N- and O-Heterocycles

The l,3-oxazin-2-ones and 1,3-oxazine-2-thiones previously synthesized were used to prepare various N- and O-heterocyclic systems fused with 1,3-oxazine rings.172 For example, furan-l,3-oxazin-2-one or furan-l,3-oxazine-2-thiones (190a,b) and pyran-l,3-oxazin-2-ones or pyran-l,3-oxazine-2-thiones (190c,d) were prepared in very good yields, ranging from 83% to 90%, by montmorillonite K-10 clay-catalyzed cyclodehydration of 189a,b and 189c,d, respectively (Scheme 35). 

The same reactions, carried out with potassium carbonate as base in place of a secondary amine, yield exocyclic dienes in good yield, although double-bond isomerization sometimes occurs (equation 38).93 Inclusion of tetra-zi-butylammonium chloride in the reaction mixture stops the double-bond isomerization. Thus, the reaction in equation (38) with the chloride yields only the bis(exomethylene) product in 45% yield in a slow reaction. Some N- and O-heterocyclic products, also, have been prepared by the intramolecular vinyl substitution reaction.94 A 16-membered ring lactone was made by the ring closure of a vinylic iodide group with a vinyl ketone group. The yield, based upon the reactant, was 55% but a stoichiometric amount of bis(acetonitrile)palladium dichloride was employed. The catalyst was prereduced with formic acid so that the reaction proceeded at 25 C (equation 39).95... 

Synthesis of N- and O-heterocycles, peri-fused naphthacenequinone derivatives 93UK1078. 

Radical reactions in the syntheses of natural N- and O-heterocycles 91CRV1237. 

N- and O-Heterocycles bioactive metabolites of symbiotic marine microorganisms 93CRV1753. 

In hdn of indole and quinoline and hdo of benzofuran N- and O-heterocyclics of the type occurring in petroleum residua, shale oils, and coal) over a sulphided Co-Mo/AI2O3 catalyst (617 K, 48 atm) ring hydrogenation preceded C-N or C-0 fission and was rate-determining. Selectivity to alkylcyclohexanes over alkylbenzenes was > 90%. 

As in the case of <%-amino carboxylic acids, the zwitterions of N- and O-heterocyclic a-carboxylic acids can be decarboxylated thus <%-picolinic, thiazole-2-carboxylic, quinaldic, and chelidonic acid afford, respectively, pyridine, thiazole, quinoline, and 4-pyrone. Furan is best prepared by removal of carbon dioxide from pyromucic acid (2-furoic acid) by heat in early work this was effected by heating the acid in a sealed tube or with soda-lime, but Wilson19 has described a convenient method that involves only simple apparatus and affords the very good yields of 72-78% ... 

Metathetic ring closure. Five-, six-, and seven-membered carbocycles as well as N and O heterocycles are constructed from dienes in the presence of a Ru-carbene complex. For unhindered amines, prior protonation is necessary. Fused bicyclic structures are accessible from dienynes. ... 

With increasing emphasis on the single-enantiomer synthesis of pharmaceuticals, there is a need for efficient methods for the preparation of enantiomerically-enriched N and O heterocycles. 

The synthetic polymers based on N-acryloyl amino acid-derivatives developed by Blaschke in the 1970 and transferred to silica-bonded phases in the 1980 are especially useful for the separation of 5- and 6-membered N- and O-heterocycles with chiral centers (Review in Kinkel, 1994). Their wide chemical variety has been intensively exploited by Bayer Healthcare for their portfolio of chiral molecules. One example of this approach has been published in a joint work of Merck and Bayer (Schulte, 2002). This work explicitly shows how important it is to screen different intermediates in addition to the final dmg compound. Due to different selectivities and solubilities, the productivity for the preparative separation can be dramatically different. 

Structures of new terpenoids with N- and O-heterocyclic fragments from Chinese herbal medicine 98PAC431. 

From one-photon to two-photon probes Caged compounds, actuators, and photoswitches (among the probes are N- and O-heterocycles) 13AG(E)4526. 

In 2006, Trost and co-workers reported a one-pot synthesis of enantiopure N- and O-heterocyclic compounds using the combination of an achiral ruthenium catalyst and a chiral palladium complex. After the completion of the ruthenium-catalysed alkene-alkyne cross-coupling reaction between the... 

Wittig reactions have also been employed in domino processes. For example, Schobert and coworkers developed an effective addition/Wittig reaction protocol which provides access to a, 3-disubstituted tetronic acids, tetronates, as well as to five-, six- and seven-membered O-, N-, and S-heterocycles [149]. 

A series of heterocyclic compounds, containing the P—C—N and o-substituted aminophenylene fragment have been synthesized [Eq. (36)]. These are benzazaphospholenes (71), benzazaphosphorinanes (72), and benzazaphosphepanes (73) (70-71 Mil 74MI1 76MI1). 

Chiral 10 to 12-membered nitrogen and oxygen heterocycles, fused to isoxazo-line rings have been prepared with high regio- and stereoselectivity by INOCs of tethered N- and O-allyl carbohydrate derivatives. The use of a -Y-Ar-CH2 tether, containing a 1,2-disubstituted aromatic ring between the heteroatom attached to... 

Schwesingefs phosphazene base 2-tert-butylamino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (PS-BEMP has a pKb = 27.5 in MeCN) has been immobilized and shown to have immense utility in the N- and O-alkylation of many weakly acidic heterocycles. Kim et al. has made extensive use of this reagent in the multi-step synthesis of a small collection of guanines possessing potential antiviral activity [90]. The generic procedure involved the direct alkylation of the purine moiety (20) (Scheme 2.64), promoted by PS-BEMP, resulting in a mixture... 

The 5-oxazolones or oxazolin-5-ones are very interesting heterocyclic compounds that have been used as intermediates in the synthesis of a variety of organic molecules. Two structural classes are possible, the 5(27T)-oxazolones (or 3-oxazo-lin-5-ones) and 5(47T)-oxazolones (or 2-oxazolin-5-ones). These structures differ only in the position of the double bond. Apart from the presence of the heteroatoms (N and O), the carbonyl group and the double bond, the 2- or 4-position, respectively, can be saturated or unsaturated. The isomeric 5-oxazolones are... 

With [Ti6-(0-dichlorobenzene)FeCp]+, selective mono- and di-substitution can be achieved with a variety of N- and O- and stabilized C-nucleophiles.77 With a bisheteroatom nucleophile, benzo-fused heterocycles are produced (equation 23).74... 

Heterocycles are known to have O—S, S—N, and O—N bonds. The cyclization of peri-hydroxy and peri-amino-substituted naphthalene sulfonic acids gives rise to 1,8-naphthosultone 246 and 1,8-naphthosultam 247, respectively (33MI2 63MI1). On gas phase photolysis of naphtho[/>c]-... 

The cyclic carbopalladation-cross-coupling tandem reaction has been extensively developed over the past several years. Despite earlier favorable findings with A1 and Zr [84], these metals are still scarcely used. On the other hand, organometals containing Sn and B have been widely used, and favorable results have been obtained for the formation of ffve-membered car-bocycles and heterocycles containing N and O from halodienes [88] (Eqs. 1 and 2 in Scheme 29), haloenynes [89-92] (Eqs. 3-5 in Scheme 29), haloaryl-alkynes [94,95] (Eqs. 6 and 7 in Scheme 29), and allenene derivatives [93,96] (Eqs. 8 and 9 in Scheme 29). 

The common heteroatoms of heterocyclic molecules are more electronegative than carbon. Thus, for N and O, for which the sizes are comparable with C, an isoelectronic substitution of C should lead to a stabilization of the system. Figure 1 exemplifies this by comparing the simple Hiickel MOs for... 

Five- to seven-membered O-, N-, and S-heterocycles Acyl ylides with a tethered terminal ester function requisite for the construction of five- to seven-membered heterocycles are very conveniently accessible by reaction of the cumulated ylide ketenylidenetriphenylphosphorane 11 with various carboxylic esters bearing OH-, NHR-, and SH-groups in a-, -, or y-position. 

It is important to recall that the reactivity pattern of phosphoies is very different from that of the related S, N, and O ring systems due to their limited aromatic character. For example, electrophilic substitution takes place only with a handful of phosphoies that have been specifically tailored via increasing the bulkiness of the P substituent (see Section 3.15.10.4, Scheme 83). In fact, electrophiles react at the phosphoms atom affording a panel of neutral and cationic CN 4 derivatives (Scheme 8). Phosphoies are also versatile synthons for the preparation of other heterocyclic systems via Diels-Alder reactions. The cycloaddition can involve the dienic moiety of the phosphole ring or can occur following a 1,5-shift of the P-substituent (Scheme 8). Finally, phosphoies can be transformed into phospholide ions, which are powerful nucleophiles that have found a variety of applications (Scheme 8). All these facets of phosphole reactivity are presented in this section. It should also be noted that CN 3 phosphoies exhibit a rich coordination chemistry toward transition metals (see Section 3.15.12.2). 

S-adenosyl-L-methionine (SAM)-dependent methyl-ation was briefly discussed under Thiomethylation (see Figure 14). Other functional groups that are methylated by this mechanism include aliphatic and aromatic amines, N-heterocyclics, monophenols, and polyphenols. The most important enzymes involved in these methylation reactions with xenobiotics are catechol O-methyltransferase, histamine N-methylt-ransferase, and indolethylamine N-methyltransferase - each catalyzes the transfer of a methyl group from SAM to phenolic or amine substrates (O- and N-methyltransferases, respectively). Methylation is not a quantitatively important metabolic pathway for xenobiotics, but it is an important pathway in the intermediary metabolism of both N- and O-contain-ing catechol and amine endobiotics. 

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