Aerobic Oxidative Olefination of Benzamides with Styrenes Catalyzed by a Moderately Electron-Deficient CpRh(III) Complex with a Pendant Amide

Article abstract of DOI:10.1021/acs.joc.8b02875

It has been established that a newly developed moderately electron-deficient cyclopentadienyl (Cp)-Rh(III) complex, bearing ester and pendant amide moieties on the Cp ring [Cp^ARh(III)], is able to catalyze the aerobic oxidative olefination of b

Full text of DOI:10.1021/acs.joc.8b02875

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Article
Aerobic Oxidative Olefination of Benzamides with Styrenes Catalyzed by
a Moderately Electron-Deficient CpRh(III) Complex with a Pendant Amide
Ryo Yoshimura, Yu Shibata, Takayuki Yamada, and Ken Tanaka
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Jan 2019
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Aerobic Oxidative Olefination of Benzamides with Sty-
renes Catalyzed by a Moderately Electron-Deficient
CpRh(III) Complex with a Pendant Amide
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Ryo Yoshimura, Yu Shibata,* Takayuki Yamada, and Ken Tanaka*
Department of Chemical Science and Engineering, Tokyo Institute of Technology, O-okayama, Meguro-
ku, Tokyo 152-8550, Japan
ABSTRACT: It has been established that a newly developed moderately electron-deficient cyclopenta-
dienyl (Cp)-Rh(III) complex, bearing ester and pendant amide moieties on the Cp ring [CpARh(III)], is
able to catalyze the aerobic oxidative olefination of benzamides, bearing non-special carbamoyl groups,
with styrenes including disubstituted ones at relatively low temperature (60–80 °C). The presence of
both the ester and pendant acidic N-phenylcarbamoyl moieties on the CpA ligand play important roles in
facilitation of the catalysis without sacrificing thermal stability of the complex.
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INTRODUCTION
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The transition-metal catalyzed oxidative C–H olefination of arenes with olefins (i.e., the Fujiwara-
Moritani and oxidative Heck reactions) are atom- and step-economical methods for the synthesis of sub-
stituted styrenes.1,2 In particular, the use of directing groups realized regioselective ortho-directed trans-
formations.3 In this area, benzamides are commonly investigated substrates and a number of amide-
directed oxidative olefinations catalyzed by a Cp*Rh(III) complex has been reported (Scheme 1).4
However, there are limitations on the reaction conditions and substrate scope of these transformations.
In terms of the reaction conditions, high reaction temperature and a stoichiometric amount of a metal
oxidant are typically required. In terms of the substrate scope, the use of styrenes giving stilbenes gener-
ally results in lower yields than the use of activated alkenes bearing electron-withdrawing groups. Addi-
tionally, the use of disubstituted alkenes is scarce.
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In 2010, the neutral pentamethylcyclopentadienyl (Cp*)-Rh(III) complex-catalyzed oxidative ole-
fination of benzamides was first reported using acrylates and a stoichiometric amount of a silver oxidant
at 110 °C.4a A single example using styrene was demonstrated, while the yield of the corresponding stil-
bene derivative was moderate. The use of a cationic Cp*Rh(III) complex broadened the scope of sty-
renes and improved the yields of stilbene products; however, a stoichiometric amount of a copper(II)
oxidant and the high reaction temperature (120 °C) were still required.4b Subsequently, the low-
temperature (60 °C) C–H olefination of benzamides with styrenes was reported, but the N-
methoxycarbamoyl group was necessary as an oxidizing-directing group.4c Recently, the aerobic oxida-
tive olefination of benzamides was achieved at 80 °C, even when styrenes were employed, but the high-
ly acidic N-pentafluorophenylcarbamoyl directing group was necessary.4e Therefore, the aerobic oxida-
tive olefination of benzamides bearing non-special carbamoyl groups with styrenes remains a chal-
lenge.5 Following the above Rh-catalyzed reactions, Ru,4d,6,7 Ir,8 Co,9 and Pd10-catalyzed variants were
reported, and the use of Pd(OAc)2 enabled the oxidative olefination-cyclization of benzamides with sty-
renes at 90 °C using O2 as a terminal oxidant. However, the directing group was still limited to the N-
methoxycarbamoyl group.8b
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Furthermore, usable disubstituted alkenes in the previously reports were limited to electron-deficient
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acrylate derivatives, and so the aerobic oxidative olefination using disubstituted styrenes is highly chal-
lenging.5,7 In this paper, we have established that a newly developed moderately electron-deficient
CpRh(III) complex bearing ester and pendant amide moieties on the Cp ring is able to catalyze the aero-
bic oxidative olefination of benzamides with styrenes, including disubstituted ones, at relatively low
temperature (60–80 °C).
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Scheme 1. Oxidative Olefinations of Benzamides
Our research group previously developed modified CpRh(III) complexes through the reductive
complexation of RhCl3 with substituted fulvenes (Scheme 2).11–13 These complexes exhibited high cata-
lytic activities in various C–H functionalizations.11 For example, a highly electron-deficient CpERh(III)
complex bearing two ester moieties on the Cp ring catalyzed the aerobic oxidative annulation and ole-
fination of anilides with various alkynes and alkenes, respectively, including unactivated ones, under
ambient conditions.11a–e Subsequently, CpARh(III) complex 1a bearing a pendant N-phenylcarbamoyl
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moiety on the Cp ring also catalyzed the aerobic oxidative annulation of acetanilide with diphenylacety-
lene under ambient conditions.11f We believe that increasing electrophilicity of the CpERh(III) com-
plex11a,13 and contribution of intramolecular C–H extraction by the pendant acidic N-phenylcarbamoyl
moiety of 1a accelerate the C–H cleavage. Interestingly, CpARh(III) complex 1b bearing a pendant N,N-
dimethylcarbamoyl moiety on the Cp ring catalyzed not the usual [4+2] annulation but the unusual for-
mal Lossen rearrangement/[3+2] annulation of N-pivaloyl benzamides with alkynes. Coordination of the
pendant N,N-dimethylcarbamoyl moiety to rhodium may accelerate ring contraction rearrangement.11h
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Scheme 2. Modified CpRh(III) Complexes
RESULTS AND DISCUSSION
Thus, we attempted the oxidative olefination of pyrrolidine-based benzamide 2a with styrene (3a)
by using these modified CpRh(III) complexes as well as the Cp*Rh(III) complex in the presence of
AgSbF6/Cu(OAc)2•H2O co-catalysts in 1,2-dichloroethane at 60 °C under air. Interestingly, the use of
our modified CpRh(III) complexes afforded the desired olefinated product 4aa in significantly higher
yields than the use of the Cp*Rh(III) complex (Table 1, entry 1 vs. entries 2–4). The electron-deficient
CpERh complex exhibited the highest catalytic activity (entry 2), and CpARh(III) complex 1a bearing a
pendant N-phenylcarbamoyl moiety exhibited higher catalytic activity than CpARh(III) complex 1b
bearing a pendant N,N-dimethylcarbamoyl moiety (entry 3 vs, entry 4). As the CpCyRh complex bearing
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two phenyl groups13,14 showed lower activity than 1a and 1b (entry 5), the pendant amide moiety cer-
tainly improve the catalytic activity. Subsequently, we synthesized moderately electron-deficient
CpARh(III) complex 1c bearing both the ester and pendant N-phenylcarbamoyl moieties on the Cp ring
to increase the electrophilicity of the complex (Scheme 2). Pleasingly, the use of 1c increased the yield
of 4aa to 60% (entry 6). Although further screening of counter anions, additives (Table S1), and sol-
vents (Table S2) failed to improve the yield of 4aa, elevation of the reaction temperature to 80 °C im-
proved the yield to 79% (entry 7). Instead, a prolonged reaction time and high catalyst loading did also
improve the yield to 85% (entries 8 and 9). Under the same conditions, the use of the highly electron-
deficient CpERh(III) complex did not improve the yield of 4aa, because of generation of doubly ole-
finated 5aa (entry 10). In terms of the total yield, CpERh(III) resulted in the lower yield than 1c presum-
ably due to its instability at 60 °C [entry 9 (93%) vs. entry 10 (78%)].15
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Table 1. Optimization of Reaction Conditionsa
entry
[Rh2]
time (h)
yield (%)b
4aa
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5aa
<3
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85 (90e)
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[CpERhCl2]2
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3a (0.150 mmol), and (CH2Cl)2 (0.5 mL) were used. b Determined by 1H NMR spectroscopy. c At 80 °C.
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d 1 (5 mol %, 0.0050 mmol) and AgSbF6 (20 mol %, 0.020 mmol) were used. Isolated yield for the re-
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actions using 1c (0.010 mmol), AgSbF6 (0.040 mmol), Cu(OAc)2•H2O (0.040 mmol), 2a (0.200 mmol),
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Scheme 3. Scope of Benzamides and Styrenesa
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a
1c (0.010 mmol), AgSbF6 (0.040 mmol), Cu(OAc)2•H2O (0.040 mmol), 2 (0.200 mmol), 3
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(0.300 mmol), and (CH2Cl)2 (1.0 mL) were used. b For 72 h. c At 80 °C.
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The substrate scope of the reaction was then examined, as shown in Scheme 3. In terms of the am-
ide-directing group, not only tertiary (2a–c) but also secondary (2d) and primary (2e) amides were ap-
plicable, although the yields were moderate. In addition, various electron-donating (2f and 2g) and elec-
tron-withdrawing (2h and 2i) substituents were tolerated at the para-position of the benzene ring. In the
reaction of meta-substituted benzamide 2j, the olefination proceeded selectively at the sterically vacant
position. Fortunately, less reactive 3,5-disubstituted 2k and ortho-substituted 2l could be employed, alt-
hough high temperature (80 °C) and/or prolonged reaction time (72 h) were required. In terms of the
styrenes, electronically and sterically diverse ones (3b–g) reacted with 2a to give the corresponding
products 4ab–ag in high yields. Notably, extremely bulky ortho-disubstituted styrene 3g, which has not
been explored in the previously reported oxidative olefinations, could also be applicable to the present
CpARh catalysis.
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The reactions of aliphatic alkenes were also investigated. Bulky 3,3-dimethyl-1-butene (3h) that was
unusable in our previously reported CpERh(III)-catalyzed olefination of anilides11c reacted with 2a at
80 °C to give olefinated product 4ah in 71% yield (Scheme 4a). Less bulky 1-octene (3i) also reacted
with 2a under the same conditions to give the corresponding oxidative olefination products in good
yields, but a mixture of linear/branch and double bond isomers were generated with low selectivity
(Scheme 4b).
Scheme 4. Olefination with Aliphatic Alkenes
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This successful use of bulky and less reactive 3g and 3h prompted our investigation into the use of
less reactive disubstituted alkenes. To our delight, 1,2-disubstituted styrene 3j reacted with 2a to give
4aj accompanied by its isomer 4aj’ in moderate yield (Table 2, entry 1). Elevation of the reaction tem-
perature to 80 °C improved the total yield (entry 2, left column). Not only 3j but also 1,1-disubstituted
styrene 3k equally employed to give 4ak in good yield (entry 3, left column). Under the conditions, the
use of the CpE and Cp* ligands afforded 4aj and 4ak in lower yields (entries 2 and 3, middle and right
columns), especially in the reactions of far less coordinative 3j (entry 2). The reactions of mono- and
disubstituted acrylates 3l–n with 2a were also catalyzed by 1c to give 4al–an at room temperature in
higher yields than the use of the CpERh(III) and Cp*Rh(III) catalysts (entries 4–6). The reactions of 2a
with acrylate 3l and crotonate 3m were also catalyzed by 1c to give 4al and 4am at room temperature in
higher yields than the use of the CpERh(III) and Cp*Rh(III) catalysts (entries 4 and 5). In these reactions,
(E)-trisubstitued alkenes were generated as sole or major isomers (76–100% selectivity). However, the
reaction of 2a with methacrylate 3n at room temperature afforded disubstituted alkene 4an’ (allylation
product) as a major isomer. This disubstituted alkene 4an’ may be a kinetic product, thermodynamically
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stable (E)-trisubstituted alkene 4an was generated as a major isomer at elevated temperature (80 °C).
Finally, the reactions of (E)- and (Z)-stilbenes with 2a were also tested, but no reaction was observed
even at the elevated temperature of 80 °C.
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Table 2. Scope of Disubstituted Alkenes and Ligand-Effectsa
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entry
% yield [ratio of (E)-4/(Z)-4/4’]b
3
temp.
(°C)
CpA (1c)
CpE
Cp*
–
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80
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–
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70 (84:14:2)
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80
57c (16:14:70)
81c (58:27:15)
52 (15:15:70)
<3 (–)
–
–
a
[CpXRhCl2]2 complexes (0.0050 mmol), AgSbF6 (0.020 mmol), Cu(OAc)2•H2O (0.020 mmol), 2a
(0.100 mmol), 3 (0.150 mmol), and (CH2Cl)2 (0.5 mL) were used. b Determined by 1H NMR. The prod-
c
ucts were obtained as a mixture of E/Z stereoisomers 4 and regioisomers 4’ as shown below. The
yields are isolated yields using 1c (0.010 mmol), AgSbF6 (0.040 mmol), Cu(OAc)2•H2O (0.040 mmol),
2a (0.200 mmol), 3 (0.300 mmol), and (CH2Cl)2 (1.0 mL).
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Preparative scale reactions (Scheme 5) were also conducted, giving 4aa without any significant de-
crease in yield. Although high temperature (80 °C) was necessary, the low catalyst loading reaction
(1 mol % 1c) proceeded to give 4aa in satisfactory yield.
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Scheme 5. Preparative Scale Reactions
Based on previous reports,4 a plausible reaction mechanism was proposed as outlined in Scheme 6.
First, the catalytically active rhodium(III) acetate A generated from 1c, AgSbF6, and an acetate anion
reacts with 2 to form rhodacycle B via an electrophilic concerted metalation-deprotonation pathway.
Subsequent alkene coordination and insertion afford rhodacycle D via C. β-Hydride elimination and ox-
idation with a Cu(II) oxidant afford product 4-coordinating rhodium(III) acetate E. Finally, dissociation
of the product 4 regenerates the catalytically active species A.
Scheme 6. Plausible Reaction Mechanism
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To explore the effect of the Cp ligand on the catalytic cycle, deuterium kinetic isotope effects (KIEs)
of the olefination of 2a with 3a were measured by the two parallel reactions (Scheme 7a) and the inter-
molecular competition reactions (Scheme 7b) using the Cp* and CpA (1a and 1c) Rh(III) complexes as
the catalysts. We found that the reactions using the Cp*Rh(III) complex resulted in the significantly dif-
ferent KIE values (2.2 vs. 4.9), while no significant H/D exchange of the recovered 2a-d5 with H2O was
observed in the parallel reactions (Scheme S1). These observations suggest that not only the irreversible
C–H cleavage step but other rate-limiting steps may also exist in the Cp*Rh(III)-based catalysis.15 In
contrast, in the reactions using 1a and 1c, no significant KIE difference was observed between the two
measurements (3.9 vs. 5.8 using 1a, 2.4 vs. 3.0 using 1c), which suggests that not only the C–H bond
cleavage step but also the other rate-limiting steps may be accelerated by the pendant amide moiety of
the CpARh(III) catalyst.
Scheme 7. Deuterium Kinetic Isotope Effects
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Thus, the roles of the ester and amide moieties of 1c may be the followings. The ester moiety accel-
erates the C–H bond cleavage even with a weakly coordinating directing group and the alkene insertion
due to the electron-deficient nature of the rhodium center.5 On the other hand, the pendant secondary
amide moiety accelerates the C–H bond cleavage by intramolecular C-H extraction, and controls the
coordination equilibrium of substrates and products by its hemilabile coordination to rhodium, which
facilitates the alkene coordination and product dissociation giving intermediates C and A, respectively.16
In the reaction of far less coordinative 1,2-disubstituted styrene 3j, the alkene coordination and in-
sertion steps would be more rate-limiting than the C–H cleavage step. Indeed, the parallel reactions us-
ing 3j resulted in no KIE (Scheme 7c). In this reaction, 1c showed the significantly higher catalytic ac-
tivity than the CpERh(III) complex (Table 2, entry 2). Time course of these reactions revealed that 1c is
significantly more stable than the CpERh(III) complex at 80 °C (Scheme 8, Figure 1),17 which accounts
for the high catalytic activity of 1c. The pendant acidic N-phenylcarbamoyl moiety on the CpA ligand
may accelerate the C–H cleavage without introducing two ester moieties that cause low thermal stability
of the complex.
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Scheme 8. Reaction Profiles for Oxidative Olefination of 2a with 3j
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Figure 1. Reaction profiles for the oxidative olefination of 2a with 3j in the presence of complex 1c
(red square) or [CpERhCl2]2 (blue diamond). The total yields of (E/Z)-4aj and 4aj’ are shown.
CONCLUSION
In conclusion, we have established that a newly developed moderately electron-deficient cyclopen-
tadienyl (Cp)-Rh(III) complex, bearing ester and pendant amide moieties on the Cp ring [CpARh(III)], is
able to catalyze the aerobic oxidative olefination of benzamides, bearing non-special carbamoyl groups,
with styrenes including disubstituted ones at relatively low temperature (60–80 °C). The presence of
both the ester and pendant acidic N-phenylcarbamoyl moieties on the CpA ligand play important roles in
facilitation of the catalysis without sacrificing thermal stability of the complex. Future works will in-
clude the further application of the CpARh(III) complex in the problematic C–H bond functionalization
reactions.
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EXPERIMENTAL SECTION
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General: Anhydrous (CH2Cl)2 (No. 28,450-5) was obtained from Aldrich used as received. Sol-
vents for the synthesis of substrates were dried over Molecular Sieves 4A (Wako) prior to use. Rh(III)
complexes 1a,11f 1b,11f [CpERhCl2]2,11a [CpCyRhCl2]2,13 benzamides 2a,18 2b,18 2f,18 2g,18 2h,18 2i,18 2j,18
2k,19 2l,20 and alkene 3c21 were prepared according to the literature procedures. All other reagents were
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obtained from commercial sources and used as received. H and 13C{1H} NMR data were collected on a
Bruker AVANCE III HD 400 (400 MHz) at ambient temperature. HRMS data were obtained on a Bruker
micrOTOF Focus II. All reactions were carried out in oven-dried glassware with magnetic stirring. An
oil bath was used for the reactions that require heating (60 °C or 80 °C).
Methyl -5-[2-oxo-2-(phenylamino)ethylidene]-6-phenyl-3,5-dihydro-1H-cyclo-penta[c]furan-4-
carboxylate: Segphos (12.2 mg, 0.0200 mmol) and [Rh(cod)2]BF4 (8.1 mg, 0.0200 mmol) were dis-
solved in CH2Cl2 (2.0 mL) and the mixture was stirred at room temperature (28 °C) for 10 min. H2 was
introdced to the resulting solution in a Schlenk tube. After stirring at room temperature (28 °C) for 30
min, the resulting mixture was concentrated and dissolved in (CH2Cl)2 (0.5 mL). To the solution were
added a solution of 2-cyclopropylidene-N-phenylacetamide11f (38.2 mg, 0.220 mmol) in (CH2Cl)2 (0.5
mL) and methyl 4-[(3-phenylprop-2-yn-1-yl)oxy]but-2-ynoate22 (45.6 mg, 0.200 mmol) in (CH2Cl)2
(1.0 mL) in this order and the resulting mixture was stirred at 40 °C for 16 h. The resulting solution was
concentrated and purified by a silica gel preparative TLC (eluent: EtOAc), which furnished the title
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compound (42.3 mg, 0.113 mmol, 57% isolated yield, E/Z = 77:23) as an orange amorphous. H NMR
(CDCl3, 400 MHz) of (E)-isomer: δ 7.87 (s, 1H), 7.58 (s, 1H), 7.47–6.95 (m, 9H), 4.86 (s, 2H), 4.69 (s,
2H), 3.79 (s, 3H); 1H NMR (CDCl3, 400 MHz) of (Z)-isomer: δ 8.24 (s, 1H), 7.61 (s, 1H), 7.47–6.95 (m,
8H), 6.72 (s, 1H), 4.86 (s, 2H), 4.71 (s, 2H), 2.38 (s, 3H); C{1H} NMR (CDCl3, 100 MHz) δ 163.3,
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163.3, 163.2, 149.9, 148.0, 146.0, 136.8, 133.9, 133.3, 132.4, 129.8, 129.3, 129.0, 128.9, 128.6, 128.3,
127.9, 127.7, 124.5, 119.9, 119.8, 113.4, 68.2, 67.9, 66.3, 60.3, 51.7, 51.4; HRMS (ESI) calcd for
C23H19NNaO4 [M+Na]+ 396.1206, found 396.1216.
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CpARh Complex 1c: To a solution of RhCl3•nH2O (39.15 wt% Rh, 29.4 mg, 0.113 mmol) in EtOH
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(1.0 mL) was added a solution of methyl 5-[2-oxo-2-(phenylamino)ethylidene]-6-phenyl-3,5-dihydro-
1H-cyclo-penta[c]furan-4-carboxylate (42.3 mg, 0.113 mmol, E/Z = 77:23) in EtOH (1.0 mL) and the
mixture was stirred at 60 °C for 16 h. The resulting mixture was concentrated under reduced pressure
and the residue was diluted with CH2Cl2 (2.0 mL) and filtered. The filtrate was poured into n-hexane
(10.0 mL) and the resulting precipitates were collected, washed with Et2O (2.0 mL) twice and dried un-
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der vacuum to give 1c (50.1 mg, 0.0446 mmol, 79% isolated yield) as a red solid. Mp >300 °C; H
NMR (CD3CN, 400 MHz) δ 8.59 (br, 2H), 7.73–7.71 (m, 4H), 7.51–7.42 (m, 10H), 7.30–7.26 (m, 4H),
7.09–7.05 (m, 2H), 4.73 (d, 13.9 Hz, 2H), 4.57 (d, 12.8 Hz, 2H), 4.43–4.40 (m, 4H), 4.23 (d, 16.8 Hz,
2H), 3.82 (s, 6H), 3.66 (d, 16.8 Hz, 2H); 13C{1H} NMR (CD3CN, 100 MHz) δ 166.1, 165.1, 139.0,
130.5, 130.3, 129.5, 129.43, 129.36, 128.0, 124.6, 110.7, 109.5, 69.1, 66.5, 65.8, 53.5, 34.7; HRMS
(ESI) calcd for C23H19ClNNaO4Rh [M−HCl+Na]+ 533.9950, found 533.9950.
Representative procedure for rhodium-catalyzed oxidative olefination (Table 1, entry 12): To a
Schlenk flask was added AgSbF6 (13.6 mg, 0.0400 mmol), complex 1c (11.0 mg, 0.0100 mmol),
Cu(OAc)2•H2O (8.0 mg, 0.0400 mmol), 2a (35.0 mg, 0.200 mmol), 3a (31.2 mg, 0.300 mmol), and
(CH2Cl)2 (1.0 mL) in this order. The mixture stirred at 60 °C under air for 16 h. The resulting mixture
was diluted with diethyl ether, filtered through a silica gel pad, and washed with EtOAc. The solvent
was concentrated under reduced pressure and the residue was purified by a preparative TLC (tolu-
ene/EtOAc = 1:1) to give 4aa (49.9 mg, 0.180 mmol, 90% yield) as a colorless oil and 5aa (6.15 mg,
0.0162 mmol, 8% yield).
Procedure for preparative scale reactions (Scheme 5): To a Schlenk flask was added AgSbF6
(13.6 mg, 0.0400 mmol), complex 1c (11.0 mg, 0.0100 mmol), Cu(OAc)2•H2O (8.0 mg, 0.0400 mmol),
2a (175 mg, 1.00 mmol), 3a (156 mg, 3.00 mmol), and (CH2Cl)2 (1.0 mL) in this order. The mixture
stirred at 80 °C under air for 72 h. The resulting mixture was diluted with diethyl ether, filtered through
a silica gel pad, and washed with EtOAc. The solvent was concentrated under reduced pressure and the
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residue was purified by a preparative TLC (toluene/EtOAc = 1:1) to give 4aa (198 mg, 0.714 mmol,
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71% yield).
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(E)-Pyrrolidin-1-yl(2-styrylphenyl)methanone (4aa): Colorless oil; 49.9 mg, 0.180 mmol, 90%
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yield; H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 7.8 Hz, 1H), 7.49–7.46 (m, 2H), 7.41–7.24 (m, 5H),
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7.19–7.08 (m, 2H), 3.70 (t, J = 7.0 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.96–1.77 (m, 4H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 169.5, 137.1, 137.0, 133.7, 131.1, 129.1, 128.7, 128.0, 127.7, 126.7, 126.5, 125.7,
125.3, 48.3, 45.6, 26.0, 24.6; HRMS (ESI) calcd for C19H19NNaO [M+Na]+ 300.1359, found 300.1379.
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{2,6-Di[(E)-Styryl]phenyl}(pyrrolidin-1-yl)methanone (5aa): Colorless oil; 6.15 mg, 0.0162
mmol, 8% yield; 1H NMR (CDCl3, 400 MHz) δ 7.61 (d, J = 7.8 Hz, 2H), 7.50–7.548 (m, 4H), 7.39–7.33
(m, 5H), 7.29–7.26 (m, 2H), 7.12 (s, 4H), 3.76 (t, J = 7.0 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.95–1.88
(m, 2H), 1.80–1.74 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.6, 137.1, 136.1, 134.0, 131.4,
128.9, 128.7, 128.0, 126.8, 125.2, 124.6, 47.7, 45.4, 25.9, 24.7; HRMS (ESI) calcd for C27H25NNaO
[M+Na]+ 402.1828, found 402.1802.
(E)-Morpholino(2-styrylphenyl)methanone (4ba): Colorless oil; 52.2 mg, 0.176 mmol, 88%
isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J = 7.9 Hz, 1H), 7.49–7.47 (m, 2H), 7.42–7.25 (m,
6H), 7.17–7.07 (m, 2H), 3.91–3.74 (br, 4H), 3.51–3.50 (br, 2H), 3.20 (t, J = 4.8 Hz, 2H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 169.7, 136.8, 134.8, 134.2, 131.6, 129.4, 128.8, 128.2, 127.8, 126.7, 126.7, 125.7,
125.0, 70.0, 66.9, 47.4, 42.1; HRMS (ESI) calcd for C19H19NNaO2 [M+Na]+ 316.1308, found 316.1316.
(E)-N,N-Dimethyl-2-styrylbenzamide (4ca)6b: Colorless oil; 45.7 mg, 0.182 mmol, 91% isolated
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yield; H NMR (CDCl3, 400 MHz) δ 7.68 (d, J = 7.8 Hz, 1H), 7.49–7.47 (m, 2H), 7.40–7.24 (m, 6H),
7.10 (s, 2H), 3.16 (s, 3H), 2.79 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 171.1, 137.1, 135.9, 134.0,
131.2, 129.1, 128.7, 128.0, 127.7, 126.7, 126.6, 125.6, 125.2, 38.6, 34.8.
(E)-N-Benzyl-2-styrylbenzamide (4da)23: Colorless solid; 29.2 mg, 0.0930 mmol, 47% isolated
yield; Mp 119.8–120.6 °C; 1H NMR (CDCl3, 400 MHz) δ 7.65 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 7.6 Hz,
1.1 Hz, 1H), 7.43–7.24 (m, 13H), 7.01 (d, J = 16.2 Hz, 1H), 6.19 (br, 1H), 4.62 (d, J = 5.9 Hz, 2H);
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13C{1H} NMR (CDCl3, 100 MHz) δ 169.3, 138.2, 137.0, 135.50, 135.48, 131.6, 130.3, 128.8, 128.7,
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128.0, 127.9, 127.8, 127.6, 127.5, 126.8, 126.2, 125.9, 44.1.
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(E)-2-Styrylbenzamide (4ea)4b: Colorless solid; 25.9 mg, 0.118 mmol, 59% isolated yield, reaction
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time: 72 h; Mp 189.5–190.8 °C; H NMR (CDCl3, 400 MHz) δ 7.70 (d, J = 7.8 Hz, 1H), 7.59–7.44 (m,
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5H), 7.38–7.26 (m, 4H), 7.07 (d, J = 16.3 Hz, 1H), 5.87 (br, 2H); C{1H} NMR (CDCl3, 100 MHz) δ
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171.3, 137.0, 135.9, 134.3, 131.7, 130.7, 128.7, 128.1, 127.9, 127.5, 126.9, 126.5, 126.1.
(E)-(4-Methyl-2-styrylphenyl)(pyrrolidin-1-yl)methanone (4fa): Colorless oil; 46.4 mg, 0.159
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mmol, 90% isolated yield; H NMR (CDCl3, 400 MHz) δ 7.42–7.39 (m, 3H), 7.29–7.25 (m, 2H), 7.21–
7.16 (m, 1H), 7.13–7.00 (m, 4H), 3.61 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 6.7 Hz, 2H), 2.32 (s, 3H), 1.88–
1.80 (m, 2H), 1.76–1.67 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.7, 138.9, 137.3, 134.4, 133.6,
130.7, 128.7, 128.5, 127.9, 126.7, 126.5, 1276.2, 125.5, 48.4, 45.6, 26.0, 24.6, 21.4; HRMS (ESI) calcd
for C20H21NNaO [M+Na]+ 314.1515, found 314.1522.
(E)-(4-Methoxy-2-styrylphenyl)(pyrrolidin-1-yl)methanone (4ga): Colorless oil; 55.2 mg, 0.180
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mmol, 90% isolated yield; H NMR (CDCl3, 400 MHz) δ 7.49–7.46 (m, 2H), 7.37–7.33 (m, 2H), 7.28–
7.26 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.17 (d, J = 16.2 Hz, 1H), 7.08 (d, J =
16.2 Hz, 1H), 6.84 (dd, J = 8.4, 2.5 Hz, 1H), 3.87 (s, 3H), 3.68 (t, J = 7.0 Hz, 2H), 3.14 (t, J = 6.7 Hz,
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2H), 1.95–1.88 (m, 2H), 1.83–1.77 (m, 2H); C{1H} NMR (CDCl3, 100 MHz) δ 169.5, 160.1, 137.1,
135.5, 131.2, 130.0, 128.7, 128.1, 128.0, 126.7, 125.5, 113.5, 110.6, 55.4, 48.5, 45.7, 26.0, 24.7; HRMS
(ESI) calcd for C20H21NNaO2 [M+Na]+ 330.1465, found 330.1470.
(E)-Pyrrolidin-1-yl[2-styryl-4-(trifluoromethyl)phenyl]methanone (4ha): Colorless solid; 60.5
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mg, 0.176 mmol, 88% isolated yield, reaction time: 72 h; Mp 120.0–120.4 °C; H NMR (CDCl3, 400
MHz) δ 7.93 (s, 1H), 7.55–7.53 (m, 1H), 7.50–7.48 (m, 2H), 7.42–7.35 (m, 3H), 7.32–7.26 (m, 1H),
7.21–7.12 (m, 2H), 3.71 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 6.7 Hz, 2H), 1.98–1.91 (m, 2H), 1.87–1.78 (m,
2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.1, 140.0, 136.5, 134.7, 133.0, 131.4 (q, J = 32.5 Hz),
128.9, 128.5, 127.1, 126.9, 124.2 (q, J = 3.7 Hz), 123.8 (q, J = 272.5 Hz), 123.8, 122.7 (q, J = 3.8 Hz),
48.3, 45.7, 26.0, 24.5; HRMS (ESI) calcd for C20H18F3NNaO [M+Na]+ 368.1233, found 368.1238.
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(E)-(4-Chloro-2-styrylphenyl)(pyrrolidin-1-yl)methanone (4ia): Colorless oil; 49.9 mg, 0.160
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mmol, 80% isolated yield; H NMR (CDCl3, 400 MHz) δ 7.67 (d, J = 1.8 Hz, 1H), 7.48–7.46 (m, 2H),
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2H), 1.97–1.90 (m, 2H), 1.86–1.79 (m, 2H); C{1H} NMR (CDCl3, 100 MHz) δ 168.5, 136.6, 135.7,
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135.3, 135.1, 132.4, 128.8, 128.4, 127.9, 127.6, 126.9, 125.6, 124.0, 48.4, 45.7, 26.0, 24.6; HRMS (ESI)
calcd for C19H18ClNNaO [M+Na]+ 334.0969, found 334.0973.
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(E)-(5-Methyl-2-styrylphenyl)(pyrrolidin-1-yl)methanone (4ja): Colorless oil; 43.2 mg, 0.148
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mmol, 74% isolated yield, reaction time: 72 h; H NMR (CDCl3, 400 MHz) δ 7.50 (d, J = 8.0 Hz, 1H),
7.40–7.37 (m, 2H), 7.28–7.25 (m, 2H), 7.20–7.16 (m, 1H), 7.12–7.10 (m, 1H), 7.07–6.96 (m, 3H), 3.62
(t, J = 7.0 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.28 (s, 3H), 1.89–1.82 (m, 2H), 1.77–1.70 (m, 2H);
13C{1H} NMR (CDCl3, 100 MHz) δ 169.7, 137.8, 137.3, 137.0, 130.8, 130.1, 129.9, 128.7, 127.7, 127.0,
126.6, 125.6, 125.3, 48.3, 45.6, 26.0, 24.6, 21.1; HRMS (ESI) calcd for C20H21NNaO [M+Na]+
314.1515, found 314.1519.
(E)-(3,5-Dimethyl-2-styrylphenyl)(pyrrolidin-1-yl)methanone (4ka): Colorless solid; 43.0 mg,
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0.140 mmol, 70% isolated yield, reaction time: 72 h; Mp 120.0–120.4 °C; H NMR (CDCl3, 400 MHz)
δ 7.45–7.43 (m, 2H), 7.35–7.31 (m, 2H), 7.26–7.22 (m, 1H), 7.15 (d, J = 16.4 Hz, 1H), 7.02–6.99 (m,
2H), 6.83 (t, J = 16.4 Hz, 1H), 3.55 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H), 2.37 (s, 3H), 2.31 (s,
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3H), 1.81–1.70 (m, 4H); C{1H} NMR (CDCl3, 100 MHz) δ 170.5, 137.7, 137.3, 137.0, 136.6, 133.4,
131.6, 130.1, 128.7, 127.7, 126.4, 125.2, 124.5, 47.9, 45.6, 25.9, 24.5, 21.0, 20.6; HRMS (ESI) calcd for
C21H23NNaO [M+Na]+ 328.1672, found 328.1658.
(E)-(2-Methoxy-6-styrylphenyl)(pyrrolidin-1-yl)methanone (4la): Colorless oil; 31.9 mg, 0.104
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mmol, 52% isolated yield, reaction temperature: 80 °C, reaction time: 72 h; H NMR (CDCl3, 400
MHz) δ 7.52–7.46 (m, 2H), 7.35–7.22 (m, 5H), 7.14–7.04 (m, 2H), 6.85–6.81 (m, 1H), 3.84 (s, 3H),
3.81–3.74 (m, 1H), 3.70–3.64 (m, 1H), 3.17–3.11 (m, 1H), 3.09–3.03 (m, 1H), 1.98–1.75 (m, 4H);
13C{1H} NMR (CDCl3, 100 MHz) δ 167.1, 155.5, 137.1, 135.1, 131.4, 129.5, 128.7, 127.9, 126.8, 126.6,
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125.1, 117.8, 109.9, 55.9, 47.4, 45.3, 25.8, 24.7; HRMS (ESI) calcd for C20H21NNaO2 [M+Na]+
330.1465, found 330.1453.
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(E)-[2-(4-Methoxystyryl)phenyl](pyrrolidin-1-yl)methanone (4ab): Colorless oil; 54.0 mg, 0.176
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mmol, 88% isolated yield; H NMR (CDCl3, 400 MHz) δ 7.66 (d, J = 7.9 Hz, 1H), 7.43–7.34 (m, 3H),
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7.29–7.24 (m, 2H), 7.09–6.99 (m, 2H), 6.90–6.87 (m, 2H), 3.82 (s, 3H), 3.70 (t, J = 7.0 Hz, 2H), 3.12 (t,
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J = 6.7 Hz, 2H), 1.96–1.89 (m, 2H), 1.84–1.77 (m, 2H); C{1H} NMR (CDCl3, 100 MHz) δ 169.6,
159.6, 136.8, 134.0, 130.6, 130.0, 129.1, 128.0, 127.3, 126.4, 125.5, 123.2, 114.2, 55.3 48.3, 45.6, 26.0,
24.6; HRMS (ESI) calcd for C20H21NNaO2 [M+Na]+ 330.1465, found 330.1448.
Methyl (E)-3-[2-(pyrrolidine-1-carbonyl)styryl]benzoate (4ac): Colorless oil; 54.5 mg, 0.162
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mmol, 81% isolated yield; H NMR (CDCl3, 400 MHz) δ 8.13–8.12 (m, 1H), 7.95–7.92 (m, 1H), 7.69–
7.65 (m, 2H), 7.44–7.36 (m, 2H), 7.34–7.30 (m, 2H), 7.25–7.11 (m, 2H), 3.94 (s, 2H), 3.71 (t, J = 7.0
Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H), 1.98–1.78 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.4, 166.9,
137.5, 137.1, 133.3, 130.8, 130.7, 130.1, 129.2, 128.9, 128.8, 128.0, 127.9, 126.6 126.5, 125.9, 52.2,
48.4, 45.7, 26.0, 24.6; HRMS (ESI) calcd for C21H21NNaO3 [M+Na]+ 358.1398, found 358.1414.
(E)-[2-(2-Chlorostyryl)phenyl](pyrrolidin-1-yl)methanone (4ad): Colorless oil; 56.4 mg, 0.181
mmol, 90% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.73 (d, J = 7.9 Hz, 1H), 7.62 (dd, J = 7.7 Hz,
1.7 Hz, 1H), 7.49 (d, J = 16.2 Hz, 1H), 7.42–7.36 (m, 2H), 7.34–7.28 (m, 2H), 7.27–7.17 (m, 2H), 7.15
(d, J = 16.2 Hz, 1H), 3.69 (t, J = 7.0 Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H), 1.967–1.79 (m, 4H); C{1H}
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NMR (CDCl3, 100 MHz) δ 169.4, 137.2, 135.3, 133.5, 133.5, 129.8, 129.2, 128.8, 128.1, 128.0, 127.1,
127.0, 126.8, 126.5, 126.2, 48.4, 45.6, 26.0, 24.6; HRMS (ESI) calcd for C19H18ClNNaO [M+Na]+
334.0969, found 334.0958.
(E)-{2-[2-(Naphthalen-1-yl)vinyl]phenyl}(pyrrolidin-1-yl)methanone
(4ae):
Colorless
1
amorphous; 46.4 mg, 0.142 mmol, 71% isolated yield; H NMR (CDCl3, 400 MHz) δ 8.19 (d, J = 8.0
Hz, 1H), 7.91–7.85 (m, 2H), 7.82–7.77 (m, 2H), 7.70 (d, J = 7.1 Hz, 1H), 7.56–7.38 (m, 4H), 7.34–7.33
(m, 2H), 7.21 (d, J = 16.0 Hz, 1H), 3.68 (t, J = 7.0 Hz, 2H), 3.17 (t, J = 6.7 Hz, 2H), 1.93–1.77 (m, 4H);
13C{1H} NMR (CDCl3, 100 MHz) δ 169.5, 137.2, 134.8, 134.0, 133.7, 131.4, 129.2, 128.7, 128.41,
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128.38, 128.35, 127.9, 126.6, 126.22, 126.16, 125.9, 125.7, 123.9, 123.7, 48.4, 45.6, 26.0, 24.6; HRMS
(ESI) calcd for C19H18NNaO [M+Na]+ 350.1515, found 350.1503.
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(E)-{2-[2-(Perfluorophenyl)vinyl]phenyl}(pyrrolidin-1-yl)methanone (4af): Colorless solid; 57.3
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mg, 0.156 mmol, 78% isolated yield, reaction time: 72 h; Mp 121.2–121.6 °C; H NMR (CDCl3, 400
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MHz) δ 7.70 (d, J = 7.5 Hz, 1H), 7.48–7.32 (m, 4H), 6.98 (d, J = 16.7 Hz, 1H), 3.70 (t, J = 7.0 Hz, 2H),
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3.15 (t, J = 6.7 Hz, 2H), 2.01–1.83 (m, 4H); C{1H} NMR (CDCl3, 100 MHz) δ 168.9, 146.2–146.0
(m), 143.7–143.5 (m), 141.4–141.1 (m), 139.2–138.6 (m), 137.9, 136.8–136.4 (m), 134.1 (td, 12.4 Hz,
2.4 Hz), 132.7, 129.3, 129.1, 126.6, 125.6, 114.9, 112.3 (td, 20.9 Hz, 4.2 Hz), 48.4, 45.6, 26.0, 24.6;
HRMS (ESI) calcd for C19H14F5NNaO [M+Na]+ 390.0888, found 390.0876.
(E)-Pyrrolidin-1-yl[2-(2,4,6-trimethylstyryl)phenyl]methanone (4ag): Colorless oil; 42.2 mg,
0.132 mmol, 66% isolated yield, reaction temperature: 80 °C, reaction time: 72 h; 1H NMR (CDCl3, 400
MHz) δ 7.69 (d, J = 7.9 Hz, 1H), 7.40–7.36 (m, 1H), 7.31–7.25 (m, 2H), 7.11 (d, J = 16.5 Hz, 1H), 6.89
(s, 2H), 6.66 (d, J = 16.6 Hz, 1H), 3.62 (t, J = 6.9 Hz, 2H), 3.15 (t, J = 6.7 Hz, 2H), 1.95–1.78 (m, 4H);
13C{1H} NMR (CDCl3, 100 MHz) δ 169.5, 137.0, 136.6, 136.1, 134.1, 133.7, 130.5, 129.4, 129.0, 128.8,
127.6, 126.2, 125.5, 48.6, 45.5, 25.9, 24.6, 21.1, 21.0; HRMS (ESI) calcd for C22H25NNaO [M+Na]+
342.1828, found 342.1847.
(E/Z)-[2-(3,3-Dimethylbut-1-en-1-yl)phenyl](pyrrolidin-1-yl)methanone (4ah): The title com-
pounds were isolated as a mixture of (E)-4ah and (Z)-4ah [(E)-4ah:(Z)-4ah= 94:6]. Colorless oil; 36.3
mg, 0.141 mmol, 71% isolated yield, reaction time: 72 h; 1H NMR (CDCl3, 400 MHz) (E)-4ah: δ 7.47–
7.45 (m, 1H), 7.32–7.22 (m, 3H), 6.33 (dd, J = 16.1 Hz, 1H), 6.22 (d, J = 16.1 Hz, 1H), 3.67–3.60 (m,
2H), 3.08 (d, J = 6.7 Hz, 2H), 1.96–1.90 (m, 2H), 1.86–1.79 (m, 2H), 1.09 (s, 9H); partial protons of
(Z)-4ah: 6.36 (d, J = 12.8 Hz, 1H), 5.60 (d, J = 12.9 Hz, 1H), 3.20 (d, J = 6.7 Hz, 2H), 0.98 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz) δ 169.8, 144.7, 136.5, 134.3, 128.9, 127.0, 126.2, 125.9, 121.7, 47.9,
45.5, 33.6, 31.0, 29.5, 26.0, 24.7; HRMS (ESI) calcd for C17H23NNaO [M+Na]+ 280.1672, found
280.1662.
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(E)-[2-(Oct-1-en-1-yl)phenyl](pyrrolidin-1-yl)methanone
(4ai-l),
(E)-[2-(oct-2-en-1-
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yl)phenyl](pyrrolidin-1-yl)methanone (4ai-l’), [2-(oct-1-en-2-yl)phenyl](pyrrolidin-1-yl)methanone
(4ai-b) and (E)-[2-(oct-2-en-2-yl)phenyl](pyrrolidin-1-yl)methanone (4ai-b’): The title compounds
were isolated as a mixture of 4ai-l, 4ai-l’, 4ai-b, and 4ai-b’ [4ai-l/4ai-l’/4ai-b/4ai-b’ = 40:8:24:28].
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Colorless oil; 36.7 mg, 0.129 mmol, 64% isolated yield, reaction time: 72 h; H NMR (CDCl3, 400
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MHz) of 4ai-l: δ 7.48 (d, J = 7.8 Hz, 1H), 7.34–7.19 (m, 3H), 6.40 (d, J = 15.8 Hz, 1H), 6.23 (dt, J =
15.6 Hz, 6.9 Hz, 1H), 3.68–3.56 (m, 2H), 3.21–3.08 (m, 2H), 2.21–2.09 (m, 2H), 1.97–1.78 (m, 4H),
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1.47–1.24 (m, 8H), 0.92–0.83 (m, 3H); H NMR (CDCl3, 400 MHz) of 4ai-l’: δ 7.34–7.19 (m, 4H),
5.57–5.43 (m, 2H), 3.68–3.56 (m, 2H), 3.43–3.36 (m, 4H), 3.21–3.08 (m, 2H), 1.97–1.78 (m, 4H), 1.47–
1.24 (m, 6H), 0.92–0.83 (m, 3H); 1H NMR (CDCl3, 400 MHz) of 4ai-b: δ 7.34–7.19 (m, 4H), 5.11 (d, J
= 1.4 Hz, 1H), 5.05 (br, 1H), 3.68–3.56 (m, 2H), 3.21–3.08 (m, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.97–1.78
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(m, 4H), 1.47–1.24 (m, 8H), 0.92–0.83 (m, 3H); H NMR (CDCl3, 400 MHz) of 4ai-b’: 7.34–7.19 (m,
4H), 5.57–5.43 (m, 1H), 3.68–3.56 (m, 2H), 3.21–3.08 (m, 2H), 2.21–2.09 (m, 2H), 1.99 (s, 3H), 1.97–
1.78 (m, 4H), 1.47–1.24 (m, 6H), 0.92–0.83 (m, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 170.29, 169.9,
169.8, 149.3, 142.2, 140.1, 136.25, 136.22, 136.18, 134.13, 134. 05, 134.0, 132.4, 131.44, 131.37, 129.7,
129.5, 129.3, 128.94, 128.86, 128.80, 128.75, 128.7, 128.1, 127.9, 127.3, 127.2, 126.9, 126.7, 126.6,
126.5, 126.4, 126.12, 126.09, 126.07, 125.84, 125.80, 125.7, 114.2, 48.6, 48.4, 48.13, 48.08, 45.50,
45.48, 45.38, 45.36, 36.6, 36.2, 33.2, 32.8, 32.5, 31.73, 31.70, 31.6, 31.5, 31.4, 30.8, 29.33, 29.30, 29.2,
29.1, 29.0, 28.9, 28.7, 28.2, 27.3, 25.99, 25.96, 25.95, 24.6, 24.55, 24.52, 22.62, 22.60, 22.57, 22.5, 17.2,
14.09, 14.06, 14.0; HRMS (ESI) calcd for C19H27NNaO [M+Na]+ 308.1985, found 308.1981.
(E/Z)-[2-(2-Phenylprop-1-en-1-yl)phenyl](pyrrolidin-1-yl)methanone
(4aj)
and
[2-(2-
Phenylallyl)phenyl](pyrrolidin-1-yl)methanone (4aj’): The title compounds were isolated as a mix-
ture of (E)-4aj, (Z)-4aj, and 4aj’ [(E)-4aj/(Z)-4aj/4aj’ = 40:38:22]. The stereochemistry of 4aj was de-
1
termined by the comparison of H NMR spectrum with N,N-diisopropyl-2-(2-phenylprop-1-en-1-
1
yl)benzamide.24 The structure of 4aj’ was determined by H NMR of partial protons and the result of
hydrogenation as shown below. Colorless oil; 42.0 mg, 0.144 mmol, 72% isolated yield, reaction tem-
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1
perature: 80 °C; H NMR (CDCl3, 400 MHz) of (E)-4aj: δ 7.48–7.15 (m, 9H), 6.859–6.856 (m, 1H),
3.63 (t, J = 7.0 Hz, 2H), 3.10 (t, J = 6.7 Hz, 2H), 2.22 (d, J = 1.4 Hz, 3H), 2.00–1.75 (m, 4H); 1H NMR
(CDCl3, 400 MHz) of (Z)-4aj: δ 7.48–7.15 (m, 6H), 7.08 (td, J = 11.2, 0.96 Hz, 1H), 6.94 (td, J = 11.6,
1.09 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.49 (s, 1H), 3.68 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 6.7 Hz, 2H),
2.20 (d, J = 1.5 Hz, 3H), 2.00–1.75 (m, 4H); 1H NMR (CDCl3, 400 MHz) of 4aj’: δ 7.48–7.15 (m, 9H),
5.41 (d, J = 1.3 Hz, 1H), 5.00 (d, J = 1.4 Hz, 1H), 3.93 (s, 2H), 3.65–3.61 (m, 2H), 3.12–3.07 (m, 2H),
2.00–1.75 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz) of the mixture of (E)-4aj, (Z)-4aj, and 4aj’ δ
169.7, 169.64, 169.60, 146.9, 143.2, 141.6, 140.9, 140.3, 138.7, 138.2, 137.8, 137.7, 136.1, 134.6, 134.1,
130.5, 130.0, 129.7, 128.8, 128.5, 128.39, 128.36, 128.25, 128.18, 128.0, 127.51, 127.45, 127.1, 126.4,
126.3, 126.2, 126.1, 126.0, 125.8, 124.7, 123.4, 114.7, 48.7, 48.3, 48.0, 45.5, 45.4, 38.4, 26.8, 26.1,
26.04, 25.96, 24.60, 24.58, 24.5, 17.4; HRMS (ESI) calcd for C20H21NNaO [M+Na]+ 314.1515, found
314.1511.
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Hydrogenation of a mixture of 4aj and 4aj’: To a solution of a mixture of (E)-4aj, (Z)-4aj, and
4aj’ (29.1 mg, 0.100 mmol, (E)-4aj/(Z)-4aj/4aj’ = 40:38:22) in CH2Cl2 (1.0 ml) was added Pd/C (21.3
mg, 5 wt% Pd) in CH2Cl2 (1.0 ml). H2 was introduced to the resulting suspension in a Schlenk tube. The
mixture stirred at room temperature (28 °C) for 16 h. The resulting mixture was filtered, concentrated
under reduced pressure, and purified by a preparative TLC (hexane/acetone = 2:1) to give [2-(2-
Phenylpropyl)phenyl](pyrrolidin-1-yl)methanone (27.9 mg, 0.0951 mmol, 95% yield) as a colorless oil.
1H NMR (CDCl3, 400 MHz) δ 7.27–7.12 (m, 9H), 3.66 (J = 7.0 Hz, 2H), 3.13–2.98 (m, 3H), 2.93–2.77
(m, 2H), 1.98–1.74 (m, 4H), 1.24 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 169.7, 147.0,
137.8, 137.3, 130.5, 128.5, 128.3, 127.1, 126.01, 125.99, 48.5, 45.5, 42.3, 41.1, 26.0, 24.6, 21.3; HRMS
(ESI) calcd for C20H23NNaO [M+Na]+ 316.1672, found 316.1672.
(E/Z)-[2-(1-Phenylprop-1-en-2-yl)phenyl](pyrrolidin-1-yl)methanone (4ak, Table 2) and [2-(3-
Phenylandprop-1-en-2-yl)phenyl](pyrrolidin-1-yl)methanone (4ak’ , Table 2): The title compounds
were isolated as a mixture of (E)-4ak, (Z)-4ak, and 4ak’ [(E)-4ak/(Z)-4ak/4ak’ = 85:12:3]. The stereo-
chemistry of 4ak was determined by the comparison of 1H NMR spectrum with (E)-N,N-dimethyl-2-(1-
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phenylprop-1-en-2-yl)benzamide.25 The structure of 4ak’ was determined by 1H NMR of partial protons
and the result of hydrogenation as shown below. Colorless oil; 43.2 mg, 0.148 mmol, 74% isolated yield,
reaction temperature: 80 °C; 1H NMR (CDCl3, 400 MHz) of (E)-4ak: δ 7.40–7.17 (m, 9H), 6.61 (s, 1H),
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3.59 (t, J = 6.9 Hz, 2H), 3.17 (t, J = 6.6 Hz, 2H), 2.243–2.240 (m, 3H), 1.92–1.70 (m, 4H); H NMR
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(CDCl3, 400 MHz) of (Z)-4ak: δ 7.40–7.17 (m, 4H), 7.09–7.02 (m, 3H), 6.93–6.91 (m, 2H), 6.46 (s, 1H),
3.44 (t, J = 7.0 Hz, 2H), 2.67 (br, 2H), 2.243–2.240 (m, 3H), 1.92–1.70 (m, 2H), 1.43–1.34 (m, 2H); 1H
NMR (CDCl3, 400 MHz) of 4ak’: δ 7.40–7.17 (m, 9H), 5.19 (s, 1H), 5.01 (d, J = 1.4 Hz, 1H), 3.72 (s,
2H), 3.61–3.58 (m, 2H), 2.98 (t, J = 6.8 Hz, 2H), 1.92–1.70 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz)
δ 170.0, 168.7, 142.2, 140.8, 138.9, 137.9, 137.7, 137.0, 136.4, 136.1, 130.2, 130.1, 129.3, 129.1, 129.0,
128.9, 128.8, 128.7, 128.3, 128.22, 128.18, 127.9, 127.4, 127.2, 126.90, 126.87, 126.8, 126.7, 126.5,
126.2, 126.0, 48.3, 48.2, 45.6, 45.4, 43.2, 27.8, 26.0, 25.9, 24.5, 24.2, 19.1; HRMS (ESI) calcd for
C20H21NNaO [M+Na]+ 314.1515, found 314.1516.
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Hydrogenation of a mixture of 4ak and 4ak’: To a solution of a mixture of (E)-4ak, (Z)-4ak, and
4ak’ (29.1 mg, 0.100 mmol, (E)-4ak/(Z)-4ak/4ak’ = 85:12:3) in CH2Cl2 (1.0 ml) was added Pd/C (21.3
mg, 5 wt% Pd) in CH2Cl2 (1.0 ml). H2 was introduced to the resulting suspension in a Schlenk tube. The
mixture stirred at room temperature (28 °C) for 16 h. The resulting mixture was filtered, concentrated
under reduced pressure, and purified by a preparative TLC (hexane/acetone = 2:1) to give [2-(1-
Phenylpropan-2-yl)phenyl](pyrrolidin-1-yl)methanone (27.4 mg, 0.0934 mmol, 93% yield) as a color-
less oil. 1H NMR (CDCl3, 400 MHz) δ 7.44–7.34 (m, 2H), 7.21–7.07 (m, 7H), 3.66–3.56 (m, 2H), 3.18–
2.92 (m, 3H), 2.80–2.68 (m, 1H), 2.39 (br, 1H), 1.91–1.84 (m, 2H), 1.77–1.69 (m, 2H), 1.26 (d, J = 6.6
13
Hz, 3H); C{1H} NMR (CDCl3, 100 MHz) δ 169.7, 143.1, 141.1, 137.5, 129.2, 128.9, 128.1, 126.6,
126.0, 125.8, 125.7, 48.4, 45.4, 44.3, 38.9, 26.0, 24.6, 22.2; HRMS (ESI) calcd for C20H23NNaO
[M+Na]+ 316.1672, found 316.1671.
Butyl (E)-3-[2-(pyrrolidine-1-carbonyl)phenyl]acrylate (4al, Table 2)6b: Colorless oil; 53.9 mg,
0.179 mmol, 90% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, J = 16.0 Hz, 1H), 7.66–7.62 (m,
1H), 7.44–7.37 (m, 2H), 7.36–7.31 (m, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.69 (t, J
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= 7.0 Hz, 2H), 3.09 (t, J = 6.7 Hz, 2H), 2.01–1.82 (m, 4H), 1.71–1.64 (m, 2H), 1.47–1.38 (m, 2H), 0.96
(t, J = 7.4 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.5, 166.6, 141.1, 138.5, 130.8, 130.2, 129.3,
126.8, 126.7, 120.6, 64.5, 48.5, 45.7, 30.7, 26.0, 24.5, 19.2, 13.7.
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(E/Z)-Methyl 2-methyl-3-[2-(pyrrolidine-1-carbonyl)phenyl]acrylate (4am) and Methyl 2-[2-
(pyrrolidine-1-carbonyl)benzyl]acrylate (4am’): The title compounds were isolated as a mixture of
(E)-4am, (Z)-4am, and 4am’ [(E)-4am/(Z)-4am/4am’ = 1:3:96]. The stereochemistry of 4am was de-
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termined by the comparison of H NMR spectrum with butyl 3-[2-(diethylcarbamoyl)phenyl]-2-
methylacrylate.4b Colorless oil; 31.1 mg, 0.114 mmol, 57% isolated yield, reaction temperature: 28 °C;
1H NMR (CDCl3, 400 MHz) of 4am’: δ 7.32–7.19 (m, 4H), 6.22 (br, 1H), 5.53 (q, J = 1.4 Hz, 1H), 3.72
(s, 2H), 3.70 (s, 3H), 3.61 (t, J = 7.0 Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H), 1.98–1.91 (m, 2H), 1.87–1.80 (m,
1
2H); H NMR (CDCl3, 400 MHz) of (E)-4am: δ 7.68 (s, 1H), 7.32–7.19 (m, 4H), 3.79 (s, 3H), 3.63–
1
3.59 (m, 2H), 3.16–3.13 (m, 2H), 2.04 (d, J = 1.5 Hz, 3H), 1.98–1.91 (m, 2H), 1.87–1.80 (m, 2H); H
NMR (CDCl3, 400 MHz) of (Z)-4am: δ 7.32–7.19 (m, 4H), 6.86 (s, 1H), 3.89 (s, 3H), 3.63–3.59 (m,
2H), 3.16–3.13 (m, 2H), 2.07 (d, J = 1.6 Hz, 3H), 1.98–1.91 (m, 2H), 1.87–1.80 (m, 2H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 169.5, 167.2, 139.0, 137.8, 135.2, 130.3, 128.9, 126.9, 126.5, 126.1, 51.8, 48.8,
45.4, 35.2, 26.0, 24.6; HRMS (ESI) calcd for C16H19NNaO3 [M+Na]+ 296.1257, found 296.1253.
(E/Z)-Methyl 3-[2-(pyrrolidine-1-carbonyl)phenyl]but-2-enoate (4an): The title compounds were
isolated as a mixture of (E)-4an and (Z)-4an [(E)-4an:(Z)-4an = 81:19]. The stereochemistry of 4an
was determined by the comparison of 1H NMR spectrum with butyl 3-[2-(diethylcarbamoyl)phenyl]but-
1
2-enoate.4b Colorless oil; 42.0 mg, 0.154 mmol, 77% isolated yield, reaction temperature: 28 °C; H
NMR (CDCl3, 400 MHz) of (E)-4an: δ 7.40–7.27 (m, 4H), 5.93 (q, J = 1.3 Hz, 1H), 3.73 (s, 3H), 3.60–
1
3.53 (m, 2H), 3.14 (t, J = 6.6 Hz, 2H), 2.49 (d, J = 1.4 Hz, 3H), 1.96–1.76 (m, 4H); H NMR (CDCl3,
400 MHz) of (Z)-4an: δ 7.40–7.27 (m, 3H), 7.11–7.09 (m, 1H), 5.90 (q, J = 1.4 Hz, 1H), 3.60–3.55 (m,
2H), 3.53 (s, 3H), 3.34 (t, J = 6.6 Hz, 2H), 2.27 (d, J = 1.4 Hz, 3H), 1.96–1.76 (m, 4H); 13C{1H} NMR
(CDCl3, 100 MHz) of the mixture of (E)-4an and (Z)-4an: δ 169.1, 168.8, 166.8, 165.8, 157.8, 155.9,
140.7, 139.6, 136.1, 135.2, 129.1, 128.9, 128.4, 128.0, 127.2, 126.9, 126.9, 126.3, 119.2, 117.3, 51.1,
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50.8, 48.8, 48.5, 45.6, 45.5, 28.0, 26.2, 26.0, 24.5, 24.4, 19.8; HRMS (ESI) calcd for C16H19NNaO3
[M+Na]+ 296.1257, found 296.1271.
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Deutrium kinetic isotope effect for parallel reaction of 2a with 3a (Scheme 7a): The reaction
was carried out according to the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex 1c
(5.5 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2a (17.5 mg, 0.100 mmol), 3a (15.6 mg,
0.150 mmol), and (CH2Cl)2 (0.5 mL) at 28 °C for 2 h, which furnished 4aa (18.9 mg, 0.0681 mmol,
68% yield).
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Deutrium kinetic isotope effect for parallel reaction of 2a-d5 with 3a (Scheme 7a): The reaction
was carried out according to the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex 1c
(5.5 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2a-d5 (18.0 mg, 0.100 mmol), 3a (15.6
mg, 0.150 mmol), and (CH2Cl)2 (0.5 mL) at 28 °C for 2 h, which furnished 4aa-d4 (7.79 mg, 0.0277
mmol, 28% yield) and revovered 2a-d5 (11.8 mg, 0.0656 mmol, 65% recov.)
Deutrium kinetic isotope effect for intermolecular competition of 2a and 2a-d5 with 3a (Scheme
7b): The reaction was carried out according to the general procedure using AgSbF6 (6.8 mg, 0.020
mmol), complex 1c (5.5 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2a (8.8 mg, 0.0500
mmol), 2a-d5 (9.0 mg, 0.0500 mmol), 3a (15.6 mg, 0.150 mmol), and (CH2Cl)2 (0.5 mL) at 28 °C for 2
h, which furnished a mixture of 4aa and 4aa-d4 (10.8 mg, 0.0388 mmol, 39% yield, 4aa/4aa-d4 = 75:25).
Deutrium kinetic isotope effect for parallel reaction of 2a with 3f (Scheme 7c): The reaction was
carried out according to the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex 1c (5.5 mg,
0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2a (17.5 mg, 0.100 mmol), 3f (17.7 mg, 0.150
mmol), and (CH2Cl)2 (0.5 mL) at 80 °C for 2 h, which furnished 4af (4.80 mg, 0.0173 mmol, 17%
yield).
Deutrium kinetic isotope effect for parallel reaction of 2a-d5 with 3f (Scheme 7c): The reaction
was carried out according to the general procedure using AgSbF6 (6.8 mg, 0.020 mmol), complex 1c
(5.5 mg, 0.0050 mmol), Cu(OAc)2•H2O (4.0 mg, 0.020 mmol), 2a-d5 (18.0 mg, 0.100 mmol), 3f (17.7
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mg, 0.150 mmol), and (CH2Cl)2 (1.0 mL) at 80 °C for 2 h, which furnished 4af-d4 (4.53 mg, 0.0161
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3
mmol, 16% yield).
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Reaction profiles for oxidative olefination of 2a with 3f (Figure 1): To a Schlenk flask was added
AgSbF6 (13.6 mg, 0.0400 mmol), complex 1c or [CpERhCl2]2 (0.0100 mmol), Cu(OAc)2•H2O (8.0 mg,
0.0400 mmol), 2a (35.0 mg, 0.200 mmol), 3f (31.2 mg, 0.300 mmol), diethyl terephthalate (38.8 mg,
0.200 mmol, internal standard) and (CH2Cl)2 (1.0 mL) in this order. Aliquots (~0.1 mL) from the mix-
ture were removed at 1, 2, 4, 8, and 22 hour intervals. Each aliquot wasdiluted with diethyl ether, fil-
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1
tered through a silica gel pad, and washed with EtOAc. The filtrate was analyzed by H NMR spectros-
copy.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Table S1, Scheme S1, and copies of 1H and 13C{1H} NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Authors
* E-mail: yshibata@apc.titech.ac.jp
* E-mail: ktanaka@apc.titech.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported partly by ACT-C (No. JPMJCR1122YR) from JST (Japan), and Grants-in-Aid
for Scientific Research (No. JP26102004) for Young Scientists (No. 17K14481) and Research Fellow
(No. 18J13654) from JSPS (Japan). We thank Umicore for generous support in supplying RhCl3·nH2O.
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