Scheme 1
Table 2. Intramolecular Heck Reaction of Sulfinylated Dienes
3a
entry
diene
ligand
conv(%)b
4:5 ratiob
A:B ratiob
1
2
3
4
5
6
7
(Z)-3a
(Z)-3b
(Z)-3c
(Z)-3c
(Z)-3c
(Z)-3c
(E)-3c
PPh3
PPh3
PPh3
>98
60
>98
14
35
80
>98:<2
>98:<2
86:14
>98:<2
>98:<2
>98:<2
40:60
54:46c
83:17c
>98:<2
>98:<2
>98:<2
>98:<2
20:80
dppp
d p p f
PPh3
>98
sulfoxides 3 as model substrates due to the precedented Heck
cyclizations of 2-halo-1,6-dienes.2 Dienes 3 were readily
prepared as E/Z mixtures by Wadsworth-Emmons olefina-
tion of the phosphonates 17 with the aldehyde 28 (Scheme
1, Table 1). The major Z isomers9 were separated by flash
a Reaction conditions: Pd(OAc)2 (10 mol %), ligand (ratio P/Pd ) 2:1),
Ag2CO3 (200 mol %), CH3CN, rt, 24 h. b Estimated by 1H NMR on the
crude mixtures. c The stereochemical assignment of both isomers has not
been established.
A clean reaction was observed at rt using PPh3 as the
ligand (entries 1-3). The bulky tert-butyl sulfoxide 3b (entry
2) was significantly less reactive than the aryl sulfoxides 3a
and 3c. As expected, 1,6-dienes 3 reacted exclusively by a
5-exo cyclization mode. Furthermore, selectivity was ob-
served between the two possible final â-hydride elimination
pathways. The (Z) dienes afforded predominantly 1,4-diene
4 (entries 1-6), and the opposite regiochemical behavior was
observed from the (E) dienes (entry 7). Interestingly, a
remarkable dependence of the stereoselectivity with the
substitution at sulfur was observed. The cyclization stereo-
selectivity of p-tolyl sulfoxide (Z)-3a was low (entry 1), and
tert-butyl sulfoxide (Z)-3b gave moderate stereoselectivity
(entry 2). In contrast, the Heck reaction of 2-(N,N-dimethyl-
amino)phenylsulfoxide (Z)-3c occurred with complete dia-
stereocontrol,10 leading to the exclusive formation of 4cA
(entry 3), along with the minor formation of 1,3-diene 5c.
After a brief study of the effect of the ligand (entries 3-6),
we found that in the presence of dppf the cyclization was
completely regioselective and diastereoselective (entry 6).
As optimal experimental conditions, the reaction of (Z)-3c
with Pd(OAc)2 (10 mol %), Ag2CO3 (200 mol %), and dppf
(10 mol %) in acetonitrile at 60 °C for 5 h afforded 4cA in
75% yield after chromatographic purification. Although we
were unable to establish the relative configuration of isomers
4A and 4B by NMR, the configuration of 4cA could be
unequivocally deduced from that of its diol 6, a crystalline
derivative obtained by dihydroxylation of 4cA (OsO4, Me3-
NO) whose configuration was determined by X-ray analysis11
(Figure 1).
Table 1. Synthesis of Sulfinylated Dienes 3 by
Wadsworth-Emmons Olefination
phosphonate
R
diene
Z:Ea
yield (%)b
1a
1b
1c
p-Tol
t-Bu
o-(Me2N)C6H4
3a
3b
3c
50:50
98:2
85:15
77
83 (83)c
88 (60)c
a Determined by 1H NMR on the crude mixtures. b In pure products.
c Yield in pure (Z) diene.
chromatography, and their Heck reactions were carried out
in the presence of the couple Pd(OAc)2/Ag2CO3 (Scheme 2,
Scheme 2
Table 2), which was found optimal in the case of the Heck
reactions of sulfinyldihydrofurans.5b
(6) The use of sulfoxides as chiral auxiliaries in metal-catalyzed reactions
has not been extensively explored. Recent references: (a) Adrio, J.;
Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7411. (b) Henrich, M.;
Delgado, A.; Molins, E.; Roig, A.; Llebaria, A. Tetrahedron Lett. 1999,
40, 4259. (c) Paley, R. S.; Estroff, L. A.; McCulley, D. J.; Mart´ınez-Cruz,
L. A.; Jime´nez Sa´nchez, A.; Cano, F. H. Organometallics 1998, 17, 1841.
(d) Paley, R. S.; Rubio, M. B.; Ferna´ndez de la Pradilla, R.; Dorado, R.;
Hundal, G.; Mart´ınez-Ripoll, M. Organometallics 1996, 15, 4672. For the
use of sulfoxides as chiral ligands, see: Hiroi, K.; Suzuki, Y.; Abe, I.
Tetrahedron: Asymmetry 1999, 10, 1173 and references therein.
(7) Racemic phosphonates 1 (as mixtures of both diastereomers) were
readily prepared in two steps: initial phosphorylation of the R-sulfinyl
carbanion of the corresponding methyl sulfoxide with diethyl chlorophos-
phate followed by methylation (LDA, THF, and then MeI).
To determine the generality of this type of diastereo-
selective Heck reaction, the chain-unsubstituted substrate (Z)-
7, the ethyl derivative (Z)-8, and the 1,7-diene (Z)-9 were
readily prepared,12 and their Heck reactions were studied
under the optimized conditions previously found for (Z)-3c.
(8) Aldehyde 2 was prepared from diethyl malonate by two sequential
alkylations (bromoacetaldehyde diethyl acetal first and 3-bromo-2-iodo-1-
propene second) and acid hydrolysis of the acetal moiety.
(9) The E/Z configuration of olefins 3 was clear from spectral evidence.
For instance, the chemical shift of the olefinic proton is significantly higher
in the E isomers than in the Z ones (∆δ ) 0.47-0.53 ppm, CDCl3) as a
consequence of the deshielding cis-effect of the sulfinyl group. This
assignment has also been corroborated by NOE experiments.
(10) With these preliminary results, it does not appear to be easy to
determine unequivocally the origin of the high stereochemical control
exerted by the 2-(N,N-dimethylamino)phenylsulfinyl group in the Heck
reactions. At present, we are investigating if this effect could be mainly
due to steric reasons, conformational preferences around the C-S bond in
the reactants, or a chelation control directed by a previous coordination of
the intermediate palladium cationic species with the dimethylamino moiety
prior to the insertion step.
1452
Org. Lett., Vol. 2, No. 10, 2000