Transition-metal-free regioselective synthesis of alkylboronates from arylacetylenes and vinyl arenes

Article abstract of DOI:10.1039/c5gc02633d

A transition-metal-free synthesis of alkylboronates, utilizing arylacetylenes or vinyl arenes and bis(pinacolato)diboron through tandem borylation and protodeboronation, has been developed. This reaction is efficient, practical and environmentally benign, leading to anti-Markovnikov products with excellent regioselectivity, broad functional group tolerance and excellent yields in both small and gram scales.

Full text of DOI:10.1039/c5gc02633d

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DOI: 10.1039/C5GC02633D
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Transition-Metal-Free Regioselective Synthesis of Alkylboronates
from Arylacetylenes and Vinyl Arenes
Received 00th January 20xx,
Accepted 00th January 20xx
Kai Yanga and Qiuling Songa, b
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A transition-metal-free synthesis of alkylboronates, utilizing regioselective transition-metal-free synthesis of alkylboronates
arylacetylenes or vinyl arenes and bis(pinacolato)diboron through tandem from terminal arylacetylenes and B2pin2 via tandem borylation and
borylation and protodeboronation, has been developed. This reaction is protodeboronation under basic condition (Scheme 1e). There are
efficient, practical and environmentally benign, leading to anti- several advantages of the present method: (1) the reaction is
Markovnikov products with excellent regio- and chemoselectivities, broad environmentally sustainable because it is transition-metal-free; (2)
functional group tolerance and excellent yields in both small and gram the reaction shows broad substrate scope and functional group
scale.
tolerability; (3) the experimental protocol is simple which should
make it potential to be used in industrial applications.
Organoboron compounds are valuable synthetic building blocks
in C-C1 and C-X (X = N,1 O,1 S,2 P3 etc) bond-forming reactions.
Numerous methods have been developed for the synthesis of
organoboron compounds.4-9 Among them, the reaction of terminal
alkynes with bis(pinacolato)diboron has received substantial
attention due to prevalence and easy accessibility of alkynes and
diboron reagents. Significant progress has been achieved to
produce β-vinylboronates,10 α-vinylboronates,11  ,  -diborated
alkanes12 and  ,  -diborated alkenes (Scheme 1).13 Despite such
progress, the direct preparation of alkylboronates through
borylation of alkynes under transition-metal-free conditions has yet
to be reported. In very recent times, great effort has been devoted
to the development of advantageous methods with high chemo- or
regio-selectivity, ready accessibility of starting materials, simple
operation, good functional group tolerance and environmental
sustainability. Achieving a transition-metal-free method would fulfill
the above demands and address the drawbacks of existing methods
to access alkylboronates by eliminating the need for precious metal
catalysts, avoiding harsh reaction conditions and improving
functional group tolerance. Recently, Verkade’s super base
(C9H21N4P) and phosphine ligands have been applied in
organocatalytic β-borylation reaction to provide alkyl boron
compounds.14 However, the substrate scope was limited to α,β-
unsaturated carbonyl compounds. Herein, we report a highly
Scheme 1. Overview of the Reaction between Alkynes and B2pin2
Phenylacetylene (1a) and B2pin2 (2a) were chosen as the
substrates to test if transition-metal-free synthesis of alkyl
boronates could be achieved (Table 1). To our delight, the desired
product 3a was formed in 81% yield (Table 1, entry 1) with 4.0 equiv
of Cs2CO3 and 5.0 equiv of MeOH in dioxane at 100 oC under N2. To
optimize this result further, the effect of solvent was investigated
(Table 1, entries 2-4). We found that CH3CN was the optimal one
among THF, toluene and dioxane (Table 1, entries 1-4). The reaction
was found very sensitive to the atmosphere: replacing nitrogen
with air reduced the yield of the transformation (Table 1, entry 5).
o
o
Interestingly, the temperature decreasing from 100 C to 70 C did
not reduce the desired product 3a, which were obtained in nearly
quantitative yield. Reducing the reaction temperature to 60 °C,
however, caused the isolated yield of desired product to drop to
91% (Table 1, entries 6-8). Screening different bases revealed that
Cs2CO3 was superior to KOtBu, Na2CO3, K3PO4, NaOtBu and KOH
(Table 1, entries 9-12).15 Gratifyingly, shortening the reaction time
from 12 hours to 4 hours did not affect the efficiency of the
reaction, and the desired product was obtained in 99% in GC with
a Institute of Next Generation Matter Transformation, College of Chemical
Engineering at Huaqiao University, 668 Jimei Blvd, Xiamen, Fujian, 361021, P. R.
China
b National Laboratory for Molecular Sciences, Institute of Chemistry, CAS, Beijing,
100190, P. R. China
E-mail:qsong@hqu.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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85% isolated yield (Table 1, entry 14). A slightly lower yield was ethynylquinoline and 6-ethynyl-2-methylquinolineVieww Aerrteicle Ognolioned
observed when the reaction time was reduced to 3 hours (Table 1, substrates for this transformation as well toDgOivI:e1t0h.1e03c9o/rCre5sGpCo0n2d6i3n3gD
entry 13).
desired products in 45%, 71% and 75% yields, respectively (Scheme
2, 2o–3p).
Table 1. Condition screening.a
On the basis of the above transformation, we envisioned that
such process might be further applied to another important class of
unsaturated compounds: aromatic alkenes. Recently several
elegant works about borylation of vinyl arenes under transition-
metal free conditions have been reported,16 yet only diborated
products were obtained even with styrene case. Chemo- and
regioselected monoborylation of vinyl arenes under transition-
metal free condition with diboron as borylating reagent has not yet
been reported. To our delight, the desired alkyl boronate 2a was
obtained in 56% when styrene 3a was treated with B2Pin2 under the
above standard conditions. After simple modification (Table S1,
Supporting Information), the optimal conditions emerged as: B2pin2
(1.5 eq), Cs2CO3 (2.5 eq), MeOH (5 equiv) in dioxane at 100 oC under
N2 for 12 hours. A wide range of electron-rich and electron-deficient
substituted aromatic and heteroaromatic alkenes were investigated
to afford corresponding alkylboronate esters (2a-2u) in moderate to
good yields (Scheme 3). However, it should be mentioned that
steric hindrance highly affects the reaction efficiency and the 1,1-
diphenylethylene just gave 24% of desired product based on 33%
conversion (Scheme 3, 2u).
Scheme 3. Synthesis of Alkylboronates from Aromatic Alkenes a, b
With the optimized reaction conditions in hand, the substrate
scope of the arylacetylenes was explored (Scheme 2). Both
electron-rich and electron-deficient substituents on the aromatic
rings of arylacetylenes 1 worked well with B2Pin2 under standard
conditions to afford desired products in moderate to good yields
(Scheme 2, 2b−2m). The reaction tolerated halo-substitutions,
Scheme 2. Synthesis of Alkylboronates from Terminal Arylalkynes a,
b
In order to rule out the possibility of the trace amount of
transition metal in the reaction mixture, 99.99% purity of Cs2CO3
was used in the two standard conditions and the results were listed
below:
which can be used for further functionalizations (Scheme 2, 2e−2h).
In addition to these halides, the borylation of arylacetylenes
proceeded smoothly in the presence of other functional groups
including trifluoromethyl, ketones, esters, nitriles and
methylsulfonyl (Scheme 2, 2i−2m). Moreover, the acetylene derived
from 2-naphthalene was also
a good candidate for this
transformation (Scheme 2, 2n). Further investigation showed that
heteroaromatic acetylenes, such as 2-ethynylthiophene, 3-
2 | J. Name., 2012, 00, 1-3
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As we can see, with high purity of Cs2CO3, desired product 3aa
was obtained in very high GC yields, which are consistent to the
results listed in Scheme 2 and 3 with regular Cs2CO3. Therefore we
have reasons to believe that this is a transition-metal free reaction
(see SI for detailed information).
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DOI: 10.1039/C5GC02633D
The importance of these transformations can be further featured
by hydroboration of bioactive moieties on the structural scaffolds
as well (Scheme 4). For instance, alkylboronate 5 could be readily
obtained in 69% yield from a pipecolic acid derivatived alkyne,
which might be as a small molecule inhibitor of MIP (the
macrophage infectivity potentiator) (Scheme 4a).17 Natural
occurred substituents, such as protected galactose and cholesterol
were also well-tolerated under the standard conditions to afford
corresponding desired products 7 and 9 in 72% and 76% yields
respectively, underscoring the broad substrate scope and the
potential utility of these protocols in synthesis (Scheme 4b and 4c).
Scheme 6. Further Transformation of Alkylboronate Esters
To gain insight into the mechanism of alkylboronate synthesis
from arylacetylenes or vinyl arenes, vinylboronate 14, tris(boronate)
15 and diboronate 16 were prepared according to methods in the
literature. Vinylboronate 14 was readily accessible from alkynes
with B2pin2,10h so it was considered as the potential intermediate in
the transformation of arylacetylenes. According to the literature,
triboronated compound 15 could be afforded from monoboronate
14 under proper conditions.19 In terms of 16, it was readily available
when styrene was subjected under basic conditions.16a So both 15
and 16 were considered as possible intermediates in arylacetylenes
and vinyl arenes transformation as well. When 14 was conducted
under the standard conditions for arylacetylenes with and without
B2pin2 respectively, the desired product 2a was obtained in 99% GC
yield in former case, yet in the latter one no desired product was
obtained at all (scheme 7a). Independently synthesized
tris(boronate) 15 and diboronate 16 were subjected to
corresponding standard conditions with B2pin2 as well as the
conditions without B2pin2, interestingly, not like the case shown in
scheme 7a, quantitative yield of the desired product 2a were
generated in all above four conditions (scheme 7b and 7c). These
reactions suggested that 14, 15 and 16 might be the intermediates
in our transformations, in which 14 might be the initial intermediate
(since B2pin2 was still needed for the success of the transformation),
and 15 might be derived from 14 and B2pin2 does not play any role
from 15 and 16 to 2a.
Scheme 4. Synthesis of Alkylboronates Containing Bioactive
Moieties
Gratifyingly, this reaction could be easily scaled up to 20 mmol
without loss of the efficiency. As shown below, phenylacetylene (1a,
20 mmol) or styrene (1a, 20 mmol) were reacted with B2pin2 under
corresponding standard conditions to render desired product 3a in
83% and 86% yield respectively (Scheme 5).
Scheme 5. Scale-up Reaction with Phenylacetylene (1a) or Styrene
(3a) with B2Pin2
An attractive feature of the alkylboronate esters is that they are
versatile intermediates that can be transformed into a variety of
functional groups in organic syntheses (Scheme 6). Alkylboronate
ester 2a, which was made from the above scale-up reaction, could
react with chlorobenzene to afford the Suzuki–Miyaura cross-
coupling products using a Pd/RuPhos catalyst system (Scheme 6, eq
1).18 When 2a was treated with aqueous KHF2, the corresponding
trifluoroborate 12 was obtained in 92% yield (Scheme 6, eq 2), and
organotrifluoroborates are valuable synthetic blocks in Suzuki cross-
couplings. When 2a was treated with H2O2 and NaOH, phenylethyl
alcohol, which is one type of edible perfume, was formed in 93%
yield (Scheme 6, eq 3).
Scheme 7. Control Experiments of Preliminary Mechanistic Study
20
On the basis of the above results and literature,16a,
we
proposed
a
mechanism involving tandem borylation and
protodeboronation for the formation of the alkylboronates
(Scheme 8). Hydroboration of arylacetylene (1) produces
vinylboronate 14 which was confirmed by GC and GCMS under the
basic condition. Lewis base-mediated diboration of 14 produces
tris(boronate) 15, which undergoes selective protodeborylation to
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Org. Chem. 2013, 3910. (c) A. Kar, I. A. Sayyed, W. FV.iLewo,AHrtic.lMe O.nline
produce alkyl boronate 2. This boronate 2 can be produced from
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diborylation produces diboronate 16, which undergoes selective
protodeborylation to afford 2.
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a similar pathway: Lewis base-mediated
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Scheme 8. Plausible Reaction Mechanisms
In order to verify our hypothesis on the above mechanisms, alkyl
acetylene 17 and alkyl olefin 18 were subjected to the
corresponding standard conditions and the same bis-boronates 19
were obtained in 67% and 74% yields respectively (scheme 9), no
further deboronated product 20 was detected. These results
indicated that the benzylic position is critical for the success of the
transformations. For compound 19 in Scheme 9a, it might be
derived from trisboronate 21, since the geminal boronates on 21
were vulnerable in basic condition21 and one boronate will be lost
to lead to 19 (Scheme 9).
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Scheme 9. Examples of Alkyl Acetylene and Alkyl Alkene Leading to
Bis Boronates
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In summary, we have discovered a transition-metal-free
synthesis of alkylboronates from arylacetylenes or vinyl arenes
with B2pin2 via tandem borylation and protodeboronation
strategy. This method requires no transition metal catalyst and
features high regio- and chemoselectivity, good to excellent
yields and broad functional group tolerance. We believe that
this practical, efficient and environmentally benign protocol is
a good choice and alternative way to synthesize alkylboronates.
Acknowledgements
Financial support from the National Science Foundation of
China (21202049), the Recruitment Program of Global Experts
(1000 Talents Plan) and Fujian Hundred Talents Plan and
Program of Innovative Research Team of Huaqiao University
are gratefully acknowledged. We also thank Instrumental
Analysis Center of Huaqiao University for analysis support and
Prof. Tom Driver from UIC for manuscript proofreading.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5GC02633D
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DOI: 10.1039/C5GC02633D
Transition-Metal-Free Regioselective Synthesis of
Alkylboronates from Arylacetylenes and Vinyl Arenes
Kai Yang,a Qiuling Song*a, b
ABSTRACT
A transition-metal-free synthesis of alkylboronates, utilizing arylacetylenes or vinyl
arenes and bis(pinacolato)diboron through tandem borylation and protodeboronation,
has been developed. This reaction is efficient, practical and environmentally benign,
leading to anti-Markovnikov products with excellent regioselectivities, broad
functional group tolerance and excellent yields in both small and gram scale.