QH BrQH QBr R2NHDMSQrnnh peptoids

Scheme 8.10. Solid-phase peptoid synthesis.

The straightforward synthesis has mostly been developed by Chiron researchers. Exploiting the great number of available amines, they were able to identify rapidly nanomolar ligands for ^-adrenergic and opiate receptors out of huge peptoid libraries.

Peptoids offer a good example of the evolution of methods that mimic natural oligomers with easy-to-make unnatural compounds. A recent similar development has been peptide nucleic acids (PNAs). PNAs resemble DNA with the phospho-diester backbone of the DNA being replaced by an oligo-[N-(2-aminoethyl)glycine] motif. They have been investigated for diagnostic and antisense purposes [30].

The SN reaction of alkylating agents with secondary amines can be controlled to give tertiary amines selectively. Thus, reaction of polymer-bound alkyl sulfonates with secondary amines gives immobilized tertiary amines [31]. In solution-phase synthesis, selective monoalkylation of secondary amines has been achieved mostly with monosubstituted piperazine substrates (see Scheme 8.11) [32]. The reaction can be performed with an excess of piperazine or with an additional base. To facilitate product isolation in solution-phase chemistry, either a water-soluble base in combination with an aqueous work-up [33] or a polymer-bound base [34] can be employed.

Scheme 8.11. Solution-phase piperazine alkylation.

Scheme 8.11. Solution-phase piperazine alkylation.

Intramolecular amine alkylation does not usually bear the risk of overalkyla-tion and is an excellent way to close heterocyclic rings. An Epibatidine synthesis using polymer-supported reagents provides an example that involves a mesylate substitution [35]. Even strained rings such as aziridines can be formed (Gabriel-Cromwell reaction) [36].

Epoxide opening with amine nucleophiles is frequently used in combinatorial chemistry since it leads to the attractive aminoalcohol substructure. When catalyzed with Lewis acids, for example lithium perchlorate, the reaction proceeds smoothly with a range of alkyl amines, anilines, and heteroaromatic amines. The reaction is useful in solution-phase synthesis (see Scheme 8.12) [37] as well as in solid-phase synthesis [38].

Scheme 8.12. Solution-phase epoxide opening by amines.

Scheme 8.12. Solution-phase epoxide opening by amines.

The nucleophilic attack of an epoxide by amines can be followed by reactions involving the newly generated hydroxyl function. In Scheme 8.13 a carbamate group at a suitable distance is attacked by the hydroxyl group that is exposed during epoxide opening. The resulting oxazoline formation occurs with concomitant cleavage off the resin [39].

Scheme 8.13. Solid-phase oxazolidinone synthesis.

Scheme 8.13. Solid-phase oxazolidinone synthesis.

Other nucleophiles that are readily alkylated on the solid phase by alkyl halides or sulfonates include hydroxyl amine [40], O-benzyl hydroxylamine [41], hydrazine derivatives [42], azide ion [43], and sulfonamides [44].

Nitrogen compounds bearing hydrogens of sufficient acidity can also be alkylated under Mitsunobu conditions (see above). Thus, a polymer-bound imidodicar-bonate can be alkylated with primary and secondary alcohols using the standard reagents TPP and DEAD. After cleavage off the resin, primary amines are obtained (see Scheme 8.14) [45].

O O 0 0 /^W A A TPP, DEAD ^^ A A TFA D „1LJ (J^O N OtBu + R-OH -- (JTO N OtBu -- R"NH2

Scheme 8.14. Solid-phase Mitsunobu reaction of imidodicarbonate.

254 | 8 Nucleophilic Substitution in Combinatorial and Solid-phase Synthesis 8.2.6

Ring-closing Reactions

The formation of medium-sized or large rings in combinatorial synthesis is frequently accomplished with SN reactions. Especially S-alkylation reactions are used in the ring-closing step. Representative examples involve the syntheses of b-turn mimetics containing nine- or ten-member rings [46] and a cyclic oligocarbamate consisting of a 26-membered ring [47].

An unusual case of macrocyclization is observed in solid-phase synthesis of [Arg-8]-vasopressin. The thiol groups of two cysteines of the peptide can be linked by a methylene unit to form a macrocyclic methylenedithioether [48]. The transformation is achieved by simply treating the resin with tetrabutylammonium fluoride in dichloromethane.

Nucleophilic Substitution at Aromatic Carbons

General Remarks

Nucleophilic aromatic substitution (SNAr) is an attractive approach to the func-tionalization of electron-deficient aromatic systems, in solution phase as well as on solid support. It has become an invaluable part of combinatorial transformations, particularly for the installation of nitrogen- or oxygen-linked substituents. A wide range of readily accessible nucleophiles can be introduced, making SN Ar reactions as popular as amide formations and outstanding for the synthesis of combinatorial libraries.

The large majority of these reactions is based on two classes of reactive scaffolds. Di- and trihalogenated heterocycles with two or more heteroatoms in the hetero-cyclic ring (mostly nitrogen atoms) have been used extensively. In these molecules the halogen atoms can be replaced selectively and sequentially with various nucleophiles, making the reaction ideal for combinatorial library production. On the other hand, there is a large number of examples for attractive and practical methods to cleanly and efficiently prepare novel libraries using substituted halo-geno-nitrobenzenes as templates. First, the nitro group activates the aromatic system for nucleophilic attack. After halogen substitution the nitro group can be reduced easily and used in an excellent way for further diversification of the libraries. If the chloro derivatives prove not to be reactive enough in the SNAr reactions, the chloro substrates can be transformed into the fluoro analogs by halex reaction (which is a SNAr reaction in itself). Fluoroaromatics are significantly more reactive toward nucleophiles [49].

Nitrogen Nucleophiles

From a historical point of view, the first template for SN Ar reactions was cyanuric chloride (2,4,6-trichloro-1,3,5-triazine), which is commercially available and inexpensive [50]. Compounds containing this core element have shown biological activity, e.g. as herbicides (Atrazin).

A research group at ArQule showed that the selective and sequential derivati-zation of cyanuric chloride could be achieved by simply controlling the reaction temperature. The generality of the research group's method has been proven by the solution-phase synthesis of a large combinatorial library of over 40,000 individual compounds (see Scheme 8.15) [51]. The first chloride substitution proceeds at —20 °C using N,N-diisopropylethylamine (DIPEA) as the base and acetonitrile as the solvent. Even anilines react with the very reactive cyanuric chloride in the proposed way. Usually, the arylation of the primary amine reduces its nucleophi-licity strongly. Therefore, no bis-arylation occurs at this position and the second chlorine atom can be substituted at room temperature. Owing to the relatively low reactivity of the third position, heating is required for the last exchange and only strong nucleophiles such as secondary amines give pure products and high conversions. Besides amines and anilines, also carbohydrates, dipeptides, amidines, and a-ketoamides can be incorporated, giving access to more complex structures. Upon screening of these compounds, a series of hits in the cardiovascular area has emerged.








Scheme 8.15. Sequential displacement of the chlorines of cyanuric chloride.

Using the cyanuric chloride template for solid-phase synthesis has become a very efficient method for the production of large combinatorial libraries. This was also demonstrated by the synthesis of a 12,000-compound library by Stankova and Lebl [52]. The first chlorine atom was selectively substituted by coupling the tem-

plate to a resin loaded with amino acids (see Scheme 8.16). Taking advantage of the decreasing reactivity of tri-, di-, and monochlorotriazines, various nucleophiles (amines, anilines, hydrazines) were introduced at different temperatures [53]. Likewise, an 8000-membered library on a cellulose-based polymeric membrane has been synthesized [54].

aa o


DIEA, OCM, 25'C (^J ^ N N N R3 dioxane, 90"C N N ,N N

R4 R5

1. side-chain 9 H F2

R4 R5

Scheme 8.16. Solid-phase library based on the triazine template.

The reaction sequence can be extended to related starting materials such as 2,6-dichloropurines, although the reaction conditions need to be harsher [55]. In a representative example, the dichloropurine was treated with a primary amine at elevated temperature. For the second substitution, reflux conditions and five equivalents of amine were necessary. Excess amine was removed by the use of formyl-polystyrene beads. The compounds could be benzylated at the N-9 position by an alkylation protocol or by using the Mitsunobu reaction (see Scheme 8.17) [56].

Scheme 8.17. Liquid-phase synthesis of a purine-based library.

SNAr reactions on perhalogenated heterocyclic systems are well established in solution phase and these reactions have been well adapted to solid-phase synthesis. They have been shown to be useful - indeed, more advantageous in many cases -than their solution-phase counterparts. Special attention in this area should be given to purine templates as purines are involved in signal pathways and metabolic processes in all living organisms (see Scheme 8.18). For example, the discov-

Scheme 8.18. Natural products containing the purine core.

ery of the biologically active natural product olomoucine stimulated attempts to generate diverse analogs based on the adenosine template on solid support [57].

First an aldehyde-functionalized resin preloaded with benzylamines was reacted with the purine scaffold. The authors chose N-9-SEM (SEM: trimethylsilylethoxy-methylene)-protected 2-fluoro-6-chloropurine as the starting material because of the activating potential of the SEM group in the amination reaction. After removal of this group using tetrabutylammonium fluoride in tetrahydrofuran (THF), a Mitsunobu reaction introduces the isopropyl moiety. A second nucleophilic substitution and final cleavage from the resin led to the desired purine analogs (see Scheme 8.19). Since the molecules were attached to the resin via the amino group at position 6, only primary amines could be introduced into the reaction sequence [58]. As a result, myoseverin, a novel microtubule-binding molecule, was identified upon screening these libraries [59].




2. Mitsunobu


Scheme 8.19. Synthesis of myoseverin on solid support.



2. Mitsunobu

Scheme 8.19. Synthesis of myoseverin on solid support.

The production of new compound libraries from polyhalogenated heterocycles is very common in combinatorial chemistry - for example reactions involving nucleophilic amines. Besides cyanuric chloride and chloropurines, many other templates have been used as starting materials (see Scheme 8.20) [50b] [60]. For example, for the synthesis of a library of 160 pyrimidine carboxamides, Suto et al. [61b] took advantage of the difference in reactivity between the two reactive sites of the substituted 2-chloropyrimidine-5-carboxylic acid chloride core (see Scheme 8.21). After amidation of the carboxylic function, some of the products were treated with amines to increase the polarity [61].

CI-^N^R 2,4-dichloro-6-alkylpyrimldines n



cr n



2,3-dichloroquinoxalines 2,4-dichloroquinazolines 2-fluoro-6-chloropurlne Scheme 8.20. Useful templates for SNAr reactions.

Aniline, Amberlyst, 25'C, 15 min

Scheme 8.21. Liquid-phase synthesis of a pyrimidine-based library.

Alternatively, structurally diverse pyrimidines can be obtained by a de novo synthesis. The synthesis commencing with isothiouronium salts (R1 = Ar-CH2- or resin-CH2-, see Section 2.3) is amenable to solution as well as to solid-phase applications. When condensing the isothiouronium salts with ketene derivatives, a pyrimidine skeleton with versatile functional groups is obtained. Oxidation of the alkylthio-linkage with m-chloroperbenzoic acid (m-CPBA) activates the molecule for SNAr derivatization (see Scheme 8.22). The corresponding sulfinyl or sulfonyl compounds are then easily substituted with various amines [62].

In a very similar approach, the solution- and solid-phase synthesis of libraries of trisubstituted 1,3,5-triazines has been described previously [63].

Arylpiperazines have been identified as a privileged structural element in various biologically active compounds. Besides strategies involving the cyclization of a

*NH2Hal- + J EtOH, DIEA 2. Pyrrolidine, dioxane

Scheme 8.22. De novo synthesis of pyrimidines.

substituted aniline with bis-(2-chloroethyl)amine, a synthetic route based on nu-cleophilic aromatic substitutions was also required. Different fluorobenzenes with a nitro group either at the ortho or para position underwent SNAr reactions with N-Boc-piperazine (see Scheme 8.23). After removal of the protection group, acyla-tion under Schotten-Baumann conditions with a set of eight carboxylic acid chlorides gave 48 N-alkyl-N'-acylpiperazines [64]. This methodology has been well adapted to solid-phase chemistry, as reflected in recent reviews.

n°2 hn^NBoc NO2 NBoc NO2

Scheme 8.23. Synthesis of an arylpiperazine library.

Resin-bound 4-fluoro-3-nitrobenzoic acid is also an outstanding template for nucleophilic aromatic substitution reactions with nitrogen nucleophiles. An enormous number of publications report the syntheses of benzodiazepin-2-ones, ben-zimidazoles, and related structures. Not surprisingly, only a short selection of examples can be described here.

Owing to the importance of benzodiazepines in many therapeutic areas, fundamental work in the area of solid-phase synthesis has been carried out using this structural element [65].

The 4-fluoro-3-nitrobenzoic acid has been immobilized via the acid group and reacted with a variety of a- and/or b-substituted b-amino esters in DMF in the presence of DIEA. The reduction of the arylic nitro compound to the aniline was carried out using standard conditions [2 M SnCl2H2O in DMF, room temperature (rt)] (see Scheme 8.24). After hydrolysis of the ester with a mixture of 1 N NaOH/

Scheme 8.24. Benzodiazepine synthesis on solid support.

Scheme 8.24. Benzodiazepine synthesis on solid support.

THF, the resulting compound was cyclized with DIC and HOBt and the 1,5-benzodiazepin-2-one was obtained. Alternatively, selective alkylation at the N-5 position adds further diversity to the library [66].

Using a-amino acids in the place of the b-amino acids, the [6,6]-fused ring system of quinoxalin-2-ones has been accessed [67]. The synthetic strategy is an adaptation of TenBrinks and coworkers' solution-phase synthesis on solid phase [68]. Variably substituted tetrahydroquinoxalin-2-ones can also be prepared based on 4-fluoro-3-nitrobenzoic acid. After substitution of the fluorine with primary aliphatic amines at room temperature and reduction of the nitro group, double acy-lation with chloroacetic anhydride has been shown to be the key step in the synthesis [69].

Further ring contraction to [6,5]-fused systems such as benzimidazoles has been the aim of other synthetic efforts - in solution and in solid-phase synthesis. Again, 4-fluoro-3-nitroarenes were linked to a solid support via an ether linkage [70] or via a carboxylic acid [71]. Commonly, both strategies use a SNAr displacement reaction of the fluorine atom by an amine with subsequent reduction of the nitro group. Whereas Phillips and Wie [70] achieved immediate cyclization by condensation with benzimidates, a research group at Affymax acylated the intermediate with an activated bromoacetic acetic acid first (see Scheme 8.25). After displacement of the bromide groups by nucleophiles, cyclization occurred upon cleavage with a concomitant dehydration [72].

Scheme 8.25. Solid-phase synthesis of benzimidazoles.

Finally, benzimidazolones can also be prepared from solid-supported 4-fluoro-3-nitrobenzoic acid. The key step in the synthesis was again the displacement of fluorine by a nitrogen nucleophile. The nitro group was reduced as described above and the resulting molecules underwent cyclization with the phosgene equivalent disuccinimidocarbonate [73].

An efficient liquid-phase synthesis of substituted benzimidazolones has also been described using a soluble polymer support [MeO-PEG, molecular weight (MW) 5000] [74]. This polymer support dissolves in many organic solvents (e.g.

DMF, THF) and precipitates in particular solvents (e.g. diethyl ether) (see Scheme 8.26). Again, 4-fluoro-3-nitrobenzoic acid was loaded onto the support and was then allowed to react with a variety of amines. After reduction of the nitro group, cyclization was achieved with trichlorophosgene.

soluble polymer support

Scheme 8.26. Benzimidazolones via solid-phase chemistry.

NH 1 triphosgene, NEt3, 8h, 25'C

soluble polymer support

Scheme 8.26. Benzimidazolones via solid-phase chemistry.

R1 N

Recently, a synthetic route to substituted 7-azabenzimidazoles was published. As a key template the highly reactive 6-chloro-5-nitro-nicotinyl chloride was used. The sequential alkylation with different amines by replacement of the strongly activated chloro atoms proceeds easily at room temperature [75].

Another scaffold well suited to the generation of huge libraries by combinatorial methods is 1,5-difluoro-2,4-dinitrobenzene. The two fluoro groups in the ortho positions of two aromatic nitro groups can be sequentially substituted with two amines. As the scaffold is planar and symmetrical, no problems with regio-selectivity occur. Lam and coworkers [76] demonstrated the viability of this concept by the production of a 2485-membered library designed for screening for antibacterial activity (see Scheme 8.27) - whereas the first substitution takes place within hours, the second runs overnight [76]. The authors then used the same concept for a solid-phase synthesis on 2-chloro-trityl resin, demonstrating that the two methods are complementary.

R1 R1 R2

Scheme 8.27. 1,5-Difluoro-2,4-dinitrobenzene as a scaffold for combinatorial libraries.

The displacement of activated halides with nucleophilic amines such as piper-azines is also a key step in the synthesis of antiviral quinolones and other phar-maceutically relevant compounds [77].

The starting materials, suitably substituted 3-oxo-3-phenyl-propanoates, are converted into enamines and cyclized to the quinolone core via an intramolecular SNAr reaction (see Scheme 8.28). After ester hydrolysis, a wide range of amines can be introduced by displacement of an activated halogen, e.g. a fluorine atom. A library of related compounds was synthesized and screened for human immunodeficiency virus (HIV) suppression [78].

A solid-phase approach to quinolones was published using the same cyclo-arylation procedure (see Scheme 8.29). A resin-bound b-keto ester was transferred

2. aminonaphthalene, 3 h, EtOH, -10'Cto25'C

2. aminonaphthalene, 3 h, EtOH, -10'Cto25'C

Scheme 8.28. Synthesis of quinolones. O O


2. cyclo-propylamine, F F NH

Scheme 8.29. Solid-phase approach to Ciprofloxacin.

Ciprofloxacin into the enamine and cyclized using tetramethylguanidine (TMG). Many amines can be incorporated by displacement of the fluorine atom at C-7 before the products are cleaved off the resin [79].

Oxygen Nucleophiles

Reactive arenes such as fluoro-nitroarenes, halopyridines, halopyrimidines, and halotriazines are preferred for reactions with oxygen nucleophiles [80]. Diary-lethers can be prepared by simply reacting the well-known 4-fluoro-3-nitrobenzoic acid template with a wide range of functionalized phenols in a solid-phase reaction (see Scheme 8.30) [81].

SNAr with phenol KgCOg, DMF, 40* C, 16h ac

1. reduction

Scheme 8.30. Diaryl ether via SNAr reaction on solid support.

In solution-phase chemistry, diarylethers can be produced utilizing a polymer-supported guanidine base. The reaction requires an excess of phenol to achieve complete conversion. The polymer-supported base deprotonates the phenol and also traps unreacted starting material (see Scheme 8.31). Since numerous phenols are commercially available, the method is well suited to library synthesis in an automated and parallel manner [82].

polymer supported base polymer supported base

Scheme 8.31. Diaryl ether synthesis using polymer-supported reagents.

The seven- and eight-member ring systems of dibenzoxazepins and dibenzox-azocines, respectively, have been well investigated in combinatorial chemistry using solution- and solid-phase synthesis [83]. The target heterocycles are efficiently assembled via intramolecular aromatic substitution of the fluorine in 2-fluoro-5-nitroarenes with the OH function of various phenols (see Scheme 8.32). For the solid-phase approach, the cyclization step was achieved using a 5% solution of DBU in DMF. DBU was found to give superior results when compared with TMG or N-methylmorpholine. The authors preferred a solid-phase approach rather than a solution-phase approach because yields were generally better while purities were identical.

Scheme 8.32. Solution- and solid-phase synthesis of medium-sized rings.

The value of trichlorotriazine as a template for library synthesis by sequential substitution of the chloro atoms is discussed in Section 8.3.2. Besides this, trichlorotriazine can react with a soluble polymer support (MeO-PEG-OH, MW 5000) to give PEG-bound dichlorotriazine, a new soluble electrophilic scavenger (see Scheme 8.33). Because of the high reactivity of the scavenger toward nucleophiles, it was used to remove alcohols at the end of ester or silyl ether-forming reactions [84].


Scheme 8.33. Ester synthesis using dichlorotriazine scavenger. 8.3.4

Sulfur Nucleophiles

The fluoro-nitroarene motif is also the most preferred template for SNAr for sulfur nucleophiles. In many applications, a suitably protected form of cysteine as a b-mercapto acid is reacted with 4-fluoro-3-nitrobenzoic acid to form 1,5-benzothia-zepin-4-ones, an important class of drugs in the treatment of cardiovascular disorders. For example, 4-fluoro-3-nitrobenzoic acid was treated with 1.5 equivalents of 9-fluorenylmethoxycarbonyl (Fmoc)-l-cysteine in DMF to be converted to the 2-nitro-thioether (see Scheme 8.34) [85]. After the reduction of the nitro group and a subsequent reductive alkylation (difficult because of the poor nucleophilicity of some anilines), the resulting secondary anilines were cyclized to form the seven-member thiazepine ring.

Scheme 8.34. Solid-phase synthesis of 1,5-benzothiazepin-4-ones.

Fmoc-homocysteine reacts with similar effectiveness to a nucleophile in the same reaction sequence. Shortening the side-chain from b-mercapto acid to a-mercapto acids, the SNAr reaction is also reliable in this case. However, the synthetic utility is limited owing to the fact that only a very small number of a-mercapto acids are commercially available.

Using a reversed synthetic strategy, a great variety of other fused heterocycles is accessible [86]. Wang resin loaded with cysteine via a carbamate linker can be reacted with numerous halo-nitroarenes bearing diverse functional groups.



Scheme 8.34. Solid-phase synthesis of 1,5-benzothiazepin-4-ones.


Recently, immobilized 4-fluoro-3-nitrobenzoic acid was transformed into 2-amino-4-carboxythiophenol as an intermediate for the synthesis of several classes of heterocyclic compounds such as benzothiazoles or 3,4-dihydro-1,4-benzothia-zines (see Scheme 8.35) [87]. The resin-bound 2-amino-4-carboxythiophenol was prepared by displacement of the fluorine atom with triphenylmethylmercaptan, reduction of the nitro group, and removal of the sulfur-protecting group.

Scheme 8.35. Solid-phase synthesis of 2-amino-4-carboxythiophenol. 8.3.5

Macrocyclization Reactions

In this section the reaction for closing large rings by nucleophilic substitution of activated arenes will be discussed. Cyclorelease reactions such as those used in the well-established syntheses of hydantoins [88] or diketopiperazines [89] will not be covered.

At first sight, the closure of medium-sized or large rings by nucleophilic displacement does not meet the demands of combinatorial synthesis. No new sub-stituents are incorporated and therefore no diversification is achieved. On closer inspection, the great importance of this reaction becomes obvious in view of the immense difference between the three-dimensional structure of a linear oligopep-tide and the corresponding cyclic analog. So SNAr macrocyclizations have become an important part of solid-phase organic synthesis, especially for the preparation of libraries of b-turn mimics.

Based on the experiences presented earlier in this chapter, suitably substituted fluoro-nitrobenzoic acids are the substrates of choice for intramolecular SNAr reactions [90].

Small libraries of 14-membered macrocyclic diaryl ethers and thioethers can be produced using a very similar procedure. Precursors are synthesized by the acyla-tion reaction of solid-supported peptides with 3-fluoro-4-nitro benzoic acid. The substrates undergo cyclization by displacement of the fluorine with the phenolic oxygen of a tyrosine derivative [91] or with the thiol group of cysteines [92] under exceptionally mild conditions (see Scheme 8.36). Diversity could be increased via postmodification reactions of the nitro group.

Recently, Burgess and coworkers reported in detail on their research on libraries of peptide turn mimetics [93]. The effects on nucleophilicity, product ring size, resins, and other reaction conditions were examined. Optimized procedures to produce 13- to 16-membered ring systems are described [93].

Larger rings are synthesized by the replacement of the fluorine atom in three regioisomeric fluoro-nitrobenzoic acids to prepare analogs of tocinoic acid (see Scheme 8.37) [94]. In this synthesis the amino group of lysine serves as an internal nucleophile for the closure of the macrocycle.

Scheme 8.36. Macrocyclizations using SNAr reactions.

R1, R2 = side chains of amino acids

1. cyclization

2. cleavage

Scheme 8.37. Synthesis of large-ring systems.


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