Understanding the Chemoselectivity in Palladium-Catalyzed Three-Component Reaction of o-Bromobenzaldehyde, N-Tosylhydrazone, and Methanol

Article abstract of DOI:10.1021/acs.orglett.0c01040

To understand the ligand-controlled palladium-catalyzed coupling of o-bromobenzaldehyde, N-tosylhydrazone, and methanol to give methyl 2-benzylbenzoic ester or methyl ether, we herein investigated the mechanisms which account for how C-C and C-O bonds are

Full text of DOI:10.1021/acs.orglett.0c01040

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Letter
Understanding the Chemoselectivity in Palladium-Catalyzed Three-
Component Reaction of o‑Bromobenzaldehyde, N‑Tosylhydrazone,
and Methanol
Xiaojian Ren,§ Lei Zhu,§ Yinghua Yu, Zhi-Xiang Wang,* and Xueliang Huang*
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ABSTRACT: To understand the ligand-controlled palladium-
catalyzed coupling of o-bromobenzaldehyde, N-tosylhydrazone,
and methanol to give methyl 2-benzylbenzoic ester or methyl ether,
we herein investigated the mechanisms which account for how C−
C and C−O bonds are formed and why bidentate dppf/dppb
ligands afford ester, whereas P(o-tolyl)3 ligand gives ether. The
ester chemoselectivity of the bidentate ligands is attributed to the
strong electron-donating effect that disfavors the C,Br-reductive
elimination of the coupling intermediate of o-bromobenzaldehyde
and N-tosylhydrazone.
Scheme 1. Ligand-Dependent Three-Component Reaction
of o-Bromobenzaldehyde, N-Tosylhydrazone, and Methanol
ransition-metal-catalyzed divergent synthesis by variation
Tof the ancillary ligands is a simple but useful method to
access functional molecules with rich structural diversity. 2-
Benzylbenzoic acid derivatives are synthetically useful building
blocks.1 Traditional approaches to these compounds normally
require the employment of air- and moisture-sensitive
organometallic reagents.2,3 Therefore, the development of a
general method by using abundant feedstock chemicals as
reactants is in high demand. In line with our continuous
research interest in carbene-bridging C−H activation,4 we have
launched a project on a palladium-catalyzed three-component
reaction of o-bromobenzaldehyde, N-tosylhydrazone,5 and
methanol, aiming to prepare 2-benzylbenzoic esters in a
modular fashion.6 This reaction exhibits broad substrate scope
and good functional group compatibility, which may render
our protocol practically and synthetically useful. An intriguing
observation is that the backbone of phosphine ligands exerted
profound effects on the outcome of the reaction. As compared
in Scheme 1, the bidentate ligands (e.g., L1−L3) mainly afford
the formation of desired 2-benzylbenzoic ester 3b, while the
reactions with the bulky monodentate ligands (e.g., L4 and L5)
tend to give methyl ether 4b as the major product while
leaving the pendant aldehyde functionality intact. It is
interesting to know how the ligands control the chemo-
selectivty of the reactions. In addition, while we could envision
that the C−C bond could be constructed via migratory
insertion of in situ generated palladium carbene,7 we are
unclear how methanol was involved to form the C−O bond in
the ester group. With these questions in mind, we combined
experiments and DFT calculations to gain insight into the
reaction mechanism, using the reaction of 1a and 2a (i.e.,
simplified 2b with Ar = C6H5) with dppb (L2) or P(o-tolyl)3
(L5) ligands as representatives.
All structures were optimized at the B3LYP8,9 level with the
LANL2DZ10−12 basis set for Pd and Br and the 6-31G* basis
set for the rest of the atoms and subsequently verified to be
energy minima or transition states by vibrational frequency
calculations at the same level. The energies were then
improved by single-point energy calculations using the
M0613 functional combined with the def2-TZVP14 basis set
for all atoms with solvation effect accounted for by the SMD15
Received: March 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01040
© XXXX American Chemical Society
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A

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Figure 1. Energy profiles for the reactions of 1a and 2a′ with L2 (dppb) (A and B) and L5 (P(o-tolyl)3)(C) ligands, respectively. In (C) the
pathways to generate IM6a and that from IM18a to 3a are given in Figure S1 in the SI. Note that it was confirmed IM17a is lower than TS14a and
TS16a in terms of electronic energy. Q(Pd) values are NBO charges.20
B
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Figure 2. Optimized structures of key stationary points for C−O bond formation. Key bond lengths are given in angstroms.
continuum solvation model in methanol (the experimentally
used solvent). The single-point energies were corrected to
Gibbs free energies with the thermal corrections obtained from
vibrational frequency calculations. The free energies were
discussed in the main text. All calculations were performed
with the Gaussian09 package.16 The 3D structures of
molecules were generated using CYLview.17
their unfavorable energies, compared to their respective
competitors.
After the coupling of 1a and 2a′, methanol as the third
component begins to participate. First, IM6 reacts with K2CO3
−
to replace its Br− with KCO3 , resulting in IM12. As shown by
its structure (Figure 2), the basic KCO3− group of IM12 allows
it to deprotonate methanol via a concerted metalation−
deprotonation (CMD) transition state (TS7), resulting in
IM13. Note that prior to TS7 a weak complex between
methanol and IM12 is not shown. Subsequently, IM13
undergoes migratory insertion to insert the aldehyde carbonyl
bond into the Pd−O(Me) bond through TS8 to form a C−O
bond, resulting in IM14. Finally, a β-H elimination process via
TS9 converts IM14 to IM15, followed by a 1,2-H shift via
TS10 for depalladation, which takes place to afford the ester
product 3a and regenerate the active catalyst Pd-dppb.
In the above mechanism for C−O bond formation,
methanol deprotonation takes place before depalladation. We
further considered an opposite sequence, namely, a “through-
space” 1,4-palladium shift.19 Referring to IM6, the mechanism
breaks the Pd−C1 bond and forms the Pd−C2 bond by
transferring the aldehyde hydrogen to C.1 TS14 describes one
of the transition states for the process. Relative to IM6, the
barrier (24.2 kcal/mol) is not insurmountable but 6.0 kcal/mol
higher than the highest TS9 along the black pathway. Thus, we
exclude the mechanism in the present reaction. Similarly, the
1,4-palladium shift starting from IM12 via TS15 can also be
ruled out.
According to the previous studies, under the reaction
conditions, it could be reasoned that Pd(OAc)2 was reduced to
a Pd(0)18 active species Pd-dppb, and 2a was activated to 2a′
via Bamford−Stevens reaction. Using the active Pd-dppb and
2a′, Figure 1A and B illustrate the pathways of the reaction. To
begin with, 1a first coordinates to Pd-dppb to form a
coordination complex IM1, followed by oxidative addition via
crossing a barrier of 9.8 kcal/mol (TS1). Because the resultant
IM2 possesses a square planar structure without a vacant site
to interact with 2a′, it converts to a tricoordinate intermediate,
i.e., IM4, via dissociating a phosphine arm of the dppb ligand
(the black pathway) or to a cationic species IM7+ via removing
Br− with base K2CO3 (the blue pathway). As such, 2a′ could
interact with IM4/IM7+ at their vacant sites for dediazonation
through TS2/TS4+. Along the black pathway, TS2 leads to a
palladium carbene IM5 which then undergoes migratory
insertion via TS3 to fulfill the coupling of 1a and 2a′, giving
IM6. In contrast to the stepwise dediazonation and C−C bond
formation, TS4+ releases N2 and forms a C−C bond
simultaneously, giving IM8+. Supportively, geometric optimi-
zation of a cationic species starting with the structure of IM5
converged to IM8+. However, by combing with KBr and
Overall, the reaction has a rate-determining barrier of 29.9
kcal/mol (TS2 relative to IM2) for dediazonation and is
exergonic by 89.9 kcal/mol. The relatively high kinetic barrier
rationalizes the necessity of the elevated temperature (100.0
°C) for effective transformation. The step involving aldehyde
hydrogen transfer has a barrier of 27.2 kcal/mol (TS9 relative
to IM11), which is lower than the rate-determining barrier. To
KCO3 (released from the process from IM2 to IM7+), IM8+
−
can also reach the intermediate IM6 after passing through
IM11. Kinetically, the two C,C-coupling mechanisms are
competitive, as indicated by the small energy difference of 0.3
kcal/mol between TS2 and TS4. Other possible alternatives
described by the green pathways could be excluded because of
C
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affirm this, kinetic isotopic effect experiments were conducted.
As demonstrated by eq (a) in Scheme 2, no significant kinetic
elimination and the carbonyl insertion to be the cause of the
different chemoselectivites of the two ligands. However, the
reductive elimination barrier (TS11 and TS11a) for both
ligands is much higher than the highest transition states (TS8
and TS9a, respectively) in the pathway leading to 3a, which
explains the chemoselectivity of dppb but not of P(o-tolyl)3.
Moreover, the reductive elimination barrier (42.3 kcal/mol,
TS11a relative to IM6a) is too high to produce 4a.
Interestingly, we found that IM6a can undergo C,Br-reductive
elimination via TS12a with a feasible barrier of 22.9 kcal/mol,
leading to IM16a. Thermodynamically, the conversion of
IM15a to 4a is exergonic by 17.8 kcal/mol. To see if IM16a
could convert to 4a, we conducted an experimental study. As
we were not able to prepare separate IM16a due to its
instability, an analogue could be prepared successfully (eq (f)
in Scheme 2). Indeed, the analogue could be transformed to
the 4a analogue facilely.
Scheme 2. Mechanistic Experiments
The C,Br-reductive mechanism rationalizes the production
of 4a with P(o-tolyl)3, but the energetic difference (8.3 kcal/
mol) between TS12a and TS9a is too large for the observed
ratio (80/9) of 4a:3a. Thus, there must be a more favorable
alternative to afford 3a, encouraging us to reconsider the
pathway via a 1,4-palladium shift starting from IM6a. As
described by the green pathway in Figure 1C and Figure S1 in
the SI, the mechanism can also lead to 3a. Kinetically, the 1,4-
palladium shift mechanism is 5.8 kcal/mol more favorable than
the black pathway. Thus, the production of 3a as the minor
product with P(o-tolyl)3 actually takes place with a mechanism
completely different from that of the dppb ligand. The kinetic
preference of 2.5 kcal/mol to give 4a over to 3a explains the
major product 4a for P(o-tolyl)3.
We further crosschecked if the C,Br-reductive elimination
could take place with the dppb ligand. As compared in Figure
1A, the two reductive elimination transition states (TS12 and
TS13) are 3.7 and 18.0 kcal/mol higher than TS9, respectively.
Thus, the reaction with the dppb ligand could not produce 4a,
further supporting our mechanism on the production of ether
4a.
isotopic effect was observed, supporting our prediction of
dediazonation as the rate-determining step. To further
corroborate our mechanism, we traced the source of the
benzylic hydrogen in 3a through deuterium-labeling experi-
ments. Indeed, eq (b) demonstrates that the hydrogen
originates from the aldehyde group of 1, in line with our
mechanism. Puzzlingly, eq (c) suggests that methanol could
also be the hydrogen source, seemingly contradicting our
mechanism, because, as shown by TS7, the methanol hydroxyl
The discussions above indicate that the chemoselectivity of
the reaction is determined by how difficult it is for the C,C-
coupling intermediate (IM11 or IM6a) to undergo C,Br-
reductive elimination. Given that palladium catalysis generally
disfavors reductive elimination to form a C−heteroatom bond,
it is interesting to understand why IM6a could undergo the
reductive elimination but IM11 could not. We compared the
NBO charges of the palladium centers of IM6a and IM11. The
positive charge (0.08e) in IM6a, compared to the negative
charge (−0.12e) in IM11, agrees with that the former with a
barrier of 22.9 kcal/mol more easily undergoes reductive
elimination than the latter with a barrier of 30.9 kcal/mol. The
negatively charged palladium in IM11 could be attributed to
the stronger electron donation of the bidentate dppb ligand.
This explanation also holds true for the higher C,O-reductive
elimination barriers of IM13 (35.8 kcal/mol) than that of
IM13a (24.0 kcal/mol) because the Pd atom bears more
positive charge in IM13a (0.26e) than that in IM13 (0.09e).
On the basis of above mechanistic studies, Scheme 3
sketches the catalytic cycle of the reactions. After generation of
the activated catalyst (Pd-L), the reaction takes place via the
following steps: oxidative addition from Pd-L to A,
dediazonation from A to B which could proceed via either a
neutral or cationic mechanism, methanol deportation from B
to C, and sequential hydrogen transfers from C to D to E,
−
hydrogen is extracted by KCO3 to enter KHCO3. To
reconcile the disagreement, we conducted the control
experiments (eqs (d)−(e)). As shown by eq (d), the methanol
hydroxyl hydrogen can exchange with the benzylic hydrogen of
N-tosylhydrazone facilely, thus resulting in the scrambling in
eqs (c) and (e).
To understand the chemoselectivity of the reaction, the
reaction with L5 (i.e., P(o-tolyl3)) was also calculated. The
reaction also includes two stages. The pathway for the coupling
stage 1a and 2a′ is displayed in Figure S1 in the SI. In contrast
to the competitive two dediazonation mechanisms of dppb
(see TS2 and TS4+ in Figure 2A), the dediazonation pathway
of L5 via migratory insertion of palladium carbene is 8.7 kcal/
mol more favorable, compared to the cationic concerted
pathway. The difference of the two ligands can be ascribed to
the stronger electron-donating effect of the bidentate dppb
ligand than the monodentate P(o-tolyl)3 ligand which favors
the stabilization of the cationic species
Figure 1C displays the pathways for the C−O bond
formation stage. Analyzing IM13 and IM13a, intuitively, one
may consider the competition between C,O-reductive
D
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Authors
Scheme 3. Simplified Catalytic Cycle
Xiaojian Ren − School of Chemical Sciences, University of the
Chinese Academy of Sciences, Beijing 100049, China
Lei Zhu − Key Laboratory of Coal to Ethylene Glycol and Its
Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, Fujian College, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Fuzhou, Fujian 350002,
China
Yinghua Yu − Key Laboratory of Coal to Ethylene Glycol and Its
Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, Fujian College, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Fuzhou, Fujian 350002,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01040
Author Contributions
§X.R. and L.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
giving the final product 3a. In the case with the monodentate
phosphine ligand, B prefers reductive elimination to form the
C−Br bond, leading to the product 4a.
■
We acknowledge financial support by the NSFC (21773240,
21871259, and 21901244), the Hundred-Talent Program, and
the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000).
In summary, combing DFT calculations and experiments, we
have studied the catalytic mechanisms of the Pd-catalyzed
three-component coupling of o-bromobenzaldehyde, N-tosyl-
hydrazone, and methanol. The study unveils that the coupling
proceeds via two stages including C−C bond formation via
migratory insertion of palladium carbene and C−O bond
formation via aldehyde carbonyl insertion into the Pd−OMe
bond of the intermediate of methanol deprotonation. The
selective production of the ester product with the bidentate
ligand originates from its strong electron-donating effect that
prevents the C,Br-reductive elimination pathway of the Pd(II)
intermediate generated from the coupling of o-bromobenzal-
dehyde and N-tosylhydrazone.
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ASSOCIATED CONTENT
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Experimental procedures and computational details
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AUTHOR INFORMATION
Corresponding Authors
■
Zhi-Xiang Wang − School of Chemical Sciences, University of
the Chinese Academy of Sciences, Beijing 100049, China;
orcid.org/0000-0001-5815-3032; Email: zxwang@
ucas.ac.cn
Xueliang Huang − Key Laboratory of Coal to Ethylene Glycol
and Its Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, Fujian College, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Fuzhou, Fujian 350002,
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