Transition metal-free synthesis of pinacol arylboronate: Regioselective boronation of 1,3-disubstituted benzenes

Article abstract of DOI:10.1071/CH13642

The regioselective synthesis of pinacol arylboronate has been achieved from 1,3-disubstituted benzene through directed ortho-metallation (DoM)-borylation sequence. A wide range of substituents and borylating reagents were investigated. In situ lithiation and subsequent boronation predominantly occurred at the ortho-position to afford the desired products in moderate yields. CSIRO 2014.

Full text of DOI:10.1071/CH13642

CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 675–678
Full Paper
http://dx.doi.org/10.1071/CH13642
Transition Metal-Free Synthesis of Pinacol Arylboronate:
Regioselective Boronation of 1,3-Disubstituted Benzenes
A
A
A
Yan Wang, Le Wang, Ling-Yan Chen,
A
A B
,
Pinaki S. Bhadury, and Zhihua Sun
A
College of Chemistry and Chemical Engineering, Shanghai University
of Engineering Science, Shanghai, 201620, China.
B
Corresponding author. Email: sungaris@gmail.com
The regioselective synthesis of pinacol arylboronate has been achieved from 1,3-disubstituted benzene through directed
ortho-metallation (DoM)–borylation sequence. A wide range of substituents and borylating reagents were investigated.
In situ lithiation and subsequent boronation predominantly occurred at the ortho-position to afford the desired products
in moderate yields.
Manuscript received: 20 November 2013.
Manuscript accepted: 13 December 2013.
Published online: 17 January 2014.
Introduction
as the model compound to prepare the regioisomer 1b using
different electrophilic borylating reagents (Fig. 1).
Boronation of arenes and heteroaromatic compounds often leads
to reactive synthetic intermediates, which are used to execute
useful synthetic transformations via transition metal-catalyzed
cross-coupling reactions[1–4] and conversion into other func-
tional groups.[5–8] In fact, selective transition metal-mediated
incorporation of boryl moiety into arene system has gained
widespread attention in recent times.[9–12] However, the repor-
ted methods have several disadvantages such as harsh reaction
conditions, long reaction times, and use of expensive metal cat-
alysts associated with poor yields.[13–15] Moreover, the reaction
system is not eco-friendly as the borylated arene is often con-
taminated with heavy metals.[16] Consequently, development of
a practical, transition metal-free approach for the incorporation
of boron into an organic core has become highly desirable.[17,18]
Although some examples of regioselective borylation of
mono- and poly-substituted arenes are available,[19,20] the litera-
ture furnishes much less information for 1,3-disubstituted aro-
matic systems which possess multiple active sites that are
prone to attack by electrophilic agents. In our earlier study,[21]
1,3-disubstituted arenes were subjected to deprotonation/metal-
lation sequence with n-butyl lithium. The in situ lithiated species
generated through directed ortho-metallation (DoM) was reacted
with the electrophile, dimethylformamide, under optimal condi-
tions to afford formylated products in good yields and regio-
selectivities. The practical utility of this transition metal-free
protocol was further extended in the current investigation to
prepare a more important type of synthetic intermediate, pinacol
arylboronate. The resultsofour finding are reportedinthisarticle.
The results of our initial exploration are presented in Table 1.
The regioisomeric distribution of products was established using
19F NMR spectroscopy. It is evident from the data presented in
Table 1 that in situ lithiation of the substrate 1a by n-BuLi/N,N,
N0,N0-tetramethylethylenediamine (TMEDA)/diisopropylamine
(DIPA) and subsequent reaction with the electrophile, i-PrOB-
Pin,[17,18] afforded inferior result when 1.1 equivalents (equiv.)
of the electrophile was employed (Table 1, entry 1). To our
delight, excellent regioselectivity (.98 %) and much higher
yield (67 %) for the isomer 1b were obtained by increasing the
reaction time from 1 to 12 h and by increasing the amount of the
boron reagent to 1.5 equiv. (Table 1, entry 2). However, the yield
of the product was not affected significantly by increasing the
amount of i-PrOBPin to 3.0 equiv. or by prolonging the reaction
time to 24 h (Table 1, entry 3). Under comparable conditions,
B2Pin2 afforded similar results in terms of selectivity albeit
lower yield of the isomer (Table 1, entry 4). The outcome of the
reaction practically remained unaltered in the presence of the
CuCl catalyst (Table 1, entry 5). On the other hand, the
electrophilic reagents (MeO)3B,[22] PinB-BRe,[23] and Ph3SiB-
Pin[24,25] proved to be far less effective (Table 1, entries 6–8).
Having established the optimal conditions, regioselective
borylation of a series of 1,3- disubstituted benzene was con-
ducted either with 1.5 equiv. of i-PrOBPin or 1.5 equiv. of
B2Pin2 at room temperature for 12 h. From the data presented
in Table 2, borylation of 1,3-disubstituted benzene, in general,
afforded the desired product in moderate to high yields
(28–69 %). However, the electrophile i-PrOBPin proved to be
more efficient compared with B2Pin2 in terms of overall yields
of the final products (entries 1–11). In situ lithiation and
subsequent borylation of 1,3-disubstituted benzene preferen-
tially leads to the generation of 2,6-disubstituted phenylboronic
acid pinacol ester. In a few cases for compounds bearing
Results and Discussion
At the outset, we varied the reaction parameters such as time,
temperature, and molar ratios of the reagents to obtain optimal
selectivity and yield of the borylated regioisomer. Due to its
excellent DoM property,[21] 1,3-difluorobenzene was selected
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

676
Y. Wang et al.
trifluoromethyl groups, the incoming electrophile was directed
to the ortho-position (Table 2, entries 10–11). This is perhaps
attributed to the fact that the relatively bulky CF3 group not only
imposes steric restrictions to the incoming borylating agent
adjacent to it but also greatly polarizes the p-electrons at other
positions.[26]
using oven-dried glassware. NMR spectra were recorded on
Bruker Avance II spectrometer at 400MHz for 1H NMR,
100MHz for 13C NMR, and 396 MHz for 19F NMR; chemical
shifts are given in parts per million. Electrospray ionization–
atmosphericpressure ionization (ESI–API) analyses were carried
out with an Agilent 1100 LC/MSD trap mass spectrometer. Gas
chromatography–mass spectrometry (electron impact ionization,
EI) analyses were carried out on a Thermo Fisher DSQ apparatus
(70 eV) with ions given in m/z. High-resolution mass spectra
were recorded on a Shimadzu liquid chromatograph mass spec-
trometer (LCMS-IT-TOF).
Conclusion
In summary, we developed a transition metal-free regioselective
boronation protocol to prepare a series of pinacol boronates,
which are useful synthetic intermediates in many organic trans-
formations. The methodisoperationallysimple andcheap, witha
wide substrate scope, and utilises both i-PrOBPin and B2Pin2 as
electrophilic sources. This novel approach is expected to find
vast applications for the synthesis of aromatic boron compounds.
General Procedure for Metallation–Boronation
of 1,3-Disubstituted Benzene
Method A
To a oven-dried 100 mL flask was added 1,3-disubstituted
benzene (3.0mmol), TMEDA (1.1equiv., 3.3 mmol), DIPA
(5mol-%, 0.16mmol), and THF (10.0 mL). The solution was
cooled to ꢀ788C for 10min and then n-BuLi (1.1equiv.,
3.3 mmol) was added dropwise. The mixture was maintained at
this temperature for 1.5 h followed by the addition of B2Pin2
(1.5equiv., 4.5 mmol). The mixture was stirredfor another30min
at ꢀ788C. The system was allowed to warm up to room tempera-
ture (r.t.) and stirring was continued for 1–12 h and a saturated
aqueousNH4Cl solution(5mL) was added toquenchthe reaction.
The mixture was extracted using ethyl acetate (3ꢁ 10mL). The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under vacuum. The regioselectivity of
the crude product was confirmed by 19F NMR and then subjected
to flash chromatography to obtain the desired products, which
were characterized by 1H, 13C, and 19F NMR spectral data, and
liquid chromatography mass spectrometry analyses.
Experimental
General Experimental Procedure
THF was heated at reflux over sodium benzophenone ketyl
before use. All reactions were carried out under N2 atmosphere
O
O
O
O
O
B
O
O
B
B
B
O
O
O
(MeO)3B
i-PrOBPin
B2Pin2
Ph
Ph
O
O
O
B
O
O
O
Si
Ph
HN
B
B
sp2-sp3-hybridized mixed diboron
PinB-BRe
Ph3SiBPin
Method B
Instead of the B2Pin2 electrophile, i-PrOBPin was used. The
rest of the procedure was the same as that of Method A.
Fig. 1. Different electrophilic borylating reagents employed for
optimization.
Table 1. Regioselective ortho-borylation of 1,3-difluorobenzene
F
F
O
F
B
n-BuLi, TMEDA, DIPA
THF, Ϫ78ЊC, 1.5 h
Li
F
O
Electrophile
F
F
1a
Li-1a
1b
Entry
Reaction conditionsA
Isomer selectivityB [%]
YieldE [%]
1
i-PrOBPin 1.1 equiv., r.t., 1 h
i-PrOBPin 1.5 equiv., r.t., 12 h
i-PrOBPin 3.0 equiv., r.t., 24 h
B2Pin2 1.5 equiv., r.t., 12 h
n.d.C
.98
.95
.98
.95
n.d.C
n.d.C
n.d.C
,10
67
2
3
64
4
43
5
6D
CuCl, 1.1 equiv. in first step, B2Pin2 1.5 equiv., r.t., 12 h
PinB-BRe, 5.0 equiv., r.t., 24 h
40
,5
,5
,5
7
(MeO)3B, 5.0 equiv., r.t., 24 h
8
Ph3SiBPin, 5.0 equiv., r.t., 24 h
AUnless otherwise noted, all the reactions were carried out with 1.0 equiv. of the substrate 1a, 1.1 equiv. each of
n-BuLi and TMEDA, and 5 mol-% of DIPA at ꢀ788C for 1.5 h followed by 1.1–5.0 equiv. of the electrophile.
BDetermined by 19F NMR.
CNot determined.
D2.2 equiv. of n-BuLi was added before reaction with the electrophile.
EOverall crude yield.

Regioselective Boronation of 1,3-Disubstituted Benzenes
677
Table 2. Regioselective boronation of 1,3-disubstituted benzene under optimal conditions with electrophiles,
i-PrOBPin and B2Pin2A
R1
R1
R1
BPin
R2
PinB
1. Lithiation: n-BuLi/TMEDA/DIPA, Ϫ78ЊC, THF
2. Electrophile: i-PrOBPin or B2Pin2
ϩ
R2
R2
1-11a
1-11b
1-11c
Entry
Product
YieldB [%]
i-PrOBPin B2Pin2
Entry
Product
YieldB [%]
i-PrOBPin
B2Pin2
F
F
F
Cl
BPin
O
BPin
F
1
67
69
57
52
63
68
43
7
64
35
1b
2b
3b
7b
Cl
BPin
Cl
BPin
O
2
3
4
5
6
45
34
33
44
47
8
9
53
55
56
59
28
34
34
31
O
8b
O
BPin
CF3
BPin
CF3
9b
Cl
F
PinB
BPin
10
11
CF3
O
O
4b
10c
CF3
F
PinB
BPin
O
CF3
5b
6b
11c
Cl
BPin
Cl
AUnless otherwise noted, all reactions were carried out with 1.0 equiv. of the substrate 1a, 1.1 equiv. each of n-BuLi and
TMEDA, and 5 mol-% of DIPA at ꢀ788C for 1.5 h, followed by 1.5 equiv. of the electrophile.
BIsolated yields using electrophiles, i-PrOBPin and B2Pin2.
2,6-Difluorophenylboronic Acid Pinacol Ester (1b)
24.6. dF (CDCl3) ꢀ59.94 (3F), ꢀ103.13 (F). m/z (HR-MS ESI)
291.1168; [MþH]þ requires 291.1101.
Yellow solid, mp 50.1–51.88C. dH (CDCl3) 7.38 (m, 1H), 6.86 (t,
J 8.0, 2H), 1.41 (s, 12H). dC (CDCl3) 167.8, 165.3, 133.1, 111.1,
84.3, 77.0, 24.8. dF (CDCl3) ꢀ100.66. m/z (HR-MS ESI)
241.1211; [MþH]þ requires 241.1133.
2-Fluoro-6-methoxymethylphenylboronic
Acid Pinacol Ester (4b)
Yellow solid, mp 96.3–97.28C. dH (CDCl3) 7.27 (m, 1H), 6.82
(d, J 8.4, 1H), 6.70 (t, J 8.0, 1H), 5.18 (s, 2H), 3.49 (s, 3H),
1.40 (s, 12H). dC (CDCl3) 167.4, 164.9, 161.3, 161.2, 132.1,
109.6, 94.6, 83.5, 77.0, 56.6, 25.0. dF (CDCl3) ꢀ103.88. m/z (EI)
282 [Mþ].
2-Chloro-6-fluorophenylboronic Acid Pinacol Ester (2b)
Yellow solid, mp 68.3–69.68C. dH (CDCl3) 7.29 (m, 1H), 7.15
(d, J 8.0, 1H), 6.94 (t, J 8.0, 1H), 1.43 (s, 12H). dC (CDCl3)
166.7, 164.2, 138.4, 131.9, 124.7, 113.2, 84.8, 77.0, 24.7. dF
(CDCl3) ꢀ102.64. m/z (HR-MS ESI) 257.0895; [MþH]þ
requires 257.0838.
2-Fluoro-6-methoxyphenylboronic Acid Pinacol Ester (5b)
Yellow solid, mp 68.6–70.18C. dH (CDCl3) 7.29 (m, 1H), 6.64
(m, 2H), 1.41 (s, 12H), 3.56 (s, 3H). dC (CDCl3) 167.5, 165.1,
164.0, 132.1, 107.7, 105.8, 84.1, 77.0, 56.0, 24.7. dF (CDCl3)
ꢀ104.17. m/z (HR-MS ESI) 253.1400; [MþH]þ requires
253.1333.
2-Fluoro-6-trifluoromethylphenylboronic
Acid Pinacol Ester (3b)
Yellow oil. dH (CDCl3) 7.47 (m, 2H), 7.22 (d, J 8.0, 1H), 1.42
(s, 12H). dC (CDCl3) 131.5, 131.5, 121.3, 118.4, 118.1, 85.1,

678
Y. Wang et al.
2,6-Dichlorophenylboronic Acid Pinacol Ester (6b)
ZZGJD13020), and Start-up Funding of Shanghai University of Engineering
Science (2013–01).
Yellow solid, mp 78.5–79.68C. dH (CDCl3) 7.24 (s, 3H), 1.45
(s, 12H). dC (CDCl3) 138.1, 131.2, 126.8, 85.0, 77.0, 24.8. m/z
(ESI) 295 [MþNa]þ. m/z (HRMS ESI) 273.0610; [MþH]þ
requires 273.0542.
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Supplementary Material
Details of experimental procedures, characterization data of
compounds as well as 1H, 13C, and 19F NMR spectra are avail-
able on the Journal’s website.
Acknowledgements
Financial support for this work was provided by Shanghai Municipal Edu-
cation Commission (14ZZ159) and Shanghai Municipal Science and
Technology Commission (No.12430501300). The authors are also grateful
for financial support from the Special Scientific Foundation for Outstanding
Young Teachers in Shanghai Higher Education Institutions (shgcjs023,