Amidines: Synthesis from o-alkenylanilines and cyclization in polyphosphoric acid

Article abstract of DOI:10.1023/A:1011346231766

Condensation of 2-[(E)-pent-3-en-2-yl]-4-, 2-[(E)-pent-2-en-2-yl]-4-, or 2-(cyclopent-1-enyl)-6-methylaniline with 1-chloro-1-(N-methylimino)-or 1-chloro-1-(N-phenylimino)ethane affords the corresponding amidines. Cyclization of the N-methylimino derivatives in polyphosphoric acid gives 3,4-dihydroquinazolines in high yields.

Full text of DOI:10.1023/A:1011346231766

Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 545—547, March, 2001
545
Amidines: synthesis from o-alkenylanilines
and cyclization in polyphosphoric acid
R. R. Gataullin,« I. S. Afon´kin, I. B. Abdrakhmanov, and G. A. Tolstikov
Institute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6066. E-mail: chemorg@anrb.ru
Condensation of 2-[(E)-pent-3-en-2-yl]-4-, 2-[(E)-pent-2-en-2-yl]-4-, or 2-(cyclopent-
1-enyl)-6-methylaniline with 1-chloro-1-(N-methylimino)- or 1-chloro-1-(N-phenyl-
imino)ethane affords the corresponding amidines. Cyclization of the N-methylimino deriva-
tives in polyphosphoric acid gives 3,4-dihydroquinazolines in high yields.
Key words: 2-(alk-2-enyl)anilines, 2-(alk-1-enyl)anilines, amidines, intramolecular cy-
clization, 3,4-dihydroquinazolines.
Scheme 1
Quinazolines, which exhibit a variety of biological
properties, are of noticeably increasing interest in recent
years.1—12 The methods for preparing compounds of this
class mostly involve derivatives of anthranilic and
aminocinnamic acids, 3,1-benzooxazines, or 2-amino-
methylanilines. The use of derivatives of anthranilic
acid1—5 or 3,1-benzooxazines6—8 affords quinazolin-4-
ones, while cyclization of N´-phenyl-N´´-acylureas in
polyphosphoric acid (PPA) gives quinazolin-2-ones.13
3,4-Dihydroquinazolines are usually synthesized from
2-aminomethylanilines9,10 or by addition of alkyl isocy-
anates to organic 2-aminocinnamates.11
NH2
NH2
a
1
2
b
b
2
1
N
NHMe
N
NHMe
3″
1″
In continuation of our work on heterocyclization of
alkenylarylamines, we synthesized amidines from
o-alkenylanilines and studied their cyclization into
3,4-dihydro-1,3-quinazolines under the action of PPA.
Thus, condensation of 2-[(E)-pent-3-en-2-yl]-4- (1),14
2-[(E)-pent-2-en-2-yl]-4- (2),15 and 2-(cyclopent-1-
enyl)-6-methylaniline (3)16 with N-methylimino-1-
chloroethane17 in benzene at 80 °C lead to amidines
4—6 in high yields (Scheme 1). Semiempirical quan-
tum-chemical calculations (AM1) suggest18 a Z-con-
figuration of their double bond, because such a structure
is more stable (by ∼13 kJ) than the trans-arrangement of
the phenyl and methylamino groups.
4″
2″
1´
6´
5´
2´
3´
4´
4
5
c
c
R1 R2
R3
R5
4a
4
5
8
3 N
2
6
7
1
8a
N
R4
c
7, 8, 10
When kept in PPA at 150—160 °C for 4 h, amidines
4 and 5 undergo cyclization into quinazoline 7, while
amidine 6 gives quinazoline 8. The cyclization of amidine
4 into quinazoline 7 starts with a shift of the double
bond toward the aromatic ring to give a vinyl derivative
5 (identified in the reaction mixture by GLC). An
analogous shift of the double bond is well known when
amine 1 itself reacts with PPA at 100—140 °C. The
reaction occurs in several steps to give, through
alkenylaniline 2 as a first intermediate,19 a mixture of
2-ethyl-2-methylindoline and 1-amino-4,4-dimethyl-
indane.20
NH2
N
NHR
b
6: R = Me, 9: R = Ph
3
R1
Me
R2
Pr
R3
R4
R5
7
Me
Me
Ph
H
Me
H
8
10
(CH2)4
(CH2)4
Me
Me
H
Replacement of the MeNH group in the amidine by
the PhNH group (when passing from compound 6 to 9)
Reagents and conditions: a. KOH, 300 °C; b. MeC(Cl)NMe
or MeC(Cl)NPh, C6H6, 80 °C; c. PPA, 150—160 °C.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 522—524, March, 2001.
1066-5285/01/5003-545 $25.00 © 2001 Plenum Publishing Corporation

546
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Gataullin et al.
H(5´)); 6.9 (s, 1 H, H(3´)). 13C NMR (CDCl3), δ: 14.2
(C(5″)); 16.3 (C(2)); 17.8 (C(4″)); 20.8 (C(1″)); 21.8 (4 CH3Ar);
28.5 (NMe); 122.5 (C(3´)); 127.8 (C(5´)); 129.8 (C(3″)); 131.2
(C(2″)); 131.2 (C(6´)); 136.1 (C(4´)); 138.3 (C(2´)); 141.0
(C(1´)); 156.1 (C(1)).
1-Methylamino-1-[2´-methyl-6´-(cyclopent-1-enyl)phenyl-
(Z)-imino]ethane (6). Yield 4.3 ã (94%), amorphous mass.
Found (%): C, 78.60; H, 8.53; N, 11.94. C15H20N2. Calcu-
lated (%): C, 78.89; H, 8.83; N, 12.27. IR, ν/cm–1: 3220 (NH).
1H NMR (CDCl3), δ: 1.4 (s, 3 H, Me); 1.9 (m, 2 H, CH2); 2.0
(s, 3 H, Me); 2.3—2.7 (m, 4 H, 2 CH2); 2.8 (s, 3 H, Me); 4.9
(s, 1 H, NH); 5.9 (s, 1 H, =CH); 6.9 (t, 1 H, H(6´),
J = 7.5 Hz); 7.0 (d, 1 H, H(3´)); 7.1 (d, 1 H, H(5´)). 13C NMR
(CDCl3), δ: 16.9 (C(2)); 18.1 (C(2´)Me); 23.7 (C(4″)); 27.7
(NMe); 33.2 (C(3″)); 35.5 (C(5″)); 121.1 (C(4´)); 126.1 (C(2″));
129.2 (C(6´)); 127.9 (C(5´)); 128.2 (C(3´)); 142.1 (C(1″));
147.8 (C(1´)); 155.2 (C(1)).
1-Phenylamino-1-[2´-methyl-6´-(cyclopent-1-enyl)phenyl-
(Z)-imino]ethane (9). Yield 5.4 ã (93%), amorphous mass.
Found (%): C, 82.40; H, 7.31; N, 9.29. C20H22N2. Calcu-
lated (%): C, 82.72; H, 7.63; N, 9.65. IR, ν/cm–1: 3270 (NH).
1H NMR (CDCl3), δ: 1.6 (s, 3 H, Me); 1.7—2.7 (m, 6 H,
3 CH2); 2.1 (s, 3 H, Me); 5.9 (s, 1 H, H(2″)); 6.7—7.4 (m, 8 H,
Ar); 9.4 (br.s, 1 H, NH). 13C NMR (CDCl3), δ: 16.4 (C(2));
18.2 (Me); 23.4 (C(4″)); 33.1 (C(3″)); 35.4 (C(5″)); 123.0,
125.4, 125.8, 126.3, 128.6, 128.8, 129.0, 130.3, 132.9, 133.3,
137.8, 140.6 (C(1″), C(2″), C arom.); 160.2 (C(1)).
Cyclization of amidines in PPA. A corresponding amidine
4—6 or 9 (2 mmol) was mixed with PPA (1.5 g) and heated at
150—160 °C for 4 h (the reaction course was monitored by
GLC). The reaction mixture was cooled to 20 °C, and a
concentrated solution of Na2CO3 was added to alkaline reac-
tion. The product was extracted with ethyl acetate (3½10 mL).
The extract was dried with Na2SO4 and concentrated in vacuo,
and the residue was purified by column chromatography on
silica gel (3 g) in CHCl3 as an eluent.
decreases the yield of quinazoline from 70% (in the case
of product 8) to 40% (10), owing to the formation of by-
products.
The structures of the compounds synthesized were
determined by spectroscopic methods and confirmed by
elemental analysis data. The IR spectra of amidines 4—6
–1
and 9 contain an absorption band at 3200 cm corre-
sponding to the NH groups. Their 13C NMR spectra
show a singlet at δ 156—160 for the N=C—N fragment.
The 13C NMR spectra of quinazolines 7, 8, and 10 have
a characteristic singlet at δ 61—68 for the C(4) atom. In
addition, the 13C NMR spectra of spiroheterocycles 8
and 10 exhibit two triplets at δ 23—26 and 38—40 for
the C(2´), C(5´) and C(3´), C(4´) atoms, respectively.
Thus, the reactions of o-alkenylanilines 1—3 with
N-methyl- or N-phenylimino-1-chloroethane easily yield
the corresponding amidines, which undergo PPA-pro-
moted cyclization into 3,4-dihydroquinazolines.
Experimental
1
H (300.13 MHz) and 13C NMR (75.47 MHz) spectra were
recorded on a Bruker AM-300 instrument with Me4Si as the
internal standard. IR spectra were recorded on a UR-20 instru-
ment. The purity of the products was checked by TLC using
Silufol UV-254 plates in C6H6—MeOH (19 : 1) as an eluent.
17
Synthesis of amidines 4—6 and 9
(general procedure).
N-Methylacetamide or acetanilide (0.02 mol) was added slowly,
in small portions, at 0 °C to a solution of PCl5 (4.8 g,
2.3 mmol) in 20 mL of CHCl3 or C6H6. After the reaction was
completed, a corresponding alkenylaniline 1—3 (0.02 mol) in
10 mL of CHCl3 or C6H6 was added. The reaction mixture was
refluxed for 2.5 h, cooled to 20 °C, and washed with 10%
NaOH. The organic phase was separated, and the products were
extracted with CHCl3 (2½10 mL) from the aqueous layer. The
combined extracts were dried with Na2SO4 and concentrated in
vacuo. Amidines 4, 6, and 9 were isolated by column chroma-
tography on silica gel (10 g) in CHCl3. Amidine 5 was recrystal-
lized from hexane.
1-Methylamino-1-[4´-methyl-2´-(pent-3″-(E)-en-2″-yl)phe-
nyl-(Z)-imino]ethane (4). Yield 4.3 g (93%); amorphous mass.
Found (%): C, 77.89; H, 9.33; N, 11.80. C15H22N2. Calcu-
lated (%): C, 78.21; H, 9.63; N, 12.16. IR, ν/cm–1: 3216 (NH).
1H NMR (CDCl3), δ: 1.2 (d, 3 H, C(1″)H3, J = 7.0 Hz); 1.6 (d,
3 H, C(5″)H3, J = 6.1 Hz); 1.7, 2.3, 2.9 (all s, each 3 H, Me);
3.7 (m, 1 H, (H″)); 4.4 (s, 1 H, NH); 5.4 (dq, 1 H, H(3″),
JH(3′′),Me = 6.0 Hz, JH(3′′),H(2′′) = 15.4 Hz); 5.5 (dq, 1 H, H(2″),
JH(2′′),Me = 7.4 Hz); 6.6 (d, 1 H, H(6´), J = 7.1 Hz); 6.8 (s,
1 H, H(3´)); 6.9 (d, 1 H, H(5´)). 13C NMR (CDCl3), δ: 17.4,
17.9, 20.0, 21.0, 28.5 (5 Me); 37.4 (C(2″)); 122.3, 122.7, 126.8,
127.3, 131.8, 136.9, 138.0, 142.3 (C(3″), C(4″), C arom.);
156.0 (C(1)).
4-Propyl-2,3,4,6-tetramethyl-3,4-dihydro-1,3-quinazoline
(7). Yield 70%, Rf 0.4 (C6H6—MeOH, 19 : 1). Found (%):
C, 77.93; H, 9.29; N, 11.85. C15H22N2. Calculated (%): C,
1
78.22; H, 9.62; N, 12.16. H NMR (CDCl3), δ: 0.8 (t, 3 H,
Me, J = 7.3 Hz); 1.3—1.9 (m, 4 H, 2 CH2); 1.5, 2.2, 2.8, 2.9
(all s, each 3 H, Me); 6.7—6.9 (m, 3 H, Ar). 13C NMR
(CDCl3), δ: 13.9 (C(3´)); 17.5 (C(2´)); 21.0, 23.2, 28.7, 31.3
(4 Me); 43.2 (C(1´)); 61.2 (C(4)); 122.5 (C(8)); 124.6 (C(7));
127.3 (C(4a)); 132.8 (C(6)); 138.9 (C(8a)); 156.4 (C(2)).
2,3,8-Trimethyl-4-spirocyclopentane-3,4-dihydro-1,3-quin-
azoline (8). Yield 70%, Rf 0.4 (C6H6—MeOH, 19 : 1).
Found (%): C, 78.53; H, 8.69; N, 11.97. C15H20N2. Calcu-
1
lated (%): C, 78.91; H, 8.82; N, 12.27. H NMR (CDCl3),
δ: 1.5—2.3 (m, 8 H, 4 CH2); 2.1, 2.3 (both s, each 3 H, Me);
2.9 (s, 3 H, MeN); 6.9—7.9 (m, 3 H, Ar). 13C NMR (CDCl3),
δ: 17.8 (CH3C(2)); 24.3 (CH3C(8)); 26.2 (C(3´), C(4´)); 32.7
(MeN); 40.8 (C(2´), C(5´)); 66.3 (C(4)); 121.6 (C(7)); 123.2
(C(5)); 128.8 (C(6)); 130.8 (C(8)); 131.6 (C(4a)); 139.8 (C(8a));
156.4 (C(2)).
2,8-Dimethyl-3-phenyl-4-spirocyclopentane-3,4-dihydro-
1,3-quinazoline (10). Yield 40%, Rf 0.35 (C6H6—MeOH, 19 : 1).
Found (%): C, 82.31; H, 7.35; N, 9.22. C20H22N2. Calcu-
lated (%): C, 82.72; H, 7.63; N, 9.65. 1H NMR (CDCl3),
δ: 1.5—2.3 (m, 8 H, 4 CH2); 1.9, 2.5 (both s, each 3 H, Me);
6.6—7.5 (m, 8 H, Ar). 13C NMR (CDCl3), δ: 17.7 (CH3C(2));
24.4 (CH3C(8)); 23.3 (C(3´), C(4´)); 38.3 (C(2´), C(5´)); 63.3
(C(4)); 105.6, 122.1, 123.2, 123.7, 125.0, 126.7, 129.7, 130.5,
134.3, 141.2 (C arom.); 154.8 (C(2)).
1-Methylamino-1-[4´-methyl-2´-(pent-2″-(E)-en-2″-yl)phe-
nyl-(Z)-imino]ethane (5). Yield 4.5 ã (97%), m.p. 95—96 °C
(hexane). Found (%): C, 78.02; H, 9.21; N, 11.83. C15H22N2.
Calculated (%): C, 78.21; H, 9.63; N, 12.16. IR, ν/cm–1: 3210
(NH). 1H NMR (CDCl3), δ: 1.0 (t, 3 H, Me, J = 7.6 Hz); 1.6,
1.9 (both s, each 3 H, Me); 2.1 (m, 2 H, CH2); 2.2, 2.8 (both s,
each 3 H, Me); 4.9 (s, 1 H, NH); 5.4 (t, 1 H, C=CH,
J = 7.1 Hz); 6.6 (d, 1 H, H(6´), J = 7.8 Hz); 6.8 (d, 1 H,

Amidines: synthesis and cyclization
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
547
12. US Pat. 5 214 114, 1994.
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