Stitching Ynones with Nitromethanes: Domino Synthesis of Functionally Enriched Benzofurans and Benzothiophenes

Article abstract of DOI:10.1021/acs.joc.1c01104

A convenient one-pot benzannulation of regioisomeric 2- or 3-substituted furan and thiophene ynones with a range of nitromethanes has been discovered to directly access densely and diversely functionalized benzofurans and benzothiophenes. In this protocol, the nitro group in nitromethanes functions as recursive carbanion activator to setup tandem Michael addition-6π-electrocyclization, and its eventual sacrificial elimination facilitates aromatization and overall benzannulation. This benzannulation was also explored with furan/thiophene based o-halo ynones wherein a Michael addition-SNAr process operates and nitromethanes leave their imprint to deliver nitro substituted benzo-furans and -thiophenes.

Full text of DOI:10.1021/acs.joc.1c01104

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Article
Stitching Ynones with Nitromethanes: Domino Synthesis of
Functionally Enriched Benzofurans and Benzothiophenes
Shweta Singh, Sharanya Nerella, Srihari Pabbaraja,* and Goverdhan Mehta*
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ABSTRACT: A convenient one-pot benzannulation of regioisomeric 2- or 3-substituted furan and thiophene ynones with a range of
nitromethanes has been discovered to directly access densely and diversely functionalized benzofurans and benzothiophenes. In this
protocol, the nitro group in nitromethanes functions as recursive carbanion activator to setup tandem Michael addition-6π-
electrocyclization, and its eventual sacrificial elimination facilitates aromatization and overall benzannulation. This benzannulation
was also explored with furan/thiophene based o-halo ynones wherein a Michael addition-SNAr process operates and nitromethanes
leave their imprint to deliver nitro substituted benzo-furans and -thiophenes.
diabetes and as antibacterials among others. Benzothiophenes
are also part of many useful materials, e.g., end group caps in
organic solar cells.7
INTRODUCTION
■
Among heterocyclic compounds, benzofurans are considered
as privileged structural motifs and are frequently encountered
among natural products and pharmaceuticals in their myriad
substitution patterns and with diverse add-on appendages.
Such pharmacophoric constructs engage many targets and key
pathways to display a wide array of biological activities that
range from anti-inflammatory, antibacterial, antimicrobial,
antitumor, anticonvulsant, etc.1,2 Indeed, there are estimated
30 FDA approved drugs that are based on benzofuran motif.2
Recently, several benzofuran derivatives have been implicated
as inhibitors of protein tyrosine phosphatases (PTPs), in the
etiology of diabetes mellitus and neural diseases like
Alzheimer’s and Parkinson’s as well as regulation of allergy
and inflammation, thereby opening future possibilities with this
scaffold.3 Benzofurans have also shown promise as radio tracer
ligands for Positron Emission Tomography (PET) in
diagnostics.2 Some representative examples of bioactive
benzofurans are gathered in Figure 1. Interestingly, benzothio-
phenes, the sulfur containing siblings of benzofurans also
exhibit PTPs inhibitory activity4 besides diverse bioactivity
profile of their own and find application in medicine5 and in
material science.6 For example, sertaconazole is an antifungal
drug in dermatology/gynecology and raloxifene is used in the
prevention of osteoporosis and exhibits promising leads in
Owing to their growing importance as pharmaceuticals and
in material science benzofurans and benzothiophenes have
been targets of numerous synthetic approaches in recent
years.8−10 The more commonly pursued methodology to these
scaffolds involves heteroannulation of either a furan or
thiophene ring on to a preassembled aryl precursor or
“front-to-back” type approach9,11 and many variations of this
tactic have been demonstrated in diverse contexts. On the
other hand, an alternate tactic involving benzannulation of
either furan or thiophene, “back-to-front” type approach has
been lesser explored10,11 despite its inherent advantage in
delivering dense and variegated functionalization on the aryl
ring which can otherwise be problematic, thereby underscoring
the need for devising newer “back-to-front” type11 approaches
Received: June 17, 2021
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© XXXX American Chemical Society
A

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Figure 1. Representative benzofuran and benzothiophene natural products and pharmaceuticals.
Scheme 1. Selected Benzannulation Approaches to Benzofurans and Benzothiophenes
Scheme 2. New Approach to Benzofurans and Benzothiophenes
to bioactive benzofurans and benzothiophenes (Scheme 1). A
selection of recently disclosed benzannulation protocols on
furan and thiophene based platforms are featured in (Scheme
1).
B
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Recently, we have unveiled a one-pot, domino benzannula-
tion approach12 to polyfunctional aromatics via intramolecular
strapping of o-halo-arylynones (acting as dual acceptor for a
tandem Michael addition and SNAr substitution) with
nitromethanes (one-carbon source and a dual donor) and
applied it toward a general synthesis of carbazoles,12d
naphthalenes,12e quinolines, and isoquinolines.12c While
adapting this approach to furan and thiophene derived o-
haloarylynones to deliver benzofurans and benzothiophenes,
respectively, through tandem Michael addition-SNAr protocol
as shown in (Scheme 2a) (see also, vide infra), we have
discovered a new one-pot benzannulation variant that directly
delivers benzofurans and benzothiophenes from the corre-
sponding furan and thiophene ynones, bereft of any additional
functionality, in the presence of base and nitromethanes.
Interception through a 6-π-electrocyclization process and a
sacrificial nitro group elimination facilitating aromatization are
possibly the key events leading to the products, see Scheme 2b.
Interestingly, these benzannulations proceed with equal facility
with both 2- or 3-substituted furan and thiophene ynones,
thereby shuffling functionalities and providing access to
functionality at all the positions of the arene ring of
benzofurans and benzothiophenes. The generality of this de
novo synthesis of benzo-furans and -thiophenes has been
broadly probed (42 examples), and the findings are disclosed
in this report. It may also be noted that o-haloarylynones have
been attracting attention owing to their use as handy tools in
different contexts for building several interesting scaffolds.13
Scheme 3. Benzofurans and Benzothiophenes Synthesis
from Furan- and Thiophene-3-ynones
RESULTS AND DISCUSSION
■
During a pilot experiment, involving reaction between furan 3-
ynone 10a [1-(furan-3-yl)-3-phenylprop-2-yn-1-one] and
nitromethane 11a in the presence of a base, unexpected
formation of benzofuran 12a was observed, and we set out to
optimize the reaction by varying bases, solvents, and
temperature, and Cs2CO3 in DMF at 90 °C was found to be
the optimal condition (see optimization table, SI) that led to
the formation of 6-phenylbenzofuran-4-ol 12a in 76% yield
(Scheme 3). Encouraged by this unanticipated but welcome
outcome, the reaction was initially explored through reaction
of ynone 10a with nitromethanes 11b−d to furnish the
corresponding 4,6,7-trisubstituted benzofurans 12b−d in
comparable yields. To further scope the generality of the
protocol, the reaction between diverse aryl substituted 3-
furanyl-ynones (10b−d) with nitromethane partners 11a and
11d were studied to furnish corresponding benzofuran
derivatives (12e−g) in good yields. When alkyl substituted
ynones 10e and 10f were employed as reaction partners with
nitromethanes 11a and 11d, corresponding benzofurans 12h
and 12i, respectively, were obtained with equal facility, Scheme
3. To further enhance the scope and diversity of substitution
pattern, reactions of ethylnitroacetate 11e and benzoylnitro-
methane 11f with furan-3-ynones (10a−c,e) were probed and
smoothly led to benzofurans (12j−o) with three contiguous
and differentiated functionalities at 4,5,6-positions (Scheme 3)
through the formation of cyclobutene intermediate and “C−C
split” (vide infra).
11f led to diversely functionalized benzothiophenes 12s−u,
and the structures were unambiguously confirmed through a
single crystal X-ray analysis of 12g and 12r.
To further amplify the applicability of this benzannulation
protocol, our strategy has been extended to various 2-
substituted furan and thiophene ynones 13a−f, and their
reaction with nitromethanes 11a,b and 11e,f conveniently
afforded the corresponding benzofurans and benzothiophenes
14a−i, respectively, in good yields (Scheme 4). The structures
Gratifyingly, the benzannulation reaction worked equally
well with thiophene-3-ynones as well. Thus, aryl and alkyl
substituted thiophenes ynones 10g and 10h with nitro-
methanes 11a and 11d furnished the corresponding
benzothiophenes 12p−r (Scheme 3). Similarly, thiophene
ynone 10g and 10h with substituted nitromethanes 11e and
C
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Scheme 4. Benzofurans and Benzothiophenes Synthesis
from Furan and Thiophene-2-ynones
Scheme 5. Synthesis of Benzofurans and Benzothiophenes
from 2- and 3-Substituted Furan and Thiophene o-Bromo
Ynones with Nitromethanes
of products were secured through internally consistent spectral
data (see SI) and single crystal X-ray structure of 14c, 14d, and
14h (Scheme 4). The furan and thiophene benzannulations
outlined here display several interesting features that include
the nitro group of nitromethanes acting as sacrificial, traceless
carbanion activator for recursive anion generation, intervention
of a “6π electrocyclization” as the key step, and mechanistic
intervention in some cases through the intermediacy of a
cyclobutene intermediate (vide infra).
The new benzofuran and benzothiophene synthesis
disclosed above had its origin in our earlier work on
benzannulations employing o-haloaryl ynones with nitro-
methanes.12e It was therefore of interest and relevance to
demonstrate the efficacy of this tactic employing o-halo furan
and o-halothiophene ynones with nitromethanes to amplify
substitution pattern on the benzofuran and benzothiophene
frameworks, see Scheme 2a. Thus, 2- and 3-bromofuran
ynones 15a,b and 2- and 3-bromothiophene ynones 15c,d
were reacted with nitromethanes 11a,e,f under our optimized
protocol (Cs2CO3 in DMF at 100 °C) to smoothly deliver
corresponding benzofurans 16a−f and benzothiophenes 16g−l
in good yields (Scheme 5). The mechanism of these
nitromethane mediated benzannulations of o-haloynones
involving tandem Michael addition and SNAr reaction is fairly
well documented12 and need no further elaboration here (see
mechanism in SI).
between ynone 10a and nitromethane was performed at room
temp, only the Michael addition product 17 was obtained.
However, 17 on heating at 90 °C in DMF did not lead to the
formation of benzannulated product 12a. On the other hand,
17 in the presence of Cs2CO3 under the same reaction
In order to delineate the mechanism of the newly observed
benzannulation reaction, a control experiment was conducted
as depicted in Scheme 6. Accordingly, when the reaction
D
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intermediate C well poised for in situ 6π-electrocyclization to
furnish D. Aromatization in D proceeds spontaneously through
elimination of HNO2 leading to the benzannulated products
14a,b. On the other hand, when doubly activated nitro-
methanes 11e−f were employed, the anion of A intra-
molecularly adds to the carbonyl group to form strained
cyclobutane intermediate E. Retro-Aldol process through a C−
C bond split in E leads to intermediate F, which tautomerizes
to a enol-diene G, which then undergoes 6-π electrocyclization
to form cyclized intermediate H. This upon elimination of the
nitro group in the form of HNO2 completes aromatization to
deliver 14c−i (Scheme 8).
We end through implementation of a few utilitarian
transformations on the benzothiophenes, applicable to
benzofurans as well, that indicate possibilities for functional
group amplification and readjustment. An additional sub-
stitution on aromatic ring of 12p was introduced through O-
allylation and Claisen rearrangement to furnish allylated
product 18. Activation of phenolic group as triflate and Pd-
mediated Suzuki coupling15 and cyanation reaction16 delivered
the corresponding arylated and cyanated products 19 and 20,
respectively (Scheme 9).
Scheme 6. Control Experiments
conditions readily afforded 12a, thereby underscoring the need
for both base and heat for driving the reaction (Scheme 6).
On the basis of these observations and literature
precedences,12,14 a possible general mechanism can be
proposed for the benzannulations leading to a variety of
benzofurans and benzothiophenes. Michael addition of
carbanion derived from nitroalkanes 11a−d to ynones 10a−
h affords an intermediate A which on protonation to enone B
and generation of second carbanion leads to the push−pull
type diene intermediate C well poised for in situ 6π-
electrocyclization to furnish D. However, an alternate
mechanism involving an intramolecular Michael addition of
carbanion generated in B onto C2 position of heteroaryl
system to deliver the common intermediate D cannot be ruled
out. Aromatization in D proceeds spontaneously through
elimination of HNO2 leading to the benzannulated products
12a−i and 12p−r. However, when doubly activated nitro-
methanes like 11e−f are deployed, the enolate A intra-
molecularly engages the pendent electrophilic carbonyl group
to render a cyclobutene intermediate E. Retro-Aldol ring
opening in E to F and further deprotonation to diene G sets up
the 6π-electrocyclization to H. Base promoted nitro group
elimination with concomitant aromatization furnishes benzan-
nulated products 12j−o and 12s−u (Scheme 7) in a one-pot
operation.
CONCLUSION
■
In summary, an efficient, one-pot benzannulation strategy of
wide applicability employing furan/thiophene derived ynones
and assorted nitromethanes is outlined. A unique feature of
this new benzo-furan and -thiophene synthesis is that the nitro
group of nitroalkanes functions as a sacrificial activator that
vanishes at the end to facilitate aromatization when simple
ynones were employed (Scheme 3, 4); on the other hand, nitro
group retention takes place with o-halo ynones when employed
as reaction partners (Scheme 5). Significantly, this benzannu-
lation works with equal facility employing both 2- and 3-
substituted furan and thiophene ynones with nitromethanes to
furnish functionally embellished benzofurans and benzothio-
phenes.
A plausible reaction mechanism for the formation of
benzofurans and benzothiophenes from corresponding 2-
ynones is depicted in Scheme 8. Michael addition of carbanion
derived from nitroalkanes (11a−d) to ynones 13a−f forms the
Michael addition intermediate A, which upon tautomerization
through intermediate B generates the push−pull type diene
EXPERIMENTAL SECTION
■
Scheme 7. Plausible Mechanism Leading to Benzofurans
and Benzothiophenes 12a−u from Corresponding 3-Ynones
General Methods. Unless otherwise mentioned, all the reagents
were purchased and used as collected from commercial vendors. All
the moisture and air sensitive reactions were performed under
nitrogen or argon atmosphere using flame-dried or oven-dried
glassware with magnetic stirring. The dimethylformamide (DMF)
used in the reaction was commercial HPLC grade solvent and was
used directly. Anhydrous tetrahydrofuran (THF) was distilled over
Na, benzophenone prior to use. Anhydrous toluene used in the
reactions was freshly distilled from the toluene, CaH2 mixture. For
reactions requiring heating, a magnetic stirrer with digital heating was
used and glass oil bath was used with heavy paraffin oil. For low
temperature reactions, −78 °C EYELA built in a compact circulator
bath with stirrer was used, and for reactions at 0 °C, crushed ice in
plastic tub was used. Progress of the reactions was monitored by thin-
layer chromatography (TLC) using precoated silica gel plates (silica
gel 60 F254, Merck) with the help of UV-light, iodine, and p-
anisaldehyde stains. Purification of the compounds was done using
silica gel column chromatography (60−120 mesh or 100−200 mesh)
packed in a glass column. Distilled EtOAc and petroleum ether were
used for column chromatography. The 1H NMR and 13C NMR
spectral data were obtained by using CDCl3 or DMSO-d6 as solvent
and using either 300 or 400 or 500 MHz spectrometers at ambient
temperature. The coupling constant J is represented in Hz. The
chemical shift values (δ) are shown in ppm, on scale downfield from
TMS and using CDCl3 (H δ = 7.26 and C δ = 77.0 ppm) or TMS (δ
= 0.0) residual solvent peaks as internal standard and peak splitting
E
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Scheme 8. Plausible Mechanism for the Formation of Benzofurans and Thiophenes from Corresponding Furan/Thiophene-2-
ynones with Nitromethanes
Scheme 9. Typical Functional Group Alterations
patterns are designated as follows: s = singlet, d = doublet, dd =
doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, qd =
quartet of doublet, m = multiplet, br = broad, tt = triplet of triplet.
Bruker Infrared spectrophotometer was used to record IR spectra and
was shown as cm−1. Waters-TOF spectrometer was used to record
high-resolution mass spectra (HRMS).
Hexane); 1H NMR (500 MHz, CDCl3) δ 8.24−8.23 (m, 1H), 7.64−
7.61 (m, 2H), 7.49−7.45 (m, 2H), 7.42−7.39 (m, 2H), 6.88−6.87
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.9, 150.1, 144.5,
132.9, 130.7, 129.2, 128.6, 119.8, 108.4, 89.9, 86.9.
1-(Furan-3-yl)-3-(p-tolyl)prop-2-yn-1-one (10b). By following
general procedure 1 compound 10b was prepared as brown solid
1
General Procedure for the Preparation of Ynones (10a−h,
13a−f, and 15a−d). n-BuLi (5.5 mmol) was added to a stirring
solution of alkyne (6.0 mmol) in anhydrous THF (15.0 mL) at −78
°C, and the resulting reaction mixture was stirred for another 15 min
at the same temperature. To this aldehyde (5.0 mmol) in THF (10.0
mL) was added dropwise and allowed to warm to room temperature
and the reaction was monitored by TLC. After complete consumption
of the starting material (monitored by TLC), the reaction mixture was
quenched by dropwise addition of saturated aq. NH4Cl (25 mL)
solution and diluted with H2O (25 mL) and EtOAc (25 mL). The
layers were separated and the aqueous layer was extracted with EtOAc
(2 × 15 mL). The combined organic layer was washed with brine
solution and dried over anhydrous Na2SO4, concentrated under
reduced pressure to afford the crude propargyl alcohol, which was
used for oxidation directly. To a stirred solution of secondary alcohol
(5.0 mmol) in DMSO (15.0 mL) at room temperature was added IBX
(6.0 mmol) and the reaction mixture was stirred for 2 h. After
complete consumption of the starting material (monitored by TLC),
the reaction mixture was filtered through Celite with the aid of EtOAc
and the resulting filtrate was washed with cold H2O (10 mL × 2) and
brine solution (10 mL) and the organic layer was dried over
anhydrous Na2SO4. Volatiles were removed under reduced pressure
and the obtained crude mixture was purified by silica gel column
chromatography to yield the substituted ynones.
(0.76 g, 73%); Rf = 0.6 (10% EtOAc + Hexane); mp 80−82 °C; H
NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 1.5, 0.8 Hz, 1H), 7.56−7.49
(m, 2H), 7.49−7.44 (m, 1H), 7.21 (dd, J = 8.4, 0.5 Hz, 2H), 6.88 (dd,
J = 1.9, 0.8 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 171.2, 150.1, 144.6, 141.6, 133.1, 129.5, 129.3, 116.8, 108.5, 90.7,
86.9, 21.8; IR (neat) υmax 3127, 3026, 2198, 1624, 1509, 1155, 1046,
820, 738 cm−1; HRMS (ESIMS) calcd for C14H11O2 [M + H]+ m/z
211.0759, found 211.0757.
3-(2-Fluorophenyl)-1-(furan-3-yl)prop-2-yn-1-one (10c). By fol-
lowing general procedure 1 compound 10c was prepared as a light
brown solid (0.69 g, 65%); Rf = 0.3 (10% EtOAc + Hexane); mp 58−
60 °C; 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 0.6 Hz, 1H), 7.62
(td, J = 7.7, 1.6 Hz, 1H), 7.54−7.40 (m, 2H), 7.24−7.10 (m, 2H),
6.96−6.81 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.7,
165.1, 162.5, 150.8, 144.7, 134.7, 132.9, 132.8, 129.2, 124.5, 124.45,
116.0, 115.8, 108.9, 108.8, 108.4, 91.6, 83.2; IR (neat) υmax 3024,
2761,1702, 1673, 1491, 1097, 994, 840, 745 cm−1; HRMS (ESIMS)
calcd for C13H8O2 F [M + H]+ m/z 215.0508, found 215.0503.
1-(Furan-3-yl)-3-(4-methoxyphenyl)prop-2-yn-1-one (10d). By
following general procedure 1 compound 10d was prepared as pale
brown solid (0.77 g, 68%); Rf = 0.3 (10% EtOAc + Hexane); mp 70−
72 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 1.4, 0.8 Hz, 1H),
7.62−7.54 (m, 2H), 7.47 (t, J = 1.7 Hz, 1H), 6.95−6.89 (m, 2H),
6.88 (dd, J = 1.9, 0.7 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 171.2, 161.7, 150.0, 144.5, 135.1, 129.3, 114.5, 111.6,
108.5, 91.2, 87.0, 55.45; IR (neat) υmax 3122, 2944, 2197, 1627, 1512,
Ynones Spectral Data. 1-(Furan-3-yl)-3-phenylprop-2-yn-1-one
(10a).17b By following general procedure 1 compound 10a was
prepared as pale yellow liquid (0.70 g, 71%); Rf = 0.4 (10% EtOAc +
F
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1261, 1158, 1027, 827, 737 cm−1; HRMS (ESIMS) calcd for
C14H11O3 [M + H]+ m/z 227.0708, found 227.0706.
3-Cyclopropyl-1-(furan-3-yl)prop-2-yn-1-one (10e). By following
(101 MHz, CDCl3) δ 169.8, 145.0, 135.3, 135.1, 133.1, 130.9, 128.7,
128.4, 120.0, 91.8, 86.5.
1-(5-Bromothiophen-2-yl)-3-phenylprop-2-yn-1-one (13e). By
following general procedure 1 compound 13e was prepared as a
white flaky solid (1.14 g, 78%); Rf = 0.4 (10% EtOAc + Hexane); mp
78−80 °C; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 4.0 Hz, 1H),
7.71−7.60 (m, 2H), 7.47 (dq, J = 14.5, 7.2 Hz, 3H), 7.17 (d, J = 4.0
Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 168.5, 146.1, 135.0,
133.1, 131.6, 131.1, 128.8, 124.3, 119.7, 92.5, 85.9; IR (neat) υmax
2195, 1625, 1438, 1299, 1045, 926, 794, 679 cm−1; HRMS (ESIMS)
calcd for C13H8BrOS [M + H]+ m/z 290.94737, found 290.94739.
1-(5-Methylthiophen-2-yl)-3-phenylprop-2-yn-1-one (13f). By
following general procedure 1 compound 13f was prepared as a
pale yellow solid (0.90 g, 80%); Rf = 0.5 (10% EtOAc + Hexane); mp
76−78 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 3.8 Hz, 1H),
7.69−7.62 (m, 2H), 7.52−7.45 (m, 1H), 7.45−7.38 (m, 2H), 6.87
(dd, J = 3.8, 1.0 Hz, 1H), 2.58 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 169.5, 151.8, 142.8, 135.9, 133.0, 130.7, 128.7, 127.2, 120.2,
91.2, 86.4, 16.3; IR (neat) υmax 2191, 1602, 1438, 1300, 1054, 946,
762, 679 cm−1; HRMS (ESIMS) calcd for C14H11OS [M + H]+ m/z
227.0531, found 227.0530.
1-(2-Bromofuran-3-yl)-3-phenylprop-2-yn-1-one (15a). 2-Bro-
mofuran-3-carboxylic acid18 (1.0 g, 5.23 mmol) was dissolved in
CH2Cl2 (50 mL) in single neck RB flask and it was cooled to 0 °C. To
this EDC·HCl (1.5 g, 7.85 mmol), HOBt (1.06 g, 7.85 mmol) were
added at 0 °C. The reaction mass was stirred for 15 min at the same
temperature and then N,O-dimethyl hydroxylamine hydrochloride
(762 mg, 7.85 mmol) and diisopropyl ethyl amine (2.7 mL, 15.7
mmol) were added and continued stirring for 10 min at 0 °C. Further
the reaction mixture was stirred for 12 h at 30 °C (TLC showed total
consumption of starting material). Water (15 mL) was added and
reaction mixture was extracted with CH2Cl2 (30 mL × 2). The
combined organic layers were successively washed with cold water
(10 mL × 2), saturated sodium bicarbonate and brine, dried over
sodium sulfate. Organic layer was concentrated under reduced
pressure gave the crude product which was purified over silica gel
column chromatography with 15−25% EtOAc:hexane as eluent
afforded the corresponding Weinreb amide (1.16 g) as thick syrup in
95% yield. This was directly used for next reaction.
general procedure 1 compound 10e was prepared as pale brown solid
1
(0.57 g, 71%); Rf = 0.5 (10% EtOAc + Hexane); mp 54−56 °C; H
NMR (400 MHz, CDCl3) δ 8.11−8.06 (m, 1H), 7.42 (t, J = 1.5 Hz,
1H), 6.82−6.77 (m, 1H), 1.47 (tt, J = 8.3, 5.0 Hz, 1H), 1.07−0.92
(m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 150.1, 144.56,
129.4, 108.67, 97.9, 75.9, 10.0, 0.02; IR (neat) υmax 3134, 2208, 1633,
1358, 1159, 892, 744 cm−1; HRMS (ESIMS) calcd for C10H9O2 [M +
H]+ m/z 161.0603, found 161.0599.
1-(Furan-3-yl)hept-2-yn-1-one (10f).17e By following general
procedure 1 compound 10f was prepared as pale brown oil (0.60 g,
69%); Rf = 0.3 (10% EtOAc + Hexane); 1H NMR (400 MHz,
CDCl3) δ 8.12 (dd, J = 1.4, 0.8 Hz, 1H), 7.43 (t, J = 1.7 Hz, 1H), 6.81
(dd, J = 1.9, 0.7 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 1.68−1.57 (m, J =
7.3, 5.4 Hz, 3H), 1.56−1.40 (m, 3H), 0.96 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 150.1, 144.4, 129.3,
108.4, 93.5, 80.0, 29.8, 22.0, 18.7, 13.5.
3-Phenyl-1-(thiophen-3-yl)prop-2-yn-1-one (10g).17c By follow-
ing general procedure 1 compound 10g was prepared as pale yellow
1
oil (0.74 g, 70%); Rf = 0.3 (10% EtOAc + Hexane); H NMR (500
MHz, CDCl3) δ 8.36 (dd, J = 3.0, 1.2 Hz, 1H), 7.71−7.61 (m, 3H),
7.53−7.45 (m, 1H), 7.45−7.39 (m, 2H), 7.36 (dd, J = 5.1, 3.0 Hz,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.5, 143.0, 135.5, 133.0,
130.8, 128.7, 126.9, 120.1, 91.4, 87.4.
3-Cyclopropyl-1-(thiophen-3-yl)prop-2-yn-1-one (10h). By fol-
lowing general procedure 1 compound 10h was prepared as brown
solid (0.63 g, 72%); Rf = 0.5 (10% EtOAc + Hexane); mp 64−66 °C;
1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 3.0, 1.2 Hz, 1H), 7.58
(dd, J = 5.1, 1.2 Hz, 1H), 7.31 (dd, J = 5.1, 3.0 Hz, 1H), 1.51 (ddt, J =
8.4, 7.9, 5.1 Hz, 1H), 1.07−0.96 (m, 4H); 13C{1H} NMR (101 MHz,
CDCl3) δ 171.6, 143.1, 135.1, 126.9, 126.6, 99.2, 76.0, 9.9, 0.02; IR
(neat) υmax 3097, 2176, 1672, 1280, 1029, 843, 767 cm−1; HRMS
(ESIMS) calcd for C10H9OS [M + H]+ m/z 177.0374, found
177.0367.
1-(Furan-2-yl)-3-phenylprop-2-yn-1-one (13a).17a By following
general procedure 1 compound 13a was prepared as yellow solid
1
(0.72 g, 74%); Rf = 0.2 (10% EtOAc + Hexane); mp 49−51 °C; H
NMR (400 MHz, CDCl3) δ 7.72−7.60 (m, 3H), 7.53−7.46 (m, 1H),
7.44−7.40 (m, 3H), 6.61 (dd, J = 3.6, 1.7 Hz, 1H); 13C{1H} NMR
(126 MHz, CDCl3) δ 164.8, 153.3, 148.1, 133.1, 130.9, 128.7, 121.0,
119.9, 112.7, 91.9, 86.3.
n-Butyl lithium (4 mL, 1.6 M in hexane, 5.98 mmol) was added
dropwise to a cooled solution of phenyl acetylene (0.72 mL, 6.41
mmol) in anhydrous THF (10 mL) at −10 °C and reaction mixture
was stirred for 15 min at the same temperature. A solution of Weinreb
amide (1 g, 4.27 mmol) in anhydrous THF (5 mL) was added to the
reaction flask and stirred reaction mixture for 2 h at 0 °C. The
reaction was quenched with aqueous NH4Cl solution and diluted with
EtOAc. Organic layer was separated; aqueous layer was extracted with
ethyl acetate (20 mL × 2), washed with brine, dried over Na2SO4 and
filtered. All organic layers were concentrated under reduced pressure
to give the crude mixture which was purified by column
chromatography with 5% EtOAc + hexane as an eluent to afford
ynone 15a (1.08 g) in 92% yield as pale yellow powder. Rf = 0.5 (5%
1-(5-Bromofuran-2-yl)-3-phenylprop-2-yn-1-one (13b). By fol-
lowing general procedure 1 compound 13b was prepared as an orange
solid (1.05 g, 76%) ; Rf = 0.4 (10% EtOAc + Hexane); mp 50−52 °C;
1H NMR (400 MHz, CDCl3) δ 7.68−7.60 (m, 2H), 7.50 (ddd, J =
6.6, 3.9, 1.4 Hz, 1H), 7.46−7.39 (m, 2H), 7.37 (d, J = 3.6 Hz, 1H),
6.57 (d, J = 3.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.3,
154.7, 133.2, 131.1, 130.7, 128.8, 122.6, 119.7, 114.8, 92.6, 85.7; IR
(neat) υmax3129, 2200, 1716, 1619, 1520, 1406, 1237, 1179, 969, 798,
713, 669 cm−1; HRMS (ESIMS) calcd for C13H8O2Br [M + H]+ m/z
274.9708, found 274.9712.
1
EtOAc + Hexane); mp 52−54 °C; H NMR (400 MHz, CDCl3) δ
1-(5-Methylfuran-2-yl)-3-phenylprop-2-yn-1-one (13c). By fol-
lowing general procedure 1 compound 13c was prepared as a brown
solid (0.77 g, 74%); Rf = 0.5 (10% EtOAc + Hexane); mp 60−62 °C;
1H NMR (500 MHz, CDCl3) δ 7.66−7.60 (m, 2H), 7.51−7.44 (m,
1H), 7.44−7.34 (m, 3H), 6.24 (dd, J = 3.5, 0.8 Hz, 1H), 2.44 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 164.0, 160.0, 152.2, 133.0,
130.7, 128.7, 123.6, 120.1, 109.7, 91.1, 86.3, 14.3; IR (neat) υmax
2993, 2182, 1615, 1444, 1301, 1042, 950, 761, 680 cm−1; HRMS
(ESIMS) calcd for C14H11O2 [M + H]+ m/z 211.0759, found
211.0750.
7.70−7.63 (m, 2H), 7.50−7.46 (m, 2H), 7.45−7.38 (m, 2H), 6.96 (d,
J = 2.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.2, 144.6,
133.0, 131.0, 129.9, 128.7, 125.6, 120.0, 112.4, 93.3, 87.3; IR (neat)
υmax 2200, 1628, 1557, 1495, 1308, 1166, 964, 747, 692 cm−1; HRMS
(ESIMS) calcd for C13H8O2Br [M + H]+ m/z 274.97022, found
274.97026.
1-(3-Bromofuran-2-yl)-3-phenylprop-2-yn-1-one (15b). By fol-
lowing general procedure 1 compound 15b was prepared as an off
white solid (0.90 g, 66%); Rf = 0.5 (10% EtOAc + Hexane); mp 60−
62 °C; 1H NMR (400 MHz, CDCl3) δ 7.71−7.65 (m, 2H), 7.62 (d, J
= 1.8 Hz, 1H), 7.49 (ddt, J = 6.6, 5.0, 1.4 Hz, 1H), 7.41 (ddd, J = 6.8,
4.5, 1.3 Hz, 2H), 6.70 (d, J = 1.8 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 164.0, 148.5, 146.9, 133.2, 131.1, 128.7, 120.0, 117.9, 109.9,
94.3, 86.8; IR (neat) υmax 3002, 2992, 1705, 1622, 1404, 1311, 1089,
899, 740, 665 cm−1; HRMS (ESIMS) calcd for C13H8O2Br [M + H]+
m/z 274.9702, found 274.9708.
3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-one (13d).17d By follow-
ing general procedure 1 compound 13d was prepared as a pale yellow
solid (0.76 g, 72%); Rf = 0.3 (10% EtOAc + Hexane); mp 54−56 °C;
1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 3.8, 1.2 Hz, 1H), 7.73
(dd, J = 4.9, 1.2 Hz, 1H), 7.69−7.63 (m, 2H), 7.53−7.45 (m, 1H),
7.45−7.38 (m, 2H), 7.19 (dd, J = 4.9, 3.8 Hz, 1H); 13C{1H} NMR
G
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1-(2,5-Dibromothiophen-3-yl)-3-phenylprop-2-yn-1-one (15c).
By following general procedure 1 compound 15c was prepared as a
pale yellow solid (1.24 g, 67%); Rf = 0.4 (10% EtOAc + Hexane); mp
62−64 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 5.2, 3.2 Hz,
2H), 7.54 (s, 1H), 7.52−7.47 (m, 1H), 7.46−7.38 (m, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 169.3, 139.0, 133.1, 132.1, 131.2, 128.8,
119.8, 119.6, 111.9, 93.9, 87.7; IR (neat) υmax 3102, 2996, 1708, 1611,
1343, 1001, 982, 790, 687, 654 cm−1; HRMS (ESIMS) calcd for
C13H7OBr2S [M + H]+ m/z 368.8578, found 368.8599.
1-(3-Bromothiophen-2-yl)-3-phenylprop-2-yn-1-one (15d). By
following general procedure 1 compound 15d was prepared as a
pale yellow solid (1.03g, 71%); Rf = 0.5 (10% EtOAc + Hexane); mp
74−76 °C; 1H NMR (400 MHz, CDCl3) δ 7.71−7.65 (m, 2H), 7.62
(d, J = 5.2 Hz, 1H), 7.53−7.45 (m, 1H), 7.45−7.37 (m, 2H), 7.17 (d,
J = 5.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 138.0,
134.1, 133.7, 133.1, 131.1, 128.8, 120.0, 116.5, 94.1, 87.4; IR (neat)
υmax 3021, 1631, 1507, 1318, 1082, 985, 790, 687 cm−1; HRMS
(ESIMS) calcd for C13H8OBrS [M + H]+ m/z 290.9473, found
290.9481.
(s, 1H), 3.58 (s, 3H), 3.17−3.05 (m, 2H), 2.62−2.49 (m, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 155.5, 147.5, 143.8,
141.0, 138.8, 129.3, 128.2, 127.0, 115.8, 114.3, 110.4, 103.9, 51.9,
34.4, 22.3; IR (neat) υmax 3381, 3027, 2952, 1710, 1324, 1163, 1043,
704 cm−1; HRMS (ESIMS) calcd for C18H17O4 [M + H]+ m/z
297.1127, found 297.1125.
6-(p-Tolyl)benzofuran-4-ol (12e). By following general procedure
2 by using ynone 10b and nitromethane 11a compound 12e was
prepared as brown sticky liquid (33.6 mg, 75%); Rf = 0.2 (10% EtOAc
+ Hexane); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.2 Hz, 1H),
7.50 (d, J = 8.1 Hz, 2H), 7.33 (t, J = 1.0 Hz, 1H), 7.26−7.24 (m, 2H),
6.88 (d, J = 1.2 Hz, 1H), 6.85 (dd, J = 2.2, 0.9 Hz, 1H), 5.22 (s, 1H),
2.40 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.2, 149.1,
144.1, 139.1, 138.2, 137.2, 129.5, 127.2, 115.6, 107.3, 103.3, 103.1,
21.1; IR (neat) υmax 3354, 3119, 2923, 2853, 1602, 1540, 1373, 1169,
1058, 815, 766 cm−1; HRMS (ESIMS) calcd for C15H13O2[M + H]+
m/z 225.0916, found 225.0911.
6-(2-Fluorophenyl)benzofuran-4-ol (12f). By following general
procedure 2 by using ynone 10c and nitromethane 11a compound
12f was prepared as off white solid (32.4 mg, 71%); Rf = 0.5 (20%
EtOAc + Hexane); mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ
8.30 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.33−
7.24 (m, 2H), 7.05 (td, J = 7.5, 1.1 Hz, 1H), 6.93 (dd, J = 2.2, 0.9 Hz,
1H), 6.90−6.84 (m, 1H), 5.06 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 156.2, 152.5, 148.11, 146.1, 130.1, 129.8, 129.4, 127.0,
125.7, 121.4, 118.3, 115.7, 115.0, 107.3; IR (neat) υmax 3328, 3098,
2974, 2745, 1593 1324, 1086, 898, 760 cm−1; HRMS (ESIMS) calcd
for C14H10FO2[M + H]+ m/z 229.0665, found 229.0665.
General Procedure for the Preparation of Benzohetero-
cycles. In an oven-dried Ace pressure tube (15 mL), was taken ynone
(0.2 mmol, 1.0 equiv) and nitromethane (0.6 mmol, 3.0 equiv) [when
nitromethanes 11d,e,f are employed as reaction partners with ynones,
only 1.5 equiv/0.3 mmol of nitromethane derivatives were used], to
this DMF (2 mL) and Cs2CO3 (0.4 mmol, 2.0 equiv) were added and
the cap was closed tightly; it was then placed in a preheated oil bath at
90 °C and was stirred for 10 h at the same temperature. The reaction
mixture was cooled to room temperature, diluted with cold H2O (5
mL) and extracted with EtOAc (3 × 5 mL). The combined organic
extract was washed with brine (10 mL) and dried over Na2SO4;
volatiles were removed under reduced pressure to get the crude
compound which was purified by silica gel flash column
chromatography (EtOAc/Hexane) to give benzoheterocycles.
6-Phenylbenzofuran-4-ol (12a). By following general procedure 2
by using ynone 10a and nitromethane 11a compound 12a was
prepared as off white solid (31.9 mg, 76%); Rf= 0.3 (10% EtOAc +
Methyl 3-(4-hydroxy-6-(4-methoxyphenyl)benzofuran-7-yl)-
propanoate (12g). By following general procedure 2 by using
ynone 10d and nitromethane 11d compound 12g was prepared as off
white solid (52.2 mg, 80%); Rf = 0.2 (10% EtOAc + Hexane); mp
1
113−115 °C; H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.2 Hz,
1H), 7.24−7.17 (m, 2H), 6.97−6.90 (m, 2H), 6.85 (d, J = 2.2 Hz,
1H), 6.52 (s, 1H), 5.67 (s, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 3.17−3.08
(m, 2H), 2.62−2.52 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
173.8, 158.7, 155.6, 147.2, 143.8, 138.5, 133.3, 130.4, 115.5, 114.7,
113.7, 110.5, 103.7, 55.4, 51.7, 34.3, 22.3; IR (neat) υmax 3399, 2952,
2838, 1710, 1492, 1245, 1173, 1037, 836 cm−1; HRMS (ESIMS)
calcd for C19H18O5Na [M + Na]+ m/z 349.1052, found 349.1049.
6-Cyclopropylbenzofuran-4-ol (12h). By following general
procedure 2 by using ynone 10e and nitromethane 11a compound
12h was prepared as a yellow liquid (25.7 mg, 74%); Rf = 0.2 (10%
1
Hexane); mp 116−118 °C; H NMR (500 MHz, CDCl3) δ 7.63−
7.54 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 7.38−7.30 (m, 2H), 6.88 (d, J
= 0.9 Hz, 1H), 6.85 (d, J = 1.3 Hz, 1H), 5.24 (s, 1H); 13C{1H} NMR
(126 MHz, CDCl3) δ 157.2, 149.2, 144.3, 141.1, 139.1, 128.8, 127.4,
115.9, 107.6, 103.4, 103.3; IR (neat) υmax 3323, 2940, 1724, 1424,
1284, 1142, 1056, 763 cm −1; HRMS (ESIMS) calcd for C14H11O2[M
+ H]+ m/z 211.0759, found 211.0750.
1
7-Methyl-6-phenylbenzofuran-4-ol (12b). By following general
procedure 2 by using ynone10a and nitromethane 11b compound
12b was prepared as a viscous liquid (32.3 mg, 72%); Rf = 0.3 (10%
EtOAc + Hexane); H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.2
Hz, 1H), 6.85 (s, 1H), 6.76 (dd, J = 2.2, 0.7 Hz, 1H), 6.39 (d, J = 0.7
Hz, 1H), 5.12 (s, 1H), 1.94 (tt, J = 8.4, 5.1 Hz, 1H), 1.02−0.93 (m,
2H), 0.74−0.65 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.1,
148.8, 143.3, 142.3, 114.4, 106.3, 103.1, 101.6, 15.8, 9.4; IR (neat)
υmax 3283, 2949, 2365, 1868, 1773, 1522, 1429, 1289, 862, 756, 705
cm−1; HRMS (ESIMS) calcd for C11H11O2 [M + H]+ m/z 175.0759,
found 175.0759.
1
EtOAc + Hexane); H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 2.0
Hz, 1H), 7.45−7.31 (m, 5H), 6.87 (d, J = 2.0 Hz, 1H), 6.60 (s, 1H),
4.97 (s, 1H), 2.37 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
155.9, 146.5, 144.0, 141.2, 138.5, 129.6, 128.1, 126.8, 115.3, 112.1,
110.1, 103.7, 12.4; IR (neat) υmax 3353, 2766, 2681, 1608, 1487, 1362,
1154, 1043, 773, 704 cm−1; HRMS (ESIMS) calcd for C15H13O2[M +
H]+ m/z 225.0916, found 225.0913.
Methyl 3-(6-butyl-4-hydroxybenzofuran-7-yl)propanoate (12i).
By following general procedure 2 by using ynone 10f and
nitromethane 11d compound 12i was prepared as pale brown sticky
7-Ethyl-6-phenylbenzofuran-4-ol (12c). By following general
procedure 2 by using ynone 10a and nitromethane 11c compound
12c was prepared as a yellow liquid (37.6 mg, 79%); Rf = 0.3 (10%
1
liquid (37.5 mg, 68%); Rf = 0.2 (10% EtOAc + Hexane); H NMR
(400 MHz, CDCl3) δ 7.49 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 2.2 Hz,
1H), 6.47 (s, 1H), 5.42 (d, J = 18.0 Hz, 1H), 3.70 (s, 3H), 3.21−3.11
(m, 2H), 2.71−2.60 (m, 4H), 1.55 (tt, J = 7.7, 6.4 Hz, 2H), 1.38 (dq,
J = 14.4, 7.2 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 174.0, 155.7, 147.3, 143.2, 138.0, 114.6, 114.3, 109.5,
103.5, 51.8, 34.5, 34.2, 32.2, 22.7, 21.5, 14.1; IR (neat) υmax 3405,
2986, 2765, 1698, 1371, 1178, 982, 765 cm−1; HRMS (ESIMS) calcd
for C16H21O4 [M + H]+ m/z 277.1440, found 277.1440.
1
EtOAc + Hexane); H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.2
Hz, 1H), 7.42−7.26 (m, 5H), 6.85 (d, J = 2.2 Hz, 1H), 6.53 (s, 1H),
5.67 (s, 1H), 2.78 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 146.4, 143.9, 141.4,
138.3, 129.5, 128.1, 126.9, 118.9, 115.7, 110.3, 103.6, 20.2, 15.1; IR
(neat) υmax 3365, 2978, 2935, 1699, 1487, 1370, 1154, 1047, 841, 763
cm−1; HRMS (ESIMS) calcd for C16H15O2[M + H]+ m/z 239.1072,
found 239.1070.
Methyl 3-(4-hydroxy-6-phenylbenzofuran-7-yl)propanoate
(12d). By following general procedure 2 by using ynone 10a and
nitromethane 11d compound 12d was prepared as pale brown solid
(48.5 mg, 82%); Rf = 0.2 (10% EtOAc + Hexane); mp 108−110 °C;
1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 1.8 Hz, 1H), 7.30 (ddd, J
Ethyl 4-hydroxy-6-phenylbenzofuran-5-carboxylate (12j). By
following general procedure 2 by using ynone 10a and nitromethane
11e compound 12j was prepared as an off white solid (45.7 mg,
1
81%); Rf = 0.5 (20% EtOAc + Hexane); mp 162−164 °C; H NMR
(500 MHz, CDCl3) δ 7.54 (d, J = 2.2 Hz, 1H), 7.38−7.27 (m, 5H),
6.86 (d, J = 2.2 Hz, 1H), 6.62 (s, 1H), 6.50 (s, 1H), 4.13 (q, J = 7.1
Hz, 2H), 0.96 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3)
= 22.6, 14.4, 6.7 Hz, 5H), 6.85 (d, J = 1.8 Hz, 1H), 6.53 (s, 1H), 6.45
H
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δ 166.9, 155.2, 151.3, 144.7, 141.2, 140.8, 128.6, 128.0, 127.2, 116.4,
110.8, 109.4, 103.5, 61.2, 13.6; IR (neat) υmax 3320, 2985, 1681, 1600,
1321, 1266, 1138, 1034, 671 cm−1; HRMS (ESIMS) calcd for
C17H15O4[M + H]+ m/z 283.0970, found 283.0968.
6.97 (d, J = 1.1 Hz, 1H), 5.40 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 150.9, 142.5, 140.9, 139.1, 128.9, 128.4, 127.4, 127.3, 125.4,
119.6, 113.7, 108.6; IR (neat) υmax 3228, 2985, 2103, 1421, 1208,
1130, 1022, 754 cm−1; HRMS (ESIMS) calcd for C14H10OS [M −
H]+ m/z 225.03686, found 225.03735.
(4-Hydroxy-6-phenylbenzofuran-5-yl)(phenyl)methanone (12k).
By following general procedure 2 by using ynone 10a and
nitromethane 11f compound 12k was prepared as an off white solid
(49.0 mg, 78%); Rf = 0.4 (20% EtOAc + Hexane); mp 178−180 °C;
1H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 7.62 (d, J = 2.2 Hz,
1H), 7.37−7.28 (m, 2H), 7.18−7.12 (m, 4H), 7.06−7.01 (m, 5H),
6.99−6.95 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.9,
158.2, 156.2, 144.8, 141.7, 141.4, 140.0, 131.6, 129.9, 129.4, 128.1,
127.5, 127.2, 116.4, 115.4, 106.4, 105.0; IR (neat) υmax 3195, 3119,
2925, 2343, 2130,1728, 1626, 1425, 1174, 778 cm−1; HRMS
(ESIMS) calcd for C21H15O3[M + H]+ m/z 315.1021, found
315.1024.
(4-Hydroxy-6-(p-tolyl)benzofuran-5-yl)(phenyl)methanone (12l).
By following general procedure 2 by using ynone 10b and
nitromethane 11f compound 12l was prepared as off white solid
(49.8 mg, 76%); Rf = 0.4 (20% EtOAc + Hexane); mp 118−120 °C;
1H NMR (500 MHz, CDCl3) δ 11.06−10.84 (m, 1H), 7.62 (d, J = 1.9
Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H), 7.12 (s,
1H), 7.08−7.00 (m, 5H), 6.84 (d, J = 7.9 Hz, 2H), 2.15 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 202.0, 158.2, 156.1, 144.7,
Methyl 3-(6-cyclopropyl-4-hydroxybenzo[b]thiophen-7-yl)-
propanoate (12q). By following general procedure 2 by using
ynone 10h and nitromethane 11d compound 12q was prepared as an
off white solid (44.7 mg, 81%); Rf = 0.2 (10% EtOAc + Hexane); mp
1
114−116 °C; H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 2.9, 1.2
Hz, 1H), 7.59 (dd, J = 5.1, 1.2 Hz, 1H), 7.34 (dd, J = 5.1, 2.9 Hz,
1H), 7.14 (s, 1H), 3.71 (s, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.73 (dd, J =
8.4, 7.0 Hz, 2H), 1.72 (tt, J = 8.4, 5.7 Hz, 1H), 0.81 (ddd, J = 8.4, 6.1,
4.7 Hz, 2H), 0.41−0.34 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3)
δ 174.1, 149.5, 142.3, 138.1, 127.3, 125.5, 123.8, 120.5, 107.6, 51.9,
33.3, 27.1, 12.8, 7.9.; IR (neat) υmax 3323, 2887, 1745, 1295, 1172,
983, 757 cm−1; HRMS(ESIMS) calcd for C15H16O3S [M + H]+ m/z
277.0898, found 277.0898.
Methyl 3-(4-hydroxy-6-phenylbenzo[b]thiophen-7-yl)-
propanoate (12r). By following general procedure 2 by using
ynone 10g and nitromethane 11d compound 12r was prepared as off
white solid (51.8 mg, 83%); Rf = 0.4 (20% EtOAc + Hexane); mp
1
132−134 °C; H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 5.6 Hz,
1H), 7.42−7.31 (m, 4H), 7.30−7.24 (m, 2H), 6.62 (s, 1H), 5.86 (s,
1H), 3.60 (s, 3H), 3.15−3.04 (m, 2H), 2.58−2.48 (m, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 173.7, 149.0, 142.3, 141.1, 138.9, 129.2,
128.6, 128.3, 127.2, 124.8, 123.8, 120.7, 112.1, 51.8, 33.6, 27.2; IR
(neat) υmax 3385, 2952, 1724, 1392, 1200, 1150, 1008, 706 cm−1;
HRMS (ESIMS) calcd for C18H16O3NaS [M + Na]+ m/z 335.0718,
found 335.0718.
141.8, 140.0, 138.5, 136.9, 131.5, 129.8, 129.4, 128.8, 127.5, 116.2,
115.4, 106.2, 105.0, 20.9; IR (neat) υmax 3067, 2998, 2343, 2141,1724,
1626, 1592, 1432, 1198,1091, 778 cm−1; HRMS (ESIMS) calcd for
C22H16O3 [M]+ m/z 328.10994, found 328.10930.
(6-(2-Fluorophenyl)-4-hydroxybenzofuran-5-yl)(phenyl)-
methanone (12m). By following general procedure 2 by using ynone
10c and nitromethane 11f compound 12m was prepared as off white
solid (49.8 mg, 75%); Rf = 0.3 (20% EtOAc + Hexane); mp 126−128
°C; 1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 7.65 (s, 1H), 7.37
(d, J = 7.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.16−7.03 (m, 5H), 6.96
(dd, J = 13.3, 7.2 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.66 (t, J = 9.3
Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.7, 159.9, 158.1,
157.5, 156.7, 145.0, 139.7, 134.6, 131.9, 131.9, 131.6, 129.6, 129.5,
129.3, 129.2, 129.0, 127.5, 123.9, 123.9, 117.1, 115.5, 115.3, 107.6,
105.1; IR (neat) υmax 3051, 2932, 1721, 1650, 1495, 1234, 1174, 776
cm−1; HRMS (ESIMS) calcd for C21H13FO3 [M]+ m/z 332.08487,
found 332.08420.
Ethyl 6-cyclopropyl-4-hydroxybenzofuran-5-carboxylate (12n).
By following general procedure 2 by using ynone 10e and
nitromethane 11e compound 12n was prepared as pale brown solid
(38.8 mg, 79%); Rf = 0.5 (20% EtOAc + Hexane); mp 112−114 °C;
1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.2 Hz, 1H), 7.16 (s, 1H),
6.80 (d, J = 2.2 Hz, 1H), 6.30 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.47
(tt, J = 8.5, 5.4 Hz, 1H), 1.44 (t, J = 7.1 Hz, 3H), 0.94−0.86 (m, 2H),
0.63−0.52 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.3,
155.5, 152.1, 143.9, 143.0, 115.3, 110.2, 106.4, 103.4, 61.4, 14.4, 14.0,
8.9; IR (neat) υmax 3254, 2872, 1708, 1689, 1512, 1265, 1180, 968,
750 cm−1; HRMS(ESIMS) calcd for C14H15O4[M + H]+ m/z
247.0970, found 247.0968.
(6-Cyclopropyl-4-hydroxybenzofuran-5-yl)(phenyl)methanone
(12o). By following general procedure 2 by using ynone 10e and
nitromethane 11f compound 12o was prepared as pale brown solid
(39.4 mg, 71%); Rf = 0.2 (10% EtOAc + Hexane); mp 96−98 °C; 1H
NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 7.71 (dd, J = 5.2, 3.3 Hz,
2H), 7.57−7.50 (m, 2H), 7.47−7.40 (m, 2H), 6.95 (dd, J = 2.2, 0.8
Hz, 1H), 6.77 (s, 1H), 1.50 (tt, J = 8.0, 5.7 Hz, 1H), 0.62−0.50 (m,
4H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.9, 158.8, 155.1, 144.1,
142.6, 141.1, 132.4, 129.3, 128.3, 117.3, 115.3, 104.8, 102.4, 17.9,
11.0; IR (neat) υmax 3045, 2923, 1689, 1498, 1189, 974, 767 cm−1;
HRMS(ESIMS) calcd for C18H15O3 [M + H]+ m/z 279.1021, found
279.1021.
Ethyl 4-hydroxy-6-phenylbenzo[b]thiophene-5-carboxylate
(12s). By following general procedure 2 using ynone 10g and
nitromethane 11e compound 12s was prepared as pale brown solid
(50.6 mg, 85%); Rf = 0.5 (20% EtOAc + Hexane); mp 206−208 °C;
1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.70 (d, J = 5.6 Hz,
1H), 7.53 (d, J = 5.6 Hz, 1H), 7.45−7.33 (m, 3H), 7.32−7.24 (m,
2H), 6.72 (s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 0.80 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.9, 160.2, 148.2, 148.1,
147.5, 134.1, 133.5, 133.1, 133.0, 132.1, 125.1, 119.5, 117.5, 65.4,
18.5; IR (neat) υmax 3426, 2932, 1652, 1560, 1368, 1285, 1176, 764,
705, 655 cm−1; HRMS (ESIMS) for C17H15O3S [M + H]+ calcd m/z
299.0742, found 299.0743.
Ethyl 6-cyclopropyl-4-hydroxybenzo[b]thiophene-5-carboxylate
(12t). By following general procedure 2 using ynone 10h and
nitromethane 11e compound 12t was prepared as light brown solid
(43.0 mg, 82%); Rf = 0.4 (20% EtOAc + Hexane); mp 136−138 °C;
1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 13.8, 5.7 Hz, 2H), 6.48
(s, 1H), 5.83 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.80 (tt, J = 8.6, 5.5
Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.02 (ddd, J = 8.5, 6.2, 4.6 Hz, 2H),
0.76−0.67 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.5,
153.5, 145.7, 144.4, 127.7, 127.1, 118.7, 117.9, 108.4, 61.2, 15.2, 14.5,
9.1; IR (neat) υmax 3360, 2954, 1714, 1655, 1565, 1293, 1174, 960,
757 cm−1; HRMS (ESIMS) calcd for C14H15O3S [M + H]+ m/z
263.0742, found 263.0739.
(6-Cyclopropyl-4-hydroxybenzo[b]thiophen-5-yl)(phenyl)-
methanone (12u). By following general procedure 2 using ynone 10h
and nitromethane 11f compound 12u was prepared as pale brown
1
liquid (47.0 mg, 80%); Rf = 0.5 (20% EtOAc + Hexane); H NMR
(500 MHz, CDCl3) δ 10.64 (s, 1H), 7.75−7.69 (m, 2H), 7.58 (d, J =
5.5 Hz, 1H), 7.55−7.50 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.32 (d, J =
5.5 Hz, 1H), 7.10 (s, 1H), 1.50 (ddd, J = 10.5, 8.3, 5.5 Hz, 1H),
0.62−0.50 (m, 4H); 13C{1H} NMR (126 MHz, CDCl3) δ 202.0,
155.8, 145.8, 141.0, 140.7, 132.4, 129.2, 128.3, 124.78, 121.7, 117.7,
112.2, 17.7, 10.5; IR (neat) υmax 3301, 3120, 2771, 1795, 1650, 1452,
1261, 1019, 858, 718 cm−1; HRMS (ESIMS) calcd for C18H15O2S [M
+ H]+ m/z 295.0793, found 295.0783.
5-Phenylbenzofuran-7-ol (14a). By following general procedure 2
using ynone 13a and nitromethane 11a compound 14a was prepared
as pale brown liquid (27.7 mg, 66%); Rf = 0.5 (20% EtOAc +
Hexane); 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.44 (s, 6H),
6-Phenylbenzo[b]thiophen-4-ol (12p). By following general
procedure 2 by using ynone 10g and nitromethane 11a compound
12p was prepared as brown viscous liquid (51.8 mg, 78%); Rf = 0.5
1
(20% EtOAc + Hexane); H NMR (400 MHz, CDCl3) δ 7.68 (s,
1H), 7.65−7.56 (m, 2H), 7.50−7.41 (m, 3H), 7.41−7.32 (m, 2H),
I
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6.79 (d, J = 3.4 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3) δ 151.8, 143.5, 136.5, 135.4, 132.3, 129.1,
128.8, 128.7, 128.1, 125.1, 112.2, 107.7; IR (neat) υmax 3229, 2956,
1501, 1187, 1024, 769 cm−1; HRMS (ESIMS) calcd for C14H11O2 [M
+ H]+ m/z 211.07536, found 211.07421.
155.3, 143.8, 141.4, 141.0, 139.5, 131.9, 129.8, 129.4, 128.2, 128.1,
127.6, 127.3, 127.2, 121.2, 116.5, 115.4; IR (neat) υmax 3102, 1736,
1604, 1400, 1280, 1168, 1073, 966, 761, 705, 667 cm−1; HRMS
(ESIMS) calcd for C21H14O2BrS [M + H]+ m/z 408.9898, found
408.9900.
4-Methyl-5-phenylbenzofuran-7-ol (14b). By following general
procedure 2 using ynone 13a and nitromethane 11b compound 14b
was prepared as pale brown liquid (27.7 mg, 62%); Rf = 0.5 (20%
Ethyl 7-hydroxy-2-methyl-5-phenylbenzo[b]thiophene-6-car-
boxylate (14h). By following general procedure 2using ynone 13f
and nitromethane 11e compound 14h was prepared as a white solid
(39.9 mg, 64%); Rf = 0.5 (10% EtOAc + Hexane); mp 106−108 °C;
1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 7.37−7.29 (m, 3H),
7.29−7.23 (m, 2H), 7.08 (s, 1H), 6.95 (d, J = 1.1 Hz, 1H), 3.99 (q, J
= 7.1 Hz, 2H), 2.63 (d, J = 1.1 Hz, 3H), 0.75 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 157.3, 146.9, 144.7,
143.7, 140.8, 128.5, 127.5, 126.4, 122.4, 116.9, 105.5, 60.9, 16.5, 13.0;
IR (neat) υmax 3127, 1714, 1650, 1519, 1403, 1181, 1056, 844, 713,
668 cm−1; HRMS (ESIMS) calcd for C18H17O3S [M + H]+ m/z
313.0898 , found 313.0901.
Ethyl 2-bromo-7-hydroxy-5-phenylbenzo[b]thiophene-6-car-
boxylate (14i). By following general procedure 2 using ynone 13e
and nitromethane 11e compound 14i was prepared as a white solid
(45.9 mg, 61%); Rf = 0.6 (10% EtOAc + Hexane); mp 118−120 °C;
1H NMR (500 MHz, CDCl3) δ 11.79 (s, 1H), 7.38−7.31 (m, 3H),
1
EtOAc + Hexane); H NMR (400 MHz, CDCl3) δ 7.45−7.39 (m,
5H), 6.69 (s, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz,
1H), 2.50 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.4, 146.6,
144.4, 141.6, 133.7, 128.6, 127.5, 126.6, 122.7, 111.4, 106.6, 104.6,
13.2; IR (neat) υmax 3327, 2806, 1442, 1311, 1124,1062, 774, 690
cm−1; HRMS (ESIMS) calcd for C15H13O2 [M + H]+ m/z 225.0916,
found 225.0916.
(2-Bromo-7-hydroxy-5-phenylbenzofuran-6-yl)(phenyl)-
methanone (14c). By following general procedure 2 using ynone 13b
and nitromethane 11f compound 14c was prepared as a pale yellow
solid (51.1 mg, 65%); Rf = 0.4 (10% EtOAc + Hexane); mp 136−138
1
°C; H NMR (500 MHz, CDCl3) δ 10.51 (s, 1H), 7.34 (dt, J = 8.4,
1.5 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.16−7.12 (m, 2H), 7.09 (s,
1H), 7.07−7.02 (m, 4H), 6.99 (dt, J = 9.5, 4.3 Hz, 1H), 6.80 (s, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 201.5, 145.8, 143.5, 141.0,
7.28 (s, 1H), 7.27−7.23 (m, 2H), 7.11 (s, 1H), 4.00 (q, J = 7.1 Hz,
2H), 0.76 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
171.3, 156.6, 143.4, 143.1, 141.5, 128.5, 128.0, 127.6, 127.1, 126.7,
121.0, 116.8, 106.5, 61.2, 13.0; IR (neat) υmax 3107, 1708, 1647, 1544,
1397, 1309, 1261, 1170, 954, 854, 711, 667 cm−1; HRMS (ESIMS)
calcd for C17H12O3BrS [M − H]+ m/z 374.96850 , found 374.96863.
7-Nitro-6-phenylbenzofuran-4-ol (16a). By following general
procedure 2 using ynone 15a and nitromethane 11a compound 16a
was prepared as a white solid (42.8 mg, 84%); Rf = 0.6 (20% EtOAc +
Hexane); mp 113−115 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J
= 2.2 Hz, 1H), 7.45−7.31 (m, 5H), 6.96 (d, J = 2.2 Hz, 1H), 6.62 (s,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.9, 149.2, 145.8, 137.4,
135.8, 128.7, 128.3, 128.1, 117.8, 111.2, 104.1; IR (neat) υmax 3390,
1594, 1521, 1429, 1328, 1216, 1148, 1077, 763, 710 cm−1; HRMS
(ESIMS) calcd for C14H8O4N [M − H]+ m/z 254.04478 , found
254.04435.
Ethyl 4-hydroxy-7-nitro-6-phenylbenzofuran-5-carboxylate
(16b). By following general procedure 2 using ynone 15a and
nitromethane 11e compound 16b was prepared as off white solid
(48.4 mg, 74%); Rf = 0.5 (20% EtOAc + Hexane); mp 119−121 °C;
1H NMR (400 MHz, CDCl3) δ 12.28 (s, 1H), 7.70 (d, J = 2.2 Hz,
1H), 7.41−7.32 (m, 3H), 7.25−7.21 (m, 2H), 7.11 (d, J = 2.2 Hz,
1H), 3.96 (q, J = 7.2 Hz, 2H), 0.71 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 170.8, 159.0, 149.3, 146.1, 136.1, 134.9,
128.6, 128.0, 127.8, 118.6, 106.8, 105.6, 61.8, 12.9; IR (neat) υmax
3116, 2987, 1677, 1528, 1443, 1361, 1315, 1189, 1022, 779, 700
cm−1; HRMS (ESIMS) calcd for C17H12O6N [M − H]+ m/z
326.06591 , found 326.06509.
140.1, 139.4, 133.7, 132.2, 131.9, 129.9, 129.3, 128.1, 127.6, 127.1,
117.1, 113.0, 109.3; IR (neat) υmax 3108, 1768, 1646, 1604, 1396,
1255, 1169, 953, 804, 711, 667 cm−1; HRMS (ESIMS) calcd for
C21H14O3Br [M + H]+ m/z 393.0126, found 393.0126.
(7-Hydroxy-2-methyl-5-phenylbenzofuran-6-yl)(phenyl)-
methanone (14d). By following general procedure 2 using ynone 13c
and nitromethane 11f compound 14d was prepared as pale yellow
solid (47.8 mg, 73%); Rf = 0.5 (20% EtOAc + Hexane); mp 178−180
1
°C; H NMR (400 MHz, CDCl3) δ 10.73 (s, 1H), 7.34 (dt, J = 8.4,
1.6 Hz, 2H), 7.20−7.11 (m, 3H), 7.07−7.00 (m, 5H), 6.99−6.92 (m,
1H), 6.46 (d, J = 1.0 Hz, 1H), 2.56 (d, J = 0.9 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 201.8, 159.9, 146.4, 142.1, 141.6, 139.8,
139.4, 134.7, 131.6, 130.0, 129.4, 128.0, 127.5, 126.8, 116.3, 113.6,
103.8, 14.5; IR (neat) υmax 3229, 1623, 1284, 1089, 946, 889, 670
cm−1; HRMS (ESIMS) calcd for C22H17O3 [M + H]+ m/z 329.1178,
found 329.1176.
(7-Hydroxy-5-phenylbenzo[b]thiophen-6-yl)(phenyl)methanone
(14e). By following general procedure 2 using ynone 13d and
nitromethane 11f compound 14e was prepared as a yellow solid (46.8
1
mg, 71%); Rf = 0.2 (10% EtOAc + Hexane); mp 138−140 °C; H
NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 7.72 (d, J = 5.3 Hz, 1H),
7.44 (s, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.38−7.33 (m, 2H), 7.21−7.14
(m, 3H), 7.09−7.02 (m, 4H), 7.01−6.95 (m, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 201.8, 156.7, 144.2, 141.4, 140.8, 139.7, 131.9,
131.7, 129.9, 129.4, 128.4, 127.6, 127.2, 127.0, 124.6, 117.4, 115.0; IR
(neat): 3743, 3059, 2924, 2857, 1715, 1610, 1366, 1278, 767 cm−1;
HRMS (ESIMS) calcd for C21H15O2S [M + H]+ m/z 331.0793, found
331.0784.
4-Hydroxy-7-nitro-6-phenylbenzofuran-5-yl)(phenyl)methanone
(16c). By following general procedure 2 using ynone 15a and
nitromethane 11f compound 16c was prepared as a pale yellow solid
(61.7 mg, 86%); Rf = 0.6 (10% EtOAc + Hexane); mp 139−141 °C;
1H NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 7.76 (d, J = 2.1 Hz,
(7-Hydroxy-2-methyl-5-phenylbenzo[b]thiophen-6-yl)(phenyl)-
methanone (14f). By following general procedure 2 using ynone 13e
and nitromethane 11f compound 14f was prepared as a pale yellow
solid (47.4 mg, 69%) ; Rf = 0.4 (10% EtOAc + Hexane); mp 136−138
1
°C; H NMR (500 MHz, CDCl3) δ 11.19 (s, 1H), 7.36−7.30 (m,
1H), 7.25−7.20 (m, 3H), 7.15 (d, J = 2.1 Hz, 1H), 7.11−7.00 (m,
7H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.1, 156.0, 149.5, 146.5,
139.2, 134.6, 134.5, 132.3, 130.1, 128.8, 128.7, 128.4, 127.8, 118.6,
117.3, 105.6; IR (neat) υmax3155, 1639, 1581, 1526, 1441, 1326, 1268,
1164, 1089, 754, 696, 640 cm−1; HRMS (ESIMS) calcd for
C21H12O5N [M − H]+ m/z 358.07100 , found 358.07064.
4-Nitro-5-phenylbenzofuran-7-ol (16d). By following general
procedure 2 using ynone 15b and nitromethane 11a compound
16d was prepared as a dark yellow solid (38.2 mg, 75%); Rf = 0.6
(50% EtOAc + Hexane); mp 60−62 °C; 1H NMR (500 MHz,
CDCl3) δ 7.78 (d, J = 2.1 Hz, 1H), 7.46−7.36 (m, 3H), 7.32 (dd, J =
7.7, 1.6 Hz, 2H), 7.26 (d, J = 1.8 Hz, 1H), 6.81 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 147.9, 144.4, 142.4, 138.5, 136.1, 133.7,
128.5, 128.1, 127.9, 126.0, 114.2, 107.7; IR (neat) υmax 3182, 2989,
2H), 7.19−7.11 (m, 3H), 7.07−7.00 (m, 6H), 6.99−6.93 (m, 1H),
2.67 (d, J = 1.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.8,
156.3, 147.3, 145.2, 141.6, 140.9, 139.9, 131.6, 129.9, 129.4, 128.0,
127.5, 126.9, 126.5, 122.6, 116.7, 114.5, 16.6; IR (neat) υmax 3119,
1730, 1605, 1402, 1291, 1184, 1071, 969, 853, 763, 710, 667 cm−1;
HRMS (ESIMS) calcd for C22H17O2S [M + H]+ m/z 345.0949, found
345.0954.
(2-Bromo-7-hydroxy-5-phenylbenzo[b]thiophen-6-yl)(phenyl)-
methanone (14g). By following general procedure 2 using ynone 13f
and nitromethane 11f compound 14g was prepared as a yellow solid
(53.2 mg, 65%); Rf = 0.4 (20% EtOAc + Hexane); mp 116−118 °C;
1H NMR (500 MHz, CDCl3) δ 10.98 (s, 1H), 7.37 (s, 1H), 7.35−
7.32 (m, 2H), 7.30 (s, 1H), 7.20−7.13 (m, 3H), 7.08−7.02 (m, 4H),
7.01−6.96 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 201.6,
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1598, 1487, 1239, 1037, 952, 706 cm−1; HRMS (ESIMS) calcd for
C14H10O4N [M + H]+ m/z 256.0610 , found 256.0610.
1H NMR (400 MHz, CDCl3) δ 12.43 (s, 1H), 7.83 (d, J = 5.4 Hz,
1H), 7.44−7.31 (m, 4H), 7.30−7.19 (m, 2H), 3.98 (q, J = 7.2 Hz,
2H), 0.72 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
170.7, 159.4, 139.4, 136.4, 136.4, 134.3, 134.0, 129.1, 128.6, 127.9,
127.8, 121.9, 106.1, 61.9, 12.9; IR (neat) υmax 3243, 2981, 1712, 1618,
1597, 1365, 1309, 1298, 1075, 954, 728, 659 cm−1; HRMS (ESIMS)
calcd for C17H12NO5S [M − H]+ m/z 342.0430, found 342.0420.
(7-Hydroxy-4-nitro-5-phenylbenzo[b]thiophen-6-yl)(phenyl)-
methanone (16l). By following general procedure 2 using ynone 15d
and nitromethane 11f compound 16l was prepared as a pale yellow
solid (58.2 mg, 77%); Rf = 0.5 (40% EtOAc + Hexane); mp 118−120
°C; 1H NMR (400 MHz, CDCl3) δ 10.55 (s, 1H), 7.87 (d, J = 5.4 Hz,
1H), 7.52 (d, J = 5.4 Hz, 1H), 7.28−7.20 (m, 3H), 7.11−7.01 (m,
7H); 13C{1H} NMR (101 MHz, CDCl3) δ 200.9, 156.6, 139.2, 138.5,
136.6, 135.0, 134.4, 133.9, 132.3, 130.0, 128.9, 128.8, 128.5, 128.4,
127.7, 122.0, 116.5; IR (neat) υmax 3102, 2893, 1689, 1530, 1367,
1164, 1008, 976, 832, 743, 668 cm−1; HRMS (ESIMS) calcd for
C21H14O4NS [M + H]+ m/z 376.0638, found 376.0646.
(Z)-1-(Furan-3-yl)-4-nitro-3-phenylbut-2-en-1-one (17). In an
oven-dried Ace pressure tube (15 mL), was taken ynone 10a (0.2
mmol, 1.0 equiv) and nitromethane 11a (0.6 mmol, 3.0 equiv), to this
DMF (2 mL) and Cs2CO3 (0.4 mmol, 0.2 equiv) were added and the
cap was closed tightly; it was then placed in a preheated oil bath at 90
°C and was stirred for 1 h at the same temperature. The reaction
mixture was cooled to room temperature, was diluted with cold H2O
(5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic
extract was washed with brine (10 mL) and dried over Na2SO4;
volatiles were removed under reduced pressure to get the crude
compound which was purified by silica gel flash column
chromatography (EtOAc/Hexane) to give 17 (33.5 mg, 65%) as a
pale-yellow liquid. 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H),
7.54−7.48 (m, 3H), 7.47−7.43 (m, 3H), 7.11 (s, 1H), 6.86 (d, J = 1.4
Hz, 1H), 6.05 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 184.1,
147.7, 144.8, 144.0, 138.2, 130.3, 129.3, 127.7, 126.7, 108.9, 74.1; IR
(neat) υmax 2892, 1690, 1570, 1384, 1102, 984, 754 cm−1; HRMS
(ESIMS) calcd for C14H12NO4 [M + H]+ m/z 258.0766, found
258.0766.
5-Allyl-6-phenylbenzo[b]thiophen-4-ol (18). To a stirring solution
of 6-phenylbenzo[b]thiophen-4-ol 12p (22.6 mg, 0.1 mmol) in
anhydrous acetone (3.0 mL) were added K2CO3 (27.6 mg, 0.2 mmol)
and allyl bromide (18 μL, 0.15 mmol), the resulting reaction mixture
was heated at 80 °C for 3 h. After completion of the reaction, it was
filtered through a short plug of Celite and the filtrate was
concentrated under reduced pressure to give crude compound
which was dissolved in toluene (2 mL) and placed in an ace pressure
tube and heated at 150 °C for 12 h. The reaction mixture was directly
purified by silica gel column chromatography to afford the rearranged
allyl compound 18 as a viscous liquid (19.6 mg, 74%). Rf = 0.4 (20%
EtOAc + Hexane); 1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 5.5,
0.7 Hz, 1H), 7.43−7.38 (m, 3H), 7.38−7.31 (m, 4H), 6.06 (ddt, J =
17.2, 10.3, 5.6 Hz, 1H), 5.57 (s, 1H), 5.21 (ddq, J = 29.9, 17.3, 1.8
Hz, 2H), 3.44 (dt, J = 5.5, 1.8 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 149.9, 141.7, 140.6, 139.6, 136.6, 129.2, 129.2, 128.1, 127.1,
125.2, 120.0, 116.8, 116.3, 32.1; IR (neat) υmax 3423, 3015, 2947,
1611, 1474, 1254, 1089, 856, 760 cm−1; HRMS (ESIMS) calcd for
C17H15OS [M + H]+ m/z 267.08381, found 267.08440.
6-Phenylbenzo[b]thiophen-4-yltrifluoromethanesulfonate. To a
stirring solution of benzothiophene 12p (67.8 mg, 0.3 mmol) in
dichloromethane (5.0 mL) at 0 °C were added pyridine (48 μL, 0.6
mmol) and Tf2O (0.11 mL, 0.4 mmol) and the reaction was warmed
to room temperature and allowed to stir for 2 h. After completion of
the reaction (monitored by TLC), the reaction mixture was diluted
with dichloromethane (5 mL), quenched by adding sat. aq. NaHCO3
(5 mL) and H2O (5 mL), layers were separated and the aqueous layer
was extracted with dichloromethane (2 × 5 mL). The combined
organic extract was dried over Na2SO4 and volatiles were removed
under reduced pressure to give crude compound, which was purified
by silica gel column chromatography to afford the triflate compound
as a pale-yellow liquid (52.8 mg, 78%). Rf = 0.6 (10% EtOAc +
Hexane); 1H NMR (500 MHz, CDCl3) δ 8.11−8.06 (m, 1H), 7.65−
Ethyl 7-hydroxy-4-nitro-5-phenylbenzofuran-6-carboxylate
(16e). By following general procedure 2 using ynone 15b and
nitromethane 11e compound 16e was prepared as a yellow solid (53.1
mg, 81%); Rf = 0.4 (40% EtOAc + Hexane); mp 86−88 °C; 1H NMR
(400 MHz, CDCl3) δ 12.16 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.43−
7.31 (m, 3H), 7.25−7.17 (m, 2H), 7.04 (d, J = 2.1 Hz, 1H), 3.97 (q, J
= 7.2 Hz, 2H), 0.72 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 170.7, 151.1, 149.9, 142.8, 136.8, 134.4, 128.5, 127.7, 108.6,
106.7, 61.9, 12.8; IR (neat) υmax 3118, 2992, 1709, 1622, 1568, 1365,
1311, 1298, 1081, 954, 767, 680 cm−1; HRMS (ESIMS) calcd for
C17H12NO6 [M − H]+ m/z 326.06591, found 326.06603.
(7-Hydroxy-4-nitro-5-phenylbenzofuran-6-yl)(phenyl)-
methanone (16f). By following general procedure 2 using ynone 15b
and nitromethane 11f compound 16f was prepared as a brown solid
(56.7 mg, 79%); Rf = 0.4 (50% EtOAc + Hexane); mp 90−92 °C; 1H
NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.32−7.23 (m, 4H), 7.14
(dd, J = 19.4, 11.8 Hz, 3H), 7.05 (s, 5H); 13C{1H} NMR (101 MHz,
CDCl3) δ 199.9, 149.9, 146.9, 142.6, 138.8, 135.1, 133.9, 132.6, 130.0,
128.8, 128.3, 128.2, 127.9, 127.6, 120.4, 107.0; IR (neat) υmax 3113,
2887,1701, 1644, 1518, 1378, 1098, 982, 844, 758, 667 cm−1; HRMS
(ESIMS) calcd for C21H14O5N [M + H]+ m/z 360.0866, found
360.0875.
2-Bromo-7-nitro-6-phenylbenzo[b]thiophen-4-ol (16g). By fol-
lowing general procedure 2 using ynone 15c and nitromethane 11a
compound 16g was prepared as a yellow solid (55.3 mg, 78%); Rf =
0.3 (50% EtOAc + Hexane); mp 136−138 °C; 1H NMR (500 MHz,
DMSO-d6) δ 12.09 (s, 1H), 7.77 (d, J = 1.1 Hz, 1H), 7.48−7.40 (m,
3H), 7.37 (dd, J = 7.8, 1.5 Hz, 2H), 6.74 (s, 1H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 156.9, 140.5, 139.8, 139.4, 132.4, 129.5, 128.8,
128.2, 124.0, 117.1, 115.1; IR (neat) υmax 3018, 2892, 1701, 1620,
1593 1408, 1171, 1015, 782, 667 cm−1; HRMS (ESIMS) calcd for
C14H9NO3SBr [M + H]+ m/z 349.9487, found 349.9489.
Ethyl 2-bromo-4-hydroxy-7-nitro-6-phenylbenzo[b]thiophene-5-
carboxylate (16h). By following general procedure 2 using ynone 15c
and nitromethane 11e compound 16h was prepared as a yellow solid
(63.3 mg, 75%); Rf = 0.4 (30% EtOAc + Hexane); mp 88−90 °C; 1H
NMR (500 MHz, CDCl3) δ 7.73 (s, 1H), 7.44−7.31 (m, 3H), 7.22−
7.12 (m, 2H), 3.95 (q, J = 7.2 Hz, 2H), 0.73 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 170.6, 159.4, 141.4, 138.1,
137.4, 130.3, 127.9, 127.8, 127.7, 124.1, 118.7, 109.5, 62.1, 12.9; IR
(neat) υmax 3034, 1711, 1682, 1524, 1395, 1320, 1241, 1179, 1082,
854, 711, 658 cm−1; HRMS (ESIMS) calcd for C17H11O5NBrS [M −
H]+ m/z 419.95358, found 419.95429.
(2-Bromo-4-hydroxy-7-nitro-6-phenylbenzo[b]thiophen-5-yl)-
(phenyl)methanone (16i). By following general procedure 2 using
ynone 15c and nitromethane 11f compound 16i was prepared as a
pale yellow solid (73.5 mg, 82%); Rf = 0.4 (40% EtOAc + Hexane);
mp 174−176 °C; 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.30−
7.23 (m, 2H), 7.23−7.16 (m, 2H), 7.10 (t, J = 7.7 Hz, 2H), 7.07−
6.98 (m, 5H); 13C{1H} NMR (101 MHz, DMSO) δ 194.7, 151.8,
137.9, 137.7, 135.0, 134.8, 134.1, 134.0, 133.2, 129.6, 129.5, 129.5,
129.1, 128.5, 128.3, 123.3, 122.1; IR (neat) υmax 3027, 1746, 1622,
1590, 1498, 1396, 1211, 1048, 967, 809, 705 cm−1; HRMS (ESIMS)
calcd for C21H11O4NBrS [M − H]+ m/z 451.9586, found 451.9569.
4-Nitro-5-phenylbenzo[b]thiophen-7-ol (16j). By following gen-
eral procedure 2 using ynone 15d and nitromethane 11a compound
16j was prepared as a brown solid (39.6 mg, 72%); Rf = 0.4 (30%
1
EtOAc + Hexane); mp 62−64 °C; H NMR (500 MHz, CDCl3) δ
7.68 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 5.5 Hz, 1H), 7.48−7.31 (m,
5H), 6.72 (s, 1H), 6.45 (s, 1H).; 13C{1H} NMR (101 MHz, CDCl3)
δ 153.0, 137.9, 136.4, 135.7, 130.9, 128.8, 128.2, 128.0, 127.9, 122.5,
111.2. IR (neat) υmax 3126, 2874, 1627, 1592, 1423, 1389, 1038, 965,
748 cm−1; HRMS (ESIMS) calcd for C14H8NO3S [M − H]+ m/z
270.02194, found 270.02233.
Ethyl 7-hydroxy-4-nitro-5-phenylbenzo[b]thiophene-6-carboxy-
late (16k). By following general procedure 2 using ynone 15d and
nitromethane 11e compound 16k was prepared as an off white solid
(55.1 mg, 80%); Rf = 0.4 (30% EtOAc + Hexane); mp 130−132 °C;
K
https://doi.org/10.1021/acs.joc.1c01104
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
7.61 (m, 2H), 7.59 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H),
7.52−7.45 (m, 3H), 7.44−7.39 (m, 1H); 13C{1H} NMR (101 MHz,
DMSO) δ 144.3, 143.3, 139.4, 139.1, 131.6, 129.3, 128.3, 127.5,
121.1, 119.3, 116.3; IR (neat) υmax 2947, 2852, 2346, 1437, 1221,
1137, 1082, 847, 754 cm−1; HRMS (ESIMS) calcd for C15H8O3F3S2
[M − H]+ m/z 356.98615, found 356.98700.
Authors
Shweta Singh − Department of Organic Synthesis and Process
Chemistry, CSIR − Indian Institute of Chemical Technology,
Hyderabad 500007, India; School of Chemistry, University of
Hyderabad, Hyderabad 500046, India
Sharanya Nerella − Department of Organic Synthesis and
Process Chemistry, CSIR − Indian Institute of Chemical
Technology, Hyderabad 500007, India
4,6-Diphenylbenzo[b]thiophene (19). To a stirring solution of
above triflate (35.8 mg, 0.1 mmol) and phenylboronic acid (14.6 mg,
0.12 mmol) in toluene (3 mL) were added Pd(PPh3)4 (11.6 mg, 0.01
mmol) and K2CO3 (27.6 mg, 0.2 mmol) and the reaction mixture was
heated at 100 °C for 12 h. After completion, the reaction mixture was
filtered through short pad of Celite with the aid of EtOAc (5 mL), the
combined organic extract was dried over Na2SO4 and volatiles were
removed under reduced pressure to give crude compound, which was
purified by silica gel column chromatography to afford the phenylated
compound 19 as pale-yellow liquid (24.0 mg, 84%). Rf = 0.4 (20%
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01104
Notes
The authors declare no competing financial interest.
1
ACKNOWLEDGMENTS
EtOAc + Hexane); H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 1.2
■
Hz, 1H), 7.70 (dt, J = 3.1, 1.8 Hz, 2H), 7.66−7.57 (m, 3H), 7.55−
7.33 (m, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 141.3, 141.0,
141.0, 138.1, 137.8, 137.1, 129.1, 128.9, 128.8, 128.6, 127.6, 127.5,
127.4, 127.3, 127.2, 126.6, 124.5, 123.1, 119.9; IR (neat) υmax 3028,
2991, 1617, 1396, 1209, 782, 687 cm−1; HRMS (ESIMS) calcd for
C20H15S [M + H]+ m/z 287.0894, found 287.0892.
This research was carried out under the Indo-French “Joint
Laboratory for Natural Products and Synthesis towards
Affordable Health (NPSAH)” and supported by the Council
of Scientific and Industrial Research (CSIR) and Department
of Science and Technology (DST), New Delhi, under Project
Code GAP-584. S.S. thanks UGC for a D. S. Kothari
postdoctoral fellowship (DSKPDF). G.M. thanks Dr. Reddy’s
Laboratory (DRL) for the award of a Dr. Kallam Anji Reddy
Chair Professorship. IICT manuscript communication no.
IICT/PUBS/2021/045.
6-Phenylbenzo[b]thiophene-4-carbonitrile (20). To a stirring
solution of triflate (36.0 mg, 0.1 mmol) in DMF (2.0 mL) were
added Pd(PPh3)4 (11.6 mg, 0.01 mmol) and Zn(CN)2 (35.0 mg, 0.3
mmol), the reaction mixture was heated at 120 °C for 18 h. After
completion of the reaction, solids were filtered, the filtrate was diluted
with cold H2O and was extracted with EtOAc (3 × 5 mL), the
combined organic extract was dried over Na2SO4 and volatiles were
removed under reduced pressure to give the crude compound, which
was purified by silica gel column chromatography (5% EtOAc +
Hexane) to afford the cyano compound 20 as white solid (16.0 mg,
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68%). Rf = 0.5 (10% EtOAc + Hexane); mp 96−98 °C; H NMR
(400 MHz, CDCl3) δ 8.28 (dd, J = 1.4, 0.8 Hz, 1H), 7.95 (d, J = 1.5
Hz, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.64−7.60 (m, J = 5.4, 3.5, 1.1 Hz,
3H), 7.53−7.46 (m, 2H), 7.46−7.38 (m, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 141.3, 139.3, 139.0, 137.7, 130.5, 129.2, 129.0, 128.2,
127.3, 125.4, 122.1, 117.9, 107.1; IR (neat) υmax 2874, 2240, 1452,
1109, 764, 660 cm−1; HRMS (ESIMS) calcd for C15H10NS [M + H]+
m/z 236.0534, found 236.0534.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01104.
■
sı
Detailed mechanisms and 1H and 13C spectra for all new
compounds (PDF)
Accession Codes
CCDC 2053609−2053612 and 2064536−2064537 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Srihari Pabbaraja − Department of Organic Synthesis and
Process Chemistry, CSIR − Indian Institute of Chemical
Technology, Hyderabad 500007, India; orcid.org/0000-
0002-1708-6539; Email: srihari@iict.res.in
Goverdhan Mehta − School of Chemistry, University of
Hyderabad, Hyderabad 500046, India; orcid.org/0000-
0001-6841-4267; Email: gmehta43@gmail.com
L
https://doi.org/10.1021/acs.joc.1c01104
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