Acids annulation

The pyran-4-one ring (whether annulated to benzene or not) exerts an effect on some attached groups, for example, on the ease with which protons are detached from methyl groups and on the pKa of some carboxylic acids. Annulation of a benzene ring to the pyran-4-one increases the latter s stability to electrophiles and the effect is even more marked when two benzene rings are fused to the pyran, as in xanthone. 

A side-chain t-alcohol group as in (99.4) undergoes cyclodehydration when heated with sulphuric acid. Annulation of a phenylethanol with a nitrile and sulphuric acid can give fairly high yields of an isoquinoline the usefulness of nitriles in the synthesis of heterocycles has been reviewed [3332a]. 

Amino-4-hydroxyfurazan reacts with a-haloacety 1 compounds in the presence of NEts to yield ethers which on heating in a mixture of acetic acid with ethanol gave annulated oxazines 268 in 35-80% yields (Scheme 175) (96UP1). 

Benzimidazole is also aromatic (65AX573, 97T13111), less acidic and more basic in the gas phase than imidazole (83AGE323), although in solution the basicity trend is reverted. This is ascribed to the polarization effects of the annulation. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

The 6-endo activated epoxy alcohol cyclization process was also expected to play a central role in the annulation of pyran ring G of the natural product (see Scheme 22). Silylation of the free secondary hydroxyl group in compound 131 furnishes, after hydrobora-tion/oxidation of the double bond, compound 132. Swern oxidation of alcohol 132 produces an aldehyde which reacts efficiently with (ethoxycarbonylethylidene)triphenylphosphorane in the presence of a catalytic amount of benzoic acid in benzene at 50 °C, furnishing... 

Benzo-annulated dihydrooxepinones are readily accessible (see Houben-Weyl, Vol. 6/4, pp453) and can be converted to the corresponding hydroxy derivatives by reduction of the ketone function. The elimination of water from 10,ll-dihydrodibenz[fc,/]oxepin-10-ol to give 1 was accomplished with /t-toluenesulfonic acid.165-167... 

H-. 3H-, and 5//-Benzodiazepines are all known. The 3/7-compounds readily isomerize to the 1//-tautomers in the presence of bases or acids. It is noteworthy that in contrast to mono-cyclic 1 //-1,2-diazepines, stable A-unsubstituted 1 //-compounds exist in the series of 1,2-benzodiazepines and other annulated 1,2-diazepines. 

Benzocyclobutene-l,2-dione (11) can be condensed with benzene-1.2-diamine to provide an annulated quinoxaline (cf. Houben-Weyl, Vol. E9b/Part 2, p203), which on oxidation with hydrogen peroxide in acetic acid leads to the 1,4-diazocine derivative 12.34... 

This ring system could be prepared by building either of the two heterocycles and then doing an annulation. Thus, cyclization of ethyl o-nitrophenylhydrazonocyanoacetyl carbamate 552 afforded 553. Reduction of 553 by the action of iron(II) sulfate gave 554, which on acid hydrolysis gave 558. Cyclization of o-aminophenyl derivatives 554 and 558 to 555 and 559, respectively, was effected (77CCC894) by treatment with acid. Phthalimido derivatives of 554 could also be cyclized to this... 

Naphtho analogues, naphtho[2,l-e]tetrazolo[l,5-6][l,2,4]triazine, naph-tho[l,2-e]tetrazolo[l,5-b][l,2,4]triazine, and naphtho[2,3-e]tetrazolo[l,5-Zj][1, 2,4]triazine, were prepared (82JOC3168 84JOC3199) by cyclization of the respective hydrazine with sodium nitrite in acetic acid or by azide displacement of a leaving group. Elucidation of the site of annulation of the tetrazole ring was accomplished by X-ray analysis and l3C-NMR spectroscopy (Scheme 189). 

For 10 years, attention has been focused on the intramolecular additions ofallylic and alkynyl-silanes to enones. In early studies, a variety of Lewis acids were tested and reaction conditions were optimized to make this reaction a powerful tool in the synthesis of spiro-annulated, and 1,2-fused ring systems, which can be utilized in the total synthesis of natural products34,35. 

The annulation of a methylenecyclopentane ring has a peculiarity Lewis acids are ineffective as catalysts the reaction, however, takes place in the presence of fluoride42. 

Ring closure of functionalized dienones occurs again in 1,4-fashion to give an annulated six-membered ring. Both Lewis acid (ethylaluminum dichloride) and fluoride ion can be employed, but the chemical yield of this particular cyclization is low and no stereoselection regarding the position of the vinyl side chain was achieved35. 

Dienones, such as 4-[4-(trimethylsilyl)-2-butenyl]-3-vinyl-2-cyclohexenone, are useful precursors for these particular transformations the allylsilane side chain is too short for effective 1,4-addition, but just right for 1,6-addition, resulting in six-ring annulation. Three different Lewis acids can be used titanium(IV) chloride, boron trifluoride diethyl ether complex, and ethylaluminum dichloride. The best chemical yields and complete asymmetric inductions were obtained with ethylaluminum dichloride. 

Table 2. Stereoselective Annulation with 1,3-Asymmetric Induction Using Ethylaluminum Dichloride as Lewis Acid...

If the substance shared between two solvents can exist in different molecular states in them, the simple distribution law is no longer valid. The experiments of Berthelot and Jungfleiscli, and the thermodynamic deduction show, however, that the distribution law holds for each molecular state separately. Thus, if benzoic acid is shared between water and benzene, the partition coefficient is not constant for all concentrations, but diminishes with increasing concentration in the aqueous layer. This is a consequence of the existence of the acid in benzene chiefly as double molecules (C6H5COOH)2, and if the amount of unpolymerised acid is calculated by the law of mass action (see Chapter XIII.) it is found to be in a constant ratio to that in the aqueous layer, independently of the concentration (cf. Nernst, Theoretical Chemistry, 2nd Eng. trans., 486 Die Verteilnngssatz, W. Hertz, Ahrens h annulling, Stuttgart, 1909). 

Amino acids, sulphoxide, radiolysis of 909 a-Amino acids, reactions of 776, 777 a-Aminosulphones, synthesis of 176 Aminosulphonyl radicals 1093 Aminosulphoxides rearrangement of 740 synthesis of 336 Andersen synthesis 60 / -Anilinosulphoxides, synthesis of 334, 335 Anion radicals 1048-1050 ESR spectra of 1050-1054 formation of during electrolysis 963 during radiolysis 892-897, 899, 903 Annulation 778, 781, 801, 802 Antibiotics, synthesis of 310 Arenesulphenamides 740 Arenesulphenates 623 reactions of 282 rearrangement of 719 Arenesulphinates 824, 959 chiral 618... 

Quinone-mono-ketals 46 and 47 are also low reactive dienophiles and are sensitive to Lewis-acid catalysts. The use of high pressure overcomes this limitation [17]. As shown in Equation 5.7, cycloadditions with a variety of substituted 1,3-butadienes 48 occur regioselectively and c This approach provides access to a variety of annulated benzenes and naphthalenes after aromatization of adducts 49. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Several syntheses of annulated uracils of biological value were recently reported. The key reaction was a microwave-assisted one-pot [4 -i- 2] cycloaddition of oxazino[4,5-d]-, pyrano-[2,3-d]-, pyrido[2,3-dj- and pyrimido[4,5-djpyrimidines, in the sohd state [134] and under solvent-free conditions [135]. The synthetic approach was based on the reaction of NJ -di-methyl-5-formylbarbituric acid 208 with maleimide in the sohd state for 5 min under microwave irradiation at 120 °C to give the pyrano[2,3-d]pyrimi-dine derivative 209 in 90% yield (Scheme 76). The reaction of 208 with phenyl isocyanate under microwave irradiation in the absence of solvent... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Application of Pd-Catalyzed Annulation to the Synthesis of the Indole Acetic Acid... 

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