Synthesis of 3-indolylarylmethanamides by samarium triiodide catalyzed Friedel-Crafts amidoalkylation

Article abstract of DOI:10.1055/s-2008-1067192

The amidoalkylation of indoles with N-(α-benzotriazol-1-ylalkyl) amides was smoothly realized with samarium triiodide as a catalyst to give a series of novel 3-indolyl arylmethanamides with good yields and selectivities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067192

2582
PAPER
Synthesis of 3-Indolylarylmethanamides by Samarium Triiodide Catalyzed
Friedel–Crafts Amidoalkylation
Amidoalkylation
o
u
f
Indole
s
i Mao, Xiaoxia Wang,* Wencun Wang, Liang He, Lichun Kong, Junhua Liu
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University,
Jinhua 321004, P. R. of China
Fax +86(579)82282595; E-mail: wangxiaoxia@zjnu.cn
Received 31 January 2008; revised 9 May 2008
N-protected imines, such as: 1) modification of the imine
Abstract: The amidoalkylation of indoles with N-(a-benzotriazol-
nitrogen with sulfonyl4a–4d using a chiral copper-complex
1-ylalkyl)amides was smoothly realized with samarium triiodide as
or organic phosphoric acid as the catalyst; 2) introduction
a catalyst to give a series of novel 3-indolyl arylmethanamides with
of trifluoromethyl4e,f to the imino nitrogen, catalyzed by
good yields and selectivities.
boron trifluoride; 3) employment of N-alkoxycarbonyl
Key words: amidoalkylation, N-(a-benzotriazol-1-ylalkyl)amides,
protected a-imino esters4g,h with a copper complex or bi-
phenylphosphine–palladium(II) complex as the catalyst.
In addition, treatment of 3-lithio-1-TBDMS-indole with
indoles, samarium triiodide, catalysis
aromatic tosylaldimines offered another approach to the
3-Substituted indoles usually possess numerous biologi-
functionalized 3-indolylarylmethanamines.5 The ald-
cal activities, act as important intermediates for the syn-
imines may also be transformed into N-acyl iminium salts
thesis of indole-based alkaloids or pharmaceutical
in the presence of acyl chlorides,6a,b which has realized the
compounds, and constitute a key structural unit for many
amidoalkylation of indoles smoothly without any catalyst.
natural products.1 Among them, the 3-indolyl arylmethan-
Although the method seems simple and practical, N-acyl
amine derivatives exist in a number of natural and unnat-
iminium salts are generally hygroscopic and sensitive to
ural products with significant biological activities2 and
hydrolysis6a and must be prepared under extreme anhy-
have attracted the attention of many synthetic chemists in
drous conditions, along with the involvement of environ-
recent years.
mentally toxic media. The aminoalkylbenzotriazoles have
The aza-Friedel–Crafts reaction of indole with imines cat-
been used to alkylate the 3-position of indoles to afford 3-
alyzed by Lewis acids provide straightforward access to
indolylmethyleneamines in the presence of such Lewis
acids as AlCl3 or ZnCl2.6c Unfortunately, the method was
limited to the preparation of compounds without aryl sub-
stitution on the methylene. Herein we wish to report the
synthesis of 3-indolylarylmethanamides by amidoalkyl-
ation of indoles with N-(a-benzotriazol-1-ylalkyl)amides.
3-indolylarylmethanamines, however, only moderate
yields have been obtained3a,b and the bisindolylmethanes
were always formed as a by-product in significant
amounts3a,b or even as the sole product.3c Very recently, a
three-component aza-Friedel–Crafts reaction3d of alde-
hyde, amine, and indole in water was developed, cata-
lyzed by carboxylic acid, which provided the 3-
indolylarylmethanamine. Despite the mild reaction condi-
tions and avoidance of the bisindolyl compound forma-
tion, the amine was limited only to o-anisidine. Good
yields of the 3-indolylarylmethanamine derivatives as
well as high enantioselectivities could be obtained by an
alternative method involving the reaction of indoles with
N-(a-Benzotriazol-1-ylalkyl)amides are readily accessi-
ble amidoalkylation reagents, which are prepared from the
three-component condensation of a primary (or second-
ary) amide, benzotriazole and an aldehyde.7 The reagents
have been used for amidoalkylation of many compounds,
such as active methylene compounds,7a,8 alcohols and thi-
ols,9 active aromatic compounds10 and amines.11 In the
O
O
Bt
OMe
HN
catalyst
reflux
+
N
H
N
H
OMe
N
H
3a
1a
2a
N
N
N
Bt =
Scheme 1
SYNTHESIS 2008, No. 16, pp 2582–2588
x
x.
x
x
.
2
0
0
8
Advanced online publication: 24.07.2008
DOI: 10.1055/s-2008-1067192; Art ID: F02708SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Amidoalkylation of Indoles
2583
Table 1 Lewis Acid Catalyzed Friedel–Crafts Amindoalkylation of
Indoles with 1aa
Table 2 Samarium Triiodide Catalyzed Friedel–Crafts Amido-
alkylation of Indoles with N-(a-Benzotriazol-1-ylalkyl)amides
Entry R1
R2
Indole
ProductTime Yield
(h) (%)a
Entry Lewis acid Catalyst Solvent
(mol%)
Time
(h)
Yield
(%)b
c
1
2
3
4
5
6
7
8
ZnCl2
AlCl3
FeCl3
SmI3
SmI3
SmI3
SmI3
SmI3
100
100
100
50
THF
20
20
20
16
16
16
16
16
–
c
1
Me
4-MeOC6H4
3a
16
84
THF
–
N
H
c
THF
–
2a
2a
2
3
4
Me
Ph
Ph
Ph
3b
3c
3d
16
20
16
86
73
87
THF
85
84
56
63
34
Ph
2a
2a
20
THF
4-O2NC6H4
20
MeCN
CH2Cl2
Toluene
20
5
6
7
8
Me
Me
Me
Me
4-MeOC6H4
Ph
3e
3f
16
20
20
24
75
80
70
76
N
H
20
2b
2b
a All reactions were carried out under reflux unless otherwise speci-
fied.
b Isolated yield.
c No reaction.
Ph
4-MeOC6H4
Ph
3g
3h
N
H
process of the amidoalkylation reaction, N-(a-benzotriaz-
ol-1-ylalkyl)amides furnish the azomethine electrophile
by acid-promoted elimination of the benzotriazolyl group,
which reacts with nucleophiles.12 In this paper, we present
the results of our studies on the reaction between N-(a-
benzotriazol-1-ylalkyl)amides and indoles catalyzed by
samarium triiodide, providing 3-indolylarylmethanamine
derivatives in good yields.
2c
2c
9
Me
4-MeOC6H4
3i
20
72
N
Bn
2d
2d
10 Me
11 Ph
12 Me
Ph
Ph
Ph
3j
3k
3l
20
20
20
75
63
65
The reaction of N-[(a-benzotriazol-1-yl)(4-methoxyphe-
nyl)methyl]acetamide (1a) with indole catalyzed by
Lewis acids was initially performed in order to optimize
the reaction conditions (Scheme 1).
Br
N
H
2e
2e
A series of Lewis acids were screened to promote the re-
action shown in Scheme 1, and the results are listed in
Table 1. Surprisingly, commonly used and less expensive
Lewis acids (ZnCl2, AlCl3 and FeCl3) tested in refluxing
tetrahydrofuran showed no catalytic activity here; how-
ever, the employment of 50 mol% of samarium triiodide
(SmI3) afforded the desired product 3a in 85% yield
(Table 1, entry 4). Reducing the catalyst load to 20 mol%
did not decrease the reaction efficiency and afforded a
comparable yield in the same period of time (Table 1, en-
try 5).
NO2
b
13 Ph
Ph
–
20
–
N
H
2f
14 Ph
15 Me
4-O2NC6H4
3m
3n
20
20
76
68
N
H
2g
The effect of the solvent was also investigated; the reac-
tion of 1a and 2a catalyzed by samarium triiodide (20
mol%) was performed in tetrahydrofuran, acetonitrile,
dichloromethane and toluene, respectively (Table 1, en-
tries 5–8). Product 3a could be obtained in 34–84% yields
in 16 hours. The reaction carried out in tetrahydrofuran af-
forded the highest yield (Table 1, entry 5), thus, reflux in
THF with 20 mol% of SmI3 catalyst was established as the
optimized reaction conditions.
4-MeOC6H4 2g
16 Me
4-MeOC6H4
3o
16
20
78
–
N
H
2h
O2N
b
17 Me
4-MeOC6H4
–
N
H
A
variety of indoles and N-(a-benzotriazol-1-yl-
2i
alkyl)amides reacted under the established conditions,
demonstrating the generality of the method for the prepa-
a Yield of pure isolated product.
b No reaction.
Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York

2584
H. Mao et al.
of 3-indolylarylmethanamine
PAPER
ration
derivatives tunately, instead of the desired amidoalkylation product 5,
the bisindole compound 6 was formed (determined by
comparison with an authentic sample).
(Scheme 2). The results are listed in Table 2.
As can be seen, unsubstituted indole 2a underwent 3-ami-
doalkylation smoothly to afford 3a–d in 73–87% yields A control experiment in the absence of indole showed that
(Table 2, entries 1–4). 2-Methylindole also showed good decomposition of 4 took place under the reaction condi-
reactivity, leading to 3e and 3f in 75% and 80% yield, re- tions in one hour (benzaldehyde and benzotriazole were
spectively, in 16–20 hours (Table 2, entries 5 and 6). detected). Apparently, compound 4 underwent samarium
However, with a bulky group such as phenyl at the 2-po- triiodide catalyzed decomposition in preference to ami-
sition of the indole, the reaction required longer times to doalkylation of the indole. It was reported that indoles
afford satisfactory yields (Table 2, entries 7 and 8). Long- were prone to dimerization with aldehydes or ketones in
er reaction times were also necessary when N-benzylin- the presence of a Lewis acid.13 Therefore, the formation of
dole was used (Table 2, entries 9 and 10). The electronic 6 could be ascribed to the reaction of indole with the in
effect of the substituent on the indole also exerted influ- situ produced benzaldehyde.
ence on the amidoalkylation reaction; with electron-do-
nating groups such as methyl, the reaction gave 68–78%
yields (Table 2, entries 14, 15 and 16), while with elec-
A possible mechanism may also be proposed for the for-
mation of 3. According to previous reports that, assisted
by Lewis acids, benzotriazole adducts could form a ben-
tron-withdrawing groups such as bromo, it afforded lower
zotriazole anion and the corresponding carbocation that
yields (Table 2, entries 11 and 12). Although the reaction
could then react with nucleophiles,10,14 the samarium tri-
seems general, we did encounter two failures: substrates
iodide catalyzed amidoalkylation of indoles with N-(a-
benzotriazol-1-ylalkyl)amides could be described as
2f and 2i with a strongly electron-withdrawing nitro group
located at the 4- or 5-position of the indole failed to pro-
shown in Scheme 4. It should be mentioned that when R2
duce the expected amidoalkylation products and no reac-
is an aryl group, loss of the benzotriazole anion involves
tion occurred (Table 2, entries 13 and 17). In all the cases,
the cleavage of a more active benzylic C–N bond and
could facilitate the amidoalkylation process. However, in
the R1 group in amidoalkylation reagents 1 could be either
methyl or phenyl, and R2 should be an aryl. When R2 is an
cases where R2 is an alkyl group such as propyl, breaking
alkyl such as propyl, the amidoalkylation could not occur
the C–N bond becomes quite difficult even with the assis-
and the starting materials were recovered almost quantita-
tance of catalyst, therefore no reaction could be observed.
tively.
In conclusion, we have developed a samarium triiodide
catalyzed amidoalkylation of indoles with N-(a-benzotri-
azol-1-ylalkyl)amides, thus providing a facile and clean
To extend the application scope of the reaction, methyl 1-
benzotriazol-1-yl phenylmethylcarbamate (4) was reacted
with indole under the same conditions (Scheme 3). Unfor-
synthesis of 3-indolyl arylmethanamides.
R1
O
R2
R3
R6
HN
R6
R5
O
Bt
R5
SmI3 (20 mol%)
THF, reflux
R3
+
R1
N
R2
N
R4
H
N
R4
2
1
3
Scheme 2
MeO
O
H
N
5
X
N
H
O
Bt
SmI3 (20 mol%)
THF, reflux
+
MeO
N
H
N
H
2a
4
HN
NH
6
62%
Scheme 3
Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York

PAPER
Amidoalkylation of Indoles
2585
SmI3
R2
O
O
O
Bt
R1
N
R2
R1
N
H
R2
R1
N
H
H
1
BtSmI3
H+
BtH
SmI3
R4
N
R4
R4
N
R3
R2
R3
N
R5
SmI3
O
R3
R5
R6
R5
R6
H
2
NH
R1
R6
R1
N
R2
N
R2
O
I3Sm
O
R1
3
SmI3
Scheme 4
THF was distilled from sodium-benzophenone immediately prior to
use. 1H NMR (400 MHz) spectra were recorded on a Bruker AV400
NMR instrument as DMSO or CDCl3 solutions using TMS as inter-
nal standard. Chemical shifts (d) are reported in ppm and coupling
constants (J) are given in Hz. IR spectra were recorded as films or
using KBr disks with a NEXUS 670 FTIR spectrometer. Mass spec-
tra were performed on a Thermo Finnigan GC-MS instrument
(Trace DSQ). Elemental analyses were performed on a Vario-ELIII
instrument. N-(a-Benzotriazol-1-ylalkyl)amides 1 were easily pre-
pared from benzotriazole, aldehydes and an amide in toluene by a
previously described method.7 Methyl 1-benzotriazol-1-yl phenyl-
methylcarbamate (4) was prepared according to the general proce-
dure for the preparation of benzyloxycarbonylamino-1-(1-
benzotriazolyl)alkanes.15 Petroleum ether (PE), where used, had a
boiling range of 60–90 °C.
MS (EI, 70 eV): m/z (%) = 295 (5.4) [M + H]+, 177 (99.2) [M – in-
dole]+, 162 (100) [177 – CH3]+, 134 (99.5), 107 (29.7), 92 (46.3), 77
(57.1).
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C,
73.63; H, 5.90; N, 9.63.
N-[(1H-Indol-3-yl)(phenyl)methyl]acetamide (3b)
White powder; mp 176–179 °C.
IR (KBr): 3407, 3381, 3305, 1646, 1538, 742 cm–1.
1H NMR (400 Hz, CDCl3): d = 2.01 (s, 3 H), 6.13–6.22 (m, 2 H),
6.52–6.71 (m, 1 H), 6.69 (s, 1 H), 7.07–7.11 (m, 1 H), 7.19–7.34
(m, 5 H), 7.44 (m, 1 H), 8.41 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 23.4, 50.4, 111.5, 117.2, 119.3,
119.9, 122.5, 123.6, 125.9, 127.0, 127.2, 128.5, 136.7, 141.3, 169.2.
MS (EI, 70 eV): m/z (%) = 265 (75.1) [M + H]+, 264 (100) [M]+,
222 (98.9) [M + H – CH3CO]+, 205 (99.1), 145 (52.5), 118 (98.3),
104 (90.7), 77 (30.0).
Friedel–Crafts Amidoalkylation of Indoles with N-(a-Benzotri-
azol-1-ylalkyl)amides Catalyzed by SmI3; General Procedure
To samarium powder (0.03 g, 0.2 mmol) in a flask was added anhy-
drous THF (10 mL) and I2 (0.076 g, 0.3 mmol) and the mixture was
stirred at r.t. for 1 h. To the SmI3–THF suspension thus prepared
was added N-(a-benzotriazol-1-ylalkyl)amide 1 (1.0 mmol) and in-
dole 2 (1.0 mmol). The reaction mixture was stirred until the disap-
pearance of 1 was observed, then the reaction was quenched with aq
HCl (0.1M, 3 mL) and extracted with EtOAc (3 × 30 mL). The com-
bined organic extracts were washed with sat. Na2S2O3 (10 mL), sat.
Na2CO3 (10 mL), then with brine (2 × 10 mL) and were dried over
anhydrous Na2SO4. Removal of the solvent under reduced pressure
afforded the crude product, which was purified by column chroma-
tography (EtOAc–PE, 1:2) to give the desired product 3.
Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C,
77.47; H, 5.87; N, 10.43.
N-[(1H-Indol-3-yl)(phenyl)methyl]benzamide (3c)
White powder; mp 178–180 °C.
IR (KBr): 3410, 3299, 3309, 1642, 1524, 701 cm–1.
1H NMR (400 Hz, DMSO-d6): d = 6.63 (d, J = 8.0 Hz, 1 H), 6.88 (s,
1 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.07–7.10 (t, J = 8.0 Hz, 1 H), 7.28–
7.53 (m, 10 H), 7.93 (d, J = 8.0 Hz, 2 H), 9.19 (d, J = 8.0 Hz, 1 H),
11.0 (s, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 50.3, 112.1, 116.9, 119.2, 121.7,
124.4, 126.6, 127.3, 127.8, 128.0, 128.1, 128.6, 128.8, 131.6, 135.1,
137.0, 143.3, 166.2.
N-[(1H-Indol-3-yl)(4-methoxyphenyl)methyl]acetamide (3a)
White powder; mp 162–165 °C.
IR (KBr): 3370, 3300, 1642, 1513, 1400, 743 cm–1.
MS (EI, 70 eV): m/z (%) = 207 (16.3) [M – indolyl]+, 206 (100) [M
1H NMR (400 Hz, CDCl3): d = 2.03 (s, 3 H), 3.80 (s, 3 H), 6.12 (d,
J = 8.0 Hz, 1 H), 6.46 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.86 (d,
J = 8.0 Hz, 2 H), 7.07 (t, J = 8.0 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H),
7.25–7.29 (m, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz,
1 H), 8.24 (br s, 1 H).
13C NMR (100 Hz, CDCl3): d = 23.1, 49.0, 55.5, 112.0, 114.0,
117.4, 119.0, 119.4, 121.7, 123.8, 126.4, 128.7, 135.5, 137.1, 158.5,
168.6.
– PhCONH]+, 105 (32.0), 91 (38.2).
Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C,
81.25; H, 5.68; N, 8.66.
N-[(1H-Indol-3-yl)(4-nitrophenyl)methyl]benzamide (3d)
White powder; mp 107–110 °C.
IR (KBr): 3415, 3299, 1642, 1520, 744 cm–1.
Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York

2586
H. Mao et al.
PAPER
1H NMR (400 Hz, DMSO-d6): d = 6.68–6.73 (m, 1 H), 6.91–6.98
(m, 2 H), 7.06–7.10 (m, 1 H), 7.43–7.51 (m, 4 H), 7.76 (d, J = 8.0
Hz, 2 H), 7.90 (d, J = 8.0 Hz, 2 H), 8.22 (d, J = 8.0 Hz, 2 H), 9.33
(d, J = 8.0 Hz, 1 H), 11.00 (s, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 50.2, 112.2, 115.5, 119.0, 119.4,
122.0, 124.0, 124.7, 126.4, 128.1, 128.7, 129.0, 131.8, 134.7, 137.0,
147.0, 151.1, 166.5.
IR (KBr): 3418, 3269, 3060, 1657, 1495, 743 cm–1.
1H NMR (400 Hz, CDCl3): d = 2.07 (s, 3 H), 6.30 (s, 1 H), 6.70 (d,
J = 8.0 Hz, 1 H), 7.01 (t, J = 8.0 Hz, 1 H), 7.19–7.31 (m, 6 H), 7.40–
7.49 (m, 4 H), 7.59 (d, J = 8.0 Hz, 2 H), 8.25 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 22.9, 49.3, 111.8, 112.6, 119.2,
120.9, 121.9, 126.9, 127.1, 127.2, 128.3, 128.6, 129.0, 129.2, 132.9,
136.3, 136.8, 142.9, 169.2.
MS (EI, 70 eV): m/z (%) = 207 (100) [M + H – NO2 – PhCONH2]+,
178 (16.5), 129 (26.4), 117 (99.2), 91 (96.3), 77 (61.1).
MS (EI, 70 eV): m/z (%) = 220 (100) [M – Ph – COCH3]+, 205
(99.8), 177 (95.3), 145 (98.3), 105 (66.8), 57 (99.7).
Anal. Calcd for C22H17N3O3: C, 71.15; H, 4.61; N, 11.31. Found: C,
70.99; H, 4.46; N, 11.15.
Anal. Calcd for C23H20N2O: C, 81.15; H, 5.92; N, 8.23. Found: C,
80.96; H, 6.07; N, 8.32.
N-[(4-Methoxyphenyl)(2-methyl-1H-indol-3-yl)methyl]acet-
amide (3e)
White powder; mp 160–163 °C.
IR (KBr): 3405, 3268, 3058, 1630, 1544, 696 cm–1.
1H NMR (400 Hz, DMSO-d6): d = 1.92 (s, 3 H), 2.34 (s, 3 H), 3.35
(s, 3 H), 6.33 (d, J = 8.0 Hz, 1 H), 6.85–6.93 (m, 2 H), 7.18–7.37
(m, 6 H), 8.63 (s, 1 H), 10.80 (s, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 21.8, 23.1, 40.0, 49.6, 111.7,
116.5, 118.8, 123.3, 124.0, 126.6, 127.1, 127.5, 128.5, 135.4, 143.6,
168.7.
N-[(1-Benzyl-1H-indol-3-yl)(4-methoxyphenyl)methyl]acet-
amide (3i)
White powder; mp 174–176 °C.
IR (KBr): 3327, 3131, 1693, 1543, 753 cm–1.
1H NMR (400 Hz, DMSO-d6): d = 1.87 (s, 3 H), 3.72 (s, 3 H), 5.34
(s, 2 H), 6.29 (d, J = 8.0 Hz, 1 H), 7.39–6.87 (m, 14 H), 8.62 (d,
J = 8.0 Hz, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 23.1, 48.9, 49.4, 55.5, 110.7,
114.0, 117.3, 119.4, 119.7, 122.0, 127.0, 127.4, 127.6, 127.8, 128.7,
129.0, 135.2, 136.9, 138.8, 158.5, 168.6.
MS (EI, 70 eV): m/z (%) = 218 (30.1) [M – H – OCH3
–
MS (EI, 70 eV): m/z (%) = 327 (3.1) [M + H – NHCOCH3]+, 221
(98.3), 205 (100) [M + H – PhCH2 – OCH3 – CH3CONH]+, 177
(66.4), 145 (75.9), 119 (99.1), 91 (99.7), 64 (99.5).
NHCOCH3]+, 207 (78.9), 117 (96.3), 91 (100) [PhCH2]+, 77 (22.6).
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C,
74.13; H, 6.40; N, 9.17.
Anal. Calcd for C25H24N2O2: C, 78.10; H, 6.29; N, 7.29. Found: C,
78.32; H, 6.16; N, 7.17.
N-[(2-Methyl-1H-indol-3-yl)(phenyl)methyl]acetamide (3f)
White powder; mp 160–163 °C.
IR (KBr): 3382, 3324, 3057, 1639, 1536, 744 cm–1.
N-[(1-Benzyl-1H-indol-3-yl)(phenyl)methyl]acetamide (3j)
White powder; mp 181–184 °C.
1H NMR (400 Hz, CDCl3): d = 2.05 (s, 3 H), 2.37 (s, 3 H), 6.25 (d,
J = 8.0 Hz, 1 H), 6.54 (d, J = 8.0 Hz, 1 H), 6.92–6.96 (m, 1 H), 7.09
(d, J = 8.0 Hz, 2 H), 7.21–7.30 (m, 5 H), 8.23 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 12.0, 23.4, 49.2, 110.7, 111.5,
118.5, 119.6, 121.3, 126.6, 126.9, 128.4, 129.1, 133.3, 135.5, 141.2,
169.5.
MS (EI, 70 eV): m/z (%) = 279 (30.6) [M + H]+, 278 (100) [M]+,
235 (40.5), 220 (95.2), 204 (31.7), 148 (99.3), 132 (45.0), 106
(94.3).
IR (KBr): 3300, 3059, 1641, 1538, 741 cm–1.
1H NMR (400 Hz, CDCl3): d = 2.05 (s, 3 H), 5.23 (s, 2 H), 6.10 (d,
J = 8.0 Hz, 1 H), 6.54 (d, J = 8.0 Hz, 1 H), 6.74 (s, 1 H), 7.08 (t,
J = 6.8 Hz, 3 H), 7.19 (s, 1 H), 7.25–7.29 (m, 5 H), 7.32–7.40 (m,
4 H), 7.48 (d, J = 8.0 Hz, 1 H).
13C NMR (100 Hz, CDCl3): d = 23.4, 50.1, 50.3, 110.1, 116.5,
119.6, 119.8, 122.4, 126.7, 127.0, 127.3, 127.55, 127.59, 127.7,
128.5, 128.8, 137.1, 137.3, 141.3, 169.2.
MS (EI, 70 eV): m/z (%) = 341 (100) [M + 2H – CH3]+, 298 (51.3),
Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C,
77.48; H, 6.64; N, 9.89.
204 (73.1), 117 (34.6), 104 (70.9), 91 (18.3).
Anal. Calcd for C24H22N2O: C, 81.33; H, 6.26; N, 7.90. Found: C,
81.54; H, 6.32; N, 7.79.
N-[(4-Methoxyphenyl)(2-phenyl-1H-indol-3-yl)methyl]acet-
amide (3g)
White powder; mp 200–202 °C.
IR (KBr): 3421, 3270, 1662, 1510, 747 cm–1.
1H NMR (400 Hz, CDCl3): d = 2.03 (s, 3 H), 3.77 (s, 3 H), 6.30 (d,
J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 2 H),
7.02 (t, J = 8.0 Hz, 1 H), 7.18–7.26 (m, 3 H), 7.38–7.46 (m, 4 H),
7.57 (d, J = 8.0 Hz, 2 H), 8.30 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 23.4, 49.3, 55.3, 111.4, 112.0,
113.8, 119.7, 120.1, 122.5, 126.9, 128.0, 128.48, 128.53, 129.1,
132.2, 133.6, 136.2, 136.5, 158.5, 169.4.
N-[(5-Bromo-1H-indol-3-yl)(phenyl)methyl]benzamide (3k)
White powder; mp 179–181 °C.
IR (KBr): 3310, 3127, 1656, 1510, 826 cm–1.
1H NMR (400 Hz, CDCl3): d = 6.64 (d, J = 8.0 Hz, 1 H), 6.73 (d,
J = 7.6 Hz, 1 H), 6.81 (s, 1 H), 7.21–7.52 (m, 8 H), 7.62 (s, 1 H),
7.79–7.84 (m, 3 H), 8.36 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 50.8, 112.9, 113.3, 116.9, 121.9,
124.9, 125.5, 125.9, 127.0, 127.1, 127.2, 127.6, 128.7, 131.7, 134.2,
135.4, 140.8, 166.7.
MS (EI, 70 eV): m/z (%) = 220 (67.4), 205 (100) [M – Br – Ph-
MS (EI, 70 eV): m/z (%) = 193 (99.5) [2-phenyl-3-indolyl]+, 163
(68.8), 115 (26.4), 92 (98.9), 77 (29.7), 71 (69.3).
CONH]+, 177 (30.7), 145 (32.0), 115 (15.8), 105 (21.1), 81 (21.1).
Anal. Calcd for C22H17BrN2O: C, 65.20; H, 4.23; N, 6.91. Found: C,
65.53; H, 4.21; N, 6.81.
Anal. Calcd for C24H22N2O2: C, 77.81; H, 5.99; N, 7.56. Found: C,
77.65; H, 6.12; N, 7.38.
N-[(5-Bromo-1H-indol-3-yl)(phenyl)methyl]acetamide (3l)
White powder; mp 140–143 °C.
IR (KBr): 3298, 3122, 1668, 1517, 1401, 750 cm–1.
N-[Phenyl(2-phenyl-1H-indol-3-yl)methyl]acetamide (3h)
White powder; mp 250 °C (dec.).
Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York

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Amidoalkylation of Indoles
2587
1H NMR (400 Hz, DMSO-d6): d = 1.90 (s, 3 H), 6.32 (d, J = 8.0 Hz,
1 H), 7.00 (s, 1 H), 7.17–7.27 (m, 2 H), 7.34–7.36 (m, 5 H), 7.49 (s,
1 H), 8.68 (d, J = 8.0 Hz, 1 H), 11.2 (s, 1 H).
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C,
74.19; H, 6.37; N, 9.15.
13C NMR (100 Hz, DMSO-d6): d = 23.0, 49.3, 111.7, 114.1, 116.8,
121.6, 124.2, 125.7, 127.2, 127.5, 128.1, 128.7, 135.7, 143.0, 168.8.
Acknowledgment
We thank the Department of Science and Technology, Zhejiang
Province (Project No. 2006C11262) for financial support.
MS (EI, 70 eV): m/z (%) = 342 (2.3), 220 (64.1), 205 (100) [M –
Br – PhCONH]+, 177 (20.9), 145 (25.0), 115 (8.1), 105 (15.5), 81
(16.7), 57 (42.8).
Anal. Calcd for C17H15BrN2O: C, 59.49; H, 4.41; N, 8.16. Found: C,
59.28; H, 4.52; N, 8.02.
References
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic
Press: New York, 1970, 105. (b) Sundberg, R. J. Indoles;
Academic Press: San Diego, 1996, 113. (c) Saxton, J. E.
Nat. Prod. Rep. 1997, 14, 559. (d) Lounasmaa, M.;
Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (e) Somei, M.;
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W. G.; Labroo, R. B.; Cohen, L. A.; King, M. M. J. Org.
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L.; Piettre, S. R. Org. Lett. 2001, 3, 515. (j) Molina, P.;
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(b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1. (c) Bosch,
J.; Bennasar, M.-L. Synlett 1995, 587.
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N-[(5-Methyl-1H-indol-3-yl)(4-nitrophenyl)methyl]benzamide
(3m)
Red powder; mp 205–209 °C.
IR (KBr): 3419, 3098, 1641, 1521, 720 cm–1.
1H NMR (400 Hz, DMSO-d6): d = 2.30 (s, 3 H), 6.69 (d, J = 8.0 Hz,
1 H), 6.90 (m, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.43–7.57 (m, 3 H),
7.75 (d, J = 8.0 Hz, 2 H), 7.90–7.96 (m, 2 H), 8.22 (d, J = 8.0 Hz,
2 H), 9.29 (d, J = 8.0 Hz, 1 H), 10.93 (s, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 21.8, 50.1, 111.9, 114.9, 118.5,
124.0, 124.8, 126.3, 126.7, 127.9, 128.1, 128.7, 128.9, 131.8, 134.7,
135.3, 146.9, 151.2, 166.5.
MS (EI, 70 eV): m/z (%) = 340 (3.8) [M + H – NO2]+, 250 (100)
[M – CH3 – PhCONH]+, 235 (98.2), 220 (98.5), 143 (70.6), 134
(99.1), 117 (99.4).
Anal. Calcd for C23H19N3O3: C, 71.67; H, 4.97; N, 10.90. Found: C,
71.78; H, 5.06; N, 10.78.
N-[(4-Methoxyphenyl)(5-methyl-1H-indol-3-yl)methyl]acet-
amide (3n)
(4) (a) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 8156. (b) Jia, Y.; Xie, J.; Duan, H.;
Wang, L.; Zhou, Q. Org. Lett. 2006, 8, 1621. (c) Kang, Q.;
Zhao, Z. A.; You, S. L. J. Am. Chem. Soc. 2007, 129, 1484.
(d) Esquivias, J.; Arrayás, R. G.; Carretero, J. C. Angew.
Chem. Int. Ed. 2006, 45, 629. (e) Gong, Y.; Kato, K.;
Kimoto, H. Synlett 2000, 1058. (f) Gong, Y. Tetrahedron:
Asymmetry 2001, 12, 2121. (g) Johannsen, M. Chem.
Commun. 1999, 2233. (h) Hao, J.; Taktak, S.; Aikawa, K.;
Yusa, Y.; Hatano, M.; Mikami, K. Synlett 2001, 1443.
(5) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850.
(6) (a) Venkov, A. P.; Statkova-Abeghe, S. M.; Donova, A. K.
Cent. Eur. J. Chem. 2004, 2, 234. (b) Sheinkman, A. K.;
Kucherenko, A. P. Chem. Heterocycl. Compd. 1974, 9,
1296. (c) Katritzky, A. R.; Yang, Z.; Lam, J. N. Tetrahedron
1992, 48, 4971.
White powder; mp 194–197 °C.
IR (KBr): 3399, 3285, 2650, 1648, 1511, 745 cm–1.
1H NMR (400 Hz, DMSO-d6): d = 1.89 (s, 3 H), 2.67 (s, 3 H), 3.69
(s, 3 H), 6.29 (d, J = 8.0 Hz, 1 H), 6.77–6.84 (m, 3 H), 6.93 (d,
J = 8.0 Hz, 1 H), 7.14–7.22 (m, 4 H), 8.48 (d, J = 8.0 Hz, 1 H),
10.83 (s, 1 H).
13C NMR (100 Hz, DMSO-d6): d = 12.2, 23.0, 48.1, 55.5, 110.9,
111.9, 113.8, 118.6, 119.1, 120.4, 127.3, 128.1, 133.2, 135.0, 135.6,
158.3, 168.8.
MS (EI, 70 eV): m/z (%) = 310 (3.2) [M + 2H], 220 (99.3), 205
(100) [M + H – CH3 – CH3O – CH3CONH]+, 177 (44.7), 161 (16.1),
145 (52.5), 115 (9.8), 105 (32.6), 57 (98.9).
Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C,
74.26; H, 6.65; N, 8.86.
(7) (a) Katritzky, A. R.; Drewniak, M. J. Chem. Soc., Perkin
Trans.1 1988, 2339. (b) Katritzky, A. R.; Pernak, J.; Fan, W.
Q.; Saczewski, F. J. Org. Chem. 1991, 56, 4439.
(c) Katritzky, A. R.; Drewniak, M. Tetrahedron Lett. 1988,
29, 1755.
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Chem. 1995, 60, 4002. (b) Katritzky, A. R.; Fan, W.-Q.;
Black, M.; Pernak, J. J. Org. Chem. 1992, 57, 547.
(c) Katritzky, A. R.; Takahashi, I.; Fan, W.-Q.; Pernak, J.
Synthesis 1991, 1147.
(10) Katritzky, A. R.; Pernak, J.; Fan, W. Q. Synthesis 1991, 868.
(11) Katritzky, A. R.; Urogdi, L.; Mayence, A. J. Org. Chem.
1990, 55, 2206.
N-[(4-Methoxyphenyl)(4-methyl-1H-indol-3-yl)methyl]acet-
amide (3o)
White powder; mp 199–202 °C.
IR (KBr): 3401, 3380, 3003, 2955, 2838, 1652, 1511, 1253, 748
cm–1.
1H NMR (400 Hz, CDCl3): d = 2.02 (s, 3 H), 2.58 (s, 3 H), 3.79 (s,
3 H), 6.09 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 6.8 Hz, 2 H), 6.85–6.88
(m, 3 H), 7.07–7.11 (m, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.25 (d,
J = 6.8 Hz, 2 H), 8.24 (s, 1 H).
13C NMR (100 Hz, CDCl3): d = 20.1, 23.4, 50.8, 55.3, 109.2, 113.8,
118.4, 121.7, 122.6, 124.3, 124.9, 128.1, 130.9, 134.4, 137.2, 158.7,
168.6.
MS (EI, 70 eV): m/z (%) = 220 (91.8), 205 (100) [M + H – CH3 –
(12) Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K.
Tetrahedron 2005, 61, 2555.
CH3O – CH3CONH]+, 177 (51.2), 145 (36.6), 117 (20.0), 57 (96.3).
Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York

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H. Mao et al.
PAPER
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Synthesis 2008, No. 16, 2582–2588 © Thieme Stuttgart · New York