Topics in amine chemistry

Abstract

The thesis entitled “Topics in Amine Chemistry” is in three parts-A, B and C-as well as an Appendix. Part A describes, in two chapters, the development of an alternative to Gabriel’s amine synthesis based on the chemistry of 1H naphtho 1,8 [de] 1,2,3 triazine. Part B describes, in two chapters, improved methodologies for the well known Lossen and Beckmann rearrangements. Part C describes approaches to novel amino sulphoxides and their synthetic utility in Kornblum type oxidations. The Appendix describes some exploratory studies with amide model systems, aimed at understanding the effects of hydrogen bonding in solvolytic reactions.

Part A Chapter 1 These studies develop the synthetic potential of N 2 alkyl derivatives of 1H naphtho 1,8 [de] 1,2,3 triazine (1), which yield functionalised amines upon reductive cleavage. It has been demonstrated in this laboratory that epoxides react with the anion of 1 to yield the ring opened regioisomers 2 and 3. A detailed study of this reaction was undertaken. The study of solvent effects revealed that the yield of 2 could be greatly improved by the use of polar protic solvents and increased ionic strength. Triazine 2 was reductively cleaved using Pd/C or Raney Ni to give amino alcohols or amines. A series of epoxides was studied; reductive cleavage of the resulting 2 provided a route to hydroxy amines. Chapter 2 This chapter describes the use of a triazine based glycine enolate equivalent in C alkylation reactions. Deprotonation of 2 (ethoxycarbonylmethyl) 1H naphtho 1,8 [de] 1,2,3 triazine (4) with NaH or LDA generated the anion, which was quenched by various electrophiles to obtain alkylated triazines 5. Reductive cleavage with Al–Hg provided ethyl esters of amino acids. Reduction of the alkylated triazine 5 with NaBH gave alcohol 6, which on reductive cleavage yielded amino alcohols regioisomeric with those obtained in Chapter 1.

Part B Chapter 3 This chapter describes studies aimed at developing a pre formed Lossen reagent for converting carboxylic acids to amines or amine derivatives without the intermediacy of hydroxamic acids. It was envisioned that N,O bis(ethoxycarbonyl)hydroxylamine (7) could be N acylated to 8, which would undergo a Lossen type reaction in base via cyclic intermediate 9. Earlier work in this laboratory had shown that 4 nitroaniline could be obtained starting from 4 nitrobenzoyl chloride and 7 in a one pot reaction. This scheme has now been extended to a series of acid chlorides to obtain amines or carbamates in good yields. The same strategy was applied to carboxylic acids using DCC as the condensing agent. Chapter 4 This chapter extends the Beckmann rearrangement to oxime carbamates (10) and oxime carbonates (11) under mild conditions.

Oxime carbamates were rearranged via diazotisation at 0 °C followed by warming to room temperature, giving excellent yields of amides and lactams. Oxime carbonates underwent rearrangement when treated with BF ·Et O in CH Cl at room temperature.

An attempted rearrangement–cyclisation strategy under these conditions was unsuccessful.

Part C Chapter 5 This chapter describes the synthesis of novel amino sulphoxides, which incorporate a latent oxygen function and a base in the same molecule in proper mutual orientation. The Kornblum type oxidation of various primary benzylic halides to aldehydes with one such sulphoxide (12) was demonstrated. The S oxide oxygen acts as a nucleophile to displace the halogen, while the pyridine nitrogen abstracts the proton through a six membered transition state, forming the aldehyde. Aliphatic amino sulphoxides are unstable and rearrange to aminoalkyl sulphenates. A stereoelectronic requirement is expected-the nitrogen lone pair should be antiperiplanar to the C–S bond. This could be prevented in a bicyclic amino sulphoxide (13) where the bridgehead nitrogen does not have a properly oriented lone pair. Two synthetic routes to this bicyclic skeleton, starting from 3 quinuclidone and 4 phenyl 2 quinuclidinol, were attempted but unsuccessful.

Appendix The Appendix describes attempts to determine whether multiple hydrogen bonds can stabilise ionic transition states, a concept relevant to enzyme mechanisms. Preliminary studies of the solvolysis rate of 15 by UV spectroscopy revealed no detectable difference compared with 14. Conformationally restricted systems such as 16 behaved similarly. Unsuccessful attempts at synthesising an oligophenanthridinone are also described.