Palladium(II)-Catalyzed Directed anti-Hydrochlorination of Unactivated Alkynes with HCl

Article abstract of DOI:10.1021/jacs.7b00892

A regioselective anti-hydrochlorination of unactivated alkynes is reported. The reaction utilizes in situ generated HCl as the source of both the Cl^- and H⁺ and is catalyzed by palladium(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-aminoquinoline bidentate directing groups are used to control the regioselectivity of the chloropalladation step and stabilize the resulting alkenylpalladium(II) intermediate for subsequent protodepalladation. This method provides access to a broad array of substituted alkenyl chlorides in excellent yields and with high regioselectivity. The products from this transformation were successfully derivatized via Stille coupling to a variety of trisubstituted alkene products. Reaction progress kinetic analysis was performed, shedding light on a possible mechanism for this catalytic process.

Full text of DOI:10.1021/jacs.7b00892

Subscriber access provided by University of Newcastle, Australia
Article
Palladium(II)-Catalyzed Directed anti-
Hydrochlorination of Unactivated Alkynes with HCl
Joseph Derosa, Annabelle L. Cantu, Mark N. Boulous, Miriam L. O'Duill,
Joshua L. Turnbull, Zhen Liu, Daizy M. De La Torre, and Keary M. Engle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00892 • Publication Date (Web): 07 Mar 2017
Downloaded from http://pubs.acs.org on March 7, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Palladium(II)-Catalyzed Directed anti-Hydrochlorination of
Unactivated Alkynes with HCl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Joseph Derosa, Annabelle L. Cantu, Mark N. Boulous, Miriam L. O’Duill, Joshua L. Turnbull, Zhen Liu, Daizy
M. De La Torre and Keary M. Engle*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
Supporting Information Placeholder
ABSTRACT: A regioselective anti-hydrochlorination of unactivated alkynes is reported. The reaction utilizes in situ generated HCl as the
source of both the Cl– and H+ and is catalyzed by palladium(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-
aminoquinoline bidentate directing groups are used to control the regioselectivity of the chloropalladation step and stabilize the resulting
alkenylpalladium(II) intermediate for subsequent protodepalladation. This method provides access to a broad array of substituted alkenyl
chlorides in excellent yields and with high regioselectivity. The products from this transformation were successfully derivatized via Stille-
coupling to a variety of trisubstituted alkene products. Reaction progress kinetic analysis (RPKA) was performed, shedding light on a possible
mechanism for this catalytic process.
spective of atom economy is the direct addition of HCl across an
1. Introduction
alkyne in a regio- and stereocontrolled fashion. In the absence of an
activating substituent on the alkyne,14 such a reaction has been
With the advent of metal-catalyzed cross-coupling chemistry,
difficult to achieve. For example, direct treatment of an unactivated
alkyne with HCl typically results in low yield of the desired alkenyl
chloride, and the method has limited functional group tolerance.15
alkenyl halides have emerged as versatile building blocks for the
synthesis of structurally complex target molecules.1 Though alkenyl
bromides and iodides have historically been more commonly used,
recent developments in ligand design have rendered alkenyl chlo-
rides equally potent coupling partners.2 In addition to their utility
as functional handles for carbon–carbon and carbon–heteroatom
bond formation, alkenyl chloride moieties are also found in natural
products and other bioactive compounds (Scheme 1a).3
Scheme 1. Examples of alkenyl chlorides in natural products
and bioactive compounds, synopsis of directed hydromet-
alation and of this work.
a. Natural products and bioactive compounds containing vinyl chlorides
O
H
H
OH
H
While alkenyl chlorides are academically and industrially useful,
current methods for their synthesis remain limited. With existing
routes originating from carbonyl or alkyne precursors, highly sub-
stituted stereochemically pure internal alkenyl chlorides remain
challenging to prepare. Additionally, these classical methods typi-
cally generate large quantities of waste and/or employ hazardous
reagents, making them non-ideal for large-scale applications.5 For
example, Wittig chloroolefination reactions require the use of stoi-
chiometric chloromethyltriphenylphosphonium halide salts,6 and
Takai chloroolefination depends on a large excess of CrCl2 in chlo-
roform solvents.7 In a similar vein, hydrometalation/chlorination
approaches from alkynes generally utilize stoichiometric quantities
of the metal hydrides ([M–H], M = B, Al, Si, or Zr), have limited
functional group compatibility due to the reducing nature of the
reactive metal hydrides involved, and require two steps.8–10 Never-
theless, substrate-directed variants of this chemistry constitute one
of the most effective ways to access highly substituted alkenyl chlo-
rides with control of regio- and stereochemistry (Scheme 1b).
Me
HO
H
Cl
H2N
Ph
NH2 Cl
Cl
Me
Cl
1
2
3
red algal metabolite
(from Plocamium cruciferum)
antibacterial agent
(from Amanita pseudoporphilia)
BPAO inhibitor
b. Directed hydrometalation /electrophilic chlorination
[H–]
Cl
Cl+
RO
M
M
H
RO
RO
R
n
hydro-
metalation
electrophilic
quenching
R
R
n
n
H
H
• stoichiometric metal hydride • strongly reducing conditions • inert atmosphere • NCS as Cl+ source
• stereo- and regiochemistry dependent on reaction conditions, metal hydride, and tether length
c. This work: Catalytic vinyl chloride synthesis via chloropalladation /protodepalladation
H
Cl–
H+
DG PdII
PdII
DG
DG
R
n
chloro-
palladation
proto-
R
R
n
n
Cl
depalladation
Cl
• 25 ppm PdII catalyst loading • broad functional group tolerance • compatible with air and moisture
• HCl as H+ and Cl– source • regiochemistry controlled by palladacycle stability •
Some success has been found using transition metal catalysts to
promote HX addition to alkynes.16 In particular, Sadighi, Miller,
and Nolan have employed gold(I) to facilitate HF addition across
alkynes.17 Notably, Miller demonstrated >20:1 regioselectivity with
internal dialkyl alkynes using a directing group approach.17b Recent-
While several different transition-metal-catalyzed approaches
towards alkenyl chlorides and other alkenyl halides have also been
disclosed,11–13 one underdeveloped route that is ideal from the per-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
ly, Dérien and colleagues reported that a ruthenium(II) complex Scheme 2. Examples of catalytic reactions involving alkyne
1
2
3
4
5
6
7
8
could catalyze Markovnikov syn-hydrochlorination with HCl,
though the method was limited to terminal aryl acetylenes and
symmetric internal alkynes.18
chloropalladation
a
Cl
Ph
10 mol% PdCl2(PhCN)2
rt, 2 h
Ph
Ph
Cl
+
Ph
Our group has recently developed a series of palladium(II)-
catalyzed alkene and alkyne hydrofunctionalizations that proceed
by directed nucleopalladation followed by protodepalladation.19
We thus questioned whether an analogous directed halopallada-
tion/protodepalladation sequence could be employed in a catalytic
synthesis of alkenyl halides from alkynes (Scheme 1c). In conceiv-
ing this approach, we took inspiration from the aforementioned
directed hydrometallation/X+ quenching approach,9–11 Miller’s
gold-catalyzed directed alkyne hydrofluorination,17b and the rich
history of alkyne halopalladation reactions (vide infra).20–23
4, 95%
(Kaneda, 1974)
(solvent)
b
c
O
Cl
O
5 mol% PdCl2(PhCN)2
MeCN, rt, N2, 1 h
(Lu, 1990)
Cl
O
H
O
9
5
6, 81%
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
CO2Me
MeO2C CO2Me
10 mol% Pd(OAc)2
LiCl, BQ
Cl
H
HOAc / acetone, 20 °C
(Bäckvall, 1994)
Cl
8, 65% (Z:E = 1.5:1)
7
2. Background and Historical Context
2 mol% Pd(OAc)2
d
Cl
CO2Me
5 equiv
4 equiv LiCl
CHO
Several literature precedents spoke to the viability of the pro-
posed chloropalladation/protodepalladation sequence. The mech-
anism of alkyne chloropalladation, which can proceed with syn or
anti stereochemistry depending on the reaction conditions, has
been extensively studied, and several examples of well-defined chlo-
ropalladated complexes have been published.20 Moreover, alkyne
chloropalladation has been employed as an elementary step in vari-
ous catalytic alkyne 1,2-difunctionalization reactions.21 In 1974,
Kaneda discovered that chloroallylation of alkynes could be cata-
lyzed by PdCl2(PhCN)2.21a,b Subsequently, Lu described several
examples of tandem reactions involving chloropalladation of an
propynoate derivative followed by cyclization onto a pendant al-
kene.21c,d,f In 1994, Bäckvall reported a closely related reaction that
is initiated by alkyne chloropalladation, followed by cyclization
onto a tethered 1,3-diene; 1,4-benzoquinone (BQ)-induced C–Cl
formation from the resultant π-allylpalladium(II) species then gen-
erates the final product.21e Shortly thereafter, Lu disclosed a tandem
reaction in which the alkenylpalladium(II) species formed via chlo-
ropalladation of an propynoic ester can participate in 1,4-conjugate
addition with an α,β-unsaturated carbonyl compound to achieve
net 1,2-chloroalkylation of an alkyne.21g
H
CO2Me
O
HOAc, rt
H
(Lu, 1996)
9, 81%
Herein, we report a regiocontrolled anti-hydrochlorination of
unactivated terminal and internal alkyne substrates, including those
lacking obvious steric or electronic bias. The reaction takes ad-
vantage of removable bidentate auxiliaries, which mask commonly
encountered amine and carboxylic acid functional groups, to pro-
mote reactivity and control regioselectivity.
Scheme 3. Previously published examples of palladium(II)-
catalyzed hydrochlorination of alkynes
5.3 mol% Pd(OAc)2
26 mol% CuCl2
3.3 equiv LiCl
a
R
H
R
DG
H
DG
9:1 MeCN:H2O
rt, 24 h
Cl
10 (DG = NMe2, R = H)
11 (DG = SPh, R = H)
12 (DG = SPh, R = Me)
13 (DG = NMe2, R = H)
14 (DG = SPh, R = H)
15 (DG = SPh, R = Me)
(Dupont, 1997)
b
2.6 mol% [(allyl)PdCl])2
10 mol% cod
X
2 equiv LiCl
Cl
H
Examples of palladium(II)-catalyzed alkyne hydrochlorination
have also been reported with terminal alkynes and haloalkynes.22 In
1997, in a study focusing on the synthesis and characterization of
anti-chloropalladated palladacycles, Dupont showed that a series of
internal alkynes (namely, propargylic amines and sulfides) readily
formed palladacycles when treated with Pd(II) and a Cl– source.23
In contrast, the authors reported that terminal alkynes instead un-
derwent hydrochlorination under these conditions, and disclosed
that this reaction could be rendered catalytic following reaction
optimization. Specifically, in the main text, three substrates, 10-12,
are described as providing 80–95% yield with catalytic Pd(OAc)2.
In the experimental section of Ref. 23, a yield of 69% is listed for the
conversion of 10 into 13, while no yields are reported for the other
two entries. Additionally, Zhu has previously demonstrated palla-
dium(II)-catalyzed anti-hydrochlorination of haloalkynes to pre-
pare 1,2-dihaloalkenes.22
Ph
X
Ph
HOAc , 80 °C, 5–6 h
(Zhu, 2012)
16 (X = Cl)
17 (X = Br)
18 (X = Cl), 85%
19 (X = Br), 87%
3. Results and Discussion
3.1 Attempts to Reproduce Previously Published
Procedure
To initiate our study, we selected substituted propargyl amines
as the pilot substrate class. In addition to the synthetic utility of the
resultant chloroallylamine products, our motivation for studying
these substrates stemmed from the unique bioactivity of these
products.3
Our investigation commenced with revisiting the previous litera-
ture report from Dupont and coworkers, in which anti-
hydrochlorination of terminal alkyne substrates 10–12 was de-
scribed.23 In our hands, although stoichiometric anti-
chloropalladation of two representative internal alkynes proceeded
as described (see Supporting Information), the catalytic hydro-
chlorination did not yield detectable quantities of the desired
product 13. Instead, only Glaser homodimerization product was
observed 20. (Table 1, entry 1)
Generally speaking, the aforementioned previous reports on cat-
alytic transformations involving chloropalladation have involved
terminal alkyne substrates, symmetrically substituted internal al-
kynes, or electronically activated alkynes. In the absence of steric
and electronic bias, controlling the regioselectivty of this elemen-
tary step has remained a challenge.
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
Table 1. Attempts to reproduce reported hydrochlorination of N,N-dimethylpropargyl amine (10), as described in Ref. 23.a
1
2
3
4
5.3 mol% Pd(OAc)2
26 mol% CuCl2
3.3 equiv LiCl
H
NMe2
+
NMe2
H
NMe2
Me2N
9:1 MeCN:H2O
rt, 24 h
Cl
13
(desired)
10
20
5
6
7
8
9
LiCl
Pd(OAc)2
Entry
CuCl2
Temp. (ºC) Atmosphere Co-solvent % Glaser (20) % Alkenyl Chloride (13) % SM (10)
10
1
2
3
4
5
Johnson Matthey, 98%
Johnson Matthey, 98%
Johnson Matthey, 98%
Johnson Matthey, 98%
Johnson Matthey, 98%
rt
rt
air
H2O
H2O
H2O
H2O
H2O
32
39
22
27
29
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
35
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
O2
N2
rt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
30
50
air
air
n.d.
n.d.
6
7
8
Johnson Matthey, 98%
Johnson Matthey, 98%
Johnson Matthey, 98%
Sigma-Aldrich, 99%
Alfa Aesar, 99.995%
Acros, 98%
rt
rt
rt
air
air
air
H2O
H2O
H2O
25
30
28
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
9
Combi-Blocks, 98%
Oakwood, 98%
rt
rt
rt
rt
air
air
air
air
H2O
H2O
H2O
H2O
26
31
28
36
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
<5
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Alfa Aesar, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
10
11
Ark Pharm, 98%
12 Sigma-Aldrich, 99.98%
13
14
15
Johnson Matthey, 98%
Johnson Matthey, 98%
Johnson Matthey, 98%
rt
rt
rt
rt
rt
rt
air
air
air
air
air
air
H2O
H2O
28
28
23
29
26
23
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
Ward Science, 98%
MP Biomedical, 95%
MP Biomedical, 95%
MP Biomedical, 95%
Acros Organics, 99%
Sigma-Aldrich, >99.9%
Sigma-Aldrich, 99%
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
Acros Organics, 99%
H2O
16 Johnson Matthey, 98%
17 Johnson Matthey, 98%
18 Johnson Matthey, 98%
H2O
H2O
2 M HCl (aq.)
MP Biomedical, 95%
a Percentages correspond to 1H NMR yields using CH2Br2 as an internal standard. n.d. = not detected.
Details pertinent to several reaction variables were not enumer-
ated in the publication by Dupont, including atmosphere, tempera-
ture, and metal salt supplier/purity (Table 1). Thus, we next sought
to systematically exclude these variables as possible origins of the
discrepancy between our results and the published results. The
authors did not specify the reaction atmosphere, and our isolation
of Glaser homodimerization product 20 suggested to us that O2
could be responsible for facilitating consumption of the starting
material along this undesired pathway. To probe this, we compared
the results when the reaction was run under air, O2 (1 atm), and N2
(1 atm) (entries 1–3). While the use of N2 did suppress starting
material consumption as hypothesized, this was not accompanied
with formation of the desired product 13 (entry 3). Next, we
probed reaction temperature. In the published procedure, the reac-
tion was described as proceeding at room temperature, which can
obviously vary from laboratory to laboratory. In our own laborato-
ry, room temperature corresponds to an average temperature of
20–22 °C. Performing the reaction at elevated temperatures of 30
and 50 °C did not significantly change the product distribution
(entries 4 and 5). In the published manuscript, the authors stated
that all chemicals were used as received from commercial suppliers,
but the suppliers were not specified. Thus, we obtained samples of
10, Pd(OAc)2, CuCl2, and LiCl of varying purities and from differ-
ent suppliers (entries 6–17). Notably, the purity and crystal form of
Pd(OAc)2 is special importance given the well documented effects
of different forms of Pd(OAc)2 on reaction outcome in catalysis.23
No difference in reaction outcome was observed as a function of
changing these variables. Lastly, based on observations that we
discuss later in this paper, we reasoned that substitution of H2O for
an aqueous solution of HCl could potentially promote product
formation. However, when this was attempted, no substantial
change in product distribution was observed (entry 18).
Finally, authentic samples of 13 and 14 were prepared using the
procedure developed in this manuscript (see Supporting Infor-
mation). Some of the analytical data from our samples agreed with
the previously reported data, while other data did not. Notably, 13
is volatile (estimated b.p. = 40–60 °C), which made it most conven-
ient to isolate as a solution in Et2O. In Ref. 23, 13 is reportedly
isolated in pure form after an aqueous workup, extraction with
Et2O, and removal of solvents; the volatility of 13 is not discussed.
No original spectra were provided in the previous report. Thus, no
firm conclusions could be drawn from comparison of the two sets
of analytical data.
Overall, though we were unable to pinpoint the origin of the dis-
crepancies between our results and those of Dupont, we did man-
age to rule out several possibilities. Plausible remaining explana-
tions include the presence of an as of yet unidentified impurity that
suppressed the reaction in our case or enhanced reactivity in the
case of Dupont, or differences in the purity or crystal form of the
metal salts involved. These issues were not examined further in the
present investigation. A detailed description of experimental pro-
cedures, original NMR spectra, and accompanying data tables can
be found on the Supporting Information.
Owing to the potential synthetic utility of a generally applicable
directed alkyne hydrochlorination to synthesize alkenyl chlorides
and based on the difficulty in reproducing this existing method and
the limited scope described in the initial publication, we reasoned
that it would be valuable to develop a procedure that was robust,
operated at low (<1 mol%) catalyst loading, displayed good func-
tional group tolerance, and gave high regioselectivity with internal
alkyne substrates.
3.2. Optimization of Reaction Conditions
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
Table 2. Optimization of Alkyne Hydrochlorinationa,b
Among many mono- and bidentate directing groups tested (en-
cat. PdII, [Cl–]
additive
1
2
3
4
5
6
7
8
tries 15–22), Daugulis’s N,N-bidentate picolinamide (PA) direct-
ing group delivered the highest yield. Interestingly, besides the PA
group, only the pyrimidine-2-carboxamide (entry 19) and N,N-
dimethylamino (entry 22) analogs provided detectable quantities
of the desired product under optimized conditions. Other directing
groups resulted in either no reaction or substrate decomposition. In
all three cases where the product was observed, only a single regioi-
somer was detected.
H
DG
Ph
DG
solvent (1.0 M), 2 h
Cl– Source
Additive
Ph
Cl
cat. PdII
Yield (%)
Solvent Temp. (ºC)
Entry
DG
1
2
3
4
5
6
7
10% PdCl2
10% PdCl2
10% PdCl2
--
--
80
80
80
80
80
80
80
10
33
36
0
A
A
A
A
A
A
A
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
DMF
DMF
CuCl2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DMF
DMF
9
It is important to note that use of anhydrous HCl in 1,4-dioxane
as the chloride source also led to reasonably high yield of the prod-
uct (entries 23 and 24), though the reaction was not as efficient as
with the in situ HCl source, possibly due to inhibition by 1,4-
dioxane.
10% PdCl2
10% PdCl2
10% PdCl2
13
16
38
MeCN
toluene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMA
8
10% PdCl2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
--
Cu(OTf)2
80
80
<5
54
71
74
56
69
83
96
A
A
A
A
A
A
A
A
DMA
DMA
DMA
DMA
DMA
NMP
DMA
DMA
9
SOCl2
Cu(OTf)2
10
11
12
13
14
15
AcCl/H2O
AcCl/H2O
BzCl/H2O
AcCl/H2O
AcCl/H2O
AcCl/H2O
Cu(OTf)2
80
Table 3. Hydrochlorination with Different Catalyst Load-
ingsa
--
--
--
--
--
80
80
cat. Pd(OAc)2
4 equiv AcCl
80
6 equiv H2O
NHPA
100
120
Ph
DMA, 120 °C
21a
22a
[X-ray]
16
17
18
19
20
21
22
23c
24
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
AcCl/H2O
AcCl/H2O
--
120
120
120
120
120
120
120
120
120
0
0
B
C
D
E
F
DMA
DMA
DMA
DMA
DMA
DMA
Pd(OAc)2 (mol%)
Yield 22a (%)
Entry
Time (h)
--
1
5
1
2
6
96
AcCl/H2O
--
0
2
93
AcCl/H2O
--
64
0
3
0.1
12
16
24
24
94
AcCl/H2O
--
--
4
0.01
0.0025
0
91
G
H
A
A
5b
6
92 [90]
n.d.
AcCl/H2O
0
5% Pd(OAc)2
5% Pd(OAc)2
AcCl/H2O
--
61
81
79
DMA
DMA
HCl in dioxane
HOAc
--
1
aYields were determined by H NMR using CH2Br2 as an inter-
5% Pd(OAc)2 HCl in dioxane
DMA
b
nal standard. n.d. = not detected The value in brackets corre-
sponds to the yield from a trial without the magnetic stir bar.
O
N
O
O
O
i-Pr
O
S
N
Under our optimal reaction conditions, we ultimately found
that the catalyst loading could be reduced to 25 ppm Pd(OAc)2,
while still delivering 92% (36,800 TON) of the desired product
over a longer reaction time of 24 h (Table 3). To exclude the possi-
bility that trace metal contaminants on a previously used magnetic
stir bar were contributing to the observed results, we performed the
reaction without a stir bar and found a similar yield (entry 5). The
connectivity of 22a was verified by X-ray crystallography, confirm-
ing the anticipated regio- and stereochemistry. In the absence of
the Pd(OAc)2 catalyst, hydrochlorination product was not ob-
served (entry 6). Moreover, no changes in catalyst performance
were noted as a result of the commercial supplier of Pd(OAc)2.
We next considered whether any other transition metals could
also promote directed alkyne hydrochlorination (Table 4). Our
motivation here was threefold. First, we were curious whether other
transition metals might give different stereo- or regiochemical out-
comes based on their size and/or electronegativity. Second, we
thought alternatively, that if a less expensive metal (e.g., Co(II))
demonstrated some level of reactivity, even if it was lower, it could
be a valuable starting point for further optimization towards indus-
trial applications. Third, the effectiveness of extremely low amounts
of Pd(OAc)2 prompted us to consider whether trace quantities of
another highly reactive metal contaminant in the commercial
Pd(OAc)2 could be at the root of our observations. Hence, we ex-
amined several common representative metal salts under optimized
conditions, and in all cases that we tested, we generally observed
unreacted starting material accompanied by no more than 5% of
22a, as determined by 1H NMR of the crude reaction mixture.
N
N
i-Pr
N
H
N
H
H
H
N
N
O
MeO
A (NHPA)
B
C
D
DG =
N
O
O
O
Me
N
N
H
N
N
H
H
Me
N
S
E
F
G
H
aAlkyne (1.0 equiv), chloride source (4.0 equiv), additive (30
1
mol%). b Yields were determined by H NMR using CH2Br2 as an
internal standard. c HOAc (6 equiv).
To develop an effective alkyne hydrochlorination with 3-
arylpropargylamine substrates, the reaction conditions and direct-
ing group structure were optimized in parallel (Table 2).25 Using
Daugulis’s N,N-bidentate picolinamide (PA) directing group,25a we
first focused on reactions involving LiCl and Cu(II) additives (Ta-
ble 1, entries 1–8). Compared with LiCl as the sole chloride source
(entry 1), the addition of a copper(II) salt improved the yield (en-
tries 2 and 3). Using LiCl and Cu(II) additives, we optimized with
respect to plausible variables, including palladium source, solvent,
temperature, ligand, and reaction time, without success (selected
examples of which are shown in Table 1). Eventually, we turned to
alternative chloride sources, and we were delighted to observe a
dramatic increase in yield when the chloride nucleophile was gen-
erated in situ from hydrolysis of a suitable precursor and water (en-
tries 9–16). Under these conditions, we discovered that copper(II)
additive was no longer required (entries 10 and 11). After extensive
screening, the optimal conditions were found to be with 5 mol%
Pd(OAc)2 as the catalyst and AcCl/H2O as the chloride source in
DMA at 120 °C for 2 h (entry 15).
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
Table 4. Hydrochlorination with Different Metal Catalystsa
favor of product 22b is possibly attributable to neighboring group
1
2
3
4
5
6
participation of the amide in stabilizing the putative vinyl carbo-
cation intermediate prior to Cl– attack. These results reaffirm that
the optimized hydrochlorination reaction is indeed catalyzed by
Pd(OAc)2 and establish that alternative non-metal-mediated HCl
alkyne addition pathways to 21a and 21b have higher activation
energies and are far less selective.
5 mol% Catalyst
4 equiv AcCl
6 equiv H2O
H
NHPA
Ph
NHPA
Ph
DMA, 120 ºC, 2h
Cl
21a
Entry
22a
Catalyst
% 21a
% 22a
7
8
9
10
11
12
13
Cu(OTf)2
[RhCl(cod)]2
NiCl2•glyme
Fe(acac)3
Ru(acac)3
CoCl2
1
2
3
4
5
6
91
81
80
76
93
97
<5
<5
3.3. Evaluation of Substrate Scope
We next investigated the substrate scope of this palladium(II)-
catalyzed alkyne hydrochlorination (Table 3). Reasoning that end-
users sometimes desire the shortest possible reaction time, while at
other times, they prioritize achieving the lowest possible catalyst
loading, we tested starting materials under two sets of reaction
conditions: (1) 5 mol% Pd(OAc)2 for 2 h and (2) 25 ppm
Pd(OAc)2 for 24 h.
n.d.
n.d.
n.d.
n.d.
a Yields were determined by H NMR using CH2Br2 as an inter-
nal standard. n. d. = not detected.
1
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Additional control experiments in the absence of
a
Table 6. Substrate Scope with PA Directing Groupa
Pd(OAc)2
5 mol% Pd(OAc)2
4 equiv AcCl
6 equiv H2O
R2
O
(PA)
H
R2
a
4 equiv AcCl
6 equiv H2O
H
Cl
N
H
R1
NHPA
n
n
R1
N
NHPA
21a
DMA, 120 °C, 2 h
+
Cl
H
Ph
NHPA
Ph
NHPA
Ph
21
(n = 1, 2)
22
DMA, 2 h
Cl
H
22a
22a'
[no metal catalyst]
H
NHPA
H
NHPA
H
NHPA
H
NHPA
NHPA
Entry
Temp. (°C) % 21a
% 22a
% 22a'
H
Et
Me
n-Bu
Cl
22e
Cl
Cl
22b
Cl
Cl
22d
1
2
120
150
88
n.d.
<5
n.d.
n.d.
22a
22c
85% (5 mol%)
87% (25 ppm)
82% (5 mol%)
85% (25 ppm)
96% (5 mol%)
87% (5 mol%)
88% (25 ppm)
83% (5 mol%)
82% (25 ppm)
n.d.
95% (25 ppm)b
H
NHPA
H
NHPA
H
NHPA
H
NHPA
Me
b
4 equiv AcCl
6 equiv H2O
H
H
Cl
Cl
Cl
Cl
Cl
F3C
Me
F
NHPA
+
Et
NHPA
Et
NHPA
22f
22g
22h
22i
Et
DMA, 2 h
89% (5 mol%)
82% (25 ppm)
94% (5 mol%)
91% (25 ppm)
88% (5 mol%)
89% (25 ppm)
92% (5 mol%)
87% (25 ppm)
Cl
H
21b
[no metal catalyst]
22b
22b'
H
NHPA
H
NHPA
H
NHPA
O
H
NHPA
Me
Entry
Temp. (°C) % 21b
% 22b
n.d.
% 22b'
n.d.
Cl
Cl
Cl
Cl
Br
Cl
H2N
83
1
120
150
22j
22k
22l
22m
91% (5 mol%)
92% (25 ppm)
2b
94% (5 mol%)
92% (25 ppm)
93% (5 mol%)
78% (5 mol%)
72% (25 ppm)
n.d.
37
19
91% (25 ppm)b
H
NHPA
H
NHPA
a Yields were determined by H NMR using CH2Br2 as an inter-
OMe H
NHPA
1
H
NHPA
b
nal standard. n. d. = not detected. Products 22b and 22b’ were
inseparable. Compound 22b was independently prepared (see
Table 6), allowing for assignment of its stereochemistry as Z (anti
addition). Compound 22b’ was tentatively assigned as Z by analo-
gy and on the basis of relevant literature precedents of HCl addi-
tion to alkynes (Ref. 15). The regiochemistry of 22b’ was assigned
based on the splitting pattern in the 1H NMR spectrum of the crude
reaction mixture.
Cl
Cl
Cl
22q
82% (5 mol%)
75% (25 ppm)
Cl
22p
N
CO2Me
OMe
22n
22o
94% (5 mol%)
91% (25 ppm)
91% (5 mol%)
71% (5 mol%)
68% (25 ppm)
91% (25 ppm)b
H
NHPA
H
NHPA
H
NHPA
H
NHPA
Me
S
Cl
22r
TMS
Cl
Cl
Cl
22u
91% (5 mol%)
94% (25 ppm)
22s
22t
82% (5 mol%)
83% (25 ppm)
55% (5 mol%)
50% (25 ppm)
68% (5 mol%)
70% (25 ppm)
NHPA
NHPA
NHPA
NHPA
H
H
H
H
Lastly, we performed a final set of control experiments (Table 5).
As mentioned above, in the absence of Pd(OAc)2, the optimized
reaction conditions at 120 °C resulted in recovery of substrate 21a.
When the temperature was raised to 150 °C, significant decomposi-
tion of starting material was observed, accompanied by only trace
amounts of hydrochlorination. Given the low yield (<5%) in this
experiment, we could not conclusively determine the regioselectivi-
ty of the reaction. We speculated a dialkyl alkyne substrate (21b)
could potentially be more reactive with HCl in the absence of
Pd(OAc)2; however, again no reaction took place at 120 °C. At an
elevated temperature of 150 °C, alkyne hydrochlorination was ob-
served in the absence of Pd(OAc)2; however, the reaction pro-
duced an approximately 2:1 mixture of regioisomers 22b:22b’ in
combined 56% yield (1H NMR), compared to 87% yield of 22b as
a single regioisomer in the presence of catalytic Pd(OAc)2 (vide
infra). The fact that the reaction showed modest regioselectivity in
MeO2C
H
Cl
Cl
22w
Cl
Cl
22v
22x
22y
54% (5 mol%)c
53% (25 ppm)
81% (25 ppm)
83% (25 ppm)
73% (25 ppm)
a Reaction conditions: 21a–y (0.1 mmol), AcCl (0.4 mmol), H2O
(0.6 mmol), Pd(OAc)2 (5 mol% or 25 ppm), DMA (1 mL), 120
ºC, 2 h or 24 h. Percentages represent isolated yields via column
chromatography. b 1.0 mmol scale. c 42% yield of hydroacetoxyla-
tion byproduct (see Ref. 26).
We first tested dialkyl alkynes (21b–d), which have no inherent
steric bias between the two positions and no substituents in conju-
gation with the alkyne π-system. These substrates underwent the
desired transformation with high efficacy and selectivity (22b–d),
as did terminal alkyne substrates (22e and 22f). Aryl rings on the
ACS Paragon Plus Environment

Journal of the American Chemical Society
alkyne with both electron-donating and -withdrawing substituents
Page 6 of 11
3.4. Synthetic Applications
1
were well tolerated, providing products 22g–p in excellent yields.
Notably, carbonyl-containing functional groups (22m and 22n),
which are susceptible to reduction in classical hydromet-
alation/electrophilic halogenation sequences (vide supra), were
preserved under these reaction conditions. Moreover, the reaction
was also tolerant of a potentially coordinating free amine and a
sterically encumbering ortho-substituent (22l and 22p). We were
also pleased to observe compatibility with two heterocycles, pyri-
dine and thiophene (22o and 22r). Functional handles that could
enable downstream diversification were preserved under the reac-
tion conditions, such as pendant halides (22j and 22k), a TMS-
substituted alkyne (22s), and a vinyl group (22t). We then ex-
plored the effect of alkyl branching and found that while mono α-
substitution was well-tolerated (22f and 22u), gem-α,α-
disubstitution led to no reaction, presumably due to added steric
hindrance during approach of the chloride anion to the backside of
Pd(II)-bound alkyne (see Supporting Information).
To demonstrate that the reaction was scalable, three representa-
tive products, 22a, 22j, and 22n, were prepared on 1 mmol scale
with 25 ppm catalyst loading, and the yields in all three cases were
comparable to those in the smaller scale trials (Table 6). We then
scaled up the reaction further, synthesizing 22a on gram scale,
without noticeable drop in yield. With ample quantities of a repre-
sentative alkenyl chloride product in hand, we then sought to iden-
tify reaction conditions to enable removal of the PA directing group
in high yield. Given that alkenyl halides are known to be susceptible
to HX elimination in the presence of strong base, we were con-
cerned that this might complicate deprotection. In practice, how-
ever, the PA directing group was readily cleaved via KOH hydroly-
sis in ethanol to produce free amine 23a in 92% yield (Scheme 2).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Gram-scale reaction and removal of Picolinoyl
(PA) Group
a
1 mol% Pd(OAc)2
4 equiv AcCl
H
In order to probe the effects of a longer tether length on reaction
performance, four homopropargyl substrates were tested. We were
pleased to find that the products 22w–22y (presumably proceed-
ing via a six-membered palladacycle) were formed in generally
good yields. In the case of 22v, a lower yield of 54% was obtained,
and a hydroacetoxylation byproduct was also formed in 42% yield,
which is believed to arise from competitive acetate addition.26 The
presence of an electron-withdrawing group (as in the case of 22x)
appeared to suppress formation of this byproduct.
6 equiv H2O
NHPA
Ph
NHPA
Ph
DMA, 120 ºC, 6 h
Cl
21a
[gram-scale]
22a, 91% yield, 1.23 g
b
H
H
KOH
EtOH, reflux
Ph
NHPA
Ph
NH2
Cl
21a
Cl
23a, 92%
Table 7. Substrate Scope with AQ Directing Groupa
To showcase the versatility of the products, we selected one rep-
resentative cross-coupling reaction, Stille coupling with organos-
tannanes, and tested several different reaction partners under unop-
timized standard conditions. To our delight, we found that het-
eroaryl, vinyl and alkynyl stannanes could be coupled in high yields,
5 mol% Pd(OAc)2
4 equiv AcCl
6 equiv H2O
R1
O
Cl
AQ
Cl
R1
N
DMA, 120 ºC, 2 h
H
H
O
N
(AQ)
24
23
delivering
hydro(hetero)arylation,
the
products
of
anti-hydroacylation,
-
-
Cl
Cl
-hydroalkenylation,
and
AQ
AQ
AQ
Et
Me
n-Pr
hydroalkynylation over two high-yielding steps (26–30). The tri-
substituted alkene products would be difficult to access using other
methods.
H
O
H
O
H
O
24a, 84%
24c, 81%
24b, 79%
aReaction conditions as in Table 3. Percentages represent isolated
yields.
Scheme
5.
Product
Diversification
via
Stille
Couplinga
OEt
Having demonstrated the scope of this hydrochlorination pro-
tocol with propargyl and homopropargyl picolinamides, we turned
our attention to alternative bidentate directing groups that could be
used to mask functional groups other than amines. Based on our
previous success using Daugulis’s 8-aminoquinoline (AQ) auxilia-
ry25a to direct palladium(II)-catalyzed alkene hydrofunctionaliza-
tion,19 we investigated a series of 3-butynoic acid derivatives bear-
ing the AQ group. We were pleased to discover that the hydrochlo-
rination reaction was also compatible with this substrate class, de-
livering the corresponding chlorovinylacetic acid products 24a–c
in high yields (Table 7). Similar to examples with the PA directing
group, hydrochlorination with the AQ group was highly stereo- and
regioselective. However, in contrast to the PA-directed examples
with amine-derived substrates, with 3-butynoic acid bearing the
AQ auxiliary, the chloride is installed distal to the directing group.
Presumably the origin of this observation is again rooted in the
propensity of chloropalladation to proceed to form the more ther-
modynamically stable 5-membered palladacycle. In this case, that
would involve attack of Cl– at the γ position of the substrate (exo to
the thusly formed palladacycle).
X
H
H
Bu3Sn
Bu3Sn
Ph
Me
NHPA
Ph
NHPA
O
X
26, 74%
21a
+
RSnBu3
(1.5 equiv)
27 (X = S), 84%
28 (X = O), 87%
15 mol% Pd(OAc)2
30 mol% XPhos
2 equiv KOAc
THF, 100 °C, 12 h
H
H
Ph
NHPA
Ph
NHPA
Ph
Bu3Sn
Ph
Bu3Sn
30, 82%
29, 85%
Ph
Ph
aReaction conditions: 21a (0.1 mmol), RSnBu3 (0.15 mmol), 15
mol% Pd(OAc)2, 30 mol% XPhos, KOAc (0.2 mmol), THF (0.5
mL). Percentages represent isolated yields.
3.5. Mechanistic Discussion
We next considered the mechanism of this directed alkyne hy-
drochlorination reaction. This transformation could be envisioned
to follow two general pathways (Scheme 6). In the first (Pathway
A), the reaction would proceed as discussed in the introduction.
Namely, binding of PA directing group to palladium(II) brings the
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
alkyne moiety in close proximity to the palladium(II) center. π- To identify the origin of the hydrogen atom under catalytic con-
1
2
3
4
5
6
7
8
Lewis acid activation would induce anti-chloropalladation. Proto-
depalladation of the resultant alkenylpalladium(II) species then
would form the final product without a change in oxidation state at
palladium. In an alternative scenario (Pathways B1 and B2),27 the
reaction would begin with coordination of the palladium(II) cata-
lyst to the π-system of the alkyne (presumably without simultane-
ous binding of the directing group due to geometric constraints),
which would trigger O-cyclization of the tethered amide to gener-
ate an alkyenylpalladium(II) species.28,29 This species could either
undergo protodepalladation followed by chloride-mediated oxazo-
line ring opening (Pathway B2)30 or could be attacked by chloride,
triggering rearrangement to intercept the chloropalladated pal-
ladacycle intermediate in Pathway A (Pathway B1).
ditions, we carried out a deuterium incorporation study where H2O
was substituted with D2O in dry DMA under otherwise standard
reaction conditions (Scheme 7). The resulting product contained
approximately 52% deuterium at the vinylic position, with no other
position showing deuterium incorporation. The N–H bond of the
substrate presumably serves as the source of hydrogen atoms in this
experiment. This result is consistent with a protodepalladation
mechanism. Additionally, given that there are ≥4 equiv of reactive
D+ relative to H+ and only 52% deuterium incorporation is ob-
served, it also suggests that there is a large kinetic isotope effect
(KIE) (vide infra).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.100
a
Scheme 6. Potential Pathways for Product Formation
Pathway A
0.080
Standard
Standard
O
O
Cl–
H
Cl–
H+
N
N
0.060
0.040
0.020
0.000
PPrerem-mixix (AcCl+H2O)
Cl
PA
R
N
H
PdII
X
N
N
PdII
L
intermolecular
anti-chloro-
palladation
proto-
depalladation
Cl
R
R
Cl–-mediated
oxazoline ring opening
Cl–
Cl–
B1
B2
Pathways B1 and B2:
R
R
[PdII
]
H
O
H+
O
O
N
H
proto-
depalladation
N
N
intramolecular
anti-oxy-
palladation
R
N
[PdII
]
N
N
0
20
40
60
80
100
120
Time (min)
To distinguish between these possibilities, we first noted that the
hydrochlorination reaction still proceeded (albeit in diminished
yield) using a dimethylamino directing group (Table 2, entry 22),
which lacks the requisite carbonyl moiety for Pathways B1 and B2.
To probe this further, we independently prepared putative oxazo-
line intermediate 31 and resubmitted it to the reaction conditions
in the presence and absence of Pd(OAc)2 (Table 8). These exper-
iments led to substrate decomposition, accompanied by at most
trace product formation. These results are inconsistent with Path-
way B2. While we were unable to definitely rule out Pathway B1,
we favor Pathway A given the aforementioned results with the di-
methylamino directing group and in light of it being more con-
sistent with the extensive body of literature on alkyne chloropal-
ladation.
0.100
b
0.080
0.060
0.040
0.020
0.000
Standard
Standard
21a [excess] = 0.08 M
21a [excess] = 0.08 M
H O [excess] = 0.3 M
H2O [excess] = 0.3 M
2
AcCl [excess] = 0.2 M
AcCl [excess] = 0.2 M
Pd(OAc)2 [excess] = 0.01 M
Pd(OAc)2 [excess] = 0.01 M
Table 8. Oxazoline Control Experimentsa
0
20
40
60
80
100
120
cat. Pd(OAc)2
Ph
4 equiv AcCl
6 equiv H2O
O
Time (min)
H
H
Figure 1. Probing the effect of acid chloride hydrolysis on global
kinetics by carrying out different [“excess”] experiments in con-
junction with a “pre-mix” addition experiment.
Ph
NHPA
N
DMA, 2 h
Cl
N
31
22a
a) Hydrochlorination using Pd(OAc)2 (0.005 M), 21a (0.1 M);
red curve (standard): H2O (0.6 M) added prior to AcCl (0.4 M);
blue curve (pre-mix): solution of H2O (0.6 M) and AcCl (0.4 M)
stirred at 120 ºC for 1 h and then added; b) Hydrochlorination
different-excess experiments; red curve (standard): 21a (0.1 M),
Pd(OAc)2 (0.005 M), H2O (0.6 M), AcCl (0.4 M); all other exper-
iments correspond to the standard, with different-excess compo-
nents as listed above.
Pd(OAc)2
Entry
Temp. (°C)
% 31
% 22a
120
150
120
150
1
2
3
4
n.d.
<5
--
--
34
<5
41
<5
5 mol%
5 mol%
n.d.
<5
a Yields were determined by H NMR using CH2Br2 as an inter-
nal standard. n. d. = not detected.
1
Scheme 7. Deuterium Incorporation Study
5 mol% Pd(OAc)2
4 equiv AcCl
6 equiv D2O
We next performed reaction progress kinetic analysis (RPKA),
which is an established tool for elucidating the mechanistic details
of catalytic processes from a minimum number of experiments.31
After first establishing a robust, standard protocol for monitoring
reaction kinetics by injecting AcCl to a preheated solution of the
H/D
NHPA
Ph
NHPA
Ph
DMA, 120 ºC
Cl
21a
22a, 92% yield
(52% D)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
other reactants and Pd(OAc)2 in DMA, we wanted to determine kinetics in substrate. A lesser concentration of AcCl led to a lower
1
2
3
4
5
6
7
8
whether the rate of acetyl chloride hydrolysis was relevant the glob-
al rate of hydrochlorination. To test this, we compared the rate
profile of a reaction under standard conditions to one in which the
acetyl chloride and water had been premixed. Specifically, in this
latter trial, a solution of acetyl chloride and water in DMA was
heated to 120 °C for one hour, at which point an aliquot was taken
and injected into a solution of the other reaction components to
initiate the reaction. The resulting overlay of the premixed trial and
the standard trial allowed us to conclude that the hydrolysis of acid
chloride to release HCl in solution does not influence the global
rate, consistent with the notion that the AcCl is completely hydro-
lyzed at the beginning of the reaction. This means that provided
[H2O]0 ≥ [AcCl]0, [HCl]0 = [AcCl]0 (Figure 1a). In the alternative
scenario where H2O is the limiting reagent in hydrolysis, more
complex kinetics are anticipated, which outside of the scope of the
current discussion.
rate, indicating positive-order kinetics in [AcCl]. Finally, an in-
crease in the concentration of Pd(OAc)2 led to a higher rate, indi-
cating the reaction is positive-order in catalyst. Notably, the rate
dependence on [Pd(OAc)2] is consistent with a palladium(II)-
catalyzed process but not the possible acid-catalyzed process dis-
cussed in Section 3.2 (see Table 5). In summary, experiments re-
vealed that the reaction exhibits apparent zero-order kinetics in
[21a], positive-order kinetics in [Pd(OAc)2], and positive-order
kinetics in [HCl]. More precise rate orders of acetyl chloride and
water could not be determined under the experimental conditions.
In addition to these different-excess experiments, we ran a same-
excess experiment. The lack of overlay between the two rate pro-
files indicated that there was potential for product inhibition or
catalyst deactivation (Figure 2a). Subsequently, a same excess ex-
periment with added product led to overlay with the standard
curve, consistent with product inhibition (Figure 2b).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To follow up on the deuterium incorporation experiment dis-
cussed above, we measured the reaction rate when H2O was re-
placed with D2O. The experiments revealed a KIE of 1.8. We note
that this experimental KIE value likely understates the true KIE,
given that the N–H bond of the substrate introduces exchangeable
H+ equivalents into the system. Taken together, these mechanistic
experiments are consistent with catalyst saturation by the alkyne
substrate prior to protodepalladation, which is the rate-limiting
step in the catalytic cycle.
0.100
a
Standard
Standard
0.080
0.060
0.040
0.020
0.000
Same-excess
Same-exces
Same-excess
Same-exces (Time
(Time-Adjusted)
Adjustment)
Scheme 8. Proposed Catalytic Cycle
0
10
20
30
40
50
60
H
O
Time (min)
PA
N
R
N
H
Cl–
Cl
PdII
N
0.100
product inhibition
R
X
A
b
PA
N
ligand
exchange
anti-chloro-
palladation
R
H
0.080
0.060
0.040
0.020
0.000
Standard
Standard
H
Pd(OAc)2
Same-excess + 22a
Same-exces +22a
O
O
R
N
N
Same-excess + 22a
Same-exces +22a
(Time-Adjusted)
(Time Adjustment)
Cl
X
Cl
PdII
L
PdII
L
N
N
R
proto-
depalladation
C
B
H+
r.d.s
O
O
in situ
H2O
HCl
+
+
Me
Cl
Me
OH
0
20
40
60
80
100
120
Time (min)
A potential catalytic cycle for the hydrochlorination reaction is
depicted in Scheme 4. Initially, palladium(II) acetate coordinates
to the picolinamide directing group, exchanging an acetate for the
deprotonated amide via ligand transfer to form chelated intermedi-
ate A. Upon hydrolysis of acetyl chloride, chloride addition to the
alkyne favors the formation of the more stable 5-membered pal-
ladacycle, intermediate B. Upon treatment with acid at elevated
temperatures, a protodepalladation event affords hydrochlorinated
intermediate C, which can exchange off the product for a new sub-
strate molecule to close the catalytic cycle.
Figure 2. Same-excess experiments designed to identify the po-
tential product inhibition or catalyst deactivation.
a) Hydrochlorination using Pd(OAc)2 (0.005 M); red curve
(standard): 21a (0.1 M), H2O (0.6 M), AcCl (0.4 M); blue curve
(same-excess): 21a (0.08 M), H2O (0.58 M), AcCl (0.38 M); b)
Hydrochlorination using Pd(OAc)2 (0.005 M); red curve (stand-
ard), same as above; orange curve (same-excess + 22a): 21a (0.08
M), 22a (0.02 M), H2O (0.58 M), AcCl (0.38 M).
4. Conclusion
We next sought to understand the orders of the various reaction
components. To do this, we performed a series of different excess
experiments (Figure 1b). A change in concentration of alkyne sub-
strate (21a) did not change the rate, indicating apparent zero-order
In summary, we have established a new method for regioselec-
tive hydrochlorination of terminal and internal alkynes with broad
substrate scope and high functional group tolerance using 25 ppm
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
Pd(OAc)2 as the catalyst. The removable bidentate PA and AQ Biochemistry 1989, 28, 2111–2116. (c) Kim, J.; Zhang, Y.; Ran, C.;
1
2
3
4
5
6
7
8
auxiliaries direct the regiochemical course of the reaction and stabi-
lize the resulting palladacycle intermediates. After the reaction they
can be cleaved to reveal synthetically useful functional groups. The
hydrochlorinated products can conveniently be converted to a
variety of synthetically versatile trisubstituted alkenes via cross-
Sayre, L. M. Bioorg. Med. Chem. 2006, 14, 1444–1453.
(4) Newhouse, T.; Baran, P. S.; Hoffman, R. W. Chem. Soc. Rev.
2009, 38, 3010–3021.
(5) (a) Sotaro, M.; Yu, I.; Katsuo, F.; Yutaka, O.; Harukichi, H.
Bull. Chem. Soc. Jpn. 1979, 52, 1197–1202. For related examples to
access other alkenyl halides, see: (b) Stork, G.; Zhao, K. Tetrahe-
dron Lett. 1989, 30, 2173–2174. (c) Olpp, T.; Bruckner, R. Synthe-
sis 2004, 2135–2152. (d) Hodgson, D. M.; Arif, T. J. Am. Chem.
Soc. 2008, 130, 16500–16501.
coupling.
A plausible catalytic cycle involving directed anti-
chloropalladation followed by rate-limiting protodepalladation was
supported by RPKA. Broadly speaking, this work establishes di-
rected halopalladation as a potentially versatile strategy for carbon–
halogen bond formation.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408–7410. (b) Takai, K.; Ichiguchi, T.; Hikasa, S. Synlett
1999, 1268–1270.
ASSOCIATED CONTENT
Supporting Information
(7) For selected examples of stoichiometric hydromet-
alation/halogenation sequences with alkynes, see: (a) Brown. H.
C.; Hamaoka, T.; Ravindran, N.; Subrahmanyam, C.; Somayaji, V.;
Bhat, N. G. J. Org. Chem. 1989, 54, 6075–6079. (b) Masuda, Y.;
Hoshi, M.; Arase, A. J. Chem. Soc. Perkin Trans. 1 1992, 2725–2726.
(c) Barluenga, J.; Alvarez-García, L. J.; González, J. M. Tetrahedron
Lett. 1995, 36, 2153–2156. (d) Gao, F.; Hoveyda, A. H. J. Am.
Chem. Soc. 2010, 132, 10961–10963.
1
Experiment details, spectra data, copies of H and 13C NMR spec-
tra, and X-ray crystallographic data. These materials are available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: keary@scripps.edu
(8) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307–1370.
Notes
(9) In a pioneering early study on directed anti-hydroalumination
followed by quenching with I2, it was shown that the regiochemistry
of the hydroalumination step could be modulated by careful tuning
of the reaction conditions: Corey, E. J.; Katzenellenbogen, J. A.;
Posner, G. H. J. Am. Chem. Soc. 1967, 89, 4245–4247.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by TSRI and Pfizer, Inc. We
gratefully acknowledge the NIH for a RISE fellowship (Award
Number R25GM071638, A. L. C.), the DAAD for a postdoctoral
fellowship (M. L. O.), the Chemistry Department at King’s Col-
lege, London for an Alumni Overseas Summer Studentship (J. L.
T.), and the Life Sciences Summer Internship program (D. M. D.).
We thank Dr. Dee-Hua Huang for assistance with NMR spectros-
copy. We are grateful to Prof. Donna G. Blackmond (TSRI) for
assistance with design and interpretation of RPKA experiments. We
further thank Prof. Phil S. Baran (TSRI), Prof. Jin-Quan Yu
(TSRI), Prof. Ryan A. Shenvi (TSRI), Prof. Will R. Gutekunst
(Georgia Tech), Dr. Kin S. Yang (Gilead), and Dr. Zachary Wick-
ens (Harvard). Jacob T. Edwards (Baran Lab, TSRI) and Tyler G.
Saint-Denis (Yu lab, TSRI) are acknowledged for support and en-
couragement.
(10) For examples of directed hydrometalation followed by
quenching with NCS to access alkenyl chlorides, see: (a) Gu, Y.;
Snider, B. B. Org. Lett. 2003, 5, 4385–4388. (b) Martín, M. J.;
Coello, L.; Fernández, R.; Reyes, F.; Rodríguez, A.; Murcia, C.;
Garranzo, M.; Mateo, C.; Sánchez-Sancho, F.; Bueno, S.; de Eguil-
ior, C.; Francesch, A.; Munt, S.; Cuevas, C. J. Am. Chem. Soc. 2013,
135, 10164–10171. (c) Xu, S.; Unabara, D.; Uemura, D.; Arimoto,
H. Chem. Asian J. 2014, 9, 367–375. (d) Ray, A.; Mukherjee, S.;
Das, J.; Bhandari, M. K.; Du, H.; Yousufuddin, M.; Lovely, C. J.
Tetrahedron Lett. 2015, 56, 3518–3522.
(11) For a review on catalytic approaches to C–X bond formation,
see: Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116,
8003–8104.
(12) Olefin metathesis approaches to alkenyl halides: (a) Mac-
naughtan, M. L.; Johnson, M. J. A.; Kampf, J. W. J. Am. Chem. Soc.
2007, 129, 7708–7709. (b) Koh, M. J.; Nguyen, T. T.; Zhang, H.;
Schrock, R. R.; Hoveyda, A. H. Nature 2016, 531, 459–465.
REFERENCES
(1) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442–4489. (b) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054–3131. (c) Jana, R.; Pathak, T. P.; Sig-
man, M. S. Chem. Rev. 2011, 111, 1417–1492.
(13) Alkenyl bromide synthesis from alkynes using catalytic [CuH]
and Br+, see: Uehling, M. R.; Rucker, R. P.; Lalic, G. J. Am. Chem.
Soc. 2014, 136, 8799–8803.
(2) For selected examples of cross-coupling with vinyl chlorides,
see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020–4028. (b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
2719–2724. (c) Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade,
J. G. J. Am. Chem. Soc. 2004, 126, 16433–16439.
(14) Regioselective hydrohalogenation of electron-rich or -poor
alkynes with H+/X– sources: (a) Ma, S.; Lu, X.; Li, Z. J. Org. Chem.
1992, 57, 709–713; (b) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122,
9840–9841; (c) Su, M.; Yu, W.; Jin, Z. Tetrahedron Lett. 2001, 42,
3771–3774; (d) Duncan, D.; Livinghouse, T. J. Org. Chem. 2001,
66, 5237–5240. (e) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.;
Coverdale, H.; Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett.
2003, 5, 1547–1550; Coelho, A.; Novoa, H.; Peeters, O. M.; Bla-
ton, N.; Alvarado, M.; Sotelo, E. Tetrahedron 2005, 61, 4785–4791.
(3) Examples of vinylchlorides in natural products and bioactive
compounds: (a) Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.;
Yorke, S. C. Tetrahedron Lett. 1978, 19, 4417–4418. (b) Esaki, N.;
Takada, H.; Moriguchi, M.; Hatanaka, S.; Tanaka, H.; Soda, H., K.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
(f) Feray, L.; Perfetti, P.; Bertrand, M. P. Synlett 2009, 2009, 89– W. A.; Bradley, J.; Sarwar, M.; Colacot, T. J. Org. Lett. 2015, 17,
1
2
3
4
5
6
7
8
91. (g) Kawaguchi, S.-i.; Ogawa, A. Org. Lett. 2010, 12, 1893–1895.
5472–5475. (c) Carole, W. A.; Colacot, T. J. Chem. Eur. J. 2016, 22,
7686–7695.
(15) (a) Carothers, W. H.; Coffman, D. C. J. Am. Chem. Soc. 1932,
54, 4071–4076. (b) Fahey, R. C.; Lee, D.-J. J. Am. Chem. Soc. 1966,
88, 5555–5560. (c) Fahey, R. C.; Lee, D.-J. J. Am. Chem. Soc. 1968,
90, 2124–2131. (d) Cousseau, J.; Gouin, L. J. Chem. Soc. Perkin
Trans. 1 1977, 1797–1801. (e) Griesbaum, K.; Rao, V. V. R.;
Leifker, G. J. Org. Chem. 1982, 47, 4975–4981. (f) Hudrlik, P. F.;
Kulkarni, A. K.; Jain, S.; Hudrlik, A. M. Tetrahedron 1983, 39, 877–
882. (g) Kropp, P. J.; Crawford, S. D. J. Org. Chem. 1994, 59, 3102–
3112.
(25) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154–13155. (b) Shabashov, D.; Daugulis, O. J.
Am. Chem. Soc. 2010, 132, 3965–3972. (c) Wang, C.; Chen, C.;
Zhang, J.; Han, J.; Wang, Q.; Guo, K.; Liu, P.; Guan, M.; Yao, Y.;
Zhao, Y. Angew. Chem. Int. Ed. 2014, 53, 9884–9888. (d) Fan, M.;
Ma, D. Angew. Chem. Int. Ed. 2013, 125, 12374–12377; (e) Rodri-
guez, N.; Romero-Revilla, J. A.; Fernandez-Ibanez, M. A.; Carret-
ero, J. C. Chem. Sci. 2013, 4, 175–179. For reviews on bidentate
directing groups in C–H activation, see: (f) Rouquet, G.; Chatani,
N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743. (g) Daugulis, O.;
Roane, J.; Tran, L. D. Acc. Chem. Res. 2015, 48, 1053–1064.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) HgCl2-mediated Markovnikov HCl addition to propargyl
alcohol: Reppe, W. Justus Liebigs Ann. Chem. 1955, 596, 38–79.
(17) For HF addition to alkynes catalyzed by gold, see: (a) Akana,
J. A.; Bhattacharyya, K. X.; Müller, P.; Sadighi, J. P. J. Am. Chem.
Soc. 2007, 129, 7736–7737. (b) Gorske, B. C.; Mbofana, C. T.;
Miller, S. J. Org. Lett. 2009, 11, 4318–4321. (c) Nahra, F.; Patrick,
S. R.; Bello, D.; Brill, M.; Obled, A.; Cordes, D. B.; Slavin, A. M. Z.;
O’Hagan, D.; Nolan, S. P. ChemCatChem 2015, 7, 240− 244.
(26) Under the reaction conditions described, it is believed that
acetic acid generated in situ can also undergoes an analogous reac-
tion to yield the vinyl acetate. The hydroacetoxylation product has
the opposite regio- and stereochemical configuration. For selected
examples of palladium(II)-catalyzed hydroacetoxylation/hydration
of alkynes, see: (a) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001,
66, 7676–7684. (b) Zhang, Z.; Wu, L.; Liao, J.; Wu, W.; Jiang, H.;
Li, J.; Li, J. J. Org. Chem. 2015, 80, 7594-7603. (c) Vinoth, P.; Na-
garajan, S.; Maheswari, C. U.; Sudalai, A.; Pace, V.; Sridharan, V.
Org. Lett. 2016, 18, 3442–3445. For a representative example with
Au(I) involving neighboring group participation, see: (d) Wang,
W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640–1643.
(18) Dérien, S., Klein, H.; Bruneau, C. Angew. Chem. Int. Ed. 2015,
54, 12112–12115.
(19) (a) Gurak, J. A., Jr.; Yang, K. S.; Liu, Z.; Engle, K. M. J. Am.
Chem. Soc. 2016, 138, 5805–5808. (b) Yang, K. S.; Gurak, J. A., Jr.;
Liu, Z.; Engle, K. M. J. Am. Chem. Soc. 2016, 138, 14705–14712.
(c) Liu, Z.; Derosa, J.; Engle, K. M. J. Am. Chem. Soc. 2016, 138,
13076–13081.
(27) We note that in the metal-free control experiments in Table 5,
alkenyl chloride product formation was observed at 150 °C (albeit
in low yields). A variant of Pathway B2 in which palladium(II) is
replaced with H+ may account for the apparent regiochemical pref-
erence for 22b over 22b’ in the absence of palladium(II). In the
case of 22a, the conversion was too low in the absence of metal to
accurately measure the regiochemical ratio.
(20) (a) Yakawa, T.; Tsutsumi, S. Inorg. Chem. 1968, 7, 1458–
1460. (b) Bäckvall, J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organo-
metallics 1995, 14, 4242–4246. (c) Zanini, M. L.; Meneghetti, M.
R.; Ebeling, G.; Livotto, P. R.; Rominger, F.; Dupont, J. Inorg.
Chim. Acta 2002, 350, 527–536. (d) Tsuji, J. Palladium Reagents
and Catalysts, John Wiley & Sons: Chichester, U. K., 2004. For an
analogous example of directed anti-chlorometalation of alkynes
with platinum(II), see: (e) Dupont, J.; Casagrande Jr, O. L.; Aiub,
A. C.; Beck, J.; Hörner, M.; Bortoluzzi, A. Polyhedron 1994, 13,
2583–2587.
(28) (a) Bacchi, A.; Costa, M.; Della Cá, N.; Gabriele, B.; Salerno,
G.; Cassoni, S. J. Org. Chem. 2005, 70, 4971–4979. (b) Beccalli, E.
M.; Borsini, E.; Broggini, G.; Palmisano, G.; Sottocornola, S. J. Org.
Chem. 2008, 73, 4746–4749.
(21) For examples of Pd-catalyzed alkyne difunctionalization via
chloropalladation, see: (a) Kaneda, K.; Kawamoto, F.; Fujiwara, Y.;
Imanaka, T.; Teranishi, S. Tetrahedron Lett. 1974, 15, 1067–1070.
(b) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Terani-
shi, S. J. Org. Chem. 1979, 44, 55–63. (c) Ma, S.; Lu, X. J. Chem.
Soc., Chem. Commun. 1990, 733–734. (d) Ma, S.; Lu, X. J. Org.
Chem. 1993, 58, 1245–1250. (e) Bäckvall, J.-E.; Nilsson, Y. I. M.;
Andersson, P. G.; Gatti, R. G. P.; Wu, J. Tetrahedron Lett. 1994, 35,
5713–5716 (f) Ji, J. Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 1160–
1169. (g) Wang, Z.; Lu, X. Chem. Commun. 1996, 535–536. (h)
Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4321–4323. (i)
Zhu, G.; Zhang, Z. J. Org. Chem. 2005, 70, 3339–3341. (j) Lu, Z.;
Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem. 2011, 76,
8524–8529. (k) Topolovcan, N.; Panov, I.; Kotora, M. Org. Lett.
2016, 18, 3634–3637.
(29) Compound 31 was prepared via a palladium(II)-catalyzed
cycloisomerization of 21a, which takes place in the absence of Cl–
under slightly modified reaction conditions. For more details, see
the Supporting Information.
(30) Jin, C.; Burgess, J. P.; Kepler, J. A.; Cook, C. E. Org. Lett.
2007, 9, 1887–1890.
(31) (a) Blackmond, D. G. Angew. Chem. Int. Ed. 2005, 44, 4302–
4320; (b) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.;
Futran, A.; Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem.
2006, 71, 4711–4722; (c) Blackmond, D. G. J. Am. Chem. Soc.
2015, 137, 10852–10866.
(22) Zhu, G.; Chen, D.; Wang, Y.; Zheng, R. Chem. Commun.
2012, 48, 5796–5798.
(23) Dupont, J.; Basso, N. R.; Meneghetti, M. R.; Konrath, R. A.;
Burrow, R.; Horner, M. Organometallics 1997, 16, 2386–2391.
(24) (a) Bajwa, S. E.; Storr, T. E.; Hatcher, L. E.; Williams, T. J.;
Baumann, C. G.; Whitwood, A. C.; Allan, D. R.; Teat, S. J.; Raithby,
P. R.; Fairlamb, I. J. S. Chem. Sci. 2012, 3, 1656-1661. (b) Carole,
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
cat. PdII
H+, Cl–
H
DG
DG
R
n
R
n
7
Cl
8
9
• PdII loadings as low as 25 ppm
• high regio- and stereoselectivity
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
• removable directing groups (DGs)
ACS Paragon Plus Environment