Nickel-Catalyzed Conversion of Enol Triflates into Alkenyl Halides

Article abstract of DOI:10.1002/anie.201906815

A Ni-catalyzed halogenation of enol triflates was developed and it enables the synthesis of a broad range of alkenyl iodides, bromides, and chlorides under mild reaction conditions. The reaction utilizes inexpensive, bench-stable Ni(OAc)₂?4 H₂O as a precatalyst and proceeds at room temperature in the presence of sub-stoichiometric Zn and either 1,5-cyclooctadiene or 4-(N,N-dimethylamino)pyridine.

Full text of DOI:10.1002/anie.201906815

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Ni-Catalyzed Conversion of Enol Triflates to Alkenyl Halides
Authors: Julie Lynn Hofstra, Kelsey E Poremba, Alex Shimozono, and
Sarah E. Reisman
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906815
Angew. Chem. 10.1002/ange.201906815
Link to VoR: http://dx.doi.org/10.1002/anie.201906815
http://dx.doi.org/10.1002/ange.201906815

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
Ni-Catalyzed Conversion of Enol Triflates to Alkenyl Halides
Julie L. Hofstra†, Kelsey E. Poremba†, Alex M. Shimozono†, and Sarah E. Reisman*
Abstract: A Ni-catalyzed halogenation of enol triflates was
developed that enables the synthesis of a broad range of alkenyl
iodides, bromides, and chlorides under mild reaction conditions.
The reaction utilizes inexpensive, bench stable Ni(OAc)2·4H2O as
a pre-catalyst and proceeds at room temperature in the presence
of sub-stoichiometric Zn and either cod or DMAP.
Indeed, Buchwald has reported a Pd-catalyzed reaction to
convert alkenyl triflates to alkenyl bromides and chlorides;11,12
however, there are no examples of alkenyl iodide formation,
and the reaction requires an expensive ligand, temperatures
greater than 100 °C, and additives such as fluoride salts or
iBu3Al. These additives limit the functional group compatibility
of the transformation, particularly with commonly used groups
such as silyl ethers. More recently, Hayashi reported a Ru-
catalyzed method to convert enol triflates to iodides, bromides,
or chlorides that proceeds at ambient temperature; however,
the requisite ruthenium catalyst is not commercially available
and limited examples of alkenyl iodide formation are
reported.13
Alkenyl halides are versatile functional groups that can be
used in a variety of carbon–carbon and carbon–heteroatom
bond-forming reactions. For example, alkenyl halides are
commonly used as substrates in transition metal-catalyzed
cross-coupling reactions1 or are converted via metal-halogen
exchange to nucleophiles for 1,2-additions to carbonyl
compounds (Scheme 1). 2 Furthermore, the alkenyl halide
moiety appears in some natural products and bioactive
R1
3
molecules. Whereas acyclic alkenyl halides are easily
cross-coupling
common methods:
Barton protocol
(via hydrazone)
prepared from the corresponding alkynes4 or aldehydes,5 most
cyclic alkenyl halides are synthesized from the corresponding
ketones. A commonly employed method is the Barton alkenyl
halide synthesis (and variations thereof),6,7, 8 which proceeds
through an intermediate hydrazone. These reactions are
notoriously capricious: the formation of the requisite hydrazone
can be challenging on sterically encumbered substrates and
the halogenation step often produces mixtures of alkenyl
halide isomers or dihalide side products.9
O
X
or
R2
HO
metal-catalyzed
stannylation then
halogenation
(via triflate)
1,2-addition
X = I, Br or Cl
via organolithium or
organomagnesium;
requires X = I, Br
strategic
intermediate
This work:
OTf
X
cat. Ni(OAc)2·4H2O, Zn0
cod or DMAP
NaI, LiBr, or LiCl
25% DMA/THF, 23 °C
As a result, enol triflates, which can be prepared directly
from cyclic ketones under either kinetic or thermodynamic
control, have emerged as attractive “pseudohalides” for
• simple catalyst
• mild conditions
X = I, Br or Cl
transition
metal-catalyzed
cross-coupling
processes.
Scheme 1. Synthesis and utility of alkenyl halides.
Unfortunately, enol triflates cannot be directly converted to the
corresponding alkenyllithium or alkenylmagnesium species
commonly employed in 1,2-addition reactions. In cases where
the Barton alkenyl halide synthesis is poor yielding, a multistep
alternative is frequently employed: 1) conversion of the ketone
to enol triflate, 2) conversion of the triflate to the stannane, and
3) conversion of the stannane to the halide.10 Direct, mild
methods to convert enol triflates to alkenyl halides, without
proceeding through organostannane intermediates, can
streamline the preparation of these valuable synthons.
During our investigations of Ni-catalyzed asymmetric
14
reductive coupling reactions of alkenyl bromides,
we
observed an off-pathway halide exchange process that
generated alkenyl chlorides and iodides. Whereas Ni-
catalyzed aryl15 and alkenyl halide exchange processes have
been previously reported and extensively investigated,15b,16
development of the corresponding reactions of enol triflates
have been limited to a single report describing bromination of
dihydropyranyl enol triflates.17,18a Having observed promising
reactivity with enol triflates in our investigation of asymmetric
reductive coupling reactions, 19 we hypothesized that an
appropriate Ni catalyst and inexpensive halide salts might
enable the direct conversion of enol triflates to alkenyl halides
under mild conditions. In this communication, we report the
development of a Ni-catalyzed triflate-halide exchange (triflex)
reaction, which provides access to alkenyl iodides, bromides,
and chlorides in good to excellent yields (Scheme 1).
[*]
J. L. Hofstra[†], K. E. Poremba[†], A. M. Shimozono[†], and Prof. S. E.
Reisman
The Warren and Katharine Schlinger Laboratory of Chemistry and
Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology
Pasadena, CA 91125 (USA)
Email: reisman@caltech.edu
Homepage: http://reismangroup.caltech.edu
These authors contributed equally to this research and are listed
alphabetically.
[†]
Supporting information for this article can be found under:
LINK HERE
This article is protected by copyright. All rights reserved.

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
coordinates ZnI2 salts that are generated as part of the initial
Ni(II) reduction. 21, 22, 23 This is consistent with the observation
that addition of exogenous ZnI2 inhibits the reaction, but that
reactivity can be restored by addition of DMAP.20 Although 2a
could be obtained in good yield with 5 mol % Ni (Table 1, entry
10), incomplete conversions were obtained for many
substrates when the scope of the iodination was investigated.
Increasing the Ni loading to 10 mol % generally improved the
conversion and allowed shorter reaction times, which was
necessary to minimize the formation of reduction product
(Method A).24
Having identified satisfactory reaction conditions, the
substrate scope of the Ni-catalyzed halogenation reaction was
investigated (Table 2). The halide exchange was found to be
compatible with a variety of common functional groups,
including amines (4), carbamates (5, 13), pyridines (20),
alkenes (12), dienes (10, 14), esters (19), ketals (6, 14), and
enones (11). Chemoselective halogenation of alkenyl triflates
was observed in preference to aryl triflates (15, 20), aryl
chlorides (9, 21), and aryl boronates (22); however,
competitive halide exchange was observed in the presence of
aryl bromides and iodides.20
Although the Ni-catalyzed halogenation exhibits good
functional group tolerance, the iodination, bromination, and
chlorination did not perform equally well. The iodination
conditions (Method A) proved optimal for roughly half of the
substrates. In cases where iodination was sluggish (6, 8, 10,
11, 13-16), longer reaction times and 5.0 equiv NaI improved
conversions; however, the improved reactivity was often
accompanied by increased amounts of protodetriflation (or
protodehalogenation, approximately 5-10% yield), and the
alkene could be difficult to chromatographically separate from
the alkenyl iodides (8a, 10a, 11a, 13a, 15a). For a subset of
these substrates (10, 11, 13), the competing reduction was
eliminated by use of Ni(cod)2 in conjunction with the enol
nonaflate, which afforded access to the pure alkenyl iodides.18
Method A
Ni(OAc)2•4H2O (10 mol %)
Zn (20 mol %), cod (20 mol%)
DMAP (20 mol%), NaI (1.5 equiv.)
1:3 DMA/THF (0.25M), 23 °C, 6h
OTf Me
X
Me
or
Me
Me
Method B
Ni(OAc)2·4H2O (5 mol%)
Zn (10 mol%), cod (10 mol%)
LiBr or LiCl (1.5 equiv)
Me
Me
2a, X = I
2b, X = Br
2c, X = Cl
1a
1:3 DMA/THF (0.25M), 23 °C, 16h
Deviation from Standard
Conditions
Yield 2a
(%)[b]
Yield 2b
(%)[b][c]
Yield 2c
(%)[b][c]
Entry
1
2
None
Ni(acac)2
Ni(X)2
87
14
75
70
12
82
0
92
85
82
94
0
90
90
0[d]
94
0
3
[e]
4
Ni(cod)2
5
DMA
THF
6
69
18
33
94
96
94
40
0
7
DMF
8
MeCN
24
33
90
87
8
9
-DMAP (I) / + DMAP (Br/Cl)
½ x Ni(OAc)2•4H2O loading
2 x Ni(OAc)2•4H2O loading
91
94
93
10
11
[a] Reactions conducted in 1:3 DMA/THF (0.25M) under inert atmosphere
on 0.1 mmol scale. [b] Determined by 1H NMR spectroscopy versus 1,2,4,5-
tetrachloronitrobenzene as an internal standard. [c] Products 2b and 2c
were found to be volatile. [d] NiCl2 was insoluble under these conditions. [e]
No Zn or additional cod were added.
Our reaction development began with enol triflate 1a,
prepared in one step from menthone, with the goal of
identifying general conditions that could provide the alkenyl
iodide, bromide, or chloride simply by changing the halide salt.
Initial optimization efforts using Ni(cod)2 as a catalyst revealed
that a mixed DMA/THF solvent system and short reaction times
were optimal, and that bidentate ligands (phosphine, amine,
and pyridine) inhibited the reaction.20 Informed by these results,
we screened a variety of Ni(II) pre-catalysts in combination with
Zn0 and cod and ultimately found that Ni(OAc)•4H2O afforded
promising yields across all three reactions. Whereas the
alkenyl bromides and chlorides could be obtained in good
yields in 16 h using 5 mol % Ni(OAc2)•4H2O and 10 mol % cod
(Method B), the iodination proceeded in modest yield under
these conditions (Table 1, entry 9). In an effort to improve the
yield of the iodination, an additive screen was conducted. This
study revealed that use of 20 mol% DMAP, in conjunction with
higher catalyst loadings, (10 mol % Ni(OAc)4, 10 mol% cod)
improved the yield of 2a. Since similar yields of 2b and 2c are
formed in the presence and absence of DMAP (Table 1, entry
9), this additive was omitted for the standard bromination and
chlorination conditions (Method B). The precise role of DMAP
in the iodination remains unclear; our hypothesis is that it
The bromination and chlorination reactions were generally
more efficient and robust. For most substrates, complete
conversions were achieved with 5 mol% Ni and without the
need for DMAP, although addition of DMAP improved the
yields for substrates where incomplete conversion was
observed with only cod (14-16). In addition, for 1-arylvinyl
triflates (19-22, Table 2) the use of Ni(cod)2 (Method C)
provided cleaner reaction profiles for the bromination and
iodination reactions.25 To demonstrate the scalability of the
reaction, bromide 13b was prepared in 95% yield on 1 mmol
scale using a benchtop setup (13b).
At this time, the mechanism of the reaction remains unclear.
Preliminary investigations of the iodination using Ni(cod)2 as
the catalyst revealed that the reaction of 1a exhibits an
induction period at low [Ni] (e.g. 0.5 mol %, 1 mol %, see
Scheme 2a).26 Plotting Vmax vs. [Ni] revealed that the reaction
has a positive-order dependence on [Ni] that negatively
deviates from first order at higher [Ni], suggesting the formation
of dimeric (or higher order) off-cycle species at higher [Ni].27
No change in the rate of iodination of 1a is observed when the
amount of NaI is increased beyond 1 equiv, however the rate
This article is protected by copyright. All rights reserved.

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Scope of alkenyl halides.[a]
Reaction was conducted on 0.2 mmol scale. [h] Reaction was conducted at
0.125 M due to poor solubility of enol triflate.
Method A
Ni(OAc)2•4H2O (10 mol %)
Zn (20 mol %), cod (20 mol%)
DMAP (20 mol%), NaI (1.5 equiv.)
dependence on [1a] was more complex.20 One possibility is
that the induction period is required to form an active NiI
catalyst. During the reaction, a signal is present in the EPR
spectrum that is consistent with a NiI-X species. However,
quantification of this signal determined that it was only 2% of
the total [Ni], and additional experiments to identify the resting
state of the catalyst have been inconclusive.
1:3 DMA/THF (0.25M), 23 °C, 6h
OTf
X
or
Method B
Ni(OAc)2·4H2O (5 mol%)
Zn (10 mol%), cod (10 mol%)
LiBr or LiCl (1.5 equiv)
1
2–23
1:3 DMA/THF (0.25M), 23 °C, 16h
A crossover experiment was designed to evaluate the
reversibility of triflate-halide exchange: treatment of a 1:1
mixture of 24-OTf and 25-Br with Ni(cod)2 (10 mol %) in 1:3
DMA/THF at 23 °C resulted in complete recovery of 24-OTf
and 25-Br, without detection of crossover products 25-OTf or
24-Br (Scheme 2b). Addition of 0.1 or 1.0 equiv LiBr resulted
in conversion of 24-OTf to 24-Br in 10% and 90% yield,
respectively;28,29 no 25-OTf was detected at any point in either
reaction. Monitoring the reaction by 1H NMR spectroscopy
confirms that no oxidative addition of 24-OTf occurs in the
absence of halide salt. Subjection of alkenyl iodide 25-I to
Ni(cod)2 (10 mol %) and metal triflate salts (e.g. NaOTf) did not
result in enol triflate formation (Scheme 2c).30 Taken together,
these experiments suggest that oxidative addition of the
alkenyl triflate is irreversible, or that halide exchange for triflate
X
X
X
Me
X
N
Me
N
Cbz
Bn
PhthN
Me
2a (I): 95%
2b (Br): 78%
2c (Cl):
3a (I):
3b (Br): 79%
3c (Cl): 83%
73%
4a (I): 91%
4b (Br): 92%
4c (Cl):
5a (I): 68%
5b (Br): 89%
5c (Cl):
73%
90%
87%
X
X
X
X
Cl
O
O
Ph
O
Cl
6a (I): 82%[b] 7a (I): 83%
6b (Br): 94%
6c (Cl): 88%
8a (I): (90%)[b]
8b (Br): 89%
8c (Cl): 95%
9a (I):
77%
7b (Br): 94%
7c (Cl): 93%
9b (Br): 92%
9c (Cl): 87%
Me
X
Me
Me
Me
Me
TBSO
X
O
Scheme 2. Mechanistic investigation.[a]
X
10a (I): (70%)[b], 54%[c,d] 11a (I): (70%)[b], 53%[c,d] 12a (I): 91%
10b (Br): 84%
10c (Cl): 88%
11b (Br): 95%
11c (Cl): 93%
12b (Br): 91%
12c (Cl): 83%
(a) Kinetic analysis.
Me
Me
X
O
Me
H
X
Me
O
Me
H
H
H
H
H
N
H
H
Boc
TfO
X
13a (I): (74%)[b], 53%[c,d]
13b (Br): 95%[e]
13c (Cl): 95%
14a (I): 85%[b,g,h]
14b (Br): 93%[f,g,h]
14c (Cl): 83%[f,g,h]
(60%)[b]
95%[f,g]
90%[f,g]
15a (I):
15b (Br):
15c (Cl):
(b) Crossover experiment.
Me
OTf
Br
Br
OTf
X
X
X
Me
X
H
H
Ni(cod)2 (10 mol %)
+
+
Me
Me
25% DMA/THF
23 °C, 2 h
H
Me
H
H
MeO2C
iPr
tBu
iPr
tBu
25-OTf
Me
16a (I): 62%[b] 17a (I): 89%
16b (Br): 78%[f] 17b (Br): 93%
16c (Cl): 75%[f] 17c (Cl): 95%
18a (I): 90%
18b (Br): 92%
18c (Cl): 88%
19a (I): 64%[d]
19b (Br): 90%[d]
24-OTf
(1 equiv)
25-Br
(1 equiv)
24-Br
24-OTf (%)[b] 25-Br (%)[b] 24-Br (%)[b] 25-OTf (%)[b]
no change
X
X
X
X
100
90
0
100
100
100
0
10
90
0
0
0
w/ LiBr (0.1 equiv)
w/ LiBr (1.0 equiv)
F
(c) Attempt to observe halide-triflate exchange.
TfO
N
Cl
pinB
I
OTf
Ni(cod)2 (10 mol %)
NaOTf (1 equiv)
20a (I): 54%[d]
20b (Br): 80%[d]
21a (I): 69%[d]
21b (Br): 73%[d]
22a (I): 68%[d]
22b (Br): 64%[d]
23a (I): 86%
23b (Br): 88%
23c (Cl): 83%
NaI (0 or 10 mol %)
25% DMA/THF
tBu
tBu
25-OTf
23 °C, 2 h
[a] Reactions conducted under inert atmosphere on 0.3 mmol scale. Isolated
yields. Yields in parentheses were determined by 1H NMR spectroscopy
versus 1,2,4,5-tetrachloronitrobenzene as an internal standard. [b] 5 equiv
NaI was used in the absence of cod, 36 h reaction time. [c] Enol nonaflate
was employed instead of enol triflate. [d] Method C: Ni(cod)2 (10 mol %),
MX (1.5 equiv), 25% DMA/THF (0.25M), 23 °C, 16 h. [e] 1 mmol scale,
benchtop protocol. [f] DMAP (10 mol %) was used instead of cod. [g]
25-I
not observed
[a] Reactions conducted under inert atmosphere on 0.2 mmol scale. [b]
Determined by GC analysis versus undecane as an internal standard.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
in the oxidative addition complex is rapid and irreversible. In
either scenario, the fact that the enol triflate is irreversibly
consumed enables the reaction to proceed in good yield to the
respective alkenyl halides. This is in contrast to Ni-catalyzed
halide exchange reactions, which are thermodynamically
driven equilibrium processes.15b For example, after 2 h, an
85:15 mixture of 25-Br:25-I is obtained for both the Ni-
catalyzed reactions of 25-Br with LiI, or 25-I with LiBr.20
In conclusion, a mild Ni-catalyzed halogenation of alkenyl
triflates has been developed. By modifying the halide salt,
alkenyl iodides, bromides, or chlorides can be obtained using
a simple, inexpensive catalyst system. These reactions
proceed at room temperature, afford the alkenyl halides in
good to excellent yields, and exhibit good functional group
tolerance.
We thank the following Caltech staff for their help: Dr. Scott
Virgil and the Caltech Center for Catalysis and Chemical
Synthesis for access to experimental and analytical
equipment; Dr. Mona Shahgholi and Naseem Torian for
assistance with mass spectrometry measurements; and Dr.
Paul Oyala for assistance with EPR experiments. We also
thank Jordan C. Beck for assistance in the preparation of
alkenyl triflates 1e and 1k. Fellowship support was provided by
the National Science Foundation (graduate research
fellowship to J. L. H. and K. E. P, Grant No. DGE-1144469). S.
E. R. is a Heritage Medical Research Institute Investigator.
Financial support from the NIH (R35GM118191-01) is
gratefully acknowledged.
Keywords: nickel • halogenation • enol triflates • catalysis •
alkenyl halides
Acknowledgements
1 (a) Metal-catalyzed Cross-Coupling Reactions; De Meijer, A., Diederich, F.,
Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: 2004; Vols. 1 & 2. (b) K.
C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem., Int. Ed. 2005,
44, 4442.
substrates, and alkenyl chlorides and bromides were not prepared. A.
G. Martinez, R. M Alvarez, A. G. Fraile, L. R. Subramanian, M.
Hanack, Synthesis 1986, 3, 222.
13 (a) E. Shirakawa, Y. Imazaki, T. Hayashi, Chem. Commun. 2009, 5088.
(b) E. Imazaki, E. Shirakawa, R. Ueno, T. Hayashi, J. Am. Chem. Soc.
2012, 134, 14760.
14 (a) A. H. Cherney, S. E. Reisman, J. Am. Chem. Soc. 2014, 136, 14365.
(b) N. Suzuki, J. L. Hofstra, K. E. Poremba, S. E. Reisman, Org. Lett.
2017, 19, 2150.
2 M. Schlosser, Ed.; John Wiley & Sons, Inc.: 2013.
3 (a) G. W. Gribble, Springer-Verlag: Wien, Austria, 1996. (b) G. W. Gribble,
Springer-Verlag: Wien, Austria, 2010. (c) G. W. Gribble, Mar. Drugs.
2015, 13, 4004.
4 (a) D. W. Hart, T. F. Blackburn, J. Schwartz, J. Am. Chem. Soc. 1975, 97,
679. (b) H. C. Brown, C. Subrahmanyam, T. Hamaoka, N. Ravindran,
D. H. Bowman, S. Misumi, M. K. Unni, V. Smayaji, N. G. Bhat, J. Org.
Chem. 1989, 54, 6068. (c) F. Gao, A. H. Hoveyda, J. Am. Chem. Soc.
2010, 132, 10961. (d) M. R. Uehling, R. P. Rucker, G. Lalic, J. Am.
Chem. Soc. 2014, 136, 8799. (e) J. Derosa, A. L. Cantu, M. N.
Boulous, M. L. O’Duill, J. L. Turnbull, Z. Liu, D. M. De La Torre, K. M.
Engle, J. Am. Chem. Soc. 2017, 139, 5183.
15 (a) K. Takagi, N. Hayama, T. Okamoto, Chem. Lett. 1978, 191. (b) T. T.
Tsou, J. K. Kochi, J. Org. Chem. 1980, 45, 1930.
16 (a) K. Takagi, N. Hayama, S. Inokawa, Chem. Lett. 1978, 1435. (b) M. C.
J. M. Hooijdonk, T. H. A. Peters, S. F. Vasilevsky, L. Brandsma, Syn.
Commun. 1994, 24, 1261. For reviews, see: (c) D. A. Petrone, J. Ye,
M. Lautens, Chem. Rev. 2016, 116, 8003. (d) G. Evano, A. Nitelet,
P. Thilmany, D. F. Dewez, Front. Chem. 2018, 6:114.
5 (a) K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408. (b)
17 (a) J. E. Milne, K. Jarowicki, P. J. Kocienski, Synlett, 2002, 4, 607. (b) The
authors note that chlorination and iodination is also feasible, but no
yields are reported. Application of these conditions to substrate 1a
provided products 2a, 2b, and 2c in <10% yield. See the Supporting
Information.
G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173.
6 (a) D. H. R. Barton, R. E. O’Brien, S. Sternhell, J. Chem. Soc. 1962, 470.
Modified Barton procedure: (b) M. E. Furrow, A. G. Myers, J. Am.
Chem. Soc. 2004, 126, 5436. (c) D. P. Ojha, K. R. Prabhu, Org. Lett.
2015, 17, 18.
18
A Ni-catalyzed trifluoromethylthiolation of alkenyl triflates was recently
7 Alkenyl bromides and chlorides can be prepared from ketones using in situ
generated P(V) reagents. However, ketones bearing multiple
enolizable positions or strained ring systems afford mixtures of
isomers: A. Spaggiari, D. Vaccari, P. Davoli, G. Torre, F. Prati, J. Org.
Chem. 2007, 72, 2216.
reported: A. Dürr, G. Yin, I. Kalvet, F. Napoly, F. Schoenebeck, Chem.
Sci. 2016, 7, 1076. Use of an enol nonaflate in place of the enol triflate
improved the yield for one example in the above report.
19 J. L. Hofstra, A. H. Cherney, C. M. Ordner, S. E. Reisman, J. Am. Chem.
Soc. 2018, 140, 139.
8
The trisilylhydrazones can be converted directly to the corresponding
20 See Supporting Information.
21
alkenyllithium reagents. (a) J. E. Stemke, A. R. Chamberlin, F. T.
Bond, Tetrahedron Lett. 1976, 34, 2947. (b) A. R. Chamberlin, J. E.
Stemke, F. T. Bond, J. Org. Chem. 1978, 43, 147. For a review, see:
(c) R. M. Adlington, A. G. M. Barrett, Acc. Chem. Res. 1983, 16, 55.
9 For a discussion of the challenges associated with hydrazone synthesis,
see ref 5b, and references found therein.
10 For a recent example of this sequence in total synthesis, see: A. D. Huters,
K. W. Quasdorf, E. D. Styduhar, N. K. Garg, J. Am. Chem. Soc. 2011,
133, 15797.
Zn(II) inhibition of Co and Ni mediated reactions has recently been
reported. (a) X. Zhang and A. McNally, ACS Catal. 2019, 9, 4862. (b)
L. Huang, L. K. G. Ackerman, K. Kang, A. M. Parsons, D. J. Weix, J.
Am. Chem. Soc. 2019, 141, 10978.
22 A XantphosNi(Br)•ZnBr2 adduct has recently been isolated from reduction
of the corresponding Ni(II) complex with Zn, demonstrating that Zn
salts can alter the Ni speciation. J. Dicciani, C. T. Hu, T. Diao, Angew.
Chem. Int., Int. Ed. 2019, in press. doi: 10.1002/ange.201906005
23 DMAP is used as an additive in aryl and alkenyl cyanation reactions using
Zn(CN)2 (a) X. Zhang, A. Xia, H. Chen, Y. Liu, Org. Lett. 2017, 19,
2118. (b) Y. Gan, G. Wang, X. Xie, Y. Liu, J. Org. Chem. 2018, 83,
14036.
11 (a) X. Shen, A. M. Hyde, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132,
14076. (b) J. Pan, X. Wang, Y. Zhang, S. L. Buchwald, Org. Lett.
2011, 13, 4974.
12
The conversion of enol triflates to alkenyl iodides using anhydrous
24 Reduction was observed in up to equimolar amounts with respect to Ni
loading; the amount of reduction observed was also dependent on
substrate and reaction time. It is possible that the reduction product
magnesium iodide and triethylamine has been reported; however,
forcing conditions were required, the scope was limited to four
This article is protected by copyright. All rights reserved.

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
alkenyl halide (2a-c) was observed concomitantly with the formation
of a Ni(I)-X species. The same Ni(I)-X species were detected upon
mixing 2a-c and Ni(cod)2 (5 mol %). Oxidative addition of aryl triflates
to (dppf)Ni(cod) was previously shown to result in Ni(I) complexes via
comproportionation: S. Bajo, G. Laidlaw, A. R. Kennedy, S. Sproules,
D. J. Nelson, Organomet. 2017, 36, 1662–1672. (b) I. Kalvet, Q. Guo,
G. J. Tizzard, F. Schoenebeck, ACS Catal. 2017, 7, 2126.
29 Relevant mechanistic studies: M. M. Beromi, A. Nova, D. Balcells, A. M.
Brasacchio, G. W. Brudvig, L. M. Guard, N. Hazari, D. J. Vinyard, J.
Am. Chem. Soc. 2017, 139, 922.
arises from the initially formed alkenyl halide and not the enol triflate
directly.
25 The treatment of 1-arylvinyl triflates with LiCl results in a competitive, non-
Ni-mediated elimination to afford the aryl acetylenes. Yang, D. Wu, Z.
Lu, H. Sun, A. Li, Org. Biomol. Chem. 2016, 14, 5591–5594.
26 Addition of exogenous cod inhibits the rate of the reaction, indicating that
ligand dissociation could also be the source of the induction period.
27 D. G. Blackmond, J. Am. Chem. Soc. 2015, 137, 10852.
28 No evidence of oxidative addition is observed when enol triflate 1a and
Ni(cod)2 (5 mol %) were mixed in the presence or absence of NaOTf.
However, upon addition of a metal halide salt, conversion of 1a to the
30 The reaction was sampled every 5 minutes, but at no time was enol triflate
25-OTf detected.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906815
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
J. L. Hofstra†, K. E. Poremba†, A. M.
Shimozono†, S. E. Reisman*
OTf
X
cat. Ni(OAc)2, Zn,
cod or DMAP
NaI, LiBr, or LiCl
25% DMA/THF, 23 °C
Page No. – Page No.
Ni-Catalyzed Conversion of Enol
Triflates to Alkenyl Halides
• simple catalyst
• mild conditions
X = I, Br or Cl
A Ni-catalyzed halogenation of alkenyl triflates was developed that enables the
synthesis of a broad range of alkenyl iodides, bromides, and chlorides under mild
reaction conditions. The reaction utilizes inexpensive, bench stable Ni(OAc)2·4H2O
as a pre-catalyst and proceeds at room temperature in the presence of sub-
stoichiometric Zn and either cod or DMAP.
This article is protected by copyright. All rights reserved.