Ov V X ooS X

Scheme 16.19. Aza-Diels-Alder reaction using Lewis acids for catalysis.

In order to generate triazolopyridazines, urazines as electron-poor diaza dieno-philes are used in a hetero-Diels-Alder reaction with dienes [25]. Therefore, di-ethylphosphonoacetic acid is coupled to resin-bound amino acids and submitted to Horner-Wadsworth-Emmons reaction conditions with different a,b-unsaturated aldehydes (Scheme 16.20) [26]. The dienes thus obtained then react with different urazines, generated in situ from urazoles and iodobenzene diacetate.

Phl(OAc)2

Scheme 16.20. Hetero-Diels-Alder reaction with in situ-generated urazines. (PyBOP, benzotriazole-1-yl-oxy-tis-pyrrolidino-phosphonium hexafluorophosphate, NMM, N-methylmorpholine).

Diels-Alder Reaction in Solution Phase

It is true that transformations on solid support have some advantages over those in solution, such as the use of an excess of reagents and the ease of removal of non-resin-bound byproducts; in contrast, solution-phase chemistry often requires minimal investment of time during method development, has feasible scale-up, has easy reaction monitoring, and no attachment points are required. A variety of imag inative techniques have been developed to rapidly purify the many reactions of a solution-phase library in a parallel fashion. Some of these techniques include acid/ base extraction [27], fluorous-phase extraction [28], polymer-supported reagents [29] and catalysts [30], solid-phase extraction [31], or polymer-supported quench/ scavenging reagents [32].

The reaction with imines and dienes is well suited to solution-phase combinatorial chemistry using the scavenger methodology. Scheme 16.21 outlines the cycloaddition to 2,3-dihydro-4-pyridones under Lewis acid catalysis [33]. An equimolar mixture of aldehydes and primary amines in trimethylorthoformate reacts to form the imines. After evaporation of the solvent the cycloadducts are formed using an excess of Danishefsky diene under ytterbium triflate catalysis, which finally hydro-lyzes both the cycloadducts to the desired pyridones and the excess of the diene to the corresponding ketone. The diene decomposition product and, if the reaction does not go to completion, any unreacted imine are removed with a polyamine resin. After simple filtration followed by an acidic aqueous work-up dihydropyri-done products are obtained with good yields (up to 90%) and high purities (8090%). A variety of different imines, derived from alkyl, alkylaryl, pyridyl amines, and from substituted anilines, undergo the cyclization.

2) Filter

Scheme 16.21. Diels-Alder reaction using polymer-supported scavengers.

Even whole natural products are synthesized using an organized array of polymer-supported reagents. Scheme 16.22 shows the synthesis of epibatidine with a purity > 90%, avoiding the use of chromatographic purification steps [34]. A key step in the synthesis is a cycloaddition reaction between a nitro alkene derivative and an excess of a silyl-protected 2-oxadiene. Beginning with chloronicotinic acid, chloride - the dienophile - is obtained by a reduction/oxidation sequence to the aldehyde and addition of nitromethane with a subsequent elimination step. Treatment with an excess of the volatile silyl-protected 2-oxadiene at 120 °C provides the cycloadduct in a quantitative yield. Hydrolysis to the corresponding ketone, reduction to the alcohol, mesylation, and reduction of the nitro group to the amine with final cyclization forms the endo isomer of epibatidine.

CH3N02

OTBDMS

Scheme 16.22. Synthesis of epibatidine by Diels-Alder reaction.

16.3

[3 + 2] Cycloadditions

The most widely studied cycloadditions in solid-phase combinatorial synthesis are [3 + 2] cycloadditions, which have been shown to comprise a wide range of dipoles (nitrones, nitrile oxides, pyridinium salts, azomethine ylides, etc.) and dipolaro-philes (alkenes, dienes, and alkynes). Depending on the nature of the 1,3-dipoles employed in the transformations, various heterocycles such as isoxozazoles, iso-xazolines, pyrrolidines, indolizines, and pyrrazoles are obtained [35]. These five-member ring systems represent a branch of unique pharmacophores and some are also versatile synthetic intermediates in further functional group interconversions.

As mentioned in the introduction to this chapter, most applications of these transformations are aimed at solid-phase combinatorial chemistry, while only one solution-phase example has been reported to date [36].

Formation of Isoxazoles, Isoxazolines, and Isoxazolidines

Isoxazoles and isoxazolines are obtained by [3 + 2] cycloaddition of nitrile oxides to alkynes or alkenes [37], while isoxazolidines are formed through reactions of endo epibatidine endo epibatidine nitrones and olefins (Scheme 16.23). As nitrile oxides often suffer from decomposition and dimerization in solution [38], these transformations should be carried out on solid phase on which either the dipolarophile or the 1,3-dipole can be immobilized.

Scheme 16.23. Synthesis strategies for the preparation of isoxazoles, isoxazolines, and isoxazolidines.

In a representative example of the preparation of isoxazoles and oxazolines [39], a polymer-bound olefin or alkyne is treated with nitrile oxides (Scheme 16.24), which are typically generated in situ either by using Mukaiyama's method utilizing phenyl isocyanate and triethylamine [40] or by oxidizing oximes with sodium hy-porchloride [41]. The conversions observed are generally high, although in some cases the cycloaddition step has to be repeated up to three times when less stable nitrile oxides are used.

Scheme 16.24. Formation of isoxazoles from resin-bound alkynes.

Intramolecular modifications of the above-mentioned [3 + 2] process have also been well established on solid-phase [42]. In a generic example, polymer-supported nitro olefins undergo 1,3-dipolar cycloadditions, giving three stereogenic centers in the resulting tetrahydrofuroisoxazolines (Scheme 16.25). This highly stereoselective process proceeded after obtaining the nitro olefins from Michael additions of dienol alkoxides to b-nitrostyrene.

Scheme 16.25. Intramolecular addition of a polymer-bound nitrile oxide to an olefin.

Scheme 16.25. Intramolecular addition of a polymer-bound nitrile oxide to an olefin.

During the synthesis of a natural product-like library (see also Chapter 21), an intramolecular cycloaddition is used as the key step in building up a polycyclic template [43]. This product is formed by a Tamura tandem reaction [44] of a polymer-bound epoxycyclohexanol and a set of nitrone carboxylic acids (Scheme 16.26). After initial coupling of the 1,3-dipoles to a shikimic acid-derived alcohol, the subsequent [3 + 2] cycloaddition proceeds with high stereo- and regioselectivity. A variety of reagents and conditions have been screened for further manipulations of the tetracyclic core thus formed and a split-and-mix library of more than 2 million compounds has been synthesized.

PyBroP, DIEPA,

HO jQ O O DMAP, DCM, 0 *C->rt ^ ^ + HO-^R -"

Scheme 16.26. Syntheses of tetracyclic cores by tandem transesterification cycloadditions of epoxycyclohexanols and nitrone carboxylic acids.

On the other hand, when nitrones are prepared in situ from 2-bromobenzalde-hyde and methyl hydroxylamine and consequently reacted with polymer-bound acrylates through a nontethered transition state (Scheme 16.27), they were found to be less suitable for solid-phase combinatorial synthesis [45]. The yields recorded are in the range of 24-45% and even boosting the excess of reagent up to 40 equiv. and extending the reaction times does not improve the results. In the latter case, cleavage of the acids from the 2-chlorotrityl resin is observed owing to the prolonged exposure to heat.

MeNHOH

toluene, 80'C

Scheme 16.27. Syntheses of isoxazolidines by reactions of polymer-bound olefins and nitrones.

More success is encountered by the same research group when polymer-bound hydroxylamines are reacted with aldehydes and electron-deficient olefins such as vinylsulfones and N-substituted maleimides (Scheme 16.28). Moreover, it is worth mentioning that the electronic nature of the aldehydes employed has little impact on the synthesis of isoxazolidines, whereas nitrones derived from ketones do not react at all. The superiority of this alternative approach over the route involving immobilized olefins is demonstrated by the synthesis of a small split-and-mix library comprising ten compounds.

nh toluene, 80'C

Scheme 16.28. Syntheses of isoxazolidines by reactions of polymer-bound nitrones and olefins.

Scheme 16.28. Syntheses of isoxazolidines by reactions of polymer-bound nitrones and olefins.

In order to avoid elevated temperatures, ytterbium triflate was successfully introduced to [3 + 2] cycloaddition reactions, which were then found to proceed at room temperature (Scheme 16.29) [46]. Acrylates of 1,3-oxazolin-2-ones are the best olefinic reaction partners, which can be attributed to their favorable electronics. When other dipolarophiles such as methyl vinyl ketones or substituted acetylenes are used, reduced yields are observed, which can be attributed to the reduced ability of Lewis acid coordination of the unsaturated systems screened.

o ^ tmof/ch2ci2

Yb(OTf)3, toluene, rt

Scheme 16.29. Yb(Otf)3-catalyzed 1,3-dipolar cycloadditions of polymer-bound nitrones.

The isoxazolidines thus obtained are then derivatized further and consequently converted to their corresponding isoxazolines by oxidative cleavage using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). During the initial work-up, ascorbic acid is added in order to reduce the amount of remaining oxidant, but chromatography on silica gel is still found to be necessary.

Isoxazolidines can also be prepared from immobilized nitrile oxides, which are easily generated through oxidation of polymer-bound aldoximes. In one case, N-chlorosuccinimide (NCS) was used as the oxidant and the corresponding hydrox-imoyl chlorides were converted to the reactive species by the dropwise addition of triethylamine (Scheme 16.30) [47]. Immediate trapping with an excess of olefins gave the desired heterocycles with yields of 60-80% and purities of >90%. Iso-xazoles can also be prepared using this methodology.

EtnN

Scheme 16.30. Syntheses of isoxazolines by oxidation of a polymer-bound oxime with NCS and subsequent olefinic trapping.

In another example, the use of an additional amine base can be avoided when a polymer-bound aldoxime is oxidized with commercially available household bleach. After elimination of hydrogen chloride, the corresponding nitrile oxides are obtained [48]. The generality and ease of this protocol is demonstrated when the inverse strategy is pursued and resin-bound acrylates are successfully converted to isoxazolines.

Solid-supported reagents can also be used for the in situ preparation of nitrones with regard to the solution-phase synthesis of isoxazolidines (Scheme 16.31) [49]. This process has been carried out using polymer-supported perruthenate (PPS) as the oxidant, but this procedure is limited to symmetrical hydroxylamines only. In order to circumvent this limitation, aldehydes are normally condensed with primary hydroxylamines in the presence of solid-supported acetate. After removal of the polymer-bound reagent and transfer of the crude nitrone to a solution of methyl acrylate, the desired cycloaddition product is isolated with an 81% yield.

NMe,

aNMe3+ C02Me

Scheme 16.31. Synthesis of isoxazolidines using polymer-supported reagents.

458 I 16 Cycloadditions in Combinatorial and Solid-phase Synthesis 16.3.2

Formation of Pyrrolidines

Pyrrolidines are typically formed by [3 + 2] cycloaddition reactions of stabilized azomethine ylides and alkenes - a well-documented process using solid support (Scheme 16.32) [50]. Generation of the reactive dipoles can be achieved thermally by Lewis acid activation or under basic conditions. The neighboring effects of a stabilizing electron-withdrawing group are thereby required and, for that reason, amino acids are the preferred building blocks as they are commercially available in large numbers. Strategically, either the azomethine ylide or the dipolarophile can be immobilized on solid support and both strategies have been used successfully. Less commonly, ylides have been formed through transmetalation processes.

Scheme 16.32. Formation of pyrrolidines by [3 + 2] cycloaddition of azomethine ylides to olefins.

In a representative example of a heat-induced cycloaddition, a polymer-bound amino acid was first condensed with aldehydes and then reacted with N-substituted maleimides (Scheme 16.33) [51]. The resulting prolines were obtained with high diastereoselectivities and with satisfactory yields and purities of >72%.

Alternatively, the process can be carried out as a multicomponent procedure [52] when amino acids and maleimides are reacted together with polymer-bound aldehydes.

Scheme 16.33. Solid-phase synthesis of substituted prolines.

Pursuing the inverse strategy, resin-bound dipolarophiles can also be reacted with azomethine ylides [53], but the introduction of a base and a Lewis acid is vital for the success of the transformations. After condensation of aromatic aldehydes to 3-hydroxyacetophenone attached to Wang resin, the resulting a,b-unsaturated ketones are treated with N-metalated azomethine ylides in the presence of 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) and LiBr (Scheme 16.34). Highly substituted pyrrolidines are obtained with satisfying regio- and diastereoselectivities, but chal-cones derived from sterically demanding aldehydes, for example 2,6-dichlorobenz-

R"

R"

R"

R"

Scheme 16.33. Solid-phase synthesis of substituted prolines.

Scheme 16.34. Formation of pyrrolidines from polymer-supported chalcones. rt, room temperature.

Scheme 16.34. Formation of pyrrolidines from polymer-supported chalcones. rt, room temperature.

aldehyde, do not yield any products. There has been no success using silver(I) acetate as an additive - the catalyst most often used in imine cycloaddition reactions [54].

Other examples that make use of silver salts include the silver acetate-induced cycloaddition of tryptophan-derived imines to polymer-bound acrylates (Scheme 16.35) [55] and synthetic efforts toward a split-and-mix library of mercaptoacyl proline-based inhibitors of angiotensin-converting enzyme (ACE) [56]. Silver nitrate has also been used in the synthesis of fully substituted prolines derived from histidine precursors [57], while intramolecular cycloadditions have yielded poly-cyclic cores when both the imine and the enone are immobilized on solid support [58]. It is worth mentioning that, during the syntheses of hydantoin-containing

2. Acylation O R

~SAc

~SAc

AgOAc, DIEA

MeCN, rt

Scheme 16.35. Silver(I) salt-induced formation of substituted prolines.

heterocycles, the insertion of 1,3-propanediol as a spacer moiety between the polymeric backbone and the glycinate generally facilitates the cycloaddition (Scheme 16.35). The desired tetracyclic cores are released from the resin after treatment with isocyanates and base, whereas the latter reagent epimerizes the stereogenic center at C7a. Another example of the tandem azomethine ylide cycloaddition and carbanilide cyclization strategy uses zinc acetate and DBU as the catalytic system [59].

Other conventionally used Lewis acids such as cesium fluoride [60], silver triflate [61], or cobalt dichloride [62] have not yet been adapted to solid-phase combinatorial synthesis.

More reactive dipoles can be generated by transmetalation of 2-aza-allyl-stannanes and butyl lithium (Scheme 16.36) [63], and the resulting unstabilized anions are able to undergo [2 + 3] cycloadditions with electron-rich alkenes. Although mixtures of regio- and stereoisomers are generally obtained, this protocol complements the related azomethine ylide transformations which usually require electron-poor olefins.

Scheme 16.36. Synthesis of pyrrolidines via aza-allyl anion cycloadditions.

SnBUj

Formation of Furans

Efficient traceless solid-phase syntheses of furans derived from polymer-supported isomiinchnones have been reported [64]. The highly reactive 1,3-dipolar intermediates which participate in the cycloaddition reactions with electron-deficient acetylenes are generated in situ by the decomposition of diazoesters with Rh(II) catalysts. Upon heating, the intermediate bicyclic cycloadduct rearranges to the desired furans and leaves polymer-supported isocyanate behind (Scheme 16.37).

Isomûchnone

Isomûchnone

Scheme 16.37. Traceless synthesis of furans via 1,3-dipolar cycloaddition reactions of isomunchnones.

Formation of Imidazoles, Pyrroles, Pyrazoles, and Other Nitrogen-containing Heterocycles

Imidazoles have also been synthesized on solid support utilizing a munchnone [3 + 2] cycloaddition reaction with aryltosylimines as the key bond-forming step (Scheme 16.38) [65]. This methodology has been successfully executed in solution phase before, but the reaction yields are reduced by the tendency of miinchnones to undergo self-condensation [66]. This problem can be readily circumvented by attaching the dipoles to AgroGelTM-MB-CHO.

Scheme 16.38. Formation of imidazoles via munchnone intermediates.

Miinchnones are prepared by reaction of an acylated polymer-bound amino acid and N'-(3-dimethylaminopropyl)-N-ethylene carbodiimide (EDC) and should immediately be reacted with tosylimines in one pot. It is difficult to cleave the immobilized imidazoles thus obtained from the polymeric support but their release can be achieved by boiling the resins in neat acetic acid, which takes advantage of the robustness of the polymer-bound heterocycles, and unreacted starting materials or nonimidazole byproducts are removed through simple washing with tri-fluoroacetic acid (TFA) prior to the cleavage step. This new linking strategy has allowed the preparation of an exploratory library containing 12 heterocycles (Scheme

When miinchnones are combined with electron-deficient acetylenes, pyrroles are obtained (Scheme 16.39) [67]. The precursors for the 1,3-dipolar cycloaddition are available through the Ugi four-component condensation (4UCC) (see Chapter 23.7.5) and undergo an acid-catalyzed cycloelimination step. The resulting

OMs R1

Scheme 16.38. Formation of imidazoles via munchnone intermediates.

OMs R1

Scheme 16.39. Formation of pyrroles via mUnchnone intermediates.

Scheme 16.39. Formation of pyrroles via mUnchnone intermediates.

1,3-oxazolinium-2-ones are then trapped with dimethyl acetylenedicarboxylate (DMAD) or other electron-deficient acetylenes [68] and yield pyrroles after aroma-tization and loss of carbon dioxide.

In another example of a [2 + 3] cycloaddition reaction involving electron-deficient acetylenes, DMAD reacts with polymer-bound azomethine imines, forming pyrazoles (Scheme 16.40) [69]. The 1,3-dipoles employed are generated from a-silylnitrosoamides by a 1,4-silatropic shift and give heterocyclic Michael adducts in up to 70% yield. The ratio of the regioisomers obtained is highly dependent on the size of the adjacent substituents, whereas in the case of R = H only one isomer can be detected. Another interesting aspect of this strategy is the cyclization-release methodology, avoiding the need for the cleavage operation. However, purification by silica gel chromatography was still found to be necessary.

-CO,Me toluene, 80C

OSiMe,

Me02C C02Me

MeOX

CO,Me

Me02C C02Me N

Scheme 16.40. Traceless synthesis of pyrazoles.

Indolizines have also been synthesized on solid support by [3 + 2] cycloaddition reactions of pyridinium ylides with electron-deficient olefins [70]. After alkylation of polymer-bound isonicotinic acid with 2-bromoacetophenones, the resulting pyr-idinium salts are treated with a,b-unsaturated ketones at elevated temperatures (Scheme 16.41). However, the resulting tetrahydroindolizines rearrange upon

acidic cleavage with TFA, a phenomenon also observed during the transfer of the Tsuge reaction to solid-phase chemistry [71].

The formation of the open-chain pyridinium salts is suppressed through oxidation of the bicyclic core with the bimetallic complex TPCD [Co(pyridine)4-(HCrO4)2]. After treatment with TFA, aromatic indolizines are obtained and an exploratory library of nine members has been prepared.

16.4

[2 + 2] Cycloadditions

The [2 + 2] cycloaddition reaction is one of the most synthetically efficient methods used for the preparation of four-member rings. However, only a limited number of protocols have been adapted to solid-phase combinatorial chemistry, while particular focus has been turned toward the synthesis of mono-cyclic b-lactams via the venerable Staudinger reaction [72]. In a representative example (Scheme 16.42), the cycloaddition reaction is initiated through the slow addition of acid chlorides to a suspension of the imine resins in the presence of triethylamine [73]. Owing to the high reactivity and the accompanying tendency to undergo polymerization reactions, the use of a multifold excess of the reagent is required. However, even cycloadditions to imines derived from highly hindered amino acids usually give satisfying results and the scope of the reaction can be extended to amino, O-protected and vinyl ketenes.

Scheme 16.42. b-Lactams through [2 + 2] cycloaddition reactions of ketenes to resin-bound imines.

The thus formed highly functionalized four-member ring heterocycles are also valuable precursors for further chemical manipulations, particularly, when the b-lactam strain is used to facilitate ring-opening reactions. A striking example of b-lactams as versatile intermediates was given en route to a split-and-mix library of 4140 dihydroquinolinones (Scheme 16.43) [74]. Here, the nitro group of a [2 + 2] cycloadduct is reduced and used as an internal nucleophile for the ring expansion reactions.

Scheme 16.42. b-Lactams through [2 + 2] cycloaddition reactions of ketenes to resin-bound imines.

Scheme 16.43. Dihydroquinolinones via polymer-supported b-lactam intermediates.

Scheme 16.43. Dihydroquinolinones via polymer-supported b-lactam intermediates.

Another method for the solid-phase preparation of b-lactams from imines involves titanium ester enolates derived from 2-pyridinethiols (Scheme 16.44) [75].

o r1,JLso2CI 0r,yJ-R"

Scheme 16.44. Solid-phase synthesis ofb-sultams.

Moreover, when sulfenes are used in the cycloaddition reactions to polymer-supported imines, structurally analogous b-sultams are obtained [76]. Both reactive species are generated in situ and smoothly react at —78 °C. While the imines are prepared by the condensation of aldehydes to immobilized amino acids, the sul-fenes are formed by the addition of pyridine to methylchlorosulfonyl acetates.

In agreement with the solution-phase synthesis of sultams, two trans diaster-eomers are obtained [77], but the success of the reaction is reduced when sterically more demanding amino acids such as aspartic acid tert-butyl ester are used. On the other hand, the utility of this method is indisputably high - the entire reaction sequence can be carried out with an acid-labile and a photolabile linker. It nicely allows for the tiered release of compounds from polymeric beads onto live cells during high-throughput screening (HTS). Further chemical modifications of the thiazetidine core also extend the scope of this strategy.

A [2 + 2] keteneiminium cycloaddition reaction has been used to prepare cy-clobutanones on solid support (Scheme 16.45) [78]. The alkene resins are thereby added to a fivefold excess of the keteneiminium salts generated in situ from N,N-dialkylamides according to the method of Ghosez and coworkers [79]. The resulting iminium salts are then hydrolyzed to the corresponding ketones with aqueous sodium bicarbonate solution and further converted to /-lactams and /-lactones. This solid-phase protocol is superior to the analogous chemistry carried out in solution, as generally higher conversions are obtained and the purification of the cyclobutanone iminium salts is facilitated by the immobilization on solid phase.

O Dill

TfaO, DCM, base

Scheme 16.45. Solid-phase synthesis of cyclobutanes.

16.5

[6 + 3] Cycloadditions on Solid Support

The [6 + 3] cycloaddition is an example of a more exotic reaction in combinatorial solid-phase chemistry. One example of a [6 + 3] cycloaddition is the reaction be tween fulvenes and benzoquinones forming heterosteroid frameworks (Scheme 16.46) [80]. In order to build up the resin-bound fulvene derivatives, different acids are attached to polystyrene amino resin employing standard conditions (dicyclo-hexyl carbodiimide (DCC), hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP)). Treatment with Meerwein salt and different sodium cyclopentadienides provides the desired resin-bound fulvenes. Through cycloaddition with benzoqui-nones the tricyclic adduct is released in a traceless fashion from the resin, which can be recovered and used again. After purification by filtration through a short pad of silica gel, the products are isolated in good yields and purity. In addition to benzoquinones, iminobenzoquinones are also used in this type of cycloaddition.

Scheme 16.46. [6 + 3] cycloaddition on solid support. 16.6

Rearrangements

Among cycloadditions, sigmatropic rearrangements also belong to the group of pericyclic reactions. New carbon-carbon bonds are formed and, owing to the peri-cyclic mechanism, there is the possibility of building up stereogenic centers in a stereoselective fashion using chiral induction. Until now only Claisen rearrangements have been applied to combinatorial chemistry. A typical example is the polymer-supported Ireland-Claisen rearrangement (Scheme 16.47) [81]. In this solid-phase synthesis, a trialkylsilane linker is used that is first converted to the more reactive silyl triflate. Treatment with different enolizable allylic esters provides the resin-bound silyl enol ethers as the reactive precursors for rearrange-

Scheme 16.46. [6 + 3] cycloaddition on solid support. 16.6

Rearrangements o o

O R2 R3

2) CF3SOaH/DCM

O R2 R3

2) CF3SOaH/DCM

Scheme 16.47. Polymer-supported Ireland-Claisen rearrangement.

Scheme 16.47. Polymer-supported Ireland-Claisen rearrangement.

ment. After completion of the reaction at 50 °C in tetrahydrofuran, cleavage from the resin is realized by methanolysis of the resin-bound silyl esters. The products are isolated in good yields and high purity.

Not only polystyrene-based resins but also silica gel or mesoporous molecular sieves have been used as solid support. Their thermal resistance at high temperatures and the opportunity of using polar solvents such as methanol or water make these materials superior to traditional resins. Several different silica gels and molecular sieves, which are capped with aminopropyltriethoxysilane and which vary in their average mean pore size, are employed in a Claisen rearrangement (Scheme 16.48) [82]. Attachment of hydroxymethylbenzoic acid with diisopro-pylcarbodiimide gives the hydroxy-methylated support, which is coupled to further acids bearing allylic side-chains. The Claisen rearrangement is then performed at 225 °C without using any solvent and the products are cleaved as their methyl esters after treatment with methanolic sodium methanolate. When silica gel is used as the solid support, three major products have been isolated by column chroma-tography that have been identified as two Claisen products (ratio 1.6:1) and a phenol. In contrast, using the mesoporous molecular sieves gave only the desired Claisen product. It is therefore concluded that higher selectivity correlates with the greater distance between the molecules attached to the mesoporous molecular sieves.

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Main Group Organometallics

Christopher Kallus 17.1

Introduction

Main group organometallics represent a class of powerful carbon nucleophiles that allow the construction of C-C single bonds. Moreover, they can act as strong bases and metalating agents, but also possess chelating and Lewis acid characteristics. They are indispensable tools for the construction of organic molecular frameworks which receive strong interest in classical syntheses of physiologically active substances. In contrast, the use of main group organometallics in combinatorial chemistry is underrepresented. This situation may be due to two major factors. First, the number of commercially available compounds is limited, as is their "diversity" in terms of structural variety. Second, the organometallic species are rather moisture-sensitive and decompose rapidly in the presence of air. On the other hand, almost no combinatorial equipment provides fully inert reaction conditions, making many combinatorial syntheses involving organometallic reagents difficult to carry out. Reagents carrying more sophisticated residues have to be freshly prepared, but not every desirable chemical functionality is compatible with the high reactivity of this reagent class. As a consequence, only robust anchoring groups such as Ellman's tetrahydropyranyl linker or Wang ethers can be applied in solid-phase chemistry, whereas standard linkers such as Wang esters or Rink amides are mostly excluded. The resins used have to be dried carefully and the reactions need to be carried out in dry glassware where deep cooling can be applied. In practice, batches of resins for library synthesis have been prepared simultaneously prior to further diversification by easy reaction steps carried out in common parallel synthesis equipment. Novel synthetic technologies such as Chemspeed™ or the IroriTM system may lead to new trends.

All these factors in a very small number of combinatorial protocols in the area in question. Moreover, not a single large library has been prepared with main group organometallics, but only small collections of single compounds. In the context of combinatorial chemistry, organometallic reagents have also been used for the synthesis of novel resin-anchor conjugates. Generally, the published protocols describe solid-phase syntheses. However, an increasing number of interesting

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

solutions to this enormously challenging field have been presented and will be reviewed in this chapter.

C-C bonds are formed by the attack of metalated carbon nucleophiles onto electrophiles such as alkyl and aryl halides, carbonyl groups such as aldehydes, ketones, and their heteroanalogs, as well as carbonic acid derivatives. Among meta-lated species, organomagnesium and -lithium reagents are most commonly used in combinatorial chemistry, whereas cuprates have drawn less attention. Only occasionally and in special cases have organoaluminum, -boron, or -indium species been employed.

Since the chemistry of the different metalated species is quite often similar, the structure of this chapter is not guided by the various main group elements. Instead, it is organized by the type of chemical transformation, thus avoiding double citations of the literature examples, where different organometallics are used for the same transformation. Rather than dividing the subject into a strictly mechanistic sense, the order is completely practical, following the synthetic intention focused on a diversifiable substrate (organonucleophile or electrophile) which can be modified in a combinatorial sense. For instance, metalated aromatics are used to make structurally diverse aromatic compounds by reaction with different types of electrophiles while resin-bound ketones give diverse alcohols when reacted with organometallics.

17.2

Reactions of Metalated Aromatics

Aryl lithium species are versatile precursors in the preparation of substituted aromatics. Major applications include the syntheses of different functionalized resins in polymer-assisted synthesis and of ''mini-libraries'' of substituted hetero-cycles. Metalated aromatics are generally prepared from the corresponding aryl halides with n-BuLi in tetrahydrofuran (THF) at low temperatures. Their reactions with electrophiles are among the most frequently applied in combinatorial synthesis owing to the fact that not only a broad range of electrophiles can be applied under formation of different functional motifs, but also a large number of aryl bromides as direct precursors of aryl lithiums are commercially available or can be obtained by bromination during the combinatorial synthesis. Additionally, some heterocyclic systems can be directly lithiated, which makes this type of reaction even more interesting in a combinatorial sense. This feature represents an elegant alternative to the functionalization of aromatics by Suzuki reactions, avoiding the preparation of boronic acid building blocks.

Metalation of aromatic rings is one of the most fundamental reactions in solidphase synthesis. It has become the standard way of functionalizing simple polystyrene in order to couple handles, linkers, and reagents for further modifications. A typical reaction sequence consists of bromination of polystyrene in the presence of Tl(OAc)3 or with ferric(III) chloride as a catalyst, and subsequent lithiation using n-BuLi. Direct lithiation can be performed using n-BuLi and tetramethyl-

ethylene diamine or triethylene diamine. Lithiated polystyrene can serve as the starting material for the preparation of polymer-bound carboxylic acids, thiols, sulfides, boronic acids, amides, silyl chlorides, phosphines, alkyl bromides, aldehydes, alcohols, or trityl functional groups for applications in polymer-assisted syntheses using the corresponding electrophiles (Scheme 17.1) [1-6]. It also serves as the starting material for sodium tris-ethoxyborane on selenylpolystyrene, one of the first selenium-based linker systems that allows a ''traceless'' cleavage [7]. The exchange was achieved by treating the lithiated polystyrene with selenium powder in dry THF. This material also reacts with SO2 in THF to give polymer-bound lithium phenyl sulfinate, a well-established linker for the synthesis of trisubstituted olefins (see below) [8].

Scheme 17.1. Reactions of polymer-supported aryl lithiums.

A direct lithiation-substitution sequence on solid support has been described with several five-member ring heterocycles. Substituted hydroxyimidazoles are obtained from O-imidazolyl-hydroxypolystyrene and n-BuLi followed by reactions with various electrophiles such as alkyl halides, amides, aldehydes, carbon tetrachloride, disulfides, or acid chlorides (Scheme 17.2). Interestingly, in contrast to the solution-phase procedure, solid-phase lithiation acylation occurs without any formation of tertiary alcohols. The compounds thus synthesized have been purified by crystallization or chromatography [9]. In a similar manner, 2- and 2,5-functionalizations of 3-polystyrenyl-O-trityl-hydroxymethylfurans and -thiophenes can be achieved. The first substitution takes place at the least hindered a-position, presumably because of the steric bulk of the trityl linker. A subsequent lithiation r—X >jj

PS-trltyl

I. n-BuLI, -30 'C, THF, 4h ii. electrophile, THF, -30 "C - rt, 2 h a

5% TFA, EtjSIH, CH2CI2

i. n-BuLi, -30 'C, THF, 4 h ii. electrophile, THF, -30 -C - rt, 2 h

i. n-BuLi, -60 'C, THF, 20 min ii. electrophile, THF, -60 'C - rt, 2 h

TFA, 100'C

Scheme 17.2. Lithiation-substitution sequences of resin-bound heteroaromatics.

provides access to an attack on the position between the heteroatom and the hy-droxymethyl group [10].

Solid-supported phenyl lithium and thiophenyl lithium serve as versatile precursors to the preparation of the corresponding resin-bound aryl isopropylsquarene by reaction with diisopropyl squarate. The reactive intermediates provide a reaction platform to generate several completely different cores, the so-called Multiple Core Structure Libraries (MCSLs). From various possible compound shapes, quinones, hydroquinones, and vinylogous amines derived from arylsquarenes have been realized in small libraries. Further transformations at the squarene carbonyl group are also possible (see below) [11].

In a similar fashion, the replacement of bromine with Grignard reagents leads to magnesiated heterocycles as useful intermediates for further diversification. This procedure has successfully been applied to the synthesis of several function-alized thiophenes (Scheme 17.3). In contrast to reactions with the very polar orga-nolithiums, the ester linkage and other functional groups are stable below —20 °C in the presence of an excess of Grignard reagent. Moreover, selective exchanges on thiophene dibromides can be achieved at low temperatures. It should be mentioned that, in contrast to the alkoxymethyl thiophenyl lithium species, the first exchange and reaction with an electrophile takes place at the sterically more hindered position between the heteroatom and the linking ester group. The directing effect of the anchoring group is based on a complexation between the magnesium and the ester group. The reaction is typically performed in the presence of CuCN-2LiCl in THF [12, 13].

Furthermore, organozinc bromides serve as building blocks for the solid-phase synthesis of substituted aromatics. Since this reaction is catalyzed by Pd, it will be discussed in Chapter 19.

aY v ii. CuCN2LiCI, - Of n plmrtrnnhlle.

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