NHC-Nickel Catalyzed C-N Bond Cleavage of Mono-protected Anilines for C-C Cross-Coupling

Article abstract of DOI:10.1021/acs.orglett.0c03660

A Ni-catalyzed aryl C-N bond cleavage of mono-protected anilines, N-arylsulfonamides, has been developed. A new N-heterocyclic carbene derived from benzoimidazole shows high reactivity for the C-N cleavage/C-C cross-coupling reaction. The ortho-directing group is not required to break the C-N bond of sulfonyl-protected anilines, which are not limited to π-extended anilines. The mechanistic studies have revealed that a sulfamidomagnesium salt is the key coupling intermediate.

Full text of DOI:10.1021/acs.orglett.0c03660

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Letter
NHC-Nickel Catalyzed C−N Bond Cleavage of Mono-protected
Anilines for C−C Cross-Coupling
Zheng-Bing Zhang and Ji-Bao Xia*
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ABSTRACT: A Ni-catalyzed aryl C−N bond cleavage of mono-
protected anilines, N-arylsulfonamides, has been developed. A new
N-heterocyclic carbene derived from benzoimidazole shows high
reactivity for the C−N cleavage/C−C cross-coupling reaction. The
ortho-directing group is not required to break the C−N bond of
sulfonyl-protected anilines, which are not limited to π-extended
anilines. The mechanistic studies have revealed that a sulfamidomagnesium salt is the key coupling intermediate.
he sulfonamide is one of the ubiquitous functional groups
much weaker chemical bond, which is more easily broken. In
comparison, cleavage of the C−N bond in the N-arylsulfona-
mides is rare and challenging.5 Remarkably, Fan and co-workers
developed an interesting stepwise oxidative aromaticity
destruction−reconstruction process for the cleavage of N-Ts
anilines to form a C−C bond (Scheme 1b).6 To the best of our
knowledge, there is no precedent example for metal-mediated
coupling of the C−N bond in N-arylsulfonamides to form a C−
C or C−heteroatom bond.
1
Tin organic and medicinal chemistry. As a robust and
extensively utilized protecting group for amines, sulfonamide is
a useful synthetic intermediate.2 For instance, N-arylsulfona-
mides, easily accessed from anilines, have been used as sulfonyl
group transfer reagents for protection of amines and alcohols
(Scheme 1a).3 Meanwhile, addition of Grignard or organic
lithium reagents to sulfonamides produces sulfones by S−N
bond cleavage.4 Obviously, the S−N bond in sulfonamides is a
The formation of an aryl C−N bond is among the central
topics in modern synthetic chemistry.7 Inversely, The trans-
formation of neutral aryl C−N bonds to other chemical bonds
is rarely investigated because they are chemically inert.8
Conventionally, the methods used to break aryl C−N bonds
usually involve highly reactive cationic compounds, such as
diazonium and ammonium salts (Scheme 1c).9 Because of the
strong coordinating ability of both aniline and its anionic amino
species (R2N−), metal-mediated cleavage of the neutral aryl C−
N bond is more difficult in the absence of a directing group on
anilines.10 In the past decade, a progressive ortho-directing
group assisted strategy has been developed by Kakiuchi,11
Snieckus,12 Zeng,13 Szostak,14 and Wu et al.15 for the metal-
catalyzed cross-coupling of neutral aryl C−N bonds. As a
limitation, additional manipulations are needed for prior
installation of the ortho-directing group on the anilines and
for its removal after the reactions. Impressively, Ni-catalyzed
cross-coupling of the neutral aryl C−N bond in the absence of
an ortho-directing group has been achieved by Chatani,16 Shi,17
and our group.18 However, these reactions are restricted to π-
Scheme 1. Selective Cleavage of S−N or C−N Bond in N-
Arylsulfonamides
Received: November 3, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03660
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
extended anilines with N,N-diprotection. To date, there is no
report for coupling of the aryl C−N bond in simple NH-
containing anilines in the absence of a directing group.
Table 1. Reaction Development
Direct aryl C−N bond cleavage of mono-protected anilines
(ArNHR) is know to face several challenges. First, a formidable
enthalpy barrier is encountered.10 Second, because of the
presence of a free amine (NH) group, mono-protected anilines
are prone to amination under metal catalysis.19 To solve these
problems, we anticipated to introduce an electron-withdrawing
protecting group onto the nitrogen of aniline. First, this type of
protecting group would weaken the intrinsic bond strength of
the aryl C−N bond. Second, due to the acidity of the NH being
increased by the electron-withdrawing protecting group, the
corresponding amido salt would be formed easily in the
presence of a suitable deprotonation reagent. Then, the aryl C−
N bond might be further activated by the formation of amido
salt. In addition, the amido anion has a good σ-donor ability,
which may bind to the metal catalyst to activate the aryl C−N
bond. Thus, the selective cleavage of the aryl C−N bond of
simple anilines in the absence of a directing group would be
achieved. Based on this strategy, we report herein the first
nondirected aryl C−N bond cleavage of mono-protected
anilines under mild NHC−nickel catalysis (Scheme 1d).
We started the research by investigating the aryl C−N bond
cleavage of trifluoromethanesulfonyl (Tf) protected p-toluidine
1a under nickel catalysis. With PhMgBr 2 as both a coupling
and deprotonation reagent, a trace amount of desired biaryl
product 3 was observed with Ni(PCy3)2Cl2 as catalyst and
toluene and THF as mixed solvent at 130 °C (Table 1, entry 1;
for details, see Table S1 in Supporting Information). Different
ligands were then tested, and 3 was obtained in 24% yield with
N-heterocyclic carbene (NHC) precursor ICy·HCl (Table 1,
entry 2). The yield of 3 was increased to 30% when switching
the mixed solvent to toluene/nBu2O (Table 1, entry 3). Further
improvement was observed when the NHC precursor
benzimidazolium salt (L1) was employed, which gave rise to
the desired product 3 in 67% yield (Table 1, entry 4). Then,
new NHC ligands L2−8 were designed and synthesized by
modification of the ligand L1 with assembly of a methyl, tert-
butyl, or phenyl group at its 4-, 5-, 6-, and/or 7-position to
enhance the σ-donor ability of the ligand. After screening these
new NHC ligands, we found that ligand L7 with a methyl group
at 4-position improved the yield of 3 to 78% (Table 1, entry
10). Subsequently, an attempt to lower the dosage of Grignard
reagent to 3 equiv led to a significant decrease in the yield of
product 3 (Table 1, entry 12). However, when 2 equiv of
MeMgBr were used as an additive, product 3 was obtained in
65% yield with 3 equiv of PhMgBr (Table 1, entry 13). The
yield was not improved by addition of a catalytic amount of
organic base, such as DABCO (Table 1, entry 14). A further
increase of the reaction scale and evaluation of the reaction
temperature showed that the yield of 3 was improved to 86%
with 0.2 mmol of 1a at 70 °C (Table 1, entry 16). Finally, 3 was
obtained in 82% yield with Ni(cod)2 as the catalyst precursor,
indicating that an active NHC-Ni(0) catalyst may exit in the
catalytic cycle (Table 1, entry 17).
b
Entry
Ligand
Additive (x equiv)
T (°C) Yield (%)
c
1
−
−
−
−
−
−
−
−
−
−
−
−
−
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
70
trace
24
30
67
57
6
17
6
16
78
68
8
65
66
84
86
82
c
2
ICy·HCl
ICy·HCl
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
L7
L7
L7
3
4
5
6
7
8
9
10
11
d
12
d
13
MeMgBr (2)
MeMgBr (2), DABCO (0.25)
d
14
e
15
−
−
−
e
16
e f
,
17
70
a
All reactions were carried out with 1a (0.1 mmol) and 2 (0.5 mmol)
if otherwise noted. Determined by GC with n-dodecane as an
b
c
internal standard. With toluene/THF (1 mL/1 mL) as solvent.
d
e
f
With 2 (0.3 mmol). With 1 (0.2 mmol), 2 (1.0 mmol). With
Ni(cod)2 (10 mol %) as catalyst.
a
Scheme 2. N-Substituent Effect on the Anilines
a
Conditions: 1 (0.2 mmol), 2 (1.0 mmol), Ni(PCy3)2Cl2 (10 mol %),
L7 (15 mol %), toluene/nBu2O (1 mL/1 mL), 70 °C, 12 h, and the
yield was determined by GC with n-dodecane as an internal standard.
Then, we investigated different protecting groups on the
nitrogen of 4-methylaniline in this Ni-catalyzed nondirected
C−N cleavage/C−C cross-coupling reaction (Scheme 2). It
comes as no surprise that no reaction occurred with N-methyl
aniline 1b. A lower yield was observed with N-pivaloyl or N-
pivalate protected 4-methylaniline as substrate (1c and 1d).
However, no reaction occurred with aniline bearing a N-
methanesulfonyl or N- benzenesulfonyl group on the nitrogen
(1e and 1f). When we used the N-Me-N-Tf-aniline 1g as
substrate, 3 was obtained in 35%yield. These results suggest
B
https://dx.doi.org/10.1021/acs.orglett.0c03660
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a
Scheme 3. Reaction Scope
a
b
All reactions were run with 1 (0.2 mmol) and ArMgBr (1.0 mmol) in toluene/nBu2O (1 mL/1 mL), isolated yield. Determined by GC with n-
c
d
e
f
g
h
dodecane as an internal standard. With 1 (0.2 mmol), ArMgBr (0.6 mmol), MeMgBr (0.6 mmol). Gram scale. 24 h. 36 h. 90 °C. 130 °C.
that the N-trifluoromethylsulfonyl (N-Tf) group as a strong
electron-withdrawing group may feature an activation group to
weaken the aryl C−N bond strength and enhance the acidity of
NH to form an amido salt intermediate.
ring with aryl C−N bonds occurred smoothly, giving the biaryl
products 22−26 in moderate to good yields (40−92%).
Unfortunately, no reaction occurred when alkenyl or alkyl
Grignard reagents were used in this Ni-catalyzed nondirected
C−N cleavage/C−C cross-coupling reaction.
Having identified conditions to achieve the selective aryl C−
N bond cleavage, we evaluated the Ni-catalyzed C−C coupling
of N-Tf-anilines with Grignard reagents (Scheme 3). First, we
test the reactivity of different anilines with a methyl substituent
at the para-, meta-, or ortho-position, affording the biaryl
products 3−5 in good yields (82−86%). Next, the cross-
coupling of aniline substrates bearing an alkyl substituent, such
as tert-butyl, n-dodecyl, and benzyl, at the para-position was
conducted, and the desired biaryl products 6−8 were obtained
in 80−95% yields. In addition, a variety of functionalities were
tolerated on the aniline, such as phenyl, functionalized alkyl,
alkenyl, and silyl groups, leading to the corresponding biaryls
9−12 in moderate to excellent yields (64−95%). Remarkably,
selective cleavage of the aryl C−N bond of N-Tf-anilines was
achieved affording the corresponding products 13−15 in 57−
81% yield, with the N,N-dialkyl group on the benzene ring
untouched. The cross-coupling of the C−N bond in π-extended
2-naphthylamine also occurred smoothly delivering 16−17 in
good yields. Moreover, the cleavage of the N-containing
heteroaryl C−N bond, such as 5-indolamine and 2-carbazol-
amine, took place selectively leading to the corresponding
products 20 and 21 in 83% and 55% yield. Furthermore, the
coupling of aromatic Grignard reagents containing alkyl
substituents at the para-, meta-, or ortho-position of benzene
Biaryls are ubiquitous core structures in drug molecules, such
as antifungal bifonazole (27) and antiphlogistic analgesic
felbinacethyl (28). Gram-scale synthesis of biaryl 8 was
achieved in 75% total yield in two steps through mono-
protection of 4-benzylaniline with Tf2O and our Ni-catalyzed
cross-coupling of N-Tf-aniline with PhMgBr via C−N bond
cleavage (Scheme 4). Subsequently, benzylic oxidation of 8 to
ketone followed by Eschweiler−Clarke reductive alkylation of
imidazole delivered 27 in 66% yield. Similarly, the biaryl 12 was
Scheme 4. Synthetic Applications
C
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obtained in 73% yield over two steps via mono-protection of 4-
(trimethylsilyl)aniline followed by Ni-catalyzed cross-coupling
via C−N bond cleavage. Then, desilylative iodination of 12 led
to the corresponding aryl iodide, which was subjected to the
Cu-catalyzed α-arylation of ethyl acetoacetate generating 28 in
67% yield after deaceylation.
transition state 33. Finally, the C−C bond reductive elimination
produces the desired biaryl product 35 and regenerates the
NHC-Ni catalyst 30.
In summary, we have developed the first nickel-catalyzed C−
C cross-coupling reaction by aryl C−N bond cleavage of N-Tf-
anilines with a new NHC ligand (4-Me-Benz-ICy). The ortho-
directing group is not needed on the aniline substrates. And the
aniline substrates are not limited to π-extended aryl amines.
The N-trifluoromethylsulfonyl (N-Tf) group features as an
activation group to weaken the aryl C−N bond strength and
enhance the acidity of NH to form the amido salt intermediate.
Mechanistic studies have revealed that the in situ generated
sulfamidomagnesium salt is the key coupling intermediate. We
have disclosed a new strategy for the direct cleavage of the
neutral aryl C−N bond to synthesize useful biaryl compounds.
Further studies based on this strategy are ongoing in our
laboratory.
Control experiments have been conducted to understand the
reaction mechanism. Based on our previous computational
studies on cross-coupling of the aryl C−N bond with a
Grignard reagent18 and the conditions used for the current
reaction, this reaction should take place via a Ni(0)/Ni(II)
catalytic pathway. We attempted to verify the starting reactant
in the catalytic cycle. The NH-containing sulfonamide could be
deprotonated easily to form a sulfamidomagnesium salt in the
presence of Grignard reagent. To capture the sulfamidomagne-
sium salt intermediate, deprotonation of N-Tf-2-naphthalen-
amine (1t) was performed with MeMgBr in THF. As expected,
the corresponding sulfamidomagnesium salt 29 was isolated
with two coordinated THF molecules (monomer or dimer),
ASSOCIATED CONTENT
* Supporting Information
■
1
which was confirmed by H NMR (eq 1). Then, the cross-
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03660.
Experimental procedures, characterization data for new
compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ji-Bao Xia − State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; orcid.org/0000-0002-
2262-5488; Email: jibaoxia@licp.cas.cn
coupling of 29 with PhMgBr afforded 16 in 93% isolated yield
(eq 2). These results indicate that the monomeric sulfamido-
magnesium salt is a key intermediate in this aryl C−N bond
cross-coupling reaction.
Based on the mechanistic studies, a possible catalytic pathway
is proposed as shown in Scheme 5. In the presence of an NHC
Author
Scheme 5. Proposed Catalytic Pathway
Zheng-Bing Zhang − State Key Laboratory for Oxo Synthesis
and Selective Oxidation, Center for Excellence in Molecular
Synthesis, Suzhou Research Institute of LICP, Lanzhou
Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China; University of Chinese
Academy of Sciences, Beijing 100049, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03660
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from NSFC (21772208),
Key Research Program of Frontier Sciences of CAS
(QYZDJSSW-SLH051). We thank Dr. Chong-Lei Ji and Prof.
Xin Hong of Zhejiang University for helpful discussions on the
mechanism.
ligand and Grignard reagent, the nickel catalyst precursor
Ni(PCy3)2Cl2 is first reduced to NHC coordinated Ni(0)
species 30. Meanwhile, deprotonation of N-Tf-aniline 1 with
the Grignard reagent generates sulfamidomagnesium salt 31.
The following oxidative addition of the aryl C−N bond with 30
leads to arylnickel intermediate 32, which may be facilitated by
coordination of nickel catalyst with the magnesium or the ether
solvent on the sulfamidomagnesium salt 31.20 Subsequent
transmetalation with the aryl Grignard reagent generates
diarylnickel 34, which may be through a six-membered
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