General Synthetic Methods

Methods of heterocyclic synthesis can be divided into two main types those in which the ring system is built up from aliphatic components and those in which derivatives of other heterocyclic systems are used as starting materials. The essential step in most pyrazine syntheses from aliphatic components is C-N bond formation and various schemes for the synthesis of the required C4N2 ring system are illustrated below. The primary product is in many cases a reduced 

108b yy. W. Paudler and S. A. Humphrey, Org. Mass. Spectrometry Suppl. 4, 

3-dioxobutane and a,/3-diaminopropionic acid gives, after aerial oxidation of the intermediate dihydropyrazine, 5,6-diphenyl- and 5,6-dimethylpyrazine-2-carboxylic acid, respectively.113 114 2-Amino-pyrazine and its alkyl and aryl derivatives have been obtained from the condensation of a,/3-dicarbonyl compounds with aminoacet-amidine [NH2CH2C(=NH)NH2] [Eq. (2)]115 and 2-aminopyrazine-3-carboxamides are obtained from the analogous condensation of a,/S-dicarbonyl compounds and aminomalonamidamidine [NH2CH(CONH2)C(=NH)NH2].116 

Condensation of a,/3-carbonyl compounds and aminomalonamide [NH2CH(CONH2)CONH2] similarly affords 2-hydroxy-3-carbox-amidopyrazines.117 

The self-condensation of two molecules of an a-aminoketone to a 2,5-dihydropyrazine and subsequent oxidation represents an important method for the preparation of 2,5-disubstituted and 2,3,5,6-tetra-substituted pyrazines. The second step may proceed spontaneously in the presence of air, or be carried out with oxidizing agents such as hydrogen peroxide or mercuric chloride. The required a-aminoketones are by no means easily accessible intermediates and an alternative route to tetrasubstituted pyrazines has been developed which involves 

108a F. XJchimaru, S. Okada, A. Kosasayama, and T. Konno, J. Heterocyd. 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde 

Considering the high efficiency of enzymes, model compounds have been developed that mimic their functions (Fig. 4-21). Among them, -cyclodextrin occupies a prominent place, as it forms inclusion complexes with suitably constructed ferrocene derivatives that then may undergo kinetic resolution (Fig. 4-21 d). An ester of an unsaturated acid derived from a 1,2-ferrocenophane is the best substrate for this technique the rate of hydrolysis of one enantiomer is enhanced by 3.2 x 10 [133]. 

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

Chiral phosphines are readily available from lithiated or palladated tertiary ferrocenylalkyl amines by reaction with chlorodiarylphosphine or chlorodialkyl-phosphine. As the chemistry of such phosphines is the topic of a separate chapter of this book (see Chapter 2), we will mention just a few aspects here. As with the phosphines, the corresponding derivatives of arsenic are obtained from chloro-diarylarsines [139], 

Monoterpenes are widely used as substrates in the development of new synthetic reagents and routes. However, many of these studies refer to a one-off use of a particular compound as one of many models and such are not discussed here unless of especial interest. We rather review the salient work involving specific functionalization and modification of the class. 

The ene reaction of aldehydes with alkenes provides a potentially valuable route to homoallylic alcohols [cf. (14a) (14b)]. Coupling of isoprene with 3-methyl- 

Reagents i, BF3 etherate-MeOH ii, KOBu -DMSO iii, H+-MeOH 

Pandy-Szekeres, G. Deleris, J. P. Picard, J.-P. Pillot, and R. Callas, Tetrahedron Lett., 1980, 21, 4267. 

Hiyama, A. Kanakura, H. Yamato, and H. Nozari, Tetrahedron Lett. 1978, 3051. 

The anion-exchange reaction of the counterion in viologens is performed from the corresponding halides using an anion-exchange resin loaded with a given anion. 

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II. General Synthetic Methods for Thiazole and Thiazolium Salts... 

The first chapter discusses thiazole itself, its structure, and its phyacal and chemical properties. The second chapter describes the general synthetic methods for thiazoles and thiazolium salts. 

General Synthetic Methods for ITiiazole and Thiazolium Saits... 

General Synthetic Methods for Thiazoie and Thiazolium Salts Ph—C=-= - - N... 

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