Regioselective Friedel-Crafts Reactions of N-Substituted Glyoxylamide with Indoles Catalyzed by Bronsted Acid

Article abstract of DOI:10.1055/s-0035-1560462

An efficient regioselective Friedel-Crafts reaction of a series of N-substituted glyoxylamide with indoles catalyzed by Bronsted acid was developed. The reactions proceeded smoothly at room temperature and the corresponding N-substituted 2-hydroxy-2-(1H-i

Full text of DOI:10.1055/s-0035-1560462

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2261–2266
letter
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Letter
Synlett
Regioselective Friedel–Crafts Reactions of N-Substituted Glyoxyl-
amide with Indoles Catalyzed by Brønsted Acid
R2
R3
Zhen Zhan
Renjun Li
Yang Zheng
Yan Zhou
Li Hai
N
OH
H
H
AcOH
N
N
CHO
2 M HCl
R1
dioxane, r.t., 0.5 h
+
3
R1
H
R3
R
N
dioxane, r.t., 0.5 h
N
R2
R1
O
O
R3
N
R2
O
N
R2
Yong Wu*
26 examples
up to 89% yield
14 examples
up to 91% yield
R1 = aryl, benzyl
R2 = H, Me
R3 = 2-Me, 5-OH, 5-Br, 5-CN, 6-Cl, 6-alkoxy
Key Laboratory of Drug-Targeting and Drug Delivery
System of the Education Ministry, Department of
Medicinal Chemistry West China School of Pharmacy,
Sichuan University, Chengdu 610041, P. R. of China
wyong@scu.edu.cn
Dedicated with admiration to Professor K. Peter C. Vollhardt
Received: 10.06.2015
Accepted after revision: 17.07.2015
Published online: 25.08.2015
ceuticals (Figure 1).2 The C3 substituted indole derivatives,
in particular containing 1-hydroxy-1-(1H-indol-3-yl)pro-
pan-2-one structure moiety is an emerging new scaffold for
drug discovery with a broad spectrum of biological activi-
ties including antidiabetic, analgesic, antibacterial, antitu-
bercular, anti-inflammatory, antiangiogenic, antifungal, an-
ticonvulsant, and some are treated as the new targets for
cancer chemotherapy.3
Therefore, there has been a strong demand for the de-
velopment of efficient methods to form the C3-functional-
ized indoles that contain the 1-hydroxy-1-(1H-indol-3-
yl)propan-2-one structure moiety. Many methods have
been developed for the synthesis of 1-hydroxy-1-(1H-in-
dol-3-yl)propan-2-one derivatives4 and the bisindole com-
pounds,5 among them Friedel–Crafts reaction, which could
introduce the new carbon–carbon bond, is an important
way.6,7
DOI: 10.1055/s-0035-1560462; Art ID: ss-2015-w0429-l
Abstract An efficient regioselective Friedel–Crafts reaction of a series
of N-substituted glyoxylamide with indoles catalyzed by Brønsted acid
was developed. The reactions proceeded smoothly at room tempera-
ture and the corresponding N-substituted 2-hydroxy-2-(1H-indol-3-yl)
acetamides were afforded in moderate to good yields (up to 89%).
When 2 M HCl was used, the bisindole compounds were obtained in
good to excellent yield (up to 91%) resulting from a double Friedel–
Crafts reaction.
Key words regioselective Friedel–Crafts reaction, Brønsted acid, N-
substituted glyoxylamide, indole, N-substituted 2-hydroxy-2-(1H-indol-
3-yl) acetamide, bisindole compound
From the early days of pharmaceutical science, indole is
a key structural unit existing in a variety of natural prod-
ucts and drug candidates.1 Notably, C3-substituted indole is
one of the most important structural motif present in a vast
array of biologically active natural products and pharma-
As 3-indolyl-3-hydroxy oxindole and trisindoline (Fig-
ure 2), and their derivatives, have a broad spectrum of in-
teresting biological activities, a variety of studies on their
O
HO
O
NH2
NH2
O
H
O
N
N
N
H
O
O
OH
HO
NH
F3C
Cl
OEt
N
O
N
N
O
CN
N
H
H
N
H
Cl
oncolytic drugs
CF3
trisindoline
antibiotics
oncolytic drugs
antiobesity drugs
antidiabetic drugs
analgesic drugs
oncolytic drugs
Figure 1 Selected biologically active molecules containing C3-functionalized indole moiety
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2261–2266

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synthesis methods and biological activities were report-
ed.8,9 However, to the best of our knowledge, the synthesis
and bioactivity for their open-chain analogues N-substitut-
ed 2-hydroxy-2-(1H-indol-3-yl) acetamide and the bisin-
dole compounds have not yet been reported. Herein, we re-
port our study on the Brønsted acid catalyzed regioselective
Friedel–Crafts reaction of N-substituted glyoxylamide with
indoles to afford the N-substituted 2-hydroxy-2-(1H-indol-
3-yl) acetamide and the bisindole compounds.
such as PhCO2H, PTSA, (CO2H)2, concd HCl, HCl (2mol/L),
H3PO4, CF3SO3H, ClCH2CO2H, TFA, HCO2H, and AcOH were
used (Table 1, entries 1–11). The good selectivity for 3a was
obtained by using AcOH as catalyst (Table 1, entry 11),
while the formation of 4a was nearly not observed. When
the catalytic amount of concd HCl, HCl (2 mol/L), H3PO4, or
CF3SO3H was employed in the reaction, only 4a was forming
rapidly and isolated (Table 1, entries 4–7) in good yield.
In addition, the screening of solvent (Table 1, entries
11–19) led to the discovery that dioxane was most suitable
(Table 1, entries 11–19). Further optimization by changing
the amount of AcOH revealed that, to our delight, when the
addition of AcOH decreased to 5 mmol, the best result was
obtained (Table 1, entry 21, 84% yield) while 1 mmol AcOH
led to the incompletion of the reaction (Table 1, entry 20).
Although prolonging the reaction time to 24 hours to go to
completion, the product 3a decreased a little (Table 1, entry
22). Further increasing the reaction temperature to 50 °C
and even higher to 80 °C, 3a did not increase and the reac-
tion became complicated (Table 1, entries 23 and 24). In a
word, we could selectively get the product 3a with 84%
yield by using AcOH as catalyst and dioxane as the solvent
and 4a with 89% yield by using HCl (2 mol/L) as catalyst and
dioxane as the solvent.
H
N
OH
O
H
ring opening
N
OH
O
N
N
H
H
3a
oncolytic drugs
H
N
HN
O
ring opening
H
N
N
N
O
H
H
N
H
4a
trisindoline
antibiotics
With the optimal catalytic conditions in hand, we con-
sequently investigated the substrate scope of the reaction. A
series of regioselective Friedel–Crafts reactions of N-substi-
tuted glyoxylamide with indoles proceeded smoothly to
give the corresponding products in high yields. The results
are summarized in Table 2. Among various tested sub-
strates, both electron-donating substituents such as Me and
OMe at the 4-position of the benzene ring (Table 2, entries
2, 3) and electron-withdrawing substituents such as Cl, NO2
at the 4-position (Table 2, entries 4, 6) or Cl at the 3,5-posi-
tions of the benzene ring (Table 2, entry 5) could be tolerat-
ed, and the corresponding products 3b–f were isolated in
moderate to good yields. Moderate yields of N-phenyl gly-
oxylamide derivatives owing electron-donating groups
linked to the benzene ring were obtained (3b,c), while N-
phenyl glyoxylamide derivatives owing electron-withdraw-
ing groups linked to the benzene ring resulted in good
yields (3d–f). These results suggested that the reactivity of
the N-phenyl glyoxylamide derivative substrates was influ-
enced by the electronic property of the substituent of the
benzene ring of N-phenyl glyoxylamide derivatives. The re-
activity of N-phenyl glyoxylamide derivatives could be re-
duced by an electron-donating group linked to the benzene
ring. To further define the scope of this transformation, a
wide range of N-phenyl glyoxylamide derivatives and in-
doles containing different substituents at the 1-, 2-, 5-, or 6-
positions were reacted under the optimized reaction condi-
tions. Indoles containing electron-withdrawing groups re-
sulted in only moderate yields (3i–o), while good to excel-
lent yields of indoles with electron-donating groups were
obtained in most cases (3p–z). However, N-substituted gly-
oncolytic drugs
Figure 2 3-Indolyl-3-hydroxy oxindole, trisindoline, and their tem-
plates used for structural modification
In the exploratory study of our newly proposed Friedel–
Crafts reaction for the preparation of N-substituted 2-hy-
droxy-2-(1H-indol-3-yl) acetamide, we carried out a first
experiment by reacting N-phenyl glyoxylamide (1a) with
indole (2a) in the presence of PhCO2H in dioxane at room
temperature (Table 1, entry 1).10 To our delight, the desired
2-hydroxy-2-(1H-indol-3-yl)-N-phenyl acetamide (3a) was
isolated in 76% yield. And another side product was found.
Separation and confirmation of this side product suggested
it was the bisindole product 4a, as shown in Table 1. How-
ever, poor selectivity was found when a mixture of N-phe-
nyl glyoxylamide with indole was treated under PhCO2H
conditions. We hypothesized that the reaction selectivity
could be controlled by using an appropriate Brønsted acid
catalyst. Therefore, we were interested in looking for an ef-
ficient and highly selective Brønsted acid as the catalyst in
the synthesis of 3a and 4a, respectively.
To begin our investigation, N-phenyl glyoxylamide (1a)
and indole (2a) were chosen as the reaction substrates in
the model reaction. As shown in Table 1, both catalyst and
solvent had dramatic effects on this regioselective Friedel–
Crafts reaction. Generally, N-phenyl glyoxylamide (1a) was
reacted with indole (2a) at room temperature and afforded
a mixture of 2-hydroxy-2-(1H-indol-3-yl)-N-phenylacet-
amide (3a) and bisindole product 4a. Various Brønsted acid
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Table 1 Screening Studies for the Regioselective Friedel–Crafts Reaction of N-Phenyl Glyoxylamide with Indolea
HN
OH
H
N
H
CHO
+
N
H
catalyst
solvent
N
+
O
O
N
N
H
H
O
N
2a
3a
1a
H
4a
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yield of 3a (%)b
Yield of 4a (%)b
1
2
PhCO2H
PTSA
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
EtOH
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
50
80
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
24
76
8
77
35
87
89
83
85
25
82
12
trace
4
6
3
(CO2H)2
42
4c
concd HCl
HCl (2 mol/L)
H3PO4
CF3SO3H
ClCH2CO2H
TFA
trace
trace
trace
trace
53
5c
6c
7c
8
9
8
10
11
12
13
14
15
16
17
18
19
20d
21e
22e
23e
24e
HCO2H
AcOH
69
81
AcOH
80
AcOH
MeCN
72
6
AcOH
DMSO
36
23
6
AcOH
THF
76
AcOH
acetone
toluene
CH2Cl2
EtOAc
79
4
AcOH
68
14
8
AcOH
76
AcOH
78
7
AcOH
dioxane
dioxane
dioxane
dioxane
dioxane
67
trace
trace
trace
15
31
AcOH
84
AcOH
82
AcOH
0.5
0.5
64
AcOH
38
a Unless noted otherwise, reactions were performed with N-phenyl glyoxylamide (1a, 1 mmol), indole (2a, 1.1 mmol), and catalyst (10 mmol) in solvent (8 mL).
b Isolated yield.
c Conditions: 0.1 mmol catalyst was added.
d Conditions:1 mmol AcOH was added.
e Conditions:5 mmol AcOH was added.
oxylamide even the N-(4-nitrophenyl)glyoxylamide whose
reactivity was preferable could not be reacted with indoles
containing the strong electron-withdrawing groups such as
CN or CO2Me at the 5-position (Table 2, entries 14, 15).
These results suggested that the reactivity of the indole
substrate was remarkably influenced by the electronic
property of the substituent of the indole. The reactivity of
the indole substrate could be reduced by an electron-with-
drawing group linked to indole. Therefore, these results
clearly demonstrated that AcOH served as a useful Brønsted
acid catalyst for the N-substituted glyoxylamide and indoles
to produce the corresponding N-substituted 2-hydroxy-2-
(1H-indol-3-yl) acetamide.
Furthermore, with optimized conditions in hand, a se-
ries of bisindole compounds resulting from the regioselec-
tive Friedel–Crafts reactions were carried out. The results
were summarized in Table 3. Among various tested sub-
strates, N-phenyl glyoxylamide derivatives with either elec-
tron-donating (4b,c) or electron-withdrawing substituents
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Table 2 Substrate Scope in Regioelective Friedel–Crafts Reaction of N-
(4d–g) on the benzene ring could be tolerated, and the cor-
responding products were isolated in good yields. The reac-
tivity of the regioselective Friedel–Crafts reaction could be
reduced by an electron-withdrawing group linked to the 5-
or 6-position of indole.
Substituted Glyoxylamide with Indolesa
H
N
CHO
R1
R3
OH
O
H
N
1
+
R1
AcOH
Table 3 Substrate Scope in Double Friedel–Crafts Reaction of N-Sub-
stituted Glyoxylamide with Indolesa
O
dioxane, r.t., 0.5 h
N
R3
R2
R3
H
R2
3
N
R2
N
CHO
R1
N
O
1
+
2
2 M HCl
H
Entry R1
R2
R3
Product 3 Yield (%)b
N
R1
R3
dioxane, r.t., 0.5 h
R3
1
2
Ph
H
H
3a
3b
3c
3d
3e
3f
84
71
73
84
82
86
88
79
75
66
73
78
63
n.r.d
n.r.d
61
82
81
85
82
83
89
86
81
84
86
80
85
O
N
R2
N
R2
4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3,5-Cl2C6H3
4-O2NC6H4
Bn
H
H
3
H
H
2
4
H
H
Entry R1
R2
R3
Product 4 Yield (%)b
5
H
H
6
H
H
1
2
Ph
H
H
4a
4b
4c
4d
4e
4f
89
82
76
85
80
88
83
79
74
69
71
72
89
87
7
H
H
3g
3h
3i
3,5-MeO2C6H3
4-MeOC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
8
2-naphthyl
Ph
H
H
3
H
9
H
6-Cl
6-Cl
6-Cl
6-Cl
5-Br
5-CN
4
H
10c
11
12
13c
14
15
16c
17
18
19
20
21
22
23
24
25
26
27
28
4-MeC6H4
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
3,5-Cl2C6H3
Bn
H
3j
5
3-ClC6H4
H
H
3k
3l
6
4-O2NC6H4
3,5-Cl2C6H3
2-naphthyl
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
H
H
7
H
4g
4h
4i
H
3m
–
8
H
H
9
6-Cl
5-CN
6-Cl
5-CN
2-Me
H
5-CO2Me
6-Cl
–
10
11
12
13
14
4j
H
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
3z
4k
4l
H
6-Cl
Ph
Me
H
6-OCH2CO2Et
5-OH
4m
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3,5-Cl2C6H3
Bn
Bn
6-OCH2CO2Et 4n
Me
H
6-OCH2CO2Et
2-Me
a Unless noted otherwise, reactions were performed with N-substituted gly-
oxylamide 1 (1 mmol), indoles 2 (2 mmol), and HCl (2 mol/L, 0.1 mmol) in
dioxane (8 mL) at 25 °C for 0.5 h.
b Isolated yield.
H
5-OH
Me
Me
H
6-OCH2CO2Et
6-OCH2CONH2
5-OH
Moreover, the product 3 could also be transformed to 4
in the presence of a catalytic amount of HCl (2 mol/L) at
room temperature. For example, 3c and 3f were reacted
with indole and catalyzed by HCl (2 mol/L) at room tem-
perature to afford the corresponding bisindole products 4c
and 4f in high yields. And then, a series of different-substi-
tuted bisindole products could be obtained in the presence
of 3. For example, 3d was reacted with ethyl 2-[(1-methyl-
1H-indol-6-yl)oxy]acetate to afford the corresponding dif-
ferent substituted bisindole products 3d′. Furthermore, 3v
could be reacted with pyrrole and catalyzed by the catalytic
amount of HCl (2 mol/L) at room temperature to afford 4v′
(Scheme 1).
Me
Me
Me
6-OCH2CO2Et
6-OCH2CO2Et
6-OCH2CO2Et
a Unless noted otherwise, reactions were performed with N-substituted gly-
oxylamide 1 (1 mmol), indoles 2 (1.1 mmol) and AcOH (5 mmol) in dioxane
(8 mL) at 25 °C for 0.5 h.
b Isolated yield.
c Reaction time was 5 h.
d No reaction.
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OH
HN
O
H
2 M HCl
N
+
(1)
R
dioxane, r.t., 0.5 h
N
H
O
H
N
N
H
R
3c,f
N
H
2a
4c,f
4c, R = 4-MeOC6H4, 82%
4f, R = 4-O2NC6H4, 85%
O
O
OH
O
OEt
Me
Me
H
N
O
N
N
2 M HCl
+
OEt
(2)
O
dioxane, r.t., 0.5 h
N
Cl
H
N
H
3d
O
N
Cl
H
3d' 84%
NH
OH
H
N
Cl
H
2 M HCl
H
N
N
Cl
+
(3)
dioxane, r.t., 0.5 h
Cl
O
N
Cl
O
H
N
H
3v
4v' 71%
Scheme 1 Applications of the regioselective Friedel–Crafts reactions
In conclusion, we have demonstrated a mild and highly
efficient system for the regioselective Friedel–Crafts reac-
tion of N-substituted glyoxylamide11 with indoles.12 The re-
actions13 proceed well for various indoles, and the Friedel–
Crafts adducts are obtained in high yields. We anticipate
such reactions to be a straightforward and practical way to
prepare various N-substituted 2-hydroxy-2-(1H-indol-3-yl)
acetamide and 2,2-di(1H-indol-3-yl)-N,N-phenylacetamide
derivatives. Further work is in progress to develop catalytic
enantioselective Friedel–Crafts reactions and bioactivity of
the bisindole compounds.
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We sincerely thank the National Science Foundation of China
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560462.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(b) Soueidan, M.; Collin, J.; Gil, R. Tetrahedron Lett. 2006, 47,
5467.
(6) For selected examples, see: (a) Choudhary, V. R.; Jha, R.;
Choudhary, P. A. J. Chem. Sci. 2005, 117, 635. (b) Dong, H. M.; Lu,
H. H.; Lu, L. Q.; Chen, C. B.; Xiao, W. J. Adv. Synth. Catal. 2007,
349, 1597. (c) Zhuang, W.; Jørgensen, K. A. Chem. Common.
2002, 1336. (d) Xu, X. H.; Kusuda, A.; Tokunaga, E.; Shibata, N.
Green Chem. 2011, 13, 46. (e) Hui, Y. H.; Zhang, Q.; Jiang, J.; Lin,
L. L.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2009, 74, 6878. (f) Li, H.
M.; Wang, Y. Q.; Deng, L. Org. Lett. 2006, 8, 18.
Huang, H.; Xu, G. Z.; Fitzgerald, M.; Haertlein, B. J.; Mohan, V.;
Crysler, C.; Eisennagel, S.; Dasgupta, M.; McMillan, M.; Spurlino,
J. C.; Huebert, N. D.; Maryanoff, B. E.; Tomczuk, B. E.; Damiano,
B. P.; Player, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 2865.
(13) N-Substituted 2-Hydroxy-2-(1H-indol-3-yl) Acetamides 3;
General Procedure
To a stirred mixture of N-substituted glyoxylamide (1.0 mmol),
indoles (1.1 mmol) in dioxane (8 mL) was added AcOH (5.0
mmol) at 25 °C for 0.5 h. After the completion of the reaction
(monitored by TLC), the mixture was diluted with H2O and
extracted with EtOAc (4 × 20 mL). The organic layer was washed
with sat. brine, dried over anhydrous Na2SO4, and the solvent
was evaporated to dryness. The crude residue was purified by
flash chromatography on silica gel (CH2Cl2–MeOH, 80:1) to
afford pure N-substituted 2-hydroxy-2-(1H-indol-3-yl) acet-
amides 3 (61–89% yield).
2,2-Di(1H-indol-3-yl)-N,N-phenyl Acetamide Derivatives 4;
General Procedure
To a stirred mixture of N-substituted glyoxylamide (1.0 mmol),
indoles (2.0 mmol) in dioxane (8 mL) was added HCl (2 mol/L,
0.1 mmol) at 25 °C for 0.5 h. After completion of the reaction
(monitored by TLC), the mixture was diluted with H2O and
extracted with EtOAc (3 × 20 mL). The organic layer was washed
with sat. brine, dried over anhydrous Na2SO4, and the solvent
was evaporated to dryness. The crude residue was purified by
flash chromatography on silica gel (CH2Cl2–MeOH, 100:1) to
afford pure 2,2-di(1H-indol-3-yl)-N,N-phenyl acetamide deriva-
tives 4 (69–91% yield).
(7) (a) Bartoli, G.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.;
Sambri, L. Synthesis 2004, 895. (b) Huo, C. D.; Sun, C. G.; Wang,
C.; Jia, X. D.; Chang, W. J. ACS Sustainable Chem. Eng. 2013, 1,
549.
(8) For selected examples, see: (a) Parvathaneni, S. P.; Pamanji, R.;
Janapala, V. R.; Uppalapati, S. K.; Balasubramanian, S.;
Mandapati, M. R. Eur. J. Med. Chem. 2014, 84, 155. (b) Pankaj, C.;
Singh, C. S. Chem. Eur. J. 2010, 16, 7709. (c) Kurosh, R. M.; Negin,
D. J. Mol. Catal. A: Chem. 2014, 392, 97. (d) Kurosh, R. M.;
Masoumeh, S. K.; Homayun, T. A. Tetrahedron 2010, 66, 2316.
(9) For selected examples, see: (a) Gibbs, T. J. K.; Tomkinson, N. C. O.
Org. Biomol. Chem. 2005, 3, 4043. (b) Yadav, J. S.; SubbaReddy, B.
V.; Gayathri, K. U.; Meraj, S.; Prasad, A. R. Synthesis 2006, 4121.
(c) Kinthada, L. K.; Ghosh, S.; De, S.; Bhunia, S.; Dey, D.; Bisai, A.
Org. Biomol. Chem. 2013, 11, 6984. (d) Chakrabarty, M.;
Mukherjee, R.; Mukherji, A.; Arima, S.; Harigaya, Y. Heterocycles
2006, 68, 1659. (e) Abe, T.; Nakamura, S.; Yanada, R.; Choshi, T.;
Hibino, S.; Ishikura, M. Org. Lett. 2013, 15, 3622.
Analytical Data of Some Typical Compounds
2-Hydroxy-2-(1H-indol-3-yl)-N-phenylacetamide (3a)
Yield 84%; yellow solid, mp 150–152 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 11.00 (s, 1 H), 9.90 (s, 1 H), 7.70 (s, 3 H), 7.33–
7.28 (m, 4 H), 7.03–6.96 (m, 3 H), 6.08 (s, 1 H), 5.32 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): δ = 171.9, 138.9, 136.6, 128.8,
128.0, 126.0, 124.3, 123.6, 121.4, 119.9, 118.9, 114.8, 111.7,
68.9. ESI-HRMS: m/z [M
+
Na+] calcd for C16H14N2O2Na:
289.0947; found: 289.0961. Anal. Calcd: C, 72.17; H, 5.30; N,
10.52. Found: C, 72.10; H, 5.35; N, 10.53.
2,2-Di(1H-indol-3-yl)-N-phenylacetamide (4a)
(10) (a) Deng, J.; Zhang, S. L.; Ding, P.; Jiang, H. L.; Wang, W.; Li, J. Adv.
Synth. Catal. 2010, 352, 833. (b) Sasaki, S.; Ikekame, Y.;
Tanayama, M.; Yamauchi, T.; Higashiyama, K. Synlett 2012, 23,
2699.
(11) N-Substituted glyoxylamides 1 were prepared according to the
reported procedures, see: (a) Chen, W. S.; Liu, Y. Z.; Chen, Z. R.
Eur. J. Org. Chem. 2005, 1665. (b) Wu, W. B.; Yuan, X. Q.; Hu, J.;
Wu, X. X.; Wei, Y.; Liu, Z. W.; Lu, J. Z.; Ye, J. X. Org. Lett. 2013, 15,
17.
Yield 89%; yellow solid, mp 139–141 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 10.90 (s, 2 H), 10.34 (s, 1 H), 7.65–7.57 (m, 4 H),
7.35 (m, 2 H), 7.28 (t, J = 8.0 Hz, 2 H), 7.19 (s, 2 H), 7.07–7.00 (m,
3 H), 6.95 (t, J = 8.0 Hz, 2 H) 5.55 (s, 1 H). 13C NMR (150 MHz,
DMSO-d6): δ = 171.0, 138.9, 137.0, 128.8, 126.9, 126.1, 124.1,
121.5, 120.4, 119.3, 118.0, 112.8, 111.0, 42.0. ESI-HRMS: m/z [M
+ Na+]: calcd for C24H19N3ONa: 388.1420; found: 388.1425. Anal.
Calcd: C, 78.88; H, 5.24; N, 11.50. Found: C, 78.79; H, 4.23; N,
9.49.
(12) Indoles 2 were purchased from ASTATECH and J&K Scientific
Ltd. except ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate and 2-
[(1-methyl-1H-indol-6-yl) oxy]acetamide. Ethyl 2-[(1-methyl-
1H-indol-6-yl)oxy]acetate was synthesized according to the lit-
erature procedures, see: (a) Finefield, J. M.; Williams, R. M. J.
Org. Chem. 2010, 75, 2785. (b) Akao, A.; Nonoyama, N.; Mase, T.;
Yasuda, N. Org. Process Res. Dev. 2006, 10, 1178. (c) Choy, P. Y.;
Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2011, 76, 80. (d) Ontoria, J.
M.; Marco, S. D.; Conte, I.; Francesco, M. E. D.; Gardelli, C.; Koch,
U.; Matassa, V. G.; Poma, M.; Steinkühler, C.; Volpari, C.; Harper,
S. J. Med. Chem. 2004, 47, 6443. 2-[(1-methyl-1H-indol-6-yl)
oxy]acetamide was synthesized from ethyl 2-[(1-methyl-1H-
indol-6-yl)oxy]acetate according to the literature procedures,
see: (e) Kreutter, K. D.; Lu, T. B.; Lee, L.; Giardino, E. C.; Patel, S.;
2-[(3-{2-[(4-chlorophenyl)amino]-1-(1H-indol-3-yl)-2-
oxoethyl}-1-methyl-1H-indol-6-yl)oxy]acetate (3d′)
Yield 84%; brown solid, mp 194–196 °C. 1H NMR (600 MHz,
DMSO-d6): δ = 10.92 (s, 1 H), 10.47 (s, 1 H), 7.67 (d, J = 8.4 Hz, 2
H), 7.57 (d, J = 8.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.36–7.18 (m,
2 H), 7.18 (m, 1 H), 7.07–7.04 (m, 2 H), 6.96–6.94 (m, 2 H), 6.69–
6.67 (m, 1 H), 5.48 (s, 1 H), 4.77 (s, 2 H), 4.17 (q, J = 7.2 Hz, 2 H),
3.67 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H). 13C NMR (150 MHz, DMSO-
d6): δ = 171.9, 169.2, 154.5, 139.3, 137.8, 136.9, 132.5, 131.0,
128.5, 127.0, 122.9, 122.1, 121.6, 121.0, 120.7, 119.8, 112.5,
109.9, 98.6, 65.6, 42.6, 40.7, 32.4, 14.2. ESI-HRMS: m/z [M + Na+]
calcd for C29H26ClN3O4Na: 538.1504; found: 538.1501. Anal.
Calcd: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.56; H, 5.00; N,
8.19.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2261–2266