In 2000, Mukaiyama and co-workers reported on N-tert-
butylphenylsulfinimidoyl chloride,12 1, as a versatile oxida-
tion reagent for use in organic synthesis.13 In particular, this
reagent can be employed in the oxidation of alcohols, amines,
and hydroxylamines13b,c and in the dehydrogenation of
ketones to enones under mild reaction conditions.14 Recently,
the Nicolaou group have applied this species in a dehydro-
genation of a structurally complex ketone to an enone in
their total synthesis of azaspiracid-1.15 Additionally, Mu-
kaiyama and co-workers have themselves employed their
alcohol oxidation methodology with 1 in efforts toward the
syntheses of taxanes.16
Our first attempt at this one-pot transformation used
benzaldehyde 6 with methylmagnesium chloride serving as
the nucleophile (Scheme 2). The Grignard reagent was
Scheme 2. Initial One-Pot Aldehyde to Ketone
Transformations; Preparation of Acetophenone 7 and
Valerophenone 8 from Benzaldehyde 6
In attempts to expand the utility of the sulfinimidoyl
chloride, 1, recent work from our own laboratory17 and from
Matsuo and co-workers18 has, independently, shown how this
reagent can be employed in the formation of â-substituted
enones from unsubstituted enones in a single, practical
operation. Based on this, we envisaged that this same
commercially available19 reagent could be applied within a
novel and general one-pot process to allow the expedient
synthesis of ketones from aldehydes. This concept is depicted
in Scheme 1. Specifically, we believed that the alkoxide 3,
allowed to react with 6, over 0.5 h at -78 °C, before addition
of 1. Following another 0.5 h at -78 °C, no desired product
formation was observed. Undaunted, we made a second
attempt with slight variations in procedure. In this case, the
reaction was allowed to warm to room temperature with the
reaction time, following addition of 1, extended to 20 h. This
minor change resulted in a 70% yield of acetophenone 7
and supported our initial reaction concept. At this stage we
went on to apply an alkyllithium reagent, with the view that
the resultant lithium alkoxide could react even more readily
with sulfinimidoyl chloride, 1.20 In this case, n-butyllithium
was added to benzaldehyde, followed by 1, and after 5 h at
-78 °C a 12% yield of valerophenone, 8, was obtained.
Analysis of the product mixture showed that 68% of
1-phenylpentan-1-ol had also been formed, indicating that
alkylation had indeed occurred, and suggesting that the
second stage of our reaction process was slow at low
temperatures. To our delight, simply performing the reaction
under the same conditions, but this time allowing the mixture
to warm slowly to ambient temperature, afforded 88% of
the desired ketone product.
Scheme 1. Concept for a One-Pot Transformation from
Aldehyde to Ketone, via Reaction between Intermediate
Alkoxide 3 and 1
A further brief program of optimization showed that the
complete reaction sequence could be performed within 1 h:
the nucleophile is added to the aldehyde in THF at -78 °C
and the mixture stirred for 20 min, before addition of the
electrophilic oxidant 1 (1.5 equiv); after a further 20 min at
-78 °C, the reaction is allowed to warm over 20 min before
final workup. Monitoring of the internal reaction temperature
showed that this reached approximately 20 °C over this latter
time period.
Using benzaldehyde 6 as the substrate with PhLi as the
nucleophile, we also investigated changing the reaction
solvent to diethyl ether or benzene. It was thus demonstrated
that the reactions could also be performed in these alternative
solvents, although THF appeared to provide the optimal
results (Table 1, entries 1-3) and, more specifically, an
excellent 93% yield of benzophenone, 9. Additionally, a
comparison study of the organometallic species used was
derived from nucleophilic addition of an organometallic
reagent to an aldehyde 2, could react with 1 directly to afford
the desired ketone 4, via sulfinimidate intermediate 5.
(12) (a) For the first report on the preparation of N-tert-butylphenyl-
sulfinimidoyl chloride, see: Markovskii, L. N.; Dubinina, T. N.; Levchenko,
E. S.; Kirsanov, A. V. J. Org. Chem. USSR 1973, 9, 1435. (b) For a more
recent and practically-utilizable preparation, see: Matsuo, J.; Iida, D.; Tatani,
K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2002, 75, 223.
(13) (a) Mukaiyama, T.; Matsuo, J.; Yanagisawa, M. Chem. Lett. 2000,
29, 1072. For reviews, see: (b) Mukaiyama, T. Angew. Chem. 2004, 116,
5708; Angew. Chem., Int. Ed. 2004, 43, 5590. (c) Matsuo, J. J. Synth. Org.
Chem. Jpn. 2004, 62, 574.
(14) (a) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. Chem. Lett, 2000, 1250.
(b) Matsuo, J.; Aizawa, Y. Tetrahedron Lett. 2005, 46, 407.
(15) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.;
Yamada, Y. M. A.; Tang, W.; Frederick, M. O. Angew. Chem. 2004, 116,
4418; Angew. Chem., Int. Ed. 2004, 43, 4318.
(16) Matsuo, J.; Ogawa, Y.; Pudhom, K.; Mukaiyama, T. Chem. Lett.
2004, 33, 125.
(17) Kerr, W. J.; Pearson, C. M.; Thurston, G. J. Org. Biomol. Chem.
2006, 4, 47.
(18) Matsuo, J.; Aizawa, Y. Chem. Commun. 2005, 2399.
(19) TCI Organic Chemicals, TCI Europe, B-2070 Zwijndrecht, Belgium.
(20) (a) Schlosser, M. In Organometallics in Synthesis; Schlosser, M.,
Ed.; Wiley: New York, 2002; Chapter 1. (b) Wakefield, B. J. Organo-
magnesium Methods in Organic Synthesis; Academic Press: London, 1994.
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