Solid-Phase Synthetic Approach Toward the Synthesis of Oxygen-Containing Heterocycles

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Solid-Phase Synthetic Approach toward the Synthesis ofOxygen Containing HeterocyclesNavjeet Kaur a & Dharma Kishore aa Department of Chemistry , Banasthali University , Banasthali , Rajasthan , IndiaAccepted author version posted online: 03 Jul 2013.

To cite this article: Synthetic Communications (2013): Solid-Phase Synthetic Approach toward the Synthesis of OxygenContaining Heterocycles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic OrganicChemistry

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Synthetic Communications Reviews

Solid-phase synthetic approach toward the synthesis of oxygen containing heterocycles

Navjeet Kaur1,*, Dharma Kishore1

1Department of Chemistry, Banasthali University, Banasthali, Rajasthan, India

, Email: [email protected]

Abstract

Solid-phase organic synthesis is a rapidly expanding area of synthetic chemistry which is

being widely exploited in the search for new medicinally important compounds by

combinatorial techniques. In recent decades, a large number of reports related to solid-

phase synthesis of heterocycles have appeared owing to a wide variety of their biological

activity. In this review, we report the important role of solid-phase synthesis in the

synthesis of oxygen bearing heterocycles.

KEYWORDS: Solid-phase synthesis, Oxygen, Heterocycles, Solvent-free synthesis.

INTRODUCTION

Since Merrifield pioneered solid-phase synthesis in 1963, the subject has evolved

radically, thereafter, Merrifield’s solid phase synthetic concept, first developed for

biopolymer, has spread in every field where organic synthesis is involved. Since then

many laboratories and companies have been focusing on the development of technologies

and chemical procedures suitable to solid-phase synthesis. This resulted in the spectacular

outburst of combinatorial chemistry, which profoundly changed the approach for new

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drugs discovery. Combinatorial chemistry has emerged as a powerful methodology for

the preparation of libraries of small organic molecules and in accelerating the drug

discovery process. Combinatorial chemistry is a technique not only useful in drug

discovery processes, but also attractive to all disciplines of chemistry where large

numbers of compounds are desirable.[1,2] Combinatorial chemistry and parallel synthesis

have been applied extensively by medicinal chemists as one approach to the discovery

and optimization of molecules. While solution phase parallel synthesis is being used

more routinely in the laboratory, solid-phase synthesis continues to be an important

approach to synthesize combinatorial libraries, especially for heterocyclic compounds

requiring multi-step synthesis. Solid-phase approach is interesting since the reaction can

be driven to completion by using excess reagents, which are subsequently removed by

simple filtration. The work-up is therefore easy and can be automated.[3-5]

Heterocycles have a central position in organic chemistry, because of the useful

medicinal properties of many members of these compounds. Due to their impressive

properties, heterocycle systems play an important role as potentially active compounds in

drug design and synthesis.[6-8] Heterocycles have been shown to possess wide range of

biological activity, including antibacterial, antifungal, antihypertensive, antiasthmatic,

CCK antagonist, bronchodilatory, and lipoxygenase inhibition. In addition, these

heterocycles serve as intermediates in the preparation of various biologically important

compounds.[9-11]

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Numerous methods have been developed for their synthesis. They often require harsh

reaction conditions if the carbon-carbon double bond or triple bond is not sufficiently

polarized.12 Some studies have been published on the solid-phase synthesis of a wide

variety of heterocycles. The preparation of combinatorial libraries of heterocyclic

compounds by solid-phase synthesis is of great interest for accelerating pharmaceutical

research. There has been an emphasis on the preparation of heterocycles with extensive

chemical diversity, which can give rise to structural members with more desirable

physical and biological properties. This has permitted dramatic increase in the speed of

synthesis through both simplification of work-up, and automation.[13-15]

The preparation of oxygen containing heterocyclic compounds on the solid-phase has

become an accepted and powerful drug discovery tool. In this respect, various approaches

for the preparation of these privileged structures with drug-like properties have been

developed on solid-phase strategies. As a result, an increasing range and number of

pharmaceutically useful oxygen containing heterocyclic compounds recently have been

prepared using solid-phase methodology.[16-19]

In particular, access to oxygen containing heterocyclic compounds by solid-phase

synthesis is urgently required, since small, substituted heterocycles offer a high degree of

structural diversity and they are proven to be exceptionally useful in pharmaceutical

applications.20 This article provides an overview of emerging applications of

combinatorial approaches in oxygen containing heterocycles. In this review, we focus on

methods for the synthesis of oxygen containing heterocyclic rings on solid support, since

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it has emerged as an efficient method for the diversificiation and for the preparation of

heterocycle ring system.

SOLID-PHASE SYNTHESIS OF HETEROCYCLIC COMPOUNDS

Five-Membered Heterocycles

Benzisoxazole

Lepore et al.21 described a synthetic pathway to isoxazoles (scheme-1). The Boc-

protected amine was loaded on the Kaiser resin and treated with trifluoroacetic acid. This

resin was treated with different electrophiles to give oximes, which were cyclized by

cleavage from the solid support to give the isoxazoles in good yields and high purities.

Stephensen and Zaragoza22 used the partial reduction of nitro groups to hydroxylamines

and subsequent cyclization with ketones as the synthesis strategy (scheme-2). In the first

step, the fluoride ion was substituted by the arylacetonitrile. Reductive cyclization and

cleavage of the solid support resulted in the benzisoxazole.

BENZOFURAN

The use of a dithiane protected 3-alkoxybenzoin allows the elaboration of molecules,

linked as carbonates to the secondary hydroxy of the benzoin, prior to deprotection of the

dithiane and photocleavage (scheme-3).23

Fancelli et al.24 prepared 2-substituted benzofurans through the copper/palladium

heteroannulation of terminal acetylenes with resin bound aryl iodides (scheme-4).

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De Maesmaeker and Wendeborn25 studied the functionalization of cyclohexendiol

derivatives via radical cyclization on solid phase (scheme-5). Cyclization was performed

using an aryl radical and a vinyl radical, giving in both cases a mixture of products.

Du and Armstrong26 provided a milder approach to the synthesis of solid-supported

benzofurans via radical cyclization, which is based on the use of SmI2 (scheme-6).

Berteina and De Maesmaeker27 tested the 5-exo-trig cyclization to form 2,3-dihydro-

benzofurans (scheme-7). Either the aryl iodide or the unsaturated counterpart, tethered by

means of an oxygen atom, was directly anchored to aminomethylphenyl functionalized

polystyrene beads. Usually, a spacer was inserted between the resin and the reactive

molecule. As first attempt, the radical cyclization was performed under usual radical

conditions.

A more traditional approach was used by Balasubramanian and coworkers,28 who

performed aryl radical cyclization into alkenes to prepare benzofuran derivatives and

alkyl radicals cyclization into alkynes to prepare functionalized furans (scheme-8).

BENZOXAZOLES

Beebe et al.29 described a new strategy (scheme-9) for synthesizing benzoxazoles in

2001. A modified Wang resin was used as the solid support. In the first two steps, the

primary amine was converted into a tertiary amine. Subsequently, the phenol was

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esterified and the nitro group was reduced to the diamino ester. The final step was a

dehydrative cyclization to the benzoxazoles.

FURANE

Gowravaram and Gallop30 have developed a traceless synthesis (scheme-10) of

substituted furans using 1,3-dipolar cycloadditions of isomunchones.

The radical reaction was carried out starting from bromo-Wang resin according to the

procedures applied in solution, commonly used for the synthesis of CC-1065 derivatives.

To measure the efficacy of the reaction on solid phase, the product of cyclization was

first acetylated and then cleaved, to yield a total 74% (scheme-11).31

Recently, the reactions of the polymer-bound aryl halides with 2,4-disubstituted

allenecarboxylic acids leading to the polymer-bound butenolides have been reported.

After cleavage from the polymer, the substituted butenolides can serve as important

building blocks in the synthesis of natural products (scheme-12).32

Another interesting cleavage methodology was reported by Engman and coworkers,33

(scheme-13) who studied the radical carbonylation/cyclization to make tetrahydrofuran-

3-ones. The method was first developed in solution, exploiting alkyl phenyl selenides and

then applied to a selenium-based resin, prepared in a few steps from cross-linked (1%)

polystyrene.

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An efficient three-step solid-phase synthesis of diverse 3,5-disubstituted-2-

aminofuranones has been developed (scheme-14). α-Hydroxy acids loaded on a

nitrophenyl carbonate derivative of Wang resin are used as acylating agents for the C-

acylation of active methylene compounds and the resulting intermediates provided,

through a cyclative cleavage reaction, the desired product.34

In an example of solid-supported organotin reagents, Ueno and coworkers35 compared in

solution radical cyclizations under classical conditions (Bu3SnH/AIBN) with the use of

polymer-bound radical carrier (Bu3SnCl/NaBH4) for the synthesis of 2-

alkoxytetrahydrofurans (scheme-15).

Reaction of polystyrene-supported selenium bromide with α-βunsaturated acids and

subsequent cleavage from the polymer by treatment with methyl iodide efficiently

afforded 5-iodomethyl-dihydrofuran-2-ones in excellent yields (scheme-16).36

ISOXAZOLE

Pei and Moos37 have demonstrated the ease with which heterocycles can be incorporated

onto a peptoid backbone (scheme-17). Various nitrile oxides were generated from either

the corresponding nitroalkanes or oximes and reacted with Rink resin-bound tripeptoids

which contained an allyl or propargyl amide. Generally, the cleaved products (via TFA,

CH2C12) were of high purity.

Reissert intermediates allowed the coupling of the isoquinoline skeleton to a resin and

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concomitantly activate the C1 position for deprotonation/alkylation. Thus, polymer-

bound benzoyl chloride was swollen in CH2C12 and reacted with isoquinoline and

Me3SiCN to form Reissert compound. Alkylation occurs smoothly in >95% yield with

LDA and allyl bromide in THE. With 5 equiv of nitrile oxide the terminal olefin

underwent cycloaddition. The substrate was liberated from the resin via hydrolysis (1 M

KOH in THF/H2O) to afford the product (scheme-18).38

The BOC-protected amine was prepared and loaded onto the Kaiser resin in 53% yield.

The resin was then treated with 25% TFA/CH2Cl2 for 2 h, rinsed, and vacuum-dried. The

resin washing solutions from this reaction were concentrated and provided no UV-active

material by TLC. Resin was then treated with a variety of electrophiles to give oxazole

(scheme-19). 39

Polymer-supported perruthenate (PSP) has been used in a number of multistep sequences.

The oxidation of secondary hydroxylamines in the presence of electron-poor

dipolarophiles afforded the corresponding isoxazolidine in good yield (scheme-20).40

Benzoxazoles were constructed in a straightforward manner by Mitsunobu by reactions

of the precursor o-hydroxyanilides (scheme-21).41

The NSG scaffold afforded by sub-monomer synthesis is extremely amenable to further

functionalization and can be easily tranformed into alternate scaffolds. For example,

incorporation of unsaturation in the side chains of NSG dimers and trimers allows for

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addition of 1,3-dipolar species such as nitrile oxides, affording isoxazoles in good yields

(scheme-22).42

The nitrile oxide 1,3-dipolar cycloaddition with alkynes was reported by Fukazawa et

al.,43 who used it to prepare a library of liquid crystalline isoxazoles (scheme-23).

Immobilization of the alkynes on Rink amide resin was followed by cycloaddition with

nitrile oxides generated in situ from chlorooximes upon reaction with TEA. Tf2O

treatment yielded the expected isoxazoles.

Microwave irradiation is very applicable not only to solution-phase chemistry, but also to

solid-phase organic synthesis. There are many different supports, including polystyrene

(PS), polyamide, poly(ethyleneglycol)-polystyrene (PEG-PS) graft resins, poly(ethylene

glycol)-polyacrylamide (PEGA) resins, and even silica, to name a few. One interesting

application is the use of cellulose beads for preparing pyrazole and isoxazole libraries.

Cellulose swells nicely in both polar and aqueous solvents and is biodegradable.

Following scheme shows two-step, open-vessel application, which produces excellent

yields of the corresponding isoxazoles (scheme-24).44

Huang et al.45 prepared the 1,2,3-triazolyl and isoxazolinyl derivatives (scheme-25) from

the selenenyl bromide resin, which is a PS-functionalyzed solid support cleavable

through a selenoxide syn elimination to introduce a new double bond. The resin was

treated with NaBH4 and propargyl bromide to give the corresponding propargyl-

functionalized resin. 1,2,3-Triazoles were formed through a one-pot 1,3-dipolar

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cycloaddition of the resin with NaN3 and aryl halides in the presence of CuI, proline, and

TEA at 65°C for 12 h in dimethyl sulfoxide (DMSO).

Back and Zhai46 synthesized isoxazolyl sulphones from the resin-bound acetylenic

sulphones and nitrile oxide (scheme-26). Upon completion of the cycloaddition, the

resulting adducts were released from the resin with LiOH to afford the sulphones in

yields ranging from 48 to 69% and with a crude purity of >95%.

Wang et al. described a one-pot synthesis of isoxazoles and isoxazolines on soluble

polymer support (PEG 4000), in which the nitrile oxide is trapped with an alkene or

alkyne. The authors developed two procedures according to polymer-bound component

involved in the cycloaddition. In the first, (scheme-27) the PEG-bound acrylate was

reacted with nitrile oxides generated in situ, whereas in the second, (scheme-28) the

PEG-supported oxime provided the corresponding nitrile oxide, which then underwent

cycloadditions with alkenes or alkynes. In both procedures, the one-pot isoxazoline and

isoxazole syntheses were performed by stirring the oxime with N-chlorosuccinimide in

DCM at 25-30°C, followed by addition of the dipolarophile and TEA and, finally, stirring

of the reaction mixture at room temperature. Cleavage of the products from the support

using NaOMe in methanol or aqueous 2N NaOH afforded the target isoxazolines and

isoxazoles.47

A similar approach was employed by Kurth and Quan48 in the preparation of an 18-

member library of isoxazol-4-yl-[1,2,4]oxadiazoles (scheme-29). The resin-bound

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alkynes were synthesized from Wang resin in a three-step sequence and then were

reacted with benzaldehyde oximes in the presence of excess bleach for 3 days. The

corresponding nitrile oxides were generated in situ, leading to the 3,4,5-trisubstituted

isoxazoles through a [3+2] cycloaddition. Subsequent formation of the 1,2,4-oxadiazole

ring was achieved by hydrolysis of the methyl esters, followed by a Porco’s two-step,

one-pot condensation with diverse benzamidoxime derivatives. After TFA cleavage of

the products from the resin and purification final compounds were obtained.

Ruck-Braun and Wiershem49 recently synthesized isoxazolo-[2,3-a]pyrazinones from the

polymer-supported cyclic nitrone (scheme-30). Using alkenes as dipolarophiles,

isoxazolidines obtained in >85% purity after basic cleavage from the resin and 27-82%

yields after HPLC purification.

OXADIAZOLE

Wang et al.50 reported the first one-pot SPS of 1,2,4-oxadiazolines through a [3+2]

cycloaddition of imines with resin-bound nitrile oxides (scheme-31). Conversion of the

resin-supported oxime to the chlorooxime and subsequent cycloaddition between the

corresponding nitrile oxide and the imines were performed in a parallel one-pot fashion.

The resulting cycloadducts were cleaved from the resin by treatment with either NaOMe

in methanol and THF or 70% ethylamine in THF.

Liu and Huang51 described the solid-phase synthesis of 2-aryl-5-alkylthio-1,3,4-

oxadiazoles from resin-bound acylhydrazines (scheme-32). The Merrifield resin was first

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converted to the polymer-supported methyl ester resin by reacting it with excess methyl

4-hydroxybenzoate. The methyl ester resin was treated with hydrazine hydrate in HMPA

at 90°C for several hours to give the corresponding hydrazide resin. The resin was then

reacted with carbon disulfide and KOH at reflux to afford the 2-mercapto-1,3,4-

oxadiazole resin. Further reaction with NaOH and a variety of electrophilic reagents gave

the corresponding resin. Release of the final 2-aryl-5-alkylthio-1,3,4-oxadiazoles was

achieved after cleavage by treatment with 10% TFA in CH2Cl2.

Reactions of the acyldithiocarbazate resin with EDC, HCl and DCC both gave 1,3,4-

oxadiazole as a major product but in low yield, whereas the use of SOCl2 to promote this

cyclization process leads to the 1,3,4-oxadiazole as a major product with high

chemoselectivity (99:1). The desired products are cleaved from the resins by sequential

treatment with mCPBA and NaOH in aqueous dioxane and piperidine in 1,4-dioxane at

100oC (scheme-33).52

1,2,4-Oxadiazole-4-oxides have been prepared on Wang resin by 1,3-dipolar

cycloaddition of nitrile oxides to amidoximes (scheme-34). Hence, reaction of the resin-

bound nitrile oxide with excess benzamidoxime in toluene at room temperature for 48 h

led to the 1,2,4-oxadiazole-4-oxides, which are linked to the Wang resin through position

3.53

A similar approach was employed by Kurth and Quan48 in the preparation of an 18-

member library of isoxazol-4-yl-[1,2,4]oxadiazoles (scheme-35). The resin-bound

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alkynes were synthesized from Wang resin in a three-step sequence and then were

reacted with benzaldehyde oximes in the presence of excess bleach for 3 days. The

corresponding nitrile oxides were generated in situ, leading to the 3,4,5-trisubstituted

isoxazoles through a [3+2] cycloaddition. Subsequent formation of the 1,2,4-oxadiazole

ring was achieved by hydrolysis of the methyl esters, followed by a Porco’s two-step,

one-pot condensation with diverse benzamidoxime derivatives.

Polymer-supported selenopropionic acid was prepared by treatment of a THF-swollen

suspension of cross linked polystyrene bound selenium bromide with LiBH4, followed by

treatment with 2-bromopropionic acid. The best result was obtained by treatment of resin

with amidoximes in the presence of excess EDC in DMF through a two-step one-pot

condensation. As expected, subsequent oxidation-elimination of resin was very rapid and

efficient with excess of 30% hydrogen peroxide to afford the corresponding 5-vinyl

1,2,4-oxadiazoles in good yields (scheme-36).54

Aliphatic and aromatic nitriles linked to solid support were converted to amide oximes,

and cyclized to oxadiazoles using N-protected amino acid anhydrides (scheme-37). The

amino protecting group was removed and the products acylated or sulfonylated on resin

to provide combinatorial libraries of oxadiazoles.55

1,3-Dipolar cycloadditions of nitrile oxide generated in situ on soluble polymer with a

variety of imines provided a library of 4,5-dihydro-1,2,4-oxadiazoles in good yields and

purity (scheme-38).56

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The one-pot preparation of the 5-substituted-2-amino-1,3,4-oxadiazoles analogues by

Baxendale et al. through a three component coupling of an acylhydrazine, an isocyanate

and sulphonyl chloride promoted by a polymer-supported phosphazine base was carried

out under microwave dielectric heating (scheme-39).57

OXAZOLE

Kurth et al. have reported a two step reaction iterative process for the construction of

polyisoxazolines and polyisoxazoles (scheme-40).58

In the synthesis of oxazolidinones, Buchstaller used a cyclisation cleavage strategy

(scheme-41).59 Reaction of isocyanates with Wang resin provided resin-bound

carbamates which were alkylated with glycidyltosylate to the corresponding epoxide.

Nucleophilic opening of the epoxide with pyrollidine and subsequent cyclisation

provided oxazolidinones in high yield and purity, with any by-products formed during the

reaction remaining bound to the solid phase.

A versatile method for the solid phase synthesis of oxazolidin-2-ones is described

(scheme-42). A resin bound phenolic group was treated with (±)-epichlorohydrin

followed by opening of the epoxide ring with sodium azide. The resulting 1-azido-3-

aryloxypropan-2-ol was treated with p-nitrophenylchloroformate and subsequent

Staudinger’s cyclization using PPh3 yielded a 5-substituted oxazolidinone.60

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Solid-phase [2+2] cycloadditions of chlorosulphonyl isocyanate to chiral vinyl ethers

were studied by Chmielewski et al. for different solid supports. The reported strategy

consisted of binding of the vinyl ether to the polymer support through a sulfonyl linker,

followed by the cycloaddition. The bicyclic compounds were obtained through a

cyclization/cleavage step by treatment of the cycloaddition product with a strong organic

base such as 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-

diazaphosphorine or 1,8-diazabiciclo[5.4.0] undec-7-ene (scheme-43).61

1,3-Oxazolidines were synthesized by using a solid support (scheme-44). Regioselective

ring opening of resin-bound epoxy ether with ammonium chloride followed by

nucleophilic substitution with sodium azide gave azido alcohol. Reduction of provided 1-

amino-2-alkanol, which was treated with various aldehydes and acyl chlorides or

isocyanates afforded the corresponding 1,3-oxazolidines immobilized on Wang resin.

Oxidative cleavage with DDQ from the solid support yielded 1,3-oxazolidines.62

TETRAHYDROFURAN

A nitrile oxide plus alkene cycloaddition methodology used the isoxazoline intermediate

in a subsequent electrophilic cyclization, yielding 2,5-disubstituted tetrahydrofurans

(scheme-45). The strategy involved [3+2] cycloaddition of a nitrile oxide with diene to

yield a 5-homoallylisoxazoline which could be electrophilically activated to produce the

desired cyclic ether. When the cycloadduct is polymer-bound, the urea is easily removed

by washing with various solvents (e.g., THF, THF/H2O, CH2C12). The resulting polymer-

bound isoxazoline was now poised for concomitant ring closure/resin liberation which

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could be effected with a variety of electrophiles (e.g., I2, ICl, IBr, etc.). This process

proved ideal as only the desired tetrahydrofuran product would be liberated, providing a

pure mixture of diastereomers.63

SIX-MEMBERED HETEROCYCLES

Benzopyran

Hydroxymethylpolystyrene has been transformed into the polymer-supported o-

quinodimethane and subsequently used as a diene for hetero-Diels-Alder reactions.

Dihydrobenzopyrans and tetrahydroisoquinolines were then obtained in moderate to good

yields by treatment with the proper aldehydes or imines followed by Bronsted or Lewis

acid nucleophilic cleavage (scheme-46).64

Selenenyl bromide resin was conveniently prepared from commercial polystyrene by

lithiation followed by treatment with dimethyl diselenide to give methyl selenide, a

conjugate whose subsequent oxidation with bromine gave a dark red polymer. Simply

stirring resin in CH2Cl2 at 0-8oC with a threefold excess of various ortho-prenylated

phenols and then treated with H2O2 which resulted in the facile oxidation of the selenide

to the corresponding selenoxide (scheme-47). The high yield and purity of these products

suggested that the simultaneous cyclization and loading (cyclo-loading) step proceeded

efficiently, regardless of the electronic environment of the phenolc substrate.65

The biomimetic synthesis of carpanone, first accomplished by Chapman, involves

diastereoselective oxidative homocoupling of an electron-rich o-hydroxystyrene followed

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by rapid, endo-selective, inverse electron-demand Diels-Alder cycloaddition (scheme-

48). To construct a library of carpanone analogues, Lindsley et al. expanded on the

original chemistry to include intermolecular oxidative heterodimerization of o-

hydroxystyrenes. The use of electronically distinct o-hydroxystyrenes under the influence

of a suitable oxidant, the oxidatively more-reactive electron-rich phenol, immobilized in

the solid-phase to reduce its propensity for homodimerisation, reacted preferentially with

the oxidatively less-reactive electron-deficient phenol.66

The use of an amide-based linker attached to the resin through a silyl linkage diminished

competitive intrabead coupling. In the six experiments reported, the reaction tolerated

diverse functional groups, making it amenable to diversity-oriented synthesis. The

procedure was recently used for the synthesis of a 10 000-member library of carpanone

analogues (scheme-49).67

BENZOXAZINE

An approach consisting of three steps was employed for synthesis through which first the

surface of silica gel was converted to silica chloride by means of reaction with thionyl

chloride. The silica chloride was heated with 4-hydroxybenzoic acid to form the silica-

bound benzoic acid. Then it was washed with acetone to remove excess 4-

hydroxybenzoic acid. Finally, the silica-bound benzoyl chloride was obtained from the

reaction with thionyl chloride. The solid-phase synthesis of 4H-3,1-benzoxazin-4-ones

was achieved using silica-bound benzoyl chloride as dehydrating agent in reaction with

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2-acylaminobenzoic acids (scheme-50). The silica-grafted reagent was simply recovered

after reaction and reused several times.68

PYRAN

Resin-bound dienophiles, including the carboxypolystyrene-bound vinyl ether of 1,4-

butanediol, have been used in efficient, endo-selective hetero-Diels-Alder reactions under

Lewis-acid conditions with heterodienes bearing methyl ester, trifluoromethyl, and p-

tolylsulphinylmethyl groups at the C-2 position. Reductive cleavage of the supported

adducts afforded functionalized dihydropyrans, which are particularly interesting for

combinatorial synthesis (scheme-51).69

Polymer supported electron-rich dienes were prepared by Mann et al.70 using Merrifield

resin and propanol as spacer. Preparation of functionalized resin was performed

following a literature procedure. The reactivity of resin in the hetero-Diels-Alder reaction

was examined using various aldehydes and ketones and several Lewis acids (e.g.,

BF3Et2O, ZnCl2, MgBr2, and Me2AlCl) (scheme-52). Cycloaddition and cleavage were

achieved in a single step.

Tietze et al.71 reported the first SPS of a 3,4-dihydropyran, which involved the

Knoevenagel transformation of a polystyrene resin-linked acetoacetate into an α,β-

unsaturated ketone (an oxabutadiene) that then underwent inverse electrondemand Diels-

Alder cycloaddition. The resin-bound heterodiene, obtained by esterification of the free

OH groups of a Wang resin with benzylidenepyruvic acid in the presence of

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diisopropylcarbodiimide (DIC), has been reacted with various soluble electron-rich

dienophiles in [4+2] heterocycloadditions catalyzed by Eu-(fod)3. Reductive cleavage of

the heterocycloadducts using LiAlH4 in ether/THF at 20°C, followed by mild hydrolysis

with aq Na2SO4, proceeded smoothly to afford epimeric mixtures of the primary allylic

alcoholsproducts endo- (major epimer) and exo- in high overall yields (scheme-53).

SEVEN-MEMBERED HETEROCYCLES

1.5.-Benzoxazepine

Ouyang et al.72 reported a synthetic strategy toward the benzoxazepine ring (scheme-54).

The resin was prepared by the reductive amination of o-aminophenol on AMEBA

polystyrene resin. This resin was further modified to afford the immobilized substrate,

which was ready for the assembly of the desired derivative. Cleavage of the solid support

amounts the benzoxazepine in quantitative yield.

BENZOXAZOCINES

Ouyang and Kiselyov72 have described an efficient approach to dibenzo[b,g]1,5-

oxazocines on solid support (scheme-55). They modified the Rink amide resin with

salicylaldehyde. The subsequent attachment of the 2-fluoro-5-nitrobenzoic acid to the

resulting resin afforded the intermediate. The cyclization took place by nucleophilic

aromatic substitution, and the resultant immobilized nitrodibenz[b,f]oxazocine was

reduced to the amino derivative, which was acylated and cleaved to provide in good

yields.

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CONCLUSION

The combinatorial synthesis of oxygen containing heterocyclic organic molecules plays a

significant role in the area of drug discovery. Solid-phase oxygen containing heterocycle

synthesis has been established as an important tool for preparative chemistry with a broad

range of applications in modern organic synthesis. In very few reaction steps, libraries of

molecularly diverse compounds can be synthesized by taking advantage of the efficient

removal of excess or unconsumed reagents by extraction and filtration as simple workup

operations, in high purity without time-consuming purification steps.

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Scheme 1.

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Scheme 2.

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Scheme 3.

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Scheme 4.

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Scheme 5.

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Scheme 6.

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Scheme 7.

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Scheme 8.

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Scheme 9.

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Scheme 10.

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Scheme 11.

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Scheme 12.

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Scheme 13.

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Scheme 14.

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Scheme 15.

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Scheme 16.

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Scheme 17.

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Scheme 18.

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Scheme 19.

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Scheme 20.

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Scheme 21.

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Scheme 22.

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Scheme 23.

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Scheme 24.

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Scheme 25.

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Scheme 26.

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Scheme 27.

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Scheme 28.

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Scheme 29.

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Scheme 30.

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Scheme 31.

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Scheme 32.

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Scheme 33.

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Scheme 34.

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Scheme 35.

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Scheme 36.

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Scheme 37.

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Scheme 38.

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Scheme 39.

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Scheme 40.

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Scheme 41.

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Scheme 42.

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Scheme 43.

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Scheme 44.

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Scheme 45.

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Scheme 46.

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Scheme 47.

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Solid-Phase Synthetic Approach Toward the Synthesis of Oxygen-Containing Heterocycles

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Transcript of Solid-Phase Synthetic Approach Toward the Synthesis of Oxygen-Containing Heterocycles