Amines heterocyclic substrates

Commonly used drugs (other than isoniazid) affected by NAT2 polymorphism were procainamide, hydralazine, dapsone, and sulfonamides with an increase of side effects in all cases. A selective substrate of NATl is -aminosalicylic acid (PAS), but its genetic variation was never clinically important (52). Because of such lack of importance, more attention is often paid to the fact that various industrial chemicals with carcinogenic potential, and mutagenic heterocyclic amines, are substrates of both N-acetyltransferases (53). The presence or absence of these transferases will determine some incidences of cancer (54). Attempts have been made to ascribe cancer incidences in different populations to acetyltransferase differences (55). 

The use of a strong base in the palladium-catalyzed amination of aryl halides precludes the use of many substrates, such as those with aromatic nitro groups or enolizable hydrogens, esters other than tert-butyl esters, and many substrates with base-sensitive stereochemistry such as some protected amino acids and heterocyclic substrates [191]. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those used for reactions conducted with sodium tert-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts. 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

Remarkable enantiocontrol was obtained using N heterocyclic substrates such as protected indole 34 and pyrazole 38, showing the potential of this method in the synthesis of biologically active chiral amines. Another striking element of this catalyst is its reactivity toward alkene substrates. While rhodium tetracarboxylate catalysts tend to promote both C H insertion and aziridination, the Rh2(S nap)4 (32) is particularly selective for C H insertion, cis Olefins were well tolerated, providing the aminated product in good yield and enantioselectivity (39, 41). However, the use of trans isomers resulted in reduced yield and selectivity (e.g., 40). 

Lithium diisopropylamide (LiN(i-Pr)2 LDA) is the most widely used lithium amide but lithium 2,2,6,6-tetramethylpiperidide (LiTMP) is rather more basic and less nucleophilic - it has found particular use in the metallation of diazines. Alkyllithiums are stronger bases than the lithium amides, but usually react at slower rates. Metallations with the lithium amides are reversible so for efficient conversion, the heterocyclic substrate must be more acidic ( > 4 pAT units) than the corresponding amine. 

Obvious to the success of the Fischer indole synthesis is the availability of arylhydrazines and arylhydrazones. Several groups have pursued new methods for these syntheses, which are listed in chronological order in Table 5 [128-134]. Several conditions are typically used depending on the substrate, but only one is shown for each entry. Entry 4 features a reaction scale of 1.6kg of 4-chlorotolnene, and aryl chlorides also function in this amination protocol, as do heterocyclic substrates (entry 7). 

Scheme 20.2S describes the work published by Kawasaki s group where they used a combination of dimethylsulfoxide and trifluoroacetic anhydride as source of trifluoroacetylated sulfonium ion 109 which reacted with 108 generating the new sulfonium salt 110 that underwent the loss of the sulfur-containing moiety promoted by nucleophilic attack. The nucleophile could be an alcohol, thiol, amine or organometallic species, or even another heterocyclic substrate. In cases where the nucleophile was a sulfoxide, the reaction led to an overall CH2 oxidation (Scheme 20.2S). Kawasaki s results suggest that this transformation, based on an interrupted Pummerer rearrangement, could be applied in the synthesis of biologically active tetrahydrocarbazoles and analogues fFigure 20.2T...

Acid catalysis in nucleophilic aromatic displacements with amines has been observed only with heterocyclic substrates. Banks (86) has shown that the reaction rates of 2-chloro-4,6-diamino-s-triazene and of 2-amino-4-chloropyrimidine with aniline and with ring-substituted anilines in aqueous solution or suspension are accelerated by an increase in the hydrogen ion concentration. This catalysis is due to conversion of the substrate to its conjugate acid, since the heterocyclic nitrogen is a better activating group for the displacement reaction in the ammonium form than in the amino form. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Formylation with Zn(CN)2 and HCI is called the Gatterman reaction It can be applied to alkylbenzenes, phenols and their ethers, and many heterocyclic compounds. However, it cannot be applied to aromatic amines. In the original version of this reaction, the substrate was treated with HCN, HCI, and ZnCl2, but the use of Zn(CN)2 and HCI (HCN and ZnCF are generated in situ) makes the reaction more... 

If an aliphatic amino group is to a COOR, CN, CHO, COR, and so on, and has an a hydrogen, treatment with nitrous acid gives not a diazonium salt, but a diazo compound Such diazo compounds can also be prepared, often more conveniently, by treatment of the substrate with isoamyl nitrite and a small amount of acid. Certain heterocyclic amines also give diazo compounds rather than diazonium salts. ... 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

Type I MCRs are usually reactions of amines, carbonyl compounds, and weak acids. Since all steps of the reaction are in equilibrium, the products are generally obtained in low purity and low yields. However, if one of the substrates is a bi-funchonal compound the primarily formed products can subsequently be transformed into, for example, heterocycles in an irreversible manner (type II MCRs). Because of this final irreversible step, the equilibrium is forced towards the product side. Such MCRs often give pure products in almost quantitative yields. Similarly, in MCRs employing isocyanides there is also an irreversible step, as the carbon of the isocyanide moiety is formally oxidized to CIV. In the case of type III MCRs, only a few examples are known in preparative organic chemistry, whereas in Nature the majority of biochemical compounds are formed by such transformations [3]. 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring opening of 3-aryl-2-benzoyl-l,l-cyclopropanedicarbonitriles 14 with hydrazine provided a new process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. 

Reaction of isothiocyanate with amine gives the corresponding thioureas. Many reports are appeared.102 111 The thiourea derivatives have been prepared by reactions of isothiocyanates with arylamines (Scheme 39) and reacted with some substrates to afford heterocyclic compounds, such as 2-amino-4//-ben-zothiazine, 1,3-thiazine, 1,3-thiazinone and l,3-thiazolidin-4-one.112 115... 

The proposed catalytic cycle of the ruthenium-catalyzed intermolecular Alder-ene reaction is shown in Scheme 21 (cycle A) and proceeds via ruthenacyclopentane 100. Support for this mechanism is derived from the observation that the intermediate can be trapped intramolecularly by an alcohol or amine nucleophile to form the corresponding five-or six-membered heterocycle (Scheme 21, cycle B and Equation (66)).74,75 Four- and seven-membered rings cannot be formed via this methodology, presumably because the competing /3-hydride elimination is faster than interception of the transition state for these substrates, 101 and 102, only the formal Alder-ene product is observed (Equations (67) and (68)). 

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