Synthesis of cinnoline 1-oxides by the reaction of ortho- fluoronitrobenzenes with enediamines

Article abstract of DOI:10.1007/s11172-012-0123-5

Reaction of α-carbonylacetamidines existing in the enediamine tautomeric form with the substituted ortho-fluoronitrobenzene afforded products of the replacement of the fluorine by the α-C atom of amidine. The latter underwent cyclization into cinnoline 1-

Full text of DOI:10.1007/s11172-012-0123-5

Russian Chemical Bulletin, International Edition, Vol. 61, No. 4, pp. 877—880, April, 2012
877
Synthesis of cinnoline 1ꢀoxides by the reaction of
orthoꢀfluoronitrobenzenes with enediamines
A. V. Vypolzov, D. V. Dar´in, and P. S. Lobanov
Saint Petersburg State University,
26 Universitetsky prosp., 198504 Saint Petersburg, Petrodvorets, Russian Federation.
Eꢀmail: pslob@mail.ru
Reaction of ꢀcarbonylacetamidines existing in the enediamine tautomeric form with the
substituted orthoꢀfluoronitrobenzene afforded products of the replacement of the fluorine by
the ꢀC atom of amidine. The latter underwent cyclization into cinnoline 1ꢀoxides on treatꢀ
ment with sodium hydride.
Key words: orthoꢀfluoronitrobenzenes, ꢀcarbonylacetamidines, enediamines, cyclization,
cinnoline 1ꢀoxides.
Scheme 1
Cyclocondensation of aromatic and heteroaromatic diꢀ
electrophiles with ꢀcarbonylacetamidines, which in the
form of free bases are predominantly exist as the enediꢀ
amine tautomers, is a convenient synthetic approach toꢀ
wards fused azines (isoquinolines, naphthyridines, and
pyridopyrimidines). Aldehydes,1—3 ketones,4 esters,5 and
nitriles4,6 bearing a mobile halogen atom at the ortho posiꢀ
tion can play a role of dielectrophiles. In these reactions,
ꢀcarbon atom of enediamines (amidine) replaces the
halogen atom of aromatic compound and one of the nitroꢀ
gen atoms bounds to the carbonyl (or nitrile) Cꢀatom of
aromatic dielectrophile.
The present work was undertaken in the framework of
the investigation of the synthetic potential of this reaction
and extension of a series of fused azines. The aim of the
work was to involve orthoꢀhalonitroarenes in the reactions
with enediamines (amidines) using an aromatic nitro group
as electrophile and development of synthetic procedures.
The ability of the aromatic nitro group to play a role of
heteroanalog of the carbonyl group in intramolecular conꢀ
densations has been known for a long time.7 In recent
years, this strategy is widely used for the synthesis of 1,2,4ꢀ
benzotriazine 1ꢀoxides exhibiting antitumor activity,8—10
cinnoline Nꢀoxides,11—13 and fused cinnolines.14,15
In our preliminary report,16 it was shown that reacꢀ
tions of 1ꢀflouroꢀ2,4ꢀdinitrobenzene (1a) with enediꢀ
amines (amidines) 2a,b at ambient temperature gave staꢀ
ble products 3a,b arising from the replacement of the fluoꢀ
rine atom by the ꢀC atom of enediamines. Compounds
3a,b on treatment with sodium hydride at ambient temꢀ
perature underwent cyclization into cinnoline 1ꢀoxides
4a,b (Scheme 1, Table 1). The aim of the present work was
to involve the other orthoꢀfluoronitrobenzenes in this reacꢀ
tion and synthesize various substituted cinnoline 1ꢀoxides.
1: R = NO2 (a), CO2Me (b), CN (c), H (d)
2: X = OEt (a), Ph (b), N(CH2)4 (c)
Comꢀ
R
X
Comꢀ
pound
3e, 4e
3f
R
X
pound
3a, 4a
3b, 4b
3c, 4c
3d, 4d
NO2
NO2
NO2 N(CH2)4
CO2Me OEt
OEt
Ph
CN OEt
H
H
OEt
OH
4f
Among enediamines (amidines) studied recently in our
group, pyrrolidide of 3,3ꢀdiaminoacrylic acid 2c exhibits
the highest nucleophilic reactivity towards aromatic diꢀ
electrophiles (see Ref. 4). When this compound was used,
we also able to achieve the highest yields.
Indeed, enediamine 2c reacted with 1ꢀfluoroꢀ2,4ꢀdiniꢀ
trobenzene faster as compared with enediamines 2a,b. The
synthesis of 3c was completed within 1 h, while synthesis
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 0873—0876, April, 2012.
1066ꢀ5285/12/6104ꢀ0877 © 2012 Springer Science+Business Media, Inc.

878
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
Vypolzov et al.
Table 1. Synthetic conditions and yields of comꢀ
pounds 3, 4, and 6
of enediamine 3f and compound 3f underwent ring cloꢀ
sure under conditions similar to those used for its analogs
with two electronꢀwithdrawing groups. It is of note that in
the case of 3f, cyclization was accompanied by hydrolysis
of the ester to give the known acid 4f (see Ref. 12).
Publication12 describes the synthesis of cinnolineꢀ4ꢀ
carboxylic acid 1ꢀoxides related to compounds 4 employꢀ
ing similar strategy. Treatment of orthoꢀnitrophenyl cyanoꢀ
acetate with hydroxylamine gave aminoisooxazolone, the
latter was subjected to ring closure involving the nitro and
amino groups and subsequent ring opening of the fiveꢀ
membered ring. The present work is the development of
this study. The proposed by us synthetic procedure toꢀ
wards cinnolines 4 is more simple then described12 and
allows performance of the cyclization key step in a much
milder conditions (at 20 C instead of 100 C).
Compound
/h
T/C
Yield (%)
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
20
20
1
24
12
5
24
24
24
24
2
20
20
20
20
20
130
20
20
20
20
20
20
20
91
90
85
86
92
53
68
56
31
23
90
52
68
24
1
6
The attempt to synthesize Nꢀoxide 7 from nitropyrimꢀ
idine 5 failed. Pyrimidine 5 reacted with enediamine 2a
much faster as compared with nitrobenzenes 1a—d afꢀ
fording arylated enediamine 6 in good yield (Scheme 2).
However, treatment of the latter with sodium hydride led
to resinification and no products were isolated from the
reaction mixture. This failure can apparently be explained
by the replacement of the second chlorine atom in pyrimꢀ
idine or by instability of the pyrimidine ring under nucleoꢀ
philic conditions. It is also possible that the second subꢀ
stituent in the ortho position to the nitro group is unfavorꢀ
able for the desired reaction. An example of similar negaꢀ
tive effect of the orthoꢀsubstituent on the cyclization have
been described.7
of compounds 3a,b required about 20 h. In spite of this,
cyclization of arylated enediamine 3c into cinnoline
1ꢀoxide 4c proceeded in low yield, our attempts to imꢀ
prove the yield of the reaction failed. Thus, comparison of
the reactions of 1ꢀfluoroꢀ2,4ꢀdinitrobenzene with enediꢀ
amines 2a—c (see Table 1) indicated that ethyl 3,3ꢀdiꢀ
aminoacrylate (2a) provided the best preparative results.
As an electronꢀwithdrawing substituent, this diamine conꢀ
tains ethoxycarbonyl group, which is the most interesting
from the viewpoint of further cinnoline functionalization.
Therefore, we studied the reactions of the other orthoꢀ
fluoronitrobenzenes on the example of ethyl 3,3ꢀdiamiꢀ
noacrylate.
Fluorobenzenes 1b—d reacted with enediamine 2a simꢀ
ilarly to 1ꢀfluoroꢀ2,4ꢀdinitrobenzene. Compound 1b bearꢀ
ing the methoxycarbonyl moiety in the aromatic ring readiꢀ
ly reacted with enediamine to give compound 3d in high
yield. However, the ring closure of arylated enediamine 3d
to give cinnoline 4d was accompanied by formation of
large amounts of unidentified side products. Therefore,
the yield of cinnoline 4d was only 23%. Reaction of nitrile
1c with enediamine 2a is proceeded smoothly affording
arylated enediamine 3e, which unexpectedly easy (within
2 h at ambient temperature instead of 24 h for the other
cases) underwent cyclization into cinnoline 4e. Both these
reactions proceeded in high yields and pure target cinnoꢀ
line 4e can easily be isolated from the reaction mixture.
Thus, this reaction sequence is versatile and effective
synthetic route towards cinnoline 4e with advanced funcꢀ
tionality; this compound is a potentially useful starting
material for the further syntheses. As expected, orthoꢀ
fluoronitrobenzene 1d bearing only one electronꢀwithꢀ
drawing substituent reacted with 3,3ꢀdiaminoacylate much
slower in respect to the other aromatic compounds under
consideration. This reaction proceeded readily only at
130 C. However, the absence of the second electronꢀwithꢀ
drawing group did not virtually affect the rate of cyclization
Scheme 2
Experimental
1
H and 13C NMR spectra were run on a Bruker DPX 300
instrument in DMSOꢀd6 at working frequencies of 300 (1H) and
75 MHz (13C). Elemental analyses were performed on a Hewlettꢀ

Cinnolines synthesis from oꢀfluoronitrobenzenes
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
879
Packard HPꢀ185B C,H,Nꢀanalyzer. High performance mass
spectra were obtained on a Brucker micrOTOF instrument.
Cinnolines 4a,b were synthesized by the known procedure.16
Arylated enediamines 3c—e (general procedure). A solution
of the aromatic compound (9 mmol) and enediamine (11 mmol)
in anhydrous DMF (10 mL) was kept at ambient temperature;
the reaction time is given in Table 1.
3,3ꢀDiaminoꢀ2ꢀ(2,4ꢀdinitrophenyl)ꢀ1ꢀ(pyrrolidinꢀ1ꢀyl)propꢀ
2ꢀeneꢀ1ꢀone (3c). After completion of the reaction, the solvent
was removed in vacuo at ambient temperature. To the residue,
a solution of sodium hydrogen carbonate (500 mg) in water
(25 mL) was kept at 5 C for 3 h, the crystals formed were filtered
off and dried in vacuo, m.p. 146—148 C. 1H NMR, : 1.68
(t, 4 H, N(CH2CH2)2, J = 6.2 Hz); 3.10 (t, 4 H, N(CH2CH2)2,
J = 6.2 Hz); 6.92 (s, 4 H, 2NH2); 7.52 (d, 1 H, H(6), J = 9.0 Hz);
7.99 (dd, 1 H, H(5), J = 9.0 Hz, J = 3.0 Hz); 8.44 (d, 1 H, H(3),
J = 3.0 Hz). 13C NMR, : 25.85; 47.47; 86.56; 123.14; 125.74;
132.06; 138.68; 143.49; 144.13; 161.67; 169.98. MS (ESIꢀTOF),
found: m/z 322.1175 [M + 1]+; C13H15N5O5; calculated: m/z
322.1125.
Ethyl 3,3ꢀdiaminoꢀ2ꢀ(4ꢀmethoxycarbonylꢀ2ꢀnitrophenyl)ꢀ
acrylate (3d). After completion of the reaction, the reaction mixꢀ
ture was poured in water (30 mL), the crystals formed were
filtered off and the product was recrystallized from isopropyl
alcohol, m.p. 182—184 C. 1H NMR, : 0.93 (t, 3 H, Me,
J = 6.9 Hz); 3.77 (m, 2 H, CH2); 3.89 (s, 3 H, OMe); 4.3—7.3
(s, 4 H, 2 NH2); 7.50 (d, 1 H, H(6), J = 8.0 Hz); 8.02 (dd, 1 H,
H(5), J = 8.0 Hz, J = 2.2 Hz); 8.26 (d, 1 H, H(3), J = 2.2 Hz).
13C NMR, : 15.01; 53.35; 58.30; 74.85; 125.34; 127.96; 133.01;
136.62; 138.28; 151.32; 161.50; 165.74; 167.17. Found (%):
C, 50.29; H, 4.62; N, 13.59. C13H15N3O6. Calculated (%):
C, 50.49; H, 4.89; N, 13.59.
Ethyl 3,3ꢀdiaminoꢀ2ꢀ(4ꢀcyanoꢀ2ꢀnitrophenyl)acrylate (3e).
After completion of the reaction, the reaction mixture was poured
in water (30 mL), the crystals formed were filtered off and the
product was recrystallized from MeCN, m.p. 228—230 C.
1H NMR, : 0.95 (t, 3 H, Me, J = 7.2 Hz); 3.77 (q, 2 H, CH2,
J = 7.2 Hz); 4.0—7.3 (s, 4 H, 2 NH2); 7.52 (d, 1 H, H(6),
J = 8.0 Hz); 7.92 (dd, 1 H, H(5), J = 8.0 Hz, J = 2.0 Hz); 8.34
(d, 1 H, H(3), J = 2.0 Hz). 13C NMR, : 15.01; 58.40; 74.65;
109.11; 118.50; 128.73; 135.95; 137.18; 138.49; 151.55; 161.59;
166.96. Found (%): C, 52.12; H, 4.23; N, 20.01. C12H12N4O4.
Calculated (%): C, 52.17; H, 4.38; N, 20.28.
mixture was stirred at ambient temperature for 1 h and diluted
with water. The crystals formed were filtered off and dried on
air. The product was purified by chromatography (silica gel,
elution with ethyl acetate—hexane (1 : 1)), m.p. 139—141 C.
1H NMR, : 1.08 (t, 3 H, Me, J = 7.0 Hz); 3.85 (q, 2 H, CH2,
J = 7.0 Hz); 6.0—8.7 (br.s, 4 H, 2 NH2); 8.72 (s, 1 H, (H)).
13C NMR, : 14.81; 59.15; 77.78; 140.08, 151.82; 158.78;
160.64; 162.69; 167.79. Found (%): C, 37.61; H, 3.68; N, 24.45.
C9H10N5O4Cl. Calculated (%): C, 37.58; H, 3.50; N, 24.35.
Cinnolines 4c—f (general procedure). To a 0 C solution of
arylated diamine 3 (2 mmol) in anhydrous DMF (5 mL), sodium
hydride (60% dispersion in mineral oil, 2.4 mmol) was added.
The reaction mixture was stirred at ambient temperature; the
reaction time is given in Table 1.
3ꢀAminoꢀ7ꢀnitroꢀ4ꢀ(pyrrolidineꢀ1ꢀcarbonyl)cinnoline 1ꢀoxide
(4c). After completion of the reaction, the solvent was removed
in vacuo at ambient temperature. The residue was neutralized
with aqueous AcOH, the crystals formed were filtered off. The
product was purified by chromatography (silica gel, elution
with dichloromethane—ethanol (10 : 1)), m.p. 238—240 C.
1H NMR, : 1.85 (m, 4 H, N(CH2CH2)2); 3.11 (m, 1 H,
N(CH2CH2)2); 3.34 (m, 1 H, N(CH2CH2)2); 3.57 (m, 2 H,
N(CH2CH2)2); 7.24 (s, 2 H, NH2); 7.62 (d, 1 H, H(5),
J = 9.5 Hz); 8.28 (dd, 1 H, H(6), J = 9.5 Hz, J = 2.2 Hz); 8.94
(d, 1 H, H(8), J = 2.2 Hz). 13C NMR, : 24.83; 26.19; 46.36;
47.24; 102.75; 119.05; 125.86; 126.68; 131.46; 135.35; 144.29;
153.85; 162.73. Found (%): C, 51.49; H, 4.32; N, 23.09.
C13H13N5O4. Calculated (%): C, 52.22; H, 4.57; N, 22.69.
3ꢀAminoꢀ4ꢀethoxycarbonylꢀ7ꢀ(methoxycarbonyl)cinnoline
1ꢀoxide (4d). After completion of the reaction, the reaction mixꢀ
ture was poured in water and neutralized with aqueous AcOH,
the crystals formed were filtered off. The product was purified
by chromatography (silica gel, elution with dichloromethꢀ
1
ane—ethanol (10 : 1)), m.p. 189 C. H NMR, : 1.39 (t, 3 H,
Me, J = 7.0 Hz); 3.90 (s, 3 H, OCH3); 4.41 (q, 2 H, CH2,
J = 7.0 Hz); 7.93 (s, 2 H, NH2); 8.05 (d, 1 H, H(6), J = 8.8 Hz);
8.55 (d, 1 H, H(5), J = 8.8 Hz); 8.72 (s, 1 H, H(8)). 13C NMR,
: 14.93; 53.37; 62.15; 90.45, 123.68; 125.96; 126.30; 132.86;
133.58; 136.21; 158.10; 165.69; 166.51. Found (%): C, 53.61;
H, 4.50; N, 14.43. C13H13N3O5. Calculated (%): C, 54.26;
H, 4.70; N, 13.88.
3ꢀAminoꢀ7ꢀcyanoꢀ4ꢀ(ethoxycarbonyl)cinnoline 1ꢀoxide (4e).
After completion of the reaction, the reaction mixture was poured
in water and neutralized with aqueous AcOH, the crystals formed
were filtered off. The product was recrystallized from MeCN,
Ethyl 3,3ꢀdiaminoꢀ2ꢀ(2ꢀnitrophenyl)acrylate (3f). A solution
of orthoꢀfluoronitrobenzene (0.99 g, 7 mmol) and enediamine 2a
(1.37 g, 10.5 mmol) in anhydrous DMF (10 mL) was heated at
130 C for 5 h and the solvent was removed in vacuo. The prodꢀ
uct was purified by column chromatography (silica gel, elution
with ethyl acetate—hexane (1 : 1)), m.p. 149—151 C. 1H NMR,
: 0.92 (t, 3 H, Me, J = 7.2 Hz); 3.80 (m, 2 H, CH2); 5.53 (s, 2 H,
NH2); 5.75 (s, 2 H, NH2); 7.32 (dd, 1 H, H(6), J = 8.5 Hz,
J = 1.5 Hz); 7.37 (dt, 1 H, H(4), J = 8.5 Hz, J = 1.5 Hz); 7.54
(dt, 1 H, H(5), J = 8.5 Hz, J = 1.5 Hz); 7.80 (dd, 1 H, H(3),
J = 8.5 Hz, J = 1.5 Hz). 13C NMR, : 14.54; 57.41; 74.09;
123.99; 126.92; 131.89; 132.51; 135.48; 151.43; 160.71; 167.08.
Found (%): C, 52.54; H, 5.26; N, 16.59. C11H13N3O4. Calculatꢀ
ed (%): C, 52.59; H, 5.22; N, 16.72.
1
m.p. 215—217 C. H NMR, : 1.39 (t, 3 H, Me, J = 6.5 Hz);
4.41 (q, 2 H, CH2, J = 6.5 Hz); 7.95 (dd, 1 H, H(6), J = 9.0 Hz,
J = 2.0 Hz); 8.03 (s, 2 H, NH2); 8.60 (d, 1 H, H(5), J = 9.0 Hz);
8.69 (d, 1 H, H(8), J = 2.0 Hz). 13C NMR, : 14.96; 62.25;
90.46; 107.66; 118.74; 126.70; 127.79; 133.39; 134.83; 135.97;
158.33; 166.32. MS (ESIꢀTOF), found: m/z 259.0848 [M + 1]+;
C12H10N4O3; calculated: m/z 259.0826.
3ꢀAminoꢀ4ꢀcarboxycinnoline 1ꢀoxide (4f). After completion
of the reaction, the reaction mixture was poured in water and
neutralized with aqueous AcOH, the crystals formed were filꢀ
tered off. The product was recrystallized from MeCN, m.p.
1
214—215 C (cf. Ref. 12: 215 C). H NMR, : 7.40 (t, 1 H,
Ethyl 3,3ꢀdiaminoꢀ2ꢀ(6ꢀchloroꢀ5ꢀnitropyrimidinꢀ4ꢀyl)acrylꢀ
ate (6). To a solution of 4,6ꢀdichloroꢀ5ꢀnitropyrimidine (5) (1.00 g,
5.15 mmol) in anhydrous DMF, enediamine 2a (0.78 g, 6 mmol)
and potassium carbonate (0.85 g, 6.18 mmol) were added. The
H(6), J = 8.0 Hz); 7.72 (m, 3 H, H(7) + NH2, J = 8.0 Hz); 8.29
(d, 1 H, H(5), J = 8.7 Hz); 8.71 (d, 1 H, H(8), J = 8.7 Hz).
13C NMR, : 91.44; 121.58; 125.83; 126.22; 134.03; 134.16;
134.25; 157.53; 168.89.

880
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Received November 22, 2011;
in revised form January 10, 2012