Solid heterocyclic compounds

A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

Identification of the product(s) resulting from the reaction of heterocyclic compounds with diazomethane has been used in attempts to elucidate their tautomeric composition (for summaries, see references 7 and 41). This work was based on the assumption that if a compound which is capable of existing in both an —NH and an —OH form produced only the =NMe derivative when it w as treated with diazomethane, it existed entirely in the =NH form. On the other hand, formation of the —OMe derivative was interpreted to mean that a finite amount of the compound existed in the —OH form. In some cases the tautomer present in the solid state w as concluded to be different from that present in solution for example, 41 42 gave a higher proportion of the 3,4-dimethoxy derivative when ethereal diaz-... 

The imbalance between and NMR studies in the solid state (Section VI,F) partly reflects the fact that it is easier to introduce N than into heterocyclic compounds, particularly azoles (DNMR in the solid state usually requires isotopic enrichment). Compared to solution studies, solid-state intermolecular proton transfer between tautomers has the enormous advantage that the structure of the species involved is precisely defined. 

Solid supports such as silica gel and alumina have also been used in the generation of 1,3-dipoles to obtain heterocyclic compounds. However, changes in regios-electivity were not observed under microwave irradiation conditions. The regioselec-tivity can be modified by changing the polarity of the solid support [90], De la Hoz reported the reaction of pyridinium dicyanomethylidene ylide (130) with ethyl phenyl-propiolate (73), and found that the selectivity changes from 88 12 to 98 2 when the support is changed from celite, to neutral bentonite (Scheme 9.39). 

At first, combinatorial chemistry focused on peptide and nucleotide libraries synthesis, but because poor pharmacokinetical properties cause poor oral availability of this kind of molecule, there is increasing interest in the development of new methods to prepare small, drug-tike molecules which obey lipinski s mle of five [303]. Heterocyclic compounds can offer a high degree of structural diversity and have proven to be useful as therapeutic agents. For these, there are recent advances in the preparation of heterocycles on solid supports [304]. The examples reported in this section are organized by their ring size. 

The thermal [2-1-2] dimerization of solid dicyclohexylcarbodiimide 377 requires the action of gaseous sulfur dioxide at 0 °C as an easily removable catalyst. The interesting heterocyclic compound 378 is quantitatively obtained [33] (Scheme 61). 

Dipolar additions are a fertile field in quantitative solid-state chemistry. For example, solid diphenylnitrone (392) adds phenylisocyanate vapor (393) at room temperature to give a 100% yield of the interesting heterocyclic compound 394 (Scheme 63) [22]. 

In 1970s, first application of metal-chelate affinity chromatography which is later named as "immobilized-metal (ion) affinity chromatography (IMAC) was perfomed. Metal-chelate chromatography technique exploits selective interactions and affinity between transition metal immobilized on a solid support (resin) via a metal chelator and amino acid residues which act as electron donors in the protein of interest [25-26]. As well as aromatic and heterocyclic compounds, proteins such as histidine, tyrosine, tyriptophane and phenylalanine posses affinity to transition metals which form complexes with compounds rich in electrons [25,27]. 

For more than two decades, most developments in solid-phase chemistry were focussed on the preparation of biopolymers. Only in recent years has interest in other synthetic targets, including heterocyclic compounds, begun to grow. Today, the field of solid-phase heterocyclic chemistry is rapidly expanding, and numerous preparations have been reported. 

Figure 2. Equilibrium concentrations in mole fractions of selected compounds at 500°K. and 1 atm. with composition of 40% oxygen, the indicated percentage of carbon, and the rest hydrogen. To this basic composition is added an amount of nitrogen equal to the amount of carbon. The nitrogen remains primarily as N2 but produces significant quantities of some interesting compounds. The free energy of carbon in the system equals that of graphite at the composition indicated by the arrow. At this point solid carbon would be precipitated if it could be formed there is no inflection of the curves at this point. The asphalt threshold is shown as a sharp inflection, sharpest of all for the aromatic and related heterocyclic compounds. If an atmosphere such as this were to condense, there would be about 1 molecule of glycine per droplet of condensate (6).

The first account on the carbonylation of heterocyclic compounds with metallo-dendrimers was recently reported by Lu and Alper using Rh-complexed dendrimers on a resin [207]. The building-block techniques of solid-phase chemistry were used to synthesize dendrimers, followed by phosphonation of the dendrimers with diphenylphosphinomethanol. The resulting phosphonated dendrimers were then reacted with chloro(dicarbonyl)rhodium(I) dimer to give dendritic catalysts A and B (31P NMR, 8 - 25 ppm loading of rhodium A, 0.74 mmol g-1 B, 0.83 mmol g ). As a model study, the reaction of l-ferf-butyl-2-phenylaziridine with carbon monoxide in catalytic presence of A afforded the desired [3-lactam... 

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

Solid-Phase Synthesis of Heterocyclic Compounds from Resin-Bound Amino Acids, Short Peptides, and Polyamines... 

Fig. 2. Solid-phase synthesis of heterocyclic compounds from resin-bound amino acids.

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

For l,3,2(A2)-diazasilacyclopentene 83, the following Raman lines at 650, 991, 1178, 1566, 1573 cm-1 were reported in the solid state. The intensive doublet at 1566 and 1573 cm-1 was assigned to the (C=C) stretch vibration. The observed bathochromic shift of this band in the spectra of compound 83 compared to heterocyclic compounds having a tetravalent silicon, for example, 93, and the significant intensity enhancement of this band indicates cyclic conjugation in molecule 83 <2000JST329, 2004JA4114>. 

Nefzi A, Ostresh JM, Meyer JP, Houghten RA, Solid phase synthesis of heterocyclic compounds from linear peptides cyclic ureas and thioureas, Tetrahedron Lett., 38 931-934, 1997. 

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