Alkylation intermolecular reactions

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

With a radical-scavenging compound present in the reaction mixture, an alkyl radical species like 5 can be trapped, thus suggesting a fast conversion of the alkoxy radical 3 by intramolecular hydrogen abstraction, followed by a slow intermolecular reaction with nitrous oxide. 

The most common rearrangement reaction of alkyl carbenes is the shift of hydrogen, generating an alkene. This mode of stabilization predominates to the exclusion of most intermolecular reactions of aliphatic carbenes and often competes with intramolecular insertion reactions. For example, the carbene generated by decomposition of the tosylhydrazone of 2-methylcyclohexanone gives mainly 1- and 3-methylcyclohexene rather than the intramolecular insertion product. 

Rh2(OAc)4 has become the catalyst of choice for insertion of carbene moieties into the N—H bond of (3-lactams. Two cases of intermolecular reaction have been reported. The carbene unit derived from alkyl aryldiazoacetates 322 seems to be inserted only into the ring N—H bond of 323 246). Similarly, N-malonyl- 3-lactams 327 are available from diazomalonic esters 325 and (3-lactams 326 297). If, however, the acetate function in 326 is replaced by an alkylthio or arylthio group, C/S insertion rather than N/H insertion takes place (see Sect. 7.2). Reaction of ethyl diazoacetoacetate 57b with 328 also yields an N/H insertion product (329) 298>, rather than ethyl l-aza-4-oxa-3-methyl-7-oxabicyclo[3.2.0]hex-2-ene-2-earboxylate, as had been claimed before 299). 

In this type of process an excited molecule adds to a second — identical — molecule in its ground state, usually with formation of a ring. These dimerizations are thus most commonly intermolecular reactions, but obviously the two reactive moieties can also be linked together, e.g. by an alkyl chain. Such intramolecular photodimerization reactions have been studied in detail422). 

Illuminati el al., 1974, 1975, 1977. The reference intermolecular reaction is the alkylation of o-ethylphenolate anion by n-butyl bromide under the same conditions. Reactions were run using the fully ionized substrate in 75% ethanol-water... 

Bell el al., 1974. The reference intermolecular reaction is of the anion of p-hydroxy-acetophenone with EtCOCHjBr under the same conditions As for note j except that the reference reaction is alkylation of the guaiacol anion m Borchardt and Cohen, 1972. EM s based on relative rates assuming equal EM s for the bromide and mesylate, B.5.10 and B.5.12... 

FIGURE 6.7 (A) Rearrangement to the substituted phenol during acidolytic debenzylation of O-benzyltyrosine. Alkylation also occurs by intermolecular reaction. (B) Alkylation does not occur during acidolysis of 2-bromobenzyloxycarbonyltyrosine. The oxycarbonylphenol produced is a weaker nucleophile than phenol, and the cation that is generated is farther away from the nucleophile. 

Table 5.25). Diazacycloalkanes are also obtained from the reaction of a,(o-dibromoalkanes with the bis(tosylamino)alkanes, whereas intermolecular reaction of l-bromo-10-tosylaminodecane yields both 1 1 and 2 2 cyclic products (55% and 8%) under the basic conditions (Scheme 5.13). The reaction of p-tolucncsulphonamide with H-bromododecane yields the di-A-alkylated sulphonamide (84%) [50],... 

This has been applied to the cyclization of dihalides [45, 46], nonconjugated, unsaturated ketones [47] and esters [48], oxoalkylpyridinium salts [49], aldehydes and unsaturated nitriles [50], halides, and unsaturated esters [51], The umpoled acceptors, mostly radical anions or carban-ions (see Scheme 1), can also be used in intermolecular reactions such as acylation, alkylation, or carboxylation (Eq. 5). 

Few examples of preparatively useful intermolecular C-H insertions of electrophilic carbene complexes have been reported. Because of the high reactivity of complexes capable of inserting into C-H bonds, the intermolecular reaction is limited to simple substrates (Table 4.9). From the results reported to date it seems that cycloalkanes and electron-rich heteroaromatics are suitable substrates for intermolecular alkylation by carbene complexes [1165]. The examples in Table 4.9 show that intermolecular C-H insertion enables highly convergent syntheses. Elaborate structures can be constructed in a single step from readily available starting materials. Enantioselective, intermolecular C-H insertions with simple cycloalkenes can be realized with up to 93% ee by use of enantiomerically pure rhodium(II) carboxylates [1093]. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

The use of mediators to improve reactivity or selectivity in nitrone cycloaddition chemistry begins with the nitrone generation step. As is well known, the N-alkyla-tion of oximes provides one of the most direct and convenient synthetic routes to N-alkylated nitrones from readily available aldehydes and ketones. Electrophilic mediators have been employed to activate alkenes for N-alkylation, both in intramolecular and intermolecular reactions. They include activation of the internal alkene function by the action of (a) strong nonmetallic electrophiles such as phenyl-selenenyl sulfate (159), and (b) metallic catalysts such as Ag(I) (160) and Pd(II) ions... 

Several approaches are available to determine a rate-constant ratio for intermolecular reactions. (1) The most general method is much like that used to determine rate constants with a single nucleophile. However, by employing a pair of nucleophiles, the concentration of the alkylating agent need not be known. Equation (17) is used to calculate a rate-constant ratio. Both small and large conversions of reactant to product are conveniently handled by the equation it is written in a form to be used when a reactant concentration, [Het], is determined as well as when a product concentration, [MeHet], is obtained. The zero subscript designates an initial concentration. 

Numerous examples of different variants of this cyclization/cleavage protocol have been reported. Diketopiperazine formation (Section 15.22.1), an unwanted side reaction in solid-phase peptide synthesis, is also an example of this type of compound release. Because intramolecular processes generally take place more readily than the corresponding intermolecular reactions, cyclization/cleavage can occur with alkyl... 

Carbenoids derived from the metal catalysed decomposition of diazo compounds undergo various chemical transformations. Control of chemoselectivity by choice of the appropriate catalyst has significantly increased the synthetic viability of catalytic cyclopropanation reactions. Intermolecular reaction of unsaturated alcohols with carbenoids derived from catalytic decomposition of alkyl diazoesters has been reported by Noels and... 

The final modes of enantioselective allyl alkylations catalyzed by palladium involve the use of chiral nucleophiles447 and chiral leaving groups.448-449 Chiral enamines were found to undergo allylation in 100% optical yield in an intramolecular case and in up to 50% optical yield in intermolecular reactions (equation 358). 

The overall mechanistic picture of these reactions is poorly understood, and it is conceivable that more than one pathway may be involved. It is generally considered that cycloheptatrienes are generated from an initially formed norcaradiene, as shown in Scheme 30. Equilibration between the cycloheptatriene and norcaradiene is quite facile and under acidic conditions the cycloheptatriene may readily rearrange to give a substitution product, presumably via a norcaradiene intermediate (Schemes 32 and 34). When alkylated products are directly formed from the intermolecular reaction of carbenoids with benzenes (Scheme 33 and equation 36) a norcaradiene considered as an intermediate alternatively, a mechanism may be related to an electrophilic substitution may be involved leading to a zwitterionic intermediate. A similar intermediate has been proposed143 in the intramolecular reactions of carbenoids with benzenes, which result in substitution products (equations 37-40). It has been reported,144 however, that a considerable kinetic deuterium isotope effect was observed in some of these systems. Unless the electrophilic attack is reversible, this would indicate that a C—H insertion mechanism is involved in the rate-determining step. 

Less basic malonic ester anions may be employed for the twofold alkylation of dibromides. Cyclic 1,1-dicarboxylic esters are formed, if the reaction is executed in an appropriate manner. In the synthesis of cyclobutane diester A the undesired open-chain tetraester B was always a side product (J.A. Cason, 1949), the malonic ester and its monoalkylation product were always only partially ionized. Alkylation was therefore slow and intermolecular reactions of mono-alkyl intermediates with excess malonic ester prevailed. If the malonic ester was dissolved in ethanol containing sodium ethoxide, and 1,3-dibromopropane as well as more sodium ethoxide were added slowly to the solution, 63% of A and only 7% of B were isolated. The latter operations kept the malonic ester and its monoalkylated product in the ionic form, and the dibromide concentration low, so that the intramolecular reaction was favored against intermolecular reactions. The continuous addition of base during the reaction kept the ethoxide concentration low, which helped to prevent decomposition of the bromide by this nucleophile. 

Technically, the addition of carbon-centered radicals to C-N double bonds is as yet of little if any importance. In the free-radical chemistry of DNA it plays, however, a considerable role in the formation of the C(5 )-C(8) linkage between the sugar moiety and the purines (Chap. 10.5). Because of its importance, even an immune assay has been developed for the sensitive detection of this kind of damage in DNA (Chap. 13.2). The addition of the C(5 ) radical to the C(8) position of a purine is obviously facilitated for steric reasons (formation of a six-membered ring), but the same kind of reaction also occurs as an intermolecular reaction. Since alkyl radicals are nucleophilic, the rate of this reaction is noticeably increased upon protonation of the purine (Aravindakumar et al. 1994 for rate constants see Chap. 10.5). 

The precise mechanism of these intermolecular reactions is not known. Transient disproportionation processes, although well documented in less acidic media (see below and Section V.A.l), seem unlikely if alkyl cations alone are involved. Two possible explanations for the observed results may be considered. Small amounts of polymeric impurities may be present in the reaction mixture which could serve as a hydride source, catalyzing the intermolecular reaction as indicated in Eq. (16)4°). Alternatively, the intermolecular reactions may result from inefficient mixing during reaction initiation. In this case, unionized alcohols would serve as the hydride source. This latter alternative is consistent with the observation 4°1 that the deuterium in the 1-adamantanol obtained from the rearrangement of 38 is distributed between bridgehead and methylene positions. Unless more than one re-... 

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