Palladium-Catalyzed Chemoselective Negishi Cross-Coupling of Bis[(pinacolato)boryl]methylzinc Halides with Aryl (Pseudo)Halides

Article abstract of DOI:10.1021/acs.orglett.9b02050

We describe a palladium-catalyzed chemoselective Negishi cross-coupling of a bis[(pinacolato)boryl]methylzinc halide with aryl (pseudo)halides. This reaction affords an array of benzylic 1,1-diboronate esters, which can serve as useful synthetic handles f

Full text of DOI:10.1021/acs.orglett.9b02050

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Chemoselective Negishi Cross-Coupling of
Bis[(pinacolato)boryl]methylzinc Halides with Aryl (Pseudo)Halides
Hyojae Lee, Yeosan Lee, and Seung Hwan Cho*
Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea
S
* Supporting Information
ABSTRACT: We describe a palladium-catalyzed chemo-
selective Negishi cross-coupling of a bis[(pinacolato)boryl]-
methylzinc halide with aryl (pseudo)halides. This reaction
affords an array of benzylic 1,1-diboronate esters, which can
serve as useful synthetic handles for further transformations.
The developed coupling reaction is compatible with various functional groups and can be easily scaled up. The coupling of
bis[(pinacolato)boryl]methylzinc halides with pharmaceuticals and the subsequent late-stage manipulations demonstrate the
power of the developed protocol.
alladium-catalyzed cross-coupling reactions are of central
importance in organic and medicinal chemistry as a
Scheme 1. 1,1,1-Triorganometallics for Sequential
Functionalizations
P
prominent route for the construction of carbon−carbon
bonds.1 Over the past decades, these types of reactions have
enabled synthetic chemists to increase the complexity and
diversity of their target molecules. Recent advances in this field
have established efficient tools for the production of diverse
complex molecules via the sequential couplings of bifunction-
alized reagents.2 In this context, Transition-metal-catalyzed
chemoselective cross-coupling has been successfully developed
by using organo di(pseudo)halides.3 The cross-coupling
reaction of substrates containing both electrophilic and
nucleophilic groups is also well established.4 Chemoselective
cross-coupling reactions involving diorganometallics, which
comprise two metal centers bound to the same or different
carbons, have recently been achieved.5,6 However, despite the
extensive efforts invested in this research field, the transition-
metal-catalyzed chemoselective cross-coupling of polyorgano-
metallics that have three organometallic moieties at the single
sp3-hybridized carbon center have rarely been studied (Scheme
1a). In 1999, Matsubara and Utimoto prepared dizincboryl-
methane from dibromomethane via three-step sequences;6
however, the synthetic applications of the organometallic
species were very limited due to the instability of the
compound. Williams and Knochel synthesized bis(silyl)methyl
magnesium bromide or bis(silyl)methylzinc chloride from
bis(silyl)methyl halides, but the disilicon units of these
compounds were less effective for further chemical modifica-
tions.7 Although protocols for synthesizing diborylsilylme-
thanes8 and triborylalkanes9 have also been reported,
functionalization of one of the boron units of the obtained
species required the use of a strong base. More importantly,
the low functional group tolerance of these organometallic
intermediates makes them unsuitable for further synthetic
applications.
species have two identical boron moieties and a zinc halide
moiety bound to the same sp3-hybridized carbon center, and
undergo reactions that proceed with unique chemoselectivity
to give 1,1-diboron-substituted products bearing useful
synthetic handles for further transformations. We envisioned
a reaction wherein a bis[(pinacolato)boryl]methylzinc halide is
coupled with an organo (pseudo)halide via palladium catalysis.
Herein, we describe the chemoselective palladium-catalyzed
cross-coupling with organo (pseudo)halides and their utilities
in late-stage diversifications of drug-like intermediates (Scheme
1b).
Recently, our group reported an efficient transmetalation of
bis[(pinacolato)boryl]methyllithium and zinc(II) halides to
synthesize bis[(pinacolato)boryl]methylzinc halides.10 These
Received: June 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
solvent for the coupling process.11 We found that 4-
iodoanisole was proved to be a competent substrate for the
coupling with 1-ZnBr (entry 10), whereas 4-chloroanisole
(entry 11) and 4-methoxyphenyl triflate (2-OTf) (entry 12)
did not provide the product 3 in the presence of L4 as a ligand.
Considering that various compounds of pharmaceutical
interest contain a phenol moiety and that can be easily
converted to organotriflates, we tried to optimize the reaction
further by employing 2-OTf as an electrophile. The results
from optimization experiments indicated that the reaction of 2-
OTf with 1-ZnX was very sensitive to the identity of the added
ligand. When L4 was replaced by L6, the corresponding 1,1-
diboronate ester 3 was obtained in a good yield (entry 13). By
performing the reaction at an elevated temperature (80 °C),
the yield of 3 was improved (entry 14), and the highest yield
was obtained when 1-ZnCl was used (entry 15) as a coupling
reagent. No reaction with either 2-Br or 2-OTf (entries 16 and
17) occurred when 1-Li was utilized instead of 1-ZnBr or 1-
ZnCl under the standard coupling conditions. These results
indicated that the generation of 1-ZnX is the key to the success
of the desired transformation.
With the optimal conditions in hand, the scope of aryl
(pseudo)halides as substrates was examined (Scheme 2). Aryl
bromides with electron-donating substituents (3, 4, 5, and 6),
an electron-neutral substituent (7), and an electron-with-
drawing substituent (8) in the C4 position of the arene ring
afforded the corresponding benzylic 1,1-diboronate esters in
good yields. Note that product 6 was isolated by recrystalliza-
tion using n-hexane under a N2 atmosphere because 6 easily
underwent oxidation or decomposition after exposure to air.
Intriguingly, the coupling process developed is compatible with
a wide range of functional groups. Aryl bromides bearing
halides (9 and 10), a silyl-protected phenol (11), an ester
(12), a nitrile (13), an acetyl-protected amine (14), and a Bpin
(pin = pinacolato) group (16) provided the desired products
in good-to-moderate yields, although 13 required use of L6 as
a ligand for the full conversion. Intriguingly, when 4-
bromophenyltriflate was treated with 1-ZnBr in the presence
of 1.0 mol % Pd2(dba)3 and 2.0 mol % L4 at 60 °C in THF,
the bromo group reacted preferentially and yielded the triflate-
containing benzylic 1,1-diboronate ester 15 in good yield. On
the contrary, the use of L6 as a ligand instead of L4 resulted in
poor chemoselectivity; the reaction provided in this case is a
mixture of mono- and dicoupled products.11 These results
reveal that the chemoselectivity of coupling reactions involving
di(pseudo)halogenated arenes as substrates could be con-
trolled by the choice of ligand.1 Coupling reactions involving
aryl bromides with substituents in meta- and ortho-positions
proceeded smoothly, thus providing the corresponding
products 16, 17, and 18 in excellent yields. 2-Bromonaph-
thalene also participated in the coupling process, resulting in
the formation of 19 in high yield. In addition to aryl bromides,
various aryl triflates smoothly reacted with 1-ZnCl in the
presence of 1.0 mol % of Pd2(dba)3 and 2.0 mol % of X-Phos
in THF at 80 °C to produce the corresponding benzylic 1,1-
diboronate esters in good-to-excellent yields, which were
comparable with those of reactions involving aryl bromides
(3−5, 7−13, and 17−19).
Table 1. Optimization Study for the Palladium-Catalyzed
Coupling of 1-ZnX with Aryl (Pseudo)Halide
a
b
entry
[M]X
Y
ligand
yield (%)
1
2
3
4
5
6
7
8
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnCl·LiCl (1-ZnCl)
ZnI·LiI (1-ZnI)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnBr·LiBr (1-ZnBr)
ZnCl·LiCl (1-ZnCl)
Li (1-Li)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
Br (2-Br)
I (2-I)
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
L6
L6
L6
L4
L6
53
68
26
99 (82)
74
95
11
95
22
85
<1
<1
73
85
99 (83)
<1
c
9
10
11
12
13
14
15
Cl (2-Cl)
OTf (2-OTf)
OTf (2-OTf)
OTf (2-OTf)
OTf (2-OTf)
Br (2-Br)
OTf (2-OTf)
d
d
c
16
17
d
Li (1-Li)
<1
a
Conditions: 2 (0.20 mmol), 1 (1.5 equiv), Pd2(dba)3 (1.0 mol %),
b
ligand (2.0 mol %), and THF (1.0 mL) at 60 °C for 3 h. 1H NMR
yield of 3 using 1,1,2,2-tetrachloroethane as an internal standard. The
numbers in parentheses indicate isolated yields. The reaction was
c
d
performed at 80 °C. pin = pinacolato. dba = dibenzylideneacetone.
We investigated the feasibility of the palladium-catalyzed,
cross-coupling reaction of 1-ZnX with aryl (pseudo)halides.
The reaction of 4-bromoanisole (2-Br) and 1-ZnBr in the
presence of 1.0 mol % of Pd2(dba)3 and 2.0 mol % of PPh3
(L1) in THF at 60 °C afforded the desired benzylic 1,1-
diboronate ester 3 in 53% yield (Table 1, entry 1). Notably,
the reaction proceeded with excellent chemoselectivity, and
both boron moieties remained intact after the transformation.
When the reaction was conducted using P(p-tolyl)3 (L2) as a
ligand instead of L1, a slightly higher yield of 3 was obtained
(entry 2); when L1 was replaced by P(p-CF3C6H4)3 (L3), the
yield of the reaction decreased (entry 3). An almost
quantitative yield of 3 was obtained when P(o-tolyl)3 (L4)
was used as a ligand (entry 4). The use of tricyclohexyl-
phosphine (L5) as a ligand also afforded product 3, albeit with
a diminished yield (entry 5). The use of dicyclohexyl-
phosphino-2′,4′,6′-triisopropyl biphenyl (X-Phos, L6) as a
ligand was also proved facile in the reaction, leading to the
formation of 3 in a high yield (entry 6). Lowering the reaction
temperature from 60 °C to room temperature gave a poor
yield of 3 (entry 7). The use of 1-ZnCl (entry 8) as a coupling
reagent produced a similar yield as the reaction with 1-ZnBr,
while 1-ZnI deteriorated the reaction efficiency (entry 9).
Solvent screening showed that THF was the most effective
Thereafter, we investigated the scope of heteroaryl bromides
as substrates. The reactions of electron-rich N-heteroaryl
bromides, such as 3-bromothiophene, 3-bromofuran, 5-bromo-
N-Ts-indole, 2-bromobenzothiophene, 3-bromo-9-ethyl-carba-
zole, and 4-bromodibenzofuran, with 1-ZnBr delivered the
B
DOI: 10.1021/acs.orglett.9b02050
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Letter
a
Scheme 2. Substrate Scope of (Hetero)Aryl Electrophiles in the Palladium-Catalyzed Coupling with 1-ZnX
a
Conditions A: aryl bromide (0.20 mmol), 1-ZnBr (1.5 equiv), Pd2(dba)3 (1.0 mol %), L4 (2.0 mol %), THF (1.0 mL) at 60 °C for 3 h.
Conditions B: aryl triflate (0.20 mmol), 1-ZnCl (1.5 equiv), Pd2(dba)3 (1.0 mol %), L6 (2.0 mol %), THF (1.0 mL) at 80 °C for 3 h. In all cases,
isolated yields were indicated.
corresponding benzylic 1,1-diboronate esters (20−25) in
moderate-to-good yields under Pd2(dba)3/L4 catalytic con-
ditions. We found that 3-bromoisooxazole and 4-bromo-1,3,5-
trimethyl-pyrazole were also suitable electrophiles for the
coupling reaction and afforded 26 and 27 in synthetically
acceptable yields. Although several examples of the synthesis of
benzylic 1,1-diboronate esters have been reported that proceed
via the transition-metal-catalyzed C−H activation of methyl
arenes9f,12 or carbon insertion of diazo compounds into
B2pin2,13 these strategies showed a limited scope, particularly
in the case of heteroaryl substrates. Therefore, the developed
procedure provides a convenient and complementary synthetic
route that enables heteroaryl containing benzylic 1,1-
diboronate esters to be obtained.
C
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Scheme 3. Scale-up Reaction and the Late-Stage Sequential Functionalization of δ-Tocopherol
Next, we attempted the coupling of 1-ZnBr or 1-ZnCl with
various compounds of pharmaceutical relevance. To our
delight, (−)-menthol and lopid derivatives bearing a bromide
on the arene ring readily underwent coupling with 1-ZnBr in
the presence of 1.0 mol % of Pd2(dba)3 and 2.0 mol % of L4 in
THF at 60 °C, affording the corresponding 1,1-diboronate
esters 28 and 29 in good yields. Aryl triflates derived from γ-
oryzanol, ezetimibe, arbutin, capsaicin, and estrone were also
amenable to the coupling reaction with 1-ZnCl under
Pd2(dba)3/L6 catalytic conditions in THF at 80 °C, leading
to the formation of 30−34 in good-to-excellent yields.
type reaction between the in situ generated diboryllithium
species of 36 and CH2I2 at 60 °C provided the internal alkenyl
boronate ester 41.17c Compound 41 could be converted to the
1,1-diarylated alkene 43 via palladium-catalyzed cross-coupling
with 4-iodoanisole. An analogous boron-Wittig reaction
between 36 and benzaldehyde gave the alkenyl boronate
ester 42 in good yield and 83:17 E/Z selectivity.12a,17 Alkenyl
boronate ester 42 transformed to the corresponding ketone 44
by oxidation with NaOH and H2O2. We believe that these late-
stage modifications of 1,1-diboron groups would provide
efficient and streamlined routes for the synthesis of various
pharmaceutical libraries.
To demonstrate the practicability of the developed process,
we conducted the coupling reaction on a gram scale (Scheme
3). The palladium-catalyzed coupling reaction of δ-tocopherol-
derived triflate (35, 5.0 mmol) with 1-ZnBr under the
standard reaction conditions afforded the corresponding 1,1-
diboronate ester 36 with a yield of 82% (2.7 g). Because the
benzylic 1,1-diboronate ester could serve as a valuable
synthetic intermediate for further manipulations, we immedi-
ately tried to convert 36 to various functionalized molecules.
The oxidation of the diboron groups of 36 in the presence of
H2O2 and NaHCO3 in THF afforded the corresponding
aldehyde 37, which could be used as a valuable synthon in
various organic transformations. After the generation of the
diboryllithium species via the treatment of 36 with lithium
diisopropylamide (LDA) in THF at 0 °C, the reaction with
ethyl acetate at 50 °C generated an α-boron enolate, which
could be readily trapped by N-fluorobenzenesulfonimide
(NFSI) to benzylic 1,1-difluorinated ketone 38.14 In addition,
we could achieve the deborylative alkylation of 36 with (3-
bromopropyl)benzene in the presence of NaOMe, giving the
corresponding benzylic boronate ester 39 in excellent yield.15
The reaction of 39 with C2-lithiated thiophene and subsequent
quenching of the reaction with N-bromosuccinimide resulted
in the formation of 40 in moderate yield.16 The boron-Wittig
In conclusion, we have developed the palladium-catalyzed
cross-coupling reaction of bis[(pinacolato)boryl]methylzinc
halides with aryl (pseudo)halides, which offers a unique
platform for the modular, late-stage functionalization of
pharmaceutical analogues. The reaction leads to the synthesis
of a broad range of benzylic 1,1-diboronate esters, which are
easy-to-handle intermediates for further transformations, with
excellent functional-group tolerance. Furthermore, the reaction
is suitable for gram-scale synthesis, and pharmaceutically
interesting compounds can be used as substrates for it. We also
demonstrate the late-stage functionalization of the diboron
groups of the coupling products, thus offering a powerful
method for the divergent synthesis of pharmaceutical
analogues. Further efforts are underway in our laboratory to
utilize bis[(pinacolato)boryl]methyl metallic species in other
metal-catalyzed transformations, and the relevant develop-
ments of this research efforts will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02050.
D
DOI: 10.1021/acs.orglett.9b02050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, characterization of all new
Letter
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compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: seunghwan@postech.ac.kr.
ORCID
Seung Hwan Cho: 0000-0001-5803-4922
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
This work was financially supported by the National Research
Foundation of Korea, which is funded by the Korean
government (NRF-2018R1A4A1024713 and NRF-
2019R1A2C2004925). Y.L. (NRF-2017H1A2A1045655)
thanks the National Research Foundation of Korea (NRF)
for the global Ph.D. fellowship.
́
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