Palladium-Catalyzed Three-Component Reaction: A Novel Method for

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

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Palladium-Catalyzed Three-Component Reaction: A Novel Method for the Synthesis of N‑Acyl Propiolamides Yan He,†,§ Yingchun Wang,‡,§ Xinping Liang,† Bin Huang,† Hengshan Wang,*,† and Ying-Ming Pan*,† †

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State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China ‡ College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, People’s Republic of China S Supporting Information *

ABSTRACT: Palladium-catalyzed three-component reactions between terminal alkynes, isonitriles, and sodium carboxylates have been developed. This novel and operationally simple methodology provides an alternative for the synthesis of N-acyl propiolamide derivatives under mild conditions using isonitriles as the amine source and sodium carboxylates as the oxygen and acyl source.

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chemical diversity in recent years.8 Inspired by this perspective, we have recently been interested in the application of isonitriles as a three- or two-atom unit for various types of multicomponent reactions to prepare nitrogen-containing compounds.9 Herein, we present a Pd-catalyzed threecomponent reaction between terminal alkynes, isonitriles, and sodium carboxylates for the synthesis of N-acyl propiolamide derivatives. This three-component reaction employs isonitriles as the amine source and sodium carboxylates as the oxygen and acyl source. To the best of our knowledge, such a construction of N-acyl propiolamides from simple, easily available terminal alkynes, isonitriles, and sodium carboxylates has not been reported, and it offers an attractive alternative method for the synthesis of many propiolamide derivatives. We began the N-acyl propiolamide synthesis using phenylacetylene (1a), benzyl isocyanide (2a), and sodium acetate (3a) as model substrates. After a series of experiments, the optimized reaction conditions for the formation of N-acyl propiolamide 4a were obtained when a mixture of 1a, 2a, and 3a (1:2.5:2 mol ratio) was treated with 20 mol % Pd(dppf)Cl2 in CH3CN at 60 °C for 2 h under air, whereby N-acyl propiolamide 4a was obtained in 85% isolated yield (Table 1, entry 1). No conversion was observed in the absence of any

ropiolamides are a highly versatile class of intermediates for the synthesis of heterocycles1 and biologically relevant molecules.2 To date, extensive studies have generated a number of approaches for the synthesis of propiolamides, as follows: (a) Pd/Cu-catalyzed cross-coupling reaction of alkynes with carbamoyl chlorides;3 (b) aminocarbonylation of alkynes or arylpropiolic acid with amines and CO gas;4 (c) cross dehydrogenative coupling of terminal alkynes or alkynyl acid with formamides;5 (d) aminocarbonylation of alkynes or bromoalkynes with amines using metal carbonyls as the carbonyl source.6 Despite the utility of such processes, some disadvantages still remain: (a) usage of stoichiometric amounts of catalysts and oxidants; (b) utilization of highly toxic, flammable, and explosive CO gas as the carbonyl source; (c) requirement of special pressure reaction setups and high temperature; and (d) moreover, the fact that many reported processes are limited to preparation of N-alkyl/aryl propiolamides without additional functionalities. In the interest of atom economy and green chemistry, new approaches to propiolamides from readily available starting materials, in addition to generating minimal waste, are highly desirable. Multicomponent reactions (MCRs) are one of the most ideal processes in organic synthesis from an atom- and stepeconomical point of view, which can allow for the straightforward and selective construction of complex structures in a one-pot manner from simple precursors.7 Among them, the Pd-catalyzed isonitriles-based multicomponent synthesis has played a pivotal role in the generation of © XXXX American Chemical Society

Received: September 25, 2018

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DOI: 10.1021/acs.orglett.8b03068 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of Reaction Conditions for N-Acyl Propiolamide 4aa

entry

catalyst

solvent

temperature

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Pd(dppf)Cl2 none Pd(PPh3)4 Pd(OAc)2 PdCl2 PdO Pd(OH)2 Pd(CF3COO)2 Cu(OAc)2 In(OTf)3 [Rh(COD)Cl]2 Ce(OTf)3 FeCl3 Pd(dppf)Cl2 Pd(dppf)Cl2 Pd(dppf)Cl2 Pd(dppf)Cl2 Pd(dppf)Cl2 Pd(dppf)Cl2 Pd(dppf)Cl2

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMSO DMF toluene DCE 1,4-dioxane CH3CN CH3CN

60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 60 °C 25 °C 100 °C

85 0 20 40 49 15 23 43 0 0 0 0 0 50 34 25 30 50 35 82

Table 2. Substrate Scope for the Synthesis of N-Acyl Propiolamide Derivatives 4a,b

a

Reaction conditions: 1a (0.3 mmol), 2a (0.75 mmol), 3a (0.6 mmol), catalyst (20 mol %) in solvent (2 mL) at 60 °C for 2 h under air. bIsolated yield of pure product based on 1a.

catalyst (Table 1, entry 2). Various palladium catalysts were examined, and Pd(dppf)Cl2 was found to be the most effective catalyst (Table 1, entry 1 vs entries 3−8). Other common metal catalysts, such as Cu(OAc)2, In(OTf)3, [Rh(COD)Cl]2, Ce(OTf)3, or FeCl3, were not productive for this conversion (Table 1, entries 9−13). In the solvent screening, CH3CN provided the highest yield among all tested (Table 1, entry 1 vs entries 14−18). When the reaction was performed at 25 °C, the product yield decreased significantly to 35% (Table 1, entry 19), while an increase in the reaction temperature had no significant effect on the yield (Table 1, entry 20). The scope of the reaction was examined using the optimized experimental conditions (Table 2). The formation of N-acyl propiolamides 4 occurred in very high yields for substituted aromatic terminal alkynes. The substitution on the benzene ring had no influence on the outcome of the reaction, as phenylacetylene substituted with neutral (4b−f), electrondonating (4g−i), or electron-withdrawing groups (4j−l) provided similar results. Notably, several sensitive functional groups such as methoxy (4g), amino (4h), and hydroxyl (4i) were unaffected under the present reaction conditions. Naphthyl-substituted alkyne afforded 4m in 81% yield. Heteroaryl-substituted alkynes were also tolerated in this transformation, generating the corresponding N-acyl propiolamides 4o and 4p in 76% and 78% isolated yields, respectively. Furthermore, the aliphatic terminal alkyne could be smoothly transformed into the corresponding product in 74% yield (4q); however, other aliphatic terminal alkynes, such as prop-1-yne, 3-chloroprop-1-yne, oct-1-yne, and ethynylcyclohexane, failed to generate the desired products.

a

Reaction conditions for 4a−4q: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol), Pd(dppf)Cl2 (20 mol %) in CH3CN (2 mL) at 60 °C for 2 h under air. bReaction conditions for 4u: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol), Pd(dppf)Cl2 (20 mol %), Cu(OAc)2 (20 mol %) in CH3CN (2 mL) at 60 °C for 2 h under air. cIsolated yield of pure product based on 1.

Figure 1. X-ray crystal structure of N-acyl propiolamide 4s (CCDC 1560346).

As for the sodium salt substrates, obviously, the nature of the substituent (R3 group) exhibited little influence on the reactivity of the substrate, and the desired N-acyl propiolamide products were produced in high yields (4r and 4s). The structure of the product 4s was unambiguously confirmed by B

DOI: 10.1021/acs.orglett.8b03068 Org. Lett. XXXX, XXX, XXX−XXX

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N-acyl propiolamide product was not originated from H2O or O2. On the basis of the above results, a proposed mechanism is listed in Scheme 2. The sodium carboxylates (R3COONa) presumably react first with Pd(II) to afford intermediate A. The alkyne-complexed Pd species B is then formed. Subsequently, the formed intermediate B reacts with isocyanide to give intermediate C via isocyanide insertion, which undergoes reductive elimination to form D while the resultant Pd(0) species is reoxidized to Pd(II) by molecular oxygen (from air).11 Finally, intermediate D undergoes cyclization and isomerization to give N-acyl propiolamides 4. In summary, a convenient and efficient three-component reaction between terminal alkynes, isonitriles, and sodium carboxylates has been developed for the synthesis of N-acyl propiolamide derivatives under mild conditions. The use of sodium carboxylates as the oxygen and acyl source, easily available starting materials, and an experimentally convenient catalytic process are the added advantages of the present protocol. Further investigations on the synthetic applications of this reaction are ongoing in our laboratory.

Scheme 1. Control Experiments

Scheme 2. Proposed Mechanism for the Formation of NAcyl Propiolamides

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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.8b03068. Spectral data for all new compounds (1H NMR, NMR, HRMS) (PDF)

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C

Accession Codes

CCDC 1560346 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 [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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X-ray crystallography (Figure 1). Finally, different isocyanides such as 2,6-dimethylphenyl isocyanide, 4-methoxyphenyl isocyanide, 2-chloro-6-methylphenyl isocyanide, 4-fluorophenyl isocyanide, 2-naphthyl isocyanide, ethyl isocyanoacetate, ptoluenesulfonylmethyl isocyanide, cyclohexyl isocyanide, and tert-butyl isocyanide were investigated, and only the 2,6dimethylphenyl isocyanide can be smoothly transformed, affording the desired product 4t in 72% yield. Interestingly, when the reaction of 4-methoxyphenyl isocyanide was carried out under the same conditions as previously used, no conversion was observed. By adding 20 mol % Cu(OAc)2 to the reaction system, the desired N-acyl propiolamide 4u was obtained in 71% yield after 2 h. We guess that the addition of Cu(OAc)2 oxidant instead of O2 could improve the activity of the Pd catalyst.9,10 Some control experiments were carried out in order to explore the possible reaction pathway. The reaction of 1a, 2a, and 3a in the presence of 20 mol % Pd(dppf)Cl2 in ultradry CH3CN under N2 only generated trace amounts of 4a (Scheme 1, eq 1). However, no 18O-labeled product [18O]4a was detected in the presence of H218O or 18O2 under the standard conditions (Scheme 1, eqs 2 and 3; the 18O was determined by GCMS), indicating that the oxygen atom of the

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hengshan Wang: 0000-0001-6474-8323 Ying-Ming Pan: 0000-0002-3625-7647 Author Contributions §

Y.H. and Y.W. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank the National Natural Science Foundation of China (21362002, 81260472, 81760626 and 21762017), Guangxi Natural Science Foundation of China (2016GXNSFEA380001 and 2016GXNSFGA380005), Ministry of Education of China (IRT_16R15), Guangxi Funds for Distinguished Experts and Bagui Scholar Program of Guangxi for financial support. C

DOI: 10.1021/acs.orglett.8b03068 Org. Lett. XXXX, XXX, XXX−XXX

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03068 Org. Lett. XXXX, XXX, XXX−XXX