Michael addition of imidazole

The microwave activation of Michael additions in the preparation of N-substituted imidazoles afforded excellent yields in very short reaction times under mild reaction conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were found to be very active and selective catalysts for the Michael addition of imidazole and ethyl acrylate [54]. 

Scheme 10.9 Michael addition of imidazole with ethyl acrylate.

Some Michael additions of imidazoles to unsaturated reagents involve the neutral heterocycles, but others may be reactions of the anion. Fluoride ion-catalyzed addition of 2-methyl-4-nitroimidazole 129 to a suitable Michael acceptor gives almost quantitative yields of the 1-substituted 4-nitroisomers 130. Scheme 22 illustrates the use of microwave heating in such processes <2001T5421>. 

Regioselective Michael addition of imidazole to levoglucosenone 475 is effectively catalyzed by cathodic electrolysis. The electrochemical conditions are milder and provide higher yields as compared to the base-catalyzed reactions (Scheme 110) <1996JOC8786>. 

Michael addition of imidazole (1) and benzimidazole (5) to alkyl propiolate (2) can be promoted by KIO montmorillonite clay affording alkyl 3-(imidazol-l-yl)acrylate (3) and alkyl 3-(benzimidazol-l-yl)acrylates (6), respectively. Michael adduct of 2-mercaptobenz-imidazole (8) undergoes cyclization in the presence of clay catalyst to 4-oxo-4H-[ 1,3]thiazino[3,2-a]benzimidazole (9). 

A similar approach employing an ionic liquid as a susceptor was adopted by Leadbeater and Torenius for base-catalyzed Michael addition of imidazole to methyl acrylate [25], At 200 °C after 5 min and with triethylamine (TEA) in equimolar quantities, a 75% yield was obtained (Scheme 3.5). 

In reversing the two steps, i.e. first imidazole addition on a conjugated double bond, then a N-alkylation, the same derivatives may be obtained. The Michael addition of imidazole or its derivatives on an activated double bond can be catalyzed by various reagents enzyme catalysis (Cai et al., 2004), Montmorillonite catalysis (Martin Aranda et al., 1997, 2002) and activated microwave or ultrasound (Zaderenko et al, 1994), or molecular sieve graft (Blasko-Jimenez et al, 2009), KF(Yang et al, 2005), Cu (Acac)2(Lakshmi Kantam et al, 2007), liquid ion ([bMIM] OH) (Xu et al, 2007). 

Cai,Y., Yao S-P., Wu Q. Lin X.F. (2004). Michael addition of imidazole with acrylates catalysed by alkaline protease from Bacillus subtilis in organic media. Biotechnology letters, vol.26, n°6, pp.525-528, (March 2004), ISSN 0141-5492... 

Michael Addition of Imidazole N-alkyl-imidazoles were also S5mthesized over amino-grafted MCM-41 and NbMCM-41 catalysts by Michael addition between imidazole and ethyl acrylate, at 333K, under sonic... 

As a consequence of direct observation of enamine intermediates, it has been concluded that the failure to achieve organocatalytic aza-Michael additions of imidazoles to enals is due to unfavourable proton transfer within the adduct from the imidazolium fragment to the enamine unit. ... 

Nitrogen nucleophiles Investigation of the Michael addition of imidazole to ethyl acrylate in dry media over basic catalysts by the in situ real-time Raman spectroscopy confirmed that the reactions proceed via a direct C-N bond formation no intermediate has been detected. ... 

A basic ionic liquid, l-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and l-butyl-3-methyl-methylimidazolium tetrafluoroborate ([bmim]BF4), has been introduced as a catalyst and reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC3991 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the a,P-unsaturated ester <06S3859>. 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

Enantioselective Michael additions of pyrroles to a,(3-unsaluralcd 2-acyl imidazoles were accomplished by Sc(III)triflate-bis(oxazolinyl)pyridine com-... 

Replacement of phenyl groups with AT-methyl imidazole moieties in the catalyst Cl structure led to catalyst C4 (Figure 8.2). ° This catalyst worked efficiently in aqueous media. Catalyst C4 catalysed Michael additions of aldehydes to nitroalkenes in a mixture of brine and NaHCOs. 

Imidazolide ionic liquids [Bmimjlm (2 mol%) have been reported to catalyse aza-Michael addition of, for example, imidazole to acrylates and acrylonitriles. Samarium diiodide has been identified as an efficient catalyst for the aza-Michael addition of 0-benzylhydroxylamine to a,/8-unsaturated Af-acyloxazolidinones. The 1,1-bi-2-naphthol (BINOL)-Sml complex afforded the Michael adducts with <88% ee. An isoinversion effect with temperature was observed for the highest enantiomeric excess at -40°C.205... 

In a first step, the reaction (R = Me) was performed at 50°C during 48h. Along with the desired IL, we observed the presence of a by-product resulting from the Michael addition of N-methyl imidazole on the activated double boimd of the (methjaciylate compound(Fig.l2). 

A number of -acyl- and thioureido-derivatives of 3 -amino-3 -deoxythymidine have been prepared. 1 0 Michael addition of phthalimide to enal (81) was used in the synthesis of the 3 -amino-2 ,3 -dideoxyhexo-furanose nucleosides (82) (all four isomers, R=H, Me, halogen),191 and a similar enal prepared by mercuric-ion catalysed hydrolysis of L-rhamnal was used in the same way to make the L-acosaminyl nucleoside (83) and its -anomer, and the L-ristosaminyl systems (epimers at C-3 ). 2 Michael addition of 1,2,4-triazole to (81) led, after base-sugar condensation, to the triazolyl-substituted nucleosides (84, B=T, U), together with the analogous hexopyranose systems. 93 xhe imidazolyl nucleosides (85) can be made by reaction of 3 -amino-3 -deoxythymidine with l,4-dinitroimidazoles, 9 whilst the unsaturated imidazole nucleoside (87) was made by treating the phenylselenone (86) (see Section 6) with imidazole. 195... 

Imidazole has been condensed via a 1,4 Michael addition with ethyl acrylate by use of basic clays (Li+ and Cs+ montmorillonites) under solvent-free conditions with microwave irradiation [77] (Eq. 24). 

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