Diversity-oriented synthesis of libraries based on benzofuran and 2,3-dihydrobenzofuran scaffolds

Article abstract of DOI:10.1021/acscombsci.7b00014

Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1.9-4.7.

Full text of DOI:10.1021/acscombsci.7b00014

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Article
Diversity-oriented Synthesis of Libraries Based on
Benzofuran and 2,3-Dihydrobenzofuran Scaffolds
Liena Qin, Duc-Duy Vo, Azadeh Nakhai, C. David Andersson, and Mikael Elofsson
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00014 • Publication Date (Web): 17 Mar 2017
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Diversityꢀoriented Synthesis of Libraries Based on
Benzofuran and 2,3ꢀDihydrobenzofuran Scaffolds
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Liena Qin, DucꢀDuy Vo, Azadeh Nakhai, C. David Andersson, and Mikael Elofsson*
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Department of Chemistry, Umeå University, SE90187 Umeå, Sweden
Abstract
Benzofuran and 2,3ꢀdihydrobenzofuran scaffolds are core components in a large number of
biologically active natural and synthetic compounds including approved drugs. Herein, we
report efficient synthetic protocols for preparation of libraries based on 3ꢀcarboxy 2ꢀaryl
benzofuran and 3ꢀcarboxy 2ꢀaryl transꢀ2,3ꢀdihydrobenzofuran scaffolds using commercially
available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines.
The building blocks were selected to achieve variation in physicochemical properties and
statistical molecular design and subsequent synthesis resulted in 54 leadꢀlike compounds with
molecular weights of 299ꢀ421 and calculated octanol/water partition coefficients of 1.9ꢀ4.7.
TOC graphic
Keywords
diversity oriented synthesis, benzofuran, 2,3ꢀdihydrobenzofuran
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Introduction
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Benzofuran and 2,3ꢀdihydrobenzofuran scaffolds are ubiquitous structural motifs found in a
vast number of natural products and synthetic compounds of which many display a wide
range of activities including antiviral, antibacterial, antiꢀinflammatory, antiangiogenic and
antimitotic activities (Figure 1).1 Our own interest in these scaffolds originates from the
finding that the resveratrol tetramer (ꢀ)ꢀhopeaphenol, a complex plant stilbenoid isolated from
the Papua Guinean species Anisoptera thurifera and Anisoptera polyandra, blocks type III
secretion (T3S) of toxins in the gramꢀnegative bacteria Yersinia pseudotuberculosis and
Pseudomonas aeruginosa (Figure 1).2 We have therefore initiated studies to expand our
knowledge on the chemistry and biology of these scaffolds and recently we published total
syntheses of (+/ꢀ)ꢀεꢀviniferin3, (+/ꢀ)ꢀampelopsin3, viniferifuran, a resveratrolꢀpicetannol
hybrid and anigopreissin A4. However, compared with complex natural products, successful
lead compounds are typically smaller and simpler and have more drugꢀlike properties.5 To
address this, we have directed our attention towards preparation of libraries suitable for
screening and identification of novel bioactive structures based on benzofuran and 2,3ꢀ
dihydrobenzofuran scaffolds.
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Figure 1. Examples of compounds based on benzofuran and 2,3ꢀdihydrobenzofuran scaffolds.
Natural compounds: (ꢀ)ꢀhopeaphenol2, (+)ꢀlithospermic acid6, (+)ꢀεꢀviniferin7, conocarpan8
and (ꢀ)ꢀephedradine9. Synthetic compounds: nesbuvir10, a COXꢀ2 inhibitor11, two inhibitors of
tubulin polymerization12, and an inhibitor of methicillin resistant Staphylococcuccus aureus13.
Building on Larock’s publications describing palladium catalyzed heteroannulation of alkynes
for indole synthesis14, a number of methods for preparation of 2ꢀarylbenzofuranꢀ3ꢀ
carboxylates by palladium catalyzed carbonylative heteroannulation of oꢀ
hydroxylarylacetylenes have been decribed15 (reference 19 and publications cited therein).
However, these methods require extra steps for preparation of oꢀhydroxylarylacetylenes by
Sonogashira couplings and the us of alkynes as starting material also limits the scope by
excluding heterocycle substrates. Preparation of 2,3ꢀtrans disubstituted 2,3ꢀ
dihydrobenzofurans is however less straightforward16 and most efforts have been directed
towards total synthesis of resveratrolꢀbased natural products. To the best of our knowledge,
designed libraries of 2ꢀarylbenzofuranꢀ3ꢀcarboxylates and 2,3ꢀtrans disubstituted
dihydrobenzofurans have not been reported. Herein we describe the design and synthesis of
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leadꢀlike libraries based on 3ꢀcarboxy 2ꢀaryl benzofuran and 3ꢀcarboxy 2ꢀaryl transꢀ2,3ꢀ
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dihydrobenzofuran scaffolds.
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Results and discussion
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We designed the libraries of 2ꢀarylbenzofuranꢀ3ꢀcarboxamides and 2,3ꢀdihydroꢀ2ꢀarylꢀ
benzofuranꢀ3ꢀcarboxamides based on the analysis outlined in Scheme 1. By using readily
available salicylaldehydes, aryl boronic acids or aryl halides and amines as building blocks,
diverse target compounds can be achieved based on the flat benzofuran scaffold as well as the
topographically distinct cisꢀ and transꢀsubstituted 2,3ꢀdihydrobenzofuran scaffolds. The
salicylaldehydes can be reacted with ethyl 2ꢀdiazoacetate to form the 3ꢀcarboxyfunctionalized
benzofurans. Subsequent arylation furnishes the 2,3ꢀdisubstituded benzofuran that can be
reduced to the cisꢀ2,3ꢀdihydrobenzofuran by catalytic hydrogenation. Reduction with
NH4Cl/Mg would on the other hand produce the corresponding transꢀ2,3ꢀdihydrobenzofurans.
Ester hydrolysis and amide coupling would eventually provide the flat, cis and trans target
series. The benzofuran and 2,3ꢀdihydrobenzofuran scaffolds were decorated with substituent
originating from the building blocks shown in Figure 2. A statistical molecular design
(SMD)17 was performed to select a subset of compounds to be synthesized from the pool of
possible building block combinations. In effect, SMD predisposes a set of compounds for a
robust structureꢀactivity relationship analysis after biological testing by making sure that the
building blocks systematically appear in several molecules but in different combinations. This
gives a more robust basis for identification of combination effects and avoids a situation
where two building blocks always appear together in the molecules, thus making it impossible
to elucidate the effect of the individual structural features. The building blocks in Figure 2
giving rise to the compounds in Figure 3 were selected to vary in their physicochemical
features. The salicylaldehydes and the arylboronic acids contained both electron withdrawing
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(fluorine) and electron donating (methoxy) substituents, and for the arylboronic acids,
heteroaromatic features affect size, polarity and basicity. The amines were varied even more
in size, and basicity with both aromatic and aliphatic ring structures and aliphatic chains
affecting flexibility.
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Scheme 1. Synthetic strategy to achieve 3ꢀcarboxy 2ꢀaryl benzofuran and 3ꢀcarboxy 2ꢀaryl
transꢀ2,3ꢀdihydrobenzofuran scaffolds starting from salicylaldehydes, arylboronic acids or
arylhalides and amines.
The designed compounds were analyzed for their physicochemical properties and they were
generally drugꢀlike (80 of 81 compounds) and leadꢀlike (77 of 81 compounds) according to
definitions of Lipinski18 and Oprea,19 respectively. The molecular weights were in the range
228.2—421.5 (median of 299.8) and a calculated octanol/water partition coefficient between
1.9 and 5.3 (median of 3.0). Calculation details are provided in the Supporting Information.
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Figure 2. Selected salicylic aldehydes, arylboronic acids or arylhalides and amines.
The concise synthetic route for 2ꢀarylbenzofuranꢀ3ꢀcarboxamide derivatives is described in
Scheme 2. Despite numerous efforts to synthesize benzofuran core structures, routes to
benzofuranꢀ3ꢀcarboxylate are rare. We applied a recently developed method described by
Hossain and coꢀworkers.20 Starting from the salicylaldehyde and derivatives 1{1ꢀ3} we first
constructed the 3ꢀcarboxylate benzofurans via reaction with ethyl 2ꢀdiazoacetate under
.
catalysis by HBF4 OEt2 followed by dehydratation in concentrated H2SO4 to furnish 2{1ꢀ3} in
66, 20 and 73% yield, respectively. These were then transformed into benzofuranꢀ2ꢀboronic
acid derivatives 3{1ꢀ3} in excellent yields (88ꢀ98%) using trimethyl borate and lithium
diisopropylamide (LDA) at ꢀ78 °C for 15 min. The boronic acid 3{1ꢀ3} were then submitted
to a Suzuki couplings using PdCl2(dppf)·DCM (5 mol %) as catalyst. Coupling of 3{1} with
4ꢀiodoanisole and 4ꢀiodopyridine gave 5{1,2} and 5{1,3} in 70% and 50% yield respectively.
However, when reacting 4ꢀiodopyridine with 3{2} and 3{3} no or <10% coupling product was
obtained, respectively. The second heteroaryl coupling partner 3ꢀbromofuran followed this
pattern and only 3{3} reacted to give 5{3,1} in 11% yield. To overcome the low efficiency of
Suzuki couplings with the heteroaromatic coupling partners, we used a reversed strategy and
prepared the 2ꢀiodobenzofuran derivatives 4{1ꢀ3} by treatment of 2{1ꢀ3}, iodine and LDA in
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43, 39 and 16% yield, respectively. Transformation of the boronic acids 3{1ꢀ3} into the
corresponding iodo derivatives 4{1ꢀ3} did not result in improved yields. Applying Suzuki
couplings on the iodo derivatives 4{1ꢀ3} with 4ꢀpyridine boronic acid and 3ꢀfuran boronic
acid gratifyingly produced 5{1ꢀ3,1ꢀ5} in 45ꢀ92% yield. Subsequent hydrolysis of the ester
coupling products 5{1ꢀ3,1ꢀ5} under basic condition gave carboxylic acid derivatives 6{1ꢀ3,1ꢀ
5} in 64ꢀ100% yield. Amide couplings applied on 6{1ꢀ3,1ꢀ5} using N,N,N′,N′ꢀtetramethylꢀOꢀ
(benzotriazolꢀ1ꢀyl)uronium tetrafluoroborate (TBTU) as coupling reagent gave the target
compounds 7{1ꢀ3,1ꢀ5,1ꢀ6} in 14ꢀ88% yield (Figure 3). N,Nꢀdimethylethylenediamine proved
to be the most challenging amine and the target compounds were only isolated in 14ꢀ28%
yield.
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Scheme 2. Synthetic route to 2ꢀarylbenzofuranꢀ3ꢀcarboxamide derivatives. Reagents and
conditions: a) ethyl 2ꢀdiazoacetate (1.6ꢀ2.0 equiv.), HBF4·OEt2 (0.1 equiv.), rt, 1 h then conc.
H2SO4, 15 min, rt, 23ꢀ73%; b) trimethylborate (2.2 equiv.), LDA solution (2.2 equiv.), THF, ꢀ
78 °C, 15 min, 88ꢀ98%; c) I2 (2.5 equiv.), LDA (3.5 equiv.), THF, ꢀ78 °C ꢀ rt, 24 h, 16ꢀ43%; d)
NIS (1 equiv.), CH3CN, rt, 24 h, 13%. e) iodo derivatives (1.0 ꢀ2.0 equiv.), PdCl2(dppf)·DCM
(5 mol%), DME/H2O (1:1), Na2CO3 (4 equiv.), 70 °C, 30ꢀ80%; f) boronic acid (1.5ꢀ2.0
equiv.), PdCl2(dppf)·DCM (5 mol%), DME/H2O (1:1), Na2CO3 (4.0 equiv.), 70 °C, 45ꢀ92%;
g) NaOH (4.0 equiv.), THF/MeOH/H2O (1:1:1), 70 °C, 64ꢀ100%; h) amine (1.5ꢀ2.5 equiv.),
TBTU (1.2 equiv.), DMF, rt, 24 h, 14ꢀ88%. DCM = dichloromethane; DME = 1,2ꢀ
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dimethoxyethane; dppf = 1,1′ꢀBis(diphenylphosphino)ferrocene; NIS = Nꢀiodosuccinimide; rt
= room temperature; THF = tetrahydrofuran.
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Figure 3. Synthesized and characterized compounds in the benzofuran series.
We then turned our attention to preparation of the cis series. Enantioꢀ and diastereoꢀselective
synthesis of cisꢀ2,3ꢀdihydrobenzofuran can be achieved by rhodiumꢀcatalyzed intramolecular
C−H insertion reaction of aryldiazoacetates or donorꢀdonor carbenoid chemistry.16,
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However, synthesis of products carrying a 3ꢀcarboxamide functional group have not been
reported using these efficient protocols. Only one example of rhodiumꢀcatalyzed enantioꢀ
selective synthesis of cisꢀ2ꢀamideꢀ3ꢀarylꢀ2,3ꢀdihydrobenzofuran have been reported and the
synthetic sequence involves a multistep procedure to prepare the carbenoid precursor22.
Instead we attempted to synthesize the cisꢀ2,3ꢀdihydrobenzofuran series by reducing the 2ꢀ
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arylꢀ3ꢀethoxycarbonyl benzofuran by hydrogen catalyzed by palladium on carbon. The cisꢀ
ester could be isolated but the subsequent ester hydrolysis resulted in epimerization under
both acidic and basic conditions (Scheme 3). In an alternative approach, we attempted to
reduce the benzofuran ring after ester hydrolysis. However, in our hands this strategy failed to
provide the target compounds. Based on these results we concluded that current methodology
does not provide general procedures and we decided abandon our efforts towards the cis
series.
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Scheme 3. Attempts to synthesize the cisꢀ2,3ꢀdihydrobenzofuran series.
Instead we focused our efforts on preparation of the trans series employing NH4Cl/Mg in
methanol that predominantly produces trans 2,3ꢀdihydrobenzofurans. The trans series was
thus obtained by reduction followed by ester hydrolysis and amide formation as outlined in
Scheme 4 to give the target 9{1ꢀ3,1ꢀ5} and 10{1ꢀ3,1ꢀ5,1ꢀ6} (Figure 4). The reduction typically
resulted in a mixture of the desired trans isomer together with the cisꢀisomer as minor sideꢀ
product. By performing the subsequent ester hydrolysis of the mixture at 70 °C the cis isomer
was epimerized to the target transꢀdihydrobenzofuranꢀ3ꢀcarboxylic acid derivatives 9{1ꢀ3,1ꢀ
5} as racemates in 25ꢀ80% yield over two steps. Next, coupling of 9{1ꢀ3,1ꢀ5} with
corresponding
amines
using
Oꢀ(benzotriazolꢀ1ꢀyl)ꢀN,N,N′,N′ꢀtetramethyluronium
tetrafluoroborate/triethyl amine (TBTU/Et3N) as coupling reagent afforded the target amides
10{1ꢀ3,1ꢀ5,1ꢀ6} in moderate to good yields (41ꢀ88%). However, in the case of amide
couplings with N,Nꢀdimethylethylenediamine the yields were modest (14ꢀ28%). The trans
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configuration was verified by comparing J coupling constants of the compounds with selected
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examples of cis and trans 2,3ꢀdihydrobenzofurans22ꢀ23
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Scheme 4. Synthetic sequence leading to the trans series consisting of compounds 9{1ꢀ3,1ꢀ5}
and 10{1ꢀ3,1ꢀ5,1ꢀ6}. Reagents and conditions: a) Magnesium crumbles (10ꢀ30 equiv.), NH4Cl
(2.0 equiv.), THFꢀMeOH, 0 °C to rt; b) NaOH (2 M, 4.0 equiv.), THFꢀMeOHꢀH2O, rt; c)
amine (1.5 equiv.), TBTU (1.2 equiv.), triethyl amine (2.0 equiv.), N,Nꢀdimethylformamide, rt.
All chiral compounds were prepared and isolated as racemates.
Figure 4. Synthesized and characterized compounds in the trans 2,3ꢀdihydrobenzofuran
series.
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In conclusion, we applied statistical molecular design and prepared leadꢀlike libraries based
on 3ꢀcarboxyꢀ2ꢀarylꢀbenzofuran and 3ꢀcarboxyꢀ2ꢀarylꢀtransꢀ2,3ꢀdihydrobenzofuran scaffolds
using commercially available salicylaldehydes, aryl boronic acids or halides and primary or
secondary amines. The approach is flexible and allows variation of structural features and
physicochemical properties. The current compounds fall into the definition of leadꢀ and drugꢀ
likeness with respect to molecular weights and calculated octanol/water partition coefficients.
The compounds are thus well suited for incorporation in screening collection and the robust
chemistry allow post screening medicinal chemistry to elucidate structureꢀactivity
relationships.
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Experimental procedures
General procedure for preparation of intermediate 2 represented by the synthesis of
ethyl benzofuran-3-carboxylate 2{1}. The compound was synthesized according to a
reported procedure20. To a solution of salicylaldehyde (1.00 g, 8.2 mmol, 1.0 equiv.) in
dichloromethane (7 mL) was added HBF4·OEt2 (132.6 mg, 0.819 mmol, 0.1 equiv.) at rt with
stirring, to give a dark red mixture. The solution of ethyl diazoacetate (1.50 g, 13.2 mmol, 1.6
equiv.) in dichloromethane (5 mL) was added dropwise to the stirring mixture during a period
of 10 min, resulting a steady release of nitrogen. The mixture was stirred for an extra h before
removing the solvent on rotary evaporator. To the mixture was added concentrated sulfuric
acid (0.4 mL); and the mixture was stirred for 10 min before neutralized with saturated
aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate (50 mL) and washed
with water (25 mL) and brine (25 mL) consecutively. The desired product was purified by
silica gel chromatography (heptane/ethyl acetate 97:3) and obtained as slightly yellow viscous
oil (1.00 g, 66% yield).
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General procedure for preparation of intermediate 3 represented by the synthesis of (3-
(ethoxycarbonyl)-benzofuran-2-yl)boronic acid 3{1}. The compound was prepared
according to a reported procedure24. A mixture of ethyl benzofuranꢀ3ꢀcarboxylate 2{1} (1.57
g, 8.3 mmol, 1.0 equiv.) and trimethyl borate (1.91 g, 18.4 mmol, 2.2 equiv.) dissolved in dry
THF (25 mL) was precooled at ꢀ78 °C in dry iceꢀacetone bath under the protection of
nitrogen. LDA (9.2 mL, 2 M in THF/heptane/ethylbenzene, 2.2 equiv.) was added via syringe
to the solution with stirring; and the resulting mixture was kept stirring at the same
temperature for additional 15 min before quenched with HCl solution (30 mL, 4 M in H2O).
The reaction mixture was then allowed to stir at rt for 10 min before extraction with ethyl
acetate (150 mL). The organic phase was washed with water (50 mL) and brine (50 mL)
consecutively. The desired product was obtained after removal of solvents under reduced
pressure as white solid (1.89 g, 98 % yield) and used for next step without further
purification.
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General procedure for preparation of intermediate 4 represented by the synthesis of
ethyl 2-iodo-benzofuran-3-carboxylate 4{1}. The compound was prepared according to a
reported procedure25. To a mixture of ethyl benzofuranꢀ3ꢀcarboxylate 2{1} (1.54 g, 8.1 mmol,
1.0 equiv.) and iodine (5.13 g, 20.2 mmol, 2.5 equiv.) in THF (30 mL) at ꢀ78 °C in dry iceꢀ
acetone bath under the protection of nitrogen, was added LDA (14.2 mL, 2 M in
THF/heptane/ethylbenzene, 3.5 equiv.). The mixture was allowed to warm up to room
temperature and stirred overnight; and then quenched with saturated NH4Cl solution (50 mL).
The mixture was extracted with ethyl acetate (150 mL); and the organic phase was washed
with water (50 mL) and brine (50 mL) consecutively. The solvents were evaporated under
reduced pressure to give a resinꢀlike residue (1.66 g), which was suspended in cold
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cyclohexane (5 mL). The solid formed was triturated and kept cold at 0 °C for 15 min and
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General procedure for Suzuki coupling represented by the synthesis of ethyl 2-(4-
methoxyphenyl)benzofuran-3-carboxylate 5{1,2} and ethyl 2-(furan-3-yl)benzofuran-3-
carboxylate 5{1,1}. Compound 5{1,2}: A mixture of (3ꢀ(ethoxycarbonyl)ꢀbenzofuranꢀ2ꢀ
yl)boronic acid 3{1} (300 mg, 1.28 mmol. 1.0 equiv.), 4ꢀidodoanisole (330 mg, 1.41 mmol,
1.1 equiv.), PdCl2(dppf)·DCM (53.3 mg, 0.064 mmol, 0.05 equiv.) and sodium carbonate (544
mg, 5.13 mmol, 4.0 equiv.) were placed in a sealed tube with rubber septum. The reaction
tube was evacuated under vacuum and refilled with nitrogen three times using schlenk line.
MilliꢀQ water (6 mL) and 1,2ꢀdimethoxyethane (6 mL) were degassed under nitrogen gas
before adding to the reaction tube via syringe. The reaction mixture was stirred at 70 °C
overnight; and monitored by thinꢀlayer chromatography (TLC). After completion of the
reaction, the reaction mixture was flushed through a pad of silica gel with ethyl acetate to
remove some insoluble salts. The desired product was obtained by silica gel chromatography
(heptane/ethyl acetate 97:3) as yellowish viscous oil (267 mg, 70% yield). Compound 5{1,1}:
A mixture of ethyl 2ꢀiodoꢀbenzofuranꢀ3ꢀcarboxylate 4{1} (67.0 mg, 0.21 mmol. 1.0 equiv.), 3ꢀ
furan boronic acid (35.9 mg, 0.32 mmol, 1.5 equiv.), PdCl2(dppf)·DCM (8.9 mg, 0.011 mmol,
0.05 equiv.) and sodium carbonate (90.6 mg, 0.85 mmol, 4 equiv.) were placed in a sealed
tube with rubber septum. The reaction tube was evacuated under vacuum and refilled with
nitrogen three times using schlenk line. MilliꢀQ water (1 mL) and 1,2ꢀdimethoxyethane (1
mL) were degassed under nitrogen gas before adding to the reaction tube via syringe. The
reaction mixture was stirred at 70 °C and monitored by TLC. After completion of the reaction,
the mixture was diluted with ethyl acetate (10 mL). The organic phase was washed with water
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(3 mL) and brine (3 mL) consecutively. Silica gel chromatography (heptane/ethyl acetate
99:1) furnished the desired product as white solid (39 mg, 71% yield).
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General procedure of ester hydrolysis for preparation of 2-arylbenzofuran-3-carboxylic
acids 6{1-3,1-5}. To the solution of corresponding ethyl benzofuranꢀ3ꢀcarboxylate (0.2 mmol,
1.0 equiv.) dissolved in a mixed solvent of tetrahydrofuran, methanol and water (1 mL each)
was added NaOH (2 M in H2O, 0.8 mmol, 4 equiv.). The resulting solution was stirred at 70
°C overnight under the protection of nitrogen. The reaction mixture was acidified with HCl (1
M, aq.) to pH 1 and the most of the product directly precipitated as a solid. Removal of the
organic solvent under reduced pressure increased formation of product precipitation. The
product was subsequently washed with water, filtered and dried under vacuum; and used for
next step without further purification.
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General procedure of amide coupling for preparation of compound 7{1-3,1-5,1-6}. To a
reaction tube was added the corresponding 2ꢀarylbenzofuranꢀ3ꢀcarboxylic acid (0.175 mmol,
1.0 equiv.), free amine (0.262 mmol, 1.5 equiv.), TBTU (62.0 mg, 0.193 mmol, 1.1 equiv.),
triethyl amine (35.4 mg, 0.350 mmol, 2.0 equiv.) and DMF (1 mL). The reaction mixture was
stirred at rt overnight. The completion of reaction was monitored by TLC and liquid
chromatography mass spectrometry (LCMS). DMF was removed under reduced pressure.
Dichloromethane (15 mL) was added to the residue; and the resulting solution was washed
with water (5 mL) and brine (5 mL). The combined organic phases were dried over
magnesium sulfate, filtered and concentrated under reduced pressure. The desired product was
obtained by silica gel chromatography (typically dichloromethane/MeOH).
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General procedure for reducing 2-arylbenzofuran-3-carboxylate 5{1-3,1-5} to trans-2-
aryl-2, 3-dihydrobenzofuran-3-carboxylate 8{1-3,1-5} followed by hydrolysis to generate
trans-2-aryl-2,3-dihydrobenzofuran-3-carboxylic acid 9{1-3,1-5}. The transꢀ2ꢀarylꢀ2, 3ꢀ
dihydrobenzofuranꢀ3ꢀcarboxylate 8{1ꢀ3,1ꢀ5} was prepared according to a reported
procedure26. To a solution of 2ꢀarylbenzofuranꢀ3ꢀcarboxylate 5{1ꢀ3,1ꢀ5} (0.34 mmol, 1.0
equiv.) dissolved in a mixture solvent of THFꢀMeOH (8 mL, 1:1 ratio) precooled at ꢀ15 °C
under nitrogen atmosphere, magnesium crumbles (10.10 mmol, 30.0 equiv.) were added
followed by the addition of ammonium chloride (0.68 mmol, 2 equiv.) The reaction mixture
was stirred at the same temperature for 90 min and then allowed to warm up to rt and stirred
for additional 30 min. The reaction mixture was quenched with saturated ammonium chloride
solution (aq., 30 mL) at ꢀ15 °C, before dilution with water (30 mL) and extraction with
dichloromethane (30 mL). The aqueous phase was extracted with dichloromethane (30 mL x
2). The combined organic phases were dried over magnesium sulfate, filtered and
concentrated under reduced pressure. The crude product was purified by silica gel
chromatography (heptane/ethyl acetate) to provide transꢀ2ꢀarylꢀ2,3ꢀdihydrobenzofuranꢀ3ꢀ
carboxylate 8{1ꢀ3,1ꢀ5}. The corresponding methyl ester was identified as side product due to
the fact that the reduction was performed in methanol. To the solution of corresponding transꢀ
2ꢀarylꢀ2, 3ꢀdihydrobenzofuranꢀ3ꢀcarboxylate 8{1ꢀ3,1ꢀ5} (0.15 mmol, 1.0 equiv.) dissolved in
a mixture solvent of tetrahydrofuran, methanol and water (2 mL each) was added NaOH (2M
in H2O, 0.6 mmol, 4.0 equiv.). The resulting solution was stirred in 70 °C overnight under the
protection of nitrogen. The reaction mixture was acidified with HCl (1M in H2O) to pH 1. The
mixture was extracted with ethyl acetate (15 mL x 3), dried over sodium sulfate, filtered and
concentrated. The product of transꢀ2ꢀarylꢀ2, 3ꢀdihydrobenzofuranꢀ3ꢀcarboxylic acid 9{1ꢀ3,1ꢀ
5} was obtained and used for next step without further purification.
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General procedure of amide couplings to prepare compound 10{1-3,1-5,1-6}. To a
reaction tube was added the corresponding 2ꢀarylbenzofuranꢀ3ꢀcarboxylic acid (0.10 mmol,
1.0 equiv.), amine (0.15 mmol, 1.5 equiv.), TBTU (38.5 mg, 0.12 mmol, 1.2 equiv.), triethyl
amine (30.3 mg, 0.30 mmol, 3.0 equiv.) and DMF (1 mL). The reaction mixture was stirred at
rt overnight. Completion of the reaction was monitored by TLC and LCMS. DMF was
removed under reduced pressure. Dichloromethane (15 mL) was added to the residue; and the
resulting solution was washed with water (5 mL) and brine (5 mL). The organic phase was
dried over magnesium sulfate, filtered and concentrated under reduced pressure. The desired
product was obtained by silica gel chromatography (heptane/ethyl acetate or
dichloromethane/MeOH).
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Supporting information
Details on the statistical molecular design, calculated physicochemical properties, analytical
data for compounds and copies of NMR spectra for all final compounds.
Acknowledgements
We are grateful for financial support from the Swedish Research Council and the Swedish
Foundation for Strategic Research.
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