Preparation of Nitrogen-Substituted Ferrocene Derivatives by Aza-Wittig Methodologies

MICROREVIEW

DOI: 10.1002/ejoc.201100099

Preparation of Nitrogen-Substituted Ferrocene Derivatives by Aza-WittigMethodologies

Pedro Molina,*[a] Alberto Tárraga,[a] and María Alfonso[a]

Keywords: Aza-Wittig reaction / Sandwich complexes / Ferrocenes / Nitrogen heterocycles / Cyclophanes / Cyclization

Several methodologies based on the aza-Wittig reaction,mainly developed by our research group, have been used forthe preparation of a wide variety of ferrocenes containingnitrogen functionalities. Syntheses of mononuclear and nitro-gen-rich multinuclear ferrocenophanes, ferrocenyl-pyrazine,

Introduction

Iminophosphoranes were first prepared at the beginningof the 19th century, by Staudinger, and have nowadays be-come a powerful tool in organic synthetic strategies directedtowards the construction of nitrogen-containing heterocy-

[a] Departamento de Química Orgánica, Universidad de Murcia,Facultad de Química,Campus de Espinardo, 30100 Murcia, SpainFax: +34-968-884149E-mail: [email protected]

Prof. Pedro Molina was born in Totana (Murcia). He graduated with honours in chemistry from the University of Murciain 1968 and he obtained his Ph.D. in 1973. During the period 1976–1978 he joined the group of Prof. A. R. Katriztky atthe University of East Anglia (Norwich, UK). Since 1980 he has been full professor atthe Department of OrganicChemistry at the University of Murcia. He is recipient of the Spanish Royal Society of Chemistry Award in OrganicChemistry. His research has been mainly devoted to the area of heterocyclic chemistry, although in the last few years hehas turned his interests to the synthesis of new derivatives of ferrocene for study as molecular receptors.

Prof. Alberto Tárraga Tomás was born in Almansa (Albacete) and obtained his degree in chemistry at the University ofMurcia (Spain), where he also received his Ph.D. in 1979. After carrying out postdoctoral studies in Prof. A. Katriztky’sgroup at the University of East Anglia, Norwich (UK) in 1980 and at the University of Florida (USA) in 1981, he joinedthe group of Prof. P. Molina at the University of Murcia. In 1984 he obtained a position as Assistant Professor at theUniversity of Murcia, and since 2004 he has been Full Professor at the Department of Organic Chemistry at the sameuniversity. The major focus of his research interest relates to heterocyclic chemistry, synthesis of products with biologicalinterest and novel molecular receptors.

María Alfonso was born in Murcia (Spain) in 1983. She graduated in Chemistry from the University of Murcia in 2008and she is a Ph.D. student under the supervision of Profs. Pedro Molina and Alberto Tárraga. Her research interest isfocused on the development of new fluorescent, electrochemical and chromogenic chemosensors.

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quinoline, imidazole and oxazole derivatives have been per-formed through aza-Wittig reactions and by aza-Wittig/heterocumulene-mediated annulation, aza-Wittig/electro-cyclic ring-closure and aza-Wittig/intramolecular halide dis-placement methodologies.

cles.[1] Reactions of iminophosphoranes are often similar tothose of the isoelectronic phosphoranes. The reactivities ofthese compounds are a consequence of the polarity of theirphosphorus-nitrogen bonds, as well as the high basicities ofthese systems, influenced by the substituents on the phos-phorus atom and, in particular, by those on the nitrogenatom. Iminophosphoranes undergo reactions with carbonylcompounds in a similar way to phosphonium ylides, leadingto an excellent method for the construction of iminicdouble bonds through intramolecular and intermolecularprocesses (aza-Wittig reaction). This method provides one

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEWof the best procedures for the formation of C=N bondsunder mild and neutral reaction conditions.

Recently, the intramolecular version of the aza-Wittig re-action has attracted considerable attention because of itsgreat potential for the synthesis of nitrogen-containing het-erocycles. The readily available iminophosphoranes, pre-pared either from azides or from primary amines, and theiraza-Wittig reactions with a wide variety of carbonyl com-pounds, such as aldehydes, ketones, esters, amides, carbox-ylic acid anhydrides and acyl chlorides, provide a valuablemethod for the regiospecific formation of cyclic imines.

On the other hand, aza-Wittig-type reactions betweenfunctionalised iminophosphoranes and carbon dioxide, car-bon disulfide, iso(thio)cyanates or ketenes provide access tofunctionalised heterocumulenes as highly reactive interme-diates capable of undergoing a plethora of heterocyclisationreactions. In this context, we have developed two ap-proaches for iminophosphorane-based syntheses of aza-heterocycles: a) tandem aza-Wittig/electrocyclic ring-clo-sure, and b) tandem aza-Wittig/heterocumulene-mediatedannulation.

a) Tandem Aza-Wittig/Electrocyclic Ring-Closure

This methodology (Figure 1) is based on Staudinger re-actions between 1,3-diene azides and triphenylphosphaneand subsequent aza-Wittig reactions either with carbonylcompounds or with heterocumulenes to give 2-azahexa-1,2,5-triene moieties. Thermally induced 6π-electrocycli-sation followed either by a 1,5-hydrogen shift or by oxidationaffords pyridine rings.[2]

Figure 1. Aza-Wittig electrocyclic ring-closure.

b) Tandem Aza-Wittig/Heterocumulene-MediatedAnnulation

Aza-Wittig-type reactions between functionalised imino-phosphoranes, bearing an amino or hydroxy group placedat an appropriate position, and carbon dioxide, carbon di-sulfide or iso(thio)cyanates (Figure 2) can lead to function-alised heterocumulenes capable of undergoing intramolecu-lar nucleophilic attack by the amino or hydroxy group onthe central carbon atom of the heterocumulene moiety togive five-, six- or even seven-membered heterocycles.[3] Aninteresting variation of this methodology involves the useof iminophosphoranes derived from azido esters. In thiscase, aza-Wittig-type reactions with iso(thio)cyanate lead tothe expected carbodiimides, which on reaction with primaryamines affords guanidine derivatives, which in turn undergointramolecular cyclisation across the ester functionality togive 2-amino-substituted imidazoles.[4]

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Figure 2. Aza-Wittig/heterocumulene-mediated annulation.

The application of these iminophosphorane-based meth-odologies in the area of the ferrocenes forms the basis ofthis microreview. Intramolecular aza-Wittig reactions havebeen successfully applied to syntheses of mononuclear andmultinuclear azaferrocenophanes, whereas tandem aza-Wit-tig/electrocyclic ring-closure has allowed the formation offerrocenyl quinolines and quinazolinones. Tandem aza-Wit-tig/carbodiimide-mediated annulation has allowed the for-mation of ferrocenyl imidazoles, amino diaza[3]ferroceno-phanes (ferrimidazoles) and multinuclear nitrogen-rich[3.3]ferrocenophanes. Three-component reactions betweenα-(azidoacetyl)ferrocene, as carbonyl component, tri-phenylphosphane and acyl chlorides have been demon-strated to represent a reliable route for the synthesis of awide variety of ferrocenyl-substituted oxazoles, as well ashomotrimetallic ferrocene complexes containing at leasttwo oxazole ring in their conjugation chains.

The Aza-Wittig Reaction

The intramolecular version of the aza-Wittig reactionhas been successfully applied for the preparation of mono-nuclear azaferrocenophanes, whereas the intermolecularversion has proved to be a suitable method for the prepara-tion of nitrogen-rich multinuclear ferrocenophanes.

The reaction between 1,1�-diacetylferrocene (1,Scheme 1) and o-azidobenzaldehyde in a basic medium canbe driven towards the formation either of 3-(o-azido-phenyl)[5]ferrocenophane (2) or of 1,1�-bis(o-azidocinnam-oyl)ferrocene (3) as the only reaction products, simply bychanging the sequence of addition of the reagents and theamount of base. Interestingly, a Staudinger reaction be-tween the bis-azide 3 and 1,2-bis(diphenylphosphanyl)eth-ane afforded the 18-membered macrocycle 4 in 20% yield.This macrocycle could be valuable for the construction ofheterobimetallic ferrocene-based complexes, because theiminophosphorane group has demonstrated its versatility inthe formation of M–N σ bonds to transition metals.[5] Anintramolecular aza-Wittig reaction between the [5]ferrocen-ophane 2 and nBu3P in dichloromethane at room tempera-ture gave the cryptand 5 in 55 % yield. A better yield (80%)was obtained, however, when the aza-Wittig reaction wascarried out with diphenylmethylphosphane in toluene at re-flux temperature.[6] The unusual structure of 5 can be re-garded either as a [5]ferrocenophane bearing a 2,4-bridgeddihydroquinoline ring or as a [4](2,4)quinolinophane con-taining a 1,1�-disubstituted ferrocene bridge.

The transformation 2� 5, involving an intramolecularaza-Wittig reaction, constitutes the first example of the con-version of a ferrocenophane into a cryptand bearing a fer-rocene moiety and also shows the applicability of this reac-tion for the construction of strained C=N bonds.[7] More-

Nitrogen-Substituted Ferrocene Derivatives

Scheme 1. [5]Ferrocenophanes.

over, this [5]ferrocenophane derivative 2 constitutes thestarting material for the preparation of a new range ofstrained 2-aza-[3]ferrocenophanes in which all the atomswithin the aza-substituted bridge belong to a rigid aza-fused tricyclic ring system.

Syntheses of multinuclear nitrogen-rich [2.2]- and [3.3]-ferrocenophanes, ruthenocenophanes and mixed ferroceneand ruthenocene metallocenophanes have also beenachieved from the appropriate bis(iminophosphoranes) andsuitable partners through aza-Wittig reactions.

The preparation of multinuclear [2.2]metallocenophaneslinked by aza-unsaturated chains in the guise of aldiminicfunctionalities was thus achieved by starting from thecorresponding 1,1�-bis(triphenylphosphoranylidenamino)-metallocenes 8 (Scheme 2).[8] These bis(iminophosphor-ane)s are readily available through Staudinger reactions be-

Scheme 2. Metallocenyl bis(iminophosphorane)s.

Scheme 3. [2.2]Homo- and heterometallocenophanes.

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tween triphenylphosphane and the 1,1�-diazidometallocenederivatives 7, which are in turn prepared from the appropri-ate 1,1�-dilithiometallocenes through the use of 2,4,6-triiso-propylbenzenesulfonyl azide (trisyl azide) as a strong azide-transfer agent.[8a]

The bis(iminophosphorane)s 8 display the typical reac-tivity shown by the monoiminophosphoranes in aza-Wittigtype reactions with carbonyl compounds.[1e] Aza-Wittig re-actions between the bis(iminophosphoranes) 8 and suitable1,1�-diformylmetallocenes as carbonyl partners thus gaverise to the new diaza[2.2]homometallocenophane structuralmotifs 9 and 11 (Scheme 3), as well as the heterometallocen-ophanes 10 and 12.

The combined effects of the binding capabilities of thebridges and the close proximities between the redox unitshave made these new rigid structural motifs good candi-dates for displaying selective cation-sensing properties.Moreover, the close proximity between the redox centresand the binding sites endows these ferrocene derivatives notonly with the property of monitoring the binding of metalcations but also with the additional and exciting propertyof being able to behave as actuators through the progressiveelectrochemical release of the metal cation with the conse-quent decrease of the binding constant upon electrochemi-cal oxidation.[8d]

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEWInterestingly, the rigid and well-defined architecture of

the [2.2]ferrocenophane made it possible to obtain a suit-able model for a study of how conformational changes caninduce modifications of the intramolecular electron transfer(IET) energy in the mixed-valence system generated fromit, either electrochemically or chemically.[8c]

It is noteworthy that whereas the aza-Wittig type reac-tions between the iminophosphoranes 8 and carbon disulf-ide gave the 1,1�-bis(isothiocyanate)ferrocenes 13,[9] the re-action between carbon dioxide and 8a directly yielded thebis(carbodiimide) 14a (Scheme 4), with an unprecedentedtetraaza[3,3]ferrocenophane framework, although in a pooryield. However, when 1,1�-bis(isocyanato)ferrocene[10] wasused, compound 14a was obtained as the only reactionproduct in a high yield. Similarly, the aza-Wittig reactionbetween 1,1�-bis(triphenylphosphoranylideneamino)ruthen-ocene and 1,1�-bis(isocyanato)ferrocene resulted in the finaltetraaza[3,3](1,1�)ferrocenoruthenocenophane structure14b, in which ferrocenyl and ruthenocenyl moieties are di-rectly attached through carbodiimide functions.

Scheme 4. Tetraaza[3.3]homo- and heterometallocenophanes.

One-flask iminophosphorane-mediated syntheses of sim-ple ferrocene-based urea, thiourea and guanidine com-pounds bearing two or three ferrocene redox units linkedeither linearly or joined in a star-shape fashion have also

Scheme 5. Multinuclear ferrocenylurea, -thiourea and -guanidine derivatives.


been reported[11] (Scheme 5). These derivatives are preparedfrom the triphenyliminophosphorane 15, easily preparedthrough a Staudinger reaction between ferrocenemethylaz-ide (16)[12] and triphenylphosphane. It is worth mentioningthat bis(ferrocenyl)urea (17a) was prepared by one-flaskprocess involving the initial formation of the unisolated fer-rocenemethyl isocyanate (18). Sequential treatment of theazide 16 with triphenylphosphane, followed by addition ofcarbon dioxide and subsequent treatment with ferrocenyl-methylamine, thus gave bis(ferrocenyl)urea (17a). Alterna-tively, this compound could also be prepared in an excellentyield by treatment of the carbodiimide 19 with water intetrahydrofuran solution at room temperature. The interme-diate carbodiimide 19 was prepared in situ by simple ad-dition of the iminophosphorane 15 to the unisolated isocy-anate 18.

Moreover, tris(ferrocenylmethyl)guanidine (20, Scheme 5)was also easily produced by treatment of the carbodiimide19 with ferrocenylmethylamine, promoted by tetrabutyl-ammonium fluoride (TBAF).[13] On the other hand, theaza-Wittig reaction between the iminophosphorane 15 andcarbon disulfide, followed by addition of ferrocenylmethyl-amine to the intermediate isothiocyanate, yielded the corre-sponding thiourea 17b.

α-Azidoacetylferrocene (22, Scheme 6), prepared from α-bromoacetylferrocene (21), available in turn by metallationof acetylferrocene with LDA at –78 °C and sequential treat-ment with chlorotrimethylsilane and an excess of NBS,through halogen/azido substitution in the presence of poly-meric quaternary ammonium azide,[14] has proven to be auseful building block for the preparation of 2,5-bis(ferro-cenyl)pyrazine (24).[15] Interestingly, when α-azidoacetylfer-rocene (22) was treated with triphenylphosphane in dryethyl ether at 0 °C, formation of the expected iminophos-phorane was not observed. However, when the Staudingerreaction was carried out at room temperature, the azaheter-ocycle 24 was isolated. The formation of compound 24 wasexplained in terms of the initial formation of the corre-sponding iminophosphorane 23, which underwent cy-


clocondensation through a double intermolecular aza-Wit-tig reaction and eventual dehydrogenation of the resultingdihydropyrazine intermediate.

Scheme 6. Bis(ferrocenyl)pyrazine.

The use of α-azidoacetylferrocene (22) as a valuablebuilding block for the preparation of chiral ferrocenyl-thiaz-oline ligands has also been described. This process involvesthe initial enantioselective reduction of 22 to (R)-2-azido-1-ferrocenylethanol (25, Scheme 7) in the presence of the Co-rey–Bakshi–Shibata (CBS) catalyst,[16] which can then beconverted into the corresponding β-hydroxyamides 27through the following two-step sequence: a) pretreatment of25 with nBuLi in THF at –78 °C followed by addition ofthe corresponding acyl chlorides at the same temperatureto yield the 2-azido esters 26, and b) O�N acyl transferpromoted by triphenylphosphane at room temperature, toyield 27. The conversions 2-azido ester � β-hydroxyamidesrepresent a modification of the “Staudinger ligation”,which allows the chemoselective formation of amide-linkedproducts from azides and alkoxycarbonyl-linked triarylpho-sphanes.[17] In this case, the ester group, positioned adjacentto the azido functionality, traps the iminophosphorane inan intramolecular fashion, resulting in the β-hydroxyamides27 and triphenylphosphane oxide after hydrolysis. Finally,

Scheme 7. Staudinger ligation.


when the β-hydroxyamides 27 were treated with Lawessonreagent (LR) in excess in THF the corresponding ferrocenylthiazolines 28 were isolated[18] (Scheme 7).

Tandem Aza-Wittig/Electrocyclic Ring-Closure

This methodology offers a means for pyrido annulationby a simple two-step reaction sequence, mostly performedin a one-pot procedure. It is important to note that whenthe terminal carbon-carbon double bond of the 2-azahexa-1,3,5-triene moiety formed in the aza-Wittig step belongsto a ring, a b-fused pyridine is formed.

In this context, the 1-ferrocenylpropenone derivative 31(Scheme 8), obtained in 74% yield by condensation of ace-tylferrocene (29) with o-azidobenzaldehyde (30)[19] understandard conditions, has proven to be a useful starting ma-terial for the preparation of 3-ferrocenecarbonyl quin-olines.[20] A Staudinger reaction between 31 and tri-phenylphosphane afforded the iminophosphorane 32 (85%yield), which on treatment with the appropriate isocyanateswas transformed into the corresponding carbodiimides 33.These carbodiimides, used without further purification,underwent electrocyclisation on heating to give the 2-aryl-amino-3-ferrocenecarbonyl quinolines 34 (Scheme 8) inmoderate yields.

Scheme 8. Ferrocenecarbonyl quinoline derivatives.

Tandem Aza-Wittig/Heterocumulene-MediatedAnnelation

Very efficient preparations of novel ferrocene derivativessuch as β-ferrocenylvinyl heterocumulenes and ferrocene-containing imidazole rings, bearing one, two or three ferro-cene subunits by this protocol have also been reported.[21]

The method is based on aza-Wittig reactions between the

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEW[β-ferrocenylvinyl]iminophosphorane 37 (Scheme 9) andisocyanates, carbon dioxide or carbon disulfide and furtherheterocyclisation by use of the appropriate reagents andconditions.

Scheme 9. Ferrocenylmethylideneimidazolone derivatives.

Condensation of ferrocenecarboxaldehyde (35) with ethylazidoacetate at –10 °C provided the ferrocenylvinylazidoester 36 in good yield, and treatment with triphenylphos-phane yielded the iminophosphorane 37. This (vinylimino)-phosphorane 37 was converted, in one-flask fashion, intothe corresponding highly functionalised ferrocenylimidazo-lones 40. These conversions involved aza-Wittig reactionswith benzyl or alkyl isocyanates at room temperature andfurther treatment of the resulting carbodiimides 38 with ali-phatic or aromatic primary amines to give the ferrocenylgu-anidines 39 as intermediates, which underwent cyclisationat room temperature to give compounds 40. The imino-phosphorane 37 also reacted with aromatic isocyanates togive the expected carbodiimides 41, which on reaction withaliphatic amines also provided the imidazolone derivatives40.

Monoimidazolones such as 42 (Scheme 10), with 1-allyl-2-(allylamino) substituents, have also been prepared by theabove protocol but with use of allyl isocyanate and allyl-amine in the first and second reaction steps, respectively.Moreover, ring-closing metathesis (RCM) of the N-BOC-protected form of 42 in the presence of the Grubbs catalystresulted in the formation of a condensed diazepine ring,which after deprotection gave rise to the imidazo[1,2-a]-(1,3)diazepine 45 (Scheme 10). On starting from the appro-


priate 1,1�-disubstituted ferrocene 46 (Scheme 11) under thesame reaction conditions as described above, the corre-sponding bis(imidazolone) 47 was obtained.[22]

Scheme 10. Ferrocenylimidazodiazepine.

Scheme 11. 1,1�-Bis(imidazodiazepinyl)ferrocene.

On the other hand, the β-ferrocenylvinyl carbodiimides48 (Scheme 12) have been converted into new ferrocenyl-imidazolone and ferrocenyloxazolinone derivatives underdifferent reaction conditions.[15] On simple heating in a se-aled tube at 110 °C they was transformed into the ferrocen-

Scheme 12. Alternative cyclisation pathways for β-ferrocenylvinylcarbodiimides.


ylimidazoles 49, whereas on treatment with tetrabutylam-monium fluoride (TBAF) solution in THF the ferrocenyl1,3-oxazolin-5-ones 50 were obtained.

A tentative mechanism for the conversions 48 � 49 and48 � 50 has been reported (Scheme 13). The process in-volves initial formation of the intermediates 51, promotedeither thermally or by the action of the TBAF. Under ther-mal conditions the intermediates 51, in which both thenegative and the positive charges are highly delocalised,could undergo ring-closure across the nitrogen atom of theisourea moiety to provide 50. With regard to the TBAF-promoted cyclisation, the intermediates 51 could afford 49through the action of the water present in TBAF/THF solu-tion. Factors supporting these assumptions are: firstly, theextraordinary stability exhibited by α-ferrocenylalkyl carbo-cations[23] could promote the formation of the intermediates51, and secondly, the well known fact[24] that TBAFstrongly increases the electrophilic character of the centralcarbon atom of the carbodiimide function.

Scheme 13. Proposed mechanism of cyclisation of β-ferrocenylvinylcarbodiimides.

The (vinylimino)phosphorane 37 also reacted with car-bon dioxide at 110 °C in a sealed tube to afford the corre-sponding β-ferrocenylvinylisocyanate 52 (Scheme 14). How-ever, when this reaction was carried out at 160 °C a mixtureof the isocyanate 52 (70 %) and the bis(β-ferrocenylvinyl)-carbodiimide 53 (20%) was obtained. The latter compoundwas also obtained in 95% yield through an intermolecularaza-Wittig reaction between the (vinylimino)phosphorane37 and the vinylisocyanate 52 in toluene at reflux(Scheme 14).

Moreover, the ureas 54 (Scheme 14) were also preparedeither by treatment of the (vinylimino)phosphorane 37 witharylisocyanates and subsequent hydrolysis of the formedcarbodiimides 56 or by passing a carbon dioxide stream


Scheme 14. Cyclisation reactions of β-ferrocenylvinyl heterocumul-enes.

through mixtures of the (vinylimino)phosphorane 37 andthe corresponding amines heated at 80 °C. Such ureasunderwent cyclisation on thermal treatment to give theferrocenylmethylideneimidazolinones 55 in modest yields(24–34%). In a similar way, the (vinylimino)phosphorane37 provided the corresponding 2-thioxoimidazolin-4-ones57 in better yields on sequential treatment with carbon di-sulfide and with primary amines and further heating of theresulting thiourea intermediates[15] (Scheme 14).

The carbodiimide 53 (Scheme 15) has also been used asbuilding block to prepare the bis(ferrocenyl)imidazole de-rivatives 59 and 60 in high yields when treated with α-un-substituted amines. The behaviour of the carbodiimide 53toward primary amines can be explained by the initial for-mation of the guanidine derivatives 58, which undergocyclisation across either the alkylamino group or the (β-ferrocenylvinyl)amino group, depending on the degree ofsubstitution on the carbon atom adjacent to the aminogroup.[21]

The carbodiimide 53 also reacted with ferrocenylmethyl-amine[25] in dichloromethane at room temperature to givethe tris(ferrocenyl) compound 62 in moderate yield(Scheme 16).[21]

Preparation of other azaheterocyclic systems containingferrocenyl moieties in their structures by aza-Wittig meth-odologies has also been reported. The 2-arylamino-3-(o-ferrocenecarbonyl)phenyl-3H-quinazolin-4-ones 65(Scheme 17) have been prepared from the carbodiimides 64,which were in turn synthesised through aza-Wittig reactionsbetween the iminophosphorane 63 and aryl or benzyl isocy-anates. Under the reaction conditions used, the carbodi-imides 64 undergo cyclisation to the azaheterocycles 65through nucleophilic attack of the NH groups of the amido

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEW

Scheme 15. Bis(ferrocenyl)imidazolone derivatives.

Scheme 16. Tris(ferrocenyl)imidazolone derivative.

functions on the central sp-hybridised carbon atoms of thecarbodiimide moieties[20] (Scheme 17).

The synthesis of dihydroquinazoline and 4H-3,1-benzo-thiazine derivatives has also been reported[26] through intra-molecular heteroconjugate additions of carbodiimides orisothiocyanates, each bearing one o-substituted α,β-unsatu-rated carbonyl fragment, promoted by the CS2/TBAF sys-tem. Treatment of the carbodiimides 66 (Scheme 18), avail-able from iminophosphorane 32 and isocyanates, with theCS2/TBAF system (4:1 molar ratio) gave the dihydroquin-azoline-2-thiones 67 in moderate yields. The iminophos-phorane 32 also reacted with CS2 at 40 °C to give the ex-pected isothiocyanate 68, which on treatment with the CS2/TBAF system under the same reaction conditions affordedthe 4H-3,1-benzothiazine-2-thione 69.

When the carbodiimides 66 were treated with a solutionof aqueous TBAF in tetrahydrofuran (1:4 molar ratio) inthe presence of anhydrous MgSO4/Na2SO4 the acetylferro-cenyl-substituted dihydroquinazoline derivatives 70


Scheme 17. Ferrocenyl quinazolinone derivatives.

Scheme 18. Ferrocenyl quinazoline and benzothiazine derivatives.

(Scheme 19) were obtained. It is noteworthy that when thereactions were carried out in the absence of the dehydratingagent, the corresponding ureas derived from the carbodi-imides 66 were found to be the major products along withsmall amounts of the cyclised products 70. In the presenceof aromatic amines the carbodiimides 66 were also directlyconverted into the dihydroquinazoline derivatives 72.[15]

It was reported[15] that ureas derived from 66 were reco-vered unchanged after further treatment with TBAF/THFat room temperature. Therefore, as far as the mechanism ofthe conversions 66 � 70 is concerned, it is thought that theTBAF strongly increases the nucleophilic character of thenitrogen atoms of the carbodiimides 66, promoting intra-molecular N-conjugate addition to the o-unsaturated sidechains in a Michael-type fashion, followed by hydrolysis ofthe resulting cyclised product by the water present in theTBAF/THF solution.[24,27] On the other hand, the conver-sions 66 � 72 are explained in terms of a mechanism in-volving the initial formation of guanidines as intermediates,with these undergoing cyclisation through N-conjugate ad-


Scheme 19. Cyclisation reactions of o-ferrocenyl-substituted arylcarbodiimides.

ditions onto the o-unsaturated side chains under the reac-tion conditions to give the cyclised products. It was re-ported that the intermediate guanidines could be isolatedwhen tosyl isocyanate and phenacylamine were used as rea-gents.

Other types of ferrocene-azaheterocycles, such as ferro-cenyl-substituted oxazoles, are also available by the imino-phosphorane methodology through the use of isocyanatesas reagents. α-Azidoacetylferrocene (22) reacted with aro-matic isocyanates to give the intermediate carbodiimides73a (Scheme 20), which in the presence of arylaminesunderwent cyclisation to give the corresponding 2-aryl-amino-5-ferrocenyl oxazoles 74. However, when benzyl iso-cyanate was used as aza-Wittig reagent two different com-pounds were formed from 73b: the expected 2-benzylamino-5-ferrocenyloxazole (75a), together with the second com-

Scheme 22. Bis(ferrocenyl)guanidines.


Scheme 20. Amino-substituted ferrocenyl oxazoles.

pound 75b, formed through the reaction between 75a anda second equivalent of benzyl isocyanate, with 75b beingthe major product.[15]

The previously mentioned 1,1�-bis(isocyanato)ferrocene14a has also been used as an important building block toprovide the 1,3,10,12-tetraaza[3,3]ferrocenophane 76(Scheme 21), in which the ferrocenyl termini are directly at-tached through carbodiimide functions. Treatment of 14awith hydrazine in dichloromethane gave rise to the ex-tremely nitrogen-rich (12 nitrogen atoms) ferrocene deriva-tive 76, which could be regarded as a new type of ferroceno-phane: namely a [2,2]bis[3,3]ferrocenophane, in which theorganometallic fragments are linked by four guanidine moi-eties.[8a]

Scheme 21. [2.2]Bis[3.3]ferrocenophane.

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEWSimilarly, the [3,3]ferrocenophane 14a, available through

an aza-Wittig protocol, could also be used to prepare a newset of [3,3]ferrocenophanes (Scheme 22) in which the twoferrocene subunits have similar electronic environments andare linked by two naphthyl-, (substituted) phenyl-, ferro-cenyl- or pyridyl-appended guanidine moieties[28].

On the other hand, 1,1�-bis(isothiocyanato)ferrocene(13a) has also been used as a valuable tool for the prepara-tion of 81a and 81b (Scheme 23), representatives of a newtype of bis(thioureido)-[11]ferrocenophanes, on treatmentwith 1,3-bis(aminomethyl)-4,6-diisopropylbenzene and m-xylylenediamine, respectively.[29]

Scheme 23. Bis(thioureido)[11]ferrocenophanes.

Tandem Aza-Wittig/Intramolecular HalideDisplacement

The three-component reactions between an α-azido-ketone, triphenylphosphane and an acyl halide lead directlyto 2,5-disubstituted oxazoles.[30] The reactions take placethrough initially formed iminophosphoranes, which un-dergo acylation and further elimination of triphenylphos-phane oxide to give imidoyl chlorides as intermediates,which undergo cyclisation to give the five-membered rings.This method has been utilised for the preparation of natu-rally occurring oxazole alkaloids.[31]

The carbonyl component used for the preparation offerrocenyl-substituted oxazoles was α-(azidoacetyl)ferro-cene. However, because of the previously mentioned easewith which its iminophosphorane derivative undergoesauto-cyclocondensation to give 2,5-bis(ferrocenyl)pyrazine(24, Scheme 6), a modification of the standard protocol inorder to achieve the desired functionalised oxazole ring hasbeen reported.

The reaction was thus carried out with the acyl chloridepresent before addition of the triphenylphosphane. As aconsequence, the initially formed triazaphosphadiene inter-mediate reacts directly with the acyl chloride aza-Wittigreagent to form a new intermediate, termed the triazaphos-phadiene adduct,[32] which decomposes to give the aza-Wit-tig product. No iminophosphorane is detected under theseconditions.

This methodology also allowed one-flask preparations ofthe 2-aryl-5-ferrocenyloxazoles 83 (Scheme 24) from 22,


with use of substituted benzoyl chlorides as aza-Wittig rea-gents. In this case, cyclisation of the intermediate imidoylchlorides 82 takes place without the need for a base.[15]

Scheme 24. Ferrocenyl oxazoles.

This efficient formation of oxazolo-ferrocene derivativeshas also been applied to the preparations both of ferroceneligands linked to two oxazole rings and of bis(ferrocene)-ligands in which the two redox units are connected throughspacers containing two oxazole rings.[33] The required aza-substituted ferrocenes were α-(azidocarbonyl)ferrocene[15]

(22) or the bis azide 89 (Scheme 26,below). The bis azide89 was prepared from 1,1�-diacetylferrocene by the follow-ing two-step sequence: i) metallation with LDA at –78 °C,followed by sequential treatment with chlorotrimethylsilaneand NBS, and ii) treatment with sodium azide or polymericquaternary ammonium azide.

It is worth mentioning that formation of the ligands de-scribed above by the triazaphosphadiene pathway tookplace in very disappointing yields (less than 10%), probablydue to the fact that the HCl liberated from the aza-Wittigreaction adds to the highly basic iminophosphorane or tri-azaphosphadiene, leading to diminished yields or pre-venting the cyclisation step. However, upon addition of ba-sic polymer-supported BEMP (2-tert-butylimino-2-diethyl-amino-1,3-dimethylperhydro-1,3,2-diazaphosphorine), usedas a scavenger of HCl in diverse alkylation and acylationreactions,[34] the yields of the desired oxazole derivatives(Scheme 25) were increased considerably (around 50 %).Only in one case, in which phthaloyl chloride was used, wasthe monocyclised product 87 (Scheme 25) obtained, in 40 %yield. All attempts to promote the formation of the secondoxazole ring in compound 87, with use of conventional de-hydrating agents and even the powerful Appel system dehy-drating agent (Ph3P/I2/Et3N or Ph3P/CCl3CCl3/Et3N) orthe Burgess reagent [methyl N-(triethylammoniumsulfonyl)-carbamate] failed. This could be ascribed to steric factors.

The three-component bisazide 89/triphenylphosphane/aroyl chloride reaction also allowed the preparation of thenew 1,1�-bis(oxazolyl)ferrocenes 90 (Scheme 26). The onlyexception to this behaviour was observed when 4-nitroben-zoyl chloride was used. In this case, the reaction productwas found to be the unsymmetrical 1,1�-disubstituted ferro-cene 92. The unexpected formation of this compound prob-ably involves the initial formation of the ferrocene-1,1�-bis-(imidoyl chloride) 91, in which one of the imidoyl chloridemoieties undergoes cyclisation to give the oxazole ring, fol-


Scheme 25. Poliferrocenyloxazole derivatives.

lowed by nucleophilic counterattack of the leaving chlorideon the other side chain with concomitant elimination of 4-nitrobenzonitrile (Scheme 26).

Scheme 26. 1,1�-Bis(oxazolyl)ferrocene derivatives.

The aza-Wittig reactions between α-(azidoacetyl)ferro-cene (22) or 1,1�-bis(α-azidoacetyl)ferrocene 89 and mono-,di- or triacyl chlorides and triphenylphosphane allow theformation of homodimetallic complexes containing two ox-azole rings.

Thanks to these excellent results for the preparation offive-membered rings through the reactions of azides withtertiary phosphanes and acyl chlorides by the triazaphos-phadiene pathway,[27a] the method has also been success-fully used for the preparation of a homotrimetallic complexcontaining three oxazole units. The addition of tri-


phenylphosphane to a mixture of α-azidoacetylferrocene(22) and the acyl chloride 93 (Scheme 27) derived from1,3,5-benzenetricarboxylic acid, in the presence of polymer-supported BEMP, afforded the homotrimetallic complex94.[35]

Scheme 27. Star-shaped ferrocenyloxazole derivative.

The related homotrimetallic complexes 96 and 98(Scheme 28), in which the three ferrocene units are linkedby two oxazole rings, have also been prepared by use of1,1�-bis(chlorocarbonyl)ferrocene[36] (95) and (chloro-carbonyl)ferrocene[37] (97), respectively, as carbonyl compo-nents.[35]

The clear advantage of the approach described above isflexibility with respect to the tethering groups between themetal centres, which allows systematic variation of the elec-tronic structure and/or the length of the spacer betweensuch organometallic moieties and consequently permitsstudy of the redox behaviour of those oxazolo-ferrocene li-gands prepared.

The preparation of a series of new 4-(ferrocenyl)methyl-idene-2-aryloxazolones 100 (Scheme 29) by a related proto-col has also been reported.[38] In this case, the intermediate

P. Molina, A. Tárraga, M. AlfonsoMICROREVIEW

Scheme 28. Trisferrocenyloxazole derivatives.

imidoyl chlorides 99 undergo ring-closure through elimi-nation of ethyl chloride, as previously reported in the litera-ture.[2c,39]

Scheme 29. (Ferrocenyl)methylideneoxazolones.

Miscellany

The development of convenient synthetic routes to thepreviously unreported 1,n-diaza[n]ferrocenophane struc-tural motif, in which the two nitrogen atoms are linkedthrough a carbon chain, is an interesting research area. Anideal tool with which to build the diazaferrocenophaneframeworks is 1,1�-bis(isocyanato)ferrocene (101,Scheme 30), prepared from the corresponding 1,1�-ferro-cenedicarboxylic acid via its acyl derivative.[10] 1,1�-Bis(iso-cyanato)ferrocene (101) was thus treated with 2-(triphenyl-phosphoranylidene)aminopyridine (102)[40] in THF at 0 °Cto give the heteroligand 104 in 62% yield.[41] This unprece-dented structural motif can be regarded as an aza-contain-ing heterocycle 1,2-fused to a 1,3-diaza[3]ferrocenophane.The formation of 104 can be understood in terms of aninitial aza-Wittig reaction between one isocyanate moietyof 101 and 1 equiv. of the iminophosphorane 102 to give

Scheme 31. Ferrimidazole.


103 as highly reactive intermediate. This difunctionalisedcompound undergoes an intramolecular hetero-Diels–Aldercycloaddition, in which the heteroaryl carbodiimide moietyfunctions as a 1,3-diazabuta-1,3-diene, through one cumu-lative double bond and one carbon-nitrogen double bondof the pyridine ring, with the C=N bond of the remainingisocyanate group taking the role of the dienophile.[2e,42]

Scheme 30. Diaza[3]ferrocenophanes.

In an exploration of parameters that could influence thecourse of the reaction between the bis(isocyanate) 101 andthe iminophosphorane 102 it was found that under condi-tions similar to those described above, but with use ofshorter reaction times and addition of water to terminatethe reaction, the new [3]ferrocenophane 107 was isolated,although in only 10% yield, which did not improve underother different experimental conditions. The formation of107 could be explained in terms of the same highly reactiveintermediate 103, which could lead to 105a through hydrol-ysis of the remaining isocyanate group. The subsequent nu-cleophilic attack of the generated amino function on thecarbodiimide moiety would give rise to the formation of the[3]ferrocenophane framework.

Intimately related to the above results is the reportedpreparation of the new 2-arylamino-1,3-diaza[3]ferroceno-phane structural motif 110 (Scheme 31) by the aza-Wittigprotocol.[43] The formation of compound 110 could be ex-plained in terms of an initial aza-Wittig-type reaction be-tween one iminophosphorane group of compound 8a andone equivalent of the isocyanate to give the carbodiimide108, which could undergo cyclisation by nucleophilic attackof the nitrogen atom of the remaining iminophosphorane


moiety on the central carbon atom of the carbodiimidefunctionality to give the zwitterionic compound 109. Thisintermediate could undergo hydrolytic cleavage during theworkup to give 110. This mechanism is consistent withthose previously reported for aza-Wittig reactions of arylor vinyl bis(iminophosphoranes) with aryl isocyanates sub-stituted with electron-withdrawing groups.[44]

Acknowledgments

We gratefully acknowledge the financial support from the Minis-terio de Ciencia e Innovación (MICINN) (project CTQ2008-01402)and the Fundación Séneca, Agencia de Ciencia y Tecnología de laRegión de Murcia (project 04509/GERM/06; Programa de Ayudasa Grupos de Excelencia de la Región de Murcia, Plan Regional deCiencia y Tecnología 2007/2010).

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Received: January 24, 2011Published Online: May 27, 2011

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Preparation of Nitrogen-Substituted Ferrocene Derivatives by Aza-Wittig Methodologies