The coupling of tertiary amines with acrylate derivatives via visible-light photoredox catalysis

Article abstract of DOI:10.1021/jo501097b

Catalyzed by Ru(bpy)₃(BF₄)₂, the photoredox coupling of tertiary amines with acrylate derivatives including Baylis-Hillman adducts under visible light irradiation was successfully established. The scope of the substrates w

Full text of DOI:10.1021/jo501097b

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Note
The Coupling of Tertiary Amines with Acrylate
Derivatives via Visible-Light Photoredox Catalysis
Xiaojun Dai, Dongping Cheng, Baochuan Guan, Wenjuan Mao, Xiaoliang Xu, and Xiaonian Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501097b • Publication Date (Web): 03 Jul 2014
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The Coupling of Tertiary Amines with Acrylate Derivatives via Visible-Light
Photoredox Catalysis
Xiaojun Dai,† Dongping Cheng,‡ Baochuan Guan,† Wenjuan Mao,† Xiaoliang Xu,*,†
Xiaonian Li*,†
†Institute of Industrial Catalysis, College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou 310014, People’s Republic of China
‡College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou
310014, People’s Republic of China
E-mail: xuxiaoliang@zjut.edu.cn; xnli@zjut.edu.cn.
ABSTRACT:
OAc
R5
COOCH3
R5
COOR6
R1
4
COOCH3 R
R4
COOR6
R1
R3
R2
N
R1
45 W CFL
Ru(bpy)3(BF4)2
R3
45 W CFL
Ru(bpy)3(BF4)2
N
R2
N
R2
R3
Catalyzed by Ru(bpy)3(BF4)2, the photoredox coupling of tertiary amines with
acrylate derivatives including Baylis-Hillman adducts under visible light irritation
was successfully established. The scope of the substrates was broad and thus an array
of γ-aminobutyric ester derivatives was obtained in moderate to good yields.
Recently visible light photoredox catalysis attracted much attention due to the rich
resource of visible light, its environment friendly and high efficiency.1 After having
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kept silence for about one century since sponsored by Ciamician,2 reports about the
visible light photoredox catalysis showed a sudden development from 2008, which
exhibited powerful ability in organic synthesis and material chemistry.3 Under
photoredox catalysis, especially Ir or Ru complexes, organic dye catalysts,4,5 several
types of novel chemical transformations through the in situ active radical
intermediates were established. Some groundbreaking literatures have reported the
unusual chemical reactions induced by photoredox catalysis, especially carbon-carbon
formation reactions.
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The direct sp3 C-H functionalization adjacent to a nitrogen atom of tertiary amine
has become one of the most important methods to synthesize more complex tertiary
amine compounds,6 which could be expediently achieved through the oxidation of
tertiary amines and subsequent coupling with appropriate reagents. Lots of oxidative
systems could achieve this goal.6 Among, photoredox catalytic oxidation of tertiary
amines is an efficient method and some advanced amine derivatives with potential
biological activity have been synthesized in simple ways.7 Generally, the path for the
photoredox oxidation of tertiary amine firstly to form amine radical cation which
subsequently loses a hydrogen atom to generate an electrophilic iminium ion or loses
a proton to generate a nucleophilic α-aminoalkyl radical is accepted.
While the research of the iminium ion routes has been drawn much attention,8 the
study of α-aminoalkyl radicals is limited for the reason that they could be easily
oxidized to form the iminium ions.9 Under photoredox catalysis, the nucleophilic
coupling of α-aminoalkyl radicals to electron-deficient substrates such as cyanoarene,
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α,β-unsaturated derivative, isocyanate and etc. was recently reported, and arrays of
diverse structure tertiary amines were synthesized.10 As far as α,β-unsaturated
derivatives were concerned, the coupling of α,β-unsaturated ketones, α,β-unsaturated
diesters with tertiary amines were fully investigated. However, due to their easy
oligomerization, research of α,β-unsaturated monoesters under the photoredox radical
conditions was very rare. Nishibayashi reported the sole example of ethyl crotonate
participating in this radical coupling reaction.10b Under the photoredox conditions
employed by Yu and Bian, methyl acrylate failed to react with N,N-dimethylaniline to
give the coupling or cyclization product.10d Herein we report a detailed investigation
on the photoredox coupling of acrylate derivatives and tertiary amines, which supply
an efficient method for the synthesis of γ-aminobutyric ester derivatives.
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Initially, methyl methacrylate 1a and N,N-dimethylaniline 2a were selected as
model substrates to examine the optimal reaction condition. Catalyzed by 1 mol%
Ru(bpy)3(BF4)2, the desired photoredox coupling product could be isolated in 39%
yield along with some oligomerized compounds under the irradiation of 45 W
1
compact fluorescent lamp in DMSO (Table 1, entry 1). Checked by H NMR
spectrum, the oligomerized compounds should be the radical coupling of one
molecule of 2a with two to four molecules of 1a. The efficiency of photoredox
catalysts such as Ru(bpy)3Cl2 and [Ir(ppy)2bpy]BF4 were poor (Table 1, entries 2-3).
Almost no desired product was detected when Ir(ppy)3 was used as the catalyst (Table
1, entry 4). To our delight, irradiation of 1 equiv. of 1a with 1.5 equiv. of 2a catalyzed
by 1 mol% Ru(bpy)3(BF4)2 in NMP under N2 atmosphere resulted in the product in 56%
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yield (Table 4, entry 5). Increasing the amount of 2a, the yield was not significantly
improved (Table 1, entry 6). The control experiment showed that no desired coupling
product was observed in the absence of photocatalyst or light.
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Table
1.
Oxidative
Coupling
Optimization
of
Acrylates
with
N,N-Dimethylanilinea
entry
catalyst
solvent
base
yield/%b
1
Ru(bpy)3(BF4)2
Ru(bpy)3Cl2
DMSO
DMSO
DMSO
DMSO
NMP
NaOAc
NaOAc
NaOAc
NaOAc
DBU
39
2
35
3
[Ir(ppy)2bpy]BF4
Ir(ppy)3
36
4
5c
6d
a
trace
56
Ru(bpy)3(BF4)2
Ru(bpy)3(BF4)2
NMP
DBU
60
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), Ru(bpy)3(BF4)2 (0.01 mmol),
base (1 mmol), solvent (4 mL), 12 hrs, 45 W compact fluorescent lamp irradiation
under N2 atmosphere and r.t. b Isolated yield based on 1a. c 1.5 mmol of 2a; d 2 mmol
of 2a.
Different anilines and acrylates were subjected to the optimal reaction conditions.
Reacting with the methyl methacrylate, several anilines were successfully used and
the corresponding products were obtained in moderate yields (Table 2, entries 4-7).
However the yields were low when methyl acrylate or ethyl acrylate were used as the
substrates due to the severe oligomerization (Table 2, entries 2-3).
Table 2. Scope of Acrylates with Tertiary Aminesa
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Entry
R1, R2
R3, R4, R5
Yield (%)b
56 (3a)
31 (3b)
29 (3c)
1
2
3
4
5
6
7
Me, COOMe (1a)
H, COOMe (1b)
H, COOEt (1c)
Ph, Me, H (2a)
Ph, Me, H (2a)
Ph, Me, H (2a)
Ph, Me, H (2a)
4-ClC6H4, Me, H (2b)
Me, COOBu (1d)
Me, COOMe (1a)
Me, COOMe (1a)
Me, COOMe (1a)
45 (3d)
37 (3e)
4-CH3OC6H4, Me, H (2c) 40 (3f)
N-phenylpyroridine (2d) 60 (3g)c
a
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), Ru(bpy)3(BF4)2 (0.01 mmol), DBU
(1 mmol), DMSO (4 mL), 12 hrs, 45 W compact fluorescent lamp irradiation under
N2 atmosphere and r.t. b Isolated yield based on 1. c dr = 1:1.
In the presence of oxygen, a radical addition/cyclization process was observed
although the yield is very low (eq. 1). Because of the same Rf value of addition and
cyclization product on TLC, the reaction mixture could not be separated and purified
1
by column chromatography on silica gel. Determined by GC-MS and H NMR
spectra, the ratio of the addition/cyclization product could be determined.
COOR
N
1 mol% Ru(bpy)3(BF4)2
COOR
(1)
+
N
+
DBU, air
NMP, 45 W CFL
N
Ph
Ph
COOR
1
2a
3
3'
3b 3b'
1b
1c
/
= 2.3/1, 15% yield
= 2.2/1, 16% yield
, R = Me
, R = Et
3c 3c'
/
Baylis-Hillman adducts are important intermediates and widely used in organic
synthesis.11 In order to expand the scope of the substrate, the reaction was applied to
Baylis-Hillman adducts. Initially, the reaction of 2-(acetoxy(phenyl)methyl)acrylate
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4a with N,N-dimethylaniline 2a was examined (Table 3). Firstly, catalyzed by
Ru(bpy)3Cl2, use of CH3CN as a solvent and K2CO3 as a base, it was found that the
oxidative coupling product was isolated in 14% yield (Table 3, entry 1). Changing the
base K2CO3 to NaOAc, Na2CO3, Cs2CO3 revealed that the final base gave a slight
better result with 28% yield (Table 3, entries 2-4). Based on these, Except DCE, the
attempts on other solvents such as toluene, THF, DMF, NMP, EtOAc almost gave
disappointing result (Table 3, entry 5). The performance of Ir(ppy)3, [Ir(ppy)2bpy]PF6,
[Ir(ppy)2bpy]BF4, Ru(bpy)3(PF6)2 was not efficient (Table 3, entries 6-9). It revealed
that the combination of Ru(bpy)3(BF4)2, NaOAc as a base and DMSO as a solvent
was most effective and the desired product can be obtained in 67% isolated yield
(Table 3, entry 11). Replacing the acetate of Baylis-Hillman to Boc group could not
promote the result. Notably, control experiment showed that no desired product was
detected in the absence of visible light or photocatalyst (Table 3, entries 12-13). In the
absence of base, just trace product was detected by TLC (Table 3, entry 14).
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Table 3. Oxidative Coupling Optimization of Baylis-Hillman Acetates with
N,N-Dimethylanilinea
entry
catalyst
base
solvent
MeCN
MeCN
yieldf
14
1
2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
K2CO3
Na2CO3
5
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3
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ir(ppy)3
Cs2CO3
NaOAc
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
NaOAc
NaOAc
NaOAc
-
MeCN
28
4
5b
MeCN
DCE
5
32
6
7c
8c
MeCN
DCE
trace
19
10
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[Ir(ppy)2bpy]PF6
[Ir(ppy)2bpy]BF4
Ru(bpy)3(PF6)2
Ru(bpy)3 (BF4)2
Ru(bpy)3(BF4)2
-
DCE
22
9
MeCN
DCE
trace
39
10b
11d
12d
13d,e
14d
DMSO
DMSO
DMSO
DMSO
67
0
Ru(bpy)3(BF4)2
Ru(bpy)3(BF4)2
0
trace
a Reaction conditions: 4a (0.5 mmol), 2a (1 mmol), photocatalyst (0.005 mmol), base
(1.5 mmol), solvent (2 mL), 24 hrs, 45 W compact fluorescent lamp irradiation under
N2 and room temperature until otherwise noted; b 1 mmol of 2a, 1 mmol of base; c 0.6
mmol of 2a, 0.5 mmol of base; 0.6 mmol of 2a, 0.6 mmol of base. In the dark.
Isolated yield based on 4a.
d
e
f
Then the scope of the substrate was examined. Baylis-Hillman acetates containing
substituents such as methyl, isopropyl and methoxy on the aryl rings underwent the
reaction smoothly (Table 4, entries 2-4). No obvious steric effect was observed (Table
4, entries 4-6). For substrates with halogenated phenyl rings, the desired products
were isolated in modest yields (Table 4, entries 7-8). While furyl substituted
Baylis-Hillman acetate was introduced, the reaction was also successfully performed
(Table 4, entry 9). The reaction of ethyl 2-(acetoxy(phenyl)methyl)acrylate proceeded
elegantly to give 5k in 62% yield (Table 4, entry 11).
Table 4. Scope of Baylis-Hillman acetatesa
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entry
1
R1, R2
yield (%)b
67 (5a)
76 (5b)
73 (5c)
74 (5d)
60 (5e)
74 (5f)
54 (5g)
44 (5h)
57 (5i)
Ph, Me (4a)
2
4-MeC6H4, Me (4b)
4-PriC6H4, Me (4c)
4-MeOC6H4, Me (4d)
3-MeOC6H4, Me (4e)
2-MeOC6H4, Me (4f)
4-FC6H4, Me (4g)
4-ClC6H4, Me (4h)
2-furyl, Me (4i)
3
4
5
6
7
8
9
10
11
Prn, Me (4j)
43 (5j)
62 (5k)
Ph, Et (4k)
a
Reaction conditions: 4a-k (0.5 mmol), 2a (0.6 mmol), Ru(bpy)3(BF4)2 (0.005
mmol), NaOAc (0.6 mmol), DMSO (2 mL), 6 hrs, 45 W compact fluorescent lamp
irradiation under N2 atmosphere and r.t. b Isolated yield based on 4a-k.
Next, a variety of tertiary amines were tried (Table 5). While the
4-chloro-N,N-dimethylaniline gave good results, the 3-chloro-N,N-dimethylaniline
afforded the corresponding product only in 34% yield for unknown reason (Table 5,
entries 1-2). The N,N-dimethylanilines bearing with Br or F atom also gave good
yields (Table 5, entries 3-4). For N,N-dimethylanilines with an electron-donating
group on the phenyl rings, the desired products were obtained in modest yields (Table
5, entries 5-6). N,N-diethylaniline and N-methyl-N-phenylaniline also participated in
the reaction to give the corresponding products in moderate yields (Table 5, entries
7-8). The desired product was isolated in 65% yield when cyclic N-phenylpyroridine
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was used (Table 5, entry 9). It was very glad to find that the aliphatic tertiary amine
6
7
8
9
ethyl diisopropylamine could give addition product in reasonable yield (Table 5, entry
10).
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Table 5. Scope of Tertiary Aminesa
entry
R1, R2, R3
yield(%)b
71 (5l)
1
2
3
4
5
6
7
8
9
H, Me, 4-ClC6H4 (2b)
H, Me, 3-ClC6H4 (2e)
H, Me, 4-FC6H4 (2f)
H, Me, 4-BrC6H4 (2g)
H, Me, 4-MeC6H4 (2h)
H, Me, 4-MeOC6H4 (2c)
H, Ph, Ph (2i)
34 (5m)
57 (5n)
74 (5o)
63 (5p)
58 (5q)
45 (5r)
51 (5s)
65 (5t)
25 (5u)
Me, Et, Ph (2j)
N-phenylpyroridine (2d)
Me, Pri, Pri (2k)
10c
a
Reaction conditions: 4a (0.5 mmol), 2b-k (0.6 mmol), Ru(bpy)3(BF4)2 (0.005
mmol), NaOAc (0.6 mmol), DMSO (2 mL), 45 W compact fluorescent lamp
b
irradiation under N2 and room temperature; see experimental section for details.
Isolated yield based on 4a. c [Ir(ppy)2bpy]BF4 as photocatalyst.
On the basis of literatures1 and the aforementioned experimental results, a plausible
reaction pathway is proposed in Scheme 1. Upon irradiation, Ru2+ is excited to
provide Ru*2+, which is then reductively quenched by 2 to produce Ru+ and amine
radical cation 6 via single electron transfer oxidation. The amine radical cation 6 can
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be deprotonated by NaOAc to generate the tertiary α-amino carbon radical 7, which
can react with Baylis-Hillman acetate 4 to produce the alkyl radical 8. The key
intermediate alkyl anion 9 was generated from the reduction of 8 by photocatalyst
(Ru+) which itself was oxidized to initial photocatalyst (Ru2+). Subsequently,
elimination of AcO- from the alkyl anion 9 formed the unsaturated γ-aminobutyric
ester derivative 5.
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Scheme 1. Possible Mechanism
In case of simple methyl 2-(acetoxymethyl)acrylate 4l, the double coupling product
5v was obtained, which indicated that 4l could react with two molecules of
N,N-dimethylaniline 2a (eq 2). Because 4l was oligomerized easily or AcO- was more
difficult to leave, the yield of 5v was very low although considerable reaction
conditions were screened.
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COOCH3
N
OAc
1 mol% Ru(bpy)3(BF4)2
N
COOCH3
+
(2)
NaOAc
DMSO, 45 W CFL
Ph
N
4l
2a
Ph
Ph
5v
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18% yield
Finally, the reactions of Baylis-Hillman alcohols with N,N-dimethylaniline 2a were
investigated. The normal corresponding addition products were obtained in the
presence of the hydroxyl group (eq 3). The dr ratio of product 5w is about 5.8:1.
OH
COOCH3
OH
R
COOCH3
+
1 mol% Ru(bpy)3(BF4)2
R
N
(3)
NaOAc
DMSO, 45 W CFL
N
Ph
2a
Ph
4
5
4m
, R = Ph
4n, R = H
5w
, dr = 5.8 :1; 68% yield
5x, 57% yield
In summary, we have developed an efficient method for the synthesis of
γ-aminobutyric ester derivatives via visible-light-promoted addition of α-aminoalkyl
radicals to acrylates or Baylis-Hillman derivatives. The advantages of reaction are
mild condition, broad scope of substrates. This reaction expands the synthetic
application of α-aminoalkyl radicals under visible-light photoredox catalysis.
EXPERIMENTAL SECTION
General Experimental Methods. All reactions were carried out under dry nitrogen
atmosphere until otherwise noted. Solvents were dried by the general methods, and
degassed before use. Baylis-Hillman acetates 4a~l12,13, Baylis-Hillman alcohols
4m~n12 and tertiary amines 2b~c14, 2e~h14, 2i15, 2d16 were prepared according to
17,18
19,20
literature.
Photoredox
catalysts
Ir(ppy)3
,
[Ir(ppy)2bpy]PF6
,
21
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[Ir(ppy)2bpy]BF419,10b, Ru(bpy)3(PF6)2 , Ru(bpy)3Cl2 , Ru(bpy)3(BF4)2
were
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prepared according to literature. H and 13C NMR spectra were recorded at room
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temperature in CDCl3 on 500 MHz instrument with TMS as internal standard.
Low-resolution MS was obtained using EI or ESI ionization. HRMS was obtained
using ESI ionization by TOF LC/MS. GC-MS spectra were obtained using normal
analysis method, which MS spectra were obtained using EI ionization.
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General Procedure for Synthesis of 3 under N2. In a typical procedure: In a 10 mL
two-necked round-bottom flask were placed acrylate 1 (1 mmol), DBU (152 mg, 1
mmol), Ru(bpy)3(BF4)2 (7.4 mg, 0.01 mmol, 1 mol%) under N2, and then amine 2 (0.6
mmol) and NMP (4 mL) were added. The reaction mixture was placed at a distance of
about 5 cm from a 45 W compact fluorescent lamp (Arrow BHSL 45) and stirred at
room temperature. After 12 hrs, the reaction mixture was diluted with CH2Cl2 (30 mL)
and H2O (20 mL). The layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 x 20 mL). The combined organic layers washed with H2O (2 x 10 mL),
then were dried over Na2SO4. Purification was done by column chromatography on
silica gel (200-300 mesh) with petroleum ether/ethyl acetate (20/1) as the eluent to
give the pure product 3.
Methyl 2-methyl-4-(methyl(phenyl)amino)butanoate (3a): 123 mg, 56% Yield;
Yellow oil; IR (thin film): 2950, 2360, 1735, 1600, 1507, 1460, 1370, 1194, 1172,
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990, 748, 692 cm−1; H NMR (500 MHz, CDCl3) δ 7.31 – 7.20 (m, 2H), 6.79 – 6.66
(m, 3H), 3.70 (s, 3H), 3.42 – 3.29 (m, 2H), 2.94 (s, 3H), 2.58 – 2.47 (m, 1H), 2.05 –
13
1.93 (m, 1H), 1.77 – 1.65 (m, 1H), 1.24 (d, J = 7.1 Hz, 3H); C NMR (125 MHz,
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CDCl3) δ 176.7, 149.2, 129.2, 116.3, 112.3, 51.6, 50.7, 38.3, 37.3, 30.5, 17.5; MS
(ESI): ([M+H]+) 222.1; HRMS (ESI) calcd for C13H20NO2 ([M+H]+) 222.1494, found
222.1498.
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Methyl 4-(methyl(phenyl)amino)butanoate (3b):23 65 mg, 31% Yield; Colorless oil;
1H NMR (500 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 6.77 – 6.69 (m, 3H), 3.69 (s, 3H),
3.40 – 3.35 (m, 2H), 2.95 (s, 3H), 2.38 (t, J = 7.3 Hz, 2H), 1.98 – 1.89 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 173.7, 149.3, 129.2, 116.3, 112.3, 51.9, 51.6, 38.3, 31.3,
22.2; MS (EI): 207, 176, 146, 132, 120, 104, 91, 77, 69, 59, 51, 42, 28, 15.
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Ethyl 4-(methyl(phenyl)amino)butanoate (3c):24 64 mg, 29% Yield; Colorless oil; H
NMR (500 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 6.78 – 6.69 (m, 3H), 4.16 (q, J = 7.1
Hz, 2H), 3.41 – 3.36 (m, 2H), 2.95 (s, 3H), 2.37 (t, J = 7.2 Hz, 2H), 1.97 – 1.89 (m,
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2H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (125 MHz, CDCl3) δ 173.3, 149.3, 129.2,
116.3, 112.3, 60.4, 52.0, 38.3, 31.6, 22.2, 14.2; MS (EI): 221, 176, 146, 132, 120, 104,
91, 77, 69, 59, 51, 42, 28, 15.
Butyl 2-methyl-4-(methyl(phenyl)amino)butanoate (3d): 119 mg, 45% Yield; Yellow
oil; IR (thin film): 2960, 2935, 2874, 1731, 1600, 1507, 1464, 1372, 1177, 748, 692
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.27 – 7.22 (m, 2H), 6.77 – 6.67 (m, 3H), 4.10 (t,
J = 6.7 Hz, 2H), 3.43 – 3.28 (m, 2H), 2.93 (s, 3H), 2.55 – 2.45 (m, 1H), 2.03 – 1.92
(m, 1H), 1.76 – 1.66 (m, 1H), 1.66 – 1.56 (m, 2H), 1.45 – 1.35 (m, 2H), 1.23 (d, J =
13
7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); C NMR (125 MHz, CDCl3) δ 176.33, 149.2,
129.2, 116.3, 112.3, 64.3, 50.7, 38.3, 37.5, 30.7, 30.5, 19.2, 17.6, 13.7; MS (ESI):
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([M+H]+) 264.2; HRMS (ESI) calcd for C16H26NO2 ([M+H]+) 264.1964, found
264.1969.
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Methyl 4-((4-methoxyphenyl)(methyl)amino)-2-methylbutanoate (3e): 92 mg, 37%
Yield; Yellow oil; IR (thin film): 2950, 2832, 1735, 1514, 1463, 1361, 1179, 1040,
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816 cm−1; H NMR (500 MHz, CDCl3) δ 6.87 – 6.82 (m, 2H), 6.72 (d, J = 9.0 Hz,
2H), 3.77 (s, 3H), 3.68 (s, 3H), 3.28 – 3.22 (m, 2H), 2.85 (s, 3H), 2.56 – 2.47 (m, 1H),
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2.00 – 1.90 (m, 1H), 1.71 – 1.61 (m, 1H), 1.21 (d, J = 7.0 Hz, 3H); C NMR (125
MHz, CDCl3) δ 176.7, 151.8, 144.3, 114.8, 55.8, 51.9, 51.5, 39.0, 37.3, 30.4, 17.4;
MS (ESI): ([M+H]+) 252.2; HRMS (ESI) calcd for C14H22NO3 ([M+H]+) 252.1600,
found 252.1600.
Methyl 4-((4-chlorophenyl)(methyl)amino)-2-methylbutanoate (3f): 103 mg, 40%
Yield; Yellow oil; IR (thin film): 2974, 2950, 2878, 1733, 1597, 1503, 1461, 1375,
1193, 1040, 810 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.20 – 7.14 (m, 2H), 6.62 (d, J
= 8.3 Hz, 2H), 3.68 (s, 3H), 3.38 – 3.25 (m, 2H), 2.90 (s, 3H), 2.53 – 2.45 (m, 1H),
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2.00 – 1.90 (m, 1H), 1.72 – 1.62 (m, 1H), 1.22 (d, J = 7.1 Hz, 3H); C NMR (125
MHz, CDCl3) δ 176.5, 147.7, 128.9, 121.1, 113.4, 51.6, 50.8, 38.4, 37.2, 30.3, 17.5;
MS (ESI): ([M+H]+) 256.1; HRMS (ESI) calcd for C13H19ClNO2 ([M+H]+) 256.1104,
found 256.1101.
Methyl 2-methyl-3-(1-phenylpyrrolidin-2-yl)propanoate (3g): 140 mg, 60% Yield, 1:1
dr; Diastereomer 1: White solid, m.p. 34-37 °C; IR (thin film): 2969, 2950, 1735,
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1599, 1506, 1460, 1363, 1196, 1164, 747, 694 cm−1; H NMR (500 MHz, CDCl3) δ
7.39 – 7.12 (m, 2H), 6.79 – 6.56 (m, 3H), 3.78 (s, 3H), 3.71 – 3.64 (m, 1H), 3.50 –
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3.38 (m, 1H), 3.23 – 3.10 (m, 1H), 2.65 – 2.47 (m, 1H), 2.31 – 2.17 (m, 1H), 2.11 –
1.92 (m, 3H), 1.88 – 1.76 (m, 1H), 1.39 – 1.26 (m, 1H), 1.23 (d, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 176.8, 147.3, 129.2, 115.6, 111.9, 56.8, 51.6, 48.3, 37.3,
37.0, 30.1, 23.3, 18.7; MS (ESI): ([M+H]+) 248.2; HRMS (ESI) calcd for C15H22NO2
([M+H]+) 248.1651, found 248.1662. Diastereomer 2: Yellow oil; IR (thin film):
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2969, 2950, 2876, 1736, 1598, 1505, 1460, 1365, 1193, 1161, 747, 693 cm−1; H
NMR (500 MHz, CDCl3) δ 7.24 (dd, J = 8.5, 7.4 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H),
6.58 (d, J = 8.1 Hz, 2H), 3.84 – 3.78 (m, 1H), 3.62 (s, 3H), 3.46 – 3.40 (m, 1H), 3.20
– 3.13 (m, 1H), 2.14 – 2.04 (m, 1H), 2.04 – 1.93 (m, 2H), 1.85 – 1.75 (m, 3H), 1.30 (d,
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J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) δ 176.7, 147.1, 129.2, 115.6, 111.9,
56.5, 51.5, 48.3, 37.3, 36.8, 30.3, 23.4, 17.2; MS (ESI): ([M+H]+) 248.2; HRMS (ESI)
calcd for C15H22NO2 ([M+H]+) 248.1651, found 248.1659.
General Procedure for Synthesis of 3 under air. In a 10 mL two-necked
round-bottom flask were placed acrylate 1 (1 mmol), DBU (152 mg, 1 mmol),
Ru(bpy)3(BF4)2 (7.4 mg, 0.01 mmol, 1 mol%) under air, and then amine 2 (0.6 mmol)
and NMP (2 mL) were added. The reaction mixture was placed at a distance of about
5 cm from a 45 W compact fluorescent lamp (Arrow BHSL 45) and stirred at room
temperature. After 12 hrs, the reaction mixture was purified by column
chromatography on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (20/1)
as the eluent to give the mixture products of 3 and 3’.
A
mixture of methyl 4-(methyl(phenyl)amino)butanoate (3b) and methyl
1-methyl-1,2,3,4-tetrahydroquinoline-4-carboxylate (3b’): 29 mg, 15% Yield,
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3b/3b’=2.3/1; Yellow oil; 3b: H NMR (500 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H),
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6.77 – 6.69 (m, 3H), 3.69 (s, 3H), 3.40 – 3.35 (m, 2H), 2.95 (s, 3H), 2.38 (t, J = 7.3
Hz, 2H), 1.98 – 1.89 (m, 2H); 3b’: 1H NMR (500 MHz, CDCl3) δ 7.19 – 7.11 (m, 2H),
6.69 – 6.64 (m, 2H), 3.81 (t, J = 5.0 Hz, 1H), 3.73 (s, 3H), 3.45 – 3.40 (m, 1H), 3.23 –
3.17 (m, 1H), 2.93 (s, 3H), 2.35 – 2.28 (m, 1H), 2.13 – 2.04 (m, 1H).
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mixture of ethyl 4-(methyl(phenyl)amino)butanoate (3c) and ethyl
1-methyl-1,2,3,4-tetrahydroquinoline-4-carboxylate (3c’): 36 mg, 16% Yield,
3c/3c’=2.2/1; Yellow oil; 3c: 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 6.78
– 6.69 (m, 3H), 4.16 (q, J = 7.1 Hz, 2H), 3.41 – 3.36 (m, 2H), 2.95 (s, 3H), 2.37 (t, J =
1
7.2 Hz, 2H), 1.97 – 1.89 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H); 3c’: H NMR (500 MHz,
CDCl3) δ 7.19 – 7.12 (m, 2H), 6.69 – 6.62 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.79 (t, J
= 5.1 Hz, 1H), 3.46 – 3.41 (m, 1H), 3.23 – 3.17 (m, 1H), 2.94 (s, 3H), 2.34 – 2.27 (m,
1H), 2.13 – 2.05 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).
General Procedure for Synthesis of 5. In a typical procedure: In a 10 mL
two-necked round-bottom flask were placed Baylis-Hillman acetate or alcohol 4 (0.5
mmol), NaOAc (49.2 mg, 0.6 mmol), Ru(bpy)3(BF4)2 (3.7 mg, 0.005 mmol, 1 mol%)
under N2, and then amine 2 (0.6 mmol) and DMSO (2 mL) were added. The reaction
mixture was placed at a distance of about 5 cm from a 45 W compact fluorescent
lamp (Arrow BHSL 45) and stirred at room temperature. After 6 hrs, the reaction
mixture was diluted with CH2Cl2 (30 mL) and H2O (20 mL). The layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined
organic layers washed with H2O (2 x 10 mL), then were dried over Na2SO4.
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Purification was done by column chromatography on silica gel (200-300 mesh) with
petroleum ether/ethyl acetate (20/1) as the eluent to give the pure product 5.
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(E)-Methyl 2-benzylidene-4-(methyl(phenyl)amino)butanoate (5a): 99 mg, 67% Yield;
Light yellow oil; IR (thin film): 3058, 3025, 2948, 2821, 1713, 1600, 1505, 1434,
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1373, 1256, 1195, 1128, 748, 693 cm−1; H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H),
7.42 – 7.34 (m, 5H), 7.21 (dd, J = 8.4, 7.4 Hz, 2H), 6.74 – 6.63 (m, 3H), 3.88 (s, 3H),
3.55 – 3.48 (m, 2H), 2.92 (s, 3H), 2.84 – 2.77 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 168.6, 148.8, 141.1, 135.5, 130.6, 129.1, 128.8, 128.6, 128.5, 116.2, 112.2, 52.1,
51.9, 38.0, 24.8; MS (ESI): ([M+H]+) 296.2; HRMS (ESI) calcd for C19H22NO2
([M+H]+) 296.1651, found 296.1645.
(E)-Methyl 4-(methyl(phenyl)amino)-2-(4-methylbenzylidene)butanoate (5b): 117 mg,
76% Yield; Light yellow solid, m.p. 34-36 °C; IR (thin film): 3025, 2948, 1715, 1600,
1505, 1435, 1372, 1256, 1128, 747, 692 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.79 (s,
1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 – 7.16 (m, 4H), 6.72 (d, J = 7.6 Hz, 3H), 3.88 (s,
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3H), 3.57 – 3.49 (m, 2H), 2.95 (s, 3H), 2.88 – 2.79 (m, 2H), 2.41 (s, 3H); C NMR
(125 MHz, CDCl3) δ 168.75, 148.8, 141.1, 138.7, 132.6, 129.7, 129.3, 129.1, 128.9,
116.2, 112.2, 52.0, 51.8, 38.0, 24.8, 21.3; MS (ESI): ([M+H]+) 310.2; HRMS (ESI)
calcd for C20H24NO2 ([M+H]+) 310.1807, found 310.1814.
(E)-Methyl 2-(4-isopropylbenzylidene)-4-(methyl(phenyl)amino)butanoate (5c): 112
mg, 73% Yield; Yellow oil; IR (thin film): 3025, 2960, 2870, 1709, 1600, 1506, 1435,
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1373, 1256, 1195, 1129, 748, 692 cm−1; H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H),
7.36 (d, J = 8.1 Hz, 2H), 7.31 – 7.22 (m, 4H), 6.82 – 6.67 (m, 3H), 3.89 (s, 3H), 3.60
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– 3.49 (m, 2H), 3.05 – 2.91 (m, 1H), 2.98 (s, 3H), 2.87 – 2.80 (m, 2H), 1.33 (s, 3H),
1.31 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.8, 149.6, 148.9, 141.1, 133.0, 129.7,
129.2, 129.1, 126.7, 116.2, 112.3, 52.1, 51.9, 38.1, 34.0, 24.9, 23.9; MS (ESI):
([M+H]+) 338.2; HRMS (ESI) calcd for C22H28NO2 ([M+H]+) 338.2120, found
338.2139.
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2-(4-methoxybenzylidene)-4-(methyl(phenyl)amino)butanoate
(5d):
121mg, 74% Yield; Light yellow solid, m.p. 62-64 °C; IR (thin film): 3025, 2949,
2837, 1705, 1603, 1510, 1435, 1355, 1255, 1176, 1128, 749, 693 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.76 (s, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 6.91 (d,
J = 8.6 Hz, 2H), 6.78 – 6.69 (m, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.58 – 3.50 (m, 2H),
2.96 (s, 3H), 2.88 – 2.82 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.9, 159.9, 148.9,
140.7, 130.7, 129.2, 128.4, 127.9, 116.2, 114.0, 112.3, 55.3, 52.0, 51.8, 38.1, 24.8;
MS (ESI): ([M+H]+) 326.2; HRMS (ESI) calcd for C20H24NO3 ([M+H]+) 326.1756,
found 326.1766.
(E)-Methyl 2-(3-methoxybenzylidene)-4-(methyl(phenyl)amino)butanoate (5e): 97 mg,
60% Yield; Yellow oil; IR (thin film): 3025, 2948, 2837, 1709, 1599, 1506, 1487,
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1373, 1248, 1131, 1127, 750, 693 cm−1; H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H),
7.42 – 7.35 (m, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.22 (dd, J = 8.5, 7.4 Hz, 2H), 6.98 (dd,
J = 12.4, 7.9 Hz, 2H), 6.74 – 6.64 (m, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.55 – 3.49 (m,
13
2H), 2.94 (s, 3H), 2.81 – 2.73 (m, 2H); C NMR (125 MHz, CDCl3) δ 168.5, 157.3,
148.7, 137.6, 130.5, 129.9, 129.3, 129.1, 124.5, 120.2, 115.9, 111.9, 110.6, 55.4, 51.9,
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51.9, 37.9, 24.8; MS (ESI): ([M+H]+) 326.2; HRMS (ESI) calcd for C20H24NO3
([M+H]+) 326.1756, found 326.1756.
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(E)-Methyl 2-(2-methoxybenzylidene)-4-(methyl(phenyl)amino)butanoate (5f): 120
mg, 74% Yield; Yellow oil; IR (thin film): 3025, 2949, 2835, 1708, 1600, 1506, 1434,
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1372, 1245, 1195, 1128, 748, 692 cm−1; H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H),
7.32 (t, J = 7.8 Hz, 1H), 7.24 – 7.18 (m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.94 – 6.88 (m,
2H), 6.74 – 6.65 (m, 3H), 3.88 (s, 3H), 3.81 (s, 3H), 3.55 – 3.47 (m, 2H), 2.93 (s, 3H),
2.86 – 2.79 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.6, 159.7, 148.8, 141.0, 136.9,
130.8, 129.6, 129.1, 121.1, 116.1, 114.3, 114.0, 112.1, 55.2, 52.1, 51.9, 38.0, 24.8;
MS (ESI): ([M+H]+) 326.2; HRMS (ESI) calcd for C20H24NO3 ([M+H]+) 326.1756,
found 326.1770.
(E)-Methyl 2-(4-fluorobenzylidene)-4-(methyl(phenyl)amino)butanoate (5g): 85 mg,
54% Yield; Yellow oil; IR (thin film): 3025, 2949, 2886, 1709, 1600, 1508, 1436,
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7.34 (dd, J = 8.4, 5.5 Hz, 2H), 7.23 (t, J = 7.9 Hz, 2H), 7.08-7.03 (m, 2H), 6.75 – 6.64
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(m, 3H), 3.88 (s, 3H), 3.55 – 3.49 (m, 2H), 2.92 (s, 3H), 2.83 – 2.75 (m, 2H); C
NMR (125 MHz, CDCl3) δ 168.5, 163.6, 161.6, 148.7, 140.0, 131.5, 130.8, 130.7,
130.6, 129.2, 116.4, 115.7, 115.5, 112.2, 52.2, 51.8, 38.2, 24.7; MS (ESI): ([M+H]+)
314.2; HRMS (ESI) calcd for C19H21FNO2 ([M+H]+) 314.1556, found 314.1553.
(E)-Methyl 2-(4-chlorobenzylidene)-4-(methyl(phenyl)amino)butanoate (5h): 73 mg,
44% Yield; Yellow solid, m.p. 44-46 °C; IR (thin film): 3026, 2949, 2886, 1712, 1600,
1506, 1490, 1434, 1372, 1253, 1196, 1129, 1090, 749, 693 cm−1; 1H NMR (500 MHz,
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CDCl3) δ 7.73 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.30 – 7.25 (m, 2H), 7.22 (t, J = 7.9
Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 2H), 3.88 (s, 3H), 3.54 – 3.48
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(m, 2H), 2.91 (s, 3H), 2.81 – 2.74 (m, 2H); C NMR (125 MHz, CDCl3) δ 168.4,
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148.7, 139.8, 134.4, 133.9, 131.2, 130.1, 129.2 128.8, 116.4, 112.2, 52.2, 51.8, 38.2,
24.8; MS (ESI): ([M+H]+) 330.1; HRMS (ESI) calcd for C19H21ClNO2 ([M+H]+)
330.1261, found 330.1267.
Methyl 2-(furan-2-ylmethylene)-4-(methyl(phenyl)amino)butanoate (5i): 80 mg, 57%
Yield (E/Z=63/27); Yellow oil; IR (thin film): 3025, 2949, 2885, 1712, 1633, 1600,
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1506, 1434, 1365, 1258, 1210, 1128, 747, 693 cm−1; H NMR (500 MHz, CDCl3) δ
7.55 (d, J = 1.3 Hz, 0.63H), 7.47 (s, 0.63H), 7.43 (d, J = 1.6 Hz, 0.37H), 7.32 – 7.22
(m, 2H), 6.93 (d, J = 3.4 Hz, 0.37H), 6.88 (d, J = 7.8 Hz, 1.13H), 6.75 (dd, J = 18.2,
7.7 Hz, 1.87H), 6.64 (d, J = 3.3 Hz, 0.63H), 6.56 (s, 0.37H), 6.54 – 6.51 (m, 0.63H),
6.47 – 6.44 (m, 0.37H), 3.855 (s, 1.13H), 3.851 (s, 1.87H), 3.61 – 3.48 (m, 2H), 3.10
– 3.06 (m, 1.26H), 3.05 (s, 1.87H), 2.98 (s, 1.13H), 2.70 – 2.61 (m, 0.74H); 13C NMR
(125 MHz, CDCl3) δ 168.7, 168.5, 151.5, 150.5, 148.9, 148.7, 144.4, 143.1, 129.2,
129.1, 126.8, 126.5, 126.1, 124.9, 116.3, 116.0, 113.2, 112.1, 112.0, 52.6, 52.1, 51.9,
51.7, 38.5, 38.0, 32.8, 25.3; MS (ESI): ([M+H]+) 286.1; HRMS (ESI) calcd for
C17H20NO3 ([M+H]+) 286.1443, found 286.1452.
(E)-Methyl 2-(2-(methyl(phenyl)amino)ethyl)hex-2-enoate (5j): 56 mg, 43% Yield;
Light yellow oil; IR (thin film): 3025, 2958, 2872, 1709, 1600, 1507, 1435, 1365,
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1373, 1278, 1251, 1198, 1145, 748, 693 cm−1; H NMR (500 MHz, CDCl3) δ 7.31 –
7.23 (m, 2H), 6.87 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.1 Hz, 2H), 6.72 (t, J = 7.2 Hz,
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1H), 3.80 (s, 3H), 3.48 – 3.37 (m, 2H), 2.98 (s, 3H), 2.64 – 2.55 (m, 2H), 2.23 – 2.13
(m, 2H), 1.54 – 1.43 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
168.2, 148.8, 144.6, 129.3, 129.2, 116.0, 112.0, 51.9, 51.7, 38.3, 30.6, 24.1, 22.1, 13.9;
MS (ESI): ([M+H]+) 262.2; HRMS (ESI) calcd for C16H24NO2 ([M+H]+) 262.1807,
found 262.1814.
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(E)-Ethyl 2-benzylidene-4-(methyl(phenyl)amino)butanoate (5k): 96 mg, 62% Yield;
Yellow oil; IR (thin film): 3059, 3025, 2979, 2903, 2820, 1705, 1600, 1507, 1447,
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1372, 1254, 1194, 1129, 748, 693 cm−1; H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H),
7.43 – 7.34 (m, 5H), 7.22 (t, J = 7.9 Hz, 2H), 6.70 (d, J = 7.5 Hz, 3H), 4.35 (q, J = 7.1
Hz, 2H), 3.57 – 3.48 (m, 2H), 2.93 (s, 3H), 2.86 – 2.77 (m, 2H), 1.43 (t, J = 7.1 Hz,
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3H). C NMR (125 MHz, CDCl3) δ 168.1, 148.8, 140.9, 135.6, 130.8, 129.1, 128.8,
128.5, 128.4, 116.1, 112.1, 61.0, 51.9, 38.0, 24.6, 14.3; MS (ESI): ([M+H]+) 310.2;
HRMS (ESI) calcd for C20H24NO2 ([M+H]+) 310.1807, found 310.1810.
(E)-Methyl 2-benzylidene-4-((4-chlorophenyl)(methyl)amino)butanoate (5l): 117 mg,
71% Yield; Yellow oil; IR (thin film): 3054, 3025, 2949, 1713, 1630, 1597,1504,
1434, 1373, 1196, 1129, 810, 764, 702, 629 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.81
(s, 1H), 7.43 – 7.36 (m, 3H), 7.35 – 7.30 (m, 2H), 7.12 (d, J = 8.9 Hz, 2H), 6.55 (d, J
= 8.5 Hz, 2H), 3.87 (s, 3H), 3.52 – 3.43 (m, 2H), 2.88 (s, 3H), 2.81 – 2.74 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 168.5, 147.3, 141.3, 135.5, 130.4, 128.9, 128.7, 128.6,
128.5, 120.1, 113.2, 52.1, 51.9, 38.2, 24.6; MS (ESI): ([M+H]+) 330.1; HRMS (ESI)
calcd for C19H21ClNO2 ([M+H]+) 330.1261, found 330.1258.
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(E)-Methyl 2-benzylidene-4-((3-chlorophenyl)(methyl)amino)butanoate (5m): Reation
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time is 18 hrs; 56 mg, 34% Yield; Yellow oil; IR (thin film): 3025, 2949, 2821, 1712,
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1594, 1561, 1495, 1434, 1371, 1258, 1199, 1130, 987, 761, 702, 683 cm−1; H NMR
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(500 MHz, CDCl3) δ 7.82 (s, 1H), 7.44 – 7.38 (m, 2H), 7.38 – 7.32 (m, 3H), 7.09 (t, J
= 8.1 Hz, 1H), 6.70 – 6.62 (m, 2H), 6.52 (d, J = 7.0 Hz, 1H), 3.90 (s, 3H), 3.53 – 3.47
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(m, 2H), 2.89 (s, 3H), 2.82 – 2.77 (m, 2H); C NMR (125 MHz, CDCl3) δ 168.5,
149.8, 141.5, 135.4, 135.1, 130.1, 130.0, 128.7, 128.63, 128.60, 115.9, 111.9, 110.2,
52.2, 51.7, 38.1, 24.7; MS (ESI): ([M+H]+) 330.1; HRMS (ESI) calcd for
C19H21ClNO2 ([M+H]+) 330.1261, found 330.1275.
(E)-Methyl 2-benzylidene-4-((4-fluorophenyl)(methyl)amino)butanoate (5n): 90 mg,
57% Yield; Yellow oil; IR (thin film): 3025, 2950, 2821, 1709, 1517, 1435, 1356,
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1256, 1227, 1169, 1128, 1085, 816, 766, 700 cm−1; H NMR (500 MHz, CDCl3) δ
7.81 (s, 1H), 7.43 – 7.32 (m, 5H), 6.94 – 6.87 (m, 2H), 6.65 – 6.54 (m, 2H), 3.87 (s,
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3H), 3.51 – 3.43 (m, 2H), 2.88 (s, 3H), 2.82 – 2.74 (m, 2H); C NMR (126 MHz,
CDCl3) δ 168.6, 156.2, 154.4, 145.5, 141.1, 135.5, 130.5, 128.8, 128.6, 128.5, 115.5,
115.4, 113.4, 113.3, 52.5, 52.1, 38.5, 24.5; MS (ESI): ([M+H]+) 314.2; HRMS (ESI)
calcd for C19H21FNO2 ([M+H]+) 314.1556, found 314.1563.
(E)-Methyl 2-benzylidene-4-((4-bromophenyl)(methyl)amino)butanoate (5o): 138 mg,
74% Yield; Yellow oil; IR (thin film): 3025, 2999, 2821, 1716, 1590, 1497, 1374,
1256, 1194, 1129, 1085, 808, 761, 700, 506 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.81
(s, 1H), 7.43 – 7.36 (m, 3H), 7.36 – 7.31 (m, 2H), 7.27 – 7.23 (m, 2H), 6.50 (d, J =
9.0 Hz, 2H), 3.87 (s, 3H), 3.50 – 3.43 (m, 2H), 2.87 (s, 3H), 2.82 – 2.74 (m, 2H); 13C
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NMR (125 MHz, CDCl3) δ 168.5, 147.7, 141.4, 135.5, 131.8, 130.4, 128.7, 128.6,
128.5, 113.7, 108.0, 52.1, 51.8, 38.2, 24.6; MS (ESI): ([M+H]+) 374.1; HRMS (ESI)
calcd for C19H21BrNO2 ([M+H]+) 374.0756, found 374.0768.
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(E)-Methyl 2-benzylidene-4-(methyl(p-tolyl)amino)butanoate (5p): 98 mg, 63% Yield;
Yellow oil; IR (thin film): 3025, 2948, 2821, 1712, 1619, 1521, 1434, 1355, 1255,
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1190, 1127, 1085, 804, 766, 700 cm−1; H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H),
7.44 – 7.35 (m, 5H), 7.04 (d, J = 8.3 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H),
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3.54 – 3.45 (m, 2H), 2.91 (s, 3H), 2.85 – 2.76 (m, 2H), 2.28 (s, 3H); C NMR (125
MHz, CDCl3) δ 168.7, 146.8, 141.0, 135.6, 130.7, 129.7, 128.9, 128.6, 128.5, 125.5,
112.7, 52.2, 52.1, 38.2, 24.6, 20.2; MS (ESI): ([M+H]+) 310.2; HRMS (ESI) calcd for
C20H24NO2 ([M+H]+) 310.1807, found 310.1803.
(E)-Methyl 2-benzylidene-4-((4-methoxyphenyl)(methyl)amino)butanoate (5q): 94 mg,
58% Yield; Yellow oil; IR (thin film): 3024, 2949, 2904, 2832, 1713, 1630, 1514,
1435, 1356, 1245, 1128, 1084, 1039, 816, 766, 698 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.79 (s, 1H), 7.45 – 7.29 (m, 5H), 6.82 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H),
3.87 (s, 3H), 3.78 (s, 3H), 3.49 – 3.41 (m, 2H), 2.87 (s, 3H), 2.81 – 2.73 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 168.6, 151.6, 143.8, 140.9, 135.6, 130.7, 128.9, 128.6,
128.5, 114.8, 114.4, 55.8, 52.9, 52.1, 38.6, 24.5; MS (ESI): ([M+H]+) 326.2; HRMS
(ESI) calcd for C20H24NO3 ([M+H]+) 326.1756, found 326.1749.
(E)-Methyl 2-benzylidene-4-(diphenylamino)butanoate (5r): 81 mg, 45% Yield;
White solid, m.p. 95-97 °C; IR (thin film): 3058, 3024, 2950, 2926, 1707, 1589, 1494,
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7.79 (s, 1H), 7.31 (dt, J = 12.4, 4.8 Hz, 5H), 7.25 (t, J = 7.5 Hz, 2H), 7.20 (d, J = 7.4
Hz, 2H), 7.08 (d, J = 7.8 Hz, 4H), 7.00 (t, J = 7.3 Hz, 2H), 3.98 – 3.92 (m, 2H), 3.90
(s, 3H), 3.00 – 2.92 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.6, 147.6, 141.1,
135.3, 129.9, 129.3, 129.0, 128.5, 128.5, 121.3, 121.0, 52.2, 51.3, 25.6; MS (ESI):
([M+H]+) 358.2; HRMS (ESI) calcd for C24H24NO2 ([M+H]+) 358.1807, found
358.1800.
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(E)-Methyl 2-benzylidene-4-(ethyl(phenyl)amino)pentanoate (5s): 82 mg, 51% Yield;
Yellow oil; IR (thin film): 3058, 3023, 2972, 2871, 1716, 1596, 1504, 1435, 1375,
747, 694 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.72 (s, 1H), 7.46 – 7.39 (m, 2H), 7.39
– 7.31 (m, 3H), 7.19 (dd, J = 8.8, 7.2 Hz, 2H), 6.74 – 6.64 (m, 3H), 4.29 – 4.19 (m,
1H), 3.82 (s, 3H), 3.14 – 2.96 (m, 2H), 2.92 (dd, J = 13.5, 6.5 Hz, 1H), 2.80 (dd, J =
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13.6, 8.0 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H); C NMR (125
MHz, CDCl3) δ 168.9, 148.3, 140.4, 135.8, 131.3, 129.0, 128.5, 128.2, 116.2, 113.7,
53.2, 52.0, 37.6, 31.3, 18.0, 14.3; MS (ESI): ([M+H]+) 324.2; HRMS (ESI) calcd for
C21H26NO2 ([M+H]+) 324.1964, found 324.1967.
(E)-Methyl 3-phenyl-2-((1-phenylpyrrolidin-2-yl)methyl)acrylate (5t): 104 mg, 65%
Yield; Yellow oil; IR (thin film): 3058, 3024, 2949, 2874, 2841, 1712, 1597, 1505,
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1435, 1367, 1259, 1225, 1118, 991, 747, 693 cm−1; H NMR (500 MHz, CDCl3) δ
7.86 (s, 1H), 7.46 – 7.39 (m, 2H), 7.39 – 7.32 (m, 3H), 7.22 (t, J = 7.9 Hz, 2H), 6.70 –
6.61 (m, 3H), 4.04 – 3.95 (m, 1H), 3.91 (s, 3H), 3.30 (t, J = 8.2 Hz, 1H), 3.09 (dd, J =
16.0, 8.7 Hz, 1H), 2.96 (dd, J = 13.4, 4.4 Hz, 1H), 2.68 (dd, J = 13.4, 10.0 Hz, 1H),
1.85 – 1.76 (m, 1H), 1.76 – 1.69 (m, 1H), 1.69 – 1.56 (m, 2H); 13C NMR (125 MHz,
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CDCl3) δ 168.8, 147.1, 141.6, 136.0, 131.34, 129.2, 128.8, 128.6, 128.2, 115.4, 111.9,
57.7, 52.1, 48.0, 29.5, 29.2, 23.0; MS (ESI): ([M+H]+) 322.2; HRMS (ESI) calcd for
C21H24NO2 ([M+H]+) 322.1807, found 322.1809.
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(E)-Methyl 2-benzylidene-4-(diisopropylamino)pentanoate (5u): Reation time is 24
hrs; 38 mg, 25% Yield; Yellow oil; IR (thin film): 3025, 2962, 2869, 1715, 1447,
1435, 1396, 1365, 1264, 1189, 774, 699 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.64 (s,
1H), 7.44 – 7.37 (m, 4H), 7.34 – 7.29 (m, 1H), 3.82 (s, 3H), 3.27 – 3.17 (m, 1H), 3.07
– 2.94 (m, 2H), 2.78 – 2.71 (m, 1H), 2.68 – 2.61 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H),
0.95 (d, J = 6.6 Hz, 6H), 0.88 (d, J = 6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
169.5, 138.9, 136.3, 133.2, 129.3, 128.4, 128.1, 51.9, 49.2, 44.3, 34.2, 23.5, 22.4, 20.4;
MS (ESI): ([M+H]+) 304.2; HRMS (ESI) calcd for C19H30NO2 ([M+H]+) 304.2277,
found 304.2287.
Methyl 4-(methyl(phenyl)amino)-2-(2-(methyl(phenyl)amino)ethyl)butanoate (5v): 30
mg, 18% Yield; Yellow oil; IR (thin film): 3025, 2949, 1732,1600, 1506, 1449, 1371,
1193, 991, 748, 693 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.27 – 7.22 (m, 4H), 6.76 –
6.68 (m, 6H), 3.70 (s, 3H), 3.40 – 3.26 (m, 4H), 2.91 (s, 6H), 2.51 – 2.43 (m, 1H),
2.03 – 1.93 (m, 2H), 1.83 – 1.73 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 175.8, 149.2,
129.2, 116.5, 112.4, 51.6, 50.8, 41.0, 38.3, 29.3; MS (ESI): ([M+H]+) 341.2; HRMS
(ESI) calcd for C21H29N2O2 ([M+H]+) 341.2229, found 341.2234.
Methyl 2-(hydroxy(phenyl)methyl)-4-(methyl(phenyl)amino)butanoate (5w): 107 mg,
68% Yield, 5.8:1 dr; Major diastereoisomer: Colorless oil; IR (thin film): 3482,
3029, 2949, 1732,1600, 1507, 1452, 1435, 1364, 1193, 1035, 750, 701 cm−1; 1H NMR
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(500 MHz, CDCl3) δ 7.41 – 7.30 (m, 5H), 7.23 – 7.15 (m, 2H), 6.70 (t, J = 7.2 Hz,
1H), 6.60 (d, J = 8.0 Hz, 2H), 4.84 (d, J = 7.6 Hz, 1H), 3.71 (s, 3H), 3.32 – 3.23 (m,
1H), 3.23 – 3.14 (m, 1H), 2.88 (s, 1H), 2.86 – 2.80 (m, 1H), 2.80 (s, 3H), 1.95 – 1.85
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(m, 1H), 1.66 – 1.56 (m, 1H); C NMR (125 MHz, CDCl3) δ 175.2, 149.1, 141.5,
129.1, 128.7, 128.3, 126.5, 116.5, 112.5, 75.4, 51.9, 50.8, 38.1, 26.3; MS (ESI):
([M+H]+) 314.2; HRMS (ESI) calcd for C19H24NO3 ([M+H]+) 314.1756, found
314.1749. Minor diastereoisomer: Colorless oil; IR (thin film): 3479, 3028, 2950,
1732,1600, 1506, 1453, 1371, 1201, 1168, 1035, 749, 701 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.39 – 7.34 (m, 4H), 7.33 – 7.28 (m, 1H), 7.24 – 7.17 (m, 2H), 6.71 (t, J =
7.3 Hz, 1H), 6.65 (d, J = 8.1 Hz, 2H), 5.05 (d, J = 5.3 Hz, 1H), 3.62 (s, 3H), 3.35 –
3.26 (m, 1H), 3.26 – 3.17 (m, 1H), 2.94 (s, 1H), 2.82 – 2.74 (m, 4H), 2.07 – 1.91 (m,
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2H); C NMR (125 MHz, CDCl3) δ 174.9, 149.3, 141.4, 129.1, 128.4, 127.8, 126.0,
116.6, 112.7, 74.1, 51.8, 51.3, 50.6, 38.1, 24.1; MS (ESI): ([M+H]+) 314.2; HRMS
(ESI) calcd for C19H24NO3 ([M+H]+) 314.1756, found 314.1761.
Methyl 2-(hydroxymethyl)-4-(methyl(phenyl)amino)butanoate (5x): 67 mg, 57% Yield;
Colorless oil; IR (thin film): 3444, 3025, 2951, 2883, 1732,1600, 1507, 1436, 1372,
1194, 1037, 750, 694 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.22 (m, 2H), 6.78 –
6.70 (m, 3H), 3.83 – 3.77 (m, 2H), 3.74 (s, 3H), 3.46 – 3.32 (m, 2H), 2.93 (s, 3H),
2.69 – 2.61 (m, 1H), 2.42 (s, 1H), 2.02 – 1.92 (m, 1H), 1.89 – 1.79 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 175.2, 149.2, 129.2, 116.8, 112.7, 63.3, 51.9, 50.8, 45.4, 38.4,
25.6; MS (ESI): ([M+H]+) 238.1; HRMS (ESI) calcd for C13H20NO3 ([M+H]+)
238.1443, found 238.1440.
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Spectroscopic data for all products 3a-g and 5a-x (PDF version). This material is
available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xuxiaoliang@zjut.edu.cn.
*E-mail: xnli@zjut.edu.cn.
Author Contributions
All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are grateful to Zhejiang Provincial Natural Science Foundation of China
(No. LY12B02017) and National Basic Research Program of China (973 Program)
(No. 2011CB710800).
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