An expedient reductive method for conversion of ketoximes to the corresponding carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2010.04.131

A wide array of readily prepared pivalates of ketoximes can be converted to the corresponding ketones in good yields by treatment with iron powder in THF containing catalytic amounts of both trimethylsilyl chloride and glacial acetic acid at room temperature for 30 min, followed by a brief aqueous workup.

Full text of DOI:10.1016/j.tetlet.2010.04.131

Tetrahedron Letters 51 (2010) 3555–3557
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Tetrahedron Letters
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An expedient reductive method for conversion of ketoximes to the
corresponding carbonyl compounds
Max M. Majireck, Jason A. Witek, Steven M. Weinreb *
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide array of readily prepared pivalates of ketoximes can be converted to the corresponding ketones in
good yields by treatment with iron powder in THF containing catalytic amounts of both trimethylsilyl
chloride and glacial acetic acid at room temperature for 30 min, followed by a brief aqueous workup.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 April 2010
Revised 28 April 2010
Accepted 30 April 2010
Available online 7 May 2010
Keywords:
Oximes
Reduction
We have recently been actively involved in developing a meth-
odology for effecting both inter- and intramolecular Michael-type
conjugate additions of carbon nucleophiles to in situ-produced
vinylnitroso compounds.1 Thus, we have found that nitrosoalkene
if DMF is used as a solvent, and also that the reaction is initiated by
the addition of a catalytic amount of trimethylchlorosilane.6b More
recently, we reported that other acylating reagents can be used in
,2
6c
this process. We considered the possibility of using a variation of
species 2 can easily be generated from
using a fluoride source in the presence of a carbon nucleophile to
form -alkylated oximes 3 (Scheme 1). For many of our intended
purposes, however, it was necessary to regenerate the carbonyl
compounds 4 from the resulting oximes 3.
a
-chloro-O-TBS-oximes 1
this methodology for converting oximes to carbonyl compounds
by omitting the acylating reagent in order to form the NH imine,
which would be susceptible to rapid hydrolysis. It should also be
noted that an iron(0)-promoted cleavage of oximes has been re-
ported, but which requires forcing conditions (Fe powder/concd
a
7
,8
Numerous methods have previously been described for con-
verting oximes and their O-acyl derivatives to carbonyl com-
HCl/MeOH, reflux).
In initial exploratory experiments, the oxime 5 (12:1 E/Z mix-
ture) was used as a test system (Eq. 1). However, exposure of this
compound to iron powder and a catalytic amount of trimethylsilyl
chloride in THF, MeOH, or toluene at either room temperature or at
reflux led to no observable cleavage reaction but rather only oxime
E/Z isomerization occurred. On the other hand, we were pleased to
find that the corresponding oxime acetate 6, when treated with
3
pounds. These procedures generally involve either hydrolytic,
oxidative or reductive conditions. After some disappointing results
using a few of the more common literature cleavage procedures
4
5
(
3
e.g., TiCl , Dess–Martin periodinane, etc.), we decided to explore
a new methodology for this transformation. In particular, we were
interested in developing a mild general procedure which would
utilize inexpensive, commercially available reagents having long
shelf lives. Moreover, since hydrolytic methods usually involve
stringent reaction conditions, and oxidative procedures are often
incompatible with the functionality in some of our systems (e.g.,
amines, indoles, etc.), we primarily focussed on devising a reduc-
tive protocol.
TBSO
TBAF
Nuc-
O
N
N
Cl
In 1998, Burk and coworkers discovered that N-acetyl enamides
can be prepared in moderate to good yields directly from ketoximes
by heating at 70 °C in toluene/acetic anhydride in the presence of
iron powder. In an improvement of this methodology, Zhang
et al. found that these reactions can be effected at room temperature
1
2
HO
6
a
N
O
Nuc
Nuc
3
4
*
Corresponding author. Tel.: +1 814 863 0189; fax: +1 814 865 3292.
E-mail address: smw@chem.psu.edu (S.M. Weinreb).
Scheme 1.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.131

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M. M. Majireck et al. / Tetrahedron Letters 51 (2010) 3555–3557
Table 1
Conversion of oxime pivalates to the corresponding carbonyl compounds
Entry
Oxime pivalate
Ketone product
Isolated yield (%)
81
PivO
N
O
A
N
Ts
N
Ts
OPiv
EtO C
O
2
EtO C
N
2
EtO C
B
C
D
2
54
71
95
EtO C
2
OPiv
O
N
Me
Me
OPiv
O
O
N
N
OPiv
E
F
91
75
OPiv
O
N
OPiv
O
N
N
N
G
H
79
Bz
Bz
OPiv
N
Ts
Ts
TMSEO C
N
2
O
TMSEO C
N
2
84a,b,c
N
Boc
N
Boc
CO Me
2
CO Me
2
a
b
c
This reaction was run at 0.03 M concentration.
Under the same conditions the corresponding oxime acetate gave 57% of the ketone.
These compounds are mixtures of diastereomers. Full spectral data will be reported in a subsequent publication.
iron powder in THF containing a catalytic amount of TMSCl at room
temperature for about 1 h, followed by stirring with water for an
additional hour, afforded the desired ketone 7 in reasonable yield
5. Therefore, in an attempt to avoid this problem, we decided to ex-
plore the cleavage of other O-acyl oxime derivatives.
Fe, THF
TMSCl (cat)
HOAc (cat)
RO
(
>60%). Although this transformation worked as planned, we ob-
N
O
served that the reaction was highly irreproducible. Surprisingly,
in some runs ketone 7 was formed cleanly and in others no reac-
tion occurred. After some detective work, it was discovered that
the successful reactions had been run in round-bottomed flasks
that were previously cleaned in a concentrated nitric acid bath, fol-
lowed by washing with water several times before drying. Reac-
tions run in flasks which had not been treated in this manner
only led to recovery of starting material. Thus, it became evident
that the oxime acetate reduction by iron(0) is apparently catalyzed
by a trace of the acid remaining in the flask. In fact, addition of a
catalytic amount of either nitric acid, p-toluenesulfonic acid, or tri-
fluoroacetic acid led to successful reactions, but the best yields of
ketone 7 (68%) were obtained by addition of a small amount of gla-
cial acetic acid to the mixture. It should also be noted that omission
of the TMSCl shuts down the cleavage. However, during the course
of these studies it was also observed that some deacetylation of 6
was occurring under these conditions, leading to unreactive oxime
then H O
2
N
N
ð1Þ
Ts
Ts
68%
5
6
R = H
7
R = Ac
These studies were conducted on acyl derivatives 8–11 pre-
pared from the oxime of 4-phenylcyclohexanone, and the results
are outlined in Eq. 2. Thus, it was found that the pivalate ester9
of this oxime gave the best yield of ketone 12. The acetate 8, ben-
zoate 9, and ethyl carbonate 10 all produced 12 in significantly
lower yields. Using pivalate 11, further optimization studies
showed that the cleavage works best if the reduction step is carried
out at room temperature for 30 min, followed by addition of water,
and stirring for 15 min to effect imine hydrolysis. Longer reaction
times for the reduction step generally led to lower yields of the ke-

M. M. Majireck et al. / Tetrahedron Letters 51 (2010) 3555–3557
3557
tone and to the formation of significantly larger amounts of by-
products. Also, using DMF as the solvent gave lower isolated yields
of product 12 than the reactions run in THF.
and TMSCl (one drop). After stirring for 30 min at room tempera-
ture, the reaction mixture was diluted with H O (1 mL) and stirred
2
for an additional 15 min. The liquid phase was separated from the
remaining Fe powder using a pipette and transferred to a separato-
ry funnel. The Fe powder was then washed with EtOAc (3 ꢀ 2 mL)
which was added to the separatory funnel. The organic layer was
separated and the aqueous layer was extracted with EtOAc. The
Fe, THF
TMSCl (cat)
HOAc (cat)
RO
N
O
then H O
2
4
combined organic layers were dried over MgSO and concentrated
Ph
ð2Þ
Ph
in vacuo to give a residue, which was purified by flash column
chromatography on silica gel eluting with a mixture of ethyl ace-
tate and hexanes. Isolated yields of carbonyl products formed from
a series of oxime pivalates are shown in Table 1.
8
9
1
1
R = Ac
R = Bz
12 R = Ac
R = Bz
R = CO Et (44%)
2
R = Piv
(68%)
(27%)
0 R = CO Et
2
1 R = Piv
(88%)
Acknowledgment
Using what was learned above, a general procedure has been
We are grateful to the National Institutes of Health (9R56GM-
9
developed for the cleavage of a broad range of ketoxime pivalates
to their corresponding ketones under the reaction conditions
shown in Eq. 3. This methodology has been applied to the repre-
sentative examples listed in Table 1. It should be noted, however,
that aldehyde oxime pivalates gave mixtures of the aldehyde and
the corresponding nitrile under these reaction conditions. Thus,
the work described here provides a very mild, general method
for converting readily prepared pivalates of ketoximes to their cor-
responding ketones.
0
87733) for the financial support of this research.
References and notes
1
.
.
For reviews of vinylnitroso compounds see: (a) Gilchrist, T. L. Chem. Soc. Rev.
1983, 11, 53; (b) Lyapkalo, I. M.; Ioffe, S. L. Russ. Chem. Rev. 1998, 67, 467.
(a) Korboukh, I.; Kumar, P.; Weinreb, S. M. J. Am. Chem. Soc. 2007, 129, 10342; (b)
Li, P.; Majireck, M. M.; Witek, J. A.; Weinreb, S. M. Tetrahedron Lett. 2010, 51,
2
2
032.
3. For reviews see: (a) Corsaro, A.; Chiacchio, U.; Pistara, V. Synthesis 2001, 1903;
b) Corsaro, A.; Chiacchio, U.; Pistara, V. Curr. Org. Chem. 2009, 13, 482; (c) Sahu,
S.; Sahu, S.; Patel, S.; Dash, S.; Mishra, B. K. Ind. J. Chem. 2008, 47B, 259.
4. Wildsmith, E.; Timms, G. H. Tetrahedron Lett. 1971, 12, 195.
(
1
) Fe powder
OPiv
R2
TMSCl (cat)
HOAc (cat)
N
O
5
6
.
.
Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760.
(a) Burk, M. J.; Casey, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084; (b) Zhu, G.;
Casalnuovo, A. L.; Zhang, X. J. Org. Chem. 1998, 63, 8100; (c) Sun, C.; Weinreb, S.
M. Synthesis 2006, 3585.
R1
R1
R2
ð3Þ
THF, rt, 30 min
) H O, rt, 15 min
2
2
7
.
Pradhan, P. K.; Dey, S.; Jaisankar, P.; Giri, V. S. Synth. Commun. 2005, 35, 913.
R , R = alkyl, aryl
1
2
8. N–O bonds of oxazolines have been cleaved with iron: Jiang, D.; Peng, J.; Chen, Y.
Org. Lett. 2008, 10, 1695.
9.
For synthesis of oxime pivalates see: Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc.
003, 125, 13486.
2
General procedure for cleavage of oxime pivalates: To a solution of
9
the oxime pivalate (0.10 mmol) in THF (1 mL) was added iron
powder (55.8 mg, 1.0 mmol) followed by glacial AcOH (one drop)