Novel Zn/ZnI2-promoted cross-coupling of acrylic acid esters with arylaldehydes to α-aroyladipic acid esters

Article abstract of DOI:10.1039/b208608e

Cross-coupling of alkyl acrylates and arylaldehydes was achieved by treatment with metallic zinc and zinc(II) iodide in DMF, giving dialkyl α-aroyladipates in moderate yields.

Full text of DOI:10.1039/b208608e

Novel Zn/ZnI2-promoted cross-coupling of acrylic acid esters with
arylaldehydes to a-aroyladipic acid esters†
Hidehiro Sakurai, Hiroki Takeuchi and Toshikazu Hirao*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Yamada-oka, Suita, Osaka
565-0871, Japan. E-mail: hirao@chem.eng.osaka-u.ac.jp
Received (in Cambridge, UK) 3rd September 2002, Accepted 6th November 2002
First published as an Advance Article on the web 20th November 2002
Cross-coupling of alkyl acrylates and arylaldehydes was
achieved by treatment with metallic zinc and zinc(II) iodide
in DMF, giving dialkyl a-aroyladipates in moderate yields.
solvent such as DMA, DMI or NMP, DMF gave the best
result.
The benzoyl group at the a-position seems to be derived by
aldol-type reaction, followed by oxidation of the thus-generated
alcoholic intermediate. When PhCDO was treated with Zn/ZnI2
in the presence of tert-butyl acrylate under the similar
conditions, the deuterium was selectively introduced into the d-
position of 1b. A reaction path via intermolecular Oppenauer
oxidation between the alcoholic intermediate and benzaldehyde
might be excluded because only one D was detected in the co-
produced benzyl alcohol (Scheme 2).
The reaction was found to be affected by the substituent on
aldehydes (Scheme 3).6 The yields of 1 in the reaction of tert-
butyl acrylate with p-methyl- (weakly electron-donating group)
and p-chloro- (weakly electron-withdrawing group) benzalde-
hyde were 36% and 38%, respectively, which are almost the
same as that with benzaldehyde (38%). On the other hand, the
reaction did not take place with the aldehydes bearing a strongly
donating group such as p-methoxybenzaldehyde. As for the
aldehydes with a strong electron-withdrawing group such as p-
trifluoromethylbenzaldehyde, 1g was not obtained with the
quantitative formation of the pinacol coupling product.
No reductive coupling of methyl acrylate proceeded in the
absence of an aldehyde, indicating that the aldehyde might be
indispensable for the reductive process. As a possible explana-
tion, a complex generated from Zn, ZnI2, and an aldehyde might
be involved to promote the reductive 1,4-coupling (Scheme 4).
The thus-formed zinc dienolate A reacts with the aldehyde to
afford the zinc chelate C. Another pathway to C depends on the
Reductive coupling of carbonyl compounds (pinacol coupling)1
or a,b-unsaturated carbonyl/carboxyl compounds2 is one of the
important methods for the construction of a highly function-
alized framework. Cross-coupling of carbonyl compounds with
a,b-unsaturated esters can also be achieved by SmI2, giving the
g-hydroxy esters or g-lactones with good stereoselectivity.3
Metallic zinc is widely utilized as a relatively mild reducing
reagent and addition of an activator such as acids or Lewis acids
is required to enhance the reactivity.4 Another role of zinc is
based on a reductant towards a co-existing metallic salt,
generating the reactive low-valent metal species. For example,
recent reports from our laboratory have demonstrated a catalytic
pinacol coupling reaction promoted by the combination of a
catalytic amount of vanadium or titanium salt with metallic zinc
in the presence of a silylating or acylating reagent.5 In this paper
we report that Zn/ZnI2 promotes the novel 2+1 coupling of an
acrylic acid ester and an aromatic aldehyde to give the
corresponding a-aroyladipate.
When methyl acrylate (1 mmol) and benzaldehyde (2 mmol)
were treated with metallic zinc (4 mmol) and zinc(II) iodide (1
mmol) in DMF at 70 °C for 24 h, dimethyl a-benzoyladipate
(1a) was obtained in 50% yield, accompanied by the benzyl
alcohol and the pinacol coupling derivative in 19% and 11%
yields, respectively (Scheme 1).
It is noteworthy that 1a was not produced in the absence of
Zn(II) salt. g-Hydroxy ester, g-lactone and other reductive cross-
coupling products were not detected in the reaction mixture.
Other Zn(II) salts such as Zn(OAc)2 or ZnCl2 also promoted the
reaction, but ZnI2 was found to be more effective. The reaction
did not take place using a less polar solvent such as THF or a
protic solvent such as MeOH. Among the non-protic polar
Scheme 2
Scheme 1
† Electronic supplementary information (ESI) available: typical experi-
mental procedure and characterization data. See http://www.rsc.org/
suppdata/cc/b2/b208608e/
Scheme 3
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This journal is © The Royal Society of Chemistry 2002

Scheme 4
3 (a) K. Otsubo, J. Inanaga and M. Yamaguchi, Tetrahedron Lett., 1986,
27, 5763; (b) M. Kawatsura, F. Matsuda and H. Shirahama, J. Org.
Chem., 1994, 59, 6900; (c) M. Kawatsura, F. Dekura, H. Shirahama and
F. Matsuda, Synlett, 1996, 373; (d) S. Fukuzawa, K. Seki, M. Tatsuzawa
and K. Mutoh, J. Am. Chem. Soc., 1997, 119, 1482.
4 (a) E. Erdik, Organozinc Reagents in Organic Synthesis, CRC Press,
Boca Raton, FL, 1996; (b) Organozinc Reagents: A Practical Approach,
eds. P. Knochel and P. Jones, Oxford University Press, Oxford, 1999.
5 (a) T. Hirao, H. Takeuchi, A. Ogawa and H. Sakurai, Synlett, 2000, 1658;
(b) T. Hirao, B. Hatano, Y. Imamoto and A. Ogawa, J. Org. Chem., 1999,
64, 7665; (c) T. Hirao, B. Hatano, M. Asahara, Y. Muguruma and A.
Ogawa, Tetrahedron Lett., 1998, 39, 5247; (d) T. Hirao, M. Asahara, Y.
Muguruma and A. Ogawa, J. Org. Chem., 1998, 63, 2812; (e) T. Hirao,
T. Hasegawa, Y. Muguruma and I. Ikeda, J. Org. Chem., 1996, 61, 366.
A review: T. Hirao, Synlett, 1999, 175.
6 A typical procedure: a 30 mL two-necked round-bottomed flask was
charged with 260 mg (4 mmol) of zinc powder, flame-dried, and then
purged with argon. A DMF (4 mL) solution of ZnI2 (319 mg, 1 mmol) and
methyl acrylate (90 mL, 1 mmol) was added via syringe. After the mixture
was heated at 70 °C, benzaldehyde (212 mg, 2 mmol) was added to the
mixture, which was stirred at 70 °C for 24 h. After cooling down to room
temperature, the mixture was diluted with ether (10 mL) and then 1.5 M
HCl solution (10 mL) was added. After stirring for 10 min, the mixture
was filtered through Celite and the aqueous phase extracted with ether (20
mL 3 3). The combined organic phase was washed with H2O then brine,
dried over MgSO4, and evaporated in vacuo. Purification by silica-gel
colomn chromatography gave the pure product 1a as a colorless oil (139
mg, 50% yield). 1a: 1H NMR (400 MHz, CDCl3) d 1.92–2.13 (2H, m),
2.46 (2H, t, J = 7.0 Hz), 3.04–3.17 (2H, m), 3.50–3.56 (1H, m), 3.71 (3H,
s), 3.74 (3H, s), 7.44 (2H, t, J = 8.5 Hz), 7.52 (1H, t, J = 8.5 Hz), 7.94
(2H, d, J = 8.5 Hz). 13C NMR (100 MHz, CDCl3) d 27.1 (CH2), 31.8
(CH2), 39.7 (CH), 40.5 (CH2), 51.8 (OCH3), 52.0 (OCH3), 128.0 (CH),
128.5 (CH), 133.2 (CH), 136.4 (C), 173.0 (CNO, ester), 175.0 (CNO,
ester), 197.4 (CNO, ketone) ppm. IR (neat) 2920, 1735, 1685, 1444, 1371,
1218, 1169 cm21. Anal. Found: C, 64.68; H, 6.55%. Calc. for C15H18O5:
C, 64.74; H, 6.53%.
Scheme 5
Lewis-acid promoted Baylis–Hillman reaction7 to generate B,
followed by the reductive 1,4-coupling with the acrylate.8 From
the zinc chelate C, 1,5-hydrogen transfer takes place to give 1,
which is supported by the result with PhCDO as shown in
Scheme 2. The 1,5-hydrogen shift could be similar to Ti-
shchenko reaction.9 In the present reaction, however, the zinc
species appears to affect a redox process. If the proton or
hydride shift takes place, the chelated Zn2+ would be reduced to
Zn0. Zn+ would be generated in the radical process. In both
cases, the combination of Zn/ZnI2 is assumed to play an
important role to promote such a process.
As described above, Zn/ZnI2 promoted the 2+1 cross-
coupling reaction of acrylic acid ester and aromatic aldehyde to
give the a-aroyladipic acid ester. Combination of Zn, Zn(II) salt
and aromatic aldehyde appears to be essential to promote the
reaction effectively. Further investigations including the mech-
anistic study and scope of the reaction are in progress.
The use of the facilities of the Analytical Center, Faculty of
Engineering, Osaka University is acknowledged. H. S. thanks
the Fujisawa Foundation for financial support.
7 (a) H.-X. Wei, S.-H. Kim, T. D. Caputo, D. W. Purkiss and G. Li,
Tetrahedron, 2000, 56, 2397; (b) M. Shi, J.-K. Jiang and S.-C. Cui,
Tetrahedron, 2001, 57, 7343; (c) M. Shi and C.-J. Wang, Helv. Chim.
Acta, 2002, 85, 841.
Notes and references
1 (a) T. Mukaiyama, Angew. Chem., Int. Ed. Engl., 1977, 16, 817; (b) C.
Betschart and D. Seebach, Chimia, 1989, 43, 39; (c) A. Fürstner and B.
Bogdanovic, Angew. Chem., Int. Ed. Engl., 1996, 35, 2442.
8 An lternative mechanism involving a one-electron reduction process is
2 (a) K. Takaki, F. Beppu, S. Tanaka, Y. Tsubaki, T. Jintoku and Y.
Fujiwara, J. Chem. Soc., Chem. Commun., 1990, 516; (b) J. Inanaga, Y.
Handa, T. Tabushi, K. Otsubo, M. Yamaguchi and T. Hanamoto,
Tetrahedron Lett., 1991, 32, 6557; (c) S. P. Chavan and K. S. Ethiraj,
Tetrahedron Lett., 1995, 36, 2281; (d) L. Zhou, D. Shi, Y. Gao, W. Shen,
J. Dai and W. Chen, Tetrahedron Lett., 1997, 38, 2729; (e) N. Kise, S.
Machida and N. Ueda, J. Org. Chem., 1998, 63, 7931; (f) L. Zhou and T.
Hirao, Tetrahedron Lett., 2000, 41, 8517 and references cited therein.
also possible. Zn(I) species, generated from Zn(0) and Zn(II) reacts with
arylaldehyde to give a benzyl radical, which adds to the a-position of the
acrylate. The chelate radical intermediate then reacts with another
acrylate via 1,4-addition to generate C (Scheme 5). The authors
acknowledge the suggestion of a referee.
9 (a) D. A. Evans and A. H. Hoveyda, J. Am. Chem. Soc., 1990, 112, 6447;
(b) Y. Horiuchi, M. Taniguchi, K. Oshima and K. Uchimoto, Tetrahedron
Lett., 1995, 36, 5353.
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