R1 53

a) DIEA, dioxane, 80 °C, 16 h; b) 0.1 M NaOEt, 85 °C, 24 h Scheme 22.5. Tetramic acid synthesis on solid support.

lonic half esters, aryl acetic acids, and acetic acids bearing electron-withdrawing groups, with the last two reagents providing convenient access to diversity at position C3 on the heterocycle.

22.2.5 Pyrroles

Tetra- and penta-substituted pyrroles were first prepared by Mjalli and coworkers via the 1,3-dipolar cycloaddition of alkynes to polymer-bound munch-nones (Scheme 22.6A) [22]. Resin-bound amino acids 54 are subjected to a four-component condensation with aldehydes, carboxylic acids, and either phenyl or pyridinylisocyanates to yield Ugi products (55, 56). Hydrolysis of the terminal amide bond in 55 and 56 to 57 is carried out after Boc anhydride activation. The selection of either phenyl or pyridinylisocyanate stems from the necessity to hy-drolyze the amide bond in 55 and 56 under conditions compatible with resin linkage. Originally, benzylisocyanate was used in this process, but the rate of hydrolysis of the corresponding amide is too slow (t1=2 > 7 days) to be of practical utility. The reaction of 57 with electron-deficient alkynes either in neat acetic anhydride as solvent or in a toluene solution of Et3N and isobutyl chloroformate at 100 °C (2448 h) leads to sequential in situ formation of miinchnones 58 and 1,3-dipolar cycloaddition. Some ten pyrroles were obtained in 26-76% overall yield using this protocol (TFA cleavage). The purity of all the products was exceptional.

A slight variant of this reaction was reported by Armstrong wherein resin-bound succinate 61 is used in the Ugi condensation employing 1-isocyanocyclohexene as a convertible isocyanide (Scheme 22.6B) [23]. Miinchnone precursors 62 are sufficiently reactive such that heating 62 in toluene containing 10 equiv. HCl and 25 equiv. dimethyl acetylenedicarboxylate (DMAD) affords the pyrrole ring, negating the earlier requirement for intermediate amide hydrolysis (55, 56 to 57; Scheme 22.6A).

Resin-bound enaminones 69 are particularly versatile intermediates with respect to pyrrole synthesis (Scheme 22.7). They are prepared from the condensation of resin derivative 68 and primary amines [trimethylorthoformate (TMOF)] as the dehydrating reagent in DMF. The intramolecular net reaction of 69 with a-alkyl-substituted nitroalkenes (neat or prepared in situ from nitroalkanes and aldehydes) affords pyrroles in 46-90% yields [24]. Enaminones 69 readily react with a-bromo-ketones in the classical Hantzch pyrrole synthesis [25]. The key to the success of this reaction is the use of the non-nucleophilic Lewis base 2,6,-di-t-butyl-pyridine and DMF as solvent.

Piperidine and Derivatives

The aza-Diels-Alder reaction provides convenient access to a range of nitrogen-containing heterocycles. In an operationally simple one-pot solid-phase synthesis of 3,4-dihydropiperidines 76 [26], a solution of aminomethylated polystyrene resin

R1 COaR3

H r2

R2 O

61 O

62 O R3

Me02C C02Me 66 ~


Me02C' "C02Me 67

a) R1CHO, R2C02H, PhNC (or 2-PyrNC); b) B002O, TEA, DMAP, CH2CI2; c) neat Ac20 or /-BuOCOCI, TEA, toluene, 65 °C ; then R4CCC02R3; d) TFA; e) R2NH2, R3CHO, (cyolohexenyl)-NC; f) HCI-toluene, DMAD, 100 °C.

Scheme 22.6. Pyrroles via immobilized munchnones.

71, an aldehyde (72), a diene (73), and ytterbium triflate (10 mol%) in methylene chloride is shaken at room temperature for @24 h (Scheme 22.8). Traceless cleavage of adducts 75 is performed using ACE chloride (N-debenzylation) to give collections of 76. Electron-rich dienes in combination with ethyl glyoxylate, phenyl-glyoxal, and 37% aqueous formaldehyde are the preferred reagents.

ii y

N R1 70

a) R1NH2, DMF, TMOF (2x), 24 h; b) R3HC=CR2N02; DMF-EtOH (1:1), 60 °C, 2 h; c) 20% TFA-CH2CI2, 30 min; d) R2COCH(Br)R3, DitBuPyr, DMF, 17 h; e) R2CH2N02, RCHO, DMF-EtOH (1:1), 70 °C, 5 h. Scheme 22.7. Pyrroles from enaminones.



Scheme 22.8. Multicomponent condensation to dihydropiperidines.

The construction of b-aryl-2,3-dihydro-4-pyridones 80 on solid support has been described by Wang and Wilson (Scheme 22.9) [27]. Resin-bound imines 78, prepared from resin-bound aldehyde 77 (Mitsunobu reaction of 4-hydroxyben-zaldehyde and Wang resin) and primary amines, undergo a tandem MannichMichael reaction with Danishefsky's diene 78 catalyzed by Yb(OTf)3 in dry THF. A wide range of amines may be employed in the chemistry, including aliphatic and arylalkyl amines, as well anilines. Product purities average over 85% after TFA cleavage.

A resin-bound divinyl ketone equivalent (82) was utilized in the construction of 2-substituted-piperidine-4-ones (Scheme 22.10) [28]. Reagent 82 is generated via a six-step sequence: (1) reaction of Merrifield's chloromethyl resin with potassium thioacetate; (2) LiBH4-mediated reduction of the thioester to methylmercaptan; (3)

a) RNH2, HC(OMe)3; b) Yb(OTf)3, THF; c) TFA, CH2CI2

Scheme 22.9. Efficient solid-phase synthesis of piperidinones.

a) RNH2, HC(OMe)3; b) Yb(OTf)3, THF; c) TFA, CH2CI2

Scheme 22.9. Efficient solid-phase synthesis of piperidinones.

Scheme 22.10. Piperidinone synthesis via cyclorelease strategy.

Scheme 22.10. Piperidinone synthesis via cyclorelease strategy.

Michael addition with 3-butenone in EtOH; (4) oxidation to the sulfide to sulfone 81; (5) bromination; and (6) reaction with triphenylphosphine. Phosphonium salt 82 undergoes Wittig condensation to 83 in high yield with a variety of aldehydes using NaOMe as base. Treatment of vinyl ketones 83 with an excess of benzyl-

amine for 3 days at room temperature provides N-benzyl-2-subsititued-piperidin-4-ones 86 in 50-75% yield. Benzylamine serves as both nucleophile (Michael addition; 83 to 84) and base (1,4-elimation; 84 to 85) in this ring construction.

A second example of a traceless linker strategy utilizing Ru-catalyzed ring-closing metathesis (RCM) was reported by Rutjes and coworkers (Scheme 22.11) [29]. Substrates 89, readily prepared from the Mitsunobu coupling of 87 with al-lylic sulfonamide 88, undergo RCM in >90% yield at 50 °C in toluene.

Ol R

87 hov

87 hov



a) DEAD, PPh3, toluene, 50 °C; b) 0.05 equiv Grubbs' Ru-catalyst, 1 equiv styrene, toluene, 50 °C, 18 h

Scheme 22.11. Metathesis release method for the synthesis of N-heterocycles.


The dihydropyridine (DHP) pharmacophore, well known for its affinity for calcium channels, is regarded as a privileged scaffold possessing broad-based biological activity. The synthesis of DHPs has been largely explored by Gordeev and coworkers at Affymax [30, 31]. Their synthesis is based on the multicomponent cyclocondensation of resin-bound enamino esters 92 with either 2-benzylidine b-keto esters 93 or b-keto esters and aldehydes (94, 95) followed by TFA cleavage from solid support (Scheme 22.12A). The success of the cyclocondensation relies upon the use of pyridine as solvent, which facilitates the formation of the thermo-dynamically favored enamine 97 from imine 96 (isomerization of the p-bond). An elegant application of 13C-labeled substrates and 13C-NMR was used to define the reaction mechanism. Acyclic adducts 97 are cleaved from resin prior to cycli-zation. The solid-phase protocol is sufficiently robust for the construction of a 300-member DHP library (Scheme 22.12B). Rink amine resin was split into ten portions and condensed with one often b-keto esters. The enamines were then combined and portioned into 30 reaction vessels. Each enamine lot was treated with one of three 1,3-dicarbonyl building blocks and ten aldehydes in pyridine at 45 °C. Each resin lot was cleaved with 3% TFA in CH2Cl2 to yield 30 pools often DHPs per pool. All 30 pools were evaluated for Ca2+ channel binding (rat brain membranes). Two of the pools displayed binding affinities at @10 nM. All 20 com-

660 I 22 Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom) A. Solid-phase DHP synthesis a R2°-

rVy o o



a) 4A mol. sieves, CH2CI2; b) 4A mol. sieves, pyridine, 45 °C; c) 3% TFA-CH2CI2

B. DHP library synthesis split R2Q^

O R1

10 pools of

71 (10synthons)


split ^ (101)(3synthons) ^ ^ fV^3 30 lots * RCHO (102) " R1

10 enamines

(10 synthons)


r2o y ii r3 screening


(calcium channel blocker)

Scheme 22.12. Dihydropiperidine library synthesis.

pounds from the two pools were resynthesized as discrete analogs from which 3,5-dicarboxymethyl-2,6-dimethyl-4-(2-fluorophenyl) DHP 105 was identified with an IC50 = 14 nM.

22.2.8 Pyridines

The facile oxidation of dihydropyridines to pyridines prompted the development of a solid-phase pyridine synthesis exploiting this transformation (Schemes 22.13 and 22.14) [32]. Immobilized b-keto esters 106 are reacted with aliphatic or aryl aldehydes 95 to furnish Knoevenagel derivatives 107 (Scheme 22.13). These products then undergo Hantzsch-type condensation with g-oxo-enamines 108 to yield DHPs that in turn are oxidized to pyridines 110 with cerium ammonium nitrate (CAN). TFA-mediated cleavage affords 111. This chemistry also serves as the basis for the solid-phase synthesis of 2,2'-bipyridines [33].

110 111

a) cat. piperidine, /PrOH-C6H6, 60 °C; b) DMF, 80 °C; c) CAN, MeCONMe2; d) TFA

Scheme 22.13. Solid-phase synthesis of pyridines.

Ellingboe and coworkers [35] generated 1,5-diketones (114) on resin from immobilized hydroxyacetophenones via Claisen-Schmidt reaction with an aromatic aldehyde followed by Michael addition of trimethylsilyl enol ether (112 ! 113 ! 114; Scheme 22.14). Heterocycle formation 116 occurs upon heating 114 with NH4OAc in HOAc/DMF at 100 °C in an atmosphere of air. Presumably, DHPs 115 initially form and spontaneously oxidize to the corresponding aromatic pyridines. The yield and purity of ten examples (117) range from 19% to 62% and 21% to 70%, respectively.

Jung [34] condensed the same enone substrates 113 with 1-(2-oxo-2-arylethyl) pyr-idinium salts (118) and ammonium acetate in a Krohnke-type pyridine synthesis a) R2CHO, NaOMe, MeOH, TMOF, 1-2 h; b) H2C=CR3OTMS, CsF, DMSO, 70 °C, 3 h; c) NH4OAc, HOAc, DMF, 100 °C, 18 h; d) 50% TFA-CH2CI2, 1 h; e) NH4OAc, DMF-HOAc (5:3), 90 °C, 24 h.

Scheme 22.14. Pyridine-derived biaryls.

(Scheme 22.14). DMF containing glacial acetic acid (1:1) is the preferred solvent. Conducting the reaction in the absence of acetic acid gives a side product arising from the addition of pyridine to 113.

Azepanes, Benzazepines, and Derivatives

To date, the solid-phase synthesis of seven- and eight-member ring nitrogen heterocycles has relied primarily on the use of the ring-closing metathesis (RCM) reaction (Schemes 22.15-22.17) [36-38]. Metathesis reactions generally proceed in good yield with minimal intermolecular cross-linking. The challenge is devising a synthetic scheme that permits the introduction of diversity elements in the requisite bis-olefin substrates. The traceless linker strategies reported by Piscopio introduce up to three points of diversity in azepinone structures (Schemes 22.15 and 22.16). In one example, bis-olefin substrates 123 with two points of diversity are prepared by sequential Fukuyama-Mitsunobu and acylation reactions [39]. Ugi four-component coupling of resin-bound cinnamyl amine 125, aldehyde 128, iso-cyanate 127, and olefin-bearing carboxylic acid 126 conveniently introduces three diversity parameters in a single reaction (Scheme 22.16) [36]. Elevated temperature is generally required for successful RCM. For example, treatment of substrate 129 with Grubb's catalyst (5-10 mol%) in CH2Cl2 at 25 °C fails to generate metathesis products. However, conducting the RCM reaction in dichloroethane at 80 °C for 24 h gives the corresponding lactams as a 1:1 mixture of diastereomers in good yield.

a) DEAD, PPh3, THF, 16 h; b) TFA, CH2CI2; c) DEAD, PPh3, R1R2CHOH, 12 h; d) BuNH2, CH2CI2,1 h; e) H2C=CHCH2CHRC02H, PyBroP, DIEA, DMF, 48 h; f) Grubb's catalyst Scheme 22.15. Solid-phase azepine synthesis.


II NHl 11 (126) — C02H a s^^K^NHj? =N-R2 (127) 125 R3CHO (128)




R3 130

a) CH2CI2-MeOH, 48 h; b) Grubb's catalyst

Scheme 22.16. Azepines via multicomponent condensation and metathesis cyclorelease.

Immobilized diene substrates for azepane synthesis may also be prepared by the addition of allyl lithium to tethered imine ethers (132 to 133 to 134; Scheme 22.17) [37].

Polyhydroxylated azepane scaffold 137 was obtained upon the reaction of Rink linker 71 with chiral L-iditol bis-epoxide 135 (Scheme 22.18) [40]. The intramolecular ring closure required heating for 5 days at 80 °C in DMF. Azepanes 137 are obtained following acylation of diol 136 and resin cleavage.

Bolten and Hodges [41] at Parke-Davis Pharmaceuticals (now Pfizer) developed a solid-phase synthesis of substituted benzazepines (147) via intramolecular Heck reaction of allyl or propargyl glycines bearing a 2-iodophenyl group (140, 144)

133 134

a) KOH, PrOH, CH2CI2, 40 °C, 12 h; b) ArCHO, toluene, 3 h; c) CH2=CHCH2Li, C6H6,12 h; d) RCOCI, pyridine; e) Grubb's catalyst; f) 2% TFA-CH2CI2

Scheme 22.17. Metathesis approach to azepines.

H 137

a) DMF, 80°C, 5 days; b) RCOX, pyridine; c) 10% TFA, CH2CI2

Scheme 22.18. Solid-phase azepine synthesis via a chiral pool.

(Scheme 22.19A,B). Resin-bound N-(3-nitro)sulfonyl allylglycine is methylated with Mel in the presence of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) to give the key cyclization precursor 140, after N-deprotection and acylation with o-iodobenzoyl chloride. Heating 140 in DMF with catalytic Pd(0) cleanly provides the benzazepinone 142 in @65% overall yield following TFA-mediated resin cleavage and treatment with diazomethane. The propargyl substrates 144 give the analogous Heck products 146 following the same protocol. The latter sequence was further exemplified via the synthesis of several benzazepinones (148-153). Yields for the multistep sequence ranged from 40% to 70%.

Octahydrobenzazepinones [42] were synthesized via intracyclative ring closure of resin-bound intermediate 156 (Scheme 22.20). Intermediate 156 is efficiently prepared via sequential yne-ene cross-metathesis (154 and an alkyne) and Diels-Alder cycloaddition reactions (155, 156).



a) (2-N02)PhS02CI, EtN, CH2CI2; b) MTBD, Mel, DMF; d) PhSH, K2C03, DMF; e) (2-l)PhCOCI, Et3N, CH2CI2; f) Pd(OAc)2, PPh3, Bu4NCI, KOAo, DMF, 70°C; g) 50% TFA-CH2CI2; h) CH2N2

0 I 143

0 I 143

Ph 146

O I 144

O I 144

Ph 145

Ph 145

a) (PPh3)2PdCI2, Cul, Phi, Et3N, CH2CI2; b) Pd(OAc2)2, PPh3, Bu4NCI, HC02Na, DMF, 70°C; c) TFA-CH2CI2; d) CH2N2

Ph 146

149 Ph H 4-CONHBu 55

150 Ph H 3-CF3 50

152 Ph 7,8-dlOMe H 47

153 CH2CH2Ph H H 73

Scheme 22.19. Intramolecular Heck reaction to produce benzazepinones.

22.2.10 Indoles

The synthesis of the indole system has received more attention from combinatorial chemists than any other heterocycle. This is a reflection of the broad-based biological activity ascribed to indole-containing compounds. Some 11 reports from eight laboratories describe the solid-phase methodology used to synthesize substituted

666 | 22 Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom) 154 155

666 | 22 Solid-phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom) 154 155

a) R'CH2CCH, 10% Ru, CH2CI2, 45 °C, 24 h; b) 1.0M R2COCH=CH2, 0.1 M MeAICI2, CH2CI2-toluene; c) R3NH2, CH2CI2-HC(OMe)3 2 h, then BU4NBH4, DMF, AcOH, 12 h; d) 0.2M Me3AI, CH2CI2-toluene, 30 min, then Et3N, CH2CI2-toluene, 60 °C

Scheme 22.20. Tetrahydroazepinones on solid phase.

indoles [43-52; see also 141, 144]. With the exception of the classical Fischer indole synthesis by Merck [51], all of the examples employ Pd catalysis as a central theme. The requisite o-iodoanilines are generally tethered to solid support through an appended carboxylate function. The immobilized substrates are then subjected to the Sonogashira protocol for terminal alkyne coupling followed by Pd-catalyzed cyclization. The overall yield and efficiency of the reaction sequence are highly dependent on the structure of the alkyne and the base used in the heteroannulation step (Schemes 22.21 and 22.22) [44]. Because of its ability to provide homogeneous reaction conditions, tetramethylguanidine (TMG) is the preferred base in many of the reported protocols.

Indoles with three points of diversity were generated by Collini and Ellingboe (Scheme 22.23) [45] by coupling trifluoracetylated alkyne intermediates 168 with vinyl triflates 170 using catalytic Pd(PPh3)4 and potassium carbonate as base. Removal of the trifluoroacetyl protecting group followed by N-alkylation gave a set of functionalized indoles (173).

Using an intramolecular Heck reaction, o-iodoanilines 176, bearing a N-allyl substituent, may be cyclized to give indoles 177 (Scheme 22.24) [43, 46]. Several variations on this theme have been published, including the synthesis of 2-oxindoles [52] (178 to 179; 180 to 181).

Solid-phase reaction conditions have been optimized for Fischer indole synthesis (Scheme 22.25) [51]. In a single step, resin-bound arylketones 182 are treated with a solution of an arylhydrazine (183) and ZnCl2 in glacial acetic acid at 70 °C for 18-20 h. Methanolysis of the resin generates indole esters 186. Because acid catal-

a) Pd(PPh3)2Cl2, Cul, tetramethylguanidine, dioxide, 90 °C, 18 h; b) 0.3M NaOH-iPrOH, 50 °C, 5 h; c) R2CCR3, LiCI, K2CO3, PPh3, Pd(OAc)2, DMF, 80°C; d) TFA-CH2CI2

Scheme 22.21. Indoles via intramolecular Heck cyclization.

a) Pd(PPh3)2Cl2, Cul, tetramethylguanidine, dioxide, 90 °C, 18 h; b) 0.3M NaOH-iPrOH, 50 °C, 5 h; c) R2CCR3, LiCI, K2CO3, PPh3, Pd(OAc)2, DMF, 80°C; d) TFA-CH2CI2

Scheme 22.21. Indoles via intramolecular Heck cyclization.

a) 2-idoaniline, PPTS, DCE, 70°C, 2 h; b) R'CHCHR2, Pd(PPh3)2CI2, TMG, DMF, 110°C, 5-16 h; c) 10% TFA-CH2CI2 Scheme 22.22. Application of tetrahydropyran linkage to indole synthesis.

ysis is required for the reaction, the acid-stable hydroxymethylbenzoic acid (HMB) is the preferred linker (ester linkage). A survey of resins revealed that polystyrene was superior to polyethylene glycol (PEG) polystyrene (PEG-PS), minimizing resin-based impurities in the indole products. Electron-rich, electron-deficient, and even sterically demanding 2,5-disubstituted hydrazines can be used in this solidphase synthesis.

(CF3C0)20, pyr, CH2CI2; b) R2OTf, Pd(PPh3)4, K2C03,

DMF, 24 h; c) R3X, NaH, DMF, 4 h; d) TFA-CH2CI2, 2 h.

Scheme 22.23. Multicomponent indole synthesis on solid phase.

(CF3C0)20, pyr, CH2CI2; b) R2OTf, Pd(PPh3)4, K2C03,

DMF, 24 h; c) R3X, NaH, DMF, 4 h; d) TFA-CH2CI2, 2 h.

Scheme 22.23. Multicomponent indole synthesis on solid phase.



In a series of three publications, Kiselyov and coworkers described the synthesis of diverse arrays of tetrahydroquinolines via a three-component condensation reaction (Schemes 22.26 and 22.27) [53-55]. Approximately a decade earlier, Grieco reported this multicomponent reaction in solution based on the condensation of substituted anilines, electron-rich olefins, and aldehydes in the presence of TFA in acetonitrile.

In his initial disclosure, Kiselyov anchored 4-nitrobenzoic acid (191) to Wang resin (Scheme 22.26) [53]. The nitro group is selectively reduced to the aniline 192 by SnCl2 in DMF/water. Aniline 121 is then suspended in a 1M solution of benzaldehyde (189) and cyclopentadiene (188) with a catalytic amount of TFA. After 12 h at room temperature, the resin is filtered, washed, and treated with 15% TFA to give tetrahydroquinoline 190 in 76% yield, free of any byproducts. A library of 80 members was generated using aniline (192), five alkenes (187, 194-197), and eight aldehydes (189, 198-204). With the exception of 189, aliphatic aldehydes do not participate in the reaction. Thus, the inputs are largely limited to aryl aldehydes. The yield of library compounds ranges from 53% to 92% with purities in excess of 90%. The highest yields were obtained using electron-deficient aryl aldehydes.




a) 20% piperidine-DMF, 30 min; b) R'COCI, pyridine, CH2CI2, 2 h; c) nBuLi, 4-benzyl-2-oxazol¡dinone, R2CH=CHCH2Br, THF-DMF, -78 °C to 22 °C, 6 h, 2x; d) Pd(PPh3)4, PPh3, Et3N, DMA, 85 °C, 6 h; e) TFA

Variations on the theme:


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