A-aminocarbonyls

Dihydropyrazines are formed by the self-condensation of a-aminocarbonyl compounds and they are relatively stable, although again they are easily oxidized to the corresponding pyrazines. Tetrahydropyrazines are less well documented and structures such as (87) appear to be more stable than the enediamine (88). 

Bromural [A -(aminocarbonyl)-2-bromo-3-methylbutanamide, bromisovalum] [496-67-3] M 223.1, m 154-155 . Crystd from toluene, and air dried. 

The phenylhydrazone of acetone gave on hydrogenation over colloidal platinum a 90% yield of A(-isopropyl-A(-phenylhydrazine [950], and the semi-carbazone of benzil on electroreduction a 70% yield of A(-aminocarbonyl-N - 1,2-diphenyl-2-ketoethyl)hydrazine [95/]. 

Due to the synthetic and biological importance of amines and a-aminoketones, acids and esters, the introduction of amino functionality into carbon nucleophiles provides a convenient and practical route for their synthesis "In addition, a number of electrophilic amination methodologies have been developed for the asymmetric synthesis of amines and a-aminocarbonyl compounds " ". 

For the synthesis of a-aminocarbonyl compounds, a number of O-organylhydroxyl-amine-type reagents have been used. Several 0-alkylhydroxylamines la-e were screened for amination of a-lithiated carboxylic acids (Scheme 11) °. However, the yields are... 

A-Metal derivatives of A-(aUtoxycarbonyl) 0-(arenesulfonyl)hydroxylamines, [alkyl A-metal A-(arenesulfonyloxy)carbamates] 3i-o have been used in the amination of a-metallated carbonyl compounds to give A-Boc [N(COOBu-f)] or A-Alloc [N(COOCH2 CH=CH)] protected a-aminocarbonyl compounds. 

For stereoselective synthesis of a-aminocarbonyl compounds using 0-phosphinyl-hydroxylamines, a few procedures have been developed. Attempted amination of enolates of chiral alkyl 3-hydroxybutanoates with 0-(diphenylphosphinyl)hydroxylamine 4a or with its A,A-diisopropyl derivative 4d were found to be unsuccessful". ... 

Triazaphosphapentalenes, 1,3,2-benzodiazaphospholes, 1,3,2-benzoxazaphospholes, and 1,3,2-benzothiazaphospholes are contained in a review on anellated heterophospholes <9477675). The synthesis of 1,3,2-oxazaphospholes from a-aminocarbonyl compounds has also been reviewed <92RHA25>. 

Die wichtigsten Methoden zur Synthese der notwendigen a-Aminocarbonyl-Verbindungen werden nachfolgend kurz diskutiert, da ihre Herstellung und ihre Umsetzung zu 2-Mercapto-imid-azolen oft als Eintopfsynthese durchgefiihrt werden. 

Weitere, gelegentlich im Zusammenhang mit der Herstellung von 2-Mercapto-imidazolen ver-wendete Methoden zur Herstellung von a-Aminocarbonyl-Verbindungen sind ... 

Diese Cyclisierungs-Reaktionen sind mit den Synthesen auf S. 65-77 und mit den entsprechenden Eintopfreaktionen (s. S. 49,57,62) verwandt. Statt a-Aminocarbonyl-Verbindungen werden Derivate von a-Aminosauren cyclisiert. Als Produkte erhalt man 4- bzw. 5-Hetero-substituierte... 

Azodicarboxylates are attractive aminating reagents, since a-aminocarbonyl compounds are not only useful building blocks in organic synthesis, but also essential tools for biological studies.33 Hence, the development of general and efficient methods for the preparation of these compounds is an important issue in organic synthesis. 

The formation of pyrazines is generally linked to the Strecker degradation (see Chapter 2), in which the dicarbonyl reagent undergoes transamination, leading to an a-aminocarbonyl. Two molecules of this readily condense to a dihydropyrazine, as shown in Scheme 5.8. 

The a-aminocarbonyls are not only precursors of pyrazines, but can also lead to pyrroles,242 as well as imidazoles and oxazoles.243 Pyrolysis-GC-MS is relatively readily available and provides a productive technique. As mentioned previously, Wnorowski and Yaylayan212 had shown that, although more products are formed on pyrolysis than in aqueous media, most of the products identified in aqueous systems are present in pyrolysates with identical label distribution, even though the proportions may differ. Pyrolysates (250 °C, 20 s) of model systems of carbonyl and [2-13C]Gly or Ala were analysed. In the butanedione-Gly system, acetaldehyde and formaldehyde formed by decomposition of the carbonyl are unlabelled, but formaldehyde by Strecker degradation is labelled. 2,4,5-Trimethyloxazole was found to be unlabelled, being formed from acetaldehyde, but 4,5-dimethyloxazole was 15% mono-labelled, i.e., 15% of the precursor formaldehyde had been derived by Strecker degradation. 

For the application of trialkylamine/TMSOTf as a selective method for the formation of kinetic silyl enol ethers of some a-aminocarbonyl cyclohexanones see L. Rossi and A. Pecunioso, Tetrahedron Lett.,... 

The Marckwald synthesis116 employed the reaction of a-amino-ketones with cyanates, thiocyanates, and isothiocyanates to yield 3 -imidazol-2-ones or AH-imidazole-2-thiones which are readily converted into imidazoles. The chief limitation of this method, which has been discussed adequately in earlier reviews,1-3 is in the synthesis of the a-aminocarbonyl compounds. The most convenient procedure is by reduction with sodium amalgam of a-amino acids.117 Among recent applications of the method118 119 is the synthesis118 of 4,5-... 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

If cyanamide is used in place of isocyanate or thiocyanate, the cycloaddition reaction with an a-aminocarbonyl compound gives a 2-aminoimidazole (80AHC(27)24l). Alkylation of the sulfur atom of ethyl 2-thiooxamate gives products (85) which contain nucleophilic... 

From Alkyl Anthranilatcs and -Cyano-/l-(dimethylamino)crotonamide or A-Aminocarbonyl-A, . V -dimethylformiinidamide... 

Heating of a-cyano-)3-(dimethylamino)crotonamide (15a) or A -aminocarbonyl-iV. A -dimethyl-formimidamide (15b) with ethyl anthranilate in glacial acetic acid yields quinazoline-2,4(1/f,3/f)-dione. The enaminoamide 15a or formimidamide 15b is decomposed in situ on heating in glacial acetic acid into isocyanic acid which subsequently reacts with ethyl anthrani-... 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

Reactions between a-aminocarbonyl compounds (or their acetals) and cyanates, thiocyanates and isothiocyanates are accomplished in the presence of acid, usually at a pH around 4. Table 4.1.1 lists some examples. Acetals are usually much more stable than a-aminoaldehydes, and they become the substrates of choice in many instances, being hydrolysed in situ [21]. 

Imidazolin-2-thiones (1), (2) (X=S) made from a-aminocarbonyls (or their acetals) with thiocyanates or isothiocyanates... 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

Reduction of A -(aminocarbonyl)-a-amino esters 1134 and A -(aminothiocarbonyl)-a-amino esters 1135 with DIBALH affords 4-hydroxyimidazolidin-2-ones 1136 and 4-hydroxyimidazolidine-2-thiones 1137, respectively. These substances eliminate a water molecule upon acidic work-up to give imidazol-2-ones 1138 and imidazole-2-thiones 1139 (Scheme 276) <1997SL521>. 

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