Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129–168) Cross-coupling of copper arylacetylides with N-(o-iodoaryl)hydrazines as a new method of synthesising 2-substituted indoles Tat’yana A. Prikhod’ko and Sergey F. Vasilevsky* Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation. Fax: +7 3832 34 2350; e-mail: vasilev@ns.kinetics.nsc.ru A new method is proposed for synthesising 2-substituted indoles by cross-coupling of copper(I) arylacetylides with N-(o-iodophenyl)hydrazines in DMF.We have already reported on the cyclocondensation of activated o-chloroarylacetylenes with hydrazine which results in substituted indazoles.1 This method is, however, limited by the necessity of using both aryl halides and acetylenic components which possess only electron-withdrawing substituents.In addition, the cyclocondensation of o-chloro-substituted arylacetylenes with NH2NH2·H2O fails to give the intermediate compounds, N-(o-acetylenylaryl)hydrazines (substitution of a chlorine atom by a hydrazine group is the rate determining stage). Thus, it is impossible to study the cyclization of intermediates in a ‘pure form’ depending on the experimental conditions.It is also known that the direction of cyclization of (o-acetylenylaryl)carboxylic acid hydrazides, also containing two nitrogen atoms of differing nucleophilicity, may be controlled by varying the reaction conditions.2 We assume that an alternative way of synthesising N-(o-acetylenylaryl)hydrazines by interaction of N-(o-iodoaryl) hydrazines with either terminal acetylenes or their acetylide allows us not only to isolate intermediates but also to study the direction of N-(o-arylethynyl)hydrazine cyclization in the absence of acceptor substituents or even in the presence of donors.This, in turn, would make it possible to determine more precisely the influence of both internal (character of substituents) and external (conditions of cyclization) factors on the route of cyclization, its generality and limitations, and to synthesise other condensed heterocyclic systems.The interaction between N-(o-iodophenyl)hydrazine 1 and p-nitrophenylacetylene 2 under standard cross-coupling conditions (Scheme 1) gives rise to 3-substituted indazole 3 in 38% yield.We have failed to isolate the expected intermediate 4. Using chloride (1·HCl) as a more stable substrate, we managed to increase the yield of 3† to 43%. All attempts to condense 1 with p-methoxyphenylacetylene failed, since the reaction was followed by resinification. These results and the comparatively low yield of 3 are attributed to † All compounds synthesised have satisfactory analytical and spectral data. 3: mp 117–118 °C (from benzene–hexane); 1H NMR (CDCl3) d: 4.45 (s, 2H, CH2), 7.0–8.2 (m, 8H, arom. H), 10.6 (br. s, 1H, NH); IR (CHCl3, n/cm–1): 1350 and 1530 (NO2), 3480 (br., NH). both the lability of initial iodohydrazine 1 and the low reactivity of halide atom due to the +M-effect of the hydrazine group. A similar result was observed for the reaction of arylacetylenes with vicinal iodoaminopyrazoles.To avoid complications, the authors used acylic protection of the amino group and replaced the catalytic variant of cross-coupling by the acetylide method of synthesis.3 We used this method in the present work. The acetylation of hydrazine 1 does indeed cause substrate stabilization and makes it possible to carry out cross-coupling of copper(I) p-nitrophenyl- 5a, phenyl- 5b and even of p-methoxyphenylacetylide 5c with a-N-(o-iodophenyl)-b-N-(acetyl)hydrazine 6 (Scheme 2, Table 1).However, we failed to isolate intermediates 7a–c upon condensation. The reaction leads to the 2-substituted indoles 8a–c‡ (30–75%). As expected, the reaction with 5a proceeds most smoothly. It is interesting that compounds 8a–c exist in a tautomeric equilibrium 8a–c 8'a–c in solution (see NMR spectra).The formation of the pyrrole rather than the pyrazole ring is related to the greater nucleophilicity of the amine nitrogen atom as compared with the amide nitrogen. The application of pyridine as a solvent in the reaction of iodide 6 with 5a changes the route of cyclocondensation. The I NHNH2 C C NO2 NHNH2 i N N H H2C NO2 1 C NO2 HC 2 3 4 Scheme 1 Reagents and conditions: i, N2, Pd(PPh3)2Cl2–CuI, Et3N, 80 °C, 4.5 h.I NHNHCOMe C C R NHNHCOMe N NHCOMe R 6 C R CuC 5a–c 9 7a–c N N H2C NO2 COMe i ii 8a–c N N R 8'a–c C OH Me Scheme 2 Reagents and conditions: i, N2, DMF, 155 °C, 3–7 h; ii, N2, Py, 110 °C, 3.5 h. Table 1 Cyclocondensation of copper arylacetylides CuCºC–C6H4–R-p with a-N-(o-iodophenyl)-b-N-(acetyl)hydrazine 6.Acetylide 5 R Indole 8 DMF, 155 °C Yield (%) a NO2 a 3 h 74.7 b H b 5 h 32.0 c OMe c 7 h 41.0Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129-168) formation of isoindazole 9§ (30%) is probably related to the generation of a stronger N-anion nucleophile from the ‘acidic’ MeCONH group in the presence of base (Py).All our attempts to carry out condensation of iodohydrazine 6 with copper(I) acetylide 5c under similar conditions (Py) failed, probably due to the opposing polarization of a triple bond in intermediate 7c (compared to 7a) and due to the impossibility of forming an aromatic system. We have managed to synthesize intermediate 7a from 6 and 2 by using a catalytic variant of cross-coupling and decreasing the temperature to 80 °C.The yield of 7a¶ reached 68%. The interaction between iodide 6 and p-methoxyphenylacetylene under similar conditions fails to give the corresponding product 7c (the reaction mass still contains initial 6) and the reaction is accompanied by strong resinification. We assume that this is caused by the lower CH-acidity of p-methoxyphenylacetylene compared to that of p-nitrophenylacetylene.4 In attempting to remove the acylic protection in 7a by boiling in n-butanol in the presence of K2CO3 we failed to isolate the expected intermediate 4 because the reaction was followed by cyclization into indazole 3 (48%).We therefore suggest the direction of heterocyclization to be different in the absence of the base because the amine nitrogen atom is a stronger nucleophile than the amide one.Indeed, heating of 7a in DMF in the presence of CuI at 120 °C gives indole 8a in 75% yield (Scheme 3). Thus, we have demonstrated the possibility of cross-coupling 1-alkynes and their acetylides with N-(o-iodophenyl)hydrazine and a-N-(o-iodophenyl)-b-N-(acetyl)hydrazine to produce condensed heterocyclic systems in a one-pot reaction: 1.The condensation of a-N-(o-iodophenyl)-b-N-(acetyl)- hydrazine with substituted copper(I) arylacetylides in DMF proceeds with the formation of a pyrrole ring and leads to the corresponding indoles. This is a new method for synthesising 2-substituted indoles. The same compounds are obtained by the cyclization of a-N-[(o-arylacetylenyl)phenyl]-b-N-(acetyl)- hydrazine in DMF in the presense of CuI.‡ 8a: mp 287.5–288 °C (from EtOH); 1H NMR (CDCl3) d: 1.52 and 2.22 [s, 3H, =C(OH)CH3 and COCH3], 6.83 and 6.95 (s, 1H, H-3 and H-3'), 7.2–8.45 (m, 8H, arom. H); IR (CHCl3, n/cm–1): 1340 and 1510 (NO2), 1680 (C=O), 3200, 3380 (br., NH, OH). 8b: mp 216–217 °C (from EtOAc); 1H NMR (CDCl3) d: 1.55 and 2.10 [s, 3H, =C(OH)CH3 and COCH3], 6.65 and 6.75 (s, 1H, H-3 and H-3'), 7.10–8.25 (m, 9H, arom.H); IR (CHCl3, n/cm–1): 1710 (C=O), 3230, 3400 (br., NH, OH). 8c: mp 193–194 °C (from EtOAc); 1H NMR (CDCl3) d: 1.53 and 2.12 [s, 3H, =C(OH)CH3 and COCH3], 3.83 and 3.85 (s, 3H, OCH3 and OCH3 ' ), 6.55 and 6.65 (s, 1H, H-3 and H-3'), 6.9–8.1 (m, 8H, arom. H); IR (CHCl3, n/cm–1): 1040 (OCH3), 1705 (C=O), 3250, 3390 (br., NH, OH).§ 9: mp 123–125 °C (from EtOAc); 1H NMR (CDCl3) d: 2.75 (s, 3H, CH3), 4.41 (s, 2H, CH2), 7.3–7.6 [m, 5H, H(b,b',4,5,6)], 8.17 [d, 2H, H(a,a'), J 11.25 Hz], 8.46 (d, 1H, H-7, J 8.4 Hz); IR (CHCl3 n/cm–1): 1350 (and 1330) and 1530 (NO2), 1720 (and 1710) (C=O). ¶ 7a: mp 165–166 °C (from EtOH–benzene); 1H NMR (CDCl3) d: 2.15 (s, 3H, CH3), 6.8–7.62 (m, 6H, H-2,3,4,5,2',6'), 8.20 (d, 2H, H-3',5', J 8.6 Hz); IR (CHCl3, n/cm–1): 1350 and 1530 (NO2), 1710 (C=O), 2220 (CºC), 3450 (br., NH). 2. The cyclocondensation of a-N-(o-iodophenyl)-b-N-(acetyl)- hydrazine with copper(I) acetylides with electron-withdrawing substituents gives 3-substituted isoindazoles under the effect of bases. 3. The Pd–Cu-catalysed cross-coupling of N-(o-iodophenyl) hydrazine with 1-alkynes bearing electron-withdrawing substituents in the presence of base is followed by cyclization to 3-substituted indazoles. This work was supported by the Russian Foundation for Basic Research (grant no. 95-03-08928a).References 1 S. F. Vasilevsky and T. A. Prikhod’ko, Mendeleev Commun., 1996, 98. 2 S. F. Vasilevsky, A. V. Pozdnyakov and M. S. Shvartzberg, Izv. Akad. Nauk SSSR, Ser. Khim., 1985, 1367 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1985, 34, 1250). 3 E. V. Tretyakov, PhD Thesis., Inst. Chem. Kinetics and Combustion, SB RAS, Novosibirsk, 1997, p. 130. 4 M. I. Terekhova, E. S. Petrov, S. F. Vasilevsky, V. F. Ivanov and M. S. Shvartzberg, Izv. Akad. Nauk SSSR, Ser. Khim., 1984, 923 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1984, 33, 850). C C NO2 NHNHCOMe N NHCOMe NO2 6 + 2 3 7a N N H2C NO2 i 8a H K2CO3 BunOH CuI DMF Scheme 3 Reagents and conditions: i, N2, Pd(PPh3)2Cl2–CuI, Et3N, 80 °C, 4.5 h. Received: Moscow, 9th April 1998 Cambridge, 11th May 1998; Com. 8/02798F