A POCl₃-mediated synthesis of substituted fused azoacridones derivatives

Abstract

A highly facile and efficient approach to synthesize fused azoacridone derivatives containing various functional groups has been developed. This reaction starts with a substitution reaction between the corresponding benzoic acids and pyrimidines, followed by POCl₃-mediated cyclization reaction. The desired pure fused azoacridones were afforded in high yields.

---

Introduction

Acridone and acridine derivatives are naturally occurring compounds that have π-conjugated planar structure and exhibit a wide range of physical, physicochemical, biological and pharmacological activities.¹ A large number of acridones and acridines, as well as their synthetic methods, have been developed due to their diverse properties.² Usually, the Ullman–Jourdan reaction occurs to form diphenylamine-2-carboxylic acids,³ which are then cyclized to the corresponding acridones or acridines under strong acids (such as H₂SO₄, polyphosphoric acid/PPA) or phosphoryl chloride (Scheme 1A). Using this method we have synthesized a series of acridine derivatives with antitumor activity.^1j,4 Comparison to a huge amount of acridone and acridine derivatives, their azo-derivatives are little reported because of their limited synthetic methods.⁵ As replacement of just one carbon atom of carbocyclic ring with a heteroatom could lead to great changes in physical as well as chemical properties, such as anthracene and acridine, development of azoacridones, azoacridines and their synthetic methods to broaden the application of acridine derivatives are very important.^1j Herein, we report a simple efficient route for the synthesis of fused azoacridone derivatives.

Scheme 1 (1A) Traditional synthesis methods for acridine derivatives; (1B) rational construction of fused azoacridones; (1C) our synthesis methods for fused azoacridones.

Our work was inspired by the traditional synthetic routes for the preparation of the acridine and acridone derivatives. As shown in Scheme 1A, acridone 2a and acridine 2b were obtained by the cyclization reaction between the carboxyl group and C2-position of the benzene ring. According to the traditional methods, we speculated that the replacement of carbon to nitrogen in the C2-position could lead to three cyclization products, 2c, 2d and 2e. As nitrogen has higher electron density than carbon, 2d may be the main product,⁶ as seen in Scheme 1B. If both C2 and C6 positions were replaced by nitrogens, one product (2f) will be obtained with lower yields or stronger reaction conditions needed because of the reduced electron density of the nitrogen. Furthermore, if 2,2′-(2,4-pyrimidinediyldiimino)-bisbenzoic acid (5a) was synthesized,⁷ two cyclodehydration reactions would be occurred, and the novel fused azoacridone derivatives 6a might be yielded.

Results and discussion

Our study began with an examination of the importance of electron density in A ring on the cyclization reaction. As shown in Scheme 2, compound 1b with one nitrogen at 2 position and 1c with two nitrogens at 2 and 6 positions were firstly obtained,⁸ which were then reacted in PPA or POCl₃ to try to get the cyclization products. In accordance with our analysis, compound 1b reacted smoothly in PPA, and the primary product was 2d in 38% isolated yield, with no 2c detected. Under the same reaction conditions, compound 1c showed much lower reactivity and no azoacridone 2f was detected, which indicated that the electron density in the A ring played an important role in the reaction. When compound 1b was treated in POCl₃,⁹ to our surprise, no 2e or other 9-chloroacridine derivatives were detected, but we were delighted to find that azoacridone compound 2d was obtained in 85% yield, which inspired us to synthesize azoacridones using POCl₃. We then tried to use the reaction conditions to get compound 2f. Unfortunately, compound 1c did not react, and no compound 2f was detected, which might be due to the low electro-density in the pyrimidine ring. If electron-donating groups were introduced to the pyrimidine, the scaffold of compound 2f may be obtained. The intermediate 1e with aniline group at 4-position was synthesized from the commercial material 2,4-dichloropyrimidine, which was then cyclized in POCl₃. The cyclization reaction occurred and compounds 2ga and 2gb might be existed simultaneously (Scheme 2B). Interestingly, we only obtained one product in 93% yield, and the structure of which was characterized by ¹H NMR (Fig. 1), The signals of hydrogens of C5 and C6 positions of compound.

Scheme 2 Preliminary study of synthesizing azoacridones.

Fig. 1 ¹H NMR of compounds 1e and its cyclization product.

1e (Scheme 1B) are 7.33 ppm and 8.90 ppm, respectively. If the cyclization occurred between N1 and the carboxy group, the δ value of hydrogen of C6 would have a big change. Compared with ¹H NMR spectra of 1e and its cyclization product, the chemical shift of hydrogen of C5 position reduced greatly from 7.33 ppm to 6.72 ppm, while only small change was seen for δ value of hydrogen of C6 (from 8.90 ppm to 8.80 ppm), which suggested that 2ga was the only product.

The similar results were also observed when 2-aminobenzoic acid was introduced to the C4-position of pyrimidine (1f–j, Fig. 2). For compound 1f, no cyclization product 2h was obtained due to the electro-withdrawing chloro group. However, when electro-donating groups were introduced to the pyrimidine ring, such as 1g with methoxyl group and 1h–j with anilino group, the cyclization reaction occurred and compound 2i–k were obtained in good yields. The results indicated that the cyclization reaction was obviously dependent on the substitution pattern of the pyrimidine part.

Fig. 2 Electronic effects on cyclization reaction.

The above results suggested that whenever 2-aminobenzoic acid was introduced to the C2-position or C4-position of pyrimidine ring, the cyclization reaction selectively occurred at N3-position. If both hydrogens of C2 and C4 positions of pyrimidine were substituted by 2-aminobenzoic acid (5a), four cyclization products (Fig. 3) might be formed. Under the similar reaction conditions (5a in POCl₃ was stirred overnight at 100 °C), only one product 6a was obtained in high yield (85%). To optimize the reaction conditions, the temperature, time, molar ratio between 5a and POCl₃, and solvents were screened. Under these reaction conditions, no compounds 6aa–ac were detected. As shown in Table 1, the yield of 6a decreased with temperature decreased and 100 °C was found to be suitable (Table 1, entries 1–4). We next evaluated the reaction time (Table 1, entries 5–8), and found that 3 h is enough for this reaction. As POCl₃ is corrosive and extremely toxic, the reaction was further carried out in various solvents containing equivalent amount of POCl₃, and dioxane was found to be the best choice (Table 1, entries 9–14). However, the yield (64%) in dioxane is needed to be further improved. Therefore, the molar ratio between 3a and POCl₃ was investigated (Table 1, entries 15–19), and 1 : 13.2 was found to be suitable for this reaction.

Fig. 3 Predicted products from the reaction of 5a.

Table 1 Optimization of the cyclization reaction conditions^a

Entry	Temp (°C)	Time (h)	Solvent	Ratio (5a : POCl3)	Yield^b (%)
a All reactions were started with compound 5a (175 mg, 0.5 mmol) which was dissolved in 5 mL solvent. The pure product 6a was obtained after filtration without further purification, as the starting material 5a is easy to dissolve in alkaline aqueous solution and no byproducts were detected.b Isolated yield.
1	100	6	POCl3	—	91
2	80	6	POCl3	—	43
3	60	6	POCl3	—	26
4	40	6	POCl3	—	0
5	100	1	POCl3	—	51
6	100	2	POCl3	—	76
7	100	3	POCl3	—	90
8	100	12	POCl3	—	85
9	100	3	Dioxane	1 : 8.8	64
10	100	3	ClCH2CH2Cl	1 : 8.8	11
11	100	3	Toluene	1 : 8.8	31
12	100	3	Cyclohexane	1 : 8.8	0
13	100	3	Acetonitrile	1 : 8.8	0
14	100	3	Benzene	1 : 8.8	0
15	100	3	Dioxane	1 : 2.2	33
16	100	3	Dioxane	1 : 4.4	43
17	100	3	Dioxane	1 : 13.2	81
18	100	3	Dioxane	1 : 17.6	81
19	100	3	Dioxane	1 : 26.4	85

---

With the optimal reaction conditions (Table 1, entry 17), the substrate scope for the cyclization reaction was investigated. As shown in Table 2, most of the substrates examined provided moderate to good yields. For pyrimidine group, the substrates containing methyl group at C5 (5b) or C6 (5c) position showed reduced reactivity (Table 2, entries 1–3). As 5b produced higher yield (70%) than 5c (58%), the reactivity of compounds 5d–h with different electron properties at C5 position was conducted (Table 2, entries 4–7). For the substituted 5-halo-pyrimidine derivatives, their relative reactivity was in the order of aryl fluorides (5d, 81%) > aryl chlorides (5e, 74%) > aryl bromides (5f, 62%).

Table 2 The scope of POCl₃-mediated cyclization reaction^a

Entry	Compound 5		Compound 6		Yield^b (%)
	Label	Structure	Label	Structure
a Reaction conditions: 5 (0.5 mmol), POCl3 (0.6 mL) in dioxane (5 mL) at 100 °C for 3 h.b Isolated yield.c The yields were measured after the reactions were prolonged to 12 h.
1	5a		6a		81
2	5b		6b		70
3	5c		6c		58 (82^c)
4	5d		6d		81
5	5e		6e		74
6	5f		6f		62 (88^c)
7	5g			—	0
8	5h		6h		36 (77^c)
9	5i		6i		54 (91^c)
10	5j		6j		62 (85^c)
11	5k		6k		88
12	5l		6l		82
13	5m		6m		7 (84^c)
14	5n		6n		9 (87^c)
15	5o		6o		9 (67^c)
16	5p		6p		85

---

However, compound 5g with nitro group did not afford the corresponding cyclization product. The results suggested that the electron-negativity and steric hindrance in the pyrimidine ring might play an important role in the cyclization reaction activity. For substituted o-aminobenzoic acid group, the beneficial substituted position was firstly investigated (Table 2, entries 8–10), among which compound 5j with methyl group at C6 position displayed the highest reactivity. Although 5i displayed a lower yield (54%) than 5j (62%), we can obtain a series of 5-substituted-2-aminobenzoic acid commercially (Table 2, entries 11–16). Therefore, the electronic properties at C5 position in the benzene ring were examined in reactivity. High yields were observed for methoxyl and fluoryl substituted azoacridone derivatives (6k and 6l). Interestingly, when the reaction time was prolonged to 12 h, the corresponding cyclization products (6c, 6f, 6h–j, 6m–o) were also obtained in higher yields (Table 2, entries3, 6, 8–10, 13–15). The results indicated that the reactions showed broad substrate scope and good tolerance of functional groups.

In addition, the cyclization of compound 5q–5t with different substituted anthranilic acid was investigated (Scheme 3). As 5-bromo-anthranilic acid was less active than anthranilic acid (Table 2, entry 14 and entry 1), two cyclization products may be formed, and 6qb may be the main product (Fig. 4). However, the result indicated that no 6qb was detected even if the reaction conversion was less than 10%, and compound 6qa was the only product. The similar products 6r–t were obtained from the cyclization reaction of 5r–t.

Scheme 3 Cyclization reaction of compound 5q–t with asymmetrically substituted anthranilicacids^a. ^aReaction conditions: 5 (0.5 mmol), POCl₃ (0.6 mL) in dioxane (5 mL) at 100 °C.

Fig. 4 Possible cyclization reactions of 5q.

Conclusions

To summarize, we have developed a simple and efficient method for the synthesis of fused azoacridone derivatives. This protocol uses readily available inexpensive substituted 2,4-dichloropyrimidine and anthranilic acid as the starting materials, and the corresponding fused azoacridone derivatives were prepared in good yields. Investigations on further application of this reaction are in progress.

Experimental section

See ESI† for synthetic methods of compounds 1b, 1e–i, 5a–t.

The general experimental procedure for the synthesis of compounds 2d, 2ga–2k

Compound 1 (1b, 1e, 1g, 1h) (0.5 mmol) was dissolved in POCl₃ (5.0 mL), and the solution was refluxed for 6 h, which was then pooled into ice water. 20% sodium hydroxide solution was used to adjust the pH to 7–8. After stirring for 0.5 h, the precipitate was filtered, and washed with EtOH and dried to give the pure products 2d, 2ga–2k.

11H-Pyrido[2,1-b]quinazolin-11-one (2d). White powder. Yield: 84 mg, 85%. M.p. 214–215 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.82 (d, 1H, J = 6.8 Hz), 8.32 (d, 1H, J = 7.6 Hz), 7.92 (dd, 1H, J = 6.4 Hz), 7.81 (d, 1H, 8.0 Hz), 7.76 (dd, 1H, J = 6.8 Hz), 7.60 (d, 1H, J = 9.2 Hz), 8.32 (dd, 1H, J = 6.8 Hz), 7.09 (s, 1H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 158.7, 148.6, 148.0, 135.9, 135.5, 127.2, 127.1, 127.0, 126.2, 125.5, 116.2, 113.8. ESI-MS [M + H]⁺: 197.0715, found: 197.0717.

4-(Phenylamino)-6H-pyrimido[2,1-b]quinazolin-6-one (2ga). White powder. Yield: 134 mg, 93%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.38 (s, 1H), 8.80 (d, 1H, J = 7.6 Hz), 8.15 (d, 1H, J = 7.6 Hz), 7.96 (d, 1H, J = 6.4 Hz), 7.79 (dd, 1H, J = 7.4 Hz), 7.59 (d, 1H, J = 8.4 Hz), 7.43 (dd, 2H, J = 7.8 Hz), 7.35 (dd, 1H, J = 7.4 Hz), 7.16 (dd, 1H, J = 7.2 Hz), 6.72 (d, 1H, J = 7.6 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.5, 158.0, 150.8, 148.5, 139.2, 135.6, 134.5, 129.3, 127.2, 126.7, 124.4, 123.9, 121.0, 115.8, 105.0. ESI-MS [M + H]⁺: 289.1089, found: 289.1089.

1-Chloro-4-methoxy-10H-pyrimido[6,1-b]quinazolin-10-one (2i). White powder. Yield: 100 mg, 78%. M.p. 218–220 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.80 (dd, 1H, J = 8.0 Hz), 7.93 (dd, 1H, J = 8.4 Hz), 7.76 (d, 1H, J = 8.0 Hz), 7.59 (d, 1H, J = 8.0 Hz), 7.52 (s, 1H), 3.94 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 170.2, 158.9, 147.1, 146.2, 143.6, 136.2, 131.7, 127.4, 127.2, 121.7, 120.1, 57.4. ESI-MS [M + H]⁺: 262.0383, found: 262.0379.

1-(Phenylamino)-10H-pyrimido[6,1-b]quinazolin-10-one (2j). White powder. Yield: 105 mg, 73%. M.p. 183–184 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.49 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 8.15 (ddd, 1H, J = 8.0 Hz), 7.73 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 6.4 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.48 (dd, 1H, J = 7.6 Hz), 7.41 (dd, 2H, J = 8.0 Hz), 7.17 (d, 1H, J = 7.6 Hz), 6.58 (d, 1H, J = 6.4 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 164.7, 148.9, 147.9, 147.2, 138.1, 139.7, 129.3, 129.0, 125.9, 124.9, 122.3, 119.0, 109.1. ESI-MS [M + H]⁺: 289.1089, found: 289.1085.

1-((4-Chlorophenyl)amino)-10H-pyrimido[6,1-b]quinazolin-10-one (2k). Light green powder. Yield: 137 mg, 85%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.54 (s, 1H), 8.22 (d, 1H, J = 8.0 Hz), 7.88 (dd, 1H, J = 7.6 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.66 (d, 1H, J = 6.4 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.48 (dd, 1H, J = 7.6 Hz), 7.45 (d, 2H, J = 8.4 Hz), 6.60 (d, 1H, J = 6.4 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 164.60, 148.77, 148.68, 147.89, 146.91, 137.05, 136.74, 129.21, 128.44, 127.66, 126.52, 125.97, 123.79, 118.95, 109.56. ESI-MS [M + H]⁺: 323.0700, found: 323.0706.

General procedure for the synthesis of 6a–f, 6h–t

Compound 5 (0.5 mmol) was dissolved in dioxane (5.0 mL), then POCl₃ (0.6 mL) was added. After stirring for 3 h at 100 °C, the solvent was removed under reduce pressure. Water was added to the residue, and 20% sodium hydroxide solution was used to adjust the pH to 7–8. After stirring for 0.5 h, the precipitate was filtered, and washed with EtOH and dried to give the pure products 6a–f, 6h–t.

Pyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6a). White powder. Yield: 126 mg, 81%. M.p. 269–271 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.40 (d, 1H, J = 8.0 Hz), 8.23 (dd, 2H, J = 7.5 Hz), 7.95–7.87 (m, 2H), 7.69 (d, 2H, J = 7.6 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.62–7.57 (m, 2H), 6.67 (d, 1H, J = 8.0 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.2, 158.2, 146.4, 145.9, 145.7, 139.7, 136.4, 135.8, 128.9, 127.8, 127.7, 127.6, 127.5, 127.1, 121.6, 118.7, 110.4. ESI-MS [M + H]⁺: 315.0882, found: 315.0896.

6-Methylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6b). White powder. Yield: 115 mg, 70%. M.p. 258–260 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.34 (s, 1H), 8.20 (dd, 2H, J = 7.6 Hz), 7.91–7.86 (m, 2H), 7.69 (d, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 8.0 Hz), 7.59–7.54 (m, 2H), 6.67 (d, 1H, J = 8.0 Hz), 2.25 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.5, 158.0, 146.5, 145.8, 145.6, 139.9, 136.2, 135.8, 127.8, 127.6, 127.5, 127.4, 127.3, 125.4, 121.6, 118.7, 117.5. ESI-MS [M + H]⁺: 329.1039, found: 329.1044.

7-Methylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6c). White powder. Yield: 95 mg, 58%. M.p. 253–255 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.17–8.14 (m, 2H), 7.91–7.83 (m, 2H), 7.64–7.61 (m, 2H), 7.58–7.51 (m, 2H), 6.42 (s, 1H), 2.67 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 160.8, 158.9, 146.6, 146.0, 144.6, 144.5, 139.6, 136.1, 135.8, 127.6, 127.4, 127.2, 127.0, 121.3, 120.9, 110.2. ESI-MS [M + H]⁺: 329.1039, found: 329.1047.

6-Fluoropyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6d). Light brown powder. Yield: 134 mg, 81%. M.p. 252–254 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.67 (d, 1H, J = 6.4 Hz), 8.24 (dd, 2H, J = 7.4 Hz), 7.94 (dd, 2H, J = 7.6 Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 8.0 Hz), 7.67–7.62 (m, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 158.6, 157.39, 145.5, 145.2, 142.8, 141.1, 140.8, 138.6, 136.5, 136.1, 128.7, 127.8(4), 127.7(9), 127.6(9), 127.6(7), 127.4, 121.9, 118.2, 114.4, 114.0. ESI-MS [M + H]⁺: 333.0788, found: 333.0782.

6-Chloropyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6e). Light brown powder. Yield: 129 mg, 74%. M.p. 282–285 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.67 (d, 1H, J = 6.4 Hz), 8.24 (dd, 2H, J = 7.4 Hz), 7.94 (dd, 2H, J = 7.6 Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.70 (d, 1H, J = 8.0 Hz), 7.67–7.62 (m, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 158.6, 157.39, 145.5, 145.2, 142.8, 141.1, 140.8, 138.6, 136.5, 136.1, 128.7, 127.8(4), 127.7(9), 127.6(9), 127.6(7), 127.4, 121.9, 118.2, 114.4, 114.0. ESI-MS [M + H]⁺: 349.0492, found: 349.0499.

6-Bromopyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6f). Light brown powder. Yield: 122 mg, 62%. M.p. 298–300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.69 (s, 1H), 8.25–8.22 (m, 2H), 7.94–7.92 (m, 2H), 7.68 (d, 1H, J = 8.0 Hz), 7.66–7.59 (m, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.1, 157.4, 145.6, 145.2, 143.4, 139.2, 136.7, 136.1, 129.2, 128.6, 127.7, 127.6, 121.4, 118.5, 105.2. ESI-MS [M + H]⁺: 392.9987, found: 392.9979.

3,12-Dimethylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6h). Light brown powder. Yield: 62 mg, 36%. M.p. 254–256 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.34 (s, 1H), 8.08 (s, 2H), 7.46 (s, 2H), 7.39 (s, 2H), 6.62 (s, 1H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.0, 158.0, 147.4, 146.6, 146.5, 146.0, 145.8, 139.7, 129.1, 129.0, 128.8, 127.5, 127.4, 127.3, 126.8, 119.2, 116.2, 110.2, 21.9, 21.8. ESI-MS [M + H]⁺: 343.1195, found: 343.1190.

2,11-Dimethylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6i). Light brown powder. Yield: 93 mg, 54%. M.p. 291–293 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.34 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 10.0 Hz), 7.73 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.4 Hz), 6.61 (d, 1H, J = 8.4 Hz), 2.47 (s, 6H). ESI-MS [M + H]⁺: 343.1195, found: 343.1188.

1,10-Dimethylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6j). Light brown powder. Yield: 106 mg, 62%. M.p. 291–293 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.33 (d, 1H, J = 7.6 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.46 (d, 2H, J = 6.4 Hz), 7.34 (s, 2H), 7.58 (d, 1H, J = 8.0 Hz), 2.80 (s, 3H), 2.77 (s, 3H). ESI-MS [M + H]⁺: 343.1195, found: 343.1194.

2,11-Dimethoxypyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6k). Light brown powder. Yield: 165 mg, 88%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.34 (d, 1H, J = 7.6 Hz), 7.62 (s, 4H), 7.53–7.47 (m, 2H), 6.63 (d, 1H, J = 8.0 Hz), 3.92 (s, 6H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 163.5, 163.2, 155.0, 150.5, 135.3, 124.2, 117.5, 115.2, 108.5, 56.0. ESI-MS [M + H]⁺: 375.1093, found: 345.1094.

2,11-Difluoropyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6l). Light brown powder. Yield: 145 mg, 82%. M.p. 299–300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.37 (d, 1H, J = 8.0 Hz), 7.91 (s, 2H), 7.81–7.75 (m, 4H), 6.68 (d, 1H, J = 8.0 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 163.7, 162.7, 160.5, 158.9, 156.6, 150.5, 137.7, 134.9, 125.2, 125.0, 123.6, 123.4, 122.5, 121.2, 118.2, 118.1.115.6, 115.5, 112.7, 112.5, 112.3, 112.1. ESI-MS [M + H]⁺: 351.0694, found: 351.0689.

2,11-Dichloropyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6m). Light brown powder. Yield: 160 mg, 84%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.41 (d, 1H, J = 8.4 Hz), 8.18 (dd, 2H, J = 6.0 Hz), 7.97–7.92 (m, 2H), 7.71 (dd, 2H, J = 8.6 Hz), 6.71 (d, 1H, J = 8.4 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 163.6, 162.4, 161.3, 158.8, 150.5, 140.0, 137.1, 136.7, 135.3, 133.5, 127.0, 126.2, 121.8, 121.0, 118.1, 116.0. ESI-MS [M + H]⁺: 383.0102, found: 383.0087.

2,11-Dibromopyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6n). Light brown powder. Yield: 205 mg, 87%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.39 (d, 1H, J = 8.0 Hz), 8.27 (dd, 2H, J = 8.0 Hz), 8.06–8.01 (m, 2H), 7.60 (dd, 2H, J = 8.4 Hz), 6.68 (d, 1H, J = 8.0 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 163.5, 162.2, 150.4, 140.5, 138.0, 129.7, 129.3, 118.3, 116.6, 114.4. ESI-MS [M + H]⁺: 470.9092, found: 470.9100.

2,11-Diiodopyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6o). Light brown powder. Yield: 192 mg, 67%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.45 (d, 2H, J = 7.6 Hz), 8.38 (d, 1H, J = 8.0 Hz), 8.18 (dd, 2H, J = 9.4 Hz), 7.44 (dd, 2H, J = 8.4 Hz), 6.67 (d, 1H, J = 8.0 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 163.6, 162.2, 161.4, 150.5, 145.0, 143.5, 140.7, 135.2, 118.3, 116.7. ESI-MS [M + H]⁺: 566.8815, found: 566.8815.

6-Fluoro-2,11-dimethoxypyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6p). Light brown powder. Yield: 170 mg, 87%. M.p. 285–287 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.61 (d, 1H, J = 6.4 Hz), 7.40 (d, 1H, J = 8.8 Hz), 7.66–7.62 (m, 2H), 7.59 (d, 1H, J = 2.8 Hz), 7.56–7.51 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.4, 158.6, 158.5, 157.7, 143.0, 139.8, 139.1, 136.8, 129.5, 129.4, 126.0, 125.0, 122.9, 119.0, 113.6, 113.2, 108.5, 107.3, 56.37, 56.33. ESI-MS [M + H]⁺: 393.0999, found: 393.0992.

2-Bromopyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6qa). Light brown powder. Yield: 151 mg, 77%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.41 (d, 1H, J = 8.0 Hz), 8.30 (s, 1H), 8.23 (d, 1H, J = 7.6 Hz), 8.03 (d, 1H, J = 8.4 Hz), 7.93 (dd, 1H, J = 8.0 Hz), 7.68 (d, 1H, J = 8.4 Hz), 7.63–7.61 (m, 2H), 6.67 (d, 1H, J = 8.0 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 158.2, 146.9, 145.6, 145.0, 139.5, 138.6, 136.5, 129.7, 129.5, 129.4, 127.7, 127.5, 123.1, 120.0, 118.8, 110.3. ESI-MS [M + H]⁺: 392.9987, found: 392.9991.

11-Methylpyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6r). Light brown powder. Yield: 120 mg, 73%. M.p. 266–268 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.37 (d, 1H, J = 8.4 Hz), 8.19 (d, 1H, J = 7.6 Hz), 8.00 (s, 1H), 7.87 (dd, 1H, J = 7.6 Hz), 7.2 (dd, 1H, J = 8.0 Hz), 7.66 (d, 1H, J = 8.0 Hz), 7.59–7.56 (m, 2H), 6.63 (d, 1H, J = 8.0 Hz), 2.47 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 158.1, 146.4, 146.0, 143.7, 137.8, 137.5, 135.8, 129.0, 127.7, 127.6, 127.5, 127.1, 126.8, 121.6, 118.5, 110.3, 21.2. ESI-MS [M + H]⁺:329.0978, found: 329.0974.

6-Fluoro-2-methoxypyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6s). Light brown powder. Yield: 153 mg, 85%. M.p. 281–283 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.61 (d, 1H, J = 6.0 Hz), 8.23 (d, 1H, J = 7.6 Hz), 7.94 (dd, 2H), 7.74 (d, 1H, J = 8.8 Hz), 7.68–7.60 (m, 3H), 7.20 (dd, 1H, J = 8.4 Hz), 3.94 (s, 3H). ¹³C NMR (DMSO-d₆, 100 MHz) δ 159.4, 158.5, 158.0, 145.5, 139.1, 138.7, 136.5, 129.5, 127.8, 127.6, 127.4, 125.1, 122.9, 118.2, 113.5, 113.1, 108.5, 56.39. ESI-MS [M + H]⁺: 363.0893, found: 363.0885.

2-Chloropyrimido[2,1-b:4,3-b′]diquinazoline-9,16-dione (6t). Light brown powder. Yield: 142 mg, 82%. M.p. over 300 °C. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.37 (d, 1H, J = 8.0 Hz), 8.20 (d, 1H, J = 8.0 Hz), 8.16 (s, 1H), 7.95–7.89 (m, 2H), 7.70 (dd, 1H, J = 8.0 Hz), 7.59 (dd, 1H, J = 8.0 Hz), 6.70 (d, 1H, J = 8.4 Hz). ¹³C NMR (DMSO-d₆, 100 MHz) δ 146.19, 145.87, 144.53, 136.45, 135.95, 131.71, 129.84, 128.83, 127.90, 127.70, 127.22, 126.35, 121.58, 120.05, 110.94. ESI-MS [M + H]⁺: 349.0492, found: 349.0506.

Acknowledgements

The authors would like to thank the financial supports from the Ministry of Science and Technology of China (2012AA020305, 2011DFA30620), the Chinese National Natural Science Foundation (21272134 and 21372141), and Shenzhen Sci& Tech Bureau (ZDSY20120619141412872 and JCYJ20120831165730905).

Notes and references

1. (a) M. Demeunynck, F. Charmantray and A. Martelli, Curr. Pharm. Des., 2001, 7, 1703–1724; (b) W. A. Denny, Curr. Med. Chem., 2002, 9, 1655–1665; (c) M. Demeunynck, Expert Opin. Ther. Pat., 2004, 14, 55–70; (d) P. Belmont, J. Bosson, T. Godet and M. Tiano, Anti-Cancer Agents Med. Chem., 2007, 7, 139–169; (e) P. Belmont and I. Dorange, Expert Opin. Ther. Pat., 2008, 18, 1211–1224; (f) S. Neidle, FEBS J., 2010, 277, 1118–1125; (g) G. Cholewinski, K. Dzierzbicka and A. M. Kolodziejczyk, Pharmacol. Rep., 2011, 63, 305–336; (h) J. Kaur and P. Singh, Expert Opin. Ther. Pat., 2011, 21, 437–454; (i) M. R. Galdino-Pitta, M. G. R. Pitta, M. C. A. Lima, S. L. Galdino and I. R. Pitta, Mini-Rev. Med. Chem., 2013, 13, 1256–1271; (j) B. Zhang, X. Li, B. Li, C. Gao and Y. Jiang, Expert Opin. Ther. Pat., 2014, 24, 647–664.
2. (a) J. A. Seijas, M. P. Vazquez-Tato, M. M. Martinez and J. Rodriguez-Parga, Green Chem., 2002, 4, 390–391; (b) J. Zhao and R. C. Larock, J. Org. Chem., 2007, 72, 583–588; (c) A. Natrajan and D. Wen, Green Chem., 2011, 13, 913–921; (d) W. Zhou, Y. Liu, Y. Yang and G.-J. Deng, Chem. Commun., 2012, 48, 10678–10680; (e) J. Huang, C. Wan, M.-F. Xu and Q. Zhu, Eur. J. Org. Chem., 2013, 1876–1880; (f) P.-C. Huang, K. Parthasarathy and C.-H. Cheng, Chem.–Eur. J., 2013, 19, 459–463; (g) J. Yu, H. Yang, Y. Jiang and H. Fu, Chem.–Eur. J., 2013, 19, 4271–4277; (h) W. Zhou, Y. Yang, Y. Liu and G.-J. Deng, Green Chem., 2013, 15, 76–80.
3. (a) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382–2384; (b) P. E. Fanta, Synthesis-Stuttgart, 1974, 9–21; (c) J. Lindley, Tetrahedron, 1984, 40, 1433–1456; (d) R. Gujadhur, D. Venkataraman and J. T. Kintigh, Tetrahedron Lett., 2001, 42, 4791–4793; (e) A. Klapars, J. C. Antilla, X. H. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727–7729; (f) F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 5, 793–796.
4. (a) C. Gao, Y. Jiang, C. Tan, X. Zu, H. Liu and D. Cao, Bioorg. Med. Chem., 2008, 16, 8670–8675; (b) C. Gao, F. Liu, X. Luan, C. Tan, H. Liu, Y. Xie, Y. Jin and Y. Jiang, Bioorg. Med. Chem., 2010, 18, 7507–7514; (c) X. Luan, C. Gao, Q. Sun, C. Tan, H. Liu, Y. Jin and Y. Jiang, Chem. Lett., 2011, 40, 728–729; (d) X. Luan, C. Gao, N. Zhang, Y. Chen, Q. Sun, C. Tan, H. Liu, Y. Jin and Y. Jiang, Bioorg. Med. Chem., 2011, 19, 3312–3319; (e) X. Lang, L. Li, Y. Chen, Q. Sun, Q. Wu, F. Liu, C. Tan, H. Liu, C. Gao and Y. Jiang, Bioorg. Med. Chem., 2013, 21, 4170–4177.
5. (a) M. J. Deetz, J. P. Malerich, A. M. Beatty and B. D. Smith, Tetrahedron Lett., 2001, 42, 1851–1854; (b) A. Maity, S. Mondal, R. Paira, A. Hazra, S. Naskar, K. B. Sahu, P. Saha, S. Banerjee and N. B. Mondal, Tetrahedron Lett., 2011, 52, 3033–3037; (c) D. Liang, Y. He and Q. Zhu, Org. Lett., 2014, 16, 2748–2751; (d) H. Lu, Q. Yang, Y. Zhou, Y. Guo, Z. Deng, Q. Ding and Y. Peng, Org. Biomol. Chem., 2014, 12, 758–764.
6. (a) R. F. Pellon, M. L. Docampo, Z. Kunakbaeva, V. Gomez and H. Velez-Castro, Synth. Commun., 2006, 36, 481–485; (b) R. F. Pellon, A. Martin, M. L. Docampo and M. Mesa, Synth. Commun., 2006, 36, 1715–1719.
7. (a) L. B. Delvos, J.-M. Begouin and C. Gosmini, Synlett, 2011, 2325–2328; (b) H. R. Lawrence, M. P. Martin, Y. Luo, R. Pireddu, H. Yang, H. Gevariya, S. Ozcan, J.-Y. Zhu, R. Kendig, M. Rodriguez, R. Elias, J. Q. Cheng, S. M. Sebti, E. Schonbrunn and N. J. Lawrence, J. Med. Chem., 2012, 55, 7392–7416.
8. (a) Y. Liu, Y. Bai, J. Zhang, Y. Li, J. Jiao and X. Qi, Eur. J. Org. Chem., 2007, 6084–6088; (b) Q. Shen, T. Ogata and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 6586–6596.
9. I. L. Aleksanyan and L. P. Hambardzumyan, Russ. J. Org. Chem., 2013, 49, 1851–1853.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra16476h

---