Interrupting Base-Mediated Benzofuran Ring Transformation with Michael Acceptors

Article abstract of DOI:10.1021/acs.joc.7b01267

A simple two-stage approach for the synthesis of 3-(2-arylbenzofuran-3-yl)propanoates and propanamides has been developed employing simple acrylates and acrylamides and readily available 3-aroylbenzofurans. The key step of this process involves a base-mediated ring opening of the 3-aroylbenzofurans and subsequent Michael addition of the resulting 1,3-dicarbonyl intermediate with acrylate/acrylamide, followed by the deformylation in one-pot. The resulting products undergo an acid-mediated dehydrative cyclization to arrive at these targets.

Full text of DOI:10.1021/acs.joc.7b01267

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Note
Interrupting Base-Mediated Benzofuran Ring
Transformation with Michael Acceptors
Kolluru Srinivas, Rashmi Sharma, and Chepuri V. Ramana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01267 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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Interrupting Base-Mediated Benzofuran Ring Transformation with Michael
Acceptors
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Kolluru Srinivas, Rashmi Sharma and Chepuri V. Ramana*
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Division of Organic Chemistry, CSIRꢀNational Chemical Laboratory, Dr. Homi Bhabha Road,
Pune, Maharashtra, Indiaꢀ 411008.
*Corresponding author: Tel.: +91 20 25902577; Fax: (+91) 20 2590 2629
Eꢀmail: vr.chepuri@ncl.res.in
ABSTRACT: Simple twoꢀstage approach for the synthesis of 3ꢀ(2ꢀarylbenzofuranꢀ3ꢀ
yl)propanoates and propanamides has been developed employing simple acrylates and
acrylamides and readily available 3ꢀaroylbenzofurans. The key step of this process involves a
baseꢀmediated ring opening of the 3ꢀaroylbenzofurans and subsequent Michael addition of the
resulting 1,3ꢀdicarbonyl intermediate with acrylate/acrylamide followed by the deformylation in
oneꢀpot. The resulting products undergo an acidꢀmediated dehydrative cyclization to arrive at
these targets.
The alkaliꢀmediated ring transformation of the benzofuran skeleton via the opening of the
O(1)–C(2) bond constitutes an interesting area for mechanistic studies [Figure 1].1 This has been
pioneered by Royer and his coꢀworkers in the latter half of the last century.2,3 Specifically, the
benzofurans bearing an electron withdrawing group such as carbonyl at the C(3) undergo a facile
opening of O(1)–C(2) and subsequent dealkanoylation [losing C(2)] followed by dehydrative
ring closure with the carbonyl on C(3) resulting in a new benzofuran derivative wherein the
substituent attached to carbonyl becomes the C(2) substituent [Figure 1a]. This has been
projected as a simple tool for the synthesis of 2ꢀarylbenzofurans. However, its applicability in
synthetic design has not been explored. After a longꢀinterval, in 2015, Chi and coꢀworkers have
tapped into the potential of such a benzofuran ring transformation [Barbier has earlier reported a
similar rearrangement of the natural product marginalin (Figure 1b)]4 to prepare C(2)ꢀsubstituted
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benzofuranꢀ3ꢀcarboxylates which otherwise are prepared in general by crossꢀcoupling chemistry
[Figure 1c].5 In a seminal contribution, Xie and coꢀworkers have identified such an opening and
ring transformation during the amidation of 2ꢀarylbenzofuranꢀ3ꢀcarboxylate intermediate used in
the synthesis of the HCV polymerase inhibitor GSK852A [Figure 1d].6 Given the facile opening
of the 3ꢀaroylbenzofurans [via a Michael addition of hydroxide anion at the C(2) of benzofuran
followed by benzofuran ring opening leading to a phenoxide ion (see Scheme SIꢀ1 for a detailed
mechanism]3b and deformylation with strong alkali bases, we speculated that when mild bases
such as a carbonate were employed, there existed the possibility of trapping the intermediate
enolate of 1,3ꢀdicarbonyl with a Michael acceptor prior to the deformylation.7 The cyclization of
the resulting Michael addition product after the deformylation should result in the synthesis of a
2,3ꢀdisubstituted benzofuran derivative.
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Figure 1. Representative benzofuran ring transformations
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For example, as shown in Scheme 1, when an acrylate is employed as a Michael acceptor
during the ring transformation of 3ꢀbenzoyl benzofuran, the expected product is the 3ꢀ(2ꢀ
phenylbenzofuranꢀ3ꢀyl)propanoate that had been earlier synthesized by a Rhꢀcatalyzed
cyclization of oꢀalkynylphenols followed by intermolecular conjugate addition.8
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Scheme 1. Proposal on interrupting baseꢀmediated benzofuran transformation with Michael
acceptors to synthesize 2,3ꢀdisubstituted benzofurans
With this proposal, our initial experimentation began by screening various solvents
employing benzofuran 1a9 and acrylate 2a as substrates and K2CO3 (5 equiv) as a base. The
reactions were initiated at rt and heated up to 140 °C. For the cases where there was a new
product, the reactions were subjected for a simple aqueous work up and the resulting crude was
immediately treated with 1 equiv of camphorsulphonic acid (CSA) in dichloromethane to obtain
the newly formed benzofuran directly. The reaction of benzofuran 1a with acrylate 2a in the
presence of K2CO3 in 1,2ꢀdichloroethane did not result in the formation of the product either at
room temperature or at 110 ºC (Table 1, entries 1, 2). Further, the reaction in aqueous medium at
110 ºC also failed to generate the desired product (Table 1, entry 3). The reactions in toluene and
1,4ꢀdioxane are not fruitful for the projected transformation (Table 1, entries 4, 5). In polar
solvents like DMSO, NMP and DMF, the formation of a new product was noticed which upon
treatment with CSA gave the intended product in 65%, 57% and 69% yields respectively (Table
1, entries 6–8). Considering the better yields obtained in DMF solvent, further
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optimization/control experiments proceeded with the same solvent. Variable temperature
experiments employing DMF as solvent and K2CO3 as base revealed that the reaction was
incomplete at lower temperatures with 44% and 28% starting material recovered at 100 °C and
120 °C respectively (Table 1, entries 9, 10). Further, on reducing K2CO3 from 5 to 2 equiv, the
formation of product 3aa after CSA cyclization was observed in 73% yield (Table 1, entry 11).
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Table 1. Optimization of reaction conditionsa
entry
1.
base
solvent
1,2ꢀDCE
1,2ꢀDCE
H2O
temp.
rt
yieldb
ꢀꢀ
K2CO3
K2CO3
K2CO3
K2CO3
2.
110 °C
110 °C
140 °C
ꢀꢀ
3.
ꢀꢀ
4.
toluene
ꢀꢀ
5.
K2CO3 1,4ꢀdioxane 140 °C
ꢀꢀ
6.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
DMSO
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
140 °C
140 °C
140 °C
100 °C
120 °C
140 °C
140 °C
140 °C
140 °C
140 °C
140 °C
140 °C
65%
57%
69%
46%c
67%d
73%e
ꢀꢀ
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Cs2CO3
KtOBu
CsOAc
NaOAc
63%
52%
61%f
ꢀꢀ
17. NaHCO3
ꢀꢀ
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aReaction conditions: i) 1a (0.22 mmol), 2a (0.44 mmol), base (1.1 mmol), DMF (3 mL), ꢀ, 16 h. ii) CSA (0.22 mmol), CH2Cl2
(10 mL). bIsolated yields after CSA reaction. cReaction at 100 °C and Yield based on 44% recovered S.M. dReaction at 120 °C and
yield based on 28% recovered 1a. eReaction with (0.44 mmol) of K2CO3. f Yield based on 46% recovered 1a.
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Next examined was the compatibility of other bases for the current transformation. As
shown in Table 1, there was no reaction when NaOAc and NaHCO3 were used as the bases. With
both Cs2CO3 and KtOBu, the reaction proceeds smoothly and provides the final product 3aa in
63% and 52% yields respectively (Table 1, entries 13, 14). On the other hand, with CsOAc, the
reaction was sluggish and recovered 46% of the starting material (Table 1, entry 15) along with
the isolation of 3aa in 61% yield. Further, the compatibility of the Lewis acids for the cyclization
step was examined by employing other Lewis acids such as PTSA, ZnCl2, HCl and Cu(OTf)2. The
reaction proceeded in all cases resulting in the product 3aa in 52%, 68%, 70% and 71% yields
respectively. This suggests that CSA was better and for further experiments we proceeded by
employing the same.
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After optimizing the conditions, the scope of different acrylates, acrylonitrile and
acrylamides has been explored using benzofuran 1a. All these reactions have been carried out by
employing 2 equiv. K2CO3 in DMF at 140 ºC for 16 h (Scheme 2). The crude products that
resulted after the aqueous workups were directly subjected for the cyclization with CSA to get the
desired disubstituted benzofuran. Coming to the different acrylates employed, with methylꢀ, ethyl
acrylates, nearly 33% of the ester hydrolysed product was observed along with the desired
products 3ab, 3ac. In other cases, the reactions proceeded smoothly and provided the
corresponding disubstituted benzofurans in good yields.
Scheme 2. Scope of Michael acceptors and benzofuransa
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aReaction conditions: i) 1 (1 equiv), 2 (2 equiv), DMF (3 mL). ii) CSA (1 equiv for acrylate and 3 equiv for acrylamide), CH2Cl2
b
(10 mL). Isolated yields after CSA reaction. For 3ab, 3ac – the corresponding acid resulting from the ester hydrolysis were
c
obtained in 30% and 32% respectively and the combined yields were given. Yield based on 28% recovered starting material.
dYield based on 24% recovered starting material.
Interestingly, when methyl crotonate 2o was employed as a Michael acceptor, a complex
reaction mixture was obtained10 On the other hand; acrylonitrile was found to be compatible for
the current transformation and provided the corresponding product in 58% yield. Coming to the
acrylamides, initially N,N’ꢀdimethylacrylamide has been employed as the Michael acceptor along
with 1a, which provided the desired benzofuran 3ah in 85% yield. Similarly, the reaction of
benzofuran 1a with other acrylamides 2i–2m proceeded smoothly resulting in the disubstituted
benzofurans 3ai–3am in very good yields. The generality of this methodology has been further
examined by employing benzofuran substrates 1b–1f8 having different substituents either on
benzofuran or on the aroyl phenyl ring and employing the acrylate 2a and acrylamide 2l. With
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benzofurans 1b, 1c, 1e and 1f, the reactions proceeded well and resulted in the isolation of the
corresponding disubstituted benzofurans in good yields. However, in case of benzofuran 1d, the
reactions with both 2a and 2l were sluggish and the starting material was recovered along with
the required product. Prolonged heating during the first step was found to be of no use in this
case. In case of the benzofurans 1g and 1h where the pendant aryl ring has an electron
withdrawing group positioned para to the carbonyl, their reactions with acrylate 1a were found to
be unsuccessful resulting in either complex mixture or the decomposition of the starting
aroylbenzofuran This is anticipated considering the earlier Royer’s report on similar 3ꢀ
aroylbenzofurans which undergo oxidative dearylation under the baseꢀmediated ring
transformation conditions leading to the corresponding benzofuranꢀ3ꢀcarboxylic acid.
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Next, we examined the compatibility of the simple acrylamide under these conditions
employing benzofuran 1b as a substrate (Scheme 3). Interestingly, after following the usual twoꢀ
step sequence, the product isolated in 71% yield was found to be a 12:1 inseparable mixture of
cyclized product 4bn and disubstitued benzofuran 3bn.11 Similarly, when we explored this
reaction with the other benzofurans 1a, 1c–1e, the products obtained were found to be the
separable mixtures of cyclized and uncyclized derivatives in varying proportions. However
benzofuran 1f gave inseparable mixtures of cyclised and uncyclized products. In case of
benzofuran 1d, the reaction was incomplete, with the recovery of the starting material. As
observed with the acrylates, the reaction of benzofuran 1g with acrylamide 2n also led to a
complex mixture.
Scheme 3. Reactions with simple acrylamide and substrate scopea
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aReaction conditions: i) 1 (1 equiv), 2 (2 equiv), DMF (3 mL). ii) CSA (3 equiv), CH2Cl2 (10 mL). Isolated yields after CSA
reaction. bYield based on 48% recovered S.M. The ratio in the parenthesis is that of 4:3.
After having established the proposed hypothesis, next we carried out some control
experiments to track the reaction pathway. As a first step, we conducted experiments to examine
what happens to benzofuran 1a in the absence of a Michael acceptor. As shown in Scheme 4,
heating 1a in DMF along with 2 equiv of K2CO3 at 140 °C for 16 h led to the isolation of the
known deformylated product 612 in 88% yield. This proved the point that K2CO3 is sufficiently
basic enough to open the benzofuran, that the deformylation proceeds as expected under the
current conditions and that the subsequent dehydrative cyclization requires an acid. To learn
about the occurrence of the Michael addition prior or after deformylation, we subjected the
resulting ketone 6 under current conditions in the presence of acrylate 2a. As expected, even
after heating for 16 h, the starting ketone 6 was found to be intact. No traces of the expected
product 3aa were seen after subjecting the crude product isolated from this reaction to CSAꢀ
mediated cyclization. These results suggested that Michael addition with acrylates preceedes
over the deformylation event.
Scheme 4. Control experiments
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In conclusion, we have hypothesized the possibility of trapping the baseꢀmediated ring
opened [O(1)–C(2)] products of 3ꢀaroylbenzofurans with Michael acceptors prior to the
decarbonylation as a simple means of preparing the 3ꢀ(2ꢀarylbenzofuranꢀ3ꢀyl)propanoates and
propanamides and executed it successfully. Acrylates, methacrylates, acrylonitrile and
acrylamides have been found to be suitable Michael acceptors although crotonates are not. Given
the use of simple commercial reagents (including those used in the preparation of starting 3ꢀ
aroylbenzofurans) to arrive at these endꢀproducts and reasonable yields without any metalꢀ
catalysts, the current approach for their synthesis underscores its suitability in preparing these
key intermediates on large scales.
EXPERIMENTAL SECTION
General information:
Airꢀ and/or moistureꢀsensitive reactions were carried out in anhydrous solvents under an
atmosphere of argon in ovenꢀdried glassware. Commercial reagents were used without
purification. DMF was used directly from the commercial bottle and CH2Cl2 distilled over CaH2
was used. Column chromatography was carried out by using silica gel (60−120, 100−200,
1
13
230−400 mesh). H and C NMR chemical shifts are reported in ppm relative to chloroformꢀD
(δ = 7.25) or TMS and coupling constants (J) are reported in hertz (Hz). The following
abbreviations have been used to designate signal multiplicity: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, b = broad. The multiplicity of carbons has been assigned with the help
of DEPT spectra. IR spectra were recorded as films. High Resolution Mass Spectra (HRMS)
were recorded on a Q Exactive Hybrid Quadrupole Orbitrap Mass Spectrometer, where the mass
analyser used for analysis is orbitrap.
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General experimental procedure : 3ꢀAroylbenzo[b]furan (0.1 mmol) was placed in a screw cap
pressure tube and dissolved in DMF (3mL), which was then evacuated and back filled with
argon. To this, were added acrylate or acrylamide (0.2 mmol) and K2CO3 (0.2 mmol) and the
o
contents were stirred at 140 C (bath temperature) for 16 h. The reaction mixture was cooled to
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room temperature, diluted with water and compound extracted using ethylacetate. The combined
organic layer was dried over Na2SO4 and concentrated. The crude reaction mixture, without
column chromatography, was dissolved in CH2Cl2 (10 mL). To this camphorsulphonic acid (0.1
mmol for acrylate/0.3 mmol for acrylamide) was added and stirred for 8 h at room temperature.
After completion of reaction, as indicated by TLC, the reaction mixture was diluted with water
and extracted with CH2Cl2. The combined organic layer was washed with water, dried over
Na2SO4 and concentrated. The resulting crude product was purified by column chromatography
(petroleum ether/ethyl acetate).
tert-Butyl 3-(2-phenylbenzofuran-3-yl)propanoate (3aa): Isolated by column chromatography
1
(petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 73%, (53 mg); Brown liquid; H NMR
(500 MHz, CDCl3): δ 1.42 (s, 9H), 2.63–2.67 (m, 2H), 3.23–3.26 (m, 2H), 7.24–7.27 (m, 1H
(chloroform peak merged)), 7.30 (td, J = 1.4, 8.0 Hz, 1H), 7.38 (tt, J = 1.2, 7.4 Hz, 1H), 7.47–
7.50 (m, 3H), 7.60 (dd, J = 1.1, 7.4 Hz, 1H), 7.80 (dd, J = 1.3, 8.6 Hz, 2H); 13C NMR (125 MHz,
CDCl3): δ 20.0 (t), 28.0 (q, 3C), 35.3 (t), 80.6 (s), 111.1(d), 114.5 (s), 119.6 (d), 122.5 (d), 124.4
(d), 126.9 (d, 2C), 128.3 (d), 128.7 (d, 2C), 130.0 (s), 131.0 (s), 151.0 (s), 153.9 (s), 172.1 (s)
ppm; IR (CHCl3) 692, 744, 1147, 1365, 1453, 1727, 2925 cm–1; HRMS (ESI) calcd for
C21H22O3Na: 345.1461 [M+Na]+; found: 345.1461.
Methyl 3-(2-phenylbenzofuran-3-yl)propanoate (3ab): Isolated by column chromatography
(petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 62%, (20 mg, (32%) ester, 18 mg, (30%)
acid); Pale yellow liquid; 1H NMR (400 MHz, CDCl3): δ 2.72–2.76 (m, 2H), 3.26–3.30 (m, 2H),
3.66 (s, 3H), 7.25 (td, J = 1.1, 7.3 Hz, 1H), 7.30 (td, J = 1.3, 7.5 Hz, 1H), 7.36–7.40 (m, 1H),
7.48 (t, J = 7.7 Hz, 3H), 7.57 (dd, J = 1.1, 7.2 Hz, 1H), 7.77–7.80 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 19.8 (t), 33.8 (t), 51.8 (q), 111.1 (d), 114.2 (s), 119.3 (d), 122.5 (d), 124.5 (d), 126.9
(d, 2C), 128.4 (d), 128.8 (d, 2C), 129.8 (s), 130.9 (s), 151.1 (s), 153.9 (s), 173.2 (s) ppm; IR
(CHCl3) 741, 1213, 1364, 1447, 1733, 3021 cm–1; HRMS (ESI) calcd for C18H16O3Na: 303.0992
[M+Na]+; found: 303.0985.
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Ethyl 3-(2-phenylbenzofuran-3-yl)propanoate (3ac): Isolated by column chromatography
(petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 71%, (26 mg, (39%) ester, 19 mg, (32%)
acid); Pale yellow liquid; 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J = 7.1 Hz, 3H), 2.67 (t, J = 8.2
Hz, 2H), 3.23 (t, J = 8.2 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 7.18–7.22 (m, 1H), 7.23–7.27 (m,
1H), 7.33 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 3H), 7.53 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 7.8
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 14.1 (q), 19.8 (t), 34.1 (t), 60.6 (t), 111.1 (d), 114.3 (s),
119.4 (d), 122.5 (d), 124.5 (d), 126.9 (d, 2C), 128.3 (d), 128.8 (d, 2C), 129.9 (s), 130.9 (s), 151.1
(s), 153.9 (s), 172.8 (s) ppm; IR (CHCl3) 757, 1155, 1367, 1457, 1725, 2925 cm–1; HRMS (ESI)
calcd for C19H19O3: 295.1329 [M+H]+; found: 295.1325.
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Isobutyl 3-(2-phenylbenzofuran-3-yl)propanoate (3ad): Isolated by column chromatography
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(petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 70%, (51 mg); Pale yellow liquid; H
NMR (500 MHz, CDCl3): δ 0.81 (d, J = 6.7 Hz, 6H), 1.81 (sep, J = 6.7 Hz, 1H), 2.68 (t, J = 8.1
Hz, 2H), 3.22 (t, J = 8.2 Hz, 2H), 3.78 (d, J = 6.7 Hz, 2H), 7.17–7.20 (m, 1H), 7.22–7.25 (m,
1H), 7.31 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 3H), 7.51 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.9
Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 19.0 (q, 2C), 19.9 (t), 27.6 (d), 34.1 (t), 70.8 (t), 111.1
(d), 114.3 (s), 119.4 (d), 122.5 (d), 124.5 (d), 126.9 (d, 2C), 128.3 (d), 128.8 (d, 2C), 129.9 (s),
130.9 (s), 151.1 (s), 153.9 (s), 172.9 (s) ppm; IR (CHCl3) 690, 743, 1217, 1368, 1454, 1731,
2963 cm–1; HRMS (ESI) calcd for C21H22O3Na: 345.1461 [M+Na]+; found: 345.1457.
Cyclohexyl
3-(2-phenylbenzofuran-3-yl)propanoate
(3ae):
Isolated
by
column
chromatography (petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 72%, (56 mg); White
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solid; Mp 65–66 °C; H NMR (400 MHz, CDCl3): δ 1.18–1.33 (m, 5H), 1.43–1.47 (m, 1H),
1.59–1.64 (m, 2H), 1.70–1.73 (m, 2H), 2.65 (t, J = 8.2 Hz, 2H), 3.20 (t, J = 8.2 Hz, 2H), 4.68 (m,
1H), 7.16–7.20 (m, 1H), 7.21–7.25 (m, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.39–7.43 (m, 3H), 7.52 (d,
J = 7.4 Hz, 1H), 7.72 (d, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 20.0 (t), 23.7 (t, 2C),
25.3 (t), 31.5 (t, 2C), 34.5 (t), 72.9 (d), 111.1 (d), 114.4 (s), 119.5 (d), 122.5 (d), 124.5 (d), 126.9
(d, 2C), 128.3 (d), 128.8 (d, 2C), 129.9 (s), 131.0 (s), 151.1 (s), 153.9 (s), 172.3 (s) ppm; IR
(CHCl3) 693, 737, 1009, 1056, 1170, 1359, 1448, 1726, 2927 cm–1; HRMS (ESI) calcd for
C23H24O3Na: 371.1618 [M+Na]+; found: 371.1611.
tert-Butyl 2-methyl-3-(2-phenylbenzofuran-3-yl)propanoate (3af): Isolated by column
chromatography (petroleum ether/ethyl acetate = 19:1, Rf = 0.5); Yield 61%, (46 mg); Pale
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yellow liquid; H NMR (500 MHz, CDCl3): δ 1.08 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H), 2.76–2.83
(m, 1H), 2.91 (dd, J = 8.9, 14.4 Hz, 1H), 3.26 (dd, J = 6.3, 14.4 Hz, 1H), 7.16–7.18 (m, 1H), 7.22
(t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.9 Hz, 3H), 7.53 (d, J = 7.6 Hz, 1H),
7.78 (d, J = 7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 16.9 (q), 27.9 (q, 3C), 28.3 (t), 40.5 (d),
80.3 (s), 111.0 (d), 113.8 (s), 120.0 (d), 122.4 (d), 124.4 (d), 126.9 (d, 2C), 128.2 (d), 128.7 (d,
2C), 130.4 (s), 131.1 (s), 151.5 (s), 153.8 (s), 175.4 (s) ppm; IR (CHCl3) 691, 751, 1155, 1366,
1455, 1726, 2928, 2970 cm–1; HRMS (ESI) calcd for C22H24O3Na: 359.1618 [M+Na]+; found:
359.1614.
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3-(2-Phenylbenzofuran-3-yl)propanenitrile (3ag): Isolated by column chromatography
(petroleum ether/ethyl acetate = 9:1, Rf = 0.3); Yield 58%, (32 mg); Brown liquid; 1H NMR (400
MHz, CDCl3): 2.74 (t, J = 7.4 Hz, 2H), 3.32 (t, J = 7.5 Hz, 2H), 7.29 (td, J = 1.1, 7.4 Hz, 1H),
7.34 (td, J = 1.4, 7.3 Hz, 1H), 7.42 (tt, J = 1.4, 7.4 Hz, 1H), 7.48–7.57 (m, 4H), 7.74 (dd, J = 1.4,
8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): 17.4 (t), 20.8 (t), 111.4 (d), 112.1 (s), 118.9 (d),
119.0 (s), 122.9 (d), 124.9 (d), 127.1 (d, 2C), 128.9 (d), 129.0 (d, 2C), 129.1 (s), 130.3 (s), 152.2
(s), 154.0 (s) ppm; IR (CHCl3) 691, 748, 1448, 1639, 2245, 2923, 3420 cm–1; HRMS (ESI) calcd
for C17H13ONNa: 270.0889 [M+Na]+; found: 270.0888.
N,N-Dimethyl-3-(2-phenylbenzofuran-3-yl)propanamide (3ah): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.2); Yield 85%, (56 mg); Yellow
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solid; Mp 64–65 °C; H NMR (400 MHz, CDCl3): δ 2.59 (t, J = 8.2 Hz, 2H), 2.75 (s, 3H), 2.82
(s, 3H), 3.20 (t, J = 8.1 Hz, 2H), 7.11–7.20 (m, 2H), 7.24–7.26 (m, 1H), 7.34–7.39 (m, 3H), 7.46
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(d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.7 Hz, 2H); C NMR (125 MHz, CDCl3): δ 19.9 (t), 32.9 (t),
35.4 (q), 37.1 (q), 111.1 (d), 115.0 (s), 119.4 (d), 122.5 (d), 124.5 (d), 126.7 (d, 2C), 128.2 (d),
128.8 (d, 2C), 130.1 (s), 131.0 (s), 150.9 (s), 153.9 (s), 172.1 (s) ppm; IR (CHCl3) 756, 1145,
1260, 1456, 1641, 2926 cm–1; HRMS (ESI) calcd for C19H20O2N: 294.1489 [M+H]+; found:
294.1487.
N-Phenyl-3-(2-phenylbenzofuran-3-yl)propanamide
(3ai):
Isolated
by
column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 81%, (62 mg); Pale white
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solid; Mp 153–155 °C; H NMR (400 MHz, CDCl3): δ 2.76 (t, J = 7.9 Hz, 2H), 3.40 (t, J = 7.8
Hz, 2H), 7.05–7.09 (m, 2H), 7.22–7.32 (m, 4H), 7.36–7.38 (m, 3H), 7.46–7.51 (m, 3H), 7.61 (d,
J = 7.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 20.0 (t), 37.0 (t), 111.1
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(d), 114.4 (s), 119.5 (d), 120.0 (d, 2C), 122.6 (d), 124.4 (d), 124.6 (d), 126.8 (d, 2C), 128.4 (d),
128.8 (d, 2C), 128.9 (d, 2C), 129.8 (s), 130.8 (s), 137.5 (s), 151.1 (s), 153.9 (s), 170.2 (s) ppm;
IR (CHCl3) 697, 757, 1250, 1446, 1542, 1667, 2925, 3295 cm–1; HRMS (ESI) calcd for
C23H20O2N: 342.1489 [M+H]+; found: 342.1477.
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N-Benzyl-3-(2-phenylbenzofuran-3-yl)propanamide
(3aj):
Isolated
by
column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 69%, (55 mg); White
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solid; Mp 149–151 °C; H NMR (400 MHz, CDCl3): δ 2.56 (t, J = 7.5 Hz, 2H), 3.29 (t, J = 7.6
Hz, 2H), 4.28 (d, J = 5.6 Hz, 2H), 5.52 (br. s., 1H), 7.00–7.01 (m, 2H), 7.16–7.20 (m, 4H), 7.24
(dt, J = 1.2, 8.1 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.41 (dd, J = 7.6, 14.2 Hz, 3H), 7.54 (d, J =
7.36 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 20.3 (t), 36.3 (t), 43.7 (t),
111.1 (d), 114.5 (s), 119.6 (d), 122.6 (d), 124.5 (d), 126.8 (d, 2C), 127.5 (d), 127.7 (d, 2C), 128.4
(d), 128.6 (d, 2C), 128.8 (d, 2C), 130.0 (s), 130.9 (s), 137.9 (s), 151.1 (s), 153.9 (s), 171.7 (s)
ppm; IR (CHCl3) 669, 764, 1215, 1517, 1668, 3022 cm–1; HRMS (ESI) calcd for C24H21O2NNa:
378.1465 [M+Na]+; found: 378.1458.
N-Dodecyl-3-(2-phenylbenzofuran-3-yl)propanamide (3ak)
:
Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.3); Yield 78%, (76 mg); Grey solid;
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Mp 105–106 °C; H NMR (200 MHz, CDCl3): δ 0.93 (t, J = 6.7 Hz, 3H), 1.29–1.35 (m, 20H),
2.61 (t, J = 7.6 Hz, 2H), 3.17 (q, J = 6.6 Hz, 2H), 3.36 (t, J = 7.6 Hz, 2H), 5.38 (t, J = 6.2 Hz,
1H), 7.24–7.35 (m, 2H), 7.37–7.46 (m, 1H), 7.49–7.57 (m, 3H), 7.62–7.66 (m, 1H), 7.84–7.88
(m, 2H); 13C NMR (125 MHz, CDCl3): δ 14.1 (q), 20.4 (t), 22.7 (t), 26.8 (t), 29.2 (t), 29.3 (t, 2C),
29.5 (t), 29.6 (t, 3C), 31.9 (t), 36.3 (t), 39.6 (t), 111.1 (d), 114.6 (s), 119.6 (d), 122.5 (d), 124.5
(d), 126.8 (d, 2C), 128.3 (d), 128.8 (d, 2C), 130.0 (s), 130.9 (s), 151.0 (s), 153.8 (s), 171.8 (s)
ppm; IR (CHCl3) 756, 1458, 1551, 1639, 2853, 2919, 3304 cm–1; HRMS (ESI) calcd for
C29H40O2N: 434.3054 [M+H]+; found: 434.3052.
N-Isopropyl-3-(2-phenylbenzofuran-3-yl)propanamide
(3al):
Isolated
by
column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 71%, (49 mg); White
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solid; Mp 132–134 °C; H NMR (500 MHz, CDCl3): δ 0.97 (d, J = 6.6 Hz, 6H), 2.54 (t, J = 7.6
Hz, 2H), 3.30 (t, J = 7.6 Hz, 2H), 3.95–4.02 (m, 1H), 5.10 (d, J = 6.5 Hz, 1H), 7.24 (td, J = 1.0,
7.4 Hz, 1H), 7.29 (td, J = 1.3, 7.8 Hz, 1H), 7.37 (tt, J = 1.2, 7.4 Hz, 1H), 7.46–7.51 (m, 3H), 7.60
(d, J = 7.6 Hz, 1H), 7.80–7.82 (m, 2H); 13C NMR (125 MHz, CDCl3): 20.3 (q, 2C), 22.6 (t), 36.4
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(d), 41.4 (t), 111.1 (d), 114.7 (s), 119.6 (d), 122.5 (d), 124.5 (d), 126.8 (d, 2C), 128.3 (d), 128.8
(d, 2C), 130.0 (s), 130.9 (s), 151.0 (s), 153.8 (s), 170.9 (s) ppm; IR (CHCl3) 623, 769, 1452,
1636, 2923, 3294, 3387 cm–1; HRMS (ESI) calcd for C20H22O2N: 308.1645 [M+H]+; found:
308.1640.
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N-Cyclohexyl-3-(2-phenylbenzofuran-3-yl)propanamide (3am): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 66%, (52 mg); White
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solid; Mp 183–185°C; H NMR (400 MHz, CDCl3): δ 0.84–0.91 (m, 2H), 0.98–1.04 (m, 1H),
1.16–1.29 (m, 3H), 1.46–1.50 (m, 2H), 1.67–1.70 (m, 2H), 2.51 (t, J = 7.6 Hz, 2H), 3.27 (t, J =
7.6 Hz, 2H), 3.63–3.65 (m, 1H), 5.09 (d, J = 7.2 Hz, 1H), 7.21–7.26 (m, 2H), 7.34 (t, J = 7.4 Hz,
1H), 7.40–7.45 (m, 3H), 7.56 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 20.4 (t), 24.7 (t, 2C), 25.4 (t), 32.9 (t, 2C), 36.5 (t), 48.2 (d), 111.1 (d), 114.7 (s), 119.6
(d), 122.5 (d), 124.5 (d), 126.8 (d, 2C), 128.3 (d), 128.8 (d, 2C), 130.0 (s), 131.0 (s), 151.0 (s),
153.9 (s), 170.9 (s) ppm; IR (CHCl3) 758, 1218, 1548, 1641, 2931, 3288 cm–1; HRMS (ESI)
calcd for C23H26O2N: 348.1958 [M+H]+; found: 348.1955.
tert-Butyl 3-(5-methoxy-2-phenylbenzofuran-3-yl)propanoate (3ba): Isolated by column
chromatography (petroleum ether/ethyl acetate = 9:1, Rf = 0.5); Yield 62%, (43 mg); Pale yellow
liquid; 1H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 2.63 (t, J = 8.2 Hz, 2H), 3.20 (t, J = 8.2 Hz,
2H), 3.88 (s, 3H), 6.89 (dd, J = 2.2, 8.8 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 7.35–7.38 (m, 2H),
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7.47 (t, J = 7.5 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H); C NMR (100 MHz, CDCl3): δ 20.0 (t), 28.0
(q), 28.1 (q, 2C), 35.2 (t), 56.0 (q), 80.6 (s), 102.2 (d), 111.5 (d), 113.0 (d), 114.6 (s), 126.8 (d,
2C), 128.2 (d), 128.7 (d, 2C), 130.5 (s), 131.1 (s), 148.9 (s), 151.9 (s), 155.8 (s), 172.2 (s) ppm;
IR (CHCl3) 759, 1153, 1215, 1469, 1723, 2929 cm–1; HRMS (ESI) calcd for C22H25O4: 353.1747
[M+H]+; found: 353.1745.
N-Isopropyl-3-(5-methoxy-2-phenylbenzofuran-3-yl)propanamide (3bl): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 75%, (50 mg); White
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solid; Mp 193–194 °C; H NMR (400 MHz, CDCl3): δ 0.99 (d, J = 6.6 Hz, 6H), 2.52 (t, J = 7.6
Hz, 2H), 3.26 (t, J = 7.7 Hz, 2H), 3.87 (s, 3H), 3.94–4.05 (m, 1H), 5.12 (d, J = 6.5 Hz, 1H), 6.89
(dd, J = 2.5, 8.8 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.34–7.37 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H),
7.78 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 20.3 (t), 22.6 (q, 2C), 36.4 (t), 41.4 (d),
56.1 (q), 102.1 (d), 111.5 (d), 113.2 (d), 114.9 (s), 126.7 (d, 2C), 128.3 (d), 128.8 (d, 2C), 130.5
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(s), 131.0 (s), 148.8 (s), 151.8 (s), 155.9 (s), 171.0 (s) ppm; IR (CHCl3) 767, 1216, 1467, 1554,
1636, 2966, 3293 cm–1; HRMS (ESI) calcd for C21H24O3N: 338.1751 [M+H]+; found: 338.1745.
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column chromatography (petroleum ether/ethyl acetate = 9:1, Rf = 0.4); Yield 77%, (46 mg);
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Brown liquid; H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 2.60 (t, J = 8.0 Hz, 2H), 3.16 (t, J =
8.0 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.86 (dd, J = 2.4, 8.8 Hz, 1H), 7.00 (dd, J = 3.0, 5.9 Hz,
3H), 7.34 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 20.0 (t),
28.0 (q, 3C), 35.2 (t), 55.3 (q), 56.0 (q), 80.6 (s), 102.1 (d), 111.3 (d), 112.4 (d), 113.2 (s), 114.2
(d, 2C), 123.8 (s), 128.3 (d, 2C), 130.7 (s), 148.7 (s), 152.1 (s), 155.8 (s), 159.6 (s), 172.3 (s)
ppm; IR (CHCl3) 672, 763, 1030, 1165, 1216, 1252, 1468, 1608, 1720, 2972, 3018 cm–1; HRMS
(ESI) calcd for C23H27O5: 383.1853 [M+H]+; found: 383.1847.
N-Isopropyl-3-(5-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)propanamide
(3cl):
Isolated by column chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.4); Yield 60%,
(39 mg); Light brown solid; Mp 136–137 °C; 1H NMR (400 MHz, CDCl3): δ 0.98 (d, J = 6.5 Hz,
6H), 2.50 (t, J = 7.5 Hz, 2H), 3.22 (t, J = 7.5 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.94–4.03 (m,
1H), 5.12 (d, J = 6.6 Hz, 1H), 6.86 (dd, J = 0.6, 8.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 3H), 7.34 (d, J
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= 8.8 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H); C NMR (125 MHz, CDCl3): δ 20.3 (t), 22.6 (q, 2C),
36.3 (t), 41.4 (d), 55.3 (q), 56.0 (q), 102.0 (d), 111.3 (d), 112.5 (d), 113.3 (s), 114.3 (d, 2C),
123.7 (s), 128.2 (d, 2C), 130.7 (s), 148.6 (s), 152.0 (s), 155.8 (s), 159.6 (s), 171.1 (s) ppm; IR
(CHCl3) 761, 1030, 1215, 1466, 1644, 2925, 3022, 3408 cm–1; HRMS (ESI) calcd for
C22H26O4N: 368.1856 [M+H]+; found: 368.1854.
tert-Butyl 3-(5-methoxy-2-phenylnaphtho[1,2-b]furan-3-yl)propanoate (3da): Isolated by
column chromatography (petroleum ether/ethyl acetate = 9:1, Rf = 0.5); Yield 60%, (29 mg), 14
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mg S.M recovered; Light brown solid; Mp 124–126 °C; H NMR (500 MHz, CDCl3): δ 1.43 (s,
9H), 2.67 (t, J = 7.7 Hz, 2H), 3.29 (t, J = 7.7 Hz, 2H), 4.07 (s, 3H), 6.94 (s, 1H), 7.37 (t, J = 6.7
Hz, 1H), 7.46–7.51 (m, 3H), 7.60 (t, J = 7.1 Hz, 1H), 7.85 (d, J = 7.3 Hz, 2H), 8.30 (t, J = 9.6
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Hz, 2H); C NMR (125 MHz, CDCl3): δ 20.1 (t), 28.1 (q, 3C), 35.5 (t), 56.0 (q), 80.6 (s), 95.3
(d), 116.1 (s), 119.8 (d), 121.6 (s), 123.1 (d), 124.2 (s), 124.5 (d), 124.7 (s), 126.5 (d, 2C), 126.9
(d), 127.8 (d), 128.8 (d, 2C), 131.4 (s), 144.4 (s), 150.5 (s), 152.1 (s), 172.3 (s) ppm; IR (CHCl3)
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667, 758, 1143, 1216, 1367, 1732, 2926, 2965 cm–1; HRMS (ESI) calcd for C26H27O4: 403.1904
[M+H]+; found: 403.1900.
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N-Isopropyl-3-(5-methoxy-2-phenylnaphtho[1,2-b]furan-3-yl)propanamide (3dl): Isolated
by column chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.5); Yield 81%, (40 mg),
12 mg S.M recovered; Brown solid; Mp 190–192 °C; 1H NMR (400 MHz, CDCl3): δ 0.96 (d, J =
6.6 Hz, 6H), 2.56 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 3.96–4.03 (m, 1H), 4.06 (s, 3H),
5.13 (d, J = 7.0 Hz, 1H), 6.96 (s, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.46–7.52 (m, 3H), 7.60 (t, J = 7.6
Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 8.29 (t, J = 9.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 20.5
(t), 22.6 (q, 2C), 36.7 (t), 41.4 (d), 56.0 (q), 95.4 (d), 116.4 (s), 119.9 (d), 121.6 (s), 123.2 (d),
124.3 (s), 124.6 (d), 124.8 (s), 126.4 (d, 2C), 126.9 (d), 127.9 (d), 128.9 (d, 2C), 131.4 (s), 144.3
(s), 150.4 (s), 152.2 (s), 171.1 (s) ppm; IR (CHCl3) 623, 763, 1224, 1377, 1456, 1639, 2928,
2967, 3293 cm–1; HRMS (ESI) calcd for C25H26O3N: 388.1907 [M+H]+; found: 388.1905.
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tert-Butyl 3-(6-methyl-2-phenylbenzofuran-3-yl)propanoate (3ea): Isolated by column
chromatography (petroleum ether/ethyl acetate = 9:1, Rf = 0.5); Yield 63%, (45 mg); Pale yellow
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liquid; H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 2.49 (s, 3H), 2.62–2.66 (m, 2H), 3.20–3.24
(m, 2H), 7.08 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.46–7.49 (m, 3H), 7.78
(d, J = 7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 20.0 (t), 21.7 (q), 28.0 (q, 3C), 35.3 (t), 80.6
(s), 111.3 (d), 114.4 (s), 119.1 (d), 123.8 (d), 126.7 (d, 2C), 127.5 (s), 128.0 (d), 128.7 (d, 2C),
131.2 (s), 134.7 (s), 150.4 (s), 154.3 (s), 172.2 (s) ppm; IR (CHCl3) 748, 1148, 1216, 1366, 1727,
2971 cm–1; HRMS (ESI) calcd for C22H24O3Na: 359.1618 [M+Na]+; found: 359.1614.
N-Isopropyl-3-(6-methyl-2-phenylbenzofuran-3-yl)propanamide (3el): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.5); Yield 59%, (40 mg); White
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solid; Mp 164–165 °C; H NMR (400 MHz, CDCl3): δ 0.98 (d, J = 6.5 Hz, 6H), 2.47 (s, 3H),
2.52 (t, J = 7.8 Hz, 2H), 3.27 (t, J = 7.8 Hz, 2H), 3.94–4.02 (m, 1H), 5.18 (br. d, J = 6.8 Hz, 1H),
7.06 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.33–7.36 (m, 1H), 7.44–7.49 (m, 3H), 7.77–7.79 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 20.4 (t), 21.7 (q), 22.6 (q, 2C), 36.4 (t), 41.4 (d), 111.3 (d), 114.6
(s), 119.1 (d), 123.9 (d), 126.6 (d, 2C), 127.5 (s), 128.1 (d), 128.8 (d, 2C), 131.1 (s), 134.8 (s),
150.4 (s), 154.3 (s), 171.1 (s) ppm; IR (CHCl3) 762, 1217, 1545, 1639, 2925, 3293 cm–1; HRMS
(ESI) calcd for C21H24O2N: 322.1802 [M+H]+; found: 322.1802.
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tert-Butyl
3-(2-(m-tolyl)benzofuran-3-yl)propanoate
(3fa):
Isolated
by
column
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chromatography (petroleum ether/ethyl acetate = 9:1, Rf = 0.5); Yield 53%, (38 mg); Pale yellow
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liquid; H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 2.44 (s, 3H), 2.63–2.67 (m, 2H), 3.22–3.26
(m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 7.25 (ddd, J = 1.1, 6.6, 7.5 Hz, 1H), 7.30 (td, J = 1.5, 7.7 Hz,
1H), 7.37 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.58–7.62 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 20.0 (t), 21.6 (q), 28.0 (q, 3C), 35.3 (t), 80.6 (s), 111.0 (d), 114.4 (s), 119.5 (d), 122.4
(d), 124.1 (d), 124.3 (d), 127.6 (d), 128.6 (d), 129.1 (d), 130.0 (s), 130.9 (s), 138.4 (s), 151.2 (s),
153.9 (s), 172.2 (s) ppm; IR (CHCl3) 744, 1148, 1217, 1365, 1453, 1726, 2928, 2972 cm–1;
HRMS (ESI) calcd for C22H24O3Na: 359.1618 [M+Na]+; found: 359.1614.
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N-Isopropyl-3-(2-(m-tolyl)benzofuran-3-yl)propanamide (3fl): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.5); Yield 62%, (42 mg); White
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solid; Mp 125–126 °C; H NMR (400 MHz, CDCl3): δ 0.97 (d, J = 6.6 Hz, 6H), 2.43 (s, 3H),
2.53 (t, J = 7.7 Hz, 2H), 3.29 (t, J = 7.7 Hz, 2H), 3.94–4.03 (m, 1H), 5.17 (d, J = 6.9 Hz, 1H),
7.19 (d, J = 7.6 Hz, 1H), 7.23 (td, J = 7.4, 0.9 Hz, 1H), 7.28 (td, J = 7.4, 1.6 Hz, 1H), 7.36 (t, J =
13
7.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.58–7.63 (m, 3H); C NMR (100 MHz, CDCl3): δ 20.3
(t), 21.6 (q), 22.6 (q, 2C), 36.4 (t), 41.3 (d), 111.0 (d), 114.6 (s), 119.6 (d), 122.5 (d), 123.9 (d),
124.4 (d), 127.4 (d), 128.7 (d), 129.1 (d), 130.0 (s), 130.8 (s), 138.5 (s), 151.1 (s), 153.8 (s),
171.0 (s) ppm; IR (CHCl3) 744, 1217, 1368, 1454, 1645, 2926, 3299 cm–1; HRMS (ESI) calcd
for C21H24O2N: 322.1802 [M+H]+; found: 322.1801.
9a-Phenyl-3,4,4a,9a-tetrahydrobenzofuro[2,3-b]pyridin-2(1H)-one (4an): Isolated by column
chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.4); Yield 80%, (48 mg); Brown
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gummy liquid; H NMR (500 MHz, CDCl3): δ 2.18–2.33 (m, 4H), 3.68 (br. s., 1H), 6.35 (br. s.,
1H), 6.86 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.7
13
Hz, 1H), 7.29–7.35 (m, 3H), 7.49 (d, J = 7.2 Hz, 2H); C NMR (125 MHz, CDCl3): δ 22.5 (t),
27.3 (t), 47.7 (d), 98.7 (s), 110.2 (d), 121.8 (d), 123.8 (d), 125.1 (d, 2C), 126.6 (s), 128.8 (d, 2C),
129.0 (d), 129.3 (d), 142.2 (s), 158.0 (s), 173.1 (s) ppm; IR (CHCl3) 761, 1229, 1470, 1670,
2928, 3387 cm–1; HRMS (ESI) calcd for C17H16O2N: 266.1176 [M+H]+; found: 266.1172.
Inseparable mixture of 6-methoxy-9a-phenyl-3,4,4a,9a-tetrahydrobenzofuro[2,3-b]pyridin-
2(1H)-one (4bn) and 3-(5-methoxy-2-phenylbenzofuran-3-yl)propanamide (3bn): Isolated
by column chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.4); Yield 71%, (42 mg) ;
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Brown solid; Mp 103–107 °C; 1H NMR (500 MHz, CDCl3): δ 2.19–2.27 (m, 2H), 2.29–2.42 (m,
2H), 2.68–2.71 (m, 0.16H), 3.18–3.21 (m, 0.16H), 3.71 (t, J = 4.5 Hz, 1H), 3.77 (s, 3H), 3.84 (s,
0.23H), 6.45 (br. s., 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 2.3, 8.7 Hz, 1H), 6.83 (d, J = 8.6
Hz, 1H), 6.88 (dd, J = 2.4, 8.8 Hz, 0.08H), 6.99 (d, J = 2.2 Hz, 0.09H), 7.35–7.41 (m, 3H), 7.45
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(d, J = 7.7 Hz, 0.14H), 7.55 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.8 Hz, 0.17H); C NMR (125
MHz, CDCl3): δ 19.7 (t), 22.2 (t), 27.3 (t), 33.7 (t), 48.1 (d), 56.0 (q), 98.9 (s), 101.8 (d), 110.0
(d), 110.3 (d), 111.5 (d), 113.2 (d), 113.9 (d), 114.5 (s), 125.1 (d, 2C), 126.7 (d, 2C) 127.6 (s),
128.2 (d), 128.7 (d, 2C), 128.8 (d, 2C), 128.9 (d), 142.2 (s), 148.8 (s), 151.9 (s), 152.0 (s), 155.1
(s), 155.8 (s), 173.0 (s) ppm; IR (CHCl3) 764, 1213, 1484, 1673, 2931, 3219 cm–1; HRMS (ESI)
calcd for C18H17O3NNa: 318.1101 [M+Na]+; found: 318.1095.
6-Methoxy-9a-(4-methoxyphenyl)-3,4,4a,9a-tetrahydrobenzofuro[2,3-b]pyridin-2(1H)-one
(4cn): Isolated by column chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.3); Yield
40%, (23 mg); White solid; Mp 163–166 °C; 1H NMR (500 MHz, CDCl3): δ 2.19–2.22 (m, 2H),
2.29–2.37 (m, 2H), 3.68 (t, J = 4.2 Hz, 1H), 3.77 (s, 3H), 3.81 (s, 3H), 6.13 (s, 1H), 6.67 (d, J =
2.0 Hz, 1H), 6.75 (dd, J = 2.4, 8.7 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H),
7.47 (d, J = 8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): 22.1 (t), 27.3 (t), 48.2 (d), 55.4 (q), 56.0
(q), 99.0 (s), 110.1 (d), 110.4 (d), 113.9 (d), 114.0 (d, 2C), 126.5 (d, 2C), 127.7 (s), 134.3 (s),
152.0 (s), 155.1 (s), 160.0 (s), 172.8 (s) ppm; IR (CHCl3) 623, 1029, 1252, 1480, 1600, 1670,
2923, 3329 cm–1; HRMS (ESI) calcd for C19H20O4N: 326.1387 [M+H]+; found: 326.1386.
3-(5-methoxy-2-(4-methoxyphenyl)benzofuran-3-yl)propanamide (3cn): Isolated by column
chromatography (petroleum ether/ethyl acetate = 1:1, Rf = 0.3); Yield 43%, (25 mg); Pale white
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solid; Mp 164–165 °C; H NMR (500 MHz, CDCl3): δ 2.61 (t, J = 8.1 Hz, 2H), 3.24 (t, J = 7.9
Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 5.27–5.32 (m, 2H), 6.86 (dd, J = 2.6, 8.8 Hz, 1H), 6.99–7.00
(m, 3H), 7.35 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): 19.9
(t), 35.1 (t), 55.3 (q), 56.0 (q), 101.9 (d), 111.4 (d), 112.5 (d), 113.0 (s), 114.3 (d, 2C), 123.6 (s),
128.2 (d, 2C), 130.6 (s), 148.7 (s), 152.1 (s), 155.8 (s), 159.6 (s), 174.4 (s) ppm; IR (CHCl3) 763,
1215, 1468, 1649, 2927, 3407 cm–1; HRMS (ESI) calcd for C19H19O4NNa: 348.1206 [M+Na]+;
found: 348.1203.
5-Methoxy-10a-phenyl-7,8,10,10a-tetrahydronaphtho[2',1':4,5]furo[2,3-b]pyridin-9(6bH)-
one (4dn): Isolated by column chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.3);
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Yield 39%, (23 mg); Brown solid; Decomposed at 235 °C; 1H NMR (500 MHz, CDCl3): δ 2.28–
2.34 (m, 3H), 2.38–2.42 (m, 1H), 3.91 (br. S, 1H), 3.96 (s, 3H), 6.36 (s, 1H), 6.57 (s, 1H), 7.36–
7.42 (m, 3H), 7.48–7.56 (m, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.97 (d, J = 8.2 Hz, 1H), 8.23 (d, J =
8.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): 23.1 (t), 27.6 (t), 49.4 (d), 56.0 (q), 98.8 (s), 99.3 (d),
118.0 (s), 120.8 (s), 121.3 (d), 122.7 (d), 125.1 (d, 2C), 125.7 (d), 126.1 (s), 126.6 (d), 128.9 (d,
2C), 128.9 (d), 142.7 (s), 147.2 (s), 151.4 (s), 173.6 (s) ppm; IR (CHCl3) 670, 764, 1215, 1652,
3021, 3412 cm–1; HRMS (ESI) calcd for C22H19O3NNa: 368.1257 [M+Na]+; found: 368.1255.
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3-(5-methoxy-2-phenylnaphtho[1,2-b]furan-3-yl)propanamide (3dn): Isolated by column
chromatography (petroleum ether/ethyl acetate = 1:1, Rf = 0.3); Yield 20%, (11 mg); Brown
solid; Decomposed at 173 °C; 1H NMR (500 MHz, CDCl3): δ 2.66 (t, J = 7.7 Hz, 2H), 3.37 (t, J
= 7.7 Hz, 2H), 4.06 (s, 3H), 5.34 (br. s., 2H), 6.95 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.50 (t, J =
7.8 Hz, 3H), 7.60 (t, J = 7.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 8.28 (d, J = 8.2 Hz, 1H), 8.30 (d, J
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= 8.5 Hz, 1H); C NMR (125 MHz, CDCl3): δ 20.1 (t), 35.5 (t), 56.0 (q), 95.2 (d), 116.0 (s),
119.8 (d), 121.6 (s), 123.1 (d), 124.3 (s), 124.7 (d), 126.4 (d, 2C), 127.0 (d), 127.9 (d), 128.9 (d,
2C), 128.9 (s), 131.4 (s), 144.4 (s), 150.5 (s), 152.2 (s), 174.3 (s) ppm; IR (CHCl3) 623, 770,
1646, 2926, 3421 cm–1; HRMS (ESI) calcd for C22H20O3N: 346.1438 [M+H]+; found: 346.1433.
7-Methyl-9a-phenyl-3,4,4a,9a-tetrahydrobenzofuro[2,3-b]pyridin-2(1H)-one (4en): Isolated
by column chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.3); Yield 61%, (36 mg);
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Brown gummy liquid; H NMR (500 MHz, CDCl3): δ 2.19–2.24 (m, 2H), 2.25–2.33 (m, 2H),
2.35 (s, 3H), 3.70 (br. s, 1H), 6.31 (br. s., 1H), 6.75 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.98 (d, J =
13
7.5 Hz, 1H), 7.35–7.41 (m, 3H), 7.55 (d, J = 7.4 Hz, 2H); C NMR (125 MHz, CDCl3): δ 21.6
(q), 22.6 (t), 27.3 (t), 47.5 (d), 98.9 (s), 110.9 (d), 122.5 (d), 123.4 (d), 123.5 (s), 125.1 (d, 2C),
128.8 (d, 2C), 128.9 (d), 139.6 (s), 142.3 (s), 158.3 (s), 173.1 (s) ppm; IR (CHCl3) 700, 759, 945,
1262, 1453, 1673, 2924, 3216 cm–1; HRMS (ESI) calcd for C18H18O2N: 280.1332 [M+H]+;
found: 280.1330.
Inseparable mixture of 9a-(m-Tolyl)-3,4,4a,9a-tetrahydrobenzofuro[2,3-b]pyridin-2(1H)-
one (4fn) & 3-(2-(m-Tolyl)benzofuran-3-yl)propanamide (3fn): Isolated by column
chromatography (petroleum ether/ethyl acetate = 6:4, Rf = 0.3); Yield 54%, (32 mg); Brown
gummy liquid; 1H NMR (400 MHz, CDCl3): δ 2.18–2.27 (m, 4H), 2.30 (s, 3H), 2.35 (s, 0.75H),
2.67 (t, J = 8.2 Hz, 0.45H), 3.18 (t, J = 7.9 Hz, 0.45H), 3.68 (br. s., 1H), 6.52 (br. s., 1H), 6.87 (d,
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J = 7.9 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1.35H),
7.16–7.24 (m, 3.11H), 7.29 (d, J = 8.4 Hz, 2.44H), 7.42 (d, J = 8.0 Hz, 0.31H), 7.48–7.53 (m,
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0.83H); C NMR (100 MHz, CDCl3): δ 19.7 (t), 21.5 (q), 21.6 (q), 22.3 (t), 27.3 (t), 33.8 (t),
47.7 (d), 98.8 (s), 110.3 (d), 111.1 (d), 114.1 (s), 119.4 (d), 121.8 (d), 122.2 (d), 122.5 (d), 123.8
(d), 124.0 (d), 124.4 (d), 125.8 (d), 126.6 (s), 127.6 (d), 128.7 (d), 128.8 (d), 129.2 (d), 129.3 (d),
129.7 (d), 129.9 (s), 130.8 (s), 138.5 (s), 138.7 (s), 142.1 (s), 151.4 (s), 153.9 (s), 158.1 (s), 173.4
(s), 176.6 (s) ppm; IR (CHCl3) 749, 1460, 1480, 1641, 3442 cm–1; HRMS (ESI) calcd for
C18H18O2N: 280.1332 [M+H]+; found: 280.1330.
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3-(2-Phenylbenzofuran-3-yl)propanoic acid (9): Isolated by column chromatography
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(petroleum ether/ethyl acetate = 8:2, Rf = 0.3); Light brown solid; Mp 104–105 °C; H NMR
(400 MHz, CDCl3): 2.83 (t, J = 8.3 Hz, 2H), 3.33 (t, J = 8.0 Hz, 2H), 7.29–7.31 (m, 1H), 7.33–
7.36 (m, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.51–7.55 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.81 (d, J =
7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): 19.6 (t), 33.7 (t), 111.2 (d), 113.9 (s), 119.3 (d),
122.6 (d), 124.6 (d), 126.9 (d, 2C), 128.4 (d), 128.8 (d, 2C), 129.8 (s), 130.9 (s), 151.3 (s), 153.9
(s), 178.3 (s) ppm; IR (CHCl3) 756, 1153, 1250, 1452, 1678, 2926, 3408 cm–1; HRMS (ESI)
calcd for C17H14O3Na: 289.0835 [M+Na]+; found: 289.0833.
tert-Butyl 4-(2-hydroxyphenyl)-5-oxo-5-phenylpentanoate (7): Isolated by column
chromatography (petroleum ether/ethyl acetate = 8:2, Rf = 0.3); Yield 82%, (63 mg); Pale yellow
liquid; 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 2.12–2.29 (m, 3H), 2.36–2.44 (m, 1H), 4.94
(t, J = 7.0 Hz, 1H), 6.78 (dt, J = 0.9, 7.4 Hz, 1H), 6.93–6.98 (m, 2H), 7.09–7.13 (m, 1H), 7.39 (t,
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J = 7.6 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.99–8.01 (m, 3H); C NMR (100 MHz, CDCl3): δ
27.0 (t), 28.0 (q, 3C), 32.7 (t), 47.1 (d), 81.3 (s), 117.9 (d), 120.9 (d), 124.8 (s), 128.6 (d, 2C),
128.8 (d, 2C), 128.9 (d), 129.2 (d), 133.5 (d), 136.0 (s), 154.4 (s), 174.1 (s), 201.6 (s) ppm; IR
(CHCl3) 623, 692, 1153, 1248, 1593, 1676, 2926, 3413 cm–1; HRMS (ESI) calcd for
C21H24O4Na: 363.1567 [M+Na]+; found: 363.1562.
4-(2-Hydroxyphenyl)-N-isopropyl-5-oxo-5-phenylpentanamide (8): Isolated by column
chromatography (petroleum ether/ethyl acetate = 7:3, Rf = 0.3); Yield 85%, (62 mg); Light
brown solid; Mp 164–165 °C; 1H NMR (500 MHz, CDCl3): δ 1.14 (d, J = 6.6 Hz, 3H), 1.16 (d, J
= 6.6 Hz, 3H), 2.07–2.11 (m, 1H), 2.14–2.21 (m, 2H), 2.27–2.34 (m, 1H), 4.05–4.14 (m, 1H),
5.10 (dd, J = 5.7, 8.5 Hz, 1H), 5.62 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.86 (dd, J =
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1.5, 7.7 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 7.07–7.11 (m, 1H), 7.34 (t, J = 7.7 Hz, 2H), 7.44 (t, J
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= 7.4 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 9.70 (s, 1H); C NMR (100 MHz, CDCl3): δ 22.5 (q,
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2C), 28.5 (t), 33.1 (t), 41.9 (d), 45.3 (d), 118.5 (d), 120.7 (d), 125.6 (s), 127.8 (d), 128.5 (d, 2C),
128.8 (d, 3C), 133.1 (d), 135.8 (s), 154.7 (s), 173.5 (s), 200.3 (s) ppm; IR (CHCl3) 766, 1452,
1592, 1629, 2923, 3374 cm–1; HRMS (ESI) calcd for C20H23O3NNa: 348.1570 [M+Na]+; found:
348.1564.
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2-(2-Hydroxyphenyl)-1-phenylethan-1-one (6): Isolated by column chromatography
(petroleum ether/ethyl acetate = 9:1, Rf = 0.5); Yield 88%, (42 mg); Light yellow solid; Mp 107–
108 °C; 1H NMR (400 MHz, CDCl3): δ 4.28 (s, 2H), 6.87 (td, J = 1.2, 7.4 Hz, 1H), 6.95 (dd, J =
1.2, 8.6 Hz, 1H), 7.15–7.18 (m, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.61 (tt, J = 1.2, 7.3 Hz, 1H), 7.69
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(s, 1H), 8.08–8.10 (m, 2H); C NMR (100 MHz, CDCl3): δ 41.1 (t), 117.7 (d), 120.8 (d), 121.0
(s), 128.8 (d, 2C), 129.1 (d, 3C), 131.0 (d), 134.1 (d), 135.8 (s), 155.6 (s), 201.2 (s) ppm; IR
(CHCl3) 738, 1007, 1208, 1446, 1674, 2918, 3408, 3672 cm–1; HRMS (ESI) calcd for
C14H12O2Na: 235.0730 [M+Na]+; found: 235.0728.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
•
1H/13C NMR and HRMS spectra for all new compounds (PDF).
• Xꢀray crystallographic file for compound 4dn
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: vr.chepuri@ncl.res.in
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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We acknowledge CSIR (India) for funding this project under 12FYP NICE program (CSC0108)
and for a research fellowship to KS, and thank Dr. Rajesh G. Gonnade for the crystallographic
studies.
9
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