Aldol-type cyclization reaction

Dichloropyridine-4-carboxaldehyde reacts with thiophenol to produce a diaryl sulfide. The diaryl compound and methyl thioglycolate undergo an aldol-type cyclization reaction in the presence of a weak base to afford 4-substituted thieno[2,3-f]pyridine derivative 121 (Scheme 38) <2002JOC943>. 

Scheme 17. Key intramolecular aldol-type cyclization reaction of 42 and 43...

Next, we examined the synthesis of a 4a,8a-/rans-fused ring system such as 49 using the same aldol-type cyclization reaction of 48. The methyl ketone 9 was converted to alcohol 46, which was treated with sodium hydride to afford the oxazolizinone 47. The terminal olefin in 47 was cleaved oxidatively to give rise to the keto aldehyde 48. However, the aldol-type cyclization reaction of 48 under the same reaction conditions as for 42 or 43 was very messy and no cyclized product was isolated. 

According to the above observation, we anticipate that the aldol-type cyclization reaction of 42 should proceed via not /ram-enone T but epimeric aldehyde E as shown in Fig. 9. 

Owing to the high Lewis acidity the group 14 organometallic cations are polymerization catalysts par excellence. so Silanorbonyl cations and triethylsilyl arenium have been shown to be efficient catalysts for metal-free hydrosilylation reactions. Chiral silyl cation complexes with acetonitrile have been applied as cata -lysts in Diels Alder-type cyclization reactions °792 intramolecularly stabilized tetracoordinated silyl cations have been successfully used as efficient catalysts in Mukaiyama-type aldol reactions. 

We have described (88TL4855) a simple synthesis of pyridin-2-ones by a two-step annulation of 2 with aliphatic acid chlorides (Scheme 27). The acylation of aminoazadienes 2 in pyridine furnished 4-amidoyl-l-azabutadienes 107 in high yields (85JOC802) lithium diisopropylamide-catalyzed aldol-type cyclization of 107 afforded pyridin-2-ones 108 in 83-94% yield. Extension of this reaction to methanesulfonyl chloride permitted preparation of open-chain derivatives 109 in 88-90% yield, which in turn cyclized in the presence of lithium diisopropylamide to 2//-l,2-thiazines 110 in 82-92% yield (89TL4705). Earlier work by the Komatsu-Ohshiro group showed that the reaction of simple 1-azadienes... 

The Ferrier (II) reaction is quite efficient to form six membered carbocycles, but is unsuitable to prepare cyclopentitols. Five membered enollactone 14 was converted to the cyclopentanone derivative 16 as a single epimer upon treatment by LiAlH(OtBu)3 (Scheme 4) [41]. Spectroscopic studies established some mechanistic details. Accordingly, the hydride of the reducing agent rapidly added to the carbonyl and formed with the metal a stable alu-minate complex. The carbocydization occurred by protonation followed by fragmentation and aldol type cyclization process. 

Treatment of cycloprop [c]pyrans 520 with acid leads to chromans 521 with a 5,8-substitution pattern, which is difficult to obtain by other synthetic methods (Scheme 114). This novel reaction is believed to proceed via a retro-hDA opening of the dihydropyran ring to afford 522 followed by an acid-catalyzed aldol-type cyclization and dehydration (Scheme 114) <20040L3191>. 

The reactions of malonate derivatives 62 and Michael acceptor 63 have delivered cyclohexene derivatives 67 in moderate to good yields in the presence of DBU (Scheme 4.22). This domino process involves the sequential Michael addition of 62 to the appropriate Michael acceptor 63 to give 64, intramolecular aldol-type cyclization to 65, dehydration to 66, and DBU-promoted dealkoxycarbonylation to 67. This method provides an efficient construction of highly functionalized cyclohexene derivatives starting from easily available MBH adducts. 

The proposed mechanism of the Ferrier carbocyclization reaction is oudined in Scheme 12.13. First, oxymercuration of the exo-olefin in 48 affords mercurial-hemiacetal 49, whose aglycon moiety (-OMe) eliminates to give mercurial-aldehyde derivative 50. This mercurial intermediate 50 was isolable when a stoichiometric amount of Hg salt was employed at low temperature. Intramolecular aldol-type cyclization of 50 provides product 51. 

An unexpected result from the same series of work as above by Perumal et al was obtained when cycloalkenones were used as dienophiles [187]. Instead of the imino Diels-Alder product, azabicyclic ketones were obtained (Figure 8.79). The authors proposed a novel Diels-Alder reaction between In-dienolate ions as dienes, and the imines as dienophiles. Another possibility brought up by the authors was that the products were the result of a tandem aldol reaction on the imine, followed by a Michael-type cyclization reaction. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

Induction of Asymmetry by Amino Acids. No fewer than sis types of reactions can be carried out with yields of 75—100% usiag amino acid catalysts, ie, catalytic hydrogenation, iatramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosdylation, and epoxidations (91). 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

It can be assumed that, upon irradiation, tautomer 5-40-II reacts with the alkene 5-41 in a highly regioselective [2+2] cycloaddition to give the cyclobutane 5-42 as an intermediate. Subsequent retro-aldol-type reaction and hemiacetal formation produces 5-44 via 5-43. After addition of the Lewis acid (BF3-Et20), cyclization takes place to give the desired products. It should be noted that the excess of alkene must be removed under reduced pressure before addition of the Lewis acid in order to avoid polymerization. 

This approach to the five-membered pyrrole ring reacts an a-aminoketone with a P-ketoester. The mechanism will probably involve imine formation then cyclization via an aldol-type reaction using the enamine nucleophile. Dehydration leads to the pyrrole. Only the key parts of this sequence are shown below. 

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). 

Pent-2-ene-l,5-diones may be formed in situ (usually by an aldol-type reaction) and subsequently cyclized. Thus, malic acid (i.e. hydroxy succinic acid) with sulfuric acid gives carboxy acetaldehyde (155) which cyclizes spontaneously to coumalic acid (156). 

Cyclizative condensations based on aldol-type reactions which conform to the llbd pattern have also been developed. Condensation of bis(alkoxycarbonylmethyl)amines or bis(cyanomethyl)amines with benzil affords 3,4-diarylpyrrole-2,5-dicarboxylic add esters or nitriles. These reactions frequently lead to partial hydrolysis of at least one of the alkoxycarbonyl substituents and if the 3,4-diarylpyrrole is the ultimate objective, work-up involving complete hydrolytic decarboxylation is appropriate (equation 119) (6lLA(639)l02, 65JOC859). 

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