Neighboring-Group Participation Involving the Oxygen Atom of the O,O- or O,N-Acetal Functional Groups

Neighboring-Group Participation Involving the Oxygen Atom of the O,Oor O,NAcetal Functional Groups M. Kimatrai, O. Cruz-López, M. E. García-Rubiño, F. Morales, V. Gómez-Pérez and J. M. Campos* Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain Abstract: The application of the neighboring-group participation involving the oxygen atom of O,Oor O,N-acetals can be very fruitful. For instance, the naphthoate ester derivatives of (Z)-hex-3-ene-1,5-diyne were used to generate biradicals via -oxo ketene acetal intermediates, and a synthesis of tricyclic 9-crown-3 ethers bearing a chiral oxathiane ring was achieved by utilizing nucleophilic displacement of a triflic ester leaving-group assisted by neighbouring-group participation of a 1,3-dioxolane function. In a different field, the reaction between o-(hydroxymethyl)phenoxyacetaldehyde dimethyl acetals, or (+/-)-3-methoxy-2,3-dihydro-5H-1,4-benzodioxepins with 5fluorouracil was studied. The intramolecular cyclization may be explained through a neighbouring-group attack to give a 2-(5fluorouracil1-yl)oxyranium ion that can be attacked by the silylated benzylic hydroxyl group to yield the benzannelated sevenmembered O,N-acetals. Before carrying out the synthesis of 7or 9-substituted (+/-)-2-methoxy-2,3-dihydro-5H-1,4-benzodioxepins it is necessary to protect the phenolic hydroxy group of the 2-hydroxybenzyl alcohol. Among other functionalities, the 2methoxyethoxylmethyl (MEM) group was developed as a protective group of alcohols and phenols. Accordingly, it was decided to use the MEM group for the preparation of 7or 9-substituted (+/-)-2-methoxy-2,3-dihydro-5H-1,4-benzodioxepins and their ten-membered benzo-fused analogs. The importance of the ten-membered O,O-acetals sheds light on the mechanism of reaction in which the neighbouring-group participation plays a pivotal role. Transannular versions of the reaction result in the facile ring contraction of 12-membered intermediates to the 10and to 7-membered benzene-fused O,O-acetals. Acetals with several oxygen atoms in their side-chains have been used in the preparation of highly oxygenated cyclic ether compounds. Keywords: Acetals, Bisfuran, Medium-ring heterocycles, Methoxyethoxymethyl group, Neighbouring group participation,  -Oxo ketene acetal, Steroidal sapogenins, Triciclycic 9-crown-3 ether derivatives. INTRODUCTION Neighboring-group participation is a term which encompasses all intramolecular reactions and all reactions which involve nonelectrostatic through-space interactions between groups within the same molecule. The term was invented in 1942 by Saul Winstein. Neighboring-group participation is well documented as far as the mechanism and scope of the reaction are concerned [1]. We will concentrate on neighboring-group participation on O,Oand/or O,Nacetals with one or more oxygen atoms in their side-chains. As far as we know, this subject has not been reviewed yet. We have made an attempt to take into account the largest possible number of original papers (SciFinder and PubMed), including our research and others. It is difficult to write a comprehensive review on a subject as broad as this, since too many examples are hidden away in papers whose titles and, in many cases, abstracts, give no mention of a relationship to neighbouringgroup participation. Publications that appeared after 1998 are included. This review is organized according to the publication date of the manuscripts, starting from the earliest ones (1998) and finishing with the most recent ones. Several investigators have been attracted to studies of neighboring-group effects in order to improve our understanding of basic chemical reactivity as well as to unravel some anomalous results. The most widely studied type of neighboring-group participation is where the neighboring group acts as a nucleophile. When describing nucleophilic participation it is frequently convenient to use the symbol G-n, where G is the participating group and n the size of the ring that is formed in the transition state. Acetals or ketals participate in far less displacement reactions than simple ethers. *Address correspondence to this author at the Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain; Tel: +34 958 243848; Fax: +34 958 243845; E-mail: jmcampo[email protected] 1. CYCLOAROMATIZATION OF ENEDIYNE COMPOUNDS VIA  -OXO KETENE ACETAL INTERMEDIATES Various acyclic (Z)-1,2,4-heptatrien-6-ynes, which undergo cycloaromatization to produce reactive dehydrotoluene biradicals (Myers-Saito-type cyclization) [2], have been investigated as chemical models for a class of potent antitumor antibiotics, neocarzinostatin (NCS) [3]. The preparation of enyne-allene models possessing characteristic triggering devices which initiate the generation of dehydrotoluene biradicals is a challenging problem [4]. Naoe et al. reported that the cis-enediyne derivative 1 generates the toluene biradical 3 via the fixed s-cis-enyne-allene intermediate 2 by means of intramolecular triggering action of the hydroxy group under acidic conditions (Fig. ( 1 )) [5]. For further development of this class of cascade reaction, Suzuki et al. described the MyersSaito-type cyclization via  -oxo ketene acetal intermediates 4 generated by the neighboring group participation of the naphthoate ester moieties of enediyne derivatives in acidic media. In typical examples, the naphthoate esters 8a and 8b were synthesized having the  -hydroxy naphthoate moiety. The synthesis of naphthoate esters 8a,b (Fig. ( 2 )) started with the known (Z)- bromoenyne 5 [6] which was condensed with 1-methoxy-1,ldiphenyl-2-propyne to give the enediyne 6 . The alcohol 7 was obtained by reduction of the ester 6 with excess of DIBAL-H (diisobutylaluminum hydride). A naphthoate group was introduced by the reaction of 7 with 2-hydroxy-1-naphthalenecarboxylic acid or 2hydroxy-7-methoxy-5-methyl-1-naphthalenecarboxylic acid [7] in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and subsequent desilylation with tetra-n-butylammonium fluoride to afford the desired naphthoate esters 8a and 8b, respectively. The reaction of naphthoate 8a with trifluoroacetic acid (0.6 v/v%) in the presence of 1,4-cyclohexadiene (50 equiv) in benzene at room temperature afforded a mixture of several products from which diphenyl acetal 9a (10% yield), the diol 10a (5% yield) and OH O Ph H O O OH O OH Ph Ph OR Ph 1 2 Ph 3 Fig. (1). EtO2C Br 5 TMS i) Ph Ph OMe EtO2C Ph Ph OMe TMS 6 (62%) Ph Ph OMe TMS 7 (77%) R 2 iii)-iv) R 1 R 2 OMe (1.2 equiv) R1 OH (2.0 equiv) 8a R1 = R2 = H (82%) 8b R1 = OMe; R2 = Me (40%) Fig. (2). Reagents: i) Pd(PPh3)4 (0.05 equiv), CuI (0.2 equiv), n-PrNH2 (1.8 equiv), toluene, 60 ºC; ii) DIBAL-H (2.1 equiv), THF, -78 ºC; iii) EDC (40 equiv), CH2Cl2, rt; iv) (n-C4H9)4NF (1.0 equiv), THF, 0 ºC. HO OMe i) HO Ph Ph + + 8a 9a 10a 11a Fig. (3). Table 1. Acid-Catalyzed Cyclization of Naphthoates 8a and 8b [CF3CO2H (0.3 v/v%), Cyclohexadiene (50 equiv), Benzene, 25 ºC] Compound Conditions Reaction time Products (yield) 8a under Ar 14 h 10a (7%), 11a (24%) 8a under O2 24 h 9a (65%) 8b under Ar 15 min 11b (14%) 8b under O2 30 min 9b (55%) the triol 11a (28% yield) were isolated (Fig. ( 3 )). These results suggest that the enediyne 8a proceeded via an acid-catalyzed reaction to the enyne-allene intermediate followed by subsequent MyersSaito-type reaction to form cyclized products. In order to examine the formation pathways of these products, the reaction was conducted in a degassed solvent as well as in oxygen atmosphere (Table 1 ) [6]. When the reaction of 8a was carried out in a degassed solvent, the acetal 9a was not detected in the mixture of reaction. OH ii) OH Ph O O Ph OH Ph O O Ph Ph O O O O HO O O Ph OH OH Ph O On the other hand, the reaction under oxygen atmosphere afforded 9a, but not 10a nor 11a . While the reactions of 8a required more than 14 h at 25 ºC, 8b reacted within 0.5 h under similar conditions. The latter reaction gave a more intricate mixture, from which 11b (under Ar) and 9b (under O 2 ) could be isolated. These results strongly suggest the naphthoate participation and incorporation of molecular oxygen into the acetals 9a,b . Thus, the R 2 R R 2 R 2 2 R 1 OMe R 1 O H + 4 R 1 O O O 12 R 1 O Ph O O Ph Ph Ph H Fig. (4). following mechanism was proposed for these cycloaromatization reactions as represented in Fig. ( 4 ). In the first step, the naphthoate migration to acetylenic carbon with the concomitant elimination of the methoxy group is likely to occur in acidic media. The  -oxo ketene acetal intermediates 4 thus formed should undergo the cycloaromatization to give the biradical intermediates 12 . Under anaerobic conditions, 12 would be converted into diol 10 by hydrogen abstraction from cyclohexadiene, followed by the addition of adventitious water or by hydrolysis under work-up conditions. Alternatively, biradicals 12 would be transformed into triol 11 via the ionization process [9]. When the reactions were carried out under oxygen atmosphere, hydrogenperoxy intermediates 13 would be formed by hydrogen abstraction, followed by molecular oxygen incorporation. The addition of water or trifluoroacetic acid to the ketene acetal 13 should provide 9 via the epoxy intermediates 14 . The final rearrangement pathway is similar to that of the well-known phenol synthesis from cumene hydroperoxide under acidic conditions [10]. The relatively fast reaction of 8b compared with 8a is presumably due to the presence of electron-releasing substituents on its naphthalene ring. 2. PREPARATION OF 9-CROWN-3 ETHER DERIVATIVES THROUGH THE DIOXOLANE ACETAL RING EXPANSION ON A SUGAR TRIFLATE The nucleophilic displacement of sugar triflates by oxygen nucleophiles represents an efficient route towards substituted products with inverted configuration at the electrophilic centres [11]. Accordingly, it was assumed that solvolysis of the L-talo-derivative 19 , in the presence of benzoate anion as the nucleophile, might be used for the preparation of the L-manno-isomer 20 (Fig. ( 5 )), a O OBz S OH H 2 H 7 O 4 S 3 O 1 5 O 3 O O O O O CH2NMe3 MsOH2C MsO O OR Me X 15 R = H i) 16 R = Bz 20 (-)-allo-Muscarine ii) O O v) 8 7 O 4 O 5 O 6 8 + 6 BzO 1 S 2 BzO iii) iv) 17 R = Bz 18 R = H 19 R = Tf 21 22 Fig. (5). Reagents: i) BzCl, py, rt, 24 h; ii) NaSH, DMF, N2, 80 ºC, 40 min; iii) NaOH, MeOH, 80 ºC, 40 min; iv) Tf2O, py, CH2Cl2, O ºC → rt, 30 min; v) LiOBz, DMF, 24 h. possible intermediate in the synthesis of (-)-allo-muscarine from Dglucose [12]. The triflic ester 19 was thus prepared starting from the known 2,5-anhydro-L-idose derivative 15 [13]. Reaction of 15 with benzoyl chloride in dry pyridine gave the expected 4-O-benzoyl derivative 16 which was further treated with sodium hydrogen sulfide in DMF (N,N-dimethylformamide) to give the oxathiane derivative 17 . O-Debenzoylation of 17 with sodium hydroxide in dry methanol afforded the unstable alcohol 18 which was subsequently treated with triflic anhydride in a mixture of dichloromethane and pyridine to afford the triflate ester 19 . The fourstep sequence 15 → 19 was carried out without purification of intermediates 16-18 , whereby the desired product 19 was isolated by flash column chromatography in an overall yield of 53% with respect to the starting compound 15 [14]. Although most sugar triflates have been shown to be rather reactive towards a variety of nucleophiles [11,15], the triflic ester 19 remained unchanged even after prolonged treatment with an excess of potassium benzoate in DMF at 140 °C. This implied that the approach of an external nucleophile to the electrophilic centre was sterically hindered by the  -orientated dioxolane acetal ring. Therefore, the reaction was carried out in boiling DMF, whereupon the conversion of the starting compound was completed after 48 h. However, this reaction did not afford the substitution product 20 , but resulted in the formation of the 9-crown-3 ether derivative 21 , isolated by flash column chromatography in 26% yield. A somewhat different result was obtained by using lithium benzoate as the nucleophilic agent. Treatment of compound 19 with an excess of lithium benzoate in boiling DMF for 24 h gave an approximately 12:1 mixture of the stereoisomers 21 and 22 in a 42% combined yield. The assignment of diastereomer configuration of 21 and 22 was discussed by Popsavin et al. [14]. A possible mechanism of the solvolytic reaction may involve dioxolane neighboring-group participation in the first step. As outlined in Fig. ( 6 ), both stereochemically distinct intermediates 19a and 19b might be formed from 19 . Further reaction of the exooxonium ion 19a with benzoate anion would give the major product 21 having the S-configuration at C-1. Similar reaction of the endooxonium ion 19b would lead to the 1R-stereoisomer 22 isolated as a minor product from the reaction mixture. Presumably this is because the endooxonium ion 19b is too strained to form readily [14]. In fact, semiempirical PM3 calculations [16] performed on both 19a and 19b confirmed a lower stability of 19b (AE = 10.16 kJ/mol in favor of 19a ). This is mainly due to the repulsive van der Waals interactions between the syn-orientated O-1 and O-2(5) atoms. The calculated distance between these atoms in an optimized structure 19b is 2.68 Å, that is less than the sum of the corresponding van der Waals radii (2.80 Å) [17]. On the other hand, the intermediate 19a is less strained since the distance between H-1 and O2(5) atom (2.59 Å) is similar to the sum of their van der Waals radii (2.60 Å), as calculated from the optimized structure 19a . Consequently, the exo-ion is preferentially formed, leading to the stereoisomer 21 as the major reaction product. Alternatively, the second step of the rearrangement ( 19a → 21 ), may well be an S N 1 type of process the attack of the nucleophile being carried out preferentially from the less hindered face. 3. REARRANGEMENT OF SPIROSTANES TO BISFURAN SYSTEMS The sapogenins are aglycones of saponins, a group of glycosides widely distributed in plants. The most common sapogenins are spirostanols with the normal-type spiroacetal form (22R). With regard to the configuration at C-25, there are two types: an  - oriented methyl group (25R as in hecogenin acetate 23 ) and a  - oriented methyl group (25S as in sarsasapogenin acetate 27 ). It is well known that sapogenins can be selectively brominated at C-23. The observations of Morzycki and Jastrzębska [18] confirm O OR S the reports that 25R-sapogenins form two isomeric 23-bromo 4 OTf O 1 O H 5 O 2 3 S 7 O 4 O 5 1 O 3 2 S H 7 O 4 O 5 1 O 3 2 S H 8 8 7 6 19 4 OTf BzO 19a 8 7 H O O 1 S 6 BzO 21 8 4 8 O 5 1 O 6 7 O 3 S H 2 2 3 S O 5 BzO 6 6 Fig. (6). 19 21 O 18 20 O 26 25 27 19b 22 12 17 11 19 13 22 X 23 24 O NH , H O 1 9 H 14 3 2 2 AcO 3 10 H 5 4 H 6 16 8 H 15 7 nBuOH, 7 days 95% RO H 23 X = H 24 X = Br Br O O 26 (R = H or Ac) AcO O H H H H 25 NH3, H2O n-BuOH, 7 days Fig. (7). AcO H 27 X = H 28 X = Br 97% RO H 29 (R = H or Ac) derivatives 24 and 25 (no bromination product at C-11 was detected). Bromination of the 25S-sapogenins yields only a single 23bromo product 28 due to steric hindrance from the axial methyl group at C-25. All three bromo derivatives (23S,25R; 23R,25R and 23S,25S) were subjected to weak alkaline hydrolysis (NH 3 or K 2 CO 3 , H 2 O, nBuOH, under reflux several days). Compound 25 with an axial bromine atom did not react under these conditions (Fig. ( 7 )). The other compounds ( 24 and 28 ) yielded bisfuran prod7 8 O BzO O 4 H 1 2 3 O 5 6 HO O O O H H H O O O X H H H HO O O O H H H ucts with a tertiary hydroxy group (as proved by failure of acetylation attempts). Mass spectra showed a very characteristic pattern of molecular ion fragmentation involving loss of water or methyltetrahydrofuran (M-C 5 H 10 O) + [19]. 1 H and 13 C NMR spectra confirmed the hemiacetal structure of the products ( 26 and 29 , respectively). The analysis of NOE effects in their 1 H NMR spectra suggests the 23R configuration in these compounds [18]. Fig. (13). Reagents: i) K2CO3, anhydrous acetone, MEMCl; ii) BrCH2CH(OMe)2, NaH, anhydrous DMF; iii) BF3·OEt2 in anhydrous Et2O. OH O 10 O R 2 R 2 R 2 i) ii) OMe OMe R1 OH R1 O O OMe R1 O OMe 81 R1 = OMe; R2 = H 82 R1 = H; R2 = OMe 83 (57%) 84 (47%) 85 (26%) 86 (33%) R2 OMe O R1 R 2 R1 OMe 70 (-) 71 (15%) 42 (40%) 43 (70%) Fig. (14). Reagents: i) K2CO3, anhydrous acetone, MEMCl; ii) BrCH2CH(OMe)2, NaH, anhydrous DMF; iii) BF3·OEt2 in anhydrous Et2O. Table 5. 13C NMR Chemical Shifts (ppm) for the 2,3-dihydro-5H-1,4-dioxepin Moiety in 64-66 and 42,43 for CDCl3 Solutions 64 65 66 42a 43a C-2 103.99 103.99 104.04 73.00 72.37 C-3 74.86 74.85 74.85 101.54 101.25 C-5 72.87 72.37 72.32 63.23 62.85 C-10 154.30 152.85 153.45 152.91 147.90 C-11 133.26 134.80 135.27 131.15 130.49 aSee [20] methyl acetal, using sodium hydride as a base and anhydrous DMF as solvent; and c) the cleavage of the MEM moiety and subsequent cyclization to yield the target molecules 64-66 . In the original paper, which introduced the MEM group as a protective group for the hydroxyl function [28], the advantages of using anhydrous ZnBr 2 or TiCl 4 over other Lewis acids were highlighted. It has been reported the BF 3 ·OEt 2 -mediated seven-membered cyclization of acyclic O,O-acetals [20,23,30] and accordingly, we supposed that the use of such a catalyst could lead to the target molecules 64-66 in a one-step/pot reaction, as a consequence of the simultaneous deblocking/cyclization process. The experimental results confirmed the hypothesis but, in addition to the expected benzofused seven-membered O,O-acetals 64-66 , the ten-membered O,O-acetals 67-69 were also produced (Fig. ( 13 )). In order to confirm the structures of the compounds, the attention was focused on the NMR chemical shift of the benzylic carbon atoms and found that in the case of 75-77 , the range covers a narrow interval of ≈  1 ppm (in CDCl 3 ): δ 61.58 ppm ( 75 ), δ 60.62 ppm ( 76 ), and δ 60.41 ppm ( 77 ). 5.2. Reaction Between 2-Hydroxybenzyl Alcohols 81,82 and MEMCl Nevertheless, when we tried to extend this series of reactions with the aim of obtaining the 5-methoxy-2-(2-methoxyethoxymethoxy)benzylic and the 3-methoxy-2-(2-methoxyethoxyO O O 7 O OH iii) methoxy)benzylic alcohols, starting from the salicyl alcohols 81,82 , their 13 C NMR chemical behavior was not compatible with such structures on the basis of the chemical shifts of the benzylic carbon atoms, i.e. δ 66.80 ppm when the benzene ring had a 5-OMe group or δ 64.55 ppm when the aromatic substituent was the 3-OMe moiety. These two low-field chemical shifts, in relation to the corresponding values of 75-77 cannot be explained by the field/inductive effects of the aromatic methoxy fragments because there is a great distance between the two atoms involved in both cases. However, such a chemical shift difference could be justified should the oxygen atom of the benzylic alcohol be alkylated by the MEM moiety, instead of the oxygen atom of the phenol group. Should this be the case, the sequence of reactions (Fig. ( 14 )) would lead to the previously reported seven-membered O,O-acetals 42,43 (with the acetalic -OMe fragment in position 3), together with 71 in the case of starting from 82 . Fig. ( 14 ) shows the synthetic route followed, whose difference with respect to Fig. ( 13 ), is the different alkylation site achieved by the reactant MEMCl. Another key point is the chemical shift of the benzylic carbon atoms of both target molecules 64-66 and 42,43 . For compounds 42,43 , such carbons are in  position (an 1,3-relationship) in relation to the acetalic methoxy groups, their 13 C chemical shifts being very sensitive to steric compression. As a rule, it is found that the 13 C NMR chemical shifts of carbon atoms in spatially crowded alkyl groups are more upfield than similar carbon atoms in unperturbed systems. Therefore, such an effect is negligible for com- Fig. (15). Molecular structure of (+/-)-1-(7-methoxy-2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil 35 (ORTEP drawing at 50% probability) [31]. pounds 64-66 because the proximity relationship between both groups is even higher (delta or an 1,4-relationship). Table 5 shows the 13 C chemical shifts of the corresponding seven-membered moieties of the cyclic O,O-acetals. In spite of the accurate 13 C NMR reasoning carried out to prove the structures of 42,43 , the confirmation of such compounds needed to be corroborated because this point is critical for the confirmation of the alkylation site of 81 by MEMCl. There is always the chance that the structure of 42 with the acetalic –OMe group at position 3 could have been mistaken for the corresponding analog having the acetalic –OMe group at position 2 (the hypothetical molecule 65 ) because their 1 H and 13 C NMR data are very close. Accordingly, we decided to unequivocally elucidate the structure of the acetal ( 65 or 42 ) by its reaction with 5-FU, HMDS and TMSCl, under acid catalysis (SnCl 4 ) in acetonitrile during 144 h. Such a process led to 1- (7-methoxy-2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil 35 [20], whose structure was unambiguously determined by X-ray crystallography (Fig. ( 15 )). Therefore, the regioselective protection of the primary hydroxy group of the corresponding salicyl alcohol was finally proved by a synthetic method, which ensured the previous structural assignments. The explanation of the different chemical behavior (see Figs. ( 13 ) and ( 14 )) is very simple: the acidity of phenolic compounds is modulated by electronic effects. ortho and para electron-donating groups in relation to the phenol group decrease acidity, whilst electron-withdrawing groups at the same position act in the opposite manner. As a result of both resonance and field/inductive effects, charge concentration leads to lesser stability of phenoxy anions and to a decrease in acidity [32]. Accordingly, the electronic properties of the ortho and para substituents to the hydroxy phenoxy group modify the selectivity of the alkylation site by MEMCl. 5.3. Mechanistic Aspects of the Synthesis of (+/-)-2-methoxy-2,3dihydro-5 H -1,4-benzodioxepins 64-66 and (+/-)-5-methoxy2,3,5,6-tetrahydro-8 H -benzo-[1,4,7]-trioxecins 67-69 This process is effected by the reaction of 78-80 (1 equiv) in THF at 0 o C under an inert atmosphere with 0.5 equiv of BF 3 ·OEt 2 . If the structures of the starting material 78-80 and of the final compounds 64-66 and 67-69 are compared, one comes to the conclusion that the MEM moiety of 78-80 should suffer two different cleavage processes from a formal point of view: a) on one hand, with the breaking of the methoxyethoxymethyl moiety, then the nucleophilic attack of the phenoxy group to the acetalic function with the concomitant cyclization process should give rise to the sevenmembered acetal 64-66 ; and b) the formation of the ten-membered acetal 67-69 is not so obvious: the terminal methyl ether and the internal methylene-oxy group of the MEM fragment should be eliminated before or after the corresponding cyclization step takes place. Such processes are likely to occur through concerted processes and rearrangements on common intermediates. It must be emphasized that outside the protective group arena, MEMCl has been used to alkylate enolates [33] and aryllithium reagents in the presence of Ph 2 TlBr [34]. MEM ethers have also proved to be a good one-carbon source for the preparation of isochromans [35]. Fig. ( 16 ) shows a possible mechanism for the formation of both cyclic O,O-acetals. First of all, the complexation of the ethereal oxygen atom of the methoxy group of the MEM moiety takes place with the concomitant O-5 participation of the ethereal phenoxy atom and formation of a 1,3-dioxolane-1-ylium cation (The  p+ values for H, Cl and Br are the following: 0.00, 0.11 and 0.15, which means that Cl and Br are weak electron-withdrawing groups [36]). The intermediates 90-92 may undergo  -bond rotation about the C Ph -O bond, and then its highly electrophilic carbon atom of the methylenedioxy fragment could be attacked by one of the acetalic - OMe groups. This would give rise to the 12-membered transition state 93-95 , which could suffer a reduction of the ring size to the 10membered intermediate 96-98 by means of an intramolecular reaction and the later leaving of the methoxymethanol fragment. An O-5 participation of the oxygen atom at position 1 and the acetalic carbon of 96-98 gives rise to a ring contraction leading to 64-66 through the intermediacy of the seven-membered oxonium ion 99101 . It could be thought that, rather than the formation of 99-101 through the intermediates 87-98 , the synthesis of 64-66 could be considered more directly and simply from the open acetals 78-80 by nucleophilic attack of the phenoxy oxygen to the acetalic functionality, after complexation by BF 3 of one of the acetalic oxygens. Then the intermediate analogous to 99-101 should arise, but in this case substituted on the oxonium oxygen by a 2-methoxyethoxymethyl group. Cleavage of this group should also deliver 64-66 . Nevertheless, the proof of the presence of the by-product 2- (methoxymethoxy)ethanol, formed through 87-98 , and the absence of methoxyethoxymethanol, arising directly from 78-80 , allow us to settle the proposed mechanism. On the other hand, it has been checked that the seven-membered rings 64-66 (major products of O O OMe O OM O OM OMe O O 10 O OM OMe O OMe O 7 O 64,65,66 O O 10 R1 OMe O 67,68,69 O O O e O i) R 1 OMe O Me BF 3 R1 MeOBF 3 O O OMe O OMe OMe OMe 78 R1= H 79 R 1 = Cl 80 R 1 = Br 87 R 1 = H 88 R 1 = Cl 89 R 1 = Br 90 R 1 = H 91 R 1 = Cl 92 R 1 = Br -bond rotation MeOBF3 e Route a) MeOBF3 O O 12 MeOBF3 R 1 R 1 b) a) O Me e 96 R1= H 97 R 1 = Cl 98 R 1 = Br ii) Route b) O 93 R 1 = H 94 R 1 = Cl 95 R 1 = Br OMe 90 R 1 = H 91 R 1 = Cl 92 R 1 = Br + MeOCH2OH + HF + B(OH)3 + MeOH MeO OMe ii) + MeOCH2OCH2CH2OH + HF + B(OH)3 + MeOH 99 R 1 = H 100 R1= Cl 101 R1= Br Fig. (16). Reagents: i) BF3·OEt2, THF; ii) H2O. the rearrangements) do not arise from the ten-membered rings 6769 , upon treatment of the latter with boron trifluoride diethyl etherate under the conditions of the rearrangement. 5.4. Mechanistic Aspects of the Synthesis of (+/-)-3-methoxy-2,3dihydro-5 H -1,4-benzodioxepins 42,43 and (+/-)-3,12-dimethoxy2,3,5,6-tetrahydro-8 H -benzo-[1,4,7]-trioxecin 71 When the starting materials are 85 and 86 , both the nature and the yields of the final compounds, are determining factors to shed light on the two different mechanisms that could explain the course O O 7 O of the cyclization/contraction reaction. The mechanism of the transformation 85 → 42 is best represented as in Fig. ( 17 ). The aromatic -OMe substituent has an influence on the course of the reaction: the phenolic oxygen atom (O-1), whose nucleophilicity may be strongly influenced by the electronic character of the 4-OMe moiety, should intervene as a neighboring group. It has been previously reported a similar feature [20]. According to this hypothesis, the intermediate 102 suffers the neighboring group attack to give the oxyranium ion 103 , which is much more reactive than its predecessor. After a  -bond rotation through the C-O + bond of this highly O OMe OMe i) O OMe OMe O OM O 7 OMe MeO O 42 MeO MeO BF3 e MeO MeOBF 3 OMe O O O O O OMe 85 102 103 OMe MeO 103 Route b) Routes c) and d) MeO OMe MeO O OMe 9 O Route c) OMe O O d) c) 12 O O OMe MeO O MeOBF3 MeOBF3 O 106 OMe 105 104 MeOBF3 Fig. (17). Reagents: i) BF3·OEt2, THF; ii) H2O. + MeOCH2OCH2CH2OH + HF + B(OH)3 + MeOH reactive species, the acetalic-like carbon atom could be attacked by any of the three oxygen atoms of the adjacent lateral chain [routes a), b), or c) and d)]. Through any of the twelveor nine-membered intermediates ( 104 and 105 , respectively), the final destiny is the seven-membered intermediate 106 , which after work-up leads to 42 . The characterization of the by-product methoxymethoxyethanol justifies the proposed mechanism. The most important feature of this mechanism is the electrophilic character of the acetalic carbon atom. Nevertheless, the course of the reaction that leads to 43 and 71 is different (Fig. ( 18 )). In this case, via a different mechanism, closely related to the one shown in Fig. ( 16 ), the acetalic -OMe group acts as a nucleophile and the MEMderived chain as a good electrophile through the 1,3ii) Route d) O 7 O MeOBF3 -bond rotation O OMe a) b) c) and d) O O OMe O Route a) Me dioxolane-1-ylium cation 108 . Again, the proof of the presence of methoxymethoxyethanol and methoxymethanol strongly supports the mechanism. An important question that needs to be answered is the following: Why this different behavior is observed when the aromatic – OMe groups in 85 and in 86 are para and ortho, respectively, in relation to the phenolic oxygen atom that carries the acetaldehyde dimethyl acetal moiety? Although the electronic effects of the – OMe group in both positions are composed of field/inductive and resonance effects, the latter is far more important and, in principle, the mechanisms of the transformations 85 → 42 (Fig. ( 17 )) and 86 → 43 + 71 (Fig. ( 18 )) should have been the same. Should this be the case, the two key intermediates are shown in Fig. ( 19 ), one of OMe OMe O OMe O 10 O OMe 86 OMe OMe OMe O OMe O -bond rotation OMe OMe O MeOBF3 MeOBF3 107 108 108 MeOBF3 111 O OMe 110 ii) 109 O MeOBF3 + MeOCH2OCH2CH2OH + HF + B(OH)3 + MeOH + MeOCH2OH + HF + B(OH)3 + MeOH Fig. (18). Reagents: i) BF3·OEt2, THF; ii) H2O. MeOBF3 '  MeOBF3 OMe OMe O O OMe 103 112 Fig. (19). Two key intermediates: 112 is highly unstable due to the closeness of both positive charges. them ( 112 ) is highly unstable due to the closeness of both positive charges and accordingly very unlikely. In short, when in the doubly protected salicyl alcohol the substituent R 1 , para in relation to the phenolic oxygen atom, is electronically neutral (H), electron-withdrawing (Cl, Br) or electronreleasing groups the phenolic O-linked moiety acts as an electrophile and the alcoholic O-linked fragment acts as a nucleophile OMe OMe O O 10 O 71 O OMe i) Me O O O BF3 OMe O 7 OMe O OMe OMe Me O O 12 O O OMe O O ii) OMe O 7 OMe O 43 O OMe MeO  O O OMe ' O (Figs. ( 16 ) and ( 17 )). Nevertheless, the differences in nucleophilicity and electrophilicity of such groups are so subtle that the presence of an electron-releasing group ortho in relation to the phenolic O-linked fragment can invert the reactivity of both lateral chains: that is to say, the unstability of the intermediate 112 makes the upper O-phenolic fragment to act as electrophile and, accordingly the lower alcoholic O-linked moiety to work as nucleophile (Fig. ( 18 )).