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 = H1c /2c R1 = F, R2 = H1 d /2 d R1 = H, R2 = F
71
2
1e /2e R1 , R2 = H1f /2f R1 = Cl, R2 = H1 g /2 g R1 = H, R2 = Cl1 h /2 h R1 = F, R2 = H1i /2i R1 = H, R2 = F1j /2j R1 = F, R2 = Cl1k /2k1
= Cl, R2 = F
78
3
1 l/2 l R1 = H1 m/2 m R1 = OMe
43
4
1n/2n R1 , R2 = H1o/2o R1 = Cl, R2 = H1 p/2 p R1 = F, R2 = H1q/2q R1 = H, R2 = F
79
5
1r/2r R1 = H1 s/2 s R1 = F
78
6
1 t/2 t R1 , R2 = H1 u/2 u R1 = Cl, R2 = H1v/2v R1 = F, R2 = H
80
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 Na2 CO3 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 K3 PO4 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 CH2 Cl2 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.
