Design, synthesis and anticancer activity of functionalized spiro-quinolines with barbituric and thiobarbituric acids

Investigation of the [1,5]-hydride shift as a route to nitro-Mannich cyclisations

“…The known 2-aminobenzaldehydes were synthesised by the literature procedure based on the work of Rabong, 3 involving the SNAr reaction between the requisite fluorobenzaldehydes and amines to give the known precursor benzaldehydes to nitroalkenes 1, 3 3, 16 6, 4 9, 23 10, 24 12, 25 13, 25 14, 26 15, 27 and 16. 28 General procedure B for the Pd catalysed synthesis of aminobenzaldehydes.…”

“…A 2-bromoaryl aldehyde (1 equivalent) was added to a suspension/solution of Cs2CO3 (1.4 equivalents), Pd(OAc)2 (0.01 equivalents) and (±)BINAP (0.03 equivalents) in PhMe (10 mL per mmol). The reaction mixture was stirred at rt for 5 min before a secondary amine (1.1 equivalents) was added and the resulting mixture heated to 90 °C (heating block) for 18 h. Following cooling to rt, the solvent was removed in vacuo and the crude product was purified by column chromatography to give the known precursor benzaldehydes to nitroalkenes 11, 24 17, 29 and 19. 30 General Procedure C for the Synthesis of Nitroalkenes.…”

“…The requisite aldehyde 24 (340 mg, 1.64 mmol), prepared by General procedure B, was subjected to General procedure C and gave after purification by column chromatography (10% EtOAc/hexane), 11 (260 mg, 63%) as a light red crystalline solid: mp 80 -82 °C; IR υmax (neat) 3098, 2952, 2912, 2878, 2831, 1624, 1596, 1505 cm -1 ; 1 (12). The requisite aldehyde 25 (14).…”

“…(CH), 130.1 (CH), 128.3 (CH), 121.7 (C), 118.1 (CH), 114.4 (CH), 111.7 (CH), 85.8 (CH), 55.4 (CH3), 51.2 (CH2), 46.4 (CH), 39.3 (CH3); HRMS (ES) [M+2H-OCH3] + Calcd for C16H17N2O2 269.1290 Found: 269.1294 4.3.7. 1-Butyl-3-nitro-2-propyl-1,2,3,4-tetrahydroquinoline(24). The nitroalkene 14 (83 mg, 0.30 mmol) was subjected to General procedure D and after purification by column chromatography (0-2% EtOAc/hexane) gave diastereomerically pure 24 (61 mg, 74%) as a yellow oil: IR υmax (neat) 3036, 2954, 292, 2868, 1601, 1575, 1544, 1498 cm -1 ; 1 H NMR (600 MHz, CDCl3) δ 7.10 (1H, t, J = 7.8 Hz), 7.07 (1H, d, J = 7.3 Hz), 6.68 (1H, td, J = 7.4, 0.8 Hz), 6.58 (1H, d, J = 8.3 Hz), 4.75 (1H, m), 4.04 (1H, m), 3.52 (1H, d, J = 18.1 Hz), 3.43 (1H, ddd, J = 14.6, 9.7, 5.0 Hz), 3.12 (1H, dd, J = 18.1, 5.6 Hz), 2.99 (1H, ddd, J = 14.7, 9.8, 6.4 Hz), 1.60 (2H, ddd, J = 10.2, 6.8, 2.7 Hz), 1.55 -1.34 (4H, m), 1.33 -1.25 (2H, m), 0.97 (3H, td, J = 7.2, 2.6 Hz), 0.93 (3H, t, J = 7.4 Hz); 13 C NMR (150 MHz, CDCl3) δ 142.5 (C), 129.2 (CH), 127.7 (CH), 117.0 (C), 116.7 (CH), 111.9 (CH), 81.1 (CH), 60.8 (CH), 50.9 (CH2), 34.4 (CH2), 29.8 (CH2), 26.2 (CH2), 20.2 (CH2), 19.4 (CH2), 14.2 (CH3), 14.1 (CH3); Calcd for C16H25N2O2 277.19160 Found: 277.19169.…”

Synthesis and Reactivity of 3′,5′‐Dichloro‐1H‐spiro(quinazoline‐2,4′‐[1,2,6]thiadiazin)‐4(3H)‐ones

“…More recently, the degradation of tetrachlorothiadiazine 4 with phosphines, BnEt 3 NCl, or reducing metal conditions revealed the unexpected forma- tion of the spirocyclic perchloro-9-thia- 1,5,8,10-tetraazaspiro[5.5]undeca -1,4,7,10-tetraene (11) (Figure 2). [19] Spirocyclic heterocycles are useful in medicinal chemistry and examples include barbituric acids such as spiroquinoline 12 investigated as an anticancer agent [20] and dihydropyrazole 13 investigated as a hypnotic agent [21] (Figure 2). Spirocycle 11 has numerous sites of reactivity, but its chemistry to date has been limited to its transformation to pyrimidine 14 upon treatment with BnEt 3 NCl (Scheme 2).…”