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Vestnik FEB RAS. 2018. № 6 Supplement
UDC 547.655.6 DOI: 10.25808/08697698.2018.202.6S.024
G.I. MEL'MAN, V.L. NOVIKOV, V.A. DENISENKO, VP. GLAZUNOV, V.Ph. ANUFRIEV
Reactions of polyhydroxynaphthazarins and their methyl ethers with aqueous ammonia
Key words: (poly)hydroxynaphthazarins, (poly)methoxynaphthazarins, amination, aminohydroxynaphthazarins, aminomethoxynaphthazarins.
Naphthazarins (5,8-dihydroxy-1,4-naphthoquinones) bearing a different number of hydroxy groups in the P-positions of their skeletons are widely distributed in nature. In most cases, they are produced by marine invertebrates. All polyhydroxynaphthazarins are antioxidants, the effectiveness of which depends on the number of P-hydroxy groups and their positions [7]. Echinochrome A is the most famous among them. On the basis of this pigment a new drug «Histochrome» was created [6]. Recently, previously unknown metabolites, echinamines A and B, and spinamine have been isolated from different sea urchin species. These metabolites contain NH2 groups in the P-positions of the cyclic backbone [5]. Theoretical studies of the mechanisms of antioxidant action of echinamines A and B showed that they are much more active as antioxidants than the parent echinochrome A [2]. In this connection, the development of methods for the amination of functionally substituted naphthazarins is of considerable interest. These approaches can open the way for the synthesis of both natural and related compounds containing amino functions in different positions of the naphthazarin skeleton.
We have shown that the reaction of 2-hydroxynaphthazarin (1) (naphthopurpurin) with a 25% aqueous solution of ammonia at room temperature proceeds rapidly (10 - 20 min), giving product 2 with a quantitative yield [3].
oh o o nh2 oh o oh o oh o
OH A 1 OH Me i Jl OH Me J Jl O Me, I Jl O
N
"-H
In the case of substrates with vicinal OH groups, the interaction with ammonia leads to the formation of products of a different type. Under amination reaction conditions 2,3-dihydroxynaphthazarin 3 are converted to 5,8-dihydroxyisoquinoline-1,3,4(2^)-trione derivatives 4 [1]. This can be explained by the fact that the substrate 3 exists partially in the tautomeric form 3b. The reaction of electrophilic C-atom of C(2)=O group of 3b with NH3 gives rise to amino intermediate that is turned to 4 by the action of O2.
Substrates with three P-OH groups, for example, echinochrome A 5, react with the formation of aminohydroxynaphthazarins 6 (48%) and 7 (47%) [3]. Because of the asymmetry of echinochrome A, the tautomeric forms 5b and 5c are not equivalent as a result of which the formation
* MELMAN Galina Ivanovna - Junior Researcher, NOVIKOV Vyacheslav Leonidovich - DSc, Leading Researcher, DENISENKO Vladimir Anatolievich - PhD, Leading Researcher, GLAZUNOV Valery Petrovich - PhD, The Head of The Laboratory, ANUFRIEV Viktor Philippovich - DSc, The Head of The Laboratory (G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS, Vladivostok, Russia). *E-mail: galamelman@gmail.com
of isomers 6 and 7 is observed. In the case of substrate 5, the reaction comes to rest at the stage of the formation of 6 and 7. In the case of substrate 3, the reaction proceeds via intermediates of the type 6 and 7 but is not brought to rest on this stage. We do not know yet why this happens. Undoubtedly, the nature of the C(6) and C(7) substituents at intermediates of these processes exerts a significant influence on the final result of these reactions. Substrate 3 has at these positions the relatively weak electronodonating substituents whereas substrate 5 has the ionized C(6) -OH group which is the strongest electronodonor.
1. nh3
2. h*
1. nh3
2. h*
From the above, the question arises: will the aqueous solution of ammonia react with naph-thazarin substrates where the P-OH groups are protected as OMe ethers? We found that the reaction of 2-methoxynaphthazarin 8 (naphthopurpurin monomethyl ether) with aqueous ammonia leads to the formation of aminonaphthoquinone 9 with a yield close to quantitative. In compound 8, the most electrophilic center is the carbon atom of the C = O group at the position 1, since the electronodonating substituent at the position 2 partially desactivates the C = O group at the position 4.
OH
OMe
Substrate 10 with vicinal OMe groups reacted with aqueous ammonia giving a mixture of products 11 (70%) and 12 (15%). As large as this difference in the yields of these products is a consequence of the strong dominance of tautomer 10a in the tautomeric equilibrium of this substrate. This dominance is due to the electronodonating properties of OMe groups, that greatly exceed the same properties of Me groups. As a result, the electron density on the oxygen atoms of the C = O groups of tautomer 10a will be larger than this density on the oxygen atoms of the C = O groups of tautomer 10b. Such a electron density redistribution will increase the force of intramolecular hydrogen bond in tautomer 10a compared to 10b and will make 10a dominate in the tautomeric mixture of the substrate 10. Theoretical calculations have shown that the ratio of tautomers 10a and 10b in the alkaline medium is 70 to 30%.
och3 och3
o oh nh oh nh, o
OCH3>ttt me^^^^^oc^ me^^l^l^och
och3
Oh o 12b
As a result of the reaction of trimethyl ether of echinochrome 13 with aqueous ammonia, two products 14 (77%) and 15 (13%) were obtained. Their structures were assigned on the basis of the dates of IR-, NMR-, and mass - spectra [4]. By analogy with what has been said above regarding the ratio of tautomers 10a and 10b in the case of substrate 10, for substrate 13, a tautomer 13a with two OMe groups in the quinoid nucleus should dominate in the solution. Obviously, in the case of tautomer 13b an attack of the nucleophile will proceed on the carbon atom of the C = O group at the position 1, that will result in the formation of a minor product 15b (13%). In the case of tautomer 13a, the direction of the nucleophile attack is not obvious as for tautomer 13b. Probably, a definite orienting effect in this case is exerted by the C (6)-OMe group whose donor effect reduces the positive charge on the carbon atom of the C = O group at the position 1 and, as would be expected, makes an attack on the C = O group at the position 4 more advantageous. As a result, the formation of the principal product 14b (77%) takes place.
h
6
o nh
oh o
och, och3 h3c
i^ochj h3cc
och3
'ch3 h3c
och3
'chi
NH2
As is evident from the foregoing, naphthazarins with one P-OH group at the position 2 react with NH3 giving derivatives with the NH2 group at the position 5(8); with two P-OH groups at the positions 2 and 3 give 2(3)-amino derivatives that are further oxidized to the corresponding isoquinolinetrions by atmospheric O2; with three P-OH groups at the positions 2, 3, and 6 give 2(3)-amino derivatives that are resistant to further oxidation with air oxygen. At the same time, OMe ethers of these naphthazarins react with NH3 to form derivatives where the NH2 group locates only at the position 5(8).
o oh
o oh
oh o
oh o
o oh
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4. Mel'man G. I., Denisenko V. A., Anufriev V. Ph. Reaction of echinochrome trimethyl ether with aqueous ammonia // Russ. Chem. Bull, Int., Ed. 2010. Vol. 59. No. 9. P. 1781-1785.
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