Synthesis of benzofused 1,4-azaborinols via [4 + 2] annulation strategy and its application in indole synthesis

Abstract

We disclose herein, the first general synthesis of benzofused 1,4-azaborinols via [4 + 2] annulation strategy. These compounds have been synthesised from 2-amino phenylboronic acids/boronates and alkynes in excellent yields. Additionally, we demonstrate their synthetic application by reporting the first transformation of benzofused 1,4-azaborinols into functionalized indoles.

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Introduction

Boron containing compounds have found medical application as preventive, diagnostic and therapeutic tools¹ and in material science applications.^2,3 The inclusion of boron in medicinally active structures is emerging as an attractive approach to expand the structural diversity of organic compounds. Boron has a unique geometry with empty p-orbitals that can form stable covalent bonds.⁴ Benzoxaboroles (1), a stable cyclic form of boron heterocycle is in clinical development as antifungal, anti-bacterial, and anti-inflammatory agent.⁵ Diazaborines (2-3) are part of a first-in-class of boron-containing compound family and have demonstrated activity against Gram-negative bacteria,⁶ Mycobacterium tuberculosis⁷ and have shown promise as steroid mimics (Fig. 1).⁸

Fig. 1 Examples of cyclic boron-containing compounds.

Recently, Xu and co-workers reported the synthesis of monobenzofused 1,4-azaborines using ring-closing metathesis (Fig. 2).⁹ Few literature methods have been reported to synthesise benzofused polycylic 1,4-azaborines from halogenated diarylamines.¹⁰ Braunschweig and co-workers have reported the synthesis of non-benzannulated 1,4-azaborine by using tandem [2 + 2]/[2 + 4] cycloaddition reactions.¹¹ Our research program was initiated to explore the druggability of boron compounds as covalent inhibitors of an essential cell wall biosynthesis pathway in Mycobacterium tuberculosis. In the course of our work, we uncovered a method to synthesise a novel heterocycle, as well as develop a new synthetic route to make functionalized indoles. We describe the first general synthesis of substituted benzofused 1,4-azaborinols from 2-amino phenylboronic acids/boronates and alkynes via [4 + 2] annulations strategy in excellent yields. In addition, the conversion of benzofused 1,4-azaborinols to corresponding substituted indoles has been demonstrated using palladium catalyzed reaction in good yield.

Fig. 2 Reported and present work.

Results and discussion

We envisioned that a benzofused 1,4-azaborinol could be synthesised by the condensation of 2-aminophenylboronic acid with alkynes. In order to facilitate the reaction, we chose dimethyl acetylene dicarboxylate (DMAD), a highly electrophilic and widely used dienophile in cycloaddition reactions.^12,13

We tested this hypothesis by carrying out condensation of 1a with 2a in dichloromethane at RT for 16 h (Scheme 1). Gratifyingly the reaction afforded the expected product. However the yield was poor (20%) and we recovered unreacted starting material (60%). The product 3aa was confirmed by NMR spectroscopy¹⁴ and single-crystal X-ray analysis (Fig. 3). Encouraged by the feasibility of this transformation we started optimization of reaction conditions to improve the yield. Reaction conditions were optimised systematically at various temperatures in presence/absence of base (Table 1). A dramatic change in the yield was observed when the reaction mixture was heated at 80 °C for 30 min (entry 5, 88%). However, no significant improvement in the yield was observed when the reaction mixture was heated for a longer time (entry 6). This indicated good thermal stability of the product. When the reaction was carried out in the presence of base (entries 7 & 8) slightly diminished yields were observed. High boiling solvent such as dichloroethane did allow a reduced time under microwave conditions (entries 10 & 11).

Scheme 1 Synthesis of benzofused 1,4-azaborinol.

Fig. 3 X-ray structure of compound 3aa.

Table 1 Optimization of reaction conditions^a

Entry	Solvents	T (°C)	Base	Time	Yield^b (%)
a Reaction conditions: reactions were performed in a sealed vial 1a (0.22 mmol), 2a (0.23 mmol), base (0.44 mmol) in solvent (1.5 mL).b Yield of isolated product 3aa.c Under microwaves.
1	DCM	RT	—	16 h	20
2	DCM	RT	—	2 h	22
3	DCM	40	—	2 h	45
4	DCM	60	—	2 h	62
5	DCM	80	—	30 min	88
6	DCM	80	—	2 h	84
7	DCM	80	Hunigs base	30 min	72
8	DCM	80	Na2CO3	30 min	78
9	DCE	80	—	30 min	85
10^c	DCE	80	—	10 min	72
11^c	DCE	80	—	30 min	70
12	DME	80	—	30 min	68
13	THF	80	—	30 min	35

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After the optimization of reaction conditions, we investigated the reaction scope. A variety of 2-amino phenylboronic acids/boronates (1a–1i) were subjected to reaction with dialkyl acetylenedicarboxylate (2a and 2b) to give the desired benzofused 1,4-azaborinols (3aa–3ia) in moderate to excellent yields (65–88%, Table 2). Interestingly, reaction using boronate ester under similar conditions (Scheme 2) gave the uncyclized alkene 3ba-i (52%) along with desired product 3ba (35%).

Table 2 Synthesis of benzofused 1,4-azaborinols^a,b

Entry	Reactant	R1	Product	Yield^c (%)
a Reaction conditions: 1 (0.36 mmol), 2 (0.38 mmol), in DCM (2.5 mL), 80 °C, 30 min–1 h.b 1b (0.32 mmol), 2a (0.34 mmol), in DCE (3 mL), 110 °C, 30 min, MW.c Isolated product.d Isolated product under microwaves.
1	1a	2a		88
2	1a	2b		84
3	1b	2a		75^d
4		2a		65
5		2a		78^d
6		2a		68
7		2a		68
8		2a		77
9		2a		80
10		2a		66

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Scheme 2 Synthesis of substituted benzofused 1,4-azaborinol.

This observation indicated that a temperature of 80 °C was not sufficient to hydrolyse the boronate ester to boronic acid to enable reaction completion. It also gave us insight into a possible mechanism (Scheme 3). Therefore, the reaction mixture was subjected to microwave irradiation at 110 °C for 30 min in dichloroethane to afford exclusively the required product 3ba in good yield (75%). Under these microwave conditions, condensation of 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 1d with DMAD 2a afforded the required product 3da in 78% yield. In general, boronic acids/boronates bearing electron donating groups such as methyl and methoxy (3ba, 3da & 3ha) were smoothly transformed into desired products in very good yields. Electron-withdrawing groups such as cyano, trifluoromethyl, ester groups on phenyl boronic acids (3ca, 3ea, 3fa & 3ia) were transformed into desired products in moderate yields (65–68%). As anticipated, these electron-withdrawing groups decreased the reactivity of amine which in turn affected the yield.

Scheme 3 Proposed mechanism for cyclization.

We attempted to understand the reaction mechanistically (Scheme 3). Nucleophilic addition of 2-aminophenylboronic acid to the alkyne (DMAD) likely generates zwitterionic/dipole intermediate [I], followed by further nucleophilic attack of alkene anion to the boron atom to generate the tetrahedral boronate complex [II]. Final step involves the elimination of water to give the corresponding benzofused 1,4-azaborinol derivative.

Next, we turned our attention to discovering useful applications for benzofused 1,4-azaborinol. Recognizing the susceptibility of a boron flanked by two sp² carbon atoms to insertion reactions, we sought to explore the utility of these benzofused 1,4-azaborinol in coupling chemistry. We wanted to treat the substrate with palladium catalyst with the expectation of an intermolecular coupling reaction. An initial attempt was made by way of palladium catalyzed carbonylation (Scheme 4) following a reported procedure.¹⁵

Scheme 4 Synthesis of indoles.

We expected a substituted quinolone as a product, but were surprised to see that the reaction yielded exclusively the indole derivative (4aa) in 18% yield and recovered 75% starting material. To further exploit this new reaction to synthesise indoles, we screened different catalysts under a few conditions (Table 3). When the reaction was performed using Pd(OAc)₂ (10 mol%) and Xantphos/dppf at 80 °C in dichloroethane for 12 h, formation of substituted indole (4aa) was observed in 15% and 8% yield (entries 1 & 2). This result indicated perhaps that catalytic amount of Pd(OAc)₂ was not sufficient for this intramolecular cyclisation. When the quantity of Pd(OAc)₂ was increased gradually from catalytic to equimolar, the yield of indole was improved to 78% (entry 12). No significant improvement in the yield was observed when the reaction was carried out using other solvents (entries 14–16). Other palladium catalysts such as Pd(PPh₃)₄, Pd₂(dba)₃, Pd(dppf)Cl₂ did not afford the desired product.

Table 3 Optimization of reaction conditions^a

Entry	Catalyst	Ligand	Solvent	Time	Yield^b (%)
a Reaction conditions: reaction were performed in a sealed vial, 3a (0.13 mmol), Pd-catalyst, ligand (10 mol%), in solvent (1.25 mL), 80 °C.b Yield of isolated product.
1	0.1 eq. Pd(OAc)2	Xantphos	DCE	12 h	15
2	0.1 eq. Pd(OAc)2	dppf	DCE	12 h	8
3	0.1 eq. Pd(OAc)2	—	DCE	1 h	10
4	0.1 eq. Pd2(dba)3	Xantphos	DCE	12 h	—
5	0.1 eq. Pd(PPh3)4	—	DCE	12 h	—
6	0.1 eq. Pd(dppf)Cl2	—	DCE	12 h	—
7	0.1 eq. Pd(OAc)2	Air	DMSO/MeOH	12 h	14
8	0.1 eq. Pd(OAc)2	—	DCE	30 min	12
9	0.2 eq. Pd(OAc)2	—	DCE	30 min	21
10	0.5 eq. Pd(OAc)2	—	DCE	30 min	35
11	0.8 eq. Pd(OAc)2	—	DCE	30 min	62
12	1 eq. Pd(OAc)2	—	DCE	30 min	78
13	1 eq. Pd(OAc)2	—	DCE	2 h	75
14	1 eq. Pd(OAc)2	—	Dioxane	12 h	65
15	1 eq. Pd(OAc)2	—	DME	12 h	70
16	1 eq. Pd(OAc)2	—	DMF	12 h	55

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Mechanistically, we envision that the first step involves the electrophilic palladation of 3aa to get either [III] or [IV] followed by transmetallation to afford V. The intermediate [V] then undergoes reductive elimination to give the indole (Scheme 5).

Scheme 5 Proposed mechanism for indole transformation.

By using the optimized reaction conditions, all the synthesized benzofused 1,4-azaborinols (3aa–3ha) were transformed into the corresponding substituted indoles (4aa–4ha) in good yields (70–80%). It was observed that electron-withdrawing and electron-donating substitution had no impact on the conversion (Table 4). The physical and analytical data of all the reported indoles was found to be in accordance with the literature.¹⁶

Table 4 Synthesis of substituted indoles^a

Entry	Reactant	Product	Yield^b (%)
a Reaction conditions: 3 (0.19 mmol), Pd(OAc)2 (0.19 mmol), in DCE (2 mL), 80 °C, 30 min.b Isolated product.
1	3aa		78
2	3ab		75
3	3ba		76
4	3ca		70
5	3da		80
6	3ea		74
7	3fa		72
8	3ga		76
9	3ha		78

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Expecting that benzofused 1,4-azaborinol could be intermediate for the synthesis of indole, we explored a one-pot palladium catalyzed cyclization reaction. We were gratified to find that reaction worked as expected with an overall yield of 30% (Scheme 6).

Scheme 6 One pot synthesis of indoles.

Conclusions

In summary, we have developed the first general synthetic protocol for the synthesis of benzofused 1,4-azaborinols using [4 + 2] annulations strategy from commercially available 2-amino phenylboronic acids/boronates and alkynes in excellent yields. This class of benzofused 1,4-azaborinol compounds may generate new opportunities in the field of drug discovery. Furthermore, we have demonstrated the smooth conversion of benzofused 1,4-azaborinols to its corresponding indole and thereby developed a new synthesis for indoles.

Acknowledgements

We thank Dr Shridhar Narayanan for his support and encouragement of this work. We thank the management of AstraZeneca India Pvt. Ltd for providing the facilities to carry out this research work. We also thank SAS, Chemistry Division, VIT University, Vellore. We acknowledge Dr Shankar Markad for his valuable scientific discussions and for proof reading this article. We deeply acknowledge Prof. Dr G. Sekar (IITM, Chennai) for crystal structure data and analytical support provided by Suresh Rudrapatna and Lavakumar Nahiri.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1025191. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra05082k

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