Addition Followed by Elimination

Many carbonyl additions yield intermediates that undergo further transformations that restore the original carbonyl carbon to a doubly bonded state. These changes are fundamentally the same as the reverse steps of the additions considered in the previous sections, and differ only in that departure of some group other than the original nucleophile is possible. Equations 8.33 and 8.34, where Nuc and Nuc are generalized nucleophiles, illustrate two possibilities. 

The product of the elimination step may still contain a highly electrophilic doubly bonded carbon, as would be the case in Equation 8.33. In that case, a third step may follow in which a second molecule of the nucleophile adds to yield a final product in which the original carbonyl carbon is tetrahedrally bonded (Equation 8.35). In this section we consider reactions of this kind, and in Sections 8.4 and 8.5 we take up reactions that stop at the stage indicated by Equation 8.33 or 8.34. 

Addition of an alcohol to a carbonyl group is the most straightforward extension of the hydration process. The first product formed will be a hemiacetal (7) in the presence of an acid catalyst this intermediate may eliminate the OH 

Since rapid conversion of hemiacetal to acetal requires more acidic conditions than does formation of the hemiacetal, it is possible to measure the rate of hemiacetal production without complication from the second stage of the reaction.52 As might be expected, the hemiacetal formation displays characteristics similar to those of hydration general acid and general base catalysis are observed.53 

53 See note 52. For further references, see Y. Ogata and A. Kawasaki, in The Chemistry of the Carbonyl Group, J. Zabicky, Ed., Wiley-Interscience, London, 1970, Vol. 2, p 1. 

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The N-oxides readily undergo nucleophilic addition followed by elimination, which forms the basis of several useful syntheses of 2-substituted pyridines. Chlorination of (13) with POCl to give 2-chloropyridine (17) is a good example (eq. 4) some chlorination may occur also at C-4 (11). 

Ballini and coworkers have developed a new strategy for alkenylation of carbonyl compounds based on the Michael addition followed by elimination of HN02 (see Section 7.3). A variety of 2-alkylidene 1,4-dioles have been conveniently prepared, in two steps, by the Michael addition of a nitroalkane to the appropriate enedione derivatives under basic conditions, followed by chemoselective reduction with LiAlH4 (Eq. 4.123).170... 

Dicarbonyl compounds can be converted into furans by methods other than the classical Feist- Benary method, the essential feature of which is alkylation by a haloketone or similar species. A curious variation is provided by the use of trichloronitroethene, Cl2C=CCIN02, which condenses with two moles of a 1,3-dicarbonyl compound by Michael addition followed by elimination of two chloride ions the third chloride is lost at the aroma-tization step so that, for example, methyl 3-oxobenzenepropanoate is converted into the nitrofuran 38."... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Mechanistically, the compounds (162 X = O or S) and (163) represent two extremes in the base hydrolysis of phosphoramidates and phosphoramidothioates the former hydrolyse in an elimination-addition (EA) process whereas for the latter the sequence is one of addition followed by elimination AE). Further exploration of... 

In troponoid chemistry cine substitution occurs frequently. In many cases it can be explained by the intermediacy of dehydrotropolone species ( tro-polonyne ) as trapped, for example, by azides (Section II,A,3,h Scheme 34). An alternative mechanism may be a Michael-type addition followed by elimination. The intramolecular cyclizations depicted in Scheme 47 very likely proceed via Michael-type attack (73CRV293, p.351). 

Another example is the reaction of l-(17f-benzotriazol-l-yl)-l-(arylhydrazono)acetones 263 with DMFDMA. The intermediate 264 undergoes Michael addition followed by elimination of dimethylamine yielding pyridazin-4(l//)-ones 265 (Scheme 66) <2000JHC167>. 

B. 1,2- or 1,4-ADDITION followed by ELIMINATION further ADDITION REARRANGEMENT then ELIMINATION etc. (Schemes 48 and 49) ... 

In some instances, especially with the oxygen and sulfur heterocycles, the overall reaction leading to a substituted product does not involve an SEAr mechanism but proceeds by an addition followed by elimination sequence, as outlined for the bromination of coumarin in equation (4). The choice of experimental conditions can affect the outcome of the reaction, as illustrated in the formation of (114) and (115) in Section 3.2.1.4.7. 

The above reactions in this section have been examples of addition alone or addition followed by elimination. Ligand reactions involving nucleophilic substitution are also known and these are of the dealkylation type. Lewis acids such as aluminum chloride or tin(IV) chloride have been used for many years in the selective demethylation of aromatic methyl ethers, where chelation is involved (Scheme 27). Similar cleavage of thioethers, specially using mercury(II) salts, is commonly used to remove thioacetal functions masking ketones (equation 27).104 In some cases, reactions of metal ions with thioether ligands result in isolation of complexes of the dealkylated organic moiety (equations 28 and 29).105-107... 

In this sequence, substitution by 1 mol of dimethylamine first replaces the benzylmercaptan leading to 5-acetyl-2-dimethylamino-6//-l,3-thiazine (197). The thiazine then undergoes attack by dimethylamine excess at C-6, leading to the thiourea (198). The benzylmercaptan liberated in the first reaction may act as a nucleophile (BzS",H2NMe2+), and a different thiourea substituted by dimethylamino and benzylthio groups is obtained. The action of pyrrolidine on 1,3-thiazine-4-ones (194) can be seen as a Michael addition followed by elimination of H2S. In acidic media, the linear compound obtained is cyclized to the pyrimidone (200) (Scheme 80)... 

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. 

If the nucleophilic addition is the rate limiting step, the order of reactivity of the individual ring positions should run parallel to the order found by nucleophilic addition followed by elimination as discussed in Section I.5.I.3. With azole N-oxide as the starting material, the net result... 

The reaction is a Michael addition followed by elimination of cyanide ion. 

Very different and distinct ion chemistry has been observed in the reaction between the fragment ions obtained by electron ionization of tetramethoxygermane, Ge(OMe)4, and the parent neutral81. Reactions in this system proceed by nucleophilic addition followed by elimination of formaldehyde and/or elimination of methanol. An overview of the reactions of the different ions with Ge(OMe)4 is shown in Scheme 13 for the even electron ions, and in Scheme 14 for the radical ions originating from tetramethoxygermane. In these schemes, the neutral reagent of the ion/molecule reactions, Ge(OMe)4, is not shown for the sake of simplicity but the schemes include the neutral products that are eliminated upon addition of the reagent ion to the parent neutral molecule. 

Quantum chemical calculations have shown that the reaction depicted in Scheme 1 (addition followed by elimination ) has a lower barrier than that in Fig. 5 [129,132]. Since ammonia is more basic than formaldehyde, a swift proton transfer is kinetically favoured. For this reason, the prototype Schiff base forming reaction of Scheme 1 was overlooked for a long time, but a few years ago it was demonstrated that 1% of the gas phase collisions give protonated methylene imine, while 99% give protonated ammonia [132]. 

In order to protect the proton, and thereby suppress the kinetically favoured proton transfer route, it has been found out that gas-phase addition followed by elimination can be enhanced by reacting the proton bound dimer of the carbonyl compound rather than the protonated monomer [ 134]. In cases where the carbonyl compound has a higher proton affinity than the nucleophile, proton transfer is of course no problem. Alternatively, if the nucleophile already is protonated, as in the reactions between NH] and various carbonyl compounds, proton catalysed addition/elimination is possible as demonstrated experimentally by observation of immonium ion formation [135-137]. Likewise, the hydrazo-nium ion has been found to react with formaldehyde and a wide range of other aldehydes and ketones [138]. 

It corresponds to addition followed by elimination, and is symbolised by AE + De. The departing X+ is often a proton, while Z is a general substituent. The key step in this scheme is the formation of an intermediate arenium ion (Wheland intermediate, a complex), and the relative stability of this species is crucial to the outcome of the reaction. Isolable arenium ions are known, and the benzenonium ion itself C6Hy has been inferred from NMR of strongly acidic solutions [255],... 

Generally, negatively substituted furans require more severe substitution conditions. Presumably these substitutions take place initially with 2,5-addition, followed by elimination. Substitution at the 3-position is also expected, but has not been observed when a-positions are free. 

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