LETTER
Suzuki Cross-Coupling Approach towards Conjugated Dienoic Esters and Dienones
3459
isolated in a yield of 83% with a E/Z ratio of about 19:1. In addition, we were able to prepare both stereoisomers of
Boronic acids 12c and 12d gave similar results, the yield 5-ethyl-7-phenylhepta-4,6-dien-3-one (2) using two dif-
being 83% for 13c and 71% for 13d, respectively, with ferent approaches. Direct Suzuki cross-coupling of (E)-
E/Z ratios in the same range as in the first two cases. The phenylvinylboronic acid 3 with ketone-derived triflate 5
heteroatom-substituted aromatic systems 12e and 12f provided a separable 1:1 mixture of isomers in a yield of
proved to be more difficult substrates in this reaction. 64%, thus enabling us to produce (E)-2 and (Z)-2 in a
When (E)-2-(fluorophenyl)vinylboronic acid (12e) was yield of 32%. Further transformations using conjugated
used, the desired product 13e could be obtained in a yield dienoic ester derivative 10 led to the formation of (Z)-2 in
of 86%, but with a moderate E/Z ratio of 3:1. A possible a yield of 39% over three steps starting from (Z)-4. The
explanation could be the electron-withdrawing aromatic corresponding E isomer could be obtained in a yield of
fluorine substituent that also requires a lowered electron- 45%.
density in the conjugated olefinic bonds, possibly facili-
tating base-catalysed isomerisation of the terminal double
bond. In contrast, when (E)-2-(4-methoxyphenyl)vinyl-
References and Notes
(1) For example: (a) Carotenoids: Isolation and Analysis, Part
1A; Britton, G.; Liaaen-Jensen, S.; Pfander, H., Eds.;
Birkhäuser: Basel, 1995. (b) Key to Carotenoids; Pfander,
H., Ed.; Birkhäuser: Basel, 1987.
(2) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953,
580, 44.
(3) (a) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem.
Ber. 1958, 91, 61. (b) Horner, L.; Hoffmann, H. M. R.;
Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499.
(c) Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961,
83, 1733.
boronic acid (12f) as employed, the reaction showed an
improved E/Z ratio of 19:1 under standard conditions, but
a lower reaction yield of 38%. Substantial amount of
boronic acid 12f could be reisolated from the reaction
mixture, indicating a slower reaction in this special case.
This finding can be attributed to the fact that the Suzuki
reaction requires electrophilic attack on the formed palla-
dium intermediate, which is slower due to the electron-
donating properties of the aromatic methoxy substituent.
With these results in hand, we studied the conversion of
conjugated esters (E)-10 and (Z)-10 into the desired
ketone 2. To achieve the transformation, we relied upon
the two-step strategy which is summarised in Scheme 4.
(4) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833.
(5) For example: (a) Wada, A.; Ieki, Y.; Nakamura, S.; Ito, M.
Synthesis 2005, 1581. (b) Wada, A.; Fukunaga, K.; Ito, M.
Synlett 2001, 800.
(6) (a) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457.
(b) Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I.; de Meijere, A., Eds.; Wiley-
Interscience: New York, 2002.
(7) Saulnier, M. G.; Kadow, J. F.; Tun, M. M.; Langley, D. R.;
Vyas, D. M. J. Am. Chem. Soc. 1989, 111, 8320.
(8) Hansen, A. L.; Skrydstrup, T. J. Org. Chem. 2005, 70, 5997.
(9) (a) Lyapkalo, I. M.; Webel, M.; Reißig, H.-U. Eur. J. Org.
Chem. 2002, 1015. (b) Bräse, S.; de Meijere, A. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2545; Angew. Chem. 1995,
107, 2741. (c) Voigt, K.; von Zezschwitz, P.; Rosauer, K.;
Lansky, A.; Adams, A.; Reiser, O.; de Meijere, A. Eur. J.
Org. Chem. 1998, 1521. (d) Bräse, S. Synlett 1999, 1654.
(e) Rottlaender, M.; Knochel, P. J. Org. Chem. 1998, 63,
203. (f) Kreis, M.; Friedmann, C. J.; Bräse, S. Chem. Eur. J.
2005, 11, 7387.
OMe
O
i-PrMgCl, MeNHOMe·HCl
THF, –20 °C, 16 h
83% (75% Z)
10
Me
OMe
O
N
EtMgBr
THF, 0 °C to r.t., 20 h
2
71% (65% Z)
11
Scheme 4 Synthesis of (E)-2 and (Z)-11 (shown for E isomer, yields
for Z isomer in parentheses)
(10) Chan, T. H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
The esters were first transformed into the corresponding
Weinreb amides12 in 83% (E isomer) and 75% (Z isomer)
yields with complete retention of the double-bond stereo-
chemistry. The amides were then subjected to a Grignard
reaction using ethylmagnesium bromide13 which provided
the stereoisomeric ketones (E)-214 and (Z)-215 in 71% and
65% yields, respectively. Again, this transformation did
not lead to a substantial degree of isomerisation of the
double-bond geometry.
(11) Representative Experimental Procedure: Na2CO3 (1.15 g,
10.8 mmol, 1.5 equiv) was dissolved in H2O (5.4 mL) under
an argon atmosphere. (E)-Trifluoromethanesulfonyloxy-
pent-2-enoic acid methyl ester [(E)-4; 1.89 g, 7.20 mmol,
1.0 equiv] and (E)-2-phenylvinylboronic acid (3; 1.08 g,
7.20 mmol, 1.0 equiv) in dioxane (16 mL) were added. The
solution was degassed, Pd(PPh3)4 (333 mg, 0.29 mmol,
0.04 equiv) was added and the mixture was heated to 80 °C
for 20 h. After cooling, the reaction was quenched with H2O
(75 mL). Et2O (80 mL) was added, the phases were
separated and the aqueous phase was extracted with Et2O
(3 × 60 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude product was
purified by column chromatography (silica gel, hexanes–
Et2O, 19:1) yielding (E)-10 as a yellow oil (1.20 g, 5.55
mmol, 77%).
In conclusion, the Suzuki cross-coupling approach toler-
ates a wide variety of vinylboronic acid derivatives and
provides the desired conjugated dienoic esters in good to
excellent yields and stereoselectivities. Thus, this strategy
provides a novel versatile entry into this class of sub-
stances which is difficult to synthesise by other methods.
(12) Williams, J. M.; Johnson, R. B.; Yasuda, N.; Marchesini, G.
Tetrahedron Lett. 1995, 36, 5461.
Synlett 2006, No. 20, 3457–3460 © Thieme Stuttgart · New York