Methyl (Z)-2-[(benzyloxycarbonyl)amino]-3-dimethyl-aminopropenoate in the synthesis of heterocyclic systems. Synthesis of (benzyloxycarbonyl)amino substituted fused pyrimidinones

Article abstract of DOI:10.1135/cccc19990177

Methyl (Z)-2-[(benzyloxycarbonyl)amino]-3-dimethylaminopropenoate (1) was used as a reagent for preparation of 3-[(benzyloxycarbonyl)amino] substituted 4H-pyrido[1,2-a]pyrimidin-4-ones 17-21, 4H-pyrimido[1,2-b]pyridazin-4-ones 22 and 23, 5H-[1,2,4]triazolo[2,3-a]-pyrimidin-5-one 24, 5H-thiazolo[3,2-a]pyrimidin-5-one 25, and 4H-pyrazino[1,2-a]pyrimidin-4-one 26. Removal of the benzyloxycarbonyl group by catalytical transfer hydrogenation with Pd/C in the presence of cyclohexene is selective to give 3-amino-4H-pyrido[1,2-a]-pyrimidin-4-ones 27-30 in 85-92% yields, or with hydrogen bromide in acetic acid to give 3-amino-4H-pyrimido[1,2-b]pyridazin-4-one (31) and 6-amino-5H-thiazolo[3,2-a]pyrimidin-5-one (32) in 80% yields.

Full text of DOI:10.1135/cccc19990177

Synthesis of Heterocyclic Systems
177
METHYL (Z)-2-[(BENZYLOXYCARBONYL)AMINO]-3-DIMETHYL-
AMINOPROPENOATE IN THE SYNTHESIS OF HETEROCYCLIC
SYSTEMS. SYNTHESIS OF (BENZYLOXYCARBONYL)AMINO
SUBSTITUTED FUSED PYRIMIDINONES
a
a,
b
Renata TOPLAK , Jurij SVETE *, Simona GOLIČ GRDADOLNIK
a1,
and Branko STANOVNIK
*
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,
P.O. Box 537, 1001 Ljubljana, Slovenia; e-mail: branko.stanovnik@uni-lj.si
LO1, Department of NMR and Molecular Modeling, National Institute of Chemistry,
Hajdrihova 19, P.O. Box 3430, 1001 Ljubljana, Slovenia; e-mail: simona.golic@ki.si
1
b
Received August 11, 1998
Accepted Novem ber 12, 1998
Dedicated to the memory of the late Dr Miroslav Protiva.
Meth yl (Z)-2-[(ben zyloxycarbon yl)am in o]-3-dim eth ylam in opropen oate (1) was used as a re-
agen t for preparation of 3-[(ben zyloxycarbon yl)am in o] substituted 4H-pyrido[1,2-a]pyrim i-
din -4-on es 17–21, 4H-pyrim ido[1,2-b]pyridazin -4-on es 22 an d 23, 5H-[1,2,4]triazolo[2,3-a]-
pyrim idin -5-on e 24, 5H-th iazolo[3,2-a]pyrim idin -5-on e 25, an d 4H-pyrazin o[1,2-a]pyrim i-
din -4-on e 26. Rem oval of th e ben zyloxycarbon yl group by catalytical tran sfer h ydrogen ation
with Pd/C in th e presen ce of cycloh exen e is selective to give 3-am in o-4H-pyrido[1,2-a]-
pyrim idin -4-on es 27–30 in 85–92% yields, or with h ydrogen brom ide in acetic acid to give
3-am in o-4H-pyrim ido[1,2-b]pyridazin -4-on e (31) an d 6-am in o-5H-th iazolo[3,2-a]pyrim idin -
5-on e (32) in 80% yields.
Key w ord s: Pyrido[1,2-a]pyrim idin es; Pyrim ido[1,2-b]pyridazin es; 1,2,4-Triazolo[2,3-a]py-
rim idin es; Th iazolo[3,2-a]pyrim idin es; Pyrazin o[1,2-a]pyrim idin es; Fused h eterocycles.
Syn th esis of various derivatives of pyran -2-on es an d fused pyran -2-on es h as
attracted great in terest, sin ce m an y of th em h ave been foun d to be
nonpeptide HIV protease inhibitors1 and 3-am ino-4H-pyrido[1,2-a]pyrim idin-
4-on es h ave been recen tly studied as fluorescen t probes for h ypoxic cells in
solid tum ors2,3
.
Recently, we have prepared a series of substituted alkyl 2-[(2,2-disubstituted
eth en yl)am in o]-3-dim eth ylam in opropen oates as versatile reagen ts in th e
syn th esis of m an y h eterocyclic system s, such as in dolizin es, quin olizin es,
pyran on es, ben zo- an d n aph th opyran on es, pyran opyrim idin es, azolo- an d
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178
Toplak et al.:
azin opyrim idin es, with a m on osubstituted am in o group in th e n ewly
form ed rin gs4–18
.
In con tin uation of our studies, m eth yl (Z)-2-[(ben zyloxycarbon yl)-
am in o]-3-dim eth ylam in opropen oate (1), as a n ew reagen t in th is series, was
recen tly prepared, an d used for th e syn th esis of trisubstituted pyrroles, sim -
ple an d fused 3-am in o-2H-pyran -2-on es, an d 1,4-dih ydropyridin -4-on es19.
In th is paper, we report th e reaction s of m eth yl (Z)-2-[(ben zyloxy-
carbon yl)am in o]-3-dim eth ylam in opropen oate (1) with n itrogen n ucleo-
ph iles. 4-Meth oxyben zylam in e an d piperazin e were tran sform ed in to
m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-[(4-m eth oxyben zyl)am in o]prop-
en oate (2) an d dim eth yl 3,3’-(piperazin e-1,4-diyl)bis{2-[(ben zyloxycarbo-
n yl)am in o]propen oate} (3) in 73 an d 64% yields, respectively (Sch em e 1).
Arom atic am in es such as an ilin e, 3-brom oan ilin e, 2-n itroan ilin e,
NHCOOCH Ph
2
NH
H
COOMe
MeO
CH NH
2 2
H
COOMe
NHCOOCH Ph
2
OMe
Me N
2
2
HN
NH
1
PhCH OOCHN
2
H
COOMe
N
N
H
MeOOC
SCHEME 1
NHCOOCH Ph
2
3
3-n itroan ilin e, an d 1-am in on aph th alen e afforded th e correspon din g
m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-(arylam in o)propen oates 4–8 in
65–98% yields (Sch em e 2). An alogously, h eteroarom atic am in es, such as
2-am in o-6-m eth ylpyridin e, 2-am in o-4,6-dim eth ylpyrim idin e, 3-am in o-5-
H
COOMe
NHCOOCH Ph
H
COOMe
2
+
2
R
NH
2
R
NH
Me N
2
NHCOOCH Ph
2
2
1
1
R
R
4-8
1
1
2
R
R
H
H
H
4
5
6
7
8
Br
H
NO
H
2
NO
2
-CH=CH-CH=CH-
SCHEME 2
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Synthesis of Heterocyclic Systems
179
m eth ylisoxazole, 3-am in oquin olin e, 2-am in o-4-ch loroben zoth iazole, 5-
am in o-3-ph en yl-1,2,4-th iadiazole, 2-am in opyrazin e, an d 3-am in o-6-ch loro-
pyridazin e afforded by h eatin g in acetic acid or in a m ixture of acetic acid
an d m eth an ol (2
: 3) m eth yl (Z)-2-[(ben zyloxycarbon yl)am in o]-3-
(h etarylam in o)propen oates 9–16 in 66–96% yields (Sch em e 3). On th e
oth er h an d, som e h eteroarom atic am in es, such as 2-am in opyridin e,
H
COOMe
NHCOOCH Ph
H
COOMe
Het NH
+
2
Het NH
Me N
2
NHCOOCH Ph
2
2
9-16
1
9-16
9
10
11
12
N
H C
3
N
Het
H C
3
N
O
N
H C
3
N
CH
3
13
14
15
16
S
N
S
N
N
N
N
N
N
Cl
Ph
SCHEME 3
Cl
2-am in o-4-m eth yl-,
2-am in o-3-m eth yl-,
2-am in o-3-h ydroxy-,
an d
2-am in o-5-ch loropyridin e, 3-am in opyridazin e, 3-am in o-6-ch loropyrid-
azin e, 1H-3-am in o-1,2,4-triazole, 2-am in oth iazole, an d 2-am in opyrazin e,
were tran sform ed in to th e correspon din g fused pyrim idin -4-on es:
3-[(ben zyloxycarbon yl)am in o]-4H-pyrido[1,2-a]pyrim idin -4-on e (17), an d
its 8-m eth yl (18), 9-m eth yl (19), 9-h ydroxy (20), an d 7-ch loro (21) deriva-
tives, 3-[(ben zyloxycarbon yl)am in o]-4H-pyrim ido[1,2-b]pyridazin -4-on e
(22) an d its ch loro derivative (23), 6-[(ben zyloxycarbon yl)am in o]-7H-
[1,2,4]triazolo[2,3-a]pyrim idin -5-on e (24), 6-[(ben zyloxycarbon yl)am in o]-
5H-th iazolo[3,2-a]pyrim idin -5-on e (25), an d 3-[(ben zyloxycarbon yl)am i-
n o]-4H-pyrazin o[1,2-a]pyrim idin -4-on e (26) in 69–96% yields (Sch em e 4).
Rem oval of ben zyloxycarbon yl group by catalytic tran sfer h ydrogen ation
with Pd/C in th e presen ce of cycloh exen e turn ed out to be selective20,21 (n o
h ydrogen ation of pyran -2-on e, an d 4H-pyridin -4-on e rin g system s h as been
observed) to give un substituted am in o com poun ds in over 80% yields19. In
th is m an n er, 3-am in o-4H-pyrido[1,2-a]pyrim idin -4-on e (27) an d its
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

180
Toplak et al.:
8-m eth yl (28), 9-m eth yl (29), an d 9-h ydroxy (30) derivatives were prepared
in 85–92% yields (Sch em e 4). Rem oval of ben zyloxycarbon yl group in com -
poun ds 22 an d 25 was ach ieved with h ydrogen brom ide in acetic acid ac-
cordin g to th e procedure used in peptide ch em istry22
.
Cyclohexene
Pd/C
N
N
O
H
COOMe
NH
2
N
+
N
N
Me N
2
NHCOOCH Ph
2
NH
NHCOOCH Ph
2
2
O
1
17-26
27-32
Products
N
Starting amine
NH
Products
Starting amine
NH
N
N
2
2
2
N
N
N
N
N
NHR
NHR
O
N
17, 27
O
N
22, 31
H C
3
H C
3
NH
2
NH
N
N
O
N
N
N
NHR
Cl
NHR
Cl
N
N
O
18, 28
23
CH
CH
3
3
NH
NH
N
N
N
NH
2
2
N
N
N
N
N
N
H
NHR
NHR
H
O
O
19, 29
24
OH
OH
N
S
N
N
NH
2
2
S
N
N
N
N
NHR
NHR
O
N
O
N
25,32
20, 30
NH
NH
2
2
N
N
N
O
N
N
O
NHR
Cl
Cl
NHR
26
21
SCHEME 4
Th e structure of com poun d 1 h as been establish ed previously19. In th is
paper we were in terested in th e orien tation of groups aroun d th e C=C dou-
ble bon d in substituted propen oates. Two com poun ds were selected for th is
purpose: m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-(2-n itroan ilin o)propen -
oate (6) an d m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-[(pyrazin -2-yl)-
am in o]propen oate (15). Both com poun ds sh ow in 1H NMR two sets of sig-
n als in dicatin g th at th ere is an equilibrium between two isom ers for each
com poun d. Th e couplin g con stan t for th e structural elem en t CH–NH,
JCH–NH ≈ 11 Hz, clearly in dicates th e trans (an tiperiplan ar) orien tation of
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Synthesis of Heterocyclic Systems
181
3
both h ydrogen s. Th e couplin g con stan t JH–C=C–13C = 4.0 Hz an d NOE be-
tween both NH groups suggest th e Z-orien tation (6a), wh ile th e couplin g
3
con stan t JH–C=C–13C = 9.0 Hz is sign ifican t for trans orien tation aroun d th e
double bon d (Fig. 1, Sch em e 5). Th e ratio 6a : 6b is 10 : 3 both in ch loro-
form an d DMSO-d6. Sim ilar is th e situation in com poun d 15, in wh ich two
isom ers exist in equilibrium . Th e m agn itude of couplin g con stan t for th e
CH–NH structural elem en t, JCH–NH
=
11 Hz, in dicates th e trans
3
J = 4 Hz
3
J = 9 Hz
H
COOMe
H
NHCOOCH Ph
2
NCOOCH Ph
2
COOMe
H
H
H
NO
NO
2
2
6b
NOE
6a
6a : 6b = 10 : 3
3
J = 4 Hz
3
J > 10 Hz
H
COOMe
H
NHCOOCH Ph
2
N
N
NCOOCH Ph
2
COOMe
N
H
N
H
H
H
H
NOE
15a
NOE
15b
15a : 15b = 10 : 4
SCHEME 5
H
H
163
164
165
166
167
ppm
COOMe
FIG. 1
COOMe
Carbonyl part of the HMBC spectrum
(DMSO-d6) of methyl 2-[(benzyloxycarbonyl)-
am ino]-3-(2-nitroanilino)propenoate (6). Th e
cross-peaks of th e m in or con form er are in -
dicated in italics
168
169
170
8.0
7.0
6.0
5.0
ppm
4.0
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

182
Toplak et al.:
(an tiperiplan ar) orien tation of both h ydrogen atom s in both isom ers. Th e
orien tation of th e rin g again st th e NH group at position 3, was establish ed
on th e basis of NOE, wh ile th e orien tation of th e groups aroun d th e double
bon d was establish ed by NOESY experim en ts23. Th e lon g-ran ge 13CO–1H
couplin g con stan ts were evaluated from th e an tiph ase splittin g of cross
3
peaks in the HMBC spectrum24,25. The coupling constants, JH–C=C–COOMe ≈ 4 Hz
3
for on e an d JH–C=C–COOMe > 10 Hz for th e oth er isom er, clearly in dicate th at
th ere is an equilibrium between th e Z- an d E-isom ers 15a an d 15b, respec-
tively (10 : 4) (Sch em e 5).
EXPERIMENTAL
Meltin g poin ts were taken on a Kofler h ot m icrostage. Th e 1H NMR spectra (δ, ppm ; J, Hz)
were obtain ed on a Bruker Avan ce DPX 300 spectrom eter, IR spectra on a Perkin –Elm er 1310
in strum en t an d C, H an d N m icroan alyses on a Perkin –Elm er An alyzer 2400. Mass spectra
were obtain ed on an Autospeck Q spectrom eter. Reaction s were followed by TLC (Merck
pre-coated plates silica gel 60 F 254, ch loroform –m eth an ol 25 : 1, if n ot oth erwise stated).
Meth yl 2-[(ben zyloxycarbon yl)am in o]-3-dim eth ylam in opropen oate (1) was prepared ac-
cordin g to th e procedure described in th e literature19
.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(4-m eth oxyben zyl)am in o]propen oate (2)
To a solution of 4-m eth oxyben zylam in e (0.137 g, 1.0 m m ol) in acetic acid (5 m l), m eth yl
2-[(ben zyloxycarbon yl)am in o]-3-dim eth ylam in opropen oate (1; 0.278 g, 1.0 m m ol) was
added an d th e m ixture was refluxed for 2.5 h . Th en acetic acid was evaporated in vacuo an d
th e solid residue was recrystallized from a m ixture of m eth an ol an d water to give 2 (0.270 g,
73%) , m .p. 128–131 °C. For C20H22N2O5 (370.4) calculated: 64.85% C, 5.99% H, 7.56% N;
foun d: 64.74% C, 6.15% H, 7.77% N. 1H NMR (CDCl3): 3.68 s, 3 H (ArOCH3); 3.81 s, 3 H
(COOCH3); 4.31 d, 2 H, J(CH2,NH) = 5.7 (CH2); 5.12 s, 2 H (CH2); 5.51 br s an d 6.78 br s,
2 H (NH); 6.89 d, 2 H, J(2,3) = 8.1 (H-3, H-5); 7.19 d, 2 H, J(5,6) = 8.1 (H-2, H-6);
7.31–7.34 m , 6 H (Ph , –CH=).
Dim eth yl 3,3’-(Piperazin e-1,4-diyl)bis{2-[(ben zyloxycarbon yl)am in o]propen oate} (3)
To a solution of piperazin e h exah ydrate (0.194 g, 1.0 m m ol) in a m ixture of acetic acid
(2 m l) an d m eth an ol (3 m l), m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-dim eth ylam in o-
propen oate (1; 0.556 g, 2.0 m m ol) was added an d th e m ixture was refluxed for 4 h . Th e resi-
due after evaporation was recrystallized from a m ixture of m eth an ol an d water to give 3
(0.357 g, 64%); m .p. 193–194 °C. For C28H32N4O8 (552.6) calculated: 60.86% C, 5.84% H,
10.14% N; foun d: 60.68% C, 5.84% H, 10.15% N. 1H NMR (CDCl3): 3.36 s, 8 H (piperazin e
H); 3.67 s, 6 H (CH3); 5.14 s, 4 H (CH2); 5.57 br s, 2 H (NH); 7.19 s, 2 H (–CH=);
7.32–7.34 m , 10 H (Ph ).
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Synthesis of Heterocyclic Systems
183
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-(arylam in o)propen oates (4–8).
Gen eral Procedure
To a solution of arom atic am in e (1.0 m m ol) in a m ixture of eth an ol (5 m l) an d con cen -
trated h ydroch loric acid (0.1 m l), m eth yl 2-[(ben zyloxycarbon yl)am in o]-3-dim eth yl-
am in opropen oate (1; 0.278 g, 1.0 m m ol) was added an d th e m ixture was refluxed for several
h ours. Th e solid residue after evaporation was recrystallized from an appropriate solven t.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-an ilin opropen oate (4)
Reaction tim e 2 h . Yield 95%; m .p. 125–127 °C (m eth an ol–water). For C18H18N2O4 (326.4)
calculated: 66.25% C, 5.56% H, 8.58% N; foun d: 66.24% C, 5.47% H, 8.79% N. 1H NMR
(CDCl3): 3.77 s, 3 H (CH3); 5.17 s an d 5.19 s, 2 H (CH2); 5.91 br s an d 6.53 br s, 1 H (NH);
6.94–7.03 m , 3 H (Ph ); 7.26–7.39 m , 7 H (CH2Ph , Ph ); 7.71 d, 1 H, J(CH–NH) = 12.2 (–CH=);
7.97 br s an d 9.59 br s, 1 H (CHNH); Z/E = 86 : 14.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-(3-brom oan ilin o)propen oate (5)
Reaction tim e 2 h . Yield 98%; m .p. 153–155 °C (m eth an ol–water). For C18H17BrN2O4 (405.3)
calculated: 53.35% C, 4.23% H, 6.91% N; foun d: 53.56% C, 4.25% H, 6.80% N. 1H NMR
(CDCl3): 3.79 s, 3 H (CH3); 5.17 s an d 5.19 s, 2 H (CH2); 6.64 br s, 1 H (NH); 6.86 m , 1 H
(Ph ); 7.08–7.17 m , 3 H (Ph ); 7.36–7.40 m , 5 H (CH2Ph ); 7.57 d, 1 H, J(CH–NH) = 12.4
(–CH=); 8.21 br s, 1 H (CHNH); Z/E = 88 : 12.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-(2-n itroan ilin o)propen oate (6)
Reaction tim e 30 m in . Yield 65%; m .p. 145–148 °C (eth an ol). For C18H17N3O6 (371.4) calcu-
lated: 58.22% C, 4.61% H, 11.32% N; foun d: 58.47% C, 4.60% H, 11.19% N. 1H NMR
(CDCl3): 3.81 s an d 3.95 s, 3 H (CH3); 5.18 s an d 5.25 s, 2 H (CH2); 6.38 br s an d 6.43 br s,
1 H (NH); 7.02 ddd, 1 H, J(3,4) = 8.6, J(4,5) = 7.2, J(4,6) = 1.1 (H-4); 7.31–7.42 m , 6 H (Ph ,
H-6); 7.60 ddd, 1 H, J(3,5) = 1.5, J(4,5) = 7.2, J(5,6) = 8.7 (H-5); 7.84 d, 1 H, J(CH–NH) = 11.7
(–CH=); 8.24 dd, 1 H, J(3,4) = 8.6, J(3,5) = 1.5 (H-3); 10.30 br s an d 11.74 br s, 1 H (CHNH);
Z/E = 76 : 24.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-(3-n itroan ilin o)propen oate (7)
Reaction tim e 20 m in . Yield 69%; m .p. 153–155 °C (m eth an ol–water). For C18H17N3O6
(371.4) calculated: 58.22% C, 4.61% H, 11.32% N; foun d: 58.26% C, 4.62% H, 11.32% N.
1H NMR (CDCl3): 3.82 s, 3 H (CH3); 5.18 s an d 5.21 s, 2 H (CH2); 6.78 br s, 1 H (NH);
7.23 d, 1 H, J(5,6) = 8.7 (H-6); 7.34–7.46 m , 6 H (Ph , H-5); 7.58 d, 1 H, J(CH–NH) = 11.7
(–CH=); 7.79–7.81 m , 2 H (H-2, H-4); 8.68 br s, 1 H (CHNH;, Z/E = 92 : 8.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-(1-n aph th ylam in o)propen oate (8)
To a solution of 1-am in on aph th alen e (0.144 g, 1.0 m m ol) in acetic acid (5 m l), com poun d
(1; 0.278 g, 1.0 m m ol) was added an d th e m ixure was refluxed for 30 m in . Th e solid residue
after evaporation was recrystallized from a m ixture of m eth an ol an d water to give 8
(0.327 g, 87%); m .p. 123–125 °C. For C22H20N2O4 (376.4) calculated: 70.20% C, 5.36% H,
7.44% N; foun d: 70.52% C, 5.56% H, 7.70% N. 1H NMR (CDCl3): 3.80 s, 3 H (CH3); 5.19 s
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

184
Toplak et al.:
an d 5.27 s, 2 H (CH2); 5.98 br s an d 6.78 br s, 1 H (NH); 7.11 d an d 7.20 d, 1 H, J(4,5) = 7.1
(H-4); 7.36–7.54 m , 9 H (Ph , H-3, H-5, H-6, H-7); 7.78 d an d 7.93 d, 1 H, J((Z)-CH–NH) =
11.7, J((E)-CH–NH) = 12.3 (–CH=); 7.83–7.85 m , 1 H (H-2); 8.03 d, 1 H, J(7,8) = 7.9 (H-8);
8.95 br s an d 10.48 br s, 1 H (CHNH); Z/E = 74 : 26.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-h etarylam in opropen oates (9–16).
Gen eral Procedure
To a solution of h eterocyclic am in e (1.0 m m ol) in 5 m l acetic acid (com poun ds 9–14) or
5 m l of a 2 : 3 m ixture of acetic acid an d m eth an ol (com poun ds 15–16) com poun d 1
(0.278 g, 1.0 m m ol) was added an d th e m ixture was refluxed for several h ours. Th e solid res-
idue after evaporation was recrystallized from an appropriate solven t.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(6-m eth yl-2-pyridyl)am in o]propen oate (9)
Reaction tim e 3.5 h . Yield 66%; m .p. 173–175 °C (eth an ol–water). For C18H19N3O4 (341.4)
calculated: 63.33% C, 5.61% H, 12.31% N; foun d: 63.32% C, 5.64% H, 12.11% N. 1H NMR
(CDCl3): 2.67 s, 3 H (CH3); 3.79 s, 3 H (COOCH3); 5.19 s, 2 H (CH2); 6.53 d, 1 H, J(4,5) =
7.9 (H-5); 6.60 br s, 1 H (NH); 6.72 d, 1 H, J(3,4) = 7.5 (H-3); 7.33–7.39 m , 5 H (Ph ); 7.45 dd,
1 H, J(3,4) = 7.5, J(4,5) = 7.9 (H-4); 8.27 d, 1 H, J(CH–NH) = 11.9 (–CH=); 8.44 br s, 1 H
(CHNH).
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(4,6-dim eth ylpyrim idin -2-yl)am in o]-
propen oate (10)
Reaction tim e 2.5 h . Yield 83%; m .p. 154–156 °C (m eth an ol–water). For C18H20N4O4 (356.4)
calculated: 60.66% C, 5.66% H, 15.72% N; foun d: 60.60% C, 5.69% H, 15.82% N. 1H NMR
(CDCl3): 2.38 s, 6 H (CH3); 3.80 s, 3 H (COOCH3); 5.19 s, 2 H (CH2); 6.52 br s, 1 H (NH);
6.59 s, 1 H (H-5); 7.31–7.37 m , 5 H (Ph ); 8.37 d, 1 H (–CH=); 8.53 br s, 1 H, J(CH–NH) =
11.9 (CHNH).
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(5-m eth ylisoxazol-3-yl)am in o]propen oate (11)
Reaction tim e 1.5 h . Yield 92%; m .p. 165–167 °C (m eth an ol–water). For C16H17N3O5 (331.3)
calculated: 58.00% C, 5.17% H, 12.68% N; foun d: 57.72% C, 4.97% H, 12.87% N. 1H NMR
(CDCl3): 2.36 s, 3 H (CH3); 3.77 s, 3 H (COOCH3); 5.15 s an d 5.17 s, 2 H (CH2); 5.75 s, 1 H
(H-4); 6.73 br s, 1 H (NH); 7.34–7.36 m , 5 H (Ph ); 7.61 d, 1 H, J(CH–NH) = 11.8 (–CH=),
8.39 br s, 1 H (CHNH); Z/E = 94 : 6.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(quin olin -3-yl)am in o]propen oate (12)
Reaction tim e 3 h . Yield 94%; m .p. 170–173 °C (m eth an ol–water). For C21H19N3O4 (374.4)
calculated: 66.83% C, 5.07% H, 11.13% N; foun d: 66.47% C, 5.00% H, 11.26% N. 1H NMR
(CDCl3): 3.83 s, 3 H (COOCH3); 5.19 s an d 5.23 s, 2 H (CH2); 6.07 br s an d 6.77 br s, 1 H
(NH); 7.34–7.44 m , 5 H (Ph ); 7.48–7.59 m an d 7.68–7.74 m , 5 H (Het); 7.93 d an d 8.03 d,
1 H, J(CH–NH) = 8.0 (–CH=); 8.56 br s an d 9.86 br s, 1 H (CHNH); 8.64–8.67 m , 1 H (H-2);
Z/E = 87 : 13.
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Synthesis of Heterocyclic Systems
185
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(4-ch loroben zoth iazol-2-yl)am in o]-
propen oate (13)
Reaction tim e 3 h . Yield 89%; m .p. 183–185 °C (m eth an ol–water). For C19H16ClN3O4S
(417.9) calculated: 54.61% C, 3.86% H, 10.06% N; foun d: 54.42% C, 3.72% H, 10.01% N.
1H NMR (CDCl3): 3.84 s, 3 H (COOCH3); 5.18 s an d 5.21 s, 2 H (CH2); 6.94 br s, 1 H (NH);
7.14 dd, 1 H, J(5,6) = 7.9, J(6,7) = 7.9 (H-6); 7.36–7.42 m , 6 H (Ph , H-7); 7.50 dd, 1 H,
J(5,6) = 7.9, J(5,7) = 1.0 (H-5); 7.82 d, 1 H, J(CH–NH) = 10.2 (CHNH); 9.89 br s, 1 H (CHNH);
Z/E = 96 : 4.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(3-ph en yl-1,2,4-th iadiazol-5-yl)am in o]-
propen oate (14)
Reaction tim e 2.5 h . Yield 96%; m .p. 178–180 °C (m eth an ol–water). For C20H18N4O4S
(410.5) calculated: 58.53% C, 4.42% H, 13.65% N; foun d: 58.80% C, 4.39% H, 13.98% N.
1H NMR (CDCl3): 3.87 s, 3 H (COOCH3); 5.19 s an d 5.22 s, 2 H (CH2); 7.26 br s, 1 H (NH);
7.38–7.44 m , 5 H (CH2Ph ); 7.45–7.46 m , 3 H (Ph ); 7.69 d, 1 H, J(CH–NH) = 10.9 (–CH=);
8.23–8.26 m , 2 H (Ph ); 10.21 br s, 1 H (CHNH); Z/E = 91 : 9.
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(pyrazin -2-yl)am in o]propen oate (15)
Reaction tim e 3.5 h . Yield 80%, m .p. 150–152 °C (m eth an ol–water). For C16H16N4O4 (328.3)
calculated: 58.53% C, 4.91% H, 17.06% N; foun d: 58.56% C, 4.85% H, 17.28% N. 1H NMR
(CDCl3): 3.82 s, 3 H (COOCH3); 5.17 s an d 5.21 s, 2 H (CH2); 6.91 br s, 1 H (NH); 7.35–7.42 m ,
5 H (Ph ); 8.09 d, 1 H, J(3,5) = 2.3 (H-3); 8.14–8.17 m , 3 H (H-5, H-6, –CH=); 9.22 br s, 1 H
(CHNH).
Meth yl 2-[(Ben zyloxycarbon yl)am in o]-3-[(6-ch loropyridazin -3-yl)am in o]-
propen oate (16)
Reaction tim e 6.5 h . Yield 93%, m .p. 199–201 °C (m eth an ol–water). For C16H15ClN4O4
(362.8) calculated: 52.97% C, 4.17% H, 15.44% N; foun d: 52.77% C, 3.81% H, 15.59% N.
1H NMR (CDCl3): 3.81 s, 3 H (COOCH3); 5.19 s, 2 H (CH2); 6.91 d, 1 H, J(4,5) = 9.1 (H-4);
6.99 br s, 1 H (NH); 7.32 d, 1 H, J(4,5) = 9.1 (H-5); 7.35–7.41 m , 5 H (Ph ); 8.27 d, 1 H,
J(CH–NH) = 11.1 (–CH=); 9.40 br s, 1 H (CHNH).
(Ben zyloxycarbon yl)am in o Substituted Fused Pyrim idin on es 17–26.
Gen eral Procedure
To a solution of h eterocyclic am in e (1.0 m m ol) in acetic acid (5 m l), com poun d 1 (0.278 g,
1.0 m m ol) was added an d th e m ixture was refluxed for several h ours or (com poun ds 23 an d
26) after 1 h of reflux, sodium acetate (0.08 g, 1 m m ol) was added an d th e m ixture was
refluxed for addition al 4 h . After reaction was com pleted, acetic acid was evaporated in
vacuo an d th e solid residue was recrystallized from an appropriate solven t.
3-[(Ben zyloxycarbon yl)am in o]-4H-pyrido[1,2-a]pyrim idin -4-on e (17)
Reaction tim e 2.5 h . Yield 82%; m .p. 146–148 °C (m eth an ol–toluen e). For C16H13N3O3
(295.3) calculated: 65.08% C, 4.44% H, 14.23% N; foun d: 65.27% C, 4.51% H, 14.24% N.
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1H NMR (CDCl3): 5.25 s, 2 H (CH2); 7.10 ddd, 1 H, J(6,7) = 7.7, J(7,8) = 7.5, J(7,9) = 1.2
(H-7); 7.36-7.44 m , 5 H (Ph ); 7.57 s, 1 H (H-2); 7.61 ddd, 1 H, J(6,8) = 1.2, J(7,8) = 7.5,
J(8,9) = 9.0 (H-8); 7.66 dd, 1 H, J(7,9) = 1.2, J(8,9) = 9.0 (H-9); 8.92 dd, 1 H, J(6,7) = 7.7,
J(6,8) = 1.2 (H-6); 9.24 s, 1 H (NH).
3-[(Ben zyloxycarbon yl)am in o]-8-m eth yl-4H-pyrido[1,2-a]pyrim idin -4-on e (18)
Reaction tim e 2.5 h . Yield 89%; m .p. 178–179 °C (eth an ol–toluen e). For C17H15N3O3 (309.3)
calculated: 66.01% C, 4.89% H, 13.58% N; foun d: 66.19% C, 4.80% H, 13.98% N. 1H NMR
(CDCl3): 2.46 s, 3 H (CH3); 5.24 s, 2 H (CH2); 6.94 dd, 1 H, J(6,7) = 7.4, J(7,9) = 1.9 (H-7);
7.32–7.44 m , 7 H (Ph , NH, H-9); 8.82 d, 1 H, J(6,7) = 7.4 (H-6); 9.18 s, 1 H (H-2).
3-[(Ben zyloxycarbon yl)am in o]-9-m eth yl-4H-pyrido[1,2-a]pyrim idin -4-on e (19)
Reaction tim e 2 h . Yield 69%; m .p. 154–156 °C (m eth an ol–toluen e). For C17H15N3O3 (309.3)
calculated: 66.01% C, 4.89% H, 13.58% N; foun d: 65.93% C, 5.05% H, 13.43% N. 1H NMR
(CDCl3): 2.60 s, 3 H (CH3); 5.25 s, 2 H (CH2); 7.01 dd, 1 H, J(6,7) = 7.2, J(7,8) = 6.8 (H-7);
7.26–7.46 m , 6 H (Ph , H-8); 7.50 br s, 1 H (NH); 8.83 d, 1 H, J(6,7) = 7.2 (H-6); 9.25 s, 1 H
(H-2).
3-[(Ben zyloxycarbon yl)am in o]-9-h ydroxy-4H-pyrido[1,2-a]pyrim idin -4-on e (20)
Reaction tim e 2.5 h . Yield 90%; m .p. 227–229 °C (m eth an ol–toluen e). For C16H13N3O4
(311.3) calculated: 61.73% C, 4.21% H, 13.50% N; foun d: 61.63% C, 4.37% H, 13.35% N.
1H NMR (CDCl3): 5.26 s, 2 H (CH2); 7.01–7.26 m , 2 H (H-7, H-8); 7.35–7.44 m , 5 H (Ph );
7.51 s, 1 H (NH); 8.44 dd, 1 H, J(6,7) = 6.0, J(6,8) = 2.6 (H-6); 9.17 s, 1 H (H-2).
3-[(Ben zyloxycarbon yl)am in o]-7-ch loro-4H-pyrido[1,2-a]pyrim idin -4-on e (21)
Reaction tim e 3 h . Yield 92%; m .p. 189–191 °C (m eth an ol–toluen e). For C16H12ClN3O3
(329.7) calculated: 58.28% C, 3.67% H, 12.74% N; foun d: 58.28% C, 3.62% H, 12.34% N.
1H NMR (CDCl3): 5.25 s, 2 H (CH2); 7.36–7.42 m , 5 H (Ph ); 7.49 dd, 1 H, J(6,8) = 1.9,
J(8,9) = 9.4 (H-8); 7.54 br s, 1 H (NH); 7.59 dd, 1 H, J(6,9) = 0.8, J(8,9) = 9.4 (H-9); 8.93 dd,
1 H, J(6,8) = 1.9, J(6,9) = 0.8 (H-6); 9.23 s, 1 H (H-2).
3-[(Ben zyloxycarbon yl)am in o]-4H-pyrim ido[1,2-b]pyridazin -4-on e (22)
Reaction tim e 3.5 h . Yield 93%; m .p. 187–190 °C (m eth an ol–toluen e). For C15H12N4O3
(296.3) calculated: 60.81% C, 4.08% H, 18. 91% N; foun d: 60.77% C, 4.18% H, 19.03% N.
1H NMR (CDCl3): 5.26 s, 2 H (CH2); 7.30 d d , 1 H, J(7,8) = 4.1, J(8,9) = 9.3 (H-8);
7.37–7.42 m , 5 H (Ph ); 7.77 br s, 1 H (NH); 7.87 dd, 1 H, J(7,9) = 1.8, J(8,9) = 9.3 (H-9);
8.62 dd, 1 H, J(7,8) = 4.1, J(7,9) = 1.8 (H-7); 9.22 s, 1 H (H-2).
3-[(Ben zyloxycarbon yl)am in o]-7-ch loro-4H-pyrim ido[1,2-b]pyridazin -4-on e (23)
Yield 50%; m .p. 182–184 °C (m eth an ol–toluen e). For C15H11ClN4O3 (330.7) calculated:
54.47% C, 3.35% H, 16.94% N; foun d: 54.27% C, 3.14% H, 17.11% N. 1H NMR (CDCl3):
5.26 s, 2 H (CH2); 7.37–7.42 m , 5 H (Ph ); 7.26 d, 1 H, J(8,9) = 9.4 (H-8); 7.76 br s, 1 H (NH);
7.78 d, 1 H, J(8,9) = 9.4 (H-9); 9.18 s, 1 H (H-2).
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Synthesis of Heterocyclic Systems
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6-[(Ben zyloxycarbon yl)am in o]-5H-[1,2,4]triazolo[2,3-a]pyrim idin -5-on e (24)
Reaction tim e 2.5 h . Yield 84%; m .p. 215–217 °C (m eth an ol–toluen e). For C13H11N5O3
(285.3) calculated: 54.74% C, 3.89% H, 24.55% N, foun d: 54.70% C, 3.87% H, 24.57% N.
1H NMR ((CD3)2SO): 5.13 s, 2 H (CH2); 7.33–7.41 m , 5 H (Ph ); 8.23 s, 1 H (H-2); 8.28 s, 1 H
(H-6); 8.76 br s, 1 H (NH); 13.41 br s, 1 H (NH).
6-[(Ben zyloxycarbon yl)am in o]-5H-th iazolo[3,2-a]pyrim idin -5-on e (25)
Reaction tim e 2.5 h . Yield 96%; m .p. 183–184 °C (m eth an ol–toluen e). For C14H11N3O3S
(301.3) calculated: 55.81% C, 3.68% H, 13.95% N; foun d: 55.80% C, 3.52% H, 14.00% N.
1H NMR (CDCl3): 5.23 s, 2 H (CH2); 7.04 d, 1 H, J(2,3) = 4.9 (H-2); 7.33–7.43 m , 6 H
(Ph , NH); 7.93 d, 1 H, J(2,3) = 4.9 (H-3); 8.92 s, 1 H (H-7).
3-[(Ben zyloxycarbon yl)am in o]-4H-pyrazin o[1,2-a]pyrim idin -4-on e (26)
Yield 51%; m .p. 192–195 °C (m eth an ol–toluen e). For C15H12N4O3 (296.3) calculated:
60.81% C, 4.08% H, 18.91% N; foun d: 60.54% C, 3.84% H, 19.07% N. 1H NMR (CDCl3):
5.27 s, 2 H (CH2); 7.37–7.43 m , 5 H (Ph ); 7.68 br s, 1 H (NH); 8.04 d, 1 H, J(7,9) = 1.2 (H-9);
8.56 dd, 1 H, J(7,9) = 1.2, J(6,7) = 4.9 (H-7); 9.06 d, 1 H, J(6,7) = 4.9 (H-6); 9.34 s, 1 H (H-2).
Am in o Substituted Fused Pyrim idin on es 27–32
Method A. A solution of com poun ds 17–19 or 20 in eth an ol was m ixed with cycloh exen e
(in excess) an d com m ercial 10% Pd/C catalyst (catalyst–substrate ratio 1 : 2 to 1 : 5 by
weigh t). Th e m ixtu re was reflu xed for 30–90 m in . Th e reaction was followed by TLC
(ch loroform –m eth an ol 5 : 1). Th e catalyst was rem oved by filtration of a warm m ixture. Th e
filtrate was evaporated in vacuo an d th e solid residue was recrystallized from an appropriate
solven t.
3-Am in o-4H-pyrido[1,2-a]pyrim idin -4-on e (27)
Th is com poun d was prepared from 3-[(ben zyloxycarbon yl)am in o]-4H-pyrido[1,2-a]-
pyrim idin -4-on e (17; 0.295 g, 1.0 m m ol), 30 m in reflux. Yield 85%; m .p. 176–179 °C
(wash ed with m eth an ol) (ref.13: 176–178 °C). For C8H7N3O (161.2) calculated: 59.62% C,
4.38% H, 26.07% N; foun d: 59.55% C, 4.46% H, 26.15% N. 1H NMR (CDCl3): 4.04 s, 2 H
(NH2); 7.01 ddd, 1 H, J(6,7) = 7.2, J(7,8) = 6.8, J(7,9) = 1.5 (H-7); 7.38 ddd, 1 H, J(6,8) = 1.5,
J(7,8) = 6.8, J(8,9) = 9.0 (H-8); 7.52 dd, 1 H, J(7,9) = 1.5, J(8,9) = 9.0 (H-9); 8.01 s, 1 H (H-2);
8.88 dd, 1 H, J(6,7) = 7.2, J(6,8) = 1.5 (H-6).
3-Am in o-8-m eth yl-4H-pyrido[1,2-a]pyrim idin -4-on e (28)
Th is com poun d was prepared from 3-[(ben zyloxycarbon yl)am in o]-8-m eth yl-4H-pyrido-
[1,2-a]pyrim idin -4-on e (18; 0.174 g, 0.7 m m ol), 1.5 h reflux. Yield 92%; m .p. 223–225 °C
(eth an ol) (ref.13: 225–226 °C). For C9H9N3O (175.2) calculated: 61.70% C, 5.18% H,
23.99% N; foun d: 61.72% C, 5.25% H, 24.00% N. 1H NMR (CDCl3): 3.94 s, 2 H (NH2);
6.84 dd, 1 H, J(6,7) = 7.4, J(7,9) = 1.7 (H-7); 7.28 d, 1 H, J(7,9) = 1.7 (H-9); 7.97 s, 1 H (H-2);
8.79 d, 1 H, J(6,7) = 7.4 (H-6).
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3-Am in o-9-m eth yl-4H-pyrido[1,2-a]pyrim idin -4-on e (29)
Th is com poun d was prepared from 3-[(ben zyloxycarbon yl)am in o]-9-m eth yl-4H-pyrido-
[1,2-a]pyrim idin -4-on e (19; 0.128 g, 0.4 m m ol), 30 m in reflux. Yield 89%; m .p. 183–185 °C
(wash ed with m eth an ol). For C9H9N3O (175.2) calculated: 61.70% C, 5.18% H, 23.99% N;
foun d: 61.47% C, 5.45% H, 24.04% N. 1H NMR ((CD3)2SO): 5.15 s, 2 H (NH2); 7.02 dd, 1 H,
J(6,7) = 7.2, J(7,8) = 6.8 (H-7); 7.34 d, 1 H, J(7,8) = 6.8 (H-8); 7.93 s, 1 H (H-2); 8.66 d, 1 H,
J(6,7) = 7.2 (H-6).
3-Am in o-9-h ydroxy-4H-pyrido[1,2-a]pyrim idin -4-on e (30)
Th is com poun d was prepared from 3-[(ben zyloxycarbon yl)am in o]-9-h ydroxy-4H-pyrido-
[1,2-a]pyrim idin -4-on e (20; 0.118 g, 0.4 m m ol), 30 m in reflux. Yield 89%; m .p. 206–209 °C
(eth an ol) (ref.13: 213–215 °C); MS: 177 (M+). For C8H7N3O2 (177.2) calculated: 54.24% C,
3.98% H, 23.72% N; foun d: 53.55% C, 3.89% H, 24.07% N. 1H NMR ((CD3)2SO): 5.19 s, 2 H
(NH2); 6.74 d, 1 H, J(7,8) = 7.5 (H-8); 6.98 dd, 1 H, J(6,7) = 7.2, J(7,8) = 7.5 (H-7); 7.89 s, 1 H
(H-2); 8.28 d, 1 H, J(6,7) = 7.2 (H-6).
Method B. A m ixture of N-(ben zyloxycarbon yl)am in e 22 or 25 (1 m m ol) an d a 33% solu-
tion of h ydrogen brom ide in acetic acid (5 m l) was stirred at 40 °C un til evolution of carbon
dioxide ceased (30 m in ). Th e products were purified by ion exch an ge ch rom atograph y in
th e followin g m an n er: th e reaction m ixture was diluted with 20 m l of water, poured on a
stabilized colum n (Dowex 50 W, 80 g), wash ed con secutively with water (500 m l), m eth a-
n ol (500 m l), an d th en th e product was eluted with 2 M m eth an olic NH3 (300 m l). Fraction s
con tain in g th e product were com bin ed, solven t evaporated in vacuo an d th e solid residue
recrystallized from an appropriate solven t.
3-Am in o-4H-pyrim ido[1,2-b]pyridazin -4-on e (31)
Th is com poun d was prepared from 3-[(ben zyloxycarbon yl)am in o]-4H-pyrim ido[1,2-b]-
pyridazin -4-on e (22; 0.306 g, 1 m m ol). Yield 84%; m .p. 253–256 °C (eth an ol–toluen e). For
C7H6N4O (162.2) calculated: 51.85% C, 3.73% H, 34.55% N; foun d: 51.73% C, 3.68% H,
34.35% N. 1H NMR (CDCl3): 5.60 s, 2 H (NH2); 7.21 dd, 1 H, J(7,8) = 4.1, J(8,9) = 9.4 (H-8);
7.76 dd, 1 H, J(7,9) = 1.9, J(8,9) = 9.4 (H-9); 7.81 s, 1 H (H-2); 8.58 dd, 1 H, J(7,8) = 4.1,
J(7,9) = 1.9 (H-7).
6-Am in o-5H-th iazolo[3,2-a]pyrim idin -5-on e (32)
Th is com poun d was prepared from 6-[(ben zyloxycarbon yl)am in o]-5H-th iazolo[3,2-a]-
pyrim idin -5-on e (25; 0.301 g, 1 m m ol). Yield 81%; m .p. 165–168 °C (eth an ol–toluen e)
(ref.18: 169–172 °C). For C6H5N3OS (167.2) calculated: 43.11% C, 3.01% H, 25.13% N;
foun d: 42.96% C, 2.92% H, 25.31% N. 1H NMR (CDCl3): 4.88 s, 2 H (NH2); 7.43 d, 1 H,
J(2,3) = 4.9 (H-2); 7.52 s, 1 H (H-7); 7.91 d, 1 H, J(2,3) = 4.9 (H-3).
The authors wish to express their gratitude to the Ministry of Science and Technology, Slovenia, for
financial support.
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Collect. Czech. Chem. Commun. (Vol. 64) (1999)