Synthesis of 1-p-tolysulfinyl-1,3-dienes by intramolecular heck reactions

Article abstract of DOI:10.1016/S0040-4039(00)00079-4

The first examples of the synthesis of 1,3-dienyl sulfoxides by Heck reactions are described. Both racemic and enantiomerically pure exocyclic 1- p-tolylsulfinyl-1,3-dienes 1 are readily prepared by the intramolecular Heck reaction of their corresponding vinyl iodides in the presence of Pd(OAc)₂ as catalyst and Ag₂CO₃ as base. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00079-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1983–1986
Synthesis of 1-p-tolylsulfinyl-1,3-dienes by intramolecular Heck
reactions
M. Mar Segorbe, Javier Adrio and Juan C. Carretero ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Received 10 November 1999; accepted 11 January 2000
Abstract
The first examples of the synthesis of 1,3-dienyl sulfoxides by Heck reactions are described. Both racemic and
enantiomerically pure exocyclic 1-p-tolylsulfinyl-1,3-dienes 1 are readily prepared by the intramolecular Heck
reaction of their corresponding vinyl iodides in the presence of Pd(OAc)2 as catalyst and Ag2CO3 as base. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: Heck reaction; sulfoxides; 1,3-dienes; palladium; cyclization.
During the last two decades the use of sulfoxides as chiral auxiliaries in important C–C forming reac-
tions has been intensively investigated and a wide variety of synthetic applications for the enantioselective
synthesis of natural and non-natural products has been reported.1 For instance, 1,3-dienyl sulfoxides have
received considerable attention as chiral dienes in asymmetric Diels–Alder reactions due to the usually
very high diastereocontrol promoted by the sulfinyl group.2 Among the methods for the stereoselective
synthesis of 1-sulfinyl-1,3-dienes, the oxidation of appropriate thioether precursors,3 the condensation
of stabilized sulfinyl carbanions with carbonyl compounds4 (especially the Wadsworth–Emmons olefi-
nation between sulfinylmethanephosphonates and α,β-unsaturated carbonyl compounds), and the Stille
coupling reaction of vinyl stannanes with β-iodo-α,β-unsaturated sulfoxides,5 have been the most widely
used. As part of an ongoing series of investigations into the applications of sulfoxides in metal-catalyzed
reactions,6 we envisaged that the central C2–C3 bond of 1-sulfinyl-1,3-dienes could be constructed via
a Heck type vinylation reaction on simple α,β-unsaturated sulfoxides. In this direction, we report here
that the previously unreported exocyclic 1-p-tolylsulfinyl-1,3-dienes 1 can be readily prepared by an
intramolecular Heck reaction.7
The model substrate (E)-2 was prepared in two steps from the readily available 5-iodo-5-hexenal8 by
addition of the α-sulfinylcarbanion of p-tolyl methyl sulfoxide (THF, −78°C) and dehydration of the
resulting β-hydroxysulfoxide (MsCl, Et3N; then DBU, CH2Cl2) to give the α,β-unsaturated sulfoxide
2 as a 77/23 mixture of E/Z isomers, which were easily separated by flash chromatography (60% and
∗
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)00079-4
tetl 16357

1984
18% yields, respectively). With substrate (E)-2 in hand, extensive experimentation was undertaken in
order to find appropriate conditions for its intramolecular Heck reaction. In the presence of Pd(OAc)2 as
catalyst, after testing different bases, ligands and solvents, we found that the cyclization occurred mildly
using Ag2CO3 as base6b,c and phosphines as ligands (Scheme 1). As optimal conditions, the reaction of
substrate (E)-2 with Pd(OAc)2 10 mol%, PPh3 20 mol%, Ag2CO3 (2 equiv), in acetonitrile at rt for 24
h afforded cleanly the desired 1-sulfinyl-1,3-diene (E)-1a (78% yield of crude product), which proved to
be rather unstable to chromatographic purification (41% yield after a fast chromatographic purification
on deactivated silica gel).9
Scheme 1. (a) MeSOTol, LDA, THF, −78°C; (b) MsCl, Et3N, CH2Cl2, rt; (c) DBU, rt; (d) Pd(OAc)2, PPh3, Ag2CO3, CH3CN,
rt
To investigate the generality of this kind of Heck reaction the malonate derivatives (E)-3, (E)-4 and
(E)-5 were readily prepared from diethyl malonate following straightforward synthetic sequences based
on successive alkylations and further Wadsworth–Emmons olefinations of the corresponding aldehydes
with ethyl p-tolysulfinylmethanephosphonate.10 The Heck reactions were carried out under the optimal
conditions found for (E)-2 [Pd(OAc)2, PPh3, Ag2CO3, CH3CN, rt] and we found that, although no
reaction at all was observed from the bromo derivative (E)-3, the iodo derivatives (E)-4 and (E)-5 reacted
mildly at rt to give the expected 1,3-dienes (E)-1b and (E)-1c in better yields (64% and 81%, respectively
after chromatographic purification) than in the case of the synthesis of (E)-1a probably due to their
significantly higher stability. We also investigated the Heck reaction of the olefin (Z)-410 under the same
experimental conditions. The cyclization took place at a similar rate to that observed for the isomer (E)-
4, but the process was not stereospecific, affording a 3:1 mixture of both E:Z 1,3-dienes 1b (60% yield)
instead of the exclusive formation of the expected isomer (Z)-1b11 (Scheme 2).
Scheme 2. (a) Pd(OAc)2, PPh3, Ag2CO3, CH3CN, rt
As a synthetically more elaborate case, that could eventually be used in the stereoselective synthesis
of pyrrolizidines,12 the pyrrole derivative (E)-6 was readily prepared from pyrrole 2-carboxaldehyde by
N-allylation with 3-bromo-2-iodopropene under basic conditions (50% NaOH/CH2Cl2, benzyltriethyl-
ammonium chloride, rt) and subsequent olefination with ethyl p-tolysulfinylmethanephosphonate to give
a 67/33 mixture of E/Z isomers (82% yield), which were separated by flash chromatography (Scheme
3). However, the pyrrole (E)-6 failed to react under the usual Heck reaction conditions [Pd(OAc)2, PPh3,
Ag2CO3, CH3CN, rt], its lack of reactivity probably being due to the strain associated with the formation
of the bicyclic 1,3-diene (Z)-1d. After some experimentation, we found that the Heck reaction of (E)-6
occurred under somewhat harsher conditions: Pd(PPh3)4 (20 mol%), Ag2CO3 (2 equiv.) in acetonitrile at
50°C for 5 h, furnishing after chromatographic purification the diene (Z)-1d in 44% yield (74% based on
converted product) along with 40% of starting (E)-6.

1985
Scheme 3.
Having developed a new approach to the stereoselective synthesis of 1-sulfinyl-1,3-dienes, in order to
apply this methodology to asymmetric synthesis the preparation of this type of diene in enantiomerically
pure form was required. To this end, applying the same synthetic procedures, but starting with the
readily available optically pure (S)-ethyl p-tolylsulfinylmethylphosphonate13 instead of its racemic form,
the optically pure substrate (E)-4 of (R) configuration at sulfur was prepared (ee>98%, HPLC, Daicel
Chiralpack AS). Heck reaction of (R)-(E)-4 under the usual conditions afforded the 1,3-diene (R)-(E)-
1b14 without any loss of optical purity (ee>99%, HPLC, Daicel Chiralpack AS), proving that there is no
racemization at sulfur under the experimental conditions of the Heck reaction.
In conclusion, we have demonstrated that 1-p-tolylsulfinyl-1,3-dienes 1 can be readily synthesized
in both racemic and optically pure form by formation of the C2–C3 bond via an intramolecular Heck
reaction. The reactivity of the exocyclic dienes 1 in asymmetric Diels–Alder reactions is currently being
investigated in our laboratory.
Acknowledgements
We are grateful to DGICYT (Ministerio de Educación y Cultura, project PB96-0021) for financial
support.
References
1. For recent reviews, see: (a) Carreño, M. C. Chem. Rev. 1995, 6, 1717. (b) Walker, A. J. Tetrahedron: Asymmetry 1992, 3,
961.
2. For very recent reviews on sulfoxides in asymmetric Diels–Alder reactions, see: (a) García Ruano, J. L.; Cid de la Plata,
B. Top. Curr. Chem. 1999, 204, 1. (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Tetrahedron: Asymmetry
1997, 8, 1339.
3. See, for instance: (a) Gaonac’h, O.; Maddaluno, J.; Chauvin, J.; Duhamel, L. J. Org. Chem. 1991, 56, 4045. (b) Posner, G.
H.; Harrison, W.; Wettlaufer, D. G. J. Org. Chem. 1985, 50, 5041. (c) Overman, L. E.; Petty, C. B.; Ban, T.; Huang, G. T. J.
Am. Chem. Soc. 1983, 105, 6335.
4. For recent references, see: (a) Pindur, U.; Lutz, G.; Rogge, M. J. Heterocycl. Chem. 1995, 32, 201. (b) Arce, E.; Carreño,
M. C.; Cid, M. B.; García Ruano, J. L. Tetrahedron: Asymmetry 1995, 1757. (c) Otten, P. A.; Davies, H. M.; van der Gen, A.
Tetrahedron Lett. 1995, 36, 781. (d) Arce, E.; Carreño, M. C.; Cid, M. B.; García Ruano, J. L. J. Org. Chem. 1994, 59, 3421.
(e) Carreño, M. C.; Cid, M. B.; Colobert, F.; García Ruano, J. L.; Solladié, G. Tetrahedron: Asymmetry 1994, 5, 1439. (f)
Burke, S. D.; Shankaran, K.; Helber, M. J. Tetrahedron Lett. 1991, 32, 4655. (g) Solladié, G.; Ruiz, P.; Colobert, F.; Carreño,
M. C.; García Ruano, J. L. Synthesis 1991, 1011.
5. (a) Paley, R. S.; de Dios, A.; Estroff, L. A.; Lafontaine, J. A.; Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura, M. P.;
Weers, H. L.; Fernández de la Pradilla, R.; Castro, S.; Dorado, R.; Morente, M. J. Org. Chem. 1997, 62, 6326. (b) Paley,
R. S.; de Dios, A.; Fernández de la Pradilla, R. Tetrahedron Lett. 1993, 34, 2429. (c) Farina, V.; Hauck, S. I. J. Org. Chem.
1991, 56, 4317. See also: Bell, A. S.; Fishwick, C. W. G.; Reed, J. E: Tetrahedron 1999, 55, 12313.
6. (a) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7411. (b) Priego, J.; Carretero, J. C. Synlett 1999, 1603. (c) Díaz
Buezo, N.; Alonso, I. Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129.

1986
7. For a review on the intramolecular Heck reaction, see: Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447. For
examples of synthesis of 1,3-dienes by intramolecular Heck reactions, see for instance: Meyer, F. E.; Ang, K.-H.; Steinig,
A. G.; de Meijere, A. Synlett 1994, 191.
8. 5-Iodo-5-hexenal was readily prepared from commercially available 5-hexyn-1-ol by iodination at the triple bond (TMSCl,
NaI, H2O, CH3CN, rt) and PCC oxidation (celite, CH2Cl2, rt).
9. Diene (E)-1a was very prone to suffer isomerization of the exocyclic methylenic double bond to the endocyclic position and
other side reactions. This compound must be rapidly purified by flash chromatography on deactivated silica gel (previously
treated with a 9:1 solution of hexane:Et3N) and kept in the freezer under an argon atmosphere.
10. The malonate derivatives (E)-3, (E)-4 and (E)-5 were readily prepared from diethyl malonate as indicated below (for the
synthesis of related acyclic precursors, see: Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1998,
120, 5335). The Wadsworth–Emmons olefination was in all cases moderately stereoselective, affording mixtures of E/Z
isomers which were easily separated by chromatography.
11. The stereochemical assignment of isomers E/Z 1b was unequivocally established from the important observed NOEs
between the olefinic protons of both double bonds in (E)-1b. As possible mechanistic hypotheses, the low stereoselectivity
in the cyclization of (Z)-4 could be due to either a thermodynamically Z/E palladium catalyzed isomerization of the α,β-
unsaturated sulfinyl moiety [in either the starting compound (Z)-4 or the product 1b] or to the epimerization of the α-
alkylpalladium intermediate generated after the syn-insertion step (for an example of epimerization of an α-alkylpalladium
species in a Heck reaction, see: Friestad, G. K.; Branchaud, B. P. Tetrahedron Lett. 1995, 36, 7047).
12. For a recent review, see: Liddell, J. R. Nat. Prod. Rep. 1998, 15, 363.
13. Mikolajczyk, M.; Midura, W.; Grzejszczak, S.; Zatorski, A.; Chefczynska, A. J. Org. Chem. 1978, 43, 473. Alternatively,
this optically pure phosphonate can be prepared by phosphorylation of the carbanion of (R) p-tolyl methyl sulfoxide with
diethyl chlorophosphate.
14. General procedure: Synthesis of (R)-(E)-1b. To a suspension of Pd(OAc)2 (2.2 mg, 0.01 mmol), PPh3 (5.4 mg, 0.02 mmol)
and Ag2CO3 (32 mg, 0.12 mmol) in 4 mL of dry CH3CN, was added 1,3 diene (R)-(E)-4 (50 mg, 0.1 mmol) in 2 mL of
CH3CN under an argon atmosphere. The mixture was vigorously stirred at rt for 20 h, filtered over Celite and concentrated.
The residue was purified by flash chromatography (hexane/ethyl acetate, 5/1) to afford 1,3 diene (R)-(E)-1b (24 mg, 64%).
1
[α]D=−26 (c 1, acetone); ee>99% (HPLC, Daicel Chiralpack AS, 75:25 hexane:isopropanol). H NMR (CDCl3): 1.25 (t,
J=7.1 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 2.39 (s, 3H), 2.97 (dt, J=16.7 and 2.1 Hz, 1H), 3.15 (dt, J=16.7 and 2.1 Hz, 1H), 3.45
(d, J=2.1 Hz, 2H), 4.20 (m, J=7.1 Hz, 4H), 5.17 (t, J=1.7 Hz, 1H), 5.47 (t, J=2.1 Hz, 1H), 6.44 (t, J=2.1 Hz, 1H), 7.31 and
7.40 (AA0BB0 system, 4H). 13C NMR (CDCl3): 13.9, 21.2, 38.7, 40.2, 57.7, 61.7, 110.8, 124.0, 126.5, 129.8, 141.0, 143.2,
147.7, 169.7, 170.4. HRMS: (EI) m/z calcd for M+: 376.1351, found: 376.1345.