Reductive Cross-Coupling between Unactivated C(aryl)-N and C(aryl)-O Bonds by Chromium Catalysis Using a Bipyridyl Ligand

Article abstract of DOI:10.1021/jacs.0c05730

Reductive cross-coupling between two chemically inert bonds remains a great challenge in synthetic chemistry. We report here the reductive cross-coupling between unactivated C(aryl)-N and C(aryl)-O bonds that was achieved by chromium catalysis. The simple and inexpensive CrCl2 salt, combined with important bipyridyl ligand and magnesium reductant, shows high reactivity in the successive cleavage of C(aryl)-N bonds of aniline derivatives and C(aryl)-O bonds of aryl esters, allowing the cross-coupling of these two unactivated and different bonds to occur in a reductive fashion to form a C(aryl)-C(aryl) bond. Mechanistic studies by deuterium-labeling experiments indicate that the C(aryl)-N bonds in anilines are preferentially cleaved by reactive Cr species, in which the ligation of bipyridyl with Cr by adopting a coordination model in 1:1 ratio can be considered.

Full text of DOI:10.1021/jacs.0c05730

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Article
Reductive Cross-Coupling between Unactivated C(aryl)–N and
C(aryl)–O Bonds by Chromium Catalysis Using a Bipyridyl Ligand
Jinghua Tang, Fei Fan, Xuefeng Cong, Lixing Zhao, Meiming Luo, and Xiaoming Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Jun 2020
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Reductive Cross-Coupling between Unactivated C(aryl)–N and
C(aryl)–O Bonds by Chromium Catalysis Using a Bipyridyl Lig-
and
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Jinghua Tang,† Fei Fan,† Xuefeng Cong,† Lixing Zhao, Meiming Luo, and Xiaoming Zeng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
ABSTRACT: Reductive cross-coupling between two chemically inert bonds remains a great challenge in synthetic chemistry. We
report here the reductive cross-coupling between unactivated C(aryl)–N and C(aryl)–O bonds that was achieved by chromium
catalysis. The simple and inexpensive CrCl2 salt, combined with important bipyridyl ligand and magnesium reductant, shows high
reactivity in the successive cleavage of C(aryl)–N bonds of aniline derivatives and C(aryl)–O bonds of aryl esters, allowing the
cross-coupling of these two unactivated and different bonds to occur in a reductive fashion to form C(aryl)–C(aryl) bond. Mecha-
nistic studies by deuterium-labeling experiments indicate that the C(aryl)–N bonds in anilines are preferentially cleavage by reac-
tive Cr species, in which the ligation of bipyridyl with Cr by adopting a coordination model in 1:1 ratio can be considered.
1. INTRODUCTION
Cross-coupling reactions are one of the most powerful
Scheme 1. C(aryl)–C(aryl) Bond Formation via Cross-
Coupling of Aryl Electrophiles
tools in organic chemistry.1,2 In general, nucleophiles such as
organometallic or organoboron reagents are used as precur-
sors to couple with electrophiles.3 Recently, reductive cross-
(a) Electrophile-based cross-coupling reactions
path a
coupling using two electrophiles as partners has appeared as
a
+
Ar
X
[M] Ar'
powerful strategy to forge C–C bonds.4 This cross-
(common)
(X = I, Br, Cl
O, N…)
(M = B, Mg, Zn
Li, Sn…)
electrophile reaction shows high step-economy and attrac-
tive selectivity that is orthogonal to conventional strategies
(Scheme 1a). Progress in the reductive coupling of aryl elec-
trophiles with alkyl electrophiles has been made recently.5
However, the cross couplings between two aryl electrophiles
are underdeveloped and traditionally limited to classic
Ullmann reactions of aryl halides.6 Since Weix and co-
workers pioneered the cross-electrophile reaction of aryl
bromides with aryl triflates,7 the use of two different aryl
electrophiles as precursors in the reductive cross-coupling
has attracted great synthetic and mechanistic interest.8
Cross-electrophile reaction between two chemically inert and
different aryl electrophiles by catalytic cleavage of two unac-
tivated bonds leading to reductive coupling remains an un-
solved challenge.
path c
Ar NR2
+
R'CO2 Ar'
Ar Ar'
(unknown)
Prominent issues:
Successive cleavage of two unactivated
bonds by metals in catalytic cycle
path b
Ar X1
X2 Ar'
+
Promoting the orthogonal cross-coupling
(underdeveloped)
(X1 ≠ X2)
(b) Reductive cross-coupling of unactivated C(aryl)–N/C(aryl)–O bonds
H
H
Ligand-enabled coupling
NtBu
O
CrCl2/dtbpy
+
RCO2
Ar'
Ar
Ar'
Ar
NMe2
Mg, THF, 40 o
then HCl (aq)
C
Cross-Electrophile Reaction
associated with this cross-electrophile reaction include: (1)
the successive cleavage of unactivated C(aryl)–N and C(aryl)–
O bonds by metals in one catalytic cycle, (2) promoting the
orthogonal cross-coupling, and (3) inhibiting the competing
homocoupling reactions in obtaining high chemoselectivity.
Herein, we report a reductive cross-coupling between unacti-
vated C(aryl)–N and C(aryl)–O bonds that was achieved by
cost-effective chromium catalysis with a bipyridyl ligand,
allowing for the development of a cross-electrophile reaction
of chemically inert aniline derivatives with aryl esters under
mild conditions (Scheme 1b).
Aromatic C–N and C–O bonds are common in organic
chemistry and although they are usually chemically unreac-
tive, the catalytic cleavage and coupling of these bonds is of
significant synthetic and mechanistic interest.9 Elegant cou-
pling strategies of C(aryl)–N bonds in anilines as well as
C(aryl)–O bonds in esters with nucleophiles of organoboron
and organometallic reagents have been developed, respec-
tively.10–14 We have considered whether unactivated C(aryl)–
N bonds in electronically neutral anilines could undergo
straightforward coupling with unactivated C(aryl)–O bonds
of esters in a reductive fashion to afford C–C bonds.15 Issues
2. RESULTS AND DISCUSSION
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Scheme 2. Reductive Cross-Coupling Between Unactivated
H
CrCl2/ligand
C(aryl)–N and C(aryl)–O Bonds Using dtbpy Ligand with Cra
NtBu
H
1
2
3
4
5
6
7
8
NtBu
Mg
H
Ar
Ar'
H
CrCl2/dtbpy
(10 mol %)
NtBu
Ar
NMe2
O
LnCr
+
Mg
PivO
Ar
Mg (4 equiv)
THF, 40 oC, 48 h
then HCl (aq)
NMe2
Ar
Mg(O2CR)2
O2CR
H
1
2a'
3
NtBu
H
NtBu
Cr
Ln
H
O
H
H
H
Ar
O
O
O
Cr NMe2
Ln
Ar
Ar'
F
Me
Mg
3c (85%)
3d (98%)
H
3a (90%)
3b (82%)
9
H
NtBu
H
O
H
10
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Mg(NMe2)2
O
CrLn
O
Ar
Ar'
RCO2
R
MeO
3f: R = H (89%)
3j: R = 4-TMS (80%)
Figure 1. Working hypothesis for reductive cross-coupling of
C(aryl)–N/C(aryl)–O bonds by Cr catalysis.
3e (38%) (50%)b
3m (84%)
3g: R = 4-Me (81%) 3k: R = 4-SMe (65%)
3h: R = 4-OMe (95%) 3l: R = 4-OCF3 (83%)
3i: R = 4-F (98%)
H
H
O
O
3o: R = H (84%)
3p: R = 2-Cl (40%) (17%)b
3q: R = 4-OMe (83%)
3r: R = 4-F (96%)
Recent advances in Cr-catalyzed reactions have encour-
aged us to probe the reactivity of this group 6 metal in reduc-
tive cross-coupling between two unactivated bonds.16,17 Bull-
ock reported that the zero-valent state of Cr could result
from the reduction of Cr(II) complex with magnesium.18 The
reactive Cr can facilitate coordination with the nitrogen moi-
ety of aniline with an ortho-imino chelation, by cleavage of
the C(aryl)–N bond to afford cyclochromate(II) (Figure 1).19,20
The latter may be reduced by Mg to form low-valent Cr in situ,
thus, opening up the opportunity for continuous activation of
the C(aryl)–O bond of an aryl ester for the orthogonal cross-
coupling. Based on the mechanistic considerations, we start-
ed our research by studying the reaction of ortho-imino-
bearing aniline 1a with bulky 1-adamantyl aryl ester 2a (Table
1).10 Without external ligands, the simple CrCl2 salt was an
3s: R = 4-OCF3 (84%)
3t: R = 4-SMe (46%) (37%)b
3n (59%)
R
H
O
H
O
H
O
O
Me2N
MeO
3v (36%) (24%)b
3w (47%) (43%)b
3u (93%)
Me
H
O
H
O
H
O
O
O
OMe
O
3x (76%)
3y (30%) (41%)b
3z (71%)
O
H
H
H
H
amino
groups:
Me
O
NtBu
N
NtBu
NEt2
NtBu
NBn2
III (87%)
3aa (75%)
II (71%)
I (65%)
aReactions were conducted on a 0.2 mmol scale. Isolated yields
are given. bRecovery of aryl aldehyde containing an ortho-C−N
bond.
Table 1. Studying the Effect of Ligands, First-Row Metal
Salts, and Aryl Esters on Reductive Cross-Couplinga
H
H
CrCl2/dtbpy
(10 mol %)
O
NtBu
ineffective precatalyst with magnesium in promoting the
cross-electrophile reaction (entry 2). The cross coupling did
not occur when 2,2’-bipyridyl was used as ligand (entry 3).
Gratifyingly, the electron-rich 4,4'-dimethyl-2,2'-bipyridyl
showed appealing ligand behavior in assisting Cr in the suc-
cessive cleavage of unactivated C(aryl)–N bond of aniline and
the C(aryl)–O bond of the aryl ester, allowing for the reduc-
tive cross-coupling to occur smoothly to form the ortho-
arylated benzaldehyde 3a in good yield (entry 4). The use of
4,4'-di-tert-butyl-2,2'-bipyridyl (dtbpy) improved the trans-
formation, giving 3a in 77% yield (entry 1). Compared with
CrCl2, the CrCl3·3THF complex exhibited low performance in
the coupling (entry 10). Other first-row metal complexes,
such as NiCl2(PPh3)2, CoCl2, and FeCl2, showed no reactivity in
the reductive cross-coupling (entries 13–15). The replace-
ment of 1-adamantyl group with tert-butyl in the aryl ester
led to high conversion, affording 3a in excellent yield (entry
16). Other C(aryl)–O bond-containing aryl electrophiles such
as aryl triflate and acetate were not suitable coupling part-
ners (entries 17 and 18).
AdCO2
+
NMe2
Mg (4 equiv)
THF, 40 oC, 48 h
then HCl (aq)
1a
2a
3a
entry
deviation from standard conditions
yield (3a)
R
R
1
2
3
4
none
77%
0
without dtbpy
N
N
bpy instead of dtbpy
dmbpy instead of dtbpy
0
dtbpy: R = tBu
bpy: R = H
62%
5
6
7
dmobpy instead of dtbpy
1,10-Phen instead of dtbpy
IPr instead of dtbpy
56%
dmbpy: R = Me
0
0
dmobpy: R = OMe
8
dppe instead of dtbpy
without CrCl2
0
9
0
N
N
10
11
12
CrCl3⋅3THF instead of CrCl2
Cr(acac)3 instead of CrCl2
Cr(CO)6 instead of CrCl2
45%
0
1,10-Phen
0
N
N
Dipp
Dipp
Ph
13
14
15
NiCl2(PPh3)2 instead of CrCl2
FeCl2 instead of CrCl2
0
0
0
IPr
CoCl2 instead of CrCl2
Ph
16
tBu instead of 1-Ad in 2a (2a')
90%
13%
0
P
P
Ph
17
18
19
OtBu instead of 1-Ad in 2a
OTf or OAc instead of 1-Ad in 2a
without Mg
Ph
dppe
0
The scope of the reductive cross-coupling between C(aryl)–
N and C(aryl)–O bonds was examined. Aniline derivatives
containing methyl or cyclopropyl substituents reacted with
aryl ester smoothly, forming the corresponding ortho-
arylated benzaldehydes (Scheme 2, 3b and 3c). Compared
aStandard conditions: 1a (0.2 mmol), 2a (0.8 mmol), CrCl2
(0.02 mmol), dtbpy (0.02 mmol), Mg (0.8 mmol), THF, 40 °C, 48
h; and then quenched with HCl (aq), 0.5 h.
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with electron-rich arene (3e), the C(aryl)–N bond in electron-
under Cr catalysis (I–III).
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2
3
4
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deficient arene facilitates the coupling with C(aryl)–O bond in
giving high conversion (3d). The incorporation of either elec-
tron-rich or electron-poor aryl scaffolds into anilines did not
greatly influence the cross-electrophile coupling, providing
access to substituted aldehyde-bearing teraryls 3f–t in mod-
erate to excellent yields. In contrast to methoxy-substituted
aniline (3u), the reaction with allyloxy-containing electro-
philes formed the coupling product in a relatively low yield
(3v). The cross-coupling showed high site-selectivity, with
the ortho-C(aryl)–N bond being arylated, allowing the amino
substituent at other positions to be maintained intact. The
method provides a strategy to access amino-substituted and
aldehyde-containing biaryl 3w. The application of this strate-
gy to the preparation of benzo[d][1,3]dioxol-5-yl-bearing
compounds was also successful (3x and y). The incorporation
of methoxy into the ortho position of amino did not influence
the cross-coupling of C(aryl)–N bond to afford the product 3z.
Whereas the use of ortho-phenyl-substituted aniline deriva-
tive formed the related coupling product in trace amount of
yield. The methyl at the another ortho position of imino has
no effect on the reductive coupling, giving 2,6-disubstituted
benzaldehyde 3aa in 75% yield. The reactions were inhibited
by the replacement of methyl with phenyl and dimethyla-
mino group, indicating that the ortho substituents to both
the amino and imino scaffolds could impact on the reductive
cross-coupling of C(aryl)–N bonds. Beside dimethyl amino,
the C(aryl)–N bonds in diethylamino, dibenzylamino, and
pyrrolidinyl coupled with C(aryl)–O bonds of esters smoothly
The installation of substituents such as alkoxy, silyloxy, cy-
clopropyl and trimethylsilyl groups onto the arenes did not
affect the cross-electrophile reaction of aryl esters with ani-
line 1a (Scheme 3, 3ab–ag). When the use of (tetrahydro-2H-
pyran-2-yl)oxy-substituted naphthyl pivalate, the reaction
formed the related hydroxyl-containing coupling product 3ah
after workup with acid. The C(aryl)–O bonds in 2-naphthyl
esters bearing substituted phenyl groups coupled with
C(aryl)–N bonds effectively, providing access to benzalde-
hyde derivatives 3ai–aq. Phenanthren-9-yl-substituted ester
allowed the coupling with aniline to form 3ar in good yield.
The reductive cross-coupling of 1-naphthyl or phenyl pivalate
ester with 1a did not take place. The formation of 1-naphthol
or phenol (ca. 25% yield) by the cleavage of (O)C–O bonds
was observed. In contrast, the C(aryl)–O bond in 1-
adamantyl-substituted 1-naphthyl ester coupled with
C(aryl)–N bond effectively to furnish 3as. Only a trace
amount of naphthol was detected in the reaction (<3% yield).
The reductive cross-coupling with 1-adamantyl phenyl esters
containing fluoro, polyfluoro, trifluoromethoxy, or substitut-
ed phenyl scaffolds occurred smoothly under mild conditions
(3at–ay). Relatively low conversion was obtained in the
transformation of the C(aryl)–O bond of 1-adamantyl phenyl
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Scheme 4. Mechanistic Studies
H
H
H
O
OMe
O
NtBu
D
NMe2
CrCl2
(20 mol %)
MeO
O
Mg
(4 equiv)
1u
(0.4 mmol)
MeO
D-4 (7%)
MeO
40 oC, 12 h
H
5 (<2%)
+
+
(eq 1)
H
O
THF, 40 o
48 h
C
NHtBu
NMe2
Scheme 3. Cr-Catalyzed Reductive Cross-Coupling of Unac-
tivated C(aryl)–N/C(aryl)–O Bondsa
dtbpy
(20 mol %)
then D2O, 1 h
treating with HCl (aq) and
NMe2
neutralization by K2CO3 (aq)
H
H
MeO
NtBu
7 (61%)a
CrCl2/dtbpy
(10 mol %)
MeO
O
6 (17%)
+
Ar
RCO2
CrCl2
(20 mol %)
NMe2
Ar
Mg (4 equiv)
THF, 40 oC, 48 h
then HCl (aq)
Mg
(4 equiv)
2a
D
(0.4 mmol)
2
+
(eq 2)
(95% recovery)
+
2a
+
1a
(R = tBu or Ad)
3
THF, 40 o
48 h
C
40 oC, 12 h
dtbpy
(20 mol %)
then D2O
D-8 (nd)b
9 (nd)b
R = tBu
H
tBu
Si Me
Me
H
OMe
H
O
H
H
O
H
O
O
NtBu
O
O
O
F
D
F
NMe2
CrCl2
(1 equiv)
Mg
(4 equiv)
1d
H
3ac (50%) (35%)b
D-10
3ab (76%)
3ae (83%)
3ad (72%)
(0.1 mmol)
NHtBu
NMe2
O
(eq 3)
+
+
40 oC, 2 h
THF, 40 oC, 5 h
then filtration
H
O
dtbpy
(X equiv)
Me Me
Si Me
H
O
then D2O, 1 h
F
F
NMe2
H
OH
H
Me
Si Me
Me
treating with HCl (aq) and
O
O
11
12
neutralization by K2CO3 (aq)
X
Yield (D-10)a
Yield (11)a
6%
Yield (12)a
3ah (78%)c
3af (70%)
1
2
3
20%
7%
65%
71%
75%
3ag (88%)
3ar (68%)
10%
12%
F
H
H
O
2%
O
H
O
H
O
R =
R
F
H
3as (75%)
OCF3
3at (47%)
CrCl2/dtbpy
3ai: R = H (81%) 3an: R = 4-OMe (74%)
3aj: R = 2-OMe (93%) 3ao: R = 4-F (62%)
F
(1 equiv)
THF, 40 oC, 12 h
Mg (4 equiv)
H
13 (nd)b
+
H
O
NHtBu
H
O
F
F
3ap: R = 4-Cl (44%) (31%)b
+
(eq 4)
3ak: R = 2-F (66%)
O
THF, 40 oC, 12 h
treating with HCl (aq)
neutralization by
K2CO3 (aq)
then removal of THF,
washing with hexane,
extraction with CH2Cl2,
and removal of volatiles
3al: R = 3-OMe (76%) 3aq: R = 3,5-OMe (76%)
3am: R = 4-Me (70%)
1a
NMe2
15 (93%)a
(0.2 mmol)
NMe2
14 (nd)b
3au (61%)
3av (53%)
OCF3
H
O
F
H
O
H
O
X = 10 (3a, 77%)a
= 20 (3a, 75%)a
= 30 (3a, 51%)a
= 40 (3a, nd)b
= 50 (3a, nd)b
= 60 (3a, nd)b
H
O
CrCl2 (10 mol %)
dtbpy (X mol %)
1a
+
2a
3a
(eq 5)
Mg (4 equiv)
THF, 40 oC, 48 h
3az (21%) (52%)b
3aw (34%) (48%)b
3ay (62%)
3ax (59%)
then HCl (aq)
aThe coupling with 1-adamantyl aryl esters was carried out by
using 20 mol % of CrCl2/dtbpy at 60 oC. bRecovery of aryl aldehyde
CrCl2
(10 mol %)
+
dtbpy
(X mol %)
Mg
(4 equiv)
1a (0.2 mmol)
2a (0.8 mmol)
X = 10 (3a, 63%)a
= 21 (3a, <2%)a
= 30 (3a, nd)b
3a
(eq 6)
THF, 40 o
12 h
C
THF, 40 oC, 48 h
then HCl (aq)
containing
yl)oxy)naphthalen-2-yl pivalate was used.
ortho-C−N
bond.
c7-((Tetrahydro-2H-pyran-2-
aGC yields were given using n-tridecane as internal standard. bNot detected by GC/MS analysis.
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Journal of the American Chemical Society
40 mol% of dtbpy was used (eq 5). The formation of off-cycle
Page 4 of 8
ester (3az).
1
2
3
4
5
6
7
8
resting Cr species is proposed upon the addition of excess
dtbpy, which may be ligation saturated and not have addi-
tional sites available to coordinate with the amino/ester
groups for the cleavage of the C(aryl)–N/C(aryl)–O bonds.
Interestingly, by initial treatment of CrCl2/Mg with 21 mol%
of dtbpy for overnight and then adding the resulting solution
to the reaction mixture, only a trace amount of 3a was de-
tected (eq 6). The ligation of dtbpy with Cr by adopting a
coordination model in 1:1 ratio to afford reactive species can
be considered.
To obtain mechanistic insight into which bonds are prefer-
entially broken with Cr, deuterium-labeling experiments
based on the reaction of aniline (1u) and aryl ester (2a) with
Cr species were performed, respectively (Scheme 4). By
quenching the reaction of 1u with reactive Cr that was
formed in situ with D2O, the deuterated compound (D-4),
formed by the cleavage of C(aryl)–N bond, was identified,
accompanied by a trace amount of homocoupling compound
5 (Scheme 4, eq 1). In contrast, the deuterated species of
C(aryl)–O bond cleavage and homocoupling product were
not detected upon reaction with the aryl pivalate (eq 2). The
preferential cleavage of C(aryl)–N bond in aniline by Cr with
an imino chelation can be considered. Subsequently, we car-
ried out the stoichiometric reaction of CrCl2/dtbpy with Mg
followed by treatment with fluoro-substituted aniline 1d (eq
3). After the mixture was stirred at 40 oC for 2 h and
quenched with D2O, the deuterated compound D-10 was
formed in 20% yield, by the cleavage of C(aryl)–N bond. The
formation of reactive low-valent Cr that was then ligated
with aniline for the breakage of C(aryl)–N bond can be con-
sidered. The increase of the amount of dtbpy ligand to 2 or 3
equivalents led to a very low yield of D-10. A saturated coor-
dination of Cr with dtbpy may be unfavorable to breakage of
the C(aryl)–N bond. Compared with these, the reduction of
the Cr complex that was formed by stoichiometric reaction of
CrCl2, 1a and dtbpy using Mg gave the benzylic amine 15 by
reduction of the imino scaffold, indicating that reducing ani-
line-supported Cr(II) species by Mg cannot lead to the cleav-
age of C(aryl)–N bonds.
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Considering that the arenes contain ortho-C(aryl)–N and
C(aryl)–H bonds adjacent to the imino group, we next probed
the possibility of sequential transformations of these unacti-
vated bonds for the synthesis of ortho-disubstituted benzal-
dehydes with Cr catalysis. By the reaction of 1a with naphthyl
pivalate under standard conditions, the reductive coupling
between C(aryl)–N and C(aryl)–O bonds gave naphthylated
compound 3a, which was isolated and further treated with
Grignard reagents under Cr catalysis (Scheme 5). The substi-
tuted aryls that contain tert-butyl, methoxy, amino, thiome-
thyl, trimethylsilyl, fluoride and chloride were incorporated
into the another ortho position of imino group, giving ortho-
diarylated benzaldehydes 16a–h in 68–82% total yields. The
Cr-catalyzed sequential functionalization of ortho-C(aryl)–N
and C(aryl)–H bonds was used in the preparation of 4-
propylcyclohexylphenyl- and naphthyl-substituted motifs 16i
and j. The reductive coupling of C(aryl)–N bond followed by
an oxidative coupling of C(aryl)–H bond with installation of
heterocyclic 2,2-difluorobenzo[d][1,3]dioxolyl was successful
(16k). In addition, selective incorporation of aryl and aliphatic
scaffolds by this protocol led to the formation of 2-ethyl-6-
(naphthalen-2-yl)benzaldehyde 16l. Trisubstituted benzal-
dehydes bearing naphthyl, phenyl, and fluoride/methoxy in
the arenes were accessible using the strategy (16m and n).
To further understand the ligand behavior, the influence of
the amount of dtbpy on the reductive cross-coupling was
studied. Increasing the amount of dtbpy resulted in low con-
version for 3a. The reaction was completely inhibited when
Scheme 5. Cr-Catalyzed Sequential Reductive and Oxida-
tive Couplings of Unactivated C(aryl)–N/C(aryl)–H Bonds
for the Synthesis of 2,6-Disubstituted Benzaldehydesa
1) BnNH2, MeOH, reflux
The aldehyde group in biaryl compounds can be easily
modified and converted into a difluorovinyl scaffold, provid-
ing a strategy to prepare organic semiconducting material-
relevant 5-fluorochrysene (18) by a subsequent annulation
(Scheme 6). The oxidation of aldehyde functionality to car-
boxyl enables the formation of naphthylated benzoic acid
(19). By the annulation and amidation of the carboxyl group,
both 5H-dibenzo[c,g]chromen-5-one (20), which is of interest
for material science, and biologically active muscarinic ace-
2) CrCl2 (10 mol %)
PivO
NtBu
NMe2
R-MgBr/DCP
THF, 40 oC, 12 h
then HCl (aq)
H
H
O
2a'
"standard condition"
H
R
Ar
Ar
Reductive coupling
of C–N bonds
Oxidative coupling
of C–H bonds
3
1
16
Me
H
O
R
H
O
Scheme 6. Applications in the Preparation of Material-
and Medicinally Relevant Compounds
16a: R = H (77%)
16e: R = 4-SMe (75%)
16f: R = 4-SiMe3 (79%)
16g: R = 3-F (82%)
16b: R = 4-t-Bu (77%)
16c: R = 4-OMe (68%)
16d: R = 4-NMe2 (74%)
H
F
PdCl2 (15 mol %)
AgOTf (30 mol %)
ClCF2CO2Na (1.2 equiv)
PPh3 (1.5 equiv)
16h: R = 4-Cl (81%)
CF2
O
16i (80%)
DMF, 110 oC, 2 h
BF3•Et2O (1 equiv)
HFIP, 60 oC, 2 h
H
O
H
O
O
O
F
F
3a
17 (82%)
18 (63%)
NaClO2 (1.5 equiv)
NaH2PO4 (1 equiv)
O
O
16k (83%)
16j (82%)
CH3CN/H2O
K2S2O8 (3 equiv)
0~25 o
C
H
O
CH3CN/H2O
50 oC, 12 h
HO
H
O
H
O
O
20 (64%)
HN
Me
H2N
1)
OMe
F
NBoc
NH
O
16l (49%)
19 (87%)
16m (84%)
16n (83%)
HOAt, EDC, DCM, rt, 16 h
2) TFA/DCM, rt
aThe sequential transformations of ortho-C(aryl)–N and
C(aryl)–H bonds by Cr-catalyzed couplings were performed on a
0.2 mmol scale of 1. Total yields are given.
21 (98%)
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tylcholine receptor agonist 21 were prepared.21
Author Contributions
†J. Tang, F. Fan, and X. Cong contributed equally.
1
2
3. CONCLUSIONS
In summary, we have developed a reductive cross-coupling
between unactivated C(aryl)–N and C(aryl)–O bonds through
ligand-enabled Cr catalysis. This reaction was accomplished
by using the low-cost CrCl2 as precatalyst, accompanied by
dtbpy as an effective ligand and magnesium as a reductant.
The approach enables the cross-electrophile coupling be-
tween two chemically inert and different bonds to form C–C
bonds under mild conditions. Further mechanistic studies
involving the isolation and characterization of reactive inter-
mediates are ongoing.
3
4
5
6
7
8
9
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(Nos. 21572175, 21871186 and 21971168) and the Fundamental
Research Funds for the Central Universities (20826041D4117) for
financial support of this research.
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ASSOCIATED CONTENT
Supporting Information. Detailed optimization data; experi-
mental procedures; characterization data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*E-mails: zengxiaoming@scu.edu.cn
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activated C(aryl)–O Bonds Enabled by Chromium Catalysis. J. Am.
Chem. Soc. 2020, 142, 7715–7720. (m) Chen, M.; Doba, T.; Sato, T.;
Razumkov, H.; Ilies, L.; Shang, R.; Nakamura, E. Chromium(III)-
Catalyzed C(sp2)–H Alkynylation, Allylation, and Naphthalenation
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Page 8 of 8
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Cross-electrophile coupling of C–N/C–O bonds
H
H
NtBu
NMe2
CrCl2/dtbpy
O
(10 mol %)
+
RCO2
Ar'
Ar
Ar'
Ar
Mg, THF, 40 o
then HCl (aq)
C
(R = 1-Ad or tBu)
NR
NMe2
H
Cleavage of unactivated C–N/C–O bonds for coupling
Cr catalysis
H
Chemoselectivity
Mild conditions
Ar
Sequential transformations
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