New Synthetic Potential of Pteridine Derivatives: Direct Substitution of H in 1,3-Dimethyllumazine During Reaction with C-Nucleophiles

Full text of DOI:10.1007/s10600-016-1650-3

DOI 10.1007/s10600-016-1650-3
Chemistry of Natural Compounds, Vol. 52, No. 2, March, 2016
NEW SYNTHETIC POTENTIAL OF PTERIDINE DERIVATIVES:
DIRECT SUBSTITUTION OF H IN 1,3-DIMETHYLLUMAZINE
DURING REACTION WITH C-NUCLEOPHILES
1*
1
1
Yu. A. Azev, O. S. Ermakova A. M. Gibor,
2
2
1,2
M. A. Ezhikova, M. I. Kodess, and O. N. Chupakhin
The pteridine core is a heterocyclic scaffold for a large series of significant natural and synthetic biologically active
compounds. Many natural pteridines are involved in cellular metabolism. Therefore, the regioselective synthesis of new
H
pteridine derivatives with potential biological activity is exceedingly crucial [1]. Use of S -functionalization of C–H bonds
N
via direct substitution of H by C-nucleophiles and production of products with C–C bonds was promising during development
of effective synthetic methods for natural and synthetic biologically active heterocyclic compounds [2, 3].
Chichibabin substitution of H in unsubstituted 1,3-dimethyllumazine was reported for the reaction with alkylamines
in the presence of oxidizers to give 7-substituted 1,3-dimethyl-2,4-dioxopyrimido-[4,5-b]pyrazine derivatives [4]. The C-6
atom of 1,3-dimethyllumazine was alkoxylated regioselectively during the reaction with N-bromosuccinimide in alcohols [5].
Examples of direct functionalization of C–H bonds using C-nucleophiles are unknown for 1,3-dimethyllumazine.
The goals of the present work were to investigate the specifics and features of direct H substitution in reactions of
1,3-dimethyllumazine with C-nucleophiles, to study ways of activating the substrate and reagents, and to determine the points
of nucleophilic attack.
O
O
O
5
3
N
H C
3
N
N
N
H C
4a
N
3
H C
3
4
N
N
OH
CH
3
R
2
1'
8
N
1
N
CH
7
3'
8a
O
N
CH
N
H
O
N
CH
3
O
N
N
7'a'
7'
3a'
R
1
3
3
N
O
OH
Ph
7
3a - c
a: R = R = H
b: R = H, R = CH
5
5'
2a - c
AcOH
AcOH
O
4
6
1
2
AcOH
1
2
3
N
H C
3
c: R = CH , R = H
N
N
1
3
2
H
N
Ph
CH H C
3
3
O
N
N
4
Ph
8
N
N
N
CH
3
Et N
3
1
AcOH
H
O
O
HO
O
H C
3
CH
3
N
N
OH
H C
3
H
N
OH
N
N
N
OH
OH
N
O
N
CH
N
Ph
N
N
H
Ph
H C
3
CH
3
HO
O
N
Ph
Ph
3
9
10
OH
OH
OH
OH
R
2
Nu =
N
Ph
N
OH
R
1
O
2a - c
4
6
8
1) B. N. Yeltsin Ural Federal University, 19 Mira St., Ekaterinburg, 620002 Russia, e-mail: azural@yandex.ru;
2) I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Ekaterinburg, 620990 Russia,
e-mail: nmr@ios.uran.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2016, pp. 323–325. Original
article submitted September 17, 2015.
©
0009-3130/16/5202-0373 2016 Springer Science+Business Media New York
373

H-6
Me-N(1)
ppm
121.0
121.5
122.0
122.5
ppm
C-5
ꢀ
147.0
147.5
148.0
C-8a
C-4a
C-6
ꢀ
148.5
ppm
ppm
3.65
3.60
8.90
8.85
13
1
Fig. 1. Portions of 2D H– C HMBC spectra (500 MHz, DMSO-d ) of 3b.
6
We found that unsubstituted 1,3-dimethylumazine (1) reacted with heating with C-nucleophiles [indoles 2a–c,
3-methyl-1-phenylpyrazolone-5 (4), polyphenols 6 and 8] in the presence of acids to give products of nucleophilic substitution
of the C-7 H (3a–c, 5, 7, and 9).
The reaction of lumazine 1 with indoles 2 was carried out with heating in AcOH for 35–40 h at 110°C. The yield of
substitution products was 20–25% (3a), 30–35% (3b), and 15–20% (3c). Lumazine 1 reacted with pyrazolone 4 under analogous
conditions to give 5 in 25–30% yields.
Substitution products of 1 with polyphenols formed under these conditions only in trace amounts. However, performing
the reaction of 1 with polyphenols in trifluoroacetic acid afforded substitution products 7 and 9 in 45–50% yields.
1
13
2D H– C HSQC and HMBC experiments proved that H-7 in 1 was substituted during the reactions with
C-nucleophiles. Thus, the HMBC spectrum of 3b showed a cross peak corresponding to spin–spin coupling of H-6 and
quaternary C-4a (Fig. 1).
Another analogous coupling between H-7 and C-8a would have been observed if an alternative reaction course
(substitution of H-6) had occurred. However, a cross peak corresponding to this was missing in the spectrum. In turn,
bridging C atoms C-4a and C-8a had readily differentiated chemical shifts (the C-4a resonance appeared at stronger field than
that of C-8a). Furthermore, C-8a was identified unambiguously from a cross peak with the N-1 methyl protons in the HMBC
spectrum.
Acid catalysis was found during the course of the work to play a decisive role in the nucleophilic substitution of H in
the pyrazine portion of 1. Moreover, such transformations were not observed without an acid.
Substitution product 5 was not produced during the reaction of 1 with pyrazolone 4 in DMSO in the presence of Et N.
3
The known dipyrazolylmethane 10 was identified in the reaction mixture using TLC and GC-MS [6].
We found earlier that the reaction of quinoxaline (or 3-phenyl-1,2,4-triazine) with 3-methyl-1-phenylpyrazolone-5 in
the presence of Et N led to elimination of a C–C moiety from the pyrazine (or triazine) core and formed the tetrapyrazolylethane
3
derivative, which was readily converted to dipyrazolylmethane [6, 7].
It could be assumed that base catalysis caused the analogous elimination of a C–C moiety from the pyrazine core of
1 to give the tetrapyrazolylethane derivative, which transformed into dipyrazolylmethane 10 during the course of the reaction.
1
1,3-Dimethyl-7-(1ꢀH-indol-3ꢀ-yl)pteridine-2,4(1H,3H)-dione (3a). Yield 20–25%, mp > 300ꢁÑ. Í NMR spectrum
(400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.33, 3.70 (3Í each, s, NMe), 7.23–7.29 (2Í, m, H-5ꢀ, 6ꢀ), 7.53 (1Í, m, H-7ꢀ), 8.48 (1Í,
6
m, H-4ꢀ), 8.68 (1Í, d, J = 3.2, H-2ꢀ), 9.10 (1Í, s, H-6), 12.16 (1Í, br.s, NH). Mass spectrum (EI, 70 eV), m/z (I , %): 307
rel
+
([M ], 100), 195 (23), 140 (30). C H N O .
16 13
5 2
1
1,3-Dimethyl-7-(2ꢀ-methyl-1ꢀH-indol-3ꢀ-yl)pteridine-2,4(1H,3H)-dione (3b). Yield 30–35%, mp > 300ꢁÑ. Í NMR
spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.80 (3H, s, CH -2ꢀ), 3.33 (3H, s, CH -N3), 3.64 (3H, s, CH -N1), 7.16–7.21
6
3
3
3
13
(2H, m, H-5ꢀ, 6ꢀ), 7.43 (1H, m, H-7ꢀ), 8.20 (1H, m, H-4ꢀ), 8.88 (1H, s, H-6), 11.98 (1H, s, NH). C NMR spectrum (126 MHz,
DMSO-d , ꢂ, ppm): 15.03 (CH -2ꢀ), 28.22 (CH -N3), 29.05 (CH -N1), 108.35 (C-3ꢀ), 111.44 (C-7ꢀ), 119.85 (C-4ꢀ), 121.18
6
3
3
3
(C-5ꢀ), 121.88 (C-4a), 122.02 (C-6ꢀ), 126.29 (C-3ꢀa), 135.49 (C-7ꢀa), 137.39 (C-6), 141.51 (C-2ꢀ), 147.56 (C-8a), 150.72
+
(C-2), 153.79 (C-7), 159.64 (C-4). Mass spectrum (EI, 70 eV), m/z (I , %): 321 ([M ], 100). C H N O .
rel
17 15 5 2
1
1,3-Dimethyl-7-(1ꢀ-methyl-1ꢀH-indol-3ꢀ-yl)pteridine-2,4(1H,3H)-dione (3c). Yield 15–20%, mp > 300ꢁÑ. Í NMR
spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.34, 3.71 (3Í each, s, NÑÍ ), 3.94 (3Í, s, ÑÍ -N1ꢀ), 7.30–7.37 (2Í, m, H-5ꢀ,
6
3
3
6ꢀ), 7.63 (1Í, m, H-7ꢀ), 8.50 (1Í, m, H-4ꢀ), 8.70 (1Í, s, H-2ꢀ), 9.03 (1Í, s, H-6). Mass spectrum (EI, 70 eV), m/z (I , %): 321
rel
+
([M ], 100), 209 (20), 140 (17). C H N O .
17 15
5 2
374

1,3-Dimethyl-7-(3ꢀ-methyl-5ꢀ-oxo-1ꢀ-phenyl-1ꢀ,5ꢀ-dihydropyrazol-4ꢀ-ylidene)-7,8-dihydropteridine-2,4(1H,3H)-
1
dione (5). Yield 25–30%, mp > 300ꢁÑ. Í NMR spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 2.65 (3Í, s, ÑÍ -3ꢀ), 3.25
6
3
(1H, br.s, NH + H O), 3.31, 3.56 (3Í each, s, NÑÍ ), 7.28 (1Í, t, J = 7.3, H ), 7.48 (2Í, t, J = 7.5, H ), 7.74 (2Í, d, J = 7.7, H ),
2
3
p
m
o
+
9.40 (1Í, s, H-6). Mass spectrum (EI, 70 eV), m/z (I , %): 364 ([M ], 100). C H N O .
1,3-Dimethyl-7-(2ꢀ,4ꢀ-dihydroxyphenyl)pteridine-2,4(1H,3H)-dione (7). Yield 45–50%, mp > 300ꢁÑ. Í NMR
spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.37, 3.62 (3Í each, s, NÑÍ ), 6.38–6.40 (2Í, m, H-3ꢀ, 5ꢀ), 7.95 (1Í, d,
rel
18 16 6 3
1
6
3
+
J = 9.2, H-6ꢀ), 9.23 (1Í, s, H-6), 9.92 (1Í, s, ÎÍ), 11.06 (1Í, s, ÎÍ). Mass spectrum (EI, 70 eV), m/z (I , %): 300 ([M ],
rel
100). C H N O .
14 12
4 4
1
1,3-Dimethyl-7-(2ꢀ,3ꢀ,4ꢀ-trihydroxyphenyl)pteridine-2,4(1H,3H)-dione (9). Yield 40–45%, mp > 300ꢁÑ. Í NMR
spectrum (400 MHz, DMSO-d , ꢂ, ppm, J/Hz): 3.38, 3.63 (3Í each, s, NÑÍ ), 6.48 (1Í, d, J = 8.8, H-5ꢀ), 7.50 (1Í, d, J = 8.8,
H-6ꢀ), 8.5 (1H, br.s, OH), 9.20 (1Í, s, H-6), 9.5, 10.7 (1H each, br.s, OH). Mass spectrum (EI, 70 eV), m/z (I , %): 316 ([M ],
6
3
+
rel
100). C H N O .
14 12
4 5
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1.
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375