Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper

Letter pubs.acs.org/OrgLett

Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper Catalyzed Oxidative Cyclization and Ketonization Tzuen-Yang Ye,† Manikandan Selvaraju,† and Chung-Ming Sun*,†,‡ †

Department of Applied Chemistry, National Chiao-Tung University, 1001, Ta-Hseuh Road, Hsinchu 300-10, Taiwan Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan First Road, Kaohsiung 807-08, Taiwan

‡

S Supporting Information *

ABSTRACT: A three-component cascade reaction of 2aminobenzimidazole, aldehyde, and terminal alkyne has been explored for an efficient synthesis of benzimidazole-linked tetrasubstituted pyrroles. The reaction sequence involves the formation of propargylamine, insertion of a terminal alkyne, and a ring opening reaction followed by an intramolecular carbonylative cyclization under aerobic conditions. It represents a novel strategy to the construction of CN, CC, CO bonds and a new five-membered 2-ketopyrrole ring. In this process, the reaction conditions are crucial and an attempt to elucidate the novel reaction pathway is well supported by X-ray crystallography.

D

The conventional methods for the construction of a pyrrole ring containing carbonyl group include the Hantzsch reaction,8 the Paal−Knorr synthesis,9 and various cycloaddition reactions.10 In addition, many transition-metal-catalyzed reactions to deliver these sacffolds were also reported.11 Despite these significant achievements, development of general and efficient strategies for the synthesis of pyrroles containing a carbonyl group from simple and readily available precursors are of great interest. Recently, a transition-metal-promoted three-component coupling reaction of amine, aldehyde, and alkyne, commonly called A3-coupling, has emerged as a powerful tool toward the synthesis of propargylamines in a one-pot fashion.12 Propargylamine is a versatile building block to synthesize various nitrogen-containing compounds by concomitant electrophilic cycloisomerization (exo/endo) reaction, and several modifications of this method have developed according to the same strategy.13 Recently, we demonstrated an efficient synthesis of benzoimidazo[1,2-a]imidazolone through oxidative 5-exo-dig cycloisomerization of 2-aminobenzimidazole, aldehyde, and terminal alkyne under aerobic conditions (Scheme 1).14 However, in the current work, a reaction of 2-aminobenzimidazole, aldehyde, and 2 equiv of terminal alkynes in a stepwise manner delivered different compound-benzimidazole linked 2keto pyrroles. We reasoned that, under an inert atmosphere (N2), the in situ formed propargylic amine first underwent regioselective 6-endo-dig cyclization to benzimidazo[1,2-a]pyrimidine 5 which acts as a potential intermediate.15 Subsequently, in the presence of oxygen gas, the benzimidazo[1,2-a]pyrimidine 5 performed an alkyne insertion and ring opening reaction followed by oxidative ketonization to give bisheterocycle 7. This new class of compound cannot be obtained

iversified and highly functionalized nitrogen-containing heterocycles are common structural units in many natural products and synthetic drugs. They have tremendous applications in drug discovery and functional materials.1 In particular, benzimidazoles are found in many synthetic drugs such as Omeprazole, a proton pump inhibitor, and Veliparib (ABT-888), a PARP inhibitor (Figure 1).2 On the other hand, pyrrole

Figure 1. Biological active compounds and commercial available medicines with benzimidazole or 2-ketopyrrole scaffolds.

containing a C2 carbonyl (keto or formyl) group is a prevalent structure in many biological active scaffolds.3 For example, Zomepirac is an effective nonsteroidal anti-inflammatory drug and Atorvastatin (Lipitor) is a primary cholesterol-lowering agent to treat dyslipidemia (Figure 1).4,5 Moreover, 2-ketopyrrole acts as a key building block for the total synthesis of various natural products and polyheterocycles.6 In recent years, compounds composed of two or more prestigious scaffolds exhibit novel biological profiles in drug discovery, since numerous bis-heterocycles have been identified as lead compounds.7 The conglomeration of these two different heterocycles in a single molecule may increase the structural diversity of the lead compounds and may demonstrate interesting biological properties. As a consequence, the reported unique chemical/pharmacological properties prompted us to develop a new method to synthesize a novel bis-heterocyclic system consisting of benzimidazole and pyrroles functionalities. © 2017 American Chemical Society

Received: April 23, 2017 Published: June 5, 2017 3103

DOI: 10.1021/acs.orglett.7b01224 Org. Lett. 2017, 19, 3103−3106

Letter

Organic Letters Scheme 1. Previous and Present Study on the Cascade Reaction of 2-Aminobenzimidazole, Aldehyde, and Terminal Alkynes under Aerobic Conditions

Table 1. Optimization of the Reaction Conditions for the Three-Component Coupling Reactiona

from previously known benzoimidazo[1,2-a]imidazolone by the same synthetic conditions. Additionally, it is worth noting that this reaction renders several distinguishing features: (i) a simple modification of well-known A3 coupling reaction used to obtain novel benzimidazole linked 2-ketopyrroles; (ii) the incorporation of an important carbonyl group on pyrrole is easily accomplished by molecular oxygen; (iii) development of ligand/additive-free reaction conditions under a copper/oxygen catalytic system. Hence, as part of our research interest aimed at the development of structurally important heterocycles,16 we report herein a novel cascade reaction of 2-aminobenzimidazole, aldehyde, and terminal alkynes through a copper catalyzed oxidative 6-endodig cyclization and ketonization, enabling facile access to benzimidazole linked 2-ketopyrroles. Initially, the Schiff base 4a is prepared from the reaction of methyl 2-amino-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5carboxylate 1a and benzaldeyde 2a in the presence of piperidine under toluene reflux for 4 h (see Supporting Information). Next, we examined a reaction of methyl (E)-2-(benzylideneamino)-1(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate 4a and 4-methyl phenyl acetylene 3a in the presence of copper iodide and DIPEA in toluene under oxygen atmosphere. The unexpected product 7a was obtained in 32% yield (Table 1, entry 1). Changing the copper catalysts to CuCl and CuBr did not give any satisfactory results (Table 1, entries 2−3). It is noted that Cu(II) and In(III) salts were not suitable in such a transformation (Table 1, entries 4−6). However, a poor yield was obtained when the reaction was performed in a cocatalytic system, CuI/ Cu(OAc)2 (Table 1, entry 7). Next, we employed various bases for this one-pot transformation (Table 1, entries 8−10). When the reaction was carried out with Cs2CO3, the product was obtained in 22% yield (entry 8). Altering the base to K2CO3 did not improve the reaction yield. To our delight, compound 7a was obtained in 72% yield with triethylamine in refluxing toluene (entry 10). However, the reaction yield was reduced to 36% under open-air conditions instead of molecular oxygen (entry 11). A systematic screening of various solvents was carried out in the same catalytic system (CuI/Et3N/O2). Lower yields were observed with solvents such as EtOH, DMF, and acetonitrile (Table 1, entries 12−14). No product 7a formation was observed when a coupling reaction was carried out under aqueous conditions (entry 15). Moreover, increasing the amount of catalyst to 50 mol % failed to improve the reaction yield (entry 16). With the optimized reaction conditions in hand (entry 10, Table 1), we proceeded to explore the reaction scope with an array of 2-aminobenzimidazoles, aldehydes, and terminal alkynes as shown in Scheme 2. A wide range of aromatic aldehydes 2 and alkynes 3 bearing electron-neutral, -withdrawing, or -donating groups were

entry

catalyst

base

solvent

yield (%)b

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

CuI CuCl CuBr Cu(OAc)2 CuCl2 InBr3 CuI/Cu(OAc)2 CuI CuI CuI CuI CuI CuI CuI CuI CuI

DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA DIPEA Cs2CO3 K2CO3 Et3N Et3N Et3N Et3N Et3N Et3N Et3N

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene EtOH DMF CH3CN H2O toluene

32 12 27 18 20 0 34 22 29 72 36 28 45 25 0 62

a Reaction conditions: 4a (0.3 mmol), 3a (0.6 mmol), catalyst (20 mol %), base (0.9 mmol), solvent (5 mL) under O2 at refluxing conditions for 12 h. bIsolated yield. cOpen air conditions. dThe reaction is conducted at 120 °C. eUsed 50 mol % of CuI.

employed as suitable coupling substrates with variously substituted 2-aminobenzimidazoles. Notably, heterocyclic aldehydes (entries 7k, 7q, 7t) were smoothly transformed to the corresponding products with good yields. Aliphatic aldehydes and alkynes were found to be nonfeasible substrates for this transformation. Next, we evaluated the reactivity of several substituted 2-aminobenzimidazoles bearing methyl ester, chloro, methoxy, and methyl groups which furnished the corresponding products in moderate yields. The structure of representative compound 7k was ascertained by X-ray single crystal analysis as represented in Figure 2. To gain mechanistic insights, various control experiments were carried out as shown in Scheme 3 (eqs 1−4). The reaction of 4a and phenylacetylene in the presence of CuI and triethylamine under an inert atmosphere delivered compound 5n in 80% yield (eq 1). When 5j was treated with phenylacetylene under an oxygen atmosphere, intermediate 6j was furnished in 82% yield together with 7j in 8% yield. The structure of the intermediate 6j is confirmed by single crystal X-ray analysis (Figure 3). When the above-mentioned reaction was carried out under a N2 atmosphere, instead of an O2 atmosphere, no products (6 or 7) were formed (eq 3a). Furthermore, when the same reaction was carried out in the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO,1 equiv), the formation of 6 or 7 was completely inhibited (eq 3b) suggesting that radical intermediates might be involved in the reaction. Finally, the reaction of 6j under optimized reaction conditions yielded the final compound 7j in 85% yield. Hence, these experiments proved that benzimidazo[1,2-a]pyrimidine 5 and 4-alkynylated benzimidazo[1,2-a]pyrimidine 6 were the possible intermediates for the formation of benzimidazole-linked pyrrole 7. It is also implied that the oxygen atom in the product is originated from molecular oxygen. Although the actual reaction mechanism for the cascade 3104

DOI: 10.1021/acs.orglett.7b01224 Org. Lett. 2017, 19, 3103−3106

Letter

Organic Letters Scheme 2. Domino Synthesis of Benzimidazole Linked Pyrroles 7

Scheme 3. Control Experiments for a Mechanistic Study

Figure 3. ORTEP diagram of compound 6j.

Scheme 4. A Plausible Mechanism for the Possible Formation of 7

Figure 2. ORTEP diagram of compound 7k.

formation of 7 remains unclear at this stage, a possible mechanism is proposed in Scheme 4 on the basis of our experimental observation and several related literature reports.14,15,17 Initially under highly inert gas conditions, the imine 4 derived from 2-aminobenzimidazole 1 and aldehyde 2 reacts with terminal alkyne 3 in the presence of copper furnished propargylamine which undergoes intramolecular 6-endo-dig cyclization followed by demetalation to give imidazo[1,2-a]pyrimidine 5 (isolated). Then, a copper-phenylacetylide radical is generated from the second equivalent of alkyne in the presence of copper and molecular oxygen, which then is added to intermediate 5 to furnish intermediate 6 (isolated) via a likely radical pathway. The addition of TEMPO in a control experiment failed to afford

intermediate 6 or pyrrole product 7 is supporting the proposed radical process. Subsequently, oxidative addition of a copper− oxygen adduct with the intermediate 6 leads to homolytic C−N cleavage to generate the radical intermediate A, which undergoes a sequential O−O bond cleavage and ring closing reaction of B to deliver benzimidazole linked 2-ketopyrrole 7 and CuOH. The 3105

DOI: 10.1021/acs.orglett.7b01224 Org. Lett. 2017, 19, 3103−3106

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Organic Letters

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catalytic cycle is then regenerated with the formation of copper iodide from the reaction of CuOH with hydrogen iodide. In conclusion, we have discovered a copper-catalyzed tandem synthesis of benzimidazole-linked 2-ketopyrroles from readily available 2-aminobenzimidazole, aldehydes, and alkynes. The cascade process was proposed to involve regioselective 6-endo-dig cyclization to deliver benzimidazopyrimidine which underwent oxidative ketonization in the presence of copper and molecular oxygen through a cooperative catalytic system. The process opens a novel avenue toward the unprecedented formation of benzimidazole-linked pyrroles substituted with a carbonyl group. The mechanistic study shows that the carbonyl oxygen in the product is derived from dioxygen by a pathway that takes place via a peroxo−copper intermediate. Ongoing efforts in our laboratory are directed toward the establishment of the generality of this protocol on other heterocyclic systems.

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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.7b01224. Experimental details plus spectroscopic and other data for compounds (PDF) X-ray data for 6j (CIF) X-ray data for 7k (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chung-Ming Sun: 0000-0002-1804-1578 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Ministry of Science and Technology of Taiwan for the financial assistance. REFERENCES

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DOI: 10.1021/acs.orglett.7b01224 Org. Lett. 2017, 19, 3103−3106