Nucleophilic substitutions reactions derivatives

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

In those reactions where the fV-oxide group assists electrophilic or nucleophilic substitution reactions, and is not lost during the reaction, it is readily removed by a variety of reductive procedures and thus facilitates the synthesis of substituted derivatives of pyrazine, quinoxaline and phenazine. 

Compound 40 has not yet been synthesized. However, there is a large body of synthetic data for nucleophilic substitution reactions with derivatives of 41 [synthesized from aliphatic and aromatic aldehydes, pyridine, and trimethylsilyl triflate (92S577)]. All of these experimental results reveal that the exclusive preference of pathway b is the most important feature of 41 (and also presumably of 40). 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

These types of compounds are expected to be produced by utilizing nucleophile substitution reaction at the 2 position of l-methoxyindole-3-carbaldehyde (115a) and 3-acetyl-1-methoxyindole (107). In practice, after conversion of 115a to 195a (53%) as described in Section IV.J, 195a is allowed to react with various amines. Consequently, many derivatives of 271 are obtained. Typical examples (271a-c) are shown in the scheme (99H1157). 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

When the lactone was introduced, the temperature reached 165 and then 180 C very quickly even though an attempt was made to cool the medium. The reactor detonated and a fire broke out. It seems obvious that the temperature rise is due to the high reactivity of lactone, but the main factor in this accident seems to be related to the behaviour of dichlorophenoi, which in such conditions gives rise to an aromatic nucleophilic substitution reaction that leads to the formation of a dichlorodioxin (see halogen derivative on p.283). 

Sulfoximines bearing a chiral sulfur atom have recently emerged as valuable ligands for metal-catalysed asymmetric synthesis.In particular, C2-symmetric bis(sulfoximines), such as those depicted in Scheme 1.51, were applied to the test reaction, achieving enantioselectivities of up to 93% ee. The most selective ligand (R = c-Pent, R = Ph) of the series was also applied to the nucleophilic substitution reaction of l,3-diphenyl-2-propenyl acetate with substituted malonates, such as acetamido-derived diethylmalonate, which provided the corresponding product in 89% yield and 98% ee. 

Almost no attention has been paid to diphosphine sulfides employed as chiral ligands for palladium-catalysed nucleophilic substitution reactions. In this context, enantiomerically pure diphosphine sulfides derived from 2,2 -biphosphole, which combined axial chirality and phosphorus chiralities, were synthesised, in 2008, by Gouygou et al. through a four-step synthetic sequence. Among various palladium catalytic systems derived from this type of ligands and evaluated for the test reaction, that depicted in Scheme 1.62... 

This is clearly incompatible with a one-step pathway like the above, in which there would be no opportunity for attack by Y . It is, of course, important to establish that (4) does not arise merely by subsequent attack of Y on first formed (3), but it is found in practice that the formation of (4) is much more rapid than nucleophilic substitution reactions would be under these conditions. A possible explanation is competition by Y and Br (derived from Br2) for a common intermediate (see below). 

Brand-new results show the existence of heptacoordinated silicon as described in some of the following papers of this chapter, which also contribute to the discussion of mechanistical pathways in the course of nucleophilic substitution reactions at silicon. From these results one may speculate whether compounds with octa- and nonacoordinated silicon may be characterised in the near future. Although it is a problem to assign coordination numbers in -w-bound systems, it is worthwhile to note Jutzi s dccamethylsilicocene with a formal Si-coordination number ten in the oxidation state +2 in this context. With respect to Si(U)-compounds it should be stated that there are further derivatives with the... 

Nucleophilic substitution reactions in the selenophene series have attracted some interest. Debromination of bromonitro compounds [(50, X = S, Se) and (53, X = S, Se)] with sodium thiophenoxide and sodium selenophen-oxide72 was studied. Selenophene compounds were four times more reactive than the thiophene derivatives. The position of attack, a or /), had very little influence on the rate ratio. The kinetics of the side-chain nucleophilic reactions of selenophene derivatives, shown in Scheme 4, has been reported.7 3... 

The first evidence that an elimination-addition mechanism could be important in nucleophilic substitution reactions of alkanesulfonyl derivatives was provided by the observation (Truce et al., 1964 Truce and Campbell, 1966 King and Durst, 1964, 1965) that when alkanesulfonyl chlorides RCH2S02C1 were treated in the presence of an alcohol R OD with a tertiary amine (usually Et3N) the product was a sulfonate ester RCHDS020R with exactly one atom of deuterium on the carbon alpha to the sulfonyl group. Had the ester been formed by a base-catalysed direct substitution reaction of R OD with the sulfonyl chloride there would have been no deuterium at the er-position. Had the deuterium been incorporated by a separate exchange reaction, either of the sulfonyl chloride before its reaction to form the ester, or of the ester subsequent to its formation, then the amount of deuterium incorporated would not have been uniformly one atom of D per molecule. The observed results are only consistent with the elimination-addition mechanism involving a sulfene intermediate shown in (201). Subsequent kinetic studies... 

We have examined the competing isomerization and solvolysis reactions of 1-4-(methylphenyl)ethyl pentafluorobenzoate with two goals in mind (1) We wanted to use the increased sensitivity of modern analytical methods to extend oxygen-18 scrambling studies to mostly aqueous solutions, where we have obtained extensive data for nucleophilic substitution reactions of 1-phenylethyl derivatives. (2) We were interested in comparing the first-order rate constant for internal return of a carbocation-carboxylate anion pair with the corresponding second-order rate constant for the bimolecular combination of the same carbocation with a carboxylate anion, in order to examine the effect of aqueous solvation of free carboxylate anions on their reactivity toward addition to carbocations. 

As the last point in Sect. IV, we discuss briefly the reactions of chiral sulfur compounds with electrophilic reagents. In contrast to nucleophilic substitution reactions, the number of known electrophilic reactions at sulfur is very small and practically limited to chiral tricoordinate sulfur compounds that on reacting with electrophilic reagents produce more stable tetracoordinate derivatives. It is generally assumed that the electrophilic attack is directed on the lone electron pair on sulfur and that the reaction is accompanied by retention of configuration. As typical examples of electrophilic reactions at tricoordinate sulfur, we mention oxidation, imination, alkylation, and halogenation. All these reactions were touched on in the section dealing with the synthesis of chiral tetracoordinate sulfur compounds. 

Consider a proposed nucleophilic substitution reaction on the secondary alcohol shown using aqueous HBr. As a secondary alcohol, either Sn2 or SnI mechanisms are possible (see Section 6.2.3), but SnI is favoured because of the acidic environment and the large fert-butyl group hindering approach of the nucleophile. The expected SnI bromide product is formed, together with a smaller amount of the El-derived alkene in a competing reaction. 

Self-condensations are another set of important reactions of organolithium compounds. Tamao and Kawachi had reported that [(tert-butoxy diphenyl)silyl]lithium (20) exhibited ambiphUic character, and underwent a self-condensation reaction to give a [2- tert-butoxy)disilynyl]lithium derivative in THF as shown in Scheme 4, and also a nucleophilic substitution reaction with n-butyllithium . 

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