DESC:FIELD OF THE INVENTION:
The present invention relates to a novel method for preparing Benzodioxepinones compounds compound of formula(I) and intermediates thereof.
BACKGROUND OF THE INVENTION:
Benzodioxepinones are of use in fragrances to impart marine and ozone nuances to perfume compositions. Watermelon ketone or Calone is the ingredient responsible for many occean breeze fragrances. Since the discovery of Calone 1951® (7-methyl-2H-1,5- benzodioxepin-3(4H)-one), first synthesised by Beereboom, Cameron and Stephens (Pfizer) (U.S. Patent 3,517,031) many other substituted benzodioxepinones such as Transluzone, Aldolone, Azurone, Cascalone, Conoline have been used in fragrances.
The preparation of these benzodioxepinones has been based on the base catalysed Dieckmann condensation of the respective substituted catechol diesters or dinitriles as shown. (US3,517,031)

Other patents describe the preparation of Calone using 4-methyl Catechol and 1,3 dichloro acetone or its protected ketals under base catalysis as described in EP1405851.

There are various drawbacks of method described in prior art; first and foremost is the starting substrate is pyrocatechol, which is important raw material required for synthesis of benzodioxepinone compounds. This starting material has various disadvantages, first it has significantly high cost secondly catechol was found to be a more harmful toxin than phenol, since it provokes statistically significant changes in the function of erythrocytes even at low doses.
Another major drawback of the present method is formation of impurities; for example in synthesis of these compounds, benzodioxane compounds are found to be the major impurities as shown below:

In the preparation of fragrance chemicals, as structurally related impurities are often difficult to remove and can persist in the benzodioxepinone products, causing erroneous olfactory evaluation.
The methods described in the prior art for synthesis of benzodioxepinone compounds were using catechol as a starting material which is more toxic in nature and difficult to handle on large scale.
The present invention describes a novel method for synthesis of benzodioxepinone compounds using ortho-halo phenols which are safer as compared to the catechol compounds.
OBJECTS OF THE INVENTION:
The main objective of the present invention is to provide a simple and environment-friendly and cost-effective method for the synthesis of benzodioxepinone compounds of formula (I) based on easily available starting materials.
Another objective of the present invention to provide the method for synthesis of compounds of formula (III) and compounds of formula (IV).
SUMMARY OF THE INVENTION:
Accordingly, in one aspect, it is an objective of the present invention to provide an industrially amenable and convenient method for the preparation of benzodioxepinone compounds of formula (I) and intermediates thereof:

wherein R, R1, R2, X and n are as defined in detail description.
In another aspect the present invention provides a method for the preparation of compound of formula (II), compound of formula (III) and compound of formula (Y).
In another aspect the present invention provides novel intermediates, compound of formula (II) and compound of formula (Y).
Surprisingly the present invention provides a solution to this objective by providing a novel method that allows the preparation of benzodioxepinone compounds of formula (I), overcoming at least one of the shortcomings of the method described in the prior art.
DETAILED DESCRIPTION OF THE INVENTION:
The said objective was achieved according to the present invention by providing a novel method for preparing benzodioxepinones compounds of formula (I),

wherein,
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
A. cyclising a compound of formula (III) into a compound of formula (II) in the presence of a suitable catalyst, a suitable ligand, and optionally in presence of a suitable base and a suitable solvent, as shown in below scheme,
Scheme:

wherein, X represents halogen selected from the group of Cl, Br, F or I; R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl; or R and R2a together with the atom they are attached may form a 5 or 6 membered ring; and R1 as defined above;
B. hydrolysing the compound of formula (II) in presence of suitable acid and any suitable solvent to get compound of formula (I), as shown in below scheme,
Scheme:
.
In another embodiment, the present invention provides the method for synthesis of compound of Formula (III):

wherein,
X represents halogen selected from the group of Cl, Br, F or I;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl;
or R and R2a together with the atom they are attached may form a 5 or 6 membered ring;
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain the compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;

alternatively, the compound of formula (III) can be obtained from ortho halo phenol compound of formula (V):
c) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
d) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,

Scheme-
wherein, X, R1 and n are as defined above;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
g) hydrolysing the compound of formula (XI) to obtain the compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.

In yet another embodiment, the present invention provides the method for synthesis of compound of Formula (III) comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain the compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;
In yet another embodiment, the present invention provides the method for synthesis of compound of Formula (III) comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
b) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-
wherein, X, R1 and n are as defined above;
c) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
d) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
e) hydrolysing the compound of formula (XI) to obtain the compound of formula reacting a ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-
wherein, X, R1 and n are as defined above;
g) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
h) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
i) hydrolysing the compound of formula (XI) to obtain the compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.

In another embodiment, the compound of formula (X) is obtained from compound of formula (VII) comprising the steps of:
a) reacting the compound of formula (VII) with halogenating reagent in presence of a suitable acid, and a suitable solvent to afford the compound of formula (VIII), as shown in following scheme,
Scheme:
wherein, X, R1 and n are as defined above;
b) oxidising the compound of formula (VIII) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (IX), as shown in following scheme,
Scheme:
wherein, X, R1 and n are as defined above;
c) converting the compound of formula (IX) to a compound of formula (X) in the presence of a suitable acetate reagent, and a suitable solvent, as shown in following scheme,
Scheme:
wherein, X, R1 and n are as defined above.

In another embodiment the present invention by providing a novel method for preparing benzodioxepinones compounds of formula (I),

wherein,
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
A. cyclising a compound of formula (III) into a compound of formula (II) in the presence of a suitable catalyst, a suitable ligand, and optionally in presence of a suitable base and a suitable solvent, as shown in below scheme,
Scheme:

wherein, X represents halogen selected from the group of Cl, Br, F or I; R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl; or R and R2a together with the atom they are attached may form a 5 or 6 membered ring; and R1 as defined above;
B. hydrolysing the compound of formula (II) in presence of suitable acid and a suitable solvent to get compound of formula (I), as shown in below scheme,
Scheme:
;
wherein the compound of Formula (III) is obtain further comprising the steps of:
a) reacting an ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain the compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;
alternatively, the compound of formula (III) can be obtained from ortho halo phenol compound of formula (V):
c) reacting an ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above.
d) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-
wherein, X, R1 and n are as defined above;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
g) hydrolysing the compound of formula (XI) to the compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.

The definition of “alkyl” and “C1-C6-alkyl” includes, for example, the meanings of methyl, ethyl, n-isopropyl, n-iso-, sec and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl.
The definition of “C2-C6-alkenyl” includes for example allyl, prop-1-enyl, but-2-enyl, pent-3-enyl, or hex-4-enyl.
The definition of “C3-C6-cycloalkyl” includes for example substituted and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The definition of “halogen” includes for example, Fluorine, Chlorine, Bromine, Iodine.

In one preferred embodiment, the present invention provide method for the preparation of compounds of formula (I), wherein the compound of formula (I) is selected from:
wherein, R1 is as defined above;
In one more preferred embodiment, the present invention provide method for the preparation of compounds of formula (I), wherein the compound of formula (I) is selected from:

wherein, R1 is as defined above;
In one embodiment, the present invention provides a compound of formula (II),

Wherein,
X represents halogen selected from the group of Cl, Br, F or I;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl, and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl;
or R and R2a together with the atom they are attached may form a 5 or 6 membered ring; and R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl
n represents integer of 2,3.
In one preferred embodiment, the present invention provide method for the preparation of compounds of formula (II), wherein the compound of formula (II) is selected from:

wherein, Bn represents benzyl group

In one more preferred embodiment, the present invention provide method for the preparation of compounds of formula (II), wherein the compound of formula (II) is selected from:

wherein, Bn represents benzyl group; R1 is as defined above;
In another embodiment, the present invention provides a compound of formula (Y),

wherein,
X represents halogen selected from the group of Cl, Br, F or I;
A represent OH, OAc, or OBz; wherein Ac and Bz represent acetyl and benzoyl group;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl;
or R and R2a together with the atom they are attached may form a 5 or 6 membered ring;
or OR and R2 together with the atom they are attached represent =O;
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl and n represents integer of 0-3; provided that when A is OH and R2 is OR2a then n is 1.

In another embodiment, the present invention provide method for the preparation of compounds of formula (Y) comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;
alternatively, the compound of formula (III) obtained from ortho halo phenol compound of formula (V):
c) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above.
d) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-
wherein, X, R1 and n are as defined above;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
g) hydrolysing the compound of formula (XI) to a compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.

In one another embodiment, the present invention the present method for the preparation of compounds of formula (IV) comprising the steps of:
a) reacting an ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above.

In one preferred embodiment, the present invention provide method for the preparation of compounds of formula (Y), wherein the compound of formula (Y) is selected from:

wherein, R is methyl or ethyl; Bn represents benzyl group; A, R1, R2a and n are defined above;
In one more preferred embodiment, the present invention provide method for the preparation of compounds of formula (Y), wherein the compound of formula (Y) is selected from:

wherein, “Bn” represents benzyl group; “Bz” represents benzoyl group; R, R1, R2a and n are defined above;
In one embodiment, OR and OR2a mentioned in compound of formula (II) or in compound of formula (Y) , represent OMe and OEt or OR and OR2a together with the atom they are attached may form a
.
In one embodiment, reactions of the present invention are performed within a temperature range from 10°C to +150°C.
In yet another embodiment the reaction can be carried under irradiation of light generated by LED, or other lamps. Preferably blue or white LED.
Particularly, the step A is carried under irradiation of light generated by LED, or other lamps. Preferably blue or white LED.
In one embodiment, the suitable catalyst is selected from but not limited to metals like palladium, nickel or copper; alloys such as copper bronze, Pd-Au nanoclusters; metal containing zeolites, metal organic frameworks, metal doped covalent organic framework, or metals deposited on polymeric substrates; metallic salts such as palladium diacetate, palladium chloride, nickel bromide, nickel chloride, copper powder, copper bronze, copper (II) acetate, copper (I) oxide, copper (II) oxide, copper (I) iodide or copper (I) bromide. Preferably copper (I) iodide.
In another embodiment, the suitable ligand is selected from but not limited to 1,3 diketones such as bis(dibenzylideneacetone); ferrocene derivatives; imidazolidine carbenes; N containing heteroycles such as 2-amino pyridine derivatives, Di-tertbutyl bipyridine, 1,10-phenanthroline, bis-pyrazolyl, 4-pyrrolidinopyridine, 8-Hydroxy Quinoline; phosphine ligands such as trialkyl and triaryl phosphines, amino acids such as N,N dimethyl glycine, Proline, Picolinic acid, diamines such as N,N'-dimethylcyclohexane-1,2-diamine, N’,N’ dimethyl ethylene diamine, trans-1,2-diaminocyclohexane; salicylamides such as N,N diethyl salicylamide, salicylaldoxime; or oxalic diamides . Preferably diamine ligands.
In one embodiment the suitable solvent is selected from but not limited to aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, mesitylene or decalin; halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, methyl t-butyl ether, methyl tert-amyl ether, or anisole; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide, or sulphones such as sulpholane; alcohols such as methanol, ethanol or isopropanol; water or mixture thereof.
In yet another embodiment the suitable base is selected from but not limited to inorganic bases such as alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkali metal carbonates, for example Li2CO3, Na2CO3, K2CO3, or Cs2CO3 and acetates, for example NaOAc, KOAc, LiOAc, and alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu. or organic bases such as trialkylamines, alkylpyridines, phosphazenes and 1,8-diazabicyclo[5.4.0]undecene (DBU). Preferably alkali metal carbonates.
In one embodiment the suitable halogenating reagent is selected from but not limited to, from HX, CuX2, ZnX2, SOCl2, SO2CI2, COCl2, X2, C(=O)(OC13)2, t-BuOCl, NaOCl, Chloramine-T, N-halosuccinimides, methane sulfonyl chloride, POX3, PX3, PX5 or metal halides; wherein X is Cl, Br, I or F.
In yet another embodiment the suitable acid is selected from but not limited to mineral acids, for example H2SO4, HCl, HSO3Cl, HF, HBr, HI, H3PO4, or organic acids, for example CF3COOH, p-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid.
In one embodiment the hydrolysis is carried out in the presence of a suitable acid or a base; the acid is selected from but not limited to H2SO4, HCl, or organic acids, such as CF3COOH, p-toluenesulphonic acid; and the base is selected from but not limited to alkali metal hydroxides, for example lithium, sodium or potassium hydroxide. Preferably acid.
In one embodiment the suitable reagent is selected from trialkylorthoformate (like trimethyl orthoformate, triethylorthoformate, tripropyl orthoformate), ethylene glycol or propylene glycol, preferably trimethyl orthoformate or triethylorthoformate and the weak acid selected from acetic acid, p-toluenesulphonic acid or oxalyl chloride. Preferably p-toluenesulphonic acid.
In one embodiment suitable acetate reagent is selected from but not limited to sodium acetate, sodium benzoate. Preferably sodium acetate.
In one embodiment the suitable oxidising agent is selected from, but are not limited to, hydrogen peroxide, oxone, t-buty1-hydroperoxide, tungstic peroxide, m-chloroperbenzoic acid, benzoyl peroxide, hypohalgenous acids, ceric ammonium nitrate, hypoceric ammonium nitrate, oxone, periodic acid, peracetic acid, performic acid, hydrogen peroxide urea-adduct, sodium perborate, pyridinium chlorochromate, pyridinium dichromate, ruthenium (II) oxide, manganese (II) oxide, copper(II) acetate / O2. Preferably the suitable oxidizing agent is pyridinium dichromate or hydrogen peroxide or oxone.
In one embodiment the phase transfer catalyst is selected from TBABr, TBAF, TBACl, TBAI, acetyl trimethylammonium bromide, n-octyltrimethylammonium bromide. Preferably TBACl.
In one embodiment the method for preparation of compound of formula (I) can be carried out in one pot without isolation of intermediates.
The two regioisomers can be separated by chromatography, crystallization, or the mixture can be converted further without purification.
Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions.
Without further elaboration, it is believed that any person skilled in the art who is using the preceding description can utilize the present invention to fullest extent. The following examples are therefore to be interpreted as merely illustrative and not limiting of the disclosure in any way whatsoever.
General Scheme:

The definitions of R, R1, R2, A, L, X and n in the schemes below are as defined herein before in the description unless otherwise noted.

Experimental Section:
Example-1: Synthesis of 7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one

2-bromo-4-methylphenol was synthesized following the procedure described in CN102766028A.
Synthesis of 2-[(2-bromo-4-methylphenoxy)methyl]oxirane:
To 2-bromo-4-methyl phenol(25 gms), KOH (8.2 gms) and TBAB (20 mol%), Epichlorohydrin (37 gms) was added in one portion and stirred at rt for 6-8 hrs. Reaction mixture was filtered to remove insoluble and extracted out with EtOAc, washed with water, dried over Na2SO4 and concentrated to get 2-[(2-bromo-4-methylphenoxy)methyl]oxirane (84%) which can be taken ahead without further purification.
1H NMR (400 MHz, DMSO-d6): d 7.39 (s, 1H, Ar-H), 7.11 (d, 1H, Ar-H, J=8Hz), 6.99 (d, 1H, J=8.4Hz), 4.35 (dd, 1H, J= 2.4Hz, 11.6Hz, CH2), 3.88 (dd, 1H, CH2, J= 6Hz, 11.6Hz), 3.32 (m, 1H, CH), 2.83 (t, 1H, J= 4.8Hz, CH2), 2.72 (dd, 1H, J= 2.6Hz, 5Hz, CH2), 2.22 (s, 3H, CH3).
Synthesis of 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-ol:
To 2-[(2-bromo-4-methylphenoxy)methyl]oxirane (10 gms) in THF (80 ml), LiCl (2.7 gms) followed by acetic acid (7 gms) were added and stirred at rt for 18 hrs. The reaction mixture was filtered to remove insoluble contents. The filtrate was concentrated, and the crude was worked up. The residue was taken in EtOAc and washed with water, brine and finally dried over Na2SO4. The crude was concentrated to get 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-ol (86 %). This can be taken ahead after GC analysis without further purification.
1H NMR (400 MHz, DMSO-d6): d 7.388 (d, 1H, J= 1.6 Hz Ar-H), 7.118 (dd, 1H, J= 8.4Hz, 1.6 Hz, Ar-H), 7.004 (d, 1H, J=8.4Hz, Ar-H), 5.561 (d, 1H, OH, J= 4.8 Hz), 4.059-3.939 (m, 3H), 3.794 (dd, 1H, J= 4.0 Hz, 11.2 Hz) 3.696 (dd, 1H, J= 5.2 Hz, 11.2 Hz), 2.221 (s, CH3, 3H).
Synthesis of 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-one:
To 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-ol (0.750 gms) in EtOAc (6 ml), NaHCO3 (0.645 gms), TEMPO (5 mol %), NaBr (20 mol %) and water (3 ml) were added and stirred between -5oC - 0oC. To this stirring solution NaOCl (2.5 gms, 11.5%) was added slowly at -5oC - 0oC. After addition, the reaction mass was stirred at same temperature for 1 hr. and warmed up to rt and stirred for 2 hrs. The reaction was quenched with saturated Na2S2O3 solution, extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to get 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-one (0.710 g, 93%) which can be taken ahead without further purification.
1H NMR (400 MHz, DMSO-d6): d 7.42 (d, 1H, J= 1.6 Hz Ar-H), 7.108 (dd, 1H, J= 8.4Hz, 1.2 Hz, Ar-H), 6.905 (d, 1H, J=8.4Hz, Ar-H), 5.00 (s, 2H, OCH2), 4.698 (s, 2H, OCH2), 2.238 (s, 3H, CH3.
Synthesis of 3-(2-bromo-4-methylphenoxy)-2-oxopropyl acetate:
To 1-(2-bromo-4-methylphenoxy)-3-chloropropan-2-one (4.10 gms) in DMF (74 ml), sodium acetate (4.83 gms) was added, and the mixture was stirred at 60oC for 6-7 hrs. The mixture was cooled and DMF was evaporated. The residue was extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to get 3-(2-bromo-4-methylphenoxy)-2-oxopropyl acetate (4.13 gms). This was taken ahead without further purification.
1H NMR (400 MHz, DMSO-d6): d 7.41 (s, 1H, Ar-H), 7.09 (d, 1H, J= 8.4Hz, Ar-H), 6.87 (d, 1H, Ar-H, J=8.4Hz), 4.97 (s, 2H, OCH2), 4.95 (s, 2H, OCH2), 2.23 (s, 3H, OCH3), 2.09 (s, 3H, CH3).
Synthesis of 3-(2-bromo-4-methylphenoxy)-2,2-dimethoxypropan-1-ol:
To 3-(2-bromo-4-methylphenoxy)-2-oxopropyl acetate (4 gms) in anhydrous methanol, p-TsOH (10 mol%) and trimethyl orthoformate (6.3 gms) were added under N2 and stirred under reflux for 6-7 hrs. Methanol was evaporated and the crude was extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to get the crude which was purified by column chromatography (H:E::80:20) to get 3-(2-bromo-4-methylphenoxy)-2,2-dimethoxypropan-1-ol (3.28 g , 82%)
1H NMR (400 MHz, DMSO-d6): d 7.38 (d, 1H, Ar-H, J= 8Hz), 7.14-7.04 (m, 2H, Ar-H), 4.86 (t, 1H, OH, J=5.6Hz), 3.96 (s, 2H, OCH2), 3.53 (d, 2H, OCH2, J= 5.6Hz), 3.17 (s, 6H, OCH3), 2.23 (s, 3H, CH3).
Synthesis of 3,3-dimethoxy-7-methyl-3,4-dihydro-2H-1,5-benzodioxepine:
To K2CO3 (3mmole), CuI (10mol %), ligand-DMEDA (N, N’-dimethylethylenediamine) (20mol %) in mesitylene, 3-(2-bromo-4-methylphenoxy)-2,2-dimethoxypropan-1-ol (1 mmole) in mesitylene (0.2 M) was added and the reaction mixture was stirred at reflux temperature for 24 hrs. Reaction mixture was allowed to cool down to room temperature. Reaction mixture was then filtered through a celite bed, washed with EtOAc. The filtrate was then concentrated under reduced pressure to get the crude material. This was purified by column chromatography to get 3,3-dimethoxy-7-methyl-3,4-dihydro-2H-1,5-benzodioxepine (52% yield).
1H NMR (400 MHz, DMSO-d6): d 7.38 (d, 1H, Ar-H, J= 8Hz), 6.71 (m, 1H, Ar-H), 6.61 (s, 1H, Ar-H), 4.11 (s, 2H, OCH2), 4.09 (s, 2H, OCH2), 3.2 (s, 6H, OCH3), 2.17 (s, 3H, CH3).
Synthesis of 7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one:
3,3-dimethoxy-7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (1 mmole) was taken in 80% HCOOH (0.25 M) and stirred at 50-55°C for 4-5hrs. At the end of the reaction, reaction mixture was diluted with water and neutralized with 10N NaOH solution, extracted into EtOAc. Organic fraction was then washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was purified by column chromatography to get pure 7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one (82% yield).
1H NMR (400 MHz, DMSO-d6): d 7.37 (d, 1H, Ar-H, J= 8Hz), 6.68 (m, 1H, Ar-H), 6.61 (s, 1H, Ar-H), 4.1 (s, 4H, OCH2), 2.16 (s, 3H, CH3).

Example -2: Synthesis of 6-ethyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one

Synthesis of 3-(2-bromo-6-ethyl-4-methylphenoxy)-2,2-dimethoxypropan-1-ol:
Synthesized according to the process described in example-1 with appropriate starting material.
1H NMR (400 MHz, DMSO-d6): d 7.256 (s, 1H, Ar-H,), 7.04 (s, 1H, Ar-H), 4.833 (t, 1H, OH, J=5.4 Hz), 3.829 (s, 2H, OCH2), 3.595 (d, 2H, OCH2, J= 5.2 Hz), 3.245 (s, 6H, OCH3), 2.681 (q, 2H, J= 7.6 Hz), 2.236 (s, 3H, CH3), 1.131(t, 3H, J=7.44 Hz).
Synthesis of 6-ethyl-3,3-dimethoxy-8-methyl-3,4-dihydro-2H-1,5-benzodioxepine:
Synthesized according to the process described in example-1.
1H NMR (400 MHz, DMSO-d6): d 6.618 (s, 1H, Ar-H), 6.573 (s, 1H, Ar-H), 4.10 (d, 4H, OCH2*2, J=1.6Hz), 3.226 (s, 6H, OCH3), 2.498 (q, 2H, ethyl CH2), 2.158 (s, 3H, CH3), 1.092 (t, 3H, J= 7.4 Hz), ethyl CH3).
Synthesis of 6-ethyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one:
6-ethyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one
Synthesized according to the process described in example-1.
1H NMR (400 MHz, DMSO-d6): d 6.706 (s, 1H, Ar-H), 6.679 (s, 1H, Ar-H), 4.734 (d, 4H, J=4 Hz, OCH2*2), 2.527 (q, 2H, J=7.6 Hz, ethyl CH2 merged with DMSO), 2.194 (s, 3H, CH3), 1.120 (t, 3H, J= 7.4 Hz, ethyl CH3).

Example-3: Synthesis of 7-propyl-2H-benzo[b][1,4]dioxepin-3(4H)-one

Synthesis of 2-((2-bromo-4-propylphenoxy)methyl)oxirane was obtained according to procedure described in example-1.
Synthesis of 3-(2-bromo-4-propylphenoxy)-2-hydroxypropyl acetate:
A mixture of acetic acid (1.1 mmole) and (2 mol%) Jacobsen catalyst [(S,S)-(+)-N,N'-Bis(3,5-di-tert-butylsylicylidene)-1,2-cyclohexanediaminocobalt(II)] in (1 mL) TBME was stirred under open air for 30-45 mins. This solution was then cooled to 0-5°C, DIPEA (1.1mmole) was added to this followed by addition of 2-((2-bromo-4-propylphenoxy)methyl)oxirane (1mmole) dissolved in (1mL) TBME. The resulting solution was stirred at 0-5°C for 26hrs. Reaction mixture was then diluted with EtOAc and washed with dil. HCl, sat. NaHCO3 solution and brine solution. The organic fractions were pooled and concentrated under reduced pressure to afford crude product. The crude product was purified by column chromatography to obtain 3-(2-bromo-4-methylphenoxy)-2-hydroxypropyl acetate. (Yield :82%).
1H NMR (400 MHz, DMSO-d6): d 7.38 (s, 1H, Ar-H), 7.14 (d, 1H, Ar-H, J=8.4Hz), 7.05 (d, 1H, J=8.4Hz), 5.36 (s, 1H, OH), 4.45 (dd, 1H, J=4.4Hz, 11.2Hz, CH2), 4.33 (dd, 1H, J=6Hz, 11.2Hz, CH2), 4.2-4.01 (m, 3H, OCH2 & CH), 2.5 (m, 2H, CH2), 1.5 (m, 2H, CH2), 0.87 (t, 3H, J=7.2Hz, CH3).
Synthesis of 3-(2-bromo-4-propylphenoxy)-2-oxopropyl acetate:
To 3-(2-bromo-4-propylphenoxy)-2-hydroxypropyl acetate (1 mmole) in DCM (0.25 M), activated molecular sieves was added followed by addition of PDC (pyridinium dichromate). The resulting solution was stirred at rt for 2 days. The reaction mixture was filtered through a celite bed, bed was washed with DCM. The DCM filtrate was washed with water, brine and dried over Na2SO4. The organic fraction was concentrated under reduced pressure to afford a solid crude product which was purified by column chromatography to obtain 3-(2-bromo-4-methylphenoxy)-2-oxopropyl acetate (72%).
1H NMR (400 MHz, DMSO-d6): d 7.41 (s, 1H, Ar-H), 7.15(dd, 1H, J= 8.4Hz, 2Hz, Ar-H), 6.98 (d, 1H, Ar-H, J=8.4Hz), 5.28(s, 2H, OCH2), 5.07 (s, 2H, OCH2), 2.5 (s, 2H, CH2), 1.5 (m, 2H, CH2), 0.87 (t, 3H, J=7.2Hz, CH3).
Synthesis of 3-(2-bromo-4-propylphenoxy)-2,2-dimethoxypropan-1-ol:
To 3-(2-bromo-4-propylphenoxy)-2-oxopropyl acetate (1 mmole) in dry MeOH (0.2 M), p-TsOH (2 mol%) and trimethyl orthoformate (6 mmole) were added under N2 and stirred under reflux for 6-7 hrs. Methanol was evaporated and the crude was extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to get the crude which was purified by column chromatography to get 3-(2-bromo-4-methylphenoxy)-2,2-dimethoxypropan-1-ol (82% yield).
1H NMR (400 MHz, DMSO-d6): d 7.38 (s, 1H, Ar-H), 7.15(d, 1H, J= 8.4Hz, 2Hz, Ar-H), 7.08 (d, 1H, Ar-H, J=8.4Hz) , 4.74 (t, 1H, OH, J=5.8Hz), 3.97 (s, 2H, OCH2), 3.54 (d, 2H, OCH2, J= 6Hz), 3.18 (s, 6H, OCH3), 2.5 (m, 2H, CH2), 1.5 (m, 2H, CH2), 0.86 (t, 3H, J=7.4Hz, CH3).
Synthesis of 3,3-dimethoxy-7-propyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine:
To K2CO3 (3 mmole), CuI (10mol %), ligand-DMEDA (N,N’-dimethylethylenediamine) (20 mol %) in mesitylene, 3-(2-bromo-4-propylphenoxy)-2,2-dimethoxypropan-1-ol (1 mmole) in mesitylene (0.2 M) was added and the reaction mixture was stirred at reflux temperature for 24 hrs. Reaction mixture was allowed to cool down to room temperature. The reaction mixture was then filtered through a celite bed, washed with EtOAc. The filtrate was then concentrated under reduced pressure to get crude material. The crude material was purified by column chromatography to get 3,3-dimethoxy-7-methyl-3,4-dihydro-2H-1,5-benzodioxepine (52% yield).
1H NMR (400 MHz, DMSO-d6): d 7.35 (d, 1H, Ar-H, J= 8Hz), 6.74 (m, 1H, Ar-H), 6.6 (s, 1H, Ar-H), 4.08 (s, 2H, OCH2), 4.09 (s, 2H, OCH2), 3.23 (s, 6H, OCH3), 2.5 (m, 2H, CH2), 1.55 (m, 2H, CH2), 0.82 (t, 3H, J=7.4Hz, CH3).
Synthesis of 7-propyl-2H-benzo[b][1,4]dioxepin-3(4H)-one:
3,3-dimethoxy-7-propyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (1mmole) was taken in 80% HCOOH (0.25 M) and stirred at 50-55°C for 4-5hrs. At the end of the reaction, reaction mixture was diluted with water and neutralized with 10N NaOH solution, extracted into EtOAc. Organic fraction was then washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was purified by column chromatography to get pure 7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one (86% yield).
1H NMR (400 MHz, DMSO-d6): d 7.91(d, 1H, Ar-H, J= 8Hz), 6.8 (m, 2H, Ar-H), 4.7 (s, 4H, OCH2), 2.16 (s, 3H, CH3), 2.5 (m, 2H, CH2), 1.5 (m, 2H, CH2), 0.9 (t, 3H, J=7.2Hz, CH3)

Example-4: Synthesis of 6-chloro-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one

Synthesis of 3-(2-bromo-6-chloro-4-methylphenoxy)-2,2-dimethoxypropan-1-ol:
Synthesized according to the process described in example-3
1H NMR (400 MHz, DMSO-d6): d 7.45 (d, 1H, Ar-H, J=1.2 Hz), 7.34 (d, 1H, Ar-H, J= 1.2 Hz), 4.7(t, 1H, J= 5.2 Hz), 3.92 (s, 2H, OCH2), 3.65 (d, 2H, J= 5.2 Hz, OCH2), 3.25 (s, 6H, OCH3), 2.25 (s, 3H, CH3).
Synthesis of 6-chloro-3,3-dimethoxy-8-methyl-3,4-dihydro-2H-1,5-benzodioxepine-3-one:
Synthesized according to the process described in example-3
1H NMR (400 MHz, DMSO-d6): d 6.95 (d, 1H, Ar-H, J=1.6 Hz), 6.75 (d, 1H, Ar-H, J= 1.2 Hz), 4.3 (s, 2H, OCH2), 4.2 (s, 2H, OCH2), 3.23 (s, 6H, OCH3), 2.18 (s, 3H, CH3).
Synthesis of 6-chloro-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one:
Synthesized according to the process described in example-3
1H NMR (400 MHz, DMSO-d6): d 7.0 (d, 1H, Ar-H, J= 1.2 Hz), 6.8 (d, 1H, Ar-H, J= 1.2 Hz), 4.85 (s, 2H, OCH2), 4.80 (s, 2H, OCH2) 2.20 (s, 3H, CH3.

Example-5: Synthesis of 7-(tert-butyl)-2H-benzo[b][1,4]dioxepin-3(4H)-one

Synthesis of 2-bromo-1-(3-bromo-2,2-dimethoxypropoxy)-4-(tert-butyl)benzene:
To 2-bromo-4-(tert-butyl)phenol (1 eq), K2CO3 (2.5 eq), 18-crown-6 (0.25 eq) were taken in a round bottom flask. DMF (0.25 M) was added to this and stirred at room temperature under N2 atmosphere. A solution of 1,3-dibromo-2,2-dimethoxypropane (1.3 eq) in DMF was added to this solution slowly and the reaction mixture was continued stirring at reflux temperature. Reaction was stopped after 32 hrs, DMF was evaporated under reduced pressure. The reaction mixture obtained was extracted with ethyl acetate and washed with water,. The combined ethyl acetate fraction was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. This was purified by column chromatography to obtain 2-bromo-1-(3-bromo-2,2-dimethoxypropoxy)-4-methylbenzene ( Yield, 45%).
1H NMR (400 MHz, DMSO-d6): d 7.36 (s, 1H, Ar-H), 7.14 (m, 2H, Ar-H), 4.19 (s, 2H, CH2), 3.71 (s, 2H, CH2), 3.24 (s, 6H, OCH3), 1.22 (s, 9H, CH3).
Synthesis of 3-(2-bromo-4-(tert-butyl)phenoxy)-2,2-dimethoxypropan-1-ol:
2-bromo-1-(3-bromo-2,2-dimethoxypropoxy)-4-(tert-butyl)benzene (1eq) and KOH (40 eq) were taken in a hydrothermal autoclave containing a mixture of water and dimethylacetamide (DMA) or trimethyl benzene (2:3 ratio, 0.3 M). The reaction mixture was stirred at 140°C overnight (30 hrs). Reaction mixture was washed with dil. HCl, extracted with ethyl acetate washed with water and brine. The combined ethyl acetate fractions were concentrated under reduced pressure to give the crude product. This was purified by column chromatography to obtain 3-(2-bromo-4-methylphenoxy)-2,2-dimethoxypropan-1-ol (Yield, 35%).
1H NMR (400 MHz, DMSO-d6): d 7.52 (s, 1H, Ar-H), 7.32 (d, 1H, J= 8.8Hz, Ar-H), 7.08 (d, 1H, Ar-H, J=8.8Hz) , 4.86 (t, 1H, OH, J=5.8Hz), 3.98 (s, 2H, OCH2), 3.54 (d, 2H, OCH2, J= 6Hz), 3.1 (s, 6H, OCH3), 1.25 (s, 9H, CH3)
Synthesis of 7-(tert-butyl)-3,3-dimethoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine:
To K2CO3 (3 mmole), CuI (10 mol %), ligand-DMEDA (N, N’-dimethylethylenediamine) (20 mol%) in mesitylene, 3-(2-bromo-4-(tert-butyl)phenoxy)-2,2-dimethoxypropan-1-ol (1 mmole) in mesitylene (0.2 M) was added and the reaction mixture was stirred at reflux temperature for 24 hrs. Reaction mixture was allowed to cool down to room temperature. Reaction mixture was then filtered through a celite bed, washed with EtOAc. The filtrate was then concentrated under reduced pressure to get the crude material. This was purified by column chromatography to get pure 3,3-dimethoxy-7-methyl-3,4-dihydro-2H-1,5-benzodioxepine, (53% yield).
1H NMR (400 MHz, DMSO-d6): d 6.95 (m, 2H, Ar-H), 6.8 (m, 1H, Ar-H), 4.08 (s, 2H, OCH2), 4.15 (d, 4H, J= 5.2Hz, OCH2), 3.26 (s, 6H, OCH3), 1.23 (s, 9H, CH3).
Synthesis of 7-(tert-butyl)-2H-benzo[b][1,4]dioxepin-3(4H)-one:
7-(tert-butyl)-3,3-dimethoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine (1 mmole) was taken in 80% HCOOH (0.25 M) and stirred at 50-55°C for 4-5hrs. At the end of the reaction, reaction mixture was diluted with water and neutralized with 10N NaOH solution, extracted into EtOAc. Organic fraction was then washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was purified by column chromatography to get pure 7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one (off-white solid, 85% yield).
1H NMR (400 MHz, DMSO-d6): d 7.0 (m, 2H, Ar-H), 6.95 (m, 1H, Ar-H), 4.75 (s, 4H, OCH2), 1.23 (s, 9H, CH3).

Example-6: Synthesis of 6-methyl-8-(2-methylpropyl)-3,4-dihydro-2H-1,5 benzodioxepin-3-one

Synthesis of 3-[2-bromo-6-methyl-4-(2-methylpropyl)phenoxy]-2,2-dimethoxypropan-1-ol:
Synthesized according to the process described in example-5
1H NMR (400 MHz, DMSO-d6): d 7.22 (d, 1H, Ar-H, J=1.4 Hz), 7.00 (d, 1H, Ar-H, J= 1.6 Hz), 4.82 (t, 1H, J= 5.4 Hz, OH), 3.838 (s, 2H, OCH2), 3.608 (d, 2H, J= 5.6 Hz, OCH2), 3.243 (s, 6H, 2*OCH3), 2.362 (d, 2H, J= 7.2 Hz, CH2), 2.296 (s, 3H, CH3), 1.797 (sept, 1H, J= 6.8 Hz), 0.847 (d, 6H, J= 6.8 Hz).
Synthesis of 3,3-dimethoxy-6-methyl-8-(2-methylpropyl)-3,4-dihydro-2H-1,5-benzodioxepine:
Synthesized according to the process described in example-5
1H NMR (400 MHz, DMSO-d6): d 6.58 (d, 1H, Ar-H, J=1.6 Hz), 6.52 (d, 1H, Ar-H, J= 2.0 Hz), 4.11 (d, 4H, J= 4.4 Hz, 2*OCH2), 3.21 (s, 6H, 2*OCH3), 2.272 (d, 2H, J= 7.2 Hz, CH2), 2.103 (s, 3H, CH3), 1.742 (sept, 1H, J= 6.8 Hz), 0.826 (d, 6H, J= 6.4 Hz).
Synthesis of 6-methyl-8-(2-methylpropyl)-3,4-dihydro-2H-1,5-benzodioxepin-3-one:
Synthesized according to the process described in example-5
1H NMR (400 MHz, DMSO-d6): d 6.68 (d, 1H, Ar-H, J=1.6 Hz), 6.64 (d, 1H, Ar-H, J= 2.0 Hz), 4.74 (d, 4H, J= 3.6 Hz, 2*OCH2), 2.319 (d, 2H, J= 7.2 Hz, CH2), 2.158 (s, 3H, CH3), 1.78 (sept, 1H, J= 6.8 Hz), 0.853 (d, 6H, J= 6.2 Hz).

Example-7: Synthesis of 7-isopropyl-2H-benzo[b][1,4]dioxepin-3(4H)-one

1-{[2-(benzyloxy)-3-[(4-methylbenzenesulfonyl)oxy]propoxy]sulfonyl}-4-methylbenzene was synthesized following the procedure described by Qi Wang and Harri Lönnberg; J. Am. Chem. Soc. 2006, 128, 33, 10716–10728.
2-(benzyloxy)-3-(2-bromo-4-isopropylphenoxy)propyl 4-methylbenzenesulfonate:
2-bromo-4-isopropylphenol (1mmol) was taken in DMF (0.25 M) along with (1.3 mmol) K2CO3 and stirred under N2 atmosphere at 80°C. A solution of 1-{[2-(benzyloxy)-3-[(4-methylbenzenesulfonyl)oxy]propoxy]sulfonyl}-4-methylbenzene (1.05 mmol) in DMF was added slowly into the reaction mixture. Reaction was kept stirring for 20 hrs at 80°C. At the end of the reaction, solvent was removed under reduced pressure, crude residue was diluted with EtOAc, washed with water followed by brine solution. EtOAc was removed under reduced pressure to give a crude residue which was purified by column chromatography to afford 2-(benzyloxy)-3-(2-bromo-4-methylphenoxy)propyl-4-methylbenzene-1-sulfonate (Yield-73%).
1H NMR (400 MHz, DMSO-d6): d 7.71 (d, 2H, Ar-H, 8Hz), 7.43 (d, 3H, Ar-H, J= 8.4Hz), 7.35-7.26 (m, 5H, Ar-H), 7.2 (d, 1H, J= 8Hz, Ar-H), 6.95 (d, 1H, J= 8.4Hz, Ar-H), 4.6 (m, 2H, CH2-Ph), 4.32 (dd, 1H, CH2, J= 3.2Hz, 10.8Hz), 4.23 (dd, 1H, CH2, J= 5.2Hz, 10.6Hz), 4.04 (d, 2H, CH2, J= 4.5Hz), 3.96 (m, 1H, CH), 2.37 (s, 3H, CH3), 2.45 (m, 1H, CH).1.26 (s, 6H, CH3).
Synthesis of 2-(benzyloxy)-3-(2-bromo-4-isopropylphenoxy)propan-1-ol :
2-(benzyloxy)-3-(2-bromo-4-isopropylphenoxy)propyl 4-methylbenzenesulfonate (1 mmol) was dissolved in dry MeOH. Activated magnesium turnings (10 mmol) were added into the solution and stirred under N2 atmosphere at RT for 20 hrs. At the end of the reaction, MeOH was removed under reduced pressure. The obtained crude residue was washed with sat. NH4Cl solution followed by water and brine. The combined EtOAc fractions were concentrated in the rotavapor. The crude residue obtained was purified by column chromatography to get 2-(benzyloxy)-3-(2-bromo-4-methylphenoxy)propan-1-ol (Yield – 72%).
1H NMR (400 MHz, DMSO-d6): d 7.44-7.23 (m, 6H, Ar-H), 7.13 (d, 1H, Ar-H, J= 8.4Hz), 6.90 (d, 1H, Ar-H, J= 8.4Hz), 4.83 (t, 1H, J= 5.64Hz, OH), 4.72 (d, 2H, J= 4.4Hz, CH2-Ph), 4.29 (dd, 1H, CH2, J= 3.6Hz, 10.4Hz), 4.06 (t, 1H, CH2, J= 10.4Hz), 3.76 (quintet, 1H, J= 4 Hz, CH), 3.64 (t, 2H, CH2, J= 5.4Hz), 2.51 (m, 1H, CH).1.23 (s, 6H, CH3).
Synthesis of 3-(benzyloxy)-7-isopropyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine:
To K2CO3 (3 mmol), CuI (10 mol %), ligand-DMEDA (N, N’-dimethylethylenediamine) (20 mol %) in mesitylene, 2-(benzyloxy)-3-(2-bromo-4-isopropylphenoxy)propan-1-ol (1 mmol) in mesitylene (0.2 M) was added and the reaction mixture was stirred at reflux temperature for 24 hrs. Reaction mixture was allowed to cool down to room temperature. Reaction mixture was then filtered through a celite bed, washed with EtOAc. The filtrate was then concentrated under reduced pressure to get the crude material. This was purified by column chromatography to get pure product, (light yellow liquid, 45- 52% yield).
1H NMR (400 MHz, DMSO-d6): d 7.36(m, 5H, Ar-H), 6.82 (d, 1H, Ar-H, J= 8Hz), 6.74 (s, 1H, Ar-H), 6.71 (d, 1H, Ar-H, J=8Hz), 4.63 (s, 2H, CH2), 4.27 (m, 4H, CH2), 4.04 (quintet, 1H, CH, J= 9.4Hz), 2.45 (m, 1H, CH).1.2 (s, 6H, CH3).
Synthesis of 7-isopropyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-3-ol:
3-(benzyloxy)-7-isopropyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine was dissolved in MeOH (0.2 M). 10% Pd/C (7 mol%) was added to this solution followed by bubbling H2 gas into the reaction. After the reaction was complete, the mixture was diluted with MeOH and filtered through a celite bed. The filtrate was evaporated under reduced pressure. The crude residue was purified by column chromatography. (Yield- 92%)
1H NMR (400 MHz, DMSO-d6): d 6.83 (d, 1H, Ar-H, J= 8.4Hz), 6.78 (s, 1H, Ar-H), 6.75 (d, 1H, Ar-H, J=8.4Hz), 5.31 (d, 1H, J=5.6Hz, OH), 4.22 (m, 2H, CH2), 4.05 (quintet, 1H, CH, J= 5.4Hz), 3.94 (m, 2H, CH2), 2.53 (m, 1H, CH). 1.23 (s, 6H, CH3).
Synthesis of 7-isopropyl-2H-benzo[b][1,4]dioxepin-3(4H)-one:
To 7-isopropyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-3-ol (1 mmol) in EtOAc (4 ml), NaHCO3 (2 mmol), TEMPO (5 mol %), NaBr (1 mmol) and water (3 ml) were added and stirred between -5oC - 0oC. To this stirring solution NaOCl (10% solution, 3 mL) was added slowly at -5oC - 0oC. After addition, the reaction mass was stirred at same temperature for 1 hr. and warmed up to RT and stirred for 2 hrs. The reaction was quenched with saturated Na2S2O3 solution, extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated to get the crude product which was purified by column chromatography. (Yield- 82%).
1H NMR (400 MHz, DMSO-d6): d 6.95 (d, 2H, Ar-H, J=8.4Hz), 6.89-6.85 (m, 2H, Ar-H), 4.75 (s, 4H, OCH2), 2.5 (m, 1H, CH).1.2 (s, 6H, CH3).

Example-8: Synthesis of 6-butyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one

Synthesis of 2-(benzyloxy)-3-(2-bromo-6-butyl-4-methylphenoxy)propan-1-ol:
Synthesized according to the process described in example-7
1H NMR (400 MHz, DMSO-d6): d 7.43-7.34 (m, 5H, Bn-H), 6.80 (d, 1H, Ar-H, J= 7.8 Hz), 6.58 (d, 1H, Ar-H, J= 8.0 Hz), 4.80 (t, 1H, J= 5.4 Hz, OH), 4.68 (d, 2H, J= 4.2 Hz, CH2-Ph), 4.20 (dd, 1H, CH2, J= 3.4 Hz, 10.4 Hz), 4.10 (t, 1H, CH2, J= 10.2 Hz), 3.80 (quintet, 1H, J= 4.2 Hz, CH), 3.59 (t, 2H, CH2, J= 5.2Hz), 2.65 (t, 2H, J=7.8 Hz), 2.23 (s, 3H, CH3), 1.49(quintet, 2H, J= 7.2 Hz), 1.292(sextet, 2H, J=7.2 Hz), 0.894(t, 3H, J=7.2 Hz).
Synthesis of 3-(benzyloxy)-6-butyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepine:
Synthesized according to the process described in example-7
1H NMR (400 MHz, DMSO-d6): d 7.3-7.29 (m, 5H, Bn-H), 6.796 (d, 1H, Ar-H, J= 8 Hz), 6.70 (d, 1H, Ar-H, J= 8.0 Hz), 4.61 (s, 2H, CH2-Ph), 4.4-4.21 (m, 4H, 2*OCH2), 3.90 (quintet, 1H, J= 4.4 Hz, CH), 2.6 (t, 2H, J=7.8 Hz), 2.2 (s, 3H, CH3), 1.49(quintet, 2H, J= 7.2 Hz), 1.292(sextet, 2H, J=7.2 Hz), 0.894(t, 3H, J=7.2 Hz).
Synthesis of 6-butyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ol:
Synthesized according to the process described in example-7
1H NMR (400 MHz, DMSO-d6): d 6.8 (d, 1H, Ar-H, J=1.8 Hz), 6.6 (d, 1H, Ar-H, J= 2.0 Hz), 5.31(d, 1H, J= 5.4 Hz, OH), 4.2- 4.14 (m, 2H, OCH2), 4.0 (quintet, 1H, J= 5.4 Hz, CH), 3.9-3.86 (m, 2H, OCH2), 2.53 (t, 2H, J= 7.4 Hz, CH2), 2.16 (s, 3H, CH3), 1.51(quintet, 2H, J= 7.4 Hz), 1.3(sextet, 2H, J=7.6 Hz), 0.89(t, 3H, J=7.4 Hz).

Synthesis of 6-butyl-8-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-one:
Synthesized according to the process described in example-7
1H NMR (400 MHz, DMSO-d6): d 6.668 (s, 1H, Ar-H), 4.719 (d, 4H, J= 8.0 Hz,2*OCH2), 2.58 (t, 2H, J= 7.8 Hz, CH2), 2.185 (s, 3H, CH3), 1.485(quintet, 2H, J= 7.2 Hz), 1.298(sextet, 2H, J=7.6 Hz), 0.896(t, 3H, J=7.4 Hz).
,CLAIMS:
WE CLAIM:
1. A method for the preparation of benzodioxepinones compounds of formula (I),

wherein,
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
A. cyclising a compound of formula (III) into a compound of formula (II) in presence of a suitable catalyst with a suitable ligand, optionally in presence of a suitable base and a suitable solvent, as shown in following scheme,
Scheme:
, wherein, X represents halogen selected from the group of Cl, Br, F or I; R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen and OR2a, wherein R2a is methyl or ethyl; or R and R2a together with the atom they are attached may form a 5 or 6 membered ring; and R1 as defined above.
B. hydrolysing the compound of formula (II) in presence of suitable acid and a suitable solvent to get the compound of formula (I), as shown in following scheme,
Scheme:
.

2. A method for preparing a compound of formula (III):

wherein,
X represents halogen selected from the group of Cl, Br, F or I;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl;
or R and R2a together with the atom they are attached may form a 5 or 6 membered ring;
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
a) reacting an ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford a compound of formula (IV), as shown in following scheme,
Scheme:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), triflates (-OTf), benzylsulfonates and trityl (-OTr); R, R1, R2 and n are as defined in claim 1;
b) hydrolysing the compound of formula (IV) in the presence of in the presence of a suitable acid or base and a suitable solvent to obtain a compound of formula (III), as shown in below scheme:

wherein, X, R, R1, R2, L and n are as defined above;
alternatively, the compound of formula (III) obtained from ortho halo phenol compound of formula (V) comprising the steps of:
c) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, ( ) in the presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:
;
wherein, X, R1 and n are as defined above;
d) reacting the compound of formula (VII) with a Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-

wherein, X, R1 and n are as defined in claim 1;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined in claim 1;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined in claim 1;
g) hydrolysing the compound of formula (XI) to a compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:
wherein, X, A, R, R1, R2 and n are as defined in claim 1.
3. The method as claimed in claim 2, wherein said method comprises the steps of preparing compound of formula (X):
a. reacting the compound of formula (VII) with halogenating reagent in presence of a suitable acid, and a suitable solvent to afford the compound of formula (VIII), as shown in following scheme,
i. Scheme-
wherein, X, R1 and n are as defined in claim 1;
b. oxidising the compound of formula (VIII) or compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (IX), as shown in following scheme,
Scheme:
wherein, X, R1 and n are as defined in claim 1;
c. converting the compound of formula (IX) to a compound of formula (X) in the presence of a suitable acetate reagent, and a suitable solvent, as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined in claim 1.
4. A method for preparing benzodioxepinones compounds of formula (I),

wherein,
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3;
comprising the steps of:
A. cyclising a compound of formula (III) into a compound of formula (II) in the presence of a suitable catalyst, a suitable ligand, and optionally in presence of a suitable base and a suitable solvent, as shown in below scheme,
Scheme:

wherein, X represents halogen selected from the group of Cl, Br, F or I; R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl; R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl; or R and R2a together with the atom they are attached may form a 5 or 6 membered ring; and R1 as defined above;
B. hydrolysing the compound of formula (II) in presence of suitable acid and a suitable solvent to get the compound of formula (I), as shown in below scheme,
Scheme:
;
wherein the compound of Formula (III) is obtain further comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;
alternatively, the compound of formula (III) obtained from ortho halo phenol compound of formula (V):
c) reacting an ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above.
d) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,

Scheme-
wherein, X, R1 and n are as defined above;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
g) hydrolysing the compound of formula (XI) to a compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.
5. The method as claimed in claim 2, wherein said method for preparing compound of formula (III),
comprising the steps of:
a) reacting an ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford a compound of formula (IV), as shown in following scheme,
Scheme:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), triflates (-OTf), benzylsulfonates and trityl (-OTr); R, R1, R2 and n are as defined in claim 1;
b) hydrolysing the compound of formula (IV) in the presence of in the presence of a suitable acid or base and a suitable solvent to obtain a compound of formula (III), as shown in below scheme:

wherein, X, R, R1, R2, L and n are as defined above.
6. The method as claimed in claim 2, wherein said method for preparing compound of formula (III) comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, ( ) in the presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:
;
wherein, X, R1 and n are as defined above;
b) reacting the compound of formula (VII) with a Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,
Scheme-

wherein, X, R1 and n are as defined in claim 1;
c) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined in claim 1;
d) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined in claim 1;
e) hydrolysing the compound of formula (XI) to a compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:
wherein, X, A, R, R1, R2 and n are as defined in claim 1.

7. A method for preparing compound of formula (IV) comprising the step of:
reacting an ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined in claim 1.
8. The method as claimed in claim 1, wherein reaction conversions of the present invention are performed within a temperature range from 10°C. to +150°C.
9. The method as claimed in claim 1, wherein step A is carried under irradiation of light generated by LED, or other lamps.
10. The method as claimed in claim 1, wherein the solvent is selected from aliphatic, alicyclic or aromatic hydrocarbons, halogenated hydrocarbons, nitriles, ethers, amides, sulphoxides, sulphones. alcohols, water or mixture thereof.
11. The method as claimed in claim 1, wherein the solvent is selected from petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, acetonitrile, propionitrile, n- or isobutyronitrile, benzonitrile; dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, methyl t-butyl ether, anisole, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoramide; dimethyl sulphoxide, sulpholane; methanol, ethanol, isopropanol. water or mixture thereof.
12. The method as claimed in claim 1, wherein the suitable catalyst is selected from copper powder, copper bronze, copper oxide (I), copper iodide (I) or copper bromide (I).
13. The method as claimed in claim 1, wherein the suitable ligand is selected from N’,N’ dimethyl ethylene diamine, 4-pyrrolidinopyridine, 8-HQ, trans-1,2-diaminocyclohexane picolinic acid N,N'-dimethylcyclohexane-1,2-diamine or 1,10-phenanthroline.
14. The method as claimed in claim 1, wherein the suitable acid for hydrolysis is selected from H2SO4, HCl, CF3COOH or p-toluenesulphonic acid.
15. The method as claimed in claim 1, wherein the suitable base for hydrolysis is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
16. The method as claimed in claim 2 or 3, wherein the suitable oxidising agent is selected from, hydrogen peroxide, oxone, t-buty1-hydroperoxide, tungstic peroxide, m-chloroperbenzoic acid, benzoyl peroxide, hypohalgenous acids, ceric ammonium nitrate, hypoceric ammonium nitrate, oxone, periodic acid, peracetic acid, performic acid, hydrogen peroxide urea-adduct, sodium perborate, pyridinium chlorochromate, pyridinium dichromate, manganese (II) oxide.
17. A compound of formula (II),

wherein, X represents halogen selected from the group of Cl, Br, F or I;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a,
wherein R2a is methyl or ethyl; or R and R2a together with the atom they are attached may form a 5 or 6 membered ring;
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 1.
18. A compound of formula (Y),

wherein,
X represents halogen;
A represent OH, OAc, or OBz; wherein Ac and Bz represent acetyl and benzoyl respectively;
R is selected from the group consisting of hydrogen, methyl, ethyl, allyl and benzyl;
R2 is selected from the group consisting of hydrogen, OR2a, wherein R2a is methyl or ethyl;
or R and R2a together with the atom they are attached may form a 5 or 6 membered ring;
or O-R and R2 together with the atom they are attached represent =O;
R1 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl and C3-C6 cycloalkyl;
and n represents integer of 0-3; provided that when A is OH and R2 is OR2a then n is 1.
19. A method for preparing compound as claimed in claim 17, comprising the steps of:
In another embodiment, the present invention the present invention provide method for the preparation of compounds of formula (Y) comprising the steps of:
a) reacting a ortho halo phenol compound of formula (V) with the compound of formula (VI), in presence of suitable base and suitable solvent to afford the compound of formula (IV), as shown in below scheme,
Scheme-:

wherein, L is leaving group selected from halogen, tosylates (-OTs), mesylates (-OMs), benzylsulfonates, and triflates (-OTf), R, R1, R2 and n are as defined above;
b) hydrolysing the compound of formula (IV) in the presence of a suitable acid or base and a suitable solvent to obtain compound of formula (III), as shown in below scheme:
wherein, X, R, R1, R2, L and n are as defined above;
alternatively, the compound of formula (III) obtained from ortho halo phenol compound of formula (V):
c) reacting a ortho halo phenol compound of formula (V) with epihalohydrin, [ ] in presence of a suitable base, a suitable phase transfer catalyst and a suitable solvent to afford the compound of formula (VII), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above.
d) reacting the compound of formula (VII) with Jacobsen catalyst in presence a suitable solvent to afford the compound of formula (VIII-A), as shown in following scheme,

Scheme-
wherein, X, R1 and n are as defined above;
e) oxidising the compound of formula (VIII-A) in the presence of a suitable oxidising agent, and suitable solvent to afford the compound of formula (X), as shown in following scheme,
Scheme:

wherein, X, R1 and n are as defined above;
f) reacting the compound of formula (X) with a suitable reagent in the presence of a weak acid, and a suitable solvent, to obtain a compound of formula (XI) as shown in following scheme,
Scheme:

wherein, X, R, R1, R2 and n are as defined above;
g) hydrolysing the compound of formula (XI) to a compound of formula (III) in the presence of a suitable acid or base, and suitable solvent, as shown in following scheme,
Scheme:

wherein, X, A, R, R1, R2 and n are as defined above.