Synthesis of polycyclic nitrogen-containing heterocyclic [1]: One pot formation of 1,6-naphthyridine ring system by reaction of amino-cyano-methylthio-heterocycles with dialkyl acetyeledicarboxylates

Article abstract of DOI:10.1002/jhet.5570380518

Reaction of 3-amino-3-methylthio-2-cyanoacrylonitrile (1) with excess dimethyl acetylenedicarboxylate(DMAD) in the presence of potassium carbonate in dimethyl sulfoxide gave a novel tricyclic heterocycle, hexamethyl 1H-1,4,7-triazaphenalene-2,3,5,6,8,9-he

Full text of DOI:10.1002/jhet.5570380518

Sep-Oct 2001
Synthesis of Polycyclic Nitrogen-containing Heterocyclic [1]:
One Pot Formation of 1,6-Naphthyridine Ring System by
Reaction of Amino-cyano-methylthio-heterocycles
with Dialkyl Acetyeledicarboxylates
1135
Yoshinori Tominaga*, Kenichi Nomoto and Noriko Yoshioka
Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan
Received August 8, 2000
Reaction of 3-amino-3-methylthio-2-cyanoacrylonitrile (1) with excess dimethyl acetylenedi-
carboxylate(DMAD) in the presence of potassium carbonate in dimethyl sulfoxide gave a novel tricyclic
heterocycle, hexamethyl 1H-1,4,7-triazaphenalene-2,3,5,6,8,9-hexacarboxylate (5a). When one equivalent
of DMAD was used in this reaction, dimethyl 4-amino-3-cyano-2-methylthiopyridine-5,6-dicarboxylate
(3a), a key intermediate of 5a, was obtained.
J. Heterocyclic Chem., 38, 1135 (2001).
The reaction of 5-amino-6-cyano-1,3-dimethyl-7-
as intermediates of biologically active compounds. At the
start of the present study, the reaction of 1 with DMAD
was studied under various basic conditions. The results are
shown in Table 1. This reaction gave a cyclized product,
4-amino-3-cyano-2-methylthiopyridine-5,6-dicarboxyl-
ate(3a) from basic solution. Michael product, 3-(N-1',2'-
bis(methoxy-carbonyl)ethenylamino-2-cyano-3-methyl-
thioacrylonitrile (2a) was obtained by acidification of the
mother liquor. However, the pyrido[4,3-c]pyridine
derivative (4a) of intermediate 5a could not be detect in
any reaction mixture. Most crucial to the formation of 5a
by reaction of 1 with DMAD was that of 3. Potassium
carbonate as a base gave the most effective results in the
reaction of 1 with DMAD at room temperature in dimethyl
sulfoxide. Other bases such as potassium hydrogen
phosphate, potassium phosphate n-hydrate and potassium
tert-butoxide also served efficiently as catalysts to give the
methylthiopyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
with DMAD in the presence of potassium carbonate in
dimethyl sulfoxide gave tetramethyl 8,9,10,11-tetrahydro-
8,10-dimethyl-9,10-dioxo-4H-pyrimido[4',5':5,6]pyrido-
[2,3,4-cb][1,6]-naphthyridine-2,3,5,6-tetracarboxylate
(5c) in good yield. The reaction of other heterocycles
bearing amino, cyano, and methylthio groups with DMAD
or DEAD (diethyl acetylenedicarboxylate) under the same
reaction conditions gave also the corresponding tetracyclic
heterocycles containing the fundamental 1,6-naphthyri-
dine ring system in moderate yields.
In connection with our program of preparing new poly-
heterocyclic compounds which are of interest from both
theoretical and practical standpoints and which might also
exhibit potential biological activity, we have recently
described the synthesis of 4-aminopyrazolo[3,4-d]pyri-
dine-5,6-dicarboxylate by the reaction of 5-aminopyra-
zole-4-carbonitrile in the presence of the base potassium
carbonate in moderate yield [2]. This reaction can be
conveniently applied to the formation of dimethyl
4-aminopyridine-2,3-dicarboxylate derivatives. We now
wish to report the reaction of various pyridine or
pyrimidine derivatives bearing amino, cyano, and
methylthio groups with dialkyl acetylenedicarboxylates in
the presence of a base such as potassium carbonate to
obtain the polycyclic nitrogen-containing tri- or tetracyclic
heterocycles by one pot formation of the 1,6-naphthyridine
ring system, as shown in Scheme 1.
3-Amino-3-methylthio-2-cyanoacrylonitrile (1)[3],
readily prepared by reaction of bis-(methylthio)methylene-
propanedinitrile [3] with ammonium hydroxide in good
yield, is one of the simplest compounds in a large number
of ketene N,S-acetals and enaminonitriles [4]. This
compound should prove useful for the synthesis of
nitrogen-containing heterocyclic compounds.
Reactions of enaminonitriles with DMAD give a variety
of compounds [5]. We examined the reaction of 1 with
DMAD in the presence of a base to give dimethyl
2-methylthiopyridine-5,6-dicarboxylate, possibly for use

1136
Y. Tominaga, K. Nomoto and N. Yoshioka
Vol. 38
Table 1
These heterocycles are generally obtained by the reaction
of ketene dithioacetals [6] with various nucleophiles.
Reaction of 1a with DMAD in the presence of potassium
carbonate as a base in dimethyl sulfoxide (DMSO) gave
an expected tricyclic heterocycle, hexamethyl 1H-1,4,7-
triazaphenalene-2,3,5,6,8,9-hexacarboxylate (5a), in 68%
yield. When potassium phosphate hydrate is employed as
the base in this reaction a yield of 70% is obtained.
Diethyl acetylenedicarboxylate (DEAD) also reacted with
1a under a same reaction condition to give 5b in 63%
yield.
Reactions of Ketene N, S-Acetal
with DMAD in the Presence of a Base [a]
No
Base (mmol)
Reaction Time Yield (%) Yield (%)
2a
3a
1
2
3
4
5
6
7
8
9
10
K CO (12)
8 hr
24 hr, 4 hr (at 60°)
48 hr
37.3
48.6
29.3
37.5
20.9
39.6
22.0
11.8
27.7
33.0
24.8
18.1
30.0
16.5
14.6
25.6
-----
6.5
2
3
This synthesis of tricyclic heterocycles is applicable to
the preparation of tetracyclic heterocycles. At first, the
reaction of 4-amino-3-cyano-2-methylthioquinoline (3c)
with DMAD in the presence of potassium carbonate in
DMSO gave the corresponding tetramethyl 1H-quino-
lino[2,3,4-de][1,6]naphthyridine-2,3,5,6-tetracarboxylate
(5c) in 33% yield. The IR spectrum of this compound
K CO (30)
2
3
K CO (30)
2
3
K CO (40)
72 hr
48 hr
48 hr
48 hr
48 hr
48 hr
2
3
K HPO (12)
2
4
K PO H O (15)
3
4 2
KOH (20)
t-BuOK (12)
AcONa (20)
13.4
29.0
-1
clearly shows a broad peak at 3240 cm due to an amino
K HPO (10), K CO (10)
48 hr
2
4
2
3
-1
group and a peak at 1740 cm due to the carbonyl groups.
1
The H-NMR spectrum exhibited a four-spin system in the
[a] Reactions were carried out in a system of 1 (10 mmol) and DMAD
(10 mmol) at room temperature in DMSO.
aromatic region at δ 7.42(d), 7.45(t), 7.69(t), and 8.84(d)
and four singlet signals due to the methoxy protons at δ
3.98, 3.99, 4.05, and 4.07(each 3H) and a broad singlet
signal corresponding to the amino group at δ 12.10. In the
nuclear Overhauser effect (NOE) experiment, NOE
enhancement between the 11-H doublet ( δ 7.42) and the
N-H singlet at δ 12.10 was observed.
In a similar manner, the reaction of 5-amino-6-
cyanopyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3d),
which was prepared by the condensation of 6-aminouracils
with ketene dithioacetal, bis(methylthio)methylene-
propanedinitrile [7], with DMAD in the presence of potas-
sium carbonate or tripotassium phosphate gave the tetra-
cyclic heterocycle, 5d, in 53 and 35 % yields, respectively.
As shown in Entry 3, the reaction of 3d with DEAD was
also carried out under the same reaction conditions to give
the corresponding tetra cyclic compound, 5e, in 59% yield.
corresponding 2a and 3a, but potassium hydroxide and
sodium hydroxide were not effective for conversion to 3a
or 5a. This reaction did not occur without a base and
starting material 1 was recovered. When excess DMAD
(1.2 equivalents) was used, a third product (5a) was
obtained in 0.6% yield along with 2a in 20.7% and 3a in
19.2% yield. The yield of 5a via triple cyclization was
improved by increasing the amount of DMAD in the
presence of potassium carbonate in DMSO at room
temperature, as shown in Table 2.
A system of amino-cyano-methylthio-heterocycles
containing pyridine or pyrimidine rings is a very
important and versatile synthetic starting material for
construction of fused pyridine or pyrimidine derivatives.
Table 2
Reaction of Ketene N, S-Acetal with DMAD in The Presence of Base [a]
No
DMAD (mmol)
Base (mmol)
Reaction Time
Yield (%)
2a
3a
5a
1
2
3
4
12
22
32
30
K CO (30)
24 hr
48 hr
48 hr
48 hr
20.7
18.0
17.7
16.5
19.2
----
----
----
0.6
2
3
K CO (30)
17.1
21.5
21.1
2
3
K CO (60)
2
3
K PO H O (40)
3
4 2
[a] The reactions were carried out at room temperature in DMSO.

Sep-Oct 2001
Synthesis of Polycyclic Nitrogen-containing Heterocyclic
1137

1138
Y. Tominaga, K. Nomoto and N. Yoshioka
Vol. 38
323 spectrometer. Nuclear magnetic resonance (nmr) spectra
were obtained on JEOL-PS-100(100 MHz), JEOL-FX-90Q(90
MHz), and JEOL-GX-400(400MHz) spectrometers with tetra-
methylsilane as an internal standard. Mass(ms) spectra were
recorded on JEOL-01SG mass spectrometer. Elemental analyses
were performed at the Microanalytical Laboratory of the Center
for Instrumental Analysis in Nagasaki University.
The corresponding pyrazolopyridine derivatives, 3e and f
[8], was allowed to react with DMAD giving the
corresponding tetracyclic compounds, 5f and g, in 75 and
56% yields, respectively. The above reaction could be
readily applied to synthesis of fused pyrimido[4,5,6-d,e]-
[1,6]naphthyridine derivatives (5h, i), which were
prepared by reaction of the corresponding triazolo[1,5-a]-
pyrimidine derivative (3g) with DMAD or DEAD in the
presence of potassium carbonate, in 43 and 23% yields,
respectively. Similarly, reaction of pyrazolo[1,5-a]pyrimi-
dine derivative (3h) with DMAD was carried out to give
the corresponding tetracyclic compound, 5j, in 47% yield.
In conclusion, ketene N,S-acetal, 1, is a very useful
starting material for the preparation of poly functionalized
pyridine and derivatives of the novel tricyclic heterocycle,
1H-1,4,7-triazaphenalene, which should prove useful for
the synthesis of poly fused heterocyclic compounds as
starting materials for obtaining biologically active
compounds. The tandem addition-cyclization reaction of
amino-cyano-methylthio-pyridine or pyrimidine
derivatives with dialkyl acetylenedicarboxylates in the
presence of appropriate base was found to be a versatile
method of forming polycyclic heterocycles containing the
1,6-naphthyridine ring system.
Dimethyl 4-Amino-5-cyano-6-methylthiopyridine-1,2-dicarboxy-
late (3a).
To a stirred mixture of 1.39 g (10 mmol) of (amino)-
(methylthio)methylene-propanedinitrile (1), 4.14 g (30 mmol) of
anhydrous potassium carbonate and 20 ml of dimethyl sulfoxide, a
solution of 1.6 g (11.3 mmol) of DMAD in 5 ml of dimethyl
sulfoxide was added dropwise during 20 minutes with ice-water
cooling. Stirring was continued for an additional 48 hours at room
temperature. The color of the reaction mixture changed from brown
to dark greenish brown. The reaction mixture was poured into
300 ml of ice-water and stirred for 30 minutes. The gray precipitate
was collected by filtration. After drying in air the product was
recrystallized from methanol to give 0.411 g (1.5 mmol, 15%) of
colorless needles, mp 173-175°; ir (potassium bromide): ν 3390,
-1
3290(NH), 2205(CN), 1745, 1705(CO), 1612, 1535, 1265 cm ; uv
1
(EtOH) λ max nm(log ε): 256(4.56), 310(3.97); H nmr (deuterio-
chlorofom): δ 2.61(s, 3H, SMe), 3.87(s, 3H, OMe), 3.94(s, 3H,
+
OMe), 6.87(br s, 2H, NH); ms: m/z(%) 281(M , 95), 249(81),
234(87), 222(36), 189(51), 174(59), 123(100).
Anal. Calcd for C H N O S (281.288): C, 46.97; H, 3.94; N,
14.94; S, 11.40. Found: C, 47.07; H, 3.93; N, 14.91; S, 11.08.
11 11
3 4
EXPERIMENTAL
Dimethyl N-(2,2-Dicyano-1-methylthio)ethylenaminofumalate (2a).
All melting points were determined in a capillary tube and are
uncollected. Infrared (ir) spectra were recorded in potassium
bromide pellets on JASCO 810 spectrometer and ultraviolet (uv)
absorption spectra were determined in 95% ethanol on a Hitachi
The above filtrate was acidified with 10% hydrochloric acid
solution. The resulting precipitate was collected by filtration and
recrystallized from methanol to give 0.588 g (2.1 mmol, 21%

Sep-Oct 2001
Synthesis of Polycyclic Nitrogen-containing Heterocyclic
1139
yield) of 2a as colorless needles. An analytical sample was
obtained by recrystallized from methanol to give colorless
needles, mp 120-121°; ir (potassium bromide): ν 3225(NH),
chromatographed on a silica gel column using Hexane:ethyl
acetate (3:1) as the eluent affording as the first fraction in 18%
(0.50 g, 1.77 mmol) yield pure 2a.
-1
2210(CN), 1730, 1685(CO), 1630, 1542, 1435, 1280, 1240 cm ;
Method b.
1
uv (ethanol) λ nm(log ε): 288(4.12), 340(3.97); H nmr
(deuteriochcloroform): δ 2.60 (s, 3H, SMe), 3.83 (s, 3H, OMe),
3.91 (s, 3H, OMe), 6.11 (s, 1H, =CH), 10.00 (br s, 1H, NH).
Anal. Calcd for C H N O S (281.288): C, 46.97; H, 3.94; N,
To a stirred mixture of 1.39 g (10 mmol) of dimethyl 4-amino-
5-cyano-6-methylthiopyridine-2,3-dicarboxylate (3a), 6.90 g
(50 mmol) of anhydrous potassium carbonate and 20 ml of
dimethyl sulfoxide, a solution of 1.6 g (11.3 mmol) of DMAD in
5 ml of dimethyl sulfoxide was added dropwise during -
20 minutes with ice-water cooling. Stirring was continued for an
additional 48 hours at room temperature. The color of the
reaction mixture changed from brown to dark greenish brown.
The reaction mixture was poured into 300 ml of ice-water and
acidified with 10% hydrochloric acid solution. The gray
precipitate was collected by filtration. After drying in air the
product was recrystallized from methanol to give 3.52 g
(6.8 mmol, 68%) of yellow prisms, mp 231-241°; ir (potassium
bromide): ν 3195(NH), 2955(Me), 1750, 1740(CO), 1610, 1435,
11 11
3 4
14.94; S, 11.40. Found: C, 47.18; H, 3.90; N, 14.90; S, 11.21.
Diethyl 4-Amino-5-cyano-6-methylthiopyridine-2,3-dicarboxy-
late (3b).
This compound (1.24 g, 12.4 mol) was prepared in 20% from
amino-methylthio-methylenepropanedinitrile (1) (2.78 g,
20 mmol) and DEAD (3.40 g, 20 mmol) in a manner similar to
that described for the preparation of 2a. An analytical sample was
recrystallized from ethanol to give colorless needles, mp
130-132°; ir (potassium bromide): ν 3450, 3320(NH), 2210(CN),
-1
1740, 1690(CO), 1610, 1545, 1270 cm ; uv (ethanol) λ max
-1
1
1280, 1260, 1220 cm ; uv (ethanol) λ max nm(log ε): 214(4.62),
nm(log ε): 256(4.62), 310(4.02); H nmr (deuteriochlorom): δ
1
367(4.31); H nmr (deuteriochloroform): δ 3.97 (s, 6H, OMe),
1.35(t, 3H, J=7.2 Hz, O-CH -CH ), 1.39(q, 3H, J=7.2 Hz,
2
3
3.98 (s, 3H, OMe), 4.00 (s, 3H, OMe), 4.05 (s, 3H, OMe), 4.09
(s, 3H, OMe), 12.45 (br s, 1H, NH); fab ms: m/z 518(M +1).
O-CH -CH ), 2.61(s, 3H, SMe), 4.33(q, 2H, J=7.2 Hz, O-CH -),
2
3
2
+
4.39(q, 2H, J=7.2 Hz, O-CH -), 7.24(br s, 2H, NH); ms: m/z(%)
2
+
Anal. Calcd for C H N O (517.409): C, 51.07; H, 3.70; N,
309(M , 100), 264(17), 234(69), 207(11), 191(37), 163(94).
22 19
3 12
8.12. Found: C, 50.93; H, 3.69; N, 14.91.
Anal. Calcd for CHNOS (309.342): C, 50.48; H, 4.89; N,
13.58; S, 10.36. Found: C, 50.51; H, 4.84; N, 13.54; S, 10.26.
Hexaethyl 1H-1,4,7-Triazaphenalene-2,3,5,6,8,9-hexacarboxy-
late (5b).
Diethyl N-(2,2-Dicyano-1-methylthio)ethylenaminofumalate (2b).
This compound was prepared from 3b and DEAD in a manner
similar to that described for the synthesis of 5a and yellow nee-
dles were obtained in 63% yield, mp 153-154°; ir (potassium bro-
mide): ν 3330(NH), 2955(Me), 1740, 1720(CO), 1605, 1280,
The above filtate was acidified with 10% hydrochloric acid
solution. The resulting precipitate was collected by filtration
and recrystallized from methanol to give 1.30 g (4.21 mmol,
21% yield) of 3b as colorless needles. An analytical sample was
obtained by recrystallized from methanol to give colorless
needles, mp 106-108°; ir (potassium bromide): ν 3250(NH),
-1
1260, 1250 cm ; uv (ethanol) λ max nm(log ε): 212(4.65),
1
367(4.36); H nmr (deuteriochlorofom): δ 1.15-1.56 (18H, m,
-1
6xOCH -CH ), 4.31-4.65 (12H, m, 6xOCH -CH ), 12.43 (1H, br
2205(CN), 1720, 1680(CO), 1615, 1540, 1265, 1235 cm ; uv
2
3
2
3
+
1
s, NH); fab ms: m/z 602(M +1).
Anal. Calcd for C H N O (601.572): C, 55.91; H, 5.19; N,
(ethanol) λ max nm(log ε): 289(4.16), 337(3.99); H nmr
(deuteriochclorofom): δ 1.33(t, 3H, J=7.1 Hz, O-CH -CH ),
28 31 3 12
2
3
6.99. Found: C, 55.81; H, 5.18; N, 7.00.
1.38(t, 3H, J=7.1 Hz, O-CH -CH ), 2.59(s, 3H, SMe),
2
3
4.27(q, 2H, J=7.1 Hz, O-CH -), 4.36(q, 2H, J=7.1 Hz, O-CH -),
2
2
4-Amino-3-cyano-2-methylthioquinoline (3c).
6.10(s, 1H, =CH).
Anal. Calcd for C H N O S (309.342): C, 50.48; H, 4.89; N,
A mixture of 0.46 g (2.0 mmol) of 4-chloro-3-cyano-2-
methylthioquinoline [10] and 20 ml of 28% ammonium
hydroxide was heated at 180° for 1 hour in mini-autoclave
(nichidenn rika garasu). After cooling, the precipitate that
appeared was collected by filtration to give 0.40 g (1.86 mmol)
colorless needles in 93% yield. An analytical sample was recrys-
tallized from methanol to give colorless needles, mp 189-190°; ir
(potassium bromide): ν 3440, 3350(NH), 2920(Me), 2200(CN),
13 15
3 4
13.58; S, 10.36. Found: C, 50.44; H, 4.83; N, 13.56; S, 10.43.
Hexamethyl 1H-1,4,7-Triazaphenalene-2,3,5,6,8,9-hexacarboxy-
late (5a).
Method a.
To a stirred mixture of 1.39 g (10 mmol) of (amino)-
(methylthio)-methylenepropanedinitrile (1), 8.28g (60 mmol) of
anhydrous potassium carbonate and 20 ml of dimethyl sulfoxide,
a solution of 5.11 g (36 mmol) of DMAD in 5 ml of dimethyl
sulfoxide was added dropwise during 5 minutes with ice-water
cooling. Stirring was continued for an additional 48 hours at
room temperature. The color of the reaction mixture changed
from brown to dark greenish brown. The reaction mixture was
poured into 300 ml of ice-water and stirred for 30 minutes. The
mixture was acidified with 10% hydrochloric acid solution. The
resulting brown solid was collected by filtration. After drying in
air the product was recrystallized from methanol to give 1.112 g
(2.15 mmol, 22%) of yellow prisms, mp 231-241°. After
evaporation of the solvent of the above filtrate, the residue was
-1
1655, 1505, 750 cm ; uv (ethanol) λ max nm(log ε): 214(4.33),
1
265(4.65), 298(3.99); H nmr (deuteriochloroform): δ 2.70
(s, 3H, SMe), 5.60 (br s, 2H, NH ), 7.43 (m, 1H, 6-H), 7.68
2
(m, 1H, 8-H), 7.71 (m, 1H, 7-H), 7.86 (m, 1H, 5-H).
Anal. Calcd for C H N S (215.2725): C, 61.37; H, 4.21; N,
11
9 3
19.52; S, 14.89. Found: C, 61.55; H, 4.26; N, 19.49; S, 14.81.
Tetramethyl 1H-Quinolino[2,3,4-de][1,6]naphthyridine-2,3,5,6-
tetracarboxylate (5c).
This compound was prepared from 3c and DEAD in a manner
similar to that described for the synthesis of 5a and yellow
needles were obtained in 33% yield, mp 282-285°; ir (potassium
bromide): ν 3240(NH), 2950(Me), 1740(CO), 1610, 1440, 1245

1140
Y. Tominaga, K. Nomoto and N. Yoshioka
Vol. 38
-1
cm ; uv (ethanol) λ max nm: 233, 321, 386: λmin nm: 315, 340;
Tetraethyl 9-(4-Chlorophenyl)-7-nitro-1H-pyrazolo[5',1':5,1]-
pyrido[2,3,4-bc][1,6]naphthyridine-2,3,5,6-tetrcarboxylate (5g).
1
H nmr (deuteriochloroform) δ: 3.98 (s, 3H, OMe), 3.99 (s, 3H,
OMe), 4.04 (s, 3H, OMe), 4.06 (s, 3H, OMe), 7.42 (d, 1H, J=7.5
Hz, 8-H), 7.46 (dd, 1H, J=7.0. 7.3 Hz, 10-H), 7.69 (dd, 1H. J=7.5,
7.3 Hz, 9-H), 8.84 (d, 1H, J=7.0 Hz, 11-H), 12.10 (br s, 1H, NH):
Compound 5c was differentiated using an noe-difference
experiment. For 5c irradiation of the singlet at δ=12.10
transferred only one nOe was observed at the singlet at δ=8.84,
This compound was prepared from 3f and DEAD in a manner
similar to that described for synthesis of 5a and yellow needles
were obtained in 56% yield, mp 270° (dec.); ir (potassium
bromide): ν 3130, 2960(NH), 1735, 1690(CO), 1582, 1445, 1220
-1
cm ; uv (ethanol) λ max nm: 270, 330, 509: λ min 225, 320,
1
420; H nmr (deuteriodimethyl sulfoxide): δ 1.24-1.40 (m, 8H,
+
verifying the structure of 5c; ms: m/z 452(M +1, 23),
OCH -Me), 4.18-4.45 (m, 12H, OCH -Me ), 7.55 (d, 2H, J=8.5
+
2
2
3
451(M , 100), 420(27), 419(40), 303(30), 194(13), 105(22),
Hz, phenyl-H), 7.70 (s, 1H, 8-H), 8.15 (d, 2H, J=8.5 Hz,
43(89).
+
phenyl-H); ms: m/z(%) 651(M -1, 7), 632(19), 623(18), 620(51),
Anal. Calcd for C H N O (451.3923): C, 58.54; H, 3.80; N,
22 17
3 8
606(25), 547(18), 502(14), 476(36), 474(15), 473(26), 58(20),
45(100).
9.31. Found: C, 55.52; H, 3.81; N, 9.22.
Tetramethyl 8,9,10,11-Tetrahydro-8,10-dimethyl-9,10-dioxo-4H-
pyrimido[5',4':5,6]pyrido[2,3,4-cb][1,6]naphthyridine-2,3,5,6-
tetrcarboxylate (5d).
Anal. Calcd for C H ClN O (652.022): C, 55.26; H, 4.02;
30 21
5 10
N,10.74. Found: C, 55.11; H, 4.12; N, 10.57.
Tetramethyl 4H-s-Triazolo[5',1':2,3]pyrimido[4,5,6-bc][1,6]-
naphthyridine-2,3,5,6-tetrcarboxylate (5h).
This compound was prepared from 3d and DMAD in a manner
similar to that described for synthesis of 5a and yellow needles
were obtained in 53% yield, mp 290-293°; ir (potassium bromide):
ν 3130(NH), 1750, 1725, 1710, 1650, 1630(CO), 1615, 1440, 1280
This compound was prepared from 3g and DMAD in a manner
similar to that described for synthesis of 5a and yellow leaflets
were obtained in 43% yield, mp 217-219°; ir (potassium
-1
cm ; uv (ethanol) λ max nm: 237, 291, 334, 368: λ min 220, 255,
-1;
1
bromide): ν 3200(NH), 1730, 1690(CO), 1625, 1580, 1290 cm
285, 340; H nmr (deuteriodimethyl sulfoxide): δ 3.33 (s, 3x1/3H,
uv (ethanol) λ max nm(log ε): 222(4.61), 326(4.00), 382(4.11);
1/3NMe), 3.34 (s, 3x2/3H, 3x2/3NMe), 3.54 (s, 3x1/3H, 1/3NMe),
3.55 (s, 3x2/3H, 3x2/3NMe), 3.86 (s, 3x1/3, 1/3NMe), 3.89
(s, 3x1/6, OMe), 3.90 (s, 3x1/6H, OMe), 3.92 (s, 3x2/3H,
2/3OMe), 4.03 (s, 3x2/3H, 2/3OMe), 8.42 (s, 1/3x1/2, NH), 8.49
1
H nmr (deuteriodimethyl sulfoxide): δ 3.18(s, 3H, MeOH),
3.90(s, 3H, OMe), 3.92(s, 3H, OMe), 3.93(s, 3H, OMe),
+
3.96(s, 3H, OMe), 8.80(s, 1H, 9-H); ms: m/z(%) 442(M , 16),
+
411(4), 385(4), 384(18), 321(8), 268(17), 45(100).
(s, 1/3x1/2, NH), 12.91 (br s, 2/3H, NH); fab ms: m/z 514(M +1).
Anal. Calcd for C
H N O •CH OH: C, 48.10; H, 3.82;
Anal. Calcd for C H N O (513.420): C, 51.47; H, 3.73;
18 14 6 8 3
22 19
5 10
N,17.72. Found: C, 48.13; H, 3.75; N, 17.72.
N,13.64. Found: C, 51.60; H, 3.77; N, 13.90.
Tetraethyl 4H-s-Triazolo[5',1':2,3]pyrimido[2,3,4-bc][1,6]naph-
thyridine-2,3,5,6-tetrcarboxylate (5i).
Tetraethyl 8,9,10,11-Tetrahydro-8,10-dimethyl-9,10-dioxo-4H-
pyrimido[5',4':5,6]pyrido[2,3,4-cb][1,6]naphthyridine-2,3,5,6-
tetrcarboxylate (5e).
This compound was prepared from 3g and DMAD in a manner
similar to that described for the synthesis of 5a and yellow
leaflets were obtained in 23% yield, mp 197-199°; ir (potassium
bromide): ν 2975(NH), 1735, 1682(CO), 1625, 160, 1592, 1300
This compound was prepared from 3e and DMAD in a manner
similar to that described for synthesis of 5a and yellow needles
were obtained in 59% yield, mp 225-231°; ir (potassium bromide):
-1
cm ; uv (ethanol) λ max nm(log ε): 221(4.64), 326(4.03),
-1
ν 3520, 3425, 3190(NH), 1730, 1710, 1650, 1630(CO), 1610 cm ;
1
383(4.19); H nmr (deuteriodimethyl sulfoxide): δ 1.46 (m, 8H,
1
uv (ethanol) λ max nm(log ε): 237(4.67), 290(4.26), 366(4.18); H
OCH CH ), 4.55 (m, 12H, OCH CH ), 8.58 (s, 1/2H, 9-H), 8.59
2
3
2
3
nmr (deuteriodimethyl sulfoxide): δ 1.23-1.45 (m, 12H,
+
(s, 1/2H, 9-H), 12.70 (br s, 1H, NH); ms: m/z(%) 499(M +1, 9),
498(M , 30), 354(21), 353(14), 282(24), 69(23), 45(100).
OCH CH ), 3.33 (s, 3H, NMe), 3.56 (s, 3H, NMe), 4.30-4.52
2
3
+
(m, 8H, OCH CH ), 8.44 (br s, 1/5H, NH), 12.89 (s, 4/5H, NH);
2
3
+
Anal. Calcd for C H N O •0.5H O: C, 52.83; H, 4.43;
ms: m/z 569(M , 4), 496(3), 425(5), 354(5), 277(5), 44(100).
Anal. Calcd for C H N O (569.533): C, 54.83; H, 4.78;
22 22 6 8 2
N,17.60. Found: C, 52.51; H, 4.37; N, 17.45.
26 27
5 10
N,12.30. Found: C, 54.30; H, 4.72; N, 12.40.
5-Amino-6-cyano-2-methyl-7-methylthiopyrazolo[1,5-a]pyrimi-
dine (3h).
Tetramethyl 7-Nitro-9-phenyl-1H-pyrazolo[5',1':5,1]pyrido-
[2,3,4-bc][1,6]naphthyridine-2,3,5,6-tetrcarboxylate (5f).
A mixture of 9.71 g (0.1 mol) of 3-amino-5-methylpyrazole
and 17.0 g (0.1 mol) of bis(methylthio)methylenemalononitrile
was heated at 15-180° for 1 hour. After cooling, the reaction
mixture was washed methanol. The product was recrystallized
from a mixture of methanol and ethyl acetate (2:1) to give
14.23 g (64.98 mmol) of colorless needles, mp 277-279°; ir
(potassium bromide): ν 3510, 3180(NH), 2210(CN), 1660,
This compound was prepared from 3f and DMAD in a manner
similar to that described for synthesis of 5a and orange yellow
needles were obtained in 75% yield, mp 282-287°; ir (potassium
bromide): ν 3290, 3180 (NH), 1740, 1690(CO), 1630, 1605,
-1
11580, 11440, 1300 cm ; uv (ethanol) λ max nm: 268, 331, 514:
1
λ min 200, 300, 410; H nmr (deuteriodimethyl sulfoxide): δ 3.87
-1
1600 cm ; uv (ethanol) λ max nm(log ε): 222(4.2), 258(4.75),
(s, 9H, OMe), 3.91 (s, 3H, OMe), 7.22-7.52 (m, 3H, phenyl-H),
1
305(4.05). H nmr (deuteriodimethyl sulfoxide): δ 2.37 (s, 3H,
7.61 (s, 1H, 7-H), 8.03-8.13 (m, 2H, phenyl-H); ms: m/z(%)
+
SMe), 2.53 (s, 3H, 2-Me), 6.22 (s, 1H, 3-H), 8.56 (br s,
561(M , 3), 529(100), 515(36), 498(41), 483(57), 419(26),
2H, NH ).
413(54), 45(40).
2
Anal. Calcd for C H N O (561.469): C, 55.62; H, 3.41;
Anal. Calcd for C H N S (219.266): C, 49.30; H, 4.14; N,
26 27
5
10
9 9 5
N,12.47. Found: C, 55.61; H, 3.39; N, 12.38.
31.94; S, 14.62. Found: C, 49.61; H, 4.14; N, 31.87; S, 14.83.

Sep-Oct 2001
Synthesis of Polycyclic Nitrogen-containing Heterocyclic
1141
[5a] H, Matsunaga, M. Sonoda, Y. Tomioka, and M. Yamazaki,
Chem. Pharm. Bull., 34, 396 (1986); [b] H. Matsunaga, M. Sonoda,
Y. Tomioka, and M. Yamazaki, Chem. Pharm. Bull., 32, 2596 (1984) .
[6a] A. Kumar, H. Ila and H. Junjappa, J. Chem. Soc., Perkin Trans
I, 857 (1978); [b] M. Yokoyama and K. Sato, Synthesis, 813 (1988);
[c] R. T. Chakrasali, H. Ila, and H. Junjappa, Synthesis, 453 (1988);
[d] D. Pooranchand, H. Ila, and H. Junjappa, Synthesis, 1136 (1987);
[e] F. Ye, B. Chen, and X. Huang, Synthesis, 317 (1989); [f] A. Hosomi,
Y. Miyashiro, R. Yoshida, Y. Tominaga, T. Yanagi, and M. Hojo , J. Org.
Chem., 55, 5308-5310 (1990); [g] R. C. Anand and A. K. Sinha, J. Chem.
Soc., Perkin . Trans I, 2339 (1991); [h] Y. Tominaga and Y. Matsuda,
J. Heterocyclic Chem., 22, 937 (1985); [i] Y. Tominaga and Y. Matsuda,
Yuki Gousei Kyoukaishi (J. Synth. Org. Chem. Japan), 43, 669 (1985);
[j] R. K. Dieter, Tetrahedron, 42, 3029-3096 (1986); [k] Y. Tominaga,
Yuki Gousei Kyoukaishi (J. Synth. Org. Chem. Japan), 47, 413 (1989);
[l] Y. Tominaga. S. Kohra, H. Honkawa, and A. Hosomi, Heterocycles,
29, 1409 (1989); [m] M. Kolbe, Synthesis, 171 (1990); [n] H. Junjappa,
H. Ila, and C. W. Asokan, Tetrahedron, 46, 5423 (1990); [o] Y. Tominaga,
Trends in Heterocyclic Chemistry, 2, 43 (1991).
[7] Y. Tominaga, S. Kohra, H. Okuda, A. Ushirogochi,
Y. Matsuda, and G. Kobayashi, Chem. Pharm. Bull., 32, 122 (1984).
[8] Compounds 3f and g were prepared by reaction of
5-nitromethyl-3-phenylpyrazoles with bis(methylthio)methylene-
malononitrile in the presence of potassium carbonate in DMSO in 87and
91% yields, respectively. Details will be published in a forthcoming
paper.
[9] A proton of N-H in 5a, b, and c is clearly shown in IR and
NMR spectra, while N-H protons in compounds 5c-i are not fixed by a
particular nitrogen atom. In the present paper, we are drawing by tentative
assignment of configuration to N-H group in Table 3.
Tetramethyl 9-Methyl-4H-pyrazolo[5',1':2,3]pyrimido[4,5,6-bc]-
[1,6]naphthyridine-2,3,5,6-tetrcarboxylate (5j).
This compound was prepared from 3h and DMAD in a manner
similar to that described for synthesis of 5a and yellow needles
were obtained in 47% yield, mp 245-247°; ir (potassium
bromide): ν 3350 (NH), 1745, 1722, 1662 (CO), 1620, 1590,
-1
1440, 1335, 1340, 1250 cm ; uv (ethanol) λ max nm(log ε):
1
239(4.56), 286(4.00), 311(4.09), 396(3.94). H nmr (deuterio-
dimethyl sulfoxide): δ 2.42(s, 3H, 9-Me), 3.18(s, 3H, MeOH),
3.90(s, 3H, OMe), 3.95(s, 3H, OMe), 3.96(s, 6H, 2xOMe),
+
+
6.45(s, 1H, 8-H); ms: m/z(%) 456(M +1, 18), 455(M , 73),
+
425(M -1, 6), 424(32), 423(100), 307(32), 279(21), 45(12).
Anal. Calcd for C
H N O •MeOH: C, 51.74; H, 4.34;
20 17 5 8
N,14.37. Found: C, 51.69; H, 4.27; N, 14.30.
REFERENCES AND NOTES
[1] A part of the work has been published as preliminary commu-
nications: [a] Y. Tominaga and K. Nomoto, Heterocycles, 37, 235 (1994);
[b] Y. Tominaga and N. Yoshioka, Heterocycles, 42, 53 (1996).
[2a] Y. Tominaga, J.-K. Luo, L. W. Castle, and R. N. Castle,
J. Heterocyclic Chem., 30, 267 (1993); [b] Y. Tominaga, R. N. Castle, and
N. K. Dalley, J. Heterocyclic Chem., 30, 295 (1993).
[3] R. Gompper and W. Topfl, Chem. Ber., 95, 2861 (1962).
[4a] E. C. Taylor, A. McKillop, Advances in Organic Chemistry,
Vol. 7; "The Chemistry of Cyclic Enaminonitrile and o-Aminonitrile",
E. C. Taylor, Ed., Interscience; New York, (1970); [b] J. M. Robinson,
L. W. Brent, C. Chau, K. A. Floyd, S. L. Gillham, T. L. McMaham,
D. J. Magda, T. J. Motycka, M. J. Pack, A. L. Roberts, L. A. Seally,
S. L. Simpson, R. R. Smith, and K. N. Zalesny, J. Org. Chem., 57, 7352
(1992).
[10] Y. Tominaga, T. Michioka, K. Moriyama, and A. Hosomi,
J. Heterocyclic Chem., 27, 1217(1990).