Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Mediated Trifluoromethylation−Allylation of Arynes Xinkan Yang and Gavin Chit Tsui* Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR S Supporting Information *
ABSTRACT: An unprecedented three-component copper-mediated vicinal trifluoromethylation−allylation of arynes is described. A wide range of structurally diverse trifluoromethylated allylarenes can be quickly assembled in one step. The application of the method has been demonstrated in the expedient synthesis of the CF3-containing analogue of the antispasmodic drug papaverine. The new reactivity of the [CuCF3] reagent, which is generated from the inexpensive industrial byproduct fluoroform, is revealed with unique advantages.
F
one of which is a C−CF3 bond, via trifluoromethylation− allylation of arynes using a CuCF3 reagent (Scheme 1b). Arynes are versatile reactive intermediates which have been frequently employed as powerful tools for the rapid construction of multifunctionalized arenes.10 Despite the available records of transition-metal-catalyzed/-mediated multicomponent reactions using arynes (mainly Pd,10a Ag,10b and Cu11), their applications in trifluoromethylation have been rarely reported. The pioneering work from Hu’s group on silver-mediated trifluoromethylation−iodination of arynes to construct adjacent C−I and C−CF3 bonds onto arenes was the only example.12 We envisioned that a copper-mediated trifluoromethylation−functionalization of arynes could be developed on the basis of the readily available CuCF3 reagents5 and the rich chemistry of organocopper reactions for C−C bond formations.13 This hypothesis was tested in the three-component reaction using 2-(trimethylsilyl)phenyl triflate 1a as a benzyne precursor,14 allyl bromide 2a, and a suitable [CuCF3] reagent for the synthesis of trifluoromethylated allylbenzene 3aa (Table 1). The [CuCF3] A generated in situ from CuI/TMSCF3/ CsF2e,12a gave the desired product 3aa only in 10% yield (entry 1). Hartwig’s [(phen)CuCF 3 ] B 5 b and Grushin’s [(PPh3)3CuCF3] C and [(phen)(PPh3)CuCF3] D complexes5a did not afford the product (entries 2−4). Vicic’s NHC copper complex [(IPr)CuCF3] E5e provided the product in 38% yield (entry 5). Significantly higher yield (57%) was obtained from Grushin’s fluoroform-derived [CuCF3] (entry 6).15,16 Excess KF was commonly used to generate benzyne from precursor 1a (entries 1−4) in the preparation of [CuCF3] reagents E and F, triethylamine trihydrofluoride (Et3N·3HF) was added as a stabilizer which also conveniently served as a fluoride source for benzyne generation; therefore, no KF was needed (entries 5 and 6). By using HF−pyridine (Olah’s reagent) as a stabilizer in the fluoroform-derived [CuCF3], the yield was further increased
luorinated molecules continue to be of major interest for their applications in pharmaceuticals, agrochemicals, and functional materials.1 As a result, rapid development of efficient methods for the synthesis of organofluorine compounds can be witnessed to date.2 Trifluoromethylated arenes have drawn increasing attention owing to their roles as central building blocks in widely used pharmaceuticals and agrochemicals, including fluoxetine, bicalutamide, fipronil, trifluralin, and so on.3 Since the pioneering work by Swarts in 1892 for introducing the trifluoromethyl (CF3) group onto an aromatic ring,4 tremendous progress has been made in the synthesis of trifluoromethylated arenes. Modern methods largely rely on transition-metal-catalyzed/-mediated cross-coupling of prefunctionalized aryl species with CF3 sources.5−7 More advanced approaches involve the direct C−H trifluoromethylation via metal-catalyzed or radical processes.8,9 The copper-catalyzed/mediated cross-coupling of aryl halides,5a−e,q arylboronic acids/ esters,5f−n anilines or diazonium salts,5o and arylsilanes5p and C− H trifluoromethylation8a with nucleophilic or electrophilic trifluoromethylating reagents are among the most established methods for preparing trifluoromethylated arenes (Scheme 1a). However, these methods universally feature monofunctionalization of arenes with only one C−C bond-forming event (trifluoromethylation). In this paper, we report a novel vicinal difunctionalization of arenes with two C−C bond formations, Scheme 1. Copper-Mediated Synthesis of Trifluoromethylated Arenes
Received: January 9, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b00101 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Scope of Arynes 1.a
Table 1. Trifluoromethylation−Allylation of Benzyne with [CuCF3]a
entry
[CuCF3]
additive (equiv)
yieldb (%)
1 2 3 4 5 6 7 8
A B C D E F G G
KF (4.0) KF (4.0) KF (4.0) KF (4.0) none none none TBAF·3H2O (1.5)
10 0 0 0 38 57 63 76, 60c
a General conditions: 1a (0.1 mmol), 2a (0.3 mmol), [CuCF3] (0.2 mmol) in DMF (2 mL). bDetermined by 19F NMR analysis using benzotrifluoride as the internal standard. cIsolated yield.
(63%) due to the absence of Et3N which also could react with benzyne (entry 7). We observed the formation of allyl-CF3 product as a major competing side reaction between [CuCF3] and allyl bromide (along with various amounts of benzyne dimerization and oligomerization side products). Adding TBAF· 3H2O as a soluble fluoride source, which may accelerate the benzyne generation, significantly inhibited the formation of the allyl-CF3 byproduct and increased the yield of 3aa to 76% (entry 8). Other reaction parameters including allylic leaving group, concentration, temperature, and additives were screened and showed no further improvement (see the Supporting Information for full details). The scope of the aryne component was subsequently studied in the trifluoromethylation-allylation reaction using the fluoroform-derived [CuCF3] G (Table 2). Arynes containing an acetal, chloro, or silyl group were compatible (entries 3, 8, and 9). Electron-rich arynes were generally better yielding (entries 3 and 7), and the 3,4-difluoro-substituted aryne only gave 14% yield. Remarkably, products 3ca and 3ka were obtained as single regioisomers (entries 2 and 10). Other substrates afforded a mixture of regioisomeric products with varying ratios (entries 4− 9). A wide range of trifluoromethylated allylbenzenes 3 were generated by varying the allylic bromides 2 under the optimized conditions using aryne precursor 1d (Scheme 2). Arylsubstituted allylic bromides showed good reactivities, including those with eletron-donating and -withdrawing groups (3df, 3di, and 3dj). Even sensitive aryl chloride and bromide, which were known to undergo aromatic trifluoromethylation with [CuCF3],15b were tolerated (3dk and 3dl). Substituents were tolerated at the para-, meta-, and ortho-positions of the benzene ring, although the ortho-substituent gave a lower yield (3df-di). Alkyl-substituted allylic bromides were also demonstrated (3dm−do). The bromo- and ester-substituted substrates were useful for the synthesis of products containing vinyl bromide 3dp and α,β-unsaturated ester 3dq, which are susceptible to further functionalization via cross-coupling and conjugate addition, respectively. Cyclic allylic bromide was also compatible and
General conditions: 1 (0.4 mmol), 2a (3.0 equiv), fluoroform-derived [CuCF3] G (2.0 equiv), TBAF·3H2O (1.5 equiv) in DMF (0.05 M). b Isolated yield. cRatio was determined by 19F NMR analysis prior to isolation. d1.0 mmol scale reaction. a
afforded product 3dr containing the cyclohexene ring. Finally, crotyl and prenyl bromide gave a mixture of regioisomers favoring the linear products (3ds and 3dt). The utility of the reaction was demonstrated in the expedient synthesis of the trifluoromethylated analogue of papaverine, a non-narcotic antispasmodic drug (Scheme 3).17a The coppermediated trifluoromethylation−allylation between aryne substrate 1l and allylic bromide 2i constructed the key aryl−allyl and aryl−CF3 bonds. Subsequent oxidative cleavage of the alkene moiety gave the ketone intermediate 4, which was further converted into the O-acetyl oxime 5. By adopting a recently reported Rh-catalyzed C−H activation/annulation protocol,17b the isoquinoline ring of the final product 6 was furnished. The strategic positioning of a CF3 group in drug candidate is often important yet challenging,2 our method offered a simple approach to rapidly assemble complex fragments with no ambiguity of the CF3 group position. Such trifluoromethylated analogues could be useful in the structure−activity relationship (SAR) studies to further improve the drug properties. Additional studies were performed to gain mechanistic insights. Control experiment using aryne precursor 1d without allyl bromide revealed that the starting material was completely consumed and gave a trace amount of protonated aryl-CF3 product 7 and a mixture of CF3-containing dimer 7′ and trimer B
DOI: 10.1021/acs.orglett.8b00101 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Allylic Bromides 2a,b
the fluoroform-derived [CuCF3].16c To investigate the possibility of a radical mechanism, aryne 1m containing an allyl group was employed to react with allyl bromide 2a (eq 2). The reaction gave the expected bis-allylic products 3ma in high yield as a regioisomeric mixture without any cyclization products. Alternatively, allylic bromide 2u containing two alkene moieties was used to react with aryne 1d (eq 3). The expected product 3du was obtained, along with dimer product 8, again without any cyclization products. When radical scavengers were added to the reaction between 1d and 2a under standard conditions, yields were not affected significantly (71−80%, see the SI cf. 80% and Table 2, entry 3). These radical clock and quenching experiments seemed to rule out the radical mechanism. Based on these studies and known literature examples, we proposed the following plausible reaction pathway (Scheme 4). Scheme 4. Proposed Reaction Pathways
General conditions: 1d (0.4 mmol), 2 (3.0 equiv), fluoroform-derived [CuCF3] G (2.0 equiv), TBAF·3H2O (1.5 equiv) in DMF (0.05 M). b Isolated yield. cRatio was determined by 19F NMR analysis prior to isolation. a
Scheme 3. Synthesis of the Trifluoromethylated Analogue of Papaverine
Insertion of the Cu−CF3 bond to aryne A, which is generated from precursor 1 in situ, provides the key o-trifluoromethyl arylcopper species B. Similar types of insertion of metal−CF3 bond12a or copper−carbon bond11b,d−g to arynes have been reported. The control experiment (eq 1) also provided strong evidence for such insertion process because of the detectable CF3-containing products in the absence of allyl bromide. The arylcopper B gives rise to a Cu−π-allyl species C18 via oxidative addition with allyl bromide 2a.11f Final reductive elimination affords the corresponding trifluoromethylated allylarene 3. Overall, the vicinal trifluoromethylation−allylation is achieved. Two side reaction pathways could also take place, including the dimerization/oligomerization between B and another molecule of aryne A, or the trifluoromethylation of allyl bromide 2a with [CuCF3] to give allyl-CF3 product D. These side reactions were significantly inhibited under the optimized conditions. In conclusion, we have developed an unprecedented one-step protocol of copper-mediated trifluoromethylation−allylation of arynes. The corresponding trifluoromethylated allylarenes, which are versatile building blocks toward complex CF3containing natural product or drug analogues, can be synthesized with wide scope and good functional group tolerability. The reaction conditions are mild using easily accessible materials, and the ultimate CF3 source is the inexpensive industrial byproduct fluoroform. Further exploration of such types of arene vicinal difunctionalization for novel C−C bond formation is ongoing in our laboratory.
7″ products, determined by 19F NMR and GC−MS (eq 1). We have previously observed the involvement of radical species using
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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.8b00101. Experimental procedures and characterization data for all new compounds (PDF) C
DOI: 10.1021/acs.orglett.8b00101 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Gavin Chit Tsui: 0000-0003-4824-8745 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Research Grants Council of Hong Kong (CUHK 24301217) and the Chinese University of Hong Kong (the Faculty Strategic Fund for Research from the Faculty of Science and the Direct Grant for Research 4053199).
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DOI: 10.1021/acs.orglett.8b00101 Org. Lett. XXXX, XXX, XXX−XXX
