Nitriles, conjugated, reaction with

The reaction of conjugated nitroalkenes with oc,P-unsaturated esters, ketones, nitriles, and sulfones is catalyzed by TMG to give the Michael adduct of allylic nitro compounds (Eq. 4.108).142... 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

The formation of the latter compounds can be attributed to the result of the direct attack of the nucleophile R on the a- or p-carbon atoms of SENAs after elimination of the corresponding protons. However, it is most likely that the reaction proceeds through nitrile oxides or conjugated nitrosoalkenes (see Scheme 3.93). This interpretation is evidenced by generation of silyl esters of hydroxamic acids R CONHOSi as by-products. The reactions with more saturated solutions give the latter compounds as the major products. 

The latter can be involved in coupling reactions with various electrophiles to give interesting products (550). The development of this strategy is hindered by the lack of convenient procedures for the synthesis of a-silylated conjugated ene nitriles (see, e.g., Ref. 551). 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

Nitrodienes undergo intermolecular Diels-Alder reactions with appropriate dienophiles. The resulting nitro compounds can then be cyclized via a nitrile oxide intermediate.49 Thus, the 2-chloroacrylonitrile Diels-Alder adduct of 8-nitro-l,3-octadiene was prepared and cyclized to give (105) as a 3 1 mixture of diastereomers (Scheme 30). The Diels-Alder adduct of dimethyl acetylenedicarboxylate and 8-nitro-l,3-octadiene cyclized exclusively at the conjugated double bond, activated by the ester groups. Similarly, the quinone Diels-Alder adduct (106) cyclized at the conjugated double bond reduction of the conjugated double bond permitted cyclization on the cycloalkenyl double bond. 

In the presence of Et20-B] 3. (Me3Si)2Se reacts with nitriles to give selenoamides while cyanates give the selenourea. Amides and tetramethylurea behave similarly, but the reaction with benzoates gives benzoin and 2,3,5,6-tetraphenyl-l,4-diselenin via selenoesters. These selenoesters can be trapped as conjugated diene cycloadducts (Scheme 5)78. 

RCu-BF3 (8,334-335 9,333). Yamamoto etal.,15 have reviewed and extended their research on the RCu-BF3 system. This system is superior to R2CuLi for conjugate addition to sterically hindered a,/(-unsaturated ketones and esters, but is less useful in reactions with a,/3-unsaturated acids and is unsatisfactory for additions to a,/l-unsaturated nitriles. A typical example is formulated in equation (I). 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

A few nitrile oxides are stable enough to be isolated (those with electron-withdrawing or highly conjugating substituents, for example) but most are prepared in the presence of the alkyne by one of these methods because otherwise they dimerize rapidly. Both methods of forming nitrile oxides are compatible with their rapid reactions with alkynes. Reaction with aryl alkynes is usually clean and regioselective. 

Conjugate addition to acyclic Michael acceptors. Sakurai and Hosomi (9, 445-446) reported one example of the fluoride ion-catalyzed reaction of allyltrimethylsilane with an acyclic enone. In that case (reaction with C6H5CH=CHCOCH,). 1.2- and 1,4-adducts are obtained in the ratio 2 1.1,4-Addition is enhanced by use of DMF and HMPT as solvent and by increase in the size of the group adjacent to the carbonyl group. 1,4-Addition is the main or predominant reaction with a,3-unsaturated esters or nitriles. In this case, it is superior to or competitive with allylation with lithium diallylcuprate. Yields in 1,4-additions to a,p-enones can compare favorably with those obtained with reactions catalyzed by TiC. ... 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

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