Experimental mechanistic studies of the tail-to-tail dimerization of methyl methacrylate catalyzed by N-heterocyclic carbene

Article abstract of DOI:10.1021/jo401477b

We and others have previously reported the intermolecular umpolung reactions of Michael acceptors catalyzed by an N-heterocyclic carbene (NHC). The representative tail-to-tail dimerization of methyl methacrylate (MMA) has now been intensively investigated

Full text of DOI:10.1021/jo401477b

Article
pubs.acs.org/joc
Experimental Mechanistic Studies of the Tail-to-Tail Dimerization of
Methyl Methacrylate Catalyzed by N‑Heterocyclic Carbene
Terumasa Kato, Yoshiya Ota, Shin-ichi Matsuoka,* Koji Takagi, and Masato Suzuki
Department of Materials Science and Engineering, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho,
Showa-ku, Nagoya, Aichi 466-8555, Japan
S
* Supporting Information
ABSTRACT: We and others have previously reported the intermolecular umpolung reactions of Michael acceptors catalyzed by
an N-heterocyclic carbene (NHC). The representative tail-to-tail dimerization of methyl methacrylate (MMA) has now been
intensively investigated, leading to the following conclusions: (1) The catalysis involves the deoxy-Breslow intermediate, which is
quite stable and remains active after the catalysis. (2) Addition of the intermediate to MMA and the final catalyst elimination are
the rate-limiting steps. Addition of the NHC to MMA and the proton transfers are relatively very rapid. (3) The two alkenyl
protons of the first MMA undergo an intermolecular transfer to C3 and C5 of the dimer. (4) The initial proton transfer is
intermolecular. (5) Compared with the benzoin condensation, noticeable differences in the kinetics, reversibility, and stability of
the intermediates are observed.
tail-to-tail dimerization of activated olefins (Scheme 1b).13,14
These are analogues of the benzoin condensation and provide
INTRODUCTION
■
Umpolung or polarity reversal of functional groups is an
facile access to useful difunctional compounds. The other
important concept in the design of synthetic strategies.
umpolung reactions, such as the rearrangement15 or Rauhut−
Recently, the N-heterocyclic carbene1 (NHC)-catalyzed
Currier reactions16 of vinyl sulfones and three-component
umpolungs of aldehydes have been well-explored,2 thereby
reactions using isocyanates,17 have also been reported. The key
allowing a variety of bond-forming reactions of aldehydes with
deoxy-Breslow intermediate derived from an imidazolium-based
electrophiles, including asymmetric syntheses. The beginning of
NHC and methyl methacrylate (MMA) was isolated and
this type of reaction, in fact, dates back half a century. Ukai
reported the first benzoin condensation catalyzed by thiamine
structurally characterized.18 The intermediates can also be
formed from NHCs and alkyl halides,19 and importantly, their
in 1943,3 and Breslow proposed a reaction mechanism
nucleophilic reactivities have been disclosed.20 In contrast to
involving an enaminol intermediate (the Breslow intermediate)
in 1958 (Scheme 1a).4 In addition to the homocouplings,
aldehydes, however, the NHC-catalyzed umpolung of other
electrophiles is largely underdeveloped. In view of the fact that
Stetter described the selective cross-coupling between
aldehydes and Michael acceptors via Breslow intermediates.5
there is no other general procedure to introduce electrophiles at
the β-carbon of Michael acceptors, their NHC-catalyzed
Since these initial reports, significant efforts have been directed
toward mechanistic studies, including kinetics,6 analysis and
umpolungs are particularly promising. However, the reaction
isolation of the intermediate,7 effects of the catalyst8 and
scope and catalytic activity still remain low. To overcome such
additives,9 and theoretical considerations.10 These fundamental
difficulties, fundamental mechanistic studies are required. We
have now experimentally investigated a representative inter-
studies have advanced the recent development of NHC
molecular umpolung reaction of a Michael acceptor catalyzed
catalysis and are still in progress.
by an NHC, namely, the tail-to-tail dimerization of MMA,21 to
In addition to aldehydes, the NHC-catalyzed umpolung of
Michael acceptors has also become possible. The first
understand the reversibility, rate-limiting step, and proton-
transfer mechanism. In addition, we have compared the
publication appeared in 2006, showing an intramolecular SN2
reaction of deoxy-Breslow intermediates.11 Subsequently, this
mechanism of this reaction with that of the benzoin
condensation.
interesting reactivity was computationally studied by compar-
ison with the Me3P-catalyzed Morita−Baylis−Hillman-like
reaction.12 In 2011, we and others independently reported
Received: July 9, 2013
NHC-catalyzed intermolecular umpolung reactions involving
Published: August 13, 2013
© 2013 American Chemical Society
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Scheme 1. NHC-Catalyzed Umpolung Reactions: (a) Benzoin Condensation; (b) Tail-to-Tail Dimerization of Activated Olefins
Figure 1. Reaction mechanism for the tail-to-tail dimerization of MMA catalyzed by NHC 1.
RESULTS AND DISCUSSION
Scheme 2. Deuterium Labeling of in-Situ Generated II Using
CF3CO2D
■
Deoxy-Breslow Intermediate and Rate-Limiting Steps.
We previously reported that the intermediates II and IV
(Figure 1) were detected by ESI-MS,13 and we17 and Glorius
and co-workers14 obtained the proton adducts of II. On the
basis of these results, the catalytic cycle shown in Figure 1 was
proposed. We initially investigated the detailed mechanistic
aspects of the first half of the catalytic cycle (1 → II). When the
reaction of MMA with an equimolar amount of 1 for 10 min
was quenched by CF3CO2D, compound 3 with selective
deuterium incorporation at the β-carbon was obtained in 96%
yield without the formation of 4 (Scheme 2). This experiment
indicated that the proton transfer of the ester enolate I rapidly
proceeds to generate relatively stable species II. In addition, the
in situ generation of II supports the fact that this catalysis
involves the umpolung at the β-carbon. The selective
generation of II enables the stoichiometric codimerization. As
expected, the reaction of II with ethyl methacrylate (EMA)
produced codimer 5, and the regenerated 1 catalyzed the
dimerization of the excess amount of EMA to give 6 (Scheme
3). The MMA dimer 2 was not formed, suggesting that the
reaction step 1 → II is apparently irreversible under these
conditions.
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Scheme 3. Stoichiometric Codimerization of MMA with EMA
Scheme 4. Codimerization of MMA and EMA To Examine the Activities of Intermediates II and IV
Although the isolation of intermediary species derived from 1
and two molecules of MMA has been unsuccessful, compound
IV would be a stable intermediate capable of being detected by
ESI-MS. Throughout the catalysis, only II and IV were detected
by ESI-MS, and no intermediary adducts derived from trimers
and tetramers were observed. To examine the activities of the in
situ-generated II and IV, the codimerization was performed as
shown in Scheme 4. The dimerization of MMA with 10 mol %
1 for 10 min gave the dimer 2 in 20% GC yield. NHC 1 was
completely consumed, and II and IV were detected by ESI-MS.
Subsequently, the unreacted MMA was excluded in vacuo, and
then the mixture was reacted with an equimolar amount of
EMA for 1 or 4 h to give dimers 2, 5, and 6 and intermediates
VI, VII, and VIII. During this second stage, the yield of 2
increased from 20% to 25% as a result of the elimination of 2
from IV. Codimer 5 was produced in yields of 3 and 4% by the
reaction of II and EMA for 1 and 4 h, respectively. These
processes regenerated 1, which subsequently catalyzed the
dimerization of EMA to give 6 in yields of 7 and 39%.
Collectively, the active intermediates II and IV are quite stable
during the catalysis and would be involved in the rate-limiting
steps.
We then studied the short-time reactions of MMA with 1
(100, 50, and 10 mol %). The reactions were quenched after 5
min by the addition of HCl (Table 1). In all cases, the
conversions of MMA were almost consistent with the yields of
the HCl adduct of II (7). The absence of further reaction of II
with a large amount of unreacted MMA is particularly
noteworthy (entry 3). The time−conversion plot for the
catalysis also suggests a higher rate for the conjugate addition of
1 to MMA (Figure S17 in the Supporting Information). Under
the conditions of entry 3 in Table 1, the conversion reached
10% within 3 min, and then the reaction proceeded much more
slowly. Therefore, the reaction of 1 with MMA to form II is
Table 1. Reactions of MMA with 1 for 5 min
yield (%)
a
b
a
entry
[1] mol %
conv. (%)
7
2
1
2
3
100
50
83
51
13
77
45
9
0
0
1
10
a
b
Determined by GC. Isolated yields.
much more rapid than the subsequent conjugate addition of II
to MMA.
The deuterium kinetic isotope effect using MMA-d8 was next
examined. The time−yield plots for the dimerizations of MMA
and MMA-d8 show that the yields at the initial stage increased
linearly with the reaction time without an induction period
(Figures S18−S22 in the Supporting Information). As shown in
Table 2, the rate of the dimerization of MMA-d8 was slightly
higher than that of MMA (kH/kD = 0.81 0.13), suggesting an
inverse secondary deuterium kinetic isotope effect. When the
competitive dimerization using an equimolar mixture of MMA
and MMA-d8 was performed (Figure 2), GC analysis of the
product showed three peaks assignable to the two homodimers
(25% GC yield each) and the codimer (50% GC yield). The
relative intensity among the three peaks was a constant 1:2:1
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incorporation at C3 and C5, accompanied by the trans-
esterification (Scheme 5). Since no H/D exchange occurs at C3
and C5 of 2 under these conditions, intermolecular transfers of
these two protons are involved during the catalysis.
Table 2. Kinetic Isotope Effect in the Dimerizations of MMA
and MMA-d8
a
b
entry
substrate
dimerization rate (10−4 mol L−1 s−1
)
1
2
3
4
5
MMA
1.17
1.06
1.15
1.24
1.53
The initial proton transfer (I → II) was examined next. The
reaction of in situ-generated II with an excess amount of
CD3OD at room temperature followed by the addition of HCl
gave 10, indicating that H/D exchange at the β-carbon of II
takes place (Scheme 6). Compound 11 with deuterium
incorporation at the α-carbon, which would be produced via
intermediate I, was not formed, suggesting that there is no
equilibrium between I and II under these conditions. To
further examine the proton transfer of I to form II, we
performed the reaction of the mixture of MMA and MMA-d8
with a stoichiometric amount of 1 (Scheme 7). ESI-MS analysis
of the reaction mixture quenched with HCl indicated the
presence of not only 7 but also H/D-exchanged intermediates
such as 11. In addition, the stoichiometric reaction of MMA
with 1 in the presence of an excess of CD3OD led to deuterium
incorporation at the α- and β-carbons to give 12 (Scheme 8).
Since II does not undergo the H/D exchange reaction at the α-
carbon under these conditions (Scheme 6), intermediate I
reacts with CD3OD, leading to the deuterium incorporation at
the α-carbon in 12. On the basis of the results shown in
Schemes 6−8, we postulate that the proton-transfer process
from I to II is intermolecular.
MMA
MMA
MMA-d8
MMA-d8
a
10 mol % of 1, 3.0 mmol of substrate, 0.70 mL of toluene, at 80 °C.
Initial stage of the reactions (yield <12%). Caluculated by GC.
b
throughout the catalysis (Figure 2a). This result also supports
the conclusion that the reactivities of the two substrates are
similar and that there is no primary deuterium kinetic isotope
effect. Accordingly, all three proton-transfer processes in the
catalysis are relatively very rapid, and it is reasonable to assume
that the proton transfers in the second half of the catalytic cycle
(III → IV and IV → V) are faster than the final elimination
step (V → 1). Collectively, we propose that the conjugate
addition of II to MMA (II → III) and the final elimination of 1
(V → 1) are partially rate-limiting. In addition, this final step is
irreversible, as no reaction of 1 with 2 occurs at all.
Proton-Transfer Mechanism. In the competitive dimeri-
zation, 11 signals corresponding to the Na+ adducts of the
homo- and codimers were observed in the ESI-MS spectrum
(Figure 2b). The MMA dimer showed three isotope signals at
m/z 223, 224, and 225 with the statistical intensity ratio of
1:2:1. A similar splitting of signals was observed for the dimer
of MMA-d8. These results indicate that two intermolecular H/
D exchanges can take place for two protons or deuteriums
during the catalysis. The dimerization of MMA in the presence
of 1.3 equiv of CD3OD produced dimer 9 with deuterium
To reveal the proton-transfer mechanism of the second half
of the catalytic cycle (II → 1), deuterium-labeling experiments
involving the stoichiometric dimerizations were performed
(Schemes 9 and 10). The reaction of II with MMA-d8 produced
codimer 13 deuterated at C4 accompanied by the formation of
MMA-d8 dimer 8 and isomers of the deuterated dimers
(Scheme 9). When intermediate IX (prepared as shown in
●
Figure 2. Dimerization of the mixture of MMA and MMA-d8 catalyzed by 1 in toluene at 80 °C for 8 h. (a) Fractions of the dimers vs conversion:
,
□
△
codimer; , MMA dimer; ; MMA-d8 dimer. The fractions were estimated by GC. (b) ESI-MS spectrum of the obtained dimers. (c) Assignment of
signals (m/z 229−233) observed in the ESI-MS spectrum.
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Scheme 5. Dimerization of MMA in the Presence of CD3OD
Scheme 6. H/D Exchange Reaction of the β-Carbon of II in the Presence of CD3OD
Scheme 7. Reaction of the Mixture of MMA and MMA-d8 with 1
Scheme 8. Reaction of MMA with 1 in the Presence of CD3OD
Scheme 9. Reaction of II with MMA-d8
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Scheme 10. Reaction of IX with MMA
Scheme 6) was reacted with MMA, the dimer deuterated at C3
and C5 was obtained with moderate deuterium incorporations
(Scheme 10). The ESI-MS spectrum of the product showed
three signals at m/z 226, 227, and 228 with the statistical
intensity ratio of 1:2:1, corresponding to dimers 21, 22, 23, and
24. These results indicate that the α- and β-protons of II
undergo intermolecular scrambling and transfer to C3 and C5
of 2.
Scheme 11. NHC-Catalyzed Benzoin Condensation
Collectively, the alkenyl protons of the first MMA are
transferred to C3 and C5 of the dimer, while the transfer of the
protons of the second MMA does not take place at all. The first
proton-transfer step (I → II) is intermolecular, and the second
(III → IV) and third (IV → V) steps involve complex
intermolecular transfer processes. This finding agrees well with
the result of the competitive dimerization (Figure 2). As shown
in Figure 2b, the five isotope codimers were observed at m/z
229−233 with the statistical intensity ratio of 1:2:2:2:1. On the
basis of the proton-transfer mechanisms, the structures of the
eight isotope codimers can be reasonably assigned as shown in
Figure 2c.
Comparison with Benzoin Condensation. The dimeri-
zation of MMA is analogous to the benzoin condensation, as
both reactions involve an NHC-catalyzed umpolung for bond
formation between a couple of electrophilic unsaturated
carbons to produce a dimer. The mechanism of the benzoin
condensation, including the rate-limiting steps, proton-transfer
process, and reversibility, have been accepted (Scheme 11).
Although there are a few examples showing that the initial
proton transfer to generate the Breslow intermediate is
irreversible, depending on the catalyst used,6e,8e,f it is generally
accepted that the overall benzoin condensation is reversible.5,22
Previous reports have demonstrated that no significant
difference in the rate-limiting steps of the benzoin condensation
is observed between the experimental and theoretical studies
using a thiazolium-based catalyst6d and a triazolium variant,10g
respectively, showing that the initial addition (X → XI), the
initial proton transfer (XI → XII), and the C−C bond
formation (XII → XIII) are partially rate-limiting. The
differences and similarities between these two reactions are
summarized in Table 3. In contrast to the benzoin
condensation, the 1 → II and V → 1 steps in the dimerization
Table 3. Comparison of the Dimerization of MMA and the
Benzoin Condensation
a
dimerization of MMA
benzoin condensation
initial addition
1 → I: fast
X → XI: slow
initial proton
transfer
I → II: fast,
intermolecular
XI → XII: slow,
intermolecular
intermediate
II: stable
XII: unstable
II → 1: irreversible
II → III: slow
V → 1: slow
XII → 25: reversible
XII → XIII: slow
XIII → 25: fast
elimination
product
2 → V: irreversible
26 → XII: reversible
a
See refs 6d and 10g.
of MMA are apparently irreversible, the initial addition (1 → I)
and the initial proton transfer (I→II) are relatively fast, and the
rates of the final eliminations of the catalysts (V → 1) are
relatively slow. Similar to the benzoin condensation, the initial
proton transfer (I → II) is intermolecular, and the addition of
II to MMA is partially rate-limiting. Efforts have been directed
toward the isolation and characterization of the Breslow
intermediates, but successful examples are very limited. In
contrast, the isolation of the deoxy-Breslow intermediate
derived from the imidazolium-based NHC and MMA was
previously reported,18 and the selective generation of II has
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Stoichiometric Codimerization of MMA and EMA (Scheme
3). To a solution of 1 (89 mg, 0.30 mmol) in 1,2-dimethoxyethane
(0.6 mL) was added MMA (27 mg, 0.27 mmol) at 80 °C. After the
mixture was stirred for 1 h, EMA (0.34 g, 3.0 mmol) was added, and
stirring was continued for 4 h. Kugelrohr distillation under reduced
pressure gave 0.14 g of a mixture of 5 (0.18 mmol, 67% 1H NMR yield
based on MMA) and 6 (0.45 mmol, 30% H NMR yield). H NMR
(400 MHz, CDCl3) δ: 1.18−1.31 (9.2H), 1.85 (3.1H), 2.29−2.36
(1.0H), 2.50−2.61 (2.1H), 3.74 (0.87H), 4.11−4.21 (3.8H), 6.69−
6.72 (1.0H). HRMS (ESI) m/z: calcd for C11H18O4Na [5 + Na]+
237.1103, found 237.1104; calcd for C12H20O4Na [6 + Na]+ 251.1259,
found 251.1264.
been established. Thus, the deoxy-Breslow intermediates are
much more stable than the Breslow variants.
CONCLUSIONS
■
We have reported detailed experimental mechanistic studies of
the NHC-catalyzed dimerization of MMA. A series of
experiments, including kinetic isotope effects, competitive
reactions, deuterium-labeling studies, reactions of the inter-
mediates, and codimerizations have been performed to reveal
the rate-limiting steps, proton-transfer process, and reversibility.
NHC 1 rapidly adds to the first MMA to generate I, and this is
followed by an intermolecular proton transfer to give the key
deoxy-Breslow intermediate II. This process is apparently
irreversible, and II is selectively generated in situ, thereby
allowing the stoichiometric codimerizations. The addition of II
to the second MMA to form the C−C bond is partially rate-
limiting. The final electron transfer to produce 2 is irreversible
and also partially rate-limiting. All of the proton transfers are
1
1
Codimerization of MMA and EMA (Scheme 4). To a solution
of 1 (0.89 mg, 0.30 mmol) in toluene (0.7 mL) was added MMA (0.30
g, 3.0 mmol) at 80 °C. After the mixture was stirred for 1 h, the
volatiles were evaporated under reduced pressure at room temper-
ature. A toluene solution of n-dodecane (0.13 mol/L, 0.7 mL) was
added, and a small aliquot was sampled and subjected to GC and ESI-
MS analyses. To the mixture, EMA (0.34 g, 3.0 mmol) and toluene
(0.7 mL) were added. After the mixture was stirred at 80 °C for 4 h, a
small aliquot of the mixture was subjected to GC and ESI-MS analyses.
Kugelrohr distillation under reduced pressure gave 0.22 g of a mixture
of dimers of 2, 5, and 6 in 25, 4, and 39% yield, respectively. The yields
relatively very rapid, and the kH/kD value of 0.81
0.13
suggests an inverse secondary deuterium isotope effect. The
alkenyl protons of the first MMA are transferred to C3 and C5
of 2 through an intermolecular exchange. We have summarized
the similarities and differences between this dimerization and
the benzoin condensation in regard to the kinetics, reversibility,
and stability of the intermediates. This fundamental study can
provide opportunities for the discovery of new NHC-catalyzed
umpolung reactions. Further studies along this line are now in
progress in our laboratory.
1
of the dimers were estimated by H NMR and GC analyses, and the
1
intermediates VI, VII, and VIII were detected by ESI-MS. H NMR
(400 MHz, CDCl3) δ: 1.18−1.31 (7.5H), 1.85 (3.1H), 2.29−2.36
(1.0H), 2.50−2.62 (2.1H), 3.69 (1.1H), 3.74 (1.4H), 4.11−4.21
(2.7H), 6.69−6.72 (1.0H). HRMS (ESI) m/z: calcd for C26H26N3O2
[VI + H]+ 412.2025, found 412.2027; calcd for C31H34N3O4 [VII +
H]+ 512.2549, found 512.2550; calcd for C32H36N3O4 [VIII + H]+
526.2706, found 526.2714.
Reaction of MMA with 1 for 5 min (Table 1, Entry 1). To a
solution of 1 (89 mg, 0.3 mmol) in toluene (0.6 mL) at 80 °C was
added a solution of MMA (30 mg, 0.3 mmol) and n-dodecane in
toluene (0.13 mol/L, 0.3 mL) at 80 °C. The reaction mixture was
stirred for 5 min and then quenched with HCl in 1,4-dioxane (0.2 mL,
3.0 mol/L). A small aliquot was sampled and subjected to GC analysis
to estimate the yield of 2 (0%). The crude product was purified by
silica gel column chromatography using CH2Cl2/MeOH as the eluent
EXPERIMENTAL SECTION
■
General. All of the reactions were performed under a nitrogen
atmosphere using standard Schlenk techniques. MMA, EMA, and 1,2-
dimethoxyethane were distilled from CaH2 under reduced pressure
before use. Other chemicals were used as received. MMA-d8 (98.8
atom % D) was purchased from a commercial supplier. The GC yields
and conversions were estimated using n-dodecane as an internal
standard. Purification by Kugelrohr distillation under reduced pressure
(<1 Torr) at 110 °C for 2 or 135 °C for 6 gave dimers as transparent
liquids. The deoxy-Breslow intermediates could be purified by silica gel
column chromatography using CH2Cl2/MeOH as the eluent, but this
purification caused an undesired H/D exchange reaction at the β-
carbon. The ESI-MS measurements on the deuterated intermediates
also resulted in H/D exchange. NMR spectra were recorded on
spectrometers at 600, 500, and 400 MHz. Chemical shifts were
expressed relative to tetramethylsilane (0.0 ppm) for 1H and the
CDCl3 resonance (77.1 ppm) for 13C. The NMR peak assignments of
the dimers and the deoxy-Breslow intermediates were performed using
COSY, HMQC, and DEPT135 measurements. ESI-MS was performed
using a quadrupole orthogonal acceleration time-of-flight instrument
equipped with a Z-spray nanoelectrospray ionization source. GC
analysis was performed on an instrument equipped with a flame
ionization detector and a fused silica capillary column (30 m × 0.25
mm i.d. × 0.25 μm film thickness). All of the dimers were also
characterized by GC.
1
to give 7 (0.10 g, 0.23 mmol) in 77% isolated yield. For the H and
13C NMR, HRMS, and IR data of 7, see ref 17.
Kinetics of the Dimerizations (Table 2). To a solution of 1 (89
mg, 0.30 mmol) and n-dodecane (0.09 mmol) in toluene (0.70 mL) at
80 °C was added MMA (0.3 g, 3.0 mmol) at 80 °C. Aliquots were
sampled from the reaction mixture at various times for 30 min and
then subjected to GC analysis to estimate the yield of 2. The reaction
rate was estimated as the slope of the time−yield plot at less than 12%
yield.
Competitive Dimerization of MMA and MMA-d8 (Figure 2).
To a solution of 1 (0.13 g, 0.44 mmol) in toluene (0.89 mL) were
added MMA (0.22 g, 2.2 mmol) and MMA-d8 (0.24 g, 2.2 mmol) at
room temperature. The temperature was increased to 80 °C, and the
mixture was stirred for 8 h. Kugelrohr distillation under reduced
pressure gave 0.37 g of a mixture of the dimers in 75% yield. HRMS
(ESI) m/z: calcd for C10H16O4Na 223.0946, found 223.0943; calcd for
C10H15DO4Na 224.1009, found 224.1002; calcd for C10H14D2O4Na
225.1072, found 225.1065; calcd for C10H10D6O4Na 229.1323, found
229.1320; calcd for C10H9D7O4Na 230.1386, found 230.1379; calcd
for C10H8D8O4Na 231.1448, found 231.1448; calcd for C10H7D9O4Na
232.1511, found 232.1506; calcd for C10H6D10O4Na 233.1574, found
233.1566; calcd for C10H2D14O4Na 237.1825, found 237.1822; calcd
for C10HD15O4Na 238.1888, found 238.1882; calcd for C10D16O4Na
239.1951, found 239.1940.
Deuterium-Labeling Experiment of II (Scheme 2). To a
solution of 1 (89 mg, 0.30 mmol) in 1,2-dimethoxyethane (0.6 mL)
was added MMA (30 mg, 0.30 mmol) at 80 °C. After the mixture was
stirred for 10 min, CF3CO2D (0.14 g, 1.23 mmol) was added, and
stirring was continued for 1 h. The reaction mixture was filtered
through a Celite pad and dried in vacuo to give 3 as a yellow liquid in
96% crude yield (0.15 g, 0.29 mmol). 1H NMR (600 MHz, CDCl3) δ:
1.04 (3H, d, J = 7.0 Hz), 2.27 (1H, brs), 3.10 (0.48H, brs), 3.57 (3H,
s), 3.70 (0.48H, brs). 7.35−8.01 (15H, m). 13C NMR (150 MHz,
CDCl3) δ: 173.9, 160.9, 160.5, 160.1, 159.7, 120.0−134.7, 120.0,
117.2, 114.3, 111.4, 52.5, 35.7, 35.6, 28.2, 16.9.
Dimerization of MMA in the Presence of CD3OD (Scheme 5).
To a solution of 1 (89 mg, 0.30 mmol) in 1,2-dimethoxyethane (0.7
mL) were added CD3OD (0.14 g, 3.9 mmol) and MMA (0.30 g, 3.0
mmol). The mixture was stirred at 80 °C for 72 h. Kugelrohr
distillation under reduced pressure gave 9 in 62% yield (0.19 g, 0.93
1
mmol). H NMR (600 MHz, CDCl3) δ: 1.19 (3H, m), 1.84 (3H, s),
2.31 (1H, m), 2.53 (1H, m), 2.60 (0.3H, m), 3.67 (1.3H, s), 3.73
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2
(1.2H, s), 6.69 (0.3H, t, J = 7.1 Hz). H NMR (77 MHz, CHCl3) δ:
ASSOCIATED CONTENT
■
2.56 (1.1D), 3.63(3.2D), 3.68 (3.0D), 6.70 (1.0D). 13C NMR (150
MHz, CDCl3) δ: 175.9, 168.3, 138.7, 138.4, 138.3, 138.2, 129.3, 129.2,
51.7, 51.1, 51.0, 50.8, 38.7, 38.5, 38.3, 38.2, 32.7, 32.4, 32.3, 32.2, 16.8,
16.7, 12.4. HRMS (ESI) m/z: calcd for C10H8D8O4Na [9 + Na]+
231.1448, found 231.1449.
S
* Supporting Information
1H, 13C, and 2H NMR spectra; data from the kinetic study; and
a GC profile. This material is available free of charge via the
Internet at http://pubs.acs.org.
H/D Exchange Reaction of the β-Carbon of II in the Presence
of CD3OD (Scheme 6). To a solution of 1 (89 mg, 0.30 mmol) in
toluene (0.6 mL) at 80 °C was added MMA (30 mg, 0.30 mmol).
After the mixture was stirred for 5 min, CD3OD (0.11 g, 3.0 mmol)
was added at room temperature, and the stirring was continued for 1 h.
After the volatiles were removed under reduced pressure, CH2Cl2 (0.6
mL) was added, and the reaction was quenched with HCl in 1,4-
dioxane (0.2 mL, 3.0 mol/L). Precipitation of the mixture into hexane
AUTHOR INFORMATION
Corresponding Author
*E-mail: matsuoka.shinichi@nitech.ac.jp. Fax: +81-52-735-
7254. Tel: +81-52-735-7254.
■
Notes
The authors declare no competing financial interest.
1
gave 10 as a white solid in 96% crude yield (0.13 g, 0.29 mmol). H
ACKNOWLEDGMENTS
NMR (400 MHz, CDCl3) δ: 1.01 (3H, d, J = 6.9 Hz), 2.27 (1H, m),
3.22 (0.48H, m), 3.54 (0.88H, s), 4.15 (0.48H, m), 7.29−8.24 (15H,
m). 13C NMR (100 MHz, CDCl3) δ: 174.0, 154.8−120.8, 52.4, 35.7,
35.68, 35.66, 35.60, 29.6, 17.29, 17.26, 17.24.
■
This work was partially supported by a Grant-in-Aid for
Scientific Research for Young Scientists (B) (24750102).
Reaction of the Mixture of MMA and MMA-d8 with 1
(Scheme 7). To a solution of 1 (89 mg, 0.30 mmol) in 1,2-
dimethoxyethane (0.6 mL) was added a mixture of MMA (15 mg, 0.15
mmol) and MMA-d8 (16 mg, 0.15 mmol) in toluene (0.3 mL) at 80
°C. After the mixture was stirred for 5 min, HCl in 1,4-dioxane (0.2
mL, 3.0 mol/L) was added, and the mixture was stirred at room
temperature for 1 h. The crude product was filtered through a Celite
pad using CH2Cl2 as the eluent and dried in vacuo to give isomers of
the deoxy-Breslow intermediates (80 mg, white solid). HRMS (ESI)
m/z: calcd for C25H24N3O2 [7 − Cl]+ 398.1869, found 398.1877; calcd
for C25H23DN3O2 [11 − Cl]+ 399.1931, found 399.1930.
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1
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2
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1
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