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Abstract: The photooxygenation of heterocycles represents a versatile and widely ... photooxygenation with particular attention to the reaction of Type II involving ...

Current Organic Chemistry, 2005, 9, 109-139

109

Photooxygenation of Heterocycles M. Rosaria Iesce*, Flavio Cermola and Fabio Temussi Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, Complesso Universitario Monte S. Angelo, via Cinthia 4, I-80126 – Napoli, Italy Abstract: The photooxygenation of heterocycles represents a versatile and widely accepted tool for introducing oxygenated functions in a mild, simple and selective way. The review evidences the synthetic potential of the photooxygenation with particular attention to the reaction of Type II involving singlet oxygen in the first electronically excited state (1∆g), which has been applied to the most studied heterocycles as furans, thiophenes, pyrroles, oxazoles, imidazoles, indoles, nitrogen-containing six-membered systems. The singlet oxygenation of these systems occurs mainly via [4+2] cycloaddition leading to unstable endoperoxides which, in addition to the classical transformations of peroxides (reduction, hydrolysis, deoxygenation, generally performed at low temperature), afford characteristic rearranged products depending on the heteroatom, substitution pattern and experimental conditions. 1,2-Oxygen addition can sometimes compete with the Diels-Alder-type reaction, especially for pyrroles, imidazoles and indoles. The attention has been also focused to the oxygenation of some biomolecules as histidine, triptophan and guanine which play a significant role in biological processes as photodynamic effects or in the photoinduced deactivation of nucleic acids.

1. INTRODUCTION The photooxygenation of heterocycles leads to a variety of products and serves as an important tool in the synthesis of many natural products or compounds of special interest [1-3]. There are a number of instances in which butenolides or enediones from furans have been incorporated into the framework of more complex molecules [1, 3]. Likewise, oxazoles have been used as protecting-activating groups for carboxylic acids [4], and indoles have been employed as key intermediates in the synthesis of alkaloids [2]. Currently, great attention is devoted to the photooxygenation of biomolecules as histidine, purines or sulfur-containing compounds due to their involvement in photobiological and photodynamic phenomena [5] as well as to the role of the photooxygenation reaction in the light-induced degradation of drugs [6], pesticides [7] or polymers [8, 9]. The photooxygenation can be described as a reaction in which the substrate R gives an initial oxygen adduct (Scheme 1). It consists of a combination of a substrate, light and oxygen in the absence or in the presence of a sensitizer which absorbs light. The role of the sensitizer is important to determine the type of mechanism. According to Gollnick classification [10], in the Type I the substrate is activated by the sensitizer triplet. This latter can abstract a hydrogen from a substrate leading to the radical R• which then reacts with the ground state oxygen molecule (Eq. 1). On the other hand, the triplet energy of the sensitizer can be transferred to the ground state oxygen molecule to produce singlet oxygen (reaction of Type II) (Eq. 2) [10]. It is also possible that an electron transfer occurs between the excited sensitizer and the substrate with formation of a radical cation R•+, and this reacts with O2 or superoxide anion O2•- [11]. This mechanism is currently defined as Type III (Eq. 3) [12].

*Address correspondence to this author at the Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II Complesso Universitario Monte S. Angelo, Via Cinthia 4, I-80126, Napoli, Italy; Tel: +39081674334; Fax: +39081674393; E-mail [email protected] 1385-2728/05 $50.00+.00

1

Sens hν

1

Sens*

Sens

ISC

SensH RH

R

1 3

3

Sens R

Sens*

(1)

O2 O2 RO2

R (3)

O2

3

(2)

3

O2 1

RO2 1

O2

R

Sens

O2

RO2

RO2

Eq. 1; Type I Eq. 2; Type II Eq. 3; Type III

Scheme 1.

In a typical procedure a solution of the substrate and the sensitizer (generally from 0.1 to 0.01 eq.) is irradiated by tungsten sources (when using dyes) or mercury lamp (UV filtered). When exposed to the halogen lamp the reactor has to be cooled and it is kept at the desired temperature by immersion into a thermostated bath. For preparative uses, an immersion system is ideal, as this arrangement uses the output of the lamp most efficiently [13]. The diverse modes of oxygenation often lead to the same products or may be in competition. However a suitable choice of the reaction conditions may address the reaction to one type. So, halogenated or deuterated solvents, low temperatures, continuous flow of oxygen, halogenated lamps and dyes may favour reactions of Type II. UV light, highenergy sensitizers (9,10-dicyanoanthracene, ketones), polar solvents, oxygen saturated solutions may favour the other two ways. The reactions of Type II are retarded in the presence of diazabicyclo[2.2.2]octane (DABCO) [13] or NaN3 [5], well known quenchers of singlet oxygen. © 2005 Bentham Science Publishers Ltd.

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of Type II, involving singlet oxygen ( ∆g), with the most used heterocycles. Attention will also be devoted to molecules involved in biological processes as histidine, triptophan, purines. It will start from some excellent reviews [2, 4, 14, 15] and books [1, 11, 16, 17] and will focus particularly on recent developments, so covering the last two decades. 1

O O +

O

(2)

O*

H OOH

O

1

O

O2

(1)

R

(3)

RX (5) (4)

R

RO2

+

O2

RX-O-O

R + O2

Scheme 2.

The oxygenation of Type II by singlet oxygen is mostly used, whenever possible, due to the high selectivity of this species and the mild reaction conditions. Indeed, the use of halogen lamps prevents the possibility of the decomposition of the peroxidic or hydroperoxidic products which may occur with UV lamps. Moreover, due to the high number of the dye-sensitizers available the reaction can be carried out in a variety of organic solvents, from apolar to polar, as well as water. Singlet oxygen reacts by the following five modes (Scheme 2) [8, 11, 13]: a. gives [4+2] cycloaddition to cisoid conjugated dienic systems leading to endoperoxides (Eq. 1); b. adds to activated double bonds to give 1,2-dioxetanes which undergo fragmentation to two carbonyl fragments, one in an excited state (Eq. 2); c. gives ene-type reaction with olefins having allylic hydrogens (Eq. 3); d. adds to heteroatoms to give an initial RX +OO- species which undergoes further reactions (Eq. 4); e. undergoes an electron transfer with particularly electron-rich substrates to give a cation radicalsuperoxide ion pair or charge-transfer complex (Eq. 5) which gives the oxygenated product or undergoes a backelectron transfer leading to triplet oxygen and starting compound (physical quenching). Due to the presence of heteroatom(s) photooxygenation of heterocycles may involve all the above reaction modes. Furthermore the fate of primary adducts may follow unusual courses depending on the heteroatom, substitution pattern and experimental conditions. However a great similarity is also present in many reactions of photooxygenation and the aim of this work is to illustrate the generality and scope. The review will evidence the synthetic potential of the photooxygenation, with particular attention to the reactions

2. FIVE-MEMBERED HETEROCYCLES The photooxidation of pentatomic aromatic heterocycles by singlet oxygen occurs mainly via [4+2] cycloaddition leading to unstable endoperoxides which, in addition to the classical transformations of peroxides (e.g. low temperature reduction, hydrolysis, deoxygenation), can afford characteristic rearranged products. The reactions can sometimes be complicated by the formation of products deriving from both 1,4- and 1,2oxygen addition (Scheme 3, Eq. 1 and 2), especially in the photooxygenation of pyrroles and imidazoles. On contrary, 1,2-addition takes place with condensed derivatives as benzofurans or indoles, (Eq. 3). In vinyl derivatives singlet oxygen generally gives 1,4-addition involving the exocyclic double bond (Eq. 4 and 5). 2.1 Furans Thermal stability of the furan endoperoxides appears to depend on the α-substituent and follows the order Me > Ph > H > OMe [18-20]. The Scarpati research group has shown that the presence of an electron-withdrawing group at the β position in the furan ring enhances the thermal stability of the corresponding endoperoxides, which may be stable enough to be isolated and characterized by analytical and spectroscopic data [21]. Y

[4+2]

(1)

X Y

O

1

O2

X

O

O [2+2]

Y

(2)

O X

1

O O2

O

X

(3)

X

1

O2

X

O X O

1

O2

X

Scheme 3.

(4)

O

O (5)

X

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2 R3

R

R3 O 4

R O

4

R2

OMe

R2

R3

111

R

O

O

R2

1

R

1

R1

4

O

O

O

1

O2

(1)

(10) R3

R

R2 R4

O

R1

R1

O

R1

O

R2

4

(2)

(9)

O O

R3

2

R

R

O R4

3

O

O

O

2 (8)

R3

R2

R4

(3)

R

(7)

COR1 O

3

R

2

(4) (6)

R

(5)

R1

4

O

O

O R R

3

R3

2

R

4

R2

O R1

O O

R3

O

R2

R3

R4

R2

O R1

O

O OH O

O

H

O

O

R1

Scheme 4.

1. 3O2, hν toluene/MeOH O

2. SiO2

3

O

O O

4

Scheme 5.

The subsequent rearrangements of the intermediate endoperoxide also depend on the nature of the α-substituents as well as on reaction conditions. The most representative products from endoperoxides 2, formed by photooxygenation of the corresponding furans 1, are reported in Scheme 4. The presence of an aryl group can induce the formation of diacyloxiranes (Eq. 1) and/or aroylenolesters (Eq. 2), and a polar solvent and high dilution favour the latter [22]. Enediones have been sometime found (Eq. 3) especially from 2-alkoxyfurans (R1=OR) [20]. Symmetrically dialkylor diarylsubstituted endoperoxides give cis-diepoxides (Eq. 4), which are structurally related to the antitumoral crotepoxide [23]. Epoxylactones are formed (Eq. 6), in addition to cis-diepoxides and 4-hydroxybutenolides (Eq. 5), by thermal conversion of endoperoxides of α,α’unsubstituted furans [19, 23].

Recently, a stable epoxy γ-lactone 4 has been obtained by self-sensitized photooxygenation of a furan fulluren 3, presumably via SiO2-catalysed conversion of the related 4hydroxybutenolide (Scheme 5) [24]. The obtainment of butenolides (Eq. 5) represents one of the most useful applications of the furan oxygenation and a great effort is devoted to improve this approach due to the wide synthetic and biological interest of this compound class [3, 25]. The first synthesis of 4-hydroxybutenolides was obtained by oxygenation in ethanol of furfural derivatives [26]. This process may very probably involve a homolytic cleavage of the O-O bond with loss of the formyl radical. An example of this approach applied to the synthesis of 5aminolevulinic acid hydrochloride 8 is reported in Scheme 6. Indeed, oxygenation of 5 followed by selective reduction of the butenolide 6 with zinc in acetic acid under sonication leads to the γ-oxo acid 7, which by hydrolysis gives 8 [27].

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Iesce et al. 1O 2

R

H O O

5

C 2H5OH 58-90 %

R HO

O

O 6

Zn/AcOH )))) O

∆, HCl (3N) 70 %

HCl . H2N

COOH

64-87 %

O R

COOH

for R=NHAc 7

8

Scheme 6.

O

O

O

O2,TPP, hν , CH2Cl2 H

O

OH

H

-78 °C, 30 min

H

O

74%

H

O O

TMS HO OAc

H H

TPP = Tetraphenylporphyrine

Spongianolide A

OH O O

Scheme 7.

The oxygenation of α,α’-unsubstituted furans may be addressed mainly to the butenolides (Scheme 4, Eq. 5) (> 50%) by carrying out the reaction in the presence of a hindered base [28] or by using a basic solvent as acetone [29]; moreover, the regiospecific generation of the carbonyl function may be achieved starting from 2trimethylsilylfurans by the very fast intramolecular silyl migration of the intermediary endoperoxides [30]. The method has been employed as key step in the synthesis of spongianolide A, an antitumoral natural sesquiterpenoid (Scheme 7) [31]. The Katsamura protocol [30b] represents the crucial successful oxidation in the multi-step stereoselective synthesis of zoanthamine alkaloids 9, which display potent antinflammatory activity (Scheme 8) [32]. Endoperoxides of suitably α-substituted furans undergo Baeyer-Villiger-like rearrangements (Scheme 4, Eq.7). It has been shown that the reaction proceeds selectively starting from C-glycosylfurans 10 with the exclusive migration of the sugar moiety (Scheme 9) [33].

This pathway was already employed with crown furans and led to macrocyclic lactones containing a γ-keto-α,βunsaturated ester function [34]. This unit is common to various natural antibiotic macrolides and the method offers the possibility for an easy introduction of this structural part into macrocycles. Evidences for the intermediacy of carbonyl oxides (Scheme 4, Eq. 8) in the thermal conversion of 5unsubstituted 1-alkoxyendoperoxides have been obtained by trapping reactions with methanol, alkenes, carbonyl compounds, heterocumulenes and oximes leading to compounds 11-16, respectively (Scheme 10) [20]. The primary acetals 16 are generally unstable and evolve to hydroperoxynitrones 17 [35]. The latter have been prepared by a one-pot procedure by oxygenating suitable starting furans in the presence of oximes at –20 °C and have been used as starting material for hydroperoxyoxaziridines 18 [36], hydroperoxyisoxazolines 19 [37], oxazinones 20 [38] (Scheme 11).

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2 OAc

OAc

1. 3O2, hν, RB O

CO2M e

CH2Cl2, 0 °C

TMS

O

2. s at. NH4Cl aq. 3. TMSCHN2 CH2Cl2-MeOH O

O

(62 %) O

R

H

O H H O

N RB= Rose Bengal

O

O

Scheme 8.

9

R R

O

BnO

O

BnO

CH2Cl2, -20 °C

OBn

O O O

O

BnO

hν, Sens, 3O2

BnO

OBn

OBn 10

OBn ∆ O O

BnO

O

R

O

a; R=H BnO

b; R=Me

OBn OBn

Scheme 9.

R3

R2

R2 4

R4 HOO

O

R5

N R6

R O

R4 HOO

CO2Me OMe

R1= OM e 16

CO2Me Ph

11

R 3= H

R2

N

R2

1

O O 2

6R5RC

R4 O

R

CO2Me

Ph-NCO

R4

R2 R4

O

CO2Me

EtO

CO2Me O

O 15

R2

MeOH

NOH

O O

O

OEt 12

Me 2CO CO2Me R2 R4

R2 R4

CO2Me O O

Scheme 10.

14

O Me Me

CO2Me O O 13

CO2Me

113

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R1

R2

OMe

O i

R1 Ar

CO2Me N

O

O

20 (37-50% from furan)

O

O

iv

N R6

R1=

CO2Me R2= Ar R5= Me

R5

ii

CO2Me

N

R1= R2= H

R2

R5 OOH

OOH 17

R6= H R1=R2=H

18

i: 1O2, -20 °C, CH2Cl 2, R5R6C=NOH

(45-88%)

iii R7

MeO2C R6

CO2Me

R6

N

R 5 OOH

O

R7

ii: hν, pyrex, MeCN, r. t. 19

R7 iii: R7 iv: 1. Et 2S; 2. SiO2

(crude > 73%, isolated 30-90%)

Scheme 11.

H 3C CHO O

O

H3C

O O2, TPP, hν

21

O

CH3 O

O

O

O

CH3

H 3C O

O

H3C O2, TPP, hν

H 3C

HOO

O O

O

H3C H 3C

22

H2C

23

Scheme 12.

Rearrangements to peroxidic species as dioxetanes (Schema 4, Eq. 9) [20, 39] or 3H-1,2-dioxoles (Schema 4, Eq. 10) [20] have been also described. Starting from 5and/or 6-substituted 1-alkoxyendoperoxides these species have been observed by NMR studies and characterized by some simple reactions run at low temperature [20]. Sometimes dioxetanes are the primarily detected oxygenadducts as in the reaction of benzofurans [40], naphtofurans and naphtodifurans [41], furonaphthopyrones as 21 [42] and lead to the characteristic cleavage products. An anomalous behaviour has been observed in the oxygenation of furanopyrone 22. Indeed, differently from 21 which gives the corresponding dicarbonyl compound, 22 leads to the stable allyl hydroperoxide 23 by an ene-type reaction (Scheme 12) [42].

Although unstable, furan endoperoxides may undergo a number of reactions working at low temperatures. Hence, the selective reduction of the double bond can be carried out by using diimide [43], while the use of NaBH4 leads to the unsaturated diol as well [44]. The sequential oxygenation and sodium borohydride reduction have been used to synthetize useful intermediates for glycoaldehyde phosphodiesters [44a] or compound 24 which is a key intermediate in the construction of the zaragozic acid/squalestatin backbone (Scheme 13) [44b]. The treatment of furan endoperoxides with reductants as triphenylphosphine or dialkyl sulfides gives almost quantitatively enediones [16, 45]. The oxidative ring opening of furans leading to enediones is an important synthetic operation due to the versatility of these compounds. An

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2 OBn

OBn

R3

R3

R2 1O

O

O

1. 3O2, hν, RB CH2OTBS 2. NaBH4 3. TBSCl OH imid, DM F (60%)

O

O

R4

CH2OTBS

O

R3

OTBS 24

R1O HOOC

R2

O

interesting application of the photooxygenation-reduction is depicted in Scheme 14 and represents a simple and regioselective method for oxidative cyanation of furans [46]. Indeed, the in situ treatment of enediones with trimethylsilyl cyanide (TMSCN) provides 2-cyano-5-hydroxy-2,5dihydrofurans which can be converted to 4-cyanobutenolides (Scheme 14). R2 O Me3SiCN R2 NC

R2 O

O

R1=H

NC

R1 O

OH

Scheme 14.

A convenient alternative to the use of endoperoxides for enediones is to carry out the reduction on the methanoltrapping products (Scheme 15, Eq. 2). These compounds are simply prepared by oxygenating furans in methanol (Scheme 15, Eq. 1) and are generally obtained regiospecifically and often entirely stereoselectively [23]. Indeed, the mechanism appears to be a nucleophilic substitution assisted by the concomitant formation of a H-bonded peroxy group according to Eq. 3 in Scheme 15 [23]. The pathway is taken if the developing cation is well-stabilized and with the preferred addition of methanol to the most hindered site of the endoperoxide [47]. Oxygenation in methanol followed by alkyl sulfide reduction is a simple and mild method to obtain enediones in high yields, and, generally, does not require the isolation of

R

Scheme 16.

1. 3O2, hν, RB MeOH O

(CH2) nPO(OEt) 2

2. DMS 3. NaI, HCl acetone, H2O

(3)

O H

δ

R

the alcohol adducts. An example is depicted in Scheme 16 where the tandem reaction is the key step in the synthesis of compounds 25 starting from 2-furyl-alkyl-phosphonates [48]. The method represents a convenient strategy for the synthesis of naturally occurring cyclopentenones. The alternative to use alkoxyhydroperoxides rather than the corresponding endoperoxides is more advantageous since: 1) the thermal rearrangement of endoperoxides is often competitive and a mixture of products can be obtained [33]; 2) hydroperoxides are readily reduced by the milder alkyl sulfides so preventing side-reactions (mainly cis–trans isomerization or cyclization to furans) which are found with PPh3 [45]; 3) the methanol-adducts are stable at room temperature and hence, more manageable than the related endoperoxides. Methoxyhydroperoxides 26, deriving from the highly unstable alkoxyendoperoxides (short half-life at –70 °C), react with Et2S at room temperature to afford functionalized alkenoates 27 stereoselectively and in very high yields [49]. Moreover, they have been conveniently used to synthesize cis-dicarbonyloxiranes 28 [50] by treatment with NaH or hydroperoxyfuranones 29 [51] in acidic media (Scheme 17). Suitable manipulations starting from the methanol adducts of furanoeremophilanes may lead to the synthesis of steroidal and nonsteroidal 8α-substituted eremophilenolides as 30a and 30b (Scheme 18) [52]. The alcohol addition to furan endoperoxides is almost general. However, as above described (Scheme 6), endoperoxides of α-substituted furans lead, in alcohol, to the butenolides as the only isolable products. Moreover alcohol addition fails with endoperoxides of electron-poor

R1 O

(2)

O

OOH

RO

O

Scheme 15.

2. Me 2S

R1 O

O

δ

Scheme 13.

R1

R2

O

O COOH

O

O

OMe

R4

OMe

OH zaragozic acids

R2

(1)

Et 2S

OH

HOOC

1. 1O2

O

R3 R1

O

R1

HOO

R2

R4 HOO

R4

-20 °C

OH

TBSO

R2

M eOH

R1

O

2

115

O

O R (CH2) nPO(OEt) 2 O 25

NaOH 50 °C MeOH 3h

(CH2) nPO(OEt) 2

R

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Iesce et al.

R2

R1

R3 for R 2= H MeOH -20 °C R2

HCl O

1O

R2

R1

R3 HOO

OR

O 2

R1

R3

O

R2 OR

O

HOO

29

R1

Et 2S R3

OMe

CO2R O

26

27 NaH

O

R2 R3

R1 CO2R

O 28

Scheme 17.

OH OH Ac2O Pyr

HOO

OH

O OH

OMe

1O 2

H

OH

MeOH

O

OH

H

Ac2O

HOO OMe H OAc

steroidal: 30a

O

2

HOO

R

CHCl3

O

R

31

Me H

O 32

R HO

R

R 1O 2

R2

Scheme 19.

O 33

R1

R

O

MeOH

OMe

O OAc

O Me

1O

O H Me

Me

AcO

Scheme 18.

H

O

Me

COR1 R2 OOH 34

α,α’unsubstituted furans [19], and with encumbered alcohols as tert-butanol, a rearrangement to enolacetates may be

30b

Pyr

O

OH

30a

OMe

Me Me nonsteroidal: 30b

observed as in the oxygenation of α,α’-dimethylsubstituted furans [23]. An intramolecular nucleophilic attack has been observed in the oxygenation of suitable furans as 31 which affords spirohydroperoxides 32 [47]. Moreover, for furans 33 (R1=OMe) the intramolecular trapping by the hydroxyl group at C4 overcomes the methanol addition affording 2-oxetanyl hydroperoxides 34 [53] (Scheme 19). The photooxygenation of 2,5-bis-(thio)-furans (R1=Me, Ph) in methanol leads in high yields to the formation of O,Sdimethyl and O-methyl-S-phenyl thiomaleates, and so, the method represents a mild and direct access to these compounds (Scheme 20) [54]. The trapping by a diverse protic species different from alcohols has been realized in the oxygenation of suitably substituted alkoxyfurans. Indeed, the reaction performed in

Photooxygenation of Heterocycles

R2

Current Organic Chemistry, 2005, Vol. 9, No. 2

R2

Br

Br

i R3S

O

SR1

MeO

SR 1

O

O

i: 3O2, hν, M B, CH3OH, - 40 °C MB= Methylene blue

Scheme 20.

the presence of 4-nitrobenzaldehyde oxime leads to compounds 35 regio- and stereoselectively (Scheme 21) [55]. R1

R1

R2

1O

2, -20 °C, CH 2Cl2 4-NO2C6H4CH=NOH

OMe

O

R2

23) [59]. The formation of these compounds has been explained through the ring-chain tautomerism of cis-γketoamides produced from furan endoperoxides. 2.2 Thiophenes As expected on the basis of higher aromaticity than pyrroles or furans, thiophenes undergo hardly addition of singlet oxygen [17, 60]. The parent is unreactive, while alkyl groups favour the reaction [61]. According to the low reactivity of the diene part of thiophene, photooxygenation of vinyl-derivative involves exclusively the exocyclic double bond (Scheme 3, Eq. 4 and 5) [62]. Thiophene endoperoxides are detectable at very low temperatures [63], since they decompose easily leading to cis-sulfines (Scheme 24, Eq. 1) and, sometimes, to enediones with extrusion of sulfur (Eq. 2) [60, 61, 63, 64].

OMe

HOO

O

R

O

R

R O2

Me

35

S

Me

Me

(1)

R

R

Me

Ac

Me

O O

Ac

Ar

O

Ac

Me O

Ac

Ar

Ac

O

O 36

Scheme 22.

Enediones have been obtained by a triphenylpyryliumsalt-sensitized electron transfer oxygenation of arylfurans [57]. They can be sometimes obtained by air oxidation of easily oxidable furans (substituted with alkoxy or aminic groups) [49, 58, 59] and the reaction can be strongly accelerated by irradiation [58]. By this way the antitumoral jatropham (R1= CO2CH2C6H5, R2=CH3, R3= R4= H) and other hydroxypyrrolynones have been obtained in the unsensitized photooxygenation of furylcarbamates (Scheme R3

R4

Scheme 23.

R3

R2

O

3O

NHR1

2,



C 6H6

O

R

Me

Me O

O

Scheme 24. Ar

∆ or hν HO

R

O

2

Me

O

(2) S

S

Ar

Me O

C6H4-4-NO2

Recently enediones have been obtained in good yields by treatment of the endoperoxides of 3-acetyl-5-arylfurans with water, while the UV irradiation or raising temperature gives the enols 36 (16-39% yields) through a homolytic cleavage of the O-O bond (Scheme 22) [56]. Ac

S O

(12-38%)

Scheme 21.

R

1

N

1O

117

R2

R4 HO

N R1

O

Thiophene endoperoxides are able to transfer sulfur to strained cycloalkanes forming thiiranes [65, 66]. The episulfidation is particularly efficient starting from thiophene 37 and occurs with high diastereoselectivity (Scheme 25) [66]. A concerted process presumably via an oxathiirane intermediate has been proposed [66b]. Transfer of oxygen to norbornene has also been observed [65]. Conversion of thiophenes to furans has been obtained by oxygenation of 37 followed by treatment with triphenylphosphine (Scheme 26) [67]. A nucleophilic attack on sulfur and biphilic insertion into the peroxide bond account for the novel chemistry. 2.3 Pyrroles Pyrroles react with singlet oxygen to give highly unstable endoperoxides whose existence has been proven by lowtemperature NMR (Scheme 27, Eq. 1) [68]. However, the oxidation process often gives a mixture of products derived from both 1,4- (Eq. 1) and 1,2-oxygen addition (Eq. 2) [2b, 17] as well as from hydroperoxides (Eq. 4) or zwitterionic intermediates (Eq. 3) [69]. The final product distribution depends essentially upon the substituents and on the reaction conditions (Scheme 27). The photooxidation of N-substituted α- or α,α‘unsubstituted pyrroles leads to maleimides, 3-hydroxy- and 5-hydroxylactames (eqs. 5-7) [2b, 17]. The latter are important synthons for the preparation of a variety of

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O

Me Me

Me

S Me 37 1O

2, CDCl3

-30 °C, 3.5 h O

O

Me

Me

Me

20 °C

S O O

Me Me

Me

Me Me R1

R1

R2

R2

O

O

S

> 50% R1

R2

= norbornene, cyclopentene, cycloheptene, cyclooctene, 2-, 3-, 4-cyclooctenol

Scheme 25.

O

R

O

R

Me S Me Me

O Ph

1O

2, CDCl3

Me

O Ph

P

Me Me

Ph3P

S

Ph 37

Ph3P=O

O

O

R Me

R

O

Ph3P=S

R

Me

or

Me Me Me

O

S

Me Me

S

O

Ph3P

Me

O Me

a: R = CH3; b: R = Ph

Scheme 26.

biologically active compounds, for example mitomycin derivatives [70]. They are also obtained when the pyrrole αposition is substituted by alkyl, formyl, carbomethoxy or acyl groups. This reaction has been recently applied to homochiral 2methyl substituted pyrroles furnishing chiral 5-methylene pyrrol-2(5H)-ones via the related hydroxypyrrolones (Scheme 28) [71]. Hydroxypyrrolinones are formed predominantly or exclusively in the oxygenation of pyrroles 2-carboxylic acids

followed by a CO2 elimination from the related endoperoxides (Scheme 29, Eq. 1) [72]. This singlet oxygen mediated oxidative decarboxylation has been used to obtain d,l- and meso-isochrysohermidin, effective interstrand DNA cross-linking agents (Eq. 2) [72b]. Competition between 1,4- (Scheme 30, Eq. 1) and 1,2addition (Eq. 2) has been observed in the singlet oxygenation of some substituted pyrroles [73]. Formation of the dicarbonyl compounds from 1,2-adducts followed by acidcatalysed dihydrocyclization has been used as the key step in the synthesis of 4,4-bis(trifluoromethyl)imidazolines 38

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119

Scheme 27.

Scheme 28.

Scheme 29.

which have shown potent acyl CoA:cholesterol acyltransferase (ACAT) and cholesterol biosynthesis inhibitory activities [73].

Compounds 40 and 41 have been obtained in the oxygenation of derivative 39. It has been suggested that they are formed via a dioxetane intermediate which undergoes

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Iesce et al.

Ar

CF3

Ar CF3

Ar

N

O2 (2)

CF 3

Ar

N

N

Ar

NH2 CF3

H

1O

NH2 O

O

NH2

H (1)

O

1

CF 3

F 3C

O

Ar

H

2

1N HCl

Ar CF 3

Ar

N H O

CF3 CF3

F3C

M eOH Ar

O

Ar

H

Ar

O

N

Ar

N

Ar MeOH

HO

N

NH2

O

M eO

H

O

N

38

H

(49%)

Ar = p-F-C6H4

Scheme 30. HO

O H H

N

S

1O

N

2,

CH3OH

R

R

R 40

39 Thiazolidine

41

Thiazolidine

S O

N O

O

HO

OH CO2t Bu O H H N S

+

N

- 78 °C

O

S O

N

O

CO2t Bu H H S

O

OH CO2t Bu H H N S

N

40

N

O

O R

Scheme 31.

O

OH CO2t Bu H H N S

CO2t Bu

R

R = CO2CH2CH=CH2

deoxygenation by attack of the sulfide grouping in the thiazolidine ring (Scheme 31) [74]. It has been found that the oxygenation of pyrroles occurs under more control when both electron-releasing and electron-withdrawing groups are present on the hetero ring. The tert-butyl ester of 3-methoxy-2-pyrolecarboxylic acids show different oxygenation pathways, depending on the substitution on the nitrogen. Indeed, while the Nalkylpyrroles lead to a complex mixture of products, among the others epoxy derivatives probably deriving from zwitterionic intermediates, the N-unsubstitued ones, as 42 (Scheme 32), show a high selectivity leading, by the proton shift, to the dipole deriving from the initial addition of singlet oxygen, to the corresponding hydroperoxides (Eq. 1)

[69, 75]. The latter easily undergo addition-elimination reactions with a variety of nucleophiles yielding 5substituted pyrroles [75]. This sequence has been successfully used by Wasserman to prepare α,α’-bipyrroles, precursors of bioactive natural products in the prodigiosin family and ring A analogs (Scheme 32, Eq. 2) [75b]. 2-Substituted pyrroles can also be synthetized by oxygenation of the N-carbomethoxypyrroles and treatment of the corresponding endoperoxides with nucleophiles in the presence of stannous chloride (Scheme 33) [76]. The twostep reaction has been employed with diverse nucleophiles such as trimethylsilylated ketones, vinyl ethers, N-methyl pyrrole, indole to afford the related compounds in good yields [76].

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Current Organic Chemistry, 2005, Vol. 9, No. 2

OMe CO2But

N

OM e

OMe 1O , 2

NuH

-78 °C

CH2Cl 2

N

H

121

CO2But OOH

(1) Nu

-H2O2

CO2But

N H

42

(48-78%) 1O

2

N H OMe

N H

N H

OMe

CO2But

N H

N H

OMe

N H

CHO

HCl

N H

N

C H

(2) N H

prodigiosin analog (43%)

Scheme 32.

1O 2

SnCl2 X

N

O

O

O

Nu

X

X

O

O

Cl

Cl

Sn

CO2Me

Cl

Nu O

Nu

N

Nu

CO2Me

Sn Cl

N

X = N-CO2Me

Nu

Nu

CO2Me

Scheme 33.

2-Cyanopyrrole can be obtained through a 1,4elimination of trimethylsilyl hydroperoxide from the 1,4adduct of trimethylsilyl cyanide (TMSCN) to the endoperoxide at low temperature (Scheme 34) [77]. 3O

N

2,

hν, TPP, -70 °C

TMSCN (5 eq)

H

H NC

N

OOSiMe3

Me

Me

NC

N Me

Scheme 34.

The ability of substituted pyrroles to trap 1O2 (produced from the photolysis of analyte molecules) has been exploited in a postcolumn reaction detection HPLC system for organic compounds called 1O2-sensitizers (PCBs, nitrogen heterocycles, nitro- and chloroaromatics, etc). Following separation, the analytes are excited by an Hg pen-ray lamp

and promote oxygen to the excited state. This reacts with pyrrole derivative which is added to the mobile phase and the detection is based on the loss of the pyrrole [78]. 2.4 Indoles The dye-sensitized photooxygenation of indoles has received great attention due to the important role that these heterocycles play in the synthesis of diverse alkaloids [1, 2] as well as in photodynamic damage to biological systems [79]. Although the main reaction with singlet oxygen is the dioxetane mode, indoles provide a significant variability depending on the substituents and reaction conditions. So, electron-rich N-alkylated indoles react readily to give carbonyl and amide fragments via oxidative 2,3-bond cleavage (Scheme 35, Eq. 1, R1= Alkyl, R2= Me), while Nunsubstituted indoles give ene reaction products (3hydroperoxyindolenines) (Eq. 2, R1= H, R2= Me, H) [17]. In N-acyl derivatives, the 2,3-bond cleavage (Eq. 1, R1= Acyl, R2= Me) and the dioxetane rearrangement into 3hydroperoxyindolines (Eq. 4, R1= Acyl, R2= CHR4R5, R3= Isopropyl) compete with the formation of 2hydroperoxyindolines (Eq. 3, R1= Acyl, R2= CHR4R5, R3= Ethyl), depending on the steric hindrance at the 3 position [80, 81]. Moreover, N-acylation stabilizes the labile dioxetanes sufficiently to be spectroscopically and

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O

O

R3

H

O R3

O Me N R4

R2

R2

N

(1)

N

R1

Me

R1

O

Hc O

(7) R3

O N

R3 OOH

(6)

H

R2 +

R1

N (5)

1O 2

R2 (2)

N

R1

R4 Hc

R5

(4)

R4

(3)

O O N

R 3 OOH R5

H

OOH R2

N

R1 R1 R4

N R1

Scheme 35. HOO i N

N

H ii HO

O iii N

N

H i: 3O2, hν, polymer supported RB ii: Na 2SO3/H2O (10%) iii: H2SO4/H2O (10%)

Scheme 36.

chemically characterized [81]. The particular thermal stability has been explained with the electron-withdrawing effect of the acyl group which prevents the lone-pair electron of the nitrogen from participating in breaking the C-O bond of the 1,2-dioxetane [80]. Formation of dioxetanes as primary products has been evidenced, in addition to the characteristic fragmentation products, by deoxygenation to epoxides with sulfides [81] or by intercepting the zwitterionic peroxide precursors by methanol [82] or suitable agents as trimethylsilyl cyanide [77]. 3-Vinylindole derivatives react with singlet oxygen to afford dioxacarbazole endoperoxides, in most cases stereospecifically (Eq. 5, R1= Me, R2= H, R3= cisCH=CHR4, and Eq. 6 R1= Me, R2= H, R3= transCH=CHR4). When the s-cis conformation is blocked by

substituents at the 2 and β-positions, [2+2] cycloaddition occurs at the vinyl bond (Eq. 7, R1= R2= Me, R3= CH=CHOMe) [83]. The most significant application of the photooxygenation of indole derivatives is in the synthesis of alkaloids. The photooxygenation of 1,2,3,4-tetrahydrocarbazole is the starting step in the synthesis of spiro derivatives (Scheme 36), which would be used as a starting material for the synthesis of spiro analogues of the ergot alkaloids. The reaction leads to the corresponding hydroperoxide which upon reduction with an aqueous solution of sodium sulfite followed by treatment with a mineral acid catalyst gives the final product in good yield [84]. Oxygenation of tryptamine derivatives by O2/hν/RB in methanol followed by reduction with dimethyl sulfide leads to an amine which can be involved in the formation of further rings. This oxidative ring closure has been used as an approach to β-carboline ring systems [85a] (Scheme 37) or to tetracyclic compounds which have the skeleton and stereochemistry of some fungal metabolites, sporidesmins [85b]. It has also been used in the asymmetric synthesis of pentacyclic compounds as brevianamide E (Scheme 37) [85c]. Recently the sequence has been carried out in an enantioselective mode by irradiating Nmethoxycarbonyltryptamine in the presence of a chiral tertiary amine, (-)nicotine followed by reduction [85d]. The same route starting from indole-3-acetaldehydes leads, through treatment with a mixture of acetic acidtetrahydrofuran-water (3:2:2), to quinolines (Scheme 38) [86]. The photooxidative double bond cleavage has been usefully adopted for the construction of large heterocyclic rings containing a carbonyl group. Utilizing this type of

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123

OO HN

N

hν, RB,3O2 MeOH

CO2Me

NHCO2Me

N

M e2S HO N

N

CF3CO2H CO2Me

N

N

CO2M e

carbinoline OH

Cl

O HO

OM e MeO

N MeO

H

Me

H N

O

N

O

N

N H

N

H

Me

O

MeO Me brevianamide E

sporidesmin

Scheme 37. O

CHO

R N

1. 1O2 2. Me 2S 3. AcOH, THF, H2O

O

R N N

O

H

O 2

CO2Me H CO2Me

Me

N H

O

CO2tBu

Me

43

44

Scheme 38.

2.5 Oxazoles Photooxygenation of oxazoles proceeds exclusively via 1,4-addition of singlet oxygen to give particularly unstable peroxides which can be detected at very low temperatures by spectroscopic means [88, 89]. The main rearrangement is to triamides, e.g. 48. [17, 88, 89] (Scheme 41). However, formation of imino anhydrides 47 [17, 89] or dioxazoles 46 [89] has also been evidenced. NMR studies at low temperature have allowed defining the mechanism involved

O

CO2tBu

R= H, Me, Ph

reaction the quinine alkaloid camptothecin has been synthetized by quinoline 45 obtained via photooxygenation of indole 43, followed by the basic treatment of the resulting keto-amide 44 (Scheme 39) [86]. A peculiar application of singlet oxygenation of indoles is reported in Scheme 40. The reaction of 2-arylderivatives in methanol, followed by acid-catalyzed nucleophilic substitution of the resulting methoxy-1,2-dihydro-3H-indol3-ones with aryl nucleophiles, leads to 2,2-diarylindolones in one-pot in good yields [87].

H

N

O

H

N

1O

NaHCO3

O

N

N

O

N

N

H

H CO2Me

Me O

CO2t Bu

HO camptothecin

O

O

O

45

Scheme 39.

R2 N R1

Scheme 40.

1. 3O2, hν, MB MeOH 2. ArH, AcOH

O Ar N R1

R2

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R2

R2 N

R3

1O 2

O

anhydrides 47, and the latter collapse into triamides 48 (Scheme 41). Oxygenation of 5-alkoxyoxazoles leads to thermally stable 3H-1,2,4-dioxazoles, and a simple and high-yield route has been described (Scheme 42) [90]. There is an other competing mode of transformation of the C-2 unsubstituted oxazole endoperoxides which leads to the cleavage at the 2-3 and 4-5 positions yielding a 1:1 mixture of a nitrile (or HCN) and an anhydride [17, 88b]. In particular, fused ring oxazoles lead, in apolar solvents, to cyano-anhydrides 49 followed by hydrolysis or CO loss. This sequence has been efficienlty used to prepare ω-cyano carboxylic acids 50 (Scheme 43) [91]. The rearrangement to triamides has many potential applications in organic synthesis since it provides a means of generating a masked carboxyl group [4, 92]. The reaction transforms all three C atoms of the oxazole to activated carboxylate derivatives. By carefully choosing the substituents, it is possible to limit the reaction with nucleophiles to one of the three CO groups. In particular, the diphenyloxazole group appears particularly useful and its use in total synthesis is reported (Scheme 44, Eq. 1) [4, 92]. The oxidation-acylation sequence may be successfully employed for the preparation of medium-membered rings which are normally difficult to obtain by conventional routes. Indeed, with 2,5-diphenyloxazoles in which the alkyl

N R1

O O

R2

R3OC

N R3

R1

Iesce et al.

O

R1

O

O

46

R2

O

COR2 N

R 3OC

N R1

O

COR 1

O R3

48

47

Scheme 41. R2

R2 N R 3O

O

3O , 2

R 3O2C

hν, MB, CHCl 3

N O

R1 DABCO 3-5 h

R1

O (73-97 %)

Scheme 42.

in the formation of triamides [89a]. Indeed, three subsequent rearrangements take place. The first leads to the dioxazoles 46, which in the second stage rearrange into imino

CO 1O

N

(CH2) n

2

O

N

(CH2) n

N

(CH2) n

H

COOH O O

H O 50

Scheme 43.

n= 4,5,6

49

(CH2R) Ph

(CH2R) Ph N

Ph

(80-90 %)

O

1O

NuH N

2

Ph

CH2R (Ph)

O O

CH2R (Ph)

O

PhOC

O

N OH Ph

Ph

1

O N

Ph O

OH

93% Me

O

O

O

CPTS, benzene, heat 47% Me

O O

Me

O O

HO O

Scheme 44.

(1)

O2

Me O

COCH2R

COPh

Ph O

N

pyrenolide C

O

O

(2)

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Current Organic Chemistry, 2005, Vol. 9, No. 2

O

O O

O

Ph

H

O Ph

i

O

CH2

C

HO

ii

125

O

Ph

N

N

N

Ph

Ph

Ph iii

O

O CH2

CH2

iv

O

Ph

COOH N Ph

methylenomycin analogue

i; Diethyl 2-oxo-1-isopropylphosphonate, LDA, -78 °C. ii; α-Lithio-α-(methoxymethy)allene, -78 °C. iii; (CF3CO) 2O, 2,6-lutidine, -25 °C. iv; 1O2, ClCH2CH2Cl, 25 °C.

Scheme 45. Ph

Ph N

N

i

Ph

OH

O

O

Ph

OH

O

51 ii O

O O MeO

O O

iii OH

Ph

53

OH

N Ph

O 52

Scheme 46.

i; Sharpless, (+)-DET. ii; 1. Ac2O; 2. 1O2. iii; MeOH, TsOH,benzene

group at the 4-position is substituted by a functionalised carbon chain terminating in a hydroxyl group, the conversion to triamide generates an activated carboxylate which is now available for cyclization with the terminal hydroxyl group. The synthesis of pyrenolide C has been achieved by this way (Scheme 44, Eq. 2) [93]. The oxazole group as a means of protecting a carboxyl group has proven to be particularly useful in the synthesis of some analogues of cyclopentanoid antibiotics as methylenomycins (Scheme 45) [94]. Here, the oxazole serves effectively in a protecting-activation role. Indeed, in the reaction sequence it facilitates the cyclization reaction by stabilizing the cationic intermediate, in addition to serving as a latent carboxyl function. Another application is in the synthesis of leukotrienes [95]. While the conventional carboxylate protecting groups interfere with the course of the reaction, the enantioselective epoxidation [95] and photooxygenation of the oxazole 51 followed by hydrolysis of triamide 52 affords the ester 53 in good yield with the desired stereochemistry (Scheme 46) [92]. An α,β-unsaturated lactone has been elegantly prepared by appropriately placing a phenylselenenyl group on the alkyl chain. Indeed, the photooxidation of 54 leads to the triamide formation as well as to a selenoxide function which

takes part in an elimination reaction leading to 55 in a one pot (Scheme 47) [92]. Ph N Ph

OR O PhSe

1O

Ph

O OH

2

O

N Ph

CHCH2CH2CH3 O

54 PTSA O CHCH2CH2CH3

O

Scheme 47.

55

An interesting recent application of oxazole dyesensitized photooxidation is in photoimaging processes [96]. Oxazole rings attached to a copolymer backbone, which is composed of 2-[3-methacryloxypropyl]-4,5-diphenyl-1,3oxazole and N-isopropylacrylamide, are transformed efficiently to the corresponding triamide derivatives in a thin

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CH3 CH2

N Ph

CH3

CH3 CH2

C C

Iesce et al.

C

O

CH2

C

C

O

(CH2) 3

(CH2) 3

O

1O

O

H3C

CH

C

2

CH3

C

O

C

O

O

NH

(CH2) 3 N

N

CH

H3C

CH

CH3

O

O

Ph

Ph

CH2

CH

Ph

Ph

CH3 CH2

C C

CH2

O O

CH2

O

(CH2) 3 CH3

Ph

H2NCH2CH2OH

C

O

O

Ph

CH3 CH2

C

NH

N

Ph

CH

O

O

CH2

O

C C

O

O

C

O

(CH2)3

O

NH

(CH2) 3

H3C

O

CH

CH3

N

NH

O

CH2

Ph Ph

CH2 OH

Scheme 48.

R2

R2 1O

N R3

R1

S

R3

R1

S O

O

(1)

2

R2

R1

N

O R3

56 (3)

O N

S 57

(2) O

1O 2

S Ph

O N H 58

NH2

Scheme 49.

film by dye-sensitized photooxygenation (Scheme 48). This transformation has been found to be applicable to a panchromatic photoresist with positive tone by development with an aqueous solution of amines to dissolve the exposed areas of the film [96]. 2.5.1 Isoxazoles, oxadiazoles and thiazoles Isoxazoles, 1,2,5-oxadiazoles and 1,3,4-oxadiazoles are apparently inert under dye-sensitized photooxygenation [88a]. Thiazoles react with singlet oxygen in a similar fashion to oxazoles affording the corresponding endoperoxides. However, while thiotriamide 57 (Scheme 49, Eq. 1, R1=R2=R3=Ph) [97a] and compound 58 (Eq. 2, R1= NH2, R2=Ph,R3=H) [97b] have been found in the photooxygenation of arylthiazoles 56, the derivative 56 (Eq. 3, R1=Me,R2= Ph, R3=H) does not undergo oxygenation.

2.6 Imidazoles The highly unstable endoperoxides of imidazoles, sometime spectroscopically detected [98], rearrange to dioxetanes or hydroperoxides, or rapidly fragment or polymerize [17, 2b]. The choice of the reaction path depends on the nature of the substituents on the imidazole ring. In some cases, the initial adduct looses oxygen to regenerate the starting material [98]. Fragmentation products deriving from C4-C5 bond cleavage, namely diacylamidines, are often found especially when the heterocyclic ring is fully substituted (Scheme 50, Eq. 1) [99]. The starting 4,5dioxetane has been sometime chemically characterized (Eq. 2) [99c]. Proton transfer of the N-H to oxygen is a facile path in N-unsubstituted derivatives [100]. In particular, a 4hydroperoxide (Eq. 3, R4= H) has been shown to be the precursor to the light emitter (dioxetane) for the

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Current Organic Chemistry, 2005, Vol. 9, No. 2

R2

R2

N R2

R3

NH

O

R1

N

R2

2

R2 O

R1 (7)

OMe

R3

(6) MeOH

R1= H

60

R4

O

R2 N R3

(4) 1O

HOO

2

R2

R3

N R3

N R4

Scheme 50.

O N H

R1

N

R2

N

N

(2)

R4

(5) R1

R1

N

(3)

NH N

N

O R3

R1

N O

R2

O

(1)

R2 N

59

MeO

R1

R4 1O

N N H

O

N

NH CO2

O

N

R3

R4 R3

N

OOH R1

O

O NH

i N

R1

HN R1 R2

R2

62

61 > 94%

O NH

ii

R1 R2

127

77-85 % iii O

O NH

HN * R1

i; 1O2, DBU

Scheme 51.

ii; t-BuOK, THF/t-BuOH iii; H2, Rh(NBD)Cl2-(R,R)-DIPAMP

chemiluminescence in the reaction of lophine and its derivatives [100]. 2-Hydroperoxides are obtained almost quantitatively by photooxygenation of 2-alkyl derivatives and are reduced with PPh 3 to the corresponding 2-hydroxides (Eq. 4, R1= Alkyl, R4= H) [101]. Isomeric imidazolones 59 and 60 (Eq. 6, R3= R4= H) have been obtained by oxygenation of 2,4-disubstituted imidazoles in methanol [102]. It has been suggested that 59 is formed by dehydration of the 5-hydroperoxide deriving from a nucleophilic attack of methanol to the endoperoxide, while formation of 60 has been interpreted in terms of rearrangement of the endoperoxide to the dioxetane, nucleophilic attack of methanol on this intermediate and dehydration. A diimine and loss of CO2 have been also found (Eq. 7, R1=R4=H) and a detailed mechanistic study of isotope-labeled imidazoles

63 > 95 %

R2

has revealed that this can occur with 2-H, N1-H imidazoles, but not in 2-substituted derivatives. The carbon of CO2 derives from the C-2 of the imidazole ring, while both oxygen atoms originate mainly from one molecule of oxygen [103]. Photooxygenation of imidazoles offers interesting applications in the peptide synthesis [104]. Indeed, the reaction has been pointed out by Lipshutz as a general asymmetric synthesis of N-protected amino acids/dipeptides via appropriately substituted imidazoles. The three-step protocol (photooxygenation in the presence of DBU/imine 61 to enamine 62 isomerization/hydrogenation with optically active Rh(I)/DIPAMP combination as catalyst) leads in high yields and excellent e.e. to the final products 63 (Scheme 51). A racemic mixture of 63 can be obtained cleanly and

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R2

R2 N

1O

2

HN MeO

O O

OMe

R NH

R-M

R1

HN MeO

R1

N

R2

N

R1 O O

65

66

64

Scheme 52.

regiospecifically by treating acyl imines 61 with NaBH4 [104]. In a further application dialkylated amino acids have been obtained starting from imidazoles. N-Substitution with OMe group, such as in imidazoles 64, increases the electrophilicity of the imines 65 which react smoothly and quickly with diverse organometallic reagents (R-M = RLi, RMgX, R2Cu(CN)Li2, RLi.CeCl3, R3ZnLi) to give αalkylated amino acid derivatives 66 [105]. Dialkylated amino acids are difficult to prepare by other known procedures. The preparation of these compounds is of interest since incorporation into certain peptides imparts valuable bioactivity profiles, including enzyme inhibiting properties. Photooxygenation of tetramethyl-4H-pyrazole 67 produces diketone 68 and N2 via the corresponding endoperoxide [105], whereas 1,3,4-triazole turns out to be inert toward singlet oxygen (Scheme 53) [106].

3 SIX-MEMBERED HETEROCYCLES The reaction of singlet oxygen with nitrogen-containing six-membered heterocycles has received poor attention due to the scarce reactivity of these systems. So, for example, in the reaction of polynuclear heteroaromatics singlet oxygen addition does not occur at the heterocyclic ring [11]. Furthermore electron-transfer reactions involving superoxide anion may occur as in the photooxygenation of indolizines 69 (Scheme 54) [108]. The reaction carried out in mixed solvents benzenemethanol gives methyl α-phenyl-β-(2-pyridinyl)propenoic esters 70, 71 as main products. It has been suggested that a charge transfer complex is initially formed which leads to ion radical pairs. The oxygenation of six-membered heterocycles has been largely limited to dihydroderivatives, leading in certain cases to interesting synthetic applications.

Me Me

M e Me Me

presence of the heterocyclic system in molecules of biological interest, such as histidine or purines and their role as predominant target in photosensitized oxidation of DNA (see below).

Me

1O

2

Me

Me O O

N N N2

67

3.1 Pyridines The oxygenation of 1,2-dihydropyridines leads to the corresponding endoperoxides in high yields, which are particularly reactive with nucleophiles in the presence of stannous chloride to give 6-substituted derivatives [109]. It has been suggested that the role of SnCl2 is to form the complex A which is attacked by the nucleophile via the SN2

68

Scheme 53.

Despite the scarce synthetic interest [2b, 17, 103], great attention is paid to the mechanistic aspects of the photooxygenation of imidazoles and this is related to the

Ar

3O

2,



Ar

N

N

O2

69 C6H6/MeOH

Ar N H3CO

Ar

N O

H

OH OO O

Ar N 70

Scheme 54.

OMe

+ O

OMe

N

Ar 71

OCH3

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2

R4

R4

R3

R3

R5

R2

1O

2

R2

N

and from the opposite side of the leaving peroxidic group [109]. The method has been applied to various derivatives [110], and used in total synthesis of a variety of natural products such as sedacryptine [110a] or palustrine [110b] or alkaloids as sedinine [110c] (Scheme 56). Using indole as nucleophile the above reaction has been employed for the synthesis of complex molecules which are in the framework of aspidosperma alkaloids (Scheme 57) [111]. The oxygenation followed by treatment with sodium cyanoborohydride and an ethyl acetate suspension of tin (II) chloride appears particularly useful in the preparation of 1,2,3,6-tetrahydro-3-pyridinols 75, which are the starting materials for interesting compounds related to antineoplastic alkaloid tetrahydropseudodistomins (Scheme 58) [112]. The photooxygenation of 2-dicyanomethylene-1,2dihydropyridines 76 in DMF/ethanol represents a method to obtain 2-pyridincarboxylates 77 (Scheme 59), compounds for which classical preparation by reaction of the alcohol

R5 O O N

CO2R 1

CO2R1

72

73 R (nucleophile) SnCl2

Cl Cl Sn O R 1O2C

O

R4

R3

HO R4

R5

R3

N R2

R2

R5

N

R

CO2R1

R

129

74 A

Scheme 55. H O

HO

O H N

H OH

Me H

N

HO H N

N

H OH

Me

H

H

H

H

Me

N

H

Me HO H

sedacryptine

palustrine

sedinine

Scheme 56.

mechanism (Scheme 55). Starting from 2-substituted-1,2dihydropyridines 72, regio- and stereochemically definite products as 2,6-cis substituted derivatives 74 can be prepared in good yields. Indeed, endoperoxides 73 are formed with high stereoselectivity by the approach of singlet oxygen from the opposite side of the substituent (R2). The subsequent nucleophilic attack takes place to the less substituted carbon Cbz Cbz

N

N 1O

2

O

indole SnCl2

with acids or acid chlorides gives poor or moderate yields [113]. In the photooxygenation of 1,4-dihydropyridine 78 an unstable hydroperoxide 79 is formed which readily decomposes to 3(4H)-pyridone 80 (Schema 60). In aromatic solvents or methylene chloride the dicarbonyl hydroperoxide 81 is found, probably deriving from a further oxygenation of an unsaturated dioxetane intermediate [114].

OH H

1O

R

O

N H

N

2

NaBH3CN

HO

SnCl2 R

Z

O

N Z

O

75

Me

Y N

NH2

H H

N H Cbz = PhCH2OCO-

Scheme 57.

OH

a; R=

b; R= Me

O H

R

N H

tetrahydrops eudodistomins c; R= M e

aspidosperma alkaloids

Scheme 58.

130

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Ar NC

H2N

Ar CN

3O

CN

N H

2, hν,

NC

RB

[117]. 5,6-Diphenyl-2,3-dihydropyrazines are inert toward photooxygenation [116b]. 1,4-Endoperoxides have also been found from pyrazin-2ones 91 or condensed derivatives as pteridin-2,4,7-trione 95 (Scheme 63) [118]. Compounds 91 lead to unsymmetrical imides 93 and nitriles 94 via electrocyclic ring opening [118b] of endoperoxides 92. On contrast, peroxide 96 on warming generates singlet oxygen or can be trapped by methanol [118c].

CN

EtOH/DMF H2N

N

CN

CO2Et

77

76

(70 - 81%)

Scheme 59.

3.3 Pyrimidines As for pyrazines, the singlet oxygenation occurs difficulty except for activated products bearing alkoxy group which afford the 2,5-adducts [115]. An unexpected result has been obtained in the photooxygenation of 2,4diaminopyrimidines 97 which affords 4-amino-1,3,5-triazin2-yl ketones 101 (Scheme 64) [119]. The authors suggest dipolar ion 98 as the key intermediate. Attack by the peroxide anion upon C(6) should lead to the dioxetane 99 which undergoes the usual cleavage yielding dicarbonyl compound 100. By protonation/deprotonation-assisted rotation, the former 4-amino group acquires a position suitable for condensation which yields the 1,3,5-triazines 101. Electron-deficient derivatives (R1=CO2Et or only 4aminosubstituted) are not attacked by 1O2 [119]. 1,4-Dihydropyrimidines 102 behave with singlet oxygen in the same way as above reported for 1,4-dihydropyridines (Schema 60) [120]. Indeed, the oxygenation leads, by ene-

3.2 Pyrazines Formation of endoperoxides 83 has been observed in the oxygenation of pyrazines 82 bearing alkoxy substituents [115]. One stable derivative (R1= R2= Me) has been chemically characterized by treatment with PPh3 and NaBH 4 affording unsaturated bicycle 84 and diol 85, respectively (Scheme 61). Suitably alkyl-substituted 2,3-dihydropyrazines 86 react with singlet oxygen yielding 1-isocyano-2(acylamino)ethanes 87 and aldehydes 88 (Scheme 62) [116, 117]. The most likely precursor appears an unstable hydroperoxide 90, and on the basis of solvent effects, it has been suggested that it derives from a perepoxide intermediate 89 [117]. Replacement of a methyl by a phenyl substituent increases singlet oxygen quenching ability due to the stabilizing interaction of the negative charge on the free oxygen of the perepoxide with the aromatic π system as in A

Ph

Ph

N H

O - H2O

Ph

Ph 1O

N

Ph

Ph

Ph

Ph aromatic solvents or CH2Cl2

N 80

79

2

78

Ph

OOH H

acetone Ph

Ph

Ph

Ph H

HOO

O

H Ph

O

N Ph 81

Scheme 60.

R2

EtO

N

N

OEt

R1

1O

R2 2

EtO

82

N O O N

OEt

R1

NaBH4

N

OEt OH

EtO

N 85

Scheme 61.

R2

N

OEt

EtO

O N

R1

84

83

HO R2

Ph3P

R1

Ph

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2

N

R 3O

N

O 2,

hν, Sens.

CN-CH2-CH2-NH-CO-R

+ X

CH2X

86

N

R

N

R

N

N

CH2X

N

CHX

N

88

O

O H

OOH

O

R OH

X

90

δ δ O O

N

C

R

O + OH

87

+

X

N N

H

87

89

131

C

CH3

H 88

X=H, M e A

Scheme 62. R3

R2

N

R4

N

1O

R3 2

O R4

O

R4 O

R1

N 94

O

92 O

Me

N

Ph

N

Me

1O 2

N

N

O

O

Me 1O

95

N Me

Me

2

N

R2

OMe NH

Me

MeOH

N

O

O

O

Ph

O

N

N

Me

Me

O

96 NH2

R1

N

Ph

O O N

NH2

H2N

O N



N

Me

NH2 OO

1O

R1

N

2

H2N

R2

N

97

N

O

R1

N

N N

O N

reaction, to 5-hydroperoxy-4,5-dihydropyrimidines 103 which by silica gel treatment afford 5(4H)-pyrimidones 104. Compounds 103 can be easily reduced to give stable hydroxyderivatives 105 (Scheme 65).

R2

99

R1

O

NH2

N

O

R2 H2O

101

R1 O

H2N

98

H2N

Scheme 64.

R3

+

93

O

Scheme 63.

R2

N

R1

91

O

O



O

N

R1

O

R2

N

H2N

N 100

R2

4. BIOMOLECULES Although many studies have been made and are being currently made to isolate and characterize intermediates and products, the mechanism of photosensitised oxidation of

132

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Ph

R

Ph

N H

H2O

R

H

1O 2

N Ph

Iesce et al.

Ph

SiO2

N

HOO Ph

N

102

Ph

R

O

N

Ph

Ph

N

103

Ph

104 P(OEt) 3

Ph

R

H N

HO Ph

N

Ph

105

Scheme 65. COOH

N

H2N

COOH

1O 2

H2O

N H

O +

H2N

COOH

106

H2N

107

NH2

108

Scheme 66. N R

1O

N R

N H

N H

H

O

109

R

H 1O

2

111

H

O NH

N R 112

N 113

O

N H

HO

O

110

NH R

N

2

O

HO H

R

NH N

O

114

O OH R=

Scheme 67.

N H O

biomolecules as histidine or triptophan or DNA bases is still not completely clear. Investigation is difficult owing to the low solubility of these compounds, the instability of the intermediates, the difficulties in the separation and characterization of the products. Consequently, derivatives and organic solvents are often used to study the detailed mechanisms. The non-physiological conditions, however, may lead to different mechanisms and kinetics of photooxidation; and this could result in the formation of intermediates and final products different from those occurring in biological systems. 4.1 Histidine The photooxidation of histidine proceeds by Type II process via an unstable endoperoxide as evidenced spectroscopically at low temperature with histidine models [121]. In water oxidation presents a marked increase of rate

with pH and the inflection point is about pH 5.8 corresponding to the pka of the imidazole ring, so indicating that the unprotonated imidazole ring is oxidized [122]. Under aqueous conditions histidine 106 produces various products among which aspartic acid 107 and urea 108 have been identified (Scheme 66) [123]. Using N-benzoylhistidine (BzHis) the same products have been found with a dependence of yields on the sensitizer used [123, 124]. Two imidazolones, such as 111 and 114 (Scheme 67), have also been found deriving from the O-O bond cleavage and the prototropy of two endoperoxides. Bz-His may produce two endoperoxide isomers 110 and 113 since the imidazole has two isomers 109 and 112, the τ and π forms [122]. Recently in the bengal rose-photosensitised oxygenation of N-benzoylhistidine 109 in water at physiological pH (7.4) the formation of His-His crosslink products has been found

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2

N R

OH

N

1

O2

R

HN

N H

N H

O

N H

R=

N H

111

H N

OH

R

N

H N

R

O

O

N

R

O O

110

109

133

HN

R HN

R

N

OH

O

N

R

O N

N

116

115

Scheme 68. O OOH

H CO2H

1O 2

NH2

N H

CO2H

CO2H NH2

N H

117

NH2 NHCHO 119

118

i, 1O2 ii, Me2S OH

OOH H

H N H

N H

CO2H

121

N H

N H

CO2H

120

HCl H

N H

CO2H

O

NH2

122

Scheme 69.

[125]. The main dimeric product 116 has been isolated and characterized and is reported in Scheme 68 together with its suggested pathway. It has been assumed that the endoperoxide 110 changes to 111 which undergoes a nucleophilic addition of a further His molecule leading, via the elimination of one water molecule, to the crosslinked product 116 [125]. The result appears of particular interest since reactions involving His residues play a key role in the photodynamic cross-linking of proteins as mediated by singlet oxygen pathway [126], and model studies using 14C free amino acids and amino acids attached to sepharose gel have demonstrated that His can cross-link with itself, Lys, Cys, Trp, Tyr, and even with Arg on photosensitised treatment [127]. The photosensitised cross-linking of proteins is involved in several kinds of processes of

biomedical importance, including the photodynamic therapy of tumors and other diseases [128] or the sunlight photoaging of skin [129]. 4.2 Triptophan Many reports dealing with production of Nformylkynurenine 119 and its derivatives from Trp 117 have been accumulated with riboflavin or methylene blue as a photosensitizer in the presence of oxygen molecules (Scheme 69) [5, 130, 131]. The hydroperoxide 118 has been suggested as the primary intermediate and diverse pathways have been proposed for the transformation of 117 to 119 but none of the various postulated intermediates has been obtained except for the hydroperoxide 120, the cyclic tautomer of 118. This compound has been isolated and has

134

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117 i. hν, O2, RB Na2HPO4-KH2PO4 ii. Me 2S O

OH HO

CO2H

HO

121 +

H N H

N H

NH2

+

CO2H

NHCHO 124

123

Scheme 70. O

O

O NH

HN

O N

HN

+ HN

N N H

R

O

H2N

1O

O

2

N

N

H2N

R

O NH

H N

H NHR

O

O

N

N

N

127

125

N

N

R

126

HN

H N

HN

N

H

H

N R H N H

NH2 NH2

N

128

H

131

N dR

O

130

O H2N H2N

Scheme 71.

N 129

NHR a; R=deoxyrybosyl

been found to rearrange to 119 under various conditions [132]. The hydroxide 121 has also been found by reduction of the crude oxygenation mixture. It gives oxytryptophan 122 under acidic conditions [133]. In the dye-sensitized oxygenation of Trp in water the pH has a profound influence on the reaction rate and product distribution. Kinurenine 119 is formed mainly at pH 7 and hydroxide 121 under acidic conditions. When using bengal rose as sensitizer instead of methylene blue, the oxygenation proceeds more slowly and, in addition to 121, 123 and 124 are isolated which should derive from a further oxidation in para position from compound 120 (or 121) [131]. It has been found that Trp is oxidized more rapidly with increasing pH (Scheme 70) [5]. 4.3 Guanine Derivatives Oxidation reactions of DNA are known to be involved in mutagenesis, carcinogenesis and lethality, [134] and many studies are currently focused on the identification of oxidative damage to DNA in order to understand the biological role of these modifications [15, 135]. A source of oxidative damage involves UV-A radiation or visible light with an endogenous photosensitizer [15, 135]. Such oxygen-

dependent photosensitization processes can occur either through the Type I or Type II mechanism. Photooxidative nucleobase damage commonly involves guanine which among the four DNA bases is the most easily oxidable base [136]. This is explained by the fact that guanine has the lowest ionisation potential [137]. However it is also a major target of 1O2 [138] as well as it undergoes photooxygenation of Type I, mainly with flavin sensitizers [139]. The reaction of deoxyguanosine (dG, 125) with singlet oxygen leads to diverse products depending upon the reaction conditions and the structural context (Scheme 71). The predominant formation of a spiroiminodihydantoin nucleoside (dS, 126) is observed, particularly above pH 7 [140], together with 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dG, 127), an amino-imidazolone nucleoside (dIz, 128) and its hydrolysed product, diamino-oxazolone nucleoside (dZ, 129) [140, 141, 142]. More recently a diimino-imidazole nucleoside (dD, 130) has also been observed which in turn hydrolyses to dIz and dZ and Iz [143]. Compound 8-oxo-dG predominates in cellular DNA [144] while a cationic base, guanidinohydantoin (Gh, 131) is the major product at pH < 7 [140].

Photooxygenation of Heterocycles

Current Organic Chemistry, 2005, Vol. 9, No. 2

O

O

O

HN

HN

O O

H N

NH

HN

N

H2N

NHR'

N

N

127

N R'

O

134

O

2, -78 °C CDCl3

N

OH

HN

O

O N

HN R''HN

O O

133

1O

for R''= H

N R'

O

R'

132

NH

NH

O HN

135

N

1O

RHN 2,

N

N

135 + O

R'

< -100 °C

N

CBr 2F2

R'

for c

+

132

125

13CO

2

NH HN

O

O

TBDMSO

RN

N

N

R' = TBDMSO

R'

136

OTBDMS

OH

b; R''=H c; R'' = TBDMS TBDM S = t-butyldimethylsilyl

Scheme 72. O

O 1O

dG

N N H2N

N

O

O

NH

N

HN

HN

2

O

CO2 HN

OOH

H 2N

N

N

R

HN

N

R

137

138 H 2O

O

O N

N H2N

O N

N

N

H2O H2N

O N

N 140

pH < 7

pH > 7

In apolar solvents different products have been observed by low temperature NMR starting from 13C, 15N-labeled guanosine derivatives in the photosensitised oxidation of 2’,3’,5’-O-(tert-butyldimethylsilyl)guanosine 125b. NMR analysis has allowed compounds 127b, 132b, 133b and 134b to be evidenced [145], while in the oxygenation of 2’,3’,5’O-tert-butyldimethylsilyl-N-tert-butyldimethylsilyl-8-13Cguanosine 125c two transient intermediates have been observed which have been reported as carbamic acids 135c and 136c based on 13C NMR and 2D-NMR [146] (Scheme 72). They decompose directly to final major product 132c and 8-13CO2 [146]. Even at –100 °C, no intemediate as an endoperoxide or a dioxetane has been detected [145, 146].

OH H N

R

R 139

Scheme 73.

NHR

132

126

131

However, in the photooxygenation of 8-methylguanosine the corresponding diastereomeric endoperoxides have been identified by low temperature NMR. They undergo a retro Diels-Alder reaction to regenerate the starting 8methylguanosine and singlet oxygen upon warming [147]. This result suggests that the presence of a labile 8-H or NH is important for the thermal stability as well as for the rearrangement of the endoperoxide to form the decomposed products as observed for imidazoles [103]. So, the most conceiving mechanism is the formation of an endoperoxide 137 via a [4+2] cycloaddition of singlet oxygen to the imidazole ring that undergoes ring opening to 8-OOH-G 138 (Scheme 73) [15, 103, 140].

136

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Iesce et al.

O NH

HN H2N

O N

1O 2

+

NR

(127)

O

O OOH NH

N H2N

O HN

NR

N

HN

H 2N

O

HN

NH

NR

N

N R

O 141

O

NH

O

O

O

H N

O

142 143 CO2

O NH H2N

NH N

O

NR

O

O

144

NH

NH

HN

O CO2, NH2

O

NH

O

N R

O

N R'

H2N

N

O

O O

N R

N H

O

146

145

134

NH

NH

NH

O

128 133

O

O

H 2N

NH2

CO2

147

H2O O 129

O H 2N

TBDMSO

HO a; R =

or OH

HN

NH

O

O

NH2 148

TBDMSO

OTBDMS

O

N R

O

149

Scheme 74.

Recently a rationale which explains all the major nucleoside products observed from 1O2 both in aqueous and nonaqueous solvents [140] has been reported and is depicted in Scheme 73. The 8-OOH-derivative 138 in a nonaqueous solvent loses CO2, likely via a dioxirane intermediate [145, 146] while in water its fate is the loss of H2O to form a reactive oxidized form of 8-oxo-dG 139 that is trapped by H2O at C5, generating 5-OH-8-oxo-dG 140, the common precursor to dS 126 and Gh 131. Formation of 8-oxo-dG 127 as product of singlet oxygen oxygenation of DNA should be due to interception of the hydroperoxide intermediate 138 by cellular reductants [143]. Many of the products formed by singlet oxygenation of guanosine have been shown to derive from 8-oxo-7,8dihydro-2-deoxyguanosine (127) which is a much better substrate than dG for the reaction with 1O2 [148] as well as for other oxidation reactions due to the lower redox potential than that of the parent nucleoside (0.58 V vs. 1.29 V) [149]. It is considered one of the most important lesions in DNA so that special attention has been focused on the formation and the fate of this product under photooxidative conditions. A

plethora of products have been shown to derive from this compound (scheme 74) [5, 15]. Under aqueous conditions photosensitizers as methylene blue and rose bengal have been found to efficiently photooxidize 8-oxo-dG via a Type II mechanism (1O2) whereas riboflavin and benzophenone, which act mostly by a Type I mechanism, are less efficient [150]. Photooxidation studies with singlet oxygen generation suggest initial formation of a dioxetane 142 which has been observed by low temperature NMR starting from a sylilated derivative [148], followed by a cascade of pathways (Scheme 74) [148, 150, 151] One route leads to the 5hydroperoxy species 141, that has been proposed to go on the intermediate 144, the final products being imidazolone 128 and oxazolone 129 [150, 151], two of the same products that are observed in the radical oxidation of guanine [137]. The hydroperoxide 141 could also be formed directly by 8oxo-dG through an electron transfer to singlet oxygen with formation of the superoxide anion (O2•¯) and the intermediary radical cation of 8-oxo-dG [151]. The major pathway from dioxetane 142 is explained by ring opening to macrocycle 143, followed by intramolecular ring closure

Photooxygenation of Heterocycles

with extrusion of CO 2 yielding 145 that slowly hydrolyses to urea (148) plus cyanuric acid nucleoside 149 [150]. Five and seven-membered heterocycles as parabanic acid derivatives 134 and 146 and compound 133 are also formed.

Current Organic Chemistry, 2005, Vol. 9, No. 2 [22] [23] [24] [25]

CONCLUSION One objective in preparing this review was to evidence the high potential of the photooxygenation of heterocycles, in particular that involving singlet oxygen. This reaction represents a simple and green means to introduce oxygenated functions and confirms the role of heteroaromatics as latent functionality. However the relevance of the photooxygenation is not limited to its use in organic synthesis. The wide-spread presence of heteroaromatics in the environment as well as in biological systems make the reaction of high interest for the obvious implications in the deactivation processes or in the transformation to noxious products of bioactive molecules. ACKNOWLEDGEMENT Financial support from MIUR (FIRB 2003-2005) is gratefully acknowledged. Thanks are due to Maurizio Esposito for his great help in searching and providing most of the cited references. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

Matsumoto, M. In Singlet Oxygen; Frimer, A. A., Ed.; CRC Press: Boca Raton (Fl), 1985; Vol. II, pp. 205-263. a) Ihara, M.; Noguchi, K.; Fukumoto, K.; Kametani, T. Tetrahedron 1985, 41, 2114; b) George, M. V.; Bhat, V. Chem. Rev. 1979, 79, 447. Esser, P.; Pohlmann, B.; Scharf, H-D. Angew. Chem. Int. Ed. Engl. 1994, 33, 2009. Wasserman, H. H.; MCCarthy, K. E.; Prowse, K. S. Chem. Rev. 1986, 86, 845. Straight, R. C.; Spikes, J. D. In Singlet Oxygen; Frimer, A. A., Ed.; CRC Press: Boca Raton (Fl), 1985; Vol. IV, pp. 91-143. Albini, A.; Fasani, E. Drugs: Photochemistry and Photostability, The Royal Society of Chemistry: Cambridge (UK), 1998. Burrows, H. D.; Canle, M. L.; Santaballa, J. A.; Steenken, S. J. Photochem. Photobiol. B: Biol. 2002, 67, 71. Akasaka, T.; Ando, W. In Organic Peroxides; Ando, W., Ed.; John Wiley: New York, 1992; pp. 599-659. Rabek, J. F. In Singlet Oxygen; Frimer, A. A., Ed.; CRC Press: Boca Raton (Fl), 1985; Vol. IV, pp. 1. Gollnick, K. Adv. Photochem. 1968, 6, pp. 1-90. Matsuura, T.; Saito, I. In Photochemistry of Heterocyclic Compounds; Buchardt, O., Ed.; John Wiley: New York, 1976; pp. 456-523. a) Foote, C. S. Photochem. Photobiol. 1991, 54, 659; b) Fox, M. A. Photoinduced Electron Transfer; Fox, M. A., Chanon, M., Eds.; Elsevier: Amsterdam, 1988; Vol. D. Foote, C. S.; Clennan, E. L. In Active Oxygen in Chemistry; Foote, C. S., Valentine, J. S., Greenberg, A., Liebman, J. F., Eds.; Chapman & Hall: London, 1995; pp. 105-140. Wasserman, H. H.; Ives, J. L. Tetrahedron 1981, 37, 1825. Burrows, C. J.; Muller, J. G. Chem Rev. 1998, 98, 1109. Bloodworth, A. J.; Eggelte, H. J. In Singlet Oxygen; Frimer, A. A., Ed.; CRC Press: Boca Raton (Fl), 1985; Vol. II, pp. 93-203. Wasserman, H. H.; Lipshutz, B. H. In Singlet Oxygen; Wasserman, H. H., Murray, R. W., Eds.; Academic Press: New York, 1979; pp. 430-509. Graziano, M. L.; Iesce, M. R.; Scarpati, R. J. Chem. Soc., Perkin Trans. I 1982, 2007. Graziano, M. L.; Iesce, M. R.; Cinotti, A.; Scarpati, R. J. Chem. Soc., Perkin Trans. I 1987, 1833. Scarpati, R.; Iesce M. R.; Cermola, F.; Guitto, A. Synlett 1998, 17 Graziano, M. L.; Iesce M. R.; Scarpati, R. J. Chem. Soc., Perkin Trans. I 1980, 1955.

[26]

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