5-formyl-2-furylboronic acid as a versatile bifunctional reagent for the synthesis of π-extended heteroarylfuran systems

Article abstract of DOI:10.1039/b302767h

5-Formyl-2-furylboronic acid reacts cleanly with a range of heteroaryl bromides under Suzuki-Miyaura cross-coupling conditions to produce 2-formyl-5-heteroarylfuran derivatives. Subsequent Wittig olefination reactions afford π-conjugated alkene-pyridyl-furan derivatives.

Full text of DOI:10.1039/b302767h

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5-Formyl-2-furylboronic acid as a versatile bifunctional reagent for
the synthesis of ꢀ-extended heteroarylfuran systems†
Paul R. Parry,a Martin R. Bryce*a and Brian Tarbitb
a Department of Chemistry, University of Durham, Durham, UK DH1 3LE.
E-mail: m.r.bryce@durham.ac.uk
b Seal Sands Chemicals Ltd., Seal Sands, Middlesbrough, Cleveland, UK TS2 1UB
Received 10th March 2003, Accepted 26th March 2003
First published as an Advance Article on the web 4th April 2003
5-Formyl-2-furylboronic acid reacts cleanly with a range
of heteroaryl bromides under Suzuki–Miyaura cross-
coupling conditions to produce 2-formyl-5-heteroarylfuran
derivatives. Subsequent Wittig olefination reactions afford
ꢀ-conjugated alkene–pyridyl–furan derivatives.
Biaryl/heteroaryl derivatives are extremely important com-
ponents of pharmaceutical and agrochemical compounds1 and
optoelectronic materials.2 For their synthesis, the Suzuki–
Miyaura protocol for palladium-catalysed cross-coupling of
aryl- or heteroarylboronic acids with aryl- or heteroaryl halides
Scheme 1 i nBuLi, THF, trimethylborate, Ϫ78 to 25 ЊC, aqueous
workup; ii Het–Br, Pd(PPh3)4, Na2CO3, DMF, 80 ЊC (conditions A);
iii Het–Br, Pd(PPh3)2Cl2, Cs2CO3, 1,4-dioxane, 95 ЊC (conditions B).
is particularly versatile,3 and there has been a recent upsurge of
interest in the development of new heteroarylboronic acids
(especially pyridyl derivatives)4 and new catalysts5 for this
purpose.
pyridyl derivatives. It is notable that electron-withdrawing sub-
stituents on the pyridyl ring (entries 4, 6 and 7) resulted in lower
yields. This is consistent with previous reactions of pyridyl-
boronic acids with halogenated heterocycles.4e We note that
entries 3–7 represent a new route to pyridylfuran derivatives
which hitherto have been obtained via the Paal reaction of
intermediate pyridyl-1,4-diketones,15 or via a Hantzsch-type
reaction from pyridinoylacetates.16
Extension of the π-system of 5–7 was readily achieved
by Wittig olefination using (ethoxycarbonylmethylene)-
triphenylphosphorane under standard conditions17 to afford
π-conjugated alkene–pyridyl–furan derivatives 11–13 in high
yields (Scheme 2). To illustrate further the scope of these
reactions, the more elaborate Wittig and Horner–Wadsworth–
Emmons reagents 1418 and 15,19 respectively, were employed.
Deprotonation of 14 and 15 with n-butyllithium followed
by reaction with compound 6 gave products 16 and 17 in 51
and 11% yields, respectively (Scheme 3). The low yield of the
latter reaction was due to the presence of many unidenti-
fied byproducts (TLC evidence) and the known instability of
reagent 15.19
A reagent possessing both boronic acid and aldehyde func-
tionalities should offer considerable scope for the synthesis of
π-extended biaryl/heteroaryl systems.6 Remarkably, very few
such bifunctional reagents are known, and for those which
are known their use in sequential Suzuki and Wittig reactions
has not been reported. 4-Formylphenylboronic acid,7 3-formyl-
phenylboronic acid,8 3-formyl-4-methoxyphenylboronic acid9
and 5-formyl-2-thienylboronic acid10 are known. Within the
furan series, deboronation of formylfurylboronic acids is a
common problem;11 however, 2-formyl-3-furylboronic acid has
been well characterised.12 A recent report claimed the prepar-
ation of crude 5-formyl-2-furylboronic acid 2, although no
spectroscopic or analytical data were presented to support this
structure.13
We now report that 5-formyl-2-furylboronic acid 2 can be
readily obtained and purified, and we establish that it is a vers-
atile reagent in the synthesis of a range of new π-extended furan
derivatives.‡ The attraction of 2,5-disubstitution on the furan
(as opposed to other isomers) is that π-conjugation through the
system will be maximised (see below). Lithiation of acetal 114
using n-butyllithium followed by reaction with trimethylborate
and aqueous workup concomitantly introduced the boronic
acid group and liberated the aldehyde group to afford com-
pound 2 in 52% yield after purification (Scheme 1). Cross-
coupling reactions of 2 with a range of heteroaryl bromides
were explored under standard conditions, using either tetra-
kis(triphenylphosphine)palladium as catalyst and sodium
carbonate as base in DMF at 80 ЊC (conditions A) or bis(tri-
phenylphosphine)palladium dichloride and caesium carbonate
in 1,4-dioxane at 95 ЊC (conditions B). As shown in Table 1 for
entries 1–4, conditions B consistently gave higher yields of the
desired products 3–6, so conditions A were not used for the
other examples (entries 5–8). These results establish that cross-
coupling of 2 occurs with both electron-rich heterocyclic part-
ners (furyl and thienyl: entries 1, 2 and 8) and electron-deficient
Scheme 2 i Ph3PCHCO2Et, MeCN, reflux.
The UV-Vis absorption spectra of compounds 16 and 17
established that effective intramolecular charge-transfer arises
from combining an electron-donating 1,3-dithiol-2-ylidene
moiety and an electron-deficient pyridyl unit at opposing
† Electronic supplementary information (ESI) available: synthesis and
characterisation data for 3–17. See http://www.rsc.org/suppdata/ob/b3/
b302767h/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 4 7 – 1 4 4 9
1447

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Table 1 Cross-coupling reactions of reagent 2
Isolated yield (%)
Conditions A
Entry
1
Boronic acid
Br–Het
Product
Conditions B
64
2
34
30
16
2
3
2
2
61
52
4
5
6
2
2
2
24
—
—
31
57
15
7
8
2
2
—
—
44
54
Conditions A: tetrakis(triphenylphosphine)palladium as catalyst and sodium carbonate as base in DMF at 80 ЊC; Conditions B: bis(triphenyl-
phosphine)palladium dichloride and caesium carbonate in 1,4-dioxane at 95 ЊC.
Experimental
5-Formyl-2-furylboronic acid (2)
To a solution of 1 (1.0 g, 5.9 mmol) in anhydrous THF (20 cm3)
at Ϫ78 ЊC was added nBuLi (1.6 M in hexane, 2.2 cm3,
3.5 mmol) dropwise. The reaction mixture was stirred for 5 h at
Ϫ78 ЊC then TMB (815 mg, 9.6 mmol) was added dropwise and
the reaction mixture was allowed to warm to 25 ЊC with stirring
overnight. The organic solvent was evaporated in vacuo and the
remaining aqueous layer was taken to pH 10 (with 5% NaOH)
and washed with ether. The aqueous layer was then carefully
acidified to pH 4 (with 48% HBr) to precipitate a product which
was filtered then washed with ether (10 cm3) to afford 2 as a
1
brown solid (428 mg, 52%), mp 150–151 ЊC; H NMR (250
MHz, acetone-d6) δ 9.70 (1H, s, CHO), 7.92 (2H, s, OH), 7.40
Scheme 3 i 14 or 15, nBuLi, THF, Ϫ78 ЊC, then reflux.
(1H, d, J = 3.5 Hz), 7.19 (1H, d, J = 3.5 Hz); 13C NMR (100
MHz, acetone-d6) δ 178.44, 155.97, 122.79, 121.63. Anal. calc.
for C5H5BO2: C, 42.93; H, 3.60. Found: C, 42.72; H, 3.70%.
termini of the conjugated π-system. There is a red shift in the
lowest energy absorption band in dichloromethane solution
in the sequence 6 (λmax 329 nm), 16 (λmax 403 nm) and 17
General procedure for the cross-coupling reactions
(λmax 430 nm) which is consistent with enhanced electron
donating ability of the dimethyl-1,3-dithiole unit in 17 com-
pared with its dimethoxycarbonyl analogue 16.20
The boronic acid 2, the halide, and the catalyst (5 mol% relative
to 2) were added sequentially to degassed solvent (10 cm3) and
the mixture was stirred at 20 ЊC for 30–60 min. Degassed
aqueous base solution was added and the mixture was heated
under N2 until TLC monitoring showed that the reaction was
complete. Solvent was evaporated in vacuo and ethyl acetate
was added. Then the organic layer was purified by column
chromatography on silica gel.
In summary, we have demonstrated
a new route to
π-extended heteroarylfuran systems by exploiting the rare
combination of functional groups in compound 2. Further
extension of this sequential Suzuki–Miyaura and Wittig
methodology will be applicable to other 2-heteroarylfuran
derivatives and derived π-extended systems of particular
relevance to conjugated molecular wires of well-defined
conjugation lengths.6,21
Conditions A: Pd(PPh3)4, Na2CO3, DMF, 80 ЊC.
Conditions B: Pd(PPh3)2Cl2, Cs2CO3, 1,4-dioxane, 95 ЊC.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 4 7 – 1 4 4 9
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Acknowledgements
We thank Seal Sands Chemicals Ltd. for funding.
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Notes and references
‡ All new compounds gave satisfactory spectroscopic and analytical
data. Detailed characterisation is given in the ESI.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 4 4 7 – 1 4 4 9
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