Selective reduction and functionalization of diethyl 1-alkyl-1H-indole-2,3-dicarboxylates

Article abstract of DOI:10.1016/j.tet.2008.03.011

A convenient and highly selective reduction of easily accessible indole-2,3-dicarboxylates is described. Ten different 1-alkyl-2-formyl-1H-indole-3-carboxylates are obtained in high yield and represent interesting building blocks for novel indoles.

Full text of DOI:10.1016/j.tet.2008.03.011

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4590e4595
www.elsevier.com/locate/tet
Selective reduction and functionalization of diethyl
1-alkyl-1H-indole-2,3-dicarboxylates
Iliyas Ali Sayyed, Karolin Alex, Annegret Tillack, Nicolle Schwarz,
*
Anke Spannenberg, Dirk Michalik, Matthias Beller
Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 25 January 2008; received in revised form 28 February 2008; accepted 3 March 2008
Available online 7 March 2008
Abstract
A convenient and highly selective reduction of easily accessible indole-2,3-dicarboxylates is described. Ten different 1-alkyl-2-formyl-1H-
indole-3-carboxylates are obtained in high yield and represent interesting building blocks for novel indoles.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
improved methods for the synthesis of indoles.8,9 In recent
years especially domino sequences provided efficient comple-
mentary access to various indoles.10 Though, many catalytic
methods exist for the preparation of indoles, still the most
famous route for the construction of the indole ring constitutes
the Fischer indole synthesis.9
For some time, we have been interested in the improve-
ment and exploration of methodologies for the synthesis and
functionalization of indoles. For example, we developed a
titanium-catalyzed as well as zinc-mediated synthesis of func-
tionalized tryptamines and tryptophol derivatives starting from
commercially available arylhydrazines and alkynes.11 More
recently, we reported also a transition-metal-free one-pot syn-
thesis of indole-2,3-dicarboxylates 1 from arylhydrazines and
acetylene dicarboxylates.12 Based on this work, we became in-
terested in the selective reduction of indole-2,3-dicarboxylates
(Scheme 2). Obviously, such a selective protocol would offer
direct access to a variety of novel indole derivatives. Here,
we report our results on this project.
Indole and its derivatives have been termed as ‘privileged
pharmacologic structures’ since they bind to many biological
receptors with high affinity.1 In addition, the indole moiety
is found in numerous natural products and is an important
building block of several families of alkaloids.2 Many of
them have significant biological activity such as Indometha-
cin3 (anti-inflammatory), Vincristine4 (anti-cancer), Fluvasta-
tin5 (cholesterol-lowering), Vinblastine6 (anti-cancer), and
tryptophan, which is an essential amino acid7 (Scheme 1).
CO2H
CO2H
NH2
Me
N
O
N
H
Tryptophan
Indomethacin
Cl
Scheme 1. Selected biologically active indoles.
Clearly, reduction of carboxylic acids, esters, and amides is
an essential tool for the synthesis of aldehydes, alcohols, and
amines.13 Especially, selective reduction to aldehydes is im-
portant, as the highly reactive formyl group can be easily em-
ployed in numerous CeC-, and CeN-coupling reactions as
well as other transformations.
Due to their importance as one of the most represented
building blocks in natural products and known marketed
drugs, there is a continuing interest in the development of
* Corresponding author. Tel.: þ49 (0)381 1281113; fax: þ49 (0)381
12815000.
E-mail address: matthias.beller@catalysis.de (M. Beller).
As shown in Scheme 2, chemoselective reduction of 1H-in-
dole-2,3-dicarboxylates 1 could provide different functionalized
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.011

I.A. Sayyed et al. / Tetrahedron 64 (2008) 4590e4595
4591
CHO
CHO
(2.0 equiv) as well as the reaction time (3 min) afforded the al-
dehyde 5a with an excellent yield of 90% as the only product
of the reaction. To the best of our knowledge, there is no report
on chemoselective reduction of one of the ester group of in-
dole-2,3-dicarboxylates to give 2-formyl-1-alkyl-1H-indole-
3-carboxylates.
N
2
R
OH
CO2Et
OH
OH
N
N
R
CO2Et
CO2Et
N
R
R
3
8
CH3
CO2Et
OH
Table 2
Chemoselective reduction of indole-2,3-dicarboxylates: substrate scopea
1
CH3
N
N
R
R
4
7
Entry
Substrate
Product
CO2Et
Yieldb (%)
CO2Et
CHO
CO2Et
CO2Et
1
CO2Et
CHO
90
CHO or
N
N
N
N
5a
5b
5c
1a
1b
1c
Me
CO2Et
CO2Et
Me
CO2Et
CHO
R
R
6
5
Scheme 2. Potential reductions of the indole-2,3-dicarboxylates.
2
3
4
5
6
7
8
9
62
75
75
86
60
90
67
67
60
N
N
indoles such as 1-alkyl-1H-indole-2,3-dicarbaldehyde 2, (1-al-
kyl-1H-indole-2,3-diyl)-dimethanol 3, 1-alkyl-2,3-dimethyl-
1H-indole 4, isomeric 2,3-formylindole-carboxylates 5 or 6,
and 2,3-hydroxymethylindole-carboxylates 7 or 8.
Bn
Bn
CO2Et
CO2Et
CO2Et
CHO
N
N
Ph
CO2Et
CO2Et
Ph
2. Results and discussion
8
Me
CO2Et
4
3
Me
3a
2
5
6
At the starting point of our investigations, we studied the
reaction of indole 2,3-diester 1a in the presence of standard
metal hydrides at different temperatures. However, in the pres-
ence of NaBH4 and NaCNBH3 only the recovered starting
material was obtained.
Unfortunately, under more drastic conditions treatment of
1a with LiAlH4 (reflux temperature) afforded a complex mix-
ture of several products.
As shown in Table 1 reduction using DIBAL-H at room
temperature was more selective but also afforded a mixture
of products. Here, aldehyde 5a and alcohol 7a along with
the recovered starting material are observed. When the reduc-
tion was carried out in the presence of an excess (2.5 equiv) of
DIBAL-H at ꢀ78 ꢁC for 5 min, full conversion is seen and the
alcohol 7a is obtained as major product in 60% yield along
with some aldehyde 5a. Reducing the amount of DIBAL-H
CHO
1
N
7a N
7
5d
1d
1e
1f
Bn
Bn
CO2Et
CHO
CO2Et
CO2Et
N
Bn
N
Bn
5e
CO2Et
CO2Et
MeO
MeO
CO2Et
CHO
N
Bn
N
Bn
5f
CO2Et
CO2Et
F
F
CO2Et
CHO
N
N
5g
1g Bn
Bn
CO2Et
CO2Et
Cl
Cl
Table 1
Reduction of 1a under different conditions
CO2Et
CHO
N
Bn
N
5h
1h
Bn
CO2Et
CO2Et
CO2Et
CH2OH
reduction
DIBAL-H
+
CO2Et
CO2Et
CO2Et
CHO
Br
Br
N
N
Me
N
CO2Et
CHO
1a
5a
7a
Me
Me
N
Bn
N
5i
1i
Bn
Entry
DIBAL-H
(equiv)
Temp
(ꢁC)
Time
(min)
Yielda
(%) (5a)
Yielda
(%) (7a)
Yielda
(%) (1a)
CO2Et
CO2Et
O2N
O2N
1
2
3
4
5
a
1.5
2.0
2.5
2.0
2.0
0
0
5
5
5
5
3
23
9
24
40
60
30
d
50
49
d
d
d
10
CO2Et
CHO
N
Me
N
Me
5j
1j
ꢀ78
ꢀ78
ꢀ78
30
60
90
a
Reaction conditions: indole 2,3-dicarboxylates (1.0 equiv), DIBAL-H
(2.0 equiv), CH2Cl2, ꢀ78 ꢁC, 3 min.
b
Isolated yield.
Isolated yield.

4592
I.A. Sayyed et al. / Tetrahedron 64 (2008) 4590e4595
presence of NaCNBH3 proceeded smoothly at the formyl
group to give 10 in 80% yield (Scheme 3). Notably, there is
no side reaction at the ester group observed.
Moreover, addition of organometallic reagents progressed
highly selectively at the 2-position. Hence, the reaction of
the vinyl magnesium bromide with 5a yielded the correspond-
ing allylic alcohol 9 in 82%. As expected in the NOESY spec-
trum of compound 9 correlations are found for the proton H-4
with OCH2 and OCH2CH3 as well as NMe with the protons
H-7, H-9, H-10, and H-11 confirming the proposed structure.
3. Conclusion
In conclusion, we have developed a convenient and fast re-
duction of 1H-indole-2,3-dicarboxylates. The resulting prod-
ucts 5aej are obtained with excellent selectivity in good
yield. It is predicted that alkyl 2-formyl-1-alkyl-1H-indole-3-
carboxylates constitute useful building blocks, which will
lead in three easy steps to a variety of novel 2,3-disubstituted
indoles from commercially available arylhydrazines and acet-
ylene dicarboxylates.
Figure 1. X-ray crystal structure of ethyl 2-formyl-1-methyl-1H-indole-3-carb-
oxylate 5a. The thermal ellipsoids correspond to 30% probability.
At this point, it should be noted that there are only few
methods known in the literature for the preparation of
2-formyl-indole-3-carboxylates.14
The promising results obtained with the model compound
encouraged us to study the general scope and limitations of
this protocol for the reduction of different substituted indole-
2,3-dicarboxylates (Table 2). Fluoro-, chloro-, and bromo-
substituted diethyl indole-2,3-dicarboxylates 1ge1i readily
underwent reduction with DIBAL-H to afford the correspond-
ing aldehydes 5ge5i in good yield (67e90% yield) with no
over-reduction of the halide substituents observed. Likewise,
the nitro-substituted indole 1j gave the corresponding alde-
hyde 5j in 60% isolated yield. Previously, the product 1j has
been obtained by nitration of 1a.15 Noteworthy, all isolated
indole-2-aldehydes are stable solids, which did not oxidize
easily in air. In all cases, spectroscopic characterization of
the products by NMR revealed the presence of one aldehyde
and one ester group. The position of the formyl group is estab-
lished unambiguously by NOE measurements. For example, in
the two-dimensional NOESY spectrum of 5d correlations are
found for the proton H-4 with methyl substituent on the phenyl
ring, the OCH2, and the OCH2CH3 confirming the ester group
being placed in C-3 position. In addition, we were able to con-
firm the regioselective reduction by X-ray crystallographic
analysis of 5a (Fig. 1).16 Suitable crystals were obtained by re-
crystallization from dichloromethane.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere.
Chemicals were purchased from Aldrich, Fluka, Acros, and
Strem, and unless otherwise noted were used without further
1
purification. All compounds were characterized by H NMR,
13C NMR, MS, HRMS, and IR spectroscopy. 1H and 13C
NMR spectra were recorded on Bruker AV 300, AV 400,
and AV 500 spectrometers. The H and 13C NMR chemical
shifts are reported relative to the center of solvent resonance
1
(CDCl3: 7.25 (1H), 77.0 (13C)). For compounds 5d, 9, and
10, a complete assignment of the H- and 13C-signal is given
1
based on two-dimensional NMR spectra (COSY, NOESY, and
C,H-correlation). EI mass spectra were recorded on an AMD
402 spectrometer (70 eV, AMD Intectra GmbH). IR spectra
were recorded on an FTIR Nicolet 6700 (Thermo ELECTRON
CORPORATION). GC was performed on a HewlettePackard
HP 6890 chromatograph with a 30 m HP5 column. All yields
reported in Tables 1 and 2 refer to isolated yields.
Obviously, 2-formyl indole-3-carboxylates are versatile
building blocks for selective reactions either at the 2- or 3-po-
sition of the indole ring. Therefore, we turned our attention to
further functionalization reactions of 5a. In some preliminary
studies, the reductive amination with benzylamine in the
4.2. General procedure for the preparation of aldehydes
A solution of diethyl 1-alkyl-1H-indole-2,3-dicarboxylate
(0.25 mmol) in CH2Cl2 at ꢀ78 ꢁC was treated with DIBAL-
H (0.42 ml, 0.5 mmol, 1 M solution in toluene). The reaction
CO2Et
CO2Et
CHO
CO2Et
4
3
3
4
11
BzNH2
MgBr
3a
7a
3a
7a
5
6
5
6
2
9
10
2
NaCNBH3
THF, -78 °C
9
N1
HN
N
N
1
OH
10
7
7
9
Me
Me
Me
10
8
5a
8
Yield: 80%
Yield: 82%
Scheme 3. Potential reduction examples of the indole-2,3-dicarboxylates.

I.A. Sayyed et al. / Tetrahedron 64 (2008) 4590e4595
4593
mixture was stirred at ꢀ78 ꢁC for 3 min and then quenched
with 1 M HCl and MeOH. After warming up to room temper-
ature, H2O was added and the aqueous layer was extracted
three times with Et2O. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in va-
cuo. Chromatography on silica gel with hexaneeEtOAc (95:5)
as the eluent afforded the aldehydes 5aej.
1502, 1482, 1454, 1395, 1381, 1343, 1263, 1241, 1183, 1123,
1065, 1020, 1065, 1020, 940, 773, 753, 698, 562.
4.2.4. Ethyl 1-benzyl-2-formyl-5-methyl-1H-indole-
3-carboxylate (5d)
1
Isolated yield: 75% (mp: 97e98 ꢁC). H NMR (500 MHz,
3
CDCl3): d (ppm)¼1.48 (t, J¼7.2 Hz, 3H, OCH2CH3), 2.48
3
(s, 3H, Me(8)), 4.49 (q, J¼7.2 Hz, 2H, OCH2), 5.87 (s, 2H,
H-8), 7.04 (m, 2H, o-Ph), 7.18e7.25 (m, 4H, H-6, m-, p-
4.2.1. Ethyl 2-formyl-1-methyl-1H-indole-3-carboxylate (5a)
3
1
Ph), 7.30 (d, J6,7¼8.5 Hz, 1H, H-7), 8.09 (br s, 1H, H-4),
Isolated yield: 90% (mp: 76e77 ꢁC). H NMR (400 MHz,
10.79 (s, 1H, CHO). 13C NMR (125.8 MHz, CDCl3):
d (ppm)¼14.5 (OCH2CH3), 21.7 (Me(8)), 48.5 (C-8), 60.8
(OCH2), 110.9 (C-7), 115.3 (C-3), 123.1 (C-4), 126.0 (C-3),
126.4 (o-Ph), 127.5 (p-Ph), 128.7 (m-Ph), 129.3 (C-6), 133.1
(C-5), 135.7 (C-2), 137.0, 137.2 (C-7a, i-Ph), 164.4 (COO),
186.1 (CHO). MS (EI, 70 eV): m/z (relative intensity)¼321
(Mþ, 28), 276 (18), 275 (71), 274 (62), 256 (57), 247 (20),
218 (15), 111 (14), 97 (20), 95 (16), 91 (100), 83 (20), 71
(20), 69 (22), 57 (31), 55 (28). HRMS (EI) calcd for
C20H19NO3: 321.1359; found: 321.1358. FTIR: (KBr,
cmꢀ1)¼3066, 3033, 2985, 2922, 1693, 1669, 1515, 1482,
1452, 1413, 1384, 1351, 1304, 1270, 1234, 1164, 1133, 1030,
1011, 909, 871, 799, 772, 718, 694.
CDCl3): d (ppm)¼1.47 (t, J¼7.2 Hz, 3H), 4.05 (s, 3H), 4.45
(q, J¼7.2 Hz, 2H), 7.26e7.45 (m, 3H), 8.23 (br d,
J¼8.0 Hz, 1H), 10.77 (s, 1H). 13C NMR (100 MHz, CDCl3):
d (ppm)¼14.4 (CH3), 32.5 (CH3), 60.8 (CH2), 110.5 (CH),
115.0, 123.2 (CH), 123.8 (CH), 125.5, 126.9 (CH), 136.3,
136.7, 164.3, 186.5 (CHO). MS (EI, 70 eV): m/z (relative in-
tensity)¼231 (Mþ, 76), 203 (21), 202 (42), 188 (21), 186
(32), 175 (26), 159 (16), 158 (100), 157 (26), 131 (16), 130
(17), 103 (12), 89 (12), 77 (12). HRMS (EI) calcd for
C13H13NO3: 231.0890; found: 231.0889. FTIR: (KBr, cmꢀ1)¼
3077, 3025, 2987, 2906, 1699, 1662, 1612, 1516, 1447, 1396,
1383, 1338, 1267, 1218, 1175, 1160, 1106, 1036, 908, 890,
785, 752, 740, 726, 517.
4.2.5. Ethyl 1-benzyl-2-formyl-5-isopropyl-1H-indole-
3-carboxylate (5e)
4.2.2. Ethyl 1-benzyl-2-formyl-1H-indole-3-carboxylate (5b)
Isolated yield: 62% (mp: 112e113 ꢁC). 1H NMR
(400 MHz, CDCl3): d (ppm)¼1.48 (t, J¼7.2 Hz, 3H), 4.48
(q, J¼7.2 Hz, 2H), 5.87 (s, 2H), 7.04 (m, 2H), 7.17e7.42
(m, 6H), 8.31 (br d, J¼8.0 Hz, 1H), 10.83 (s, 1H). 13C NMR
(100 MHz, CDCl3): d (ppm)¼14.4 (CH3), 48.4 (CH2), 60.9
(CH2), 111.2 (CH), 115.9, 123.3 (CH), 123.9 (CH), 125.7,
126.4 (2CH), 127.2 (CH), 127.5 (CH), 128.6 (2CH), 135.8,
136.8, 138.6, 164.2, 186.1 (CHO). MS (EI, 70 eV): m/z (rela-
tive intensity)¼307 (Mþ, 16), 262 (12), 261 (42), 260 (37),
233 (14), 232 (36), 204 (17), 157 (11), 149 (37), 123 (48),
121 (18), 119 (21), 115 (14), 111 (15), 109 (15), 105 (22),
97 (23), 95 (29), 91 (100), 83 (29), 81 (24), 77 (27), 69
(71), 57 (50). HRMS (EI) calcd for C19H17NO3: 307.1208;
found: 307.1202. FTIR: (KBr, cmꢀ1)¼3058, 3030, 2932,
1699, 1671, 1518, 1469, 1450, 1415, 1384, 1338, 1274,
1238, 1175, 1161, 1146, 1026, 913, 868, 785, 747, 730.
1
Isolated yield: 86% (mp: 73e74 ꢁC). H NMR (400 MHz,
CDCl3):
d
(ppm)¼1.31 (d, J¼7.0 Hz, 6H), 1.49 (t,
J¼7.2 Hz, 3H), 3.05 (sep, J¼7.0 Hz, 1H), 4.49 (q, J¼7.2 Hz,
2H), 5.85 (s, 2H), 7.05 (m, 2H), 7.19e7.35 (m, 5H), 8.15
(m, 1H), 10.80 (s, 1H). 13C NMR (100 MHz, CDCl3):
d (ppm)¼14.4 (CH3), 24.2 (2 CH3), 34.2 (CH), 48.5 (CH2),
60.8 (CH2), 111.0 (CH), 115.5, 120.3 (CH), 125.9, 126.4
(2CH), 127.0 (CH), 127.4 (CH), 128.6 (2CH), 135.6, 136.9,
137.4, 144.2, 164.3, 186.0 (CHO). MS (EI, 70 eV): m/z (rela-
tive intensity)¼349 (Mþ, 34), 304 (21), 303 (80), 302 (90),
276 (12), 275 (16), 274 (64), 260 (17), 232 (10), 91 (100),
65 (11). HRMS (EI) calcd for C22H23NO3: 349.1672; found:
349.1669. FTIR: (KBr, cmꢀ1)¼3064, 3033, 2959, 2929,
2870, 1701, 1671, 1621, 1606, 1516, 1482, 1454, 1411, 1383,
1353, 1282, 1235, 1187, 1163, 1130, 1030, 998, 906, 890,
806, 705.
4.2.3. Ethyl 2-formyl-1-phenyl-1H-indole-3-carboxylate (5c)
4.2.6. Ethyl 1-benzyl-2-formyl-5-methoxy-1H-indole-
3-carboxylate (5f)
1
Isolated yield: 75% (mp: 83e84 ꢁC). H NMR (300 MHz,
CDCl3):
d
(ppm)¼1.48 (t, J¼7.2 Hz, 3H), 4.50 (q,
Isolated yield: 60% (mp: 101e102 ꢁC). 1H NMR
(400 MHz, CDCl3): d (ppm)¼1.48 (t, J¼7.2 Hz, 3H), 3.89
(s, 3H), 4.48 (q, J¼7.2 Hz, 2H), 5.86 (s, 2H), 7.02e7.09 (m,
3H), 7.22e7.33 (m, 4H), 7.73 (d, J¼2.0 Hz, 1H), 10.78 (s,
1H). 13C NMR (100 MHz, CDCl3): d (ppm)¼14.4 (CH3),
48.6 (CH2), 55.6 (CH3), 60.8 (CH2), 103.2 (CH), 112.2
(CH), 114.9, 119.3 (CH), 126.4 (2CH), 126.7, 127.5 (CH),
128.7 (2CH), 134.1, 135.6, 136.9, 156.7, 164.4, 185.9
(CHO). MS (EI, 70 eV): m/z (relative intensity)¼337 (Mþ,
35), 292 (14), 291 (51), 290 (53), 263 (17), 262 (47), 149
(11), 97 (14), 91 (100), 83 (18), 71 (16), 69 (22), 57 (28).
HRMS (EI) calcd for C20H19NO4: 337.1308; found:
J¼7.2 Hz, 2H), 7.05 (m, 1H), 7.22e7.37 (m, 4H), 7.51 (m,
3H), 8.36 (m, 1H), 10.75 (s, 1H). 13C NMR (75 MHz, CDCl3):
d (ppm)¼14.5 (CH3), 61.0 (CH2), 111.9 (CH), 115.9, 123.6
(CH), 123.6 (CH), 125.4, 127.2 (CH), 127.6 (2CH), 128.8
(CH), 129.3 (2CH), 136.7, 137.4, 139.8, 164.3, 184.3
(CHO). MS (EI, 70 eV): m/z (relative intensity)¼293 (Mþ,
32), 264 (40), 248 (36), 247 (95), 237 (12), 221 (15), 220
(100), 219 (53), 218 (35), 193 (18), 191 (49), 190 (20), 165
(27), 158 (15), 77 (12), 57 (13), 55 (10). HRMS (EI) calcd
for C18H15NO3: 293.1046; found: 293.1044. FTIR: (KBr,
cmꢀ1)¼3054, 2980, 2952, 2899, 1700, 1679, 1597, 1516,

4594
I.A. Sayyed et al. / Tetrahedron 64 (2008) 4590e4595
337.1301. FTIR: (KBr, cmꢀ1)¼3117, 3030, 3007, 2981, 2927,
2843, 1697, 1661, 1617, 1575, 1509, 1487, 1467, 1408, 1384,
1342, 1303, 1219, 1205, 1179, 1148, 1126, 1081, 1031, 988,
918, 867, 846, 816, 775, 742, 711.
C19H16BrNO3: 385.0308; found: 385.0302. FTIR: (KBr,
cmꢀ1)¼3100, 3037, 2981, 2923, 1695, 1676, 1515, 1452,
1412, 1383, 1347, 1290, 1259, 1234, 1160, 1130, 1112, 1056,
1030, 987, 921, 878, 865, 799, 781, 732, 698.
4.2.7. Ethyl 1-benzyl-2-formyl-5-fluoro-1H-indole-
4.2.10. Ethyl 1-methyl-2-formyl-5-nitro-1H-indole-
3-carboxylate (5g)
3-carboxylate (5j)
Isolated yield: 90% (mp: 103e104 ꢁC). 1H NMR
(400 MHz, CDCl3): d (ppm)¼1.49 (t, J¼7.2 Hz, 3H), 4.49
(q, J¼7.2 Hz, 2H), 5.87 (s, 2H), 7.03 (m, 2H), 7.16 (dt,
JH,F¼9.0 Hz, J¼9.0, 2.5 Hz, 1H), 7.22e7.28 (m, 3H), 7.35
(dd, J¼9.0 Hz, JH,F¼4.5 Hz, 1H), 7.94 (dd, JH,F¼9.5 Hz,
J¼2.5 Hz, 1H), 10.84 (s, 1H). 13C NMR (100 MHz, CDCl3):
d (ppm)¼14.4 (CH3), 48.7 (CH2), 61.0 (CH2), 108.5 (d,
JF,C¼25.2 Hz, CH), 112.5 (d, JF,C¼9.5 Hz, CH), 115.5
(d, JF,C¼5.5 Hz), 116.5 (d, JF,C¼27.4 Hz, CH), 126.2 (d,
JF,C¼11.0 Hz), 126.4 (2CH), 127.7 (CH), 128.7 (2CH),
135.1, 136.5, 136.8, 159.6 (d, JF,C¼241.0 Hz), 163.9, 186.1
(CHO). MS (EI, 70 eV): m/z (relative intensity)¼325 (Mþ,
28), 280 (20), 279 (72), 278 (65), 251 (20), 250 (61), 222
(24), 92 (10), 91 (100), 65 (16). HRMS (EI) calcd for
C19H16FNO3: 325.1108; found: 325.1100. FTIR: (KBr,
cmꢀ1)¼3105, 3043, 2982, 2926, 1705, 1657, 1513, 1493,
1461, 1413, 1390, 1260, 1237, 1214, 1176, 1160, 1144,
1126, 1028, 993, 939, 876, 857, 810, 786, 714.
Isolated yield: 60% (mp: 185e186 ꢁC). 1H NMR
(400 MHz, CDCl3): d (ppm)¼1.49 (t, J¼7.2 Hz, 3H), 4.20
(s, 3H), 4.50 (q, J¼7.2 Hz, 2H), 8.16 (dd, J¼9.0, 2.0 Hz,
1H), 8.40 (d, J¼9.0 Hz, 1H), 8.42 (d, J¼2.0 Hz, 1H), 10.87
(s, 1H). 13C NMR (100 MHz, CDCl3): d (ppm)¼14.4 (CH3),
33.0 (CH3), 61.3 (CH2), 107.6 (CH), 114.7, 117.7 (CH),
124.6 (CH), 129.5, 137.3, 139.7, 146.3, 163.4, 186.8 (CHO).
MS (EI, 70 eV): m/z (relative intensity)¼276 (Mþ, 56), 248
(23), 247 (23), 220 (30), 203 (100), 202 (28), 185 (20), 157
(25), 128 (18), 102 (12), 87 (11). FTIR: (KBr, cmꢀ1)¼3121,
3091, 1703, 1672, 1515, 1471, 1406, 1397, 1340, 1260, 1218,
1162, 1123, 1070, 1027, 933, 887, 837, 736.
4.3. Ethyl 2-(1-hydroxyallyl)-1-methyl-1H-indole-
3-carboxylate (9)
To a solution of ethyl 2-formyl-1-alkyl-1H-indole3-carbox-
ylate (0.151 mmol) in 5 mL dry THF at ꢀ78 ꢁC was treated
with allyl-magnesium-bromide (0.166 mmol). The reaction
mixture was stirred at ꢀ78 ꢁC for 30 min. After removal of
the solvent and purification by column chromatography (elu-
ent: hexaneeEtOAc¼80:20) yielded 9 (82%) as colorless
4.2.8. Ethyl 1-benzyl-2-formyl-5-chloro-1H-indole-
3-carboxylate (5h)
1
Isolated yield: 67% (mp: 88e89 ꢁC). H NMR (400 MHz,
CDCl3):
d
(ppm)¼1.47 (t, J¼7.2 Hz, 3H), 4.47 (q,
oil. 1H NMR (500 MHz, CDCl3):
d
(ppm)¼1.48 (t,
J¼7.2 Hz, 2H), 5.84 (s, 2H), 7.00 (m, 2H), 7.14e7.33 (m,
5H), 8.27 (br s, 1H), 10.80 (s, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm)¼14.4 (CH3), 48.7 (CH2), 61.1 (CH2),
112.4 (CH), 115.2, 123.2 (CH), 126.4 (2CH), 126.5, 127.7
(CH), 127.8 (CH), 128.8 (2CH), 129.4, 136.4, 136.5, 136.9,
163.8, 186.0 (CHO). MS (EI, 70 eV): m/z (relative in-
tensity)¼341 (Mþ, 20), 297 (16), 296 (28), 295 (46), 294
(48), 267 (20), 266 (37), 204 (10), 91 (100), 65 (13). HRMS
(EI) calcd for C19H16ClNO3: 341.0813; found: 341.0811.
FTIR: (KBr, cmꢀ1)¼3101, 3068, 3057, 2958, 2983, 2925,
2856, 1695, 1676, 1515, 1499, 1462, 1453, 1412, 1384,
1347, 1291, 1259, 1233, 1160, 1129, 1069, 1031, 996, 987,
923, 877, 866, 801, 781, 759, 738, 701.
3J¼7.2 Hz, 3H, Me), 3.78 (s, 3H, NMe), 4.38e4.48 (m, 2H,
OCH2), 5.15e5.21 (m, 2H, H-11), 5.70 (m, 1H, H-9), 6.17
(ddd, 3J10,11(trans)¼17.0 Hz, 3J10,11(cis)¼10.4 Hz, 3J9,10
¼
5.7 Hz, 1H, H-10), 6.35 (d, J¼10.5 Hz, 1H, OH), 7.25e7.31
(m, 2H, H-5,6), 7.34 (m, 1H, H-7), 8.13 (m, 1H, H-4). 13C
NMR (125.8 MHz, CDCl3): d (ppm)¼14.4 (Me), 30.6
(NMe), 60.6 (OCH2), 68.1 (C-9), 104.1 (C-3), 109.7 (C-7),
115.7 (C-11), 122.0 (C-4), 122.3 (C-5), 122.9 (C-6), 126.3
(C-3a), 136.6 (C-7a), 137.4 (C-10), 149.0 (C-2), 167.7 (CO).
MS (EI, 70 eV): m/z (relative intensity)¼259 (Mþ, 36), 214
(24), 213 (100), 186 (29), 185 (31), 184 (54), 170 (10), 169
(13), 168 (15), 158 (21), 157 (23), 130 (10). HRMS (EI) calcd
for C15H17NO3: 259.1202; found: 259.1200. FTIR: (neat,
cmꢀ1)¼3409, 3054, 2980, 2936, 1689, 1661, 1523, 1472,
1404, 1376, 1351, 1330, 1287, 1219, 1163, 1104, 1032, 990,
928, 878, 790, 753, 741.
4.2.9. Ethyl 1-benzyl-2-formyl-5-bromo-1H-indole-
3-carboxylate (5i)
Isolated yield: 67% (mp: 109e110 ꢁC). 1H NMR
(300 MHz, CDCl3): d (ppm)¼1.48 (t, J¼7.2 Hz, 3H), 4.49
(q, J¼7.2 Hz, 2H), 5.85 (s, 2H), 7.01 (m, 2H), 7.20e7.30
(m, 4H), 7.47 (dd, J¼9.0, 2.0 Hz, 1H), 8.45 (d, J¼2.0 Hz,
1H), 10.82 (s, 1H). 13C NMR (75 MHz, CDCl3): d (ppm)¼
14.4 (CH3), 48.6 (CH2), 61.1 (CH2), 112.8 (CH), 115.0,
117.1, 126.3 (2CH), 126.4 (CH), 127.0, 127.7, 128.8 (2CH),
130.3, 136.3, 136.4, 137.1, 163.8, 186.0 (CHO). MS (EI,
70 eV): m/z (relative intensity)¼387 (Mþ2, 15), 385 (Mþ,
15), 341 (39), 340 (39), 339 (39), 338 (28), 312 (28), 310
(22), 304 (12), 91 (100), 65 (10). HRMS (EI) calcd for
4.4. Ethyl 2-(benzylamino)methyl-1H-indole-
3-carboxylate (10)
A solution of ethyl 2-formyl-1-alkyl-1H-indole-3-carboxyl-
ate (0.216 mmol), benzylamine (0.259 mmol), and NaCNBH3
(0.216 mmol) in 6 mL methanol was stirred for 20 h at room
temperature. After removal of the solvent and purification by
column chromatography (eluent: EtOAc) yielded 10 (80%)
1
as colorless oil. H NMR (500 MHz, CDCl3): d (ppm)¼1.43
3
(t, J¼7.2 Hz, 3H), 2.24 (br, 1H, NH), 3.73 (s, 3H, Me(8)),

I.A. Sayyed et al. / Tetrahedron 64 (2008) 4590e4595
4595
3.89 (s, 2H, H-10), 4.27 (s, 2H, H-9), 4.42 (q, 3J¼7.2 Hz, 2H,
OCH2), 7.26e7.40 (m, 8H, H-5,6,7,Ph), 8.17 (m, 1H, H-4).
13C NMR (125.8 MHz, CDCl3): d (ppm)¼14.5 (Me), 29.8
(Me(8)), 42.8 (C-9), 53.5 (C-10), 59.6 (OCH2), 105.0 (C-3),
109.5 (C-7), 121.8 (2), 122.6 (C-4,5,6), 126.2 (C-3a), 127.0
(p-Ph), 128.2 (o-Ph), 128.3 (m-Ph), 136.7 (C-7a), 140.0
(i-Ph), 145.9 (C-2), 165.8 (CO). MS (EI, 70 eV): m/z (relative
intensity)¼325 (26), 280 (16), 279 (56), 278 (61), 252 (11),
251 (17), 250 (53), 222 (23), 91 (100), 65 (14). FTIR: (neat,
cmꢀ1)¼3300, 3105, 3042, 3031, 2925, 1704, 1657, 1513,
1492, 1461, 1452, 1412, 1389, 1372, 1351, 1260, 1236,
1214, 1176, 1160, 1143, 1126, 1027, 993, 939, 875, 856,
810, 784, 736, 713.
42, 3042e3044; (i) Onitsuka, K.; Suzuki, S.; Takahashi, S. Tetrahedron
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Verspui, G.; Elbertse, G.; Sheldon, F. A.; Hacking, M. A. P. J.; Sheldon,
R. A. Chem. Commun. 2000, 1363e1364; (m) Beller, M.; Breindl, C.;
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Acknowledgements
Tetrahedron Lett. 2004, 45, 9541e9544; (d) Kohling, P.; Schmidt,
¨
A. M.; Eilbracht, P. Org. Lett. 2003, 5, 3212e3216; (e) Cao, C.; Shi,
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This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF (Bundesministerium fur Bil-
¨
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dung und Forschung), the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg and Leibniz-price), and the Fonds der
Chemischen Industrie (FCI). We thank all the members of
the analytical group for their support.
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ciency in Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
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3. Physicians Desk Reference, 51st ed.; Medical Economics: Oradell, New
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4. Physicians Desk Reference, 51st ed.; Medical Economics: Oradell, New
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14. (a) Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.
J. Chem. Soc., Perkin Trans. 1 1995, 2677e2678; (b) Johnson, T. B.;
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16. X-ray crystallographic study of complex 5a. Data were collected with an
STOE-IPDS diffractometer using graphite-monochromated Mo Ka radia-
tion. The structures were solved by direct methods [Sheldrick, G. M.
7. Meister, A. The Biochemistry of the Amino Acids, 2nd ed.; Academic: New
York, NY, 1965; p 202.
SHELXS-97; University of Gottingen: Germany, 1997;] and refined by
¨
8. Selected recent examples: (a) Cariou, K.; Ronan, B.; Mignani, S.; Fenster-
bank, L.; Malacria, M. Angew. Chem. 2007, 119, 1913e1916; Angew.
Chem., Int. Ed. 2007, 46, 1881e1884; (b) Yin, Y.; Ma, W.; Chai, Z.;
Zhao, G. J. Org. Chem. 2007, 72, 5731e5736; (c) Liu, K. G.; Robicahud,
A. J.; Lo, J. R.; Mattes, R. F.; Cai, Y. Org. Lett. 2006, 8, 5769e5771; (d)
Kaspar, L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311e11316; (e)
Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6,
79e82; (f) Hong, K. B.; Lee, C. W.; Yum, E. K. Tetrahedron Lett.
2004, 45, 693e697; (g) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett.
2003, 5, 3843e3846; (h) Siebeneicher, H.; Bytschkov, I.; Doye, S.
Angew. Chem. 2003, 115, 3151e3153; Angew. Chem., Int. Ed. 2003,
full-matrix least-squares techniques against F2; [Sheldrick, G. M.
SHELXL-97; University of Gottingen: Germany, 1997;]. XP (BRUKER
¨
AXS) was used for structural representations. Space group P21/c,
monoclinic, a¼14.294(3), b¼9.846(2), c¼7.841(2) A, b¼101.05(3)ꢁ,
˚
3
V¼1130.8(4) A , Z¼4, rcalcd¼1.358 g cmꢀ3, 3972 reflections measured,
˚
2048 were independent of symmetry, of which 1291 were observed
(I>2s(I)), R1¼0.056, wR2 (all data)¼0.151, 154 parameters. The crystal-
lographic data for the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC (3). Copies of the data can be obtained free of charge
on application to http://www.ccdc.cam.ac.uk/data_request/cif.