O-TBS-N-tosylhydroxylamine: A reagent for facile conversion of alcohols to oximes

Article abstract of DOI:10.1021/ol800677p

(Chemical Equation Presented) A variety of oximes were synthesized from the corresponding alcohols, alkyl halides, or alkyl sulfonates without using external oxidants. With this simple two-step procedure involving substitution with readily available TsNHOTBS and subsequent treatment with CsF, a range of oximes were prepared including the ones hardly preparable with conventional procedures.

Full text of DOI:10.1021/ol800677p

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2259-2261
O-TBS-N-tosylhydroxylamine: A Reagent
for Facile Conversion of Alcohols to
Oximes
Katsushi Kitahara, Tatsuya Toma, Jun Shimokawa, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received March 25, 2008
ABSTRACT
A variety of oximes were synthesized from the corresponding alcohols, alkyl halides, or alkyl sulfonates without using external oxidants. With
this simple two-step procedure involving substitution with readily available TsNHOTBS and subsequent treatment with CsF, a range of oximes
were prepared including the ones hardly preparable with conventional procedures.
Oxime is a frequently used functionality in organic synthesis.
Its synthetic utility is prominent as the precursor for important
Scheme 1
functionalities such as amines, nitriles, amides, and nitrile
oxides, to name a few.1 Preparation of this versatile
functionality has been dependent primarily on the reaction
between hydroxylamine and the corresponding aldehydes or
ketones. However, there are cases where the oxidative
preparation of aldehydes or ketones is not desirable due to
the presence of the other readily oxidizable functionalities.
In addition, the highly reactive nature of some ketones and
aldehydes would make them unsuitable for preparation of
the corresponding oximes. Herein, we describe a novel two-
of a fluoride ion. The hydroxylamine derivative 3 could be
step protocol for the preparation of a variety of oximes from
easily synthesized from the corresponding alcohols or alkyl
the corresponding alcohols without going through ketones
halides by the Mitsunobu reaction4 or by conventional
or aldehydes.
substitution reactions with O-silyl-N-arylsulfonylhydroxyl-
Our idea of preparing oximes stems from the fact that
amine 4.5
nitrosoalkane 2 readily tautomerizes to the corresponding
We employed a tosyl group and a TBS group for
oxime 1 (Scheme 1).1,2 We envisaged that nitrosoalkane 2
N-activating and O-protecting hydroxylamine simply because
would be obtained by the extrusion of sulfinate3 from the
O-silyl-N-arylsulfonylhydroxylamine 3 with the assistance
(4) Mitsunobu, O. Synthesis 1981, 1.
(5) An N-arylsulfonyl hydroxylamine derivative is known as an excellent
(1) For a review, see: Yamane, M.; Narasaka, K. In Science of Synthesis;
Padwa, A., Ed.; Georg Thieme Verlag: Stuttgart, 2004; Vol. 27, pp
605-647.
substrate for Mitsunobu reaction: Yamashita, T.; Kawai, N.; Tokuyama,
H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038. (a) Similar
substitution reactions using hydroxylamine derivatives are known: Maurer,
P. J.; Miller, M. J. J. Am. Chem. Soc. 1982, 104, 3096. (b) Hanessian, S.;
Yang, R.-Y. Synlett 1995, 633. (c) Knight, D. W.; Leese, M. P. Tetrahedron
Lett. 2001, 42, 2593.
(2) (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E; Pecht, M. M. J. Am.
Chem. Soc. 1960, 82, 2640. (b) Touster, O. Org. React. 1953, 7, 327
.
(3) Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2007, 9, 3195.
10.1021/ol800677p CCC: $40.75
Published on Web 04/30/2008
2008 American Chemical Society

they are inexpensive and readily available. As this species
was hitherto unknown in the literature,6 we tried to prepare
5 by sulfonylation of O-TBS-hydroxylamine.7 Since O-TBS-
hydroxylamine could be synthesized easily by silylation of
hydroxylamine, we could develop a facile one-pot synthesis
of the reagent O-TBS-N-tosylhydroxylamine (TsNHOTBS
5). Thus, hydroxylamine hydrochloride (1.1 equiv) was
mixed with TBSCl (1.1 equiv) and Et3N (5.0 equiv) in DMF
(0.3 M) at room temeperature, and after completion of the
silylation, p-toluenesulfonyl chloride (1.0 equiv) was added
to the mixture. After crystallization from hexane, 5 was
obtained in 82% yield as stable white crystals.8 To test our
working hypothesis, 5 was reacted with 3-phenylpropan-1-
ol (6) under Mitsunobu conditions, and much to our delight,
7 was obtained in 99% yield (Scheme 2). Subsequent
Table 1. Two-Step Formation of Oximes from Alcoholsa
Scheme 2
desilylative elimination of p-toluenesulfinate by treatment
with CsF9 proceeded uneventfully, providing the desired
oxime 8 in 99% yield as a mixture of E,Z isomers.
To investigate the scope and limitations of this novel
transformation, a number of alcohols were subjected to the
reaction conditions. As is evident from the results shown in
Table 1, various oximes were obtained in high yields. Secondary
alcohol led to ketoxime in the same manner as aldoxime (entry
2). Benzyl, allyl, and propargyl alcohols are also good substrates
for this reaction (entries 6-9). While cis-R,ꢀ-unsaturated
aldehyde tends to give a mixture of cis- and trans-R,ꢀ-
unsaturated oximes under conventional conditions,10 no such
isomerization of the double bond was observed in entry 10.
Similarly, avoidance of the intermediacy of a carbonyl inter-
mediate makes our method reliable for the synthesis of ꢀ,γ-
unsaturated oxime (entry 11). Equally noteworthy is the fact
a Standard conditions for Mitsunobu reaction: 1.1 equiv of alcohol,13
1.0 equiv of TsNHOTBS, 1.5 equiv of DEAD, 2.0 equiv of PPh3,
toluene-THF (3:1, 0.2 M), 0 °C. Standard conditions for oxime formation:
2.0 equiv of CsF, MeCN (0.1 M), 60 °C. b Isolated yields for Mitsunobu
reaction/oxime formation reaction. c Mitsunobu reaction was conducted with
2.5 equiv of DEAD and 3.0 equiv of PPh3. d A minimal amount (1.05 equiv)
of DEAD was used because of the unstability of the product to the reagent.
e 2.0 equiv of AcOH was added for buffering the basicity. f Mitsunobu
reaction was conducted with 1.5 equiv of alcohol and 2.0 equiv of DEAD
at 40 °C.
(6) For other reports of O-silyl-N-sulfonylhydroxylamines, see: (a)
Bruynes, C. A.; Jurriens, T. K. J. Org. Chem. 1982, 47, 3966. (b) Pohlman,
G.; Brink, K.; Bliefert, C. Z. Naturforsch., B: Anorganische Chemie,
Organische Chemie 1980, 35B, 1494.
(7) West, R.; Boudjouk, P. J. Am. Chem. Soc. 1973, 95, 3983.
(8) For experimental details, see: Supporting Information.
(9) While several fluoride sources including TBAF were examined, CsF
gave the best result.
(10) Enev, V. S.; Drescher, M.; Ka¨hlig, H.; Mulzer, J. Synlett 2005,
2227. According to the authors, this was the first example of a stereoselective
synthesis of cis-R,ꢀ-unsaturated oxime.
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Org. Lett., Vol. 10, No. 11, 2008

that the presence of a ketone does not interfere with the
Mitsunobu reaction and thus does not require protection during
the oximation (entry 13).11 Furthermore, this method proved
to be applicable to the preparation of hindered oximes. There
are cases where the very long reaction time is needed for the
completion of the formation of oxime from the corresponding
hindered ketones. One such example is the 2′,4′,6′-trimethyl-
acetophenone oxime, which requires 32 days at room temper-
ature in the strongly basic medium for completing the reaction.12
The present method requires only 3 h to prepare the oxime
(entry 14).
Scheme 3
To further expand the scope of the reaction, we next
examined the substitution reactions with alkyl bromide,
mesylate, and tosylate using TsNHOTBS and Cs2CO3
(Scheme 3).13,14 As expected, these substrates underwent
smooth, one-pot conversion to give the corresponding oxime
in excellent yields.15
In conclusion, we have developed a general method for
synthesizing oximes from the corresponding alcohols, alkyl
bromides, and alkyl sulfonates by means of a substitution
reaction with TsNHOTBS. Since the present method does
not need to use carbonyl compounds for synthesizing oximes,
it is likely to find a unique niche in synthetic organic
chemistry.
(11) Since aldehydes react with TsNHOTBS to give silylated hydroxamic
acids presumably by the mechanism similar to Angeli-Rimini’s reaction,
they are not compatible with the present method. For Angeli-Rimini’s
reaction, see: (a) Hassner, A.; Wiederkehr, R.; Kascheres, A. J. J. Org.
Chem. 1970, 35, 1962. (b) Porcheddu, A.; Giacomelli, G. J. Org. Chem.
2006, 71, 7057.
(12) (a) Pearson, D. E.; Keaton, O. D. J. Org. Chem. 1963, 28, 1557.
(b) Greer, F.; Pearson, D. E. J. Am. Chem. Soc. 1955, 77, 6649.
(13) Excess alcohols were used in these cases because the hydroxylamine
intermediates have similar polarity to 5 and could not be isolated in pure
form. From the synthetic point of view, an excess amount of 5 could be
used if it is not necessary to isolate the intermediate in pure form, because
5 decomposes upon treatment with CsF.
Acknowledgment. We are grateful for the Grant-in-Aid
(15109001 and 18890048) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
Supporting Information Available: Experimental details
and spectroscopic data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Use of K2CO3 instead of Cs2CO3 substantialy decreases the
efficiency of the elimination of toluenesulfinate, often resulting in incomplete
reactions
.
(15) A one-pot procedure was employed because partial desilylation was
observed in the first step.
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