Baeyer-Villiger-Including Domino Two-Step Oxidations of β -O-Substituted Primary Alcohols: Reﬂection of the Migratory Aptitudes of O-Substituted Alkyl Group in the Outcome of the Reaction

: Following the recent development of the one-pot two-step oxidation protocol for primary β -alkoxy alcohols, additional primary β -oxy alcohols were examined under similar conditions. The outcome of these reactions closely follows the migratory aptitudes of the related α -oxy-alkyls in Baeyer-Villiger oxidation vs. that of hydrogen. Thus, these experiments helped to establish the correct order of these aptitudes for α -oxy-alkyls. Furthermore, in the case of primary β , β -dialkoxyalcohols, the formation of dialkoxymethyl formates by the domino oxidation reaction was followed by secondary reactions, forming a number of interesting products.

With this notion in mind, we turned to study the reaction of other types of β-O-substituted primary alcohols under the abovementioned one-pot reaction conditions, aiming both to expand the scope of the reaction and compare the migratory aptitudes of additional oxyalkyl groups in BV oxidation. Herein we describe the results of these studies.

Results and Discussion
Our previous experiments already demonstrated the following order of migratory aptitudes: αacyloxyalkyl < H < α-alkoxyalkyl. The position of α-hydroxyalkyl should be to the right of H in this series, in line with the abovementioned formation of transient gem-diol monoesters from β-hydroxy alcohols. Furthermore, the course of the reaction of 1,4-anhydroerythritol (a secondary alcohol, Scheme 3) hints that the migratory aptitude of α-hydroxyalkyl is stronger than that of α-alkoxyalkyl [32,35].  While attempting to expand the new methodology to additional types of substrates we found that the regioselectivity of the BV step is strongly dependent on the nature of the oxy-substituent on the α-to-carbonyl carbon. Thus, β-acyloxy alcohols yielded carboxylic acids, while γ-alkoxy-β-hydroxyalcohols formed transient gem-diol monoesters, which underwent an additional oxidation step after eliminating formic acid (Scheme 1b,c). Obviously, the course of the domino reaction and, particularly, of the second (Baeyer-Villiger) step reflects the migratory aptitudes of various α-O-substituted alkyl groups. It occurred to us that the reaction enables easy comparison of these aptitudes with that of hydrogen as the reference point [34] (Scheme 2).
Catalysts 2020, 10, x FOR PEER REVIEW 2 of 13 hydroxyalcohols formed transient gem-diol monoesters, which underwent an additional oxidation step after eliminating formic acid (Scheme 1b,c). Obviously, the course of the domino reaction and, particularly, of the second (Baeyer-Villiger) step reflects the migratory aptitudes of various α-Osubstituted alkyl groups. It occurred to us that the reaction enables easy comparison of these aptitudes with that of hydrogen as the reference point [34] (Scheme 2).
With this notion in mind, we turned to study the reaction of other types of β-O-substituted primary alcohols under the abovementioned one-pot reaction conditions, aiming both to expand the scope of the reaction and compare the migratory aptitudes of additional oxyalkyl groups in BV oxidation. Herein we describe the results of these studies.

Results and Discussion
Our previous experiments already demonstrated the following order of migratory aptitudes: αacyloxyalkyl < H < α-alkoxyalkyl. The position of α-hydroxyalkyl should be to the right of H in this series, in line with the abovementioned formation of transient gem-diol monoesters from β-hydroxy alcohols. Furthermore, the course of the reaction of 1,4-anhydroerythritol (a secondary alcohol, Scheme 3) hints that the migratory aptitude of α-hydroxyalkyl is stronger than that of α-alkoxyalkyl [32,35]. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 13 Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 13 Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 13 Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin.  The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin.
Catalysts 2020, 10, x FOR PEER REVIEW 3 of 13 Scheme 3. Preference for the migration of the hydroxy alkyl over alkoxyalkyl in the domino reaction [32].
The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. The position of some other oxyalkyl groups in the series describing their migratory aptitudes remained, however, unclear. Accordingly, we tested a number of additional primary alcohol substrates in the domino oxidation reaction (Table 1). 2-phenoxyethanol (1a), for instance, exhibited slow conversion into both the corresponding hemiacetal formate 2a and the corresponding carboxylic acid 3a [36] (entry 1). In order to achieve full consumption of the starting material, the TEMPO/TBAB loading should be increased to 5 molar %, while that of mCPBA to 6.6 equiv. Under these conditions, a ratio of 1:0.4 between the hemiacetal formate product and the carboxylic acid product is achieved. This ratio, as well as the reaction rate, indicate that though the propensity of phenoxymethyl to migrate during the BV reaction is stronger than that of hydrogen, it is so only by a relatively small margin. Subsequently, we decided to examine primary alcohols substituted at the β-position with a single acetal oxygen (i.e., by alkoxyalkoxy group, entries 2-4). When substrates 1b and 1c were subjected to the reaction conditions [37], the corresponding carboxylic acids 3b and 3c were invariably formed as sole products. In the case of similarly substituted 1d, a mixture of products, with carboxylic acid 3d being the major product, was produced. Four additional minor products are two diastereomeric pairs of hemiacetal esters, formates and m-chlorobenzoates, presumably derived from a single hemiacetal formate product 2d (Scheme 4). The overall ratio between 3d and 2d-derived products was 6.7:1. The results of the experiments with alcohols 1b-d demonstrate that the migratory aptitude of alkyls substituted by a single acetal oxygen is lower than that of hydrogen, but probably higher than that of acyloxyalkyls. Furthermore, the substrates of this kind cannot be successfully converted into hemiacetal esters under our domino reaction conditions. Subsequently, we decided to examine primary alcohols substituted at the β-position with a single acetal oxygen (i.e., by alkoxyalkoxy group, entries 2-4). When substrates 1b and 1c were subjected to the reaction conditions [37], the corresponding carboxylic acids 3b and 3c were invariably formed as sole products. In the case of similarly substituted 1d, a mixture of products, with carboxylic acid 3d being the major product, was produced. Four additional minor products are two diastereomeric pairs of hemiacetal esters, formates and m-chlorobenzoates, presumably derived from a single hemiacetal formate product 2d (Scheme 4). The overall ratio between 3d and 2d-derived products was 6.7:1. The results of the experiments with alcohols 1b-d demonstrate that the migratory aptitude of alkyls substituted by a single acetal oxygen is lower than that of hydrogen, but probably higher than that of acyloxyalkyls. Furthermore, the substrates of this kind cannot be successfully converted into hemiacetal esters under our domino reaction conditions. The next type of substrates we wanted to examine were primary alcohols with an acetal carbon as the β-carbon (i.e., with the β-carbon substituted by two alkoxy groups). Three compounds of this type, 1e-g, were prepared (Scheme 5) and examined under standard domino reaction conditions ( Table 1, Entries 5-7). If such a substrate undergoes the reaction in a mode similar to that of β-alkoxy alcohols, one may expect generation of 2-formyloxy-1,3-dioxolane or -dioxane products 2e-g (Scheme 6). While rare, such dialkoxymethyl carboxylates are not unprecedented [38]. However, such formates are particularly unstable and, accordingly, under the reaction conditions, their subsequent hydrolytic decomposition is possible. Indeed, diol mono-formate esters 4e,f were identified as the major products of the reaction of substrates 1e,f, presumably via 2-step hydrolysis of 2e,f (Scheme 6). In the reaction mixture of 1e, minor products 5e-1 and 5e-2, presumably resulting from interception of one of the hydrolysis intermediates by the substrate or the major product, were observed. In the case of substrate 1g, diol mono-formate 4g constitutes the minor product of the reaction, while the major product was identified as the cyclic carbonate 5g, likely formed by an additional TEMPOcatalyzed oxidation of one of the hydrolytic intermediates (Scheme 6) [39]. These results prove that β,β-dialkoxy alcohols react in the domino oxidation reaction in a way similar to β-alkoxy alcohols, but form unstable products. Furthermore, it demonstrated that the migratory aptitude of the α,αdialkoxymethyl in the BV reaction is higher than that of hydrogen. Finally, these experiments demonstrated selective formation of diol monoesters from diols by their conversion to hydroxyacetaldehyde-derived acetals, followed by the domino oxidation-hydrolysis sequence. The next type of substrates we wanted to examine were primary alcohols with an acetal carbon as the β-carbon (i.e., with the β-carbon substituted by two alkoxy groups). Three compounds of this type, 1e-g, were prepared (Scheme 5) and examined under standard domino reaction conditions ( Table 1, Entries 5-7). If such a substrate undergoes the reaction in a mode similar to that of β-alkoxy alcohols, one may expect generation of 2-formyloxy-1,3-dioxolane or -dioxane products 2e-g (Scheme 6). While rare, such dialkoxymethyl carboxylates are not unprecedented [38]. However, such formates are particularly unstable and, accordingly, under the reaction conditions, their subsequent hydrolytic decomposition is possible. Indeed, diol mono-formate esters 4e,f were identified as the major products of the reaction of substrates 1e,f, presumably via 2-step hydrolysis of 2e,f (Scheme 6). In the reaction mixture of 1e, minor products 5e-1 and 5e-2, presumably resulting from interception of one of the hydrolysis intermediates by the substrate or the major product, were observed. In the case of substrate 1g, diol mono-formate 4g constitutes the minor product of the reaction, while the major product was identified as the cyclic carbonate 5g, likely formed by an additional TEMPO-catalyzed oxidation of one of the hydrolytic intermediates (Scheme 6) [39]. These results prove that β,β-dialkoxy alcohols react in the domino oxidation reaction in a way similar to β-alkoxy alcohols, but form unstable products. Furthermore, it demonstrated that the migratory aptitude of the α,α-dialkoxymethyl in the BV reaction is higher than that of hydrogen. Finally, these experiments demonstrated selective formation of diol monoesters from diols by their conversion to hydroxyacetaldehyde-derived acetals, followed by the domino oxidation-hydrolysis sequence.
In order to compare the aptitudes of α,α-dialkoxyalkyl and α-alkoxyalkyl, we examined the reaction of a secondary alcohol 1h with both groups flanking the hydroxyl-bearing carbon ( Table 1, Entry 8). In this experiment the formation of product 2h, generated by oxidation of the secondary alcohol followed by the oxygen insertion between the formed carbonyl and the alkoxy-substituted neighboring carbon, indicates that the migratory tendency of α-alkoxyalkyl is stronger (in the BV reaction). In order to compare the aptitudes of α,α-dialkoxyalkyl and α-alkoxyalkyl, we examined the reaction of a secondary alcohol 1h with both groups flanking the hydroxyl-bearing carbon ( Table 1, Entry 8). In this experiment the formation of product 2h, generated by oxidation of the secondary alcohol followed by the oxygen insertion between the formed carbonyl and the alkoxy-substituted neighboring carbon, indicates that the migratory tendency of α-alkoxyalkyl is stronger (in the BV reaction).
Another aspect that was examined during our experiments is the influence of the solvent on the domino reaction course. We focused our attention on two substrates, which in DCM gave both the hemiacetal formate and the carboxylic acid products, namely Bz(OCH2CH2)2OH (1i) that was reported in our previous communication and 1d (Table 2). Three solvents, apolar benzene, moderately polar ethyl acetate and polar acetonitrile, were compared to the originally used DCM. In both cases the best solvent for the formation of hemiacetal esters was benzene, while acetonitrile, the most polar of the three solvents, most favored the formation of carboxylic acid. Lower conversions observed in ethyl acetate are attributed to the absence of TBAB in these experiments due to its insolubility in this solvent. In the past, similar solvent dependence was observed in oxidation of aldehyde by dioxygen or peracids, with the increase in acid formation attributed to the disruption of the transition state, preferentially leading to acetal formates, by polar solvents [40]. Interestingly, the opposite trend was observed in aqueous organic solvents in the related Dakin reaction [41].  In order to compare the aptitudes of α,α-dialkoxyalkyl and α-alkoxyalkyl, we examined the reaction of a secondary alcohol 1h with both groups flanking the hydroxyl-bearing carbon ( Table 1, Entry 8). In this experiment the formation of product 2h, generated by oxidation of the secondary alcohol followed by the oxygen insertion between the formed carbonyl and the alkoxy-substituted neighboring carbon, indicates that the migratory tendency of α-alkoxyalkyl is stronger (in the BV reaction).
Another aspect that was examined during our experiments is the influence of the solvent on the domino reaction course. We focused our attention on two substrates, which in DCM gave both the hemiacetal formate and the carboxylic acid products, namely Bz(OCH2CH2)2OH (1i) that was reported in our previous communication and 1d (Table 2). Three solvents, apolar benzene, moderately polar ethyl acetate and polar acetonitrile, were compared to the originally used DCM. In both cases the best solvent for the formation of hemiacetal esters was benzene, while acetonitrile, the most polar of the three solvents, most favored the formation of carboxylic acid. Lower conversions observed in ethyl acetate are attributed to the absence of TBAB in these experiments due to its insolubility in this solvent. In the past, similar solvent dependence was observed in oxidation of aldehyde by dioxygen or peracids, with the increase in acid formation attributed to the disruption of the transition state, preferentially leading to acetal formates, by polar solvents [40]. Interestingly, the opposite trend was observed in aqueous organic solvents in the related Dakin reaction [41]. Another aspect that was examined during our experiments is the influence of the solvent on the domino reaction course. We focused our attention on two substrates, which in DCM gave both the hemiacetal formate and the carboxylic acid products, namely Bz(OCH 2 CH 2 ) 2 OH (1i) that was reported in our previous communication and 1d (Table 2). Three solvents, apolar benzene, moderately polar ethyl acetate and polar acetonitrile, were compared to the originally used DCM. In both cases the best solvent for the formation of hemiacetal esters was benzene, while acetonitrile, the most polar of the three solvents, most favored the formation of carboxylic acid. Lower conversions observed in ethyl acetate are attributed to the absence of TBAB in these experiments due to its insolubility in this solvent. In the past, similar solvent dependence was observed in oxidation of aldehyde by dioxygen or peracids, with the increase in acid formation attributed to the disruption of the transition state, preferentially leading to acetal formates, by polar solvents [40]. Interestingly, the opposite trend was observed in aqueous organic solvents in the related Dakin reaction [41].

Materials and Techniques
All reactions, requiring anhydrous conditions, were conducted under an atmosphere of nitrogen in oven-dried glassware in dry solvents. Commercially available materials were purchased at the highest available purity and were used as received. Thin layer chromatography (TLC) was performed on silica gel plates Merck 60 F 254 , and the compounds were visualized by irradiation with UV light or by staining with KMnO 4 . Flash column chromatography was carried out using silica gel Merck 60 (particle size 0.040-0.063 mm); the eluent is given in parentheses. 1  A solution of (S)-1,2,4-butanetriol (531 mg, 5.0 mmol, 1.0 equiv), benzaldehyde dimethyl acetal (841 mg, 5.5 mmol, 1.1 equiv) and camphorsulfonic acid (59 mg, 0.25 mmol, 5 mol%) in CH 2 Cl 2 (21 mL) was stirred at room temperature for 20 h. Imidazole was added in one portion (34 mg, 0.5 mmol, 0.1 equiv) and the resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1:3 to 3:1 EtOAc/hexane) to yield the product as a colorless oil (399 mg, 41%) [42].
TLC: R f = 0.3 (1:9 EtOAc/hexane eluent). 1  (5,5-dimethyl-1,3-dioxan-2-yl)methanol (1e) [43]: 2-((benzyloxy)methyl)-5,5-dimethyl-1,3-dioxane (800 mg, 3.38 mmol) was dissolved in methanol (5 mL) in a round-bottom flask equipped with a magnetic stir bar. A small spoonful of 5% Pd/C was added, and a hydrogen-filled balloon was attached to the flask via a suitable adapter. After flushing the flask with hydrogen a few times, the mixture was allowed to stir overnight at room temperature. The mixture was then filtered through celite and the resulting clear solution was concentrated under reduced pressure to give the desired product (470 mg, 3.21 mmol, 95% yield) as a colorless oil, which was used without further purification. 1 5.04 mmol, 2 equiv) and OsO 4 (4% w/w in water, 0.12 mL, 0.02 mmol, 0.8 mol %) were dissolved in a mixture of 3.5 mL acetone, 3.5 mL of water and 0.35 mL of t BuOH in a vial charged with a magnetic stir bar. The mixture was allowed to stir and was monitored by TLC every half an hour until no more starting material was observed, after an hour and a half. The solvent mixture was removed under reduced pressure, and the crude was purified by column chromatography (silica gel, 1:3 EtOAc/hexane to EtOAc) to give the desired product (253 mg, 1.53 mmol, 61% yield) as a colorless liquid.
TLC: R f = 0. 35  (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)methanol (1g): The abovementioned protected alcohol (870 mg, 3.48 mmol, 1 equiv) was dissolved in methanol. A spoon of activated 10% Pd/C was added to a vial charged with a magnetic stir bar, a hydrogen balloon was attached and the mixture was allowed to stir for 24 h at room temperature. The resulting solution was filtered through celite and concentrated under reduced pressure to give 1g (260 mg, 1.62 mmol, 47% yield) as a yellow oil, which was used in the next step without further purification. 1 H-NMR (400 MHz, CDCl 3 ): δ 5.09 (t, J = 3.9 Hz, 1H), 3.60 (dd, J = 6.5, 3.9 Hz, 2H), The substrate (1.0 equiv, 0.1 mmol) was placed in a small vial charged with a magnetic stir bar, and the solutions of TEMPO (0.1 M, 20-50 µL, 2-5 molar %) and TBAB (0.1 M, 20-50 µL, 2-5 molar %) were added by syringe at room temperature. mCPBA (2.2-6.6 equiv.) solution in 0.70-0.76 mL DCM was added, resulting in a total volume of 0.80 mL DCM, and the reaction was allowed to stir for 1 to 17 h, depending on the substrate. In some cases, the solvent was removed under reduced pressure, and the crude reaction mixture was analyzed by NMR spectroscopy in DMSO-d6. In other cases, aqueous saturated NaHCO 3 solution (5.0 mL) was added, the mixture was stirred for 5 min, the organic phase was separated, and the aqueous phase was extracted with DCM (4 × 2.5 mL). Subsequently, the combined organic phase was washed with brine (5 mL), dried over Na 2 SO 4 , filtered, concentrated in vacuo, and the crude was analyzed by NMR spectroscopy.

Conclusions
In conclusion, we examined a number of additional classes of β-oxy-substituted primary alcohols in the domino two-step oxidation reaction that we disclosed recently. Furthermore, in a number of cases, formation of useful end-products was observed. Finally, the experiments helped to establish the order of migratory aptitudes of α-oxy-substituted alkyls in the BV reaction and compared them to that of hydrogen (α-hydroxyalkyl > α-alkoxyalkyl > α,α-dialkoxyalkyl > α-aryloxyalkyl > hydrogen > α-alkoxyalkoxyalkyl > α-acyloxyalkyl).
Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/10/11/1275/s1, 1 H-and 13 C-NMR spectra of the synthesized substrates and identified products, as well as indicative MS spectra of some of the compounds.