TMSBr-Catalyzed Rapid Synthesis of

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FeCl3 ·6H2O/TMSBr-Catalyzed Rapid Synthesis of Dihydropyrimidinones and Dihydropyrimidinethiones under Microwave Irradiation Fei Zhao *

ID

, Xiuwen Jia, Pinyi Li, Jingwei Zhao, Jun Huang, Honglian Li and Lin Li

Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, 168 Hua Guan Road, Chengdu 610052, China; [email protected] (X.J.); [email protected] (P.L.); [email protected] (J.Z.); [email protected] (J.H.); [email protected] (H.L.); [email protected] (L.L.) * Correspondence: [email protected]; Tel.: +86-187-8025-5276 Received: 22 August 2017; Accepted: 7 September 2017; Published: 11 September 2017

Abstract: An efficient and practical protocol has been developed to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl3 ·6H2 O/TMSBr-catalyzed three-component cyclocondensation under microwave irradiation. This approach features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones. Keywords: FeCl3 ·6H2 O; TMSBr; dihydropyrimidinones; dihydropyrimidinethiones; microwave irradiation

1. Introduction Dihydropyrimidinones and dihydropyrimidinethiones have received great attention in synthetic organic chemistry because of their ubiquitous presence in a large number of natural products and pharmaceutical agents [1–10]. For example, they act as key components in natural marine alkaloids such as batzelladine A-I [11–13], ptilocaulin [14], and saxitoxin [15]. Moreover, they exhibit a broad spectrum of pharmacological activities such as antibacterial [16], antitumor [17–20], anti-inflammatory [20], antiviral [21], and antihypertensive activities [22,23]. They are also known as calcium channel blockers [24–27] and α1A -adrenergic receptor (α1A -AR) antagonists [28,29]. In addition, dihydropyrimidinones display as a key precursor in the synthesis of pyrimidine bases which constitute the basic skeleton of nucleic acids [30]. Therefore, an efficient access to these two structures is highly desirable for both organic synthesis and drug discovery. The first synthetic method for the preparation of dihydropyrimidinones and dihydropyrimidinethiones was reported by Biginelli in 1893 [31]. However, this method suffered from low yields and the usage of strong acids. Consequently, improved procedures, including the employment of Lewis acid catalysts [32–56], bases [57,58], ionic liquids [59–62], ultrasound irradiation [63], and nanocomposites [64–66] have been developed. Despite the remarkable achievements made, however, many of these methods still suffer from major or minor drawbacks, such as long reaction time, harsh reaction conditions, low yields, the stoichiometric requirements of the metal catalysts and the involvement of expensive or toxic reagents. Therefore, the development of a faster, milder, high-yielding and environmentally benign approach for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones is still of great significance. Herein, we present our efforts towards FeCl3 ·6H2 O/TMSBr- (TMSBr = Bromotrimethylsilane) catalyzed three-component cyclocondensation Molecules 2017, 22, 1503; doi:10.3390/molecules22091503

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under microwave irradiation to synthesize dihydropyrimidinones and dihydropyrimidinethiones. Our protocol features high yields, broad substrate scope, short reaction time, mild reaction conditions, Molecules 2017, 22, 1503 and easy work-up, thus affording a rapid and convenient approach 2 of 16 operational simplicity for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones. and dihydropyrimidinethiones. Our protocol features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a 2. Results and Discussion rapid and convenient approach for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones. We began our study by investigating the reaction of 1-tetralone (1a), benzaldehyde (2a)

and thiourea (3a) in CH3 CN at 90 ◦ C in an oil bath for 10 h employing FeCl3 ·6H2 O as the 2. Results and Discussion catalyst, considering the potential of FeCl3 ·6H2 O in Biginelli-like reactions [45,67,68] (Table 1, began our study by investigating of 1-tetralone (1a), benzaldehyde (2a) and that entry 1). We Pleasingly, the desired product 4a the wasreaction obtained, albeit with low yield. Considering thiourea (3a) in organic CH3CN at 90 °C in(MAOS) an oil bath for and 10 h energy-saving employing FeCl[69–71] 3∙6H2O and as the microwave-assisted synthesis is time itscatalyst, applications 3∙6H2O in Biginelli-like reactions [45,67,68] (Table 1, entry 1). considering the potential of FeCl in Biginelli-like reactions [57,72–81], we then chose this technology to conduct the three-component Pleasingly, the desired product 4a was obtained, albeit with low yield. Considering that microwavecondensation reaction. As a result, a similar yield was obtained under the same catalytic conditions assisted organic synthesis (MAOS) is time and energy-saving [69–71] and its applications in Biginelliwhen the reaction was carried out under microwave irradiation for just 2 h (Table 1, entry 2). Then, like reactions [57,72–81], we then chose this technology to conduct the three-component condensation we tried to optimize the reaction conditions under microwave heating. At first, various catalysts reaction. As a result, a similar yield was obtained under the same catalytic conditions when the suchreaction as ZnClwas O, CuBr evaluated (Table 1, entries 3–6), of 2 , FeSO 4 ·7H 2 , and AlCl 3 werefor carried out2 under microwave irradiation just 2 h (Table 1, entry 2). Then, weand triednone to themoptimize exhibited higher catalytic than heating. FeCl3 ·6H Next, employing ·6H theareaction conditionsperformance under microwave At2 O. first, various catalysts FeCl such 3as ZnCl 2 O2,as the catalyst, series additives were added and screened order 3–6), to improve theofreaction yield (Table 1, FeSOa4∙7H 2O, of CuBr 2, and AlCl 3 were evaluated (Table 1,inentries and none them exhibited a higher catalytic performance than FeCl 3∙6H2O. Next, employing FeCl 3∙6H2of O as the catalyst, a series entries 7–12). Both BF · OEt and BBr caused no obvious enhancement the reaction yield (Table 1, 3 2 3 of additives added and screened inOTf) ordercompounds to improve the reaction yield (Table 1, entries 7–12).which entries 7 and 8). were As TMS-X-type (X = Cl, I, were proved to be efficient reagents Both BF 3∙OEt2 and BBr3 caused no obvious enhancement of the reaction yield (Table 1, entries 7 and 8). could significantly promote Biginelli-like reactions [44,45,56,82–102], we then explored the effects of As TMS-X-type (X = Cl, I, OTf) compounds were proved to be efficient reagents which could this kind of additive. We found that TMSOTf, TMSCl, TMSBr and TMSI could improve the yield to significantly promote Biginelli-like reactions [44,45,56,82–102], we then explored the effects of this different degrees (Table 1, entries 9–12). To our delight, TMSBr was found to be the most efficient kind of additive. We found that TMSOTf, TMSCl, TMSBr and TMSI could improve the yield to additive, with which(Table product 4a was obtained 88% yield filtration entry 11). This different degrees 1, entries 9–12). To our in delight, TMSBrby was found to(Table be the 1, most efficient might be because TMSBr could4aactivate the carbonyl group of 1a to (Table promote the 11). reaction [103–105]. additive, with which product was obtained in 88% yield by filtration 1, entry This might Subsequently, furthercould screening of the the reaction polarity[103–105]. of the solvent be becausea TMSBr activate the solvents carbonyl revealed group of that 1a toincreasing promote the generally had a positive effect on theof reaction yieldrevealed (Table 1,that entry 13–16), the andpolarity CH3 CN Subsequently, a further screening the solvents increasing ofdisplayed the solventas the generally had a positive effect on the reaction yield (Table 1, entry 13–16), and CH 3 CN displayed best choice to promote the transformation, although ethanol could be an alternative solvent withaswhich the lower best choice promote the transformation, ethanol could be an alternative solvent with were a slight yieldto(84%) was observed (Table although 1, entry 16). In addition, solvent-free conditions which a slight lower yield (84%) was observed (Table 1, entry 16). In addition, solvent-free conditions also tested, and only a moderate yield (52%) was obtained because of the recovery of the materials were also tested, and only a moderate yield (52%) was obtained because of the recovery of the (Table 1, entry 17). By contrast, a lower yield (80%) was observed when the reaction was heated with materials (Table 1, entry 17). By contrast, a lower yield (80%) was observed when the reaction was an oil bath for 8 h under the optimal reaction conditions because of the incomplete consumption of heated with an oil bath for 8 h under the optimal reaction conditions because of the incomplete the substrates (Table entry 18), and1,itentry took18), 10 and hours to finish thetoreaction obtaintoa obtain comparable consumption of the1,substrates (Table it took 10 hours finish thetoreaction a yieldcomparable (87%) using an oil bath (Table 1, entry 19). These results highlighted the efficiency of microwave yield (87%) using an oil bath (Table 1, entry 19). These results highlighted the efficiency of irradiation. In this way, FeCl synthesis of dihydropyrimidinethiones through microwave irradiation. In this way, FeCl3∙6H2O/TMSBr-catalyzed synthesis of dihydropyrimidinethiones 3 ·6H 2 O/TMSBr-catalyzed three-component cyclocondensation under microwave heating waswas developed. through three-component cyclocondensation under microwave heating developed. a. a Table Optimization of of the Table 1. 1.Optimization the reaction reactionconditions conditions .

Entry Entry Catalyst Catalyst 1c FeCl3∙6H2O c 1 FeCl3 ·6H2 O 2 FeClFeCl 3∙6H2·O 2 3 6H2 O 3 ZnClZnCl 2 3 2 4 7H2 O 4 FeSOFeSO 4∙7H42·O 5 2 5 CuBrCuBr 2 6 AlCl3 6 AlCl 7 FeCl3 3 ·6H2 O 7 FeClFeCl 3∙6H2·O 8 3 6H2 O 8 FeCl3∙6H2O

Additive Additive - - - - - ·OEt BF 3 2 BF3∙OEt 2 BBr 3 BBr3

Solvent Solvent CH3CN CH3 CN CH 3CN CH 3 CN CH 3CN CH 3 CN CH 3 CN CH 3CN CH 3 CN CH3CN CH3 CN CH 3CN CH 3 CN CH 3CN CH 3 CN CH3CN

Time Yield (%) Yield (%) b Time 10 h

10 h 2 h2 h 2 h2 h 2 h2 h 2 h2 h 2h 2 h2 h 2 h2 h

2h

38 37 trace trace 16 18 43 41

38 37 trace trace 16 18 43 41

b

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FeCl 3∙6H TMSOTf CH 3CN 9 9 FeCl 3∙6H 2O2O TMSOTf CH 3CN FeCl 3∙6H TMSCl CH 3CN 1010 FeCl 3∙6H 2O2O TMSCl CH 3CN Table 1. Cont. FeCl 3∙6H TMSBr CH 3CN 1111 2017, 22,FeCl 3∙6H 2O2O TMSBr CH 3CN Molecules 1503 Molecules 1503 Molecules 2017,22, 22,FeCl 1503 FeCl 3∙6H TMSI CH 3CN 1212 2017, 3∙6H 2O2O TMSI CH 3CN Entry FeCl3∙6H Catalyst Additive Solvent 2O TMSOTf CH 3CN FeCl 3∙6H TMSBr Toluene 1313 9 FeCl 3∙6H 2O2O TMSBr Toluene FeCl33FeCl ∙6H2232O CH CN 910 FeCl CH 333CN 9 2017, 22, 3∙6H 2O TMSOTf 3CN 9 1503 ·O 6H2 O TMSOTf TMSOTf CH FeCl 3∙6H TMSCl CH 3 CN 14 3∙6H TMSBr THF 14Molecules FeCl 3∙6H 2O2O TMSBr THF Molecules 2017, 10 22, FeCl 1503 3 2 3 FeCl · 6H O TMSCl CH 10 FeCl 3 ∙6H 2 O TMSCl CH 3 CN 3 2 10 FeCl 3 ∙6H 2 O TMSCl CH 3 CN 11 2017, 22, 1503 3 2 TMSBr 3 3 CN 15 11 FeCl 3∙6H TMSBr 1,4-Dioxane 15Molecules FeCl 3∙6H 2O2O 11 FeCl ·O 6H2 O TMSBr TMSBr 1,4-Dioxane CH 3 3 CN 3 2 3 FeCl 3 ∙6H 2 O TMSBr CH 3 11 FeCl 3 ∙6H 2 TMSBr CH 3CN FeCl TMSOTf CH 33CN 12 99 3 3∙6H 2 2O TMSI FeCl 3∙6H·26H O TMSOTf CH 3CNCN 12 FeCl O TMSI CH 3 2 3 FeCl 3∙6H 2O TMSBr EtOH 1616 12 FeCl 3∙6H 2O TMSBr EtOH FeCl 333∙6H 222O TMSI CH 333CN 9 FeCl 3∙6H 2O TMSOTf CH TMSCl 1210 FeCl 3∙6H 2O TMSI CH 3CN 13 TMSBr Toluene FeCl TMSBr Toluene 10 13 FeCl 3∙6H O 2O TMSCl CH 3CN 3 ·26H FeCl 3∙6H 2O TMSBr 1717 13 FeCl 3FeCl ∙6H 23∙6H O TMSBr neat FeCl 3∙6H 26H O TMSCl CH 3neat CN 11 TMSBr 33FeCl 222O TMSBr Toluene 1310 TMSBr Toluene 14 3∙6H THF TMSBr THF 32·O 11 14 FeCl FeCl 3∙6H 2O 2 O TMSBr CH 3CN c c 14 3 2 11 FeCl 3 ∙6H 2 O TMSBr CH 3 12 TMSI 15 FeCl · 6H O TMSBr 1,4-Dioxane FeCl 3 ∙6H 2 O TMSBr CH 3CN FeCl 3 ∙6H 2 O TMSBr THF 1818 FeCl 3 ∙6H 2 O TMSBr CH 3 CN 14 FeCl 3 ∙6H 2 O TMSBr THF 32 2O 2 15 12 3 3∙6H 1,4-Dioxane FeCl TMSI CH3CN CN 16 FeCl · O TMSBr 12 FeCl 3∙6H 26H O TMSI CH 3EtOH CN 13 TMSBr Toluene c 3 2 c 3 2 15 FeCl 3 ∙6H 2 O TMSBr 1,4-Dioxane 15 FeCl 3 ∙6H 2 O TMSBr 1,4-Dioxane FeCl 3∙6H 2O TMSBr CH 3CN 32O 2 2O EtOH 1919 16 13 FeCl 3∙6H TMSBr CH 3CN FeCl 3∙6H TMSBr Toluene

2 h2 h 6565 2 h2 h 8282 2 h2 h 883 88 of 16 33of of16 16 73 2 h2 h 73 b Time 22hh2 hYield (%) 65 4444 h 65 653 of 16 22 h22hh 65 82 61 h2 h 82 61 of 16 22 h22 hh 82 8233 of 88 16 2 h 71 h 71 22 h2 88 88 2 2hhh 6588 73 22hh2 h2 h 73 65 8484 2hhh 73 82 73 222h2 44 65 h 8244 2 h 2 h 2 h 82 88 2 h 44 2 h 44 22hh 61 8861 5252 h 73 2222 h2 71 88 8 h h 8 h h 61 8080 71 h 7361 222 h2 84 h 73 44 h 71 h 71 8787 hh 2 10 h 10 4484

17 FeCl TMSBr neat 22hh 52 44 32·O 13 FeCl 3∙6H 26H O 2O TMSBr Toluene 14 THF 61 16noted, FeCl 3∙6H ∙6H TMSBr EtOH 84 16 333∙6H 222O TMSBr EtOH a Unless 17 FeCl O TMSBr neat 22hh hh 3a 52 14 reactions FeCl 3∙6H 2O TMSBr THF 22 6184 c FeCl reactions were performed with (0.5 mmol), 2a (0.5 mmol), (0.75 catalyst Unless noted, were performed with 1a 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), catalyst 18 FeCl · 6H O TMSBr CH CN 8 h 80mmol), 3 2 3 14 FeCl 3∙6H 2O TMSBr THF 222 hhh 61 15 1,4-Dioxane 71 3 2 c 17 FeCl 3 ∙6H 2 O TMSBr neat 52 c 17 FeCl 3 ∙6H 2 O TMSBr neat 52 15 FeCl 3∙6H 26H O TMSBr 1,4-Dioxane 2 h 71 18 FeCl 3∙6H 2O TMSBr CH 3CN 8 h 80 19 FeCl · O TMSBr CH CN 10 h 87 (0.05 mmol) and additive (0.5 mmol) in CH 3 CN (3.0 mL) at 90 °C under microwave irradiation (sealed 3 2 in CH3CN (3.0 mL) at 90 °C 3 under microwave irradiation (sealed (0.05 mmol) and additive (0.5 mmol) FeCl 3∙6H 2O TMSBr 1,4-Dioxane 288hhh 71 16 EtOH 84 18cccc15 FeCl 3∙6H ∙6H 2O O TMSBr CH 3CN CN 80 18 FeCl 333∙6H 222O TMSBr CH 333CN 80 16 FeCl 3∙6H 2bO b TMSBr EtOH 2 h 84 19 FeCl TMSBr CH 10 h 87 a Unless c c noted, reactions were performed with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol),=catalyst (0.05 mmol) yield; Heated with bath; = Trimethylsilyl vessel fixed power, 30 W); Isolated yield; Heated with oiloil bath; Trimethylsilyl vessel at at fixed power, 30 W); FeCl 3∙6H2OIsolatedTMSBr EtOH 2TMSOTf hTMSOTf 84 17 neat 52 19cc c16 FeCl 3CH ∙6H 2O TMSBr CH 3CN 10 87 power, a Unless 17 (0.5 FeCl 3∙6H 2O performed TMSBr neat h(sealed 52fixed 19 FeCl 22O TMSBr CH 33CN 10 hh(0.75 mmol), 87 noted, reactions were with (0.5 mmol), 2a (0.5 mmol),2 3a and additive mmol) in33∙6H (3.0 mL) atChlorotrimethylsilane, 90 ◦ C1a under microwave irradiation vessel atcatalyst 3 CN c trifluoromethanesulfonate, TMSCl = TMSBr = Bromotrimethylsilane, trifluoromethanesulfonate, TMSCl = Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, 17 FeCl 3 ∙6H 2 O TMSBr neat 2 h 52 18 CH 3 CN 8 80 cnoted, reactions a aUnless b c a 18 FeCl 3 ∙6H 2 O TMSBr CH 3 CN 8 h 80 were performed with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), catalyst 30 W); Isolated yield; Heated oilinbath; TMSOTf = mmol), Trimethylsilyl trifluoromethanesulfonate, TMSCl = Unless noted, reactions were performed 1a (0.5 2aunder (0.5 mmol), 3a (0.75 mmol), catalyst (0.05 mmol) and additive (0.5with mmol) CHwith 3CN (3.0 mL) at 90 °C microwave irradiation (sealed c 18 FeCl 2O TMSBr CH 3CN 8 hh 80 19 10 87 TMSI = Iodotrimethylsilane. TMSI =(0.05 Iodotrimethylsilane. Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, = Iodotrimethylsilane. 19 c and additive FeCl33∙6H ∙6H 2O TMSBr CH 10 h irradiation (sealed 87 b cTMSI mmol) (0.5 mmol) in CH 3CN (3.0 mL) at 903CN °C under microwave a

(0.05 mmol) and ininCH °C microwave irradiation (sealed (0.05 mmol) andadditive additive(0.5 (0.5mmol) mmol) CH3CN 3CN(3.0 (3.0mL) mL)atat90 90 °Cunder under microwave irradiation (sealed Isolated yield; Heated with oil bath; TMSOTf = Trimethylsilyl vessel at c fixed power, 30 W); a

19 FeCl3∙6Hwere 2O performed TMSBr CH3CN 87 Unless noted, reactions with 1ac (0.5 mmol), 2a (0.5 mmol),10 3ah(0.75 mmol), catalyst b

bperformed b Isolated Unless noted, reactions with 1ac c(0.5 mmol), 2athen (0.5 mmol), (0.75 mmol), catalyst yield; Heated with oil bath; TMSOTf ==general Trimethylsilyl vessel atat fixed power, 30 W); Isolated yield; Heated with oil bath; TMSOTf Trimethylsilyl vessel fixed power, 30 were W); trifluoromethanesulfonate, TMSCl = Chlorotrimethylsilane, TMSBr =3a Bromotrimethylsilane, After determining the optimal reaction conditions, we examined the general applicability After determining the optimal reaction conditions, we then the applicability a(0.05 mmol) and additive (0.5 mmol) in CH 3CN 1a (3.0(0.5 mL) at 90 °C microwave irradiation (sealed Unless noted, reactions were performed with mmol), 2aunder (0.5examined mmol), 3a (0.75 mmol), catalyst (0.05 mmol) and additive (0.5 mmol) in CH 3CN (3.0 mL) at 90 °C under microwave irradiation (sealed trifluoromethanesulfonate, TMSCl = Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, trifluoromethanesulfonate, TMSCl = Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, TMSI = Iodotrimethylsilane. After determining the optimal reaction conditions, we then examined the general applicability b c this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones easily of ofthis process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were easily Isolated with oil bath; TMSOTfirradiation = Trimethylsilyl vesselmmol) at fixed W); (0.05 andpower, additive30(0.5 mmol) in CH3yield; CN (3.0 Heated mL) at 90 °C under microwave (sealed were vessel at fixed power, 30 W); b Isolated yield; c Heated with oil bath; TMSOTf = Trimethylsilyl TMSI Iodotrimethylsilane. TMSI ==Iodotrimethylsilane. b c trifluoromethanesulfonate, TMSCl =reaction Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, Isolated yield; Heated with oil bath; TMSOTf =general Trimethylsilyl vessel atIn fixed power, 30 W); of this process. general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were easily prepared in good to high yields by ketones, benzaldehydes and thiourea under prepared inAfter good to high yields by thethe reaction of of ketones, benzaldehydes and thiourea under thethe determining the optimal reaction conditions, we then examined the applicability trifluoromethanesulfonate, TMSCl = Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, TMSI =3Iodotrimethylsilane. TMSCl = The Chlorotrimethylsilane, TMSBr = Bromotrimethylsilane, After determining the optimal reaction conditions, then examined the general applicability After the optimal reaction conditions, we then examined the general applicability prepared intrifluoromethanesulfonate, good to yields by the reaction of3,4-dihydropyrimidin-2(1H)-thiones ketones, benzaldehydes andelectron-donating thiourea under the of of this process. In general, various substituted were easily catalysis of FeCl 2high O/TMSBr (Table 2). reactions of benzaldehydes carrying electron-donating catalysis FeCl 3determining ∙6H 2O/TMSBr (Table 2). The reactions ofwe benzaldehydes carrying TMSI = ∙6H Iodotrimethylsilane. TMSI of this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were easily of(Me, this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were prepared in =good highthe yields by the reaction of ketones, benzaldehydes and thiourea under the catalysis ofMeO) FeCl ·Iodotrimethylsilane. 6H O/TMSBr (Table 2). Theconditions, reactions of benzaldehydes electron-donating After optimal reaction we then examined the general applicability groups (Me, MeO) furnished the corresponding products 4b–4d 80%–86% yields (Table 2, entries groups furnished the corresponding products 4b–4d in in 80%–86% yields (Table 2,easily entries 3determining 2to After determining the optimal reaction conditions, we then examined thecarrying general applicability prepared in good to high yields by the reaction of ketones, benzaldehydes and thiourea under the prepared in good to high yields by the reaction of ketones, benzaldehydes and thiourea under the catalysis of FeCl 3 ∙6H 2 O/TMSBr (Table 2). The reactions of benzaldehydes carrying electron-donating After determining the optimal reaction conditions, we then examined the general applicability of this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were easily groups (Me, MeO) furnished the corresponding products 4b–4delectron-withdrawing in 80%–86%were yields (Table 2, 2–4). The protocol was also compatible with benzaldehydes bearing electron-withdrawing groups 2–4). The was also compatible with benzaldehydes bearing groups ofprotocol this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones easily catalysis of FeCl 33∙6H 22to O/TMSBr (Table 2). The of carrying electron-donating catalysis of FeCl 3∙6H 2O/TMSBr (Table 2). Thereactions reactions ofbenzaldehydes benzaldehydes carrying electron-donating of this process. In general, various substituted 3,4-dihydropyrimidin-2(1H)-thiones were prepared in good yields by the reaction of benzaldehydes and thiourea the groups (Me, MeO) furnished the corresponding products 4b–4d in high 80%–86% yields (Table 2,easily entries entries 2–4). The protocol was also compatible with bearing electron-withdrawing prepared in good to high high yields by the reaction of ketones, ketones, benzaldehydes and thiourea under the (CN, COOMe) and afforded the desired products 4e–4f in good yields (Table 2,under entries 5 and (CN, COOMe) and afforded the desired products 4e–4f inbenzaldehydes good to to high yields (Table 2, entries 5 and 6).6). groups (Me, MeO) the corresponding products 4b–4d inin80%–86% yields (Table 2,2,entries prepared in good to 2high by the reaction of ketones, benzaldehydes and thiourea under the catalysis of FeCl 3furnished ∙6H O/TMSBr 2). The reactions of benzaldehydes carrying electron-donating groups (Me, MeO) furnished the(Table corresponding products 4b–4d 80%–86% yields (Table entries 2–4). The protocol was alsoyields compatible with benzaldehydes bearing electron-withdrawing groups catalysis ofBr) FeCl 3∙6Hand 2O/TMSBr (Table 2). The reactions ofyields benzaldehydes carrying groups (CN, COOMe) afforded the desired products 4e–4f in good toelectron-donating high yields (Table Halogens (F, Cl, Br) were tolerated well and excellent yields (89%–90%) were obtained Halogens (F, Cl, were tolerated well and excellent (89%–90%) were obtained (Table 2, 2, catalysis of FeCl 3was ∙6H 2O/TMSBr (Table 2). The reactions of benzaldehydes carrying electron-donating groups (Me, MeO) furnished the corresponding products 4b–4d in 80%–86% yields (Table 2, entries 2–4). The protocol also compatible with benzaldehydes bearing electron-withdrawing groups 2–4). The protocol was also compatible with benzaldehydes bearing electron-withdrawing groups (CN, COOMe) and afforded the desired products 4e–4f in good to high yields (Table 2, entries 5 and 6). groups (Me, MeO) furnished the corresponding products 4b–4d in 80%–86% yields (Table 2, entries entries 57–9). and 6). and Halogens (F, Cl,corresponding Br)products were tolerated well and excellent yields (89%–90%) were Subsequently, substituents the 1-tetralones were investigated. As aand result, the entries 7–9). Subsequently, thethe substituents onon the 1-tetralones were investigated. As agroups the groups (Me, MeO) furnished the products 4b–4d in 80%–86% yields (Table 2, entries 2–4). The was compatible with bearing electron-withdrawing (CN, COOMe) afforded the desired 4e–4f iningood toto high yields (Table 2, 5(Table and 6). (CN, COOMe) andBr) afforded the desired products 4e–4f good high yields (Tableobtained 2,entries entries 5result, 6). Halogens (F,protocol Cl, werealso tolerated well and benzaldehydes excellent yields (89%–90%) were 2, 2–4). The protocol was also compatible with benzaldehydes bearing electron-withdrawing groups obtained (Table 2, entries 7–9). Subsequently, the substituents on the 1-tetralones were investigated. reactions of 1-tetralones with electron-donating group (MeO), halogen (Br) and electronreactions of 1-tetralones with electron-donating group (MeO), halogen (Br) and electron2–4). The protocol was also compatible with benzaldehydes bearing electron-withdrawing groups (CN, COOMe) the desired products 4e–4f in good to high yields (Table entries and 6). Halogens (F, Cl, Br) were well and were obtained (Table 2,2, Halogens (F,Subsequently, Cl,and Br)afforded weretolerated tolerated well and excellent yields (89%–90%) were2, (Table entries the onexcellent the 1-tetralones were investigated. As a 55result, (CN, 7–9). COOMe) and afforded thesubstituents desired products 4e–4f in yields good to(89%–90%) high yields (Table 2,obtained entries and 6).the (CN, COOMe) andBr) the desired products 4e–4f incorresponding good to high yields (Table 2, 4j–4l entries 5result, and 6). Halogens (F, Cl, tolerated well and excellent yields (89%–90%) were obtained (Table 2, As aentries result, the reactions ofthe 1-tetralones with electron-donating group (MeO), halogen (Br) and withdrawing group 2were ) on the benzene ring gave the corresponding products 4j–4l in high yields withdrawing group (NO 2afforded ) on benzene ring gave the products high yields 7–9). the substituents on the 1-tetralones were investigated. As aain result, entries 7–9). Subsequently, the substituents on the 1-tetralones were investigated. As the reactions ofSubsequently, 1-tetralones with electron-donating group (MeO), halogen (Br) and electronHalogens (F, Cl,(NO Br) were tolerated well and excellent yields (89%–90%) were obtained (Table 2,the Halogens Cl, In Br)In were tolerated well and excellent yields (89%–90%) were obtained (Table 2, entries 7–9). Subsequently, the substituents on the 1-tetralones were investigated. As aaand the electron-withdrawing group on the benzene gave the corresponding products 4j–4l in high reactions of 1-tetralones with electron-donating group (MeO), halogen (Br) electron(Table entries 10–12). addition, a high yield (89%) was observed when 1-indanone was subjected reactions of(F, 1-tetralones with electron-donating group (MeO), halogen (Br) electron(Table 2, 2, entries 10–12). addition, high yield (89%) was observed when 1-indanone was subjected entries 7–9). Subsequently, the on thering 1-tetralones were investigated. Asand result, the withdrawing group (NO 2) (NO on the benzene ring gave the corresponding products 4j–4l inresult, high yields 2 )asubstituents entries 7–9). Subsequently, the substituents on the the 1-tetralones were halogen investigated. As a result, the reactions of 1-tetralones electron-donating group (MeO), (Br) and electronwithdrawing group (NO 22)2)on the benzene ring gave corresponding products 4j–4l in high yields reactions of 1-tetralones with electron-donating group (MeO), halogen (Br) and electronwithdrawing group (NO onwith the benzene ring gave the corresponding products 4j–4l in1-indanone high yields was (Table 2,reaction entries 10–12). In addition, a high yield (89%) waswhen observed when (Table 2, entries 10–12). In addition, a high yield (89%) was observed 1-indanone was subjected to optimal conditions (Table entries 13). toyields thethe optimal reaction conditions (Table 2, 2, entries 13). reactions of 1-tetralones with electron-donating group (MeO), halogen (Br) and electronwithdrawing group (NO 2) on the benzene ring gave the corresponding products 4j–4l in high yields withdrawing group (NO 2addition, ) on the benzene ring gave the corresponding products 4j–4l inwas high yields (Table 2, 10–12). In aahigh (89%) was observed 1-indanone subjected (Table 2,entries entries 10–12). Inaddition, high2,yield yield (89%) was observed when 1-indanone was subjected to the optimal reaction conditions (Table entries 13). subjected to the optimal reaction conditions (Table 2,the entries 13). when withdrawing group (NO on the benzene ring gave corresponding products 4j–4l was in high yields (Table 2, entries 10–12). In2)addition, a high yield (89%) was observed when 1-indanone subjected a

(Table 2, entries 10–12). In addition, a high yield (89%) was observed when 1-indanone was subjected totothe optimal conditions (Table 2,2,entries 13). a. a. the optimal reaction conditions (Table entries 13). Table 2.reaction FeCl 3∙6H 2O/TMSBr catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-thiones Table FeCl 3∙6H 2O/TMSBr catalyzed ofwas 3,4-dihydropyrimidin-2(1H)-thiones (Table 2,2.entries 10–12). In addition, a high2,synthesis yield (89%) observed when 1-indanone was subjected to reaction conditions (Table 13). to the the optimal optimal reaction conditions 2, entries entries 13).of 3,4-dihydropyrimidin-2(1H)-thiones a. a. Table 2. FeCl 3∙6H 2O/TMSBr (Table catalyzed synthesis Table 2. FeCl synthesis 3 ·6H2 O/TMSBr to the optimal reaction conditions catalyzed (Table 2, entries 13). of 3,4-dihydropyrimidin-2(1H)-thiones a a.a Table 22O/TMSBr Table2.2.FeCl FeCl33∙6H 3∙6H 2O/TMSBrcatalyzed catalyzedsynthesis synthesisofof3,4-dihydropyrimidin-2(1H)-thiones 3,4-dihydropyrimidin-2(1H)-thiones . a

Table 2. FeCl3∙6H2O/TMSBr catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-thiones a. Table 2. FeCl3∙6H2O/TMSBr catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-thiones . Table 2. FeCl3∙6H2O/TMSBr catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-thiones a.

Entry Ketones Entry (1)(1)(1) Entry Ketones Ketones Entry Entry Entry Entry Entry Entry

1 1

1 11 11 1

2

Ketones (1) Ketones (1)(1) Ketones Ketones Ketones(1) (1) Ketones (1)

Benzaldehydes (2) Benzaldehydes Benzaldehydes(2) (2) Benzaldehydes (2) Benzaldehydes (2) Benzaldehydes (2) Benzaldehydes Benzaldehydes (2) (2) Benzaldehydes (2)

Products Products (4)(4) Products (4) Products (4)

Products (4) Products(4) (4) Products Products (4) Products (4)

b b b (%) Yield Yield Yield (%)(%) Yield (%)b b

b bb Yield (%) Yield (%) Yield (%) b Yield (%) Yield (%) b

88 8888

88 88 88 8888 88

86

2 2 22 22 2

86 8686 868686 86 86

3 3 3 3 3 3 33 3

83 83 8383 83 83 838383

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Entry

Ketones (1)

Table 2. Cont. Benzaldehydes (2)

Products (4)

44of of16 16 4 of 16 of 16 444of of 16 of 16 16 of 16 of16 16 4444of 4of of16 16 of 16 of 16 444b

Yield (%)

44 4 444444 4 4444

80 80 80 80 80 80 80 80 80 8080 80 80 80

55 5 55555 5 5555

91 91 91 91 91 91 91 91 9191 91 91 91

66 66666 6 6 6 6666

76 76 76 76 76 76 76 7676 76 76 76 76 76

77 7 7777

89 89 89 89 89 89 89 8989 89 89 89 89 89

88

90 90 90 90 90 90 9090 90 90 90 90 90

7 7777777

8 888888

8888

9999

90 90 90 90 90 90 90 9090 90 90 90 90 90

10 10 10 1010 10 10 10

10 10 10 10 10 10 10

84 84 84 84 84 84 84 8484 84 84 84 84 84

11 11 1111 11 11 11

11 11 11 11 11 11 11

86 86 86 86 86 86 86 8686 86 86 86 86 86

12 12 12 12 12 12 12 12 12 12

92 92 92 92 92 92 92 92 92 92 92 92 92 92

1313 13

89 89 89 89 89 89 89 89 89 89 89 89 89 89

99

9 9999999

12 1212 12 12

13 13 13 13 13 13 13 13 13 13 13

aaaReaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3a (0.75 mmol), FeCl33∙6H22O (0.05 mmol) and TMSBr Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3a (0.75 mmol), FeClO3∙6H 2O (0.05 mmol) and TMSBr a Reaction Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3a (0.753a mmol), FeCl3 ·FeCl 6H (0.05 mmol) and TMSBr (0.5 mmol) in 2 33∙6H conditions: (0.5 mmol), mmol), 2 (0.5 (0.5 mmol), mmol), (0.75 mmol), mmol), ∙6H 2O (0.05 mmol) and TMSBr TMSBr aaaaaaaaaaReaction Reaction conditions: 1111(0.5 (0.5 3a (0.75 FeCl O (0.05 mmol) and 3∙6H 2O Reaction conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl 33∙6H ∙6H 22O O (0.05 mmol) and TMSBr Reaction conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl 3∙6H ∙6H 2O O (0.05 mmol) and TMSBr conditions: mmol), 22222222(0.5 mmol), 3a mmol), FeCl 33333 222222 mmol) and TMSBr Reaction conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl (0.05 mmol) and TMSBr ◦ C333for bTMSBr Reaction conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl (0.05 mmol) and Reaction conditions: (0.5 mmol), (0.5for mmol), 3a(0.75 (0.75 mmol), FeCl ∙6H O(0.05 (0.05 mmol) andat TMSBr a (0.5 mmol) in CN mL) at °C 2irradiation microwave irradiation (sealed vessel fixed (0.5 mmol) in CH CH CN112111(3.0 (3.0 mL) at 90 90 °C for 2 hh under under microwave irradiation (sealed vessel at fixed yield. CH3 CNa(0.5 (3.0 mL) at 90 h under microwave (sealed vessel at fixed power, 30 W); Isolated Reaction conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl 3∙6H 2O (0.05 mmol) and TMSBr a aa Reaction mmol) in CH 3CN 1 (3.0 mL) at 90 °C for 2h hhunder under microwave irradiation (sealed vessel at fixed Reaction conditions: 1(3.0 (0.5 mmol), (0.5 mmol), 3a(0.75 (0.75 mmol),FeCl FeCl 3∙6H ∙6H 2O O(0.05 (0.05 mmol) and TMSBr conditions: (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl ∙6H O (0.05 mmol) and TMSBr Reaction conditions: 1(3.0 (0.5 mmol), (0.5 mmol), 3a (0.75 mmol), FeCl (0.05 mmol) and TMSBr Reaction conditions: (0.5 mmol), 2222(0.5 mmol), 3a mmol), 333∙6H 222O mmol) and TMSBr (0.5 mmol) in CH CN mL) at 90 °C for microwave irradiation (sealed vessel at fixed (0.5 mmol) in CH 3CN CN mL) at 90 °C for under microwave irradiation (sealed vessel at fixed bbCH 33CN 3CN (0.5 mmol) in 333333 mL) °C microwave irradiation (sealed vessel at bCH (0.5 mmol) in CH (3.0 mL) at 90 °C for hhhunder under microwave irradiation (sealed vessel at fixed (0.5 mmol) in (3.0 mL) at 90 °C for under microwave irradiation (sealed vessel at fixed (0.5 mmol) inCH CN1(3.0 (3.0 mL)at at90 90 °Cfor for2222222h under microwave irradiation (sealed vessel atfixed fixed Isolated yield. power, 30 Isolated yield. power, 30W); W); (0.5 mmol) in CH 3CN (3.0 mL) at 90 °C for h under microwave irradiation (sealed vessel at fixed b Isolated yield. power, 30 W); W); b b (0.5 mmol) in CH 3CN CN (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed (0.5 mmol) in CH 33CN CN (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed bbb (0.5 mmol) in CH (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed b (0.5 mmol) in CH 3 (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed b Isolated yield. power, 30 b b b Isolated yield. power, 30 W); Isolated yield. power, 30 W); Isolated yield. power, 30 W); Isolated yield. power, 30 W); Isolated yield. power, 30 W); Isolatedyield. yield. power,30 30W); W);b Isolated power, b Next, aa30 wide of structurally diverse and to Next, wide range ofyield. structurally diverse ketones, ketones, benzaldehydes benzaldehydes and urea urea were were subjected subjected to Isolated yield. power, 30 W);bbbrange Isolated power, W); Isolated yield. power, 30 W); Isolated W); Next, apower, wide range of structurally diverse ketones, benzaldehydes and urea were subjected Next, a30 wide range ofyield. structurally diverse ketones, benzaldehydes and urea were subjected to

a

to Next, a wide wide range of structurally diverse ketones, benzaldehydes and urea were subjected to Next, range of structurally diverse ketones, benzaldehydes and urea were subjected to Next, wide range of structurally diverse ketones, benzaldehydes and urea were subjected to Next, wide range of structurally diverse ketones, benzaldehydes and urea were subjected to Next,aaaaareaction widerange range ofstructurally structurally diverse ketones, benzaldehydes andurea ureawere weresubjected subjectedto to the conditions to the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal optimal reaction conditions to produce produce theketones, corresponding 3,4-dihydropyrimidin-2(1H)-ones in Next, wide of diverse benzaldehydes and the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in Next,aaaareaction widerange range ofstructurally structurally diverse ketones, benzaldehydes andurea ureawere weresubjected subjectedin to Next, wide range of structurally diverse ketones, benzaldehydes and urea were subjected to Next, wide range of structurally diverse ketones, benzaldehydes and urea were subjected to Next, wide of diverse benzaldehydes and to the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones theoptimal optimal reaction conditions toof produce theketones, corresponding 3,4-dihydropyrimidin-2(1H)-ones in high yields 3). The benzaldehyde furnished product 3, high yields (Table (Table 3).conditions The reaction reaction of benzaldehyde furnished the the product 6a 6a in in 90% 90% yield yield (Table (Tablein 3, the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, theoptimal optimal reaction conditions toof produce thecorresponding corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the optimal reaction conditions to produce the corresponding 3,4-dihydropyrimidin-2(1H)-ones in the reaction conditions to produce the 3,4-dihydropyrimidin-2(1H)-ones in high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, high yields (Table 3). The reaction benzaldehyde furnished the product 6a in 90% yield (Table 3, highyields yields(Table (Table3). 3).The Thereaction reactionofofbenzaldehyde benzaldehydefurnished furnishedthe theproduct product6a 6ainin90% 90%yield yield(Table (Table3,3, 3, high high yields(Table (Table3). 3). Thereaction reactionof ofbenzaldehyde benzaldehyde furnished theproduct product6a 6ain in90% 90%yield yield (Table 3, , CN) high yields The furnished the (Table 3, high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, high yields (Table 3). The reaction of benzaldehyde furnished the product 6a in 90% yield (Table 3, entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO 2 and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields (Table 3, entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group (MeO),

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entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO2, CN) entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) entry 1). 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) entry Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO 222,,2,,CN) and halogens (F, Cl, Br) also reacted smoothly togroup achieve the desired products 6b–6g in high yields 22, CN) entry 1).Benzaldehydes Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO entry 1). Benzaldehydes with electron-donating (Me), electron-withdrawing groups (NO 222,,, CN) entry with electron-donating group (Me), electron-withdrawing groups (NO 2222,, CN) entry 1).1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) entry 1). Benzaldehydes with electron-donating group (Me), electron-withdrawing groups (NO CN) and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields 3, entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group halogen(Table (Br) and electron-withdrawing group (NO ) on the benzene ring afforded the corresponding and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields 2 and halogens (F, Cl, Br) also reacted smoothly to achieve the desired products 6b–6g in high yields and halogens (F, Cl, Br) also reacted smoothly to the desired products 6b–6g in yields andand halogens (F, (F, Cl,Cl, Br)Br) also reacted smoothly to achieve achieve thethe desired products 6b–6g in high high yields halogens also reacted smoothly to achieve desired products 6b–6g in high yields (Table 3, entries entries 2–7). In addition, thethe reactions of 1-tetralones carrying electron-donating group (Table 3, entries 2–7). In addition, reactions of 1-tetralones carrying electron-donating group (Table 3, entries entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group (MeO), halogen (Br) and electron-withdrawing group (NO 2) on carrying the benzene ring were afforded the (Table entries 2–7). Inaddition, addition, the reactions of1-tetralones 1-tetralones carrying electron-donating group (Table 3, entries 2–7). In addition, the reactions of 1-tetralones electron-donating group (Table 3, 2–7). In reactions of carrying electron-donating group (Table 3, entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group products 6h–6j yields (Table 3, entries 8–10). Pleasingly, high yields also obtained (Table 3, 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group (Table 3,in entries 2–7). In addition, thethe reactions of 1-tetralones carrying electron-donating group (Table 3,3,81%–88% entries 2–7). In addition, the reactions of 1-tetralones carrying electron-donating group (MeO), halogen (Br) and electron-withdrawing group (NO on the benzene ring afforded the (MeO), halogen (Br) and electron-withdrawing group (NO 2) ) on thePleasingly, benzene ring afforded thethe (MeO), halogen (Br) and electron-withdrawing group (NO 2on )2))) on on the benzene ring afforded the corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). high yields were (MeO), halogen (Br) and electron-withdrawing group (NO on the benzene ring afforded the 222) (MeO), halogen (Br) and electron-withdrawing group (NO 2 on the benzene ring afforded the (MeO), halogen (Br) and electron-withdrawing group (NO 2 the benzene ring afforded (MeO), halogen (Br) and electron-withdrawing group (NO on the benzene ring afforded (MeO), halogen (Br) and electron-withdrawing group (NO 2 ) the benzene ring afforded the (MeO), halogen (Br)(Br) andand electron-withdrawing group (NO 2) 2on the benzene ring afforded thethe (MeO), halogen electron-withdrawing group (NO 2) on the benzene ring the when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11afforded and 12), these corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11 corresponding products 6h–6j in81%–88% 81%–88% yields (Table 3,entries entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in yields (Table 3, 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were corresponding products 6h–6j in 81%–88% yields (Table 3, entries 8–10). Pleasingly, high yields were findings further broadened the substrate scope of this methodology. It should be noted that the also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3, noted entries 11 also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11 and 12), these findings further broadened the substrate scope of this methodology. It should also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11 also obtained when 1-indanone and 4-chromanone were employed assubstrates substrates (Table entries 11 also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3, entries 11 also obtained when 1-indanone and 4-chromanone were employed as substrates substrates (Table 3, be entries 11 11 also obtained when 1-indanone and 4-chromanone were employed as (Table 3, entries also obtained when 1-indanone and 4-chromanone were employed as (Table 3, also obtained when 1-indanone and 4-chromanone were employed as substrates (Table 3,3,entries entries 11 1 H-NMR 1311 structures of compounds 4 and 6 were confirmed by (see Supplementary Files), C-NMR 1H-NMR 13Cand 12), these findings further broadened the substrate scope of this methodology. It should should be noted and 12), these findings further broadened the substrate scope of this methodology. It be noted that the structures of compounds 4broadened and 6 were confirmed byscope (see Supplementary Files), and 12), these findings further broadened the substrate scope of this methodology. It should be noted and 12), these findings further broadened the substrate scope ofthis this methodology. should be noted and 12), these findings further broadened the substrate scope of this methodology. It should be noted and 12), these findings further broadened thethe substrate scope of this this methodology. It should should be be noted and 12), these findings further broadened the substrate scope of methodology. It be noted and 12), these findings further substrate of methodology. It noted and 12), these findings further broadened the substrate scope of this methodology. ItItshould should be noted 13 13C111H-NMR 13 13 13 (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). that the structures of compounds 4 and 6 were confirmed by (see Supplementary Files), Cthat the structures of compounds 4 and 6 were confirmed by H-NMR (see Supplementary Files), that the structures of compounds 4 and 6 were confirmed by (see Supplementary Files), C111by 13 NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). 1111H-NMR 13 13 1 13 that the structures of compounds 4 and 6 were confirmed H-NMR (see Supplementary Files), Cthat the structures of compounds 4 and 6 were confirmed by H-NMR (see Supplementary Files), C1 13 that the structures of compounds 4 and 6 were confirmed by H-NMR (see Supplementary Files), C13C13Cthat the structures of 44 and 66 were confirmed by H-NMR (see Supplementary Files), that structures of 44 and 66 were confirmed H-NMR (see Supplementary Files), that thethe structures of compounds compounds and were confirmed byby H-NMR (see Supplementary Files), Cthat the structures of compounds compounds and were confirmed by H-NMR (see Supplementary Files), CNMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) and high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) andand high-resolution mass (HRMS). NMR (see Supplementary Files), Low-resolution mass (LRMS) high-resolution mass (HRMS). a Table 2O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones . Table 3. FeCl3.3 FeCl ·6H23∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones a . aa aa Table 3. FeCl FeCl synthesis of 3,4-dihydropyrimidin-2(1H)-ones Table 3. FeCl 333∙6H 222O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones Table 3. FeCl 33∙6H 22O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones aaa... aaaaa...a. . Table FeCl 3∙6H 2O/TMSBr-catalyzed O/TMSBr-catalyzed synthesis of3,4-dihydropyrimidin-2(1H)-ones 3,4-dihydropyrimidin-2(1H)-ones Table 3. ∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones Table 3. FeCl ∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones Table 3. FeCl ∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones Table 3. 333∙6H 222∙6H O/TMSBr-catalyzed synthesis of Table 3. 3333∙6H 2222O/TMSBr-catalyzed synthesis of Table 3. FeCl FeCl ∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones 3,4-dihydropyrimidin-2(1H)-ones . .. Table 3.3.FeCl FeCl ∙6H O/TMSBr-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Entry Ketones (1) Benzaldehydes (2) Ketones (1) Benzaldehydes (2) Entry Ketones (1) Benzaldehydes (2) Entry Ketones (1) Benzaldehydes (2)(2) Entry Ketones (1) Benzaldehydes Entry Ketones Ketones (1) Benzaldehydes Benzaldehydes (2) Entry Ketones (1) Benzaldehydes (2) Entry Ketones (1) Benzaldehydes (2) Entry (1) (2) Entry Ketones Benzaldehydes Entry Ketones (1)(1) Benzaldehydes (2)(2) Entry Ketones (1) Benzaldehydes (2)

EntryEntry Entry 1

1

111 111111

2

2

2222 222222

3

3

3333 333333

4

4

4444 444444

5

5

555 555555

6

6

6666 666666

7

7

7777 777777

8

8

888 888888

Products (6) Products (6) Products (6) Products (6)(6) Products Products (6) Products (6) Products (6) Products (6) Products Products (6)(6) Products (6)

Yield (%) b b Yield (%) b b bb b Yield (%) Yield (%)(%) Yield bb b bb Yield (%) Yield (%) Yield (%) b b b Yield (%) Yield Yield (%)(%) Yield (%) 90 90 90 90 90 90 90 90 90 90 90

86 86 86 86 86 86 86 86 86 86 86 86

91 91 91 91 91 91 91 91 91 91 91 91

84 84 84 84 84 84 84 84 84 84 84 84

82 82 82 82 82 82 82 82 82 82 82

90 90 90 90 90 90 90 90 90 90 90 90

80 80 80 80 80 80 80 80 80 80 80 80

81 81 81 81 81 81 81 81 81 81 81

Molecules 2017, 22, 22, 1503 Molecules 2017, 22, 1503 1503 Molecules 2017,

9

6 of6616 of 16 16 of

9 99

83 83 83 83

10 10 10

88 88 88

11 11 11

87 87 87

Molecules 2017,Molecules 22, 1503 2017, 22, 1503

6 of 16

616 of16 16 of 16 of66616 16 666of of 16 of of

Molecules 2017, 22, 1503 Molecules 2017, 22,1503 1503 Molecules 2017, 22, Molecules 2017, 22, 1503 1503 Molecules 2017, 22, 1503 Molecules 2017, 22,

Table 3. Cont. 99 999

Entry

83 83 83 83 83

Ketones (1)

Benzaldehydes (2)

Products (6)

Yield (%) b

10 10 10 10 10

88 88 88 88 88

11 11 11 11 11 11

87 87 87 87 87 87

12 12 12 12 12 12

82 82 82 82 82 82

aaaaReaction aaa Reaction Reaction conditions: (0.5 mmol), (0.5 mmol), 5a(0.75 (0.75 mmol), FeCl 32∙6H 2O(0.05 (0.05 mmol) and TMSBr conditions: (0.5 mmol), (0.5 mmol), 5a(0.75 (0.75 mmol), FeCl ∙6H O(0.05 (0.05 mmol) and TMSBr 111(0.5 mmol), 222(0.5 mmol), 5a mmol), FeCl 333∙6H 22(0.05 mmol) and TMSBr conditions: 111(0.5 mmol), 222(0.5 mmol), 5a mmol), FeCl 333∙6H mmol) and TMSBr Reaction conditions: mmol), (0.5 mmol), 5a (0.75 mmol), FeCl ∙6H 2O O (0.05 mmol) and TMSBr Reaction conditions: (0.5 mmol), (0.5 mmol), 5a (0.75 mmol), FeCl ∙6H 22O O mmol) and TMSBr Reaction Reaction conditions: 1conditions: (0.5 mmol), 2(0.5 (0.5 mmol), 5a (0.75 mmol), FeCl 3 ·6H2 O (0.05 mmol) and TMSBr (0.5 mmol) in 3 CN (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed (0.5 mmol) in CH 3 CN (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed 3 CN (3.0 mL) at 90 °C for 2 h under microwave irradiation (sealed vessel at fixed (0.5 mmol) in CH (0.5 mmol) in CH bat 3CH mL) at 2for microwave irradiation (sealed vessel fixed (0.5 mmol) in CN (3.0 mL) at°C 90 for °C under microwave irradiation (sealed vessel at fixed fixed (0.5 mmol) infor 3CN CN (3.0 mL) at 90 90 °C forirradiation 2 hh22under under microwave irradiation (sealed vessel atIsolated fixed (0.5(0.5 mmol) in◦CH CH (3.0 mL) at 90 °C for hh under microwave (sealed vessel at mmol) in CH CH3 CN (3.0 mL) at 90 C 233CN h(3.0 under microwave (sealed vessel atirradiation fixed power, 30 W); yield. b Isolated bbbbIsolated b Isolated yield. power, 30 W); b yield. power, 30 W); yield. power, 30 W); Isolated yield. power, 30 Isolated yield. power, 30 W); Isolated yield. power, 30W); W);

a

3. Materials and Methods 3.Materials Materials and Methods 3. and Methods 3. and Methods 3. Materials and Methods 3.Materials Materials and Methods 3.1. General Information 3.1. General Information General Information 3.1. General Information 3.1. General Information 3.1.3.1. General Information The reagents were purchased from commercial suppliers and used without further purification. The reagents were purchased from commercial suppliers and used without further purification. The reagents were purchased from commercial suppliers and used without further purification. The reagents were purchased from commercial suppliers and used without further purification. The reagents were purchased from commercial suppliers and used without further purification. The reagents were purchased from commercial suppliers and used without further purification. Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), Analytical thin-layer chromatography (TLC) was performed on HSGF 254 (0.15–0.2 mm thickness), visualized by irradiation with UV light (254 nm). Column chromatography was performed using visualized irradiation with UV light (254 nm). Column chromatography was performed using visualized by irradiation with UV light (254 nm). Column chromatography was performed using visualized by irradiation with UV light (254 nm). Column chromatography was performed using visualized byby irradiation with UV light (254 nm). Column chromatography was performed using visualized by irradiation with UV light (254 nm). Column chromatography was performed using silica gel FCP 200–300. Melting points were measured with micro melting point apparatus. Nuclear silica FCP 200–300. Melting points were measured with aaamicro melting point apparatus. Nuclear silica gel FCP 200–300. Melting points were measured with aamicro melting point apparatus. Nuclear silica gel FCP 200–300. Melting points were measured with micro melting point apparatus. Nuclear silica gelgel FCP 200–300. Melting points were measured with micro melting point apparatus. Nuclear silica gelmagnetic FCP 200–300. Melting points were measured withAMX-300 aAMX-300 micro melting point apparatus. Nuclear magnetic resonance spectra were recorded Brucker AMX-300 or 400 400 or 500 500 MHz instrument magnetic resonance spectra were recorded aaa Brucker or or MHz instrument resonance spectra were recorded on aon or or MHz instrument magnetic resonance spectra were recorded on Brucker AMX-300 or 400 or 500 MHz instrument magnetic resonance spectra were recorded onon a Brucker Brucker AMX-300 or 400 400 or 500 500 MHz instrument magnetic resonance spectra were recorded on a Brucker AMX-300 or 400 or 500 MHz instrument [TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts per [TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts [TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts per [TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts perper million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as [TMS (Tetramethylsilane) as IS (Internal Standard)]. Chemical shifts were reported in parts per million million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns were described as as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low and high-resolution singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low and high-resolution singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low and high-resolution (s), (s), doublet triplet (t), (t), quartet (q),Proton multiplet (m),(m), andand broad (br).(br). Low and high-resolution singlet doublet (d), triplet quartet (q), multiplet broad Low and high-resolution (ppm, δ)singlet downfield from(d), tetramethylsilane. coupling patterns were described as singlet (s), mass (LRMS and HRMS) were measured bythe the EI(Electron (Electron Ionization) method with Tsou-EI mass mass (LRMS and HRMS) were measured EI Ionization) method with aaaTsou-EI mass (LRMS and HRMS) were measured by the EI Ionization) method with aaTsou-EI mass mass (LRMS and HRMS) were measured by the EI (Electron Ionization) method with Tsou-EI mass mass (LRMS and HRMS) were measured byby the EI(Electron (Electron Ionization) method with Tsou-EI mass doublet mass (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low and high-resolution mass spectrometer. All the microwave-assisted reactions were performed insealed sealed tubes (capacity 10mL) mL) spectrometer. microwave-assisted reactions were performed in tubes (capacity 10 spectrometer. All the microwave-assisted reactions were performed in tubes (capacity 10 spectrometer. All the microwave-assisted reactions were performed in sealed tubes (capacity 10 mL) spectrometer. AllAll thethe microwave-assisted reactions were performed insealed sealed tubes (capacity 10mL) mL) (LRMS andunder HRMS) were atmosphere measured under by the EI (Electron Ionization) method with athe Tsou-EI mass nitrogen microwave heating system (CEM Discover at the specified under aaa nitrogen atmosphere under aaamicrowave heating system (CEM Discover at specified under aa nitrogen atmosphere under aa microwave heating system (CEM Discover )) at specified under nitrogen atmosphere under microwave heating system (CEM Discover at the specified under nitrogen atmosphere under microwave heating system (CEM Discover at)))the the specified spectrometer. All the microwave-assisted reactions were performed in sealed tubes (capacity 10 temperature. A feedback feedback mechanism was involved in the the temperature control system, and themL) temperature. A mechanism was involved temperature control system, and temperature. A mechanism was involved in the temperature control system, and the temperature. A feedback mechanism was involved in the temperature control system, and the temperature. A feedback feedback mechanism was involved in in the temperature control system, and thethe under areaction nitrogen atmosphere under a microwave heating system (CEM Discover) at the specified reaction temperature which could be read from the temperature display screen was real-time reaction temperature which could read from temperature display screen was real-time temperature which could be read from the temperature display screen was real-time reaction temperature which could be read from the temperature display screen was real-time reaction temperature which could be be read from thethe temperature display screen was real-time monitored. Itshould should benoted noted that fixed power (30 W) was found toappropriate beappropriate appropriate toachieve achieve the temperature. A feedback mechanism was in the temperature control system, and the reaction monitored. It be that aaainvolved fixed power was found to be to the monitored. ItItshould be that aafixed power (30 W) was found to to the monitored. It should be noted that fixed power (30 W) was found to be appropriate to achieve the monitored. should be noted noted that fixed power (30(30 W)W) was found tobe be appropriate toachieve achieve the reaction temperature (90 °C) without overheating since a higher power led to the loss of efficacy of reaction temperature (90 °C) without overheating since a higher power led to the loss of efficacy reaction temperature (90 °C) without overheating since a higher power led to the loss of efficacy of reaction temperature without since a higher power led towas the loss of efficacy of of temperature which could (90 be °C) read fromoverheating the temperature display screen real-time monitored. the temperature control system which resulted in overheating. the temperature control system which resulted in overheating. the temperature control system which resulted in overheating. thebe temperature control system which resulted in overheating. It should noted that a fixed power (30 W) was found to be appropriate to achieve the reaction ◦ temperature (90 C)Procedure without a higher power led to the 3.2. General Procedure foroverheating the Synthesis ofsince 3,4-Dihydropyrimidin-2(1H)-thiones (4) loss of efficacy of the General the Synthesis of 3,4-Dihydropyrimidin-2(1H)-thiones 3.2. General Procedure for the Synthesis ofof3,4-Dihydropyrimidin-2(1H)-thiones (4) 3.2. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-thiones (4) 3.2.3.2. General Procedure forfor the Synthesis 3,4-Dihydropyrimidin-2(1H)-thiones (4)(4) temperature control system which resulted in overheating. A high-pressure high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol), A microwave vessel (capacity mL) was loaded with ketones (0.5 mmol), A microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol), A high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol), A high-pressure high-pressure microwave vessel (capacity 10 10 mL) was loaded with ketones (0.5 mmol), benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl 3∙6H 2O O(0.05 (0.05 mmol) and TMSBr (0.5 mmol) in 22(0.05 benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl 333∙6H 2(0.05 O mmol) and TMSBr (0.5 mmol) benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl 333∙6H 2∙6H mmol) and TMSBr (0.5 mmol) in benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl (0.05 mmol) and TMSBr (0.5 mmol) in benzaldehydes (0.5 mmol), thiourea (0.75 mmol), FeCl ∙6H 22O O mmol) and TMSBr (0.5 mmol) in in 3.2. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-thiones (4) 3CN CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was 333CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then mixture was CH 3CH (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was CH (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was CHCH 33CN CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then thethe mixture was heated to°C 90for °C 2under under microwave irradiation using CEM Discover (fixed power, 30W). W). After heated to 90 °C for hhunder microwave irradiation aawas CEM Discover (fixed power, 30 After heated to90 90 °C for 2hh2under microwave irradiation using CEM Discover (fixed power, 30W). W). After heated to 2for microwave irradiation using aaCEM Discover (fixed power, 30 After A high-pressure microwave vessel (capacity 10using mL) loaded with ketones (0.5 mmol), cooling, the solids which had precipitated out were separated by filtration, and the solids obtained cooling, the solids which had precipitated out were separated by filtration, and the solids obtained cooling, the solids which had precipitated out were separated by filtration, and the solids obtained cooling, the which had precipitated out were separated by filtration, and theTMSBr solids obtained benzaldehydes (0.5solids mmol), thiourea (0.75 mmol), FeCl · 6H O (0.05 mmol) and (0.5 mmol) in 3 2 were washed with 3CN CN togive give the desired products 4. were washed with CHCH CN togive give thethe desired products were washed with 333CN to desired products were washed with CH 3CH to the desired products 4.4. 4. were washed with CH to give the desired products 4. 33CN

CH3 CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was ◦ C for 2 h under microwave irradiation using a CEM Discover (fixed power, 30 W). After heated to 90 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246– 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246– 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246– 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246– 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246– 111H-NMR 1H-NMR 1 1 248 °C. H-NMR (500 MHz, DMSO) δ 9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35 (m, 1 cooling,248 the solids which had precipitated out were separated by filtration, and the solids obtained 248 °C. (500 MHz, DMSO) δ 9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35 (m, 2H), 248 °C. (500 MHz, DMSO) δ 9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35 (m, 2H), °C. H-NMR (500 MHz, DMSO) δ 9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35 (m, 2H),2H), were washed with CH3 CN to give the desired products 4.

4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4a): White solid (128.7 mg, 88%), m.p. 246–248 ◦ C. 1 H-NMR (500 MHz, DMSO) δ 9.76 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.39–7.35 (m, 2H), 7.34–7.28 (m, 3H), 7.24–7.16 (m, 2H), 7.15 (d, J = 6.6 Hz, 1H), 4.95 (s, 1H), 2.77–2.65 (m, 1H), 2.61–2.52 (m, 1H), 2.22–2.12 (m, 1H), 1.88–1.77 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.28, 142.90,

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135.45, 128.75, 127.98, 127.81, 127.75, 127.64, 127.02, 126.69, 126.38, 121.71, 111.23, 58.51, 27.37, 23.65. LRMS (EI): 292 (M+ ); HRMS (EI) calcd. for C18 H16 N2 S (M+ ) 292.1034, found: 292.1031. 4-p-Tolyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4b): White solid (131.3 mg, 86%), m.p. 230–232 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 9.04 (s, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.23–7.15 (m, 7H), 4.90 (s, 1H), 2.71 (dt, J = 15.4, 7.6 Hz, 1H), 2.64–2.53 (m, 1H), 2.28 (s, 3H), 2.23–2.10 (m, 1H), 1.89–1.77 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.15, 139.99, 137.20, 135.43, 129.25, 127.78, 127.75, 127.61, 126.96, 126.59, 126.35, 121.67, 111.37, 58.21, 27.36, 23.62, 20.75. LRMS (EI): 306 (M+ ); HRMS (EI) calcd. for C19 H18 N2 S (M+ ) 306.1191, found: 306.1192. 4-(3,4,5-Trimethoxyphenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4c): White solid (158.6 mg, 83%), m.p. 224–226 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 9.01 (s, 1H), 7.75–7.53 (m, 1H), 7.31–7.09 (m, 3H), 6.64 (s, 2H), 4.92 (s, 1H), 3.74 (s, 6H), 3.65 (s, 3H), 2.80–2.70 (m, 1H), 2.70–2.58 (m, 1H), 2.29–2.12 (m, 1H), 2.04–1.84 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.21, 152.99, 138.30, 137.12, 135.51, 127.76, 127.73, 127.60, 126.92, 126.32, 121.65, 111.01, 104.22, 59.99, 58.43, 55.86, 27.39, 23.59. LRMS (EI): 382 (M+ ); HRMS (EI) calcd. for C21 H22 N2 O3 S (M+ ) 382.1351, found: 382.1349. 4-O-tolyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4d): White solid (122.9 mg, 80%), m.p. 241–242 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.97 (s, 1H), 7.70 (dd, J = 8.3, 6.4 Hz, 1H), 7.33–7.07 (m, 7H), 5.25 (d, J = 2.0 Hz, 1H), 2.76–2.64 (m, 1H), 2.60–2.52 (m, 1H), 2.41 (s, 3H), 2.18–1.99 (m, 1H), 1.77–1.59 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 173.94, 140.83, 135.64, 135.41, 130.60, 128.42, 127.85, 127.71, 127.68, 127.56, 126.74, 126.59, 126.33, 121.62, 111.15, 55.55, 27.28, 23.31, 18.83. LRMS (EI): 306 (M+ ); HRMS (EI) calcd. for C19 H18 N2 S (M+ ) 306.1191, found: 306.1193. 4-(3-Nitrilephenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4e): White solid (144.1 mg, 91%), m.p. 243–244 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.12 (s, 1H), 7.83–7.78 (m, 1H), 7.73 (s, 1H), 7.72–7.59 (m, 3H), 7.26–7.19 (m, 2H), 7.19–7.13 (m, 1H), 5.09 (s, 1H), 2.78–2.67 (m, 1H), 2.66–2.54 (m, 1H), 2.26–2.14 (m, 1H), 1.90–1.79 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.51, 144.24, 135.50, 131.83, 131.76, 130.51, 130.21, 127.94, 127.61, 127.47, 127.21, 126.31, 121.81, 118.63, 111.50, 110.19, 57.53, 27.22, 23.34. LRMS (EI): 317 (M+ ); HRMS (EI) calcd. for C19 H15 N3 S (M+ ) 317.0987, found: 317.0979. methyl 4-(2-Thioxo-1,2,3,4,5,6-hexahydrobenzo[h]quinazolin-4-yl)benzoate (4f): White solid (133.8 mg, 76%), m.p. 188–190 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 9.17 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 6.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.31–7.07 (m, 3H), 5.08 (s, 1H), 3.84 (s, 3H), 2.77–2.67 (m, 1H), 2.63–2.53 (m, 1H), 2.27–2.10 (m, 1H), 1.90–1.72 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.49, 165.99, 147.92, 135.49, 129.73, 129.18, 127.95, 127.66, 127.61, 127.37, 126.99, 126.38, 121.79, 110.49, 58.13, 52.24, 27.31, 23.52. LRMS (EI): 350 (M+ ); HRMS (EI) calcd. for C20 H18 N2 O2 S (M+ ) 350.1089, found: 350.1085. 4-(4-Fluorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4g): White solid (138.3 mg, 89%), m.p. 242–243 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 9.10 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.38–7.32 (m, 2H), 7.24–7.19 (m, 4H), 7.18–7.13 (m, 1H), 4.99 (s, 1H), 2.78–2.66 (m, 1H), 2.64–2.53 (m, 1H), 2.28–2.03 (m, 1H), 1.90–1.72 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.23, 161.77 (d, JC–F = 243.9 Hz), 139.13, 135.48, 129.07 (d, JC–F = 8.3 Hz), 127.86, 127.68, 127.64, 126.82, 126.37, 121.76, 115.55 (d, JC–F = 21.4 Hz), 111.05, 57.66, 27.34, 23.55. LRMS (EI): 310 (M+ ); HRMS (EI) calcd. for C18 H15 FN2 S (M+ ) 310.0940, found: 310.0933. 4-(4-Chlorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4h): White solid (146.8 mg, 90%), m.p. 226–228 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.11 (s, 1H), 7.72–7.64 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.23–7.18 (m, 2H), 7.07 (s, 1H), 4.99 (s, 1H), 2.78–2.66 (m, 1H), 2.67–2.54 (m, 1H), 2.24–2.12 (m, 1H), 1.88–1.75 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.26, 141.74, 135.43, 132.45, 128.84, 128.70, 127.83, 127.58, 126.87, 126.31, 121.72, 110.69, 57.64, 27.26, 23.46. LRMS (EI): 326 (M+ , Cl35 ), 328 (M+ , Cl37 ); HRMS (EI) calcd. for C18 H15 ClN2 S (M+ ) 326.0644, found: 326.0636. 4-(4-Bromophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4i): White solid (166.5 mg, 90%), m.p. 229–230 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 9.12 (s, 1H), 7.73–7.65 (m, 1H), 7.59

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(d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.24–7.13 (m, 3H), 4.97 (s, 1H), 2.77–2.65 (m, 1H), 2.64–2.54 (m, 1H), 2.27–2.09 (m, 1H), 1.89–1.74 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.27, 142.14, 135.44, 131.63, 129.20, 127.85, 127.59, 126.89, 126.32, 121.73, 121.05, 110.64, 57.72, 27.27, 23.46. LRMS (EI): 370 (M+ , Br79 ), 372 (M+ , Br81 ); HRMS (EI) calcd. for C18 H15 BrN2 S (M+ ) 370.0139, found: 370.0134. 8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4j): White solid (135.0 mg, 84%), m.p. 247–248 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 9.06 (s, 1H), 7.73–7.55 (m, 1H), 7.38 (dd, J = 8.9, 5.7 Hz, 2H), 7.34–7.27 (m, 3H), 6.82–6.69 (m, 2H), 4.92 (s, 1H), 3.74 (s, 3H), 2.76–2.63 (m, 1H), 2.63–2.53 (m, 1H), 2.22–2.10 (m, 1H), 1.87–1.72 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 174.20, 158.91, 143.10, 137.53, 128.74, 127.93, 127.01, 126.53, 123.12, 120.63, 113.97, 110.85, 108.56, 58.51, 55.18, 27.78, 23.62. LRMS (EI): 322 (M+ ); HRMS (EI) calcd. for C19 H18 N2 OS (M+ ) 322.1140, found: 322.1139. 9-Bromo-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4k): White solid (159.1 mg, 86%), m.p. 225–226 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 9.12 (s, 1H), 7.96 (s, 1H), 7.42–7.35 (m, 3H), 7.35–7.28 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 4.96 (s, 1H), 2.74–2.63 (m, 1H), 2.60–2.52 (m, 1H), 2.28–2.09 (m, 1H), 1.93–1.74 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 174.38, 142.67, 134.76, 130.27, 129.94, 129.58, 128.81, 128.07, 127.03, 125.93, 124.67, 119.60, 112.85, 58.44, 26.74, 23.51. LRMS (EI): 370 (M+ , Br79 ), 372 (M+ , Br81 ); HRMS (EI) calcd. for C18 H15 BrN2 S (M+ ) 370.0139, found: 370.0145. 9-Nitro-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione (4l): White solid (154.8 mg, 92%), m.p. 228–229 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 9.18 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 8.2, 2.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.43–7.37 (m, 2H), 7.36–7.31 (m, 3H), 5.00 (d, J = 2.4 Hz, 1H), 2.93–2.81 (m, 1H), 2.72 (ddd, J = 16.0, 9.0, 6.9 Hz, 1H), 2.37–2.15 (m, 1H), 2.02–1.78 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 174.53, 146.49, 143.72, 142.50, 129.21, 128.81, 128.09, 127.06, 125.73, 122.63, 116.89, 113.98, 58.33, 27.34, 23.02. LRMS (EI): 337 (M+ ); HRMS (EI) calcd. for C18 H15 N3 O2 S (M+ ) 337.0885, found: 337.0889. 4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2(5H)-thione (4m): White solid (123.4 mg, 89%), m.p. 199–201 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 9.07 (s, 1H), 7.96–7.71 (m, 1H), 7.42–7.24 (m, 7H), 7.22–7.11 (m, 1H), 5.51 (s, 1H), 3.33 (d, J = 23.8 Hz, 1H), 2.88 (d, J = 23.2 Hz, 1H). 13 C-NMR (126 MHz, DMSO) δ 174.24, 143.42, 142.26, 136.48, 132.95, 128.76, 127.75, 126.57, 126.40, 125.45, 124.09, 118.84, 115.34, 57.56, 34.92. LRMS (EI): 278 (M+ ); HRMS (EI) calcd. for C17 H14 N2 S (M+ ) 278.0878, found: 278.0877. 3.3. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones (6) A high-pressure microwave vessel (capacity 10 mL) was loaded with ketones (0.5 mmol), benzaldehydes (0.5 mmol), urea (0.75 mmol), FeCl3 ·6H2 O (0.05 mmol) and TMSBr (0.5 mmol) in CH3 CN (3.0 mL). The vessel was degassed, refilled with nitrogen, and sealed. Then the mixture was heated to 90 ◦ C for 2 h under microwave irradiation using a CEM Discover (fixed power, 30 W). After cooling, the solids which had precipitated out were separated by filtration, and the solids obtained were washed with CH3 CN to give the desired products 6. 4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6a): White solid (124.1 mg, 90%), m.p. 270–272 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.58 (dd, J = 13.4, 6.3 Hz, 1H), 7.39–7.30 (m, 5H), 7.30–7.24 (m, 1H), 7.25–7.12 (m, 3H), 4.94 (s, 1H), 2.75–2.65 (m, 1H), 2.62–2.52 (m, 1H), 2.19–2.03 (m, 1H), 1.84–1.65 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.49, 144.20, 135.47, 128.85, 128.65, 127.72, 127.67, 127.54, 127.52, 126.95, 126.40, 121.27, 108.16, 59.16, 27.66, 23.58. LRMS (EI): 276 (M+ ); HRMS (EI) calcd. for C18 H16 N2 O (M+ ) 276.1263, found: 276.1260. 4-M-tolyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6b): White solid (124.9 mg, 86%), m.p. 273–275 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.27–7.17 (m, 4H), 7.16–7.08 (m, 4H), 4.89 (s, 1H), 2.75–2.65 (m, 1H), 2.62–2.52 (m, 1H), 2.29 (s, 3H), 2.19–2.02 (m, 1H), 1.84–1.67 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.41, 144.19, 137.71, 135.47, 128.87, 128.54, 128.31,

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127.63, 127.54, 127.49, 127.47, 126.39, 124.14, 121.25, 108.17, 59.18, 27.66, 23.56, 21.16. LRMS (EI): 290 (M+ ); HRMS (EI) calcd. for C19 H18 N2 O (M+ ) 290.1419, found: 276.1412. 4-(4-Nitrophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6c): White solid (146.1 mg, 91%), m.p. 214–216 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.64–7.56 (m, 3H), 7.46 (s, 1H), 7.24–7.11 (m, 3H), 5.14 (s, 1H), 2.77–2.65 (m, 1H), 2.64–2.52 (m, 1H), 2.22–2.09 (m, 1H), 1.81–1.68 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 153.18, 146.62, 143.71, 143.66, 130.27, 128.66, 127.74, 126.93, 126.78, 122.34, 116.19, 110.97, 58.94, 27.59, 22.92. LRMS (EI): 321 (M+ ); HRMS (EI) calcd. for C18 H15 N3 O3 (M+ ) 321.1113, found: 321.1114. 3-(2-Oxo-1,2,3,4,5,6-hexahydrobenzo[h]quinazolin-4-yl)benzonitrile (6d): White solid (127.1 mg, 84%), m.p. 286–287 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.81–7.73 (m, 2H), 7.68 (s, 1H), 7.65–7.56 (m, 2H), 7.41 (s, 1H), 7.26–7.10 (m, 3H), 5.07 (s, 1H), 2.78–2.66 (m, 1H), 2.64–2.54 (m, 1H), 2.20–2.08 (m, 1H), 1.81–1.69 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 153.33, 145.69, 135.58, 131.95, 131.62, 130.59, 130.22, 128.64, 128.38, 127.78, 127.64, 126.46, 121.47, 118.86, 111.46, 107.09, 58.35, 27.62, 23.34. LRMS (EI): 301 (M+ ); HRMS (EI) calcd. for C19 H15 N3 O (M+ ) 301.1215, found: 301.1210. 4-(4-Fluorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6e): White solid (120.9 mg, 82%), m.p. 209–210 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.66–7.51 (m, 1H), 7.40–7.32 (m, 2H), 7.30 (s, 1H), 7.25–7.10 (m, 5H), 4.97 (s, 1H), 2.76–2.66 (m, 1H), 2.63–2.53 (m, 1H), 2.19–1.99 (m, 1H), 1.81–1.67 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 161.58 (d, JC–F = 243.1 Hz), 153.27 (s), 140.43 (s), 135.45 (s), 128.90 (d, JC–F = 8.2 Hz), 128.75 (s), 127.82 (s), 127.51 (s), 126.35 (s), 121.29 (s), 115.35 (d, JC–F = 21.4 Hz), 107.89 (s), 58.30 (s), 27.61 (s), 23.45 (s). LRMS (EI): 294 (M+ ); HRMS (EI) calcd. for C18 H15 FN2 O (M+ ) 294.1168, found: 294.1168. 4-(3-Chlorophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6f): White solid (140.1 mg, 90%), m.p. 279–280 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.59 (d, J = 6.6 Hz, 1H), 7.42-7.33 (m, 4H), 7.30 (d, J = 7.4 Hz, 1H), 7.24–7.12 (m, 3H), 4.94 (s, 1H), 2.77–2.65 (m, 1H), 2.63–2.53 (m, 1H), 2.21–2.03 (m, 1H), 1.87–1.70 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.33, 146.67, 135.50, 133.23, 130.68, 128.67, 128.11, 127.66, 127.62, 127.59, 126.77, 126.41, 125.61, 121.36, 107.46, 58.50, 27.62, 23.42. LRMS (EI): 310 (M+ , Cl35 ), 312 (M+ , Cl37 ); HRMS (EI) calcd. for C18 H15 ClN2 O (M+ ) 310.0873, found: 310.0864. 4-(2-Bromophenyl)-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6g): White solid (142.7 mg, 80%), m.p. 271–273 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.63–7.57 (m, 2H), 7.49–7.39 (m, 2H), 7.33 (s, 1H), 7.27–7.16 (m, 3H), 7.16–7.11 (m, 1H), 5.54–5.38 (m, 1H), 2.75–2.64 (m, 1H), 2.59–2.52 (m, 1H), 2.22–2.01 (m, 1H), 1.81–1.58 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.15, 142.77, 135.53, 132.70, 130.12, 129.79, 128.72, 128.64, 128.22, 127.66, 127.55, 126.42, 121.95, 121.38, 107.18, 58.35, 27.55, 22.97. LRMS (EI): 354 (M+ , Br79 ), 356 (M+ , Br81 ); HRMS (EI) calcd. for C18 H15 BrN2 O (M+ ) 354.0368, found: 354.0366. 8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6h): White solid (124.4 mg, 81%), m.p. 247–249 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.39–7.30 (m, 4H), 7.30–7.23 (m, 2H), 6.82–6.67 (m, 2H), 4.90 (s, 1H), 3.74 (s, 3H), 2.75–2.63 (m, 1H), 2.60–2.52 (m, 1H), 2.15–2.03 (m, 1H), 1.80–1.68 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 158.66, 153.45, 144.37, 137.44, 128.57, 127.55, 127.50, 126.91, 122.59, 121.71, 113.81, 110.81, 105.43, 59.11, 55.10, 28.03, 23.50. LRMS (EI): 306 (M+ ); HRMS (EI) calcd. for C19 H18 N2 O2 (M+ ) 306.1368, found: 306.1367. 9-Bromo-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6i): White solid (147.2 mg, 83%), m.p. 277–279 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.78 (s, 1H), 7.40–7.27 (m, 7H), 7.10 (d, J = 7.9 Hz, 1H), 4.90 (s, 1H), 2.72–2.61 (m, 1H), 2.59–2.52 (m, 1H), 2.24–2.05 (m, 1H), 1.89–1.65 (m, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.25, 143.94, 134.73, 131.04, 129.98, 129.48, 128.91, 128.68, 127.74, 126.95, 124.17, 119.62, 109.87, 59.06, 27.02, 23.40. LRMS (EI): 354 (M+ , Br79 ), 356 (M+ , Br81 ); HRMS (EI) calcd. for C18 H15 BrN2 O (M+ ) 354.0368, found: 354.0371. 9-Nitro-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazolin-2(1H)-one (6j): White solid (141.1 mg, 88%), m.p. 319–321 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.2, 2.2 Hz,

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1H), 7.45–7.40 (m, 1H), 7.40–7.31 (m, 5H), 7.32–7.26 (m, 1H), 4.97 (s, 1H), 2.84 (m, 1H), 2.77–2.64 (m, 1H), 2.27–2.14 (m, 1H), 1.81 (m, 1H). 13 C-NMR (126 MHz, DMSO) δ 153.18, 146.62, 143.71, 143.66, 130.27, 128.66, 127.74, 126.93, 126.78, 122.34, 116.19, 110.97, 58.94, 27.59, 22.92. LRMS (EI): 321 (M+ ); HRMS (EI) calcd. for C18 H15 N3 O3 (M+ ) 321.1113, found: 321.1108. 4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-2(5H)-one (6k): White solid (114.3 mg, 87%), m.p. 269–270 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.45–7.20 (m, 8H), 7.20–7.08 (m, 1H), 5.45 (s, 1H), 3.26 (d, J = 22.9 Hz, 1H), 2.78 (d, J = 22.8 Hz, 1H). 13 C-NMR (101 MHz, DMSO) δ 153.38, 144.46, 142.76, 137.51, 134.82, 128.63, 127.42, 126.40, 126.23, 125.11, 123.95, 118.19, 112.24, 57.18, 34.66. LRMS (EI): 262 (M+ ); HRMS (EI) calcd. for C17 H14 N2 O (M+ ) 262.1106, found: 262.1103. 4-Phenyl-3,4-dihydro-1H-chromeno[4,3-d]pyrimidin-2(5H)-one (6l): White solid (113.8 mg, 82%), m.p. 251–252 ◦ C. 1 H-NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 7.63 (dd, J = 7.8, 1.3 Hz, 1H), 7.47 (s, 1H), 7.43–7.27 (m, 5H), 7.24–7.14 (m, 1H), 7.00–6.90 (m, 1H), 6.83–6.75 (m, 1H), 4.98 (s, 1H), 4.74–4.68 (m, 1H), 4.21 (d, J = 13.6 Hz, 1H). 13 C-NMR (126 MHz, DMSO) δ 153.48, 152.99, 143.11, 129.61, 128.78, 127.90, 126.76, 125.17, 121.97, 121.22, 117.40, 115.83, 101.30, 64.80, 56.08. LRMS (EI): 278 (M+ ); HRMS (EI) calcd. for C17 H14 N2 O2 (M+ ) 278.1055, found: 278.1049. 4. Conclusions In conclusion, we have developed an efficient and practical approach to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl3 ·6H2 O/TMSBr-catalyzed three-component cyclocondensation under microwave heating. This protocol features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up. These advantages demonstrate the great potential of this method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones. More importantly, our ongoing research has revealed that the simple derivatives of compounds 4 or 6 are found to be potential EV71 3C protein inhibitors, which are worthy of further investigation for the development of medical therapies for hand, foot and mouth disease (HFMD). We anticipate that these important heterocyclic compounds may find their potent pharmaceutical applications after further exploration. Supplementary Materials: Supplementary Files (Copies of 1 H and 13 C-NMR spectra of compounds 4 and 6) are available online. Acknowledgments: We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21602022), the Open Project Program of Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province (No. ARRLKF15-01), Chengdu University New Faculty Start-up Funding (No. 2081915037) and the Open Project Program of Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department (No. 10Y201711). Author Contributions: F.Z. conceived and designed the experiments; X.J., P.L., J.Z. and J.H. performed the experiments; F.Z. analyzed the data; H.L. and L.L. contributed reagents and materials; F.Z. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

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