One-pot and step-wise synthesis of thieno[3,2-c]pyridin-4-ones

Abstract

Both one pot and step wise synthesis of methyl 3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylates 6 have been delineated by the reaction of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3, methyl mercaptoacetate and hydrazine hydrate. During the stepwise synthesis, functionalized thieno[3,2-c]pyran-4-ones 4 were isolated and treated with hydrazine hydrate to afford the desired products. Analogously, condensation–cyclisation of 5 with hydrazine hydrate delivered identical products, thieno[3,2-c]pyridin-4-ones 6, in excellent yields. The structure of isolated product 6 was ascertained by spectroscopic and single crystal X-ray diffraction analyses.

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Introduction

Fusion of thiophene with different sites of a pyridinone ring can result in numerous possible isomers of thienopyridinones, including thieno[2,3-b]-, thieno[3,2-b]-, thieno[2,3-c]-, thieno[3,2-c]- and thieno[3,4-b]pyridinones, etc. They are known for their diverse pharmacological activities, as inhibitors of glycogen synthase kinase-3β (GSK-3β), which play a role in glycogen metabolism, and for regulating diverse cell functions (Fig. 1, compound I).¹ The AMP-activated protein kinase (AMPK), which is known as a sensor and regulator for energy metabolism in the body,² and some other thienopyridines also acts as checkpoint-1 kinase (Chk-1) activators working to repair damaged DNA.³ A literature survey revealed that various N-substituted thienopyridinones act against Gram negative bacteria. 2-Chloro-7-ethyl-4-oxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid⁴ and many more derivatives act as antibacterials⁵ and DNA gyrase inhibitors prevent the growth of MCF-7 breast tumor and A549 lung cancer cells.⁶ Thieno[3,4-c]pyridin-4(5H)-ones are reported as poly(ADP-ribose)polymerase (PARP) inhibitors, and are implicated in the repair of damaged DNA and potentiate chemotherapy of cancer.⁷ The isomeric thieno[2,3-b]pyridinones are reported as antagonists of N-methyl-D-aspartate (NMDA), a contributor to excitatory neurotransmission⁸ and synaptic plasticity,⁹ as well as neurodegenerative disorders and neurological bipolar disorders¹⁰ like stroke, epilepsy, Parkinson's disease, Huntington's chorea, Alzheimer's disease and HIV dementia. However, an extensive literature survey revealed that the chemistry and therapeutic importance of isomeric thieno[3,2-c]pyridin-4-ones have not been extensively explored.

Fig. 1 Biologically active fused thienopyridinones (I–IV).

The synthesis of isomeric 7-hydroxythieno[3,2-b]pyridin-5(4H)-ones and 7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-ones¹¹ require appropriately substituted aminothiophenes¹² as key precursors. However, this methodology is limited to the introduction of an aryl functional group in the pyridine ring. Furthermore, the 3-aminothiophen-2-carboxylate precursors are difficult to access with different substituents at position 5. Rodinovskaya et al. have developed a one pot approach for the synthesis of tricyclic 4-hydroxy-7-methoxypyridino[2,3-d]thieno[3,2-b]pyridin-2(1H)-one.¹³ Another compound, 7-hydroxy-4H-thieno-[3,2-b]pyridin-5-one was synthesized by the reaction of ethyl-3-aminothiophene-2-carboxylate and diethyl malonate.¹⁴ Lee and co-worker have developed an excellent method for the synthesis of 4-alkyl- and 2-aryl-6-diazo-4H-thieno[3,2-b]pyridin-5,7-diones by the reaction of 3-(3-alkyl and aryl-amino-5-arylthieno-2-yl)-2-diazo-3-oxopropanoates and TMSOTf in presence of Et₃N in CH₂Cl₂.¹⁵ In addition, a one pot synthesis of functionalized 7-hydroxythieno[3,2-b]pyridin-5(4H)-ones from the corresponding β-substituted β-chloropropenonitrile was also performed.¹⁶

Herein, we are providing a novel approach for the synthesis of functionalized N-aminothieno[3,2-c]pyridin-5-ones 6 by the reaction of pyranothiophenes with hydrazine hydrate under solvent free conditions.

Results and discussion

We previously reported a synthesis of tetrasubstituted thiophene¹⁸ 5 by coupling methyl 3,3-dimethylthio-2-cyanoacrylate 1 and aryl methyl ketone 2 in the presence of powdered KOH in DMSO; subsequent product of the above mentioned reactants yielded 3,¹⁷ which was coupled with methyl mercaptoacetate in the presence of triethylamine, and the resultant lactone 4 was further subjected to methanolysis, as shown in Scheme 1.

Scheme 1 Reagent and conditions (a) KOH, DMSO, rt (b) SHCH₂COOMe, Et₃N, 80 °C (c) DMF, NaOMe, rt.

We envisaged an efficient and economical synthesis of N-aminothieno[3,2-c]pyridin-4-ones 6 from thieno[3,2-c]pyran-4-ones 4, which can be prepared from 3. In order to optimize the reaction conditions, the model substrate methyl 3-amino-4-oxo-6-(p-tolyl)-4H-thieno[3,2-c]pyran-2-carboxylate 4d was generated in situ by the reaction of 4-(methylthio)-2-oxo-6-(p-tolyl)-2H-pyran-3-carbonitrile 3d and methyl mercaptoacetate, which on addition of hydrazine hydrate, delivered N-aminothieno[3,2-c]pyridin-4-one 6d.

We performed the reaction in various solvents, like methanol, DMF and DMSO, and found that if we perform the reaction using DMF at 80 °C, it provides a better yield of the desired product (entry 2, Table 1). However, if the same reaction is carried out in THF for 24 h at room temperature, only a trace amount of the desired product was observed on TLC, possibly due to the low dielectric constant of the solvent (entry 4, Table 1). Further, attempts to improve the yield were made by the addition of KOH, NaNH₂ and NaH bases in conjunction with Et₃N in aprotic solvents, such as DMF and DMSO, under analogous reaction conditions.

Table 1 Optimization of reaction conditions^a

Entry	Additional base	Solvent	Temp (°C)	Time (h)	Yield (%)
a Reactions were carried out by stirring 3d (0.5 mmol), methyl thioglycolate (0.75 mmol), Et3N (1.0 mmol) for 2 h and then hydrazine hydrate (0.75 mmol) was added at a different temperature.b Reactions were carried out at room temperature for 5 h upto intermediate stage, followed by addition of hydrazine hydrate.c Furthermore, Et3N, other bases were added while adding hydrazine and reaction was carried out for given time at mentioned temperature.d Room temperature was ranging between 30 °C and 35 °C.
1	—	CH3OH	80	10	30
2	—	DMF	80	3	80
3	—	DMSO	80	3	75
4^b	—	THF	rt^d	30	Trace
5^c	KOH	DMF	90	4	50
6^c	NaNH2	DMF	90	4	40
7^c	NaH	DMF	90	5	45
8^c	NaH	DMSO	90	5	45

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Additional base did not improve the yield of thieno[3,2-c]pyridin-4-one 6d, which ranged between 40% and 50% (entry 5–8, Table 1).

From the optimization study, we have concluded that triethylamine in DMF (entry 2, Table 1) is the best reaction condition for the formation of 6.

Generality of the protocol was tested for the synthesis of various derivatives of N-aminothieno[3,2-c]pyridin-4-ones 6. The yields of various isolated thieno[3,2-c]pyridin-4-ones from different reactions are reported in Table 2. Two step synthesis were also performed in which 6 was obtained in good yields from isolated thieno[3,2-c]pyran-4-one 4 by reaction with hydrazine hydrate at 80 °C in DMF.

Table 2 One pot synthesis of various N-aminothieno[3,2-c]pyridin-4-ones 6^a

6	Ar	R	Yield^b%
a All reactions were carried out by stirring 3 (0.5 mmol), methyl thioglycolate (0.75 mmol) and Et3N (1.0 mmol) at 80 °C in DMF (4.0 mL) followed by the addition of hydrazine hydrate (0.75 mmol) after consumption of 3.b Yields are reported after purification through column chromatography.
a	C6H5	H	68
b	p-OCH3·C6H4	H	70
c	o-OCH3·C6H4	H	73
d	p-CH3·C6H4	H	75
e	p-Cl·C6H4	H	68
f	P-F·C6H4	H	72
g	P-Br·C6H4	H	76
h	2-Naphthyl	H	70
i	1-Naphthyl	H	74
j	2-Theinyl	H	68
k	2-Furyl	H	55
l	C6H5	C6H5	60

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A chemical research, always has an environmental concern.¹⁹ Thus, call for a clean procedure, which avoids the use of harmful organic solvent, is inevitable. In anticipation of this, we examined the reaction of methyl 6-aryl-3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylate 4 and hydrazine hydrate under solvent free conditions, and surprisingly, were afforded the desired products in good yields. The required precursor 4 can be synthesized using L-proline¹⁹ as a catalyst and overall synthesis can be made environmentally friendly. When the yield of the desired product is compared in solvent and under solvent free conditions, in most cases the latter gives the best result (Table 3). Apart from the work-up, the solvent free reactions are easier to perform.

Table 3 Synthesis of methyl 6-aryl-3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylates (6)

6	Ar	R	Yield^a^,^c% (in DMF)	Yield^b^,^c% (solvent free)
a All reactions were carried out by stirring 4 (0.5 mmol) and hydrazine hydrate (0.75 mmol) at 80 °C in DMF (4 mL) as solvent.b Reaction was carried out by stirring 4 (0.5 mmol) and hydrazine hydrate (1 mL) at 80 °C.c Yields are reported after purification through column chromatography.
a	C6H5	H	77	65
b	p-OCH3·C6H4	H	77	84
c	o-OCH3·C6H4	H	72	80
d	p-CH3·C6H4	H	74	80
e	p-Cl·C6H4	H	82	81
f	P-F·C6H4	H	82	85
g	P-Br·C6H4	H	79	76
h	2-Naphthyl	H	78	81
i	1-Naphthyl	H	70	76
j	2-Theinyl	H	73	80
k	2-Furyl	H	60	72
l	C6H5	C6H5	70	77

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A plausible mechanism for the reaction is depicted in Scheme 2. Possibly, the reaction is initiated by attack of hydrazine at the C2 position of pyranothiophene, followed by ring opening to afford intermediate A. Involvement of the amide nitrogen in cyclization, followed by loss of water leads to the product N-aminothieno[3,2-c]pyridin-4-one 6. The structure of the isolated product was confirmed on the basis of spectroscopic as well as single crystal X-ray diffraction (see ESI†) analyses of methyl 3,5-diamino-6-(2-methoxyphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate 6c.‡

Scheme 2 A plausible mechanism for the formation of N-aminothieno[3,2-c]pyridin-4-ones 6.

To further enhance the scope of starting material, we used tetrasubstituted thiophene^18a (Scheme 3) as a precursor and performed the reaction with hydrazine hydrate in DMF at 80 °C. Usual work-up and purification afforded N-aminothieno[3,2-c]pyridin-4-ones 6 in good yield. Therefore, another protocol was developed for the preparation of N-aminothieno[3,2-c]pyridin-5-ones 6 from suitably functionalized tetrasubstituted thiophenes by condensation–cyclization with hydrazine hydrate.

Scheme 3 Synthesis of N-aminothieno[3,2-c]pyridin-4-ones 6 from tetrasubstituted thiophenes 5.

Attempts were made to transform methyl 3-amino-10,11-dihydrothieno[3,2-c]chromene-4-one-2-carboxylate to methyl 3,5-diamino-10,11-dihydrothieno[3,2-c]benzo[h]quinilin-4-one-2-carboxylate, obtained¹⁹ from the reaction of 4-methylthio-2H-benzo[h]chromene-2-one-3-carbonitrile and methyl mercaptoacetate using Et₃N as a base in DMF at 80 °C, but failed and starting material was recovered. The failure of this reaction was possibly due to steric crowding present at position C10b.

The structure of one of the compounds (6c) was confirmed by single crystal X-ray (please see ESI†).

Conclusion

In conclusion, we developed both a one pot and a step wise approach for the synthesis of methyl 3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylates 6 by the reaction of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles 3, methyl mercaptoacetate and hydrazine hydrate. During the stepwise synthesis, functionalized thieno[3,2-c]pyran-4-one 4 was isolated and treated with hydrazine hydrate to afford the desired product. Analogously, condensation–cyclisation of tetrasubstituted thiophenes 5 with hydrazine hydrate delivered identical products, thieno[3,2-c]pyridin-4-ones 6 in excellent yields. The structure of the isolated product 6 was ascertained by spectroscopic and single crystal X-ray diffraction analyses. This procedure is simple, efficient and economical. It does not require any metal catalyst.

Experimental

General remarks

Relevant reagents and solvents were obtained commercially and used without further purification. ¹H and ¹³C NMR spectra were recorded on 400 MHz and 100 MHz NMR spectrometers, respectively. CDCl₃ and DMSO-d₆ were used as solvents for NMR. Chemical shift (δ) is reported in ppm, considering CDCl₃ δ 7.24 ppm for ¹H NMR and δ 77.0 ppm for ¹³C NMR, and DMSO δ 2.49 and 3.33 ppm for ¹H NMR and δ 39.51 ppm ¹³C NMR as an internal standard. Signal patterns are indicated as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet), and br s (broad singlet). Coupling constants (J) are in hertz (Hz). Infrared (IR) spectra were recorded on AX-1 spectrophotometer and reported as wave number (cm⁻¹). HRMS was recorded on Agilent G6530AA (LC-HRMS-Q-TOF) mass spectrometer.

Intensity data for 6c were collected at 298(2) K on a OXFORD CrysAlis 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.²⁰ The structures were solved by direct methods (SHELXS-97)²¹ and refined by a full-matrix least squares procedure based on F².²² All the calculations were carried out using WinGX system Ver-1.64.²³

General procedure for the synthesis of methyl 6-aryl-3,5-diaminothieno[3,2-c]pyridin-4-one-2-carboxylate

Method A. A mixture of 4-(methylthio)-2-oxo-6-aryl-2H-pyran-3-carbonitriles¹⁷ (0.5 mmol) and methyl thioglycolate (0.75 mmol) in 4.0 mL DMF in presence of triethylamine (1.0 mmol) was stirred for 2 h at 80 °C. Complete formation of intermediate (3-amino-2-carbmethoxy-6-aryl-4H-thieno[3,2-c]pyran-2-one) was monitored by TLC. Thereafter, hydrazine hydrate (0.75 mmol) was added to the reaction mixture and further stirred for 3 h. Formation of the desired product was monitored on TLC. The reaction mixture was poured onto crushed ice with vigorous stirring. Obtained precipitate was filtered, dried and purified over silica-gel column chromatography using 30% ethyl acetate in hexane as an eluent.

Method B. First, we have synthesized 3-amino-2-carbethoxy-6-aryl-4H-thieno[3,2-c]pyran-2-one (4) according to the previously reported procedure.¹⁸ Then, a mixture of thienopyranone (0.5 mmol) and hydrazine hydrate (0.75 mmol) in DMF were stirred at 80 °C for 2–3 h. Formation of the desired product was monitored by TLC. The reaction mixture was poured onto crushed ice with vigorous stirring. Obtained precipitate was filtered, dried and purified over silica-gel column chromatography using 30% ethyl acetate in hexane as an eluent.

In another approach, we stirred compound 4 in hydrazine hydrate (1.0 mL) for 3 h at 80 °C. After completion and usual work-up of the reaction we isolated the desired product. The product was further purified by silica-gel column chromatography using 30% ethyl acetate in hexane as an eluent.

Method C. Compound 6 was also synthesized by stirring 5 (0.5 mmol) and hydrazine hydrate (0.75 mmol) in DMF at 80 °C for 2 h. The reaction mixture was poured onto crushed ice with vigorous stirring. Obtained precipitate was filtered, dried and purified over silica-gel column chromatography using 30% ethyl acetate in hexane as an eluent.

Methyl 3,5-diamino-4-oxo-6-phenyl-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6a)

Yield: 68% (107 mg); yellow solid; mp: 198–200 °C; IR (KBr): 3464, 3345, 1680 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.75 (s, 3H, OCH₃), 5.59 (s, 2H, NH₂), 6.80 (s, 1H, CH), 7.44–7.45 (m, 3H, ArH), 7.58–7.60 (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.1, 93.2, 102.6, 116.2, 127.7, 128.8, 129.3, 134.3, 147.8, 148.4, 152.0, 158.8, 163.8; HRMS (m/z, ESI) calculated for C₁₅H₁₃N₃O₃S, (M + H⁺) 316.0750; found 316.0765.

Methyl 3,5-diamino-6-(4-methoxyphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6b)

Yield: 70% (120 mg); yellow solid; mp: 217–218 °C; IR (KBr): 3470, 3350, 1673 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H, OCH₃), 3.77 (s, 3H, OCH₃), 5.58 (s, 2H, NH₂), 6.74 (s, 1H, CH), 6.97 (d, J = 9.16 Hz, 2H, ArH), 7.53 (d, J = 9.16 Hz, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.1, 55.3, 102.4, 113.2, 115.8, 126.5, 127.8, 130.9, 147.7, 148.5, 152.1, 158.9, 159.8, 163.9; HRMS (m/z, ESI) calculated for C₁₆H₁₅N₃O₄S, (M + H⁺) 346.0856; found 346.0866.

Methyl 3,5-diamino-6-(2-methoxyphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6c)

Yield: 73% (126 mg); yellow solid; mp: 187–188 °C; IR (KBr): 3467, 3348, 1673 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H, OCH₃), 3.74 (s, 3H, OCH₃), 5.45 (s, 2H, NH₂), 6.70 (s, 1H, CH), 7.00 (t, J = 7.25 Hz, 1H, ArH), 7.08 (d, J = 8.39 Hz, 1H, ArH), 7.26 (d, J = 6.87 Hz, 1H, ArH), 7.43 (t, J = 7.01 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.2, 55.6, 102.9, 110.8, 116.3, 120.2, 123.7, 129.8, 130.9, 145.7, 148.3, 152.1, 156.7, 158.3, 163.9; HRMS (m/z, ESI) calculated for C₁₆H₁₅N₃O₄S, (M + H⁺) 346.0856; found 346.0869.

Methyl 3,5-diamino-4-oxo-6-(p-tolyl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6d)

Yield: 75% (123 mg); yellow solid; mp: 198–200 °C; IR (KBr): 3469, 3349, 1675 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 2.35 (s, 3H, CH₃), 3.74 (s, 3H, OCH₃), 5.60 (s, 2H, NH₂), 6.77 (s, 1H, CH), 7.25 (d, J = 7.63 Hz, 2H, ArH), 7.48 (d, J = 8.39 Hz, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 20.9, 51.1, 102.5, 116.0, 128.3, 129.3, 131.5, 138.6, 147.9, 148.4, 152.1, 158.8, 163.9; HRMS (m/z, ESI) calculated for C₁₆H₁₅N₃O₃S, (M + H⁺) 330.0907; found 330.0907.

Methyl 3,5-diamino-6-(4-chlorophenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6e)

Yield: 68% (118 mg); yellow solid; mp: 228–229 °C; IR (KBr): 3469, 3350, 1678 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.75 (s, 3H, OCH₃), 5.58 (s, 2H, NH₂), 6.83 (s, 1H, CH), 7.52 (d, J = 9.16 Hz, 2H, ArH), 7.61 (d, J = 8.39 Hz, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.2, 102.84, 116.4, 127.8, 131.3, 133.2, 133.8, 146.8, 148.4, 152.07, 158.9, 163.8; HRMS (m/z, ESI) calculated for C₁₅H₁₂ClN₃O₃S, (M + H⁺) 350.0361; found 350.0360.

Methyl 3,5-diamino-6-(4-fluorophenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6f)

Yield: 72% (120 mg); yellow solid; mp: 190–192 °C; IR (KBr): 3462, 3343, 1675, 1508 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H, OCH₃), 5.56 (s, 2H, NH₂), 6.78 (s, 1H, CH), 7.01 (br s, 2H, NH₂), 7.26 (t, J = 8.77 Hz, 2H, ArH), 7.60–7.64 (m, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.2, 102.8, 114.7 (d, J = 22.04 Hz), 116.3, 129.9, 130.8, 131.8, (d, J = 8.63 Hz), 147.0, 148.4, 152.0, 158.9, 162.4, (d, J = 246.33 Hz), 163.91; HRMS (m/z, ESI) calculated for C₁₅H₁₂FN₃O₃S, (M + H⁺) 334.0656; found 334.0674.

Methyl 3,5-diamino-6-(4-bromophenyl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6g)

Yield: 76% (149 mg); yellow solid; mp: 207–209 °C; IR (KBr): 3461, 3351, 1674 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.72 (s, 3H, OCH₃), 5.50 (s, 2H, NH₂), 6.79 (s, 1H, CH), 7.51 (d, J = 8.39 Hz, 2H, ArH), 7.62 (d, J = 8.39 Hz, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.2, 102.7, 116.4, 122.5, 124.6, 129.9, 130.7, 137.5, 133.6, 146.8, 148.4, 152.0, 158.9, 163.8; HRMS (m/z, ESI) calculated for C₁₅H₁₂BrN₃O₃S, (M + H⁺) 393.9856; found 393.9853.

Methyl 3,5-diamino-6-(naphthalen-2-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6h)

Yield: 70% (128 mg); yellow solid; mp: 194–196 °C; IR (KBr): 3468, 3350, 1675 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.75 (s, 3H, OCH₃), 5.66 (s, 2H, NH₂), 6.93 (s, 1H, CH), 7.37 (br s, 2H, NH₂) 7.54–7.60 (m, 2H, ArH), 7.74–7.77 (m, 1H, ArH) 7.93–7.98 (m, 3H, ArH), 8.11 (s, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.2, 93.3, 103.0, 116.3, 126.5, 126.6, 127.0, 127.3, 127.5, 128.2, 132.1, 132.3, 132.7, 147.9, 148.5, 152.1, 158.9, 163.9; HRMS (m/z, ESI) calculated for C₁₉H₁₅N₃O₃S, (M + H⁺) 366.0907; found 366.0899.

Methyl 3,5-diamino-6-(naphthalen-1-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6i)

Yield: 74% (125 mg); yellow solid; mp: 218–220 °C; IR (KBr): 3465, 3350, 1676 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.85 (s, 3H, OCH₃), 4.91 (br s, 2H, NH₂), 6.61 (s, 1H, CH), 7.06 (br s, 2H, NH₂), 7.46–7.57 (m, 5H, ArH), 7.92 (d, J = 7.63 Hz, 1H, ArH), 7.97 (d, J = 8.39 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.3, 104.0, 117.3, 124.3, 125.1, 126.4, 126.8, 127.4, 128.7, 130.0, 131.2, 131.6, 133.1, 145.3, 148.9, 152.6, 158.7, 164.8; HRMS (m/z, ESI) calculated for C₁₉H₁₅N₃O₃S, (M + H⁺) 366.0907; found 366.0928.

Methyl 3,5-diamino-4-oxo-6-(thiophen-2-yl)-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6j)

Yield: 68% (109 mg); yellow solid; mp: 209–210 °C; IR (KBr): 3466, 3349, 1673 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.74 (s, 3H, OCH₃), 5.84 (s, 2H, NH₂),7.00 (br s, 2H, NH₂), 7.16 (t, J = 3.81 Hz, 1H, ArH), 7.30 (s, 1H, CH), 7.79 (d, J = 5.34 Hz, 1H, ArH), 7.88 (d, J = 3.81 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.1, 99.9, 115.2, 126.7, 130.2, 131.9, 133.7, 141.8, 148.7, 152.0, 159.0, 163.8; HRMS (m/z, ESI) calculated for C₁₃H₁₁N₃O₃S₂, (M + H⁺) 322.0315; found 322.0315.

Methyl 3,5-diamino-6-(furan-2-yl)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6k)

Yield: 55% (83 mg); asparagus solid; mp: 248–249 °C; IR (KBr): 3472, 3353, 1675 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 3.74 (s, 3H, OCH₃), 5.92 (s, 2H, NH₂), 6.71–6.72 (m, 1H, ArH), 7.01 (br s, 2H, NH₂), 7.24 (s, 1H, ArH), 7.56 (d, J = 3.05 Hz, 1H, ArH), 7.92 (s, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 51.1, 98.7, 112.6, 115.2, 116.8, 137.0, 145.0, 148.2, 151.9, 158.5, 163.8; HRMS (m/z, ESI) calculated for C₁₃H₁₁N₃O₄S, (M + H⁺) 306.0543; found 306.0538.

Methyl 3,5-diamino-4-oxo-6,7-diphenyl-4,5-dihydrothieno[3,2-c]pyridine-2-carboxylate (6l)

Yield: 60% (mg); pale yellow solid; mp: 256–258 °C; IR (KBr): 3468, 3348, 1677 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.78 (s, 3H, OCH₃), 5.02 (br s, 2H, NH₂), 7.08–7.27 (m, 10H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ 51.2, 116.7, 127.8, 128.0, 128.3, 128.8, 130.0, 132.4, 135.0, 142.9, 151.6, 157.9, 164.8; HRMS (m/z, ESI) calculated for C₂₁H₁₇N₃O₃S, (M + H⁺) 392.1063; found 392.1063.

Acknowledgements

RP thank Department of Science and Technology, New Delhi [purse grant], ICMR, New Delhi, India and University of Delhi, Delhi [R & D Grant] for financial support. RP thank University of Delhi, India for providing study leave to visit Kyoto University as JSPS visiting Prof. SS and RS thank Council of Scientific and Industrial Research (CSIR, New Delhi) and SNS and Shally thank University Grants Commission (UGC, New Delhi) for research fellowship. Authors thank USIC, University of Delhi for providing instrumentation facility.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: All the proton and ¹³C NMR spectra are given. CCDC 1484442. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra17315b

‡ Crystal data for 6c (CCDC 1484442): C₁₆H₁₅N₃O₄S, FW = 345.37, monoclinic, P21/c, bond precision: C–C = 0.0032 Å, wavelength = 0.71073 Å, cell: a = 11.6062(6), b = 18.6702(6), c = 7.5550(3), α = 90°, β = 107.089(5), γ = 90°, T = 293 K, V = 1564.82(12), Z = 4, Mu (mm⁻¹) = 0.234, R₁ [I > 2σ(I)] = 0.0467, wR₂ = 0.1195, R₁ [all data] = 0.0592, wR₂ = 0.1267.

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