Reactions of vinamidines and benzotropones and dynamic processes in norbornene-7-ols

Abstract

The research described in this thesis, entitled “Reactions of Vinamidines and Benzotropones and Dynamic Processes in Norbornen-7-ols”, reflects the diversified interests of the work that is being carried out in these laboratories. It had been found in earlier investigations that vinamidinium salts of type 1a or 1b, dissolved in a suitable solvent, undergo dimerisation with elimination on exposure to ammonia and moderate heat. The products were substituted pyridines and pyrimidines: 3,5-diaryl pyridines (2) and 5-aryl pyrimidines (3) from 1a, 2,6-diaryl pyridines (4) and 4-aryl pyrimidines (5) from 1b or mixtures, including 2,5-diaryl pyridines (6), from 1a and 1b. This observation provoked experiments directed towards synthesising other substituted pyridines and pyrimidines by carrying out cyclodimerisations of salts 1 bearing marker substituents at the para-position of the phenyl ring. A careful analysis of the products showed that the reactive species generated when salts 1 are exposed to ammonia cyclodimerise in specific ways exhibiting high orientation preference (in that only the pyridines and pyrimidines are formed) in conjunction with low regioselectivity (in that both are formed) as well as a product preference that implied highly specific modes of cyclodimerisation. An overall view of the patterns of substitution on the pyridines indicated that, while species 7a generated from salts 1a could react as both 4-centre and 2-centre participants, 7b (the ones from salts 1b) react only as 4-centre participants and the others, 7c, only as 2-centre participants (Scheme 1). As a part of the efforts to unravel the reasons underlying such specificities, a qualitative application of FMO theory was attempted on the assumption that the cyclodimerisations were the result of concerted [4+2] cycloadditions. While the reasons for high orientation selectivity being coupled with low regioselectivity were clarified, the further stage of selectivity implied by the formation of only specific products among several possibilities, apparently dependent on steric factors, could not be accounted for satisfactorily. A qualitative appraisal, assisted by molecular mechanics, of the steric demands of various substituents (-NMe?, Ph) pointed to a possibility that the reactive species 7a, 7b and 7c could be highly preferentially stabilised in particular conformations, allowing each of them to react either only as a 4-centre participant or only as a 2-centre participant in the cyclodimerisations. Such conformational factors would be effective whether the cyclodimerisations were concerted or involved charge transfers/charge delocalisations in attaining the transition states leading to the intermediary species. A comparative analysis of the feasibility of various pathways of eliminations from the initial species leading to the aromatised products actually isolated, that provided the necessary further information for eliciting the mechanisms in detail, is the subject of Chapter 1. Investigations of observations incidental to an exploration of possible ways of constructing benzo-bridged vinamidinium salts (8a–f: X = Cl, ClO?, BF? etc.), which can be considered as aminoiminium derivatives of benzotropones (9a–f), are the subject of Chapter 2. Results from a comparison of the energies of formation by semiempirical methods (MNDO, MOPAC) of the benzo-salts (8a–f) and their parent systems (10a–c) not only allowed an evaluation of the relative stabilities of the former but also gave an indication that attempting to synthesise some of them may not be wholly misguided. While the objective of obtaining any of such systems was not realised, incidental observations during the preliminary synthetic work demanded detailed and systematic investigations. One of the observations, that no apparent reaction takes place when direct amination of benzotropones (e.g., 9f) or their hydrochlorides (e.g., 11: R = H, X = Cl) is attempted, prompted a look at an alternate avenue viz. preparing alkoxy-oxonium salts (e.g., 11: R = Me, Et etc.; X = MeSO?, BF? etc.) and attempting to displace the oxygen function. In them by the corresponding nitrogen functions. The required alkoxy benzotropones (keto-ethers 12b, 13b, 14b & 15b) were conveniently secured by the reaction of bromo-benzotropones 12a and 13a with alkoxide. Both cine and ipso substitution of bromine were found to take place but at different ratios in the two cases. Besides advancing an aryne-type mechanism, the reasons for the difference in the ipso:cine ratios, possibly pivoted on the differences intrinsic to the aryne intermediates (16 & 17), are discussed. Treatment of the keto-ethers with dialkyl sulphate, though failing to furnish the desired oxonium salts 18, mediated an unexpected transformation of one of them (15b) into its carbonyl-ether transposed product (19: R = Me or Et). Explanations for the lack of generality of this transformation, insofar as it is not observed with the other keto-ethers, are suggested. In further endeavours, direct amination of bromo benzotropones (12a & 13a) was tried. An interesting finding was that the ratios at which the ipso and cine substitution takes place depend on the temperature at which the aminations are conducted. An aryne-type mechanism was ruled out on the ground that the range of change in the ipso:cine ratio with the temperature was large (nearly wholly cine at low temperature to nearly wholly ipso at the higher temperature). The sequence envisaged for the two types of amination required that the eventual formation of the cine product (14c or 15c) involves a specific C-protonation step while that of the ipso product (12c or 13c) needs depend only on the elimination of bromide ion (Scheme 2). The predominance of cine products in the low-temperature reactions and that of ipso products in the high-temperature reactions could be ascribed to the loss of competitiveness in cine-product formation relative to ipso-product formation when the temperature chosen for reaction is higher: there was a possibility that, of the two modes available for C-protonation, the internal one could be superseded by a less efficient external one, implying that the temperature coefficient of the rate of C-protonation can only be moderate while that of the elimination of bromide can be high, enabling the rate of formation of the ipso product via the latter process to overtake that of the cine product via the former. Presentation of the work described in Chapter 3 required detailed information on the earlier investigations of the complex dynamic behaviour evident from the temperature-dependent changes in the NMR spectra of the substituted norborn-2-en-7-ones 20a and 20b, respectively distally and proximally monoanisylated in relation to the methoxycarbonyl function, and their dianisylated analogue 20c. A degree of coordination appeared to exist among the pendant groups (the aryl and ester functions) in assuming different stabilised-rotational conformations but only two forms seemed to be stabilised at low temperature (223 K). An attempt was made to assign specific rotational conformations (inward- or outward-oriented) to the anisyls in the stabilised forms, noting that the ratio of such forms, 10:7 in the case of 20a, was different from that in the cases of the other two (10:1). Methods of assignment tried consisted both in qualitative assessment of the effects of particular possible conformations adopted by the aryl groups on the chemical shifts of the C- and O-methyls used as probes and comparison of heats of formation of such conformations optimised by the method of molecular mechanics. A self-consistent picture appeared to have been attained from the two methods. Continued investigations were directed towards an examination of the sensitivity of the ratios of the stabilised forms to factors generated on introducing a possibility of internal and/or external hydrogen bonding. It was hoped that the manner in which changes in the stabilisation ratios take place may provide information, even indirectly, on the correctness of the earlier assignments. Experimentally, this implied the selective reduction of the 7-oxo function in the keto-esters 20a–c and measuring the ratios of the stabilised forms in the pairs of secondary alcohols formed with the hydroxyl function syn and anti to the aromatic group. Taking the syn alcohol 21 from system 20a as an illustration, changing the solvent to a strong acceptor like acetone-d? from a relatively weak donor like chloroform-d could disrupt any intramolecular hydrogen bonding involving the anisyl methoxyl oxygen and the syn-OH group originally present, crowding out the ?-oriented anisyl into an ?-orientation. Remarkably, sodium borohydride reduction gave single products in each case, and primary physical evidence, though identifying each of them as a C-7 alcohol, was not of assistance in deciding its configuration. Resort to X-ray crystallographic structure determination disclosed the somewhat disappointing fact that all the reduction products had the anti configuration, and only marginal effects or none at all could be expected in the dynamic behaviour on changing the solvent to acetone from chloroform. NMR spectra of the anti alcohols, recorded of solutions in chloroform-d, showed the chemical shifts of the probe lines and the ratios of the stabilised forms had changed only marginally in the two monoanisylated cases compared with their 7-oxo analogues. Changing to acetone-d reversed the stabilisation of the anisyl from major outward-oriented to major inward-oriented in the distal case 22a while effecting no change at all in the proximal case 22b. The following interpretations are suggested for these pairs of observations: i) Chloroform stabilises the ?-orientation of the anisyl group in the distal case by hydrogen bonding the anisyl methoxyl since there is enough room only on the ? face. That influence is removed when acetone displaces chloroform as the solvent, and the conformational preference of the anisyl is more freely reflected in the ?:? ratio (10:8) observed in acetone. ii) Even without the influence of chloroform, the anisyl in the proximal case may be expected to prefer greatly the ?-orientation since, in ?-orientation, it would encounter steric hindrance from the C-5 endo ester function. The situation is not altered when the solvent is changed to acetone. iii) In the dianisylated case, the change in the more-to-less stabilised ratio from 10:1 to 10:4 on reduction to the C-7 alcohol (22c) was accompanied by dramatic changes in the chemical shifts of the probe lines. With further changes in chemical shifts taking place on changing the solvent from chloroform to acetone, the task of keeping track of the line assignments became difficult. The relative merits of alternative scenarios of what could be taking place are considered in the full awareness that the situation being attempted to be analysed is complex, several different factors—steric, conformational, dipolar, solvent-interactive, etc.—playing their specific roles. It is felt that further work is needed here. The exclusive formation of anti alcohols can happen only because the ?-faciality of attack by borohydride has been specifically conditioned in the norbornenones 20. The manner of such conditioning appears not to be directly explainable in terms of recent but controversial interpretations of the basis of faciality of nucleophilic attack (Cieplak’s ‘hyperconjugative’ or Houk’s ‘electrostatic’ model). The steric and coordinative effects peculiar to system 20 are considered in trying to find an alternative explanation. All the chapters comprise descriptions of the backgrounds of the topics dealt with in the necessary detail, the planning of experiments, analysis and identification of products, proposed explanations and conclusions. Detailed experimental conditions, spectroscopic and other data on the materials identified, etc., are included. Pertinent references follow at the end of each chapter. Technical information regarding general experimental methods has been given in an Appendix.