Palladium-catalyzed Z-selective oxidative amination of ortho-substituted primary anilines with olefins under an open air atmosphere

Article abstract of DOI:10.1021/jo4010734

The Pd-catalyzed oxidative amination of olefins with primary anilines has been achieved using molecular dioxygen as the sole oxidant. The use of ortho-substituted primary anilines such as ortho-toluidine was the key to the successful development of this r

Full text of DOI:10.1021/jo4010734

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Note
Palladium Catalyzed Z-Selective Oxidative Amination of ortho-
Substituted Primary Anilines with Olefins Under an Open Air Atmosphere
Yohei Mizuta, Kaoru Yasuda, and Yasushi Obora
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4010734 • Publication Date (Web): 04 Jun 2013
Downloaded from http://pubs.acs.org on June 5, 2013
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Palladium Catalyzed Z-Selective Oxidative Amination of ortho- Substituted Primary Anilines
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with Olefins Under an Open Air Atmosphere
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Yohei Mizuta, Kaoru Yasuda, Yasushi Obora*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University,
Suita, Osaka 564-8680, Japan
obora@kansai-u.ac.jp
The Pd-catalyzed oxidative amination of olefins with primary anilines has been achieved using molecular dioxygen as
the sole oxidant. The use of ortho-substituted primary anilines such as ortho-toluidine was the key to the successful
development of this reaction, providing the corresponding N-alkenyl substituted anilines in high yields with unusually high
levels of Z-selectivity.
Enamine derivatives are an important class of N-containing compounds and intermediates for the synthesis of
heterocycles and biologically active compounds.1 For example, β-enaminoesters are well known as starting materials
for the syntheses of pyridines,1a 1,4-dihydropyridines,1b,c pyrazoles,1d and furans.1e
The transition metal catalyzed oxidative coupling reactions of olefins through sp2 C-H bond activation represent
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an important series of reactions in organic chemistry because they allow for a variety of different functional groups to
be directly connected to the C=C bond of olefins.2 The oxidative amination of olefins is an efficient and powerful
method for the synthesis of enamine derivatives. In particular, the oxidative amination reaction involving the use of
Pd(II) as a catalyst and dioxygen as a reoxidant, which is known as the aza-Wacker type reaction, has recently been the
subject of considerable research efforts.3 For example, Pd and Rh-catalyzed the oxidative amination of olefins has been
carried out by the use of amides and imides as amination reagents.4 In addition, White reported the use of Pd and Fe
catalysts for the allylic amination of olefins with sulfonamides.5 These reactions, however, can be limited by their
requirement for the use of nonbasic amination reagents in the presence of an external oxidant source such as
benzoquinone (BQ), PhBQ, PhI(OAc)2, or PhI(OPiv)2. With this in mind, the development of an oxidative olefin
amination method amenable to the use of simple amines using molecular dioxygen as sole oxidant is highly desired.
To date, several methods have been developed for the oxidative amination of olefins using simple amines. Beller6
reported the oxidative amination of olefins with secondary amines using a rhodium catalyst. In this particular case,
however, a variety of by-products were formed together with the desired oxidative amination products, including the
corresponding hydroamination and hydrogenation products of the olefins. We recently reported that Pd(II) catalyzed
the oxidative amination reaction of olefins and secondary amines.7 In this particular transformation, the
hydroamination and hydrogenation products of the olefins were not obtained as by-products. In contrast, for the
heterocyclic compounds that were difficult to prepare from the secondary amines, such as quinolines,8 pyrroles,9
indoles,10 dihydropyridines,11 and pyrazoles,1d the enamine derivatives of the corresponding primary amines were
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important compounds as starting materials for these compounds. The oxidative amination of olefins using primary
amines was initially reported in 1981 by Hegedus, with the reactions being conducted in the presence of an excess of
reoxidant and salt.12 The development of an oxidative amination protocol with primary amines using molecular
dioxygen as sole oxidant is therefore highly desired.
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We recently reported that Pd(II) catalyzes the reaction of olefins and aromatic secondary amines in both an
intermolecular aerobic allylic amination13 and an oxidative C-H olefination of aromatic secondary amines14 to give (E)-
allylamines and olefin substituted aromatic amines, respectively, in good yields with levels of high regioselectivity.
In this Note, we report the Pd-catalyzed oxidative amination reaction of olefins and aromatic primary amines in the
presence of air and without the need for an external reoxidant, to give the corresponding enamine derivatives in high
yields with unusual high levels of Z-selectivity. In this reaction, the introduction of substituents at the ortho position of
the aniline was particularly important, in that the desired products were given in excellent yields only when the anilines
were ortho-substituted.
To confirm the optimum reaction conditions for this transformation, the reaction of o-toluidine with butyl acrylate
was selected as a model reaction and conducted under a variety of different reaction conditions. The results for the
aerobic oxidative amination are shown in Table 1. The reaction of o-toluidine (1a, 3 mmol) with butyl acrylate (2a, 1
mmol) was performed in the presence of Pd(OAc)2 (0.03 mmol, 3 mol %), and pivalic acid (PivOH, 0.25 mmol) in
NMP (0.5 mL) under ambient air at 60°C for 15 h, giving 3a in 96% yield (Table 1, entry 1). In the absence of
Pd(OAc)2, no reaction occurred, highlighting the importance of the Pd catalyst (Table 1, entry 2). Experimentation also
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revealed the crucial nature of the PivOH additive for carrying out the aerobic oxidative amination with higher levels of
conversion (Table 1, entry 3). Furthermore, when the reaction was conducted under an Ar atmosphere, a low yield of
3a was observed, indicating the importance of the oxygen in the air (Table 1, entry 4). Under solvent free conditions,
the aerobic oxidative amination product 3a was obtained in moderate yield (Table 1, entry 5). The best yield was
achieved when the reaction of 1a and 2a was carried out with a 3:1 ratio (entry 1). However, when 1a and 2a was
carried out to react with 1:1 ratio, the yield of 3a was still high (entry 6). Next, we proceeded to investigate a variety of
different Pd-catalysts. When Pd(OCOCF3)2 was used, the desired product 3a was obtained in a yield similar to that of
Pd(OAc)2 (Table 1, entry 7). The reaction also proceeded in a moderate yield when PdCl2 was used (Table 1, entry 9).
It became clear that excellent yields for 3a were observed when Pd(dba)2 of zerovalent palladium was used as the
catalyst (Table 1, entry 10). Our investigation of the additive revealed that 2,4,6-trimethylbenzoic acid (TMBA) and
phenol were only moderately beneficial to the reaction (Table 1, entries 11 and 12). When p-toluenesulfonic acid (p-
TsOH) and AlCl3 were added, a significant decrease in the yield of 3a was observed (Table 1, entries 13 and 14). We
found that only pivalic acid had provided a positive improvement to the extent of the reactivity. Polar solvent such as
2-methyl-2-butanol (tAmOH) showed a good trend for this reaction (Table 1, entry 15), whereas the reaction performed
poorly in nonpolar and halogen based solvents to give the desired product 3a in low yields because they favored the
formation of the undesired hydroamination by-product (Table 1, entries 16 and 17).
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To investigate the overall scope of the reaction, a variety of different primary amines and olefins were subjected to
the aerobic oxidative amination, under the same conditions as those used for entry 1 in Table 1. The different substrates
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and associated results are shown in Table 2. The reaction of o-toluidine (1a) with butyl acrylate (2a) gave the
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Table 1. Pd-catalyzed aerobic oxidative amination of o-toluidine (1a) with butyl acrylate (2a)a
Yield/%b,c
Entry
Pd-catalyst
Additive
Solvent
3a
PivOH
PivOH
None
NMP
NMP
NMP
NMP
None
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
96 (90)
<1
80
3
65
79
88
80
65
92
88
85
3
1
2
Pd(OAc)2
None
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OCOCF3)2
Pd(acac)2
PdCl2
3
4d
5
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
TMBA
Phenol
p-TsOH
AlCl3
6e
7
8
9
Pd(dba)2
10
11
12
13
14
15
16
17
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
PivOH
PivOH
PivOH
tAmOH
Toluene
DCE
87
72
35
a Conditions: 1a (3 mmol) was allowed to react with 2a (1 mmol) in the presence of a Pd-catalyst (0.03 mmol) and additive (0.25 mmol) in solvent (0.5 mL)
at 60°C for 15 h under ambient air. b GC yields except the value in the parenthesis. c E:Z = 1:>20. d Reaction was performed under Ar. e 1a (1 mmol) and 2a
(1 mmol) were used. PivOH = pivalic acid. TMBA = 2,4,6-Trimethylbenzoic acid. tAmOH = 2-Methyl-2-butanol. DCE = 1,2-Dichloroethane.
corresponding product 3a in 90% yield with high levels of regio- and stereoselectivity (E:Z =1: >20) (Table 2, entry 1).
m- and p-Toluidine (1b and 1c) were also used, providing the corresponding product 3b and 3c in low yields, but with
high levels of regio- and stereoselectivity (E:Z =1: >20) (Table 2, entries 2 and 3). Consideration of entries 2 and 3 in
Table 2 suggested that the o-substituent was important to obtain the desired product in excellent yield. When o-
anisidine (1d) bearing an electron donating group was used (Table 2, entry 4), the desired product 3d was obtained in
good yield. However, when the electron withdrawing o-trifluoromethylaniline (1e) was used (Table 2, entry 5), the
desired product 3e was produced in only moderate yield and required much harsher conditions. The use of the
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sterically hindered o-substituent in o-isopropylaniline (1f) proved to be a suitable substrate for this reaction (Table 2,
entry 6). When the disubstituted aniline 2,5-dimethyl aniline (1g) was employed, the desired product was also obtained
in excellent yield (Table 2, entry 7). In contrast, when aniline itself (1h) was used in the reaction, the desired product
(3h) was produced in only low yield (Table 2, entry 8). To examine a range of olefins, a variety of different electron-
deficient olefins were used in this reaction. When methyl acrylate (2b) was used as the coupling partner, the desired
product (3i) was obtained in good yield (Table 2, entry 9). However, when tert-butyl acrylate (2c) bearing a sterically-
hindered substituent was used, the desired product (3j) was produced in only moderate yield (Table 2, entry 10). When
acrylonitrile (2e) was employed, the desired product was also only obtained in low yield (Table 2, entry 12). In
addition, a poor level of stereoselectivity was observed in the desired product (E:Z =7:3). The reaction also proceeded
using acrylamide (2f). The yield of the desired product, however, was low because of deactivation of the Pd-catalyst by
the amide group (Table 2, entry 13). Thus, these results indicated that the carbonyl group plays a critical role in
generating a high level of stereoselectivity (E:Z =1: >20) in the coupling product. Although we found that styrene
could also be applied to this oxidative amination reaction with a high level of regioselectivity, the conversion of
styrene was low and gave the corresponding coupling product (3n) in a relatively lower yield (15%). Under these
reaction conditions, the use of phthalimide (as less-basic amide), cyclooctylamine (as more-basic aliphatic amine), and
simple alkenes such as 1-octene are totally inactive toward the oxidative amination.
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For this transformation, the reaction has the potential to proceed either through the Wacker-type or hydroamination
pathways followed by the hydrogenation pathway. To elucidate the reaction pathway, the hydroamination product 3-
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(o-tolylamino)propanoate (4a) was synthesized and then examined under the optimized reaction condition with 3-(o-
tolylamino)propanoate. Analysis revealed that no (Z)-butyl 3-(o-tolylamino)acrylate (3a) was obtained from 3-(o-
Table 2. Pd-catalyzed oxidative amination of aniline derivatives (1) with olefins (2)a
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entry
R1
R2
Product
Yield (%)b
n
1
2
3
4
5c
6
7
o-Me (1a)
m-Me (1b)
p-Me (1c)
o-OMe (1d)
o-CF3 (1e)
o-iPr (1f)
CO2 Bu (2a)
90
30
42
71
56
89
89
3a
3b
3c
3d
3e
3f
n
CO2 Bu (2a)
n
CO2 Bu (2a)
n
CO2 Bu (2a)
n
CO2 Bu (2a)
n
CO2 Bu (2a)
n
2,5-Me2 (1g)
CO2 Bu (2a)
3g
3h
3i
38d
n
8
9
H (1h)
CO2 Bu (2a)
o-Me (1a)
CO2Me (2b)
82
t
10
11
o-Me (1a)
o-Me (1a)
CO2 Bu (2c)
3j
58
69
n
CO2 Cy (2d)
3k
12
13
o-Me (1a)
o-Me (1a)
CN (2e)
3l
40e
43
CONMe2 (2f)
3m
a Conditions: Same as those for entry 1, Table 1.b E:Z = 1:>20 unless otherwise noted. c Reaction was performed under O2 (1 atm). d E:Z = 1:4. e E:Z = 7:3.
tolylamino)propanoate, indicating that the hydrogenation pathway was not possible within the aerobic oxidative
amination process (Scheme 1). In addition, labeling experiment by using aniline-d7 suggested that the reaction imine-
enamine interconversion would be involved during reaction course (Scheme 2).
Scheme 1. The Reaction of 3-(o-Tolylamino)propanoate (4a) under the Optimized Conditions.
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Scheme 2. Oxidative Amination of Aniline-d7 (1h-d7) with Butyl Acrylate (2a)
In the current transformation, the o-substituents on the aniline derivatives played a critical role in the smooth
completion of the reaction. Indeed, when the reaction of aniline (1h) and butyl acrylate (2a) was performed using a
catalyst prepared from Pd(OAc)2 (3 mol % with respect to 2a) and 1a (6 mol %) in NMP (0.5 mL) prior to the reaction
of 1h and 2a, a substantial increase in the yield of 3h from 38% to 48% was observed. This result suggested that the
bulky o-methyl substituent of 1a may have hampered excessive coordination of the aniline nitrogen to the Pd center,
likely preventing deactivation of the catalyst through over-coordination (or saturation).
A plausible reaction mechanism for the transformation is shown in Figure 1.15 The reaction may be initiated by
the coordination of olefin 2 to Pd(II) leading to palladium(II) complex [A]. Nucleophilic attack of the o-substituted
primary amine to the more electron deficient end of the olefin then occurs to give the six-membered palladium
complex [B].16 β-Hydride elimination from the six-membered palladium complex [B] then occurs, liberating a
palladium hydride species to give the amination product (Z)-3. The palladium hydride species then readily undergoes
reductive elimination to give Pd(0), with the resulting Pd(0) being reoxidized by O2 to Pd(II).
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OR1
Pd(II)L2
O
2
Reoxidation
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Pd(II)L
R1O
Pd(0)
OR1
O
N
O
[A]
H
NH2
R2
R2
(Z)-3
HL
1
HL
Pd(II)L
OR1
H
Pd(II)L
N
O
H
R2
[B]
Figure 1. Plausible reaction mechanism for the oxidative amination of ortho-substituted amines with olefins.
In conclusion, we have demonstrated the aerobic oxidative amination of o-substituted primary amines with olefins,
which is catalyzed by palladium under mild reaction conditions. The reactions proceeded to give the desired N-alkenyl
substituted anilines with high levels of regio- and stereoselectivity using primary amines.
Experimental Section
General
GLC analysis was performed with a flame ionization detector using a 0.22 mm × 25 m capillary column (BP-5). 1H,
13C and 19F NMR were measured at 400, 100 and 376 MHz, respectively, in CDCl3 with Me4Si as the internal standard.
The products were characterized by H NMR, 13C and 19F NMR, and GC-MS. The yields of products were estimated
1
from the peak areas based on the internal standard technique using GC. All starting materials were commercially
available and used without any purification.
Experimental Procedure
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A typical reaction was carried out as follows (Table 1, entry 1): A mixture of butyl acrylate (2a) (128 mg, 1 mmol)
and o-toluidine (1a) (322 mg, 3 mmol) was allowed to react with Pd(OAc)2 (6.7 mg, 0.03 mmol, 3 mol %), pivalic acid
(26 mg, 0.25 mmol) in NMP (0.5 mL) at 60 °C for 15 h under open air in an 30 mL round-bottomed flask. The crude
reaction mixture was cooled to room temperature. EtOAc (30 mL) was added to the dark solution. The residue was
purified by column chromatography on silica gel (EtOAc/Hexane = 1:40) to provide (Z)-butyl 3-(o-tolylamino)acrylate
(3a) (210 mg, 90%).
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3a: Yield 90% (210 mg), yellow liquid, 1H NMR (400 MHz, CDCl3) δ 10.01 (d, J = 12.2 Hz, 1H), 7.28 (dd, J = 12.5,
8.4 Hz, 1H), 7.17-7.14 (m, 2H), 7.00 (d, J = 7.7 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 4.87 (d, J = 8.2 Hz, 1H), 4.13 (t, J =
6.8 Hz, 2H), 2.31 (s, 3H), 1.69-1.62 (m, 2H), 1.43-1.40 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz, CDCl3)
δ 170.6 (C=O), 143.1 (CH), 139.0 (C), 130.9 (CH), 127.0 (CH), 125.1 (C), 122.1 (CH), 112.6 (CH), 87.5 (CH), 63.2
(CH2), 30.8 (CH2), 19.1 (CH2), 17.4 (CH3), 13.7 (CH3);IR (neat, cm-1) 3308, 2989, 2934, 2874, 1667, 1630, 1603, 1470,
1458, 1300, 1288, 1244, 1202, 1184, 789, 750;GC-MS (EI) m/z (relative intensity) 233 (36) [M]+, 207 (20), 160 (26),
159 (100), 158 (11), 131 (36), 130 (71), 118 (57), 117 (22), 91 (11), 77 (13), 65 (13); HRMS (EI-TOF) m/z calcd for
C14H19NO2 [M]+ 233.1416, found 233.1416.
3b: Yield 30% (70 mg), yellow liquid, 1H NMR (400 MHz, CDCl3) δ 9.86 (d, J = 12.7 Hz, 1H), 7.23 (dd, J = 12.7, 8.6
Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.80-6.75 (m, 3H), 4.82 (d, J = 8.2 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H),
1.69-1.61 (m, 2H), 1.43-1.40 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 170.4 (C=O), 143.0
(CH), 140.6 (C), 139.5 (C), 129.4 (CH), 123.3 (CH), 116.0 (CH), 112.3 (CH), 87.0 (CH), 63.1 (CH2), 30.9 (CH2), 21.4
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(CH3), 19.2 (CH2), 13.7 (CH3); IR (neat, cm-1) 3374, 2959, 2932, 2872, 1732, 1668, 1627, 1603, 1587, 1495, 1466,
1281, 1250, 1198, 1065, 853, 773, 692; GC-MS (EI) m/z (relative intensity) 233 (93) [M]+, 207 (20), 193 (14), 177
(21), 164 (13), 161 (13), 160 (57), 159 (100), 133 (14), 132 (31), 131 (63), 130 (91), 119 (12), 118 (38), 117 (26), 116
(12), 102 (14), 96 (12), 91 (11), 89 (16), 77 (20), 65 (10), 52 (13), 39 (25), 29 (15), 27 (15); HRMS (EI-TOF) m/z calcd
for C14H19NO2 [M]+ 233.1416, found 233.1417.
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3c: Yield 42% (98 mg), yellow liquid, 1H NMR (400 MHz, CDCl3) δ 9.76 (d, J = 12.8 Hz, 1H), 7.11 (dd, J = 12.8, 8.2
Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 2H), 4.71 (d, J = 8.2 Hz, 1H), 4.03 (t, J = 6.9 Hz, 2H), 2.19 (s,
3H), 1.59-1.52 (m, 2H), 1.34-1.31 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H);13C NMR (100 MHz, CDCl3) δ170.4 (C=O), 143.3
(CH), 138.2 (C), 131.9 (C), 130.0 (CH), 115.2 (CH), 86.5 (CH), 63.0 (CH2), 30.9 (CH2), 20.5 (CH3), 19.1 (CH2), 13.7
(CH3); IR (neat, cm-1) 3308, 3028, 2959, 2872, 1668, 1628, 1584, 1522, 1481, 1292, 1263, 1236, 1194, 810, 789; GC-
MS (EI) m/z (relative intensity) 233 (3) [M]+, 160 (13), 159 (100), 158 (25), 131 (28), 130 (67), 103 (11), 77 (15);
HRMS (EI-TOF) m/z calcd for C14H19NO2 [M]+ 233.1416, found 233.1417.
3d: Yield 71% (177 mg), yellow liquid, 1H NMR (400 MHz, CDCl3) δ 10.13 (d, J = 13.1 Hz, 1H), 7.24 (dd, J = 12.9,
8.4 Hz, 1H), 7.02-6.99 (m, 1H), 6.92-6.86 (m, 3H), 4.86 (d, J = 8.6 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H),
1.69-1.62 (m, 2H), 1.43-1.39 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ170.0 (C=O), 147.6 (C),
141.6 (CH), 130.1 (C), 121.9 (CH), 120.9 (CH), 111.8 (CH), 110.6 (CH), 87.6 (CH), 63.1 (CH2), 55.6 (CH3), 30.8
(CH2), 19.1 (CH2), 13.7 (CH3); IR (neat, cm-1) 3374, 2989, 2872, 1732, 1668, 1628, 1603, 1587, 1495, 1466, 1281,
1250, 1198, 1065, 853, 773, 692; GC-MS (EI) m/z (relative intensity) 249 (100) [M]+, 176 (24), 175 (58), 174 (11),
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161 (30), 149 (20), 147 (23), 146 (57), 134 (28), 133 (18), 132 (17), 130 (26), 121 (11), 120 (79), 119 (13), 118 (10),
108 (10), 104 (19), 93 (17), 78 (14), 77 (13), 41 (15), 29 (21), 28 (13); HRMS (EI-TOF) m/z calcd for C14H19NO3 [M]+
249.1365, found 249.1364.
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3e: Yield 56% (161 mg), colorless liquid, H NMR (400 MHz, CDCl3) δ 10.43 (d, J = 10.9 Hz, 1H), 7.58 (d, J = 7.7
Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.26-7.15 (m, 2H), 7.06 (t, J = 7.7 Hz, 1H), 4.97 (d, J = 8.6 Hz, 1H), 4.16 (t, J = 6.8
Hz, 2H), 1.69-1.62 (m, 2H), 1.43-1.39 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 169.9 (C=O),
141.9 (CH), 139.0 (C), 133.2 (CH), 126.9 (CH, q, J = 5 Hz), 124.1 (CF3, q, J = 274 Hz), 121.7 (CH), 117.7 (C, q, J =
30 Hz), 115.3 (CH), 90.7 (CH), 63.6 (CH2), 30.8 (CH2), 19.1 (CH2), 13.7 (CH3);19F NMR (376 MHz, CDCl3) δ -61.6;
IR (neat, cm-1) 3314, 2961, 1674, 1637, 1609, 1517, 1464, 1323, 1285, 1244, 1199, 1165, 1117, 1061, 1036, 793, 756;
GC-MS (EI) m/z (relative intensity) 287 (35) [M]+, 269 (15), 232 (11), 231 (25), 214 (33), 213 (100), 194 (40), 187
(13), 186 (11), 185 (14), 172 (23), 166 (22), 165 (49), 146 (24), 145 (13), 41 (17), 29 (17); HRMS (EI-TOF) m/z calcd
for C14H16F3NO2 [M]+ 287.1133, found 287.1131.
3f: Yield 89% (233 mg), light yellow liquid, 1H NMR (400 MHz, CDCl3) δ 10.18 (d, J = 12.2 Hz, 1H), 7.26-7.23 (m,
2H), 7.16 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.2 Hz, 2H), 4.86 (d, J = 8.6 Hz, 1H), 4.13 (t, J = 6.8 Hz, 2H), 3.19-3.09 (m,
1H), 1.69-1.61 (m, 2H), 1.43-1.40 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H), 0.94 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz,
CDCl3) δ 170.7 (C=O), 144.0 (CH), 137.9 (C), 135.9 (C), 126.7 (CH), 125.9 (CH), 122.9 (CH), 114.2 (CH), 87.3 (CH),
63.1 (CH2), 30.8 (CH2), 27.6 (CH), 22.5 (CH3), 19.1 (CH2), 13.7 (CH3); IR (neat, cm-1) 3310, 2961, 1665, 1628, 1599,
1499, 1458, 1202, 1188, 789, 750; GC-MS (EI) m/z (relative intensity) 261 (24) [M]+, 209 (14), 207 (40), 147 (20),
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146 (100), 145 (11), 144 (42), 131 (12), 43 (12), 41 (18), 32 (30), 29 (12), 28 (16), 17 (40); HRMS (EI-TOF) m/z calcd
for C16H23NO2 [M]+261.1729, found 261.1729.
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3g: Yield 89% (220 mg), saffron yellow liquid, 1H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 12.2 Hz, 1H), 7.27 (dd, J =
12.5, 8.4 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J = 7.7 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.12 (t, J =
6.8 Hz, 2H),2.29 (s, 3H), 2.26 (s, 3H), 1.68-1.61 (m, 2H), 1.43-1.39 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H);13C NMR (100
MHz, CDCl3) δ 170.6 (C=O), 143.1 (CH), 138.8 (C), 136.7 (C), 130.7 (CH), 122.9 (CH), 122.0 (C), 113.4 (CH), 87.2
(CH), 63.1 (CH2), 30.8 (CH2), 21.2 (CH3), 19.1 (CH2), 16.9 (CH3), 13.7 (CH3); IR (neat, cm-1) 2959, 2934, 1665, 1634,
1597, 1466, 1298, 1279, 1254, 1194, 791; GC-MS (EI) m/z (relative intensity) 247 (85) [M]+, 207 (25), 175 (10), 174
(38), 173 (80), 163 (10), 159 (10), 158 (16), 147 (18), 145 (46), 144 (60), 143 (17), 132 (100), 131 (54), 130 (33), 127
(13), 117 (14), 116 (14), 105 (12), 104 (12), 85 (12), 79 (18), 77 (15), 65 (13), 53 (12), 41 (11), 29 (25), 28 (20), 17
(12); HRMS (EI-TOF) m/z calcd for C15H21NO2 [M]+ 247.1572, found 247.1570.
3h: E, Z mixture (E:Z = 1:4) Yield 38% (83 mg), light yellow liquid, 1H NMR (400 MHz, CDCl3) for the E, Z mixture:
δ 9.88 (d, J = 12.4 Hz, 1H (for the Z isomer)), 7.96-7.90 (t, J = 13.2 Hz, 1H (for the E isomer)), 7.30-7.21 (m, 5H),
7.15 (d, J = 12.4 Hz, 1H (for the E isomer)), 7.00-6.92 (m, 6H), 5.24-5.21(d, J = 12.8 Hz, 1H (for the E isomer)), 4.84
(d, J = 8.8 Hz, 1H (for the Z isomer)), 4.13 (t, J = 6.6 Hz, 4H), 1.69-1.58 (m, 4H), 1.46-1.35 (m, 4H), 0.95 (t, J = 7.3
Hz, 6H); 13C NMR (100 MHz, CDCl3) for the E, Z mixture:δ 170.4 (C=O), 169.1 (C=O), 142.9 (C), 142.8 (C), 140.62
(CH), 140.58 (CH), 129.6 (2CH), 122.4 (CH), 122.3 (CH), 115.4 (CH), 115.2 (CH), 92.4 (CH), 87.3 (CH), 63.4 (CH2),
63.2 (CH2), 30.9 (CH2), 30.8 (CH2), 19.6 (CH2), 19.1 (CH2), 13.71 (CH3), 13.68 (CH3); IR (neat, cm-1) 3308, 2959,
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2934, 2874, 1668, 1630, 1601, 1587, 1508, 1481, 1449, 1304, 1290, 1238, 1196, 789, 750, 692; GC-MS (EI) for Z
isomer :m/z (relative intensity) 219 (38) [M]+, 146 (40), 145 (100), 119 (14), 118 (21), 117 (76), 104 (13), 91 (10), 90
(14), 77 (17); HRMS (EI-TOF) for Z isomer :m/z calcd for C13H17NO2 [M]+ 219.1259, found 219.1260; GC-MS (EI)
for E isomer :m/z (relative intensity) 219 (16) [M]+, 162 (47), 118 (100), 92 (32), 77 (13), 15 (8); HRMS (EI-TOF) for
E isomer :m/z calcd for C13H17NO2 [M]+ 219.1259, found 219.1257.
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3i: Yield 82% (157 mg), light yellow liquid, H NMR (400 MHz, CDCl3) δ10.00 (d, J = 11.8 Hz, 1H), 7.29 (dd, J =
12.5, 8.4 Hz, 1H), 7.18-7.15 (m, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 4.88 (d, J = 8.2 Hz, 1H), 3.72
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9 (C=O), 143.4 (CH), 139.0 (C), 131.0 (CH), 127.2 (CH),
125.3 (C), 122.3 (CH), 112.8 (CH), 87.1 (CH), 50.7 (CH3), 17.5 (CH3); IR (neat, cm-1) 1670, 1630, 1603, 1462, 1300,
1246, 1206, 787, 750; GC-MS (EI) m/z(relative intensity) 191 (68) [M]+, 160 (29), 159 (55), 132 (14), 131 (25), 130
(100), 118 (84), 117 (30), 91 (22), 77 (17), 65 (23); HRMS (EI-TOF) m/z calcd for C11H13NO2 [M]+ 191.0946, found
191.0945.
3j: Yield 58% (135 mg), white solid, m.p. 70-71°C;1H NMR (400 MHz, CDCl3) δ 9.92 (d, J = 12.2 Hz, 1H), 7.19 (dd,
J = 12.2, 8.6 Hz, 1H), 7.14-7.12 (m, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 4.78 (d, J = 8.6 Hz, 1H),
2.30 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.2 (C=O), 142.3 (CH), 139.3 (C), 130.9 (CH), 127.0
(CH), 125.1 (C), 121.9 (CH), 112.7 (CH), 89.6 (CH), 79.1 (C), 28.4 (CH3), 17.5 (CH3); IR (neat, cm-1) 3292, 2984,
1661, 1634, 1603, 1470, 1456, 1391, 1366, 1308, 1288, 1244, 1227, 1167, 1155, 793, 756; GC-MS (EI) m/z (relative
intensity) 233 (23) [M]+, 177 (69), 160 (42), 159 (93), 132 (11), 131 (23), 130 (73), 119 (10), 118 (100), 117 (22), 91
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(18), 65 (19), 57 (16), 41 (21), 39 (13), 29 (12); HRMS (EI-TOF) m/zcalcd for C14H19NO2 [M]+ 233.1416, found
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233.1421.
3k: Yield 69% (179 mg), light yellow solid, m.p. 50-51°C;1H NMR (400 MHz, CDCl3) δ 9.90 (d, J = 12.2 Hz, 1H),
7.16 (dd, J = 12.5, 8.4 Hz, 1H), 7.06-7.04 (m, 2H), 6.89 (d, J = 7.7 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 4.76 (d, J = 8.2
Hz, 1H), 4.76-4.70 (m, 1H), 2.21 (s, 3H), 1.83-1.81 (m, 2H), 1.66-1.64 (m, 2H), 1.48-1.43 (m, 1H), 1.37-1.29 (m, 4H),
1.20-1.13 (m, 1H);13C NMR (100 MHz, CDCl3) δ 169.9 (C=O), 142.8 (CH), 139.0 (C), 130.8 (CH), 127.0 (CH), 125.0
(C), 122.0 (CH), 112.5 (CH), 88.1 (CH), 71.3 (CH), 31.9 (CH2), 25.3 (CH2), 23.9 (CH2), 17.4 (CH3); IR (neat, cm-1)
2940, 2862, 1661, 1630, 1603, 1470, 1456, 1306, 1288, 1244, 1209, 1042, 1018, 976, 962, 792, 752, 716; GC-MS (EI)
m/z (relative intensity) 259 (43) [M]+, 178 (13), 177 (49), 160 (52), 159 (100), 158 (14), 132 (18), 131 (27), 130 (64),
119 (12), 118 (88), 117 (22), 91 (17), 65 (12), 55 (31), 51 (11), 41 (20), 39 (12), 29 (11), 28 (11); HRMS (EI-TOF) m/z
calcd for C16H21NO2 [M]+ 259.1572, found 259.1574.
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3l: E,Z mixture (E:Z = 7:3) Yield 40% (63 mg), light brown liquid, H NMR (400 MHz, CDCl3) for the E isomer: δ
7.36 (dd, J = 13.6, 11.8 Hz, 1H), 7.23-7.17 (m, 2H), 7.02-6.93 (m, 3H), 4.55 (d, J = 13.6 Hz, 1H), 2.27 (s, 3H);1H
NMR (400 MHz, CDCl3)for the Z isomer: δ7.23-7.17 (m, 3H), 7.02-6.93 (m, 2H), 6.74 (d, J = 12.2 Hz, 1H), 4.23 (d, J
= 8.2 Hz, 1H), 2.25 (s, 3H);13C NMR (100 MHz, CDCl3) for the E,Zmixture:δ 147.4 (CH), 145.5 (CH), 138.0 (C),
137.9 (C), 131.1 (CH), 131.0 (CH), 127.3 (CH), 127.2 (CH), 127.0 (C), 125.4 (C), 123.8 (CH), 123.3 (CH), 121.0 (C),
117.9 (C), 116.9 (CH), 114.8 (CH), 67.9 (CH), 66.3 (CH), 17.4 (CH3), 17.0 (CH3); IR (neat, cm-1) 3323, 3069, 2924,
2199, 1645, 1605, 1506, 1474, 1383, 1294, 1051, 966, 748, 712, 604; GC-MS (EI) for the E isomer: m/z (relative
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intensity) 159 (100) [M]+, 158 (12), 131 (32), 130 (66), 118 (26), 117 (13), 91 (10), 77 (16); HRMS (EI-TOF) for the E
isomer: m/z calcd for C10H10N2 [M]+158.0844, found 158.0844; GC-MS (EI) for the Z isomer: m/z (relative intensity)
159 (82) [M]+, 132 (100), 106 (4), 91 (28), 77 (13), 15 (9); HRMS (EI-TOF) for the Z isomer: m/z calcd for C10H10N2
[M]+158.0844, found 158.0846.
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3m: Yield 43% (88 mg), yellow liquid, H NMR (400 MHz, CDCl3) δ 10.98 (d, J = 11.3 Hz, 1H), 7.24 (dd, J = 11.8,
8.6 Hz, 1H), 7.18-7.13 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 5.05 (d, J = 8.6 Hz, 1H), 3.02 (s, 6H),
2.34 (s, 3H);13C NMR (100 MHz, CDCl3) δ 170.7 (C=O), 140.8 (CH), 139.7 (C), 130.8 (CH), 126.9 (CH), 125.1 (C),
121.4 (CH), 112.1 (CH), 86.5 (CH), 37.4 (CH3), 35.1 (CH3), 17.7 (CH3); IR (neat, cm-1) 2928, 1636, 1607, 1576, 1489,
1369, 1285, 1146, 775, 748; GC-MS (EI) m/z (relative intensity) 204 (55) [M]+, 161 (11), 160 (100), 159 (53), 131(21),
130 (50), 117 (16), 91 (10), 77 (12), 65 (11); HRMS (EI-TOF) m/z calcd for C12H16N2O [M]+204.1263, found
204.1261.
3n: E, Z mixture (E: Z=35:65). Yield 15% (31 mg), yellow solid, m.p. 149-151oC; 1H NMR (400 MHz, CDCl3) :δ 8.28
(d, 2H), 7.85-7.95 (m, 4H), 7.04-7.49 (m, 17H), 6.86 (d, J = 8.0 Hz, 1H (for the Z isomer)), 2.29 (s, 6H); 13C NMR
(100 MHz, CDCl3) for the E, Z mixture :δ 159.5 (CH), 159.4 (CH), 151.2 (C), 151.1 (C), 136.51 (C), 136.46 (C), 131.8
(CH), 131.2 (CH), 130.4 (CH), 130.2 (CH), 128.8 (CH), 128.7 (CH), 128.3 (CH), 128.32 (CH), 127.12 (CH), 127.10
(CH), 126.70 (CH), 126.69 (CH), 126.4 (C), 126.3 (C), 125.7 (CH), 125.6 (CH), 117.7 (CH), 117.6 (CH), 17.9 (CH3),
17.8 (CH3); IR (neat, cm-1) 3323, 3034, 2924, 1518, 1364, 1244, 1211, 1196, 1098, 833, 758; GC-MS (EI) m/z(relative
intensity) for Z-isomer: 209 (52) [M]+, 194 (100), 132 (13), 106 (1), 103 (4), 91 (42), 77 (8), 27 (3), 15 (1); HRMS (EI-
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TOF) for Z-isomer: m/z calcd for C15H15N [M]+209.1204, found 209.1208; GC-MS (EI) for E-isomer: m/z (relative
intensity) 209 (6) [M]+, 194 (55), 118 (100), 91 (46), 77 (6); HRMS (EI-TOF) for E-isomer: m/z calcd for C15H15N
[M]+209.1204, found 209.1203.
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Synthesis of 3-(o-Tolylamino)propanoate (4a)
3-(o-tolylamino)propanoate (4a) was synthesized substrate according the literature procedure.17 In a 10 mL glasstube
were placed butyl acrylate (2a) (1281 mg, 10mmol) and o-toluidine (1a) (1071 mg, 10mmol), acetic acid (60mg,
1.0mmol), and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwave cavity where it
was sealed with a pressure lock. The reaction mixture was heated from rt to 200 °C where it was held by modulating
microwave power for a total reaction time of 20 min. Upon completion, the reaction mixture was cooled to room
temperature. EtOAc (30 mL) was added to the yellow solution. The residue was purified by column chromatography
on silica gel (EtOAc/Hexane = 1:20) to provide butyl 3-(o-tolylamino)propanoate (4a) (777 mg, 33%).
4a: Yield 33% (777 mg), light yellow liquid, 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.3
Hz, 1H), 6.68-6.61 (m, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.97 (s, 1H), 3.49 (t, J = 6.2 Hz, 2H), 2.64 (t, J = 6.2 Hz, 2H),
2.12 (s, 3H), 1.64-1.57 (m, 2H), 1.39-1.35 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ172.5
(C=O), 145.5 (C), 130.2 (CH), 127.1 (CH), 122.4 (C), 117.1 (CH), 109.6 (CH), 64.5 (CH2), 39.3 (CH2), 33.9 (CH2),
30.6 (CH2), 19.1 (CH2), 17.4 (CH3), 13.6 (CH3); IR (neat, cm-1) 3429, 2961, 2874, 1732, 1607, 1587, 1516, 1452, 1317,
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1256, 1179, 1130, 1061, 746, 716; GC-MS (EI-TOF) m/z (relative intensity) 235 (18) [M]+, 120 (100), 118 (13);HRMS
(EI) m/z calcd for C14H21NO2 [M]+ 235.1572, found 235.1572.
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Reaction of 3-(o-Tolylamino)propanoate (4a) (Scheme 1).
A mixture of 3-(o-tolylamino)propanoate (4a) (235 mg, 1.0mmol) was allowed to react with Pd(OAc)2 (6.7 mg,
0.03 mmol, 3 mol %), pivalic acid (26 mg, 0.25 mmol) in NMP (0.5 mL) at 60 °C for 15 h under open air in an 30 mL
round-bottomed flask.
Reaction of Aniline-d7 (1h-d7) with Butyl Acrylate (2a) (Scheme2).
A mixture of butyl acrylate (2a) (128 mg, 1 mmol) and Aniline-d7 (1h-d7) (301 mg, 3 mmol) was allowed to react
with Pd(OAc)2 (6.7 mg, 0.03 mmol, 3 mol %), pivalic acid (26 mg, 0.25 mmol) in NMP (0.5 mL) at 60 °C for 15 h
under open air in an 30 mL round-bottomed flask. The crude reaction mixture was cooled to room temperature. EtOAc
(30 mL) was added to the dark solution. The residue was purified by column chromatography on silica gel
(EtOAc/Hexane = 1:40) to provide (Z)-butyl 3-(phenylamino)acrylate-d6 and (Z)-butyl 3-(phenylamino)acrylate-d5 (3h-
d6 and 3h-d5, 79 mg, 35%, 3h-d6: 3h-d5 = 3:2).
3h-d6 and 3h-d5 mixture: Yield 35% (79 mg, 3h-d6: 3h-d5= 3:2), light yellow liquid, 1H NMR (400 MHz, CDCl3) for
the 3h-d6: δ9.89 (d, J = 11.4 Hz, 1H), 7.24 (d, J = 12.4 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.44-1.40
(m, 2H), 0.95 (t, J = 7.3 Hz, 3H);1H NMR (400 MHz, CDCl3) for the 3h-d5: δ 9.89 (d, J = 11.4 Hz, 1H) 7.24 (dd, J =
12.8, 8.2 Hz, 1H), 4.84 (d, J = 8.2 Hz, 1H),4.12 (t, J = 6.6 Hz, 2H), 1.69-1.62 (m, 2H), 1.44-1.40 (m, 2H), 0.95 (t, J =
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7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) for the 3h-d6, 3h-d5 mixture δ 170.42, 170.39 (2C=O, 3h-d6 and 3h-d5),
142.9, 142.8 (2CH, 3h-d6 and 3h-d5), 140.5 (C), 129.1 (CD), 121.9 (CD), 114.8 (CD), 87.3 (CH), 63.2 (CH2), 30.9
(CH2), 19.2 (CH2), 13.7 (CH3); IR (neat, cm-1) 3308, 2959, 2934, 2872, 1665, 1626, 1572, 1560, 1391, 1199, 783; GC-
MS (EI) for the 3h-d6, 3h-d5 mixture; m/z (relative intensity) 225 (38) [M]+, 224 (39) [M]+, 152 (27), 151 (98), 150
(100), 149 (27), 124 (22), 123 (74), 122 (91), 121 (29), 109 (18), 96 (14), 95 (14), 94 (18), 93 (12), 82 (29), 70 (11);
HRMS (EI-TOF) m/z calcd for C13H11D6NO2 [M]+225.1636, found 225.1633; C13H12D5NO2 [M]+ 224.1573, found
224.1573.
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ACKNOWLEDGMENT
This work was supported by MEXT-Supported Program for the Strategic Research Foundation at Private
Universities (2010-2014), and the Kansai University Research Grants: Grant-in Aid for Encouragement of Scientists,
2012.
1
Supporting Information.: H, and 13C NMR spectra for products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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