Imidazolines dehydrogenation

Dehydrogenation of A -imidazolines (294 Z = NR) gives imidazoles, but requires quite high temperatures and a catalyst such as nickel or platinum. Alternatively, hydrogen acceptors such as sulfur or selenium can be used (70AHC(12)103). 

The N-bis-silylated o-phenylenediamine 1511 reacts with DMF at 120°C to give benzimidazole, in 97% yield, and dimethylamine and hexamethyldisiloxane 7, whereas reaction of benzaldehyde with 1511 gives only 29% 2-phenylbenzimida-zole 1513, because the intermediate benzimidazoline 1512 is only rather slowly dehydrogenated to 1513 [52]. Heating of N,N -bis(trimethylsilyl)ethylenediamine 1514 with DMF affords imidazoline 1515 and dimethylamine and HMDSO 7 ]52] (Scheme 9.32). The lactam 1516 cycHzes analogously with SiCU 57/triethylamine in 63% yield to give 1517 ]53]. 

Imidazole nitrones 127 reacted with dimethyl acetylenedicarboxylate to yield imidazo[l,5-fc]isoxazoles 128, which in the presence of base afforded imidazoles 129 <00TL5407>. Chiral imidazoline nitrone 130 participated in a [3+2] cycloaddition reaction with various dienophiles to furnish imidazoisoxazoles 131 <00SL967>. A convenient synthesis of AyvyV -trisubstituted ethylenediamine derivatives from 2-methyl-2-imidazoline has been reported <00SC3307>. Dehydrogenation of 1,3-di- and 1,2,3-trisubstituted imidazolidines afforded l//-4,5-dihydroimidazolium salts <00SC3369>... 

Dehydrogenation of 2-imidazolines.1 Barium manganate is superior to MnCK (2, 258) for dehydrogenation of 2-imidazolines to imidazoles (three examples, 75 95% yield). 

Reactions of 1,2-diaminoalkenes with alcohols, aldehydes, or carboxylic acids and derivatives at high temperatures in the presence of a dehydrogenating agent are common approaches to the synthesis of 2-substituted imidazoles (89KFZ1246). In the absence of the dehydrogenating agent the products are imidazolines. 

The specific synthesis of 1,4- and 1,5-substituted imidazoles109 in 70% yields can be accomplished by cyclization of a-amino-/3-methyl-aminopropionic acid (or a-methylamino-j9-aminopropionic acid) in triethylorthoformate with a catalytic amount of hydrochloric acid, followed by dehydrogenation, under mild conditions, of the resulting 2-imidazoline. 

Usually the 2- or 4-imidazolines that are formed in the cyclization of 3- or 2-aza-l,3-butadienylnitrenes are dehydrogenated under the reaction conditions to imidazoles. There are, however, some cases in which the hydrogenated diazoles can be isolated in moderate yields (79CHE467). 

The specific synthesis of 1,4- and 1,5-disubstituted imidazoles in 70% yields has been achieved by cyclizing 2-amino-3-methylaminopropionic acid with triethyl orthoformate. The products are isolated after dehydrogenation with active manganese dioxide of the 2-imidazoline (69 Scheme 37) (70AHC(12)103). 

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. 

Syntheses of imidazoles which involve dehydrogenation of imidazolines have been discussed in Section 4.07.2.2.2, as have oxidations of benzimidazoles (Section 4.07.3.1.1). 

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]. 

To 2-methyl-2-imidazoline (0.5 g, 5.95 mmol) dissolved in dry dioxane (15 ml) under nitrogen is added, in small portions with stirring, potassium permanganate (1.5 g, 9.5 mmol). The mixture is then refluxed (12 h), allowed to cool to room temperature, and filtered through Celite. The filtrate is evaporated under reduced pressure to a yellowish solid, which is recrystallizcd from toluene (0.352 g, 72%), m.p. 140-142°C. Similar dehydrogenations of the 2-ethyl-and 2-propyl-2-imidazolines were accomplished with 48 and 50% efficiencies, respectively. 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Selenium has been found to be an efficient hydrogen acceptor in the dehydrogenation of 2-aryl-2-imidazolines to 2-arylimidazoles. When 2,4,4,5-tetraphenyl-4H-imidazole is heated, it rearranges to the 1,2,4,5-tetraphenyl isomer. ... 

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