Synthesis of 2,3-dihydrobenzofuran-2-ones and 2,3- dihydrobenzothiophen-2-and 3-ones by rearrangements of 3-hydroxy analogs

Reactions of 2-hydroxybenzophenones 7a–c and 2-sulfanylbenzophenones 13a–c with 1-(1-chloroalkyl)benzotriazoles 8a–c gave 2-(1-benzotriazolylalkoxy)- and 2-(1-benzotriazolylalkylsulfanyl)-benzophenones 9a–h and 14a–h , respectively. Treatment of 9a–h and 14a–h with lithium diisopropylamide (LDA) formed 2-(benzotriazol-1-yl)-3-substituted-2,3-dihydrobenzofuran-3-ols 10a–h and -2,3-dihydrobenzothiophen-3-ols 15a–h . Rearrangement of derivatives 10a–h by ZnBr 2 afforded 3-alkyl-3-aryl-2,3-dihydrobenzofuran-2-ones 11a–h . Rearrangement of derivatives 15a–h gave 2-alkyl-2-aryl-2,3-dihydrobenzothiophen-3-ones 16a– g , 3-alkyl-3-aryl-2,3-dihydrobenzothiophen-2-ones 17b,c,g , and benzothiophenes 18g,h depending on reaction conditions and substituents.


Introduction
The homologation of aldehydes and ketones by the insertion of a carbon atom next to the carbonyl group is an important transformation in synthetic organic chemistry, and one which has been extensively investigated.Available methods for the insertions of a single carbon carrying § e-mail: p.steel@chem.canterbury.ac.nz.substituents next to a carbonyl have been summarized in several reviews 1 and in our own recent publications. 2he reported benzotriazole-mediated one-carbon insertion -functionalizations of ketones and aldehydes involve intermolecular reaction of a carbonyl group with a benzotriazole-activated nucleophile prior to rearrangement.Recently, we reported the preparation of 2,3-disubstituted benzofurans 3 and benzothiophenes 4 of common structure 3 (X = O and S respectively) starting from 2-hydroxy-and 2-sulfanyl-benzophenones 1 (X = O and S) via intermediate 2,3-dihydrobenzofurans and -benzothiophenes 2 (X = O and S).According to our previous work on the homologation of ketones and aldehydes, 2a,c,d the Lewis Acid promoted rearrangement of intermediates 2 should provide ketones of structure 5 via oxiran 4 formation followed by the oxiran ring opening and migration of the 3-aryl group into the 2-position.2a,c,d However, previous literature work shows that 2-alkyl-3-aryl-2,3-dihydrobenzofuran epoxides of the structure 4 (X = O) can undergo tetraethylammonium bromide catalyzed rearrangement into 3-alkyl-3-aryl-2,3dihydrobenzofuran-2-ones 6 (X = O) via the shift of a 2-alkyl group into the 3-position. 5No information on possible formation of benzothiophene epoxides 4 (X = S) or their involvement in similar transformations has been previously reported.

Results and Discussion
Intermediates 9a-h were prepared by the reaction of 2-hydroxybenzophenones 7a-c with compounds 8a-c (available from aldehydes, benzotriazole and thionyl chloride in 87-96% yields 6 ) similar to published procedure, 3,7 but in the presence of anhydrous potassium carbonate as a base instead of sodium hydroxide in DMF solution at 20-25 °C.

Scheme 3
Intermediates 9a-h were treated with an equimolar amount of LDA in THF at temperatures ranging from -78 °C to 0 °C to give the corresponding lithium salts of 2-(benzotriazolyl)-2,3dihydrobenzofuran-3-ols 10a-h 3 (mixtures of diastereoisomers according to TLC analysis; for 9a, a single isomer was observed), which were treated without isolation with 2-3 equivalents of zinc bromide in 1,1,2,2-tetrachloroethane under reflux for 24 h to give new products.The 1 H NMR spectra of these products show no signals corresponding to those assigned to the Nsubstituted benzotriazole groups of intermediates 9a-h (7.2-8.1 ppm).The 13 C NMR spectra of these compounds also no longer show signals for a N-substituted benzotriazole group (in this particular case our assignments were based on signals with chemical shifts around 120 ppm and 146 ppm) and carbonyl carbon (in the range 195-196 ppm) of 9a-h.
We isolated intermediate 10a (82%, single isomer) to support the proposed reaction pathway (Scheme 2).The structure of 10a was deduced from its 1 H NMR, 13 C NMR spectra (see experimental section).The 1 H NMR spectrum of 10a shows no signals assigned to ethoxy group protons of 9a (doublet at 1.8 ppm and multiplet in the range 6.92-7.08ppm), but shows a singlet at 1.77 ppm assigned to the 2-methyl group and a singlet at 3.03 ppm assigned to the 3-hydroxy group of 10a.The 13 C NMR spectrum shows no carbonyl carbon signal, while two new signals at 106.0 ppm and 86.7 ppm were assigned to C-2 and C-3 carbons of the 2,3-dihydrobenzofuran ring.
Following our previous work, 4 intermediates 14a-h were prepared from 2sulfanylbenzophenones 13a-c and compounds 8a-c in the presence of anhydrous potassium carbonate in DMF at 20-25 °C under a nitrogen atmosphere.On treatment with an equimolar amount of LDA in THF at temperatures ranging from -78 °C to 0 °C, 14a-h give the corresponding 2,3-dihydrobenzothiophen-3-ols 15a-h 4 as mixtures of diastereoisomers (for 14d, the single isomer 15d was isolated).
We isolated and characterized intermediates 15c (two diastereoisomers, (2R Compounds 15a-h were treated without separation or further purification with 2-3 equivalents of anhydrous zinc bromide in 1,1,2,2-tetrachloroethane at 100-110 °C for 0.3-2 h to give the corresponding 2,3-dihydrobenzothiophen-3-ones 16a-f admixed in two cases with the benzothiophenes 18g,h. The structures 16a-f were deduced from their 1 H and 13 C NMR spectra (see experimental section).The 1 H NMR spectra of 16a-f show no signals at 7.2-8.0ppm characteristic for the Nsubstituted benzotriazolyl groups in intermediates 14a-f and 15c,d.In the 13 C NMR spectra of 16a-f, the signals assigned to the N-substituted benzotriazolyl groups of 14a-f around 110 ppm, 120 ppm, 132 ppm, and 146 ppm are no longer present, while the new signals at 200.6-203.2ppm were assigned to the carbonyl groups of 16a-f.
For intermediates 15g,h, concurrent processes of dehydration -benzotriazole elimination occur to form 2-(1-propenyl)benzothiophenes 18g,h.Structures 18g,h were deduced from their 1 H and 13 C NMR.The 1 H NMR spectra of 18g,h show no characteristic signals of a Nsubstituted benzotriazolyl group as found for intermediates 14g,h at 7.2-8.0ppm, and no propyl group signals.The doublet of doublets around 1.83 ppm, multiplet at 6.13-6.28ppm, and doublet of quartets at 6.52-6.54ppm with J = 15.5 Hz were assigned to trans-propenyl groups in 18g,h.The 13 C NMR spectra of 18g,h show no carbonyl carbon signals and no characteristic benzotriazolyl signals; the only single signals in the aliphatic region at 18.6-18.7 ppm were assigned to the methyl carbon of the propenyl groups in 18g,h.
To optimize the procedure, compounds 14b,c,g were treated with LDA (1 equivalent) in THF at temperatures ranging from -78 °C to 0 °C followed by addition of anhydrous zinc bromide (2-3 equivalents) to lithium salts of 15b,c,g formed and rearrangement at 90-100 °C for 0.5-2 h in a sealed tube.These rearrangements, unlike the previous in tetrachloroethane, gave three pairs of products.For compounds 14b,c, one of the products was identical to 16b,c according to NMR data.The 1 H and 13 C NMR spectra of one product for 14g show peaks similar to the 16a-f pattern of signals (carbonyl group signal at 202.7 ppm).The 1 H and 13 C NMR spectra of the second products for 14b,c,g showed sets of signals that are also in agreement with the expected structures 16b,c,g, with the only difference being in the appearance of carbonyl signals at 207.2-208.0ppm.The formation of pairs of two carbonyl compounds suggested simultaneous 4 → 5 type and 4 → 6 type transformations of 14b,c,g.The IR spectra of these products showed absorption bands in the range 1696-1701 cm -1 for products with carbonyl group signals in the range 201-203 ppm and in the range 1712-1707 cm -1 for products with carbonyl group signals in the range 207.4-208.0ppm.These data suggest 2,3-dihydrobenzothiophen-3-ones structures 16b,c,g for products with signals of the carbonyl group in 13 C NMR spectra at 201-203 ppm (IR absorption bands at 1696-1701 cm -1 ) and structures 17b,c,g for products with carbonyl group signals at 207.4-208.0ppm (IR 1712-1707 cm -1 ).A single crystal X-ray structure determination for the product from 14c with carbonyl group signal at 207.4 ppm (IR 1707 cm -1 ) unambiguously confirmed the thiolactone structure 17c (Figure 1).3-Alkyl-3-aryl-2,3-dihydrobenzofuran-2-ones are important intermediates for the synthesis of the anti-cancer compound diazonamide A, 9 analgesics 10 and antidepressants. 103-Alkyl-3-aryl-2,3-dihydrobenzofuran-2-one derivatives also possess antispasmodic, 11 antihypoxic, 12 and nootropic activity. 123]16 ISSN Scheme 4 2,3-Dihydrobenzothiophen-3-ones are useful intermediates for the preparation of tetrahydro-1,2-benzothiazepin-5-ones and 3-vinyl-1,2-benzoisothiazoles. 17Typical ring syntheses of 2,3dihydrobenzothiophen-3-ones (Scheme 5) involve two steps: cyclization to a 2,3dihydrobenzothiophen-3-one-1,1-dioxide followed by reduction of the sulfonyl group.17b These ring closures include (Scheme 5): a) the cyclization of o-methoxycarbonylphenyl methyl sulfones by base; 18 b) the cyclization of α-chlorocarbonyl sulfones under Lewis acid catalysis; 19 c) the cyclization of lithiated aryl alkyl sulfones with phosgene; 19 d) the cyclization of ocarboxyphenylsulfonylacetic acid with acetic anhydride in the presence of potassium acetate; 20 e) the cyclization of a benzoylacetic ester in oleum. 212,3-Dihydrobenzothiophen-3-ones have also been obtained by ring transformation of 2-substituted 3-chlorothiochromen-4-ones (Scheme 2, route f). 22

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus and are uncorrected.NMR spectra were recorded on a Varian Gemini 300 spectrometer in CDCl 3 with TMS as the internal standard for 1 H (300 MHz) or a solvent as the internal standard for 13 C (75 MHz).The elemental analyses were performed on a Carlo Erba EA-1108 instrument.DMF was dried over molecular sieves.THF was dried over sodium / benzophenone and used freshly distilled.LDA was used freshly prepared from n-butyllithium and di-iso-propylamine.Di-isopropylamine was dried over calcium hydride.Column chromatography was conducted with silica gel 200-425 mesh.
X-Ray crystallography.Data were collected with a Siemens SMART CCD area detector, using graphite monochromatized MoKα  radiation (λ = 0.71073 Å).The intensities were corrected for Lorentz and polarization effects and for absorption. 23The structure was solved by direct methods using SHELXS 24 and refined on F 2 , using all data, by full-matrix least-squares procedures using SHELXTL. 25All non-hydrogen atoms were refined with anisotropic displacement parameters.Hydrogen atoms were included in calculated positions, with isotropic displacement parameters 1.2 times the isotropic equivalent of their carrier carbons.The crystal data and refinement details are listed along with the other data for the compound.

General procedure for the preparation of 11a-h
To a stirred solution of the intermediate 9a-h (1.0 mmol) in THF (10 mL), a solution of LDA (0.6 mL, 1.2 mmol, 2M) was added at -78 °C and the reaction mixture was stirred for 12 h at temperatures ranging from -78 °C to 0 °C.(In the case of 9a, saturated aqueous ammonium chloride (20 mL) was added and the product 10a was extracted with ethyl acetate; the extract was washed with water, dried and concentrated in vacuum.Intermediate 10a was isolated using column chromatography on silica gel).Then a solution of anhydrous zinc bromide in THF (2.0-3.0 mL, 1M) was added followed by the addition of anhydrous 1,1,2,2-tetrachloroethane (30 mL) and THF was distilled off at normal pressure followed by reflux for 12-24 h (under nitrogen atmosphere).The reaction progress was monitored by TLC analysis.Upon completion, chloroform (20 mL) was added to the reaction mixture and it was washed with dilute hydrochloric acid and then with water.The organic layer was dried over magnesium sulfate and evaporated under vacuum.The product was purified by column chromatography to give 11a-h.

General procedure for the preparation of ortho-substituted benzophenones 14a-h
To a stirred solution of 13a-c (4.0 mmol) and 1-(1-chloroalkyl)benzotriazole 8a-c (5.0 mmol) in DMF (20 mL) under a nitrogen atmosphere, K 2 CO 3 (0.83 g, 6.0 mmol) was added at room temperature and the reaction mixture was stirred for 4 h.After starting material 13 had disappeared, iced water was added slowly and a product was extracted with ethyl acetate.The extract was dried over magnesium sulfate and evaporated under vacuum.The residue was purified by column chromatography using ethyl acetate / hexanes mixture to give pure 14a-h.

General procedure for the preparation of 16a-f
To a stirred solution of the intermediate 14a-f (1.0 mmol) in THF (10 mL), LDA (0.6 mL, 1.2 mmol, 2M) was added at -78 °C and the reaction mixture was stirred for 12 h at temperatures ranging from -78 o C to 0 o C (under a nitrogen atmosphere).Then, saturated aqueous ammonium chloride was added and 15a-f was extracted with ethyl acetate.The extract was washed with water, dried over magnesium sulfate and evaporated under vacuum to dryness (in the case of 14d, the intermediate 15c,d was purified by column chromatography on silica gel and characterized).The mixture of crude 15a-f with anhydrous zinc bromide (0.68 g, 3.0 mmol) in (dd, J = 2.0 Hz, J = 8.7 Hz, 1H),3.88(s, 3H), 2.00 (s, 3H); 13

General procedure for the preparation of benzothiophenes 18g,h
By following the same procedure described for 16a-f, benzothiophenes 18g,h were prepared from 14g,h respectively.General procedure for the preparation of 16b,c,g and 17b,c,g To a stirred solution of the intermediate 14b,c,g (1.0 mmol) in THF (10 mL), LDA (0.6 mL, 1.2 mmol, 2M) was added at -78 °C and the reaction mixture was stirred for 12 h at temperatures ranging from -78 °C to 0 °C (under nitrogen atmosphere).A solution of anhydrous zinc bromide in THF (1M, 3 mL, 3.0 mmol) was added to the reaction mixture.The reaction mixture was transferred to a sealed tube and stirred at 90-100 °C for 1-2 h (a suspension of benzotriazole / zinc bromide usually appears at 80 °C).The reaction mixture was cooled down to 20-25 °C and

ISSN 1424-6376 Page 31 © ARKAT USA, Inc reaction route described. The structures of 15c', 15c'' and 15d were
.5 ppm in13C NMR spectrum of the major diastereoisomer 15c', as well as at 90.3 ppm, 86.3 ppm in the spectrum of the minor isomer 15c'', were assigned to the C-2 and C-3 carbons of the 2,3-dihydrobenzothiophene ring in 15c.