A stereoselective Suzuki cross-coupling strategy for the synthesis of ethyl-substituted conjugated dienoic esters and conjugated dienones

Article abstract of DOI:10.1055/s-2006-958406

A stereoselective approach towards ethyl-substituted conjugated dienoic esters and dienones utilising a Suzuki cross-coupling reaction has been achieved. In addition, a method for their conversion into the corresponding ethyl ketones is presented. Georg T

Full text of DOI:10.1055/s-2006-958406

LETTER
3457
A Stereoselective Suzuki Cross-Coupling Strategy for the Synthesis of
Ethyl-Substituted Conjugated Dienoic Esters and Conjugated Dienones
S
uzuki Cross-Coup
a
ling Appro
n
ach towards
i
Conjug
e
a
ted Dieno
l
ic
E
ster
s
and
K
Dienones eck, Thierry Muller, Stefan Bräse*
University of Karlsruhe (TH), Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)6088581; E-mail: braese@ioc.uka.de
Received 24 July 2006
OH
B
Abstract: A stereoselective approach towards ethyl-substituted
conjugated dienoic esters and dienones utilising a Suzuki cross-cou-
pling reaction has been achieved. In addition, a method for their
conversion into the corresponding ethyl ketones is presented.
OH
3
Key words: cross-coupling, dienoic esters, Suzuki reaction, stereo-
selective, triflate
O
R
TfO
O
2
Conjugated dienoic esters and conjugated dienones 1
(Figure 1) are useful building blocks for organic synthe-
(E)-4 R = OMe
(E)-5 R = Et
sis, being precursors for prominent structural features of a
Scheme 1 Retrosynthetic analysis of 5-ethyl-7-phenylhepta-4,6-
dien-3-one (2)
number of natural products, including carotenoids.1
R2
R3
R1 = aryl, alkyl
R2 = alkyl
Thus, 2 can be formed by reaction of inexpensive com-
mercially available (E)-2-phenylvinylboronic acid (3) and
vinyl triflate precursor 4 or 5. The ester derivative 4 was
first synthesised starting from 3-oxopentanoic acid
methyl ester (6) following a literature precedence on a
very similar system7 using triethylamine and trifluo-
romethanesulfonic anhydride, which provided the product
in a combined yield of 61% in a 5:7 ratio in favour of the
undesired Z isomer (Z)-4 (Scheme 2). The isomers could
be separated by column chromatography. When sodium
hydride and N-phenylbis(trifluoromethanesulfonimide)8
were utilised, the desired E isomer (E)-4 could be ob-
tained exclusively in a yield of 71%.
R1
O
R3 = alkyl, alkoxy
1
Figure 1 Alkyl-substituted dienoic esters (only E,E isomer shown
for simplicity)
The unsubstituted and methyl-substituted compounds
(R2 = H, Me) can be easily prepared by aldol reaction,
though care has to be taken to establish the correct stereo-
chemistry across the double bonds. Other possibilities in-
clude the utilisation of Wittig-type,2 Horner–Wadsworth–
Emmons-type,3 or Julia-type4 olefination strategies for the
formation of the double bonds. However, all these
reactions suffer from a sometimes insufficient degree of
stereocontrol and low reaction yields in the case of bulkier
side chains. To the best of our knowledge, Suzuki cross-
coupling strategies involving vinyl triflates have not been
applied in the synthesis of ethyl-substituted dienoic ester
and dienone derivatives, though there are a number of
examples of other cross-coupling reactions, namely Heck
and Stille reactions, in the synthesis of retinal and ana-
logues.5 In this paper we present a novel stereoselective
approach towards conjugated dienoic esters featuring a
Suzuki cross-coupling reaction.6 In addition, we present a
synthesis of 5-ethyl-7-phenylhepta-4,6-dien-3-one (2) by
cross-coupling of a ketone-derived vinyl triflate and a
versatile synthetic strategy for the conversion of the cor-
responding dienoic ester into the ketone 2. The synthetic
strategy for 2 is summarised in Scheme 1.
Unknown ketone derivative 5 was obtained from heptane-
3,5-dione (7) using trifluoromethanesulfonic anhydride
and triethylamine in a combined yield of 90% as a 1:1
mixture of both isomers. The isomers could also be sepa-
rated by column chromatography, but the E isomer (E)-5
decomposed rapidly.
Et3N, Tf2O
CH2Cl2
–78 °C to r.t., 20 h
O
O
O
O
O
O
OMe
O
OMe
OMe
TfO
TfO
TfO
61%, E/Z = 5:7
6
6
4
NaH, PhN(Tf)2
THF, r.t., 3 h
OMe
O
71%
(E)-4
Et3N, Tf2O
CH2Cl2
–78 °C to r.t., 20 h
O
90%, E/Z = 1:1
SYNLETT 2006, No. 20, pp 3457–3460
Advanced online publication: 08.12.2006
1
8
.1
2
.2
0
0
6
7
5
DOI: 10.1055/s-2006-958406; Art ID: G24306ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of vinyl triflates 4 and 5

3458
D. Keck et al.
LETTER
As the desired triflate isomer (E)-5 could not be isolated the stereochemical information across the double bond
due to its latent lability, a nonaflate analogue was pre- conjugated to the ester, possibly due to a pronounced con-
pared as these are also known to be potent leaving groups figurational lability of triflate 5 under the reaction condi-
in cross-coupling reactions.9 Starting from heptane-3,5- tions. Gratifyingly, the products were again separable by
dione (7), the corresponding trimethylsilyl ether 8 was column chromatography. Nonaflate 9 did not provide any
synthesised using triethylamine und trimethylsilyl chlo- product.
ride in hexanes.10 Ether 8 was then transformed into nona-
To explore the scope and limitations of the Suzuki
approach to conjugated dienoic acid esters, a series of
flate 9 by addition of tetrabutylammonium fluoride and
nonaflate fluoride9a yielding the desired product in 54%
commercially available vinylboronic acid derivates was
yield over both steps as a single stereoisomer (Scheme 3).
employed under the standard conditions. The results are
summarised in Table 2.
Et3N, TMSCl
O
O
hexanes, r.t., 20 h
Table 2 Cross-Coupling of Boronic Acids 12 with Vinyl Triflate
(E)-4a
TMSO
O
7
8
Pd(PPh3)4, Na2CO3,
triflate (E)-4
dioxane–H2O
80 °C, 20 h
TBAF, NfF
THF, r.t., 50 h
OMe
O
OH
B
NfO
O
R
R
OH
54% over 2 steps
9
12a–f
13a–f
Scheme 3 Synthesis of vinyl nonaflate 9
R
Yield (E + Z)
E/Z ratio
77%
9:1
The three triflates (E)-4, (Z)-4 and 5 and nonaflate 9 were
then employed in a Suzuki reaction6 using standard condi-
tions [Pd(PPh3)4, Na2CO3, dioxane–H2O].11 The results
are summarised in Table 1.
12a
12b
12c
83%
53%
71%
19:1
9:1
Table 1 Results of the Cross-Coupling Reactiona
Pd(PPh3)4, Na2CO3
triflate/nonaflate
dioxane–H2O
80 °C, 18–21 h
OH
B
R
OH
O
19:1
3
10 R = OMe
R = Et
2
Reactant
Yield
72%
77%
81%
64%
E:Z ratio
5:7
12d
12e
12f
(E)-4/(Z)-4 (5:7)
(E)-4
86%
38%
3:1
F
pure E
pure Z
1:1
(Z)-4
19:1
(E)-5
MeO
(E)-9
no reaction
–
a Reaction conditions: Pd(PPh3)4 (0.04 equiv), Na2CO3 [2 M in H2O;
1.5 equiv], boronic acid (1.0 equiv), triflate/nonaflate (1.0 equiv),
dioxane (2 mL/mmol), 80 °C, 18–21 h.
a Reaction conditions: Pd(PPh3)4 (0.04 equiv), Na2CO3 [2 M in H2O;
1.5 equiv], boronic acid (1.0 equiv), triflate (E)-4 (1.0 equiv), dioxane
(2 mL/mmol), 80 °C, 20 h.
The reaction of ester derivatives (E)-4 and (Z)-4 proceed-
ed uneventfully. When the crude mixture of isomers was
subjected to the cross-coupling conditions, the same ratio
of product isomers was obtained in a combined yield of
72%. When the pure isomers, (E)-4 and (Z)-4, were em-
ployed the corresponding esters (E)-10 and (Z)-10 were
formed in 77% and 81% yields, respectively, and no signs
of the other isomer were detected. When ketone derivative
5 was used under the same reaction conditions, dienone 2
was formed in a yield of 64%, but with complete loss of
When (E)-1-heptenylboronic acid (12a) was subjected to
the standard conditions, the desired product (E)-13a was
obtained in a satisfactory combined yield of 77% along
with approximately 10% of the Z isomer. The reason for
this partial isomerisation could not be resolved; explana-
tions are the possible potential configurational lability of
the vinyl triflate 4 or a base-catalyzed isomerisation of the
reaction product. Steric interactions contribute to these
findings. When (E)-2-cyclohexylvinylboronic acid (12b)
was employed, conjugated dienoic ester 13b could be
Synlett 2006, No. 20, 3457–3460 © Thieme Stuttgart · New York

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

3460
D. Keck et al.
LETTER
(13) Prepared according to: Paterson, I.; Florence, G. J.; Gerlach,
K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123,
9535.
(15) Spectroscopic data for (Z)-2: Rf = 0.58 (hexanes–Et2O, 9:1).
1H NMR (400 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H,
CH3CH2C=C), 1.13 (t, J = 7.5 Hz, 3 H, CH3CH2CO), 2.39–
2.45 (m, 2 H, CH3CH2C=C), 2.44–2.50 (m, 2 H,
(14) Spectroscopic data for (E)-2: Rf = 0.65 (hexanes–Et2O, 9:1).
1H NMR (400 MHz, CDCl3): d = 1.18 (t, J = 7.3 Hz, 3 H,
CH3CH2C=C), 1.23 (t, J = 7.5 Hz, 3 H, CH3CH2CO), 2.60 (q,
J = 7.3 Hz, 2 H, CH3CH2C=C), 2.95 (q, J = 7.5 Hz, 2 H,
CH3CH2CO), 6.27 (s, 1 H, C=CHCO), 6.76 (d, J = 16.2 Hz,
1 H, PhC=CH), 7.07 (d, J = 16.2 Hz, 1 H, PhCH=C), 7.32–
7.45 (m, 3 H, ArH), 7.51–7.62 (m, 2 H, ArH). 13C NMR (100
MHz, CDCl3): d = 8.2 (CH3), 14.1 (CH3), 21.1 (CH2), 37.8
(CH2), 123.0 (CH), 125.6 (CH), 127.0 (CH), 127.4 (CH,
CAr), 128.6 (CH), 128.7 (CH, CAr), 130.9 (CH, CAr), 134.6
(CH), 136.5 (C, CAr), 156.5 (C), 201.3 (C). IR (film on
KBr): 3031 (w), 2973 (m), 2935 (w), 2876 (w), 1677 (m),
1615 (w), 1577 (m), 1466 (w), 1448 (w), 1391 (w), 1172 (w),
1125 (m), 1040 (m), 962 (m), 836 (w), 750 (m), 691 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 214 (73) [M+], 199 (30),
185 (100), 157 (32), 141 (43), 129 (54), 115 (41), 91 (32).
HRMS: m/z calcd for C15H18O: 214.1358; found: 214.1357.
Anal. Calcd for C15H18O: C, 84.07; H, 8.47. Found: C, 84.15;
H, 8.44.
CH3CH2CO), 6.02 (s, 1 H, C=CHCO), 6.76 (d, J = 16.2 Hz,
1 H, PhC=CH), 7.17–7.30 (m, 3 H, ArH), 7.45–7.50 (m, 2 H,
ArH), 8.27 (d, J = 16.7 Hz, 1 H, PhCH=C). 13C NMR (100
MHz, CDCl3): d = 8.1 (CH3), 13.9 (CH3), 26.8 (CH2), 37.8
(CH2), 123.0 (CH), 125.9 (CH), 127.0 (CH), 128.5 (CH,
CAr), 128.6 (CH), 128.7 (CH, CAr), 130.9 (CH, CAr), 135.3
(CH), 136.8 (C, CAr), 154.4 (C), 202.0 (C). IR (film on
KBr): 2973 (m), 2936 (w), 2876 (w), 1676 (m), 1615 (m),
1579 (m), 1449 (w), 1375 (w), 1199 (w), 1127 (m), 1040
(w), 973 (m), 753 (w), 691 (m) cm–1. MS (EI, 70 eV): m/z
(%) = 214 (29) [M+], 185 (100), 141 (17), 129 (34), 115 (20),
91 (12). HRMS: m/z calcd for C15H18O: 214.1358; found:
214.1354. Anal. Calcd for C15H18O: C, 84.07; H, 8.47.
Found: C, 84.44; H, 8.43.
Synlett 2006, No. 20, 3457–3460 © Thieme Stuttgart · New York