Purines, pyrimidines, and related fused systems 20.* Heterocyclizations of 6-alkynyl-1,3-dimethyllumazines. Synthesis of pyrrole and thiophene analogs of some natural pteridines

Article abstract of DOI:10.1023/A:1024891530684

Sonogashira cross-coupling of 6-chloro-1,3-dimethyllumazine with terminal alkynes gave 6-alkynyl derivatives in good yields. Oxidative amination of the latter with primary alkylamines was accompanied by the pyrrole-ring closure to form 1-R′-2-R-6,8-dimeth

Full text of DOI:10.1023/A:1024891530684

Russian Chemical Bulletin, International Edition, Vol. 52, No. 6, pp. 1403—1410, June, 2003
1403
Purines, pyrimidines, and related fused systems
0.* Heterocyclizations of 6ꢀalkynylꢀ1,3ꢀdimethyllumazines. Synthesis of pyrrole
and thiophene analogs of some natural pteridines
2
ꢀ
A. V. Gulevskaya, Dang Van Shee, and A. F. Pozharskii
Rostov State University,
7
pr. Zorge, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863 2) 22 3958. Eꢀmail: AGulevskaya@chimfak.rsu.ru
Sonogashira crossꢀcoupling of 6ꢀchloroꢀ1,3ꢀdimethyllumazine with terminal alkynes gave
ꢀalkynyl derivatives in good yields. Oxidative amination of the latter with primary alkylꢀ
6
amines was accompanied by the pyrroleꢀring closure to form 1ꢀR´ꢀ2ꢀRꢀ6,8ꢀdimethylpyrroꢀ
lo[3,2ꢀg]pteridineꢀ5,7(6H,8H )ꢀdiones. The addition of bromine to 6ꢀalkynyllumazines afꢀ
forded the corresponding dibromoalkenes whose treatment with sodium trithiocarbonate gave
rise to 2ꢀRꢀ6,8ꢀdimethylthieno[3,2ꢀg]pteridineꢀ5,7(6H,8H )ꢀdiones. The latter compounds are
close analogs of the metabolite of molybdenum cofactor (molybdopterine).
Key words: 6ꢀchloroꢀ1,3ꢀdimethyllumazine, alkynes, metal complex catalysis, Sonogashira
reaction, 6ꢀ(alkynꢀ1ꢀyl)ꢀ1,3ꢀdimethyllumazines, oxidative amination, pyrrolo[3,2ꢀg]pteridineꢀ
5
,7(6H,8H )ꢀdiones, thieno[3,2ꢀg]pteridineꢀ5,7(6H,8H )ꢀdiones.
Various acetylene derivatives became readily accesꢀ
sible due to considerable recent progress in metal comꢀ
plex catalysis.2 These compounds are finding ever inꢀ
creasing use in organic synthesis for performing various
7,9(6H,8H )ꢀdiones (3) (Scheme 2). We believed that this
method of the pyrroleꢀring annelation would be particuꢀ
larly useful in the synthesis of isomeric pyrrolo[3,2ꢀg]pteriꢀ
dineꢀ5,7(6H,8H )ꢀdiones (4), which can be considered as
analogs of natural pteridines, for example, of the yellow
,3
4
—9
heterocyclization reactions.
In the general case,
1
0
heterocyclization proceeds according to Scheme 1 and
requires a catalyst (a base, transition metal complex, or
electrophile).
pigment russupteridine (5) and the metabolite of moꢀ
1
1
lybdenum cofactor, viz., urothione (6).
Scheme 2
Scheme 1
X = N, O, S; LG = H or another leaving group;
Cat is a catalyst
Recently,1 we have demonstrated that oxidative
SNHꢀamination of 3ꢀ(alkynꢀ1ꢀyl)ꢀ6,8ꢀdimethylpyrimiꢀ
do[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdiones (1) with primary
alkylamines afforded oꢀaminoacetylenes 2, which underꢀ
went spontaneous cyclization to give 1ꢀR´ꢀ2ꢀRꢀ6,8ꢀdiꢀ
methylpyrrolo[3´,2´:3,4]pyrimido[4,5ꢀc]pyridazineꢀ
We used 6ꢀchloroꢀ1,3ꢀdimethyllumazine (7) as the
1
2
*
For Part 19, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1328—1334, June, 2003.
066ꢀ5285/03/5206ꢀ1403 $25.00 © 2003 Plenum Publishing Corporation
starting compound. Its reactions with terminal alkynes
1

1404
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
Gulevskaya et al.
8
a,b,d in DMF under an argon atmosphere in the presꢀ
The structures of hetarylacetylenes 9 were confirmed
by the data of spectroscopy and elemental analysis
(Tables 1 and 2). Compounds 9 are virtually colorless
(λmax 353—369 nm). Their IR spectra each have a lowꢀ
ence of palladium complexes and catalytic amounts of
CuI and K CO afforded 6ꢀ(alkynꢀ1ꢀyl) derivatives 9a,b,d
in 56—79% yields (Scheme 3). Crossꢀcoupling of 7 with
volatile trimethylsilylacetylene 8c giving rise to 9c was
carried out in a sealed tube in the absence of a solꢀ
vent using the Pd dba /PPh system as the catalyst
2
3
–
1
intensity absorption band at 2167—2207 cm (ν(C≡C)).
1
The H NMR spectra show singlets of two Nꢀmethyl
groups at δ ∼ 3.5 and ∼ 3.7 and signals of the alkynyl fragꢀ
ment and the H(7) proton at δ 8.6—8.7. The mass spectra
of hetarylacetylenes 9 show molecular ion peaks with the
intensities of 30—100%.
2
3
3
(
dba is dibenzylideneacetone as the ligand) and Et N as
3
the base.
Oxidative amination of 6ꢀ(alkynꢀ1ꢀyl)lumazines 9a,b
with primary alkylamines in the presence of AgPy MnO
Scheme 3
2
4
at 20 °C afforded 1ꢀR´ꢀ2ꢀRꢀ6,8ꢀdimethylpyrroꢀ
lo[3,2ꢀg]pteridineꢀ5,7(6H,8H)ꢀdiones (4a—f) in 32—75%
yields (Scheme 4). Treatment of trimethylsilylacetylene
9
c with propylamine gave rise not to the expected pyrrole
but to its desilylation product 4g in 74% yield. Comꢀ
pounds 9a,b did not react with KNH in liquid ammonia
2
in the presence of KMnO at temperatures from –60 to
4
–
9
55 °C. Under these conditions, trimethylsilyl derivative
c underwent, apparently, desilylation and polymerꢀ
ization.
Evidently, the ease of oxidative amination and subseꢀ
quent heterocyclization of hetarylacetylenes 9 depends
on the bulkyness of the amine used and the nature of the
substituent R. Thus, the reactions of 9a,b with tertꢀbutylꢀ
amine required a longer reaction time and gave products
in low yields (see Table 1). The reactions of tertꢀbutylꢀ
amine with compound 9c afforded a mixture of pyrrole 4h
8
, 9: R = Ph (a), nꢀC H (b), SiMe (c),
6 13 3
1
ꢀpiperidinocyclohexyl (d)
t
Reagents and conditions: Pd dba —PPh , K CO , CuI, DMF,
and oꢀaminoacetylene 10a (R = H, R´ = Bu ) in a ratio of
2
3
3
2
3
9
0—100 °C, Ar.
1 : 0.85, which we failed to separate.
Scheme 4
4
R
R´
a
b
Ph
Pri
c
Ph
Bu
d
Ph
Bu
e
f
g
h
H
But
Ph
nꢀC H
nꢀC H
H
6
Pr
13
6
13
n
n
t
n
t
n
Pr
Bu
Pr

Heterocyclizations of 6ꢀalkynyllumazines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
1405
Table 1. Physicochemical characteristics and elemental analysis data for the compounds synthesized
Comꢀ
pound
R
R´
τa
Yield
(%)
M.p.
/°C
Rf
Found
Calculated
Molecular
formula
(%)
C
H
N
4
4
4
4
4
4
4
4
9
9
9
9
1
1
1
1
1
1
1
1
a
Ph
Ph
Ph
Ph
Prn
Pri
Bun
But
Prn
But
Prn
Me
—
10 min
1.5 h
6 h
75
68
65
38
68
32
74
81
69
79
56
63
—
156—157
182—184
136—138
209—211
109—112
182—183
180—182
227—229
221—223
84—87
0.40
0.35
0.30
0.30
0.35
0.25
0.30
0.40
0.60
0.65
0.85
0.30
—
65.57
5.33
65.16
5.33
66.25
6.12
66.33
6.12
64.00
3.87
64.83
4.69
57.30
7.14
63.43
3.55
265.64
5.75
64.03
4.00
54.25
4.17
5.30
5.44
5.32
5.44
5.69
5.79
5.58
5.79
7.70
7.56
7.53
7.82
5.27
5.49
4.89
4.67
4.17
4.11
6.55
6.67
5.39
5.56
7.21
7.09
2.51
2.65
5.11
5.26
5.50
5.33
2.61
2.65
4.22
4.35
3.45
3.57
3.42
3.70
6.27
6.02
19.83
20.06
20.23
20.06
19.43
19.28
19.23
19.28
19.54
19.61
18.72
18.87
25.76
25.64
21.63
21.81
19.31
19.18
18.93
18.67
19.59
19.44
18.53
18.37
27.58
27.40
21.23
21.05
16.75
16.57
12.57
12.39
12.34
12.17
12.81
12.50
17.41
17.28
16.70
16.87
C H N O
19 19 5
2
2
2
2
2
6
b
C H N O
19 19 5
6
c
C H N O
20 21 5
6
d
7 days
10 min
7 days
10 min
—
C H N O
20 21 5
6
e
nꢀC H
C H N O
19 27 5
6
13
13
6
f
nꢀC H
C H N O
20 29 5
6
2
2
2
2
2
6
g
H
C H N O
13 15 5
5
i
Ph
Ph
C H N O
17 15 5
6
a
2 h
C H N O
16 12 4
6
b
nꢀC H
—
2 h
C H N O
16 20 4
6
13
6
c
SiMe3
—
2 h
112—115
191—193
—
C H N O Si
13
16
4
2
2
5
d
1ꢀPiperidinoꢀ
cyclohexyl
—
—
45 min
—
66.36
66.14
42.45
C H N O
21 27 5
1b
3
—
C H N O Cl
9 10 5 2
4
2.27
67.82
7.67
63.79
3.91
42.34
2.48
41.56
1.74
35.01
4.82
59.29
9.26
57.68
7.83
—
—
—
—
—
—
—
C H N O
15 14 4
6
4
—
—
—
—
—
C H N O
18 18 4 3
6
6ac
6bd
6cf
7ag
7bh
Ph
—
—
70
70
88
61
58
213—216
0.75
0.75
0.90
0.60
0.65
C H Br N O
16 12 2 4 2
4
e
nꢀC H
—
—
C H Br N O
16 20 2 4 2
6
13
4
SiMe3
Ph
—
—
104—106
316—319
175—177
C H Br N O Si
13 16 2 4 2
3
—
—
C H N O S
16 12 4 2
5
nꢀC H
—
—
C H N O S
16 20 4 2
6
13
5
a
b
c
d
e
f
Reaction time.
Found (%): Cl, 13.75. Calculated (%): Cl, 13.89.
Found (%): Br, 35.23. Calculated (%): Br, 35.40.
Found (%): Br, 34.91. Calculated (%): Br, 34.78.
The compound was prepared as an oil.
Found (%): Br, 35.67. Calculated (%): Br, 35.71.
Found (%): S, 10.04. Calculated (%): S, 9.88.
Found (%): S, 9.47. Calculated (%): S, 9.64.
g
h
Apparently, the transformation 9 → 4 resulted from
spontaneous heterocyclization of intermediate oꢀaminoꢀ
hetarylacetylenes 10. This is evidenced by the fact that
crossꢀcoupling of 6ꢀchloroꢀ7ꢀmethylaminolumazine 11
with phenylacetylene performed under the aboveꢀdeꢀ
scribed conditions afforded exclusively pyrrole 4i in 81%

1
406
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
Gulevskaya et al.
Table 2. Spectroscopic data for 6ꢀ(alkynꢀ1ꢀyl)ꢀ1,3ꢀdimethyllumazines 9
1
IR, ν/cm–1
Comꢀ
pound
MS,
m/z
H NMR (CDCl ), δ (J/Hz)
UV,
λmax/nm (logε)
3
N—Me H(7)
R
C=O
C≡C
9
9
a
b
292
300
3.54; 8.75
.71
3.52; 8.60
.68
7.39 (m, 3 Н, Ph);
7.60 (m, 2 Н, Ph)
0.88 (t, 3 Н, Me, J = 6.8);
1.26—1.32 (m, 4 H, (CH ) (CH )Me); 1720
1671,
1720
1673,
2207
259 (4.05), 297 (4.41),
303 (4.41), 369 (4.41)
277 (4.26), 281 (4.26),
358 (3.93)
3
2200
3
2 3 2
1
1
2
.40—1.46 (m, 2 H, (CH ) CH C H );
2 2 2 3 7
.56—1.65 (m, 2 H, CH CH C H );
2
2
4
9
.45 (t, 2 Н, CH C H , J = 7.2)
2
5
11
9
9
c
d
288
381
3.51; 8.65
.68
3.48; 8.61
.65
0.26 (s, 9 H, SiMe3)
1673,
1723
1692,
1727
2167
2212
285 (4.29), 357 (3.99)
3
1.23—1.80 (m, 12 H, H , H
piperidino and cyclohexyl);
259 (4.22), 282 (4.26),
353 (3.97)
γ
β
3
2
2
.06 (m, 4 H, cyclohexyl);
.61 (m, 4 H, H piperidino)
α
Scheme 5
Reagents and conditions: Pd dba —PPh , K CO , CuI, DMF, 90—100 °C, Ar.
2
3
3
2
3
Scheme 6

Heterocyclizations of 6ꢀalkynyllumazines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
1407
yield (Scheme 5). However, treatment of acetylene 9a
with piperidine in the presence of an oxidizer gave rise not
to the expected amino derivative 12 but to carboxamide
pounds (λmax 343—381 nm). Their IR spectra have abꢀ
–
1
sorption bands at 1650—1710 cm (ν(C=O)). The
1
H NMR spectra show a signal for the H(3) proton of the
1
3 as the product of uracilꢀring opening (7.5% yield) and
pyrrole ring at δ 6.54—6.82 characteristic of fused pyrꢀ
1
5
ketone 14 (10%) (Scheme 6). The formation of the latter
can be considered as a result of hydrolysis of enamine 15.
The ability of acetylenes to add amines giving enamines is
well known.13 As regards the transformation of pteridineꢀ
dione 9a into compound 13, it should be noted that the
uracilꢀring opening under the action of nucleophiles is
one of the most widespread reactions of uracilꢀcontaining
compounds.1
roles. The protons of the αꢀCH groups and the αꢀCH
2
substituent at N(1) in compounds 4 are deshielded
by the N(9) aza group and are observed at low field
(δ 4.18—4.67). The mass spectra of pyrroles 4 show moꢀ
lecular ion peaks, which are most intense in the spectra
of 4a—c,g.
As mentioned above, the structure of urothione is based
on thieno[3,2ꢀg]pteridine. We attempted to annelate the
thiophene ring to 6ꢀalkynyllumazines 9 according to a
4
The physicochemical characteristics of pyrroles 4 are
given in Tables 1 and 3. Pyrroles 4 are paleꢀyellow comꢀ
1
6
procedure reported recently. This method involves
Table 3. Spectroscopic data for 1ꢀR´ꢀ2ꢀRꢀ6,8ꢀdimethylpyrrolo[3,2ꢀg]pteridineꢀ5,7(6H,8H )ꢀdiones 4a—g,i
1
Comꢀ
pound
MS,
m/z
H NMR (CDCl ), δ (J/Hz)
IR,
ν(C=O)
cm–1
UV,
λmax/nm
(logε)
3
N—Me H(3)
3.57; 6.82
R´
R
/
NCH (NCH)
Other groups
2
4
4
4
a
b
c
349
349
363
4.29
(t, 2 Н,
J = 7.4)
4.67 (sept,
1 Н,
J = 6.9)
4.33
(t, 2 Н,
J = 7.3)
0.76 (t, 3 Н, Me,
J = 7.5); 1.69 (m, 2 Н,
СH СH Me)
7.52 (s, 5 Н, Ph)
1673,
1708
266 (4.41),
344 (4.04),
378 (4.14)
261 (4.37),
343 (3.99),
378 (4.07)
266 (4.37),
344 (3.99),
378 (4.11)
3
.78
2
2
3.58; 6.76
.79
1.71 (d, 6 Н, CНMe2,
J = 6.8)
7.47—7.54 (m,
5 Н, Ph)
1665,
1703
3
3.57; 6.81
.78,
0.80 (t, 3 Н, Me,
7.50—7.55 (m,
5 Н, Ph)
1659,
1705
3
J = 7.3); 1.17 (m, 2 Н,
(CH ) CH Me); 1.63
2
2
2
(
m, 2 Н, CH CH C H )
2 2 2 5
t
4
4
d
e
363
357
3.57; 6.64
.78
—
1.66 (s, 9 Н, Bu )
7.43 (s, 5 Н, Ph)
1653,
1703
270 (4.30),
340 (3.97),
3
3
71 (3.96)
3.55; 6.54
.75
4.18
(t, 2 Н,
J = 7.4)
0.94 (t, 3 Н, Me,
J = 7.4); 1.81 (m, 2 Н,
0.89 (t, 3 Н, Me,
J = 6.9); 1.31—1.48
(m, 8 H,
1660,
1700
270 (4.18),
340 (3.96),
365 (3.91)
3
CH CH Me)
2
2
CH (CH ) Me);
2
2 4
2
.78 (t, 2 Н,
CH C H , J = 7.6)
0.89 (t, 3 Н, Me,
2
5
11
4
4
f
371
3.55; 6.59
.72
—
1.91 (s, 9 Н, But)
1660,
1700
271 (4.21),
339 (3.95),
366 (3.90)
3
J = 7.0); 1.29—1.48
(
m, 6 H,
(
CH ) (CH ) Me);
2
2
2 3
1
.70—1.82 (m, 2 H,
CH CH C H );
2
2
4
9
3
.00 (t, 3 Н,
CH C H , J = 7.7)
2
5
11
g
i
273
321
3.55; 6.82
.75 (d,
Н,
J = 3.8)
3.57; 6.85
.79
4.22
(t, 2 Н,
J = 7.1)
0.93 (t, 3 Н, Me,
J = 7.4); 1.91 (m, 2 Н,
CH CH Me)
7.53* (d, 1 Н,
J = 3.8)
1660,
1699
262 (4.09),
343 (3.98)
3
1
2
2
4
—
3.81 (c, 3 Н, Me)
7.50—7.60
(m, 5 Н, Ph)
1665,
1711
267 (4.40),
343 (3.98),
3
3
81 (4.14)
*
The chemical shift of H(2).

1408
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
Gulevskaya et al.
Scheme 7
1
6, 17: R = Ph (a), nꢀC H (b), SiMe (c)
6 13 3
the addition of bromine to the triple bond of hetarylꢀ
acetylene followed by vicarious nucleophilic substituꢀ
tion of hydrogen under the action of sodium trithioꢀ
carbonate.
sorption bands of the C=O groups at 1657—1717 cm–1.
The H NMR spectra show signals for the protons of two
1
N—Me groups (δ 3.5 and 3.8) and the substituent R as
well as a signal for the H(3) proton at δ 7.26—7.79 charꢀ
1
5
We found that 6ꢀalkynyllumazines 9a—c readily added
acteristic of fused thiophenes. The mass spectra of
bromine in a solution in CHCl to give dibromovinyl
compounds 16 have two molecular ion peaks correspondꢀ
3
3
2
34
derivatives 16a—c (Scheme 7, Table 4). The reactions of
compounds 9a,b afforded the only stereoisomer (apparꢀ
ently, the E isomer). The reaction of 9c with bromine
gave a mixture of Eꢀ and Zꢀdibromides 16c in a ratio of
ing to the S and S isotopes with the intensity raꢀ
+
tio of 100 : 4. The intensities of the [M – S] and
+
[M – SH] ions typical of the fragmentation of thiophenes
1
5
are < 5%.
2
.7 : 1. The resulting mixture was not separated beꢀ
To summarize, we developed an efficient approach to
pyrroloꢀ and thieno[3,2ꢀg]pteridineꢀ5,7(6H,8H )ꢀdiones
involving the synthesis of 6ꢀalkynylpteridines under the
conditions of the Sonogashira reaction followed by nuꢀ
cleophilic substitution of hydrogen in alkynyl derivatives
or their dibromination products.
cause both isomers can be used in the reaction with
Na CS .
The reactions of compounds 16a,b with sodium
trithiocarbonate in an aqueousꢀmethanolic soluꢀ
tion afforded 2ꢀRꢀ6,8ꢀdimethylthieno[3,2ꢀg]pteridineꢀ
2
3
5
,7(6H,8H )ꢀdiones (17a,b) in 58—61% yields. The reacꢀ
tion of 16c with Na CS gave rise to a complex mixture of
products due, apparently, to rapid desilylation of the startꢀ
ing compound followed by polymerization.
2
3
Experimental
Thienopteridines 17 (see Table 4) are yellow comꢀ
pounds (λmax 374—392 nm). Their IR spectra have abꢀ
The IR spectra were recorded on a Specord IRꢀ71 instruꢀ
ment in Nujol mulls. The H NMR spectra were measured on
1
Table 4. Spectroscopic data for 6ꢀ(2ꢀRꢀ1,2ꢀdibromovinylꢀ1)ꢀ1,3ꢀdimethyllumazines 16 and 2ꢀRꢀ6,8ꢀdimethylthieno[3,2ꢀg]pteridineꢀ
,7(6H,8H )ꢀdiones 17
5
1
Comꢀ
pound
MS,
m/z
H NMR (CDCl ), δ (J/Hz)
IR,
UV,
λmax/nm
(logε)
3
ν(C=O)
N—Me
H arom.
R
–
1
/
cm
1
1
6a
6b
—
3.55, 3.75
3.52, 3.71
8.86
8.67
7.37—7.47 (m, 3 Н, Ph);
.54—7.58 (m, 2 Н, Ph)
0.89 (t, 3 Н, Me, J = 6.7); 1.30—1.50
1680, 1727
1677, 1721
—
—
7
—
(
m, 6 H, CH (CH ) С H ); 1.60—1.75
2 2 3 2 5
(
m, 2 H, CH CH С H );
2 2 4 9
2
.85 (t, 2 Н, CH C H , J = 7.6)
2 5 11
1
1
6с
7a
—
3.53, 3.71 (E)
8.78 (E),
8.63 (Z )
7.79
0.03 (s, 9 H, SiMe ) (E);
1673, 1721
1660, 1713
—
3
3
.53, 3.71 (Z )
0.43 (s, 9 H, SiMe ) (Z)
3
324
3.58, 3.79
7.45—7.52 (m, 3 Н, Ph);
259 (4.28),
291 (4.42),
7
.72—7.75 (m, 2 Н, Ph)
3
92 (4.19)
1
7b
332
3.55, 3.74
7.26
0.87 (t, 3 Н, Me, J = 7.0); 1.28—1.42
1673, 1717
276 (4.32),
329 (3.57),
374 (3.90)
(
m, 6 H, (CH ) (CH ) Me);
2 2 2 3
1
2
.71—1.82 (m, 2 H, CH CH C H );
2 2 4 9
.96 (t, 3 Н, CH C H , J = 7.5)
2
5
11

Heterocyclizations of 6ꢀalkynyllumazines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
1409
Brukerꢀ250 (250 MHz) and Unityꢀ300 (300 MHz) spectromꢀ
one week and then concentrated to dryness. The residue was
eters with Me Si as the internal standard. The UV spectra were
extracted with CHCl . The extract was concentrated to ∼ 5 mL,
4
3
recorded on a Specord Mꢀ40 instrument in CHCl . The mass
chromatographed on a column with Al O , and eluted with
3
2
3
spectra were obtained on an MKhꢀ1321A spectrometer. Chroꢀ
CHCl . The yellow fraction with R 0.70 was collected and
3 f
matography was carried out on Al O3 (Brockmann activꢀ
concentrated to obtain Nꢀmethylamide of 3ꢀmethylaminoꢀ6ꢀ
(2ꢀphenylethynyl)pyrazineꢀ2ꢀcarboxylic acid (13) in a yield of
2
ity III—IV) using chloroform as the eluent; visualization
was carried out with iodine vapor. The melting points were
measured in glass tubes on a PTP instrument (an instruꢀ
ment for measurements of melting points manufactured at the
Khimlaborpribor JointꢀStock Company, Russia) and were not
corrected.
i
20 mg (7.5%) as yellow crystals, m.p. 101—103 °C (from Pr OH).
–1
IR, ν/cm : 3400, 3380, 3313 (N—H); 2207 (C≡C); 1656 (C=O).
1
H NMR (CDCl ), δ: 2.97 (d, 3 H, NHMe, J = 5.1 Hz); 3.06 (d,
3
3 H, NHMe, J = 5.0 Hz); 7.32—7.57 (m, 5 H, Ph); 7.91 (m,
1 H, NH); 8.38 (s, 1 H, H(7)); 8.86 (m, 1 H, NH).
The physicochemical characteristics and elemental analysis
data for the compounds synthesized are given in Table 1. The
spectroscopic data are listed in Tables 2—4.
6ꢀBenzoylmethylꢀ1,3ꢀdimethyllumazine (14) was obtained
from the orange fraction with R 0.50 in a yield of 31 mg (10%)
f
i
as orange crystals with t.decomp. 165 °C (from Pr OH). IR,
ν/cm : 1703, 1659, 1650 (C=O). H NMR (CDCl ), δ: 3.54 (s,
–
1
1
Synthesis of 6ꢀ(alkynꢀ1ꢀyl)ꢀ1,3ꢀdimethyllumazines (9a,b,d)
3
(
general procedure). A mixture of compound 7 (1 mmol),
3 H, N(1)Me); 3.75 (s, 3 H, N(3)Me); 4.72 (s, 2 H, CH );
2
alkyne 8 (1.25 mmol), K CO (1.5 mmol), Pd dba (0.02 mmol),
7.47—7.65 (m, 3 H, Ph); 8.02—8.05 (m, 2 H, Ph); 8.67
(s, 1 H, H(7)).
2
3
2
3
PPh (0.16 mmol), and CuI (0.05 mmol) in anhydrous DMF
3
(
3 mL) was stirred at 90—100 °C under argon (reactions times
6ꢀChloroꢀ1,3ꢀdimethylꢀ7ꢀmethylaminolumazine (11). A soꢀ
lution of compound 7 (454 mg, 2 mmol) in methylamine (50 mL)
was stirred at the temperature from –65 to –55 °C for 10 min.
Then KMnO4 (306 mg, 2 mmol) was added. The reaction
mixture was stirred at this temperature for 10 min and then
concentrated to dryness. The residue was extracted with hot
are given in Table 1). The reaction mixture was concentrated to
dryness and the residue was extracted with CHCl . The extract
was concentrated to ∼ 5 mL, chromatographed on a column with
Al O , and eluted with CHCl . The colorless fraction was colꢀ
lected (R are listed in Table 1). The product was recrystallized
from Pr OH.
3
2
3
3
f
i
i
Pr OH (30 mL). The extract was concentrated to dryness and
i
1
,3ꢀDimethylꢀ6ꢀtrimethylsilylethynyllumazine (9c). A mixture
the product was recrystallized from Pr OH. Compound 11
of compound 7 (227 mg, 1 mmol), trimethylsilylacetylene
was obtained in a yield of 400 mg (78%) as colorless crystals,
–
1
(
0.2 mL, 1.2 mmol), Pd dba (20 mg, 0.02 mmol), CuI (10 mg,
m.p. > 300 °C. IR, ν/cm : 3353 (N—H); 1708, 1649 (C=O).
2
3
1
0
.05 mmol), PPh (42 mg, 0.16 mmol), and Et N (7 mL) was
H NMR (CDCl ), δ: 3.15 (d, 3 H, NHMe, J = 4.8 Hz); 3.46 (s,
3
3
3
heated in a sealed tube under argon at 100 °C for 2 h and then
treated as described above. The product was recrystallized
from MeOH.
3 H, N(1)Me); 3.62 (s, 3 H, N(3)Me); 6.01 (br.s, 1 H, NH).
Synthesis of 6ꢀ(2ꢀRꢀ1,2ꢀdibromovinylꢀ1)ꢀ1,3ꢀdimethyllumꢀ
azines (16) (general procedure). Bromine (1.3 mmol) was added
portionwise to a solution of compound 9 (1 mmol) in CHCl3
(3 mL). The reaction mixture was stirred at ∼ 20 °C for 2 h and
concentrated to dryness. The residue was extracted with CHCl3.
The extract was concentrated to ∼ 5 mL, chromatographed on a
column with Al O , and eluted with CHCl . The yellow fraction
Synthesis of 1ꢀR´ꢀ2ꢀRꢀ6,8ꢀdimethylpyrrolo[3,2ꢀg]pteridineꢀ
5
,7(6H,8H )ꢀdiones (4a—g) (general procedure). A solution of
compound 9 (1 mmol) in amine (30—40 mL) was stirred at
0 °C for 15 min and then AgPy MnO (1 mmol) was added.
2
2
4
The completion of the reaction was monitored by chromatograꢀ
phy (reaction times are given in Table 1). The reaction mixture
was concentrated to dryness and the residue was extracted with
2
3
3
with R 0.75 was collected. The product was recrystallized
f
i
from Pr OH.
CHCl . The extract was concentrated to ∼ 5 mL, chromatoꢀ
Synthesis of 2ꢀRꢀ6,8ꢀdimethylthieno[3,2ꢀg]pteridineꢀ
5,7(6H,8H )ꢀdiones (17) (general procedure). A solution of comꢀ
pound 16 (1 mmol) in MeOH (30 mL) was heated to boiling, a
30% Na CS solution (5 mL) was added, and the mixture was
3
graphed on a column with Al O , and eluted with CHCl . The
2
3
3
first yellow fraction was collected (R are listed in Table 1). The
f
i
product was recrystallized from Pr OH.
2
3
1
,6,8ꢀTrimethylꢀ2ꢀphenylpyrrolo[3,2ꢀg]pteridineꢀ
stirred at this temperature for 1 h (in the case of compound 16b,
at 20 °C for 30 min). The completion of the reaction was moniꢀ
tored by chromatography. The reaction mixture was concenꢀ
5
0
,7(6H,8H )ꢀdione (4i). A mixture of compound 11 (128 mg,
.5 mmol), phenylacetylene (0.15 mL, 0.75 mmol), K CO3
2
(
105 mg, 0.75 mmol), Pd dba (9 mg, 0.01 mmol), PPh (20 mg,
trated to dryness and the residue was extracted with CHCl . The
2
3
3
3
0
.08 mmol), and CuI (5 mg, 0.025 mmol) in anhydrous DMF
extract was concentrated to ∼ 5 mL, chromatographed on a colꢀ
(
3 mL) was stirred under argon at 90—100 °C for 2 h. The
umn with Al O , and eluted with CHCl . The colorless fraction
2
3
3
reaction mixture was concentrated to dryness and the residue
was collected (R are given in Table 1). The product was recrysꢀ
tallized from Pr OH.
f
i
was extracted with CHCl . The extract was concentrated to
3
∼
5 mL, chromatographed on a column with Al O , and eluted
2 3
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
with CHCl . The brightꢀyellow fraction with R 0.40 was
3
f
i
collected. The product was recrystallized from Pr OH. The
physicochemical characteristics of compound 4i are given in
Tables 1 and 3.
3
2338).
Reaction of 1,3ꢀdimethylꢀ6ꢀ(2ꢀphenylethynꢀ1ꢀyl)lumazine
References
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9a) with piperidine in the presence of an oxidizer. A solution of
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2
1
mmol) was added. The reaction mixture was kept at 20 °C for

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6
Received February 19, 2003