One-pot NHC-assisted access to 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones

Abstract

An efficient N-heterocyclic carbene-assisted one-pot reaction for the synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 2-(ethoxymethylene)malononitrile, guanidines (or amidines) and ketones (or aldehydes) has been developed. This highly efficient method includes a series of conversions such as Michael addition, cyclisation, isomerization, aromatization, then nucleophilic attack and Dimroth rearrangement. And it avoids complicated reagents and multiple steps.

---

Introduction

Pyrimidine and fused cyclic compounds are widely present in many natural and biologically active compounds.¹ As a subtype, pyrimidopyrimidinones possess a wide range of biological activities such as anti-inflammatory,¹ antitumor,² inhibition of dihydrofolate reductase,³ type-II kinase inhibition,⁴ tyrosine kinase inhibition,⁵ and as a surrogate for both T and A in duplex DNA.⁶ The traditional approaches relay on multiple steps reactions,^6a,7 such as the condensation of aldehyde and acid anhydride with 4-aminopyrimidine-5-carboxamides, which are always hydrolyzed from the corresponding o-aminonitriles,⁸ or with the 5-aminopyrimidine-4-carbonitriles,⁹ the cyclization of ethyl 5-aminopyrimidine-4-carboxylates with acrylamides,¹⁰ the treatment of 6-aminouracil/6-amino-5,6-dihydropyrimidin-4(3H)-one with phosphorus oxychloride in DMF under the Vilsmeier reaction conditions.^3,6 However, they usually suffer from drawbacks such as multistep sequences,¹¹ complicated reagents,¹² longer reaction time and lower yields.^3,13

One-pot reaction improves the efficiency of reaction. It saves time and resources, and avoids the lengthy separation and purification process of intermediate compounds.¹⁴ N-hetero-cyclic carbenes (NHCs) as the small organic molecular catalysts have been used widely as powerful tool for the construction of complex compounds.¹⁵ NHCs can catalyze the Benzoin condensation,¹⁶ Stetter reaction,¹⁷ transesterification/acylation reactions,^19c,18 nucleophilic substitution reaction,¹⁹ and domino reaction.²⁰ In our previous studies, NHC-PPIm was easily prepared via concentration of a 1,3-dipropylimidazolium hydroxide aqueous solution and excellent catalytic activity was found in the cyclocondensation of cyclohexanone and 2-aminobenzonitrile.²¹ Inspired by this good result, especially taking into account both the synthesis of dihydropyrimidinone through PDF conversion²² and the synthesis of 4-amino-5-cyanopyrimidine in the catalyst of base,²³ we designed a novel one-pot NHC-PPIm assisted three component heterocyclization of 2-(ethoxymethylene)malononitrile, guanidines and ketones for the synthesis of dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (Scheme 1). To the best of our knowledge, this is a first convenient method for the construction of pyrimido[4,5-d]pyrimidin-4(1H)-one core by NHC-PPIm assisted three components cyclization, and this one-pot approach is mild, inexpensive, energy efficient and avoids transition metal catalyst.

Scheme 1 The retrosynthetic design of reaction.

Results and discussion

To find the appropriate reaction conditions, we chose the reaction of 2-(ethoxymethylene)malononitrile (1.2 mmol), guanidine (1 mmol) and cyclohexanone as the model. Different reaction conditions were evaluated, and the results were summarized in Table 1. It is shown that inorganic bases and organic weak bases didn't promote this reaction (Table 1, entries 1–4). However, organic strong base could promote it easily (Table 1, entries 5–7). NHC-PPIm could promote this reaction under mild conditions, and the yield is higher in ethanol (Table 1, entries 8–11). Although higher temperature improved the reaction, NHC-PPIm was unstable at this case, so the appropriate temperature was 40 °C (Table 1, entries 12–14). The amount of NHC-PPIm has a little effect on the reaction when it is more than 0.4 equivalent. So 0.4 equivalent amount of NHC-PPIm was an appropriate choice (Table 1, entries 15–18).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	NHC-PPIm (eqiv.)	Time (h)	Temp (°C)	Yield^b (%)
a Reactions conditions: 1 (1.2 mmol), 2 (1 mmol), 3a (1.2 mmol) and catalyst in solvent (10 ml).b Isolated yields.
1	EtOH	NaOH (1.0)	7	Reflux	Trace
2	EtOH	Na2CO3 (1.0)	7	Reflux	0
3	EtOH	DBU (1.0)	7	Reflux	0
4	EtOH	pyridine (1.0)	7	Reflux	0
5	EtOH	NaOMe (1.0)	7	Reflux	79
6	EtOH	NaOEt (1.0)	7	Reflux	80
7	EtOH	KOBu-t (1.0)	7	Reflux	70
8	EtOH	NHC-PPIm (1.0)	2	25	75
9	PhMe	NHC-PPIm (1.0)	2	25	60
10	(CH2)5CO	NHC-PPIm (1.0)	2	25	72
11	H2O	NHC-PPIm (1.0)	2	40	72
12	EtOH	NHC-PPIm (1.0)	2	40	84
13	EtOH	NHC-PPIm (1.0)	2	60	70
14	EtOH	NHC-PPIm (1.0)	2	80	49
15	EtOH	NHC-PPIm (0)	2	40	0
16	EtOH	NHC-PPIm (0.2)	2	40	42
17	EtOH	NHC-PPIm (0.4)	2	40	85
18	EtOH	NHC-PPIm (0.8)	2	40	84

---

With the optimal conditions in hand, a series of ketones (or benzaldehyde) and guanidines (or amidines) were investigated, and the results were summarized in Table 2. Theoretically, different carbonyl compounds had effect on this reaction because of the steric hindrance and ring tension, but all carbonyl compounds reacted with guanidine were in good yields (Table 2, entries 1–9), and partially the N,N-dimethylguanidine also gave the corresponding compounds in good yields (Table 2, entries 10–14). To expand the scope of this one-pot reaction methodology, a set of guanidines and amidines were selected and the corresponding compounds were obtained in good to excellent yields (Table 2, entries 15–19). These results illustrated the universality of NHC-PPIm and the advantages of one-pot method.

Table 2 NHC-PPIm-assisted three-component one-pot synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones^a

Entry	R1	R2	R3	Time (h)	Product	Yield^b (%)
a Reactions conditions: 1 (1.2 mmol), 2 (1 mmol), 3a (1.2 mmol) and NHC-PPIm (0.4 mmol) in ethanol (10 ml).b Isolated yields.
1	R1 + R2=(CH2)5		NH2	2	4a	85
2	R1 + R2=(CH2)6		NH2	3	4b	81
3	CH3	CH3	NH2	3	4c	88
4	CH3	CH3CH2	NH2	5	4d	87
5	CH3	CH3CH2CH2	NH2	4	4e	92
6	CH3CH2	CH3CH2	NH2	5	4f	90
7	CH3	(CH3)2CH	NH2	6	4g	82
8	CH3	Ph	NH2	4.5	4h	78
9	H	Ph	NH2	5	4i	75
10	R1 + R2=(CH2)5		(CH3)2N	2.5	4j	82
11	CH3	CH3	(CH3)2N	3	4k	86
12	CH3	CH3CH2	(CH3)2N	6	4l	85
13	CH3	CH3CH2CH2	(CH3)2N	5	4m	86
14	CH3	(CH3)2CH	(CH3)2N	5.5	4n	79
15	R1 + R2=(CH2)5		PhNH	2	4o	91
16	R1 + R2=(CH2)6		CH3NH	4	4p	81
17	R1 + R2=(CH2)5		C2H5NH	4	4q	86
18	CH3	CH3	Ph	4.5	4r	81
19	CH3	CH3	CH3	6	4s	75

---

To rationalize the above results, a possible reaction mechanism is envisioned as depicted in Scheme 2. It is proposed that the 2-(ethoxymethylene)malononitrile undergoes a Michael addition reaction with guanidines (or amidines), then followed by cyclisation, isomerization and aromatization to afford intermediate 4-aminopyrimidine-5-carbonitrile 5. The Breslow intermediate 6 nucleophilic attacks the cyano of the 5 to provide 7. Then 7 releases NHC-PPIm and 3,1-oxazine 8 is formed, which subsequently rearranges to afford the final product 4 (Dimroth rearrangement²⁴).

Scheme 2 The possible mechanism of the formation of 4.

In order to prove this mechanism, we tried to seperate the intermediate 5j, and fortunately, 4-amino-2-dimethylamino-pyrimidine-5-carbonitrile (5j) was detected by LC after 10 minutes. As the reaction proceeded, the final product 4j increased and the intermediate 5j decreased (Fig. 1). The product 4j was also obtained by the condensation of the seperated intermediate 5j with cyclohexanone in the same conditions in 83% yield.

Fig. 1 Percentage of intermediate and product: (●)5j, (▼)4j.

All products were characterized by IR, ¹H NMR, ¹³C NMR, ESI spectra, and elemental analysis. And the structure 4b was undoubtedly confirmed by X-ray crystallographic analysis (Fig. 2).²⁵

Fig. 2 ORTEP representation of 4b.

Conclusions

In summary, an efficient method for combining two fairly well-known reactions into one-pot reaction and synthesizing 2,3-dihydropyrimido[4,5-d]pyrimidin4(1H)-ones was developed. It is a highly efficient method for synthesizing pyrimido[4,5-d]pyrimidine ring without starting from any nitrogen-containing heterocyclic compound. The reaction conducted under mild conditions and the most products deposited from the solvent when the reaction completed.

Experimental section

General methods

The starting materials including 2-(ethoxymethylene)malononitrile (1), guanidines/amidines (2) and ketones (3) are commercially available. Melting points were determined using XT4 microscope melting point apparatus (uncorrected). Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrophotometer with KBr pellets. ¹H and ¹³C NMR spectra were recorded at a Bruker 400 or 500 MHz spectrometer with TMS as the internal standard. Mass spectra were recorded on a ZAB-HS mass spectrometer using ESI ionization. Elemental analyses were performed on an Elementar Vario EL. The percentage of intermediate and product were determined by HPLC using an Shimadzu LC-20AT instrument with Hanbon column YWG C18.

General procedure for the synthesis of 4

2-(Ethoxymethylene)malononitrile (1, 1.2 mmol) and guanidine/amidine (2, 1 mmol) were mixed in ethanol at room temperature, then ketone (3, 1.2 mmol) and NHC-PPIm (0.4 mmol) was added. The mixture was warmed to 40 °C. At the end of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature. The solid was filtered and recrystallized from methanol or purified by column chromatography on silica gel (200–300 mesh silica gels) to afford pure 4a.

4-Amino-2-(dimethylamino)pyrimidine-5-carbonitrile (5j). White solid; m.p. 217–219 °C; IR (KBr, v, cm⁻¹): 3424, 3390, 3336, 3203, 2215, 1661, 1602, 1555, 1529, 1487; ¹H NMR (400 MHz, CDCl₃) (δ, ppm): 8.22 (s, 1H), 5.17 (s, 2H), 3.19 (s, 3H), 3.14 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) (δ, ppm): 162.6, 161.6, 161.4, 117.6, 77.7, 36.4; ESI-MS (m/z) = 164 ([M + H]⁺).

7′-Amino-1'H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4a). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3315, 3180, 2935, 2851, 1662, 1609, 1472, 1446, 1421; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.18 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 6.64 (s, 2H), 1.66–1.64 (m, 5H), 1.60–1.55 (m, 5H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.2, 161.1, 156.7, 97.6, 67.7, 38.1, 24.5, 20.7; ESI-MS (m/z) = 232 ([M − H]⁻). Anal. calcd for C₁₁H₁₅N₅O: C, 56.64; H, 6.48; N, 30.02%. Found: C, 56.44; H, 6.58; N, 30.07%.

7′-Amino-1′'H-spiro[cycloheptane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4b). Light yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3413, 3339, 3173, 2933, 2845, 1659, 1624, 1600, 1473, 1408; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.17 (s, 1H), 7.89 (s, 1H), 7.88 (s,1H), 6.61 (s, 2H), 1.87–1.84 (m, 4H), 1.4 (s, 8H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.0, 161.0, 156.7, 97.4, 71.8, 42.0, 29.4, 20.7; ESI-MS (m/z) = 248 ([M + H]⁺); Anal. calcd for C₁₂H₁₇N₅O : C, 58.28; H, 6.93; N, 28.32%. Found: C, 58.14; H, 6.76; N, 28.62%.

7-Amino-2,2-dimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4c). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3464, 3229, 3148, 2943, 1663, 1615, 1482, 1455, 1418; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.18 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 6.68 (s, 2H), 1.37 (s, 6H);¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.9, 162.0, 161.0, 156.8, 97.2, 66.7, 29.9; ESI-MS (m/z) = 216 ([M + Na]⁺); Anal. calcd. for C₈H₁₁N₅O : C, 49.73; H, 5.74; N, 36.25%. Found: C, 49.55; H, 5.70; N, 36.36%.

7-Amino-2-ethyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4d). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3228, 2969, 1648, 1611, 1447; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.14 (s, 1H), 7.67 (s, 2H), 6.60 (s, 2H), 1.62–1.59 (m, 2H), 1.33 (s, 3H), 0.81 (t, J = 6.8 Hz 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.0, 161.3, 156.4, 96.9, 69.2, 34.6, 29.0, 7.9; ESI-MS (m/z) = 206 ([M − H]⁻); Anal. calcd for C₉H₁₃N₅O : C, 52.16; H, 6.32; N, 33.79%. Found: C, 52.22; H, 6.52; N, 33.66%.

7-Amino-2-methyl-2-propyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4e). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3336, 3225, 3142, 2962, 1678, 1608, 1574, 1474, 1415; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.13 (s, 1H), 7.69 (s, 2H), 6.62 (s, 2H), 1.60–1.55 (m, 2H), 1.33 (s, 3H), 1.28 (t, J = 8 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.0, 161.0, 156.4, 97.0, 68.9, 44.5, 29.2, 16.4, 13.9; ESI-MS (m/z) = 220 ([M − H]⁻); Anal. calcd for C₁₀H₁₅N₅O : C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.38; H, 6.78; N, 31.58%.

7-Amino-2,2-diethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4f). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3156, 2970, 2936, 1671, 1600, 1477, 1419; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.11 (s, 1H), 7.54 (s, 1H), 7.49 (s,1H), 6.54 (s, 2H), 1.60–1.53 (m, 4H), 0.81 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.3, 161.5, 156.1, 96.5, 79.2, 72.1, 34.2, 7.5; ESI-MS (m/z) = 244 ([M + Na]⁺); Anal. calcd for C₁₀H₁₅N₅O : C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.55; H, 6.72; N, 31.59%.

7-Amino-2-isopropyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4g). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3416, 3173, 2970, 1657, 1605, 1566, 1482, 1414; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.12 (s, 1H), 7.75 (s, 1H), 7.72 (s,1H), 6.58 (s, 2H), 1.77–1.86 (m, 1H), 1.32 (s, 3H), 0.85 (d, J = 1.6 Hz, 3H), 0.83 (d, J = 2.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 161.8, 161.0, 156.2, 97.1, 71.3, 38.9, 25.9, 16.6; ESI-MS (m/z) = 244 ([M + Na]⁺); Anal. calcd for C₁₀H₁₅N₅O : C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.42; H, 6.93; N, 31.50%.

7-Amino-2-methyl-2-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4h). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3453, 3329, 1665, 1577, 1444; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.58 (s, 1H), 8.52 (s, 1H), 8.12 (s,1H), 7.45 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.72 (s, 2H), 1.65 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.6, 163.0, 161.8, 157.2, 147.6, 128.2, 127.4, 124.7, 98.2, 69.6, 30.1; ESI-MS (m/z) = 254 ([M − H]⁻); Anal. calcd for C₁₃H₁₃N₅O : C, 61.17; H, 5.13; N, 27.43%. Found: C, 61.34; H, 5.33; N, 27.16%.

7-Amino-2-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4i). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3464, 3299, 3090, 2938, 1673, 1643, 1606, 1565, 1475, 1420; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.21 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.39–7.38 (m, 4H), 7.33 (q, J = 4.4 Hz, 1H), 6.78 (s, 2H), 5.73 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.7, 162.2, 161.5, 156.9, 142.5, 128.4, 128.3, 126.0, 98.0, 64.9; ESI-MS (m/z) = 264 ([M + Na]⁺); Anal. calcd for C₁₂H₁₁N₅O : C, 59.74; H, 4.60; N, 29.03%. Found: C, 59.62; H, 4.33; N, 29.23%.

7′-(Dimethylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4j). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3170, 3055, 2930, 2860, 1647, 1606, 1547, 1503, 1448; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.25 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 3.00 (s, 6H), 1.68–1.57 (m, 8H), 1.34–1.25 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 163.6, 163.1, 161.4, 156.7, 97.5, 66.6, 38.7, 37.4, 25.3, 21.3; ESI-MS (m/z) = 262 ([M + H]⁺); Anal. calcd for C₁₃H₁₉N₅O : C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.81; H, 7.30; N, 26.68%.

7-(Dimethylamino)-2,2-dimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4k). Light yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3251, 3139, 2973, 1737, 1633, 1607, 1575, 1440; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.27 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 3.10 (s, 6H), 1.39 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 162.9, 162.1, 160.5, 156.1, 96.4, 66.7, 36.6, 29.8; ESI-MS (m/z) = 222 ([M + H]⁺); Anal. calcd for C₁₀H₁₅N₅O : C, 54.28; H, 6.83; N, 31.65%. Found: C, 54.41; H, 6.81; N, 31.58%.

7-(Dimethylamino)-2-ethyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4l). White solid; m.p. 257–259 °C; IR (KBr, v, cm⁻¹): 3207, 2979, 2924, 1635, 1608, 1583, 1542, 1517, 1459; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.26 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 3.10 (s, 6H), 1.67–1.62 (m, 2H), 1.36 (s, 3H), 0.83 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 162.9, 162.3, 160.7, 155.8, 96.1, 69.3, 36.6, 34.9, 29.2, 7.9; ESI-MS (m/z) = 236 ([M + H]⁺); Anal. calcd for C₁₁H₁₇N₅O : C, 56.15; H, 7.28; N, 29.77%. Found: C, 55.99; H, 7.32; N, 29.81%.

7-(Dimethylamino)-2-methyl-2-propyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4m). White solid; m.p. 252–254 °C; IR (KBr, v, cm⁻¹): 3202, 2958, 2934, 2873, 1638, 1608, 1583, 1542, 1519, 1459; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.24 (s, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 3.10 (s, 6H), 1.63–1.57 (m, 2H), 1.35 (s, 3H), 1.32–1.28 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 162.9, 162.1, 160.6, 155.7, 96.1, 69.0, 44.6, 36.6, 29.4, 16.5, 13.9; ESI-MS (m/z) = 250 ([M + H]⁺); Anal. calcd for C₁₂H₁₉N₅O : C, 57.81; H, 7.68; N, 28.09%. Found: C, 57.75; H, 7.72; N, 28.21%.

7-(Dimethylamino)-2-isopropyl-2-methyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4n). Light yellow solid; m.p. 279–281 °C; IR (KBr, v, cm⁻¹): 3242, 3180, 2967, 2935, 1641, 1606, 1577, 1541, 1515, 1449, 1389; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.23 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 3.10 (s, 6H), 1.89–1.82 (m, 1H), 1.35 (s, 3H), 0.86 (d, J = 6 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 162.9, 162.0, 160.5, 155.6, 96.3, 71.5, 36.6, 26.1, 16.6; ESI-MS (m/z) = 250 ([M + H]⁺); Anal. calcd for C₁₂H₁₉N₅O : C, 57.81; H, 7.68; N, 28.09%. Found: C, 57.61; H, 7.75; N, 28.18%.

7′-(Phenylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4o). White solid; m.p. 292–294 °C; IR (KBr, v, cm⁻¹): 3200, 2923, 1647, 1594, 1574, 1531, 1498, 1443; ¹H NMR (500 MHz, DMSO-d₆) (δ, ppm): 9.53 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.99(s, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 8.5 Hz, 1H), 1.75–1.61 (m, 8H), 1.39–1.29 (m, 2H); ¹³C NMR (500 MHz, DMSO-d₆) (δ, ppm): 162.5, 161.9, 161.2, 156.7, 140.7, 128.9, 122.1, 120.0, 99.2, 66.6, 38.6, 24.9, 21.0; ESI-MS (m/z) = 310 ([M + H]⁺); Anal. calcd for C₁₇H₁₉N₅O : C,66.00; H, 6.19; N, 22.64%. Found: C, 66.11; H, 6.17; N, 22.58%.

7′-(Methylamino)-1′H-spiro[cycloheptane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4p). Yellow solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3253, 2929, 1655, 1595, 1530, 1461, 1380; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.17 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.18 (s, 1H), 2.78 (s, 3H), 1.88–1.82 (m, 4H), 1.50 (s, 8H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 164.6, 162.6, 161.2, 156.7, 96.9, 72.3, 31.2, 30.0, 28.5, 21.3; ESI-MS (m/z) = 262 ([M + H]⁺); Anal. calcd for C₁₃H₁₉N₅O : C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.88; H, 7.31; N, 26.74%.

7′-(Ethylamino)-1′H-spiro[cyclohexane-1,2′-pyrimido[4,5-d]pyrimidin]-4′(3′H)-one (4q). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3195, 2935, 1633, 1587, 1517, 1454, 1432, 1389; ¹H NMR (500 MHz, DMSO-d₆) (δ, ppm): 8.18 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.26 (s, 1H), 3.26 (m, 2H), 1.67–1.58 (m, 8H), 1.36–1.24 (m, 2H), 1.09 (t, J = 5.4 Hz, 3H); ¹³C NMR (500 MHz, DMSO-d₆) (δ, ppm): 164.0, 162.3, 161.3, 157.0, 97.2, 68.0, 38.6, 35.8, 25.1, 21.1, 15.3; ESI-MS (m/z) = 262 ([M + H]⁺); Anal. calcd for C₁₃H₁₉N₅O : C, 59.75; H, 7.33; N, 26.80%. Found: C, 59.68; H, 7.32; N, 26.84%.

2,2-Dimethyl-7-phenyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4r). White solid; m.p. 282–284 °C; IR (KBr, v, cm⁻¹): 3234, 3061, 2960, 1674, 1611, 1592, 1448, 1440; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.65 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 8.32 (d, J = 2 Hz, 2H), 7.52–7.50 (m, 3H), 1.48 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 166.9, 160.9, 160.3, 154.9, 137.1, 131.1, 128.5, 128.0, 104.2, 67.2, 30.1; ESI-MS (m/z) = 255 ([M + H]⁺); Anal. calcd for C₁₄H₁₄N₄O : C, 66.13; H, 5.55; N, 22.03%. Found: C, 66.27; H, 5.53; N, 21.98%.

2,2,7-Trimethyl-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (4s). White solid; m.p. > 300 °C; IR (KBr, v, cm⁻¹): 3190, 3050, 2923, 1684, 1613, 1555, 1424; ¹H NMR (400 MHz, DMSO-d₆) (δ, ppm): 8.43 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 2.37 (s, 3H), 1.41 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) (δ, ppm): 170.6, 161.0, 159.9, 154.4, 103.3, 67.0, 30.0, 25.8; ESI-MS (m/z) = 193 ([M + H]⁺); Anal. calcd for C₉H₁₂N₄O : C, 56.24; H, 6.29; N, 29.15%. Found: C, 56.12; H, 6.31; N, 29.21%.

Acknowledgements

This work was supported by the grant of Beijing Institute of Technology. We are grateful for analytical help of Institute of Chemistry, Chinese Academy of Sciences and Beijing Normal University.

Notes and references

1. M. W. Martin, J. Newcomb, J. J. Nunes, C. Boucher, L. Chai, L. F. Epstein, T. Faust, S. Flores, P. Gallant, A. Gore, Y. Gu, F. Hsieh, X. Huang, J. L. Kim, S. Middleton, K. Morgenstern, A. Oliveira-dos-Santos, V. F. Patel, D. Powers, P. Rose, Y. Tudor, S. M. Turci, A. A. Welcher, D. Zack, H. L. Zhao, L. Zhu, X. T. Zhu, C. Ghiron, M. Ermann and D. Johnston, J. Med. Chem., 2008, 51, 1637.
2. (a) H. T. Abdel-Mohsen, F. A. F. Ragab, M. M. Ramla and H. I. E. Diwani, Eur. J. Med. Chem., 2010, 45, 2336; (b) P. Palanisamy, S. J. Jenniefer, P. T. Muthiah and S. Kumaresan, RSC Adv., 2013, 3, 19310.
3. M. G. Gebauer, C. Mckinlay and J. E. Gready, Eur. J. Med. Chem., 2003, 38, 719.
4. H. G. Choi, P. D. Ren, F. Sun, F. X. Sun, H. S. Lee, X. Wang, Q. Ding, G. B. Zhang, Y. P. Xie, J. M. Zhang, Y. Liu, T. Tuntland, M. Warmuth, P. W. Manley, J. Mestan, N. S. Gray and T. Sim, J. Med. Chem., 2010, 53, 5439.
5. L. A. McDermott, B. Higgins and M. Simcox, Bioorg. Med. Chem. Lett., 2006, 16, 1950.
6. (a) D. Shin and Y. Tor, J. Am. Chem. Soc., 2011, 133, 6926; (b) H. Zhao, S. L. He, M. L. Yang, X. R. Guo, G. Xin, C. Y. Zhang, L. Ye, L. Y. Chu, Z. H. Xing, W. Huang, Q. M. Chen and Y. He, Chem. Commun., 2013, 49, 3742.
7. Y. P. Patil, P. J. Tambade, K. M. Deshmukh and B. M. Bhanage, Catal. Today, 2009, 148, 355.
8. (a) A. R. Arthur and N. Y. Middleport, US Pat. 3830812, 1974; (b) E. C. Taylor, R. J. Knopf and R. F. Meyer, J. Am. Chem. Soc., 1960, 82, 5711.
9. S. B. Katiyar, A. Kumar and P. M. S. Chauhan, Synth. Commun., 2006, 36, 2963.
10. M. Dymicky and W. T. Caldwell, J. Org. Chem., 1962, 27, 4211.
11. L. Rachel, J. A. Beingessner, U. D. Diaz and H. Fenniri, Tetrahedron Lett., 2011, 52, 661.
12. (a) A. C. Basel, H. D. Loerrach, U. G. Efringen-Kirchen, N. A. K. Sool, H. K. Loerrach, R. N. Saint-Louis, C. G. P. Bottmingen, J. U. P. Grenzach-Wyhlen and F. R. Hombourg, US Pat. 0234277, 2008; (b) M. Kidwai and K. Singhal, J. Heterocycl. Chem., 2007, 44, 1253.
13. L. Y. Zheng, F. Z. Yang, Q. Dang and X. Bai, Org. Lett., 2008, 10, 889.
14. R. Robinson, J. Chem. Soc., Trans., 1917, 111, 762.
15. (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606; (b) J. L. Moore and T. Rovis, Top. Curr. Chem., 2009, 291, 77; (c) E. M. Phillips, A. Chan and K. A. Scheidt, Aldrichimica Acta, 2009, 42, 55; (d) P. C. Chiang and J. W. Bode, in N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools, ed. S.Díez-González, Royal Society of Chemistry, Cambridge, 2011, ch. 14, pp. 339–435; (e) C. D. Campbell, K. B. Ling and A. D. Smith, in N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis, ed. C. S. J.Cazin, Springer, Dortrecht, 2011, vol. 32, ch. 12, pp. 263–297; (f) X. Bugaut and F. Glorius, Chem. Soc. Rev., 2012, 41, 3511; (g) K. Thai, E. Sánchez-Larios and M. Gravel, in Comprehensive Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-VCH, 2013, ch. 18, pp. 495–522; (h) N. Marion, S. Díez-Gonzalez and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2988; (i) V. Nair, S. Vellalath and B. P. Babu, Chem. Soc. Rev., 2008, 37, 2691.
16. K. A. Scheidt and E. A. O'Bryan, in Comprehensive Organic Synthesis II, eds. P.Knochel and G. A.Molander, Elsevier, Amsterdam, 2nd edn, 2014, vol. 3, ch. 12, pp. 621–655.
17. (a) H. Stetter, Angew. Chem., Int. Ed., 1976, 15, 639; (b) H. Stetter and H. Kuhlmann, Org. React., 1991, 40, 407; (c) J. Read de Alaniz and T. Rovis, Synlett, 2009, 8, 1189; (d) M. Gravel and J. M. Holmes, in Comprehensive Organic Synthesis II, ed. P.Knochel and G. A.Molander, Elsevier, Amsterdam, 2nd edn, 2014, vol. 4, ch. 23, pp. 1384–1406; (e) Y. S. Jiang, W. Z. Chen and W. M. Lu, RSC Adv., 2012, 2, 1540.
18. I. Chiarotto, M. Feroci, G. Sotgiu and A. Inesi, Eur. J. Org. Chem., 2013, 2013, 326.
19. (a) Y. Suzuki, S. Ota and Y. Fukuta, J. Org. Chem., 2008, 73, 2420; (b) C. Fischer, S. W. Smith, D. A. Powell and G. C. Fu, J. Am. Chem. Soc., 2006, 128, 1472; (c) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev., 2013, 42, 4906.
20. (a) A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314; (b) C. S. Yao, W. H. Jiao, Z. X. Xiao, Y. W. Xie, T. J. Li, X. S. Wang, R. Liu and C. X. Yu, RSC Adv., 2013, 3, 10801.
21. B. Zhen, Q. Z. J, Y. P. Zhang, Q. Wu, H. S. Li, D. X. Shi and J. R. Li, Catal. Commun., 2013, 32, 1.
22. J. R. Li, L. J. Zhang, D. X. Shi, Q. Li, D. Wang, C. X. Wang, Q. Zhang, L. Zhang and Y. Q. Fan, Synlett, 2008, 2, 233.
23. (a) K. Helmut and R. Marianne, Z. Chem., 1981, 21, 101; (b) P. C. Wyss, P. Gerber, P. G. Hartman, C. Hubschwerlen, H. Locher, H. P. Marty and M. Stahl, J. Med. Chem., 2003, 46, 2304; (c) T. Karoli, S. K. Mamidyala, J. Zuegg, S. R. Fry, E. H. L. Tee, T. A. Bradford, P. K. Madala, J. X. Huang, S. Ramu, M. S. Butler and M. A. Cooper, Bioorg. Med. Chem. Lett., 2012, 22, 2428.
24. (a) O. Dimroth, Ann. Chem., 1909, 364, 183; (b) D. J. Brown and J. S. Harper, J. Chem. Soc., 1963, 1276.
25. ESI.†.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 896461. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra05346j

---