Copper-mediated regioselective hydrodifluoroalkylation of alkynes

Article abstract of DOI:10.1039/c8ob00256h

A highly regioselective copper-mediated hydrodifluoroalkylation of alkynes with ethyl bromodifluoroacetate or bromodifluoroacetamides has been developed. This strategy provides straightforward access to a variety of difluoroalkylated alkenes under mild reaction conditions with low-cost cuprous bromide and metabisulfite as reduction agents. A wide range of alkynes are applicable under these reaction conditions. The excellent functional-group compatibility and good regio- and stereoselectivities are the notable features of this transformation.

Full text of DOI:10.1039/c8ob00256h

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Feng, X. Wang,
H. Chen, X. Tang, M. Guo, W. Zhao and G. Wang, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB00256H.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C8OB00256H
Journal Name
COMMUNICATION
Copper‐Mediated Regioselective Hydrodifluoroalkylation of
Alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaorui Feng,a Xiaoyang Wang,a Hongtai Chen,a Xiangyang Tang,a Minjie Guo,b Wentao Zhao,a*
and Guangwei Wanga*
DOI: 10.1039/x0xx00000x
www.rsc.org
A highly regioselective copper‐mediated hydrodifluoroalkylation cross‐coupling of α,β‐unsaturated carboxylic acids,7 and
of alkynes with ethyl bromodifluoroacetate or transition metal‐catalyzed cross‐coupling reactions involving
bromodifluoroacetamides has been developed. This strategy alkenyl metals8 or halides.9
provides a straightforward access to a variety of difluoroalkylated Scheme 1. Synthesis of difluoroalkylated alkenes from terminal
alkenes under mild reaction conditions with low‐cost cuprous alkynes
bromide and metabisulfite as reduction agent. A wide range of
alkynes are applicable with these reaction conditions. The
excellent functional‐group compatibility and good regio‐ and
stereoselectivities are the notable features of this transformation.
Fluorine atom is generally considered as an extraordinary
atom due to its small atomic radius and high electronegativity.
Introduction of fluorine can generally enhance the lipophilicity,
bioavailability, and metabolic stability of their parent
molecules.1 However, only a very limited number of fluorine‐
containing compounds, which can be used as potential starting
fluorinated material, has been produced by nature. Due to the
ubiquity of fluorine‐containing molecules in the fields of
materials, pesticides, and pharmaceuticals, the increasing
demand for fluorine‐containing organic compounds has made
them urgent synthetic targets in organic chemistry.2
Consequently, incorporation of fluorine and fluorine‐
containing groups has been an intensive topic of
organofluorine synthetic chemistry.
Recently, the synthesis of difluoromethylene‐containing
Traditionally, the alkenyl metals or alkenyl halides are
derived from alkynes through hydrometalation or electrophilic
addition reactions (Scheme 1a). Therefore, the direct addition
of difluoroalkyl groups to alkynes to generate difluoroalkylated
alkenes in a regio‐ and stereo‐controlled fashion would
prevent additional steps for the preparation of alkenylmetal
species or alkenyl halides, thus improving their synthetic
efficiency and applicability. However, it is challenging due to
the difficulty in control of stereoselectivity (Scheme 1b).10‐13
For instance, Chen et al. and Piettre et al. respectively
reported the transition metal‐free hydrodifluoroalkylations of
compounds
has
attracted
considerable
attention.3
Difluoromethylene (‐CF2‐) is regarded as a bioisostere for
oxygen atom, carbonyl, and methylene,4 and it can affect the
electronic properties, chemical properties, and reactivities of
the adjacent functional group.5 During the last decades, the
synthesis of difluoroalkylated alkenes have been accomplished
by direct C−H difluoroalkylation of alkenes,6 decarboxylative
a. Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of
Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China.
b. Institute for Molecular Design and Synthesis, School of Pharmaceutical Science
and Technology, Tianjin University, Tianjin 300072, P. R. China
11
alkynes with Na2S2O4 or AIBN12 as a radical initiator, and
Shibuya et al. reported a Cu‐mediated hydrodifluoroalkylation
of alkynes.13 However, only low to moderate yields and poor
stereoselectivities have been acheived. Recently, Song and co‐
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
workers reported the reaction of ethyl bromodifluoroacetate that copper(I) was more efficient than copper(II) (VeienwtrAyrtic3levOsn6lin)e,
and alkynes in the presence of B2pin2.14 Although good cis‐ and CuBr gave the best yield and steDreOoI:s1e0l.e10ct3i9v/iCty8.OBN0e0x2t5,6Ha
hydrodifluoroalkylation have been realized for aromatic number of other additives were investigated (entry 7 vs 8) and
alkynes bearing an electron‐donating group, the Na2S2O5 proved the most efficient additive in this reaction.
stereoselectivities are lower for aliphatic alkynes. Furthermore, Moreover, various solvents were screened (entries 9−12) and
stoichiometric amount of bis(pinacolato)diboron has been DMF was found to be the best option. However, our attempt
employed as reductant which is expensive, thus limiting its to decrease the amount of copper to a catalytic amount (0.2
application in scaled up industrial synthesis. Herein, we report equiv) failed due to the decrease of yield to 23% (entry 13). A
our results of direct hydrodifluoroalkylation of alkynes in the control experiment in the absence of TMEDA only gave the
presence of low‐cost copper(I) and sodium metabisulfite, desired product 3a in 6% yield (entry 14). Consequently,
undergoing different reaction pathway. Through this strategy, Na2S2O5 as additive, TMEDA as base, and DMF as solvent in the
trans‐fluoroalkylated alkenes could be accessed with good to presence of CuBr were chosen as the optimized conditions.
excellent yields and high E‐stereoselectivities for both
aromatic and aliphatic alkynes (Scheme 1d).
With the optimal reaction conditions in hand, the substrate
scope of this hydrodifluoroalkylation reaction was explored. A
wide range of alkynes, including both aromatic and aliphatic
ones, were examined and the results were depicted in Table 2.
For the aromatic alkynes, diverse substituents on the aromatic
ring were compatible under the standard conditions and gave
moderate to high yields of the corresponding difluoroalkylated
RESULTS AND DISCUSSION
Initially, the radical addition of phenylacetylene (1a) with
ethyl bromodifluoroacetate (2a) was chosen as a model
reaction to optimize the reaction conditions. When using
TMEDA (2.0 equiv) as base in the presence of CuBr (1.5 equiv)
in DMF, the desired product 3a was obtained in only 19% yield
products (3a‐3o). Both phenylacetylenes bearing an electron‐
Scheme 2. Scope of alkynesa,b
along with the homo‐coupling byproduct
4 (75%) (Table 1,
entry 1). When KF (1.5 equiv) was added, the yield of 3a was
improved to 74% (Table 1, entry 2) and the yield of byproduct
4
dropped to 21%. It is noteworthy that in the presence of
Na2S2O5 (1.5 equiv), the desired product 3a can be obtained
with an excellent yield of 97%, with the generation of being
4
sufficiently suppressed (entry 3). Various copper salts were
subsequently screened (entries 3 to 6), which implied
Table 1. Optimization of reaction conditionsa
yieldb (%)
Entry
Cu salt
additive
Solvent
3a (E/Z)
19(>99:1)
74(21:1)
97(96:1)
95(94:1)
94(46:1)
53(>99:1)
71(22:1)
62(8:1)
4
75
21
0
0
0
33
30
35
73
51
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
CuCl
CuI
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
none
KF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
toluene
1,4‐
dioxane
CH3CN
DMF
Na2S2O5
Na2S2O5
Na2S2O5
Na2S2O5
Na2SO3
NaHSO3
Na2S2O5
Na2S2O5
Na2S2O5
22(10:1)
43(13:1)
41(7:1)
10
11
49
12
13c
14d
CuBr
CuBr
CuBr
Na2S2O5
Na2S2O5
Na2S2O5
55(54:1)
23(>99:1)
6(>99:1)
36
0
0
DMF
aReaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (0.45 mmol, 1.5 equiv),
Cu salt (0.45 mmol, 1.5 equiv), TMEDA (0.6 mmol, 2.0 equiv), additive (0.45
mmol, 1.5 equiv), DMF (3 mL), 80 oC, under argon. bThe yield was
determined by HPLC analysis. TMEDA = N, N, N’, N’‐tetramethylethane‐1,2‐
diamine. cCatalytic amount (0.2 equiv) of CuBr was used. dWithout the
addition of TMEDA.
aReaction conditions: 1 (0.5 mmol, 1.0 equiv), 2a (0.75 mmol, 1.5 equiv), CuBr (0.75
mmol, 1.5 equiv), TMEDA (1.0 mmol, 2.0 equiv), Na2S2O5 (0.75 mmol, 1.5 equiv), DMF
(5 mL), 80 oC, under argon, 6‐8 h. bIsolated yield. The ratios in parentheses are E/Z
ratios, determined by 19F NMR spectroscopy.
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
donating group on the aryl ring (3b
substituted phenylacetylenes 3e
‐
3d
)
,
3m
‐
3p) and halogen It is remarkable that the amide containing compounds (5e‐5i)
View Article Online
DOI: 10.1039/C8OB00256H
(
‐
3g
gave the desired cannot
be
accessed
through
previous
reported
products with high yields and excellent stereoselectivities. difluoromethylation of alkenes16 or hydrodifluoromethylation
Meanwhile, for phenylacetylenes with strong electron‐ of alkynes,17 both of which led to further cyclized products.
withdrawing groups (3h
‐
3l), relatively lower yields and lower Notably,
reaction
of
phenylalanine
derived
stereoselectivities were obtained, which might be due to the bromodifluoroamide with phenylacetylene afforded the
low isomerization barrier of alkenyl radicals.15 Moreover, 2‐ fluorinated alkene (5f) in good yield with an excellent
ethynylthiophene
(
3q), 2‐ethynylnaphthalene
(3r), and functional group tolerance. Thus, unsaturated fluorinated
aliphatic alkynes (3s
‐3v) also proceeded smoothly to afford the amino acids can be efficiently accessed for further biologically
desired products with good yields and excellent active peptides and protein engineering studies.18
stereoselectivities. It is noteworthy that various functional
groups, such as cyano (3h), nitro (3i), alkoxycarbonyl (3k), experiments were carried out (for details, see the Supporting
formyl (3l), and hydroxyl (3s‐3v) can be well tolerated. Information). When a radical inhibitor 2,2,6,6‐tetramethyl‐1‐
To exploit the reaction mechanism, several control
To further demonstrate the generality of this method, piperidinyloxy (TEMPO) was added into the reaction system,
different functionalized difluoromethyl bromides were also the reaction was quenched and thus implied that a radical
explored with the results being summarized in Table 3. As pathway might be involved in this reaction (Scheme 4, eq. 1).
expected,
a variety of bromodifluoroacetamides were To gain further insight into the source of the two protons in
compatible with the transformation and gave the desired the desired product, two deuterium‐labeling experiments
products (5a
‐
5i) with high yields and good stereoselectivities.
were performed. When excessive amount of deuterated water
was added to the reaction, the corresponding product 3c was
obtained with 77% deuterated at α‐C and 44% deuterated at
β‐C (Scheme 4, eq. 2). When deuterated 4‐
propylphenylethylene was subjected to the reaction condition,
the corresponding product 3c was obtained with 21%
deuterated at α‐C and less than 5% deuterated at β‐C (Scheme
4, eq. 3). When the reaction of 1a with 2a was run under
anhydrous conditions, the yield dropped sharply. All above
results indicate that water should be involved in this reaction
as a hydrogen source.
Scheme 3. Scope of bromodifluoroacetamidesa,b
CuBr (1.5 equiv)
TMEDA (2.0 equiv)
Na2S2O5 (1.5 equiv)
F
F
F
F
R
DMF, 80 o
C
R
Br
O
O
1a
2
5
O
F
F
F F
N
N
O
O
Scheme 4. Control experiments for mechanism insight
5a, 78%(50:1)
5b, 74%(50:1)
F
F
NH
F
F
nHex
N
O
O
5c, 70%(10:1)
5dc, 73%(45:1)
F
F
F
F
NH
O
NH
O
O
O
5e, 70%(32:1)
5f, 70%(30:1)
F
F
F F
NH
NH
O
O
F
O
5g
5h
, 63%(38:1)
, 78%(42:1)
F
F
NH
Based on the above experimental results and previous
reports,7,19 a plausible mechanism was proposed in Scheme 5.
First, BrCF2CO2Et is reduced by copper(I) salt via a single‐
electron transfer to afford the difluoroalkyl radical, which adds
O
5i, 82%(45:1)
aReaction Conditions: 1a (0.5 mmol, 1.0 equiv),
(0.75 mmol, 1.5 equiv), TMEDA (1.0 mmol, 2.0 equiv), Na2S2O5 (0.75 mmol, 1.5
equiv), DMF (5 mL), 80 oC, under argon, 6‐8 h. bIsolated yield. The ratios in
parentheses are E/Z ratios, determined by 19F NMR spectroscopy.
to the in situ formed (phenylethynyl)copper
A
to afford vinyl
could
2
(0.75 mmol, 1.5 equiv), CuBr
radical intermediate . Subsequently, vinyl radical
B
B
abstract the hydrogen from solvents and give vinyl‐copper
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
F.‐L. Qing, F. Zheng, Synlett, 2011,
8, 1052. (d) CV.iNewi,AJr.ticHleuO,nline
intermediate
in the reaction system, giving the desired product
C
, which was quenched by proton from moisture
. The diyne
Synthesis, 2014, 46, 842; (e) J. Xie, T. Zhang, F. Chen, N.
DOI: 10.1039/C8OB00256H
3
Mehrkens, F. Rominger, M. Rudolph, A. S. K. Hashmi, Angew.
Chem. Int. Ed., 2016, 55, 2934.
(a) D. O’Hagan, H. S. Rzepa, Chem. Commun., 1997, 0, 645; (b)
D. O’Hagan, Y. Wang, M. Skibinski, A. M. Z. Slawin, Pure Appl.
Chem., 2012, 84, 1587; (c) Q. Wang, L. Zheng, Y.‐T. He, Y.‐M.
Liang, Chem. Commun., 2017, 53, 2814.
byproduct
4 might be derived from homocoupling of terminal
alkynes in the presence of Cu(II) or Cu(III).20 Therefore, Na2S2O5
was applied as reductant to suppressed the side reaction.21
5
6
Scheme 5. Proposed mechanism
(a) X. Wang, S. Zhao, J. Liu, D. Zhu, M. Guo, X. Tang, G. Wang,
Org. Lett., 2017, 19, 4187. (b) Y. Li, J. Liu, S. Zhao, X. Du, M.
Guo, W. Zhao, X. Tang, G. Wang, Org. Lett. 2018, 20, 917; (c)
Z. Feng, Q.‐Q. Min, H.‐Y. Zhao, J.‐W. Gu, X. Zhang, Angew.
Chem., Int. Ed., 2015, 54, 1270; (d) Z. Feng, Y.‐L. Xiao, X.
Zhang, Org. Chem. Front., 2016, 3, 466.
7
(a) G. Li, Y.‐X. Cao, C.‐G. Luo, Y.‐M. Su, Y. Li, Q. Lan, X.‐S.
Wang, Org. Lett., 2016, 18, 4806; (b) G. Li, T. Wang, F. Fei, Y.‐
M. Su, Y. Li, Q. Lan, X.‐S. Wang, Angew. Chem. Int. Ed., 2016,
55, 3491; (c) Z. He, T. Luo, M. Hu, Y. Cao, J. Hu, Angew. Chem.
Int. Ed., 2012, 51, 3944; (d) Q. Chen, C. Wang, J. Zhou, Y.
Wang, Z. Xu, R. Wang, J. Org. Chem., 2016, 81, 2639; (e) H.‐R.
Zhang, D.‐Q. Chen, Y.‐P. Han, Y.‐F. Qiu, D.‐P. Jin, X.‐Y. Liu,
Chem. Commun., 2016, 52, 11827.
8
9
M. K. Schwaebe, J. R. McCarthy, J. P. Whitten, Tetrahedron
Lett., 2000, 41, 791.
Conclusions
In summary, an economic copper/Na2S2O5‐mediated
hydrodifluoroalkylation
bromodifluoroacetate has been developed. Through this
strategy, a number of difluroalkylated alkenes can be obtained
in good yields and stereoselectivities. Further explorations to
reveal the reaction mechanism are currently underway in our
laboratory.
(a) T. Taguchi, O. Kitagawa, T. Morikawa, T. Nishiwaki, H.
Uehara, H. Endo, Y. Kobayashi, Tetrahedron Lett., 1986, 27
,
of
alkynes
with
ethyl
6103; (b) K. Sato, R. Kawata, F. Ama, M. Omote, A. Ando, I.
Kumadaki, Chem. Pharm. Bull., 1999, 47, 1013; (c) J. Zhu, W.
Zhang, L. Zhang, J. Liu, J. Zheng, J. Hu, J. Org. Chem., 2010, 75
5505; (d) P. S. Fier, J. F. Hartwig, J. Am. Chem. Soc., 2012, 134
5524; (e) G. K. S. Prakash, S. K. Ganesh, J.‐P. Jones, A.
Kulkarni, K. Masood, J. K. Swabeck, G. A. Olah, Angew. Chem.
Int. Ed., 2012, 51, 12090; (f) D. Chang, Y. Gu, Q. Shen, Chem.
Eur. J., 2015, 21, 6074.
,
,
10 (a) K. Nakamura, T. Nishikata, ACS Catal., 2017, 7, 1049; (b)
J.‐J. Ma, W.‐B. Yi, Org. Biomol. Chem., 2017, 15, 4295.
11 Z.‐Y. Long, Q.‐Y. Chen, J. Org. Chem., 1999, 64, 4775.
12 S. Pignard, C. Lopin, G. Gouhier, S. R. Piettre, J. Org. Chem.,
2006, 71, 31.
Conflicts of interest
There are no conflicts to declare.
13 T. Yokomatsu, K. Suemune, T. Murano, S. Shibuya, J. Org.
Chem., 1996, 61, 7207.
Acknowledgment
We thank the National Basic Research Program of China (No.
2015CB856500) and the Natural Science Foundation of Tianjin
(No. 16JCYBJC20100) for support of this research.
14 M. Ke, Q. Feng, K. Yang, Q. Song, Org. Chem. Front., 2016, 3,
150.
15 The reaction might proceed through vinyl radical B, which is
prone to isomerize due to its a low isomerization barrier.
When its lifetime increases, it would have more chance to
isomerize. Since lifetime of the vinyl radical B is elongated by
stabilizing effect of the electron‐withdrawing substituent on
phenyl ring (see ref. 11), E/Z ratio of the corresponding
product will decrease.
Notes and references
1
2
(a) B. E. Smart, J. Fluorine Chem., 2001, 109, 3; (b) P. Kirsch,
Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley‐VCH, Weinheim, 2013. (c) K. Müller, C.
Faeh, F. Diederich, Science, 2007, 317, 1881; (d) T. Besset, T.
Poisson, X. Pannecoucke, Chem. Eur. J., 2014, 20, 16830.
(a) M. Schlosser, Angew. Chem. Int. Ed., 2006, 45, 5432; (b) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev., 2008, 37, 320; (c) W. K. Hagmann, J. Med. Chem., 2008,
51, 4359; (d) K. L. Kirk, Org. Process Res. Dev., 2008, 12, 305;
(e) J. Wang, H. Liu, Chin. J. Org. Chem., 2011, 31, 1785. (f) O.
A. Tomashenko, V. V. Grushin, Chem. Rev., 2011, 111, 4475;
16 H. Chen, X. Wang, M. Guo, W. Zhao, X. Tang, G. Wang, Org.
Chem. Front., 2017, 4, 2403.
17 Y. Lv, W. Pu, Q. Chen, Q. Wang, J. Niu, Q. Zhang, J. Org.
Chem., 2017, 82, 8282.
18 F. Zhang, Q.‐Q. Min, X. Zhang, Synthesis, 2015, 47, 2912.
19 M.‐C. Belhomme, D. Dru, H.‐Y. Xiong, D. Cahard, T. Besset, T.
Poisson, X. Pannecoucke, Synthesis, 2014, 46, 1859.
20 G. Zhang, H. Yi, G. Zhang, Y. Deng, R. Bai, H. Zhang, J. T. Miller,
A. J. Kropf, E. E. Bunel, A. Lei, J. Am. Chem. Soc., 2014, 136
,
924.
21 (a) C. M. R. Abreu, P. V. Mendonça, A. C. Serra, A. V. Popov, K.
(g) X.‐F. Wu, H. Neumann, M. Beller, Chem. Asian J., 2012, 7,
Matyjaszewski, T. Guliashvili, J. F. J. Coelho, ACS Macro Lett.,
2012, , 1308; (b) C. M. R. Abreu, A. C. Serra, A. V. Popov, K.
Matyjaszewski, T. Guliashvili, J. F. J. Coelho, Polym. Chem.,
2013, , 5629.
1744; (h) J. Zhang, C. Jin, Y. Zhang, Chin. J. Org. Chem., 2014,
34, 662; (i) C. Ni, L. Zhu, J. Hu, Acta Chim. Sinica, 2015, 73, 90.
(a) T. Besset, T. Poisson, X. Pannecoucke, Eur. J. Org. Chem.,
2015, 2015, 2765; (b) M.‐C. Belhomme, T. Besset, T. Poisson,
X. Pannecoucke, Chem. Eur. J., 2015, 21, 12836.
1
3
4
4
(a) J. A. Erickson, J. I. McLoughlin, J. Org. Chem., 1995, 60
,
1626; (b) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (c)
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB00256H
A highly regioselective copper-mediated hydrodifluoroalkylation of alkynes with ethyl
bromodifluoroacetate or bromodifluoroacetamides has been developed.