Access to Hetero-Benzyl Scaffolds via Transient-Ligand-Enabled Direct γ-C(sp3)-H Arylation of 3-Methylheteroarene-2-Carbaldehydes

Article abstract of DOI:10.1021/acs.joc.0c00154

An efficient and straightforward method has been developed for the synthesis of β-benzyl-substituted 5-membered heterocyclic carbaldehydes via transient directing-group-enabled direct γ-C(sp3)-H arylation of 3-methylheteroarene-2-carbaldehydes. A wide range of 3-methylheteroarene carbaldehydes undergo coupling with a variety of aryl iodides, including less reactive iodo pyridine derivatives to provide a library of highly selective functionalized products in good to excellent yields. Some of these products have been successfully utilized in synthesizing useful synthetic intermediates.

Full text of DOI:10.1021/acs.joc.0c00154

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Article
Access to Hetero-Benzyl Scaffolds via Transient-Ligand-Enabled
Direct #-C(sp3)-H Arylation of 3-Methylheteroarene-2-Carbaldehydes
Chennakesava Reddy, Javed Y. Shaikh, and Ramakrishna G. Bhat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00154 • Publication Date (Web): 29 Apr 2020
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Access to Hetero-Benzyl Scaffolds via Transient-Ligand-Enabled
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Direct
Carbaldehydes
γ-C(sp3)−H
Arylation
of
3-Methylheteroarene-2-
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Chennakesava Reddy, Javed Y. Shaikh and Ramakrishna G. Bhat*
Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr.
Homi Bhabha Road, Pashan, 411008, Pune, Maharashtra, India.
E-mail: rgb@iiserpune.ac.in
ABSTRACT: An efficient and straightforward method has been developed for the synthesis
of β-benzyl-substituted five-membered heterocyclic carbaldehydes via transient directing group-
enabled direct γ-C(sp3)−H arylation of 3-methylheteroarene-2-carbaldehydes. A wide range of 3-
methylheteroarene carbaldehydes undergoes coupling with a variety of aryl iodides including
less reactive iodo pyridine derivatives to provide a library of highly selective functionalized
products in good to excellent yields. Some of these products have been successfully utilized in
synthesizing useful synthetic intermediates.
INTRODUCTION
The β-benzyl-substituted five-membered heterocyclic scaffolds are important class of
compounds and are extensively used as key intermediates for the synthesis of bio-active1 and
fused ring compounds2,3 as well as polycyclic aromatic hydrocarbons.4 Although this class of
compounds is of high significance, only a few literature reports for the synthesis are known.
Some of these include Suzuki-Miyaura cross-coupling reaction of (3-formyl-2-
heteroaryl)boronic acid with benzyl halides,2b,3a Vilsmeier-type formylation of 3-benzyl-
heteroaromatic compounds,2c domino reaction of 1,3-enynes with mercaptoacetaldehydes5 and
Stille-type coupling reaction of 3-bromo-2-heterocarbaldehyde with tributyl(1-
phenylvinyl)stannane.2a Regardless of these reports, the effective methodology for the rapid
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access to these useful motifs with a broad substrate scope is very much limited. Many of the
available methods have limitations such as poor substrate tolerance, multi-step syntheses and
requirement of commercially unavailable pre-functionalized starting materials as well as
stoichiometric use of relatively expensive reagents.
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During the past two decades, C−H activation strategy has emerged as a powerful tool in the
organic synthetic transformations.6 Usually most of the strategies require a covalently attached
directing group (DG) on the substrate that forms a bidentate coordination with a transition-metal
to facilitate high reactivity and controlled-selectivity.7 The preinstallation of an auxiliary as DG
in the substrate and the subsequent removal of DG post functionalization costs additional two
steps to the overall synthetic transformation. In spite of this limitation, significant progress has
been made on the relatively challenging γ-C(sp3)−H or distal C-H activation.7c,d
Employing an auxiliary as the transient directing group has become an emerging and
attractive strategy in the field of C-H activation in recent times. The transient directing group
(TDG)-enabled C-H activation reactions8 proceed through in situ binding of ligand with reacting
substrate followed by coordination to the metal in a reversible manner. The TDG bears intrinsic
advantages of free installation and effortless removal of ligand without disturbing the
functionality of the substrate. In this direction, various groups have disclosed the use of new as
well as modified transient directing groups for the C-H functionalization of carbonyl
compounds9 and free amino derivatives.10
Since Yu’s first remarkable discovery of glycine as transient directing group,11 amino acids
have emerged as efficient TDGs for the selective cleavage of C-H bond. This leads to effective
C(sp2)-H functionalization and C(sp3)-H arylation of carbonyl compounds.12,13 In 2016, for the
first time, Yu and co-workers11 as well as Hu and co-workers13 have independently reported the
effective method for the direct benzylic C(sp3)−H arylation of benzaldehydes by employing α-
amino acids and acetohydrazide respectively as TDGs (Scheme 1a).
Very recently, Zhang and co-workers have performed the glycine-enabled ortho-C(sp3)−H
arylation of thiophene aldehydes with aryl diiodides to synthesize just two representative
examples to access polycyclic aromatic hydrocarbons (PAHs).4 However, we observed that this
reported protocol was not very effective and workable for different substrates.14
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Despite the recent progress of TDG enabled transition metal catalyzed C-H arylations, the
development of novel transition-metal catalyst system for the selective arylation of less reactive
benzylic γ-C(sp3)−H bond of 3-methyl substituted heterocyclic carbonyl compounds is always
challenging.
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Hence, it is significant to explore the direct chemoselective γ-C(sp3)−H arylation and the
substrate scope owing to their high synthetic utility. To the best of our knowledge, there is no
efficient report and a detailed study for the rapid access of these functionalized molecules
through the direct γ-C(sp3)−H arylation of five-membered heterocyclic carbonyl compounds via
transient-ligand-directed strategy. Hence the TDG-enabled strategy would be the most direct and
efficient approach to access a wide variety of hetero-benzyl derivatives. Herein, we report TDG
enabled strategy for the regio- and chemo-selective direct γ-C(sp3)−H arylation of 3-
methylheteroarene-2-carbaldehydes (Scheme 1b).
Scheme 1. Transient-ligand-enabled direct γ-C(sp3)−H arylation of 2-methylbenzaldehydes
and heteroaryl-aldehydes
RESULTS AND DISCUSSION
To start our investigation, we chose the arylation of 3-methylthiophene-2-carbaldehyde
1a with iodobenzene 2a as a model reaction by screening various amino acids (L1-L9) as TDGs
in combination with various other parameters such as catalysts, additives, solvents, etc. as shown
in Table 1.
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Table 1. Optimization of Reaction Conditionsa
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aReaction conditions: 1a (0.2 mmol), PhI (2a), Pd catalyst (10 mol%), Ligand L (20-40 mol%), additive (0.3 mmol),
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solvent (1.6 mL), 110 C, N2, 24 h. Isolated yields based on 1a using column chromatography. HFIP (0.72
mL)/AcOH (0.08 mL). dIsolated yield based on 2a.
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Initially, we investigated the arylation of 1a with iodobenzene 2a by employing the ligands L1-
L3 as TDGs in acetic acid/water mixture (entries 1-3, Table 1) following the reported protocol
for aryl diiodides.4,14 Glycine L3 as TDG in presence of Pd(OAc)2 (10 mol%) and AgTFA (2
equiv.) in acetic acid/water (9:1) gave the desired 3-methyl-2-thiophene-carbarladehyde (3aa) in
moderate yield (entries 1-3, Table 1). In order to optimize the reaction further, we explored the
arylation of 1a with iodobenzene 2a in the presence of L2-L4 in newer solvent system
(HFIP:AcOH, 9:1) to give the corresponding product 3aa in 20, 55, and 5% yields respectively
(entries 4-6, Table 1). The ligand L2 and L4 (β-amino acids) proved to be not effective probably
due to the less favourable [6,6]-bicyclic palladium intermediate during course of the reaction.
Interestingly, ligands L1 and L3 proved to be not highly effective for the heterocyclic scaffold
even in the reported solvent system for the previous procedures for the direct benzylic C(sp3)−H
arylation of benzaldehydes (entries, 1 and 3, Table 1).11,13
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In this regard, we planned to screen different natural and non-natural α-amino acids due
to their inherent reactivity and effective rigidity for the possible and efficient chemoselective
C(γ)-H arylation. We screened various α-amino acids (L5-L9) as TDGs to perform the arylation
of 1a with PhI 2a (2 equiv.) (entries 7-11, Table 1). We observed that L-valine (L8, 40 mol%)
proved to be most suitable TDG in combination with Pd(OAc)2 (10 mol%) and AgTFA (2
equiv.) in HFIP:AcOH (9:1) to obtain the desired product 3aa in 93% yield (entry 10, Table 1).
In order to optimize the reaction further, arylation of 1a was carried out separately in both HFIP
and AcOH to furnish the product 3aa in 37% and 75% yields respectively (entries 12-13, Table
1).
Next, an exhaustive screening was carried out by changing the various parameters such as
solvent ratios (HFIP/AcOH and AcOH/H2O), quantity of solvent, catalyst [Pd(OTFA)2], additive
[AgOAc], stoichiometric amount of PhI (0.8 - 2 equiv.) (entries 14-23, Table 1). These results
indicated that the combination of HFIP and acetic acid as a solvent system is more advantageous
for the effective transformation. The arylation of 1a did not proceed in the absence of Pd-
catalyst, additive-AgTFA or ligand L8 respectively under the identical reaction conditions
(entries 24-26, Table 1). These results clearly indicated that Pd-catalyst, ligand and additive are
necessary for the desired transformation. Based on the exhaustive screening, 1a (1 equiv.), PhI
(1.5 equiv.) in presence of Pd(OAc)2 (10 mol%), AgTFA (1.5 equiv.) and L-valine L8 (40 mol%)
in HFIP/AcOH (9:1) at 110 oC for 24 h proved to be the optimized reaction condition.
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Table 2. A library of 3-benzyl-substituted five-membered heteroarene carbaldehydesa,b
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aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (0.02 mmol), AgTFA (0.3 mmol), L8 (0.08 mmol),
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HFIP (1.44 mL), AcOH (0.16 mL), 110 C, 24 h. bIsolated yields; b’0.3 g scale; b’’0.5 g scale; c1 (0.24 mmol), 2 (0.2
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mmol); 36 h, 30 h; Pd(OAc)2 (0.03 mmol); AgTFA (0.4 mmol), 113 C; 40 h; Pd(OAc)2 (0.03 mmol) and
AgTFA (0.6 mmol)
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Having the optimized reaction conditions in hand, we further explored the reaction and substrate
scope of this protocol by carrying out the arylation of 3-methylthiophene-2-carbaldhyde 1a with
a broad range of aryl/heteroaryl iodides 2 (Table 2). The reaction of 1a with a variety of aryl
iodides (2a-2v) having electron withdrawing groups (EWGs) as well as electron donating groups
(EDGs) underwent smoothly to afford the corresponding 3-benzylthiophene derivatives (3aa-
3av) in moderate to excellent yields (46-98%) (Table 2). Moreover, di-substituted aryl iodides
(2n, 2s-v) with EWGs as well as EDGs and 3-bromo-6-iodo-9H-fluorene 2w reacted smoothly
with 1a to furnish the corresponding desired products (3an, 3as-3aw) in moderate to good yields
(50-70%, Table 2).
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Further, in order to generalize the scope of this strategy, we performed the direct arylation by
employing 5-bromothiophene-2-carbaldehyde 1b, 3-methyl benzothiophene carbaldehyde 1c and
3-methyl benzofuran 2-carbaldehyde 1d with other aryl/heteroaryl iodides (Table 2). To our
delight, the arylation of these heteroaromatic carbaldehydes (1b-1d) with different aryl iodides
(2b, 2h, 2c, 2z) afforded the corresponding products (3bh, 3cb, 3ch, 3dh, 3db, 3dc, 3cz) in 46-
75% yields (Table 2). Further, the substrate containing free carboxylic acid such as 4-
iodobenzoic acid (2x), 6-iodoindole derivative (2y) and 5-iodopyridine derivatives(2z-2zc’)
underwent direct γ-C(sp3)-H arylation under the optimum reaction conditions to afford the
corresponding functionalized products (3ax-3azc’) in moderate to good yields (45-73%) under
the optimum reaction conditions. Unfortunately, indole-2-carbaldehyde 1e, reacted too
sluggishly under the optimum reaction conditions to furnish the desired product 3eh in very poor
yield (~10%). In spite of our repeated attempts, we could not isolate the pure 3eh using column
chromatography. Further, the practicality of this protocol has been established by scaling up (0.3-
0.5 g) the reactions to afford the desired products 3aa and 3ab in good yields (see Table 2).
The electron deactivating halo groups (F, Cl, Br), strong EWGs such as nitro, nitrile, ester,
aldehyde and keto groups and EDGs, such as, methyl, isopropyl, methoxy tolerated the
optimized reaction conditions to afford the corresponding functionalized products smoothly. The
protocol worked smoothly with relatively less reactive iodo pyridine derivatives.
Owing to the importance of benzyl-heteroaryl carbaldehydes as active synthetic intermediates,
we successfully utilized them (3aa, 3ao, 3au, 3ae, 3ab) in synthesizing very useful compounds
as an application to this strategy (Scheme 2).
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The functionalized fused compound 4a was synthesized starting from 3aa following the
reported procedure.3b The fused naphtho-thiophene 4a was obtained in 65% yield through the
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condensation reaction of 3aa in presence of TsNH2 and BF3 Et2O. It is very important to note
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that we could access 4a in lesser synthetic steps than the reported procedure.3b
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Scheme 2. Some of the selective synthetic transformations as an application to the strategy
Likewise, benzothiophene derivatives can be easily accessed using this protocol.2b The
LAH reduction of 3ao and Grignard addition of MeMgBr with 3au afforded the corresponding
alcohols 4b and 4c in 70% and 98% respectively. The reductive amination of 3ae in presence of
p-anisidine and NaCNBH3 gave the corresponding substituted amine 4d in 79% yield. The
reaction of 3ab with Wittig reagent and the reaction of 3ao under Schmidt-type reaction
conditions afforded the corresponding α,β-unsaturated carbonyl compound 4e and 2-cyano 3-
benzyl thiophene derivative 4f respectively (Scheme 2). There is a great scope of this strategy to
generate a diverse range of structural motifs as crucial intermediates for biologically active
molecules, target-organic synthesis and pharmaceuticals.
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CONCLUSIONS
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In summary, we have developed an efficient and straightforward palladium-catalyzed
strategy for the direct arylation of unactived γ-C(sp3)−H bond of 3-methylheteroarene-2-
carbaldehydes with a variety of aryl iodides by employing (S)-2-amino-3-methylbutanoic acid
(L-valine) as a transient ligand. The highly regio- and chemoselective reaction of various 3-
methylheteroarene carbaldehydes with a wide range of aryl iodides facilitated a straightforward
access to a library of β-benzyl-substituted five-membered heterocyclic carbaldehydes in good to
excellent yields. The main importance of this strategy is the high functional group tolerance,
broad substrate scope and the smooth arylation of even relatively less reactive pyridine-based
hetero-aryl iodides. Further investigation to access different functionalized heterocycles and
enantioselective bioactive intermediates is under progress.
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EXPERIMENTAL SECTION
General Information. All reagents were purchased from commercial sources and used as as
received, unless otherwise indicated. Thin-layer chromatography (TLC) was performed using
silica gel 60 GF254 precoated aluminum backed plates (2.5 mm) with detection by UV light. The
column chromatography was performed using silica gel (100-200 mesh) eluting with petroleum
ether and ethyl acetate. Melting points of the compounds are uncorrected. IR spectra of
compounds were recorded as thin films or KBr pellets. Unless otherwise specified, proton (1H)
and proton-decoupled carbon [13C{1H}] NMR spectra were recorded operating at 400 MHz for
1
proton and 100 MHz for carbon nuclei. For H NMR spectra, signals arising from the residual
protio-forms of the solvent were used as the internal standards. Chemical shifts (δ) are reported
1
in ppm downfield from CDCl3 (δ = 7.26 ppm) for H NMR and relative to the central CDCl3
resonance (δ = 77.16 ppm) for 13C NMR spectroscopy. Mass samples were analyzed by high
resolution mass spectrometry (HRMS) using electrospray ionization (ESI-TOF). All the
reactions were performed in anhydrous solvent under a nitrogen atmosphere.
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Starting materials (3-methylheteroaryl-2-carbaldehydes (1a, 1c)) and aryl iodides (2a-2x, 2y-
2zc') were commercially bought from Sigma-Aldrich, Alfa Aesar, Avra Synthesis Pvt. Ltd., etc.
and were utilized as such without any further purifications. Further, 5-bromo-3-methylthiophene-
2-carbaldehyde (1b)15 and 5-iodo-1-tosyl-1H-indole (2y)16 compounds were known in literature
and synthesized them by following reported literature procedures15,16
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Synthetic Procedure for the LAH Reduction17a 3-Methylbenzofuran-2-carboxylic acid
followed by PCC-based Oxidation17b and Synthesis of 3-Methylbenzofuran-2-carbaldehyde
(1d).
To a stirred solution of 3-methylbenzofuran-2-carboxylic acid (400 mg, 2.27 mmol, 1 equiv) in
o
THF (15 mL) at 0 C under Ar was added LiAlH4 (4.54 mmol, 2 equiv.). Then the mixture was
allowed to room temperature and stirred overnight at 25-30 oC. After the complete consumption
o
of starting material (monitored by TLC), the reaction mass was cooled down to 0 C and
quenched carefully with sat. NH4Cl solution (10 mL). The mixture was extracted with EtOAc
(2x30 mL) and combined organic phase was dried over Na2SO4, filtered, and concentrated in
vacuo to obtain the corresponding crude alcohol which was used as such for the next step PCC
oxidation reaction without any further purification. To a another dry 100 mL RB flask containing
the above crude alcoholic solution in DCM (15 mL) was charged pyridinium chlorochromate
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(3.40 mmol, 1.5 equiv) at 0-5 C under nitrogen atmosphere and allowed to stir at RT for 5 hrs.
After the completion of reaction (monitored by TLC), the solvent was distilled off completely
under vaccum to obtain the corresponding crude aldehyde and purified the crude by silica
chromatography (EtOAc/petroleum ether = 10:90) to obtain 3-methylbenzofuran-2-carbaldehyde
°
(1d) as a white solid: Rf = 0.49 (EtOAc/petroleum ether = 10:90), mp: 86-88 C; 210 mg (60%
yield); 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.1 Hz,
1H), 7.53 – 7.49 (m, 1H), 7.44 (dd, J = 8.0, 7.1 Hz, 1H), 2.79 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 184.1 143.1, 142.2, 140.2, 137.6, 128.5, 124.9, 124.0, 123.4, 12.2.
Synthetic Procedure for N-benzylation18 of 3-Methyl-1H-indole-2-carbaldehyde and
Synthesis of 1-Benzyl-3-methyl-1H-indole-2-carbaldehyde (1e).
To a stirred solution of NaH (3.14 mmol, 2 equiv.) in dry THF (10 mL) was charged 3-methyl-
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1H-indole-2-carbaldehyde (250 mg, 1.57 mmol, 1 equiv.) at 0 C under Ar and stirred at the
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same temperature for 10-15 minutes. Then, benzyl bromide (1.1 equiv) was charged gradually at
0-5 oC, the reaction mixture was allowed to room temperature and stirred overnight at 25-30 oC.
After the complete consumption of starting material (monitored by TLC), the reaction mass was
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cooled down to 5 C and quenched carefully with few drops of MeOH followed by the addition
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of water (10 mL). The mixture was extracted with EtOAc (2 x 25 mL) and combined organic
phase was dried over Na2SO4, filtered, and concentrated in vacuo. The corresponding crude
product was purified by silica chromatography (EtOAc/petroleum ether = 15:85) to obtain 1-
Benzyl-3-methyl-1H-indole-2-carbaldehyde (1e) as a pale yellow solid: Rf = 0.49
°
1
(EtOAc/petroleum ether = 15:85), mp: 80-82 C; 313 mg (80% yield); H NMR (400 MHz,
CDCl3) δ 10.15 (s, 1H), 7.72-7.70 (m, 1H), 7.39-7.30 (m, 2H), 7.25-7.13 (m, 4H), 7.08-7.05 (m,
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2H), 5.78 (s, 2H), 2.65 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 181.3, 139.6, 138.2, 130.6,
128.6, 127.6, 127.3, 127.2, 127.2, 126.6, 121.41, 120.43, 110.80, 47.8, 8.7. HRMS (ESI): m/z [M
+ H]+ calcd for C17H16NO: 250.1231; found 250.1218.
General Procedures for γ-C(sp3)‒H Arylation of 3-Methylheteroarene-2-carbaldehydes
Using a Transient Directing Group.
General Procedure A:
A 15-mL dry pressure tube equipped with a stir bar was charged with 3-methylthiophene-2-
carbaldehyde 1a (25.2 mg, 0.20 mmol, 1.0 equiv.), iodobenzene 2a (61.1 mg, 0.3 mmol, 1.5
equiv.), Pd(OAc)2 (4.5 mg, 0.02 mmol, 0.1 equiv.), L8 (9.36 mg, 0.08 mmol, 0.4 equiv.),
AgTFA (61.4 mg, 0.3 mmol, 1.5 equiv.), and followed by the addition of the mixture of (1.44
mL) and AcOH (0.16 mL) at room temperature. Then the resulting reaction mixture was
degassed under N2 atmosphere for 2 min and stirred vigorously at room temperature for 15 min.
Then the reaction mixture was heated to 110 °C for 24 h in heating block. After which, the
reaction mixture was cooled to room temperature, followed by the dilution with EtOAc (15 mL)
and subsequently it was filtered through pad of celite. The filtrate was concentrated in vacuo.
The residue was purified by column chromatography on silica gel to furnish the desired product
3aa in 94% yield (38 mg) as yellow oil.
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General Procedure B:
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A 15-mL dry pressure tube equipped with a stir bar was charged with ethyl 3-iodobenzoate 2c
(56 mg, 0.2 mmol, 1.0 equiv.), 3-methylthiophene-2-carbaldehyde 1a (30.7 mg, 0.24 mmol, 1.2
equiv.), Pd(OAc)2 (4.5 mg, 0.02 mmol, 0.1 equiv.), L8 (9.36 mg, 0.08 mmol, 0.4 equiv.),
AgTFA (61.4 mg, 0.3 mmol, 1.5 equiv.), and followed by the addition of the mixture of HFIP
(1.44 mL) and AcOH (0.16 mL) at room temperature. Then the resulting reaction mixture was
degassed under N2 atmosphere for 2 min and it was stirred vigorously at room temperature for 15
min followed heating at 110 °C for 24 h in heating block. After which the reaction mixture was
cooled to room temperature followed by dilution with EtOAc (15 mL). Later, the reaction
mixture was filtered through pad of celite and the filtrate was then concentrated in vacuo. The
residue was purified by column chromatography on silica gel to afford the desired product 3ac in
75% yield (41 mg) as brown color semi solid.
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Following General Procedure B, the compounds 3ac, 3ag-aj, 3dh, 3ay-3azc´ were synthesized
(as shown in Scheme 2)
3-Benzylthiophene-2-carbaldehyde (3aa). Following the general procedure A described above,
3aa was obtained after purification by column chromatography on silica gel as a yellow oil: Rf =
0.49 (EtOAc:petroleum ether = 10:90), 38 mg (94% yield); FTIR (cm-1): 3028, 1652, 1424,
1
1225; H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.63 (dd, J = 5.0, 1.0 Hz, 1H), 7.34 – 7.27
13
(m, 2H), 7.25 – 7.15 (m, 3H), 6.93 (d, J = 5.0 Hz, 1H), 4.33 (s, 2H). C{1H} NMR (100 MHz,
CDCl3) δ 182.5, 150.1, 139.2, 138.9, 134.7, 131.5, 128.9, 128.7, 126.8, 34.6. HRMS (ESI): m/z
[M + H]+ calcd for C12H11OS: 203.0531; found 203.0532.
3-(3-Nitrobenzyl)thiophene-2-carbaldehyde (3ab). Following the general procedure A
described above, 3ab was obtained after purification by column chromatography on silica gel as
a yellow brownish solid: Rf = 0.46 (EtOAc:petroleum ether = 12:88), mp: 86-88 °C; 45 mg (91%
yield); FTIR (cm-1): 3099, 1658, 1526, 1350, 717; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H),
8.12 – 8.06 (m, 2H), 7.72 (d, J = 5.0 Hz, 1H), 7.56 – 7.47 (m, 2H), 6.97 (d, J = 5.0 Hz, 1H), 4.48
(s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.1, 148.6, 147.3, 141.3, 138.3, 135.2, 134.9,
131.3, 129.8, 123.6, 122.0, 34.2. HRMS (ESI): m/z [M + H]+ calcd for C12H10NO3S: 248.0381;
found 248.0384.
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Ethyl 3-((2-formylthiophen-3-yl)methyl)benzoate (3ac). Following the general procedure B
described above, 3ac was obtained after purification by column chromatography on silica gel as
a brown colour semi solid: Rf = 0.46 (EtOAc:petroleum ether = 12:88), 41 mg (75% yield); FTIR
(cm-1): 2982, 1712, 1656, 1273, 1188 ; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.93 – 7.89
(m, 2H), 7.65 (d, J = 5.0 Hz, 1H), 7.38 – 7.36 (m, 2H), 6.92 (d, J = 5.0 Hz, 1H), 4.38 (s, 2H),
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4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 182.3,
166.5, 149.1, 139.6, 138.2, 134.9, 133.8, 131.4, 131.1, 129.8, 128.9, 128.1, 61.2, 34.3, 14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H14NaO3S: 297.0561; found 297.0559.
3-(3-Fluorobenzyl)thiophene-2-carbaldehyde (3ad). Following the general procedure A
described above, 3ad was obtained after purification by column chromatography on silica gel as
a yellow oil: Rf = 0.49 (EtOAc:petroleum ether = 10:90), 40 mg (90% yield); FTIR (cm-1): 2924,
1658, 1526, 1242, 737; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.67 – 7.66 (m, 1H), 7.30-
7.24 (m, 1H), 6.94 (d, J = 5.0 Hz, 1H), 6.98 – 6.86 (m, 3H), 4.34 (s, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ 182.3, 163.2 (d, JC-F = 246.6 Hz), 148.8, 141.7 (d, JC-F = 7.2 Hz), 138.3, 134.9,
131.4, 130.4 (d, JC-F = 8.3 Hz), 124.8 (d, JC-F = 2.9 Hz), 115.7 (d, JC-F = 21.6 Hz), 113.8 (d, JC-F
= 21.0 Hz), 34.2 (d, JC-F = 1.8 Hz). HRMS (ESI): m/z [M + H]+ calcd for C12H10FOS: 221.0436;
found 221.0433.
3-(3-Chlorobenzyl)thiophene-2-carbaldehyde (3ae). Following the general procedure A
described above, 3ae was obtained after purification by column chromatography on silica gel as
a yellow oil: Rf = 0.48 (EtOAc:petroleum ether = 10:90), 38 mg (81% yield); FTIR (cm-1): 1737,
1428, 1227, 724; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.67 – 7.66 (m, 1H), 7.26 – 7.16
(m, 3H), 7.08 – 7.06 (m, 1H), 6.93 (d, J = 5.0 Hz, 1H), 4.32 (s, 2H). C{1H}NMR (100 MHz,
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CDCl3) δ 182.3, 148.7, 141.2, 138.2, 134.9, 134.7, 131.4, 130.2, 128.8, 127.1, 126.9, 34.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H10ClOS: 237.0141; found 237.0147.
3-(3-Bromobenzyl)thiophene-2-carbaldehyde (3af). Following the general procedure A
described above, 3af was obtained after purification by column chromatography on silica gel as a
brown colour semi solid: Rf = 0.49 (EtOAc:petroleum ether = 10:90), 42 mg (76% yield); FTIR
(cm-1): 2924, 1658, 1470, 1229, 720; H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.66 (d, J =
1
4.9 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.18 (t, J = 7.7 Hz, 1H), 7.13 – 7.10 (m, 1H), 6.93 (d, J = 5.0
Hz, 1H), 4.31 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 182.3, 148.7, 141.5, 138.3, 134.9,
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131.7, 131.4, 130.5, 130.0, 127.4, 122.9, 34.2. HRMS (ESI): m/z [M + H]+ calcd for
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C12H10BrOS: 280.9636; found 280.9635.
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3-(3-Formylbenzyl)thiophene-2-carbaldehyde (3ag). Following the general procedure B
described above, 3ag was obtained after purification by column chromatography on silica gel as
a yellow semi solid: Rf = 0.49 (EtOAc:petroleum ether = 14:86), 21 mg (46% yield); FTIR (cm-
1): 3098, 1693, 1654, 1425, 1230; 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 9.99 (s, 1H), 7.77
– 7.73 (m, 1H), 7.72 (s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.51 – 7.46 (m, 2H), 6.95 (d, J = 5.0 Hz,
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1H), 4.44 (s, 2H). C{1H}NMR (100 MHz, CDCl3) δ 192.2, 182.2, 148.5, 140.5, 138.3, 136.9,
135.0, 134.8, 131.4, 129.6, 129.5, 128.6, 34.3. HRMS (ESI): m/z [M + H]+ calcd for C13H11O2S:
231.0480; found 231.0481.
Methyl 4-((2-formylthiophen-3-yl)methyl)benzoate (3ah). Following the general procedure B
described above, 3ah was obtained after purification by column chromatography on silica gel as
°
a brown solid: Rf = 0.48 (EtOAc:petroleum ether = 13:87), mp: 54-56 C; 50 mg (98% yield);
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FTIR (cm-1): 2923, 1717, 1660, 1523, 1281; H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.98
(d, J = 8.4 Hz, 2H), 7.66 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 5.0 Hz, 1H),
4.40 (s, 2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.2, 166.9, 148.5, 144.5, 138.3,
134.9, 131.4, 130.2, 128.8, 128.7, 52.2, 34.5. HRMS (ESI): m/z [M + H]+ calcd for C14H13O3S:
261.0585; found 261.0588.
4-((2-Formylthiophen-3-yl)methyl)benzonitrile (3ai). Following the general procedure B
described above, 3ai was obtained after purification by column chromatography on silica gel as
°
yellow crystalline solid: Rf = 0.49 (EtOAc:petroleum ether = 15:85), mp: 103-105 C; 35 mg
1
(77% yield); FTIR (cm-1): 1736, 1646, 2224, 1424, 1280; H NMR (400 MHz, CDCl3) δ 10.03
(s, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.94 (d, J =
5.0 Hz, 1H), 4.42 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.1, 147.3, 144.7, 138.3, 135.1,
132.7, 131.3, 129.5, 118.8, 110.7, 34.6. HRMS (ESI): m/z [M + H]+ calcd for C13H10NOS:
228.0483; found 228.0481.
3-(4-Acetylbenzyl)thiophene-2-carbaldehyde (3aj). Following the general procedure B
described above, 3aj was obtained after purification by column chromatography on silica gel as a
°
brown solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), mp: 61-63 C; 33 mg (67% yield);
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FTIR (cm-1): 2924, 1665, 1527, 1423, 1266; H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.90
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(d, J = 8.3 Hz, 2H), 7.68 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 5.0 Hz, 1H),
4.41 (s, 2H), 2.58 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 182.2, 148.4, 144.7, 138.3,
135.8, 134.9, 131.4, 129.0, 128.9, 34.5, 26.7. HRMS (ESI): m/z [M + H]+ calcd for C14H13O2S:
245.0636; found 245.0637.
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3-(4-Fluorobenzyl)thiophene-2-carbaldehyde (3ak). Following the general procedure A
described above, 3ak was obtained after purification by column chromatography on silica gel as
a yellow oil: Rf = 0.49 (EtOAc:petroleum ether = 10:90), 38 mg (86% yield); FTIR (cm-1): 2926,
1732, 1511, 1225; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.16 –
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7.13 (m, 2H), 7.01 – 6.96 (m, 2H), 6.91 (d, J = 5.0 Hz, 1H), 4.31 (s, 2H). C{1H} NMR (100
MHz, CDCl3) δ 182.4, 161.7 (d, JC-F = 245.3 Hz), 149.7, 138.1, 134.9 (d, JC-F = 3.0 Hz), 134.9,
131.4, 130.2 (d, JC-F = 8.0 Hz), 115.7 (d, JC-F = 21.4 Hz), 33.7. HRMS (ESI): m/z [M + H]+ calcd
for C12H10FOS: 221.0436; found 221.0433.
3-(4-Chlorobenzyl)thiophene-2-carbaldehyde (3al). Following the general procedure A
described above, 3al was obtained after purification by column chromatography on silica gel as
a brown semi solid: Rf = 0.49 (EtOAc:petroleum ether = 10:90), 31 mg (65% yield); FTIR (cm-
1): 3099, 1653, 1422, 1296, 1091 cm-1; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.66 – 7.64
(m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 5.0 Hz, 1H), 4.31 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 182.3, 149.1, 138.2, 137.7, 134.9, 132.7, 131.4, 130.1,
129.0, 33.9. HRMS (ESI): m/z [M + H]+ calcd for C12H10ClOS: 237.0141; found 237.0139.
3-(4-Bromobenzyl)thiophene-2-carbaldehyde (3am). Following the general procedure A
described above, 3am was obtained after purification by column chromatography on silica gel as
°
a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 10:90), mp: 81-83 C; 35 mg (63% yield);
FTIR (cm-1): 3098, 1657, 1486, 1297, 744; 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 7.65 (d,
J = 5.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 5.0 Hz, 1H), 4.29
(s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.3, 149.0, 138.3, 138.2, 134.9, 131.9, 131.4,
130.5, 120.7, 34.0. HRMS (ESI): m/z [M + H]+ calcd for C12H10BrOS: 280.9636; found
280.9625.
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3-(3,4-Dichlorobenzyl)thiophene-2-carbaldehyde (3an). Following the general procedure A
described above, 3an was obtained after purification by column chromatography on silica gel as
°
a brown solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), mp: 50-52 C; 33 mg (62% yield);
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FTIR (cm-1): 3096, 1659, 1423, 1228; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.69 (d, J =
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4.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.2, 2.1 Hz, 1H),
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6.93 (d, J = 5.0 Hz, 1H), 4.31 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 182.1, 147.9, 139.5,
138.3, 135.0, 132.9, 131.3, 130.9, 130.8, 130.6, 128.2, 33.7. HRMS (ESI): m/z [M + H]+ calcd
for C12H9Cl2OS: 270.9751; found 270.9756.
3-(3-Methylbenzyl)thiophene-2-carbaldehyde (3ao). Following the general procedure A
described above, 3ao was obtained after purification by column chromatography on silica gel as
a brownish yellow oil: Rf = 0.49 (EtOAc:petroleum ether = 09:91), 34 mg (80% yield); FTIR
(cm-1): 2921, 1659, 1488, 1229; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.63 (d, J = 5.0 Hz,
1H), 7.21- 7.17 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.94 (d,
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J = 5.0 Hz, 1H), 4.29 (s, 2H), 2.32 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 182.6, 150.3,
139.1, 138.6, 138.1, 134.7, 131.5, 129.5, 128.8, 127.6, 125.7, 34.5, 21.5. HRMS (ESI): m/z [M +
H]+ calcd for C13H13OS: 217.0687; found 217.0692.
3-(4-Methylbenzyl)thiophene-2-carbaldehyde (3ap). Following the general procedure A
described above, 3ap was obtained after purification by column chromatography on silica gel as
a brown oil: Rf = 0.49 (EtOAc:petroleum ether = 09:91), 37 mg (85% yield); FTIR (cm-1): 3018,
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1656, 1424, 1226, 767; H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.62 (d, J = 5.0 Hz, 1H),
7.11 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 5.0 Hz, 1H), 4.29 (s, 2H), 2.32 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.5, 150.5, 138.1, 136.4, 136.2, 134.7, 131.5, 129.6,
128.6, 34.2, 21.1. HRMS (ESI): m/z [M + H]+ calcd for C13H13OS: 217.0687; found 217.0690.
3-(4-Isopropylbenzyl)thiophene-2-carbaldehyde (3aq). Following the general procedure A
described above, 3aq was obtained after purification by column chromatography on silica gel as
a brownish yellow oil: Rf = 0.49 (EtOAc:petroleum ether = 09:91), 34 mg (70% yield); FTIR
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(cm-1): 2960, 1659, 1425, 1227, 734; H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.63 (d, J =
5.0 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 5.0 Hz, 1H), 4.30 (s,
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2H), 2.91 – 2.84 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.57,
150.44, 147.5, 138.2, 136.6, 134.6, 131.6, 128.6, 126.9, 34.1, 33.8, 24.1. HRMS (ESI): m/z [M +
H]+ calcd for C15H17OS: 245.1000; found 245.0994.
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3-(4-Methoxybenzyl)thiophene-2-carbaldehyde (3ar). Following the general procedure A
described above, 3ar was obtained after purification by column chromatography on silica gel as
a brown oil: Rf = 0.49 (EtOAc:petroleum ether = 12:88), 35 mg (75% yield); FTIR (cm-1): 2925,
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1656, 1511, 1244, 1033; H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.62 (d, J = 5.0 Hz, 1H),
7.10 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 5.0 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 4.27 (s, 2H), 3.78 (s,
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3H). C{1H} NMR (100 MHz, CDCl3) δ 182.5, 158.5, 150.7, 138.0, 134.7, 131.5, 131.3, 129.7,
114.3, 55.4, 33.7. HRMS (ESI): m/z [M + H]+ calcd for C13H13O2S: 233.0636; found 233.0643.
3-(3,4-Dimethylbenzyl)thiophene-2-carbaldehyde (3as). Following the general procedure A
described above, 3as was obtained after purification by column chromatography on silica gel as
a brown semi solid: Rf = 0.49 (EtOAc: petroleum ether = 09:91), 29 mg (64% yield); FTIR (cm-
1): 2925, 1738, 1437, 1371,1130, 697; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.61 (d, J =
5.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.94 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 7.7 Hz,
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1H), 4.25 (s, 2H), 2.22 (s, 3H), 2.22 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 182.6, 150.7,
138.1, 137.1, 136.6, 135.1, 134.6, 131.5, 130.1, 129.9, 126.0, 34.1, 19.9, 19.5. HRMS (ESI): m/z
[M + H]+ calcd for C14H15OS: 231.0844; found 231.0845.
3-(3,5-dimethylbenzyl)thiophene-2-carbaldehyde (3at). Following the general procedure A
described above, 3at was obtained after purification by column chromatography on silica gel as a
brown oil: Rf = 0.49 (EtOAc:petroleum ether = 09:91), 23 mg (50% yield); FTIR (cm-1): 2919,
1
1714, 1424, 1227, 728; H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.63 (d, J = 5.0 Hz, 1H),
6.95 (d, J = 5.0 Hz, 1H), 6.87 (s, 1H), 6.79 (s, 2H), 4.25 (s, 2H), 2.28 (s, 3H), 2.28 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 182.6, 150.5, 139.1, 138.5, 138.1, 134.7, 131.5, 128.5,
126.5, 34.4, 21.4. HRMS (ESI): m/z [M + H]+ calcd for C14H15OS: 231.0844; found 231.0840.
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3-(4-Bromo-3-methylbenzyl)thiophene-2-carbaldehyde (3au). Following the general
procedure A described above, 3au was obtained after purification by column chromatography on
silica gel as a yellow semi solid: Rf = 0.49 (EtOAc:petroleum ether = 10:90), 41 mg (70% yield);
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FTIR (cm-1): 2923, 1734, 1661, 1474, 1227; H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.65
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(d, J = 5.0 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.92 (d, J = 5.0 Hz, 1H), 6.87 (d, J =
7.6 Hz, 1H), 4.25 (s, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.3, 149.3, 138.5,
138.4, 138.1, 134.8, 132.8, 131.4, 131.2, 127.7, 123.2, 33.9, 23.0. HRMS (ESI): m/z [M + H]+
calcd for C13H12BrOS: 294.9792; found 294.9785.
3-(4-Bromo-3-fluorobenzyl)thiophene-2-carbaldehyde (3av). Following the general procedure
A described above, 3av was obtained after purification by column chromatography on silica gel
°
as a brownish yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), mp: 61-63 C; 37 mg
1
(62% yield); FTIR (cm-1): 3100, 1661, 1528, 1424, 1235; H NMR (400 MHz, CDCl3) δ 10.03
(s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.47 (dd, J = 8.1, 7.2 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.93 (d,
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J = 4.9 Hz, 1H), 6.89 – 6.86 (m, 1H), 4.31 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 182.1,
159.3 (d, JC-F = 248.0 Hz), 147.9, 141.0 (d, JC-F = 6.5 Hz), 138.3, 135.0, 133.8, 131.3, 125.6 (d,
JC-F = 3.5 Hz), 116.9(d, JC-F = 22.5 Hz), 107.2 (d, JC-F = 20.9 Hz), 33.9 (d, JC-F = 1.5 Hz). HRMS
(ESI): m/z [M + H]+ calcd for C12H9BrFOS: 298.9542; found 298.9533.
3-((6-Bromo-9H-fluoren-3-yl)methyl)thiophene-2-carbaldehyde (3aw). Following the general
procedure A described above, 3aw was obtained after purification by column chromatography on
°
silica gel as a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 10:90), mp: 173-175 C; 37 mg
(51% yield); FTIR (cm-1): 3072, 2925, 1663, 1423, 746; 1H NMR (400 MHz, CDCl3) δ 10.12 (s,
1H), 7.68 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.66 – 7.64 (m, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.48 (d,
J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 5.0 Hz, 1H), 4.40 (s, 2H),
3.84 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.5, 150.1, 145.3, 143.7, 140.4, 139.5,
138.4, 138.2, 134.8, 131.5, 130.1, 128.4, 127.7, 125.4, 121.2, 120.6, 120.3, 36.8, 34.7. HRMS
(ESI): m/z [M + H]+ calcd for C19H14BrOS: 368.9949; found 368.9950.
Methyl 4-((5-bromo-2-formylthiophen-3-yl)methyl)benzoate (3bh). Following the general
procedure A described above, 3bh was obtained after purification by column chromatography on
silica gel as a yellow crystalline solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), mp: 131-133
°C; 51 mg (75% yield); FTIR (cm-1): 3002, 1717, 1664, 1419, 1280; 1H NMR (400 MHz, CDCl3)
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δ 9.96 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H), 4.43 (s, 2H), 3.90
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 181.8, 166.9, 146.4, 143.2, 139.1, 132.5, 130.2,
128.8, 128.5, 115.8, 52.3, 33.6. HRMS (ESI): m/z [M + H]+ calcd for C14H12BrO3S: 338.9691;
found 338.9686.
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3-(3-Nitrobenzyl)benzo[b]thiophene-2-carbaldehyde (3cb). Following the general procedure
A described above, 3cb was obtained after purification by column chromatography on silica gel
as a light yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 14:86), mp: 171-173 °C; 38 mg (65%
yield); FTIR (cm-1): 2924, 1712, 1524, 1349, 1205; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H),
8.11 (s, 1H), 8.10 – 8.07 (m, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.55 – 7.39
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(m, 4H), 4.75 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 183.8, 148.7, 142.7, 142.1, 140.6,
139.2, 139.1, 134.3, 129.9, 128.7, 125.6, 124.3, 123.8, 123.2, 122.2, 31.9. HRMS (ESI): m/z [M
+ H]+ calcd for C16H12NO3S: 298.0538; found 298.0542.
Methyl 4-((2-formylbenzo[b]thiophen-3-yl)methyl)benzoate (3ch). Following the general
procedure B described above, 3ch was obtained after purification by column chromatography on
°
silica gel as a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), mp: 132-134 C; 44 mg
1
(72% yield); FTIR (cm-1): 3067, 1719, 1663, 1436, 1282; H NMR (400 MHz, CDCl3) δ 10.32
(s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.51 – 7.47
(m, 1H), 7.39 – 7.35 (m, 1H), 7.26 (d, J = 8.4 Hz, 2H), 4.68 (s, 2H), 3.88 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 184.0, 166.8, 143.8, 143.4, 142.6, 139.5, 139.1, 130.3, 128.9, 128.5, 128.3,
125.3, 124.5, 123.6, 52.3, 32.3. HRMS (ESI): m/z [M + H]+ calcd for C18H15O3S: 311.0742;
found 311.0732
Methyl 4-((2-formylbenzofuran-3-yl)methyl)benzoate (3dh). Following the general procedure
A described above, 3dh was obtained after purification by column chromatography on silica gel
°
as a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 14:86), mp: 129-131 C; 29 mg (49%
yield); FTIR (cm-1): 2945, 1720, 1663, 1436, 1283; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H),
7.95 (d, J = 8.4 Hz, 2H), 7.91 – 7.89 (m, 1H), 7.78 – 7.75 (m, 1H), 7.52 – 7.48 (m, 1H), 7.39 –
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7.35 (m, 1H), 7.26 (d, J = 8.6 Hz, 2H), 4.68 (s, 2H), 3.88 (s, 3H). C{1H} NMR (100 MHz,
CDCl3) δ 184.0, 166.8, 143.8, 143.4, 142.6, 139.5, 139.1, 130.3, 128.9, 128.6, 128.3, 125.3,
124.5, 123.6, 52.3, 32.4. HRMS (ESI): m/z [M + H]+ calcd for C18H15O4: 295.0926; found
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3-(3-Nitrobenzyl)benzofuran-2-carbaldehyde (3db). Following the general procedure A
described above, 3db was obtained after purification by column chromatography on silica gel as
a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 15:85), mp: 175-177 °C; 28 mg (50% yield);
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FTIR (cm-1): 3059, 1661, 1529, 1352, 1211; H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.11
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(s, 1H), 8.10 – 8.07 (m, 1H), 7.94 – 7.92 (m, 1H), 7.79 – 7.77 (m, 1H), 7.55 – 7.39 (m, 4H), 4.75
(s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 183.8, 148.7, 142.7, 142.0, 140.7, 139.2, 139.1,
134.3, 129.9, 128.7, 125.6, 124.3, 123.8, 123.2, 122.2, 31.9. HRMS (ESI): m/z [M + H]+ calcd
for C16H12NO4: 282.0722; found.282.0727
Ethyl 3-((2-formylbenzofuran-3-yl)methyl)benzoate (3dc). Following the general procedure A
described above, 3dc was obtained after purification by column chromatography on silica gel as
°
a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 15:85), mp: 91-93 C; 32 mg (52% yield);
FTIR (cm-1): 2981, 1714, 1661, 1558, 1278; 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 7.97
(s, 1H), 7.91 – 7.88 (m, 2H), 7.81 – 7.79 (m, 1H), 7.51 – 7.47 (m, 1H), 7.39 – 7.28 (m, 3H), 4.68
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(s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ
184.1, 166.5, 143.8, 142.6, 139.5, 139.1, 138.9, 132.5, 131.2, 129.4, 129.1, 128.5, 128.2, 125.3,
124.6, 123.6, 61.3, 32.2, 14.4. HRMS (ESI): m/z [M + H]+ calcd for C19H17O4: 309.1127; found
309.1122.
4-((2-Formylthiophen-3-yl)methyl)benzoic acid (3ax). Following the general procedure B
described above, 3ax was obtained after purification by column chromatography on silica gel as
a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 50:50), mp: 169-171 °C; 22 mg (45% yield);
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FTIR (cm-1): 2943, 1656, 1450, 1020; H NMR (400 MHz, CDCl3+CD3OD) δ 10.05 (s, 1H),
7.99 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.9 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 5.0 Hz,
1H), 4.43 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3+CD3OD) δ 182.7, 168.4, 149.2, 144.3,
137.7, 135.1, 131.2, 130.0, 128.7, 128.3, 34.0. HRMS (ESI): m/z [M + H]+ calcd for C13H11O3S:
247.0429; found 247.0436.
3-((1-Tosyl-1H-indol-5-yl)methyl)thiophene-2-carbaldehyde (3ay). Following the general
procedure B described above, 3ay was obtained after purification by column chromatography on
silica gel as a yellowish semi solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), 49 mg (63%
yield); FTIR (cm-1): 3056, 1735, 1427, 1265; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.90
(d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 4.9 Hz, 1H), 7.54 (d, J = 3.7 Hz, 1H),
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7.30 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 5.0 Hz, 1H), 6.57 (d,
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J = 3.7 Hz, 1H), 4.38 (s, 2H), 2.34 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 182.5, 150.2,
145.2, 138.1, 135.4, 134.7, 134.4, 133.7, 131.6, 131.3, 130.1, 127.0, 126.9, 125.4, 121.2, 113.9,
108.9, 34.4, 21.7. HRMS (ESI): m/z [M + H]+ calcd for C21H18NO3S2: 396.0728; found
396.0729.
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3-((6-Fluoropyridin-3-yl)methyl)thiophene-2-carbaldehyde (3az). Following the general
procedure B described above, 3az was obtained after purification by column chromatography on
silica gel as a brownish yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), mp: 47-49 °C;
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32 mg (73% yield); FTIR (cm-1): 3098, 1657, 1482, 1242; H NMR (400 MHz, CDCl3) δ 10.05
(s, 1H), 8.11 (s, 1H), 7.70 (d, J = 5.0 Hz, 1H), 7.63 – 7.58 (m, 1H), 6.94 (d, J = 5.0 Hz, 1H), 6.88
(dd, J = 8.4, 3.0 Hz, 1H), 4.36 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.1, 162.7 (d, JC-F
= 238.7 Hz), 147.6, 147.3 (d, JC-F = 14.6 Hz), 141.4 (d, JC-F = 7.8 Hz), 138.1, 135.2, 132.6 (d, JC-
F = 4.6 Hz), 131.2, 109.7 (d, JC-F = 37.5 Hz), 30.9 (d, JC-F = 1.4 Hz). HRMS (ESI): m/z [M + H]+
calcd for C11H9FNOS : 222.0389; found 222.0393.
3-((6-Bromopyridin-3-yl)methyl)thiophene-2-carbaldehyde (3aza´). Following the general
procedure B described above, 3aza´ was obtained after purification by column chromatography
on silica gel as a brown solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), mp: 58-60 °C; 34 mg
1
(62% yield); FTIR (cm-1): 3089, 1659, 1448, 1294, 1087; H NMR (400 MHz, CDCl3) δ 10.03
(s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.37 (dd, J =
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8.2, 2.5 Hz, 1H), 6.93 (d, J = 5.0 Hz, 1H), 4.33 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ
182.0, 150.2, 146.9, 140.5, 138.9, 138.1, 135.2, 134.3, 131.2, 128.2, 31.2. HRMS (ESI): m/z [M
+ H]+ calcd for C11H9BrNOS: 281.9588; found 281.9589.
3-((6-Chloropyridin-3-yl)methyl)thiophene-2-carbaldehyde (3azb´). Following the general
procedure B described above, 3azb´ was obtained after purification by column chromatography
on silica gel as a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), mp: 59-61 °C; 30 mg
(65% yield); FTIR (cm-1): 3094, 1660, 1460, 1234, 1023; 1H NMR (400 MHz, CDCl3) δ 9.96 (s,
1H), 8.22 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.39 (dd, J = 8.2, 2.5 Hz, 1H), 7.19 (d, J
= 8.2 Hz, 1H), 6.86 (d, J = 5.0 Hz, 1H), 4.28 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.0,
150.0, 149.7, 147.1, 139.1, 138.1, 135.2, 133.9, 131.2, 124.4, 31.2. HRMS (ESI): m/z [M + H]+
calcd for C11H9ClNOS: 238.0093; found 238.0097.
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3-((6-Fluoropyridin-3-yl)methyl)benzo[b]thiophene-2-carbaldehyde (3cz). Following the
general procedure B described above, 3cz was obtained after purification by column
chromatography on silica gel as a yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), mp:
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CDCl3) δ 10.32 (s, 1H), 8.17 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.56 –
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7.50 (m, 2H), 7.44 – 7.40 (m, 1H), 6.83 (dd, J = 8.5, 2.9 Hz, 1H), 4.63 (s,2H). C{1H} NMR
(100 MHz, CDCl3) δ 183.7, 162.8 (d, JC-F = 239.1 Hz), 147.0 (d, JC-F = 14.7 Hz), 142.7, 142.2,
140.8 (d, JC-F = 7.9 Hz), 139.2, 138.9, 131.9 (d, JC-F = 4.7 Hz), 128.7, 125.6, 124.3, 123.8, 109.9
(d, JC-F =37.6Hz), 28.8 (d, JC-F = 1.4 Hz). HRMS (ESI): m/z [M + H]+ calcd for C15H11FNOS:
272.0545; found 272.0547.
3-((6-Chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thiophene-2-carbaldehyde
(3azc´).
Following the general procedure B described above, 3azc´ was obtained after purification by
column chromatography on silica gel as a brown solid: Rf = 0.49 (EtOAc:petroleum ether =
20:80), mp: 53-55 °C; 39 mg (65% yield); FTIR (cm-1): 3086, 1662, 1427, 1237, 1142; 1H NMR
(400 MHz, CDCl3) δ 10.00 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.76 (d, J
= 5.0 Hz, 1H), 6.98 (d, J = 5.0 Hz, 1H), 4.44 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 182.0,
152.3, 147.3, 145.4, 138.1, 136.8 (q, JC-F = 5.0 Hz), 135.5, 134.2, 131.2, 125.3 (d, JC-F = 33.2
Hz), 122.1 (d, JC-F = 273.0 Hz), 31.2. HRMS (ESI): m/z [M + H]+ calcd for C12H8ClF3NOS:
305.9967; found 305.9965.
Scale Up Procedure for the Synthesis of 3-Benzylthiophene-2-carbaldehyde (3aa).
A 30-mL dry pressure tube equipped with a stir bar was charged with 3-methylthiophene-2-
carbaldehyde 1a (0.3 g, 2.38 mmol, 1.0 equiv.), iodobenzene 2a (0.727 g, 3.57 mmol, 1.5
equiv.), Pd(OAc)2 (0.053 g, 0.24 mmol, 0.1 equiv.), L8 (0.111 g, 0.95 mmol, 0.4 equiv.), AgTFA
(0.730 g, 3.57 mmol, 1.5 equiv.), and followed by the addition of the mixture of HFIP (12.96
mL) and AcOH (1.44 mL) at room temperature. Then the resulting reaction mixture was
degassed under N2 atmosphere for 2 min and stirred vigorously at room temperature for 15 min.
Then the reaction mixture was heated to 110 °C for 24 h in heating block. After which, the
reaction mixture was cooled to room temperature, followed by the dilution with EtOAc (25 mL)
and subsequently it was filtered through pad of celite. The filtrate was concentrated in vacuo.
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The residue was purified by column chromatography on silica gel to furnish the desired product
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Scale Up Procedure for the Synthesis of 3-(3-Nitrobenzyl)thiophene-2-carbaldehyde (3ab).
A 30-mL dry pressure tube equipped with a stir bar was charged with 3-methylthiophene-2-
carbaldehyde 1a (0.5 g, 3.96 mmol, 1.0 equiv.), 1-iodo-3-nitrobenzene 2b (1.48 g, 5.94 mmol,
1.5 equiv.), Pd(OAc)2 (0.088 g, 0.40 mmol, 0.1 equiv.), L8 (0.185 g, 1.59 mmol, 0.4 equiv.),
AgTFA (1.22 g, 5.94 mmol, 1.5 equiv.), and followed by the addition of the mixture of HFIP
(14.40 mL) and AcOH (1.60 mL) at room temperature. Then the resulting reaction mixture was
degassed under N2 atmosphere for 2 min and stirred vigorously at room temperature for 15 min.
Then the reaction mixture was heated to 110 °C for 24 h in heating block. After which, the
reaction mixture was cooled to room temperature, followed by the dilution with EtOAc (30 mL)
and subsequently it was filtered through pad of celite. The filtrate was concentrated in vacuo.
The residue was purified by column chromatography on silica gel to furnish the desired product
3ab in 70% yield (0.69 g) as a yellow brownish solid.
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Procedure for the synthesis of naphtho[2,3-b]thiophene (4a).3b An oven dried round bottom
flask (25 mL) was charged with 1a (30.4 mg, 0.15 mmol), tosylamine 2a (25.7 mg, 0.15 mmol)
and toluene (2 mL). BF3·Et2O (30 mol%) was then added to the mixture and the solution was
stirred at room temperature for 2 h. Then, the reaction mixture was purified by column
chromatography (EtOAc:petroleum ether = 25:75) to obtain the white solid 4a: Rf = 0.49
(EtOAc:petroleum ether = 15:85), mp: 188-190 °C; 18 mg (65% yield); FTIR (cm-1): 3054, 2927,
1729, 1267, 1447; 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.32 (s, 1H), 7.98 – 7.90 (m, 2H),
7.50 (d, J = 5.6 Hz, 1H), 7.48 – 7.45 (m, 2H), 7.42 (d, J = 5.7 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 139.0, 138.3, 131.1, 131.1, 128.4, 128.3, 127.4, 125.4, 125.1, 123.6, 121.9, 120.8.
HRMS (ESI): m/z [M ]+ calcd for C12H8S: 184.0347; found 184.0353.
(3-(3-Methylbenzyl)thiophen-2-yl)methanol (4b).19 To an oven dried two-necked round
bottom flask was charged with a stir bar, LiAlH4 (0.22 mmol, 1.5 equiv.) and solution of 3-(3-
methylbenzyl)thiophene-2-carbaldehyde 3ao (0.15 mmol, 1 equiv.) were added in THF (3 mL) at
°
0 C under argon atmosphere. The reaction mixture was allowed to warm to room temperature
and stirred overnight. After the complete consumption of starting material (monitored by TLC),
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the reaction mixture was cooled down to 0 °C and quenched carefully with 2 M HCl. The
reaction mixture was extracted with EtOAc (2 x 15 mL) and the combined organic phase was
dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by
silica chromatography (EtOAc:petroleum ether = 20:80) to afford the corresponding alcohol
product 4b as a yellow semi solid: Rf = 0.49 (EtOAc:petroleum ether = 20:80), 22 mg (70%
yield); FTIR (cm-1): 2920, 1605, 1441, 1264; 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.15 (m, 2H),
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7.02 – 6.94 (m, 3H), 6.83 (d, J = 5.1 Hz, 1H), 4.77 (s, 2H), 3.94 (s, 2H), 2.30 (s, 3H). C{1H}
NMR (100 MHz, CDCl3) δ 140.6, 138.4, 138.4, 137.6, 130.0, 129.3, 128.6, 127.1, 125.6, 124.3,
57.9, 34.3, 21.6. HRMS (ESI): m/z [M + H]+ calcd for C13H15OS: 219.0799; found 219.0809
Procedure for the synthesis of 1-(3-(4-Bromo-3-methylbenzyl)thiophen-2-yl)ethanol (4c).20
In an oven dried two-necked round bottom flask charged with a stir bar, 3 M MeMgBr solution
in THF (0.1 mL, 0.3 mmol, 2 equiv.) was added to a solution of 3-(4-bromo-3-
methylbenzyl)thiophene-2-carbaldehyde 3au (0.15 mmol, 1 equiv.) in THF (3 mL) at -78 °C
°
under argon atmosphere. The reaction mixture was continued to stir at -78 C for 1 h. After the
completion of reaction (monitored by TLC), the reaction mixture was quenched with saturated
NH4Cl solution (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers was
dried over Na2SO4, filtered, and concentrated in vacuo and purified by column chromatography
using silica gel (EtOAc:petroleum ether = 15:85) to furnish the desired product 4c as yellow
semi solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), 45 mg (98% yield); FTIR (cm-1): 2970,
1473, 1375, 1026; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 5.1 Hz,
1H), 7.02 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 5.1 Hz, 1H), 5.21 (q, J = 6.4 Hz, 1H),
13
3.90 (s, 2H), 2.34 (s, 3H), 1.82 (brs, 1H), 1.55 (d, J = 6.4 Hz, 3H). C{1H} NMR (100 MHz,
CDCl3) δ 144.1, 139.9, 138.1, 135.9, 132.5, 131.1, 129.7, 127.6, 123.5, 122.6, 64.5, 33.7, 25.4,
23.0. HRMS (ESI): m/z [M + H]+ calcd for C14H16BrOS: 312.0007; found 312.0017
N-((3-(3-Chlorobenzyl)thiophen-2-yl)methyl)-4-methoxyaniline (4d).21
To the solution of 3-(3-chlorobenzyl)thiophene-2-carbaldehyde 3ae (0.15 mmol, 1 equiv.) in
DCM (3 mL) was added the corresponding amine (0.15 mmol, 1 equiv.) and sodium sulphate
(0.90 mmol, 6 equiv.) under a nitrogen atmosphere and the reaction mixture was stirred at rt for 2
°
h. Then, NaCNBH3 (0.22 mmol, 1. 5 equiv.) was added at 0 C and the reaction mixture was
allowed to warm to room temperature and stirred for overnight. After the completion of reaction
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(monitored by TLC), the reaction was quenched by adding water (7 mL). The resulting mixture
was extracted with EtOAc (2x15 mL) and combined organic phase was dried over Na2SO4,
filtered, and concentrated under vacuo. The resulting residue was purified by silica
chromatography (EtOAc:petroleum ether = 20:80) to afford the corresponding alcohol product.
Following the general procedure described above, 4d was obtained after purification by column
chromatography on silica gel as a brownish semi solid: Rf = 0.49 (EtOAc:petroleum ether =
15:85), 40 mg (79% yield); FTIR (cm-1): 2922, 1511, 1238, 1036; 1H NMR (400 MHz, CDCl3) δ
7.22 – 7.18 (m, 2H), 7.15 (d, J = 5.1 Hz, 1H), 7.13 – 7.12 (m, 1H), 7.04 – 7.02 (m, 1H), 6.81 (d,
J = 5.1 Hz, 1H), 6.77 (d, J = 9.0 Hz, 2H), 6.57 (d, J = 9.0 Hz, 2H), 4.35 (s, 2H), 3.95 (s, 2H),
3.74 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.8, 142.6, 141.9, 137.5, 136.3, 134.5,
129.9, 129.7, 128.7, 126.8, 126.6, 123.8, 115.0, 114.7, 55.9, 42.8, 34.1. HRMS (ESI): m/z [M +
H]+ calcd for C19H19ClNOS: 344.0876; found 344.0870.
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Procedure for the synthesis of (E)-3-(3-(3-Nitrobenzyl)thiophen-2-yl)-1-(p-tolyl)prop-2-en-
1-one (4e).22
3-(3-Nitrobenzyl)thiophene-2-carbaldehyde 3ab (0.15 mmol, 1.0 equiv.) and 1-(p-tolyl)-2-
(triphenylphosphoranylidene)ethanone (0.18 mmol, 1.2 equiv.) were dissolved in toluene (3 mL)
and refluxed for 12 h. After the completion of the reaction (monitored by TLC), the solvent was
removed under vacuo and the residue was purified by column chromatography to furnish the
desired product 4e as yellow solid: Rf = 0.49 (EtOAc:petroleum ether = 12:88), mp: 128-130 °C;
1
43 mg (80% yield); FTIR (cm-1): 3096, 1654, 1582, 1526, 1345; H NMR (400 MHz, CDCl3) δ
8.09 – 8.01 (m, 3H), 7.91 (d, J = 8.2 Hz, 2H), 7.51 – 7.44 (m, 2H), 7.38 (d, J = 10.1 Hz, 1H),
7.35 (s, 1H), 7.30 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 5.2 Hz, 1H), 4.23 (s, 2H), 2.44 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 189.2, 148.6, 144.0, 143.0, 141.1, 136.1, 135.6, 134.9,
134.2, 130.7, 129.7, 129.5, 128.7, 128.1, 123.5, 121.8, 121.4, 34.1, 21.8. HRMS (ESI): m/z [M +
H]+ calcd for C21H18NO3S: 364.1007; found 364.1012.
Procedure for the synthesis of 3-(3-Methylbenzyl)thiophene-2-carbonitrile (4f).23
To a stirred mixture of 3-(3-methylbenzyl)thiophene-2-carbaldehyde 3ao (0.15 mmol, 1 equiv.)
and sodium azide (0.15 mmol, 1 equiv.), phosphorus oxychloride (0.75 mmol, 5 equiv.) was
added (in the open vessel with a guard tube) and stirred for 1 h at room temperature. After
completion of reaction (monitored by TLC), the reaction mixture was quenched with crushed ice.
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Then the reaction mixture was extracted with ethyl acetate (15 mL), and washed with sodium
bicarbonate solution (15 mL), water (15 mL) and brine solution (15 mL). The organic layer was
separated and dried over anhydrous Na2SO4. The solvent was removed under vacuo and the
residue was purified by column chromatography using silica gel to give the desired product 4f as
yellow liquid: Rf = 0.49 (EtOAc:petroleum ether = 14:86), 25 mg (79% yield); FTIR (cm-1):
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2921, 2215, 1605, 1415; H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 5.1 Hz, 1H), 7.22-7.18 (m,
1H), 7.06 (d, J = 8.0 Hz, 1H), 7.05 – 7.00 (m, 1H), 6.88 (d, J = 5.1 Hz, 1H), 4.08 (s, 2H), 2.33 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.0, 138.7, 138.4, 132.1, 129.6, 129.1, 128.8, 127.7,
125.8, 114.4, 106.1, 36.0, 21.5. HRMS (ESI): m/z [M + H]+ calcd for C13H12NS: 214.0690;
found 214.0679.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H NMR, 13C NMR spectra for the compounds 1d-1e, 3aa-3aw, 3bh, 3cb, 3ch, 3dh, 3db, 3dc,
3ax, 3ay, 3az, 3aza’. 3azb’, 3cz, 3azc’, 4a-4f are available. The Supporting Information is available
free-of-charge on the ACS Publications website at DOI:
AUTHOR INFORMATION
Corresponding Author
Ramakrishna G. Bhat - Department of Chemistry, Indian Institute of Science Education
and Research (IISER)-Pune, Dr. Homi Bhabha Road, Pashan, 411008, Pune, Maharashtra,
India
E-mail: rgb@iiserpune.ac.in
Notes: The authors declare no competing financial interest.
ACKNOWLEDGMENTS
R. G. B. thanks Science and Engineering Research Board-Department of Science and
Technology (SERB-DST), New Delhi, Govt. of India (File No: CRG/2019/005753) for the
generous research grant. Authors also thank IISER Pune for the financial assistance. This work
was funded by Department of Science and Technology, India under SERB-N-PDF Program
(Project File No. PDF/2016/003407/CS). J. S. and C. R. thank CSIR-JRF, New Delhi and SERB-
National Postdoctoral Fellowship (N-PDF), New Delhi for providing fellowship.
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