Decarbonylative Coupling of α-Keto Acids and Ynamides for Synthesis

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

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Decarbonylative Coupling of α‑Keto Acids and Ynamides for Synthesis of β‑Keto Imides Renjie Chen,† Linwei Zeng,† Bo Huang,† Yangyong Shen,† and Sunliang Cui*,†,‡ †

Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China

‡

S Supporting Information *

ABSTRACT: A novel decarbonylative coupling of α-keto acids and ynamides with extrusion of CO for synthesis of β-keto imides is reported. This process features mild reaction conditions, a broad substrate scope, and high efficiency. An isotope-labeling reaction and GC analysis were conducted to elucidate a plausible reaction mechanism.

α-Keto acid is a versatile synthon in organic synthesis and is an important unit in biology, as it is involved in the Krebs citric acid cycle and in glycolysis.1,2 In the biological system, the NAD+ would drive the α-keto acid to a decarboxylative coupling to constitute acylation of CoA with release of CO2 (Scheme 1A). This process is part of the tricarboxylic acid

metabolic pathway. Meanwhile, the decarboxylative coupling of α-keto acid in organic synthesis has also received much attention. For example, Bode’s group reported a decarboxylative α-keto acid-hydroxylamine amide-forming ligation, and the mechanism was extensively explored (Scheme 1B).3 Additionally, the well-known Minisci reaction disclosed that the α-keto acid could undergo decarboxylative radical formation, upon treatment with an oxidant, and couples with heterocycles to constitute a formal acylation.4 In recent times, decarboxylative cross-coupling of α-keto acids and αoxocarboxylate has also been well investigated for the synthesis of ketones (Scheme 1D).5 Despite these advances in the decarboxylative coupling reactions, the decarbonylative coupling of α-keto acids received much less attention and remains a challenge.6 Ynamides are unique alkynes with carbon−carbon triple bonds attached to the nitrogen atom and exhibiting dual nucleophilic and electrophilic properties.7 Therefore, ynamides could serve as flexible reagents and several reactions involving ynamides have been reported by Hsung, Liu, Ye, Maulide, and other groups.8 Recently, Zhao established that ynamides could be used as racemization-free coupling reagents for amide and peptide synthesis.9 Meanwhile, our group reported that ynamides could also act as C2 building blocks in a multicomponent reaction toward the synthesis of β-amino imides.10 Recently, Zhu reported an annulation process between αketo acids and alkynes for the formal synthesis of γhydroxybutenolides11 Herein, we report a decarbonylative coupling of α-keto acids and ynamides for the synthesis of βketo imides (Scheme 1E). We commenced our study by investigating α-keto acid 1a and ynamide 2a. Inspired by the fact that the carboxylic acid could undergo metal-free hydroacyloxylation with ynamides,12 we initially investigated the reaction in CH2Cl2 at room

Scheme 1. Coupling of α-Keto Acids

Received: April 24, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01302 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Substrate Scopea

temperature without any additives, and the known αacyloxyenamide was isolated (Table 1, entry 1). At this stage, Table 1. Reaction Optimizationa

entry

catalyst (20 mol %)

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13b,c

none AgOTf Cu(OTf)2 Zn(OTf)2 Sc(OTf)3 AuCl3 FeCl3 BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O BF3−Et2O

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE toluene THF dioxane CH2Cl2

− 45 60 82 87 82 54 93 90 78 − − 93 (85)

a

Reaction conditions: A solution of 1a (0.2 mmol) and 2a (0.2 mmol) was stirred in solvent (2 mL) at room temperature for 1 h, and then catalyst (20 mol %) was added and kept for 10 min. Yields refer to isolated yields. b5 mol % catalyst was used. cThe yield in parentheses was the reaction yield with 1 mmol scale.

we hypothesized that the addition of a Lewis acid would enhance the activity of the keto-carbonyl group. Thus upon addition of 20 mol % AgOTf, a vigorous gas expulsion was observed and a new product 3a was detected (entry 2). The standard identification including 1H NMR, 13CNMR, and MS analysis showed that the product was a β-keto imide, indicating the occurrence of a decarbonylative coupling. This encouraged us to further optimize the reaction, and various Lewis acids were screened. The utilization of Cu(OTf)2, Zn(OTf)2, Sc(OTf)3, and AuCl3 could significantly improve the yield to 60%, 82%, 87%, and 82% respectively (entries 3−6), while the use of FeCl3 only gave a slight improvement of yield to 54% (entry 7). Gratifyingly, employing BF3−Et2O delivered the product in 93% yield (entry 8). A survey of the solvents revealed that DCE was optimal to give a comparable 90% yield (entry 9), and the use of toluene decreased the yield to 78% (entry 10). THF and dioxane were found to be inferior and mitigated the reactivity completely (entries 11−12). Moreover, when 5 mol % BF3−Et2O was used, the β-keto imide 3a could still be obtained in 93% yield (entry 13). With the optimized reaction conditions in hand, we explored the substrate scope. Both the α-keto acids and ynamides could be prepared easily. As shown in Scheme 2, various α-keto acids, including the aryl and alkyl substitution, participated in this decarbonylative coupling to deliver structurally diverse β-keto imides in good to excellent yields. The substitution in the aromatic ring of α-keto acids, regardless of the electrondonating or electron-withdrawing groups, was tolerated well in this process (3b−3g). The naphthyl and heterocyclic α-keto acids, such as furan, thiophene, pyrrole, and indole, also afforded the corresponding products. Furthermore, the structure of compound 3l was unambiguously confirmed by X-ray analysis (CCDC 1828913). Regarding the alkyl α-keto acids, the methyl, cyclopropyl, and 2-phenylethyl substituted α-

a

Reaction conditions: A solution of 1 (0.2 mmol) and 2 (0.2 mmol) was stirred CH2Cl2 (2 mL) at room temperature for 1 h, and then BF3−Et2O (5 mol %) was added and kept for 10 min. Isolated yields are shown. bSc(OTf)3 was used as catalyst.

keto acids could undergo the coupling process smoothly to give the products in good yields (3m−3o). On the other hand, a variety of ynamides, including functionalized internal ynamides and terminal ynamides, were subjected to the reaction. The aryl- and styryl-substituted ynamides produced the functionalized β-keto imides in good yields (3p−3r), while the alkylsubstituted ynamides furnished the products in excellent yields (3s and 3t). The terminal ynamides were also tolerated in the process with Sc(OTf)3 as catalyst to give the products in good yields (3u and 3v). Moreover, the N-substitution of ynamides B

DOI: 10.1021/acs.orglett.8b01302 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Furthermore, the IR analysis showed that the 18O remained in the carbonyl of the ketone. Moreover, a GC analysis for the reaction was also conducted and a thermal conductivity detector (TCD) was used. Initially, we conducted a GC-TCD analysis for pure CO and CO2 as the standard. Then, we set up our reaction and the reaction vessel was connected to a GC apparatus through a manual injection valve. Upon the mixing of BF3−Et2O and compound 7, vigorous gas was released and the retention time of the gas was consistent with the CO standard (for details, see Supporting Information). This confirmed that CO was indeed generated in the process. Based on these results, a plausible reaction mechanism is proposed in Scheme 5. Initially, the reaction of α-keto acid 1

was also tested, and the phenyl, furan-2-methyl, (R)-1phenyethyl, allyl, and ethynyl moieties were amenable to deliver the β-keto imides in good to excellent yields (3w−3a′). The (R)-1-phenyethyl substitution led to the newly formed quarternary carbon with a 3:2 diastereomeric ratio. Considering the wealth of β-keto imides in organic synthesis, this method provided a distinct and direct approach toward these compounds. Next, the β-keto imide 3p was subjected to cyclization with hydroxylamine and hydrazine. Treatment of 3p with hydroxylamine and hydrazine in ethanol at 70 °C furnished the cyclic isoxazol-5(2H)-one 4, and inseparable tautomeric mixture of 1H-pyrazol-5(4H)-one (5a) and 1H-pyrazol-3-ol (5b) respectively. When β-keto imide 3x was treated with Togni reagent in the presence of catalytic CuI in DMF at 60 °C, the trifluoromethyl substituted cyclic 2-pyrrolidinone 6 was generated in 57% yield (Scheme 3).

Scheme 5. Proposed Reaction Mechanism

Scheme 3. Synthetic Application

and ynamide 2 gives the electron-donating acyloxyenamide intermediate A. The keto carbonyl group was activated by BF3−Et2O to form the intermediate B and an intramolecular addition occurred to give intermediate C. Following elimination and fragmentation gave the β-keto imide product 3 with the release of CO, constituting the decarbonylative coupling process. In summary, a decabonylative coupling of α-keto acids and ynamides for the synthesis of β-keto imides has been developed. This process features mild reaction conditions, a broad substrate scope, and other valuable synthetic utility. An isotope labeling reaction and CO detection were conducted to elucidate a plausible reaction pathway. Moreover, this protocol offers a new dimension for decabonylative coupling of α-keto acids.

To gain an insight into the reaction mechanism, an isotopelabeling reaction was conducted (Scheme 4). The α-keto acid Scheme 4. Isotope-Labelling Reaction

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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.8b01302. Experimental procedures, characterization of the products (PDF)

1o was treated with ynamide 2a to deliver the αacyloxyenamide intermediate 7 in 92% yield, to which BF3− Et2O and H2O18 were added. The isolated product 3o was identified, and there was no 18O incorporation in 30. This suggested that H2O18 was not involved in this process, and the oxygen atom of imide should be original from the α-keto acid. On the other hand, when the 18O-1o was prepared and subjected to standard conditions, the α-acyloxyenamide intermediate and the β-keto imide were found 18O-labeled.

Accession Codes

CCDC 1828913 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. C

DOI: 10.1021/acs.orglett.8b01302 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Zhang, S.-S.; wang, H.; Li, Q. Org. Lett. 2017, 19, 6108. (o) GallardoDonaire, J.; Ernst, M.; Trapp, O.; Schaub, T. Adv. Synth. Catal. 2016, 358, 358. (9) Hu, L.; Xu, S.; Zhao, Z.; Yang, Y.; Peng, Z.; Yang, M.; Wang, C.; Zhao, J. J. Am. Chem. Soc. 2016, 138, 13135. (10) (a) Huang, B.; Zeng, L.; Shen, Y.; Cui, S. Angew. Chem., Int. Ed. 2017, 56, 4565. (b) Shen, Y.; Huang, B.; Zeng, L.; Cui, S. Org. Lett. 2017, 19, 4616. (11) Mao, W.; Zhu, C. Chem. Commun. 2016, 52, 5269. (12) Xu, S.; Liu, J.; Hu, D.; Bi, X. Green Chem. 2015, 17, 184.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sunliang Cui: 0000-0001-9407-5190 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (21472163). We thank Prof. Yong Wang in Department of Chemistry, Zhejiang University for kind help in GC-TCD analysis.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01302 Org. Lett. XXXX, XXX, XXX−XXX