Electrophilic Substitution in Combinatorial and Solidphase Synthesis

Jan-Gerd Hansel and Stephan Jordan 9.1

Introduction

Reactions in which an electron-deficient reagent attacks a substrate and an electron-deficient leaving group is displaced are called electrophilic substitutions (SE). The most common leaving group is the proton. While the reaction is typical for aromatic systems, aliphatic substrates only react when hydrogens of sufficient acidity are available. This chapter focuses on the application of SE in the generation of chemical diversity.

Compared with nucleophilic substitution reactions (see Chapter 8) the use of SE in the context of combinatorial chemistry is rare. Much still remains to be done in this area of research. Although a number of functional group transformations involving SE mechanisms have been applied to solution- and solid-phase synthesis, the potential of the reaction to link building blocks in a combinatorial sense is restricted to very special cases. The wide application of acid-labile linkers in solidphase synthesis often prohibits the use of electrophilic reagents since the linkers are electron-rich aromatics and thus highly susceptible to aromatic SE.

Reactions involving SE mechanisms are frequently used in building-block synthesis. Despite its importance in the overall workflow of combinatorial chemistry, this aspect is beyond the scope of this chapter and will not be covered. Reference will only be made to the use of SE in the preparation of linkers and solid supports (see also Chapter 4). SE reactions involving organometallic reagents or carbon nu-cleophiles will be dealt with in the appropriate chapters. Traditional synthetic methods involving SE have been supplemented by modern transition metal-catalyzed substitution reactions. Please refer to other Chapters for their applications in combinatorial chemistry.

Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 1. Edited by K. C. Nicolaou, R. Hanko, and W. Hartwig Copyright © 2002 WILEY-VCH Verlag GmbH, Weinheim ISBN: 3-527-30509-2

Electrophilic Substitution at Aliphatic Carbons

Halogen Electrophiles

Halogenated carbonyl compounds are important synthetic intermediates, especially in the formation of heterocycles. Suitable reaction conditions have been devised for the transformation of enolizable carbonyl compounds into the corresponding a-bromo derivatives. The reagent of choice is pyridinium perbromide, which can be employed in both solid-phase [1] and solution-phase synthesis. In the latter case the commercially available polymer-bound version of the reagent has been frequently used [2].

As an example of this transformation the solution-phase bromination of aceto-phenones to a-bromo-acetophenones will be discussed. The transformation has been incorporated in an oxidation, bromination, and nucleophilic substitution reaction sequence (see Scheme 9.1). Notably, this sequence is performed by adding all the necessary polymer-supported reagents to the starting phenylethanol at the same time in a single reaction vessel. The final yield in this multistep/one-chamber solution-phase synthesis is higher than the combined yields of the three steps performed sequentially [3].

Polymer-

cyclohexene, 65'C, 12h

Scheme 9.1. Solution-phase bromination of acetophenones.

Nitrogen Electrophiles

The formation of hydrazones by the reaction of diazonium salts with activated methylene compounds can be adapted to parallel synthesis by linking either of the reactants to a polymer support. Polymer-supported aryl diazonium cations have been treated with the potassium salt of Meldrum's acid at 25 °C to give the corresponding 5-phenylhydrazone derivatives of Meldrum's acid in good yield [4]. Alternatively, polymer-supported Meldrum's acid anion reacts with various aryl diazonium fluoroborates at 25 °C in acetonitrile, yielding the same products [5].

Aliphatic diazo compounds are obtained on solid support from the reaction of tosyl or mesyl azide with immobilized activated methylene compounds. The substrates used are b-ketoesters [6], b-ketoamides [7] (see Scheme 9.2), or malonic acid derivatives [8]. Typically, the reaction is carried out at room temperature using an excess of the azide and an even larger excess of triethylamine or diisopropyle-thylamine.

Wang resin

Scheme 9.2. Solid-phase diazotation. 9.2.3

Carbon Electrophiles

CX/O^NY

rrV-

Wang resin

Scheme 9.2. Solid-phase diazotation. 9.2.3

Carbon Electrophiles

Enamines react with a number of electrophiles such as electron-poor olefins. The reaction is used in heterocycle chemistry, as shown in a solid-phase synthesis of dihydropyridines (see Scheme 9.3) [9].

Electrophilic Substitution at Aromatic Carbons

General Remarks

Almost all kinds of SE reactions involving arene substrates are used in solution-phase chemistry as a powerful synthetic tool. In solid-phase chemistry the use of this reaction is limited owing to its incompatibility with electron-rich linkers. With the exception of a few examples mentioned below, aromatic SE is restricted to the functionalization of polystyrene-based supports [10].

Polystyrene can be brominated, nitrated, and acylated or alkylated applying Friedel-Crafts conditions in solvents such as carbon tetrachloride or nitrobenzene. For example, in 1988 Ajayaghosh and Pillai [11] demonstrated the preparation of a photosensitive resin using SE reactions (see Scheme 9.4). Commercially available

SASRIN resin

Scheme 9.3. Solid-phase enamine substitution and cyclization.

SASRIN resin

Scheme 9.3. Solid-phase enamine substitution and cyclization.

Scheme 9.4. Solid-phase Friedel-Crafts acylation.

Scheme 9.4. Solid-phase Friedel-Crafts acylation.

polystyrene (crosslinked with 1% divinylbenzene) was first acylated with acetyl chloride under typical Friedel-Crafts conditions. The resulting ketone was reduced to the corresponding alcohol and then halogenated. Using a second SE reaction, a nitro group was introduced with fuming nitric acid at low temperature.

Higher reaction temperatures applied during acylation of solid-supported material may lead to side-reactions such as partial dealkylation of phenyl groups and hence to soluble polymers. Although Friedel-Crafts alkylations on polystyrene are possible under harsh conditions (strong acids), there are more suitable methods for this kind of C-C bond formation. Reaction of an immobilized organometallic compound (most commonly lithiated by a halogen-lithium exchange reaction) [12] with alkyl halides can be considered as the method of choice.

Halogen Electrophiles

In accordance with their inherent preference for electrophilic substitutions, many heterocycles are easily halogenated. For example, a simple bromination can serve as a starting point for further diversification when followed by palladium-catalyzed C-C bond formation (see Scheme 9.5). In addition to Suzuki couplings, the 6-bromonalidixic acid derivative obtained in the bromination step can also undergo Heck reaction [13].

Scheme 9.5. Solution-phase arene bromination and subsequent Suzuki coupling.

There are only a few examples of arene brominations on solid support in the literature. Using N-bromosuccinimide in dimethyl formamide at room temperature, electron-rich arenes such as thiophenes can be brominated (see Scheme 9.6). Combination with a Stille coupling and reiteration of the reaction sequence leads to oligothiophenes - new materials with interesting optical and electronic properties [14].

Scheme 9.5. Solution-phase arene bromination and subsequent Suzuki coupling.

Scheme 9.6. Solid-phase arene bromination and subsequent Stille coupling.

Scheme 9.6. Solid-phase arene bromination and subsequent Stille coupling.

A rare example of direct halogenation on a solid support has been reported for phenols. The phenolic moiety of tyrosine undergoes iodination when treated with bis-(pyridine) iodonium(I) tetrafluoroborate (Ipy2BF4) for no more than 10 min (see Scheme 9.7) [15].

Scheme 9.7. Solid-phase iodination.

Scheme 9.7. Solid-phase iodination.

The only example in this chapter in which the leaving group in an SE reaction is not a proton involves germanium-based linkers. These linkers have been developed for solid-phase synthesis as a means of traceless linkage (see Chapter 4). However, reaction of germanium-linked substrates with bromine rapidly releases the corresponding aryl bromides by ipso substitution of the germanium by bromine (see Scheme 9.8). Aryl iodides can be prepared by the same method using iodomonochloride [16].

Scheme 9.8. Solid-phase ipso substitution of germanium by bromine

Nitrogen Electrophiles

Very recently the diazotization of aromatic compounds has found applications in combinatorial chemistry. The formation of diazonium salts and the coupling to electron-rich aromatics to give azo dyes can be performed using polymer-supported reagents (see Scheme 9.9) [17].

Polymer-bound aryl diazonium salts also play a pivotal role in the chemistry of triazene linkers.

9.3 Electrophilic Substitution at Aromatic Carbons | 275 R2

Scheme 9.9. Solution-phase diazotation and azo coupling.

Carbon Electrophiles

Friedel-Crafts chemistry is rarely used to generate diversity. One of the few examples is the superacid-induced solution-phase synthesis of a small library of 3,3-diaryloxindoles (see Scheme 9.10) [18]. The reaction proceeds smoothly in pure triflic acid at room temperature.

P cf3so3h

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