Generation of ynolates via reductive lithiation using flow microreactors

Article abstract of DOI:10.1016/j.tetlet.2014.01.147

A new method has been developed for the generation and subsequent reaction of ynolates in a micro flow reactor system. This new procedure allowed for ynolates to be prepared at 0 C or ambient temperature within 1 min via a reductive lithiation reaction, whereas the corresponding batch processes generally require low temperature control and extended reaction times of up to 1 h. The resulting ynolates were applied to the olefination of carbonyl compounds, with the reactions reaching completion in a much shorter reaction time in the continuous flow reactor than the batch reactor. These results highlight the practical utility of the ynolate reaction, and represent the first reported example of the use of lithium naphthalenide in a flow microreactor, which would contribute to progress of the flash chemistry.

Full text of DOI:10.1016/j.tetlet.2014.01.147

Tetrahedron Letters 55 (2014) 1822–1825
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Generation of ynolates via reductive lithiation using flow
microreactors
Satoshi Umezu a, Toshiya Yoshiiwa a, Manabu Tokeshi c, Mitsuru Shindo b,
⇑
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga-koen, Kasuga 816-8580, Japan
b Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasuga-koen, Kasuga 816-8580, Japan
c Faculty of Engineering, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method has been developed for the generation and subsequent reaction of ynolates in a micro flow
reactor system. This new procedure allowed for ynolates to be prepared at 0 °C or ambient temperature
within 1 min via a reductive lithiation reaction, whereas the corresponding batch processes generally
require low temperature control and extended reaction times of up to 1 h. The resulting ynolates were
applied to the olefination of carbonyl compounds, with the reactions reaching completion in a much
shorter reaction time in the continuous flow reactor than the batch reactor. These results highlight the
practical utility of the ynolate reaction, and represent the first reported example of the use of lithium
naphthalenide in a flow microreactor, which would contribute to progress of the flash chemistry.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 November 2013
Revised 21 January 2014
Accepted 28 January 2014
Available online 6 February 2014
Keywords:
Flow microreactor
Li/halogen exchange
Reductive lithiation
Ynolate
We have reported a variety of new reactions with ynolates 1,1
including formal [n + 1] type cycloaddition reactions to give
multisubstituted carbocycles2 and heterocycles,3 as well as a
torquoselective olefination reaction for the construction of stereo-
defined multisubstituted olefins.4 We have already developed a
convenient and facile method for the preparation of ynolates via
the thermal cleavage of ester dianions derived from the double
slower than the first one (2 ? 3), the lithium ynolate 3 generated
by the initial Li/Br exchange may react with the unreacted starting
ester 2 and other undesired reactions can also occur when the reac-
tion is performed at higher temperatures. The lithium ester enolate
intermediate 3, in particular, is generally unstable over ꢀ20 °C and
decomposes with the loss of lithium ethoxide to give a highly reac-
tive ketene.6 To suppress these self-condensation and ketene for-
mation processes, the low temperature control must be applied.
Microflow systems have the potential to overcome the
limitations encountered in batch systems, because they provide
constant reaction parameters, such as temperature, reaction time,
concentration, and mixing, which can be readily assured via time
and space integration.7 It was envisaged that microflow systems
could be used to control the increase in temperature associated with
the critical exothermic lithiation reaction that takes place during
the preparation of ynolates.8 Herein, we report the successful gener-
ation of ynolates via reductive lithiation using a microflow reactor.
Importantly, these reactions did not need to be cooled to ꢀ78 °C.
We initially evaluated a variety of different microflow reactors
for the preparation of ynolates via a Li/Br exchange reaction. The
mixing of a hexane solution of n-butyllithium (1.5 M) and a THF
solution of dibromoester in an integrated glass chip microchannel
lithiation of
performed, in that it involves the treatment of a THF solution of
the
-dibromo ester with 4 equiv of t-, s- or n-BuLi at ꢀ78 °C
a,a
-dibromo esters 2.5 This procedure can be readily
a,a
for 10–15 min, with the resulting mixture being allowed to warm
to 0 °C for 30 min (Scheme 1). Although this method is both
practical and reproducible in a batch system on the bench-scale,
where the butyllithium must be added slowly to maintain the
low temperature, the exothermic nature of this step is difficult to
control when scaling up the batch reaction because of differences
in the ratio of the surface area to the reaction volume as the batch
size increases. Our attempts to prepare ynolates at ambient tem-
perature in a batch system were unsuccessful, even at a scale of
less than 1 mmol, because the Li/Br exchange reactions of
compounds such as 2 are extremely exothermic and result in
numerous undesired side products following the reaction of the
lithiated mixture with benzophenone. During the preparation of
ynolates, since the second Li/Br exchange reaction (3 ? 4) is
reactor (200 lm width and 100 lm depth) resulted only in the
formation of a blockage at the junction, most likely because of
the precipitation of lithium salts. This precipitation issue would
not be observed in a batch system, and occurred at the contact area
of the laminar flow (hexane–THF) in the microfluidic system. To
⇑
Corresponding author. Tel.: +81 92 583 7802; fax: +81 92 583 7875.
E-mail address: shindo@cm.kyushu-u.ac.jp (M. Shindo).
http://dx.doi.org/10.1016/j.tetlet.2014.01.147
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Umezu et al. / Tetrahedron Letters 55 (2014) 1822–1825
1823
1.0 mL/min
x-BuLi
O
OLi
OEt
OLi
OEt
φ = 1.0 mm
L = 289 cm
tR = 67 s
(4 equiv)
s-BuLi (1.0 M)
in cyclohexane
OEt
T °C
Br Br
15 min
Li
Br
3
mixer
Me
4
2
(exothermic)
OLi
1.2 equiv
O
EtOLi
T = -78 °C >90% (t-BuLi)
20 °C 0% (t-BuLi)
1.0 mL/min
O
CO2H
Ph
Ph
Ph
-78 °C >90% (s-BuLi)
OEt
CO2H
Ph
-78 °C
-50 °C
-30 °C
83% (n-BuLi)
73% (n-BuLi)
53% (n-BuLi)
0 °C
O
OLi
20 °C
<10 min
Ph
(0.25 M)
in THF
Br Br
30 min
1
5
2
Ph
Ph
Ph
5
in THF
64-67% yield
Scheme 1. Generation and reaction of ynolate.
rt. for 30 min
Figure 2. A flow microreactor system with a static mixer for the generation of an
ynolate via a Li/Br exchange reaction.
avoid the formation of a blockage, we proceeded to evaluate an
alternative microtube reactor consisting of a stainless steel static
micromixer, which was originally designed for HPLC (Fig. 1,
150
l
L, GL Science, Tokyo, Japan), and a stainless steel tube with
RBr
Li
O
Li
Br
an internal diameter of 1000
l
m as a microreactor. The reaction
6
was carried out at room temperature and the residence time (tR)
was controlled by the length of the tube reactor. The ynolate
generated in the microreactor was subsequently trapped by its
reaction with benzophenone in a flask at room temperature. The
isolated yield of the resulting olefin was determined to allow for
the efficiency of this method to be evaluated.
s-BuLi
OH
Ph
O
7
Ph
Ph
Ph
HO s-Bu
Ph
Ph
8
Solutions of sec-butyllithium (0.92 M in cyclohexane) and
dibromoester (0.22 M in THF) were pumped into the reactor at a
flow rate of 1.0 mL/min and mixed in the mixer at 20 °C, where
the residence time was approximately 67 s. The resulting ynolate
(1.2 equiv based on benzophenone) was reacted with a solution
of benzophenone in THF at room temperature in a separate flask.
Pleasingly, no blockages were observed in the reactor when the
procedure was performed on a 1 mmol scale. After the flow was
stopped, the reaction mixture was stirred for an additional
30 min before being worked up as usual to afford the desired olefin
in 64–67% isolated yield (Fig. 2). These preliminary results indi-
cated that the ynolate could be generated in the microreactor at
ambient temperature. Given that this result could not be achieved
with a batch system without low-temperature control, the use of a
flow microreactor system in this regard proved to be particularly
useful for the preparation of ynolates.
It is well known that butyllithium can readily react with THF at
ambient temperature to give several byproducts such as ethylene,9
which can itself react with butyllithium to form small amounts (a
couple of percent of yields) of the byproducts 6 and 7. These
byproducts, as well as several other byproducts, such as 8, which
resulted from the reaction of s-BuLi with benzophenone, were
detected by GC analysis (Fig. 3). To prevent the occurrence of these
side reactions, we investigated the use of diethyl ether as the
Figure 3. Byproducts derived from sec-butyllithium in a flow system.
reaction solvent under various reaction conditions because it is
not as reactive as THF. The use of diethyl ether, however, resulted
in lower product yields in the range of 14–51%, probably due to the
lower activation ability to alkyllithium.
We then proceeded to investigate the possibility of generating
the ynolate and subjecting it to an olefination reaction in a flow mi-
cro system consisting of two micromixers (M1 and M2), as shown
in Figure 4. A solution of the ynolate in THF, which was generated
in M1 and R1, was mixed with a solution of benzophenone in THF
in M2 with a flow rate of 2.0 mL/min and a residence time (tR) of
3 s. When the reaction was conducted at temperatures of 0 and
30 °C (tR1 = 30–60 s), it gave product yields in the range of 50–65%.
The stainless steel flow microreactor was equipped with a
quartz glass tube (/ = 1 mm, L = 10 mm) for the visualization of
the flow (Fig. 5). Through this tube, we became aware of the gen-
eration of gas bubbles inside R1 when the reaction was conducted
at ambient temperature. These gases were most likely butane and/
or butene analogues, derived from butyllithium, and ethylene gen-
erated by the reaction of THF with butyllithium, as described
temperature-controlled area
s-BuLi (1.0 M)
φ = 1 mm
X s
in cyclohexane/hexane
M1
flow rate = 1.0 mL/min
R1
R2
20 cm, 3 s
M2
O
OEt
Br Br
O
0.25 M in THF
Ph
Ph
flow rate = 1.0 mL/min
in THF
HO2C
Ph
Ph
stirred at rt.
for 30 min
Figure 1. A static micromixer.
Figure 4. Generation and reaction of ynolate in flow microreactor.

1824
S. Umezu et al. / Tetrahedron Letters 55 (2014) 1822–1825
Table 1
Microfluidic reductive lithiation methoda
T (°C)
R1 (s)
30
3
60
ꢀ10
0
25
40
—
—
46%
55%
62%
82%
73%
—
62%
79%
76%
—
a
The reaction conditions are shown in Figure 6.
Figure 5. Flow microreactor system equipped with a quartz glass tube.
above. The formation of these bubbles prevented the steady flow of
the substrate solutions through the system and led to inconsistent
and moderate yields.
The formation of byproducts derived from butyllithium would
also be a problem as long as this reagent was being used to affect
the Li/Br exchange reaction, and the use of an alternative lithiation
method would be required to avoid this issue. With this in mind,
we decided to use reductive lithiation instead of Li/Br exchange
reaction to generate the ynolate species.10 Lithium metal was
added to a solution of naphthalene in THF in a batch system to give
a lithium naphthalenide solution, which was mixed with a THF
solution of dibromoester in M1 in a flow system. The resulting
ynolate solution in R1 was mixed with a benzophenone solution
in M2, and this olefination reaction mixture afforded a residence
time of 50 s in R2 before being quenched into a flask of water
(Fig. 6). The ynolate formation reaction was investigated over a
variety of different residence times (i.e., tR = 3, 30, 60 s) in R1 at
temperatures in the range of ꢀ10–40 °C (Table 1). At ꢀ10 °C, the
desired product was produced in 62% yield, and the yield increased
up to 82% at 0 °C. Furthermore, the generation of the ynolate ap-
peared to reach completion within 30 s at this temperature. Fur-
ther increases in the temperature did not lead to further
improvements in the yield, with a reaction temperature of 0 °C
appearing to be optimal in terms of the yield. Since no bubbles
were detected during the course of the ynolate formation using
the reductive lithiation method, this method was therefore
deemed to be more suitable for the preparation of ynolates than
the Li/Br exchange method using butyllithium. Under the opti-
mized reaction conditions for this flow system (i.e., T = 0 °C,
φ1000 μm
φ250 μm
φ500 μm
a
b
c
Figure 7. A mixer of micro flow reactor, Comet X contains three kinds (a, b and c) of
round plates bearing micro holes.
The inner structure of this Teflon mixer consisted of 18 round
plates bearing three different micro-hole plates inside each plate
(Fig. 7 a, b and c) and, by changing the combination of these plates,
the size of the flow channel could be readily adjusted. Although M1
could be used as a default combination (plates a, b and c) without
having an adverse impact on the outcome on the reaction, the plate
combination in M2 had to be tuned to avoid the formation of a
blockage in the flow. Finally, using eight a plates and eight c plates
in M2, we succeeded in achieving continuous flow without
clogging the system to obtain 1.18 g of the product in 75% yield
(Fig. 8).12
Using this flow system, we investigated the olefination of a
variety of different ketones to afford the corresponding alkenes
in good yield (Table 2).13 Although the products were formed in
similar yields to those obtained in a batch system,14 the current
flow system provided several advantages over the batch system,
including the ability to readily control the temperature on
scaling-up the reaction, as well as the reaction reaching comple-
tion in only one minute.
t
R1 = 30 s), we investigated the use of this continuous flow system
on the gram scale. Unfortunately, however, the flow system failed
on this scale because of the formation of a blockage in M2 follow-
ing several min of the reaction. The use of an M2 mixer with a lar-
ger inner diameter may have allowed for this reaction to be
successfully conducted on a gram scale, but it was not possible
to adjust of the inner diameter of this device.
Lithium
naphthalenide
To achieve a gram-scale flow reaction, we investigated the use
of Comet X-01 mixer (Techno Applications Co., Ltd, Tokyo, Japan).11
0 o
C
in THF (1.0 M)
1 mL/min
R1
30 s
M1
R2
32 s
T ºC
Lithium
M2
Naphthalenide
R1
O
in THF (1.0 M)
1 mL/min
M1
X sec
OEt
substrate
Br Br
in THF (0.24 M)
1 mL/min
R2
50 s
M2
in THF
2 mL/min
H2O
product
O
OEt
HO2C
Ph
Br Br
O
Figure 8. Schematic representation of the flow reactor system used for the
preparation of the ynolate via the reductive lithiation reaction using the Comet X
mixer. M1 contained the default combination of the three different kinds of micro
plates (a, b and c) shown in Figure 7, whereas M2 had only two different types of
micro plate (a and c).
in THF
in THF (0.075 M)
Ph 2 mL/min
Ph
(0.24 M)
Ph
H2O
1 mL/min
Figure 6. Generation and reaction of the ynolate via reductive lithiation.

S. Umezu et al. / Tetrahedron Letters 55 (2014) 1822–1825
1825
Table 2
Flow synthesis of tetrasubstituted alkenes via the ynolate using the system shown in Figure 8
O
lithium
O
CO2H
R'
naphthalenide
R
R'
THF
OEt
THF
R
Br Br
OLi
0 ºC, 30 sec
0 ºC, 35 sec
(1.5 equiv)
Entry
R
R0
Flow reactiona (%)
E:Z
Batch reaction (%) (E:Z)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
80
—
—
84:16
79:21
<1:>99
<1:>99
70
70
75b
60
Me
PhCH = CH
TMS
76 (81:19)
82 (79:21)
59 (<1:>99)
43 (<1:>99)
66
74b
79
CH(OTBS)Ph
a
0.5 mmol scale.
20 °C in R2.
b
A. Adv. Synth. Catal. 2012, 354, 17; (d) Wegner, J.; Ceylan, S.; Kirschning, A.
Chem. Commun. 2011, 4583; (e) Geyer, K.; Gustafsson, T.; Seeberger, P. H.
Synlett 2009, 2382; (f) Yoshida, J.; Nagaki, A.; Yamada, T. Chem. Eur. J. 2008, 14,
7450; (g) Fukuyama, T.; Rahman, Md. T.; Sato, M.; Ryu, I. Synlett 2008, 151.
8. Lithium/halogen exchange reactions in flow microreactors: (a) Usutani, H.;
Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc.
2007, 129, 3046; (b) Nagaki, A.; Tomida, Y.; Usutani, H.; Kim, H.; Takabayashi,
N.; Nokami, T.; Okamoto, H.; Yoshida, J. Chem. Asian J. 2007, 2, 1513; (c) Nagaki,
A.; Kim, H.; Yoshida, J. Angew. Chem., Int. Ed. 2008, 47, 7833; (d) Goto, S.; Velder,
J.; Sheikh, S. E.; Sakamoto, Y.; Mitani, M.; Elmas, S.; Adler, A.; Becker, A.;
Neudorfl, J-M.; Lex, J.; Schmalz, H-G. Synlett 2008, 1361; (e) Tomida, Y.; Nagaki,
A.; Yoshida, J. Org. Lett. 2009, 11, 3614; (f) Nagaki, A.; Kim, H.; Yoshida, J. Angew.
Chem., Int. Ed. 2009, 48, 8063; (g) Nagaki, A.; Takizawa, E.; Yoshida, J. J. Am.
Chem. Soc. 2009, 131, 1654; (h) Nagaki, A.; Kenmoku, A.; Moriwaki, Y.; Hayashi,
A.; Yoshida, J. Angew. Chem., Int. Ed. 2010, 49, 1; (i) Nagaki, A.; Kim, H.; Usutani,
H.; Matsuo, C.; Yoshida, J. Org. Biomol. Chem. 2010, 8, 1212; (j) Nagaki, A.;
Ichinari, D.; Yoshida, J. Chem. Commun. 2013, 3242; (k) Nagaki, A.; Uesugi, Y.;
Kim, H.; Yoshida, J. Chem. Asian J. 2013, 8, 705.
We have succeeded in developing a reaction for the generation
of ynolates and their subsequent reaction with a range of ketones
in the micro flow systems. The ynolate preparation process can be
readily carried out at 0 °C or ambient temperature within 1 min.
This represents a significant improvement over the corresponding
batch systems, which require low temperature control and 1 h for
the reaction to reach completion. The success of this process can be
attributed to quick heat exchange properties of flow microreactors,
which allowed for the decomposition of the ester enolate interme-
diate and self-condensation reactions that occurred before the
second lithiation step to be avoided. The olefination of a series of
carbonyl compounds with the ynolate proceeded to completion
in much shorter overall reaction time using the continuous flow
reactor. This result highlights the practical utility of the current
method for the synthesis of ynolates, even though the overall
yields were close to those obtained using batch systems. Further-
more, this work is the first example of use of lithium naphthale-
nide (reductive lithiation) in microreactors, and therefore
represents a significant contribution towards general progress in
flow chemistry.
9. Bates, R. B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972, 37, 560.
10. Shindo, M.; Koretsune, R.; Yokota, W.; Itoh, K.; Shishido, K. Tetrahedron Lett.
2001, 42, 8357.
11. A micromixing device, ‘Comet X-01’, is available from Techno Applications Co.,
Ltd, 34-16-204, Hon, Denenchofu, Oota, Tokyo, 145-0072, Japan. Since it is
made of teflon, the surface of the inlet port of mixer was partially blackened by
lithium naphthalenide, but it was not a problem for the flow.
12. Naphthalene was recovered in more than 84%.
13. Representative procedure (flow reaction): A flow microreactor consisting of
two teflon mixers (M1 and M2), two teflon microtube reactors (1000 lm,
Acknowledgements
L = 100 cm (R1), 300 cm (R2)) was used. A twin syringe pump was charged
with two 5 mL syringes, one containing lithium naphthalenide (1.0 mmol) in
THF (4.1 mL), which was taken from a stock solution freshly prepared from
lithium metal (100 mg, 14.4 mmol) and naphthalene (1.65 g, 12.9 mmol) in
THF (13 mL) at 0 °C, and the other dibromoester 2 (1.03 mmol, 267 mg) in
THF (4.1 mL). M1, M2, R1 and R2 were dipped in a cooling bath at 0 °C.
Solutions of lithium naphthalenide in THF and dibromoester in THF were
introduced to M1 (containing plates a, b, and c) by the syringe pumps in a
flow rate of 1.0 mL/min each. The resulting solution was passed through R1
This work was supported by the Program for Science and
Technology Research Promotion Program for Agriculture, Forestry,
Fisheries and Food Industry, and the Japan Society for the Promotion
of Science (JSPS) KAKENHI (Grant Nos. 24106731 and 22390002).
Reference and notes
and was mixed with
a THF solution (8.2 mL) of benzophenone (121 mg,
0.665 mmol) in M2 in a flow rate of 2.0 mL/min. The resulting solution was
poured into water. After a steady state was reached, the product solution
was collected for 60 s (corresponding to 0.162 mmol of benzophenone
in 2 mL of 0.081 M THF solution). The collected mixture was extracted
with 2% NaOH solution. The aqueous solution was acidified with 3 M HCl
and extracted with AcOEt (3 ꢁ 25 mL), The combined organic layer was
washed with brine, dried over MgSO4 and concentrated. The residue was
purified with silica gel column chromatography (60% AcOEt/Hexane then
1. Reviews, see: (a) Shindo, M. Tetrahedron 2007, 63, 10; (b) Shindo, M. The
Chemistry of Metal Ynolates. In The Chemistry of Metal Enolates; The Chemistry
of Functional Groups, Zabicky, Jacob, Eds.; Patai Series, John Wiley & Sons,
2009; pp 739–786.
2. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507; (b) Shindo,
M.; Matsumoto, K.; Sato, Y.; Shishido, K. Org. Lett. 2001, 3, 2029; (c) Shindo, M.;
Sato, Y.; Shishido, K. J. Org. Chem. 2001, 66, 7818.
100% AcOEt) to yield the carboxylic acid
benzophenone).
5
(31 mg, 80% based on
3. Shindo, M.; Yoshimura, Y.; Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto,
K.; Shishido, K. Org. Lett. 2007, 9, 1963.
14. Representative procedure (batch reaction): To
a
solution of naphthalene
4. (a) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65, 5443; (b) Shindo, M.;
Matsumoto, K.; Mori, S.; Shishido, K. J. Am. Chem. Soc. 2002, 124, 6840; (c)
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Yoshikawa, T.; Itou, Y.; Mori, S.; Nishii, T.; Shishido, K. Chem. Eur. J. 2006, 12,
524; (f) Shindo, M.; Kita, T.; Kumagai, T.; Matsumoto, K.; Shishido, K. J. Am.
Chem. Soc. 2006, 128, 1062; (g) Yoshikawa, T.; Mori, S.; Shindo, M. J. Am. Chem.
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Matsumoto, K. Top. Curr. Chem. 2012, 327, 1.
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Matsumoto, K.; Shishido, K. Org. Synth. 2007, 84, 11.
6. (a) Haner, R.; Laube, T.; Seebach, D. J. Am. Chem. Soc. 1985, 107, 5396; (b)
Tomioka, K.; Shindo, M.; Koga, K. J. Org. Chem. 1990, 55, 2276.
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(520 mg, 4.0 mmol) in THF (8 mL) was added lithium metal (30 mg,
4.3 mmol). The deep blue mixture was stirred for 3 h at room temperature
under argon., A solution of ethyl 2,2-dibromopropionate (259 mg, 1.0 mmol)
in THF (2 mL) was then added dropwise to the solution of lithium
naphthalenide at ꢀ78 °C. The solution was stirred for 3 h at ꢀ78 °C and
allowed to warm to 0 °C. After 30 min, 1,2-dibromoethane (1 drop) was added
to quench the excess lithium naphthalenide, the resulting pale yellow
solution was warm to room temperature and then
a solution of
benzophenone (120 mg, 0.66 mmol) in THF (2 mL) was added. After 1 h, the
resulting mixture was quenched with H2O, and extracted with aqueous 10%
NaOH solution. The aqueous phase was acidified with 3 M HCl, and extracted
with ethyl acetate. The organic phase was washed with brine, dried over
MgSO4, filtered and concentrated to give residue, which was purified by
column chromatography to afford the 2-methyl-3,3-diphenylacrylic acid
(109 mg, 70%).