Coupling Reactions of Anhydro-Aldose Tosylhydrazones with Boronic Acids

A catalyst-free coupling reaction between O-peracetylated, O-perbenzoylated, O-permethylated, and O-permethoxymethylated 2,6-anhydro-aldose tosylhydrazones (C-(β-d-glycopyranosyl)formaldehyde tosylhydrazones) and aromatic boronic acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope. The main products in most of the transformations were open-chain 1-C-aryl-hept-1-enitol type compounds while the expected β-d-glycopyranosylmethyl arenes (benzyl C-glycosides) were formed in subordinate yields only. A mechanistic rationale is provided to explain how a complex substrate may change the well-established course of the reaction.


Introduction
N-Tosylhydrazones have extensively been used in organic synthesis for more than half a century. In the past decade N-tosylhydrazones were generally applied in a variety of carbon-carbon and carbon-heteroatom bond forming reactions [1][2][3][4][5][6]. These transition metal catalyzed or catalyst-free cross-coupling reactions proceed through the in situ generated diazo compounds, followed by the formation of metal-carbene or carbene intermediates, which lead to the corresponding coupled products. Carbohydrate tosylhydrazones are also known, but their application in coupling reactions is poorly investigated.
In our research group an easy, one-step method was worked out for the synthesis of anhydro-aldose tosylhydrazones from readily accessible glycosyl cyanides [7][8][9]. We began a systematic study aimed at the investigation of the applicability of anhydro-aldosetosylhydrazones 1 [7][8][9] in coupling reactions. In this project C-O [10], C-S [11], and C-N [12] bonds were successfully formed under metal-free conditions, while C-C bonds [13,14] were obtained in Pd-catalyzed reactions (Scheme 1).
The metal-free reaction between the diazo precursor N-tosylhydrazones and alkyl, alkenyl, and arylboronic acids has been established in recent years as a powerful C(sp 3 )-C bond-forming transformation (Scheme 2a) that avoids the application of precious metal catalysts and highly air/moisture-sensitive or expensive coupling partners [15,16]. However, this reaction was primarily limited to benzylic, α-heterocyclic, and/or aldehyde-derived tosylhydrazones at the substrate level, with lower yields observed for substrates that differed from these [15,[17][18][19][20]. Dai and coworkers expanded this reductive coupling to acylferrocene tosylhydrazones, producing highly substituted α-arylalkylferrocenes [21]. N-Tosylhydrazones derived from 2-, 3-, and 4-substituted cyclohexanones and 4-substituted cyclopentanone were also used in couplings with alkenyl boronic acids [22]. The reductive coupling of N-tosylhydrazones under the standard reaction conditions was also examined with diarylborinic acids (Ar 2 B(OH)) to give diarylmethanes with good yields [23]. Kirschning developed a flow protocol for the reductive coupling reaction of N-tosylhydrazones Scheme 1. Synthetic applications of anhydro-aldose tosylhydrazones in coupling reactions.
The metal-free reaction between the diazo precursor N-tosylhydrazones and alkyl, alkenyl, and arylboronic acids has been established in recent years as a powerful C(sp 3 )-C bond-forming transformation (Scheme 2a) that avoids the application of precious metal catalysts and highly air/moisture-sensitive or expensive coupling partners [15,16]. However, this reaction was primarily limited to benzylic, α-heterocyclic, and/or aldehyde-derived tosylhydrazones at the substrate level, with lower yields observed for substrates that differed from these [15,[17][18][19][20]. Dai and coworkers expanded this reductive coupling to acylferrocene tosylhydrazones, producing highly substituted α-arylalkylferrocenes [21]. N-Tosylhydrazones derived from 2-, 3-, and 4-substituted cyclohexanones and 4-substituted cyclopentanone were also used in couplings with alkenyl boronic acids [22]. The reductive coupling of N-tosylhydrazones under the standard reaction conditions was also examined with diarylborinic acids (Ar2B(OH)) to give diarylmethanes with good yields [23]. Kirschning developed a flow protocol for the reductive coupling reaction of N-tosylhydrazones with aryl boronic acids. To increase the practical applicability of the reaction, a two-step continuous flow protocol, starting with carbonyl compounds and tosylhydrazide, was also developed [24]. Nakagawa and coworkers expanded the scope of the transformation to a set of challenging heterocycle-containing aldehyde tosylhydrazones, such as those of protected azetidine, imidazole, and azaindole derivatives. These cou-Scheme 1. Synthetic applications of anhydro-aldose tosylhydrazones in coupling reactions.
As the tosylhydrazone-boronic acid coupling can be of a great potential to avoid the utility of costly and poisonous metals and ligands, metal-free coupling reactions of boronic acids with anhydro-aldose tosylhydrazones were examined as a new type of substrate with higher complexity in comparison to the previous ones (Scheme 2e). This transformation offers a simple possibility for the formation of C-glycosylmethyl derivatives whose preparation is rather cumbersome in the literature [13,[35][36][37][38][39][40][41][42][43]. Herein we disclose our experiences with this reaction using various sugar configurations, protecting groups and boronic acids. As the tosylhydrazone-boronic acid coupling can be of a great potential to avoid the utility of costly and poisonous metals and ligands, metal-free coupling reactions of boronic acids with anhydro-aldose tosylhydrazones were examined as a new type of substrate with higher complexity in comparison to the previous ones (Scheme 2e). This transformation offers a simple possibility for the formation of C-glycosylmethyl derivatives whose preparation is rather cumbersome in the literature [13,[35][36][37][38][39][40][41][42][43]. Herein we disclose our experiences with this reaction using various sugar configurations, protecting groups and boronic acids.

Results and Discussion
We started our study with the reaction between O-perbenzoylated C-(β-D-glucopyranosyl)formaldehyde tosylhydrazone 1a [7][8][9] and phenylboronic acid (Table 1). First, the literature conditions [15] were applied using 1.5 equivalents of boronic acid and 1.5 equivalents of K2CO3 as the base in dry dioxane at reflux temperature (entry 1). The transformation resulted in a complex mixture, containing heptenitols 3a and 4a and exo-glucal 5 [8,44,45] but we did not observe the formation of the expected C-glucoside 2a [13]. However, it can be assumed that the formation of the open chain compounds might occur by a base mediated ring-opening process, whose driving force could be the resonance stabilization of styrene 3a. Similar heptenitols were obtained by the Wittig reaction [46,47].

Scheme 2.
Selected examples of N-tosylhydrazone-boronic acid coupling (a-d) and the reaction studied in this work (e).

Results and Discussion
We started our study with the reaction between O-perbenzoylated C-(β-D-glucopyran osyl)formaldehyde tosylhydrazone 1a [7][8][9] and phenylboronic acid (Table 1). First, the literature conditions [15] were applied using 1.5 equivalents of boronic acid and 1.5 equivalents of K 2 CO 3 as the base in dry dioxane at reflux temperature (entry 1). The transformation resulted in a complex mixture, containing heptenitols 3a and 4a and exo-glucal 5 [8,44,45] but we did not observe the formation of the expected C-glucoside 2a [13]. However, it can be assumed that the formation of the open chain compounds might occur by a base mediated ring-opening process, whose driving force could be the resonance stabilization of styrene 3a. Similar heptenitols were obtained by the Wittig reaction [46,47]. Migration of a benzoyl protecting group could result in 4a, and intramolecular carbene insertion into the C-2-H bond yielded exo-glucal 5 [8,44,45]. With other bases (Bu 4 NF, LiOtBu, and K 3 PO 4 ) the formation of the coupled product 2a could also not be observed (entries [2][3][4]. Instead, we obtained variable amounts of the heptenitols 3a and 4a, and exo-glucal 5. Increasing the amount of K 3 PO 4 raised the yield of heptenitol 3a to 43% (entry 5). The effects of solvents other than dioxane were also studied, but in each case, complex reaction mixtures were obtained (entries [6][7][8]. On the other hand, performing the reaction in the presence of five equivalents of phenylboronic acid with three or four equivalents of K 3 PO 4 gave the C-glucoside 2a in a very low yield beside 3a, while 4a and 5 were also isolated (entries 9 and 10). Raising the base excess gave exo-glucal 5 in moderate yield and heptenitols 3a and 4a in traces (entry 11). The best result was achieved with 20-fold excess of phenylboronic acid and 10-fold excess of K 3 PO 4 , to give heptenitol 3a in 70% yield (entry 12). Thus, instead of the expected C-glycosylmethylarene derivative 2a, an open chain compound, 3a, proved to be the main product of the transformation. Table 1. Optimization of the coupling reaction of 1 with phenylboronic acid.
Migration of a benzoyl protecting group could result in 4a, and intramolecular carbene insertion into the C-2-H bond yielded exo-glucal 5 [8,44,45]. With other bases (Bu4NF, Li-OtBu, and K3PO4) the formation of the coupled product 2a could also not be observed (entries [2][3][4]. Instead, we obtained variable amounts of the heptenitols 3a and 4a, and exoglucal 5. Increasing the amount of K3PO4 raised the yield of heptenitol 3a to 43% (entry 5). The effects of solvents other than dioxane were also studied, but in each case, complex reaction mixtures were obtained (entries [6][7][8]. On the other hand, performing the reaction in the presence of five equivalents of phenylboronic acid with three or four equivalents of K3PO4 gave the C-glucoside 2a in a very low yield beside 3a, while 4a and 5 were also isolated (entries 9 and 10). Raising the base excess gave exo-glucal 5 in moderate yield and heptenitols 3a and 4a in traces (entry 11). The best result was achieved with 20-fold excess of phenylboronic acid and 10-fold excess of K3PO4, to give heptenitol 3a in 70% yield (entry 12). Thus, instead of the expected C-glycosylmethylarene derivative 2a, an open chain compound, 3a, proved to be the main product of the transformation. To avoid base mediated side reactions, such as the acyl migration, C-(β-D-glucopyranosyl)formaldehyde tosylhydrazone Li-salt 1b [10,12]  To avoid base mediated side reactions, such as the acyl migration, C-(β-D-glucopyra nosyl)formaldehyde tosylhydrazone Li-salt 1b [10,12] was used for the couplings, where no added base is needed. Attempted reactions under UV irradiation (λ = 254 nm and 368 nm) carried out in a quartz tube proved to be totally ineffective, resulting in complex reaction mixtures. However, thermic conditions gave, generally, 3a as the main product, besides C-glucoside 2a and exo-glucal 5 (entries 13 and 14). Although the application of 10 equivalents of boronic acid significantly increased the yields (entry 15), the Li-salt reactions appeared less effective. Thus, tosylhydrazone 1a and 1.5 or 20-fold excess of a boronic acid and 3 or 10-fold excesses of K 3 PO 4 were used in further transformations.
The coupling reaction of 1a was also examined with a variety of aryl boronic acids under the conditions selected above. These reactions resulted in varying yields of compound types 2-5, among which the heptenitols 3 and 4 were the main products (Table 2). Application of higher excess of boronic acids and K 3 PO 4 improved the yields in couplings with 4-(dibenzofuranyl) and 4-methoxyphenyl boronic acids (compare entries 3-4 and 6-7), but in other cases, this had no significant effect on the reaction outcome (compare entries 1-2, 10-11 and 12-13). The coupling was found to be significantly affected by the substituents on the aromatic ring; boronic acids with electron-releasing (entries 1-7) and chloro (entries 8 and 9)-substituents gave better yields. However, with the strong electron-withdrawing nitro group (entries 10-13) exo-glucal 5 was the main product, the coupled compound 2h was observed in only one case. Isolation of the products in pure state often encountered difficulties. Due to very similar mobilities in silica gel column chromatography, C-glucosyl compounds 2 were polluted with the exo-glucal 5, and heptenitols 3 and 4 polluted each other, therefore the yields were generally calculated on the basis of the 1 H NMR spectra (Supplementary Materials). nm) carried out in a quartz tube proved to be totally ineffective, resulting in complex reaction mixtures. However, thermic conditions gave, generally, 3a as the main product, besides C-glucoside 2a and exo-glucal 5 (entries 13 and 14). Although the application of 10 equivalents of boronic acid significantly increased the yields (entry 15), the Li-salt reactions appeared less effective. Thus, tosylhydrazone 1a and 1.5 or 20-fold excess of a boronic acid and 3 or 10-fold excesses of K3PO4 were used in further transformations. The coupling reaction of 1a was also examined with a variety of aryl boronic acids under the conditions selected above. These reactions resulted in varying yields of compound types 2-5, among which the heptenitols 3 and 4 were the main products ( Table 2). Application of higher excess of boronic acids and K3PO4 improved the yields in couplings with 4-(dibenzofuranyl) and 4-methoxyphenyl boronic acids (compare entries 3-4 and 6-7), but in other cases, this had no significant effect on the reaction outcome (compare entries 1-2, 10-11 and 12-13). The coupling was found to be significantly affected by the substituents on the aromatic ring; boronic acids with electron-releasing (entries 1-7) and chloro (entries 8 and 9)-substituents gave better yields. However, with the strong electronwithdrawing nitro group (entries 10-13) exo-glucal 5 was the main product, the coupled compound 2h was observed in only one case. Isolation of the products in pure state often encountered difficulties. Due to very similar mobilities in silica gel column chromatography, C-glucosyl compounds 2 were polluted with the exo-glucal 5, and heptenitols 3 and 4 polluted each other, therefore the yields were generally calculated on the basis of the 1 H NMR spectra (Supplementary Materials).  The coupling of O-peracetylated C-(β-D-galactopyranosyl)formaldehyde tosylhydrazone (6, Table 3) with phenylboronic acid was also investigated. With 1.5 equivalents of phenylboronic acid and 3 equivalents of potassium carbonate, only traces of the known compound types 7, 8, and 10 [8,46,47] were detected in the complex product mixture (entry 1), but with a 20-fold excess of the boronic acid C-(galactosyl)phenylmethane 7 was formed in low yield and heptenitols 8 and 9 proved to be the main products (entry 2). A compound with a free 6-OH (analogue of 3), though might be formed, could not be detected possibly due to a faster acetyl migration to give 8 and 9. The NMR analysis provided evidence for the structure of all of the above derivatives and these are illustrated here by the examples of compounds 2, 3, and 4. Anhydro-heptitol 2a, synthesized in our group earlier [13], showed characteristic 1 H NMR resonances for the C-1 methylene (δ 2.96 ppm (H-1a), 2.92 ppm (H-1b), with a great geminal coupling constant (12.3 Hz) between them) and the H-2 ('anomeric') protons (4.00 ppm). The characteristic 13  showed quite different spectral data. Signals characteristic for C-1 and C-2 of compounds 2 in the above ranges were missing in the 13 C NMR spectra of 3 and 4, instead resonances for -CH= type carbons in the ranges 130.8-136.9 ppm (for C-1) and 119.6-125.9 ppm (for C-2) appeared to prove the presence of a double bond in the molecules. The acyclic form was evidenced by the small vicinal coupling constants (in the range of 0.8-8.9 Hz). The great values (14.9-16.3 Hz) of coupling constant 3 J1,2 proved the E-configured double bond C-1=C-2 in these structures. The position of the free OH groups of heptenitols 3 and 4 were confirmed by observing cross peaks between OH and H-6 in heptenitols 3 and OH and H-5 in molecules 4 in their 1 H-1 H COSY spectra.
To further prove the formation of heptenitols and acyl group migration, benzoylation/acetylation of the corresponding compounds under standard conditions were carried out. Benzoylation [47] of the mixture of heptenitols 3 and 4 resulted in a single product 11 (Table 4) while acetylation [48] of heptenitol 9 gave O-peracetylated product 12 in good to excellent yields (Scheme 3).

Entry
Reaction The NMR analysis provided evidence for the structure of all of the above derivatives and these are illustrated here by the examples of compounds 2, 3, and 4. Anhydro-heptitol 2a, synthesized in our group earlier [13], showed characteristic 1 H NMR resonances for the C-1 methylene (δ 2.96 ppm (H-1 a ), 2.92 ppm (H-1 b ), with a great geminal coupling constant (12.3 Hz) between them) and the H-2 ('anomeric') protons (4.00 ppm). The characteristic 13  Ring-opened heptenitols 3 and 4 showed quite different spectral data. Signals characteristic for C-1 and C-2 of compounds 2 in the above ranges were missing in the 13 C NMR spectra of 3 and 4, instead resonances for -CH= type carbons in the ranges 130.8-136.9 ppm (for C-1) and 119.6-125.9 ppm (for C-2) appeared to prove the presence of a double bond in the molecules. The acyclic form was evidenced by the small vicinal coupling constants (in the range of 0.8-8.9 Hz). The great values (14.9-16.3 Hz) of coupling constant 3 J 1,2 proved the E-configured double bond C-1=C-2 in these structures. The position of the free OH groups of heptenitols 3 and 4 were confirmed by observing cross peaks between OH and H-6 in heptenitols 3 and OH and H-5 in molecules 4 in their 1 H-1 H COSY spectra.
To further prove the formation of heptenitols and acyl group migration, benzoylation/acetylation of the corresponding compounds under standard conditions were carried out. Benzoylation [47] of the mixture of heptenitols 3 and 4 resulted in a single product 11 (Table 4) while acetylation [48] of heptenitol 9 gave O-peracetylated product 12 in good to excellent yields (Scheme 3).  To get an insight into the effect of hydrolytically resistant ether type protecting groups on the outcome of the studied coupling reactions, O-permethylated (β-D-glucopyranosyl)formaldehyde tosylhydrazone 17 was synthesized. Methyl glucoside 13 was Opermethyled to get 14 [49] which was converted to the acetate derivative 15 [50] (Scheme 4). On reacting 15 with trimethylsilyl cyanide in the presence of boron trifluoride etherate, cyanide 16 [51] was obtained. The anomers were separated by column chromatography.   To get an insight into the effect of hydrolytically resistant ether type protecting groups on the outcome of the studied coupling reactions, O-permethylated (β-D-glucopyranosyl)formaldehyde tosylhydrazone 17 was synthesized. Methyl glucoside 13 was Opermethyled to get 14 [49] which was converted to the acetate derivative 15 [50] (Scheme 4). On reacting 15 with trimethylsilyl cyanide in the presence of boron trifluoride etherate, cyanide 16 [51] was obtained. The anomers were separated by column chromatography. Then, β-cyanide 16β was reduced in the presence of tosylhydrazide to give β-D-glucosyl tosylhydrazone 17 as a mixture of E and Z isomers. Couplings with 17 gave cleaner product mixtures in better yields, and resulted in Cglucosides 18 (Table 5, entries 2, 4, and 8) or open-chain heptenitols 19 and 20 as the main products (entries 1,5,6,7,9,10). Exo-glucal 21 [52] was always formed as a by-product. To get an insight into the effect of hydrolytically resistant ether type protecting groups on the outcome of the studied coupling reactions, O-permethylated (β-D-glucopyranosyl)for maldehyde tosylhydrazone 17 was synthesized. Methyl glucoside 13 was O-permethyled to get 14 [49] which was converted to the acetate derivative 15 [50] (Scheme 4). On reacting 15 with trimethylsilyl cyanide in the presence of boron trifluoride etherate, cyanide 16 [51] was obtained. The anomers were separated by column chromatography. Then, β-cyanide 16β was reduced in the presence of tosylhydrazide to give β-D-glucosyl tosylhydrazone 17 as a mixture of E and Z isomers. To get an insight into the effect of hydrolytically resistant ether type protecting groups on the outcome of the studied coupling reactions, O-permethylated (β-D-glucopyranosyl)formaldehyde tosylhydrazone 17 was synthesized. Methyl glucoside 13 was Opermethyled to get 14 [49] which was converted to the acetate derivative 15 [50] (Scheme 4). On reacting 15 with trimethylsilyl cyanide in the presence of boron trifluoride etherate, cyanide 16 [51] was obtained. The anomers were separated by column chromatography. Then, β-cyanide 16β was reduced in the presence of tosylhydrazide to give β-D-glucosyl tosylhydrazone 17 as a mixture of E and Z isomers. Couplings with 17 gave cleaner product mixtures in better yields, and resulted in Cglucosides 18 (Table 5, entries 2, 4, and 8) or open-chain heptenitols 19 and 20 as the main products (entries 1,5,6,7,9,10). Exo-glucal 21 [52] was always formed as a by-product.  Couplings with 17 gave cleaner product mixtures in better yields, and resulted in C-glucosides 18 (Table 5, entries 2, 4, and 8) or open-chain heptenitols 19 and 20 as the main products (entries 1,5,6,7,9,10). Exo-glucal 21 [52] was always formed as a by-product. Compounds 18 and 21 proved inseparable, similar to open chain isomers 19 and 20.
The transformation was extended to the acetal protected galactose derivative 24, which was synthesized from the galactosyl cyanide 22 in two steps. Compound 22 was reacted with methoxymethyl chloride to obtain cyanide 23 [53], then a reduction step in the presence of tosylhydrazide gave a mixture of E and Z isomers of 24 (Scheme 5).  The transformation was extended to the acetal protected galactose derivative 24, which was synthesized from the galactosyl cyanide 22 in two steps. Compound 22 was reacted with methoxymethyl chloride to obtain cyanide 23 [53], then a reduction step in the presence of tosylhydrazide gave a mixture of E and Z isomers of 24 (Scheme 5). The coupling reation of 24 with phenylboronic acid resulted in E heptenitol 26 as the main product and an inseparable mixture of C-(galactopyranosyl)phenylmethane 25 and exo-galactal 28 [53]. The Z isomer 27 was also detected in the mixture (Scheme 6).   The transformation was extended to the acetal protected galactose derivative 24, which was synthesized from the galactosyl cyanide 22 in two steps. Compound 22 was reacted with methoxymethyl chloride to obtain cyanide 23 [53], then a reduction step in the presence of tosylhydrazide gave a mixture of E and Z isomers of 24 (Scheme 5).
The coupling reation of 24 with phenylboronic acid resulted in E heptenitol 26 as the main product and an inseparable mixture of C-(galactopyranosyl)phenylmethane 25 and exo-galactal 28 [53]. The Z isomer 27 was also detected in the mixture (Scheme 6).  were confirmed by observing cross peaks between OH and H-6 in their 1 H-1 H COSY spectra.
To obtain more information about the formation of the open-chain heptenitols, first we checked the possibility of the ring opening of the anhydro-heptitols under the reaction conditions. Thus, 2a was reacted with K3PO4 but partial deprotection of 2a was observed only, without the formation of 3a (Table 6, entry 1). The methyl protected derivatives 18c or 18g reacted neither in the presence of K3PO4, nor of a boronic acid or both (entries 2-4). Next, formation of C-(glycosyl)arylmethane derivatives 18c,d,e was examined from the corresponding heptenitols 19c,d,e and 20c,d,e. Attempted reactions in the presence of base and/or boronic acid resulted in no conversion (Table 7). we checked the possibility of the ring opening of the anhydro-heptitols under the reaction conditions. Thus, 2a was reacted with K3PO4 but partial deprotection of 2a was observed only, without the formation of 3a (Table 6, entry 1). The methyl protected derivatives 18c or 18g reacted neither in the presence of K3PO4, nor of a boronic acid or both (entries 2-4). Next, formation of C-(glycosyl)arylmethane derivatives 18c,d,e was examined from the corresponding heptenitols 19c,d,e and 20c,d,e. Attempted reactions in the presence of base and/or boronic acid resulted in no conversion (Table 7). To obtain more information about the formation of the open-chain heptenitols, first we checked the possibility of the ring opening of the anhydro-heptitols under the reaction conditions. Thus, 2a was reacted with K 3 PO 4 but partial deprotection of 2a was observed only, without the formation of 3a (Table 6, entry 1). The methyl protected derivatives 18c or 18g reacted neither in the presence of K 3 PO 4 , nor of a boronic acid or both (entries 2-4).
Next, formation of C-(glycosyl)arylmethane derivatives 18c,d,e was examined from the corresponding heptenitols 19c,d,e and 20c,d,e. Attempted reactions in the presence of base and/or boronic acid resulted in no conversion (Table 7).
Based on these observations, it can be concluded that the cyclic C-glycosylmethyl derivatives and the open-chain heptenitols are not interconvertible under the applied conditions, they must be formed from the same intermediate during the reaction.
To explain these experiences, the following mechanistic possibilities can be considered (Scheme 7). Loss of a sulfinate ion from tosylhydrazones I upon deprotonation or from Li-salt V may lead to the diazo intermediate VI which can give rise to carbene VII by eliminating a nitrogen molecule. The zwitterionic intermediate VIII, which arises from carbene VII (path a) or boronate complex X, formed from the diazo compound VI (path b), may lead to intermediate IX. Then, protodeboronation of IX under basic conditions can give anhydro-heptitol type products III (path c). Nevertheless, in intermediate IX, the ring oxygen, as a Lewis base, can attack the electron deficient boron atom to form the open chain heptenitol borate XI (path e) which, upon hydrolysis, can lead to the isolated heptenitols IV. The driving force of this rearrangement may be the conjugation of the double bond with the aromatic system, leading to an energetically more stable species. The standard by-product exo-glycal II can be formed by an intramolecular insertion reaction of carbene VII (path d).
ditions, they must be formed from the same intermediate during the reaction.
To explain these experiences, the following mechanistic possibilities can be considered (Scheme 7). Loss of a sulfinate ion from tosylhydrazones I upon deprotonation or from Li-salt V may lead to the diazo intermediate VI which can give rise to carbene VII by eliminating a nitrogen molecule. The zwitterionic intermediate VIII, which arises from carbene VII (path a) or boronate complex X, formed from the diazo compound VI (path b), may lead to intermediate IX. Then, protodeboronation of IX under basic conditions can give anhydro-heptitol type products III (path c). Nevertheless, in intermediate IX, the ring oxygen, as a Lewis base, can attack the electron deficient boron atom to form the open chain heptenitol borate XI (path e) which, upon hydrolysis, can lead to the isolated heptenitols IV. The driving force of this rearrangement may be the conjugation of the double bond with the aromatic system, leading to an energetically more stable species. The standard by-product exo-glycal II can be formed by an intramolecular insertion reaction of carbene VII (path d).

Conclusions
This study on the metal-free coupling reactions of C-(β-D-glycopyranosyl)formaldehyde (2,6-anhydro-aldose) tosylhydrazones with aromatic boronic acids revealed that the main reaction pathway was the formation of ring-opened hept-1-enitol derivatives, while the expected C-glycopyranosyl compounds (benzyl C-glycosides) were formed only in low to moderate yields. The corresponding exo-glycals always appeared as unavoidable by-products. O-Acyl protecting groups on the carbohydrate moieties underwent migrations which further increased the number of products in the otherwise rather complex reaction mixtures. Tosylhydrazones with ether type O-protections gave cleaner reactions but resulted in the same product types in similar ratios. The suggested mechanistic rationale explained how the complex sugar-derived tosylhydrazone substrates changed the

Conclusions
This study on the metal-free coupling reactions of C-(β-D-glycopyranosyl)formaldehyde (2,6-anhydro-aldose) tosylhydrazones with aromatic boronic acids revealed that the main reaction pathway was the formation of ring-opened hept-1-enitol derivatives, while the expected C-glycopyranosyl compounds (benzyl C-glycosides) were formed only in low to moderate yields. The corresponding exo-glycals always appeared as unavoidable byproducts. O-Acyl protecting groups on the carbohydrate moieties underwent migrations which further increased the number of products in the otherwise rather complex reaction mixtures. Tosylhydrazones with ether type O-protections gave cleaner reactions but resulted in the same product types in similar ratios. The suggested mechanistic rationale explained how the complex sugar-derived tosylhydrazone substrates changed the reaction pathway. We think that this study also highlights the importance of transformations of high complexity which, though resulting in several products, may lead to a better understanding of their mechanism and may thus inspire further work.

General Procedure I: Conditions for the Reaction of Anhydro-Aldose Tosylhydrazones with Boronic Acids
A boronic acid (1.5 or 20 mmol, specified with the particular reactions) and K 3 PO 4 (3 or 10 mmol, specified with the particular reactions) were suspended in dry 1,4-dioxane (15 mL). The suspension was stirred and heated to reflux, and then a solution of a tosylhydrazone (1; 17 or 24, 1 mmol) in dry 1,4-dioxane (15 mL) was added dropwise over~20 min. When TLC (1:2 EtOAc-hexane for 1 and 17, 1:1 EtOAc-hexane for 24) indicated complete consumption of the starting compound (20 min-4 h), the mixture was cooled down and the insoluble material was filtered off and washed thoroughly with dry 1,4-dioxane (3 × 20 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography, with eluents indicated for the particular compounds to give anhydro heptitols and hept-1-enitols.

General Procedure I: Conditions for the Reaction of Anhydro-Aldose Tosylhydrazones with Boronic Acids
A boronic acid (1.5 or 20 mmol, specified with the particular reactions) and K3PO4 (3 or 10 mmol, specified with the particular reactions) were suspended in dry 1,4-dioxane (15 mL). The suspension was stirred and heated to reflux, and then a solution of a tosylhydrazone (1; 17 or 24, 1 mmol) in dry 1,4-dioxane (15 mL) was added dropwise over ~20 min. When TLC (1:2 EtOAc-hexane for 1 and 17, 1:1 EtOAc-hexane for 24) indicated complete consumption of the starting compound (20 min-4 h), the mixture was cooled down and the insoluble material was filtered off and washed thoroughly with dry 1,4-dioxane (3 × 20 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography, with eluents indicated for the particular compounds to give anhydro heptitols and hept-1-enitols.