Imines a,P-unsaturated

An efficient procedure for the synthesis of 2,4,6-trisubstituted and 2,3.4,6-tetrasubstituted pyridines 5 and 6 involves the one-pot reaction of in situ generated a,p-unsaturated imines with carbanions <95TL(36)9297>. 

Here we discuss several examples of the multicomponent processes involving aminoazoles, aldehydes, and other organic components such as mercaptoacids, haloacetic acids and their ester, a,p-unsaturated imines, etc., which were not incorporated into the previous two sections of the review. 

In addition, an interesting treatment of in situ-generated a,p-unsaturated imines with aminoazoles was described in [150]. This one-pot procedure yielded the anticipated pyrazolo[l,5-a]- and imidazo[l,2-a]pyrimidine derivates 112 (Scheme 52). 

Other types of allylic amination reactions include a variety of indirect approaches such as reduction of a,P-unsaturated imines and oximes, rearrangement of aziridines, and elimination of water from vicinal amino alcohols. However, these reactions will not be considered in this chapter [2]. 

The various possibilities for the preparation of chiral allylic amines or a aryl substituted amines are outlined in Figure 1.9. Although the addition reaction of a carbon nucleophile to an imine derived from an aryl substituted aldehyde is very efficient (B), the related addition to an a,p unsaturated imine (A) can sometimes proceed via a 1,4 addition pathway. Similarly, the asymmetric C=N reduction reaction (C and D) is sometimes hampered by the possibility of either obtaining conjugate reduction (in the case of C) or low enantioselectivities (in D when R = aryl). The addition of sp hybridized carbanions to imines (E) is a particularly effective... 

Diels-Alder 4tr participation of simple a,P-unsaturated imines rarely is observed and typically sufiers low conversions, competitive imine addition, and/or imine tautomerization precluding [4 2] cycloaddi-... 

The synthesis of aziridines from imines and sulfur ylides has been reviewed in previous editions of PHC and is a well-known reaction. A current study reveals that telluronium ylides add to a,p-unsaturated imines through a Michael addition-elimination to the olefin followed by a second equivalent of telluronium ylide addition to the imine, which subsequently eliminates to form aziridines 137 and 138 in a ratio of 13 1 <05JA12222>. 

Reduction of a,p-unsaturated imines to allylic amines with bismuth chloride-sodium borohydride typical procedure... 

Submission of secondary amines such as 21 to Sommelet reaction conditions provided the corresponding two benzaldehydes such as 22 and 23.20 In addition, a variant of the Sommelet reaction transformed a,P-unsaturated imines into the corresponding a, (3-unsaturated ketones.21... 

In a recent approach [66], 2,4,6-trisubstituted or 2-aminosubstituted pyridines 173/174 can be prepared in a one-pot cyclocondensation of methyl phosphonate anion with nitriles, aldehydes and enolates of methyl ketones or nitrile a-carbanions (followed by dehydrogenation) via in-situ generated a,p-unsaturated imines 172. 

Attack on Unsaturated Carbon.- Bis(trimethylsilyl)phosphonite (14), prepared from ammonium phosphinate and hexamethyldisilazane, adds to o,p-unsaturated ketones (IS) to give high yields of mono- or disubstituted phosphinic acids. Low yields were obtained for enolisable ketones if (14) was prepared in situ from trimethylsilylchloride and triethylamine instead. Diethyl trimethyl-silyl phosphite (16) reacts readily with a,p-unsaturated imines to give solely 1,2-addition products (17), even in the presence of bulky Y-substituents, provided R Ws an aryl group. ... 

Scheme 5 [2+2] and [4+2] periselectivity in the reaction between ketenes and a,P unsaturated imines... 

TABLE 4.1 REACTION OF AZLACTONES WITH a,p-UNSATURATED IMINES, 483... 

Intermolecular cycloaddition reactions of 1-aza- and 2-azadienes are generally sluggish and therefore the intramolecular reaction, in which the entropy factor is more favourable, can lead to a more efficient cycloaddition of these heterodienes. Acylation of A-silyl-a,p-unsaturated imines provides a convenient one-pot method for the formation of 1-azadienes required for the Diels-Alder reaction. For example, addition of allyl chloroformate to the A-trimethylsilyl imine of acrolein gave, after heating, the cycloadduct 99 (3.81). 

Some recent work has been directed towards the use of organocatalysts, in particular Lewis basic pipecolinic formamides, in the asymmetric hydrosilylation of N-arylimines. These catalysts function by activating the silane and exhibit broad substrate scope. For example formamide (3.186) effects enantioselective hydrosilylation of aryl-derived ketimines along with isopropyl-substituted imine (3.187) and a,P-unsaturated imine (3.188). 

Polysubstituted pyrimidines were synthesized from in situ generated a,p-unsaturated imines and the corresponding amidine or guanidine derivatives in a convenient one-pot procedure. It was proposed that the described transformations proceed via the initial formation of o,P-imsaturated imine that undergo nucleophilic attack by a bidentate nucleophile (amidine or guanidine). This step is then followed by elimination of ammonia and aromatization to yield the observed polysubstituted pyrimidine. 

In the reaction of nitroxyl with tertiary phosphines the corresponding aza-ylide was formed along with the phosphine oxide as the by-product (HNO + 2R3P R3P = NH + R3P = O). " A novel synthesis of pyrroles involves the reaction of a,p-unsaturated imines and acid chlorides. The cyclization is mediated by triphenylphosphine that is converted to the P-oxide during the reaction. In the reaction of phosphonoallenes with 2-iodophenol in the presence of Pd(OAc)2/PPh3, in addition of the expected benzofurans, the oxidized derivative of triphenylphosphine oxide (2-hydroxyphenyl-diphenylphosphine oxide) was also formed as a minor by-product. ... 

Scheme 7.47 NHC-catalyzed asymmetric cross-annulation of ethyl trans-A-oxo-2-butenoate with a,P-unsaturated imines reported by Rovis.

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

Scheme 7.67 NHC-catalyzed asymmetric formal Diels-Alder reaction of enals with a,p-unsaturated imines reported by Bode.

Synthesis of nitrogen-containing heterocycles using conjugate addition reactions of nucleophiles to a,P-unsaturated imines 12H(85)993. Synthesis of quaternary a-aminophosphonic adds, including quaternary azacycloalk-2-ylphosphonates 12T6369. 

Another example of a single-pot-type reaction involved replacement of the carbon nucleophile with aniline 76, thus affording the a,P-unsaturated imine 77. Both aromatic and alkyl amines afford the desired imine in good-to-excellent yields. The use of triethylsilanes afforded greater Z E ratios in 77.f l... 

In 2013, the first successful generation of ds-homoenolate equivalents from ds-enals under the catalysis of N-heterocyclic carbene D4 was developed by the Chi group. The ds-homoenolate intermediates I undergo effective reaction with a,p-unsaturated imines to afford chiral cyclic ketones 62. Compared to the trans-enals, ds-enals show different stereoselectivities and new reactivity patterns (Scheme 20.29). 

Catalytic asymmetric formal [4-1-2] cycloaddition reactions offer a versatile and elegant approach to the asymmetric synthesis of six-membered heterocycles. In 2006, Bode and coworkers demonstrated NHC-catalysed generation of enolate equivalents from enals for enantioselective Diels-Alder reactions. Reaction with a,p-unsaturated imine 100 provided the dihy-dropyridinones 101 in good yield and with remarkable enantioselectivities (Scheme 20.44). 

Catalytic carbonylative [4-Hl]cycloaddition is also considered to be a type of carbonylation with ruthenium catalysts via the intramolecular flve-membered ring structure. The substrates are a,p-unsaturated imines. A p,y-unsaturated y-lactam is prepared in a high yield by reaction with carbon monoxide at 180 °C for 20 h in the presence of Ru3(CO)i2 [99]. Representative reactions and their reaction mechanisms are shown in Eq. (7.49) and Scheme 7.13, respectively [99]. 

Scheme 7.13 Catalytic carbonylative [4-t-l] cycloaddition of a, p-unsaturated imines with carbon monoxide via a cyclometalation reaction [99]...

The p-dicarbonyl group is the most acidic site, being easily deprotonated by ethoxide under the conditions of the reaction, and the a, P-unsaturated imine is the most electrophilic site. 

P-Dicarbonyl groups are very acidic, being easily deprotonated by ethoxide, and forming a very reactive nucleophilic enolate. This will react with a suitable electrophile in this case the a, p-unsaturated imine. 

The reaction of a ketene with an a,P-unsaturated imine may be expected to afford either a P-lactam, resulting fi-om [2 -i- 2] addition, or a 8-lactam, resulting from [4 -i- 2] addition. 

The formation of both types of products has been observed experimentally. While the influence of steric and electronic effects on the outcome of the reaction have been analyzed, the reaction of a ketene with an a,P-unsaturated imine still proceeds by the two-step mechanism and the... 

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