Concise synthesis of 6-cyanobenzo[ b ]furan, a useful building block

Article abstract of DOI:10.1080/00397911.2013.855788

A new three-step synthesis of 6-cyanobenzo[b]furan (6) was developed, starting from commercially available 6-hydroxybenzo[b]furan-3-one (18). Key steps in this process were the first step, which was the reductive dehydration of 18 to produce 6-hydroxybenzo[b]furan (19), and the last step, which converted the aryl triflate 20 to the aryl cyanide 6 in a palladium-catalyzed cross-coupling protocol. Overall yield for this new synthesis was 49%.

Full text of DOI:10.1080/00397911.2013.855788

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Concise Synthesis of 6-
Cyanobenzo[b]furan, a Useful Building
Block
Son T. Nguyen a , John D. Williams a , Helena Majgier-Baranowska a
,
Bing Li a , Venugopal R. Neelagiri b , Hwa-Ok Kim b & Norton P. Peet a
a Department of Chemistry, Microbiotix Inc. , Worcester ,
Massachusetts , USA
b CreaGen Biosciences Inc., Woburn , Massachusetts , USA
Accepted author version posted online: 02 Dec 2013.Published
online: 28 Mar 2014.
To cite this article: Son T. Nguyen , John D. Williams , Helena Majgier-Baranowska , Bing
Li , Venugopal R. Neelagiri , Hwa-Ok Kim & Norton P. Peet (2014) Concise Synthesis of 6-
Cyanobenzo[b]furan, a Useful Building Block, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:9, 1307-1313, DOI:
10.1080/00397911.2013.855788
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Synthetic Communications®, 44: 1307–1313, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.855788
CONCISE SYNTHESIS OF 6-CYANOBENZO[b]FURAN,
A USEFUL BUILDING BLOCK
Son T. Nguyen,1 John D. Williams,1 Helena Majgier-
Baranowska,1 Bing Li,1 Venugopal R. Neelagiri,2 Hwa-Ok Kim,2
and Norton P. Peet1
1Department of Chemistry, Microbiotix Inc., Worcester, Massachusetts, USA
2CreaGen Biosciences Inc., Woburn, Massachusetts, USA
GRAPHICAL ABSTRACT
Abstract A new three-step synthesis of 6-cyanobenzo[b]furan (6) was developed, starting
from commercially available 6-hydroxybenzo[b]furan-3-one (18). Key steps in this process
were the first step, which was the reductive dehydration of 18 to produce 6-hydroxybenzo[b]
furan (19), and the last step, which converted the aryl triflate 20 to the aryl cyanide 6 in a
palladium-catalyzed cross-coupling protocol. Overall yield for this new synthesis was 49%.
Keywords Aryl cyanide synthesis; cross-coupling; 6-cyanobenzo[b]furan; reductive dehydration
INTRODUCTION
Benzo[b]furans are important components of drugs and biologically active
compounds. Examples of benzo[b]furan-containing drugs include (−)-1-(benzo-
furan-2-yl)-2-propylaminopentane ((−)-BPAP),[1] dronedarone,[2] and amiodarone.[3]
Consequently, there has been significant effort directed toward the design of new syn-
theses for benzo[b]furans.[4,5]
We have described previously the syntheses of specific benzo[b]furan building
blocks. 5-Formylbenzo[b]furan-2-carbonitrile was a previously unknown compound
that we required for the preparation of a compound library. We recently reported[6]
a seven-step, practical synthesis for this new compound in 17% overall yield. More
recently, we developed a new synthesis for 6-cyanobenzo[b]furan (6), which is
Received September 6, 2013.
Address correspondence to Norton Peet, Department of Chemistry, Microbiotix Inc., One Innovation
Drive, Worcester, MA 01605, USA. E-mail: npeet@comcast.net
1307

1308
S. T. NGUYEN ET AL.
Scheme 1. Preparation of 6-cyanobenzo[b]furan (6) from 3-hydroxybenzonitrile (1).
shown in Scheme 1.[7] Starting from 3-hydroxybenzonitrile (1), we prepared triiodo
compound 2 in 88% yield by treatment with iodine and then selectively removing
two iodo groups from 2 with N-methylmorpholine to give 3-hydroxy-4-iodobenzo-
nitrile (3) in 28% yield. Compound 3 underwent a Sonagashira reaction,[8] using the
procedure of Wishka et al.[9] to produce the intermediate phenylacetylene 4 in 79%
yield. Subsequent cyclization of 4 with cuprous iodide catalysis gave a 93% yield of
6-cyanobenzo[b]furan (6), after treatment of the initial mixture with sodium hydrox-
ide to convert the 2-trimethylsilylbenzofuran intermediate 5 to the desired product 6.
Although this sequence was relatively short, and four of the five steps proceeded in
good yield, the deiodination of compound 2 to produce 3-hydroxy-4-iodobenzonitrile
(3) was a poor-yielding reaction that we were unable to improve, and this prompted us
to evaluate new methods for the preparation of 6. This report describes an improved,
concise synthesis of 6-cyanobenzo[b]furan (6).
RESULTS AND DISCUSSION
In Scheme 2 is shown another known route to 6-cyanobenzo[b]furan (6), start-
ing from 4-nitrosalicylic acid (7). Reduction of 7 with borane-dimethylsulfide complex
gave benzyl alcohol 8 in 95% yield.[10] Oxidation of 7 with manganese dioxide furnished
4-nitrosalicylaldehyde (9) in 75% yield.[10] Aldehyde 9 was then used to install the fused
furan ring, by treatment with 2-bromomalonic acid diethyl ester under basic condi-
tions.[11] This reaction was reported to produce ester 10 in 59% yield, which actually
is a reasonably good yield in view of the complexity of this conversion that involves
alkylation, condensation, hydrolysis and decarboxylation processes. Hydrolysis of 10
with potassium hydroxide afforded the corresponding acid 11 in 92% yield,[12] and
subsequent decarboxylation with copper and quinoline at high temperature gave
6-nitrobenzo[b]furan (12) in 63% yield.[12] Chemical reduction of the nitro group of 12
with ferric chloride in the presence of N,N-dimethylhydrazine gave 6-aminobenzo[b]
furan (13) in 79% yield.[12] Conversion of the amino group in 13 to a cyano group to
produce the desired compound 6 was accomplished in a two-step Sandmeyer reaction,
in the presence of sodium cyanide.[13] The yield for this reaction was not reported.

SYNTHESIS OF 6-CYANOBENZO[b]FURAN
1309
Scheme 2. Preparation of 6-cyanobenzo[b]furan (6) from 4-nitrosalicylic acid (7) based on literature
reports.
The overall process for the preparation of benzofuran 6 shown in Scheme 2 is
unattractive because of its length, poor yields with two of the conversions, and an
unknown yield for the last two-step Sandmeyer reaction. Also, the Sandmeyer con-
version involved the use of sodium cyanide under acidic conditions, which we wished
to avoid. Although this chemistry is basically a compilation of known reactions that
would undoubtedly work to produce product, it underscored the need for a better
synthesis of benzofuran 6.
We looked for cost-effective, commercially available starting materials that
potentially could be converted to 6-cyanobenzo[b]furan (6). In Fig. 1 are shown four
such materials that we identified and attempted to convert to compound 6. All of
these potential starting materials had structural elements common to 6, and we made
several attempts to use these materials to devise a new route to benzofuran 6.
We first attempted to alkylate 3-hydroxybenzoic acid (14) with a two-carbon
synthon, such as bromoacetaldehyde diethyl acetal, reasoning that a subsequent
annulation of this unit to the 4-position of the benzene ring could provide a pre-
cursor to compound 6. However, the alkylation conditions that we explored all gave
mixtures of alkylated products, where alkylation had occurred to produce the desired
ether but had also partially produced a dialkylated ether-ester product. Because this
complication would lengthen an already long planned sequence, we moved next to
3-bromophenol (15), where only monoalkylation of the phenol could occur.
Figure 1. Potential cost-effective starting materials for the preparation of 6-cyanobenzo[b]furan (6).

1310
S. T. NGUYEN ET AL.
Alkylation of 15 with bromoacetaldehyde diethyl acetal, using sodium hydride in
dimethylformamide, gave us the desired ether in 98% yield. However, when we treated
this ether with acidic reagents (e.g., p-toluenesulfonic acid in toluene or xylene; or
polyphosphoric acid) in an attempt to produce the desired benzofuran, we observed
mixtures of 4-bromobenzo[b]furan and 6-bromobenzo[b]furan. These mixtures were
very difficult to separate and yields of either isomer were low (less than 2%).
5-Bromo-2-chlorophenol (16) was a potentially attractive starting material,
because problems of regiochemistry would no longer be an issue. We were able
to replace the bromo group with cyano in compound 16, using zinc cyanide and
Pd(Ph3P)4 in dimethylformamide, in 94% yield. We planned to attempt a Sonagashira
reaction with this compound (2-chloro-5-cyanophenol), but became discouraged by
literature reports that described the lower reactivity of chlorobenzenes.[14] However,
it was very useful to develop the cyanation conditions with compound 16, because
this replacement reaction was a critical feature of our ultimate, successful route to
compound 6.
3-Cyanophenol (17) was also used as a starting point for alkylations that could
ultimately produce the desired benzofuran. Treatment of 17 with bromoacetalde-
hyde diethyl acetal gave a 72% yield of the expected O-alkylated product. Treatment
of this ether with polyphosphoric acid, however, gave a mixture from which only
4-cyanobenzo[b]furan could be isolated. We were also able to alkylate 17 with allyl
bromide, using potassium carbonate in acetone at 0 °C, to provide a 94% yield of
the expected propargyl ether. We had planned to do a Claisen rearrangement with
this ether using diethylaluminum chloride,[15] evaluate the regiochemistry of the prod-
uct or products, and subsequently convert the desired o-allylphenol, if formed, by
ozonolysis to 2-hydroxy-4-cyanophenylacetaldehyde, which could then be cyclized to
benzofuran 6. However, we did not proceed with this plan because of the result we
obtained with the diethyl acetal.
In Scheme 3 is shown the new procedure for the synthesis of 6-cyanobenzo[b]
furan (6), starting from commercially available 6-hydroxybenzo[b]furan-3-one (18). We
believe that this concise method is now the best procedure that has been reported for the
synthesis of 6. The first step in this process involved conversion of 6-hydroxybenzo[b]
furan (18) to 6-hydroxybenzo[b]furan (19) using a reductive dehydration protocol.
Thus, treatment of 18 (which can be prepared from resorcinol in two steps[16]) with
lithium borohydride in tetrahydrofuran, followed by treatment with acid, produced
6-hydroxybenzo[b]furan (19) in 68% yield. Compound 19 has previously been pre-
pared from 18 in a three-step process from 18, by protection of the hydroxyl group
using tert-butylsilyl chloride, reduction of the ketone with sodium borohydride, and
dehydration of the resulting alcohol by treatment with acid.[17] Conversion of 19 to
the triflate 20 proceeded in 88% yield; compound 20 then underwent a cross-coupling
Scheme 3. New synthesis of 6-benzo[b]furan (6) from 6-hydroxybenzo[b]furan-3-one (18).

SYNTHESIS OF 6-CYANOBENZO[b]FURAN
1311
Scheme 4. Reductive dehydration of compound 18.
Table 1. Reaction conditions attempted for the reductive
dehydration of 18
Products (%)a
Reagent
Solvent
19
21
LiBH4
THF
THF
THF
THF
THF
MTBE
68
45
17
44
3
<5
<5
47
<5
<5
<5
DIBAL
.
BH3 THF
Red-Al
NaBH4, AcOH
LiAlH4
27
aIsolated yields.
reaction with zinc cyanide, in the presence of palladium-tetrakis(triphenylphosphine)
palladium(0), to give 6 in 82% yield. Palladium-catalyzed cyanation of aryl triflates is
useful methodology for the preparation of aryl cyanides.[18]
The conditions shown in Scheme 3 for the reductive dehydration of compound
18 are the optimized conditions that were found after several attempts. In Scheme
4 is shown our first attempt, with lithium aluminum hydride in tetrahydrofuran,[19]
which made us realize that overreduction to the dihydrobenzofuran 21 was a problem-
atic side reaction that needed to be minimized. To improve the yield of the reductive
dehydration process, we screened various other conditions, using different reducing
reagents, as shown in Table 1. All reactions in Table 1 were performed at room tem-
perature, which helped to minimize the production of 21. The best conditions found
were LiBH4 in tetrahydrofuran (THF) followed by a HCl/H2O quench, which pro-
vided 19 in 68% yield (first entry). Interestingly, it was observed that if the reaction
mixture was quenched with water and kept neutral, we could isolate the intermediate
2,3-dihydrobenzo[b]furan-3,6-diol (22). Thus, addition of HCl was necessary for the
elimination of the secondary alcohol to give 19.
SUMMARY
Insummary,wehavedevelopedaconcise,three-stepsynthesisfor6-cyanobenzo[b]
furan (6), starting from commercially available 6-hydroxybenzo[b]furan-3-one (18),
in 49% overall yield. Key steps that were used in this synthesis were the reductive
dehydration of 18 to 6-hydroxybenzo[b]furan (19) and conversion of triflate 20 to
6-cyanobenzo[b]furan (6) with zinc cyanide, using a palladium-catalyzed cyanation
protocol.

1312
S. T. NGUYEN ET AL.
EXPERIMENTAL
6-Hydroxybenzofuran (19)
LiBH4 (1.83 mL, 2M in THF) was added to a stirred solution of 6-hydroxybenzo[b]
furan-3-one (18) (0.5 g, 3.33 mmol) in THF (10 mL) cooled in an ice bath over 15 min.
The ice bath was removed, and after 16 h, ice water (3 mL) was slowly added, followed
by HCl (1 mL, concentrated solution). The product was extracted with hexanes (3×10
mL). The combined organic extracts were dried (MgSO4) and concentrated by rotary
evaporation. The residue was purified by silica-gel column chromatography (24 g of
SiO2, hexanes–CH2Cl2, 1:0 to 0:1, 20 min) to provide 0.30 g (68% yield) of 19 as a
1
colorless oil. Rf: 0.23 (12% ethyl acetate in hexanes); H NMR (CDCl3): δ 7.51 (d,
J=2.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.99 (d, J=1.8 Hz, 1H), 6.78 (dd, J=8.4, 2.1
Hz, 1H), 6.68 (dd, J=2.1, 0.6 Hz, 1H), 5.40 (br s, 1H).
6-Cyanobenzo[b]furan (6)
Zn(CN)2 (0.8 g, 4.5 mmol) and Pd(Ph3P)4 (0.26 g, 0.22 mmol) were added to
a stirred solution of triflate 20 (prepared as described by Coleman et al.[17]) (0.4 g,
1.5 mmol) in DMF (10 mL) under argon. The reaction mixture was placed in an oil
bath maintained at 100 oC. After 3 h, the oil bath was removed, and the reaction mix-
ture was allowed to cool to rt. Water (10 mL) was added, and the product was extracted
with ether (3×10 mL). The combined organic extracts were dried (MgSO4) and concen-
trated by rotary evaporation. The residue was purified by silica-gel column chromatog-
raphy (24 g of SiO2, hexanes–CH2Cl2, 1:0 to 0:1, 20 min) to provide 0.176 g (82% yield)
of 6-cyanobenzo[b]furan (6) as a colorless oil, which solidified on standing. Rf: 0.29
1
(12% ethyl acetate in hexanes); H NMR (CDCl3): δ 7.83 (s, 1H), 7.79 (d, J=6.9 Hz,
1H), 7.69 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1, 1.2 Hz, 1H), 6.86 (dd, J=2.4, 0.9 Hz, 1H).
FUNDING
Research reported in this publication was supported by the National Institutes
of Health under Award No. U01AI082052. The content is solely the responsibility
of the authors and does not necessarily represent the official views of the National
Institutes of Health.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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