Copper-Catalyzed Coupling of 2-Siloxy-1-alkenes and Diazocarbonyl Compounds: Approach to Multisubstituted Furans, Pyrroles, and Thiophenes

Article abstract of DOI:10.1021/acs.joc.6b00904

We report herein copper(II)-catalyzed cyclization reactions of silyl enol ethers derived from methyl ketones with α-diazo-β-ketoesters or α-diazoketones to afford 2-siloxy-2,3-dihydrofuran derivatives or 2,3,5-trisubstituted furans, respectively, under mild conditions. The former cyclization products serve as versatile 1,4-diketone surrogates, allowing facile preparation of 2,3,5-trisubstituted furans, pyrroles, and thiophenes.

Full text of DOI:10.1021/acs.joc.6b00904

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Article
Copper-Catalyzed Coupling of 2-Siloxy-1-alkenes and Diazocarbonyl
Compounds: Approach to Multisubstituted Furans, Pyrroles, and Thiophenes
Wei Wen Tan, and Naohiko Yoshikai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00904 • Publication Date (Web): 03 Jun 2016
Downloaded from http://pubs.acs.org on June 5, 2016
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CopperꢀCatalyzed Coupling of 2ꢀSiloxyꢀ1ꢀalkenes and Diazocarbonyl Compounds:
Approach to Multisubstituted Furans, Pyrroles, and Thiophenes
Wei Wen Tan and Naohiko Yoshikai*
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Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
Eꢀmail: nyoshikai@ntu.edu.sg
Abstract: We report herein copper(II)ꢀcatalyzed cyclization reactions of silyl enol ethers derived
from methyl ketones with αꢀdiazoꢀβꢀketoesters or αꢀdiazoketones to afford 2ꢀsiloxyꢀ2,3ꢀ
dihydrofuran derivatives or 2,3,5ꢀtrisubstituted furans, respectively, under mild conditions. The
former cyclization products serve as versatile 1,4ꢀdiketone surrogates, allowing facile preparation
of 2,3,5ꢀtrisubstituted furans, pyrroles, and thiophenes.
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Introduction
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Transition metal carbenoids generated through the decomposition of diazocarbonyl compounds
have been extensively utilized as electrophilic reactive intermediates for a diverse set of catalytic
transformations.1 Olefins represent the most frequently employed nucleophilic reaction partners
to electrophilic carbenoids, which typically take part in cyclopropanation.2 In this context, the
reactivity of silyl enol ethers, typical electronꢀrich olefins utilized in numerous organic reactions,
has been extensively studied. Their reactions with common αꢀdiazoesters under copper or
rhodium catalysis lead to donor/acceptorꢀsubstituted cyclopropane derivatives (Scheme 1a),3
which have proved to serve as useful intermediates for natural product synthesis.4 On the other
hand, Kitamura and coworkers recently reported a rhodiumꢀcatalyzed reaction of enol silyl ether
and diazonaphthoquinone to afford a dihydronaphthofuran derivative (Scheme 1b).5 As
Kitamura's study was specifically focused on the reaction of ketene silyl acetal and
diazonaphthoquinone, this [3 + 2] mode of cycloaddition remains largely unexplored with respect
to both enol silyl ethers and diazocarbonyl compounds regardless of its potential utility for the
synthesis of furans and other fiveꢀmembered heterocycles.6
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Recently, we have developed a copperꢀcatalyzed condensation reaction of ketimines and
αꢀdiazoꢀβꢀketoesters to afford multisubstituted pyrroles.7 The reaction is considered to involve a
copper carbenoid stabilized by two adjacent carbonyl groups, which serves as an electrophile
toward the nitrogen atom of ketimine to generate an azomethine ylide.7ꢀ8 In this connection as
well as in light of the aforementioned background on the reaction of enol silyl ethers, we became
interested in the reactivity of the same or similar copper carbenoids towards silyl enol ethers. We
report here that a simple copper(II) salt, Cu(hfacac)2 (hfacac = hexafluoroacetylacetonate), is
capable of promoting a coupling reaction of silyl enol ethers derived from methyl ketones with a
variety of αꢀdiazoꢀβꢀketoesters (R3 = ester) and αꢀdiazoketones (R3 = aryl) (Scheme 1c). The
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former diazo compounds afford 2ꢀsiloxyꢀ2,3ꢀdihydrofurans that serve as 1,4ꢀdiketone surrogates
for facile preparation of multisubstituted furan, pyrrole, and thiophene derivatives, while the
latter directly furnish trisubstituted furans.
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Scheme 1. Transition MetalꢀCatalyzed Reaction of Silyl Enol Ether and Diazocarbonyl
Compound
Results and Discussion
The present study commenced with screening of reaction conditions for the condensation of
acetophenoneꢀderived silyl enol ether 1a and ethyl acetoacetateꢀderived diazo compound 2a (1.2
equiv). Treatment of these starting materials with a catalytic amount of Cu(hfacac)2 (10 mol%) in
CH2Cl2 at 40 °C resulted in a smooth denitrogenative coupling reaction to afford a 2ꢀsiloxyꢀ2,3ꢀ
dihydrofuran derivative 3aa in 84% isolated yield (Table 1, entry 1). The same reaction could
also be followed by direct treatment of crude 3aa with pꢀTsOH, which furnished a trisubstituted
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furan 4aa in 86% overall yield. In a sharp contrast, less Lewis acidic Cu(tfacac)2 (tfacac =
trifluoroacetylacetonate) completely failed to promote the reaction (entry 2), although it was the
optimum catalyst for our previously developed pyrroleꢀforming reaction using ketimine as a
nucleophilic reaction partner. In this case, the silyl enol ether 1a was mostly recovered, whereas
the diazo compound 2a underwent complete decomposition to unidentified products. We
speculate that the copper carbenoid derived from Cu(tfacac)2 and 2a was not electrophilic enough
toward 1a. Not unexpectedly, even less Lewis acidic Cu(II) salts such as Cu(acac)2, and
Cu(OAc)2 were entirely ineffective as well (entries 3 and 4). The reaction using Rh2(OAc)4 as a
catalyst resulted in a much lower yield (entry 5). An attempt to reduce the loading of Cu(hfacac)2
to 5 mol% resulted in a decreased yield (entry 6). Note that αꢀ(tertꢀbutyldimethylsiloxy)styrene,
instead of 1a, could also be converted to the furan product 4aa under the standard conditions
albeit in a slightly lower yield (entry 7).
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Table 1. Coupling of Silyl Enol Ether 1a and αꢀDiazoꢀβꢀKetoester 2aa
entry
deviation from standard conditions
none
yield (%)b
84c (86)d
0
1
2
Cu(tfacac)2 instead of Cu(hfacac)2
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Cu(acac)2 instead of Cu(hfacac)2
0
Cu(OAc)2 instead of Cu(hfacac)2
Rh2(OAc)4 instead of Cu(tfacac)2
5 mol% of Cu(hfacac)2
none
0
12
65
(72)e
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aThe reaction was performed using 0.2 mmol of 1a and 0.24 mmol of 2a. bDetermined by GC or
1H NMR. Isolated yield. Isolated yield of furan 4aa obtained by direct treatment of crude 3aa
c
d
with pꢀTsOH. eαꢀ(tertꢀButyldimethylsiloxy)styrene was used instead of 1a.
Having identified Cu(hfacac)2 as an effective catalyst for the coupling of 1a and 2a, we
explored the scope of the present furan synthesis. First, a series of αꢀdiazoꢀβꢀketoesters and
related compounds 2a–2n were subjected to the reaction with silyl enol ether 1a (Table 2). The
reaction proved to tolerate a variety of R1 groups such as primary and secondary alkyl groups
(4aa–4ae), aryl and heteroaryl groups with electronꢀdonating or withdrawing groups (4af–4al),
and a trifluoromethyl group (4am), thus affording the corresponding trisubstituted furans in
moderate to good yields. Besides the αꢀdiazoꢀβꢀketoesters, αꢀdiazoꢀβꢀketosulfone also smoothly
participated in the reaction with 1a to afford 3ꢀsulfonylfuran 4an in a good yield. Unfortunately,
the reaction of αꢀdiazoꢀβꢀdiketone such as the one derived from acetylacetone did not afford a
desired furan product but gave an intractable mixture of products.
Table 2. Reaction of Silyl Enol Ether 1a with Various αꢀDiazoꢀβꢀketoestersa
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aThe reaction was performed using 0.2 mmol of silyl enol ether and 0.24 mmol of diazo
compound. b100 mol % of pꢀTsOH was used.
When αꢀdiazoketone 2o–2r were used as reaction partners for 1a, the Cuꢀcatalyzed
reaction directly afforded 2,3,5ꢀtrisubstituted furan products 4ao–4ar in good yields, without a
need for the treatment with pꢀTsOH (Scheme 2a). We consider that the lack of electronꢀ
withdrawing groups on the 4ꢀposition of the corresponding 2ꢀsiloxyꢀ2,3ꢀdihydrofuran
intermediates makes them prone to loss of silanol, which is presumably assisted by the Lewis
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acidic copper catalyst. Note also that the reaction of 1a with αꢀdiazoester 2s directly afforded a
1,4ꢀketoester derivative 5 in a good yield (Scheme 2b), without a trace of cyclopropane or other
cyclic intermediates.
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Scheme 2. Reaction of Silyl Enol Ether 1a with αꢀDiazoketone or αꢀDiazoester.a
aThe reaction was performed using 0.2 mmol of silyl enol ether and 0.24 mmol of diazo
compound.
Silyl enol ethers derived from various methyl ketones were amenable to the Cuꢀcatalyzed
coupling with αꢀdiazoꢀβꢀketoester 2a, thus furnishing the desired trisubstituted furans in
moderate to good yields (Table 3). Tolerable R groups on silyl enol ether include functionalized
aryl (4ba–4ga), heteroaryl (4ha and 4ia), alkyl (4ja–4la), and alkenyl (4ma) groups. Silyl enol
ether derived from 1,4ꢀdiacetylbenzene underwent twofold coupling with 2a to afford a teraryl
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product 4na in a modest yield. Unfortunately, reactions of trisubstituted silyl enol ethers, such as
those derived from propiophenone, tetralone, and cyclohexanone, with 2a under the present
conditions resulted in full recovery of the silyl enol ethers and complete decomposition of 2a.
Note also that the reaction of ketene silyl acetal was rather sluggish. For example, the Cuꢀ
catalyzed coupling of phenyl acetateꢀderived ketene silyl acetal with 2a afforded the
corresponding 2ꢀsiloxyꢀ2,3ꢀdihydrofuran in only 16% yield (data not shown).
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Table 3. Reaction of Various Silyl Enol Ethers with αꢀDiazoꢀβꢀketoester 2aa
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aThe reaction was performed using 0.2 mmol of silyl enol ether and 0.24 mmol of diazo
compound. b0.2 mmol of bisꢀsilyl enol ether and 0.48 mmol of diazo compound were used.
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2ꢀSiloxyꢀ2,3ꢀdihydrofuran serves as a 1,4ꢀdiketone surrogate for the preparation of fiveꢀ
membered heteroarenes other than furan (Table 4). Thus, fluorideꢀmediated desilylation of the
crude coupling product 3aa was followed by treatment with ammonium acetate in acetic acid
under heating conditions, affording a NꢀH pyrrole derivative 6a in 83% overall yield. This
protocol was effective for a series of silyl enol ether/αꢀdiazoꢀβꢀketoester coupling products, thus
enabling facile preparation of trisubstituted NꢀH pyrroles 6b–6f in moderate to good yields.
Likewise, the use of Lawesson's reagent instead of ammonium acetate in the above procedure
allowed preparation of trisubstituted thiophenes 7a–7f in moderate to good yields.
Table 4. Preparation of Multisubstituted Pyrroles and Thiophenesa
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aThe reaction was performed using 0.2 mmol of silyl enol ether and 0.24 mmol of diazo
compound.
Scheme 3 shows plausible reaction pathways for the present copperꢀcatalyzed reaction.
Decomposition of the diazocarbonyl compound with the copper catalyst generates an
electrophilic copper carbenoid A. The silyl enol ether then undergoes nucleophilic attack on the
carbenoid carbon to give an intermediate B bearing oxonium and enolate moieties. Intramolecular
attack of the enolate oxygen to the oxonium carbon would directly afford 2ꢀsiloxyꢀ2,3ꢀ
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dihydrofuran 3 while liberating the copper catalyst. An alternative pathway involving a
siloxycyclopropane intermediate C, its ringꢀopening, and recyclization may not be fully
excluded, however. When the R3 substituent of 3 is not electronꢀwithdrawing, loss of the siloxy
group would be facilitated by the copper catalyst, thus leading to direct formation of the furan
product 4.
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Scheme 3. Plausible Reaction Pathways
Conclusion
In summary, we have demonstrated that 2ꢀsiloxyꢀ1ꢀalkenes serve as excellent nucleophiles
toward copper carbenoids generated from αꢀdiazoꢀβꢀketoesters or αꢀdiazoketones, affording 2ꢀ
siloxyꢀ2,3ꢀdihydrofuran derivatives or 2,3,5ꢀtrisubstituted furans, respectively. By simple followꢀ
up operations, the former products can be transformed into 2,3,5ꢀtrisubstituted furans, pyrroles,
and thiophenes. While the same type of multisubstituted furans may be directly prepared by
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transition metalꢀcatalyzed coupling of αꢀdiazoꢀβꢀketoesters and terminal alkynes8c,8d,9 or by other
means,10,11 the accessibility to analogous pyrroles12 and thiophenes would make the present
approach useful alternative to existing synthetic methods for fiveꢀmembered heteroarenes.13
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Experimental Section
General Information. All reactions dealing with airꢀ and moistureꢀsensitive compounds were
carried out in oven dried reaction vessels under a nitrogen atmosphere using standard Schlenk
techniques. All commercial materials were used without further purification. Silyl enol ethers14
and diazocarbonyl compounds7 were prepared according to the literature procesures. Analytical
thinꢀlayer chromatography (TLC) was performed on Merck 60 F254 silica gel plates. Standard
flash chromatography was performed on silica gel 60 (300–400 mesh). Melting points (°C) were
determined using a capillary melting point apparatus and are uncorrected. H and 13C NMR
1
spectra were recorded on 400 MHz NMR spectrometers. Chemical shifts are reported in ppm
relative to an internal standard, tetramethylsilane (0.00 ppm) or to residual protiated solvent. Data
are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, sept = septet, m = multiplet), coupling constant J (Hz), and integration. Highꢀresolution
mass spectra (HRMS) were obtained by ESI method using a QꢀTof Premier LC HR mass
spectrometer.
General Procedure for Furan Synthesis from Silyl Enol Ethers and αꢀDiazoꢀβꢀketoesters
(Tables 2 and 3). A 10 mL Schlenk tube equipped with a stirrer bar was charged with silyl enol
ether (0.20 mmol), Cu(hfacac)2 (9.6 mg, 0.020 mmol, 10 mol %), and diazocarbonyl compound
(0.24 mmol), followed by the addition of dichloromethane (1.0 mL). The resulting mixture was
stirred at 40 °C for 6 h. Upon cooling to room temperature, pꢀtoluenesulfonic acid monohydrate
(11.4 mg, 0.030 mmol, 30 mol %) was added, followed by the addition of toluene (1.0 mL). The
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resulting mixture was stirred at 110 °C for 1.5 h and then cooled to room temperature. The
reaction mixture was diluted with ethyl acetate (5 mL), passed through a pad of silica gel, and
concentrated under reduced pressure. The residue was purified by flash chromatography on silica
gel to afford the furan product.
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Ethyl
2ꢀmethylꢀ5ꢀphenylꢀ5ꢀ((trimethylsilyl)oxy)ꢀ4,5ꢀdihydrofuranꢀ3ꢀcarboxylate
(3aa).
Synthesized without the treatment with pꢀtoluenesulfonic acid monohydrate. Colourless oil (54
1
mg, 84% yield, eluent = hexane/EtOAc (98:2)); H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.3
Hz, 2H), 7.42–7.32 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 3.18 (dd, J = 15.9, 1.1 Hz, 1H), 3.09 (dd, J
13
= 15.9, 1.7 Hz, 1H), 2.38 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 0.09 (s, 9H); C NMR (100 MHz,
CDCl3): δ 165.8, 165.0, 144.2, 128.1, 128.1, 124.8, 109.5, 102.0, 59.6, 47.2, 14.4, 14.3, 1.3;
HRMS (ESI) Calcd for C17H25O4Si [M + H]+ 321.1522, found 321.1524.
Ethyl 2ꢀmethylꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate10b (4aa). Colourless oil (40 mg, 86% yield, eluent
1
= hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.65ꢀ7.63 (m, 2H), 7.38 (t, J = 7.7 Hz,
2H), 7.34–7.21 (m, 1H), 6.88 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 164.1, 158.6, 151.7, 130.1, 128.7, 127.6, 123.6, 115.4,
105.5, 60.2, 14.4, 13.9; HRMS (ESI) Calcd for C14H15O3 [M + H]+ 231.1021, found 231.1025.
Ethyl 2ꢀisopropylꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate10b (4ab). Yellow oil (46 mg, 90% yield, eluent
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= hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.58–7.51 (m, 2H), 7.29 (t, J = 7.7 Hz,
2H), 7.19ꢀ7.15 (m, 1H), 6.79 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.72 (hept, J = 7.0 Hz, 1H), 1.28
(t, J = 7.1 Hz, 3H), 1.26 (d, J = 4.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 166.8, 164.1, 151.5,
130.5, 128.9, 127.8, 123.8, 113.7, 105.7, 60.3, 27.6, 21.1, 14.6; HRMS (ESI) Calcd for C16H19O3
[M + H]+ 259.1334, found 259.1340.
Ethyl 2ꢀcyclopropylꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4ac). Colourless oil (31 mg, 60% yield,
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eluent = hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.59–7.53 (m, 2H), 7.36 (t, J =
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Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.19ꢀ1.13 (m, 1H), 1.13–1.06 (m, 1H); C NMR (100 MHz,
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CDCl3): δ 164.6, 162.9, 150.5, 130.3, 128.9, 127.7, 123.7, 115.2, 106.1, 60.4, 14.7, 9.6, 9.2;
HRMS (ESI) Calcd for C16H17O3 [M + H]+ 257.1178, found 257.1170.
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Methyl 2ꢀcyclohexylꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4ad). Yellow oil (51 mg, 90% yield, eluent
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= hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.65ꢀ7.62 (m, 2H), 7.37 (t, J = 7.7 Hz,
2H), 7.33–7.16 (m, 1H), 6.86 (s, 1H), 3.84 (s, 3H), 3.47 (tt, J = 11.9, 3.5 Hz, 1H), 1.97–1.78 (m,
4H), 1.79–1.62 (m, 3H), 1.53–1.19 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 166.7, 164.6, 151.6,
130.4, 128.9, 127.8, 123.8, 113.4, 105.5, 51.5, 37.2, 31.2, 26.4, 26.1; HRMS (ESI) Calcd for
C18H21O3 [M + H]+ 285.1491, found 285.1501.
Ethyl 2ꢀ(adamantanꢀ2ꢀyl)ꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4ae). White solid (48 mg, 68% yield,
eluent = hexane/EtOAc (97:3)); Mp = 135–137 °C; 1H NMR (400 MHz, CDCl3): δ 7.64ꢀ7.62 (m,
2H), 7.37 (t, J = 7.7 Hz, 2H), 7.28–7.11 (m, 1H), 6.93 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.25 (d, J
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= 2.6 Hz, 6H), 2.09 (s, 3H), 1.89–1.74 (m, 6H), 1.39 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
CDCl3): δ 167.9, 164.0, 149.9, 130.5, 128.9, 127.7, 123.8, 114.4, 107.7, 60.5, 39.2, 37.3, 36.9,
28.7, 14.7; HRMS (ESI) Calcd for C23H27O3 [M + H]+ 351.1960, found 351.1956.
Ethyl 2,5ꢀdiphenylfuranꢀ3ꢀcarboxylate9b (4af). Colourless solid (41 mg, 70% yield, eluent =
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hexane/EtOAc (97:3)); Mp = 80–82 °C (lit. 79–80 °C15); H NMR (400 MHz, CDCl3): δ 8.09–
8.06 (m, 2H), 7.80–7.68 (m, 2H), 7.53–7.35 (m, 5H), 7.35–7.25 (m, 1H), 7.08 (s, 1H), 4.33 (q, J
= 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.8, 156.7, 152.6,
130.0, 129.6, 129.0, 128.6, 128.34, 128.28, 124.2, 116.0, 108.1, 60.9, 14.5; HRMS (ESI) Calcd
for C19H17O3 [M + H]+ 293.1178, found 293.1180.
Ethyl 2ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4ag). White solid (44 mg, 68%
yield, eluent = hexane/EtOAc (97:3)); Mp = 95–97 °C; 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J
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= 8.9 Hz, 2H), 7.78–7.65 (m, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H),
6.98 (d, J = 8.9 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 163.9, 160.7, 157.1, 151.9, 130.20, 130.15, 129.0, 128.1, 124.1, 122.7,
114.7, 113.8, 108.1, 60.7, 55.6, 14.6; HRMS (ESI) Calcd for C20H19O4 [M + H]+ 323.1283, found
323.1296.
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Ethyl 2ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate16 (4ah). Yellow solid (53 mg, 79%
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yield, eluent = hexane/EtOAc (92:8)); Mp = 126–128 °C (lit. 128–129 °C16); H NMR (400
MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H), 7.85 – 7.67 (m, 2H), 7.47ꢀ7.43
(m, 2H), 7.40 – 7.33 (m, 1H), 7.13 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 163.3, 154.1, 153.3, 147.7, 135.6, 129.3, 129.2, 129.0, 128.8, 124.5,
123.7, 118.9, 108.9, 61.4, 14.5; HRMS (ESI) Calcd for C19H16NO5 [M + H]+ 338.1028, found
338.1025.
Ethyl 2ꢀ(2ꢀbromophenyl)ꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4ai). Yellow oil (65 mg, 88% yield,
eluent = hexane/EtOAc (97:3)); 1H NMR (400 MHz, CDCl3): δ 7.75–7.70 (m, 2H), 7.68 (dd, J =
8.0, 1.1 Hz, 1H), 7.54 (dd, J = 7.6, 1.7 Hz, 1H), 7.42ꢀ7.37 (m, 3H), 7.34 – 7.27 (m, 2H), 7.09 (s,
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1H), 4.21 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3): δ 163.2,
155.7, 153.8, 133.1, 132.7, 132.0, 131.1, 130.0, 129.0, 128.4, 127.0, 124.3, 124.2, 118.4, 106.3,
60.7, 14.2; HRMS (ESI) Calcd for C19H16BrO3 [M + H]+ 371.0283, found 371.0283.
Methyl 2ꢀ(naphthalenꢀ1ꢀyl)ꢀ5ꢀphenylfuranꢀ3ꢀcarboxylate (4aj). White solid (49 mg, 74%
yield, eluent = hexane/EtOAc (97:3)); Mp = 145–147 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d,
J = 8.2 Hz, 1H), 7.93 – 7.89 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.76ꢀ7.72 (m, 3H), 7.60–7.54 (m,
1H), 7.53ꢀ7.46 (m, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.19 (s, 1H), 3.66 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 163.9, 156.9, 153.8, 133.8, 132.2, 130.5, 130.1, 129.7,
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129.1, 128.6, 128.4, 127.8, 126.9, 126.3, 125.8, 125.1, 124.3, 118.1, 106.8, 51.7; HRMS (ESI)
Calcd for C22H17O3 [M + H]+ 329.1178, found 329.1184.
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Methyl 5ꢀphenylꢀ[2,2'ꢀbifuran]ꢀ3ꢀcarboxylate (4ak). Colourless solid (35 mg, 66% yield,
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eluent = hexane/EtOAc (97:3)); Mp = 93–95 °C; H NMR (400 MHz, CDCl3): 7.74 (d, J = 7.3
Hz, 2H), 7.57 (dd, J = 7.0, 2.3 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.03 (s,
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1H), 6.57 (dd, J = 3.5, 1.8 Hz, 1H), 3.89 (s, 3H); C NMR (100 MHz, CDCl3): δ 163.5, 152.6,
148.4, 144.8, 143.7, 129.8, 129.0, 128.4, 124.3, 114.3, 113.7, 112.3, 107.3, 51.9; HRMS (ESI)
Calcd for C16H13O4 [M + H]+ 269.0814, found 269.0820.
Methyl 5ꢀphenylꢀ2ꢀ(thiophenꢀ2ꢀyl)furanꢀ3ꢀcarboxylate (4al). White solid (40 mg, 71% yield,
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eluent = hexane/EtOAc (97:3)); Mp = 71–73 °C; H NMR (400 MHz, CDCl3): δ 8.12 (dd, J =
3.8, 1.0 Hz, 1H), 7.74–7.68 (m, 2H), 7.46–7.37 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.13 (dd, J =
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5.0, 3.9 Hz, 1H), 7.02 (s, 1H), 3.90 (s, 3H); C NMR (100 MHz, CDCl3): δ 164.0, 152.4, 152.0,
131.8, 129.7, 129.0, 128.4, 128.2, 127.8, 124.2, 114.0, 107.6, 51.9; HRMS (ESI) Calcd for
C16H13O3S [M + H]+ 285.0585, found 285.0582.
Ethyl 5ꢀphenylꢀ2ꢀ(trifluoromethyl)furanꢀ3ꢀcarboxylate17 (4am). Colourless solid (27 mg, 48%
yield, eluent = hexane/EtOAc (95:5)); Mp = 38–41 °C (lit. 37–39 °C17); H NMR (400 MHz,
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CDCl3): δ 7.77–7.69 (m, 2H), 7.52–7.37 (m, 3H), 7.08 (d, J = 0.9 Hz, 1H), 4.40 (q, J = 7.1 Hz,
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2H), 1.41 (t, J = 7.1 Hz, 3H).; C NMR (100 MHz, CDCl3): δ 160.9, 154.9, 142.2 (q, JCꢀF = 42
Hz), 129.3, 128.9, 128.4, 121.4, 118.7 (q, JCꢀF = 267 Hz), 106.9, 61.5, 13.9; HRMS (ESI) Calcd
for C14H12F3O3 [M + H]+ 285.0739, found 285.0747.
2,5ꢀDiphenylꢀ3ꢀ(phenylsulfonyl)furan (4an). Synthesized by a modified procedure using 100
mol % of pꢀtoluenesulfonic acid monohydrate. White solid (58 mg, 80% yield, eluent =
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hexane/EtOAc (95:5)); Mp = 148–150 °C; H NMR (400 MHz, CDCl3): δ 7.96 (dd, J = 6.7, 2.9
Hz, 2H), 7.86 (d, J = 8.1 Hz, 2H), 7.76– 7.70 (m, 2H), 7.56ꢀ7.52 (m, 1H), 7.50–7.40 (m, 7H),
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7.36 (t, J = 7.3 Hz, 1H), 7.12 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 154.1, 152.8, 141.8, 133.3,
130.1, 129.0, 128.9, 128.72, 128.67, 128.4, 127.1, 125.7, 124.2, 107.3; HRMS (ESI) Calcd for
C22H17O3S [M + H]+ 361.0898, found 361.0895.
Ethyl 5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate10b (4ba). Colourless solid (45 mg,
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87% yield, eluent = hexane/EtOAc (97:3)); Mp = 62–64 °C (lit. 54–56 °C9a); H NMR (400
MHz, CDCl3): δ 7.56 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.73 (s, 1H), 4.30 (q, J = 7.1
Hz, 2H), 3.82 (s, 3H), 2.63 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
164.4, 159.5, 158.2, 152.0, 125.3, 123.4, 115.5, 114.4, 104.0, 60.3, 55.5, 14.6, 14.1; HRMS (ESI)
Calcd for C15H17O4 [M + H]+ 261.1127, found 261.1134.
Ethyl 5ꢀ(4ꢀfluorophenyl)ꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate10b (4ca). White solid (35 mg, 70%
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yield, eluent = hexane/EtOAc (98:2)); Mp = 63–65 °C; H NMR (400 MHz, CDCl3): 7.82–7.40
(m, 2H), 7.07 (t, J = 8.8 Hz, 2H), 6.81 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.37 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 164.2, 162.5 (d, JC-F = 246 Hz), 158.8 , 151.1, 126.7
(d, JC-F = 4 Hz), 125.7 (d, JC-F = 8 Hz), 116.0 (d, JC-F = 22 Hz), 115.7, 105.4, 60.5, 14.6, 14.1;
HRMS (ESI) Calcd for C14H14FO3 [M + H]+ 249.0927, found 249.0935.
Ethyl 5ꢀ(4ꢀbromophenyl)ꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate10b (4da). White solid (46 mg, 74%
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yield, eluent = hexane/EtOAc (97:3)); Mp = 75–77 °C; H NMR (400 MHz, CDCl3): δ 7.48 (s,
4H), 6.87 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 163.8, 158.9, 150.7, 131.9, 129.0, 125.1, 121.4, 115.6, 106.1, 60.3, 14.4, 13.9;
HRMS (ESI) Calcd for C14H14BrO3 [M + H]+ 309.0126, found 309.0131.
Ethyl 2ꢀmethylꢀ5ꢀ(4ꢀnitrophenyl)furanꢀ3ꢀcarboxylate (4ea). Yellow solid (21 mg, 38% yield,
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eluent = hexane/EtOAc (92:8)); Mp = 131–133 °C; H NMR (400 MHz, CDCl3): δ 8.25 (d, J =
9.0 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.12 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.39 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.4, 160.6, 149.4, 146.6, 135.7, 124.4, 123.8,
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116.3, 109.6, 60.5, 14.4, 14.0; HRMS (ESI) Calcd for C14H14NO5 [M + H]+ 276.0872, found
276.0876.
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Ethyl 2ꢀmethylꢀ5ꢀ(oꢀtolyl)furanꢀ3ꢀcarboxylate18 (4fa). Colourless oil (27 mg, 56% yield, eluent
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= hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): 7.87–7.62 (m, 1H), 7.36–7.17 (m, 3H),
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6.77 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.49 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); C
NMR (100 MHz, CDCl3): δ 164.2, 158.2, 151.2, 134.6, 131.2, 129.4, 127.7, 126.8, 126.0, 115.2,
109.1, 60.2, 21.9, 14.4, 13.9; HRMS (ESI) Calcd for C15H17O3 [M + H]+ 245.1178, found
245.1169.
Ethyl 2ꢀmethylꢀ5ꢀ(naphthalenꢀ2ꢀyl)furanꢀ3ꢀcarboxylate18 (4ga). White solid (49 mg, 87%
yield, eluent = hexane/EtOAc (97:3)); Mp = 91–93 °C (lit. 96 °C18); H NMR (400 MHz,
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CDCl3): δ 8.08 (s, 1H), 7.80 (dd, J = 17.4, 8.4 Hz, 3H), 7.69 (dd, J = 8.5, 1.6 Hz, 1H), 7.52–7.38
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(m, 2H), 6.98 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); C NMR
(100 MHz, CDCl3): δ 164.2, 159.1, 152.0, 133.7, 133.0, 128.7, 128.4, 128.0, 127.6, 126.8, 126.3,
122.3, 122.2, 115.8, 106.3, 60.4, 14.6, 14.2; HRMS (ESI) Calcd for C18H17O3 [M + H]+
281.1178, found 281.1183.
Ethyl 5ꢀmethylꢀ[2,2'ꢀbifuran]ꢀ4ꢀcarboxylate19 (4ha). Brown oil (38 mg, 86% yield, eluent =
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hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.41 (dd, J = 1.7, 0.7 Hz, 1H), 6.77 (s,
1H), 6.54 (d, J = 3.3 Hz, 1H), 6.45 (dd, J = 3.4, 1.8 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.63 (s,
3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.8, 158.4, 145.7, 144.3, 142.1,
115.1, 111.3, 105.5, 60.3, 14.3, 13.8; HRMS (ESI) Calcd for C12H13O4 [M + H]+ 221.0814, found
221.0821.
Ethyl 2ꢀmethylꢀ5ꢀ(thiophenꢀ2ꢀyl)furanꢀ3ꢀcarboxylate10b (4ia). Colourless oil (37 mg, 78%
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yield, eluent = hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.26ꢀ7.25 (m, 2H), 7.05
(dd, J = 5.0, 3.7 Hz, 1H), 6.75 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 1.39 (t, J = 7.1 Hz,
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3H); 13C NMR (100 MHz, CDCl3): δ 163.9, 158.3, 147.3, 132.8, 127.6, 124.4, 122.9, 115.4,
105.4, 60.3, 14.4, 13.8; HRMS (ESI) Calcd for C12H13O3S [M + H]+ 237.0585, found 237.0596.
Ethyl 5ꢀbutylꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate10a (4ja). Colourless oil (31 mg, 73% yield, eluent =
hexane/EtOAc (98:2)); 1H NMR (400 MHz, CDCl3): 6.24 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.67–
2.43 (m, 5H), 1.70–1.58 (m, 2H), 1.42ꢀ1.34 (m, 5H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 164.4, 157.5, 154.4, 113.8, 105.4, 59.9, 29.9, 27.3, 22.2, 14.4, 13.8, 13.7; HRMS
(ESI) Calcd for C12H19O3 [M + H]+ 211.1334, found 211.1324.
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Ethyl 5ꢀcyclopropylꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate (4ka). Colourless oil (32 mg, 82% yield,
eluent = hexane/EtOAc (97:3)); 1H NMR (400 MHz, CDCl3): δ 6.17 (s, 1H), 4.26 (q, J = 7.1 Hz,
2H), 2.51 (s, 3H), 1.90 – 1.71 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 0.95–0.78 (m, 2H), 0.77–0.55 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 164.3, 157.2, 155.3, 113.9, 104.1, 59.9, 14.4, 13.7, 8.3, 6.4;
HRMS (ESI) Calcd for C11H15O3 [M + H]+ 195.1021, found 195.1024.
Ethyl 5ꢀcyclohexylꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate (4la). Colourless oil (36 mg, 76% yield,
eluent = hexane/EtOAc (97:3)); 1H NMR (400 MHz, CDCl3): δ 6.19 (d, J = 0.7 Hz, 1H), 4.26 (q,
J = 7.1 Hz, 2H), 2.52 (s, 4H), 2.09–1.96 (m, 2H), 1.89–1.73 (m, 2H), 1.40–1.17 (m, 9H); 13C
NMR (100 MHz, CDCl3): δ 164.5, 158.8, 157.2, 113.6, 103.5, 59.9, 36.9, 31.3, 26.0, 25.8, 14.4,
13.7; HRMS (ESI) Calcd for C14H21O3 [M + H]+ 237.1491, found 237.1488.
(E)ꢀEthyl 2ꢀmethylꢀ5ꢀstyrylfuranꢀ3ꢀcarboxylate (4ma). Yellow oil (47 mg, 91% yield, eluent =
hexane/EtOAc (97:3)); 1H NMR (400 MHz, CDCl3): 7.44 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.6 Hz,
2H), 7.24 (dd, J = 8.6, 6.0 Hz, 1H), 7.00 (d, J = 16.3 Hz, 1H), 6.78 (d, J = 16.3 Hz, 1H), 6.56 (s,
1H), 4.29 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 164.1, 159.1, 151.2, 137.0, 128.2, 128.0, 127.7, 126.6, 116.0, 115.6, 109.1, 60.4, 14.6,
14.2; HRMS (ESI) Calcd for C16H17O3 [M + H]+ 257.1178, found 257.1185.
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Diethyl 5,5'ꢀ(1,4ꢀphenylene)bis(2ꢀmethylfuranꢀ3ꢀcarboxylate) (4na). The reaction was
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44% yield, eluent = hexane/EtOAc (97:3)); Mp = 149–151 °C; H NMR (400 MHz, CDCl3): δ
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7.66 (s, 4H), 6.92 (s, 2H), 4.34 (q, J = 7.1 Hz, 4H), 2.67 (s, 6H), 1.40 (t, J = 7.1 Hz, 6H); C
NMR (100 MHz, CDCl3): δ 164.0, 158.8, 151.3, 129.1, 123.9, 115.6, 105.8, 60.2, 14.4, 13.9;
HRMS (ESI) Calcd for C22H23O6 [M + H]+ 383.1495, found 383.1499.
General Procedure for Furan Synthesis from Enol Silyl Ethers and Diazoketones (Scheme
2). A 10 mL Schlenk tube equipped with a stirrer bar was charged with silyl enol ether (0.20
mmol), Cu(hfacac)2 (9.6 mg, 0.020 mmol, 10 mol %) followed by the addition of
dichloromethane (0.5 mL). A dichloromethane solution (0.5 mL) of diazoketone (0.26 mmol)
was added dropwise over 5 min at room temperature. The resulting mixture was then stirred at 40
°C for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate
(5 mL), passed through a pad of silica gel, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel to afford the furan product.
2ꢀMethylꢀ3,5ꢀdiphenylfuran11a (4ao). Brown oil (39 mg, 84% yield, eluent = hexane/EtOAc
(97:3)); 1H NMR (400 MHz, CDCl3): δ 7.58 (dd, J = 8.3, 1.1 Hz, 2H), 7.36–7.23 (m, 6H), 7.22–
7.09 (m, 2H), 6.68 (s, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.9, 147.8, 134.3,
131.1, 128.89, 128.85, 127.7, 127.3, 126.7, 123.7, 123.3, 106.7, 13.4; HRMS (ESI) Calcd for
C17H15O [M + H]+ 235.1123, found 235.1133.
2,3,5ꢀTriphenylfuran11a (4ap). White solid (49 mg, 83% yield, eluent = hexane/EtOAc (97:3));
Mp = 91–93 °C (lit. 91–92 °C11a); 1H NMR (400 MHz, CDCl3): δ 7.85–7.81 (m, 2H), 7.74–7.63
(m, 2H), 7.56–7.52 (m, 2H), 7.50–7.42 (m, 4H), 7.42–7.29 (m, 5H), 6.88 (s, 1H); 13C NMR (100
MHz, CDCl3): δ 152.8, 148.1, 134.6, 131.3, 130.8, 129.0, 128.94, 128.91, 128.6, 127.8, 127.7,
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127.5, 126.4, 124.8, 124.1, 109.7; HRMS (ESI) Calcd for C22H17O [M + H]+ 297.1279, found
297.1284.
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3ꢀ(4ꢀFluorophenyl)ꢀ2ꢀmethylꢀ5ꢀphenylfuran (4aq). Brown oil (49 mg, 98% yield, eluent =
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hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.75–7.68 (m, 2H), 7.46–7.38 (m, 4H),
7.31ꢀ7.27 (m, 1H), 7.19–7.10 (m, 2H), 6.78 (s, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
161.7 (d, JC-F = 244 Hz), 151.7, 147.4, 130.7, 130.1 (d, JC-F = 4 Hz), 129.0 (d, JC-F = 8 Hz),
128.7, 127.1, 123.5, 122.2, 115.5 (d, JC-F = 21 Hz), 106.4, 13.1; HRMS (ESI) Calcd for
C17H14FO [M + H]+ 253.1029, found 253.1034.
2ꢀMethylꢀ5ꢀphenylꢀ3ꢀ(pꢀtolyl)furan11d (4ar). Brown oil (35 mg, 71% yield, eluent =
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hexane/EtOAc (97:3)); H NMR (400 MHz, CDCl3): δ 7.63–7.54 (m, 2H), 7.32–7.20 (m, 4H),
7.14 (t, J = 7.8 Hz, 3H), 6.68 (s, 1H), 2.42 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
151.5, 147.3, 136.2, 131.2, 131.0, 129.3, 128.7, 127.4, 127.0, 123.4, 123.0, 106.6, 21.2, 13.2;
HRMS (ESI) Calcd for C18H17O [M + H]+ 249.1279, found 249.1284.
Methyl 4ꢀoxoꢀ2,4ꢀdiphenylbutanoate20 (5): Synthesized employing the general procedure for
the reaction of αꢀdiazoꢀβꢀketoester (vide intra) without the treatment with pꢀtoluenesulfonic acid
monohydrate. Colourless solid (47 mg, 88% yield, eluent = hexane/EtOAc (95:5)); Mp = 100–
102 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t,
J = 7.7 Hz, 2H), 7.35 (d, J = 4.1 Hz, 4H), 7.33–7.22 (m, 1H), 4.30 (dd, J = 10.3, 3.9 Hz, 1H),
3.95 (dd, J = 18.0, 10.3 Hz, 1H), 3.69 (s, 3H), 3.27 (dd, J = 18.0, 4.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 197.6, 173.9, 138.4, 136.4, 133.3, 128.9, 128.6, 128.1, 127.8, 127.6, 52.4, 46.4,
42.8; HRMS (ESI) Calcd for C17H17O3 [M + H]+ 269.1178, found 269.1176.
Synthesis of Multisubstituted Pyrroles (Table 4): Method A. The copperꢀcatalyzed reaction of
silyl enol ether and αꢀdiazoꢀβꢀketoester was performed in the same manner as described above.
The reaction mixture was then cooled to 0 °C, followed by the addition of THF (1.0 mL). A THF
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solution of tetrabutylammonium fluoride (1 M, 0.24 mL, 0.24 mmol) was added dropwise, and
the resulting mixture was stirred at 0 °C for 15 min. The resulting solution was concentrated
under reduced pressure using the Schlenk line, followed by the addition of ammonium acetate
(123 mg, 1.6 mmol) and acetic acid (1.0 mL). The resulting mixture was stirred at 120 °C for 20
h. The reaction was cooled to room temperature and the solvents were removed under reduced
pressure. The residue was purified by flash chromatography on silica gel to afford the pyrrole
product.
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Synthesis of Multisubstituted Pyrroles (Table 4): Method B. Method A was slightly modified.
After desilylation with tetrabutylammonium fluoride, the resulting solution was concentrated
under reduced pressure using the Schlenk line, followed by the addition of ammonium acetate
(616 mg, 8.0 mmol). The resulting mixture was stirred at 120 °C for 14 h. The reaction was
cooled to room temperature and diluted with ethyl acetate (20.0 mL), followed by extraction with
water. The organic phase was dried over magnesium sulphate and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica gel to afford the pyrrole
product.
Ethyl 2ꢀmethylꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate12a (6a). Synthesized by Method A. Brown
solid (38 mg, 83% yield, eluent = hexane/EtOAc (90:10)); Mp = 114–116 °C (lit. 115–116 °C12a);
1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 7.53–7.45 (m, 2H), 7.42–7.34 (m, 2H), 7.24 (dt, J =
9.0, 4.3 Hz, 1H), 6.87 (d, J = 2.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.61 (s, 3H), 1.39 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.7, 136.2, 131.9, 130.0, 128.9, 126.6, 123.7, 113.4,
107.4, 59.6, 14.5, 13.4; HRMS (ESI) Calcd for C14H16NO2 [M + H]+ 230.1181, found 230.1184.
Ethyl 5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (6b): Synthesized by Method
B. Brown solid (38 mg, 74% yield, eluent = hexane/EtOAc (90:10)); Mp = 146–148 °C; 1H NMR
(400 MHz, CDCl3): δ 8.61 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.71 (d, J =
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2.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 2.56 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); C
NMR (100 MHz, CDCl3): δ 165.8, 158.5, 135.1, 130.1, 125.2, 124.9, 114.4, 113.1, 106.1, 59.5,
55.3, 14.5, 13.3; HRMS (ESI) Calcd for C15H18NO3 [M + H]+ 260.1287, found 260.1300.
Ethyl 5ꢀ(furanꢀ2ꢀyl)ꢀ2ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (6c). Synthesized by Method B.
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Brown solid (19 mg, 44% yield, eluent = hexane/EtOAc (90:10)); Mp = 134–136 °C; H NMR
(400 MHz, CDCl3): δ 8.54 (s, 1H), 7.34 (d, J = 1.7 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.42 (dd, J
= 3.4, 1.8 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H), 1.35 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 165.4, 147.3, 140.6, 135.5, 121.9, 113.1, 111.6, 106.6,
102.8, 59.5, 14.5, 13.3; HRMS (ESI) Calcd for C12H14NO3 [M + H]+ 220.0974, found 220.0985.
Ethyl 5ꢀcyclopropylꢀ2ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (6d). Synthesized by Method A.
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Colourless solid (32 mg, 82% yield, eluent = hexane/EtOAc (90:10)); Mp = 55–57 °C; H NMR
(400 MHz, CDCl3): δ 8.35 (s, 1H), 6.14 (d, J = 2.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.47 (s,
3H), 1.79–1.64 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.84–0.71 (m, 2H), 0.66–0.52 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 165.9, 134.9, 132.6, 111.2, 105.4, 59.3, 14.5, 13.2, 7.7, 6.4; HRMS
(ESI) Calcd for C11H16NO2 [M + H]+ 194.1181, found 194.1184.
Ethyl 2,5ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate12b (6e): Synthesized by Method A. Yellow solid
(39 mg, 66% yield, eluent = hexane/EtOAc (90:10)); Mp = 149–151 °C (lit. 149–151 °C12c); H
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NMR (400 MHz, CDCl3): δ 8.72 (s, 1H), 7.63ꢀ7.61 (m, 2H), 7.54–7.49 (m, 2H), 7.43–7.32 (m,
5H), 7.25 (dd, J = 8.8, 5.9 Hz, 1H), 7.00 (d, J = 3.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.26 (t, J =
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7.1 Hz, 3H); C NMR (100 MHz, CDCl3): δ 164.9, 137.8, 131.9, 131.8, 131.5, 129.04, 129.03,
128.4, 128.2, 127.0, 124.0, 113.8, 109.1, 59.8, 14.3; HRMS (ESI) Calcd for C19H18NO2 [M + H]+
292.1338, found 292.1336.
Ethyl 2ꢀisopropylꢀ5ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate21 (6f). Synthesized by Method A.
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(400 MHz, CDCl3): δ 8.46 (s, 1H), 7.54–7.42 (m, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.25ꢀ7.20 (m,
1H), 6.84 (d, J = 2.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.86 (hept, J = 7.0 Hz, 1H), 1.38ꢀ1.32 (m,
9H); 13C NMR (100 MHz, CDCl3): δ 165.3, 146.0, 132.0, 129.7, 129.0, 126.6, 123.8, 112.0,
107.7, 59.5, 26.1, 22.0, 14.5; HRMS (ESI) Calcd for C16H20NO2 [M + H]+ 258.1494, found
258.1502.
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Synthesis of Multisubstituted Thiophenes (Table 4). The copperꢀcatalyzed reaction and the
TBAFꢀmediated desilylation were performed by the same procedure as described for the pyrrole
synthesis. After desilylation, Lawesson’s reagent (194 mg, 0.48 mmol) was added, and the
resulting mixture was stirred at 50 °C for 12 h. The reaction was cooled to room temperature and
the solvents were removed under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the thiophene product.
Ethyl 2ꢀmethylꢀ5ꢀphenylthiopheneꢀ3ꢀcarboxylate (7a). Colourless oil (37 mg, 74% yield,
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eluent = hexane/EtOAc (95:5)); H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.58–7.53 (m, 2H),
7.37 (t, J = 7.6 Hz, 2H), 7.31–7.25 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.75 (s, 3H), 1.39 (t, J = 7.1
Hz, 3H).; 13C NMR (100 MHz, CDCl3): δ 163.7, 148.5, 139.3, 133.7, 129.2, 128.9, 127.6, 125.6,
124.6, 60.4, 15.6, 14.4; HRMS (ESI) Calcd for C14H15O2S [M + H]+ 247.0793, found 247.0796.
Ethyl 5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylthiopheneꢀ3ꢀcarboxylate (7b). Yellow solid (35 mg, 64%
yield, eluent = hexane/EtOAc (95:5)); Mp = 84–86 °C; 1H NMR (400 MHz, CDCl3): δ 7.54–7.45
(m, 3H), 6.92 (d, J = 8.8 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.76 (s, 3H), 1.41 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.7, 159.3, 147.6, 139.2, 129.1, 126.9, 126.5,
123.5, 114.3, 60.3, 55.4, 15.6, 14.4; HRMS (ESI) Calcd for C15H17O3S [M + H]+ 277.0898, found
277.0889.
Ethyl 5ꢀ(furanꢀ2ꢀyl)ꢀ2ꢀmethylthiopheneꢀ3ꢀcarboxylate (7c). Reddish oil (22 mg, 47% yield,
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0.7 Hz, 1H), 6.50–6.35 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.73 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 163.4, 148.6, 147.9, 141.8, 129.0, 128.8, 124.0, 111.7, 105.1,
60.4, 15.4, 14.4; HRMS (ESI) Calcd for C12H13O3S [M + H]+ 237.0585, found 237.0584.
Ethyl 5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylthiopheneꢀ3ꢀcarboxylate (7d). Yellow oil (28 mg, 66%
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yield, eluent = hexane/EtOAc (95:5)); H NMR (400 MHz, CDCl3): δ 7.01 (d, J = 0.6 Hz, 1H),
4.28 (q, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.02–1.86 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 0.96ꢀ0.91 (m,
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2H), 0.70ꢀ0.66 (m, 2H); C NMR (100 MHz, CDCl3): δ 163.7, 146.3, 143.4, 127.7, 124.2, 60.1,
15.4, 14.4, 10.6, 9.2; HRMS (ESI) Calcd for C11H15O2S [M + H]+ 211.0793, found 211.0796.
Ethyl 2,5ꢀdiphenylthiopheneꢀ3ꢀcarboxylate22 (7e). Yellow solid (38 mg, 62% yield, eluent =
hexane/EtOAc (95:5)); Mp = 44–46 °C (lit. 45–46 °C22); 1H NMR (400 MHz, CDCl3): δ 7.74 (s,
1H), 7.65 (d, J = 7.4 Hz, 2H), 7.58ꢀ7.55 (m, 2H), 7.45ꢀ7.41 (m, 5H), 7.35 (t, J = 7.4 Hz, 1H),
4.25 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 163.3, 149.7,
142.5, 133.4, 133.5, 129.8, 129.0, 128.6, 128.0, 127.9, 125.7, 125.4, 60.6, 14.0; HRMS (ESI)
Calcd for C19H17O2S [M + H]+ 309.0949, found 309.0954.
Methyl 2ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀphenylthiopheneꢀ3ꢀcarboxylate (7f). White solid (40 mg, 62%
yield, eluent = hexane/EtOAc (95:5)); Mp = 143–145 °C; 1H NMR (400 MHz, CDCl3): δ 7.69 (s,
1H), 7.64–7.52 (m, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz,
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1H), 6.94 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H); C NMR (100 MHz, CDCl3): δ 163.8,
160.1, 150.4, 141.9, 133.5, 131.1, 129.0, 128.0, 127.8, 125.7, 125.50, 125.45, 113.5, 55.3, 51.6;
HRMS (ESI) Calcd for C19H17O3S [M + H]+ 325.0898, found 325.0893.
Supporting Information
1H and 13C NMR spectra of all compounds
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This work was supported by Ministry of Education of Singapore and Nanyang Technological
University (RG 5/14).
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References
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Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wileyꢀ
Interscience: New York, 1998. (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (d)
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