Rh₂(II)-Catalyzed Synthesis of Carbazoles from Biaryl Azides

Abstract

An array of carbazoles (23 examples) can be synthesized from substituted biaryl azides at 60 °C using substoichiometric quantities of Rh₂(O₂CC₃F₇)₄ or Rh₂(O₂CC₇H₁₅)₄.

A long-standing goal of organic synthesis is the development of new methods that access nitrogen heterocycles,¹ such as carbazoles, because of their prevalence in important medicinal compounds and materials.^1,2 Historically, methods that access these N-heterocycles have relied on transformations of pre-existing functional groups, such as halides or carbonyls.³ Such prerequisites can lead to an increased number of synthetic steps necessary to generate the starting materials. Recent efforts to circumvent this functional group manipulation have produced carbazoles through transition metal-mediated oxidative C–H bond functionalization.^4–8

Dirhodium(II) complexes are well known atom-transfer catalysts.⁹ They are particularly effective in aliphatic C–N bond formation,¹⁰ enabling access to nitrogen heterocycles efficiently and stereoselectively by the decomposition of sulfonyliminoiodinanes^11,12 and N-tosyloxycarbamates.^10c,f Employing azides as substrates would complement these existing technologies as well as related deoxygenation methods,^13,14 as azides are easily obtained,¹⁵ intrinsically prone to decomposition,^16,17 and produce N₂ as the only by-product. Despite the proclivity of rhodium(II) dimers to mediate atom transfer reactions,¹⁰ their use in the decomposition of azides is uncommon.^18,19

We reported recently that rhodium(II) carboxylates can catalyze the intramolecular formation of C–N bonds from vinyl- or aryl azides to provide indoles and pyrroles.²⁰ We envisioned that our method might be extended to biaryl azides for the synthesis of carbazoles. The requisite biaryl azides (3) were synthesized from 2-bromoaniline 1 by a Suzuki crosscoupling reaction²¹ followed by a diazotization/azidation sequence^15,22 (Scheme 1). We found that substoichiometric quantities of rhodium(II) perfluorobutyrate or rhodium(II) octanoate efficiently generated the desired carbazole 5 from 2-azidobiphenyl (method A or B).²³ As before, crushed 4 Å molecular sieves (100 wt %) were required to achieve reproducible yields.

Scheme 1.

Synthesis of Biaryl Azides for Carbazole Study.

To examine the scope and limitations of the reaction, we tested our method on substrates, which varied the electronic-and steric environments on each ring of the azidobiaryl. As shown in Table 1, electron-donating groups and electron-withdrawing groups were well tolerated for R¹ (entries 1 – 6). The reaction could be performed on a gram-scale: 3.17 mmol of bromo-substituted biaryl azide 6f was converted smoothly to the corresponding carbazole in 85% yield. In contrast to the nearly uniform reactivity of substrates 6a – 6f, we found that carbazole formation depended more strongly on the electronicand steric identity of the R²-, R³-, or R⁴-substituent. Electron-deficient R²-groups (e.g. F and Cl, entries 8 and 9) were high yielding, whereas reduced conversion and yield were observed for R² = Me (entry 7). Both electron-donating and electron-withdrawing R⁴-groups were allowed (entries 10 – 18). Low reaction conversion, however, was observed for biaryl azide 6m bearing an R⁴-methyl (entry 13) for reasons not apparent at this time.²⁴ No reaction was observed for R⁴ = CN (entry 19), presumably due to nitrile coordination to the rhodium(II) catalyst.²⁵ Diminished reactivity was also observed for dimethoxy-substituted biaryl azide 6t (entry 20): modest amounts of carbazole 7t were obtained only when rhodium octanoate was employed. In general, the reaction was more efficient when a new C–N bond to an electron-deficient arene was formed (compare entry 18 to entry 20).

Table 1.

Scope and Limitations of Rhodium-Catalyzed Carbazole Formation from Biaryl Azides.

entry	biaryl azide	yield (%)a	entry	biaryl azide	yield (%)a
1		71	11		72
2		86	12		87
3		98	13		44c
4		86	14		71
5		83	15		88d
6		85b	16		91
7		60c	17		91
8		93	18		91d
9		92	19		n.r.
10		82	20		n.r. (65)e

^aYield after flash chromatography over SiO₂.

^bReaction performed on gram scale.

^cRemainder of material was aryl azide 6.

^d2 mol % Rh₂(O₂CC₃F₇)₄.

^e5 mol % Rh₂(O₂CC₇H₁₅)₄.

The lack of reactivity observed for dimethoxy-substituted 6t motivated us to study additional substrates substituted at the 3’-position of the biaryl azide (Table 2). We discovered that both the regioselectivity and reaction conversion depended upon the electronic identity of the R⁵-substituent. While reduced selectivity and conversion were observed with electron-rich aryl groups (entries 1 and 2), substrates bearing electron-withdrawing groups led to increased yields and substantially improved regioselectivities (entries 3 – 5). The positive effect of an electron-withdrawing R⁵-substituent, however, was attenuated when an R⁴-methyl group was added: exposure of biaryl azide 8f to reaction conditions produced carbazoles 9f and 10f in diminished yield and with reduced regioselectivity (compare entry 6 with entry 3).

Table 2.

Regioselectivity of Rhodium-Catalyzed Carbazole Formation from Biaryl Azides.

entry	biaryl azide	regioselectivity (9:10)a	yield (%)b
1		52:48	33a,c
2		66:34	25a,c
3		89:11	65a,c
4		>95:5	82
5		>95:5	84
6		39:61	59a,c

^aAs determined using ¹H NMR spectroscopy.

^bYield after flash chromatography over SiO₂.

^cRemainder of reaction mixture was aryl azide 8.

The conversion and selectivity of carbazole formation was also affected by the identity of the carboxylate ligand (Scheme 2). Switching from electron-poor Rh₂(O₂CC₃F₇)₄ to electron-rich Rh₂(O₂CC₇H₁₅)₄ reduced the formation of 6h from 93% to just 34% conversion. This decreased reactivity observed for rhodium octanoate was not general: improved conversion and regioselectivity was seen in the decomposition of the electron-rich biaryl azide 8a. Exposure of 8a to Rh₂(O₂CC₃F₇)₄ resulted in only a 33% conversion to afford a 52:48 mixture of carbazoles 9a and 10a. Employing Rh₂(O₂CC₇H₁₅)₄, however, afforded a 94:6 mixture of 9a and 10a in 71% yield. In contrast, metal-free thermolysis of aryl azide 8a favored the formation of the opposite carbazole, 10a (31:69). We interpret the ability of the rhodium carboxylate catalyst to reverse the thermal regioselectivity of carbazole formation as evidence against the intermediacy of free nitrene.^17,21 The enhanced regioselectivity exhibited by Rh₂(O₂CC₇H₁₅)₄ could be explained by the increased steric interactions between the larger octanoate ligand and the substrate to favor functionalization of the less sterically congested C–H bond.

Scheme 2.

Influence of the Carboxylate Ligand on Reaction Conversion and Selectivity.

In conclusion, we have shown that substituted carbazoles can be accessed from readily available biaryl azides using a Rh₂(II)-carboxylate catalyst. Quantitative mechanistic experiments that probe the relationship between the carboxylate ligand and reaction rate are underway. Future experiments are also aimed at determining the origin of regioselectivity observed for aryl azides 8. The results of these studies will guide further method development.

EXPERIMENTAL SECTION

4-Methoxy-2-phenylaniline

In a dry 100 mL round bottom flask, phenylboronic acid (0.400 g, 3.29 mmol, 1.3 equiv), K₂CO₃ (1.65 g, 12.0 mmol, 4.0 equiv), and Pd(PPh₃)₄ (0.345 g, 0.299 mmol, 0.1 equiv) were dissolved in 20 mL of toluene, 10 mL of H₂O, and 5 mL of EtOH. 2-Bromo-4-methoxyaniline (0.604 g, 2.99 mmol, 1.0 equiv) was added, and the resulting mixture was heated to 95 °C for 16 hours. After cooling, the biphasic solution was diluted with 100 mL of saturated aqueous NH₄Cl and 100 mL of CH₂Cl₂ and separated. The aqueous phase was extracted with an additional 2 × 100 mL of CH₂Cl₂, and the combined organic phases were washed 1 × 100 mL of water and 1 × 100 mL of saturated aqueous NaHCO₃. The organic phase was dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to afford a brown oil. Purification by MPLC (0:100 – 30:70 EtOAc:hexanes) afforded 4-methoxy-2-phenylaniline as a brown oil (0.490 g, 82 %): R_f = 0.27 (20:80 EtOAc:hexanes). ¹H NMR (CDCl₃, 500 MHz): δ 7.49-7.43 (m, 4H), 7.38-7.34 (m, 1H), 6.80-6.72 (m, 3H), 3.78 (s, 3H), 3.51 (br s, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 152.8 (C), 139.5 (C), 137.2 (C), 129.1 (CH), 128.8 (2CH), 127.3 (CH), 116.9 (CH), 115.7 (CH), 114.5 (CH), 55.8 (CH₃); IR (thin film): 3356, 2830, 1602, 1505, 1416, 1273, 1215, 1175, 1041 cm⁻¹; HRMS (EI) m / z calcd for C₁₅H₁₃ON (M⁺): 199.0997, found: 199.0998.

4-Azido-3-phenylanisole (6a)

In a 20 mL scintillation vial, 4-methoxy-2-phenylaniline (0.353 g, 1.77 mmol, 1.0 equiv) was dissolved in 10 mL of HOAc and 5 mL of H₂O and chilled in an ice bath. NaNO₂ (0.171 g, 2.48 mmol, 1.4 equiv) was added slowly, and the resulting mixture was stirred at 0 °C for one hour. NaN₃ (0.172 g, 2.65 mmol, 1.5 equiv) was then added slowly, and the resulting mixture was warmed to ambient temperature, and stirred for 30 minutes. The solution was diluted with 20 mL of water and 20 mL of CH₂Cl₂ and basified by the slow addition of K₂CO₃ until bubbling ceased. The phases were separated and the aqueous phase was extracted with an additional 2 × 20 mL of CH₂Cl₂. The combined organic phases were washed 1 × 20 mL of water and 1 × 20 mL of brine. The resulting organic phase and dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to afford an oil. Purification by MPLC (0:100 – 30:70 EtOAc:hexanes) afforded azide 6a as a yellow oil (0.313 g, 70%): R_f = 0.63 (20:80 EtOAc:hexanes). ¹H NMR (CDCl₃, 500 MHz): δ 7.55-7.48 (m, 4H), 7.46-7.42 (m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.00 (dd, J₁ = 8.5 Hz, J₂ = 3.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 156.9 (C), 138.2 (C), 134.9 (C), 129.7 (C), 129.5 (CH), 128.3 (CH), 127.8 (CH), 120.0 (CH), 116.6 (CH), 114.4 (CH), 55.7 (CH₃); IR (thin film): 2119, 1483 cm⁻¹; HRMS (EI) m / z calcd for C₁₃H₁₁ON₃ (M⁺): 225.0902, found: 225.0900.

4-Methoxycarbazole (7a)

To a mixture of 0.049 g of 4-azido-3-phenylanisole 6a (0.217 mmol), 0.013 g of Rh₂(O₂CC₃F₄)₄ (0.012 mmol, 5 mol %), and 0.049 g of crushed 4 Å molecular sieves was added 0.47 mL of toluene (0.5 M). The resulting mixture was stirred at 60 °C for 16 h. The heterogenous mixture was filtered through SiO₂, and the filtrate was concentrated in vacuo. Purification by MPLC (0:100 – 30:70 EtOAc:hexanes) afforded 4-methoxycarbazole 7a as a white powder (0.031 g, 71%): mp 147–148 °C, R_f = 0.32 (20:80 EtOAc:hexanes). ¹H NMR (CDCl₃, 500 MHz): δ 8.05 (d, J = 7.5 Hz, 1H), 7.87 (br s, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.30 (d, J = 9.0 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.08 (dd, J₁ = 9.0 Hz, J₂ = 2.5 Hz, 1H), 3.95 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 153.9 (C), 140.3 (C), 134.4 (C), 125.8 (CH), 123.8 (C), 123.4 (C), 120.3 (CH), 119.1 (CH), 115.1 (CH), 111.4 (CH), 110.8 (CH), 103.2 (CH), 56.13 (CH3); IR (thin film): 3403, 2361, 1459 cm⁻¹; HRMS (EI) m / z calcd for C₁₃H₁₁ON (M⁺): 197.0841, found: 197.0840.

Supplementary Material

1_si_001. Supporting Information Available.

Complete experimental procedures, spectroscopic and analytical data for the products (PDF) is available free of charge via the Internet at http://pubs.acs.org.