Three-component reaction for the synthesis of diverse unsaturated α-amino esters

Article abstract of DOI:10.1016/j.tet.2013.11.107

We describe an efficient multicomponent reaction for the preparation of unsaturated α-amino esters by ytterbium triflate catalyzed reaction of potassium organotrifluoroborate salts, aniline and ethyl glyoxalate. The synthetic viability of this protocol wa

Full text of DOI:10.1016/j.tet.2013.11.107

Tetrahedron 70 (2014) 3243e3248
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Three-component reaction for the synthesis of diverse
b-unsaturated
a-amino esters
a
,
b
a
a
*
ꢀ
ꢀ
Helio A. Stefani , Flavia Manarin , Ariane C.S. Sousa , Frederico B. Souza ,
Witor Ribeiro Ferraz a
Faculdade de Ciencias Farmaceuticas, Departamento de Farmacia, Universidade de Sao Paulo, 05508-900 Sao Paulo, SP, Brazil
a
^
^
ꢀ
~
b
^
ꢀ
Centro de Engenharias e Ciencias Exatas, Universidade Estadual do Oeste do Parana, PR, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 October 2013
Received in revised form 25 November 2013
Accepted 29 November 2013
Available online 7 December 2013
We describe an efficient multicomponent reaction for the preparation of b-unsaturated a-amino esters
by ytterbium triflate catalyzed reaction of potassium organotrifluoroborate salts, aniline and ethyl
glyoxalate. The synthetic viability of this protocol was demonstrated by moderate to high yields, short
reaction time ranging from 0.5 to 12 h, and efficiency with respect to substrate scope.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organotrifluoroborates
Lewis acid
Aniline
Ytterbium triflate
Multicomponent reaction
1. Introduction
Among the available methods to synthesize b-unsaturated a-
amino acid derivatives, a few of them have been successfully
employed: one of the approaches has been based on the addition of
Multicomponent reactions (MCRs) occupy a prominent role in
organic chemistry due to the possibility of synthesizing both small
and large organic molecules with increased diversity and
complexity.1,2
This approach is particularly important because it minimizes
production of wastes, is rapid, and utilizes simplified workup pro-
cedures allowing the construction of diverse chemical libraries of
drug-like molecules.3,4
The potential of multiple bond formations among more than
two building blocks in a one-step procedure has been widely
exploited in combinatorial and medicinal chemistry.5,6 Many
complex molecules have been synthesized using these methodol-
ogies, such as bile acids,7 chimeric peptide-steroids,2 and antican-
cer peptides8 (Fig. 1).
terminal alkynes to
a
-imino esters using different catalysts (path
a).11 An alternative path (b) is the coupling reaction of
a
-hal-
oglycinates with an excess of alkynyltin reagents (environmentally
unfriendly) under reflux conditions.12 However the most conve-
nient strategy is represented by a three-component coupling re-
action of an aldehyde, an amine and alkyne (path c).13 This class of
reaction has emerged as an attractive and versatile strategy for the
generation of novel heterocycles in a step- and atom-economical
fashion14 (Scheme 1).
Unsaturated
a-amino acid derivatives are members of non-
proteinogenic amino acids isolated from natural products.9 In
particular, the
b-alkynyl a-amino acids, such as ethynylglycine
(FR-900130) isolated from Streptomyces catenulae,10 were
shown to have antimicrobial activity against Gram-positive
bacteria.
* Corresponding author. E-mail address: hstefani@usp.br (H.A. Stefani).
Fig. 1. Structures of polyfunctionalized molecules.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.107

3244
H.A. Stefani et al. / Tetrahedron 70 (2014) 3243e3248
Table 2
Products of the multicomponent reactions
Scheme 1. Synthetic strategies to b-unsaturated a-amino acid derivatives.
To the best of our knowledge, there are no reports describing the
Lewis acid-catalyzed multicomponent reaction with alkynyltri-
fluoroborate salts, ethyl glyoxalate, and anilines. Therefore, as part
of our ongoing studies to search for new carbonecarbon bond
formation processes using potassium organotrifluoroborate com-
pounds,15 we decided to design a simple, mild, and efficient method
Entry
1
ReBF3K
Product
Time (h) Yield (%)
0.5
84
for the synthesis of
b-unsaturated a-amino acid derivatives.
2
3
4
1.0
70
2. Results and discussion
Using the three-component reaction to synthesize unsaturated
-amino acid derivatives, a preliminary study was developed to
a
evaluate the feasibility of our approach of mixing ethyl glyoxalate,
aniline, potassium phenyl ethynyltrifluoroborate, and various Lewis
acids as catalysts in dichloromethane as solvent at room temper-
ature as model reagents (Table 1).
2.0
53
85
Table 1
Optimizing the reaction conditions for the synthesis of 4a
12
5
6
2.0
3.0
64
65
Entry
Catalyst (mol %)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Sc(OTf)3 (10)
Yb(OTf)3 (10)
Cu(OTf)2 (10)
CuI (10)
MnCl2 (10)
FeCl3 (10)
In(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
CH3NO2
Dioxane
CH2Cl2
1
0.5
2
4
2
35
84
20
44
31
67
68
64
43
44
32
68
2
1
0.5
3
0.5
0.3
1
9
10
11
12
7
8
3.0
4.0
62
79
We started screening using different Lewis acids as shown in
Table 1, and we observed that all afforded the desired product.
However, ytterbium triflate gave the best yield (Table 1, entry 2,
84%) and manganese chloride led to a very poor yield (Table 1, entry
5, 31%). We observed a similar yield when we employed indium and
iron (Table 1, entries 6 and 7), but the use of iron has a minor in-
convenience, i.e., its hygroscopic nature complicates handling.
Next we investigated the influence of the solvent in the reaction
and despite of the fact that all others afforded the product,
dichloromethane was the most efficient (Table 1, entry 2) and led to
completion of the reaction in a short time. Also, we investigated
lower catalyst loading (5 mol %), but a decrease in the yield of the
reaction was observed (Table 1, entry 12, 68%).
9
24
62
76
10
1.0
0.6
The optimized reaction conditions were extended to create
11
90
a library of 10 derivatives of
(Table 2) and five -alkenyl-
which were obtained in poor to high yields.
b
-alkynyl-a-amino acid derivatives
b
a-amino acid derivatives (Table 3),

H.A. Stefani et al. / Tetrahedron 70 (2014) 3243e3248
3245
Table 3
entries 2, 5e7, and 9). In the case of cyclopropyl and thiophenyl, the
yields were good with 79% and 76%, respectively (Table 1, entries 8
and 10).
Scope of MCRs employing potassium alkenyl and allyltrifluoroborate salts
Using the same reaction conditions, we tried to prepare vinyl-
and allyl-a-amino acid derivatives employing potassium alkenyl-
and allyltrifluoroborates as the nucleophilic species (Table 3). In the
case of alkenyls, the best yield was achieved with phenyl-
ethenyltrifluoroborate with 57% yield (Table 3, entry 1) and to the
other two examples poor yields, 30% and 38%, respectively (Table 3,
entries 2 and 3). For allyltrifluoroborates, we observed a moderate
yield of 53% (Table 3, entry 4) and to entry 5 a poor yield of 46%.
An advantageous aspect of the use of rare earth metal triflates16
is that the catalyst can easily be recovered from the reaction me-
dium and recycled. We evaluated this possibility of reusing the
Yb(OTf)3 in our reactions. The catalyst was separated from the re-
action medium by simple filtration, sequentially washed with
dichloromethane, and dried at 70 ꢀC for 2 h. This process was re-
peated affording the desired product in 76% (first run) and 65%
(second run) recovery as shown in Fig. 2.
Entry
1
ReBF3K
Product
Time (h)
2
Yield (%)
57
2
3
2
2
30
38
4
5
6
1.6
2
53
46
40
1
7
8
1
51
75
Fig. 2. Recyclability of the catalyst.
The structures of all products were characterized by 1H NMR, 13
NMR, and HRMS analysis.
C
50 min
3. Conclusion
In conclusion, a convergent and mild three-component to syn-
thesize alkynyl-, alkenyl-, and allyl- -amino esters was developed
a
9
0.5
0.5
81
61
using ytterbium triflate as catalyst, ethyl glyoxalate, aromatic
amine, and organotrifluoroborate salts, affording the products in
yields ranging from poor to good. Features of this strategy include
mild conditions, convenient one-pot operation, and the possibility
of reusing the catalyst. Further investigations are in progress to
evaluate the mechanism and their biological activity.
10
4. Experimental section
4.1. General
This procedure was efficient for aromatic alkynyltri-
fluoroborates, such as benzene and biphenyl that afforded the
product in 84% and 85% yield, respectively (Table 2, entries 1 and 4).
However, with the phenyl group bearing electron-withdrawing
species, such as F, the yield drops dramatically to 53% (Table 2,
entry 3). For alkynyltrifluoroborates containing electron-donor
species, we observed yields ranging from 62% to 70% (Table 2,
Proton nuclear magnetic resonance spectra (1H NMR) were
obtained at 300 MHz. Spectra was recorded in CDCl3 solution, some
of them in DMSO. Chemical shifts are reported in parts per million,
referenced to the solvent peak of CDCl3 or tetramethylsilane (TMS)

3246
H.A. Stefani et al. / Tetrahedron 70 (2014) 3243e3248
as the external reference. Data are reported as follows: chemical
shift ( ), multiplicity, coupling constant (J) in Hertz and integrated
d
(ppm): 7.56e7.33 (m, 9H), 6.82 (d, J¼9.0 Hz, 2H), 6.75 (d, J¼9.0 Hz,
2H), 4.97 (s, 1H), 4.31 (q, J¼7.1 Hz, 2H), 3.74 (s, 3H), 1.32 (t, J¼7.1 Hz,
3H). 13C NMR: CDCl3, 75 MHz,
(ppm): 168.9, 153.4, 141.4, 140.2,
d
intensity. Carbon-13 nuclear magnetic resonance spectra (13C NMR)
were obtained at 75 MHz. Spectra was recorded in CDCl3 solution.
Chemical shifts are reported in ppm, referenced to the solvent peak
of CDCl3. Abbreviations to denote the multiplicity of a particular
signal are s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), st (sextet), and m (multiplet). Column chromatography
was performed using silica gel (230e400 mesh). Thin-layer chro-
matography (TLC) was performed using silica gel UV254, 0.20 mm
thickness. For visualization, TLC plates were either placed under
ultraviolet light, or stained with iodine or acidic vanillin solution.
Dichloromethane was dried and purified.17 All other solvents were
ACS or HPLC grade unless otherwise noted. Air- and moisture-
sensitive reactions were conducted in flame-dried or oven-dried
glassware equipped with tightly fitted rubber septa and under
a positive atmosphere of dry nitrogen. Reagents and solvents were
handled using standard syringe techniques.
d
139.5, 132.3 (2C), 128.8 (2C), 127.7, 127.0 (2C), 126.9 (2C), 121.0, 116.1
(2C), 114.8 (2C), 84.9, 84.2, 62.4, 55.7, 50.7, 14.1. HRMS calcd for
C
25H23NO3 (MþHþ): 386.1750; found: 386.1748.
4.2.1.5. Ethyl 2-(4-methoxyphenylamino)-4-(4-pentylphenyl)but-
3-ynoate (4e). Yield 0.121 g (64%). 1H NMR: CDCl3, 300 MHz,
d
(ppm): 7.31 (d, J¼8.1 Hz, 2H), 7.09 (d, J¼8.1 Hz, 2H), 6.80 (d,
J¼9.0 Hz, 2H), 6.73 (d, J¼9.0 Hz, 2H), 4.93 (s, 1H), 4.29 (q, J¼7.1 Hz,
2H), 3.73 (s, 3H), 2.56 (t, J¼7.1 Hz, 2H), 1.58 (qui, J¼7.1 Hz, 2H),
1.33e1.27 (m, 7H), 0.87 (t, J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
d
(ppm): 169.1, 153.4, 143.8, 139.6, 131.8 (2C), 128.3 (2C), 119.3, 116.0
(2C),114.8 (2C), 84.6, 83.5, 62.3, 55.6, 50.7, 35.8, 31.4, 30.8, 22.5,14.1,
14.0. HRMS calcd for
380.2221.
C
24H29NO3 (MþHþ): 380.2226; found:
4. 2.1. 6. Ethyl 4-(6-methoxynaphthalen-2-yl)-2-(4-
4.2. Representative procedure for Yb(III)-catalyzed multi-
methoxyphenylamino)but-3-ynoate (4f). Yield 0.126 g (65%). 1H
component reaction of alkynyl- or alkenyltrifluoroborate
NMR: CDCl3, 300 MHz, d (ppm): 7.84 (s, 1H), 7.65e7.60 (m, 2H), 7.39
(dd, J¼1.5, 8.5 Hz,1H), 7.14e7.06 (m, 2H), 6.82 (d, J¼9.0 Hz, 2H), 6.76
To the sodium sulfate (5 equiv, 0.355 g), aniline (0.5 mmol,
0.616 g), and ethyl glyoxalate (0.5 mmol, 0.1 mL) in CH2Cl2 (5 mL),
ytterbium triflate (10 mol %, 0.030 g) and potassium alkynyl-,
alkenyl-, and allyltrifluoroborates (0.6 mmol) was added. The re-
action mixture was stirred at room temperature until total con-
sumption of the starting material. Afterward, the reaction mixture
was extracted with ethyl acetate (3ꢁ5 mL), and washed with sat-
urated NaCl solution. The organic phase was dried using MgSO4,
filtered, and the solvent was removed under reduced pressure.
(d, J¼9.0 Hz, 2H), 4.98 (s,1H), 4.31 (q, J¼7.1 Hz, 2H), 3.89 (s, 3H), 3.74
(s, 3H), 1.33 (t, J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
d (ppm):
168.5, 157.9, 152.9, 139.0, 133.8, 131.2, 128.8, 128.5, 127.8, 126.2,
118.9, 116.5, 115.6 (2C), 114.3 (2C), 105.3, 84.4, 83.3, 61.8, 55.1, 54.8,
50.3, 13.6. HRMS calcd for C24H23NO4 (MþHþ): 390.1700; found:
390.1700.
4.2.1.7. Ethyl 2-(4-methoxyphenylamino)oct-3-ynoate
(4g). Yield 0.089 g (62%). 1H NMR: CDCl3, 300 MHz,
d (ppm): 6.78
(d, J¼9.0 Hz, 2H), 6.67 (d, J¼9.0 Hz, 2H), 4.69 (s, 1H), 4.25 (q,
J¼7.1 Hz, 2H), 3.73 (s, 3H), 2.17 (t, J¼7.1 Hz, 2H), 1.47e1.37 (m, 4H),
1.29 (t, J¼7.1 Hz, 3H), 0.87 (t, J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
4.2.1. Recycling procedure for Yb(OTf)3. The catalyst is separated
from the reaction medium by simple filtration, sequentially washed
with dichloromethane and dried at 70 ꢀC for 2 h.
d
(ppm): 169.5, 153.2, 139.7, 115.9 (2C), 114.7 (2C), 85.3, 75.1, 62.0,
55.6, 50.2, 30.4, 21.7, 18.3, 14.0, 13.5. HRMS calcd for C17H23NO3
4.2.1.1. Ethyl 2-(4-methoxyphenylamino)-4-phenylbut-3-ynoate
(MþHþ): 290.1750; found: 290.1749.
(4a). Yield 0.129 g (84%). 1H NMR: CDCl3, 300 MHz,
d (ppm):
7.41e7.38 (m, 2H), 7.30e7.24 (m, 3H), 6.77 (dd, J¼9.0 Hz, 4H), 4.94
4.2.1.8. Ethyl 4-cyclopropyl-2-(4-methoxyphenylamino)but-3-
(s, 1H), 4.30 (q, J¼7.1 Hz, 2H), 3.74 (s, 3H), 1.32 (t, J¼7.1 Hz, 3H). 13
C
ynoate (4h). Yield 0.107 g (79%). 1H NMR: CDCl3, 300 MHz,
d
NMR: CDCl3, 75 MHz,
d
(ppm): 168.9, 153.3, 139.4 (2C), 131.8, 128.5
(ppm): 6.70 (d, J¼8.9 Hz, 2H), 6.57 (d, J¼8.9 Hz, 2H), 4.58 (s, 1H),
(2C), 128.1, 122.1, 116.0 (2C), 114.7 (2C), 84.3, 84.2, 62.3, 55.6, 50.6,
4.17 (q, J¼7.1 Hz, 2H), 3.65 (s, 3H), 1.20 (t, J¼7.1 Hz, 3H), 1.15e1.09
14.0. HRMS calcd for
310.1435.
C
19H19NO3 (MþHþ): 310.1437; found:
(m, 1H), 0.68e0.60 (m, 2H), 0.58e0.53 (m, 2H). 13C NMR: CDCl3,
75 MHz,
d (ppm): 169.3, 153.1, 139.5, 115.7 (2C), 114.6 (2C), 88.2,
70.1, 61.9, 55.5, 50.1, 13.9, 8.1 (2C). HRMS calcd for C16H19NO3
4.2.1.2. Ethyl 4-(4-methoxyphenyl)-2-(4-methoxyphenylamino)
(MþHþ): 274.1437; found: 274.1435.
but-3-ynoate (4b). Yield 0.118 g (70%). 1H NMR: CDCl3, 300 MHz,
d
(ppm): 7.33 (d, J¼8.8 Hz, 2H), 6.80 (d, J¼8.8 Hz, 4H), 6.72 (d,
4.2.1.9. Ethyl 2-(4-methoxyphenylamino)-4-(trimethylsilyl)but-3-
J¼8.8 Hz, 2H), 4.93 (s,1H), 4.28 (q, J¼7.1 Hz, 2H), 3.76 (s, 3H), 3.73 (s,
ynoate (4i). Yield 0.094 g (62%). 1H NMR: CDCl3, 300 MHz,
d (ppm):
3H), 1.30 (t, J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
d
(ppm): 169.1,
6.87 (d, J¼9.0 Hz, 2H), 6.75 (d, J¼9.0 Hz, 2H), 4.81 (s, 1H), 4.35 (q,
159.9, 153.3, 139.6, 133.3 (2C), 116.0 (2C), 114.8 (2C), 114.2, 113.9
(2C), 84.3, 82.8, 62.3, 55.6, 55.2, 50.7, 14.1. HRMS calcd for
J¼7.1 Hz, 2H), 3.82 (s, 3H), 1.37 (t, J¼7.1 Hz, 3H), 0.22 (s, 9H). 13C
NMR: CDCl3, 75 MHz,
d (ppm): 168.8, 153.3, 139.5, 116.0 (2C), 114.7
C
20H21NO4 (MþHþ): 340.1543; found: 340.1541.
(2C), 100.0, 89.7, 62.2, 55.6, 50.9, 13.9, 0.3. HRMS calcd for
C
16H23NO3Si (MþHþ): 306.1520; found: 306.1518.
4.2.1.3. Ethyl 4-(4-fluorophenyl)-2-(4-methoxyphenylamino)but-
3-ynoate (4c). Yield 0.086 g (53%). 1H NMR: CDCl3, 300 MHz,
d
4.2.1.10. Ethyl 2-(4-methoxyphenylamino)-5-(phenylthio)pent-3-
(ppm): 7.30e7.25 (m, 2H), 6.90e6.84 (m, 2H), 6.87 (t, J¼8.8 Hz,
ynoate (4j). Yield 0.134 g (76%). 1H NMR: CDCl3, 300 MHz,
2H), 6.68 (dd, J¼8.9 Hz, 4H), 4.84 (s, 1H), 4.20 (q, J¼7.1 Hz, 2H), 3.64
d
(ppm): 7.39 (m, 2H), 7.28e7.21 (m, 3H), 6.76 (d, J¼9.0 Hz, 2H), 6.61
(s, 3H), 1.22 (t, J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
d
(ppm):
(d, J¼9.0 Hz, 2H), 4.69 (t, J¼2.1 Hz, 1H), 4.22 (dq, J¼2.1, 7.1 Hz, 2H),
168.7, 164.2, 160.9, 153.3, 139.3, 133.6 (d, J¼8.5 Hz), 118.2 (d,
3.72 (s, 3H), 3.57 (d, J¼2.1 Hz, 2H), 1.25 (t, J¼7.1 Hz, 3H). 13C NMR:
J¼3.5 Hz), 115.9 (2C), 115.4 (d, J¼22 Hz) (2C), 114.7 (2C), 83.9, 83.2,
CDCl3, 75 MHz,
d (ppm): 168.6, 153.2, 139.2, 134.8, 130.3, 128.8,
62.3, 55.5, 50.5, 13.9. HRMS calcd for
328.1343; found: 328.1343.
C
19H18FNO3 (MþHþ):
126.8, 115.8 (2C), 114.7 (2C), 80.4, 78.5, 62.2, 55.5, 49.9, 22.9, 13.9.
HRMS calcd for C20H21NO3S (MþHþ): 356.1315; found: 356.1313.
4.2.1.4. Ethyl 4-(biphenyl-4-yl)-2-(4-methoxyphenylamino)but-
4.2.1.11. Ethyl 2-(4-bromophenylamino)-4-cyclopropylebut-3-
3-ynoate (4d). Yield 0.163 g (85%). 1H NMR: CDCl3, 300 MHz,
ynoate (4k). Yield 0.114 g (71%). 1H NMR: CDCl3, 300 MHz,

H.A. Stefani et al. / Tetrahedron 70 (2014) 3243e3248
3247
d
(ppm): 7.21 (d, J¼8.8 Hz, 2H), 6.48 (d, J¼8.8 Hz, 2H), 4.60 (s, 1H),
CDCl3): d 172.7, 152.6,145.5,140.7,120.7, 115.2,114.7, 61.2, 59.9, 55.6,
4.38 (s, NH), 4.17 (q, J¼7.1 Hz, 2H), 1.23 (t, J¼7.1 Hz, 3H), 1.11e1.15
33.1, 29.3, 14.1; HRMS (m/z): [MH]þcalcd for C17H25NO3: 292.1907;
(m, 1H), 0.69e0.60 (m, 2H), 0.58e0.54 (m, 2H). 13C NMR: CDCl3,
found: 292.1900.
75 MHz,
d (ppm): 169.4, 145.1, 1392.5, 116.2, 111.3, 89.2, 70.1, 62.9,
49.48, 14.6, 8.8. HRMS calcd for C15H16NO2Br (MþHþ): 322.0364;
4.2.1.19. Ethyl 2-(4-methoxy-2-methylphenylamino)-3,4-
found: 322.0361.
dimethylpent-3-enoate (4s). Yield 0.109
(300 MHz, CDCl3):
g
(75%). 1H NMR
d
6.60 (d, J¼2.8 Hz, 1H), 6.53 (dd, J¼8.9, 2.8 Hz,
4.2.1.12. (E)-Ethyl 2-(4-methoxyphenylamino)-4-phenylbut-3-
1H), 6.25 (d, J¼8.9 Hz, 1H), 4.89 (s, 1H), 4.14e4.04 (m, 2H), 3.61 (s,
enoate (4l). Yield 0.089 g (57%). 1H NMR: CDCl3, 300 MHz,
3H), 2.12 (s, 3H), 1.86 (s, 3H), 1.63 (s, 3H), 1.43 (s, 3H), 1.18 (t,
d
(ppm): 7.38e7.25 (m, 5H), 6.80e6.75 (m, 3H), 6.65 (d, J¼8.9 Hz,
J¼7.11 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 172.6,151.2,138.5,130.7,
2H), 6.32 (dd, J¼15.9, 5.8 Hz, 1H), 4.66 (d, J¼5.8 Hz, 1H), 4.25e4.22
124.3, 123.9, 116.9, 111.2, 61.1, 58.4, 55.6, 21.4, 20.5, 17.6, 14.1, 12.5;
HRMS (m/z): [MH]þcalcd for C17H25NO3: 292.1834, found:
292.1830.
(m, 2H), 3.73 (s, 3H), 1.30 (t, J¼7.13 Hz, 3H). 13C NMR: CDCl3,
75 MHz, d (ppm): 171.9, 152.7, 140.5,136.3,132.8, 128.6,126.6,125.4,
115.1, 114.9, 61.7, 59.9, 55.7. HRMS calcd for C19H21NO3 (MþHþ):
312.1594; found: 312.1593.
4.2.1.20. Ethyl 2-(4-iodophenylamino)-4-methylpent-3-enoate
(4t). Yield 0.145 g (81%). 1H NMR (300 MHz, CDCl3):
d 7.41 (d,
4.2.1.13. Ethyl 2-(4-methoxyphenylamino)-3,4-dimethylpent-3-
J¼8.8 Hz, 2H), 6.37 (d, J¼8.8 Hz, 2H), 5.07 (d, J¼8.7 Hz, 1H), 4.66 (d,
enoate (4m). Yield 0 g (30%). 1H NMR: CDCl3, 300 MHz,
d (ppm):
J¼8.4 Hz, 1H), 4.20e4.16 (m, 2H), 1.84 (s, 3H), 1.76 (s, 3H), 1.27 (t,
6.75 (d, J¼8.8 Hz, 2H), 6.52 (d, J¼8.8 Hz, 2H), 4.94 (s, 1H), 4.19e4.16
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 172.4, 146.0, 139.2, 137.8,
121.0, 115.6, 78.8, 61.4, 55.4, 25.7, 18.7, 14.1; HRMS (m/z):
(m, 2H), 3.71 (s, 3H), 1.93 (s, 3H), 1.71 (s, 3H), 1.53 (s, 3H), 1.24 (t,
J¼7.1 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
d
(ppm):
d
172.4, 152.2,
[MH]þcalcd for C14H18INO2: 360.0455, found: 360.0449.
140.7, 131.0, 124.3, 114.8, 114.6, 61.1, 58.6, 55.7, 21.4, 20.5, 14.1, 12.7.
HRMS calcd for C16H23NO3 (MþHþ): 278.1751; found: 278.1749.
4.2.1.21. (E)-Ethyl
enoate (4u). Yield 0.105 g (61%). 1H NMR (300 MHz, CDCl3):
7.20e7.11 (m, 5H), 7.10e6.91 (m, 2H), 6.70e6.48 (m, 3H), 6.24 (dd,
2-(2-chlorophenylamino)-4-phenylbut-3-
4.2.1.14. (E)-Ethyl 2-(4-methoxyphenylamino)-3-methylpent-3-
d
enoate (4n). Yield 0.050 g (38%). 1H NMR: CDCl3, 300 MHz,
J¼15.9, 5.8 Hz, 1H), 5.30 (d, J¼5.8 Hz, 1H), 4.25e4.22 (m, 2H), 3.90
(s, NH), 1.23 (t, J¼7.13 Hz, 3H); 13C NMR (75 MHz, CDCl3): 171.0,
142.3, 136.1, 129.3128.6, 128.6, 127.8, 124.5, 119.8, 118.2, 112.3, 62.6,
58.7, 14.2.
d
(ppm): 6.68 (d, J¼8.9 Hz, 2H), 6.53 (d, J¼8.9 Hz, 2H), 5.04 (tdd,
J¼1.2, 2.6, 8.6 Hz, 1H), 4.57 (d, J¼8.7 Hz, 1H), 4.09 (dq, J¼2.0, 7.1 Hz,
2H), 3.65 (s, 3H), 1.75 (d, J¼1.2 Hz, 3H), 1.68 (s, 3H), 1.15 (t, J¼7.1 Hz,
3H). 13C NMR: CDCl3, 75 MHz,
d (ppm): 172.9, 152.9, 140.2, 138.8,
121.3, 115.4, 114.8, 81.1, 56.9, 55.7, 25.7, 18.7, 14.1. HRMS calcd for
C
Acknowledgements
15H21NO3 (MþHþ): 264.1594; found: 264.1589.
~
The authors gratefully acknowledge the Sao Paulo Research
4.2.1.15. Ethyl 2-(4-methoxyphenylamino)pent-4-enoate
Foundation (FAPESP e fellowship to F.M. 2010/15677-58, grant
2012/00424-2) for financial support and The National Council for
Scientific and Technological Development (CNPq) for a fellowship
(308.320/2010-7 to H.A.S.).
(4o). Yield. 0.066 g (53%). 1H NMR: CDCl3, 300 MHz,
d (ppm):
6.69 (d, J¼9.0 Hz, 2H), 6.58 (d, J¼9.0 Hz, 2H), 5.72 (dt, J¼7.1, 17.3 Hz,
1H), 5.05e5.11 (m, 2H), 4.11 (tt, J¼3.9, 7.7 Hz, 2H), 3.98 (t, J¼6.2 Hz,
1H) 3.67 (s, 3H), 2.52 (t, J¼6.7 Hz, 2H), 1.17 (t, J¼7.1 Hz, 3H). 13C
NMR: CDCl3, 75 MHz, d (ppm): 173.9,153.2,132.8,118.8,115.8,114.9,
61.1, 57.8, 55.7, 37.0, 14.3. HRMS calcd for C14H19NO3 (MþHþ):
Supplementary data
250.1438; found: 250.1431.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.107
4.2.1.16. (E)-Ethyl 2-(4-methoxyphenylamino)hex-4-enoate
(4p). Yield. 0.060 g (46%). 1H NMR: CDCl3, 300 MHz,
d (ppm):
6.68 (d, J¼8.9 Hz, 2H), 6.56 (t, J¼7.4 Hz, 2H), 5.65e5.80 (m, 1H),
5.01e5.10 (m, 2H), 4.036e4.136 (m, 2H), 3.79 (dd, J¼5.8, 16.4 Hz,
1H), 3.65 (s, 3H), 2.63 (td, J¼7.1, 15.2 Hz, 1H), 1.16 (dt, 1H, J¼4.3,
7.1 Hz, 3H), 1.08 (dd, J¼2.2, 6.9 Hz, 3H). 13C NMR: CDCl3, 75 MHz,
References and notes
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ꢀ
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2. Rivera, D. G.; Leon, F.; Concepcion, O.; Morales, F. E.; Wessjohann, L. A. Chem.
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d
(ppm): 173.2,153.0,141.0,139.1,116.3,115.8,115.5,114.9, 62.8, 61.0,
55.7, 41.3, 40.6, 16.4, 14.3. HRMS calcd for C15H21NO3 (MþHþ):
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d 6.77 (d,
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d 172.5, 152.6, 140.6, 135.0, 125.5, 115.1,
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d 6.68
(d, J¼8.9 Hz, 2H), 6.52 (d, J¼8.9 Hz, 2H), 5.83 (d, J¼15.7 Hz, 1H) 5.37
(dd, J¼15.7, 6.2 Hz, 1H), 4.37 (d, J¼6.2 Hz, 1H), 4.13e4.09 (m, 2H),
3.63 (s, 3H), 1.18 (t, J¼7.1 Hz, 3H), 0.92 (s, 3H); 13C NMR (75 MHz,
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