Amino-alcohols with nitrous acid

A synthesis of cycloheptanone (5) starts with the base-catalyzed addition of nitromethane to cyclohexanone " the procedure calls for a ratio of 3.25 moles of nitromethane to 2.5 moles of ketone. The sodium enolate (2) separates and is collected and iicldifled to liberate the nitro alcohol (3), which Is hydrogenated to the amino alcohol (4). Nitrous acid then elfects deamlnatlve rearrangement with ring expansion to c) cluheptanone (5). 

These hydrazides on treatment with nitrous acid are converted into azides, which with appropriate amino-alcohols, furnish ergometrine and its isomerides and analogues. The four pairs of stereoisomeric ergo-metrines and ergometrinines in the following list have been prepared in this way with l-( -(-)-)S-aminopropyl alcohol or its d-( —)-isomeride. 

When a cyclic /3-amino alcohol—e.g. 1—is treated with nitrous acid, a deamination reaction can take place, to give a carbenium ion species 2, which in turn can undergo a rearrangement and subsequent loss of a proton to yield a ring-enlarged cyclic ketone 3. This reaction is called the Tiffeneau-Demjanov reactionit is of wider scope than the original Demjanov reaction ... 

A 2-amino group in chroman is more labile than its isomers and is hydrolyzed to the alcohol by acids for example both the amines (699) and (700) give the corresponding alcohols by treatment with nitrous acid and 50% hydrochloric acid, respectively. 6-Amino-chromans are of interest because of their chemical and biological resemblance to the tocopherols. The tocopheramines (701 R1, R2, R3 = H or Me) show antioxidant and other properties of the corresponding phenols and are no more toxic. They may be obtained by catalytic or chemical reduction of the nitrochromans (81HC(36)189). 

Tertiary amines do not react with nitrous acid, acetyl chloride, benzoyl chloride, benzenesulfonyl chloride, but react with alkyl halides to form quaternary ammonium halides, which are converted by silver hydroxide to quaternary ammonium hydroxides. Quaternary ammonium hydroxides upon heating yield (1) tertiary amine pins alcohol (or, for higher members, olefin plus water). Tertiary amines may also be formed (2) by alkylation of secondary amines, e.g., by dimethyl sulfate, (3) from amino acids by living organisms, e g, decomposition of fish in the case of trimethylamine. 

Ot-Hydroxy Acid and Epoxide as Building Blocks. Deamination of an a-amino acid with nitrous acid is known to give the corresponding a-hydroxy acid with retention of configuration. An a-hydroxy acid can be converted to an epoxide. Both a-hydroxy acids and epoxides are versatile chiral building blocks in natural products syntheses (3). Alcohol as a Chiral Building Block... 

It is obvious that other compounds in which a positive charge can be placed on a carbon a to one bearing an OH group can also give this rearrangement. This is true for p-amino alcohols, which rearrange on treatment with nitrous acid (this is called... 

Treatment of a primary aliphatic amine with nitrous acid or its equivalent produces a diazonium Ion which results in the formation of a variety of products through solvent displacement, elimination and solvolysis with 1,2-shift and concurrent elimination of nitrogen. The stereochemistry of the deamination-substitution reaction of various secondary amines was investigated as early as 1950, when an Swl-type displacement was suggested. Thus, the process can hardly be utilized for the preparation of alcohols except in cases where additional factors controlling the reaction course exist. Deamination-substitution of a-amino acids can be utilized for the preparation of chiral alcohols. 

The semipinacol rearrangement is not restricted to 2-heterosubstituted alcohols. Thus, the addition of diazoalkanes to ketones yields homologated ketones (equation 4), via rearrangement of the adduct (3). This process is closely related to the rearrangement of 2-amino alcohols on treatment with nitrous acid (equation 5). Similarly, 2-hydroxyimines undergo rearrangement to 2-amino ketones in a related process (equation 6). 

In the pinacol-pinacolone rearrangement a 1,2-diol rearranges to give a carbonyl group that is adjacent to a quaternary carbon. There are many variations of this reaction for example, the semipinacol rearrangement, in which a (P-amino alcohol is treated with nitrous acid. This reaction may be modified so that a ring expansion takes place, in which case it is called the Tiffeneu-Demyanov ring expansion. 

Tiffeneau-Demjanov ring expansion. Rearrangement of (i-amino alcohols on diazotization with nitrous acid to give ring-expanded carbonyl compounds. 

Rearrangement of (3-amino alcohols upon diazotization with nitrous acid to give carbonyl compounds. Cyclic alcohols yield ring expanded or contracted products ... 

---