Readily prepared 3-Chloro-1 -(phenylthio)propene, a versatile three-carbon annulating agent

Article abstract of DOI:10.1021/ol901818j

3-Chloro-1-(phenylthio)propene, simply generated by chlorination of commercial allyl phenyl sulfide, is a versatile 3-carbon annulating agent for ketones and phenols.

Full text of DOI:10.1021/ol901818j

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4576-4579
Readily Prepared
3-Chloro-1-(phenylthio)propene, a
Versatile Three-Carbon Annulating
Agent
Taoping Liu,‡ Xiaoming Zhao,*,†,‡ Long Lu,‡ and Theodore Cohen*,§
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China, and
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
cohen@pitt.edu; xmzhao08@mail.tongji.edu.cn
Received August 6, 2009
ABSTRACT
3-Chloro-1-(phenylthio)propene, simply generated by chlorination of commercial allyl phenyl sulfide, is a versatile 3-carbon annulating agent
for ketones and phenols.
Allyl phenyl sulfide 1 and a variety of analogues have been
widely used, after deprotonation, as nucleophiles, mainly to
generate substituted allyl phenyl sulfides 2 (eq 1).1
In 1975, the American laboratory reported3 that allylic
phenyl sulfides such as 1 are readily chlorinated by N-
chlorosuccinimide (NCS) or trichlorisocyanuric acid (Chlo-
real) to 3-chloro-1-(phenylthio)propenes such as 4 (eq 3).
NCS is not as reactive and far more expensive than Chloreal
but it is more highly stereoselective for the trans product. In
the same paper, both stereoisomers were shown to be capable
of undergoing nucleophilic attack by organometallic reagents
mainly to directly displace the chloride group to provide
products such as 5. Subsequent publications reported similar
displacements with a variety of nucleophiles.4 Since vinyl
sulfides can be readily converted to aldehydes or ketones,3,5
reagents such as 4 behave as synthons of R,ꢀ-unsaturated
aldehydes or ketones in a Michael sense.3 In view of the
potential versatility of the nucleophilic substitution products
such as 5, it is rather surprising that the only reported uses
are as precursors of aldehydes3 or thioacetals.4b
In a recent publication,2 our groups reported a one pot
conversion of allyl phenyl sulfide, via an interesting rear-
rangement, into a versatile electrophile 3 that is particularly
useful as a three-carbon annulating agent.
‡ Chinese Academy of Sciences.
§ University of Pittsburgh.
† Current address: Department of Chemistry, Tongji University, 1239
Siping Road, Shanghai, 200092, P. R. China.
(1) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. ReV. 1999,
99, 665–722.
(2) Chen, W.; Zhao, X.; Lu, L.; Cohen, T. Org. Lett. 2006, 8, 2087–
2090.
(3) Mura, A. J., Jr.; Bennett, D. A.; Cohen, T. Tetrahedron Lett. 1975,
50, 4433–4436.
10.1021/ol901818j CCC: $40.75
Published on Web 09/22/2009
 2009 American Chemical Society

In the present paper, we demonstrate the utility of 4 as a
three-carbon annulating agent by taking advantage of the
ability of the activated alkene linkage of 5 to undergo
intramolecular additions of organolithiums or phenols. Since
divalent sulfur stabilizes both negative and positive charges
on the carbon atom to which it is attached, the alkene
linkages in compounds such as 5 are quite versatile.
It has been demonstrated that vinyl sulfides undergo
reductive lithiation by aromatic radical anions far more
slowly than do saturated phenyl thioethers even though the
product vinyllithiums are far more stable than alkyllithiums,
thus making selective reductive lithiation possible in mol-
ecules with both types of phenylthio groups; this has allowed
convenient cyclizations to cyclopropanes and cyclobutanes.6
This concept is herein extended to cyclopentanes.
hydroxyl group and the CH2SPh group of 10 was established
by crystallography (Figure 1).10
Figure 1. X-ray crystal structure of 10.
We have found that R-1-(phenylthio)allylation of cyclohex-
anone by 4 gives much better yields of 7 when the correspond-
ing enol silyl ether 6 is treated with 4 in the presence of a Lewis
acid than when the lithium enolate of cyclohexanone is treated4b
directly with 4. Smooth addition7 of (phenylthio)methyllithium8
to 7 gave the tertiary alcohols 8a and 8b. Deprotonation of this
mixture with butyllithium followed by reductive lithiation with
lithium 4,4′-di-tert-butylbiphenylide (LDBB) generated the
alkyllithium group that added to the activated alkene as shown
to provide a sulfur-stabilized organolithium capable of sulfe-
nylation to the thioacetal 9 or protonation to the alkyl sulfide
10. The terminal phenylthio substituent on the alkene linkage
of 8a and 8b is not essential for cyclization by carbolithiation9
but it allows greatly enhanced versatility as in the production
of 9 (Scheme 1).
It was anticipated that a similar sequence starting from
the trimethylsilyl enol ether 11 of cyclopentanone would be
challenging because of the notorious strain of trans-fused
diquinanes.9c As shown in Scheme 2, R-allylated cyclopen-
Scheme 2. Preparation and Cyclization of the R-Allylated
Cyclopentanone Adduct of (Phenylthio)methyllithium
Scheme 1. Preparation and Cyclization of the R-Allylated
Cyclohexanone Adduct of (Phenylthio)methyllithium
tanone 12 and its adduct 13 with (phenylthio)methyllithium
were readily obtained. However, after reductive lithiation,
no cyclization was observed at -78 °C. Gratifyingly, at -20°
cyclization occurred to the diquinane 14, albeit in lower yield
than in the formation of 10 in which the generated 5-mem-
bered ring is fused to a 6-membered ring. The trans
stereochemistry of 13 and therefore of 14 is assumed on the
basis of the high probability that the organolithium attacks
the cyclopentanone 12 from the least hindered side as occurs
in the case of the addition of the same organolithium to the
closely analogous cyclohexanone 7 in Scheme 1.
A similar sequence starting with the cycloheptanone silyl
ether should be particularly useful if successful since it would
(9) Terminal alkenes readily undergo cyclization by intramolecular
carbolthiation to generated cyclopenylmethyllithiums. Reviews: (a) Mealy,
M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59–67. (b) Hogan,
A. M. L.; O’Shea, D. F. Chem. Commun. 2008, 3839–3851, Recent papers:
(c) Deng, K.; Bensari-Bouguerra, A.; Whetstone, J.; Cohen, T. J. Org. Chem.
2006, 71, 2360–2372, and citations therein. (d) Sanz, R.; Ignacio, J. M.;
Rodriguez, M. A.; Fananas, F. J.; Barluenga, J. Chem.sEur. J. 2007, 13,
4998–5008. (e) Groth, U.; Kottgen, P.; Langenbach, P.; Lindenmaier, A.;
Schutz, T.; Wiegand, M. Synlett 2008, 1301–1304. (f) Bahde, R. J.;
Rychnovsky, S. D. Org. Lett. 2008, 10, 4017–4020. (g) Tsuchida, S.;
Kaneshige, A.; Ogata, T.; Baba, H.; Yamamoto, Y.; Tomioka, K. Org. Lett.
2008, 10, 3635–3638.
The stereochemistry of 9 was supported by 1H NMR, 13
NMR, and an NOE effect. The cis relationship between the
C
(4) (a) Cohen, T.; Bennett, D. A.; Mura, A. J., Jr. J. Org. Chem. 1976,
41, 2506–2507. (b) Ritter, R. H.; Cohen, T. J. Am. Chem. Soc. 1986, 108,
3718–3725. (c) Fitt, J. J.; Gschwend, H. W. J. Org. Chem. 1979, 44, 303–
305.
(5) Mura, A. J., Jr.; Majetich, G.; Grieco, P. A.; Cohen, T. Tetrahedron
Lett. 1975, 4437–4440.
(6) Chen, F.; Mudryk, B.; Cohen, T. Tetrahedron 1999, 55, 3291–3304.
(7) Hannaby, M.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1989, 303–
311.
(10) Crystallographic data of 10 (CCDC 278769) can be obtained free
of charge from the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB 1EZ, UK; email: deposit@ccdc.cam.ac.uk.
(8) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097–4099.
Org. Lett., Vol. 11, No. 20, 2009
4577

result in the formation of a usefully functionalized hydra-
zulane, a widespread natural ring system.11 However, the
zinc chloride catalyzed allylation of the enol silyl ether 15
led to an inseparable mixture. The allylation of the lithium
enolate, generated by the treatment of 15 with butyllithium,
produced 16 in satisfactory yield. Subsequent processing in
the usual way did indeed yield the functionalized hydrazulene
18 (Scheme 3). Only the trans alkene 17 could be isolated
To demonstrate an entirely different type of cyclization
afforded by the vinyl sulfide group, namely one depending
on the ability of the phenylthio group to stabilize a positive
rather than a negative charge, the ortho 3-(phenylthio)ally-
lation of phenol was attempted by treating a zinc salt of
phenol with the allylic chloride 4. The hope was that the
zinc ion attached to the oxygen atom would behave as a
Lewis acid toward the chloride and remove it in a 6-mem-
bered ring transition state to deliver the allylic group mainly
or exclusively to the ortho position.14 In the event, when
phenol was deprotonated by i-PrZnCl•MgCl2, generated by
mixing i-PrMgCl and ZnCl2, and the product was treated
with 4, the ortho allylated phenol 22 was indeed isolated in
54% yield. In the presence of acid, the alkene was protonated
to a sulfur-stabilized carbocation that was captured by the
phenolic group to deliver 2-(phenylthio)chroman 2315 in 73%
yield. As in the case of other R-(phenylthio)ethers,16 reduc-
tive lithiation generates the R-lithioether; in this case, it was
captured by isobutyraldehyde to produce a 1:1 mixture of
syn-24a and anti-24b in 53% unoptimized yield (Scheme
5).
Scheme 3. Preparation and Cyclization of the R-Allylated
Cycloheptanone Adduct of (Phenylthio)methyllithium
although a small amount of the cis isomer was probably also
formed in the addition.
To demonstrate the introduction of still more functionality
into the cyclized product, 7 was treated with the 1-(phe-
nylthio)allyltitanium reagent 19, readily prepared12 by depro-
tonation of allyl phenyl sulfide followed by transmetalation,
to generate 20 (Scheme 4). Deprotonation and reductive
Scheme 5. Preparation and Cyclization of an
o-(3-Phenylthio)allylated Phenol
Scheme 4. Preparation and Cyclization of the R-Allylated
Ketone Adduct of 1-(Phenylthio)allyltitanium
In summary, 3-chloro-1-(phenylthio)propenes such as 4,
readily prepared by chlorination of allyl phenyl sulfide, are
useful electrophiles which can be incorporated into the
R-position of ketones and the ortho-position of phenols to
provide cyclization precursors. For the cyclization step, use
is made of the ability of divalent sulfur to stabilize either a
(11) Heathcock, C. L.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White,
C. T. The Total Synthesis of Natural Products, Vol. 5; ApSimon, J., Ed.; J.
Wiley and Sons: New York, 1982; pp 333-384.
(12) Ikeda, Y; Furuta, K.; Meguriya, N.; Ikeda, N.; Yamamoto, H. J. Am.
Chem. Soc. 1982, 104, 7663–7665.
lithiation of the latter, as in the case of 8, produced the highly
functionalized bicyclic system 21. Its stereochemistry was
established by crystallography (Figure 2).13
(13) Crystallographic data of 21 (CCDC 739965) can be obtained free
of charge via from the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge CB 1EZ, UK; email: deposit@ccdc.cam.ac.uk.
(14) The potassium salts of several phenols were reported to undergo
ortho-allylation in the presence of various allylic halides and catalytic
amounts of zinc chloride but neither other products nor a mechanism were
discussed: Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Synthesis 1981,
310–312. However, a 6-member ring transition state can be surmised from
a subsequent review by some of the same authors: Casnati, G.; Casiraghi,
G.; Pochini, A.; Sartori, G.; Ungaro, R. Pure Appl. Chem. 1983, 55, 1677–
1688.
(15) The replacement of the phenylthio group of 23 by allyl, Cl, and F
as well as its oxidation to a sulfoxide is recorded in the literature but
curiously no synthesis of 23 appears. Nishiyama, H.; Narimatsu, S.; Sakuta,
K.; Itoh, K. J. Chem. Soc., Chem. Commun. 1982, 459–460. Ringom, R.;
Benneche, T. Acta Chem. Scand. 1999, 53, 41–47.
Figure 2. X-ray crystal structure of 21.
(16) Cohen, T.; Matz, J. R. J. Am. Chem. Soc. 1980, 102, 6900–6902.
Cohen, T.; Lin, M. J. Am. Chem. Soc. 1984, 106, 1130–1131.
4578
Org. Lett., Vol. 11, No. 20, 2009

negative and or a positive charge at the carbon to which the
sulfur atom is attached. In view of the fact that various
substituted allyl phenyl sulfides can be similarly chlorinated
to provide substituted analogues of 4, this simple annulation
protocol should prove quite general.
of X.M.Z.’s work. We also thank Dr. Steven Geib for help
with the crystallographic data.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds as
well as crystallographic data for compounds 10 and 21. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge Shanghai
Institute of Organic Chemistry, Chinese Academy of Sci-
ences (Grant from 2004 to 2006) for the financial support
OL901818J
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4579