Oxidative coupling of indoles with ethyl 2-(disubstituted amino)acetates: An approach to achieve indolylglycine derivatives

Article abstract of DOI:10.1021/jo301035h

An efficient method for the synthesis of indolylglycine derivatives is described. The oxidative coupling reactions of ethyl 2-(disubstituted amino)acetates with indoles proceeded smoothly in the presence of meta-chloroperoxybenzoic acid (mCPBA) under ambi

Full text of DOI:10.1021/jo301035h

Note
pubs.acs.org/joc
Oxidative Coupling of Indoles with Ethyl 2‑(Disubstituted
Amino)Acetates: An Approach to Achieve Indolylglycine Derivatives
Zhanwei Xu, Xiaoqiang Yu,* Xiujuan Feng, and Ming Bao*
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
S
* Supporting Information
ABSTRACT: An efficient method for the synthesis of
indolylglycine derivatives is described. The oxidative coupling
reactions of ethyl 2-(disubstituted amino)acetates with indoles
proceeded smoothly in the presence of meta-chloroperox-
ybenzoic acid (mCPBA) under ambient conditions to produce
indolylglycine derivatives in satisfactory to excellent yields.
he development of convenient and efficient methods for
optimization included selecting the most suitable solvents and
Tthe synthesis of indolylglycine derivatives has attracted proportions of substrates as well as oxidant mCPBA under
ambient conditions for 24 h (Table 1). Different solvents
considerable attention. Indolylglycine derivatives are important
synthetic intermediates or building blocks for drug develop-
ment1 and natural product synthesis.2 Over the past three
decades, many methods have been developed for the
preparation of indolylglycine derivatives.3 Among them, the
direct coupling of indoles with imines4 or iminium ions5
generated in situ through Mannich-type Friedel−Crafts
reaction appears more useful in the indolylglycine derivative
synthesis (Scheme 1, eqs 1 and 2). However, these reactions
need to use unstable alkyl glyoxylate as a starting material or
require suitable leaving groups and Lewis acid catalysts.
a
Table 1. Reaction Condition Screening
b
entry
2a (equiv)
mCPBA (equiv)
solvent
yield (%)
1
1.2
1.2
1.2
1.2
1.2
1.2
1.1
1.1
1.5
1.6
2.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2
1.5
2.0
CH2Cl2
THF
66
23
2
3
toluene
DMF
trace
27
Scheme 1. Indolylglycine Derivative Synthesis via Mannich-
type Friedel−Crafts Reaction
4
5
EtOH
22
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
77
7
74
8
70
9
84
10
11
89
90
a
Reaction conditions: N-benzylindole (1a, 0.25 mmol, 51.8 mg), ethyl
2-morpholinoacetate (2a, 1.1−2.2 equiv), and mCPBA (1.1−2.0
equiv) in CH3CN (2.0 mL) under ambient conditions for 24 h.
b
Isolated yield.
including CH2Cl2, THF, toluene, DMF, EtOH, and CH3CN
were initially tested using 1.2 equiv of 2a and 1.1 equiv of
mCPBA (entries 1−6). CH3CN proved to be the best solvent
(entry 6). The proportions of substrates and oxidant mCPBA
were then screened using CH3CN as the solvent (entries 6−
11). To facilitate the complete transformation of the indole
substrate 1a to product, slight excesses of 2a and mCPBA were
used. The results indicated that the yield of product 3a was
increased by 2a to a slightly greater extent than mCPBA.
In the course of the continuous research of our group on new
strategies for the direct functionalization of sp3 C−H bonds
adjacent to a nitrogen atom via tertiary amine N-oxide
intermediates,6 the oxidative coupling of ethyl 2-(disubstituted
amino)acetates with indoles has been found to proceed in the
presence of meta-chloroperoxybenzoic acid (mCPBA) under
metal-free conditions to provide indolylglycine derivatives in
satisfactory to excellent yields (Scheme 1, eq 3). The results are
reported in the current work.
In our initial studies, the reaction of N-benzylindole (1a)
with ethyl 2-morpholinoacetate (2a) was chosen as a model
reaction for optimizing the reaction conditions. The
Received: May 25, 2012
Published: July 31, 2012
© 2012 American Chemical Society
7114
dx.doi.org/10.1021/jo301035h | J. Org. Chem. 2012, 77, 7114−7118

The Journal of Organic Chemistry
Note
Finally, the yield of product 3a was improved to 89% when 1.6
equiv of 2a and 1.5 equiv of mCPBA were employed (entry
10). However, the yield of 3a could not be further considerably
improved with increased amounts of 2a and mCPBA to 2.2 and
2.0 equiv, respectively (90%, entry 11). Therefore, the
subsequent reactions of indoles with ethyl 2-(disunstituted
amino)acetates were performed in the presence of mCPBA (1.5
equiv) as an oxidant in CH3CN under ambient conditions for
24 h.
The tertiary amine substrate 2a was used as a starting
material to determine the scope of indole substrates under the
optimized reaction conditions. The results are shown in Table
2. The reactions of indoles 1a−1e with various N-protecting
also be involved in this type of oxidative coupling reaction.
Products 3j−3o were obtained in good to excellent yields
(entries 10−15, 85−93%). Similar to the reaction of bromine-
substituted N-Me indole 1i described above, the reaction of
bromine-substituted free (NH)-indole 1n required a long
reaction time (36 h) to complete. Finally, the reactions of 1-
methyl-1H-pyrrolo[2,3-b]pyridine (1p) was examined to
expand further the substrate scope. The reaction of 1p with
2a was completed within 36 h to afford coupling product 3p in
78% yield (entry 16).
The reactions of the indole substrates 1a, 1e, and 1j with the
ethyl 2-(disubstituted amino)acetates 2b−2d were then
examined to explore the scope of amine substrates, and the
results are shown in Table 3. As expected, the reactions of the
Table 2. Oxidative Coupling of various Indole Derivatives
with Ethyl 2-Morpholinoacetate
a
Table 3. Oxidative Coupling of Indole Derivatives with Ethyl
2-(Disubstituted amino)acetates
a
b
entry
indole 1
product 3
yield (%)
1
1a, R1 = H, R2 = Bn
1b, R1 = H, R2 = allyl
3a
3b
3c
3d
3e
3f
89
86
87
93
91
85
87
87
2
n
3
1c, R1 = H, R2 = Bu
n
4
1d, R1 = H, R2 = Hep
5
1e, R1 = H, R2 = Me
1f, R1 = 5-OMe, R2 = Me
1g, R1 = 7-Me, R2 = Me
1h, R1 = 5-Me, R2 = Me
1i, R1 = 5-Br, R2 = Me
1j, R1 = H, R2 = H
6
7
3g
3h
3i
8
c
9
76
10
11
12
13
14
15
16
3j
89
91
93
87
1k, R1 = 5-OMe, R2 = H
1l, R1 = 7-Me, R2 = H
1m, R1 = 5-Me, R2 = H
1n, R1 = 5-Br, R2 = H
1o, R1 = 2-Me, R2 = H
1p, R1 = H, R2 = Me
3k
3l
3m
3n
3o
3p
c
85
86
c
a
78
Reaction conditions: indole (0.25 mmol), ethyl 2-(disubstituted
a
amino)acetate (0.4 mmol), and mCPBA (0.38 mmol, 76.0 mg, 85%
Reaction conditions: indole (0.25 mmol), ethyl 2-morpholinoacetat
purity) in CH3CN (2.0 mL) under ambient conditions for 24 h.
(0.4 mmol, 69.3 mg), and mCPBA (0.38 mmol, 76.0 mg, 85% purity)
in CH3CN (2.0 mL) under ambient conditions for 24 h. Isolated
yield. The reaction was performed for 36 h.
b
b
Isolated yield.
c
indole substrates 1a, 1e, and 1j with ethyl 2-(piperidin-1-
yl)acetate (2b) proceeded smoothly to give corresponding
coupling products 3q−3s in good to excellent yields (entries
1−3, 76−90%). When the indole substrates 1a and 1e were
treated with ethyl 2-(benzyl(methyl)amino)acetate (2c), a
noncyclic amine derivative, coupling products 3t and 3u were
obtained in moderate yields (entries 4 and 5, 51 and 65%,
respectively). Coupling product 3v was isolated in 87% yield
from the reaction of 1j with ethyl 2-(4-tosylpiperazin-1-
yl)acetate (2d). These results indicated that the reactivities of
cyclic amine substrates were higher than those of noncyclic
ones. The relatively low reactivity of noncyclic amine
derivatives is perhaps due to their steric effect.
To explore the mechanism of this type of oxidative coupling
reaction, ethyl 2-morpholinoacetate N-oxide (4) was isolated
from the reaction of 2a with mCPBA in good yield and short
reaction time (Scheme 2, 83% yield, 5 min). Valuable
information for understanding the present reaction mechanism
was obtained by treating a mixture of indole (1j) and 4
groups such as benzyl (Bn), allyl, n-butyl (nBu), n-heptyl
(nHep), and methyl (Me) proceeded smoothly to provide
corresponding products 3a−3e in good to excellent yields
(entries 1−5, 86−93%). This result indicated that the size of
the N-protecting group did not influence the reactivity of the
indole substrate. The N-Me indoles 1f−1h bearing the
electron-donating groups OMe and Me on benzene rings can
also undergo the desired oxidative coupling reaction smoothly
to give products 3f−3h in good yields (entries 6−8, 85−87%).
However, the N-Me indole 1i bearing a bromine atom, an
electron-withdrawing group, on a benzene ring exhibited
relatively low reactivity in this type of oxidative coupling
reaction. Product 3i was obtained in 76% yield when the
reaction of 1i with 2a was performed for a long time (entry 9,
36 h). These results indicated that the reaction yield was
remarkably influenced by the electronic property of the
substituent linked to the benzene ring of indole. Subsequent
studies revealed that the free (NH)-indole substrates 1j−1o can
7115
dx.doi.org/10.1021/jo301035h | J. Org. Chem. 2012, 77, 7114−7118

The Journal of Organic Chemistry
Note
Scheme 2. Preparation of Ethyl 2-Morpholinoacetate N-
Oxide
Scheme 5. Gram-Scale Synthesis of the Indolylglycine
Derivative 3j
(Scheme 3). The reaction of 1j with 4 did not proceed in the
absence of an acid catalyst but proceeded smoothly when 3-
reaction of ethyl 2-(disubstituted amino)acetates with indoles.
The proposed oxidative coupling reaction proceeded smoothly
under ambient conditions to provide indolylglycine derivatives
in satisfactory to excellent yields. mCPBA and its derivative, 3-
chlorobenzoic acid, acted as an oxidant and an acid catalyst in
this type of oxidative coupling reaction, respectively.
Scheme 3. Acid-Catalyzed Coupling Reaction of Indole with
Ethyl 2-Morpholinoacetate N-Oxide
EXPERIMENTAL SECTION
■
General Procedure for Oxidative Coupling Reaction. To a
solution of ethyl 2-(disubstituted amino)acetate (2, 0.4 mmol) in
CH3CN (2.0 mL), mCPBA (0.38 mmol, 76.0 mg, 85% purity) and
indole (1, 0.25 mmol) were added. After the resulting mixture was
stirred under ambient conditions for 24 h, the solvent was then
removed under reduced pressure. The residue obtained was purified
via silica gel chromatography (eluent: petroleum ether/ethyl acetate =
3:1) to afford indolylglycine derivatives 3.
chlorobenzoic acid was used as a catalyst. Product 3j was
obtained in 84% yield. These results indicated that the present
oxidative coupling proceeds via 3-chlorobenzoic acid-catalyzed
reaction between indoles and amine N-oxide intermediates.
Both 3-chlorobenzoic acid and amine N-oxide intermediate
were generated in situ.
The plausible mechanism for the oxidative coupling reaction
of indoles with ethyl 2-aminoacetate derivatives is shown in
Scheme 4. mCPBA oxidized 2a to N-oxide 4 before being
Ethyl 2-(1-benzyl-1H-indol-3-yl)-2-morpholinoacetate (3a). Yield
89%, 84.2 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.19 (t, J =
7.1 Hz, 3H), 2.53−2.62 (m, 4H), 3.70−3.72 (m, 4H), 4.10−4.21 (m,
2H), 4.40 (s, 1H), 5.27 (s, 2H), 7.08−7.30 (m, 9H), 7.86 (d, J = 7.4
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 50.3, 51.4, 60.9, 66.4,
67.1, 109.2, 110.0, 120.0, 122.3, 126.9, 127.8, 128.0, 128.4, 128.9,
136.7, 137.2, 171.6; IR (neat) 742, 1030, 1116, 1153, 1182, 1496,
1736, 2814, 2854, 2958, 3031 cm−1. HRMS (EI) calcd for
C23H26N2O3: 378.1943 [M]+. Found: 378.1952.
Ethyl 2-(1-allyl-1H-indol-3-yl)-2-morpholinoacetate (3b). Yield
86%, 70.6 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.21 (t, J =
7.1 Hz, 3H), 2.51−2.61 (m, 4H), 3.70−3.72 (m, 4H), 4.10−4.23 (m,
2H), 4.37 (s, 1H), 4.68 (d, J = 4.5 Hz, 2H), 5.07 (d, J = 17.1 Hz, 1H),
5.19 (d, J = 10.2 Hz, 1H), 5.92−6.02 (m, 1H), 7.14 (dd, J = 7.8, 7.1
Hz, 1H), 7.19−7.24 (m, 2H), 7.29 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 49.0, 51.4, 60.9, 66.4,
67.1, 108.9, 109.8, 117.7, 119.8, 120.1, 122.1, 127.86, 127.92, 133.2,
136.5, 171.7; IR (neat) 743, 923, 1032, 1117, 1266, 1336, 1370, 1466,
1550, 1614, 1644, 1732, 2814, 2854, 2958, 3051 cm−1. HRMS (EI)
calcd for C19H24N2O3: 328.1787 [M]+. Found: 328.1796.
Scheme 4. Proposed Mechanism for Oxidative Coupling of
Indoles with Ethyl 2-Aminoacetate Derivatives
Ethyl 2-(1-butyl-1H-indol-3-yl)-2-morpholinoacetate (3c). Yield
87%, 74.0 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.92 (t, J =
7.4 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.27−1.37 (m, 2H), 1.77−1.84
(m, 2H), 2.51−2.61 (m, 4H), 3.70−3.72 (m, 4H), 4.06−4.22 (m, 4H),
4.36 (s, 1H), 7.13 (dd, J = 7.9, 7.0 Hz, 1H), 7.20−7.25 (m, 2H), 7.32
(d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H); 13C NMR (CDCl3, 100
MHz) δ 13.9, 14.4, 20.3, 32.3, 46.4, 51.6, 60.9, 66.5, 67.2, 108.4, 109.7,
119.6, 120.1, 122.0, 127.9, 128.0, 136.4, 171.9; IR (neat) 742, 1033,
1117, 1153, 1182, 1467, 1548, 1732, 2855, 2958, 3049 cm−1. HRMS
(EI) calcd for C20H28N2O3: 344.2100 [M]+. Found: 344.2097.
Ethyl 2-(1-heptyl-1H-indol-3-yl)-2-morpholinoacetate (3d). Yield
93%, 89.8 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.86 (t, J =
7.1 Hz, 3H), 1.20−1.29 (m, 11H), 1.80−1.83 (m, 2H), 2.54−2.60 (m,
4H), 3.71 (t, J = 4.6 Hz, 4H), 4.05−4.13 (m, 4H), 4.36 (s, 1H), 7.13−
7.32 (m, 4H), 7.82 (d, J = 7.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 14.1, 14.3, 22.6, 27.0, 28.9, 30.1, 31.7, 46.5, 51.5, 60.8, 66.3, 67.1,
108.3, 109.6, 119.5, 120.0, 121.8, 127.8, 127.9, 136.3, 171.8; IR (neat)
741, 1033, 1117, 1152, 1181, 1468, 1548, 1732, 2855, 2929, 3049
cm−1. HRMS (EI) calcd for C23H34N2O3: 386.2569 [M]+. Found:
386.2576.
transformed into 3-chlorobenzoic acid. The interaction of 4
with 3-chlorobenzoic acid led to the generation of the iminium
ion 5 and 3-chlorobenzoate anion.7 The Mannich-type
Friedel−Crafts reaction of 5 with indole may have occurred
to generate the coupling product 3j. The generated 3-
chlorobenzoate anion acted as a proton acceptor.
To prove the practicality of the present method in the
synthesis of indolylglycine derivatives, a gram-scale synthesis of
the indolylglycine derivative 3j was performed, and the result is
shown in Scheme 5. When 2.34 g of the indole 1j and 5.54 g of
2a were utilized, 4.61 g of product 3j was obtained in 80% yield.
In conclusion, a new strategy for the functionalization of sp3
C−H bonds adjacent to a nitrogen atom via tertiary amine N-
oxide intermediates was successfully applied to the coupling
Ethyl 2-(1-methyl-1H-indol-3-yl)-2-morpholinoacetate (3e).4b
1
Yield 91%, 68.7 mg, colorless oil: H NMR (CDCl3, 400 MHz) δ
7116
dx.doi.org/10.1021/jo301035h | J. Org. Chem. 2012, 77, 7114−7118

The Journal of Organic Chemistry
Note
1.23 (t, J = 7.1 Hz, 3H), 2.54−2.60 (m, 4H), 3.70−3.72 (m, 4H), 3.77
(s, 3H), 4.10−4.22 (m, 2H), 4.36 (s, 1H), 7.13−7.31 (m, 4H), 7.83 (d,
J = 7.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 33.0, 51.5, 61.0,
66.5, 108.7, 109.5, 119.7, 120.2, 122.1, 127.8, 129.0, 137.2, 171.9.
Ethyl 2-(5-methoxy-1-methyl-1H-indol-3-yl)-2-morpholinoace-
Ethyl 2-(5-methyl-1H-indol-3-yl)-2-morpholinoacetate (3m).
Yield 87%, 65.8 mg, colorless oil: H NMR (CDCl3, 400 MHz) δ
1
1.21 (t, J = 7.1 Hz, 3H), 2.46 (s, 3H), 2.53−2.60 (m, 4H), 3.70−3.72
(m, 4H), 4.07−4.26 (m, 2H), 4.35 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H),
7.22−7.25 (m, 2H), 7.61 (s, 1H), 8.46 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.3, 21.7, 51.6, 61.0, 66.5, 67.1, 109.5, 111.1, 119.4,
124.2, 124.6, 127.4, 129.4, 134.6, 171.9; IR (neat) 732, 796, 918, 1030,
1116, 1179, 1265, 1330, 1450, 1731, 2246, 2858, 2916, 2961, 3322,
3398 cm−1. HRMS (ES) calcd for C17H22N2O3Na: 325.1528 [M +
Na]+. Found: 325.1531.
1
tate (3f). Yield 85%, 70.6 mg, colorless oil: H NMR (CDCl3, 400
MHz) δ 1.23 (t, J = 7.1 Hz, 3H), 2.50−2.61 (m, 4H), 3.70−3.71 (m,
7H), 3.86 (s, 3H), 4.08−4.21 (m, 2H), 4.30 (s, 1H), 6.89 (dd, J = 2.2,
8.8 Hz, 1H), 7.12 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.3 (d, J = 2.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 33.1, 51.4, 56.0, 60.8, 66.5,
67.1, 101.8, 107.9, 110.1, 112.3, 128.0, 129.3, 132.4, 154.2, 171.8; IR
(neat) 731, 898, 1034, 1116, 1179, 1223, 1264, 1454, 1492, 1578,
1623, 1732, 2247, 2852, 2956, 3112 cm−1. HRMS (EI) calcd for
C18H24N2O4: 332.1736 [M]+. Found: 332.1742.
Ethyl 2-(1,7-dimethyl-1H-indol-3-yl)-2-morpholinoacetate (3g).
Yield 87%, 68.8 mg, white solid: mp 76−78 °C; 1H NMR (CDCl3, 400
MHz) δ 1.23 (t, J = 7.1 Hz, 3H), 2.51−2.61 (m, 4H), 2.75 (s, 3H),
3.70 (t, J = 4.6 Hz, 4H), 4.02 (s, 3H), 4.07−4.25 (m, 2H), 4.34 (s,
1H), 6.92 (d, J = 7.0 Hz, 1H), 6.99 (dd, J = 7.1, 7.8 Hz, 1H), 7.06 (s,
1H), 7.64 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4,
19.8, 37.0, 51.5, 60.9, 66.2, 67.2, 108.2, 118.0, 119.9, 121.5, 124.8,
128.9, 130.6, 135.8, 171.8; IR (KBr) 746, 1032, 1117, 1185, 1260,
1326, 1459, 1732, 2853, 2928, 2957 cm−1. HRMS (EI) calcd for
C18H24N2O3: 316.1787 [M]+. Found: 316.1781.
Ethyl 2-(1,5-dimethyl-1H-indol-3-yl)-2-morpholinoacetate (3h).
Yield 87%, 68.6 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.22
(t, J = 7.1 Hz, 3H), 2.47 (s, 3H), 2.51−2.61 (m, 4H), 3.70−3.71 (m,
7H), 4.06−4.24 (m, 2H), 4.34 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.11
(s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.3, 21.6, 32.9, 51.4, 60.8, 66.3, 67.0, 107.7, 109.1, 119.4,
123.7, 127.9, 128.9, 129.0, 135.5, 171.8; IR (neat) 790, 861, 1033,
1117, 1149, 1264, 1378, 1451, 1491, 1736, 2243, 2854, 2919, 2956
cm−1. HRMS (EI) calcd for C18H24N2O3: 316.1787 [M]+. Found:
316.1795.
Ethyl 2-(5-bromo-1H-indol-3-yl)-2-morpholinoacetate (3n). Yield
85%, 78.0 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.24 (t, J =
7.1 Hz, 3H), 2.51−2.59 (m, 4H), 3.71−3.73 (m, 4H), 4.09−4.24 (m,
2H), 4.33 (s, 1H), 7.22−7.30 (m, 3H), 8.02 (s, 1H), 8.49 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.4, 51.4, 61.1, 66.5, 67.1, 110.1, 112.8,
113.5, 122.8, 125.6, 128.8, 135.0, 171.5; IR (neat) 732, 887, 1029,
1114, 1261, 1452, 1729, 2245, 2857, 2961, 3314 cm−1. HRMS (ES)
calcd for C16H19N2O3BrNa: 389.0477 [M + Na]+. Found: 389.0491.
Ethyl 2-(2-methyl-1H-indol-3-yl)-2-morpholinoacetate (3o). Yield
1
86%, 65.0 mg, white solid: mp 140−142 °C; H NMR (CDCl3, 400
MHz) δ 1.14 (t, J = 7.1 Hz, 3H), 2.42−2.48 (m, 7H), 3.71−3.73 (m,
4H), 4.00−4.17 (m, 2H), 4.22 (s, 1H), 7.06−7.12 (m, 2H), 7.20−7.22
(m, 1H), 7.93 (d, J = 6.7 Hz, 1H), 8.14 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 12.3, 14.3, 51.9, 60.8, 66.9, 67.2, 105.9, 110.2, 119.8,
120.2, 121.4, 127.7, 134.4, 135.2, 171.7; IR (KBr) 735, 911, 1033,
1116, 1142, 1187, 1263, 1459, 1727, 2245, 2812, 2857, 2961, 3056,
3396 cm−1. HRMS (ES) calcd for C17H22N2O3Na: 325.1528 [M +
Na]+. Found: 325.1534.
Ethyl 2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-morpholinoa-
1
cetate (3p). Yield 78%, 59.2 mg, colorless oil: H NMR (CDCl3, 400
MHz) δ 1.23 (t, J = 7.1 Hz, 3H), 2.49−2.58 (m, 4H), 3.71 (t, J = 4.6
Hz, 4H), 3.87 (s, 3H), 4.11−4.24 (m, 2H), 4.31 (s, 1H), 7.07−7.10
(m, 1H), 7.27 (s, 1H), 8.18−8.20 (m, 1H), 8.34−8.35 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.3, 31.3, 51.4, 61.0, 66.9, 67.1, 107.4,
115.9, 119.8, 128.8, 128.9, 143.5, 148.1, 171.3; IR (neat) 772, 886,
1033, 1117, 1182, 1303, 1459, 1541, 1733, 2814, 2854, 2956, 3056
cm−1. HRMS (EI) calcd for C16H21N3O3: 303.1583 [M]+. Found:
303.1591.
Ethyl 2-(5-bromo-1-methyl-1H-indol-3-yl)-2-morpholinoacetate
(3i). Yield 76%, 72.4 mg, white solid: mp 86−88 °C; 1H NMR
(CDCl3, 400 MHz) δ 1.24 (t, J = 7.1 Hz, 3H), 2.49−2.56 (m, 4H),
3.70−3.74 (m, 7H), 4.08−4.26 (m, 2H), 4.29 (s, 1H), 7.29 (d, J = 7.1
Hz, 1H), 7.98 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 33.2,
51.4, 61.0, 66.4, 67.1, 108.4, 111.0, 113.2, 122.8, 125.0, 129.2, 130.1,
135.9, 171.5; IR (KBr) 790, 886, 1031, 1117, 1182, 1268, 1474, 1733,
2852, 2956, 3071 cm−1. HRMS (EI) calcd for C17H21N2O3Br:
380.0736 [M]+. Found: 380.0741.
Ethyl 2-(1-benzyl-1H-indol-3-yl)-2-(piperidin-1-yl)acetate (3q).
1
Yield 76%, 71.5 mg, colorless oil: H NMR (CDCl3, 400 MHz) δ
1.19 (t, J = 7.1 Hz, 3H), 1.42−1.56 (m, 6H), 2.47−2.55 (m, 4H),
4.09−4.24 (m, 2H), 4.38 (s, 1H), 5.27 (s, 2H), 7.08−7.29 (m, 10H),
7.83 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.3, 24.6,
26.1, 50.3, 52.3, 60.7, 66.7, 110.0, 110.2, 119.7, 120.2, 122.1, 126.9,
127.7, 128.3, 128.4, 128.9, 136.6, 137.4, 172.3; IR (neat) 740, 1029,
1117, 1151, 1466, 1731, 2852, 2933, 3031 cm−1. HRMS (EI) calcd for
C24H28N2O2: 376.2151 [M]+. Found: 376.2158.
Ethyl 2-(1H-indol-3-yl)-2-morpholinoacetate (3j).8 Yield 89%,
1
64.1 mg, colorless oil: H NMR (CDCl3, 400 MHz) δ 1.21 (t, J =
7.1 Hz, 3H), 2.53−2.61 (m, 4H), 3.70 (t, J = 4.6 Hz, 4H), 4.08−4.23
(m, 2H), 4.39 (s, 1H), 7.12−7.21 (m, 2H), 7.25 (d, J = 2.2 Hz, 1H),
7.33 (d, J = 8.0 Hz, 1H), 8.63 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ
14.3, 51.5, 61.0, 66.5, 110.0, 111.4, 119.95, 120.02, 122.5, 124.5, 127.1,
136.3, 171.9.
Ethyl 2-(1-methyl-1H-indol-3-yl)-2-(piperidin-1-yl)acetate (3r).4b
Yield 90%, 67.6 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.22
(t, J = 7.1 Hz, 3H), 1.41−1.60 (m, 6H), 2.45−2.55 (m, 4H), 3.74 (s,
3H), 4.07−4.25 (m, 2H), 4.36 (s, 1H), 7.10−7.29 (m, 4H), 7.80 (d, J
= 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 24.6, 26.1, 32.9,
52.3, 60.7, 66.6, 109.3, 119.4, 120.0, 121.9, 128.1, 128.8, 137.0, 172.5.
Ethyl 2-(1H-indol-3-yl)-2-(piperidin-1-yl)acetate (3s). Yield 83%,
59.4 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.20 (t, J = 7.1
Hz, 3H), 1.40−1.59 (m, 6H), 2.49−2.56 (m, 4H), 4.07−4.25 (m, 2H),
4.38 (s, 1H), 7.11−7.26 (m, 3H), 7.32 (d, J = 7.3 Hz, 1H), 7.82 (d, J =
7.9 Hz, 1H), 8.62 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 24.6,
26.0, 52.4, 60.8, 66.8, 110.9, 111.4, 119.8, 119.9, 122.2, 124.5, 127.6,
136.2, 172.6; IR (neat) 739, 910, 1027, 1113, 1181, 1456, 1732, 2246,
2854, 2935, 3058, 3405 cm−1. HRMS (ES) calcd for C17H23N2O2:
287.1760 [M + H]+. Found: 287.1764.
Ethyl 2-(5-methoxy-1H-indol-3-yl)-2-morpholinoacetate (3k).
1
Yield 91%, 72.4 mg, colorless oil: H NMR (CDCl3, 400 MHz) δ
1.22 (t, J = 7.1 Hz, 3H), 2.53−2.62 (m, 4H), 3.70−3.72 (m, 4H), 3.86
(s, 1H), 4.09−4.22 (m, 2H), 4.34 (s, 1H), 6.86 (dd, J = 2.3, 8.8 Hz,
1H), 7.21−7.23 (m, 2H), 7.33 (d, J = 2.1 Hz, 1H), 8.51 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.4, 51.5, 56.0, 61.0, 66.7, 67.2, 101.8,
109.8, 112.1, 112.8, 125.1, 127.6, 131.5, 154.4, 171.9; IR (neat) 732,
921, 1029, 1115, 1184, 1213, 1252, 1455, 1488, 1731, 2248, 2830,
2856, 2959, 3329, 3400 cm−1. HRMS (ES) calcd for C17H22N2O4Na:
341.1477 [M + Na]+. Found: 341.1471.
Ethyl 2-(7-methyl-1H-indol-3-yl)-2-morpholinoacetate (3l). Yield
93%, 70.3 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.21 (t, J =
7.1 Hz, 3H), 2.47 (s, 3H), 2.52−2.61 (m, 4H), 3.70−3.72 (m, 4H),
4.08−4.21 (m, 2H), 4.38 (s, 1H), 7.01 (d, J = 7.0 Hz, 1H), 7.07 (dd, J
= 7.2, 7.8 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H),
8.36 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 16.7, 51.5, 61.0,
66.6, 67.1, 110.7, 117.7, 120.3, 120.6, 123.1, 124.2, 126.7, 135.9, 171.9;
IR (neat) 733, 912, 1031, 1116, 1187, 1262, 1345, 1450, 1729, 2245,
2816, 2857, 2961, 3053, 3321 cm−1. HRMS (ES) calcd for
C17H23N2O3: 303.1709 [M + H]+. Found: 303.1706.
Ethyl 2-(benzyl(methyl)amino)-2-(1-benzyl-1H-indol-3-yl)acetate
(3t). Yield 51%, 52.6 mg, colorless oil: 1H NMR (CDCl3, 400 MHz) δ
1.24 (t, J = 7.1 Hz, 3H), 2.28 (s, 3H), 3.64−3.72 (m, 2H), 4.14−4.26
(m, 2H), 4.71 (s, 1H), 5.26 (s, 2H), 7.06−7.32 (m, 14H), 7.83−7.85
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 39.1, 50.2, 58.6, 60.6,
64.6, 109.9, 110.7, 119.8, 120.4, 122.2, 126.7, 127.0, 127.7, 127.9,
128.3, 128.4, 128.9, 129.1, 136.9, 137.4, 139.6, 172.1; IR (neat) 741,
7117
dx.doi.org/10.1021/jo301035h | J. Org. Chem. 2012, 77, 7114−7118

The Journal of Organic Chemistry
Note
1028, 1337, 1454, 1466, 1729, 2843, 2980, 3029 cm−1. HRMS (EI)
calcd for C27H28N2O2: 412.2151 [M]+. Found: 412.2163.
Mobilio, D.; Noureldin, R.; Schmid, J.; Shah, U.; Engen, D. V.; Chau,
T. T.; Weichman, B. M. J. Med. Chem. 1988, 31, 1244.
Ethyl 2-(benzyl(methyl)amino)-2-(1-methyl-1H-indol-3-yl)-
(2) (a) Higuchi, K.; Takei, R.; Kouko, T.; Kawasaki, T. Synthesis
2007, 5, 669. (b) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.;
Chen, J.-J.; Zhang, X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127.
(c) Kouko, T.; Matsumura, K.; Kawasaki, T. Tetrahedron 2005, 61,
2309. (d) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.;
Inagawa, M.; Sakamoto, M. Org. Lett. 2000, 2, 3027. (e) Casapullo, A.;
Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000, 63, 447. (f) Capon,
R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A.
P.; Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998, 61, 660.
(3) Jiang, B.; Huang, Z.-G. Synthesis 2005, 13, 2198 and references
therein.
1
acetate (3u). Yield 65%, 54.6 mg, colorless oil: H NMR (CDCl3,
400 MHz) δ 1.26 (t, J = 7.1 Hz, 3H), 2.27 (s, 3H), 3.62−3.72 (m,
5H), 4.13−4.29 (m, 2H), 4.69 (s, 1H), 7.12−7.33 (m, 9H), 7.82 (d, J
= 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 32.9, 39.0, 58.5,
60.6, 64.6, 109.4, 109.8, 119.5, 120.3, 122.0, 126.9, 127.7, 128.2, 128.8,
129.1, 137.2, 139.6, 172.3; IR (neat) 741, 1029, 1176, 1454, 1473,
1729, 2842, 2979, 3027 cm−1. HRMS (EI) calcd for C21H24N2O2:
336.1838 [M]+. Found: 336.1848.
Ethyl 2-(1H-indol-3-yl)-2-(4-tosylpiperazin-1-yl)acetate (3v). Yield
1
87%, 96.0 mg, white solid: mp 177−179 °C; H NMR (CDCl3, 400
MHz) δ 1.19 (t, J = 7.1 Hz, 3H), 2.43 (s, 3H), 2.58−2.70 (m, 4H),
3.00−3.03 (m, 4H), 4.07−4.21 (m, 2H), 4.40 (s, 1H), 7.10 (dd, J =
7.6, 7.3 Hz, 1H), 7.18−7.24 (m, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.36 (d,
J = 7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H),
8.23 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 21.7, 46.4, 50.0,
61.1, 65.6, 109.9, 111.6, 119.8, 120.1, 122.6, 124.6, 126.9, 128.0, 132.5,
136.4, 143.9, 171.6; IR (KBr) 734, 948, 1166, 1348, 1732, 2255, 2855,
2981, 3059, 3394 cm−1. HRMS (ES) calcd for C23H27N3O4NaS:
464.1620 [M + Na]+. Found: 464.1638.
(4) (a) Jia, D.-M.; Xu, M.-H. Chem. Commun. 2010, 46, 1550.
(b) Ghandi, M.; Taheri, A. Molecules 2009, 14, 1056. (c) Kang, Q.;
Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65, 1603. (d) Wanner, M. J.;
Hauwert, P.; Schoemaker, H. E.; Gelder, R.; van Maarseveen, J. H.;
Hiemstra, H. Eur. J. Org. Chem. 2008, 180. (e) Abid, M.; Teixeira, L.;
Torok, B. Org. Lett. 2008, 10, 933. (f) Zhao, J.-L.; Liu, L.; Zhang, H.-
̈
̈
B.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synlett 2006, 1, 96. (g) Janczuk,
A.; Zhang, W.; Xie, W.; Lou, S.; Cheng, J. P.; Wang, P. G. Tetrahedron
Lett. 2002, 43, 4271.
Ethyl 2-morpholinoacetate N-oxide (4). White solid: mp 77−79
°C; 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.1 Hz, 3H), 3.22 (d, J
= 10.8 Hz, 3H), 3.78−3.84 (m, 4H), 4.09 (s, 2H), 4.25−4.31 (m, 2H),
4.48−4.54 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 14.1, 61.6, 62.1,
64.5, 72.0, 164.7; IR (KBr) 861, 1029, 1113, 1211, 1643, 1740, 2985,
3423 cm−1. HRMS (EI) calcd for C8H15NO4: 189.1001 [M]+. Found:
189.1010.
Treatment of Indole (1j) and Ethyl 2-Morpholinoacetate N-
Oxide (4) in the Absence of Acid Catalyst. To a solution of ethyl
2-morpholinoacetate N-oxide (4, 0.4 mmol, 75.7 mg) in CH3CN (2.0
mL), indole (1j, 0.25 mmol, 29.3 mg) was added. The resulting
mixture was stirred under ambient conditions for 36 h. The desired
reaction did not take place, and the starting materials 1j and 4 were
recovered.
(5) (a) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T. Tetrahedron
2008, 64, 9208. (b) Grumbach, H.-J.; Merla, B.; Risch, N. Synthesis
1999, 6, 1027.
(6) Xu, Z.; Yu, X.; Feng, X.; Bao, M. J. Org. Chem. 2011, 76, 6901.
(7) Iminium ion intermediate can be generated by Lewis acid- or
acetic anhydride-promoted decomposition of corresponding tertiary
amine N-oxide; see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev.
2004, 104, 2311. (b) Rosenau, T.; Potthast, A.; Kosma, P.; Chen, C.-
L.; Gratzl, J. S. J. Org. Chem. 1999, 64, 2166. (c) Grierson, D. Org.
React. 1990, 39, 85.
(8) Joehl, A.; Stoll, W. G. DE 1097990, 1959.
Oxidative Coupling Reaction of Indole (1j) with Ethyl 2-
Morpholinoacetate N-Oxide (4) Catalyzed by 3-Chlorobenzoic
Acid. To a solution of ethyl 2-morpholinoacetate N-oxide (4, 0.4
mmol, 75.7 mg) in CH3CN (2.0 mL), indole 1j (0.25 mmol, 29.3 mg)
and 3-chlorobenzoic acid (3.9 mg, 10 mol %) were added. The
reaction mixture was stirred under ambient conditions for 36 h, and
the solvent was then removed under reduced pressure. The residue
obtained was purified via silica gel chromatography (eluent: petroleum
ether/ethyl acetate = 3:1) to afford ethyl 2-(1H-indol-3-yl)-2-
morpholinoacetate (3j) as a colorless oil (60.5 mg, 84%).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Characterization for compounds, including copies of H and
13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yuxiaoqiang@dlut.edu.cn; mingbao@dlut.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21002010 and 21072023) for their financial
support.
REFERENCES
■
(1) Katz, A. H.; Demerson, C. A.; Shaw, C.-C.; Asselin, A. A.;
Humber, L. G.; Conway, K. M.; Gavin, G.; Guinosso, C. N.; Jensen, P.;
7118
dx.doi.org/10.1021/jo301035h | J. Org. Chem. 2012, 77, 7114−7118