Non-aerobic and One-Pot Synthesis of Carbazoles from Cyclohex­anones and Arylhydrazines

Abstract

The reaction of cyclohexanones with phenylhydrazines proceeded under an ethylene atmosphere in the presence of a catalytic amount of Pd/C and an equimolar amount of p-toluenesulfonic acid monohydrate to afford a variety of substituted carbazoles in good to high yields. The present reaction was carried out under completely non-aerobic conditions, which is in contrast with the previously reported aerobic system. This protocol was also applied to the synthesis of symmetrical carbazoles using hydrazine monohydrate in place of phenylhydrazines. The reaction would proceed in a manner similar to the Fischer indole synthesis, involving a [3,3]-sigmatropic rearrangement and advancing with 1,2,3,4-tetrahydrocarbazole as an intermediate.

Key words

carbazoles - non-aerobic conditions - phenylhydrazines - Pd/C - p-toluenesulfonic acid monohydrate - [3,3]-sigmatropic rearrangement

Publication History

Received: 29 November 2024

Accepted after revision: 18 January 2025

Accepted Manuscript online:
20 January 2025

Article published online:
04 March 2025

• References

• 1a Chakraborty DP. In The Alkaloids: Chemistry and Pharmacology, Vol. 44. Cordell GA. Academic Press; New York: 1993: 257-364
• 1b Joule JA, Mills K. Heterocyclic Chemistry, 4th ed. Blackwell Science; Oxford (U.K.): 2000
• 1c Knölker H.-J, Reddy KR. The Alkaloids: Chemistry and Biology, Vol. 65. Cordell GA. Academic Press; Amsterdam: 2008: 1-430
• 2a Xu Z, Wu D, Fang C, Li Y. Des. Monomers Polym. 2023; 26: 90
• 2b Meragelman KM, McKee TC, Boyd MR. J. Nat. Prod. 2000; 63: 427
• 2c Knölker H.-J, Reddy KR. Chem. Rev. 2002; 102: 4303
• 2d Laronze M, Boisbrun M, Leonce S, Pfeiffer B, Renard P, Lozach O, Meijer L, Lansiaux A, Bailly C, Sapi J, Laronze JY. Bioorg. Med. Chem. 2005; 13: 2263
• 2e Hsu M.-J, Chao Y, Chang Y.-H, Ho F.-M, Huang L.-J, Huang Y.-L, Luh T.-Y, Chen C.-P, Lin W.-W. Biochem. Pharmacol. 2005; 70: 102
• 2f Howard-Jones AR, Walsh CT. J. Am. Chem. Soc. 2006; 128: 12289
• 2g Hu L, Li Z, Qu J, Ling Y.-H, Jiang J, Boykin DW. J. Med. Chem. 2006; 49: 6273
• 3 Organic Light Emitting Devices: Synthesis, Properties, and Applications. Müllen K, Scherf U. Wiley-VCH; Weinheim: 2006
• 4a Thomas KR. J, Lin JT, Tao Y.-T, Ko C.-W. J. Am. Chem. Soc. 2001; 123: 9404
• 4b Diaz JL, Dobarro A, Villacampa B, Velasco D. Chem. Mater. 2001; 13: 2528
• 4c Chen C.-T. Chem. Mater. 2004; 16: 4389
• 4d Brunner K, van Dijken A, Bärner H, Bastiaansen JJ. A. M, Kiggen NM. M, Langeveld BM. W. J. Am. Chem. Soc. 2004; 126: 6035
• 4e Yeh S.-J, Wu M.-F, Chen C.-T, Song Y.-H, Chi Y, Ho M.-H, Hsu S.-F, Chen CH. Adv. Mater. 2005; 17: 285
• 4f Tsai M.-H, Hong Y.-H, Chang C.-H, Su H.-C, Wu C.-C, Matoliukstyte A, Simokaiteiene S, Grigalevicius S, Grazulevicius JV, Hsu C.-P. Adv. Mater. 2007; 19: 862
• 5a Matsubara R, Shin Y.-S, Shimada T, Hayashi M. Asian J. Org. Chem. 2014; 3: 1054
• 5b Matsubara R, Shimada T, Kobori Y, Yabuta T, Osakai T, Hayashi M. Chem. Asian J. 2016; 11: 2006
• 5c Matsubara R, Yabuta T, Md Idros U, Hayashi M, Ema F, Kobori Y, Sakata K. J. Org. Chem. 2018; 83: 9381
• 5d Matsubara R, Kuang H, Yabuta T, Xie W, Hayashi M, Sakuda E. J. Photochem. Photobiol. 2023; 15: 100176
• 5e Matsubara R, Md Idros U, Yabuta T, Ma H, Hayashi M, Eda K. ChemPhotoChem. 2018; 2: 1012
• 5f Yabuta T, Hayashi M, Matsubara R. J. Org. Chem. 2021; 86: 2545
• 5g Xie W, Xu J, Md Idros U, Katsuhira J, Fuki M, Hayashi M, Yamanaka M, Kobori Y, Matsubara R. Nat. Chem. 2023; 15: 794
• 6a Cadogan JI. G, Cameron-Wood M, Mackie RK, Searle RJ. G. J. Chem. Soc. 1965; 4831

From aromatic azides, see:
• 6b Iddon B, Meth-Cohn O, Scriven EF. V, Suschitzky H, Gallagher PT. Angew. Chem., Int. Ed. Engl. 1979; 18: 900
• 6c Söderberg BC. G. Curr. Org. Chem. 2000; 4: 727
• 7 Åkermark B, Eberson L, Jonson E, Pettersson E. J. Org. Chem. 1975; 40: 1365
• 8a Tanaka T, Okunaga K, Hayashi M. Tetrahedron Lett. 2010; 51: 4633

See also:
• 8b Robinson R. Chem. Rev. 1963; 63: 373
• 8c Robinson R. Chem. Rev. 1969; 69: 227
• 9 Xiao F, Liao Y, Wu Y, Deng G.-J. Green Chem. 2012; 14: 3277
• 10 Karki M, Araujo HC, Magolan J. Synlett 2013; 24: 1675
• 11a Chen S, Li Y, Ni P, Huang H, Deng G.-J. Org. Lett. 2016; 18: 5384
• 11b Wu J, Chen X, Xie Y, Guo Y, Zhang Q, Deng G.-J. J. Org. Chem. 2017; 82: 5743
• 12 Alekseyev RS, Kurkin AV, Yurovskaya MA. Chem. Heterocycl. Compd. 2011; 47: 584
• 13 When we employed the reaction of cyclohexanone (1a) with phenylhydrazine (2a) in the presence of 1-octene (2 equiv) instead of ethylene gas, carbazole (3a) was obtained in 93% yield. The reactions for the synthesis of indoles using 1-octene as a hydrogen acceptor, instead of ethylene, were recently reported by our group. See: Dong X, Matsubara R, Hayashi M. Synthesis 2025; 57: 800
• 14 Guerra WD, Rossi RA, Pierini AB, Barolo SM. J. Org. Chem. 2015; 80: 928
• 15 Takamatsu K, Hirano K, Satoh T, Miura M. Org. Lett. 2014; 16: 2892
• 16 Ullah E, McNulty J, Robertson A. Eur. J. Org. Chem. 2012; 2127
• 17 Budén ME, Vaillard VA, Martin SE, Rossi RA. J. Org. Chem. 2009; 74: 4490
• 18 King FE, King TJ. J. Chem. Soc. 1945; 824
• 19 Bedford RB, Betham M. J. Org. Chem. 2006; 71: 9403
• 20 Ackermann L, Althammer A. Angew. Chem. Int. Ed. 2007; 46: 1627
• 21 Yang L, Zhang Y, Zou X, Lu H, Li G. Green Chem. 2018; 20: 1362
• 22 Rasheed S, Rao DN, Reddy KR, Aravinda S, Vishwakarma RA, Das P. RSC Adv. 2014; 4: 4960
• 23 Plant SG. P, Williams SB. C. J. Chem. Soc. 1934; 1142
• 24 Humne V, Dangat Y, Vanka K, Lokhande P. Org. Biomol. Chem. 2014; 12: 4832
• 25 Chen F, Liu N, Ji E, Dai B. RSC Adv. 2015; 5: 5151
• 26 Mayer L, Kohlbecher R, Müller TJ. J. Chem. Eur. J. 2020; 26: 15130
• 27 Inoue H, Hara T, Ishisone T, Suzuki K, Hamada T, Kanamoto M. WO Patent WO2016012910, 2016
• 28 Kuroki M, Tsunashima Y. J. Heterocycl. Chem. 1981; 18: 709
• 29 Wentrup C, Gaugaz M. Helv. Chim. Acta 1971; 54: 2108
• 30 Gruzdev MS, Chervonova UV, Venediktov EA, Rozhkova EP, Kolker AM, Mazaev EA, Dudina NA, Domracheva NE. Russ. J. Gen. Chem. 2015; 85: 1431
• 31 Inoue M, Suzuki T, Nakada M. J. Am. Chem. Soc. 2003; 125: 1140
• 32 Hodgson HH, Habeshaw J. J. Chem. Soc. 1947; 1573