3,4-Dihydropyrimidine-2 -thione

The following syntheses all proceeded regioselectively 4,6-diaryl-3,4-dihydropyrimidine-2-thiones with 3-bromopropionic acid in a Ac20/AcOH system <2001MI407, 2000IJH49>, or with acrylonitrile in pyridine followed by hydrolysis <1996IJB915> resulted 6,8-diaryl-2,3-dihydro+//,6//-pyrirnido[2,l+][l,3]thiazin-4-ones in good yield 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thiones with benzylidenemalonitrile in a NaOAc/AcOH system... 

Cyclocondensation of l,6-dimethyl 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thione with ClCO-Ph-Cl I—(—() in alcohol-free chloroform or with 2-methylmalonyl dichloride in DCM resulted in the thiazinium... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Comas H, Buisson DA, Najman R, Kozielski F, Rousseau B, Lopez R (2009) Synthesis of 5-Acyl-3,4-dihydropyrimidine-2-thiones via solvent-free, solution-phase and solid-phase Biginelli procedures. Synlett 1737-1740... 

A Pd(0)-catalyzed/Cu(l)-mediated carbon-carbon cross-coupling of 3,4-dihydropyrimidine-2-thiones 520 and boronic acids occurs under microwave-assisted conditions to give 2-aryl-l,4-dihydropyrimidines 521 in moderate to high yield <20040L771>. In contrast, Gu(ll)-mediated reaction of the same substrates leads to carbon-sulfur cross-coupling. 

As already mentioned at the beginning of this chapter, one of the facile methods for the synthesis of dihydropyrimidine derivatives is the treatment of oc,(3-unsaturated carbonyls with urea and its analogues—thiourea, guanidine and amidines. However, the majority of the publications have dealt with syntheses involving thiourea. Most likely is the possibility of the modification of 3,4-dihydropyrimidine-2-thiones or their heteroaromatized analogues, which produces a diverse class of heterocycles. The reagent involved in this modification process can act like a,(3-unsaturated carbonyls [16] (Scheme 3.9). 

Liu et al. [123] reported the synthesis of 3,4-dihydropyrimidin-2-thiones 79 via Biginelli reaction of aldehydes, acetoacetates, and thiourea in the presence of iodine under solvent-free conditions using microwave irradiation as the energy source. This environmentally benign protocol had the advantages of shorter reaction times, good yields, and simple and easy workup without chromatographic separation (Scheme 10.58). 

Quan et al. and Wang et al. have been reported the synthesis of thiazolo[3,2-ajpyrimidines 55 (Seheme 25) by treatment of 3,4-dihydropyrimidine-2-thiones 24 with bromoaeetone in refluxing water [49, 50],... 

Membered Non-Aromatic Ring Compounds a) Dihydropyrimidine Thione Compounds... 

Karami, B., Haghighijou, Z., Farahi, M. and Khodabakhshi, S. 2012d. One-pot synthesis of dihydropyrimidine-thione derivatives using tungstate sulfuric acid (TSA) as recyclable catalyst. Phosphorus Sulfur Silicon Relat. Elem. 187(6) 754—761. 

Amino-2-arylazo-2-butenoic acids (289) have been prepared by two pathways from acetoacetic esters. The reaction of these compounds with bligomeric a-mercapto-aldehydes leads to substituted thiazoleacetic esters (290), which appear to be useful intermediates for the synthesis of penicillin analogues. Most syntheses of 2,4-dioxa-l,3-thiazolidines (292), which show an interesting spectrum of biological activity, involve oxidation of thiol precursors. A new method uses readily available dihydropyrimidine thiones in reaction with chloro-acetic acid. The reaction does not proceed if R = H in (291). 

Surprisingly, Kashima et al. (83TL209) reported the formation of individual 1,4-dihydro- and 1,6-dihydropyrimidines on desulfurization of the corresponding pyrimidine-2-thiones with Raney Ni and claimed that no tautomerization occurs under the reaction conditions (heating under reflux in MeOH). 

Other examples of CN/CC replacement are observed in reactions of l-phenyl-pyrimidin-2(l//)-one with active methylene compounds, such as diethyl malonate and benzoylacetate, giving in good yield 2-oxo-l,2-dihydro-3-pyridinecarboxylate and 3-benzoylpyridin-2(l H)-one, respectively (84CPB2942, 87H2223) (Scheme 8). In a similar way 4,6-dimethyl-1-phenylpyrimidin-2( 1 //)-one, 4,6-dimethyl-1 -phenylpyrimidine-2( 1 //)-thione and 4,6-dimethyl-1 -phenyl-2-phenylimino-1,2-dihydropyrimidine yield with malonitrile 2-amino-4,6-dimethyl-3-pyridinecarbonitrile. In a similar way 2,3-diarylpyrimidin-4(3//)-thiones give with malonitrile CN/CC replacement (84H763) (Scheme 8). The reaction takes a similar course as described in Scheme 7. 

Substituted 4,4,6-trimethyl-1,4-dihydropyrimidine-2(3//)-thiones behave as enamines [49] to yield dichlorocyclopropanes (Scheme 7.35). Further reaction... 

Hydrogenation over Raney nickel can be used to reduce dihydropyrimidinethiones to dihydropyrimidines and thus the thione 535 was converted to the dihydropyrimidine 536 in 95% yield using a continuous flow hydrogenation method <2005JC0641>. 

With K2CO3 in aqueous ethanol, 1,3-thiazines (166) substituted at C-2 by an imino group rearrange to l,2-dihydropyrimidine-2-thiones (167). The... 

The analysis of literature data shows that irrespective of the catalyst used the reaction time varies from 30 min to 12 h with yields of 40-80%. But under microwave irradiation the treatment of chalcone 43 with thiourea was completed in 4 min with 85% yield of dihydropyrimidine-2-thione 44 [59] (Scheme 3.13). 

A modification of the dihydropyrimidone MCR was performed by applying isothiocyanates 107 as the fourth component, which resulted in the formation of 2-aminothiazines 108 which upon microwave heating could rearrange (Dimroth rearrangement) to dihydropyrimidine-2-thiones 109 [87]. 

With thioxopurines, thiazolopyrimidines are usually obtained. Thus 4,5-diamino-6-thioxo-l,6-dihydropyrimidine with acetic anhydride mainly afforded the thiazolopyrimidine (257 Scheme 78) (59JA193) which unlike the unsubstituted derivative was stable to alkali treatment and hence failed to produce the 6-thioxopurine by this route. However 5-acetylamino-6-aminopyrimidine-2-thione with phosphorus pentasulfide in pyridine gave a mixture of 6-oxo-2-thioxo- and 2,6-dithioxo-purines (Scheme 79). 

Trimethyl-l,6-dihydropyrimidine-2-thione (113), on condensation with aromatic aldehydes in ethanolic KOH, gives arylidene derivatives 114 which react with chloroacetic acid in the presence of anhydrous sodium acetate in acetic anhydride to afford a cyclized product formulated as 115 (81 Mil) that can also be represented by the alternate structure 116 (Scheme 25). Similarly, the thione 113 reacts with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride to furnish a cyclized product for which structure 117 has been assigned without any evidence (81 Mil). The cyclized product can also be represented by the other isomeric structure 118. The bicyclic compound (115 or 116) condenses with aromatic aldehydes to give arylidene derivatives that are also obtained in a single-step synthesis involving the reaction of 114 with chloroacetic acid and aromatic aldehydes in the presence of anhydrous sodium acetate in acetic acid and acetic anhydride. 

The preparation of 9-niethyl and 9-butyl-2-hydroxy-8,9-dihydro-7H-purine-8-thione (XXVa Table 7) is somewhat unusual. Brown [45) has obtained these compounds from carbon disulfide and respectively f-methyl and 1 -butyl-5,6-diamino-1,2-dihydropyrimidin-2-one (XXIVa.). Evidently a shift of the alkyl group from the 3-N to the 9 N atom must occur during the ring closure. The structure of these two purines has been confirmed by their independent synthesis from 4-methylamino and 4-butylamino-5-amino-2-hydroxy pyrimidine. 

The reaction of l-substituted-4.4.6-trimethyl-1.4-dihydropyrimidine-2(3//)-thiones 139 with 11 M HCI was temperature dependent and the rearrangement results at lower temperature via the dehydrative recyclization of the initial hydrolytic product involving attack of the thioureido sulfur on the carbonyl carbon to give 2-substituted amino-4.4.6-trimethyl-4//-l,3-thiazines 140 [80JCS(P1) 1013], On the other hand, intramolecular ther-... 

A mixture of 6-methyl-4-phenyl-3,4-dihydropyrimidine-2(1/7)-thione (1 4 g, 19.7 mmol), HCIIO (4 g, 133 mmol), and MeNH2 HCI (1.4 g, 20.7 mmol) in EtOH (70 mL) was slightly warmed, then set aside at rt for 2 h. After removal of the solvent in vacuo the residual hydrochloride was triturated with acetone, filtered off, and recrystallized from acetonc/ll20. The salt was dissolved in H O and the product was precipitated by addition of 5% aq NaOH yield 4.5 g (83%) mp 182CC (from EtOH). 

Most reactions in this subgroup have been between a methylene ketone, an aromatic aldehyde and urea or thiourea. The product is a dihydropyrimidin-2-one or -2-thione . 

Scheme 15.72. Swift phenylation of a dihydropyrimidin-2-thione using phenyl boronic acid under stoichiometric Cu(ll) conditions.

N-1 benzoxazolyl 3,4-dihydropyrimidinones/thiones 33 have been obtained by reacting carbomethoxy benzoxazole 30 with semicarbazide/ thiosemicarbazide 31 (X = O, S) in refluxing ethanol using a catalytic amount of piperidine to obtain intermediate 2-(2- alkylbenzoxazole-5-car-bonyl)hydrazine carboaxo/thioamide 32 (R = H, Me X = O, S), which upon cyclocondensation with an aromatic aldehyde and p-ketoester in the presence of tiifluoromethane sulfonic acid at room temperature afforded benzoxazolyl 3,4-dihydropyrimidin-2(lH)-ones/thiones 33 (R = H, Me R = Me, CF3), in excellent yield (Scheme 12) (09M16). 

The C-2 position of 3,4-dihydropyrimidin-2(lT/)-thiones 22 (X = S) derivatives has been alkylated with an alkyl halide in the presence of a mild base to the corresponding S-alkylated 1,4-dihydropyrimidines 34 (Scheme 14), in excellent yields (87H1185, 87IJC(B)556, 89KGS1076, 90JMC1510). 

Kashima et al. have explored the synthesis of N-1 substituted, C-2 unsubstituted dihydropyrimidines 39 and 40 through Raney-Ni induced desulfurization of N-1 derivatives 37 and 38 (Scheme 17) (83JCS(P1)1799). However, the 4,6-dimethyl-l-phenylpyrimidin-2-(lH)-thione required an H2 atmosphere at room temperature. The higher oxidation potential of these products than 1-benzyl 1,4-dihydronicotinamide (Ep = 0.700 V), showed their propensity to transfer hydride. Thus, the desulfurized DHPMs 39 as well as 40, reduced malachite green to its leuco derivative (83TL209). 

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