Addition with Proton Elimination

3-Oxazine derivatives can be formed from 1,3-oxazinium salts substituted in positions 4, 5, and 6 by aromatic residues by addition of active CH compounds in position 6 of the oxazinium salt.4 The product can be subjected to further transformations [as described in Section m,F,2,c Eq. (82)]. 

The 2//-l,3-oxazine ring was first described by King and Durst202 who revised earlier work of Kohler and Blatt203 and established that the anhydro compounds formed by the action of alkalis on isoxazolium salts are 2H-1,3-oxazines (66) [Eq. (52)]. The same ring system is obtained from an a-cyano-a-bromo ester with triisopropyl phosphite through an 

The first representative of this group, a /3-acylamino-a,/8-unsaturated ester, yielded 67 through pyrolysis in diphenyl ether205-207 [Eq. (53)]. A modification of this method used a Schiff s base instead of die TV-acyl derivative of a j8-amino-a,j8-unsaturated acid.208 Similarly, enamino esters react with benzoyl chloride to yield 6//-l,3-oxazines.209 

210 and Krantz and Hoppe211 obtained 6//-l,3-oxazin-6-one (68) by pyrolysis (650°C) of 3-ethoxycarbonylaminoprop-2-enal.211 It shows interesting properties, described in Section III,E. 

According to Sasaki et al.,212 diphenylcyclopropenone reacts with A-iminopyridinium ylids on refluxing in benzene to produce 2,4,5-trisubstituted-6//-1,3-oxazine-6-one (69) [Eq. (54)]. Matsukubo and Kato213 described the reaction of diphenylcyclopropenone and benzo-nitrile oxide through a hypothetical spiro intermediate to give 69 (R = Ph) in 40% yield [Eq. (55)]. 

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In an attempt to synthesize fused aromatic systems of a pentalene-like structure, Boekelheid and Fedoruk (332) submitted the dicyanomethyl ylide of thiazole (77) to the addition reaction with dimethyl acetylenedi-carboxylate (DMA). They unexpectedly observed the formation of a fused six-membered (80) rather than a five-membered-ring (78). This ylide (77) was readily afforded by the reaction of thiazole (73) with tetracyanoethylene oxide and then put into reaction with DMA. The initially formed thiazolopyrrole derivative (78) is strongly polarized by the gcm-dicyano group, and its pyrrole ring is spontaneously cleaved with proton elimination. The ring dosure of the intermediate (79) leads to the final stable derivative of 5-FT-thiazolo[3,2-a]pyridine (80). More recently. 

There are only a few studies of the bromination products of congested alkenes. Such products generally consist of the corresponding allylic bromo-derivatives, which are consistent with /5-proton elimination by the counter-ion from the bromonium ion. For example, the ionic bromination of octamethyl-cyclopentene in CC14 leads exclusively to l,2-di(bromomethyl)hexamethyl-cyclopentene as in Scheme 12 (Mayr et al, 1986). Bromine addition (30) to... 

Since similar compounds are found in the reaction of the same diene with hydroiodic acid, it has been assumed that the monoiodides were formed by electrophilic addition of HI, which may be due to proton elimination from the first formed ion pair intermediate (equation 80). 

Deactivation can take place if the intermediate hydride or alkyl species react with HCN. The result is the formation of nickel dicyanides, which cannot be reconverted to active species. We think that Lewis acids, in addition to promoting reductive elimination, may also have a retarding effect on this reaction, see Figure 11.4, as a more positively charged nickel species will react more slowly with protons. On the other hand, though, stronger acids are formed as a result of the interaction of HCN with the Lewis acids. 

Homolytic alkylation of homocyclic aromatic substrates is of much less interest than homolytic arylation because, in addition to the low selectivity, which also characterizes arylation, yields are usually poor, due to side reactions which compete seriously with the simple substitution reaction. The behavior of nonprotonated heteroaromatic substrates is similar. The case is quite different with protonated heteroaromatic bases because side reactions are eliminated or minimized, yields are generally good, and, above all, the selectivity is very high. Moreover, very versatile and easily available sources of alkyl radicals can be used under simple experimental condition it follows that homolytic alkylation of protonated heteroaromatic bases can be considered one of the main reactions of this class of compounds. 

The formation of orthoester may be explained tiy the preferential addition of tlie ketene acetal to the most reactive alcohol function (primary hydroxyl g,roup) giving thc f non - i so 1 a t ed) acyclic orthoester whicti is attacked by the neighbouring OH-4 with subsequent elimination of methanol. The partial hydrolysis of the diacetate is assumed to proceed through protonation of the methoxyl group (7), via the dioxocarbenium ion 8 and the orthoacid 9. collapse of 9 by either [lath b or path a accor-ding to the mechanism generally proposed (see, for instance, ref. 29 and refs. cited therein) affords the compounds 5 or respectively. 

The equilibrium can be easily forced to the right by addition of an excess of amine which will be protonated by HX with overall elimination of the amine salt. Hence, boron halides form the corresponding amides on reaction with excess of amine (equation 5).14... 

Nucleophiles can be introduced at C4 of 1,2-type 64 (Scheme 15) and at C4 or C5 of 1,3-type N-alkoxyazolium salts 67 (Scheme 16) by an allylic displacement of ROH and loss of a proton. This reaction mode competes with the nucleophilic addition followed by elimination of ROH described in Section 1.5.1.3. Consequently all ring protons in 1,2-type and 1,3-type azoles become activated but predictions of product distribution turn difficult. In all cases the net result is replacement of hydrogen at the heteroaromatic nucleus with a nucleophile. The sequence can be performed in one pot. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

S-adenosyl-L methionine (ADO-Met) dependent DNA methyl transferase catalyzed the transfer of a methyl group from AdoMet to a specific nucleotide within the DNA helix (Cheng et al., 1993). In a concerted reaction in the enzyme active site (Fig X) with a simultaneous addition of methyl residue of AdoMet to the cytosine ring and with an elimination of the ring proton by a water molecule requires involving seven heavy nuclei (two ofCys 81, four of AdoMet and one of water. An estimation with aid of Eq. 2.44 leads to value of the reaction synchronization factor asyn 10 4, that does not rule out the concerted mechanism, if the activation energy is less than 10 kcal/mole Nevertheless, a... 

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