Copper-Mediated Aerobic Oxidative Trifluoromethylation of Terminal Alkynes
with Me 3SiCF 3
Lingling Chu †and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry,Shanghai Institute of Organic Chemistry,Chine Academy of Sciences,345Lingling Lu,Shanghai 200032,China and College of Chemistry,Chemical Engineering and
Biotechnology,Donghua Uni V ersity,2999North Renmin Lu,Shanghai 201620,China
Received March 15,2010;E-mail:flq@mail.
Trifluoromethylated compounds are of particular interest in the fields of polymers,agrochemicals,and pharmaceuticals due to the unique characteristics of the trifluoromethyl group (-CF 3),such as high electronegativity,electron density,steric hindrance,and hydrophobicity.1Hence,it has been of great synthetic interest to develop an efficient method for incorporation of CF 3into organic structures.2The cross-coupling reactions between CuCF 3and electrophiles,such as aromatic halides,3and nucleophilic additions of CF 3-to carbonyls 4or imines 5provide a number of powerful methods to access the valuable compounds.However,to the best of our knowledge,no example relating direct cross-coupling of CuCF 3with nucleophiles has ever been reported so far,albeit this alternative strategy may open up a new viewpoint to prepare trifluoromethylated compounds.Recently,metal-catalyzed oxidative coupling reactions via functionalization of C -H bonds have received a great deal of interest and attention due to their atom and step economy.6Among the impressive rearch,significant progress has also been made in the arena of metal-catalyzed oxidative cross-coupling of terminal alkynes with nucleophiles,7which inspired us to hypothesize that the direct cross-coupling of terminal alkynes with CuCF 3may be possible (Scheme 1).
On the other hand,as versatile building blocks,trifluoromethy-lated acetylenes have found widespread u in medicinal,agro-chemical,and material science.8Usually,they can be prepared by Pd(0)catalyzed cross-coupling reactions of trifluoro-propynyl metal reagents with aryl iodides or dehalogenation of trifluoromethyl-ethenes.9Electrophilic trifluoromethylation of alkynyl metal re-agents have also been reported.10However,this “prefunctional-ization”process suffers from tedious procedures and great caution for preparation of alkynyl metal reagents or using toxic substrates,thus the formation of alkynyl -CF 3bonds remains an elusive goal.Herein,we described the first example of a copper-mediated protocol for C sp -C sp 3oxidative trifluoromethylation of terminal alkynes with nucleophilic (trifluoromethyl)trimethylsilane (Ruppert -Prakash re-agent,Me 3SiCF 3)(eq 1).11This reaction reprents a straightforward
and functional group compatible approach to a broad range of trifluoromethylated acetylenes in moderate to good yields.
To test our hypothesis,initially,phenylacetylene 1a was chon as a model substrate for direct trifluoromethylation.When a mixture of 1a ,Me 3SiCF 3(1.5equiv),KF (1.5equiv),and CuI (1.0equiv)in DMF was heated at 100°C under air atmosphere,a diyne byproduct 3a was formed in 98%yield instead of our desired product 2a (Table 1,entry 1).We ascribed that this negative result is presumably becau the formation of Cu(alkynyl)(trifluoromethyl)complex C via path I or path II was inhibited by the competitive formation of bis-alkynyl-Cu complex D which will produce the undesired diyne byproduct (Scheme 1).Thus,we assumed that using a pregenerated CuCF 3to avoid the formation of complex B might be possible to drive the reaction via path II to furnish 2a .
As expected,when 1a was added by using a syringe pump over a period of 4h to CuCF 33a -h generated in situ by mixing Me 3SiCF 3,KF,and CuI in DMF under air atmosphere,the desired product 2a was formed in 16%yield,but the diyne 3a was still the major product (78%yield)(entry 2).With this preliminary result in hand,the improvement of the reaction efficiency was conducted by screening of the diamine ligands as additive.To our delight,the yield of 2a was improved to 51%and the byproduct 3a was reduced to 43%in the prence of 1,10-phenanthroline (phen)(entries 3-5).The beneficial effects of phen included stabilizing the reactive Cu -CF 3by chelation 3h and increasing the electron density on the copper center by coordination and thus promoting the formation of Cu(II)
12or Cu(III)13complex C ,which then undergoes reductive elimination to deliver 2a (Scheme 1).However,the mechanism of the formation of Cu(II)(or Cu(III))complex from E (Scheme 1)was not clear at the moment.The 19F NMR of the reaction mixture showed that Me 3SiCF 3was fully consumed,and it indicated the decomposition of Me 3SiCF 3took place under the reaction conditions,so the amount of Me 3SiCF 3was incread to 5equiv and we were plead to find that the yield of 2a was enhanced to 93%(entry 6).Other Cu(I)salts were less effective than CuI (entries 7-9).The screening of solvents showed that DMF was the optimal solvent (entries 10-11).When the loading of CuI was reduced to 0.5equiv,the yield of 2a dramatically dropped to 43%(entry 12).Surprisingly,when air was replaced with O 2,the reaction was completely inhibited and only 3a was generated (entry 13).We surmid that the reactive CuCF 3was quenched by the high concentration of oxygen.3a
The scope with respect to terminal alkynes is prented in Table 2.Aromatic alkynes (1a -1p )as well as aliphatic alkynes (1q -1r )afforded the corresponding trifluoromethylated products in moderate to good yields.Both electron-rich (1a -1b ,1e ,1j ,1p )and electron-†Shanghai Institute of Organic Chemistry.‡
Donghua University.
Scheme 1.Plausible Reaction Pathways for
梦见打架
Trifluoromethylation
10.1021/ja102175w XXXX American Chemical Society
J.AM.CHEM.SOC.XXXX ,xxx ,000
9
A
deficient aryl alkynes(1g-1i,1k-1l)were effective.A variety of functionalities,such as alkoxyl,amino,ester,and nitro groups were tolerated under the reaction conditions(1b,1e,1j-1l,1p,1r). Importantly,both chloro-and bromo-containing aryl alkynes were effective and further trifluoromethylated products were not obrved while aryl chlorides and bromides are reactive coupling partners in Cu-mediatedfluoro-alkyl cross-coupling reactions(1h-1i).3a-h The heterocyclic alkynes were also suitable in this reaction (1m-1n).It is particularly noteworthy that the reactions can be scaled up efficiently.2a,2b,and2m were successfully prepared on10mmol scales and the isolated yields after distillation were moderate,indicating the good reliability of the process.
In conclusion,we have developed an efficient copper-mediated trifluoromethylation of terminal alkynes with a nucleophilic tri-fluoromethylating reagent(Me3SiCF3).This reaction provides a general,straightforward,and practically uful method to prepare trifluoromethylated acetylenes.
Acknowledgment.National Natural Science Foundation of China(20832008)is gratefully acknowledged for funding this work.
Supporting Information Available:Detailed experimental proce-dures and spectral data for all new compounds are provided.This material is available free of charge via the Internet at References
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JA102175W
Table1.Initial Studies for Copper-Mediated Trifluoromethylation of
Terminal Alkynes a
entry CuX(equiv)ligand(equiv)solvent
%yield
2a(3a)b
沙漠怎么画
1c,d CuI(1.0)/DMF0(98)
2d CuI(1.0)/DMF16(78)
3d CuI(1.0)TMEDA(1.0)DMF8(71)
4d CuI(1.0)Bipy(1.0)DMF25(69)
5d CuI(1.0)phen(1.0)DMF51(43)
6CuI(1.0)phen(1.0)DMF93(2)
7CuCl(1.0)phen(1.0)DMF77(16)
8CuBr(1.0)phen(1.0)DMF65(23)
9CuCN(1.0)phen(1.0)DMF49(44)
10CuI(1.0)phen(1.0)Toluene24(54)
11CuI(1.0)phen(1.0)CH3CN35(49)
12CuI(0.5)phen(0.5)DMF43(49)
13e CuI(1.0)phen(1.0)DMF<5(92)
a Reaction conditions:1a(0.2mmol),Me3SiCF3(1.0mmol),KF(1.0
mmol),air(1atm),solvent(2mL),100°C;1a was added to the
reaction mixture over a4h period by using a syringe pump.b2a:yield
was determined by19F NMR using benzotrifluoride as an internal
standard.3a:yield was determined by GC.c1a was added in a single
aliquot.d1.5equiv of Me3SiCF3.e Reaction was performed under O2
atmosphere.phen)1,10-phenanthroline,TMEDA)N,N,N′,N′-tetra-
三角函数的定义域methylethylenediamine,Bipy)2,2′-bipyridine.
Table2.CuI-Mediated Trifluoromethylation of Terminal Alkynes a
a Reactions were conducted on0.2mmol scale under the reaction
conditions of entry6in Table1;Isolated yield.b Isolated yield after
distillation on10mmol scale.c27%of1j remained.
B J.AM.CHEM.,NO.xx,XXXX
C O M M U N I C A T I O N S
