A convenient and general method for the synthesis of indole-2,3- dicarboxylates and 2-arylindole-3-carboxylates

Article abstract of DOI:10.1002/ejoc.200700310

A transition-metal-free, simple and efficient one-pot method for the synthesis of indole-2,3-dicarboxylates and 2-aryl-indole-3-carboxylates is described. The corresponding products are obtained by a domino hydroamination/Fischer indole cyclization in goo

Full text of DOI:10.1002/ejoc.200700310

FULL PAPER
DOI: 10.1002/ejoc.200700310
A Convenient and General Method for the Synthesis of Indole-2,3-
dicarboxylates and 2-Arylindole-3-carboxylates
Iliyas Ali Sayyed,[a] Karolin Alex,[a] Annegret Tillack,[a] Nicolle Schwarz,[a] Dirk Michalik,[a]
and Matthias Beller*[a]
Keywords: Alkynes / Hydroamination / Indoles
A transition-metal-free, simple and efficient one-pot method
for the synthesis of indole-2,3-dicarboxylates and 2-aryl-
indole-3-carboxylates is described. The corresponding prod-
available 1-alkyl-1-phenylhydrazines and acetylene carbox-
ylates.
ucts are obtained by
indole cyclization in good-to-excellent yields from easily
a
domino hydroamination/Fischer
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
The catalytic addition of organic amines and their deriv- hydrazine (1a) with diethyl acetylenedicarboxylate (2) in the
atives to alkenes and alkynes (hydroamination) to produce presence of 10 mol-% of Ti(NEt2)4 as the catalyst at 100 °C.
nitrogen-containing molecules is of significant importance Subsequent treatment of the reaction mixture with 3 equiv.
for synthetic chemists in basic research as well as for those of ZnCl2 allowed the cyclization of the in-situ-generated hy-
in the chemical industry.[1] Today intermolecular hydroami- drazone to give the corresponding diethyl 1-methylindole-
nations are known to be catalyzed by a variety of transition 2,3-dicarboxylate 3a in 55% yield (Table 1, Entry 1).
metals (d- and f-block metals),[2] alkali metals[3] and
Table 1. Reaction of 1-methyl-1-phenylhydrazine (1a) with diethyl
Brönsted and Lewis acids.[4] However, most of these cata-
acetylenedicarboxylate (2).[a]
lysts are rather limited with respect to their substrate toler-
ance.
Various biologically active amine alkaloids, especially in-
doles, continue to attract the interest of organic chemists.
Though many catalytic methods exist for the synthesis of
indoles,[5] still the most famous synthesis for indoles and
Entry
Hydrazine 1a
Alkyne 2
Yield 3a
their derivatives constitutes the Fischer indole synthesis.[6]
We have been interested for some time in the improvement
and exploration of methodologies for the synthesis of in-
dole heterocycles.[7] For example, we developed a one-pot
synthesis of tryptamines and tryptopholes by a titanium-
catalyzed hydrohydrazination of chloro- and silyloxo-sub-
stituted alkynes.[7a,8] In continuation of this work, we be-
came interested in the hydrohydrazination reaction of ace-
tylenedicarboxylates, which are easily available. Some re-
lated carboxy-2,3-disubstituted indole derivatives are
known to be potent inhibitors of thromboxane synthase,[9]
phospholipase-A2,[10] cyclooxygenase-2,[11] steroid-5α-reluc-
tase[12] and glycine/NMDA antagonists.[13] In addition to
their biological activity, indole-2,3-dicarboxylate esters may
serve as valuable synthetic intermediates for other indole
derivatives and more complex indole heterocycles.[14]
[equiv.]
[equiv.]
[%]
1[b]
2
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
55
63
30
60
66
78
87
3[c]
4[d]
5
6
7
[a] Reaction conditions: i) toluene, 100 °C, 24 h; ii) ZnCl2 (3 equiv.),
100 °C, 24 h. [b] 10 mol-% Ti(NEt2)4, 20 mol-% 2,6-di-tert-butyl-4-
methylphenol. [c] Reaction temperature 80 °C. [d] Reaction tem-
perature 120 °C.
Interestingly, the same reaction occurred in 63% yield
when performed in the absence of any titanium catalyst
(Table 1, Entry 2). This observation is in agreement with the
previous work of Acheson[15] and Miki et al.[16] who pre-
pared selected dimethyl indole-2,3-dicarboxylates in yields
of 13–62%. Interestingly, in 1935 Diels and Reese had al-
ready described the condensation of 1-benzyl-1-phenylhy-
drazine with acetylenedicarboxylate; however, no product
yield of the respective indole-2,3-dicarboxylate was
given.[17]
On the basis of our previous hydroamination protocols,
we initially investigated the reaction of N-methyl-N-phenyl-
[a] Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
E-mail: matthias.beller@catalysis.de
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I. A. Sayyed, K. Alex, A. Tillack, N. Schwarz, D. Michalik, M. Beller
FULL PAPER
Because of the limited information available, we decided the yield of the corresponding indoledicarboxylate was ob-
to perform a systematic study to improve the yield of this served when an excess of alkyne 2 was used. Hence, 1.5 and
domino hydroamination/cyclization sequence. Selected ex- 2.0 equiv. of 2 gave 78 and 87% yield of 3a, respectively.
periments are shown in Table 1. The use of an excess This is explained by oligomerization side reactions of 2. We
amount of phenylhydrazine 1a (1.5 equiv.) improved the also examined the effect of temperature to improve the yield
yield of 3a slightly. In contrast, a considerable increase in of the indole product. However, neither an increase in the
Table 2. Synthesis of indole-2,3-dicarboxylates.[a]
[a] Reaction conditions: i) hydrazine (1 equiv.), acetylenedicarboxylate (2 equiv.), toluene, 100 °C, 24 h; ii) ZnCl2 (3 equiv.), 100 °C, 24 h.
[b] Yield of isolated products.
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Synthesis of Indole-2,3-dicarboxylates and 2-Arylindole-3-carboxylates
3.0 mmol), diethyl acetylenedicarboxylate (1.02 g, 6.0 mmol) and
dry toluene (5 mL). The pressure tube was fitted with a Teflon cap
and heated at 100 °C for 24 h in an oil bath. Then, the reaction
mixture was cooled to r.t. and anhydrous ZnCl2 (1.22 g, 9.0 mmol)
was added. The reaction mixture was further heated at 100 °C for
24 h. The excess toluene was distilled off under reduced pressure,
and the residue was purified by chromatography on silica gel (hex-
ane/ethyl acetate, 9:1) to afford 3a as a gummy liquid. Isolated
yield: 0.717 g (87%). 1H NMR (500 MHz, CDCl3): δ = 8.13 (br. d,
3J4,5 = 8.0 Hz, 1 H, 4-H), 7.37–7.33 (m, 2 H, 6,7-H), 7.28 (m, 1 H,
reaction temperature to 120 °C nor a lowering to 80 °C gave
a better yield of 3a. Also, attempts to improve the yield
further by using different solvents such as benzene, meth-
anol, THF, 1,4-dioxane and NMP were not fruitful. Note-
worthy is that when ZnCl2 was added in the beginning of
reaction, the desired product was also obtained, albeit in
lower yield.
As already described by Acheson et al.[15] we were also
able to isolate the intermediate hydrazone of the reaction
between N-methyl-N-phenylhydrazine (1a) and acetylene- 5-H), 3.83 [s, 3 H, Me(8)], 4.48 [q, 3J = 7.3 Hz, 2 H, CH2(10)], 4.38
3
3
[q, J = 7.2 Hz, 2 H, CH2(12)], 1.42 [t, J = 7.3 Hz, 3 H, Me(10)],
1.40 [t, 3J = 7.2 Hz, 3 H, Me(12)] ppm. 13C NMR (125.8 MHz,
CDCl3): δ = 164.1 (C-11), 162.8 (C-9), 136.8 (C-7a), 135.0 (C-2),
125.4 (C-3a), 124.3 (C-6), 122.3, 122.5 (C-4,5), 110.0 (C-7), 108.0
(C-3), 62.3 [CH2(10)], 60.2 [CH2(12)], 31.3 [Me(8)], 14.0 [Me(10)],
14.4 [Me(12)] ppm (numbering according to Table 2, Entry 1). IR
dicarboxylate 2 in the absence of ZnCl2. After 24 h at
100 °C in toluene, a hydrazone/indole ratio of 83:17 was
found. The hydrazone immediately underwent Fischer in-
dole cyclization in the presence of the Lewis acid. At this
point it is noteworthy that Schwesinger et al. demonstrated
that the reaction of phenylhydrazine and acetylenedicarbox-
ylate also yielded the corresponding hydrazone.[18] How-
ever, as a result of the strong intramolecular hydrogen
bond, subsequent Fischer indole cyclization to yield the in-
(neat): ν = 3055, 2982, 2938, 2905, 1733, 1717, 1700, 1615, 1539,
˜
1471, 1444, 1412, 1379, 1273, 1247, 1210, 1157, 1103, 1034, 1014,
860, 788, 753, 742 cm–1. MS (EI, 70 eV): m/z (%) = 275 (100)
[M]+, 230 (40), 229 (30), 203 (28), 202 (91), 200 (20), 158 (18), 157
dole-2,3-dicarboxylate was prevented. Apparently, the pres- (22), 89 (6). HRMS (EI): calcd. for C15H17NO4 275.1153; found
275.1152.
ence of two substituents at the hydrazine nitrogen atom fa-
cilitates the Fischer indole cyclization. Thus, we next ap-
plied the improved hydroamination–cyclization protocol to
indole products 3a–k (Table 2).
Acknowledgments
However, lower yields (26–40%) were obtained for the
This work has been supported by the State of Mecklenburg-
reaction of N-(4-bromophenyl)- and N-(4-chlorophenyl)-N-
Western Pomerania, the BMBF (Bundesministerium für Bildung
benzylhydrazine, presumably owing to the lower reactivity und Forschung), the Deutsche Forschungsgemeinschaft (Leibniz-
price), and the Fonds der Chemischen Industrie (FCI). We thank
all members of the analytical group for their support.
in the Fischer indole cyclization step. Notably, the method-
ology is also applicable to other activated acetylenecarbox-
ylic acid derivatives. Hence, the regioselective synthesis of
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Scheme 1. Reaction with ethyl propiolate.
In conclusion, we presented the synthesis of various
diethyl indole-2,3-dicarboxylates by a domino hydro-
amination/Fischer indole cyclization synthesis. The corre-
sponding products are obtained easily from commercially
available substrates in general in good yield. We believe that
this methodology constitutes the most convenient access to
this class of compounds.
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Experimental Section
Representative Procedure: An Ace pressure tube under an argon
atmosphere was charged with 1-methyl-1-phenylhydrazine (0.366 g,
Eur. J. Org. Chem. 2007, 4525–4528
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Received: April 5, 2007
Published Online: July 10, 2007
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