Stereoselective cobalt-catalyzed halofluoroalkylation of alkynes

Article abstract of DOI:10.1039/c7sc04916a

Stereoselective additions of highly functionalized reagents to available unsaturated hydrocarbons are an attractive synthetic tool due to their high atom economy, modularity, and rapid generation of complexity. We report efficient cobalt-catalyzed (E)-halofluoroalkylations of alkynes/alkenes that enable the construction of densely functionalized, stereodefined fluorinated hydrocarbons. The mild conditions (2 mol% cat., 20 °C, acetone/water, 3 h) tolerate various functional groups, i.e. halides, alcohols, aldehydes, nitriles, esters, and heteroarenes. This reaction is the first example of a highly stereoselective cobalt-catalyzed halo-fluoroalkylation. Unlike related cobalt-catalyzed reductive couplings and Heck-type reactions, it operates via a radical chain mechanism involving terminal halogen atom transfer which obviates the need for a stoichiometric sacrificial reductant.

Full text of DOI:10.1039/c7sc04916a

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Stereoselective Cobalt-Catalyzed Halofluoroalkylation of Alkynes
Guojiao Wua and Axel Jacobi von Wangelin*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
Stereoselective additions of highly functionalized reagents to available unsaturated hydrocarbons are an
attractive synthetic tool due to their high atom economy, modularity, and rapid generation of complexity.
We report efficient cobaltꢀcatalyzed (E)ꢀhalofluoroalkylations of alkynes/alkenes that enable the
construction of densely functionalized, stereodefined fluorinated hydrocarbons. The mild conditions
(2 mol% cat., 20 °C, acetone/water, 3 h) tolerate various functional groups, i.e. halides, alcohols,
10 aldehydes, nitriles, esters, and heteroarenes. This reaction is the first example of a highly stereoselective
cobaltꢀcatalyzed haloꢀfluoroalkylation. Unlike related cobaltꢀcatalyzed reductive couplings and Heckꢀtype
reactions, it operates via a radical chain mechanism involving terminal halogen atom transfer which
obviates the need for a stoichiometric sacrificial reductant.
R
(Hu, 2014)
[Fe]
1 Introduction
RF
I
RF-I
15 Fluorinated hydrocarbons constitute key structural motifs in
many bioactive molecules, agrochemicals, and pharmaceuticals
R = alkyl, Ph; R' = H
60 °C, >16 h
due to their high metabolic stability, lipophilicity, and bioavailaꢀ
R
(Besset, 2014)
1 equiv. [Cu]
bility compared with the parent compounds.[1] Fluoroalkylation
RF
Br
EtO2CCF2-Br
methods of easily accessible precursors have therefore attracted
R = Ar; R' = H; low E/Z ratio
20 great interest in the past years.[2],[3] While many protocols are
120 °C, 2 h
R
R'
substitution processes that require highly preꢀfunctionalized
starting materials and produce unwanted byꢀproducts, direct
additions to unsaturated hydrocarbons exhibit higher modularity
and atomꢀefficiency and provide ample opportunities of regioꢀ
25 and stereocontrol. The addition of haloꢀfluoroalkanes to alkynes
is an especially attractive tool due to the easy availability of the
reagents and the great synthetic versatility of the resultant haloꢀ
fluoroalkenes. Many methods operate via an atom transfer radical
addition (ATRA) mechanism in the presence of radical initiators
30 (e.g. BEt3, AIBN, Na2S2O3 or light)[4] that showed narrow
substrate scope and poor selectivity. Mechanistically closely
related transition metalꢀmediated haloꢀfluoroalkylations have
been recently reported, but with a narrow focus on iodofluoroꢀ
alkylations and/or moderate stereoꢀcontrol (Scheme 1). Hu et al.
35 devised an ironꢀcatalyzed addition of perfluoroalkyl iodide to
alkynes with moderate to good E/Zꢀselectivities in the presence of
Cs2CO3. The radical reaction with alkylꢀsubstituted alkynes
required long reaction times at 60 oC and could not convert
perfluoroalkyl bromides.[5] Besset et al. postulated a different
40 mechanism for the copperꢀmediated synthesis of difluoromethyl
alkenes from BrCF2CO2Et and alkynes. However, significantly
lower stereoselectivities were obtained and stoichiometric
amounts of copper salt were employed.[6] Very recently, Wang
and coꢀworkers reported a copperꢀcatalyzed decarboxylative
45 ATRA reaction between ICF2CO2Et and substituted propiolic
acids.[7]
R
[Cu/Phen]
(Wang, 2016)
RF
I
EtO2CCF2-I
100 °C, 12 h
R = alkyl, Ar; R' = CO2H
R
this work
[Co/dppbz]
RF
X
RF-X
- 1st Co catalysis
- mild conditions
- wide scope
R'
20 °C, 3 h
R = alkyl, Ar, TMS
R' = H, alkyl, CO2Me
X = Br, I
- high E/Z selectivity
Scheme 1. Metalꢀmediated haloꢀfluoroalkylations of alkynes.
Despite the developments of novel ironꢀ and copperꢀcatalyzed
50 procedures, the reactions generally utilize expensive fluoroalkyl
iodides as starting materials, high catalyst loadings, long reaction
times, and high reaction temperatures. An efficient and robust yet
highly stereoselective method that operates at mild conditions and
low catalyst loadings and that is applicable to various fluoroalkyl
55 halides would constitute a significant advancement of the current
technology and have considerable use in the synthesis of densely
functionalized fluorinated building blocks. To the best of our
knowledge, there are no literature reports of ATRA reaction
between alkyl halides and alkynes with lowꢀvalent cobalt
60 catalysts. Here, we report the cobaltꢀcatalyzed halofluoroꢀ
alkylation of alkynes which enables the highly regioselective and
stereoselective synthesis of a diverse set of halofluoroalkenes
under unprecedentedly mild conditions (Scheme 1).
The utility of alkyl halides in crossꢀcouplings and reductive
65 additions has recently been greatly enhanced by the development
of lowꢀvalent iron group metal catalysts (Fe, Co, Ni)[8ꢀ10] that
engage in facile alkylꢀX activation. The high propensity of late 3d
transition metals to undergo singleꢀelectron transfer (SET)
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Table 1. Selected optimization experiments.[a]
processes often results in the intermediacy of carbonꢀcentered
radical species.[8g,8h,9h,10f] The reductive formation of alkyl
radicals from alkylꢀX electrophiles is thermodynamically
favoured when the formal electron septetꢀcarbon is stabilized by
heteroatoms, conjugation, hyperconjugation, or inductive effects.
Efficient cobalt catalysts have been reported for several reductive
coupling reactions between alkyl halides and Michaelꢀtype
acceptors as well as for Heckꢀtype reactions between alkyl
halides and alkenes.[11] These processes mostly follow the same
10 mechanistic scenarios involving (i) initial formation of a lowꢀ
valent Co(I) species from a Co(II,III) precursor in the presence of
a reductant; (ii) reductive cleavage of the alkyl halide to give an
alkyl radical R• and a Co(II) complex (by SET activation or
homolysis of RꢀCo(III)), (iii) addition of R• to the olefin and
15 formation of an organocobalt species that is subject to disproporꢀ
tionation (Heckꢀtype reaction) or hydrolysis (reductive coupling)
to release the Co(III) complex, (iv) regeneration of the Co(I)
catalyst with a stoichiometric reductant (Scheme 2, left). We
surmised that an ATRA reaction between alkyl halides and
20 alkynes could follow a similar mechanism using lowꢀvalent Co
catalysts but would require only catalytic amounts of a reductant
(Scheme 2, right). Cobaltꢀcatalyzed Heckꢀtype and reductive
coupling reactions were realized in the presence of stoichiometric
reductants such as Zn, Mn, and Grignard reagents[11] which effect
25 the Co(III)→Co(I) reduction. Cobaltꢀcatalyzed ATRA reactions
of alkynes with alkyl halides have not been reported.
5
Entry
1
Deviations from conditions above
none
3a [%] [b]
87 (63)[c]
69
2
without H2O
3
MeCN instead of acetone
without CoBr2 or Zn or dppbz
dppe instead of dppbz
dppen instead of dppbz
dppf instead of dppbz
bipy instead of dppbz
FeBr2 instead of CoBr2
NiCl2 instead of CoBr2
CrCl3 instead of CoBr2
Cp2TiCl2 instead of CoBr2
CoCl2 instead of CoBr2
CoCl2·4H2O instead of CoBr2
65
4
0
5
29 [d]
31 [d]
0 [d]
6
7
8
0 [d]
9
0 [d]
10
11
12
13
14
0 [d]
0 [d]
0 [d]
82 [d]
83 [d]
[a] Conditions: 1a (0.3 mmol), 2a (0.45 mmol), CoBr2 (2 mol%), dppbz (2
mol%), Zn (5 mol%), 0.6 mL acetone/H2O, 20 °C, 3 h. [b] GC yield vs.
internal nꢀdodecane. [c] 1 mol% CoBr2, 1 mol% dppbz, 10 mol% Zn. [d]
5
Reductive coupling & Heck-type reaction
Atom transfer radical addition (this work)
mol% CoBr2, 5 mol% dppbz, 20 mol% Zn.
45 2.2 Substrate Scope
The substrate scope of reactions between terminal and internal
aryl acetylenes and 2a (Scheme 3). Many substitution patterns
were tolerated (ortho, meta, para, electronꢀwithdrawing, electronꢀ
donating substituents). The reaction displayed remarkable compaꢀ
50 tibility with functional groups including aldehydes, halides,
nitriles, amides, hydroxyl, pyridines, thiophenes. All products
were obtained with perfect regiocontrol and high E/Z diastereoꢀ
selectivity (>50/1). However, alkylꢀsubstituted terminal alkynes
fared poorer (Scheme 4). Reactions of 2a with 1ꢀheptyne and 4ꢀ
55 phenylꢀ1ꢀbutyne, respectively, afforded mixtures of bromoꢀ
difluoroꢀalkylation and hydrodifluoroalkylation products in low
yields.
Scheme 2. Generalized mechanistic dichotomy of radical addition
reactions under lowꢀvalent cobalt catalysis.
30 2 Results and Discussion
We then examined the cobaltꢀcatalyzed halofluoroalkylation with
different fluoroalkyl halides (Scheme 5). Iododifluoroacetate
60 ICF2CO2Et, perfluoroalkyl iodides such as C4F9I, C6F13I and
C8H17I, and the perfluoroalkyl bromide C8F17Br were competent
electrophiles which afforded the desired adducts in good to
excellent yields. The fluoroalkyl bromides gave generally better
E/Z selectivities than the iodides. While this trend is in full agreeꢀ
65 ment with the literature, it can now be harnessed at much milder
conditions (room temp., 2 mol% catalyst, 3 h). BrCF2PO(OEt)2,
CF3I, and CF2Br2 afforded slightly lower yields; the reaction with
CF3I exhibited low stereocontrol. Reactions of alkylꢀsubstituted
alkynes with fluoroalkyl iodides gave good yields and moderate
70 E/Z selectivities (3acꢀ3af). The reaction conditions were also
applied to reactions of (cyclo)alkenes with halofluoroacetates
(3agꢀ3ak). A method extension to reactions of simple bromoꢀ
acetates with alkenes gave the desired adducts 3al-3an.
2.1 Discovery of a cobalt-catalyzed ATRA reaction
We commenced our investigations with the reaction of phenylꢀ
acetylene (1a) and ethyl bromodifluoroacetate (2a). Variations of
reaction conditions, solvents, and catalysts led to an optimized
35 procedure that utilized a threeꢀcomponent catalyst comprising of
CoBr2, dppbz (1,2ꢀbis(diphenylphosphino)benzene) and zinc in
acetone/water at 20 °C to furnish the synthesis of the desired
adduct ethyl 4ꢀbromoꢀ2,2ꢀdifluoroꢀ4ꢀphenylbutꢀ3ꢀenoate (3a) in
83% yield (87% GC yield, Table 1, entry 1). Significantly lower
40 yields were obtained when replacing dppbz with other bidentate
phosphines or 2,2’ꢀbipyridine (entries 5ꢀ8). Other transition
metals were inactive (entries 9ꢀ12). CoCl2 and CoCl2·4H2O
exhibited similar activity (entries 13, 14).
2
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10
Scheme 5. Cobaltꢀcatalyzed haloꢀfluoroalkylation of alkynes and alkenes.
Standard conditions: 1 (0.3 mmol), 2 (0.45 mmol), CoBr2 (2 mol%),
dppbz (2 mol%), Zn (5 mol%), 0.6 mL acetone/H2O, 20 °C, 3 h under N2.
Isolated yields given; E/Z ratios in parentheses (by 19F NMR). [a] 20 mol%
15 Zn. [b] RFꢀBr (1.0 equiv.), 10 mol% Zn. [c] RFꢀX (3.0 equiv.), 10 mol% Zn.
[d] E/Z ratio of isolated products. [e] 10 mol% Zn. [f] 6 h.
The synthetic utility of the stereoselective cobaltꢀcatalyzed haloꢀ
fluoroalkylation protocol was demonstrated in a gramꢀscale setup
which delivered pure ethyl (E)ꢀ4ꢀbromoꢀ2,2ꢀdifluoroꢀ4ꢀphenylꢀ
20 butꢀ3ꢀenoate (3a) in 86% isolated yield (1.32 g) after 3 h.
Substitution of the Br substituent in 3a by Sonogashira and
Suzuki crossꢀcoupling reactions, respectively, afforded the
fluorinated alkenes in very good yields and with complete
retention of stereochemistry (Scheme 6).
Scheme 3. Cobaltꢀcatalyzed bromoꢀcarboxydifluoromethylation of
alkynes. Standard conditions: 1 (0.3 mmol), 2a (0.45 mmol), CoBr2
(2 mol%), dppbz (2 mol%) and Zn (5 mol%), 0.6 mL acetone/H2O, 20 °C,
5
3 h under N2. Isolated yields are given; E/Z ratios in parentheses (by 19
F
NMR). [a] 20 mol% Zn. [b] 40 mol% Zn, 8 h.
Scheme 4. Reactions with alkylꢀsubstituted terminal alkynes.
25
Scheme 6. PostꢀATRA transformations by crossꢀcoupling reactions.
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2.3 Mechanistic studies
Further attention was devoted to the study of the reaction
mechanism. In addition to the initial optimization reactions
(Table 1), key mechanistic experiments were conducted. The
model reaction between 1a and 2a was completely inhibited in
the presence of 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO).
The TEMPOꢀCF2CO2Et adduct was observed by mass spectroꢀ
metry (Scheme 7, eq. 1). The TEMPOꢀCF2CO2Et adduct was not
detected when treating 2a with equimolar Zn which supports the
5
10 notion that the SET reduction of the alkyl halide is induced by the
cobalt catalyst (Scheme 7, eq. 2). Upon employment of cycloꢀ
propylacetylene (4), the vinylcyclopropane product was formed
in 11% yield while ringꢀopening to the 7ꢀbromoheptaꢀ3,4ꢀ
dienoate (56%) was the major pathway. This is in full agreement
15 with the intermediacy of an internal vinyl radical formed by
radical addition of EtO2CCF2• to the alkyne (Scheme 7, eq. 3).
Identical rates and yields were observed in reactions where 1a
and 2a were successively added to the catalyst solution. The
reverse order of addition (2a, then 1a) gave an identical result.
20 Importantly, no product was formed when –prior to the addition
of 1a and 2a ꢀ the catalyst suspension (CoBr2, dppbz, Zn) was
filtered (to remove residual zinc) or when the supernatant
solution was decanted into a new reaction vessel (eq. 4). These
experiments suggest that the initially formed Co(I) species alone
25 cannot catalyze the reaction but requires the presence of zinc, at
least for the first turnover of the catalytic mechanism. Zn is
employed only in catalytic amounts (5 mol%, i.e. 2.5 equiv. per
Co)! The addition of sodium iodide and sodium bromide,
respectively, shed light on the nature of the operating halogen
30 transfer. 1a and 2a reacted with added NaI (1.5 equiv.) to give the
iodo adduct 3u as major product (3a:3u = 1:20, Scheme 7, eq. 6).
With NaBr added, the reaction between 1a and 2b gave 3a and
3u in a 1:6 ratio (Scheme 7, eq. 7). Control experiments docuꢀ
mented that no EtO2CCF2I was converted into EtO2CCF2Br using
35 NaBr as additive; only minimal amounts of EtO2CCF2Br (<2%)
were converted to EtO2CCF2I with NaI as additive under the
same conditions. A similar outcome was observed when the
standard reaction was performed with 50 mol% CoBr2/dppbz
(3a:3u = 1:7, Scheme 7, eq. 8). These experiments document that
40 the halogen atom X in the product does not originate from the
electrophilic RFX via a direct radical chain transfer but is
transferred from the cobalt catalyst. This is a fine but important
distinction from previously reported ATRA reactions that all
involved halogen transfer from RFX to the vinyl radical. This has
45 great implications for catalyst design and reaction development as
the thermodynamics and kinetics of the halogen atom transfer
step are no longer depending on the nature of the employed
substrates but can be finely tuned through the stereoelectronic
properties of the catalyst. We further believe that halogen atom
50 transfer to a vinyl radical intermediate (rather than a vinyl cation)
is operative: (i) The addition of water (as a nucleophile) resulted
in no product bearing oxo functions; (ii) the presence of methyl
acrylate as a radical acceptor led to the formation of the hepteneꢀ
1,7ꢀdioate via radical insertion of the acrylate (eq. 9). A cationic
55 intermediate would not add to this Michael acceptor.
60
Scheme 7. Key mechanistic experiments.
species with a 31P resonance at 75.2 ppm. The 1H NMR spectrum
of this lowꢀspin Co(I) complex gave signals 7ꢀ8 ppm. No changes
were observed in 31P and 1H NMR spectra when phenyl acetylene
(1a) was added to Co(I) which suggests the absence of significant
65 alkyneꢀcatalyst coordination. On the other hand, complete
1
disappearance of the 31P (75.2 ppm) and H (7ꢀ8 ppm) signals
was observed upon addition of EtO2CCF2Br (2a). This is a direct
consequence of the reductive activation of 2a which leads to a
paramagnetic Co(II,III) species and the carbonꢀcentered
70 radical.[12] These results are consistent with the UVꢀVis spectra
(Figure 2). Reduction of Co(II) with Zn (and removal of residual
Catalyst formation and substrate additions were monitored by 31
P
NMR and 1H NMR spectroscopy (Figure 1). The reduction of the
(NMR silent) CoBr2/dppbz mixture with Zn resulted in a Co(I)
4
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Zn) resulted in an intense absorption of the Co(I) complex at 15 The standard reaction between 1a and 2a went to completion
428 nm (green curve). Addition of 1a to this solution gave no
change of the absorption in this region (blue curve), whereas the
addition of 2a to Co(I) led to immediate colour change and the
appearance of two weak bands at 412 and 451 nm (yellow curve).
within 90 min (with 2 mol% catalyst) and 12 min (4 mol%
catalyst), respectively. Analysis of the initial rates (0.5ꢀ8 min, 1ꢀ4
mol% catalyst) displayed a nearꢀ2nd order behavior of the catalyst
concentration. We postulate the following reaction mechanism
20 (Scheme 8). Complexation of dppbz with CoBr2 leads to the
formation of [CoII(dppbz)2Br]+ as observed by the soft and inert
mass spectrometric technique for sensitive organometallics
LIFDIꢀMS (liquid injection field desorption ionization mass
spectrometry). Reduction of the Co(II) complex with equimolar
25 Zn generates the catalytically active [CoI(dppbz)2Br].[12d]
Exposure to oxygen/air gives [CoIII(dppbz)2Br(O2)] (LIFDIꢀMS).
[CoI(dppbz)2Br] effects the reductive singleꢀelectron activation of
RFBr to give a [RFCoIII(dppbz)2Br]+ species (LIFDIꢀMS)[12]
which is presumably a direct result of rapid combination of the
30 intermediate Co(II) complex and free radical RF•.[14] We have
demonstrated that in the absence of residual zinc
[RFCoIII(dppbz)2Br]+ is not a catalyst (vide supra). Therefore, we
5
propose ꢀ in contrast to the lightꢀinduced CoꢀR homolysis[11g,13]
ꢀ
the reduction of [RFCoIII(dppbz)2Br]+ by Zn in the first catalytic
35 turnover to form the unstable complex [RFCoII(dppbz)2Br].
Dissociation of the fluoroalkyl radical RF• regenerates
[CoI(dppbz)2Br][12hꢀ12j] which can undergo another reductive
activation of RFX to give [RFCoIII(dppbz)2Br]+. The catalytic
amounts of Zn present in the reaction dictate that another
40 mechanism operates from the 2nd turnover on, most likely an
ATRA reaction involving halogen atom transfer from the cobalt
complex [RFCoIII(dppbz)2Br]+. Accordingly, the addition of RF•
to the alkyne results in the formation of a vinyl radical
intermediate which undergoes rapid halogen atom abstraction
45 from [CoIII(dppbz)2Br]+ to form the catalytically active Co(I)
complex and RF•.[15] The high Eꢀselectivity of the radical addition
is a direct consequence of the steric hindrance by the RF group in
the vinyl radical.[16] The higher E/Z stereoselectivity of the
bromoalkylation over the iodoalkylation reactions can be
50 explained by the shorter CoꢀBr bond (vs. CoꢀI) in the key
catalytic Co(III) species which effects an enhanced facial
differentiation of the vinyl radical. The facile operation of this
halogen atom transfer step with the intermediate vinyl radical is
the key to the realization of an overall process that is catalytic in
55 both metals, Co and Zn.
Figure 1. 31P NMR (top) and 1H NMR (bottom) monitoring of catalyst
formation and reductive electrophile activation.
3 Conclusions
We have developed a convenient cobaltꢀcatalyzed halofluoroꢀ
alkylation that exhibits wide substrate scope including terminal
and internal alkynes, alkenes, and various fluoroalkyl and alkyl
60 bromides and iodides. The protocol enables the highly regio-
selective and stereoselective synthesis of densely functionalized
halogenated (E)ꢀalkenes under very mild reaction conditions
(2 mol% catalyst, 5 mol% Zn, acetone/water, 20 °C, 3 h).
Contrary to literature reports, mechanistic studies documented for
65 the first time that the halogen atom transfer is a cobalt-mediated
process. The RFCoIIIX complex is the key catalytic intermediate
which generates the free RF• radical and mediates the halogen
atom transfer to the terminal vinyl radical. This mechanistic
deviation from substrate control to catalyst control may provide
70 the basis for the development of related halogen atom transfer
10
Figure 2. UVꢀVis absorption spectra: CoBr2/dppbz (orange); after
reduction of Co(II) with Zn to Co(I) (green); Co(I) with 1 equiv 1a (blue);
Co(I) with 1 equiv of 2a (yellow).
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reactions through catalyst design. Further, this ATRA reaction
operates without a stoichiometric reductant for the regeneration
of the lowꢀvalent Co(I) catalyst. The high functional group
tolerance and mild reaction conditions make this protocol highly
attractive in the context of complex molecule synthesis with
potential utility for medicinal chemistry endeavours.
5
Scheme 8. Proposed reaction mechanism.
Wu, R. J. Phipps and F. D. Toste, Chem. Rev., 2015, 115, 826; (l) C.
Notes and references
40 Alonso, E. M. Marigotra, G. Rubiales and F. Palacios, Chem. Rev.,
2015, 115, 1847; (m) P. Gao, X.ꢀR. Song, X.ꢀY. Liu and Y.ꢀM.
Liang, Chem. Eur. J., 2015, 21, 7648.
10 a Institute of Organic Chemistry, University of Regensburg
Universitaetsstr. 31, 93053 Regensburg, Germany
b Department of Chemistry, University of Hamburg
Martin Luther King Pl. 6, 20146 Hamburg, Germany
E-mail: axel.jacobi@chemie.uni-hamburg.de
3
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15 † Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
‡ This work was generously supported by the Deutsche Forschungsꢀ
gemeinschaft (DFG, JA 1107/6ꢀ1) and the European Research Council
(ERC, CoG 683150). We thank Dr. Michal Majek and Dr. Uttam
20 Chakraborty for insightful discussions and technical support.
1
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DOI: 10.1039/C7SC04916A
ABSTRACT: Stereoselective additions of highly functionalized reagents to available unsaturated hydrocarbons are an
attractive synthetic tool due to their high atom economy, modularity, and rapid generation of complexity. We report an
cobalt-catalyzed (E)-halofluoroalkylation of alkynes/alkenes that enables the construction of densely functionalized,
stereodefined fluorinated hydrocarbons. The mild conditions (2 mol% cat., 20 °C, acetone/water, 3 h) tolerate various
functional groups, i.e. halides, alcohols, aldehydes, nitriles, esters, and heteroarenes. This reaction is the first example
of a highly stereoselective cobalt-catalyzed radical halo-fluoroalkylation of alkynes and exceeds the efficiency and
selectivity of related protocols. The ATRA mechanism involves an unprecedented cobalt-catalyzed halogen atom
transfer and avoids the use of a stoichiometric reductant.