Crotonaldehyde, derivative

M.P. (2006) Orientation of the crotonaldehyde-derived N2-[3-oxo-l(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formahon in the 5 -CpG-3 sequence. Chem. Res. Toxicol, 19, 1019-1029. 

An unexpected reaction catalyzed by baker s yeast with potential synthetic utility was observed as a side reaction during an attempt to asymmetrically reduce substituted crotonaldehyde derivatives (Scheme 2.213). Thus, a lyase-catalyzed addition of water occurred in presence of a 4-benzyloxy- (X = 2 H) or benzoyloxy substituent (X = O) in the substrate [1474, 1586]. 

The related addition of acrolein and crotonaldehyde derivatives has found application in the Friedel-Crafts-type alkylation of indoles (eq S). The reaction affords products issued from the 1,4-addition of the indole to the enal in a chemo- and enantioselective manner. This selectivity contrasts the metal salt-mediated addition, which results preferentially in the 1,2-adducts. The reaction tolerates alkyl and alkoxy functions at the crotonaldehyde C-... 

The pumiliotoxins are a group of more than 60 alkaloids isolated from the toxic skin secretions of the frog Dendrobates pumilis and related species. Many of the alkaloids have, as a central feature, the unusual c/s-decahydroquinoline structure, and since they possess interesting neurological activities they are an attractive target for total synthesis. A new total synthesis of rf,/-pumiliotoxin C has been reported. The main feature of the new synthesis is the Diels-Alder reaction of an activated N-acylaminodiene and a crotonaldehyde derivative leading to an intermediate with two chiral centres which can be utilized to control the introduction of the third chiral centre (Scheme 67). The method, which is short and efficient, should be useful in the synthesis of other cis-decahydroquinoline alkaloids. The overall yield of c/,/-pumiliotoxin C was 51%. 

An excess of crotonaldehyde or aUphatic, ahcyhc, and aromatic hydrocarbons and their derivatives is used as a solvent to produce compounds of molecular weights of 1000—5000 (25—28). After removal of unreacted components and solvent, the adduct referred to as polyester is decomposed in acidic media or by pyrolysis (29—36). Proper operation of acidic decomposition can give high yields of pure /n j ,/n7 j -2,4-hexadienoic acid, whereas the pyrolysis gives a mixture of isomers that must be converted to the pure trans,trans form. The thermal decomposition is carried out in the presence of alkaU or amine catalysts. A simultaneous codistillation of the sorbic acid as it forms and the component used as the solvent can simplify the process scheme. The catalyst remains in the reaction batch. Suitable solvents and entraining agents include most inert Hquids that bod at 200—300°C, eg, aUphatic hydrocarbons. When the polyester is spHt thermally at 170—180°C and the sorbic acid is distilled direcdy with the solvent, production and purification can be combined in a single step. The solvent can be reused after removal of the sorbic acid (34). The isomeric mixture can be converted to the thermodynamically more stable trans,trans form in the presence of iodine, alkaU, or sulfuric or hydrochloric acid (37,38). 

Other aldehydes which have been used in the reaction are pro-panal, butanal, glycolaldehyde, 3-hydroxybutanal, and a number of phenylacetaldehydeand benzaldehyde derivatives. Whereas condensation of tryptophan with acetaldehyde takes place even at room temperature and pH 6.7, the reactions with chloral, chloroacetaldehyde, and crotonaldehyde fail entirely. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

Helmchen and colleagues used equimolar amounts of L-valine derived oxazaboroli-dine 361a to catalyze the reaction of methacrolein with cyclopentadiene (equation 103). Cycloadduct 322 was obtained with 64% ee229. The enantioselectivity was increased to 86% ee by using 60 mol% of 361a and donor solvents like THF. The same catalyst afforded the endo cycloadduct of crotonaldehyde and cyclopentadiene with 76% ee. 

Crossed reactions of the two aldehydes under phase-transfer catalytic conditions with the intermediate thioacetates, which can be isolated under controlled reaction conditions [14], leads to the formation of three products [13], as result of retro-Michael reactions (Scheme 4.18). In the case of the reactions involving crotonaldehyde, the major product results from the reaction of the aldehyde with the released thiolacetic acid, with lesser amounts of the expected crossed reaction products (Table 4.23). In contrast, the reaction of acrolein with the thioacetate derived from crotonaldehyde produces, as the major product, the crossed cycloadduct. These observations reflect the relative stabilities of the thioacetates and the relative susceptibilities of acrolein and crotonaldehyde to the Michael reaction. 

Better reagents than lithium aluminum hydride alone are its alkoxy derivatives, especially di- and triethoxyaluminohydrides prepared in situ from lithium aluminum hydride and ethanol in ethereal solutions. The best of all, lithium triethoxyaluminohydride, gave higher yields than its trimethoxy and tris(/er/-butoxy) analogs. When an equimolar quantity of this reagent was added to an ethereal solution of a tertiary amide derived from dimethylamine, diethylamine, W-methylaniline, piperidine, pyrrolidine, aziridine or pyrrole, and the mixture was allowed to react at 0° for 1-1.5 hours aldehydes were isolated in 46-92% yields [95,1107], The reaction proved unsuccessful for the preparation of crotonaldehyde and cinnamaldehyde from the corresponding dimethyl amides [95]. 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

The 2-methylenecyclopentanone initially formed presumably rearranges into 2-methyl-2-cyclopentenone under the reaction conditions. The final step of the mechanism, elimination of the cobalt carbonyl group, is not well understood but the same kind of elimination and reduction reactions occur with known 3-ketocobalt complexes. As mentioned above, crotonaldehyde, acrolein (27), and glyddaldehyde (38) react rapidly with cobalt hydrocarbonvl under similar conditions to give reduction products, rather than forming stable alkyl- or acyl-cobalt tetracarbonyl derivatives. 

The simple 1,2-dithiolenes, viz, 1,2-dithiolene (3, R H), 3-methyl-l,2-dithiolene (3, R Me) and the saturated derivative of the latter were detected by Takken and co-workers (2) with crotonaldehyde and butanedione as the starting materials. Ledl (33) identified 2-ethyl-4-methyl-l,3-dithiolene (4) in the reaction mixture containing propionaldehyde, hydrogen sulfide and ammonia, and the isomeric 2,4,5-trimethyl-l,3-dithiolane (5) was obtained by Sultan (29) from the reaction of acetaldehyde, aceto-in, and ammonium sulfide. 

Under comparable conditions the submitters found that the corresponding dihydropyran derivatives were similarly obtained by the condensation of acrolein with methyl vinyl ether in 80-81% yield, with ethyl vinyl ether (77-85% yield), with w-butyl vinyl ether (82% yield), with ethyl isopropenyl ether (50% yield), and with w-butyl cyclohexenyl ether (40% yield). Other <, /3-un-saturated carbonyl compounds that have thus been condensed with ethyl vinyl ether are crotonaldehyde (87% yield), meth-acrolein (40% yield), a-ethyh/3-n-propylacrolein (54% yield), cinnamaldehyde (60% yield), /3-furylacrolein (85% yield), methyl vinyl ketone (50% yield), benzalacetone (75% yield), and benzal-acetophenone (74% yield). 

Polarographic methods of analysis of the derivatives of formaldehyde and crotonaldehyde without chromatography were developed. Analysis by HPLC was later considered so as to achieve greater resolution between the individual aldehydes and potential interferences. Methods validated using HPLC analysis include acetaldehyde and furfural. Tests indicated that HPLC analysis may be applicable to the Girard-T derivatives of other aldehydes, such as formaldehyde, propionaldehyde, and benzaldehyde. 

Girard-T derivatives of chloroacetaldehyde, crotonaldehyde, and acrolein were not stable. Alternative methods were developed based upon the derivative formed by reaction of crotonaldehyde with hydroxylamine, and the formation of the hydrate of chloroacetaldehyde. 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

Iersel ML, Ploemen JP, Struik I, van Amersfoort C, Keyzer AE, Schefferlie JG, van Bladeren PJ. 1996. Inhibition of glutathione S-transferase activity in human melanoma cells by alpha,beta-unsaturated carbonyl derivatives. Effects of acrolein, cinnamaldehyde, citral, crotonaldehyde, curcumin, ethacrynic acid, and trans-2-hexenal. Chem Biol Interact 102 117-132. 

---