Asymmetric synthesis of 1-aryl and 1,3-diarylcyclopentenes by the Heck reaction of 1-sulfinylcyclopentenes with iodoarenes

Article abstract of DOI:10.1016/S0040-4039(00)00579-7

The asymmetric synthesis of 1-aryl and 1,3-diarylcyclopentenes by Heck reaction of (R)-1-[o-(N,N-dimethylamino)phenylsufinyl]cyclopentene with iodoarenes is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00579-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4107–4111
Asymmetric synthesis of 1-aryl and 1,3-diarylcyclopentenes by
the Heck reaction of 1-sulfinylcyclopentenes with iodoarenes
Juan Carlos de la Rosa, Nuria Díaz and Juan C. Carretero ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Received 18 February 2000; accepted 5 April 2000
Abstract
The asymmetric synthesis of 1-aryl and 1,3-diarylcyclopentenes by Heck reaction of (R)-1-[o-(N,N-
dimethylamino)phenylsufinyl]cyclopentene with iodoarenes is described. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: Heck reaction; cyclopentenes; sulfoxides; palladium; asymmetric synthesis.
The palladium-catalyzed arylation and alkenylation of olefins with organic halides (the Heck reaction1)
has become one of the most useful reactions for the formation of carbon–carbon bonds. Furthermore,
in the last decade, the development of new reaction conditions, the use of other types of organic
electrophiles, the discovery of new efficient catalysts, and the progress in enantioselective variants
have greatly improved its synthetic efficiency.2 Regarding the asymmetric Heck reaction,3 we recently
described that certain sulfoxides can be used as suitable chiral auxiliaries bonded to the alkene moiety.4
In particular, the o-(N,N-dimethylamino)phenylsulfinyl group proved to be very efficient in the Heck
reaction of sulfinyldihydrofurans with iodoarenes.4a We report here that the use of this chiral auxiliary
can be extended to less reactive cyclic alkenes, such as cyclopentenes.
First, to study the viability of the Heck reaction, the racemic 1-sulfinylcyclopentene 1 was readily
prepared by sulfenylation of cyclopentenyllithium with o-(N,N-dimethylamino)phenyl disulfide5 and
further oxidation at sulfur (MCPBA, 68% overall yield). In Scheme 1 and Table 1 are summarized
the results obtained in the Heck reaction of 1 with several iodoarenes under the optimal conditions
previously found for other α,β-unsaturated sulfoxides:4 Pd(OAc)2 10 mol%, Ag2CO3 200 mol%, dppp
10 mol%, DMF, 100°C. Interestingly, in spite of the well known sensitivity of the Heck reaction to steric
hindrance, the rather bulky trisubstituted alkene6 1 reacted completely after several hours (control by
TLC), affording cleanly the Heck products 2–4 (Table 1) without formation of double bond isomerized
cyclopentene by-products7 (76–83% yields). Concerning the diastereoselectivity of the reaction, the
stereochemical behavior of 1 parallels that of sulfinyldihydrofurans.4a In all cases, the reaction took
∗
Corresponding author. Fax: 34 913973966; e-mail: juancarlos.carretero@uam.es (J. C. Carretero)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00579-7
tetl 16858

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place with a significant stereocontrol, affording mixtures of A+B isomers in which the B isomer largely
predominated.8 Remarkably, under quite similar experimental conditions, but using longer reaction times
(control by TLC), these A+B mixtures of α,β-unsaturated sulfoxides underwent a second Heck reaction
to give 1,3-diarylated products 5–7 in satisfactory yields (50–80% after chromatography) and with very
high stereocontrol: a single isomer was detected by 1H NMR regardless the starting ratio of A+B isomers
(Scheme 1 and Table 2). The (3R*,SR*) configuration of these compounds was unequivocally established
in the case of 5 (in optically pure form) by X-ray difraction.9 In agreement with these results, the 1,3-
diphenylcyclopentene 5 was directly obtained from 1 (81% yield) by monitoring the progress of the Heck
reaction by TLC until the complete disappearance of the intermediate phenylcyclopentenes 2.
Scheme 1.
Table 1
First Heck reaction
Table 2
Second Heck reaction
Next, in order to apply these diastereoselective Heck reactions in asymmetric synthesis, the sulfinyl-
cyclopentene 1 had to be prepared in enantiomerically pure form. Unlike the widely applied synthesis
of enantiopure p-tolylsulfoxides by reaction of carbon nucleophiles with menthyl p-tolylsulfinate, the
preparation of other types of substituted sulfoxides is frequently much complicated.10 Among the

4109
methods displaying some structural flexibility, we focused our attention on Kagan’s procedure based
on the reaction of the enantiopure cyclic sulfite 8 with organometallic reagents.11 The reaction of
commercially available 8 with o-(N,N-dimethylamino)phenyllithium (generated in situ by treatment of
the corresponding iodide with n-BuLi) in diethyl ether at −78°C led to a 3:1 mixture of the sulfinates
9:10, which were readily separated by flash chromatography (61 and 21% yields, respectively). The
further reaction of 9 with the cyclopentenyl organometallic reagent furnished in good yields the required
sulfoxide (R)-1.12 However, it is important to note that while this second substitution at sulfur occurred
with a little racemization when cyclopentenyllithium was used as nucleophile (ee=88%, HPLC, Chiralcel
OD column), (R)-1 was obtained in very high optical purity by reaction with the corresponding Grignard
reagent (ee=97%) (Scheme 2).
Scheme 2.
The application of (R)-1 to the enantioselective synthesis of substituted cyclopentenes, in particular
to the preparation of (S) 3-phenylcyclopentene 117a and (S) 1,3-diphenylcyclopentene 12, is shown in
Scheme 3. As indicated before, the Heck reaction of (R)-1 with phenyl iodide can be directed either
to the preparation of the 3-phenylcyclopentenes 2 (A+B isomers) or to the 1,3-diphenylcyclopentane 5,
both in high optical purity as it was confirmed in the case of (3R,SR)-512 (ee=97%, HPLC, Chiralcel OD
column), which proved otherwise that sulfoxide (R)-1 is configurationally stable under the experimental
conditions of the Heck reaction. Finally, we found that an appropriate method for the cleavage of the
chiral auxiliary was the palladium catalyzed reductive desulfurization [Pd(acac)2 5 mol%, iPrMgBr 300
mol%, THF]13 of either the sulfoxide 5 or the sulfones derived from 2. Thus, the A+B mixture of isomers
2 was transformed into (S)-1112 (55% yield, ee=90%, GC Cyclosilb column), while (3R,SR)-5 afforded
(S)-1212 (77%, ee=94%, HPLC, Chiralpak AS column).
Scheme 3.
In summary, the results shown here indicate that the Heck reactions of the sulfinylcyclopentene (R)-1

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with iodoarenes occur with a synthetically useful stereoselectivity. 3-Arylated or 1,3-diarylated cyclopen-
tenes can be selectively prepared in high optical purity after Heck reaction and further desulfinylation.
Acknowledgements
We are grateful to DGES (Ministerio de Educación y Cultura, project PB96-0021) for financial support.
N.D. thanks the Ministerio de Educación y Cultura for a fellowship.
References
1. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518.
2. Recent reviews of Heck and related reactions: (a) Bräse, S.; de Meijere, A. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 3. (b) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427.
(c) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447. (d) Tsuji, J. Palladium Reagents and Catalysts-
Innovations in Organic Synthesis; Wiley: Chichester, 1995. (e) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (f) de
Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 36, 2379.
3. Reviews on the asymmetric Heck reaction: (a) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371. (b)
Guiry, P. J.; Hennessy, A. J.; Cahill, J. P. Top. Catal. 1997, 4, 311.
4. (a) Díaz Buezo, N.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129. (b) Priego, J.; Carretero, J. C. Synlett
1999, 1603.
5. o-(N,N-Dimethylamino)phenyl disulfide was readily prepared by methylation (CH3I, K2CO3, CH3CN, rt) of o-aminophenyl
disulfide, which was prepared by oxidation of o-iodoaniline according to a reported procedure (Fristad, W. E.; Peterson, J.
R. Synthetic Commun. 1985, 15, 1).
6. Trisubstituted alkenes are rarely used in intermolecular Heck reactions due to their scarce reactivity. For a review on the
insertion of transition metal alkyl complexes on alkenes, see: Soderberg, B. C. In Comprehensive Organometallic Chemistry
II; Vol. 3, Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Pergamon: Oxford, 1995; pp. 241–297. See also: Hillers, S.
O.; Reiser, O. Synlett 1995, 153.
7. The Heck products of cyclopentene are very prone to suffer C_C bond migration in the presence of the palladium catalysts.
For examples of Heck reactions of cyclopentene, see: (a) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis
1997, 1338. (b) Amatore, A.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375. (c) Prashad, M.; Tomesch, J. C.;
Wareing, J.; Smith, H. C.; Cheon, S. H. Tetrahedron Lett. 1989, 30, 2877. (d) Larock, R. C.; Gong, W. H.; Baker, B. E.
Tetrahedron Lett. 1989, 30, 2603. (e) Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905.
8. The chemical shifts differences of the protons contiguous to the sulfur atom (H1 and H3) in both A and B isomers constitute
an excellent criteria for its configurational assignment (Ref. 4). Thus, due to the highly deshielding effect induced by the
sulfinylic oxygen on the hydrogens in 1,3-parallel relationship, H1 appears significantly more deshielded in isomers A than
in isomers B, whereas the opposite was observed for H3 (figures below). On the other hand, this stereochemical assignment
was confirmed by chemical correlation of optically pure 2B (3R,SR configuration) into (S) 3-phenylcyclopentene (Scheme
3).The high reactivity and stereoselectivity of the tribustituted alkenes 1–4 in Heck reactions could be attributed to a
intramolecular like process facilitated by the previous coordination of the dimethylamino group to the palladium cationic
species prior to the insertion step (see graphic for (R)–1 and Ref. 4a). For the participation of Pd–N coordinated complexes
in the Heck reaction of amino olefins, see: Larhed, M.; Andersson, C.; Hallberg, A. Tetrahedron 1994, 50, 285 (and
references cited therein).

4111
9. X-Ray data of (3R,SR)-5 (C25H35NOS): monoclinic, space group P21, a=8.431 (2), b=14.141 (3), c=8.867 (2) Å, V=1033
Å3, Z=2, Mcalcd=387.52, ρcalcd=1.245 Mg/m3. Crystals were obtained from dichloromethane/n-hexane, crystal dimensions
0.17×0.25×0.25 mm. θ max=57.14°, Cukα radiation (λ=1.54178 Å). The scan mode was Omega. T=296 K. Reflections
collected 1972, independent reflections 1595 (Rint=0.0279). Empirical absorption correction. The structure was solved with
program SHELXTL, version 5.1, Bruker AXS. Refinement method full-matrix least-squares on F2. Automatic treatment
of H atoms. Parameters refined: 254. Final R indices [I>2σ(I)]: R1=0.0327, wR2=0.1052. R indices (all data): R1=0.0329,
wR2=0.1056. Residual electron density: 0.275 and –0.185 e Å−3
.
10. (a) Carreño, C. Chem. Rev. 1995, 95, 1717. (b) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961.
11. Rebiere, F.; Samuel, O.; Ricard, L.; Kagan, H. B. J. Org. Chem. 1991, 56, 5991.
12. Specific rotations: (R)-1, ee=97% [α]2D5=+190 (c=1, CHCl3); (3R,SR)-5, ee=97% [α]D25=+204 (c=1, CHCl3); (S)-11,
ee=90% [α]2D5=−190 (c=1, CHCl3);. [(R)-11 (Ref. 7a) ee=91% [α]2D5=+184 (c=1, CHCl3)]; (S)-12, ee=94% [α]2D5=+204
(c=1, CHCl3).
13. Julia, M.; Fabre, J. L. Tetrahedron Lett. 1983, 24, 4311. All attempts to remove the chiral auxiliary by reaction with other
desulfurizating agents (activated zinc, Al–Hg, Na–Hg or Raney nickel) were unsuccessful due to the lack of reactivity or
formation of mixtures of products.