Synthesis of 2,3-Disubstituted Carbazoles, Benzo[c]carbazoles, and Phenanthrenes Through FeCl₃-Mediated Cyclization of Triene Frameworks

Abstract

A facile synthesis of 2,3-disubstituted carbazoles through electrocyclization of 2,3-divinylindoles using FeCl₃ in DMF at reflux is reported. The methodology was found to be applicable for smooth transformation of 3-aryl-2-vinylindole as well as 2-styrylbiphenyl into the respective benzo[c]carbazole and phenanthrene.

Key words

carbazoles - electrocyclization - Iron(III) chloride - 2,3-di­vinylindole - benzocarbazole - phenanthrene

Over the years, our research group has exploited electro­cyclization of 1-phenylsulfonyl-2,3-divinylindoles as a key step for the syntheses of quinocarbazoles,[1a] staurosporine aglycone,[1b] [1c] and also for accessing a wide variety of substituted carbazoles.[2] We have also accomplished a Lewis acid mediated electrocyclization strategy for accessing calothrixin B and its derivatives.[3] In all these reports, the thermal electrocyclization followed by aromatization of 2,3-divinylindoles could be performed using 10 % Pd/C in xylenes at reflux to give the respective carbazoles in good yields. However, the inconsistent quality of 10 % Pd-C, difficulty in the aromatization of intermediate dihydrocarbazole, coupled with prolonged reaction time at elevated temperature, makes this protocol unsuitable for performing the reaction on a multi-gram scale. We sought to develop an alternative procedure that avoids the use Pd/C and also overcomes the disadvantages noted above. Hence, in a further continuation of our work on the synthesis of carbazoles,[1] [2] [3] we report herein the synthesis of a wide variety of carbazole derivatives 2 through FeCl₃-mediated[4] [5] electrocyclization as a key step. The synthesis of benzo[c]carbazoles 3 could also be achieved from the respective 2-vinyl-3-arylindoles (Scheme [1]).

Scheme 1 Synthesis of carbazoles 2 and 3 using FeCl₃-mediated cyclization

To realize this objective, the required 2,3-divinylindoles 1a – v were prepared (Scheme [2]) from the respective phosphonate esters.[6] As a representative case, thermal electrocyclization of 1a in the presence of anhydrous FeCl₃ in anhydrous DMF at reflux for 6 h afforded 2-nitrophenyl carbazole 2a [7] in 74 % yield (Scheme [3]).

Scheme 2 List of 2,3-divinylindoles 1a – v

To our delight, FeCl₃-mediated electrocyclization of a wide variety of 2,3-divinylindoles could be smoothly performed to afford the respective carbazoles.

Scheme 3 FeCl₃-mediated electrocyclization of divinylindole 1a

Table 1 FeCl₃-Mediated Electrocyclization of 1-Phenylsulfonyl-2,3-divinylindoles 1b – v

Entry	2,3-divinylindolea		Carbazole	Yield (%)b
1		1b/2b R1 = Cl, R2 = H 1c/2c R1 = F, R2 = H 1 d/2 d R1 = H, R2 = F		71 73 78
2		1e/2e R1, R2 = H 1f/2f R1 = Cl, R2 = H 1 g/2 g R1 = H, R2 = Cl 1 h/2 h R1 = F, R2 = H 1i/2i R1 = H, R2 = F 1j/2j R1 = F, R2 = Cl 1k/2k1  = Cl, R2 = F		78 75 76 78 73 71 70
3		1 l/2 l R1 = H 1 m/2 m R1 = OMe		43 38
4		1n/2n R1, R2 = H 1o/2o R1 = Cl, R2 = H 1 p/2 p R1 = F, R2 = H 1q/2q R1 = H, R2 = F		79 82 81 78
5		1r/2r R1 = H 1 s/2 s R1 = F		78 72
6		1 t/2 t R1, R2 = H 1 u/2 u R1 = Cl, R2 = H 1v/2v R1 = F, R2 = H		80 72 74

^a Reactions were carried out using 1a – v (1 equiv), FeCl₃ (0.5 – 2 equiv) in DMF (10 mL) at reflux for 3 – 12 h.

^b Isolated yield by column chromatography.

The structures of various types of divinylindoles employed and the resulting carbazoles obtained are presented in Table [1]. The reaction of 1-phenylsulfonyl-2,3-divinylindoles 1b – d with FeCl₃ in anhydrous DMF at reflux afforded carbazoles 2b – d in 71 – 78 % yields, respectively (entry 1). The FeCl₃-mediated elctrocyclization could be smoothly performed with 2,3-divinylindoles 1e – k to afford the expected 4-methylcarbazoles 2e – k in good yields (entry 2). However, the reaction was found to proceed slowly with 2,3-divinylindole 1 l/1 m, containing a phenyl or p-anisyl unit, yielding the respective carbazole 2 l and 2 m in 43 % and 38 % yields (entry 3). The isolation of compounds 2 l and 2 m in low yields confirms that the electron-donating nature of the aryl unit present in 2,3-divinylindole 1 l or 1 m is not conducive for the FeCl₃-mediated electrocyclization reaction. As expected, the 2,3-divinylindoles 1n – q, containing a cyanovinyl unit, upon reaction with 50 mol% FeCl₃ in DMF at reflux furnished the respective 3-cyano-2-(2′-nitrophenyl)carbazoles 2n – q in 78 – 82 % yields (entry 4). Under identical conditions, the isomeric 3-(2′-nitrophenyl)vinylindoles­ 1r – v, containing 2-vinyl ester as well as a 2-vinyl cyanide unit, could be smoothly transformed into the appropriate carbazoles 2r – v (entries 5 and 6).

The synthesis of benzo[c]carbazole analogues employing the FeCl₃-mediated cyclization was then initiated. Accordingly, Wittig – Horner reaction of phosphonate ester 4 [6] with substituted benzaldehydes in the presence of NaH in tetrahydrofuran (THF) at 0 °C for 3 h afforded 3-bromo-2-arylindoles 5a and 5b. As expected, the Suzuki coupling of bromo compound 5a/5b with aryl boronic acid using Pd(PPh₃)₄ and Na₂CO₃ in 1,2-dimethoxyethane (DME) at reflux furnished 3-aryl-2-strylindoles 6a – d as colorless solids in good yields. As expected, the reaction of 6a – d with 50  mol% FeCl₃ in anhydrous 1,2-dichloroethane (DCE) at room temperature or at reflux furnished 2-aryl benzo[c]carbazoles 3a – d [7] in good yields (Scheme [4]).

Scheme 4 FeCl₃-mediated cyclization of 3-aryl-2-vinylindoles 6a – d

Subsequently, 3-bromo-2-methylindole, upon benzylic bromination followed by hydrolysis and MnO₂ oxidation of corresponding alcohol, led to 3-bromoindole-2-aldehyde 7. The Suzuki coupling of bromo compound 7 with veratryl boronic acid using Pd(PPh₃)₄ in the presence of K₃PO₄ in DME reflux afforded 2-formyl-3-arylindole 8 as a colorless solid in 87 % yield. Indole aldehyde 8, upon Wittig reaction with (carbethoxymethylene)triphenylphosphorane in anhydrous­ CH₂Cl₂ at room temperature, led to 3-veratryl-2-vinylindole 9 in 93 % yield. The 2-vinyl ester 9, upon cyclization using 50 mol% FeCl₃ in anhydrous 1,2-DCE reflux, furnished benzo[c]carbazole 10 in a moderate yield (Scheme [5]). Attempts to improve the yield of the benzo[c]carbazole 10 either by increasing the number of equivalents of FeCl₃ or by prolonging the reaction time was not found to be useful.

Scheme 5 FeCl₃-mediated cyclization of 2-vinyl-3-veratrylindole 9

Next, the Wittig – Horner reaction of phosphonate ester 11 [8] with 2-bromo-veratraldehyde 12 in the presence of t-BuOK in toluene at reflux afforded vinyl compound 13. As expected, the Suzuki coupling of 13 with boronic acids furnished the required triene compounds 14a and 14b in 85 % and 91 % yields. The triene frame work of 14a and 14b underwent cyclization upon interaction with 50 mol% FeCl₃ in anhydrous 1,2-DCE at reflux to give 9-arylphenanthrenes 15a [7] and 15b in 62 % and 65 % yields, respectively (Scheme [6]).

Scheme 6 FeCl₃-mediated cyclization of 2-styrylbiphenyl compounds 14a and 14b

In summary, we have achieved the syntheses of 2,3-disubstituted carbazoles, benzo[c]carbazoles, and phenanthrene derivatives by employing FeCl₃-mediated cyclization of the corresponding triene frameworks. For the first time, the FeCl₃-mediated cyclization of two vinylic carbons as well as phenyl and vinylic carbons could be achieved in acceptable yields.

Acknowledgment

We thank the CSIR, New Delhi for financial support. P.R. and T.M thank the University Grants Commission (UGC), New Delhi for fellowships. For NMR facilities, the authors thank the Department of Science and Technology Funds for the Improvement of Science and Technology (DST-FIST).

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• 7 Representative procedure for 2a : To a stirred solution of 2,3-divinyl compound 1a (0.2 mmol) in anhydrous DMF (10 mL) at r.t., anhydrous FeCl₃ (0.4 mmol) was added and the reaction mixture was heated at reflux for 6 h. After completion of the reaction (monitored by TLC), the mixture was poured over crushed ice (50 g) containing conc. HCl (3 mL). The crude product was extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was dried (Na₂SO₄). Removal of solvent followed by column chromatographic purification (1% EtOAc/hexane) afforded carbazole 2a (74 mg, 74%) as a colorless solid. Mp 220–222 °C; ¹H NMR (300 MHz_, CDCl₃): δ = 8.26 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 8.15 (s, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 2 H), 7.61 (m, 8 H), 4.05 (q, J = 6.5 Hz, 2 H), 1.01 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 166.1, 148.4, 140.1, 139.1, 138.9, 137.6, 137.1, 134.2, 132.6, 131.5, 129.2, 128.4, 128.3, 126.4, 126.1, 125.7, 125.1, 124.7, 124.0, 123.1, 120.5, 116.5, 115.3, 61.1, 13.8 ppm. Representative procedure for 3a : To a stirred solution of 3-aryl-2-vinylindole 6a (0.1 g, 0.21 mmol) in anhydrous 1,2-DCE (8 mL) at r.t., anhydrous FeCl₃ (18 mg, 0.10 mmol) was added and the reaction mixture was stirred at reflux for 3 h. After completion of the reaction (monitored by TLC), the mixture was poured over ice water (20 mL) and acidified with conc. HCl (2 mL). It was then extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic layer was dried (Na₂SO₄). Removal of solvent followed by column chromatographic purification (Silica gel; EtOAc–hexane, 2:8) gave benzo[c]carbazole 3a as a colorless solid (79 mg, 79%). Mp 168–170 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.69 (d, J = 8.4 Hz, 1 H), 8.46–8.40 (m, 2 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.42–7.32 (m, 7 H), 7.24–7.17 (m, 2 H), 7.00 (d, J = 8.4 Hz, 2 H), 3.84 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 159.2, 140.7, 138.2, 137.9, 136.1, 133.8, 133.0, 131.3, 129.8, 129.1, 129.0, 127.6, 127.1, 127.0, 126.3, 126.1, 124.8, 124.4, 123.7, 122.1, 119.0, 115.6, 115.3, 113.8, 55.4 ppm. Dept-135 (75 MHz, CDCl₃): δ = 133.8, 131.3, 129.0, 127.5, 127.1, 126.3, 126.0, 124.8, 124.4, 123.7, 122.0, 115.6, 115.3, 113.7, 55.3 ppm. HRMS (EI): m/z [M⁺] calcd for C₂₉H₂₁NO₃S: 463.1242; found: 463.1220. Representative procedure for 15a : To a stirred solution of 2-styrylbiphenyl compound biphenyl vinylene 14a (0.1 g, 0.26 mmol) in anhydrous 1,2-DCE (10 mL) at r.t., anhydrous FeCl₃ (21 mg, 0.13 mmol) was added and the reaction mixture was stirred at reflux for 3 h. Following a similar work up procedure to that for 6a afforded 2,3-dimethoxyphenanthrene 15a (62 mg, 62%) as a colorless solid. Mp 170–172 °C; ¹H NMR (300 MHz, CDCl₃): δ = 8.63 (d, J = 8.4 Hz, 1 H), 8.06 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.27 (d, J = 3.3 Hz, 1 H), 7.12–7.02 (m, 3 H), 4.17 (s, 3 H), 4.06 (s, 3 H), 4.00 (s, 3 H), 3.93 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 149.6, 149.3, 148.6, 148.3, 136.9, 133.7, 130.5, 130.0, 127.0, 126.7, 126.5, 126.0, 125.5, 124.4, 122.4, 122.3, 113.5, 111.0, 108.2, 103.2, 56.1, 56.0, 55.9, 55.8 ppm. HRMS (EI): m/z [M⁺] cacld for C₂₄H₂₂O₄: 374.1518; found: 374.1515.
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