Methods of synthesis of cyclobutenediones

Cyclobutenediones have been used as versatile starting materials for the synthesis of a wide range of multifunctional molecules. There have been continued efforts to develop general and practical methods to access the cyclobutenediones, which led to the discovery of several new methodologies over the last two decades. A review of various methods of synthesis of cyclobutenediones is presented.


Introduction
Cyclobutenediones are considered as quinones of unstable cyclobutadienes because of their formal resemblance to cyclobutadienes by virtue of all sp 2 hybridised carbons in a four membered ring. 1 Phenylcyclobutenedione was the first cyclobutenedione to be synthesized by J. D. Roberts et al. 1a in 1955.The initial studies on cyclobutenediones were limited primarily to their unusual stability, 1 reactivity toward nucleophiles 2 and aromaticity of their oxoanions. 3xtraction of moniliformin 1a, a fungal toxin, from Fusarium moniliforme by Cole et al. 4 led to the synthesis and testing of wide range of cyclobutenediones.Subsequently, a number of biological and pharmaceutical applications of cyclobutenediones were discovered.For example, the di-n-butylsquarate 1c (R = n-C 4 H 9 ) is a potent allergen and has been used in the treatment of alopecia areata, and in immunotherapy for warts in children. 5Squaric acid 1c (R = H) itself is an inhibitor of glyoxylase I, 6a semisquaric acid 1b is an inhibitor for pyruvate dehydrogenase and transketolase 6a and 1d is an inhibitor for PTPases (protein tyrosine phosphatases).6c Recently, the diamide of squaric acid 1e was used as a replacement for one of the phosphate diester linkages in an oligodeoxynucleotide, 7 while 1f as antagonist of the NMDA (N-methyl-D-aspartate) receptor. 8Also, some of the cyclobutenedione derivatives are useful as high-affinity ligands for exitatory amino acid receptors 9 and anion recognition systems. 10xtensive studies by Liebeskind,11 Moore, 12 Paquette 13 and others 14 have shown that cyclobutenediones are highly versatile starting materials for the synthesis of an array of multifunctional carbocyclic and heterocyclic compounds.Recently, squarate diamides have been used in the construction of chiral auxiliaries. 15Also, cyclobutenedione derivatives (squaraines) are used as NLO materials 16 and photoconductors. 17ethods of synthesis of cyclobutenediones reported before 1980 were already reviewed. 2ccordingly, in this review emphasis is on the methods developed in the last 2 decades.The methods of discussion are arranged under the following topics.

Scheme 14
Palladium chloride induced cyclodimerization of di-t-butoxyethyne leads directly to di-tbutyl squarate 1c (R = t-C 4 H 9 ) via intramolecular t-BuCl elimination (Scheme 15). 21-Bu A novel cycloaddition of nickel complex to alkyne was reported.It was found that an equimolar ratio of tetrakis(arylisocyanide)nickel and diphenylacetylene upon refluxing in toluene yielded di-iminocyclobutene 19, which after aqueous HCl work up gave diphenylcyclobutenedione (Scheme 16).

Scheme 16
Oxidation of tetrakis(diethylamino)cyclopentadienone 20 with bromine and aqueous work up affords a novel cyclobutenedione with an interesting functionality 22. 33

Scheme 17
It was reported that the FeCl 3 oxidation of ferrole complex formed in the reaction of acetylene with an alkaline solution of Fe(CO) 5 leads to cyclobutenedione in low yield (Scheme 18). 34

Scheme 18
Herrera et al. 35 reported that the nickelcyclopentenediones 23, prepared by reaction of (bpy)Ni(CO) 2 with alkyne in THF at 20 ºC, affords cyclobutenediones with maleic anhydride or carbon monoxide (Scheme 19).Nickel complex 23 can also be obtained from the reaction of (bpy)Ni(alkyne) with molecular CO.35a

Scheme 19
It was reported from this laboratory that the reaction of NaHFe(CO) 4 /CH 3 I reagent combination with alkynes at 60 ºC gives the corresponding cyclobutenediones along with unsaturated carboxylic acids after CuCl 2• 2H 2 O oxidation (Scheme 20).36a

Scheme 21
Also, it was observed that the [HFe 3 (CO) 11 ] -species, prepared in situ using Fe(CO) 5 /NaBH 4 /CH 3 COOH, reacts with alkynes to give the corresponding cyclobutenediones in good yields (60-73%) after CuCl 2• 2H 2 O oxidation (Equation 2). 37(CO) 5  NaBH 4 Further, it was found that the iron carbonyl species, prepared by the reduction of FeCl 3 /NaBH 4 in THF at 25 °C in the presence of CO, reacts with alkynes at room temperature to give a complex that gives the corresponding cyclobutenediones after CuCl

Cyclobutenediones from cyclopropene derivatives
Though, this is not a method of choice due to the difficulty associated with starting material preparation, cyclobutenediones could be obtained from cyclopropenones by ring expansion.Reaction of sodium trichloroacetate with dialkylcyclopropenone 25a under thermal conditions gives 5 via dichlorodialkylcyclobutenone (Scheme 23). 40

Scheme 23
Similarly, base hydrolysis of 25b directly gives the corresponding cyclobutenedione (Equation 5). 415) Also, it has been reported that isonitriles react with cyclopropenones to give cyclobutenedione in the presence of triphenylphosphine via iminocyclobutenone 26. 42The formation of 26 involves Michael addition of P(Ph) 3 to generate ketene-phosphorane followed by concerted rearrangement of P-C bonds as shown in Scheme 24.

Ph
Scheme 24

Cyclobutenediones from other simple cyclobutenediones
Synthesis of cyclobutenediones based on cycloaddition reactions is limited to either to squaric acid or aryl and simple alkyl derivatives.Hence, cyclobutenediones with a wide range of substituents have been synthesized from simple diones such as ynthesi, halo or alkoxy substituted cyclobutenediones by reacting with a variety of carbon as well as hetero atom nucleophiles.The underlying principle in all these reactions is the vinylogous behaviour of cyclobutenediones i.e. ynthesi, halo and alkoxy cyclobutenediones show the reactivity similar to that of acid, acid chloride and ester, respectively (Scheme 25). 2

Halogen derivatives of cyclobutenedione
It has been reported that the reaction of squaric acid with SOCl 2 in the presence of DMF leads to the replacement of both the OH groups to form dichlorocyclobutenedione in good yields 27 (Equation 6). 43Also, phenylcyclobutenedione is readily halogenated in glacial acetic acid (Equation 7).1b

Alkoxy derivatives of cyclobutenedione
Alkoxy derivatives of cyclobutenedione, squaric acid esters, have been synthesized from squaric acid following different strategies as outlined in Scheme 26.2d, 44 The chemical properties of squaric acid are mainly determined by its acid character and its reactivity is comparable to that of dicarboxylic acids.Ethyl or butyl alcohol treatment of squaric acid gives the corresponding diesters, whereas methanol gives monoester 30b.However, dimethylsquarate was synthesized by the action of diazomethane on 1b or by the reaction of methyl iodide with 30d.A similar reaction of halocyclobutenediones with alcohols give good yields of squaric acid esters (Scheme 27).2b,44b As described later in this section, dialkoxy squarates are extensively used in the synthesis of a variety of cyclobutenediones.

Amino derivatives of cyclobutenedione
Amine derivatives of cyclobutenedione are known as amides of squaric acid.44a Diamides of squaric acid 36 are prepared under more basic conditions using large excess of amine or by adding triethylamine (Scheme 31).2d Also, halocyclobutenediones react with amines but provide the corresponding amides 43 in lower yields. 49This reaction could also be performed in a buffered solution (pH 7), which is appropriate for biopolymers.Hence, this controlled nucleophilic substitution forms the basis for the use of diethyl squarate as a coupling reagent to conjugate oligosaccharides to proteins or polyazamacrocycles. 50Several biologically active and drug molecules such as 44a-44c have been synthesized following similar methods (Scheme 32).

Scheme 34
Also, dimethyl squarate undergoes nucleophilic substitution reaction with ortho and paraphenylenediamine to provide 49 and 50, respectively (Scheme 35

Scheme 35
Macrocyclic bridged squaric acid diamides of type 51-54 have been ynthesized in good yields by the reaction of 1,ω-diamines with 1,2-dimethoxycyclobutenedione under high dilution conditions (Scheme 36). 54Cryptands of type 55 are obtained from 1,2dimethoxycyclobutenedione and monocyclic crown ether amines.Recently, it has been reported that BF 3 .Et 2 O or H 2 SO 4 induces oxidation of some 4hydroxycyclobutenone 56a to furnish the corresponding cyclobutenediones 56 (Equation 8).

Alkyl, alkenyl, alkynyl and aryl derivatives of cyclobutenedione
Arylcyclobutenediones can be obtained by the reaction of halocyclobutenediones with renas under Friedel-Craft acylation conditions.Dichlorocyclobutenedione 27 affords either mono 29 or diarylcyclobutenediones 9 depending upon the amount of catalyst (AlCl 3 ), the molar ratio of reactants and reaction conditions (Scheme 37). 57,583-Amino-4-aryl-and 3-aryl-4-hydroxy-3-cyclobutene-1,2-diones have been obtained by the Meerwein arylation reaction of diazonium salts with squaramides and semisquaric acid, respectively (Equation 10). 60Functionalised cyclobutenediones were obtained by the reaction of squarates with compounds having acidic hydrogen on carbon atom in the presence of sodium alkoxide in alcoholic solution.For example, alkoxycyclobutenediones condense smoothly with diethylmalonoate and 1,3-diketones to afford 63 and 64 respectively. 63Also, diethylsquarate condenses with 2-methylpyrrole in acetic anhydride to form dipyrrolyl cyclobutenedione 65 (Scheme 41). 64 few simple alkyl derivatives of cyclobutenediones are prepared by the reaction of diethylsquarate 32 with Grignard reagents.These reactions proceed in lower yields. 67An efficient process was independently developed by Moore 68 and Liebeskind 69 via nucleophilic 1,2 addition of organolithium to dialkoxycyclobutenediones followed by hydrolysis of the resulting hydroxycyclobutenone 68 (Scheme 44).Also, differentially disubstituted cyclobutenediones 5 obtained through step-wise addition of two different alkyllithium reagents (Scheme 44, Path b). 69hese methods, which rely on the introduction of substituents on to cyclobutenedione core as organolithium nucleophiles, are restricted to substituents that are compatible with strongly basic and nucleophilic conditions.Liebeskind et al. 70  Also, a variety of acyl substituted cyclobutenediones were prepared following a similar strategy (Equation 12).71b Also, a reverse reaction of above methods has been reported in which cyclobutenediones act as halide partner of Stille cross-coupling, to give a broad array of substituted cyclobutenediones (Equation 14). 73 (14)  Analogous method for the preparation of highly functionalized cyclobutenediones was developed by Knochel et al. 75 based on zinc-copper reagents (Scheme 47).

Synthesis of benzocyclobutenediones
As discussed in section 1.2.7, some benzocyclobutenediones were prepared via Diels-Alder addition reactions of some dienes with olefins.Benzocyclobutenediones were also synthesized starting from certain aromatic compounds.Benzocyclobutenedione 78 was first synthesized by Cava et al. 76 using simple organic transformations from 1,2-diiodobenzocyclobutene as shown in Scheme 48.

55
C to 25 o CDichlorocyclobutenedione as well as bromophenylcyclobutenedione 29 condenses with electron rich olefins such as enamines, ketene acetals in the presence of triethylamine (Scheme 39).2b,61 Similarly, phosphrous and sulphur ylides react with 29 to give the products 61 and 62 with cyclobutenedione moiety acting as a stabilizing acceptor (Scheme 40).62