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Article

Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas †

by
Svetlana O. Baykova
,
Kirill K. Geyl
,
Sergey V. Baykov
and
Vadim P. Boyarskiy
*
Institute of Chemistry, Saint Petersburg State University, 7/9 Universitetskaya Nab., Saint Petersburg 199034, Russia
*
Author to whom correspondence should be addressed.
†
In commemoration of the 300th anniversary of Saint Petersburg State University’s founding.
Int. J. Mol. Sci. 2023, 24(8), 7633; https://doi.org/10.3390/ijms24087633
Submission received: 29 March 2023 / Revised: 18 April 2023 / Accepted: 19 April 2023 / Published: 21 April 2023
(This article belongs to the Special Issue Heterocyclic and Heteroatom Compounds: Design, Synthesis, and Applications)
Browse Figures
Versions Notes

Abstract

:
A new route for the synthesis of quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones substituted by pyridyl/quinolinyl moiety in position 3 has been developed. The proposed method concluded in an annulation of substituted anthranilic esters or 2-aminothiophene-3-carboxylates with 1,1-dimethyl-3-(pyridin-2-yl) ureas. The process consists of the formation of N-aryl-N′-pyridyl ureas followed by their cyclocondensation into the corresponding fused heterocycles. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields (up to 89%). The scope of the method is more than 30 examples, including compounds with both electron-withdrawing and electron-donating groups, as well as diverse functionalities. At the same time, strong electron-acceptor substituents in the pyridine ring of the starting ureas reduce the product yield or even prevent the cyclocondensation step. The reaction can be easily scaled to gram quantities.

1. Introduction

The quinazoline-2,4-dione fragment is part of many clinical candidates: selurampanel (an AMPA/kainate receptor antagonist for epilepsy treatment) [1,2], elinogrel (a P2Y12 receptor antagonist for the treatment of cardiovascular atherothrombotic disease) [3,4,5], zenarestat (an aldose reductase inhibitor for the management of diabetic peripheral neuropathy) [6,7], ketanserin (a 5-HT2 receptor antagonist with the hypotensive action) [8,9], carotegrast (α4 integrin antagonist for the treatment of ulcerative colitis) [10,11], senaparib (a PARP inhibitor for the therapy of solid tumors) [12,13,14], and BMS-986142 (a Bruton’s tyrosine kinase inhibitor for the treatment of rheumatoid arthritis) [15,16,17]. In addition, quinazoline-2,4-dione derivatives were recognized as inhibitors of several cancer-related enzymes [18] (including carbonic anhydrases IX and XII [19], histone deacetylase-6 [20], VEGFR-2 [21], tankyrases [22], aminopeptidase [23]) and as modulators of autoimmune processes [24,25,26,27]. Moreover, they are widely used to combat viral [28,29], bacterial [30,31,32], parasitic [33,34,35], and fungal [36] infections.
Thienopyrimidine-2,4-diones is another class of medicinally important annulated dicarbonyl heterocycles [37]. These compounds found application in the design of gonadotropin-releasing hormone receptor antagonists [38,39,40,41,42,43] and acetyl-CoA carboxylase inhibitors [44,45,46].
In agriculture, both scaffolds (quinazoline-2,4-diones and thienopyrimidine-2,4-diones) are employed for weed control [47,48].
Among the quinazoline and thienopyrimidine diones described in the literature, most of the compounds contain a substituent in position 3. The biological significance causes the emergence of a number of methods for the synthesis of 3-substituted quinazoline-2,4-diones, including (i) the treatment of 2-aminobenzamides with phosgene, (ii) the reaction of isatoic anhydride with amines or isocyanates, (iii) the condensation of 2-halobenzoates with monoalkylureas, (iv) Baeyer–Villiger oxidation of 4-iminoisatins, (v) the three-component catalytic condensation of 2-haloanilines with CO2 and isocyanides (Scheme 1) [49,50]. Instead of phosgene, various phosgene surrogates can be used as a carbonylating agent, including phenylisocyanate [51] or Troc-group [52]. Recently, an alternative route for the synthesis of quinazoline-2,4-diones has been proposed, which consists of benzannulation strategy—the heteroaromatic condensed system is created by closing not the hetero-, but the carbocycle (Scheme 1, route vi) [53]. All these methods have a number of disadvantages; for example, poorly available or highly toxic reagents, harsh reaction conditions, difficulty in purifying target products, and low yields. Despite this, the synthesis of 3-substituted quinazolin-2,4-diones is still attractive due to their potential therapeutic application. Therefore, the development of convenient methods for the synthesis of new quinazolin-2,4-dione derivatives is an important task for organic and medicinal chemistry.
The access to 3-substituted thienopyrimidine-2,4-diones is another significant point that does not have a convenient and general synthetic solution. In the literature, only two methods for the preparation of these compounds are described. One of them is a nucleophilic attack of an aminothiophene derivative on an isocyanate in the presence of a catalytic amount of triethylamine in refluxing 1,4-dioxane followed by treatment of formed intermediates with NaOR in refluxing ROH [54,55,56]. The other is a reaction of aminothiophene carboxamides with 2,2,6-trimethyl-4H-1,3-dioxin-4-one in xylene followed by formed enamino amides’ fragmentation and cyclization [57].
Another significant goal is the introduction of the pyridyl moiety into organic molecules. In addition to being important pharmacophore themselves, this heterocycle can improve pharmacokinetic properties such as aqueous solubility and permeability through biological membranes. Therefore, it is of considerable interest to find convenient access to quinazolin-2,4-diones substituted in position 3 with pyridyl moiety. Unfortunately, a general synthetic method for obtaining a wide range of substituted 3-(pyridin-2-yl)quinazolin-2,4-diones is unknown hitherto. One of the best synthetic approaches to these compounds is a copper-catalyzed domino C–C bond cleavage of 2,3-unsubstituted indole/indolines/oxindoles through oxidation followed by insertion of 2-aminopyridines [58]. However, this method utilizes pyridine-2-amines, which are characterized by insufficient diversity and a rather high cost of commercially available compounds.
At present, our research is focused on the development of simple methods for introducing pyridin-2-yl and quinolin-2-yl fragments into organic and organometallic compounds based on the use of masked isocyanates—N,N-dialkyl-N′-(pyridine-2-yl)ureas [59,60,61,62,63,64]. These compounds are easily synthesized from the corresponding pyridines [65,66,67,68]. In this paper, we report a simple one-step protocol for the synthesis of 3-pyridyl-substituted quinazoline- and thienopyrimidine-2,4-diones from anthranilic or 2-aminothiophene-3-carboxylic acid esters that uses this approach. Taking into account the wide range of commercially available pyridines, the proposed method has potential in the design of pharmaceutically relevant fused heterocycles.

2. Results and Discussion

Recently, we described the reaction of N-pyridyl ureas with a broad spectrum of amines [59]. During this study, the reaction of 1,1-dimethyl-3-(4-methylpyridin-2-yl)urea (1a) with anthranilic acid ethyl ester 2a was carried out and unexpectedly quinazoline-2,4-dione 3a was identified as the main product (the isolated yield of 51%). The more detailed study showed that the initially formed ethyl 2-(3-(5-methylpyridin-2-yl)ureido)benzoate (4a) undergoes further cyclocondensation under the reaction conditions to afford quinazolin-2,4-dione 3a (Scheme 2).
Product 3a was characterized by high-resolution mass spectrometry and 1H and 13C NMR spectroscopies. The structure of the compound was confirmed by single-crystal X-ray diffraction (XRD, Figure 1 and Table S1).
We investigated the influence of the reaction conditions on the yield of 3a (Table 1). We have determined that increasing the reaction time and temperature does not affect the yield (Table 1, entries 1 and 2). We enlarged the excess of anthranilic acid ethyl ester 2a step by step in the reaction mixture and found that 5 equiv. of the one affords a higher yield (Table 1, entries 3–5). Then, we carried out the reaction under solvent-free conditions and the desired product 3a was obtained in a better yield (Table 1, entry 6). A further increase in the 2a excess reduced the yield of the product (Table 1, entry 7), so for the further experiments we used a 5-fold excess. Finally, we tested whether anthranilic acid could be used instead of its ester and found that the desired quinazoline-2,4-dione 3a was formed, albeit in a lower yield (Table 1, entry 8).
After finding the optimal reaction conditions, we determined the range of possible substrates that can participate in the process. First, we studied various substituted (pyridin-2-yl)ureas 1 and showed that the reaction proceeds in all cases, but the reaction yields vary. This indicates the sensitivity of the reaction to electronic effects of substituents in the pyridine ring (Scheme 3), but the nature of this influence is ambiguous. It can be said that electron-donating groups in positions 4 and 5 of the pyridine ring have a positive effect on the yields of quinazoline-2,4-diones 3. The presence of two methyl groups at positions 3 and 5 of the pyridine ring (ortho and para with respect to the nitrogen atom of the ureide fragment entering into the cyclocondensation) provides the target product 3e with the highest yield (86%). It should be noted that quinazoline-2,4-dione 3c bearing 5-methylpyridyl moiety was obtained in a slightly lower yield (48%).
The presence of electron-withdrawing groups in the heterocyclic ring also decreased the yield of products 3. Perhaps this is due to such substituents adversely affecting the cyclocondensation step. Particularly, in the case of the substrate containing a nitro-group at position 4 of the pyridine ring, the desired quinazoline-2,4-dione was formed in only 19% yield (according to 1H NMR data for the reaction mixture), whereas the main product was the corresponding intermediate urea. Moreover, the presence of the electron-withdrawing cyano-group in position 5 (para with respect to the nitrogen atom of the ureide fragment) completely suppressed the cyclocondensation. In this case, urea 4b was isolated in 40% yield as the main product. The prolonged heating of 4b at 120 °C only led to its degradation to the 2-aminopyridine 5 and the starting anthranilic acid ethyl ester 2a (Scheme 4).
Substituents in position 6 of the starting N–pyridylureas 1 slightly reduced the yield of target quinazolin-2,4-diones 3 (Scheme 3). The reason for this is the steric hindrances, but their effect is not very significant. Therefore, using ureas bearing quinoline and isoquinoline moieties 1l–q as starting compounds, we synthesized 6 corresponding quinazolin-2,4-diones (3l–q) in moderate to good yields (47–78%, Scheme 3).
Next, we checked the possibility of synthesizing quinazolin-2,4-diones bearing substituents in the quinazoline fragment via the developed procedure. For this goal, the scope of functionalized anthranilic esters was investigated. Reactions were carried out with 1.5 equiv. of esters 2b–j in DMF at 120 °C. We found that neither electron-donating nor electron-withdrawing substituents prevented the reaction and the corresponding quinazolin-2,4-diones (3r–x,z) were successfully obtained in 47–89% yields (Scheme 5). In addition, this method allows us to obtain N1-alkylsubstituted quinazolin-2,4-diones, however, with less yield. Particularly, the reaction between urea 1a and N-methyl anthranilic ester 2h provided target product 3y with 32% yield only. Presumably, such poor yield of 3y is caused by instability of N-alkyl-N-aryl urea (the proposed intermediate) in the reaction conditions and its side transformation into 1,3-bis(4-methylpyridin-2-yl)urea, which was also detected in the reaction mixture. This process was described in our previous work [59].
To expand the reaction scope, we studied the reactivity 2-aminothiophene-3-carboxylates (products of the Gewald reaction) in this process. It turned out that when ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a) was used as a starting amine, the reaction stopped at the stage of the urea 7a formation and any traces of a desired thienopyrimidine-2,4-dione were not observed in the reaction mixture (Scheme 6).
Then, the conditions search for the implementation of the cyclocondensation was performed. Since the occurrence of similar reactions under basic conditions is described in the literature [50,69], we tested several bases and t-BuONa gave the best results. Having chosen the conditions for the cyclocondensation of the intermediate urea 7, we synthesized thienopyrimidine-2,4-diones 8a–f in the overall yield of 35–56% according to the two-stage one-pot procedure (Scheme 7).
Finally, to highlight the practicality of this method, the scale-up syntheses of quinazoline-2,4-dione 3a and thienopyrimidine-2,4-dione 8a were performed (Scheme 8).

3. Material and Methods

3.1. General

The starting N-oxides, used to obtain the N-piridyl ureas, were synthesized according to the literature procedures [65,70,71,72]. All other reagents and solvents were purchased and were used as is. Column chromatography was carried out with silica gel grade 60 (0.040–0.063 mm) 230–400. NMR spectra were recorded on Bruker Avance DPX 400 (400 MHz, 101 MHz, and 376 MHz for 1H, 13C, and 19F, respectively) in DMSO–d6 or CDCl3. Chemical shifts are reported as parts per million (δ, ppm). The 1H and 13C spectra were calibrated using the residual signals of nondeuterated solvents as internal reference (2.50 ppm for residual 1H and 39.50 ppm for 13C in DMSO–d6, 7.26 ppm for residual 1H and 77.16 ppm for 13C in CDCl3). 19F NMR spectra were referenced through the solvent lock (2H) signal according to IUPAC recommended secondary referencing method and the manufacturer’s protocols and the chemical shifts are reported relative to CFCl3 (δ 0.0 ppm). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants, J, are reported in Hertz (Hz). Melting points were determined in open capillary tubes on Electrothermal IA 9300 series digital melting point apparatus. High–resolution mass spectra (HRMS) were measured on Bruker Maxis HRMS–ESI–qTOF (ESI ionization).
Singe crystal for X-ray studying was obtained by slow evaporation of DMSO solution of quinazoline-2,4,-dione 3a at RT in air. X-ray diffraction data were collected via Rigaku XtaLAB Synergy–S diffractometer using CuKα (λ = 0.154184 nm) radiation. The structure was solved with the ShelXT [73] structure solution program using intrinsic phasing and refined with the ShelXL [74] refinement program incorporated in the OLEX2 program package [75] using least squares minimization. Empirical absorption correction was applied in the CrysAlisPro [76] program complex using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Supplementary crystallographic data for this paper have been deposited at Cambridge Crystallographic Data Centre and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (CCDC number 2249286) (accessed on 28 March 2023).

3.2. Preparation of Starting Ureas 1a–r

Ureas 1a–d,f,i–k,r [65], 1e,g,m [59], 1l,q [61] were prepared according to the previously reported protocols. Ureas 1h,n–p were synthesized and characterized for the first time.
Synthesis of methyl 6-(3,3-dimethylureido)picolinate 1h. A mixture of N-oxide (1 mmol), dimethylcyanamide (1.5 mmol), and acetonitrile (2 mL, 20 mmol) was stirred at RT for 2 min, and then methanesulfonic acid (1.5 mmol) was added dropwise over 3 min. Then, the reaction mixture was gently heated to 60 °C and stirred for 3 h, cooled to RT, diluted with a saturated aq. Na2CO3 (2 mL) and aq. NaCl solution (5 mL) and extracted with ethyl acetate (4×15 mL). Combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated in a rotary evaporator. The crude product was subjected to column chromatography on silica gel (EtOAc/hexane) to give target urea 1h in 40% yield (90 mg) as a light-yellow powder; mp 74–75 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 7.7, 1.5 Hz, 1H), 7.74–7.82 (m, 2H), 7.48 (s, 1H), 3.98 (s, 3H), 3.07 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.5, 154.9, 153.2, 145.5, 139.0, 119.8, 117.3, 52.9, 36.6 (2C). HRMS (ESI), m/z: [M + Na]+ calcd. for C10H13N3O3 246.0849; found 246.0849.
Synthesis of ureas 1n–p. A mixture of substituted quinoline N-oxide (1 mmol), dimethylcyanamide (2 mmol), and acetonitrile (0.5 mL, 5 mmol) was stirred at RT for 2 min, and then methanesulfonic acid (1.1 mmol) was added dropwise over 3 min. Then, the reaction mixture was gently heated to 60 °C and stirred for 2 h, cooled, and diluted with a saturated aq. Na2CO3 (2 mL) and distilled water (5 mL). The precipitate formed was filtered off, washed with diethyl ether (10 mL) to give compounds 1n–p.
1,1-Dimethyl-3-(6-methylquinolin-2-yl)urea 1n. Beige powder; 47 yield (108 mg); mp 140–141 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 3.11 (s, 6H), 2.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.1, 152.0, 145.2, 137.6, 134.2, 132.0, 126.7 (2C), 125.9, 114.2, 36.6 (2C), 21.4. HRMS (ESI), m/z: [M + H]+ calcd. for C13H15N3O 230.1287; found 230.1290.
1,1-Dimethyl-3-(7-methylquinolin-2-yl)urea 1o. Beige powder; 51% yield (117 mg); mp 101–103 °C. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.05 (s, 1H), 7.80–7.42 (m, 3H), 7.22 (d, J = 8.2 Hz, 1H), 3.09 (s, 6H), 2.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.1, 152.7, 147.0, 140.8, 140.2, 138.0, 127.3, 126.7, 126.1, 113.3, 36.6 (2C), 22.0. HRMS (ESI), m/z: [M + H]+ calcd. for C13H15N3O 230.1288; found 230.1290.
3-(6-Methoxyquinolin-2-yl)-1,1-dimethylurea 1p. Beige powder; 99% yield (242 mg); mp 56–58 °C. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.51 (br s, 1H), 7.30 (dd, J = 9.2, 2.9 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 3.92 (s, 3H), 3.11 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 156.5, 155.3, 150.9, 142.3, 137.2, 128.2, 126.5, 122.1, 114.6, 105.8, 55.6, 36.6 (2C). HRMS (ESI), m/z: [M + H]+ calcd. for C13H15N3O2 246.1237; found 246.1226.

3.3. Synthesis of Quinazoline-2,4-Diones 3

General procedure A. Urea 1 (0.2 mmol) and ethyl anthranilate 2 (1 mmol) were placed in a vial and the resulting mixture was stirred at 120 °C for 20 h. The reaction mixture was cooled to RT, treated with diethyl ether (5 mL), and the precipitate was separated, then the precipitate was washed with diethyl ether to give compounds 3a–q.
General procedure B. Urea 1 (0.2 mmol), substituted ethyl anthranilate 2 (1 mmol), and DMF (0.1 mL) were placed in a vial and the resulting mixture was stirred at 120 °C for 20 h. The reaction mixture was cooled to RT, DMF was removed by a rotary evaporator, and the residue was treated with diethyl ether (5 mL). The resulting precipitate was separated and washed with diethyl ether to give compounds 3r–z.
3-(4-Methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3a [58]. White powder; 70% yield (35 mg); mp 266–268 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.51–8.41 (m, 1H), 7.99–7.89 (m, 1H), 7.78–7.67 (m, 1H), 7.39–7.31 (m, 2H), 7.31–7.20 (m, 2H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 149.9, 149.7, 149.2, 148.9, 139.9, 135.5, 127.5, 125.0, 124.8, 122.8, 115.4, 114.1, 20.3. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H11N3O2 276.0743; found 276.0750.
3-(Pyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3b [58]. White powder; 57% yield (27 mg); mp 266–267 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.63–8.58 (m, 1H), 8.00 (td, J = 7.7, 1.9 Hz, 1H), 7.95 (dd, J = 8.3, 1.6 Hz, 1H), 7.76–7.70 (m, 1H), 7.54–7.48 (m, 2H), 7.28–7.22 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 149.9, 149.3, 149.3, 139.9, 138.7, 135.5, 127.5, 124.4, 124.1, 122.7, 115.4, 114.5. HRMS (ESI), m/z: [M + Na]+ calcd. for C13H9N3O2 262.0587; found 262.0587.
3-(5-Methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3c [58]. White powder; 65% yield (33 mg); mp 230–232 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.97–7.91 (m, 1H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 7.75–7.68 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.27–7.20 (m, 2H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 150.0, 149.3, 146.8, 139.9, 138.9, 135.4, 133.6, 127.5, 123.6, 122.7, 115.4, 114.2, 17.5. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H11N3O2 276.0743; found 276.0745.
3-(6-Methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3d [58]. White powder; 48% yield (24 mg); mp 285–287 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.94 (dd, J = 8.3, 1.6 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.75–7.68 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.27–7.21 (m, 2H), 2.49 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 158.1, 149.9, 148.5, 139.9, 138.8, 135.4, 127.4, 123.4, 122.7, 121.3, 115.4, 114.2, 23.6. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H11N3O2 276.0743; found 276.0747.
3-(3,5-Dimethylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3e. White powder; 86% yield (46 mg); mp 261–263 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.77–7.70 (m, 1H), 7.69–7.64 (m, 1H), 7.31–7.23 (m, 2H), 2.35 (s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.7, 149.4, 147.0, 145.8, 140.0 (2C), 135.6, 133.9, 131.0, 127.5, 122.9, 115.5, 113.9, 17.3, 16.2. HRMS (ESI), m/z: [M + Na]+ calcd. for C15H13N3O2 290.0900; found 290.0905.
3-(4-Methoxypyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3f. White powder; 79% yield (42 mg); mp 240–242 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.40 (d, J = 5.8 Hz, 1H), 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.76–7.69 (m, 1H), 7.28–7.22 (m, 2H), 7.15 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 5.8, 2.5 Hz, 1H), 3.86 (s, 3H). 13C NMR (101 MHz, DMSO) δ 167.1, 162.0, 150.8, 150.1, 149.8, 139.9, 135.5, 127.5, 122.7, 115.4, 114.2, 110.5, 110.4, 55.8. HRMS (ESI), m/z: [M + H]+ calcd. for C14H11N3O3 270.0873; found 270.0877.
3-(6-Phenylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3g. White powder; 42% yield (26 mg); mp 279–280 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.13–8.01 (m, 4H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.78–7.71 (m, 1H), 7.54–7.44 (m, 4H), 7.31–7.23 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.1, 156.3, 149.9, 149.2, 140.0, 139.8, 137.7, 135.5, 129.4, 128.8, 127.5, 126.7, 123.0, 122.8, 120.4, 115.5, 114.2. HRMS (ESI), m/z: [M + Na]+ calcd. for C19H13N3O2 338.0900; found 338.0902.
Methyl 6-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)picolinate 3h. Light beige powder; 51% yield (30 mg); mp 247–249 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.26–8.16 (m, 2H), 7.99–7.93 (m, 1H), 7.82 (dd, J = 7.5, 1.3 Hz, 1H), 7.78–7.72 (m, 1H), 7.32–7.24 (m, 2H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.5, 162.1, 149.8, 149.3, 147.3, 140.3, 140.0, 135.6, 128.4, 127.5, 125.2, 122.9, 115.5, 114.1, 52.6. HRMS (ESI), m/z: [M + Na]+ calcd. for C15H11N3O4 320.0642; found 320.0638.
Methyl 2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)isonicotinate 3i. Beige powder; 56% yield (33 mg); mp 233–235 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.83 (dd, J = 5.0, 0.8 Hz, 1H), 8.10–8.01 (m, 1H), 7.99–7.92 (m, 2H), 7.77–7.70 (m, 1H), 7.29–7.23 (m, 2H), 3.93 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.5, 162.2, 150.6, 150.5, 149.9, 140.0, 139.5, 135.5, 127.5, 123.7, 123.0, 122.8, 115.5, 114.2, 53.0. HRMS (ESI), m/z: [M + H]+ calcd. for C15H11N3O4 298.0822; found 298.0836.
6-(2,4-Dioxo-1,4-dihydroquinazolin-3(2H)-yl)picolinonitrile 3j. Light beige powder; 55% yield (29 mg); mp 295–297 °C (dec.). 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.31 (t, J = 7.8 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.01–7.90 (m, 2H), 7.79–7.72 (m, 1H), 7.32–7.22 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.0, 150.4, 149.6, 141.0, 140.0, 135.7, 132.0, 129.6, 129.4, 127.5, 122.9, 116.7, 115.6, 114.0. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H8N4O2 287.0539; found 287.0541.
2-(2,4-Dioxo-1,4-dihydroquinazolin-3(2H)-yl)isonicotinonitrile 3k. White powder; 30% yield (16 mg); mp 306–308 °C (dec.). 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.90 (d, J = 5.1 Hz, 1H), 8.16–8.09 (m, 1H), 8.03 (dd, J = 5.0, 1.5 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.79–7.73 (m, 1H), 7.31–7.24 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.0, 151.0, 150.2, 149.6, 139.9, 135.8, 127.5, 126.7, 126.2, 123.0, 121.6, 116.1, 115.6, 114.0. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H8N4O2 287.0539; found 287.0536.
3-(Quinolin-2-yl)quinazoline-2,4(1H,3H)-dione 3l. White powder; 60% yield (35 mg); mp 256–259 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.87–7.82 (m, 1H), 7.78–7.70 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.32–7.25 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 150.0, 149.0, 146.9, 140.0, 138.8, 135.5, 130.1, 128.6, 127.9, 127.6, 127.5 (2C), 122.8, 122.1, 115.5, 114.3. HRMS (ESI), m/z: [M + Na]+ calcd. for C17H11N3O2 312.0743; found 312.0747.
3-(4-Methoxyquinolin-2-yl)quinazoline-2,4(1H,3H)-dione 3m. White powder; 78% yield (50 mg); mp 284–285 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.21 (dd, J = 8.5, 1.5 Hz, 1H), 8.00–7.93 (m, 2H), 7.85–7.79 (m, 1H), 7.78–7.72 (m, 1H), 7.70–7.64 (m, 1H), 7.33–7.22 (m, 3H), 4.05 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.5, 162.1, 150.4, 149.9, 147.4, 140.0, 135.5, 130.4, 128.4, 127.4, 126.6, 122.8, 121.6, 120.4, 115.5, 114.2, 101.7, 56.6. HRMS (ESI), m/z: [M + H]+ calcd. for C18H13N3O3 320.1030; found 320.1033.
3-(6-Methylquinolin-2-yl)quinazoline-2,4(1H,3H)-dione 3n. White powder; 66% yield (40 mg); mp 310–311 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.09–7.88 (m, 2H), 7.87 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.40–7.14 (m, 2H), 2.56 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 150.0, 148.2, 145.5, 140.0, 138.0, 137.0, 135.5, 132.2, 128.3, 127.7, 127.5, 126.6, 122.8, 122.1, 115.5, 114.3, 21.2. HRMS (ESI), m/z: [M + H]+ calcd. for C18H13N3O2 304.1081; found 304.1089.
3-(7-Methylquinolin-2-yl)quinazoline-2,4(1H,3H)-dione 3o. White powder; 48% yield (29 mg); mp 279–281 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 7.98 (t, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.78–7.71 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.34–7.22 (m, 2H), 2.56 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 150.0, 149.0, 147.2, 140.1, 140.0, 138.4, 135.5, 129.6, 127.6, 127.5, 127.4, 125.7, 122.8, 121.2, 115.5, 114.3, 21.4. HRMS (ESI), m/z: [M + H]+ calcd. for C18H13N3O2 304.1081; found 304.1078.
3-(6-Methoxyquinolin-2-yl)quinazoline-2,4(1H,3H)-dione 3p. White powder; 58% yield (37 mg); mp 303–305 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.79–7.71 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.53–7.44 (m, 2H), 7.32–7.22 (m, 2H), 3.94 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 157.9, 150.1, 146.7, 142.8, 140.0, 137.5, 135.5, 130.0, 128.9, 127.5, 122.7, 122.5, 122.3, 115.5, 114.3, 105.8, 55.6. HRMS (ESI), m/z: [M + H]+ calcd. for C18H13N3O3 320.1030; found 320.1029.
3-(Isoquinolin-1-yl)quinazoline-2,4(1H,3H)-dione 3q. Light beige powder; 47% yield (27 mg); mp 269–271 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.03 (s, 1H), 8.02–7.99 (m, 1H), 7.97 (dd, J = 7.9, 1.5 Hz, 1H), 7.88–7.83 (m, 1H), 7.81–7.75 (m, 1H), 7.69–7.64 (m, 1H), 7.35–7.27 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.4, 149.9, 148.6, 141.6, 140.3, 137.4, 135.7, 131.0, 128.7, 127.5, 127.0, 125.7, 124.5, 122.9, 122.3, 115.7, 114.1. HRMS (ESI), m/z: [M + Na]+ calcd. for C17H11N3O2 312.0743; found 312.0746.
6-Methyl-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3r. White powder; 77% yield (41 mg); mp 304–305 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.44 (dd, J = 4.9, 0.8 Hz, 1H), 7.79–7.70 (m, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.37–7.28 (m, 2H), 7.16 (d, J = 8.2 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.4, 149.8, 149.6, 149.3, 148.9, 137.7, 136.5, 132.0, 126.8, 124.9, 124.8, 115.4, 113.9, 20.3, 20.2. HRMS (ESI), m/z: [M + H]+ calcd. for C15H13N3O2 268.1081; found 268.1082.
8-Methyl-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3s. White powder; 74% yield (40 mg); mp 268–270 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.51–8.41 (m, 1H), 7.82 (dd, J = 7.8, 0.8 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.40–7.29 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 2.41 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.2, 150.1, 149.7, 149.3, 148.9, 138.3, 136.5, 125.3, 125.0, 124.7, 124.3, 122.5, 114.3, 20.3, 17.2. HRMS (ESI), m/z: [M + H]+ calcd. for C15H13N3O2 268.1081; found 268.1083.
1-Methyl-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3t. White powder; 32% yield (17 mg); mp 224–225 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 5.1 Hz, 1H), 8.06 (dd, J = 7.8, 1.6 Hz, 1H), 7.89–7.82 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.39–7.30 (m, 3H), 3.54 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.2, 150.1, 149.7, 149.6, 148.9, 140.8, 135.8, 127.8, 125.0, 124.6, 122.9, 115.2, 114.9, 30.4, 20.3. HRMS (ESI), m/z: [M + H]+ calcd. for C15H13N3O2 268.1081; found 268.1087.
6,7-Dimethoxy-3-(4-methoxypyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3u. White powder; 74% yield (49 mg); mp 238–240 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.39 (d, J = 5.7 Hz, 1H), 7.28 (s, 1H), 7.14–7.05 (m, 2H), 6.74 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H). 13C NMR (126 MHz, DMSO) δ 167.1, 161.5, 155.3, 151.0, 150.1, 149.9, 145.3, 135.7, 110.4 (2C), 107.5, 106.0, 97.7, 55.9, 55.8 (2C). HRMS (ESI), m/z: [M + H]+ calcd. for C16H15N3O5 330.1084; found 330.1090.
6-Fluoro-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3v. White powder; 89% yield (48 mg); mp 293–294 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.49–8.41 (m, 1H), 7.70–7.59 (m, 2H), 7.34 (d, J = 3.9 Hz, 2H), 7.32–7.26 (m, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.8 (d, J = 3.1 Hz), 157.9 (d, J = 240.4 Hz), 150.2, 150.1, 149.5, 149.4, 137.1 (d, J = 1.3 Hz), 125.5, 125.2, 124.0 (d, J = 24.4 Hz), 118.3 (d, J = 7.9 Hz), 115.7 (d, J = 8.0 Hz), 112.9 (d, J = 24.0 Hz), 20.8. 19F NMR (376 MHz, DMSO-d6) δ –119.63. HRMS (ESI), m/z: [M + H]+ calcd. for C14H10FN3O2 272.0830; found 272.0829.
6-Chloro-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3w. White powder; 66% yield (38 mg); mp 301–302 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.45 (dd, J = 4.8, 1.0 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.78 (dd, J = 8.7, 2.5 Hz, 1H), 7.37–7.31 (m, 2H), 7.27 (d, J = 8.7 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.1, 149.7, 149.6, 149.0, 148.9, 138.8, 135.4, 126.7, 126.3, 125.1, 124.7, 117.7, 115.6, 20.3. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H10ClN3O2 310.0354; found 310.0356.
7-Chloro-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3x. White powder; 47% yield (27 mg); mp 254–255 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.54–8.38 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.38–7.31 (m, 2H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H), 2.39 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 161.4, 149.8, 149.7, 148.9, 141.0, 139.8, 129.6, 125.1, 124.7, 123.0, 114.8, 113.2, 20.3. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H10ClN3O2 310.0354; found 310.0351.
6-Bromo-3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione 3y. Light beige powder; 62% yield (41 mg); mp 293–295 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.45 (dd, J = 4.9, 0.9 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 8.7, 2.3 Hz, 1H), 7.38–7.31 (m, 2H), 7.21 (d, J = 8.7 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.5, 149.2, 149.1, 148.5 (2C), 138.7, 137.5, 128.8, 124.6, 124.2, 117.4, 115.5, 113.7, 19.8. HRMS (ESI), m/z: [M + Na]+ calcd. for C14H10BrN3O2 353.9849; found 353.9843.
Methyl 3-(4-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline- 7-carboxylate 3z. White powder; 65% yield (41 mg); mp 266–267 °C (dec.). 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.45 (d, J = 5.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 8.2, 1.6 Hz, 1H), 7.39–7.30 (m, 2H), 3.92 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 161.5, 149.8, 149.8, 149.0 (2C), 140.0, 135.3, 128.2, 125.1, 124.7, 122.5, 117.4, 116.3, 52.8, 20.3. HRMS (ESI), m/z: [M + H]+ calcd. for C16H13BrN3O4 312.0979; found 312.0972.
Ethyl 2-(3-(5-cyanopyridin-2-yl)ureido)benzoate 4b. Compound 4b was obtained according to the general procedure A from urea 1r (0.15 mmol) and ethyl anthranilate (0.75 mmol). Beige powder; 40% yield (19 mg); mp 193–195 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.69 (s, 1H), 8.73 (d, J = 2.3 Hz, 1H), 8.29–8.22 (m, 1H), 8.17 (dd, J = 8.8, 2.3 Hz, 1H), 7.93 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.63–7.55 (m, 1H), 7.20–7.13 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.4, 155.2, 151.8, 151.6, 141.5, 139.6, 133.5, 130.5, 122.6, 121.9, 118.1, 117.4, 111.8, 101.7, 61.0, 14.0. HRMS (ESI), m/z: [M + H]+ calcd. for C16H14N4O3 311.1139; found 311.1149.

3.4. Synthesis of Thienopyrimidine-2,4-Diones 8

General procedure C. Urea 1 (0.2 mmol), amino ester 6 (0.3 mmol), and DMF (0.1 mL) were placed in a vial; the resulting mixture was stirred at 120 °C for 20 h. Then, the reaction mixture was cooled to RT and sodium tert-butoxide (0.2 mmol) and DMF (0.6 mL) were added. The reaction mixture was stirred for another 2 h at 120 °C. After completion of the reaction, the reaction mixture was cooled to RT, and DMF was removed by a rotary evaporator. The residue was purified by column chromatography (gradient from n–hexane/ethyl acetate to hexane/ethyl acetate/methanol) to give compounds 8a–f.
3-(4-Methylpyridin-2-yl)-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 8a. White powder; 54% yield (34 mg); mp 281–282 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.24 (br s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.23 (s, 1H), 2.67 (dt, J = 29.1, 6.4 Hz, 4H), 2.37 (s, 3H), 1.82–1.65 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 158.8, 150.5, 150.2, 149.5, 149.5, 148.9, 131.0, 125.7, 124.9, 124.8, 112.4, 24.9, 23.9, 22.7, 21.6, 20.3. HRMS (ESI), m/z: [M + H]+ calcd. for C16H15N3O2S 314.0958; found 314.0960.
3-(Pyridin-2-yl)-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 8b. White powder; 50% yield (30 mg); mp 276–278 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.58 (dd, J = 5.0, 1.9 Hz, 1H), 7.97 (td, J = 7.7, 2.0 Hz, 1H), 7.51–7.41 (m, 2H), 2.76–2.61 (m, 4H), 1.83–1.67 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 158.7, 150.1 (2C), 149.4, 149.3, 138.6, 131.1, 125.9, 124.5, 123.9, 112.5, 24.9, 23.9, 22.7, 21.6. HRMS (ESI), m/z: [M + H]+ calcd. for C15H13N3O2S 300.0801; found 300.0804.
3-(4-Methoxypyridin-2-yl)-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 8c. White powder; 45% yield (29 mg); mp 257–260 °C.1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.40–8.34 (m, 1H), 7.10–7.01 (m, 2H), 3.85 (s, 3H), 2.68 (dt, J = 29.4, 6.3 Hz, 4H), 1.83–1.66 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 167.0, 158.6, 150.9, 150.1, 150.1, 150.0, 131.0, 125.8, 112.5, 110.4, 110.3, 55.7, 24.9, 23.8, 22.7, 21.6. HRMS (ESI), m/z: [M + H]+ calcd. for C16H15N3O3S 330.0907; found 330.0910.
3-(6-Phenylpyridin-2-yl)-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 8d. Light yellow powder; 48% yield (36 mg); mp 293–294 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.13–7.93 (m, 4H), 7.56–7.38 (m, 4H), 2.70 (dt, J = 29.8, 6.3 Hz, 4H), 1.88–1.64 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 158.7, 156.3, 150.1, 150.1, 149.3, 139.7, 137.7, 131.0, 129.4, 128.8, 126.6, 125.9, 123.1, 120.2, 112.6, 24.9, 23.9, 22.7, 21.6. HRMS (ESI), m/z: [M + Na]+ calcd. for C21H17N3O3S 398.0934; found 398.0939.
3-(Quinolin-2-yl)-5,6,7,8-tetrahydrobenzo [4,5]thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione 8e. Light yellow powder; 56% yield (39 mg); mp 308–310 °C (dec.). 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.09 (dd, J = 8.4, 0.8 Hz, 1H), 8.01 (dd, J = 8.4, 1.0 Hz, 1H), 7.87–7.80 (m, 1H), 7.74–7.68 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 2.70 (dt, J = 26.9, 6.3 Hz, 4H), 1.84–1.66 (m, 4H). 13C NMR (101 MHz, DMSO-d6) δ 158.9, 150.3, 150.2, 149.2, 147.0, 138.7, 131.1, 130.0, 128.6, 127.9, 127.6, 127.4, 125.9, 122.3, 112.6, 24.9, 23.9, 22.7, 21.6. HRMS (ESI), m/z: [M + H]+ calcd. for C19H15N3O3S 350.0958; found 350.0957.
3-(4-Methylpyridin-2-yl)-1,5,6,7-tetrahydro-2H-cyclopenta [4,5]thieno [2,3-d]pyrimidine-2,4(3H)-dione 8f. Brown powder; 35% yield (21 mg); mp 103–104 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 2.86–2.75 (m, 4H), 2.41–2.32 (m, 5H). 13C NMR (101 MHz, DMSO-d6) δ 158.3, 154.6, 150.2, 149.6, 149.3, 148.9, 140.1, 130.7, 124.9, 109.8, 28.4, 28.3, 27.5, 20.3. HRMS (ESI), m/z: [M + Na]+ calcd. for C15H13N3O2S 322.0621; found 322.0618.
Preparation of ethyl 2-(3-(4-methylpyridin-2-yl)ureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 7a. Urea 1 (0.2 mmol), ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 6a (0.3 mmol) and DMF (0.1 mL) were placed in a vial, the resulting mixture was stirred at 120 °C for 20 h. After completion of the reaction, the reaction mixture was cooled to RT, DMF was removed by a rotary evaporator. The residue was washed with diethyl ether to give compound 7a in 56% yield (40 mg) as a white powder; mp 237–238 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.21 (br s, 1H), 10.27 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 6.90 (dd, J = 5.2, 1.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.76–2.66 (m, 2H), 2.64–2.54 (m, 2H), 2.29 (s, 3H), 1.77–1.67 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.2, 152.3, 151.5, 149.6, 147.4, 146.0, 130.4, 125.2, 119.1, 111.9, 110.6, 59.7, 26.0, 23.7, 22.5, 22.4, 20.8, 14.3. HRMS (ESI), m/z: [M + H]+ calcd. for C18H21N3O3S 360.1376; found 360.1374.

3.5. Gram-Scale Synthesis of 3a and 8a

3a. Urea 1a (5.6 mmol, 1 g) and ethyl anthranilate 2a (27.9 mmol, 4.61 g) were placed in a 100 mL round-bottom flask and the resulting mixture was stirred at 120 °C for 20 h. The reaction mixture was cooled to RT, treated with diethyl ether (20 mL), and the precipitate was separated. Then, the precipitate was washed with diethyl ether and dried at 50 °C in air to give quinazoline-2,4-dione 3a in 71% (1.01 g) yield.
8a. Urea 1a (5.6 mmol, 1 g), ester 6a (8.4 mmol, 1.89 g), and DMF (4 mL) were placed in a 100 mL round-bottom flask, the resulting mixture was stirred at 120 °C for 20 h. Then, the reaction mixture was cooled to RT and sodium tert-butoxide (5.6 mmol, 0.54 g) and DMF (17 mL) were added. The reaction mixture was stirred for another 2 h at 120 °C. After completion of the reaction, the reaction mixture was cooled to RT, and DMF was removed by a rotary evaporator. The residue was dissolved in isopropyl alcohol (150 mL) and the resultant solution was diluted with water (350 mL). The precipitate formed was filtered off and dried at 50 °C in air to give thienopyrimidine-2,4-dione 8a in 61% (1.06 g) yield.

4. Conclusions

Thus, we developed a new route to 3-pyridyl-substituted quinazolin-2,4(1H,3H)-diones and thieno [2,3-d]pyrimidine-2,4(1H,3H)-diones via the annulation of anthranilic esters with N-pyridyl ureas, which act as masked isocyanates. The process consists of the formation of N-aryl-N′-pyridyl ureas followed by their cyclocondensation into the corresponding diones. The reaction does not require the use of metal catalysts and proceeds with moderate to good yields. The synthetic route we propose will successfully complement the method developed by Ravi et al. [58] for the preparation of quinazolin-2,4(1H,3H)-diones based on aminopyridines in cases where the corresponding aminopyridines or quinolines are not commercially available.
Although the nature of the substituent in the pyridine ring has little effect on the product yield, strong electron-withdrawing functionalities such as cyano-group decrease the yield of the desired products or even prevent the cyclocondensation step. The proposed method is characterized by uncomplicated workup and easy gram-scalability.

Supplementary Materials

The supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms24087633/s1.

Author Contributions

Conceptualization, S.V.B. and V.P.B.; methodology, S.V.B. and V.P.B.; formal analysis, S.O.B. and S.V.B.; investigation, S.O.B. and K.K.G.; data curation, S.O.B.; writing—original draft preparation, S.O.B., S.V.B. and V.P.B.; writing—review and editing, V.P.B.; visualization, S.O.B.; supervision, V.P.B.; project administration, S.V.B.; funding acquisition, V.P.B. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Russian Science Foundation (project No. 19-13-00008).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are grateful to the Center for Magnetic Resonance, Center for Chemical Analysis and Materials Research, and Center for X-ray Diffraction Studies (all belonging to Saint Petersburg State University) for physicochemical experiments.

Conflicts of Interest

The authors declare no conflict of interest.

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Ijms 24 07633 sch001 550
Scheme 1. Methods for synthesis of substituted quinazolin-2,4-diones.
Scheme 1. Methods for synthesis of substituted quinazolin-2,4-diones.
Ijms 24 07633 sch001
Ijms 24 07633 sch002 550
Scheme 2. Formation of 3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione (3a).
Scheme 2. Formation of 3-(4-methylpyridin-2-yl)quinazoline-2,4(1H,3H)-dione (3a).
Ijms 24 07633 sch002
Ijms 24 07633 g001 550
Figure 1. Molecular structure of quinazoline-2,4-dione 3a (Olex2 view).
Figure 1. Molecular structure of quinazoline-2,4-dione 3a (Olex2 view).
Ijms 24 07633 g001
Ijms 24 07633 sch003 550
Scheme 3. Synthesis of quinazolin-2,4-diones substituted in the pyridine moiety.
Scheme 3. Synthesis of quinazolin-2,4-diones substituted in the pyridine moiety.
Ijms 24 07633 sch003
Ijms 24 07633 sch004 550
Scheme 4. Formation and destruction of ethyl 2-(3-(5-cyanopyridin-2-yl)ureido)benzoate 4b under the reaction conditions.
Scheme 4. Formation and destruction of ethyl 2-(3-(5-cyanopyridin-2-yl)ureido)benzoate 4b under the reaction conditions.
Ijms 24 07633 sch004
Ijms 24 07633 sch005 550
Scheme 5. Investigation of the reactivity of various anthranilic esters.
Scheme 5. Investigation of the reactivity of various anthranilic esters.
Ijms 24 07633 sch005
Ijms 24 07633 sch006 550
Scheme 6. Coupling of ureas 1a with 2-aminothiophene-3-carboxylates 6a.
Scheme 6. Coupling of ureas 1a with 2-aminothiophene-3-carboxylates 6a.
Ijms 24 07633 sch006
Ijms 24 07633 sch007 550
Scheme 7. Two-stage one-pot synthesis of thienopyrimidine-2,4-diones 8a–f.
Scheme 7. Two-stage one-pot synthesis of thienopyrimidine-2,4-diones 8a–f.
Ijms 24 07633 sch007
Ijms 24 07633 sch008 550
Scheme 8. Gram-scale syntheses of 3a and 8a. To achieve these yields, a 100 mL flask has to be used.
Scheme 8. Gram-scale syntheses of 3a and 8a. To achieve these yields, a 100 mL flask has to be used.
Ijms 24 07633 sch008
Table
Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
EntryEquiv. of 2aSolventTemperature, °CTime, hYield, %
11.2DMF1202452
21.2DMF1402450
31.5DMF1202058
42.0DMF1202062
55.0DMF1202063
65.0neat1202070
710.0neat1202059
8 *1.5DMF1202046
* Anthranilic acid was used instead ester 2a.
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Baykova, S.O.; Geyl, K.K.; Baykov, S.V.; Boyarskiy, V.P. Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas. Int. J. Mol. Sci. 2023, 24, 7633. https://doi.org/10.3390/ijms24087633

AMA Style

Baykova SO, Geyl KK, Baykov SV, Boyarskiy VP. Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas. International Journal of Molecular Sciences. 2023; 24(8):7633. https://doi.org/10.3390/ijms24087633

Chicago/Turabian Style

Baykova, Svetlana O., Kirill K. Geyl, Sergey V. Baykov, and Vadim P. Boyarskiy. 2023. "Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1H,3H)-diones via Annulation of Anthranilic Esters with N-pyridyl Ureas" International Journal of Molecular Sciences 24, no. 8: 7633. https://doi.org/10.3390/ijms24087633

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