Role of the methoxy group in product formation via TiCl 4 promoted 4-phenyldioxolane isomerizations

The product distribution obtained from the TiCl 4 initiated intramolecular isomerizations of 4- methoxyphenyl-and trimethoxyphenyldioxolanes at -78 o C, -30 o C and 0 o C provided insights into the important regiochemical role played by these groups in such Mukaiyama-type rearrangements through their resonance effects on the aryl ring of the dioxolanes.


Introduction
Our interest in naphthopyranquinones as potential antimicrobial and antibiotic agents has extended over two decades [1][2][3][4][5][6] as a result of their well documented importance. 7,8Additionally, the synthesis of benzopyrans as model systems has received attention by ourselves 6,[9][10][11][12][13] and others. 14- 16Of particular interest to us was our earlier discovery of a TiCl4 -induced intramolecular isomerization in which phenyl-and naphthyldioxolanes were stereoselectively transformed into their corresponding benzo-and naphthopyrans. 17hus, treatment of the naphthyldioxolane 1 with TiCl4 at -78 o C in dichloromethane afforded the two angular naphthopyrans 2 and 3 in yields of 39% and 13% respectively (Scheme 1).In an attempt to promote linear naphthopyran formation, the bromonaphthyldioxolane 4, in which it was hoped the Br would sterically inhibit cyclization at C-1, was similarly treated to again afford angular naphthopyrans 5 (45%) and 6 (18%) representing both debromination for the former product and an example of bromine-migration for the latter.This result indicated that the steric environment of the C4-isopropoxy group was sufficient to prevent formation of the linear naphthopyran which required cyclization at C-3 in the naphthyldioxolanes 1 and 4. Subsequently, the C4-methoxy analog 7, was treated with TiCl4 at -78 o  quantities of the debrominated linear naphthopyran were isolated as its acetate 8 (13%) together with the debrominated angular naphthopyran, also isolated as its acetate 9 (28%). 18These results support, in part, our hypothesis that the steric environment at C-3 of the naphthyl ring plays a significant role in these intramolecular cyclizations.Kaufman et al. 19 investigated the structural consequences of substituents at the C-2 and C-4 positions in the dioxolane ring on the relative relationship of the formed 1,3-disubstituted 4hydroxybenzopyrans, while Giles et al. 20 investigated the influence of two substituents on the phenyl ring of 4-phenyldioxolanes on the formation of benzopyrans at different temperatures when treated with TiCl4.This latter work established that when a C-4 phenyl ring of a dioxolane has an ortho-and meta-methoxy group viz., 10, upon treatment with TiCL4 at -78 o C, the benzopyran 11 was formed in 45% yield and the stereochemistry at C-4 and C-5 of the dioxolane ring of 10 had been transferred unaltered to C-4 and C-3, respectively, in the benzopyran 11.The second product isolated from this reaction proved to be the ring-opened chlorohydrin 12 in a yield of 31%.Since the third stereogenic centre, C-1 of the benzopyran, is derived from C-2 of the parent dioxolane, its temperature dependence has also been investigated. 20eplacing the electron-donating ortho-methoxy group in 10 by Cl, i.e. in 13 and treating this compound with TiCl4 at -78 o C, served to dramatically increase the formation of benzopyrans 14 and 15 to give a combined yield of 97%, in a 1:1 ratio. 21On the other hand, attempted isomerization of the aryldioxolane 16, which has a para-TBSO group at C4 in the aryl ring, failed to produce any benzopyran products.Only ring-opened products were isolated viz., the diastereoisomeric chlorohydrins 17, in a yield of 83%. 22It is thus possible that the increased availability of electrons from the aryl ring attached at C4 of the dioxolane favors ring-opening rather than intramolecular cyclization.
It was recently reported that a 4-(3-methoxy-2-tosyloxyphenyl)-1,3-dimethyldioxolane produced the corresponding benzopyran in 95% yield when treated under the standard conditions with TiCl4. 23To the best of our knowledge, investigations of the electronic role played by a meta-or para-methoxyphenyl group in 4-phenyldioxolanes when treated with TiCl4 has neither been established nor published.In this Paper, we address the above issues, and extend them to include C-4-substituted trimethoxyphenyl-1,3-dimethyldioxolanes as well as the influence of temperature on the product profile.

Results and Discussion
Methylation of m-hydroxybenzaldehyde with methyl iodide and potassium carbonate in dimethylformamide afforded the corresponding m-methoxybenzaldehyde 18a in 91% yield.Wittig olefination with ethyltriphenylphosphorane afforded the olefin 18b as a 1:2 ratio (by NMR) of an E/Z-mixture, in a combined yield of 96%.Isomerization of this mixture into the virtually pure E-isomer 18c was achieved by the use of bis-acetonitriledichloropalladium (II), 24 in 95% yield.This was necessary since we required stereochemically pure products in the subsequent transformations.Thus, treatment of olefin 18c with osmium tetroxide and Nmethylmorpholine N-oxide in aqueous acetone afforded the threo-diol 18d, in 92% yield, which was then converted into the C-2 epimeric dioxolane mixture 18e by reaction with 1,1dimethoxyethane in the presence of a catalytic amount of camphorsulfonic acid, in a yield of 95% (summarized in Fig. 1 and Table 1).In an analogous manner, the p-methoxybenzaldehyde 19a was transformed via the same sequence 19a > 19b > 19c > 19d > 19e, in similar yields (Fig. 1 and Table 1).
Since our broader intention was aimed at investigating the electronic influence of three methoxy groups in the phenyl ring of 4-phenyldioxolanes upon the nature of the products of TiCl4-induced isomerizations, other 4-trimethoxyphenyldioxolanes viz., 20e and 21e, were synthesized using the same protocols, with the yields illustrated in Fig   In a further study, we investigated the effect the all-cis relative stereochemistry of the groups in the dioxolane ring had on the products of isomerization, under our conditions.Thus, we required a molecule in which there was no para-methoxy group in the C-4-aryldioxolane.Thus, the 4-trimethoxyphenyldioxolanes 22f and 22h were synthesized as shown in Figure 2.For the former molecule, the E-olefin 22c was treated with m-CPBA in the presence of solid sodium hydrogen carbonate to afford the pure trans-epoxide 22d, in an un-optimized yield of 57%.This epoxide was subsequently ring-opened in a trans-manner, using dilute aqueous potassium hydroxide in dimethyl sulfoxide, giving the pure erythro-diol 22e, in 88% yield after chromatography.Finally, conversion of 22e into the corresponding dioxolane 22f was effected by treatment with dimethoxyethane in the presence of camphorsulfonic acid, in quantitative yield.For the latter molecule, the E-olefin 22c was converted into the threo-diol 22g and subsequently into the dioxolane 22h, as described earlier.The yields are given in Fig. 2 and Table 2.
Thus, having all the methoxyphenyldioxolanes in hand, each was treated under a standard set of conditions.Namely, the dioxolane in dry dichloromethane at -78 o C, -30 o C, or 0 o C was treated under nitrogen with four equivalents of TiCl4 and stirred for 30 min.The product was then quenched with methanol and allowed to reach 24 o C, and the products isolated by PLC.
Treatment of the C-2-epimeric trans-4-(3-methoxyphenyl)-2,5-dimethyldioxolanes 18e under the standard set of conditions afforded the all-cis-2-benzopyran 23 in 78% yield, together with the ring-opened chlorohydrins 24 in 20% yield (Scheme 2).The stereochemistry of the pyran ring in 23 was assigned on the basis of the 1 H-NMR spectrum which demonstrated inter alia the following signals; a 1-proton doublet at  = 1.95 (J = 7.0 Hz) assigned to the 4-OH; a 1-proton doublet of quartets at  = 3.80 ( J = 6.6 and 1.5 Hz) assigned to 3-H; a 1-proton doublet of doublet of doublets at  = 4.19 ( J = 7.0, 1.5 and 1.0 Hz), 4-H, and a 1-proton doublet of quartets at  = 4.76 ( J = 6.2 and 1.0) assigned to 1-H.The relatively small J of 1.5 Hz between 3-H and 4-H signifies that the 4-OH-and C-3-methyl groups are cis-related.Additionally, the greater shielding value for 3-H at  = 3.80 is typical for 3-H in cis-1,3-dimethyl-2-benzopyrans compared to their trans-1,3-dimethyl-epimers. 20,21The 5 J of ~ 1.0 Hz observed for coupling between the pseudo-axial 1-H and pseudo-equatorial 4-H is also noted for these systems. 20,21Further confirmation for the 4-hydroxypyran ring was provided by acetylation of the hydroxyl group to form the corresponding acetate 27 in 84% yield, in which the 1 H-NMR spectrum indicated a strong deshielding effect of the 4-H signal from the ddd at  = 4.19 to a doublet of doublets at  = 5.78 with 3 J = 1.8 Hz, illustrating coupling with 3-H, and with 5 J = 1.0 Hz showing coupling with the pseudo-axial 1-H.Conducting the reaction at -30 o C produced quite a large change in the product distribution.The only benzopyran isolated was the dehydrated analog 25, in 10% yield, while the major product was the benzofuran mixture 26, isolated in 74% yield, with the chlorohydrins 24 accounting for the rest.It is known that similar benzofuran mixtures are formed from initially formed benzopyrans' rearranging under these reaction conditions. 20It is of interest to note that in the 1 H-NMR spectrum of 25 the signal for the C-3-Me group appeared at  = 1.92 as a doublet ( 4 J = 0.7 Hz) and 4-H appeared at  = 5.57 as a quartet ( 4 J = 0.7 Hz).The same three products were Treatment of the para-methoxyphenyldioxolane 19e under the standard conditions produced no benzopyran products.The only products isolated were the ring-opened methoxyphenylpropanone, 28 (16%), and the methoxyphenylpropanols, 29 and 30, in yields of 16% and 64% respectively (Scheme 3).From the same reaction at -30 o C only two products were isolated, the arylpropanone 28 and the corresponding propanol 30, in yields of 30% and 66% respectively, while at 0 o C the yield of the propanone 28 increased to 80% and the substituted propanol 30 was reduced to 16%.In formulating a plausible mechanism for the formation of the benzopyran 18e it is more than likely that electronic effects play a major role.Thus, subsequent to initial complexation with On the other hand, complexation by TiCl4 at O-1 and O-3 of 19e induces fission between O-3 and C-4 owing to the electron-donating ability of the para-methoxy group ring at C-4 of the dioxolane ring, to produce the para-quinone methides, 31 arising from further fission between O-1 and C-2, and 32 from the alternative loss of chloride.In the former case, a hydride migration would give the arylpropanone 28 while the latter intermediate might afford the substituted propanol 29 resulting from attack by methoxide, and 30 from attack by chloride (Scheme 5).As a consequence of the study by Giles et al. 20 in which the influence of a C-4-orthomethoxyphenyl dioxolane was investigated when treated under the standard conditions, we wished to broaden the scope of our investigations to include C-4-phenyl scaffolds having combinations of ortho-, meta-and para-trimethoxy groups.Our research required investigation of the influence of three methoxy groups on the product distribution of 4-(trimethoxyphenyl)-2,5-dimethyldioxolanes when treated under the standard conditions, and to define the regiochemical pattern needed for benzopyran ring formation.
The first trimethoxyphenyl-dioxolane investigated was 20e which has ortho-, meta-and para-methoxy groups relative to the ring-C attached to C-4 of the dioxolane moiety, viz., two groups favoring ring-opening of the dioxolane moiety and one group favoring benzopyran ring formation.Thus treatment of 20e under the standard conditions afforded a low yield of the benzopyrene 33 (3%) together with the products of ring opening viz., the substituted propanone 34 (15%), the trimethoxyarylpropanol 35 (60%) and the substituted propanol 36 (15%) illustrated in Scheme 6.As the temperature of reaction was increased, so too did the proportions of the trimethoxyarylpropanone 34, andto a much lesser extentthe benzopyrene 33.The second trimethoxyphenyldioxolane investigated, viz.21e, represents a molecule with a subtle change in the regiochemistry of the methoxy groups.Not only does it have ortho-, metaand para-methoxy groups relative to the ring-C attached to C-4 of the dioxolane moiety, but additionally it has steric and electronic effects that do not support pyran ring formation, as shown in Schemes 4 and 5. Thus, it was not surprising that treatment of 21e under the standard set of conditions yielded only ring-opened products viz., the aryl propanone 37 together with the two arylpropanols 38 and 39, as illustrated in Scheme 7. The third of the trimethoxyphenyldioxolanes investigated was 22h, having two meta-and one ortho-methoxy groups relative to the phenyl ring-C attached to C-4 of the dioxolane moiety.In this case, there was only one methoxy group that strongly favored cyclization, in spite of the steric demand at the C-6 position which is similar to that found in 21e.The results of the treatment regime are shown in Scheme 8.The influence of the C-3-methoxy group is clear at low temperature since it induces sufficient nucleophilic character at C-6 to attack the intermediate oxonium ion depicted in Scheme 4 to subsequently form the benzopyran 40, and it thus overrides any adverse steric effects of the C-5-methoxy group.An increase in the reaction temperature results in a decrease in formation of benzopyran 40 and chloropropanols 44, and an increase in the formation of benzofurans 42 resulting from the rearrangement of the initially formed benzopyran 40.follows from 1 H-and 13 C-NMR spectral data which had inter alia; a 3-proton triplet at  = 1.02 (J = 7.4 Hz) coupled to a 2-proton quartet at  = 2.50 (J = 7.4 Hz), a 3-proton singlet at  = 2.18, a 2-proton singlet at  = 3.77, and a 1-proton singlet at  = 6.44.The ketone group was evident from a signal at  = 207.0 in the 13  The results of treatment of the all-cis trimethoxyphenyldioxolane 22f under the standard conditions are summarized in Scheme 10.At -78 o C, by far the major product is the benzopyran 47, isolated in 94% yield, in which the stereochemistries of C-4 and C-5 of the dioxolane ring have been incorporated unaltered at C-4 and C-3 respectively in the pyran ring.In addition, the C-1-methyl group is in the pseudo-axial position, owing to the steric environment of the peri-C-8-methoxy group.At -30 o C the yield of the benzopyran 47 dropped to 40% while the amount of dehydration product 41 increased to 11%, and the rearranged benzofurans 42 increased to 30%.This trend continued at 0 o C where it was noted that the C-1 epimer of 47, viz., the benzopyran 48 was isolated in 5% yield.It is of interest that the yield of benzofurans 42 is the same starting from either 22f or 22h, but that the proportion of the benzopyrans 47 and 40 differed by more than 44%.This differential trend is maintained, although not to the same extent, as the temperature increased to 0 o C. Finally, the benzopyrans 47 and 40 were oxidized to the corresponding quinones 49 (42%) and 51 (51%) in aqueous cerium(IV) ammonium nitrate.In this procedure the two corresponding ortho-quinones, 50 (28%) and 52 (17%) were also produced as unstable red oils (Scheme 11).

Conclusions
The meta-methoxyphenyl group attached to C-4 of the dioxolane moiety, viz., 18e, is sufficient, through resonance, to provide the necessary nucleophilic character to C-6 in order to promote the intramolecular Mukaiyama-type cyclization at -78 o C.This produces the corresponding 2- benzopyran 23, while at higher temperatures the initially formed 2-benzopyran 23 is further isomerized to the benzofurans 26.When there is a para-methoxyphenyl group attached to C-4 of the dioxolane moiety, i.e., 19e, no benzopyran formation occurs under the same conditions, but rather products of dioxolane ring opening, viz., the propanone 28, as a consequence of the electron-releasing property of the methoxy group.
The trimethoxyphenyldioxolanes 20e and 21e, in which the methoxy groups are ortho-, meta-and para-in the phenyl ring at C4 of the dioxolane moiety, do not yield benzopyran products of isomerization, although with 20e minor quantities ( ~5%), of 2-benzopyrene 33 were detected.Thus, since ortho-and meta-methoxy groups favor intramolecular cyclization under the standard conditions, the presence of the para-methoxy group is sufficient to direct the course of reaction to that of dioxolane ring opening.On the other hand, the dioxolanes 22h and 22f, both of which possess one ortho-and two meta-, but no para-methoxy substituents in the phenyl ring, the products of TiCl4 -induced isomerization are indeed the 2-benzopyrans 40 and 47 respectively.In comparing the relative yields of this latter isomerization, it appears that the allcis-phenyldioxolane 22f affords a much higher quantity of the 2-benzopyran 47 (94%) than that of the epimeric mixture 22h which produces 40 (60%).It is our contention that the reason for this is the fact that in 47 the C-1-methyl group adopts a pseudo-axial orientation and thus experiences relatively less steric interaction with the C-8 -perimethoxy group, while in 40 the C-1-methyl group adopts a pseudo-equatorial orientation resulting in an unfavorable periinteraction with the C-8-methoxy group.

Experimental Section
General. 1 H-and 13 C-NMR spectra were recorded on a Varian 200 MHz spectrometer using deuteriochloroform with TMS as internal standard;  values are recorded in ppm.In the 13 Cspectra, assignments with the same superscripts may be interchanged.IR spectra were recorded on a Perkin Elmer FT-IR Paragon 2000 spectrometer either as oils or Nujol mulls.Mass spectra were performed on a Finnigan-MAT GCQ, and elemental analyses were performed on a Carlo Erba 1500 NA analyzer.Melting points were recorded on a Fisher-Johns melting point apparatus and are uncorrected.Preparative chromatography was done on dry columns using Merck Silica Gel 60, particle size 0.063-0.2mm.Hexane refers to the fraction boiling between 67-70 o C and the term, "residue obtained upon work-up" refers to drying of the extract over magnesium sulfate, filtration, and removal of solvent under reduced pressure.

E-(3-Methoxyphenyl)prop-1-ene (18c
).General procedure.n-Butyllithium (14.5 mmol) was added dropwise to a stirred suspension of ethyltriphenylphosphonium bromide (5.30 g; 14.29 mmol) in dry THF (50 mL) under a nitrogen flow, and at -78 o C. The temperature of the mixture was allowed to rise to 0 o C for 30 min after which it was again cooled to -78 o C and then the 3methoxybenzaldehyde (18a, 1.39 g; 10.2 mmol) dissolved in THF ( 10 mL) was added dropwise over 30 min.The reaction mixture was stirred for an additional 20 min at this temperature, then allowed to warm to 25 o C, and stirred for a further 3 h.It was then quenched with water and extracted with EtOAc, and the residue obtained upon work-up was chromatographed using EtOAc: hexane (1:9) as eluent to afford an E/Z-mixture of olefins 18b as an oil (1.45 g; 96%) in a ratio of 1:2 (determined by NMR).This mixture was taken up in chloroform (50 mL) to which bis-(acetonitrile)dichloropalladium(II) 20 (35 mg) was added, the mixture was stirred at 25 o C for 72 h and then chromatographed on a short column using EtOAc: hexane (1:9) as eluent to yield the (E)-alkene 18c (1.38 g; 95%) as a colorless oil.IR (NaCl, film): max = 1666 (C=C) cm -1 .

Standard conditions for treatment of dioxolanes with TiCl4.
To a solution of the dioxolane mixtures (200 mg) in dichloromethane (20 mL) at the specified temperature was added TiCl4 (4 mol equivalents of a 9.2M solution in dichloromethane) via syringe under a nitrogen atmosphere, and stirring was continued for 30 min.The reaction mixture was quenched by the addition of methanol (0.6 mL) and allowed to reach 24 o C. Water (20 mL) and saturated aqueous sodium hydrogencarbonate (10 mL) were added and the aqueous solution exhaustively extracted with dichloromethane.The residue obtained upon workup was chromatographed using PLC with EtOAc: hexane (1:4) as eluent to afford the products in order of Rf.

Scheme 3 .
Scheme 3. Products of the reaction of 19e with TiCl4.

Scheme 7 .
Scheme 7. Products of reaction of the dioxolane with TiCl4.

Scheme 9 .
Scheme 9. Mechanism of formation of the ketone 43.

Scheme 10 .
Scheme 10.Products of reaction of the dioxolane 22f with TiCl4.
Scheme 11.Oxidation products of the benzopyrans 47 and 40.

Table 1 .
Yields of products of transformations of methoxybenzaldehydes in Figure1

Table 2 .
Yields of products of transformation of the trimethoxybenzaldehydes 22a

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at 0 o C but with increased proportions of the benzopyrene 25 to 14%, while that of the benzofurans 26 increased to 83% (Scheme 2).