Bisalkylation

The same nitrotetraphenylporphyrin 14 (M = Cu) undergoes bisalkylation by conjugative addition with malononitrile to give the stereochemically pure chlorin 16 with the thermodynamically favored trans arrangement of the introduced malononitrile residues.22... 

Alkylation of corrole anions (RI, K2C03, acetone) gives a mixture of A21- and A22-alkylated corroles 2 and 3, respectively, in which the A2 -product predominates.6 8i At elevated temperatures bisalkylated JV.A-dialkyl corroles 4 are formed. 

The rates of radical-forming thermal decomposition of four families of free radical initiators can be predicted from a sum of transition state and reactant state effects. The four families of initiators are trarw-symmetric bisalkyl diazenes,trans-phenyl, alkyl diazenes, peresters and hydrocarbons (carbon-carbon bond homolysis). Transition state effects are calculated by the HMD pi- delocalization energies of the alkyl radicals formed in the reactions. Reactant state effects are estimated from standard steric parameters. For each family of initiators, linear energy relationships have been created for calculating the rates at which members of the family decompose at given temperatures. These numerical relationships should be useful for predicting rates of decomposition for potential new initiators for the free radical polymerization of vinyl monomers under extraordinary conditions. 

Predictive equations for the rates of decomposition of four families of free radical initiators are established in this research. The four initiator families, each treated separately, are irons-symmetric bisalkyl diazenes (reaction 1), trans-phenyl, alkyl diazenes (reaction 2), tert-butyl peresters (reaction 3) and hydrocarbons (reaction 4). The probable rate determining steps of these reactions are given below. For the decomposition of peresters, R is chosen so that the concerted mechanism of decomposition operates for all the members of the family (see below)... 

Equation 6 would hold for a family of free radical initiators of similiar structure (for example, the frarw-symmetric bisalkyl diazenes) reacting at the same rate (at a half-life of one hour, for example) at different temperatures T. Slope M would measure the sensitivity for that particular family of reactants to changes in the pi-delocalization energies of the radicals being formed (transition state effect) at the particular constant rate of decomposition. Slope N would measure the sensitivity of that family to changes in the steric environment around the central carbon atom (reactant state effect) at the same constant rate of decomposition. 

In Table I are listed the radical products (R )(column 2), AE(x) values (column 3), EA values (column 4) and the experimental temperatures for the one- and ten hour half life rates for the decomposition of trona-symmetric bisalkyl diazenes (columns 5 and 6), (rona-phenyl,alkyl diazenes (columns 7 and 8), peresters (columns 9 and 10) and hydrocarbons (columns 11 and 12). 

The quality of fit to the linear equation 7 is excellent for the radical forming decompositions of Irons-symmetric bisalkyl diazenes (reaction 1 - Table II) and Irons-phenyl, alkyl diazenes (reaction 2 - Table II). The quality of fit to equation 7 is not as high for the radical forming decompositions of lerl-butyl peresters (reaction 3 - Table II) and hydrocarbons (reaction 4 - Table II). This suggests that transition state arguments may be used to rationalize the rates of reactivity very well for reactions 1 and 2, and fairly well for reactions 3 and 4. 

Since the quantum chemical calculations used to parameterize equations 6 and 7 are relatively crude semiempirical methods, these equations should not be used to prove or disprove differences in mechanisms of decomposition within a family of initiators. The assumption made in the present study has been that the mechanism of decomposition of initiators does not change within a particular family of initiators (reactions 1-4). It is generally accepted that trow5-symmetric bisalkyl diazenes (1) decompose entirely by a concerted, synchronous mechanism and that trans-phenyl, alkyl diazenes (2) decompose by a stepwise mechanism, with an intermediate phenyldiazenyl radical (37). For R groups with equal or larger pi-... 

The linear free energy equations generated in this study are useful for reasonably accurate predictions of rates of radical forming decompositions of Irons-symmetric bisalkyl diazenes (1),... 

Richter, S. N. Maggi, S. Colloredo-Mels, S. Palumbo, M. Freccero, M. Binol quinone methides as bisalkylating and DNA cross-linking agents. J. Am. Chem. Soc. 2004, 126, 13973-13979. 

Di Antonio, M. Doria, F. Mella, M. Merli, D. Profumo, A. Freccero, M. Novel naphthalene diimides as activatable precursors of bisalkylating agents, by reduction and base catalysis. J. Org. Chem. 2007, 72, 8354—8360. 

In the conversion of 3,4,5,6-tetrabromo-l,2-bis(bromomethyl)benzene into the tetrabromoisoindole (Scheme 5.4), the bisalkylation of the primary amine in the First step of the reaction is promoted by the addition of benzyltrimethylammonium methoxide [22]. 2-Chloromethylpyridine reacts with a series of a,co-diaminoalkanes, as well as 1,2-diaminobenzene, to produce Af V -dialkylated and N,N,N N -tctra-alkylated products [23]. 

Scheme 10 Cathodic bisalkylation of azobenzene with 1,4-dibromobutane.

The mechanism of bisalkylation by isophosphoramide mustard (39) has been studied. The /3, /3, P, P -d4 derivative was used to demonstrate bisalkylation through sequential aziridinyl intermediates. 

Bisalkylation of the tetraester 3 is nearly quantitative, completely exo selective and gives the two products 4 and 572. The conditions for the allylation of 3 are unusual potassium hydride (2.3 equiv at-----20 °C) followed by addition of allyl iodide. 

Pericas and Jeong demonstrated independently that sulfur-tethered substrates, when subjected to the PKR conditions, afforded the desired bicyclic products. The sulfur tether is removed cleanly by Pummerer reaction after oxidation of sulfur to sulfoxide or 1,4-addition of bisalkyl cuprate followed by hydrogenolysis of sulfide with Raney nickel. It is worth mentioning that the regioselectivity regarding the acetylene part is opposite to that of the intermolecular version (Equation (30)). 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

When deuterium-labeled mustard 6.b reacts with a nucleophile (thiosulfate anion, S2O3-2), a nearly 1 1 mixture of products (6.c and 6.d) is observed. Explain how both products can be formed in approximately equal amounts. (Springer, I. B., Colvin, M. E., Colvin, O. M., Ludeman, S. M. Isophosphoramide Mustard and Its Mechanism of Bisalkylation. J. Org. Chem. 1998, 63, 7218-7222.)... 

Carbodiimides undergo [2+2] cycloaddition reactions to furnish l,3-disubstituted-2,4-bisalkyl or arylimino-l,3-diazeti-dine. For example, dibenzyl carbodiimides undergo dimerization to yield l,3-diazetidin-2,4-diimines 296 on heating. The reaction can be catalyzed by the addition of tributylphosphine (1%) (Equation 36) <1940CB1114, 1968CB174>. 

Fig. 13.32. Regiocontrolled bisalkylation of a bisenolate. The enolate C is formed with one equivalent of the alkylating reagent. C can be alkylated again, and B is formed in that way.

Tietze and coworkers found a symmetrical bisalkylation of a silyl dithiane with 2 equivalents of an epoxide involving 1,4-silyl migrations369. Smith and Boldi applied the method to the unsymmetrical bisalkylation of silyldithiane 233 (equation 150)368. 

Elimination of nitrogen from the triazolo[4,5-d]pyrimidine 208 took place on the reaction with BuLi followed by MeCHBrCONH2 to afford the bisalkylated pyrimidine 209 (90TL6103) (Scheme 44). 

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