Vinylic olefin-amine reaction

The major value of the vinylic halide-olefin-amine reaction is for synthesizing polyfunctional aliphatic compounds. The compounds are constructed from the vinylic halide, the olefinic reactant with the necessary substituents, and a secondary amine (or tertiary amine if activating groups are present in the appropriate positions). It is possible to have various functional groups present in either the halide or the olefinic compound and there is a choice of which part of the molecule is the olefinic reactant and which part is the vinylic halide. 

In this reaction, carbamate esters were obtained after long reaction times (70 h), in 0.06-11% yield, depending on the olefin/amine molar ratio (l-10mol/mol) and temperature (308-353 K). Since 1-ethoxyethyl carbamate was formed as the sole regio-isomer product, but there was no formation of the 2-ethoxyethyl ester, the reaction was believed to proceed by an electrophilic addition to the vinyl ether of carbamic acid, formed by reversible reaction of C02 with amine (see Equation 6.1). 

Allyl p-tolyl sulphoxide 535 reacts with sodium methoxide in methanol by initial prototropic isomerization and subsequent addition of methanol to give 536 (equation 333). Protic solvents are photochemically incorporated by the open chain olefinic bond of trans methyl )S-styryl sulphoxide 537 in a Markovnikov regiospecificity (equation 334). Mercaptanes and thiophenols add to vinyl sulphoxides in a similar manner (compare also Reference 604 and Section IV.B.3) to give fi-alkylthio(arylthio)ethyl sulphoxides 538 (equation 335). Addition of deuteriated thio-phenol (PhSD) to optically active p-tolyl vinyl sulphoxide is accompanied by a low asymmetric a-induction not exceeding 10% (equation 336) . Addition of amines to vinyl sulphoxides proceeds in the same way giving )S-aminoethyl sulphoxides in good to quantitative yields depending on the substituents at the vinyl moiety When optically active p-tolyl vinyl sulphoxides are used in this reaction, diastereoisomeric mixtures are always formed and asymmetric induction at the p- and a-carbon atoms is 80 20 (R = H, R = Me) and 1.8 1 (R = Me, R = H), respectively (equation 337) ... 

The acetylene substitution reaction proceeds much more rapidly than the related olefin reaction. The acetylene products and starting materials also undergo side reactions such as polymerization concurrently with the substitution. The best yields are obtained when the reactants are diluted with a large excess of amine, or carried out at lower temperatures in methanol with sodium methoxide as the base. Vinylacetylene derivatives can also be prepared by this reaction starting with vinylic halides. For example, ( )-methyl 3-bromo-2-methylpropenoate and r-butylacetylene react in 2 hours at 100° to form the expected vinylacetylene derivative in 59% yield ... 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

Some success has been achieved using all of the above olefinic compounds in reactions with vinylic halides and amines to add the number of carbons indicated, selectively to form one isomeric product or one which is separated easily from a mixture that may have been formed. Numerous other similar reagents may be imagined, but either they have not been tried or successful reactions were not found. 

The choice as to which fragment of the molecule to be synthesized should be the vinylic halide and which should be the olefin will depend on several factors. In the cases where elimination to form conjugated dienes is the favored reaction, either possible combination of vinylic halide and olefin may produce the same diene however, different intermediates are involved and in some instances different products may be formed. The situation is more complex when allylic amines are produced since these products always will be different from the two different combinations of reactants. For example, Z-... 

A very useful three-carbon olefin is acrolein dimethyl acetal (5). Acrolein itself cannot be used because it polymerizes and/or reacts with amines under the normal reaction conditions. With piperidine or morpholine as the base, acrolein acetals react in good yield with a wide variety of vinylic bromides to give dienal acetals and/or ami-noenal acetals. These product mixtures, after being treated with excess aqueous oxalic acid and being steam distilled, yield E,E-conjugated dienals, usually in good yields. Methacrolein acetals and 3-buten-2-one ethylene ketal also react well, but the crotonaldehyde acetals do not. 

Four-carbon-chain extensions have been very successful with conjugated dienes as the functionalized olefins. We have used a few other compounds also, but they are of limited value, such as N-3-butenylphthalimide. The last compound is only useful with aromatic or certain vinyl halides where mixtures of allylic amines would not be formed. A typical diene example is the reaction of vinyl bromide with butadiene and piperidine which gives E-N-(2,5-hexadienyl)-piper-idine in 70% yield (7). The product of this reaction can be reacted again and used to extend the carbon chains by six atoms (see below). The reactions of conjugated dienes can be used to produce conjugated trienes also (4). 

This very brief survey of the palladium-triarylphosphine-catalyzed reaction of vinylic halides with olefins and amines is intended to show the wide applicability of the reaction to synthesizing numerous types of polyfunctional aliphatic (and aromatic) compounds. We have much more to do in several areas, but it is already clear that the reaction will be very valuable for synthesizing numerous types of organic compounds. 

The transfer of a carbamate moiety to olefins has been documented only in very few cases, using activated unsaturated substrates. For example, Yoshida and Inoue reported the selective (100%) formation of 1-ethoxyethyl N,N-dialkylcarbamate esters by the reaction of C02 (5 MPa) with ethyl vinyl ether and secondary amines R2NH (R = Me, Et) in the absence of any catalyst (Equation 6.11) [85]. 

Michael addition is a facile reaction between nucleophiles and activated olefins and alkynes in which the nucleophile adds across a carbon-carbon multiple bond [25], For the preparation of hydrogels, the hydroxyl, thiol or amine functionalities have been reacted with vinyl sulfones [26-28], acrylates [29-31], acrylamides [32], and maleimides [33, 34] (Scheme 2). 

As electron-rich olefins are more reactive, vinyl-sulfones are the most reactive species and are capable of reacting with thiols, amines, and even with small nucleophilic alcohol groups. Less reactive are acrylamides and acrylates, which are reactive towards amines and thiols. Maleimides are the least reactive of the mentioned species and allow selective addition of thiols in the presence of amines in the pH range 6.5-7.5. However, hydrolysis of the imide, especially at elevated pH values [35], may be a concern for certain applications. The mentioned Michael addition reactions do not require organic solvents and can be carried out at physiological temperature and pH [36], In acidic conditions, the reaction is either very slow or does not proceed because protonation removes the nucleophilic form in the case of amines, and the thiolate anion is usually the active species in Michael additions involving thiols [25],... 

Migration of the double bond of the cyclic olefin formed by the RCM has also been observed [35]. RCM of the diene 77 by 69 in refluxing dichloromethane resulted in the formation of considerable amounts of the unexpected cyclic olefin 79 in addition to 78 (Eq. 12.31) [35a[. It was also noted that the formation of 79 was effectively suppressed by the addition of amine to the dichloromethane solution or employment of diethylether as solvent, which implies participation of proton in the isomerization reaction. It was also noted that a terminal vinyl group with a free tertiary allylic hydroxyl group accelerates RCM, rather than its methyl ether derivative. These results suggested some interaction between the alkylidene complex 69 with hydroxyl proton in situ. 

Olefin isomerization catalyzed by ruthenium alkylidene complexes can be applied to the deprotection of allyl ethers, allyl amines, and synthesis of cyclic enol ethers by the sequential reaction of RCM and olefin isomerization. Treatment of 70 with allyl ether affords corresponding vinyl ether, which is subsequently converted into alcohol with an aqueous HCl solution (Eq. 12.37) [44]. In contrast, the allylic chain was substituted at the Cl position, and allyl ether 94 was converted to the corresponding homoallylic 95 (Eq. 12.38). The corresponding enamines were formed by the reaction of 70 with allylamines [44, 45]. Selective deprotection of the allylamines in the presence of allyl ethers by 69 has been observed (Eq. 12.39), which is comparable with the Jt-allyl palladium deallylation methodology. This selectivity was attributed to the ability of the lone pair of the nitrogen atom to conjugate with a new double bond of the enamine intermediate. 

Due to the chelating effect of the amino group, allylic amines readily undergo nucleophilic addition reaction on their double bond. For example, carbopallada-tion of allyl-dimethylamine with malonates readily yields a chelating complex. Subsequent olefin insertion of methyl vinyl ketone into this complex gives co-amino enones23) (Scheme 17). An interesting application of the facile earbopalladation de-... 

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