Design, generation, and synthetic application of borylzincate: Borylation of aryl halides and borylzincation of benzynes/terminal alkyne

Article abstract of DOI:10.1021/ja409748m

Borylzincate was generated in situ from dialkylzinc, diboron, and metal alkoxide. Model DFT calculations showed that although the formation of borylzincate is kinetically favorable, it is thermodynamically unfavorable. Therefore, we designed a successive reaction sequence that would provide a compensating energy gain. This enabled Zn-catalyzed borylation of aryl halides and borylzincation of benzynes and terminal alkyne from diborons without the need for any cocatalyst.

Full text of DOI:10.1021/ja409748m

Communication
pubs.acs.org/JACS
Design, Generation, and Synthetic Application of Borylzincate:
Borylation of Aryl Halides and Borylzincation of Benzynes/Terminal
Alkyne
†
,†
‡
†
,†,‡
Yuki Nagashima, Ryo Takita,* Kengo Yoshida, Keiichi Hirano, and Masanobu Uchiyama*
†
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry
‡
Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
*
S Supporting Information
ABSTRACT: Borylzincate was generated in situ from
dialkylzinc, diboron, and metal alkoxide. Model DFT
calculations showed that although the formation of
borylzincate is kinetically favorable, it is thermodynami-
cally unfavorable. Therefore, we designed a successive
reaction sequence that would provide a compensating
energy gain. This enabled Zn-catalyzed borylation of aryl
halides and borylzincation of benzynes and terminal alkyne
from diborons without the need for any cocatalyst.
rganozincate compounds have opened new avenues in
1
O
organic and organometallic chemistry. Recently, increas-
ing attention has been devoted to heteroelement (heteroleptic)
zincates, in addition to the large body of homoleptic alkylzinc-
Figure 1. Energy profile for generation of borylzincate species from
diboron, Lewis base, and dialkylzinc.
2
−4
Scheme 1. Proposed Borylation Reaction Mechanism
ates, because of their unique reactivities and selectivities. For
example, dialkylhydride zincate complexes, which can be readily
prepared from dialkylzinc and NaH or LiH, act as efficient
2
hydride reductants for carbonyl compounds. Dialkylamidozinc-
ates and dianionic silylzincates promote directed ortho-zincation
3
of a wide range of (hetero)aromatics and regioselective
silylzincation of terminal alkynes without any transition metal
4
catalyst, respectively. Borylzincates are also potentially attractive
5
as novel functional zincates and synthetic tools. However, boryl
anions have been regarded as difficult to generate, with a few
6
sophisticated exceptions, such as a finely stabilized borylanion
7
reported by Yamashita, Nozaki et al. and the borylcopper−
8
,9
NHC complex reported by Sadighi et al. However, all of our
model calculations implied that the generation of borylzincate
species is not so difficult (activation barriers <20 kcal/mol), and
the key issue appears to be overcoming the rather large
10
endothermicity (>10 kcal/mol, Figure 1). Thus, we speculated
that borylzincate species could be useful in organic synthesis if
the unfavorable energy loss could be compensated by successive
reaction(s). We disclose here the in situ generation of
borylzincate complexes from diborons via B−B bond cleavage,
which enables some unprecedented and highly chemoselective
borylation reactions.
and regeneration of dialkylzinc. The energy gain is a result of the
formation of the stable C−B bond in D from the unstable B−Zn
bond in A in the reaction sequence.
We commenced our “proof of concept” by exploring the
borylation of 4-iodoanisole (1a) with bis(pinacolato)diboron
(
%
°
2a) in the presence of a catalytic amount of diethylzinc (10 mol
) and various Lewis base “activators” (1.1 equiv) in THF at 75
C (Table 1). In the absence of activator, only a trace amount of
First, we envisioned the catalytic borylation reaction of aryl
9
,11,12
halides
via a halogen−zinc exchange reaction with in situ
generated borylzincate species A (Scheme 1) to afford the
corresponding arylzincate B and boryl halide C, a potent
electrophile, which results in the formation of arylboronate D
Received: September 20, 2013
Published: November 22, 2013
©
2013 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Optimization of Conditions
Table 2. Zn-Catalyzed Borylation of Aryl Halides
a
1
NMR yield determined by H NMR analysis.
the desired product was obtained (entry 1). The use of fluoride
anion promoted the reaction moderately (entries 2−5). When
alkoxide anion was employed as an activator, the starting
t
iodoarene 1a was completely consumed. The use of NaO Bu
gave 3a in excellent yield (82%, entry 7). Other metal alkoxides
among those examined did not improve the reaction outcome
(
entries 8−11). The chemical yield was slightly decreased (72%)
with Me Zn (entry 12), and no product formation was observed
2
with ZnCl (entry 13). The formation of borylzincate is essential
2
for this catalytic borylation; the yield of the product 3a was <1%
13
when R Zn was omitted (entry 14).
2
With the optimized conditions in hand, we examined the scope
of the present borylation, as summarized in Table 2. Iodo-
benzene and its derivatives substituted with electron-donating
groups, including methoxy and methyl groups, were efficiently
converted to the corresponding boronates 3a−f (entries 1−6).
In particular, the substituent position (ortho, meta, or para) of the
methoxy group had no effect on the reaction (entries 1−3), and
some sterically demanding substrates reacted without difficulty
(
entries 3, 5, 15, and 21). Electron-withdrawing substituents,
such as CF , halogens, amide, ester, and CN groups, which are
3
sensitive to base or metal reagents, are compatible with the
present borylation reaction, affording the corresponding boron-
ates in good to excellent yield (entries 7−14). Besides aryl
iodides, aryl bromides can be utilized at higher temperature (120
°
C) (entries 1, 3, 7, and 20), and 3j was the sole product (75%
yield) from the reaction of 4-bromo-iodobenzene at 75 °C (entry
0). Other types of aryl iodides, including naphthyl and a variety
Bis(pinacolato)diboron 2a (entries 1−22), bis(catecholato)diboron 2b
(entry 23), and bis(neopentylglycolato)diboron 2c (entry 24) were
a
b
1
1
used as diborons 2. Isolated yield. NMR yield determined by H
c
of heteroaromatics, were applicable (entries 15−20). Substrates
having an allyloxy group at an ortho or para position afforded the
desired products in good yield (entries 21 and 22). These results
clearly suggest the utility of the Zn-catalyzed borylation, since
these substrates are not compatible with Pd-catalyzed boryl-
NMR analysis. Isolated yield using aryl bromides instead of aryl
d
iodides as starting materials 1, with heating to 120 °C. Isolated yield,
with heating to 120 °C.
DFT model calculations provide a clear rationale for the
proposed mechanism of the borylzincate-mediated ionic boryl-
ation of aryl halides. The calculated potential energy profiles are
summarized in Figure 2. The primary role of borylzincate is to
stabilize the pre-reaction intermediate and the halogen−zinc
exchange TS by cooperative synergy of the countercation,
1
1,12a
ation.
Moreover, the results of entry 21 provided some
mechanistic insight; i.e., the radical mechanism is not plausible,
since the 5-exo-trig cyclization byproduct was not detected at
all. To our knowledge, this reaction is the first example of an
ionic borylation of aryl halides using diborons without any
transition metal catalysts.
1
3
−
Me Zn, and B(OR) moiety (see Supporting Information for
2
2
The structural requirement of diboron was also examined.
Using bis(catecholato)diboron (2b) and bis(neopentyl-
glycolato)diboron (2c), the corresponding aryl boronates 3w
and 3x were obtained in 72% and 64% yield, respectively (entries
details). Also noteworthy is that the successive reaction sequence
provides a large energy gain (26.6 + 50.0 kcal/mol) to regenerate
dialkylzinc for the next catalytic cycle. Thus, the zincate serves to
mediate boron transfer through the two IMs/TSs.
Next, we examined the borylzincation of unsaturated bonds
with the in situ-generated borylzincate species. Benzyne was
2
3 and 24). Thus, the present Zn-catalyzed borylation has a
broad substrate generality.
1
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Communication
Table 3. Borylzincation of Benzyne
Figure 2. Energy profile for borylzincate-mediated ionic borylation of
aryl iodides (B3LYP/LANL2DZ for I, SVP for Zn, and 6-31+G* for
others; energy in kcal/mol).
14
selected as the first substrate, because the relief of strain of the
unstable” triple bond of benzynes should provide a large energy
“
gain in the borylzincation process (Figure 1). When benzyne,
prepared from (2-trimethylsilyl)phenyl trifluoromethane-
15
sulfonate (4k) with KF/18-crown-6, was treated with diethyl-
zinc, 2a, and KF, followed by quenching with H O, the borylated
2
product 3f was obtained in 66% yield (eq 1, bottom of Table 3).
16
The reaction did not proceed at all in the absence of Et Zn,
2
supporting the idea that borylzincation of benzyne occurs via in
situ generation of borylzincate species.
One of our group previously reported another benzyne
formation reaction of o-halo-iodobenzene derivatives using
trialkylzincate, which provided a chemoselective and regio-
3b
controlled method for generation of functionalized benzynes.
In addition, silylzincation of the generated substituted benzynes
to give a multifunctionalized zincate, (o-silylaryl)zincate species,
was achieved using a silylzincate, Me Zn(SiMe Ph)Li, prepared
2
2
3d
from Me Zn and Me PhSiLi. We therefore investigated similar
2
2
borylzincations of functionalized benzynes (Table 3). After
t
intensive screening of activators, Mg(O Bu) was found to be the
2
1
7
best. The reaction of 2-bromoiodobenzene (4a) provided the
-borylphenylzincate species, which reacted with allyl bromide to
2
afford (2-allylphenyl)boronic acid pinacol ester 5a in 84% yield.
The use of 4b or 4c caused no problems (entries 2 and 3), and
trapping of the generated arylzincate with I gave the desired
2
product in good yield (78%, entry 4). 3-Substituted benzynes
were also examined, in the expectation of obtaining 1,2,3-
trisubstituted benzene derivatives. When 2-iodo-3-bromoanisole
(
4d) was used under the optimized conditions, 3b was
exclusively obtained in 84% yield after quenching with H O
2
a
Isolated yield. Yield determined by 1H NMR analysis. The
b
c
(
entry 5). Trapping with allyl bromide or I also gave the desired
2
reactions with electrophiles were carried at room temperature with
multifunctionalized benzene in a highly regioselective manner
entries 6 and 7). In addition to the methoxy group, other
H O for 5 min or with I for 3 h, or at 75 °C with allyl bromide for 12
2
2
(
d
h. The amount of 2a was 3 equiv.
directing groups, such as F, Cl, and CN, induced highly selective
borylzincation, affording the corresponding products after
electrophilic trapping (entries 8−13). 4-Fluoro- and 4-methyl-
Scheme 2. Borylzincation of Terminal Alkyne
2
-iodobromobenzene (4j and 4k) gave the borylated products as
mixtures of regioisomers (1:2.6 and 1:1.1, respectively, entries 14
and 15). In other words, the low selectivity with these substrates
reflects the fact that benzyne formation was involved prior to the
borylzincation.
The present borylzincation was finally applied to a terminal
18
alkyne (Scheme 2). Phenylacetylene (6) was treated under
conditions similar to those used for benzynes, and after
compensating energy gain. This method enables borylation of
aryl halides with broad substrate generality. The high nucleo-
philicity of the boryl ligand in borylzincate was crucial for
efficient halogen−zinc exchange reaction and for catalytic use of
dialkylzinc. Regioselective borylzincation of benzynes was also
achieved under similar conditions, affording multifunctionalized
aromatic compounds. We believe that a successive reaction
approach utilizing in situ-generated unstable and highly reactive
species is a powerful strategy with potentially broad applicability
for developing further functions of zincates. Efforts to apply this
approach to a variety of reactions and to elucidate the present
electrophilic trapping with H O, the borylated product was
2
obtained in moderate (51%) yield, presumably reflecting the fact
that reactivity of the C−C triple bond of 6 is lower than that of
benzyne.
In summary, we have developed a method for in situ generation
of borylzincate species using dialkylzinc and diboron activated by
Lewis basic metal alkoxide. Calculations suggested that the
formation of borylzincate would be thermodynamically unfav-
orable, but this could be overcome by designing the overall
reaction sequence so that the subsequent step provides a
1
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Journal of the American Chemical Society
Communication
reaction pathway/mechanism with the help of theoretical and
spectroscopic studies are in progress in our laboratory.
(8) (a) Laitar, D. S.; Mu
̈
ller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005,
1
27, 17196. See also: (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. J.
Organomet. Chem. 2001, 625, 47.
(
9) Recently, activation of the B−B bond in diborons by Lewis basic
ASSOCIATED CONTENT
Supporting Information
Experimental details and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
compounds and its utilization for several borylation reactions in the
presence or absence of transition metal catalysts has been reported. For
reviews, see: (a) Cid, J.; Gulyas
*
S
́ ́ ́
, H.; Carbo, J. J.; Fernandez, E. Chem. Soc.
Rev. 2012, 41, 3558. (b) Takaya, J.; Iwasawa, N. ACS Catal. 2012, 2,
1
993. See also refs 8 and 11.
AUTHOR INFORMATION
(10) For example, DFT analysis of a possible pathway for generation of
borylzincate species from bis(ethyleneglycolato)diboron, LiOMe, and
■
Corresponding Authors
takita@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
Me Zn as model substrates is depicted below:
2
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partly supported by JSPS KAKENHI (S) (No.
4229011), Takeda Science Foundation, The Asahi Glass
■
2
(
11) Borylations of aryl halides using diborons catalyzed by transition
Foundation, Daiichi-Sankyo Foundation of Life Sciences,
Mochida Memorial Foundation, Tokyo Biochemical Research
Foundation, Foundation NAGASE Science Technology Devel-
opment, Yamada Science Foundation and Sumitomo Founda-
tion (to M.U.), JSPS Grant-in-Aid for Young Scientists (A) (to
R.T.) (No. 25713001), and JSPS Grant-in-Aid for Young
Scientists (Start-up) (to K.H.) (No. 24850005). The calculations
were performed on the Riken Integrated Cluster of Clusters
metal catalysts have been reported. For Pd-catalyzed reactions, see:
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̈
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(
RICC). We gratefully acknowledge Advanced Center for
Computing and Communication (RIKEN) for providing
precious computational resources.
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2
2
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(
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(
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