Intramolecular alkylation of an α-sulfinyl vinylic carbanion without loss of optical purity: A novel access to chiral cyclic vinylic sulfoxides

Article abstract of DOI:10.1039/a905320d

Novel cyclisation via intramolecular α-alkylation of vinylic sulfoxides was studied and cyclic vinqlic sulfoxides of various ring sizes (5-7) were synthesised from both (E)- and (Z)-isomers without loss of optical purity.

Full text of DOI:10.1039/a905320d

Intramolecular alkylation of an a-sulfinyl vinylic carbanion without loss of
optical purity: a novel access to chiral cyclic vinylic sulfoxides
Naoyoshi Maezaki, Mayuko Izumi, Sachiko Yuyama, Chuzo Iwata and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: t-tanaka@phs.osaka-u.ac.jp
Received (in Cambridge, UK) 1st July 1999, Accepted 9th August 1999
Novel cyclisation via intramolecular a-alkylation of vinylic
sulfoxides was studied and cyclic vinylic sulfoxides of
various ring sizes (5–7) were synthesised from both (E)- and
(Z)-isomers without loss of optical purity.
1–3). However, an eight-membered ring could not be formed
even under highly dilute conditions (0.001 M), yielding instead
many unidentified products together with the dimer 6 (22%)
(entry 4). Then, we focused on the intramolecular alkylation of
(Z)-isomers. As expected, cyclisation of (Z)-1a,e,f proceeded
via isomerisation of their olefin geometry followed by cyclisa-
1-Alkenyl aryl sulfoxides are deprotonated at the a-position and
generate vinylic carbanion species, which react with a variety of
electrophiles such as alkyl halides, epoxides, aldehydes and
ketones.1 This methodology is very useful for the synthesis of
substituted vinylic sulfoxides, which can be transformed into a
variety of functional groups and which also have potential use
for asymmetric reactions.2 However, research on the inter-
molecular reactions of a-lithio vinylic sulfoxides has revealed
two problems: (i) contamination of the geometric isomer by
isomerisation of its olefin moiety, and (ii) racemisation of the
stereogenic center on the sulfur atom during isomerisation.3
During the course of our research on the reaction of a-sulfinyl
carbanions,4 we have become interested in intramolecular a-
alkylation of vinylic sulfoxides, which, to the best of our
knowledge, has never been discussed in the literature (Scheme
1). This reaction has two advantages. (i) Not only (E)-isomers
but also (Z)-isomers could be cyclised into the same product via
rapid isomerisation; this would then provide a cyclic vinylic
sulfoxide. Therefore, neither selective preparation of the
geometric isomers nor their separation is required. (ii) The loss
of enantiomeric excess is expected to be overcome since the
intramolecular reaction is generally milder than the correspond-
ing intermolecular version, due to the reduced decrease in the
entropy of the intramolecular system.
Table 1 Intramolecular alkylation of a-sulfinyl vinyl carbaniona
Entry
Substrate (X) Base
Additive Solvent Yield (%)b
1
2
3
4
5
1a (I)
LDA
LDA
LDA
LDA
—
—
—
—
THF
THF
THF
THF
THF
82
79
24
complex
55
1b (Br)
1c (OTs)
1d (OMs)
1a (I)
LDA
HMPA
6
7
8
9
1a (I)
1a (I)
1a (I)
1a (I)
1a (I)
1a (I)
1a (I)
1a (I)
LDA
TMEDA THF
62
75
65
complex
complex
39
10
21
LICAc
LTMPd
NaHMDS
KHMDS
LDA
—
—
—
—
—
—
—
THF
THF
THF
THF
DME
Et2O
toluene
10
11
12
13
a
Here we report a novel cyclisation via intramolecular
alkylation of a-sulfinyl vinylic carbanions generated from (E)-
and (Z)-isomers; this process provides cyclic vinylic sulfoxides
without a subsequent loss of optical purity.
LDA
LDA
The substrate was treated with 1.5 equiv. of the base at 278 °C under
N2. b Isolated yield. c LICA = lithium cyclohexylisopropylamide. d LTMP
= lithium 2,2,6,6-tetramethylpiperidide.
We began our study employing (E,R)-6-iodohex-1-en-1-yl p-
tolyl sulfoxide (E)-1a. On treatment of (E)-1a with LDA (1.5
equiv.) in THF at 278 °C, rapid cyclisation proceeded to give
cyclohex-1-enyl p-tolyl sulfoxide 2 in 82% yield; neither
elimination of iodide nor the rearrangement of the double bond
to the b,g-position was observed (Table 1, entry 1). The
corresponding bromide (E)-1b also afforded 2 in a comparable
yield (79%) (entry 2). On the other hand, the tosylate and
mesylate analogues caused the production of many products and
therefore resulted in poor results (entries 3 and 4). Variation of
the additive, base and solvent used did not improve the yield
(entries 5–13).
Table 2 Cyclisation of (E)- and (Z)-1 and optical purities of the
productsa
Next, we examined cyclisation of w-iodo vinylic sulfoxides
(E)-1e,f with different chain lengths. Five- to seven-membered
rings were formed in a good yield (79–82%; Table 2, entries
Entry
Substrate Product n (ring size) Yield (%)b [a]D Eec
1
2
3
4
5
6
7
a
(E)-1e
(E)-1a
(E)-1f
(E)-1g
(Z)-1e
(Z)-1a
(Z)-1f
3
2
4
5
3
2
4
1 (5)
2 (6)
3 (7)
4 (8)
1 (5)
2 (6)
3 (7)
81
82
79
0
66
71
64
+57 98
+9 98
+10
—
—
—
+57 96
+9 98
+10
—
The substrate was treated with 1.5 equiv. of the base at 278 °C under
N2. b Isolated Yield. c Determined by chiral HPLC.
Scheme 1
Chem. Commun., 1999, 1825–1826
1825

A typical experimental procedure is described for the reaction
of 7-iodohept-1-en-1-yl tolyl sulfoxide with LDA. A solution of
the iodide 1f (43 mg, 0.12 mmol) in dry THF (2.3 ml) was added
to a solution of LDA (1.5 equiv.) [prepared from Pri2NH (25 ml,
0.18 mmol) and 1.58 M BuLi in hexane (115 ml, 0.18 mmol) in
dry THF (2.3 ml)]. The solution was stirred at 278 °C under N2.
After 30 min, the reaction was quenched with saturated aqueous
NH4Cl and extracted with EtOAc. The extract was washed with
brine prior to drying and solvent evaporation. The crude sample
was purified by preparative TLC on silica gel with hexane–
EtOAc (2+1) to give cyclohex-1-enyl p-tolyl sulfoxide (22 mg,
79%).
In summary, we found a ring-forming reaction via intra-
molecular alkylation of the a-lithio vinylic sulfoxides, which
proceeded in moderate to good yield. Interestingly, even vinylic
sulfoxides with (Z)-configuration were cyclised via rapid
isomerisation; no racemisation occurred at the sulfur atoms.
Further study of this method of cyclisation is currently
underway.
Fig. 1 Reaction mechanism.
tion to give 2–4, respectively, in moderate yield (64–71%;
entries 5–7).
Posner reported that a-deprotonation of optical pure (E,R)-
undec-1-en-1-yl p-tolyl sulfoxide followed by reprotonation
produced no racemisation, whereas similar treatment of the
corresponding (Z)-isomer produced racemisation (ca. 30% loss
of optical purity).3 Therfore, the specific rotations of the
cyclised products of intramolecular alkylation from the (E)- and
(Z)-isomers were compared. The cyclic vinylic sulfoxides from
the (Z)-isomers have almost the same specific rotations as those
from the corresponding (E)-isomers. Furthermore, the products
2 and 3 prepared from (E)- and (Z)-w-iodo vinylic sulfoxides 1a
and 1e were confirmed to be highly optically pure (!96% ee) by
chiral HPLC (Daisel Chiralcel OB). As we expected, racemisa-
tion did not occur appreciably during (Z)- to (E)-isomerisation
with the intramolecular alkylation of a-lithio vinylic sulf-
oxides.
The mechanism of racemisation in the a-carbanion of the (Z)-
vinylic sulfoxide has not been revealed. However, the results of
Posners’ experiments indicate that racemisation occurs during
isomerisation because no racemisation occurs in the corre-
sponding reaction of the (E)-isomer. This means that the
intramolecular alkylation of the (Z)-isomer is not a stepwise
reaction involving isomerisation and cyclisation. We assumed
the concerted mechanism shown in Fig. 1, wherein the s*-
orbital of the internal C–X bond participates in the olefin
isomerisation by accepting the carbanion extending through the
sp2 carbon and assists the isomerisation.1c,5 This interaction
with the internal electrophile would prevent the racemisation of
the sulfoxide.
Notes and references
1 (a) R. R. Schmidt, H. Speer and B. Schmid, Tetrahedron Lett., 1979,
4277; (b) G. H. Posner, P.-W. Tang and J. P. Mallamo, Tetrahedron Lett.,
1978, 42, 3995; (c) H. Okamura, Y. Mitsuhira, M. Miura and H. Takei,
Chem. Lett., 1978, 517.
2 Review: M. C. Carren˜o, Chem. Rev., 1995, 95, 1717.
3 G. H. Posner, in Asymmetric Synthesis, ed. J. D. Morrison, Academic
Press, New York, 1983, vol. 2A, pp. 225–241; G. H. Posner, J. P.
Mallamo and K. Mirua, J. Am. Chem. Soc., 1981, 103, 2886.
4 N. Maezaki, A. Sakamoto, T. Tanaka and C. Iwata, Tetrahedron:
Asymmetry, 1998, 9, 179; N. Maezaki, A. Sakamoto, M. Soejima, I.
Sakamoto, Y.-X. Li, T. Tanaka, H. Ohishi, K. Sakaguchi and C. Iwata,
Tetrahedron: Asymmetry, 1996, 7, 2787 and references cited therein.
5 Concomitant isomerisation–alkylation of an a-sulfinyl carbanion on an
sp3 carbon has been reported, see: G. Chassaing, R. Lett and A. Marquet,
Tetrahedron Lett., 1978, 471.
Communication 9/05320D
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Chem. Commun., 1999, 1825–1826