Azido-Schmidt reaction

Scheme 41 Mechanism of the azido-Schmidt reaction catalyzed by FeCl3...

About 15 years ago, Aube et al. reported that alkyl azides undergo Lewis acid-mediated reactions with ketones 76 to give the corresponding lactams 78 via 77 (Azido-Schmidt reaction Scheme 14A) [44-48]. However, this reaction pathway does not proceed when a,/3-unsaturated ketones are used. It was recently shown that Lewis acid-activated enones like 79 undergo a [3-P2] cycloaddition with alkylazides, likely via an 1,2,3-triazoline intermediate 80, to give the corresponding enaminone 80 (Scheme 14B) [49]. 

Scheme 14 A Azido-Schmidt reaction. B Lewis acid-mediated reactions of alk)4azides with a, 8-unsaturated ketones [49]...

Following the introduction of the intramolecular azido-Schmidt reaction, it was reported that potent Lewis acids such as TiCL were found to facilitate certain intermolecular... 

Domino reactions, which combine sequential transformations in a single pot, can allow the rapid development of complex products from simple starting materials. One design feature required for successful domino process involves control over the order of reaction events. Since Bronsted acids or Lewis acids are required for the initiation of nearly all azido-Schmidt reactions, combining such reactions with other acid-accelerated processes presents a logical starting point for assembling Schmidt-centric tandem reactions. 

Azido-9-phenylxanthene undergoes a Schmidt reaction on heating to give 11-phenyldibenz-[/>,/][l,4]oxazcpinc (9).42... 

Carboxylic acids and esters can also be converted to amines with loss of the carbonyl group by reaction with hydrazoic acid, HN3, which is known as the Schmidt reaction,278 The mechanism is related to that of the Curtius reaction. An azido intermediate is generated by addition of hydrazoic acid to the carbonyl group. The migrating group retains its stereochemical configuration. 

An example of ring enlargement is the intramolecular Schmidt reaction of azidoalkyl ketone 53 that gives, by the action of titanium tetrachloride, through intermediate azidohydrin, lactam 20 (95JA10449). Because of the large distance between keto and azido groups, the usual catalyst trifluoroacetic acid does not work. 

The acid-catalyzed ring expansions of tertiary cyclohexylazides to tetrahydroazepines may be viewed as an intramolecular version of the Schmidt reaction and in general proceed in high yield. Unfortunately, the reaction is of little synthetic value as the imines formed are readily hydrolyzed to w-aminoketones in the strong acid media (B-67MI51600). However, the reaction is successful with 9-azido-9-phenylacridone, which on thermolysis or photolysis ring-expands to a mixture of 9-phenyliminoacridone (15-35%) and 6-phenyl-11//-dibenz[6,e]azepin-ll-one (65-85%) (76TL3141). 

Amides lactams. Dimethyl thioketals of cyclic or acyclic ketones react with iodine azide to form an a-azido sulfide in 75-95% yield. The product rearranges to an amide or a lactam in high yield in the presence of trifluoroacctic acid. This sequence is an attractive alternative to the Beckmann rearrangement or Schmidt reaction. 

Although l,2-benzofluoren-9-ol does not react directly under conditions normally employed in the Schmidt reaction, it may be converted to 9-azido-l,2-benzofluorene, which in trifluoroacetic acid rearranges after protonation (75) to a mixture of 3,4-benzophenan-... 

In recent reviews of the chemistry of organic azido compounds attention has been focused mainly on the reactions rather than the synthesis of azides ". The last comprehensive account of the introduction of the azido group was published by Boyer and Canter in 1954 and for the purposes of this chapter we have concerned ourselves primarily with developments subsequent to this review. Reference to work cited in the review of Boyer and Canter is made only where it is pertinent to the discussion. Because of the very large number of azide syntheses described in the chemical literature no attempt has been made at an encyclopaedic coverage. Instead, each major synthetic method has been discussed from a mechanistic viewpoint with representative examples being used as illustration. Only reactions in which a carbon-azide bond is formed are considered reactions in which organic azides are implicated as intermediates but are not isolated, e.g. the Schmidt reaction, were deemed to be outside the scope of this chapter. 

A novel synthesis of amphimedine 105 has been reported by Prager et al. (89H847 91AJC277). It involves an azido ring expansion of a pyridyla-zafluorenol 185, by the Schmidt reaction, to 5-(4-pyridyl)benzo[a]-... 

Similarly l,2,3-benzotriazin-4(3//)-one (13, R = H) or its 3-aryl derivatives (R = Ar) decompose in refluxing acetic acid containing sodium azide or sodium iodide to afford 2-azido- and 2-iodobenzamides 14 (X = N3, I), respectively, in high yields.340 Schmidt reaction (sodium acid, 40% sulfuric acid, 1,2-dichloroethane, 40-50°C) of 13 (R = H) afforded 2-azidobenz-amide (X = N3 R = H 49%).341... 

Oxazacycles. Aldehydes combine with 1,2- and 1,3-azido alcohols in Jhe presence of BFj-OEt to give heterocyclic products (21 examples, 18-96%). Mechanistically, the intramolecular reaction of oxonium intermediates with the azido group is akin to the Schmidt reaction. 

Reaction with Cyclic Enones. Conjugate addition of azide ion to cyclic enones in water using sodium azide in the presence of Lewis base resulted in the formation of 8-azido carbonyl compounds (eq 55). The Schmidt reaction of benzopyranones with sodium azide led to pyrano[3,2-b]azepines in reasonable yields (eq 56). 

The Schmidt reaction of a simple cyclic ketone yields lactams with the ring expanded, while the intramolecular Schmidt reaction of cyclic ketone with an azido group at the side chain leads to the formation of bicyclic lactams with nitrogen at the position of fusion. It is interesting that the reaction between a cyclic ketone and 2-azido ethanol can form either a lactam or a lactone by means of the treatment with a different base, in which the lactam is formed when the reaction system is treated with KOH, whereas lactone is generated when NaHCOs is used as the base. Especially, the reaction between 4-ferf-butylcyclohexanone and 3-azido-2-methyl-2-phenylpropanol gives lactam in 19 1 stereoselectivity. ... 

The intramolecular Schmidt reactions of azido tertiary benzylic and propargylic alcohols 32 lead to l-azabicyclo[5.3.0]decanes or 1-azabicyclo[4.3.0]decanes (indolizidines) 36 without formation of the products derived from cation rearrangement. However, simple tertiary alcohols such as 37 undergo cation rearrangement prior to cyclization to give a mixture of regioisomeric indolizidines. 

The gold(I)-catalyzed intramolecular Schmidt reaction of azido alkynes 49 provides easy entry to a series of pyrroles 54 with a variety of substitution patterns. The proposed mechanism involves gold(I)-induced activation of the alkyne toward addition by the proximal nitrogen of the azide. Subsequent loss of nitrogen leads to cationic intermediate 52, which is... 

The acid-promoted intramolecular Schmidt reaction of azido-alkene 114 is featured in the formal synthesis of gephyrotoxin. Treatment of 114 with trifluoromethanesulfonic acid followed by L-Selectride reduction of the resultant iminium ions 115 and 116 generates a mixture of diastereomeric bromo-amines. The bromide is replaced with acetate ion, and the acetate is reduced to give alcohol 117, a known intermediate in the synthesis of gephyrotoxin. 

In what appears to be a dramatically different process, carboxylic adds that are resistant to attack by sulfuric add (H2SO4) can undergo substitution on the carbon of the carbonyl of the hydroxyl group (-OH) by the azido group (-N3) (in a process called the Schmidt reaction). While it is occasionally possible to isolate the acid azide, rearrangement to the corresponding isocyanate is common. A schematic representation in concert with available experimental data for the prcx ess of azide formation and subsequent rearrangement is shown in Scheme 9.120 for the case of benzenecarboxylic acid (benzoic acid). It is particularly important to note that in contrast to the typical formation of a tetrahedral intermediate so common for the... 

Thiazolidine rings are normally easy to prepare but this year a new reaction has appeared in which the ring system was produced during a thermally-induced intramolecular eliminative rearrangement. The azido-enones (364) were heated to 140 C leading to a mixture of the products (365) and (366) in equal proportions. The authors have determined that an intramolecular acid-catalysed Schmidt reaction is not involved, and have proposed the triazoline (367) as a reasonable intermediate. They have also shown that in certain cases rearrangement coupled with desulphurization provides a completely regioselective method for conversion of 2-cycloalkenones to the ene lactams (368). 

The first synthetically useful Schmidt reactions of alkyl azides with ketones were intramolecular. Thus, it was shown that azido-tethered ketones, when treated with Brpnsted or Lewis adds in CH2CI2 at room temperature, were converted to lactams in good to excellent yields (Table 7.1). Mono- and bicyclic ketones are attractive substrates for the preparation of fused bi- and tricyclic lactams and the range of ring sizes accommodated... 

---