832

Chemistry Letters Vol.38, No.8 (2009)

Eﬃcient Alkenation of Aldehydes and Ketones to , -Unsaturated Esters
Using , -Bis(dimethylsilyl)-substituted Esters
Katsukiyo Miura,1 Masaru Ebine,2 Kazunori Ootsuka,2 Junji Ichikawa,2 and Akira Hosomi2
1
Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, Sakura-ku, Saitama 338-8570
2
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba 305-8571(Received May 26, 2009; CL-090520; E-mail: kmiura@apc.saitama-u.ac.jp), -Bis(dimethylsilyl)-substituted esters 1 were found to bequite valuable for alkenation of various aldehydes and ketones to, -unsaturated esters. The reaction of aldehydes with 1 proceeded spontaneously in DMSO at 30  C to give , -unsaturated esters with good to high E selectivity. Under the same conditions, ketones were insensitive to 1; however, Li2 SO4 and CaCl2
eﬀectively accelerated their alkenation.

mize the reaction conditions. When DMSO was used as solvent,the desired alkenation proceeded spontaneously at 30  C to giveethyl cinnamate (3a) in high yield with high E selectivity (eq 3).8
HMPA was as eﬀective as DMSO, but no alkenation was observedin other polar solvents (DMF, MeCN, THF, etc.). Use of an equimolar amount of DMSO largely reduced the reaction rate.
1) LDA
RCH2CO2Et

Alkenation of aldehydes and ketones provides a convenientroute to , -unsaturated esters, which serve as versatile synthetic intermediates convertible to highly functionalized organic
molecules. Wittig, Horner–Wadsworth–Emmons (HWE), andPeterson reactions have frequently been utilized for this transformation.1 However, these reactions require deprotonative preformation of reactive alkenating agents from -phosphorus- and silicon-substituted esters under basic conditions. The HWE andPeterson reactions are carried out usually at low temperatures
such as 78  C for ﬁne control of the deprotonation and subsequent alkenation. The conventional methods, therefore, havemuch room for improvement toward a simple reaction operationand mild reaction conditions.
In this context, Palomo and co-workers have reported thatt-butyl bis(trimethylsilyl)acetate is valuable for alkenation ofcarbonyl compounds to , -unsaturated esters under catalysis
by TASF, a ﬂuoride ion source.2 This alkenation involves a ﬂuoride-catalyzed aldol reaction3 and the subsequent Peterson elimination. It can be conducted at ambient temperature by a simple
operation; however, the applicability is rather limited. The alkenation of enolizable carbonyl compounds competes with theformation of their silyl enolates because the intermediary
metal-free enolate generated from the alkenating agent is basic
enough for deprotonation of the carbonyl compounds.4 We havepreviously reported that -(dimethylsilyl)-substituted esters
smoothly add to aldehydes and ketones at 30  C in the presenceof metal chlorides.5,6 Since this aldol reaction is applicable to awide range of carbonyls, we expected that , -bis(dimethylsilyl)-substituted esters 1 would act as versatile alkenating
agents in the tandem aldol-Peterson reaction. Expectedly, 1
aﬀected carbonyl compounds to aﬀord , -unsaturated esters.
We herein report the scope of this carbonyl alkenation using
the newly designed organosilicon reagents.
Bis(dimethylsilyl)-substituted esters 1 were prepared by stepwise double silylation of esters using LDA and Me2 SiHCl (eq 1).7
Later, we developed direct synthesis of 1a by treatment withMe2 SiHOTf and Et3 N (eq 2). The organosilicon reagents 1 arestorable without any degradation under anhydrous conditions.
The reaction of benzaldehyde (2a) with 1a was selected to opti-Si2) Si Cl

CO2Et
R

Si = Me2HSi

1) LDA

SiCO2Et2) Si ClSiR

1a (R = H), 41%
1b (R = Me), 43%

R = H, 60%
R = Me, 91%

Si OTf, Et3N

CH3CO2Et

ð1Þ1a, 65%

ð2ÞPhð3ÞTHF
Solvent (0.5 M)

PhCHO + 1a2a30 °C

DMSO, 1 h:
HMPA, 1 h:
DMSO (1 equiv), 24 h:

CO 2Et
3a96%, E :Z = 98:284%, E :Z = 95:580%, E :Z = 94:6

The uncatalyzed alkenation using 1a in DMSO is applicable
to a variety of aldehydes (Table 1). Substituted benzaldehydes
were less reactive than 2a. Elongation of the reaction timebrought about good to high yields of 3 except for the case of2d (Entries 1–7). The reaction of 4-acetylbenzaldehyde (2g)took place chemoselectively at the formyl site, not at the acetylsite. Aldehydes 2i–2j, bearing an acidic functionality, successfully underwent the alkenation with a two-fold amount of 1a(Entries 8 and 9). The alkenation of aliphatic aldehydes also proceeded eﬃciently with E selectivity (Entries 10–12). Notably
phenylacetaldehyde (2m), a readily enolizable aldehyde, could
be converted into 3m with high E selectivity.9 Cinnamaldehyde(2n) reacted smoothly with 1a to give ester-conjugated 1,3-diene
3n in high yield.
Bissilylated ester 1b is similar in reactivity to 1a. Alkenationof aldehydes with 1b proceeded spontaneously in DMSO toaﬀord trisubstituted alkenes 4 with E selectivity (eq 4).
MeO+R

1bH

DMSO, 30 °C

2R = Ph, 1 h:
R = c -C6H11, 24 h:
R = (E )-PhCH=CH, 24 h:

ð4Þ

R

CO2Et
481%, E :Z = 98:271%, E :Z = 79:2189%, E :Z = 73:27

Acetophenone (5a) hardly reacted with 1a under the uncatalyzed conditions. We found that Li2 SO4 eﬃciently promoted thealkenation of 5a to , -disubstituted acrylate 6a (Entry 1 inCopyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.8 (2009)

833

Table 1. Alkenation of aldehydes 2 with 1aaO+RH

1aEntryc

12345678d9d
101112e13

Li2SO4OR+

CO2Et

DMSO, 30 °C, 24 h2

Table 2. Alkenation of ketones 5 with 1aa
R1

31aR1DMSO, 30 °C, 24 h

R2CO2Et
R25b

R in aldehyde 2Yield/%

E:Z

4-MeC6 H4 (2b)4-MeOC6 H4 (2c)
4-Me2 NC6 H4 (2d)4-ClC6 H4 (2e)4-MeO2 CC6 H4 (2f)
4-Me(O)CC6 H4 (2g)
4-O2 NC6 H4 (2h)4-HOC6 H4 (2i)4-HO2 CC6 H4 (2j)
Ph(CH2 )2 (2k)c-C6 H11 (2l)PhCH2 (2m)(E)-PhCH=CH (2n)

90
99
59
88
80
72
85
89
75
83
79
60
90

96:4
90:10
99:1
98:298:298:298:2
96:4
98:290:10
91:9
99:1
75:25

aConditions: 2 (0.50 mmol), 1a (0.60 mmol), DMSO (1.0mL), 30  C, 24 h. b Determined by GC or 1 H NMR analysisof the puriﬁed product. c For 4 h. d An increased amount of
1a (1.20 mmol) was used. e For 1 h.

Table 2). In the presence of Li2 SO4 , aromatic ketone 5b and aliphatic ketones 5f–5h underwent the alkenation in good yield(Entries 2 and 6–8). CaCl2 was more eﬀective than Li2 SO4 in
the alkenation of-functionalized acetophenones 5c–5d(Entries 3 and 4). It is noteworthy that 5d was converted into
6d with retention of the C–Cl bond. The alkenation of 2,2,2-triﬂuoroacetophenone (5e) with 1a occurred spontaneously withhigh E selectivity (Entry 5). The high reactivity of 5e is probably
due to the electron-withdrawing eﬀect of the CF3 group. TheCaCl2 -promoted reaction enabled eﬃcient alkenation of , -unsaturated ketones 5i–5l (Entries 9–12). No conjugate adducts
were formed in these cases. When Li2 SO4 was used as promoter,the carbonyl alkenation competed with conjugate addition of1a.10
In the presence of CaCl2 or Li2 SO4 , alkenation of ketones
with 1b also proceeded eﬃciently to give tetrasubstituted alkenes 7 (eq 5).
Unlike 1a ethyl bis(trimethylsilyl)acetate was insensitive to2a even in DMSO. As described above, less polar solvents suchas DMF, MeCN, and THF were not eﬀective in the alkenation
with 1a. These results indicate that nucleophilic attack of aDMSO molecule to the sterically less hindered dimethylsilylgroup activates the Si–C bond of 1 to initiate the tandem aldol-Peterson reaction. Li2 SO4 and CaCl2 also would serve fornucleophilic activation of the Si–C bond by attack of the counter
anions.5,6
In conclusion, we have developed a new alkenation method
for the synthesis of , -unsaturated esters from aldehydes andketones. The present alkenation using 1 can be conducted under
neutral conditions by a one-step procedure. This method can efﬁciently convert a variety of aldehydes and ketones into the corresponding , -unsaturated esters, in some cases, with high stereoselectivity. Mechanistic aspects of the E selective alkenationof aldehydes and modiﬁcation of 1 towards highly stereoselective alkenation are now under investigation.1161Entry

2

R and R in ketone 5Yield/%

E:Zb

8878
97616780
75
76779091
86

63:3763:37
25:75
44:56
97:335:65

1 Ph, Me (5a)2 3,4,5-(MeO)3 C6 H2 , Me (5b)3c Ph, CH(OEt)2 (5c)4c,d Ph, CH2 Cl (5d)5e Ph, CF3 (5e)6 Ph(CH2 )2 , Me (5f)
7 –(CH2 )4 – (5g)
8 –(CH2 )5 – (5h)9c –(CH2 )3 CH=CH– (5i)10c (E)-PhCH=CH, (E)-PhCH=CH (5j)11c (E)-PhCH=CH, Me (5k)12c (E)-PhCH=CH, Ph (5l)

27:73
62:38
59:41aConditions: 5 (0.50 mmol), 1a (0.60 mmol), Li2 SO4 (050mmol), DMSO (1.0 mL), 30  C, 24 h. b Determined by 1 H NMR
analysis of the puriﬁed product. c CaCl2 was used instead ofLi2 SO4 . d An increased amount of 1a (1.20 mmol) was used.
eWithout Li2 SO4 .
additive (1 equiv)

O+R1R2

1bDMSO, 30 °C, 24 h5
R1 = Ph, R2 = Me, CaCl2:
R1, R2 = -(CH2)5-, Li2SO4:CO2Et
R1MeR2

ð5Þ

783%, E :Z = 31:6970%

References and Notes
1a) T. Takeda, Modern Carbonyl Oleﬁnation, Wiley-VCH,Weinheim, 2004. b) S. E. Kelly, in Comprehensive Organic Synthesis, ed. by B. M. Trost, I. Fleming, Pergamon, Oxford, 1991,Vol. 1, Chap. 3.1, pp. 729–817.
2 C. Palomo, J. M. Aizpurua, J. M. Garcı́a, I. Ganboa, F. P. Cossio,
B. Lecea, C. López, J. Org. Chem. 1990, 55, 2498.
3 E. Nakamura, M. Shimizu, I. Kuwajima, Tetrahedron Lett. 1976,17, 1699.
4 The metal-free enolate generated from ethyl (trimethylsilyl)acetate and Bu4 NF is suﬃciently basic to cause deprotonation of enolizable ketones. See Ref. 3 and See also: E. Nakamura, K.
Hashimoto, I. Kuwajima, Tetrahedron Lett. 1978, 19, 2079.
5 K. Miura, T. Nakagawa, A. Hosomi, Synlett 2005, 1917.
6 For related works, see: a) K. Miura, T. Nakagawa, A. Hosomi,
J. Am. Chem. Soc. 2002, 124, 536. b) K. Miura, T. Nakagawa,A. Hosomi, Synlett 2003, 2068.
7 K. Miura, H. Sato, K. Tamaki, H. Ito, A. Hosomi, Tetrahedron
Lett. 1998, 39, 2585.
8 For DMSO-promoted reactions of organosilicon reagents, see:a) K. Iwanami, T. Oriyama, Synlett 2006, 112. b) Y. Génisson,L. Gorrichon, Tetrahedron Lett. 2000, 41, 4881.
9 The CaCl2 -promoted reaction of 2m with 1a in DMF gave 3m in
91% yield without stereoselectivity (E:Z = 49:51).
10 The Li2 SO4 -promoted reaction of 5l with 1a gave 6l and ethyl 5oxo-3,5-diphenylpentanoate (a conjugate adduct) in 48% and 30%
yields, respectively.
11 Supporting Information is available electronically on the CSJJournal Web site, http://www.csj.jp/journals/chem-lett/index.html.

Published on the web (Advance View) July 18, 2009; doi:10.1246/cl.2009.832