Palladium-Catalyzed ipso-Borylation of Aryl Sulfides with Diborons

Article abstract of DOI:10.1021/acs.orglett.6b01305

A catalytic Miyaura-type ipso-borylation of aryl sulfides with diboron reagents has been achieved, providing arylboronate esters of synthetic use. The key conditions to transform inherently reluctant C-S bonds into C-B bonds include a palladium-NHC (N-heterocyclic carbene) precatalyst, bis(pinacolato)diboron, and lithium hexamethyldisilazide. This protocol is applicable to a reasonable range of aryl alkyl sulfides. Twofold borylation was observed in the reaction of diphenyl sulfide.

Full text of DOI:10.1021/acs.orglett.6b01305

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed ipso-Borylation of Aryl Sulfides with Diborons
M. Bhanuchandra, Alexandre Baralle, Shinya Otsuka, Keisuke Nogi, Hideki Yorimitsu,*
and Atsuhiro Osuka
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: A catalytic Miyaura-type ipso-borylation of aryl sulfides with diboron
reagents has been achieved, providing arylboronate esters of synthetic use. The key
conditions to transform inherently reluctant C−S bonds into C−B bonds include a
palladium-NHC (N-heterocyclic carbene) precatalyst, bis(pinacolato)diboron, and
lithium hexamethyldisilazide. This protocol is applicable to a reasonable range of aryl
alkyl sulfides. Twofold borylation was observed in the reaction of diphenyl sulfide.
a
Table 1. Optimization of Borylation Conditions
ue to the tremendous versatility of organoboron
compounds not only as reagents but also as functional
D
materials and bioactive agents by themselves, new protocols for
constructing C−B bonds have long been actively developed.1
Among them, the Miyaura ipso-borylation of aryl halides or
pseudohalides represents an important tool.2,3 While aryl
bromides, iodides, and triflates have been widely used as
electrophilic partners in this catalytic borylation, less reactive
aryl chlorides are now available with the help of electron-rich
transition metal catalysts.4 Further research has now realized
catalytic ipso-borylation of aryl fluorides5 and aryl ethers6
bearing very strong C−F and C−O bonds, respectively.
Aryl sulfides are found widely in nature as well as useful as
synthetic intermediates and final products, thus occupying a
unique position in organic chemistry.7 While aryl sulfides may
be regarded as surrogates for aryl halides in transition-metal-
catalyzed substitution reactions, they have received much less
attention.8,9 This undeveloped situation would be surprising
when one considers that aromatic C−S bonds are strong, yet
weaker than the corresponding C−F and C−O bonds.10
Instead, the reluctance of aryl sulfides to catalytic substitution
reactions would be explained by the broad recognition that
sulfur-containing substrates can serve as catalyst poisons. Even
worse, concomitantly formed thiolate anions are much more
poisonous.11 A strong affinity between a transition metal center
and the anionic thiolate moiety in an oxidative adduct renders
the key transmetalation step highly challenging.
As a part of our research interest in catalytic C−S bond
cleavage,12 we envisioned transforming aryl sulfides to
arylboronate esters of synthetic versatility. By overcoming
unfavorably strong interactions of organosulfur species with
transition metals as well as catalyst deactivation, here we report
Miyaura-type catalytic ipso-borylation of aryl sulfides.13
As a model reaction, the palladium-catalyzed borylation
reaction of methyl p-tolyl sulfide (1a) with bis(pinacolato)-
diboron (2a, B2pin2) was selected (Table 1). To avoid
dissociation of ligands on palladium, which results in catalyst
deactivation, we chose highly coordinating N-heterocyclic
carbenes (NHCs) as promising ligands. Furthermore, to
facilitate smooth boryl transfer to reluctant arylpalladium
b
entry
catalyst
base
solvent
yield /%
1
SingaCycle-A1
SingaCycle-A3
[IPrPdCl(π-allyl)]
Pd-PEPPSI-SIPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiOtBu
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
DME
28
62
64
75
2
3
4
c
5
81
6
3
22
0
7
8
9
LiF
0
10
11
12
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
33
59
8
toluene
a
b
The reaction was carried out with 0.5 mmol of 1a. Determined by
1H NMR experiments using (CHCl2)2 as an internal standard.
c
Isolated yield.
methanethiolate, we presumed the choice of the activator
would be crucial. We thus focused on screening Pd-NHC
precatalysts and basic activators. As selectively summarized in
Table 1, in the presence of LiN(SiMe3)2 as an activator, a series
of palladium precatalysts bearing N-2,6-diisopropylphenyl
groups (Figure 1) exhibited promising results (entries 1−
5).14,15 Among them, Pd-PEPPSI-IPr14c−e was found to be
optimal, providing the corresponding borylated product 3a in
81% isolated yield (entry 5). The choice of LiN(SiMe3)2 is of
decisive importance: other hexamethyldisilazides such as the
sodium or potassium analogues were far less effective (entries 6
and 7). Other lithium bases including LiOtBu and LiF were
totally ineffective (entries 8 and 9). The reactions in other
ethereal solvents such as dioxane and 1,2-dimethoxyethane
Received: May 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and 1m reacted smoothly. Electron-rich sulfides 1c−l required
a larger amount (15 mol %) of the palladium precatalyst and a
longer reaction time of 24 h to achieve full conversions.
Notably, typical protecting groups such as benzyl, methox-
ymethyl, and triisopropylsilyl (TIPS) groups in 3g−i survived
under the basic conditions. With 4.5 equiv of LiN(SiMe3)2,
unprotected hydroxythioanisole (1j) was borylated, albeit in
moderate yield. The azole units in 1k and 1l survived under the
reaction conditions and did not suppress the borylation.
Notably, the borylation proceeded with sterically demanding
substrates, including o-phenylated thioanisole 1r, to yield 3q−s
in high yields after 24 h. This offers an advantage for synthetic
chemistry because ortho-substituted aryl sulfides can be readily
synthesized by ortho-lithiation of thiophenols.16 A strongly
electron-withdrawing trifluoromethyl group retarded the
reaction to yield 3t in fair yield. While electron-withdrawing
carbonyl groups are not compatible under the basic conditions,
acetal protections were compatible to obtain 3u and 3v in good
yields. Unfortunately, carbonyl functionalities including an
amide group were not compatible with the borylation
conditions. The reaction of 4-PhCON(Me)C6H4SMe afforded
not only the desired product 4-PhCON(Me)C6H4Bpin but also
debenzoylated product (4-MeNHC6H4Bpin) in ca. 20% NMR
yields for both (not shown in Scheme 1). Although para-
fluorinated aryl sulfide 1w afforded the desired product 3w in
moderate yield, a diborylated compound was also formed in
19% yield through the borylation of the C−F bond. When 4-
ClC6H4SMe was employed, a mixture of the desired product
(4-ClC6H4Bpin, 23% NMR yield) and diborylated product
(27% NMR yield) was obtained (not shown in Scheme 1).
Methyl 2-, 3-, and 4-pyridyl sulfides afforded no borylated
products, and the starting materials were decomposed in all
cases. Instead of an aryl sulfide, attempted borylation of benzyl
methyl sulfide (BnSMe) gave a complex mixture.
Figure 1. Palladium precatalysts employed in Table 1 (IPr = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene; SIPr = 1,3-bis(2,6-di-
isopropylphenyl)-4,5-dihydroimidazol-2-ylidene).
(DME) gave 3a in lower yields (entries 10 and 11). Less polar
and noncoordinating toluene was an inappropriate solvent
(entry 12).
With the optimized conditions (entry 5 in Table 1) in hand,
the scope of aryl sulfides was surveyed (Scheme 1).
Electronically neutral para-substituted aryl sulfides 1a, 1b,
Scheme 1. Palladium-Catalyzed Borylation of Aryl Sulfides
a
with B2pin2
As the borylating agent, bis(pinacolato)diboron (B2pin2) was
the best (Scheme 2): Bis(neopentyl glycolato)diboron (2b)
a
Scheme 2. Scope of Diborons
a
b
Isolated yield. NMR yield.
and bis(hexylene glycolato)diboron (2c) were less reactive to
give the corresponding p-tolylboronate esters 4b and 4c in 38%
yields, respectively. No borylation took place with bis-
(catecholato)diboron (2d).
Next we turned our attention to the effect of the leaving
sulfanyl groups in the aryl sulfides (Scheme 3, yields
determined by NMR). Ethylsulfanyl and dodecylsulfanyl
groups were found to be inferior to methylsulfanyl as leaving
groups probably because of the more electron-donating
character of longer alkyl chains. Benzylsulfanyl showed high
leaving group ability, owing to the electron-withdrawing nature
a
b
c
d
Isolated yield. 15 mol % Pd-PEPPSI-IPr, 24 h. NMR yield. 4.5
e
f
equiv of LiN(SiMe3)2. Reaction time: 24 h. Reaction time: 10 h.
g
h
Reaction time: 48 h. Diborylated product (4-pinBC6H4Bpin) was
formed in 19% yield.
B
DOI: 10.1021/acs.orglett.6b01305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Effect of Sulfanyl Leaving Groups
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yori@kuchem.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
of the phenyl ring. Interestingly, a 180% yield of 3b was
obtained when diphenyl sulfide was used as a substrate. This
result suggests that the leaving benzenethiolate species should
undergo the second borylation with another equivalent of
B2pin2.
A plausible mechanism is outlined in Scheme 4. The main
catalytic cycle can follow the accepted mechanism. The most
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Numbers
25107002 (“Science of Atomic Layers”), 16H01019 (“Precisely
Designed Catalysts with Customized Scaffolding”), 16H01149
(“Middle Molecular Strategy”), and (16H04109 (B)) as well as
by ACT-C, JST. H.Y. thanks Japan Association for Chemical
Innovation and The Naito Foundation for financial support.
A.B. and S.O. thank JSPS for postdoctoral and predoctoral
fellowship, respectively.
Scheme 4. Plausible Catalytic Cycle
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01305.
Experimental details, characterization data, and NMR
spectra of the products (PDF)
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DOI: 10.1021/acs.orglett.6b01305
Org. Lett. XXXX, XXX, XXX−XXX