One pot synthesis of tetrasubstituted thiophenes: [3 + 2] annulation strategy

Abstract

A simple, efficient and economical synthesis of dimethyl 3-amino-5-(2-oxo-2-arylethyl)thiophene-2,4-dicarboxylates has been reported by ring opening of methyl 3-amino-6-aryl-4-oxo-4H-thieno[3,2-c]pyran-2-carboxylates by alkoxide ions. Pyranothiophenes have been obtained by the reaction of methyl thioglycolate and 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles in the presence of triethylamine. A one-pot multicomponent protocol for the synthesis of tetrasubstituted thiophenes has been developed by reaction of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles and methyl thioglycolate in the presence of sodium methoxide in excellent yields. The structure of the isolated compound was confirmed by single crystal X-ray diffraction and spectroscopic studies.

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Thiophene is one of the important class of heterocyclic scaffolds of biological importance, widely present in various natural products¹ and therapeutics as a substructure. These are very useful as allosteric agonists and modulators of the adenosine A1 receptor 2A3BTs² and PD81, 723 ³ (Fig. 1). Besides, they are useful as potent PI3K inhibitors⁴ and check point kinase inhibitors.⁵ Articaine,⁶ a thiophene derivative is commonly used as an anesthetic in dental surgery and also PaTrin-2 inhibitor of the DNA repair enzyme, O6-methylguanine-DNA methyl transferase.⁷ Recently, numerous thiophene derivatives are reported to display significant activity towards CB1 receptors with good CB1/CB2 selectivity.⁸ Additionally, thiophene scaffolds have wide applications as anthelmintics,⁹ antiviral,¹⁰ antitumor,¹¹ anti-inflammatory,¹² antimicrobials¹³ and antiplatelet¹⁴ agents. Further, various thiophene derivatives have broad applications as functional materials in electrically conducting organic materials,¹⁵ semiconductors,¹⁶ light emitting diodes (OLEDs),¹⁷ organic field effect transistors (OFETs),¹⁸ organic solar cells,¹⁹ laser,²⁰ liquid crystals and molecular wires.²¹

Fig. 1 Biologically active thiophenes.

The conventional synthetic approaches for the construction of polysubstituted thiophene scaffold include the Gewald,²² Paal–Knorr,²³ and Fiesselmann²⁴ syntheses. There is also one report for the construction of tetrasubstituted thiophenes from the reaction of aroyl isothiocyanates with ethyl bromopyruvate in the presence of enaminone in good to excellent yields.²⁵ El-Saghier et al.²⁶ have reported numerous highly functionalized thiophene scaffolds via ketene S,S- and S,N-acetals.²⁷ Recently, a novel approach to the synthesis of tetrasubstituted thiophenes is reported in two steps from trans-2-aroyl-arylcyclopropane-1,1-dicarboxylates and 1,4-dithianes-2,5-diol.²⁸ Amongst various approaches, modification of pre-existed thiophene ring system through α-metalation or β-halogenation also provided an alternative route to deliver highly functionalized thiophenes.²⁹ A regioselective synthesis of polysubstituted thiophenes from Baylis–Hillman adducts has been reported by Kim and coworkers.³⁰ Further, development in the synthetic methodology opened a new avenue for the construction of trisubstitutedthiophenes by reacting β-ketothioesters with dialkyl acetylenedicarboxylates.³¹ Recently, thiophenes are prepared by annulation of β-ketothioamides with arylglyoxal and 5,5-dimethyl-1,3-cyclohexanedione in CF₃CH₂OH.³² Ram et al.³³ have also reported an elegant approach to the synthesis of trisubstitutedthiophenes through ring transformation of suitably functionalized 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles³⁴ by alkyl thioglycolate in the presence of NaOH in methanol under reflux condition. Although the existing procedures are very useful for the construction of various thiophene derivatives but most of them suffer with certain limitations of harsh reaction conditions, use of expensive catalysts, long reaction time, multistep approach, use of strong base, difficulty in purification and compatibility of functional groups towards reagents under applied reaction conditions. Therefore, search for highly efficient and economical route was inevitable in view of their wide-ranging applications in the field of material science and pharmaceuticals.

Our quest to develop an efficient and economical protocol for the construction of tetrasubstituted thiophenes did not diminish by using 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles (3)³⁴ as precursors, obtainable from the reaction of ethyl 3,3-dimethylthio-2-cyanoacrylate (1) and aryl methyl or aryl aralkyl ketones (2) separately, Scheme 1.

Scheme 1 Synthesis of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles (3).

From the structural dissection, 3 may be considered as a cyclic ketenehemithioacetal and can be exploited for the construction of thiophene scaffolds. Thus, the reaction of 3 with ethyl thioglycolate in the presence of NaOH in methanol at reflux temperature delivered a mixture of ethyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4) as major product and trisubstitutedthiophene, ethyl 5-aryl-3-cyanomethyl-2-carboxylates (5) in 30–60% yields, Scheme 2.

Scheme 2 Synthesis of ethyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4) and ethyl 6-aryl-3-cyanomethylthiophen-2-carboxylates (5).

Therefore, we planned an entirely new synthetic strategy through ring transformation of 3 by oxazolidene-2,4-dione in the presence of CH₃ONa under reflux condition. This reaction after usual workup delivered a complex mixture. However, we succeeded to isolate a compound in poor yield, which was characterized as methyl 3-amino-5-(2-oxo-2-arylethyl)thiophene-2,4-dicarboxylate by X-ray diffraction and spectroscopic studies. A plausible mechanism of this reaction is depicted in Scheme 3. The ring opening of lactone (3) in alkoxide provides methyl 2-cyano-3-methylthio-3-aroylmethylacrylate (6), while thiozolidenedione under analogous reaction conditions is reported³⁵ to give methyl thioglycolate in situ. Both the reactants 6 and methyl thioglycolate generated in situ from thiozolidenedione react under basic conditions at reflux temperature to afford polyfunctionalized thiophene 10. The first step in the formation of tetrasubstituted thiophene (10) is the ring opening of lactone 3 and thiazolidinedione (7) in the presence of CH₃ONa to give 6 and methyl thioglycolate, which underwent Michael addition followed by elimination of methyl mercaptan to afford intermediate 8, which on recyclization produced tetrasubstituted thiophene (10), Scheme 3.

Scheme 3 A plausible mechanism for the formation of tetrasubstituted-thiophene (10).

Albeit, we succeeded to synthesize tetrasubstituted thiophenes (10) in single step but the yield was poor. From careful topographical analysis of 4, we envisaged that alkoxide mediated ring opening of methyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4)^33,36 may deliver the desired thiophene in high yield. Therefore, methyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4) was stirred in freshly prepared solution of CH₃ONa in methanol for 1–2 h at room temperature, which produced ring opened compound, similar in all respect to 10. It was conspicuous that long duration of stirring provides conversion of 10 to parent compound 4. Therefore, it was important to monitor the reaction time critically for better yield of 10 (50–80%). For improving the yields of desired product, we modified the reaction conditions using triethylamine in methanol for the ring opening of 4 at 90 °C, but net result was fiasco. Thereafter, ring opening of 4 was conducted in NaOCH₃ in DMF at room temperature, which after usual work up gave desired product in excellent yield. Under this condition, the reaction was not reversible and even no trace of starting material was observed on TLC (Table 1). It was interesting to note that the change of solvent from methanol to DMF provided excellent results. We contemplated that the recyclization is more facile in polar protic solvent rather than in polar aprotic solvent. Thus, DMF was found as a choice of solvent for better yields and clean reaction (Scheme 4).

Table 1 Synthesis of tetrasubstituted thiophenes (10)^a

10	Ar	Yield (%) (in methanol) and (in DMF)
a All the reaction were carried out by using 4 (0.5 mmol) and sodium methoxide (1.0 mmol) in a solvent (4 mL) at room temperature.b Yields are reported without further purification through column chromatography.c Yield are reported after purification through column chromatography.
a	C6H5	76^c	90^b
b	p-CH3·C6H4	68^c	88^b
c	p-F·C6H4	71^c	80^b
d	p-Cl·C6H4	65^c	71^b
e	o-Cl·C6H4	70^c	71^b
f	p-Br·C6H4	60^c	70^b
g	m-Br·C6H4	50^c	65^b
h	2-Naphthyl	65^c	87^b
i	1-Naphthyl	68^c	84^b
j	p-OCH3·C6H4	65^c	78^b
k	3,4-(OMe)2·C6H3	70^c	80^b
l	o-OMe·C6H4	65^c	80^b
m	2-Theinyl	65^c	77^b
n	2-Furyl	80^c	83^b
o	p-NO2·C6H4	78^b	60^c

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Scheme 4 Synthesis of tetrasubstituted thiophenes 10.

Mechanistically, the ring opening of 4 is initiated with attack of methoxide ion at carbonyl carbon at C4 to form a transition state which stabilized after ring opening to form tetrasubstituted thiophene (10). If reaction was not monitored carefully, the formed product 10 in methanol in the presence of methoxide ion cyclized to parent compound 4 in significant amount (Scheme 5).

Scheme 5 A plausible mechanism for the ring opening and ring closure.

After success of two steps strategy for the synthesis of tetrasubstituted thiophenes, our prime objective was to synthesize 10 in single step using 2-pyranones as a precursor. For one pot synthesis of 10, optimization of reaction was carried out in various solvents and bases. We conducted our screening by refluxing a mixture of 3b and methyl thioglycolate in methanol using triethylamine (1.0 mmol) as a base for 24 h which exclusively delivered thieno[3,2-c]pyrans (4). This indicated that methanol only acts as solvent in the reaction and not as nucleophile (entry 1, Table 2). In other set of experiment, a mixture of lactone 3b, methyl thioglycolate and triethylamine in methanol was refluxed at 90 °C for 2.5 h. There after, sodium methoxide was added and reaction mixture was stirred further at room temperature for 1.5 h. Usual work-up delivered 60% of desired product (Table 2, entry 2). In another set of experiment, pyranothiophene formed by the reaction of 3b and methyl thioglycolate using triethylamine in methanol, sodium methoxide was added and ring opening was performed at 90 °C. This reaction afforded 62% of desired product and stirred further for 2.5 h (entry 3, Table 2). In quest for better yield and to avoid reversibility of the reaction, we performed a reaction of 3b and methyl thioglycolate in the presence of NaOCH₃ and DMF at 90 °C, which produced a complex mixture (entry 4, Table 2). In another set of experiment, we performed the reaction using Et₃N in DMF at room temperature for 40 h and thereafter sodium methoxide was added and stirred further for additional 2 h at room temperature. Usual work up afforded 80% of tetrasubstituted thiophene (10) (entry 5, Table 2). To reduce the duration of reaction, A mixture of 3b and methyl thioglycolate was stirred in the presence of triethylamine as a base in DMF at 90 °C for 2.5 h to generate pyranothiophene in situ. Thereafter, NaOMe was added and stirred further at room temperature. Usual work up delivered 86% of the desired product 10 (entry 6, Table 2).

Table 2 Optimization of reaction conditions^a,b,d

Entry	Solvent	Base 1/t, °C/T, h	Base 1/t, °C/T, h	Yield (%)
a Reactions were carried out by stirring 3b (0.5 mmol), methyl thioglycolate (0.75 mmol), triethylamine (1.0 mmol) and sodium methoxide (1.0 mmol) at various temperature.b 1st and 2nd bases were added sequentially and reaction was carried out for given time at mentioned temperature.c Thieno[3,2-c]pyran was isolated.d Room temperature was ranging between 30–35 °C.
1	CH3OH	Et3N/rt/24 h	—	—^c
2	CH3OH	Et3N/90/2.5 h	NaOCH3/rt/1.5	60
3	CH3OH	Et3N/90/2.5 h	NaOCH3/90/1	62
4	DMF	NaOCH3/90/2 h	NaOCH3/90/4	Complex mixture
5	DMF	Et3N/rt/40 h	NaOCH3/rt/2	80
6	DMF	Et3N/90/2.5 h	NaOCH3/rt/2	86

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After optimization of reaction condition, we have synthesized various derivatives of tetrasubstituted thiophene in good to excellent yields in one pot (Scheme 6). It was interesting to note that methyl 3-amino-6,7-diaryl-4-oxo-4H-thieno[3,2-c]pyran-2-carboxylates (4) under similar reaction conditions did not form tetrasubstituted thiophene, possibly the presence of additional aryl group at position 6 stabilized the pyran ring and not allow the ring opening from alkoxide ion.

Scheme 6 One pot approach for the synthesis of tetrasubstituted thiophenes 10.

The presence of various functional group in aryl ring present at position 6 of 2-pyranone does not follow any specific trend on reactivity. The presence of 4-nitrophenyl and 4-bromophenyl ring greatly reduces the yield of tetrasubstituted thiophenes. Overall, it is very difficult to assess the role of aryl ring in the reaction.

The molecular view (ORTEP) for the compounds 10a with atom numbering scheme is presented in Fig. 2.‡ The compound crystallizes in monoclinic crystal system having P₁2₁/C₁ space group with four molecules in the unit cell. The dihedral angle between the two aromatic rings viz. thiophene and the phenyl ring is 76.89°. The torsion angles O(1)–C(7)–C(1)–C(6) and O(1)–C(7)–C(8)–C(9) are 170.29(17)° and 30.9(2)°, respectively. The torsion angles associated with the two ester functions and the 1° amine group viz. N(1)–C(13)–C(14)–C(15), C(11)–C(10)–C(13)–N(1), C(13)–C(10)–C(11)–O(3) and C(13)–C(14)–C(15)–O(4) are 0.9(3), −0.6(3), −1.4(3) and −3.2(3), respectively. These torsion angle data indicates that N(1), O(4) and O(3) are almost coplanar and the two hydrogens over 1° amine can display intramolecular hydrogen bonding.

Fig. 2 ORTEP diagram of 10a at 30% probability with atom numbering scheme.

The intramolecular N(1)–H(1′)⋯O(3) and N(1)–H(1′′)⋯O(4) interaction distances and angles are 2.09(2) Å; 130(2)° and 2.21(2) Å; 129(2)°, respectively (Fig. 3). The supramolecular aggregation in 10a is stabilized by a pair of weak intermolecular N–H⋯O interactions (Fig. 3) that lead to the formation of centro symmetric dimers. The N(1)–H(1′′)⋯O intermolecular interaction distance is 2.199 Å and the N–H⋯O is non-linear having magnitude of 130.74°.

Fig. 3 Centro symmetric dimer held by pair of weak N–H⋯O interactions (intramolecular N–H⋯O interaction pairs are also presented).

The analysis of the interaction energy in the crystal structures of 10a by means of dimer unit bound by pair of N–H⋯O interactions at the DFT level of theory yields the interaction energy −20.82 kJ mol⁻¹ for pair of interaction and −10.41 kJ mol⁻¹ for individual N–H⋯O interaction. To further confirm the nature of these weak interactions, bond critical points (bcp) were calculated for the different dimers by using the Atoms in Molecules theory.³⁷ The bond critical points observed between the interacting atoms, confirmed the presence of weak non-covalent interactions between the two molecules of 10. The value of electron density (ρ); Laplacian of the electron density (∇²ρ_bcp); bond ellipticity (ε) electron density (ρ) and total energy density (H) at the bond critical point for all the three interactions are presented in Table 3. As indicated in the table, the electron density for all the three types of interactions at bond critical point (ρ_bcp) are less than +0.10 au which indicates a closed shell hydrogen bonding interactions. Additionally, the Laplacian of the electron density ∇²ρ_bcp in all the three cases are greater than zero which indicated the depletion of electron density in the region of contact between the H⋯O atoms. The bond ellipticity (ε) which measures the extent to which the electron density is preferentially accumulated in a given plane containing the bond path indicates that all the three interactions are not cylindrically symmetrical in nature.

Table 3 Selected topographical features for various interactions computed at B3LYP/6-31G** level of theory

Interaction Type	ρbcp	∇^2ρbcp	E	H (au)
Intra N–H⋯O	+0.016769	+0.056219	+0.100692	+0.029323
Intra N–H⋯O	+0.025872	+0.081472	+0.023475	+0.028191
Inter N–H⋯O	+0.014931	+0.054220	+0.088161	+0.018966

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Conclusions

One pot expeditious, economical and convenient synthesis of dimethyl 3-amino-5-(2-oxo-2-arylethyl)thiophene-2,4-dicarboxylates has been developed for the first time through [3 + 2] donor–acceptor heteroannulation of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles and methyl thioglycolate followed by ring opening using sodium methoxide. We have also demonstrated the ring opening reaction of methyl 3-amino-6-aryl-4-oxo-4H-thieno[3,2-c]pyran-2-carboxylates in methanol and DMF and given some interesting finding. If we perform ring opening in methanol rather than DMF, it was observed that prolonged stirring of reaction mixture reverted to parent compound 4. The various functional groups present in thiophene ring at positions 2,3,4,5 are very reactive and can be utilized as precursors for the construction of various fused heterocycles not easily obtainable by conventional route. The mild reaction conditions, easy workup and non-involvement of metal catalyst make this protocol attractive for practical applications.

Experimental section

General remarks

Commercially available reagents and solvents were used without further purification. ¹H and ¹³C NMR spectra were recorded on 400 MHz and 100 MHz NMR spectrometer respectively. CDCl₃ were used as solvent for NMR. Chemical shift reported in ppm considering (CDCl₃) δ 7.24 ppm for ¹H NMR and δ 77.00 ppm for ¹³C NMR as an internal standard. Signal patterns are indicated as s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m, multiplet; br s, broad singlet. Coupling constants (J) are given in hertz (Hz). Infrared (IR) spectra were recorded on AX-1 spectrophotometer and reported as wave number (cm⁻¹). Intensity data for 10 were collected at 298(2) K on a Sapphire2-CCD, OXFORD diffractometer system equipped with graphite monochromated Mo Kα radiation λ = 0.71073 Å. The final unit cell determination, scaling of the data, and corrections for Lorentz and polarization effects were performed with CrysAlis RED.³⁸ The structure was solved by direct methods (SHELXS-97)³⁹ and refined by a full-matrix least-squares procedure based on F².⁴⁰ All the calculations were carried out using WinGX system Ver-1.64.⁴¹ All non-hydrogen atoms were refined anisotropically; hydrogen atoms were located at calculated positions and refined using a riding model with isotropic thermal parameters fixed at 1.2 times the U_eq value of the appropriate carrier atom.

General procedure for the synthesis of dimethyl 3-amino-5-(2-oxo-2-(aryl)ethyl)thiophene-2,4-dicarboxylate: two steps and one pot approach were established

One pot synthetic approach (method A). A mixture of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles (0.5 mmol), methyl thioglycolate (0.75 mmol) and triethylamine (1.0 mmol) in DMF (4.0 mL) was stirred for 2.5 h at 90 °C. Thereafter, the reaction mixture was brought to room temperature and sodium methoxide (1.0 mmol) was added to the reaction mixture and stirred for additional 2 h at room temperature. The reaction mixture was poured onto crushed ice with vigorous stirring followed by neutralization with 10% HCl. The precipitate obtained was filtered, dried and recrystallized from methanol to obtain the desired product in good to excellent yields.

Ring opening approach in methanol (method B). Methyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4, 0.5 mmol) obtained by the procedure reported³³ earlier was treated with freshly prepared NaOCH₃ solution (23 mg Na in 4.0 mL MeOH) for 1–2 h and completion of reaction was monitored by TLC. After completion, the excess of methanol was removed under reduced pressure followed by addition of cold water. Reaction mixture was neutralized with 10% HCl and filtered the precipitate. The crude product was purified by silica gel column chromatography using 50% dichloromethane in hexane as an eluent.

Ring opening approach in DMF (method C). A mixture of methyl 3-amino-6-arylthieno[3,2-c]pyran-4-one-2-carboxylates (4, 0.5 mmol) and sodium methoxide (1.0 mmol) in DMF (4.0 mL) was stirred for 1–2 h at room temperature. Completion of reaction was monitored by TLC. Thereafter, the reaction mixture was poured onto crushed ice with vigorous stirring followed by neutralization with 10% HCl. The precipitate obtained was filtered dried and recrystallized from methanol to obtain the pure product.

Dimethyl 3-amino-5-(2-oxo-2-phenylethyl)thiophene-2,4-dicarboxylate (10a). Yield: 87% (144 mg) R_f = 0.32 (1 : 1 hexane in dichloromethane); yellow solid; mp: 142–144 °C; IR (KBr): 3476, 3365, 1685, 1597, 1448, 1326 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.62 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.66 (s, 2H, CH₂), 6.83 (br s, 2H, NH₂), 7.49 (t, J = 7.62 Hz, 2H, ArH), 7.58–7.59 (m, 1H, ArH), 7.98 (d, J = 7.32 Hz, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.6, 51.2, 51.4, 117.8, 128.0, 128.7, 133.5, 136.2, 151.1, 155.1, 163.4, 164.2, 194.3; HRMS (ESI): calculated for C₁₆H₁₅NO₅S, 334.0744 (M + H⁺) found for m/z, 334.0741.

Dimethyl 3-amino-5-(2-oxo-2-(p-tolyl)ethyl)thiophene-2,4-dicarboxylate (10b). Yield: 86% (144 mg) R_f = 0.31 (1 : 1 hexane in dichloromethane); white solid; mp: 162–164 °C; IR (KBr): 3478, 3359, 1702, 1687, 1579, 1274 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.41 (s, 3H, CH₃), 3.61 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.64 (s, 2H, CH₂), 6.83 (br s, 2H, NH₂), 7.28 (d, J = 7.93 Hz, 2H, ArH), 7.88 (d, J = 7.93 Hz, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 21.6, 40.5, 51.1, 51.3, 97.7, 117.7, 128.1, 129.4, 133.7, 144.3, 151.3, 155.1, 163.4, 164.2, 193.9; HRMS (ESI): calculated for C₁₇H₁₇NO₅S, 348.0900 (M + H⁺); found for m/z, 348.0891.

Dimethyl 3-amino-5-(2-(4-fluorophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10c). Yield: 85% (149 mg) R_f = 0.21 (1 : 1 hexane in dichloromethane); yellow solid; mp: 152–153 °C; IR (KBr): 3476, 3359, 1702, 1595, 1528, 1273 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.63 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.60 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 7.16 (t, J = 8.77 Hz, 2H ArH), 8.00–8.02 (m, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.5, 51.2, 51.4, 115.9, (d, J = 22.04 Hz), 117.8, 124.9, 128.4, 130.7, (d, J = 9.58 Hz), 132.6, 150.8, 155.0, 163.3, 164.1, 165.9 (d, J = 255.9), 192.8; HRMS (ESI): calculated for C₁₆H₁₄FNO₅S, 352.0649 (M + H⁺); found for m/z, 352.0648.

Dimethyl 3-amino-5-(2-(4-chlorophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10d). Yield: 68% (124 mg) R_f = 0.30 (1 : 1 hexane in dichloromethane); white solid; mp: 147–149 °C; IR (KBr): 3482, 3363, 1701, 1589, 1459, 1273 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.63 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.63 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 7.46 (d, J = 8.54 Hz, 2H ArH), 7.93 (d, J = 8.54 Hz, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.5, 51.2, 51.5, 117.8, 129.1, 129.5, 134.5, 140.0, 150.6, 155.0, 163.3, 164.2, 193.2; HRMS (ESI) calculated for C₁₆H₁₄ClNO₅S, 368.0354 (M + H⁺); found for m/z, 368.0348.

Dimethyl 3-amino-5-(2-(2-chlorophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10e). Yield: 70% (128 mg) R_f = 0.30 (1 : 1 hexane in dichloromethane); cinnamon solid; mp: 90 °C; IR (KBr): 3461, 3348, 1707, 1664, 1587, 1269 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.69 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.65 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 7.34–7.36 (m, 1H, ArH), 7.38–7.45 (m 2H, ArH), 7.53–7.55 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 44.6, 51.2, 51.5, 117.8, 127.02, 129.5, 130.7, 131.0, 132.2, 138.2, 150.0, 155.0, 163.4, 164.2, 196.6; HRMS (ESI): calculated for C₁₆H₁₄ClNO₅S, 368.0354 (M + H⁺); found for m/z, 368.0352.

Dimethyl 3-amino-5-(2-(4-bromophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10f). Yield: 62% (127 mg) R_f = 0.28 (1 : 1 hexane in dichloromethane); yellow solid; mp: 141–143 °C; IR (KBr): 3475, 3359, 1699, 1599, 1458, 1275 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.63 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.62 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 7.63 (d, J = 8.54 Hz, 2H ArH), 7.85 (d, J = 8.54 Hz, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.5, 51.2, 51.5, 117.8, 128.7, 129.6, 132.1, 134.9, 150.6, 155.0, 163.3, 164.1, 193.4; HRMS (ESI) calculated for C₁₆H₁₄BrNO₅S, 411.9849 (M + H⁺); found for m/z, 411.9840.

Dimethyl 3-amino-5-(2-(3-bromophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10g). Yield: 55% (112 mg) R_f = 0.24 (1 : 1 hexane in dichloromethane); chocolate solid; mp: 134 °C; IR (KBr): 3467, 3350, 1699, 1582, 1517, 1270 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.65 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.63 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 7.37 (t, J = 7.63 Hz, 1H, ArH), 7.72 (d, J = 9.92 Hz, 1H, ArH); 7.91 (d, J = 7.63 Hz, 1H, ArH), 8.11–8.12 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.6, 51.2, 51.5, 117.9, 123.1, 126.6, 130.3, 131.1, 136.3, 137.9, 150.4, 155.0, 163.3, 164.1, 193.0; HRMS (ESI) calculated for C₁₆H₁₄BrNO₅S, 411.9849 (M + H⁺); found for m/z, 411.9839.

Dimethyl 3-amino-5-(2-(naphthalen-2-yl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10h). Yield: 83% (158 mg) R_f = 0.21 (1 : 1 hexane in dichloromethane); carrot orange solid; mp: 170–172 °C; IR (KBr): 3476, 3361, 1702, 1586, 1529, 1274 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.59 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.80 (s, 2H, CH₂), 6.85 (br s, 2H, NH₂), 7.56–7.62 (m, 2H, ArH), 7.87–8.02 (m, 4H, ArH), 8.53 (s, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.7, 51.2, 51.4, 117.8, 123.7, 126.9, 127.8, 128.7, 129.5, 129.8, 132.4, 133.5, 135.7, 151.2, 155.1, 163.4, 164.2, 194.2; HRMS (ESI): calculated for C₂₀H₁₇NO₅S, 384.0900 (M + H⁺) found for m/z, 384.0895.

Dimethyl 3-amino-5-(2-(naphthalen-1-yl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10i). Yield: 80% (153 mg) R_f = 0.22 (1 : 1 hexane in dichloromethane); buff solid; mp: 151–153 °C; IR (KBr): 3459, 3346, 1706, 1686, 1586, 1273 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.58 (s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 4.74 (s, 2H, CH₂), 6.86 (br s, 2H, NH₂), 7.50–7.55 (m, 3H, ArH), 7.87 (d, J = 8.24 Hz, 1H, ArH); 7.99 (dd, J = 7.33 Hz, 7.79 Hz, 2H, ArH), 8.56 (d, J = 8.24 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 43.8, 51.2, 51.5, 117.8, 124.2, 125.6, 126.6, 127.6, 128.2, 128.4, 130.0, 133.2, 133.9, 134.7, 151.0, 163.5, 164.2, 197.5; HRMS (ESI) calculated for C₂₀H₁₇NO₅S, 384.0900 (M + H⁺) found for m/z, 384.0900.

Dimethyl 3-amino-5-(2-(4-methoxyphenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10j). Yield: 80% (144 mg) R_f = 0.17 (1 : 1 hexane in dichloromethane); yellow solid; mp: 142–144 °C; IR (KBr): 3475, 3353, 1700, 1582, 1451, 1278 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.62 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 4.61 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 6.95 (d, J = 8.54 Hz, 2H ArH), 7.96 (d, J = 9.16 Hz, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.3, 51.2, 51.4, 55.5, 113.9, 117.7, 129.2, 130.4, 151.6, 155.1, 163.5, 163.7, 164.2, 192.8; HRMS (ESI) calculated for C₁₇H₁₇NO₆S, 364.0849 (M + H⁺); found for m/z 364.0847.

Dimethyl 3-amino-5-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10k). Yield: 80% (157 mg) R_f = 0.18 (1 : 1 hexane in dichloromethane); buff solid; mp: 183–184 °C; IR (KBr): 3475, 3345, 1707, 1590, 1512, 1265 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.64 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃), 3.94 (s, 3H, OCH₃) 4.64 (s, 2H, CH₂), 6.82 (br s, 2H, NH₂), 6.91 (d, J = 8.39 Hz, 1H, ArH), 7.52–7.53 (m, 1H, ArH), 7.62–7.64 (m, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.2, 51.1, 51.4, 55.9, 56.0, 110.0, 110.1, 117.7, 122.7, 129.3, 149.1, 151.6, 153.5, 155.0, 163.4, 164.2, 192.9; HRMS (ESI): calculated for C₁₈H₁₉NO₇S, 394.0955 (M + H⁺); found for m/z, 394.0947.

Dimethyl 3-amino-5-(2-(2-methoxyphenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10l). Yield: 75% (136 mg) R_f = 0.18 (1 : 1 hexane in dichloromethane); yellow solid; mp: 115–117 °C, IR (KBr): 3471, 3354, 1690, 1586, 1508, 1274 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.61 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 4.63 (s, 2H, CH₂), 6.83 (br s, 2H, NH₂), 6.97–7.02 (m, 2H, ArH), 7.48 (t, J = 7.63 Hz, 1H, ArH), 7.70 (d, J = 7.63 Hz, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 45.6, 51.1, 51.2, 55.4, 97.4, 111.4, 117.5, 120.7, 127.2, 130.5, 134.0, 152.1, 155.2, 158.5, 163.5, 164.2, 196.0; HRMS (ESI): calculated for C₁₇H₁₇NO₆S, 364.0849 (M + H⁺); found for m/z, 364.0847.

Dimethyl 3-amino-5-(2-oxo-2-(thiophen-2-yl)ethyl)thiophene-2,4-dicarboxylate (10m). Yield: 70% (118 mg) R_f = 0.33 (1 : 1 hexane in dichloromethane); white solid; mp: 145–147 °C; IR (KBr): 3481, 3365, 1685, 1589, 1439, 1272 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.66 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.59 (s, 2H, CH₂), 6.83 (br s, 2H, NH₂), 7.15 (dd, J = 4.88, 4.88 Hz, 1H, Ar-H), 7.67 (d, J = 4.27 Hz, 1H, ArH), 7.78 (dd, J = 1.22, 1.49 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 41.2, 51.2, 51.4, 117.8, 128.2, 132.1, 134.1, 143.0, 150.2, 163.4, 164.2, 187.0; HRMS (ESI): calculated for C₁₄H₁₃NO₅S₂, 340.03068 (M + H⁺); found for m/z 340.0307.

Dimethyl 3-amino-5-(2-(furan-2-yl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10n). Yield: 77% (124 mg) R_f = 0.25 (1 : 1 hexane in dichloromethane); yellow colored solid; mp: 149–151 °C; IR (KBr): 3481, 3363, 1701, 1587, 1466, 1257 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.66 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃), 4.53 (s, 2H, CH₂), 6.56 (m, 1H, Ar-H), 6.82 (br s, 2H, NH₂), 7.25 (d, J = 3.66 Hz, 1H, ArH), 7.61 (s, 1H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 40.2, 51.2, 51.4, 112.5, 117.4, 117.8, 146.5, 150.0, 151.9, 155.0, 163.4, 164.2, 183.3; HRMS (ESI): calculated for C₁₄H₁₃NO₆S, 324.0536 (M + H⁺); found for m/z, 324.0536.

Dimethyl 3-amino-5-(2-(4-nitrophenyl)-2-oxoethyl)thiophene-2,4-dicarboxylate (10o). Yield: 65% (122 mg) R_f = 0.17 (1 : 1 hexane in dichloromethane); yellow solid; mp: 194–196 °C; IR (KBr): 3467, 3363, 1699, 1608, 1530, 1257 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.61 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 4.64 (s, 2H, CH₂), 6.74 (br s, 2H, NH₂), 8.09–8.11 (m, 2H, ArH), 8.28–8.30 (m, 2H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 41.1, 51.3, 51.6, 118.0, 124.0, 129.1, 140.7, 149.8, 150.5, 163.2, 164.1, 193.0; HRMS (ESI): calculated for C₁₆H₁₄N₂O₇S, 379.0594 (M + H⁺); found for m/z, 379.0594.

Acknowledgements

Authors thank Council of Scientific and Industrial Research (CSIR, New Delhi) and Department of Science and Technology (DST, New Delhi) Delhi and ICMR New Delhi for financial support. SNS, PY, RP thank University Grants Commission (UGC, New Delhi) and SS thank Council of Scientific and Industrial Research (CSIR, New Delhi) for research fellowship. Authors thank University of Delhi for providing research funding and instrumentation facility.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: This material includes ¹H and ¹³C NMR spectra for all the reported compounds. CCDC 1038008. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra01290b

‡ Crystal data for 10a (CCDC 1038008): C₁₆H₁₅NO₅S, formula mass 333.35, monoclinic space group P₁2₁/C₁, a = 14.073(5), b = 13.465(5), c = 8.576(5) Å, β = 93.433(5)°, V = 1622.2(13) ų, Z = 4, d_calcd = 1.365 mg m⁻³, linear absorption coefficient 0.224 mm⁻¹, F(000) = 696, crystal size 0.27 × 0.25 × 0.18 mm, reflections collected 9249, independent reflections 3729 [R_int = 0.0232], final indices [I > 2σ(I)] R₁ = 0.0466, wR₂ = 0.1110, R indices (all data) R₁ = 0.0628, wR₂ = 0.1207, gof 1.042, largest difference peak and hole 0.233 and −0.232 e Å⁻³.

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