Boryl-Directed, Ir-Catalyzed C(sp3)-H Borylation of Alkylboronic Acids Leading to Site-Selective Synthesis of Polyborylalkanes

Article abstract of DOI:10.1021/acs.orglett.9b02112

Pyrazolylaniline serves as a temporary directing group attached to the boron atom of alkylboronic acids in Ir-catalyzed C(sp³)-H borylation. The reaction takes place at α-, β-, and γ-C-H bonds, giving polyborylated products including di-, tri-, tetra-, and even pentaborylalkanes. α-C-H borylation was generally found to be the preferred reaction of primary alkylboronic acid derivatives, whereas β- or γ-borylation also occurred if β- or γ-C-H bonds were located on the methyl group.

Full text of DOI:10.1021/acs.orglett.9b02112

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Boryl-Directed, Ir-Catalyzed C(sp3)−H Borylation of Alkylboronic
Acids Leading to Site-Selective Synthesis of Polyborylalkanes
Takeshi Yamamoto,* Aoi Ishibashi, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: Pyrazolylaniline serves as a temporary directing
group attached to the boron atom of alkylboronic acids in Ir-
catalyzed C(sp3)−H borylation. The reaction takes place at α-,
β-, and γ-C−H bonds, giving polyborylated products including
di-, tri-, tetra-, and even pentaborylalkanes. α-C−H borylation
was generally found to be the preferred reaction of primary
alkylboronic acid derivatives, whereas β- or γ-borylation also
occurred if β- or γ-C−H bonds were located on the methyl
group.
olyborylated organic compounds are gaining increasing
attention in organic synthesis because they allow stepwise
for the boryl-directed C(sp3)−H borylation and its site
selectivity depending upon the structure of the substrates
(Scheme 1).
P
conversion of boryl groups into various functional groups,
leading to the selective synthesis of highly functionalized organic
molecules.1 Along with constant demands for polyborylated
aromatic and heteroaromatic compounds, emerging interest has
focused on polyborylalkanes in which boryl groups are attached
to the sp3-carbon centers. Particular attention is focused on
synthetic applications of 1,1-diborylalkanes2 because they show
unique reactivities3−6 resulting from the higher reactivity of one
of the two boryl groups in synthetic transformations in addition
to their utilization as reagents for the boron−Wittig reaction.6
1,1-Diborylalkanes have been accessible by several methods7−11
such as borylation of 1,1-dihalides7 and hydroboration of 1-
borylalkenes and terminal alkynes.8 Although transition-metal-
catalyzed directed12 or nondirected13 C(sp3)−H borylation
would provide the most efficient routes,11 difficulties lie in the
site-selective introduction of multiple boryl groups into the
alkane molecule. It should be noted that the boryl group
accelerates the nondirected C−H borylation at the boron-bound
carbon atom to allow geminally polyborylated products
including 1,1,1-triborylalkane, although the substrate scope is
still limited.13j It would be most attractive if a boryl group that is
introduced initially in the molecule can serve as a directing group
in C−H borylation to help the introduction of the second and
even the third boryl groups in a site-selective manner.
Scheme 1. Preparation of PZA-Modified Alkylboronic Acid
PZA-modified 1-octylboronic acid 1a, which was easily
accessible by heating octylboronic acid with PZA in toluene
under reflux, was subjected to Ir-catalyzed C−H borylation
(Table 1). In the presence of 2.5 mol % of [Ir(OMe)(cod)]2 (A)
and 1.2 equiv of B2pin2, borylation of 1a proceeded at 50 °C.
After treatment of the reaction mixture with pinacol for
detection and quantification of the borylation product in the
form of pinacol ester,17 monoborylation product 1,1-dibor-
yloctane 2a was obtained in 59% yield (entry 1). α,α-
Diborylated 1,1,1-triboryloctane 3a was also obtained in 14%
yield. It should be noted that only a trace amount of other
borylated products was detected in the reaction mixture. Use of
3.0 equiv of B2pin2 increased the yield of 2a to 66% (entry 2).
Formation of double-borylation product 3a became predom-
inant when a larger amount (5 mol %) of [Ir(OMe)(cod)]2 was
employed (entry 3). Use of other solvents such as dimethoxy-
ethane, dichloroethane, toluene, and cyclohexane decreased the
We have developed pyrazorylaniline (PZA)14 and anthrani-
lamide (AAM)15 as easily attachable and detachable ortho-
directing boron modifiers in C(sp2)−H functionalization of
arylboronic acids such as Ru-catalyzed silylation,14a,15 Ir-
catalyzed borylation,14c and Rh-catalyzed alkenylation.14d PZA
also works as a directing group in Ru-catalyzed C(sp3)−H
silylation of methyl and ethylboronic acids.14b In this
communication, we disclose the optimized reaction conditions
Received: June 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02112
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. C(sp3)−H Borylation of PZA-Modified
a
Octylboronic Acid 1a
b
yield (%)
entry
Ir cat. (mol %)
B2pin2 (equiv)
2a
3a
1
2
3
4
5
[Ir(OMe)(cod)]2 (A) (2.5)
[Ir(OMe)(cod)]2 (A) (2.5)
[Ir(OMe)(cod)]2 (A) (5.0)
[IrCl(cod)]2 (5.0)
1.2
3.0
3.0
3.0
3.0
59
66
12
35
3
14
14
64
0
[Ir(mes)(Bpin)3] (B) (5.0)
77
a
Reaction conditions: 1a (0.10 mmol), Ir catalyst, and B2pin2 were
heated in THF (0.5 mL). To the mixture were added pinacol and p-
toluenesulfonic acid monohydrate at room temperature, and the
mixture was stirred for 5 h. GC yield.
Figure 1. Time course for polyborylation of PZA-modified
b
methylboronic acid with (a) 2.5 mol % of [Ir(OMe)(cod)]2 and (b)
■
●
2.5 mol % of [Ir(mes)(Bpin)3]. GC yields of mono- ( ), di- ( ), tri-
(
yield of 3a (see the Supporting Information (SI)). The necessity
of the pza group was confirmed by a reaction of pinacol-modified
octylboronic acid (n-octylBpin) under similar reaction con-
ditions, which gave no C−H borylation product (see the SI).
Whereas [IrCl(cod)]2 showed low catalytic activity (entry 4),
trisborylcomplex [Ir(mes)(Bpin)3] (B)16 exhibited high cata-
lytic activity, giving α,α-diborylated product 3a in 77% yield
(entry 5).
By using 2.5 mol % of [Ir(OMe)(cod)]2 (A) and 4.0 equiv of
B2pin2 at 50 °C, PZA-modified methylboronic acid 1b afforded
triborylmethane 3b through α,α-diborylation in 59% isolated
yield (Scheme 2). Use of [Ir(mes)(Bpin)3] (B) as a catalyst led
◆
▲
), and tetraborylmethane ( ) were plotted against the reaction
time.
alkylboronic acid derivatives 1c−e afforded the corresponding
α-monoborylated products in good yields (entries 3−5).
Alkylboronates 1f−h, having phenyl groups at the β-positions,
also afforded α-monoborylated products in good yields (entries
6−8). Selective C(sp3)−H borylation over C(sp2)−H bor-
ylation was also observed in the reactions of benzylic boronates
1i and 1j, even though the aromatic hydrogen atoms are located
at the γ-positions (entries 9 and 10).
In the course of our examinations of the Bpza-directed C−H
borylation of alkylboronates, we encountered low-yield
formation of expected α-borylation products. For instance,
neopentylBpza 1k underwent the C−H borylation only
sluggishly to form α-monoborylation product 2k in low yield
along with γ-monoborylation product 2k′, with the formation of
trace amounts of double-borylation products (eq 1). This result
Scheme 2. Polyborylation of PZA-Modified Methylboronic
Acid
to the formation of tetraborylmethane 4 through α,α,α-
triborylation in 73% yield. To our knowledge, this is the first
catalytic synthesis of tetraborylmethane.18
The time course of the conversion of 1b in the presence of
catalyst A or B was separately monitored by GC analysis (Figure
1). In both reactions, a diborylation product, namely, triboryl-
methane, was quickly formed with consumption of the starting
MeBpza (1b). It is notable that the initial monoborylation
product was rapidly converted into the triborylmethane. With
highly active catalyst [Ir(mes)(Bpin)3], thus formed triboryl-
methane was gradually converted into tetraborylmethane. These
results suggest that the boryl group accelerates the C−H
borylation electronically but decelerates it sterically.
Various alkylboronic acid derivatives were subjected to the
Bpza-direced C−H borylation in the presence of [Ir(OMe)-
(cod)]2 (A) or [Ir(mes)(Bpin)3] (B) as a catalyst (Table 2). In
the reactions of n-octylBpza (1a), 1,1-diboryloctane 2a was
selectively formed and isolated in 54% yield using A as a catalyst,
whereas 1,1,1-trisboryloctane 3a was obtained selectively in the
presence of B. β-Branched as well as γ-branched primary
suggests that γ-borylation can be compatible with α-borylation
and that, by incorporation of the first boryl groups at either the
α- or γ-position, the other C−H bond may become more
sterically congested, suppressing the second C−H borylation.
The reaction of isobutylboronate 1l, a β-branched alkylboro-
nate, with 2 equiv of B2pin2 afforded α-C−H borylation product
2l in only 33% isolated yield (eq 2). Careful inspection of the
reaction mixture suggested the formation of several other C−H
borylation products including those containing three boryl
groups, although structural identification of each product was
challenging.
We then subjected 1l to the reaction with 3 equiv of B2pin2
under the same reaction conditions. We found the predominant
formation of triboryl product 5, which was derived through C−
H borylation at both the α- and γ-positions (Table 3, entry 1).
B
DOI: 10.1021/acs.orglett.9b02112
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 2. α-C−H Borylation of PZA-Modified Primary
Table 3. β- and γ-C−H Borylation of PZA-Modified
a
a
Alkylboronic Acids
Alkylboronic Acids
a
b
See footnote a in Table 2. Isolated yield.
4 equiv of B2pin2 allowed us to isolate tetraboryl product 7,
which was derived through α,β,β-triple C−H borylation (entry
3). In the reaction of isopropylBpza 1o, we observed no α-
borylation but found the selective formation of pentaboryl
product 8, a quadruple β-borylation product, which was isolated
in 60% yield (entry 4). CyclohexylBpza showed no reaction
under identical reaction conditions.
CyclopropylBpza 1p was subjected to the reaction with B2pin2
using [Ir(OMe)(cod)]2 (A) as a catalyst (Scheme 3). We
Scheme 3. Borylation of PZA-Modified Cyclopropylboronic
Acids
a
Reaction conditions: 1 (0.30 mmol), Ir catalyst, and B2pin2 were
heated in THF (1.5 mL). To the mixture was added pinacol and p-
toluenesulfonic acid monohydrate at room temperature and stirred for
b
c
d
5 h. Isolated yield. 50 °C. 24 h.
isolated 1,1,3,3-tetrakisborylpropane 9 in 43% yield through
cleavage of the C−C bond in the cyclopropane ring.19 Analysis
of the crude mixture obtained by the reaction using 1.2 equiv of
B2pin2 at 50 °C for 12 h suggested the formation of 1,1,2-
trisborylcyclopropane before the C−C bond cleavage (see
the SI).
The synthetic utility of these polyborylated molecules has
been demonstrated by a cross-coupling reaction3b and boron-
Wittig reaction6 according to previous reports (Scheme 4). 1,1-
Diborylalkane 2c, which was prepared on a gram-scale reaction
under modified reaction conditions (1.5 mol % of catalyst A, see
the SI for the details), underwent cross-coupling with m-
bromotoluene at one of the two boryl groups, giving secondary
organoboronate 10 in good yield. α-Lithiated 2c reacted with 3-
phenylpropanal and gave alkenylboronate 11 through a boron-
The same trend was observed in the reaction of 2-
methylbutylboronic acid derivative 1m; in this case, α,γ-
diborylated product 6 was obtained in 74% yields with 5 equiv
of B2pin2 at 80 °C (entry 2), whereas α-monoborylated product
2m was obtained in only 25% yield with 2 equiv of B2pin2 at 50
°C. These results are interesting when compared with the
reaction of β-branched 1c and 1d shown above, which resulted
in the predominant formation of the α-C−H borylation
products (Table 2, entries 3 and 4). It is suggested that the
presence of the less sterically hindered γ-C−H bond on the
methyl group allowed γ-borylation to compete with α-
borylation. The reaction of ethylBpza 1n also suffered from
the formation of a mixture of polyborylation products under the
standard reaction conditions using 2 equiv of B2pin2. The use of
C
DOI: 10.1021/acs.orglett.9b02112
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Scheme 4. Transformation of 1,1-Diborylalkane 2c
Figure 2. Classification of site selectivity of Bpza-directed C−H
borylation by substrate structures.
at rates comparable to that of α-C−H borylation, leading to
multiple C−H borylations. Although no α-C−H borylation
takes place with secondary alkyl derivatives, borylation can
proceed at other methyl C−H bonds as exemplified by the
reaction of isopropylBpza, which undergoes quadruple β-C−H
borylation. The present boryl-directed C−H borylation enables
the efficient synthesis of polyborylated organic molecules from
unfunctionalized starting materials by employing nondirected
C−H borylation.
Wittig reaction, which was subsequently converted into ketone
12.
The present Bpza-directed borylation allows synthesis of
polyborylated organic compounds from unfunctionalized
starting materials in combination with nondirected C−H
borylation (Scheme 5). Monoboryl ether 14 was prepared by
ASSOCIATED CONTENT
* Supporting Information
Scheme 5. Synthesis of Polyborylated Ester from Diisopentyl
Ether
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02112.
Detailed experimental procedures and compound char-
acterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yamamoto@sbchem.kyoto-u.ac.jp.
*E-mail: suginome@sbchem.kyoto-u.ac.jp.
ORCID
Takeshi Yamamoto: 0000-0002-5184-7493
Michinori Suginome: 0000-0003-3023-2219
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Ir-catalyzed nondirected C−H borylation of diisopentyl ether
(13) in the presence of a catalytic amount of potassium tert-
butoxide.13g Hydrolysis of boronic acid pinacol ester followed by
condensation with PZA gave PZA-modified monoboryl ether 15
in 80% yield. In the presence of 2.0 mol % of [Ir(OMe)(cod)]2
and 2.0 equiv of B2pin2, borylation of 15 proceeded at the α-C−
H bond preferentially, giving 1,1-diboryl ether 16 in 44% yield.
In addition, by using 10 mol % of B and 5.0 equiv of B2pin2 at 80
°C for 24 h, 1,1,3-triboryl ether 17 was obtained in 57% yield.
In conclusion, we established Ir-catalyzed C(sp3)−H
borylation of alkylboronic acids by attaching PZA as a removable
directing group on the boron atom. Although the directed C−H
borylation can proceed at the α-, β-, and γ-C−H bonds, the
selectivity largely depends upon the structure of the alkyl group
(Figure 2). In general, α-borylation is the preferred reaction
pathway in the reactions of primary alkylboronic acid
derivatives. However, if there is a methyl C−H bond at either
the β- or γ-position, these C−H bonds undergo C−H borylation
■
This work was supported by JSPS KAKENHI Grant No.
JP15H05811, Precisely Designed Catalysts with Customized
Scaffolding.
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DOI: 10.1021/acs.orglett.9b02112
Org. Lett. XXXX, XXX, XXX−XXX