Ferric chloride-catalyzed synthesis of indoles using the intramolecular amination of aryl bromides

Full text of DOI:10.1007/s10593-010-0648-1

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
FERRIC CHLORIDE-CATALYZED SYNTHESIS
OF INDOLES USING THE INTRAMOLECULAR
AMINATION OF ARYL BROMIDES
F. S. Melkonyan1, A. P. Topolyan1, A. V. Karchava1*, and M. A. Yurovskaya1
Keywords: indole, ferric chloride, intramolecular N-arylation.
The great progress in the synthesis of heterocyclic compounds has been achieved due to the use of
various transition metals as catalysts [1, 2]. Palladium catalysts are most often used among the transition metal
catalysts for the synthesis of heterocyclic compounds [3-6]. However, despite the obvious advantages of such
palladium catalysts, they also have a number of considerable disadvantages related to the high cost and toxicity
of both palladium itself and the phosphine ligands often used in these reactions. The rapid recent development of
methods using copper catalysts for various cross-coupling reactions can be attributed specifically to these
disadvantages. Over the past decade, the "renewed" Ulmann reaction has become an important synthetic method for
the creation of C–C and C-X bonds (X = N, O, S) [7]. However, iron catalysts are even more promising relative to
cost and "green" chemistry. The feasibility of using such catalysts for cross-coupling reactions has recently been
demonstrated [8-11]. The use of the bimetallic Fe/Cu catalyst system sometimes proves effective [12, 13]. Recently,
Bonnamour and Bolm [14] have described the synthesis of 2-substituted benzoxazoles from the corresponding
2-haloacetanilides. The key step of this synthesis is intramolecular O-arylation using FeCl3–2,2,6,6-
tetramethylheptane-3,5-dione as the catalyst system. An additional example of a ferric chloride-catalyzed
intramolecular O-arylation is the cyclization of methyl esters of 2-(2-bromophenyl)-3-oxopropionic acid,
leading to the corresponding benzofurans [15].
In light of the advantages of using iron catalysts, we undertook a study of the feasibility of replacing
copper catalysts in a synthetic strategy, which we previously employed for the preparation of N-substituted
methyl esters of indole-3-carboxylic acids [16] and methyl esters of 1-aminoindole-3-carboxylic acids [17], with
a catalyst containing ferric salts.
Br
CO2Me
CO2Me
FeCl3
HN
K3PO4, DMF
N
R
R
2a–c
1a–c
a R = Bn, b R = p-MeOC6H4, c R = NMe2
_______
* To whom correspondence should be addressed, e-mail: karchava@org.chem.msu.ru.
1M. V. Lomonosov Moscow State University, Moscow 119991, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1429-1432, September, 2010.
Original article submitted June 11, 2010.
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0009-3122/10/4609-1158©2010 Springer Science+Business Media, Inc.

We initially carried out the synthesis of indole 1a from the corresponding enamine 2a using the
cyclization condition proposed in previous work [16], replacing CuI by FeCl3. However, the yield of the reaction
product was only 50% in this case (Table 1, experiment 1). Increasing the temperature to 110°C led to a more
rapid conversion of enamine 2a but the yield of cyclization product 1a remained almost the same. Increasing the
amount of K3PO4 to three equivalents gave indole 1a in 77% yield (experiment 3). No significant increase in the
yield of indole 1a was observed using 25 mol % FeCl3. Complete conversion of the starting reagent was noted
after 30 h but this reaction led to a mixture of unidentified compounds (experiment 5). The use of the optimal
conditions found for the cyclization of enamine 2a (15 mol % FeCl3, 3 equivalents K3PO4, DMF as solvent,
reaction temperature 110°C) permitted a high yield of indole 1b, which contains an aryl substituent at N-1. The
time for complete conversion of enamine 2b was 17 h (experiment 6). The use of a catalyst system containing 15
mol % FeCl3 and two equivalents of K3PO4 in the synthesis of the methyl ester of 1-(dimethylamino)indole-
3-carboxylic acid (1c) by cyclization of the corresponding enamine 2c proved quite effective. When the reaction
mixture in DMF was stirred at 75°C, complete conversion of starting enamine 2c was observed after 15 h and
the yield of indole 1c was 60% (experiment 7). When the reaction temperature was raised to 110°C and the
amount of K3PO4 used was increased to three equivalents, the time for complete conversion was reduced to 10 h
but the yield of indole 2c dropped to 50% (experiment 8). The use of 25 mol % FeCl3 and two equivalents of
K3PO4 proved optimal. In this case, the complete conversion of enamine 2c was observed after 15 h upon
stirring the reaction mixture in DMF at 85°C and the yield of indole 1c was 77% (experiment 9).
Thus, we have shown that ferric chloride may be used as an efficient catalyst in intramolecular
O-arylation reactions. We obtained methyl esters of indole-3-carboxylic acids containing alkyl (1a) and aryl
substituents (1b) at the nitrogen atom as well as indole 1c containing a dimethylamino group at N-1.
Methyl Ester of 1-Benzylindole-3-carboxylic Acid (1a). K3PO4 (0.636 g, 9 mmol) and FeCl3 (73 mg,
0.45 mmol) were added to a solution of enamine 2a [16] (1.038 g, 3 mmol) in DMF (3 ml). The rapidly stirred
reaction mixture was heated to 110°C and maintained at this temperature until complete conversion of
enamine 2a was achieved as indicated by thin-layer chromatography. Then, the reaction mixture was cooled and
the solvent was removed in vacuum. Water (10 ml) was added to the residue and the mixture was extracted with
two 10-ml portions of ethyl acetate. The combined organic extracts were washed with two 15-ml portions of
saturated aq. NaCl and dried over Na2SO4. The solvent was removed in vacuum. The residue was subjected to
chromatography on a silica gel column (0.040-0.063 mm) using 20:1 hexane–ethyl acetate as the eluent to give
0.604 mg (76%) indole 1a as pale-yellow crystals, mp 93-95°C (toluene–hexane). The parameters of the
1H NMR, 13C NMR, and mass spectra for the sample obtained of indole 1a were identical to the data reported by
Hwu et al. [18].
TABLE 1 Dependence of Yield of the Compounds 1a-c on the Reaction
Conditions
Experiment
Indole FeCl3, mol % K3PO4, equiv.
Т, °C
Time, h*
Yield, %
1
2
3
4
5
6
7
8
9
1а
15
15
15
25
0
2
2
3
3
3
3
2
3
2
75
110
110
110
110
110
75
27
15
15
15
30
17
15
10
15
50
55
77
78
0
1b
1c
15
15
15
25
75
60
50
77
110
85
_______
* The reaction mixture was kept until complete conversion of compound 2
(control by TLC).
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Methyl Ester of 1-(4-Methoxyphenyl)indole-3-carboxylic Acid (1b) was obtained analogously in
75% yield from enamine 2b [16] as brown crystals; mp 123-125°C (toluene–hexane). The parameters of the
1H NMR, 13C NMR, and mass spectra for the sample obtained of indole 1b were identical to the data reported by
Belinna et al. [19].
Methyl Ester of 1-Dimethylaminoindole-3-carboxylic Acid (1c) was obtained analogously in
77% yield from enamine 2c [17] as a brown oil. The parameters of the 1H NMR, 13C NMR, and mass spectra for
the sample obtained of indole 1c were identical to the data reported by Melkonyan et al. [17].
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