OnVyn2 1sclg2H20NMP oW

^ShR1

130 Ft1

16,000 compounds 131

Scheme 15.41. Synthesis of a benzimidazole library via tin-mediated nitro reduction.

cally accompany nitro reduction with SnCl2, which presents a potential problem with acid-sensitive polymer supports. Addition of a small amount of buffer such as sodium acetate often remedies this situation [35, 115]. DMF is the solvent of choice for tin reductions, but N-formylation of o-diaminobenzenes generated from 2-amino-substituted nitrobenzenes and subsequent cyclization to benzimidazoles has been observed as a side-reaction [116]. This result can be avoided by employing other solvents such as NMP or N-methylmorpholine (NMM). Tin reductions often require heating and can benefit from exclusion of oxygen [117].

Tin reductions have been used in a number of library syntheses. In an early example, the tin-mediated reduction of solid-supported substituted nitrobenzenes led to anilines that were derivatized to provide a small library of phenols following cleavage (Scheme 15.42) [118]. The synthesis of a library of 3,4,5-substituted 1,5-benzodiazepin-2-ones began with a tin-mediated nitro reduction on polymer support (Scheme 15.43) [119]. Sequential hydrolysis and intramolecular amide coupling provided the benzodiazepine core.

132 133

R4NCO * ureas

Scheme 15.42. Meyer's approach to a phenolic library via a tin-mediated nitro reduction.

O/OC

134 C02R

1. SnCI2-2H20, DMF

1. R3CH2Br, K2C03 h2n j|

1. R3CH2Br, K2C03 h2n j|

136 R3

136 R3

Scheme 15.43. Synthesis of a substituted benzodiazepin-2-one library via a tin-mediated nitro reduction.

15.2.14.3 Nitro Reductions with Alternative Reagents

Tin-mediated reductions of nitro groups can occasionally give inconsistent results or suffer from incomplete reactions [112, 120], a serious problem in library synthesis where reliability and purity are essential. Furthermore, tin impurities are known to be problematic in many drug-screening assays, especially cellular assays [121]. Therefore, a variety of reagents and conditions has been developed as alternatives to tin-mediated nitro reductions.

Sodium borohydride with Cu(acac)2 was used in the preparation of a benzimi-dazole library in which SnCl2 gave inconsistent results (Scheme 15.44) [112]. A comparative study of nitro reductions with Na2S2O4 versus SnCl2 on a set of 74 compounds has been performed [121]. The results show that Na2S2O4 is as effective as SnCl2 in nitro reductions, although resins compatible with aqueous solutions must be used with Na2S2O4. A set of sixteen different conditions for the solidphase reduction of a nitropyrimidine has also been explored [120]. In this study, SnCl2 gave only 50-65% conversion to the aminopyrimidine, while the best results were obtained with LAH/AlCl3, although the final products were contaminated with aluminum salts. Aromatic nitro groups have been successfully reduced with CrCl2 at room temperature [122]. Other metal-mediated nitro reductions have also been applied to library synthesis in both solid phase (Zn, NH4Cl [123]) and solution phase (Fe, HCl [124]).

Scheme 15.44. Preparation of a benzimidazole library via a NaBH4-Cu(acac)2-mediated nitro reduction.

15.2.14.4 Recent Examples of Nitro Reduction on Resin

A diverse set of structural motifs has been realized which incorporate a nitro reduction into the synthetic scheme of the library, typically mediated by tin. Table 15.3 lists recent libraries synthesized with incorporation of a nitro reduction. Included in this set are libraries of 1,4-benzoxa- and benzothiazin-3(4H)-ones as well as benzimidazoles. A library of 56 1,4-benzoxa- and benzothiazin-3(4H)-ones was prepared via a reduction, cyclization, and derivatization approach (Scheme 15.45) [35]. A traceless solid-phase approach to a diverse group of substituted benzimidazoles incorporated a tin-mediated nitro reduction (Scheme 15.46) [125].

15.2.15

Imine Reductions (not Reductive Amination)

There are relatively few examples of imine reductions in combinatorial chemistry that do not involve imines formed from carbonyls and amines. For the reduction of imines generated from carbonyl compounds, see Sections 15.2.12 and 15.3.1.2 (reductive amination). For an example of imine formation via an aza-Wittig reac-

Scheme 15.44. Preparation of a benzimidazole library via a NaBH4-Cu(acac)2-mediated nitro reduction.

Tab. 15.3. Recent libraries utilizing nitro reduction (since January 1999).

Library

2-Alkylthioimidazoles Benzimidazoles

Benzimidazolones Benzo[c]isoxazoles 1,5-Benzodiazepin-2-ones

1.4-Benzothiazepin-5-ones

1.5-Benzothiazepin-4-ones Benzothiazines Benzothiazoles

1,4-Benzoxa/thiazin-3(4H)-ones 2-Carboxyindoles Diaminobenzamides Dibenzo[b, f ]oxazocines 2,3-Dihydro-[1,5]-benzothiazepines

2.3-Dihydro-[1,5]-benzothiazepine-4(5 H )-ones

3.4-Dihydro-2(1H )-quinazolinones 3,4-Dihydro-1H-quinazolin-2-thiones 1,2,3,4-Tetrahydroquinoxalin-2-ones

Reducing agent

Reference

Zn, NH4Cl, methanol

123b

SnCl2, NMP

125

SnCl2, NMP

126

SnCl2, NMM

116b

Zn, NH4 Cl, methanol

123c

Zn, NH4 Cl, methanol

123a

SnCl2, DMF

127

SnCl2, DMF

119

SnCl2

128

SnCl2, DMF

129

SnCl2, DMF

84

SnCl2, DMF,

NaOAc

115

SnCl2, DMF,

NaOAc

35

SnCl2, DMF

88

Fe, HCl

124

SnCl2, DMF

130

SnCl2, DMF,

NaOAc

115

SnCl2, DMF

81

SnCl2, DMF

131

SnCl2, DMF

131

SnCl2, NMP

132

Scheme 15.45. Synthesis of 1,4-benzoxa- and thiazin-3(4H)-ones via a tin-mediated reduction.

144 145

Scheme 15.46. Synthesis of benzimidazoles via a traceless linker and tin-mediated nitro reduction.

tion and subsequent reduction, see Section 15.3.1.2. Imine reductions have been used in the synthesis of compounds on solid support as well as in linker activation prior to cleavage (see below).

Bischler-Napieralski cyclization products have been prepared on solid phase, and the resulting cyclic imines were reduced with NaBH3CN to provide tetrahy-droisoquinolines (Scheme 15.47) [133]. When NaBH4 was used in this application, the dihydroisoquinoline was cleaved at the ester-resin linkage. An indolenine intermediate, generated via a Fischer indole reaction, was reduced with NaBH4 in the synthesis of a small library of spiroindolines [134]. Resin-bound imines of amino acids, prepared from transimination with N-H ketimines, have been reduced with NaBH3CN in an approach to a library of hydantoins [135]. In a new linker application, a phenanthridine was reduced with NaBH4/BH3THF [136]. The desired acid was subsequently released via oxidative cleavage.

poci3, toluene

OyNH r1

R1 R

146 q 147

Scheme 15.47. Synthesis of tetrahydroisoquinolines involving an imine reduction.

15.2.16

Nitrile Reduction

Conti and coworkers have reported the reduction of a nitrile on solid support [137]. An aromatic nitrile was reduced with BH3SMe2 in diglyme at 80 °C to provide a benzylamine. The resulting molecule was then released from the resin using an a-chloroethyl chloroformate methanol activation-cleavage strategy.

15.2.17

N-N and N-O Bond Reductions

Samarium diiodide has been used to cleave N-O bonds in a hydroxylamine trace-less linker application [138]. Recently, a report was published that described both nitrosamine and hydrazine reductions on solid phase for the preparation of an array of a-substituted primary amines (Scheme 15.48) [139]. DIBAL reduction of the nitrosamine to the corresponding hydrazine followed by addition of an aldehyde gave the resin-bound hydrazone. Nucleophilic addition and subsequent borane reduction of the resulting derivatized hydrazine provided the target amines in mod-

1.DIBAL, THF/CH2CI2, 50'C 1. R2Li then HzO NH2 -" N^H -► I

R1 151

Scheme 15.48. Preparation of «-substituted primary amines via hydrazine reductive cleavage.

est yields. This approach has also been used to prepare chiral hydrazones and the corresponding chiral amine products with modest enantioselectivity (50-86% ee) [140].

15.2.18

Miscellaneous Reductions

There are a number of reductions performed on solid-supported functional groups for which there are relatively few examples. These reductions can be categorized as those in which the substrate remains attached to the resin, and those where it is released. Wustrow and coworkers have used a reductive cleavage performed with Pd(OAc)2 and formic acid to provide benzoate esters and benzamides from aryl sulfonates [141]. Reductions where substrates remain attached are listed in Table 15.4.

15.3

Solution-phase Reductions

Supported Reagents 15.3.1.1 Asymmetric Reagents

A number of different research groups have shown that polymer-bound amino alcohols can act as chiral ligands in asymmetric hydride reductions of various func-

Tab. 15.4. Miscellaneous reductions on solid-supported substrates.

Reduction

Reducing agent

Reference

Ozonide to alcohol

NaBH4, sonication

142

Ozonide to aldehyde

PPh3, sonication

142

Epoxide to alcohol

LiBH4

143

Peroxide to alcohol

(EtCO2)3P

144

Acetal to hydroxyether

DIBAL

145

Lactone to diol

LAH

43b

Alkyl chloride to alkane

Nal then Bu3SnH

146

Isoxazole to aldehyde

LAH

147

Hydroxybenzotriazole to benzotriazole

PCl3 or SmI2

148

Tin chloride to tin hydride

LiBH4

149

Phosphine sulfide to phosphine

TfOMe then HMPT

Fig. 15.1. Itsuno's asymmetric reduction ligands.

h2n oh

Fig. 15.1. Itsuno's asymmetric reduction ligands.

tional groups. Itsuno and coworkers attached optically active prolinol to polystyrene to give 152 and treated this product with BH3THF to derive an enantio-selective reducing agent (Figure 15.1) [151]. This reagent reduced prochiral ketones to secondary alcohols in good optical purity. The highest optical yield (80%) was obtained with a 1% crosslinked reagent (with 50% functionalization), which was 20% higher than that obtained by the solution-phase control. Following hydrolysis of the reaction mixture with 2 M HCl, the polymer was collected via filtration. Borane regeneration allowed this reagent to be used two more times. Itsuno and coworkers also attached amino alcohols to a polymer through a pendant aromatic group (Figure 15.1) [152]. An acetophenone oxime was reduced with the reagent derived from this polymer-bound amino alcohol and NaBH4/ZrCl4 or BH3THF [153]. The optical purity of the product was only 35% ee; however, the reagent could be recycled.

Adjidjonou and Caze have also synthesized polymer-bound amino alcohols that were combined with NaBH4 to reduce acetophenone [154]. These reagents delivered the product with modest enantioselectivity (up to 75% ee), which was much more enantioselective than the product obtained from a solution-phase control experiment (12% ee). Frechet et al. derived ligands from ephedrine and polystyrene resin and utilized them in the LAH-mediated reduction of acetophenone [155]. The enantiomeric excess of the product was 79% when a lightly loaded insoluble polymer species was utilized in the presence of an achiral phenol. The minimally substituted resin allows the chiral amino alcohols to act independently from one another and allows the hydride to access all of these units fully, thus providing higher enantioselectivity.

15.3.1.2 Non-asymmetric Reagents

Borane-based reagents

In 1977, Gibson and Bailey introduced the first solid-supported borohydride exchange resin (BER) [156]. It should can be noted that, following use, this reagent can be collected by filtration and regenerated. Early studies with this reagent focused on carbonyl reductions and related chemoselectivities, which were found to be better than those produced by NaBH4 in solution [157]. It was understood that this difference in selectivity was due in part to the slower reaction kinetics of the support-bound reagent.

154 155

Fig. 15.2. Macroporous polystyrene-supported borohydride and cyanoborohydride.

Despite the recognized benefits of BER, improvements have been continually sought. As has been demonstrated with solution-phase NaBH4 reductions, the addition of catalytic quantities of transition metal salts (CuSO4 [158], Ni2B [159], and Ni(OAc)2 [160]) enhances reactivity and provides the ability to reduce a broader spectrum of functional groups. This area of research has also seen the introduction of zinc [161] and zirconium [162] borohydride polymers.

Reductive amination. Commercially available solid-supported reducing agents such as BER and NaBH3CN on exchange resin (PS-BH3CN) are useful for solution-phase reductive aminations [163]. Recently macroporous polystyrene versions of NaBH4 (MP-BH4) and NaBH3CN (MP-BH3CN) have also become commercially available (Figure 15.2) [164]. All of these reagents have the same advantage: they are easily removed from the reaction mixture via filtration. PS-BH3CN and MP-BH3CN have the added advantages of avoiding contamination of final products with cyanide and providing enhanced chemoselectivities (relative to BER and MP-BH4).

Typically, reductive aminations with BER and MP-BH4 are two-step procedures, usually performed in methanol (Scheme 15.49). The imine is preformed with 3-A molecular sieves followed by addition of the reducing agent [165]. Any unreacted amine can be scavenged with an appropriate polymer-supported scavenger (e.g. Wang resin or PS-carboxaldehyde) [166].

156 157 158 3. concentrate 159

Scheme 15.49. Two-step solution-phase reductive amination with BER.

Ley et al. have contributed a number of papers on the subject of polymer-supported reagents, including reductive amination with BER [165c, 167] and PS-BH3CN in conjunction with scavenger resins [168]. Ley et al. recently described the reductive amination of substituted bicyclo[2.2.2]octanes with BER and amine scavenging with Wang resin (Scheme 15.50) [165c]. Kaldor et al. also reported the use of BER and scavenger resins in the parallel preparation of small molecules [166a]. They used PS-NCO, PS-CHO, and PS-COCl to scavenge excess primary and secondary amines from crude reaction mixtures and isolated products with purities exceeding 90% (HPLC).

<"02iBu

R 1 1.R3NH2,3AMS, MeOH

3. Wang-CHO resin, MeOH-CH2CI2

3. Wang-CHO resin, MeOH-CH2CI2

NHR3

Scheme 15.50. Ley's reductive amination/amine scavenging approach to subsituted bicyclo[2.2.2]octanes.

Aldehyde and ketone reductions. In 1983, Yoon et al. studied the chemoselectivity of carbonyl reductions in a series of competitive reduction experiments with BER (no additives) [157a]. Their results showed that aldehydes were reduced in preference to ketones. More interesting were their observations that there was selectivity between aldehydes and between ketones. Aromatic aldehydes were preferentially reduced in the presence of aliphatic aldehydes. Benzaldehydes with para-substituted electron-withdrawing groups were reduced preferentially to those with para electron-donating groups. It was also shown that unhindered ketones were reduced in preference to hindered ketones. In a separate study by Yoon et al., it was also shown that the addition of CuSO4 to BER increased the diastereoselectivity of the reduction of norcamphor to norborneol (endo/exo = 94:6 vs. 82:18) [158]. The reduction of ketones and aldehydes has also been carried out using zinc [161] and zirconium [162] borohydride reagents immobilized on polyvinylpyridine. The zinc-based reagent is completely inert toward ketones; however, addition of FeCl3 gives low to moderate yields of ketone reduction products. The solid-supported zirconium borohydride reduces both aldehydes and ketones in the absence of an additive. Further, it has been shown that the BER-Ni(OAc)2 system fully reduces aromatic aldehydes to toluene derivatives in high yield regardless of aromatic substitution [160b]. A hindered equivalent of BER, which diastereoselectively reduces ketones to secondary alcohols, has recently been introduced by Smith et al. [169].

Studies on the reduction of a,b-unsaturated aldehydes and ketones have also been carried out using these reducing agents. BER selectively adds hydride in a 1,2-fashion to these substrates, delivering allylic alcohols in high yield [157b]. The same properties are exhibited by the zirconium reagent [162]; however, the zinc reagent [161] shows chemoselectivity in that it reduces aldehydes without affecting ketones. Sim and Yoon showed that addition of 0.1 equiv. of CuSO4 to BER under standard conditions (5 equiv. BER, methanol, room temperature) fully reduced a,b-unsaturated systems to saturated alcohols [158]. However, if the amount of BER was reduced to 2 equiv., the saturated ketone was isolated [158]. Despite these results, Ley et al. recently published a report describing the isolation of the allylic alcohol from a BER-CuSO4-mediated a,b-unsaturated ketone reduction [167a]. In their synthesis of (G)-epimaritidine, Ley et al. successfully utilized BER-CuSO4 and BER-NiCl2 to carry out the 1,2-reduction of an a,b-unsaturated ketone [167a]. It should be pointed out that the structural complexity of the substrate in the Ley synthesis is much greater than that of Sim and Yoon. In the report of the synthesis of (G)-epibatidine, Ley and coworkers also used the parent BER to carry out ketone reductions in high yield [170].

Ester and acid chloride reductions. The reduction of fully oxidized carbons has also been studied, but to a much lesser extent. Esters, for example, seem to be inert to these exchange resins even when transition metal salts are employed. Acid chlorides, on the other hand, have been reduced to both aldehydes and alcohols depending on the resin used. Simple long-chain acid chlorides have been selectively reduced to aldehydes in high yield by passage through a column of BER

[171]. Depending on the reaction conditions, Tamami and Goudarzian have shown that polymeric Zn(BH4)2 can deliver either the alcohol or the aldehyde, however the products are not obtained cleanly [161b]. For example, if phenylacetyl chloride is treated with Zn(BH4)2 in hot THF, a 70:20 mixture of the alcohol and aldehyde is recovered. If the reaction is run at room temperature in CH2Cl2, a 25:65 mixture is obtained. Tamani and Lakouraj have also demonstrated that high yields of clean alcohol can be obtained by using another polymeric zinc borohydride, poly-h-(pyrazine)zinc borohydride, in THF at ambient temperature [172]. In Ley and coworkers' synthesis of (G)-epibatidine, the first step involved an aromatic acid chloride reduction to an alcohol mediated by BER [170].

Epoxide reductions. The reduction of epoxides has also been studied. BER with CuSO4 does not react with aliphatic epoxides, yet cleanly reduces styrene oxide to ethylbenzene [158]. Despite requiring additional quantities of reagents (10 equiv. BER and 0.5 equiv. CuSO4), a-methylstyrene oxide and b-methylstyrene oxide also gave the fully saturated alkylphenyl derivatives upon reduction. Supported Zn(BH4)2 was capable of reducing both aliphatic and styrenyl derivatives, however this reagent did not give fully reduced products. Instead, a mixture of the more and less substituted alcohols was obtained, with the former predominating [161b]. The poly-pyrazine zinc reagent was inert toward both types of epoxides

Halide reductions. Sim and Yoon looked at the reduction of alkyl and aryl halides in detail. BER-CuSO4 was found to be inert toward simple alkyl and aryl chlorides, while readily reducing primary and secondary alkyl bromides as well as aryl bromides and iodides [158]. It should be noted that activated chlorides (benzylic or a to an ester) can be reduced by this system. These chemoselectivities were demonstrated by performing competition experiments. For instance, 1-bromo-4-chloro-butane was readily reduced to 1-chlorobutane (95%) and p-bromochlorobenzene was cleanly reduced to chlorobenzene (99%). Since aryl bromides required heat to be effectively reduced, while aryl iodides did not, it was possible to selectively reduce p-bromoiodobenzene to bromobenzene at ambient temperature with a 97% yield. Yoon et al. have also shown that BER-Ni(OAc)2 has nearly the same selectivity profile as BER-CuSO4, and that this nickel-based system can be used to reduce 1-octyl tosylate to octane in 95% yield provided that NaI is present [160a].

Disulfide reductions. Attempts to reduce disulfides with polymer-supported reagents has given variable results. BER-CuSO4 quantitatively reduces diphenyl disulfide, yet fails to convert n-butyl disulfide to n-butylthiol [158]. On the other hand, polymeric Zn(BH4)2 has been successful in reducing both substrates (100% and 40% respectively), as well as others [161b]. The parent BER quantitatively reduces diphenyl disulfide [173].

Azide reductions. BERs and combinations with nickel or copper salts are effective at reducing alkyl and aryl azides [158, 174]. In an early application of BERs, both aryl and arylsulfonyl azides were reduced in methanol to amines and sulfo-namides [175]. BER-Ni(OAc)2 has been used to reduce a variety of azides [174]. Tamami and Lakouraj's piperazine-based zinc reagent can reduce both aryl and alkyl azides to amines [172]. Tamami and Goudarzian's pyridine-based version reduces aryl and arylsulfonyl azides but does not react with alkyl azides [161b].

Nitro reductions. A number of support-bound borohydride reagents has been used to reduce nitro groups [176]. BER-Ni(OAc)2 reduces aromatic and aliphatic nitro groups and can be easily removed via filtration in a solution-phase approach [177]. The BER-CuSO4 reagent couple also reduces aromatic and aliphatic nitro groups [158]. BER-NiCl2 was used by Ley and coworkers to reduce a nitro group in their synthesis of epibatidine [170].

Reductive cyclizations. The reductive addition of alkyl iodides to electron-deficient alkenes has been demonstrated utilizing the BER-Ni2B system [159a]. Examples of radical additions to a,b-unsaturated esters, nitriles, and ketones have been shown to occur in high yields. It has been demonstrated that the same reagent affects aliphatic alkene and vinyl ether reactions with a-bromo esters [159b].

Miscellaneous reductions. BER-Ni(OAc)2 also has been reported to reduce aldehyde oximes to amines [178].

Tin-based reagents

Polymeric tin hydrides are capable of reducing a number of functional groups, including carbonyls, alkyl halides, and alcohols [179]. The last are reduced through the intermediacy of a phenylthionocarbonate, according to the methodology set forth by Barton [179b,c]. The main advantage of these reagents over tributyltin-hydride (TBTH) is in the work-up. Separations to remove toxic tin byproducts are avoided as the tin species can be easily removed by filtration.

In 1975, Crosby and coworkers introduced the first of the supported tin reagents, a polystyrene-based n-butyldihydridotin species [179a]. This reagent directly links a tin atom to the phenyl ring of the polystyrene backbone. In 1993, Neumann and Petersheim published an optimized preparation for a polystyrene-based monohydridotin reagent that utilizes a two-carbon linker between the tin and aromatic backbone of the polymer [180]. Since aromatic tin bonds can be labile, this aliphatic carbon-linked tin reagent was believed to be more stable than Crosby's reagent. Dumartin et al. introduced tin reagents with 3- and 4-carbon linkers that more closely resemble the structure and reactivity ofTBTH [179d].

These tin reagents have been used to carry out carbonyl reductions in high yield, including the reduction of both aliphatic and aromatic aldehydes and ketones. It has also been shown that chemoselectivity can be achieved with these reagents, as alkyl halides have been reduced in the presence of ketones [179a]. Neumann and coworkers demonstrated the feasibility of alcohol deoxygenation by utilizing the Barton protocol. This methodology required the conversion of an alcohol to a phe-nylthionocarbonate, which was then reduced with a solid-supported tin reagent to give the saturated alkyl compound [179b,c]. Neumann and coworkers have also applied this reagent to the reductive cyclization of o-alkenyl halides [181].

Trialkylsilane-mediated reduction of carbonyls

A polymer-supported trialkylsilane has been used to hydrosilylate carbonyl aldehydes and ketones [182]. Treatment of the carbonyl compounds with the trialkylsilane and Wilkinson's catalyst generated resin-bound alkoxysilanes (Scheme 15.51). Cleavage of the resulting alkoxysilane with HF provided the desired alcohols in fair to good yields.

Et 0 Et

Scheme 15.51. Reduction of aldehydes and ketones via hydrosilylation.

Polymer-supported dihydrolipoic acid-mediated reduction of disulfides

Disulfides of cystamine, cysteine, 2-hydroxyethyl disulfide, and oxidized glutathione have been reduced with polymer-bound dihydrolipoic acid [183]. The polymer is prepared via NaBH4 reduction of lipoic acid on polymer (Scheme 15.52). The best results for disulfide reduction were obtained with a polyacrylamide solid support in a pH range of 7.5-8.5.

1- CXnh2

SH SH

SH SH

165 166

Scheme 15.52. Preparation of polymer-supported dihydrolipoic acid.

Polymer-supported dihydropyridine-mediated reductions

Polymer-supported 1,4-dihydropyridines (PS-DHPs) have been used as NADH-type reducing agents [184]. A divalent cation, typically magnesium, is required for reducing activity and the reactions can be run in either organic or aqueous systems.

Bourguignon and coworkers used 1,4-dihydronicotinamide on Merrifield resin to reduce C=O, C=N, C=S, and C=C double bonds [184a]. Obika and coworkers have developed a chiral sulfinyl-containing DHP on Merrifield resin that was used to reduce methyl benzoylformate to the corresponding hydroxy ester (Scheme 15.53) [184c]. Quantitative chemical yields and high optical yields (96% ee) were obtained when the reaction was run in acetonitrile-benzene (1:1) with 2.5 equiv. of supported DHP and Mg(ClO4)2, respectively. The oxidized supported DHP could be regenerated by treatment with propyl-1,4-dihydronicotinamide (PNAH).

167 H 168 169 170

Scheme 15.53. Polymer-supported chiral NADH model ketoester reduction.

Polymer-supported sulfide reductions of ozonides

Ozonide reductions have been performed with solid-supported triphenylphosphine [185] and sulfides [186]. Appell and coworkers have prepared 3,3'-thiodipropionic acid and its sodium salts as supported analogues of dimethylsulfide for reductive quenching of ozonides [186]. The best results were obtained in ozonolysis reactions with the monosodium salt; as such, a polymer-supported version 172 was prepared. The corresponding dialdehyde of ethyl 3-cyclopentenecarboxylate was generated in a 92% yield after quenching the ozonide with this polymer-supported reagent (Scheme 15.54).

Scheme 15.54. Polymer-supported sulfide for reductive ozonolysis work-up.

Polymer-supported triphenylphosphines for the reduction of azides

Polymer-supported triphenylphosphine (PS-PPh2) is similar to unsupported triphenylphosphine in solution-phase azide reductions. An added advantage of PS-PPh2 is that the phosphine oxide generated is left on the polymer and is easily removed from the product by filtration.

Polystyrene-supported triphenylphosphine has been used to reduce azides in a series of azido nucleosides [187]. Yields were nearly quantitative and were similar to those obtained with unsupported triphenylphosphine. Polyethylene glycol-supported triphenylphosphine (PEG-PPh2) has been successfully applied to azide reductions, providing amines in shorter reaction times than with PS-PPh2 [188].

Reaction of PS-PPh2 and azides provides iminophosphoranes that in turn can react with aldehydes to provide imines (aza-Wittig reaction). This approach has been used to generate a set of 20 imines which were reduced with PS-BH3CN or NaBH3CN to give amines in good to excellent yields (Scheme 15.55) [189]. Imines have also been prepared in a similar fashion using 1 equiv. of a noncrosslinked polystyrene-supported triphenylphosphine [190]. This resin-bound phosphine has a higher loading (1 mmol g-1) than PEG-PPh2 (0.5 mmol g-1) and can be used in stoichiometric quantities (PS-PPh2 is typically used in excess).

r1-n3

Q-pph2

R1-N=PPh2 175

r2cho

Q-PPh2 176

h 0-NMe3+BH3CN-

177 h 178

Scheme 15.55. Synthesis of amines via aza-Wittig reaction and imine reduction.

Supported Catalysts 15.3.2.1 Asymmetric Catalysis

Homogeneous asymmetric catalysis has been widely studied in both academic and industrial settings. A subset of this research involves the reduction of prochiral ketones to chirally enriched secondary alcohols. Two of the more efficient methods of carrying out this transformation have been described by the research groups of Noyori [191] and Corey [192]. Despite the advantages of the catalyst systems introduced by these groups, the cost of catalyst preparation is high, thereby making reuse desirable. The recovery and purification can be a difficult process; therefore, a number of research groups have pursued the preparation and use of heterogeneous analogs of these catalysts. By attaching these compounds to a solid support, it is believed that the ease with which a catalyst could be recovered and reused would be increased. However, catalyst-recycling improvements cannot come about at the expense of catalyst activity and stereoselectivity. Polymeric catalyst design has therefore taken into account the issues of active site symmetry, accessibility, and flexibility. The three major areas of research in this field include hydrogenations, transfer hydrogenations, and borane-mediated reductions.

Hydrogenations

Of the homogeneous asymmetric catalysts designed to carry out the reduction of prochiral ketones with molecular hydrogen, perhaps none has garnered more attention than the BINAP-Ru catalyst designed by Noyori [191b]. It should not be surprising therefore that this catalyst system has been chosen for exploitation by a number of research groups interested in heterogeneous catalysis. At least two

OiPr

OiPr

PPh3 PPh3

Fig. 15.3. Polymeric BINAP ligands.

PPh3 PPh3

Ph3P PPh3

Ph3P PPh3

Fig. 15.3. Polymeric BINAP ligands.

different approaches have been used to incorporate the BINAP structure into a polymer.

An approach chosen by a group from Oxford Asymmetry involved attaching this C-2-symmetric ligand to an existing polymer with the attachment point distal from the active site phosphine atoms [193]. This goal was accomplished by mono-functionalizing the ligand at the 6-position with an alkyl carboxylic acid and then coupling this group to aminomethyl polystyrene resin. The resulting non-C-2-symmetric resin-bound ligand 179 (Figure 15.3) was then treated with a ruth-enium(II) complex and methanolic HBr in acetone to give the active hydrogenation catalyst. The catalyst (1.7 mol%) was added to a methanol/THF solution of the substrate, which was then treated with 10 atm of hydrogen and heated to 70 °C. Reduction of the b-ketoester, methyl propionylacetate, was complete in 18 h with an enantioselectivity of 97%. This heterogeneous catalyst was similar in activity and selectivity to the parent homogeneous BINAP-Ru catalyst. Further, these data show that the loss of C-2 symmetry is not detrimental to the parent catalyst's selectivity. Perhaps more important is that this catalyst was easily recovered and reused two more times with only minimal losses in yield and enantioselectivity.

Another approach that has been used to incorporate BINAP into a polymer was carried out by the Lemaire group [194]. This approach involved copolymerization of a 6,6'-dimethylamine BINAP ligand with 2,6-tolylene diisocyanate to give a C-2-symmetric BINAP polymer 180 (Figure 15.3). This noncrosslinked polymer was soluble in DMF and DMSO, yet insoluble in the typical hydrogenation solvent -methanol. Utilizing conditions similar to those described above, Lemaire and coworkers were able to completely reduce methyl propionylacetate in 14 h (0.1 mol% catalyst, 40 atm., 50 °C) to the desired b-hydroxyester in 98% ee. This catalyst was also recovered and reused up to four times without any loss in activity or selectivity. Lemaire and coworkers utilized the same polymer in the presence of chiral diamines [191c] to reduce ''simple'' ketones (lacking proximal heteroatoms), such as substituted acetophenones to alcohols [195]. However, the enantiomeric excesses of the products varied between 58% and 96%. It was also shown that the absolute configuration of the added diamine is crucial to retain good enantio-selectivity.

Chan and coworkers described another example of catalytic asymmetric hydrogenation in 1999 [196]. Although the prepared catalyst was used in an olefin reduction, which is beyond the scope of this chapter, it is worthy of note. The polymer formation was conceptually similar to that described by Lemaire, in that the C-2 symmetry was retained by copolymerizing either enantiomer of a 5,5 '-difunctionalized BINAP with (2S,4S)-pentanediol and terephthaloyl chloride. These polymers contained a polyester backbone, which imparted solubility in the reaction solvent mixture of methanol and toluene (2:3, v/v). It was also possible to precipitate these catalysts with excess methanol following reaction completion. Utilization of either polymer to reduce 2-(6 '-methoxy-2 '-naphthyl)acrylic acid was complete within 18 h, giving nearly equal and opposite enantiomeric excesses (about 93% ee) of naproxen. These polymers were recycled up to ten times without any loss of activity or selectivity.

Transfer hydrogenations

The replacement of molecular hydrogen by hydrogen donors is an issue of practical importance in the field of catalytic asymmetric reduction (because of safety concerns). As was the case for standard homogeneous hydrogenations, the Noyori laboratory has made some of the most significant contributions in this area. Noyori and coworkers introduced the (1S,2S)- and (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) ligands, which carry out hydride transfermediated ketone reductions in high yields and enantioselectivities when com-plexed with ruthenium [191d].

Both the Oxford Asymmetry [197] and Lemaire [198] groups have incorporated this ligand into polymers, using handles on the aromatic sulfonyl portion of the ligand as the linkage point to the resin (Figure 15.4). Each group adopted a strategy similar to the one they took in forming the BINAP polymers, described above. The Oxford group attached the ligand via an amide bond to preformed polymers (PS and PEG-PS) whereas the Lemaire group took a copolymerization approach. The Lemaire group did not concern itself with producing a linear C-2-symmetric polymer as they had previously, because the parent TsDPEN ligand is not C-2 symmetric. They copolymerized styrene and a TsDPEN ligand, equipped with a vinyl group, in both the presence and absence of divinylbenzene, thus producing both a crosslinked and a linear polymer.

Both groups studied the reduction of acetophenone; however, each group took their own approach to optimize the reaction conditions. The Oxford group focused on the variation of the hydride source, polymer, and solvent, while keeping the

Fig. 15.4. Polymeric TsDPEN ligands.

Fig. 15.4. Polymeric TsDPEN ligands.

transition metal constant [197]. The Lemaire group varied the polymer and transition metal, while keeping the hydride source and solvent constant [198]. Regardless of which polymeric ligand (PS or PEG-PS) was used in the catalyst preparation with [RuCl2( p-cymene)]2, the Oxford group encountered difficulties with isopropanol as the hydrogen donor. In the case of ligand 181 (Figure 15.4), the activity of the catalyst and the optical purity of the products were acceptable; however, catalyst recycling failed. In the case of ligand 182, both the conversion and the enantioselectivity observed were low with the initial use of the catalyst. To circumvent these problems a switch was made from isopropanol to a mixture of formic acid and triethylamine (5:2). This combination led to successful reductions using either ligand. The catalyst formed from ligand 182, in neat HCO2H:Et3N, gave product in 97% ee with 95% conversion in 28 h and could be reused once without any loss in ee. The catalyst formed from ligand 181 required a cosolvent to deliver favorable results. Addition of either DMF or CH2Cl2 resulted in enantiomer excesses of 94% or better with a reasonable degree of conversion (> 60% at 18 h). This catalyst was also successfully subjected to recycling.

Although the Lemaire group varied both the transition metal and the polymer in their efforts to find a heterogeneous transfer hydrogenation catalyst, there was little difference in activity and selectivity between their crosslinked and non-crosslinked polymers. From these results, they chose to focus on the significance of the transition metal [198]. Both Ir(I) and Ru(II) complexes were used in the preparation of the catalysts. The iridium catalyst was prepared by combination of the polymeric TsDPEN ligand 183 and [Ir(I)(COD)Cl]2 in an isopropanolic solution of KOH, whereas the preparation of two ruthenium catalysts (from either [Ru(benzene)Cl2]2 or [Ru(p-cymene)Cl2]2) required heat (70 °C) and the replacement of KOH with triethylamine. Of these, the best results were found utilizing the iridium-based catalyst, which gave 96% conversion to the S-alcohol with 94% ee after 72 h. Unfortunately, the reuse of this catalyst led to poor results in terms of activity and selectivity. The ruthenium-based catalysts, on the other hand, were much less selective (31-64% ee), but were able to be reused up to four times.

For comparative purposes it is interesting to note that when both groups employed their ligand with [RuCl2(p-cymene)]2, a crosslinked polymer, and isopropanol (as solvent and hydride source), the optical purity of the alcohol produced was similar (84% ee for Lemaire and 90.5% ee for Oxford); however, the activities were quite different. After 48 h, the former group saw just 23% conversion while the latter group saw 88% conversion after 18 h. It must be noted that the catalyst load (2.5% vs. 1% respectively) and usage of KOH (presence vs. absence respectively) were different.

In another effort to identify a heterogeneous catalyst system capable of carrying out asymmetric reductions, the Lemaire group has copolymerized dialdimine ligands 184, 185 (Figure 15.5) with varying amounts of polystyrene and/or DVB [199]. The iridium-based catalysts formed from the resulting ligands were used in the isopropanol-mediated transfer hydrogenation of acetophenone. Although the level of activity for these catalysts was high, the enantiomeric excess of the products obtained were never greater than 70%. Catalyst recycling suffered losses in

184: R = H 185: R = OH

Me-NH HN-Me

Me-NH HN-Me

Fig. 15.5. Dialdimines and diamine used in the preparation oftransfer hydrogenation catalysts.

both activity and selectivity. It is interesting to note that ruthenium and cobalt failed to catalyze the reduction, and that a 71% crosslinked polymer gave higher optical purity than both 15% and 100% crosslinked polymers. In another example from the Lemaire group, diamine 186 (Figure 15.5) was copolymerized with both a diacid chloride and a diisocyanate to give a poly(amide) and a poly(urea), respectively [200]. Utilizing the rhodium-based catalysts prepared from these ligands, the reduction results were less than optimal. The poly(amide) gave product in only 28% ee and the poly(urea) resulted in a product of only 60% ee. The latter catalyst could be recycled at least twice.

Also worthy of mention are the Lemaire group's efforts directed toward catalyst formation using ''molecular imprinting'' [201]. In an application of this methodology, this group copolymerized a preformed diamine-rhodium complex with dii-socyanate in the presence ofthe compound to be imprinted (the alcohol product) -optically pure 1-(S)-phenylethanol. Once the polymer was formed and the alcohol was washed away, an ''imprint'' of the product was left in the catalytic site, which allowed for binding of acetophenone (or a similar substrate) and ''biased'' reduction to the desired products. In practice, the ''imprinting'' effect was found to be real, yet small. The enantiomeric excess of the product from acetophenone reduction increased modestly, from 33% to 43%, from the polymer catalyst formed in the absence of the template to the one formed in the presence of the template. Both of these optical purities were lower than those obtained using the diamine in a homogeneous control reaction (55%). A drawback to this method is that it does not allow for the reduction of a diverse set of ketones as the substrates must have a similar structure to the imprinted molecule.

Borane-based reductions

A third major area of research directed at the heterogeneous asymmetric catalysis of prochiral ketone reductions is focused on borane-based catalysts. Successful solution-phase asymmetric reductions using chiral oxazaborolidines, described by Itsuno et al. [151-153] and Corey et al. [192], have prompted much of this research.

Some of the early work carried out by Itsuno et al. involved covalent attachment

187 188

Fig. 15.6. Oxazaborolidine catalysts.

187 188

Fig. 15.6. Oxazaborolidine catalysts.

of an amino alcohol to a polystyrene backbone followed by carbonyl reduction with the amino alcohol based-borane reagent to give products with moderate enantio-selectivity [151-153]. Although this work allowed for the recovery of the ligand, it did not allow for the recovery of the intact boron catalyst for reuse. Some of the more recent work has addressed this issue by covalently linking the boron atom of the catalyst directly to the aromatic ring of polystyrene.

In an effort to capture some of the success of Corey and coworkers' CBS catalyst and apply it to the solid phase, a group from Sandoz derived a catalyst from (S)-a,a-diphenyl-2-pyrrolidinemethanol and a crosslinked polystyrene boronic acid [202]. Once in hand, this catalyst 187 was used to reduce acetophenone and cy-clohexylmethyl ketone (Figure 15.6). In both cases, 10 mol% of the catalyst was sufficient when used in combination with a stoichiometric reductant in THF at 40 ° C. In the case of the reduction of the aromatic ketone acetophenone, an excellent enantioselectivity of 98% was obtained for the product when BH3SMe2 was used as the stoichiometric reductant and care was taken to add the ketone slowly. This result was in line with that obtained when the monomeric catalyst was employed. The reduction of cyclohexylmethyl ketone also gave product with the same selectivity (about 80% ee) as was obtained by the monomer catalyst. This reduction required the use of either BH3SMe2 or BH3-1,4-oxathiane as the stoichiometric reductant. Following a methanol quench, it was shown that at least one round of recycling was possible with this catalyst.

In a conceptually similar approach, Caze et al. have prepared catalysts from (1R,2S)-(—)-norephedrine and two polystyrene boronic acids with differing degrees of crosslinking [203]. The optimized reduction conditions involved premixing 30 mol% of BH3SMe2 (the stoichiometric reductant) with 30 mol% of the lesser crosslinked catalyst 188 in THF at 20 °C, and after 30 min gradually adding all of the ketone and the remainder of the catalyst. This procedure delivered the product of propiophenone reduction in 89% ee and in high yield. Recycling of this catalyst was carried out up to three times. The more highly crosslinked catalyst, as well as a thiophene-linked catalyst [204], gave inferior results to those obtained by the less crosslinked polymer mentioned above.

More recently, Wandrey and coworkers attached a modified CBS ligand to a siloxane-based copolymer via Pt-catalyzed hydrosilylation [205]. The resulting soluble polymer is similar to the original Itsuno polymers in that the chiral amino

TMS-O

Me

Me

Si-O

Si-O-

-IMS

k

Me

1

m

Fig. 15.7. Wandrey's oxazaborolidine catalyst.

alcohol, not the boron atom, acts as the point of attachment to the polymer. The catalyst 189 is formed by combination of the polymer amino alcohol with BH3SMe2 in THF (Figure 15.7). Aryl ketone reduction is then carried out by treatment with the catalyst and stoichiometric quantities of BH3SMe2 in THF. The resulting secondary alcohols are obtained in enantiomeric excesses ranging from 89% to 98%, which compares favorably with nonpolymeric results. Unfortunately, the products still have to be purified by distillation or chromatography.

In early 2001, Zhao and coworkers reported the preparation of catalyst 190 (Figure 15.8) [206]. Unlike the amino alcohol described above, the nitrogen of this ligand is attached to the resin via a sulfonamide bond. Product ee values were good to excellent for the reduction of aromatic ketones and moderate for alkyl ke-tones when this catalyst was employed. The combination of NaBH4 and Me3SiCl (or BF3-OEt2) was used as the stoichiometric reductant. Although the catalyst could be reused up to three times, a regeneration step was required.

The asymmetric reduction of ketones has also been carried out using zinc complexes of polynaphthyl ligands. These catalysts have been shown by the Pu group to mediate the catecholborane reduction of prochiral ketones [207]. Although the reduction of arylmethyl ketones gave products in good yield with ee values as high as 80%, the reductions of alkyl and branched methyl ketones were much less successful. After quenching the reaction, the homogeneous polymer was precipitated by addition of methanol. Reuse of this catalyst also required a regeneration step.

15.3.2.2 Non-Asymmetric Catalysis

One of the main drawbacks of tributyltinhydride-mediated reductive dehalogena-tions is the tin waste stream that is created. Utilization of polymeric tin reagents reduces the difficulties associated with their removal. A further improvement has

Fig. 15.8. Zhao's polymer-supported sulfonamide.

Fig. 15.9. Enholm's tin catalyst.

Fig. 15.9. Enholm's tin catalyst.

been introduced which uses these tin reagents in catalytic quantities in the presence of stoichiometric amounts of sodium borohydride.

Enholm and Schulte developed a noncrosslinked polymer (191) that is soluble in a number of organic solvents (Figure 15.9) [208]. This reagent can easily be removed from a reaction mixture by precipitation with methanol. Alkyl and aryl halide reductions have been carried out in N,N-dimethylacetamide (DMA) with 1.5 equiv. of NaBH4, 0.1 equiv. of 191, and AIBN, as initiator. Because the reactions are homogeneous, the reaction rates are faster than those found with insoluble polymeric catalysts, with completion typically observed in just a few hours at 80 °C.

Dumartin and coworkers demonstrated the utility of a polymeric tin iodide (192) and compared it with the reducing capabilities of Neumann's tin chloride reagent (193) (Figure 15.10, see Section 15.3.1.2) [181, 209]. In the comparative analysis of 1-bromoadamantane reduction, 0.05-0.9 equiv. of polymer 192 or 193 was combined with NaBH4 (2.5 equiv.), AIBN (0.1 equiv.), and substrate in ethanol and heated to 65 °C for 12 h. When 0.2 equiv. of the catalyst 192 was used, adamantane was obtained in 93% GC yield, while 0.5 equiv. of Neumann's reagent gave only 40% of the same product. Dumartin's group also showed that catalyst 192 produces very low levels of tin pollution and can be reused.

Bergbreiter and Walker introduced a catalytic tin halide polymer that reduced alkyl and aryl bromides and iodides when combined with NaBH4 and catalytic quantities of a crown ether [210]. Blanton and Salley extended this methodology by attachment of both the crown ether and tin chloride to the same lightly crosslinked polymer [211]. Although this polymeric co-catalyst showed lower activity than the soluble catalyst controls, it showed a marked increase in activity (48%) over controls with one catalyst supported and the other in solution. It appears that this lightly crosslinked polymer was sufficiently mobile to allow the two catalysts to interact. More recently, Deleuze and coworkers introduced an insoluble maleimide-based polymer for catalytic tin reductions [212]. The reduction of 1-bromoadaman-tane was successfully demonstrated, but the high reaction temperature required (95 ° C) caused significant leaching of tin.

Fig. 15.10. The tin catalysts of Dumartin and Neumann.

Fig. 15.10. The tin catalysts of Dumartin and Neumann.

430 | 15 Reductions in Combinatorial Synthesis 15.3.3

Unsupported Reagents Using Catch-and-release Purification 15.3.3.1 Reductive Amination

A catch-and-release approach has been used for purification of reductive aminations on acid-containing products [213]. The reductive amination was performed with NaBH4 and the crude reaction was mixed with DOWEX 1 x 8-400 formate resin. The solution was drained and the resin treated with TFA to provide the clean product. A catch-and-release strategy has also been used to prepare small groups of ureas and amides via solution-phase reductive amination with Ti(OiPr)4/ NaBH4 (Scheme 15.56) [69c].

194 195 3. water quench/filter 3. NH3, MeOH 196

Scheme 15.56. Capture and release for rapid purification of a solution-phase reductive amination reaction.

15.3.3.2 Amide Reductions

Bussolari and coworkers have also reported a resin quench-capture method for the work-up of solution-phase amide reductions with BH3THF [214]. Borane-amine adducts were quenched by acidic AG 50W-X2 resin and boron-containing salts were washed away while the desired amine was captured by the resin. Subsequent treatment of the resin with ammonia released the desired amine products with excellent purities (> 95% by LCMS). This approach was used to prepare a 300-member library of 2-alkoxy- and 2-acyloxyphenylpropyl amines.

Fluorous Chemistry

All of the reductions described above required that either the substrate or the reagent be attached to a polymer support; however, a new method is emerging that allows both reactants to remain in solution which takes advantage of the fact that highly fluorinated reagents are immiscible in both standard organic and aqueous phases at ambient temperature, yet are miscible in organic solvents at elevated temperatures. This solubility profile simplifies product isolation and purification by making it possible to separate products from byproducts by straightforward extractive work-ups. Curran and coworkers has shown that "fluorous" chemistry is ideally suited to carry out tin-based reductions [215]. They demonstrated that per-fluorinated tin reagents can reduce a number of functional groups including selenides, alkyl halides, nitro groups, xanthates, and aldehydes. Alkyl halides have been reduced with both stoichiometric and catalytic quantities of the tin hydride reagent using NaCNBH3 as the stoichiometric reductant in the latter case. Curran and coworkers also described reductive additions and cyclizations of alkyl and aryl halides to alkenes.

15.4

Conclusions

Reductions have been of enormous synthetic utility in both supported and unsupported combinatorial applications. While solid-phase organic synthesis has provided many examples of reductions over the last few decades, the area of solution-phase combinatorial synthesis has emerged and has grown rapidly more recently. As the introduction of new solid-supported reagents and catalysts continues, the ability of those involved in the drug discovery process to both generate and optimize lead compounds should increase.

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