2- acetaldehyde cyclization

It is worth noting that only 1,2-dioxetanes (206) are obtained by photooxygenating 2-(phenoxymethylidene)adamantanes (205) in acetaldehyde as solvent (Equation (30)). However, these dioxetanes can be expanded to trioxanes at a later stage (see Section 6.20.6.4). Acyclic enol ethers behave in the same way. l,l-Di- -butyl-2-methoxyethylene (207), singlet oxygen and acetaldehyde cyclize to the cis and trans trioxanes (208) in 31% yield (Equation (31)). 

The possible origin of this compound can be explained by the following pathway. An aldol addition of glycine on pyruvaldehyde accompanied by decarboxylation produces the amino alcohol which, after condensation with acetaldehyde, cyclization and oxidation forms the oxazole. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

Acenaphtheno[l,2-e][l,2,4]triazolo[4,3-h][l,2,4]triazine 747 was prepared (79AP147) by cyclizing 3-hydrazinoacenaphtheno[l,2-e][l,2,4]tria-zine 746 with formic acid. Reaction of 746 with sugars gave the hydrazones, which cyclized with iron(III) chloride to give 748 (93BCJ00). Similarly, the acetaldehyde derivative of 746 was cyclized to 748. The structure of 748 (R = Me) rather than 747 (R = Me) was deduced by unequivocal synthesis of the latter by condensation of acenaphthenequinone with 3,4-diamino[l,2,4]triazole (Scheme 155). 

Condensation of 2-aminothiophenol with the /3-chlorocinnamaldehyde in the presence ofp-toluene sulfonic acid (PISA) gave good yield of benzothia-zole (Scheme 14). The mechanism suggested in this work is beUeved to proceed via a nucleophilic attack of the sulfur atom in an addition-ehmination sequence followed by a spontaneous cyclization and ejection of acetaldehyde [15]. These investigations were performed in a domestic microwave reactor and need 1.5 min for completion (65% yield). Here again, oil bath heating seems to be inferior, providing a maximum conversion of 53% after... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

In another variant of such reactions, the hemi-acetal 104, generated in situ by reaction of the corresponding allylic alcohol with acetaldehyde, undergoes cyclization in the presence of HgClOAc to afford the mercurated acetal 105.128 Under these conditions, the reaction leads to the jy -product with a high selectivity (dr > 10 1 Scheme 14). The same strategy has been applied iteratively for the stereoselective synthesis of natural products containing 1,3,5,7,9-pentaether chains.129... 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

The second method of making sulfamethizole consists of reacting 4-acetylaminobenzenesulfonyl chloride with thiosemicarbazone of acetaldehyde, and subsequent oxidative cyclization of the product (33.1.16) to the substituted 1,3,4-thiadiazole in the presence of potassium ferricyanide in base, along with the simultaneous removal of the protective acetyl group [16,17],... 

Reaction of the TMS-nitro compound 1496 and the indole carboxaldehyde 1497 with a catalytic amount of TBAF led to the desired alcohol 1498, which, on further treatment with TFAA, followed by elimination of the corresponding trifluoroacetate with DBU, afforded the frans-stilbene 1499. Reductive cyclization of 1499 under Cadogan-Sundberg conditions afforded the bisindole 1500. Finally, condensation of 1500 with (dimethylamino)acetaldehyde diethyl acetal led to tjipanazole D (359) in 71% yield (796) (Scheme 5.255). 

Optimization of the previously reported Mannich-type reaction of trimethyl (pent-2-en-3-yloxy)silane with the sulfone Is derived from phenyl acetaldehyde (Table 5, entry 11) led to the corresponding (3-amino ketone in a good yield with moderate diastereoselectivity (2 mol% Bi(0Tf)3-4H20, yield = 84%, 24v/24v syn/anti = 72 28) (Scheme 8). Reduction of the major diastereoisomer 24v with lithium tri-ferf-butoxyaluminohydride afforded 25 as the only one diastereoisomer. Further cyclization of the latter with NaH afforded 4-benzyl-6-ethyl-5-methyl-l,3-oxazinan-2-one 26. The relative configuration of the six-membered carbamate was established as cis-cis by NMR analysis. 

An additional indication of the mildness of the cyclization is provided by the synthesis of the chiral tetrahydroisoquinoline-3-carboxylic acid (294) (72HCA15) in the presence of hydrogen and palladium-on-charcoal the jV-methyl derivative was obtained. Acetaldehyde gave a mixture of diastereoisomers in which the cis isomer (295) predominated (95 5). Unstable aldehydes can sometimes be generated in situ, as when the phenylglycidate (296) replaces the much less stable phenylacetaldehyde (66T(S8)129) acetals, enol ethers and chloromethyl methyl ethers have also been used. The mild conditions also allow the isolation of 4-hydroxytetrahydroisoquinolines (297) (75H(3)311). A review is available listing syntheses of 4-oxytetrahydroisoquinolines (73AHC(15)99). 

C6Hg03, Mr 128.13, is a constituent of pineapple and strawberry aroma and is also found in other foods. It forms colorless crystals (mp 77-79 °C) with a relatively weak, nonspecific odor. Dilute solutions develop a pineapple, strawberry-like odor. It can be prepared by cyclization of hexane-2,5-diol-3,4-dione in the presence of an acidic catalyst [186]. The dione is the ozonization product of 2,5-hexynediol, which is obtained by ethynylation of acetaldehyde. 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

The first step in this sequence is the binding of a molecule of acetaldehyde ( donor ) to the aldolase to form a Schiff base with the active site lysine followed by addition to CIAA, which acts as the acceptor aldehyde. This reaction delivers the mono-addition product, which then acts as an acceptor again to react with a second molecule of AA, yielding the double addition product which cyclizes spontaneously to the stable lactol 1 (Scheme 6.4). 

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