Site-Selective and Stereoselective C(sp3)-H Borylation of Alkyl Side Chains of 1,3-Azoles with a Silica-Supported Monophosphine-Iridium Catalyst

Article abstract of DOI:10.1055/s-0035-1561599

Site-selective and stereoselective C(sp³)-H borylation of alkyl side chains of 1,3-azoles with bis(pinacolato)diboron was effectively catalyzed by a silica-supported monophosphine-iridium catalyst. The borylation occurred under relatively mild conditions (2 mol% Ir, 50-90 °C), affording the corresponding primary and secondary alkylboronates. This system was applicable to a variety of 1,3-(benzo)azoles such as thiazoles, oxazoles, and imidazoles.

Full text of DOI:10.1055/s-0035-1561599

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
cluster
A
R. Murakami et al.
Cluster
Synlett
Site-Selective and Stereoselective C(sp3)–H Borylation of Alkyl
Side Chains of 1,3-Azoles with a Silica-Supported Monophos-
phine-Iridium Catalyst
Ryo Murakami
P
Tomohiro Iwai
Silica-SMAP-Ir
(2 mol%)
Masaya Sawamura*
SiMe3
Si
O
N
N
H
H
H
Bpin
O
β
pinB–Bpin
THF, 50–90 °C
X = S, O, NR
α
γ
Department of Chemistry, Faculty of Science, Hokkaido Univer-
sity, Sapporo 060-0810, Japan
sawamura@sci.hokudai.ac.jp
X
X
R
R
Si
Si
O
O
O
O
13 examples
2-alkyl-1,3-azoles
O
O
SiO2
Silica-SMAP
Received: 28.02.2016
Accepted after revision: 18.03.2016
Published online: 30.03.2016
Me
Me
H
N
Me
Me
Muscoride A
DOI: 10.1055/s-0035-1561599; Art ID: st-2016-u0140-c
Me
N
O
(natural product)
Cl
N
Abstract Site-selective and stereoselective C(sp3)–H borylation of al-
kyl side chains of 1,3-azoles with bis(pinacolato)diboron was effectively
catalyzed by a silica-supported monophosphine-iridium catalyst. The
borylation occurred under relatively mild conditions (2 mol% Ir, 50–
90 °C), affording the corresponding primary and secondary alkylboro-
nates. This system was applicable to a variety of 1,3-(benzo)azoles such
as thiazoles, oxazoles, and imidazoles.
N
Me
Me
O
N
Me
HO
N
N
NH
O
O
O
Losartan
N
N
(hypertension medications)
Me
Ph
OH
H
S
Me
Me
Me
N
N
O
H
N
N
O
N
N
H
S
Key words 1,3-azole, C–H activation, borylation, iridium, hetero-
geneous catalyst
O
O
Me
Me
Ritonavir
(HIV protease inhibitor)
Ph
1,3-Azoles are common structures in many biologically
active natural compounds, pharmaceuticals, and organic
functional materials, and many of these molecules have an
alkyl substituent at the 2-position (Figure 1).1 Therefore,
functionalization of the alkyl side chain of 1,3-azoles is of
great importance for the construction of complex mole-
cules containing 1,3-azole scaffolds.2 Among the methods
for functionalization of alkyl groups, C(sp3)–H borylation is
attractive because alkylboron compounds are versatile syn-
thetic intermediates with broad functional group compati-
bility, and air- and moisture stability.3,4 Despite recent sig-
nificant progress in this area, the site-selective borylation of
unactivated C(sp3)–H bonds over potentially more reactive
C–H bonds such as C(sp2)–H bonds remains challenging.5–10
Moreover, the stereoselective borylation of C(sp3)–H bonds
is underdeveloped.5e,5g,5h,7,10a
Figure 1 Representative compounds containing the 2-alkyl-1,3-azole
scaffold
iridium systems based on solid-supported monophos-
phines with mono-P-ligating features (Figure 2).10 This
strategy allowed site-selective borylation of the N-adja-
cent10b or unactivated7b,10a,c,d C(sp3)–H bonds located γ to N
or O atoms on the directing groups. The regioselectivity
was due to the proximity effect by the heteroatom-to-metal
coordination. In fact, cyclic and acyclic alkyl substituents at
the 2-position of pyridines underwent the C(sp3)–H boryla-
tion with excellent site- and stereoselectivities.10a Later, we
found that 1,3-azoles also worked as suitable directing
groups for the C(sp3)–H boylation of small-ring carbocycles
such as cyclopropanes and cyclobutanes.7b However, its ap-
plicability for linear alkyl groups and normal-sized (five-to-
seven-membered) carbocycles has not been explored.
Recently, we have reported the heteroatom-directed bo-
rylation of C(sp3)–H bonds bearing N-heteroarenes or car-
bonyl-based functional groups catalyzed by rhodium or
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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R. Murakami et al.
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Table 1 Ligand Effects in Iridium-Catalyzed Borylation of 2-Ethylben-
zothiazole (1a) with Bis(pinacolato)diboron (2)a
P
P
SiMe3
O
Si
O
Si
SiMe3
O
Si
O
Si
N
N
Si
O
O
Si
Me
[Ir(OMe)(cod)]2
(Ir : 2 mol%)
O
O
O
O
O
O
O
S
S
S
Bpin
O
O
O
CH3
O
1a (3 equiv)
ligand (2 mol%)
3a
SiO2
SiO2
+
THF (1 mL)
60 °C, 15 h
(–HBpin)
Silica-SMAP
P
O
O
O
O
Silica-TRIP
P
N
Bpin
B
B
Me
PS
Bpin
Me
Me
O
PS
Me
Si
4a
pinB–Bpin, 2
Me
tBu
Si
O
(0.2 mmol)
Me
O
O
Me
Si
Si
O
Si
O
O
P
O
O
O
tBu
PS
tBu
tBu
Me
Si
O
SiO2
Si
O
tBu
Me
Me
PS-TPP
Silica-TPP
N
N
N
N
Figure 2 Solid-supported monophosphines
Ph-SMAP
Dtbpy
Me4Phen
Herein, we report a heteroatom-directed C(sp3)–H bory-
lation of alkyl side chains of 1,3-azoles with a silica-sup-
ported monophosphine-iridium catalyst. Owing to the
proximity effect by N-to-iridium coordination, the boryla-
tion occurred under relatively mild reaction conditions
with high site- and stereoselectivities. This catalytic system
was applicable for the reaction of primary and secondary
C(sp3)–H bonds of linear and cyclic alkyl substituents in
1,3-azoles, including thiazoles, oxazoles, and imidazoles.
Initially, we examined the borylation of 2-ethylbenzo-
thiazole (1a, 0.6 mmol) with bis(pinacolato)diboron
(B2pin2) (2, 0.2 mmol) in THF at 60 °C for 15 hours in the
presence of various iridium catalysts (2 mol% Ir), which
were prepared in situ from [Ir(OMe)(cod)]2 and different li-
gands. The results are summarized in Table 1.
Entry
Ligand
Yield of 3a (%)b
Yield of 4a (%)b
1
Silica-SMAP
Silica-SMAP
Silica-SMAP
Silica-TRIP
Silica-TPP
PS-TPP
82c (75)d
32
2e
3f
4
71 (54)
12
2
0
0
0
0
0
0
0
0
97 (89)g
0
0
0
0
0
0
0
0
5
6
7
Ph-SMAP
Ph3P
8
9h
10h
11
Dtbpy
Me4Phen
none
a Conditions: 1a (0.6 mmol), 2 (0.2 mmol), [Ir(OMe)(cod)]2 (2 mol% Ir), li-
gand (2 mol%), THF (1 mL), 60 °C, 15 h.
In contrast to the C(sp3)–H borylation of 2-alkylpyri-
dines reported previously,10a for which all solid-supported
monophosphines shown in Figure 1 were effective ligands
(Silica-SMAP,10a Silica-TRIP,10b Silica-TPP,10c and PS-TPP10d),
the borylation of 1a was specifically promoted by commer-
cially available Silica-SMAP, affording the terminal C(sp3)–H
borylation product 3a and the geminal bisborylation prod-
uct 4a in 82% and 32% NMR yields, respectively (Table 1, en-
try 1).11,12 The reactivity of the alkyl side chain in 1a seems
to be lower than that in the pyridine analogue. Indeed, 2-
ethylpyridine underwent efficient C(sp3)–H borylation with
the Silica-SMAP-Ir system at 25 °C,10a while 1a was intact
under identical conditions (data not shown). The ligand
specificity of Silica-SMAP in the present borylation reaction
may suggest a requirement for the high electron density of
the metal and/or sparse nature of the catalytic environment
provided by the compact ligand. The total borylation yields
over 100% based on B2pin2 (2) indicated that pinacolborane
(HBpin), which was a byproduct of the reaction with B2pin2,
also served as a borylating reagent, although it was less re-
active than 2. The C(sp2)–H bonds of the benzothiazole ring
b 1H NMR yield based on 2. Isolated yields shown in parentheses.
c The C=N reduction product of 1a (4%) was formed.
d The isolated product 3a was contaminated with 4a (<1%) and traces of
impurities.
e Conditions: 1a (15 mmol), 2 (5 mmol), [Ir(OMe)(cod)]2 (0.5 mol% Ir), Sili-
ca-SMAP (0.5 mol%), THF (5 mL), 90 °C, 24 h.
f Conditions: 1a (0.2 mmol), 2 (0.4 mmol), [Ir(OMe)(cod)]2 (2 mol% Ir), Sili-
ca-SMAP (2 mol%), THF (1 mL), 60 °C, 24 h. Yields of 3a and 4a were based
on 1a.
g The isolated product 4a was contaminated with 3a (2%).
h Arylboronates were formed in entries 9 and 10 (4% and 3%, respectively).
and the C(sp3)–H bonds at the position α to the azole group
were intact. A larger-scale reaction (5 mmol for 2) at 0.5
mol% iridium loading proceeded efficiently at 90 °C to give
3a in 54% isolated yield (Table 1, entry 2). The geminal dibo-
rylation product 4a could be obtained as a major product in
89% isolated yield by the reaction with two equivalents of 2
(2 mol% Ir, 60 °C, Table 1, entry 3).
Table 1 also shows the inefficiency of homogeneous cat-
alytic systems. The use of monophosphines such as Ph-
SMAP13 and Ph3P did not promote the C(sp3)–H borylation
(Table 1, entries 7 and 8). Bipyridine-based ligands such as
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
R. Murakami et al.
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Dtbpy and Me4Phen resulted in only aromatic C–H boryla-
tion with lower efficiencies (<4% yields of arylboronates, Ta-
ble 1, entries 9 and 10).14 No reaction occurred without an
exogenous ligand (Table 1, entry 11).
The Silica-SMAP-Ir system was applicable to various
1,3-(benzo)azoles 1, including thiazoles, oxazoles, and im-
idazoles. Some of the borylation products 3 obtained in this
manner were converted into the corresponding alcohols 5
through subsequent oxidation for facile product isolation.15
The results are summarized in Table 2.
Table 2 Silica-SMAP-Ir-Catalyzed C(sp3)–H Borylation of 2-Alkyl-1,3-azoles 1 with Diboron 2 Followed by Oxidationa
[Ir(OMe)(cod)]2 (Ir: 2 mol%)
NaBO3•4H2O
N
O
O
O
O
OH
R3
R1 R2
Bpin
N
N
Silica-SMAP (2 mol%)
(5 equiv)
+
B
B
R3
R3
X
THF, 15 h
(– HBpin)
X
THF/H2O (1:1)
r.t., 5 h
X
R1 R2
R1 R2
1 (3 equiv)
3
5
pinB–Bpin, 2
(0.2 mmol)
Entry
1
Substrate 1
Borylation product 3
Temp (°C) Yield of 3 (%)b Oxidation product 5c
Yield of 5 (%)b
N
N
60
78c–e (48)f
–
–
–
Me
O
Bpin
Bpin
O
1b
1c
1d
1e
3b
3c
N
N
N
2
50
50
38c,d,g
Me
Me
Me
–
3h
60c,d (54)i
N
N
Me
Me
N
N
N
4
5
80
80
83d
(59)
(68)
N
N
N
Bpin
OH
Me
Me
Me
Me
Me
Me
3d
3e
5d
5e
N
N
87
N
N
N
Bpin
Bpin
OH
Me Me
Me Me
Me Me
Me
Me
Me
N
N
N
Me
N
N
N
OH
6
70
86
(71)
1f
5f
3f
Me
Me
N
N
7
8
60
80
80c (63)
–
–
Me
Me
Me
S
Bpin
S
1g
3g
N
N
Bpin
N
OH
81d,e
(69)
N
N
N
Me
Me
Me
3h
5h
1h
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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Table 2 (continued)
Entry
Substrate 1
Borylation product 3
Temp (°C) Yield of 3 (%)b Oxidation product 5c
Yield of 5 (%)b
N
N
N
Bpin
N
OH
N
9
80
90
90
89d,e
89d,e
112d,e
(70)
(74)
N
N
N
Me
Me
Me
1i
3i
3j
5i
5j
Bpin
OH
N
N
N
10
11
N
N
N
Me
Me
Me
Me
Me
Me
1j
Bpin
N
OH
5k (cis): (67)
5k′ (trans): (16)j
N
N
N
Me
Me
Me
1k
3k (cis/trans = 4:1)
N
N
Bpin
N
OH
12
13
70
80
83d,e
(55)j
(43)j
N
N
N
Me
Me
Me
3l
5l
1l
Bpin
HO
N
N
N
72d,e
N
N
N
Me
Me
Me
1m
3m
5m
a Conditions for C–H borylation: 1 (0.6 mmol), 2 (0.2 mmol), [Ir(OMe)(cod)]2 (2 mol% Ir), Silica-SMAP (2 mol% P), THF (1 mL), 15 h. Conditions for oxidation: the
crude products of the C(sp3)–H borylation (3), NaBO3·4H2O (1 mmol), THF (1 mL), H2O (1 mL), r.t., 5 h.
b 1H NMR yield based on 2. Isolated yields shown in parentheses.
c Geminal diborylation products 4 were formed in entries 1–3 and 7 (26%, 19%, 31%, 34%, respectively).
d The C=N reduction products of 1 were formed in entries 1–4 and 8–13 (30%, 64%, 42%, 85%, 40%, 59%, 84%, 35%, 83%, 41%, respectively).
e Arylboronates were formed in entries 1, 8–13 (5%, 7%, 6%, 11%, 4%, 8%, 2%, respectively).
f Isolated product was contaminated with arylboronates (9%) and the diborylation product (1%).
g The C=N reduction product of 3c (structure not determined, ca. 20%) was formed.
h Cyclooctene (0.2 mmol) was used as an additive.
i Isolated product was contaminated with the diborylation product (<1%).
j Isolated products in entries 11–13 were contaminated with phenol derivatives (1%, 5%, 2%, respectively), which were derived from the corresponding arylboro-
nates.
The reaction with 2-ethylbenzoxazole (1b) proceeded
smoothly at 60 °C to give the monoborylation product 3b
and the geminal diborylation product 4b in 78% and 26%
yields, respectively, with the formation of small amounts of
C(sp2)–H borylation products (5%, Table 2, entry 1). 2-Ethyl-
benzimidazole (1c) was borylated at 50 °C, affording the
monoborylation product 3c and the diborylation product
4c in 38% and 19% yields, respectively (Table 2, entry 2).
However, the formation of a significant amount of a C=N re-
duction product of 3c (structure not determined, ca. 20%)
was observed in the 1H NMR spectrum of the crude reaction
mixture. The use of cyclooctene as an additive effectively
suppressed the C=N reduction of 3c, resulting in an increase
in yields of 3c and 4c to 60% and 31%, respectively (Table 2,
entry 3).16 Benzimidazoles bearing bulky alkyl groups, such
as isopropyl (1d) and tert-butyl (1e) groups, at their 2-posi-
tions were successfully borylated at the terminal C(sp3)–H
bonds (Table 2, entries 4 and 5). The methyl C(sp3)–H bory-
lation of polycyclic compound 1f gave primary alkylboro-
nate 3f as a sole product (Table 2, entry 6). Monocyclic 1,3-
thiazole 1g was also a suitable substrate for the terminal
C(sp3)–H borylation (Table 2, entry 7).17
Internal C(sp3)–H bonds in 2-alkyl-1,3-azoles success-
fully participated in the borylation with the Silica-SMAP-Ir
system under relatively mild conditions (2 mol% Ir, 70–90
°C), affording the corresponding secondary alkylboronates
(Table 2, entries 8–13). For example, the reactions of 1h or
1i containing a phenyl substituent proceeded with excel-
lent site selectivity at the C(sp3)–H bonds located γ to the
directing sp2-hybridized N atoms (Table 2, entries 8 and 9).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
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The site-selective borylation occurred efficiently with 2-
pentylbenzimidazole (1j) to provide alkylboronate 3j (Table
2, entry 10).
tained alkylboronates serve as precursors for C–N and C–C
bond-formation reactions. Thus, this heterogeneous iridi-
um catalysis offers a useful method for rapid access to func-
tionalized molecules with 1,3-azole scaffolds.
As was the case for the small-sized carbocycles,7b nor-
mal-sized ring compounds were also borylated site- and
stereoselectively. Specifically, the reaction of 2-cyclopentyl-
N-methylbenzimidazole (1k) at 90 °C afforded the boryla-
tion product 3k as a mixture of cis and trans isomers in a
4:1 ratio (Table 2, entry 11). The cyclohexyl and cycloheptyl
groups in 1l and 1m, respectively, reacted at 70–80 °C with
exceptional trans selectivity (Table 2, entries 12 and 13).
To demonstrate the synthetic utility of the present bor-
ylation reaction, transformations of alkylboronate 3a were
performed as shown in Scheme 1. The boronate 3a was con-
verted into tertiary amine 6 through a copper-catalyzed re-
action with N-methylaniline in the presence of Ag2CO3 as
an oxidant.18 The Suzuki–Miyaura cross-coupling of 4-chlo-
roanisole with a RuPhos-ligated palladacycle precatalyst
provided the sp3–sp2 coupling product 7.19–21 The one-car-
bon homologation–oxidation sequence afforded the corre-
sponding primary alcohol 8.22
Acknowledgment
This work was supported by Grants-in-Aid from CREST and ACT-C
(JST) to M.S. and Grants-in-Aid for Young Scientists (B) from JSPS to
T.I. R.M. thanks the JSPS for scholarship support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561599.
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References and Notes
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; John
Wiley and Sons: Chichester, 2010. (b) Joule, J. A.; Mills, K. Het-
erocyclic Chemistry at a Glance, 2nd ed.; John Wiley and Sons:
Chichester, 2013. (c) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975,
75, 389. (d) Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20,
6208. (e) Contreras, R.; Flores-Parra, A.; Mijangos, E.; Téllez, F.;
López-Sandoval, H.; Barba-Behrens, N. Coord. Chem. Rev. 2009,
253, 1979.
Cu(OAc)2 (10 mol%)
N
HNMePh (1.5 equiv)
Ph
S
Ag2CO3 (2 equiv)
N
toluene, 100 °C, 12 h
Me
(2) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991.
(3) Selected recent reviews on transition-metal-catalyzed C–H bor-
ylation: (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(b) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992. (c) Ros, A.;
Fernández, R.; Lassaletta, J. M. Chem. Soc. Rev. 2014, 43, 3229.
(4) (a) 2nd ed. Boronic Acids: Preparation and Applications in
Organic Synthesis, Medicine and Materials; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2011. (b) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457. (c) Jana, R.; Pathak, T. P.; Sigman, M. S.
Chem. Rev. 2011, 111, 1417. (d) Leonori, D.; Aggarwal, V. K. Acc.
Chem. Res. 2014, 47, 3174.
6 80%
Pd precatalyst (5 mol%)
N
4-MeOC6H4Cl (1 equiv)
N
S
K2CO3 (3 equiv)
S
Bpin
toluene/H2O (1:1)
90 °C, 24 h
OMe
3a
7 63%
1.0 equiv for 6 and 8
1.1 equiv for 7
1) BrCH2Cl (2 equiv)
nBuLi (1.8 equiv)
THF, –78 °C to rt, 3 h
N
(5) Heteroatom-directed C(sp3)–H borylation: (a) Cho, S. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8157. (b) Mita, T.;
Ikeda, Y.; Michigami, K.; Sato, Y. Chem. Commun. 2013, 49, 5601.
(c) Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan,
F.; Chen, K.; Shi, Z.-J. Angew. Chem. Int. Ed. 2014, 53, 3899.
(d) Cho, S. H.; Hartwig, J. F. Chem. Sci. 2014, 5, 694.
(e) Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K.
Angew. Chem. Int. Ed. 2015, 54, 846. (f) Murai, M.; Omura, T.;
Kuninobu, Y.; Takai, K. Chem. Commun. 2015, 51, 4583. (g) He, J.;
Jiang, H.; Takise, R.; Zhu, R.-Y.; Chen, G.; Dai, H.-X.; Murali, Dhar.
T. G.; Shi, J.; Zhang, H.; Cheng, P. T. W.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2016, 55, 785. (h) Larsen, M. A.; Cho, S. H.; Hartwig, J. F.
J. Am. Chem. Soc. 2016, 138, 762. See also ref 10. An example of
C(sp3)–H borylation of aliphatic substrates without strong
directing groups: (i) Ohmura, T.; Torigoe, T.; Suginome, M.
Chem. Commun. 2014, 50, 6333.
2) NaBO3•4H2O (3 equiv)
THF/H2O (1:1), r.t., 3 h
OH
S
8 66%
OMs
Cy2P
H2N Pd RuPhos
OiPr
OiPr
Pd precatalyst
RuPhos
Scheme 1 Transformations of 3a
In summary, a heterogeneous iridium catalyst system
with silica-supported cage-type trialkylphosphine Silica-
SMAP enabled C(sp3)–H borylation of alkyl side chains of
1,3-azoles, including thiazoles, oxazoles, and imidazoles,
under relatively mild conditions with high site- and stereo-
selectivities. The borylation occurred not only at terminal
C(sp3)–H bonds but also at internal secondary C(sp3)–H
bonds in linear alkyl groups or carbocyclic rings. The ob-
(6) Borylation of C(sp3)–H bonds located α or β to heteroatoms:
(a) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134,
12422. (b) Ohmura, T.; Torigoe, T.; Suginome, M. J. Am. Chem.
Soc. 2012, 134, 17416. (c) Ohmura, T.; Torigoe, T.; Suginome, M.
Organometallics 2013, 32, 6170. (d) Li, Q.; Liskev, C. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 8755.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
R. Murakami et al.
Cluster
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(7) C(sp3)–H borylation of cyclopropanes, see: (a) Liskey, C. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 3375. (b) Murakami,
R.; Tsunoda, K.; Iwai, T.; Sawamura, M. Chem. Eur. J. 2014, 20,
13127; see also ref. 5e,g.
200%). 1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 12 H), 1.38 (t, J =
7.6 Hz, 2 H), 3.24 (t, J = 7.6 Hz, 2 H), 7.32 (td, J = 8.4, 1.2 Hz, 1 H),
7.42 (td, J = 7.6, 0.8 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.94 (d, J =
8.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 11.10 (br), 24.75 (4
C), 28.85, 83.36 (2 C), 121.42, 122.41, 124.42, 125.67, 135.19,
153.19, 173.81. 11B NMR (128 MHz, CDCl3): δ = 32.6. IR (ATR):
2976, 2931, 1519, 1436, 1370, 1313, 1142, 1082, 967, 845, 758
(8) Borylation of benzylic C(sp3)–H bonds: (a) Shimada, S.;
Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem. Int.
Ed. 2001, 40, 2168. (b) Ishiyama, T.; Ishida, K.; Takagi, J.;
Miyaura, N. Chem. Lett. 2001, 30, 1082. (c) Mertins, K.; Zapf, A.;
Beller, M. J. Mol. Catal. A: Chem. 2004, 207, 21. (d) Boebel, T. A.;
Hartwig, J. F. Organometallics 2008, 27, 6013. (e) Larsen, M. A.;
Wilson, C. V.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 8633.
(f) Palmer, W. N.; Obligacion, J. V.; Pappas, I.; Chirik, P. J. J. Am.
Chem. Soc. 2016, 138, 766.
. ESI-HRMS: m/z [M +
cm–1 H]+ calcd for C15H21O2N10BS:
289.14169; found: 289.14170.
(12) The Silica-SMAP-Ir catalyst was easily separated from the reac-
tion mixture by filtration. However, attempts to reuse the cata-
lyst were unsuccessful.
(13) (a) Ochida, A.; Hamasaka, G.; Yamauchi, Y.; Kawamorita, S.;
Oshima, N.; Hara, K.; Ohmiya, H.; Sawamura, M. Organometal-
lics 2008, 27, 5494. (b) Ochida, A.; Hara, K.; Ho, H.; Sawamura,
M. Org. Lett. 2003, 5, 2671.
(9) Borylation of allylic C(sp3)–H bonds: (a) Caballero, A.; Sabo-Eti-
enne, S. Organometallics 2007, 26, 1191. (b) Olsson, V. J.; Szabó,
K. J. Angew. Chem. Int. Ed. 2007, 46, 6891. (c) Olsson, V. J.; Szabó,
K. J. J. Org. Chem. 2009, 74, 7715. (d) Deng, H.-P.; Eriksson, L.;
Szabó, K. J. Chem. Commun. 2014, 50, 9207.
(10) (a) Kawamorita, S.; Murakami, R.; Iwai, T.; Sawamura, M. J. Am.
Chem. Soc. 2013, 135, 2947. (b) Kawamorita, S.; Miyazaki, T.;
Iwai, T.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2012, 134,
12924. (c) Iwai, T.; Murakami, R.; Harada, T.; Kawamorita, S.;
Sawamura, M. Adv. Synth. Catal. 2014, 356, 1563. (d) Iwai, T.;
Harada, T.; Hara, K.; Sawamura, M. Angew. Chem. Int. Ed. 2013,
52, 12322.
(11) Typical Procedure for the C(sp3)–H Borylation of Alkyl Side
Chains on 1,3-Azoles with a Silica-SMAP-Ir Catalyst System
(Table 1, Entry 1)
(14) The C(sp2)–H borylation of heteroarenes including 1,3-ben-
zazoles catalyzed by the Ir-Me4Phen system: Larsen, M. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4287.
(15) In some cases, the formation of C=N reduction products of start-
ing materials 1 was indicative by 1H NMR analyses of the crude
products. Similar C=N reduction was observed in the C(sp3)–H
boylation of small-ring carbocycles bearing 1,3-azoles with the
Silica-SMAP-Ir catalyst system (ref. 7b). The desired products 3
or 5 could be isolated by bulb-to-bulb distillation or silica gel
column chromatography.
(16) Cyclooctene would act as a scavenger of H2 or HBpin. The use of
alkene derivatives as a H2 or HBpin scavenger in an Ir-catalyzed
aromatic C–H borylation of aldimines was also reported:
(a) Sasaki, I.; Amou, T.; Ito, H.; Ishiyama, T. Org. Biomol. Chem.
2014, 12, 2041. (b) Sasaki, I.; Ikeda, T.; Amou, T.; Taguchi, J.; Ito,
H.; Ishiyama, T. Synlett 2016, 27, in press; DOI: 10.1055/s-0035-
1561578.
(17) Methyl groups on the thiazole ring in 1g were necessary for the
C(sp3)–H borylation. In fact, the reaction of 2-ethylthiazole with
2 in the presence of the Silica-SMAP-Ir catalyst (2 mol%, 60 °C,
15 h) gave the corresponding arylboronates exclusively via the
C(sp2)–H borylation.
(18) Sueki, S.; Kuniobu, Y. Org. Lett. 2013, 15, 1544.
(19) Li, L.; Zhao, S.; Joshi-Pangu, A.; Diane, M.; Biscoe, M. R. J. Am.
Chem. Soc. 2014, 136, 14027.
In a glove box, Silica-SMAP (0.07 mmol/g, 57.1 mg, 0.0040
mmol, 2 mol%), bis(pinacolato)diboron (2, 50.8 mg, 0.20 mmol),
and anhydrous, degassed THF (0.3 mL) were placed in a 10 mL
glass tube containing a magnetic stirring bar. A solution of
[Ir(OMe)(cod)]2 (1.3 mg, 0.0020 mmol, 1 mol%) in THF (0.7 mL)
and 2-ethylbenzo[d]thiazole (1a, 97.9 mg, 0.60 mmol) were
added successively. The tube was sealed with a screw cap and
removed from the glove box. The reaction mixture was stirred
at 60 °C for 15 h, and filtered through a glass pipette equipped
with a cotton filter. The solvent was removed under reduced
pressure. An internal standard (1,1,2,2-tetrachloroethane) was
added to the residue. The yields of the products 3a and 4a were
determined by 1H NMR spectroscopy (82% and 32% yields,
respectively). The crude material was then purified by Kugel-
rohr distillation (1 mmHg, 145 °C), to give the corresponding
product 3a (43.1 mg, 0.15 mmol, 75% yield) contaminated with
the diborylation product 4a (<1%) and traces of impurities, as
estimated by 1H NMR spectroscopy. Total yield over 100% based
on 2 indicates that HBpin formed during catalytic turnover also
served as a borylating reagent (theoretical maximum yield is
(20) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4,
916.
(21) Isolated product 7 was contaminated with 4,4′-dimethoxy-
1,1′-biphenyl (2%), probably generated through homocoupling
of 4-chloroanisole.
(22) Matteson, D. S. Chem. Rev. 1989, 89, 1535.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F