Syn-Fluoro- and -Oxy-trifluoromethylation of Arylacetylenes

Article abstract of DOI:10.1021/acs.orglett.7b03229

One-step concurrent fluoro-trifluoromethylation across the triple bond of arylacetylenes in a syn mode is enabled by the collaboration of (phen)Cu^III(CF₃)₃ and CsF that produces chemo-, regio-, and stereoselectively (Z)-α-fluoro-β-CF₃ styrenes. This method can be extended to achieve syn-oxy-trifluoromethylation and syn-aryl-trifluoromethylation of alkynes using phenoxides, alkoxides, or phenylboronic acid in place of CsF. It opens up new opportunities for preparing various functionalized trifluoromethylated Z-alkenes and demonstrates the potential of Cu(III)-CF₃ complexes in organic synthesis.

Full text of DOI:10.1021/acs.orglett.7b03229

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
syn-Fluoro- and -Oxy-trifluoromethylation of Arylacetylenes
Song-Lin Zhang,* Hai-Xing Wan, and Wen-Feng Bie
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi, Jiangsu 214122, China
S
* Supporting Information
ABSTRACT: One-step concurrent fluoro-trifluoromethylation across the triple bond
of arylacetylenes in a syn mode is enabled by the collaboration of (phen)CuIII(CF3)3
and CsF that produces chemo-, regio-, and stereoselectively (Z)-α-fluoro-β-CF3
styrenes. This method can be extended to achieve syn-oxy-trifluoromethylation and
syn-aryl-trifluoromethylation of alkynes using phenoxides, alkoxides, or phenylboronic
acid in place of CsF. It opens up new opportunities for preparing various
functionalized trifluoromethylated Z-alkenes and demonstrates the potential of
Cu(III)−CF3 complexes in organic synthesis.
Recently, direct one-step difunctionalization of alkynes
involving trifluoromethylation, such as iodo-, amino-, oxy-,
and aryl-trifluoromethylation of alkynes, has been developed
that enables access to a range of trifluoromethylated alkenes
(Scheme 1b).3 These reactions typically rely on the use of
preformed Togni’s or Umemoto’s reagents as the CF3 source
and sometimes require an additional photosensitizer under
irradiation conditions. Notably, anti-addition of CF3 and a
nucleophilic group (Nu−) across the triple bond of alkynes is
generally achieved to produce (E)-Nu-trifluoromethylated
olefins (Scheme 1b). As far as we know, selective one-step
syn-addition of CF3 and a Nu across alkyne triple bond has never
been documented. Moreover, the selectivity of the reported
methods remains unsatisfying because a mixture of regio- and
stereoisomers were often obtained. Finally, diverse sets of
reaction conditions were developed for different types of
nucleophiles. A general methodology is still lacking that can
accommodate several types of nucleophilic groups.
ifunctionalization of alkynes by the concurrent introduc-
tion of CF3 and another functional group represents one
D
attractive, step- and atom-economical method for the
construction of multiple functionalized trifluoromethylated
alkenes with widespread applications in pharmaceuticals,
agrochemicals, and materials science.1−5 This strategy shows
superior advantages to methods relying on cascade cross-
coupling of volatile polyhalogenated olefins with organometallic
reagents (such as organolithium, Grignard reagents, organo-
boron) or other nucleophiles (such as amines, carboxylates)
(Scheme 1a).6 It is also more attractive than stepwise methods
involving Ar−CC−CF3 preparation/nucleophilic addition
where separation and purification of Ar−CC−CF3 inter-
mediates is required that adds synthetic steps and reduces atom-
and step-efficiency of the methods (Scheme 1a).7
Scheme 1. Nu-trifluoromethylation across Triple Bond of
Herein, we report an efficient, one-step, regio- and stereo-
selective method for syn-fluoro- and -oxy-trifluoromethylation of
terminal arylalkynes (Scheme 1c). The key point to this reaction
is the use of a bench-stable phenCuIII(CF3)3 (1) as the highly
reactive CF3 source (phen denotes phenanthroline), in
combination with readily available fluoride, phenoxides, and
alkoxides (as well as a phenylboronic acid) as the nucleophilic
reagents. As far as we know, this method represents the first
general method for syn-Nu-trifluoromethylation of alkynes.
This study was inspired by our recent study on the isolation
and reactivity of several stable high-valent Cu(III) CF3
complexes (L)CuIII(CF3)3 and [(L)2CuI]+[CuIII(CF3)4]− (L: a
bidentate N,N or P,P ligand).8,9 In an attempt to broaden the
chemistry of the CuIII CF3 complexes, we set out to investigate
the reaction of phenCuIII(CF3)3 (1) with p-methoxyphenylace-
tylene (2a) (Table 1). When a strong base such as NaOtBu was
used, the reaction occurred cleanly (with the complete
Alkynes
Received: October 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03229
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Organic Letters
Letter
Next, various terminal alkynes were studied under the
optimized conditions to show the synthetic compatibility of
this method (Scheme 2). All of the arylacetylenes with either
Table 1. Optimization Study for Fluoro-trifluoromethylation
Reaction of Alkyne
a
a
Scheme 2. Scope of syn-Fluoro-trifluoromethylation
b
yield (%)
entry
additive
solvent
temp (°C)
3a
4a
99
1
2
3
4
5
6
NaOtBu
KF
DMF
DMF
DMF
DMF
DMF
toluene
100
100
0
44
81
0
29
trace
0
CsF
100
AgF
100
CsF
50 or rt
100
0
99
CsF
0
75
a
Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), additive (0.5
mmol), 4,4′-biphenyl (0.1 mmol, internal standard), and solvent (2
b
mL) stirred for 6 h under N2. Determined by 19F NMR spectroscopy
based on 2a.
disappearance of 19F NMR signals at −24.4 (septet) and −37.4
(quartet) ppm for phenCuIII(CF3)3),8a and a new 19F resonance at
ca. −50 ppm (singlet) was produced quantitatively (Table 1,
entry 1, and Figure S1). The product is assigned to be the Ar−
CC−CF3 (4a) (Table 1) arising from trifluoromethylation of
alkyne C−H bond promoted by a base.10
It is exciting to see that when fluoride salt (KF) was used in
place of basic NaOtBu, in addition to the −50 ppm resonance,
two new 19F NMR signals at ca. −56 (doublet) and −102
(quartet) ppm appeared with both coupling constants of 16.3
Hz (Figure S2). The signals at −56 and −102 ppm are in an
approximately 3:1 molar ratio with the signal at −56 ppm being
the major one. These data imply the generation of a new
product with vinylic CF3 and F. Fortunately, this product was
able to be isolated in pure form after workup and column
chromatography, and extensive efforts confirmed the new
product to be (Z)-(Ar)(F)CC(CF3)(H) (3a) (Table 1).11
Notably, the vinylic proton appearing at 5.57 ppm is
characteristic with a doublet of quartet splitting (coupling
constants of 33.9 and 7.5 Hz), indicating a vicinal trans-
configuration of H and F and a geminal position of H and CF3
on the double bond. Therefore, a formal one-step syn-addition
of F and CF3 across the triple bond is achieved. As far as we
know, there is no precedent for such reactivity of fluoro-
trifluoromethylation of alkynes in the literature. Most
importantly, this reaction occurs in a regio- and stereoexclusive
way, without the detectable formation of other potential regio-
or stereoisomers.11 The syn-addition mode of the reaction is
unprecedented and particularly significant because general anti-
addition across triple bond was accomplished as aforemen-
tioned.3
Further optimization of the reaction conditions show that
CsF performed better than KF, selectively giving 3a in 81% yield
(Table 1, entry 3, and Figure S3), while AgF gave no significant
yield of 3a or 4a (entry 4). Varying the solvent from DMF to
nonpolar toluene led to the selective formation of 4a instead
(entry 6). The temperature is also crucial to this reaction;
lowering the reaction temperature to 50 °C or room
temperature (rt) gave the selective formation of 4a, without
appreciable amounts of 3a detected (entry 5). Therefore, the
reaction conditions shown in entry 3 are found to be optimal for
this fluoro-trifluoromethylation reaction.
a
Both 19F NMR and isolated yields (in parentheses) are given if
b
c
d
available. KF was used instead. 18 h. C−H trifluoromethylation
product in 60% yield. 1 (0.2 mmol) was used. 10 h.
e
f
electron-donating or electron-withdrawing substituents are
good substrates, selectively giving (Z)-α-F-β-CF3 styrenes in
moderate to quantitative yields as determined by 19F NMR
spectroscopy. A broad range of functional groups can be
tolerated for this reaction, including alkyl, alkoxy, phenyl, chloro,
bromo, nitro, amino, acetyl, ester, and even aldehyde.
Substitution patterns with either meta- or para-substituents are
all compatible, showing no appreciable differences in reactivity.
However, a dramatic ortho-steric effect was observed for o-
chlorophenyl acetylene (2p) which gave the desired 3p in only
22% yield, while the major product was C−H trifluoromethy-
lation product (60% yield). Interestingly, benzene-1,3-bisacety-
lene can produce 3q from double syn-fluoro-trifluoromethyla-
tion of both alkynyl groups. Furthermore, naphthyl acetylene 2r
and heteroaryl acetylenes including 3-pyridyl and 2-thiophenyl
acetylenes (2s, 2t) are also good substrates, producing the
desired 3r, 3s, and 3t in 98%, 84%, and 42% yields. Notably, the
Z-products from syn-fluoro-trifluoromethylation were selectively
obtained in all cases, without appreciable amounts of other
regio- or stereoisomers. It shows complementary stereo-
selectivity to the general E-selectivity observed previously for
the Nu-trifluoromethylation of alkynes.3
As a further example showcasing the potential application of
this fluoro-trifluoromethylation reaction for large complex
molecule functionalization, a spirobifluorene 2u decorated
with four acetylene groups was subjected to reaction with 4
equiv of 1. Quadruple syn-fluoro-trifluoromethylation of 2u was
B
DOI: 10.1021/acs.orglett.7b03229
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Letter
achieved to produce 3u in a good yield of 55% (isolated in 40%
Scheme 5. syn-Oxy-trifluoromethylation of 2a Using Various
Phenoxides and Alkoxides
as a yellow solid) (Scheme 3).
Scheme 3. Quadruple syn-Fluoro-trifluoromethylation of 2u
In an effort to broaden this syn-Nu-trifluoromethylation
chemistry, we were pleased to find that when sodium phenoxide
was used in place of CsF under otherwise identical conditions,
the desired syn-oxy-trifluoromethylation occurred in excellent
yields (Scheme 4). Arylacetylenes with substituents such as
a,b
Scheme 4. syn-Oxy-trifluoromethylation of Arylacetylenes
Scheme 6. syn-Aryl-trifluoromethylation of Arylacetylenes
or in nonpolar toluene, as shown in entries 5 and 6 in Table 1.
These results confirm that the formation of 4a should be
kinetically facile and 3a should be produced from the reaction of
4a with fluoride at a slower rate. Thus, direct subjection of 4a in
place of 2a under the optimized reaction conditions gave 3a in
trace amounts with 4a recovered (Scheme 7, eq 1), which
a
b
Both 19F NMR and isolated yields (in parentheses) are given. For
the synthesis of 5h, 0.2 mmol of 1 was used.
Scheme 7. Control Experiments and Radical-Trapping Study
alkoxy, alkyl, phenyl, and halides all selectively gave syn-oxy-
trifluoromethylation styrenes as the dominant products.
Interestingly, benzene-1,3-bisalkyne 2h gave the mono syn-
oxy-trifluoromethylation product 5h in a good yield of 83%.
Naphthyl and heteroaryl acetylenes can also produce the desired
5i and 5j in excellent yields. It should be emphasized that this
represents the first examples of one-step syn-oxy-trifluorome-
thylation of alkynes and also the first use of phenoxides in such
alkyne oxy-trifluoromethylation reactions.
On the other hand, a range of phenoxides can be tolerated in
the syn-oxy-trifluoromethylation of alkynes (Scheme 5).
Methoxide and ethoxide are also applicable oxy-nucleophiles.
All of the phenoxides and alkoxides examined selectively gave
the desired products 5 in good to excellent yields.
Finally, phenyl boronic acid was also found to be applicable as
a carbon nucleophile to engage in a similar syn-carbo-
trifluoromethylation of 2a to give 7 in 78% yield (Scheme 6).12
To shed mechanistic insights, particularly regarding the high
regio- and stereoselectivity, extensive control experiments were
done for the fluoro-trifluoromethylation reaction. First, 19F
NMR monitoring of the crude mixtures of the model reaction in
Table 1 in 5 min, 30 min, 2 h, 4 h, and 6 h clearly shows initial
dominant formation of 4a and the gradual consumption of 4a
and concurrent accumulation of the desired 3a (see Figure S4).
Moreover, the reactions selectively gave 4a at lower temperature
indicates that the proton of terminal alkynes is crucial to the
formation of 3a. To prove this, the explicit addition of 2 equiv of
tertbutanol as a proton source to the reaction solutions did give
the desired 3a in 62% yield (eq 2). Finally, radical trapping
experiments show that the reaction yield was significantly
diminished in the presence of stoichiometric radical scavenger
BHT (2,6-di-tert-butyl-4-methylphenol), and the reaction was
almost completely inhibited with TEMPO (2,2,6,6-tetramethyl-
piperidinyloxy) (eq 3), which suggests that radical species might
be involved.
C
DOI: 10.1021/acs.orglett.7b03229
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On the basis of the above mechanistic results, a plausible
mechanism involves the initial generation of CF3 radical from
113 and addition to alkyne triple bond to form a vinyl radical (A)
(Scheme 8). Upon single-electron transfer (SET) from A to
REFERENCES
■
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, Germany, 2004. (b) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
̈
(2) For general reviews, see: (a) Schlosser, M. Angew. Chem., Int. Ed.
2006, 45, 5432. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1.
(c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (d) Furuya, T.;
Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (e) Liang, T.;
Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214.
(3) Iodo-trifluoromethylation: (a) Iqbal, N.; Jung, J.; Park, S.; Cho, E.
J. Angew. Chem., Int. Ed. 2014, 53, 539. (b) Hang, Z.; Li, Z.; Liu, Z.-Q.
Org. Lett. 2014, 16, 3648. (c) Xu, T.; Cheung, C. W.; Hu, X. Angew.
Chem., Int. Ed. 2014, 53, 4910. Oxy-trifluoromethylation: (f) Tomita,
R.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2015, 54, 12923.
Scheme 8. Proposed Mechanism
́
(g) Janson, P. G.; Ghoneim, I.; Ilchenko, N. O.; Szabo, K. J. Org. Lett.
2012, 14, 2882. (h) Egami, H.; Shimizu, R.; Sodeoka, M. Tetrahedron
Lett. 2012, 53, 5503. Amino-trifluoromethylation: (i) Xiang, Y.; Kuang,
Y.; Wu, J. Org. Chem. Front. 2016, 3, 901. (j) Ge, G.-C.; Huang, X.-J.;
Ding, C.-H.; Wan, S.-L.; Dai, L.-X.; Hou, X.-L. Chem. Commun. 2014,
50, 3048. (k) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G. Angew. Chem.,
Int. Ed. 2015, 54, 9356. Aryl-trifluoromethylation: (l) Li, Z.; Garcia-
Dominguez, A.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 11610.
(4) (a) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294.
(b) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598.
(5) (a) Xu, T.; Wu, Y.; Yuan, Z.; Guan, H.; Liu, G. Organometallics
2016, 35, 1347. (b) Zeng, X.; Liu, S.; Shi, Z.; Liu, G.; Xu, B. Angew.
Chem., Int. Ed. 2016, 55, 10032. (c) Li, S.; Li, Z.; Yuan, Y.; Li, Y.; Zhang,
L.; Wu, Y. Chem. - Eur. J. 2013, 19, 1496.
(6) (a) Begue, J.-P.; Bonnet-Delpon, D.; Bouvet, D.; Rock, M. H. J. J.
Chem. Soc., Perkin Trans. 1 1998, 1797. (b) Goldberg, A. A.;
Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Nenajdenko, V.
G. J. J. Fluorine Chem. 2010, 131, 384. (c) Zhao, Y.; Zhou, Y.; Liu, J.;
Yang, D.; Tao, L.; Liu, Y.; Dong, X.; Liu, J.; Qu, J. J. J. Org. Chem. 2016,
81, 4797.
Cu(II), the vinyl radical (A) is transformed to vinyl cation B that
produces 4a after deprotonation.14 Then, fluoride attacks at the
electrophilic Cα position to give a syn-α-F-β-CF3 styryl
carbanion (C).15 Protonation of C produces the desired 3. By
this mechanism, both the regio- and stereoselectivity are
determined by a common step of nucleophilic addition of
fluoride to 4a. The more electrophilic Cα of 4a reacts
preferentially with fluoride to introduce the fluoride at the Cα
position. The Z-stereoselectivity with cis-orientation of F and
CF3 in intermediate C may stem from the presence of stabilizing
secondary orbital interaction of π orbital of vinyl fluoride moiety
with π*(CF3), parallel to the proposal for the reaction of ArC
C−CF3 with phenoxide to produce the (Z)-oxy-trifluoromethy-
lated styrenes.15a,b Nevertheless, more efforts are required to
fully clarify the mechanistic details of this fluoro-trifluorome-
thylation reaction.
(7) For a review of functionalization of Ar−CC−CF3, see:
Thus, a general method is developed to achieve syn-fluoro-,
-oxy-, and -aryl-trifluoromethylation across triple bond of
alkynes. It is attractive for preparing various trifluoromethylated
Z-alkenes and shows the potential of CuIII−CF3 in organic
synthesis.16
(a) Konno, T. Synlett 2014, 25, 1350.
(8) (a) Zhang, S.-L.; Bie, W.-F. RSC Adv. 2016, 6, 70902. (b) Zhang,
S.-L.; Bie, W.-F. Dalton Trans. 2016, 45, 17588.
(9) (a) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. J.
Chem. Soc., Chem. Commun. 1989, 1633. (b) Naumann, D.; Roy, T.;
Tebbe, K.-F.; Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482.
(c) Romine, A. M.; Nebra, N.; Konovalov, A. I.; Martin, E.; Benet-
Buchholz, J.; Grushin, V. V. Angew. Chem., Int. Ed. 2015, 54, 2745.
(10) (a) Chu, L.; Qing, F.-L. J. J. Am. Chem. Soc. 2010, 132, 7262.
(b) Luo, D.-F.; Xu, J.; Fu, Y.; Guo, Q.-X. Tetrahedron Lett. 2012, 53,
2769.
(11) (a) Everett, T. S.; Purrington, S. T.; Bumgardner, C. L. J. J. Org.
Chem. 1984, 49, 3702. For related isomers, see: (b) Reference 6b.
(c) Yamada, S.; Takahashi, T.; Konno, T.; Ishihara, T. Chem. Commun.
2007, 3679.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03229.
Experimental details; characterization data (PDF)
(12) Other nucleophiles, e.g., enolates, were also found to give low to
moderate NMR yields and are still under study.
(13) Evidence supporting the generation of CF3 radical from 1 is the
observation of significant 19F signal at ca. −53 ppm from heating DMF
solution of 1 in the presence of TEMPO at 100 °C, assigned to the
formation of TEMPO−CF3 adduct. See Figure S9.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slzhang@jiangnan.edu.cn.
ORCID
(14) For a similar proposal, see: (a) Ji, Y.-L.; Luo, J.-J.; Lin, J.-H.; Xiao,
J.-C.; Gu, Y.-C. Org. Lett. 2016, 18, 1000. (b) See also refs 3f and 3i..
(c) Maji, A.; Hazra, A.; Maiti, D. Org. Lett. 2014, 16, 4524. (d) Deb, A.;
Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D. Angew. Chem., Int.
Ed. 2013, 52, 9747.
Song-Lin Zhang: 0000-0002-5337-8600
Notes
The authors declare no competing financial interest.
(15) (a) Bumgardner, C. L.; Bunch, J. E.; Whangbo, M.-H.
Tetrahedron Lett. 1986, 27, 1883. (b) Bumgardner, C. L.; Bunch, J.
E.; Whangbo, M.-H. J. J. Org. Chem. 1986, 51, 4082. (c) Muzalevskiy, V.
M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.
Synthesis 2009, 2009, 2249.
ACKNOWLEDGMENTS
■
This study was supported by the National Natural Science
Foundation of China (No. 21472068). Financial support from
MOE & SAFEA for the 111 Project (B13025), is gratefully
acknowledged.
(16) For a recent related study, see: Shen, H.; Liu, Z.; Zhang, P.; Tan,
X.; Zhang, Z.; Li, C. J. J. Am. Chem. Soc. 2017, 139, 9843.
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DOI: 10.1021/acs.orglett.7b03229
Org. Lett. XXXX, XXX, XXX−XXX