Heterocyclic Syntheses

2 Heterocyclic Synthesis. - The reactions of phosphorus ylides with phenan-threne-9,10-quinone (113) have been used to prepare phenanthrene [9,10-x]-fused compounds with four, five, and six membered heterocyclic rings. (E)-4-carbethoxymethylene-l,2,3,4-tetrahydro-2-quinolones 114 have been obtained from the stereoselective reaction of 3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones and ethyl(triphenylphosphoranylidene)acetate. A -trifluoroacetylanilines 115 react with Ph3P=C02Et producing enamine derivatives 116 as a mixture of (E)- and (Z)-isomers. Enamines 116 are useful precursors for the synthesis of indoles and quinolones. 

Vinylamino phosphorane 119 reacts with a,P-unsaturated aldehydes to give a mixture of 2-aryIpyridine and 4-dihydropyridine derivatives (scheme 24). Likewise, dihydropyridines were also formed in the reaction of 119 with aromatic 

3 Tetrathiafulvalene Derivatives and Related Organic Materials. - Wittig-type reactions and reagents continue to play an important role in this burgeoning field of research. Some examples of the types of compounds being prepared using these routes are illustrated here. 

The study of heterocyclic compounds constitutes a major endeavor in the fields of organic chemistry and the life sciences. Although numerous texts on the synthesis, structure, and reactivity of heterocyclic compounds have been written [1,2], the application of solid-acid catalysts to the synthesis of heterocyclic compounds is rarely emphasized in the literature. The authors of this section of the book have chosen not to pursue an exhaustive literature review-type approach to this topic but rather to cover selected areas of this subject from the viewpoint of an industrial chemist. More specifically, an account of the synthesis of pyridines is given which relies heavily on patent literature. Pyridine bases constitute a sizable semicommodity industry that provides a platform into the pyridine derivatives that are precursors to numerous fine chemicals. In addition, this section includes selected examples of the synthesis of non-pyridine heterocycles which might be of commercial importance. 

Key products derived from pyridine (1) are the non-selective herbicides paraquat (5) and diquat (6) and the fungicide zinc pyrithione (7) used in a well-known fluh -dandruff shampoo. y5-Picoline (3) is a key precursor to vitamin B3 and both niacinamide (8) and niacin (9) are produced on the large scale (i.e. several thousand tons per year). The insecticide chloropyrifos (10) can be prepared from 6-picoline. 

The largest use of a-picoline (2) is for production of 2-vinylpyridine (11) which, with butadiene and styrene, is converted into a terpolymer latex. This latex provides a coating that stiffens fabrics (e. g. nylon, polyester, rayon) that are incorporated into biased-ply car tires. The 2-vinylpyridinc assists in binding the rubber to the fabric carcass. a-Picoline is also used as a precursor to nitrapyrin (12), which prevents nitrogen loss from soil, and the herbicide picloram (13). 

Most commercial processes nowadays use CH2O-CH3CHO-NH3 feed combinations to co-produce pyridine and 9-picoline [9]. Typically, a C1/C2 molar ratio of ca 1.0 is used, but lower ratios can be employed if more pyridine and -picoline are required [10,11], If available, acrolein (CH2=CHCHO) can be used instead of the C,-C2 components and this tends to produce a surplus of yff-picoline [3,9]. Addition of propionaldehyde to the C1-C2 feed can also be used to increase the amount of -picoline [12,13]. The yields of 1, 3, and higher alkylated pyridine by-products depends on feed composition, reaction conditions, and the choice of catalyst. 

Patents and literature reviews reveal that a wide range of catalysts has been investigated for the production of pyridine bases [5,9-11,14-18]. Up to 1980, FCC-based catalysts, often in combination with metal promoters, featured heavily as supports. The list of early solid-acid supports includes AI2O3, clays (e. g. mont-morillonite), amorphous Si02-Al203, molecular sieves (i. e. LTA), zeolites MOR and FAU (i. e. H -Y) [19], and metal phosphates [20]. 

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Table 1 lists some of the common binucleophiles utilized in heterocyclic synthesis, the numerical prefixes referring to the relative positions of the nucleophilic centers to each other. Higher order binucleophiles, e.g. 1,5-systems, come readily to mind and the above illustrative examples rapidly increase in scope when the incorporation of these structural elements into heterocyclic systems is considered. This last group offers many opportunities for ring annulations. 

Small unsaturated rings are usually very reactive undergoing ring opening in a number of ways, and this characteristic has been utilized in heterocyclic synthesis. In their role as dienophiles or dipolarophiles, the initial cycloaddition is usually followed by a valence tautomerism resulting in a six-membered or larger ring system. Several examples exist, however, where this does not occur, and these are described below. 

An interesting application of a phosphorus ylide in heterocyclic synthesis is in a ring annulation. The diazopyrazole (592) when treated with various phosphorus ylides gave the 3//-pyrazolo[5,l-c][l,2,4]triazole derivatives (593) with elimination of triphenylphosphine (79TL1567). 

The loss of one or two (or sometimes more) ring members from heterocyclics, concerted with or followed by formation of a new ring, is a highly versatile method for heterocyclic synthesis. Loss of N2, CO, CO2, S, SO, SO2, H2C=CH2, etc. is common. Diradical or dipolar intermediates are often encountered, and valence isomerization before the actual fragmentation is characteristic for some systems. 

The most useful reactions combine carbanion nucleophiles with activated aziridines. For example, the ring expansion which occurs on treatment of aziridines (219) with malonate salts typifies the heterocyclic synthesis possible. The conversion is quite general since many analogous transformations have been observed in which different carbanion stabilizing substituents were employed (73S546). 

Phosphonium hexafluorophosphate, benzotriazolyl-N-hydroxytris(dimethylamino)-in peptide synthesis, 5, 728 Phosphonium salts chromene synthesis from, 3, 753 reactions, 1, 531 Phosphonium salts, vinyl-in pyrrole synthesis, 4, 343 Phosphonium ylides in heterocyclic synthesis, 5, 165 Phosphoramide, triethylene-as pharmaceutical, 1, 157 Phosphoramide, triethylenethio-as pharmaceutical, 1, 157 Phosphorane, pentaphenyl-synthesis, 1, 532 Phosphoranes, 1, 527-537 Berry pseudorotation, 1, 529 bonding, 1, 528... 

Iminophosphoranes versatile tools in heterocyclic synthesis 95AHC(64)159. 

L. E. Tietze and G. Kettschau, in Stereoselective Heterocyclic Synthesis. I (P.Metz, ed.) [Topics in Current Chemistry, Vol. 189],p. 1. Springer-Verlag, Berlin, 1997. 

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