Chem. Commun., 2010, 46, 7822–7824
This journal is The Royal Society of Chemistry 2010

View Article Online
Table 1 Nucleophilic substitution of phenylsulfonyl oxime ether 4
with various nucleophilesa
Entry
Nucleophile
T/1C
Yield (%)a of 5
1
2
3
BuMgBr
PhMgBr
À78
À78
À78
5a (96)
5b (99)
5c (85)
4
5
À78
5d (72)
5e (95)
À78
6
NaP(O)(OEt)2
KCN
PhCH2NHLi
NaOMe
PhSLi
À78
60
0
0
0
5f (85)
5g (88)
5h (79)
5i (93)
5j (96)
7b
8
9
10
a
The reaction was carried out in THF for 2–4 h using 2 equiv. of a
b
nucleophile. DMF was used as solvent.
Scheme 6 Reaction of bis-methanesulfonyl oxime ether 8 with
nucleophiles.
The experimental results are summarized in Scheme 6 and
illustrate the scope and limitation of the present method.
Reaction of 8 with phenylmagnesium bromide in THF at
À78 1C for 2 h afforded the desired product 10a in 86% yield.
Similarly, the reaction worked well with enolates of acetophenone
and ethyl acetate under similar conditions. 8 did not react with
methanol but reacted with sodium methoxide at room
temperature. Furthermore, very soft nucleophiles such as
cyanide and azido anion reacted with 8 at room temperature.
According to the experimental data obtained here, the nucleo-
philic substitution of 8 by nucleophiles is more facile than that
of 4, indicating that 8 is more reactive than 4 toward nucleo-
philes. Further indication for this finding is observed using
benzylamine. Treatment of 8 with benzylamine (1.2 equiv.) in
THF at room temperature for 2 h gave 11 in 96% yield,
whereas 4 did not react with benzylamine at reflux. More
interestingly, when 8 was treated with an excess amount of
benzylamine (3 equiv.) in THF at room temperature for 2 h, 12
was isolated in 81% yield, indicating that 11 was much more
reactive than 4 due to the electron-donating nature of the
benzylamino group. Furthermore, the effectiveness of a
methanesulfonyl leaving group in nucleophilic substitutions
was demonstrated by the further substitution of 13 with
methylmagnesium chloride (Scheme 7). Treatment of 13 with
methylmagnesium chloride (1.2 equiv.) in THF at À78 1C for
2 h afforded 14 in 93% yield, showing that the methanesulfonyl
Scheme 5 Reaction of 6a and 6b with nucleophiles.
The experimental results obtained here suggest that phenyl-
sulfonyl oxime ether 4 is activated by the phenylsulfonyl group
and is more reactive than unactivated aldimines in nucleophilic
addition reactions.10 Furthermore, the importance of the
sulfonyl group was demonstrated by comparative studies of
nucleophilic substitution reactions with two oxime derivatives
6a and 6b. As shown in Scheme 5, when 6a was treated with
n-butyllithium in THF at À78 1C, the reaction did not occur.
Similarly, treatment of 6a with phenylmagnesium bromide in
THF at room temperature for 2 h did not afford 5b and the
starting 6a was recovered in 92% yield. 6b was also inert
toward phenylmagnesium bromide in THF and potassium
cyanide in DMF at room temperature. Thus, it is evident
that the sulfonyl group is essential for the success of the
substitution reaction.
Our next interest was given to bis-methylthio oxime ether 7
and bis-methanesulfonyl oxime ether 8.11 7 and 8 are synthetic
equivalents of phosgene derivatives 9. We initially studied
nucleophilic substitution reactions of 7 with several nucleo-
philes. When 7 was treated with phenylmagnesium bromide in
THF at room temperature and even on prolonged heating at
60 1C, the reaction did not occur. Similarly, 7 was inert to
potassium cyanide, sodium methoxide, and benzylamine in
THF at room temperature for 6 h.12 However, 8 was reactive
toward various nucleophiles and underwent clean nucleophilic
subsitution reactions.
Scheme 7 Sequential nucleophilic substitutions of 8.
Chem. Commun., 2010, 46, 7822–7824 7823
c
This journal is The Royal Society of Chemistry 2010

View Article Online
group on oxime ethers undergoes facile elimination relative to
the cyano group.13
Angew. Chem., Int. Ed., 2001, 40, 2524; (e) S. Kim and
C. J. Lim, Angew. Chem., Int. Ed., 2002, 41, 3265; (f) S. Kim and
C. J. Lim, Bull. Korean Chem. Soc., 2003, 24, 1219; (g) S. Kim, Adv.
Synth. Catal., 2004, 346, 19; (h) A.-P. Schaffner, V. Darmency and
P. Renaud, Angew. Chem., Int. Ed., 2006, 45, 5847; (i) E. Godineau
and Y. Landais, J. Am. Chem. Soc., 2007, 129, 12662.
In conclusion, we have found that sulfonyl substituted
oxime ethers undergo clean nucleophilic substitutions with a
variety of nucleophiles to give oxime ethers. Thus, bis-
methanesulfonyl oxime ether 8 is regarded as a stable
phosgene surrogate. Since oxime ethers are very important
and useful functional groups and can be transformed into the
carbonyl,11,14 amino,15 and other functional groups,16,17 the
present approach is of synthetic importance and will find many
useful synthetic applications.
9 (a) P. A. Wade and H. R. Hinney, J. Am. Chem. Soc., 1979, 101,
1319; (b) P. A. Wade, H.-K. Yen, S. A. Hardinger, M. K. Pillay,
N. V. Amin, P. D. Vail and S. D. Morrow, J. Org. Chem., 1983, 48,
1796; (c) P. A. Wade, N. V. Amin, H.-K. Yen, D. T. Price and
G. F. Huhn, J. Org. Chem., 1984, 49, 4595; (d) P. A. Wade,
S. M. Singh and M. Krishna Pillay, Tetrahedron, 1984, 40, 601;
(e) W. K. Anderson and N. Raju, Synth. Commun., 1989, 19, 2237.
10 (a) S. E. Denmark and O. J.-C. Nicaise, Chem. Commun., 1996,
999; (b) C. J. Moody and J. C. A. Hunt, Synlett, 1998, 733;
(c) H. Ishitani, S. Komiyama and S. Kobayashi, Angew. Chem.,
Int. Ed., 1998, 37, 3186; (d) S. Saito, K. Hatanaka and
H. Yamamoto, Synlett, 2001, 1859; (e) L. Yet, Angew. Chem.,
Int. Ed., 2001, 40, 875; (f) T. Akiyama, H. Morita, J. Itoh and
K. Fuchibe, Org. Lett., 2005, 7, 2583.
11 (a) S. Kim and J.-Y. Yoon, J. Am. Chem. Soc., 1997, 119, 5982;
(b) I. Ryu, H. Kuriyama, S. Minakata, M. Komatsu, J.-Y. Yoon
and S. Kim, J. Am. Chem. Soc., 1999, 121, 12190.
12 The starting materials were recovered in essentially quantitative
yields.
13 The effectiveness of the sulfonyl leaving group was also observed in
radical reactions. S. Kim and J. H. Cheong, Chem. Commun., 1998,
1143.
We gratefully acknowledge Nanyang Technological
University and CMDS at KAIST for financial support.
Notes and references
1 N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon Press,
1993 and references cited therein.
2 (a) B. M. Trost and Mikhail, J. Am. Chem. Soc., 1987, 109, 4124;
(b) B. M. Trost, Bull. Chem. Soc. Jpn., 1988, 61, 107.
3 (a) A. Senning, O. N. Sorensen and C. Jacobsen, Angew. Chem.,
Int. Ed. Engl., 1968, 7, 734; (b) R. J. Gaul and W. J. Fremuth,
J. Org. Chem., 1961, 26, 5103; (c) K. Schank, A. Frisch and
B. Zwanenburg, J. Org. Chem., 1983, 48, 4580; (d) G. Ferdinand
and K. Schank, Synthesis, 1976, 408; (e) K. Schank and F. Werner,
Liebigs Ann. Chem., 1983, 1739.
14 P. G. M. Wuts and T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, Inc., 1991, 2nd edn, pp. 213–217.
15 (a) R. O. Hutchins and M. K. Hutchins, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press,
New York, 1991, vol. 8, pp. 25–79; (b) H. Feuer and
D. M. Braunstein, J. Org. Chem., 1969, 34, 1817.
4 (a) Y. Kuroki and R. Lett, Tetrahedron Lett., 1984, 25, 197;
(b) G. H. Posner and D. J. Brunelle, J. Org. Chem., 1973, 38,
2747; (c) S. A. Hardinger and P. L. Fuchs, J. Org. Chem., 1987, 52,
2739; (d) A. Risaliti, S. Faturra and M. Forchiassin, Tetrahedron,
1967, 23, 1451; (e) D. F. Taber and S. A. Saleh, J. Org. Chem.,
1981, 46, 4817.
16 M. Yamane and K. Narasaka, Science of Synthesis, Georg Thieme
Verlag, Stuttgart, 2004, vol. 27, pp. 605–647, and references cited
therein.
17 (a) A. Dobbs and S. Rossiter, in Comprehensive Organic Functional
Group Transformation I, ed. A. R. Katritzky and R. J. K. Taylor,
Elsevier, 2005, vol. 3, pp. 451–467; (b) M. Kitamura and
K. Narasaka, Chem. Rec., 2001, 2, 268; (c) J. P. Adams,
J. Chem. Soc., Perkin Trans. 1, 2000, 125; (d) S. Kobayashi and
H. Ishiani, Chem. Rev., 1999, 99, 1069.
5 S. Kim, I. Y. Lee, J.-Y. Yoon and D. H. Oh, J. Am. Chem. Soc.,
1996, 118, 5138.
6 S. Kim and I. Y. Lee, Tetrahedron Lett., 1998, 39, 1587.
7 B. Gaspar and E. M. Carreira, J. Am. Chem. Soc., 2009, 131,
13214.
8 (a) S. Kim, J.-Y. Yoon and I. Y. Lee, Synlett, 1997, 475;
(b) G.-H. Jeon, J.-Y. Yoon, S. Kim and S. S. Kim, Synlett, 2000,
128; (c) S. Kim, N. Kim, J.-Y. Yoon and D. H. Oh, Synlett, 2000,
1148; (d) S. Kim, H.-J. Song, T.-L. Choi and J.-Y. Yoon,
c
7824 Chem. Commun., 2010, 46, 7822–7824
This journal is The Royal Society of Chemistry 2010