Synthesis of benzannulated heterocycles by twofold Suzuki-Miyaura couplings of cyclic diarylborinic acids

Article abstract of DOI:10.1039/c3ob42065e

Two-fold Suzuki-Miyaura cross-couplings of cyclic diarylborinic acids are described. This novel annulation method enables the synthesis of benzo-fused heterocycles from dihaloarenes or gem-dibromoolefins.

Full text of DOI:10.1039/c3ob42065e

Organic &
Biomolecular Chemistry
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Synthesis of benzannulated heterocycles by
twofold Suzuki–Miyaura couplings of cyclic
diarylborinic acids†
Cite this: Org. Biomol. Chem., 2014,
12, 1391
Received 15th October 2013,
Accepted 19th January 2014
Elena Dimitrijević, Madeline Cusimano and Mark S. Taylor*
DOI: 10.1039/c3ob42065e
www.rsc.org/obc
Two-fold Suzuki–Miyaura cross-couplings of cyclic diarylborinic
acids are described. This novel annulation method enables the
synthesis of benzo-fused heterocycles from dihaloarenes or
gem-dibromoolefins.
The Suzuki–Miyaura cross-coupling reaction is a powerful tool
for C–C bond construction, and extensive effort has been dedi-
cated to broadening its substrate scope. Advances in this direc-
tion include couplings of aryl chlorides,1 substrates having
C–O bonds (e.g., aryl ethers, esters, carbamates and sulfa-
mates),2 and unactivated primary or secondary alkyl halides.3
Likewise, the range of organoboron compounds that can be
employed has been expanded to encompass such species as
alkylboronic acid derivatives,4 organotrifluoroborates,5 organo-
trialkoxyborates6 and N-methyliminodiacetic acid (MIDA) boro-
nates.7 Given that the functional group compatibility and air/
moisture tolerance of organoboron compounds are key advan-
tages of the Suzuki–Miyaura reaction, it is not surprising that
relatively few attempts at cross-couplings of borinic acid
derivatives (R2BOH), which are generally more oxidation-prone
than boronic acids, have been made.8,9 Nonetheless, reactions
of this type have been reported in cases where the borinic acid
was obtained more conveniently10 or provided a higher yield11
than the corresponding boronic acid. In addition, systematic
studies of the cross-couplings of potassium diaryldifluoro-
borates,12 magnesium diorganoboronates13 and borinic
acids14 have been described recently.
Scheme 1 Preparation and envisioned twofold Suzuki–Miyaura cross-
coupling of cyclic diarylborinic acids.
acids, which undergo oxidation quite readily under ambient
conditions, these heterocyclic variants are air-stable, crystal-
line solids.16,17 The attenuated Lewis acidity at boron arising
from incorporation into a 6π electron system, and/or geometric
constraints of the heterocyclic system that kinetically disfavor
the oxidation pathway, may contribute to this property. The
prospect that such cyclic diarylborinic acids could represent
convenient (and hitherto unexplored) bis-boron reagents for
annulation reactions motivated us to study their Pd-catalyzed
couplings with dihaloarenes (Scheme 1).18
Given that 9-hetero-10-boraanthracene-derived borinic acids
are poorly Lewis acidic, and considering current mechanistic
proposals for transmetallation of boronic acids to Pd(II),19 we
anticipated that this step could be problematic. Therefore, our
initial efforts were aimed at identifying conditions for reaction
of 1a with bromobenzene by coupling of both C–B bonds, gen-
erating the 2 : 1 adduct 2a (Table 1). Relatively high reaction
temperatures were required for activation of 1a, and proto-
deboronated 2b was obtained as a side product. The 2a : 2b
ratio was found to depend on the ligand (entries 3–5), Pd pre-
catalyst (entries 6, 7), base and solvent (entries 8, 9). Optimal
results were achieved using tri-tert-butylphosphine as ligand,
dibenzylideneacetone (dba) complex Pd2(dba)3, and Cs2CO3 as
base in toluene at 100 °C. These conditions were effective for
coupling of 4-bromoanisole, but not for electron-deficient
4-bromonitrobenzene (Scheme 2). A marginal improvement
Herein, we describe two-fold Suzuki–Miyaura cross-coup-
lings of cyclic diarylborinic acids, generating benzannulated
heterocyclic products. This work builds on our studies of
9-hetero-10-boraanthracene-derived borinic acids (e.g., 1a and
1b, Scheme 1) as catalysts for monosulfonylation, alkylation
and glycosylation of di- and triols.15 Unlike most diarylborinic
Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON M5S
3H6, Canada. E-mail: mtaylor@chem.utoronto.ca
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for new compounds (.pdf); crystallographic data for 5i
(cif). CCDC 966458. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob42065e
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Table 1 Dependence of the outcome of cross-couplings of 1a and
bromobenzene on the reaction conditions employed
Entry
Deviation from standard conditions
% Yielda (2a : 2b)
Scheme 3 Synthesis of tribenzo[b,d,f]oxe- and azepines by Suzuki
couplings of 1a/1b with dibromoveratrole: solvent/temperature effects.
1
2
3
4
5
6
7
8
9
10
None
78b (13 : 1)
>95 (1 : 2.8)
79 (6 : 1)
86 (6 : 1)
81 (1 : 2)
Without t-Bu3PH(BF4)
dppfc instead of t-Bu3PH(BF4)
S-Phosd instead of t-Bu3PH(BF4)
IPr·HCle instead of t-Bu3PH(BF4)
Pd(OAc)2 instead of Pd2(dba)3
[Pd(C3H5)Cl]2 instead of Pd2(dba)3
K3PO4 instead of Cs2CO3
t-AmOH instead of PhCH3
C6H5I instead of C6H5Br
annulation process: acceptable yields were obtained using a
batch of Cs2CO3 that contained a significant quantity of the
hydrate. When anhydrous Cs2CO3 was used, deliberate
addition of water (up to 10 equiv.) was needed to restore the
yield of benzannulated product (see the ESI† for details).21
Scheme 4 illustrates the range of benzo-fused hetero-
aromatic compounds that can be prepared by this annulation
method. Although the depicted products were prepared on
0.1 mmol scale, the process is reasonably efficient for the syn-
thesis of larger quantities: for example, 5c was obtained in
73% yield (0.9 g) from a reaction conducted on 5.0 mmol
scale. Sterically hindered oxaboraanthracenes displayed
sluggish reactivity, generating methoxy-substituted 5d and
naphtho-fused 5e in relatively low yields. In the case of 5e, side
products resulting from cross-coupling followed by protode-
bromination and/or protodeboronation were identified. A
heteroaryl-fused oxepine (5f) was generated from N-methyl-2,3-
dibromoindole: as was the case for 5e, the product of cross-
coupling/protodeboronation was obtained as a side product. It
should be noted that the preparation of non-benzo-fused
oxepines by couplings of 1a with 1,2-dibromoalkenes was not
81 (3 : 1)
66 (>20 : 1)
47 (>20 : 1)
79b (2 : 1)
>95 (6.9 : 1)
a Yields determined by 1H NMR with 1,3,5-trimethoxybenzene as a
quantitative internal standard. b Isolated yields. c dppf
1,1′-bis-
2-dicyclohexylphosphino-
1,3-bis(2,6-diisopropylphenyl)-
=
(diphenylphosphino)ferrocene. d S-Phos
=
2′,6′-dimethoxybiphenyl. e IPr·HCl
=
imidazolium chloride.
Scheme 2 Preparation of substituted biaryl ethers by two-fold Suzuki
couplings of 1a.
over the latter result was obtained by using 4-iodonitrobenzene
as the coupling partner.
Having developed conditions that enabled transmetallation
of both the starting borinic acid and the boronic acid-type
intermediate, we turned our attention to the preparation of
heterocyclic compounds by sequential inter- and intramole-
cular couplings. Specifically, the synthesis of tribenzo[b,d,f ]-
oxe- and azepines by coupling of ortho-dihaloarenes with 1a/1b
was targeted. Known methods for the synthesis of tris-benzan-
nulated heterocycles of this type make use of linear, multi-step
sequences, often involving Pschorr-type or photochemical
cyclizations.20 Using 1a and 4,5-dibromoveratrole as test sub-
strates, the desired oxepine 5a was obtained in 38% yield
under the optimal conditions from Table 1 (Scheme 3). The
yield was improved to 90% by using tert-butanol (t-BuOH) as
the solvent. Under these conditions, the preparation of
azepine 5b from 9-aza-10-boraanthracene 1b was more challen-
ging, and resulted in a 22% yield. Transmetallation may be
particularly slow for 1b, which is less Lewis acidic than 1a and
possesses shorter C–B bond distances.15 Nonetheless, the
preparation of 5b was improved to 89% by using tert-amyl
alcohol (t-AmOH) as solvent at a higher temperature. The pres-
ence of water has a beneficial effect on the yield of the
Scheme 4 Synthesis of fused heterocycles by Suzuki–Miyaura cross-
couplings of cyclic borinic acids. t-BuOH solvent, 80 °C. t-AmOH
solvent, 100 °C.
a
b
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Despite the relatively poor Lewis acidity of heteroboraanthra-
cene-derived borinic acids that appears to hinder transmetalla-
tion, these species can be employed productively in Suzuki–
Miyaura cross-couplings to generate two carbon–carbon
bonds. These reactions enable the one-step synthesis of benzo-
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This work was funded by NSERC (Discovery Grants Program,
Graduate Scholarship to E.D., Canada Research Chair to
M.S.T.), Boehringer Ingelheim (Canada) Ltd., the Canada
Foundation for Innovation, the Province of Ontario and the
University of Toronto. M.S.T. is a Fellow of the A. P. Sloan
Foundation. Alan J. Lough is acknowledged for solving the
X-ray crystal structure of 5i.
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