Copper-catalyzed alkynylation/annulation cascades of N-allyl ynamides: regioselective access to medium-sized N-heterocycles

Abstract

A synthetic strategy based on sequential application of aza-Claisen rearrangement, C–H functionalization, C–N coupling and cyclization as key steps has been developed for the synthesis of various medium-sized N-heterocycles of pharmaceutical relevance. This efficient new method exhibits a broad scope and provides a highly efficient synthesis of N-heterocycles of different ring sizes (6-, 7-, 8-, and 9-membered rings) in moderate to good yields.

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N-Heterocycles continue to receive widespread attention due to their bioactivities and pharmaceutical applications. Among N-heterocycles, the 7- and 8-membered N-heterocycles are probably one of the most common structural motifs spread across natural products and drugs (Fig. 1).¹ Therefore, the development of facile and efficient methods for the selective and diverse construction of various medium-sized (7- and 8-membered rings) N-heterocycles is still required.

Fig. 1 Examples of important medium-sized N-heterocycles.

However, the synthesis of medium-sized (7- and 8-membered rings) N-heterocycles has proved to be highly challenging, mainly due to the unfavorable enthalpic (the strain in many medium-sized rings) and entropic (probability of the chain ends meeting) reasons.² Therefore, traditional ring closure approaches for 5-and 6-membered rings are problematic for medium-sized rings.³ Furthermore, methodologies to form medium-sized N-heterocycles require the consideration of a raft of compatibility and selectivity issues.

Recently, the ynamide chemistry⁴ has become a powerful entry to build N-heterocycles.⁵ In 2019, we have reported Cu^II-catalyzed annulation cascades of N-allyl-N-((2-bromoaryl)ethynyl)amides with terminal alkynes or 1,3-dicarbonyls for accessing 2,3-difunctionalized indoles. Such methods provide significant benefits toward the synthesis of a series of indole derivatives (Scheme 1a).⁶ While this reaction has been very successful in 5-membered ring synthesis, its potential for medium-sized ring formation has not been explored.⁷

Scheme 1 Synthesis of N-heterocycles.

Herein we report on the effective participation of ynamides with terminal alkynes in related processes that have provided a means for the rapid construction of a diverse range of medium-sized N-heterocyclic systems (Scheme 1b). Through the design of the substrate, the relative position of the coupling group and the ynamide group in the molecule is controlled, and N-heterocycles of different ring sizes (6-, 7-, 8- and 9-membered rings) are synthesized selectively.

To initiate our study, the reaction conditions were screened for the formation of 6-allyl-7-(phenylethynyl)-1-tosyl-2,3,4,5-tetrahydro-1H-azepine (3aa) with N-allyl-N-(6-chlorohex-1-yn-1-yl)-4-methylbenzenesulfonamide (1a) and phenylacetylene (2a) as model substrates (Table 1). The results demonstrated that a combination of CuTiO₃ with the Phen ligand plays an important role in the reaction (Table 1, entries 1–3). In a typical procedure, a mixture of 1a (0.2 mmol, 1 equiv.), 2a (3 equiv.), CuTiO₃ (10 mol%), 1,10-phenanthroline (Phen, 10 mol%) and K₂CO₃ (2 equiv.) in 2 mL of toluene was stirred under argon at 100 °C. Gratifyingly, the reaction proceeded smoothly to give the azepine 3aa in 62% isolated yield (Table 1, entry 1). The reaction failed to afford 3aa without a copper catalyst or Phen ligand (Table 1, entries 2 and 3). Notably, the amounts of CuTiO₃ and Phen affected the reaction, and a combination of 10 mol% CuTiO₃ with 10 mol% Phen was preferred (Table 1, entries 1, 4 and 5). Other copper catalysts, such as Cu(OAc)₂, CuCl₂, and Cu(OTf)₂, resulted in 3aa in 31%, 27% and 34% yields, respectively (Table 1, entries 6–8). In order to improve the yield of 3aa, other ligands such as 2,2′-bipyridine and N,N,N′,N′-tetramethylethane-1,2-diamine (TMEDA) were added to the reaction system. Unfortunately, no azepine products were obtained (Table 1, entries 9 and 10). We found that the yield of 3aa decreased from 62% to 43% when using Cs₂CO₃ instead of K₂CO₃ (Table 1, entry 11). However, the reaction failed to proceed without bases (Table 1, entry 12). Subsequently, we screened several solvents and found that acetonitrile (MeCN), tetrahydrofuran (THF), and N,N-dimethylformamide (DMF) did not give better results (Table 1, entries 13–15). The reaction in DMF even failed to afford 3aa. Finally, the screening of the reaction temperature effect revealed that either a lower (80 °C) or a higher (120 °C) temperature had a deleterious effect on the reaction (Table 1, entries 16 and 17). Therefore, the combinations listed in entry 1 were the optimal reaction conditions for this tandem cyclization.

Table 1 Optimization of reaction conditions^a

Entry	Variation from the standard conditions	Isolated yield [%]
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), CuTiO3 (10 mol%), Phen (10 mol%), K2CO3 (2 equiv.), toluene (2 mL), argon, 100 °C and 12 h.
1	None	62
2	Without Phen	0
3	Without CuTiO3	0
4	CuTiO3 (5 mol%) and Phen (5 mol%)	45
5	CuTiO3 (20 mol%) and Phen (20 mol%)	66
6	Cu(OAc)2 instead of CuTiO3	31
7	CuCl2 instead of CuTiO3	27
8	Cu(OTf)2 instead of CuTiO3	34
9	2,2′-Bipyridine instead of Phen	0
10	TMEDA instead of Phen	0
11	Cs2CO3 instead of K2CO3	43
12	Without K2CO3	0
13	MeCN instead of toluene	46
14	THF instead of toluene	39
15	DMF instead of toluene	0
16	At 80 °C	26
17	At 120 °C	57

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With the optimized reaction conditions in hand, the applicability to different ynamides was investigated (Scheme 2). A variety of ynamides transformed smoothly into medium-sized N-heterocycles in this copper/Phen catalytic system and displayed good tolerance. The substrates leading to 6-, 8- and 9-membered N-heterocycles were first examined and gave the desired cyclization products in 72%, 47% and 32% yields, respectively (3ba–3da).⁸ Unfortunately, the current reaction was not viable for 12-membered N-heterocycles (3ea). Notably, substrates 1f and 1g, containing an N-(2-methylallyl) group or an N-(but-2-en-1-yl) group, underwent the tandem cyclization, giving the corresponding aza-Claisen rearrangement products 3fa and 3ga in moderate yields. We found this transformation to be efficient for a wide range of substrates, which allowed for the synthesis of sulfonylated azepines in moderate yields. It was found that a variety of groups, including alkyl sulfonyl (3ha and 3ia), aryl sulfonyl (3ka–3na), and heterocyclic sulfonyl (3oa), were perfectly tolerated under the tandem cyclization conditions. Tandem cyclization of para-substituted aryl sulfonyl possessing electron-withdrawing (3la and 3ma) substituents proceeded with less efficiency. Unfortunately, the use of an ynamide with a large steric hindrance such as N-allyl-N-(6-chlorohex-1-yn-1-yl)-2,4,6-trimethylbenzenesulfonamide (1j) did not give the desired azepine (3ja).

Scheme 2 Scope of ynamides. Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), CuTiO₃ (10 mol%), Phen (10 mol%), K₂CO₃ (2 equiv.), toluene (2 mL), argon, 100 °C and 12 h.

This copper/Phen catalytic system was further expanded to a range of substituted alkynes (Scheme 3). The results demonstrated that tandem cyclization was compatible with a wide array of arylalkynes and several aryl groups. For instance, 4-MeC₆H₄, 4-MeOC₆H₄, 4-ClC₆H₄, 4-FC₆H₄, 4-CNC₆H₄, and 4-NO₂C₆H₄ at the terminal alkyne were well tolerated (3ab–3ag). Moreover, the electron effect had an influence on their reactivity. Arylalkynes bearing an electron-donating group were converted to azepines in good yields (3ab and 3ac), whereas arylalkynes with an electron-withdrawing group delivered azepines in lower yields (3ad–3ag). The use of para- or ortho-substituted arylalkynes afforded azepines 3ac and 3ah, respectively, in high yields, but bulky ortho-substituted arylalkyne generated azepine 3ai with a diminished yield. Notably, the optimal conditions were applicable to polysubstituted arylalkynes, thus producing 3aj in 67% yield. For alkyne derivatives of various cycles, such as naphthalene, pyridine, cyclohexene, and cyclopropane, the corresponding azepines (3ak–3ao) were efficiently constructed in 44–70% yields. Gratifyingly, the optimal conditions were applicable to an aliphatic alkyne, thus producing 3ap in 53% yield. Finally, trimethylsilicone acetylene also displayed moderate reactivity, furnishing the azepine (3aq) with 45% yield.

Scheme 3 Scope of terminal alkynes. Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), CuTiO₃ (10 mol%), Phen (10 mol%), K₂CO₃ (2 equiv.), toluene (2 mL), argon, 100 °C and 12 h.

It was worth pointing out that CuTiO₃ is a type of copper ion insertion-type material, in whose open channels, copper ions can reversibly insert in the common vacant sites of the orthorhombic Ti–O framework.⁹ In the reaction, the copper ion from CuTiO₃ can transfer easily from the T–O framework to the solution and combine with the reagents to catalyze the reaction, while the copper ions in other homogeneous copper sources such as Cu(OAc)₂ are fixed by the counterpart ions and constricted in the lattice node. Therefore, the reaction almost occurs in solution, and the heterogeneous catalyst CuTiO₃ is more efficient than that the other homogeneous copper sources used.

To understand the current tandem cyclization and the essential role of the copper catalyst and the ligand in the reaction, DFT calculations were performed assuming the reaction occurred in solution, and the energy profiles are shown in Scheme 4. According to the experimental results and previous literature reports,^4j,10 aza-Claisen rearrangement of the substrate 1a readily takes place under heating to produce the ketenimine intermediate A, which sequentially undergoes coordination with Cu^II(Phen)CCPh to form intermediate B. The resulting complex B undergoes a fairly nucleophilic addition of the alkynyl group to the C=N bond to form compound C with N–Cu bonding. The migration of Cu^II(Phen) from anionic nitrogen to the chlorine atom results in the formation of intermediate D, and the resulting structure D undergoes an intramolecular S_N2 process assisted by the Lewis acidic Cu^II group and base to give the final product 3aa and regenerate the active Cu^II(Phen) species.

Scheme 4 Energy profiles for the pathways of Cu(II)-catalyzed 1a leading to 3aa.

Conclusions

We have successfully developed a novel, efficient and facile method for the synthesis of 6-, 7-, 8-, 9-membered N-heterocycles, a longstanding challenging topic in organic synthesis. The key to success is the ketenimine intermediate generation and its chemoselective cross-coupling to the halogenated group. This protocol features a broad substrate scope and excellent functional group tolerance under copper-catalyzed reaction conditions. Efforts to expand the applications of this cascade strategy in cycle synthesis are currently underway in our laboratory. Further synthetic applications of this efficient transformation in the synthesis of natural products and pharmaceutical agents are currently in progress.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 21901255 and No. 21601204), Hunan Provincial Natural Science Foundation of China (No. 2018JJ3594) and Foundation of National University of Defense Technology (No. ZK17-03-52) for financial support. We also thank Dr Ye Zhang (National University of Defense Technology) for CuTiO₃ and very useful discussions.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental information, experimental procedure for product synthesis, full characterization data, ¹H and ¹³C NMR spectra of all products. CCDC 1910929, 1910930 and 1910931. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0qo00837k

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