Novel process to 4,4-dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines via grignard reaction

Article abstract of DOI:10.3987/COM-08-S(F)7

4,4-Dialkyl-l,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.

Full text of DOI:10.3987/COM-08-S(F)7

HETEROCYCLES, Vol. 77, No. 1, 2009
273
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 273 - 277. © The Japan Institute of Heterocyclic Chemistry
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 Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203
P.R.China; e-mail: chyang@mail.shcnc.ac.cn.
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.
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Br
Mg
R1
R1
N
R1
R1
CN
NO2
R
R
THF
+
N
H
1b-9b
1a-9a
Table 1. Reaction conditions of o-nitro phenylacetonitriles and phenylmagnesium bromide
R
H
H
R1
H
-CH2-
Centigrade(0C)
0
0
Time
2
2
Yield(%)
0
0
1
2
-78
0
-78
20
0
0
0
0
0
2
2
2
2
1.5
2
2
2
3
0
3
OMe
-CH2-
34
30
10
20
62
50
58
12
trace
trace
0
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
Me
Et
n-Bu
n-Oct
benzyl
-78
0
-78
4
3
3
9
OMe
allyl
R1
R1
R1
R1
MeO
R1
R1 MeO
Br
Mg
MeO
N
N
N
O
OMgBr
N
O
N
O
Br
N
O
Br
Mg
OMgBr
Mg
R1
R1
N
R1
R1
R1
N
MeO
R1
MeO
MeO
MgBr
H2O
N
N
N
N
H
Mg
O
MgBr
Br
OMgBr
Br
Mg
OMgBr
+
Figure 1. Possible mechanism to 4,4-dialkyl-1,4-dihydro-3-phenylcinnolines

HETEROCYCLES, Vol. 77, No. 1, 2009
275
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),
13
6.60 (dd, 1H, J = 8.5 Hz, J = 2.4Hz), 7.31 (m, 2H), 7.43 (m, 1H), 7.55 (m, 2H); C 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 =
13
2.4Hz), 6.95 (d, 1H, 2.4Hz), 7.39 (m, 2H), 7.50 (m, 1H), 7.60 (m, 2H); C 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),

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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
13
(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); C
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),
13
7.62 (m, 2H); C 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.
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