Synthesis of Alkenylboronates from N-Tosylhydrazones through Palladium-Catalyzed Carbene Migratory Insertion

Article abstract of DOI:10.1021/jacs.1c02331

The palladium-catalyzed oxidative borylation reaction of N-tosylhydrazones has been developed. The reaction features mild conditions, broad substrate scope, and good functional group tolerance. It thus represents a highly efficient and practical method for the synthesis of di-, tri-, and tetrasubstituted alkenylboronates from readily available N-tosylhydrazones. One-pot Suzuki coupling and other transformations highlight the synthetic utility of the approach. DFT calculations have revealed that palladium-carbene formation and subsequent boryl migratory insertion are the key steps in the catalytic cycle. The high stereoselectivity observed in the formation of trisubstituted alkenylboronates has been explained by distortion-interaction analysis and NBO analysis.

Full text of DOI:10.1021/jacs.1c02331

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Synthesis of Alkenylboronates from N‑Tosylhydrazones through
Palladium-Catalyzed Carbene Migratory Insertion
Yifan Ping, Rui Wang,# Qianyue Wang,# Taiwei Chang, Jingfeng Huo, Ming Lei,* and Jianbo Wang*
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ABSTRACT: The palladium-catalyzed oxidative borylation reaction
of N-tosylhydrazones has been developed. The reaction features mild
conditions, broad substrate scope, and good functional group
tolerance. It thus represents a highly efficient and practical method
for the synthesis of di-, tri-, and tetrasubstituted alkenylboronates
from readily available N-tosylhydrazones. One-pot Suzuki coupling
and other transformations highlight the synthetic utility of the
approach. DFT calculations have revealed that palladium-carbene
formation and subsequent boryl migratory insertion are the key steps
in the catalytic cycle. The high stereoselectivity observed in the
formation of trisubstituted alkenylboronates has been explained by
distortion-interaction analysis and NBO analysis.
Scheme 1. Established Methods for the Synthesis of
Alkenylboronates
INTRODUCTION
■
Organoboron compounds are valuable reagents due to their
relative stability, low toxicity, and broad applications in organic
synthesis, material sciences, and pharmaceuticals.1 As one of
the important classes of organoboron compounds, alkenylbor-
onates are versatile building blocks for the synthesis of
stereodefined alkenyl compounds through Suzuki−Miyaura
cross-coupling,2−4 Zweifel olefination,5 Petasis reaction,6 and
other functional-group transformations.7,8 In addition, alke-
nylboronates have also been applied to prepare alkylboronates
through hydrofunctionalizations,9−14 difunctionalizations,15−18
conjunctive cross-couplings,19−21 radical processes,22,23 and
cycloadditions.24 Owing to the importance of alkenylboro-
nates, the development of efficient methods for their
preparation is of great significance. Several approaches have
been established for the synthesis of alkenylboronates to
date.25 Some alkenylboronates can be prepared from the
corresponding alkenyl halides or triflates through lithiation
followed by treatment with trialkylborates (Scheme 1a)26 or
palladium-catalyzed Miyaura borylation (Scheme 1b).27
However, most of the alkenyl halides or triflates are not
commercially available and should be prepared under strongly
acidic or basic conditions.28−30 The hydroboration or
carboboration of alkynes is another common method, which
employ expensive and less abundant alkynes as the starting
materials (Scheme 1c).31,32 Whereas 1,2-disubstituted alkenyl-
boronates can be readily accessed through anti-Markovnikov
hydroboration of terminal alkynes,33−38 only few examples
have been reported for the synthesis of 1,1-disubstituted
alkenylboronates with Markovnikov selectivity.39,40 Moreover,
hydroboration or carboboration of nonsymmetric internal
alkynes toward tri- or tetrasubstituted alkenylboronates often
Received: March 1, 2021
Published: June 23, 2021
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© 2021 American Chemical Society
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bears poor regioselectivities to deliver a mixture of
regioisomers.41−44 Other methods for the synthesis of
alkenylboronates, including alkene cross-metathesis,45,46 alkene
dehydrogenative borylation,47−50 and boron-Wittig reac-
tion,51−53 also have their limitations in substrate scope.
Consequently, further development of highly efficient and
selective reactions for the diverse synthesis of alkenylboronates
is still in great demand.
Pd(PPh3)4 as the catalyst, LiOtBu as the base, and p-
benzoquinone (BQ) as the oxidant. However, we could not
observe any desired alkenylboronate 3. Carefully analyzing the
reaction, we found that a considerable amount of product 4
was generated in this system, which might come from the
oxidative dimerization of N-tosylhydrazone 1a (eq 1). To
Ketones are cheap and abundant building blocks in organic
synthesis that show versatile reactivity.54 Among them, the
conversion of ketones into N-tosylhydrazones via simple
condensation represents an important application. N-Tosylhy-
drazones are useful synthons that can undergo classic Shapiro
reaction or Bamford−Steven reaction to prepare alkenes and
diazo compounds.55,56 Recently, N-tosylhydrazones have also
been used as the coupling partners in transition-metal-
catalyzed cross-coupling reactions.57−60 In these reactions,
diazo compounds are generated in situ and then react with
organometallic species to form a metal carbene, followed by
carbene migratory insertion and subsequent transformations.
With suitable transition-metal catalysts and coupling partners,
various coupling products can be generated. Our group and
others have developed a series of cross-coupling reactions
between N-tosylhydrazones and various carbon nucleophiles or
electrophiles, which represent a type of powerful synthetic
methods for C−C bond formations.61−66 However, heter-
oatomic nucleophiles or electrophiles are still less explored for
carbene-based cross-coupling to form C−X bonds.67,68 As a
continuation of our interest in carbene-based coupling
reactions, we envisioned that diboron compounds may become
carbene coupling partners under palladium catalysis, because
boron−palladium species can be readily generated through
transmetalation under mild conditions.69 We expected that the
boron−palladium species could participate in carbene
migratory insertion followed by β-H elimination, which may
provide a new approach for the synthesis of alkenylboronates
(Scheme 2).70 Herein, we reported our detailed study on the
inhibit this side reaction, we used a sterically bulky N-
tosylhydrazone 1b as the substrate to attempt this reaction
under the same conditions. Gratifyingly, the desired
alkenylboronate 5 could be obtained in 34% yield and the
oxidative dimerization was completely inhibited (eq 2).
Encouraged by this result, we further optimized the reaction
conditions. A series of oxidants were first examined, and it was
observed that 2,5-DMBQ could afford slightly improved yields
for the reaction (Table 1, entries 1−3). Then the catalyst was
screened. We found that Pd(OAc)2 with PPh3 as the ligand
gave a better result (entry 4). Other solvents such as dioxane
and MeCN were also tested, but only a trace amount of the
product was observed (entries 5, 6). On elevating the
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of Alkenylboronates from Ketones
through Palladium-Catalyzed Carbene Migratory Insertion
b
entry
cat.
Pd(PPh3)4(5)
Pd(PPh3)4(5)
base
T (°C) yield (%)
c
1
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
Cs2CO3
NaH
80
80
80
80
80
80
90
90
90
90
90
90
90
32
41
42
45
trace
trace
60
trace
trace
61
d
2
3
4
Pd(PPh3)4(5)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/PPh3(10)
Pd(OAc)2(5)/P(m-tol)3(10)
Pd(OAc)2(2.5)/P(m-tol)3(5)
e
5
f
6
7
8
9
10
11
12
13
g
palladium-catalyzed oxidative cross-coupling reaction between
N-tosylhydrazones and diboron compounds. This reaction
provides an efficient method for diverse synthesis of di-, tri-,
and tetrasubstituted alkenylboronates from easily available
ketones.71−73 Computational studies substantiate the reaction
pathway involving palladium carbene formation and migratory
insertion of the boron group.
NaH
NaH
NaH
69
74
78
g
g
a
If not otherwise noted, the reaction was carried out with 1b (0.1
mmol), 2 (0.15 mmol), and 2,5-DMBQ (0.15 mmol) in 1.0 mL of
toluene (0.1 M). Isolated yields after silica gel column chromatog-
raphy. BQ is used as the oxidant instead of 2,5-DMBQ. 2,6-DMBQ
is used as the oxidant instead of 2,5-DMBQ. Dioxane was used as the
solvent instead of toluene. MeCN was used as the solvent instead of
toluene. 2.0 mL of toluene (0.05 M) was used. BQ: 1,4-
benzoquinone; 2,6-DMBQ: 2,6-dimethyl-1,4-benzoquinone; 2,5-
DMBQ: 2,5-dimethyl-1,4-benzoquinone; P(m-tol)3: tris(3-
methylphenyl)phosphine.
b
c
d
e
RESULTS AND DISCUSSION
f
■
g
At the outset, we investigated this transformation by
employing N-tosylhydrazone 1a derived from acetophenone
as the substrate and bis(pinacolato)diboron 2 as the borylation
reagent. The reaction was carried out in toluene at 80 °C with
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temperature to 90 °C, the yield could be improved to 60%
(entry 7). Some other bases were also examined (entries 8−
10). Despite that NaOtBu and K2CO3 showed deleterious
effects on the reaction (entries 8, 9), we found that NaH could
give a slightly improved yield (entry 10). It is noteworthy that
lower concentration is beneficial for the reaction (entry 11).
Further optimization of the ligand revealed that P(m-tol)3 led
to an increased yield of 74% (entry 12). Finally, by lowing the
catalyst loading to 2.5 mol %, the desired product could be
obtained in 78% yield (entry 13).
With the optimized conditions in hand, we then examined
the substrate scope. First, we investigated N-tosylhydrazones
bearing a secondary alkyl group adjacent to the hydrazone
moiety, which could give tetrasubstituted alkenylboronates
after β-H elimination (Scheme 3). Tetrasubstituted alkenyl-
boronates are important synthetic precursors for the synthesis
of tetrasubstituted alkenes, which are ubiquitous in bioactive
molecules and pharmaceuticals.74,75 However, the known
methods for their synthesis are relatively rare.41−44,76−80
Under the standard conditions, a variety of tetrasubstituted
alkenylboronates could be prepared with good efficiency. For
aromatic N-tosylhydrazones, the substrates bearing electron-
withdrawing or weak electron-donating substituents at the
para-position proceeded well, affording the corresponding
products in good yields (7−15, 18). For the substrates
containing strong electron-donating groups like methoxy and
dimethylamino, slightly diminished yields were obtained due
to the inhibition of 1,2-H shift (16, 17). The substituents at
meta- or ortho-position does not significantly affect the
reactivity (19−23). Notably, some sensitive functional groups
in conventional synthetic methods, including aryl chloride and
bromide, could be well tolerated (8, 9). The reaction was also
applicable to polycyclic or heterocyclic aromatic substrates
(24−26).
In addition, exocyclic alkenylboronates could be prepared by
employing the corresponding N-tosylhydrazones containing
cyclobutyl, cyclopentyl, or cyclohexyl groups (27−29). A
substrate with two different substituents at the α position (R2
≠ R3) was also suitable for the reaction, affording the product
with E/Z isomers in good yield (30). The low stereoselectivity
may come from the low diastereocontrol at the carbene
migratory insertion step. The reaction also proceeded with
aliphatic N-tosylhydrazone, albeit in low yield (31). We also
evaluated some other commercially available diboron com-
pounds, including B2neo2, B2mpd2, B2dmpd2, and Bpin-Bdan.
All of these diboron reagents worked, affording the differently
protected alkenylboronates in moderate to good yields (32−
35).
Scheme 3. Substrate Scope for the Synthesis of
Tetrasubstituted Alkenylboronates
a
Next, the reaction was extended to N-tosylhydrazones
bearing a primary alkyl group adjacent to the hydrazone
moiety for the synthesis of trisubstituted alkenylboronates
(Scheme 4). Traditional approach for the synthesis of
trisubstituted alkenylboronates usually relies on hydroboration
of internal alkynes, which often give a mixture of regioisomers
unless the substrates have large steric or electronic differ-
entiation.31,32 Moreover, Z products are often exclusively
formed by the syn-addition mechanism. Based on our strategy,
an assortment of trisubstituted alkenylboronates could be
smoothly obtained from the corresponding N-tosylhydrazones
with E isomers as the major products, which is a good
complement to the previous approach. Substrates with diverse
substitution patterns at α position (R2) were competent for the
reaction, affording the products in good yields and high E-
selectivity (36−43). Both electron-rich and electron-deficient
aryl N-tosylhydrazones underwent the oxidative borylation
successfully (44−56). A variety of functional groups were
compatible with the reaction conditions, including aryl
chloride (44, 54), bromide (45, 50), boronate (51), ester
(52), ether (47, 55, 56), amine (48), and silyl ether (53).
Reactions of heteroaromatic or aliphatic substrates also
occurred to give the corresponding products in relatively low
yields (57−59).
Furthermore, some cyclic alkenylboronates, which cannot be
prepared by alkyne hydroboration, could be readily synthesized
from the corresponding cyclic N-tosylhydrazones by our
strategy (Scheme 5). The reaction proceeded smoothly in all
cases, affording the products in moderate to good yields (60−
69).
a
Reaction conditions: N-tosylhydrazone (0.3 mmol), B2pin2 (0.45
mmol), Pd(OAc)2 (2.5 mol %), P(m-tol)3 (5 mol %), NaH (0.9
mmol), 2,5-DMBQ (0.45 mmol) in toluene (6 mL) at 90 °C for 10 h.
All the yields refer to the isolated yields after silica gel column
b
chromatography. The E/Z ratio was determined by 1H NMR of the
c
d
Due to the importance as well as the limited methodology
isolated product. B2neo2 instead of B2pin2. B2mpd2 instead of
B2pin2. B2dmpd2 instead of B2pin2. Bpin-Bdan instead of B2pin2.
for the synthesis of 1,1-disubstituted alkenylboronates,27,39,40
e
f
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Scheme 4. Substrate Scope for the Synthesis of
Trisubstituted Alkenylboronates
Scheme 5. Substrate Scope for the Synthesis of Cyclic
Alkenylboronates
a
a
a
Reaction conditions: N-tosylhydrazone (0.3 mmol), B2pin2 (0.45
mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), NaH (0.9 mmol),
2,5-DMBQ (0.45 mmol) in toluene (6 mL) at 100 °C for 10 h. All the
yields refer to the isolated yields after silica gel column
b
chromatography. Pd(OAc)2 (5 mol %), PPh3 (10 mol %).
Table 2. Optimization of the Reaction Conditions for the
a
Synthesis of 1,1-Disubstituted Alkenylboronates
b
entry
oxidant
solvent
T(°C)
yield(%)
1
2
3
4
5
6
7
2,5-DMBQ
2,5-DMBQ
BQ
2,6-DMBQ
thymoquinone
TMBQ
toluene
toluene
toluene
toluene
toluene
toluene
DCE
90
24
31
0
31
42
46
61
100
100
100
100
100
100
a
Reaction conditions: N-tosylhydrazone (0.3 mmol), B2pin2 (0.45
mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), NaH (0.9 mmol),
2,5-DMBQ (0.45 mmol) in toluene (6 mL) at 90 °C for 10 h. All the
yields refer to the isolated yields after silica gel column
chromatography. E/Z ratios were determined by 1H NMR of isolated
b
TMBQ
products. The E/Z ratio was determined by GC-MS.
a
The reaction was carried out with 1a (0.1 mmol) and 2 (0.15 mmol)
b
in 2.0 mL of solvent (0.05 M). Isolated yields after silica gel column
chromatography. Thymoquinone: 5-isopropyl-2-methyl-1,4-benzoqui-
none; TMBQ: 2,3,5-trimethyl-1,4-benzoquinone.
we further wished to expand the scope into methyl-substituted
N-tosylhydrazones as the substrates. We first explored the
reaction of 1a with bis(pinacolato)diboron 2 again under the
previously optimized reaction conditions (Table 2, entry 1),
and the 1,1-disubstituted alkenylboronate 3 was isolated in
24% yield. On elevating the temperature to 100 °C, the yield
was slightly improved (entry 2). Then, a series of BQ
derivatives were examined (entries 3−6), indicating that the
oxidant had a critical influence on this reaction. Despite that
simple BQ could not promote this reaction (entry 3), BQs
with bulky substituents are beneficial for the transformation
(entries 4−6). The use of thymoquinone as the oxidant led to
an increased yield (entry 5). With the more sterically bulky
oxidant 2,3,5-trimethyl-1,4-benzoquinone (TMBQ), the yield
could be further improved to 46% (entry 6). Finally, by
changing the solvent to DCE, the reaction could afford the 1,1-
disubstituted alkenylboronate 3 in 61% yield (entry 7).
aromatic rings were all compatible and provided the desired
products in moderate yields (70−78). Meta- and ortho-
substituted as well as disubstituted aromatic N-tosylhydrazones
were competent for this reaction, affording the corresponding
products in moderate yields (79−86). The reaction also shows
good tolerance for functional groups, such as halides (70, 71,
80, 83), ester (78), ether (73, 81, 84, 85), sulfide (76), and
boronate (77). We also applied the reaction to the
modification of complex molecules. Thus, the 1,1-disubstituted
alkenylboronates derived from bioactive natural product
estrone (87) and the fragrance tonalid (88) were successfully
obtained through this methodology in moderate yields.
To demonstrate the practical applicability of this method-
ology, the standard reaction was carried out in gram scale
(Scheme 7a). The alkenylboronate 5 (1.246 g) was
successfully obtained with satisfactory yield under the standard
reaction conditions. To simplify the reaction protocol, we also
We then evaluated a series of methyl-substituted N-
tosylhydrazones with different electronic and steric properties
(Scheme 6). Substrates bearing electron-withdrawing or
electron-donating substituents in the para-position of the
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Furthermore, the synthetic utility of this protocol was
investigated through a series of transformations of alkenylbor-
onates. We first explored the one-pot oxidative borylation/
Suzuki coupling reactions of N-tosylhydrazones, bis-
(pinacolato)diboron, and aryl bromides (Scheme 8). The
Scheme 6. Substrate Scope for the Synthesis of 1,1-
Disubstituted Alkenylboronates
a
Scheme 8. One-Pot Oxidative Borylation/Suzuki Coupling
a
Sequence
a
Reaction conditions: N-tosylhydrazone (0.3 mmol), B2pin2 (0.45
mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), NaH (0.9 mmol),
TMBQ (0.45 mmol) in DCE (6 mL) at 100 °C for 10 h. TMBQ:
trimethylquinone. All yields refer to the isolated yields after silica gel
column chromatography.
Scheme 7. Gram-Scale Synthesis and One-Pot Synthesis of
Alkenylboronates from Ketones
a
First step: reactions were performed with N-tosylhydrazone (0.3
mmol), B2pin2 (0.45 mmol), Pd(OAc)2 (2.5 mol %), P(m-tol)3 (5
mol %), NaH (0.9 mmol), 2,5-DMBQ (0.45 mmol) in toluene (6
mL) at 90 °C for 10 h. Second step: ArBr (0.45 mmol), NaOH (2 M,
0.3 mL) were added, and reactions were stirred at 90 °C for 24 h. All
yields refer to isolated yields after silica gel column chromatography.
b
First step: Pd(OAc)2 (5 mol %), PPh3 (10 mol %). E/Z ratios were
c
1
determined by H NMR of isolated products. First step: Pd(OAc)2
(10 mol %), PPh3 (20 mol %), 100 °C. Barluenga’s coupling: N-
d
tosylhydrazone (0.3 mmol), ArBr (0.3 mmol), Pd2dba3 (1 mol %),
XPhos (2 mol %), LiOtBu (0.66 mmol) in dioxane (1.8 mL) at 90 °C
for 16 h.
reactions worked well by a single palladium catalyst, providing
the polysubstituted alkenes in moderate to good yields without
the requirement for isolation of the alkenylboronates (89−98).
Notably, these sequential reactions could deliver trisubstituted
alkenes with good stereoselectivities, which could not be
achieved under Barluenga’s coupling of N-tosylhydrazones
with aryl bromides (92−96).61 With appropriate combination
of the substrates, stereodivergent synthesis of Z and E isomers
could also be realized (94, 95). A variety of functional groups,
including heterocycle (89, 92, 93), ester (90), ether (91−95,
98), nitrile (96), and ketone (97), were well tolerated.
performed the one-pot synthesis starting directly from the
corresponding ketones (Scheme 7b). After the complete
formation of N-tosylhydrazones followed by the removal of
solvent, the oxidative borylation worked smoothly to afford
alkenylboronate products (3, 36, 38, 42, 44, 74) in moderate
yields.
In addition to the one-pot oxidative borylation/Suzuki
coupling reactions, the synthetic usefulness of this borylation
protocol has also been demonstrated by the further trans-
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Scheme 9. Comparison between Miyaura Borylation and Carbene Coupling
formations of tetrasubstituted alkenylboronates (see Support-
ing Information for the details).
alkenylboronates (36, 42, 44) could be produced through one-
pot synthesis in both good yields and high E-selectivities
(Scheme 9b). Finally, sensitive functional groups such as
dimethylamino could not be tolerated in the triflation step for
Miyaura borylation, while carbene coupling shows good
compatibility of this functional group to afford the
alkenylboronate product 48 in moderate yield (Scheme 9c).
When considering the synthesis of alkenylboronates from
ketones or aldehydes, the conventional approach would be
Miyaura borylation.27 Compared with the Miyaura borylation
of ketones through alkenyltriflates, carbene coupling of N-
tosylhydrazones shows advantages in some cases (Scheme 9).
It is noteworthy that most of the alkenyltriflates derived from
aromatic ketones are not stable, which can only be generated in
situ for the Miyaura borylation. On the contrary, N-
tosylhydrazones are a stable solid that can be readily isolated
and purified through precipitation or column chromatography.
For sterically bulky ketones such as 99 and 100, the generation
of tetrasubstituted alkenyltriflates was in low efficiency with a
considerable amount of ketones remaining, so the subsequent
Miyaura borylation delivered tetrasubstituted alkenylboronates
5 and 29 in low yields. Moreover, the alkenylboronate
products could not be separated with the remaining ketones
through column chromatography due to their similar polarity.
In contrast, N-tosylhydrazones could be easily prepared from
99 and 100 to undergo carbene coupling, providing
alkenylboronates 5 and 29 in good yields with high purity
(Scheme 9a). The synthesis of trisubstituted alkenylboronates
(36, 42, 44) from the corresponding ketones 101−103
through Miyaura borylation could be achieved in good yields.
However, the stereoselectivities could not be well controlled,
and the isolation of pure alkenyl boronates 42 and 44 was
difficult because of the incomplete consumption of the ketone
substrates. With carbene coupling processes, the trisubstituted
COMPUTATIONAL STUDIES
■
On the basis of previous studies,57−60,70 we proposed a
plausible mechanism for this reaction (Scheme 10). The
reaction starts with transmetalation between bis(pinacolato)-
diboron and Pd(OAc)2 to form the boron−palladium(II)
species B. In contrast, N-tosylhydrazone generates the
corresponding diazo compound in the presence of NaH as
the base. Then, the boron−palladium species B decomposes
the diazo compound to form palladium carbene species C,
which undergoes boryl migratory insertion to generate
intermediate D. Afterward, cis β-H elimination occurs to
deliver the final product and generate the intermediate E. The
intermediate E goes through reductive elimination to form
Pd(0) species F, which is oxidized by the 2,5-DMBQ to
generate Pd(II) species A. Finally, the transmetalation between
Pd(II) species A and bis(pinacolato)diboron occurs to
regenerate the active catalytic boron−palladium(II) species B
for the next catalytic cycle II.
To gain more detailed insights into the reaction mechanism
as well as the origin of the observed stereoselectivity, a density
functional theory (DFT) study was carried out on the
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more favorable than cycle I by A1 (Y = OAc). Therefore, in
the following discussion, we only give the free energy profiles
with B1 as the active catalytic species. The free energy profiles
of cycle II are shown in Figure 1, and those of cycle I are given
in Figure S1A of the Supporting Information (SI). Both cycles
I and II consist of six fundamental steps: the carbene formation
step, the Bpin migratory insertion step, the β-hydride
elimination step, the reductive elimination step, the oxidative
addition step, and the transmetalation step.
Scheme 10. Proposed Reaction Mechanism
We chose the formation of 5 from 1b (Scheme 3 and
Scheme 7a) as the model for computational study on the
reaction pathway. As shown in Figure 1, the free energies of
stationary points along the reaction pathway are relative to B1.
First, the diazo compound 1b′ coordinates with B1 to form
intermediate B2, then B2 decomposes by extrusion of N2 gas
to generate a Pd(II)-carbene species B3 via transition state
(TS) TSB2−3 with an energy barrier of 9.25 kcal/mol (B1 →
TSB2−3). Similar to the palladium carbene species previously
reported by our group,92−94 complex B3 is unstable and could
easily undergo the Bpin migratory insertion via TSB3−4
owning a low energy barrier of 0.09 kcal/mol, resulting in
intermediate B4, which is exergonic by 23.62 kcal/mol.
Subsequently, β-hydride elimination step from B4 to B5
takes place through TSB4−5 owing to a four-membered-ring
structure, climbing an energy barrier of 0.41 kcal/mol to give π
complex B5. Then the π complex B5 dissociates into product 5
and intermediate B6. In the reductive elimination step from B6
to A7 via TSB6−A7 having an energy barrier of 14.63 kcal/
mol, the Pd(0) species A7 is formed with the release of HOAc
that could react with NaH to further enhance the
thermodynamic driving force. Then the Pd(0) species is
oxidized by 2,5-dimethyl-1,4-benzoquinone (2,5-DMBQ) to
form the intermediate A8, which is exergonic by 22.58 kcal/
mol. The B2pin2 substrate interacts with A8 to form A9
followed by a transmetalation process from A9 to B1, which is
a stepwise step. The Bpin moiety of A9 undergoes Bpin
transfer via TSA9−10 to achieve A10 with the formation of a
B−O bond. The free energy barrier for the Bpin transfer is
13.00 kcal/mol from A9 to A10. Afterward, the B−B σ-bond of
B2pin2 part is cleaved via TSA10−11 with an energy barrier of
12.60 kcal/mol, producing the intermediate A11. The formed
oxidative borylation reaction catalyzed by palladium complex
(as shown in Scheme 10) at the ωB97X-D/BSI level using the
Gaussian 09 program.81,82 BSI denotes that the effective core
potential (ECP) of Pd with a double-ζ valence basis set
(LANL2DZ) was used for the Pd center and the 6-31G (d,p)
basis sets for all the other atoms.83,84 The SMD polarizable
continuum model using toluene as the solvent was employed
in the calculation.85 Free energies were calculated at 298.15 K.
Thermal correction and entropy contribution to the Gibbs free
energy were taken from the frequency calculations at the
ωB97X-D/BSI level, in which the translational movement was
evaluated using the method presented by Whitesides and co-
workers.86−90 The geometric structures are visualized using the
VMD program.91
As shown in Scheme 10, the whole catalytic cycle could be
divided into cycle I and cycle II, and the difference between
cycle I and cycle II is the ligand Y of the active catalytic species
that is OAc in cycle I while DMBQ-Bpin in cycle II. The
calculated results indicate that cycle II by the boron−
palladium(II) species B1 (Y = DMBQ-Bpin) is energetically
Figure 1. Free energy profiles of the oxidative borylation of N-tosylhydrazones catalyzed by catalytic species B1 of cycle II. All energies are relative
to B1 (unit: kcal/mol).
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intermediate A11 then isomerizes into more stable active
catalytic species B1 for the next catalytic cycle II. The
calculated results indicate that the energy span of cycle I is
24.25 kcal/mol (A9 → TSA10−11) for the transmetalation
step.
Cycle I goes through the same fundamental steps as cycle II.
Similarly, the calculated free energy barriers of the carbene
formation step, the Bpin migratory insertion step, the β-
hydride elimination step, the reductive elimination step, the
oxidative addition step, and the transmetalation step of cycle I
are 13.32, 5.68, 0.99, 13.82, 0.00, and 24.25 kcal/mol (Figure
S1A), respectively, and those of cycle II are 9.25, 0.09, 0.41,
14.63, 0.00, and 24.25 kcal/mol, respectively. It is obvious that
changing the OAc ligand to a DMBQ-Bpin ligand can reduce
the energy barriers in the carbene formation step, Bpin
migratory insertion step, and β-hydride elimination step, while
slightly increase the energy barrier of the reductive elimination
step (Figure 2). Depending on the barrier energy, the
Figure 3. Free energy profiles for the β-hydride elimination step
catalyzed by palladium. Path E and path Z indicate that the final
product is an E isomer (in blue) and a Z isomer (in black),
respectively. All energies are denoted in kcal/mol.
complex C5E. Alternatively, that is 4.85 kcal/mol (C4 →
TSC4−5Z) along path Z leading to the Z isomer via TSC4−
5Z. To complete the cis β-hydride elimination (path Z), C4
isomerizes into INTC4, in which H2 interacts with the Pd
center via an agostic interaction. The energy barrier of the
isomerization is 4.62 kcal/mol. The calculated results indicate
that the formation of the Z product is less favorable than that
of E, explaining our observed stereoselectivity in the experi-
ment.
The origin of stereoselectivity is related to electronic
structures of stationary points along the β-hydride elimination
step. To further unveil the nature of the stereoselectivity, the
distortion-interaction analysis95−97 has been carried out for
TSC4−5E and TSC4−5Z. As shown in Figure 4A, in the
energy decomposition analysis, the transition state was divided
into two fragments. ΔEdist (mono) and ΔEdist (cat) are the
distortion energies of the monomer moiety and remaining
metal complex, respectively, and the interaction energy ΔEint
encompasses both destabilizing steric repulsions and stabilizing
electrostatic and orbital interactions between these two
fragments. DIA shows that the difference in total distortion
energy between TSC4−5E and TSC4−5Z is small (16.83 vs
16.82 kcal/mol), and the lower energy of TSC4−5E compared
with TSC4−5Z is mainly caused by the stronger interaction
between the metal complex and monomer moiety (−36.89 vs
−33.95 kcal/mol). The interaction between the organometallic
complex and unsaturated hydrocarbons could be described by
the Dewer−Chatt−Duncanson model.98−100 The metal−
ligand interaction could be considered to arise from the
electron pair delocalization, in which a donation of olefin π-
electrons into the metal and back-donation from the metal into
the olefin π* orbital occur. Meanwhile, the natural bond orbital
(NBO) analysis shows the acceptor−donor interactions
between the Pd−H bond and C1C2 bond. In TSC4−5E,
the second-order perturbative energy E(2) for the π(C1−C2)
→ σ*(Pd−H1) interaction is 92.90 kcal/mol and the E(2) for
σ(Pd−H1) → π*(C1−C2) interaction is 67.14 kcal/mol, but
in TSC4−5Z, the E(2) for the π(C1−C2) → σ*(Pd−H2)
interaction and σ(Pd−H2) → π*(C1−C2) interaction is 83.66
and 66.31 kcal/mol, respectively. This indicates that the
difference in energy between TSC4−5E and TSC4−5Z is due
to the orbital interactions, which leads to the stereoselectivity.
Figure 2. Comparison of the energy barriers of each fundamental
steps in cycle I and cycle II.
transmetalation step is the rate-determining step in the
whole cycle. In addition, the calculated results show that the
energy barrier of the Bpin migratory insertion step in cycle II is
only 0.09 kcal/mol, which indicates that the palladium carbene
species B3 could easily undergo migratory insertion and form a
more stable complex B4. It is noteworthy that our previous
computational studies in other palladium-catalyzed carbene
coupling reactions all suggest facile migratory insertion of
palladium carbene species.92−94
E isomers of trisubstituted alkenylboronates are the major
products in this oxidative borylation reaction of N-tosylhy-
drazones catalyzed by a palladium complex (see Scheme 4). It
is obvious that the selectivity-determining step is the β-hydride
elimination step leading to E/Z isomers. In order to unveil the
origin of the stereoselectivity of this reaction, we investigated
the selectivity-determining step (β-hydride elimination step)
for forming 36 shown in Scheme 4 as the model reaction. This
model reaction used Pd(OAc)2 with a PPh3 ligand as the
catalyst, and the corresponding catalytic species is boron−
palladium(II) complex C1. In this part, all relative energies of
the stationary points along the reaction pathways are relative to
C1. The β-hydride elimination step is from C4 to C5, which
could form different stereoselective products. As shown in
Figure 3, the energy barrier of the β-hydride elimination step is
1.76 kcal/mol along path E, leading to the E isomer via
TSC4−5E having a four-membered-ring structure, giving π
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02331.
■
sı
Experimental procedures and spectral data for all new
compounds (PDF)
Detailed computational study and calculated structures
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Ming Lei − State Key Laboratory of Chemical Resource
Engineering, Institute of Computational Chemistry, College of
Chemistry, Beijing University of Chemical Technology, Beijing
100029, China; orcid.org/0000-0001-5765-9664;
Email: leim@mail.buct.edu.cn
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; The
State Key Laboratory of Organometallic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China; orcid.org/
0000-0002-0092-0937; Email: wangjb@pku.edu.cn
Authors
Yifan Ping − 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
Rui Wang − State Key Laboratory of Chemical Resource
Engineering, Institute of Computational Chemistry, College of
Chemistry, Beijing University of Chemical Technology, Beijing
100029, China
Qianyue Wang − State Key Laboratory of Chemical Resource
Engineering, Institute of Computational Chemistry, College of
Chemistry, Beijing University of Chemical Technology, Beijing
100029, China
Taiwei Chang − 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
Jingfeng Huo − 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
Figure 4. (A) Distortion-interaction analysis for TSC4−5E and
TSC4−5Z. (B) NBO view for the overlap of donor and acceptor
orbitals in the TSC4−5E and TSC4−5Z.
CONCLUSIONS
■
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02331
In summary, we have developed an efficient and selective
method for the synthesis of alkenylboronates through
palladium-catalyzed oxidative borylation of N-tosylhydrazones.
The reaction shows good functional group tolerance, accessing
a broad range of di-, tri-, and tetrasubstituted alkenylboronates
in good yields. Various transformations of the products were
explored, demonstrating the synthetic utility of the method.
The one-pot oxidative borylation/Suzuki coupling processes
provide a new approach for stereoselective synthesis of
trisubstituted alkenes. DFT calculations support our proposed
mechanism that involves palladium-carbene formation and
subsequent boryl migratory insertion as the key steps. The
origin of stereoselectivity is due to the orbital interactions
between the Pd−H moiety and C1C2 moiety in the β-
hydride elimination step. This approach may bring new
opportunities for the synthesis of complex molecules.
Author Contributions
#R.W. and Q.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the NSFC (Grant Nos. 21871010,
22073005) and Laboratory for Synthetic Chemistry and
Chemical Biology of Health@InnoHK of ITC, HKSAR. We
also thank the National Supercomputing Center in Tianjin
(TianHe-1) and High Performance Computing (HPC)
Platform at Beijing University of Chemical Technology
(BUCT) for providing part of the computational resources.
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