Dimethylamine substitution in N,N-dimethyl enamines. Synthesis of aplysinopsin analogues and 3-aminotetrahydrocoumarin derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00174-0

Some new six-membered aplysinopsin analogues were prepared from 5-dimethylaminomethylidene-2,4,6(1H,3H,5H)-pyrimidinetriones and indole derivatives. Also 2-[[(2,4,6-trioxohexahydropyrimidin-5-ylidene)methyl]amino]-3- dimethylaminopropenoates were synthesized and employed in the synthesis of fused 2H-pyran-2-ones.

Full text of DOI:10.1016/S0040-4020(01)00174-0

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 3159±3164
Dimethylamine substitution in N,N-dimethyl enamines.
Synthesis of aplysinopsin analogues and
3-aminotetrahydrocoumarin derivatives
b,p
Ïa
Lovro Selic and Branko Stanovnik
a
Ï
Lek, Research and Development C20, Kolodvorska 27, 1234 Menges, Slovenia
Ï Ï
Faculty of Chemistry and Chemical Technology, University of Ljubljana, P.O. Box 537, Askerceva 5, 1000 Ljubljana, Slovenia
b
Received 7 November 2000; revised 12 January 2001; accepted 1 February 2001
AbstractÐSome new six-membered aplysinopsin analogues were prepared from 5-dimethylaminomethylidene-2,4,6+1H,3H,5H)-
pyrimidinetriones and indole derivatives. Also 2-[[+2,4,6-trioxohexahydropyrimidin-5-ylidene)methyl]amino]-3-dimethylaminopropenoates
were synthesized and employed in the synthesis of fused 2H-pyran-2-ones. q 2001 Elsevier Science Ltd. All rights reserved.
Aplysinopsins +1) +Fig. 1), isolated from various marine
organisms +sponges, corals, etc.),1±6 have aroused consider-
able interest due to their cytotoxicity towards cancer cells3
and their ability to affect neurotransmitters.2
which the hydantoin moiety is replaced with barbituric
acid, and the preparation of 3-[+2,4,6-trioxohexahydro-
pyrimidin-5-ylidene)methyl]amino-substituted 2H-1-benzo-
pyran-2-one derivatives.
Recently, a series of alkyl 2-[+2,2-disubstituted ethenyl)
amino]-3-dimethylaminopropenoates have been prepared
as versatile reagents for the synthesis of various heterocyclic
systems, such as 2H-pyran-2-ones and fused derivatives,
fused pyridinones and pyrimidinones,7,8 polysubstituted
pyrrole-2-carboxylates9 and imidazole-4-carboxylates.10
As an extension of this work, we have recently described11
a simple and stereoselective syntheses which afford aplysi-
nopsins, thioaplysinopsins and derivatives in which the
hydantoin moiety is replaced with 1,4,5,6-tetrahydro-
1,2,4+1H,4H)-triazin-6-one, with good overall yields. The
methodology, which describes a series of simple syntheses
of heterocycles from a group of simple reagents, can
perhaps be further developed into automated or semiauto-
mated parallel synthesis. In a continuation of our study, we
now present the synthesis of aplysinopsin analogues in
Barbituric acid +2a) and its 1,3-dimethyl derivative +2b)
were stirred in an appropriate solvent in the presence of
dimethylformamide dimethyl acetal +DMFDMA) to
form 5-dimethylaminomethylidene-2,4,6+1H,3H,5H)-
pyrimidinetriones 3a and b in quantitative yield. The
latter were heated with an indole derivative +viz. indole,
5-bromoindole, 7-ethylindole and 2-methylindole) in
glacial acetic acid to give 5-[+1H-indol-3-yl)methyl-
idene]-2,4,6+1H,3H,5H)-pyrimidinetriones
yield +Scheme 1).
4 in 11±85%
Compounds 4a±f show a characteristic signal for the indole
H-2 in the 9.45±9.54 ppm region, suggesting a weak hydro-
gen bond to the pyrimidinone oxo group, and a signal for the
bridge methylidene group at 8.6±8.8 ppm. Compound 4g,
with methyl group at the indole position 2, has a signal for
the bridge methylidene group at 8.48 ppm. Furthermore,
compounds 4a±f show the signal for the indole H-4 proton
at 7.68±8.03 ppm, while in 4g it appears at 7.39 ppm. Based
on these data and NMR and X-ray studies published
earlier,5,11 we conclude that compound 4g exists in a non
planar form, due to steric repulsion between the indole
methyl group and pyrimidinone oxo group, while
compounds 4a±f are probably planar, with a hydrogen
bond between the indole H-2 and a pyrimidinone oxygen
atom +Scheme 1).
H
N
R1
N
X
Y
N
R2
1
O
X=H, Br; Y=O, NH, NMe; R1,R2=H, Me.
Figure 1.
Compound 3b reacts with 2-methylindole in a different
manner from 3a. Instead of the expected 1,3-dimethyl-5-
[+2-methyl-1H-indol-3-yl)methylidene]-2,4,6+1H,3H,5H)-
Keywords: eneamines; pyrimidones; pyrones.
Corresponding author. Tel.: 1386-1-4760-500; fax: 1386-1-425-8220;
e-mail: branko.stanovnik@uni-lj.si
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00174-0

Ï
L. Selic, B. Stanovnik / Tetrahedron 57 32001) 3159±3164
3160
R3
H
R3
N
H
R1
N
R1
N
N
O
O
R1
R1
R2
O
O
O
O
N
N
DMFDMA
DMSO or MeCN
R2
AcOH
O
N
NMe2
N
R1
R1
O
O
2a R1=H
2b R1=Me
3a R1=H (98%)
3b R1=Me (98%)
4a R1=R2=R3=H (73%)
4b R1=Me; R2=R3=H (11%)
4c R1=R3=H; R2=Br (69%)
4d R1=Me; R3=H; R2=Br (29%)
4e R1=R2=H; R3=Et (56%)
4f R1=Me; R2=H; R3=Et (11%)
H
N
Me
H
N
Me
DMFDMA
AcOH
H
N
AcOH
Me
H
N
O
from 3b
from 3a
Me
O
HN
O
Me
HN
NH
NH
4g (85%)
Me
5 (71%)
Scheme 1.
pyrimidinetrione, tris+2-methyl-1H-indol-3-yl)methane +5)
was isolated in 71% yield. This is a known compound12
and was identical with a sample prepared by an unambig-
uous synthesis.
In the second part of this research, compounds 3a and b were
transformed into 2-[[+2,4,6-trioxohexahydropyrimidin-5-
ylidene)methyl]amino]-3-dimethylaminopropenoates 7 in
two steps, by reaction with methyl glycinate hydrochloride
R1
R1
O
N
O
O
N
O
H
H
N
N
COOMe
ii
R1
i
N
N
COOMe
R1
3
O
Me2N
O
7a R1=H (72%)
7b R1=Me (70%)
6a R1=H (85%)
6b R1=Me (76%)
R4
O
R4
O
AcOH
R4
R4
O
O
O
O
O
O
R4
R4
R1
O
N
H
OAlkyl
OAlkyl
N
H
N
iii
O
O
O
O
N
R1
9
8a R1=H; R4=Me (88%)
8b R1=R4=H (37%)
8c R1=R4=Me (86%)
8d R1=Me, R4=H (91%)
Scheme 2. +i) MeOOCCH2NH2´HCl, AcOH; +ii) DMFDMA, MeCN; +iii) NH2CONH2.

Ï
L. Selic, B. Stanovnik / Tetrahedron 57 32001) 3159±3164
3161
in the initial and introduction of dimethylaminomethylene
group with DMFDMA in the second step +Scheme 2), in
overall yields of 53% +7a) and 62% +7b).
and recrystallized from 2-propanol to give the title
compound 3b +10.77 g, 98%) as yellow crystals; mp 108±
1118C. +Found: C, 49.01; H, 6.37; N, 19.09.
C9H13N3O3´0.5H2O requires C, 49.09; H, 6.41; N, 19.08.);
It has been shown that all alkyl 2-[+2,2-disubstituted ethenyl)
amino]-3-dimethylaminopropenoates synthesized to date,
exist in the Z form.7c,8,13 The chemical shift of the H-3
proton in DMSO-d6 in these compounds is always
found in the narrow interval of 7.27±7.33 ppm. Compounds
7a and b exhibit the H-3 at dˆ7.32 and 7.33 ppm,
respectively, so we can assume that they exist in the Z
form as well.
nmax +KBr) 3430, 2960, 1710, 1630 cm21
.
1.2. General procedure for the synthesis of 5-[(1H-indol-
3-yl)methylidene]-2,4,6(1H,3H,5H)-pyrimidinetriones 4
Indole derivative +1 mmol) and compound 3 +1 mmol) in
glacial acetic acid +4 mL) were heated at 90±1008C for
several hours. After that, volatile components were evapo-
rated in vacuo and 2-propanol was added for the crystal-
lization or alternatively, 2-propanol was added directly into
the cooled reaction mixture to form precipitate, which was
collected by ®ltration and puri®ed with recrystallization
from an appropriate solvent. Compounds 4a±g were
prepared according to this procedure.
Propenoates 7, together with 1,3-cyclohexanedione and 5,5-
dimethylcyclohexane-1,3-dione, gave 3-[[+2,4,6-trioxo-
hexahydropyrimidin-5-ylidene)methyl]amino]-5,6,7,8-tetra-
hydro-2H-1-benzopyran-2-ones 8 in good yields +Scheme
2). Note that these compounds cannot be prepared from the
corresponding 3-[[2,2-bis+alkoxycarbonyl)ethenyl]amino]-
2H-1-benzopyranone derivatives 9 and urea derivatives,
since the ethenyl group is very sensitive to nucleophiles
and its elimination takes place preferentially.14
1.2.1. 5-[(1H-Indol-3-yl)methylidene]-2,4,6(1H,3H,5H)-
pyrimidinetrione (4a). Prepared from indole and 3a, 4 h,
187 mg +73%) of a yellow solid; mp.2608C +DMF).
+Found: C, 61.45; H, 3.42; N, 16.41. C13H9N3O3 requires
C, 61.18; H, 3.55; N, 16.46.); nmax +KBr) 3350, 3280, 3160,
In conclusion, we have demonstrated that our previously
described approach towards aplysinopsins11 can be easily
generalized to provide diverse aplysinopsin mimic struc-
tures. Apart from that, 3-[[+2,4,6-trioxohexahydropyrimi-
din-5-ylidene)methyl]amino]-5,6,7,8-tetrahydro-2H-1-benzo-
pyran-2-ones 8 were prepared from barbituric acid and its
N,N-dimethyl derivative in good overall yields.
2810, 1730, 1690, 1660, 1550, 1220 cm21
.
1.2.2. 1,3-Dimethyl-5-[(1H-indol-3-yl)methylidene]-2,4,6
(1H,3H,5H)-pyrimidinetrione (4b). Prepared from indole
and 3b, 5 h, 31 mg +11%) of a yellow solid; mp.2608C
+AcOH/2-propanol). +Found: C, 63.86; H, 4.29; N, 14.75.
C15H13N3O3 requires C, 63.60; H, 4.63; N, 14.83.); nmax
+KBr) 3420, 3270, 1720, 1660, 1630, 1550, 1220 cm21
.
1. Experimental
1.1. General
1.2.3. 5-[(5-Bromo-1H-indol-3-yl)methylidene]-2,4,6(1H,
3H,5H)-pyrimidinetrione (4c). Prepared from 5-bromoin-
dole and 3a, 3.5 h, 231 mg +69%) of a yellow solid;
mp.2608C +2-propanol). +Found: C, 45.32; H, 2.61; N,
12.01. C13H8N3O3´0.5H2O requires C, 45.50; H, 2.64; N,
12.25.); nmax +KBr) 3440, 3160, 2840, 1740, 1690, 1650,
Melting points were determined on a Ko¯er hot-plate melt-
ing point apparatus. NMR spectra were recorded on Varian
1
VXR 300 at 300 MHz for H and 75 MHz for 13C nucleus,
using DMSO-d6 as
a solvent. Microanalyses were
1530, 1190 cm21
.
performed on a Perkin±Elmer 2400C instrument, mass
spectra recorded on Autospec Q spectrometer and IR spectra
on BIO-RAD FTS 60 spectrometer. NMR data are summar-
ized in Tables 1 and 2.
1.2.4. 1,3-Dimethyl-5-[(5-bromo-1H-indol-3-yl)methyl-
idene]-2,4,6(1H,3H,5H)-pyrimidinetrione (4d). Prepared
from 5-bromoindole and 3b, 5 h, 105 mg +29%) of a
yellow solid; mp.2608C +AcOH). +Found: C, 49.98; H,
3.09; N, 11.51. C15H12BrN3O3 requires C, 49.74; H, 3.34;
N, 11.60.); nmax +KBr) 3440, 3310, 1720, 1650, 1550,
1.1.1. 5-Dimethylaminomethylidene-2,4,6(1H,3H,5H)-
pyrimidinetrione (3a). To a suspension of barbituric acid
+2a, 8.5 mmol, 1084 mg) in DMSO +5 mL), DMFDMA
+12.7 mmol, 2 mL) was added and the mixture was stirred
at rt for 3±6 h. After that, 5 mL of 2-propanol was added to
the mixture and solid residue was ®ltered off and recrystal-
lized from DMFto give the title compound 3a +1526 mg,
98%) as yellow crystals; mp.2608C; m/z +EI) 183 +M1).
+Found: C, 45.61; H, 4.78; N, 22.56. C7H9N3O3 requires C,
45.90; H, 4.95; N, 22.94.); nmax +KBr) 3430, 3000, 2810,
1190 cm21
.
1.2.5. 5-[(7-Ethyl-1H-indol-3-yl)methylidene]-2,4,6(1H,
3H,5H)-pyrimidinetrione (4e). Prepared from 7-ethyl-
indole and 3a, 1 h, 159 mg +56%) of a yellow solid;
mp.2608C +DMF). +Found: C, 61.24; H, 5.13; N, 14.70.
C15H13N3O´0.5H2O requires: C, 61.64; H, 4.83; N, 14.38.);
n
max +KBr) 3440, 3250, 2840, 1750, 1640, 1540, 1200 cm21
.
1700, 1630 cm21
.
1.2.6. 1,3-Dimethyl-5-[(7-ethyl-1H-indol-3-yl) methyl-
idene]-2,4,6(1H,3H,5H)-pyrimidinetrione (4f). Prepared
from 7-ethylindole and 3b, 40 min, 34 mg +11%) of a yellow
solid; mp.2608C +AcOH). +Found: C, 65.78; H, 5.59; N,
13.32. C17H17N3O3 requires C, 65.58; H, 5.50; N, 13.50.);
1.1.2. 1,3-Dimethyl-5-dimethylaminomethylidene-2,4,6
(1H,3H,5H)-pyrimidinetrione (3b). To a suspension of
1,3-dimethylbarbituric acid +2b, 52.1 mmol, 8.14 g) in ace-
tonitrile +5 mL), DMFDMA +67.8 mmol, 11 mL) was added
and the mixture was stirred at rt for 5±6 h. After that, 2-
propanol +10 mL) was added, solid residue was ®ltered off
nmax +KBr) 3360, 1720, 1660, 1630, 1560, 1200 cm21
.

Ï
L. Selic, B. Stanovnik / Tetrahedron 57 32001) 3159±3164
3162
Table 1. 1H and 13C NMR data for compounds 3±5
Compound
1H NMR
13C NMR
3a
3.25 and 3.39 +3H, s, NMe2),
8.02 +1H, s, ±CHv), 10.08 and
10.36 +1H, s, NH)
44.3, 48.3, 89.0, 100.4, 151.2,
156.2, 161.0
3b
4a
3.06 +3H, s, NMe), 3.10 +6H, s,
NMe2), 3.22 +3H, s, NMe), 8.11
+1H, s, ±CHv)
7.28±7.34 +2H, m, H-5, H-6),
7.58 +1H, dd, Jˆ6.0, 2.5 Hz, H-
7), 7.86 +1H, dd, Jˆ6.3, 2.9 Hz,
H-4), 8.72 +1H, s, ±CHv), 9.49
+1H, d, Jˆ2.9 Hz, H-2), 10.90
and 10.98 +1H, s, NH), 12.62
+1H, brs, NH±indole)
26.5, 27.4, 44.4, 48.2, 89.0, 95.4,
152.0, 161.9, 185.3
108.5, 111.2, 112.9, 117.4,
122.4, 123.4, 129.0, 136.2,
139.5, 143.6, 150.1, 163.0, 164.3
4b
4c
4d
3.26 and 3.27 +1H, s, NMe),
7.32±7.35 +2H, m, H-5, H-6),
7.58±7.62 +1H, m, H-7), 7.87±
7.90 +1H, m, H-4), 8.81 +1H, s, ±
CHv), 9.54 +1H, d, Jˆ2.8 Hz,
H-2), 12.82 +1H, s, NH±indole)
7.45 +1H, dd, Jˆ1.7, 8.7 Hz, H-
6), 7.57 +1H, d, Jˆ8.7 Hz, H-7),
8.03 +1H, d, Jˆ1.7 Hz, H-4),
8.61 +1H, s, ±CHv), 9.48 +1H,
s, H-2), 11.10 and 11.18 +1H, s,
NH), 12.82 +1H, s, NH±indole)
3.21 and 3.22 +3H, s, NMe), 7.42
+1H, dd, Jˆ1.6, 8.5 Hz, H-6),
7.54 +1H, d, Jˆ8.5 Hz, H-7),
7.97 +1H, d, Jˆ1.6 Hz, H-4),
8.66 +1H, s, ±CHv), 9.45 +1H,
s, H-2), 12.74 +1H, s, NH±
indole)
27.7, 28.3, 108.1, 111.6, 113.1,
117.5, 122.7, 123.7, 129.3,
136.4, 139.9, 144.5, 151.2,
161.5, 163.0
109.6, 110.7, 115.1, 115.3,
120.4, 126.2, 131.0, 135.2,
140.3, 143.3, 150.3, 163.2, 164.3
27.5, 28.1, 108.9, 110.7, 114.8,
115.2, 120.0, 126.0, 130.9,
135.0, 140.1, 143.9, 150.9,
161.2, 162.6
4e
1.29 +3H, t, Jˆ7.6 Hz, Et), 2.93
+2H, q, Jˆ7.6 Hz, Et), 7.16 +1H,
d, Jˆ7.3 Hz, H-6), 7.27 +1H, dd,
Jˆ7.3, 7.7 Hz, H-5), 7.71 +1H,
d, Jˆ7.7 Hz, H-4), 8.72 +1H, s,
±CHv), 9.50 +1H, d, Jˆ3.3 Hz,
H-2), 11.05 and 11.13 +1H, s,
NH), 12.78 +1H, s, NH±indole)
1.27 +3H, t, Jˆ7.5 Hz, Et), 2.91
+2H, q, Jˆ7.5 Hz, Et), 3.22 and
3.24 +3H, s, NMe), 7.15 +1H, d,
Jˆ7.2 Hz, H-6), 7.26 +1H, dd,
Jˆ7.2, 7.9 Hz, H-5), 7.68 +1H,
d, Jˆ7.9 Hz, H-4), 8.77 +1H, s,
±CHv), 9.47 +1H, s, H-2),
12.82 +1H, s, NH±indole)
14.6, 23.4, 108.6, 111.8, 115.3,
122.6, 123.0, 128.9, 129.2,
135.1, 139.4, 143.8, 150.4,
163.3, 164.6
4f
14.6, 23.4, 27.8, 28.4, 108.2,
112.0, 115.2, 122.7, 123.1,
128.9, 129.3, 135.1, 139.4,
144.7, 151.2, 161.6, 163.1
4g
2.54 +3H, s, 2-Me), 7.11±7.24
+3H, m, H-5, H-6, H-7), 7.39
+1H, d, Jˆ7.8 Hz, H-4), 8.48
+1H, s, ±CHv), 10.86 and 11.02
+1H, s, NH), 12.53 +1H, s, NH±
indole)
13.5, 108.9, 111.6, 112.0, 121.3,
122.6, 123.1, 126.7, 136.4,
146.0, 150.6, 151.3, 161.6, 164.4
5
1.92 +9H, s, 2-Me), 6.09 +1H, s,
CH), 6.62 +3H, dd, Jˆ7.1,
8.1 Hz, H-6), 6.79 +3H, d,
Jˆ7.1 Hz, H-7), 6.86 +3H, dd,
Jˆ8.1, 8.1 Hz, H-5), 7.19 +3H,
d, Jˆ8.1 Hz, H-4), 10.61 +3H, s,
NH±indole)
11.7, 30.5 +3), 110.1 +3), 112.2
+3), 117.8 +3), 118.2 +3), 119.3
+3), 128.8 +3), 131.6 +3), 134.8
+3)
1.2.7.
5-[(2-Methyl-1H-indol-3-yl)methylidene]-2,4,6
1.3. Tris(2-methyl-1H-indol-3-yl)methane (5)
(1H,3H,5H)-pyrimidinetrione (4g). Prepared from 2-
methylindole and 3a, 5.5 h, 229 mg +85%) of a yellow
solid; mp.2608C +DMF). +Found: C, 62.06; H, 3.93; N,
15.46. C14H11N3O3 requires C, 62.45; H, 4.12; N, 15.61.);
2-Methylindole +1 mmol) and compound 3b +1 mmol) in
glacial acetic acid +4 mL) were heated at 90±1008C for
2 h. After that, 4 mL of 2-propanol was added, precipitate
was collected by ®ltration and dissolved in boiling DMF.
After cooling, 2-propanol was added and precipitate
nmax +KBr) 3430, 3120, 3030, 2840, 1720, 1690, 1630, 1550,
1530, 1240 cm21
.

Ï
L. Selic, B. Stanovnik / Tetrahedron 57 32001) 3159±3164
3163
1
Table 2. H and 13C NMR data for compounds 6±8
Compound
1H NMR
13C NMR
6a
3.68 +3H, s, COOMe), 4.37
+2H, d, Jˆ6.1 Hz, CH2), 8.13
+1H, d, Jˆ14.4 Hz, ±CHv),
10.11 +1H, td, Jˆ6.1 Hz, 14.4,
NH), 10.60 and 10.79 +1H, s,
NH)
49.9, 52.2, 90.4, 150.9, 160.0,
163.9, 165.9, 169.6
6b
7a
3.13 and 3.14 +s, 3H, NMe),
3.68 +3H, s, COOMe), 4.41
+2H, d, Jˆ6.1, CH2), 8.23 +1H,
d, Jˆ14.6, ±CHv), 10.27 +1H,
td, Jˆ6.1, 14.6, NH)
26.8, 27.4, 50.0, 52.2, 90.4,
151.6, 160.6, 162.2, 163.7, 169.5
2.99 +6H, s, NMe2), 3.62 +3H,
s, COOMe), 7.32 +1H, s, H-3),
7.84 +1H, d, Jˆ14.3 Hz,
42.6 +2), 51.2, 90.5, 98.1, 145.0,
151.0, 160.1, 163.8, 166.1
CHNH), 10.36 and 10.67 +1H,
s, NH), 10.75 +1H, d,
Jˆ14.3 Hz, CHNH)
7b
8a
8b
8c
8d
2.98 +6H, s, NMe2), 3.14 and
3.15 +3H, s, NMe), 3.59 +3H, s,
COOMe), 7.33 +1H, s, H-3),
7.92 +1H, d, Jˆ14.1 Hz,
26.3, 26.8, 42.1 +2), 50.5, 90.3,
98.0, 144.4, 151.1, 160.0, 163.6,
165.3
CHNH), 10.83 +1H, d,
Jˆ14.1 Hz, CHNH)
1.09 +6H, s, 2£7-Me), 2.45 and
2.82 +2H, s, CH2), 7.86 +1H, s,
H4), 8.60 +1H, d, Jˆ13.7 Hz,
CHNH), 10.65 and 10.83 +1H,
s, NH), 11.68 +1H, d,
27.2 +2), 32.0, 40.0, 49.5, 94.3,
112.8, 118.3, 123.5, 149.9,
150.5, 157.1, 162.5, 165.8,
167.8, 193.0
Jˆ13.7 Hz, CHNH)
2.10 +2H, m, CH2), 2.53 and
2.89 +2H, t, Jˆ5.9 Hz, CH2),
7.86 +1H, s, H-4), 8.60 +1H, d,
Jˆ13.7 Hz, CHNH), 10.65 and
10.83 +1H, s, NH), 11.68 +1H,
d, Jˆ13.7 Hz, CHNH)
19.4, 26.6, 35.6, 94.3, 113.7,
118.5, 123.5, 149.9, 150.4,
156.8, 162.5, 165.8, 169.4, 193.2
1.09 +6H, s, 2£7-Me), 2.45 and
2.82 +2H, s, CH2), 3.18 and
3.20 +3H, s, NMe), 7.91 +1H, s,
H-4), 8.70 +1H, d, Jˆ13.9 Hz,
CHNH), 11.78 +1H, d,
26.6, 27.2, 27.3 +2), 32.0, 40.1,
49.6, 94.3, 112.8, 118.7, 123.5,
150.9, 151.2, 157.2, 161.1,
163.9, 168.0, 193.1
Jˆ13.9 Hz, NH)
2.10 +2H, m, CH2), 2.53 +2H, t,
Jˆ6.0 Hz, CH2), 2.90 +2H, m,
CH2), 3.17 and 3.18 +3H, s,
NMe), 8.00 +1H, s, H-4), 8.74
+1H, d, Jˆ13.8 Hz, CHNH),
11.86 +1H, d, Jˆ13.8 Hz, NH)
19.8, 27.0 +2), 27.7, 36.1, 94.5,
114.0, 119.0, 123.7, 151.3,
151.6, 157.4, 161.5, 164.3,
170.1, 194.0
collected by ®ltration to give the title compound 5 +96 mg,
71%) as a pink solid; mp.2608C +Lit.12 3198C). +Found:
C, 83.56; H, 6.06; N, 10.32. C28H25N3 requires C, 83.34;
H, 6.24; N, 10.41.); m/z +EI) 403 +1M1), 402 +2), 273
+100%).
crystallization. The precipitate was collected by
®ltration and recrystallized from an appropriate solvent.
Compounds 6a and b were prepared according to this
procedure.
1.4.1. Methyl N-[(2,4,6-trioxohexahydropyrimidin-5-
ylidene)methyl]glycinate (6a). Prepared from 3a,
1930 mg +85%) of white crystals; mp .2608C +DMF).
+Found: C, 42.12; H, 4.00; N, 18.25. C8H9N3O5 requires
C, 42.30; H, 3.99; N, 18.50.); nmax +KBr) 3240, 1760,
Alternative procedure: 2-methylindole +12 mmol) was
dissolved in glacial acetic acid +10 mL) and DMFDMA
+4.8 mmol) was added to the solution which was then heated
at 808C for 60 min. Precipitate was collected from the hot
suspension and washed with 2-propanol to give the title
compound 5 +1065 mg, 66%) as a pink solid.
1680, 1650, 1590, 1470 cm21
.
1.4.2. Methyl N-[(1,3-dimethyl-2,4,6-trioxohexahydro-
pyrimidin-5-ylidene)methyl]glycinate (6b). Prepared
from 3b, 1938 mg +76%) of white crystals; mp 164±
1668C +acetonitrile/2-propanol 1:1). +Found: C, 47.05; H,
5.05; N, 16.41. C10H13N3O5 requires C, 47.06; H, 5.13; N,
16.46.); nmax +KBr) 3250, 2970, 2940, 1750, 1660, 1630,
1.4. General procedure for glycinates 6
Compound 3 +10 mmol) and methyl glycinate hydro-
chloride +10 mmol) in acetic acid +12 mL) were heated at
90±1008C for 3 h. After that, volatile components were
evaporated in vacuo and 2-propanol was added for the
1480 cm21
.

Ï
L. Selic, B. Stanovnik / Tetrahedron 57 32001) 3159±3164
3164
1.4.3. (Z)-Methyl 2-[[(2,4,6-trioxohexahydropyrimidin-
5-ylidene)methyl]amino]-3-dimethylaminopropenoate
(7a). To a suspension of 6a +485 mg, 2.14 mmol) in aceto-
nitrile +4 mL), DMFDMA +0.5 mL, 3.33 mmol) was added
and the mixture was heated at 80±908C for 3 h. After that,
solution was concentrated in vacuo and 2-propanol was
added and precipitate collected by ®ltration and
recrystallized from DMFto give the title compound 7a
+435 mg, 72%) as a pale orange solid; mp.2608C.
+Found: C, 44.26; H, 4.92; N, 18.52. C11H14N4O5´H2O
requires C, 44.00; H, 5.37; N, 18.66.); nmax +KBr) 3440,
57.90; H, 5.13; N, 11.25.); nmax +KBr) 3470, 3060, 2970,
1735, 1670, 1630, 1590 cm21
.
1.5.4. 5-Oxo-3-[[(1,3-dimethyl-2,4,6-trioxohexahydro-
pyrimidin-5-ylidene)methyl]amino]-5,6,7,8-tetrahydro-
2H-1-benzopyran-2-one (8d). Prepared from 7b and 1,3-
cyclohexanedione, 2.5 h, 314 mg +91%) of a yellow solid;
mp 218±222 +dec.) +MeCN). +Found: C, 53.82; H, 4.29; N,
11.47. C16H15N3O6´0.5H2O requires C, 54.24; H, 4.55; N,
11.86.); nmax +KBr) 3430, 3060, 2960, 1735, 1670, 1630,
1590 cm21
.
3180, 3000, 2820, 1710, 1650, 1590 cm21
.
References
1.4.4. (Z)-Methyl 2-[[(1,3-dimethyl-2,4,6-trioxohexa-
hydropyrimidin-5-ylidene)methyl]amino]-3-dimethyl-
aminopropenoate (7b). To a suspension of 6b +1045 mg,
4.10 mmol) in acetonitrile +10 mL), DMFDMA +0.8 mL,
5.33 mmol) was added and the mixture was heated at 80±
908C for 10 min. Precipitate was collected by ®ltration and
recrystallized from the mixture of DMFand acetonitrile
+4:1) to give the title compound 7b +890 mg, 70%) as
white crystals; mp.2608C. +Found: C, 50.29; H, 5.73; N,
17.92. C13H18N4O5 requires C, 50.32; H, 5.85; N, 18.06.);
1. Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J.
Tetrahedron Lett. 1977, 61±64.
2. Baker, J. T.; Wells, R. J. In Natural Products as Medicinal
Reagents, Beal, J. L., Reinhard, E., Eds.; Hippokrates Verlag:
Stuttgart, 1981; pp 299±303.
3. Hollenbeak, K. H.; Schmitz, F. J. Lloydia 1977, 40, 479±481.
4. Djura, P.; Faulkner, O. J. J. Org. Chem. 1980, 45, 735±737.
5. Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv. Chim.
Acta 1989, 71, 773±782.
n
max +KBr) 3450, 2960, 1700, 1630 cm21.
6. Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv. Chim.
Acta 1988, 72, 1444±1450.
1.5. General procedure for 2H-1-benzopyran-2-ones 8
7. For reviews see: +a) Stanovnik, B. Methyl 2-Benzoylamino-3-
Dimethylaminopropenoate in the Synthesis of Heterocyclic
Systems. In Progress in Heterocyclic Chemistry, Suschitzky,
H., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1993; vol. 5, pp
34±53. +b) Stanovnik, B. Molecules 1996, 1, 123±127.
+c) Stanovnik, B.; Svete, J. Synlett 2000, 1077±1091.
To the suspension of 7 +1 mmol) in glacial acetic acid +4±
5 mL), appropriate cyclohexanedione +1 mmol) was added
and the mixture was heated at 90±1008C for several hours.
After that, volatile components were evaporated in vacuo
and 2-propanol was added for the crystallization. Precipitate
was collected by ®ltration and recrystallized from an appro-
priate solvent. Compounds 8a±d were prepared in this
manner.
Ï Ï
8. For recent publications see: +a) Selic, L.; Golic-Grdadolnik, S.;
Stanovnik, B. Helv. Chim. Acta 1997, 80, 2418±2425.
Ï
+b) Smodis, J.; Stanovnik, B. Tetrahedron 1998, 54, 9799±
9810. +c) Pizzioli, L.; Ornik, B.; Svete, J.; Stanovnik, B.
Ï
Helv. Chim. Acta 1998, 81, 231±235. +d) Selic, L.; Golic-
Ï
1.5.1.
7,7-Dimethyl-5-oxo-3-[[(2,4,6-trioxohexahydro-
Grdadolnik, S.; Stanovnik, B. Heterocycles 1998, 49, 133±
Ï
142. +e) Skof, M.; Svete, J.; Stanovnik, B.; Golic, L.; Golic-
pyrimidin-5-ylidene)methyl]amino]-5,6,7,8-tetrahydro-
2H-1-benzopyran-2-one (8a). Prepared from 7a and 5,5-
dimethylcyclohexan-1,3-dione, 2.5 h, 304 mg +88%) of a
slightly yellow solid; mp.2608C +DMF). +Found: C,
55.33; H, 4.36; N, 12.07. C16H15N3O6 requires C, 55.65;
H, 4.38; N, 12.17.); nmax +KBr) 3440, 3250, 3040, 1735,
Ï
Ï
Ï
Grdadolnik, S.; Selic, L. Helv. Chim. Acta 1998, 81, 2332±
Ï
2340. +f) Skof, M.; Svete, J.; Kmetic, M.; Golic-Grdadolnik,
Ï
Ï
S.; Stanovnik, B. Eur. J. Org. Chem. 1999, 1581±1584.
Ï Ï
+g) Selic, L.; Golic-Grdadolnik, S.; Stanovnik, B.
Ï
Heterocycles 1997, 45, 2349±2356. +h) Toplak, R.; Selic, L.;
Ï
Sorsak, G.; Stanovnik, B. Heterocycles 1997, 45, 555±565.
Ï Ï
+i) Selic, L.; Stanovnik, B.; Golic-Grdadolnik, S. Acta Chim.
1680, 1600 cm21
.
1.5.2.
5-Oxo-3-[[(2,4,6-trioxohexahydropyrimidin-5-
Slov. 2000, 47, 413±420.
Ï
9. +a) Selic, L.; Stanovnik, B. Helv. Chim. Acta 1998, 81, 1634±
Ï
1639. +b) Selic, L.; Stanovnik, B. Synthesis 1999, 479±482.
Ï
10. Selic, L.; Stanovnik, B. J. Heterocycl. Chem. 1998, 35, 1527±
1529.
ylidene)methyl]amino]-5,6,7,8-tetrahydro-2H-1-benzo-
pyran-2-one (8b). Prepared from 7a and 1,3-cyclohexane-
dione, 2 h, 117 mg +37%) of a slightly yellow solid;
mp.2608C +DMF). +Found: C, 51.62; H, 3.65; N, 12.82.
C14H11N3O6´0.5H2O requires C, 51.54; H, 3.71; N, 12.88.);
Ï
Ï
Ï
Ï
Ï
11. Selic, L.; Jakse, R.; Lampic, K.; Golic, L.; Golic-Grdadolnik,
S.; Stanovnik, B. Helv. Chim. Acta 2000, 83, 2802±2811.
12. Fischer, H.; Pistor, K. Ber. 1923, 56, 2313±2319.
nmax +KBr) 3500, 3240, 3060, 1735, 1680, 1600 cm21
.
1.5.3. 7,7-Dimethyl-5-oxo-3-[[(1,3-dimethyl-2,4,6-trioxo-
hexahydropyrimidin-5-ylidene)methyl]amino]-5,6,7,8-
tetrahydro-2H-1-benzopyran-2-one (8c). Prepared from
7b and 5,5-dimethylcyclohexan-1,3-dione, 4 h, 321 mg
+86%) of green±yellow crystals; mp 243±2468C +MeCN).
+Found: C, 57.82; H, 4.99; N, 11.34. C18H19N3O6 requires C,
Ï
13. Golic-Grdadolnik, S.; Stanovnik, B. Magn. Reson. Chem.
1997, 35, 482±486.
14. For typical examples see: Selic, L.; Strah, S.; Toplak, R.;
Ï
Stanovnik, B. Heterocycles 1998, 47, 1017±1022 and Refs.
8a,d,g.