Application of ortho -acylated phenylacetic acid esters to the synthesis of 1-substituted isochromanes

A series of 1-substituted isochromanes has been synthesized from the corresponding alkyl 2-acylphenylacetates 3 , by reduction and cyclization with a catalytic amount of p -toluenesulfonic acid monohydrate (PTSA), as compounds with potential antitumor activity and N-bearing heterocycle analogues


Introduction
The biological activity of some isochromane derivatives has provided a great deal of interest in the synthesis.3][4] Recently, Nergardh et al. reported that isochroman A 68930 is a selective dopamine D1 antagonist. 5Some isochromanes are pharmacologically active compounds in anti-migraine therapy.For example, PNU-109291 is selective 5-HT1D receptor agonist with anti-migraine potential, like sumatriptan. 6Isochromane derivatives are synthesized as aromatic analogues of Stavudine, an approved anti-Human Immunodeficiency Virus (HIV) drug. 7The isochromane analogues of the naphthylisoquinoline alkaloids michellamines and korupensamines have been synthesized because of their activity against HIV. 8ome isochromane analogues are part of complex natural products such as stephaoxocanine 9 and glucoside B. 10 Isochromane derivatives also exhibit plant-growth regulatory and herbicidal activities; 11,12 they are estrogen receptors, 13 dopamine receptor ligands, 14 and fragrances, such as galaxolide. 156,7-Dimethoxyisochromanes substituted at C-1 via a one-to three-carbon chain with arylpiperazines, p-trifluoromethylphenyl, etc., are hypotensives, which lower blood pressure presumably by both peripheral and central α-adrenoreceptor blockade. 141-Phenyl-and 1-(3methoxy-4-hydroxy)phenyl-6,7-dihydroxyisochromans have been identified in extra-virgin olive oil and have been shown to exhibit beneficial antioxidant effects 16,17 and antiplatelet activity. 18][21] Heterocyclic anthracyclines, as idarubicin's analogues, include the isochromane nucleus, have been reported to possess a potent and broad spectrum of antitumor activity. 221,6,8-Trihydroxy-3-heptyl-7-carboxyisochroman, an isochromane derivative from Penicillium sp. is an antibiotic and a topoisomerase II inhibitor. 23Another derivative, pseudoflectusin, is a selective human cancer cytotoxin found in nature from Aspergillus pseudodeflectus. 24

Results and Discussion
Isochroman derivatives are structural analogues of tetrahydroisoquinolines and have been repeatedly recognized as such. 25,26This analogy has been exploited and several studies report on the use of isochromans as starting materials or intermediates for the synthesis of iso-quinoline derivatives and vice versa , as well as for the preparation of other nitrogen-containing heterocycles. 26Numerous methods have been developed to synthesize isochromanes by intramolecular C-O 7, 27-29 or C-C bond 30,31 cyclization.Recently, the synthesis of isochromanes containing hydroxy substituents has been achieved.The key step for the synthesis of the isochromane nucleus is an oxidative mercury-mediated ring closure of phenylmethanol derivatives or the ozonolysis of the corresponding phenylmethanol derivative. 32,33The hydroxyisochromanes were prepared also by saponification of 5-formylmellein, 34 reduction of isocoumarins with hydrides, 35,36 reaction of benzocyclobutenols and aromatic aldehydes in the presence of lithium 2,2,6,6-tetramethylpiperidide, 37 photo-induced hetero-Diels-Alder reaction of 2-methylbenzldehydes, 38 oxidation of 2-(2-hydroxyethyl)-5-isopropylbenzyl alcohol, 39 2hydroxymethyl-1-(2'-hydroxyphenyl)naphthalene 40 with non-activated manganese dioxide or pyridinium chlorochromate, or by reaction of an alcohol and triethyl orthoformate catalyzed by aluminum chloride followed by catalytic hydrogenation. 41Other authors also prepared isochroman derivatives by refluxing diols in 50% aq.H 3 PO 4 42 or 85% H 3 PO 4 43 in toluene in good-to very good yields.
Isochromanes have been synthesized from acetals of phenethyl alcohols, followed by cyclization utilizing a Lewis acid or via oxa-Pictet-Spengler reaction from 2-phenylethanol and an aldehyde or ketone with a fatty acid as catalyst. 26,44,45In addition, some authors used reduction of oximes followed by intramolecular cyclization, 46 condensation of 3,4dimethoxyphenethyl alcohol with aromatic aldehydes, [2][3][4] or cyclization with p-toluenesulfonic acid. 47n a search for new approaches to the synthesis of isochromanes, we found that they can be obtained from the corresponding ethyl-(or methyl-) 2-acylphenylacetates 3 in very good yields.In our previous reports, we have shown that different ethyl 2-acyl-4,5-dimethoxyphenylacetates can be obtained from ethyl 3,4-dimethoxyphenylacetate and carboxylic acids in the presence of P 2 O 5 . 48We found that the acylation reaction in phenylacetic acid esters takes place if electrondonating groups exist on a third position of the aromatic ring in order to activate it.According to this procedure, we obtained the corresponding alkyl 2-acylphenylacetates from esters of 3methoxy-and 3,4-dimethoxyphenylacetic acid, with very good yields (Scheme 1, Table 1 The next step in this synthesis of isochromanes was the reduction of the alkyl 2acylphenylacetates, 3. We reduced the alkyl 2-acylphenylacetates to the corresponding diols using sodium borohydride-methanol system.Sodium borohydride under normal conditions does not reduce ester groups but reduces (in moderate-to good yields) double bonds in compounds, where the double bond is cross-conjugated with two carboxylic groups or where the double bond is conjugated with one carboxylic and one phenyl group. 49In these cases the reduction was carried out by using equimolar quantities of sodium borohydride and the ester in ethanol or isopropyl alcohol to react first at 0-5ºC and then at RT.
We found that the reduction of the alkyl 2-acylphenylacetates 3 with sodium borohydride in methanol easily led to the corresponding 2-hydroxy-4,5-dimethoxyphenyl-ethanols 4 with 85-90% yields (Table 2).Their cyclization in the presence of a catalytic amount of PTSA for 30 min at RT in dichloromethane afforded the corresponding isochromanes 5 (Table 2).In conclusion, six-membered oxygen-containing heterocycles with the isochromane skeleton were synthesized, as a type of compound found in nature and among bioactive compounds of interest.We have developed a convenient method for their synthesis by simple reduction of ethyl (or methyl) 2-acylphenylacetates in a sodium borohydride-methanol system, followed by cyclization in a less acidic medium with a catalytic amount of PTSA.A variety of substituents at the 1-position of the isochromane skeleton was introduced readily by changing the carboxylic acids.Some of the so-obtained isochromanes are O-analogues of isoquinoline alkaloids: 5l, the O-analogue of papaverine, 5g and 5h of cryptostiline II and III, 5a of salsolidine.

Experimental Section
General Procedures.Melting points were determined on a Boetius hot-stage apparatus and are uncorrected.IR spectra were measured (KBr pellets or film) with a Perkin-Elmer 1750 IFTS. 1 H-NMR and 13 C-NMR were recorded on a Bruker Avance DRX250 or Bruker Avance II+ 600 instrument, using CDCl 3 as solvent.Chemical shifts (δ, ppm) were referenced to TMS (δ=0.00 ppm) as an internal standard and coupling constants are indicated in Hz.All the NMR spectra were taken at RT (295 K).MS were recorded on a Jeol JMS-D300 spectrometer (70 eV).Elemental analyses were performed in the analytical laboratory at the Faculty of Chemistry, University of Plovdiv.TLC was carried out on precoated 0.2 mm Fluka silica gel 60 plates, using chloroform/diethyl ether/n-hexane: 6/3/1 as chromatographic system.Merck silica gel 60 (0.063-0.2mm) was used for chromatographic filtration.Table 1, 3a-o).General procedure. 48o a solution of ethyl (or methyl) 3,4-dimethoxyphenylacetate (10 mmol) and the corresponding carboxylic acid 2 (10 mmol) in 1,2-dichloroethane (30 mL) was added P 2 O 5 (5g).The suspension was stirred vigorously for 8-10 h at RT, then water was added dropwise to the cooled mixture.The organic layer was washed with water (50 ml), Na 2 CO 3 (30 ml), water (50 ml) and dried (Na 2 SO 4 ), then the combined extracts were dried (Na 2 SO 4 ) and filtered through a short column with neutral Al 2 O 3 .The products, after the removal of the solvent, were purified by recrystallization with MeOH.Compounds 3a,d,f,j,l were previously characterized. 46,48The spectroscopic data of new compounds follow.Methyl 2-(2-acetyl-5-methoxyphenyl)acetate (3b). 1

Preparation of 2-hydroxy-phenyl ethanols (Table 2, 4a-o). Typical procedure
To solution of 1 mmol of the corresponding ethyl (methyl) 2-acyl-4,5-dimethoxy-phenylacetates 3 in 15 mL methanol, NaBH 4 (2 mmol, 0.1 g) was added portionwise.The solution was stirred 30 min at room temperature, than the solvent was removed under vacuum.Water (30 mL) was added to the residue and the solution was extracted with CH 2 Cl 2 (3x20 mL), then the combined extracts were dried (Na 2 SO 4 ) and filtered through a short column with silica gel.The products, after evaporation of the solvent, were obtained with 85-90 % yields.

Figure 1 .
Figure 1.Structure of a synthetic analog of a korupensamine

Table 1 .
). Synthesis of alkyl 2-acylphenyl acetates * The yields were for products isolated after recrystallization.amp and spectroscopic data are given in ref.48.b mp 125-129°C in ref.46.