Synthesis of acyclic and cyclic phosphonates based on substituted 2-hydroxybenzylic alcohols
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Synthesis of acyclic and cyclic phosphonates based on substituted 2-hydroxybenzylic alcohols N. V. Terekhova,a,b D. A. Tatarinov,b E. A. Mikulenkova,b V. F. Mironov,b and V. K. Brela aA.
N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian Federation. Fax: +7 (499) 135 6549 bA. E. Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center "Kazan Scientific Center of the Russian Academy of Sciences", 8 ul. Arbuzova, 420088 Kazan, Russian Federation. Fax: +7 (843) 273 1872. E-mail: [email protected] A convenient synthesis of benzylic phosphonates and 2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxides substituted at the aromatic ring, as well as their precursors, 2-hydroxybenzylic alcohols, from the derivatives of salicylic aldehyde, salicylic acid, and 2-hydroxyacetophenone bearing an additional hydroxy or methoxy group at the para position of the aromatic ring was developed. For the first time, the possibility of selective demethylation of the methoxy group positioned ortho to the methylene phosphonate fragment with retention of the methoxy group at the para position was shown. Key words: 2-hydroxybenzyl alcohol, triethyl phosphite, benzyl phosphonates, 2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxides.
Organophosphorus compounds attract great attention due to their wide application in industry,1 biology and medicine,2—6 and organic synthesis. 7,8 Among them acyclic and cyclic phosphonates9 should be noted for their biological activity, in particular, their stability to hydrolytic enzymes. Due to this, phosphonates can be employed as the P—C-analogs of transition states at enzyme active sites during peptide synthesis and peptide bond hydrolysis10,11 or secondary metabolites in microorganisms5. In the literature, special attention is paid to the development of the synthetic methods towards phosphonates of different structure.12 In the present work, we report a synthetic approach to functionally substituted phosphonates based on 2-hydroxybenzylic alcohols. The most common method to synthesize one of the closest analogs of the target compounds is the Arbuzov-type reaction between triethyl phosphite and 2-hydroxybenzylic alcohol (1) to give diethyl 2-hydroxybenzylphosphonate (2). This method can also be used to obtain cyclic 2-ethoxy-3H-benzo[d][1,2]oxaphosphole 2-oxide (3)13—15 (Scheme 1). Nonetheless, this approach has not been used for the synthesis of salicylic alcohol derivatives with additional hydroxy or methoxy group at position 4 of the aromatic ring, probably, due to poor availability of these compounds. Hence, oxymethylation of resorcinol in the presence of boric acid16 and reduction of aldehyde 4a17 or acid 4b18,19 led only to the mixtures of oligo/polymerization products
Scheme 1
of the target 2,4-dihydroxybenzylic (-resorcylic) alcohol 5a (Scheme 2). It is known that alkylation of the phenolic Scheme 2
Mixture of the condensation products R1 = R2 = H (a); R1 = OH, R2 = H (b); R1 = H, R2 = Me (c)
Reagents and conditions: i. (
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