Some new derivatives of 5-aryl-, 2,5-diaryl-and 2-ethoxycarbonyl-5-aryl-indoles

Some derivatives of 5-aryl-, 2.5-diaryl-, and 2-ethoxycarbonyl-5-aryl-indoles are synthesized. Some reactions of ethyl 5-phenylindole-2-carboxylate are described. It is revealed that an  - ethoxycarbonyl group has a steric and electron-acceptor influence on indole substitution reactions. The structures of all novel compounds are confirmed by IR, UV, 1 H NMR, 13 C NMR and elemental analyses.


Introduction
Interest in indole and its derivatives arose at the beginning of the 20 th century, when it became known, that such compounds have a variety of physiological activities and play a vital role in the life processes of living organisms. 1The indole ring is present in many natural products and synthetic compounds having important medicinal properties.2a-c It is a structural element in many biologically and pharmaceutically active compounds with antibacterial, 3a-c antimicrobial, 4a,b antiinflammatory 5a,b and other activities.6a-c Indolic compounds are also known as antidepressants, tranquilizers and analgetics. 7arlier, 5-arylindole derivatives were obtained as by-products of bicyclization of 4,4'diarylendihydrazones with yield in 3-10%.8a-d Such low yields complicated further study of these substances.We synthesized 5-aryl-indoles and 2-aryl-indoles by the Fischer reaction using the corresponding arylhydrazones 9a-g and studied their properties.Some 2-aryl-indoles show high pharmacological activity.4b,10,11 The activity against hormone-dependent carcinoma and fluorescent and intercalation properties of the mentioned substances are of especial interest.12a-e Among 5-phenyl-indoles, some highly active substances were discovered showing the ability to inhibit serotonin receptors 5-HT1A and 5-HT2 13 and plasminogen activator inhibitors. 14The latter is of great importance for treatment of acute arterial thrombosis, atherosclerosis, diabetes, cardiovascular disease, etc.

Results and Discussion
In continuation of our research our interest was to synthesize a series of new derivatives containing one or two phenyl groups.
Our study showed that the Fischer synthesis 15a-c is the most efficient method for the preparation of 5-aryl-and 2-ethoxycarbonyl-5-aryl-indoles.We have tested almost every reported method 16 for the synthesis of indole derivatives, but the best results were achieved using polyphosphoric acid (PPA) as a catalyst in the Fischer reaction.In comparison to the published methods, Fischer's method reduces the number of steps for indole formation allowing us to carry out one-step reactions without isolation of intermediates, often unstable hydrazones.2,5-Diarylindoles 3a-d were prepared in one step by reaction of arylhydrazine 1 with a corresponding ketone 2a-d in PPA (Scheme 1, Table 1).Various other condensing agents frequently applied in Fischer's method, such as dry HCl/ethanol, H2SO4/ethanol, H2SO4/acetic acid, etc., were inefficient in these reactions.The yields of products 3a-d were in the range 12-40%.Scheme 1. Synthesis of the indole systems 3a-d.The reaction of 4-hydrazinobiphenyl and 4-acetylbiphenyl in polyphosphoric acid did not form the expected indole system.The reaction was complicated due to side processes.Biphenyl sublimed from the reaction mixture, most probably produced by decomposition of an unstable intermediate hydrazone.
We were also unable to obtain ethyl 5-phenylindole-2-carboxylate 6 under the same conditions.This compound was not firmed in polyphosphoric acid neither with the above described method nor by the preliminary isolation of hydrazone.The best result was achieved when the reaction was carried out using ethyl esters of polyphosphoric acid (PPAEE).The reaction was carried out in two steps.We first isolated the biphenylhydrazone 5 of ethyl pyruvate, which by cyclization at 80 C gave chromatographically pure compound 6 in 58% yield (Scheme 2).Scheme 2. Synthesis of ethyl 5-phenylindole-2-carboxylate 6 and conversion of ester group.
From the synthesized compounds we selected ethyl 5-phenylindole-2-carboxylate and studied its chemical properties in two ways: (1) manipulation of the ester group (Scheme 2) and (2) electrophilic substitution reactions (Scheme 3) in order to define the nature of the influence of the substituents on the reaction processes.
Saponification of the ester group and thermal decarboxylation of acid 7 was described earlier. 17The use of an inert gas by us increased the yield of compound 8 to 55% (Scheme 2).
For ethyl 5-phenylindole-2-carboxylate we carried out some classical electrophilic substitution reactions of the indole ring, such as formylation according to Vilsmeier-Haack, 18 dimethylaminomethylation according to Mannich, 19 nitrosation, 18,20  Ethyl 5-phenylindole-2-carboxylate does not enter in the azo-coupling reactionwe suppose that this failure is caused by the acceptor influence of the ester group.It also affects the nitrosation reaction, Vilsmeier-Haack formylation and Mannich aminomethylation (Scheme 3) which proceed only at temperatures 90, 60 and 90 C respectively.Considering the low reactivity of ethyl 5-phenylindole-2-carboxylate 6 at low temperatures, formylation was carried out without previous preparation of formylation complex, which noticeably simplifies the process.Formylation of compound 6 proceeded at 60 C for 3 hours and gave 3-formyl derivative 9 with a yield of 88%.
Dimethylaminomethylation of ethyl 5-phenylindole-2-carboxylate 6 with a freshly prepared mixture of dimethylamine, formalin and acetic acid also proceeded at high temperature, at 90C, and resulted in gramine-type Mannich base 10 with the yield of 65%.
The ester group has no effect on N-alkylation (Scheme 3), which we conducted in a superbasic medium similar to that described 22a,b and obtained the corresponding N-alkyl derivatives 13a-c (Scheme 3, Table 2).The ester group does appear to affect the isomerization of the nitrosation product, which was obtained in the form of an isonitroso derivative, 11, in 90% yield.Apparently isonitroso form is favoured, perhaps by an intramolecular hydrogen bond between the oxime hydrogen and the neighboring ethoxycarbonyl group.A signal (singlet, 13.05 ppm) in the 1 H NMR spectrum of the nitrosation product could be characteristic of an oxime 11b hydrogen atom, but it cold also be characteristic of an indole N-H proton of nitroso derivative 11a (analogous to a singlet signal at 12.88 ppm in the 1 H NMR spectrum of formyl derivative 9).20b-e Structure 11b is confirmed also by the fact that this compound has no UV absorption maxima in longwavelength range whereas the N-methyl-3-nitroso-2-phenylindoles, synthesized by us earlier, have maxima in 368-370 nm range.20f Such compounds form of green crystals.20f By heating a mixture of aldehyde 9 and hydrazine hydrate in glacial acetic acid, 8-phenyl-3,5-dihydro-4H-pyridazino [4,5-b]indol-4-one 15 was formed in 92% yield (Scheme 4).

Conclusions
In order to search for compounds with useful properties, new indole-containing heterocyclic compounds were synthesized, in particular, 5-aryl-and 2,5-diaryl-indoles and 2-ethoxycarbonyl-5-aryl-indoles.The preparative method for their synthesis utilized an arylhydrazine and a carbonyl compound in polyphosphoric acid without isolation of intermediate hydrazone.
Taking into consideration the results obtained it can be concluded that the 5-phenyl group has no effect on the reactions of these indoles.The reactivity is however significantly reduced by the electronic and steric influence of an α-ethoxycarbonyl group, and electrophilic substitution reactions proceeded only at high temperatures.β-Substituted products were obtained in all cases.

Experimental Section
General.Conversion of reactants and purity of the obtained compounds were monitored by TLC on silufol UV-254 plates.Melting points were determined on a NAGEMA PHMK 05 apparatus.The IR spectra were recorded on a Thermo Nicolet FTIR photometer "AVATAR 370".The UV spectra were obtained on an UV/Vis Varian "CARRY-100" instrument.Elemental analyses were carried out on a Multi EA 2000 analyzer. 1H NMR and 13 C NMR were recorded on a BRUKER DRX-500 (500 MHz) and VARIAN MERCURY 300 VX (300 MHz) in DMSO-d6 (with TMS for 1 H and 13 C as the internal standard).

Table 2 .
Conditions and yields of N-alkylindoles