Enantioselective conjugate addition of thiols to enones and enals catalyzed by chiral N-oxide-cadmium complex

Article abstract of DOI:10.1039/b005994n

A novel method of enantioselective conjugate addition of thiols to enones and enals produces sulfides with enantio-selectivities up to 78% ee, employing a cadmium complex of (S)-3,3'-dimethyl-2,2'-biquinoline N,N'-dioxide 1 as a catalyst.

Full text of DOI:10.1039/b005994n

Enantioselective conjugate addition of thiols to enones and enals catalyzed by
chiral N-oxide–cadmium complex
Makoto Saito, Makoto Nakajima* and Shunichi Hashimoto
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
E-mail: nakajima@pharm.hokudai.ac.jp
Received (in Cambridge, UK) 28h July 2000, Accepted 14th August 2000
First published as an Advance Article on the web 14th September 2000
8
A novel method of enantioselective conjugate addition of
thiols to enones and enals produces sulfides with enantio-
selectivities up to 78% ee, employing a cadmium complex of
(S)-3,3A-dimethyl-2,2A-biquinoline N,NA-dioxide 1 as a cata-
lyst.
suggest that a 1+1 complex of 1 and CdI2 functions
catalytically in this enantioselective addition. This is the first
example of an enantioselective reaction utilizing a cadmium
compound,9 exhibiting a distinctive binding to N-oxide.
Table 1 summarizes the conjugate addition of various thiols
to cyclic enones under optimized conditions.† Slight modifica-
tions of the substrate strongly influenced enantioselectivity.
Cyclohept-2-en-1-one (entry 2) gave an enantioselectivity
comparable to that of cyclohex-2-en-1-one (entry 3), while
cyclopent-2-en-1-one (entry 1) demonstrated low selectivity. It
is surprising that the reaction of 4-methylthiophenol (entry 5)
gave low selectivity compared to that of thiophenol (entry 3).
Although acyclic conjugate ketones were unsuccessful
(chalcone: 30%, 10% ee), the reaction of acyclic conjugate
aldehydes gives the corresponding sulfides in high chemical
yields with enantioselectivities up to 70% ee after conversion to
the corresponding alcohol (Table 2). The mildness of the
reaction conditions allows the enantioselective conjugate addi-
tion of thiols to enals, a reaction never previously reported due
to the lability of aldehydes.
The development of enantioselective reactions requires the
design of chiral ligands. Many recent studies have focused on
the development of novel chiral ligands for use in metal-
catalyzed reactions. Although N-oxide is a functional group
possessing a unique electron-donating property, allowing it to
form complexes with a variety of metals,1 few attempts have
been made to employ N-oxides as chiral ligands.2,3 We recently
reported an enantioselective allylation of aldehydes with
allyltrichlorosilanes utilizing a chiral N,NA-dioxide 1 as a
To determine the reaction mechanism, we investigated
several additives to the reaction of cyclohex-2-en-1-one and
thiophenol in toluene. Addition of cyclohexanone (1.0 eq.)
influenced neither chemical yield nor enantioselectivity (92%,
74% ee) of the reaction. The addition of cyclohexene (1.0 eq.),
however, dramatically reduced enantioselectivity (92%, 45%
ee). These results suggest the importance of the coordination of
the cadmium complex to the carbon–carbon double bond,
though the detail is not clear.
We have demonstrated the effectiveness of a chiral N-oxide–
cadmium iodide complex as a catalyst for enantioselective
conjugate addition of thiols to cyclic enones and enals. The
present reaction provides the first example of utilizing a
cadmium complex in an enantioselective reaction. Mechanistic
studies and the design of chiral N-oxides, currently in progress,
will further enhance enantioselectivity.
catalyst, exploiting the electron-donating property of the N-
oxide.3c Here, we describe an enantioselective conjugate
addition of thiols to enones and enals catalyzed by a chiral N-
oxide–cadmium complex.
Several chiral amine-catalyzed reactions have received
considerable attention4 since the first report on the enantio-
selective conjugate addition of thiols catalyzed by cinchona
alkaloid.4a Due to their high efficacy, catalysis of enantio-
selective conjugate addition by lithium thiolate complexes of
amino bisether,5 heterobimetallic complexes,6 and nickel
oxazoline complexes7 are of particular interest.
Recently, we described the optical resolution of 1 through the
hydrogen-bonding of 1 and optically active binaphthol.3a We
then hypothesized that thiophenol forms a hydrogen-bonding
complex with 1, controlling the nucleophilicity and steric
accessibility of thiophenol to electron-deficient olefins in its
enantioselective conjugate addition. We initially tested this
hypothesis using 10 mol% of 1 as a catalyst in the conjugate
addition of thiophenol to cyclohex-2-en-1-one in DCM. The
reaction produced a significant yield of the corresponding
sulfide, although the enantioselectivity was quite low (35%,
12% ee).
Table 1 Enantioselective conjugate addition of thiols to enones catalyzed by
CdI2–1 complex
To enhance the reactivity and enantioselectivity, we used 10
mol% metal salt as an additive expected to coordinate with
carbonyl oxygen. Among the various metal salts surveyed,
addition of CdI2 yielded the corresponding sulfide in high
chemical quantity with moderate enantioselectivity (93%, 57%
ee). Enantioselectivity increased up to 78% when the reaction
was performed in toluene, whereas polar solvents decreased
enantioselectivity substantially (THF: 99%, 0% ee; acetonitrile:
97%, 33% ee). Stoichiometric studies revealed that equimolar
amounts of 1 and CdI2 are sufficient for optimum enantio-
selectivity. The reaction was promoted by CdI2 in the absence of
N-oxide to produce the sulfide in 96% yield. These results
DOI: 10.1039/b005994n
Chem. Commun., 2000, 1851–1852
This journal is © The Royal Society of Chemistry 2000
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Table 2 Enantioselective conjugate addition of thiophenol to enals
catalyzed by CdI2–1 complex
Chiralpak AD, hexane–PriOH, 9+1, 1.0 mL min21, tR (S), 8.5 min; (R), 10.0
min).
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This work was partly supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture of Japan and Otsuka Chemical Award in
Synthetic Organic Chemistry, Japan. The authors thank the
Japan Society for the Promotion of Science for Research
Fellowships for Young Scientists (to M. S.).
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Notes and references
† The conjugate addition of thiol to enone was performed as follows:
Thiophenol (220 mg, 2.0 mmol) in toluene (1 mL) was added to a stirred
solution of cyclohex-2-en-1-one (96 mg, 1.0 mmol), N-oxide 1 (3.2 mg, 10
mmol) and CdI2 (3.6 mg, 10 mmol) in toluene (7 mL) and stirred for 6 h at
rt. The reaction mixture was diluted in toluene and successively washed
with aq. NaOH and brine. The solvent was evaporated and the residue was
chromatographed on a silica gel column (eluent, toluene–AcOEt, 100+1) to
afford 3-phenylthiocyclohexanone (198 mg, 96%) as an oil. N-Oxide 1 was
recovered by elution with 10% EtOH in DCM without a loss of optical
purity. The ee of the product was determined by chiral HPLC (Daicel
7 S. Kanemasa, Y. Oderaotoshi and E. Wada, J. Am. Chem. Soc., 1999, 121,
8675.
8 Pyridine N-oxide is known to form a complex with CdI2. See: M.
Nieuwenhuyzen, W. T. Robinson and C. J. Wilkins, Polyhedron, 1991,
10, 2111.
9 For the application of CdI2 as a catalyst, see: (a) D. Prajapati and J. S.
Sandhu, J. Chem. Soc., Perkin Trans. 1, 1993, 739; (b) B. Baruah, A.
Boruah, D. Prajapati and J. S. Sandhu, Tetrahedron Lett., 1997, 38, 1449;
(c) D. D. Laskar, D. Prajapati and J. S. Sandhu, Chem. Lett., 1999,
1283.
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