Michael addition of pyrrole

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

The intramolecular Michael addition of (—(-pyrrole 149 to give compound (—)-150, an intermediate in the asymmetric synthesis of an unique cytotoxic tetracyclic alkaloid (—)-Agelastatin A, was effected using CS2CO3 (Equation 27) <1998JOC7594, 1999JA9574, 2006ARK120>. 

An enantioselective alkylation of pyrrole with enones has been reported <05JA4154>. For example, treatment of V-methylpyrrole 59 with enone 60 in the presence of a catalytic amount (10 mol%) of bis(oxazoline) catalyst 61 provided chiral adduct 62. Different additives including iodine <05T11751> and an aluminum surfactant <05CC789> have been utilized to mediate the Michael addition of pyrroles to p-nitrostyrenes. 

Recent examples, for instance, of the catalytic application of the commercially available macroporous Amberlyst-15 include the Michael addition of pyrroles to a,P-unsaturated ketones (Scheme 10.4) [48]. In this process, the acid ion exchange resin (dry, 10% w/w) allows on to obtain mono and dialkylated pyrroles 5 and 6 in reasonable yields. Similarly, this catalyst (dry, 30% w/w) can catalyze the aza-Michael reaction of amines with a,P-unsaturated ketones, esters and nitriles to afford 7 in 75-95% yields under solvent-free conditions. Interestingly, yields were significantly lower using typical solvents such as DCM (dichloromethane), CH3CN, THF, DMF or EtOH [49], Recycling the catalyst is possible in both cases, but a smooth decrease in the yield is observed for each new run. 

This reaction can also be regarded as a Michael addition of pyrrole to maleic anhydride. Some substituted pyrroles, however, undergo a [4+2] cycloaddition with acetylene dienophiles, e.g. l-(ethoxycar-bonyl)pyrrole with acetylenedicarboxylic ester [37]. 

Silica-supported Lewis acids (Si(M)l in conjunction with microwave irradiation were employed for the Michael addition of pyrrole (63) with a-acctamidoacrylate (64) as a route to pyrrolyl alanine derivatives 65 <01T5421>. 

Scheme 18.4 Enantioselective Michael addition of pyrrole and indole derivatives promoted by imidazolidinone catalysts.

Hack and Enders developed a novel asymmetric, organocatalytic Michael addition of pyrrole (80) to enone 81 via Cinchona alkaloids derivative 83. Pyrroles such as 82 were obtained in good to excellent yields with ee s from 75 to 93% (13S2904). 

The efficient solvent-free microwave-assisted procedure for C-alkyl pyrroles synthesis using silica gel-supported reagent has been reported. Thus, a general procedure for the Michael addition of pyrroles with electron-deficient olefin has been developed. In the case of the moderately bulky electron-deficient olefins, a catalytic amount of BiCls has to be employed to promote the reaction. The experimental results indicated that BiCla exhibited a high catalytic activity and did not induce polymerization and polyalkylation under microwave (Equation 5) [26a]. 

The generation of an iminium ion of a, 3-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the cx-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a,j3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(5-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

It has been shown that the combination of water and microwave irradiation promotes the catalyst free nitro Michael addition of pyrroles and indoles with good yields (99%) (Rosa and Soriente, 2010). 

Remarkably few examples of this type of ring construction are available. The cobalt carbonyl hydride catalyzed hydroformylation of A/,A/ -diallylcarbamates has provided 3-pyrrolidinones (Scheme 61a) (81JOC4433). The pyrrole synthesis shown in Scheme 61b depends on Michael addition of ethyl a-lithioisocyanoacetate to ethyl a-isocyanocrotonate (77LA1174). 

Battersby and coworkers have developed selective methods for total synthesis of chlorins on a model system, as shown in Scheme 10.15, in which the Michael addition of 5-f3-nittoethyl pyrrole to enone and reductive cyclizadon are used as key steps. "... 

An analogous cyclization to eventually form five-membered rings has also been observed for l-metalla-l,3,5-hexatrienes with an additional heteroatom within the chain, such as in the complexes 157. These are obtained by Michael additions of imines to alkynylcarbene complexes in good to excellent yields (reaction type F in Scheme 4), and their configurations were determined to be Z (>91%) in all cases. Upon warming in THF solution, complexes 157 underwent cyclization with reductive elimination to furnish 2Ff-pyrroles 158 in up to 97% yield (Scheme 34). With two cyclopropyl substituents at the terminus in... 

The Michael addition of nitroalkanes to a, P-unsaturated ketones gives y-nitroketones, which are converted into pyrroles by reduction of the nitro group with Bu3P and PhSSPh (Eq. 10.2).4... 

Another pyrrole synthesis based on intramolecular substitution of the nitro group by amino function is presented in Eq. 10.7, in which the Michael addition of enamines to nitroalkenes is used.9... 

A one pot samarium-catalyzed three-component reaction of aldehydes, amines, and nitroal-kanes leads to pyrroles. The reaction proceeds via imines, generated from the amine and carbonyl compound, followed by the Michael addition of the nitro compound (Eq. 10.10).12a In... 

The Michael addition of lithium enolates to nitroalkenes followed by reaction with acetic anhydride gives acetic nitronic anhydrides, which are good precursors for 1,4-diketones, pyrroles, and pyrrolidines (Eq. 10.73).113... 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Nitroketones are reduced to pyrroles by diphenyl disulfide and triphenylphosphine (86JCS(Pl)2243). Since 7-nitroketones are accessible by Michael additions of nitroalkanes to enones, this is a potentially versatile method (Scheme 40). 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. 

Figure 12. Alkylation and Michael addition of ri2-pyrrole complexes.

P-Vinylpyrrole complexes with pendant electron-withdrawing groups (56, 58, 60-62) are easily synthesized by the Michael addition of activated alkynes to r 2-pyrrole complexes as described earlier in this review (see Figure 13). 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

Molecular iodine-promoted Michael addition is a simple and efficient method for generating 2-pyrrolyl-2-phenyl-l-nitroalkanes in good yields (Scheme 67) [86]. Cr+3-Catsan (Cr+3 exchanged commercially available montmorillonite clay) and ZnCl2, which were first used as Lewis acids for Michael reactions of pyrrole, showed different selectivity under the same conditions [221], In general, while the reactions catalyzed by Cr+3-Catsan... 

The synthesis of the enantiomerically enriched (74% ee) tetrahydroin-dolizine 368 is the most crucial step for synthesis of (-)-rhazinal (369), (-)-rhazinilam (6), (-)-leucunolam (370) and (+)-epz-leucunolam (371) alkaloids [239]. The selective intramolecular conjugate additions of pyrrole to N-tethered Michael acceptors were achieved by using chiral organocatalyst 320c (Scheme 77). 

The Michael addition of methyl a-acetamidoacrylate (196) with pyrrole (1) under silica-supported Lewis acid (Si(M) Si(Zn), Si(Al) and Si(Ti)) assisted by microwave irradiation (MW) afforded the alanine derivatives 395 and 396 dependent on the reaction conditions (Scheme 81) [153]. Both MW and thermal activation for pyrrole gave only Michael product 396, whereas alanine derivatives 395, which are the a-Michael addition product, and 396 were observed with A1 and Ti-catalyst. This behavior shows that aluminium and titanium Lewis acids can form a new acceptor in an irreversible way. The Si(M) or p-TsOH catalyzed reactions of N-benzylpyrrolc 397 with the acrylate 196 under MW gave the product 398 as sole product. The reaction yield has been increased by using a catalytic amount of p-TsOH (Scheme 82). 

The indole and pyrrole rings are incorporated into many biologically active molecules. Therefore, the functionalization of indole and pyrrole cores via Michael-type additions has been discussed. This chapter especially focuses on studies of the last 10 years on catalyst systems, enantioselective synthesis and the design of natural products or biological active molecules as related to Michael additions of indole and pyrrole. 

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