Conjugate 1,4-additions

Conjugate addition of ketenesilyl acetals to a,P-unsaturated carbonyl compounds (Mukaiyama-Michael reaction) with Li Lewis acid has been widely investigated. When sterically less hindered ketenesilyl acetals are utilized, the reaction proceeded smoothly, even in catalytic systems (with LiCo(B9C2Hn)2 in CICH2CH2CI or LiCl04 in CH2CI2). On the other hand, in the case of more hindered ketenesilyl acetals, high concentration of LPDE is necessary to promote the reaction 

Several ketene silyl acetals add in a conjugate fashion to a,/3-unsaturated carbonyl compounds (Mukaiyama-Michael reaction) in the presence of LiC104. The more sterically demanding the ketene silyl acetals used, the greater is the concentration of LPDE required. For example, ketene silyl acetal Si-2 subjected to an LPDE solution (1.0 m) of 2-cyclohexen-l-one (12) gave 87 % of the 1,4 adduct whereas Si-3 required 

The greater activity of LiC104 (3 mol %)-CH2Cl2 enables conjugate addition of Si-2 to 12. Complete and regioselective conversion to the desirable 1,4-adduct was, in fact, achieved within 1 h 91 % isolated yield), presumably via a group transfer-type process (Sch. 60) [72]. 

The use of catalytic amounts of [LiCo(B9C2Hn)2] (102) had several practical advantages (Sch. 60 and 61) (i) The conjugate addition of Si-1 to 12 proceeds equally fast (5 min) in Et20, dichloroethane, or CH2CI2 in the presence of 10 mol % 102. (ii) In contrast to the above mentioned dependence on the concentration of the LPDE system, in this reaction any of the substrates Si-1, Si-3, or Si-6 can be used under identical conditions using 10 mol % 102, except that reaction times range from 5 min to 1 h. (iii) When sterically encumbered substrates such as 122 are used, the combined use of equimolar amount of HMPA and 102 (10 mol % each) dramatically enhances 1,4-selectivity [112]. 

Very recent applications of the reagent LiAl[OC(Ph)(CF3)2]4 (107) in conjugate additions have been described (Sch. 62). The capacity of 107 to catalyze sterically demanding additions in toluene obviates the necessity of using either highly polar media (5.0 m LPDE) or ultra high pressure [100]. 

LPDE solution also catalyzes the conjugate allylation of quinones. This is an important reaction in the preparation of biologically active isoprenoid quinones such as vitamin E, vitamin K, coenzyme Qi, and plastoquinones. If 123 is reacted with the allylsi-lane in 5.0 m LPDE for 15 h at 40 °C, allylhydroquinone 124 is obtained in 73 % yield, together with non-allylated hydroquinone 125 (Sch. 63) [113]. 

Write down the two possible isomeric products that might be formed from the addition of one molecule of bromine to one molecule of 1,3-butadiene. 

BrH2C-CH=CH-CH2Br. The bromine molecule might add across one of the double bonds as 

Write down the initial intermediate formed by the reaction between a bromine molecule and 1,3-butadiene. 

The initial attack always occurs on the carbon at one end of the conjugated system, and so in this case it occurs at a terminal carbon. Consider the structure of the carbonium ion that would result if the bromine cation had attacked one of the non-terminal carbons, and so suggest a reason why the terminally substituted carbonium ion is favoured. 

In this latter case, the carbonium ion formed cannot be stabilised by delocalisation with the other double bond. Hence, it may be deduced that the terminally substituted carbonium ion will be formed 

The mercurio ketone 4 upon reduction with NaBH yields a radical which is trapped in situ by reactive acceptors such as vinyl ketones [37]. Treatment of a 1 3 mixture of mercurio ketone 4 and electron deficient terminal alkenes (or fumarate) in CH2CI2 with a concentrated solution of NaBH in water gives conjugate adducts, Eq. (36). 

A highly intriguing isomerization of the homoenolate radical which probably proceeds via formation of a cyclopropyloxy radical, was noted in the reaction of a mercurio aldehyde [37]. The product ratio should reflect the ratio of internal/ external trapping, and in fact the ratio of unrearranged and rearranged product depends on the concentration of the trapping reagent, Eq. (37). 

When the stabilities of the two corresponding radicals are grossly different as in the case of gem-dimethyl homoenolate, one may obtain the product originating from the more stable homoenolate radical as the sole product, Eq. (38). A related isomerization reaction, albeit proceeding in the opposite direction, has often been recorded for anionic holmoenolates. 

This has been apphed in one step of the muscopyridine synthesis [11]. 

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Conjugate addition of vinyllithium or a vinyl Grignard reagent to enones and subsequent oxidation afford the 1.4-diketone 16[25]. 4-Oxopentanals are synthesized from allylic alcohols by [3,3]sigmatropic rearrangement of their vinyl ethers and subsequent oxidation of the terminal double bond. Dihydrojasmone (18) was synthesized from allyl 2-octenyl ether (17) based on Claisen rearrangement and oxidation[25] (page 26). 

Allylic amine is a less reactive leaving group[7], but the allylic ammonium salts 214 (quaternary ammonium salts) can be used for allylalion(l30,131]. Allylic sulfonium salts are also used for the allylation[130]. The allylic nitrile in the cyclic aminonitrile 215 can be displaced probably via x-allylic complex formation. The possibility of the formation of the dihydropyridinium salts 216 and subsequent conjugate addition are less likelyfl 32],... 

Indoles can also be alkylated by conjugate addition under alkaline conditions. Under acidic conditions, alkylation normally occurs at C3 (see Section 11.1). Table 9.1 includes examples of alkylation by ethyl acrylate, acrylonitrile, acrylamide and 4-vinylpyridine. 

The major product corresponds to addition of a proton at C 1 and bromide at C 2 This mode of addition is called 1,2 addition, or direct addition The minor product has its proton and bromide at C 1 and C 4 respectively of the original diene system This mode of addition is called 1,4 addition, or conjugate addition The double bond that was... 

The tendency for conjugate addition is pronounced and E double bonds are generated almost exclusively... 

A particular kind of conjugate addition reaction earned the Nobel Prize in chemistry for Otto Diels and Kurt Alder of the University of Kiel (Germany) m 1950 The Diels-Alder reaction is the conjugate addition of an alkene to a diene Using 1 3 buta diene as a typical diene the Diels-Alder reaction may be represented by the general equation... 

Section 10 10 Protonation at the terminal carbon of a conjugated diene system gives an allylic carbocation that can be captured by the halide nucleophile at either of the two sites that share the positive charge Nucleophilic attack at the carbon adjacent to the one that is protonated gives the product of direct addition (1 2 addition) Capture at the other site gives the product of conjugate addition (1 4 addition)... 

Section 10 12 Conjugate addition of an alkene (the dienophile) to a conjugated diene gives a cyclohexene derivative in a process called the Diels-Alder reaction It is concerted and stereospecific substituents that are cis to each other on the dienophile remain cis m the product... 

This IS called direct addition ox 1 2 addition (The 1 and 2 do not refer to lUPAC locants but are used m a manner analogous to that employed m Section 10 10 to distin guish between direct and conjugate addition to conjugated dienes)... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

Conjugate addition is most often observed when the nucleophile (Y ) is weakly basic The nucleophiles m the two examples that follow are C=N and C6H5CH2S respectively Both are much weaker bases than acetylide ion which was the nucleophile used m the example illustrating direct addition... 

FIGURE 18 7 Nucleophilic addition to a p unsaturated aldehydes and ketones may take place either in a 1 2 or 1 4 manner Direct addition (1 2) occurs faster than conjugate addition (1 4) but gives a less stable product The product of 1 4 addition retains the carbon-oxygen double bond which is in general stronger than a carbon-carbon double bond... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

Both the conjugate addition step and the intramolecular aldol condensation step can be carried out in one synthetic operation without isolat mg any of the intermediates along the way For example consider the reaction... 

CONJUGATE ADDITION OF ORGANOCOPPER REAGENTS TO a,p-UNSATURATED CARBONYL COMPOUNDS... 

The preparation and some synthetic applications of lithium dialkylcuprates were described earlier (Section 14 11) The most prominent feature of these reagents is then-capacity to undergo conjugate addition to a p unsaturated aldehydes and ketones... 

Outline two ways in which 4 methyl 2 octanone can be pre pared by conjugate addition of an organocuprate to an a p unsaturated ketone... 

Conjugate addition to a (3 unsat urated carbonyl compounds (Sec tions 18 11 through 18 14) The... 

P carbon atom of an a 3 unsatu rated carbonyl compound is elec trophilic nucleophiles especially weakly basic ones yield the prod ucts of conjugate addition to a 3 unsaturated aldehydes and ketones... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Ammonia and amines undergo conjugate addition to a 3 unsaturated carbonyl compounds (Section 18 12) On the basis of this information predict the pnncipal organic product of each of the following reactions... 

Acrylonitnle (H2C=CHC=N) readily undergoes conjugate addition when treated with... 

Acrolein (H2C=CHCH=0) undergoes conjugate addition with sodium azide in aqueous solution to give N3CH2CH2CH=0 Propanal is not an a 3 unsaturated carbonyl compound and cannot undergo conjugate addition... 

Conjugate acid (Section 1 13) The species formed from a Brpnsted base after it has accepted a proton Conjugate addition (Sections 1010 and 1812) Addition reaction in which the reagent adds to the termini of the con jugated system with migration of the double bond synony mous with 1 4 addition The most common examples include conjugate addition to 1 3 dienes and to a 3 unsaturated car bonyl compounds... 

Diels-Alder reaction (Section 10 12) Conjugate addition of an alkene to a conjugated diene to give a cyclohexene denva tive Diels-Alder reactions are extremely useful in synthesis... 

The methodology used in the preparation of RU 486 (84) and other ll -steroids is shown. Conjugate addition of a cuprate reagent to the a,P-unsaturated epoxide (85) provides the liP-substituted steroid (86) stereospecificaHy (131). Subsequent steps lead to the synthesis of RU 486 (84). 

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