Pteridines, substituted

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

AT-Oxidation is very sensitive to steric effects, since 1-substituted lumazines and pterins give only 5-oxides and the presence of bulky substituents at position 7 also directs oxidation to N-5. The pteridine 5-oxide (52) and 8-oxide (53) and the 5,8-dioxide (55) contain the AT-oxide groups as such, even when the possibility of AT-hydroxy tautomers exists, as in (53) i(54). 

No simple electrophilic substitution, for example nitrosation, nitration, sulfonation or halogenation of a C—H bond, has so far been recorded in the pteridine series. The strong 7T-electron deficiency of this nitrogen heterocycle opposes such electrophilic attack, which would require a high-energy transition state of low stability. 

In contrast to electrophilic reagents, the highly -tt-deficient character of the pteridine nucleus is responsible for its vulnerability towards nucleophilic attack by a wide variety of reagents. The direct nucleophilic substitution of pteridine itself in a Chichibabin-type reaction with sodamide in diethylaniline, however, was unsuccessful (51JCS474). Pteridin-6-one, on the other hand, yielded pteridine-6,7-dione under the same conditions, via a still unknown reaction mechanism. 

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

A great variety of differently substituted pteridine derivatives have been synthesized starting from (109) or the 2,4,6,7-tetrabromo compound (60USP2940972), which shows a corresponding reactivity pattern. Amines at low temperature substitute only the 6- and... 

As a result of the 7r-deficiency of the pteridine nucleus, alkyl pteridines are activated in the a-positions. The common reactions based on C—H acidity are found with a wide variety of compounds. Bromination of 6- and 7-methyl groups leads to mono- and di-substitution selective formation of the monobromomethyl derivatives has not yet been achieved satisfactorily. 6-Methylisoxanthopterin is claimed to give the 6-bromomethyl derivative with bromine in acetic and sulfuric acids at 100 °C for 2 min (50ZN(B)132) and with 1,7-dimethyl-lumazine a 90% yield of the 7-bromomethyl derivative (60CB2668) is obtained after 4h... 

Among the substitution reactions involving the ring nitrogen atoms of the pteridine nucleus, alkylations of amide functions are preeminent. Under base-catalyzed conditions it is usually the nitrogen atom adjacent to the carbonyl function which is substituted... 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

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