Iodocyclization of N-(2-nitrophenyl)- and N-phenyl-N′-[2-(alk-1-enyl)phenyl]ethanimidamides

Article abstract of DOI:10.1070/mc2001v011n05abeh001490

The action of iodine on N-(2-nitrophenyl)- or N-phenyl-N′-[2-(alk-1-enyl)phenyl]ethanimidamides obtained by the condensation of 2-(cyclopent-1-enyl)-6-methylaniline with N-(1-chloroethylidene)aniline or N-(1-chloroethylidene)-2-nitroaniline results in corresponding spiro(3,4-dihydroquinazoline)-4,1′-(2′-iodocyclopentane) in good yields, but the analoguous reaction with 4-methyl-2-(1-methylbut-1-enyl)aniline leads to an N-[(2,3-dihydro-1H-indol-1-yl)ethylidene]aniline derivative.

Full text of DOI:10.1070/mc2001v011n05abeh001490

, 2001, 11(5), 201–202
Iodocyclization of N-(2-nitrophenyl)- and
N-phenyl-N'-[2-(alk-1-enyl)phenyl]ethanimidamides
Rail R. Gataullin, Ivan S. Afon’kin,* Akhnaf A. Fatykhov, Leonid V. Spirikhin and Il’dus B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa, Russian Federation.
Fax: +7 3472 35 6066; e-mail: chemorg@anrb.ru
10.1070/MC2001v011n05ABEH001490
The action of iodine on N-(2-nitrophenyl)- or N-phenyl-N'-[2-(alk-1-enyl)phenyl]ethanimidamides obtained by the condensation
of 2-(cyclopent-1-enyl)-6-methylaniline with N-(1-chloroethylidene)aniline or N-(1-chloroethylidene)-2-nitroaniline results in cor-
responding spiro(3,4-dihydroquinazoline)-4,1'-(2'-iodocyclopentane) in good yields, but the analoguous reaction with 4-methyl-2-
(1-methylbut-1-enyl)aniline leads to an N-[(2,3-dihydro-1H-indol-1-yl)ethylidene]aniline derivative.
In the past few years, quinazolines and their 3,4-dihydro deriva-
Me Me
NH2 Me Me
tives obtained from 2-aminomethylanilines1,2 or by the addition
of alkylisocyanates to 2-aminocinnamic acid esters3 have at-
tracted the attention of scientists due to their biological activities.
Continuing our work4 on the heterocyclization of alkenyl-
arylethanimidamides synthesised from 2-(alk-1-enyl)anilines, we
now report on the interaction with I2. Therefore, the condensa-
tion of 2-(cyclopent-1-enyl)-6-methylaniline 15 with N-(1-chloro-
ethylidene)aniline 2 or N-(1-chloroethylidene)-2-nitroaniline 36
in benzene at 80 °C gave ethanimidamides 46 or 5† in high yield
(Scheme 1). The interaction of ethanimidamides 4 and 5 with
iodine lead to spiro(dihydroquinazoline)cyclopentane 6 or 7.
Using the Overhauser effect to determine the orientation of the
H(2') proton in the cyclopentane fragment of a model of 7
suggested that the reaction proceeds via the formation of onium
complex A.
Me
PhN=C(Cl)Me
NH
Me
Me
PhN
8
9
I2
Me Me
CH2
I
CH2
Me
Me
I
– H+
H
N
NH
Me
NH
Me
PhN
PhN
Me
12
PhN
Me
In contrast, the interaction of 8 with iodine obtained from
amine 97 and acetanilide lead to basic reaction product indoline
10 (Scheme 2). The following reaction mechanism is proposed.
Carbocation 11 resulting from the reaction of iodine with 8
loses a proton to give amidine 12. By intramolecular displace-
ment of iodide, ion 12 cyclises to 10.‡
11
10
Scheme 2
axial orientation of proton H(2'). The 13C NMR spectra of com-
pounds 6 and 7, detected in the JMOD regime, show a peak in the
The structure of all new compounds was determined by spectral
methods and elemental analysis. In the 1H NMR spectra of com-
pounds 6 and 7, a signal of the H(2') proton is observed at 4.3 ppm
as a double doublet with spin–spin coupling constants at 8.2–9.0
and 9.6–11.0 Hz. The high values of these constants support the
†
General methods. 1H and 13C NMR spectra were recorded using a
Bruker AM-300 spectrometer at 300.13 and 75.47 MHz (with Me4Si as
an internal standard). IR spectra were measured on a UR-20 instrument.
Mass spectra were measured on an MX 1320 mass spectrometer (EI,
70 eV). The purity of the reaction products was checked by TCL on
Silufol UV-254 plates.
NH2
N=C(Me)Cl
X
General procedure for the synthesis of N-(2-cyclopent-1-en-1-yl-6-
methylphenyl)-N'-(2-nitrophenyl)ethanimidamide 5 and N-{4-methyl-2-
[(E)-1-methylbut-1-enyl]phenyl}-N'-phenylethanimidamide 8. The cor-
responding acetanilide (0.02 mol) was added slowly in small portions to
a stirred cooled solution of phosphorus pentachloride (4.8 g, 0.023 mol)
in chloroform or benzene (20 ml). After completion of reaction, a solu-
tion of alkenylaniline 1 or 9 (0.02 mol) in chloroform or benzene (10 ml)
was added slowly. The resulting reaction mixture was refluxed for 2.5 h.
After cooling, it was treated with a 10% sodium hydroxide solution,
extracted with chloroform or benzene and dried (MgSO4). The solvent
was evaporated, and the crude residue was purified by column chromato-
graphy using silica gel to give ethanimidamide 5 or was extracted with
hot hexane to give ethanimidamide 8.
Me
benzene
80 °C
1
2 X = H
3 X = NO2
Me
X
I
I2, Na2CO3,
CHCl3
HN
N
N
Me
X
20 °C
NH
Me
1
5: yield 91%, yellow glassy mass. H NMR (CDCl3) d: 1.8–2.2 (m,
Me
2H, CH2), 2.3 (s, 3H, Me), 2.5 (s, 3H, Me), 2.7 (m, 2H, CH2), 2.9 (m,
2H, CH2), 6.2 (s, 1H, H-2''), 7.0–7.7 (m, 5H, Ar), 8.3 (d, 1H, H-6–
PhNO2, J 8.0 Hz), 9.7 (d, 1H, H-3–PhNO2, J 6.5 Hz), 10.2 (s, 1H, NH).
13C NMR (CDCl3) d: 18.3 (C-2), 19.2 [C(2')–Me], 23.3 [C(4'')], 33.3
[C(3'')], 35.1 [C(5'')], 120.4, 121.2, 122.3, 125.4, 126.1, 127.6, 128.0,
128.5, 128.6, 134.7, 135.7, 137.8, 141.7, 145.6 [CAr, C(1''), C(2'')],
151.4 [C(1)]. IR, n/cm–1: 3270 (NH). Found (%): C, 71.28; H, 6.32; N,
12.11. Calc. for C20H21N3O2 (%): C, 71.62; H, 6.71; N, 12.53.
4 X = H
A
5 X = NO2
Ha
3
He
Ha
2
I
X
4
5
8
N3 4a
1
6
7
8: yield 95%, Rf 0.2 (C6H6–EtOAc, 2:1). H NMR (CDCl3) d: 1.0 (t,
2
8a
1
3H, Me, J 7.5 Hz), 1.9 (m, 2H, CH2), 2.0, 2.1, 2.4 (3s, 3×3H, 3Me), 5.6
(t, H-3', J 6.9 Hz), 7.0 (s, 1H, H-3), 7.1–7.4 (m, 7H, Ar), 7.6 (s, 1H,
NH). 13C NMR (CDCl3) d: 13.9, 17.0, 20.4, 24.3 (4Me), 22.3 [C(3')],
121.1 [C(6)], 127.9 [C(5)], 128.5 [C(2')], 130.7 [C(3)], 132.1 [C(2)],
133.2 [C(4)], 133.4 [C(1')], 145.2 [C(1)], 151.1 (N=C–N), 122.4, 127.7,
128.5, 130.7 (C–Ph). IR, n/cm–1: 3230 (NH). Found (%): C, 82.00; H,
8.07; N, 9.34. Calc. for C20H24N2 (%): C, 82.15; H, 8.27; N, 9.58.
Me
N
Me
6 X = H
7 X = NO2
Scheme 1
– 201 –

, 2001, 11(5), 201–202
aliphatic region, a quaternary carbon atom C(4) peak is observed
at 71.5 ppm and a cyclopentane C(2') peak, at 34.0 and 35.9 ppm.
The structure of compound 10 is supported by elemental analy-
aliphatic region, the five peaks observed are correlated using the
method of a pulse sequence of J-modulated spin echo. Three of
these signals correspond to carbon atoms of methyl groups, one
to a methylene carbon atom of ethyl group, and that at low field
(73.6 ppm) to the carbon atom C(2). There are 13 aromatic and
olefinic peaks, where the carbon atom of the amidine group
resonates at 155.0 ppm. The calculations on increments of sub-
stituents testify that these signals correspond to the given struc-
ture. The mass spectrum of compound 10 showed the presence
of a molecular ion at m/z 290, as expected.
Thus, the reaction path of the iodocyclization of N-[2-(alk-1-
enyl)phenyl]ethanimidamides depends on the nature of alkenyl
radical; thus, the derivatives of N-[2-(cyclopent-1-enyl)phenyl]-
ethanimidamide gave corresponding spiro(3,4-dihydroquinazoline)-
4,1'-(2'-iodocyclopentane), but N-phenyl-N'-[2-(1-methylbut-1-
enyl)phenyl]ethanimidamide gave an N-[(2,3-dihydro-1H-indol-
1-yl)ethylidene]aniline derivative.
1
sis and spectral data. In the H NMR spectrum, non-equivalent
alkene protons are observed at 5.2 and 5.5 ppm as two one-
proton singlets, (spin–spin coupling constant is 0–2 Hz8). A peak
corresponding to the H(2) proton is observed as a double
doublet at 4.2 ppm (J1 5.9 Hz, J2 11.3 Hz). The two-proton
multiplet peaks of the methylene group appear at 1.3–1.9 ppm
and a three-proton triplet of the methyl group at 0.6 ppm (J 7.3 Hz)
corresponds to the ethyl fragment. Moreover, two three-proton
singlet peaks at 2.2 and 2.5 ppm correspond to the other two
methyl groups. The 13C NMR data support this structure. In the
‡
General procedure for the synthesis of spiro(2,8-dimethyl-3-phenyl-
3,4-dihydroquinazoline)-4,1'-(2'-iodocyclopentane) 6, spiro[2,8-dimethyl-
3-(2-nitrophenyl)-3,4-dihydroquinazoline]-4,1'-(2'-iodocyclopentane) 7
and N-[(2-ethyl-5-methyl-3-methylene-2,3-dihydro-1H-indol-1-yl)ethyli-
dene]aniline 10. A mixture of ethanimidamide 4, 5 or 8 (1 mmol),
iodine (0.51 g, 2 mmol) and sodium carbonate (1.1 g, 10 mmol) in chloro-
form (7 ml) was stirred for 24 h at 20 °C. The progress of the reaction
was monitored by TLC (CCl4 as an eluent). The reaction mixture was
diluted with chloroform (30 ml), washed with a sodium thiosulfate solu-
tion (2×30 ml) and then with water (10 ml). The combined organic phases
were dried (MgSO4), and the solvent was evaporated in vacuo. The residue
was purified by column chromatography using silica gel (eluent: C6H6–
EtOAc, 4:1) to give product 6; the recrystallization from benzene gave
product 7; column chromatography using silica gel (eluent: C6H6–MeOH,
15:1) gave product 10.
References
1 M. A. Arozome, T. Kondo and Y. Watanabe, J. Org. Chem., 1993, 58,
310.
2 V. A. Savel’ev and V. A. Loskutov, Khim. Geterotsikl. Soedin., 1991, 791
[Chem. Heterocycl. Compd. (Engl. Transl.), 1991, 27, 621].
3 P. Molina, E. Aller and A. Lorenzo, Synthesis, 1998, 283.
4 R. R. Gataullin, T. V. Kazhanova, F. F. Minnigulov, A. A. Fatykhov, L. V.
Spirikhin and I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2000,
1789 (Russ. Chem. Bull., 2000, 49, 1769).
5 R. R. Gataullin, I. S. Afon’kin, I. V. Pavlova, I. B. Abdrakhmanov and
G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1999, 398 (Russ. Chem.
Bull., 1999, 48, 396).
1
6: yield 93%, amorphous solid, Rf 0.5 (C6H6–EtOAc, 2:1). H NMR
(CDCl3) d: 1.2–2.3 (m, 6H, 3CH2), 2.0, 2.5 (2s, 2×3H, 2Me), 4.3 (dd,
1H, H-2', J1 9.0 Hz, J2 9.6 Hz), 6.8–7.5 (m, 7H, Ar). 13C NMR (CDCl3)
d: 17.8, 24.8 (2Me), 23.2 [C(4')], 32.8 [C(5')], 34.0 [C(2')], 38.2 [C(3')],
71.5 [C(4)], 123.2, 125.2, 126.6, 128.3, 128.7, 130.1, 130.7, 130.8,
138.6, 138.9 (CAr), 155.8 [C(2)]. Found (%): C, 57.39; H, 4.76; I, 29.99;
N, 6.34. Calc. for C20H21IN2 (%): C, 57.70; H, 5.09; I, 30.48; N, 6.73.
7: yield 95%, mp 125–127 °C, Rf 0.4 (C6H6–EtOAc, 2:1). 1H NMR
(CDCl3) d: 1.3–2.3 (m, 6H, 3CH2), 2.0 (s, 3H, Me), 2.5 (s, 3H, Me), 4.3
(dd, 1H, H-2', J1 8.2 Hz, J2 11.0 Hz), 6.7–7.9 (m, 7H, Ar). 13C NMR
(CDCl3) d: 17.5 [C(8')H3], 23.1 [C(4')], 24.9 [C(2')H3], 31.6 [C(5')],
33.1 [C(3')], 35.9 [C(2')], 71.5 [C(4)], 120.6 [C(7)], 123.6 [C(5)], 124.3
[C(6)], 125.9 [C(8)], 128.4 [C(4a)], 129.8 [C(8a)], 132.2, 133.1, 133.2,
139.6, 148.6 (CAr), 153.0 [C(2)]. Found (%): C, 51.69; H, 4.16; I, 27.06;
N, 8.84. Calc. for C20H20IN3O2 (%): C, 52.07; H, 4.57; I, 27.51; N, 9.11.
6 R. R. Gataullin, I. S. Afon’kin, I. B. Abdrakhmanov and G. A. Tolstikov,
Izv. Akad. Nauk, Ser. Khim., 2001, 522 (Russ. Chem. Bull., 2001, 50, 545).
7 R. R. Gataullin, I. S. Afon’kin, A. A. Fatykhov, L. V. Spirihin, E. V.
Tal’vinskiy and I. B. Abdrakhmanov, Izv. Akad. Nauk, Ser. Khim., 2001,
633 (Russ. Chem. Bull., 2001, 50, 659).
8 B. I. Ionin, B. A. Ershov and A. I. Kol’tsov, YaMR-spektroskopiya v orga-
nicheskoi khimii (NMR Spectroscopy in Organic Chemistry), Khimiya,
Leningrad, 1983 (in Russian).
1
10: yield 62%, mp 94–96 °C (Et2O). H NMR (CDCl3) d: 0.6 (t, 3H,
Me, J 7.29 Hz), 1.3–1.9 (m, 2H, CH2), 2,27, 2.40 (s, 3H, Me), 4.2 (dd,
1H, H-2', J1 5.90 Hz, J2 11.34 Hz), 5.2 (s, 1H, H2C=), 5.5 (s, 1H, H2C=),
7.1–7.6 (m, 8H, Ar). 13C NMR (CDCl3) d: 10.1, 20.5, 25.1 (3Me), 25.0
(CH2), 73.6 [C(2')], 115.5 (H2C=C), 125.7, 126.0, 127.0, 128.1, 128.3,
129.1, 130.1, 134.6, 136.1, 142.7, 145.3, 155.0 (H2C=C, CAr, N–C=N).
MS, m/z: 290 [M]+, 275 [M – Me]+, 261 [M – Et]+, 77 [M – Ph]+. Found
(%): C, 82.31; H, 7.25; N, 9.21. Calc. for C12H17N (%); C, 82.72; H,
7.64; N, 9.65.
Received: 28th June 2001; Com. 01/1816
– 202 –