Synthesis of 1-amino-1H-indole-3-carboxylates by copper(I)-catalyzed intramolecular amination of aryl bromides

Article abstract of DOI:10.1002/ejoc.200800777

A simple route to various N-substituted 1-amino-1H-indole-3-carboxylates by use of copper(I)-catalyzed intramolecular N-arylation has been established. For the preparation of N-monosubstituted and N-unsubstituted derivatives, the cyclization of Boc-protected enehydrazines and subsequent deprotection were applied. Furthermore, 1-alkoxyindole-3-carboxylates can be synthesized by use of the same protocol Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800777

FULL PAPER
DOI: 10.1002/ejoc.200800777
Synthesis of 1-Amino-1H-indole-3-carboxylates by Copper(I)-Catalyzed
Intramolecular Amination of Aryl Bromides
Ferdinand Melkonyan,[a] Artyom Topolyan,[a] Marina Yurovskaya,[a] and
Alexander Karchava*[a]
Keywords: C–N coupling / Copper / Nitrogen heterocycles / Annulation / Indoles
A simple route to various N-substituted 1-amino-1H-indole-
3-carboxylates by use of copper(I)-catalyzed intramolecular
N-arylation has been established. For the preparation of N-
monosubstituted and N-unsubstituted derivatives, the cycli-
zation of Boc-protected enehydrazines and subsequent de-
protection were applied. Furthermore, 1-alkoxyindole-3-
carboxylates can be synthesized by use of the same protocol
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
a consequence, the development of a practical route for ac-
cessing 1-aminoindole-3-carboxylic acid derivatives remains
an important goal.
Introduction
1-Aminoindoles are an important class of compounds
that display remarkable pharmacological properties.[1] For
example, some of them exhibit psychotropic,[1c] anticonvul-
sant,[1d] analgesic,[1e] and antioxidant[1f,1g] effects. Various
1-arylaminoindole derivatives have found application as
acetylcholinesterase inhibitors for the treatment of Alzhei-
mer’s disease.[2] In view of the high significance of these
compounds, several methodologies for the construction of
1-aminoindole derivatives have been developed. The most
frequently used method is based on the direct amination of
indoles by hydroxylamine-O-sulfonic acid[3] or related rea-
gents.[4] However, this methodology has a limited scope ow-
ing to the decreased reactivity of indoles containing an elec-
tron-withdrawing substituent in the 3-position.[4a] Other ap-
proaches to 1-aminoindoles include (1) reduction of N-ni-
trosoindoles,[5] (2) the Nenitzescu reaction,[6] and (3) palla-
dium-catalyzed intramolecular cyclization of (2-chlo-
rophenyl)acetaldehyde dimethylhydrazones.[7] However,
only a few examples of the synthesis of 1-aminoindole-3-
carboxylic acid derivatives have been reported.[4] All of
these examples dealt with the direct amination protocol,
which in most cases provided poor conversion of the start-
ing materials. Moreover, to the best of our knowledge, no
examples of the preparation of N- or N,N-substituted deriv-
atives of 1-aminoindole-3-carboxylic acid have been pub-
lished so far. At the same time, indole-3-carboxylic acids are
widely used as building blocks in research and development
aimed at the production of important pharmaceuticals. As
Results and Discussion
In the past decade, the copper-catalyzed intramolecular
C–N bond-forming reaction has proven to be extremely ef-
fective for the synthesis of a wide variety of nitrogen hetero-
cycles.[8] A number of useful synthetic protocols for the as-
sembly[9] and N-derivatization[10] of the indole ring system
have been proposed as well. Very recently, our research
group published a communication that described a new, ef-
ficient method to produce N-substituted indole-3-carbox-
ylic acid derivatives by copper(I)-catalyzed intramolecular
C–N bond formation starting from easily available N-sub-
stituted methyl 3-amino-2-(2-bromophenyl)acrylates.[9e]
This procedure is very simple to operate and avoids the use
of any supporting ligand or an inert atmosphere, without
loss of yield. In continuation of our interest in the copper-
catalyzed synthesis of indole derivatives, we explored this
protocol for the preparation of 1-aminoindole-3-carboxylic
acid derivatives.
[a] Department of Chemistry, Moscow State University,
Moscow 119991, Russia
In the work described here, we aimed to find out whether
various 1-aminoindole-3-carboxylic esters could be synthe-
sized by a copper(I)-catalyzed intramolecular amination re-
action. Initially, we prepared enehydrazines 3a–h as cycliza-
Fax: +7-495-9388846
E-mail: karchava@org.chem.msu.ru
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
5952
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5952–5956

Copper(I)-Catalyzed Synthesis of 1-Amino-1H-indole-3-carboxylates
tion precursors for the preparation of various 1-aminoin- and 3g (Table 1, entries 6 and 7) resulted in the formation
dole-3-carboxylates. In our previously developed protocol, of a complex mixture of products; among them, N-unsub-
the starting materials needed for the cyclization stage were stituted methyl indole-3-carboxylate was found (≈10%)
easily prepared from methyl 2-(2-bromophenyl)-3-formyl- when the reaction mixture was analyzed by GC–MS. Nei-
acetates 1 and various primary amines by stirring a mixture ther 1-aminoindole derivatives nor the corresponding dihy-
of reagents in methanol at room temperature. Similarly, re- drocinnolines (also expected for N,NЈ-disubstituted enehyd-
action of 1 with various hydrazines 2 gave the correspond- razines) were found in the mixture, although total con-
ing enehydrazines 3 after stirring the solutions in methanol sumption of the cyclization precursors was observed.
for several hours (Scheme 1). The formation of enehydraz- Meanwhile, under the same conditions, the reaction of en-
ine 3h took 50 h to complete at room temperature or 3 h at ehydrazines 3d and 3e gave methyl N-benzylidene-1-amino-
reflux temperature. All enehydrazines 3, except for 3d and indole-3-carboxylates (E)-5d and (E)-5e as the only prod-
3e, were isolated in excellent yield and high purity and were ucts (Table 1, entries 4 and 5). The configuration of the
used in the next stage without additional purification. En- C=N bond of 5 was determined by nOe experiments. We
ehydrazines 3d and 3e were isolated in 53 and 56% yields, supposed that products 5d and 5e might have been a result
respectively, after flash-column chromatography. Cycliza- of copper-catalyzed oxidation of originally formed 1-ben-
tion of substrates 3 was carried out under the conditions zylaminoindoles 4d and 4e by oxygen in the air,[12] as we
described earlier[9e] (Scheme 1) and did not proceed as carried out the cyclization without exclusion of air. How-
smoothly as we had hoped. As shown in Table 1, expected ever, a control experiment under an inert atmosphere gave
1-aminoindole derivatives 4 were obtained in good yield essentially the same result and showed that the reaction was
only from N,N,NЈ-trisubstituted substrates 3a–c and 3h not influenced by oxygen in the air. It was previously re-
(Table 1, entries 1–3, 8). In the case of 3h, only a trace ported that N,NЈ-disubstituted hydrazines could be readily
amount of bis-Boc indole 4h was observed; monodeprotec- oxidized to the corresponding diazenes under cross-coup-
tion of the Boc group proceeded to give N-Boc-1-amino- ling reaction conditions (CuI, inorganic base, DMF).[11] On
indole-3-carboxylate (4g) as the main product in 78% yield the basis of this fact, we assumed that in the cases of sub-
(Table 1, entry 8). The elimination of the Boc group under strates 3d–g the initial formation of the corresponding diaz-
copper-catalyzed cross-coupling reaction conditions has enes 6d–g took place, although the mechanistic details of
been mentioned earlier.[11] The reaction of enehydrazines 3f the reaction remain unclear at the moment. Because azo–
hydrazone tautomerism[13] was possible only for the diaz-
enes derived from 3d and 3e, cyclization was observed only
in this cases and gave N-benzylidene products 5d and 5e.
Substrates 3f and 3g gave diazenes, which were not suitable
for cyclization and, therefore, were decomposed under the
reaction conditions (Scheme 2).
Because enehydrazines 3d–f were unsuitable for this pro-
tocol for the synthesis of N-monosubstituted 1-amino-
indole-3-carboxylates, we next investigated N-Boc-N-substi-
tuted hydrazines 3i and 3k as cyclization precursors. Enehy-
drazines 3i and 3k were prepared by heating a methanol
solution of 1 and 2g[14] or 2h[15] at reflux for 3 h and used
in the cyclization stage without further purification. As ex-
pected, the corresponding 1-aminoindoles 4i and 4k were
isolated in good yield (Table 1, entries 9 and 10). In these
cases, we did not observe any deprotection product.
Scheme 1.
Table 1. Cyclization of enehydrazines 3.[a]
Entry Starting materials Enehydrazine
R
X
RЈ
Reaction time [h][b] Expected product Isolated product Yield [%]
1
2
3
4
5
6
7
8
9
10
1a, 2a
1b, 2a
1a, 2b
1a, 2c
1b, 2c
1a, 2d
1a, 2e
1a, 2f
1b, 2g
1a, 2h
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
Me
Boc
H
H
H
H
OMe
H
H
OMe
H
H
H
OMe
H
2
2
2
2
2
2
2
10
2
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4a
4b
4c
(E)-5d
(E)-5e
82
79
81
68
65
0
CH2C6H4Me-m
CH2C6H4Me-m
Ph
Boc
Boc
CH2C6H4Cl-p
Ph
H
0
Boc
Boc
Boc
4g
4i
4k
78
86
78
3k
4k
[a] Reaction conditions: 3 (≈3 mmol), CuI (5 mol-%), K3PO4 (2 equiv.), DMF (6 mL), 85 °C. [b] The reaction was continued to Ն95%
conversion.
Eur. J. Org. Chem. 2008, 5952–5956
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5953

F. Melkonyan, A. Topolyan, M. Yurovskaya, A. Karchava
FULL PAPER
N,N,NЈ-trisubstituted enehydrazines can be employed as cy-
clization precursors for 1-aminoindoles. However, use of
Boc-protected substrates in the cyclization step and subse-
quent deprotection led to N-monosubstituted and N-unsub-
stituted 1-aminoindole-3-carboxylates. This protocol may
serve as a useful tool for the generation of libraries of com-
pounds for research laboratories in pharmaceutical and ag-
rochemical companies. Further synthetic applications of
CuI-catalyzed indole ring formation are currently ongoing
in our laboratory.
Scheme 2.
Finally, selective N-deprotection of synthesized N-Boc-1-
aminoindoles 4c, 4g, 4i, and 4k could be performed
smoothly under typical reaction conditions (Table 2). This
yielded desired compounds 7 as the trifluoroacetate salts in
high yield.
Experimental Section
General: All chemicals and solvent were purchased from commer-
cial suppliers and used as received. All reactions were performed
in an air atmosphere. Reactions were monitored by TLC until com-
pletion. 1H and 13C NMR spectra were obtained at 400 and
100 MHz, respectively, with CDCl3 or [D6]DMSO as the solvent
and internal standard. Mass spectra were recorded in electron im-
pact mode at 70 eV. Melting points were determined by the open
capillary method and are uncorrected. Analytical samples were pre-
pared by flash chromatography on silica gel (Merck, 230–
400 mesh). TLC was carried out on silica gel 60 F254 plates
(Merck), and the spots were located with UV light. Methyl 2-(2-
bromophenyl)-2-formylacetate (1a),[17] methyl 2-(2-bromo-5-meth-
oxyphenyl)-2-formylacetate (1b),[17] tert-butyl 1-methylhydraz-
inecarboxylate (2b),[18] tert-butyl 1-(4-chlobenzyl)hydrazinecar-
boxylate (2f),[14] and tert-butyl 1-phenylhydrazinecarboxylate (2g)
Table 2. N-Deprotection of N-Boc-1-aminoindoles.[a]
Entry Indole
R
Reaction time[b] Product
[h]
Yield
[%]
1
2
3
4
4c
4g
4i
Me
H
6
6
10
8
7a
7b
7c
7d
90
88
90
87
[15]
were prepared in accordance with previously reported pro-
CH2C6H4Cl-p
Ph
cedures.
4k
General Procedure for the Cu-Catalyzed Synthesis of Methyl N-
Amino-1H-indole-3-carboxylates 4: To a solution of formylacetate
1 (3 mmol) in methanol (5 mL) was added a corresponding hydraz-
ine 2 (3 mmol) by syringe at room temperature. The mixture was
stirred for 6 h at room temperature (3 h at reflux for 3h, 3i, 3k),
and the solvent was evaporated to dryness under reduced pressure
to give a crude product. Enehydrazines 3d and 3e were purified by
column chromatography (hexane/ethyl acetate, 2:1) to give the
above-mentioned products in 53 (596 mg) and 56% (680 mg) yield,
respectively. In all other cases, enehydrazines 3 were isolated in high
purity and yields and were used in the next step without further
purification. To a solution of 3 in DMF (6 mL) was added CuI
(28.5 mg, 0.15 mmol) and anhydrous K3PO4 (1.3 g, 6.0 mmol). The
reaction mixture was heated at 85 °C (bath temperature) for the
time specified in Table 1 and cooled. The solvent was evaporated
to dryness under reduced pressure. Water (8 mL) was added to the
residue, and the mixture was extracted (3ϫ4 mL) with ethyl ace-
tate. The combined organic layer was washed with brine and dried
with Na2SO4. The solvent was removed in vacuo to yield the crude
product that was purified by column chromatography (hexane/ethyl
acetate, 15:1).
[a] Reaction conditions: 4 (2 mmol), CF3CO2H (6 equiv.), CH2Cl2
(8 mL). [b] The reaction was continued to Ն95% conversion.
Additionally, this copper-mediated route to N-substi-
tuted 1H-indole-3-carboxylates could be extended to the
preparation of 1-alkoxy derivatives, which are also interest-
ing as pharmaceutical precursors but are available by only
limited methods.[16] For instance, methyl 3-(benzyloxy-
amino)-2-(2-bromo-5-methoxyphenyl)acrylate (8) was con-
verted into methyl 1-(benzyloxy)-5-methoxy-1H-indole-3-
carboxylate (9) in 87% yield (Scheme 3).
Scheme 3.
Methyl 1-(Dimethylamino)-1H-indole-3-carboxylate (4a): Yield
82% (536 mg). Tan oil. H NMR (400 MHz, CDCl3): δ = 2.97 (s,
1
Conclusions
6 H), 3.94 (s, 3 H), 7.25–7.35 (m, 2 H), 7.61 (dd, J = 6.5, 2.0 Hz,
1 H), 8.14–8.20 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
47.3, 51.1, 106.2, 110.4, 121.4, 122.4, 123.1, 123.9, 128.2, 135.6,
165.3 ppm. MS (I): m/z (%) = 218 (64) [M]+, 160 (31), 159 (100)
[M – CO2Me]+, 146 (24), 144 (75) [M – CO2Me – Me]+, 118 (36).
C12H14N2O2 (218.25): calcd. C 66.07, H 6.50; found C 66.04, H
We explored our previously reported method for the
preparation of N-substituted 1H-indole-3-carboxylates by
CuI-mediated intramolecular N-arylation and have found
that 1-aminoindole-3-carboxylic acid derivatives can be
synthesized, starting from suitable substituted hydrazines
and easily accessible starting materials, in two steps. Only 6.47.
5954
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Eur. J. Org. Chem. 2008, 5952–5956

Copper(I)-Catalyzed Synthesis of 1-Amino-1H-indole-3-carboxylates
Methyl 1-(Dimethylamino)-5-methoxy-1H-indole-3-carboxylate Methyl 1-[(tert-Butyloxycarbonyl)(phenyl)amino]-1H-indole-3-carb-
1
(4b): Yield 79% (587 mg). Tan oil. H NMR (400 MHz, CDCl3): δ
= 2.94 (s, 6 H), 3.91 (s, 3 H), 3.92 (s, 3 H) 6.95 (dd, J = 9.1, 2.5 Hz,
1 H), 7.48 (d, J = 9.1 Hz, 1 H), 7.64 (d, J = 2.5 Hz, 1 H), 8.01 (s,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 47.3, 51.0, 55.8,
102.6, 105.4, 111.2, 113.6, 124.7, 128.0, 130.5, 156.2, 165.3 ppm.
MS (I): m/z (%) = 248 (46) [M]+, 233 (37) [M – Me]+, 189 (100)
oxylate (4k): Yield 78% (856 mg). Yellow solid. M.p. 134–136 °C.
1H NMR (400 MHz, CDCl3): δ = 1.40 (s, 9 H), 3.95 (s, 3 H), 7.20
(t, J = 7.1 Hz, 1 H), 7.30–7.40 (m, 7 H), 7.94 (s, 1 H), 8.23–8.28
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0, 51.3, 83.7,
107.7, 109.3, 121.9, 122.1, 122.9, 124.2, 124.3, 126.2, 129.1, 134.2,
136.3, 140.7, 152.2, 164.9 ppm. MS (I): m/z (%) = 366 (16) [M]+,
[M – CO2Me]+, 174 (31) [M – CO2Me – Me]+. C13H16N2O3 266 (80) [M – Boc + H]+, 206 (60) [M – Boc – CO2Me]+, 92 (68),
(248.28): calcd. C 62.90, H 6.50; found C 62.89, H 6.50.
57 (100). C21H22N2O4 (366.41): calcd. C 68.84, H 6.05; found C
68.84, H 6.06.
Methyl 1-[(tert-Butyloxycarbonyl)(methyl)amino]-1H-indole-3-carb-
oxylate (4c): Yield 81% (738 mg). Tan semisolid. 1H NMR
(400 MHz, CDCl3): δ = 1.35 (s, 9 H), 3.44 (s, 3 H), 3.93 (s, 3 H),
7.21–7.35 (m, 3 H), 7.81 (s, 1 H), 8.16–8.24 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.9, 37.8, 51.2, 82.6, 107.1, 108.9,
121.9, 122.6, 123.8, 124.4, 133.5, 135.2, 154.4, 165.0 ppm. MS (I):
m/z (%) = 304 (100) [M]+, 248 (95) [M – CH2=CMe2]+, 204 (93)
[M – Boc + H]+, 144 (77) [M – Boc – CO2Me]+. C16H20N2O4
(304.34): calcd. C 63.15, H, 6.63; found C 63.14, H 6.62.
General Procedure for the Deprotection of Methyl N-Boc-1-amino-
indole-3-carboxylates: To a solution of N-Boc-1-aminoindole 4
(2 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (1.4 g,
1 mL, 12 mmol). The reaction mixture was heated at reflux for the
time indicated in Table 2 and then cooled. The solution was con-
centrated in vacuo, and the residue was washed several times with
diethyl ether and dried in high vacuo to give pure product.
Methyl 1-(Methylamino)-1H-indole-3-carboxylate Trifluoroacetate
(7a): Yield 90% (572 mg). Brown oil. 1H NMR (400 MHz, [D6]-
DMSO): δ = 2.83 (s, 3 H), 3.81 (s, 3 H), 7.18–7.30 (m, 2 H), 7.58
(d, J = 7.8 Hz, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 8.12 (s, 1 H), 10.36
(br., 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 39.5, 51.1,
104.0, 110.9, 121.2, 122.2, 123.0, 124.7, 134.3, 135.7, 164.7 ppm.
MS (I): m/z (%) = 204 (70) [M]+, 189 (20) [M – Me]+, 145 (53)
[M – CO2Me]+, 117 (39), 84 (80), 68 (68), 66 (100). C13H13F3N2O4
(318.25): calcd. C 49.06, H 4.12; found C 49.07, H 4.14.
Methyl 1-{[1-(3-Methylphenyl)methylene]amino}-1H-indole-3-carb-
oxylate (5d): Yield 68% (595 mg). White solid. M.p. 105–107 °C.
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 3.99 (s, 3 H), 7.32–
7.46 (m, 4 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.77 (s, 1 H), 7.89 (d, J =
7.8 Hz, 1 H), 8.19 (d, J = 7.6 Hz, 1 H), 8.39 (s, 1 H), 8.58 (s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 21.4, 51.4, 108.5, 111.1,
121.5, 122.3, 123.0, 124.1, 124.8, 125.6, 128.4, 128.9, 132.2, 133.1,
136.6, 138.8, 149.2, 165.3 ppm. MS (I): m/z (%) = 292 (100) [M]+,
261 (25) [M – OMe]+, 146 (34), 144 (94) [M – OMe – m-
MeC6H4CN + H]+. C18H16N2O2 (292.33): calcd. C 73.96, H 5.52;
found C 73.95, H 5.52.
Methyl 1-Amino-1H-indole-3-carboxylate Trifluoroacetate Adduct
(7b): Yield 88% (535 mg). White solid. M.p. 110–115 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 3.17 (s, 3 H), 7.18–7.35 (m, 2 H), 7.62
(d, J = 8.1 Hz, 1 H), 7.98 (s, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 9.36
(br., 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 50.8, 102.9,
110.9, 120.7, 121.8, 122.5, 124.5, 135.8, 137.3, 164.7 ppm. MS (I):
m/z (%) = 190 (99) [M]+, 175 (27) [M – Me]+, 159 (29) [M –
MeO]+, 131 (100) [M – CO2Me]+. C12H11F3N2O4 (304.22): calcd.
C 47.38, H 3.64; found C 47.37, H 3.64.
Methyl
1-{[1-(3-Methylphenyl)methylene]amino}-5-methoxy-1H-
indole-3-carboxylate (5e): Yield 65% (628 mg). White solid. M.p.
1
123–125 °C. H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.93
(s, 3 H), 3.97 (s, 3 H), 7.03 (dd, J = 9.0, 2.6 Hz, 1 H), 7.32 (d, J =
7.6 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.63–7.69 (m, 2 H), 7.70–
7.77 (m, 2 H), 8.27 (s, 1 H), 8.48 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.4, 51.2, 55.8, 102.7, 107.8, 112.0, 114.4,
122.1, 125.5, 125.6, 128.4, 128.9, 131.6, 132.2, 133.1, 138.8, 149.0,
156.6, 165.3 ppm. MS (I): m/z (%) = 322 (100) [M]+, 204 (76) [M –
H – m-MeC6H4CN]+, 190 (26), 176 (64), 175 (46). C19H18N2O3
(322.36): calcd. C 70.78, H 5.65; found C 70.79, H 5.63.
Methyl
1-[(4-Chlorobenzyl)amino]-5-methoxy-1H-indole-3-carb-
oxylate Trifluoroacetate (7c): Yield 90% (824 mg). Brown oil. 1H
NMR (400 MHz, [D6]DMSO): δ = 3.74 (s, 3 H), 3.75 (s, 3 H), 4.21
(s, 2 H), 6.84 (dd, J = 8.9, 2.5 Hz, 1 H), 7.30 (s, 4 H), 7.40–7.45
(m, 2 H), 7.88 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 51.1, 54.9, 55.7, 102.7, 103.3, 112.0, 113.0, 123.3, 128.6, 129.1,
131.2, 132.5, 134.6, 137.0, 155.9, 164.8 ppm. MS (I): m/z (%) = 346/
Methyl 1-[(tert-Butyloxycarbonyl)amino]-1H-indole-3-carboxylate
(4g): Yield 78% (678 mg). Off-white solid. M.p. 137–139 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 3.89 (s, 3 H), 7.23–
7.35 (m, 4 H), 7.78 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 28.1, 51.1, 82.9, 106.8, 109.0, 121.7,
122.7, 123.8, 124.4, 135.1, 136.6, 154.2, 165.2 ppm. MS (I): m/z (%)
= 290 (15) [M]+, 234 (25) [M – CH2=CMe2]+, 190 (53) [M – Boc
+ H]+, 131 (52) [M – Boc – CO2Me + H]+, 57 (100). C15H18N2O4
(290.32): calcd. C 62.06, H 6.25; found C 62.07, H 6.26.
344 (10/30) [M]+, 219 (100) [M
–
C7H6Cl]+, 159 (44).
C20H18ClF3N2O5 (458.82): calcd. C 52.36, H 3.95; found C 52.37,
H 3.94.
Methyl 1-(Phenylamino)-1H-indole-3-carboxylate Trifluoroacetate
(7d): Yield 87% (661 mg). Brown oil. 1H NMR (400 MHz, [D6]-
DMSO): δ = 3.84 (s, 3 H), 6.46–6.56 (m, 2 H), 6.83 (t, J = 7.3 Hz,
1 H), 7.12–7.36 (m, 5 H), 8.11–8.21 (m, 2 H), 9.63 (br., 1 H), 12.18
(br., 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 50.9, 104.9,
110.6, 112.5, 120.6, 121.1, 122.3, 123.2, 124.6, 129.3, 135.8, 135.9,
147.8, 164.3 ppm. MS (I): m/z (%) = 266 (85) [M]+, 235 (33) [M –
Methyl 1-[(tert-Butyloxycarbonyl)(4-chlorobenzyl)amino]-5-meth-
oxy-1H-indole-3-carboxylate (4i): Yield 86% (1.15 g). Yellow solid.
1
M.p. 114–115 °C. H NMR (400 MHz, CDCl3): δ = 1.36 (s, 9 H),
3.87 (s, 3 H), 3.89 (s, 3 H), 4.57 (d, J = 15.0 Hz, 1 H), 5.13 (d, J =
15.0 Hz, 1 H), 6.86–6.97 (m, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 7.28
(d, J = 8.5 Hz, 2 H), 7.37 (s, 1 H), 7.64 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.0, 51.1, 53.3, 55.8, 83.1, 103.3, 106.4,
109.9, 114.1, 125.3, 128.7, 129.0, 130.4, 134.3, 134.4, 134.5, 154.0,
156.4, 165.1 ppm. MS (I): m/z (%) = 446/444 (9/3) [M]+, 390/388
(45/15) [M – CH2C=CMe2]+, 344/346 (45/15) [M – Boc + H]+, 263
(43) [M – CH2=CMe2 – C7H6Cl]+, 219 (60), 159 (87), 125 (80), 57
(100). C23H25ClN2O5 (444.91): calcd. C 62.09, H 5.66; found C
62.07, H 5.67.
MeO]+, 234 (57), 207 (100) [M
–
CO2Me]+, 206 (72).
C18H15F3N2O4 (380.32): calcd. C 56.85, H 3.98; found C 56.87, H
3.97.
Methyl 1-(Benzyloxy)-5-methoxy-1H-indole-3-carboxylate (9): The
general procedure for the preparation of 4 was employed by start-
ing from formylacetate 1b and O-benzylhydroxylamine. Yield 87%
1
(811 mg). Tan oil. H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H),
3.91 (s, 3 H), 5.23 (s, 2 H), 6.94 (dd, J = 8.8, 2.3 Hz, 1 H), 7.28 (d,
J = 9.0 Hz, 1 H), 7.33–7.44 (m, 5 H), 7.65–7.68 (m, 2 H) ppm. 13C
Eur. J. Org. Chem. 2008, 5952–5956
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5955

F. Melkonyan, A. Topolyan, M. Yurovskaya, A. Karchava
FULL PAPER
[8] For recent reviews on Cu-catalyzed C–N bond-formation reac-
tions, see: a) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed.
2008, 47, 3096–3099; b) M. Kienle, S. R. Dubbaka, K. Brade,
P. Knochel, Eur. J. Org. Chem. 2007, 4166–4176; c) I. P. Belets-
kaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337–
2364; d) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003,
42, 5400–5449; e) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003,
2428–2439.
NMR (CDCl3): δ = 51.0, 55.8, 81.1, 102.3, 102.7, 109.9, 114.1,
123.7, 127.5, 128.9, 129.3, 129.6, 129.7, 133.8, 156.2, 165.2 ppm.
MS (I): m/z (%) = 311 (26) [M]+, 220 (53) [M – C6H7]+, 91 (100).
C18H16NO4 (311.33): calcd. C 69.46, H 5.51; found C 69.44, H,
5.50.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new compounds.
[9] For selected recent examples on the syntheses of indole deriva-
tives by Cu-catalyzed C–N bond formation, see: a) Y.-M. Zhu,
L.-N. Qin, R. Liu, S.-J. Ji, H. Katayama, Tetrahedron Lett.
2007, 48, 6262–6266; b) C. Barberris, D. Gordon, C. Thomas,
X. Zhang, K. P. Cusack, Tetrahedron Lett. 2005, 46, 8877–
8880; c) A. van den Hoogenband, J. H. M. Lange, J. A.
den Hartog, R. Henzen, J. W. Terpstra, Tetrahedron Lett. 2007,
48, 4461–4465; d) K. Yamada, T. Kubo, H. Tokuyama, T. Fu-
kuyama, Synlett 2002, 231–234; e) F. S. Melkonyan, A. V. Kar-
chava, M. A. Yurovskaya, J. Org. Chem. 2008, 73, 4275–4278;
f) H. Ohno, Y. Ohta, S. Oishi, N. Fujii, Angew. Chem. Int. Ed.
2007, 46, 2295–2298; g) M. Carril, R. SanMartin, E. Doming-
ues, I. Tellitu, Green Chem. 2007, 9, 219–220; h) K. Hasegawa,
N. Kimura, S. Arai, A. Nishida, J. Org. Chem. 2008, 73, 6363–
6368.
[10] For selected recent examples on Cu-catalyzed N-derivatization
of indoles, see: a) T. Tsuritani, N. A. Strotman, Y. Yamamoto,
M. Kawasaki, N. Yasuda, T. Mase, Org. Lett. 2008, 10, 1653–
1655; b) H.-C. Ma, X.-Z. Jiang, J. Org. Chem. 2007, 72, 8943–
8946; c) J. Mao, J. Guo, H. Song, S.-J. Ji, Tetrahedron 2008, 64,
1383–1387; d) T. Mino, Y. Harada, H. Shindo, M. Sakamoto,
T. Fujita, Synlett 2008, 614–620; e) A. Correa, C. Bolm, Adv.
Synth. Catal. 2007, 349, 2673–2676; f) F. Xue, C. Cai, H. Sun,
Q. Shen, J. Rui, Tetrahedron Lett. 2008, 49, 4386–4389; g) F.
Bellina, C. Calandri, S. Cauteruccio, R. Rossi, Eur. J. Org.
Chem. 2007, 2147–2151; h) J. C. Antilla, A. Klapars, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 11684–11688.
[11] a) K.-Y. Kim, J.-T. Shin, K.-S. Lee, C.-G. Cho, Tetrahedron
Lett. 2004, 45, 117–120; b) Y.-K. Lim, S. Choi, K. B. Park, C.-
G. Cho, J. Org. Chem. 2004, 69, 2603–2606; H.-M. Kang, H.-
Y. Kim, J.-W. Jung, C.-G. Cho, J. Org. Chem. 2007, 72, 679–
682.
[1] a) K. Andersen, J. Perregaard, J. Arnt, J. Bay Nielsen, M. Beg-
trup, J. Med. Chem. 1992, 35, 4823–4831; b) B. A. Frontana-
Uribe, C. Moinet, L. Toupet, Eur. J. Org. Chem. 1999, 419–
430; c) R. A. Le, C. Harpey, FR2911143, 2008; d) F. P. Huger,
C. P. Smith, S. Kongsamut, L. Tang, US Patent 5,776,955,
1998; e) R. C. Effland, J. T. Klein, L. Davis, G. E. Olson,
EP0402752, 1990; f) A. S. Gurkan, A. Karabay, Z. Buyukbin-
gol, A. Adejare, E. Buyukbingol, Arch. Pharm. Chem. Life Sci.
2005, 338, 67–73; g) T. Itoh, M. Miyazaki, H. Maeta, Y.
Matsuya, K. Nagata, A. Ohsawa, Bioorg. Med. Chem. 2000, 8,
1983–1989.
[2] a) C. P. Smith, G. M. Bores, W. Petko, M. Li, D. E. Selk, D. K.
Rush, F. Camacho, J. T. Winslow, R. Fishkin, D. M. Cunning-
ham, K. M. Brooks, J. Roer, H. B. Hartman, L. Davis, H. M.
Vargas, J. Pharmacol. Exp. Ther. 1997, 280, 710–720; b) J. T.
Klein, L. Davis, G. E. Olsen, G. S. Wong, F. P. Huger, C. P.
Smith, W. W. Petko, M. Cornfeldt, J. C. Wilker, R. D. Blitzer,
E. Landau, V. Haroutunian, L. L. Martin, R. C. Effland, J.
Med. Chem. 1996, 39, 570–581; c) L. L. Martin, L. Davis, J. T.
Klein, P. Nemoto, G. E. Olsen, G. E. Bores, F. Camacho, W. W.
Petko, D. K. Rush, D. Selk, C. P. Smith, H. M. Vargas, J. T.
Winslow, R. C. Effland, D. M. Fink, Bioorg. Med. Chem. Lett.
1997, 7, 157–162; d) C. P. Smith, A. T. Woods-Kettelberg, R.
Corbett, R. D. Porsolt, J. E. Roehr, G. M. Bores, A. Giovanni,
M. R. Szewczak, D. K. Rush, L. L. Martin, J. T. Klein, D. J.
Turk, E. M. DiLeo, R. C. Effland, F. P. Huger, S. Kongsamut,
CNS Drug Rev. 1997, 3, 1–23; e) L. Tang, F. P. Huger, J. T.
Klein, L. Davis, L. L. Martin, S. Shimshock, R. C. Effland,
C. P. Smith, S. Kongsamut, Drug Dev. Res. 1998, 44, 8–13.
[3] a) M. Somei, M. Matsubara, Y. Kanda, M. Mitsutaka, Chem.
Pharm. Bull. 1978, 28, 2522–2534; b) M. Somei, M. Natsume,
Tetrahedron Lett. 1974, 15, 461–462; c) F. Weiberth, G. E. Lee,
R. G. Hanna, S. Dubberke, R. Utz, J. Mueller-Lehar, WO
2005035496, 2005.
[12] a) I. E. Marko, P. R. Giles, M. Tsukazaki, S. M. Brown, C. J.
Urch, Science 1996, 274, 2044–2046; b) Y. Maeda, T. Nishi-
mura, S. Uemura, Bull. Chem. Soc. Jpn. 2003, 76, 2399–2403;
c) W. Lu, C. Xi, Tetrahedron Lett. 2008, 49, 4011–4015.
[13] J. N. Brough, B. Lythgoe, P. Waterhouse, J. Chem. Soc. 1954,
4069–4079.
[4] a) M. Belley, J. Scheigetz, P. Dube, S. Dolman, Synlett 2001,
222–225; b) J. Hynes Jr., W. W. Doubleday, A. J. Dyckman,
J. D. Godfrey Jr., J. A. Grosso, S. Kiau, K. Leftheris, J. Org.
Chem. 2004, 69, 1368–1371.
[5] a) D. I. Haddlesey, P. A. Mayor, S. S. Szinai, J. Chem. Soc.
1964, 5269–5274; b) L. S. Besford, J. M. Bruce, J. Chem. Soc.
1964, 4037–4044.
[14] a) N. Brosse, M.-F. Pinto, B. Jamart-Gregoire, Eur. J. Org.
Chem. 2003, 4757–4764; b) N. Brosse, M.-F. Pinto, B. Jamart-
Gregoire, J. Org. Chem. 2000, 65, 4370–4374.
[15] M. Wolter, A. Klapars, S. L. Buchwald, Org. Lett. 2001, 3,
3803–3805.
[6] a) V. M. Lyubchanskaya, L. M. Alekseeva, S. A. Savina, A. S.
Shashkov, V. G. Granik, Mendeleev Commun. 2004, 73–75; b)
V. M. Lyubchanskaya, S. A. Savina, L. M. Alekseeva, A. S.
Shashkov, V. V. Chernyshev, V. G. Granik, Russ. Chem. Bull.
2004, 2834–2839.
[7] a) M. Watanabe, T. Yamamoto, M. Nishiyama, Angew. Chem.
Int. Ed. 2000, 39, 2501–2504; b) M. Watanabe, T. Yamamoto,
M. Nishiyama, EP 1035114, 2000.
[16] Y. Du, J. Chang, J. Reiner, K. Zhao, J. Org. Chem. 2008, 73,
2007–2010 and references cited therein.
[17] F. S. Melkonyan, N. E. Golantsov, A. V. Karchava, Heterocy-
cles 2008, 75, COM-08–11458.
[18] W. P. Malachowski, C. Tie, K. Wang, R. L. Broadrup, J. Org.
Chem. 2002, 67, 8962–8969.
Received: August 7, 2008
Published Online: November 4, 2008
5956
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5952–5956