Purins, pyrimidines, and related condensed systems. 22. Synthesis and heterocyclization of 7-alkynyl- and 6,7-dialkynyllumazines

Article abstract of DOI:10.1007/s10593-005-0118-3

The reaction of 6,7-dichloro-1,3-dimethyllumazine with terminal alkynes under Sonogashira conditions gave 7-alkynyl-6-chloro- and 6,7-dialkynyl-1,3- dimethyllumazines. It was found that the alkynyllumazines readily add primary and secondary alkylamines at

Full text of DOI:10.1007/s10593-005-0118-3

Chemistry of Heterocyclic Compounds, Vol. 41, No. 1, 2005
PURINS, PYRIMIDINES, AND RELATED
CONDENSED SYSTEMS. 22.* SYNTHESIS AND
HETEROCYCLIZATION OF 7-ALKYNYL-
AND 6,7-DIALKYNYLLUMAZINES
Shi Van Dang, A. V. Gulevskaya, A. F. Pozharskii, and R. V. Kotelevskaya
The reaction of 6,7-dichloro-1,3-dimethyllumazine with terminal alkynes under Sonogashira conditions
gave 7-alkynyl-6-chloro- and 6,7-dialkynyl-1,3-dimethyllumazines. It was found that the
alkynyllumazines readily add primary and secondary alkylamines at the 7-alkynyl group to form stable
enamines, hydrolysis of which gives 7-(β-hydroxyvinyl)lumazines. The heterocyclization of
7-(β-aminovinyl)- and 7-(β-hydroxyvinyl)lumazines has been carried out to give pyrrolo-, pyrido-, furo-,
and pyranopteridines.
Keywords: 1-alkynes, 7-alkynyl-6-chloro-1,3-dimethyllumazines, 6,7-dialkynyl-1,3-dimethyllumazines,
6,7-dichloro-1,3-dimethyllumazine, enamines, pyrano[2,3-g]pteridine-2,4(1H,3H)-diones, pyrano-
[3,4-g]pteridine-2,4(1H,3H)-diones, pyrido[3,4-g]pteridine-2,4(1H,3H)-diones, pyrrolo[2,3-g]pteridine-
6,8(5H,7H)-diones,
furo[2,3-g]pteridine-6,8(5H,7H)-diones,
Sonogashira
cross
conjugation,
metallocomplex catalysis.
Recent years have been marked by a real revival in the chemistry of acetylenes. Efficient methods have
been devised for their synthesis based on transition metal catalyzed reactions of cross conjugated organohalides
and triflates with 1-alkynes [2], alkynylboronic acids [3], and alkynylstannanes [4]. With the growing
availability of the acetylenes they are used successfully in the synthesis of various carbo- and heterocyclic
compounds [5-8]. Because of the discovery of the enediyne antibiotics, great attention has been attached to the
so-called Bergman cyclization of (Z)-3-en-1,5-diones as well as to the synthesis of compounds containing this
fragment [9, 10].
We have recently described the synthesis of 6-alkynyl-1,3-dimethyllumazines and their heterocyclization
to pyrrolo[3,2-g]- and thieno[3,2-g]pteridine-5,7(6H,8H)-diones [11]. In extending this work we have set
ourselves the task of carrying out the synthesis and studying the cyclization reaction (including the Bergman) for
the 7-alkynyl- and 6,7-dialkynyl-1,3-dimethyllumazines. In this article we report the results of our study of the
synthesis and heterocyclization of alkynyllumazines. The results for the Bergman cyclization will be presented
in a separate communication.
_______
* For Communication 21 see [1].
__________________________________________________________________________________________
Rostov State University, Rostov-on-Don 344090, Russia; e-mail: agulevskaya@chimfak.rsu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 140-152, January, 2005. Original article
submitted May 19, 2004.
124
0009-3122/05/4101-0124©2005 Springer Science+Business Media, Inc.

6,7-Dichloro-1,3-dimethyllumazine (1) [12] was selected as the starting material since the different
mobility of the chlorine atoms can result in both mono-, and disubstitution [13]. We have found that the reaction
of compound 1 with an equimolar amount of the alkyne 2a-c under Sonogashira [2] conditions at 20-30°C gives
the 7-alkynyl derivatives 3a-c in 20-64% yields. The reaction of the dichlorolumazine 1 with a twofold excess of
the acetylenes 2a,b at a higher temperature (90-100°C) gives a 23-33% yield of the 6,7-dialkynyllumazines 4a,b.
Combination of the 6-chloro-7-phenylethynyllumazine 3a with 1-piperidinocyclohexylacetylene 2c at 90-100°C
gives a 36% yield of compound 4c.
O
Me
O
N
N
Cl
R
N
2a–c
Cat.
N
O
Me
3a–c
R
Me
O
N
Cl
Cl
4
5
N3
2c
6
7
2
Cat.
1
N
8
N
R1
Me
O
R
Me
O
N
N
1
N
2a,d
Cat.
N
Me
R
4a–c
Cat. = Pd2dba3, PPh3, CuI, K2CO3, DMF, Ar;
2, 3 a R = Ph, b R = 1-hydroxycyclohex-1-yl, с R = 1-piperidinocyclohex-1-yl;
2 d R = SiMe3; 4 a R = R1 = Ph; b R = R1 = SiMe3; c R = Ph, R1 = 1-piperidinocyclohex-1-yl
The structures of compounds 3 and 4 were confirmed by spectroscopic data and by elemental analysis
(see Tables 1-3). The IR spectra of the monoacetylenes 3 show a νC≡C band of medium intensity at
2207-2223 cm-1. The IR spectra of the dialkynyllumazines 4 show two signals for the triple bonds of moderate
intensity; in the case of the trimethylsilyl derivative 4b this signal is absent.
In spite of the lower yields, the method proposed by us for the preparation of the 6,7-dialkynyl-1,3-
dimethyllumazines 4 has the advantage over the recently reported method based on the cyclization of
5,6-diamino-1,3-dimethyluracil with diethynyl-1,2-diketones [14] in that it allows the subsequent introduction of
different alkyl groups in the molecule 1.
Based on the data in [15] we had expected that the substitution of the chlorine atom by an amino group
in the monoacetylenes 3 and the subsequent heterocyclization of amine 5 would give the pyrrolo[3,2-g]-
pteridine-6,8(5H,7H)-dione 6, isomeric with the previously prepared pyrroles 7 [11]. It was also expected that
the reaction of the 6,7-dialkynyllumazines 4 with amines would yield the [c]-condensed pyrroles 8 (cf. [16])
(Scheme 1).
However, it was found that both at 20°C and also upon refluxing the 6-chloro-7-phenylethynyllumazine
3a in propylamine gave the enamine 9a in 93% yield (Tables 1,3) instead of the expected amino derivative 5
1
(R = Ph, R1 = Pr). The H NMR spectrum of compound 9a shows a one proton singlet for the vinyl proton at
5.73 ppm and a poorly resolved triplet for the NH proton at 10.13 ppm. The position of the latter signal points to
the presence in the molecule of 9a of an intramolecular hydrogen bond between the N(8) atom of the lumazine
ring and the NH proton of the alkylamino group. The formation of enamine 9a is evidently favored by the fact
that the alkynyl group in compound 3a is conjugated to the C(4)=O carbonyl and thus is activated towards
nucleophilic attack whereas the chlorine atom is passive due to the donor effect of the N(1) heteroatom.
125

Scheme 1
R1
O
N
O
N
Me
O
N
N
NHR1
Me
N
N
N
N
N
R
O
Me
R
Me
5
6
O
O
N
R1
R2
Me
O
N
N
Me
N
N
R2NH2
N
N
N
R
4
N
N
O
R1
R
Me
Me
8
7
The 6,7-dialkynyllumazines 4a,c react similarly with amines even at -10 to 25°C to give the enamines
9b-f (Tables 1-4). Although the νC≡C bands are extremely weak or absent altogether in the IR spectra of the
latter, comparison of the 13C NMR spectra of the diacetylene 4a and the addition product 9d do not cast doubt on
the correctness of structure 9 (Table 2). Hence the spectrum of 6,7-di(phenylethynyl)lumazine 4a shows four sp-
hybridized carbon atom signals for the two acetylene bonds, two singlets at 85.4 and 86.3 ppm, and two triplets
at 96.0 (3JC,H = 5.8 Hz) and 99.9 ppm (3JC,H = 4.9 Hz) which are assigned to the carbon atoms directly bound to
the phenyl ring and interacting with its ortho-protons. The spectrum of the enamine 9d shows a singlet at 86.0
ppm and triplet at 94.5 ppm (3JC,H = 5.3 Hz) from the acetylenic carbons of the 6-alkynyl group, a doublet for the
methine carbon atom at 93.2 ppm (1JC,H = 163.7 Hz), and a doublet at 132.4 ppm (2JC,H = 3.6 Hz) from other
carbon atom of the vinyl group. The appearance of the signal for the bridging C(4a) atom as a doublet with 3JC,H
=
3 Hz is very significant in interpreting the structure of 9d since it points to an interaction of the C(4a) nucleus with
the NH proton of the alkylamino group via the hydrogen bond.
3a,b, 4a,c
HN
Y
R1NH2
O
O
X
Me
O
N
N
Me
O
N
N
X
N
H
N
N
H
H
N
N
Me
N
Ph
Me
O
R1
Y
9a–f (Z-form)
Me
O
N
N
Cl
N
10a–c (E-form)
H
N
OH
Me
N
O
10d
9 a X = Cl, R1 = Pr; b X = phenylethynyl, R1 = Et; c X = phenylethynyl, R1 = Pr; d X = phenylethynyl, R1 = Bu;
e X = 1-piperidinocyclohexyl-1-ethynyl, R1 = Et; f X = 1-piperidinocyclohexyl-1-ethynyl, R1 = Bu; 10 a X = Cl, Y = CH2;
b X = Cl, Y = O; c X = phenylethynyl, Y = O
126

TABLE 1. Spectroscopic Characteristics of the Compounds Synthesized
IR spectrum,
UV
spectrum,
max, nm
(log ε)
Com-
pound
ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
λ
С=О
С≡С
1
2
3
4
5
3a
3.52 (3H, s, CH3-3); 3.71 (3H, s, CH3-1);
7.46 (3Н, m, HPh); 7.69 (2Н, m, HPh)
1663,
1727
2207
2223
3b*
1.5-1.8 (6H, m, 3СH2 cyclohexyl);
2.10 (5H, m, 2СH2 cyclohexyl + ОН);
3.51 (3H, s, CH3-3); 3.67 (3H, s, CH3-1)
1660,
1723
3c
1.55 (12Н, m, 3СH2 cyclohexyl + β- and γ-СН2
piperidino); 2.15 (4Н, m, 2СH2 cyclohexyl);
2.71 (4Н, m, α-СН2 piperidino); 3.51 (3H, s, CH3-3);
3.68 (3H, s, CH3-1)
1600,
1714
2207
4a
4b
4c
3.53 (3H, s, CH3-3); 3.73 (3H, s, CH3-1);
7.46 (6Н, m, HPh); 7.69 (4Н, m, HPh)
1663,
1714
2200,
2213
264 (4.42),
316 (4.45),
405 (4.28)
0.27 (9Н, s, Si(CH3)3); 0.32 (9Н, s, Si(CH3)3);
3.50 (3H, s, CH3-3); 3.67 (3H, s, CH3-1)
1675,
1724
—
288 (4.31),
305 (4.32),
380 (4.12)
1.34 (2Н, m, cyclohexyl); 1.57 (12Н, m, 3СH2
cyclohexyl + β- and γ-СН2 piperidino);
1663,
1720
2207,
2233
299 (4.30),
385 (4.31)
2.13 (2Н, m, cyclohexyl); 2.66 (4Н, m, α-СН2
piperidino); 3.53 (3H, s, CH3-3); 3.71 (3H, s, CH3-1)
9a*2
0.93 (3Н, t, J = 7.1, СН2СН2CH3); 1.60 (2Н, m,
СН2СН2CH3); 3.26 (2Н, m, СН2СН2CH3);
3.49 (3H, s, CH3-3); 3.67 (3H, s, CH3-1);
5.73 (1Н, s, =СН); 7.47 (5Н, m, C6H5);
10.13 (1Н, m, NН)
1667,
1713
—
340 (3.89),
445 (4.36),
460 (4.44)
9b*2
9с*2
1.26 (3Н, t, J = 7.3, СН2CH3); 3.33 (2Н, m,
СН2CH3); 3.51 (3H, s, CH3-3); 3.69 (3H, s, 1-CH3);
5.94 (1H, s, =CH); 7.31 (3Н, m, HPh);
1675,
1710
—
293 (4.48),
383 (4.30),
455 (4.51),
468 (4.52)
7.49 (7Н, m, HPh); 10.01 (1H, m, NН)
0.92 (3Н, t, J = 7.3, СН2СН2CH3); 1.65 (2Н, m,
СН2СН2CH3); 3.27 (2Н, m, СН2СН2CH3);
3.51 (3H, s, CH3-3); 3.69 (3H, s, CH3-1);
5.95 (1H, s, =CH); 7.31 (3Н, m, HPh);
1660,
2205
294 (4.44),
383 (4.25),
452 (4.15),
460 (4.45)
1707 (weak)
7.47 (m, 7Н, HPh); 10.02 (1H, m, NН)
9d*2
9e*2
9f*2
0.87 (3Н, t, J = 7.1, СН2СН2СН2CH3);
1.34 (2Н, m, СН2СН2СН2CH3); 1.54 (2Н, m,
СН2СН2СН2CH3); 3.30 (2Н, m, СН2СН2СН2CH3);
3.52 (3H, s, CH3-3); 3.69 (3H, s, CH3-1);
5.95 (1H, s, =CH); 7.32 (3Н, m, HPh);
1663,
1700
—
293 (4.45),
384 (4.28),
455 (4.35),
470 (4.38)
7.45 (m, 7Н, HPh); 10.01 (1H, m, NН)
1.26 (3Н, t, J = 7.3, СН2CH3); 1.40-1.85 (14Н, m,
cyclohexyl + β- and γ-СН2 piperidino); 2.05 (2Н, m,
cyclohexyl); 2.57 (4Н, m, α-СН2 piperidino);
3.50 (3H, s, CH3-3); 3.68 (3H, s, CH3-1);
5.98 (1H, s, =CH); 7.43 (5Н, s, C6H5);
9.94 (1H, m, NН)
1665,
2213
260 (4.39),
365 (4.13),
446 (4.47),
465 (4.50)
1713 (weak)
0.85 (3Н, t, J = 7.1, СН2СН2СН2CH3);
1660,
2195
374 (4.18),
463 (4.42)
1.20-1.75 (18Н, m, СН2СН2СН2CH3 + cyclohexyl
+ β- and γ-СН2 piperidino); 2.03 (2Н, m, cyclohexyl);
2.56 (4Н, m, α-СН2 piperidino); 3.30 (2Н, m,
СН2СН2СН2CH3); 3.50 (3H, s, CH3-3); 3.67 (3H, s,
CH3-1); 6.00 (1H, s, =CH); 7.43 (5Н, s, C6H5);
9.92 (1H, m, NН)
1700 (weak)
10a
1.68 (6Н, m, β- and γ-СН2 piperidino);
2.56 (3H, s, CH3-1); 3.31 (4Н, m, α-СН2 piperidino);
3.36 (3H, s, CH3-3); 5.99 (1H, s, =CH);
7.25 (2Н, m, HPh); 7.40 (3Н, m, HPh)
1660,
1710
—
337 (3.85),
458 (4.43)
127

TABLE 1 (continued)
1
2
3
4
5
10b
2.59 (3H, s, CH3-1); 3.28 (4Н, m, N(СН2)2
morpholino); 3.38 (3H, s, CH3-3);
3.76 (4Н, m, O(СН2)2 morpholino);
6.00 (1H, s, =CH); 7.26 (2Н, m, HPh);
7.41 (3Н, m, HPh)
1666,
1700
—
443 (4.46)
10c
10d
2.62 (3H, s, CH3-1); 3.28 (4Н, m, N(СН2)2
morpholino); 3.40 (3H, s, CH3-3); 3.77 (4Н, m,
O(СН2)2 morpholino); 6.30 (1H, s, =CH); 7.25 (2Н,
m, HPh); 7.40 (6Н, m, HPh); 7.59 (2Н, m, HPh)
1665,
1715
—
—
294 (4.51),
369 (4.29),
445 (4.47)
1.80-2.05 (3Н, m, CH2 cyclohexyl + ОН);
2.87 (4Н, m, 2CH2 cyclohexyl); 3.35 (4Н, m,
N(СН2)2 morpholino); 3.47 (3H, s, CH3-3);
1663,
1695
351 (3.83),
464 (3.71)
3.66 (3H, s, CH3-1); 3.67 (4Н, m, 2CH2 cyclohexyl);
3.75 (4Н, m, O(СН2)2 morpholino); 5.95 (1H, s, H-9)
11a*3
11b*3
For 11а: 3.52 (3H, s, CH3-3); 3.61 (3H, s, CH3-1);
4.77 (2H, s, CH2); 7.40-7.70 (3Н, m, HPh);
8.05 (2Н, m, HPh); for 11'a: 3.50 (3H, s, CH3-3);
3.72 (3H, s, CH3-1); 6.76 (1H, s, =CH); 7.40-7.70
(3Н, m, HPh); 8.00 (2Н, m, HPh); 14.04 (1H, s, OH)
1660,
1723
—
250 (4.30),
337 (3.93),
427 (4.25),
450 (4.21)
For 11b: 3.53 (3H, s, CH3-3); 3.63 (3H, s, CH3-1);
4.85 (2H, s, CH2); 7.40-7.90 (10Н, m, HPh);
for 11'b: 3.51 (3H, s, CH3-3); 3.72 (3H, s, CH3-1);
6.93 (1H, s, =CH); 7.40-7.90 (10Н, m, HPh);
8.00 (2Н, m, HPh); 13.94 (1H, s, OH)
1680,
1725
2210
257 (4.34),
287 (4.38),
356 (4.31),
435 (4.33),
448(4.31)
12a
12b
0.71 (3H, t, J = 7.5, СН2СН2CH3); 1.69 (2Н, m,
СН2СН2CH3); 3.56 (3H, s, CH3-7); 3.80 (3H, s,
CH3-5); 4.44 (2H, t, J = 7.5, СН2СН2CH3);
6.68 (1Н, s, H-3); 7.55 (5Н, m, C6H5)
1660,
1717
—
—
371 (4.41)
0.73 (3H, t, J = 7.3, СН2СН2СН2CH3); 1.11 (2Н, m,
СН2СН2СН2CH3); 1.62 (2Н, m, СН2СН2СН2CH3);
3.57 (3H, s, CH3-7); 3.80 (3H, s, CH3-5); 4.48 (2H, t,
J = 7.5, СН2СН2СН2CH3); 6.68 (1Н, s, H-3);
7.53 (5Н, m, C6H5)
1673,
1700
373 (4.41)
13
14
3.56 (3H, s, CH3-7); 3.78 (3H, s, CH3-5);
7.24 (1Н, s, H-3); 7.54 (3Н, m, HPh); 7.98 (2H, m, HPh)
1660,
1713
—
—
344 (4.20),
378 (4.58),
398 (4.65)
1.50-2.10 (10Н, m, cyclohexyl); 3.22 (4Н, m,
N(СН2)2 morpholino); 3.48 (3H, s, CH3-3);
3.64 (3H, s, CH3-1); 3.80 (4Н, m, O(СН2)2
morpholino); 5.87 (1H, s, H-9)
1640,
1682
334 (3.78),
426 (4.43)
15a
15b
0.53 (3Н, t, J = 7.5, СН2СН2CH3); 1.36 (2Н, m,
СН2СН2CH3); 3.29 (2H, t, J = 7.1, СН2СН2CH3);
3.52 (3H, s, CH3-3); 3.67 (3H, s, CH3-1);
6.05 (1Н, s, =CH); 7.14 (1Н, s, H-9);
1676,
1720
—
—
273 (4.59),
371 (4.06),
520 (3.11)
7.37 (2H, m, HPh); 7.45-7.65 (8H, m, HPh)
0.55 (3Н, t, J = 7.3, СН2СН2СН2CH3); 0.92 (2Н, m,
СН2СН2СН2CH3); 1.30 (2Н, m, СН2СН2СН2CH3);
3.32 (2H, t, J = 7.1, СН2СН2СН2CH3); 3.52 (3H, s,
CH3-3); 3.67 (3H, s, CH3-1); 6.04 (1Н, s, =CH);
7.15 (1Н, s, H-9); 7.37 (2H, m, HPh);
1660,
1714
273 (4.59),
372 (4.05),
520 (3.08)
7.45-7.65 (8H, m, HPh)
16
3.50 (3H, s, CH3-3); 3.66 (3H, s, CH3-1); 6.51 (1Н, s,
=CH); 7.12 (1Н, s, H-9); 7.38 (3H, m, HPh);
7.52 (3H, m, HPh); 7.78 (2H, m, HPh);
7.88 (2H, m, HPh)
1660,
1717
—
275 (4.52),
399 (4.08),
498 (4.08)
_______
* νOH 3415 cm-1.
*2 νN–H ac 3100-3500 cm-1.
*3 νO–H ac 3100-3500 cm-1.
128

TABLE 2. 13C NMR Spectra of Compounds 4a, 9d
Com-
pound
Chemical shift, δ, ppm. (J, Hz)
С-2
С-4
С-4а
С-6
С-7
С-8а
С≡С(6)
C≡C(7)
С=С
СPh
Other signals
4а
150.25
(m)
158.87 (q, 143.91
125.12
136.96
145.48 (q, 85.39,
86.33,
—
120.88 (t, 2J = 8.3);
121.57 (t, 2J = 7.9);
128.50 (dm, 1J = 155.3);
128.64 (dm, 1J = 163.7);
129.62 (dt, 1J = 151.8,
2J = 7.8);
29.02 (q, 1J = 142.7,
СН3-3); 29.50 (q,
1J = 143.0, СН3-1)
3J = 2.4)
3J = 2.6)
96.02 (t,
99.94 (t,
3J = 5.8)
3J = 4.9)
130.47 (dt, 1J = 162.1,
2J = 7.8); 132.47 (dt,
1J = 164.0, 2J = 6.6);
132.04 (dt,
1J = 165.7, 2J = 6.7)
9d
163.86
(m)
159.31 (q, 156.89
117.80
145.50
(m)
150.89
(m)
85.98,
—
93.22 (d,
1J =
122.09 (t, 2J = 7.7);
13.52 (q, 1J = 125.2,
СН3); 19.78 (t, 1J = 122.3,
СН2); 28.65 (q,
3J = 2.4)
(d,
94.46 (t,
127.75 (dm, 1J = 161.0);
128.28 (dm, 1J = 162.1);
3J = 3.0)
3J = 5.3)
163.7),
132.39 (d, 128.56 (dm, 1J = 160.9);
1J = 142.1, СН3-3);
29.23 (q, 1J = 141.5,
СН3-1); 33.09 (t,
2J = 3.6)
128.96 (dt, 1J = 161.6,
2J = 7.3);
129.60 (dm, 1J = 164.0);
131.80 (dm, 1J = 163.4);
136.14 (m)
1J = 118.0, СН2);
45.27 (t, 1J = 138.1, СН2)

TABLE 3. Characteristics of the Compound Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
Cl
3a
3b
3c
4a
4b
4c
9a
C16H11ClN4O2
C16H17ClN4O3
C21H26ClN5O2
C24H16N4O2
58.65
58.81
54.92
55.09
60.64
60.65
73.56
73.47
56.45
56.25
72.34
72.35
3.43
3.37
5.03
4.88
6.33
6.26
3.94
4.08
6.14
6.25
6.31
6.44
17.01
17.15
16.19
16.07
16.67
16.85
14.10
14.29
14.61
14.58
14.49
14.55
11.05
10.87
10.12
10.19
8.38
8.54
241-243
202-205
148-150
225-227
175-177
214-216
181-183
64
46
20
33
23
54
93
—
—*
—
C18H24N4O2Si2
C29H31N5O2
C19H20ClN5O2
9.39
9.21
58.98
59.14
5.40
5.19
18.03
18.16
9b
C26H23N5O2
C27H25N5O2
C28H27N5O2
C31H38N6O2
C33H42N6O2
C21H22ClN5O2
C20H20ClN5O3
C28H25N5O3
C20H26ClN5O4
C16H13ClN4O3
C24H18N4O3
C19H19N5O2
C20H21N5O2
C16H12N4O3
C20H25N5O4
C27H25N5O2
C28H27N5O2
C24H18N4O3
71.47
71.40
71.91
71.84
72.18
72.26
70.63
70.72
71.31
71.48
61.41
61.24
58.22
58.04
70.05
70.14
55.23
55.11
55.84
55.73
70.31
70.24
65.40
65.33
66.03
66.12
62.47
62.34
60.09
60.15
72.01
71.84
5.13
5.26
5.42
5.54
5.88
5.81
7.36
7.22
7.75
7.58
5.29
5.35
5.01
4.84
5.29
5.22
6.06
5.97
3.65
3.77
4.34
4.39
5.62
5.44
5.91
5.78
4.06
3.90
6.43
6.27
5.70
5.54
16.00
16.02
15.49
15.52
15.23
15.05
15.81
15.97
15.04
15.16
17.13
17.01
17.06
16.93
14.53
14.61
16.26
16.07
16.36
16.25
13.74
13.66
19.93
20.06
19.45
19.28
18.00
18.16
17.70
17.54
15.39
15.52
230-233
197-199
195-197
185-188
165-167
216-218
276-278
215-217
191-193
118-220
225-227
192-194
186-188
273-275
278-280
278-280
198-200
292-294
54
93
84
54
80
95
99
99
97
98
90
60
73
65
55
88
85
67
—
—
—
—
—
9c
9d
9e
9f
10a
10b
10c
10d
11a
11b
12a
12b
13
8.70
8.63
8.71
8.59
—
7.94
8.15
10.31
10.30
—
—
—
—
—
—
—
—
14
15a
15b
16
72.33
72.26
70.42
70.24
5.96
5.81
4.25
4.39
14.87
15.05
13.74
13.66
_______
* Found, Si 14.38%, Calculated Si 14.58%.
The enamines 9 are extremely stable substances and do not hydrolyze, even when refluxed in 20%
sulphuric acid solution. However, when heated in 50% trifluoroacetic acid, compounds 9a,c form the ketones 11
1
which are in equilibrium with the enols 11'. According to H NMR data the ratio for 11a:11'a is 1.6:1 and for
11b:11'b is 1: 4.8
130

O
O
N
X
Me
O
X
Me
O
N
N
N
N
CF3COOH – H2O
9a,c
H
∆
N
N
H
N
CH2
Me
Me
O
Ph
O
Ph
11'a,b
11a,b
11 a X = Cl, b X = phenylethynyl
7-Alkynyl- (3) and 6,7-dialkynyllumazines 4 also form the stable enamines 10a-d with secondary
amines (piperidine and morpholine). However, in contrast to the enamines 9a-f, the compounds 10a-c have the
E-configuration as shown by their 1H NMR spectra (Table 1). Hence the signal for the N(1)-methyl group protons
in compound 10 (δ 2.6 ppm) lies about 1 ppm to higher field than the lumazines 3, 4, 9 and this can only be
related to a shielding effect of the benzene ring. By comparing the enamines 9 and 10 it is apparent that their
stability is achieved not so much by the intramolecular hydrogen bond as by conjugation of the amino group
with the heterocycle.
Overall, the reactivity of the 7-alkynyl-6-chloro- and 6,7-dialkynyl-1,3-dimethyllumazines relative to the
amines resembles their quinoxaline analogs [17, 18]. They differ in that the chlorine atom in the 2-alkynyl-3-
chloroquinoxalines is more mobile and in the dialkynylquinoxalines both C≡C bonds can add amines to give
readily hydrolysing enamines.
In contrast to the reaction with propylamine (which does not form the tricyclic product 12a) we found
that prolonged refluxing of 6-chloro-7-phenylethynyllumazine 3a in butanol gives the pyrrolopteridine 12b in
73% yield, evidently being formed via a type 9 enamine. This is supported by the fact that enamine 9a gives the
pyrrolopteridine 12a in 60% yield when treated with potassium carbonate in DMF. Under the same conditions,
the ketone 11a and compound 10d cyclize to the furopteridine 13 (65%) and pyranopteridine 14 (55%)
respectively. Characteristics of compounds 12-14 are given in Tables 1 and 3.
O
R
Me
N
N
N
DMF
N
BuNH2
9a
Ph
3a
∆
K2CO3,
∆
O
N
Me
12a,b
12 a R = Pr, b R = Bu
O
Me
O
N
O
N
DMF
K2CO3,
Ph
11a
N
N
∆
Me
13
O
O
Me
O
N
N
N
DMF
10d
∆
N
N
K2CO3,
O
Me
14
131

When heated with K2CO3 in DMF, the enamines 9c,d give the pyridopteridines 15a,b in high yield.
Compound 11b cyclizes to the pyran 16 (67%) under the same conditions. In contrast to the orange starting
materials 9, 11b (λmax 450-470 nm) the methylene anhydrobases 15 and 16 are deep-purple in color
(λmax 498-520 nm).
Ph
O
Ph
N
O
O
Me
O
N
N
R
Me
O
N
N
N
N
DMF
DMF
11b
9c,d
Ph
Ph
K2CO3,
∆
∆
K2CO3,
N
N
Me
Me
15a,b
16
15 a R = Pr, b R = Bu
It should finally be noted that the heterocyclizations 9→15 and 11b→16 are a novel way of synthesizing
[c]-condensed pyrans and pyridines. In addition, the pyrans 14 and 16 prepared in this work have a hetero
system isomeric with that found as the basis of the coenzyme molybdopterine 17.
H
N
Mo
S
S
O
N
H
H
H
N
OPO(OH)2
O
H2N
N
H
H
17
TABLE 4. Mass Spectra of the Compounds
Com-
pound
m/z (Ireal, %)*
9с
452 [M+1]+ (28), 451 [M]+ (100), 450 [M–1]+ (26), 437 [M–CH2]+ (10), 423 [M–C2H4
and M–CO]+ (13), 410 (18), 423 [M–C3H6]+ (16), 394 [M–C2H5CH=NH
and [M–CH3NCO]+ (10), 119 (20), 105 (15), 104 (40), 91 (20), 81 (18), 77 (20), 59 (30)
15a
452 [M+1]+ (23), 451 [M]+ (84), 450 [M–1]+ (58), 410 (26), 409 [M–C3H6]+ (96),
408 [M–C3H7]+ (100), 394 [M–C2H5CH=NH and M–CH3NCO]+ (10), 360 (17),
334 (13), 333 (55), 323 (14), 294 (11), 292 (11), 255 (12), 226 (12), 205 (24), 118 (23),
119 (24), 91 (78), 85 (32), 83 (49), 77 (26), 57 (18), 56 (14), 51 (13), 44 (35), 43 (55),
42 (22), 41 (48), 40 (20), 39 (18)
11b
16
410 [M]+ (17), 105 (100), 77 (33), 44 (13)
411 [M+1]+ (19), 410 [M]+ (73), 409 [M–1]+ (45), 395 [M–CH3]+ (16), 324 (13),
205 (31), 163 (10), 148 (11), 140 (10), 121 (11), 108 (12), 105 (49), 104 (16), 103 (15),
102 (10), 91 (55), 90 (19), 89 (18), 83 (18), 77 (100), 65 (12), 63 (13), 51 (27), 50 (12),
44 (20), 42 (16), 39 (17)
_______
* Peaks with intensities less than 10% are omitted.
132

EXPERIMENTAL
1
IR spectra were obtained on a Specord IR-71 instrument using vaseline oil. H NMR spectra were
measured on a Bruker-250 (250 MHz) spectrometer using CDCl3 at 20°C. The 13C NMR spectra were taken on a
Unity-300 spectrometer (75 MHz) using CDCl3 and TMS as internal standard. UV Spectra were recorded on a
Specord M-40 instrument using chloroform. Mass spectra (EI, 70 eV) were taken on an MX-1321A
spectrometer. Chromatography was carried out on Brockmann activity grade III-IV Al2O3 with chloroform eluent
and revealing using iodine vapour. Melting points were measured on a PTP instrument in a glass capillary and
are not corrected.
Characteristics of the compounds prepared are given in Tables 1-3.
Preparation of Compounds 3a-c (General Method). A mixture of 1,3-dimethyllumazine (261 mg,
1 mmol), the corresponding alkyne 2a-c (1.25 mmol), K2CO3 (103 mg, 0.75 mmol), Pd2dba3 (18.3 mg,
0.02 mmol), PPh3 (41.9 mg, 0.16 mmol), and CuI (9.5 mg, 0.05 mmol) in absolute DMF (3 ml) was stirred at
25°C for 2 h in an argon atmosphere. The separation and purification were carried out differently (see below).
6-Chloro-1,3-dimethyl-7-phenylethynyllumazine (3a). The reaction mixture was cooled to 20°C and
treated with water (5 ml). The precipitate was filtered off, washed on the filter with cold water and isopropanol,
and recrystallized from isopropanol.
6-Chloro-7-(1-hydroxycyclohexylethynyl)-1,3-dimethyllumazine (3b). The reaction mixture was
evaporated to dryness and the residue was extracted with chloroform. The extract was concentrated to about 5 ml
and chromatographed on an Al2O3 column using chloroform eluent and the yellow fraction with Rf 0.1 was
collected. It was recrystallized from isopropanol.
6-Chloro-1,3-dimethyl-7-(1-piperidinocyclohexylethynyl)lumazine (3c). The reaction mixture was
evaporated to dryness and the residue was extracted with chloroform. The extract was concentrated to about 5 ml
and chromatographed on an Al2O3 column using chloroform eluent and the colorless fraction with Rf 0.5 was
collected. It was recrystallized from methanol.
1,3-Dimethyl-6,7-di(phenylethynyl)lumazine (4a). A mixture of 6,7-dichloro-1,3-dimethyllumazine
(261 mg, 1 mmol), phenylacetylene (0.28 ml, 2.5 mmol), K2CO3 (207 mg, 1.5 mmol), Pd2dba3 (18.3 mg,
0.02 mmol), PPh3 (41.9 mg, 0.16 mmol), and CuI (9.5 mg, 0.05 mmol) in absolute DMF (3 ml) was stirred at
90-100°C for 1 h in an argon atmosphere. Phenylacetylene (0.14 ml, 1.25 mmol) was added and the stirring was
continued for a further 1 h. The product was evaporated to dryness and the residue was extracted with
chloroform. The extract was concentrated to about 5 ml and chromatographed on an Al2O3 column using
chloroform eluent and the yellow fraction with Rf 0.5 was collected. It was recrystallized from isopropanol.
1,3-Dimethyl-6,7-di(trimethylsilylethynyl)lumazine (4b).
A
mixture of 6,7-dichloro-1,3-
dimethyllumazine (261 mg, 1 mmol), trimethylsilylacetylene (0.35 ml, 2.5 mmol), Pd2dba3 (18.3 mg,
0.02 mmol), PPh3 (41.9 mg, 0.16 mmol), and CuI (9.5 mg, 0.05 mmol) in Et3N (10 ml) was heated in a sealed
ampule at 100°C for 2 h under an argon atmosphere. The product was evaporated to dryness and the residue was
extracted with chloroform. The extract was concentrated to about 5 ml and chromatographed on an Al2O3
column using chloroform eluent and the light-yellow fraction with Rf 0.75 was collected. It was recrystallized
from methanol.
1,3-Dimethyl-6-(piperidinocyclohexylethynyl)-7-phenylethynyllumazine (4c).
A
mixture of
compound 3a (326.5 mg, 1 mmol), alkyne 2c (238.8 mg, 1.25 mmol), K2CO3 (103.5 mg, 0.75 mmol), Pd2dba3
(18.3 mg, 0.02 mmol), PPh3 (41.9 mg, 0.16 mmol), and CuI (9.5 mg, 0.05 mmol) in absolute DMF (3 ml) was
heated with stirring at 90-100°C for 2 h under an argon atmosphere. The product was evaporated to dryness and
the residue was extracted with chloroform. The extract was concentrated to about 5 ml and chromatographed on
an Al2O3 column using chloroform eluent and the yellow fraction with Rf 0.2 was collected. It was recrystallized
from isopropanol.
133

6-Chloro-1,3-dimethyl-7-(2-propylamino-2-phenylvinyl)lumazine (9a). A solution of compound 3a
(163 mg, 0.5 mmol) and the amine (10 ml) was stirred at 25°C for 2 h. The amine was distilled off and the dried
residue was extracted with chloroform (10 ml). The extract was concentrated to about 5 ml and chromatographed
on an Al2O3 column using chloroform eluent and the yellow fraction with Rf 0.2-0.3 was collected. It was
recrystallized from ethanol.
7-(2-Ethylamino-2-phenylvinyl)-1,3-dimethyl-6-phenylethynyllumazine (9b).
A
solution of
compound 4a (196 mg, 0.5 mmol) in ethylamine (50 ml) was stirred at -10°C for 2 h. The product was
evaporated to dryness and the dried residue was extracted with chloroform (10 ml). The extract was concentrated
to about 5 ml and chromatographed on an Al2O3 column using chloroform eluent and the yellow fraction with Rf
0.2-0.3 was collected. It was recrystallized from ethanol.
1,3-Dimethyl-6-phenylethynyl-7-(2-propylamino-2-phenylvinyl)lumazine (9c).
A
solution of
compound 4a (196 mg, 0.5 mmol) in propylamine (10 ml) was stirred at 25°C for 2 h. The amine was distilled
off and the dried residue was extracted with chloroform (10 ml). The extract was concentrated to about 5 ml and
chromatographed on an Al2O3 column using chloroform eluent and the yellow fraction with Rf 0.2-0.3 was
collected. It was recrystallized from ethanol.
7-(2-Butylamino-2-phenylvinyl)-1,3-dimethyl-6-phenylethynyllumazine (9d) was prepared similarly
to 9c from compound 4a and butylamine.
7-(2-Ethylamino-2-phenylvinyl)-1,3-dimethyl-6-(1-piperidinocyclohexyl)ethynyllumazine (9e) was
prepared similarly to compound 9b from compound 4c and ethylamine.
7-(2-Butylamino-2-phenylvinyl)-1,3-dimethyl-6-(1-piperidinocyclohexyl)ethynyllumazine (9f) was
prepared similarly to compound 9c from compound 4c and butylamine.
6-Chloro-1,3-dimethyl-7-(2-piperidino-2-phenylvinyl)lumazine (10a) was prepared similarly to
compound 9a from compound 3a and piperidine.
6-Chloro-1,3-dimethyl-7-(2-morpholino-2-phenylvinyl)lumazine (10b) was prepared similarly to
compound 9a from compound 3a and morpholine.
1,3-Dimethyl-7-(2-morpholino-2-phenylvinyl)-6-phenylethynyllumazine (10c)
was prepared
similarly to compound 9c from compound 4a and morpholine.
7-[2-(1-Hydroxycyclohexyl)-2-morpholinovinyl]-1,3-dimethyl-6-chlorolumazine (10d) was prepared
similarly to compound 9a from compound 3b and morpholine.
6-Chloro-1,3-dimethyl-7-(2-oxo-2-phenylethyl)lumazine (11a).
A solution of compound 9a
(192.8 mg, 0.5 mmol) in 50% trifluoroacetic acid (3 ml) was refluxed for 5 min and evaporated to dryness. The
residue was extracted with chloroform. The extract was concentrated to about 5 ml and chromatographed on an
Al2O3 column using chloroform eluent and the bright-yellow fraction with Rf 0.35 was collected. It was
recrystallized from ethanol.
1,3-Dimethyl-7-(2-oxo-2-phenylethyl)-6-phenylethynyllumazine (11b) was prepared similarly to
compound 11a from compound 9c.
5,7-Dimethyl-2-phenyl-1-propylpyrrolo[2,3-g]pteridine-6,8(5H,7H)-dione (12a). A solution of
compound 9a (192.8 mg, 0.5 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in DMF (10 ml) was heated at 120°C for
20 h. The product was evaporated to dryness and the residue was extracted with chloroform. The extract was
concentrated to about 5 ml and chromatographed on an Al2O3 column using chloroform eluent and the bright
yellow fraction with Rf 0.35 was collected. It was recrystallized from ethanol.
1-Butyl-5,7-dimethyl-2-phenylpyrrolo[2,3-g]pteridine-6,8(5H,7H)-dione (12b).
A
solution of
compound 3a (163.3 mg, 0.5 mmol) and butylamine (50 ml) was refluxed for 5 days. After distilling the
butylamine the dry product was extracted with chloroform (10 ml). The extract was concentrated to about 5 ml
and chromatographed on an Al2O3 column using chloroform eluent and the light-yellow fraction with Rf 0.35
was collected. It was recrystallized from ethanol.
134

5,7-Dimethyl-2-phenylfuro[2,3-g]pteridine-6,8(5H,7H)-dione (13). A solution of compound 11a
(174.5 mg, 0.5 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in DMF (10 ml) was heated at 90°C for 2 h. The product
was evaporated to dryness and the residue was extracted with chloroform. The extract was concentrated to about
5 ml and chromatographed on an Al2O3 column using chloroform eluent and the yellow fraction with Rf 0.4 was
collected. It was recrystallized from isopropanol.
1,3-Dimethyl-8-morpholino-2,4-dioxo-1,2,3,4-tetrahydro-7-spirocyclohexane-7H-pyrano[2,3-g]-
pteridine (14). A solution of compound 10d (218 mg, 0.5 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in DMF
(5 ml) was heated at 100°C for 1 h. The product was evaporated to dryness and the residue was extracted with
chloroform. The extract was concentrated to about 5 ml and chromatographed on an Al2O3 column using
chloroform as eluent and the yellow fraction with Rf 0.15 was collected. It was recrystallized from ethanol.
6-Benzylidene-1,3-dimethyl-8-phenyl-7-propyl-6,7-dihydropyrido[3,4-g]pteridine-2,4(1H,3H)-
dione (15a). A solution of compound 9c (226 mg, 0.5 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in DMF (5 ml)
was refluxed for 1 h. The product was evaporated to dryness and the residue was extracted with chloroform. The
extract was concentrated to about 5 ml and chromatographed on an Al2O3 column using chloroform as eluent and
the purple fraction with Rf 0.6 was collected. It was recrystallized from ethanol.
6-Benzylidene-7-butyl-1,3-dimethyl-8-phenyl-6,7-dihydropyrido[3,4-g]pteridine-2,4(1H,3H)-dione
(15b) was prepared similarly to compound 15a from compound 9d.
6-Benzylidene-1,3-dimethyl-8-phenyl-6H-pyrano[3,4-g]pteridine-2,4(1H,3H)-dione (16). A solution
of compound 11b (205 mg, 0.5 mmol) and K2CO3 (41.4 mg, 0.3 mmol) in DMF (5 ml) was refluxed for 1 h. The
product was evaporated to dryness and the residue was extracted with chloroform. The extract was concentrated
to about 5 ml and chromatographed on an Al2O3 column using chloroform as eluent and the dark red fraction
with Rf 0.4 was collected. It was recrystallized from ethanol.
The work was carried out with the financial support of the RFFI (grant No. 04-03-96800).
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135