Copper-Catalyzed Ring-Expansion Cascade of Azirines with Alkynes

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Copper-Catalyzed Ring-Expansion Cascade of Azirines with Alkynes: Synthesis of Multisubstituted Pyridines at Room Temperature Chandragiri Sujatha,† Chandra Shekar Bhatt,‡ Mahesh Kumar Ravva,‡ Anil K. Suresh,‡ and Kayambu Namitharan*,†,‡ †

Organic Synthesis and Catalysis Laboratory, SRM Research Institute, SRM Institute of Science and Technology, Chennai-603203, India ‡ SRM University-AP, Amaravati-522502, India S Supporting Information *

ABSTRACT: The first intermolecular ring-expansion cascade of azirines with alkynes for the synthesis of pyridines, enabled by a copper/triethylamine catalytic system via simultaneous generation and utilization of yne-enamine and skipped-yneimine intermediates, is reported. Experimental as well as computational mechanistic studies revealed that the role of triethylamine is crucial in deciding the reaction pathway toward the pyridine products. This process offers a novel, onestep, direct, and practical strategy for the rapid construction of highly substituted pyridines under exceedingly mild conditions, and an installed alkyne functionality.

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he pyridine1 skeleton is a privileged scaffold in medicinal chemistry, because of its vital occurrence in numerous natural and unnatural compounds with significant biological activities.2 Recently, the pyridine skeleton has also been successfully utilized as organocatalysts and ligands for a variety of transition-metal catalyzed reactions.3 In addition, pyridine derivatives have also found applications in materials science as organic-light-emitting diodes4 and fluorescent sensors.5 On the other hand, three-membered cyclic-imines, azirines, have been extensively utilized in a variety of addition and cycloaddition reactions,6 in particular, ring-expansion reactions that are considered highly powerful due to their ability to give direct access to higher analogues of azacyclic compounds.6,7 However, the majority of the ring-expansion reactions of azirines are limited to the synthesis of five-membered structures and, primarily, methods that deliver six-membered azacyclic structures such as pyridines are scarce (Figure 1). In 2013, Park’s group reported the synthesis of pyridines from 2H-azirines with vinyl carbenoids and a subsequent DDQ oxidation for the first time.8 The following year, the same group described an intramolecular approach, activating azirines toward alkenes for the synthesis of pyridines, however, under much harsher conditions (130 °C and long reaction times).9 Similarly, Gagosz and co-workers have accomplished a gold-catalyzed intramolecular ring expansion of azirines with alkynes to synthesize pyridines.10 Nevertheless, these reports suffer from the following drawbacks: requirement of expensive metal catalysts, predesigned starting materials, strict inert conditions, high temperatures, and longer reaction times. Herein, we disclose a mild and efficient reaction strategy for the synthesis of highly substituted pyridines at room temperature via a copper-catalyzed ring-expansion cascade of azirines with alkynes (Figure 1c). © XXXX American Chemical Society

Figure 1. Ring expansion reactions of azirines.

Notably, this represents the first example of an intermolecular ring-expansion reaction of azirines and alkynes for the synthesis of pyridines and is strictly in contrast to the earlier reports, where five-membered pyrrole structures were commonly observed for the ring-expansion reactions of azirines with alkynes (Figure 1b).11−14 This methodology includes the following salient features: (1) utilization of a base-metal catalyst for the synthesis of highly substituted pyridines from azirines; (2) direct construction of rare alkynylpyridines, an important core found Received: April 9, 2018

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DOI: 10.1021/acs.orglett.8b01090 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters in many bioactive compounds;15 (3) reaction capability to proceed at room temperature and complete within 30 min. We have shown keen interest in exploring base-metal catalysis for developing new synthetic methods16 and have recently reported a copper-catalyzed multicomponent cascade reaction of 2H-azirines with sulfonyl azides and alkynes for the direct synthesis of triazolopyrimidines.16a During the course of our investigation on further reactions of azirines, we were pleased to isolate a highly substituted alkynylpyridine17 as the major product (3a, 56%) along with 12% of the homocoupling product when azirine 1a was reacted in the presence of alkyne 2a, CuI (0.1 equiv), and DIPEA (2 equiv) in DCM at room temperature (25 °C) for 6 h (Table 1, entry 1). Interestingly, switching the

examined as an additive with more homocoupling product (Table 1, entry 3). No improvement in the products yields was witnessed (32% and 45%, respectively) using other nitrogen based additives such as pyridine and DMAP. In contrast, with inorganic additives such as K2CO3, KtOBu, and Cs2CO3, the reactions did not yield any pyridine products, and only homocoupling products were isolated (entries 6−8). This observation suggests that the nitrogen-based additives are acting not only as a base but also as a ligand in delivering the desired product. To confirm this, additives that can act as both ligand and base were examined (entries 9−12). With ethylene diamine (EDA) and bypyridine as additives, product 3a was isolated in 47% and 11% yields. When different phosphine-based additives were tried, the reaction afforded only trace amounts of the desired product with PPh3 and a 27% yield while using PBu3. When the reaction was performed at a slightly higher temperature of 45 °C, product 3a was obtained in a relatively lesser yield of 65%, along with the formation of the homocoupling product at a yield of 18% (entry 13). Also, reduction in the yield of 3a was detected when 1 equiv of TEA was used (entry 14). Pleasingly, when the reaction duration was reduced to 30 min, the cascade reaction was relatively clean and proceeded quite efficiently with a maximum yield of 90% (entry 15). Therefore, we evaluated a variety of copper salts as catalysts, CuI, CuBr, CuCl, Cu(SO4)2·H2O, and Cu(OAc)2·H2O, among which CuI was proven to be the optimal catalyst (entries 15−19). Subsequently, a solvent screen was also undertaken; besides DCM, other solvents such as DCE, ACN, toluene, THF, CHCl3, DMF, and dioxane were tested. No significant improvement in the yields was observed. With the optimized reaction conditions, the scope of the copper-catalyzed ring-expansion reaction was studied, as illustrated in Figure 2. Generally, the reaction efficiency was not very sensitive to the electronic properties of the substituents on the aryl ring of the azirine moiety, as the substrates bearing both electron-donating (3b−d, 85%−90%) and electron-withdrawing groups (3e−g, 80%− 88%) worked very well with good to excellent yields. The scope of the reaction with respect to various alkynes was also examined and was found to proceed smoothly in all the cases (3h−s). Notably, the substrate with an n-pentyl substituent or bulky tert-butyl was also well tolerated affording the corresponding products 3j and 3k in good yields (74% and 80%, respectively). Excitingly, an aromatic alkyne bearing a strong electron-withdrawing substituent such as fluorine could also be efficiently transformed into the desired product (3m, 79%). When aliphatic alkynes were employed in the cascade reaction, the reaction proceeded as efficiently as aromatic alkynes and delivered products in good to high yields (3n−s). Most importantly, the cascade reaction was successfully applied for the gram-scale synthesis of alkynylpyridines. The alkynylpyridine 3a was isolated in a marginally lesser yield of 88% (see SI). In order to further expand the scope of this novel ringexpansion process, a one-pot sequential reaction starting from vinyl azides was investigated (see SI). This new sequential process allowed the efficient one-pot synthesis of the alkynylpyridines beginning from vinyl azides derived from the isolation of intermediate azirines. Next, we explored the synthetic utility of the obtained alkynylpyridines to more useful derivatives, because of their significant pharmaceutical properties (Scheme 1). Benzylic oxidation proceeded well with molecular oxygen under reflux conditions and delivered aryl alkynylpyridyl ketones in good yields (Scheme 1, 4a−c). Moreover, a selective alkyne reduction

Table 1. Optimization Conditionsa

3a, yield (%)b

1,3-diyne, yield (%)b

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM

56 86 15 32 45 − − − 47 11 trace 27 65 59 90 77 24 trace

12 − 27 15 22 6 11 9 − − − − 18 trace − − − −

TEA

DCM

trace

−

TEA TEA TEA TEA TEA

DCE toluene CHCl3 DMF dioxane

27 15 10 30 12

12 47 − − 33

entry

catalyst

additive

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e 16 17 18

CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuBr CuCl Cu(SO4)2· H2O Cu(OAc)2· H2O CuI CuI CuI CuI CuI

DIPEA TEA DBU pyridine DMAP K2CO3 KtOBu Cs2CO3 EDA Bi-Py PPh3 PBu3 TEA TEA TEA TEA TEA TEA

19 20 21 22 23 24 a

Conditions: 1a (0.85 mmol), 2a (0.93 mmol), base (1.7 mmol), solvent (3 mL), and catalyst (0.085 mmol), at 25 °C, 6 h. bIsolated yield. cAt 45 °C. dBase (0.85 mmol). eReaction was performed for 30 min.

additive to TEA resulted in a much better yield of 86%, and also the homocoupling product, 1,3-diyne, was completely suppressed (entry 2). The structure of alkynylated pyridine 3a was unambiguously established by spectroscopic analyses and single crystal X-ray studies (Supporting Information (SI), Figure S1), which confirmed the presence of a pyridine ring and alkyne functionality in the product. Encouraged by these results, we undertook a systematic optimization study, the results of which are summarized in Table 1. A substantial drop in the yield was observed when DBU was B

DOI: 10.1021/acs.orglett.8b01090 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Synthetic Elaboration

was also achieved using molecular hydrogen as the reductant with Pd/C in methanol to give the corresponding cis-3alkenylpyridines (Scheme 1, 5a and 5b). A plausible mechanistic pathway for our ring-expansion reaction cascade is depicted in Scheme 2. Initially, the reaction Scheme 2. Plausible Mechanistic Pathway for the RingExpansion Cascade Synthesis of Pyridines

of an alkyne with copper as a catalyst, in the presence of TEA, gives copper acetylide I. This would then undergo a ring-opening reaction with azirine 1 to provide a skipped-yne-imine intermediate II, which can further give rise to a highly nucleophilic yne-enamine intermediate IV. This intermediate can proceed through either of two pathways. Path A includes undergoing an intramolecular hydroamination or reacting with the starting azirine to give pyrrole structures; Path B includes reacting with the initially formed skipped-yne-imine II to give the intermediate V. The latter can only be possible when the relative population of these two key intermediates II and IV are high, a very crucial factor in deciding the reaction pathway. For instance, if the ring-opening process is rapid and effective, at any given point of time, the population of these intermediates will be

Figure 2. Scope of the reaction. Conditions: 1 (0.85 mmol), 2 (0.93 mmol), TEA (1.7 mmol), solvent (3 mL), and CuI (0.085 mmol), at 25 °C, 30 min. Yields are those of isolated products. IC50 is the half maximal inhibitory concentration.

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DOI: 10.1021/acs.orglett.8b01090 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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ACKNOWLEDGMENTS The authors acknowledge financial support from the Department of Science and Technology (DST), New Delhi, India under a DST-INSPIRE faculty scheme (DST/INSPIRE/04/2015/ 001003). We thank Prof. M. Sasidharan, SRM University for providing laboratory facilities.

greater than that of the starting azirines, and vice versa. Based on our optimization studies, we believe that TEA is not only acting as a base in generating copper acetylide I but also as a ligand in accelerating the copper-catalyzed ring-opening process to obtain higher concentrations of these key intermediates II and III. To gain more insight into the mechanism, we performed density functional theory calculations to study the role of TEA in the reaction between azirine and copper acetylide. As expected, the energy barrier for the reaction was ∼4 kcal/mol lower in the presence of TEA (SI, Figure S2), which clearly explains the role of TEA in the ring-opening process to access the intermediates at high concentrations. When the concentrations of II and IV are critically high, IV can readily undergo a copper-assisted hydroalkylation with II to produce intermediate V. Subsequently, spontaneous cyclization of intermediate V would provide an aminal VI, which would then eliminate ammonia and undergo tautomerization to yield product 3. As per our interest and expertise in exploring nanoparticles/ small molecules for biomedical applications,18 we evaluated the in vitro cytotoxicity of selected products (3a, 3b, and 3h) against oral cancer KB cell lines (KERATIN-forming tumor cells) using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (SI, Figure S4). The half maximal inhibitory concentration (IC50) values were determined to be 62.32, 59.28, and 53.98 μM for the samples 3a, 3b, and 3h. In summary, we have discovered and developed the interesting reactivity of yne-enamine and skipped-yne-imine intermediates generated in situ from the copper-catalyzed ring-expansion reaction of azirines and alkynes for the synthesis of highly substituted 3-alkynylpyridines, with potent anticancerous activity against oral cancerous cells. This transformation features inexpensive base-metal catalysts, proceeds at room temperature, is operationally simple, and generates high-valued products. In addition, the reaction is certainly scalable, and the products thus obtained can be easily derivatized further to more functional pyridines. Novel reactions of these unique intermediates and investigation of alkynylpyridine derivatives for biological activities are being explored in our laboratory.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01090. Experimental procedures and characterization of all new compounds, including 1H, and 13C NMR spectra (PDF) Accession Codes

CCDC 1570536 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected]. ORCID

Kayambu Namitharan: 0000-0002-4283-1895 Notes

The authors declare no competing financial interest. D

DOI: 10.1021/acs.orglett.8b01090 Org. Lett. XXXX, XXX, XXX−XXX