Syntheses of benzo[b]furan-6-carbonitrile and 6-cyanobenzo[b]furan-2- boronic acid pinacol ester

Article abstract of DOI:10.1080/00397911.2012.684086

6-Cyanobenzo[b]furan-2-boronic acid pinacol ester (10) is a potentially useful two-point scaffold for the construction of specific compounds or compound libraries with benzofuran cores. Using a per-iodination/de-iodination strategy coupled with Sonogashir

Full text of DOI:10.1080/00397911.2012.684086

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Syntheses of Benzo[b]furan-6-carbonitrile and 6-
Cyanobenzo[b]furan-2-boronic Acid Pinacol Ester
John D. Williams a , Xiaoyuan Ding a , Son Nguyen a , Kimberly K. Vines b & Norton P. Peet a
a Microbiotix, Inc., Worcester, MA
b CreaGen Biosciences, Inc., Woburn, MA
Accepted author version posted online: 11 Jan 2013.
To cite this article: John D. Williams , Xiaoyuan Ding , Son Nguyen , Kimberly K. Vines & Norton P. Peet (2013): Syntheses
of Benzo[b]furan-6-carbonitrile and 6-Cyanobenzo[b]furan-2-boronic Acid Pinacol Ester, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.684086
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Syntheses of Benzo[b]furan-6-carbonitrile and 6-Cyanobenzo[b]furan-2-boronic
Acid Pinacol Ester
John D. Williams1,, Xiaoyuan Ding1, Son Nguyen1, Kimberly K. Vines2, Norton P. Peet1
1Microbiotix, Inc., Worcester, MA, 2CreaGen Biosciences, Inc., Woburn, MA
to whom correspondence should be addressed: Email: jwilliams@microbiotix.com
Abstract
6-Cyanobenzo[b]furan-2-boronic acid pinacol ester (10) is a potentially useful 2-point
scaffold for the construction of specific compounds or compound libraries with
benzofuran cores. Using a per-iodination/de-iodination strategy coupled with a
Sonogashira alkynylation and Cu-catalyzed heteroannulation, we have developed a
procedure that allows the preparation of benzo[b]furan-6-carbonitrile (9) and 6-
cyanobenzo[b]furan-2-boronic acid pinacol ester (10) in gram quantities.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: Benzo[b]furan, Sonogashira alkynylation, heteroannulation, heterocycle
synthesis
INTRODUCTION
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Benzo[b]furans are commonly found substructures in both natural products and medicinal
compounds, and have been the frequent target of synthetic efforts by numerous groups
(see references 1–4 for reviews). The approved drugs methoxsalen, amiodarone,
saprisartan, trioxsalen, and numerous investigational drugs all contain benzo[b]furan
cores, as do the natural products machicendiol, khellin, egenol, ailanthoidol, and others.
The wide-ranging biological activity of benzo[b]furan-containing compounds has thus
spawned considerable interest from a medicinal chemistry perspective.
RESULTS AND DISCUSSION
In conjunction with our program investigating broad-spectrum antibacterial compounds,
we required the synthesis of substantial amounts of 6-cyanobenzo[b]furan-2-boronic acid
pinacol ester (10), which is conveniently obtained from benzo[b]furan-6-carbonitrile (9).
Although it is commercially available, benzo[b]furan-6-carbonitrile (9) is quite expensive
and the supply is limited. This prompted us to investigate a synthetic procedure that
would be capable of producing the desired compound efficiently, inexpensively, and in
quantities suitable for our research purposes.
There is one reported synthesis for benzo[b]furan-6-carbonitrile (9),[5] but this process
relies upon a late-stage Sandmeyer-type conversion of 6-aminobenzo[b]furan into the
corresponding nitrile. We viewed this process as impractical because of the inherently
low yields often associated with Sandmeyer-type reactions, the hazardous nature of the
intermediate diazonium species, and the lengthy synthesis that would be necessary to
synthesize the amine substrate.
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Converting other 6-subsituted benzo[b]furans, such as the 6-carboxy-, 6-formyl-, or 6-
bromo-analogs into the corresponding 6-carbonitrile (via dehydration of the
corresponding amide, dehydration of the corresponding oxime, or the Rosenmund-von
Braun reaction, respectively) can all be achieved. However, these compounds all require
lengthy syntheses to produce the necessary substrate for conversion. Availability of 6-
substituted benzo[b]furans is hindered largely by synthetic considerations. Many
common strategies involve annulations of corresponding phenol derivatives; the 5-
substituted benzo[b]furans thus do not require a directional ring closure, but the
corresponding 6-substituted benzo[b]furans are always produced in tandem with the 4-
substituted congeners using this methodology.[6,7] Alternatively, the 2-carboxy analogs of
6-substituted benzo[b]furans can be readily synthesized from the corresponding 4-
substituted salicylaldehydes, but these must be decarboxylated to provide the desired 2-
unsubstituted analogs,[8] and only limited examples of the requisite salicylaldehydes are
commercially available.
One useful entry into the benzofuran series would be the metal-catalyzed cyclization of a
2-ethynyl-5-cyanophenol,[9] which could be made from the corresponding 2-bromo- or 2-
iodo-5-cyanophenol. Our initial efforts at producing 2-iodo-5-cyanophenol (5) using
traditional methodologies (direct mono-iodination with ICl in acetic acid,[10] or with
iodine in either aqueous sodium acetate[11] or aqueous ammonia[12]) were hampered by
low yields and/or mixtures of isomers; we did not attempt analogous reactions using
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common thallium salt procedures[13] because of the inherent toxicity concerns about
working with this heavy metal.
While searching for an alternative approach to compound 5, we were intrigued by a
report from the Chern group at the National Taiwan University who reported that heating
iodinated phenols in the presence of organic bases (especially pyridine, TEA, or N-
methylmorpholine) resulted in selective de-iodination of the investigated iodophenols,
leaving the iodo substituent para to the hydroxy group intact.[14] One notable exception
was 2,4,6-triiodo-3-hydroxybenzaldehyde, in which the iodo group para to the aldehyde
was maintained (Scheme 1).
We surmised that the corresponding reaction, applied to 3-hydroxy-2,4,6-
triiodobenzonitrile (4), would provide compound 5. Indeed, after refluxing the per-
iodinated phenol in N-methylmorpholine, we isolated 3-hydroxy-4-iodobenzonitrile (5) in
modest yield. Encouraged by these results, we sought to optimize the synthesis such that
this sequence could be carried out in high yield on a multi-gram scale.
3-Hydroxy-2,4,6-triiodobenzonitrile (4) is known,[15] but no analytical data was provided
for the compound, and the reagent used (IPy2BF4) for the preparation of this material
from 3-hydroxybenzonitrile (3) was viewed as uneconomical. Fortunately, we were able
to use an alternative procedure, which has previously been used to prepare 2,4,6-triiodo-
3-hydroxybenzaldehyde,[11] to per-iodinate 3-hydroxybenzonitrile. Optimization
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provided a procedure capable of producing 3-hydroxy-2,4,6-triiodobenzonitrile (4) in
88% on a multi-gram scale.
We next used the Chern procedure to produce the desired 3-hydroxy-4-iodobenzonitrile
(4) in moderate-to-low yield (Scheme 2). Before optimizing this reaction, we wanted to
unambiguously assign the regiochemistry of the product. The NMR spectrum of 3-
hydroxy-4-iodobenzonitrile (5) matched literature precedent;[10] however, that synthesis
also relied upon an iodination reaction that could have provided multiple products. We
were, unfortunately, unable to validate the structure using HMBC/HSQC because of
overlapping resonances in the 13C spectrum. Upon synthesis of the corresponding
mesylate ester (6, Scheme 2), however, a highly crystalline product was obtained.
Determination of the X-ray crystal structure of mesylate 6 proved that the desired
material was, in fact, obtained from the de-iodination reaction (see Supplementary
Material, Figure S1, available online).
Optimization of the de-iodination procedure was hampered initially by the production of
very dark, viscous, insoluble materials using the Chern protocol. We believe that this
insoluble material contributed in part to lower yields, as unreacted or partially reacted
starting material was sequestered into the insoluble mass. Upon further exploration, we
discovered that we could eliminate the insoluble material by increasing the amount of
water in the reaction. Although the modified reaction is significantly slower, the result is
a cleaner and higher-yielding process.
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With suitable quantities of 3-hydroxy-4-iodobenzonitrile (5) in hand, we turned our
attention to the synthesis of benzo[b]furan-6-carbonitrile (9; Scheme 3). Using the
procedure of Wishka, et al.,[16] we synthesized the intermediate phenylacetylene 7, which
was subsequently cyclized to a mixture of the desired benzo[b]furan 9 and its silylated
congener (8) in a 1:1 mixture (Table 1). By lowering the reaction temperature to 50 °C,
we were able to increase the ratio of silylated material to 2:1, but further decreasing the
temperature did not further alter the product ratio, and did lower the overall yield. The
silylated material 8 was easily desilylated using aqueous base to produce the desired
benzo[b]furan-6-carbonitrile (9) in good yield.
To synthesize the requisite boronic acid ester 10 from the 2-unsubstituted benzo[b]furan
9, we used a modification of Hartwig’s boronylation procedure[17] to provide the target
compound in good yield (Scheme 3). Boronic acid ester 10 is a useful two-point scaffold
for the preparation of compounds with a benzofuran core that exhibit biological activity
CONCLUSION
By utilizing a unique sequence of per-iodination and de-iodination of 3-
hydroxybenzonitrile (3), we were able to produce 3-hydroxy-4-iodobenzonitrile (5) in
useful quantities. This useful intermediate was then further converted to benzo[b]furan-
6-carbonitrile (9) and 6-cyanobenzo[b]furan-2-boronic acid pinacol ester (10), both of
which are useful intermediates for medicinal chemistry. Additional benzo[b]furan-6-
carbonitriles, such as the corresponding 2-aryl, 2-alkyl, or 2-carboxy congeners should
also be accessible using this methodology.
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EXPERIMENTAL
3-Hydroxy-4-Iodobenzonitrile (5)
3-Cyano-2,4,6-triiodophenol (4, 21.97 g, 44.2 mmol) was dissolved in N-
methylmorpholine (160 mL) and H2O (40 mL). The resulting solution was heated to
gentle reflux (160 °C oil bath) for 24 h, then cooled to room temperature. The excess
solvent was removed by evaporation at reduced pressure, and the residual oil was
partitioned between EtOAc (300 mL) and 0.5 M aq. HCl (200 mL). The organic extract
was then washed with brine (200 mL), dried over MgSO4, filtered, and evaporated to
yield an orange oil. The oil was subjected to flash chromatography (50 × 450 mm) on
silica gel with 5:1 hex:EtOAc. Product-containing fractions were pooled and evaporated
to yield 3.38 g (28%) of 5 as a white powder: mp 121-124 °C; Rf 0.35 (3:1 hex:EtOAc);
1H-NMR (CDCl3) δ 7.79 (d, 1H), 7.23 (d, 1H), 6.95 (dd, 1H), 5.63 (s, 1H); HRMS
calculated for C7H5INO, [M+H]+, 245.9410 found 245.9411.
Benzo[b]furan-6-carbonitrile (9)
To a solution of 3-Hydroxy-4-[(trimethylsilyl)ethynyl]benzonitrile (7, 1.14 g, 5.3 mmol)
in 1:1 EtOH:triethylamine (20 mL) was added cuprous iodide (51 mg, 0.26 mmol). The
resulting solution was heated to 75 °C (oil bath) for 6.5 h, then cooled to room
temperature and evaporated to yield a brown syrup that contained a ~1:1 mixture of
silylated:desilylated material (by NMR). The crude material was dissolved in CHCl3 (70
mL), and 1.0 M aq. NaOH (50 mL) was added. The biphasic mixture was stirred
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vigorously for 18 h. The pH of the aqueous phase was adjusted by dropwise addition of
conc. aq. HCl. The organic layer was separated, and the aqueous layer was extracted
with EtOAc (3 × 30 mL). The combined organic layers were then dried over Na2SO4,
filtered, and evaporated to yield a brown oil. The oil was subjected to flash
chromatography (80 g) on silica gel with 0-25% EtOAc/hex. Product-containing
fractions were pooled and evaporated to yield 700 mg (93%) of 9 as a clear, colorless oil:
Rf 0.50 (6:1 hex:EtOAc); 1H-NMR (CDCl3) δ 7.83-7.81 (m, 2H), 7.69 (d, 1H), 7.50 (dd,
1H), 6.87-6.86 (m, 1H); HRMS calculated for C9H6NO, [M+H]+, 144.0444 found
144.0443.
ACKNOWLEDGEMENT
We wish to thank Dr. Peter Mueller of the MIT crystallography facility for expert
analysis of X-ray crystal structure data.
This publication was made possible in part by grants R43 AI082799 and U01 AI082052
from the National Institute of Allergy and Infectious Disease (NIAID) at the National
Institutes of Health NIH).
REFERENCES
[1] Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry; A. R.
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[2] Friedrichsen, W. In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W.
Rees, E. F. V. Scriven, (Eds.); Pergammon Press: Oxford, 1996; vol. 2, pp. 352–394.
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[3] Hou, X.-L.; Yang, Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry; G. W.
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pp. 395-436.
[5] (1967).
[6] Takeda, N.; Miyata, O.; Naito, T. Eur. J. Org. Chem. 2007, 1491.
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[10] Sagi, K. et al., J. Med. Chem. May 8, 2003, 46, 1845.
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[13] Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P. D. J. Chem. Soc.,
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[14] Talekar, R. S.; Chen, G. S.; Lai, S. Y.; Chern, J. W. J. Org. Chem. Oct 14, 2005, 70,
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[16] Wishka, D. G. et al., J. Med. Chem. Jul 13, 2006, 49, 4425.
[17] Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. Mar 1, 2007, 9, 757.
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Table 1. Effect of temperature on benzofuran annulation.
Entry
T (°C)
75
t (h)
2
% yield
97
7:8
1:1
1:2
1:2
a
b
c
50
5
94
25
5
72
aThe yield was determined from the weight of the crude product mixture which contained
b
only products 3 and 4. The ratio of 3 and 4 was calculated from the integrations of the
3- and 3’- protons of the crude NMR.
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Scheme 1. Reported de-iodination of 2,4,6-triiodo-3-hydroxybenzaldehyde.
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Scheme 2. Per-iodination and de-iodination of 3-hydroxybenzonitrile.
I
I
I2, NaI (cat.)
aq. Na2CO3
NC
OH
NC
OH
3
I
4
N-methylmorpholine
reflux
MsCl
I
I
pyridine
CH2Cl2
NC
NC
OSO2Me
OH
5
6
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Scheme 3. Syntheses of benzo[b]furan-6-carbonitrile and 6-cyanobenzo[b]furan-2-
boronic acid pinacol ester.
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