The acetylation of naphthoquinones. The synthesis of 3-acetyl-5-methoxy- and 3-acetyl-5,7-dimethoxy-1,4-naphthoquinones

Abstract

The conversion of 5-methoxy-and 5,7-dimethoxy-1,4-naphthoquinones into their 3-acetyl derivatives is described. A key step is the Fries rearrangement of 1,5-dirnethoxy-4-acetoxynaphthalenes to the corresponding 3-acetyl-4-naphthols with boron trifluoride-diethyl ether. Alternative Fries rearrangement of I -acetoxy-4-hydroxy-5-methoxynaphthalenes gave the 3-acetylquinols, involving meta migration of the acetyl group. A convenient new synthesis of 2-acetyl-l,4-naphthoquinone is also reported.The naphtho[2,3-c]pyran ring system occurs not infrequently in Nature as derivatives of the 5,10-quinone. Examples are the eleutherins,' the nanaomycins,2 and the p r~t o a p h i n s .~ Certain analogues lacking oxygen(s) in the aromatic ring have been synthesised using 2-acetyl-1,4-naphthoquinone (1) as starting material; for example, 9-deoxykalafungin (4) and 7,9-dideoxyquinones A (5) and A' (6),' the latter being derivatives of the protoaphins. Preparation of the natural products themselves requires appropriate regiospecific aromatic oxygenation of 2-acetylnaphthoquinone. We describe here syntheses of 3-acetyl-5-methoxy-1,4-naphthoquinone (2) t and the corresponding 5,7-dimethoxy analogue (3),7 and are currently investigating the use of these in the formation of several naturally occurring quinones or their derivatives. In the course of this work, an unusual Fries rearrangement was established.to the product was supported inter alia by a sharp lowfield singlet at 6 13.46 in its 'H n.m.r. spectrum due to the strongly hydrogen bonded hydroxy group. Oxidation of this compound with ceric ammonium nitrate gave rise to the desired 3-acetyl-5-methoxy-1,4-naphthoquinone (2) in an overall yield of 67% from (7). 0 ( 7 ) R = H ( 8 ) R = OMe M e 0 OH R OMe ( 9 ) R = H (10) R = OMe ( 4 ) ( 1 ) R ' = R~= H ( 2 ) R'=OMe, Rz:H ( 3) R'= RZ = OMe 0 Me ( 5 ) R' = O H , R~ = H ( 6 ) R 1 = H , R 2 = O H Results and DiscussionJuglone methyl ether (7) was reductively monomethylated at the less hindered oxygen to give the naphthol (9) using sodium dithionite followed by treatment with dimethyl sulphate and potassium carbonate in acetone. The corresponding acetate (1 1) was treated with boron trifluoridediethyl ether at 60 "C for 30 min to give the product (13) of Fries rearrangement, together with deacylated material (9) which could be recycled, thereby providing a high yield of (13). The assignment of structure (13) t Compound (2) is already known.6 However the yield (34%) in the final step made an alternative route desirable for further synthesis. O/H.. M e 0 0 A c R ' & M e R 03 OMe OMe (11) R = H (12) R = O M e (13) R = H (14) R OMe 5,7-Dimethoxy-1,4-naphthoquinone (8) could be converted similarly into its 3-acetyl derivative (3) via the sequence (8) --+ (10) -(12) -(14) -(3). Assignment of struc ture (10) to the product of reductive monomethylation of (8) rested on a comparison with the conversion of (7) into (9) and also the appearance of a sharp, lowfield, concentrationindependent singlet at 6 8.72 for the hydrogen-bonded hydrogen [the corr...

Synthesis of 3-azido-2,3,6-trideoxy-β-d-arabino-hexopyranosyl pyranonaphthoquinone analogues of medermycin

“…Initially attention focused on the use of an acetic acid-trifluoroacetic anhydride system, 20 which has previously been used successfully to acetylate related polyalkoxynaphthalenes. 21 Unfortunately, naphthalene 10 proved totally unreactive towards this system, even at elevated temperatures. Friedel-Crafts acetylation using acetyl chloride and aluminium chloride in dichloromethane also failed, with some decomposition observed using this system at elevated temperatures.…”

Suzuki–Miyaura homocoupling of naphthyl triflates using bis(pinacolato)diboron: approaches to the biaryl skeleton of crisamicin A

“…Considerable effort was made to effect a double Fries rearrangement of bis-acetate 37 to the desired bis-acetylnaphthalene 14 using boron trifluoride, aluminium trichloride and scandium triflate using a variety of solvents and conditions, however these attempts were fruitless. Similarly, attempts to effect introduction of acetyl groups at C-7 and C-7Ј on binaphthyl 35 using trifluoroacetic anhydride in acetic acid 22 and acetic anhydride with ruthenium trichloride 21 afforded complex mixtures.…”

Products of an Acetylation Protocol on Two Pentaalkoxynaphthalenes

“…[4] Subsequently, by blocking the C-1 position with a methoxy group viz. pentamethoxynaphthalene 5 and subjecting this compound to the same conditions of acetylation led to the isolation of the C-2 acetylated isomer 8 as the sole product.…”

“…[4,10] Thus treatment of naphthalene 18 with premixed trifluoroacetic anhydride and acetic acid in dichloromethane at 20 8C produced a chromatographically separable mixture comprising the starting material 18 (12%), followed by the desired product of acetylation viz. 20 (28%), and finally the acetoxyacetylnaphthalene 21 (27%) (Scheme 2).…”