Heterocycles, six membered

We consider six-membered tellurium-containing heterocycles in the following sequence saturated monocyclic systems (l-hetera-2(3)(4)-telluracyclohexanes), unsaturated monocyclic systems (l-hetera-4-tellura- 

As in five-membered heterocycles, ring strain in six-membered heterocycles is of little or no importance. Pyran and thiine (thiopyran), with an oxygen or sulfur atom, respectively, and pyridine, with a nitrogen atom, are the parent compounds of six-membered neutral heterocycles with one heteroatom and the maximum number of noncumulative double bonds. In contrast to pyran and thiine, pyridine exists as a cyclic conjugated system. However, by (formal) abstraction of a hydride ion, both pyran and thiine can be converted into the corresponding cyclic conjugated cations, i.e. the pyrylium and the thiinium ions (thiopyrylium ion). 

Several reports deal with studies of rearrangement rates related to various electron-donating and electron-withdrawing substituents on the ring carbons and/or ring nitrogen in l,2-dihydro-2-imino-l-methylpyrimidine. 

It has been established that in the Dimroth rearrangement of 2-imino-pyrimidines, water plays an essential role (65JCS7071). In water the imine is, in fact, in equilibrium with its hydrate, the carbinolamine 39. That participation of the hydrate is important is shown by the experimental fact that in dry tetrahydrofuran, acetone, dioxane, or ether, the imine is quite stable and is not inclined to undergo rearrangement. However, on addition of a little water, rearrangement occurs its rate is proportional to the concentration of the water (65JCS7071). 

Interesting Dimroth rearrangements in cytosine and its derivatives occur when they are allowed to react with acetic anhydride-acetic acid. Cyto- 

Similar base-induced Dimroth rearrangements have also been reported with the related iminopyrazolo[3,4-d]pyrimidines (60JA3147) and 6-imino-8-azapurines [73JCS(PI)2659]. 

68 and 69 are formed in two parallel, independent reactions. Therefore, the conclusion seems justified that the ethano derivative 69 cannot serve as the precursor of 68 [95H(41)1399]. 

The basic structure of the 4,4 -bipyridinium-salts 7qx is also included in the iso-rr-electronic bipyrylium and bithiopyrylium salts 75ox and 16ox - The more positive potentials are already expressed in the synthetic route which leads initially to 75red and 

Obviously the higher electron affinity of O and S compared to N in If provides the systems 15 and 16 with electrochemical properties similar to 1 with strongly electron attracting substituents The more positive potentials are connected to a smaller AE i.e. Ksem is reduced by two powers of ten. 

Reductive amination of 177 via the aldehyde group in the phenoxy acid 178 affords 

At least several weeks administration of virtually all antidepressant drugs, be they the classical tricyclic compounds or the newer selective serotonin reuptake inhibitors (SSRI), is required before patients see relief from their symptoms. A recently developed SSRI whose structure departs markedly from existing agents appears to differ from other agents, in that it appears to act in a much shorter time. The final step in the synthesis of this agent elzasonan (182) comprises aldol condensation of the benz-aldehyde (180) with the thiamorpholine (181).  

Hirohashi, M. Kido, Y. Yamamoto, Y. Kojima, K. Jitsikawa, S. Fuji , Chem. Pharm. Bull. 41, 1498 (1993). 

4-pyridone nitrates at the 3-position via the 0-protonated salt. ° In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic atmck on neutral pyridones is best visualised as attack on a carbonyl-conjugated enamine (N-C=C-C=0). Dimethoxypyri-dines also undergo nitration via their cations, but the balance is often delicate, for example 2-aminopyridine brominates at C-5, in acidic solution, via the free base.  

Pyridines carrying activating substituents at C-2 are attacked at C-3/C-5, those with such groups at C-3 are attacked at C-2/C-6, and not at C-4, whilst those with substituents at C-4 undergo attack at C-3. 

Positions of electrophilic attack on pyridines carrying activating substituents 

Gluco- and galactopyranosides were reacted with phosphonic and phosphoric dihalides to provide dioxaphosphorinane oxides 73 and 74 as mixtures of the two phosphorus epimers, which were separated. A similar method was used to prepare oxathiaphosphorinanes 75 from the corresponding thiopy-ranoside. Dioxaphosphorinane sulfides 76 were prepared from phospho-nothioic dichlorides [RP(S)Cl2] or by oxidation of the corresponding P(III) precursor with sulfur. Finally, oxazaphosphorinane oxides and sulfides 77 were prepared similarly.  

Fiilop and co-workers prepared tricycles 85 as mixtures of separable epimers and studied their conformation in solution in detail. More reeently the same group did a similar study, complemented with theoretieal ealeulations, on 

Spiro amino alcohols 89 were reacted with dichlorophenylphosphine and after treatment with borane provided protected oxazaphosphorinanes 90. The diastereoselectivity of the cyclisation was found to be low (0% for R = H and 43% for R = Me) but the epimers could be separated by crystallisation or column chromatography. In the case of R = H, bidentate ligands (91) could be prepared via deprotonation of the NH group and double nucleophilic substitution on dibromomethane. X-ray crystallography of 90 (R = Me) and 91 was used to determine the absolute configuration of the phosphorus atom. 

Upon deboronation of 90 and 91 with DABCO, however, it was found that the free oxazaphosphorinanes are extremely sensitive to oxidation. Although Rh complexes could be detected by NMR, they are also very sensitive and give the corresponding oxides when exposed to air. 

The extreme sensitivity of oxazaphosphorinanes is surprising and shows that there can be discrepancies between basicity and oxygen sensitivity, pointing out that factors affecting oxidation rates in tricoordinated phosphorus compounds are still not clearly understood. 

Coumaline (a-pyrone) 169 forms a diadduct 172. This apparently results from the initial diene adduct 170 losing CO2 to generate a new diene 171 

Recently, Sigal and Loew have examined the reactions of the phosphorus analogue of a-pyrone. On heating with MA at 140°C 175 gave 172 and a polymer of the phosphorus residue 176. No intermediates were isolated. 

However, the DA reaction is analogous to that of 169 with different fates of residues split from the intermediate. 

2-Styrylquinoline reacts with MA to give an ionic maleate salt correspond- 

Schonberg and Mustafa had originally formulated the product of 2,3-dimethylquinozaline 180 with MA incorrectly as 182. 

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Pd-cataly2ed reactions of butadiene are different from those catalyzed by other transition metal complexes. Unlike Ni(0) catalysts, neither the well known cyclodimerization nor cyclotrimerization to form COD or CDT[1,2] takes place with Pd(0) catalysts. Pd(0) complexes catalyze two important reactions of conjugated dienes[3,4]. The first type is linear dimerization. The most characteristic and useful reaction of butadiene catalyzed by Pd(0) is dimerization with incorporation of nucleophiles. The bis-rr-allylpalladium complex 3 is believed to be an intermediate of 1,3,7-octatriene (7j and telomers 5 and 6[5,6]. The complex 3 is the resonance form of 2,5-divinylpalladacyclopentane (1) and pallada-3,7-cyclononadiene (2) formed by the oxidative cyclization of butadiene. The second reaction characteristic of Pd is the co-cyclization of butadiene with C = 0 bonds of aldehydes[7-9] and CO jlO] and C = N bonds of Schiff bases[ll] and isocyanate[12] to form the six-membered heterocyclic compounds 9 with two vinyl groups. The cyclization is explained by the insertion of these unsaturated bonds into the complex 1 to generate 8 and its reductive elimination to give 9. 

The shapes of heterocyclic rings are very much like those of their all carbon analogs Thus six membered heterocycles such as piperidine exist m a chair conforma tion analogous to cyclohexane... 

Six-membered heterocycles with two heteroatoms are prepared by reaction of diketene with a substrate containing a C—O or C—N multiple bond. With carbonyl compounds diketene reacts in the presence of acids to give l,3-dioxin-4-ones. The best known is 2,2,6-trimethyl-4H-l,3-dioxin-4-one [5394-63-8] (15), the so-called diketene—acetone adduct, often used as a diketene replacement that is safer to handle and to transport, albeit somewhat less reactive than diketene itself (103,104), forming acetylketene upon heating. 

The H NMR spectra of aromatic six-membered heterocycles have been measured extensively. The considerable amount of data which were available by 1972 were compiled by Batterham in an excellent critical monograph (B-73NMR), which provides the basis for the general account which follows here. 

The tautomerism of six-membered heterocycles has been referred to elsewhere (Section 2.01.1), in connection with the variety of aromatic structures available to heterocyclic compounds. In this section we consider the matter in more detail. For a fuller discussion the reader should consult the monograph by Elguero et al. (76AHC(S1)) which thoroughly covers work on the subject up to 1976. 

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

Ring expansion of five- to six-membered rings such as oxazole —> pyridine derivatives via a Diels-Alder reaction is a well-established procedure. However, the conversion of a six-membered heterocycle into a five-membered ring system has not been exploited to any great extent, and those systems that have been studied usually involve a cationic species. 

This reactivity of A-unsubstituted amino-pyrazoles and -indazoles which can be regarded as 1,3-diamino derivatives has been used to build a great variety of fused six-membered heterocycles such as the 1,2,4-triazine derivatives (540) and (541), the 1,3,5-triazine derivatives (542) and (543), and benzothiadiazines (544). 

SYNTHESIS FROM OTHER HETEROCYCLIC COMPOUNDS 4.17.10.1 From Six-membered Heterocycles... 

Pfitzinger synthesis, 2, 446 six-membered heterocycles from, 2, 92 synthesis, 4, 150 Isatogens... 

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