Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides with Anhydrides

Article abstract of DOI:10.1021/acscatal.8b03396

We present the anhydride-based decarboxylative alkylation of aryl iodides catalyzed by nickel. This method of decarboxylative coupling works with a broad scope of aliphatic carboxylic anhydrides and tolerates synthetically useful aromatic substituents. Assisted by a redox system of pyridine N-oxide and zinc additives, the current reaction occurs under mild conditions and without the assistance of photocatalyst. Notably, this method features high chemoselectivity toward alkyl migration with mixed aliphatic/aromatic anhydrides. Thus, it provides a powerful synthetic tool to modify high-valued aliphatic carboxylic acids by converting them into mixed anhydrides using readily available aryl carboxylic acids such as p-toluic acid. We propose a catalytic cycle that involves the key steps of free radical-based decarboxylation and subsequent alkyl transfer to nickel that precedes an oxidatively induced C-C reductive elimination from Ni(III).

Full text of DOI:10.1021/acscatal.8b03396

Subscriber access provided by University of Sunderland
Letter
Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides with Anhydrides
Hui Chen, Lu Hu, Wenzhi Ji, Licheng Yao, and Xuebin Liao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03396 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 11, 2018
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 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 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.
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 7
ACS Catalysis
1
2
3
4
5
6
7
8
9
Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides
with Anhydrides
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
Hui Chen, Lu Hu, Wenzhi Ji, Licheng Yao, and Xuebin Liao*
School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University,
Beijing 100084, China.
ABSTRACT: We present the anhydride-based decarboxylative alkylation of aryl iodides catalyzed by nickel. This method of
decarboxylative coupling works with a broad scope of aliphatic carboxylic anhydrides and tolerates synthetically useful aromatic
substituents. Assisted by a redox system of pyridine N-oxide and zinc additives, the current reaction occurs under mild conditions
and without the assistance of photocatalyst. Notably, this
+ Ar-X
O
O
method features high chemoselectivity towards alkyl
migration with mixed aliphatic/aromatic anhydrides. Thus,
it provides a powerful synthetic tool to modify high-valued
aliphatic carboxylic acids by converting them into mixed
anhydrides using readily available aryl carboxylic acids
such as p-toluic acid. We propose a catalytic cycle that
involves the key steps of free radical-based decarboxylation
and subsequent alkyl transfer to nickel that precedes an
oxidatively induced C-C reductive elimination from Ni(III).
NiCl2 (10 mol%), bipy (15 mol%)
LiCl (4.0 equiv), KF (1.5 equiv)
Zn (3.0 equiv), DMAc
R
O
R
O
• in situ or commercially
R
available
O
Ar
R
OH
O
(1.5 equiv)
N
R=1°,2°,3° alkyl
O
R
O
Ar'
0 °C to 25 °C
•alkyl migration, chemoselectivity
• mixed anhydride
-CO2
O
Ar', Ar = aryl
bipy =
CO2=
C
O
N
N
KEYWORDS: decarboxylation, nickel catalysis, aliphatic
acid anhydrides, cross-coupling, alkylation
In the past decades, the formation of C-C bonds catalyzed
by transition metals has achieved great success in both
using a suitable oxidizing reagent that both donates oxygen
atoms and facilitate single-electron transfer (SET) redox
chemistry (Scheme 1d).
1
academia and industry. However, construction of the C(sp2)-
C(sp3) bond remains underexplored. One of the main hurdles
is that common alkyl coupling partners are less available
compared to aryl coupling reagents. Alkyl halides as the major
building blocks in this area were restricted due to their limited
availability, toxicity and instability. Notably, aliphatic
carboxylic acids are inexpensive, stable and non-toxic
substances, and they are widely present in nature. This makes
them appealingly as potential coupling partners for C(sp2)-
C(sp3) bond formation. Herein, we aim to take another
approach to decarboxylative C(sp2)-C(sp3) coupling by
exploring aliphatic carboxylic anhydrides as the alkyl sources.
In contrast to specialized esters as active substrates for
decarboxylation (Scheme 1a), organic anhydrides are common
building blocks that are either commercially available or
readily prepared from the corresponding carboxylic acids.
Catalytic application of carboxylic anhydrides in cross-
coupling has been mainly focused on decarbonylative biaryl
synthesis by Goossen2-7 and other groups.8-15 In 2003, Rovis
and coworkers have reported an example of decarbonylative
C(sp2)-C(sp3) bond formation 16 with cyclic anhydrides using a
stoichiometric amount of nickel catalyst (Scheme 1b). We
hypothesized that a corresponding catalytic decarboxylative
coupling via free-radical processes could be promoted by
More recently, decarboxylative cross-coupling has emerged
as a powerful tool to form new C-C bonds.
17-45
MacMillan,
Doyle, and other groups17-19 (Scheme 1c) made major
breakthroughs in this area and reported the couplings of aryl
halides with secondary alkyl carboxylic acids by nickel
catalysts with light assistance. Subsequently, asymmetric
decarboxylative cross-coupling of α-amino acids was realized
by Fu and MacMillan.19 Pioneering work on decarboxylative
coupling using the N-hydroxy-phthalimide esters (NHP esters)
were reported by the Okada group and later by the Overman
group (Scheme 1a).
20,21
In their studies, they used
photocatalyst to convert the NHP esters into alkyl radicals that
could be further used in numerous transformations. In 2016,
the Baran and Weix groups (Scheme 1a) almost concurrently
reported another elegant strategy on decarboxylative coupling,
24-29
which involved nickel-catalyzed C(sp2)-C(sp3) bond
formation without assistance of light.
In contrast to
MacMillan’s work, the aliphatic carboxylic acids in the Baran
and Weix studies were required to be converted into the
corresponding NHP 20,21 or other “redox-active” esters. 24-29
Alternatively, we herein report
decarboxylative coupling between aliphatic carboxylic
anhydrides and aryl iodides using pyridine N-oxide as oxidant
a
nickel-catalyzed
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 7
1
2
3
4
5
6
7
8
9
(Scheme 1d). Furthermore, our approach requires no
Table 1. Scope of Ni-Catalyzed Coupling of Aliphatic Acid
photocatalyst or preparation of NHP esters in advance. The
catalytic method of C(sp2)-C(sp3) bond formation works well
with a broad scope of symmetrical anhydrides derived from 1°,
2° and 3° alkyl carboxylic acids. Moreover, high
chemoselectivity of alkyl- over aryl-migration was observed
with unsymmetrical alkyl/aryl anhydrides. Thus, this method
provides an attractive strategy to chemically modify high-
valued aliphatic carboxylic acids by converting them into
mixed anhydrides with low-priced benzenecarboxylic acids
such as 4-toluic acid.
Anhydrides with Aryl Iodides
NiCl2(10 mol%), L1(15 mol%)
I
pyridine N-oxide (1.5 equiv)
LiCl (4.0 equiv), KF (1.5 equiv)
Alkyl
Alkyl
O
Alkyl
R
+
R
O
O
Zn (3.0 equiv), DMAc
0 °C to 25 °C
1
2
3
(1.0 equiv)
(1.5 equiv)
9
9
9
R
R
N
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
3a, R=OMe, 80%a
3g, R=COCH3, 71%a
3b, R=tBu, 91%a, 89%c 3h, R=COOEt, 90%a
3c, R=Ph, 92%a
3i, 73%a
O
Scheme 1. Recent Development of Decarboxylative
Couplings and Our Approach
3d, R=H, 89%a
9
3e, R=CN, 52%a
Previous studies:
O
9
3f, R=F, 77%a
O
R1 R3
R2
N
a)
Ni, Fe
Ir+Ni or Cu, h
O
R3-X
+
R1
N
Ph
3j, 67%a
3k, 71%a

O
-CO2
R2
O
R3= Ar, alkyl,
Okada, Overman, Baran, Weix,
Aggarwal, Glorius, Fu, Liu
Cl
boron, alkene, CN
9
9
9
N
O
b)
c)
COOH
3m, 66%a
3l, 87%a
3n-1, 53%a
Ni (
)
stoichiometric
Ar2Zn
+
O
O
R
Ar
R
-CO
n
9
n
4
Rovis
S
tBu
tBu
R
Ar
Het
R
COOH
3o, 82%a
3n-2, 37%a
3p, 71%b
Ir+Ni, h

+
Ar-X
Het
-CO2
MacMillan, Doyle, Fu
This study:
R
tBu
tBu
O
O
O
d)
Ni
(catalytic)
3r-1, R=tBu, 85%b
3r-2, R=Ph, 82%b
R
+
Ar-X
3q, 74%b
3s-1,76%b
Ar
R
O
R
R
OH
R=1°,2°,3° alkyl
N
O
in situ or commercially
available
-CO2
O
tBu
C
tBu
Ph
CO2=
O
3u, 51%b
3s-2, 89%b
3t, 66%a
O
O
Figure 1. Ni-Catalyzed Cross-Coupling of Alkyl Acid
tBu
tBu
Anhydrides with Aryl Iodides
O
NiCl2(10 mol%), L1(15 mol%)
3v, 72%b
3x, 55%b
3w, 42%b
O
I
pyridine N-oxide (1.5 equiv)
LiCl (4.0 equiv), KF (1.5 equiv)
O
Cbz
+
10
10
9
N
N
MeO
1a (
O
O
Zn (3.0 equiv), DMAc
0 °C to 25 °C
"standard" conditions
MeO
)
2a
1.0 equiv
(1.5 equiv)
3a
(80% isolated yield)
tBu
tBu
tBu
Entry
Deviation from above Yield (%)
Entry
Deviation from above Yield (%)
3x-2, 64%d
3y, 32%b
3x-1, 44%d
1
2
3
4
5
6
7
L2
L3
L4
L5
L6
48
55
65
45
47
33
66
8
9
Ni(PPh3)4
NiBr2
72
57
66
0
Reaction conditions: Reactions were run on 0.5 mmol scale with NiCl2 as
a catalyst in DMAc (5 mL) at 0 oC, 25 oC for 24h, respectively. Yields
were isolated yields. (See Supporting Information (SI)). aAlkyl acid
anhydrides were commercially available. bAlkyl acid anhydrides were
prepared after simple filtration. cReaction was run in the dark. d Using
prepared mixed anhydrides of alkyl acids with p-toluic acids
10
11
12
13
14
NiI2
No nickel or ligand
No pyridine N-oxide trace
1.2 equiv 2a 73
NMP instead of DMAc 61
L7
Ni(COD)2
R
R
R
R
In our initial studies, the alkyl acid anhydrides were
N
N
generated in situ, filtrated by sieves and directly used for the
N
N
N
N
46
coupling reaction (Scheme 1d). Different ligands, including
L7
L
R=H,
1
L
L
5
R=OMe,
R=Me,
R=H,
L
R=Phenyl,
6
3
t
bipyridines (Figure 1, entries 1-4), phenanthrolines (entries 5,
6), and phosphines (see Supporting Information (SI)) were
first attempted. 2, 2’-bipyridine was the most efficient. Then, a
variety of nickel catalysts were examined (entries 7-10) and
NiCl2 performed the best. Control reactions demonstrated that
both nickel catalyst and ligand (entry 11) were essential for the
L
R= Bu,
2
L
4
Reactions were run on 0.2 mmol scale at 0 oC, 25 oC for 24h, respectively.
Yields were determined by NMR using 1,3,5-trimethoxybenzene as the
internal standard.
ACS Paragon Plus Environment

Page 3 of 7
ACS Catalysis
1
2
3
4
5
6
7
8
9
reactions. Only a trace amount of desired product (entry 12)
Figure 3. Ni-Catalyzed Coupling of Alkyl Acid Anhydrides
(Generated in situ) with Aryl Iodides
was detected without adding pyridine N-oxide. It is
noteworthy that pyridine N-oxide was also nicely used as an
additive for light assisted trifluoromethylation by Stephenson.
22,23 Reactions with an excess of anhydride (entry 13) resulted
in a higher yield. A further optimization of the solvents (entry
14) revealed that DMAc (see Supporting Information (SI))
was optimal. In addition, zinc dusts and LiCl (see Supporting
Information (SI)) were both indispensable in the catalytic
reaction. Furthermore, addition of KF slightly increased the
yield (see Supporting Information (SI)).
I
Alkyl
O
Alkyl
Alkyl
R
+
standard conditions
R
O
O
1
2
(1.0 equiv)
(1.5 equiv)
3
9
tBu
tBu
3r-1
tBu
3b
3p
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
, 71%, isolated
, 91%, isolated
, 85%, isolated
70%, in situ
54%, in situ
76%, in situ
With the optimized conditions in hand, we first explored the
scope of aryl iodides (Table 1, 3a-3n). Electron-rich, -
deficient and -neutral substituents were well tolerated (3a-3m).
Different functional groups, including ester (3h), ketone (3g),
cyano (3e), and protected nitrogen (3i, 3j), were all compatible
with the standard conditions. Substituents at the ortho- and
meta-position did not have much impact on the yields (3k-3m).
Remarkably, heterocyclic iodide (4-iodopyridine, 3n-1) could
be coupled, providing the corresponding product in a modest
yield.
tBu
tBu
3s-1
3v
, 72%, isolated
, 76%, isolated
74%, in situ
53%, in situ
Reaction conditions: Reactions were run on 0.5 mmol scale with NiCl2 as
o
o
a catalyst in DMAc at 0 C, 25 C for 24h, respectively. Yields were
isolated yields. (See Supporting Information (SI)). [Isolated] = alkyl
anhydrides were prepared after simple filtration of related impurities. [In
situ] = alkyl anhydrides were prepared without any purification and
reaction was taken in one flask. Preparation of symmetric anhydrides (See
Supporting Information (SI)).
Next, a variety of carboxylic acid anhydrides, either
commercially available or generated from the corresponding
acids, were coupled with aryl iodides (Table 1, 3o-3z). As
anticipated, reaction using primary and secondary carboxylic
acid anhydrides proceeded smoothly (3o-3x). Among them,
cyclic alkyl acid anhydrides (3r, 3s, 3u) were coupled with
iodoarenes resulting in good yields. Large ring sized acid
anhydrides, such as cycloheptanecarboxylic anhydride (3v),
also generated the corresponding arylated product in a good
yield. Substrate (3w-3x-2) containing heteroatom also worked
smoothly under the optimized conditions. In addition,
reactions with the tertiary carboxylic acid anhydride (3y),
considered as a challenging coupling partner, also gave the
desired product, albeit in a lower yield.
Furthermore, the reaction was performed at a large scale to
showcase the utility of our protocol, and the decarboxylative
product was obtained in satisfactory yield (Figure 4a). It was
noteworthy that this method featured high chemoselectivity
towards alkyl migration with mixed aliphatic/aromatic
anhydrides (Figure 4b, c). Thus, it provided a powerful
synthetic tool to modify high-valued aliphatic carboxylic acids
by converting them into mixed anhydrides using readily
available
Figure 4. Gram Scale of Reaction and Chemical Selectivity
of Reaction
I
O
9
+
10
10
standard conditions
tBu
1b
tBu
(a)
O
O
Notably, methylation and ethylation (3z-1, 2) of arenes
3b,
(1.0 gram)
I
77%
2a
(Figure 2), 47-50 which traditionally involved the use of difficult
O
O
47
to manipulate organometallic reagents or toxic methyl,48,49
9
O
or ethyl iodides in medical chemistry,49 were achieved in
comparable yields using commercially available alkyl acid
anhydrides.
+
10
standard conditions
O
tBu
(b)
tBu
1b
Me
8
3b
, 88%
Figure 2. Methylation or Ethylation of Arenes
tBu
R
O
O
H
O
O
O
Me
MeI,Me4Sn, MeOH
conditions: ref 47-50
O
I
+
(c)
standard conditions
standard conditions
I
R
H
O
H
H
O
X
O
O
tBu
3z-1, R=Ph, 46%
+
H
H
R
O
Ph
Et
R=
H
EtI, Et4Sn
O
O
O
, 76%
standard conditions
H
Me
conditions: ref 48-49
7
R
1b
6
safe, easy to handle
toxic, difficult to manipulate
Other Approaches


3z-2, R=Ph, 58%
Standard conditions: Reactions were run on 0.5 mmol with NiCl2 as the
catalyst in DMAc at 0 oC, 25 oC for 24h, respectively. Aryl iodide (1b) was
1 equiv, anhydrides 2a is 1.2 equiv, 6 and 8 was 1.5 equiv. Yields were
recorded after isolation and purification. (See Supporting Information
(SI)).
Our Approach
Reaction conditions: Reactions were run on 0.5 mmol scale with NiCl2 as
a catalyst in DMAc (5 mL) at 0 oC, 25 oC for 24h, respectively. Yields
were isolated yields. (See Supporting Information (SI)).
Gratifyingly, this method proceeded smoothly when in situ
generated anhydrides were directly used without filtration
(Figure 3). The yields were only slightly lower than those with
preformed alkyl acid anhydrides. For example, we got the
decarboxylative coupling product (3s-1) in 76% yield when
isolated alkyl acid anhydride was used. Only 2% decreased in
the yield if we operated the reaction without any purification
of anhydrides.
aryl carboxylic acids such as p-toluic acid (Figure 4c). More
intriguingly, by testing electronically different benzoates as
part of mixed anhydrides, it was reasonable to assume that the
carboxylate anion may affect catalyst reactivity in some way
(see Supporting Information (SI), part 6, S12). This implied
that we could potentially tune the reactions by employing
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 7
1
2
3
4
5
6
7
8
9
different aryl carboxylate anion as auxiliary ligands in the
catalysis.
species II. This species was then reduced to arylnickel (I)
complex III. 51-53 Next, complex III delivered an electron into
aliphatic carboxylic anhydride adduct VII, thus producing the
Figure 5. Mechanistic Studies
radical of adduct VIII with concomitant formation of Ni (II)
O
24-29
complex IV.
The desired alkyl radical was produced with
OEt
the fragmentation of VIII by release of CO2 and generation of
pyridine. Later, complex IV was combined with a alkyl radical
to provide Ni (III) intermediate V, which then underwent
reductive elimination to afford the desired product and Ni (I)
species VI. At this point, complex VI (I) was reduced to
regenerate Ni (0) complex I using zinc powder.
2a
lauric anhydride
(1.5 equiv)
9
pyridine N-oxide (1.5 equiv)
LiCl (4.0 equiv), KF (1.5 equiv)
N
(II)
Ni
O
I
(a)
OEt
3h
Zn (3.0 equiv), DMAc
0 °C to 25 °C
N
, 43%
1h
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
1h
complex
(10% mol)
I
pyridine N-oxide (1.5 equiv)
LiCl (4.0 equiv), KF (1.5 equiv)
9
O
O
(b)
10
10
Figure 6. Proposed Mechanism
O
+
Zn (3.0 equiv), DMAc
0 °C to 25 °C
O
O
OEt
Ni(II)X2 (precatalyst)
OEt
I
Zn, bpy
3h
, 83%
2a
reduction
N
1/2 ZnX2
I
O
Ni(0)
standard conditions
TEMPO (2.0 equiv)
+
R'
10
10
no reaction
(c)
(d)
N
oxidative
addition
tBu
O
O
1/2 Zn
N
R'
1b
1b
reduction
2a
I
I
X
Ni(I)
O
O
N
(II)
Ni
standard conditions
+
tBu
1/2 Zn
O
tBu
N
I
VI
N
5
, 42%
reduction
II
R
4
Standard conditions: Reactions were run on 0.5 mmol with NiCl2 as the
catalyst in DMAc at 0 oC, 25 oC for 24h, respectively. 1h and aryl iodide
were 1 equiv, and the anhydrides were 1.5 equiv. Yields were recorded
after isolation and purification. (See Supporting Information (SI)).
Equation (a): If no pyridine N-oxides were added, no products were
detected.
1/2 ZnI2
reductive
elimination
R'
R'
R'
N
Ni(I)
III
X
N
R'
N
V
Ni(III)
O
O
R
N
Finally, to elucidate the mechanism, we performed a
stoichiometric reaction of an organonickel complex (1h) with
acid anhydride (2a). The desired product (3h) was obtained in
43% yield (Figure 5a).51-55In addition, when 1h was used as
catalyst, the decarboxylative coupling product was obtained in
83% yield (Figure 5b). Both results suggested that 1h was a
key intermediate in the catalytic cycle. The other
stoichiometric reaction indicated that pyridine N-oxide was
essential in the catalytic process (Figure 5a).56,57 Presumably,
pyridine N-oxide was used as an additive for the formation of
reducible anhydride adducts (Figure 6, VII). Although we
R
O
R
R
O
N
O
(II)
Ni
N
IV
O
O
O
SET
addition
N
= X
N
R
R
O
O
VII
carboxylate anion
O
R
+
N
O
R
N
VIII
CO2
In conclusion, we develop the nickel-catalyzed
decarboxylative alkylation of aryl iodides with alkyl acid
anhydrides. This reaction exhibits broad substrate scopes,
good functional group tolerance and chemical selectivity. In
particular, this method provided a powerful tool to modify
high-valued aliphatic carboxylic acids by simply converting
them into mixed acid anhydrides with the cheap p-toluic acid.
The decarboxylative cross-coupling of alkyl acid anhydride is
believed to involve a SET process. Initial mechanistic studies
on both the stoichiometric reactions and the catalytic reaction
of the isolated (bpy)Ni(4-benzoate)I with alky acid anhydride
support the arylnickel(II) complex as a key intermediate
involved in the catalytic cycle. Additional mechanistic studies
to further elucidate the detailed reaction mechanism are
underway.
22,23
could not isolate the combined intermediate, Stephenson
and others 56,57 have done a number of studies to confirm the
existence of such types of reducible compounds. Thus, it was
reasonable to propose that the anhydride adduct was reduced
by Ni-complex to form alkyl radical, pyridine, and CO2
(Figure 6). In line with this hypothesis, we also detected the
formation of pyridine and gas in the reactions. Additionally,
the coupling proceeded well in the dark (Table 1, 3bc) and the
effect of light was ruled out (Table 1, 3b) and the formation of
organozinc regent from aryl iodides were excluded (see
Supporting Information (SI), part6, S13). Moreover, the
reaction without addition of zinc powder or LiCl only
provided a trace amount of the desired product (See
Supporting Information (SI)), which indicated that two
additives were necessary in the catalytic cycle. Finally, the
reaction was completely suppressed in the presence of
TEMPO (Figure 5c), and the ring-opening product (5) (Figure
5d) further strongly supported the hypothesis of SET process.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on ACS
Publications website.
Detail experimental procedure and spectral data (1H, 13C, MS,
HRMS) for compounds.
Based on these studies (Figure 5) and pioneering works by
other groups, one possible catalytic cycle is proposed in Figure
6. Pre-catalyst NiCl2 was reduced by zinc to generate
AUTHOR INFORMATION
Corresponding Author
51-53
bipyridine-ligated nickel (0) I.
Then, Ni (0) underwent
oxidative addition with aryl iodide to form arylnickel (II)
ACS Paragon Plus Environment

Page 5 of 7
ACS Catalysis
1
2
3
4
5
6
7
8
Carbon in the Cross-Coupling Event. J. Am. Chem. Soc. 2003, 125,
10498-10499.
liaoxuebin@mail.tsinghua.edu.cn.
ORCID
Xuebin Liao: 0000-0002-0290-894X.
(17) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis:
Coupling of α-Carboxyl sp3-Carbons with Aryl Halides. Science.
2014, 345, 437-440.
(18) Nobel, A.; McCarver, S. J.; MacMillan, D. W. C. Merging
Photoredox and Nickel Catalysis: Decarboxylative Cross-Coupling of
Carboxylic Acids with Vinyl Halides. J. Am. Chem. Soc. 2015, 137,
624-627.
(19) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillan, D. W.
C. Enantioselective Decarboxylative Arylation of α-Amino Acids via
the Merger of Photoredox and Nickel Catalysis. J. Am. Chem. Soc.
2016, 138, 1832-1835.
(20) Okada, K.; Okamoto, K.; Morita, N., Okubo, K.; Oda, M.
Photosensitized Decarboxylative Michael Addition through N-
(Acy1oxy) Phthalimidesvia an Electron-Transfer Mechanism. J. Am.
Chem. Soc. 1991, 113, 9401-9402.
(21) Schnermann, M. J.; Overman, L. E. A Concise Synthesis of (-)-
Aplyviolene Facilitated by a Strategic Tertiary Radical Conjugate
Addition. Angew. Chem., Int. Ed. 2012, 51, 9576-9580.
(22) Beatty, J. W.; Douglas, J. J.; Cole, K. P.; Stephenson, C. R. J. A
Scalable and Operationally Simple Radical Trifluoromethylation. Nat.
Commun. 2015, 6, 7919.
(23) Beatty, J. W.; Douglas, J. J.; Miller, R.; McAtee, R. C.; Cole, K.
P.; Stephenson, C. R. Photochemical Perfluoroalkylation with
Pyridine N-Oxides: Mechanistic Insights and Performance on a
Kilogram Scale. Chem. 2016, 1, 456-472.
(24) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. A
General Alkyl-Alkyl Cross-Coupling Enabled by Redox-Active
Esters and Alkylzinc Reagents. Science. 2016, 352, 801-805.
(25) Cornella, J.; Edwards, J. T.; Qin, T.; Kawnmura, S.; Wang, J.;
Pan, C. M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P.
S. Practical Ni-Catalyzed Aryl-Alkyl Cross-Coupling of Secondary
Redox-Active Esters. J. Am. Chem. Soc. 2016, 138, 2174-2177.
(26) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T. G.; Dixon, D.
D.; Creech, G.; Baran, P. S. Redox-Active Esters in Fe-Catalyzed C-C
coupling. J. Am. Chem. Soc. 2016, 138, 11132-11135.
(27) Qin, T.; Malins, L. R.; Ewards, J. T.; Merchant, R. R.; Novak, A.
J. E.; Zhong, J. Z.; Mills, R. B.; Yan, M.; Yuan, C.; Eastgate, M. D.;
Baran, P. S. Nickel-Catalyzed Barton Decarboxylation and Giese
Reactions: A Practical Take on Classic Transforms. Angew. Chem.,
Int. Ed. 2017, 56, 260-265.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We are grateful for financial support from the Collaborative
Innovation Center for Diagnosis and Treatment of Infectious
Disease, Tsing-Peking Centre for Life Science, and “1000 Talents
Recruitment Program”. We thank Dr. Yangjie Huang and
Professor Zhixiang Weng for discussion and assistance.
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
REFERENCES
(1) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition
Metal (Pd, Ni, Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-
Organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417-
1492.
(2) Goossen, L. J.; Rodriguez, N.; Goossen, K. Carboxylic Acids as
Substrates in Homogeneous Catalysis. Angew. Chem., Int. Ed. 2008,
47, 3100-3120.
(3) Goossen, L. J.; Rodriguez, N.; Melzer, B., Linder, C.; Deng, G.;
Levy, L. M. Biaryl Synthesis via Pd-Catalyzed Decarboxylative
Coupling of Aromatic Carboxylates with Aryl Halides. J. Am. Chem.
Soc. 2007, 129, 4824-4833.
(4) Goossen, L. J.; Paetzold, J. New Synthesis of Biaryls via Rh-
Catalyzed Decarbonylative Suzuki-Coupling of Carboxylic
Anhydrides with Arylboroxines. Adv. Synth. Catal. 2004, 346, 1665–
1668.
(5) Goossen, L. J.; Ghosh, K. Palladium-Catalyzed Synthesis of Aryl
Ketones from Boronic Acids and Carboxylic Acids or Anhydrides.
Angew. Chem., Int. Ed. 2001, 113. 3566-3568.
(6) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. The
Palladium-Catalyzed Cross-Coupling Reaction of Carboxylic
Anhydrides with Arylboronic Acids: a DFT Study. 2005, 127, 11102-
11114.
(7) Goossen, L. J.; Deng, J.; Levy, L. M. Synthesis of Biaryls via
Catalytic Decarboxylative Coupling. Science.2006, 313, 662-664.
(8) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K.
Decarbonylative Organoboron Cross-Coupling of Esters by Nickel
Catalysis. Nat. Commun. 2015, 6, 7508.
(9) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. Decarbonylative
C-H Coupling of Azoles and Aryl Esters: Unprecedented Nickel
Catalysis and Application to the Synthesis of Muscoride A. J. Am.
Chem. Soc. 2012, 134, 13573-13576.
(10) Mi, P.; Liao, P.; Tu, T.; Bi, X. Decarbonylative C-C Bond-
Forming Reactions of Saccharins by Nickel Catalysis: Homocoupling
and Cycloaddition. Chem. Eur. J. 2015, 21, 5332-5336.
(11) Malapit, C. A.; Ichiishi, N.; Sanfort, M. S. Pd-Catalyzed
Decarbonylative Cross-Couplings of Aroyl Chlorides. Org. Lett. 2017,
19, 4142-445.
(12) John, A.; Hillmyer, M. A.; Tolman, W. Anhydride-Additive-Free
Nickel-Catalyzed Deoxygenation of Carboxylic Acids to Olefins.
Organometallics. 2017, 36, 506-509.
(13) Liu, Y.; Kim, K. E.; Herbert, M. B.; Fedorov, A.; Grubbs, R. H.;
Stoltz, B. M. Palladium-Catalyzed Decarbonylative Dehydration of
Fatty Acids for the Production of linear Alpha Olefins. Adv. Synth.
Catal. 2014, 356, 130-136.
(14) Jin, W.; Yu, Z.; He, W.; Ye, W.; Xiao, W-J. Efficient Rh(I)-
Catalyzed Direct Arylation and Alkenylation of Arene C-H Bonds via
Decarbonylation of Benzoic and Cinnamic Anhydrides. Org. Lett.
2009, 11, 1317-1320.
(28) Sandfort, F.; Neill, M. J. O.; Cornella, J.; Wimmer, L.; Baran, P.
S. Alkyl (Hetero) Aryl Bond Formation via Decarboxylative Cross-
Coupling: a Systematic Analysis. Angew. Chem., Int. Ed. 2017, 56, 1-
6.
(29) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.;
Spiewak, A. M.; Johnson, K. A.; Dibenedetto, T. A.; Kim, S.;
Ackerman, L. K. G.; Weix, D. J. Decarboxylative Cross-Electrophile
Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am.
Chem. Soc. 2016, 138, 5016-5019.
(30) Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-Electron
Transmetalation
in
Organoboron
Cross-Coupling
by
Photoredox/Nickel Dual Catalysis. Science. 2014, 345, 433-436.
(31) McTiernan, C. D.; Leblanc, X.; Scaiano, J. C. Heterogeneous
Titania-Photoredox/Nickel Dual Catalysis: Decarboxylative Cross-
Coupling of Carboxylic Acids with Aryl Iodides. ACS Catal. 2017, 7,
2171-2175.
(32) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. Photoinduced,
Copper-Catalyzed Decarboxylative C-N Coupling to Generate
Protected Amines: An Alternative to the Curtius Rearrangement. J.
Am. Chem. Soc. 2017, 139, 12153-12156.
(33) Tlhuext-Ace, A.; Garaz-Sanchez, A.; Glorius, F.
Multicomponent Oxyalkylation of Styrenes Enabled by Hydrogen-
Bond-Assisted Photoinduced Electron Transfer. Angew. Chem., Int.
Ed. 2017, 56, 3708-3711.
(15) Stache, E. E.; Rovis, T.; Doyle, A.G. Dual Nickel- and
Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic
meso-Anhydrides, Angew. Chem., Int. Ed, 2017, 56, 3679-3683.
(16) O’Brin, E. R.; Bercot, E. A.; Rovis, T. Decarbonylative Cross-
Coupling of Cyclic Anhydrides: Introducing Stereochemistry at an sp3
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 7
1
2
3
4
5
6
7
8
(34) Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu. G. Enantioselective
Yamaguchi, Y.; Xu, L.; Gomea-Benitez, V.; Vicic, D. A. A Five-
Coordinate Nickel(II) Fluoroalkyl Complex as a Precursor to a
Spectroscopically Detectable Ni(III) Species. J. Am. Chem. Soc. 2013,
135, 8141-8144.
(55) Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Preparation of Vinyl
Arenes by Nickel-Catalyzed Reductive Coupling of Aryl Halides with
Vinyl Bromides. Angew. Chem., Int. Ed. 2016, 55, 15544-155548.
(56) Lee, K. Y.; Kochi, J. K. Charge-Transfer Structures of Aromatic
EDA Complexes with N-Heteroatom-Substituted Pyridinium Cations.
J. Chem. Soc. Perkin. Trans. 1992, 2, 1011-1017.
Decarboxylative Cyanation Employing Cooperative Photoredox
Catalysis and Copper Catalysis. J. Am. Chem. Soc. 2017, 139, 15632-
15635.
(35) Cheng, W. M.; Shang. R.; Zhao, B.; Xing, W. L.; Fu, Y.
Isonicotinate Ester Catalyzed Decarboxylative Borylation of
(Hetero)Aryl
and
Alkenyl
Carboxylic
Acids
through
N-Hydroxyphthalimide Esters. Org. Lett. 2017, 19, 4291-4294.
(36) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.;
Aggarwal, V. K. Photoinduced Decarboxylative Borylation of
Carboxylic Acids. Science, 2017, 357, 283-286.
(37) Yoshino, Y.; Kurahashi, T.; Matsubara, S. Nickel-Catalyzed
Decarboxylative Carboamination of Alkynes with Isatoic. J. Am.
Chem. Soc. 2009, 131, 7494-7495.
(38) Li, G.; Wang, T.; Fei, F.; Su, Y. M.; Li, Y.; Lan, Q.; Wang, X. S.
Nickel-Catalyzed Decarboxylative Difluoroalkylation of α,β-
Unsaturated Carboxylic Acids. Angew. Chem., Int. Ed. 2016, 55,
3491-3495.
(39) Moon, P. J.; Yin, S.; Lundegren, R. J. Ambient Decarboxylative
Arylation of Malonate Half-Esters via Oxidative Catalysis. J. Am.
Chem. Soc. 2016, 138, 13826-13829.
(40) Jian, W.; Ge, L.; Jiao, Y.; Qian, B.; Bao, H. Iron-Catalyzed
Decarboxylative Alkyl Etherification of Vinylarenes with Aliphatic
Acids as the Alkyl Source. Angew. Chem., Int. Ed. 2017, 56, 3650-
3654.
(41) Proctor, R. S. J.; Davis, H. J.; Phipps, R. J. Catalytic
Enantioselective Minisci-Type Addition to Heteroarenes. Science.
2018, 360, 419-422.
(42) Till, N. A.; Smith. R. T.; MacMillan, D. W. C. Decarboxylative
Hydroalkylation of Alkynes. J. Am. Chem. Soc. 2006, 140, 5710-5705.
(43) Moon, P. J.; Fahandej-Sadi, A.; Qian, W.; Lundgren, R. J.
Decarboxylative Benzylation of Aryl and Alkenyl Boronic Esters.
Angew. Chem., Int. Ed. 2018, 57, 4612-4616.
(44) Chatupheeraphat, A.; Liao, H. H.; Srimontree, W.; Guo, L.;
Minenkov, Y.; Poater, A.; Cavallo, L.; Rueping, M.; Ligand-
Controlled Chemoselective C(acyl)-O Bond vs C(aryl)−C Bond
Activation of Aromatic Esters in Nickel Catalyzed C(sp2 )−C(sp3 )
Cross-Couplings. J. Am. Chem. Soc. 2018, 140, 3724−3735.
(45) Lu, X.; Xiao, B.; Liu, L.; Fu, Y. Chem. Eur. J. 2016, 22,11161 –
11164.
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
(57) Cohen, T.; Song, I. H.; Fager, J. H.; Deets, G. L. Oxidative
Decarboxylation of Carboxylic Acids by Pyridine N-Oxide. J. Am.
Chem. Soc. 1967, 89, 4968-4975.
(46) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic
Asymmetricreductive
Acyl
Cross-Coupling:
Synthesis
of
Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc.
2013, 135, 7442-7445.
(47) Chen, X.; Li, J. J.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q.
Palladium-Catalyzed Alkylation of Aryl C-H Bonds with sp3
Organotin Reagents Using Benzoquinone as a Crucial Promoter. J.
Am. Chem. Soc. 2006, 128, 78-79.
(48) Hu, L.; Liu, X.; Lao, X. B. Nickel-Vatalyzed Methylation of
Aryl Halides with Deuterated Methyl Iodide. Angew. Chem., Int. Ed.
2016, 55, 9743-9747.
(49) Wang, X. C.; Gong, W.; Fang, L. Z.; Zhu, R. Y.; Li, S. H.; Engle,
K. M.; Yu, J. Q. Ligand-Enabled Meta-C–H Activation Using a
Transient Mediator. Nature, 2015, 519, 334-338.
(50) Liu, W.; Yang, X.; Zhou, Z.; Li, C-J. Simple and Clean Photo-
induced Methylation of Heteroarenes with MeOH. Chem. 2017, 2,
688-702.
(51) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing
Conventional Carbon Nucleophiles with Electrophiles: Nickel-
Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J.
Am. Chem. Soc. 2012, 134, 6146-6159.
(52) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-
Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl
Halides. J. Am. Chem. Soc. 2013, 135, 16192-16197.
(53) Weix, D. J. Mechanism and Selectivity in Nickel-Catalyzed
Cross-Electrophile Coupling of Aryl Halides with Alkyl Halides. Acc.
Chem. Res. 2015, 48, 1767-1775.
(54) Zhang, C. P.; Wang, H.; Klein, A.; Biewer, C.; Stirnat, K.;
ACS Paragon Plus Environment

Page 7 of 7
ACS Catalysis
1
2
3
O
O
+ Ar-X
NiCl2 (10 mol%), bipy (15 mol%)
LiCl (4.0 equiv), KF (1.5 equiv)
Zn (3.0 equiv), DMAc
R
O
R
O
• in situ or commercially
R
4
5
6
7
available
Ar
R
OH
O
O
(1.5 equiv)
N
O
R=1°,2°,3° alkyl groups
R
O
Ar'
0 °C to 25 °C
-CO2
•alkyl migration, chemoselectivity
• mixed anhydrides
8
9
bipy =
Ar', Ar = aryl groups
N
N
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
7
ACS Paragon Plus Environment