Membered Heterocycles

Vitamin chemistry contains a variety of structures the majority of which are heterocyclic or lipidic in type and apart from Vitamin they are obtained synthetically although with the exception of the vitamin D series few start with a natural product intermediate. For certain of the heterocyclic members attention has turned inevitably to the amino acids as possible sources of starting material. 

Since 1,2- to 1,6-difunctional opengeneral procedures (see chapter 1), it is useful to consider them as possible starting materials for syntheses of three- to seven-membered heterocycies 1,2-heterocycles can be made from 1,2-difunctional compounds, e.g. olefins or dibromides 1,3-difunctional compounds, e.g. 1,3-dibromides or 1,3-dioxo compounds, can be converted into 1,3-heterocycles etc. 

A completely different, important type of synthesis, which was developed more recently, takes advantage of the electrophilicity of nitrogen-containing 1,3-dipolar compounds rather than the nucleophilicity of amines or enamines. Such compounds add to multiple bonds, e.g. C—C, C C, C—O, in a [2 + 3 -cycioaddition to form five-membered heterocycles. 

A few typical examples indicate the large variety of five-membered heterocycles, which can be synthesized efficiently by [2 + 3]-cycloadditions. [2 + 2]-Cycloadditions are useful in the synthesis of certain four-membered heterocycles (H. Ulrich, 1967), e.g. of 8-lactams (J.R. 

Two moles of diphenylacetylene insert into the benzyl methyl sulfide complex 481 to afford the eight-membered heterocycle 482[440j. The cinnolinium Salt 483 is prepared by the insertion of alkynes into the azobenzene com-plex[44l]. 

Pd-cataly2ed reactions of butadiene are different from those catalyzed by other transition metal complexes. Unlike Ni(0) catalysts, neither the well known cyclodimerization nor cyclotrimerization to form COD or CDT[1,2] takes place with Pd(0) catalysts. Pd(0) complexes catalyze two important reactions of conjugated dienes[3,4]. The first type is linear dimerization. The most characteristic and useful reaction of butadiene catalyzed by Pd(0) is dimerization with incorporation of nucleophiles. The bis-rr-allylpalladium complex 3 is believed to be an intermediate of 1,3,7-octatriene (7j and telomers 5 and 6[5,6]. The complex 3 is the resonance form of 2,5-divinylpalladacyclopentane (1) and pallada-3,7-cyclononadiene (2) formed by the oxidative cyclization of butadiene. The second reaction characteristic of Pd is the co-cyclization of butadiene with C = 0 bonds of aldehydes[7-9] and CO jlO] and C = N bonds of Schiff bases[ll] and isocyanate[12] to form the six-membered heterocyclic compounds 9 with two vinyl groups. The cyclization is explained by the insertion of these unsaturated bonds into the complex 1 to generate 8 and its reductive elimination to give 9. 

The first member of the series. 2-imino-3,4-dimethyl-4-thiazoline (363) is obtained when the di-HBr salt of bis(methylformamidine)disulfide (362i is refluxed for 16 hr in acetone (Scheme 209) (700). The most common preparative methods involve direct heterocyclization by the Hantzsch method (see Chapter II. Section II.4), though the mechanism of this reaction suggests certain limitations according to the respective natures of R2, R3, and in 364 (Scheme 210). 

The shapes of heterocyclic rings are very much like those of their all carbon analogs Thus six membered heterocycles such as piperidine exist m a chair conforma tion analogous to cyclohexane... 

Sulfur containing heterocycles are also common Compounds m which sulfur is the heteroatom m three four five and six membered rings as well as larger rings are all well known Two interesting heterocyclic compounds that contain sulfur-sulfur bonds are hpoic acid and lenthiomne... 

The name of the parent six membered sulfur containing heterocycle is thiane It is num bered beginning at sulfur Multiple incorporation of sulfur in the ring is indicated by the prefixes di tri and so on... 

Pyranose form (Section 25 7) Six membered ring ansing via cyclic hemiacetal formation between the carbonyl group and a hydroxyl group of a carbohydrate Pyrimidine (Section 28 1) The heterocyclic aromatic com pound... 

Organic ring systems are named by replacement nomenclature. Three- to ten-membered mono-cyclic ring systems containing uncharged boron atoms may be named by the specialist nomenclature for heterocyclic systems. Organic derivatives are named as outlined for substitutive nomenclature. The complexity of boron nomenclature precludes additional details the text by Rigaudy and Klesney should be consulted. 

The furan nucleus is a cycHc, dienic ether with some aromaticity (2). It is the least aromatic of the common 5-membered heterocycles. A comparison of the aromaticity (3) of several of these compounds is shown below. 

Many of these compounds ate highly colored and have found use as dyes and photographic chemicals. Several pharmaceuticals and pesticides are members of this class. An extremely sensitive analytical method for low hydrazine concentrations is based on the formation of a colored azine. They are also useful in heterocycle formation. Several reviews are available covering the chemistry of hydrazones (80,89) and azines (90). 

Ediyleneimine (a2indine, a2acyclopropane) is the smallest cyclic itnine consisting of a three-membered A/-heterocyclic ring (n = 2) ... 

A large number of Diels-Alder-type reactions, involving both aromatic and sulfonyl isocyanates, have been reported. Heterodienes having high electron density ate found to add to isocyanates to form sis membered heterocycles as shown in Figure 2 (48—50). 

Six-membered heterocycles with two heteroatoms are prepared by reaction of diketene with a substrate containing a C—O or C—N multiple bond. With carbonyl compounds diketene reacts in the presence of acids to give l,3-dioxin-4-ones. The best known is 2,2,6-trimethyl-4H-l,3-dioxin-4-one [5394-63-8] (15), the so-called diketene—acetone adduct, often used as a diketene replacement that is safer to handle and to transport, albeit somewhat less reactive than diketene itself (103,104), forming acetylketene upon heating. 

Y = 6-membered N-contg. heterocyclic ring having at least one active halo and n = 0 or I. 

Y = 6-membered N-conig. heterocyclic ring which may be Hie dyestuffs arc of formulae (V) or (VI) ... 

The compounds of this article, ie, ftve-membered heterocycles containing two adjacent nitrogen atoms, can best be discussed according to the number of double bonds present. Pyrazoles contain two double bonds within the nucleus, imparting an aromatic character to these molecules. They are stable compounds and can display the isomeric forms, (1) and (2), when properly substituted. Pyrazoles are scarce ia nature when compared to the imidazoles (3), which are widespread and have a central role ia many biological processes. 

Of the legion of partially saturated six-membered ring heterocycles, an idea of their stability, or lack of it, can normally be gained by consideration of the thermodynamic stability of the various components which can be identified in them. Thus, those rings which contain ester or amide functions can be expected to possess the chemical reactivity and the... 

Some of the partially and fully reduced heterocyclic six-membered rings are sufficiently important to have trivial names with which the reader should be familiar. Thus hexahy-dropyridine (38) is known as piperidine, and tetrahydro-l,4-oxazine (39) is morpholine. Tetrahydropyridines are also sometimes referred to as piperideines, with the position of the double bond denoted by a A, but this system is obsolescent (at the least). 

The H NMR spectra of aromatic six-membered heterocycles have been measured extensively. The considerable amount of data which were available by 1972 were compiled by Batterham in an excellent critical monograph (B-73NMR), which provides the basis for the general account which follows here. 

The normal pattern of coupling constants for aromatic six-membered rings is found in the heterocyclic aza systems, except that the ortho coupling to a proton a to a heterocyclic nitrogen is reduced from 7-8 Hz to 4.5-6 Hz. The J2.3 of pyrylium salts is still lower... 

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