Construction of Dihydropyrido[2,3-d]pyrimidine Scaffolds via Aza-Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes.

N-Heterocyclic carbenes (NHCs) catalyzing aza-Claisen rearrangement of α,β-unsaturated enals with cyclic vinylogous amides under oxidative conditions generating potentially biologically active dihydropyridinone-fused uracils have been developed. This strategy represents a unique NHC-activation-based path with the use of 6-aminouracils as stable α,β-diEWG cyclic vinylogous amides for the efficient synthesis of bicyclic N-unprotected lactams similar to those in many useful drugs.

Introduction

The development of new synthetic methodologies for the efficient construction of bioinspired targets constitutes a highly relevant and rapidly developing field in contemporary organic chemistry.[1] Among them, dihydropyridinones and derivatives of bicyclic pyridinone-fused uracils constitute privileged heterocyclic scaffolds found in many natural active molecules displaying a wide range of biological and pharmacological properties. For instance, GSK1120212 1 and its analogues 2 and 3 were found to be highly potent and selective inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) as a highly antiproliferative drug candidate for clinical development. Structurally similar dihydropyrido[2,3-d]pyrimidine 4 is commonly investigated as a safe and highly effective antileishmanial pharmaceutical (Figure ).[2] In view of the therapeutic significance of these uracil derivatives, the development of general and concise synthetic strategies that fill the chemical space with diverse heterocyclic structures is highly desirable. Consequently, synthesis of new bicyclic dihydropyridinone-fused uracils gives hope to discover novel biologically active compounds.

Figure 1

Importance of dihydropyridinone-fused uracil structural motifs.

N-Heterocyclic carbenes (NHCs) have emerged as versatile organocatalysts for various transformations and constitute convenient methods for carbon–carbon and carbon–heteroatom bond formation.[3] In the recent years, processes in which NHC-catalyzed reactions take place via normal-polarity intermediates have gained importance. There are four well-studied paths of generating α,β-unsaturated acyl azoliums: the reactions of NHCs with α,β-unsaturated enol esters or acyl fluorides,[4] ynals,[5] 2-bromoenals,[6] or stoichiometric oxidation of Breslow intermediates.[7]

The reactions of α,β-unsaturated acyl azoliums with nucleophiles are unique organocatalytic strategies leading to annulative reactions with single, double, and even triple functionalization via domino/cascade processes.[3d,8] NHC-catalyzed annulations of acyl species with various N-protected imine derivatives are well recognized and provide facile entry to diverse heterocyclic motifs.[9] Therefore, many methods have been developed for the construction of N-protected dihydropyridinones, including reactions of various precursors of α,β-unsaturated acyl azoliums derived from α-bromoenals or enals under oxidative conditions with different partners such as N-Ts-2-aminoacrylates and cyclic and acyclic N-sulfonylimines.[10] Very recently, Enders et al. disclosed the use of benzoxazolyl and benzothiozolyl acetates as enamine precursors leading to dihydrobenzoxazolyl- or benzothiozolyl-fused dihydropyridinones with low-to-moderate enantioselectivity.[11] Bode et al. examined the ability of β-electron-withdrawing substituted enamines in the synthesis of useful dihydropyridinones from α,β-unsaturated acyl azoliums.[12] In 2017, Ye et al. utilized indolin-2-imines as enamine precursors allowing the synthesis of nonenantioselective dihydropyridinone-fused indoles.[13] Another interesting approach for their synthesis was the application of azolium dienolate intermediates with hydrazones as reported by Chi and co-workers.[14] The synthetic utility of the immediate annulation products, however, is diminished by its difficulty for use to remove protecting groups. Despite the fact of dynamically developing catalysis involving NHCs in the last few years, organocatalytic aza-Claisen rearrangements are still rare as the reported reactions are strongly limited in scope. To our knowledge, there is no organocatalytic approach for the annulative one-pot strategy for construction of bicyclic N-unprotected dihydropyrido[2,3-d]pyrimidine derivatives involving the use of sterically hindered α,β-diEWG cyclic vinylogous amides as a template for uracil functionalization (Scheme ). Our literature survey did not lead to any precedence, either metal- or organo-catalyzed, on synthesis 7. Consequently, the development of an effective synthetic method for 7, possibly metal-free and organocatalytic, is highly expected.

Scheme 1

Synthesis of Bicyclic NH Heterocycles by an NHC-Catalyzed Annulation Reaction

Given the significance of both the bicyclic pyrido[2,3-d]pyrimidine derivatives and acyl azolium chemistry, studies on the development of a general synthetic strategy leading to the novel dihydropyridinones bearing a fused uracil moiety were undertaken. Herein, we report our results on this NHC-catalyzed aza-Claisen rearrangement leading to bicyclic dihydropyridinones. The reaction reveals the new reactivity of stable α,β-diEWG cyclic vinylogous amides, which, to date, have not been used as substrates for Claisen rearrangement under oxidative conditions, introducing a new tool for the synthesis of complex bicyclic molecules.

Results and Discussion

We started the evaluation of our hypothesis by combining 4-methoxycinnamaldehyde 5a with 1,3-disubstituted 6-aminouracil 6a using different azolium salts as NHC precursors, tribasic potassium phosphate as a base, and DQ as an equimolar oxidant in toluene. To our great delight, all tested NHC precatalysts (8a–8f displayed remarkable effects on the outcome of the reaction and afforded the desired product in a wide range of yields (Table ). Gratifyingly, the desired dihydropyrido[2,3-d]-pyrimidine 7aaa could be obtained in a 95% yield when the precatalyst 8c was employed (Table , entry 3). Encouraged by this promising result, various reaction parameters were further examined. All the tested organic and inorganic bases, including NMM, HMPA, and AcOK, gave the desired product, albeit in low yields (entries 7, 8, and 10). Interestingly, when the reaction was carried out using bases, such as tert-BuOK, KHMDS, and tribasic potassium phosphate, the reactivity increased significantly, and the results indicated that K3PO4 was the best choice and furnished the desired product in a 95% yield. Moreover, the change of solvents did not improve the reaction performance, and toluene was proven to be the solvent of choice.

Table 1

Optimization of the Reaction Conditionsa,b,c

entry	preNHC	solvent	base	yieldc (%)
1	8a	toluene	K3PO4	54
2	8b	toluene	K3PO4	50
3	8c	toluene	K3PO4	95
4	8d	toluene	K3PO4	84
5	8e	toluene	K3PO4	48
6	8f	toluene	K3PO4	35
7	8c	toluene	NMM	30
8	8c	toluene	HMPA	21
9	8c	toluene	tBuOK	88
10	8c	toluene	AcOK	54
11	8c	toluene	Cs2CO3	79
12	8c	toluene	P2-Et	64
13	8c	MTBE	K3PO4	90
14	8c	DCM	K3PO4	67
15	8c	AcOEt	K3PO4	85
16	8c	1,4-dioxane	K3PO4	43

Unless otherwise noted, all reactions were carried out with preNHC 8a–8f (10 mol %), base (20 mol %), DQ (1.0 equiv), 5a (0.3 mmol), and 6a (0.3 mmol) in the solvent (3.0 mL) at rt for 20 h.

Isolated yield.

With the optimized reaction conditions in hand, we set out to explore the generality of the procedure in terms of substrates. Initially, a variety of substituted cinnamaldehyde-derived enals including those bearing electron-withdrawing and electron-donating substituents were explored under the optimized conditions. As shown in Scheme , a number of aryl-substituted cinnamaldehydes reacted smoothly and cleanly afforded the corresponding annulation products in high yields (7aaa–7iaa). Notably, the extension of the protocol to alkyl-substituted enals was also successful and gave the desired dihydropyrido[2,3-d]pyrimidines in good yields (7kba–7sba). Unfortunately, (E)-3-dimethylaminoacrylaldehyde was unreactive in this model reaction (7tba). It is worth noting that aromatic substituents on the enals afforded the expected adducts in greater yields than those of their aliphatic counterparts. Additionally, we also applied modifications in the uracil moiety by replacing the alkyl group in the N(3) position with a benzyl substituent in order to make them visible during chromatographic purification with a UV detector.

Scheme 2

Scope of the α,β-Unsaturated Aldehydes and N(3)-Substituted 6-Aminouracils

Encouraged by the above successful aza-Claisen rearrangement, we decided to further increase the attractiveness of the methodology by using unsymmetrical N,N-disubstituted alkyl–alkyl and alkyl–aryl derived 6-aminouracils (Scheme ). The influence of the length of the alkyl group in the N(3) position was first investigated.

Scheme 3

NHC-Catalyzed Aza-Claisen Rearrangement: N(1) and N(3) Substituent Variation

Pleasingly, linear or branched alkyl chains did not affect the reaction outcome, and we were able to isolate the products in good yields (7afd and 7aca–7aja). Increasing steric hindrance at the N(1) position does not affect the reaction efficiency (7abc and 7ajb). Alkyl chains containing aryl moieties with both electron-poor and electron-rich substituents at various positions of the aromatic ring were well tolerated and gave the desired adducts (7abb and 7alb–7aub). The significant influence on the yield was observed for p-substituted benzyl groups (products 7anb and 7aub).

To demonstrate the scalability of this aza-Claisen transformation, we also performed the reaction in a 50-fold larger scale. Under the optimized reaction condition, the annulation proceeded smoothly and gave the bicyclic heterocycle in a 57% yield (3.17 g) (Scheme ).

Scheme 4

Scale-Up of the NHC-Catalyzed Aza-Claisen Rearrangement and Enantioselective Approach to the Synthesis of Dihydropyrido[2,3-d]pyrimidine 7aaa

Furthermore, we also were interested in the development of an enantioselective approach to the synthesis of dihydropyridinone-fused uracils (Table ). After extensive investigations, we found that the chiral pinene-derived NHC precatalyst (8g) developed by us gave the best results in terms of enantioselectivity.[15] Unfortunately, the introduction of additives in the form of Lewis acids or Brønsted acids did not have a positive effect on the increase of enantiomeric excess (entries 8–14, Table ).

Table 2

Enantioselective Synthesis of Dihydropyridinone 7aaaa,b,c

entry	preNHC	additive	yieldc (%)	ee
1	8g		84	67
2	8h		76	38
3	8i		86	30
4	8j		78	16
5	8k		43	36
6	8l		67	22
7	8m		49	30
8	8g	Sc(OTf)3
9	8g	LiCl	38	65
10	8g	Ti(OPri)4	13
11	8g	Mg(OTf)2
12	8g	AcOH	38	67
13	8g	R-Phos	43	67
14	8g	S-Phos	45	67

Unless otherwise noted, all reactions were carried out with preNHC 8g–8l (10 mol %), K3PO4 (20 mol %), DQ (1.0 equiv), 5a (0.3 mmol), and 6a (0.3 mmol) in toluene (3.0 mL) at rt for 24 h.

Isolated yield.

The proposed catalytic cycle is presented in Scheme . First, the NHC organocatalyst I is generated by deprotonation of the triazolium salt 8. The nucleophilic addition of a free NHC I to the enal gives the Breslow intermediate II, which is oxidized to form the key α,β-unsaturated acyl azolium III. Afterward, the 1,2-addition of cyclic enamine to the acyl azolium gives an N-acylation product. The obtained hemiaminal IV undergoes aza-Claisen rearrangement via transition state V. This rearrangement is followed by the intramolecular lactamization and affords the dihydropyridinone-fused uracil and catalyst turnover. Another possibility for this NHC-catalyzed annulation is nucleophilic addition of uracil enamine to the α,β-unsaturated acyl azolium intermediate as a Michael acceptor in a 1,4-fashion, providing the enol intermediate VIII, which undergoes proton transfer and intramolecular acylation to afford the final product. One of the characteristic experimental observations of 1,2-addition is the presence of an amidation side-reaction product. The occurrence of this type of by-product depends on the construction of the NHC catalyst. In our research, for selected NHC catalysts, amidation side reactions were also observed, which indicates that the course of the reaction is not via nucleophilic 1,4-addition of enamine to the catalytically generated α,β-unsaturated acyl azolium but through 1,2-addition to give an N-acylation product. Intensive mechanistic and kinetic investigations for α,β-unsaturated acyl azoliums conducted by Bode and co-workers confirmed that NHC-catalyzed annulation reactions of α,β-unsaturated acyl azoliums proceed through Claisen rearrangement rather than direct Michael addition.[16] Based on theoretical and kinetic studies, we have adopted the above reaction mechanism as the most likely for our model reaction.[5b,17] Moreover, it is worth noting that [3 + 3] cycloaddition is rather typical for analogous aminocatalytic reactions.[18]

Scheme 5

Proposed Mechanism

Finally, the versatile functionalization of the dihydropyrido[2,3-d]pyrimidines was also carried out (Scheme ). Treating 7aaa with LiAlH4 led to the corresponding tetrahydropyridine 9 motif. Derivatization of the N–H bond in the lactam motif gave a series of highly interested results. The reaction of 7aaa with tosyl chloride in pyridine under mild conditions afforded the pyridinium zwitterion 10 in a 20% yield. The replacement of the pyridine with a Hünig base results in tosylation of the amide at the oxygen of the carbonyl group and aromatization of the pyridinone framework. Equally intriguing results were obtained using the benzylation reaction. It turns out that depending on the benzyl halide used, the reaction leads to two different products. The use of benzyl bromide with potassium carbonate in DMF at 80 °C under an inert atmosphere leads to the formation of an O-benzylated product (12) in a 63% yield. This effect can be explained by the large steric hindrance at the nitrogen atom of the amide group. Nevertheless, the replacement of bromide with benzyl chloride under analogous reaction conditions gives an O-benzylation product with simultaneous aromatization of the pyridinone motif 13. The impacts of factors on aromatization have not yet been fully understood. The influence of the chloride anion may have a decisive role, but further intensive research in this direction is needed.

Scheme 6

Synthetic Transformations of the Product 7aaa

Conclusions

In summary, we have developed a very efficient methodology for the synthesis of bicyclic dihydropyridinone-fused uracils from 1,3-disubstituted 6-aminouracils as a α,β-diEWG cyclic vinylogous amide template with various α,β-unsaturated aldehydes using a unique NHC-activation-based approach via aza-Claisen rearrangement. Furthermore, the protocol also allows access to the structural units that are difficult to prepare by traditional strategies. The mild reaction conditions, very broad reaction scope, and readily available substrates make this protocol potentially useful for the construction of dihydropyrido[2,3-d]pyrimidine derivatives in good yields. This work contributes the first use of 6-aminouracils as a cyclic enamide template, thus demonstrating the possibility of this novel approach to the design of biologically relevant molecules. Further studies toward a more sustainable synthesis for condensed cyclic heterocycles are currently an area of focus in our laboratory.

Experimental Section

General Information

Presented reactions were carried out in dry glassware under an inert atmosphere of argon. Selected reactions were monitored using thin-layer chromatography (TLC), which was visualized under a UV lamp (254 nm). Anhydrous solvents were prepared using an INERT PureSolv solvent purification system. Purification of selected products was performed by column chromatography using a CombiFlash Rf + Lumen system with UV–vis and ELSD detectors. RediSepRf GOLD 4 gram columns were used. NMR spectra were recorded on a Bruker AMX 400 [400 MHz (1H)] spectrometer and Bruker AMX 700 [700 MHz (1H)] spectrometer using CDCl3 and DMSO-d6 as solvents. Chemical shifts are reported in ppm using the residual solvent peaks as reference: CDCl3 (δ 7.24) or DMSO-d6 (δ 2.54) for 1H NMR and relative to the central CDCl3 (δ 77.23) or DMSO-d6 (δ 41.23) resonance for 13C NMR. Coupling constants (J) are provided in Hertz. Infrared spectra were registered on an Alpha FT-IR spectrometer from Bruker with an ATR module. Mass spectra were recorded on an Agilent 6530 Q-TOF LC/MS system coupled with a 1290 Infinity II liquid chromatograph. Melting points of obtained products were measured on a Stuart SMP30 and SMP50 melting point apparatus and were not corrected.

General Procedure for the Preparation of 1,3-Disubstituted 6-Aminouracils

Step I. General Procedure 1: Synthesis of 3-Unprotected 6-Aminouracils

Sodium ethoxide solution was prepared from sodium metal (2 equiv) and dry ethanol (2 M solution). To the resulting solution, 1-monosubstituted urea (1 equiv) and ethyl cyanoacetate (1 equiv) were added. The flask with the resulting mixture was immersed in an oil bath and heated under reflux for 72 h. After this time, the solvent was removed using a rotary evaporator, and the residual solid was dissolved in water. The obtained alkaline solution was neutralized by hydrochloric acid, and the precipitated solid was filtered off and washed with water and diethyl ether. The obtained solid was dried under vacuo (0.1 Torr, 2 h).

Step II. General Procedure 2: Synthesis of NH2-Protected 6-Aminouracils

To the solution of 3-unprotected 6-aminouracil (1 equiv) in DMF (0.6 M solution), DMF-DMA (1.1 equiv) was added. The flask with the resulting mixture was immersed in an oil bath and heated at 40 °C for 24 h. After this time, the solution was cooled down to room temperature, and diethyl ether was added. The precipitated solid was filtered off and washed with diethyl ether. The obtained product was dried under vacuum (0.1 Torr, 2 h).

Step III. General Procedure 3: Synthesis of 1,3-Disubstituted NH2-Protected 6-Aminouracils

NH2-protected 6-aminouracil (1 equiv) was dispersed in DMF (0.3 M solution), and potassium carbonate (2 equiv) was added. The corresponding alkyl or benzyl halide was added (10 equiv), and the flask with the resulting mixture was immersed in an oil bath and heated at 80 °C for 24 h. The majority of the solvent and unreacted halide was evaporated. To the residue, water was added, and the precipitated solid was filtered off and washed with diethyl ether. The obtained product was dried in vacuo (0.1 Torr; 2 h).

Step IV. General Procedure 4: Synthesis of 1,3-Disubstituted 6-Aminouracils

1,3-Disubstituted NH2-protected 6-aminouracil (1 equiv) was dissolved in methanol (0.2 M solution). To the resulting solution, 2 M sodium hydroxide solution (2 equiv) in water was added. The resulting mixture was stirred at room temperature for 24 h. After this time, methanol was evaporated and water was added. The resulting mixture was stirred at 0 °C for 1 h. The precipitated product was filtered off and washed with water and diethyl ether. The obtained solid was dried under vacuum (0.1 Torr; 2 h).

6-Amino-1-propylpyrimidine-2,4(1H,3H)-dione (14)

A scale of 50 mmol, solid, 5.97 g, isolated yield of 71%; 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 6.78 (s, 2H), 4.53 (s, 1H), 3.68 (t, J = 7.6 Hz, 2H), 1.51 (sxt, J = 7.5 Hz, 2H), 0.86 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.9, 156.2, 151.7, 75.7, 42.6, 21.3, 11.2; IR νmax: 3363, 3190, 2962, 1705, 1651, 1574, 1502, 1463, 1386, 1280, 1223, 1170, 1072, 1025, 851, 774, 726, 702, 649, 539, 519, 465 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C7H12N3O2 170.0930; found: 170.0928; mp 259.3–262.3 °C. The above analysis results correspond to the literature data.[19a]

6-Amino-1-benzylpyrimidine-2,4(1H,3H)-dione (15)

A scale of 57.3 mmol, solid, 10.71 g, isolated yield of 86%; 1H NMR (400 MHz, DMSO-d6) δ 10.41 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.21 (m, 2H), 6.82 (s, 2H), 5.04 (s, 2H), 4.61 (s, 4H); 13C NMR{1H} (101 MHz, DMSO-d6) δ 162.8, 156.3, 152.0, 137.1, 128.9, 127.6, 126.8, 76.0, 44.0; IR νmax: 3471, 3329, 3250, 3070, 2954, 2766, 1695, 1628, 1576, 1494, 1401, 1385, 1358, 1278, 1232, 1175, 1124, 941, 891, 822, 729, 692, 592, 538, 510, 434 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C11H12N3O2 218.0930; found: 218.0931; mp 270.5–273.1 °C (dec.). The above analysis results correspond to the literature data.[19b]

6-Amino-1-phenylpyrimidine-2,4(1H,3H)-dione (16)

A scale of 50 mmol, solid, 6.65 g, isolated yield of 65%; 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 7.45–7.57 (m, 3H), 7.27–7.37 (m, 2H), 6.11 (s, 2H), 4.69 (s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.3, 156.1, 151.4, 134.6, 130.2, 129.9, 129.7, 75.5; IR νmax: 3476, 3331, 3086, 2971, 2798, 2776, 1705, 1623, 1583, 1472, 1430, 1384, 1296, 1222, 1144, 875. 804, 777, 761, 702, 566, 531, 510 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C10H10N3O2 204.0773; found: 204.0773; mp 321.9–323.7 °C (dec.). The above analysis results correspond to the literature data.[19c]

N′-(2,6-Dioxo-3-propyl-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (17)

A scale of 30 mmol, solid, 5.48 g, isolated yield of 81%; 1H NMR (700 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.05 (s, 1H), 4.96 (s, 1H), 3.81 (t, J = 7.4 Hz, 2H), 3.10 (s, 3H), 2.97 (s, 3H), 1.52 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 163.3, 160.6, 155.9, 151.7, 82.3, 42.8, 40.3, 34.4, 21.6, 11.2; IR νmax: 3152, 3016, 2965, 1659, 1627, 1557, 1445, 1421, 1395, 1356, 1331, 1230, 1111, 865, 604, 535, 432 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C10H17N4O2 225.1352; found: 225.1350; mp 217.6–220.7 °C. The above analysis results correspond to the literature data.[19d]

N′-(3-Benzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (18)

A scale of 48.7 mmol, solid, 10.84 g, isolated yield of 82%; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.19–7.33 (m, 5H), 5.10 (s, 2H), 5.04 (s, 1H), 3.09 (s, 3H), 2.94 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 163.7, 160.8, 156.5, 152.3, 139.0, 128.7, 127.6, 127.3, 82.6, 44.7, 40.8, 35.0; IR νmax: 2976, 2784, 1694, 1646, 1611, 1549, 1491, 1452, 1427, 1389, 1329, 1256, 1215, 1152, 1121, 1088, 1060, 1019, 904, 876, 813, 787, 760, 741, 701, 600, 583, 516, 462, 431 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H17N4O2 273.1352; found: 273.1351; mp 221.7–223.4 °C. The above analysis results correspond to the literature data.[19d]

N′-(2,6-Dioxo-3-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (19)

A scale of 24.2 mmol, solid, 5.54 g; isolated yield of 89%; 1H NMR (700 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.96 (s, 1H), 7.36–7.40 (m, 2H), 7.30–7.34 (m, 1H), 7.14–7.17 (m, 2H), 5.09 (d, J = 1.9 Hz, 1H), 2.98 (s, 3H), 2.51 (s, 2H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 163.6, 161.0, 155.2, 151.5, 137.1, 129.5, 128.2, 127.5, 82.3, 40.1, 33.9; IR νmax: 2963, 2808, 1698, 1650, 1615, 1541, 1446, 1425, 1373, 1337, 1261, 1210, 1130, 1087, 879, 787, 736, 698, 588, 568, 532, 458, 424 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C13H15N4O2 259.1195; found: 259.1196; mp 276.1–279.0 °C. The above analysis results correspond to the literature data.[19d]

N′-(3-Benzyl-2,6-dioxo-1-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (20)

A scale of 21 mmol, used halide: iodide, solid, 4.86 g, isolated yield of 74%; 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.18–7.33 (m, 7H), 5.18 (s, 1H), 5.16 (s, 2H), 3.73 (t, J = 7.3 Hz, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 1.51 (sxt, J = 7.4 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.2, 156.5, 152.4, 138.9, 128.7, 127.6, 127.3, 82.2, 45.6, 42.0, 40.8, 35.0, 21.2, 11.6; IR νmax: 2961, 1690, 1648, 1618, 1569, 1496, 1448, 1414, 1363, 1224, 1125, 1096, 996, 810, 765, 693, 602, 577, 524 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C17H23N4O2 315.1821; found: 315.1821; mp 130.2–132.8 °C. The above analysis results correspond to the literature data.[19d]

N′-(2,6-Dioxo-3-phenyl-1-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (21)

A scale of 19.3 mmol, used halide: iodide, solid, 3.17 g, isolated yield of 55%; 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.37–7.40 (m, 3H), 7.18 (dd, J = 3.7, 1.5 Hz, 2H), 5.25 (s, 1H), 3.74 (t, J = 7.3 Hz, 2H), 2.99 (s, 6H), 1.54 (sxt, J = 7.4 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.9, 159.8, 155.6, 152.1, 137.9, 129.9, 129.8, 128.7, 82.2, 42.0, 34.3, 21.3, 11.7; IR νmax: 2953, 1696, 1651, 1612, 1572, 1424, 1406, 1375, 1341, 1116, 1079, 1005, 877, 798, 764, 700, 577, 536 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C16H21N4O2 301.1665; found: 301.1662; mp 183.7–186.7 °C. The above analysis results correspond to the literature data.[19d]

N′-(1-Ethyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (22)

A scale of 4.46 mmol, used halide: iodide, solid, 0.35 g, isolated yield of 31%; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.11 (s, 1H), 3.85–3.93 (m, 2H), 3.79 (q, J = 6.9 Hz, 2H), 3.11 (s, 3H), 2.99 (s, 3H), 1.49–1.61 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.4, 156.3, 151.9, 82.3, 44.1, 40.7, 35.4, 34.8, 21.9, 13.5, 11.5; IR νmax: 3088, 2965, 2934, 2875, 1687, 1648, 1614, 1566, 1448, 1416, 1362, 1337, 1233, 1116, 1037, 1001, 887, 815, 767, 666, 571, 551 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C12H21N4O2 253.1665; found: 253.1666; mp 142.0–144.3 °C.

N′-(1-Butyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (23)

A scale of 4.46 mmol, used halide: bromide, solid, 0.36 g, isolated yield of 29%; 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 5.11 (s, 1H), 3.85–3.93 (m, 2H), 3.75 (t, J = 7.1 Hz, 2H), 3.11 (s, 3H), 2.99 (s, 3H), 1.42–1.61 (m, 4H), 1.25 (dq, J = 14.9, 7.4 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.4, 156.4, 152.1, 82.3, 44.1, 40.7, 34.8, 30.1, 21.9, 20.1, 14.2, 11.6; IR νmax: 2960, 2932, 2873, 1687, 1645, 1611, 1568, 1494, 1439, 1412, 1365, 1348, 1226, 1181, 1112, 1048, 987, 886, 815, 766, 572, 550 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H25N4O2 281.1978; found: 281.1977; mp 129.0–130.2 °C.

N′-(1-Isobutyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (24)

A scale of 4.46 mmol, used halide: bromide, solid, 0.74 g, isolated yield of 59%; 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 5.11 (s, 1H), 3.90 (t, J = 7.2 Hz, 2H), 3.60 (d, J = 7.3 Hz, 2H), 3.11 (s, 3H), 2.99 (s, 3H), 2.00 (dt, J = 13.8, 6.9 Hz, 1H), 1.55 (sxt, J = 7.3 Hz, 2H), 0.79–0.85 (m, 9H), 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8, 159.34, 156.4, 152.4, 82.2, 47.2, 44.1, 40.7, 34.8, 27.1, 21.9, 20.4, 11.5; IR νmax: 2961, 2932, 2874, 1685, 1611, 1566, 1441, 1412, 1364, 1346, 1323, 1226, 1114, 1056, 992, 888, 806, 767, 577, 550 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H25N4O2 281.1978; found: 281.1980; mp 133.5–136.7 °C.

N′-(2,6-Dioxo-1-pentyl-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (25)

A scale of 4.46 mmol, used halide: bromide, solid, 1.00 g, isolated yield of 76%; 1H NMR (700 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.10 (s, 1H), 3.87 (t, J = 7.5 Hz, 2H), 3.72 (t, J = 1.0 Hz, 2H), 3.10 (s, 3H), 2.97 (s, 3H), 1.50–1.56 (m, 2H), 1.47 (dt, J = 15.0, 7.4 Hz, 2H), 1.23–1.30 (m, 4H), 0.80–0.85 (m, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 162.1, 159.0, 156.0, 151.7, 81.8, 67.4, 43.7, 40.3, 34.4, 28.6, 27.1, 21.9, 21.5, 13.9, 11.2; IR νmax: 2956, 2925, 2871, 1691, 1643, 1613, 1566, 1449, 1415, 1501, 1367, 1349, 1258, 1112, 1053, 994, 885, 807, 767, 728, 577, 553, 437 cm–1. HRMS (ESI-TOF) m/z: (M + H)+ calcd for C15H27N4O2 295.2134; found: 295.2134; mp 80.1–86.9 °C.

N′-(1-Hexyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (26)

A scale of 4.46 mmol, used halide: bromide, solid, 0.39 g, isolated yield 28%; 1H NMR (700 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.10 (s, 1H), 3.86–3.90 (m, 2H), 3.71–3.74 (m, 2H), 3.10 (s, 3H), 2.98 (s, 3H), 1.51–1.56 (m, 2H), 1.45–1.47 (m, 2H), 1.27–1.32 (m, 6 H), 0.81–0.85 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.4, 156.3, 152.1, 82.3, 44.1, 34.8, 31.4, 31.1, 27.8, 26.5, 22.4, 21.9, 14.3, 11.5; IR νmax: 3448, 3292, 3171, 2955, 2927, 1693, 1646, 1614, 1569, 1451, 1417, 1354, 1280, 1235, 1184, 1112, 1054, 999, 942, 887, 813, 789, 727, 717, 694, 555 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C16H29N4O2 309.2291; found: 309.2294; mp 95.5–99.3 °C.

N′-(1-Heptyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (27)

A scale of 4.46 mmol, used halide: bromide, solid, 0.61 g, isolated yield 42%; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 5.10 (s, 1H), 3.11 (s, 3H), 2.99 (s, 2H), 1.51–1.58 (m, 2H), 1.44–1.51 (m, 2H), 1.26–1.31 (m, 8H), 0.81–0.86 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.4, 156.3, 152.2, 82.3, 44.1, 34.8, 31.7, 28.6, 27.9, 26.8, 22.5, 21.9, 14.4, 11.6; IR νmax: 2954, 2926, 2857, 1692, 1641, 1618, 1573, 1456, 1416, 1366, 1347, 1260, 1224, 1112, 1060, 993, 888, 807, 766, 572, 549 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C17H31N4O2 323.2447; found: 323.2446; mp 70.0–75.9 °C.

N′-(1-allyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (28)

A scale of 4.46 mmol, used halide: bromide, solid, 0.36 g, isolated yield of 31%; 1H NMR (700 MHz, DMSO-d6) δ 8.09 (s, 1H), 5.79 (ddt, J = 17.2, 10.3, 5.2 Hz, 1H), 5.13 (s, 1H), 5.04 (dd, J = 10.3, 1.3 Hz, 1H), 4.99 (dd, J = 17.2, 1.5 Hz, 1H), 4.35 (d, J = 5.2 Hz, 2H), 3.88 (t, J = 7.3 Hz, 2H), 3.11 (s, 3H), 2.98 (s, 3H), 1.54 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.8, 159.2, 156.1, 151.5, 133.4, 115.8, 81.7, 43.8, 42.0, 40.4, 34.4, 21.5, 11.2; IR νmax: 2961, 2932, 2874, 1686, 1617, 1570, 1446, 1418, 1366, 1229, 1116, 994, 811, 767, 552 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C13H21N4O2 265.1665; found: 265.1663; mp: 151.1–153.0 °C.

N,N-Dimethyl-N′-(1-(2-methylallyl)-2,6-dioxo-3-propyl-1,2,3,6-tetrahydropyrimidin-4-yl)formimidamide (29)

A scale of 4.46 mmol, used halide: chloride, solid, 0.96 g, isolated yield of 77%; 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 5.14 (s, 1H), 4.68–4.74 (m, 1H), 4.46 (s, 1H), 4.28 (s, 2H), 3.90 (t, J = 7.9 Hz, 2H), 3.12 (s, 3H), 3.00 (s, 3H), 1.67 (s, 3H), 1.55 (dq, J = 14.8, 7.4 Hz, 2H), 0.82 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.6, 156.4, 152.0, 141.0, 109.2, 82.0, 45.1, 44.1, 34.8, 21.9, 20.8, 11.5; IR νmax: 3088, 2961, 2934, 2875, 1688, 1645, 1609, 1566, 1497, 1443, 1418, 1393, 1360, 1335, 1322, 1227, 1261, 1281, 1204, 1182, 1115, 1067, 1017, 993, 904, 881, 806, 764, 583, 552, 423 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H23N4O2 2279.1821; found: 279.1822; mp 87.4–90.3 °C.

N′-(1-Benzyl-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (30)

A scale of 7 mmol, used halide: chloride, solid, 1.78 g, 81% yield; 1H NMR (700 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.26–7.29 (m, 2H), 7.19–7.24 (m, 3H), 5.18 (s, 1H), 4.94 (s, 2H), 3.87–3.90 (m, 2H), 3.11 (s, 3H), 2.99 (s, 1H), 1.54 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 162.1, 159.3, 156.1, 151.8, 138.2, 128.3, 127.4, 126.9, 81.7, 43.9, 43.1, 40.4, 34.4, 21.5, 11.2; IR νmax: 2964, 2927, 2870, 1747, 1687, 1640, 1608, 1561, 1497, 1451, 1420, 1349, 1321, 1257, 1226, 1181, 1113, 1062, 1030, 989, 922, 885, 815. 691, 552 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C17H23N4O2 315.1821; found: 315.1820; mp 116.6–118.1 °C.

N′-(1-Benzyl-2,6-dioxo-3-phenyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (31)

A scale of 1.6 mmol, used halide: chloride, solid, 0.37 g, isolated yield of 65%; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.17-7.42 (m, 10H), 5.32 (s, 1H), 4.98 (s, 2H), 3.00 (s, 3H), 2.53 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8, 160.0, 155.8, 152.2, 138.4, 137.8, 129.8, 128.7, 128.0, 128.0, 127.4, 82.1, 43.7, 34.3; IR νmax: 2917, 2951, 1695, 1652, 1613, 1591, 1569, 1490, 1416, 1398, 1377, 1352, 1332, 1302, 1266, 1233, 1137, 1102, 1072, 1060, 1025, 998, 947, 890, 808, 778, 744, 731, 711, 694, 574, 531, 468 cm–1; HRMS (ESI-TOF) m/z: (M + H) calcd for C20H21N4O2 349.1665; found: 349.1668; mp 158.2–164.2 °C.

N′-(1-Allyl-3-benzyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N,N-dimethylformimidamide (32)

A scale of 3.8 mmol, used halide: bromide, solid, 1.10 g, isolated yield of 96%; 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.20–7.30 (m, 5H), 5.81 (ddt, J = 17.2, 10.4, 5.1, 5.1 Hz, 1H), 5.21 (s, 1H), 5.16 (s, 2H), 5.04 (dq, J = 2.9, 1.6 Hz, 1H), 4.37 (dt, J = 5.1, 1.5 Hz, 2H), 3.95 (d, J = 7.3 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.2, 159.4, 156.6, 152.2, 138.8, 133.7, 128.7, 127.6, 127.3, 116.3, 82.0, 45.7, 42.5, 40.8, 35.0; IR νmax: 3080, 3033, 2946, 1689, 1649, 1613, 1567, 1494, 1443, 1417, 1391, 1365, 1323, 1257, 1210, 1122, 1093, 993, 925, 900, 818, 765, 740, 692, 642, 601, 523, 565 cm–1; HRMS (ESI-TOF) m/z: (M + H) calcd for C17H21N4O2 313.1665; found: 313.1664; mp 135.0–138.5 °C.

N′-(1,3-Dibenzyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (33)

A scale of 3.8 mmol, used halide: chloride, solid, 0.88 g, isolated yield of 66%; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.17–7.35 (m, 10H), 5.26 (s, 1H), 5.17 (s, 2H), 4.97 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4, 159.5, 156.7, 152.5, 138.8, 138.4, 128.7, 128.7, 127.8, 127.6, 127.3, 82.1, 45.8, 43.6, 40.8, 35.0; IR νmax: 2965, 2934, 2875, 1687, 1613, 1567, 1448, 1415, 1362, 1338, 1233, 1116, 1001, 815, 767, 570, 551 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H23N4O2 363.1821; found: 363.1820; mp: 142.3–143.4 °C. The above analysis results correspond to the literature data.[19e]

N′-(3-Benzyl-1-(2-methylbenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (34)

A scale of 3.8 mmol, used halide: chloride, solid, 1.25 g, 91%; 1H NMR (700 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.19–7.30 (m, 6H), 7.04–7.12 (m, 2H), 6.77 (s, 1H), 5.29 (s, 1H), 5.17 (s, 2H), 4.93 (s, 2H), 3.10 (s, 3H), 2.95 (s, 2H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.5, 159.6, 156.7, 152.5, 138.8, 136.1, 135.4, 130.3, 128.7, 127.5, 127.3, 126.8, 126.2, 124.9, 82.1, 45.8, 41.4, 35.0, 19.2 IR νmax: 3030, 2955, 2922, 1694, 1642, 1615, 1562, 1492, 1448, 1423, 1368, 1324, 1258, 1215, 1125, 1094, 998, 903, 813, 759, 741, 694, 603, 574, 525, 475 cm–1. HRMS (ESI-TOF): (M + H)+ calcd for C22H25N4O2 377.1978; found: 377.1980; mp 139.4–142.7 °C.

N′-(3-Benzyl-1-(3-methylbenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (35)

A scale of 3.8 mmol, used halide: chloride, solid, 0.74 g, isolated yield of 54%; 1H NMR (700 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.26–7.30 (m, 2H), 7.19–7.25 (m, 3H), 7.13–7.18 (m, 1H), 6.99–7.04 (m, 3H), 5.24 (s, 1H), 5.16 (s, 2H), 4.92 (s, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 162.0, 159.0, 156.3, 152.1, 138.4, 138.0, 137.3, 128.3, 128.2, 127.8, 127.6, 127.2, 127.0, 124.4, 81.7, 45.3, 43.2, 40.5, 34.6, 21.1; IR νmax: 3061, 3032, 2925, 1692, 1621, 1562, 1490, 1446, 1423, 1386, 1364, 1337, 1280, 1254, 1210, 1128, 1094, 1067, 1015, 919, 899, 792, 764, 699, 597, 570, 522, 468 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H25N4O2 377.1978; found: 377.1978; mp 131.9–133.2 °C.

N′-(3-Benzyl-1-(4-methylbenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (36)

A scale of 3.8 mmol, used halide: chloride, solid, 1.00 g, isolated yield of 72%; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.19–7.34 (m, 5H), 7.05–7.17 (m, 4H), 5.25 (s, 1H), 5.16 (s, 2H), 4.92 (s, 2H), 3.09 (s, 3H), 2.95 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4, 159.4, 156.7, 152.5, 138.8, 136.4, 135.4, 129.2, 128.7, 127.9, 127.6, 127.3, 82.1, 45.7, 43.4, 40.8, 35.0, 21.1; IR νmax: 2965, 2934, 2875, 1688, 1614, 1566, 1448, 1416, 1363, 1233, 1117, 1001, 814, 767, 570, 551 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H25N4O2 377.1978; found: 377.1977; mp 156.6–159.7 °C.

N′-(3-Benzyl-1-(4-isopropylbenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (37)

A scale of 3.8 mmol, used halide: chloride, solid, 1.47 g, isolated yield of 99%; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.26 (spt, J = 7.1 Hz, 6H), 7.16 (d, J = 1.2 Hz, 3H), 5.25 (s, 1H), 5.16 (s, 2H), 4.93 (s, 2H), 3.09 (s, 3H), 2.95 (s, 3H), 2.82 (s, 1H), 1.17 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ (ppm) = 162.4, 159.4, 156.7, 152.5, 147.5, 138.8, 135.8, 133.6, 128.7, 127.9, 127.6, 126.6, 82.1, 45.8, 43.4, 40.8, 35.0, 33.6, 24.4; IR νmax: 2957, 1694, 1638, 1610, 1560, 1510, 1445, 1421, 1407, 1356, 1346, 1295, 1256, 1216, 1125, 1092, 1056, 910, 899, 805, 768, 738, 698, 600, 589, 523 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C24H29N4O2 405.2291; found: 405.2294; mp: 129.2–130.6 °C.

N′-(3-Benzyl-1-(3-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (38)

A scale of 3.8 mmol, used halide: chloride, solid, 0.80 g, isolated yield of 56%; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.17–7.32 (m, 6H), 6.75–6.84 (m, 3H), 5.26 (s, 1H), 5.18 (s, 2H), 4.95 (s, 2H), 3.70 (s, 3H), 3.10 (s, 3H), 2.96 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.4, 159.7, 159.5, 156.7, 152.5, 140.0, 138.8, 129.7, 128.7, 127.6, 127.3, 119.8, 113.4, 112.6, 82.1, 55.4, 45.7, 43.6, 40.8, 35.0; IR νmax: 2928, 2832, 1690, 1614, 1561, 1487, 1449, 1425, 1408, 1367, 1335, 1283, 1250, 1211, 1150, 1123, 1092, 1055, 921, 897, 805, 764, 699, 599, 571, 522, 476 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H25N4O3 393.1927; found: 393.1927; mp 122.5–123.5 °C.

N′-(3-Benzyl-1-(2-fluorobenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (39)

A scale of 3.8 mmol, used halide: chloride, solid, 0.86 g, isolated yield of 61%; 1H NMR (700 MHz, DMSO-d6) δ 8.14–8.16 (m, 1H), 7.25–7.30 (m, 3H), 7.19–7.25 (m, 3H), 7.14–7.18 (m, 1H), 7.08–7.12 (m, 1H), 6.98–7.02 (m, 1H), 5.28 (s, 1H), 5.16 (s, 2H), 5.02 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.9, 160.6, 159.2, 156.4, 152.0, 138.3, 128.7 (d, J = 8.2 Hz), 128.3, 127.8 (d, J = 4.1 Hz), 127.2, 127.0, 124.7 (d, J = 14.3 Hz), 124.4 (d, J = 3.3 Hz), 115.2 (d, J = 21.3 Hz), 81.6, 45.4, 40.5, 37.2 (d, J = 5.3 Hz), 34.6; IR νmax: 1693, 1645, 1614, 1579, 1560, 1490, 1441, 1421, 1360, 1327, 1218, 1125, 1093, 813, 756, 701, 600, 524, 427 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H22FN4O2 381.1727; found: 381.1725; mp 113.0–116.0 °C.

N′-(3-Benzyl-1-(3-fluorobenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (40)

A scale of 3.8 mmol, used halide: chloride, solid, 0.99 g, isolated yield of 71%; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.19–7.38 (m, 6H), 6.99–7.11 (m, 3H), 5.27 (s, 1H), 5.17 (s, 2H), 4.98 (s, 2H), 3.10 (s, 3H), 2.96 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.8, 162.3, 159.6, 156.8, 152.5, 141.4 (d, J = 7.2 Hz), 138.8, 130.7 (d, J = 7.9 Hz), 128.7, 127.6, 127.4, 123.8 (d, J = 2.4 Hz), 114.5 (d, J = 21.5 Hz), 114.2 (d, J = 20.7 Hz), 82.0, 45.8, 43.3, 40.9, 35.0; IR νmax: 1699, 1646, 1614, 1568, 1447, 1415, 1365, 1323, 1246, 1219, 1135, 1093, 985, 941, 878, 811, 765, 691, 603, 525, 465 cm–1; HRMS (ESI-TOF) m/z: (M + H) calcd for C21H22FN4O2 381.1727; found: 381.1726; mp 135.8–141.6 °C.

N′-(3-Benzyl-1-(3-bromobenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (41)

A scale of 3.8 mmol, used halide: chloride, solid, 1.53 g, isolated yield of 94%; 1H NMR (700 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.41–7.44 (m, 1H), 7.37–7.39 (m, 1H), 7.19–7.30 (m, 7H), 5.26 (s, 1H), 5.16 (s, 2H), 4.95 (s, 2H), 3.09 (s, 3H), 2.94 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.9, 159.2, 156.4, 152.0, 140.8, 138.3, 130.6, 130.0, 129.9, 128.4, 127.1, 127.0, 126.6, 121.6, 81.6, 45.4, 42.7, 40.5; IR νmax: 2961, 1691, 1643, 1618, 1567, 1495, 1443, 1412, 1354, 1315, 1258, 1220, 1128, 1096, 1066, 987, 926, 842, 803, 765, 692, 613, 602, 520, 459 cm–1. HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H22BrN4O2 441.0926; found: 441.0928; mp: 182.5–185.1 °C.

N′-(3-Benzyl-2,6-dioxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylform-imidamide (42)

A scale of 3.8 mmol, used halide: chloride, solid, 1.17 g, isolated yield of 74%; 1H NMR (700 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.60 (s, 1H), 7.55 (m, 3H), 7.19–7.29 (m, 5H), 5.28 (s, 1H), 5.17 (s, 2H), 5.05 (s, 2H), 3.09 (s, 3H), 2.94 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.6, 156.8, 152.5, 139.9, 138.7, 132.0, 129.9, 129.5 (q, J = 31.8 Hz), 128.7, 127.5, 127.4, 124.0–124.3 (m), 82.0, 45.8, 43.3, 40.9, 35.0; IR νmax: 2962, 1692, 1643, 1619, 1566, 1445, 1415, 1365, 1320, 1196, 1145, 1114, 1095, 1071, 990, 923, 889, 807, 768, 702, 695, 661, 601, 521 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H22F3N4O2 431.1695; found: 431.1694; mp 188.6–191.7 °C.

N′-(3-Benzyl-1-(4-nitrobenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethylformimidamide (43)

A scale of 3.8 mmol, used halide: chloride, solid, 1.27 g, isolated yield of 85%; 1H NMR (400 MHz, DMSO-d6) δ 8.14–8.20 (m, 3H), 7.49 (d, J = 8.8 Hz, 2H), 7.20–7.32 (m, 5H), 5.30 (s, 1H), 5.17 (s, 2H), 5.09 (s, 2H), 3.11 (s, 3H), 2.96 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 159.7, 156.8, 152.5, 147.0, 146.4, 138.7, 128.8, 127.6, 127.4, 124.2, 124.0, 81.9, 45.9, 43.4, 40.9, 35.0; IR νmax: 1695, 1644, 1621, 1562, 1515, 1447, 1424, 1367, 1339, 1221, 1129, 1096, 990, 901, 856, 809, 765, 750, 692, 603, 577, 524 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H22N5O4 408.1672; found: 408.1670; mp 176.8–182.7 °C.

6-Amino-1-benzyl-3-propylpyrimidine-2,4(1H,3H)-dione (44)

A scale of 12.7 mmol, solid, 2.89 g, isolated yield of 88%; 1H NMR (400 MHz, DMSO-d6) δ 7.31–7.38 (m, 2H), 7.23–7.30 (m, 1H), 7.16–7.22 (m, 2H), 6.73–6.83 (m, 2H), 5.04–5.11 (m, 2H), 4.72 (s, 1H), 3.69 (t, J = 7.1 Hz, 2H), 1.49 (sxt, J = 7.3 Hz, 2H), 0.82 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.4, 154.5, 151.6, 136.6, 128.5, 127.2, 126.4, 75.4, 44.6, 41.5, 20.9, 11.2; IR νmax: 3405, 3341, 3194, 2963, 1633, 1582, 1490, 1451, 1432, 1405, 1366, 1274, 1218, 1125, 1083, 809, 721, 685, 548, 517, 459 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H18N3O2 260.1399; found: 260.1400; mp 198.5–199.9 °C. The above analysis results correspond to the literature data.[19f]

6-Amino-1-phenyl-3-propylpyrimidine-2,4(1H,3H)-dione (45)

A scale of 9.8 mmol, solid, 1.07 g, isolated yield of 45%; 1H NMR (700 MHz, DMSO-d6) δ 7.46–7.54 (m, 3H), 7.29–7.34 (m, 2H), 6.10 (s, 2H), 4.79 (s, 1H), 3.66 (t, J = 7.3 Hz, 2H), 1.49 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.1, 154.6, 151.6, 135.0, 130.1, 129.8, 129.7, 75.3, 41.8, 21.4, 11.7; IR νmax: 3342, 3531, 3176, 2972, 1694, 1663, 1612, 1587, 1477, 1437, 1404, 1359, 1453, 1299, 1154, 1101, 1064, 1019, 797, 761, 695, 573, 534 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C13H16N3O2 246.1243; found: 246.1243; mp 187.7–189.5 °C. The above analysis results correspond to the literature data.[19g]

6-Amino-3-ethyl-1-propylpyrimidine-2,4(1H,3H)-dione (46)

A scale of 1.3 mmol, solid, 70 mg, isolated yield of 28%; 1H NMR (400 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.65 (s, 1H), 3.69–3.79 (m, 4H), 1.53 (sxt, J = 7.5 Hz, 2H), 1.02 (t, J = 7.0 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.5, 154.7, 151.6, 75.6, 43.5, 40.7, 35.2, 21.3, 13.7; IR νmax: 3459, 3356, 3131, 2966, 2934, 2875, 1688, 1612, 1569, 1494, 1451, 1410, 1363, 1269, 1117, 1095, 787, 695, 593, 533 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C9H16N3O2 198.1243; found: 198.1242; mp 78.7–83.5 °C. The above analysis results correspond to the literature data.[19h]

6-Amino-3-butyl-1-propylpyrimidine-2,4(1H,3H)-dione (47)

A scale of 1.3 mmol, solid, 0.12 g, isolated yield of 41%; 1H NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.65 (s, 1H), 3.65–3.78 (m, 4H), 1.53 (sxt, J = 7.5 Hz, 4H), 1.43 (quin, J = 7.4 Hz, 3H), 1.23 (dq, J = 14.9, 7.4 Hz, 6H), 0.81–0.91 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.7, 154.7, 151.8, 75.5, 43.5, 30.2, 21.3, 20.1, 14.2, 11.2; IR νmax: 3437, 3114, 2962, 2931, 2874, 1698, 1654, 1604, 1503, 1464, 1436, 1411, 1364, 1284, 1270, 1198, 1180, 1044, 788, 760, 526 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C11H20N3O2 226.1556; found: 226.1554; mp 91.4–98.1 °C.

6-Amino-3-isobutyl-1-propylpyrimidine-2,4(1H,3H)-dione (48)

A scale of 2.6 mmol, solid, 0.21 g, isolated yield of 36%; 1H NMR (700 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.64 (s, 1H), 3.73 (t, J = 1.0 Hz, 2H), 3.54 (d, J = 7.3 Hz, 2H), 1.95 (dquin, J = 13.8, 6.9, 6.9, 6.9, 6.9 Hz, 1H), 1.51 (sxt, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H), 0.78 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.6, 154.3, 151.7, 75.1, 46.6, 43.1, 26.7, 20.9, 20.0, 10.8; IR νmax: 3436, 3113, 2962, 1656, 1604, 1504, 1463, 1435, 1408, 1386, 1271, 1170, 1101, 1047, 788, 757, 548, 537 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C11H20N3O2 226.1556; found: 226.1556; mp 107.9–110.8 °C.

6-Amino-1,3-dibutylpyrimidine-2,4(1H,3H)-dione (49)

1,3-Dibutylurea (11.61 mmol; 2.00 g) and cyanoacetic acid (12,77 mmol; 1.09 g) were dissolved in acetic anhydride (12 mL). The resulting mixture was heated at 70 °C for 16 h. After this time, acetic anhydride was evaporated to give a red viscous oil. The residue was dissolved in NaOH solution in water (15 mL; 20%). The precipitated solid was filtered off, washed with water (3 × 10 mL) and diethyl ether (3 × 10 mL), and dried in vacuo (0.1 Torr, 2 h). The expected product (2.31 g) was obtained with an 83% yield; 1H NMR (700 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.64 (s, 1H), 3.75 (t, J = 7.7 Hz, 2H), 3.68 (t, J = 7.3 Hz, 2H), 1.44–1.49 (m, 2H), 1.39–1.44 (m, 2H), 1.19–1.30 (m, 4H), 0.84–0.89 (m, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.3, 154.3, 151.3, 75.2, 41.6, 29.8, 29.7, 19.7, 19.3, 13.8, 13.8; IR νmax: 3434, 3125, 2957, 2931, 2873, 1656, 1604, 1505, 1460, 1411, 1289, 790, 770, 530 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C12H22N3O2 240.1712; found: 240.1710; mp 96.5–102.2 °C.

6-Amino-3-pentyl-1-propylpyrimidine-2,4(1H,3H)-dione (50)

A scale of 3.4 mmol, solid, 0.53 g, isolated yield 65%; 1H NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.65 (s, 1H), 3.65–3.77 (m, 4H), 1.41–1.58 (m, 4H), 1.17–1.32 (m, 4H), 0.82–0.89 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.7, 154.7, 151.8, 75.6, 43.5, 29.0, 27.6, 22.3, 21.3, 14.3, 11.2; IR νmax: 3439, 3352, 3117, 2959, 2930, 1646, 1603, 1500, 1456, 1411, 1368, 1271, 1191, 1113, 1048, 790, 769, 547 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C12H22N3O2 240.1712; found: 240.1715; mp 92.2–95.5 °C.

6-Amino-3-hexyl-1-propylpyrimidine-2,4(1H,3H)-dione (51)

A scale of 1.3 mmol, solid, 0.17 g, isolated yield of 53%; 1H NMR (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 4.64 (s, 1H), 3.65–3.77 (m, 4H), 1.38–1.61 (m, 4H), 1.24 (s, 6H), 0.81–0.89 (m, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.7, 154.7, 151.8, 75.5, 43.5, 31.4, 27.9, 26.5, 22.4, 21.3, 14.3, 11.2; IR νmax: 3439, 3118, 2962, 2931, 1650, 1603, 1500, 1410, 1370, 1270, 1192, 788, 759, 545 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C13H24N3O2 254.1869; found: 254.1868; mp 89.9–92.5 °C.

6-Amino-3-heptyl-1-propylpyrimidine-2,4(1H,3H)-dione (52)

A scale of 1.9 mmol, solid, 0.15 g, isolated yield of 29%; 1H NMR (700 MHz, DMSO-d6) δ 6.77 (s, 2H), 4.63 (s, 1H), 3.72 (t, J = 7.7 Hz, 2H), 3.67 (d, J = 7.3 Hz, 2H), 1.51 (sxt, J = 7.5 Hz, 2H), 1.43 (quin, J = 7.4 Hz, 2H), 1.17–1.28 (m, 8H), 0.84 (td, J = 7.2, 2.6 Hz, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.3, 154.3, 151.4, 75.1, 43.1, 31.3, 28.5, 27.6, 26.4, 22.1, 20.9, 14.0, 10.8; IR νmax: 3438, 3138, 2961, 2928, 2855, 1651, 1603, 1501, 1462, 1436, 1410, 1367, 1270, 1192, 1085, 789, 762, 544 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H26N3O2 268.2025; found: 268.2022; mp 71.2–75.2 °C.

3-Allyl-6-amino-1-propylpyrimidine-2,4(1H,3H)-dione (53)

A scale of 1.4 mmol, solid, 0.13 g, isolated yield of 46%; 1H NMR (400 MHz, DMSO-d6) δ 6.83 (s, 2H), 5.78 (ddt, J = 17.1, 10.3, 5.2, 5.2 Hz, 1H), 4.94–5.06 (m, 2H), 4.67 (s, 1H), 4.31 (d, J = 5.1 Hz, 1H), 3.74 (t, J = 7.8 Hz, 2H), 1.53 (dq, J = 15.0, 7.5 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.3, 154.9, 151.6, 134.1, 116.0, 75.3, 43.6, 42.2, 21.2, 11.2; IR νmax: 3452, 3355, 3116, 2969, 1694, 1605, 1498, 1403, 1424, 1323, 1295, 1270, 1189, 1081, 1047, 994, 938, 776, 744, 669, 634, 546, 502, 463, 408 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C10H16N3O2 210.1243; found: 210.1244; mp: 97.9–103.9 °C.

6-Amino-3-(2-methylallyl)-1-propylpyrimidine-2,4(1H,3H)-dione (54)

A scale of 3.4 mmol, solid, 0.37 g, isolated yield of 48%; 1H NMR (700 MHz, DMSO-d6) δ 6.84 (s, 2H), 4.67–4.68 (m, 1H), 4.66 (s, 1H), 4.43 (dd, J = 1.6, 1.0 Hz, 1H), 4.21 (s, 2H), 3.73 (t, J = 1.0 Hz, 2H), 1.64 (d, J = 0.4 Hz, 3H), 1.52 (sxt, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.0, 154.5, 151.2, 140.8, 108.6, 74.8, 44.4, 43.2, 20.9, 20.4, 10.8; IR νmax: 3438, 3114, 2974, 1653, 1604, 1502, 1423, 1398, 1294, 1270, 1194, 1096, 886, 779, 746, 567, 543 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C11H18N3O2 224.1399; found: 224.1400; mp 93.0–97.0 °C.

6-Amino-3-benzyl-1-propylpyrimidine-2,4(1H,3H)-dione (55)

A scale of 4.6 mmol, solid, 1.01 g, isolated yield of 84%; 1H NMR (700 MHz, DMSO-d6) δ 7.24–7.28 (m, 2H), 7.18–7.23 (m, 3H), 6.88 (s, 2H), 4.89 (s, 2H), 4.70 (s, 1H), 3.70–3.75 (m, 2H), 1.51 (sxt, J = 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.2, 154.6, 151.5, 138.4, 128.2, 127.4, 126.8, 74.9, 43.3, 43.0, 20.9, 10.8; IR νmax: 3479, 3067, 2964, 2876, 1688, 1646, 1607, 1583, 1490, 1453, 1428, 1402, 1343, 1288, 1258, 1190, 926, 897, 784, 757, 730, 700, 672, 646, 600, 547, 511 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H18N3O2 260.1399; found: 260.1397; mp 147.3–151.9 °C.

6-Amino-3-benzyl-1-phenylpyrimidine-2,4(1H,3H)-dione (56)

A scale of 1.1 mmol, solid, 0.24 g, isolated yield of 77%; 1H NMR (400 MHz, DMSO-d6) δ 7.48–7.56 (m, 3H), 7.20–7.37 (m, 7H), 6.22 (s, 2H), 4.93 (s, 2H), 4.89 (s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.1, 154.9, 151.8, 138.6, 134.8, 130.2, 129.8, 128.6, 128.0, 127.3, 75.2, 43.4; IR νmax: 3449, 3293, 3229, 3178, 1702, 1635, 1610, 1578, 1469, 1450, 1421, 1397, 1350, 1287, 1182, 1153, 1077, 1049, 1021, 942, 789, 772, 754, 716, 691, 645, 599, 569, 522, 507, 452 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C17H16N3O2 294.1243; found: 294.1243; mp 183.3–186.6 °C.

3-Allyl-6-amino-1-benzylpyrimidine-2,4(1H,3H)-dione (57)

A scale of 4.5 mmol, solid, 0.51 g, isolated yield of 44%; 1H NMR (700 MHz, DMSO-d6) δ 7.31–7.35 (m, 2H), 7.23–7.27 (m, 1H), 7.17–7.20 (m, 2H), 6.84 (s, 2H), 5.78 (ddt, J = 17.2, 10.3, 5.2, 5.2 Hz, 1H), 5.07 (s, 2H), 5.03 (dq, J = 10.3, 1.5 Hz, 2H), 4.99 (dq, J = 17.2, 1.6 Hz, 1H), 4.73 (s, 1H), 4.33 (dt, J = 5.2, 1.5 Hz, 2H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 160.9, 154.6, 151.4, 136.6, 133.6, 128.5, 127.2, 126.4, 115.7, 75.2, 44.6, 42.0; IR νmax: 3420, 3336, 3182, 1632, 1607, 1579, 1490, 1450, 1418, 1270, 1129, 993, 925, 789, 762, 733, 692, 635, 593, 530, 437 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C14H16N3O2 258.1243; found: 258.1244; mp 198.1–203.8 °C.

6-Amino-1,3-dibenzylpyrimidine-2,4(1H,3H)-dione (58)

A scale of 1.2 mmol, solid, 0.26 g, isolated yield of 72%; 1H NMR (400 MHz, DMSO-d6) δ 7.12–7.42 (m, 10H), 6.90 (s, 2H), 5.09 (s, 2H), 4.95 (s, 2H), 4.80 (s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.6, 155.1, 152.1, 138.7, 136.9, 128.9, 128.6, 127.7, 127.6, 127.3, 126.8, 75.7, 45.2, 43.5; IR νmax: 3459, 2966, 1688, 1612, 1568, 1496, 1450, 1414, 1363, 1282, 1118, 813, 755, 738, 694, 593, 534, 507 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H18N3O2 308.1399; found: 308.1399; mp 87.4–90.3 °C. The above analysis results correspond to the literature data.[19e]

6-Amino-1-benzyl-3-(2-methylbenzyl)pyrimidine-2,4(1H,3H)-dione (59)

A scale of 3.3 mmol, solid, 0.65 g, isolated yield of 61%; 1H NMR (700 MHz, DMSO-d6) δ 7.33 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.18–7.22 (m, 2H), 7.13 (d, J = 6.9 Hz, 1H), 7.08 (quind, J = 7.0, 7.0, 7.0, 7.0, 1.4 Hz, 2H), 6.96 (s, 2H), 6.78–6.82 (m, 1H), 5.09 (s, 2H), 4.90 (s, 2H), 4.82 (s, 1H), 2.31 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.3, 154.8, 151.8, 136.6, 136.0, 134.9, 129.9, 128.5, 127.2, 126.4, 125.8, 124.6, 75.2, 44.8, 40.9, 18.8; IR νmax: 3425, 3344, 1618, 1582, 1488, 1450, 1417, 1277, 1197, 1028, 948, 790, 746, 728, 703, 648, 593, 549, 503, 430 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H20N3O2 322.1556; found: 322.1557; mp 191.3–197.5 °C.

6-Amino-1-benzyl-3-(3-methylbenzyl)pyrimidine-2,4(1H,3H)-dione (60)

A scale of 2.0 mmol, solid, 0.50 g, isolated yield of 79%; 1H NMR (700 MHz, DMSO-d6) δ 7.31–7.35 (m, 2H), 7.23–7.27 (m, 1H), 7.17–7.20 (m, 2H), 7.13–7.17 (m, 1H), 6.98–7.04 (m, 3H), 6.90 (s, 2H), 5.07 (s, 2H), 4.89 (s, 2H), 4.77 (s, 1H), 2.24 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.2, 154.7, 151.7, 138.2, 137.3, 136.6, 128.5, 128.2, 127.7, 127.5, 127.2, 126.4, 124.4, 75.2, 44.7, 43.0, 21.1; IR νmax: 3466, 3437, 3146, 1702, 1642, 1604, 1494, 1452, 1426, 1402, 1282, 936, 790, 757, 727, 689, 589, 535, 527, 464, 427 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H20N3O2 322.1556; found: 322.1556; mp 90.0–93.2 °C.

6-Amino-1-benzyl-3-(4-methylbenzyl)pyrimidine-2,4(1H,3H)-dione (61)

A scale of 2.5 mmol, solid, 0.65 g, isolated yield of 81%; 1H NMR (700 MHz, DMSO-d6) δ 7.30–7.34 (m, 2H), 7.22–7.27 (m, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.05–7.13 (m, 4H), 6.89 (s, 2H), 5.06 (s, 2H), 4.88 (s, 2H), 4.77 (s, 1H), 2.24 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.2, 154.6, 136.5, 136.0, 135.2, 128.8, 128.5, 127.4, 126.4, 79.3, 75.2, 44.7, 42.8, 20.7; IR νmax: 2965, 2933, 2875, 1687, 1612, 1568, 1449, 1416, 1362, 1233, 1116, 814, 767, 570, 551, 471 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H20N3O2 322.1556; found: 322.1555; mp 83.6–90.2 °C.

6-Amino-1-benzyl-3-(4-isopropylbenzyl)pyrimidine-2,4(1H,3H)-dione (62)

A scale of 3.6 mmol, solid, 0.97 g, isolated yield of 76%; 1H NMR (400 MHz, DMSO-d6) δ 7.13–7.34 (m, 9H), 6.87 (s, 2H) 5.08 (s, 2H), 4.89 (s, 2H), 4.76 (s, 1H), 2.84–2.82 (m, 1H), 1.17 (d, J = 7.1 Hz, 6H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 162.0, 159.0, 156.3, 152.1, 147.1, 138.4, 135.4, 128.3, 127.5, 127.2, 126.2, 81.7, 45.3, 43.0, 33.2, 24.0; IR νmax: 3179, 2958, 2869, 1608, 1491, 1451, 1422, 1400, 1351, 1279, 1209, 1188, 1117, 1054, 1018, 930, 783, 726, 694, 595, 529 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H24N3O2 350.1869; found: 350.1868; mp 89.5–93.2 °C.

6-Amino-1-benzyl-3-(3-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione (63)

A scale of 2.0 mmol, solid, 0.45 g, isolated yield of 65%; 1H NMR (400 MHz, DMSO-d6) δ 7.17–7.37 (m, 6H), 6.91 (s, 2H), 6.72–6.82 (m, 3H), 5.09 (s, 2H), 4.92 (s, 2H), 4.80 (s, 1H), 3.70 (s, 3H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.2, 159.3, 154.7, 151.7, 139.8, 136.5, 129.3, 128.5, 127.3, 126.4, 119.4, 113.0, 112.2, 75.2, 55.0, 44.7, 43.0; IR νmax: 3446, 3355, 3137, 1702, 1645, 1599, 1490, 1451, 1428, 1403, 1344, 1283, 1259, 1160, 1038, 938, 786, 776, 757, 728, 688, 591, 530, 502 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H20N3O3 338.1505; found: 338.1505; mp 89.4–91.2 °C.

6-Amino-1-benzyl-3-(2-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (64)

A scale of 2.3 mmol scale, solid, 0.49 g, isolated yield of 66%; 1H NMR (700 MHz, DMSO-d6) δ 7.31–7.35 (m, 2H), 7.23–7.28 (m, 2H), 7.19 (d, J = 7.1 Hz, 2H), 7.12–7.17 (m, 1H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 6.91–7.03 (m, 3H), 5.08 (s, 2H), 4.99 (s, 2H), 4.80 (s, 1H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.1, 159.2, 154.9, 151.7, 136.5, 128.6 (d, J = 8.2 Hz), 128.6, 127.8 (d, J = 4.5 Hz), 127.2, 126.3, 125.0 (d, J = 14.3 Hz), 124.4 (d, J = 3.7 Hz), 115.2 (d, J = 21.3 Hz), 75.1, 44.8, 37.0 (d, J = 5.3 Hz); IR νmax: 3464, 3319, 3190, 1692, 1608, 1580, 1487, 1453, 1418, 1360, 1274, 1221, 1193, 834, 778, 758, 734, 693, 523 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H17FN3O2 326.1305; found: 326.1307; mp 176.9–181.6 °C.

6-Amino-1-benzyl-3-(3-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione (65)

A scale of 2.6 mmol, solid 0.64 g, isolated yield of 75%; 1H NMR (700 MHz, DMSO-d6) δ 7.30–7.35 (m, 3H), 7.24–7.27 (m, 1H), 7.18 (d, J = 7.3 Hz, 2H), 7.03–7.06 (m, 2H), 6.98–7.01 (m, 1H), 6.95 (s, 2 H), 5.07 (s, 2H), 4.93 (s, 2H), 4.79 (s, 1H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.5, 161.1, 154.8, 151.7, 141.2 (d, J = 7.4 Hz), 136.5, 130.3 (d, J = 8.2 Hz), 128.5, 127.3, 126.4, 123.3 (d, J = 2.5 Hz), 114.0 (d, J = 21.7 Hz), 113.7 (d, J = 20.9 Hz), 75.1, 44.8, 42.7; IR νmax: 3461, 3371, 3135, 1697, 1609, 1498, 1428, 1409, 1269, 1253, 1116, 932, 793, 775, 761, 713, 684, 660, 596, 534 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H17FN3O2 326.1305; found: 326.1305; mp 90.3–95.1 °C.

6-Amino-1-benzyl-3-(3-bromobenzyl)pyrimidine-2,4(1H,3H)-dione (66)

A scale of 3.5 mmol, solid, 0.93 g, isolated yield of 69%; 1H NMR (400 MHz, DMSO-d6) δ 7.43 (dt, J = 6.3, 2.1 Hz, 1H), 7.39 (s, 1H), 7.31–7.37 (m, 2H), 7.23–7.30 (m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 6.96 (s, 2H), 5.10 (s, 2H), 4.94 (s, 2H), 4.81 (s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.5, 155.2, 152.1, 141.5, 136.9, 130.9, 130.4, 130.2, 128.9, 127.7, 126.9, 126.7, 122.0, 75.6, 45.2, 43.0; IR νmax: 3435, 3133, 1702, 1640, 1604, 1493, 1427, 1402, 1281, 1215, 1070, 935, 880, 784, 768, 725, 692, 666, 588, 534, 507, 462, 423 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H17BrN3O2 386.0504; found: 386.0502; mp 86.6–88.5 °C.

6-Amino-1-benzyl-3-(3-trifluoromethyl)benzyl)-pyrimidine-2,4(1H,3H)-dione (67)

A scale of 2.7 mmol, solid, 0.68 g, isolated yield of 67%; 1H NMR (400 MHz, DMSO-d6) δ 7.50–7.64 (m, 4H), 7.23–7.37 (m, 3H), 7.13–7.22 (m, 2H), 6.91–7.04 (m, 2H), 5.09 (s, 2H), 5.02 (s, 2H), 4.80 (s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.5, 155.2, 152.2, 140.1, 136.8, 132.0, 129.8, 129.5 (q, J = 31.8 Hz), 128.9, 127.7, 126.7, 123.8–124.4 (m), 124.7 (q, J = 271.8 Hz), 75.6, 45.2, 43.2; IR νmax: 3434, 3138, 1643, 1605, 1497, 1450, 1406, 1326, 1281, 1157, 1122, 1073, 938, 790, 728, 695, 659, 535, 509 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H17F3N3O2 376.1273; found: 376.1274; mp 95.8–102.3 °C.

6-Amino-1-benzyl-3-(4-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione (68)

A scale of 3.1 mmol, solid, 0.64 g, isolated yield of 58%; 1H NMR (700 MHz, DMSO-d6) δ 8.16 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.00 (s, 2H), 5.06 (d, J = 18.9 Hz, 4H), 4.81 (s, 1H); 13C{1H} NMR (176 MHz, DMSO-d6) δ 161.0, 154.9, 151.7, 146.6, 146.2, 136.4, 128.6, 128.2, 127.3, 126.3, 123.6, 75.1, 44.8, 42.9; IR νmax: 3428, 1689, 1643, 1602, 1518, 1493, 1451, 1405, 1343, 1285, 1215, 1208, 1110, 855, 804, 745, 693, 639, 598, 548, 522, 453 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H17N4O4 353.1250; found: 353.1247; mp 153.0–158.5 °C.

General Procedure for the Catalytic Reactions

The corresponding 1,3-disubstituted 6-aminouracil (0.3 mmol), NHC precatalyst 8c (0.03 mmol; 8 mg), Kharach oxidant DQ (0.3 mmol; 122 mg), and α,β-unsaturated aldehyde (0.3 mmol) were dispersed in anhydrous toluene (3 mL). Anhydrous potassium phosphate tribasic (0.06 mmol; 13 mg) as a base was added, and the mixture was stirred at room temperature for 24 h. The final product was isolated by flash column chromatography using gradient elution (0–100% AcOEt in hexane).

5-(4-Methoxyphenyl)-1,3-dipropyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aaa)

Solid, 106 mg, isolated yield of 95%.; 1H NMR (700 MHz, CDCl3) δ 8.61 (s, 1H), 7.14–7.18 (m, 2H), 6.79–6.83 (m, 2H), 4.43 (d, J = 6.56 Hz, 1H), 3.85–3.97 (m, 4H), 3.76 (s, 3H), 2.94–3.00 (m, 1H), 2.87 (dd, J = 1.40, 16.46 Hz, 1H), 1.61–1.73 (m, 5H), 0.96 (t, J = 7.37 Hz, 3H), 0.92 (t, J = 7.48 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 161.2, 158.8, 150.8, 143.8, 133.5, 127.5, 114.3, 93.1, 55.2, 44.2, 43.4, 37.8, 33.0, 22.1, 21.0, 11.3, 10.7; IR νmax: 3156.1, 2965.2, 2923.6, 1686.7, 1645.9, 1632.8, 1608.0, 1509.5, 1491.6, 1454.8, 1440.2, 1417.7, 1375.4, 1353.9, 1302.6, 1257.8, 1235.4, 1203.8, 1175.4, 1153.3, 1031.4, 998.3, 831.8, 776.1, 760.1, 739.0, 717.2, 687.0, 649.5, 584.3, 554.9, 530.0, 518.6, 496.6, 462.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H26N3O4 372.1923; found: 372.1924; mp 174.2–176.7 °C.

5-Phenyl-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7baa)

Solid, 113 mg, isolated yield of 83%; 1H NMR (700 MHz, CDCl3) δ 9.37 (s, 1H), 7.25–7.30 (m, 2H), 7.20–7.24 (m, 3H), 4.48 (d, J = 6.99 Hz, 1H), 3.98 (ddd, J = 6.10, 10.00, 14.90 Hz, 1H), 3.83–3.93 (m, 3H), 3.00 (dd, J = 8.01, 16.51 Hz, 1H), 2.87 (dd, J = 1.02, 16.51 Hz, 1H), 1.57–1.69 (m, 4H), 0.91 (dt, J = 2.04, 7.42 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 161.2, 150.8, 144.0, 141.4, 128.9, 127.3, 126.4, 92.7, 44.2, 43.4, 37.7, 33.8, 22.1, 21.0, 11.3, 10.7; IR νmax: 3246.8, 3217.6, 2963.0, 2933.5, 1687.6, 1654.9, 1632.6, 1504.3, 1480.4, 1471.1, 1441.4, 1417.7, 1353.8, 1300.8, 1281.2, 1242.6, 1227.0, 1173.6, 1137.5, 759.8, 741.3, 695.9, 683.2, 646.5, 565.7, 552.8, 496.2, 441.7 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H24N3O3 342.1818; found: 342.1819; mp 173.6–175.0 °C.

5-(2-Methoxyphenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7caa)

Solid, 149 mg, isolated yield of 79%; 1H NMR (700 MHz, CDCl3) δ 8.10 (s, 1H), 7.18–7.23 (m, 1H), 7.05 (dd, J = 1.72, 7.53 Hz, 1H), 6.83–6.87 (m, 2H), 4.63 (d, J = 7.96 Hz, 1H), 3.81–3.97 (m, 4H), 3.79 (s, 3H), 2.93 (dd, J = 9.09, 16.83 Hz, 1H), 2.80 (dd, J = 1.02, 16.73 Hz, 1H), 1.61 (dt, J = 1.40, 7.53 Hz, 4H), 0.98 (t, J = 7.42 Hz, 3H), 0.89 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 161.0, 157.0, 150.9, 144.6, 128.8, 128.5, 128.0, 120.5, 110.8, 90.9, 54.8, 44.1, 43.2, 36.6, 30.8, 22.1, 21.0, 11.3, 10.7; IR νmax: 3203.0, 2963.4, 2934.6, 1719.4, 1691.7, 1635.0, 1612.6, 1510.8, 1487.6, 1475.9, 1455.0, 1424.9, 1359.0, 1334.2, 1284.8, 1235.7, 1177.0, 1109.6, 1028.1, 754.1, 657.3, 488.8 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H26N3O4 372.1923; found: 372.1922; mp 219.0–220.3 °C.

3-Methoxy-4-(2,4,7-trioxo-1,3-dipropyl-1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyrimidin-5-yl)phenyl Acetate (7daa)

Solid, 124 mg, isolated yield of 72%; 1H NMR (700 MHz, CDCl3) δ 7.04 (d, J = 2.04 Hz, 1H), 6.91 (d, J = 8.17 Hz, 1H), 6.76 (d, J = 8.28 Hz, 1H), 4.50 (dd, J = 3.44, 6.02 Hz, 1H), 3.84–3.95 (m, 4H), 3.78 (s, 3H), 2.96 (d, J = 6.24 Hz, 2H), 2.29 (s, 3H), 1.60–1.75 (m, 4H), 0.99 (t, J = 7.42 Hz, 3H), 0.93 (t, J = 7.48 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 169.1, 161.3, 151.3, 150.7, 143.9, 140.3, 138.9, 122.8, 117.6, 111.7, 92.8, 55.8, 44.3, 43.4, 37.0, 33.4, 22.1, 21.0, 20.6, 11.3, 10.7; IR νmax: 2957.9, 2926.2, 1767.7, 1689.5, 1637.6, 1603.8, 1504.8, 1477.7, 1458.7, 1419.6, 1365.1, 1355.3, 1332.1, 1293.3, 1269.2, 1258.3, 1233.5, 1191.0, 1176.8, 1160.9, 1135.2, 1120.3, 1033.0, 1012.0, 892.4, 757.3, 743.8, 678.4, 502.3, 473.7, 457.7 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H28N3O6 430.1978; found: 430.1980; mp 176.3–177.4 °C.

1,3-Dipropyl-5-(p-tolyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7eaa)

Solid, 85 mg, isolated yield of 61%; 1H NMR (700 MHz, CDCl3) δ 8.07 (s, 1H), 7.11–7.16 (m, 2H), 7.07–7.10 (m, 2H), 4.45 (d, J = 6.67 Hz, 1H), 3.83–3.94 (m, 4H), 2.98 (dd, J = 7.80, 16.60 Hz, 1H), 2.89 (dd, J = 1.10, 16.50 Hz, 1H), 2.29 (s, 3H), 1.60–1.75 (m, 4H), 0.98 (t, J = 7.42 Hz, 3H), 0.92 (t, J = 7.48 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 170.7, 160.6, 150.3, 143.1, 138.0, 136.6, 129.2, 125.9, 92.6, 43.8, 43.0, 37.0, 33.1, 21.8, 20.6, 20.6, 10.9, 10.5; IR νmax: 3167.0, 2967.6, 2933.9, 1686.8, 1648.7, 1633.7, 1493.5, 1457.1, 1353.7, 1238.8, 774.0, 495.5 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H26N3O3 356.1974; found: 356.1974; mp 169.3–171.5 °C.

5-(4-Fluorophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7faa)

Solid, 110 mg, isolated yield of 77%; 1H NMR (700 MHz, CDCl3) δ 8.41 (s, 1H), 7.18–7.22 (m, 2H), 6.95–6.99 (m, 2H), 4.47 (d, J = 6.99 Hz, 1H), 3.85–3.97 (m, 4H), 3.00 (dd, J = 8.01, 16.51 Hz, 1H), 2.86 (dd, J = 1.40, 16.56 Hz, 1H), 1.61–1.75 (m, 4H), 0.97 (t, J = 7.42 Hz, 3H), 0.92 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 163.2, 161.1, 160.8, 150.7, 143.9, 137.1 (d, J = 3.18 Hz), 128.0 (d, J = 7.95 Hz), 115.8 (d, J = 21.50 Hz), 92.6, 44.3, 43.4, 37.7, 33.2, 22.1, 21.0, 11.3, 10.7; IR νmax: 3242.4, 3187.6, 2967.5, 2929.6, 1687.3, 1636.8, 1605.1, 1506.1, 1464.8, 1438.4, 1409.7, 1380.9, 1353.2, 1299.3, 1268.4, 1229.0, 1158.3, 1021.1, 833.3, 781.8, 754.2, 738.5, 684.3, 664.2, 575.4, 551.2, 496.2, 460.8 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H23FN3O3 360.1723; found: 360.1722; mp 166.3–168.7 °C.

5-(4-Chlorophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7gaa)

Solid, 148 mg, isolated yield of 98%; 1H NMR (700 MHz, CDCl3) δ 7.22–7.28 (m, 2H), 7.13–7.18 (m, 2H), 4.45 (d, J = 6.78 Hz, 1H), 4.00 (ddd, J = 6.10, 10.00, 15.10 Hz, 1H), 3.85–3.93 (m, 3H), 3.00 (dd, J = 8.07, 16.56 Hz, 1H), 2.83 (dd, J = 0.86, 16.56 Hz, 1H), 1.58–1.69 (m, 4H), 0.90–0.93 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 161.1, 150.7, 144.1, 139.8, 133.2, 129.1, 127.9, 92.3, 44.3, 43.4, 37.5, 33.3, 22.1, 21.0, 11.3, 10.7; IR νmax: 3245.9, 2958.4, 2925.1, 1688.4, 1632.8, 1506.6, 1492.8, 1470.9, 1435.8, 1422.8, 1347.7, 1299.1, 1233.4, 835.1, 784.5, 750.2, 723.0, 681.4, 669.6, 504.5, 491.7, 460.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H23ClN3O3 376.1428; found: 376.1430; mp 128.0–134.0 °C.

5-(4-Bromophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7haa)

Solid, 167 mg, isolated yield of 99%; 1H NMR (700 MHz, CDCl3) δ 9.15 (s, 1H), 7.43–7.37 (m, 2H), 7.13–7.08 (m, 2H), 4.44 (d, J = 6.8 Hz, 1H), 4.02–3.95 (m, 1H), 3.93–3.86 (m, 3H), 3.00 (dd, J = 8.1, 16.6 Hz, 1H), 2.83 (dd, J = 0.9, 16.6 Hz, 1H), 1.70–1.60 (m, 4H), 0.97–0.88 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 161.0, 150.7, 144.0, 140.4, 132.0, 128.2, 121.3, 92.2, 44.3, 43.4, 37.4, 33.4, 22.1, 21.0, 11.3, 10.8; IR νmax: 2965.6, 2930.8, 1688.2, 1643.4, 1632.5, 1490.7, 1463.8, 1453.9, 1441.8, 1422.8, 1351.3, 1316.0, 1298.8, 1240.2, 1142.3, 1075.5, 1011.2, 1000.4, 836.5, 782.4, 755.3, 743.0, 555.0, 495.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H23BrN3O3 420.0923; found: 420.0923; mp 72.0–76.0 °C.

5-(4-Nitrophenyl)-1,3-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7iaa)

Solid, 75 mg, isolated yield 65%; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.14–8.21 (m, 2H), 7.41–7.48 (m, 2H), 4.61 (d, J = 6.8 Hz, 1H), 3.87–4.03 (m, 4H), 3.10 (dd, J = 16.9, 8.1 Hz, 1H), 2.92 (dd, J = 16.9, 1.5 Hz, 1H), 1.61–1.70 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 160.9, 150.5, 148.8, 147.3, 144.1, 127.5, 124.2, 91.4, 44.4, 43.5, 36.9, 33.9, 22.2, 21.0, 11.3, 10.9; IR νmax: 3244.7, 3192.1, 2967.7, 2937.4, 2876.6, 1685.1, 1633.1, 1513.8, 1470.1, 1346.7, 1308.4, 1269.3, 1238.0, 1174.7, 1152.2, 1111.0, 856.0, 787.5, 749.8, 704.4, 685.5, 61.6, 485.8 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H23N4O5 387.1668; found: 387.1669; mp 194.4–197.9 °C.

3-Benzyl-5-(furan-2-yl)-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7jba)

Solid, 76 mg, isolated yield of 67%; 1H NMR (700 MHz, CDCl3) δ 9.00 (s, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.21–7.33 (m, 4H), 6.25 (dd, J = 3.2, 1.9 Hz, 1H), 6.09 (dt, J = 3.2, 0.8 Hz, 1H), 5.12 (dd, J = 18.1, 13.8 Hz, 2H), 4.53 (d, J = 6.7 Hz, 1H), 3.91 (dddd, J = 38.7, 15.1, 10.1, 6.0 Hz, 2H), 2.94 (dd, J = 16.4, 1.3 Hz, 1H), 2.86 (dd, J = 16.4, 7.5 Hz, 1H), 1.61–1.69 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 160.7, 153.7, 150.8, 144.4, 142.1, 136.9, 129.1, 128.4, 127.6, 110.3, 105.7, 90.5, 44.9, 44.4, 35.2, 28.6, 22.1, 10.7; IR νmax: 3164.7, 2964.7, 2933.0, 2876.4, 1688.1, 1635.7, 1500.2, 1477.0, 1350.2, 1322.5, 1290.8, 1239.0, 1147.8, 1133.3, 1012.6, 776.6, 753.5, 734.0, 714.0, 692.7, 657.4, 598.7, 542.7, 480.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H22N3O4 380.1610; found: 380.1608; mp 166.8–168.9 °C.

3-Benzyl-5-methyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7kba)

Solid, 65 mg, isolated yield of 66%; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.47–7.53 (m, 2H), 7.28–7.37 (m, 3H), 5.15 (s, 2H), 3.85–3.97 (m, 2H), 3.35 (quind, J = 7.1, 1.6 Hz, 1H), 2.73 (dd, J = 16.4, 7.3 Hz, 1H), 2.50 (dd, J = 16.4, 1.2 Hz, 1H), 1.59–1.79 (m, 2 H), 1.14 (d, J = 7.1 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 160.9, 150.9, 143.0, 137.0, 129.1, 128.4, 127.6, 94.5, 44.8, 44.3, 37.7, 24.2, 22.1, 18.8, 10.9; IR νmax: 3237.4, 3182.1, 2964.9, 2935.5, 2876.2, 1690.0, 1627.3, 1502.8, 1475.1, 1433.8, 1357.6, 1328.2, 1298.5, 1242.0, 1183.4, 1069.8, 1027.8, 770.7, 751.7, 698.5, 595.1, 495.7, 459.3 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C18H22N3O3 328.1661; found: 328.1663; 79.8–82.5 °C.

3-Benzyl-5-ethyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7lba)

Solid, 68 mg, isolated yield of 66%; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.47–7.52 (m, 2H), 7.28–7.35 (m, 3H), 5.15 (dd, J = 17.1, 13.4 Hz, 2H), 3.87 (t, J = 7.8 Hz, 2H), 3.17 (m, J = 8.7, 8.7, 5.4 Hz, 1H), 2.64–2.68 (m, 2H), 1.60–1.80 (m, 3H), 1.43 (m, J = 8.3 Hz, 1H), 0.92–1.04 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 161.1, 150.9, 143.3, 137.1, 129.1, 128.4, 127.6, 93.6, 44.8, 44.3, 34.9, 30.4, 26.0, 22.1, 11.0, 10.8; IR νmax: 3190.1, 2962.0, 2931.9, 2874.7, 1689.2, 1624.8, 1502.7, 1472.1, 1434.2, 1362.0, 1297.2, 1235.6, 1182.9, 1073.1, 768.4, 750.9, 698.1, 493.9 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H24N3O3 342.1818; found: 342.1819; mp 82.0–90.8 °C.

3-Benzyl-1,5-dipropyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7mba)

Solid, 74 mg, isolated yield of 70%; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.45–7.54 (m, 2H), 7.28–7.36 (m, 3H), 5.11–5.20 (m, 2H), 3.84–4.00 (m, 2H), 3.19–3.29 (m, 1H), 2.58–2.70 (m, 2H), 1.64–1.77 (m, 2H), 1.26–1.55 (m, 4H), 1.00 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.3, 161.1, 150.9, 143.3, 137.1, 129.0, 128.4, 127.6, 94.0, 44.8, 44.3, 35.3, 35.2, 28.7, 22.1, 19.8, 13.9, 10.8; IR νmax: 3244.9, 3193.4, 2963.8, 2934.6, 2876.4, 1690.8, 1627.5, 1512.2, 1475.7, 1433.0, 1357.0, 1300.8, 1246.3, 1184.0, 1069.9, 755.7, 699.8, 596.9, 548.4, 497.8, 460.5 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H26N3O3 356.1974; found: 356.1974; 133.5–141.8 °C.

3-Benzyl-5-pentyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7nba)

Solid, 52 mg, isolated yield of 45%; 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 7.42–7.55 (m, 2H), 7.20–7.37 (m, 3H), 5.16 (dd, J = 21.0, 13.7 Hz, 2H), 3.96 (dddd, J = 36.0, 14.9, 9.3, 6.6 Hz, 2H), 3.15–3.28 (m, 1H), 2.56–2.70 (m, 2H), 1.60–1.76 (m, 2H), 1.46–1.56 (m, 1H), 1.20–1.44 (m, 7H), 0.99 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.1, 161.2, 150.9, 143.5, 137.1, 129.0, 128.4, 127.5, 94.0, 44.8, 44.3, 35.3, 33.0, 31.7, 28.8, 26.2, 22.5, 22.1, 14.0, 10.7; IR νmax: 3235.1, 3186.1, 2960.6, 2928.1, 2854.0, 1687.6, 1634.0, 1503.3, 1468.8, 1432.3, 1360.8, 1295.2, 1242.2, 1177.0, 1072.7, 750.7, 701.5, 595.0, 493.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H30N3O3 384.2287; found: 384.2288; mp 107.5–108.9 °C.

3-Benzyl-5-hexyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7oba)

viscous oil, 72 mg, isolated yield of 60%; 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.45–7.52 (m, 2H), 7.22–7.36 (m, 3H), 5.16 (dd, J = 21.0, 13.7 Hz, 2H), 3.96 (dddd, J = 36.2, 15.2, 9.5, 6.6 Hz, 2H), 3.16–3.27 (m, 1H), 2.56–2.71 (m, 2H), 1.58–1.78 (m, 2H), 1.45–1.58 (m, 1H), 1.16–1.45 (m, 9H), 0.99 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.1, 161.2, 150.9, 143.4, 137.1, 129.0, 128.4, 127.5, 94.0, 44.8, 44.3, 35.4, 33.0, 31.7, 29.2, 28.8, 26.5, 22.5, 22.1, 14.0, 10.7; IR νmax: 3223.8, 3174.9, 2949.7, 2926.6, 2855.4, 1682.8, 1635.1, 1496.6, 1475.1, 1431.1, 1358.8, 1325.1, 1295.9, 1240.1, 1184.4, 769.6, 751.8, 723.1, 694.3, 664.4, 594.2, 489.1 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C23H32N3O3 398.2444; found: 398.2442.

3-Benzyl-5-heptyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7pba)

Viscous oil, 67 mg, isolated yield of 55%; 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 7.49 (d, J = 6.8 Hz, 2H), 7.22–7.36 (m, 3H), 5.16 (dd, J = 21.3, 13.9 Hz, 2H), 3.97 (dddd, J = 38.4, 14.9, 9.5, 7.1 Hz, 2H), 3.15–3.28 (m, 1H), 2.55–2.71 (m, 2H), 1.59–1.77 (m, 2H), 1.45–1.57 (m, 1H), 1.17–1.45 (m, 11H), 0.99 (t, J = 7.3 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.4, 161.2, 150.9, 143.5, 137.1, 129.0, 128.4, 127.6, 94.0, 44.8, 44.3, 35.3, 33.0, 31.8, 29.5, 29.2, 28.8, 26.6, 22.6, 22.1, 14.1, 10.7; IR νmax: 3234.8, 3176.0, 2953.6, 2922.4, 2851.1, 1681.9, 1639.1, 1495.1, 1475.2, 1429.8, 1360.7, 1317.2, 1289.9, 1242.4, 1185.3, 1137.5, 1090.6, 1050.2, 951.5, 751.2, 693.0, 663.9, 653.6, 593.5, 485.9, 439.9 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C24H34N3O3 412.2600; found: 412.2601.

3-Benzyl-5-nonyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7qba)

Viscous oil, 61 mg, isolated yield of 46%; 1H NMR (700 MHz, CDCl3) δ 9.53 (s, 1H), 7.43–7.50 (m, 2H), 7.21–7.32 (m, 3H), 5.14 (dd, J = 30.3, 13.8 Hz, 2H), 3.99 (ddd, J = 14.6, 10.3, 6.2 Hz, 1H), 3.90 (ddd, J = 15.0, 9.9, 5.5 Hz, 1H), 3.15–3.23 (m, 1H), 2.56–2.66 (m, 2H), 1.58–1.71 (m, 2H), 1.44–1.52 (m, 1H), 1.21–1.38 (m, 15H), 0.97 (t, J = 7.3 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 173.0, 160.8, 150.5, 143.1, 136.7, 128.6, 128.0, 127.2, 93.6, 44.4, 43.9, 34.9, 32.6, 31.5, 29.2, 29.2, 29.1, 28.9, 28.4, 26.2, 22.3, 21.7, 13.7, 10.3; IR νmax: 3234.2, 3182.2, 2924.0, 2853.0, 1690.7, 1631.9, 1503.9, 1472.5, 1435.3, 1361.0, 1299.2, 1242.4, 1183.4, 751.6, 697.8, 594.5, 493.8 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C26H37N3O3 440.2835; found: 440.2835.

3-Benzyl-5-decyl-1-propyl-5,8-dihydropyrido[2,3-d]-pyrimidine-2,4,7(1H,3H,6H)-trione (7rba)

Viscous oil, 83 mg, isolated yield of 61%; 1H NMR (700 MHz, CDCl3) δ 9.19 (s, 1H), 7.45–7.49 (m, 2H), 7.28–7.32 (m, 2H), 7.23–7.25 (m, 1H), 5.13 (dd, J = 27.6, 13.8 Hz, 2H), 3.92–3.99 (m, 1H), 3.88 (ddd, J = 14.6, 9.9, 5.4 Hz, 1H), 3.16–3.22 (m, 1H), 2.57–2.66 (m, 2H), 1.58–1.72 (m, 2H), 1.43–1.52 (m, 1H), 1.23–1.38 (m, 17H), 0.97 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 173.2, 160.8, 150.5, 143.1, 136.7, 128.6, 128.0, 127.2, 93.7, 44.4, 44.0, 34.9, 32.6, 31.5, 29.2, 29.2, 29.2, 28.9, 28.4, 26.2, 22.3, 21.7, 13.7, 10.3; IR νmax: 3234.3, 3191.5, 2923.2, 2852.7, 1691.7, 1632.6, 1504.1, 1472.8, 1435.5, 1361.6, 1299.7, 1241.7, 1183.8, 1074.1, 752.1, 698.0, 594.8, 493.5 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C27H40N3O3 454.3070; found: 454.3069.

(E)-3-Benzyl-5-(prop-1-en-1-yl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7sba)

Solid, 71 mg, isolated yield of 67%; 1H NMR (400 MHz, CDCl3 δ 9.20 (s, 1H), 7.44–7.56 (m, 2H), 7.20–7.39 (m, 3H), 5.47–5.61 (m, 1H), 5.42 (ddd, J = 15.4, 5.9, 1.5 Hz, 1H), 5.15 (s, 2H), 3.95 (dddd, J = 27.1, 14.9, 9.5, 5.9 Hz, 2H), 3.83 (td, J = 5.7, 1.3 Hz, 1H), 2.62–2.78 (m, 2H), 1.58–1.80 (m, 5H), 1.00 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 160.9, 150.9, 143.6, 137.0, 129.1, 128.6, 128.4, 127.6, 125.9, 92.3, 44.8, 44.4, 36.0, 31.1, 22.1, 17.8, 10.8; IR-ATR νmax: 3192.3, 2965.1, 2935.2, 2876.9, 1688.9, 1625.8, 1502.4, 1472.3, 1435.0, 1354.0, 1289.4, 1231.4, 1179.6, 1073.6, 964.6, 751.4, 697.6, 490.9, 466.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H24N3O3 354.1818; found: 354.1818; mp 58.9–61.5 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aab)

Solid, 97 mg, isolated yield of 77%; 1H NMR (700 MHz, CDCl3) δ 7.96 (s, 1H), 7.32–7.39 (m, 3H), 7.20–7.23 (m, 2H), 7.07–7.11 (m, 2H), 6.76–6.79 (m, 2H), 5.42 (d, J = 16.78 Hz, 1H), 5.07 (d, J = 16.78 Hz, 1H), 4.40 (dd, J = 1.18, 7.85 Hz, 1H), 3.94 (dddd, J = 6.30, 8.60, 12.80, 21.70 Hz, 2H), 3.75 (s, 3H), 2.89 (dd, J = 8.00, 16.40 Hz, 1H), 2.78 (dd, J = 1.08, 16.35 Hz, 1H), 1.68 (dddt, J = 1.24, 5.08, 6.28, 7.47 Hz, 2H), 0.94 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.5, 161.0, 158.8, 151.2, 144.0, 134.5, 133.3, 129.6, 128.7, 127.5, 126.2, 114.3, 93.7, 55.3, 46.0, 43.6, 37.7, 33.4, 21.0, 11.3; IR νmax: 3234, 3186, 2957, 1688, 1643, 1633, 1510, 1457, 1439, 1350, 1299, 1248, 1186, 1154, 1119, 1035, 848, 781, 756, 732, 692, 672, 576, 525, 505, 477, 456 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C24H26N3O4 420.1923; found: 420.1925; mp 167.4–176.8 °C.

5-(4-Methoxyphenyl)-1-phenyl-3-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aac)

Solid, 68 mg, isolated yield of 56%; 1H NMR (700 MHz, CDCl3) δ 7.57–7.62 (m, 3H), 7.30–7.35 (m, 2H), 7.21–7.24 (m, 2H), 6.82–6.86 (m, 2H), 6.74 (s, 1H), 4.48 (dd, J = 8.0, 1.5 Hz, 1H), 3.86–3.95 (m, 2H), 3.78 (s, 3H), 3.00 (dd, J = 16.7, 8.1 Hz, 1H), 2.87 (dt, J = 16.4, 1.4 Hz, 1H), 1.67 (ddt, J = 7.6, 6.3, 1.2, 1.2 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.1, 160.8, 158.4, 150.1, 142.4, 133.4, 131.9, 130.5, 130.5, 130.4, 128.9, 128.6, 127.2, 113.9, 92.0, 54.9, 43.0, 37.0, 33.0, 20.6, 11.0; IR νmax: 2961.3, 1699.4, 1638.3, 1485.1, 1241.9, 1178.4, 1029.4, 831.4, 751.9, 685.9, 520.4 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C23H24N3O4 406.1767; found: 406.1770; mp 94.9–102.3 °C.

3-Ethyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aca)

Solid, 78 mg, isolated yield of 73%; 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.15–7.20 (m, 2H), 6.80–6.86 (m, 2H), 4.46 (dd, J = 7.7, 1.3 Hz, 2H), 3.90–4.07 (m, 4H), 3.78 (s, 3H), 2.99 (dd, J = 16.4, 7.8 Hz, 1H), 2.88 (dd, J = 16.4, 1.5 Hz, 1H), 1.64–1.73 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 160.9, 158.8, 150.6, 143.6, 133.4, 127.5, 114.3, 93.2, 55.3, 44.2, 37.7, 37.0, 33.1, 22.2, 12.9, 10.8; IR νmax: 3234.5, 3190.7, 2965.0, 1688.8, 1642.4, 1508.2, 1462.4, 1346.1, 1299.6, 1234.6, 1179.7, 1028.0, 1014.0, 839.2, 742.3, 661.0, 523.2, 474.3 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C19H24N3O4 358.1767; found: 358.1765; mp 80.9–83.7 °C.

3-Butyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7ada)

Solid, 71 mg, isolated yield of 61%; 1H NMR (700 MHz, CDCl3) δ 8.63 (d, J = 4.9 Hz, 1H), 7.14–7.17 (m, 2H), 6.80–6.83 (m, 2H), 4.43 (d, J = 6.7 Hz, 1H), 3.85–3.97 (m, 4H), 3.76 (s, 3H), 2.97 (dd, J = 16.3, 8.0 Hz, 1H), 2.86 (d, J = 15.7 Hz, 1H), 1.56–1.64 (m, 4H), 1.35 (sxt, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 171.4, 160.7, 158.4, 150.3, 143.2, 133.0, 127.1, 113.9, 92.7, 54.9, 43.8, 41.3, 37.3, 32.7, 29.4, 21.8, 19.8, 13.4, 10.4; IR νmax: 3171.5, 2959.1, 2930.8, 2872.1, 1683.6, 1636.1, 1509.2, 1475.1, 1438.0, 1355.2, 1330.7, 1296.3, 1249.9, 1234.7, 1175.5, 1147.8, 1087.2, 1031.8, 834.3, 779.2, 755.0, 659.5, 529.0, 495.1, 474.1 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H28N3O4 386.2080; found: 386.2082; mp 146.3–147.7 °C.

3-Isobutyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aea)

Solid, 87 mg; isolated yield of 75%; 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 7.14–7.19 (m, 2H), 6.80–6.85 (m, 2H), 4.46 (d, J = 6.4 Hz, 1H), 3.88–4.04 (m, 2 H), 3.80 (t, J = 7.1 Hz, 2 H), 3.77 (s, 3H), 3.00 (dd, J = 16.6, 7.8 Hz, 1H), 2.88 (dd, J = 16.4, 1.5 Hz, 1H), 2.13 (spt, J = 7.0 Hz, 1H), 1.61–1.73 (m, 2H), 0.88–0.99 (m, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 161.4, 158.8, 151.0, 143.6, 133.4, 127.5, 114.3, 93.0, 55.2, 48.6, 44.2, 37.7, 33.1, 27.1, 22.1, 20.2, 20.1, 10.8; IR νmax: 3165.2, 2959.4, 2874.0, 2833.6, 1683.2, 1636.2, 1509.4, 1477.4, 1332.3, 1295.6, 1250.2, 1233.1, 1175.2, 1147.3, 1086.9, 1034.0, 834.2, 779.2, 754.2, 658.3, 474.2 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H28N3O4 386.2080; found: 386.2081; mp 153.8–156.9 °C.

1,3-Dibutyl-5-(4-methoxyphenyl)-5,8-dihydropyrido-[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7afd)

Solid, 92 mg, isolated yield of 77%; 1H NMR (700 MHz, CDCl3) δ 8.10–8.16 (m, 1H), 7.17–7.21 (m, 2H), 6.83–6.87 (m, 2H), 4.47 (d, J = 6.5 Hz, 1H), 3.90–4.00 (m, 4H), 3.79 (s, 3H), 3.00 (dd, J = 16.6, 7.7 Hz, 1H), 2.91 (dd, J = 16.7, 1.4 Hz, 1H), 1.61–1.63 (m, 4H), 1.35–1.47 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 172.0, 162.0, 159.8, 151.7, 144.4, 134.5, 128.5, 115.3, 94.2, 56.3, 43.7, 42.7, 38.6, 34.2, 31.9, 30.8, 21.2, 20.9, 14.7, 14.6; IR νmax: 3223.5, 3176.3, 2958.4, 2931.7, 2872.3, 1684.9, 1634.4, 1505.3, 1472.4, 1356.9, 1297.7, 1247.4, 1224.6, 1175.6, 1148.0, 1030.4, 831.5, 780.8, 755.3, 685.4, 658.2, 556.6, 529.2 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H30N3O4 400.2236; found: 400.2236; mp 95.7–98.9 °C.

5-(4-Methoxyphenyl)-3-pentyl-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aga)

Solid, 82 mg, isolated yield of 69%; 1H NMR (700 MHz, CDCl3) δ 8.52 (s, 1H), 7.13–7.18 (m, 2H), 6.79–6.84 (m, 2H), 4.44 (dd, J = 7.9, 1.4 Hz, 1H), 3.85–3.96 (m, 4H), 3.76 (s, 3H), 2.94–3.00 (m, 1H), 2.87 (dd, J = 16.3, 0.9 Hz, 1H), 1.56–1.66 (m, 4H), 1.27–1.35 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 161.0, 158.8, 150.7, 143.5, 133.5, 127.5, 114.3, 93.2, 55.3, 44.2, 41.9, 37.6, 33.1, 29.1, 27.3, 22.4, 22.2, 14.0, 10.9; IR νmax: 2958.8, 2932.9, 1687.4, 1634.4, 1506.1, 1474.2, 1355.6, 1296.4, 1234.6, 1176.7, 1032.2, 831.5, 780.9, 755.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C22H30N3O4 400.2236; found: 400.2235; mp 124.6–126.5 °C.

3-Hexyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aha)

Solid, 92 mg, isolated yield of 74%; 1H NMR (700 MHz, CDCl3) δ 8.84 (s, 1H), 7.13–7.17 (m, 2H), 6.79–6.83 (m, 2H), 4.43 (dd, J = 7.9, 1.4 Hz, 1H), 3.84–3.99 (m, 4H), 3.75 (s, 3H), 2.97 (dd, J = 16.4, 8.2 Hz, 1H), 2.86 (dd, J = 16.6, 1.3 Hz, 1H), 1.55–1.73 (m, 4H), 1.25–1.35 (m, 6 H), 0.95 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 171.6, 160.7, 158.3, 150.3, 143.2, 133.0, 127.1, 113.9, 92.7, 54.9, 43.8, 41.5, 37.3, 32.7, 31.1, 27.2, 26.2, 22.2, 21.8, 13.6, 10.4; IR νmax: 3246.3, 2953.0, 2927.2, 1690.1, 1637.3, 1508.9, 1465.6, 1353.0, 1299.5, 1239.0, 1176.2, 1033.4, 833.4, 754.2, 735.9, 664.9, 557.4, 510.3 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C23H32N3O4 414.2393; found: 414.2390; mp 131.9–134.7 °C.

3-Heptyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aia)

Solid, 111 mg, isolated yield of 87%; 1H NMR (700 MHz, CDCl3) δ 8.92 (s, 1H), 7.13–7.17 (m, 2H), 6.79–6.83 (m, 2H), 4.43 (dd, J = 7.9, 1.4 Hz, 1H), 3.86–3.99 (m, 4H), 3.75 (s, 3H), 2.97 (dd, J = 16.6, 8.0 Hz, 1H), 2.86 (dd, J = 16.5, 1.2 Hz, 1H), 1.56–1.67 (m, 4H), 1.21–1.34 (m, 8H), 0.95 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 171.7, 160.7, 158.4, 150.3, 143.2, 133.0, 127.1, 113.9, 92.7, 54.9, 43.8, 41.5, 37.3, 32.8, 31.8, 28.6, 27.3, 26.5, 22.2, 21.8, 13.7, 10.4; IR νmax: 3234.1, 3184.0, 2963.2, 2927.4, 2854.5, 1686.7, 1633.6, 1510.2, 1472.7, 1348.2, 1294.0, 1239.4, 1180.7, 1034.4, 826.3, 781.4, 756.4, 738.2, 485.0 cm–1; HRMS (ESI-TOF): (M + H)+ calcd for C24H34N3O4 428.2549; found: 428.2550; mp 129.9–131.6 °C.

3-Allyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aja)

Solid, 80 mg; isolated yield of 69%; 1H NMR (700 MHz, CDCl3) δ 8.43 (s, 1H), 7.13–7.17 (m, 2H), 6.80–6.83 (m, 2H), 5.82–5.91 (m, 1H), 5.24 (dq, J = 17.1, 1.4 Hz, 1H), 5.17 (dq, J = 10.2, 1.3 Hz, 1H), 4.54 (ddt, J = 19.7, 5.9, 1.3, 1.3 Hz, 2H), 4.44 (dd, J = 7.9, 1.4 Hz, 1H), 3.91 (m, J = 18.7, 9.7, 5.8 Hz, 2H), 3.76 (s, 3H), 2.97 (dd, J = 16.4, 8.0 Hz, 1H), 2.87 (dd, J = 16.5, 1.0 Hz, 1H), 1.62–1.74 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 171.1, 160.4, 158.4, 150.1, 143.3, 132.9, 131.4, 127.1, 117.6, 113.9, 92.7, 54.9, 43.9, 43.4, 37.2, 32.7, 21.7, 10.5; IR νmax: 3171.5, 2936.3, 1688.1, 1651.3, 1509.0, 1464.7, 1348.0, 1303.2, 1237.4, 1174.2, 1031.4, 934.6, 831.6, 778.3, 758.0, 686.9, 557.1, 518.2, 461.1 cm–1; HRMS (ESI-TOF): (M + H)+ calcd for C20H24N3O4 370.1767; found: 370.1766; mp 137.6–140.0 °C.

5-(4-Methoxyphenyl)-3-(2-methylallyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aka)

Solid, 90 mg, isolated yield of 79%; 1H NMR (700 MHz, CDCl3) δ 8.76 (s, 1H), 7.13–7.17 (m, 2H), 6.79–6.82 (m, 2H), 4.82–4.84 (m, 1H), 4.65 (s, 1H), 4.46–4.52 (m, 2H), 3.94–4.01 (m, 1H), 3.87–3.93 (m, 1H), 3.75 (s, 3H), 2.99 (dd, J = 16.6, 8.0 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 1.75 (d, J = 0.4 Hz, 3H), 1.62–1.73 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 172.1, 160.6, 158.4, 150.3, 143.6, 139.2, 132.9, 127.1, 113.9, 110.0, 92.6, 54.9, 46.0, 43.9, 37.4, 32.6, 21.7, 20.2, 10.3; IR νmax: 3165.1, 2965.4, 2936.3, 1683.8, 1639.4, 1508.3, 1478.2, 1436.4, 1354.4, 1296.9, 1249.5, 1232.4, 1174.4, 1148.5, 1032.4, 906.4, 839.2, 779.3, 753.4, 659.2, 528.9 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C21H26N3O4 384.1923; found: 384.1923; 154.4–156.6 °C.

3-Benzyl-5-(4-methoxyphenyl)-1-propyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aba)

Solid, 113 mg, isolated yield of 90%; 1H NMR (700 MHz, CDCl3) δ 8.73 (s, 1H), 7.45 (d, J = 7.10 Hz, 2H), 7.27–7.32 (m, 2H), 7.22–7.25 (m, 1H), 7.15 (d, J = 8.60 Hz, 2H), 6.81 (d, J = 8.71 Hz, 2H), 5.11 (dd, J = 13.70, 20.40 Hz, 2H), 4.44 (d, J = 7.10 Hz, 1H), 3.83–3.96 (m, 2H), 3.76 (s, 3H), 2.95 (dd, J = 8.00, 16.60 Hz, 1H), 2.85 (d, J = 15.38 Hz, 1H), 1.59–1.64 (m, 2H), 0.93 (t, J = 7.42 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 161.2, 158.8, 150.9, 144.0, 137.0, 133.3, 129.0, 128.4, 127.6, 127.5, 114.3, 93.1, 55.3, 44.9, 44.4, 37.8, 33.1, 22.1, 10.7; IR νmax: 3244.0, 2965.1, 2934.1, 1688.0, 1634.7, 1506.8, 1472.9, 1454.4, 1436.5, 1360.9, 1306.0, 1237.4, 1180.2, 1031.9, 828.3, 745.0, 694.4, 598.4, 550.7, 523.2, 494.7, 461.0 cm–1; HRMS (ESI-TOF) (M + H)+m/z: calcd for C24H26N3O4 420.1923; found: 420.1923; mp 164.9–177.1 °C.

3-Benzyl-5-(4-methoxyphenyl)-1-phenyl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7abc)

Solid, 98 mg, isolated yield of 72%; 1H NMR (400 MHz, CDCl3) δ 7.57–7.64 (m, 3H), 7.50–7.56 (m, 2H), 7.29–7.36 (m, 5H), 7.22–7.26 (m, 2H), 6.84–6.90 (m, 2H), 6.79 (s, 1H), 5.14 (dd, J = 21.0, 13.4 Hz, 3H), 4.51 (dd, J = 7.8, 1.2 Hz, 2H), 3.80 (s, 3H), 3.00 (dd, J = 16.6, 7.8 Hz, 2H), 2.87 (dd, J = 16.3, 0.7 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.4, 161.2, 158.9, 150.6, 143.1, 136.8, 133.7, 132.2, 130.9, 130.9, 130.8, 129.6, 129.3, 129.0, 128.4, 127.7, 127.6, 114.4, 55.3, 44.9, 37.5, 33.5; IR νmax: 2928.5, 1700.2, 1637.0, 1484.3, 1239.2, 1141.9, 1029.5, 938.6, 832.6, 746.3, 685.5 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C27H24N3O4 454.1767; found: 454.1769; mp 93.1–98.9 °C.

3-Allyl-1-benzyl-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7ajb)

Solid, 73 mg, isolated yield of 58%; 1H NMR (700 MHz, CDCl3) δ 8.00 (s, 1 H), 7.36–7.40 (m, 2H), 7.33–7.36 (m, 1H), 7.20–7.24 (m, 2H), 7.07–7.11 (m, 2H), 6.77–6.80 (m, 2H), 5.91 (ddt, J = 17.1, 10.2, 5.8, 5.8 Hz, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.27 (dq, J = 17.1, 1.4 Hz, 1H), 5.20 (dq, J = 10.3, 1.2 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 4.60 (ddt, J = 18.3, 5.8, 1.4, 1.4 Hz, 2H), 4.41 (dd, J = 8.0, 1.5 Hz, 1H), 3.74–3.76 (m, 3H), 2.90 (dd, J = 16.3, 8.0 Hz, 1H), 2.79 (dd, J = 16.3, 1.5 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ 170.2, 160.3, 158.4, 150.6, 143.8, 133.9, 132.8, 131.3, 129.6, 129.2, 128.3, 127.1, 125.8, 117.7, 113.9, 54.9, 45.7, 43.6, 37.3, 33.0; IR νmax: 3236.9, 3182.4, 1689.9, 1631.7, 1509.6, 1452.5, 1349.4, 1299.4, 1246.9, 1185.8, 1154.0, 1032.9, 933.5, 722.9, 692.5, 589.6, 522.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C24H24N3O4 418.1767; found: 418.1765; mp 143.6–145.9 °C.

1,3-Dibenzyl-5-(4-methoxyphenyl)-5,8-dihydropyrido-[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7abb)

Solid, 112 mg, isolated yield of 80%; 1H NMR (700 MHz, CDCl3) δ 7.48–7.50 (m, 3H), 7.38–7.42 (m, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.29–7.33 (m, 2H), 7.26–7.29 (m, 1H), 7.21–7.24 (m, 2H), 7.07–7.10 (m, 2H), 6.76–6.80 (m, 2H), 5.50 (d, J = 16.8 Hz, 1H), 5.19 (d, J = 13.8 Hz, 1H), 5.13 (d, J = 13.8 Hz, 1H), 4.91–4.97 (m, 1H), 4.42 (dd, J = 8.0, 1.5 Hz, 1H), 3.75 (s, 3H), 2.89 (dd, J = 16.3, 8.0 Hz, 1H), 2.78 (dd, J = 16.3, 1.5 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.8, 160.6, 158.4, 151.0, 143.8, 136.4, 133.8, 132.8, 129.3, 128.7, 128.4, 128.1, 127.3, 127.1, 125.7, 114.0, 93.3, 54.9, 45.9, 44.7, 37.3, 33.1; IR νmax: 1693.6, 1626.6, 1505.6, 1454.0, 1435.1, 1351.9, 1295.8, 1231.1, 1177.3, 1147.3, 1029.5, 830.2, 730.4, 696.6, 602.5, 525.7, 490.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C28H26N3O4 468.1923; found: 468.1922; mp 93.4–100.2 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-(2-methylbenzyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7alb)

Solid, 62 mg, isolated yield of 43%; 1H NMR (700 MHz, CDCl3) δ 8.38 (s, 1H), 7.30–7.36 (m, 3H), 7.09–7.19 (m, 7H), 7.03 (d, J = 7.3 Hz, 1H), 6.76–6.83 (m, 2H), 5.34 (d, J = 16.6 Hz, 1H), 5.12–5.23 (m, 3H), 4.44 (d, J = 6.7 Hz, 1H), 3.76 (s, 3H), 2.91 (dd, J = 16.5, 7.9 Hz, 1H), 2.76–2.84 (m, 1H), 2.42 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 170.5, 160.7, 158.4, 151.0, 144.0, 135.5, 134.2, 134.1, 132.7, 130.0, 129.1, 128.2, 127.1, 126.8, 125.8, 125.6, 125.5, 114.1, 93.2, 54.9, 45.6, 42.2, 37.3, 33.0, 19.0; IR νmax: 3235.8, 3176.8, 1684.1, 1643.2, 1508.4, 1460.7, 1301.5, 1247.5, 1230.6, 117.0, 1147.7, 1028.5, 833.1, 739.6, 700.4, 473.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C29H28N3O4 482.2080; found: 482.2079; mp 198.9–203.2 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-(3-methylbenzyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7amb)

Solid, 62 mg, isolated yield 43%; 1H NMR (700 MHz, CDCl3) δ 7.75 (s, 1H), 7.33–7.39 (m, 3H), 7.26–7.29 (m, 2H), 7.18–7.23 (m, 3H), 7.06–7.11 (m, 3H), 6.76–6.80 (m, 2H), 5.46 (d, J = 16.8 Hz, 1H), 5.15 (d, J = 14.0 Hz, 1H), 5.11 (d, J = 13.8 Hz, 1H), 5.00 (d, J = 16.8 Hz, 1H), 4.42 (dd, J = 7.7, 1.3 Hz, 1H), 3.75 (s, 3H), 2.89 (dd, J = 16.5, 7.9 Hz, 1H), 2.78 (dd, J = 16.6, 1.3 Hz, 1H), 2.32 (s, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.8, 160.6, 158.4, 151.0, 143.8, 137.7, 136.3, 133.8, 132.8, 129.3, 129.2, 128.4, 128.1, 128.0, 127.1, 125.7, 125.6, 113.9, 93.3, 54.9, 45.9, 44.7, 37.3, 33.1, 21.0; IR νmax: 1693.6, 1621.5, 1505.8, 1454.6, 1435.1, 1350.0, 1296.9, 1230.6, 1177.4, 1147.1, 1030.3, 830.8, 780.0, 755.7, 729.6, 695.8, 525.6, 467.4 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C29H28N3O4 482.2080; found: 482.2079; mp 82.2–85.5 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-(4-methylbenzyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7anb)

Solid, 50 mg, isolated yield of 34%; 1H NMR (700 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 2H), 7.29–7.33 (m, 4H), 7.16 (dd, J = 7.2, 2.3 Hz, 2H), 7.07–7.12 (m, 4H), 6.76–6.79 (m, 2H), 5.09–5.15 (m, 5H), 4.39 (dd, J = 7.7, 1.3 Hz, 1H), 3.74 (s, 3H), 2.83 (dd, J = 16.4, 8.0 Hz, 1H), 2.74 (dd, J = 16.4, 1.7 Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 161.0, 158.8, 151.4, 144.2, 137.4, 134.3, 133.9, 133.2, 129.7, 129.1, 129.1, 128.8, 127.5, 126.1, 114.4, 93.7, 55.3, 46.3, 44.9, 37.7, 33.5, 21.2; IR νmax: 1693.6, 1621.6, 1506.4, 1453.3, 1435.5, 1351.6, 1296.8, 1232.7, 1178.7, 1148.0, 1029.8, 831.2, 782.1, 729.7, 697.0, 526.0, 472.9 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C29H28N3O4 482.2080; found: 482.2080; mp 72.1–79.6 °C.

1-Benzyl-3-(4-isopropylbenzyl)-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aob)

Solid, 105 mg, isolated yield of 69%; 1H NMR (400 MHz, CDCl3) δ 7.34–7.52 (m, 6H), 7.25 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.08–7.15 (m, 2H), 6.77–6.83 (m, 2H), 5.52 (d, J = 16.9 Hz, 1 H), 5.19 (d, J = 13.7 Hz, 1 H), 5.12 (d, J = 13.7 Hz, 1H), 4.94 (d, J = 16.9 Hz, 1H), 4.44 (d, J = 5.9 Hz, 1H), 3.77 (s, 3H), 2.91 (dd, J = 13.8, 6.7 Hz, 1H), 2.76–2.84 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.3, 161.0, 158.8, 151.4, 148.3, 144.2, 134.3, 134.2, 133.2, 129.6, 129.2, 128.7, 127.5, 126.5, 126.2, 114.4, 93.8, 55.3, 46.2, 44.9, 37.7, 33.8, 33.5, 24.0, 24.0; IR νmax: 2957.8, 1694.3, 1628.9, 1506.6, 1459.9, 1352.1, 1294.7, 1231.9, 1178.0, 1147.0, 1031.0, 830.5, 780.9, 730.4, 697.1, 526.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C31H32N3O4 510.2393; found: 510.2392; mp 93.1–96.5 °C.

1-Benzyl-3-(3-methoxybenzyl)-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7apb)

Solid, 115 mg, isolated yield of 77%; 1H NMR (400 MHz, CDCl3) δ 7.37–7.45 (m, 4H), 7.22–7.27 (m, 3H), 7.03–7.13 (m, 4H), 6.78–6.86 (m, 3H), 5.52 (d, J = 16.9 Hz, 1H), 5.12–5.22 (m, 2H), 4.95 (d, J = 16.9 Hz, 1H), 4.44 (dd, J = 7.7, 1.6 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.92 (dd, J = 16.6, 7.6 Hz, 1H), 2.81 (dd, J = 16.6, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 160.9, 159.7, 158.8, 151.4, 144.2, 138.3, 134.2, 133.2, 129.7, 129.4, 128.8, 127.5, 126.1, 121.2, 114.4, 114.2, 113.4, 93.7, 55.3, 55.2, 46.3, 45.0, 37.7, 33.5; IR νmax: 1694.3, 1632.8, 1506.6, 1454.4, 1351.2, 1286.8, 1232.4, 1148.3, 1032.1, 953.8, 831.4, 780.6, 757.3, 730.8, 694.8, 526.1, 481.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C29H28N3O5 498.2029; found: 498.2031; 82.5–86.8 °C.

1-Benzyl-3-(2-fluorobenzyl)-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aqb)

Solid, 91 mg, isolated yield of 62%; 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.35–7.47 (m, 3H), 7.21–7.33 (m, 6H), 7.02–7.16 (m, 4H), 6.76–6.85 (m, 2H), 5.49 (d, J = 16.6 Hz, 1H), 5.29 (dd, J = 17.6, 14.7 Hz, 2H), 5.01 (d, J = 16.6 Hz, 1H), 4.45 (dd, J = 7.7, 1.6 Hz, 1H), 3.77 (s, 3H), 2.94 (dd, J = 16.4, 7.8 Hz, 1H), 2.82 (dd, J = 16.4, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.4, 162.0, 160.9, 159.6, 158.8, 151.2, 144.4, 134.3, 133.1, 129.6, 129.4 (d, J = 4.0 Hz), 129.1 (d, J = 7.9 Hz), 128.7, 127.5, 126.2, 124.1 (d, J = 3.2 Hz), 123.7 (d, J = 14.3 Hz), 115.5 (d, J = 21.5 Hz), 114.4, 93.6, 55.3, 46.2, 37.7, 33.4; IR νmax: 2834.9, 1694.6, 1627.3, 1505.2, 1493.2, 1454.2, 1351.8, 1296.4, 1228.6, 1177.2, 1147.2, 1094.1, 1030.5, 831.3, 751.2, 729.6, 696.5, 654.7, 525.9, 507.4, 432.3 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C28H25FN3O4 486.1829; found: 486.1828; mp 84.1–90.9 °C.

1-Benzyl-3-(3-fluorobenzyl)-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7arb)

Solid, 109 mg, isolated yield of 75%; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.34–7.44 (m, 3H), 7.16–7.33 (m, 5H), 7.07–7.15 (m, 2H), 6.92–7.03 (m, 1H), 6.77–6.86 (m, 2H), 5.45 (d, J = 16.6 Hz, 1H), 5.17 (dd, J = 23.0, 13.9 Hz, 2H), 5.06 (d, J = 16.6 Hz, 1H), 4.44 (dd, J = 7.7, 1.6 Hz, 1H), 3.77 (s, 3H), 2.92 (dd, J = 16.4, 7.8 Hz, 1H), 2.81 (dd, J = 16.4, 1.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.3, 164.0, 161.2 (d, J = 75.5 Hz), 158.9, 151.3, 144.4, 139.2 (d, J = 7.9 Hz), 134.2, 133.1, 129.9 (d, J = 8.7 Hz), 129.7, 128.8, 127.5, 126.1, 124.6, 115.8 (d, J = 22.3 Hz), 114.6 (d, J = 21.5 Hz), 114.4, 93.7, 55.3, 46.3, 44.6, 37.7, 33.5; IR νmax: 3148.5, 3058.8, 3005.0, 2955.0, 2836.6, 1686.5, 1632.4, 1508.8, 1462.3, 1439.7, 1359.0, 1309.5, 1241.9, 1184.5, 1153.5, 1137.5, 1026.5, 965.5, 948.8, 832.9, 781.2, 755.5, 689.1, 519.4, 486.7 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C28H25FN3O4 486.1829; found: 486.1829; mp 173.3–174.5 °C.

1-Benzyl-3-(3-bromobenzyl)-5-(4-methoxyphenyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7asb)

Solid, 95 mg, isolated yield of 58%; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.63 (t, J = 1.7 Hz, 1H), 7.35–7.46 (m, 5H), 7.16–7.26 (m, 3H), 7.07–7.14 (m, 2H), 6.77–6.86 (m, 2H), 5.46 (d, J = 16.9 Hz, 1H), 5.14 (dd, J = 22.0, 13.9 Hz, 2H), 5.04 (d, J = 16.6 Hz, 1H), 4.44 (d, J = 6.1 Hz, 1H), 3.77 (s, 3H), 2.93 (dd, J = 16.4, 7.8 Hz, 1H), 2.81 (dd, J = 16.4, 1.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 160.8, 158.9, 151.3, 144.4, 139.0, 134.2, 133.1, 131.8, 130.9, 130.0, 129.7, 128.8, 127.7, 127.4, 126.1, 122.5, 114.4, 93.7, 55.3, 46.3, 44.5, 37.6, 33.5; IR νmax: 3156.6, 2961.8, 2833.7, 1686.5, 1633.2, 1509.8, 1459.2, 1439.2, 1357.5, 1231.6, 1177.1, 1035.4, 779.3, 756.1, 695.5, 668.2, 650.1, 479.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C28H25BrN3O4 546.1028; found: 546.1031; mp 197.6–200.0 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-(3-(trifluoromethyl)-benzyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7atb)

Solid, 139 mg, isolated yield of 87%; 1H NMR (700 MHz, CDCl3) δ 7.72 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.34–7.47 (m, 4H), 7.20–7.25 (m, 2H), 7.07–7.11 (m, 2H), 6.75–6.82 (m, 2H), 5.48 (d, J = 16.8 Hz, 1H), 5.21 (dd, J = 25.2, 14.0 Hz, 2H), 4.97 (d, J = 16.6 Hz, 1H), 4.43 (dd, J = 7.9, 1.4 Hz, 1H), 3.75 (s, 3H), 2.92 (dd, J = 16.6, 8.0 Hz, 1H), 2.81 (dd, J = 16.5, 1.4 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.4, 160.4, 158.5, 150.9, 144.0, 137.3, 133.6, 132.6, 132.2, 129.4, 128.6, 128.5, 127.0, 125.7, 125.2 (q, J = 4.1 Hz), 124.2 (q, J = 3.7 Hz), 114.0, 93.2, 54.9, 46.0, 44.2, 37.2, 33.0; IR νmax: 1693.8, 1629.9, 1506.1, 1453.0, 1325.5, 1233.6, 1158.4, 1116.3, 1072.4, 1030.6, 830.9, 781.4, 730.0, 698.8, 657.0, 525.6, 477.5 cm–1; HRMS (ESI-TOF) m/z: (M + H): calcd for C29H25F3N3O4 536.1797; found: 536.1797; mp: 78.7–86.4 °C.

1-Benzyl-5-(4-methoxyphenyl)-3-(4-nitrobenzyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (7aub)

Solid, 44 mg, isolated yield of 29%; 1H NMR (700 MHz, CDCl3) δ 7.64–7.61 (m, 2H), 7.54 (s, 1H), 7.43–7.36 (m, 4 H), 7.24–7.20 (m, 2H), 7.10–7.05 (m, 2H), 6.82–6.77 (m, 2H), 5.50 (d, J = 16.8 Hz, 1H), 5.23 (dd, J = 14.1, 36.0 Hz, 2H), 4.96 (d, J = 16.7 Hz, 1H), 4.41 (dd, J = 1.3, 7.9 Hz, 1H), 3.76 (s, 3H), 2.92 (dd, J = 8.0, 16.5 Hz, 1H), 2.80 (dd, J = 1.3, 16.5 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ 169.3, 160.3, 158.5, 150.9, 147.1, 144.2, 143.5, 133.4, 132.6, 129.5, 129.4, 128.7, 127.0, 125.7, 123.3, 114.0, 93.2, 54.9, 46.1, 44.1, 37.2, 33.2; IR νmax: 1693.7, 1620.2, 1508.9, 1341.6, 1292.0, 1229.4, 1175.4, 1147.6, 1109.6, 1030.9, 834.3, 807.5, 696.0, 527.4, 507.7 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C28H25N4O6 513.1774; found: 513.1772; mp 150.7–159.2 °C.

5-(4-Methoxyphenyl)-1,3-dipropyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (9)

A solution of 7aaa (0.5 mmol; 0.19 g) in THF (5 mL) was added slowly to the solution of LiAlH4 (0.5 mL; 1 M) cooled down to the temperature of 0 °C. The reaction was carried out at the same temperature for 24 h. The reaction mixture was diluted with ethyl acetate (10 mL), and the precipitated solid was filtered off. The crude product was purified by flash chromatography using gradient elution (0–100% AcOEt in hexane). The expected product was obtained as solid (194 mg) with a 72% yield; 1H NMR (700 MHz, CDCl3) δ 7.03–7.07 (m, 2H), 6.79–6.83 (m, 2H), 4.54 (s, 1H), 4.19 (d, J = 5.0 Hz, 1H), 3.77–3.93 (m, 4H), 3.76 (s, 3H), 3.29 (d, J = 12.0 Hz, 1H), 3.13 (dt, J = 2.5, 12.3 Hz, 1H), 1.97 (tt, J = 5.0, 13.0 Hz, 1H), 1.87 (dd, J = 2.3, 13.0 Hz, 1H), 1.73 (sxt, J = 7.6 Hz, 2H), 1.59–1.66 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) 161.5, 158.0, 151.4, 148.9, 137.7, 128.4, 113.8, 85.6, 55.3, 43.3, 42.7, 37.5, 34.4, 28.8, 21.6, 21.3, 11.4, 11.2; IR νmax: 3301.0, 2960.2, 2932.8, 2873.3, 1685.9, 1590.3, 1538.2, 1507.9, 1443.3, 1347.7, 1336.0, 1264.4, 1241.4, 1170.1, 1032.4, 831.6, 770.3, 757.8, 549.7, 532.4, 485.6 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C20H28N3O3 358.2131; found: 358.2131; mp 69.3–81.4 °C.

5-(4-Methoxyphenyl)-2,4-dioxo-1,3-dipropyl-7-(pyridin-1-ium-1-yl)-1,2,3,4,6,7-hexahydropyrido[2,3-d]pyrimidin-7-ide (10)

To the solution of 7aaa (1 mmol; 0,37 g) in pyridine (1 mL), tosyl chloride (1.1 mmol; 0.21 g) was added at a temperature of 0 °C. The reaction was then continued at room temperature for 24 h. After the addition of 5 mL of water, the product was extracted with ethyl acetate. The crude product was purified by flash chromatography using gradient elution (0–100% AcOEt in hexane). The expected compound was obtained as solid (86 mg) with a 20% yield; 1H NMR (700 MHz, CDCl3) δ 7.25–7.22 (m, 2H), 7.10 (s, 2H), 6.96–6.93 (m, 2H), 6.37 (s, 1H), 5.08 (dtd, J = 1.1, 3.6, 7.4 Hz, 2H), 4.29–4.25 (m, 2H), 3.91–3.87 (m, 2H), 3.85–3.84 (m, 3H), 2.99 (tt, J = 1.7, 3.6 Hz, 2H), 1.80 (tsxt, J = 1.8, 7.4 Hz, 2H), 1.62 (tsxt, J = 2.1, 7.5 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 159.5, 155.8, 152.3, 151.7, 151.3, 132.3, 129.3, 123.7, 113.2, 107.3, 104.9, 100.8, 55.2, 44.6, 43.0, 23.2, 21.2, 21.1, 11.5, 11.3; IR νmax: 2958.3, 1703.4, 1656.8, 1582.8, 1544.2, 1514.1, 1426.3, 1390.3, 1361.6, 1260.2, 1236.3, 1179.2, 1105.6, 1086.4, 1026.9, 969.3, 957.8, 893.1, 820.5, 755.8, 735.4, 705.7, 676.8, 574.9, 562.4, 488.5, 453.8 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C25H29N4O3 433.2240; found: 433.2243; mp 76.6–83.8 °C.

5-(4-Methoxyphenyl)-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-7-yl 4-methylbenzene-sulfonate (11)

To the solution of 7aaa (0.5 mmol; 0,19 g) in DIPEA (1 mL) and DCM (1 mL), tosyl chloride (0.55 mmol; 0.10 g) was added at a temperature of 0 °C. The reaction was then continued at room temperature for 24 h. After the addition of 5 mL of water, the product was extracted with DCM. The crude product was purified by flash chromatography using gradient elution (0–100% AcOEt in hexane). The expected compound was obtained as solid (91 mg) with a 35% yield; 1H NMR (700 MHz, CDCl3) δ 7.92–7.89 (m, 2H), 7.41–7.37 (m, 2H), 7.24–7.21 (m, 2H), 6.96–6.93 (m, 2 H), 6.70 (s, 1H), 4.03–3.99 (m, 2H), 3.91–3.87 (m, 2H), 3.85 (s, 4H), 2.47 (s, 3H), 1.61–1.57 (m, 4H), 0.90–0.87 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 159.1, 158.9, 157.4, 151.0, 150.1, 145.3, 133.7, 129.9, 129.5, 129.1, 127.8, 113.0, 111.9, 106.2, 54.8, 44.4, 43.0, 21.4, 20.5, 20.5, 10.8, 10.7; IR νmax: 2961.6, 2932.6, 2874.3, 1713.0, 1664.7, 1580.4, 1555.5, 1514.4, 1457.7, 1378.8, 1339.4, 1247.1, 1222.7, 1193.8, 1177.2, 1156.5, 1088.8, 1031.8, 946.3, 904.5, 830.4, 804.1, 754.5, 721.1, 665.2, 577.2, 546.1 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C27H30N3O6S 524.1855; found: 524.1855; mp 76.6–83.8 °C.

7-(Benzyloxy)-5-(4-methoxyphenyl)-1,3-dipropyl-5,6-dihydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (12)

7aaa (0.25 mmol; 93 mg), benzyl bromide (1.25 mmol; 149 μL), and potassium carbonate (1.25 mmol; 0.16 g) were mixed in anhydrous DMF (1 mL) at 80 °C (oil bath) for 24 h. The reaction mixture was diluted with water (5 mL), and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography using gradient elution (0–100% AcOEt in hexane). The expected compound was obtained as solid (73 mg) with a 63% yield; 1H NMR (700 MHz, CDCl3) δ 7.39–7.31 (m, 5H), 7.04–7.01 (m, 2H), 6.77–6.74 (m, 2H), 5.41 (d, J = 13.4 Hz, 1H), 5.36 (d, J = 12.3 Hz, 1H), 4.26 (d, J = 9.3 Hz, 1H), 4.11–4.06 (m, 1 H), 4.04–3.99 (m, 1H), 3.88 (ddd, J = 3.8, 6.5, 8.7 Hz, 2H), 3.75 (s, 3H), 2.89 (dd, J = 9.4, 16.8 Hz, 1H), 2.75 (dd, J = 1.0, 16.8 Hz, 1H), 1.71–1.61 (m, 4H), 0.95–0.89 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 162.2, 158.6, 151.6, 150.7, 135.3, 134.1, 128.7, 128.5, 127.8, 127.6, 114.1, 95.5, 69.5, 55.2, 44.7, 43.0, 33.4, 33.4, 22.3, 21.0, 11.4, 11.3; IR νmax: 2962.7, 2934.6, 2875.5, 1696.3, 1640.6, 1587.8, 1508.9, 1460.3, 1398.5, 1389.7, 1339.8, 1272.6, 1243.0, 1222.7, 1174.7, 1099.4, 1033.2, 1024.0, 951.8, 909.5, 892.6, 830.5, 785.7, 750.6, 697.9, 594.5, 559.2, 527.7 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C27H32N3O4 462.2393; found: 462.2392; mp 99.4–106.6 °C.

7-(Benzyloxy)-5-(4-methoxyphenyl)-1,3-dipropyl-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13)

7aaa (0.25 mmol; 93 mg), benzyl chloride (1.25 mmol; 144 μL), and potassium carbonate (1.25 mmol; 0.16 g) were mixed in anhydrous DMF (1 mL) at 80 °C (oil bath) for 24 h. The reaction mixture was diluted with water (5 mL), and the product was extracted with ethyl acetate. The crude product was purified by flash chromatography using gradient elution (0–100% AcOEt in hexane). The expected compound was obtained as a viscous oil (52 mg) with a 45% yield; 1H NMR (700 MHz, CDCl3) δ 7.45–7.42 (m, 2H), 7.41–7.38 (m, 2H), 7.36–7.33 (m, 1H), 7.27–7.23 (m, 2H), 6.97–6.93 (m, 2H), 6.48 (s, 1H), 5.49 (s, 2H), 4.28–4.24 (m, 2H), 3.93–3.89 (m, 2H), 3.85 (s, 3H), 1.77–1.72 (m, 2H), 1.66–1.60 (m, 2H), 1.00 (t, J = 7.4 Hz, 2H), 0.90 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ 164.1, 159.6, 156.5, 150.6, 136.1, 131.1, 128.9, 128.2, 127.8, 127.1, 113.1, 112.8, 109.0, 101.8, 68.0, 44.4, 42.8, 20.9, 20.6, 11.1, 10.9; IR νmax: 3466.3, 2960.6, 2932.4, 2874.1, 1705.8, 1658.7, 1594.5, 1553.0, 1514.8, 1491.8, 1453.2, 1394.4, 1341.4, 1288.2, 1246.3, 1225.4, 1209.4, 1174.8, 1105.0, 1086.2, 1032.4, 1016.2, 996.0, 828.8, 803.4, 752.7, 731.4, 695.9, 670.9, 569.4, 526.0 cm–1; HRMS (ESI-TOF) m/z: (M + H)+ calcd for C27H30N3O4 460.2236; found: 460.2235.