Practical Intermolecular Hydroarylation of Diverse Alkenes via Reductive Heck Coupling

Article abstract of DOI:10.1021/acscatal.8b02717

The hydroarylation of alkenes is an attractive approach to construct carbon-carbon (C-C) bonds from abundant and structurally diverse starting materials. Herein we report a palladium-catalyzed reductive Heck hydroarylation of aliphatic and heteroatom-substituted terminal alkenes and select internal alkenes with an array of (hetero)aryl iodides. The reaction is anti-Markovnikov selective with terminal alkenes and tolerates a wide variety of functional groups on both the alkene and (hetero)aryl coupling partners. Additionally, applications of this method to complex molecule diversifications are demonstrated. Mechanistic experiments are consistent with a mechanism in which the key alkylpalladium(II) intermediate is intercepted with formate and undergoes a decarboxylation/C-H reductive elimination cascade to afford the saturated product and turn over the cycle.

Full text of DOI:10.1021/acscatal.8b02717

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Letter
Practical Intermolecular Hydroarylation of
Diverse Alkenes via Reductive Heck Coupling
John A. Gurak, and Keary M. Engle
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02717 • Publication Date (Web): 24 Aug 2018
Downloaded from http://pubs.acs.org on August 24, 2018
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Page 1 of 7
ACS Catalysis
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Practical Intermolecular Hydroarylation of Diverse Alkenes via Re-
ductive Heck Coupling
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John A. Gurak, Jr. and Keary M. Engle*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, Unit-
ed States
ABSTRACT: The hydroarylation of alkenes is an attractive approach to construct carbon–carbon (C–C) bonds from abundant and
structurally diverse starting materials. Herein we report a palladium-catalyzed reductive Heck hydroarylation of aliphatic and hete-
roatom-substituted terminal alkenes and select internal alkenes with an array of (hetero)aryl iodides. The reaction is anti-
Markovnikov selective for terminal alkenes and tolerates a wide variety of functional groups on both the alkene and (hetero)aryl
coupling partners. Additionally, applications of this method to complex molecule diversifications are demonstrated. Mechanistic
experiments are consistent with a mechanism in which the key alkylpalladium(II) intermediate is intercepted with formate and un-
dergoes a decarboxylation/C–H reductive elimination cascade to afford the saturated product and turn over the cycle.
KEYWORDS: reductive Heck, hydroarylation, palladium, alkene functionalization, regioselectivity
Classical Mizoroki–Heck Reaction
The Mizoroki–Heck coupling of aryl halides and alkenes is an effec-
tive means of forging C–C bonds to enable preparation of densely
PdII•Ln
R2
R2
functionalized alkenes.1 The broad functional group compatibility
and vast scope of the Mizoroki–Heck reaction have allowed it to
emerge as a staple transformation in complex-molecule synthesis.
Mechanistically, the catalytic cycle involves oxidative addition of
palladium(0) to an aryl halide followed by 1,2-migratory insertion
to access a key alkylpalladium(II) intermediate. In the classical
Mizoroki–Heck reaction, this intermediate succumbs to rapid β-
hydride (β-H) elimination to deliver the functionalized alkene
product, followed by HX reductive elimination to regenerate
Pd(0), thereby closing the catalytic cycle. Alternatively, one could
envision intercepting this intermediate with an additional reaction
partner as a general strategy for programmed conversion of alkenes
to various hydrofunctionalized or 1,2-difunctionalized products.
Our laboratory has previously utilized chelation stabilization of
organopalladium(II) intermediates to achieve hydroarylation of
alkynes2 and alkenes3 via Heck-type nucleopalladation followed by
protodepalladation. We thus became interested in exploring strate-
gies for enabling similar modes of bond construction with organo-
palladium(II) intermediates in the absence of directing substitu-
ents. To this end, the goal of the present study was to develop a
reductive Heck hydroarylation reaction of diverse aliphatic and
heteroatom-substituted alkenes.
–HX
cat Pd0•Ln
R2
R1
+
R1
R1
β-H
elimination
oxidative addition/
migratory insertion
Ar–X
Ar
Ar
Ar
Reductive Heck Reaction
[H–]
(e.g., HCO2H)
PdII•Ln
R2
H
R2
cat Pd0•Ln
R1
R2
R1
R1
oxidative addition/
C–H reductive
elimination (–CO2)
+
Ar–X
Ar
migratory insertion
R1
O
R1
R2
R
norbornenes
R2
α,β-enones/enals
alkynes
(Catellani, 1980)
(Cacchi, 1989)
(Cacchi, 1983)
(Cacchi, 1984)
(Cacchi, 1984)
(Endo, 1997)
Me
H
N
R2
R1
R
R1, R2 = Alkyl, N, O, Si
diverse alkenes
this work
I
tethered alkenes
styrenes
(Larock, 1987)
(Torii,1985)
Figure 1. Strategy and early precedents for the reductive Heck
reaction.
Reductive Heck hydroarylation involves intercepting the al-
kylpalladium(II) intermediate that is generated upon migratory
insertion with a hydride source, most commonly formate. This
transformation has been investigated since the early 1980s, and
pioneering work by Cacchi4 and others during this period led to
effective protocols with several classes of C–C-π-bond-containing
substrates that lack β-H atoms or that form stabilized π-allyl/π-
ACS Paragon Plus Environment

ACS Catalysis
benzyl/enolate intermediates, including strained alkenes (e.g., nor-
Page 2 of 7
began examining potential reaction conditions, deliberately using a
high molar ratio of triphenyl phosphine relative to palladium
(10:1). With potassium formate as the hydride source in the pres-
ence of water and a phase transfer reagent (TBABF4) as additives,
we were pleased to observe reductive Heck hydroarylation with
several different inorganic bases (entries 1–8). Moderately strong
bases provided higher yields than weaker bases, and, among those
tested, K3PO4 offered the best yield. An approximately 4:1 ratio of
anti-Markovnikov to Markovnikov addition products was observed,
and the regioisomeric ratio was roughly constant across different
conditions, reflecting earlier literature precedent of migratory inser-
tion under a neutral Heck-type mechanism.14 Next, we investigated
different formate sources (entries 9–12) and identified aqueous
tetramethylammonium formate solution (TMA•HCO2) as a supe-
rior reductant that did not require additional water or
tetraalkylammonium salts for high yield and selectivity. Lastly, we
varied the palladium and phosphine loadings and found that 1 mol
% Pd2(dba)3 with 20 mol % PPh3 performed similarly to higher
loadings (entries 13–19). Increasing or decreasing the phos-
phine:palladium ratio from 10:1 led to lower yield. Extending the
reaction time from 1 h to 4 h led to full consumption of starting
material with a combined product yield of 92% and 4:1 r.r. (entry
10). Notably, the optimized protocol is operationally convenient,
as it does not require rigorous exclusion of air or moisture and can
be conveniently performed on the benchtop without specialized
bornene),5 α,β-enones/enals,6 alkynes,7 tethered alkenes,8 and sty-
renes9 (Scheme 1).10 In contrast, application of this mode of reac-
tivity to aliphatic terminal alkenes is comparatively undeveloped,
likely due to the rapid nature of the aforementioned β-H elimina-
tion step with such substrates. To circumvent this issue, alternative
strategies for hydroarylation of terminal aliphatic alkenes have been
developed.11 In particular, Buchwald has described a CuH/Pd dual
catalytic system for anti-Markovnikov hydroarylation of terminal
alkenes with aryl bromides and electron-poor aryl chlorides.11c To
complement this approach, we became interested in developing a
general monometallic reductive Heck protocol that would be oper-
ationally simple, employ readily available reaction components, and
exhibit broad functional group compatibility, which motivated the
present study. While this manuscript was in preparation, related
catalytic systems for reductive Heck coupling of alkenes with aryl
bromides12 and aryl triflates13 were reported.
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To initiate our study, we elected to use 3-buten-1-ol (1b) and
iodobenzene as model reaction partners for optimization (Table
1). At the outset we hypothesized that two key aspects would be
vital for achieving successful reductive Heck coupling. First, the
palladium catalyst would need to be coordinatively saturated
throughout the catalytic cycle to suppress β-H elimination from the
alkylpalladium(II) intermediate. Second, the rates of decarboxyla-
tion (to form Pd–H) and C–H reductive elimination would need
to be sufficiently fast such that C–H bond formation could out-
compete β-H elimination. With these considerations in mind, we
Table 1. Optimization of reaction conditionsa
equipment
or
glassware.
Conditions
Ph
Ph
+
HO
HO
HO
Me
1b
4b
4b'
Pd2(dba)3 (%)
PPh3 (%)
Base
Reductant/Additive
Yield 4b + 4b' (%)b
4b:4b'c
1b (%)
Entry
1
2
3
4
5
50
50
50
50
50
None
KOtBu
KOH
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
3.8
3.9:1
4:1
58
31
33
39
67
2.5
2.5
2.5
2.5
2.5
24
44
51
43
18
K2CO3
KHCO3
3.8:1
3.5:1
50
50
50
50
50
50
50
50
25
10
5
KH2PO4
K2HPO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
KHCO2/H2O/TBABF4
NaHCO2/H2O/TBABF4
CsHCO2/H2O/TBABF4
NH4HCO2/H2O/TBABF4
TMA•HCO2 (aq)/TBABF4
TMA•HCO2 (aq)
ND
3.6:1
4.1:1
4:1
79
62
23
41
28
63
7
6
7
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
1
23
61
40
47
19
79
89
81
67
5
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
4.2:1
3.8:1
3.9:1
3.5:1
3.8:1
4.1:1
ND
6
TMA•HCO2 (aq)
1
TMA•HCO2 (aq)
ND
ND
10
3
TMA•HCO2 (aq)
25
20
10
20
TMA•HCO2 (aq)
67
80
67
92
3.8:1
4:1
1
TMA•HCO2 (aq)
1
TMA•HCO2 (aq)
4.6:1
4:1
ND
ND
1
TMA•HCO2 (aq)
a
1b (1 equiv), Pd2(dba)3 (X mol %), PPh3 (Y mol %), iodobenzene (2 equiv), base (2 equiv), H2O (10 equiv), TBABF4 (1 equiv), reductant (2
equiv), DMF (1.0 M), 80 °C, 1 h. TBABF4 = tetrabutylammonium tetrafluoroborate, TMA•HCO2 (aq) = tetramethylammonium formate 30% w/w
aqueous solution. b Yields were determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.
In many cases with poor mass balance, byproducts of 1-butanol, 4-phenylbutanal, and (E)-4-phenylbut-3-en-1-ol were observed in varying amounts. c
The regioisomeric ratio was determined by 1H NMR analysis of the crude reaction mixture (ND = not determined). d 4 h.
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Page 3 of 7
ACS Catalysis
meric ratio of the isolated compound. The regioisomeric ratio of the
Having identified optimal conditions, we next explored the aryl
iodide scope using allyl alcohol (1a) as the alkene partner (Table
2). This choice was motivated by the potential versatility of the
alcohol moiety in downstream functionalization and because of
the high regioselectivity observed for this substrate (vide infra),
which simplified purification and analysis in most cases. Both
electron-deficient (3a–3f) and electron-rich (3g–3i) aryl iodides
were competent coupling partners, affording the desired products
in synthetically useful yields, even when multi-substituted (3b,
3c, and 3i) or sterically congested (3k and 3l) aryl iodides were
used. A variety of heteroaryl iodides were also suitable coupling
partners for the reaction, including those containing pyridine
(3m–3o), pyrazine (3p), quinoline (3q), or furan (3r) heterocy-
cles. Additionally, the reaction was found to tolerate a range of
functional groups that can serve as handles for further diversifica-
tion, such as nitriles, ketones, halides, protected amines, and al-
dehydes. Notably, the regioselectivity of the insertion step ap-
pears to be influenced by the electronic nature of the aryl group,
with electron-deficient aryl iodides giving lower regioisomeric
ratios than electron-neutral or -rich aryl iodides.
1
2
3
4
5
6
7
8
crude reaction mixture as determined by 1H NMR analysis is given in
parenthesis if it differed from the ratio of the isolated material.
Next, we probed the alkene coupling partner scope using iodo-
benzene and 3’-iodoacetophenone as representative aryl iodides,
with the latter facilitating product isolation with non-polar al-
kenes (Table 3). High yields of the hydroarylated products were
obtained for alcohol-containing substrates of various chain
lengths (4a–4c), and the reaction was ≥4:1 selective across this
series of alkenes. Steric hindrance adjacent to the alkene could be
accommodated (4d), although higher palladium and phosphine
loadings and a longer reaction time were required. The reaction
was amenable to scale-up, providing 4a in 60% yield on a 15
mmol scale; in this case, extended reaction time was required to
achieve high conversion. The tetrahydropyran acetal protecting
group (4e) was tolerated under the reaction conditions, as were
epoxides (4f and 4g), affording moderate to high yields of the
desired products. Additionally, thioethers (4h), protected amines
(4i–4l), and silanes (4m) were found to be compatible functional
groups for this transformation. Non-activated aliphatic alkene
hydrocarbons were also suitable substrates in this reaction (4n–
4p), highlighting the broad scope of alkenes tolerated by this
method. Esters (4q and 4r) and lactams (4s), which are known
to undergo hydrolysis under basic conditions at elevated temper-
atures, were well tolerated under the conditions. Moreover, al-
kenes containing Lewis basic functional groups with the capacity
for metal binding, namely an imidazole (4t) and a urea (4u),
were compatible.
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
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36
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43
44
45
46
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Table 2. Aryl iodide scope.a–c
Pd2(dba)3 (1%)
PPh3 (20%)
HO
Ar
+
I
Ar
HO
H
K3PO4 (2 equiv)
TMA•HCO2 (aq) (2 equiv)
DMF (1.0 M), 80 °C, 4 h
(2 equiv)
1a
2a–r
3a–r
HO
HO
HO
H
H
H
CN
NO2
In addition to non-conjugated terminal alkenes, we discovered
that heteroatom-substituted terminal alkenes were also compe-
tent substrates in this reaction. Specifically, we found that a vinyl
ether (4v), a vinyl silane (4w), and N-vinyl-pyrrolidinone (4x)
reacted to give predominantly the anti-Markovnikov hydroary-
lated products, albeit in modest yield in the last two cases. To
underscore the synthetic utility of this transformation, we ex-
plored a variety of alkene-containing natural products and deriva-
tives thereof. Quinine reacted smoothly to provide the anti-
Markovnikov hydroarylation product as a single regioisomer in
quantitative yield (4y), emphasizing the power of this transfor-
mation to provide expedited access to cinchona alkaloid deriva-
tives, which are useful chiral ligands and organocatalysts. A varie-
ty of terpene derivatives, including the bicyclic diterpene sclareol
(4z) and the linear monoterpenes linalool (4aa) and (+)-β-
citronellene (4ab), were also viable substrates, providing moder-
ate to high yields of the anti-Markovnikov hydroarylation prod-
ucts as single regioisomers. Of note, the reaction is chemoselec-
tive for terminal alkenes, evidenced by 4aa and 4ab where the
trisubstituted alkene underwent neither the hydroarylation reac-
tion nor reduction to the alkane.
CF3
CF3
CF3
3a, 67%, Single
3b, 46%, Single, 16 h
3c, 40%, Single
(10:1 r.r.)
(6.3:1 r.r.)
O
HO
HO
H
Me
HO
Me
H
Br
H
O
3d, 60%, Single
3e, 75%, 8.3:1 r.r.
3f, 61%, Single
O
O
HO
HO
HO
H
H
H
NHBoc
OMe
3g, 59%, Single
3h, 62%, Single
3i, 65%, Single
Me
HO
H
HO
HO
H
H
3j, 71%, Single
3k, 63%, Single, 20 h
3l, 47%, Single, 16 h
HO
HO
HO
H
H
N
H
N
N
3m, 43%, 20:1 r.r., 16 h
3n, 49%, Single
3o, 38%, 6.4:1 r.r., 16 h
(5.5:1 r.r.)
Finally, we also tested several representative internal alkenes.
For acyclic substrates, reactivity and regioselectivity were low, as
illustrated by both Z- and E-3-hexen-1-ol (4ac). However, when
cyclic substrates were employed, moderate yields were obtained.
Specifically, cyclohexene resulted in 47% yield of the reductive
Heck product 4ad. 2,3-Dihydrofuran was a suitable substrate,
though only modest regioselectivity of 1.6:1 was observed. For-
tunately, the desired product 4ae could be isolated in 47% as a
single regioisomer. Additionally, a protected 3-pyrroline substrate
yielded 71% of the desired product 4af.
Cl
N
O
HO
HO
CHO
HO
H
H
N
H
N
3r, 71%, 5:1 r.r.
3p, 39%, 25:1 r.r.
3q, 55%, 50:1 r.r., 16 h
(3.4:1 r.r.)
(33.3:1 r.r.)
a 1a (1 equiv), Pd2(dba)3 (1 mol %), PPh3 (20 mol %), aryl iodide (2
equiv), K3PO4 (2 equiv), TMA•HCO2 (aq) (2 equiv), DMF (1.0
M), 80 °C, 4–20 h. TMA•HCO2 (aq) = tetramethylammonium
b
formate 30% w/w aqueous solution. Isolated yields. c The regioiso-
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ACS Catalysis
For all examples included in Tables 2 and 3, only trace
amounts (<5%) of the corresponding Heck products were ob-
served. However, competitive reduction of the alkene starting
material was observed in several cases. Overall, this reductive
Heck transformation is tolerant of a wide array of functional
Page 4 of 7
groups, including some that are potentially reductively labile, and
it thus represents a powerful transformation to install aryl moie-
ties over a diverse range of alkenes that complements existing
methods.
1
2
3
4
5
6
7
Table 3. Alkene scope.a–c
8
9
H
Pd2(dba)3 (1%)
PPh3 (20%)
R1
I
R1
R'
+
R2
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
R2
4a–af
K3PO4 (2 equiv)
TMA•HCO2 (aq) (2 equiv)
DMF (1.0 M), 80 °C, 4 h
R'
(2 equiv)
1a–af
Non-Conjugated Terminal Alkenes
Me Me
HO
H
HO
H
HO
O
O
H
HO
H
H
4d, 74%, Single, 16 hd
4a, 66%, Single
[15 mmol]: 60%, Single, 24 h
4b, 88%, 5:1 r.r.
4c, 84%, 4.5:1 r.r.
4e, 63%, Single
(4:1 r.r.)
O
H
H
PhHN
BocHN
O
PhS
Me
O
H
H
O
H
4g, 89%, Single, 1:1 d.r.e
4f, 30%, 3:1 r.r.
4h, 43%, Single
4i, 59%, Single
4j, 96%, 3.5:1 r.r.
(5:1 r.r.)
(20:1 r.r.)
O
H
H
TsHN
4-NsHN
H
TMS
Me
Me
Me
Ph
Me
H
9
H
O
O
4l, 41%, Singled
4m, 63%, 7.7:1 r.r.f
4k, 57%, 12.5:1 r.r.
4n, 56%, 10:1 r.r.
4o, 96%, 4:1 r.r.
(10:1 r.r.)
(3:1 r.r.)
O
H
3
Heteroatom-Substituted Terminal Alkenes
Me
EtO
Cl
H
H
H
H
O
O
Me
Me
4p, 51%, 4:1 r.r.
4q, 54%, 3:1 r.r.
n-BuO
TMS
N
(3:1 r.r.)
O
O
4w, 31%, 16.7:1 r.r.
4v, 71%, Single
4x, 36%, 25:1 r.r.
O
O
O
(5:1 r.r.)
(2.5:1 r.r.)
MeO
OMe
H
NH
H
3
Alkene-Containing Complex Molecules
Me
HO Me
H
2
Me
Ph
O
H
Me
Ph
Me
4aa, 64%, Single, 16 hd
4r, 64%, 3.5:1 r.r.
4s, 54%, 2.3:1 r.r.
HO
H
(3.8:1 r.r.)
(3.8:1 r.r.)
from linalool
HO
N
H
Me
OH
Me
N
O
MeO
H
N
Me
Me
H2N
N
H
H
H
N
Me
Me
O
Me Me
4ab, 86%, Single, 16 hd
from (+)-(β)-citronellene
4z, 71%, Single, 16 hd
4y, 99%, Single
from quinine
4t, 84%, 1.5:1 r.r., 24 hd
4u, 30%, Single
(4.2:1 r.r.)
from sclareol
Internal Alkenes
O
Ph
H
H
O
N
Me
HO
HO
from Z-alkene
O
H
H
H
Me
Me
from E-alkene
4ac, 17%, 1:1 r.r., 16 hg
4ac, 23%, 1:1 r.r., 16 hg
4ad, 47%, 16 h
4ae, 47%, Single
4af, 71%, 16 h
(1.6:1 r.r.)
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ACS Catalysis
aAlkene (1 equiv), Pd2(dba)3 (1 mol %), PPh3 (20 mol %), aryl iodide (2 equiv), K3PO4 (2 equiv), TMA•HCO2 (aq) (2 equiv), DMF (1.0 M), 80
c
°C, 4–24 h. TMA•HCO2 = tetramethylammonium formate 30% w/w aqueous solution. b Isolated yields unless otherwise specified. The regioiso-
1
2
3
4
meric ratio of the isolated compound. The regioisomeric ratio of the crude reaction mixture as determined by 1H NMR analysis is given in parenthesis
if it differed from the ratio isolated. d Pd2(dba)3 (2.5 mol %) and PPh3 (50 mol %). e The alkene starting material 3g was a 1:1 mixture of diastere-
omers. f An additional constitutional isomer was formed and isolated together with the other two products. g Yield and regioisomeric ratio determined
by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
5
Regarding selectivity patterns, across the examples described
6
7
8
9
H
A.
Ar
above, the r.r. values ranged from 1.5:1 to >50:1, with the anti-
Markovnikov product favored in all cases. Although many of the
observed regioisomeric ratios are in accordance with literature
precedents14 for a neutral Heck mechanism with these substrates,
a detailed description of the origins of the observed trends re-
mains outside of the scope of the present study. Generally speak-
ing, it appears that the steric and electronic properties of both the
alkene and the migrating aryl group contribute to the activation
energy of the product-determining step.
R
ArI
Pd0
Reductive
Elimination
Oxidative
Addition
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PPh3
H
PdIILn
Ar
I
PdII Ar
PPh3
R
R
CO2
Ligand
Exchange
Decarboxylation
Based upon our results and literature precedents,4–10 we pro-
pose the catalytic cycle in Figure 2A. The initial sequence of
events follows that of the Mizoroki-Heck reaction: oxidative addi-
tion of the aryl iodide, alkene coordination, and migratory inser-
tion of the aryl group to give the alkylpalladium(II) intermediate.
At this stage, rather than undergoing β-H elimination (as in the
Mizoroki-Heck reaction), this intermediate exchanges iodide for
formate, at which point decarboxylation generates a Pd–H spe-
cies. Upon C–H reductive elimination, the reductive Heck prod-
uct is formed and Pd(0) is regenerated to close the catalytic cycle.
To validate that formate is indeed the source of hydrogen in the
product, we performed the reaction using sodium formate-d. As
expected, full deuterium incorporation in the product with no
deuterium scrambling was observed, supporting the proposed
mechanism (Figure 2B). Lastly, to probe the viability of an alter-
native pathway involving classical Mizoroki–Heck arylation fol-
lowed by styrene reduction, we preformed the control experi-
ments in Figure 2C. When cinnamyl alcohol (1ag), a putative
intermediate in this potential pathway, was subjected to the
standard reaction conditions with and without iodobenzene, only
a minimal amount of styrene reduction was observed. This indi-
cates that this alternative mechanism is not the predominant
pathway under these conditions.
PPh3
PPh3
PdII Ar
I
HCO2 PdIILn
R
Ar
R
Ligand
Exchange
Migratory
Insertion
I–
I
PdIILn
Ar
R
–
HCO2
B.
Pd2(dba)3 (2.5%)
PPh3 (50%)
HO
HO
+
I
D
H
H
K3PO4 (2 equiv)
NaDCO2 (2 equiv)
TBABF4 (1 equiv)
H2O (10 equiv)
(>95% D)
(2 equiv)
1a
2s
4a-D, 46%
DMF (1.0 M), 80 °C, 4 h
C.
1ag
4a
conditions
w/ PhI
Pd2(dba)3 (1%)
PPh3 (20%)
H
78%
9%
HO
Ph
HO
Ph
PhI (2 equiv)
K3PO4 (2 equiv)
TMA•HCO2 (aq) (2 equiv)
DMF (1.0 M), 80 °C, 4 h
H
1ag
w/o PhI
93% <1%
4a
Figure 2. (A) Proposed catalytic cycle. (B) Deuterium-labeling
experiment. (C) Control experiments testing potential involve-
ment of a classical Mizoroki–Heck arylation/styrene reduction
mechanism. Percentages were determined by H NMR analysis of
the crude reaction mixtures with 1,3,5-trimethoxybenzene as an
internal standard.
1
In summary, we have developed a mild and operationally con-
venient palladium-catalyzed reductive Heck reaction of aliphatic
and heteroatom-substituted terminal alkenes and select internal
alkenes with (hetero)aryl iodides. Mechanistically, the catalytic
cycle follows the same initial steps as the Mizoroki–Heck reaction
to generate the alkylpalladium(II) intermediate, which then un-
dergoes decarboxylation from a bound formate ligand followed
by C–H reductive elimination to produce the hydroarylated pro-
duct. With terminal alkenes, the reaction provides predominantly
the anti-Markovnikov product. Notably, the transformation is
compatible with a wide variety of synthetically important functi-
onal groups, including many that are reductively labile, and can
accommodate heterocycles containing basic sp2-hybridized nitro-
gen atoms. Furthermore, it can be used for complex molecule
diversification. The procedure is scalable and requires only inex-
pensive, readily available components, highlighting its practicality
as a synthetic tool. We anticipate that this method will find use in
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Page 6 of 7
[Pd(OAc)2(PPh3)2]-Trialkylammonium Formate Reagent. J. Organomet.
Chem. 1986, 312, C27–C32.
both target-oriented and divergent synthesis and that the mecha-
nistic implications of this study will stimulate the development of
additional alkene functionalization reactions in the future.
1
2
3
4
5
6
7
8
(7) (a) Cacchi, S.; Felici, M.; Pietroni, B. The Palladium-Catalyzed
Reaction of Aryl Iodides with Mono and Disubstituted Acetylenes: A
New Synthesis of Trisubstituted Alkenes. Tetrahedron Lett. 1984, 25,
3137–3140. (b) Arcadi, A.; Cacchi, S.; Marinelli, F. The Palladium-
Catalysed Reductive Addition of Aryl Iodides to Propargyl Alcohols: a
Route to γ,γ-Diaryl Allylic Alcohols. Tetrahedron 1985, 41, 5121–5131.
(8) (a) Larock, R. C.; Babu, S. Synthesis of Nitrogen Heterocycles via
Palladium-Catalyzed Intramolecular Cyclization. Tetrahedron Lett. 1987,
28, 5291–5294. For representative examples of enantioselective reductive
Heck cylcizations, see: (b) Minatti, A.; Zheng, X.; Buchwald, S. L. Syn-
thesis of Chiral 3-Substituted Indanones via an Enantioselective Reduc-
tive-Heck Reaction. J. Org. Chem. 2007, 72, 9253–9258. (c) Yue, G.; Lei,
K.; Hirao, H.; Zhou, J. Palladium‐Catalyzed Asymmetric Reductive Heck
Reaction of Aryl Halides. Angew. Chem. Int. Ed. 2015, 54, 6531–6535.
(d) Shen, C.; Liu, R.-R.; Fan, R.-J.; Li, Y.-L.; Xu, T.-F.; Gao, J. R.; Jia, Y.-
X. Enantioselective Arylative Dearomatization of Indoles via Pd-
Catalyzed Intramolecular Reductive Heck Reactions. J. Am. Chem. Soc.
2015, 137, 4936–4939. (e) Kong, W.; Wang, Q.; Zhu, J. Water as a Hy-
dride Source in Palladium‐Catalyzed Enantioselective Reductive Heck
Reactions. Angew. Chem. Int. Ed. 2017, 56, 3987–3991.
AUTHOR INFORMATION
Corresponding Author
* keary@scripps.edu
Notes
9
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was financially supported by TSRI, Pfizer, Inc., the Na-
tional Institutes of Health (1R35GM125052) and Bristol-Myers
Squibb (Unrestricted Grant). We thank the Donald E. and Delia B.
Baxter Foundation and the National Science Foundation
(NSF/DGE-1346837) for predoctoral fellowships (J.A.G.). Drs.
Jason S. Chen (TSRI) and Yongxuan Su (UCSD) are acknowledged
for assistance with HRMS, and Professors Ryan A. Shenvi and Hans
Renata are acknowledged for helpful discussion.
(9) Torii, S.; Tanaka, H.; Morisaki, K. Pd(0)-Catalyzed Electro-
Reductive Hydrocoupling of Aryl Halides with Olefins and Acetylenes.
Chem. Lett. 1985, 14, 1353–1354.
REFERENCES
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Asymmetric Palladium-Catalyzed Hydroarylation of Styrenes and
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Zheng, H.; Kameyama, R.; Sakaki, S.; Nakao, Y. Reductive Cross‐
Coupling of Conjugated Arylalkenes and Aryl Bromides with Hy-
drosilanes by Cooperative Palladium/Copper Catalysis. Angew. Chem.
Int. Ed. 2016, 55, 6275–6279. (c) Xiao, L.-J.; Cheng, L.; Feng, W.-M.; Li,
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(11) For representative reports on alternative strategies to effect hy-
droarylation of terminal aliphatic alkenes, see: (a) Schramm, Y.;
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Hydroheteroarylation of Unactivated Alkenes with Indoles, Pyrroles,
Benzofurans, and Furans Catalyzed by a Nickel–N-Heterocyclic Carbene
System. J. Am. Chem. Soc. 2015, 137, 12215–12218. (b) Green, S. A.;
Matos, J. L. M.; Yagi, A.; Shenvi, R. A. Branch-Selective Hydroarylation:
Iodoarene–Olefin Cross-Coupling. J. Am. Chem. Soc. 2016, 138, 12779–
12782. (c) Friis, S. D.; Pirnot, M. T.; Dupuis, L. N.; Buchwald, S. L. A
Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl–Aryl
Cross‐Coupling of Aryl Halides and Olefins. Angew. Chem. Int. Ed. 2017,
56, 7242–7246. (d) Lu, X.; Xiao, B.; Zhang, Z.; Gong, T.; Su, W.; Yi, J.;
Fu, Y.; Liu, L. Practical Carbon–Carbon Bond Formation from Olefins
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(12) Jin, L.; Qian, J.; Sun, N.; Hu, B.; Shen, Z.; Hu, X. Pd-Catalyzed
Reductive Reck Reaction of Oefins with Aryl Bromides for Csp2–Csp3
Bond Formation. Chem. Commun. 2018, 54, 5752–5755.
(13) Wang, C.; Xiao, G.; Guo, T.; Ding, Y.; Wu, X.; Loh, T.-P. Palla-
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vated Aliphatic Alkenes. J. Am. Chem. Soc. 2018 DOI:
10.1021/jacs.8b03619.
(14) (a) Heck, R. F. Palladium-Catalyzed Reactions of Organic Hal-
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Candiani, I. Recent Developments and New Perspectives in the Heck
Reaction. Acc. Chem. Res. 1995, 28, 2–7.
(1) For selected reviews on the Heck reaction, see: (a) Beletskaya, I.
P.; Cheprakov, A. V. The Heck Reaction as a Sharpening Stone of Palla-
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Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E. Recent Advances in the
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and Related Reactions. Chem. Soc. Rev. 2011, 40, 5122–5150.
(2) Liu, Z.; Derosa, J.; Engle, K. M. Palladium(II)-Catalyzed Regiose-
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He, M.; Wang, F.; Marsters, R.; McAlpine, I.; Engle, K. M. Palladium(II)-
Catalyzed γ-Selective Hydroarylation of aAkenyl Carbonyl Compounds
with
Arylboronic
Acids.
ChemRxiv
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DOI:
10.26434/chemrxiv.5885203.
(4) For a review on early work, see: Cacchi, S. The Palladium-
Catalyzed Hydroarylation and Hydrovinylation of Carbon-Carbon Mul-
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(5) (a) Catellani, M.; Chiusoli, G. P.; Giroldini, W.; Salerno, G. New
Transition Metal-Catalyzed C–C Coupling Reactions Initiated by C–X
Bond Cleavage and Terminated by H-Transfer. J. Organomet. Chem.
1980, 199, C21–C23. (b) Arcadi, A.; Marinelli, F.; Bernocchi, E.; Cacchi,
S.; Ortar, G. Palladium-Catalyzed Preparation of exo-Aryl Derivatives of
the Norbornane Skeleton. J. Organomet. Chem. 1989, 368, 249–256.
(6) (a) Cacchi, S.; Arcadi, A. Palladium-Catalyzed Conjugate Addi-
tion Type Reaction of Aryl Iodides with α,β-Unsaturated Ketones. J. Org.
Chem. 1983, 48, 4236–4240. (b) Cacchi, S.; La Torre, F.; Palmieri, G.
The Palladium-Catalyzed Conjugate Addition Type Reaction of Aryl
Iodides with α,β-Unsaturated Aldehydes. J. Organomet. Chem. 1984, 268,
C48–C51. (c) Cacchi, S.; Palmieri, G. A One-Pot Palladium-Catalyzed
Synthesis of β,β-Diarylketones and Aldehydes from Aryl Iodides and α,β-
Unsaturated Carbonyl Compounds. Synthesis 1984, 575–577. (d) Cac-
chi, S.; Palmieri, G. The Palladium-Catalyzed Conjugate Addition Type
Reaction of 2-Bromo-Arylmercury Compounds and 2-Bromo-Aryl Io-
dides with α,β-Enones: a New Entry to 1-Indanols. J. Organomet. Chem.
1985, 282, C3–C6. (e) Arcadi, A.; Marinelli, F.; Cacchi, S. The Reaction
of Aryl Iodides with Hindered α,β,γ,δ-Dienones in the Presence of the
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ACS Catalysis
H
cat. Pd0Ln
R2
•50 examples
R2
1
2
3
4
5
6
7
R1
+
R1
I
Ar
[H−]
Ar
•Mild conditions
•Scalable
•High FG tolerance •Anti-Markovnikov-selective
PdIILn
R2
R1
oxidative addition/
migratory insertion
decarboxylation/
reductive elimination
Ar
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