Isobutyraldehyde alkylation

This method of preparation is suitable for producing primary alkyl lactates but is unsatisfactory for /3-methallyl lactate because the strong mineral acid catalyzes the rearrangement of methallyl alcohol to isobutyraldehyde. Methyl lactate can be made conveniently (80-85% yield) by heating 1 mole of lactic acid condensation polymer with 2.5-5 moles of methanol and a small quantity of sulfuric acid at 100 for 1-4 hours in a heavy-walled bottle, such as is used for catalytic hydrogenation with a platinum catalyst. 

Enamines derived from aldehydes disubstituted on the jS carbon such as those derived from isobutyraldehyde (16) are alkylated on nitrogen by alkyl... 

Oxaziranes derived from isobutyraldehyde react with ferrous salts to give only substituted formamides fEq. (23)], The chain propagating radical 30 thus suffers fission with elimination of the isopropyl group. An H-transfer would lead to substituted butyramides, which are not found. Here is seen a parallel to the fragmentation of alkoxyl radicals, where the elimination of an alkyl group is also favored over hydrogen. The formulation of the oxazirane fission by a radical mechanism is thus supported. 

Incorporation of extensive branching in the side chain similarly does not decrease pharmacologic activity. Reductive alkylation of aminoalcohol, 42, with isobutyraldehyde affords the amine, 43. Acylation of the amine with benzoyl chloride probably goes initially to the amide (44). The acid catalysis used in the reaction leads to an N to 0 acyl migration to afford iso-bucaine (45). ... 

Dioxin was deprotonated at C-6 using /-BuLi as base (—78 °C, Et20). The metalated dioxin was trapped by the boron-containing allyl chloride 182 in excellent yield (92%) (Scheme 45). The reaction products were used for the allylic alkylation of isobutyraldehyde (94%) <19990L1713>. 

Enamines with a tertiary nitrogen atom may be more basic than tertiary amines or enamines with a primary or secondary nitrogen atom [5-9]. The presence of a-alkyl substituents increases basicity, whereas /3-alkyl substituents decrease basicity [10]. Stamhuis [11a] and co-workers found that the morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions are 200-1000 times weaker bases than the starting secondary amines and 30-200 times less basic than the corresponding saturated tertiary amines [11a]. For further discussion of enamine basicity see Stollenberger and Martin [lib]. 

Phenylsulfonylcyclobutanes have sufficiently acidic a-protons to undergo a-alkylation reactions. For example, phenylsulfonylcyclobutane, on alkylation with l-bromo-4-methylpent-2-ene gave l-(4-methylpent-2-cnyl)-1-phenylsulfonylcyclobutane (8),152 and (1R, 2S, 3S )-1,2-dimethyl-3-phenylsulfonylcyclobutane gave (l/ , 2/ , 3S )-l-(l-acetoxy-2-methylpropyl)-2,3-dimethyl-1-phenylsulfonylcyclobutane (9) on reaction with isobutyraldehyde followed by treatment with acetic anhydride.133... 

An attractive alternative strategy Scheme 3.20) for the synthesis of (88b) focused on the conversion of a 3-formylthietane acetal (99) to an unsymmetri-cally substituted isobutyraldehyde acetal (100) via alkylative ring opening with p-methoxybenzyl bromide. Several subsequent steps produced a mixture of (101) and (102) which could not be fully aromatized to (102) owing to extraordinary insolubility, which, unfortunately, ultimately precluded synthesis of (88b) by this route. 

Once again proline functions as organocatalyst furnishing the desired aldol adducts 80 in yields of 41 to 85%. With the exception of alkylated aldehydes branched in the a-position, however, d.r. ratios were low, although good to excellent enantioselectivity of 85 to 97% ee was observed for all aldehydes, irrespective of their substitution pattern. The best result was obtained with isobutyraldehyde this afforded the anti-aldol product 80b in 68% yield, with diastereoselectivity of d.r. > 20.1, and enantioselectivity of 97% ee [94, 95]. 

Isobutyraldehyde is another reagent that has been applied to condensation with amino acids [261 ]. The reaction of methyl ester hydrochlorides of amino acids with isobutyraldehyde and sodium hydrogen sulphite proceeds in a solution of sodium carbonate according to Scheme 5.23. The azomethines produced were chromatographed either as such or as N.-alkyl esters after reduction with zinc powder in methanolic hydrogen chloride. N-Isobutylidene methyl esters of most of amino acids, except His, Arg, Trp,... 

Data for aliphatic aldehyde enolisation are very scarce, probably because the enolisation process is often complicated by oxidation and hydration. Nevertheless, the rate constants for base- and acid-catalysed iodination of R R2CHCHO were determined in aqueous chloroacetic acid-chloroacetate ion buffers (Talvik and Hiidmaa, 1968). The results in Table 4 show that alkyl groups R1 and R2 increase the acid-catalysed reactivity in agreement with hyperconjugative and/or inductive effects. This contrasts with aliphatic ketones for which steric interactions are important and even sometimes dominant. Data for base-catalysis are more difficult to interpret since a second a methyl group, from propionaldehyde to isobutyraldehyde, increases the chloroacetate-catalysed rate constant. This might result from a decrease of the a(C—H) bond-promoted hyperconjugative stabilisation of the carbonyl compound... 

Alkylation of aldehydes and -keto esters, This reaction can be conducted by use of solid-liquid phase-transfer catalysis using powdered sodium hydroxide as base and benzene as the solvent. Under these conditions aldehydes with only one a -hydrogen, such as isobutyraldehyde, are alkylated in reasonable yield even by less reactive halides (equation I). 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

Insertion of propene into the M-H bond can give two isomers, one with a 1° alkyl-metal bond (as shown) and one with a 2° alkyl-metal bond. The first isomer leads to n-butyraldehyde, whereas the second isomer leads to isobutyraldehyde. The first isomer predominates under all conditions, but the isomeric ratio is dependent on the metal, the temperature, and the ligands. As the technology has improved, higher and higher ratios in favor of n-butyraldehyde have been obtained. 

Alkylation of the acetylenic anion with isobutyraldehyde gave the propargylic alcohol which was then oxidized using Collin s reagent to yield the requisite ketone. 

Dianions derived from 1,2-cyclohexanediones react with aldehydes rather stereoselectively, as shown in equation (64). The anti.syn ratio of about 8 1 was shown to be kinetic rather than thermodynamic in nature, and was found to be independent of the alkyl group at C-3. The anti stereoselectivity is even higher with a-branched aldehydes (e.g. >99 1 with isobutyraldehyde). 

Chocarom Pyrazine isomers were isolated from the skin and flesh of potato Solanum tuberosum L.) cultivars after baking 4). 3,5-Dimethyl-2-isobutylpyrazine [2,5-dimethyl-3-(2-methylpropyl)-pyrazine] was isolated by Oruna-Concha, Craig, Duckham and Ames from the following potato cultivars - Cara, Nadine, Flanna and Marfona. 3,6-Dimethyl-2-isobutyl-pyrazine [3,5-dimethyl-2-(2-methylpropyl)pyrazine], was found by the same team in Cara and Marfona potato cultivars. 2,5-Dimethyl-3-isobutylpyrazine was also detected by Welty, Marshall and Grun in chocolate ice cream prepared from cocoa flavor (5). Both pyrazines were also found as key odorant compounds in dark chocolate by Counet, Callemien, Ouwerx and Collin (6). The role of amino acids in alkyl-substituted pyrazines formation in model systems containing pyruvaldehyde was examined by Mea (7). 2,5-Dimethyl-3-isobutylpyrazine was formed in the model system with valine. Both isomers were prepared synthetically by Chen (S) by reacting acetol, isobutyraldehyde and ammonium acetate, with low yield of 22.3%. Subsequent proprietary work by the author has improved the yield to 65%. 

The reaction of ( S)-1 with isobutyraldehyde in benzene provides a 92 8 mixture of cis-44 and trans-45, whereas the same reaction with pivaldehyde affords only cis-46 in 74% yield. The reaction of ( S)-1 with pivaldehyde dimethyl acetal in the presence of pyridinium p-toluenesulfonate in a refluxing mixture of cyclohexane-ethyl acetate provides a 97 3 cis trans mixture of 46, but in only 25% yield [10]. Treatment of 46 with LDA at —70 °C followed by alkylation with methyl iodide proceeds in 94% yield to provide a 93 7 mixture of cis, trans isomers. Potassium hydroxide hydrolysis affords (5)-( + )-atrolactic acid (47) possessing 85% ee (Scheme 9). 

Aldehydes can be named as the longest hydrocarbon chain (includes the carbonyl carbon atom) and affixing the suffix al to the hydrocarbon name. No number is assigned to the aldehyde functional group since by definition it is attached to the terminal carbon atom. However, numbers are assigned to any alkyl or other group attached to the main hydrocarbon chain. Formaldehyde is methanal, acetaldehyde is ethanal, propionaldehyde is propanal, n-bu-tyraldehyde is -butanal, and isobutyraldehyde is 2-methyl propanal. The common names of formaldehyde, acetaldehyde, propionaldehyde, n-butyral-dehyde, and isobutyraldehyde are most often encountered in the chemical industry. The CAS numbers (Chemical Abstract Service, American Chemical Society) for the aldehydes are listed in Table 9.1 along with the physical properties. The CAS numbers refer to the major aldehyde component. Refer to the Material Safety Data Sheet (MSDS) for CAS numbers of any minor impurities in the solvent. 

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