CC BY ND NC 4.0 · SynOpen 2018; 02(02): 0207-0212
DOI: 10.1055/s-0037-1610157
letter
Copyright with the author

A Convenient One-pot Synthesis of 2,3-Disubstituted Thieno[2,3-d]pyrimidin-4(3H)-ones from 2H-Thieno[2,3-d][1,3]oxazine-2,4(1H)-diones, Aromatic Aldehydes and Amines

Feize Liu
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, P. R. of China   Email: xlhou@ms.xjb.ac.cn   Email: guozheng.huang@yahoo.com
University of Chinese Academy of Sciences, Yuquan Rd 19 A, Beijing, 100049, P. R. of China
,
Xueling Hou*
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, P. R. of China   Email: xlhou@ms.xjb.ac.cn   Email: guozheng.huang@yahoo.com
,
Li Fei Nie
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, P. R. of China   Email: xlhou@ms.xjb.ac.cn   Email: guozheng.huang@yahoo.com
University of Chinese Academy of Sciences, Yuquan Rd 19 A, Beijing, 100049, P. R. of China
,
Khurshed Bozorov
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, P. R. of China   Email: xlhou@ms.xjb.ac.cn   Email: guozheng.huang@yahoo.com
Institute of the Chemistry of Plant Substances, Academy of Sciences of Uzbekistan, Mirzo Ulugbek Str. 77, Tashkent, 100170, Uzbekistan
,
Michael Decker
Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
,
Guozheng Huang*
Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, P. R. of China   Email: xlhou@ms.xjb.ac.cn   Email: guozheng.huang@yahoo.com
› Author Affiliations
Support from the Chinese Recruitment Program of Global Experts (G. Huang) and National Foundation for Natural Science of China (K.Bozorov, Grant No. 21550110495) is gratefully acknowledged.

Further Information

Publication History

Received: 28 February 2018

Accepted after revision: 03 May 2018

Publication Date:
13 June 2018 (online)

 

Abstract

An efficient, simple protocol has been established for convenient synthesis of novel 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-one derivatives in good to high yields through a one-pot, two-step and three-component reaction from 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-diones, aromatic aldehydes, and amines.


#

Quinazolinones, especially quinazolin-4(3H)-ones (Figure [1]) are one of the most important building blocks in medicinal chemistry. Over the past few years, quinazolinones have been applied as prospective drug candidates, demonstrating diverse biological potency, including antimicrobial, anti-inflammatory, antimalarial, antiviral, and anticancer activities.[1] Structurally similar to quinazolinones, thieno[2,3-d]pyrimidin-4(3H)-ones (Figure [1]) also serve as a privileged structure in a variety of drug candidates.[2] A broad range of thieno[2,3-d]pyrimidin-4(3H)-ones[3] have been identified with properties such as antimycrobial and antibacterial activities,[4] or as 17β-HSD1 inhibitors,[5] and zinc-binding MMP-13 inhibitors,[6] as exemplified by the structures in Figure [1]. Therefore, the development of an efficient protocol towards a simple synthetic pathway for the formation of novel thieno[2,3-d]pyrimidin-4(3H)-ones is a valid aim in organic synthesis.

Zoom Image
Figure 1 Biologically relevant quinazolin-4(3H)-one and thieno[2,3-d]pyrimidin-4(3H)-one derivatives

Previously reported syntheses of 2,3-disubstituted thieno[2,3-b]pyrimidin-4(3H)-ones usually required more than two steps starting from 2-aminothiophene-3-carboxylic acid or its ester/carboxamide analogues.[4] [7] Harsh conditions such as POCl3, P2O5 or sodium, or reaction at elevated pressure were necessary for the pyrimidinone ring cyclization.[8] [9] [10] No protocols have yet been reported for the synthesis of 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones in a one-pot reaction.

In the case of quinazolinones, several one-pot protocols using commercially available starting materials, such as anthranilic acid esters, anthranilamide, anthranilonitrile, and isatoic anhydride are reported.[1a] [b] [c] , [11] For example, Maleki et al. synthesized 2,3-dihydroquinazolin-4(1H)-ones from isatoic anhydride, aldehydes and ammonium acetate, using a magnetic silica-based nanocomposite Fe3O4/SBA-15 as catalyst.[12] Applying H3PO3 as the catalyst, Balalaie et al. investigated a one-pot protocol for the efficient synthesis of spiroquinazolinone derivatives using hydrazides and cyclic ketones.[13] Isatoic anhydride was also the starting material in the development of potent antiviral agents by Brown et al.[14] We have recently reported a straightforward synthesis of rutaecarpine and its analogues by a fusion reaction using isatoic anhydrides and 4,9-dihydro-3H-pyrido[3,4-b]indole.[15] This protocol provided a simple and fast access to large quantities of rutaecarpine and its derivatives, avoiding tedious purification procedures.

Inspired by the general application of isatoic anhydride,[16] we envisaged a very similar compound, 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-dione, could be applied to the preparation of thieno-analogues of quinazolineones and enable their biological evaluations. Herein, we present our methodology for the one-pot, two-step, three-component synthesis of 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones.

Initially, we used 5,6,7,8-tetrahydro-2H-benzo[4,5]thieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1a; 1.5 mmol), 4-chlorobenzaldehyde (2a; 1 mmol), and phenylmethylamine (1.5 mmol) to investigate the reaction conditions (Table [1]). Although condensation reactions of isatoic anhydride, aldehydes and amines have been reported in the presence of numerous catalysts,[17] and under acidic conditions,[18] application of those protocols to 1a surprisingly failed to yield the ring-closed target compounds. For example, KAl(SO4)2·12H2O was found to be a reusable catalyst to obtain 2,3-dihydroquinazolin-4(1H)-ones.[19] However, when using the same catalyst, no 4a was formed when 1a was treated with 2a and phenylmethylamine and heating the reaction mixture at reflux (Table [1], entry 1). Brønsted acids such as p-TsOH and acetic acid also did not promote the fusion reaction. When the three components were heated in ethanol at reflux in the present of potassium hydroxide (entry 12), the obtained product was confirmed to be ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, the starting material 1a having reacted with the ethanol solvent.

Table 1 Optimization of the Conditions for the One-Pot Synthesis of 2,3-Disubstituted Thieno[2,3-d]pyrimidin-4(3H)-ones 4a

Entry

Solvent

Additives

Time (h)

Temp (°C)

Yield (%)a

1

EtOH

KAl(SO4)2·12H2O

20

reflux

b

2

EtOH

p-TsOH

20

reflux

b

3

AcOH

20

reflux

b

4

EtOH

K2CO3

20c

reflux

32

5

MeOH

K2CO3

24c

80

34

6

EtOH

Cs2CO3

24

r.t

b

7

EtOH

Cs2CO3

2.5c

reflux

51

8

MeOH

Cs2CO3

2.5c

80

43

9

MeOH

NaOH

3c

80

48

10

EtOH

Et3N

20c

reflux

b

11

EtOH

N,N-diisopropylamine

20c

reflux

b

12

EtOH

KOH

2

reflux

b

13

EtOH

KOH

2c

reflux

62

14

H2O

KOH

20c

reflux

b

15

MeOH

KOH

2c

80

51

16

DMF

KOH

3c

reflux

46

17

THF

KOH

3c

reflux

b

a Isolated yield.

b No product obtained.

c The mixture of 1a, 2a and phenethylamine was heated at reflux for 12 h before the addition of catalyst.

We then investigated heating the three components in ethanol in the absence of any Brønsted acid or base. Reaction progress was monitored by thin-layer chromatography (TLC) and a yellow spot was detected on TLC plate. Attempts at isolating the yellow compound by chromatography failed. Nevertheless, it could be easily purified by recrystallization from ethanol. After spectroscopic analysis, the yellow compound was confirmed as intermediate 3. It was proposed that, by an intramolecular cyclization strategy of intermediate 3, the desired disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones could be obtained. The protocol was thus modified accordingly. The starting materials 1a, 4-chlorobenzaldehyde 2a, and phenethylamine were heated in ethanol for 12 hours to be completely converted into intermediate 3. Afterwards, potassium carbonate was added to the reaction mixture and heating was continued for 2 h. In this way, the desired target compound 4a was obtained in 32% yield (Table [1], entry 4). To explore the reaction conditions systematically, different solvents and bases were screened. In general, protic solvents (except water) were tolerated for the reaction, but tetrahydrofuran (aprotic solvent) was detrimental (entry 17). Stronger inorganic bases, such as cesium carbonate, sodium hydroxide, and potassium hydroxide also promoted the formation of the desired product, but organic bases such as trimethylamine and N,N-diisopropylamine proved ineffective (entries 10 and 11). The best yields were obtained when the three components were heated in ethanol for 12 hours, followed by additional stirring at reflux in the presence of potassium hydroxide (entry 13). Thus, the overall conversion was achieved in a one-pot, two-step, three-component model.

After determination of optimal reaction conditions, we explored the scope of various substrates in this one-pot protocol for the synthesis of 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones (Scheme [1]).[20] In general, the reaction worked for a range of fused 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-diones including cyclohexyl-, cycloheptyl-, pyranyl-, and mono or dimethyl-substituted 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-diones. Aromatic aldehydes such as benzaldehyde or thiophene-2-carbaldehyde were applicable to the reaction. Generally, electron-donating groups on the aldehyde gave improved yields compared with electron-withdrawing groups. For example, the yield of compound 4d (with fluoro-substitution) was lower for compound 4c, whereas the yield of 4c was far lower than that of 4e (possessing a methoxy-group). A hydroxyl group was compatible with the reaction conditions. Without additional protection, compound 4f was obtained in 47% yield, although with a lower yield than for compound 4e. Interestingly, tyramine (with a free hydroxyl group) was a better substrate than benzylamine. This reaction system gave high yields for substrates possessing tetramethylene- and pentamethylene-containing substituents on the thiophene component (compounds 4l, 4j, 4aa and 4ab), when phenylethylamine was used as the third component.

Zoom Image
Scheme 1 One-pot synthesis of 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones

Given that the preparation of the starting ‘anhydride’ compounds did not require any chromatographic purification (see the Supporting Information), the reaction can easily be scaled up to provide larger amounts of target compounds. For example, compound 4m (1.1 g) was obtained from thiophene-2-carbaldehyde, tyramine 5,6,7,8-tetrahydro-2H-benzo[4,5]thieno[2,3-d][1,3]oxazine-2,4(1H)-dione. All of the synthetic compounds were characterized by 1H and 13C NMR and HRMS analyses. The structure of 4w was further confirmed by X-ray diffraction analysis, as shown in Figure [2].[21]

Zoom Image
Figure 2 Crystal structure of 4w (CCDC 1813089)[21]

In conclusion, although dozens of published one-pot procedures using isatoic anhydride as the starting material have been reported for the preparation of substituted quinazolinones, the protocols proved fruitless when applied to 2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-diones, to synthesize substituted thieno[2,3-d]pyrimidin-4(3H)-ones. By changing to the two-step, one-pot and three-component strategy, we have developed an efficient method to synthesize a wide range of 2,3,5,6-substituted thieno[2,3-d]pyrimidin-4(3H)-one derivatives in good to high yields (46–86%). This strategy is tolerant of a wide range of aromatic aldehydes and amines, and enables preparation of large quantities of target compounds.


#

Acknowledgment

Appreciation is expressed to Ms. Helimay Hemit for NMR measurements and to Ms. Dilaram Nijat for LCMS analysis.

Supporting Information

  • References and Notes

    • 1a Asif M. Int. J. Med. Chem. 2014; 395637
    • 1b Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2014; 76: 193
    • 1c Jafari E. Khajouei MR. Hassanzadeh F. Hakimelahi GH. Khodarahmi GA. Res. Pharm. Sci. 2016; 11: 1
    • 1d Khan I. Zaib S. Batool S. Abbas N. Ashraf Z. Iqbal J. Saeed A. Bioorg. Med. Chem. 2016; 24: 2361
    • 2a Bozorov K. Ma HR. Zhao JY. Zhao HQ. Chen H. Bobakulov K. Xin XL. Elmuradov B. Shakhidoyatov K. Aisa HA. Eur. J. Med. Chem. 2014; 84: 739
    • 2b Bozorov K. Nie LF. Zhao J. Aisa HA. Eur. J. Med. Chem. 2017; 140: 465
    • 2c Bozorov K. Zhao J. y. Nie LF. Ma H.-R. Bobakulov K. Hu R. Rustamova N. Huang G. Efferth T. Aisa HA. RSC Advances 2017; 7: 31417
    • 3a Dewal MB. Wani AS. Vidaillac C. Oupicky D. Rybak MJ. Firestine SM. Eur. J. Med. Chem. 2012; 51: 145
    • 3b Aly AA. Ishak EA. Ramadan M. Germoush MO. El-Emary TI. Al-Muaikel NS. J. Heterocycl. Chem. 2013; 50: 451
    • 3c Thiesen L. Kehler J. Clausen RP. Frølund B. Bundgaard C. Wellendorph P. J. Pharmacol. Exp. Ther. 2015; 354: 166
    • 3d Actis ML. Ambaye ND. Evison BJ. Shao Y. Vanarotti M. Inoue A. McDonald ET. Kikuchi S. Heath R. Hara K. Hashimoto H. Fujii N. Bioorg. Med. Chem. 2016; 24: 4339
    • 3e Wang X. Chen D. Yu S. Zhang Z. Wang Y. Qi X. Fu W. Xie Z. Ye F. Chem. Biol. Drug Des. 2016; 87: 499
    • 3f Nie LF. Bozorov K. Niu C. Huang G. Aisa HA. Res. Chem. Intermed. 2017; 43: 6835
    • 4a Narasimhan B. Kumari M. Jain N. Dhake A. Sundaravelan C. Bioorg. Med. Chem. Lett. 2006; 16: 4951
    • 4b Narender M. Bhandaru JS. Kulandaivelu U. Jojula M. Adidala RR. Umadevi KR. Dusthackeer AV. N. Kaki VR. Akkinepally RR. Bioorg. Med. Chem. Lett. 2016; 26: 836
  • 5 Lilienkampf A. Karkola S. Alho-Richmond S. Koskimies P. Johansson N. Huhtinen K. Vihko K. Wähälä K. J. Med. Chem. 2009; 52: 6660
  • 6 Nara H. Sato K. Kaieda A. Oki H. Kuno H. Santou T. Kanzaki N. Terauchi J. Uchikawa O. Kori M. Bioorg. Med. Chem. 2016; 24: 6149
  • 7 Mavrova AT. Dimov S. Yancheva D. Rangelov M. Wesselinova D. Tsenov JA. Eur. J. Med. Chem. 2016; 123: 69
  • 8 Abbas SE. Abdel Gawad NM. George RF. Akar YA. Eur. J. Med. Chem. 2013; 65: 195
  • 9 Ameen MA. Karsten S. Liebscher J. Tetrahedron 2010; 66: 2141
  • 10 Theoclitou M.-E. Aquila B. Block MH. Brassil PJ. Castriotta L. Code E. Collins MP. Davies AM. Deegan T. Ezhuthachan J. Filla S. Freed E. Hu H. Huszar D. Jayaraman M. Lawson D. Lewis PM. Nadella MV. P. Oza V. Padmanilayam M. Pontz T. Ronco L. Russell D. Whitston D. Zheng X. J. Med. Chem. 2011; 54: 6734
  • 11 Maiden TM. Harrity JP. Org. Biomol. Chem. 2016; 14: 8014
  • 12 Maleki A. Rabbani M. Shahrokh S. Appl. Organomet. Chem. 2015; 29: 809
  • 13 Tajbakhsh M. Ramezanpour S. Balalaie S. Bijanzadeh HR. J. Heterocycl. Chem. 2015; 52: 1559
  • 14 Brown CE. Kong T. McNulty J. D’Aiuto L. Williamson K. McClain L. Piazza P. Nimgaonkar VL. Bioorg. Med. Chem. Lett. 2017; 27: 4601
  • 15 Huang G. Roos D. Stadtmüller P. Decker M. Tetrahedron Lett. 2014; 55: 3607
    • 16a Abbas SY. El-Bayouki KA. M. Basyouni WM. Synth. Commun. 2016; 46: 993
    • 16b Zaytsev VP. Revutskaya EL. Nikanorova TV. Nikitina EV. Dorovatovskii PV. Khrustalev VN. Yagafarov NZ. Zubkov FI. Varlamov AV. Synthesis 2017; 49: 3749
    • 17a Chen J. Wu D. He F. Liu M. Wu H. Ding J. Su W. Tetrahedron Lett. 2008; 49: 3814
    • 17b Tamaddon F. Kazemi Varnamkhasti M. Synlett 2016; 27: 2510
  • 18 Ramesh R. Kalisamy P. Malecki JG. Lalitha A. Synlett 2018; 29: 203
  • 19 Bardajee RG. Ghaedi A. Hekmat S. Abarashi G. Mahdavi M. Akbarzadeh T. J. Sulfur Chem. 2017; 38: 519
  • 20 Synthesis of 4a–ag; General ProcedureA mixture of 2H-benzo[4,5]thieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.366 mmol, 1.5 equiv), amine (0.366 mmol, 1.5 equiv) and aldehyde (0.244 mmol, 1.0 equiv) in EtOH was heated to reflux for 10–14 h. After TLC indicated that the aldehyde had been completely consumed, KOH (0.488 mmol, 2.0 equiv) was added and the mixture was heated to reflux for a further 6–10 h. Upon completion of the reaction (verified by TLC), the mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate (10:1–2:1) to obtain the pure product.3-Benzyl-2-(4-chlorophenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4a): Yield: 62%; white solid; m.p. 157–159 °C; 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 8.1 Hz, 2 H), 7.30–7.19 (m, 4 H), 6.94 (t, J = 2.4 Hz, 2 H), 5.23 (s, 2 H), 3.08 (t, J = 5.1 Hz, 2 H), 2.81 (t, J = 5.6 Hz, 2 H), 2.02–1.82 (m, 4 H); 13C NMR (100 MHz, CDCl3): δ = 161.37 (CON), 158.81, 154.72, 136.68, 136.38, 134.74, 133.46, 132.01, 129.74 (2×CH), 128.92 (2×CH), 128.82 (2×CH), 127.65, 126.80 (2×CH),121.52, 48.49 (CH2Ph), 25 .78 (CH2), 25.48 (CH2), 23.09 (CH2), 22.42 (CH2). HRMS: m/z [M+H]+ calcd for C23H20ClN2OS: 407.09849; found: 407.09697.2-(4-Fluorophenyl)-3-(4-hydroxyphenethyl)-3,5,6,8-tetrahydro-4H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one (4w): Yield: 62%; white solid; m.p.247–249 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 9.23 (s, 1 H), 7.62–7.50 (m, 2 H), 7.42–7.30 (m, 2 H), 6.71–6.55 (m, 4 H), 4.78 (s, 2 H), 4.02–3.88 (m, 4 H), 3.03 (t, J = 4.5 Hz, 2 H), 2.69 (t, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, DMSO-d 6): δ = 163.80 (CF), 161.34, 161.28, 157.59 (NCO), 155.99 (CPhOH), 155.11, 131.40, 130.83, 130.63/ 130.54, 129.27 (2×CH), 128.47, 127.76, 120.17, 115.48/115.27, 115.29 (2×CH), 64.36 (CH2), 63.94 (CH2), 46.99 (CH2N), 32.92 (CH2Ph), 26.02 (CH2); HRMS: m/z [M+H]+ calcd for C23H20FN2O3S: 423.11787; found: 423.11631.
  • 21 CCDC 1813089 contains the supplementary crystallographic data for compound 4w. The data can be obtained free of charge from www.ccdc.cam.ac.uk/getstructures

  • References and Notes

    • 1a Asif M. Int. J. Med. Chem. 2014; 395637
    • 1b Khan I. Ibrar A. Abbas N. Saeed A. Eur. J. Med. Chem. 2014; 76: 193
    • 1c Jafari E. Khajouei MR. Hassanzadeh F. Hakimelahi GH. Khodarahmi GA. Res. Pharm. Sci. 2016; 11: 1
    • 1d Khan I. Zaib S. Batool S. Abbas N. Ashraf Z. Iqbal J. Saeed A. Bioorg. Med. Chem. 2016; 24: 2361
    • 2a Bozorov K. Ma HR. Zhao JY. Zhao HQ. Chen H. Bobakulov K. Xin XL. Elmuradov B. Shakhidoyatov K. Aisa HA. Eur. J. Med. Chem. 2014; 84: 739
    • 2b Bozorov K. Nie LF. Zhao J. Aisa HA. Eur. J. Med. Chem. 2017; 140: 465
    • 2c Bozorov K. Zhao J. y. Nie LF. Ma H.-R. Bobakulov K. Hu R. Rustamova N. Huang G. Efferth T. Aisa HA. RSC Advances 2017; 7: 31417
    • 3a Dewal MB. Wani AS. Vidaillac C. Oupicky D. Rybak MJ. Firestine SM. Eur. J. Med. Chem. 2012; 51: 145
    • 3b Aly AA. Ishak EA. Ramadan M. Germoush MO. El-Emary TI. Al-Muaikel NS. J. Heterocycl. Chem. 2013; 50: 451
    • 3c Thiesen L. Kehler J. Clausen RP. Frølund B. Bundgaard C. Wellendorph P. J. Pharmacol. Exp. Ther. 2015; 354: 166
    • 3d Actis ML. Ambaye ND. Evison BJ. Shao Y. Vanarotti M. Inoue A. McDonald ET. Kikuchi S. Heath R. Hara K. Hashimoto H. Fujii N. Bioorg. Med. Chem. 2016; 24: 4339
    • 3e Wang X. Chen D. Yu S. Zhang Z. Wang Y. Qi X. Fu W. Xie Z. Ye F. Chem. Biol. Drug Des. 2016; 87: 499
    • 3f Nie LF. Bozorov K. Niu C. Huang G. Aisa HA. Res. Chem. Intermed. 2017; 43: 6835
    • 4a Narasimhan B. Kumari M. Jain N. Dhake A. Sundaravelan C. Bioorg. Med. Chem. Lett. 2006; 16: 4951
    • 4b Narender M. Bhandaru JS. Kulandaivelu U. Jojula M. Adidala RR. Umadevi KR. Dusthackeer AV. N. Kaki VR. Akkinepally RR. Bioorg. Med. Chem. Lett. 2016; 26: 836
  • 5 Lilienkampf A. Karkola S. Alho-Richmond S. Koskimies P. Johansson N. Huhtinen K. Vihko K. Wähälä K. J. Med. Chem. 2009; 52: 6660
  • 6 Nara H. Sato K. Kaieda A. Oki H. Kuno H. Santou T. Kanzaki N. Terauchi J. Uchikawa O. Kori M. Bioorg. Med. Chem. 2016; 24: 6149
  • 7 Mavrova AT. Dimov S. Yancheva D. Rangelov M. Wesselinova D. Tsenov JA. Eur. J. Med. Chem. 2016; 123: 69
  • 8 Abbas SE. Abdel Gawad NM. George RF. Akar YA. Eur. J. Med. Chem. 2013; 65: 195
  • 9 Ameen MA. Karsten S. Liebscher J. Tetrahedron 2010; 66: 2141
  • 10 Theoclitou M.-E. Aquila B. Block MH. Brassil PJ. Castriotta L. Code E. Collins MP. Davies AM. Deegan T. Ezhuthachan J. Filla S. Freed E. Hu H. Huszar D. Jayaraman M. Lawson D. Lewis PM. Nadella MV. P. Oza V. Padmanilayam M. Pontz T. Ronco L. Russell D. Whitston D. Zheng X. J. Med. Chem. 2011; 54: 6734
  • 11 Maiden TM. Harrity JP. Org. Biomol. Chem. 2016; 14: 8014
  • 12 Maleki A. Rabbani M. Shahrokh S. Appl. Organomet. Chem. 2015; 29: 809
  • 13 Tajbakhsh M. Ramezanpour S. Balalaie S. Bijanzadeh HR. J. Heterocycl. Chem. 2015; 52: 1559
  • 14 Brown CE. Kong T. McNulty J. D’Aiuto L. Williamson K. McClain L. Piazza P. Nimgaonkar VL. Bioorg. Med. Chem. Lett. 2017; 27: 4601
  • 15 Huang G. Roos D. Stadtmüller P. Decker M. Tetrahedron Lett. 2014; 55: 3607
    • 16a Abbas SY. El-Bayouki KA. M. Basyouni WM. Synth. Commun. 2016; 46: 993
    • 16b Zaytsev VP. Revutskaya EL. Nikanorova TV. Nikitina EV. Dorovatovskii PV. Khrustalev VN. Yagafarov NZ. Zubkov FI. Varlamov AV. Synthesis 2017; 49: 3749
    • 17a Chen J. Wu D. He F. Liu M. Wu H. Ding J. Su W. Tetrahedron Lett. 2008; 49: 3814
    • 17b Tamaddon F. Kazemi Varnamkhasti M. Synlett 2016; 27: 2510
  • 18 Ramesh R. Kalisamy P. Malecki JG. Lalitha A. Synlett 2018; 29: 203
  • 19 Bardajee RG. Ghaedi A. Hekmat S. Abarashi G. Mahdavi M. Akbarzadeh T. J. Sulfur Chem. 2017; 38: 519
  • 20 Synthesis of 4a–ag; General ProcedureA mixture of 2H-benzo[4,5]thieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.366 mmol, 1.5 equiv), amine (0.366 mmol, 1.5 equiv) and aldehyde (0.244 mmol, 1.0 equiv) in EtOH was heated to reflux for 10–14 h. After TLC indicated that the aldehyde had been completely consumed, KOH (0.488 mmol, 2.0 equiv) was added and the mixture was heated to reflux for a further 6–10 h. Upon completion of the reaction (verified by TLC), the mixture was concentrated under reduced pressure and purified by silica gel chromatography, eluting with petroleum ether/ethyl acetate (10:1–2:1) to obtain the pure product.3-Benzyl-2-(4-chlorophenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4a): Yield: 62%; white solid; m.p. 157–159 °C; 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 8.1 Hz, 2 H), 7.30–7.19 (m, 4 H), 6.94 (t, J = 2.4 Hz, 2 H), 5.23 (s, 2 H), 3.08 (t, J = 5.1 Hz, 2 H), 2.81 (t, J = 5.6 Hz, 2 H), 2.02–1.82 (m, 4 H); 13C NMR (100 MHz, CDCl3): δ = 161.37 (CON), 158.81, 154.72, 136.68, 136.38, 134.74, 133.46, 132.01, 129.74 (2×CH), 128.92 (2×CH), 128.82 (2×CH), 127.65, 126.80 (2×CH),121.52, 48.49 (CH2Ph), 25 .78 (CH2), 25.48 (CH2), 23.09 (CH2), 22.42 (CH2). HRMS: m/z [M+H]+ calcd for C23H20ClN2OS: 407.09849; found: 407.09697.2-(4-Fluorophenyl)-3-(4-hydroxyphenethyl)-3,5,6,8-tetrahydro-4H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one (4w): Yield: 62%; white solid; m.p.247–249 °C; 1H NMR (400 MHz, DMSO-d 6): δ = 9.23 (s, 1 H), 7.62–7.50 (m, 2 H), 7.42–7.30 (m, 2 H), 6.71–6.55 (m, 4 H), 4.78 (s, 2 H), 4.02–3.88 (m, 4 H), 3.03 (t, J = 4.5 Hz, 2 H), 2.69 (t, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, DMSO-d 6): δ = 163.80 (CF), 161.34, 161.28, 157.59 (NCO), 155.99 (CPhOH), 155.11, 131.40, 130.83, 130.63/ 130.54, 129.27 (2×CH), 128.47, 127.76, 120.17, 115.48/115.27, 115.29 (2×CH), 64.36 (CH2), 63.94 (CH2), 46.99 (CH2N), 32.92 (CH2Ph), 26.02 (CH2); HRMS: m/z [M+H]+ calcd for C23H20FN2O3S: 423.11787; found: 423.11631.
  • 21 CCDC 1813089 contains the supplementary crystallographic data for compound 4w. The data can be obtained free of charge from www.ccdc.cam.ac.uk/getstructures

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Figure 1 Biologically relevant quinazolin-4(3H)-one and thieno[2,3-d]pyrimidin-4(3H)-one derivatives
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Scheme 1 One-pot synthesis of 2,3-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones
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Figure 2 Crystal structure of 4w (CCDC 1813089)[21]