Angewandte
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Chemie
were obtained without inhibition by the functional groups
and/or loss of the functional groups at the para-positions. In
À
the case of (4-methoxyphenyl)(methyl)sulfane (1c), the C H
borylation occurred at the ortho-position of the methylthio
group, not of the methoxy group. In the case of 4-phenyl-
À
thioanisole 1g, ortho- selective C H borylated product 4g
À
was obtained using ligand 3 f, whereas C H borylation
occurred at the other aromatic ring at the 4-position (5g
and 5g’) using the dtbpy ligand. In the case of meta-
Figure 3. Control experiments using a) a bipyridine-type ligand with
a boryl group at the para-position of a phenyl group, and b) a mixture
of 2,2’-bipyridine and borylbenzene for the reaction between 1a and 2
(Scheme 1, entry 7). The [ortho/meta+para] ratios are shown in the
square brackets.
À
substituted thioanisole derivatives 1h–1u, the C H boryla-
tion proceeded regioselectively at the ortho-position with less
steric hindrance between the two possible ortho-reaction sites
using ligand 3 f. These results were in sharp contrast to those
À
of reactions using the dtbpy ligand, in which C H borylation
occurred predominantly at the meta-positions of thioanisoles.
The functional groups of thioanisoles 1h–1u remained
unchanged during the reactions. More interestingly, the
reaction proceeded only at the ortho-position of a sulfur
atom, whereas ester, amide, cyano, pyrrolidinyl, and morpho-
linyl groups in 4p, 4q, 4s, 4t, and 4u could work as Lewis basic
sites and coordinate to the boryl group of the ligand. The
desired reaction did not proceed when using 3-(methylthio)-
pyridine, 3-(methylthio)furan, and 3-(methylthio)-1-(trime-
thylsilyl)-1H-pyrrole. In the case of 3-(methylthio)thiophene,
a mixture of 5-borylated and 2,5-diborylated products was
obtained, but the ratio of regioisomers was almost the same in
both ligand 3 f and dtbpy. The yields of the borylated products
using ligand 3 f were higher than those using the dtbpy ligand
in several substrates, such as 4d–4 f, 4h, and 4k. These results
Scheme 3. Gram scale reaction.
of 1.24 g of thioanisole (1a) with diboron 2 in the presence of
iridium/3 f catalyst gave 1.79 g of ortho-borylated product 4a
in 72% yield ([ortho/meta + para] > 30). The boryl group was
converted into other various functional groups, such as
a bromine atom,[22] a trifluoromethyl group,[23] and a methoxy
group,[24] demonstrating the synthetic utility of the borylated
products (Supporting Information, Scheme S1). Furthermore,
2-borylated aryl sulfides can be used as substrates for the
Suzuki–Miyaura cross-coupling reaction.[25] As a representa-
tive application, previously reported intermediate 7[26] for the
synthesis of factor Xa inhibitors were concisely synthesized
from 4a (Scheme 4). Palladium-catalyzed Suzuki–Miyaura
cross-coupling between ortho-borylated thioanisole 4a and 5-
bromoindoline (6) gave the desired product 7 in 68% yield
without protecting the NH group of 6.
À
suggest that ligand 3 f accelerates the C H borylation
reaction by capturing the substrates using a Lewis acid–base
interaction. The corresponding ortho-borylated products
were not formed using anisole,[20] N,N-dimethylaniline, and
quinoline as substrates: anisole, 66% [meta/para = 3.8]; N,N-
dimethylaniline, 35% [meta/para = 1.8]; quinoline, no reac-
tion.[21]
We performed several experiments to confirm the exis-
tence of a Lewis acid–base interaction and revealed the
following: 1) the [ortho/meta + para] ratio in non-polar sol-
vents was much higher than that in polar solvents, such as
dioxane and ethyl acetate (Supporting Information,
Table S2); 2) the [ortho/meta + para] ratio was higher at
lower temperatures than at higher temperatures;[18] 3) the
ortho-selectivity decreased in the case of aryl sulfides with
a bulky substituent on the sulfur atom, such as isopropylth-
iobenzene ([ortho/meta + para] ratio < 0.01 (47% yield));
4) the ortho-selectivity highly depended on the Lewis acidity
of the boryl groups, as shown in Scheme 1; and 5) the ortho-
selectivity was not observed in several reactions using the
following control ligands: a) bipyridyl-type ligand 3h with
a boryl group at the para-position of the phenyl group instead
of at the ortho-position (Figure 3a); and b) a mixture of 2,2’-
bipyridine and borylbenzene 3i without covalently connect-
ing the two components (Figure 3b). These results indicate
that the Lewis acid–base interaction worked during the
reaction and played an important role in the high ortho-
selectivity.
Scheme 4. Synthesis of the intermediate for factor Xa inhibitors.
À
The ortho-selective C H borylation was applied to
bioactive compound 8,[27] which is an insecticide (Scheme 5).
Treatment of 8 with bis(pinacolato)diboron (2) in the
presence of an iridium catalyst [Ir(OMe)(cod)]2 and ligand
3 f gave ortho-borylated product 9 in 61% yield (9/10 > 30).
This result, too, was in sharp contrast to that of the reaction
using dtbpy, in which borylation proceeded mainly at the
meta-position of 8 (9/10 < 0.01). Interestingly, the reaction
occurred exclusively at the ortho-position of the sulfide group,
even though there are two sulfur-containing functional groups
(that is, sulfide and thiophosphate groups) in 8.
The borylation reaction proceeded in good yield with high
ortho-selectivity, even on a gram scale (Scheme 3). Treatment
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!
Li, Hong Liang
