Schmidt Rearrangement Reactions with Alkyl Azides

Abstract

The sobriquet ' Schmidt reaction ' refers to a number of related processes in which hydrazoic acid or an alkyl azide reacts with an electrophile. 1 -6 The product obtained will depend on the reaction partner (carboxylic acids generate amines, aldehydes give nitriles and formamides, and ketones provide amides, respectively) but all of these reactions have certain features in common. They are the initial nucleophilic addition of the azide component to an electrophile (usually promoted by acid) eventually followed by a rearrangement step driven by the energetically favorable loss of nitrogen. The classical Schmidt reaction of hydrazoic acid with ketones is generally considered to involve an intermediate dehydration step. 7,8 Despite the diversity of reactions that comprise the Schmidt family, its single most common variant is shown in Scheme 7.1 . This overall process can be regarded as an insertion of NH between the carbonyl and an α alkyl group. 9 The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt ' s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2 , it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter

Twisted Amides: From Obscurity to Broadly Useful Transition‐Metal‐Catalyzed Reactions by N−C Amide Bond Activation

“…[16] Ta king advantage of an intramolecular AubØ-Schmidt reaction, [17] rearrangement of 2-(2-azidoethyl)cyclobutanone using HBF 4 in Et 2 Oc ould be achieved to give three products, including the HBF 4 salt, the in situ-formed hydrolysis product, and the BF 3 complexi n9 7% combined yield (Scheme 2A). [16] Ta king advantage of an intramolecular AubØ-Schmidt reaction, [17] rearrangement of 2-(2-azidoethyl)cyclobutanone using HBF 4 in Et 2 Oc ould be achieved to give three products, including the HBF 4 salt, the in situ-formed hydrolysis product, and the BF 3 complexi n9 7% combined yield (Scheme 2A).…”

“…Taking advantage of an intramolecular Aubé–Schmidt reaction, rearrangement of 2‐(2‐azidoethyl)cyclobutanone using HBF 4 in Et 2 O could be achieved to give three products, including the HBF 4 salt, the in situ‐formed hydrolysis product, and the BF 3 complex in 97 % combined yield (Scheme A). As expected, reactivity studies revealed that the twisted amide, 7‐hypoquinuclidonium tetrafluoroborate, is extremely unstable.…”

“…The Aubé group reported an allylic twisted amide during the development of the allylic azide rearrangement/Schmidt reaction (not shown) . It should be noted that the intramolecular Schmidt reaction developed by the Aubé group provides one of the most general and effective methods for the synthesis of bridged bicyclic lactams …”

Synthesis of 3-aminooxindoles via acid-promoted cyclization of α-imino-N-arylamides and α-azido-N-arylamides

“…When THF was used as the solvent, a complex mixture was formed (entry 9). Besides BF 3 ⋅OEt 2 , several other acids, such as triflic acid (TfOH), TMSOTf, trifluoroacetic acid (TFA), In(OTf) 3 , Zn(OTf) 2 and BiCl 3 , were also tested for their effectiveness, and the results are listed in Table 1 as well (entries [12][13][14][15][16][17]. The optimized conditions (Table 1, entry 3) were then applied to a variety of substituted 2-(N-arylcarbamoyl)-2-iminoacetates (1b-1s), and the results are summarized in Table 2.…”

“…Organic azides are versatile compounds in organic synthesis. 11 One important type of reaction organic azides can be exploited for is the Schmidt reaction, 12,13 which has proved to be useful in the synthesis of nitrogen-containing heterocycles. In the Schmidt reaction, an alkyl azide firstly reacts with an electrophile, and the thus formed intermediate then undergoes 1,2-migration accompanied by the loss of dinitrogen.…”