Carbonyl compounds heterocyclic synthesis

Acetylenic carbonyl compounds in synthesis of heterocycles using reactions with dinucleophilic reagents 87KGS291. 

Reductions of aromatic nitro compounds provide a simple and general access to various heterocyclic compounds through the domino process (Scheme 9.23). Quinolines are important skeletal moieties present in various natural products and biologically active compounds [58]. Most common methods of their preparation involve condensation of o-amino benzaldehydes with an enolizable carbonyl compound (Friedlander synthesis) [59]. Miller et al. [60] reported an efficient synthesis of quinolines 109, in which a reduction of o-nitroaryl carbaldehyde by SnCl2 followed by condensation with an enolizable carbonyl compound in the presence of ZnCl2 yielded 109 through a domino process. In 2001, Bunce et al. [61] reported a domino nitroarene reduction/reductive amination sequence for the preparation of tetrahydroquinoline-4-carboxylic ester 110 with excellent yields. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

Coupling of organic halides with carbonyl compounds promoted by Sml2 in synthesis of heterocycles 99CRV745. 

Polyfunctional fluoroalkyl-containing carbonyl compounds in the synthesis of heterocycles 98IZV1279. 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as usefid starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, ind pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromadcs fmainly pyrroles ind indolesi ind saturated nitrogen heterocycles such as pyrrolidines ind their derivadves. 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

Thioamides and their use in the preparation of the heterocyclic compounds are widely reported in the literature. Also they attract considerable interests in peptide chemistry. Molecular and crystal structures of some thioamide derivatives have been confirmed by X-ray diffraction data.8 10 Lawesson s reagent or phosphorus pentasulfide (P4S10) is actively used for the synthesis of thio-carbonyl compounds. Their preparation methods, reactions, applications in the synthesis of heterocycles and biological effects are mainly described in this section. 

Other aromatic heterocycles undergo Patemo-Btichi reaction with carbonyl compounds, although these reactions have seldom been applied to organic synthesis. For example, thiophene reacts cleanly with benzaldehyde to afford a single exo product in 63% yield87. Pyrroles also react with aldehydes and ketones however, as a result of the lability of the presumed initial cycloadducts, the only products isolated, even with the rigorous exclusion of acid, are the 3-hydroxyalkylpyrroles 200 (equation 7)89. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

Abstract The basic principles of the oxidative carbonylation reaction together with its synthetic applications are reviewed. In the first section, an overview of oxidative carbonylation is presented, and the general mechanisms followed by different substrates (alkenes, dienes, allenes, alkynes, ketones, ketenes, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols, phenols, amines) leading to a variety of carbonyl compounds are discussed. The second section is focused on processes catalyzed by Pdl2-based systems, and on their ability to promote different kind of oxidative carbonylations under mild conditions to afford important carbonyl derivatives with high selectivity and efficiency. In particular, the recent developments towards the one-step synthesis of new heterocyclic derivatives are described. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

The synthesis of isoxazolines and pyrazolines via the Michael addition of hydro-xylamine and phenyl hydrazine to chalcones and related enones was also reported with activated Ba(OH)2 as a basic catalyst (293) (Scheme 45). In both cases, reactions were performed at reflux of ethanol, and excellent yields (65-80%) with 100% selectivity to the heterocyclic compounds were observed. Steric hindrance associated with the carbonyl compound as well as the electronic character of the substituents in the aromatic ring slightly affected the yields of the heterocyclic compounds. 

Dihydro-1,3-oxazines have served both as nucleophilic and electrophilic agents in the preparation of carbonyl compounds. The multiple uses of this heterocycle are nicely revealed in the synthesis of methyl jasmonate (739) (73JOC175). 

The most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

The reaction of nitroarenes with silyl end ethers and ketene silyl acetals in MeCNATiF with 1 equiv. of TASF, followed by in situ oxidation with Br2 or DDQ, provides an easy route to a-nitroaryl carbonyl compounds (Scheme l).12 The use of these compounds as reagents for the synthesis of arylacetic acids, propionic acids, indoles, 2-indolinones and other heterocyclic compounds has recently been described.88... 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

Pyrazolines containing aryl substituents with some functional groups can be used in the synthesis of new heterocycles. For example, the reaction of 5-(2-hydrohyphenyl)pyrazolines 111 with noncyclic 112 or cyclic carbonyl compounds under acidic conditions yields dihydropyrazolo[l,5-c]-l,3-benzox-azines 114 and 115, respectively [167, 168, 169] (Scheme 2.30). 

Cyclocondensation of aminoazoles and a,(3-unsaturated carbonyl compounds or Mannich bases is the most common method for the synthesis of dihydroa-zolopyrimidines [99, 155, 156, 157]. Various alkyl- and aryl-substituted dihy-dropyrimidines were prepared in this way. For example, cyclocondensation of 3-amino-1,2,4-triazole 147 with chalcones 148 leads to 5,7-diaryl-4,7-dihydro-l,2,4-triazolo[l,5-a]pyrimidines 149 [158], while reaction with hydrochlorides of Mannich bases 150 leads to heterocycles 151 (Scheme 3.46). 

There are some known unsuccessful attempts to carry out alkylation (Mel, Me2S04), halogenation (tert-butyl hypochloride) and nitration of aromatic dihydrobenzodiazepines [7, 105]. Such attempts only resulted in the destruction of the seven-membered heterocycle. As a rule, these destructive processes are typical of dihydrodiazepine systems and often manifest themselves during the synthesis and study of these compounds. Therefore, the results of the destruction of a seven-membered heterocycle are most widespread and include its decomposition into ortho-diamine and carbonyl compounds (Scheme 4.43, reactions A and B) [105, 106] and benzimidazole rearrangement accompanied by splitting out of a methyl aryl ketone molecule (Scheme 4.43, reaction C) [117]. 

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