A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

Abstract

We have reported herein a catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles by which a series of five-ring-fused tetrahydroisoquinolines featuring an indoline scaffold were obtained as single diastereomers in moderate to high yields without any additives under mild conditions. Moreover, the current method provides a novel and convenient approach for the efficient incorporation of two biologically important scaffolds (tetrahydroisoquinoline and indoline).

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The privileged structural motifs offer synthetic and medicinal chemists a prodigious starting point to design and synthesize new classes of drug candidates. Among various naturally occurring core scaffolds, tetrahydroisoquinoline and indoline, which are widely featured in a large number of bioactive natural products and man-made compounds, have received tremendous attention from organic chemists.^1,2 For instance, vindoline might contribute to the anti-diabetic effects of Catharanthus roseus,³ and jamtine has a significant anti-hyperglycemic activity (Fig. 1).⁴ More interesting still, compound A incorporating the two important scaffolds also exhibited efficient anti-cancer activity.⁵ In this respect, the development of concise and direct synthetic methods for the efficient combination of two or more privileged motifs to generate structurally complex candidate molecules is of great interest and significance.⁶

Fig. 1 Selected bioactive and natural compounds containing polycyclic-fused indolines and THIQs.

Up to now, different synthetic methods have been reported for the preparation of either polycyclic tetrahydroisoquinoline or indoline derivatives.^7,8 However, the methodologies for the incorporation of two such attractive skeletons have rarely been explored.^5,9 To meet such a challenge, a protocol involving indoles and either tetrahydroisoquinolines or the precursors of tetrahydroisoquinolines is undoubtedly one of the most direct strategies. In 2005, Li and co-workers first realized a direct indolation of N-aryl tetrahydroisoquinolines through a cross-dehydrogenative coupling reaction.¹⁰ And then, some related studies were also successively reported by different groups (Scheme 1a).¹¹ However, despite these advances, such transformations still suffer from some drawbacks, such as air and moisture sensitivity, the need of stoichiometric amounts of hazardous oxidants and the use of transition metals, thus seriously limiting their further applications. For these reasons, and also in response to the principle of sustainable chemistry,¹² the exploration of more cheaper, environmentally friendly, and convenient methods for the direct combination of two such privileged motifs is still in great demand. As part of our on-going efforts to synthesize C1 functionalized tetrahydroisoquinolines¹³ and indolines,¹⁴ we reported herein the first catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles by taking advantage of the significant superiorities of C,N-cyclic azomethine imines in the construction of polycyclic tetrahydroisoquinoline derivatives^15–17 and also the great potential of 3-nitroindoles as electrophilic alkenes of a new type (Scheme 1b).¹⁸ Thus, a dearomatization of 3-nitroindoles was easily realized¹⁹ and the corresponding heterocycles containing both tetrahydroisoquinoline and indoline moieties were efficiently assembled in an atom-economical and environmentally benign manner.

Scheme 1 Synthesis of C1 functionalized THIQs by involving different indoles.

At the outset of our investigation, C,N-cyclic azomethine (1a) and 3-nitroindole (2a) were selected as model substrates to optimize the reaction conditions. The cycloaddition reaction afforded the corresponding product (3aa) in only 23% conversion in the presence of 20 mol% Cu(OTf)₂ in CHCl₃ after 24 h at room temperature (Table 1, entry 1). Then, some other Lewis acids including Sc(OTf)₃, Zn(OTf)₂ and Ni(OAc)₂·4H₂O were examined, and enhanced conversion was observed by using Ni(OAc)₂·4H₂O (Table 1, entries 2–4). We then conducted the reaction in the absence of a catalyst. And to our delight, a comparable outcome was obtained with 90% conversion (Table 1, entry 5). Encouraged by this result, the effect of solvents was checked subsequently to further improve the yield (Table 1, entries 6–13). For all of the cases, the reaction proceeded smoothly and gave the product in moderate to high conversion. The best result was obtained with ethyl acetate as the solvent. Gratifyingly, the conversion of 2a could be even increased to >95% when 1.2 equiv. of 1a was used.

Table 1 Optimization of the reaction conditions^a

Entry	Metal (20 mol%)	Solvent	Conversion^b (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), metal (20 mol%), solvent (0.4 mL), r.t., 24 h. b Determined by ^1H NMR (300 MHz) analysis of the crude reaction mixture based on 2a. c Conducted with 2h. d 1.2 equiv. of 1a was used. e The yield of the isolated product. Note: a relative configuration of the product was exhibited.
1	Cu(OTf)2	CHCl3	23
2	Sc(OTf)3	CHCl3	8
3	Zn(OTf)2	CHCl3	44
4	Ni(OAc)2·4H2O	CHCl3	89
5	—	CHCl3	90
6	—	CH2Cl2	87
7	—	Toluene	84
8	—	THF	84
9	—	EtOAc	92
10	—	CH3CN	88
11	—	DMF	84
12	—	EtOH	76
13	—	MeOH	67
14^c	—	H2O	43
15	—	EtOAc	>95 (94)

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With the established optimal reaction conditions in hand, the substrate scope of the catalyst-free 1,3-dipolar cycloaddition was investigated by using 1a and a series of different substituted 3-nitroindoles. As summarized in Scheme 2, N-alkoxycarbonylated and N-Ts-protected 3-nitroindoles performed very well, and delivered the corresponding cycloadducts 3aa–3ae in high to excellent yields. N-Methyl-protected 3-nitroindole 2f failed to undergo the current transformation probably because of the reduced electrophilicity. Moreover, both electron-donating and electron-withdrawing substituents in the C5-, C6-, and C7-positions of 2 were all compatible with the standard reaction conditions (3ah–3an). It is worth noting that the 3-nitroindole 2g with a chlorine substituent at the 4-position also worked well, despite the relatively greater steric hindrance.

Scheme 2 Substrate scope with respect to 3-nitroindoles. Reaction conditions: 1a (0.12 mmol), 2 (0.10 mmol), EtOAc (0.4 mL), at room temperature for appropriate time. Isolated yields based on 2. For all of the cases, >20 : 1 d.r. values were observed.

Subsequently, various structurally diverse C,N-cyclic azomethine imines were synthesized to further explore the generality of this protocol (Scheme 3). Although benzoyl hydrazine derived azomethine imine 1b showed relatively lower reactivity, the corresponding product 3ba was obtained in 67% yield when the reaction temperature was raised to 50 °C. Different substituents at the 4-position of the phenyl ring of the arylsulfonyl protecting group had little effect on the reactivities and outcomes (3ca and 3da). Besides, azomethine imines with a methyl substituent on the aromatic ring exhibited relatively higher reactivity than that with a halogen substituent. To our delight, azomethine imine 2j with a condensed-ring system also was smoothly converted into the corresponding product with a satisfactory yield. The configuration of the products was determined by X-ray analysis of 3aa (Fig. 2).²⁰ Accordingly, related transition states (TS-1, TS-2, TS-3 and TS-4) were speculated to explain the specific stereoselectivities. The observed preference for TS-1 and TS-2 was probably caused by the π–π interaction between azomethine imines and 3-nitroindoles.²¹

Scheme 3 Substrate scope with respect to C,N-cyclic azomethine imines. Reaction conditions: 1 (0.12 mmol), 2a (0.10 mmol), EtOAc (0.4 mL), at room temperature for appropriate time. Isolated yields based on 2a. For all of the cases, >20 : 1 d.r. values were observed. ^[a]Conducted at 50 °C.

Fig. 2 X-ray structure of product 3aa and proposed transition states.

Encouraged by the above-mentioned positive results, we then employed some other dipolarophiles including alkylidene azlactone (4) and methyleneindolinone (5) to further illustrate the compatibility of this catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines (Scheme 4). Gratifyingly, both of them worked well and smoothly transformed into the corresponding spirocyclic products in good to high yields with high d.r. It should be noted that an elimination of the Ts group was observed in this process.

Scheme 4 Further extension of the dipolarophiles. ^aIsolated yields. ^bDetermined by ¹H NMR (300 MHz) spectroscopy of the crude mixture. See the ESI† for details.

To demonstrate the practicality of this protocol, a relatively large-scale reaction of 1a and 2h was conducted. It is notable that an obvious decomposition of the corresponding cycloadduct was observed in the purification process of flash chromatography, so 3ah was isolated in a relatively lower yield with an excellent d.r. value (Scheme 5a). Besides, a representative transformation of cycloadduct 3aa was carried out (Scheme 5b). Treatment of 3aa with zinc powder and TMSCl afforded the indolationalized tetrahydroisoquinoline 8 in 71% yield.^18f

Scheme 5 Relatively large-scale preparation of 3ah and transformation of 3aa.

Conclusions

In summary, the first catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles has been realized. The method gives an easy access to a series of highly functionalized five-ring-fused tetrahydroisoquinolines featuring an indoline scaffold in excellent diastereoselectivities without any use of catalysts or additives. The current methodology is of vital significance by virtue of the mild and facile reaction conditions and also the efficient incorporation of the two intriguing skeletons of medicinal value. Besides, alkylidene azlactone and methyleneindolinone were also compatible with the current protocol and provided the corresponding spirocyclic products in high yields. Further biological investigations of the newly synthesized structurally complex ring-fused tetrahydroisoquinoline derivatives are under progress in our laboratory.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (NSFC) (grant numbers 21432003 and 21272102), the Program for Chang-jiang Scholars and Innovative Research Team in University (PCSIRT: No. IRT_15R27), and the Special Research Fund for the Doctoral Program of Higher Education (20130211130005).

Notes and references

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20. CCDC 1494106 contains the supplementary crystallographic data for this paper.
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Footnote

† Electronic supplementary information (ESI) available: CCDC 1494106. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6gc02517j

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