Substituent-dependent reactivity in aldehyde transformations: 4-(phenylethynyl)benzaldehydes versus simple benzaldehydes

Article abstract of DOI:10.1016/j.tet.2013.03.056

Effects of substituents on transformations of 4-(phenylethynyl) benzaldehydes and related benzaldehydes were analyzed in aldol and thiazolidine formation reactions. The aldol reaction of 4-cyanobenzaldehyde was 54-fold faster than that of 4-methoxybenzald

Full text of DOI:10.1016/j.tet.2013.03.056

Tetrahedron 69 (2013) 4098e4104
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Substituent-dependent reactivity in aldehyde transformations:
4-(phenylethynyl)benzaldehydes versus simple benzaldehydes
,
,
,
Isamu Katsuyama a b, Pandurang V. Chouthaiwale a b, Hai-Lei Cui a b, Yuji Ito c,
Ayumi Sando c, Hiroaki Tokiwa c, Fujie Tanaka a
,b,
*
a Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
b Okinawa Institute of Science and Technology Graduate University, Mikuruma, 448-5 Kajii, Kamigyo, Kyoto 602-0841, Japan
c Department of Chemistry, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima, Tokyo 171-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Effects of substituents on transformations of 4-(phenylethynyl)benzaldehydes and related benzalde-
hydes were analyzed in aldol and thiazolidine formation reactions. The aldol reaction of 4-
cyanobenzaldehyde was 54-fold faster than that of 4-methoxybenzaldehyde. In contrast, the aldol re-
action of 4-(4-cyanophenylethynyl)benzaldehyde was only 1.4-fold faster than that of 4-(4-
methoxyphenylethynyl)benzaldehyde. Electronic features of substituents are significantly less in-
fluential in a diphenylacetylene system than in a simple benzene system.
Received 30 December 2012
Received in revised form 12 March 2013
Accepted 15 March 2013
Available online 19 March 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Substituent effect
Substituent constants
Reaction rate
Aldehyde
Aldol reaction
Thiazolidine
1. Introduction
diarylacetylene moiety are
sults suggest that electronic features of substituents attached to
one end of a diarylacetylene -system are likely to significantly
influence the reactivity of groups attached at the other end of the
system. On the other hand, the degree of the substituent effect may
vary depending on factors other than -conjugation. In this study,
p
-conjugated.3,4aec These reported re-
Electron-withdrawing and electron-donating functional groups
often determine the reactivity of molecules.1,2 Understanding the
nature of the substituent effect is important to the design and
synthesis of functionalized molecules. Although it is often consid-
p
p
-
p
ered that
p
-systems efficiently transmit the substituent effect
to provide information useful for the design, synthesis, and use of
diphenylacetylene derivatives, reactivities on 4-(phenylethynyl)
benzaldehyde with various substituents and on simple benzalde-
hyde with the same substituents were analyzed in aldol and thia-
zolidine formation reactions and changes in the reactivities were
compared.
through resonance,1,2 with the exceptions of effects on simple
benzene derivatives, there is not much information regarding to
what extent electronic features of substituents alter the reactivity
of molecules. Here we report effects of substituents in nucleophilic
addition reactions on aldehyde groups attached to diphenylacety-
lene derivatives.
Diphenylacetylene derivatives and related compounds con-
taining a p-conjugated CeC triple bond are important as synthons,
probes, and other functional molecules.3,4 In reported crystal
structures of diphenylacetylene derivatives, two phenyl groups
connected to the ethynylene group are located in a single plane (i.e.,
the coplanar conformation).5 This indicates that the phenyl groups
are conjugated.3,5 Previously reported fluorescence data of diary-
lacetylene derivatives also suggest that the two aryl groups of the
2. Results and discussion
2.1. Substituent effect in aldol reactions
First, effect of substituents was analyzed in aldol reactions. Aldol
reactions are important CeC bond forming reactions. One of po-
tential uses of the substituted 4-(phenylethynyl)benzaldehydes
is as fluorogenic probes to monitor the progress of aldol reactions.4d
Effects of substituents have previously been observed in enamine-
based aldol reactions of benzaldehydes.2c
* Corresponding author. E-mail address: ftanaka@oist.jp (F. Tanaka).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.056

I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
4099
Aldol reactions of acetone with a series of substituted benzal-
dehydes (1) and of substituted 4-(phenylethynyl)benzaldehydes (2)
were performed using proline as the catalyst4d,6 in DMSO-d6. For-
mation of aldol products (3 and 4) was monitored by 1H NMR. To
provide information useful for the design and synthesis of diphe-
nylacetylene derivatives, reaction conditions that were similar to
those used actual syntheses were used. To quickly analyze the re-
activity differences between the simple benzaldehyde series and
the 4-(phenylethynyl)benzaldehyde series under these conditions,
initial reaction rates and the ratios of the rates were determined
and compared.
For both the simple benzaldehydes (Table 1) and the 4-(phe-
nylethynyl)benzaldehydes (Table 2), reactions of aldehydes bearing
the electron-withdrawing cyano substituent were faster than those
of aldehydes bearing the electron-donating methoxy group (entries
2 vs entries 4). The degree of contribution of the substituents on 4-
(phenylethynyl)benzaldehyde to reaction velocities was very dif-
ferent from that of the substituents on the simple benzaldehyde
(Fig. 1). For the aldol reaction of benzaldehydes 1, initial rates
ranged 0.3e15 mM/h (Table 1). Formation of 3b from 1b was 54-
fold faster than the formation of 3d from 1d (Fig. 1 and Table 1
entries 2 and 4). In contrast, for 4-(phenylethynyl)benzaldehydes
2, the range of initial rates was 2.6e3.6 mM/h (Table 2). Formation
of 4b from 2b was only 1.4-fold faster than the formation of 4d from
Fig. 1. Relative initial rates (V1/V1a and V2/V1a) of proline-catalyzed aldol reactions of 2
determined by comparing with the initial rate of the reaction of 1a.
Table 1
Comparison of initial rates of aldol reactions of acetone with benzaldehyde
derivativesa
2d (Fig. 1 and Table 2 entries 2 and 4). Effect of substituents was
significantly reduced through the (phenylethynyl)phenyl moiety
compared to effects through the single phenyl group.
To estimate the contribution of the CeC triple bond within the
(phenylethynyl)benzaldehyde derivatives in transmitting elec-
tronic features of substituents, the aldol reactions of styr-
ylbenzaldehydes 5, which had a CeC double bond instead of the
CeC triple bond of 2, were analyzed (Scheme 1). Reactions of 5
were performed under the same conditions used for the aldol re-
actions shown in Tables 1 and 2. Initial rates of the formation of 6a
and 6b were 2.0 and 2.2 mM/h, respectively. The rate of the for-
mation of 6b was only 1.1-fold of that of the formation of 6a and
was slower than that of the formation of 4b (Note that formation of
4b was 1.3-fold faster than the formation of 4a). These results in-
dicated that the CeC triple bond between two phenyl groups better
transmitted the electronic features of substituents than did the CeC
c
Entry
R
1
3
V1 (mM/h)b
V1/V1a
1
2
3
4
5
6
H
CN
Me
OMe
Ethynyl
CF3
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
1.7
15
1.2
1.0
8.6
0.7
0.2
1.2
3.8
2.8ꢀ10ꢁ1
2.1
6.6
a
Reaction conditions: [acetone] 666 mM, [1] 44.4 mM, and [
L
-proline] 6.7 mM in
DMSO-d6 at 21 ꢂC.
b
Initial rate of the formation of 3.
c
Relative initial rate determined by comparing with the initial rate of the reaction
of 1a to afford 3a.
double bond. Both 2 and 5 have
p-conjugated systems; the phe-
nylethynylphenyl moiety of 2 and the trans-stilbene moiety of 5 are
coplanar in the most stable conformation.3,5,7 The CeC triple bond
is shorter than the CeC double bond. In addition, the CeC triple
Table 2
Comparison of initial rates of aldol reactions of acetone with 4-(phenylethynyl)
benzaldehyde derivativesa
bond provides stronger
p-conjugation than the CeC double bond
by bridging two benzene rings in linear structure. These features
may underline the reactivity differences between 2 and 5 (i.e., in-
fluence of substituents on reactivities: 1>>2>5).
V2 (mM/h)b
V2/V2a
V2/V1a
c
d
Entry
R
2
4
1
2
3
4
5
H
2a
2b
2c
2d
2f
4a
4b
4c
4d
4f
2.7
3.6
3.2
2.6
2.8
1.0
1.3
1.2
1.0
1.0
1.6
2.1
1.8
1.5
1.6
CN
Me
OMe
CF3
Scheme 1. Aldol reactions of styrylbenzaldehydes.
a
2.2. Substituent effect in thiazolidine formation reactions
Reaction conditions: [acetone] 666 mM, [2] 44.4 mM, and [
L-proline] 6.7 mM in
DMSO-d6 at 21 ꢂC.
b
Initial rate of the formation of 4.
Relative initial rate determined by comparing with the initial rate of the reaction
Next, effect of substituents was analyzed in the thiazolidine
formation8 reactions. Aldehydes were mixed with cysteine and the
formation of thiazolidine was monitored by 1H NMR. Initial rates
were determined and compared (Tables 3 and 4). Initial rates
c
of 2a to afford 4a.
d
Relative initial rate determined by comparing with the initial rate of the reaction
of 1a to afford 3a (Table 1).

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I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
Table 3
a six-membered transition state was used (Scheme 2). Theoretical
analysis of the aldol reactions involving an enol is simpler than that
of the corresponding proline-catalyzed11 aldol reactions. To obtain
information about the substituent effect, the simple enol route was
employed for the theoretical analysis. The transition states were
determined using the density functional theory (DFT) method at
the B3LYP/6-31G(d) level.10 Energy differences (DDG) between the
Gibbs free energies of the transition states are shown in Tables 5
and 6.
Comparison of initial rates of reactions between cysteine and benzaldehyde
derivativesa
V1 (mM/h)b
V1/V1a
c
Entry
R
1
7
1
2
3
4
5
H
CN
Me
OMe
Ethynyl
1a
1b
1c
1d
1e
7a
7b
7c
7d
7e
1.5
11
1.0
7.3
0.6
0.4
1.5
9.2ꢀ10ꢁ1
6.5ꢀ10ꢁ1
2.4
a
Scheme 2. Aldol reaction used for computation.
Reaction conditions: [cysteine] 4.7 mM, [1] 4.0 mM, in 5%(v/v) D2O/DMSO-d6 at
22 ꢂC.
b
c
Initial rate of the formation of 7.
Relative initial rate determined by comparing with the initial rate of the reaction
Table 5
of 1a to afford 7a.
Energy differences of transition states of the aldol reaction of benzaldehyde de-
rivatives and calculated and observed relative ratesa
Entry
1
Computed DD
G
Computed
k1/k1a
Observed
V1/V1a
Table 4
(kcal/mol)b
c
d
Comparison of initial rates of reactions between cysteine and 4-(phenylethynyl)
benzaldehyde derivativesa
1
2
3
1a
1b
1d
0.00
ꢁ1.22
0.84
1.00
7.77
0.24
1.0
8.6
0.2
a
Energies of transition states of the aldol reaction shown in Scheme 2 were
theoretically determined using the DFT method at the B3LYP/6-31G(d) level.
b
Calculated based on the transition state energy of the aldol reaction of 1a at
25 ꢂC.
c
Calculated from the DDG.
Experimentally obtained data; taken from Table 1.
d
Entry
R
2
8
V2 (mM/h)b
V2/V2a
V2/V1a
c
d
Table 6
1
2
3
4
H
2a
2b
2c
2d
8a
8b
8c
8d
2.3
3.0
1.7
1.9
1.0
1.3
0.7
0.8
1.5
1.9
1.1
1.3
Energy differences of transition states of the aldol reaction of 4-(phenylethynyl)
CN
Me
OMe
benzaldehyde derivatives and calculated and observed relative ratesa
Entry
2
Computed
Computed
k2/k2a
Observed
V2/V2a
c
d
DD
G
a
Reaction conditions: [cysteine] 4.7 mM, [2] 4.0 mM in 5%(v/v) D2O/DMSO-d6 at
(kcal/mol)b
22 ꢂC.
b
c
1
2
3
2a
2b
2d
0.00
ꢁ0.18
0.07
1.00
1.35
0.88
1.0
1.3
1.0
Initial rate of the formation of 8.
Relative initial rate determined by comparing with the initial rate of the reaction
of 2a to afford 8a.
d
Relative initial rate determined by comparing with the initial rate of the reaction
a
Energies of transition states of the aldol reaction shown in Scheme 2 were
theoretically determined using the DFT method at the B3LYP/6-31G(d) level.
of 1a to afford 7a (Table 3).
b
Calculated based on the transition state energy of the aldol reaction of 2a at
ranged 0.65e11 mM/h for aldehydes 1 (Table 3) and 1.7e3.0 mM/h
for aldehydes 2 (Table 4). For the thiazolidine formation, like the
aldol reaction described above, effects of electron-withdrawing and
electron-donating substituents were significantly reduced through
the (phenylethynyl)phenyl group compared to the phenyl group.
25 ꢂC.
c
Calculated from the DDG.
Experimentally obtained data; taken from Table 2.
d
The computed energy difference between transition states
generated from 1a and 1b was 1.22 kcal/mol (Table 5, entry 2); the
aldol reaction of 1b was calculated to be theoretically 7.77-fold
faster than the reaction of 1a at 25 ꢂC. For transition states of 2a
and 2b, the computed energy difference was only 0.18 kcal/mol
(Table 6 entry 2), indicating that reaction of 2b was theoretically
1.35-fold faster than the reaction of 2a at 25 ꢂC. Similarly, based on
the computed energy difference between the transition states
generated from 1a and 1d and from 2a and 2d, the reaction rate of
1d was calculated to be 0.24-fold of the reaction rate of 1a and the
reaction rate of 2d was calculated to be 0.88-fold of the reaction
rate of 2a (Tables 5 and 6). Although the reaction used in the the-
oretical analysis was not that used in actual experimental evalua-
tion of the reactivities of the aldehydes, the theoretically calculated
relative rates of the aldol reactions were highly similar to those of
the experimentally observed relative rates.
2.3. Theoretical analysis of substituent effect in aldol
reactions
To understand how the electronic features of substituents in-
fluence the reactivity of the aldehydes, stable conformations of
reactant aldehydes and transition states of an aldol reaction of the
aldehydes were determined theoretically.9 All computations were
performed using Gaussian 09 program package.10 Theoretically, the
most stable conformation of aldehydes 2a, 2b, and 2d was the co-
planar conformation in which the two benzene rings and the al-
dehyde group were on a single plane. This result is consistent with
the previous reports that the most stable conformation of diphe-
nylacetylene is the coplanar conformation.3,5 The result of the
stable conformation also supports that there is p-conjugation from
the substituent to the aldehyde group over the entire 4-(phenyl-
ethynyl)benzaldehyde derivative.
For theoretical analysis of aldol reactions of aldehydes 1 and 2
with acetone, a reaction of an enol to yield the aldol product via
The computed stable conformation of 2 is the coplanar, but
single bonds can rotate. Energy differences between the stable
conformation and other conformations, such as perpendicular
conformation, were relatively small.3,5 Computational results for

I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
4101
the aldol reaction showed that the energy differences between
substituents were relatively small in the reaction of aldehyde 2
compared to those in the reaction of aldehyde 1. These results in-
dicate that reactivity of molecules is more affected by dynamics of
molecular movement than by the most stable conformation. During
formation of the transition state, it is not necessary that aldehydes 2
1.4-fold faster than that of 4-(4-methoxyphenylethynyl)benzalde-
hyde (2d). The approximately 40-fold-difference in the influence of
the substituents between aldehyde 1 and aldehyde 2 can be at-
tributed to the combination of the changes in the acceleration and
the slowdown.
retain
p
-conjugation over the entire diphenylacetylene
p
-system.
3. Conclusion
We investigated the nature of the substituent effect on 4-
(phenylethynyl)benzaldehydes. Electronic features of the sub-
2.4. Extent of changes in the reactivity by substituents
stituent at one end of the
not significantly influence the reactivity of the group at the other
end of the -system. Changes in rates by the substituent effect on
p-system of the diphenylacetylene did
Extent of changes in relative rates of aldol reactions by the at-
tachment of substituents in aldehyde 2 were compared with those
in aldehyde 1 (Table 7). The experimentally observed acceleration
of the rate by the cyano group in the reaction of aldehyde 2 was 7-
fold less than that in the reaction of aldehyde 1. Computational
analysis also indicated that the acceleration by the cyano group in
the reaction of aldehyde 2 was 6-fold less than that in the reaction
of aldehyde 1. Slowdown of the rate by the methoxy group in the
reaction of aldehyde 2 was 5-fold and 4-fold less than in the re-
action of aldehyde 1 in the actual reaction and in the computational
analysis, respectively.
p
transformations of 4-(phenylethynyl)benzaldehydes were approx-
imately 4-fold to 7-fold less than those of simple benzaldehydes in
each of acceleration and slowdown directions. The range of the
rates of reactions of 4-(phenylethynyl)benzaldehydes with various
substituents was approximately 1/40 of that of the rates of re-
actions of benzaldehydes with the same substituents. Although
actual substituent effect may be dependent on many factors (such
as reaction type, catalyst, catalytic mechanism, and solvent), ex-
perimental and theoretical results obtained here indicate that
electronic features of substituents are significantly less influential
in a diphenylacetylene system than in a simple benzene system.
These results suggest that for the development of functional dia-
rylacetylene derivatives, design of functions of the molecules can
be the main focus without much consideration of the reactivity
differences depending on substituent.
Table 7
Changes in the reactivity in aldol reactionsa
Reaction of
Reaction of
Changes in
aldehyde 1a
aldehyde 2a
acceleration or
slowdownb
VR¼CN/VR¼H observed
[computed]
8.6
[7.77]
1.3
[1.35]
7
6
4. Experimental section
4.1. General
VR¼CF3/VR¼H observed
3.8
1.0
4
VR¼OMe/VR¼H observed
[computed]
0.2
[0.24]
1.0
[0.88]
1/5
1/4
For thin layer chromatography (TLC), compounds were visu-
alized by irradiation with UV light and/or by treatment with
a solution of p-anisaldehyde (3.7 mL), sulfuric acid (5 mL), and
acetic acid (1.5 mL) in ethanol (135 mL) followed by heating. Flash
column chromatography was performed using silica gel 60
(230e400 mesh). For 1H NMR, proton chemical shifts were given
a
Values taken from Tables 1, 2, 5 and 6. Observed values: V1/V1a and V2/V2a
.
Computed values: k1/k1a and k2/k2a
.
b
Determined as (V1/V1a)/(V2/V2a) and (k1/k1a)/(k2/k2a), respectively.
In the thiazolidine formation reaction, the acceleration by the
cyano group in the reaction of aldehyde 2 was 6-fold less than that
in the reaction of aldehyde 1, and the slowdown by the methoxy
group in the reaction of aldehyde 2 was 2-fold less than that in the
reaction of aldehyde 1 (Table 8).
in parts per million in
to residual proton signals of deuterated solvent in CDCl3
7.27 ppm) or DMSO-d6
2.50 ppm). For 1H and 13C NMR, carbon
chemical shifts were internally referenced to the deuterated sol-
vent signals in CDCl3 77.0 ppm) or DMSO-d6 39.5 ppm).
d relative to tetramethylsilane in CDCl3 or
(
d
(
d
(
d
(d
High-resolution mass spectra were recorded on an ESI ion trap
mass spectrometer.
Table 8
Changes in the reactivity in thiazolidine formation reactionsa
4.2. Determination of initial rates
Reaction of
Reaction of
Changes in
aldehyde 1a
aldehyde 2a
acceleration or
slowdownb
4.2.1. Determination of initial rates of aldol reactions (for Tables 1
VR¼CN/VR¼H
observed
7.3
0.4
1.3
0.8
6
and 2). Reaction was initiated by adding 190
line solution in DMSO-d6 to a mixture of 60
lution in DMSO-d6 and 200 L of 100 mM aldehyde solution in
m
L of 16 mM
L-pro-
m
L of 5 M acetone so-
VR¼OMe/VR¼H
observed
1/2
m
DMSO-d6 at 21 ꢂC; final concentrations: [acetone] 666 mM, [alde-
hyde] 44.4 mM, and [proline] 6.7 mM in DMSO-d6. Formation of the
aldol product was monitored by 1H NMR (Table S1, Fig. S1). For each
aldehyde, reactions were performed twice or more and identical or
very similar results were obtained. Data of one reaction for each
aldehyde were used for the rate determination. Initial rate was
determined as the slope of a linear least-squares fitting of the time-
product plots. In the absence of proline, no formation of the aldol
product was detected.
a
Values taken from Tables 3 and 4. V1/V1a and V2/V2a
Determined as (V1/V1a)/(V2/V2a).
.
b
Both the acceleration and the slowdown by the introduction of
substituents in the reactions of 4-(phenylethynyl)benzaldehyde 2
were reduced from those in the reactions of benzaldehyde 1. For
most cases, the reduction in the acceleration and in the slowdown
ranged between 4-fold and 7-fold. As described above, the reaction
rate of the aldol reaction of 4-cyanobenzaldehyde (1b) was 54-fold
faster than that of 4-methoxybenzaldehyde (1d) and the aldol re-
action of 4-(4-cyanophenylethynyl)benzaldehyde (2b) was only
4.2.2. Determination of initial rates of reactions of aldehydes with
cysteine (for Tables 3 and 4). Reaction was initiated by adding
200
mL of 10 mM aldehyde solution in DMSO-d6 to 300 mL of

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I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
7.86 mM
L
-cysteine solution in 8.6%(v/v) D2O/DMSO-d6 at 22 ꢂC;
amorphous solid. 1H NMR (400 MHz, CDCl3):
d 10.02 (s, 1H), 7.86 (d,
final concentrations: [aldehyde] 4 mM and [cysteine] 4.7 mM in
5%(v/v) D2O/DMSO-d6. Formation of the thiazolidine was moni-
tored by 1H NMR (Table S2). Initial rate was determined as the slope
of a linear least-squares fitting of the time-product plots.
J¼8.2 Hz, 2H), 7.67 (d, J¼8.2 Hz, 2H), 7.46 (d, J¼8.1 Hz, 2H), 7.19 (d,
J¼8.1 Hz, 2H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 191.4,139.3,
135.2, 132.0, 131.7, 129.8, 129.5, 129.2, 119.4, 93.8, 88.0, 21.6. HRMS:
calcd for C16H13O (MHþ) 221.0961, found 221.0964.
4.4.3. 4-(4-Methoxyphenylethynyl)benzaldehyde (2d). Flash col-
umn chromatography (CH2Cl2/hexane¼5:1), 276 mg, 75%, pale
4.3. Synthesis and characterization of standards of aldehydes
yellow amorphous solid. 1H NMR (400 MHz, CDCl3):
d 10.01 (s, 1H),
4.3.1. 4-(Phenylethynyl)benzaldehydes 2. Aldehydes 2aed and 2f
were synthesized by Sonogashira coupling reactions.4e
7.86 (d, J¼8.3 Hz, 2H), 7.65 (d, J¼8.3 Hz, 2H), 7.51 (d, J¼8.8 Hz, 2H),
6.91 (d, J¼8.8 Hz, 2H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3):
4.3.2. 4-((4-Formylphenyl)ethynyl)benzonitrile (2b).4e A mixture of
PdCl2(PPh3)2 (10.0 mg, 0.014 mmol), Et3N (4.2 mL, 30 mmol), 4-
ethynylbenzaldehyde4f,g (1e) (182 mg, 1.40 mmol), and 4-
bromobenzonitrile (260 mg, 1.43 mmol) was stirred at room tem-
perature for 5 min; CuI (5.0 mg, 0.026 mmol) was added and the
mixture was stirred at 70 ꢂC for 3 h under an argon atmosphere.
After being cooled to room temperature, the mixture was diluted
with EtOAc (30 mL) and washed with brine (2ꢀ30 mL). The organic
layer was dried over MgSO4, filtered, concentrated, and purified by
flash column chromatography (CH2Cl2/hexane¼5:1) to afford 2b
(197 mg, 61%) as a pale yellow amorphous solid. 1H NMR (400 MHz,
d
191.4, 160.2, 135.1, 133.4, 131.9, 130.0, 129.6, 114.5, 114.2, 93.8,
87.5, 55.3. HRMS: calcd for C16H13O2 (MHþ) 237.0910, found
237.0913.
4.4.4. 4-(4-Trifluoromethylphenylethynyl)benzaldehyde (2f). Reaction
was performed on a 66%-scale (i.e., using 1.02 mmol of 1e) of the
general procedure. Flash column chromatography (CH2Cl2/
hexane¼2:1), 219 mg, 78%, pale yellow amorphous solid. 1H NMR
(400 MHz, CDCl3):
d
10.05 (s, 1H), 7.90 (d, J¼8.1 Hz, 2H), 7.71 (d,
J¼8.1 Hz, 2H), 7.68 (d, J¼8.7 Hz, 2H), 7.65 (d, J¼8.7 Hz, 2H). 13C NMR
(100 MHz, CDCl3):
d
191.2,135.8,132.2,132.0, 130.5 (q, JC,F¼32.8 Hz),
CDCl3):
NMR (100 MHz, CDCl3):
d
10.04 (s, 1H), 7.90 (d, J¼8.3 Hz, 2H), 7.71e7.63 (m, 6H). 13
C
129.6, 128.7, 126.3, 125.3 (q, JC,F¼3.7 Hz), 123.8 (q, JC,F¼272 Hz), 91.6,
90.6. HRMS: calcd for C16H10OF3 (MHþ) 275.0678, found 275.0686.
d 191.2, 136.0, 132.34, 132.27, 132.2, 129.6,
128.4, 127.4, 118.3, 112.3, 92.5, 91.2. HRMS: calcd for C16H10NO
4.4.5. 4-Styrylbenzaldehyde (5a).14 Aldehyde 5a was synthesized
(MHþ) 232.0757, found 232.0762.
by the method previously reported.14
4.4.6. 4-(4-Formylstyryl)benzonitrile (5b).15 Aldehyde 5b was syn-
thesized according to a reported method.14 A mixture of 4-
bromobenzaldehyde (370 mg, 2.0 mmol), 4-cyanostyrene
(310 mg, 2.4 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol), and K3PO4
(596 mg, 2.8 mmol) in N,N-dimethylacetamide (3 mL) was stirred at
140 ꢂC for 14 h under nitrogen atmosphere. After being cooled to
room temperature, the mixture was poured into water and
extracted with CH2Cl2. Organic layers were combined, washed with
brine, dried over MgSO4, filtered, concentrated, and purified by
flash column chromatography (hexane/EtOAc¼4:1) to afford 5b
(275 mg, 59%) as a pale yellow amorphous solid. 1H NMR (400 MHz,
CDCl3):
d
9.93 (s, 1H), 7.81 (d, J¼8.0 Hz, 2H), 7.61e7.52 (m, 6H), 7.16
(s, 2H). 13C NMR (100 MHz, CDCl3):
d
191.4, 142.0, 148.8,135.8,132.4,
4.4. General procedure for the synthesis of 2a, 2c, 2d, and 2f
130.8, 130.1, 129.9, 127.2, 127.1, 118.7, 111.3. HRMS: calcd for
C16H12NO (MHþ) 234.0913, found 234.0919.
A mixture of PdCl2(PPh3)2 (11 mg, 0.016 mmol, 0.01 equiv), Et3N
(4.7 mL, 34 mmol), 4-ethynylbenzaldehyde (1e)4f,g (201 mg,
1.55 mmol, 1.0 equiv), and iodobenzene derivative (1.63 mmol) was
stirred at room temperature for 5 min; CuI (6 mg, 0.03 mmol,
0.02 equiv) was added and the mixture was stirred at 35e40 ꢂC for
17e24 h under an argon atmosphere.4e After being cooled to room
temperature, the mixture was diluted with EtOAc and washed with
brine. The organic layer was dried over MgSO4, filtered, concen-
trated, and purified by flash column chromatography to afford 2.
4.5. Synthesis and characterization of standards of aldols
4.5.1. Synthesis and characterization of standards of aldols. Aldols 3,
4, and
6 were synthesized by pyrrolidine-catalyzed aldol
reactions.4d,16
4.5.1.1. 4-Hydroxy-4-(4-phenylethynylphenyl)butan-2-one
(4a). To a solution of aldehyde 2a (33 mg, 0.16 mmol, 1.0 equiv) in
acetone (0.49 mL, 6.67 mmol, 42 equiv), a solution of pyrrolidine in
water (100 mM, 0.48 mL, 0.048 mmol, 0.3 equiv) was added at room
temperature (23 ꢂC) and the mixture was stirred. After 30 min, the
mixture was diluted with water and extracted with CH2Cl2. Organic
layers were combined, washed with brine, dried over MgSO4, filtered,
concentrated, and purified by flash column chromatography (CH2Cl2/
EtOAc¼10:1) to afford 4a (22 mg, 52%) as a pale yellow amorphous
4.4.1. 4-(Phenylethynyl)benzaldehyde (2a).4i,12 Reaction was per-
formed on a 44%-scale (i.e., using 0.68 mmol of 1e) of the general
procedure. Flash column chromatography (CH2Cl2/hexane¼5:1),
106 mg, 76%, pale yellow amorphous solid. 1H NMR (400 MHz,
CDCl3):
7.58e7.56 (m, 2H), 7.40e7.37 (m, 3H). 1H NMR (400 MHz, DMSO-
d6):
10.03 (s, 1H), 7.95 (d, J¼8.0 Hz, 2H), 7.77 (d, J¼8.0 Hz, 2H),
7.62e7.60 (m, 2H), 7.47e7.45 (m, 3H). 13C NMR (100 MHz, CDCl3):
d
10.02 (s, 1H), 7.87 (d, J¼8.1 Hz, 2H), 7.68 (d, J¼8.1 Hz, 2H),
d
solid. 1H NMR (400 MHz, CDCl3):
d
7.55e7.52 (m, 4H), 7.37e7.34 (m,
5H), 5.19e5.15 (m, 1H), 3.42 (d, J¼3.1 Hz, 1H), 2.91e2.80 (m, 2H), 2.21
d
191.4,135.4,132.4,132.1,131.8,129.6,129.0,128.5,122.5, 93.5, 88.6.
(s, 3H). 1H NMR (400 MHz, DMSO-d6):
d 7.56e7.39 (m, 9H), 5.50 (d,
HRMS: calcd for C15H11O (MHþ) 207.0804, found 207.0808.
J¼4.8 Hz, 1H), 5.04e5.02 (m, 1H), 2.78e2.66 (m, 2H), 2.12 (s, 3H). 13C
NMR (100 MHz, CDCl3): d 209.0,142.9,131.8,131.6,128.4,128.3,125.6,
4.4.2. 4-(4-Methylphenylethynyl)benzaldehyde (2c).13 Flash column
chromatography (CH2Cl2/hexane¼5:1), 298 mg, 87%, pale yellow
123.2, 122.6, 89.5, 89.1, 69.5, 51.8, 30.8. HRMS: calcd for C18H16O2Na
(MNaþ) 287.1043, found 287.1051.

I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
4103
4.6. General procedure for the synthesis of aldols 4bed
30.8. HRMS: calcd for
289.1205.
C
18H18O2Na (MNaþ) 289.1199, found
To a mixture of aldehyde 2 (0.1e0.4 mmol, 1.0 equiv), acetone
(40 equiv), and water (136 equiv or 2.45 mL/(aldehyde 1.0 mmol))
was added pyrrolidine (0.3 equiv) at room temperature (23 ꢂC) and
the mixture was stirred. After 2 h, the mixture was diluted with
water and extracted with CH2Cl2. Organic layers were combined,
washed with brine, dried over MgSO4, filtered, concentrated, and
purified by flash column chromatography (CH2Cl2/EtOAc¼10:1) to
afford aldol 4. Reaction conditions were not optimized.
4.6.6. (E)-4-(4-(1-Hydroxy-3-oxobutyl)styryl)benzonitrile (6b). To
a mixture of aldehyde 5b (85.0 mg, 0.36 mmol, 1.0 equiv), acetone
(1.5 mL, 20 mmol), and water (1.5 mL) was added pyrrolidine
(9.1 m
L, 0.11 mmol, 0.3 equiv) at room temperature (23 ꢂC) and the
mixture was stirred. After 1 h, the mixture was diluted with water
and extracted with EtOAc. Organic layers were combined, washed
with brine, dried over MgSO4, filtered, concentrated, and purified
by flash column chromatography (hexane/EtOAc¼7:3) to afford 6b
(25 mg, 24%) as a pale yellow amorphous solid. 1H NMR (400 MHz,
4.6.1. 4-Hydroxy-4-(4-(4-cyanophenylethynyl)phenyl)butan-2-one
(4b). Reaction was performed using aldehyde 2b (85 mg,
0.37 mmol) to afford 4b (28 mg, 26%) as a pale yellow amorphous
CDCl3):
5.18 (dd, J¼8.0, 3.5 Hz, 1H), 3.34 (br s, 1H), 2.93e2.82 (m, 2H), 2.22
(s, 3H). 13C NMR (100 MHz, CDCl3):
208.9, 143.2, 141.7, 135.7, 132.4,
d 7.65e7.51 (m, 6H), 7.45e7.31 (m, 2H), 7.23e7.06 (m, 2H),
solid. 1H NMR (400 MHz, CDCl3):
d
7.64e7.59 (m, 4H), 7.53 (d,
d
J¼8.1 Hz, 2H), 7.38 (d, J¼8.1 Hz, 2H), 5.20e5.16 (m, 1H), 3.45 (d,
131.9, 127.0, 126.8, 126.7, 126.1, 119.0, 110.6, 69.5, 51.7, 30.8. HRMS:
J¼3.1 Hz, 1H), 2.87e2.84 (m, 2H), 2.21 (s, 3H). 13C NMR (100 MHz,
calcd for C19H18NO2 (MHþ) 292.1332, found 292.1366.
CDCl3): d 208.8,143.9,132.1,132.06, 132.05,128.2,125.8,121.5,118.5,
111.5, 93.6, 87.8, 69.5, 51.7, 30.8. HRMS: calcd for C19H16NO2 (MHþ)
290.1176, found 290.1182.
4.7. Synthesis andcharacterization of standardsof thiazolidines
4.7.1. General procedure for the synthesis of standards of thiazoli-
4.6.2. 4-Hydroxy-4-(4-(4-methylphenylethynyl)phenyl)butan-2-one
(4c). Reaction was performed using aldehyde 2c (30 mg,
0.14 mmol) to afford 4c (5.0 mg, 13%) as a pale yellow amorphous
dines 7 and 8. A solution of L-cysteine (51 mg, 0.42 mmol) in water
(0.4 mL) was added to a solution of aldehyde (0.35 mmol) in THF
(3.5 mL) at room temperature and the mixture was stirred under an
argon atmosphere. After 2e5 h, solvent was evaporated under re-
duced pressure and water (1e2 mL) was added. Generated solid
was filtered and washed with water and CH2Cl2 to afford the cor-
responding thiazolidine.
solid. 1H NMR (400 MHz, CDCl3):
d
7.51 (d, J¼8.2 Hz, 2H), 7.43 (d,
J¼8.2 Hz, 2H), 7.35 (d, J¼8.0 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H),
5.20e5.16 (m, 1H), 3.34 (d, J¼3.1 Hz, 1H), 2.92e2.80 (m, 2H), 2.38 (s,
3H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 209.0, 142.6, 138.4,
131.7, 131.5, 129.1, 125.6, 122.8, 120.1, 89.7, 88.5, 69.6, 51.8, 30.8, 21.5.
HRMS: calcd for C19H18O2Na (MNaþ) 301.1199, found 301.1215.
4.7.1.1. 2-Phenylthiazolidine-4-carboxylic acid (7a).8a,17 Reaction
was performed on a 1.5-fold-scale of the general procedure. Col-
orless amorphous solid, 67 mg, 62%, dr 56:44. 1H NMR (400 MHz,
4.6.3. 4-Hydroxy-4-(4-(4-methoxyphenylethynyl)phenyl)butan-2-
one (4d). Reaction was performed using aldehyde 2d (28 mg,
0.12 mmol) to afford 4d (19 mg, 54%) as a pale yellow amorphous
DMSO-d6):
d
7.52 (d, J¼7.4 Hz, 2Hꢀ0.44), 7.44 (d, J¼7.4 Hz,
2Hꢀ0.56), 7.39e7.26 (m, 3H), 5.67 (s, 1Hꢀ0.56), 5.50 (s, 1Hꢀ0.44),
4.24 (dd, J¼7.0, 4.6 Hz, 1Hꢀ0.56), 3.92e3.88 (m, 1Hꢀ0.44),
solid. 1H NMR (400 MHz, CDCl3):
d
7.50 (d, J¼8.1 Hz, 2H), 7.47 (d,
J¼8.8 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H),
5.18e5.14 (m, 1H), 3.83 (s, 3H), 3.38 (d, J¼3.2 Hz, 1H), 2.91e2.79
3.40e3.05 (m, 2H). 13C NMR (100 MHz, DMSO-d6):
d 172.9, 172.2,
141.2, 138.9, 128.4, 128.3, 128.2, 127.6, 127.2, 126.9, 71.7, 71.0, 65.4,
64.9, 38.4, 37.9. HRMS: calcd for C10H12NO2S (MHþ) 210.0583,
found 210.0596.
(m, 2H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 209.0, 159.7,
142.5, 133.1, 131.6, 125.6, 122.9, 115.3, 114.0, 89.5, 87.8, 69.6, 55.3,
51.8, 30.8. HRMS: calcd for C19H19O3 (MHþ) 295.1329, found
295.1356.
4.7.1.2. 2-(4-Cyanophenyl)thiazolidine-4-carboxylic acid (7b).8a,17
Colorless amorphous solid, 56 mg, 70%, dr 61:39. 1H NMR
4.6.4. 4-Hydroxy-4-(4-(4-trifluoromethylphenylethynyl)phenyl)bu-
tan-2-one (4f). The method for the synthesis of 4a was employed
using aldehyde 2f (30 mg, 0.11 mmol) to afford 4f (22 mg, 60%) as
(400 MHz, DMSO-d6):
d
7.83 (d, J¼8.0 Hz, 2Hꢀ0.39), 7.78 (d,
J¼8.0 Hz, 2Hꢀ0.61), 7.72 (d, J¼8.0 Hz, 2Hꢀ0.39), 7.60 (d, J¼8.0 Hz,
2Hꢀ0.61), 5.80 (s, 1Hꢀ0.61), 5.59 (s, 1Hꢀ0.39), 4.14-4.11 (m,
1Hꢀ0.61), 3.95 (dd, J¼8.8, 6.8 Hz, 1Hꢀ0.39), 3.38e3.06 (m, 2H). 13C
a pale yellow amorphous solid. 1H NMR (400 MHz, CDCl3):
d 7.64 (d,
J¼8.8 Hz, 2H), 7.61 (d, J¼8.8 Hz, 2H), 7.54 (d, J¼8.3 Hz, 2H), 7.37 (d,
NMR (100 MHz, DMSO-d6): d 172.6, 171.9, 147.9, 145.1, 132.3, 132.2,
J¼8.3 Hz, 2H), 5.20e5.17 (m, 1H), 3.43 (s, 1H), 2.92e2.85 (m, 2H),
128.7, 127.6, 118.7, 118.6, 110.7, 110.0, 70.5, 69.7, 65.7, 64.9, 38.1.
2.22 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 208.9, 143.5, 131.9, 131.8,
HRMS: calcd for C11H11N2O2S (MHþ) 235.0536, found 235.0547.
129.9 (q, JC,F¼32.6 Hz), 127.1, 125.7, 125.3 (q, JC,F¼3.8 Hz), 121.8,
124.0 (q, JC,F¼272 Hz), 91.5, 88.0, 69.5, 51.7, 30.8. HRMS: calcd for
C19H15O2F3Na (MNaþ) 355.0916, found 355.0923.
4.7.1.3. 2-(4-Methylphenyl)thiazolidine-4-carboxylic acid (7c).8a
Reaction was performed on a 1.2-fold-scale of the general pro-
cedure. Colorless amorphous solid, 50 mg, 52%, dr 54:46. 1H NMR
4.6.5. (E)-4-Hydroxy-4-(4-styrylphenyl)butan-2-one (6a). To a mix-
ture of aldehyde 5a (104.1 mg, 0.5 mmol,1.0 equiv), acetone (1.0 mL,
(400 MHz, DMSO-d6):
d
7.39 (d, J¼8.0 Hz, 2Hꢀ0.46), 7.32 (d,
J¼8.0 Hz, 2Hꢀ0.54), 7.17 (d, J¼8.0 Hz, 2Hꢀ0.46), 7.13 (d, J¼8.0 Hz,
2Hꢀ0.54), 5.62 (s, 1Hꢀ0.54), 5.46 (s, 1Hꢀ0.46), 4.24 (dd, J¼7.2,
4.4 Hz, 1Hꢀ0.54), 3.90e3.85 (m, 1Hꢀ0.46), 3.39e3.34 (m,
1Hꢀ0.46), 3.28 (dd, J¼10.0, 7.2 Hz, 1Hꢀ0.54), 3.14 (dd, J¼10.0,
4.4 Hz, 1Hꢀ0.54), 3.08e3.04 (m, 1Hꢀ0.46), 2.29 (s, 3Hꢀ0.46), 2.28
14 mmol), and water (1.0 mL) was added pyrrolidine (12.5
mL,
0.15 mmol, 0.3 equiv) at room temperature (23 ꢂC) and the mixture
was stirred. After 30 min, the mixture was diluted with water and
extracted with EtOAc. Organic layers were combined, washed with
brine, dried over MgSO4, filtered, concentrated, and purified by
flash column chromatography (hexane/EtOAc¼7:3) to afford 6a
(80 mg, 60%) as a colorless amorphous solid. 1H NMR (400 MHz,
(s, 3Hꢀ0.54). 13C (100 MHz, DMSO-d6):
d 173.0, 172.2, 138.0, 137.6,
136.8, 135.8, 129.0, 128.7, 127.1, 126.9, 71.7, 71.0, 65.3, 64.8, 38.4,
37.9, 20.7, 20.6. HRMS: calcd for C11H14NO2S (MHþ) 224.0740, found
224.0750.
CDCl3):
7.03 (s, 2H), 5.09 (dd, J¼8.8 Hz, 3.5 Hz,1H), 3.20 (br s,1H), 2.86e2.73
(m, 2H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3):
209.0, 142.1,
137.2, 136.8, 128.8, 128.7, 128.1, 127.6, 126.6, 126.5, 126.0, 69.6, 51.8,
d 7.46e7.42 (m, 4H), 7.34e7.27 (m, 4H), 7.21e7.17 (m, 1H),
d
4.7.1.4. 2-(4-Methoxyphenyl)thiazolidine-4-carboxylic acid (7d).8a
Colorless amorphous solid, 14 mg, 15%, dr 1:1. 1H NMR

4104
I. Katsuyama et al. / Tetrahedron 69 (2013) 4098e4104
(400 MHz, DMSO-d6):
d
7.43 (d, J¼8.6 Hz, 2Hꢀ0.5), 7.36 (d, J¼8.6 Hz,
59:41. 1H NMR (400 MHz, DMSO-d6):
d 7.56e6.96 (m, 8H), 5.72 (s,
2Hꢀ0.5), 6.92 (d, J¼8.6 Hz, 2Hꢀ0.5), 6.88 (d, J¼8.6 Hz, 2Hꢀ0.5),
5.59 (s, 1Hꢀ0.5), 5.45 (s, 1Hꢀ0.5), 4.25 (dd, J¼7.2, 4.2 Hz, 1Hꢀ0.5),
3.88e3.83 (m, 1Hꢀ0.5), 3.75 (s, 3Hꢀ0.5), 3.74 (s, 3Hꢀ0.5), 3.36 (dd,
J¼10.0, 7.2 Hz, 1Hꢀ0.5), 3.28 (dd, J¼10.0, 7.2 Hz, 1Hꢀ0.5), 3.15 (dd,
J¼10.0, 4.2 Hz, 1Hꢀ0.5), 3.08e3.03 (m, 1Hꢀ0.5). 13C (100 MHz,
1Hꢀ0.59), 5.54 (s, 1Hꢀ0.41), 4.20 (dd, J¼6.9, 4.9 Hz, 1Hꢀ0.59), 3.91
(dd, J¼8.8, 7.0 Hz, 1Hꢀ0.41), 3.79 (s, 3H), 3.37 (dd, J¼10.0, 7.0 Hz,
1Hꢀ0.41), 3.31 (dd, J¼10.2, 6.9 Hz, 1Hꢀ0.59), 3.13 (dd, J¼10.2,
4.9 Hz, 1Hꢀ0.59), 3.09 (dd, J¼10.0, 8.8 Hz, 1Hꢀ0.41). 13C NMR
(100 MHz, DMSO-d6):
d 172.8, 172.1, 159.6, 159.5, 141.9, 139.3,
DMSO-d6):
d
173.1, 172.3, 159.2, 158.7, 132.9, 130.7, 128.5, 128.3,
132.94, 132.90, 131.2, 131.0, 127.6, 127.2, 122.5, 121.7, 114.4, 114.14,
114.06, 89.8, 89.5, 87.8, 87.7, 71.2, 70.5, 65.5, 64.9, 55.2, 38.3, 38.0.
HRMS: calcd for C19H18NO3S (MHþ) 340.1002, found 340.1011.
113.8, 113.5, 71.5, 70.9, 65.3, 64.8, 55.11, 55.07, 38.5, 37.8. HRMS:
calcd for C11H14NO3S (MHþ) 240.0689, found 240.0698.
4.7.1.5. 2-(4-Ethynylphenyl)thiazolidine-4-carboxylic
(7e). Colorless amorphous solid, 54 mg, 66%, dr 61:39. 1H NMR
(400 MHz, DMSO-d6):
acid
Acknowledgements
d
7.54e7.43 (m, 2H), 5.71 (s, 1Hꢀ0.61), 5.52
This study was supported by Okinawa Institute of Science and
Technology Graduate University and in part by MEXT Grant-in-Aid
for Scientific Research on Innovative Areas Grant Number
24105535.
(s, 1Hꢀ0.39), 4.20 (s, 1Hꢀ0.39), 4.18 (dd, J¼6.8, 4.8 Hz, 1Hꢀ0,61),
4.16 (s, 1Hꢀ0.61), 3.91 (dd, J¼8.8, 7.2 Hz, 1Hꢀ0.39), 3.36 (dd, J¼10.0,
7.2 Hz, 1Hꢀ0.39), 3.29 (dd, J¼10.0, 6.8 Hz, 1Hꢀ0.61), 3.13e3.05 (m,
1H). 13C NMR (100 MHz, DMSO-d6):
d 172.8, 172.1, 142.6, 140.0,
131.8, 131.6, 127.6, 127.1, 121.5, 120.7, 83.3, 83.1, 81.1, 80.8, 71.1, 70.4,
65.5, 64.9, 38.3, 38.0. HRMS: calcd for C12H12NO2S (MHþ) 234.0583,
found 234.0591.
Supplementary data
Data of the initial rate determination (Tables S1 and S2, Fig. S1);
NMR spectra; full authorship of Gaussian 09; Cartesian coordinates
and absolute energies of stationary points (Tables S3 and S4).
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.03.056.
4.7.1.6. 2-(4-Phenylethynylphenyl)thiazolidine-4-carboxylic acid
(8a). Reaction was performed on a 26%-scale of the general pro-
cedure. Colorless amorphous solid, 22 mg, 77%, dr 61:39. 1H NMR
(400 MHz, DMSO-d6):
d
7.57e7.42 (m, 9H), 5.73 (s, 1Hꢀ0.61), 5.54
(s, 1Hꢀ0.39), 4.20 (dd, J¼6.8, 5.2 Hz, 1Hꢀ0.61), 3.91 (dd, J¼8.8,
References and notes
7.2 Hz, 1Hꢀ0.39), 3.40e3.07 (m, 2H). 13C NMR (100 MHz, DMSO-
1. (a) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96e103; (b) Hansch, C.; Leo, A.; Taft,
R. W. Chem. Rev. 1991, 91, 165e195.
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d 172.8, 172.1, 142.4, 139.8, 131.42, 131.36, 131.28, 131.25, 128.8,
128.7, 127.7, 127.2, 122.2, 122.1, 122.0, 121.3, 89.6, 89.3, 89.2, 89.0,
71.2, 70.4, 65.6, 64.9, 38.3, 38.0. HRMS: calcd for C18H16NO2S (MHþ)
310.0896, found 310.0904.
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24674e24677.
6. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396.
7. Harada, J.; Ogawa, K. J. Am. Chem. Soc. 2004, 126, 3539e3544.
8. (a) Gududuru, V.; Hurh, E.; Dalton, J. T.; Miller, D. D. J. Med. Chem. 2005, 48,
2584e2588; (b) Tanaka, F.; Mase, N.; Barbas, C. F., III. Chem. Commun. 2004,
1762e1763.
9. Optimized structures of reactants and transition states were characterized by
analytical frequency calculations and all total electronic energies of them were
included in zero-point and thermal energy corrections at the same level.
10. Frisch, M. J., et al. Gaussian 09; Gaussian: Wallingford, CT, 2009.
11. (a) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155e5159;
(b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125,
2475e2479.
4.7.1.7. 2-(4-(4-Cyanophenylethynyl)phenyl)thiazolidine-4-
carboxylic acid (8b). Pale yellow amorphous solid, 93 mg, 80%, dr
1:1. 1H NMR (400 MHz, DMSO-d6):
d 7.92e7.49 (m, 8H), 5.74 (s,
1Hꢀ0.5), 5.56 (s, 1Hꢀ0.5), 4.19 (dd, J¼6.8, 5.2 Hz, 1Hꢀ0.5), 3.92 (dd,
J¼8.8, 6.8 Hz, 1Hꢀ0.5), 3.40e3.06 (m, 2H). 13C NMR (100 MHz,
DMSO-d6):
d 172.8, 172.0, 143.3, 140.6, 132.6, 132.12, 132.09, 131.7,
131.5, 127.8, 127.3, 127.1, 127.0, 121.1, 120.4, 118.4, 111.0, 110.9, 93.2,
93.0, 88.2, 88.0, 71.1, 70.3, 65.6, 64.9, 38.3, 38.0. HRMS: calcd for
C19H15N2O2S (MHþ) 335.0854, found 335.0869.
4.7.1.8. 2-(4-(4-Methylphenylethynyl)phenyl)thiazolidine-4-
carboxylic acid (8c). Colorless amorphous solid, 89 mg, 77%, dr 1:1.
1H NMR (400 MHz, DMSO-d6):
d 7.58e7.22 (m, 8H), 5.72 (s,
1Hꢀ0.5), 5.54 (s, 1Hꢀ0.5), 4.20 (dd, J¼6.8, 4.8 Hz, 1Hꢀ0.5), 3.92 (dd,
J¼8.8, 7.2 Hz, 1Hꢀ0.5), 3.38 (dd, J¼10.0, 7.2 Hz, 1Hꢀ0.5), 3.31 (dd,
J¼10.2, 6.8 Hz, 1Hꢀ0.5), 3.13 (dd, J¼10.2, 4.8 Hz, 1Hꢀ0.5), 3.12e3.07
(m, 1Hꢀ0.5), 2.34 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d 172.8,
172.1, 142.1, 139.5, 138.6, 138.5, 131.32, 131.27, 131.24, 131.15, 129.3,
127.7, 127.2, 122.2, 121.5, 119.2,119.1, 89.8, 89.5, 88.6, 88.4, 71.2, 70.5,
65.5, 64.9, 38.3, 38.0, 21.0. HRMS: calcd for C19H18NO2S (MHþ)
324.1053, found 324.1065.
12. Tolosa, J.; Kub, C.; Bunz, U. H. F. Angew. Chem., Int. Ed. 2009, 48, 4610e4612.
13. Shi, Y.; Li, X.; Liu, J.; Jiang, W.; Sun, L. Tetrahedron Lett. 2010, 51, 3626e3628.
14. Yao, Q.; Kinney, E. P.; Yang, Z. J. Org. Chem. 2003, 68, 7528e7531.
15. Yang, J.-S.; Lin, Y.-D.; Chang, Y.-H.; Wang, S.-S. J. Org. Chem. 2005, 70,
6066e6073.
16. Chimni, S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019e5025.
17. Liu, Y.; Jing, F.; Xu, Y.; Xie, Y.; Shi, F.; Fang, H.; Li, M.; Xu, W. Bioorg. Med. Chem.
2011, 19, 2342e2348.
4.7.1.9. 2-(4-(4-Methoxyphenylethynyl)phenyl)thiazolidine-4-
carboxylic acid (8d). Colorless amorphous solid, 85 mg, 72%, dr