An Intramolecular Cascade Cyclization of 2-Aryl Indoles: Efficient Methods for the Construction of 2,3-Functionalized Indolines and 3-Indolinones

Abstract

Efficient intramolecular N/O-nucleophilic cyclization of 2-aryl indoles has been developed to afford the corresponding 2-aza-3-oxaindolines and 3-indolinones in 80–95% yield. The methods provided convenient access to fused imidazo[1,2-c]oxazolidinone, oxazolidine, or tetrahydro -1,3-oxazine cores under mild conditions.

Functionalized indole rings are one of the most abundant and important heterocycles that occur ubiquitously in bioactive natural products, pharmaceuticals and agrochemicals.^[1,2] Consequently, practical and atom-economical modifications of the indole structure have long been a subject of immense interest in organic and medicinal chemistry.^[3–5] Among them, intramolecular C2-functionalization of indoles such as C-,^[6] N-,^[7] O-,^[8] and S-nucleophilic cyclizations^[9] have received much attention since they provide straightforward access to indolines with a fused-ring substructure (Scheme 1, a). However to date, these transformations mainly focused on indole-based substrates with a pendant nucleophile tethered at the C3 position. Intramolecular cyclization of indole with a nucleophile attached to the nitrogen atom to construct an N-fused indoline has rarely been reported.^[10] Moreover, N-fused indolines exist widely throughout nature and have considerable biological and pharmaceutical importance.^[11–12] Therefore, development of efficient synthetic methods toward the formation of N-fused indolines is important for their utility in medicinal and biological chemistry. In connection with our work on the design and synthesis of ligands to probe enzyme active site, we became interested in functionalized indole derivatives. Herein, we wish to present our studies on the cascade halogenation/intramolecular nucleophilic cyclization of 2-aryl indoles to construct 2-aza-3-oxa indolines and 3-indolinones (Scheme 1, b).

Scheme 1.

Intramolecular nucleophilic cyclization of indoles.

As indicated in Table 1, our studies commenced with the halogenation/cyclization of 5a,^[13] a model substrate that possesses an NHBoc group as the pendant nucleophile. The potential reactivity of indoles toward electrophilic halogenating reagents, such as N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), might offer a starting point to identify suitable reaction conditions. Disappointingly, the reactions of 5a with NBS in CCl₄ at 0 °C or 23 °C under argon both gave complex mixtures (entry 1) and no desired cyclization product was obtained. However, the hypothesized halogenation/cyclization can be carried out by employing NCS as an electrophilic reagent, producing an unprecedented polycyclic indoline 6a in 41% yield. As shown, the indoline derivative contains the expected imidazolidine ring along with an unexpected fused oxazolidinone functionality (entry 2). The structure of 6a was unambiguously established using ¹H, ¹³C, and 2D NMR spectra. Optimization of the reaction was next investigated by varying the solvent. The reaction yield increased to 53% when CH₂Cl₂ was used in comparison to CCl₄, toluene, or Et₂O (entries 2–5). Subsequently, reaction temperature, time and the amount of NCS were screened to improve the reaction efficiency (entries 6–9). The best result was obtained (91% yield) when the reaction was performed with 3 equiv of NCS at 0 °C under argon for 3.5 h (entry 7). It should be noted that only 3-chloroindole was observed upon treatment of 5a with 1 equiv NCS.^[14] This observation showed that excess NCS was critical to initiate the cascade cyclization and hydrogen chloride might be generated in this process (pH = 2–3). Accordingly, we attempted to add bases such as NaHCO₃, KHCO₃, or K₂CO₃ to neutralize the presumed acid. However, no obvious improvement was obtained (entries 10–12), indicating that acidic or basic conditions had no apparent influence on the reaction. Additionally, we found that when the reaction was carried out in the presence of air, the yield of 6a was substatially reduced (entry 13). Reactions described above with different conditions all gave polycyclic indoline 6a as a single cis diastereoisomer (entries 2–13), demonstrating the high diastereoselectivity of this cascade reaction. Presumably, the reaction of 5a with NCS first proceeded with the formation of 3-chloroindole 7. It then undergoes a NCS-promoted intramolecular cyclization as shown in intermediate 8 with the extrution of isobutene to provide the cyclization product 6a (Scheme 2).

Table 1.

Validation and optimization of the N-nucleophilic cyclization.^[a]

Entry	Halogenating reagent	Solvent	Temp (°C)	Time (h)	Base	Yield (%)[b]
1	NBS (2 eq)	CCl4	0/23	1	–	–
2	NCS (2 eq)	CCl4	23	2	–	41
3	NCS (2 eq)	toluene	23	2	–	46
4	NCS (2 eq)	CH2Cl2	23	2	–	53
5	NCS (2 eq)	Et2O	23	24	–	10
6	NCS (2 eq)	CH2Cl2	0	7	–	73
7	NCS (3 eq)	CH2Cl2	0	3.5	–	91
8	NCS (3 eq)	CH2Cl2	−10	24	–	85
9	NCS (4 eq)	CH2Cl2	0	2	–	65
10[c]	NCS (3 eq)	CH2Cl2	0	3.5	NaHCO3	90
11c,d]	NCS (3 eq)	CH2Cl2	0	3.5	KHCO3	88
12[c]	NCS (3 eq)	CH2Cl2	0	3.5	K2CO3	91
13[d]	NCS (3 eq)	CH2Cl2	0	3.5	–	71

^[a] All reactions were performed with 0.2 mmol of 5a in 2 mL of solvent under argon.

^[b] Isolated yield.

^[c] 3 equiv of base.

^[d] Reaction performed under air. NBS = N-bromosuccinimide, NCS = N-chlorosuccinimide.

Scheme 2.

Intramolecular cascade cyclization of 2-aryl indole 5a.

Under the optimized reaction conditions, the scope of this cascade chlorination/cyclization have been explored by varying substitutions. As summarized in Table 2, indole scaffolds possessing electron-donating (5-Me, 4-Me, 5,7- dimethyl, and 5-MeO) or halogen (5-Cl) substituents on the benzenoid ring were well-tolerated and excellent yields were obtained (81–95%, 6b–6f). In contrast, highly deactivated indole bearing a strongly electron-withdrawing group (5-NO₂) failed to afford the desired cyclization product. Furthermore, indoles incorporating various methyl-substituted pendant nucleophiles (5g and 5h) underwent the reaction to give products 6g and 6h in 86% and 84% yields, respectively. Substitution of the 2-phenyl ring with p-methyl or p-methoxy substituents (5i and 5j) were also found to be suitable substrates for cyclizations, delivering products 6i and 6j in 95% and 93% yields, respectively.

A single-crystal X-ray analysis of compound 6e further confirmed the structure of the halogenation/cyclization product (Figure 1).^[15] Of particular interest, these highly functionalized indoline products 6a–6j, which possess a new and interesting fused heterocyclic skeleton in common, might have potential applications in biological and material studies.

Figure 1.

X-ray structure of 6e.

We have also investigated the development of a parallel halogenation/cyclization of the indole substrates bearing an O-nucleophile at the N-1 position. Our initial attempt was the reaction of 2-phenylindole 9a^[16] and NCS in CCl₄ at 0 °C under air (Table 3, entry 1). Interestingly, the cyclization proceeded smoothly to afford 3-indolinone 10a in 50% yield instead of the anticipated C3 mono-chlorinated indole. The structure of 10a was confirmed using ¹H, ¹³C, and 2D NMR spectra. Considering that the oxygen of the newly formed carbonyl group in 10a might be originating from H₂O in air, we added 3 equiv H₂O in the reaction and obtained 10a in 55% yield (entry 2). Optimization of the reaction conditions was then turned to screening of solvent and reaction temperature (entries 3–5). Performing the reaction in CH₂Cl₂ at 23 °C reduced the reaction time and increased the yield to 81% (entry 5). Furthermore, a survey of base additive along with H₂O was found to accelerate the reaction and improve the yield up to 94% (entries 6–8). This observation is in contrast to the N-nucleophilic cyclization described above in which a base additive was not essential.

Table 3.

Validation and optimization of the O-nucleophilic cyclization.^[a]

Entry	Halogenating reagent	Solvent	Temp (°C)	Time (h)	Additive[b]	Yield (%)[c]
1	NCS (2 eq)	CCl4	0	15	–	50
2	NCS (2 eq)	CCl4	0	15	H2O	55
3	NCS (2 eq)	toluene	0	17	H2O	48
4	NCS (2 eq)	CH2Cl2	0	12	H2O	65
5	NCS (2 eq)	CH2Cl2	23	7	H2O	81
6	NCS (2 eq)	CH2Cl2	23	5	H2O/K2CO3	85
7	NCS (2 eq)	CH2Cl2	23	5	H2O/KHCO3	90
8	NCS (2 eq)	CH2Cl2	23	5	H2O/NaHCO3	94

^[a] All reactions were performed with 0.2 mmol of 9a in 2 mL of solvent under air.

^[b] 3 equiv of H₂O and base.

^[c] Isolated yield. NCS = N-chlorosuccinimide.

We further examined a range of indoles with different substitutions. As it turned out, the substrates also underwent the O-nucleophilic cyclization under our optimized conditions (Table 4).^[17] Indoles bearing electron-donating substituents (5-Me, 4-Me, 7-Me, 5,7-dimethyl, and 5-OMe) on the benzenoid ring worked well, leading to formation of the cyclization products 10b–10f in excellent yields (91–95%). When 7-methyl-substituted indole 9d was used, product 10d was obtained upon standard conditions. Interestingly, chlorination of the indole ring also occurred by increasing the amount of NCS (5 equiv) and prolonging the reaction time (24 h), affording 10d′ in 93% yield. The electronic nature of the substrate has a slight influence on the reactivity, as indoles 9g and 9h with an electron-withdrawing group (5-Cl and 5-NO₂) required longer reaction times and provided relatively lower yields (83% and 80%). The reaction of indoles 9i–9k with different aryl groups and substitution at the C2 position including p-MeC₆H₄, p-MeOC₆H₄, and 1-naphthyl also proceeded effectively to furnish the desired products 10i–10k in 82–93% yield. Furthermore, formation of a tetrahydro-1,3-oxazine instead of an oxazolidine in this O-nucleophilic cyclization was examined. Indole 9l with an expanded nucleophile was well-tolerated for this reaction, producing the expected product 10l in 80% yield. Other indoles 9m–9o with different substituents (5-Me, 5,7-dimethyl, and 5-OMe) on the benzenoid ring were also suitable for cyclization. In contrast to the formation of oxazolidine (10a, 10b, 10e, and 10f), the pattern with larger tethers was slightly less favored as 10l-10o were obtained in relatively lower yields (80–87%). Single-crystal X-ray analysis of 10e further confirmed the structure of the O-nucleophilic cyclization product (Figure 2).^[15] Overall, the described O-nucleophilic cyclization has proved to be efficient and economical in comparison to previous syntheses of 3-indolinone 10a and its analog.^[9a]

Table 4.

Substrate scope of the O-nucleophilic cyclization.^[a]

^[a] Substrate 9 (0.2 mmol) was dissolved in freshly distilled CH₂Cl₂ (2 mL) at 23 °C under air followed by addition of NaHCO₃ (0.6 mmol), H₂O (0.6 mmol), and NCS (0.4 mmol).

^[b] Treatment of 9d (0.2 mmol) with NaHCO₃(1.5 mmol), H₂O (1.5 mmol), and NCS (1.0 mmol) in freshly distilled CH₂Cl₂(3 mL) at 23 °C under air for 24 h. NCS = N-chlorosuccinimide.

Figure 2.

X-ray structure of 10e.

In summary, we have developed a new cascade chlorination/cyclization of 2-aryl indoles bearing an N-nucleophile. A range of polycyclic indolines were prepared in 81–95% yield by this process that simultaneously generates a fused imidazo[1,2-c]oxazolidinone skeleton and incorporates two adjacent hetero-quaternary stereocenters. Furthermore, we developed an O-nucleophilic cyclization in which a number of tricyclic tetrahydrooxazolo[3,2-a]indoles and tetrahydro-1,3-oxazino[3,2-a]indoles were effectively assembled in 80–95% yield. Mild conditions and practical convenience of both reactions deem these methods to be valuable synthetic tools. Further studies including mechanistic investigations and the potential bioactivity of these novel compounds are currently ongoing in our laboratory.

Table 2.

Substrate scope of the N-nucleophilic cyclization.^[a]

^[a] Substrate 5 (0.2 mmol) was dissolved in freshly distilled CH₂Cl₂ (2 mL) at 0 °C under argon followed by addition of NCS (0.6 mmol).

^[b] The ratio of diastereoisomers was determined by ¹H NMR. NCS = N-chlorosuccinimide.