The study of Friedel-Crafts alkylation reaction of thiophenes with glyoxylate imine catalyzed by Fe(III): An easy access to α-aminoesters

Article abstract of DOI:10.1016/j.tet.2011.01.039

A Friedel-Crafts alkylation reaction of thiophenes with glyoxylate imine was developed to give α-aminoesters. In the presence of FeCl ₃·6H₂O as the catalyst, various α-aminoesters were prepared with moderate to high yields (up to 95%

Full text of DOI:10.1016/j.tet.2011.01.039

Tetrahedron 67 (2011) 1788e1791
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The study of FriedeleCrafts alkylation reaction of thiophenes with glyoxylate
imine catalyzed by Fe(III): an easy access to a-aminoesters
,
b,
Zhong Huang a, Jingchang Zhang a , Nai-Xing Wang
*
*
a Institute of Modern Catalysis, Beijing University of Chemical Technology, State Key Laboratory of Chemical Resource Engineering, Beijing 100029, China
b Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100080, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A FriedeleCrafts alkylation reaction of thiophenes with glyoxylate imine was developed to give a-ami-
Received 29 October 2010
Received in revised form 6 January 2011
Accepted 14 January 2011
Available online 20 January 2011
noesters. In the presence of FeCl3$6H2O as the catalyst, various
moderate to high yields (up to 95%) except for some special substrates.
a-aminoesters were prepared with
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a
-Aminoesters
FriedeleCrafts reaction
Thiophenes
Imine
1. Introduction
antihypertensive drugs6j,k etc. These applications severely capture
our interest on the sulfur-containing heterocycles. There have been
several reports involving the reaction of thiophenes with imines,
but they separately studied only one thiophene as a substrate, and
no one of them specially focused on the FriedeleCrafts alkylation
reaction of thiophenes.7 In view of the great utility of sulfur-con-
taining compounds and the inconspicuous achievement of the
FriedeleCrafts alkylation reaction of thiophenes, the exploration of
the FriedeleCrafts alkylation reaction about thiophenes is still
highly desirable.
To the best knowledge of us, there has not been a special report
on the FriedeleCrafts alkylation of thiophenes with imines. This
may be due to the lower activity of thiophene ring than active ar-
omatic compounds, such as indoles and aromatic amines. Herein,
we would like to report our results on the FriedeleCrafts alkylation
of thiophenes with imine. Expected products with good yields for
the majority of the substrates were obtained.
The well-known FriedeleCrafts alkylation reaction is one of the
most fundamental and popular carbonecarbon bond-forming re-
action in organic synthesis.1 As one type of the FriedeleCrafts al-
kylation reaction, the addition of electron-rich aromatic
compounds to imines can be a very facile synthetic method to
produce nitrogen-containing compounds.2 However, the reaction
of aromatic compounds as nucleophiles with imines has been far
less studied than ketones, aldehydes, and esters etc., which contain
an active
a
hydrogen.3 And thus, the FriedeleCrafts alkylation re-
action of aromatic compounds with imines needs to be further
investigated. Recently, there have been some reports about the
FriedeleCrafts alkylation reaction of aromatic compounds with
imines, and most of these studies employed the active aromatic
compounds, such as indoles2 or aromatic amines.2a
Sulfur-containing heterocycles have diverse applications in the
areas of materials science,4 agrochemicals,5 and pharmaceuticals6
due to their unique chemical and biological properties. These
widely used drugs include the famous penicillin6a,b and cefalotin
sodium6c,d as antibiotic, prasugrel6e and clopidogrel6f as anti-
platelet drugs, raloxifene hydrochloride as a second generation
drug for osteoporosis in postmenopausal women,6g,h aminopepti-
dase N (APN) as an efficient anticancer drug,6i eprosartan as
2. Results and discussion
We initiated the study from the reaction of 2-ethylthiophene (1a)
with imines prepared from aromatic aldehyde, such as benzalde-
hyde, p-nitrobenzaldehyde, p-methoxybenzaldhyde, 2,4-dichlor-
obenzaldehyde with anisidine, but after our best efforts, no target
compound was obtained. To overcome this problem, we envisioned
that since 2-ethylthiophene (1a) is not active enough, it is necessary
to use imines that are much reactive than those aromatic imines.
On the basis of this fact, we chose glyoxylate imine (2) as the
* Corresponding authors. Tel./fax: þ86 10 64434904; e-mail address: zhangjc1@
mail.buct.edu.cn (J. Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.039

Z. Huang et al. / Tetrahedron 67 (2011) 1788e1791
1789
electrophile, which was prepared by the reaction of ethyl glyoxylate
with anisidine under ultrasound, and obtained the target product.
Therefore, the reaction of thiophenes with glyoxylate imine (2) can
CH3NO2 can improve the acidity of Lewis acid.2a,8 When the re-
action was carried out in THF and toluene, the yields were not so
high as in CH3NO2 in much longer reaction times (entries 10, 11, and
14). Moreover, when the reaction was carried out in some more
provide an easy access to a-aminoester, which can be a precursor for
the amino acid. During this preliminary exploration, we found that
the prepared glyoxylate imine (2) is so active that it is very easy to
deteriorate. And thus, we stored it in toluene with the concentration
of 1 mol/L at 0 ꢀC.
At the beginning of the selected reaction system, we in-
vestigated the reaction of 2-ethylthiophene (1a) with the imine (2)
by using the moderately acidic SnCl2 as catalyst in CH2Cl2. To our
delight, after the completion of the reaction for 48 h, we obtained
polar solvents, such as EtOH and ionic liquid, the target a-amino-
ester was not obtained (entries 12 and 13). Finally, we examined the
mole ratio of 2-ethylthiophene (1a) to the glyoxylate imine (2).
When the ratio was changed to be 1:2, the yield decreased to 50%.
With the established optimal reaction condition, we then studied
the substrate scope of thiophenes, and the results are summarized in
Table 2. With different properties of thiophenes (1aen),9 each thio-
phene performed different reactivity, leading to various results
in the yield. On the whole, the majority of thiophenes reacted
smoothly with the glyoxylate imine (2), producing the isolated cor-
the target compound, which was a a-aminoester (3a). Encouraged
by this result, we examined the reaction of 2-ethylthiophene (1a)
with imine (2) as the model reaction. Several Lewis acids and sol-
vents were screened, and the results are summarized in Table 1. Of
these Lewis acids used, FeCl3$6H2O was revealed to be the most
promising catalyst, 20 mol % of which afforded the desired Frie-
deleCrafts product in 56% yield in CH2Cl2 (entry 4). When we
changed the Lewis acid to SnCl2, Mg(ClO4)2, and CuBr, the yields
were much lower even in a much longer reaction time (entries
1e3). The lower catalytic activity of SnCl2, Mg(ClO4)2, and CuBr is
attributed to their relatively weak Lewis acidity, which is essential
for the FriedeleCrafts reaction. Then, we changed the Lewis acid to
Ni salt with the similar nature of Fe salt, but unexpectedly, no target
product (3a) was found in 48 h (entry 5). This may be attributed to
that CH3COOꢁ with a strong coordination effect prevents Ni(II)
coordinating with the substrate, resulting in that Ni(II) did not
participate in the reaction. Considering the influence of Lewis
acidity, we used BF3$Et2O and AlCl3 with a stronger acidity, finding
that the reactions quickly finished in 6 h (entries 6e7), but the
yields were much lower and many by-products were detected by
responding
2-methoxythiophene (1c) is too active, and the reaction finished very
quickly, but we failed in isolating the target -aminoester from nu-
merous by-products (entry 3). On the contrary, 3-bromothiophene
(1n) with an electron-withdrawing group (eBr) did not have enough
nucleophilic ability, so the reaction of 1n did not give the corre-
a-aminoester. With an electron-donating group (MeOe),
a
sponding
to 144 h (entry 14). Although thiophene (1i) without any substituent
could react with amine (2) to give the corresponding -aminoester
a-aminoester when the reaction time was even prolonged
a
(3i), the relatively low nucleophilic ability resulted in a yield less than
10%. In addition to the electric effect, the steric effect of substituent
also plays a very important role for the yield. Reactions of thiophenes
(1eeh, m) with bulky substituents only gave low to moderate yields
even in a very prolonged reaction time, while reactions of thiophenes
(1a,b, d, jel) with small substituents could finish in a relatively short
time, giving high yields. Additionally, we found that for 3-substituted
thiophenes, their nucleophilic reaction with the imine (2) cannot
proceed at 5-positions. The reason is that the charge density at
5-position is less than 2-position.
ꢀ
TLC. Subsequently, we added some 4 A molecular sieves to the Fe
(III)-catalyzed reaction, but the yield had a slightly decrease in the
same reaction time (entry 8).
Enlightened by previous proposed mechanism about the reaction
of indole with ethyl glyoxylate,10 we envisioned the catalytic cycle of
Table 1
Optimization of the FriedeleCrafts alkylation reaction of 1a with 2a
Table 2
Substrate scope of the FriedeleCrafts reaction of thiophenes 1aen with glyoxylate
20% Lewis acid
MeO
N
imine 2 catalyzed by Fe(III)a
H
N
+
OMe
COOEt
r.t., Solvent
S
S
R2
R2
COOEt
3a
H
N
1a
2
20% FeCl3¡6H2O
R1
MeO
N
OMe
+
COOEt
r.t., CH3NO2
R1
S
S
1a-n
COOEt
3
2
Entry
Solvent
Lewis acid
Time [h]
Yieldb [%]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
THF
Toluene
EtOH
Ionic liquid
CH3NO2
CH3NO2
SnCl2
Mg(ClO4)2
CuBr
FeCl3$6H2O
(CH3COO)2Ni
BF3$Et2O
48
48
48
15
48
6
16
Entry
R1e
R2e
Time [h]
Yieldb [%]
<10
<10
56
Trace
31
28
50
50
31
1
2
3
4
5
Ete
He
He
He
He
He
15
20
5
24
48
3a; 82
3b; 95
3c; d
3d; 93
3e; 20
Mee
MeOe
Phe
Cl
AlCl3
6
Cl
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
24
15
24
30
48
30
15
24
9c
10
11
12
13d
14
15e
6
7
He
He
24
24
3f; 58
3g; 56
49
Trace
Trace
82
MeO
Ph
50
8
He
24
3h; <10
a
Et
All reactions were performed with Lewis acid (0.02 mmol), 2-ethylthiophene 1a
(0.2 mmol), and imine gloxylate 2 (0.1 mmol) in 0.5 mL of solvent at room tem-
perature detected by TLC unless otherwise stated.
9
He
He
He
He
He
He
He
120
7
4
24
48
144
3i; <10
3j; 95
3k; 87
3l; 75
3m; 30
3n; d
b
10
11
12
13
14
MeOe
EtOe
Mee
Isolated yield 3a after flash chromatography.
c
ꢀ
4 A Molecular sieves (25 mg) were added.
d
The ionic liquid was [EtPy]þBrꢁ.
e
C10H
21e
The mol ratio of 1a and 2 was 1:2.
Bre
With FeCl3$6H2O as the selected catalyst, we screened the effect
of solvents to identify the best reaction conditions (Table 1, entries
4 and 10e14). Among the various organic solvents tested, CH3NO2
was much superior to other solvents (up to 82%). This is because
a
All reactions were performed with FeCl3$6H2O (0.02 mmol), thiophene
1
(0.2 mmol), and imine gloxylate 2 (0.1 mmol) in 0.5 mL of CH3NO2 at room tem-
perature detected by TLC.
b
Isolated yield 3 after flash chromatography.

1790
Z. Huang et al. / Tetrahedron 67 (2011) 1788e1791
the FriedeleCrafts reaction of 2-ethylthiophene (1a) with imine (2)
catalyzed by Fe(III) as shown in Scheme 1. We found that the catalyst
FeCl3$6H2O was very soluble in CH3NO2, so we labeled the catalyst as
2 equiv), and imine gloxylate 2 (0.1 mmol) in toluene (1 mol/L)
were added. The mixture was stirred at room temperature until
the imine gloxylate disappeared (by TLC). After removal of CH3NO2
under vacuum, the mixture was filtrated through a short pad of
basic aluminum oxide eluting with petroleum ethereethyl
acetate¼5:1 to remove the catalyst. After the removal of petro-
leum ether and ethyl acetate under vacuum, the target product 3
was isolated by a flash column chromatography using basic alu-
minum oxide as adsorbent and petroleum ethereethyl
acetate¼15:1 as eluant.
*
Fe for short. At the firststep, imine(2)combineswith Fe through the
*
coordination effect to give an organic ion (4), strengthening the
electrophilic abiltity of C]N, which is then more easily attacked by
2-ethylthiophene (1a) to produce a transition state (5). Consequently,
*
Fe leaves from the transition state to combine with imine (2) again,
giving out the target
a-aminoester (3a).
*Fe
4.3. Analytical data for compounds 3aen
EtO
N
OMe
4.3.1. Ethyl (4-methoxyphenylamino)(5-ethylthiophen-2-yl)acetate
(3a). Following the general procedure to yield the title compound
as a brown oil (82%); 1H NMR (400 MHz, CDCl3): 6.93 (d, J¼3.5 Hz,
1H), 6.77 (d, J¼8.9 Hz, 2H), 6.66e6.63 (m, 3H), 5.20 (s, 1H), 4.59 (s,
1H), 4.31e4.17 (m, 2H), 3.73 (s, 3H), 2.80 (q, J¼7.5 Hz, 2H), 1.31e1.26
(m, 6H); 13C NMR (400 MHz, CDCl3): 171.4, 152.9, 147.7. 140.2, 138.3,
125.3, 123.2, 115.2, 114.9, 62.0, 58.1, 55.7, 23.6, 15.8, 14.2; IR (KBr,
cmꢁ1): 3358, 3062, 2955, 2924, 2853, 1730, 1512, 1459, 1372, 1233,
1019, 807, 756; HRMS (EI): m/z calculated for C17H21NO3S: 319.1242,
found: 319.1218.
O
OMe
4
S
1a
N
EtO
O
2
*Fe
EtO
N
OMe
H
O
*Fe
S
4.3.2. Ethyl (4-methoxyphenylamino)(5-methylthiophen-2-yl)acetate
(3b). Following the general procedure to yield the title compound as
a brown oil (95%); 1H NMR (400 MHz, CDCl3): 6.90 (d, J¼3.4 Hz, 1H),
6.76 (d, J¼8.9 Hz, 2H), 6.63e6.61 (m, 3H), 5.16 (s, 1H), 4.58 (s, 1H),
4.26e4.18 (m, 2H), 3.73 (s, 3H), 2.43 (s, 3H), 1.27 (t, J¼7.1 Hz, 3H); 13C
NMR (400 MHz, CDCl3): 171.4, 153.0, 140.2, 140.1, 138.9, 125.6, 125.2,
115.3,114.9,62.1,58.1, 55.8,15.5,14.2;IR(KBr, cmꢁ1):3385, 3063, 2956,
2924, 2838, 1736, 1604, 1513, 1466, 1300, 1237, 1188, 1033, 817, 761.
5
NH
OMe
S
COOEt
3a
Scheme 1. Proposed catalytic cycle.
4.3.3. Ethyl (4-methoxyphenylamino)(5-phenylthiophen-2-yl)acetate
(3d). Following the general procedure to yield the title compound
as a brown oil (93%); 1H NMR (400 MHz, CDCl3): 7.56 (d, J¼7.4 Hz,
2H), 7.35 (t, J¼7.6 Hz, 2H), 7.28e7.25 (m, 1H), 7.18 (d, J¼3.7 Hz, 1H),
7.10 (d, J¼3.7 Hz, 1H), 6.77 (d, J¼8.9 Hz, 2H), 6.66 (d, J¼8.9 Hz, 2H),
5.24 (d, J¼5.5 Hz, 1H), 4.68 (d, J¼5.3 Hz, 1H), 4.33e4.20 (m, 2H),
3.73 (s, 3H), 1.29 (t, J¼7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3): 171.1,
153.1, 144.4, 141.1, 140.1, 134.3, 129.0, 127.7, 126.6, 125.8, 123.0, 115.4,
115.0, 62.3, 58.3, 55.8, 14.2; IR (KBr, cmꢁ1): 3379, 3058, 3024, 2953,
2916, 2847, 1728, 1599, 1512, 1451, 1300, 1242, 1185, 1029, 818, 753,
694; HRMS (EI): m/z calculated for C21H21NO3S: 367.1242, found:
367.1086.
3. Summary
In summary, we developed here the FriedeleCrafts alkylation
reaction of thiophenes with imine using FeCl3$6H2O as the catalyst
in CH3NO2. For this investigation, we chose more active glyoxylate
imine instead of aromatic amine to realize the FriedeleCrafts re-
action of wide thiophenes with glyoxylate imine. The method was
proved to be efficient for the majority of thiophenes to give target
a
-aminoesters, which are precursors for amino acids. Furthermore,
some reactions allow the desired -aminoesters to be isolated in
good yield (up to 95%). Further investigations into an asymmetric
version of the developed reaction are in progress.
a
4.3.4. Ethyl (4-methoxyphenylamino)(5-(2,4-dichlorobenzyl)thio-
phen-2-yl)acetate (3e). Following the general procedure to yield the
title compound as a brown oil (20%); 1H NMR (400 MHz, CDCl3): 7.38
(d, J¼1.9 Hz, 1H), 7.17 (d, J¼2.0 Hz, 1H), 7.15 (s, 1H), 6.93 (d, J¼3.4 Hz,
1H), 6.75 (d, J¼8.9 Hz, 2H), 6.66 (d, J¼3.5 Hz, 1H), 6.61 (d, J¼8.9 Hz,
2H), 5.16 (s, 1H), 4.54 (s, 1H), 4.27e4.18 (m, 2H), 4.15 (s, 2H), 3.73 (s,
3H), 1.25 (t, J¼7.1 Hz, 3H); IR (KBr, cmꢁ1): 3441, 3114, 2953, 2923,
2853, 1735, 1512, 1463, 1261, 1025, 740, 670, 649, 578.
4. Experimental
4.1. General information
All solvents before use were dried and degassed by standard
methods. All reactions were monitored by TLC with silica gel-coated
plates. IR spectra were recorded on an Excalibur 3100 (Varian) spec-
trophotometer using KBr optics. NMR spectra were recorded with
a Bruker spectrometer at 400 MHz using TMS as an internal standard.
Coupling constants (J) are reported in Hertz and refer to apparent peak
multiplications. Mass spectra were recorded on a Bruker Microflex
mass spectrometer. Thiophenes 1aed,1ien are commercial available,
and thiophenes 1eeh were prepared according to literature.9
4.3.5. Ethyl (4-methoxyphenylamino)(5-benzylthiophen-2-yl)acetate
(3f). Following the general procedure to yield the title compound
as a brown oil (58%); 1H NMR (400 MHz, CDCl3): 7.32e7.28 (m, 2H),
7.24e7.22 (m, 3H), 6.92 (d, J¼3.5 Hz,1H), 6.75 (d, J¼8.9 Hz, 2H), 6.63
(d, J¼3.6 Hz, 1H), 6.61 (d, J¼8.9 Hz, 2H), 5.16 (s, 1H), 4.54 (s, 1H),
4.27e4.17 (m, 2H), 4.08 (s, 2H), 3.73 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H); IR
(KBr, cmꢁ1): 3361, 3061, 3029, 2955, 2923, 2853, 1730, 1511, 1459,
1293, 1235, 1179, 1018, 815, 693.
4.2. General procedure for synthesis of a-aminoesters
In
a
closed round-bottom flask with 0.5 mL of CH3NO2,
(0.2 mmol,
4.3.6. Ethyl (4-methoxyphenylamino)(5-(4-methoxybenzyl)thiophen-
2-yl)acetate (3g). Following the general procedure to yield the
FeCl3$6H2O (0.02 mmol, 0.2 equiv), thiophene
1

Z. Huang et al. / Tetrahedron 67 (2011) 1788e1791
1791
title compound as a brown oil (56%); 1H NMR (400 MHz,
CDCl3): 7.14 (d, J¼8.7 Hz, 2H), 6.91 (d, J¼3.5 Hz, 1H), 6.84 (d,
J¼8.7 Hz, 2H), 6.75 (d, J¼8.9 Hz, 2H), 6.62e6.59 (m, 3H), 5.15 (s,
1H), 4.51 (s, 1H), 4.28e4.15 (m, 2H), 4.01 (s, 2H), 3.79 (s, 3H),
3.73 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H); IR (KBr, cmꢁ1): 3395, 3115,
2952, 2923, 2852, 1733, 1613, 1512, 1458, 1241, 1179, 1025, 816,
732.
J¼6.8 Hz, 3H); IR (KBr, cmꢁ1): 3410, 3108, 3057, 2924, 2855, 1735,
1620, 1513, 1461, 1287, 1240, 1187, 1031, 816, 731.
Acknowledgements
Support for this research was provided by the Natural Science
Foundation of China (20472090 and 10576034), and the National
973 Program (No. 2010CB732202).
4.3.7. Ethyl (4-methoxyphenylamino)(5-(1-phenylpropyl)thiophen-2-
yl)acetate (3h). Following the general procedure to yield the title
compound as a brown oil (<10%); 1H NMR (400 MHz, CDCl3):
7.31e7.27 (m, 2H), 7.26e7.17 (m, 3H), 6.89 (d, J¼3.4 Hz, 1H), 6.75
(d, J¼8.9 Hz, 2H), 6.66e6.63 (m, 1H), 6.61 (d, J¼8.9 Hz, 2H), 5.14
(d, J¼5.3 Hz, 1H), 4.49 (d, J¼6.9 Hz, 1H), 4.29e4.11 (m, 2H), 3.92
(t, J¼7.7 Hz, 1H), 3.73 (s, 3H), 2.13e1.96 (m, 2H), 1.23 (t,
J¼7.1 Hz, 3H), 0.88 (t, J¼7.3 Hz, 3H); IR (KBr, cmꢁ1): 3385, 3062,
3025, 2953, 2924, 2854, 1735, 1512, 1458, 1241, 1183, 910, 819,
734.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.01.039. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
References and notes
1. (a) Roberts, R. M.; Khalaf, A. A. FriedeleCrafts Alkylation Chemistry. A Century of
Discovery; Marcel Dekker: New York, NY, 1984; (b) Smith, M. B. Organic Syn-
thesis; McGraw-Hill: New York, NY, 1994; p 1313; (c) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550.
2. (a) Soueidan, M.; Collin, J.; Gil, R. Tetrahedron Lett. 2006, 47, 5467; (b) Zhao, J.-L.;
Liu, L.; Zhang, H.-B.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synlett 2006, 96.
3. (a) Kano, T.; Yamamoto, A.; Maruoka, K. Tetrahedron Lett. 2008, 49, 5369; (b)
Wang, W.; Wang, J.; Li, H. Tetrahedron Lett. 2004, 45, 7243; (c) Cobb, A. J. A.; Shaw,
D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84; (d)
Odedra, A.; Seeberger, P. H. Angew. Chem., Int. Ed. 2009, 48, 2699; (e) Mauksch, M.;
Tsogoeva, S. B.; Martynova, I. M.; Wei, S. Angew. Chem., Int. Ed. 2007, 46, 393; (f)
Zhang, H.; Chuan, Y.; Li, Z.; Penga, Y. Adv. Synth. Catal. 2009, 351, 2288; (g) Zhang,
H.; Mitsumori, S.; Utsumi, N.; Imai, M.; Garcia-Delgado, N.; Mifsud, M.; Al-
bertshofer, K.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc.
2008, 130, 875; (h) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F. J. Am. Chem. Soc.
2006,128, 9630; (i) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka,
F.; Barbas, C. F. J. Am. Chem. Soc. 2006,128,1040; (j) Alza, E.; Rodríguez-Escrich, C.;
4.3.8. Ethyl (4-methoxyphenylamino)(thiophen-2-yl)acetate (3i).
Following the general procedure to yield the title compound as
a brown oil (<10%); 1H NMR (400 MHz, CDCl3): 7.24 (dd, J¼5.1,
1.1 Hz, 1H), 7.13 (d, J¼3.5 Hz, 1H), 6.98 (dd, J¼5.0, 3.6 Hz, 1H), 6.76
(d, J¼8.9 Hz, 2H), 6.62 (d, J¼8.9 Hz, 2H), 5.26 (s, 1H), 4.64 (s, 1H),
4.29e4.18 (m, 2H), 3.73 (s, 3H), 1.26 (t, J¼7.1 Hz, 3H); IR (KBr, cmꢁ1):
3361, 3111, 3054, 2924, 2853, 1738, 1512, 1457, 1373, 1251, 1156, 852,
740, 703.
4.3.9. Ethyl (4-methoxyphenylamino)(3-methoxythiophen-2-yl)acetate
(3j). Following the general procedure to yield the title compound as
a brown oil (95%); 1H NMR (400 MHz, CDCl3): 7.13 (d, J¼5.5 Hz, 1H),
6.82 (d, J¼5.5 Hz, 1H), 6.74 (d, J¼8.9 Hz, 2H), 6.64 (d, J¼8.9 Hz, 2H),
5.37 (s, 1H), 4.54 (s, 1H), 4.30e4.12 (m, 2H), 3.90 (s, 3H), 3.72 (s, 3H),
1.23 (t, J¼7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3): 171.7, 155.7, 153.0,
140.2, 123.7, 118.0, 116.5, 115.4, 114.9, 61.9, 59.2, 55.8, 54.2, 14.2; IR
(KBr, cmꢁ1): 3388, 3106, 2925, 2851, 1729, 1552, 1512, 1460, 1382,
1236, 1190, 1025, 911, 818, 731; HRMS (EI): m/z calculated for
C16H19NO4S: 321.1035, found: 321.1013.
ꢁ
Sayalero, S.; Bastero, A.; Pericas, M. A. Chem.dEur. J. 2009, 15, 10167; (k) Kano, T.;
Yamaguchi, Y.; Maruoka, K. Chem.dEur. J. 2009,15, 6678; (l) Utsumi, N.; Zhang, H.;
Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2007, 46, 1878; (m) Knudsen, K. R.;
Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,1362; (n) Kobayashi, S.; Gustafsson, T.;
Shimizu, Y.; Kiyohara, H.; Matsubara, R. Org. Lett. 2006, 8, 4923; (o) Rueping, M.;
Antonchick, A. P. Org. Lett. 2008, 10, 1731; (p) Nishiwaki, N.; Knudsen, K. R.;
Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992; (q) Basra, S.;
Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 2659.
4. (a) McCullough, R. D. Adv. Mater.1998,10, 93; (b) Sebastian, M.; Hissler, M.; Fave, C.;
Rault-Berthelot, J.; Odin, C.; Reau, R. Angew. Chem., Int. Ed. 2006, 45, 6152; (c) Han,
ꢂ
Z.; Zhang, J.; Yang, X.; Zhu, H.; Cao, W. Sol. Energy Mater. Sol. Cells 2010, 94, 755.
5. (a) Hwang, I. T.; Kim, H. R.; Jeon, D. J.; Hong, K. S.; Song, J. H.; Cho, K. Y. J. Agric.
Food Chem. 2005, 53, 8639; (b) Fokialakis, N.; Cantrell, C. L.; Duke, S. O.;
Skaltsounis, A. L.; Wedge, D. E. J. Agric. Food Chem. 2006, 54, 1651.
4.3.10. Ethyl (4-methoxyphenylamino)(3-ethoxythiophen-2-yl)acetate
(3k). Following the general procedure to yield the title compound as
a brown oil (87%); 1H NMR (400 MHz, CDCl3): 7.11 (d, J¼5.5 Hz, 1H),
6.78 (d, J¼5.5 Hz, 1H), 6.74 (d, J¼9.0 Hz, 2H), 6.65 (d, J¼9.0 Hz, 2H),
5.38 (s, 1H), 4.55 (s, 1H), 4.28e4.14 (m, 2H), 4.12 (q, J¼7.0 Hz, 2H),
3.72 (s, 3H), 1.41 (t, J¼7.0 Hz, 3H), 1.23 (t, J¼7.1 Hz, 3H); IR (KBr,
cmꢁ1): 3383, 3116, 3052, 2980, 2921, 2849, 1728, 1550, 1513, 1451,
1379, 1233, 1188, 909, 817, 733.
6. (a) Sheehan, J. C.; Henery-Logan, K. R. J. Am. Chem. Soc.1957, 79,1262; (b) Sheehan,
J. C.; Henery-Logan, K. R. J. Am. Chem. Soc.1959, 81, 3089; (c) Friedman, M. J. Agric.
Food Chem. 2004, 52, 385; (d) Turner, K. Org. Process Res. Dev. 2010, 14, 311; (e)
Farid, N. A.; Smith, R. L.; Gillespie, T. A.; Rash, T. J.; Blair, P. E.; Kurihara, A.;
Goldberg, M. J. Drug Metab. Dispos. 2007, 35,1096; (f) Pereillo, J.-M.; Maftouh, M.;
Andrieu, A.; Uzabiaga, M.-F.; Fedeli, O.; Savi, P.; Pascal, M.; Herbert, J.-M.; Maf-
frand, J.-P.; Picard, C. Drug Metab. Dispos. 2002, 30, 1288; (g) Dalvie, D.; Kang, P.;
Zientek, M.; Xiang, C.; Zhou, S.; Obach, R. S. Chem. Res. Toxicol. 2008, 21, 2260; (h)
Dalvie, D.; Obach, R. S.; Kang, P.; Prakash, C.; Loi, C.-M.; Hurst, S.; Nedderman, A.;
Goulet, L.; Smith, E.; Bu, H.-Z.; Smith, D. A. Chem. Res. Toxicol. 2009, 22, 357; (i) Tu,
G. G.; Li, S. H.; Huang, H. M.; Li, G.; Xiong, F.; Mai, X.; Zhu, H. W.; Kuang, B. H.; Xu,
W. F. Bioorg. Med. Chem. 2008, 16, 6663; (j) Vase, H.; Lauridsen, T. G.; Bech, J. N.;
Pedersen, E. B. Br. J. Clin. Pharmacol. 2008, 65, 822; (k) Betz, S. F.; Zhu, Y.-F.; Chen,
C.; Struthers, R. S. J. Med. Chem. 2008, 51, 3331.
7. (a) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858; (b)
Andreassen, T.; Hansen, L.-K.; Gautun, O. R. Eur. J. Org. Chem. 2008, 4871; (c)
Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930; (d) Sakai, N.; Asano, J.; Shimano, Y.;
Konakahara, T. Tetrahedron 2008, 64, 9208; (e) Saaby, S.; Bayon, P.; Aburel, P. S.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352; (f) Esquivias, J.; Array, R. G.; Car-
retero, J. C. Angew. Chem., Int. Ed. 2006, 45, 629.
4.3.11. Ethyl (4-methoxyphenylamino)(3-methylthiophen-2-yl)acetate
(3l). Following the general procedure to yield the title compound
as a brown oil (75%); 1H NMR (400 MHz, CDCl3): 7.14 (d, J¼5.1 Hz,
1H), 6.82 (d, J¼5.1 Hz, 1H), 6.74 (d, J¼8.9 Hz, 2H), 6.56 (d,
J¼8.9 Hz, 2H), 5.22 (s, 1H), 4.67 (s, 1H), 4.30e4.12 (m, 2H), 3.72 (s,
3H), 2.36 (s, 3H), 1.24 (t, J¼7.2 Hz, 3H); IR (KBr, cmꢁ1): 3386, 3104,
3060, 2953, 2923, 2850, 1728, 1612, 1511, 1450, 1371, 1233, 1177,
1018, 819, 708.
8. (a) Kawada, A.; Mitamura, S.; Kobayashi, S. Chem. Commun. 1996, 183; (b) Ko-
bayashi, S.; Komoto, I. Tetrahedron 2000, 56, 6463.
9. For the preparation of 1eeh, please see: (a) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033; (b) Iovel, I.; Mertins, K.; Ki-
schel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913.
10. (a) Dong, H.-M.; Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J. Adv. Synth. Catal.
2007, 349, 1597; (b) Huang, Z.; Zhang, J. C.; Zhou, Y. Q.; Wang N.-X. Eur. J. Org.
Chem. doi: 10.1002/ejoc.201001455.
4.3.12. Ethyl (4-methoxyphenylamino)(3-decylthiophen-2-yl)acetate
(3m). Following the general procedure to yield the title compound
as a brown oil (30%); 1H NMR (400 MHz, CDCl3): 7.15 (d, J¼5.2 Hz,
1H), 6.86 (d, J¼5.2 Hz, 1H), 6.74 (d, J¼8.8 Hz, 2H), 6.57 (d, J¼8.9 Hz,
2H), 5.25 (s, 1H), 4.58 (s, 1H), 4.29e4.17 (m, 2H), 3.72 (s, 3H),
2.78e2.63 (m, 2H), 1.69e1.59 (m, 2H), 1.30e1.20 (m, 17H), 0.88 (t,