Synthesis of benzo[a]carbazoles and indolo[2,3-a]carbazoles via photoinduced carbene-mediated C–H insertion reaction

Abstract

A new synthesis of 5-hydroxy-benzo[a]carbazoles has been achieved by employing the photoinduced intramolecular C–H insertion of 2-aryl-3-(α-diazocarbonyl)indoles as the key step. This method is applicable to the synthesis of natural products 6-cyano-5-methoxy-indolo[2,3-a]carbazoles 8 and 11 and their derivatives.

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Carbazole is an important heterocyclic moiety that commonly appears in naturally occurring biological alkaloids and synthetic materials.¹ As subunits of carbazoles, benzo-annulated (Fig. 1) carbazole ring systems not only exhibit attractive pharmacological properties,² but also have found extensive applications in materials science.³ Unsurprisingly, many efforts have been made to develop methodologies, ranging from ionic and radical-mediated annulation over pericyclic reactions to transition metal-catalyzed C–H functionalization reactions, for the synthesis of benzocarbazole derivatives.^4,5 Despite these numerous studies, however, it is still highly desirable to explore new synthetic methods to fit with the diverse structural features of benzocarbazoles.

Fig. 1 Benzo-annulated carbazoles.

α-Diazocarbonyl compounds are versatile synthetic precursors with a long history of useful applications in organic chemistry.⁶ A prominent chemical feature of diazocarbonyl compounds is that they can be converted to carbenes through thermally or photochemically induced nitrogen expulsion, or to metal–carbene complexes (carbenoids) by reacting with transitional metals such as rhodium or copper. Carbenes and carbenoids are reactive intermediates, and their subsequent addition to double bond or C–H insertion provides powerful means for C–C bond formation.⁷ In practical synthesis concerning the utility of α-diazocarbonyl compounds in this aspect, generally rhodium and copper are employed as catalysts because the reactivity of carbenoids is easier to control and the reactions can be effected under mild conditions in a stereoselective pattern.⁸ Nevertheless, the photochemical generation of carbenes from α-diazocarbonyl compounds still remains a green and economical alternative to the metal-involved protocols.⁹ In this context, herein we wish to report a new synthesis of 6-cyano(and 6-ethoxycarbonyl)-5-hydroxy-benzo[a]carbazoles from 2-aryl-3(α-diazocarbonyl)indoles via photoinduced carbene-mediated C–H insertion reaction.

Our synthesis of benzo[a]carbazoles is outlined in Scheme 1. We envisioned that irradiation of compounds 1 and 2 would generate the corresponding carbene intermediates, which should undergo intramolecular C–H insertion to afford 5-hydroxy-benzo[a]carbazoles 3 and 4. Compounds 1 and 2 could be obtained from 5 according to the reported procedures.^10,11

Scheme 1

To achieve this goal, ethyl α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanoate (1a) was firstly prepared, and subjected to different conditions as shown in Table 1. It was found that under irradiation at λ > 300 nm (through Pyrex) with a medium-pressure mercury lamp (500 W), 1a reacted quickly, and ethyl 6-hydroxy-11-methyl-11H-benzo[a]carbazole-5-carboxylate (3a) was obtained as the sole isolated product in high yield (entries 1–2). Acetone and dichloromethane were both suitable solvents. By comparison, the yield of 3a was much lower when the reaction was performed under thermal conditions in refluxing THF or benzene (entries 3–4). Under the latter circumstances, the conversion and yield could be increased by the addition of Cu(acac)₂ (entries 5–6), but they were still inferior to those under photochemical conditions.

Table 1 Reaction of 1a under various conditions^a

Entry	Solvents	Reaction conditions	Reaction time (h)	Convn^b (%)	Yield^c (%)
a 30 mg of 1a was dissolved in different anhydrous solvents (20 mL) and proceeded under argon atmosphere.b Conversion was calculated based on 1a.c Isolated yield based on the consumed 1a.d Cu(acac)2 was used.
1	CH2Cl2	hv, rt	2.5	98	88
2	Acetone	hv, rt	2	99	92
3	THF	Reflux	24	40	78
4	Benzene	Reflux	24	55	80
5	THF^d	Reflux	18	80	83
6	Benzene^d	Reflux	18	80	83

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This photochemical protocol was then applied to a variety of substituted ethyl α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanoates (1b–f), and the results are summarized in Table 2. In general the reaction proceeded very well, and all the substrates were converted smoothly to the corresponding 6-ethoxycarbonyl-5-hydroxy-benzo[a]carbazoles 3 in good to excellent yields. The substituents at the indolyl ring (R¹ = H, CH₃, Cl) have little influence on the reaction consequence (Table 2, entries 1–3), while the electron-withdrawing group (R² = Br) at the 2-phenyl ring slightly reduced the yield (Table 2, entry 4). The products were identified by ¹HNMR, ¹³CNMR, HRMS and IR, and the structure of 3d was further confirmed by X-ray crystal analysis (Fig. 2).¹²

Table 2 Photoreaction of ethyl α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanoates 1a–1f^a

Entry	Substrate	R^1	R^2	Time (h)	Convn (%)	Yield^a (%)
a Isolated yield.
1	1a	H	H	2	99	3a 92
2	1b	Cl	H	2.1	98	3b 90
3	1c	CH3	H	1.9	99	3c 93
4	1d	H	Br	2.5	95	3d 85
5	1e	H	CH3	1.7	99	3e 94
6	1f	H	CH3O	1.5	99	3f 95

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Fig. 2 Structure of 3d.

When compounds α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanenitriles (2a–2f) were subjected to irradiation in acetone, the desired 6-cyano-5-hydroxy-benzo[a]carbazoles 4 were obtained as the major products. However, besides 4, a small amount of compounds 7 also formed after reaction. The formation of 7 can be accounted for by the carbene addition to phenyl ring followed by tautomerization (Scheme 2). Probably the reduced steric hindrance of cyano group in 2 as compared with that of ethoxycarbonyl group in 1 is beneficial to the carbene addition to the phenyl ring. Substituents at the indolyl ring (R¹ = H, CH₃, Cl; R² = H) have little effect on the reactivity, with the proportion of 4 to 7 close to 5 : 1 for 2a–2c (Table 3, entries 1–3). On the other hand, the ratio of these two products was largely influenced by the substituents at 2-phenyl ring (R¹ = H; R² = H, CH₃, CH₃O and Br) (Table 3, entries 1, 4–6). The ratio of 4 to 7 decreased following the order of R² being Br (6 : 1), H (5 : 1), CH₃ (3.6 : 1) and CH₃O (2 : 1). Apparently, the electron-donating groups facilitate the carbene addition more than C–H insertion.

Scheme 2

Table 3 Photoreaction of 2a–2f

Entry	Substrate	R^1	R^2	Time (h)	Convn (%)	Yield^a (%)
a Isolated yield.
1	2a	H	H	2.5	99	4a (73), 7a (15)
2	2b	Cl	H	2.6	98	4b (70), 7b (11)
3	2c	CH3	H	2.4	99	4c (74), 7c (14)
4	2d	H	Br	3	95	4d (64), 7d (10)
5	2e	H	CH3	2.2	99	4e (72), 7e (20)
6	2f	H	CH3O	2	99	4f (60), 7f (30)

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Following the successful preparation of 6-hydroxy-benzo[a]carbazoles 3 and 4, our attention was then turned to the synthesis of derivatives of natural products 6-cyano-5-methoxy-12-methylindolo[2,3-a]carbazole 8, 6-cyano-5-methoxy-indolo[2,3-a]carbazole 11 (Scheme 3). Compound 8 and 11 were isolated from the blue-green alga Nostoc sphaericum (strain EX-5-1),¹³ and they were found to exhibit cytotoxic and antiviral properties. Several of their derivatives, such as 9, 10, 12 and 13, also possess interesting antibacterial capacities.¹⁴ The syntheses of these compounds have been reported by Somei et al.,¹⁵ Kozikowski et al.,¹⁴ and Snieckus et al.¹⁶ The syntheses by Somei and Kozikowski feature the use of indigo as starting material, and the Snieckus strategy is grounded on a directed ortho and remote metalation-cross-coupling between the indolyl-2-boronic acid and ortho-substituted bromobenzene. In difference from these previous syntheses, our synthetic route toward 8–13 started from o-toluidine (A) as shown in Scheme 3. A was transformed to 2-(1H-indol-2-yl)-1H-indole (compound C) in two steps according to the reported methods.¹⁷ C was then converted to compound E through D following the aforementioned protocols. Irradiation of E in acetone gave rise to the desired product 10 in good yield.

Scheme 3

On the other hand, when C was treated with 1.1 equiv. of CH₃I and KOH in acetone, compounds F and H were obtained in yields of 30% and 35% respectively. From F and H, compounds 9 and 12 can be obtained through the established synthetic route. It should be noted that the reaction of F and cyanoacetic acid is highly regio-selective, with the cyanoacetyl group being attached mostly to the indole ring containing the N-methyl group (compound J, precursor of G). The structure of J was confirmed by X-ray crystal analysis (Fig. 3).¹² 9, 10 and 12 can be easily converted to 8, 11 and 13.^14,15 Therefore, the present synthetic effort represents formal syntheses of compound 8, 11 and 13.

Fig. 3 Structure of J.

In conclusion, we have developed a simple and efficient photochemical method for the synthesis of 6-cyano-5-hydroxy-benzo[a]carbazoles and 6-ethoxycarbonyl-5-hydroxy-benzo[a]carbazoles. This protocol employs the easily accessible α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanoates and α-diazo-1-methyl-β-oxo-2-phenyl-1H-indole-3-propanenitriles as the substrates, and tolerates various functional groups. The synthetic usefulness was further demonstrated by its successful application to the syntheses of biologically active compounds 8–13. With structurally simple o-toluidine as the starting material, the present synthetic strategy can provide 6-cyano-5-methoxy-12-methylindolo[2,3-a]carbazole 8, 6-cyano-5-methoxy-indolo[2,3-a]carbazole 11 and their derivatives in 6 or 7 steps.

Acknowledgements

The authors thank the National Natural Science Foundation of China (no. 21372108) and the national fund for talent training in basic science (J1103307) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental procedures, characterization data, ¹HNMR and ¹³CNMR spectra of compounds 3, 4, 7, 9, 10 and 12. CCDC 946429, 963620. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra00442f

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