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. 2013 Oct 10;144(12):1847–1853. doi: 10.1007/s00706-013-1087-3

Synthesis of pyrrolo[3,2-a]phenazines from 5-nitroindoles and anilines

Zbigniew Wróbel 1, Michał Więcław 2, Robert Bujok 1, Krzysztof Wojciechowski 1,✉
PMCID: PMC4495017  PMID: 26166877

Abstract

Abstract

Anilines react with 5-nitroindoles in the presence of t-BuOK in N,N-dimethylformamide (DMF) to form 5-nitroso-4-arylaminoindoles that in turn when treated with N,O-bis(trimethylsilyl)acetamide cyclize to pyrrolo[3,2-a]phenazines. In an alternative approach pyrrolo[3,2-a]phenazines are formed from aminoindoles and nitroarenes.

Graphical abstract

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Keywords: Amines, Anions, Heterocycles, Cyclizations, Nucleophilic substitutions, Lewis acids

Introduction

Phenazine derivatives are an important class of condensed heterocycles of natural origin [1–4]. Selected methods of synthesizing the phenazine framework are presented in Scheme 1. One of the oldest methods is the reaction of anilines with nitroarenes under basic conditions (the Wohl–Aue reaction, path a) [5]. The Holliman synthesis of phenazines (path b) is a base-induced cyclization of ortho-nitrodiphenylamines [6]. In the Bamberger–Ham reaction (path c) nitrosobenzenes dimerize under acidic conditions to form phenazines [7]. Other methods are the condensation of ortho-phenylenediamines with ortho-quinones (path d) [8], reaction of benzofuroxanes and phenols (the Beirut reaction, path e) [9], and palladium-catalyzed cyclization of 2-amino-2′-bromophenylenediamines (path f) [10].

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The classic Wohl-Aue synthesis of phenazines consists in the reaction of anilines with nitroarenes under harsh basic conditions, usually by heating of both starting materials with sodium or potassium hydroxide at 200 °C [5]. In recent years we extensively studied nucleophilic aromatic substitution reactions of hydrogen in nitroarenes [11–15]. During these studies we have found that anilines react with nitrobenzene derivatives under mild conditions in the presence of t-BuOK in DMF at −50 °C to form 2-nitrosodiphenylamines that in turn upon treatment with acetic acid cyclized to phenazines (Scheme2) [16, 17].

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Other transformations of 2-nitrosodiphenylamines into heterocyclic systems developed by us include reactions with benzyl aryl sulfones to form 1,2-diarylbenzimidazoles [18] and cyclocondensation with functionalized alkyl acetates, such as malonates, phenyl- and phosphonyl-acetates, leading to 1-arylquinoxalin-2(1H)-ones [16, 19].

1,2-Benzo- and 1,2-heteroaryl-fused phenazines are of interest owing to their potential biological activity, as intercalators [20, 21], and antimicrobial agents [22, 23]. Reports on the synthesis of pyrrolo[3,2-a]phenazines are scarce. 1-(2-Aminoethyl)pyrrolo[3,2-a]phenazine was formed from 1,2-phenylenediamine and the 4,5-indoloquinone arising from electrochemical oxidation of 5-hydroxytryptamine [24]. Dipyrrolo[3,2-a:3,2-h]phenazines were synthesized in the oxidative dimerization of 5-aminoindoles [25]. Some pyrrolo[3,2-a]phenazine-10-carboxamides, obtained from 4-aminoindole and 2-iodo-3-nitrobenzoic acid, were tested as cytotoxic agents [26].

Results and discussion

In this paper we present a simple synthesis of pyrrolo[3,2-a]phenazines from nitroindoles and anilines. Thus when we treated 5-nitroindole derivatives 1 and anilines 2 with t-BuOK in DMF at −50 °C, the expected 4-(N-arylamino)-5-nitrosoindoles 3 were formed in good yields (Scheme 3 and Table 1).

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Table 1.

Synthesis of nitrosoindoles 3 and pyrrolo[3,2-a]phenazines 4

R X Yield of 3/% Yield of 4/%
a Me Cl 65 65
b CH2Ph Cl 36a,b 88
c n-C8H17 CH3 30 88
d n-C8H17 Cl 58 80
e n-C8H17 OCH3 50 71
f n-C8H17 CF3 –b 34
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aYield of the crude product

bThe crude product without purification was subjected to cyclization to phenazine

Some of these compounds (3b and 3f) proved unstable and thus after isolation without further purification they were used in the next step to form phenazines. The 1H and 13C NMR spectra of the obtained nitrosoamines 3 and 7 deserve some comments. In the spectra of some of these compounds we observed broadening of the signals corresponding to the protons and carbon atoms of the nitroso-substituted moiety and thus their full interpretation was troublesome. Such a signal broadening is probably due to a slow rotation of the nitroso group around the C–N bond. A similar phenomenon was observed in the NMR spectra of 2-(alkylamino)- and 2-(arylamino)nitrosobenzenes [27, 28].

In our earlier papers we have shown that cyclization of N-(2-nitrosophenyl)anilines to phenazines proceeds satisfactorily in boiling acetic acid [16, 17], with K2CO3 in methanol at room temperature [17], or with N,O-bis(trimethylsilyl)acetamide (BSA) [17]. Attempted cyclization of the model nitroso compound 3d in boiling acetic acid was unsuccessful; the starting material was consumed within 90 min (TLC control) but no defined products were obtained. No reaction of 3d was observed in the presence of K2CO3 in methanol. The cyclization of 3d occurs satisfactorily in the presence of BSA in DMF at 80 °C giving the expected pyrrolophenazine 4d in good yield. These reaction conditions were adapted to reactions of other 4-(N-arylamino)indoles 3. The results are summarized in the Table 1.

Alternatively, the pyrrolo[2,3-a]phenazines can be obtained from aminoindoles and nitroarenes (Scheme 4). Thus, when we reacted 4-aminoindole 6a with 4-nitroanisole (5) under standard conditions (t-BuOK/DMF, −50 °C) the expected nitrosoaniline 7a was formed. Since the amine 7a proved unstable, it was without purification subjected to reaction with BSA and cyclized to 9-methoxypyrrolo[3,2-a]phenazine 4 g that was isolated in 90 % yield. Similarly 5-aminoindole 6b and 4-nitroanisole formed the relatively stable nitroso derivative 7b that was isolated in 40 % yield. Treatment of the compound 7b with BSA led to isomeric 8-methoxypyrrolo[3,2-a]phenazine 4 h in 64 % yield.

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These reactions show the versatility of the proposed approach to pyrrolophenazines enabling the synthesis of derivatives bearing substituents in the desired position of the heterocyclic system, as exemplified by the synthesis of 8- and 9-methoxy derivatives 4 g and 4e that can be obtained from different nitroarene–amine pairs, namely 5-nitroindole and para-anisidine or 5-aminoindole (6b) and 4-nitroanisole (5).

In summary, a novel two-step approach to pyrrolophenazines starting from easily available nitroindoles and anilines was developed. In an alternative reaction sequence the pyrrolophenazines can be obtained from nitroarenes and aminoindoles. The simplicity of this approach makes it an interesting alternative to other procedures.

Experimental

All reactions were performed under argon atmosphere. 1H and 13C NMR spectra were recorded on Bruker 500 MHz spectrometer (500 MHz for 1H and 125 MHz for 13C spectra). Chemical shifts (δ) are expressed in ppm referred to TMS, coupling constants in Hertz. Mass spectra (EI, 70 eV) were obtained on an AMD-604 spectrometer. ESI mass spectra were obtained on SYNAPT G2-S HDMS. Merck silica gel 60 F254 plates were used for TLC. Merck silica gel 60 (230–400 mesh) was used for flash column chromatography.

Typical procedure for synthesis of compounds3and7

N-(4-Chlorophenyl)-1,2-dimethyl-5-nitroso-1H-indol-4-amine (3a, C16H14ClN3O)

4-Chloroaniline (0.32 g, 2.5 mmol) in 2 cm3 DMF was added to a solution of 0.67 g t-BuOK (6 mmol) in 10 cm3 DMF cooled to −50 °C. After 5 min a solution of 0.38 g 1,2-dimethyl-5-nitroindole (2 mmol) in 3 cm3 DMF was added. The reaction was stirred at −50 to −40 °C until the starting indole disappeared (1–2 h, TLC control, SiO2, toluene/ethyl acetate 10:1). Then the reaction mixture was poured into 100 cm3 water with 5 g NH4Cl. The precipitate was dissolved in 100 cm3 EtOAc and dried with Na2SO4. After evaporation of solvent the product was purified by column chromatography (SiO2, toluene/ethyl acetate). The product 3a was obtained as a dark red solid; m.p.: >285 °C (decomp.); R f = 0.18 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3): δ = 2.21 (s, 3H), 3.61 (s, 3H), 5.41 (br s, 1H), 6.91 (br s, 1H), 7.15–7.26 (m, 2H), 7.37–7.38 (m, 2H), 8.14 (br s, 1H), 14.49 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.47, 30.00, 104.55, 105.57, 111.77, 127.35, 128.18, 128.99, 129.33, 132.57, 134.94, 137.38, 141.32, 153.62 ppm; MS (ESI): m/z = 300 ([M + H]+, 100), 282 (8); HRMS (ESI): calcd. for C16H3515ClN3O 300.0904, found 300.0905.

1-Benzyl-N-(4-chlorophenyl)-2-methyl-5-nitroso-1H-indol-4-amine (3b, C22H18ClN3O)

Dark red unstable semisolid; MS (EI, 70 eV): m/z = 375 (M+, 42), 361 (55), 358 (38), 344 (12), 323 (33), 267 (9), 253 (32), 235 (36), 219 (19), 91 (100); HRMS (ESI): calcd. for C22H18ClN3NaO 398.1031, found 398.1040.

2-Methyl-N-(4-methylphenyl)-5-nitroso-1-octyl-1H-indol-4-amine (3c, C24H31N3O)

Dark red oil; R f = 0.32 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3H), 1.26–1.32 (m, 10H), 1.70 (m, 2H), 2.16 (s, 3H), 2.42 (s, 3H), 3.93 (t, J = 7.7 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.13–7.28 (m, 3H), 14.69 (br s, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.43, 14.05, 22.59, 26.90, 29.12, 29.23, 30.47, 31.73, 31.78, 43.68, 104.56, 116.11, 111.92, 126.29, 129.24, 132.25, 133.76, 134.36, 135.78, 137.02, 140.54, 153.45 ppm; MS (ESI): m/z = 378 (M+, 100); HRMS (ESI): calcd. for C24H32N3O 378.2545, found 378.2548.

N-(4-Chlorophenyl)-2-methyl-5-nitroso-1-octyl-1H-indol-4-amine (3d, C23H28ClN3O)

Black solid; m.p.: 102–103 °C; R f = 0.40 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3H), 1.27–1.33 (m, 10H), 1.70–1.73 (m, 2H), 2.20 (s, 3H), 3.96 (t, J = 7.5 Hz, 2H), 5.40 (br s, 1H), 6.91 (br s, 1H), 7.24–7.29 m, 2H), 7.34–7.42 (m, 2H), 8.13 (br s, 1H), 14.54 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.44, 14.02, 22.55, 26.86, 29.09, 29.19, 30.43, 31.70, 43.76, 104.95, 105.90, 121.14, 127.41, 128.91, 129.38, 132.29, 133.12, 134.46, 137.34, 140.80, 153.35 ppm; MS (ESI, MeOH): m/z = 398 ([M + H]+, 100), 380 (10); HRMS (ESI): calcd. for C23H3529ClN3O 398.1999, found 398.1997.

N-(4-Methoxyphenyl)-2-methyl-5-nitroso-1-octyl-1H-indol-4-amine (3e, C24H31N3O2)

Black solid; m.p.: 77–79 °C; R f = 0.24 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3H), 1.26–1.32 (m, 10H), 1.67–1.71 (m, 2H), 2.16 (s, 3H), 3.87 (s, 3H), 3.94 (t, J = 7.8, 2H), 5.27 (s, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 9.2 Hz, 1H), 14.63 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.39, 14.03, 22.56, 26.87, 29.10, 29.20, 30.44, 31.71, 43.67, 55.50, 104.53, 106.00, 111.83, 114.42, 127.81, 131.10, 132.15, 133.77, 135.00, 140.50, 153.28, 158.66 ppm; MS (ESI, MeOH): m/z = 394 (M+, 100); HRMS (EI): calcd. for C24H32N3O2 394.2495, found 394.2494.

1-Benzyl-N-(5-methoxy-2-nitrosophenyl)-2-methyl-1H-indol-4-amine (7a, C23H21N3O2)

Dark red crystals; m.p.: >115 °C (decomp); R f = 0.48 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, DMSO-d 6): δ = 2.38 (s, 3H), 3.75 (s, 3H), 5.46 (s, 2H), 6.23 (s, 1H), 6.43 (br s, 1H), 6.68 (br s, 1H), 6.90–7.04 (m, 2H), 7.12 (dd, J = 8.0, 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.21–7.25 (m, 1H), 7.27–7.32 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 8.53 (br s, 1H), 13.21 (br s, 1H) ppm; 13C NMR (125 MHz, DMSO-d 6): δ = 46.48, 56.43, 60.20, 95.30, 98.02, 108.86, 109.98, 115.01, 121.44, 123.99, 126.57, 127.62, 129.11, 138.40, 138.55 ppm (spectrum not fully legible); MS (ESI, MeOH): m/z = 394 ([M + Na]+), 372 ([M + H]+); HRMS (ESI, [M + 1]+): calcd. for C23H22N3O2 372.1707, found 372.1718.

1-Benzyl-N-(5-methoxy-2-nitrosophenyl)-2-methyl-1H-indol-5-amine (7b, C23H21N3O2)

Dark brown crystals; yield 40 %; m.p.: >90 °C (decomp); R f = 0.38 (toluene/ethyl acetate 10:1); 1H NMR (500 MHz, DMSO-d 6): δ = 2.37 (s, 3H), 3.73 (s, 3H), 5.44 (s, 2H), 6.34 (s, 1H), 6.40 (br s, 1H), 6.64 (br s, 1H), 7.00–7.10 (m, 3H), 7.21–7.27 (m, 1H), 7.28–7.35 (m, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.50 (br s, 1H), 12.98 (br s, 1H) ppm; 13C NMR (125 MHz, DMSO-d 6): δ = 12.49, 45.87, 55.88, 93.82, 100.39, 109.09, 110.51, 115.62, 117.91, 122.85, 125.85, 126.17, 127.13, 128.19, 128.63, 135.25, 138.17, 138.46, 142.05, 153.48, 166.67 ppm; MS (ESI, MeOH): m/z = 394 ([M + Na]+), 372 ([M + H]+); HRMS (ESI, [M + 1]+): calcd. for C23H22N3O2 372.1707, found 372.1713.

Typical procedure for synthesis of compounds4

8-Chloro-2,3-dimethylpyrrolo[3,2-a]phenazine (4a, C16H12ClN3)

To 200 mg 4-arylamino-5-nitrosoindole 3 (0.66 mmol) dissolved in 10 cm3 DMF was added 0.67 g N,O-bis(trimethylsilyl)acetamide (3.3 mmol). The reaction mixture was stirred at 80 °C for 12–24 h (TLC control, n-hexane/ethyl acetate 4:1). Then the reaction mixture was poured into 100 cm3 water. The product was separated, dissolved in 50 cm3 EtOAc, and dried with Na2SO4. After evaporation of the solvent the product was purified by column chromatography (SiO2, n-hexane/ethyl acetate 4:1). Product 4a was obtained in the form of orange crystals; m.p.: >300 °C; R f = 0.22 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, DMF-d 7): δ = 2.59 (s, 3H), 3.96 (s, 3H), 7.18 (s, 1H), 7.76 (d, J = 9.4 Hz, 1H), 7.85 (dd, J = 9.0, 2.25 Hz, 1H), 8.18 (d, J = 9.4 Hz, 1H), 8.24–8.26 (m, 2H) ppm; 13C NMR (125 MHz, DMF-d 7): δ = 12.33, 27.56, 102.93, 120.37, 121.59, 122.54, 128.28, 130.63, 131.22, 133.70, 135.48, 137.46, 140.45, 140.98, 141.86, 143.19 ppm; MS (EI, 70 eV): m/z = 281 (M+, 100), 266 (8); HRMS (EI): calcd. for C16H12ClN3 281.0720, found 281.0717.

3-Benzyl-8-chloro-2-methylpyrrolo[3,2-a]phenazine (4b, C22H16ClN3)

Yellow crystals; m.p.: 223–225 °C; R f = 0.37 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 2.50 (d, J = 0.8 Hz, 3H), 5.48 (s, 2H), 6.9–7.00 (m, 2H), 7.26–7.32 (m, 3H), 7.73 (dd, J = 9.1, 2.3 Hz, 1H), 7.77 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.86, 42.14, 103.48, 118.98, 122.00, 122.26, 125.83, 127.74, 127.87, 129.02, 130.22, 130.58, 134.09, 134.58, 136.09, 136.91, 139.71, 140.39, 141.38, 142.48 ppm; MS (ESI): m/z = 358 ([M + H]+); HRMS (ESI): calcd. for C22H17ClN3 358.1111, found 358.1113.

2,8-Dimethyl-3-octylpyrrolo[3,2-a]phenazine (4c, C24H29N3)

Brown–red solid; m.p.: 133–135 °C; R f = 0.54 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 0.87 (br s, 3H), 1.15–1.45 (m, 10H), 1.82 (m, 2H), 2.54 (s, 3H), 2.64 (s, 3H), 4.18 (m, 2H), 7.26 (s, 1H), 7.63 (br d, J = 8.0 Hz, 1H), 7.75–7.87 (m, 2H), 7.95–8.07 (m, 1H), 8.21 (br d, J = 8.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.84, 14.01, 21.99, 22.56, 26.96, 29.13, 29.26, 30.97, 31.71, 43.88, 102.79, 118.16, 121.41, 122.00, 127.54, 128.38, 132.19, 133.81, 135.17, 138.76, 139.23, 140.52, 141.27, 141.77 ppm; MS (EI, 70 eV): m/z = 359 (M+, 100), 344 (7), 316 (5), 288 (8), 274 (6), 260 (47), 246 (27), 233 (99); HRMS (EI): calcd. for C24H29N3 359.2361, found 359.2357.

8-Chloro-2-methyl-3-octylpyrrolo[3,2-a]phenazine (4d, C23H26ClN3)

Yellow crystals; m.p.: 157–159 °C; R f = 0.70 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 0.86 (t, J = 7.1 Hz, 3H), 1.26–1.40 (m, 10H), 1.79–1.85 (m, 2H), 2.55 (s, 3H), 4.19 (t, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.71 (dd, J = 9.1, 2.2 Hz, 1H), 7.78 (d, J = 9.3 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 8.23–8.25 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.84, 14.01, 22.56, 26.95, 29.12, 29.25, 30.98, 31.71, 43.95, 103.11, 119.05, 121.41, 121.88, 127.79, 130.10, 130.46, 133.94, 134.06, 135.54, 139.66, 140.16, 141.20, 142.39 ppm; MS (EI, 70 eV): m/z = 379 (M+, 100), 282 (19), 281 (15), 266 (23); HRMS (EI): calcd. for C23H3526ClN3 379.1815, found 379.1818.

8-Methoxy-2-methyl-3-octylpyrrolo[3,2-a]phenazine (4e, C24H29N3O)

Yellow crystals; m.p.: 122–124 °C; R f = 0.38 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 0.86 (t, J = 7.1 Hz, 3H), 1.25–1.39 (m, 10H), 1.81 (m, 2H), 2.56 (s, 3H), 4.01 (s, 3H), 4.19 (t, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.46–7.47 (m, 2H), 7.77 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 8.16 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.86, 14.02, 22.56, 26.96, 29.13, 29.27, 30.95, 31.71, 43.83, 55.70, 102.25, 105.11, 117.89, 120.99, 122.43, 124.19, 130.07, 133.44, 135.15, 138.29, 138.89, 141.66, 142.74, 159.68 ppm; MS (EI, 70 eV): m/z = 375 (M+, 100), 276 (21), 262 (12), 233 (20), 219 (10); HRMS (EI): calcd. for C24H29N3O 375.2311, found 375.2325.

2-Methyl-3-octyl-8-(trifluoromethyl)pyrrolo[3,2-a]phenazine (4f, C24H26F3N3)

Orange crystals; m.p.: 127–129 °C; R f = 0.74 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.1 Hz, 3H), 1.26–1.40 (m, 10H), 1.84 (m, 2H), 2.57 (s, 3H), 4.22 (t, J = 7.6 Hz, 2H), 7.29 (s, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.93 (dd, J = 9.0, 2.0 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.58 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.87, 14.03, 22.57, 26.96, 29.13, 29.26, 31.02, 31.72, 44.03, 103.46, 119.40, 121.70, 121.75, 124.02 (q, J = 272 Hz), 124.49, 127.67 (q, J = 4.9 Hz), 129.61 (q, J = 32 Hz), 130.18, 134.47, 135.72, 139.79, 140.77, 142.42, 143.05 ppm; MS (EI, 70 eV): m/z = 413 (M+, 100), 315 (45), 301 (11), 300 (23), 287 (9); HRMS (EI): calcd. for C24H26F3N3 413.2079, found 413.2090.

3-Benzyl-9-methoxy-2-methylpyrrolo[3,2-a]phenazine (4g, C23H19N3O)

Yield 90 %; orange crystals; m.p.: >250 °C; R f = 0.18 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, DMSO-d 6): δ = 2.48 (s, 3H), 4.03 (s, 3H), 5.65 (s, 2H), 7.04–7.08 (m, 2H), 7.18 (s, 1H), 7.23–7.35 (m, 3H), 7.52 (dd, J = 9.3, 2.5 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H) ppm; 13C NMR (125 MHz, DMSO-d 6): δ = 13.05, 46.82, 56.37, 102.99, 105.45, 118.18, 121.75, 121.94, 123.76, 126.66, 127.77, 129.22, 130.80, 135.02, 136.36, 138.05, 138.43, 139.43, 140.03, 143.53, 160.72 ppm; MS (ESI): m/z = 354 ([M + H]+); HRMS (ESI): calcd. for C23H20N3O 354.1601, found 354.1615.

3-Benzyl-8-methoxy-2-methylpyrrolo[3,2-a]phenazine (4h, C23H19N3O)

Yield 64 %; yellow crystals; m.p.: 225–227 °C; R f = 0.22 (n-hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): δ = 2.48 (d, J = 0.7 Hz, 3H), 4.01 (s, 3H), 5.45 (s, 2H), 6.97 (br s, 1H), 7.22–7.30 (m, 3H), 7.32 (s, 1H), 7.45–7.50 (m, 2H), 7.73 (d, J = 9.3 Hz, 1H), 7.75 (d, J = 9.3 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 12.83, 47.00, 55.73, 102.75, 105.06, 117.86, 121.47, 122.73, 124.38, 125.83, 127.59, 128.93, 130.09, 133.98, 135.72, 137.17, 138.20, 138.98, 141.65, 142.82, 159.08 ppm; MS (ESI): m/z = 354 ([M + H]+); HRMS (ESI): calcd. for C23H20N3O 354.1601, found 354.1604.

Acknowledgments

This research was supported by the National Scientific Center, Grant NN 204 193 038.

References

  • 1.Laursen JB, Nielsen J. Chem Rev. 2004;104:1663. doi: 10.1021/cr020473j. [DOI] [PubMed] [Google Scholar]
  • 2.Beifuss U, Tietze M. Top Curr Chem. 2005;244:77. [Google Scholar]
  • 3.Mentel M, Ahuja EG, Mavrodi DV, Breinbauer R, Thomashow LS, Blankenfeldt W. ChemBioChem. 2009;10:2295. doi: 10.1002/cbic.200900323. [DOI] [PubMed] [Google Scholar]
  • 4.Mavrodi DV, Blankenfeldt W, Thomashow LS. Annu Rev Phytopathol. 2006;44:417. doi: 10.1146/annurev.phyto.44.013106.145710. [DOI] [PubMed] [Google Scholar]
  • 5.Wohl A, Aue W. Chem Ber. 1901;34:2442. doi: 10.1002/cber.190103402183. [DOI] [Google Scholar]
  • 6.Gaertner G, Holliman FG, Gray A. Tetrahedron. 1962;18:1105. doi: 10.1016/S0040-4020(01)99276-2. [DOI] [Google Scholar]
  • 7.Bamberger E, Ham W. Liebigs Ann Chem. 1911;382:82. doi: 10.1002/jlac.19113820105. [DOI] [Google Scholar]
  • 8.Kehrmann F, Mermod C. Helv Chim Acta. 1927;10:62. doi: 10.1002/hlca.19270100107. [DOI] [Google Scholar]
  • 9.Haddadin MJ, Issidorides CH. Heterocycles. 1993;35:1503. doi: 10.3987/REV-92-SR(T)8. [DOI] [Google Scholar]
  • 10.Emoto T, Kubosaki N, Yamagiwa Y, Kamikawa T. Tetrahedron Lett. 2000;41:355. doi: 10.1016/S0040-4039(99)02061-4. [DOI] [Google Scholar]
  • 11.Mąkosza M (2011) Synthesis 2341
  • 12.Mąkosza M, Wojciechowski K. Nucleophilic substitution of hydrogen—an efficient tool in synthesis of heterocyclic compounds. In: Attanasi O, editor. Targets in heterocyclic systems: chemistry and properties. Rome: Societa Chimica Italiana; 2011. p. 19. [Google Scholar]
  • 13.Mąkosza M. Chem Soc Rev. 2010;39:2855. doi: 10.1039/b822559c. [DOI] [PubMed] [Google Scholar]
  • 14.Mąkosza M, Wojciechowski K. Chem Rev. 2004;104:2631. doi: 10.1021/cr020086+. [DOI] [PubMed] [Google Scholar]
  • 15.Mąkosza M, Wojciechowski K. Heterocycles. 2001;54:445. doi: 10.3987/REV-00-SR(I)2. [DOI] [Google Scholar]
  • 16.Wróbel Z, Kwast A (2007) Synlett 1525
  • 17.Kwast A, Stachowska K, Trawczyński A, Wróbel Z. Tetrahedron Lett. 2011;52:6484. doi: 10.1016/j.tetlet.2011.09.113. [DOI] [Google Scholar]
  • 18.Wróbel Z, Stachowska K, Grudzień K, Kwast A (2011) Synlett 1439
  • 19.Wróbel Z, Stachowska K, Kwast A, Gościk A, Królikiewicz M, Pawłowski R, Turska I. Helv Chim Acta. 2013;96:956. doi: 10.1002/hlca.201200304. [DOI] [Google Scholar]
  • 20.Cimmino A, Evidente A, Mathieu V, Andolfi A, Lefranc F, Kornienko A, Kiss R. Nat Prod Rep. 2012;29:487. doi: 10.1039/c2np00079b. [DOI] [PubMed] [Google Scholar]
  • 21.Vicker N, Burgess L, Chuckowree IS, Dodd R, Folkes AJ, Hardick DJ, Hancox TC, Miller W, Milton J, Sohal S, Wang S, Wren SP, Charlton PA, Dangerfield W, Liddle C, Mistry P, Stewart AJ, Denny WA. J Med Chem. 2002;45:721. doi: 10.1021/jm010329a. [DOI] [PubMed] [Google Scholar]
  • 22.Hussain H, Specht S, Sarite SR, Saeftel M, Hoerauf A, Schulz B, Krohn K. J Med Chem. 2011;54:4913. doi: 10.1021/jm200302d. [DOI] [PubMed] [Google Scholar]
  • 23.Saleh O, Flinspach K, Westrich L, Kulik A, Gust B, Fiedler H-P, Heide L. Beilstein J Org Chem. 2012;8:501. doi: 10.3762/bjoc.8.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Wrona MZ, Dryhurst G. J Org Chem. 1987;52:2817. doi: 10.1021/jo00389a032. [DOI] [Google Scholar]
  • 25.Meesala R, Nagarajan R (2010) Synlett 2808
  • 26.Gamage SA, Spicer JA, Rewcastle GW, Milton J, Sohal S, Dangerfield W, Mistry P, Vicker N, Charlton PA, Denny WA. J Med Chem. 2002;45:740. doi: 10.1021/jm010330+. [DOI] [PubMed] [Google Scholar]
  • 27.Lipilin DL, Churakov AM, Ioffe SL, Strelenko YA, Tartakovsky VA (1999) Eur J Org Chem 29
  • 28.Wirth S, Wallek AU, Zernickel A, Feil F, Sztiller-Sikorska M, Lesiak-Mieczkowska K, Bräuchle C, Lorenz I-P, Czyz M. J Inorg Biochem. 2010;104:774. doi: 10.1016/j.jinorgbio.2010.03.014. [DOI] [PubMed] [Google Scholar]

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