Reductive Reformatsky-Honda reaction of α,β-unsaturated esters: Facile formation of 1,3-dicarbonyl compounds and β-hydroxy esters

Article abstract of DOI:10.1002/adsc.201100463

The reaction of tris(triphenylphosphine)rhodium chloride [RhCl(PPh ₃)₃] with diethylzinc (Et₂Zn) easily afforded a rhodium-hydride complex that effects the 1,4-reduction of α,β- unsaturated esters to give rhodium enolates. Formation of the rhodium enolate is followed by transmetalation with the zinc species to give a Reformatsky-type reagent, and this reacts with various acid chlorides at the α-position to give β-keto esters. The Reformatsky-type reagent also reacts with various electrophiles such as aldehydes, ketones and acid anhydrides to give the corresponding products in which the electrophiles were introduced reductively at the α-position of α,β-unsaturated esters. Copyright

Full text of DOI:10.1002/adsc.201100463

FULL PAPERS
DOI: 10.1002/adsc.201100463
Reductive Reformatsky–Honda Reaction of a,b-Unsaturated
Esters: Facile Formation of 1,3-Dicarbonyl Compounds and
b-Hydroxy Esters
Kazuyuki Sato,a Motoyuki Isoda,a Shizuka Ohata,a Shuhei Morita,a Atsushi Tarui,a
Masaaki Omote,a Itsumaro Kumadaki,a and Akira Andoa,*
a
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Fax : (+81)-72-866-3142; phone: +81-72-866-3140; e-mail: aando@pharm.setsunan.ac.jp
Received: June 8, 2011; Revised: September 14, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100463.
Abstract: The reaction of tris(triphenylphosphine)- reagent also reacts with various electrophiles such as
ACHTUNGTRENNUNGrhodium chloride [RhClCAHUTNGTREN(NNGU PPh3)3] with diethylzinc aldehydes, ketones and acid anhydrides to give the
(Et2Zn) easily afforded a rhodium-hydride complex corresponding products in which the electrophiles
that effects the 1,4-reduction of a,b-unsaturated were introduced reductively at the a-position of a,b-
esters to give rhodium enolates. Formation of the unsaturated esters.
rhodium enolate is followed by transmetalation with
the zinc species to give a Reformatsky-type reagent, Keywords: a-acylation; 1,3-dicarbonyl compounds;
and this reacts with various acid chlorides at the a- b-hydroxy esters; reductive coupling; Reformatsky–
position to give b-keto esters. The Reformatsky-type Honda reaction; rhodium
Introduction
It is well known that 1,3-dicarbonyl compounds are
key intermediates for the synthesis of various hetero-
cyclic compounds that, in turn, are one of the most
Scheme 2. Rh-catalyzed reductive a-acylation of a,b-unsatu-
rated esters.
important components in medicines and natural prod-
ucts.[1] However, surprisingly, there is only a limited
number of procedures for a direct synthesis of 1,3-di- complex that was easily derived from the combination
carbonyl compounds, especially 1,3-diketones, this is of RhClACTHNUGTRNEG(UN PPh3)3 with Et2Zn properly acted as the key
due to the higher acidity of the a-hydrogen of the 1,3- intermediate.[6] On the other hand, there are a lot of
dicarbonyl compounds than that of the starting car- methodologies to synthesize b-keto esters, but their
bonyl compounds.[2–4] We recently reported the direct one-pot synthesis from a,b-unsaturated ester using
synthesis of 1,3-diketones (3) by using Rh-catalyzed hydroacylation is rare.[7] We herein would like to
reductive a-acylation of a,b-unsaturated ketones (2) report the Rh-catalyzed reductive a-acylation of a,b-
(Scheme 1).[5] The acylation proceeded at the a-posi- unsaturated esters (4) with various acid chlorides (1)
À
tion of the a,b-unsaturated ketones, since the Rh H to give the corresponding b-keto esters (5) in a one-
pot procedure (Scheme 2).
Results and Discussion
Reductive a-Acylation of a,b-Unsaturated Esters
Based on the previous conditions,[5] we examined the
Scheme 1. The direct synthesis of 1,3-diketones.
reaction of methyl acrylate (4a) with benzoyl chloride
510
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 510 – 514

Reductive Reformatsky–Honda Reaction of a,b-Unsaturated Esters
(1a). As expected, the reaction proceeded smoothly yield. In addition, the reaction of acetyl chloride with
and gave the desired product (5a) in good yield. phenyl acrylate gave the corresponding the product
Then, we optimized the conditions for this reaction, (5p) in 39% yield, but the using of an aliphatic acid
and the best result was obtained in the original condi- chloride made the reaction mixture dirty (result was
tions [conditions A: 2 mol% of RhCl
ACHTUNGTRENNUNG
at 08C]. Next, the reactions using various acid chlor-
ides (1) and a,b-unsaturated esters (4) were examined tion with methyl crotonate, and found that the addi-
under these conditions. These results are summarized tion of 1,5-cyclooctadiene (COD) dramatically im-
in Table 1.
proved the rate and the yield as shown in entry 12
(PPh3)3 with 6 mol%
Although the electronic features of the acid chlor- [conditions B: 2 mol% of RhClAHCNUTGTRENNUNG
ides somewhat affected the yields and the reaction of COD in THF at 08C]. Although the role of COD
rates, all acid chlorides gave the corresponding prod- has not been clarified yet, it suppressed the side prod-
ucts in moderate to good yields as shown in entries 2– ucts. Thus we reexamined all reactions by using the
6. Heterocyclic acid chlorides also gave the corre- conditions B. The yields and/or the rates of 5j–l, and
sponding b-keto esters in moderate to good yields as 5o were improved by using COD, although further
shown in entries 7 and 8. On the other hand, other improvement in the yields of 5a–i was not observed.
a,b-unsaturated esters except benzyl acrylate gave Especially, it is interesting that 5j and 5k having an
poor results (entries 9–15). In particular, substituents unsaturated alkoxy group were obtained in moderate
on the b-position of 4 significantly decreased the yields without intramolecular cyclization.
Table 1. Scope and limitation of the Rh-catalyzed reductive a-acylation.
[a]
Conditions A: 2 mol% of RhCl
THF at 08C.
Isolated yield.
ACHTUGTNRENNUG(PPh3)3 in THF at 08C. Conditions B: 2 mol% of RhClCAHTUNGTRNEN(UGN PPh3)3 with 6 mol% of COD in
[b]
[c]
Mixture yield of the tautomer.
Adv. Synth. Catal. 2012, 354, 510 – 514
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
511

Kazuyuki Sato et al.
FULL PAPERS
Mechanistic Studies
Initially, we had thought that the Rh-catalyzed a-acy-
lation proceeded through a rhodium enolate (6) that
led to a RhACHTUNGTRENNUNG(III) complex (7) as mentioned in the pre-
vious paper.[5] Nonetheless, the whole yields of b-keto
esters (5) were fairly low to moderate in comparison
with the synthesis of 1,3-diketones. It, however, is
À
clear that Rh H complex would be involved in the re-
action, since the reaction did not give the desired
product in the absence of Rh catalyst. In addition, a
reductive double aldol-type product was obtained,
when the reaction by using benzoyl chloride with
2 equivalents of methyl acrylate was examined during
the optimization of the reaction conditions. These re-
sults would suggest the existence of another mecha-
nism, and we arrived at the conclusion that the Rh-
catalyzed reductive a-acylation might proceed
through zinc enolate (8) as shown in Figure 1.
To clarify the above mechanism, we examined
some reactions as shown in Scheme 3. In the reaction
of benzalacetone with benzoyl chloride, the corre-
sponding 1,3-diketone was obtained in a good yield
[Eq. (1)]. However, methyl cinnamate did not give
the a-acylation product (5m) but was recovered as
shown in Eq. (2). These results would relate to the ca-
Scheme 3. Mechanistic studies on the Rh-catalyzed reduc-
tive coupling reaction.
À
pability of 1,4-reduction to Rh H. In other words, an
a,b-unsaturated ketone would be more susceptible to
1,4-reduction compared with an a,b-unsaturated ester,
thus the reductive a-acylation might proceed even
though an a,b-unsaturated ketone that has a substitu-
ent on the b-position. On the other hand, methyl
vinyl ketone did not give the reductive aldol product,
but methyl acrylate gave the corresponding product
in an excellent yield in the reaction with benzalde-
hyde [Eq. (3) and Eq. (4)]. These results suggest that
the stronger nucleophilicity of zinc enolate (8) from
an ester might play an important role in the reaction.
From the above results, we proposed the following
catalytic cycle (Figure 2). RhClACHTNUTRGNE(UNG PPh3)3 reacted with
Et2Zn to give the rhodium hydride complex (11)
through the ethyl rhodium complex (9) along with the
elimination of ethylene. The 1,4-reductive addition of
Figure 2. Plausible reaction mechanism.
11 to a,b-unsaturated ester to form rhodium enolate
(12) is followed by transmetalation with zinc species
to give a Reformatsky-type reagent (8). This reagent
8 promptly reacted with acid chlorides (1) to give the
corresponding b-keto esters (5). However, the stron-
ger nucleophilicity of 8 relative to a corresponding in-
termediate that is derived from a,b-unsaturated
ketone led to the generation of side products, and
then the yields of the b-keto ester might be de-
creased.
Figure 1. Participation of another mechanism through a zinc
enolate.
512
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 510 – 514

Reductive Reformatsky–Honda Reaction of a,b-Unsaturated Esters
Table 2. Rh-Catalyzed reductive Reformatsky–Honda reac-
tion with various electrophiles.
the reaction with other electrophiles such as phenyl
formate, allyl acetate, allyl bromide and cyclohexyl
bromide did not give any products at all. These results
could be attributed to the nucleophilicity and/or steric
effect of the Reformatsky-type reagent.
Conclusions
In conclusion, we have synthesized various b-keto
esters from a,b-unsaturated esters with acid chlorides
in moderate to good yields. The reactions proceeded
smoothly and introduced the acyl groups at the a-po-
sition of the a,b-unsaturated esters, although the yield
was strongly affected by the substrates. Furthermore,
we proposed a plausible reaction mechanism, and ap-
plied this Reformatsky-type reaction to various elec-
trophiles in good to excellent yields. Now we are
trying to develop a stereoselective reductive aldol-
type reaction based on this reaction.
[a]
Isolated yield.
Diastereomeric ratio [syn:anti] after purification.
b-Lactam product was isolated in 70%, and its diastereo-
meric ratio was syn:anti=81:19.
[b]
[c]
Experimental Section
General Procedure for the Synthesis of b-Keto ester
(5) (Conditions A)
Reductive Reformatsky–Honda Reaction with
Various Electrophiles
a,b-Unsaturated ester (4, 2 mmol) and acid chloride (2,
4 mmol) were added to a solution of RhClACHTNURTGNEUNG(PPh3)3 (2 mol%)
The reductive a-acylation was assumed to proceed
through zinc enolate (8). If so, the reaction could be
applied to other electrophiles. Honda et al. reported a
rhodium-catalyzed Reformatsky-type reaction by
in THF (5 mL) at 08C. Then, 1.0M Et2Zn in hexane
(3 mmol) was gradually added to the mixture at 08C, and
the mixture was stirred at same temperature. The mixture
was quenched with 10% HCl and extracted with AcOEt.
The AcOEt layer was washed with saturated NaCl and
dried over MgSO4. The solvent was removed under vacuum,
and the residue was purified by column chromatography to
give 5.
using the combination of Et2Zn with RhClACTHNUGTRNEUNG(PPh3)3
(called the Reformatsky–Honda reaction). They ap-
plied the reaction to aldehydes and ketones or imines
to give the corresponding Reformatsky-type prod-
ucts.[8] On the other hand, various intermolecular re-
ductive aldol-type reactions toward aldehydes using
metals such as copper,[9] cobalt,[10] and rhodium cata-
lysts[11] have recently been reported, and they are
showing synthetic versatility with high stereoselectiv-
ity. In addition, there are now similar aldol-type reac-
tions via isomerization of allylic and/or homoallylic
alcohols.[12] Thus we applied the reaction to various
electrophiles (Table 2).
As expected, aldehydes and also a ketone gave the
corresponding products in good to excellent yields, al-
though their diastereomeric selectivities will need to
be improved in the future. In the reaction with N-ben-
zylidenebenzylamine (13f), the corresponding b-
lactam product (15f) was isolated in 70% yield as the
main product, and the total yields with uncyclized b-
amino ester (14f) were also good. Furthermore, the
reaction with phenyl chloroformate gave the corre-
sponding 1,3-diester (14g). Acid anhydrides also re-
acted smoothly, and the desired products (5a and 5p)
General Procedure for the Synthesis of b-Keto Ester
(5) (Conditions B)
To a solution of RhClACHTNUGTRNEGNU(PPh3)3 (2 mol%) in THF (5 mL) was
added 1,5-cyclooctadiene (6 mol%), then the mixture was
stirred at ambient temperature for 30 min. After this time,
the mixture was cooled to 08C, a,b-unsaturated ester (4,
2 mmol) and acid chloride (2, 4 mmol) were added. Then,
1.0M Et2Zn in hexane (3 mmol) was gradually added to the
mixture at 08C, and the mixture was stirred at same temper-
ature. The mixture was quenched with 10% HCl and ex-
tracted with AcOEt. The AcOEt layer was washed with sa-
turated NaCl and dried over MgSO4. The solvent was re-
moved under vacuum, and the residue was purified by
column chromatography to give 5.
General Procedure for the Reaction with
Electrophile (13)
a,b-Unsaturated ester (4, 2 mmol) and electrophile (13,
4 mmol) were added to a solution of RhClACHTNURTGNEUNG(PPh3)3 (2 mol%)
were obtained in moderate yields. On the other hand, in THF (5 mL) at 08C. Then, 1.0M Et2Zn in hexane
Adv. Synth. Catal. 2012, 354, 510 – 514
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
513

Kazuyuki Sato et al.
FULL PAPERS
(3 mmol) was gradually added to the mixture at 08C, and
the mixture was stirred at same temperature. The mixture
was quenched with 10% HCl and extracted with AcOEt.
The AcOEt layer was washed with saturated NaCl and
dried over MgSO4. The solvent was removed under vacuum,
and the residue was purified by column chromatography to
give the corresponding product (14).
2005, 127, 16042–16043; c) N. I. Petkova, R. D. Nikolo-
va, A. G. Bojilova, N. A. Rodios, C. P. Raptopoulou,
Synth. Commun. 2006, 36, 509–524.
[8] a) K. Kanai, H. Wakabayashi, T. Honda, Org. Lett.
2000, 2, 2549–2551; b) K. Kanai, H. Wakabayashi, T.
Honda, Heterocycles 2002, 58, 47–51; c) T. Honda, H.
Wakabayashi, K. Kanai, Chem. Pharm. Bull. 2002, 50,
307–308.
[9] For Cu-catalyzed reductive aldol reactions: a) T. Ooi,
K. Doda, D. Sakai, K. Maruoka, Tetrahedron Lett.
1999, 40, 2133–2136; b) H. W. Lam, P. M. A. Joensuu,
Org. Lett. 2005, 7, 4225–4228; c) J. Deschamp, O.
Chuzel, J. Hannedouche, O. Riant, Angew. Chem. 2006,
118, 1314–1319; Angew. Chem. Int. Ed. 2006, 45, 1292–
1297; d) A. Welle, S. Dꢁez-Gonzꢂlez, B. Tinant, S. P.
Nolan, O. Riant, Org. Lett. 2006, 8, 6059–6062.
[10] For Co-catalyzed reductive aldol reactions, see: a) S.
Isayama, T. Mukaiyama, Chem. Lett. 1989, 2005–2008;
b) T. G. Baik, A. L. Luis, L. C. Wang, M. J. Krische, J.
Am. Chem. Soc. 2001, 123, 5112–5113; c) L. C. Wang,
H.-Y. Jang, Y. Roh, V. Lynch, A. J. Schultz, X. Wang,
M. J. Krische, J. Am. Chem. Soc. 2002, 124, 9448–9453;
d) H. W. Lam, P. M. Joensuu, G. J. Murray, E. A. F. For-
dyce, O. Prieto, T. Luebbers, Org. Lett. 2006, 8, 3729–
3732; e) R. J. R. Lumby, P. M. Joensuu, H. W. Lam,
Org. Lett. 2007, 9, 4367–4370.
[11] For Rh-catalyzed reductive aldol reactions, see: a) A.
Revis, T. K. Hilty, Tetrahedron Lett. 1987, 28, 4809–
4812; b) S. J. Taylor, M. O. Duffey, J. P. Morken, J. Am.
Chem. Soc. 2000, 122, 4528–4529; c) A. E. Russell,
N. O. Fuller, S. J. Taylor, P. Aurriset, J. P. Morken, Org.
Lett. 2004, 6, 2309–2312; d) H. Nishiyama, T. Shiomi,
Y. Tsuchiya, I. Matsuda, J. Am. Chem. Soc. 2005, 127,
6972–6973; e) M. C. Willis, R. L. Woodward, J. Am.
Chem. Soc. 2005, 127, 18012–18013; f) C. Bee, S. B.
Han, A. Hassan, H. Iida, M. J. Krische, J. Am. Chem.
Soc. 2008, 130, 2746–2747; g) T. Hashimoto, J. Ito, H.
Nishiyama, Tetrahedron 2008, 64, 9408–9412; h) T.
Shiomi, T. Adachi, J. Ito, H. Nishiyama, Org. Lett.
2009, 11, 1011–1014.
References
[1] a) A. L. Baumstark, A. Choudhary, P. C. Vasquez, M.
Dotrong, J. Heterocycl. Chem. 1990, 27, 291–294;
b) A. P. West Jr, D. Van Engen, R. A. Pascal Jr, J. Org.
Chem. 1992, 57, 784–786; c) C. P. Felix, N. Khatimi,
A. J. Laurent, J. Org. Chem. 1995, 60, 3907–3909; d) S.
Benetti, R. Romagnoli, C. De Risi, G. Spalluto, V. Za-
nirato, Chem. Rev. 1995, 95, 1065–1114; e) M. A. P.
Martins, S. Brondani, V. L. Leidens, D. C. Flores, S.
Moura, N. Zanatta, M. Horner, A. F. C. Flores, Can. J.
Chem. 2005, 83, 1171–1177.
[2] For the synthesis of 1,3-diketones using metal enolates,
see: a) C. Wiles, P. Watts, S. J. Haswell, E. Pombo-
Villar, Tetrahedron Lett. 2002, 43, 2945–2948; b) Y.
Nishimura, Y. Miyake, R. Amemiya, M. Yamaguchi,
Org. Lett. 2006, 8, 5077–5080; c) D. Lim, F. Fang, G.
Zhou, D. M. Coltart, Org. Lett. 2007, 9, 4139–4142.
[3] For the synthesis of 1,3-diketones using transition
metals, see: a) Z. Ikeda, T. Hirayama, S. Matsubara,
Angew. Chem. 2006, 118, 8380–8383; Angew. Chem.
Int. Ed. 2006, 45, 8200–8203; b) T. Fukuyama, T. Dai, S.
Minamino, S. Omura, I. Ryu, Angew. Chem. 2007, 119,
5655–5657; Angew. Chem. Int. Ed. 2007, 46, 5559–5561.
[4] For the synthesis of 1,3-diketones from benzotriazoles
or acyl cyanides, see: a) A. R. Katritzky, A. Pastor, J.
Org. Chem. 2000, 65, 3679–3682; b) C. Wiles, P. Watts,
S. J. Haswell, E. Pombo-Villar, Chem. Commun. 2002,
10, 1034–1035; c) A. R. Katritzky, N. K. Meher, S. K.
Singh, J. Org. Chem. 2005, 70, 7792–7794; d) Z. Shen,
B. Li, L. Wang, Y. Zhang, Tetrahedron Lett. 2005, 46,
8785–8788.
[12] a) M. Wang, X.-F. Yang, C.-J. Li, Eur. J. Org. Chem.
2003, 998–1003; b) X.-F. Yang, M. Wang, R. S. Varma,
C.-J. Li, Org. Lett. 2003, 5, 657–660; c) D. Cuperly, J.
Petrignet, C. Crꢃvisy, R. Grꢃe, Chem. Eur. J. 2006, 12,
3261–3274; d) J. Petrignet, T. Roisnel, R. Grꢃe, Chem.
Eur. J. 2007, 13, 7374–7384; e) A. Bartoszewicz, M. Liv-
endahl, B. Martꢁn-Matute Chem. Eur. J. 2008, 14,
10547–10550; f) N. Ahlsten, B. Martꢁn-Matute, Adv.
Synth. Catal. 2009, 351, 2657–2666.
[5] K. Sato, S. Yamazoe, R. Yamamoto, S. Ohata, A. Traui,
M. Omote, A. Ando, I. Kumadaki, Org. Lett. 2008, 10,
2405–2408.
[6] K. Sato, Y. Ishida, E. Murata, Y. Oida, Y. Mori, M.
Okawa, K. Iwase, A. Tarui, M. Omote, I. Kumadaki, A.
Ando, Tetrahedron 2007, 63, 12735–12739.
[7] a) T. Mitsudo, Y. Watanabe, M. Yamashita, Y. Takega-
mi, Chem. Lett. 1974, 1385–1388; b) K. Kundu, J. V.
McCullagh, A. T. Morehead Jr, J. Am. Chem. Soc.
514
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 510 – 514