LiCl-Accelerated multimetallic cross-coupling of aryl chlorides with aryl triflates

Article abstract of DOI:10.1021/jacs.9b05461

While the synthesis of biaryls has advanced rapidly in the past decades, cross-Ullman couplings of aryl chlorides, the most abundant aryl electrophiles, have remained elusive. Reported here is the first general cross-Ullman coupling of aryl chlorides with aryl triflates. The selectivity challenge associated with coupling an inert electrophile with a reactive one is overcome using a multimetallic strategy with the appropriate choice of additive. Studies demonstrate that LiCl is essential for effective cross-coupling by accelerating the reduction of Ni(II) to Ni(0) and counteracting autoinhibition of reduction at Zn(0) by Zn(II) salts. The modified conditions tolerate a variety of functional groups on either coupling partner (42 examples), and examples include a three-step synthesis of flurbiprofen.

Full text of DOI:10.1021/jacs.9b05461

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Communication
LiCl Accelerated Multimetallic Cross-
Coupling of Aryl Chlorides with Aryl Triflates
Liangbin Huang, Laura K. G. Ackerman, Kai Kang, Astrid M. Parsons, and Daniel J. Weix
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05461 • Publication Date (Web): 30 Jun 2019
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LiCl Accelerated Multimetallic Cross-Coupling of Aryl Chlorides with
Aryl Triflates
Liangbin Huang,†§ Laura K. G. Ackerman,‡§ Kai Kang,† Astrid M. Parsons‡ and Daniel J. Weix†*
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†University of Wisconsin–Madison, Madison, Wisconsin 53706, United States.
‡University of Rochester, Rochester, New York 14627, United States
Supporting Information Placeholder
activated aryl bromides at a faster rate than aryl triflates; the
Pd catalyst activated aryl triflates at a faster rate than aryl
bromides. When sufficiently electron deficient aryl chlorides
were substituted for aryl bromides, they were still activated
enough to maintain catalyst selectivity. However, when less
activated aryl chlorides were used, an erosion in catalyst
selectivity led to homocoupling
ABSTRACT: While the synthesis of biaryls has advanced rap-
idly in the past decades, cross-Ullman couplings of aryl chlo-
rides, the most abundant aryl electrophiles, have remained
elusive. Reported here is the first general cross-Ullman cou-
pling of aryl chlorides with aryl triflates. The selectivity chal-
lenge associated with coupling an inert electrophile with a re-
active one is overcome using a combination of two catalysts:
nickel and palladium. Studies demonstrate that LiCl is essen-
tial for effective cross-coupling by accelerating the reduction
of Ni(II) to Ni(0) and counteracting autoinhibition of reduc-
tion at Zn(0) by Zn(II) salts. The modified conditions toler-
ate a variety of functional groups on either coupling partner
(42 examples) and examples include a three-step synthesis of
flurbiprofen.
Scheme 1. Cross-Ullman Reaction in Biaryl Synthesis.
A. Methods for biaryl synthesis
MX
H
R1
cross-coupling
R1
R2
C-H arylation
R2
CO2H
X
X
R1
R1
R1
decarboxylative
coupling
cross-Ullman
coupling
The synthesis of biaryls has become one of the most com-
monly used reactions in pharmaceutical, agrochemical, and
materials science industries, yet access to arylmetal reagents
B. Previous report: coupling of aryl bromides with aryl triflates
5 mol% PdCl2/dppp
OMe
1
OMe
X
5 mol% NiCl2(dme)/bpy
+
remains limiting. The low commercial availability of arylmetal
reagents has inspired a number of active areas of research
(Scheme 1A), including improved methods for arylmetal syn-
KF (1 equiv)
Zn (2 equiv)
1:1 NMP/DMF
80 oC, 24 h
TfO
Pd selective
Ph
X= Br, 79% yield
challenge:
X= Cl, 10% yield
Ni selective
for C–X
for C–OTf
2
3
4
thesis, C-H arylation, and decarboxylative cross-coupling.
commercial availability of aryl halide coupling partners
5
The relative abundance of aryl electrophiles (Scheme 1B )
6 7
8.1 × 104
6.4 × 105
1.5 × 106
,
would make the cross-Ullman reaction an attractive ap-
proach, however our recently reported catalytic nickel and pal-
ladium method was not broadly effective with the most abun-
I
Br
Cl
8
dant and versatile aryl electrophiles, aryl chlorides. In addi-
fast
slow
reactivity with (bpy)Ni
tion to opening up more chemical space, aryl chlorides are of-
ten lower in cost and their lower reactivity would allow for se-
C. This report: LiCl enabled coupling of aryl chlorides with aryl triflates
5 mol% PdCl2/dppb
OMe
9
quential coupling in fragment-based drug discovery or late-
OMe
Cl
5 mol% NiCl2(dme)/dtbbpy
10
+
stage coupling on complex molecules.
LiCl (2 equiv)
Zn (2 equiv)
1:1 NMP/DMF
80 oC, 24 h
TfO
Ph
Although significant advances in the use of aryl chlorides in
up to 89% yield
42 examples
Ni selective
for C–Cl
Pd selective
for C–OTf
c, , ,
7 11 12 13 14
cross-coupling have been made recently,
there are no
general methods for the direct cross-coupling of electron-neutral or
,
15 16
rather than effective cross-coupling. Preliminary studies at-
tempting to couple more electron-rich chlorides with aryl tri-
flates led to production of the triflate-derived dimer and in-
complete conversion of both the aryl chloride and the aryl
electron-rich aryl chlorides with other aryl electrophiles. In our
prior report we established that in order to promote a
successful cross-Ullman reaction, the electrophiles employed
had to be orthogonally paired in reactivity: the Ni catalyst
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Page 2 of 8
triflate. Herein we report a general, multimetallic solution that
achieves the selective coupling of a variety of aryl chlorides
with aryl triflates (Scheme 1C).
Table 1. Mechanistic Study and Optimization of Ar-Cl
Cross-Ullman Reaction.
1
2
3
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5
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7
8
Cl
Ar2
OTf
Ar1
A. Key hypothesis
slow NiII reduction
inhibits catalysis
[NiII]
[PdII]
Based upon the mechanism proposed in our earlier studies
II
IV
8
with nickel and palladium co-catalysis (Table 1A), the slow
[Ni0]
Zn
[Pd0]
consumption of the aryl chloride and aryl triflate suggested that
arylnickel (II) formation was being inhibited (Table 1A).
Arylpalladium (IV) will not consume aryl triflate without
arylnickel (II) present. The inhibition could come from slow
I
V
Ar2
Ar1
X
X
[NiII]
[PdII]
9
III
VI
17
oxidative addition (I to II), slow reduction (III to I), or an
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B. Reduction of NiII
CV data show no TfO– effecta
Zn2+ and TfO– slow reduction at Zn surface
off-cycle loss of nickel catalyst.
Reduction of (dtbbpy)NiIIX2 complexes III-Cl and III-OTf
was studied by both electrochemical and chemical methods
(Table 1B). CV studies, which are commonly used to assess
LiCl recovers activity
t-Bu
t-Bu
cod
Zn0
cod
Zn0
18
N
N
N
N
OTf
OTf
Cl
Cl
the ease of reduction of metal complexes, showed no differ-
Ni
(dtbbpy)Ni0(cod)
Ni
III-Cl
ence between III-Cl and III-OTf (Table 1B and Supporting
Information Figures S7 and S8). While CV provides infor-
mation on the thermodynamic driving force for a reduction, it
does not account for the complex kinetic picture of reduction
III-OTf
I
t-Bu
t-Bu
E1/2 = -0.86 V vs. SCE
Chemical Reduction of (L)NiII(X2) to (L)Ni0(cod)b
E1/2 = -0.86 V vs. SCE
Additive
none
Yield from III-OTf
0% yield
Yield from III-Cl
37% yield
,
19 20
at a metal surface. Indeed, the reduction of complexes III-
OTf and III-Cl over zinc flake in the presence or absence of
additives showed that III-OTf is not reduced unless chloride
salts are present (Table 1B and 1C; Supporting Information
Figures S8 and S9; Table S2). There i s al so a cat ion ef fect :
while LiCl enhances the rate of reduction of both nickel com-
plexes III-OTf and III-Cl, ZnCl2 did not. In fact, zinc chloride
and zinc triflate, salts formed during the reaction, inhibit re-
duction of (dtbbpy)NiIICl2 (37% yield with no salt, 2-5% yield
ZnCl2
2% yield
5% yield
LiCl (40 equiv)
44% yield
86% yield
C. Optimized reaction conditions
5 mol% PdCl2/dppb
5 mol% NiCl2(dme)/dtbbpy
OMe
OMe
X
+
LiCl (2 equiv), Zn (2 equiv)
1:1 NMP/DMF
TfO
1 equiv each
Ph
80 oC, 24 h
1a
2a
3a
entry
change from optimized conditionsc
none
3a (%)d
84
21
with 1 equiv of ZnCl2 or Zn(OTf)2). Lithium chloride can
1
2
3
4
5
6
overcome zinc inhibition and is generally the most useful ad-
ditive studied (Table 1, entries 1-6 and Supporting Infor-
NaCl instead of LiCl
LiBr instead of LiCl
62
,
22 23
mation Table S2). While we found that reduction of octyl
bromide to octylzinc bromide was also inhibited by zinc
59
Bu4NCl instead of LiCl
TMSCl instead of LiCl
no LiCl
53
,
salts, d reduction of palladium(II) phosphine complexes to
24 21
16
palladium(0) was fast with or without added LiCl or Zn (Sup-
,
25 26
porting Information Figures S11-S16).
<10
62
These studies show that the low reactivity observed for the
coupling of aryl chlorides with aryl triflates (Scheme 1B) is
due to autoinhibition: the zinc salts (ZnCl2 and Zn(OTf)2)
formed in reduction of III to I inhibit subsequent reductions
of III. While it had previously been noted that halide anions
7
Mn instead of Zn
8
Mn instead of Zn, LiBr instead of LiCl
without PdCl2 and dppb
without NiCl2(dme) and dtbbpy
Reaction set up on benchtope
1.2 equiv of 2a
77
9
44
10
11
12
a
<5
,
27 28
accelerate reduction of NiX2 intermediates at zinc surfaces,
80
90(89f)
the inhibitory effect of less-coordinating anions (OTf–, BF4 ,
–
–
29
PF6 ) and zinc salts have not been previously reported. This
result has broad implications for cross-electrophile coupling
reactions that rely upon metallic reductants.
In DMF. See Supporting Information for details on electro-
chemical studies. b Reduction of III was conducted in DMF at a
concentration of 0.025 M with Zn powder (40 equiv). Cyclooc-
tadiene (0.125 M) was added to stabilize the product. Salts (1 to
40 equiv) were added in some cases. See Supporting Information
The catalytic reaction behaved as expected from the stoichi-
ometric studies: the addition of LiCl enabled turnover (Table
30
1C, entries 1-6, Supporting Information Figures S1-S2).
c
for additional results and experimental details. Reactions were
8
Consistent with previous reports, these reactions were still
run on 0.5 mmol scale in 2 mL of solvent. NMP = N-methyl-2-
pyrrolidinone. d GC yield vs dodecane as internal standard. e Re-
action was set up under air with dry solvent. f Isolated yield.
promoted by the cooperativity between two metal catalysts:
reactions without palladium were poorly selective and reac-
tions without nickel did not consume starting materials
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Journal of the American Chemical Society
(entries 9 and 10). Similar to other cross-electrophile cou-
arylation (7), and reductive α-arylation (9) can all be con-
pling reactions, a the reaction was tolerant of adventitious di-
ducted while preserving the C-Cl bond. As an example of
1
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5
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7
8
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oxygen, allowing reactions to be set up on the benchtop (Ta-
ble 1, entry 11), albeit O2 in the reaction headspace resulted in
how this can be applied in synthesis, a concise, three-step syn-
thesis of flurbiprofen (9) was demonstrated that would be
36
31
amenable to rapid analog synthesis.
an induction period (Supporting Information Figure S6).
Both Zn and Mn could be utilized as reductants. As in our pre-
vious report, LiBr was superior to LiCl with Mn (Table 1, en-
This report shows how the nickel and palladium co-catalyst
system can be rationally modulated to couple less reactive sub-
strates: an unselective multimetallic reaction was made selec-
tive with the use of an additive, LiCl, that facilitates the reduc-
tion of the nickel catalyst at the zinc surface. Combined with
our previous reports, these results suggest that the Ni/Pd sys-
tem is general and that multimetallic catalysis may have broad
generality. Finally, this work demonstrates how reactivity in
cross-electrophile coupling reactions can be influenced by the
reductant choice as much as the ligand choice: salts formed in
the reaction may be autoinhibitory and new reductant combi-
nations can unlock new reactivity.
a
20
tries 7 and 8 and Supporting Information Figure S5). Fi-
nally, while dtbbpy and dppb were generally the best pair of
ligands for this coupling, PCy3 was also effective (Supporting
Information Figures S2 and S3). While 6,6´-dibromo-2,2´-bi-
pyridine was not an effective ligand for the model reaction, it
was effective for couplings of electron-poor aryl chlorides
(Scheme 2).
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With these modified reaction conditions and an effective
way to promote aryl chloride reactivity, we examined the cou-
plings of a variety of aryl chlorides and triflates containing an
array of functional groups and steric environments (Scheme
2). Electron-poor fluorine-containing substrates, neutral, and
electron-rich substrates were well tolerated, including sensi-
tive functionalities such as a Boc-protected amine (3c), an al-
dehyde (3i), an alkyl Bpin ester (3ab), and a phosphonate es-
ter (3ac). More reactive aryl halides, such as aryl chlorides
bearing strongly electron-withdrawing groups, heteroaryl hal-
ides, or aryl bromides, could be selectively coupled with an
aryl triflate by employing the hindered, electron-poor 6,6´-di-
bromo-2,2´-bipyridine ligand (3g, 3i, 3j, 3o, 3t, and 3u). Un-
der these reaction conditions ortho-substitution (3q-s) and
2,6-disubstitution on aryl bromides and chlorides (3t-v) were
also coupled efficiently. In contrast, steric hinderance was not
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
Materials, methods, compound characterization, supplementary
figures, schemes, and tables. (PDF)
AUTHOR INFORMATION
Corresponding Author
*dweix@wisc.edu
Present Addresses
,
32 33
as well tolerated in our previous report. The ability to cou-
ple unactivated aryl chlorides can be beneficial in synthesis
when the corresponding aryl bromide is either more expen-
sive or not commercially available (3w-ac). The most chal-
lenging combination was electron-rich aryl chlorides with
electron-poor aryl triflates (3l), which suffered from lower se-
lectivity (about 2.5:1 biaryl to product).
§ Laura K. G. Ackerman is at Department of Chemistry, Prince-
ton University, Princeton, New Jersey 08544, United States.
Liangbin Huang is at the Department of Chemistry, South China
University of Technology, Guangzhou, Guangdong, China.
Author Contributions
The manuscript was written through contributions of all authors.
The scope of the aryl triflate was also examined (Scheme 2),
demonstrating good yields with both electron-donating and
electron-withdrawing substituents (3ad-am). The lower
yields observed for the coupling of electron-poor aryl triflates
with electron-poor aryl chlorides (3ah and 3aj) were due to
competing homodimer formation. In these cases, the use of
6,6´-dibromo-2,2´-bipyridine as ligand did not improve
yields. The couplings with 2-cyano-1-chlorobenzene form
biaryls that could be useful for the synthesis of angiotensin II
ACKNOWLEDGMENT
The authors gratefully acknowledge funding from the NIH
NIGMS (R01GM097243 to DJW), the NSF (NSF DGE-
1419118 to AMP and LKGA), and SIOC (Fellowship to KK).
DJW is a Camille Dreyfus Teacher-Scholar. Additional funding
from Novartis and Boehringer Ingelheim is also gratefully
acknowledged. We thank Amanda Spiewak (Univ. of Wisconsin)
for assistance in the Pd complex reduction study, Yixing Guo and
Prof. Kara Bren (Univ. of Rochester) for assistance in obtaining
CV data, and Prof. Alison R. Fout for a helpful discussion on the
mechanism of action for LiCl.
34
receptor antagonists (3ad-ah).
Besides their improved availability and lower cost, an addi-
tional benefit of using aryl chlorides is that their lower reactiv-
ity facilitates multistep synthesis (Scheme 2). For example,
cross-electrophile coupling with an alkyl bromide (5), C-H
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Chlorides. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(13) Decarboxylative cross-coupling with aryl chlorides: Tang, J.; Bia-
fora, A.; Goossen, L. J. Catalytic Decarboxylative Cross-Coupling of Aryl
Chlorides and Benzoates without Activating ortho Substituents. Angew.
Chem. Int. Ed. 2015, 54, 13130-13133.
(14) C-H arylation with aryl chlorides: (a) Ackermann, L. Phosphine Ox-
ides as Preligands in Ruthenium-Catalyzed Arylations via C−H Bond Func-
tionalization Using Aryl Chlorides. Org. Lett. 2005, 7, 3123-3125; (b)
Gürbüz, N.; Özdemir, I.; Çetinkaya, B. Selective palladium-catalyzed aryla-
tion(s) of benzaldehyde derivatives by N-heterocarbene ligands. Tetrahe-
dron Lett. 2005, 46, 2273-2277; (c) Chiong, H. A.; Pham, Q.-N.; Daugulis,
O. Two Methods for Direct ortho-Arylation of Benzoic Acids. J. Am. Chem.
Soc. 2007, 129, 9879-9884; (d) Gao, K.; Lee, P.-S.; Long, C.; Yoshikai, N.
Cobalt-Catalyzed Ortho-Arylation of Aromatic Imines with Aryl Chlorides.
Org. Lett. 2012, 14, 4234-4237; (e) Zha, G.-F, Qin, H.-L, Kantchev, E. A. B.
Ruthenium-catalyzed direct arylations with aryl chlorides. RSC Adv. 2016,
6, 30875-30885.
(15) The best current alternative is probably a one-pot borylation/cross-
coupling strategy: (a) Baudoin, O.; Guénard, D.; Guéritte, F., Palladium-
Catalyzed Borylation of Ortho-Substituted Phenyl Halides and Application
to the One-Pot Synthesis of 2,2‘-Disubstituted Biphenyls. J. Org. Chem.
2000, 65, 9268-9271; (b) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L.,
Palladium-Catalyzed Borylation of Aryl Chlorides: Scope, Applications, and
Computational Studies. Angew. Chem., Int. Ed. 2007, 46, 5359-5363; (c)
Molander, G. A.; Trice, S. L. J.; Dreher, S. D. Palladium-Catalyzed, Direct
Boronic Acid Synthesis from Aryl Chlorides: A Simplified Route to Diverse
Boronate Ester Derivatives. J. Am. Chem. Soc. 2010, 132, 17701-17703; (d)
Molander, G. A.; Trice, S. L. J.; Tschaen, B., A modified procedure for the
palladium catalyzed borylation/Suzuki-Miyaura cross-coupling of aryl and
heteroaryl halides utilizing bis-boronic acid. Tetrahedron 2015, 71, 5758-
5764.
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(8) (a) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic Ca-
talysis Enabled Cross-Coupling of Aryl Bromides with Aryl Triflates. Nature
2015, 524, 454-457; (b) Olivares, A. M.; Weix, D. J. Multimetallic Ni- and
Pd-Catalyzed Cross-Electrophile Coupling To Form Highly Substituted
1,3-Dienes. J. Am. Chem. Soc. 2018, 140, 2446-2449.
(16) Qian reported one example of the coupling of 3,4,5-trimethoxybro-
mobenzene with 4-chloroanisole in 58% yield, see reference 7d. It is not clear
if this approach is general and no further reports have appeared on this mon-
ometallic strategy.
(17) Our own studies and those of others have shown that aryl chlorides
react rapidly with (N–N)Ni0 complexes of the type used in this study. For
example, carboxylation of aryl chlorides using similar catalysts and
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Soc. 2003, 125, 3867-3870; (c) Klatt, T.; Markiewicz, J. T.; Sämann, C.;
Knochel, P. Strategies To Prepare and Use Functionalized Organometallic
Reagents. J. Org. Chem. 2014, 79, 4253-4269; (d) Haas, D.; Hammann, J.
M.; Greiner, R.; Knochel, P. Recent Developments in Negishi Cross-Cou-
pling Reactions. ACS Catal. 2016, 6, 1540-1552.
(27) For a thorough discussion on iodide additives in nickel-catalyzed
cross-electrophile coupling, see reference 28a and references cited therein.
For the effect of MgCl2 and LiBr on the reduction of nickel complexes at
metal surfaces, see references 28b and 20, respectively.
(28) (a) Everson, D. A.; Jones, B. A.; Weix, D. J., Replacing Conventional
Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkyl-
ation of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134, 6146-
6159; (b) Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.;
Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl
Iodides with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2018, 140, 14490-
14497.
(29) Other non-coordinating anions also appeared to be inhibitory, such
as BF4 and PF6. While zinc appears to be inhibitory (ZnCl2 slowed reduc-
tion), both LiCl2 and Bu4NCl accelerated reduction, suggesting that there is
not a special lithium effect, but rather a special zinc effect. See Supporting
Information Table S2 for additional data.
(30) A mixture of solvents was used to help with solubility of pre-catalyst
solutions. DMF provided the same yields and selectivities as the mixture. See
Supporting Information Table S1.
(31) While most isolated reactions were run for 24 h for convenience, the
reaction in Table 1 was 90% complete in 2 h and finished in less than 8 h
when run under nitrogen.
(32) The homodimerization of hindered aryl bromides with nickel has
been reported. See the following reference and references cited therein:
Hong, R.; Hoen, R.; Zhang, J.; Lin, G.-Q. Nickel-catalyzed Ullmann-type
Coupling Reaction to Prepare Tetra-ortho-substituted Biaryls. Synlett 2001,
1527-1530.
(33) Biaryls with four different ortho-substituents are still not coupled in
high yield. For these types of substrates, cross-coupling with organometallic
reagents is the best approach: (a) Altenhoff, G.; Goddard, R.; Lehmann, C.
W.; Glorius, F. An N-Heterocyclic Carbene Ligand with Flexible Steric Bulk
Allows Suzuki Cross-Coupling of Sterically Hindered Aryl Chlorides at
Room Temperature. Angew. Chem., Int. Ed. 2003, 42, 3690-3693; (b)
Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. The
Development of Bulky Palladium NHC Complexes for the Most-Challeng-
ing Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2012, 51, 3314-3332.
(34) (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson,
A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B.; Wells, G. J. Nonpeptide an-
giotensin II receptor antagonists: the discovery of a series of N-(bi-
phenylylmethyl)imidazoles as potent, orally active antihypertensives. J. Med.
Chem. 1991, 34, 2525-2547; (b) Kubo, K.; Kohara, Y.; Yoshimura, Y.; Inada,
Y.; Shibouta, Y.; Furukawa, Y.; Kato, T.; Nishikawa, K.; Naka, T. Nonpep-
tide angiotensin II receptor antagonists. Synthesis and biological activity of
potential prodrugs of benzimidazole-7-carboxylic acids. J. Med. Chem. 1993,
36, 2343-2349; (c) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M.
R.; Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. Nonpeptide
Angiotensin II Receptor Antagonists:ꢀ The Next Generation in Antihyper-
tensive Therapy. J. Med. Chem. 1996, 39, 625-656.
(35) (a) Johnson, K. A.; Biswas, S.; Weix, D. J. Cross-Electrophile Cou-
pling of Vinyl Halides with Alkyl Halides. Chem.—Eur. J. 2016, 22, 7399-
7402; (b) Huang, L.; Hackenberger, D.; Gooßen, L. J. Iridium-Catalyzed or-
tho-Arylation of Benzoic Acids with Arenediazonium Salts. Angew. Chem.,
Int. Ed. 2015, 54, 12607-12611; (c) Durandetti, M.; Gosmini, C.; Périchon,
J. Ni-catalyzed activation of α-chloroesters: a simple method for the synthe-
sis of α-arylesters and β-hydroxyesters. Tetrahedron 2007, 63, 1146-1153.
(36) (a) Peretto, I.; Radaelli, S.; Parini, C.; Zandi, M.; Raveglia, L. F.;
Dondio, G.; Fontanella, L.; Misiano, P.; Bigogno, C.; Rizzi, A.; Riccardi, B.;
Biscaioli, M.; Marchetti, S.; Puccini, P.; Catinella, S.; Rondelli, I.; Cenacchi,
V.; Bolzoni, P. T.; Caruso, P.; Villetti, G.; Facchinetti, F.; Del Giudice, E.;
Moretto, N.; Imbimbo, B. P. Synthesis and Biological Activity of Flurbi-
profen Analogues as Selective Inhibitors of β-Amyloid1-42 Secretion. J. Med.
Chem. 2005, 48, 5705-5720; (b) Quasdorf, K. W.; Riener, M.; Petrova, K.
1
2
3
4
5
6
7
8
reductants is known. For two examples, see: (a) Fujihara, T.; Nogi, K.; Xu,
T.; Terao, J.; Tsuji, Y. Nickel-Catalyzed Carboxylation of Aryl and Vinyl
Chlorides Employing Carbon Dioxide. J. Am. Chem. Soc. 2012, 134, 9106-
9109; (b) Charboneau, D. J.; Brudvig, G. W.; Hazari, N.; Lant, H. M. C.;
Saydjari, A. K. Development of an Improved System for the Carboxylation
of Aryl Halides through Mechanistic Studies. ACS Catalysis 2019, 9, 3228-
3241.
(18) Cyclic voltammetry studies on the reduction of III showed only an
apparent two-electron reduction at -0.86 V vs SCE (Supporting Information
Figure S7). The observed reduction potential did not depend upon the
counterion on nickel (Cl or OTf) or the electrolyte (Bu4NPF6 or Bu4NCl),
suggesting that all of these species were ionized in solution. These results
match those previously reported for related catalysts: (a) Durandetti, M.;
Devaud, M.; Périchon, J. Investigation of the reductive coupling of aryl hal-
ides and/or ethylchloroacetate electrocatalyzed by the precursor
NiX(2)(bpy) with X(-)=Cl-, Br- or MeSO(3)(-) and bpy equals 2,2'-di-
pyridyl. New J. Chem. 1996, 20, 659-667; (b) Mikhaylov, D.; Gryaznova, T.;
Dudkina, Y.; Khrizanphorov, M.; Latypov, S.; Kataeva, O.; Vicic, D. A.;
Sinyashin, O. G.; Budnikova, Y., Electrochemical nickel-induced fluoroalkyl-
ation: synthetic, structural and mechanistic study. Dalton Trans., 2012, 41,
165–172.
(19) This strategy for evaluating the reduction of nickel(II) to nickel(0)
grew out of our studies on nickel(0) complexes and their reactivity. We pre-
viously reported this approach (with LiBr over Mn surfaces, reference 20a).
(20) (a) Huang, L.; Olivares, A. M.; Weix, D. J. Reductive Decarboxyla-
tive Alkynylation of N-Hydroxyphthalimide Esters with Bromoalkynes. An-
gew. Chem., Int. Ed. 2017, 56, 11901-11905; (b) Ni, S.; Muñoz Padial, N.;
Kingston, C.; Vantourout, J. C.; Schmitt, D. C.; Edwards, J. T.; Kruszyk, M.;
Merchant, R. R.; Mykhailiuk, P. K.; Sanchez, B.; Yang, S.; Perry, M.; Gallego,
G. M.; Mousseau, J. J.; Collins, M. R.; Cherney, R. J.; Lebed, P. S.; Chen, J.
S.; Qin, T.; Baran, P. S., A Radical Approach to Anionic Chemistry: Synthe-
sis of Ketones, Alcohols, and Amines. J. Am. Chem. Soc. 2019, 141, 6726-
6739.
(21) The effect of LiCl on reduction of organic halides has been studied in
some detail: (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Efficient Synthesis of Functionalized Organozinc Compounds by the Direct
Insertion of Zinc into Organic Iodides and Bromides. Angew. Chem., Int. Ed.
2006, 45, 6040-6044; (b) Koszinowski, K.; Böhrer, P. Formation of Or-
ganozincate Anions in LiCl-Mediated Zinc Insertion Reactions. Organome-
tallics 2009, 28, 771-779; (c) Feng, C.; Cunningham, D. W.; Easter, Q. T.;
Blum, S. A. Role of LiCl in Generating Soluble Organozinc Reagents. J. Am.
Chem. Soc. 2016, 138, 11156-11159; (d) Jess, K.; Kitagawa, K.; Tagawa, T.
K. S.; Blum, S. A. Microscopy Reveals: Impact of Lithium Salts on Elemen-
tary Steps Predicts Organozinc Reagent Synthesis and Structure. J. Am.
Chem. Soc. 2019, 141, 9879-9884.
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(22) These results do not conclusively show that nickel(0) is the opera-
tive oxidation state of the nickel catalyst. Love and Schaefer have recently
shown that alkene ligands can influence the relative stability of nickel(I) and
nickel(II/0). See the following reference.
(23) Beattie, D. D.; Lascoumettes, G.; Kennepohl, P.; Love, J. A.; Schafer,
L. L. Disproportionation Reactions of an Organometallic Ni(I) Amidate
Complex: Scope and Mechanistic Investigations. Organometallics 2018, 37,
1392-1399.
(24) Huo, S. Highly Efficient, General Procedure for the Preparation of
Alkylzinc Reagents from Unactivated Alkyl Bromides and Chlorides. Org.
Lett. 2003, 5, 423-425.
(25) As determined by 31P NMR vs an internal standard. The DMF/THF
solvent mixture was used because the palladium complexes were poorly sol-
uble in pure DMF. The catalytic reaction works well in DMF/THF mixtures.
For detailed conditions, see the Supporting Information Figures S9-S12.
(26) Another alternative hypothesis is insertion of zinc into Ar-Cl or Ar-
OTf bonds to form arylzinc reagents. This does not happen under our con-
ditions, consistent with the literature: (a) Jin, M.-Y.; Yoshikai, N. Co-
balt−Xantphos-Catalyzed, LiCl-Mediated Preparation of Arylzinc Reagents
from Aryl Iodides, Bromides, and Chlorides. J. Org. Chem. 2011, 76, 1972-
1978; (b) Fillon, H.; Gosmini, C.; Périchon, J. New chemical synthesis of
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functionalized arylzinc compounds from aromatic or thienyl bromides un-
der mild conditions using a simple cobalt catalyst and zinc dust. J. Am. Chem.

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V.; Garg, N. K. Suzuki–Miyaura Coupling of Aryl Carbamates, Carbonates,
and Sulfamates. J. Am. Chem. Soc. 2009, 131, 17748-17749.
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Scheme 2. Reaction Scope and Applications.a
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2
3
4
5 mol% PdCl2, 5 mol% dppb
R2
5 mol% NiCl2(dme), 5 mol% ligand
Cl
R2
1.2 equiv
R1
+
R1
LiCl (2 equiv), Zn (2 equiv)
1:1 NMP/DMF, 80 °C
TfO
5
6
7
aryl chloride scope
Ar1 = 4-(CH3O)C6H4- Ar2 = 4-(CH3O2C)C6H4-
ligands
Ar1
8
Ar1
Ar1
Ar1
Ar1
t-Bu
t-Bu
9
CF3
Me
BocHN
F
Ph2P
PPh2
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N
N
3a 89%
3b 81%
3c 65%
3d 77%
3e 74%
Ar1
dppb
dtbbpy
Ar1
Ar1
Ar1
Ar1
N
N
N
CF3O
Ac
OHC
NC
MeO2C
Br
Br
OMe
3g 64%b
dbrbpy
3i 67%b
3j 56%b
3f 84%
3h 76%
O
sterically hindered aryl substrates
tBu
Ar
Ar1
Ar1
Ar1
Ar1
Et2N
CO2Me
Ar1
Me
OMe
Ar1
Ar1
MeO
O
tBu
O
N
Ar = Ar1 3k 83%
Ar = Ar2 3l 44%
3n 82%
3o 71%b
3p 68%
3m 81%
3q 62%
3r 51%
3s 62%
aryl bromides are unavailable or 10X the cost of aryl chlorides
Me
Me
F
Ar1
Ar1
Ar1
Ac
Ar1
Me
Ar1
MeO
Ph
Ar1
Me
N
O
MeO
OCHF2
CO2Me
Me
OMe
O
CO2Me
F
F
CF3
3t 65%b,c
3u 53%b,c
3z 45%
3w 75%
3x 63%
3y 70%
3aa 78%
Me
Ar1
Ar1
Ph
O
(EtO)2P
pinB
CO2Me
3ab 48%
3ac 73%
3v 52%
aryl triflate scope
Me
Ac
O
Me
Me
Me
CO2Me
CN
CN
CN
H
H
H
R
MeO
R
Ph
MeO2C
R = H, 3ad 74%
R = tBu, 3ae 62%
R = Ph, 3af 52%
R = OMe, 3al 88%
R = CO2Me, 3am 75%
3ah 61%
3ak 60%
3ag 56%
3ai 84%
3aj 51%
utility in synthesis
Ar1 = 4-(CH3O)C6H4-
Me
OMe
O
Me
OMe
O
-
BF4 N2
Br
(bpy)NiI2
Mn (2 equiv)
[IrCp*Cl2]2
Me
as above
as above
CO2Et
CO2Et
Br
CO2Et
with Ar-OTf
(2 equiv)
with Ar-OTf
(2 equiv)
3
Cl
Ar1
Cl
F
Cl 4 72%
5 79%
6 58%
7 89%
CO2H
Ar1
Cl
Ph
Cl
Ph
Cl
NiBr2(diglyme)
Mn (2 equiv)
F
F
F
flurbiprofen
as above
9 77%
LiOH
with PhOTf
(1 equiv)
Me
3 steps,
THF/H2O
I
~$350/kg
2 isolations
Me
CO2H
Me
CO2Et
Me
CO2Me
Cl
CO2Et
8 71%
Reactions were run on 0.5 mmol of scale in 2 mL solvent for 2 to 24 h. Ar1 = 4-(CH3O)C6H4-. Ar2 = 4-(MeO2C)C6H4-. Using 5
a
b
mol% 6,6'-dibromo-2,2'-bipyridine instead of dtbbpy. c Aryl bromide was used instead of aryl chloride.
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