Palladium-Catalyzed Hydrohalogenation of 1,6-Enynes: Hydrogen Halide Salts and Alkyl Halides as Convenient HX Surrogates

Article abstract of DOI:10.1021/jacs.7b00482

Difficulties associated with handling H₂ and CO in metal-catalyzed processes have led to the development of chemical surrogates to these species. Despite many successful examples using this strategy, the application of convenient hydrogen halide (HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to accomplish a Pd-catalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction mechanism involving a crucial E-to-Z vinyl-Pd isomerization and a carbon-halogen bond-forming reductive elimination. Furthermore, rare examples of C(sp³)-Br and ?Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1-iodobutane as an alternate HI surrogate are also presented.

Full text of DOI:10.1021/jacs.7b00482

Subscriber access provided by Fudan University
Article
Palladium-Catalyzed Hydrohalogenation of 1,6-Enynes: Hydrogen
Halide Salts and Alkyl Halides as Convenient HX Surrogates
David A. Petrone, Ivan Franzoni, Juntao Ye, Jose F
Rodriguez, Amalia I. Poblador-Bahamonde, and Mark Lautens
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00482 • Publication Date (Web): 14 Feb 2017
Downloaded from http://pubs.acs.org on February 14, 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 13
Journal of the American Chemical Society
1
2
3
4
5
PalladiumꢀCatalyzed Hydrohalogenation of 1,6ꢀEnynes: Hydrogen
Halide Salts and Alkyl Halides as Convenient HX Surrogates
David A. Petrone†1, Ivan Franzoni†1, Juntao Ye1, José F. Rodríguez1, Amalia I. PobladorꢀBahamonde*2, and Mark Lautens*1
6
7
8
9
Abstract: Difficulties associated with the handling H2 and CO in metalꢀcatalyzed processes has led to the development of chemical
surrogates to these species. Despite many successful examples using this strategy, the application of convenient hydrogen halide
(HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to
accomplish a novel Pdꢀcatalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated
with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction
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
mechanism involving a crucial EꢀtoꢀZ vinyl–Pd isomerization and a carbon–halogen bondꢀforming reductive elimination.
Furthermore, rare examples of C(sp3)–Br and –Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1ꢀ
iodobutane as an alternate HI surrogate are also presented.
INTRODUCTION
palladium species were to be modified by an appropriate phosphine
ligand (i.e. PtBu3 or QPhos).2ꢀ7
The carbon–halogen bond is an essential functional group in
organic chemistry, and its high utility is made apparent by the
multitude of available methods used for their installation into
organic molecules.1 In 2010, our group reported a Pdꢀcatalyzed
synthesis of 2ꢀbromoindoles2 rooted in Hartwig’s seminal work on
reversible reductive elimination of aryl halides from Pd(II)
complexes.3,4 These studies prompted our discovery of a catalytic
alkene aryliodination involving a novel C(sp3)–I bondꢀforming
reductive elimination from an alkyl–Pd(II)–I species (Figure 1a).5
In a related study, Qiu and Tong showed that Pd(0) could catalyze
the cycloisomerization of vinyl iodides leading to various
heterocyclic scaffolds with high efficiencies (Figure 1b).6 Several
other contributions invoking this mode of reactivity have since been
made, yet all have employed substrates containing pre-installed
carbon–halogen bonds (i.e. aryl and vinyl halides).7 This functional
group facilitates substrate activation to occur via oxidative addition
of Pd(0), and it is ultimately recycled into the product.8 Despite the
complete atom economy achieved by these methodologies,9 the
prerequisite for halogenated substrates often limits their synthetic
utility. Therefore, the use of external halogen sources as a way to
develop new cyclohalogenation reactions of substrates devoid of a
Prior Work:
a) Lautens (2011): Intramolecular aryliodination of unactivated alkenes [ref 5]
I
PtBu2
Ph
Ph
R3P
Pd
I
I
R
Fe
Ph
Ph
Ph
R
Pd(QPhos)2
R
Z
PhMe, 100 °C
Z
Z
QPhos
b) Qiu and Tong (2011): Cycloisomerization of (Z)-1-iodo-1,6-dienes [ref 6]
R2
I
I
R1
Y
R1
Y
Pd(OAc)2 (10 mol%)
dppf (30 mol%)
PdLn
R2
R1
R2
PhMe, 120 °C, 16 h
Y
Z
Z
Z
c) Lautens (2012): Intermolecular alkene-alkyne coupling via aryliodination [ref 7b]
I
R
Ar2
Ar1
I
R
Pd(QPhos)2
Ar2
Pd
R
L
Ar2
PhMe, 100 C, 16 h
I
Ar1
Ar1
d) Reaction design: Hydrohalogenation of enynes using a H Pd(II) X species
II X
R1
H
R1
X
H
H
LnPd
X
R1
O
R1
O
X
II
R2
O
R2
R2
LnPd
H
PdIILn
- Pd0Ln
Z
preꢀinstalled carbon–halogen bond would be
advance.10
a significant
Z
Z
O
Z
R2
A
B
C
A 2012 report from our group regarding the synthesis of
indenes via a conjunctive alkeneꢀalkyne coupling (Figure 1c) led us
to consider catalytic cyclohalogenation reactions of nonꢀ
halogenated enynes.11 Due to their facile and modular preparation,
enynes represent an ideal framework on which to explore new
catalytic reactivity.12 More specifically, the 1,6ꢀenynes motif has
served well as a template for developing numerous cyclizative
hydrofunctionalization methods including hydroboration,13
hydrosilylation,14 hydrostannylation15 and hydrofluorination16
e) This Study: Pd-catalyzed 1,6-enyne hydrohalogenation uisng simple HX surrogates
R2
R2
Et3N—HX
R3
X
(X = Cl, Br, I)
or
R3
H
O
Pd(PtBu3)2
(cat.)
Et
I
N
R1
O
N
R1
H
2
1
II
X
LnPd
R2
- Pd0Ln
X
R2
PIdI Ln
H
O
H
E-to-Z
isomerization
among others.17 Therefore, we hypothesized that
a
novel
N
O
N
R3
R3
R1
R1
hydrohalogenation of 1,6ꢀenynes could be accomplished by using a
discrete H–Pd(II)–X species (where X is a halogen) as a catalytic
intermediate (Figure 1d).18 A regioselective hydropalladation would
act to engage the this class of substrate resulting in the formation of
Scheme 1. Previous work on Pdꢀcatalyzed aryl and vinyl iodination of
alkenes and alkynes and the design of the enyne hydrohalogenation reaction
involving simple HX surrogates.
While alkene and alkyne hydrohalogenation is a classic
transformation that has been used for over a century, reports of
metalꢀcatalyzed hydrohalogenations have been scarce.1p,20 This
a
key vinyl–Pd(II)–X intermediate (i.e. A).19
A subsequent
intramolecular alkene insertion and a terminating C(sp3)–halogen
bondꢀforming reductive elimination (via B) could be realized if the
1
1 Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Canada, M5S 3H6. 2 Department of Organic Chemistry, University of Geneva, 30 Quai
Ernest Ansermet, 1211 Geneva, Switzerland. † These authors contributed equally. * email: amalia.pobladorbahamonde@unige.ch; mlautens@chem.utoronto.ca.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
1
2
paucity of methods can be partly attributed to the limited number of
The precedence for carbon–iodine bondꢀforming reductive
practical hydrogen halide (HX) sources available. Diatomic
feedstocks like HX are routinely used industrially to upgrade the
value and function of commodity chemicals.21 Although large
quantities of these building blocks are consumed each year, the
laboratory use of these volatile and often toxic compounds can be
thwarted by the challenges associated with their safe handling. As a
result, methods exist which obviate this drawback by allowing for
in situ HX generation via the combination of reagents,22 and have
been used together with transition metals to affect catalytic
hydrohalogenation in rare instances.23 Unfortunately, these methods
commonly employ reagents which narrow functional group
tolerance and involve strongly acidic reaction media. Conversely,
catalytic methods that employ a single and wellꢀdefined reagent
which acts as a surrogate to a hazardous chemical have become
increasingly popular.24 Therein, a metal catalyst reacts with the
chosen surrogate in order to simultaneously release and activate the
problematic small molecule of interest. Transfer hydrogenations
elimination from Pd(II) promoted us to initially target the
hydroiodination reaction of enynes 1 using Et3N·HI as an HI
surrogate (Figure 1).2ꢀ6,7aꢀg During our preliminary experiments, the
expected 5ꢀmembered products of hydroiodination C were not
observed, and instead 6ꢀmembered heterocycles 2 were found to be
the sole hydroiodination products which were accompanied by 1,6ꢀ
enyne cycloisomerization products 311 and the corresponding
isomers 4. Compounds 2 and 3 are thought to arise from
hydropalladations that proceed with opposite regioselectivities (vide
infra). Pyridinone 2 originates from the hydropalladation resulting
in the transfer of the hydride moiety to the αꢀcarbon, whereas 3
(and ultimately 4) arises from a hydropalladation resulting in the
transfer of the hydride moiety to the βꢀcarbon. After screening a
wide array of parameters, Pd(PtBu3)2 (10 mol%) and Et3N·HI (1.2
equiv) in PhMe (0.05 M) at 120 °C for 2 hours was found to be the
optimal combination. Under these conditions, 1a could be
converted to 2a in 47% yield (Figure 1). Changing reaction
conditions was found to markedly affected the overall reaction
efficiency, yet had little or no impact on the key ratio of 2:(3+4).
The Nꢀprotecting group was the variable that allowed for the
greatest perturbation of this key ratio that directly relates to the
yield of desired product. We postulate that the Nꢀprotecting group
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
i
using alcohols as practical precursors to H2 (e.g. PrOH) illustrate
this concept.25 Numerous metalꢀcatalyzed transformations have also
been reported which conveniently generate CO either in situ26,27
Other recent examples relying on this concept24 include a Rhꢀ
catalyzed transfer hydroformylation by Dong and coꢀworkers,28 and
a reversible Niꢀcatalyzed transfer hydrocyanation by Morandi and
coꢀworkers.29 These technologies use aliphatic aldehydes and
nitriles as surrogates to syngas and HCN, respectively. Despite
these enabling achievements, the use of convenient HX surrogates
in transitionꢀmetal catalysis remains unexplored. Accordingly, it
would be of interest to develop a robust hydrohalogenation protocol
whereby a H–Pd(II)–X species is generated catalytically in situ by
employing a mild, simple and convenient HX surrogate.30
plays
a
key role in dictating the regioselectivity of
hydropalladation, which manifests itself in the observed changes to
the 2:(3+4) ratio.
Unprotected 1b led to product 2b being afforded in 16% yield,
while protecting the nitrogen with Nꢀparaꢀtrifluoromethylphenyl
(1c) led to only slightly improved results (35% yield). Substrates
possessing Nꢀalkyl groups such as –tBu and –Me (1d and 1e)
performed marginally better, and in both cases products were
obtained in 54% yield (2d and 2e). Substrates possessing NꢀPh 1f
and Nꢀ3,5ꢀdimethoxyphenyl groups 1g afforded similar results with
respect to the Nꢀalkyl analogs, whereas N-paraꢀmethoxyphenyl 1h
led to a moderate improvement (61% yield). In general, substrates
possessing electronꢀrich Nꢀsubstituents undergo the hydroiodination
process in higher yield, which is likely a manifestation of their
ability to promote a more regioselective hydropalladation. It was
hypothesized that employing substrates containing N–O(alkyl)
bonds could further increase the electron richness of the amide
functionality, and thus improve the resulting selectivity of the
reaction. In this regard, N–OBn 1i and N–OMe 1j were prepared
and tested under the reaction conditions. These analogs provided
incremental improvements with respect to 1h, and pyridinones 2i
and 2j could be obtained in 63% and 68% yield, respectively. In an
effort to further increase the electron richness of the substrate, the
N–SMe analog 1k was prepared. However, the products of
hydroiodination (2k) or cycloisomerization (3k/4k) were not
observed, and instead, the N–SMe bond was cleaved under these
conditions leading to enyne 1b in 64% yield. Furthermore, it was
found that the N–SMe bond was cleaved even in the absence of the
Pd(0) catalyst leading to quantitative formation of 1b. When analog
1la containing an N–OtBu moiety was utilized,34 product 2la could
be obtained in 75% yield along with 18% of cycloisomerized
products.
In the turnoverꢀenabling step of the Heck reaction, an
exogenous base (e.g. Et3N) is used to convert H–Pd(II)–X back into
the active Pd(0) catalyst while concomitantly forming an equivalent
of base·HX waste.31 Considering this sequence in reverse, we
envisioned that base·HX species could be used as practical HX
surrogates to controllably generate the desired H–Pd(II)–X species
in situ.32 This would then promote the desired enyne
hydrohalogenation via the transfer of both the hydride and halide
ligands to the substrate.
Herein, we examine the ability of Et3N·HI to act as a safe and
practical replacement for HI in the development of a conceptually
and mechanistically novel hydroiodination of 1,6ꢀenynes. Through
a combination of experiment and theory, we have demonstrated the
feasibility of a formal anti alkyne hydropalladation which occurs
via a counterꢀintuitive twoꢀstep cis alkyne hydropalladation/vinyl–
Pd(II) EꢀtoꢀZ isomerization. Our theoretical investigation has also
led to the development of the analogous hydrobromination and
hydrochlorination reactions that represent rare examples of C(sp3)–
Br and C(sp3)–Cl reductive elimination from Pd(II).33 As such, the
iodinated, brominated and chlorinated products can be obtained by
simply changing the HX surrogate. Furthermore, this report also
outlines our preliminary findings regarding the use of 1ꢀiodobutane
as a nonꢀionic HX surrogate in a novel transfer hydroiodination
involving a dehydrohalogenation/hydrohalogenation sequence.
RESULTS AND DISCUSSION
2
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Figure 1. Pdꢀcatalyzed hydroiodination of 1,6ꢀenynes using Et3N·HI as an HI surrogate: Effect of the N-protecting group. Notes: Reactions were run on a 0.2 mmol
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
1
scale, yields determined by H NMR analysis of the crude reaction mixture, values in parentheses represent the isolated yield of 2, the ratios in square brackets
represent yields in the form of [2:(3+4)]. a Subjection of 1k to the reaction conditions led to formation of 1b in 64% yield. ND = not determined.
Table 1. Pdꢀcatalyzed hydroiodination of 1,6ꢀenynes: Effect of reaction
With both the optimal reaction conditions and Nꢀprotecting
group in hand, we next examined the effect that altering various
reaction parameters had on the efficiency of the hydroiodination
reaction (Table 1). In the absence of the Pd(0) catalyst, the products
of hydroiodination 2la or cycloisomerization (3la and 4la) were not
observed, and the starting material was recovered intact (entry 2).
Moreover, the absence of products resulting from direct alkyne
hydroiodination speaks to the mild nature of the HI surrogate used
herein.22 The use of dioxane as solvent led to comparable results to
those obtained using PhMe (entry 3), while decreasing the reaction
temperature to 110 °C or 100 °C led to lower product yields and
incomplete conversion of 1la (entries 4 and 5). QPhos has been
shown by our group to be an effective ligand for aryliodination
reactions involving C(sp3)–I bondꢀforming reductive elimination
from alky–Pd(II)I species.5,7a,b,d,e,g However, the use of 10 mol% of
Pd(QPhos)2 led to greatly attenuated reactivity, and 2la was
obtained in 30% yield (entry 7). Carrow and coꢀworkers have
recently shown tri(1ꢀadamantyl)phosphine to be an isosteric, but
more electron donating analog to tri(tertꢀbutyl)phosphine.35
Remarkably, 2la could be obtained in 56% yield when this reaction
was run using Pd2(dba)3 (5 mol%) and P(1ꢀAd)3 (20 mol%) (entry
8). Furthermore, the reaction efficiency decreased significantly
when di(tertꢀbutyl)neopentylphosphine (DTBNpP)36 was used in
place of P(tBu)3, and 2la was only obtained in 24% yield (entry 9).
It is plausible that either the ability of DTBNpP to promote the
required C(sp3)–I bondꢀforming reductive elimination and/or the
stability of the resulting catalyst under the reaction conditions is
greatly diminished. Decreasing the loading of Pd(PtBu3)2 to 5 mol%
renders the hydroiodination less efficient, and incomplete
conversion of the starting material is observed in this case (entry
10). Furthermore, changing the loading of Et3N·HI to 1.0 or 2.0
equivalents led to similarly inferior results (entries 11 and 12).
parametersa
entry
variation from the
“standard” conditions
yield
2la
yield
3la+4la
(%)b
18
(%)b,c
1
2
none
75(72)
0
no Pd(PtBu3)2
0
3
4
5
6
1,4ꢀdioxane instead of PhMe
110 °C instead of 120 °C
100 °C instead of 120 °C
0.1 M instead of 0.05 M
Pd(QPhos)2 instead of Pd(PtBu3)2
P(1ꢀAd)3/Pd2(dba)3 instead of Pd(PtBu3)2
DTBNpP/Pd2(dba)3 instead of
Pd(PtBu3)2
75
61
56
72
30
56
24
21
15
13
18
15
17
9
7
8d
9d
10
11
12
13
14
5 mol% Pd(PtBu3)2
65
68
69
37
66
19
17
17
8
1.0 equiv Et3N·HI
2.0 equiv Et3N·HI
Me3N·HI instead of Et3N·HI
Me3N·HI/1,4ꢀdioxane instead of
Et3N·HI/PhMe
15
15
nBu3N·HI instead of Et3N·HI
71
24
Reactions were run on a 0.2 mmol scale. Determined by 1H NMR
a
b
analysis of the crude reaction mixture using 1,3,5ꢀtrimethoxybenzene as
c
an internal standard. Value in brackets parentheses represents the
d
isolated yield. [Pd] = 10 mol%, phosphine = 20 mol%. 1ꢀAd = 1ꢀ
adamantyl. DTBNpP = di(tertꢀbutyl)neopentylphosphine.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
1
2
3
4
5
6
7
8
We wished to determine whether changing the amine
compatible with a series of heteroaromatic groups. Substrates
containing a 3ꢀpyridyl (1lv) or a 2ꢀthienyl (1lw) group underwent
the desired transformation in 78% and 76% yield, respectively.
component of the hydroiodide salt had any significant effect. When
Et3N·HI was substituted for Me3N·HI, 2la was obtained in only
37% yield (entry 13). During this experiment, Me3N·HI appeared to
be much less soluble than Et3N·HI. This observation, in
combination with the fact that NEt3·HI was found to be more
soluble in 1,4ꢀdioxane than in PhMe, led us to examine the reaction
utilizing Me3N·HI in 1,4ꢀdioxane. Although much of the reactivity
was restored under these conditions, Et3N·HI still proved to be a
superior HI surrogate (entry 14). Interestingly, more soluble
nBu3N·HI performed nearly as well as Et3N·HI, and 2la could be
obtained in 71% yield. The scope of the Pdꢀcatalyzed enyne
hydroiodination was next examined (Figure 2).
Our optimization studies revealed that toluene and 1,4ꢀdioxane
provided nearly identical results, and all substrates were therefore
tested in both solvents to obtain the highest product yield. Electronꢀ
rich aryl substituents on the alkyne were well tolerated under the
reaction conditions, and products containing para–Me (2lb), –Ph
(2lc), –OMe (2ld) and –OTBS (2le) groups could be obtained in
56%ꢀ81% yield. Substrates with electronꢀwithdrawing para–Cl
(1lf), –CF3 (1lg) and –CN (1lh) groups were also suitable
substrates, affording the corresponding products in 69%ꢀ80% yield.
The reaction conditions were tolerant of both ketone and ester
functionalities, and products 2li and 2lj were obtained in 61% and
69% yield, respectively. Similar efficiencies were observed when
substrates containing various meta substituents were tested (1lkꢀ
1lr). Electronꢀdonating meta–Me (1lk) and –OMe (1ll) groups were
tolerated, leading to the products 2lk and 2ll in 69% and 72% yield,
respectively. Products containing phenol, aldehyde and nitrile
groups at the metaꢀposition (2lnꢀ2lp) could be obtained in 52%,
62% and 76% yield, respectively. Substrates possessing a 3,5ꢀ
difluorophenyl (1lq) or a 3,5ꢀdi(trifluoromethyl)phenyl (1lr) group
could undergo the desired hydroiodination reaction, leading to the
corresponding fluorinated pyridinones 2lq and 2lr in 67% and 70%
yield, respectively. Substrates containing various ortho substituents
(1lsꢀ1lu) could also undergo hydroiodination to generate products
3lsꢀ2lt in 40ꢀ66% yield. Notably, the conditions were also
Enyne 1lx containing
a 5ꢀN–Boc indolyl group could be
transformed to the corresponding product 2lx in 48% yield. To
highlight the scalability of this transformation, a gram scale
reaction was conducted using 1la where pyridinone 2la could be
obtained in 66% isolated yield. Substitution on the alkene which
deviates from –Me resulting in a less efficient reaction, and the
corresponding –Ph and –Et analogs were isolated in only 6% and
36% yield, respectively. The major byproducts observed in these
cases were that of alkene isomerization (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
In 2012, Fu reported a roomꢀtemperature dehydrohalogenation
of alkyl bromides catalyzed by Pd[P(tBu)2Me]2 (Scheme 2a).37 The
mechanism of this transformation involves SN2ꢀtype oxidative
addition of L2Pd(0) to an alkyl bromide leading to alkyl–Pd(II)–Br
species D which contains two phosphine ligands. Loss of a single
phosphine affords 14ꢀelectron species E, which undergoes βꢀ
hydride elimination to generate H–Pd(II)–Br species F. Alkene
dissociation presumably affords H–Pd(II)–Br species G which is
converted to L2Pd(0) in the presence of Cy2NH and phosphine. We
envisioned that this mechanistic scenario could be applied as the
basis for a transfer hydrohalogenation reaction where alkyl halides
act as HX surrogates to generate H–Pd(II)–X (H) in situ via an
analogous release mechanism (Scheme 2b).38 The preliminary
results obtained for this process are displayed in Scheme 2c. After
screening various reaction parameters, the optimal conditions were
identified to be enyne (1 equiv), Pd(PtBu3)2 (10 mol%) and 1ꢀ
iodobutane (2.0 equiv) in PhMe (0.05 M) at 120 °C for 16 hours.
Enynes possessing various Nꢀprotecting groups were tested under
these conditions. NꢀTs (1a) and NꢀMe (1e) enynes could be
converted to pyridinones 2a and 2e in 41% and 48% yield,
respectively. Nꢀaryl substrates 1f and 1h were converted to the
corresponding products 2f and 2h in 54% and 60% yield,
respectively. Substrate 1la possessing an NꢀOtBu moiety was also
converted into pyridinone 2la in 53% yield. In all cases, the
cycloisomerization products 3 and 4 were observed.
4
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
1
2
3
Figure 2. Reaction scope for the Pdꢀcatalyzed hydroiodination of 1,6ꢀenynes using Et3N·HI.. Reactions were run on a 0.2 mmol scale. Values represent isolated
yields after column chromatography. a Reaction run in PhMe. b Reaction run in 1,4ꢀdioxane. c Isolated yield from the reaction run on a 1.0 g scale in 1,4ꢀdioxane. d
Product 2lt was obtained a 1.1:1 mixture of atropdiastereomers. TBS = tertꢀbutyldimethylsilyl, Boc = tertꢀbutoxycarbonyl.
4
5
6
7
8
9
group (16% D) as well as the methylene carbon which is bonded to
Although this variation of the protocol is still less efficient than
when Et3N·HI is used, it represents the first example of a transfer
hydroiodination to the best of our knowledge.
iodine (26% D). Based on the general mechanism proposed in
Scheme 1e, observation of this specific deuteration pattern should
not be expected. However, it is reasoned that species Hꢀd can
catalyze isopropene isomerization by way of an iterative alkene
insertion/elimination mechanism that results in substrate H/D
scrambling. When this is followed by the desired
deutero/hydroiodination reaction, the partially deuterated
isopropene moiety is incorporated into the heterocyclic scaffold
resulting in deuteration at positions other than αꢀC(sp2).
Furthermore, only partial deuteration (43% D) was observed at αꢀ
C(sp2) in the product which must arise from both palladium
hydrides (generated via the aforementioned H/D scrambling or via
formation of byproduct 4) and palladium deuterides (generated
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
from
iodobutaneꢀd9)
undergoing
the
desired
hydro/deuterohalogenation reaction. It should also be noted that no
substantial difference in the amount of incorporated deuterium was
observed when PhMeꢀd8 was used as solvent in place of PhMe,
which suggests that solvent is not a factor in obtaining partial
deuteration. Byproduct 4eꢀdn was observed to have deuterium
incorporated at the same positions, albeit to a different extent (vide
infra).
To exhibit the versatility of the pyridinone products, various
synthetic manipulations were carried out using product 2la (Scheme
3). The tertꢀbutyl group could be readily cleaved using TfOH in
dioxane to unmask hydroxamic acid 5 in 87% yield. Azide 6 could
be obtained in 92% yield via a nucleophilic substitution of the
neopentyl C(sp3)–I bond using NaN3 in DMF. A Cuꢀcatalyzed
Huisgen [3+2] cycloaddition between azide 6 and propargylated
uracil derivative 7 provided triazole 8 in 92% yield. A Pdꢀcatalyzed
reduction of the C(sp3)–I bond in 2la could be employed to generate
9
containing a
γꢀgeminal dimethyl motif in 79% yield.6
Cyclopropane 10 bearing a [4.1.0] bicyclic scaffold could be
generated in 78% yield via an intramolecular conjugate cyclization
using Zn powder in AcOH.
MECHANISTIC AND COMPUTATIONAL STUDIES
A plausible mechanism for the reaction is presented in
Scheme 4. The reaction between PdL2 (L = PtBu3) and Et3N·HI
generates the active PdL2HI species that upon coordination to the
substrate 1e produces intermediate I. Insertion of the alkyne moiety
into the Pd−H bond can follow two different pathways. In Path A,
hydropalladation placing the Pd atom on the β−carbon leads to
intermediate II. A key E-toꢀZ isomerization of this vinyl–Pd(II)
intermediate affords III which after alkene coordination and 6ꢀexoꢀ
trig carbopalladation gives intermediate IV. Final C(sp3)−I bondꢀ
forming reductive elimination furnishes the desired product 2e and
regenerates PdL2. In competing Path B, a reversal in the
regioselectivity of the hydropalladation step places the Pd atom on
the α−carbon. The resulting intermediate V undergoes a 5ꢀexoꢀtrig
carbopalladation which leads to VI. In analogy to IV, neopentylꢀPd
intermediate VI could undergo C−I bondꢀforming reductive
elimination to provide alkyl iodide product X. However, the
formation of this product was not observed during our
investigations. Instead, ring closure occurs to generate
cyclopropylcarbinyl species VII, which undergoes C−C σ−bond
rotation and ring expansion via β−carbon elimination to produce
VIII.39,40 Regioselective β−hydride elimination provides
conjugated diene byproduct 3e and regenerates the active PdL2HI
catalyst.
Scheme 2. a) Catalytic cycle for the Pd(0)ꢀcatalyzed dehydrohalogenation
by Fu and coꢀworkers (Ref. 37). b) Strategy for transfer hydroiodination of
1,6ꢀenynes, c) Reaction scope for the Pdꢀcatalyzed transfer hydroiodination
of 1,6ꢀenynes using 1ꢀiodobutane as a HI surrogate. Reactions were run on a
1
0.2 mmol scale. Yields obtained by H NMR. pTol = para-tolyl. Values in
parenthesis represent yield of 4. d) Transfer hydroiodination reaction of 1e
using 1ꢀiodobutaneꢀd9 as a DI surrogate.
Enyne 1e was subjected to the transfer hydroiodination reaction
conditions using 1ꢀiodobutaneꢀd9 in place of 1ꢀiodobutane (Scheme
2d). Full consumption of 1e was observed via proton NMR analysis
of the crude reaction mixture after 16 hours at 120 °C, and 2eꢀdn
and 4eꢀdn were measured in 48% and 25% yield, respectively. The
direct cycloisomerization product (i.e. 3e) was not observed under
the reaction conditions. NMR analysis of purified 2eꢀdn indicated
that deuterium had been incorporated at three positions in the
product to various extents. Deuteration was observed on the CH3
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
1
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 3. Derivatization studies concerning pyridinone product 2la. TBTA = tris(benzyltriazolemethyl)amine, Bz = benzoyl. Tf = trifluoromethanesulfonyl, dppf
= 1,1’ꢀbis(diphenylphosphino)ferrocene.
A combined experimental and theoretical approach was
taken to better understand the mechanism of the reaction. The
proposed hydropalladation via Path A and B, leading to desired
product 2e and byproducts 3e and 4e, respectively, were studied
computationally in detail at the IEFPCM (Toluene) M06L/6ꢀ
The two corresponding transition states model a rotation of the
H−Pd−I fragment to place the H–Pd bond parallel to the C≡C
bond.42 The computed activation energy for the insertion leading to
intermediate II is slightly lower than that required to form
intermediate V (ꢀEǂ = 2.4 kcal molꢀ1 vs. 3.1 kcal molꢀ1).
Furthermore, the formation of II is 4.9 kcal molꢀ1 more favorable
than the formation of V. These results suggest that insertion leading
311G(d,p)/SDDALL//BP86/6ꢀ31G(d,p)/LANL2DZ
level
of
theory.41 In order to support our proposal for the initial formation of
a HPdL2I species, a homogeneous tolueneꢀd8 solution of a 1:1
mixture of Pd(PtBu3)2 and Bu3N·HI was analyzed by 1H NMR after
15 minutes. During this experiment, a triplet pattern consistent with
a PdL2HI species was observed at ꢀ14.23 ppm. The activation
energy for the two possible regioselective alkyne insertions of I can
be correlated to the experimental ratio of 2e:(3e+4e) (Figure 3).
to βꢀvinyl–Pd(II) species II in Path
A is kinetically and
thermodynamically favored over the insertion leading to αꢀvinyl–
Pd(II) species V in Path B. This result is in agreement with the
1.4:1 ratio measured experimentally for the reaction of 1e in favor
of the formation of 2e (path A).
Scheme 4. Proposed catalytic cycle for the formation of the hydroiodination product 2e and the cycloisomerization byproduct 3e and 4e. L = PtBu3.
6
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
corresponding product 2la in 82% and 8% NMR yield, respectively,
which supports the feasibility of this seemingly compulsory
isomerization step. The marked difference in reactivity of the two
isomers is attributed to the bulky palladium catalyst having
different oxidative addition aptitudes for the two vinyl iodide
isomers. Furthermore, the lack of byproducts 3la or 4la formation
suggests that the reaction is unidirectional which is further
corroborated by the high energy required to produce I from
intermediate II by βꢀhydride elimination (ꢀEǂ = 24.7 kcal molꢀ1).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Figure 3. Computed potential energy profile for the insertion of the alkyne
moiety into the Pd–H bond (L = PtBu3). Energies (kcal molꢀ1) refer to zeroꢀ
point corrected energies quoted relative to I with L = PtBu3 at the IEFPCM
(Toluene) M06L/6ꢀ311G(d,p)/SDDALL//BP86/6ꢀ31G(d,p)/LANL2DZ level
of theory. Gibbs free energies are presented in parentheses.
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
The isomerization of the vinyl–Pd moiety in intermediate II
from the E to the Z configuration is a prerequisite for the
subsequent carbopalladation step. There have been several reports
describing the isomerization of vinyl–Pd(II),7h,7i,10,43 however, it is
rare that this process occurs as a productive catalytic step. In 2015,
Werz and coꢀworkers described an interesting formal antiꢀ
arylpalladation of alkynes as a key step in a Pd(0)ꢀcatalyzed
domino cyclization.44 More recently, Lam and coꢀworkers
described a formal anti alkyne arylnickelation that was proposed to
occur by way of an isomerizing vinyl–Ni(II) intermediates.45 To the
best of our knowledge, our process represents the first antiꢀ
Figure 4. a) Optimized structure of the transition state for the EꢀtoꢀZ
isomerization process and selected geometrical parameters (H atoms are
omitted for clarity with exception of the vinyl proton). b) Control
experiments to support the EꢀtoꢀZ vinylꢀPd(II) isomerization step.
The computed potential energy surface for Path A is presented
in Figure 5.41 Coordination of the tethered alkene to the palladium
atom provides the higher energy intermediate III’ (ꢀE = +16.9 kcal
mol). Subsequent intramolecular alkene insertion generates
neopentyl–Pd intermediate IV. This step requires ꢀEǂ = 7.4 kcal
molꢀ1 and the corresponding transition state TS_III’_IV models a
fourꢀcentered concerted mechanism. The carbopalladation process
from III to IV requires an overall activation energy of ꢀEǂ = 24.3
kcal molꢀ1, rendering this process the rate determining step.
Carbon–iodine bondꢀforming reductive elimination provides
intermediate 2e_Pd where the Pd atom is coordinated to the product
via the halogen atom. The process requires ꢀEǂ = 18.1 kcal molꢀ1
and proceeds via TS_IV_3e. Final dissociative ligand replacement
furnishes the desired product 2e and regenerates the PdL2 catalyst.45
hydropalladation of alkynes as
a productive catalytic step.
Isomerization of the E conformer II to the slightly more stable Z
conformer III requires ꢀEǂ = 16.9 kcal molꢀ1 and the corresponding
transition state TS_II_III models the rotation around the C=C bond
placing the Cβ−Pd bond almost perpendicular to the carbonyl−Cα
bond (Figure 4a). The Cα–Cβ distance in the transition state (1.39
Å) is slightly longer than the same distance in the two intermediates
II and III (1.35 Å and 1.36 Å, respectively). Similarly, the Cβ–Pd
distance in TS_II_III (1.91 Å) is slightly shorter than in II and III
(2.01 Å and 1.98 Å, respectively). In order to experimentally
support this process, compounds (E)ꢀ9 and (Z)ꢀ9 were synthesized
and subjected to the standard reaction conditions in the absence of
the HI surrogate (Figure 4b). Both isomers provided the
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
1
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
Figure 5. Computed potential energy profile for the Path A (L = PtBu3). Energies (kcal molꢀ1) refer to zeroꢀpoint corrected energies quoted relative to I with L =
PtBu3 at the IEFPCM (Toluene) M06L/6ꢀ311G(d,p)/SDDALL//BP86/6ꢀ31G(d,p)/LANL2DZ level of theory. Gibbs free energies are presented in parentheses.
elimination to take place. The overall process requires ꢁEǂ = 34.4
kcal molꢀ1 and generates the sixꢀmembered intermediate VIII (not
shown). Stabilization of this intermediate can occur by two separate
We next studied the mechanism for the formation of byproducts
3e and 4e via Path B (Figure 6).41 After formation of intermediate
agostic interactions with the hydrogen atoms attached to the two β–
methylene carbons providing structures VIII’ and VIII’’. β–
hydride elimination can occur from both isomers to generate the
corresponding complexes 3e’_Pd and 3e_Pd (ꢀE = –3.7 kcal molꢀ
1). Of note, diene 3e was the only isomer detected experimentally
and the configuration of the exoꢀdouble bond was confirmed by
NMR spectroscopic analysis after isolation. Final isomerization
provides byproduct 4e.
V, coordination of the tethered alkene and subsequent
carbopalladation (overall ꢁEǂ = 12.4 kcal molꢀ1) produces fiveꢀ
membered intermediate VI. The structure of VI allows a successive
intramolecular carbopalladation to produce the cyclopropaneꢀ
containing intermediate VII via
a fourꢀcentered concerted
mechanism. This process only requires ꢁEǂ = 3.4 kcal molꢀ1 and is
modeled by TS_VI_VII. Facile C−C bond rotation in VII provides
intermediate VII’ (ꢁE
= a stepwise
+5.8 kcal molꢀ1) via
mechanism.41 The spatial arrangement in VII’ allows βꢀcarbon
Figure 6. Computed potential energy profile for the Path B (L = PtBu3). Energies (kcal molꢀ1) refer to zeroꢀpoint corrected energies quoted relative to I with L =
PtBu3 at the IEFPCM (Toluene) M06L/6ꢀ311G(d,p)/SDDALL//BP86/6ꢀ31G(d,p)/LANL2DZ level of theory. Gibbs free energies are presented in parentheses.
8
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
In analogy to IV, we computed the potential energy profile for
containing products 2ldꢀBr, 2lhꢀBr and 2lqꢀBr in moderate to good
yields. Pyridineꢀcontaining 2lvꢀBr could also be obtained in 62%
yield.
the C–I bondꢀforming reductive elimination from the neopentyl–Pd
intermediate VI (Figure 7). This process requires ꢁEǂ = 20.1 kcal
molꢀ1 and the corresponding transition state TS_VI_X models a
threeꢀcentered mechanism and an incipient interaction between the
Pd atom and the exoꢀdouble bond. Dissociation of the metal atom
from the resulting intermediate X_Pd releases the final product X.
Comparison of the activation energies required for the VI→VII
(ꢁEǂ = 3.4 kcal molꢀ1) and VI→X_Pd (ꢁEǂ = 20.1 kcal molꢀ1)
processes and the stability of the corresponding products VII (E = ꢀ
46.1 kcal molꢀ1) and X_Pd (E = ꢀ26.8 kcal molꢀ1) indicated that C–I
bondꢀforming reductive elimination is strongly disfavored with
respect to the intramolecular cyclopropanation to form VII. This
conclusion supports the experimental evidence where product X
was never detected in the reaction mixture.
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
L
I
H
Pd
Ph
Me
O
N
Me
TS_VI_X
ꢀ11.3
(ꢀ9.3)
ꢀ26.8
(ꢀ25.6)
L
ꢀ31.4
(ꢀ29.9)
PdL2
ꢀ33.7
(ꢀ32.2)
PdL
I
H
Ph
L
I
Me
H
Pd
H
I
O
N
Ph
Ph
Me
Me
X_Pd
Me
O
O
N
N
Me
VI
Me
X
not observed
Scheme 5. Theoretic and experimental studies involving the analogous
catalytic hydrobromination and hydrochlorination processes. a) Theoretical
comparison between the carbon–iodine, carbon–bromine and carbon–
chlorine bondꢀforming reductive elimination from Pd(II). Energies (kcal
molꢀ1) refer to zeroꢀpoint corrected energies at the IEFPCM (Toluene)
M06L/6ꢀ311G(d,p)/SDDALL//BP86/6ꢀ31G(d,p)/LANL2DZ level of theory.
Gibbs free energies are presented in parentheses. b) Substrate scope for the
Pdꢀcatalyzed hydrobromination and hydrochlorination using Et3N·HBr and
Et3N·HCl, respectively. Reactions were run on a 0.2 mmol scale. Values
Figure 7. Computed potential energy profile for the C–I bondꢀforming
reductive elimination from intermediate VI (L = PtBu3). Energies (kcal molꢀ
1) refer to zeroꢀpoint corrected energies quoted relative to I with L = PtBu3
at the IEFPCM (Toluene) M06L/6ꢀ311G(d,p)/SDDALL//BP86/6ꢀ
31G(d,p)/LANL2DZ level of theory. Gibbs free energies are presented in
parentheses.
We next computed the activation energies for the
carbon−halogen bondꢀforming reductive elimination step for
bromine and chlorine (Scheme 5a). The activation energies required
for the formation of the analogous C−Br and the C−Cl bonds are
ꢀEǂ = 19.8 and 20.8 kcal molꢀ1, respectively. These values are
higher, yet comparable to the activation energy for the C–I case
(ꢀEǂ = 18.0 kcal molꢀ1). This observation prompted us to evaluate
the reactivity of the corresponding commercially available
Et3N·HBr and HCl salts in the reaction. The reaction was successful
with both reagents and provided the corresponding products 2laꢀBr
and 2laꢀCl in 67% and 35% yield, respectively (Scheme 5b). This
reactivity trend is in good agreement with the computed activation
energies. This represents an exceedingly rare example of a catalytic
reaction involving C(sp3)−X bondꢀforming (X = Br or Cl) reductive
elimination from an alkyl–Pd(II)–X species.45 The generality of the
transformation using Et3N·HBr was evaluated using a number of
substrates. The reaction of those containing electronꢀrich and
electronꢀpoor aromatic groups provided the corresponding bromineꢀ
a
represent isolated yields after column chromatography. Reaction was run
using PhMe as solvent. b Reaction was run using 1,4ꢀdioxane as solvent.
CONCLUSIONS
We have discovered a conceptually and mechanistically novel
Pdꢀcatalyzed hydrohalogenation of enynes that affords access to
synthetically useful halogenated pyridinones. This process relies on
highly practical and crystalline ammonium halides (Et3N·HX)
which operate as surrogates to conventional toxic and corrosive
hydrogen halide sources. The use of a strategically placed –OtBu
nitrogen protecting group was instrumental in obtaining high
selectivity for the desired products containing both a C(sp3)–
halogen motif and an allꢀcarbon quaternary center at the γꢀposition
to the carbonyl. These simple catalytic conditions also enable
unprecedented C(sp3)–Br and –Cl bondꢀforming reductive
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
1
2
3
4
5
6
elimination from
a
Pd(II) species. Therefore, by simply
toꢀZ vinyl–Pd(II) isomerization. The extension of this concept to
interchanging Et3N·HX sources, iodinated, brominated and
chlorinated products can be obtained using nonꢀhalogenated
substrates. A combination of experiment and theory has provided
insight into the unprecedented reaction mechanism that involves a
formal anti alkyne hydropalladation step resulting from a crucial Eꢀ
the first example of transfer hydroiodination was also realized,
whereby a domino Pdꢀcatalyzed release and react strategy enables
the use of 1ꢀiodobutane as a nonꢀionic HI surrogate. We believe
that this report will prompt future applications of this class of
reagents
in
other
metalꢀcatalyzed
processes.
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
Rev. 2015, 115, 612ꢀ633; p) Petrone, D.A., Ye, J.; Lautens, M. Chem.
Rev. 2016, 116, 8003ꢀ8104.
Newman, S.G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416ꢀ
11417.
Roy, A.H.; Hartwig, J.F. J. Am. Chem. Soc. 2001, 123, 1232ꢀ1233.
Roy, A.H.; Hartwig, J.F. J. Am. Chem. Soc. 2003, 125, 13944ꢀ13945.
Newman, S.G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778ꢀ
1780.
Liu, H., Li, C., Qui, D.; Tong, X. J. Am. Chem. Soc. 2011, 133, 6187ꢀ
6193.
a) Newman, S.G.; Howell, J.K.; Nicolaus, N.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 14916ꢀ14919; b) Jia, X.; Petrone, D.A.;
Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 9870ꢀ9872; c) Petrone,
D.A.; Malik, H.A.; Clemenceau, A.; Lautens, M. Org. Lett. 2012, 14,
4806ꢀ4809; d) Petrone, D.A.; Lischka, M.; Lautens, M. Angew.
Chem. Int. Ed. 2013, 52, 10635ꢀ10638; e) Petrone, D.A.; Yoon, H.;
Weinstabl, H.; Lautens, M. Angew. Chem. Int. Ed. 2014, 53, 7908ꢀ
7912; f) Chen, C.; Hu, J.; Su, J.; Tong, X. Tetrahedron Lett. 2014, 55,
3229ꢀ3231; g) Petrone, D.A.; Le. C.M.; Newman, S.G.; Lautens, M.
Pd(0)ꢀCatalyzed Carboiodination: Early Developments and Recent
Advancements. In New Trends in Cross-Coupling: Theory and
Applications. Colacot, T.J., Ed.; Royal Society of Chemistry:
Cambridge, 2015; h) Le, C.M.; Menzies, P.; Petrone, D.A.; Lautens,
M. Angew. Chem. Int. Ed. 2015, 54, 254ꢀ257; i) Le, C.M.; Hou, X.;
Sperger, T.; Schoenebeck, F.; Lautens, M. Angew. Chem. Int. Ed.
2015, 54, 15897ꢀ15900.
ASSOCIATED CONTENT
The information is available free of charge via the internet at
http://pubs.acs.org.
2.
3.
4.
5.
Experimental details of synthetic procedures, Xꢀray data, and computational
details (PDF)
Crystallographic data for 2d, 4d, 2la and 10 (CIF)
6.
7.
AUTHOR INFORMATION
Corresponding Authors
* amalia.pobladorbahamonde@unige.ch
* mlautens@chem.utoronto.ca
NOTES
The authors declare no competing financial interests.
ACKNOWLEDGEMENTS
We are grateful for financial support from the Natural Sciences and
Engineering Research Council (NSERC), the University of Toronto (U of
T), the University of Geneva (U of G), and Alphora Research Inc. M.L.
(O.C.) thanks the Canada Council for the Arts for a Killam Fellowship.
D.A.P thanks NSERC for a postgraduate scholarship (CGSꢀD). Dr. Alan
Lough (U of T) is acknowledged for Xꢀray analysis. Prof. Andrei Yudin is
thanked for HPLC and Biotage access. Prof. Mark Taylor is thanked for
glovebox access and discussions. Dr. Rodrigo Mendoza Sánchez (U of T)
and Sherif Kaldas (U of T) are acknowledged for their assistance with
reverse phase purification. Prof. Robert H. Morris (U of T) and Dr. Charles
C. J. Loh (MaxꢀPlanckꢀInstitut für Molekulare Physiologie, Abteilung
Chemische Biologie) are thanked for discussions. We also thank Carmine
Chiancone (U of G) for technical support and Dr. YuꢀGang Shi (Zhejiang
Gongshang University) for preparing starting materials for preliminary
investigations.
8.
9.
Grigg, R. D.; Schomaker, J. M. Synlett 2013, 24, 401ꢀ407.
a) Trost, B.M. Science, 1991, 254, 1471ꢀ1477; b) Trost, B.M. Angew.
Chem. Int. Ed. 1995, 34, 259ꢀ281.
10. Bäckvall, J.E. in Metal-Catalyzed Cross-Coupling Reactions: Volume
1 (de Meijere, A.; Diederich, F. ed.) 479ꢀ530 (WileyꢀVCH, 2004).
11. Various transition metalꢀcatalyzed cyclohalogenations have been
reported using halogenated 1,6ꢀenynes, see: a) Ma, S.; Lu, X. J.
Chem. Soc., Chem. Commun. 1990, 733ꢀ734; b) Ma, S.; Lu, X. J.
Org. Chem. 1991, 56, 5120ꢀ5125; c) Ma, S.; Zhu, G.; Lu, X. J. Org.
Chem. 1993, 58, 3692ꢀ3696; d) Ma, S.; Lu, X. J. Org. Chem. 1993,
58, 1245ꢀ1250; e) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245ꢀ1250;
f) Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
6370ꢀ6371; g) Jackowski, O.; Wang, J.; Xie, X.; Ayad, T.; Zhang, Z.;
RatovelonanaꢀVidal, V. Org. Lett 2012, 14, 4006ꢀ4009; h) Zhu, G.;
Zhang, Z. J. Org. Chem. 2005, 70, 3339ꢀ3341; i) Hoye, T.; Wang, J.
J. Am. Chem. Soc. 2005, 127, 6950ꢀ6951, and references therein.
12. Aubert, C., Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813ꢀ
834.
REFERENCES
1.
a) Sasson, Y.; Formation of Carbon–Halogen Bonds (Cl, Br, I). In
Halides, PseudoꢀHalides and Azides; Patai, P.; Rappoport, Z., Eds.;
John Wiley and Sons: New York, 1995; b) Vigalok, A. Chem. Eur. J.
2008, 14, 5102ꢀ5108; c) Brown, J.M.; Gouverneur, V. Angew. Chem.
Int. Ed. 2009, 48, 8610ꢀ8614; d) Muñiz, K. Top. Organomet. Chem.
2010, 31, 1ꢀ18; e) Vigalok, A.; Kaspi, A.W. Top. Organomet. Chem.
2010, 31, 19ꢀ38; f) Furuya, T.; Klein, J.E.M.N.; Ritter, T. Synthesis,
2010, 11, 1804ꢀ1821, g) Lyons, T.W.; Sanford, M. Chem. Rev. 2010,
110, 1147ꢀ1169; g) Racowski, J.M.; Sanford, M.S. Top. Organomet.
Chem. 2011, 35, 61ꢀ84; h) Engle, K.M.; Mei, T.ꢀS.; Wang, X.; Yu, J.ꢀ
Q. Angew. Chem. Int. Ed. 2011, 50, 1478ꢀ1491; i) Kalyani, D.;
Sanford, M.S. Top. Organomet. Chem. 2011, 35, 61ꢀ84; j) Furuya, T.;
Kamlet, A.S.; Ritter, T. Nature, 2011, 473, 470ꢀ477; k) Jiang, X.;
Liu, H.; Gu, Z. Asian J. Org. Chem. 2012, 1, 16ꢀ24; l) Hollingworth,
C.; Grouverneur, V. Strategies Towards Challenging Fluorination
Reactions. In C–H and C–X Bond Functionalization: Transition
Metal Mediation; Ribas, X. Ed.; Royal Society of Chemistry:
Cambridge, 2013; m) Liang, T.; Neumann, C.N.; Ritter, T. Angew.
Chem. Int. Ed. 2013, 52, 8214ꢀ8264. n) Chen, C.; Tong, X. Org.
Chem. Front. 2014, 1, 439ꢀ446. o) Campbell, M.G.; Ritter, T. Chem.
13. MarcoꢀMartínez, J.; LópezꢀCarrillo, Buñuel, E.; Simancas, R.;
Cárdenas, D.J. J. Am. Chem. Soc. 2007, 129, 1874ꢀ1875.
14. a) Ojima, I.; Donovan, R.J.; Shay, W.R. J. Am. Chem. Soc. 1992, 114,
6580ꢀ6582; b) Molander, G.A.; Retsch, W.H. J. Am. Chem. Soc.
1997, 119, 8817ꢀ8825; c) Muraoka, T.; Matsuda, I.; Itoh, K.
Tetrahedron Lett. 1998, 39, 7325ꢀ7328; d) Ojima, I.; Vu, A.T.; Lee,
S.ꢀY.; McCullagh, J.V.; Moralee, A.C.; Fujiwara, M.; Hoang, T.H. J.
Am. Chem. Soc. 2002, 124, 9164ꢀ9174; e) Chakrapani, H.; Liu, C.;
Widenhoefer, R.A. Org. Lett. 2003, 5, 157ꢀ159; f) Takachi, M.;
Chatani, N. Org. Lett. 2010, 12, 5132ꢀ5134; g) Xi, T.; Lu, Z. J. Org.
Chem. 2016, 81, 8858ꢀ8866.
15. Lautens, M.; Mancuso, J. Org. Lett. 2000, 2, 671ꢀ673.
10
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
16. Peng, H.; Liu, G. Org. Lett. 2011, 13, 772ꢀ775. This transformation
25. a) Brieger, G.; Nestrick, T.J. Chem. Rev. 1974, 74, 567ꢀ580; b) Wang,
was proposed by the authors to involve an initial alkyne
fluoropalladation.
D.; Astruc, D. Chem. Rev. 2015, 115, 6621ꢀ6686.
26. a) Wu, L.; Liu, Q.; Jackstell, R.; Beller, M. Angew. Chem. Int. Ed.
2014, 53, 6310ꢀ6320; b) Morimoto, T.; Fuji, K.; Tsutsumi, K.;
Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806ꢀ3807; c) Shibata, T.,
Toshida, N.; Takagi, K. J. Org. Chem. 2002, 67, 7446ꢀ7450; d)
Mura, M.G., De Luca, L., Giacomelli, G.; Porcheddu, A. Adv. Synth.
Catal. 2012, 354, 3180ꢀ3186; e) Ueda, T.; Konishi, H.; Manabe, K.
Org. Lett. 2012, 14, 5370ꢀ5373; f) Kim, D.ꢀS.; Park, W.ꢀJ.; Lee, C.ꢀ
H.; Jun, C.ꢀH. J. Org. Chem. 2014, 79, 12191ꢀ12196; g) Ueda, T.,
Konishi, H.; Manabe, K. Angew. Chem. Int. Ed. 2013, 52, 8611ꢀ8615;
h) Gehrtz, P.H.; Hirschbeck, V.; Fleischer I. Chem. Commun. 2015,
51, 12574ꢀ12577.
27. Skrydstrup and coꢀworkers have developed reagents for the
controlled stoichiometric ex situ generation of carbon monoxide, see:
a) Hermange, P.; Lindhardt, A.T.; Taaning, R.H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061ꢀ6071; b)
Friis, S.D.; Lindhardt, A.T.; Skrydstrup, T. Acc. Chem. Res. 2016, 49,
594ꢀ605.
28. Murphy, S.K.; Park, J.ꢀW.; Cruz, F.A.; Dong, V.M. Science 2015
347, 56ꢀ60.
29. a) Fang, X.; Yu, P.; Morandi, B. Science 2016, 351, 832ꢀ836; b)
Fang, X.; Yu, P.; Cerai, G.P.; Morandi, B. Chem. Eur. J. 2016, 22,
15629ꢀ15633.
30. a) Akana, J.A.; Bhattacharyya, K.X.; Müller, P.; Sadighi, J.P. J. Am.
Chem. Soc. 2007, 129, 7736ꢀ7737; b) Gorske, B.C.; Mbofana, C.T.;
Miller, S.J. Org. Lett. 2009, 11, 4318ꢀ4321; c) Gauthier, D.;
Lindhardt, A.T.; Olsen, E.P.K.; Overgaard, J.; Skrydstrup, T. J. Am.
Chem. Soc. 2010, 132, 7998ꢀ8009; d) Zhu, J.; Tsui, G.C.; Lautens, M.
Angew. Chem. Int. Ed. 2012 51, 12353ꢀ12356; e) Hu, Y.; Shen, Z.;
Huang, H. ACS Catal. 2016, 6, 6785ꢀ6789;
31. a) Heck, R.F. Acc. Chem. Res. 1979, 12, 146ꢀ151; b) Beletskaya, I.P.;
Cheprakov, A.V. Chem. Rev. 2000, 100, 3009ꢀ3066; c) Hills, I.D.;
Fu, G.C. J. Am. Chem. Soc. 2004, 126, 13178ꢀ13179.
32. Armbruster, R.W.; Morgan, M.M.; Schmidt, J.L.; Lau, C.M.; Riley,
R.M.; Zabrowski, D.L.; Dieck, H.A. Organometallics 1986, 5, 234ꢀ
237
33. Chen, C.; Hou, L.; Cheng, M.; Su, J.; Tong, X. Angew. Chem. Int. Ed.
2015, 54, 3092ꢀ3096.
34. Miyabe, H.; Asada, R.; Takemoto, Y. Org. Biomol. Chem. 2012, 10,
3519ꢀ3530.
35. Chen, L., Ren, P.; Carrow, B. P. J. Am. Chem. Soc. 2016, 138, 6392ꢀ
6395.
36. Hill, L.L.; Moore, L.R.; Huang, R.; Craciun, R.; Vincent, A.J.; Dixon,
D.A.; Chou, J.; Woltermann, C.J.; Shaughnessy, K.H. J. Org. Chem.
2006, 71, 5117ꢀ5125.
37. Bissember, A.C.; Levina, A.; Fu, G.C. J. Am. Chem. Soc. 2012, 134,
14232ꢀ14237.
38. For a recent example using alkyl bromides as a mild hydride source
in Niꢀcatalyzed hydroamidation, see: Wang, X.; Nakajima, M.;
Serrano, E.; Martin, R. J. Am. Chem. Soc. 2016, 138, 15531ꢀ15534.
39. For a review on cyclic carbopalladation, see: Negishi, E.ꢀi.; Copéret,
C.; Ma, S.; Liou, S.ꢀY.; Liu, F. Chem. Rev. 1996, 96, 365ꢀ394.
40. For reports concerning apparent 6ꢀendo cyclizations in Pd catalysis,
see: a) Owczarczyk, Z., Lamaty, F., Vawter, E.J.; Negishi, E.ꢀi. J.
Am. Chem. Soc. 1992, 114, 10091ꢀ10092; b) Mikami, K.; Hatano, M.
Proc. Natl. Acad. Sci. 2004, 101, 5767ꢀ5769; c) Yamamoto, Y.;
Kuwabara, S.; Ando, Y.; Nagata, H.; Nishiyama, H.; Itoh, K. J. Org.
Chem. 2004, 69, 6697–6705.
17. a) Michelet, V.; Toullec, P.Y.; Genêt, J.ꢀP. Angew. Chem. Int. Ed.
2008, 47, 4268ꢀ4315; b) Toullec, P.Y.; Chao, C.ꢀM.; Chen, Q.;
Gladiali, S.; Genêt, J.ꢀP.; Michelet, V. Adv. Synth. Catal. 2008, 350,
2401ꢀ2408; c) Amijs, C.H.M.; LópezꢀCarrillo, V.; Raducan, M.;
PérezꢀGalán, P.; Ferrer, C.; Echavarren, A.M. J. Org. Chem. 2008,
73, 7721ꢀ7730; d) Chao, C.ꢀM.; Vitale, M.R.; Toullec, P.Y.; Genêt,
J.ꢀP.; Michelet, V. Chem. Eur. J. 2009, 15, 1319ꢀ1323; e) Dang, M.;
Hou, L.; Tong, X. Chem. Eur. J. 2016, 22, 7734ꢀ7738.
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
18. Grushin, V.V. Chem. Rev. 1996, 96, 2011ꢀ2034.
19. Tsuji, J. Palladium Reagents and Catalysis – New Perspectives for
the 21st Century (John Wiley & Sons, 2004) p. 565ꢀ612.
20. a) Klein, H.; Roisnel, T.; Bruneau, C.; Dérien, S. Chem. Commun.
2012, 48, 11032ꢀ11034; b) Dérien, S.; Klein, H.; Bruneau, C. Angew.
Chem. Int. Ed. 2015, 54, 12112ꢀ12115; c) Podhajsky, S.M.; Sigman,
M.S. Organometallics, 2007, 26, 5680ꢀ5686; d) Zhu, G.; Chen, D.;
Wang, Y.; Zheng, R. Chem. Commun. 2012, 48, 5796ꢀ5798; e)
Uehling, M.R.; Rucker, R.P.; Lalic, G. J. Am. Chem. Soc. 2014, 136,
8799ꢀ8803.
21. Hagen, J. Industrial Catalysis – a Practical Approach (WileyꢀVCH,
2006).
22. a) Hoffman, C.J. Inorg. Synth. 1963, 180ꢀ182; b) Cousseau, J.; Gouin,
L. Tetrahedron Lett. 1974, 33, 2889ꢀ2892; c) Cousseau, J.; Gouin, L.
J. Chem. Soc. Perkin Trans. 1 1977, 1797ꢀ1801; d) Cousseau, J.
Synthesis 1990, 33, 805ꢀ806; d) Barluenga, J.; González, J.M.;
Campos, P.J.; Asensio, G. Angew. Chem. Int. Ed. Engl. 1985, 24,
319ꢀ320; e) Stewart, L.J.; Gray, D.; Pagni, R.M.; Kabalka, G.W.
Tetrahedron Lett. 1987, 28, 4497ꢀ4498; f) Pagni, R.M.; Kabalka,
G.W.; Boothe, R.; Gaetano, K.; Stewart, L.J.; Conaway, R.; Dial, C.;
Gray, D.; Larson, S.; Liudhardt. T. J. Org. Chem. 1988, 53, 4477ꢀ
4482; g) Irifune, S.; Kibayashi, T.; Ishii, Y.; Ogawa, M. Synthesis
1988, 366ꢀ369; h) Kanai, T.; Irifune, S.; Ishii, Y.; Ogawa, M.
Synthesis 1989, 283ꢀ286; i) Reddy, C.K.; Periasamy, M. Tetrahedron
Lett. 1989¸ 30, 5663ꢀ5664; j) Kamiya, N.; Chikami, Y.; Ishii, Y.
Synlett 1990, 675ꢀ676; k) Kanai, T.; Kanagawa, Y.; Ishii, Y. J. Org.
Chem. 1990, 55, 3274ꢀ3277; l) Reddy, C.K.; Periasamy, M.
Tetrahedron Lett. 1990¸ 31, 1919ꢀ1920; m) Ma, S.; Lu, X. J. Chem.
Soc., Chem. Commun. 1990, 1643ꢀ1644; n) Ma, S.; Lu, X.; Li, Z. J.
Org. Chem. 1992, 57, 709ꢀ713; o) Kropp, P.J.; Crawford, S.D. J. Org.
Chem. 1994, 59, 3102ꢀ3112; p) Cavelier, F.; Enjalbal, C. Tetrahedron
Lett. 1996, 37, 5131ꢀ5134; q) BoisꢀChoussy, M.; Neuville, L.;
Beugelmans, R.; Zhu, J. J. Org. Chem. 1996, 61, 9309ꢀ9322; r)
Broomfield, C.E. Org. Proc. Res. Devel. 1997, 1, 88ꢀ89; s)
Nudelman, A.; Bechor, Y.; Falb, E.; Fischer, B.; Wexler, B.A.;
Nudelman, A. Synth. Commun. 1998, 28, 471ꢀ474; t) Yu, W.; Jin, Z.
J. Am. Chem. Soc. 2000, 122, 9840ꢀ9841; u) Chervin, S.M.; Abada,
P.; Koreeda, M. Org. Lett. 2000, 2, 369ꢀ372; v) Yu, W.; Jin, Z. J. Am.
Chem. Soc. 2001, 123, 3369ꢀ3370; w) Ma, S.; Li, L. Synlett 2001,
1206ꢀ1213; x) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2002, 124, 6576ꢀ
6583; y) Su, M.; Kang, Y.; Yu, W.; Hua, Z.; Jin, Z. Org. Lett. 2002,
4, 691ꢀ694; z) Mulder, J.A.; Kurtz, K.C.M.; Hsung, R.P.; Coverdale,
H.; Frederick, M.O.; Shen, L.; Zificsak, C.A. Org. Lett. 2003, 5,
1547ꢀ1550; aa) Xu, W.; Dolbier, Jr., W.R.; Salazar, J. J. Org. Chem.
2008, 73, 3535ꢀ3538; ab) Kawaguchi, S.ꢀi.; Ogawa, A. Org. Lett.
2010, 12, 1893ꢀ1895; ac) Zhu, G.; Chen, D.; Wang, Y.; Zheng, R.
Chem. Commun. 2012, 48, 5796ꢀ5798.
23. a) Zhu, G.; Chen, D.; Wang, Y.; Zheng, R. Chem. Commun. 2012, 48,
5796−5798; b) Wang, Z.; Lu, X. Chem. Commun. 1996, 535−536; c)
Wang, Z.; Lu, X. J. Org. Chem. 1996, 61, 2254−2255; d) Wen, Y.;
Huang, L.; Jiang, H.; Chen, H. J. Org. Chem. 2012, 77, 2029−2034;
e) Chen, D.; Cao, Y.; Yuan, Z.; Cai, H.; Zheng, R.; Kong, L.; Zhu, G.
J. Org. Chem. 2011, 76, 4071−4074; e) Wang, Z.; Lu, X.; Lei, A.;
Zhang, Z. J. Org. Chem. 1998, 63, 3806−3807.
41. For
a detailed potential energy profile see the Supporting
Information.
42. Henriksen, S.T., Tanner, D., Skrydstrup, T.; Norrby, P.ꢀO. Chem.
Eur. J. 2010, 16, 9494ꢀ9501.
43. a) Henry, P.M.; Acc. Chem. Res. 1973, 6, 16ꢀ24; b) Zargarian, D.;
Alper, H. Organometallics, 1991, 10, 2914ꢀ2921; c) Dyker, G.;
Keliner, A. Tetrahedron Lett. 1994, 35, 7633ꢀ7636; d) Gabriele, B.;
Salerno, G.; Veltri, L.; Costa, M.; Massera, C. Eur. J. Org. Chem.
24. Bhawal, B.N.; Morandi, B. ACS Catal. 2016, 6, 7528ꢀ7535.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
1
2
3
4
5
6
7
8
2001, 4607ꢀ4614; e) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand,
A. J. Organomet. Chem. 2004, 689, 4642ꢀ4646; f) Kamijo, S.; Sasaki,
Y.; Kanazawa, C.; Schüßeler, T.; Yamamoto, Y. Angew. Chem. Int.
Ed. 2005, 44, 7718ꢀ7721; g) Chernyak, N.; Gorelsky, S.I.;
Gevorgyan, V. Angew. Chem. Int. Ed. 2011, 50, 2342ꢀ2345; h)
Krasovskiy, A.; Lipshutz, B.H. Org. Lett. 2011, 13, 3818ꢀ3821; i) Lu,
G.ꢀP.; Voigtritter, K.R.; Cai, C.; Lipshutz, B.H. Chem. Commun.
2012, 48, 8661ꢀ8663; j) Lu, G.ꢀP.; Voigtritter, K.R.; Cai, C.;
Lipshutz, B.H. J. Org. Chem. 2012, 77, 3700ꢀ3703; k) Aziz, J.;
Frison, G.; Menez, P.L.; Brion, J.ꢀD.; Hamze, A.; Alami, M. Adv.
Synth. Catal. 2013, 355, 3425ꢀ3436.
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
44. a) Pawliczek, M.; Schneider, T.F.; Maaß, C.; Stalke, D.; Werz, D.B.
Angew. Chem. Int. Ed. 2015, 54, 4119ꢀ4123; b) Pawliczek, M.;
Milde, B.; Jones, P.G.; Werz, D.B. Chem. Eur. J 2015, 21, 12303ꢀ
12307.
45. Clarke, C., IncertiꢀPradillos, C.A.; Lam, H.W. J. Am. Chem. Soc.
2016, 138, 8068ꢀ8071.
46. Lan, Y., Liu, P., Newman, S.G., Lautens, M.; Houk, K.N. Chem. Sci.
2012, 3, 1987ꢀ1995.
12
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
3
Entry for the Table of Contents
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
13
ACS Paragon Plus Environment