Betaines intermediates

Another very important reaction initially involving nucleophilic attack on an aldehyde carbonyl is the Wittig reaction. An yUd adds to the carbonyl forming a betaine intermediate which then decomposes to produce an olefin and a tertiary phosphine oxide. 

Similarly, photooxidation of dihydrocoralyne (108) in hot methanol at pH 8, subsequent addition of sodium methoxide and additional irradiation yielded 6,7-dimethoxyisoquinolone and 3-methyl-3,5,6-trimetho-xyphthalide via the betainic intermediate 109 (77H45) (Scheme 39). It was demonstrated earlier that dihydrocoralyne is oxidized to this betaine in quantitative yields under physiological conditions (76H153). The autoox-idative degradation of the mesomeric betaine was rationalized by the addition of singlet oxygen. 

The betaine intermediate is not isolated rather, it spontaneously decomposes through a four-membered ring to yield alkene plus triphenylphosphine... 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

The proposed betaine intermediates can be formed, in a completely different manner, by nucleophilic substitution by a phosphine on an epoxide (10-50) ... 

Betaines formed in this way can then be converted to the alkene, and this is one reason why betaine intermediates were long accepted in the Wittig reaction. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

The double bond in silenes is strongly polarized. They react with phosphorus ylides, as shown by Brook and MacMillan,45 like alkenes with the strongly polar C=C bond. Therefore, it is reasonable to suggest that the reaction also occur through the betaine intermediate (12) (Scheme 6). 

In another example (Scheme 8), the intramolecular cycloaddition of an azido functionality onto an enone group afforded bicyclic derivatives with bridgehead iV atoms. The cyclopentenone derivative 28 afforded the indolizidinone 30 through the proposed compound 29 which might react through a diradical intermediate or through a betaine intermediate <2002TL5385>. 

The stereochemical outcome of the Wittig reaction can depend on the presence or absence of lithium salts. This may be due to a betaine intermediate stabilized by lithium cation. A stable adduct of this type has now been observed during a Wittig reaction. When Ph3P=CH2 is treated with 2,2 -dipyridyl ketone, P NMR shows the formation of an oxaphosphetane (72) and addition of lithium bromide gives the chelation-stabilized betaine lithium adduct (73). 

The existence of the isomeric meso-ionic compounds 156 and 162 has been recently established.The transformation 156 162, R = Me, R = Ph, is achieved by heating in ethanolic solution or with ethane-thiol in benzene this isomerization could well involve the betaine intermediate (163). ... 

Fig. 3. Equilibration of meso-ionic isomers in protic solvents (e.g., EtOH) involving a betaine intermediate.

Mechanisms that are probably associated, respectively, with these processes are (i) the formation of betaine intermediates (306) (Fig. 3) 103,143,149,197,200 homolysis or heterolysis of the X—Z bond (304) or the X—Z bond (305) giving diradicsd (307) or dipolar (308) intermediates, (iv) 1,3-dipolar cycloaddition yielding intermediate adducts (e.g, 309), The base-catalyzed rearrangements (ii) present very interesting mechanistic problems suitable for speculation and experimental enquiry. 

Betaine intermediates result from the addition of pyridines to such systems as a,(3-unsaturated esters, quinones and epoxides. The use of acetylenic esters in such reactions has been reviewed (63AHC(l)i43). 

In a general base catalysis, the pyridine forms a hydrogen bond to an alcohol function (56). This causes a polarization and increases the nucleophi-licity of the alcohol oxygen thus accelerating the reaction [46c]. The second mechanism postulates a betain intermediate 57 which is formed by a nucleophilic attack of the pyridine on the ketene 59 [46d]. 

When the triazolinic nucleus carries electron-withdrawing groups at the position, it is far more labile.250 This is attributed to the increased stabilization of the betaine intermediate (53). Thus, triazoline 52 formed by reaction of benzoyl azide with norbornene already decomposes from 40° into N-benzoylaziridine 54.107 This compound isomerizes by distillation under normal pressure quantitatively into an exo-oxazoline derivative (55). 

Analogous methyl azidoformate forms with norbornene a thermal unstable triazoline.251 The decomposition products are 40% aziridine and 55% imide. Furthermore it has been observed that the rate of nitrogen evolution of the triazoline from methyl azidoformate increases threefold when triglyme and 20-fold when dimethyl sulfoxide are substituted for 1,1-diphenylethane as solvents. This fact supports a betaine intermediate in the thermal decomposition reaction. The triazoline from 2,4-dinitrophenyl azide and norbornene could just be isolated, but from picryl azide only the aziridine was obtained.252-254 Nevertheless, the high negative value of the activation entropy (—33.4 eu) indicates a similar cyclic transition state for both reactions. 

The reactants combine to give a betaine with either A or B configuration, the two species being in equilibrium with ylide and ketone. Because of the unfavorable interaction between the negative carbomethoxy group and the oxygen atom in the A isomer, the B isomer should be preferred and so should form more rapidly. Furthermore, the betaine intermediates... 

Extensive studies on azide addition to keto-stabilized sulfur ylides have been conducted304,380-383 in addition to triazolines, various other products are also formed (Scheme 110). The betaine intermediate (44), resulting from the reaction of the azide with two molecules of the ylide, reacts in one of three ways, as determined by the nature of the R and R1 substituents. 

Triazoline thermolysis leads to aziridines, diazo compounds, imines, or enamines a diazonium betaine is postulated as the intermediate that can undergo stabilization by different pathways,16,30,806,112,465 as depicted in Scheme 161. Imine and enamine formation may occur directly from the diazonium betaine806,112,226 237 247 or via the diazo compound.32 Acceleration of the rate of thermolysis of 4,5-dialkyl-substituted triazolines in polar solvents is commensurate with the betaine intermediate,100,112,457,466 and attempts to prove a 1,3-zwitterionic intermediate have failed 467-469... 

The parent 2-vinylindole and 2-(2-methylvinyl)indole also reacted with the carbodienophiles methyl-(E)-3-benzoylacrylate, l-penten-3-one, and methyl acrylate these reactions proceeded through a Diels-Alder step to produce the corresponding carbazoles (90JOC5368). The unsymmetrical dienophiles reacted regioselectively in accordance with the predictions of the FMO concept. In none of these reactions was it possible to detect either a betaine intermediate originating from a stepwise process or a Michael-type adduct. The stereochemistry of the cycloadducts was not changed when the reactions were carried out in the polar solvent... 

Ring opening of cz s-2,3-dimethyloxirane by triphenylphosphine has been modeled using the B3LYP functional with the 6—3lG(d) basis set.43 The calculations suggest that the first step of the reaction is an SN2 process with simultaneous C-C bond rotation giving an oxaphosphetane intermediate that decomposes to the frans-alkene no betaine intermediate is formed. 

The hexaphenylcarbodiphosphorane 22 (6) can be understood as an elementorganically substituted ylide with a particular character. It reacts with Sg to form CS 2i> which immediately reacts further with one more molecule qt 13 via a betaine intermediate as described previously (7) to make thioketenylidene triphenyl-phosphorane 22 (8). 

Stoichiometric sulfur ylide epoxidation was first reported by A.W. Johnson [23] in 1958, and subsequently the method of Corey and Chaykovsky has found widespread use [24-26]. The first enantioselective epoxidations using stoichiometric amounts of ylide were reported in 1968 [27, 28]. In another early example, Hiyama et al. used a chiral phase-transfer catalyst (20 mol%) and stoichiometric amounts of Corey s ylide to effect asymmetric epoxidation of benzaldehyde in moderate to good enantiomeric excess (ee) of 67 to 89% [29]. Here, we will focus on epoxidations using catalytic amounts of ylide [30-32]. A general mechanism for sulfur ylide epoxidation is shown in Scheme 10.2, whereby an attack by the ylide on a carbonyl group yields a betaine intermediate which collapses to yield... 

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