Heterocyclic derivatives

The synthesis of (polyhydroxy)alkyl-furan, -pyrrole, and -indole derivatives, etc., by condensation of aldoses and ketoses with P-dicarbonyl compounds has been reviewed.  

1-Alkylamino-l-deoxy-D-fructoses reacted with potassium isocyanate in the presence of hydrochloric acid to give imidazole derivatives [e.g. (235)], while 1-amino-1-deoxy-D-gi/uco-heptulose gave the 4-[(polyhydroxy)a(kyl]pyrrole (236) 

Garcia Gonzalez, J. Fernandez Bolanos, and F. J. Lopez Aparicio, Amer. Chem. Soc. Symposium Ser., 1976, No. 39, Synthetic Methods Carbohydrates Symposium, 207 (Chem. Abs., 1977, 86, 190348r). 

The branched-chain ketols (241) have been prepared by reaction of 3-C-ethynyl-l,2 5,6-di-0-isopropylidene-a-D-allofuranose with an appropriate aldehyde (e.g. 

5 REACTIONS WITH ORGANOPHOSPHORUS AND RELATED COMPOUNDS 10.5.1 Heterocyclic derivatives 

The relatively stable carbon-phosphorus bond is resistant to cleavage by phosgene in a way that is similar to a carbon-carbon bond in a hydrocarbon chain. The phosphorus atom, in its formal oxidation state of +3 in an organic compound, however, may react by virtue of its unshared electron pair. 

Cis-1-alkyl(or aryl)-2,5-dimethyl-3-phospholenes were noted to isomerise to the trans-isomers in CDCI3, the isomerization being a result of small quantities of COClj in the solvent. Addition of an excess of phosgene to the cis- isomer gave the quaternary salt depicted in the following scheme, which quickly equilibrated to another salt (which could also be prepared from the reaction of the trans- isomer with an excess of phosgene [877]  

Phosphido saits are particularly reactive towards halogen-containing compounds. Not surprisingly, therefore, the lithium salt of the 2,5-diphenylphospholyl anion reacts with phosgene to give 2,2, 5,5 -tetraphenylbiphospholyi [359]  

Treatment of the tetrachlorodiaminocyclotriphosphazene (10.30) with a cold solution of phosgene in chlorobenzene gives the carbamoyl chloride as an intermediate. Heating this solution under reflux for several hours gave both a pentachloro derivative and an isocyanate [2018]  

I -epimer was encountered. Condensation of various 1-alkylamino-l-deoxy-D-arabino-hexuloses with ethyl acetoacetate afforded a series of pyrrole derivatives with a D-arabino-hexityl side chain at C-3 [e.g. (52)] and condensation of l-bromo-l-deoxy-D-nZ)o-hexulose with HSC(=NH)C02Et afforded the thiazole (53). Cyclization of D-penicillamine with 2,3,4,5-tetra-O-acetyl-flWe/ijdo-L-arabinose afforded, after f -deacetylation the thiazolidine (54) as a mixture of two diastereoisomers. The tetrazoles (55) are prepared by condensation of the appropriate benzoylated aldononitrile with ammonium azide, followed by 0-debenzoylation 

Garda-Gonzalez, J. Fernandez-Bolanos, G. Martin Jimenez de la Plata, N. Lopez Partida, and I. Robina Ramirez, An. Quim., 1978, 74, 1281 (Chem. Abs., 1979, 91, 108 169e). 

Farkas, and J. Gut, Collect. Czech. Chem. Commun., 1979, 44, 1339. 

Bognar, Z. Gyorgydeak, L. Szilagyi, P. Sandor, and L. Radies, Justus Liebigs Ann. Chem., 1979, 701. 

Lopez Aparicio and F. J. Lopez Herrera, Carbohydr. Res., 1979, 69, 243 (with M. Valpuesta Fernandez) 235. 

In a further study of dipolar addition reactions of carbohydrate acetylenic-ketone derivatives leading to heterocyclic compounds (see Vol. 11, p. 91), 

Gonzdlez s group have prepared a series of isoxazoline derivatives (22) using hydroxylamine with the corresponding acetylenic keto-sugar (23).  

Cyclocondensation of l-alkylamino-l-deoxy-D-/Arco-pentuloses with ethyl acetoacetate led to iV-alkyl-pyrrole derivatives (24). Aldonic acid lactones react with ethyl isocyanoacetate in presence of DBN to yield oxazole derivatives, e.g. 2,3 5,6-di-0-isopropylidene-D-mannono-l,4-lactone yields the oxazole (25), whereas with potassium hydride as base octenonate derivatives 

The reaction of L-rhamnose with aqueous ammonia leading to heterocyclic compounds has been studied sixty-five components of the complex product mixture were identified, which were principally pyrazine, pyrrole, and imidazole derivatives, and possible mechanisms for their formation were discussed.  

The elongation of sugar chains via heterocyclic derivatives is mentioned in Chapter 8. Thiazoline derivatives are referred to in Chapter 10. 

Reaction of 2-amino-2-deoxypentoses with pentane-2,4-dione and 1-phenyl-butane-1,3-dione afforded substituted pyrroles (e.g., 41) and the riboflavin analogue (42) was prepared by condensation of l -ribose with 5-amino-o-cresol, followed by cyclocondensation of the product with violuric acid. Reaction of dehydroascorbic acid with o-phenylenediamine followed by aroylhydrazides afforded compounds of the type (43), the side-chains of which have been further elaborated. The acid derived by oxidation of 2,3 4,5-di-0-iso- 

Condensation of glycosyl isocyanides with amines in the presence of mercuric or silver chloride gave formamidines (Gly-N=CH—NR2), but when methyl anthranilate was used with mercuric chloride, cyclization took place to give the nucleoside analogue (47). When silver chloride was used as catalyst only the intermediate formamidine was obtained 

Garcia Gonzalez, J. Femandez-Bolanos, and J. Galbis Perez, Amies de Quint., 1974, 70, 1082 iChem. Abs., 1975, 83, 193 598w). 

L-cysteine was used, the bicyclic lactone derivative (166). Computer-assisted analysis of the n.m.r. spectra of (165) (R = Me, R = Ac) and its (5)-diastereoisomer showed that the polyacetoxyalkyl side-chain possesses a 

Tsuchida, M. Komoto, H. Kato, and M. Fujimaki, Nippon Nagei Kagaku Kaishi, 1976, 50, 187 (Chem. Abs., 1976, 85, 160 428d). 

Gyorgydeik, L. Szildgyi, G. Horvath, G. Czira, and L. Radies, Annalen, 1976, 450. 

3-O-Benzyl-l, 2-O-cycIohexylidene-a-D-xylodiaIdo-l, 4-furanose reacted with the 2-lithio-derivatives of furan, pyridine, picoline, and benzothiazole to give the corresponding 5-C-heterocyclic derivatives [e.g. (169)] in low yield.  

The methyl esters of D-gluco-, D-galacto-, and D-manno-pyranosyluronic acids reacted with A N-dimethylbiguanides to give -triazine derivatives [e.g. (170)], which have found use in agriculture.  

COCH2CH3 - Obtained from sesamolyl propionate with aluminium chloride in refluxing carbon disulfide for 1 h [7885]. 

The formula of Kakuol represented in Chem. Abstr., 104,199940a (1986) was erroneous. 

3- Hydroxy-4,5-methylenedioxypropiophenone 3,4-Methylenedioxy-5-hydroxypropiophenone l-(3,4-Methylenedioxy-5-hydroxyphenyl)-propan-l-one 

From Ferula communis subsp communis (compound 20) [7905]. 

From the underground parts of Laserpitium silerL. of Slovenian origin [7907]. From the underground parts of Laser trilobum (L.) Borkh. species [7908]. From the roots of Peucedanum pauciradiatum (Umbelliferae) [7909]. 

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The formation of heterocycles derived from quinones is an important synthetic technique. The reaction may be intramolecular, eg, the reaction of (92). Either nitrogen products, eg (93) (yields of 85—91% for R = H, CH, and C H ) or oxygen products (94) are obtained (92,93). Reactions with enamines have been especially important. 

F. G. Mann, The Heterocyclic Derivatives of Phosphorus, Arsenic, Antimony and Bismuth, 2nd ed., Wiley-Interscience, New York, 1970. 

Pyrazoles have been prepared by the action of hydrazines on heterocyclic derivatives which react as masked functional groups of a 1,3-difunctional derivative (Section 4.04.3.1.2(ii)). 

Whereas the fulvalenes 1-6 are relatively unstable hydrocarbons and therefore largely of theoretical interest, their heteroatom analogs demand considerable attention in synthetic chemistry and material sciences. Tlie general principle of heterocyclic chemistry to relate heterocyclic compounds to carbocyclic ones was the driving force for the synthesis and their application to heteroful-valenes. Numerous heterocyclic derivatives iso-rr-electronic with, for example, heptafulvalene 3 were accessible in which pairs of carbon atoms linked by double bonds were replaced by heteroatoms capable of contributing two tt-electrons. By this principle, the well-known tetrathiafulvalene and its derivatives have been synthesized successfully (Scheme 2). 

Studies of Prof. S. Tobinaga in the field of 0-heterocycles derived from plants (self-review) 99YZ185. 

Heterocycles in synthesis of herbicide glyphosate heterocyclic derivatives and analogs of glyphosate 97PHC17. 

Table 2 A comparison between conventional heating and microwave-assisted synthesis in an intramolecular Heck coupling to heterocyclic derivatives of 2-quinolones 20 and 21. Note the high selectivity in (b), where two possibilities exist to fuse a six-membered ring...

Hence, microwave irradiation in DMA for 12 min at 120 °C or 30 min at 140 °C, depending on the substrate, resulted in 20 or 21 in 90-96% yields, compared to yields around 50% and a 24 h reaction time for conventional heating. As can be seen in Eq. 2 in Fig. 5, two possibilities exist to connect the heteroaryl bromide part with the five-membered heterocycle (indicated by a and fi. Table 2) that results in a six-membered 2-pyridone ring. Still, a very high selectivity was obtained yielding the 2-pyridones 21, in which the new bond had been introduced at Ca. It should be noted that the obtained structures 20 and 21 represent heterocyclic derivatives of 2-quinolones rather than true 2-quinolones. 

At the time of its discovery in 1970, few chemical methods were known for the laboratory syntheses of such molecules. Fewer still were appropriate for their industrial scale production. Unlike many other amino acid derivatives, gl rphosate is stable in strong acid or base, even at elevated temperatures. It can also tolerate strong reductants and some oxidants (1,2). This stability accounts for the diversity of synthetic methods that have been explored and developed to prepare glyphosate and its heterocyclic derivatives over the last 25+ years. 

A recent paper from Katritsky summarises all the preparations of achiral dissymmetrical thioureas and proposes a new one, based on l-(alkyl/arylthio-carbamoyl)benzotriazoles, which act as masked isothiocyanates. As described in the previous section, other N-heterocyclic derivatives can be used instead... 

The heterocyclic derivative successfully protects the acid from attack by Grignard or hydride-transfer reagents. The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol. 

The synthesis of new heterocyclic derivatives under conservation of a preformed cyclic structure is not only of particular importance for the synthesis of ionic 1,3,2-diazaphosphole or NHP derivatives but has also been widely apphed to prepare neutral species with reactive functional substituents. The reactions in question can be formally classified as 1,2-addition or elimination reactions involving mutual interconversion between 1,3,2-diazaphospholes and NHP, and substitution processes. We will look at the latter in a rather general way and include, beside genuine group replacement processes, transformations that involve merely abstraction of a substituent and allow one to access cationic or anionic heterocycle derivatives from neutral precursors. 

Mann FG (1970) The heterocyclic derivatives of phosphorus, arsenic, antimony, and bismut, 2nd edn. Wiley, New York... 

The photoelectron spectrum of selenophene vapor down to 1350 A has been studied. By analogy with the other heterocyclic derivatives, Rydberg-type transitions occur, leading to the first ionization potential of the molecule.23... 

Heterocyclic derivatives of the cyclopentadienyl ligand have been incorporated in organomagnesium species. The reaction of bis(cyclopentadienyl)-l-zircona-2,3,4,5-tetraethylcyclopenta-2,4-diene with ECI3 (E=P, As, Sb) yields... 

Inter- and intramolecular 1,3-dipolar cycloadditions of nitrones under microwave irradiation have been reported to give heterocyclic derivatives. 

The thermal hydrazone-azomethine imine isomerization can be easily performed under microwave irradiation in the absence of solvent. The subsequent 1,3-dipolar cydoadditions with electron-defident dipolarophiles occur in only a few minutes to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones 205 leads to valuable compounds, such as bipyrazoles 213, in good yields and this provides a new approach to the preparation of these heterocyclic derivatives [116] (Scheme 9.67). Reactions undertaken with dassical heating under comparable reaction conditions (time and temperature) lead to cydoadduct yields that are considerably lower and, indeed, several dipolarophiles do not react at all. 

Recent work in the chemistry of phosphorus heterocycles derived from a-hydroxyalkylphosphines and vinylphosphines, much of which has appeared in the Russian language literature, is covered by B. A. Arbuzov and G. N. Nikonov (Kazan, Russia). 

A successful solid-phase approach to libraries of asymmetrically disubstituted furazano[3,4-7 ]pyrazines 244 has been developed. By using these solid-phase synthetic protocols, 320 fused heterocyclic derivatives were synthesized (Scheme 63) <2002TL4741>. 

The most common method for the preparation of 1,2,3-benzothiadiazoles is the diazotization of 2-aminobenzenethiol. This method was discussed and exemplified in CHEC-II(1996). The method has been extended in recent years to include heterocyclic derivatives. The 2-aminothiophene 79 can be converted into the thienothiadiazole 82 on treatment with sodium nitrite in HC1 but in poor yield (16%). The bis(BOC)-protected derivative 80 or the mono(BOC)-protected derivative 81 when reacted under similar conditions afford product 82 in much higher yields (BOC = /-butoxycarbonyl Scheme 9). The increase in yield is explained in terms of hard and soft electrophilic character. The intermediate in the BOC-protected examples has a soft character allowing attack by sulfur to proceed more easily <1999JHC761>. 

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives continued in 2000. Solid-phase combinatorial chemistry of pyrazoles and benzimidazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. Notably, metal-promoted and cross-coupling reactions of all classes seemed to be a dominant theme in 2000. Applications of pyrazole-, imidazole-, and 1,2,3-benzotriazole-containing reagents to a wide array of synthetic applications remained active. 

The new heterocyclic derivative 130 has been shown to be an efficient chiral auxilliary for asymmetric desymmetrization of cyclic meso-l,2-diols via diastereoselective acetal cleavage . 

Many seven-membered ring heterocyclic derivatives show pharmacological activity, and many, for example the benzodiazepines, nevirapine (anti-HIV), trineptine (antidepressant) and artemisinin derivatives (anti-malarial) are used clinically. The number of papers reporting pharmacological activity of new compounds or pharmacological mode of action studies continues at a significant rate. 

Heterocyclic derivatives such as 59 provide a convenient route to the synthesis of many cyclic germanium compounds87. For instance, photolysis of 59 in the presence of alkynes 60 or 61, or allenes 62, produces the unsaturated heterocyclic compounds 63 or 64, respectively. 

Heterocyclic Compounds It is useful to begin this paragraph with recent syntheses of rather simple heterocyclic derivatives, important as intermediates for the preparation of more complicated products. These syntheses can also be used as models for elaboration of new syntheses, first of all, those of... 

Nucleophilic addition of metallated heterocyclic derivatives to AMetrahydro-pyranyl (THP) protected nitrones (361) makes it possible to synthesize a-branched hydroxylamines (362) (Table 2.13) (597). 

Fig-1 General structure of a stilbene heterocyclic derivative (A), and two chalcone heterocyclic derivatives (B and C). (Dashed circles represent the location of the herocydic ring)... 

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