Reactions of Hydroxyalkyl Azides

It has been shown that in addition to iminium ether hydrolysis, other heteroatom and C-based nucleophiles may be incorporated into the lactam products. Through the addition of nucleophiles in a solution of DMF at ambient temperature, a range of lactams 

When unsymmetrical ketones undergo iV-insertion reactions, two regioisomeric lactam products are possible. The regioselectivity of Lewis acid-mediated reactions of 

When 4-substituted cyclohexanones such as 4-terf-butylcyclohexanone are reacted with chiral, enantioemiched 1,2- or 1,3-hydroxyaIkyl azides, asymmetric ring expansion occurs 

When (R)-3-azido-l-phenylpropan-l-ol was reacted with 4-tert-butylcyclohexanone (BFs-OEta then KOH), diastereomeric lactams were formed quantitatively in a 95 5 ratio 

4-methylcyclohexanone and a variety of substitution patterns were tolerated about the ketone. The key stereochemical feature at work in these reactions is the conformation of the azide-containing tether. Minimization of diaxial interaction in the two chairlike intermediates probably accounts for the high diastereoselectivity of these processes (favoring 

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Schmidt Rearrangement Reactions with Alkyl Azides 201 Table 7.3 Reactions of hydroxyalkyl azides with ketones... 

An additional library was synthesized using the same reaction of hydroxyalkyl azides with aldehydes originally reported by Boyer in 1955 (Scheme 7.3, Section 7.1). Thus, a library of oxazolines and dihydrooxazmes was synthesized from aromatic aldehydes and azides by treatment with BF3-OEt2 followed by capture of the excess aldehyde (or azide, not shown) with a resin bound scavenger (Scheme 7.53). ... 

Rudy H, Cramer KE (1939) Uber den oxydativen Abbau des alloxan-2-dimethylatino anils zu 1-methyl benzimidazol. Chem Ber A 72(4) 728-744 Sahasrabudhe K, Gracias V, Furness K, Smith BT, Katz CE, Reddy DS, Aube J (2003) Asymmetric Schmidt reaction of hydroxyalkyl azides with ketones. J Am Chem Soc 125 (26) 7914-7922. doi 10.1021/ja0348896... 

Intermolecular Schmidt reactions of alkyl azides and hydroxyalkyl azides with cycloketones in the presence of a Lewis acid, lead to formation of iV-alkyl lactams and A-hydroxyalkyl lactams respectively in good yield. The synthesis of chiral lactams by an asymmetric Schmidt reaction has also been reported. ... 

Rearrangements. Cyclic ketones undergo ring expansion on reaction with hydroxyalkyl azides." Regioselectivity is dependent on steric and electronic factors. Beckmann rearrangement of ketoxime carbonates has been observed at room temperature. 

In a different approach, Alonso and Yus [18] reported a three-comporrent syrrthe-sis of P-hydroxyalkyl-1,2,3-triazoles from the three-component reaction of sodium azide, a series of epoxides and alkynes in water, in the presence of copper nanoparticles (CuNPs) on activated carbon as the catalyst (Scheme 1.12). 

Chiral 1,2,3,4-tetrahydroisoquinolines are accessible from 0-carbamyl lactates via N-oxaacyliminium cyclization (Scheme 31). The precursor for the generation of the chiral N-oxaacyliminium ion 220 is prepared by reaction of (5)-methyl lactate (97) with azide 217 followed by partial reduction of 218 with diisobutylaluminum hydride. Cyclization of 219 with formic acid at room temperature for 14 h gives the oxazolo[4,3- 2]isoquinoline (221) without racemization [78]. Reductive cleavage of the oxazoline ring with lithium aluminum hydride furnishes the corresponding l-hydroxyalkyl-l,2,3,4-tetrahydroisoquinoline in 98% yield. 

Variation 4 Asymmetric Schmidt Reaction of Ketones with Hydroxyalkyl Azides (Aube )... 

A modular synthesis of a series of y-tum mimics was enabled by the Lewis acid-mediated reactions of enantiopnre hydroxyalkyl azides with piperidinones. This involved the preparation of enantiopnre azides 103, the side chains of which corresponded to those in natnrally occnrring side amino acids. These azides were combined with piperidinones 102 in the presence of BFs-OEta or TfOH, and the resulting imininm ethers hydrolyzed to the corresponding lactams 104 (Table 7.10). 

Mechanistically, these reactions are related to the oxazoUne synthesis shown in Scheme 7.3. Both involve the initial formation of an oxonium ion followed by the now-intramolecular addition of the appended azide to this cation (Scheme 7.11). In the present case, migration with loss of N2 occurs to afford an iminium ether salt (e.g. 16), which can be isolated by precipitation with cold THE. Treatment of the iminium salt with aqueous NaHCOs then delivers an A-hydroxyalkyl lactam. 

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