Direct use of esters in the Mukaiyama aldol reaction: A powerful and convenient alternative to aldehydes

Article abstract of DOI:10.1021/ol3001443

An indium triiodide catalyst promoted the direct transformation from esters to β-hydroxycarbonyl compounds using hydrosilanes and silyl enolates by a one-stage process. Various esters were applicable, and the high chemoselectivity of this system brings compatibility to many functional groups: alkenyl, alkynyl, chloro, and hydroxy.

Full text of DOI:10.1021/ol3001443

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1168–1171
Direct Use of Esters in the Mukaiyama
Aldol Reaction: A Powerful and
Convenient Alternative to Aldehydes
Yoshihiro Inamoto, Yoshihiro Nishimoto, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received January 18, 2012
ABSTRACT
An indium triiodide catalyst promoted the direct transformation from esters to β-hydroxycarbonyl compounds using hydrosilanes and silyl
enolates by a one-stage process. Various esters were applicable, and the high chemoselectivity of this system brings compatibility to many
functional groups: alkenyl, alkynyl, chloro, and hydroxy.
The cross-aldol reaction isone ofthe mostrepresentative
tools in organic chemistry because produced β-hydroxy-
carbonyl compounds play an important role in medicinal
and agricultural chemicals. In particular, the Mukaiyama
aldol reaction using aldehydes and silyl enolates is of
central importance.1 While aldehydes are versatile electro-
philes, some have problems with stability and storage. In
this context, we sought to combine esters and hydrosilanes
instead of aldehydes, where the simple treatment of both
reagents and silyl enolates in the presence of a catalyst
would achieve a Mukaiyama aldol addition (Figure 1).
Yet, the scarcity of reports on the selective hydrosilylation
of esters into aldehydes under catalytic conditions indi-
cates the difficulty of this alternative route using esters.2
Recently, the InBr3-catalyzed hydrosilylation of esters into
the corresponding ethers via no formation of aldehydes
was investigated.3 Even in the case of an active metal
hydride, there is only one example of the use of DIBALH.
However, a two-stage process, where the completion of the
DIBALH addition to esters was followed by a treatment
with silyl enolates, was required.4a Recently, we reported
some examples of the removal of the alkoxy moiety of
esters: hydroallylation5 and FriedelÀCrafts acylation.6 In
particular, part of the hydroallylation results strongly
suggested that esters would be a promising alternative to
aldehydes. Herein, we wish to report the direct synthesis of
β-hydroxycarbonyl compounds from esters, hydrosilanes,
and silyl enolates, developing a practical alternative to the
Mukaiyama aldol reaction using aldehydes. This system
does not require a multistage process.
(1) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011–1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503–7509. (c) Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; Vol. 1, p 2.
(2) (a) Igarashi, M.; Fuchikami, T. Tetrahedron Lett. 2001, 42, 2149–
2151. (b) Nakanishi, J.; Tatamidani, H.; Fukumoto, Y.; Chatani, N.
Synlett 2006, 869–872. (c) Ojima, I.; Kumagai, M.; Nagai, Y. J.
Organomet. Chem. 1976, 111, 43–60. For reduction of carboxylic acids
and carboxylic acid derivatives to aldehydes, see: (d) Fukuyama, T.; Lin,
S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. (e) Kimura, M.;
Seki, M. Tetrahedron Lett. 2004, 45, 3219–3223. (f) Zakharkin, L. I.;
Khorlina, I. M. Tetrahedron Lett. 1962, 14, 619–620. (g) Kim, M. S.;
Choi, Y. M.; An, D. K. Tetrahedron Lett. 2007, 48, 5061–5064. (h)
Nahm, S.; Weinreb, M. Tetrahedron Lett. 1981, 39, 3815–3818.
(3) Sakai, N.; Moriya, T.; Konakahara, T. J. Org. Chem. 2007, 72,
5920–5922.
Figure 1. A conceivable strategy in this paper.
r
10.1021/ol3001443
Published on Web 02/08/2012
2012 American Chemical Society

The reaction using methyl ester 1a (1 mmol), HSiMe2Ph
(1.5 mmol), and dimethylketene trimethylsilyl methyl ace-
tal 2a (1.5 mmol) in CH2Cl2 at rt was most effectively
catalyzed by InI3 to give the desired β-hydroxycarbonyl
compound 3aa in 92% yield with a negligible amount of
β-methoxycarbonyl compound 4aa (Table 1, entry 1). The
use of InBr3 catalyst produced a low yield (entry 2). The
higher Lewis acidity of InBr3 than that of InI3 lowers the
turnover frequency because of the stronger deactivation by
the coordination of O-atoms of starting materials and
products. Almost the entire amount of starting ester 1a
was unreacted in the runs using other indium compounds
(entries 3À5). Also, representative Lewis acids such as
(OiPr)4,8 B(C6F5)3,9 and Zn(OAc)2,10 which have report-
edly reduced esters using hydrosilane, the desired product
3aa was not gained efficiently (entries 6À8). In the case of
the InI3 catalyst, the salient features are as follows: (i) the
produced ester 3aa did not incur further nucleophilic addi-
tions; (ii) despite one-stage treatment, no generation of the
reduction products 5 and 6 was observed, which is a critical
problem in the hydroallylation of esters;5,11 and (iii) the lack
of formation of ether derivatives such as 4aa and 6 provided
an interesting contrast to the reduction of esters to ethers
with the InBr3/HSiEt3 system reported by Sakai.3
Table 2 summarizes the scope and limitation of appli-
cable esters 1. The present system is highly valuable as an
alternative for the Mukaiyama aldol reaction, because
esters 1b and 1c, corresponding to acetaldehyde and
phenylacetaldehyde, respectively, were applicable (entries
1 and 2). Ingeneral, these aliphatic aldehydes are labile and
too difficult to handle.12 The product 3da was also isolated
in 92% yield from the reaction using ester 1d possessing a
cyclohexyl group near the carbonyl moiety (entry 3). In the
case of the sterically hindered ester 1e, a good result was
obtained by using H3SiPh instead of HSiMe2Ph (entries 4
and 5). The reaction of methyl benzoate 1f resulted in a low
yield due to the low electrophilicity of aromatic esters
(entry 6). The transformation of ester 1g gave 3ga with a
BF3 OEt2 and AlCl3 were ineffective.7 In the case of Ti-
3
Table 2. Scope and Limitation of Esters 1a
Table 1. Reaction of Ester 1a with HSiMe2Ph and Ketene Silyl
Acetal 2a in the Presence of Lewis Acid Catalysta
yield/ %b
entry
catalyst
3aa
4aa
5
6
1
InI3
92
17
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
InBr3
0
3c
4c
5c
6c
7
InCl3
0
In(OTf)3
In(OH)3
Ti(OiPr)4
B(C6F5)3
Zn(OAc)2
0
0
0
0
0
0
17
0
45
0
8c
a Reaction conditions: 1a (1 mmol), HSiMe2Ph (1.5 mmol), 2a
(1.5 mmol), catalyst (0.05 mmol), CH2Cl2 (1 mL), rt, 2 h. b Yields were
determined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane
as an internal standard. c >90% of 1a was recovered.
(4) (a) Kiyooka, S.; Shirouchi, M. J. Org. Chem. 1992, 57, 1–2. For
the use of DIBAL and other nucleophiles with esters, see: (b) Polt, R.;
Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992, 57, 5469–5480. (c)
Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.; Blough,
B. E. Tetrahedron Lett. 1987, 28, 3905–3906. (d) Ishihara, T.; Hayashi,
H.; Yamanaka, H. Tetrahedron Lett. 1993, 34, 5777–5780. (e) Ishihara,
T.; Takahashi, A.; Hayashi, H.; Yamanaka, H.; Kubota, T. Tetrahedron
Lett. 1998, 39, 4691–4694. (f) Hove, T. H.; Kopel, L. C.; Ryda, T. D.
Synthesis 2006, 1572–1574. (g) Yamazaki, T.; Kobayashi, R.; Kitazume,
T.; Kubota, T. J. Org. Chem. 2006, 71, 2499–2502.
a Reaction conditions: 1 (1 mmol), HSiMe2Ph (1.5 mmol), 2a
(1.5 mmol), InI3 (0.05 mmol), CH2Cl2 (1 mL), rt, 2 h. b Isolated yield.
c Yield was determined by 1H NMR spectroscopy using 1,1,2,2-tetra-
chloroethane as an internal standard. d HSiMe2Ph (3 mmol), 2a
(3 mmol), 12 h. e H3SiPh (3 mmol), 2a (3 mmol), 12 h. f HSiMe2Ph
(2 mmol), 2a (2 mmol), 5 h. g anti/syn = 92:8.
Org. Lett., Vol. 14, No. 4, 2012
1169

high anti-diastereoselectivity (entry 7). Alkenyl, alkynyl,
methoxy, and chloro groups survived the conditions
(entries 8À11). The above-mentioned outcomes suggest
that the high chemoselectivity of this work can be applied
to various fields such as natural-product synthesis.13
The effects of alkoxy moieties of ester 1 and hydrosilanes
(HSi) were investigated in Table 3. Unlike the exclusive
formation of 3aa using methyl ester 1a, the reaction of
isopropyl ester 1l with HSiMe2Ph and ketene silyl acetal 2a
furnished the mixture of β-hydroxycarbonyl product 3aa
and β-isopropoxycarbonyl 4la in 89% and 11% yields,
respectively(entries1 and 2). Theratio was almostreversed
by the usage of H3SiPh to produce the mixtures of 3aa and
4la in 20% and 80% yields, respectively (entry 3). In
contrast, 1a provided β-hydoxycarbonyl product 3aa se-
lectively even in the case of H3SiPh (entry 5). Treatment of
HSiEt3 and 1a gave 3aa along with a negligible amount of
4aa (entry 6). Ethyl ester 1m also showed high selectivity
for β-hydroxycarbonyl product 3aa (entries 7 and 8).
These results suggested that a small alkoxy moiety
leads to the selective formation of β-hydoxycarbonyl
compound 3.
A plausible mechanism is illustrated in Scheme 1. First,
InI3-catalyzed hydrosilylation of methyl ester 1 takes place
to generate acetal intermediate 7.3,5 Next, the selective
interaction between InI3 and the methoxy moiety pro-
motes the elimination of the methoxy moiety, due to a less
steric hindrance, to afford either oxonium ion 8 or alde-
hyde 9. Finally, the reaction with silyl enolate 2 produces
β-siloxycarbonyl compound 10, along with the regenera-
tion of InI3.14 The effective nucleophilic attack of 2 in a
timely manner may prevent the reduction of the electro-
philic intermediate (8 or 9) by hydrosilane to achieve a
single treatment of all substrates. The stereochemistry of
3ga was well accounted for by the FelkinÀAnh model for
oxonium cation 8 or aldehyde 9 (Table 2, entry 7).15
Table 3. Effects of Alkoxy Moieties of Ester 1 and Hydrosilanesa
Scheme 1. Plausible Mechanism
products/ %b
entry
ester 1
HSi
3
4
1
2
3
4
5
6
7
8
R2 =
Me
iPr
iPr
iPr
Me
Me
Et
1a
1l
HSiMe2Ph
HSiMe2Ph
H3SiPh
92
89
20
52
75
90
83
81
1
11
80
5
1l
1l
HSiEt3
The one-step transformation from mandelic acid ester 1n
to β-hydroxy-γ-lactone 12 with high stereoselectivity was
1a
1a
1m
1m
H3SiPh
7
HSiEt3
1
HSiMe2Ph
HSiEt3
1
Et
2
(12) Ariza, X.; Asins, G.; Garcia, J.; Hegardt, F. G.; Makowski, K.;
Serra, D.; Velasco, J. J. Label. Radiopharm. 2010, 53, 556–558.
(13) For examples of the total synthesis in which the reduction of a
carboxylic acid derivative to aldehyde followed by the Mukaiyam aldol
reaction was carried out, see: (a) Evans, D. A.; Black, W. C. J. Am.
a Reaction conditions: 1 (1 mmol), HSi (1.5 mmol), 2a (1.5 mmol), InI3
(0.05 mmol), CH2Cl2 (1 mL), rt, 2 h. b Yields were determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
^ ꢀ
Chem. Soc. 1993, 115, 4497–4513. (b) Evans, D. A.; Trotter, B. W.; Cote,
B.; Coleman, P. J. Angew. Chem., Int. Ed. 1997, 36, 2741–2744. (c) Trost,
B. M.; Sieber, J. D.; Qian., W.; Dhawan, R.; Ball, Z. T. Angew. Chem.,
Int. Ed. 2009, 48, 5478–5481.
(14) The transformation from 10 to β-hydroxycarbonyl compound 3
is performed by TBAF in the post-treatment.
(5) Nishimoto, Y.; Inamoto, Y.; Saito, T.; Yasuda, M.; Baba, A. Eur.
J. Org. Chem. 2010, 3382–3386.
(6) Nishimoto, Y.; Babu, S. A.; Yasuda, M.; Baba, A. J. Org. Chem.
2008, 73, 9465–9468.
(7) See Supporting Information for the investigation of typical Lewis
acids.
(8) (a) Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1992, 57, 3751–
3753. (b) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1995, 60, 7884–
7890.
(9) (a) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440–
9441. (b) Parks, D. J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem. 2000,
65, 3090–3098.
(15) (a) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105,
1667–1668. (b) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.;
Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990,
55, 6107–6115. (c) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997,
97, 2063–2192 and references therein.
(16) Since β-hydroxy-γ-lactones are key intermediates in the synthe-
sis of natural products, a large number of studies have reported their
preparation; see: (a) Nacro, K.; Gorrichon, L.; Escudier, J.-M.; Baltas,
M. Eur. J. Org. Chem. 2001, 4247–4258. (b) Karisalmi, K.; Koskinen,
A. M. P. Synthesis 2004, 9, 1331–1342. (c) Ghosh, A. K.; Kass, J.;
Anderson, D. D.; Xu, X.; Marian, C. Org. Lett. 2008, 10, 4811–4814.
(17) β-Hydroxy-γ-lactone was prepared from the protected R-hy-
droxy aldehydes by the Mukaiyama aldol reaction; see: (a) Kiyooka, S.;
Kira, H.; Hana, M. A. Tetrahedron Lett. 1996, 37, 2597–2600. (b) Kita,
Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishino, H.; Ke, Y. Y.; Tamura,
Y. J. Org. Chem. 1988, 53, 554–561.
€
(10) Das, S.; Moller, K.; Junge, K.; Beller, M. Chem.;Eur. J. 2011,
17, 7417–7417.
(11) The reaction of esters with hydrosilanes and allylsilanes in the
presence of InI3 catalyst produced the mixture of homoallylic alcohol
and primary alcohol in a single treatment. A drop treatment for
hydrosilane should be required to selectively obtain homoallylic alcohol.
See ref 5.
1170
Org. Lett., Vol. 14, No. 4, 2012

Table 4. Scope and Limitation of Silyl Enolates 2a
Scheme 2. One-Step Transformation from Mandelic Acid Ester
1n to β-Hydroxy-γ-lactone 12
demonstrated (Scheme 2).16 In the case of the Mukaiyama
aldol reaction, multistep syntheses involving protection of the
hydroxy moiety in unstable R-hydroxyaldehydes should be
performed.17 The stereochemistry of product 12 was ex-
plained by the Cram chelate model of 1,2-induction in the
reaction of the corresponding intermediate such as oxonium
cation 8 or aldehyde 9 with ketene silyl acetal 2a.18
Table 4 shows the scope of silyl enolates 2. Diethyl- and
phenylketene silyl acetal (2b and 2c) applied well to the
present system (entries 1 and 2). The reaction of carboxylic
acid derived ketene silyl acetal 2d also furnished β-hydro-
xycarboxylic acid 3ad in high yields (entry 3). The utiliza-
tion of 1l, H3SiPh, and 2d resulted in β-isopropoxycar-
boxylic acid 4ld as a major product (entry 4). The employment
of silyl enol ethers is a challenging subject because the
produced β-oxyketone is more sensitive to nucleophilic
attack than starting esters. This issue was resolved by the
introduction of HSiMePh2 and silyl enol ethers such as 2e
and 2f, leading to the products 3ae and 3af possessing steric
hindrance around the carbonyl group to avoid overreaction
(entries 5 and 6).
a Reaction conditions: 1a (1 mmol), HSiMe2Ph (1.5 mmol), 2a
(1.5 mmol), InI3 (0.05 mmol), CH2Cl2 (1 mL), rt, 2 h. b Isolated yields.
c E/Z = 76:24 d Diastereomer ratio 53:47. e 1l (1 mmol), H3SiPh
(1.5 mmol). f 3ad was obtained in 19% yield determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.
g HSiMePh2 (3 mmol), 2 (3 mmol), 5 h.
In conclusion, we have established the first direct intro-
duction of esters into the Mukaiyama aldol reaction
catalyzed by InI3. Various types of esters and silyl enolates
were applicable, and the high chemoselectivity lent com-
patibility to many functional groups. In addition, we
demonstrated the replacement of unstable and difficult to
handle aldehydes such as acetaldehyde, phenylacetalde-
hyde, and an R-hydroxyaldehyde with the corresponding
esters.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
(Nos. 22106527, 23105525) and Challenging Exploratory
Research (No. 23655083) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan). I.Y.
thanks the Global COE Program of Osaka University.
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81,
2748–2755. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462–468 and
references therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1171