HETEROCYCLES

Paper | Special issue | Vol. 77, No. 1, 2009, pp. 273-277
Received, 27th March, 2008, Accepted, 2nd June, 2008, Published online, 5th June, 2008.
DOI: 10.3987/COM-08-S(F)7

■ Novel Process to 4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines via Grignard Reaction

Dongdong Chen, Chunhao Yang,* Yuyuan Xie, and Jian Ding

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai 201203, China

Abstract

4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines were obtained from 2-(5-methoxy-2-nitrophenyl)acetonitrile analogues and phenylmagnesium bromide by one step, and the possible mechanism was speculated.

Cinnolines have been used as Liver-X receptor modulators, cell proliferation inhibitors, antitumor agents， and anti-inflammatory agents recently.1 H. S. Lowrie synthesized 3-phenylcinnoline-4-carboxylic acids via Stolle-Becker cinnoline synthesis.2 Yoshio Matsubara synthesized cyanocinnolines from aromatic hydrazones and TCNE,3 and 4(1H)-cinnolones from 4-cyancinnolines,4 as well as some other processes to synthesize cinnolines.5-8 To the best of our knowledge, there are very limited reports describing the preparation of dihydrocinnolines.9,10
In our estrogen receptor β ligands research, we found a new method to synthesis 4,4-dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnoline with the biphenyl as the byproduct from 2-(5-methoxy-2-nitrophenyl)acetonitrile analogues with the phenylmagnesium bromide in THF solution at ice bath, When we used alkylmagnesium bromide or benzylmagnesium bromide instead of phenylmagnesium bromide, we didn’t get the object 1,4-dihydro-3-substituted-cinnoline.
The results were summarized in Table 1. It appears that several important factors are involved in this reaction. 1) One opposite methoxy to the nitro group on the benzene ring is important, which is supposed as an electron donor that makes nitro’s eletrophilic ability weaker than the nitrile. 2) The dialkyl substitutes of the o-nitro phenylacetonitrile are important, which enlarge the steric hindrance to reduce the free rotation of nitrile to force the reaction between the nitrile and nitro groups. And the bulky groups are preferable. 3) A proper temperature is also important to get a higher yield.

We also evaluated their anti-cancer activities. The cytotoxicity of these cinnolines was conveniently determined by the conventional MTT assay against HL-60 cell line and sulforhodamine B (SRB)-assay against A-549 (human lung carcinoma). Compound 6b, 7b and 8b showed moderate inhibition to HL-60 cell line.

EXPERIMENTAL
GENERAL PROCEDURE
To the solution of phenylmagneium bromide (8 mmol) in THF (20 mL) in ice bath, the solution of 1-(5-methoxy-2-nitrophenyl)cyclopropanecarbonitrile (3a) (218mg, 1 mmol) in THF (20 mL) was added drop by drop at stirring for 5-10 min. The mixture was stirred for additional 2 h and then poured into water (20 mL). The organic phase was separated, and the water phase was extracted with EtOAc (20 mL ×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. Purification of the residue by column chromatography (silica gel CH2Cl2 : MeOH 15:1) and get (3b) 90 mg, yield 34%.
6-Methoxy-3-phenyl-1H-spiro[cinnoline-4,1’-cyclopropane] (3b)
1H NMR (CD3OD) δH: 1.66 (sym, 4H), 3.69 (s, 3H), 6.45 (d, 1H, J = 8.6Hz), 6.54 (d, 1H, J = 2.4Hz), 6.60 (dd, 1H, J = 8.5 Hz, J = 2.4Hz), 7.31 (m, 2H), 7.43 (m, 1H), 7.55 (m, 2H); 13C NMR (CD3OD)δC: 21.592, 22.272, 55.722, 105.518, 107.769, 110.738, 124.348, 127.867, 130.039, 133.022, 135.550, 138.897, 155.243, 169.753; IR 3293.9 (NH), 2933.2 (CH3), 1650.8 (C = N), 1598.7 (Ph), 1484.9 (Ph), 1388.5, 1292.1, 1201.5, 1033.7, 757.9, 698.7 (Ph); MS (EI): 57(10) 77(11) 107(30) 221(18.8) 249(16) 263(46) 264(100) 265(18).
1,4-Dihydro-6-methoxy-4,4-dimethyl-3-phenylcinnoline (4b)
1H NMR (CD3OD) δH:1.50 (s, 6H), 3.75 (s, 3H), 6.45 (d, 1H, J = 8.6Hz), 6.70 (dd, 1H, J = 8.5Hz, J = 2.4Hz), 6.95 (d, 1H, 2.4Hz), 7.39 (m, 2H), 7.50 (m, 1H), 7.60 (m, 2H); 13C NMR (CD3OD) δC: 27.462, 47.227, 56.782, 110.427, 111.279, 113.966, 129.241, 130.284, 132.019, 137.002, 139.163, 139.383, 158.206, 178.236; IR 3423.1 (NH), 2973.7, 2927.5, 1650.8 (C = N), 1598.7 (Ph), 1496.5(Ph), 1432.9, 1384.7, 1278.6. 1201.5, 1027.9, 808.1, 696.2; MS 77(8) 224(10) 236(12) 250(10) 251(85) 265(58) 266(100) 267(20); HRMS calculated for C17H18ON2: 266.1419 and found [M-H]+ 265.1345, M+ 266.1408, [M+H]+ 267.1424.
4,4-Diethyl-1,4-dihydro-6-methoxy-3-phenylcinnoline (5b)
1H NMR (CD3OD) δH: 0.7 (t, 3H, J = 7.4Hz), 1.95 (q, 2H, J = 7.3Hz), 3.75 (s, 3H), 6.45 (d, 1H, J = 8.5Hz), 6.70 (dd, 1H, J = 8.4Hz, J = 2.4Hz), 6.85 (d, 1H, 2.5Hz), 7.31 (m, 2H), 7.48 (m, 1H), 7.60 (m, 2H); 13CNMR (CD3OD) δC: 9.563, 34.462, 56.750, 57.174, 109.717, 111.470, 113.848, 129.318, 130.097, 131.987, 134.925, 137.375, 141.765, 158.011, 175.645; IR 3293.9 (NH), 2962.2, 2929.4, 1650.8 (C = N), 1598.7 (Ph), 1498.4 (Ph), 1272.8. 1201.5, 804.2, 694.3; MS 235(11) 249(12) 250(15) 251(99) 252(17) 265(69) 266(100) 267(17) 294 (75) 295(15); HRMS calculated for C19H22ON2: 294.1732, found M+294.1733, [M+H]+ 295.1753.
4,4-Dibutyl-1,4-dihydro-6-methoxy-3-phenylcinnoline (6b)
1H NMR (CD3OD) δH: 0.7 (m, 8H), 1.2 (m, 6H), 1.9 (m, 4H), 3.75 (s, 3H), 6.45 (d, 1H, J = 8.8Hz), 6.50 (dd, 1H, J = 8.5Hz, J = 2.4Hz), 6.85 (d, 1H, J = 2.3Hz), 7.30 (m, 2H), 7.46 (m, 1H), 7.60 (m, 2H); 13C NMR (CD3OD) δC: 14.677, 24.237, 27.912, 41.129, 56.851, 111.007, 111.417, 114.227, 128.960, 131.123, 132.394, 135.755, 135.978, 140.555, 158.978, 176.380; IR 3293.9 (NH), 2929.4, 2871.5, 1648.9 (C = N), 1598.7(Ph), 1484.9(Ph), 1376.9, 1276.7, 1199.5, 802.3, 696.2, 609.4; MS 251(100) 252(18) 265(12) 294(49) 307(43) 350(27)351(7); HRMS calculated for C23H30ON2: 350.2358, found M+ 350.2353 [M+H]+ 351.2393.
1,4-Dihydro-6-methoxy-4,4-dioctyl-3-phenylcinnoline (7b)
1H NMR (CD3OD) δH: 0.85 (t, 6H, J = 6.8Hz), 1.2 (m, 24H), 1.85 (t, 4H, J = 8.2Hz), 3.75 (s, 3H), 6.47 (d, 1H, J = 8.8Hz), 6.75 (dd. 1H, J = 8.5Hz, J = 2.7Hz), 6.9 (d, 1H, J = 2.5Hz), 7.31 (m, 2H, 7.50 (m, 1H), 7.62 (m, 2H); 13C NMR (CD3OD) δC: 14.913, 24.203, 25.719, 30.742, 30.806, 31.116, 33.406, 41.708, 56.231, 56.763, 110.135, 110.447, 113.829, 129.152, 130.405, 132.117, 135.810, 136.876, 141.152, 158.293, 176.226; IR 3291.9 (NH), 2960.2, 2925.5, 2854.2, 1650.8 (C = N), 1600.7 (Ph), 1484.9 (Ph), 1261.2, 1031.7, 800.3, 696.2; MS 59(12) 97(10) 251(100) 252(18) 294(23) 327(30) 350(48) 363(40) 462(17) 463(5); HRMS calculated for C31H47ON2: 462.3610, found M+ 462.3616 [M+H]+ 463.3682.
4,4-Dibenzyl-1,4-dihydro-6-methoxy-3-phenylcinnoline (8b)
1H NMR (CD3OD) δH: 3.4 (sym, 4H) 3.80 (s, 3H), 5.86 (d, 1H, J = 8.4Hz), 6.46 (m, 2H), 6.55 (dd, 1H, J = 8.6Hz, J = 2.6Hz), 6.96 (m, 4H), 7.08 (m, 6H), 7.2 (d, 1H, J = 2.6Hz), 7.35 (m, 3H); IR 3432.7 (NH), 2919.7, 2850.3, 1645.0 (C = N), 1602.6 (Ph), 1496.5 (Ph), 1384.7, 1209.2, 1029.8, 698.1; MS 59(7) 295(5) 327(100) 328(24) 418(33) 419(10); HRMS calculated for C29H26ON2: 428.2045, found M+ 418.2056 [M+H]+419.2078.

ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China 20502028 to C.H.Y.

This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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