Cu(I)-Catalyzed Three-Component Reaction of Diazo Compound with

Letter Cite This: Org. Lett. 2018, 20, 4843−4847

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Cu(I)-Catalyzed Three-Component Reaction of Diazo Compound with Terminal Alkyne and Nitrosobenzene for the Synthesis of Trifluoromethyl Dihydroisoxazoles Xinxin Lv,† Zhenghui Kang,† Dong Xing,*,† and Wenhao Hu*,†,‡ †

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Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China ‡ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China S Supporting Information *

ABSTRACT: A Cu(I)-catalyzed three-component reaction of terminal alkynes, trifluoromethyl diazo compounds, and nitrosoarenes was developed. With this method, a series of trifluoromethyl-substituted dihydroisoxazoles were effectively synthesized in high yields under mild reaction conditions. This transformation is proposed to proceed through an electrophilic trapping of the copper carbene species generated from terminal alkynes and diazo compounds by nitrosobenzenes.

M

(Scheme 1, eq 1, path a).8 In 2011, Fox and co-workers observed that the generated 3-alkynoate products could be

ulticomponent reactions (MCRs) are among the most powerful tools for the creation of chemical diversity and new chemical entities in organic synthesis.1 In the past few decades, the in situ trapping of active intermediates derived from metal carbenes has emerged as an efficient strategy for the development of different types of MCRs. In this context, our research group has developed a series of MCRs for the rapid construction of polyfunctional molecules via electrophilic trapping of metal carbene-derived ylides or zwitterionic intermediates.2 These types of MCRs, also reported by Che,3a Gong,3b Moody,3c and others,3d−f are characterized by the interception of corresponding reactive intermediates. On the other hand, the combination of alkynes with stable diazo compounds has been disclosed as an effective approach to access novel metal carbene intermediates under catalytic conditions. Recently, Ni and Montgomery reported a nickelcatalyzed [4 + 2 + 1]-cycloaddition via tandem vinyl nickel carbene formation and cyclization;4 Saá and co-workers developed a ruthenium-catalyzed cyclization from alkynes and TMSCHN2 via the vinyl ruthenium carbene intermediates.5 Wang and co-workers developed a series of threecomponent reactions by utilizing metal carbene migratory insertion as the key step.6 In view of the step-economic feature as well as the efficiency leading to heterocycles with structural complexity, the pursuit of new types of MCRs based on in situ trapping of active intermediates is highly sought after. Cu(I)-catalyzed coupling reaction of terminal alkynes with diazo compounds constitutes an efficient way for the construction of C−C bonds.7 In 2004, Fu and co-workers reported the first Cu(I)-catalyzed coupling reaction of terminal alkynes with diazoesters or diazoamides to yield 3-alkynoates © 2018 American Chemical Society

Scheme 1. Copper-Catalyzed Alkynes C−H Bond Insertion Reactions with Diazo Compounds

further isomerized into allenoate products in the presence of a base (Scheme 1, eq 1, path b).9 Afterward, a series of Cu(I)catalyzed coupling reactions between alkynes and different carbene precursors have been developed by Wang, Sun and others.10 Asymmetric versions of this transformation have also been realized.11 These coupling reactions may follow a Received: June 25, 2018 Published: July 27, 2018 4843

DOI: 10.1021/acs.orglett.8b01981 Org. Lett. 2018, 20, 4843−4847

Letter

Organic Letters

1, entries 5 and 6), and when Cu(MeCN)4BF4 was used, the desired product 4a was not observed at all (Table 1, entry 7). Other metal catalysts, such as Rh2(OAc)4 and RuCl2(pcymene)2, failed to give 4a and yielded nitrone 5 exclusively with poor efficiency (Table 1, entries 8 and 9). In the absence of CuI, 4a was not observed while nitrone 5 was obtained exclusively in 90% yield, indicating the indispensable role of CuI to this transformation (Table 1, entry 10). Finally, reducing the amount of 1a and 2a from 1.5 to 1.0 equiv added to 3a caused a decreased yield of 4a (Table 1, entry 11). When diazo esters or diazoacetophenones were used as the diazo sources, the corresponding cyclization products were not observed, indicating the unique feature of the trifluoromethyl substituent for this transformation.17 Attempts to achieve catalytic asymmetric control for this transformation by introducing chiral cocatalysts or chiral ligands were yet unsuccessful.17 With the optimized reaction conditions in hand, the scope of this three-component reaction was then investigated (Table 2).

common reaction pathway involving the alkynyl migratory insertion of copper carbene species A to form an alkyl copper intermediate B, which further undergoes reductive elimination to afford either alkynoate or allenoate products. As part of our continuous research efforts in developing new MCRs based on in situ trapping of an active intermediate, we envisioned that the alkyl copper intermediate B might be intercepted by a suitable electrophile and lead to a threecomponent product (Scheme 1, eq 1, path c).12,13 As this intermediate is liable to undergo easy protonation to give an allene or alkyne, the choice of a suitable electrophile that can undergo effective trapping would be crucial for this design. Therefore, we report our successful development of a Cu(I)catalyzed three-component reaction of trifluoromethyl diazo compounds, alkynes, and nitrosoarenes for the synthesis of 5(trifluoromethyl)-2,5-dihydroisoxazoles based on an active intermediate-trapping approach (Scheme 1, eq 2).14 Nitrosoarenes have served as both O- and N-based electrophiles in an array of transformations.15 Upon preliminary investigations, we found that the combination of phenylacetylene 1a, 2,2,2-trifluorodiazoethane 2a, and nitrosobenzene 3a in the presence of 10 mol % of CuI lead to the cyclized dihydroisoxazole product 4a in 28% yield, along with the formation of nitrone 5 in 19% yield and trifluoromethyl allene 6 in 2% yield (Table 1, entry 1).16 With this encouraging

Table 2. Substrate Scopea

Table 1. Catalyst Screening and Optimization of the Reaction Conditionsa

entry

cat.

solvent

4a, yield (%)b

5, yield (%)b

6, yield (%)b

1 2 3 4 5 6 7 8 9 10 11d

CuI CuI CuI CuI CuBr CuCl Cu(MeCN)4BF4 Rh2(OAc)4 RuCl2(p-cymene)2 − CuI

CH2Cl2 toluene THF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

28 6 30 92/90c 75 40 0 0 0 0 69

19 43 24 2 2 54 23 23 37 90/90c 2

2 0 4 5 7 5 0 0 0 0 0

entry

R1

R2

R3

4

4, yield (%)b

c

C6H5 3-BrC6H4 4-ClC6H4 4-BrC6H4 4-MeC6H4 4-OMeC6H4 H H H H H H H H 2-thiophene

H H H H H H 4-Ph 4-Br H H H H H H H

H H H H H H H H 2-CN 3-Me 4-Me 4-CO2Me 4-COMe 4-NO2 H

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o

88 73 87 69 94 96 84 54 76 94 88 88 91 47 73

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 a

1/2/3 = 1.5/1.5/1. bIsolated yield of 4. cConducted on a 2 mmol scale of 3a.

When different substituted phenylacetylenes were used, corresponding 5-(trifluoromethyl)-2,5-dihydroisoxazoles were obtained in good to excellent yields. Phenylacetylenes bearing electron-donating substituents showed superior reactivities compared to those bearing electron-withdrawing ones (Table 2, entries 2−6). The use of 4-phenyl substituted 1-phenyl2,2,2-trifluorodiazoethane as the diazo source afforded the desired 2,5-dihydroisoxazole product 4g in 84% yield (Table 2, entry 7). However, when a 4-bromo substituted diazo compound was used, the corresponding desired product 4h was obtained in only 54% yield (Table 2, entry 8). The scope of nitrosoarene was then examined. 2-Cyano-1-nitrosobenzene showed good reactivity, yielding the desired product 4i in 76% yield (Table 2, entry 9). Nitrosoarenes bearing electrondonating substituents generally exhibited higher reactivity, giving corresponding products in excellent yields (Table 2,

a

General conditions: nitrosobenzene 3a (0.1 mmol), 1a/2a/3a = 1.5/ 1.5/1. bDetermined by 19F NMR analysis using benzotrifluoride as the internal standard. cIsolated yield shown in parentheses. d1a/2a/3a = 1/1/1.

result, condition optimizations were conducted. Different solvents showed obvious effects on this transformation. While toluene and THF also gave poor yields of the desired three-component product 4a (Table 1, entries 2 and 3), the use of MeCN as the solvent was very effective, yielding 4a in 90% isolated yield along with the formation of both 5 and 6 in trace amounts (Table 1, entry 4). Compared with CuI, other copper(I) salts were less efficient: with CuBr and CuCl, the desired product 4a was obtained with moderate yields (Table 4844


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Organic Letters entries 10−13). However, when 4-nitro-1-nitrosobenzene was used, the desired product 4n was obtained in only 47% yield (Table 2, entry 14). 2-Ethynylthiophene underwent the cyclization smoothly to give the corresponding product 4o in 73% yield (Table 2, entry 15).18 Finally, the structure of 4n was confirmed by X-ray crystallographic analysis (Figure 1).19

Table 3. Reactions Starting from Copper Acetylide 8

entry

cat.

4a, yield (%)

1 2 3

none Cul Nal

no reaction 89 52

this transformation is most likely initiated from a copper carbene species rather than a copper acetylide. Interestingly, when 10 mol % of NaI was used as the catalyst, copper acetylide 8 could react with 2a and 3a to yield 4a in 52% yield (Table 3, entry 3). NaI may undergo cation exchange with 8 to release free copper salt, which decomposed 2a into copper carbene to initiate the three-component reaction. A deuterium-labeling experiment was performed by adding 10 equiv of D2O to the reaction system starting from 1f, 2a, and 3a. Upon completion of this reaction, the desired cyclization product d-4f was obtained with 85% deuterium incorporation (Scheme 3). Control experiments indicated that

Figure 1. X-ray crystal structure of 4n.

To gain some insights into the mechanism of this threecomponent transformation, several control experiments were conducted. First, nitrone 5, which had been observed as the major side product from 2a and nitrosobenzene 3a, was allowed to react with phenylacetylene 1a under standard reaction conditions.20 However, the desired cyclization product 4a was not observed (Scheme 2, eq 3), indicating

Scheme 3. Deuterium-Labeling Experiment

Scheme 2. Control Experiments

subjecting either 1f or the nondeuterium-incorporated cyclization 4f to standard reaction conditions gave no H/D exchange at all.17 These results suggested that a trace amount of H2O might be involved in this transformation, most likely acting as a proton shuttle to deliver the proton from the alkyne substrate to the cyclization product. On the basis of the above experiments and precedent reports, a plausible mechanistic pathway is present in Scheme 4. First, 2,2,2-trifluorodiazoethane 2a is catalyzed by Cu(I) to form a copper carbene species A, which further reacts with phenylacetylene 1a to form the copper acetylide species B. Next, migratory insertion of the alkynyl group of the intermediate B would form the propargyl intermediate C, which could produce allene product 6 by copper migration and protonation (path b). On the other hand, the propargyl intermediate C may react with nitosobenzene 3a to generate intermediate D, which then produces F by direct protonation. Intermediate F may further undergo cyclization to afford 4a under copper-catalyzed reaction conditions. Alternatively, intermediate D may undergo an intramolecular nucleophilic attack from the nitrogen atom to the triple bond to form an intermediate E, which then undergoes proton transfer to afford cyclization product 4a with simultaneous regeneration of the Cu(I) catalyst. In summary, we have developed a Cu(I)-catalyzed threecomponent reaction of terminal alkynes, trifluoromethyl diazo compounds, and nitrosoarenes. This transformation is proposed to proceed through an electrophilic trapping of the copper carbene species generated from terminal alkynes and diazo compounds by nitrosobenzenes. With this method under mild reaction conditions, a series of trifluoromethyl-substituted

that this transformation may not proceed through the formation of nitrone. As trifluoromethyl allene 6 had also been observed as the minor side product in this threecomponent reaction,10a,b,f a control experiment starting from 6 and nitrosobenzene 3a under standard reaction conditions was conducted. However, the desired product 4a was not observed at all (Scheme 2, eq 4). Therefore, a stepwise pathway involving the formation of trifluoromethyl allene 6 followed by cyclization with nitrosobenzene could be excluded. On the other hand, this three-component reaction may proceed through the formation of trifluoromethyl phenylacetylene 7 derived from 1a and 2a,10c,d even though it was not observed during the course of this three-component transformation. However, the control experiment starting from 721 and nitrobenzene 3a under standard reaction conditions also gave no desired product formation (Scheme 2, eq 5). To investigate whether the formation of a copper acetylide from 1a and CuI was involved in this transformation, the preformed copper acetylide 8 was used to react with 2a and 3a. However, no product formation was observed and all starting materials were retained (Table 3, entry 1). On the other hand, this reaction could be catalyzed with 10 mol % of CuI, yielding 4a in 89% yield (Table 3, entry 2). These results indicated that 4845


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Scheme 4. Proposed Mechanism of the Three-Component Reaction

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01981. Experimental procedures and full spectroscopic data for all new compounds (PDF) Accession Codes

CCDC 1582300 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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REFERENCES

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dihydroisoxazoles were synthesized in one single step with high efficiency.

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AUTHOR INFORMATION

Corresponding Authors

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

Dong Xing: 0000-0003-3718-4539 Wenhao Hu: 0000-0002-1461-3671 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the NSF of China (21332003, 21772043) is greatly acknowledged. We also acknowledge the financial support from the Guangdong Innovative and Entrepreneurial Research Team Program (No. 2016ZT06Y337) and Key Laboratory of Neutron Physics, China Academy of Engineering Physics (CAEP, 2015BB06). 4846


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Organic Letters react with benzaldehydes via carbonyl ylides formation; see: DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 1101. (14) For a Ru(II)-catalyzed three-component reaction of diazo compounds, alkynes, and nitrosoarenes to yield aziridines, see: Reddy, A. R.; Zhou, C.-Y.; Che, C.-M. Org. Lett. 2014, 16, 1048. (15) For selected reviews, see: (a) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131. (b) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514. (c) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595. (16) For selected examples by using 2,2,2-trifluorodiazoethane as the carbene source, see: (a) Brunner, J.; Senn, H.; Richards, F. M. J. Biol. Chem. 1980, 255, 3313. (b) Uehara, M.; Suematsu, H.; Yasutomi, Y.; Katsuki, T. J. Am. Chem. Soc. 2011, 133, 170. (c) Wang, X.; Xu, Y.; Deng, Y.; Zhou, Yu.; Feng, J.; Ji, G.; Zhang, Y.; Wang, J. Chem. - Eur. J. 2014, 20, 961. (d) Hyde, S.; Veliks, J.; Liégault, B.; Grassi, D.; Taillefer, M.; Gouverneur, V. Angew. Chem., Int. Ed. 2016, 55, 3785. (17) For details, see the Supporting Information. (18) Several other types of heteroaromatic substituted alkynes and nitrosobenzenes were also tested but showed poor reactivity. For details, see the Supporting Information. (19) See the Supporting Information for the X-ray structure of 4n (CCDC 1582300) containing the supplementary crystallographic data for this paper. (20) For an organocatalyzed three-component reaction of diazo compounds, nitrosobenzenes, and nitroalkenes likely through a nitrone formation, see: Wu, M.; He, W.; Liu, X.; Tan, B. Angew. Chem., Int. Ed. 2015, 54, 9409. (21) For the synthesis of trifluoromethyl phenylacetylene 7, see: (a) Ko, S.-J.; Lim, J.; Jeon, N.; Won, K.; Ha, D.-C.; Kim, B.; Lee, H. Tetrahedron: Asymmetry 2009, 20, 1109. (b) Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org. Lett. 2015, 17, 2474.

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Cu(I)-Catalyzed Three-Component Reaction of Diazo Compound with

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