Azacycle-Directed Formal Aromatic C(sp2)-H Insertion with Cr(0) Fischer Carbene Complex via Oxidative Hydrogen Migration

Article abstract of DOI:10.1021/acs.organomet.1c00352

An azacycle-directed intermolecular aromatic C(sp2)-H functionalization of Cr(0) Fischer carbene complexes under catalyst-free conditions is reported. Arenes with pyridines, pyrimidine, and pyrazole as directing groups reacted with chromium(0) carbene com

Full text of DOI:10.1021/acs.organomet.1c00352

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Azacycle-Directed Formal Aromatic C(sp2)−H Insertion with Cr(0)
Fischer Carbene Complex via Oxidative Hydrogen Migration
Xing-Qi Yao,§ Wen-Yan Tong,§ Kang Wang, Shuanglin Qu,* and Jianbo Wang*
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ABSTRACT: An azacycle-directed intermolecular aromatic C-
(sp2)−H functionalization of Cr(0) Fischer carbene complexes
under catalyst-free conditions is reported. Arenes with pyridines,
pyrimidine, and pyrazole as directing groups reacted with
chromium(0) carbene complexes in good yields and excellent
regioselectivities. According to the mechanistic studies based on
experiments and computations with density functional theory
(DFT), the reaction is proposed to follow an unconventional
mechanism via oxidative hydrogen migration and reductive
elimination, which is different from the classical electrophilic
substitution mechanism.
carbene species, the C−H insertions with Cr(0) Fischer
carbene complexes are rare.11 To the best of our knowledge,
the phenyl C(sp2)−H bond functionalization with Cr(0)
carbene is not known. In connection to our interest in aromatic
C(sp2)−H bond functionalization with metal carbenes and
unique transformation of Cr(0) Fischer carbene complexes,12
we herein report the azacycle-directed intermolecular aromatic
C(sp2)−H functionalization with chromium(0) Fischer
carbene complexes (Scheme 1c). Combining experimental
and density functional theory (DFT) mechanistic studies, we
suggest that this reaction follows an unusual mechanism, which
involves oxidative hydrogen migration and reductive elimi-
nation.
INTRODUCTION
■
Site-selective functionalization of aromatic C(sp2)−H bonds
has been established as a powerful tool for the formation of C−
C bonds.1 Among the various aromatic functionalization
transformations of C(sp2)−H bonds, the C−C bond formation
with metal carbene species has attracted considerable
attentions.2 For the transition-metal-catalyzed carbene transfer
with aromatic compounds, the reaction typically follows a
pathway including cyclopropanation and ring-opening to
generate cycloheptatrienes, a process known as Buchner
reaction. However, the reaction of carbene with an aromatic
ring may also lead to formal C(sp2)−H bond insertions.3 In
particular, for electron-rich aromatic C(sp2)−H bonds, some
successful examples of transition-metal-catalyzed C(sp2)−H
bond functionalization with diazo compounds have been
reported (Scheme 1a).4 These reactions generally involve
electrophilic addition of a metal carbene to the aromatic ring
and a subsequent proton transfer, differing mechanistically
from the aliphatic C(sp3)−H insertions, which follow
concerted mechanism in most cases.5 Carbene-based aromatic
C(sp2)−H bond functionalization may also be achieved
following migratory insertion pathway.2c,6 In this context, Yu
and co-workers first demonstrated the Rh(III)-catalyzed
activation of arene C(sp2)−H bonds with the assistance of
directing groups, followed by formation of metal-carbene
intermediate and migratory insertion.7 Later, various catalytic
aromatic C(sp2)−H functionalization with diazo compounds
using various transition-metals and directing groups were
extensively explored (Scheme 1b).8,9
RESULTS AND DISCUSSION
■
At the outset, the complex pentacarbonyl(ethoxy)(phenyl)
carbene chromium(0) 1a was selected as a model substrate to
react with 2-phenylpyridine 2a. In the initial experiment
carried out in 1,2-dichloroethane (DCE) at 110 °C with 3
equiv of 2a, the desired product 3a was obtained in 40% yield
(Table 1, entry 1). The effect of solvents was then examined.
The reaction in 1,4-dioxane gave slightly improved yield;
however, the reaction in acetonitrile gave only a trace amount
of 3a (Table 1, entries 2 and 3). To our delight, the reaction in
toluene gave the product 3a in 73% yield (Table 1, entry 4).
Received: June 13, 2021
Notably, Cr(0) Fischer carbene complexes play an
important role in organic synthesis because of their character-
istic properties.10 Although C−H bond insertion is typical for
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failed to give the corresponding C−H functionalization
product, suggesting that the directing group is crucial for the
reaction. Under the optimized reaction conditions, the product
3a could be isolated in 70% yield in 0.2 mmol scale.
Scheme 1. Conversion of Aromatic C−H Bonds into C−C
Bonds with Metal Carbene Species
With the optimized reaction conditions in hand, the scope of
this reaction was first explored by using various aryl Cr(0)
carbene complexes 1a−l (Scheme 2). The reaction was slightly
Scheme 2. Reaction Scope of Cr(0) Carbene Complexes
a
1a−l
a
Reaction conditions: 1a−l (0.2 mmol), 2a (0.6 mmol), toluene (2
b
mL), 110 °C under N2 for 10 h, isolated yield. The reaction was
conducted at 120 °C.
a
Table 1. Optimization of the Reaction Conditions
affected by ortho and meta substituents (1b−e), in which the
reaction with ortho-aryl substituent required higher reaction
temperature (1c). Next, several Cr(0) carbene complexes
bearing a para-substituted aromatic ring were evaluated (3f−j).
In these cases, the reaction was not significantly affected by the
electronic nature of the substituents. The reactions with Cr(0)
carbenes bearing a methoxy group afforded the corresponding
products 3k, l in similar yields.
b
entry
1a:2a
solvent
DCE
1,4-dioxane
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
T (°C)
yield (%)
1
2
3
4
5
6
7
8
1:3
1:3
1:3
1:3
1:1
1:2
1:3
1:3
1:3
110
110
110
110
110
110
100
120
110
40
52
trace
c
73 (70)
We then explored the scope of 2-phenylpyridines (2b−l)
under the standard reaction conditions (Scheme 3). First,
various substituents on the phenyl ring of the 2-phenylpyridine
were examined. When para- and meta-substituted substrates
bearing electron-donating or -withdrawing groups were
employed, the corresponding products (4b−e) were isolated
in moderate to good yields. However, only trace product was
obtained when using ortho-methyl-substituted substrate (4f),
which could be attributed to the steric hindrance. Next, the
scope of the pyridine substrate was assessed under the standard
conditions. For both electron-donating and -withdrawing
substituents in the pyridine ring, the reaction worked well
(4g−l). We also replaced the pyridine ring with pyrimidine or
pyrazole group. The reaction also worked well in these cases
and gave the corresponding products 4m and 4n in good
yields. Finally, for one of the products 4g, the structure was
unambiguously confirmed by X-ray crystallography.
13
20
15
52
0
d
9
a
Reaction conditions are as follows unless otherwise noted: 1a (0.1
b
mmol), 2a (0.3 mmol) in solvent (1 mL) for 10 h at 110 °C. Yields
are determined by 1H NMR analysis using nitromethane as the
c
internal standard. Isolated yield when the reaction was carried out in
0.2 mmol scale. Biphenyl was used as the substrate instead of 2a.
d
With toluene as the solvent, we attempted to reduce the
loading of 2a; however, the yield of 3a was severely diminished
when the loading of 2a was reduced (Table 1, entries 5 and
6).13 Notably, when excess amount of 2a was employed in the
reaction, most of the unreacted substrate 2a could be
recovered after the reaction. We also found the reaction was
dramatically affected by the temperature; the reaction
temperature either higher or lower than 110 °C gave
diminished yields (Table 1, entries 7 and 8).14 Finally, in a
control experiment, the reaction using biphenyl instead of 2a
This unprecedented aromatic C(sp2)−H bond insertion
raises some intriguing questions on its mechanism. Based on
the previous reactions of metal carbene with aromatic C(sp2)−
H bonds, we have initially proposed a stepwise electrophilic
substitution mechanism (Scheme 4, path a). Under high
B
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temperature, the complex A is formed through ligand exchange
between Cr(0) carbene complex 1a and substrate 2a. In
complex A, the carbene carbon is located close to the benzene
ring of 2a, which brings about electrophilic addition of Cr(0)
carbene to aromatic ring, leading to the generation of
zwitterionic intermediate B. Subsequent proton transfer affords
the final product 3a. Alternatively, a concerted aromatic
C(sp2)−H bond insertion is proposed as shown in Scheme 4b.
To substantiate the reaction mechanism, we carried out
mechanistic experiments (Scheme 5). First, the reaction was
Scheme 3. Reaction Scope of Azacycle-Substituted Arenes
2b−n
a
Scheme 5. Mechanistic Experiments
a
Reaction conditions: 1b−c (0.2 mmol), 2b−n (0.6 mmol), toluene
b
(2 mL), 110 °C under N2 for 10 h, isolated yield. The reaction was
conducted at 120 °C. The reaction was conducted at 130 °C.
c
Scheme 4. Proposed Reaction Mechanism
carried out under CO atmosphere. Under such conditions, it
was observed that the product 3b could only be obtained in 4%
yield, and most starting materials remained unchanged
(Scheme 5a). This result shows that the dissociation of
carbonyl ligand is crucial for the reaction. Notably, the reaction
of 2a with (CO)5Cr(0)C(NMe2)Ph under the standard
conditions did not afford the corresponding product, and most
(CO)5Cr(0)C(NMe2)Ph remained. The reaction of 2a with
(CO)5W(0)C(OMe)Ph gave only 7% of the corresponding
product under the standard conditions, albeit with a longer
reaction time of 20 h. Since these metal carbenes are less
electrophilic as compared to 1a, the results suggest that the
electrophilicity of the carbenic carbon is crucial for the reaction
to occur.
Next, a deuterium-labeling experiment was conducted with
substrates 2a-d5 and Cr(0) carbene complexes 1b under
standard conditions. The result shows that the deuterium atom
in the ortho position of the aromatic ring is nearly all
transferred to the carbon attached by ethoxy group in the
product 3b-d5 (Scheme 5b). The reaction of 2a and 1b in the
presence of D2O was also carried out, and no deuterium could
C
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be identified in the product (Scheme 5c). These results do not
support the proposed path a, but they are in agreement with
path b (Scheme 4).
Furthermore, kinetic isotope effect (KIE) experiments were
conducted (Scheme 5d). An evident primary KIE value was
observed (2.9 determined by intermolecular competition and
3.0 determined by parallel reaction), which suggests that the
C−H bond cleavage is involved in the rate-determining step.
The result is also not consistent with the proposed electro-
philic substitution mechanism (path a), but in agreement with
concerted C−H insertion mechanism (path b).
However, while carbene insertion into aliphatic C−H bond
mostly follows a concerted mechanism, the aromatic C−H
insertion by carbene is not considered following similar
concerted mechanism. To gain further insights into the
mechanism and to clarify the ambiguity, density functional
theory (DFT) calculations were carried out under the level of
M06/6-311++G**-SMD(toluene)//B3LYP(D3-BJ)/6-31G**
by Gaussian program.15 The model reaction in Table 1 was
used as the representative for the DFT study. We started our
computational study by examining the two classical pathways
shown in Scheme 4, using the substrate coordinated complex A
as the energetic starting point. The calculated free energies of
key steps for path a and path b are shown in Figure 1. Efforts to
Figure 2. The free-energy profiles of a stepwise mechanism via
hydrogen transfer and reductive elimination. Red values are bond
lengths (Å).
H bond has to cross a very high activation barrier, which is also
unlikely to occur.
On the basis of the above calculations, the two pathways
proposed in Scheme 4 are highly unfavorable and can be ruled
out. Instead, we find that the reaction could proceed through
an unconventional stepwise mechanism (Figure 2). Initially,
one CO group dissociates from the Cr center via TS0, which is
helpful for the following preactivation of the C(sp2)−H bond
by forming an agostic interaction with the Cr center. This leads
to the formation of the complex D. The uphill of free energy by
15.2 kcal/mol can be driven by releasing CO as gas. The C−H
bond is apparently activated by the agostic interaction, which is
supported by the elongated C−H bond length of 1.11 Å (see
the optimized geometry of D in Figure 3). Then, the hydrogen
Figure 1. Calculated free energies of key steps for path a and path b.
locate the transition state from A to B were unsuccessful.
However, the located intermediate B is highly unstable, which
is higher than A by 48.8 kcal/mol in terms of free energy. This
indicates that the electrophilic addition of the Cr(0) carbene to
the aromatic ring is highly unfavorable. Thus, it is unnecessary
to calculate the following proton transfer step of path a.
Combining the mechanistic experiments shown in Scheme 5, it
is safe to exclude path a.
Next, we try to locate the transition state for the concerted
insertion mechanism (the path b shown in Scheme 4);
however, this activation barrier is predicted to be as high as
45.3 kcal/mol, which is unlikely to be accessible under the
current experimental conditions. This is understandable
because the C(sp2)−H bond has not been effectively activated
prior to the insertion. As shown in Figure 2, the complex A is
six-coordinated with an octahedral geometry. There is no
vacant site for the coordination of the phenyl C(sp2)−H bond
that should be very helpful to activate it. We considered a
seven-coordinated complex with the phenyl group coordinated
to the Cr center, which, however, is very unstable. This can be
easily understood by the 18-electron rule. As expected, all
efforts to locate this complex were unsuccessful. Thus, the
direct insertion of Cr(0) carbene into the ortho-aromatic C−H
bond via TS_concerted without preactivation of the C(sp2)−
Figure 3. Optimized geometries of key stationary points and
transition states with selected bond lengths (Å). Trivial hydrogen
atoms are omitted for clarity.
transfer occurs through TS1 with a free-energy activation
barrier of 14.4 kcal/mol (TS1 relative to D), leading to
complex E. Finally, the reductive elimination takes place
through TS2 with a free-energy activation barrier of 24.6 kcal/
mol,16 leading to complex F, in which the final product 3a is
already formed. The rate-determining step for the whole
transformation is hydrogen transfer, crossing a free-energy
activation barrier of 29.6 kcal/mol (TS1 relative to A), which
D
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is accessible under the current experimental conditions (110
°C, 10 h). This is also in agreement with the KIE experiment.
We further analyzed the geometric and electronic structures
of the transition state TS1, aiming to determine whether the
hydrogen atom is transferred as a proton or a hydride. As
shown in Figure 3, the Cr−H distance in TS1 is only 1.62 Å,
which clearly shows hydridic characteristics. In addition,
molecular orbital analysis of TS1 shows that there is a Cr−
H σ-bond involved in the orbital of HOMO-2 (Figure 4a).
Figure 5. (a) The molecular orbital (LUMO) scheme of intermediate
D. (b) The electrostatic potential map of intermediate D.
Fischer carbene complexes. Under catalyst-free conditions, we
realized the alkylation of arenes bearing pyridines, pyrimidine,
and pyrazole as directing groups with good yields and excellent
regioselectivities. Furthermore, by combining experimental and
DFT studies, we found an unusual stepwise mechanism via
oxidative hydrogen migration and reductive elimination, which
is different from the classical electrophilic substitution
mechanism. The rate-determining step is the hydrogen
migration step, in which the C(sp2)−H bond is effectively
activated by the Cr center, leading to the hydridic character of
the transferring hydrogen atom that is accepted by the
electrophilic carbene carbon. Both experimental and DFT
results demonstrate that the prior dissociation of one CO
group from the Cr center is necessary for the hydrogen
migration step. This is the first time to report oxidative
hydrogen migration in the early transition metal carbene
system (Cr(0)-carbene in the current study, in particular), and
more potential applications of this process are undergoing in
our laboratory.
Figure 4. (a) The molecular orbital (HOMO−2) scheme of TS1. (b)
The electron density difference (Δρ) map of TS1 (The color code of
the electron flow is green → yellow). Trivial hydrogen atoms are
omitted for clarity.
Furthermore, the electron density difference (Δρ) map
displays that the carbene carbon accepts electron density
from the transferring hydrogen atom (Figure 4b). Overall,
these calculated results demonstrate that the breaking C(sp2)−
H bond in TS1 has been effectively activated by the Cr center,
resulting in the hydridic characteristics of the transferring
hydrogen atom that is accepted by the electrophilic carbene
carbon.11c,17 This activation mode needs a vacant site for the
C(sp2)−H bond to approach the Cr center, which indicates
the necessity of the dissociation of one CO group from the Cr
center. This is quite consistent with the experimental
observation that when 1 atm of CO pressure was introduced
into the reaction system, the yield was dramatically decreased
(Scheme 5a). All efforts to locate a Cr-complex with a hydride
as a minimum were failed, indicating that the seven-
coordinated hydride complex is highly unstable but can only
exist as a transition state. The Cr-center has been formally
oxidized to Cr(II) during this hydrogen transfer process, which
thus could be referred as the so-called “oxidative hydrogen
migration”.18,19 Such process was previously proposed in Pd-
catalyzed intramolecular carbene C−H functionalizations18
and some special cases of hydrogen transfer between R′-H and
M-R (usually for late transition metals).19 However, to the best
of our knowledge, no such “oxidative hydrogen migration” in
Cr-carbene systems has been reported before.
Cr(0)-carbene species is a Fischer-type carbene, which is
usually electron deficient and electrophilic. The analysis of
molecular orbital and electrostatic potential (ESP) surface of
the current Cr(0)-carbene species (D) also supports this. The
LUMO of D shows that the carbene carbon is mainly occupied
by the vacant p orbital (Figure 5a), and the ESP surface shows
that the carbene carbon is electron deficient (Figure 5b). This
agrees well with that the Cr-carbene species is favorable to
accept the hydrogen atom as a hydride via TS1 rather than as a
proton via TS_concerted.
EXPERIMENTAL SECTION
■
General Considerations. All the reactions were performed under
nitrogen atmosphere in oven-dried reaction flasks. For chromatog-
raphy, 200−300 mesh silica gel (Qingdao, China) was used. All the
solvents were distilled under nitrogen atmosphere prior to use.
Toluene and 1,4-dioxane were dried over Na with benzophenone-
ketyl intermediate as indicator. MeCN and DCE were dried over
CaH2. The boiling point of petroleum ether is between 60 and 70 °C.
Unless otherwise noted, commercially available reagents were used as
1
received. H NMR spectra were recorded on Bruker ARX 400 (400
MHz); 13C NMR spectra were recorded on Bruker ARX 400 (100
MHz). The data for NMR spectra were reported as follows: chemical
shifts (δ) were reported in ppm using tetramethylsilane (TMS) as the
internal standard, and coupling constants (J) are in Hertz (Hz). IR
spectra were recorded on Nicolet 5MX-S infrared spectrometer and
were reported in terms of frequency of absorption (cm−1). HRMS
were obtained on Bruker APEX IV FTMS. (MeCN: acetonitrile;
DCE:1,2-dichloroethane; PE: petroleum ether; EA: ethyl acetate).
General Procedure for the Preparation of Pentacarbonyl-
[(ethoxy)(phenyl)carbene] Chromium(0) Complexes. The
procedures were carried out according to a literature procedure:20
bromobenzene (0.54 mL, 5 mmol) was added to a round-bottom
Schlenk vessel which was charged with N2 for three times and 10 mL
of Et2O. To the solution was added dropwise nBuLi (2.5 M in hexane,
5.5 mL, 1.1 equiv) at −78 °C. Then the solution was stirred at −78
°C for 30 min.
Cr(CO)6 (1.1 g, 5 mmol) was added in another round-bottom
Schlenk vessel and charged with N2 and 10 mL of Et2O. To the
solution, the prepared phenyllithium solution in Et2O was added
dropwise at 0 °C. Then the solution was stirred at 50 °C for 3 h. The
solvent was removed under reduced pressure to give a crude mixture,
to which water (10 mL) was added, followed by adding Et3O·BF4 (1.6
g, 1.74 equiv, 8.7 mmol) in 0 °C. The aqueous solution was stirred at
rt for 10 min. Then it was extracted with Et2O (10 mL × 3), and the
CONCLUSIONS
■
In conclusion, we have developed the azacycle-directed
intermolecular aromatic C(sp2)−H functionalization of Cr(0)
E
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organic layer was dried over Na2SO4. Upon filtration and removal of
Et2O under reduced pressure, the crude mixture was purified by silica
gel column chromatography to afford pentacarbonyl[(ethoxy)-
(phenyl)carbene] chromium(0) 1a as a dark red solid (1.4 g, 85%,
PE as eluent).
Other chromium(0) carbene complexes were prepared via similar
procedure. 1a,20 1b,21 1c,22 1d,23 1h,24 1j,25 and 1k−1l26 were
confirmed by comparing their 1H and 13C NMR spectra. The
characterization data for unknown chromium(0) carbene complexes
are reported as follows.
General Procedure for the Preparation of 2-Phenylpyridine
Derivatives.27 To a stirred solution of arylboronic acid (1.3 equiv, 6.5
mmol, 0.8 g), Pd(PPh3)4 (3 mol %, 0.15 mmol, 0.17 g), and
Na2CO3(7.5 equiv, 37.5 mmol, 4.0 g) in toluene (17.5 mL), water
(17.5 mL), EtOH (3.75 mL) was added substituted 2-bromopyridine
(1.0 equiv, 5 mmol, 0.79 g) under nitrogen atmosphere. The reaction
was refluxed for 20 h and cooled to room temperature. To the
reaction mixture was added saturated NH4Cl solution (10 mL). The
mixture was extracted with EtOAc (15 mL × 3), dried over Na2SO4,
and evaporated in vacuum to afford the crude product, which was
purified by silica gel column chromatography with PE/EA to give the
corresponding 2-phenylpyridines. The following 2-phenylpyridines
are known compounds, and their spectral data are in agreement with
those reported in the literature.28−30
Preparation of Deuterated 2-(Pentaduteriophenyl) Pyridine
2a-d5. A solution of bromobenzene-d5 (6 mmol) in dried THF (24
mL) was added dropwise nBuLi (2.5M, 7.2 mmol, 2.9 mL) at −78 °C
and stirred for 1 h. B(OMe)3 (15.6 mmol, 1.74 mL) was then added.
The resulting mixture was further stirred at −78 °C for 1 h, and then
the reaction mixture was allowed to warm to room temperature. The
solution was acidified with 10% HCl solution and extracted with ethyl
ether. The combined organic layer was dried over Na2SO4 and
concentrated to give white solid which was used without further
purification.
To a stirred solution of phenylboronic acid-d5 (5.4 mmol),
Pd(PPh3)4 (0.13 mmol, 0.15 g), and Na2CO3 (31.5 mmol, 3.34 g) in
toluene (16 mL), water (16 mL), and ethanol (3.0 mL) was added 2-
bromopyridine (4.2 mmol) under nitrogen. The reaction was refluxed
for 20 h and cooled to room temperature. To the reaction mixture
was added saturated NH4Cl solution (10 mL), extracted with EtOAc
(15 mL × 3), dried over Na2SO4, and evaporated in vacuum to afford
the crude product, which was purified by silica gel column
chromatography with PE/EA to give 2-(pentaduteriophenyl)pyridine
(0.467 g, 2.92 mmol, 48% overall yield, 98% D). 1H NMR (400 MHz,
CDCl3) δ 8.69−8.67 (m, 1H), 7.72−7.69 (m, 2H), 7.21−7.16 (m,
1H).
General Procedure for the Reaction of Chromium(0) Fischer
Carbene Complexes with 2-Phenylpyridines. Pentacarbonyl-
(ethoxy)(phenyl)carbene chromium(0) 1a (65.2 mg, 0.2 mmol) were
added to a 25 mL Schlenk reaction flask. The reaction flask was then
degassed and charged with N2 three times, and toluene (2 mL) was
introduced using a syringe. After that, 2-phenylpyridine 2a (93 mg, 86
μL, 0.6 mmol) was added to the solution. The resulting solution was
then stirred at 110 °C for 10 h. After completion of the reaction, the
mixture was cooled to room temperature, filtered through a short plug
of silica gel (washed with EtOAc). Solvent was then removed in vacuo
to provide a crude mixture, which was purified by silica gel column
chromatography to afford the pure product.
Mechanistic Studies: The Effect of CO Pressure (Scheme
5a). Pentacarbonyl[(o-tolyl)(ethoxy)carbene]-chromium(0) 1b (68
mg, 0.2 mmol) was added to a 25 mL Schlenk reaction flask. The
reaction flask was then degassed and charged with CO gas three times
through a balloon full of CO gas, and toluene (2 mL) was introduced
using a syringe. After that, 2-(pentaduteriophenyl)pyridine 2a (93 mg,
0.6 mmol) was added to the solution. The resulting solution was then
stirred at 110 °C for 10 h. After completion of the reaction, the
mixture was cooled to room temperature and filtered through a short
plug of silica gel (washed with EtOAc). Solvent was then removed in
vacuo to provide a crude mixture, which was purified by preparative
thin-layer chromatography to afford the pure product 3b (4% yield).
Mechanistic Studies: Deuterium-Labeling Experiments
(Scheme 5b). Pentacarbonyl[(o-tolyl)(ethoxy)carbene]-chromium-
(0) 1b (68 mg, 0.2 mmol) was added to a 25 mL Schlenk reaction
flask. The reaction flask was then degassed and charged with N2 three
times, and toluene (2 mL) was introduced using a syringe. After that,
2-(pentaduteriophenyl)pyridine 2a-d5 (96 mg, 0.6 mmol) was added
to the solution. The resulting solution was then stirred at 110 °C for
10 h. After completion of the reaction, the mixture was cooled to
room temperature and filtered through a short plug of silica gel
(washed with EtOAc). Solvent was then removed in vacuo to provide
a crude mixture, which was purified by silica gel column
chromatography to afford the pure product 3b-d5 (63% yield, 98%
D). 1H NMR (400 MHz, CDCl3) δ 8.69−8.68 (m, 1H), 7.65 (td, J =
7.7, 1.8 Hz, 1H), 7.32−7.30 (m, 1H), 7.27−7.21 (m, 2H), 7.19−7.12
(m, 2H), 7.08−7.06 (m, 1H), 3.42 (dq, J = 8.8, 7.0 Hz, 1H), 3.26 (dq,
J = 8.7, 7.0 Hz, 1H), 2.02 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H).
Mechanistic Studies: Deuterium-Labeling Experiments
(Scheme 5c). Pentacarbonyl[(o-tolyl)(ethoxy)carbene]-chromium-
(0) 1b (68 mg, 0.2 mmol) was added to a 25 mL Schlenk reaction
flask. The reaction flask was then degassed and charged with N2 three
times, and toluene (2 mL) was introduced using a syringe. After that,
2-phenylpyridine 2a (93 mg, 86 μL, 0.6 mmol) and D2O (18 μL, 1.0
mmol) were added to the solution. The resulting solution was then
stirred at 110 °C for 10 h. After completion of the reaction, the
mixture was cooled to room temperature and filtered through a short
plug of silica gel (washed with EtOAc). Solvent was then removed in
vacuum to provide a crude mixture, which was purified by silica gel
column chromatography to afford the pure product 3b (67% yield, 0%
D).
Mechanistic Studies: KIE Measurements (Scheme 5d),
Intermolecular Competition. Intermolecular competition experi-
ment: Pentacarbonyl[(o-tolyl)(ethoxy)carbene]-chromium(0) 1b (68
mg, 0.2 mmol) was added to a 25 mL Schlenk reaction flask. The
reaction flask was then degassed and charged with N2 three times, and
toluene (2 mL) was introduced using a syringe. After that, 2-
phenylpyridine 2a (46.5 mg, 0.3 mmol) and 2-(pentaduteriophenyl)-
pyridine 2a-d5 (48 mg, 0.3 mmol) were successively added to the
solution. The resulting solution was then stirred at 110 °C for 20 min.
After completion of the reaction, the reaction mixture was cooled to
room temperature and filtered through a short plug of silica gel
(washed with EtOAc). Solvent was then removed in vacuum to
provide a crude mixture, which was purified by preparative thin-layer
chromatography to afford pure mixture product, the ratio of 3b:3b-d5
1
= 2.8 was determined by H NMR using nitromethane (12.2 mg) as
the internal standard.
Mechanistic Studies: KIE Measurements (Scheme 5d),
Parallel Experiments. Pentacarbonyl[(o-tolyl)(ethoxy)-carbene]
chromium (0) 1b (68 mg, 0.2 mmol) was added to a 25 mL Schlenk
reaction flask. The reaction flask was then degassed and charged with
N2 three times, and toluene (2 mL) was introduced using a syringe.
After that, 2-phenylpyridine 2a (93 mg, 0.6 mmol) was added to the
solution. In another reaction vessel, 2-(pentaduteriophenyl)pyridine
2a-d5 (96 mg, 0.6 mmol) was used instead of 2a. The two reactions
were stirred at 110 °C for 20 min simultaneously, and then the two
reactions were cooled to room temperature. The two-reactions
mixture was filtered through a short plug of silica gel (washed with
EtOAc). The solvent was removed in vacuum to provide a crude
mixture, which was purified by preparative thin-layer chromatography
to afford the mixture of the products, and the ratio of 3b:3b-d5 = 3.0
1
was determined by H NMR using nitromethane (24.4 mg) as the
internal standard.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00352.
■
sı
Experimental procedures, characterization data for new
compounds, X-ray crystallographic data (4g), and
spectroscopic data (PDF)
F
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Cartesian coordinates (XYZ)
pubs.acs.org/Organometallics
Article
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Achieving Site-Selectivity for C-H Activation Processes Based on
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2020, 142, 10571−10591.
Accession Codes
CCDC 2089497 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Jianbo Wang − Beijing National Laboratory of Molecular
Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College
of Chemistry, Peking University, Beijing 100871, China;
orcid.org/0000-0002-0092-0937; Email: wangjb@
pku.edu.cn
Shuanglin Qu − College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082 Hunan,
China; orcid.org/0000-0002-8122-9848; Email: squ@
hnu.edu.cn
Authors
Xing-Qi Yao − Beijing National Laboratory of Molecular
Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College
of Chemistry, Peking University, Beijing 100871, China
Wen-Yan Tong − College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082 Hunan,
China
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W. Catalytic Asymmetric Functionalization of Aromatic C-H Bonds
by Electrophilic Trapping of Metal-Carbene-Induced Zwitterionic
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Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. Highly Site-
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McClain, E. J.; Lan, Y.; Shi, X. Chemoselective Carbophilic Addition
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Kang Wang − Beijing National Laboratory of Molecular
Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College
of Chemistry, Peking University, Beijing 100871, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00352
Author Contributions
§X.-Q.Y. and W.-Y.T. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project is supported by National Natural Science
Foundation of China (21871010, 21903022), and the funding
from “Laboratory for Synthetic Chemistry and Chemical
Biology” under the Health@InnoHK Program launched by
Innovation and Technology Commission, The Government of
Hong Kong Special Administrative Region of China. We
dedicate this paper to Prof. Christian Bruneau for his
outstanding contribution to organometallics.
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https://doi.org/10.1021/acs.organomet.1c00352
Organometallics XXXX, XXX, XXX−XXX