Acid-catalyzed condensation aldehydes

The acid catalyzed condensation of benzaldehydes with 2-acetyIpyridine provides access to hydroxy- or amino-indolizines (Scheme 58a) (71CB1629,71CB1645). A remarkable synthesis of fused pyrrolidines in which aldehydes also provide C-2 is exemplified in Scheme 58b... 

Under appropriate conditions 1,3-dioxanes can be obtained in moderate to good yields. Below 70 °C the acid-catalyzed condensation of alkenes with aldehydes yields 1,3-dioxanes as major products, while at higher temperatures the hydrolysis of dioxanes to diols is observed. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

We have found several examples in which adjacent cationic charge centers are shown to activate carboxonium electrophiles. A convenient method for studying this activation is through the use of the hydroxyalkylation reaction, a commercially important, acid-catalyzed condensation of aldehydes and ketones with arenes.10 It is used for example in the synthesis of bis-phenol A from acetone and phenol (eq 6). While protonated acetone is able to react with activated arenes like phenol, it is not capable of reacting with less nucleophilic... 

Acid-catalyzed condensation of bicyclic ozonides with aldehydes and ketones, in the presence of hydrogen peroxide, leads to the formation of bicyclic peroxide analogs of acetals in low yields, as shown in equation 91 for the condensation of the ozonide of 1-phenylcyclopentene (266) with benzaldehyde. The structure of compound 267, with the preferred ring conformation as shown, was determined by XRD analysis . The same method served to demonstrate that the condensation compound 16c is unique, with structure 254 . 

Because of their ring-chain tautomeric character, tetrahydro-l,3-oxazines can be used as aldehyde sources in acid-catalyzed condensation reactions involving the carbon transfer via the open forms. This approach is especially advantageous in those cases where the aldehydes required for the condensations are unstable or difficult to access <2003EJ03025>. 

The cyclizations of /3-hydroxycarboxamides with aldehydes, ketones, or their equivalents results in l,3-oxazin-4-one derivatives <1996CPB734, 2006BMC584, 2006BMC1978>. In the acid-catalyzed condensation of salicylamide 422 with (—)-menthone, a 2 1 mixture of C-2-epimeric 27/-l,3-benzoxazin-4(37r)-ones 202 and 423 was formed, the equilibrium of which could be shifted toward the (23 )-enantiomer 202 by base-catalyzed isomerization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in A -methyl-2-pyrrolidone (NMP) to yield a 14 1 mixture of 202 and 423 (Equation 44) <1996TL3129>. 

A similar type of acid-catalyzed condensation of aldehydes with 4-methylene-2-oxetanone (diketene), giving 4-oxo-6-methyl-l,3-dioxins, has been patented (73GEP2149650). However, other work has established that <5-hydroxy-/3-keto acids or unsaturated keto acids are formed as the principal products (equation 24) (78CPB3877, 78CL409). The latter reaction probably involves electrophilic attack of the protonated aldehyde on the nucleophilic exocyclic methylene carbon atom of the diketone. A closely related reaction of acetals with diketene, catalyzed by titanium tetrachloride, gives the corresponding <5-alkoxy-/3-keto esters (74CL1189). 

The method ZC3Z + C is used for the preparation of reduced pyrimidines, oxazines and thiazines as well as for dioxanes, dithianes and oxathianes as mentioned above (e.g. 258 — 257, 259 Z, Z = NH, O, S). The Prins reaction yields 1,3-dioxanes (77S661) it involves the acid-catalyzed condensation of alkenes with aldehydes with 1,3-diols as intermediates. 

The condensation of thiophene with ketones in presence of 70% H2S04 gives di-2-thienylmethane derivatives (63AHC(l)l). Thus acetone leads to (85). Intramolecular versions of such acid-catalyzed condensations with aldehydes and ketones are known (Scheme 14) (73JOC1056, 70AHC(11)177). The Bradsher reaction has been used for the synthesis of thienobenzothiophenes in low to moderate yields (Scheme 15) (70CC1094). 

Furo[3,2-c][l]benzopyran-4-ones have been prepared either by acid catalyzed condensation of 4-hydroxycoumarin with a benzoin derivative (equation 11) (81IJC(B)614) or from 3-allyl-4-hydroxycoumarins on oxidation with osmium tetroxide/potassium periodate followed by cyclization of the intermediary aldehyde with PPA (equation 12) (79G109). 

Ring-constrained analogues 37 of the anti-inflammatory drug, diclofenac, have been prepared by acid-catalyzed condensation of aldehydes (or ethylene ketals of ketones) with 36 (Equation 4) <1998MI201>. This reaction presumably proceeds via intramolecular nucleophilic attack by the carboxylic acid group on an iminium ion intermediate from condensation of the secondary amine. Interestingly, the compounds 37 showed comparable activities to diclofenac in the formalin-induced rat paw edema test. 

Imines. Imines are usually prepared by acid-catalyzed condensation of aldehydes or ketones with primary amines with azeotropic removal of water. This method gives poor yields with low-boiling imines.2 A new method involves dehydrocyanation of a-cyanoamines with DCC and Dabco as catalyst (equation I).3... 

An alternative "2+2" approach (Scheme 4) involves the acid-catalyzed condensation of a-free dipyrromethanes 3 (1994T11427,05T6614,05SC929) with aldehydes to form porphyrinogens, which are then oxidized to obtain porphyrins 7. This methodology is considerably more versatile for array formation, and is frequently higher yielding and produces more soluble products as well as allows better control over substitution at the mcso-positions. 

Another antiaromatic hexapyrrolic macrocycle, [24]hexaphyrin(l. 0.1.0.1.0), rosarin 167 has been prepared by acid-catalyzed condensation of bipyrrole 166 and an aromatic aldehyde (Scheme 69) (1992JA8306). 

Oxazolidinones are the products of the acid-catalyzed condensation of a-hydroxyamides with aldehydes and ketones (equation 178). Tertiary amides derived from pyruvic acid undergo intramolecular cyclization when irradiated (equation 179) (78JOC419). Treatment of the a-bromo amide (308) with sodium hydride yields inter alia the dimeric oxazolidinone (309), presumably by way of an a-lactam, which adds to the carbonyl group of a second molecule of the amide (equation 180) (80JCS(P1)2249). 

Another entry to 1,3-benzodithiolylium salts (275) involves acid-catalyzed condensation of benzene-1,2-dithiols (273) with aldehydes followed by oxidation of the intermediates (274) using oxidizing reagents. This reaction also works with dialdehydes (80AHC(27)15l). 

Two key intermediates in the production of vitamin A are citral and the so-called C5 aldehyde. In the modem routes to these intermediates, developed by BASF and Hoffmann-La Roche, catalytic technologies are used (see Fig. 2.29 and 2.30). Thus, in the synthesis of citral, the key intermediate is 2-methyl-l-butene-4-ol, formed by acid-catalyzed condensation of isobutene with formaldehyde. Air oxidation of this alcohol over a silver catalyst at 500°C (the same catalyst as is used for the oxidation of methanol to formaldehyde) affords the corresponding aldehyde. Isomerization of 2-methyl-l-butene-4-ol over a palladium-on-charcoal catalyst affords 2-methyl-2-butene-4-ol. The latter is then reacted with the aldehyde from the oxidation step to form an enol ether. Thermal Claisen rearrangement of the enol ether gives citral (see Fig. 2.29). 

Trioxanes 726 (Z = 0) are trimers of aldehydes or ketones formed by acid-catalyzed condensations of the monomers. 1,3,5-Trithiane 726 (Z = S) is prepared by passing H2S through formaldehyde and hydrochloric acid <1943OSC(2)610>. The reaction of formaldehyde and H2S with amines affords the corresponding thiadiazines 727 (Scheme 311) <2003RCB1817, CHEC-III(9.09.9.3)511>. 

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