Bo

PdCI2(Ph3P)2 (0.1 equiv), Et3N (3 equiv), Bu4NCI (1.5 equiv) DMF-H20, 80 °C, 6-8 h , f^^r

CF,COOH, CH2CI2 R1-

,CH2CONH2

R1

R2

yield (%)

H

H

80

H

4'-CF3

74

5-COOMe

H

88

5-COOMe

4'-CF3

70

6-OMe

4'-Me

69

Scheme 19.20. Solid-phase synthesis of indoles (2).

the macrocyclic peptide 100 in 30% overall yield based on the loading of the starting resin. A benzazepine skeleton was constructed on solid support by intramolecular Heck reaction (Scheme 19.22) [37]. The Wang resin-supported (N-butenyl)-2-iodobenzamides 101 (R = CH3 or CH2Ph) underwent Heck cyclization with Pd(OAc)2-PPh3 to give 102. Acidic cleavage of the Wang ester, followed by treatment with diazomethane, gave the benzazepines 103 in high yields.

Amination of Aryl Halides

Palladium-catalyzed amination of aromatic halides [38] has become a powerful tool in solid-phase organic synthesis. Thus, various Rink resin-supported aryl bromides were coupled with aniline derivatives to give N-aryl anilines in quantitative yields, as seen in Table 19.11, entries 1, 2, 4, and 5 [39]. The aromatic ami-

30% (based on resin)

Scheme 19.21. Palladium-catalyzed formation of macrocyclic peptide on solid support.

Scheme 19.22. Solid-phase synthesis of benzazepines via intermolecular Heck reaction.
Entry Aryl halide

Amine Condition Product Yield (%)

Amine Condition Product Yield (%)

Entry Aryl halide Amine Condition Product Yield (%)

Entry Aryl halide Amine Condition Product Yield (%)

Entries 1-5, ref. 39; entries 6-10, ref. 40. Conditions: A, amine (3 equiv.), Pd2(dba)3 (5 mol%), (o-tol)3P, NaOBu-t (10-20 equiv.), toluene, 100 °C; B, amine (10 equiv.), Pd2(dba)3 (20 mol%), (o-tol)3P (80 mol%), NaOt-Bu (10-20 equiv.), toluene, 100 °C; C, amine (10 equiv.), Pd2(dba)3 (20 mol%), BINAP (80 mol% P), NaOBu-t (10-20 equiv.), toluene, 100 °C

Entries 1-5, ref. 39; entries 6-10, ref. 40. Conditions: A, amine (3 equiv.), Pd2(dba)3 (5 mol%), (o-tol)3P, NaOBu-t (10-20 equiv.), toluene, 100 °C; B, amine (10 equiv.), Pd2(dba)3 (20 mol%), (o-tol)3P (80 mol%), NaOt-Bu (10-20 equiv.), toluene, 100 °C; C, amine (10 equiv.), Pd2(dba)3 (20 mol%), BINAP (80 mol% P), NaOBu-t (10-20 equiv.), toluene, 100 °C

nations were carried out with the Pd2(dba)3/tri-(o-tolyl)phosphine catalyst system and NaOt-Bu in toluene at 100 °C to give complete conversion of the substrates. Resin-bound o-bromides showed little activity, presumably owing to their steric hindrance (Table 19.11, entry 3). PS-PEG Rink amide (TG RAM) resin-bound p-bromobenzamide was also examined for coupling with piperidine and pyrrolidine to give the N-arylpiperidine and N-arylpyrrolidine in 81% and 49% yields, respectively, under essentially the same conditions (Table 19.11, entries 6 and 7) [40]. It has been documented that primary and secondary aliphatic amines result in significant reduction of the bromide using (o-tol)3P and that the improved conditions with 2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl (BINAP) (Table 19.11, conditions C) decrease this side reaction. The yield of N-arylpyrrolidine (49%) increased to 93% with BINAP (Table 19.11, compare entry 7 with 8). The use of BINAP as a ligand also allowed for the successful coupling of primary amines. Thus, benzyl-amine reacted with the TG RAM-supported p- and m-bromobenzamide with the Pd/BINAP catalyst to give 99% and 89% yields, respectively, of the p- and m-(benzylamino)benzamide (Table 19.11, entries 9 and 10).

19.2.4.1 Heteroannulation

It has been reported that annulation of a 2-iodoaniline with an internal alkyne takes place in the presence of a palladium catalyst to give a 2,3-disubstituted indole in one step (Larock annulation) [42]. The annulation of 4-carboxamide-2-iodoani-lines (104) supported on Rink resin with an excess amount of disubstituted al-kynes was catalyzed by Pd(OAc)2-PPh3 to give the indoles 105 (Table 19.12, route A) [43]. Cleavage of the resin moiety from 105 by trifluoroacetic acid gave the 2,3,5-trisubstituted indoles 108 in excellent yields (Table 19.12, entries 1-5). The 2-iodoaniline 106 bound to the resin support at its N1 position by the THP linker reacted with alkynes under palladium-catalyzed conditions to give N-resin-bound indole 107 (Table 19.12, route B). Acidic cleavage of the N-THP linkage gave high

Tab. 19.12. Solid-phase Larock heteroannulation. n r1

f nhr

OMe

^IXX

.2 route A

CF3COOH CH2CI2

to route B ^N^R2 CF3COOH

i ch2ci2

Entry

Route

Condition

X

R

R1

R2

Yield (%)

1

A

i

conh2

H

Pr

Pr

91

2

A

i

conh2

H

Me

t-Bu

87

3

A

i

conh2

H

Me

Ph

86

4

A

ii

conh2

coch3

Pr

Pr

95

5

A

i

conh2

COCH(CH3)2

Me

t-Bu

75

6

B

iii

H

H

Ph

SiMe3

73

7

B

iii

H

H

Me

t-Bu

55

Entries 1-5, ref. 41; entries 6-7, ref. 42. Condition i, alkyne (10-15 equiv.), Pd(OAc)2 (10 mol%), Ph3P (20 mol%), LiCl (1 equiv.), K2CO3 (5 equiv.), DMF, 80 °C; ii, alkyne (10-15 equiv.), Pd(OAc)2 (10 mol%), Ph3P (20 mol%), Bu4NCl (1 equiv.), KOAc (5 equiv.), DMF, 80 °C; iii, alkyne (excess), PdCl2(Ph3P)2 (20 mol%), tetramethylguanidine (10 equiv.), DMF, 110 °C.

Entries 1-5, ref. 41; entries 6-7, ref. 42. Condition i, alkyne (10-15 equiv.), Pd(OAc)2 (10 mol%), Ph3P (20 mol%), LiCl (1 equiv.), K2CO3 (5 equiv.), DMF, 80 °C; ii, alkyne (10-15 equiv.), Pd(OAc)2 (10 mol%), Ph3P (20 mol%), Bu4NCl (1 equiv.), KOAc (5 equiv.), DMF, 80 °C; iii, alkyne (excess), PdCl2(Ph3P)2 (20 mol%), tetramethylguanidine (10 equiv.), DMF, 110 °C.

SiMe3

PdBrLn

PdBrLn

^ SiMe3

Ph

"I

3) CF3COOH, H20

OH OH

Scheme 19.23. Solid-phase synthesis of tropane derivatives via palladium-mediated three-component coupling.

3) CF3COOH, H20

yields of the 2,3-disubstituted indole 108 (X = H) (Table 19.12, entries 6 and 7) [44].

19.2.4.2 Insertion Cross-coupling Sequence (Dialkylation ofTropene)

Three-component couplings of the resin-supported tropene 109, an aryl bromide, and an arylboronic acid or phenylacetylene were promoted by palladium(O) to give vicinal disubstituted tropanes (111) (Scheme 19.23) [45]. Thus, the reaction of 109 with an aryl bromide took place in THF with palladium(O) to give the s-alkylpalla-dium intermediate 110, which coupled with an arylboronic acid or phenylacetylene successively to give 111 (R = Ar or CCPh). Tropane 112 or 113 was obtained from 111 through deprotection, reductive N-alkylation, and acidic cleavage of resin. The monosubstituted tropane 114 was obtained similarly by reductive cleavage of the s-alkylpalladium bond of the intermediate 110 with formic acid.

19.2 Carbon-Carbon and Carbon-Nitrogen Bond-forming Reactions of Aryl and Alkenyl Halides | 567 19.2.4.3 Coupling Reactions on Various Solid Supports

The Heck reaction, the Suzuki-Miyaura, Sonogashira, and Stille couplings with aryl iodide were examined on various resin supports (Table 19.13) [46]. Thus, aryl

Tab. 19.13. Palladium-catalyzed various coupling with a traceless linker.

Tab. 19.13. Palladium-catalyzed various coupling with a traceless linker.

Resin

Substrate

Coupling conditions

Resin

Substrate

Coupling conditions

Cleavage Product conditions

TentaGel

Polystyrene

ArgoPore TentaGel

TentaGel

TentaGel

Polystyrene

ArgoPore TentaGel

Polystyrene

ArgoPore TentaGel

Polystyrene

ArgoPore

Substrate (6 equiv.) Pd(OAc)2 (20 mol%) NaOAc (3 equiv.) Bu4NBr (1 equiv.) DMA, 100 °C, 24 h

Substrate (10 equiv.) Pd(Ph3P)4 (2 mol%) K3PO4 (2 equiv.) aq. DMA, 80 °C, 24 h

Substrate (6 equiv.) PdCl2(Ph3P)2 (10 mol%) Cul (20 mol%) Dioxane, Et3N, rt, 24 h

Substrate (5 equiv.) Pd2(dba)3 (10 mol%) Ph3As (40 mol%) Dioxane, 60 °C, 24 h

96 74

6G 5G

86 9G

Ref. 46: conditions A, Cu(OAc)2 (0.5 equiv.), MeOH, pyridine (10 equiv.), rt, 2 h; B, Cu(OAc)2 (0.5 equiv.), n-propylamine, rt,

iodide was connected to PS-PEG resin (TentaGel), standard PS resin, and macro-porous PS resin (ArgoPore) with a hydrazine linker. The supported aryl iodides (115) were subjected to the coupling reactions under the conditions listed in Table 19.13 to give 116. The resulting resins (116) were subsequently subjected to linker cleavage conditions A, B, or C (see Table 19.13) to give the substituted aromatics in a traceless fashion.

19.3

Solid-phase Reactions by Way of p-Allylpalladium Intermediates

Substitution reactions of allylic substrates with nucleophiles have been shown to be catalyzed by certain palladium complexes. The catalytic cycle of the reactions involves p-allylpalladium as the key intermediate (Scheme 19.24). Oxidative addition of the allylic substrate to a palladium(0) species forms a p-allylpalladium(II) complex, which undergoes attack of a nucleophile on the p-allyl moiety to give an allylic substitution product.

Scheme 19.24. Reaction pathway of allylic substitution via a p-allylpalladium intermediate. 19.3.1

Cleavage of Allyl Ester Linkers

A carboxylic acid moiety connected to a polymer resin by an allyl ester linker was released under palladium-catalyzed allylic substitution conditions. Thus, an allyl ester group of the PS resin-supported tripeptide 117 was cleaved reductively by tin hydride in the presence of a palladium-PPh3 catalyst to release the peptide in high yield. Carbon-oxygen bonds of supported allyl esters 118-120 were also readily cleaved by morpholine by way of p-allylpalladium intermediates (Scheme 19.25) [47].

Scheme 19.24. Reaction pathway of allylic substitution via a p-allylpalladium intermediate. 19.3.1

Cleavage of Allyl Ester Linkers

Nu hard nucleophHe.s x

Nu hard nucleophHe.s

Boc-Val-Gly-Phe-OH

90% (overall yield based on amino residue of starting resin)

Boc-Val-Gly-Phe-OH

90% (overall yield based on amino residue of starting resin)

NHAc

H " morpholine (excess)

AcO AcO

NHAc 76%

Pd(Ph3P)4 (14 mol%) morpholine (50 equiv)

Boc-Val-Gly-Ala-Leu-OH

Scheme 19.25. Palladium-catalyzed cleavage of allylic anchoring groups.

An allyl ester of a resin-bound carboxylic acid was activated with palladium(O) to form the Pd(h3-allyl)(OC(O)-resin) species 124 which readily undergoes attack by a nucleophile to provide functionalization and release of the allyl moiety 123 in one step (Table 19.14) [48]. Thus, the resin carboxylate ester 122 bearing a conjugated diene moiety prepared by solid-phase ruthenium-mediated metathesis reacted with an active methylene compound (Table 19.14, entries 1-4) or morpholine (Table

Tab. 19.14. Preparation of conjugated dienes via Ru-catalyzed cross-metathesis and Pd-catalyzed allylic substitution on solid support.

Tab. 19.14. Preparation of conjugated dienes via Ru-catalyzed cross-metathesis and Pd-catalyzed allylic substitution on solid support.

Entry

NuH or NuNa

Product

Entry

NuH or NuNa

Product

Ref. 48.

19.14, entry 5) in the presence of a palladium-phosphine catalyst to give the diene 123 in high yield.

Treatment of compound 125 bearing an amino group at the homoallylic position with palladium-dppe catalyst gave the exo-methylenepyrrole 126 via formation of a p-allylpalladium intermediate and subsequent intramolecular nucleophilic attack of an amino group (Scheme 19.26) [49].

Scheme 19.26. Solid-phase synthesis of pyrrolidines via palladium-catalyzed cyclization cleavage.

N-Allylation via p-Allylpalladium Intermediates

The reaction of an allyl ester with a nitrogen nucleophile bound to the PS-PEG resin gave the N-allylation product (Scheme 19.27) [50]. Thus, the reaction of 2-methoxycarbonylmethyl-2-propen-1-ol (128) with the TentaGel-bound benzylamine 127 in the presence of Pd(PPh3)4 gave the N-allylation product 129. After ester-ification of the allylic alcohol of 129, the resulting allyl acetate 130 was subjected to palladium-catalyzed allylic substitution, again with various nitrogen nucleo-philes. A resin-supported p-allylpalladium intermediate generated in situ underwent nucleophilic attack by primary, secondary, tertiary, and cyclic amines to give the corresponding allylic amines (131) on solid support. The N-(2-aminomethyl-2-propenyl)-N-benzylglycine derivatives 132 were released from the resin 131 by alkaline hydrolysis in moderate to high yields.

Insertion-p-Allylic Substitution System

Solid-phase synthesis of the (2-alkenyl)indoline derivatives 134 has been achieved in one pot by the reaction of the immobilized aryl halides 133 and conjugated di-enes which proceeded through a palladium-catalyzed insertion-p-allylic substitution sequence (Scheme 19.28) [51]. Thus, the Rink resin-supported aryl iodide 133 was added to palladium(O) oxidatively to form the arylpalladium intermediate 135. The arylpalladium intermediate 135 reacted with the diene to give the p-allylpalla-

Scheme 19.27. Solid-phase preparation ofN-benzylglycine derivatives.

Scheme 19.27. Solid-phase preparation ofN-benzylglycine derivatives.

° 90% yield, 89% purity O 91% yield, 73% purity ° 79% yield. 85% purity

Scheme 19.28. Synthesis of indoles via palladium-catalyzed annulation.

dium 137 via the alkylpalladium 136. The p-allylpalladium should readily undergo intramolecular nucleophilic attack of nitrogen atom at the ortho position to form the 2-(alkenyl)indoline 134.

Three-component coupling of an aryl halide, 1,5-hexadiene, and the Rink-supported piperidine 138 was catalyzed by palladium to give the N-(6-aryl-2-hexenyl)-piperidine 141 via the insertion-p-allylic substitution pathway (Scheme 19.29) [52]. The alkylpalladium intermediate 140 generated in solution phase underwent a b-elimination-insertion process which was terminated by the formation of thermo-dynamically stable p-allylpalladium 143. The resulting p-allylpalladium complex 143 reacted with piperidine on the resin supports to give the N-alkylated piper-idines 139 in high yield.

Scheme 19.29. Palladium-catalyzed three-component coupling.

19.4

Palladium Catalysis with Solid-supported Complexes

Homogeneous transition metal catalysts are widely used for a variety of organic transformations. High-throughput synthesis by solution-phase catalysis has also been recognized as a useful methodology with the advent of efficient methods for compound purification. One approach employs supported catalysts that can be readily removed by filtration. Several reviews have covered the synthetic use of solid-supported reagents, including transition metal complexes [53]. A number of support-bound palladium complexes, in particular palladium-phosphine complexes, have been designed and prepared to combine the advantages of both homogeneous and heterogeneous catalysts in one system [54]. This class of resin-bound palladium catalysts would solve the basic problems of homogeneous catalysts, namely the separation and recycling of the catalysts. These palladium complex catalysts are also advantageous in that contamination of the ligand residue in the products is avoided.

Preparation of Solid-supported Palladium Complexes and Their Use in Palladium Catalysis

Standard procedures for the preparation of polymer-supported catalysts usually entail surface modification of commercially available polymer resins, e.g. polysty-rene-divinylbenzene (PS-DVB) or chloromethylated PS-DVB resin. Thus, the reaction of chloromethylated polystyrene with an excess of lithium diphenylphos-phide gave the (diphenylphosphino)methylated polystyrene 145 in quantitative yield (Scheme 19.30). The palladium(O) complex 146 was obtained by the treatment of 145 with Pd(PPh3)4. The reaction of 145 with PdCl2 (or PdCl2(cod)) gave the resin-bound palladium(II) complex 147 which was readily converted to 146 by reduction with hydrazine in the presence of PPh3. The physical properties of the resin matrix and the loading value of the phosphine residue are dependent on the crosslinking value (DVB, %) and the yield of the chloromethylation step, respec-

LiPPh.

LiPPh.

CH2PPh2

CH2PPh2

CH2PPh2

Pd(ll)X2

Scheme 19.30. Preparation of phosphinylated polystyrene-palladium complexes.

tively. The resin-bound palladium-phosphine complex 146 catalyzed nucleophilic allylic substitution via p-allylpalladium intermediates [55], telomerization of dienes [56], the Heck reaction [57], the Suzuki-Miyaura coupling [58], etc.

The bisphosphines 148 and 150 bearing alkyl substituents on their phosphorus atoms were supported on PS resin by the nucleophilic substitution of the chloro-methyl groups on the resin to give 149 and 151, respectively (Scheme 19.31) [59]. A palladium complex of 149 showed moderate catalytic activity to promote the Heck reaction of iodobenzene with methyl acrylate.

Scheme 19.31. Various ligands bound to polystyrene support.

The biarylphosphines 152 also reacted with the chloromethylated PS resin under basic conditions to give the PS-supported biarylphosphines 153 (Scheme 19.32) [60]. The resin-bound biaryl-(dialkyl)phosphines 153 were the ligands designed for use in the palladium-catalyzed amination and Suzuki-Miyaura coupling of aryl halides, especially those of aryl chlorides, whereas the use of electron-rich phos-phine ligands allowed for an increase in the scope of the aryl halide substrate [61].

Scheme 19.32. Various ligands bound to polystyrene support (2).

Scheme 19.32. Various ligands bound to polystyrene support (2).

The polymer-supported carbene complexes of palladium 155 were prepared by the nucleophilic substitution of the bromomethylated Wang resin with 154 under basic reaction conditions (Scheme 19.33) [62]. The catalytic activity of 155 for the Heck reaction of aryl bromides with acrylates or styrene was found to exhibit high turnover numbers (TON) up to 5000. The supported carbene complexes 155 were air-stable and recyclable catalysts.

Scheme 19.33. Various ligands bound to polystyrene support (3).

Polymerization of ligand monomers is a useful tool for preparing polymer-supported ligands. The crosslinked polystyrene-bound ferrocenyl bisphosphine ligand 157 was prepared by the copolymerization of styrene, divinylbenzene, and 1,1 '-bis-(diphenylphosphino)-2-vinylferrocene (156) (Scheme 19.34) [63]. The loading density of the catalyst on the support was readily controlled by the ratio of the monomers used.

Scheme 19.34. Preparation of polymer-bound ferrocenylphosphine.

Carbonylative intramolecular Stille coupling to form macrocyclic molecules was investigated with a palladium complex of the polymer-bound ferrocenyl phosphine 157 (Scheme 19.35). One of the major problems encountered in the intramolecular macrocyclization is the formation of linear oligomers via an intermolecular pathway. ''Site isolation'' of the catalytic sites on a polymer backbone has been achieved with relatively low loading density of the catalyst to suppress the in-

termolecular reactions. Thus, ester 158 bearing an alkenylstannane and an alkenyl triflate gave high yields of the corresponding keto lactone 159 with the Pd(0)/157 complex and LiCl under carbon monoxide, whereas only moderate yields of the macrocycles were obtained under homogeneous conditions using Pd(PPh3)4 or PdCl2(dppf).

OTf O

Pd(dba)2/157 78 76 70

Scheme 19.35. Palladium-catalyzed macrocyclization.

The polypyrrole-bound mono- and bisphosphines 162 and 163 were prepared as their P-borane complexes from the corresponding monomers 160 and 161 via FeCl3-induced or electrochemical polymerization conditions (Scheme 19.36) [64]. These phosphine-borane complexes reacted with palladium(II) without prede-complexation to give the polypyrrole-bound palladium(0)-phosphine complexes, where the borane on the phosphorus atom served as a reducing agent of palladiu-m(II). The resulting immobilized polypyrrole palladium(0)-phosphine complexes catalyzed the Heck reaction and the p-allylic substitution of allyl acetates.

Scheme 19.36. Preparation of polypyrrole-bound phosphine-borane.

Ring-opening methathesis polymerization of the norbornene monomer 164 having a 2-endo-N,N-di-(2-pyridyl)carbamide group was carried out via a ''living polymerization'' using the Schrock catalyst (Scheme 19.37) [65]. The resulting living polymer chains were crosslinked using 1,4,4a,5,8,8a-hexahydro-1,4,5,8-exo-endo-dimethanonaphthalene (165) to give the bispyridyl ligand 166. Its palladium com plex 167 generated by treatment of 166 with H2PdCl4 catalyzed the Heck reaction of aryl bromides and even aryl chlorides. Thus, the reaction of chlorobenzene with styrene in the presence of 0.003 mol% of the palladium species 167 and tetrabuty-lammonium bromide in dimethylacetamide at 140 °C gave an 89% isolated yield of trans-stilbene where the TON observed reached 23,600.

Scheme 19.37. Ring-opening metathesis polymerization (ROMP) of monomer ligands.

Scheme 19.37. Ring-opening metathesis polymerization (ROMP) of monomer ligands.

Polyaminoamide (PAMAM) dendrimers of generation 0-4 on silica [66] and carbosilane dendrimers [67] were used as solid support for immobilization of the palladium catalysts. Thus, for example, (diphenylphosphino)methyl groups were introduced on the terminal nitrogen of PAMAM chains by treatment of 168 with paraformaldehyde and diphenylphosphine (Scheme 19.38). Treatment of the resulting dendrimer bearing diphenylphosphino groups with PdMe2(tmeda) gave the chelate complex 169, which showed good catalytic activity in the Heck reaction.

The triarylphosphine moiety was incorporated into the PS-PEG resin by a solidphase amide-forming reaction (Scheme 19.39) [68]. Thus, a mixture of the PEG-PS amino resin, 2 equiv. of 4-(diphenylphosphino)benzoic acid, 1-(3-dimethylami-nopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 1-hydroxybenzotriazole hydrate (HOBt) in DMF was agitated to give the PS-PEG resin-supported phos-phine 171. The complete consumption of the amino residue of the PEG chain was conveniently monitored by the Kaiser test. Formation of the palladium-phosphine complex 172 on the resin was performed by mixing [PdCl(p-C3H5)]2 and 171 in an appropriate organic solvent at ambient temperature for 10 min. The PS-PEG resin-supported complex 172 exhibited high catalytic activity in water due to its amphiphilic property. Allylic substitution [68], Heck reaction [69], carbonylation [70], and Suzuki-Miyaura [70] coupling took place in a single aqueous medium at room temperature by use of 172.

CONH-v

2) PdMe2(Me2NCH2CH2NMe2)

CONH-v /

Scheme 19.38. Dendrimer-bound palladium-phosphine complex.

Amphiphilic polymer-supported phosphine ligands were also prepared on poly(N-isopropyl)acrylamide (PNIPAM) resin (Scheme 19.40) [71]. The palladium complex of the PNIPAM-phosphine, formed from reaction of 174 or 175 with Pd(dba)2, showed high catalytic activity both in organic solvents and in water to promote p-allylic substitution of allyl carbonates and the Sonogashira reaction of aryl iodides.

Solid-supported Chiral Palladium Catalysts

Asymmetric reactions catalyzed by transition metal complexes containing optically active ligands have attracted great interest because of their synthetic utility. A vast

nH n

/ EDCI = l-(3-dimethylaminopropyl)-3-PPh2 I ethylcarbodiimide hydrochloride

\ HOBt = 1-hydroxybenzotriazole hydrate

[PdCI(7c-allyl)]2

Scheme 19.39. PS-PEG resin-supported amphiphilic palladium-phosphine complexes.

Scheme 19.39. PS-PEG resin-supported amphiphilic palladium-phosphine complexes.

Scheme 19.40. PNIPAM-supported amphiphilic phosphine ligands.

amount of research has been reported to date on asymmetric reactions using homogeneous catalyst systems in which activity and stereoselectivity can be tuned by varying the ligand structure. Recently, immobilization of the enantioselective catalysts has been recognized as one of the most promising strategies for achieving highly stereoselective catalysis under heterogeneous conditions [72]. Several examples of chiral ligands supported on polymer resin, which have found utility in asymmetric palladium catalysis, are shown in Scheme 19.41. Palladium complexes of the resin-supported 2-diphenylphosphino-2'-substituted-1,1'-binaphthyl (MOP) ligand 176 [73] and pyridinoxazoline 179 [74] catalyzed allylic substitution with good to high stereoselectivity. The PS-supported BINAP 177 [75] was applied to a palladium(II)-catalyzed aldol reaction of a silyl enolate [76]. A novel chiral ligand, (3R,9aS)-(2-aryl-3-(2-diphenylphosphino)-phenyl)-tetrahydro-1H-imidazo[1,5-a]indole-1-one was designed, prepared, and immobilized on an amphiphilic polystyrene-poly(ethylene glycol) graft copolymer (PS-PEG) resin (178) [77]. A palladium complex of the PS-PEG resin-supported ligand 178 catalyzed the allylic substitution of both cyclic and acyclic allylic esters in water with high enantioselectivity (up to 98% ee). The PS-PEG-supported Pd complex was readily recovered by simple filtration and reused without loss of catalytic activity or enantioselectivity.

Scheme 19.41. Resin-supported chiral ligands.

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