Bu 4 N + -Controlled Addition and Olefination with Ethyl 2-(Trimethylsilyl)acetate via Silicon Activation

Article abstract of DOI:10.1055/s-0036-1588805

Catalytic Bu ₄ NOAc as silicon activator of ethyl 2-(trimethylsilyl)acetate, in THF, was utilized for the synthesis of β-hydroxy esters, whereas employing catalytic Bu ₄ NOTMS gave α,β-unsaturated esters. The established reaction conditions were applicable to a diverse range of aromatic, heteroaromatic, aliphatic aldehydes and ketones. Reactions were achieved at room temperature without taking any of the specialized precautions that are in place for other organometallics. A stepwise olefination pathway via silylated β-hydroxy esters with subsequent elimination to form the α,β-unsaturated ester has been demonstrated. The key to selective product formation lies in use of the weaker acetate activator which suppresses subsequent elimination whereas stronger TMSO ^- activator (and base) facilitates both addition and elimination steps. The use of tetrabutyl ammonium salts for both acetate and trimethylsilyloxide activators provide enhanced silicon activation when compared to their inorganic cation counterparts.

Full text of DOI:10.1055/s-0036-1588805

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© Georg Thieme Verlag Stuttgart · New York
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M. Das et al.
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Bu4N+-Controlled Addition and Olefination with Ethyl 2-(Trimeth-
ylsilyl)acetate via Silicon Activation
Manas Dasa
Atul Manvara
Ian Foxa,b
R2 OTMS
R2
CO2Et
TMS
O
Bu4NOTMS (30 mol%)
THF, rt
Bu4NOAc (10 mol%)
THF, rt
R1
R1
+
R1
R2
CO2Et
CO2Et
Dilwyn J. Robertsb
Donal F. O’Shea*a
21 examples
15 examples
up to 87% yield
up to 99:1 E/Z
up to 90% yield
a Department of Pharmaceutical and Medicinal Chemistry,
Royal College of Surgeons in Ireland, 123 St. Stephen’s
Green, Dublin 2, Ireland
Bu4NOTMS, THF, rt
donalfoshea@rcsi.ie
b Ipsen Manufacturing Ireland Ltd, Blanchardstown Industrial
Park, Blanchardstown, Dublin 15, Ireland
Published as part of the Cluster Silicon in Synthesis and Catalysis
Received: 30.01.2017
Accepted after revision: 27.03.2017
Published online: 02.05.2017
agents has been one of the most studied protocols,3–5 al-
though this method demands in situ formation of the
organometallic reagent and immediate use owing to their
instability.6 Alternative organometallic nucleophiles con-
taining metals such as magnesium, iron, nickel, manganese,
and indium have also been shown to successfully partici-
pate in addition reactions.7 However, employment of stoi-
chiometric amount of metal reagents is a drawback and
these protocols are associated with numerous complexi-
ties.7 As an alternative, the use of α-silyl ester metalloids,
such as ethyl 2-(trimethylsilyl)acetate (1), as bench-stable
pro-nucleophiles, has been studied (Figure 1).8,9 In the first
seminal reports, the nucleophilic character of 1 was re-
vealed through a fluoride activation of silicon using tetra-
butylammonium fluoride (TBAF).8 After these initial suc-
cesses with fluoride activation for the synthesis of β-hy-
droxy esters, several successful alternative activation
conditions, such as proazaphosphatranes P(i-PrNCH2CH2)3N
in THF,9a Schwesinger imino phosphorene base P4-t-Bu in
MeCN,9b CsF in DMF,9c,d tris(2,4,6-trimethoxyphenyl)phos-
phine in DMF,9e and K[Al(OMe)4] in pyridine9f have been re-
ported by different authors for the addition of α-silyl ester
to carbonyls.
DOI: 10.1055/s-0036-1588805; Art ID: st-2017-b0077-c
Abstract Catalytic Bu4NOAc as silicon activator of ethyl 2-(trimethylsi-
lyl)acetate, in THF, was utilized for the synthesis of β-hydroxy esters,
whereas employing catalytic Bu4NOTMS gave α,β-unsaturated esters.
The established reaction conditions were applicable to a diverse range
of aromatic, heteroaromatic, aliphatic aldehydes and ketones. Reac-
tions were achieved at room temperature without taking any of the
specialized precautions that are in place for other organometallics. A
stepwise olefination pathway via silylated β-hydroxy esters with subse-
quent elimination to form the α,β-unsaturated ester has been demon-
strated. The key to selective product formation lies in use of the weaker
acetate activator which suppresses subsequent elimination whereas
stronger TMSO– activator (and base) facilitates both addition and elimi-
nation steps. The use of tetrabutyl ammonium salts for both acetate
and trimethylsilyloxide activators provide enhanced silicon activation
when compared to their inorganic cation counterparts.
Key words tetrabutyl ammonium, acetate, trimethylsilyl oxide, silicon
activation, addition, olefination
β-Hydroxy esters and α,β-unsaturated esters are im-
portant structural motifs for a wide range of industrial ap-
plications, such as flavors, graphics, plasticizers, lubricants,
perfumes, and cosmetics. For example, 2-ethylhexyl-4-me-
thoxycinnamate is the most common ingredient of sun-
screen lotions and cosmetic formulations. α,β-Unsaturated
esters also possess various pharmacological activities in-
cluding antioxidant, antimicrobial, and anticancer activi-
ties. These moieties also serve as fundamentally important
building blocks for the synthesis of various naturally occur-
ring and biologically active compounds.1,2
OSiMe3
R1
Bu4NOAc
conditions
R2
CO2Et
3
O
CO2Et
SiMe3
+
conditions
R1
R2
R1
1
2
Bu4NOTMS
conditions
R2
CO2Et
Several methodologies have been reported for the syn-
thesis of β-hydroxy esters. Historically, Reformatsky reac-
tion of ethyl 2-haloacetates and carbonyls with zinc re-
4
Figure 1 Reaction of ethyl 2-(trimethylsilyl) acetate and carbonyl com-
pounds under Lewis basic conditions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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M. Das et al.
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Mild and efficient routes to α,β-unsaturated esters re-
main a popular topic of research for chemists as they often
play the role of key synthetic intermediate in multistep
synthetic programs.10 Among them, the olefination of car-
bonyl compounds provides the most common routes. Wit-
tig,11 Horner–Wadsworth–Emmons,12 and Peterson olefina-
tion (PO)13,14 reactions have been the most widely exploited
methods for the synthesis of α,β-unsaturated esters. How-
ever, the use of an equivalent of strong base can be limiting
and in some cases the removal of crystalline byproduct can
be challenging for olefin purification. Specifically for the PO
reaction the necessity to perform an α-silyl carbanion by
employing a strong base has restricted its widespread ap-
plication.13 As such, the use of bench-stable trimethylsilyl-
acetate (1) in a silicon-activated addition with subsequent
elimination reaction sequence is synthetically attractive
(Figure 1). Recently, Verkade and co-workers reported the
use of catalytic proazaphosphatranes P(i-PrNCH2CH2)3N as
effective base for the condensation of 1 with aryl aldehydes
to produce α,β-unsaturated esters.9a
Kondo et al. also have reported the employment of cata-
lytic P4-t-Bu superbase at –78 °C in the synthesis of α,β-un-
saturated esters from 1 and corresponding aldehydes and
ketones.9b In the first report on this topic, Bellassoued et al.
reported an addition–elimination process to synthesize ole-
fins in which 1 and nonenolizable aldehydes were reacted
at 100 °C in polar DMSO utilizing catalytic amount of CsF.9c
It occurred to us that the need for very strong specialized
bases such as P(i-PrNCH2CH2)3N (pKa = 33.6)14 or P4-t-Bu
(pKa = 42.7)15 may not be necessary for such reactions and
that the high temperatures required for elimination with
CsF/DMSO conditions could be avoided by selection of more
suitable inexpensive bases.
As part of our research program into pro-nucleophile
trimethylsilane reagents, the use of Me3SiO−/Bu4N+ as a
general activator of a wide range of organotrimethylsilanes
for addition reactions16 and organobis(trimethylsilanes) for
olefination reactions17 has been established. Using the pKa
of EtOAc at 25.618 as a guide, it could be anticipated that the
activation of silicon in 1 would not require a strong base
and that both addition and olefination reactions could be
achieved with a high degree of selectivity under mild con-
ditions. In this report, we illustrate room-temperature
strategies which utilize acetate and trimethylsilyloxide bas-
es, as their Bu4N+ salts, to produce either the addition β-hy-
droxy esters or unsaturated esters olefination products, re-
spectively, in a highly selective manner (Figure 1).
In previously reported work we have shown that car-
bonyl addition reactions with ethyl 2-(trimethylsilyl)ace-
tate (1) at 0 °C in THF were very rapid (within 15 min)
when Bu4NOTMS was used to promote the reaction.16a At
that time it was noted that reactions needed to be closely
monitored and stopped as soon as completion had been
reached or olefin impurities would form. We started this in-
vestigation by employing 1 and benzaldehyde with 10 mol%
TMSOK/Bu4NCl in THF at room temperature for two hours
from which ethyl 3-phenyl-3-[(trimethylsilyl)oxy]propa-
noate (3a) was isolated in 5% yield as minor product and
ethyl cinnamate (4a) obtained as the major product in 82%
yield (E/Z = 99:1; Table 1, entry 1). In an attempt to achieve
complete conversion into olefin, an increased amount of ac-
tivator (30 mol%) was employed and the olefin 4a obtained
in 87% yield (E/Z = 99:1; Table 1, entry 2) with no silylether
3a identified. The use of stoichiometric amount of activator
was attempted under the same conditions, though it
showed no further improvement in yield (85%, E/Z = 99:1,
Table 1, entry 3). As illustration of the effect of the Bu4N+
counterion, when stoichiometric amount of TMSOK alone
was used as activator in THF at room temperature for a pro-
longed reaction time of 16 hours, a mixture of addition
product 3a (32% ), and olefin 4a (41%) was isolated, illus-
trating a loss in selectivity between the two possible reac-
tion outcomes (Table 1, entry 4). To establish a general
method for the synthesis of addition products, Bu4NOAc
was selected as a weaker base for investigation. Gratifying-
ly, under the same reaction conditions, the use of catalytic
(10 mol%) Bu4NOAc provided the silylether 3a in 90% yield
with a trace amount of the corresponding alkene 4a (Table
1, entry 5). Employment of stoichiometric Bu4NOAc gave
the similar reaction outcome, showing the preference for
addition rather than olefination product (Table 1, entry 6).
Reaction utilizing one equivalent of KOAc for 16 hours
failed to provide effective addition conditions, emphasizing
the requirement of the ammonium cation (Table 1, entry 7).
This stark reactivity difference between the organic and in-
organic counterion is clearly revealed in this case of acetate
activation. Also of note, the use of one equivalent Bu4NCl as
an even weaker silicon activator also produced the silyl-
ether 3a, though in a low 35% yield after 20 hours (Table 1,
entry 8). From the screening of reaction conditions, it be-
came apparent that 10 mol% Bu4NOAc in THF at room tem-
perature would be ideal to explore substrate scope for the
synthesis of β-hydroxy esters, whereas 30 mol%
TMSOK/Bu4NCl in THF at room temperature would be opti-
mal to determine the scope for diverse α,β-unsaturated es-
ter synthesis.
After establishing reaction conditions for the synthesis
of β-hydroxy esters, we next evaluated the addition of 1 to
various structurally and electronically different aromatic,
heteroaromatic, α,β- unsaturated, organometallic, and ali-
phatic carbonyls (Scheme 1). Addition of 1 to a diverse
range of aromatic aldehydes was achieved selectively, pro-
viding products 3b–g in good to excellent yields. Aromatic
aldehydes having ortho, meta, and para substitution or tri-
substitution all worked very well under the same reaction
conditions. Moreover, the addition to ferrocenecarboxalde-
hyde to produce 3h showcased the versatility of this meth-
od. Synthesis of β-hydroxy esters containing heterocyclic
rings 3i,j showed the tolerance of furan and pyridine moi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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M. Das et al.
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R2 OH
O
Table 1 Optimization of Reaction Conditionsa
(i) Bu4NOAc (10 mol%)
Me3Si
CO2Et
CO2Et
CO2Et
R1
+
R1
R2
THF, rt, 1 h
(ii) 2 M aq HCl, 30 min
O
OTMS
CO2Et
SiMe3
2
1
3b–o
activator (mol%)
THF, rt, time
CO2Et
+
Ph
+
Ph
H
Ph
OH
Cl
OH
OH
CO2Et
CO2Et
MeO
CO2Et
1
2a
3a
4a
MeO
Entry
Activator (mol%)
Time
(h)
Yield of 3a Yield of 4a E/Z of
(%)b,c
(%)c
4ad
3b, 80%
OH
3c, 72%
3d, 79%
OH
OH
1
2
3
4
5
6
7
8
TMSOK/Bu4NCl (10)
TMSOK/Bu4NCl (30)
TMSOK/Bu4NCl (100)
TMSOK (100)
2
2
5
–
82
87
85
41
99:1
CO2Et
MeO
CO2Et
CO2Et
99:1
99:1
93:7
–
Br
MeO
2
–
OMe
3f, 84%
16
2
32
90
88
–
3e, 86%
3g, 83%
Bu4NOAc (10)
trace
OH
OH
OH
Bu4NOAc (100)
KOAc
2
trace
–
CO2Et
OH
CO2Et
Me
CO2Et
CO2Et
16
20
–
–
–
Fe
N
O
Bu4NCl (100)
35
–
3i, 73%
3j, 70%
3kb, 78% (gram scale)
a Conditions: Benzaldehyde (0.5 mmol), ethyltrimethylsilyl acetate (0.75
mmol), solvent (2.5 mL).
3ha, 56%
b Silylether was hydrolyzed by aqueous acid workup to transform to β-hy-
droxy ester and isolated.
OH
OH
OH
Me
OH
CO2Et
Ph
c Yield of product after chromatography.
CO2Et
CO2Et
Me
CO2Et
d Determined by 1H NMR analysis.
Ph
3
3nb, 68%
3lb, 74%
3mb, 65%
3o,c 21%
Scheme 1 Addition reactions with carbonyl compounds. Reagents and
conditions: benzaldehyde (0.5 mmol), ethyltrimethylsilyl acetate (0.75
mmol), solvent (2.5 mL); yield of product after chromatography. a 1.0
equiv Bu4NOAc used, reaction time: 30 min. b 20 mol% Bu4NOAc used.
c 1.5 equiv Bu4NOAc used under reflux; reaction time: 4 h.
eties. Using crotonaldehyde as a test substrate, it was found
that the addition reaction performed equally well as a
gram-scale reaction, providing the ethyl (E)-3-hydroxyhex-
4-enoate (3k) in 78% (1.85 g) yield. The procedure was also
successful for enolizable aliphatic aldehydes with addition
of 1 to cyclohexanecarbaldehyde, 3-phenylproponal, and
pentanal providing 3l–n in good yields. Furthermore, 1 was
also added successfully to acetophenone to provide a β-hy-
droxy ester 3o with a quaternary carbon, though under
slightly more forcing reflux conditions and with unreacted
starting material remaining. In general, the substituent tol-
erance was broad, with only traces of olefin observed in the
crude products.
Next, the use of Bu4NOTMS to achieve olefination prod-
ucts under comparable conditions was evaluated by reac-
tion of 1 with a series of structurally and electronically dif-
ferent carbonyls. Olefination of electron-neutral, -rich, and
-poor aromatic aldehydes having ortho, meta, or para sub-
stituents was achieved in each case, providing the corre-
sponding alkenes 4b–l in good to high yields and with ex-
cellent E/Z ratios ranging from 93:7 to 99:1 (Scheme 2). Bi-
cyclic aromatic aldehyde, ferrocene aldehyde, and α,β-
unsaturated aldehyde all worked well under this protocol to
yield the diversely substituted alkenes (4m–o). Moreover,
pharmaceutically important alkenes (4p,q) containing het-
erocycles were also accessible with near perfect stereose-
lectivity in moderate to excellent yields. For more challeng-
ing aliphatic cyclohexanecarbaldehyde, an elevated amount
of activator was used under reflux conditions to get the ole-
fin 4s with E/Z ratio of 90:10. 2,2,2-Trifluoro-1-phenyl-
ethan-1-one also underwent olefination, providing the cor-
responding alkene 4t in 71% yield and with E/Z ratio of 99:1.
Olefination of benzophenone gave the corresponding prod-
uct 4u in 39% yield with unreacted starting material re-
maining.
From the results of Scheme 1 and Scheme 2 it is evident
that synthesis of β-hydroxy esters with Bu4NOAc activation
and α,β-unsaturated esters with TMSO–/Bu4N+ activation
both worked well in selectively delivering their respective
products. Hence, gaining an understanding of the interrela-
tionship of both methods and their reaction pathways is
important such that they may be applied to other trimeth-
ylsilane reagents.
As both activators are bases and nucleophiles, theoreti-
cally two pathways could be envisaged. The first being the
PO pathway in which deprotonation of 1 yields 5 which
upon addition to aldehyde generates 6 with in situ elimina-
tion of TMSO–giving olefin 4 (Scheme 3).13 LDA is a typical
base used to achieve the deprotonation of 1 in THF at low
temperature.19 Both of our chosen activators are relatively
weak bases, with acetate having pKa of 4.7 and trimethylsi-
lyloxide at 12.7,20 so it could be expected that silicon activa-
tion to form hypervalent silicate 7, as in route B, would be
favored over deprotonation (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
M. Das et al.
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Aldehyde addition of 7 (or its corresponding carbanion)
would lead to the silylated ether product 8. If 8 was not the
final product but was to proceed to olefin product 4 then
this would require the base elimination of trimethylsilylox-
ide. That would indicate that the differentiating feature of
the two activators used in this study is their ability to effect
the elimination of TMSO– from 8. Control of this pivot point
was achieved as Bu4NOTMS, being the stronger of the two
base systems used, is capable of doing this olefin forming–
elimination step but, under room-temperature THF condi-
tions, the weaker Bu4NOAc is not.
O
TMSOK/Bu4NCl (30 mol%)
THF, rt, 2 h
CO2Et
Me3Si
CO2Et
R1
+
R1
R2
4b–u
1
2
Cl
CO2Et
MeO
CO2Et
CO2Et
MeO
4b, 52%, 99:1
4e, 71%, 99:1
4c, 63%, 99:1
4d, 55%, 99:1
CO2Et
CO2Et
CO2Et
F
Br
F3C
Illustration of the singular silicon activating role of ace-
tate versus the dual roles of trimethylsilyloxide was
achieved in a one-pot approach as shown in Scheme 4. First,
addition of 1 to benzaldehyde was carried out using 10
mol% Bu4NOAc as silicon activator in THF at room tempera-
4g, 55%, 99:1
4f, 70%, 99:1
CO2Et
CO2Et
CO2Et
MeO2C
Ph
O
Me2N
4h, 76%, 93:7
1
ture for one hour, with H NMR analysis confirming that
4j, 74%, 99:1
4i, 73%, 99:1
complete conversion into the silylated β-hydroxy ester 3a
had occurred. At this stage, stoichiometric amount of
TMSOK/Bu4NCl was added to the same reaction flask and
stirred for one hour at room temperature. After workup, 1H
NMR analysis showed complete conversion into the corre-
sponding α,β-unsaturated ester 4a.
MeO
MeO
CO2Et
CO2Et
MeO
MeO
CO2Et
OMe
4k, 57%, 99:1
4l, 71%, 99:1
4m, 85%, 99:1
CO2Et
Bu4NOAc
(10 mol%)
TMSOK/Bu4NCl
(1.0 equiv)
CO2Et
OSiMe3
CO2Et
CO2Et
SiMe3
CO2Et
CO2Et
PhCHO
+
Ph
CO2Et
THF, rt, 1 h
rt, 1 h
Ph
Fe
O
4a
1
2a
3a
95% yield
Ph
4o, 86%, 94:6
E/Z = 99:1
N
4n, 67%, 99:1
4p, 92%, 99:1
4q, 58%, 99:1
Scheme 4 Formation of silylated β-hydroxy ester and then transforma-
tion to the corresponding olefin in one pot
CO2Et
CO2Et
CO2Et
CO2Et
In conclusion, we have demonstrated very mild and
highly selective methods for addition21 and olefination22,23
reactions with ethyl 2-(trimethylsilyl)acetate. Silicon acti-
vation of the pro-nucleophile was achieved with either
Bu4NOAc or Bu4OTMS in THF at room temperature, with the
former giving addition β-hydroxy ester products and the
latter proceeding to α,β-unsaturated esters. The use of
Bu4N+ as counterion to the nucleophilic activator is key to
successful reaction outcomes, the basis for which is cur-
rently under detailed investigation as is the potential use of
F3C
Ph
N
Ph
Ph
Boc
4s,a 21%, 90:10
4r, 32%, 99:1
4t, 71%, 99:1
4u, 39%
Scheme 2 Survey of scope for α,β-unsaturated esters. Reagents and
conditions: aldehydes or ketones (0.5 mmol), ethyltrimethylsilyl acetate
(0.75 mmol), solvent (2.5 mL), TMSOK (0.015 mmol), Bu4NCl (0.015
mmol). a TMSOK (0.50 mmol), Bu4NCl (0.50 mmol) at reflux.
X
O
PO
route A
Si activation
route B
Me3
Si
EtO2C
SiMe3
EtO2C
SiMe3
X
A
EtO
– AH
5
H
H
7
1
A
X
RCHO
RCHO
AcO
Me3SiO
or
A
X
=
(Me)3Si
X
Bu4N
=
O
O
CO2Et
CO2Et
– TMSO
X
R
X
– TMSO
CO2Et
R
R
– TMSOH
6
SiMe3
8
H
4
+ A
X
Scheme 3 Possible pathways leading to the formation of silylated β-hydroxy esters and α,β-unsaturated esters
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
M. Das et al.
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chiral ammonium salts to achieve enantioselective addi-
tions. Insight into the controlled and mild activation of
trimethylsilane pro-nucleophiles will allow for the contin-
ued expansion of their use in general synthetic chemistry.
(11) (a) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 87, 1318.
(b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654. (c) Murphy, P.
J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1. (d) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863. (e) Murphy, P. J.; Lee, S. E.
J. Chem. Soc., Perkin Trans. 1 1999, 3049.
(12) (a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733. (b) Motoyoshiya, J. Trends Org. Chem. 1998, 7, 63.
(c) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs
Ann./Recl. 1997, 7, 1283. (d) Ando, K.; Yamada, K. Green Chem.
2011, 13, 1143. (e) Claridge, T. D. W.; Davies, S. G.; Lee, J. A.;
Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Toms,
S. M. Org. Lett. 2008, 10, 5437.
Acknowledgment
We thank the European Research Association ERA-Chemistry and the
Irish Research Council (IRC) for financial support.
(13) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (b) Hudrlik, P. F.;
Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464. (c) van Staden, L.
F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195.
(d) Ager, D. J. Science of Synthesis;4V7o.al Thieme: Stuttgart, 2010, 85.
(14) Kisanga, P. B.; Verkade, J. G.; Schwesinger, R. J. Org. Chem. 2000,
65, 5431.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588805.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(15) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.;
Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele,
J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A.
V.; Ji, G. Z.; Peters, E. M.; Peters, K.; von Schnering, H. G.; Walz, L.
Liebigs Ann. 1996, 1055.
(16) (a) Das, M.; O’Shea, D. F. J. Org. Chem. 2014, 79, 5595. (b) Das,
M.; O’Shea, D. F. Chem. Eur. J. 2015, 21, 18723. (c) Das, M.;
O’Shea, D. F. Org. Lett. 2015, 17, 1962. (d) Das, M.; O’Shea, D. F.
Tetrahedron 2013, 69, 6448.
(17) (a) Das, M.; Manvar, A.; Jacolot, M.; Blangetti, M.; Jones, R. C.;
O’Shea, D. F. Chem. Eur. J. 2015, 21, 8737. (b) Manvar, A.; O'Shea,
D. F. Eur. J. Org. Chem. 2015, 7259. (c) Das, M.; O'Shea, D. F. Org.
Lett. 2016, 18, 336.
(18) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1996, 118, 3129.
(19) For example, see: Sikervar, V.; Fleet, J. C.; Fuchs, P. L. J. Org.
Chem. 2012, 77, 5132.
(1) (a) Sánchez, M.; Bermejo, F. Tetrahedron Lett. 1997, 38, 5057.
(b) Gabriel, T.; Wessjohann, L. A. Tetrahedron Lett. 1997, 38,
1363. (c) Wittenberg, R.; Beier, C.; Drager, G.; Jas, G.; Jasper, C.;
Monenschein, H.; Kirschning, A. Tetrahedron Lett. 2004, 45,
4457.
(2) (a) Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002, 43, 9405.
(b) Chen, D.; Guo, L.; Liu, J.; Kirtane, S.; Cannon, J. F.; Li, G. Org.
Lett. 2005, 7, 921. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388. (d) Lόpez, F.; Harutyunyan, S. R.; Meetsma, A.;
Minnaard, A. J.; Feringa, B. L. Angew. Chem. Int. Ed. 2005, 44,
2752. (e) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61,
10377. (f) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(3) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
(4) (a) Gensler, W. J. Chem. Rev. 1957, 57, 191. (b) Diaper, D. G. M.;
Kuksis, A. Chem. Rev. 1959, 59, 89.
(20) Baker-Glenn, C. A. G.; Barrett, A. G. M.; Gray, A. A.; Procopiou, P.
A.; Ruston, M. Tetrahedron Lett. 2005, 46, 7427.
(21) General Procedure for Addition Reactions
(5) (a) Fürstner, A. Synthesis 1989, 571. (b) Ocampo, R.; Dolbier, W.
R. Tetrahedron 2004, 60, 9325. (c) Orsini, F.; Sello, G. Curr. Org.
Synth. 2004, 1, 111.
A solution of ethyl 2-(trimethylsilyl)acetate (1, 137 μL, 0.75
mmol) and aldehyde (0.50 mmol) in anhydrous THF (2.5 mL)
was treated with dried Bu4NOAc (0.05 mmol) under N2. The
resulting solution was stirred at r.t. for 1 h. Aqueous HCl (2 M,
10 mL) was added and stirred for 30 min. The residue was
extracted with Et2O (3 × 15 mL), organic layers combined,
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure gave the crude product.
(6) (a) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452. (b) Santaniello, E.;
Manzocchi, A. Synthesis 1977, 698. (c) Csuk, R.; Fürstner, A.;
Weidmann, H. J. Chem. Soc., Chem. Commun. 1986, 775.
(7) (a) Moriwake, T. J. Org. Chem. 1996, 31, 983. (b) Durandetti, M.;
Périchon, J. Synthesis 2006, 1542. (c) Inaba, S.-I.; Rieke, R. D. Tet-
rahedron Lett. 1985, 26, 155. (d) Suh, Y. S.; Rieke, R. D. Tetrahe-
dron Lett. 2004, 45, 1807. (e) Chao, L. C.; Rieke, R. D. J. Org. Chem.
1975, 40, 2253. (f) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A.
J. Org. Chem. 2005, 70, 10408.
(8) (a) Nakamura, E.; Shimizu, M.; Kuwajima, I. Tetrahedron Lett.
1976, 20, 1699. (b) Nakamura, E.; Shimizu, M.; Kuwajima, I.;
Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983, 48, 932.
(c) Miura, K.; Sato, H.; Tamaki, K.; Ito, H.; Hosomi, A. Tetrahe-
dron Lett. 1998, 39, 2585.
(9) (a) Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009, 74, 4368.
(b) Kobayashi, K.; Ueno, M.; Kondo, Y. Chem. Commun. 2006,
3128. (c) Bellassoued, M.; Ozanne, N. J. Org. Chem. 1995, 60,
6582. (d) Latouche, R.; Texier-Boullet, F.; Hamelin, J. Bull. Soc.
Chim. Fr. 1993, 130, 535. (e) Matsukawa, S.; Okano, N.; Imamoto,
T. Tetrahedron Lett. 2000, 41, 103. (f) Birkofer, L.; Ritter, A.;
Wieden, H. Chem. Ber. 1962, 95, 971.
(10) For general reviews on the synthesis of unsaturated esters, see:
(a) Franklin, A. S. J. Chem. Soc., Perkin Trans. 1 1998, 2451.
(b) Shen, Y. Acc. Chem. Res. 1998, 31, 584.
Ethyl 3-(2-chlorophenyl)-3-hydroxypropanoate (3b)
A solution of ethyl 2-(trimethylsilyl)acetate (1, 137 μL, 0.75
mmol) and 2-chlorobenzaldehyde (70 mg, 0.50 mmol) in anhy-
drous THF (2.5 mL) was treated with dried Bu4NOAc (15 mg,
0.05 mmol) under N2. The resulting solution was stirred at r.t.
for 1 h. Aqueous HCl (2 M, 10 mL) was added and stirred for 30
min. The residue was extracted with Et2O (3 × 15 mL), organic
layers combined, washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. Purification by silica gel
chromatography eluting with cyclohexane–EtOAc (90:10)
afforded 3b as a colorless oil (91 mg, 80%). 1H NMR (400 MHz,
CDCl3): δ = 7.63 (dd, J = 7.7, 1.6 Hz, 1 H), 7.36–7.27 (m, 2 H), 7.22
(td, J = 7.6, 1.7 Hz, 1 H), 5.49 (dd, J = 9.7, 2.5 Hz, 1 H), 4.20 (q, J =
7.1 Hz, 2 H), 3.61 (br s, 1 H), 2.86 (dd, J = 16.6, 2.7 Hz, 1 H), 2.58
(dd, J = 16.6, 9.7 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.7, 140.0, 131.5, 129.5, 128.9, 127.3,
127.2, 67.2, 61.1, 41.5, 14.3 ppm. ESI–MS: m/z cald for
C
11H14O3Cl [M + H]+: 229.1; found: 229.0.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
M. Das et al.
Cluster
Synlett
(22) General Procedure for Olefination Reactions
and TMSOK (19 mg, 0.15 mmol) under N2, and the resulting
reaction mixture was stirred at r.t. for 2 h. The reaction mixture
was quenched with 2 M aq HCl (10 mL) and stirred for 5 min at
r.t. The residue was extracted with EtOAc (3 × 15 mL). Organic
layers were combined and washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. Purifi-
cation by Al2O3 chromatography eluting with cyclohexane–
EtOAc (90:10) yielded 4l (95 mg, 71%) as a colorless solid, mp
A solution of ethyl trimethylsilylacetate (1, 137 μL, 0.75 mmol)
and aldehyde (0.50 mmol) in THF (2.5 mL) was treated with
dried Bu4NCl (0.15 mmol) and TMSOK (0.15 mmol) under N2,
and the resulting reaction mixture was stirred at r.t. for 2 h. The
reaction mixture was quenched with aq 2 M HCl (10 mL) and
stirred for 5 min at r.t. The residue was extracted with EtOAc (3
× 15 mL). Organic layers were combined and washed with water
and brine, dried over Na2SO4, and concentrated under reduced
pressure to give the crude product.
1
53–55 °C. H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 16.0 Hz, 1
H), 6.74 (s, 2 H), 6.33 (d, J = 16.0 Hz, 1 H), 4.25 (q, 2 H), 3.87 (s, 9
H), 1.33 (t, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.9, 153.4,
144.5, 140.1, 129.9, 117.5, 105.2, 60.9, 60.4, 56.1, 26.9, 14.3. MS
(EI): m/z calcd for C14H18O5 [M]+: 266.1; found: 266.2.
(23) (E)-Ethyl-3-(3,4,5-trimethoxyphenyl)acrylate (4l)
A
solution of 3,4,5-trimethoxybenzaldehyde (98 mg, 0.50
mmol) and ethyl trimethylsilylacetate (1, 137 μL, 0.75 mmol) in
THF (2.5 mL) was treated with dried Bu4NCl (42 mg, 0.15 mmol)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F