Chloral, cyclization

Cyclizations of chloral hemiacetal derivatives of cyclic allyl alcohols were regio- and stereo-selective (Table 6, entry 1), but a mixture of regioisomers was obtained from analogous derivatives of acyclic allyl alcohols with a nonterminal double bond.93 Hemiacetal derivatives of allyl alcohols with a terminal vinyl group have been cyclized with mercury(II) acetate to give acetal derivatives of threo 1,2-diols with moderate selectivities (equation 54 and Table 15, entries 1 and 2).147 Moderate to excellent stereoselectivity has been observed in the iodocyclizations of carbonate derivatives of allyl alcohols (entries 3-5).94a The currently available results do not provide a rationale for the variation in observed stereoselectivity. 

High 1,3-asymmetric induction was obtained in the mercury-mediated cyclization of a carbamate containing the chloral moiety. The structure of the product 8 was determined by single crystal X-ray analysis157. 

Sandmeyer isonitrosoacetanilide isatin synthesis. Formation of isonitrosoacetodi-phenylamidine by condensation of chloral hydrate, hydroxylamine, and aniline cyclization with concentrated sulfuric acid and quantitative hydrolysis to isatin on dilution. 

Additional examples of the bismuth chloride-catalyzed C-C bond forming reactions are summarized in Scheme 5.28. Active methylene compounds can react smoothly with aldehydes and a,j8-unsaturated carbonyl compounds in the presence of bismuth chloride without using organic solvents [92CL1945, 97TL1449]. A catalytic amount of bismuth chloride (2 mol%) can efficiently induce the intramolecular ene cyclization of (-l-)-citronellal as well as the intermolecular ene reaction between (—)-)8-pinene and chloral... 

An anhydride [2309, 2323] (catalysed by mineral acid) or ethyl hippurate (ethyl 2-benzoylglycinate) [2186] cyclizes an o-aminophenol on prolonged refluxing. Chloral hydrate and hydroxylamine convert an aminophenol into a benzoxazole-2-carboxaldehyde oxime [2104]. 

Various methods are available for the preparation of the foregoing precursors to V-acyliminium ions. The most straightforward synthesis of V-(l-hydroxyalkyl)-amides or -carbamates (2 X = OH) involves the addition of primary or secondary amides (carbamates) to aldehydes or ketones. This reaction is an equilibrium process and usually disfavors the adduct except for two special cases. The first involves very reactive aldehydes like formaldehyde, chloral and glyoxylic acid and its esters (equation 4) compounds (4)-(6) are fairly stable compounds that are frequently used in amidoalkylation reactions. The second special case is the intramolecular variant (ring-chain tautomerism), if it leads to five- or six-membered rings (equations 5 and 6). Thus, for n = 1 or 2, (7) and (8) cyclize to (9) and (10), respectively, although the nature of R has an influence on this process. " ... 

A different bond-forming reaction is operative in the synthesis of the 3-formyl-2-methyl-l,3-oxazines (364) from 3-aminopropyl vinyl ethers (363), which cyclize when reacted with chloral hydrate (Scheme 99) <86ZORi556>. A novel synthesis of 5-oxa-l-azabicyclo[4.4.0]decane (366) relies upon the photosensitized single-electron oxidation of A-(3-hydroxypropyl)piperidine (365) in the presence of 1,4-dicyanonaphthalene (Equation (43)) <88TL4153>. 

Treatment of (129) with phenylhydrazine in ethanol at reflux gives (130) via initial formation of the phenylhydrazone and subsequent cyclization." The condensation of chloral hydrate, CCl3CH(OH)2, with ethene oxide in the presence of a phase-transfer catalyst (dialkylmorpholinium bromide) gave (131) (90%)." ... 

JPR8>. Mercury(II)-mediated cyclization of hemiacetals of chloral and homoallylic alcohols... 

Other aldehydic compounds, such as glyoxal and chloral, also react in a similar way with polyisoprenes and unsaturated rubbers (e.g., poly(cfs-l,4-isoprenes), poly( fs-l,4-butadiene), and copolymers of isobutylene and iso-prene). The use of strong acids, or Lewis acids, causes complications, as the acids themselves, under suitable conditions, catalyze cyclization and cis-trans isomerization, and these reactions may occur simultaneously with the addition reactions. 

It is assumed that hydroxylamine condenses with chloral to give oxime, which then undergoes the nucleophilic substitution with aniline, and hydrolyzes to give oximino intermediate under basic conditions. In the presence of a strong acid, such as concentrated sulfuric acid, the oximino compound cyclizes via nucleophilic addition of aromatic ring to C=N double bond. An illustrative mechanism is provided below. 

The formation of 1,3-oxathiolane with chloral and 1,3-dithio-lanes with cycloaliphatic thioketones occurs regioselectively to yield the sterically less hindered products. On the other hand, aromatic thioketones, e.g., thiobenzophenone or 9/ fluorene-9-thione, intercept 8 to give comparable amounts of both regio-isomeric adducts. Usually, stereoisomeric dipolarophiles such as fumaronitrile and maleonitrile as well as dimethyl fumarate and maleate form 18 in a stereoselective manner. However, in the case of extremely electron-poor dipolarophiles, e.g., dimethyl 1,2-dicyanofumarate or ( )-l,2-bis(trifluoromethyl)ethylene-l,2-dicarbonitrile, non-stereospecific formations of the corresponding tetrahydrothiophenes are described. i- s This result is interpreted in terms of a stepwise reaction mechanism with a zwitterion as the key intermediate. Alternatively, this intermediate can cyclize to form seven-membered ketenimines of type 20. With R = Cp3, this product can be isolated in a crystalline form, whereas in the case of R = CN, stable lactam 21 is obtained only after addition of water (eq 10). 

Indole-2,3-dione (isatin), red crystals, mp 204°C, is formed inter alia (cf p. 146) by the oxidation of indigo. A generally applicable synthesis of isatins 126 is the Sandmeyer synthesis, in which isonitrosoacetanilides 125 (easily accessible from primary arylamines, chloral hydrate, and hydroxylamine hydrochloride) are cyclized in acidic medium [195] ... 

Chloral (trichloroacetaldehyde) cyclizes to metachloral in the presence of chlorosulfonic acid (0.5-5%) as catalyst at —20 to 50 °C. The cyclization was performed in an airtight polyethylene reactor the mixture solidified after 3 hours and the reaction was complete after 80 hours giving a yield of 97.9%, which was much better than that obtained by the conventional method using sulfuric acid. ... 

Oximes of some carbonyl compounds can undergo further cyclization reactions (46). jS-Diketones give, for example, heterocyclic compounds. The oxime of propargylaldehyde cannot be isolated because a ring formation takes place and an oxazine is formed. The reaction of hydroxylamine with aromatic a-aminoalkyl ketones is similar to osazone formation (47). Chloral reacts with two molecules of hydroxylamine (48). Carboxylic acids or lactonic oxygen can also react with hydroxylamine (49). 

Ene Reactions. The Lewis acid-catalyzed ene reaction is synthetically useful methodology for forming new carbon-carbon bondsEne reactions utilizing reactive enophiles such as formaldehyde and chloral can be promoted by SnCU. SnCU also enhances intramolecular ene reactions, such as the cyclization of (15) which produces the a-hydroxy 8-lactone in 85% yield (eq 34). The ene cyclization of citronellal to give isopulegol has also been reported. Proton scavenging aluminum Lewis acids such as RAICU are most often used in ene reactions to eliminate proton-induced side reactions. 

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