indole synthesis remains the most important and versatile
approach for the preparation of biologically important
indole derivatives (Figure 1).14,15
indole synthesis has been reported utilizing ionic liquids.20,21
We report now a very practical and environmentally benign
Fischer indole synthesis employing low melting L-(þ) tar-
taric acid (TA)ꢀdimethyl urea (DMU) mixture.
Table 1. Fischer Indole Synthesis from Phenylhydrazine and
Cyclohexanone in Different Meltsa
entry
melt
temp (°C) time (h) yield (%)
1
2
3
Citric acid:DMU 40:60
L-(þ)-tartaric acid:DMU 30:70
Sorbitol:urea:NH4Cl 70:20:10
65
70
67
0.5
0.25
1.0
80
97
71
a Reaction conditions: phenylhydrazine HCl (1 mmol), cyclohexa-
none (1 mmol) in 1.5 g of melt.
3
Since the Fischer indole synthesis typically requires
acidic or thermal conditions, we have investigated melt
systems consisting of an organic acid as one of the melt
components. Citric acidꢀDMU (40:60) melt (65 °C) was
chosen as catalyst and as the reaction medium for the one
pot Fischer indole synthesis. A model reaction of phenyl
hydrazine and cyclohexanone was carried out in citric acid:
DMU melt at 65 °C. To our delight, within 0.5 h, the
corresponding tetrahydrocarbazole 3a was obtained in
good yield (entry 1, Table 1). In order to optimize the
reaction conditions, the Fischer indole synthesis was car-
ried out in various melt media and some of the results are
summarized in Table 1. The L-(þ)-TA:DMU (30:70) melt
(70 °C) was found to be the best melt medium in terms of
reaction rate and yield (entry 2, Table 1).22
Figure 1. Biologically active indoles.
Ever since the discovery of the Fischer indole synthesis,
different catalysts have been explored to effect the cycliza-
tion of aryl hydrazones derived from enolizable ketones
and aldehydes. Thus, various protocols based on the use of
Lewis acids (ZnCl2, TiCl4, PCl3),16 Brønsted acids (HCl,
H2SO4, PPA, AcOH, TsOH),17 solid acids (zeolite, mont-
morillonite clay)18 and solid phase synthesis19 have been
developed for the preparation of indoles. However, many
of the reported methods suffer from drawbacks such as
harsh or sensitive reaction conditions, use of hazardous
reagents or limited substrate scope. Recently, the Fischer
With these optimized conditions, the scope of the
Fischer indole synthesis in melt was investigated using
various carbonyl compounds. A variety of cyclic ketones
reacted smoothly with phenyl hydrazine to furnish the
corresponding indole derivatives in excellent yields (entry 1,
Table 2). Phenyl acetaldehyde provides the corresponding
indole derivative in good yield (entry 3, Table 2). Interest-
ingly, less reactive aromatic ketones, such as 1-indanone
and propiophenone, also provide the corresponding indole
derivatives in good yields (entry 6 and 7, Table 2).
Under the reaction conditions, cyclic enol ethers dihy-
dropyran and dihydrofuran reacted smoothly to give the
corresponding functionalized indole derivatives in very
good yields (entry 9 and 10, Table 2).
In addition, the optically active ketoester 2n on treat-
ment with phenyl hydrazine afforded, with excellent
regioselectivity, the corresponding indole derivative 3n,
an important intermediate in the total synthesis of the
indole alkaloid Tubifolidine.23
(13) Forselectedrecentexamplesofindolesynthesis, see:(a)Ackermann,
L. Org. Lett. 2005, 7, 439. (b) Asao, N.; Aikawa, H. J. Org. Chem.
2006, 71, 5249. (c) Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.;
Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 7230. (d) Stuart, D. R.;
Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 16474.
(14) For reviews, see: (a) Robinson, B. Chem. Rev. 1963, 63, 373. (b)
Robinson, B. Chem. Rev. 1969, 69, 227. (c) Gribble, G. W. J. Chem . Soc.,
Perkin Trans. 1 2000, 1045.
€
(15) For selected recent references on Fischer indole synthesis, see: (a)
Mun, H.-S.; Ham, W.-H.; Jeong, J.-H. J. Comb. Chem. 2005, 7, 130. (b)
Schmidt, A. M.; Eilbracht, P. J. Org. Chem. 2005, 70, 5528. (c) Linnepe
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(nee Kohling), P.; Schmidt, A. M.; Eilbracht, P. Org. Biomol. Chem.
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R. G. Angew. Chem., Int. Ed. 2008, 47, 3422.
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(b) Nakazaki, M.; Yamamoto, K. J. Org. Chem. 1976, 41, 1877. (c)
Baccolini, G.; Todesco, P. E. J. Chem. Soc., Chem. Commun. 1981, 563a.
(17) (a) Hegde, V.; Madhukar, P.; Madura, J. D.; Thummel, R. P.
J. Am. Chem. Soc. 1990, 112, 4549. (b) Liu, K. G.; Robichaud, A. J.; Lo,
J. R.; Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769. (c) Campos, K. R.;
Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett. 2004, 6, 79.
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(19) Mun, H. -S.; Ham, W. -H.; Jeong, J.-H. J. Comb. Chem. 2005, 7, 130.
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Z. Y. Eur. J. Org. Chem. 2007, 1007. (b) Morales, R. C.; Tambyrajah, V.;
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(22) Since L-(þ)-TA is relatively cheaper than DL-TA, the L-(þ)-TA is
used as one of the melt components in our studies.
(23) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1998, 63, 7547.
B
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