Silver-Mediated Synthesis of Substituted Benzofuran- And Indole-Pyrroles via Sequential Reaction of ortho-Alkynylaromatics with Methylene Isocyanides

Article abstract of DOI:10.1021/acs.joc.9b00528

A silver-mediated reaction between 2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)phenols or 2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)anilines and methylene isocyanides has been developed. A sequential 5-endo-dig cyclization and [3 + 2] cycloaddition process is proposed. This synthetic strategy is atom- and step-efficient and applicable to a broad scope of substrates, allowing the synthesis of valuable substituted benzofuran- and indole-pyrroles in moderate to high yields.

Full text of DOI:10.1021/acs.joc.9b00528

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Article
Silver-Mediated Synthesis of Substituted Benzofuran-
and Indole-Pyrroles via Sequential Reaction of
ortho-Alkynylaromatics with Methylene Isocyanides
Jian-Quan Liu, Xinyi Chen, Andrey Shatskiy, Markus D. Kärkäs, and Xiang-Shan Wang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019
Downloaded from http://pubs.acs.org on May 23, 2019
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Silver-Mediated Synthesis of Substituted Benzofuran- and Indole-Pyrroles via
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Sequential Reaction of ortho-Alkynylaromatics with Methylene Isocyanides
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Jian-Quan Liu,†,‡ Xinyi Chen,† Andrey Shatskiy,‡ Markus D. Kärkäs,*,‡ Xiang-Shan Wang*,†
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†
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials Jiangsu Normal University, Xuzhou, Jiangsu 221116, China
‡
Department of Chemistry, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden
* E-mail: karkas@kth.se (M.D.K.); xswang1974@yahoo.com (X.-S.W.)
ABSTRACT: A silver-mediated reaction between 2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)phenols or
2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)anilines and methylene isocyanides has been developed. A
sequential 5-endo-dig cyclization and [3+2] cycloaddition process is proposed. This synthetic strategy
is atom- and step-efficient and applicable to a broad scope of substrates, allowing the synthesis of
valuable substituted benzofuran- and indole-pyrroles in moderate to high yields.
KEYWORDS: alkynes; benzofurans; isocyanides; pyrroles; silver
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INTRODUCTION
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Isocyanides and alkynes are two classes of commercially available and extraordinarily versatile
building blocks, widely applied in organic synthesis.1,2 Although the reports describing the reactions
between methylene isocyanates and alkynes are considerably rare, there have been noteworthy
developments in the past years.3 Likhar and coworkers described the synthesis of 2,4-disubstituted
pyrroles via a Cu-catalyzed cycloaddition between isocyanides and terminal alkynes.4 In contrast to
Likhar’s work, the Bi and Lei groups realized that the cycloaddition reaction of isocyanides with
unactivated terminal alkynes in the presence of a silver catalyst afforded 2,3-disubstituted pyrroles
(Figure 1a).5 Following these reports, Bi and coworkers reported a conceptually distinct C–C
coupling/oxygen transposition of terminal propargylic alcohols with isocyanides to give a variety of
synthetically valuable 2,3-alleneamides (Figure 1b).6a Herein, we disclose our continued efforts to
further expand the synthetic utility of these reactions to the synthesis of functionalized benzofuran-
and indole-pyrroles (Figure 1c).6b Gratifyingly, a new silver-mediated sequential reaction of
2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)aromatics with activated methylene isocyanides was realized,
providing a modular approach to benzofuran- and indole-pyrroles with broad substrate scope and in
good to high yields. A reaction pathway including 5-endo-dig cyclization and regioselective [3+2]
cycloaddition is proposed.
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Figure 1. Metal-catalyzed reactions for synthesis of pyrroles.
RESULTS AND DISCUSSION
At the beginning, we concentrated on optimization of the reaction conditions with
3-(1-hydroxyprop-2-yn-1-yl)-2-(phenylethynyl)phenol (1a) and ethyl isocyanoacetate (2a) as the
model substrates (Table 1). A range of silver catalysts, including AgOAc, AgF and AgNO2, and other
metal catalysts, such as CuI and Pd(OAc)2, were initially screened in 1,4-dioxane at 80 C (Table 1,
entries 1–8). We found that Ag2O displayed the best reactivity, affording product 3a in 73% yield
(Table 1, entry 6), while other metal catalysts were found to be less efficient. Next, the solvent effect
was evaluated and proved that the use of N,N-dimethyl formamide (DMF) greatly increased the yield
of 3a to 91% (Table 1, entry 11). In contrast, aprotic and polar solvents, such as DCE and CH3CN, had
a negative effect, and delivered 3a in 68% and 59% yields, respectively (Table 1, entries 9 and 10).
Furthermore, the use of the protic solvent EtOH only resulted in formation of trace amounts of 3a. A
decrease in the reaction temperature from 80 C to 40 C or 25 C, reduced the yield of the desired
product (Table 1, entries 13 and 14). Gratifyingly, the reaction without addition of a silver catalyst
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failed to produce the product (Table 1, entry 15). The conditions highlighted in Table 1 were
therefore selected as optimal. The structure of product 3a was further established by X-ray
crystallography (CCDC 1881196, see Table 1).
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Table 1. Optimization of the Reaction Conditionsa
Entry
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[M]
AgOAc
AgF
AgNO2
Ag2CO3
AgBF4
Ag2O
Pd(OAc)2
CuI
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
--
Solvent
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCE
Yield (%)b
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Temp (C)
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31c
27c
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CH3CN
DMF
EtOH
DMF
DMF
DMF
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trace
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0
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst (0.03 mmol), solvent (2.0 mL), 80 °C
under air, 8.0 h. b Isolated yields. c 1H NMR yields using CH2Br2 as internal standard.
Guided by the preliminary findings, the scope of the transformation was explored (Scheme 1). An
assortment of substituted 2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)phenols 1 reacted under the
optimized reaction conditions with ethyl isocyanoacetate (2a) to furnish the corresponding products.
The reaction was compatible with a variety of aryl motifs substituted at the para-, meta- and
ortho-positions, furnishing benzofuran-pyrrole products 3b–3m in moderate to good yields.
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Importantly, a variety of synthetically valuable functional groups, including fluoride and chloride
were well tolerated in the reaction to deliver the functionalized products in synthetically useful yields.
The tolerance of these functional groups offers an opportunity for further elaboration of chemical
space. Similarly, propargylic derivatives bearing aromatic substituents, including fused aryl and
heteroaryl groups, underwent smooth reaction with 2a to deliver the products 3n–3p in 65–72%
yields. Gratifyingly, the alkenyl substituent 1-cyclohexenyl was tolerated, producing 3q in 74% yield.
Furthermore, under the same conditions the cyclopropyl and n-butyl-derivatized substrates 1r and 1s
generated products 3r and 3s in acceptable yields. According to NMR analysis and high resolution
mass spectra, 3r and 3s are not oxidized product, which is presumably due to the delocalization of
the electron density onto the aryl rings and is of great help to put forward a mechanism.7 Attempts
at obtaining the corresponding ketone products by prolonging the reaction time were unsuccessful.
Additionally, the methoxy substituted substrate 1t afforded the target product 3t in decent yield.
Finally, the scope with respect to isocyanides was investigated under the optimized conditions. A
range of activated methylene isocyanides including methyl isocyanoacetate and isocyanoacetamide
derivatives reacted with 1a, delivering the expected products 3u–3w in good yields.
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Scheme 1. Substrate Scope
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Encouraged by these findings, the applicability of the present transformation was evaluated by
carrying out the reaction of 3-(1-hydroxyprop-2-yn-1-yl)-2-(phenylethynyl)phenol 1a and ethyl
isocyanoacetate 2a on gram scale. The corresponding product 3a was obtained with a slightly
decreased yield of 79% (Scheme 2a). Unfortunately, subjecting the internal alkyne substrate 4a and
2a to the standard conditions resulted in no product (Scheme 2b). This implies that the formation of
the corresponding silver acetylide is essential.5,8 Furthermore, when terminating the reaction mixture
of 1a and 2c after half of the standard reaction time, intermediates 5 and 6 were obtained in
reasonable yields (Scheme 2c). Adducts 5 and 6 could be easily converted to the corresponding
product 3a in high yields, stressing the involvement of 5 and 6 as key intermediates in the developed
transformation.
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Scheme 2. Gram-Scale Synthesis and Mechanistic Studies
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Based on related precedents9,10 including previous reports on silver-catalyzed reactions of
isocyanides with terminal alkynes and propargylic alcohols, a plausible reaction mechanism for the
formation of benzofuran-pyrrole 3 was proposed (Scheme 3). Owing to the chelating effect of the
hydroxyl and alkynyl units, silver complex A is initially formed. A subsequent 5-endo-dig cyclization of
complex A generates benzofuran B.11 Next, the terminal alkyne in B undergoes a [3+2] cycloaddition
of the alkynyl unit with the isocyanide, thus affording intermediate C. Finally, oxidation of the alcohol
moiety to the corresponding carbonyl group gives the final product 3.
Scheme 3. Proposed Reaction Mechanism
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Lastly, to expand the application of this transform, substrate 7 was synthesized from
2-bromo-3-nitro-benzaldehyde (for synthetic details, see the Supporting Information). As shown in
Scheme 4, under the same reaction conditions, indole-pyrrole 8 could be generated in high yield. The
product 8 is not further oxidized, which is presumably due to the electron-rich indole ring that
increases the electron density around the hydroxy group and makes it less prone to undergo
oxidation. These observations strongly support that formation of 8 occurs through a similar pathway
as that of benzofuran-based derivatives 3.
Scheme 4. Formation of Indole-Pyrrole
CONCLUSIONS
In summary, we have developed a silver-mediated sequential cyclization reaction of isocyanides with
2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)phenols or 2-ethynyl-3-(1-hydroxyprop-2-yn-1-yl)anilines,
affording benzofuran- and indole-pyrroles in good to high yields. A mechanistic pathway for the
formation of these versatile products was proposed. Considering the relevance of
benzofuran-pyrroles as potentially useful building blocks, this practical methodology will certainly
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find promising synthetic applications in the future.
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EXPERIMENTAL SECTION
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General Information. All reagents were purchased from commercial sources (Adamas, Aladdin,
etc) and used without further treatment, unless otherwise indicated. The products were purified by
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column chromatography over silica gel. H NMR and 13C NMR spectra were recorded at 25 °C on a
Varian 400 MHz and 100 MHz, respectively, and TMS was used as internal standard. High resolution
mass spectra (HRMS) were recorded on Bruck MicroTof using ESI-TOF method.
General Procedure for the Synthesis of 1 (Using 1a as an Example). Triethylamine (0.5 mL, 3.5
mmol) and DMAP (0.012 g, 0.1 mmol) were added to
a well-stirred solution of
2-bromo-3-hydroxybenzaldehyde (0.35 g, 1.7 mmol) in CH2Cl2 (10 mL) under N2. The reaction mixture
was cooled to 0 °C, and Ac2O (0.35 mL, 3.6 mmol) was added drop-wise at the same temperature,
followed by stirring for 1 h at room temperature. The reaction mixture was then poured into an
aqueous saturated solution of NaHCO3 and extracted with CH2Cl2. The organic layer was washed with
brine, dried over MgSO4 and concentrated. Purification of the crude product by column
chromatography (silica gel; petroleum ether/ethyl acetate 7:1) afforded 2-bromo-3-formylphenyl
acetate in 95% yield as a yellow solid.
To a mixture of 2-bromo-3-formylphenyl acetate (0.39 g, 1.64 mmol), CuI (0.019 g, 0.1 mmol) and
Pd(PPh3)2Cl2 (0.07 g, 0.1 mmol) in triethylamine (10.0 mL) stirred at 50 °C was added ethynylbenzene
(219 μL, 2.0 mmol) under N2, until 2-bromo-3-formylphenyl acetate was consumed as indicated by
TLC (about 10 h). The resulting mixture was concentrated and the residue was taken up in CH2Cl2.
The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification of the
crude product by column chromatography (silica gel; petroleum ether/ethyl acetate 10:1) afforded
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3-formyl-2-(phenylethynyl)phenyl acetate in 89% yield as a white solid.12a
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A mixture of 3-formyl-2-(phenylethynyl)phenyl acetate (0.40 g, 1.5 mmol) and K2CO3 (0.42 g, 3.0
mmol) in MeOH (6.0 mL) was stirred at room temperature for 0.5 h. The reaction mixture was then
neutralized with 1 N HCl and the resulting solution was concentrated to remove MeOH. The residue
was partitioned with EtOAc and water, and the organic layer was washed with brine, dried over
MgSO4, and concentrated. Purification of the crude product by column chromatography (silica gel;
petroleum ether/ethyl acetate 4:1) afforded 3-hydroxy-2-(phenylethynyl)benzaldehyde in 80% yield
as a white solid.12b
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A solution of 3-hydroxy-2-(phenylethynyl)benzaldehyde (0.222 g, 1.0 mmol) in distilled THF (2 mL)
was treated at 0 °C with ethynylmagnesium bromide (3 mL, 1.5 mmol). The resulting mixture was
stirred at 0 °C for 1 h and for 4 h at room temperature. After treatment with a saturated aqueous
solution of NH4Cl and extractions with Et2O, the combined organic layers were washed with brine,
dried over MgSO4, and concentrated under reduced pressure. Purification of the crude product by
column chromatography (silica gel; petroleum ether/ethyl acetate 3:1) afforded 1a in 94% yield as a
yellow solid.12c
3-(1-Hydroxyprop-2-yn-1-yl)-2-(phenylethynyl)phenol (1a). Yield 94% (233 mg). Pale yellow solid;
m.p. 86–87 C; 1H NMR (400 MHz, CDCl3) δ 7.58–7.56 (m, 2H), 7.41–7.39 (m, 3H), 7.32–7.27 (m, 2H),
6.99 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 5.96 (s, 1H), 5.83 (s, 1H), 2.67 (d, J = 2.4 Hz, 1H), 2.59 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 156.9, 142.1, 131.6 (2C), 130.4, 129.2, 128.6 (2C), 121.9, 118.5, 114.9, 108.0,
101.8, 82.8, 80.3, 74.7, 63.2; HRMS (ESI-TOF) m/z calculated for C17H13O2 [M+H]+: 249.0910, found:
249.0917.
3-(1-Hydroxyprop-2-yn-1-yl)-2-((4-methoxyphenyl)ethynyl)phenol (1b). Yield 92% (256 mg). Pale
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yellow solid; m.p. 88–89 C; 1H NMR (400 MHz, CDCl3) δ 7.51–7.47 (m, 2H), 7.30–7.25 (m, 2H), 6.98–
6.96 (m, 1H), 6.92–6.88 (m, 2H), 6.00 (s, 1H), 5.81 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 3.84 (s, 3H), 2.72 (d, J =
6.0 Hz, 1H), 2.66 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.3, 156.7, 141.9, 133.1 (2C),
130.0, 118.5, 114.8, 114.2 (2C), 113.9, 108.3, 101.9, 82.8, 79.0, 74.6, 63.1, 55.4; HRMS (ESI-TOF) m/z
calculated for C18H15O3 [M+H]+: 279.1016, found: 279.1021.
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3-(1-Hydroxyprop-2-yn-1-yl)-2-(p-tolylethynyl)phenol (1c). Yield 87% (228 mg). Pale yellow solid;
m.p. 86–87 C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.29–7.25 (m, 2H), 7.19 (d, J = 8.0
Hz, 2H), 6.98 (dd, J = 7.2 Hz, 2.4 Hz, 1H), 5.98 (s, 1H), 5.82 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 2.66–2.65 (m,
2H), 2.39 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.7, 142.0, 139.5, 131.4 (2C), 130.1, 129.3 (2C),
118.8, 118.5, 114.8, 108.2, 102.1, 82.8, 79.6, 74.6, 63.1, 21.5; HRMS (ESI-TOF) m/z calculated for
C18H15O2 [M+H]+: 263.1067, found: 263.1069.
2-((4-Fluorophenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1d). Yield 81% (215 mg). Pale
yellow solid; m.p. 92–93 C; 1H NMR (400 MHz, CDCl3) δ 7.54–7.50 (m, 2H), 7.28–7.25 (m, 2H), 7.06–
7.02 (m, 2H), 6.93 (dd, J = 6.4 Hz, 2.8 Hz, 1H), 6.41 (s, 1H), 5.80 (d, J = 2.0 Hz, 1H), 3.34 (s, 1H), 2.64
(d, J = 2.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.8 (d, J = 250 Hz), 156.9, 142.4, 133.5 (d, J = 8.4
Hz, 2C), 130.2, 118.3, 118.2 (d, J = 3.6 Hz), 115.8 (d, J = 22 Hz, 2C), 114.9, 108.0, 100.1, 82.9, 80.5,
74.4, 62.8; HRMS (ESI-TOF) m/z calculated for C17H12FO2 [M+H]+: 267.0816, found: 267.0811.
2-((4-Chlorophenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1e). Yield 79% (222 mg). Pale
yellow solid; m.p. 137–138 C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 2H), 7.44–7.27 (m, 4H),
6.98 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 5.89 (s, 1H), 5.80 (s, 1H), 2.67 (d, J = 2.4 Hz, 1H), 2.51 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 157.0, 142.3, 135.5, 132.9 (2C), 130.7, 129.1 (2C), 120.5, 118.7, 115.1, 107.8,
100.7, 82.8, 81.4, 74.9, 63.2; HRMS (ESI-TOF) m/z calculated for C17H12ClO2 [M+H]+: 283.0520, found:
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2-((4-Ethylphenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1f). Yield 73% (201 mg). Pale yellow
solid; m.p. 88–89 C; 1H NMR (400 MHz, CDCl3) δ 7.89–7.84 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (d, J
= 7.2 Hz, 1H), 7.38–7.30 (m, 3H), 5.98 (s, 1H), 5.82 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 2.82–2.71 (m, 3H), 2.39
(d, J = 6.0 Hz, 1H), 1.33 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.6, 155.2, 145.3, 132.0,
128.4 (2C), 127.7, 127.4, 125.2 (2C), 123.9, 120.7, 111.7, 99.5, 83.0, 75.1, 63.5, 28.8, 15.5; HRMS
(ESI-TOF) m/z calculated for C19H17O2 [M+H]+: 277.1223, found: 277.1221.
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2-((4-(Tert-butyl)phenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1g). Yield 59% (179 mg). Pale
yellow solid; m.p. 76–77 C; 1H NMR (400 MHz, CDCl3) δ 7.59–7.54 (m, 2H), 7.48–7.45 (m, 2H), 7.36–
7.32 (m, 2H), 7.03 (dd, J = 6.4 Hz, 2.8 Hz, 1H), 6.10 (s, 1H), 5.88 (s, 1H), 2.84 (s, 1H), 2.39 (d, J = 2.0 Hz,
1H), 1.39 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.9, 152.7, 142.1, 131.4 (2C), 130.2, 125.7 (2C),
118.7, 118.5, 114.9, 108.3, 102.1, 82.9, 79.7, 74.7, 63.2, 35.0, 31.2 (3C); HRMS (ESI-TOF) m/z
calculated for C21H21O2 [M+H]+: 305.1542, found: 305.1557.
2-((4-Ethoxyphenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1h). Yield 80% (233 mg). Pale
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yellow solid; m.p. 94–96 C; H NMR (400 MHz, CDCl3) δ 7.56–7.51 (m, 2H), 7.35–7.30 (m, 2H), 7.02
(dd, J = 7.6 Hz, 2.4 Hz, 1H), 6.97–6.92 (m, 2H), 6.06 (s, 1H), 5.87 (s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 2.75 (s,
1H), 2.71 (d, J = 2.0 Hz, 1H), 1.47 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 156.8,
142.0, 133.2 (2C), 130.1, 118.5, 114.8, 114.7 (2C), 113.7, 108.5, 102.1, 82.9, 78.9, 74.7, 63.7, 63.2,
14.8; HRMS (ESI-TOF) m/z calculated for C19H17O3 [M+H]+: 293.1178, found: 293.1179.
3-(1-Hydroxyprop-2-yn-1-yl)-2-((2-methoxyphenyl)ethynyl)phenol (1i). Yield 73% (202 mg). Pale
yellow solid; m.p. 68–69 C; 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.45–7.35 (m,
1H), 7.37–7.28 (m, 2H), 7.08–6.98 (m, 3H), 6.83 (m, 1H), 5.86 (m, 1H), 4.03 (s, 3H), 3.31 (d, J = 8.0 Hz,
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1H), 2.72 (d, J = 2.4 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 157.5, 141.4, 131.5, 130.5, 130.2,
120.9, 118.5, 114.9, 111.4, 110.4, 108.4, 98.7, 86.4, 82.7, 74.8, 63.5, 55.9; HRMS (ESI-TOF) m/z
calculated for C18H15O3 [M+H]+: 279.1021, found: 279.1032.
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3-(1-Hydroxyprop-2-yn-1-yl)-2-((3-methoxyphenyl)ethynyl)phenol (1j). Yield 84% (234 mg). Pale
yellow solid; m.p. 81–82 C; 1H NMR (400 MHz, CDCl3) δ 7.40–7.30 (m, 3H), 7.24–7.20 (m, 1H), 7.15–
7.12 (m, 1H), 7.07–6.99 (m, 2H), 6.01 (s, 1H), 5.87 (dd, J = 6.4 Hz, 2.4 Hz, 1H), 3.89 (s, 3H), 2.72 (d, J =
2.4 Hz, 1H), 2.63 (d, J = 6.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 156.9, 142.2, 130.5, 129.7,
124.2, 122.9, 118.6, 116.5, 115.8, 115.0, 108.0, 101.8, 82.8, 80.1, 74.7, 63.2, 55.4; HRMS (ESI-TOF)
m/z calculated for C18H15O3 [M+H]+: 279.1021, found: 279.1036.
3-(1-Hydroxyprop-2-yn-1-yl)-2-(m-tolylethynyl)phenol (1k). Yield 85% (223 mg). Pale yellow solid;
m.p. 86–87 C; 1H NMR (400 MHz, CDCl3) δ 7.41–7.34 (m, 2H), 7.33–7.26 (m, 3H), 7.19 (d, J = 7.6 Hz,
1H), 6.97 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 5.99 (s, 1H), 5.82 (s, 1H), 2.68–2.66 (m, 2H), 2.34 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 156.9, 142.2, 138.5, 132.2, 130.4, 130.2, 128.6, 128.5, 121.8, 118.6, 115.0,
108.2, 102.2, 82.9, 80.0, 74.8, 63.3, 21.3; HRMS (ESI-TOF) m/z calculated for C18H15O2 [M+H]+:
263.1067, found: 263.1072.
2-((3-Fluorophenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1l). Yield 77% (204 mg). Pale
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yellow solid; m.p. 112–113 C; H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m, 2H), 7.38–7.34 (m, 3H),
7.19–7.13 (m, 1H), 7.03 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 6.00 (s, 1H), 5.85 (s, 1H), 2.72 (d, J = 2.4 Hz, 1H),
2.67 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.6 (d, J = 246 Hz), 157.0, 142.3, 130.8, 130.3 (d, J =
8.7 Hz), 127.5 (d, J = 3.1 Hz), 123.8 (d, J = 9.4 Hz), 118.6, 118.4 (d, J = 23 Hz), 116.6 (d, J = 21 Hz),
115.1, 107.6, 100.3 (d, J = 3.5 Hz), 82.7, 81.4, 74.8, 63.1; HRMS (ESI-TOF) m/z calculated for C17H12FO2
[M+H]+: 267.0816, found: 267.0820.
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2-((3-Chlorophenyl)ethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1m). Yield 76% (215 mg). Pale
yellow solid; m.p. 134–135 C; 1H NMR (400 MHz, CDCl3) δ 7.71–7.25 (m, 6H), 7.04 (d, J = 8.0 Hz, 1H),
5.93 (s, 1H), 5.85 (s, 1H), 2.73 (d, J = 2.4 Hz, 1H), 2.55 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.1,
142.4, 134.6, 131.5, 130.9, 129.8, 129.5, 123.9, 118.7, 115.2, 107.7, 100.3, 100.1, 82.8, 81.6, 74.9,
63.2; HRMS (ESI-TOF) m/z calculated for C17H12ClO2 [M+H]+: 283.0520, found: 283.0527.
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3-(1-Hydroxyprop-2-yn-1-yl)-2-(naphthalen-1-ylethynyl)phenol (1n). Yield 62% (185 mg). Pale
yellow solid; m.p. 143–144 C; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.4 Hz, 1H), 7.95–7.87 (m, 2H),
7.80 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.67–7.46 (m, 3H), 7.37–7.32 (m, 2H), 7.07–7.01 (m, 1H), 6.07 (s, 1H),
5.93 (dd, J = 6.0 Hz, 2.4 Hz, 1H), 2.70 (d, J = 2.0 Hz, 1H), 2.58 (d, J = 2.0 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 157.0, 142.1, 133.2, 133.0, 131.0, 130.5, 129.9, 128.5, 127.4, 126.8, 125.9, 125.3, 119.6,
118.6, 115.1, 108.3, 100.1, 84.9, 82.9, 74.9, 63.3; HRMS (ESI-TOF) m/z calculated for C21H15O2 [M+H]+:
299.1067, found: 299.1083.
3-(1-Hydroxyprop-2-yn-1-yl)-2-(naphthalen-2-ylethynyl)phenol (1o). Yield 73% (217 mg). Pale
yellow solid; m.p. 130–131 C; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.87–7.79 (m, 3H), 7.61–7.48
(m, 3H), 7.35–7.27 (m, 2H), 7.05–6.96 (m, 1H), 6.03 (s, 1H), 5.87 (dd, J = 6.0 Hz, 2.0 Hz, 1H), 2.68 (d, J
= 2.4 Hz, 1H), 2.65 (d, J = 6.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.0, 142.2, 133.2, 132.9,
131.8, 130.5, 128.4, 127.95, 127.94, 127.9, 127.3, 126.9, 119.2, 118.6, 115.0, 108.1, 102.3, 82.9, 80.7,
74.8, 63.3; HRMS (ESI-TOF) m/z calculated for C21H15O2 [M+H]+: 299.1067, found: 299.1073.
3-(1-Hydroxyprop-2-yn-1-yl)-2-(thiophen-2-ylethynyl)phenol (1p). Yield 69% (176 mg). Pale yellow
solid; m.p. 134–135 C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 2H), 7.39–7.30 (m, 2H), 7.11 (dd, J
= 5.2 Hz, 3.6 Hz, 1H), 7.02 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 6.12 (s, 1H), 5.85 (s, 1H), 2.73 (s, 1H), 2.71 (d, J =
2.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.0, 142.3, 132.9, 130.7, 128.6, 127.4, 121.8, 118.6,
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115.1, 107.9, 94.6, 84.1, 82.8, 74.7, 63.1; HRMS (ESI-TOF) m/z calculated for C15H11O2S [M+H]+:
255.0474, found: 255.0476.
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2-(Cyclohex-1-en-1-ylethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1q). Yield 53% (134 mg). m.p.
89–90 C; 1H NMR (400 MHz, CDCl3) δ 7.25–7.18 (m, 2H), 6.92 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 6.32–6.26
(m, 1H), 5.92 (s, 1H), 5.71 (dd, J = 5.6 Hz, 2.0 Hz, 1H), 2.75 (d, J = 6.0 Hz, 1H), 2.63 (d, J = 2.4 Hz, 1H),
2.29–2.12 (m, 4H), 1.75–1.57 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.5, 141.7, 136.9, 129.7,
119.9, 118.4, 114.6, 108.5, 103.9, 82.8, 77.5, 74.5, 63.1, 29.0, 25.7, 22.1, 21.2; HRMS (ESI-TOF) m/z
calculated for C17H17O2 [M+H]+: 253.1223, found: 253.1233.
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2-(Cyclopropylethynyl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1r). Yield 59% (125 mg). Yellow oil; H
NMR (400 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.21–7.15 (m, 1H), 6.65 (s, 1H), 5.68 (dd, J = 5.6 Hz, 2.0
Hz, 1H), 2.69 (d, J = 3.0 Hz, 1H), 2.23 (t, J = 5.6 Hz, 1H), 2.11–2.01 (m, 1H), 1.05–0.95 (m, 4H); 13C{1H}
NMR (101 MHz, CDCl3) δ 161.1, 154.7, 131.1, 127.1, 122.9, 120.4, 111.2, 99.1, 83.1, 74.9, 63.5, 9.4,
7.5 (2C); HRMS (ESI-TOF) m/z calculated for C14H13O2 [M+H]+: 213.0910, found: 213.0922.
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2-(Hex-1-yn-1-yl)-3-(1-hydroxyprop-2-yn-1-yl)phenol (1s). Yield 63% (143 mg). Yellow oil; H NMR
(400 MHz, CDCl3) δ 7.43–7.34 (m, 2H), 7.23–7.17 (m, 1H), 6.66 (d, J = 1.2 Hz, 1H), 5.69 (dd, J = 5.2 Hz,
2.40 Hz, 1H), 2.83–2.75 (m, 2H), 2.69 (d, J = 2.4 Hz, 1H), 2.33 (d, J = 6.0 Hz, 1H), 1.80–1.68 (m, 2H),
1.49–1.37 (m, 2H), 0.94 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.3, 155.1, 131.4, 127.0,
123.0, 120.3, 111.3, 100.6, 83.1, 74.9, 63.4, 29.8, 28.2, 22.4, 13.9; HRMS (ESI-TOF) m/z calculated for
C15H17O2 [M+H]+: 229.1223, found: 229.1227.
3-(1-Hydroxyprop-2-yn-1-yl)-5-methoxy-2-(phenylethynyl)phenol (1t). Yield 86% (239 mg). Pale
yellow solid; m.p. 139–140 C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.2 Hz, 2H), 7.47–7.28 (m, 5H),
6.73 (d, J = 8.4 Hz, 1H), 5.69 (dd, J = 5.6 Hz, 2.0 Hz, 1H), 4.03 (s, 3H), 2.71 (d, J = 2.0 Hz, 1H), 2.43–2.31
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(m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.4, 145.7, 144.3, 130.1, 128.9, 128.8, 128.7 (2C), 125.2
(2C), 124.6, 121.9, 106.1, 100.6, 83.2, 74.9, 63.2, 56.2; HRMS (ESI-TOF) m/z calculated for C18H15O3
[M+H]+: 279.1016, found: 279.1020.
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General Procedure for the Synthesis of 7. A mixture of 2-bromo-3-nitrobenzaldehyde (1.0 g, 4.3
mmol) and sodium borohydride (1.6 g, 4.3 mmol) in MeOH (8.0 mL) was stirred at room temperature
until 2-bromo-3-nitrobenzaldehyde was consumed as indicated by TLC (about 4 h). The resulting
mixture was concentrated and the residue was taken up in CH2Cl2. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give
(2-bromo-3-nitrophenyl)methanol in 98% yield as a white solid, which was used directly in the next
step without additional purification.
A reaction flask was charged with the (2-bromo-3-nitrophenyl)methanol (0.9 g, 4.0 mmol), FeCl3
(16.2 mg, 0.1 mmol), activated carbon (2.0 g) and ethanol (20.0 mL). The mixture was heated to 80 °C,
followed by drop-wise addition of hydrazine hydrate (2.0 mL, 80%) under N2. The heating was
continued until (2-bromo-3-nitrophenyl)methanol was consumed as indicated by TLC (about 2 h).
The insoluble matter was removed by filtration while hot, and the filtrate was collected. The filtrate
was concentrated under reduced pressure and the residue was taken up in CH2Cl2. The combined
organic layers were washed with brine and dried over Na2SO4. The solvent was removed under
reduced pressure to give (3-amino-2-bromophenyl)methanol in 92% yield as a white solid, which was
used directly in the next step without additional purification.
A mixture of (3-amino-2-bromophenyl)methanol (0.6 g, 3.0 mmol), p-toluenesulfonyl chloride (0.6
g, 3.2 mmol) and pyridine (325 μL, 4.0 mmol) in CH2Cl2 (10 mL) was stirred at room temperature until
(3-amino-2-bromophenyl)methanol was consumed as indicated by TLC (about 4 h). The resulting
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mixture was concentrated and the residue was taken up in CH2Cl2. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give
N-(2-bromo-3-(hydroxymethyl)phenyl)-4-methylbenzenesulfonamide in 98% yield as a white solid,
which was used directly in the next step without additional purification.
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A mixture of N-(2-bromo-3-(hydroxymethyl)phenyl)-4-methylbenzenesulfonamide (0.7 g, 2.0
mmol) and pyridinium chlorochromate (0.86 g, 4.0 mmol) in MeOH (10 mL) was stirred at room
temperature, until the N-(2-bromo-3-(hydroxymethyl)phenyl)-4-methylbenzenesulfonamide was
consumed as indicated by TLC (about 2 h). The resulting mixture was concentrated and the residue
was taken up in CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4.
The
solvent
was
removed
under
reduced
pressure
to
give
N-(2-bromo-3-formylphenyl)-4-methylbenzenesulfonamide in 87% yield as a pale yellow solid, which
was used directly in the next step without additional purification.
A mixture of N-(2-bromo-3-formylphenyl)-4-methylbenzenesulfonamide (0.53 g, 1.5 mmol), CuI
(0.019 g, 0.1 mmol) and Pd(PPh3)2Cl2 (0.07 g, 0.1 mmol) in triethylamine (10.0 mL) was stirred at
50 °C, followed by addition of 1-ethynyl-4-methoxybenzene (233 μL, 1.8 mmol) under N2. The heating
was continued until N-(2-bromo-3-formylphenyl)-4-methylbenzenesulfonamide was consumed as
indicated by TLC (about 10 h). The resulting mixture was concentrated and the residue was taken up
in CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated. Purification
of the crude product by column chromatography (silica gel; petroleum ether/ethyl acetate 8:1)
afforded N-(3-formyl-2-((4-methoxyphenyl)ethynyl)phenyl)-4-methylbenzenesulfonamide in 87%
yield as a pale yellow solid.
A solution of N-(3-formyl-2-((4-methoxyphenyl)ethynyl)phenyl)-4-methylbenzenesulfonamide (0.4
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g, 1 mmol) in distilled THF (2 mL) was treated at 0 °C with ethynylmagnesium bromide (3 mL, 1.5
mmol). The resulting mixture was stirred at 0 °C for 1 h and for 4 h at room temperature. After
treatment with a saturated aqueous solution of NH4Cl and extractions with Et2O, the combined
organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure.
Purification of the crude product by column chromatography (silica gel; petroleum ether/ethyl
acetate 4:1) afforded 7 in 92% yield as a yellow solid.
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N-(3-(1-hydroxyprop-2-yn-1-yl)-2-((4-methoxyphenyl)ethynyl)phenyl)-4-methylbenzenesulfonamide
(7). Yield 73% (314 mg). Pale yellow solid; m.p. 78–79 C; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.4
Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43–7.39 (m, 2H), 7.35–7.31 (m, 1H), 7.27–7.25 (m, 2H), 7.03 (d, J =
8.0 Hz, 2H), 6.95–6.93 (m, 2H), 6.77 (d, J = 0.4 Hz, 1H), 5.66 (s, 1H), 3.87 (s, 3H), 2.64–2.63(m, 1H),
2.43–2.33 (m, 1H), 2.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 144.6, 142.1, 138.4, 134.7,
131.8 (2C), 131.1, 129.3 (2C), 128.4, 126.8 (2C), 124.5, 124.4, 122.0, 116.9, 112.9 (2C), 110.9, 82.8,
75.2, 62.9, 55.3, 21.5; HRMS (ESI-TOF) m/z calculated for C25H22NO4S [M+H]+: 432.1264, found:
432.1271.
General Procedure for the Synthesis of 3 and 8 (Using 3a as an Example). To a 25 mL Schlenk
tube equipped with a stirring bar was added ethyl 2-isocyanoacetate (50 μL, 0.45 mmol),
1-(2-(phenylethynyl)phenyl)prop-2-yn-1-ol (131 mg, 0.3 mmol), DMF (2.0 mL) and Ag2O (11 mg, 0.05
mmol). The mixture was stirred at 80 °C for about 8 h under air. The resulting mixture was
concentrated and the residue was taken up in CH2Cl2. The organic layer was washed with brine, dried
over MgSO4, and concentrated. Purification of the crude product by column chromatography (silica
gel; petroleum ether/ethyl acetate 3:1) afforded 3a.
Ethyl 4-(2-phenylbenzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3a). Yield 91% (98 mg). Pale
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yellow solid; m.p. 166–167 C; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.91–7.89 (m, 2H), 7.72–7.69
(m, 2H), 7.59–7.58 (m, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.48–7.44 (m, 2H), 7.42–7.41 (m, 1H), 7.40–7.33
(m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.7, 161.0,
157.7, 155.4, 131.3, 130.0, 129.2, 129.0, 128.8 (2C), 128.0, 126.6, 125.2 (2C), 125.0, 124.2, 123.3,
116.4, 114.6, 101.9, 61.0, 14.4; HRMS (ESI-TOF) m/z calculated for C22H18NO4 [M+H]+: 360.1230,
found: 360.1233.
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Ethyl 4-(2-(4-methoxyphenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3b). Yield 87%
(101 mg). Pale yellow solid; m.p. 224–226 C; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.83 (d, J = 8.8
Hz, 2H), 7.68 (t, J = 8.0 Hz, 2H), 7.59–7.57 (m, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H),
6.98 (d, J = 8.8 Hz, 2H), 4.36 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 189.9, 161.0, 160.3, 157.9, 155.2, 130.9, 129.5, 128.1, 126.7 (2C), 126.6, 124.9, 124.1,
122.8, 122.7, 116.4, 114.4, 114.3 (2C), 100.3, 61.0, 55.4, 14.3; HRMS (ESI-TOF) m/z calculated for
C23H20NO5 [M+H]+: 390.1336, found: 390.1349.
Ethyl 4-(2-(p-tolyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3c). Yield 82% (92 mg). Pale
yellow solid; m.p. 171–172 C; 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.70–
7.67 (m, 2H), 7.59–7.57 (m, 1H), 7.45 (d, J = 0.4 Hz, 1H), 7.42–7.41 (m, 1H), 7.35–7.31 (m, 1H), 7.28 (s,
1H), 7.26 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 2.40 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 189.8, 161.0, 158.0, 155.3, 139.2, 131.1, 129.5 (2C), 129.3, 128.0, 127.3, 126.6, 125.2 (2C),
124.9, 124.1, 123.0, 116.4, 114.5, 101.2, 61.0, 21.4, 14.4; HRMS (ESI-TOF) m/z calculated for
C23H20NO4 [M+H]+: 374.1387, found: 374.1401.
Ethyl 4-(2-(4-fluorophenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3d). Yield 86% (97
mg). Yellow solid; m.p. 161–162 C; 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.90–7.85 (m, 2H), 7.70
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(t, J = 8.0 Hz, 2H), 7.60–7.58 (m, 1H), 7.46 (s, 1H), 7.42–7.41 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.18–7.12
(m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.7, 163.1
(d, J = 248 Hz), 161.0, 156.8, 155.3, 131.3, 129.2, 128.0, 127.1 (d, J = 8.2 Hz, 2C), 126.5, 126.3 (d, J =
3.3 Hz), 125.1, 124.2, 123.3, 116.4, 116.0 (d, J = 20 Hz, 2C), 114.6, 101.6, 61.0, 14.4; HRMS (ESI-TOF)
m/z calculated for C22H17FNO4 [M+H]+: 378.1136, found: 378.1147.
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Ethyl 4-(2-(4-chlorophenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3e). Yield 73% (86
mg). Pale yellow solid; m.p. 183–184 C; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.84–7.81 (m, 2H),
7.70 (t, J = 8.0 Hz, 2H), 7.59–7.58 (m, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.45–7.40 (m, 3H), 7.39–7.33 (m,
1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.6, 160.9,
156.6, 155.4, 134.9, 131.4, 129.1 (2C), 129.0, 128.5, 127.9, 126.5, 126.4 (2C), 125.1, 124.2, 123.6,
116.4, 114.6, 102.4, 61.0, 14.4; HRMS (ESI-TOF) m/z calculated for C22H17ClNO4 [M+H]+: 394.0841,
found: 394.0852.
Ethyl 4-(2-(4-ethylphenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3f). Yield 81% (94 mg).
Pale yellow solid; m.p. 176–177 C; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.83–7.80 (m, 2H), 7.70–
7.67 (m, 2H), 7.59–7.57 (m, 1H), 7.46 (d, J = 0.8 Hz, 1H), 7.42–7.41 (m, 1H), 7.35–7.28 (m, 3H), 4.37 (q,
J = 7.2 Hz, 2H), 2.70 (q, J = 8.0 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 189.8, 161.0, 158.1, 155.3, 145.5, 131.1, 129.4, 128.4 (2C), 128.0, 127.5, 126.6,
125.3 (2C), 124.9, 124.2, 123.0, 116.4, 114.5, 101.2, 61.0, 28.8, 15.4, 14.4; HRMS (ESI-TOF) m/z
calculated for C24H22NO4 [M+H]+: 388.1543, found: 388.1547.
Ethyl 4-(2-(4-(tert-butyl)phenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3g). Yield 67%
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(83 mg). Pale yellow solid; m.p. 185–187 C; H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.85–7.82 (m,
2H), 7.71–7.68 (m, 2H), 7.59–7.58 (m, 1H), 7.50–7.47 (m, 3H), 7.42–7.41 (m, 1H), 7.35–7.31 (m, 1H),
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4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.36 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.8,
161.0, 158.0, 155.3, 152.3, 131.1, 129.4, 128.1, 127.2, 126.6, 125.8 (2C), 125.0 (2C), 124.9, 124.2,
123.0, 116.4, 114.5, 101.3, 61.0, 34.8, 31.2 (3C), 14.3; HRMS (ESI-TOF) m/z calculated for C26H26NO4
[M+H]+: 416.1856, found: 416.1850.
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Ethyl 4-(2-(4-ethoxyphenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3h). Yield 89% (107
mg). Yellow solid; m.p. 176–178 C; 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 7.84–7.80 (m, 2H), 7.68
(t, J = 8.0 Hz, 2H), 7.59–7.57 (m, 1H), 7.42–7.41 (m, 1H), 7.37 (d, J = 0.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H),
7.00–6.95 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.38 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.8, 160.9, 159.8, 158.0, 155.2, 130.9, 129.6, 127.9,
126.8 (2C), 126.6, 124.9, 124.1, 122.7, 122.6, 116.4, 114.8 (2C), 114.4, 100.3, 63.6, 61.0, 14.8, 14.4;
HRMS (ESI-TOF) m/z calculated for C24H22NO5 [M+H]+: 404.1492, found: 404.1501.
Ethyl 4-(2-(2-methoxyphenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3i). Yield 92% (107
mg). Pale yellow solid; m.p. 195–197 C; 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.08 (dd, J = 7.6 Hz,
1.2 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.70–7.67 (m, 2H), 7.59–7.58 (m, 1H), 7.43–7.42 (m, 1H), 7.38–
7.32 (m, 2H), 7.11–7.07 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.38 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 190.0, 161.0, 157.0, 154.5, 154.2, 131.5, 129.9, 129.8,
128.0, 127.4, 126.9, 124.7, 124.2, 123.2, 120.8, 119.1, 116.5, 114.3, 111.2, 106.7, 61.1, 55.6, 14.5;
HRMS (ESI-TOF) m/z calculated for C23H20NO5 [M+H]+: 390.1336, found: 390.1338.
Ethyl 4-(2-(3-methoxyphenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3j). Yield 83% (97
mg). Pale yellow solid; m.p. 159–160 C; 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 7.72–7.69 (m, 2H),
7.59–7.58 (m, 1H), 7.52–7.49 (m, 2H), 7.44–7.41 (m, 2H), 7.39–7.34 (m, 2H), 6.95–6.92 (m, 1H), 4.37
(q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.7, 160.9,
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159.9, 157.6, 155.3, 131.3 (2C), 129.9, 129.1, 128.0, 126.5, 125.0, 124.2, 123.4, 117.8, 116.4, 115.2,
114.6, 110.1, 102.2, 61.0, 55.4, 14.4; HRMS (ESI-TOF) m/z calculated for C23H20NO5 [M+H]+: 390.1336,
found: 390.1342.
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Ethyl 4-(2-(m-tolyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3k). Yield 85% (95 mg). Pale
yellow solid; m.p. 177–178 C; 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.74–7.69 (m, 4H), 7.59–7.58
(m, 1H), 7.49 (d, J = 0.8 Hz, 1H), 7.42–7.41 (m, 1H), 7.35 (t, J = 8.8 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 4.37
(q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.7, 160.9,
157.9, 155.4, 138.5, 131.2, 129.9, 129.8, 129.2, 128.8, 127.9, 126.6, 125.8, 124.9, 124.2, 123.2, 122.4,
116.4, 114.6, 101.8, 61.0, 21.5, 14.4; HRMS (ESI-TOF) m/z calculated for C23H20NO4 [M+H]+: 374.1387,
found: 374.1397.
Ethyl 4-(2-(3-fluorophenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3l). Yield 76% (86
1
mg). Pale yellow solid; m.p. 198–199C; H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.73–7.66 (m, 3H),
7.61–7.58 (m, 2H), 7.54 (d, J = 1.2 Hz, 1H), 7.44–7.36 (m, 3H), 7.09–7.04 (m, 1H), 4.37 (q, J = 7.2 Hz,
2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.6, 163.1 (d, J = 244 Hz), 161.0, 156.3
(d, J = 3.1 Hz), 155.4, 132.1 (d, J = 8.4 Hz), 131.5, 130.4 (d, J = 8.3 Hz), 128.9, 128.1, 126.4, 125.1,
124.2, 123.8, 120.9 (d, J = 2.9 Hz), 116.4, 115.8 (d, J = 21.3 Hz), 114.7, 112.1 (d, J = 23.5 Hz), 103.0,
61.0, 14.4; HRMS (ESI-TOF) m/z calculated for C22H17FNO4 [M+H]+: 378.1136, found: 378.1144.
Ethyl 4-(2-(3-chlorophenyl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3m). Yield 71% (84
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mg). Pale yellow solid; m.p. 209–211 C; H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 7.90 (t, J = 1.6 Hz,
1H), 7.78–7.75 (m, 1H), 7.73–7.70 (m, 2H), 7.59–7.58 (m, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.42–7.33 (m,
4H), 4.37 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.6, 160.9,
156.1, 155.4, 134.9, 131.7, 131.5, 130.1, 128.9, 128.8, 127.9, 126.5, 125.2, 125.1, 124.3, 123.8, 123.3,
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116.3, 114.7, 103.0, 61.0, 14.4; HRMS (ESI-TOF) m/z calculated for C22H17ClNO4 [M+H]+: 394.0841,
found: 394.0857.
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Ethyl 4-(2-(naphthalen-1-yl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3n). Yield 65% (80
mg). Pale yellow solid; m.p. 211–213 C; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.52–8.49 (m, 1H),
7.95–7.91 (m, 3H), 7.80–7.75 (m, 2H), 7.62–7.54 (m, 5H), 7.45–7.40 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H),
1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.8, 160.9, 157.4, 155.4, 133.9, 131.5,
130.5, 129.9, 128.9, 128.6, 128.0, 127.7, 127.5, 127.1, 126.6, 126.2, 125.4, 125.2, 124.9, 124.2, 123.4,
116.4, 114.7, 106.4, 61.0, 14.4; HRMS (ESI-TOF) m/z calculated for C26H20NO4 [M+H]+: 410.1387,
found: 410.1388.
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Ethyl 4-(2-(naphthalen-2-yl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3o). Yield 72% (88
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mg). Pale yellow solid; m.p. 203–204 C; H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.41 (s, 1H), 7.96–
7.83 (m, 4H), 7.75–7.71 (m, 2H), 7.63 (d, J = 0.8 Hz, 1H), 7.61–7.60 (m, 1H), 7.55–7.48 (m, 2H), 7.44–
7.43 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 189.7, 161.0, 157.8, 155.5, 133.5, 133.3, 131.3, 129.3, 128.6, 128.5, 128.0, 127.8,
127.3, 126.7 (2C), 126.6, 125.0, 124.4, 124.2, 123.4, 122.9, 116.4, 114.6, 102.6, 61.0, 14.4; HRMS
(ESI-TOF) m/z calculated for C26H20NO4 [M+H]+: 410.1387, found: 410.1393.
Ethyl 4-(2-(thiophen-2-yl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3p). Yield 69% (76
mg). Pale yellow solid; m.p. 225–227 C; 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.72–7.66 (m, 2H),
7.59–7.58 (m, 1H), 7.55–7.54 (m, 1H), 7.41–7.33 (m, 4H), 7.14–7.11 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H),
1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.6, 160.8, 155.1, 153.2, 132.8, 131.1,
129.2, 128.0, 127.8, 126.6, 126.5, 125.4, 125.1, 124.2, 123.3, 116.3, 114.5, 101.7, 61.0, 14.4; HRMS
(ESI-TOF) m/z calculated for C20H16NO4S [M+H]+: 366.0795, found: 366.0788.
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Ethyl 4-(2-(cyclohex-1-en-1-yl)benzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3q). Yield 80% (87
mg). Pale yellow solid; m.p. 146–147 C; 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.65–7.63 (m, 1H),
7.60–7.57 (m, 1H), 7.56–7.55 (m, 1H), 7.40–7.39 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.69–
6.66 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.41–2.38 (m, 2H), 2.30–2.26 (m, 2H), 1.78–1.77 (m, 2H), 1.70–
1.66 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.9, 160.9, 159.3, 155.0,
130.9, 129.2, 127.9, 127.4, 127.2, 126.6, 124.5, 124.1, 122.8, 116.4, 114.1, 100.7, 61.0, 25.5, 24.8,
22.3, 22.0, 14.4; HRMS (ESI-TOF) m/z calculated for C22H22NO4 [M+H]+: 364.1543, found: 364.1553.
Ethyl 4-((2-cyclopropylbenzofuran-4-yl)(hydroxy)methyl)-1H-pyrrole-2-carboxylate (3r). Yield 46%
(45 mg). Pale yellow solid; m.p. 78–79 C; 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 7.29 (d, J = 8.0 Hz,
1H), 7.22–7.13 (m, 2H), 6.73 (t, J = 6.8 Hz, 1H), 6.47 (s, 1H), 6.39 (d, J = 4.4 Hz, 1H), 5.88 (t, J = 2.4 Hz,
1H), 4.59 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.04–1.95 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H) 0.96–0.93 (m, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ 161.4, 160.0, 154.4, 135.6, 134.7, 127.2, 122.6, 121.6, 120.1, 118.6,
111.1, 109.7, 99.9, 68.5, 60.8, 14.4, 9.3, 7.2 (2C); HRMS (ESI-TOF) m/z calculated for C19H20NO4
[M+H]+: 326.1387, found: 326.1389.
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Ethyl 4-((2-butylbenzofuran-4-yl)(hydroxy)methyl)-1H-pyrrole-2-carboxylate (3s). Yield 53% (54
1
mg). Pale yellow oil; H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23–7.17 (m,
2H), 6.78 (d, J = 2.8 Hz, 1H), 6.50 (d, J = 0.8 Hz, 1H), 6.41 (d, J = 4.8 Hz, 1H), 5.91 (t, J = 2.8 Hz, 1H),
4.52 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.74 (t, J = 8.0 Hz, 2H), 1.73–1.67 (m, 2H), 1.43–1.40 (m, 2H), 1.36
(t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.3, 159.3, 154.8, 134.9,
127.1, 122.9, 122.8, 121.5, 120.0, 118.7, 111.2, 109.8, 101.3, 68.6, 60.9, 29.7, 28.2, 22.3, 14.4, 13.8;
HRMS (ESI-TOF) m/z calculated for C20H24NO4 [M+H]+: 342.1700, found: 342.1707.
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Ethyl 4-(6-methoxy-2-phenylbenzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3t). Yield 85% (99
mg). Pale yellow solid; m.p. 236–237 C; 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.95–7.92 (m, 2H),
7.75 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.58–7.57 (m, 1H), 7.48–7.44 (m, 2H), 7.40–7.36 (m, 2H), 6.84 (d,
J = 8.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.13 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 188.9, 160.9, 157.8, 148.3, 144.2, 131.3, 129.9, 129.0, 128.8 (2C), 127.7, 127.4, 126.8, 125.3
(2C), 124.2, 123.9, 116.4, 105.4, 102.7, 60.9, 56.3, 14.4; HRMS (ESI-TOF) m/z calculated for C23H20NO5
[M+H]+: 390.1336, found: 390.1340.
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Methyl 4-(2-phenylbenzofuran-4-carbonyl)-1H-pyrrole-2-carboxylate (3u). Yield 88% (91 mg). Pale
yellow solid; m.p. 172–173 C; 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.91–7.89 (m, 2H), 7.70 (d, J =
7.6 Hz, 2H), 7.60–7.59 (m, 1H), 7.51 (s, 1H), 7.48–7.44 (m, 2H), 7.42–7.41 (m, 1H), 7.40–7.33 (m, 2H),
3.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 189.7, 161.3, 157.7, 155.4, 131.2, 130.0, 129.2, 129.0,
128.8 (2C), 128.1, 126.6, 125.2 (2C), 125.0, 123.8, 123.3, 116.6, 114.6, 101.9, 52.0; HRMS (ESI-TOF)
m/z calculated for C21H16NO4 [M+H]+: 346.1074, found: 346.1077.
(5-(Morpholine-4-carbonyl)-1H-pyrrol-3-yl)(2-phenylbenzofuran-4-yl)methanone (3v). Yield 83%
(100 mg). Pale yellow solid; m.p. 215–217 C; 1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), 7.90–7.88 (m,
2H), 7.70–7.65 (m, 2H), 7.47–7.43 (m, 4H), 7.39–7.32 (m, 2H), 7.12–7.11 (m, 1H), 3.90 (s, 4H), 3.78–
3.75 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 190.0, 161.5, 157.7, 155.5, 131.7, 130.1, 129.2, 129.1,
129.0 (2C), 127.8, 127.7, 126.0, 125.6, 125.3 (2C), 124.7, 123.4, 114.6, 113.4, 101.9 (2C), 66.8 (2C);
HRMS (ESI-TOF) m/z calculated for C24H21N2O4 [M+H]+: 401.1496, found: 401.1499.
(4-(2-Phenylbenzofuran-4-carbonyl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone (3w). Yield 80% (92
mg). Pale yellow solid; m.p. 203–205 C; 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 7.91–7.89 (m, 2H),
7.71–7.68 (m, 2H), 7.50–7.44 (m, 4H), 7.40–7.34 (m, 2H), 7.21–7.20 (m, 1H), 3.83 (t, J = 6.8 Hz, 2H),
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3.70 (t, J = 6.8 Hz, 2H), 2.11–2.04 (m, 2H), 1.98–1.93 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 190.1,
159.7, 157.5, 155.4, 131.8, 130.0, 129.1, 129.0, 128.8 (2C), 127.4, 127.3, 126.4, 125.2 (2C), 124.6,
123.3, 114.4, 113.1, 101.9, 48.1, 47.3, 26.6, 23.9; HRMS (ESI-TOF) m/z calculated for C24H21N2O3
[M+H]+: 385.1547, found: 385.1544.
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Ethyl 4-(hydroxy(2-(4-methoxyphenyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-pyrrole-2-carboxylate (8).
1
Yield 81% (132 mg). Pale yellow solid; m.p. 214–215 C; H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H),
8.27–8.22 (m, 1H), 7.43–7.41 (m, 2H), 7.33–7.32 (m, 2H), 7.28–7.27 (m, 1H), 7.25, (s, 1H), 7.03 (d, J =
0.8 Hz, 2H), 6.93–6.91 (m, 1H), 6.67 (t, J = 2.8 Hz, 1H), 6.62 (d, J = 0.8 Hz, 2H), 6.35 (d, J = 4.4 Hz, 1H),
5.57 (t, J = 2.4 Hz, 1H), 4.65, (s, 1H), 4.36–4.30 (m, 2H), 3.87 (s, 3H), 2.29 (s, 3H), 1.32 (t, J = 6.8 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.3, 159.9, 144.4, 141.6, 138.4, 135.7, 134.53, 134.50, 131.6
(2C), 129.1 (2C), 128.9, 126.8 (2C), 124.9, 124.5, 122.1, 121.4, 118.7, 115.9, 112.8 (2C), 112.3, 111.2,
68.1, 60.9, 55.3, 21.5, 14.4; HRMS (ESI-TOF) m/z calculated for C30H29N2O6S [M+H]+: 545.1741, found:
545.1753.
Characterization of Intermediates 5 and 6
1-(2-Phenylbenzofuran-4-yl)prop-2-yn-1-ol (5). Yield 16% (12 mg). Pale yellow solid; m.p. 48–49
1
C; H NMR (400 MHz, CDCl3) δ 7.89–7.86 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.46–7.42 (m, 2H), 7.41–
7.33 (m, 2H), 7.31–7.24 (m, 2H), 5.75 (dd, J = 6.0 Hz, 2.4 Hz, 1H), 2.71 (d, J = 2.4 Hz, 1H), 2.47 (d, J =
5.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.2, 155.2, 132.1, 130.2, 128.8 (2C), 128.7, 127.2,
125.0 (2C), 124.1, 120.7, 111.7, 100.1, 83.0, 75.1, 63.4; HRMS (ESI-TOF) m/z calculated for C17H13O2
[M+H]+: 249.0910, found: 249.0917.
(5-(Hydroxy(morpholino)methyl)-1H-pyrrol-3-yl)(2-phenylbenzofuran-4-yl)methanone (6). Yield
27% (33 mg). Pale yellow solid; m.p. 134–135 C; 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.84–7.81
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(m, 2H), 7.49–7.41 (m, 3H), 7.36–7.27 (m, 3H), 7.06 (d, J = 0.8 Hz, 1H), 6.77–6.75 (m, 1H), 6.49–6.48
(m, 1H), 6.12 (d, J = 3.2 Hz, 1H), 3.79–3.77 (m, 4H), 3.69–3.66 (m, 4H), 2.50 (d, J = 3.6 Hz, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 161.5, 155.7, 155.2, 136.4, 130.2, 128.8 (2C), 128.6, 128.0, 126.9, 124.9
(2C), 124.6, 124.1, 120.2, 119.4, 110.8, 110.6, 100.4, 69.7 (2C), 66.7 (2C); HRMS (ESI-TOF) m/z
calculated for C24H23N2O4 [M+H]+: 403.1652, found: 403.1659.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra of compounds 1, 3 and 5–8, and X-ray crystallographic data for compound 3a. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: karkas@kth.se (M.D.K.)
*E-mail: xswang1974@yahoo.com (X.-S.W.)
ORCID
Jian-Quan Liu: 0000-0002-5533-2075
Andrey Shatskiy: 0000-0002-7249-7437
Markus D. Kärkäs: 0000-0002-6089-5454
Xiang-Shan Wang: 0000-0002-0077-7819
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the NSFC of China (No. 21702078), NSF of Jiangsu Province (No. BK20170231),
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Natural Science Foundation of Jiangsu Higher Education Institution (17KJA150003), the open project
of Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028830), the
Wenner-Gren Foundations (postdoctoral fellowship to J.L.), the Olle Engkvist Byggmästare Foundation
(postdoctoral fellowship to A.S.), the KTH Royal Institute of Technology, the Priority Academic
Program Development of Jiangsu Higher Education Institution, and TAPP is gratefully acknowledged.
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REFERENCES
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