Chemoselective Cross-Coupling between Two Different and Unactivated C(aryl)-O Bonds Enabled by Chromium Catalysis

Article abstract of DOI:10.1021/jacs.0c00283

We report here the first example of cross-coupling between two different and unactivated C(aryl)-O bonds with chromium catalysis. The combination of a low-cost Cr(II) salt, 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbpy) as the ligand, and magnesium as the reductant shows high reactivity in promoting the reductive cross-coupling of aryl methyl ether derivatives with aryl esters by cleavage and coupling of two different C(aryl)-O bonds under mild conditions. The formation of active low-valent Cr species by reduction of CrCl₂ with Mg can be considered, which prefers to initially activate the C(aryl)-O bond of phenyl methyl ether with the chelation help of dtbpy and an o-imine auxiliary. The subsequent consecutive reduction, second C(aryl)-O activation, and reductive elimination allow for the achievement of selective cross-coupling of C(aryl)-O/C(aryl)-O bonds.

Full text of DOI:10.1021/jacs.0c00283

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Communication
Chemoselective Cross-Coupling Between Two Different and
Unactivated C(aryl)–O Bonds Enabled by Chromium Catalysis
Jinghua Tang, Liu Leo Liu, Shangru Yang, Xuefeng Cong, Meiming Luo, and Xiaoming Zeng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00283 • Publication Date (Web): 17 Apr 2020
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Chemoselective Cross-Coupling Between Two Different and Un-
activated C(aryl)–O Bonds Enabled by Chromium Catalysis
Jinghua Tang,†,# Liu Leo Liu,‡,# Shangru Yang,†,# Xuefeng Cong,† Meiming Luo,† and Xiaoming Zeng*,†
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†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China; ‡Department of Chemistry, University of California, Berkeley, California 94720, United States
Scheme 1. Transition-Metal-Catalyzed Cross-Electrophile
ABSTRACT: We report here the first example of cross-coupling
between two different and unactivated C(aryl)–O bonds with
Couplings for the Construction of C(aryl)–C(aryl) Bonds
chromium catalysis. The combination of low-cost Cr(II) salt, 4,4¢-
(a) Transition-metal-catalyzed cross-electrophile coupling to form C(aryl)–C(aryl) bonds
di-tert-butyl-2,2¢-dipyridyl (dtbpy) ligand and magnesium re-
cat. [M]
Competing
homocoupling reactions
X1
X2
+
ductant shows high reactivity in promoting the reductive cross-
coupling of aryl methyl ether derivatives with aryl esters, by
cleavage and coupling of two different C(aryl)–O bonds under
mild conditions. The formation of active low-valent Cr species by
reduction of CrCl2 with Mg can be considered, which prefers to
initially activate the C(aryl)–O bond of phenyl methyl ether with
the chelation help of dtbpy and ortho-imino auxiliary. The sub-
sequent consecutive reduction, the second C(aryl)–O activation
and reductive elimination allow for the achievement of selective
cross-coupling of C(aryl)–O/C(aryl)–O bonds.
R
R'
R
R
X
1 = halide
X1 = Br/Cl
X1 = OMe
X2 = halide
X2 = OTf
X2 = O2CR
Pd, Co catalysis
Ni/Pd co-catalysis
(unknown)
+
(b) Nickel-catalyzed reductive deoxygenation of dibenzyl ethers
NiBr2(glyme)
R
DPPB
O
R
R
R
B2pin2, Zn
(c) Cr-catalyzed selective cross-couplings of aryl methyl ether derivatives with aryl esters
cross-coupling of C–O/C–O bonds
H
CHO
Nt-Bu
CrCl2/dtbpy
(10 mol%)
RCO2
+
OMe
R1
Metallic Mg
THF, 40 o
Then HCl (aq)
R1
Transition-metal-catalyzed cross-coupling represents a pow-
erful and versatile tool for the linkage of two fundamental chem-
ical bonds in synthetic chemistry.1,2 Historically, methods that
have been used to form ubiquitous C(aryl)–C(aryl) bonds that
make up the basic motifs of many organic compounds common-
ly feature the coupling of aryl halides with aromatic nucleophiles
such as organoboron, organomagnesium and organozinc rea-
gents.3 Although the homocoupling of aromatic halides has been
discovered as early as the 1900s,4 attempts to form C(aryl)–
C(aryl) bonds by cross-couplings between two different aromatic
electrophiles have generally been unsuccessful; indeed, such
cross-electrophile coupling has been described as challenging.5–7
Major obstacles that have precluded the development of cross-
electrophile couplings are the competing homocoupling of aryl
electrophiles and prominent chemoselectivity issue.
R2
R2
C
(R = t-Bu, 1-Ad)
• Cleavage of two unactivated C–O bonds
• Cr catalysis
• Chemoselectivity
• Mild conditions
Ni catalysis (Scheme 1b).18 These results led us to investigate
whether it was possible to achieve the reaction by cross-coupling
between two different C(aryl)–O bonds. Such cross-electrophile
coupling has remained elusive to date. In addition to suppressing
competing homocoupling, the synchronous cleavage of two
unactivated C(aryl)–O bonds with metal catalyst remains a great
challenge in developing cross-coupling of C(aryl)–O/C(aryl)–O
bonds. Herein, we report the chemoselective cross-electrophile
coupling of phenyl methyl ether derivatives with aryl esters ena-
bled by chromium catalysis. This reaction, which was promoted
by chromium(II) chloride combined with bipyridyl-derived ligand
and magnesium reductant, allows for synchronous cleavage of
two different, unactivated C(aryl)–O bonds and achievement of
their cross-coupling (Scheme 1c).
Transition-metal-catalyzed reactions using phenols and rele-
vant derivatives have emerged as an ecological strategy to as-
semble aromatic feedstock chemicals.8 Phenol derivatives are
naturally abundant and usually non-toxic synthons compared
with their halide counterparts. These derivatives are mainly de-
rived from oxygen-rich lignocellulosic plant biomass and they
serve as common aryl electrophiles through reaction with nucle-
ophiles upon catalytic cleavage of unactivated C(aryl)–O
bonds.9–15 In contrast, phenol derivatives have rarely been uti-
lized to couple with a different electrophile.16 Recent studies by
Weix attracted our attention, wherein the authors showed that
aryl triflates coupled effectively with aryl halides under co-
operative multimetallic catalysis (Scheme 1a).17 The reductive
deoxygenation using dibenzyl ethers was disclosed by Shi using
The reductive cross-coupling of two aryl electrophiles usually
involves two oxidative addition (OA) processes.6 Reactive transi-
tion metal species in the low-oxidation state should favour the
OA of C(aryl)–O bonds.19 Our previous studies showed that low-
valent Cr species, probably formation in situ by reduction of Cr(II)
salt with Grignard reagent, shows high reactivity in promoting
the Kumada coupling of C(aryl)–O bonds.20d The succinct version
using aryl bromides as precursors for formation of the related
Grignard reagents in situ with Mg has been disclosed.20f We hy-
pothesized that an external ligand may help Cr to expedite the
cross-coupling of the C(aryl)–O bond in ortho-imino-containing
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Table 1. Optimizing Reaction Conditionsa
cleavage or cross-coupling of the ortho-C(aryl)–O bond, provid-
1
2
3
4
5
6
7
8
ing access to multiply substituted benzaldehyde compounds 3d–
3f in 83–94% yields. The installation of cyclopropyl and trime-
thylsilyl into the scaffolds of phenyl methyl ethers led to moder-
ate conversions (3i and 3j). The reductive coupling with aryl-
substituted phenyl methyl ether derivatives proceeded smoothly,
resulting in the formation of the compounds 3k–3t in prepara-
tively useful yields. The Cr-catalyzed cross-coupling of two unac-
tivated C(aryl)–O bonds was applied in modifying the biological-
ly interesting estrone scaffold, providing access to the arylated
derivative 3u.
H
CHO
Nt-Bu
metal salt/ligand
(10 mol %)
RCO2
MeO
+
OMe
MeO
Mg (2 equiv)
THF, 40 oC, 24 h
then HCl (aq)
2a: R = t-Bu
1a
3a
2b: R = 1-Ad
ligand
–
entry metal salt
reductant
Mg
3ab
ndc
ndc
1
2
3
4
CrCl2
CrCl2
CrCl2
CrCl2
2,2’-bpy
dmbpy
dtbpy
Mg
9
Mg
27%
52% (88%)d
(78%)d,e
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Scheme 2. Cr-Catalyzed Reductive Cross-Coupling of Aryl
Methyl Ether Derivatives with Naphthyl Pivalatea,b
Mg
H
5
CrCl3
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
Mg
Mg
Mg
Mg
Mg
Mg
20%
tracee
ndc
ndc
ndc
ndc
ndc
Nt-Bu
OMe
CHO
CrCl2/dtbpy
(10 mol %)
6
Cr(acac)3
Ni(cod)2
NiCl2
t-BuCO2
+
Mg (3.5 equiv)
THF, 40 oC, 48 h
then HCl (aq)
R
R
7
1
2a
3
8
CHO
CHO
CHO
CHO
9
FeCl2
MeO
Me
10
11
CoCl2
Me
CrCl2
Zn/Mn/
Cp2Co/Na
3b (95%)
3a (88%)
3c (92%)
3d (94%)
CHO
CHO
CHO
CHO
aConditions: 1a (0.2 mmol), 2a (0.7 mmol), metal salt (0.02 mmol),
MeO
MeO
F
ligand (0.02 mmol), reductant (0.4 mmol), THF, 40 oC, 24 h; and then
MeO
OMe
OMe
quenched with HCl (aq), 0.5 h. Isolated yields. Not detected. dMg (0.7
mmol) was used for 48 h. e2b was used with CrCl2/dtbpy (0.04 mmol) at
60 oC. dmbpy = 4,4'-dimethoxy-2,2'-bipyridine. dtbpy = 4,4'-di-tert-
butyl-2,2'-bipyridine.
b
c
3g (39%)
3h (99%)
3e (83%)
3f (84%)
CHO
CHO
CHO
TMS
R
3k: R = H (87%)
3l: R = 4-Me (86%)
3m: R = 4-OMe (60%)
3n: R = 4-TMS (48%)
3o: R = 4-OCF3 (42%)
3i (53%)
3j (47%)
phenyl methyl derivative with a different C(aryl)–O bond in an-
other molecule by chelation. At the outset, ortho-imino-
containing phenyl methyl ether (1a) was chosen to treat with 2-
naphthyl pivalate (2a) that was usually used as the substrate in
the functionalization of C–O bonds (Table 1).21 The inclusion of
10 mol % CrCl2 and two equiv of Mg as reductant did not pro-
mote the cross-coupling of two C(aryl)–O bonds (Table 1, entry
1).22 Gratifyingly, 4,4¢-dimethoxy-2,2¢-bipyridyl (dmbpy) allowed
the coupling of C(aryl)–O/C(aryl)–O bonds to occur, albeit giving
the product 3a in low yield (entry 3). Only the ortho-C(aryl)–O
bond of phenyl methyl ether was naphthylated with retaining
the meta-methoxy group. Replacement of the methoxy scaffold
on dmbpy ligand with a bulky tert-butyl (dtbpy) increased the
yield of 3a from 27% to 52%, and further to 88% when 3.5 equiv
of Mg were used (entry 4). The homocoupling was greatly sup-
pressed, only forming binaphthalene in 13% yield. The replace-
ment by 1-adamantyl-substituted 2-naphthyl ester (2b) in the
reaction leads to 3a in 78% yield. The use of CrCl3 led to low lev-
els of conversion and product formation (entry 5). The nickel
complex of Ni(cod)2 and transition-metal salts of NiCl2, FeCl2 and
CoCl2 showed no reactivity to promote the conversion (entries 7–
10). Studying the effect of reductants on the reaction showed
that Zn, Mn, Cp2Co and Na are inefficiency (entry 11).
CHO
CHO
R
3q: R = t-Bu (31%)
O
O
3r: R = Ad (20%)
Ph
3p (59%)
OMe
Me
H
CHO
CHO
Me
H
OHC
H
O
OBn
3s (67%)
3t (60%)
3u (55%)
aConditions: 1 (0.2 mmol), 2a (0.7 mmol), CrCl2 (0.02 mmol), dtbpy
(0.02 mmol), Mg (0.7 mmol), THF, 40 oC, 48 h; and then quenched
with HCl (aq), 0.5 h. bIsolated yields were given.
Inspired by these results, we next sought to explore the scope
of aryl esters in the cross-coupling (Scheme 3). The introduction
of substituents such as cyclopropyl, trimethylsilyl, tert-
butyldimethylsilyloxy and tetrahydropyranyloxy into naphthyl
pivalates did not largely affect the reductive coupling of C(aryl)–
O/C(aryl)–O bonds (3v–3z). Both electron-rich and electron-poor
naphthyl pivalates can be used as precursors, by the cleavage
and selective coupling of two different C(aryl)–O bonds to fur-
nish biaryl derivatives 3aa–3an. The chloro substituent on the
scaffold of naphthyl pivalate can be compatible in the reductive
coupling (3ak). Despite the inefficiency of the reaction with phe-
nyl pivalates, the pivalate group on the phenyl motif was re-
tained in the coupling, as shown by forming products 3ag and
3al. Aryl pivalate containing polycyclic aromatic hydrocarbon
motif such as 9-phenanthrene reacted effectively under Cr catal-
ysis, offering a route to access to functionalized derivative 3ao.
It should be mentioned that only π-extended aryl pivalates are
currently used for the reaction. The C(aryl)–O bonds in non-
extended aryl pivalates failed to couple with C(aryl)–OMe bonds
under standard conditions. The coupling with 1-naphthyl ada-
With the optimal conditions in hand, the scope of the reaction
with respect to aryl methyl ethers in the Cr-catalyzed cross-
coupling with 2-naphthyl pivalate was examined (Scheme 2). By
using CrCl2/dtbpy and Mg, phenyl methyl ethers containing alkyl,
alkoxy and fluoride groups reacted with 2a effectively to form
biaryl aldehydes 3c–3h with yields that increased to 99% when
an electron-withdrawing fluoro substituent was incorporated
para to the leaving methoxy group in arene (3h). Steric hin-
drance resulting from the meta-methoxy or methyl substituent
on phenyl methyl ethers did not impact either the site-selective
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mantyl ester occurred smoothly to give the product 3ap in good
Scheme 4. Cr-Catalyzed Ring-Opening/Cross-Coupling of
Cyclic C(aryl)–O Bonds with Acyclic C(aryl)–O Bondsa,b
1
2
3
4
5
6
7
8
yield. 1-Adamantyl phenyl esters containing phenyl, fluoro,
polyfluoro, trifluoromethoxy and 1-adamantanyloxy groups can
be used, albeit that low conversions were obtained in some cas-
es (3aq–ax).
CHO
H
Nt-Bu
R
CrCl2/dtbpy
(10 mol %)
R'
Scheme 3. Cross-Coupling of C(aryl)–O/C(aryl)–O Bondsa
t-BuCO2
OH
or
O
+
5
R
CHO
OH
Mg (3.5 equiv)
THF, 40 oC, 48 h
then HCl (aq)
R'
X
(X = CH2 or O)
H
Nt-Bu
OMe
CHO
CrCl2/dtbpy
(10 mol %)
2
4
RCO2
+
R'
R
Mg (3.5 equiv)
THF, 40 oC, 48 h
then HCl (aq)
6
R
2
9
(R = t-Bu, 1-Ad)
1b
3
CHO
CHO
5a: R = H (92%)
5b: R = Me (62%)
5c: R = iPr (65%)
5d: R = F (49%)
10
11
12
13
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CHO
OMe
CHO
CHO
CHO
H
Nt-Bu
O
OH
5e (83%)
R
OH
t-Bu
Si Me
Me
TMS
TMS
CHO
O
R
3v (67%)
3w (90%)
TMS
3x (88%)
CHO
3y (59%)
R
CHO
CHO
CHO
CHO
5g: R = H (93%)
5h: R = 2-OMe (36%)
5i: R = 3-OMe (84%)
OH
5f (83%)
OH
O
CHO
CHO
CHO
O
O
OMe
OBn
3z (60%)b
3ab (55%)
3ac (71%)
3aa (74%)
OMe
TMS
CHO
CHO
CHO
R
OH
OH
OH
OMe
6c (71%)
6a (79%)
6b (62%)
R
TMS
R
H
Nt-Bu
O
3ah: R = Me (78%)
3ai: R = OMe (66%)
3aj: R = F (55%)
3ak: R = Cl (45%)
3al: R = OPiv (43%)
3ad: R = H (62%)
CHO
CHO
3ae: R = OMe (92%)
3af: R = F (74%)
3ag: R = OPiv (56%)
3am (80%)
CHO
6e: R = H (58%)
6f: R = 2-OMe (74%)
6g: R = 3-OMe (58%)
O
OH
CHO
6d (69%)
CHO
OH
OMe
OMe
aConditions: 4 (0.2 mmol), 2 (0.7 mmol), CrCl2 (0.02 mmol), dtbpy
(0.02 mmol), Mg (0.7 mmol), THF, 40 oC, 48 h; and then quenched
with HCl (aq), 0.5 h. bIsolated yields were given.
3ap (78%)c
3an (62%)
3ao (88%)
CHO
CHO
F
CHO
F
CHO
oC for 1.5 h and quenching with D2O, it was found that the ortho-
C(aryl)–O bond can be deuterated, albeit giving the product D-7
in low yield. While the formation of the homocoupling product 8
was observed. Without CrCl2 salt, compounds D-7 and 8 cannot
be formed (see Supporting Information). These suggest that
ortho-C(aryl)–O bond was cleaved by reactive Cr to give the or-
tho-metalated species. In contrast, replacement of phenyl me-
thyl ether with naphthyl pivalate in the reaction cannot give the
deuterated compound of D-10 (eq 2). By addition of 1a and 2a
into the reaction and quenching with D2O, the deuterated spe-
cies D-7 can be detected (eq 3). These indicate that a prior acti-
vation of C(aryl)–O bond of phenyl methyl ether by Cr with the
chelation help of imino auxiliary can be considered. To probe
F
F
R
3aq: R = H (38%)c
F
F
3as (35%)c (46%)d
3at (58%)c
3au (60%)c
3ar: R = 4-OCF3 (65%)c
CHO
CHO
CHO
O
OAd
OCF3
3aw (31%)c
3av (63%)c
3ax (19%)c (55%)d
aConditions: 1b (0.2 mmol), 2 (0.7 mmol), CrCl2 (0.02 mmol), dtbpy
(0.02 mmol), Mg (0.7 mmol), THF, 40 oC, 48 h; then quenched with
HCl (aq); Isolated yields were given. b2-(7-Hydroxynaphthalen-2-
yl)benzaldehyde was obtained after quenching with HCl (aq). c1-
Adamantyl aryl esters were used with CrCl2/dtbpy (0.04 mmol) at 60
oC. dRecovery of the aryl aldehyde bearing ortho-C−OMe bond.
In order to construct hydroxyl-tethered benzaldehyde motifs
by this cross-electrophile coupling strategy, the coupling of cy-
clic C(aryl)–O bonds with acyclic C(aryl)–O bonds with Cr cataly-
sis was explored (Scheme 4). The cyclo-C(aryl)–O bonds of 7-
imino-containing 2,3-dihydrobenzofurans could be cleaved site-
selectively by Cr; this was followed by a ring-opening process
and subsequent coupling with naphthyl pivalate to form 2-
hydroxyethyl-tethered naphthalenylbenzaldehydes 5a–5i. The
ring-opening/cross-coupling reaction can be applied to the func-
tionalization of 1,3-benzodioxole derivative, in which only the
ortho-cyclo-C(aryl)–O bonds were cleaved and coupling with
naphthyl pivalates, allowing for the meta-C(aryl)–O bonds to be
retained in the resulting hemiacetal compounds, which were
hydrolysed during acid work up. This provides a strategy with
which to prepare ortho-aryl- and meta-carbaldehyde-containing
phenol compounds 6a–6g.
Scheme 5. Mechanistic Studies
CrCl2
(20 mol %)
CHO
OMe
CHO
Mg
(3.5 equiv)
1a
CHO
(0.4 mmol)
D
OMe
+
+
+
(eq 1)
THF, 40 o
48 h
C
40 oC, 1.5 h
dtbpy
(20 mol %)
MeO
CHO
MeO
then D2O
MeO
D-7 (7%)
8 (10%)
9 (25%)
CrCl2
(20 mol %)
Mg
(3.5 equiv)
2a
D
(0.4 mmol)
(eq 2)
(eq 3)
+
2a
+
+
THF, 40 o
48 h
C
40 oC, 1.5 h
dtbpy
(20 mol %)
then D2O
D-10 (nd)
11 (nd)
(96%)
CrCl2
(20 mol %)
+
dtbpy
(20 mol %)
Mg
(3.5 equiv)
1a (0.4 mmol)
2a (0.4 mmol)
+
+
+
+
3a
8
11
D-7
D-10
(≈ 3%)
(≈ 2%)
(≈ 3%)
(<1%)
(nd)
THF, 40 o
48 h
C
40 oC, 1.5 h
9
+
2a
then D2
O
(79%)
(65%)
H
Nt-Bu
OMe
H
NHt-Bu
OMe
F
CHO
CrCl2
(1 equiv)
CHO
Reductant
(3.5 equiv)
H
1c (0.1 mmol )
OMe
+
+
+
F
(eq 4)
40 oC, 15 min
THF, 40 oC, 1.5 h
dtbpy
F
F
then HCl (aq) and
(1 equiv) then filtration
To study which C(aryl)–O bonds in the substrates prior to
cleavage by Cr, we carried out the deuterium experiments by
reduction of CrCl2 with Mg followed by treatment with phenyl
methyl ether 1a (Scheme 5, eq 1). After stirring the mixture at 40
13
12
14
neutralization by K2CO3 (aq)
Reductant
Yield (12)
Yield (13)
Yield (14)
Mg
11%
24%
19%
nd
67%
70%
Cp2Coa
Na
15%
nd
1%
7%
78%
58%
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a Without filtration before the addition of 1c.

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Page 4 of 7
whether the intermediacy of a Grignard reagent is responsible
In summary, we have developed a chromium-catalyzed cross-
electrophile coupling by reaction of aryl methyl ether derivatives
with aryl esters under mild conditions. This reaction has enabled
previously elusive transformation of chemoselective cross-
coupling between two different and unactivated C(aryl)–O
bonds, by synchronously cleavage of these chemical bonds to
form C–C bonds. Unreactive aryl methyl ether derivatives, which
are usually used as electrophiles to couple with organometallic
nucleophiles, can now be viewed as suitable partners to couple
with another unactivated electrophile for molecule construction.
Further mechanistic exploration and development of chromium-
catalyzed reductive cross-coupling strategies are under way.
1
2
3
4
5
6
7
8
for the cross-coupling, we treated phenyl methyl ether 1a with
the related naphthyl-MgOPiv under standard conditions, even
under our previous conditions for Kumada coupling (see Figure
S5 in SI).23 The reaction cannot form the coupling product 3a.
Like the Martin’s reaction,24 the effect of LiOPiv salt that was
accompanied by the preparation of naphthylmagnesium must
be considered. Whereas the addition of LiOPiv salt into the Cr-
catalyzed reaction of 1a with naphthylmagnesium bromide did
not affect the Kumada coupling of C(aryl)–O bond. While the
addition of dtbpy ligand into the Kumada coupling of C(aryl)–O
bond led to low conversion. This is different with present reac-
tion that dtbpy ligand is required. The stoichiometric reactions
of phenyl methyl ether 1c by using Mg, Cp2Co and Na as reduct-
ants formed the compound 12 by the cleavage of C(aryl)–O bond,
whereas the use of Mn did not afford 12 (eq 4).25 It should be
noted here that the control experiments made cannot be taken
as a definitive proof, and further experiments will need to be
performed to clarify the mechanism in the near future.
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ASSOCIATED CONTENT
Supporting Information. Detailed optimization data; experi-
mental procedures; characterization data of all new compounds,
detailed optimized geometries, and free energies. This material
is available free of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Scheme 6. Plausible Mechanism Identified by DFT Calcu-
lationsa
Corresponding Author
zengxiaoming@scu.edu.cn
Nt-Bu
N
N
N
Author Contributions
#J. Tang, L. L. Liu and S. Yang contributed equally.
OMe
Mg
2 THF
Cr
N
N
t-Bu
Me
N
N
N
N
TS1
5.8
1b
O
Cr
Cr
Cr
OMe
N
Cl
Cl
THF
THF
t-Bu
MgCl2
2 THF
IN0
(0.0)
IN1
IN2
(–8.4)
IN3
(9.2)
(–39.8)
Notes
The authors declare no competing financial interest.
2a
1/2 Mg
Nt-Bu
1/2 Mg(OMe)2
+
1/2 Mg(OPiv)2
Naph
(–104.1)
1b
1/2 Mg
ACKNOWLEDGMENT
N
N
N
N
TS3
23.7
N
N
N
TS2
21.2
Naph
N
Naph
Cr
Cr
Cr
Naph
OPiv
Support of this work by the National Natural Science Foundation
of China (21572175, 21702028, 21871186 and 21971168) and De-
partment of Science and Technology of Jilin Province
(20180520206JH) is acknowledged. L.L.L thanks Prof. D. W.
Stephan at the University of Toronto for kindly providing access
to computational facilities. We thank the Reviewers for their
valuable suggestions.
O
O
OPiv
N
t-Bu
t-Bu
t-Bu
t-Bu
IN6
(–87.6)
IN4
(–46.3)
IN5
(–80.4)
t-Bu
t-Bu
N
N
=
aFree energies (ΔG, in kcal mol-1) of intermediates and transition states were given.
N
N
A plausible mechanism was proposed and supported by densi-
ty functional theory (DFT) calculations (Scheme 6; see SI for
computational details). As the formation of low-valent Cr(0) by
reduction of CrCl2 complex with Mg was demonstrated,22 a Cr(0)
complex IN1 (9.2 kcal/mol) in the ground state of quintet, locat-
ed 56.9 and 23.4 kcal/mol below the corresponding low and me-
dium spin states (singlet and triplet), respectively, was initially
formed by Mg reduction. The approach of 1b toward IN1 gave
rise to IN2 (–8.4 kcal/mol) via ligand exchange. A facile OA of the
ortho-C–O bond to Cr occurs through TS1 (–2.6 kcal/mol) to
afford IN3 (–39.8 kcal/mol). Subsequently, upon Mg reduction
the second OA of the C–O bond in 2a proceeded in TS2 (–25.1
kcal/mol), leading to IN5 (–80.4 kcal/mol). Finally, reductive
elimination at Cr enabled the forge of C–C bond, with the activa-
tion barrier of 23.7 kcal/mol, to give IN6 (–87.6 kcal/mol) that
was then reduced to complete the catalytic cycle. Concurrent
with this was the formation of the product (–104.1 kcal/mol). It is
noteworthy that direct activation of the ester C–O bond of 2a by
IN1 is energy-demanding as the computed activation barrier is
28.0 kcal/mol (see Figure S11 in SI). The kinetic studies suggest a
little deviation from the first-order dependence of the initial
rates on the concentrations of 1a, 2a and CrCl2/dtbpy, respec-
tively (Figures S6–8). A linear correlation was observed with σ
Hammett constants, indicating that the reductive cross-coupling
with para-electron-deficient phenyl methyl ethers resulted in a
higher initial reaction rate (Figure S9).
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Cross-Coupling of Unactivated C–O/C–O Bonds
H
CHO
Nt-Bu
OMe
Cr
R1
Mg, THF, 40 oC; then HCl (aq)
RCO2
+
R2
R2
R1
dtbpy ligand
(R = t-Bu, Ad)
• Cleavage and cross-coupling of two
different, unactivated C–O bonds
• Cr catalysis
• High chemoselectivity
• Mild conditions
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