Low-Valent, High-Spin Chromium-Catalyzed Cleavage of Aromatic Carbon-Nitrogen Bonds at Room Temperature: A Combined Experimental and Theoretical Study

Article abstract of DOI:10.1021/jacs.7b08579

The cleavage of aromatic carbon-nitrogen bonds catalyzed by transition metals is of high synthetic interest because such bonds are common in organic chemistry. However, few metal catalysts can be used to selectively break C(aryl)-N bonds in electronically neutral molecules. We report here the first low-valent, high-spin chromium-catalyzed cleavage of C(aryl)-N bonds in electronically neutral aniline derivatives at room temperature. By using simple and inexpensive chromium(II) chloride as precatalyst, accompanied by an imino auxiliary, the selective arylative and alkylative C-C coupling of C(aryl)-N bonds can be achieved. Crossover experiments indicate that a low-valent chromium species, formed in situ by reduction of CrCl₂ with Grignard reagent, is responsible for the catalytic cleavage of C(aryl)-N bonds. DFT calculations show that facile insertion of the C(aryl)-N bond by chromium(0) can take place in a high-spin quintet (S = 2) ground state, whereas the lower-spin singlet (S = 0) and triplet (S = 1) states are inaccessible in energy. It was found that both donation of the sole paired d electrons in the d⁶ shell of high-spin chromium(0) to the antibonding orbital of the C(aryl)-N bond and the nitrogen ligating interaction to the metal center with its lone pair play important roles in the cleavage of the C(aryl)-N bond by the zerovalent chromium species.

Full text of DOI:10.1021/jacs.7b08579

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Article
Low-Valent, High-Spin Chromium-Catalyzed Cleavage of
Aromatic Carbon–Nitrogen Bonds at Room Temperature:
A Combined Experimental and Theoretical Study
Xuefeng Cong, Fei Fan, Pengchen Ma, Meiming Luo, Hui Chen, and Xiaoming Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08579 • Publication Date (Web): 03 Oct 2017
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Low-Valent, High-Spin Chromium-Catalyzed Cleavage of
Aromatic Carbon–Nitrogen Bonds at Room Temperature: A
Combined Experimental and Theoretical Study
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Xuefeng Cong,†,§ Fei Fan,†,§ Pengchen Ma,#,§ Meiming Luo,† Hui Chen,*,# and Xiaoming Zeng*,†,‡,§
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China; ‡Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710054, China;
#Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Photochemistry, CAS Re-
search/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Bei-
jing 100190, China; §State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
ABSTRACT: The cleavage of aromatic carbon–nitrogen bonds catalyzed by transition metals is of high synthetic interest be-
cause such bonds are common in organic chemistry. However, few metal catalysts can be used to selective break C(aryl)–N
bonds in electronically neutral molecules. We report here the first low-valent, high-spin chromium-catalyzed cleavage of C(aryl)–
N bonds in electronically neutral aniline derivatives at room temperature. By using simple and inexpensive chromium(II) chloride
as precatalyst, accompanied by an imino auxiliary, the selective arylative and alkylative C–C coupling of C(aryl)–N bonds can be
achieved. Crossover experiments indicate that a low-valent chromium species, formed in situ by reduction of CrCl2 with Grignard
reagent, is responsible for the catalytic cleavage of C(aryl)–N bonds. DFT calculations show that facile insertion of the C(aryl)–N
bond by chromium(0) can take place in a high-spin quintet (S = 2) ground state, whereas the lower-spin singlet (S = 0) and triplet
(S = 1) states are inaccessible in energy. It was found that both donation of the sole paired d electrons in the d6 shell of high-spin
chromium(0) to the antibonding orbital of the C(aryl)–N bond and the nitrogen ligating interaction to metal center with its lone
pair play important roles in the cleavage of the C(aryl)–N bond by the zero-valent chromium species.
1. INTRODUCTION
Scheme 1. Transition-Metal-Catalyzed Cleavage of
C(aryl)–N Bonds in Electronically Neutral Molecules
Selective cleavage of C(aryl)–N bonds by transition metals
is of great synthetic and mechanistic interest because these
bonds, which are usually chemically inert, are common in
organic chemistry.1–6 Methods that are used to break C(aryl)–
N bonds traditionally involve highly reactive cationic com-
pounds such as diazonium and ammonium salts.7–10 However,
the cleavage of C(aryl)–N bonds in electronically neutral mol-
ecules,11 either in stoichiometric12–16 or catalytic17–21 reactions,
have rarely been achieved. To date, two robust catalysts,
RuH2(CO)(PPh3)3 and Ni(cod)2, developed by Kakiuchi17 and
Chatani,19 have been used to break aniline and amide C(aryl)–
N bonds (Scheme 1a). Whereas electron-rich ligand of phos-
phine or carbene and elevated temperatures are required for
effective cleavage of C(aryl)–N bonds. Developing an alterna-
tive platform with low-valent metal catalysis was anticipated
to offer a strategy to break C(aryl)–N bonds under mild con-
ditions because of the potential for facile oxidative addition.
Although relative methods for Suzuki coupling,17,21 alkenyla-
tion,20 borylation19 and reduction18,19 have been developed,
there is no report of Kumada coupling via cleavage of C(aryl)–
N bonds in electronically neutral molecules such as anilines,
except for those using highly reactive ammonium salts.7,8d,22–
25 On the other hand, the cleavage process may suffer from a
regio- and chemoselectivity obstacle when several C(aryl)–N
and C(aryl)–O bonds coexist in the same catalytic system.
(a) Cleavage of aniline and amide C(aryl)–N bonds by metal catalysis
R'
R''
Ar
R (M)
Ar
N
+
R–M
[M]
N
Ar
R'
(M = B, H, Mg)
A
R''
neutral σ-donor
H
NtBu
NMe2
R
O
R
N
R'
NMe2
O
NMe2
cat. RuH2(CO)(PPh3)3
cat. Ni(cod)2/PCy3/IMes
cat. CrCl2/RMgX
Kakiuchi (2007)
Suzuki coupling
alkenylation, reduction
Chatani (2014)
This work
regioselective
Kumada coupling
borylation
reduction
(b) Plausible mechanism identified by DFT calculations
CrCl2 + 2ArMgX
two-electron
DG
DG
Ar
NMe2
reduction
LnCr0
(DG = Imino)
(quintet state)
DG
donation
ligation
Cr0
Ln-2
CrIILn-2
DG
low-valent,
high-spin
Ar
NMe2
Cr catalysis
Me2NMgX
DG
CrIILn-2
ArMgX
NMe2
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In recent years, low-valent metal-mediated catalysis using ing 10 mol % FeCl2 in the system resulted in the formation of
earth-abundant first-row transition metals such as nickel,26–29
iron,30–32 and cobalt33–35 has attracted immense attention, and
the approach appears to constitute a cost-effective tool for
the catalytic cleavage of inert chemical bonds. In contrast,
the synthetic chemistry of low-valent group 6 metal chromi-
um catalysis has remained underdeveloped,36–40 and the rela-
tive reactivity, catalytic behavior and mechanism of this met-
al have been largely unexplored.41–46 Herein, we report the
first low-valent chromium-catalyzed selective cleavage of
C(aryl)–N bonds in electronically neutral aniline derivatives at
room temperature (Scheme 1b). A simple and low-cost
chromium(II) chloride salt was used as precatalyst, accompa-
nied by an imino auxiliary, to achieve regio- and chemoselec-
tive cross-coupling of C(aryl)–N bonds with Grignard rea-
gents to form C(sp2)–C(sp2) and C(sp2)–C(sp3) bonds. Mecha-
nistic studies based on both experimental observation and
density functional theory (DFT) calculations suggested that a
low-valent chromium(0) species, formed in situ via two-
electron reduction of CrCl2 with organomagnesium,47–49
adopts the high-spin quintet state to break the C(aryl)–N
bond, in a process that features a low activation energy.
ortho-phenylated benzaldehyde 3a, albeit with low yield (en-
try 4). Gratifyingly, the use of CrCl2 led to catalytic cleavage
of C(aryl)–N bond proceeding effectively, with 3a being
formed in 95% yield (entry 5). In contrast, a relatively modest
level of conversion (72%) of 1a into 3a was observed by using
trivalent chromium chloride (entry 6). Notably, Cr(acac)3
showed almost no reactivity in the catalytic cleavage of
C(aryl)–N bond, suggesting that the anion played a role in the
formation of the catalytically active chromium species (entry
7). In addition to dimethylaniline derivative, the C(aryl)–N
bonds in diethylaniline and phenylpyrrolidine substrates were
also converted smoothly at room temperature, giving 3a in
excellent yields (entries 8 and 9). Without the chromium salt,
the C(aryl)–N bond in 1a was not cleaved by nucleophilic at-
tack of organomagnesium (entry 11). It was noted that the
formation of diphenyl as byproduct in less than 5% yield was
observed when using CrCl2 (entry 5), indicating that a two-
electron reduction could be considered in forming active low-
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Scheme 2. Chromium-Catalyzed Cleavage of C(aryl)–N
Bonds for Arylative C–C Coupling
2. RESULTS AND DISCUSSION
H
H
NtBu
O
Drawing inspiration from the discoveries presented in
Scheme 1a,19 complexes of Ni(cod)2 and NiCl2(PPh3)2 were
chosen as catalysts to explore the cleavage of C(aryl)–N
bonds in dimethylaniline derivative 1a at room temperature
(Table 1). In the presence of phenylmagnesium bromide, the
related C–C coupling reaction did not take place, with the
C(aryl)–N bond being retained in the resulting aromatic alde-
hyde after hydrolysis (entries 1 and 2). Interestingly, includ-
1) CrCl2 (10 mol%)
THF, rt, 15 h
+
ArMgBr
Ar
Ar
Ar
NMe2
2) HCl (aq.)
1
2
3
CHO
CHO
CHO
F
Me
MeO
3b (93%)
CHO
3d (86%)
CHO
3c (90%)
Table 1. Exploring the Effect of First-Row Transition-Metal
Salts and Amino Groups on C(aryl)–N Bond Cleavagea
H
H
NtBu
O
1) metal salt (10 mol%)
THF, rt, 15 h
R
3j, R = H (91%)
+
PhMgBr
NR1R2
3k, R = 4-Me (95%)
3l, R = 4-OMe (94%)
3m, R = 4-F (96%)
3n, R = 2-Cl (94%)
3o, R = 3-Cl (92%)
3p, R = 3-OH (90%)a
3q, R = 4-NHBoc (85%)
3r, R = 4-CONMe2 (53%)
CHO
2) HCl (aq.)
R
3e, R = H (90%)
1a
2a
3a
3f, R = 4-OMe (93%)
3g, R = 4-F (94%)
3h, R = 2-Cl (93%)
3i, R = 2-OH (87%)a
entry
–NR1R2
–NMe2
–NMe2
–NMe2
–NMe2
–NMe2
–NMe2
–NMe2
–NEt2
metal salt
Ni(cod)2
NiCl2(PPh3)2
CoCl2
yield (3a)
ndb
ndb
1
2
3
4
5
6
7
CHO
CHO
R
tracec
Me
3s, R = OMe (85%)
3t, R= Cl (89%)
FeCl2
12%
Me
3v (91%)
3u (90%)
CrCl2
95%
CHO
CHO
CHO
CrCl3
72%
tracec
Cr(acac)3
CrCl2
OMe
Cl
8
9
90%
OMe
3x (96%)
3y (92%)
3w (89%)
CHO
CHO
CHO
N
CrCl2
91%
F
10
11
–NBn2
–NMe2
CrCl2
none
6%
ndb
3z (93%)
F
Cl
3ab (85%)
3aa (88%)
aReactions were conducted on a 0.25 mmol scale. Isolated
Reaction conditions: 1 (0.25 mmol), 2 (0.55 mmol),
CrCl2 (0.025 mmol), rt, 15 h; and then quenched with HCl
(a.q.), 3 h. Isolated yields are given. aRMgBr (0.8 mmol) was
employed.
c
yields are given. bNot detected. Estimated by GC analysis.
The purities of metal salts: CrCl2 (99.99%), CrCl3 (99.99%),
Cr(acac)3 (97%), CoCl2 (99.9%) and FeCl2 (98%).
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valent chromium species in situ.44
Journal of the American Chemical Society
Scheme 4. Chromium-Catalyzed Cleavage of C(aryl)–N
1
2
3
4
Bonds for Alkylative C–C Coupling
With the optimized catalytic conditions in hand, the scope
of the chromium-catalyzed cleavage of C(aryl)–N bonds in
aniline derivatives was evaluated. As shown in Scheme 2,
H
H
NtBu
O
1) CrCl2 (10 mol%)
THF, rt, 15 h
introducing
either
electron-donating
or
electron-
+
Alkyl–MgBr
Ar
Ar
NMe2
Alkyl
5
2) HCl (aq.)
withdrawing substituents into the scaffolds of aromatics had
no influence on the cleavage of C(aryl)–N bonds, with for-
mation of the corresponding biphenyl carbaldehyde 3b–d
being achieved in 86–93% yields. A diverse range of substi-
tuted terphenyl carbaldehyde frameworks 3e–r could be ac-
cessed by coupling of ortho-C(aryl)–N bonds. A variety of
synthetically valuable functionalities, including alkoxy, fluo-
ride, chloride, hydroxyl, Boc-protected amino, and amide
groups, were compatible with the catalytic system. Further-
more, aromatic Grignard reagents containing alkyl, alkoxy,
fluoride, or chloride substituents coupled with C(aryl)–N
bonds smoothly, leading to the products 3u–ab in prepara-
tively useful yields (85–96%). Notably, these reactions allow
a synthetically useful aldehyde functionality to be retained in
the cross-coupling product.
6
7
8
9
1
4
5
CHO
CHO
5b, R = H (68%)
5c, R = 4-Me (75%)
5d, R = 4-OMe (76%)
5e, R = 4-F (78%)
5f, R = 3-Cl (71%)
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5a (50%)
R
CHO
CHO Me
Me
CHO
CHO
Me
5g [38% (60%)a]
5h [38% (45%)a]
5i (54%)
5j (41% total yield
b/l = 2.7:1)b
Reaction conditions: 1 (0.25 mmol), 4 (0.55 mmol), CrCl2
(0.025 mmol), rt, 15 h; then HCl (a.q.), 3 h. Isolated yields are
given. aRecovery of the related aromatic aldehyde containing
ortho-C(aryl)–N bond. bThe regioisomeric ratio was deter-
mined by 1H NMR spectroscopic analysis.
We then examined the regioselectivity associated with the
catalytic cleavage of C(aryl)–N bonds when several such
bonds are presented in the same catalytic system. Treatment
of 1,3-diamino-substituted aniline 1ac with phenylmagnesi-
um bromide gave ortho-phenylated benzaldehyde 3ac as the
sole cross-coupling product, keeping the para-amino group
intact (Scheme 3, eq 1). Moreover, the amino group on phe-
nyl Grignard 2b was maintained in the arylative C–C coupling
(eq 2). However, the use of dimethylaniline, without the
imino directing group, failed to give the coupling product.
elimination led to forming a mixture of branched and linear
regioisomers of 5j when an isopropyl nucleophile was used.
To examine the catalytic activity of chromium in the cleav-
age of cyclo-C(aryl)–N bonds, 7-imino-substituted indoline
derivatives 6 was reacted with phenylmagnesium bromide
(Scheme 5, eq. 3). Unfortunately, the corresponding ring-
opening/cross-coupling products 7 were not afforded. When
compared with the arylative coupling of noncyclic C(aryl)–N
bonds, we envisioned that a rotation of the cyclo-C(aryl)–N
bond to a suitable orientation for chelating with active chro-
mium is sterically unfavorable because of the effect of the
rigid and planar indoline structure.
Scheme 3. Regioselective Cleavage of ortho-C(aryl)–N
Bonds
H
H
O
NtBu
1) CrCl2 (10 mol%)
THF, rt, 15 h
+
2a
(eq 1)
NMe2
2) HCl (aq.)
Me2N
Me2N
Scheme 5. Catalytic Cleavage of cyclo-C(aryl)–N Bonds
1ac
3ac (80%)
H
H
NtBu
O
CHO
1) CrCl2 (10 mol%)
THF, rt, 15 h
1) CrCl2 (10 mol%)
THF, rt, 5 h
BrMg
+
1a
R
N
+
2a
(eq 2)
(eq 3)
NMe2
2) HCl (aq.)
NMe2
2) HCl (aq.)
2b
3ad (87%)
6
(R = H, Me)
7
NHR
(not detected)
The success of the arylation stimulated us to probe the
possibility of chromium-catalyzed alkylative coupling of
C(aryl)–N bonds with aliphatic Grignard reagents. To our
delight, in the presence of benzylmagnesium chloride, the
coupling reaction of C(aryl)–N bonds proceeded smoothly at
room temperature, forming 2-benzylbenzaldehyde (5a) in
moderate yield (Scheme 4). Regarding the aniline counter-
parts, the incorporation of an aryl substituent para to the
C(aryl)–N bond led to the formation of 5b–f in moderate yield,
and the compatibility of C(aryl)–O, C(aryl)–F, and C(aryl)–Cl
bonds in the substrates was also demonstrated. The methyl-
ation of the C(aryl)–N bond occurred to form the desired
product 5g. Interestingly, both cyclohexyl and cyclobutyl-
containing Grignard reagents were suitable partners; this
allowed the incorporation of a secondary aliphatic scaffold
ortho to the aldehyde group (5h and 5i). However, β-hydride
tBu
H
tBu
N
H
N
CrLn
CrLn
R
N
Vs
N
Me
Me
rotation favorable
rotation unfavorable
H
NtBu
3b
2a (1.2 equiv)
NMe2
Me
(10%)
1) CrCl2 (10 mol%)
THF, rt, 5 h
1b
+
+
(eq 4)
H
2) HCl (aq.)
3d
NtBu
(50%)
NMe2
F
1d
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(a)
(b)
H
H
H
H
1
2
3
NtBu
O
Ph
NtBu
O
1) CrCl2 (10 mol%)
THF, rt
1) CrCl2 (10 mol%)
THF, rt
+
PhMgBr
+
PhMgBr
NMe2
NMe2
Ph
2) HCl (aq.)
2) HCl (aq.)
4
5
1a
2a
3a
1a
(1.0 equiv)
2a
3a
(0.5∼3.0 equiv)
(2.4 equiv)
(1.0∼3.0 equiv)
6
-4.6
7
8
9
-4.6
-4.65
-4.7
y = 1.0151x - 4.5243
R² = 0.9919
-4.7
-4.8
-4.9
-5
y = -0.4501x - 5.0286
R² = 0.96981ꢀ
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-4.75
-4.8
-4.85
-4.9
-4.95
-5
-5.1
-5.05
-5.2
-0.7
-1
-0.8
-0.6
-0.4
-0.2
0
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
log (1a [M])
log (2a [M])ꢀ
(c)
(d)
H
H
H
H
NtBu
O
Ph
1) CrCl2 (2.5∼20 mol%)
THF (0.25 M), rt
NtBu
O
1) CrCl2 (10 mol%)
THF (0.25 M), rt
1
+ PhMgBr
+ PhMgBr
NMe2
2) HCl (aq.)
NMe2
Ph
Y
Y
2) HCl (aq.)
5
2
4
3
1a
(1.0 equiv)
2a
3a
2a
1
3
X
X
(2.4 equiv)
(1.0 equiv)
(2.4 equiv)
0.2
0.1
0
5-Clꢀ
y = 0.7736x - 0.0169
R² = 0.96174ꢀ
-4.5
y = 0.546x - 3.9003
R² = 0.962
4-OMeꢀ
-4.6
-4.7
-4.8
-4.9
-5
Hꢀ
5-Fꢀ
5-Meꢀ
-0.1
-0.2
-0.3
-5.1
5-OMeꢀ
-5.2
-2.3
-2.1
-1.9
-1.7
log (CrCl2 [M])ꢀ
-1.5
-1.3
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
σꢀ
Figure 1. Kinetic profile for chromium-catalyzed cleavage of C(aryl)–N bond/C–C bond coupling reaction. (a) Plot of initial rate vs the
initial concentration of aniline 1a indicate a deviation from the inverse first-order kinetics for substrate 1a. (b) Plot of initial rate vs con-
centration of PhMgBr reveal first-order kinetics for phenylmagnesium bromide. (c) Plot of initial rate vs concentration of CrCl2 indicate a
deviation from the first-order kinetics for chromium salt. (d) Hammett-plot of substituted aniline derivatives.
To gain insight into the mechanistic details associated with
the chromium-catalyzed cleavage of C(aryl)–N bond and C–C
bond coupling, we studied the kinetic profile by choosing the
reaction of aniline 1a with PhMgBr as the model system. The
initial reaction rate (Δ[3a]/Δt) against the initial concentra-
tion of the aniline 1a ranging from 0.125 to 0.75 M showed a
negative correlation between [1a] and Δ[3a]/Δt (Figure 1a). A
slope of –0.45 was obtained from logarithm plot and linear
fitting of these data, indicating a deviation from the inverse
first-order dependence of the initial rate on the concentration
of aniline. Because of the high complexity of the reaction, we
cannot conclude definitively regarding this inhibitory effect.
A possible scenario that could be envisioned is the existence
of an off-cycle equilibrium between active chromium com-
plex and inactive species, mostly including (but are not re-
stricted to) reversible association of 1a with complex A
([Cr(1a)(THF)2]) by serving as bidentate ligand to form inac-
tive, off-cycle species [Cr(1a)2(THF)2] or even [Cr(1a)3], as well
as reversible binding of 1a as monodentate ligand to active
complex in forming off-cycle chromium species.50 No obvious
inhibitory effect was observed when putting N,N-
dimethylaniline or N-tert-butylbenzylimine (1 equivalent) into
the reaction (see Scheme S1 in Supporting Information). In-
terestingly, the use of catalytically amount or equivalent of
2,2'-bipyridine,
1,10-phenanthroline,
N,N-bis(2,6-
diisopropylphenyl)ethane-1,2-diimine or 2-methoxyphenyl-
substituted 2-(iminomethyl)-N,N-dimethylaniline as additive
partially or completely inhibited the coupling reaction of C–N
bond (see Scheme S2 in Supporting Information). These may
indicate that the former one is mostly likely. In contrast, the
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THF
Cr
THF
Me
Ph
2N
singlet
H
tBu
triplet
N
44.5
quintet
THF
Mg
ΔG
(kcal/mol)
34.2
tBu
N
Br
THF
H
28.6
THF
tBu
N
Cr
THF
TSnucleo
PhMgBr(THF)
H
THF
NMe2
tBu
N
Cr
THF
Cr
13.6
TS1
H
Ph
tBu
N
THF
tBu
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THF
Cr
THF
Cr
N
H
H
THF
7.2
TS2
THF
Ph
0.0
A
NMe2
NMe2
–14.3
Int-1
THF
Ph
–21.6
tBu
N
Mg Br
THF
PhMgBr(THF)
–18.2
Int-2
Me
2N
Cr
H
tBu
THF
–15.8
B
THF
THF
N
Cr
–24.4
Ph
H
TStransmet
PRtransmet
–37.1
Me2NMgBr(THF)
tBu
THF
Cr
RCtransmet
tBu
H
N
THF
THF
N
H
THF
NMe2
NMe2
Cr
Ph
Ph
Mg Br
THF
Mg Br
THF
Figure 2. Reaction energy profiles for the cleavage of the C(aryl)–N bond by catalytically active chromium(0) species and subsequent C–
C coupling.
initial reaction rate clear showed a positive response to [2a],
as well as to the chromium salt of CrCl2 at low concentrations
(from 6.25 to 50 mM) (Figures 1b and c). The logarithm plot
and linear fitting of the data indicated a first-order depend-
ence on PhMgBr and a deviation from the first-order de-
pendence of the initial rate on the concentration of CrCl2
(slope = 0.55), which imply that both Grignard reagent and
chromium are likely involved in the turnover-limiting step of
the Kumada coupling of C(aryl)–N bond.
The impact of electronic variation of the aniline compo-
nent on the cleavage of C(aryl)–N bond and C–C bond cou-
pling was probed by Hammett studies. A linear correlation
was observed with σ Hammett constants (ρ = +0.77, R2 = 0.96)
indicating that the Kumada coupling with para-electron-
deficient anilines resulted in a higher initial reaction rate
(Figure 1d). Competition experiments suggested that elec-
tron-deficient aromatic rings favor C(aryl)–N bond cleavage
and subsequent coupling with phenylmagnesium bromide
(eq. 4).
Scheme 6. Probing the Catalytic Activity of Chromium
Species that was Formed in-Situ in the Cleavage of C(aryl)–
N bonds
H
NtBu
Consistent with our previous investigation on the nature of
catalytically active chromium species, a low-valent chromi-
um(0) can be formed in the reaction of CrCl2 with two equiva-
lents of PhMgBr through a two-electron reduction process.44
We then conducted crossover experiments to examine the
catalytic activity of the active species in the cleavage of
C(aryl)–N bonds. After stirring a mixture of CrCl2 (0.1 equiv)
and PhMgBr (0.2 equiv) for 0.5 h, substrate 1d and a second
aromatic or aliphatic Grignard reagent (2c or 4a) were added
to the system and the reaction was continued for 15 h
(Scheme 6). The corresponding coupling products 3ae and
5k were isolated in 82 and 66% yield, respectively. Interest-
ingly, coupling compound 3d, which would form from the
coupling of C(aryl)–N bonds with phenylmagnesium, was not
detected, even when stoichiometric amounts of CrCl2 (0.5
equiv) and PhMgBr (1.0 equiv) were used (Scheme 6, eq. 5).
However, the formation of 3d was detected when increase
amounts of PhMgBr to 0.3 or 0.5 equiv combined with 0.1
equiv of CrCl2. These results suggest that phenyl Grignard,
serving as a reductant, was consumed by reacting with CrCl2
CHO
NMe2
1d
F
CrCl2
OMe
F
(X equiv)
(0.25 mmol)
3ae
CHO
THF
(eq 5)
+
rt, 30 min
MeO
MgBr
2c
(2.2 equiv)
PhMgBr
(Y equiv)
F
3d
rt, 15 h; HCl (a.q.), 3 h
X
Y
yield (3ae)a
yield (3d)
0.1
0.1
0.1
0.5
0.2
0.3
0.5
1.0
82%
83%
78%
72%
ndb
trace
8%a
ndb
aIsolated yield was based on 1d. bNot detected.
H
NtBu
CHO
NMe2
1d
(0.25 mmol)
F
CrCl2
(0.1 equiv)
THF
F
+
5k (66%)a (eq 6)
MgCl
rt, 30 min
CHO
PhMgBr
(0.2 equiv)
4a
(2.2 equiv)
F
rt, 15 h; HCl (a.q.), 3 h
3d (nd)b
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y
N
C
x
3
4
Cr
THF
THF
5
6
7
8
φ3
φ2
N
dxy(Cr)
C
σ∗(CN)
Cr
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n(N)
N C
φ1
Figure 4. The orbital interaction diagram for the transition
state (TS1) of cleavage of C(aryl)–N bond by chromium(0).
to facilitate the oxidative addition for s-bond insertion,51 as
exemplified by late-first-row transition-metals of iron(0),52
cobalt(0)53 and nickel(0),54 and by low-valent early-second-
row transition metals of molybdenum and rhodium as well.55
This result, in combination with the recent example of Mn(II)-
catalyzed oxidative addition of C(alkyl)–O bonds,56 which did
not involve the low-spin state, indicates that some early-
first-row transition metals such as chromium may tend to
adopt a high-spin state for the insertion of chemical bonds.
In contrast to the two-state reactivity of Fe(II)-mediated C–H
activation process,57 which necessitates the use of an exter-
nal ligand to stabilize the reactive low-spin metal in addition
to a directing group, current high-spin state reactivity of Cr(0)
is in line with the external ligand-free reaction conditions.
This is reminiscent of two previous studies of Mn(II)-
catalyzed cleavage of C(alkyl)–O bond56 and C(aryl)–H
bond,58 which bear an intriguing similarity with respect to the
involvement of reactive high-spin states.
Figure 3. Optimized structures of complex A, intermediate
Int-1, and the related transition states for C(aryl)–N bond
cleavage and C–C bond formation (the H atoms are not
shown for clarity, and key bond distances are labeled in Å).
to form the active low-valent chromium species that is re-
sponsible for the resulting catalytic cleavage of the C(aryl)–N
bond in 1d.
To further verify the cleavage of C(aryl)–N bonds by zero-
valent chromium, DFT theoretical calculations were per-
formed. As shown in Figure 2, DFT calculations suggest that
zero-valent chromium reactant A, supported by the imino
and amino groups, and by two THF solvent molecules as
ligands (the possibility of using three THF molecules as lig-
ands was also tried but found less favorable in free energy,
see Figure S6 in Supporting Information for the comparative
results), has a tetragonal pyramid structure with the amino
group at the axial position (Figure 3). Interestingly, the imino
ligating group in A does not act as a s-donor but rather as a
π-acceptor, coordinating with Cr(0) through the empty
π*(C=N) orbital to accept and stabilize the paired d electrons
of the high-spin Cr(0). In addition to the coordination mode
in reactant A, we will see below that the sole paired d elec-
trons of the high-spin Cr(0) play an important role in the
C(aryl)–N bond cleavage process. Only a relatively low acti-
vation barrier (13.6 kcal/mol) involving a three-membered
ring transition state TS1 (wherein the C(aryl)–N bond was
lengthened from 1.446 to 1.772 Å) to break the C(aryl)–N
bond in an oxidative addition manner needs to be overcome.
Interestingly, the calculated large energy gaps (> 30 kcal/mol)
from the quintet state to low/medium-spin states (singlet
and triplet) of chromium(0) suggested that these lower-spin
states contribute very little to the reactivity of C(aryl)–N
bond cleavage by chromium(0), which is dominated by the
high-spin quintet (S = 2) state. The involvement of the high-
spin state in C(aryl)–N bond cleavage is unusual given that
transition metals in a low-spin state have long been known
With regard to the mechanism of breakage of the C(aryl)–
N bond, as an alternative to oxidative addition, a possible
pathway featuring nucleophilic substitution with phenyl-
magnesium bromide was also examined. However, the high-
er calculated reaction barrier of 28.6 kcal/mol precludes nu-
cleophilic attack as the mechanism responsible for catalytic
cleavage of the C(aryl)–N bond (Figure 2). In the oxidative
addition manner of cleavage of C–N bond, interestingly we
found that the experimentally unreactive cyclic substrate 6
(R = H) has a higher C–N bond breaking reaction barrier of
21.7 kcal/mol, indicating that it is more difficult to cleave the
φ1
φ2
N
N
σ∗(CN)
dxy(Cr)
n(N)
C
C
dxy(Cr)
Cr
Cr
σ∗(CN)
n
(N)
dxy(Cr)
ligation
dxy(Cr)
donation
Figure 5. Two key orbital interactions for chromium(0)-
catalyzed cleavage of C(aryl)–N bond.
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We have developed a mild and selective low-valent chro-
C–N bond in cyclic amine. The comparison of the geometries
1
2
3
4
5
6
7
8
of the corresponding transition states and reactants between
acyclic amine substrate 1 and cyclic amine substrate 6 sug-
gest that rotational restriction (Scheme 5) really plays a role
in the pre-activation of C(aryl)–N bond by chromium (please
see Figure S7 in the Supporting Information for details), as
indicated by the large difference in C(aryl)–N bond rotation
between the reactants of 1 and 6.
mium catalysis for the cleavage of aniline C(aryl)–N bonds.
This protocol was enabled by using a simple and inexpensive
chromium(II) chloride salt combined with Grignard reagents,
achieving the regio- and chemoselective Kumada cross-
coupling of C(aryl)–N bonds at room temperature, leading to
ortho-arylated or alkylated aromatic aldehyde motifs. A low-
valent chromium species, which was formed in situ by a re-
duction of CrCl2 with phenylmagnesium, is responsible for
the catalytic cleavage of C(aryl)–N bonds. Theoretical studies
suggested that low-valent chromium(0) in a high-spin quin-
tet state breaks the C(aryl)–N bond through facile oxidative
addition by overcoming a relatively low activation energy.
The high-spin state reactivity in the current chromium sys-
tem echoes the external ligand-free conditions, which sets a
different paradigm for reactivity adjustment from the low-
spin state-controlled reactivity that is usually sensitive to the
supporting ligand environment. Analyses of the orbital inter-
actions in the corresponding transition state indicate that
two key points dominate the C(aryl)–N bond cleavage by
zero-valent chromium: (1) the donation of the sole d-electron
pair of high-spin Cr(0) to the s-antibonding orbital (s*(CN))
of C(aryl)–N bond to weaken such a bond; (2) ligation inter-
action of the amino scaffold through the lone pair on the
nitrogen to the chromium metal center. Studies on the appli-
cations of the low-valent chromium catalysis in synthetic
chemistry are under way.
After the initiating (aryl)–N bond cleavage, the amido
group in cyclochromate Int-1 was removed from Cr center by
a transmetalation with Grignard reagent, which then under-
goes a reductive elimination via transition state TS2 to form
the C–C bond (Figure 2). Of note is that the Grignard rea-
gent-binding cluster RCtransmet as the reactant for the
transmetalation process is quite stable, from which the fol-
lowing transmetalation and reductive elimination both need
to go uphill along the reaction profile. This result gives a pos-
sible explanation why Grignard reagent is kinetically im-
portant in the reaction by exerting a first-order correlation
with reaction rate. The reaction barrier of reductive elimina-
tion from Int-2 to B through TS2 for the final C–C coupling is
25.4 kcal/mol. Comparing the energy profile for the first step
(A→Int-1) with that of a reverse process for the last step
(B→Int-2), it appears that the low-valent chromium species
tends to cleave the more polar s-bond (C(aryl)–N) rather
than the less polar bond (C(aryl)–C(aryl)), with the former
process being favored both kinetically and thermodynami-
cally.
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4. EXPERIMENTAL SECTION
Understanding the processes underlying the facile cleav-
age of the C(aryl)–N bond by Cr(0) requires closer theoretical
scrutiny of their electronic structures. As shown in Figure 4,
at the geometry of the transition state TS1 for the catalytic
cleavage of C(aryl)–N bond, the carbon and nitrogen moie-
ties of C(aryl)–N bond, chromium, and two oxygen atoms of
THF are positioned almost in the same plane (defined by x
and y axes), in which the dxy(Cr) orbital contains the sole pair
of d electrons in the high-spin quintet chromium(0) center.
As depicted in Figures 4 and 5, two orbital interactions main-
ly dominate the catalytic cleavage of C(aryl)–N bond in the
related transition state. One interaction is the donation of
the two electrons in the dxy(Cr) orbital of chromium to the s-
antibonding orbital (s*(CN)) of the C(aryl)–N bond, as de-
picted in molecular orbital f2. The second is the dative inter-
action of the lone pair of nitrogen (n(N)) to the chromium(0)
center, as shown in molecular orbital f1. The orbital interac-
tion diagram reveals two key points that effect the catalytic
cleavage of the C(aryl)–N bond by low-valent chromium(0):
(1) the sole doubly occupied d orbital of the d6 configuration
for chromium(0) at its high-spin quintet state; (2) the lone
pair of nitrogen on the C(aryl)–N moiety. As a result, the rea-
son for the catalytic cleavage of the C(aryl)–O bond that was
found in our previous work is clear.44 The lone pair of the
heteroatom on the skeletal carbon–heteroatom backbone is
a prerequisite for chromium(0)-mediated cleavage of the
carbon–heteroatom bond. The absence of this lone pair, or
its inability to interact with the Cr(0) center (Scheme 5, eq. 3),
can both lead to reduced reactivity and prevent the cleavage
of the carbon–heteroatom bond.
General Procedure for Chromium-Catalyzed Cleavage of
C(aryl)–N Bonds for the Arylative or Alkylative Coupling.
THF (0.3–0.45 mL) was added to a dry Schlenk tube contain-
ing aniline derivative 1 (0.25 mmol) and CrCl2 (0.025 mmol).
After stirring at room temperature for 5 min, Grignard rea-
gent (0.55 mmol, 0.8–1 M in THF) was added dropwise by
using a syringe, and the resulting mixture was stirred for 15 h.
The reaction was then quenched by the addition of aqueous
HCl (3 N, 1 mL) and stirred for another 3 h. The mixture was
then neutralized with K2CO3 and extracted with ethyl acetate
(3 x 10 mL). The combined organic layer was dried over an-
hydrous Na2SO4 and concentrated under vacuum. The crude
product was purified by silica gel chromatography to give the
desired coupling product.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, characteri-
zation data for all products, detailed optimized geometries, and
computational details and results. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mails: zengxiaoming@mail.xjtu.edu.cn (X.Z.),
chenh@iccas.ac.cn (H.C.)
Author Contributions
§X. Cong, F. Fan and P. Ma contributed equally.
Notes
The authors declare no competing financial interests.
3. CONCLUSIONS
ACKNOWLEDGMENT
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(12) For a recent review of the cleavage of C–N bond by transi-
We thank the National Natural Science Foundation of China (No.
21572175 to X.Z., and Nos. 21290194, 21473215 and 21521062 to
H.C.), XJTU, BNLMS and the Institute of Chemistry for financial
support of this research.
1
2
3
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CrCl2 + 2ArMgX
DG
DG
Ar
NMe2
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LnCr0
(DG = Imino)
low-valent,
high-spin
chromium catalysis
N
DG
Cr0
IIL
Ln-2
Cr
Cr
n-2
DG
room temperature
C–N activation
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Ar
NMe2
Me2NMgX
DG
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CrIILn-2
ArMgX
NMe2
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