Mol Divers (2009) 13:399419 DOI 10.

1007/s11030-009-9136-x

REVIEW

One hundred years of Meldrums acid: advances in the synthesis of pyridine and pyrimidine derivatives
Victoria V. Lipson Nikolay Yu. Gorobets

Received: 26 December 2008 / Accepted: 25 February 2009 / Published online: 21 April 2009 Springer Science+Business Media B.V. 2009

Abstract A general review (138 references) focused on the recent advances in the application of Meldrums acid reactivity for synthesis of diverse pyridine and pyrimidine derivatives, mostly small and drug-like molecules is presented. Keywords Meldrums acid Pyridine Pyrimidine Azoloazines Tandem reactions Multicomponent cyclocondensations

Introduction One hundred years ago Scottish chemist Andrew Norman Meldrum synthesized a substance [1] that later obtained his name. To date Meldrums acid is one of the most useful reagents in the synthesis of heterocycles. In contrast to the great popularity of Meldrums acid, its discoverer remains almost unknown for the majority of chemists. Andrew Norman Meldrum [2] was born on 19th March, 1876, in a small burgh, Alloa, Scotland. In 1899 he received his B.Sc. with rst-class honors (chemistry) from the
V. V. Lipson State Institution V.Ya. Danilevsky Institute of Endocrine Pathology Problems, Academy of Medical Sciences of Ukraine, Artema St., 10, 61002 Kharkov, Ukraine e-mail: lipson@ukr.net V. V. Lipson N. Yu. Gorobets (B) Department of Chemistry of Heterocyclic Compounds, State Scientic Institution Institute for Single Crystals, National Academy of Sciences of Ukraine, Lenin Avenue, 60, 61001 Kharkov, Ukraine e-mail: gorobets@isc.kharkov.com N. Yu. Gorobets AG Limbach, Institute for Organic Chemistry, Free University of Berlin, Takustr. 3, 14195 Berlin, Germany

University of Aberdeen, where he worked as a research assistant with Francis Robert Japp [3]. Five years later he defended his D.Sc. thesis, entitled Avogadro and Dalton: The Standing in Chemistry of their Hypotheses, and in 1907 joined the laboratory of W. H. Perkin at the Victoria University of Manchester [4], and ultimately in 1912 the Indian Education Service. His rst appointment was as chair of chemistry at the Madhavlal Ranchodal Science Institute, Ahmedabad, and then in 1918 he proceeded to Bombay as professor of chemistry at the new Royal Institute of Science (University of Bombay), where he was also the principal from 1925 until his return to Edinburgh in 1931. In his rst independent publication [1], he studied the reaction between acetone and malonic acid and, following the suggestion of Prof. Japp, employed a mixture of acetic anhydride and sulfuric acid as condensing agent. From elemental analysis data, in conjunction with previous results and the acidic properties of the nal compound, he formulated the structure of the product to be -lactone of -hydroxyisopropylmalonic acid 1 (Scheme 1). Clearly, back then it was difcult to assign the correct chemical structure of product isolated from this reaction. For instance, the unusual CH acidity of Meldrums acid (pK a 4.83 in water) continues to be the focus of attention for research [5,6]. However, it was not until 1948, when more experimental data on the chemistry of this product were collected, that its correct structure was determined to be 2,2-dimethyl-4,6-diketo-1,3-dioxane 2 [7]. Prof. Meldrum also published several books regarding historical aspects of chemical science development (e.g., Avogadro and Dalton: The Standing in Chemistry of Their Hypotheses in 1906, and The Development of the Atomic Theory in 1920). He was the president of the chemical section of the Indian Science Congress (Lucknow, 1923) and editor of the Journal of Indian Chemical Society. In a detailed obituary his

123

400
O HO + HO O O Me O Me O 2 O Me Me HO O Me O 1 O HO O Me HO O Me Me O

Mol Divers (2009) 13:399419

Scheme 1 Meldrums acid synthesis

contemporary [2] remembered him as a very good professor and teacher of research. His Indian students and colleagues founded in his honer the Meldrum Memorial Prize, and his legacy is reected in the thousands of publications where 2,2-dimethyl-4,6-diketo-1,3-dioxane 2 is cited as Meldrums acid. The rst review on the chemistry of Meldrums acid by McNab [8] describes mostly the synthesis of derivatives via functionalization of the methylene group, and only a few reactions are mentioned where the 1,3-dioxane moeity is the reaction site. A more detailed literature survey [9] shows an enormous interest in Meldrums acid chemistry in the 1980s that continues to this century. Thus, recent reviews focused on more specialized subjects such as the role of Meldrums acid in multicomponent reactions [10], ash vacuum pyrolysis (FVP) techniques [11,12], and more recently in synthesis of natural products [13]. The aim of this review is to cover the role and impact of Meldrums acid and its derivatives when they have been used as building blocks for the construction of heterocyclic systems. To clearly illustrate this, and due to the considerable number of publications, we restricted the scope of this review to reactions leading to six-membered azoheterocycles, such as pyridine and pyrimidine derivatives, since these compound classes are of great importance in many elds, especially in pharmaceutical and drug discovery/medicinal chemistry [1419]. Consequently, we will primarily focus on literature concerning the synthesis of small drug-like molecules.

Meldrums acid as C1 -synthon In all cases where Meldrums acid acts as a C1 -synthon, introducing one carbon into the target heterocycle, this atom belongs to CH2 -group of the acid. Interestingly, in many cases the 1,3-benzodioxane ring survives the conditions applied for the heterocycle formation; for instance, a Biginelli-like three-component reaction with benzaldehydes and urea (Scheme 2) leads to spiro-pyrimidine compounds 6 instead of the expected products 5. This reaction proceeds smoothly with electron-withdrawing para-substituted benzaldehydes. In contrast, in the

presence of para-electron-donating groups, this leads to the exclusive formation of Knoevenagel adducts 7. Such difference in the reactivity was rationalized by the proposed cascade mechanism, where the rst stage can be a Knoevenagel condensation or a condensation of the aldehyde with urea (Scheme 2). In both cases, the electron-donating substituents should decrease the reaction rate and even stop the reaction on the following stage of the Michael-type addition [20]. Different conditions and catalysts were also applied for this kind of reaction [21,22]. An analogous known condensation is for -keto -lactams 8 [23,24], where Meldrums acid also works as one carbon atom supplier for the construction of the pyrimidine ring in the spirobicycle 9 (Scheme 3). This reaction type has also been described with the use of starting polymer-supported -keto- -lactams [23,24]. Formation of spiro-products was observed in the pyrrolidine-catalyzed reaction between Meldrums acid 2 and N,N-disubstituted 2-aminobenzaldehydes 10 (Scheme 4). Dyachenko et al. proposed that the reaction mechanism goes through a tandem Knoevenagel condensation and tertamino-effect cyclization, which leads to the formation of two new CC bonds in one stage, affording spiro-combined partially hydrogenated condensed quinolines 11 [25]. However, the Mtyus group described an analogous reaction between pyridazinecarbaldehyde 12 and Meldrums acid 2 as a two-stage process giving rst vinyl compounds 13 in nonpolar solvents under pyrrolidine catalysis (Scheme 5). The conjugates 13 were then converted into spiro-compounds 14 in polar solvents or in presence of Lewis acids [26,27]. These reaction types (Scheme 5) have also been reported to afford higher yields when performed under solvent-free conditions and microwave irradiation [28]. A literature survey indicates that similar condensation of aldehydes with ethyl malonate, ethyl cyanoacetate or malonodinitrile proceeds in the same two-stage manner via Knoevenagel adducts in nonpolar solvents, and the tertamino-effect cyclization occurs under heating in polar media [29,30]. In several recent publications devoted to this effect [3136], authors have studied these tandem transformations under various conditions (temperature, solvents), with diverse tertiary amine moieties, using hetero- and carbocyclic aldehydes, e.g., 5-dialkylaminopyrazol-4-carbaldehyde 15 (Scheme 6), and it can be concluded that these domino reactions are practically independent of the temperature and the polarity of the solvents applied, tertiary amine nature, and cyclic methylene component. Electron-withdrawing groups in the para-position to dialkylamino group in benzene ring decrease the cyclization rate into the spiro-compounds and lead to the isolation of Knoevenagel conjugates. In this way, for instance for the heterocyclic aldehydes 15 with pyridinelike nitrogen atom, the reaction proceeds as a two-stage process (Scheme 6).

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Mol Divers (2009) 13:399419 Scheme 2 Biginelli-like three-component condensation

HN Me O O 2 Me O + O O ArCHO + 3 H2N 4 Me O H2N N Ar O NH2 O N H O 5 O Ar Ar O

401

O Me Me

NH O NH O Ar 6

Me O Me O O 7 O Me O Me O O HN Ar NH2 O Me O O Ar Ar O Me O HN O N Ar Me O O

Scheme 3 Two-step one-carbon transfer in Biginelli-like condensation

O O R NH O O Ph OH + Me O O 2 Me O O R 1.DCC 2. O O Ph 8 N O
H2N

O
Ar

O H O NH2 Ar

HN O

NH
Ar

O N R 9 O O Ph
Me Me O O O

Scheme 4 Tandem Knoevenagel condensation and tert-amino-effect cyclization

2 + N

O O R X 10 R R

O O Me

i
N O X R

O Me N

R 11 32-85 %

X R

i pyrrolidine, toluene, heat

X=CH 2, (CH2 )2, CHPh, NPh, NMe, O, S R=H, Me

Scheme 5 Two-step Knoevenagel condensation and tert-amino-effect cyclization

O 2 + Me N N 12 O N X i Me N N

O O Alk O Alk N O X 13 ii Me N N

Alk O O O O N X O 14 Alk

X=CH2, (CH2)2, CH2O

53-76 %

i pyrrolidine, toluene, heat; ii AlCl3, xylene or DMF, heat

Scheme 6 Two-step Knoevenagel condensation and tert-amino-effect cyclization

Me 2 + N N N 15 i DMF, rt; ii 1-butanol, heat O i Ph N N

Me

O O Me ii

Me N N Ph

Me O Me

Ph

O 16

Me

O 17

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402 Scheme 7 Meldrums acid derivative in aza DielsAlder reaction

Mol Divers (2009) 13:399419

R1 R
2

X O + O

R1 N O O Me 18 R X = Ac, Ts
Ph O O O Me O Me O
3

X O N O O O O 19 Me Me

R1 R R
2

N CO2Me R
4

R3 R
4

O Me

20
Ph

Scheme 8 Transformations of spiro-cyclopropan derivative of Meldrums acid

SMe O + O O Me O Me

Ph N O 21

SMe +

i
O

SMe

22

O Me

23

O 24

Me

ii
SMe SMe N

SMe Ph 24 H+ O O Me O Me N SMe Ph O OH O O Me Me N O Ph O

iv
O O O 25 Me Ph 26

iii

CO2Me

Me

i 1) NaH, DMF, 80 C; 2) HCl, H2O; ii 1) DIBALH, toluene, 0 C; 2) HCl, H2O; iii TsOH, toluene, MeOH, reflux, 50 h; iv TsOH, toluene, MeOH, reflux, 5 days

An elegant synthesis of highly substituted pyridines 20 [37,38] based on the aza DielsAlder reaction of Meldrums acid derived oxyamines 18 with different dienes [39] shows the usage of such spiro-adducts 19 in heterocyclic synthesis (Scheme 7). The rst DielsAlder addition step is accomplished by simple heating in benzene, giving moderate yields of the adducts 19; however, much better yields were achieved in presence of Me2 AlCl as a Lewis acid promoter in dichloromethane at 78 C. The next step is achieved by the addition of sodium methylate and N-chlorosuccinimide to afford products 20 [37,38]. Another highly reactive Meldrums acid derivative 22 (Scheme 8) was shown to undergo a sequence of transformations, leading rst to two compounds in comparable yields (about 40%): the desired chain-extension product 23 and unexpected medium-ring fused pyrrole derivative 24 [40]. Since the anion 21 was generated by a great excess of sodium hydride, and the reduction of the product 23 with diisobutylaluminium hydride (DIBALH) led to formation of the medium ring 24, authors believed that the reduction of the benzoylpyrrol carbonyl function in 23 proceeded unusually by the action of the sodium hydride excess. Acid-catalyzed rearrangement of the middle ring in 24 leads to consequent formation of spiro-heterocycle 25 and pyrrolopyridine 26. Products 25 and 26 were obtained in moderate yields after laborious and long procedure, which decrease the synthetic value of these transformations. Nev-

ertheless, such transformations clearly illustrate the unusual reactive properties of Meldrums acid derivatives. Thus, one-carbon residue transfer of Meldrums acid involves formation of spiro-products or intermediates. Structure of these molecules supposes their interesting reactivity, which can probably be widely applied in the further synthesis of heterocycles. However, the chemical properties of such complex systems, containing the spiro-combined 1,3-dioxane and pyri(mi)dine fragments, are still not fully disclosed so far. Meldrums acid as C2 -synthon The utility of Meldrums acid reactivity as a C2 -synthon is based on the addition of electrophiles to the CH acidic function followed by intermolecular acylation with cleavage of the 1,3-benzodioxane ring and elimination of the acetone and carbon dioxide molecules. This scheme is illustrated by a recent example of the three-stage synthesis of piperidine2,4-dione 28 [41] (Scheme 9). Here, it is also possible to increase the molecular diversity of building blocks 27 and 28 by the selective 5-alkylation of tert-butyl 2,4-dioxopiperidine-1-carboxylate 27 with lithium hexamethyldisilazide (LiHMDS) [42]. This sequence and the same coupling conditions (Scheme 9, i) was described earlier, including also a reduction of the crude tri-carbonyl intermediates 30 into alkyl acids 31, which were converted under decarboxylative ring closure

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Mol Divers (2009) 13:399419 Scheme 9 Meldrums acid in synthesis of piperidin-2-one derivatives
Me Me O O NHBoc O COOH R
1

403
O O N O 27 Me Me O R
1

O COOH NHBoc

ii

Boc

iii
O 28 O Me Me O

NH

O O

iv
R
1

R1

NHBoc 29

O NHBoc 31

N O Boc 32

NHBoc

30

R2 O O

N O 33

O R3 34

R1, R2, R3= Alk N O

i Meldrums acid, DCM, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, DMAP, 0 C to rt; ii EtOAc, reflux; iii TFA, DCM, rt or 4N HCl in dioxane, rt; iv NaBH4 DCM/AcOH, 0 C; v toluene, 110 C

Scheme 10 Two-carbon transfer for annellation of heterocyclic system

N Cl 35

NH +

N N 36

i
HO 37

N N H

H N N

ii
HO O Me O Me

N N H O

H N

iii
N N N

N N 38

i NaOH, H2 O, 5-25 C; ii Meldrum's acid, EtOH, reflux; iii DMF, reflux

conditions into the chiral lactams 32 in high yields. The overall yields for this three-step reaction sequence from the Bocprotected amino acid 29 ranged between 59% and 94% [43]. The same group recently described the application of this strategy [44] for synthesis of disubstituted chiral -lactams 33 derived from aspartic acid. And the analogous protocol [45] was applied in the synthesis of tricycle 34 (Scheme 9). The additionacylation scheme may also be applied for the annellation of the existing heterocycle with additional six-membered aza ring. Thus, Saczewski and Gdaniec [46] described two-carbon residue transfer in the reaction with pseudo base 37 obtained from 2-chloroimidazoline 35 and phthalazine 36 (Scheme 10). Similarly to the pervious case (Scheme 9), the addition occurs under rather mild conditions compared with decarboxylative ring closure. This is one of the characteristic properties of Meldrums acid derivatives to give products containing the 1,3-dioxane ring under conditions of kinetic control and the decarboxylated product under tough conditions. To accomplish pyrimidine ring closure in the case of conformationally restricted anions 39 and 41 even higher temperature (Scheme 11) was required [47]. Dependent on the relative conguration of the reaction centers, formation of the pyrimidines can be accompanied by

rearrangement of the carbanion 41, leading to pyrimidine-2, 4-dione 43. Probably the most useful reactants derived from Meldrums acid are alkylidene or arylidene derivatives. They are applied as an alternative for equivalent acyclic malonic ester derivatives and often formed as intermediates in the multicomponent reactions with a use of aldehydes. In this way, a Knoevenagel reaction followed by intermolecular cyclization is reported [48] to lead to a variety of uracil derived carboxylic acids 45 (Scheme 12). There are also numerous reports that Knoevenagel adducts can act as dienes in hetero-DielsAlder reactions. A powerful methodology applying such interactions was proposed by Tietze et al. [49]. A multicomponent domino reaction (Scheme 13) between the aldehydes 46, Meldrums acid 2, and vinyl ethers in the presence of ethylenediammonium diacetate (EDDA) via cycloaddition of intermediate alkylidene Meldrums acid afforded a benzyl protected acetal 47. Subsequent hydrogenolysis of the benzyl acetal and Cbz protecting group with release of an amine and an aldehyde function, after the ring closure led to the highly substituted piperidines 48. Reliability of Meldrums acid in the two carbons transfer into azaheterocycles was repeatedly proven in total synthesis of alkaloids [13]. The listed examples show also that the

123

404 Scheme 11 Sterically controled pyrimidine ring closure

Mol Divers (2009) 13:399419

Ph Ph

H N N

O O O Li

Me Me

Ph N N

Ph

39 H N N O 41 Ph 42 Ph Ph N N

40 Ph N N

Me Me O Li

O Ph

O Ph

i
H

43

i vacuum pyrolysis 150-170 C to 280 C

O R2 O N X O R2

O X OH O

i
O

YH N R1 44

Y N 1 R 45

providing three carbon atoms into the product molecule; however, such reactions leading to pyri(mi)dine derivatives are unknown. Thus, different methylene derivatives of the acid play the role of the C3 -synthons in the three carbon transfer process. Thermal decomposition of (het)arylaminomethylene derivatives Arylaminomethylene Meldrums acid derivatives 49 can be easily obtained by a three-component reaction of the acid 2, orthoformates, and anilines. This method was initially introduced by the Polansky group [50], and these derivatives are most widely applied in the synthesis of quinolin-4-ones 47 (Scheme 14). For recent examples of such synthesis see [5157]. This transformation (Scheme 14) is performed by static pyrolysis in diphenyloxide at 260 C or under FVP conditions and proceeds via ketene intermediates 50. This mechanism is well described in reviews devoted to the FVP techniques [11]. However, this method works selectively for parasubstituted aromatic ring in the starting material 49. In a cases of meta-substituted derivatives, two possible regioisomers of the product 51 are formed, and the use of ortho-substituted ones is reported to be accompanied also by replacement of
Me O Me O Me O O n Cbz R2N OBn 47 48 N R2 R3 R1 Me O Me O O n R1

R1, R2 = H, Me, Et; X = CH, N; Y = NH, O i Meldrum's acid 2, piperidine, EtOH, reflux
Scheme 12 Knoevenage reaction followed by intermolecular cyclization

protected carboxylic function of the acid allows the nucleophilic addition of the methylene group under mild conditions, followed by intramolecular decarboxylative acylation at much higher temperature. It is an important feature that this 1,3-dioxane ring protection tolerates such basic and reductive condition as treatment with NaBH4 . These properties of the Meldrums acid moiety are extremely valuable for the design of reaction schemes that include two carbons transfer into the heterocyclic skeleton. Meldrums acid as C3 -synthon Looking at the structure of Meldrums acid, one would predict that it can be easily applied as a 1,3-bisacylating agent
Scheme 13 Tandem Knoevenagel and hetero DielsAlder reaction
R Cbz R2N
1

Me O O O n 46 n = 0, 1, 2 H +

2 O OBn

ii

O R3

i EDDA, ultra sounds, toluene, 50 C, 15 h; ii - Pd/C, H2, 1 bar, MeOH, rt, 24 h

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Mol Divers (2009) 13:399419 Scheme 14 General systhesis of quinolin-4-ones

405

Me O O 49

Me O O NH Ar Pyrolysis -CO2, -(CH3)2CO

O C C Ar N H 50

O O C Ar N R N H 51

Scheme 15 Two directions of pyrrolizis

N NH N N H O

O O Me O 52 Me 53
O N N N 57 Ar N N 58 H O

O FVP N N N N H N N + O 54
O N N 59 N N N N 60 H N

O NH R N N N H

R = H, Me
O

55

Fig. 1 Fused heterocycles obtained from heterocyclic aminomethylene Meldrums acids

O N S 56 N

N 61 H

R4 R3 R2 R1 N

Me

Me

O SO2NHR

MeO

N N H O

O O Me O 67 O O Me

O Dowtherm A 260 C 89 % 68 O N N N H Cl 72 N H O MeO N N H

i
N 62 Me N 63 N H

ii

Me

N 64

N H

i HSO3Cl; ii RNH2

Scheme 16 Versatile synthesis of pyridones and pyrimidones derived from 2-aminopyridine

MeO N 69 N H N 70 N H MeO

O O Me Me O O 65 N H N N H O

O O Me O Me

O Ph2O 250 C 91 % N N N H O 66

71 Dowtherm A - the mixture of Ph2O and Ph2

Scheme 18 Pyridopyridones obtained from 3- and 4-aminopyridine derivatives

Scheme 17 Simple route to triazaphenantrenes

the ortho-substituent [58]. In a recent detailed study of these transformations [59], the authors succeeded in the separation of the isomers derived from some meta-substituted arenes. Similar formation of two possible isomers is observed in the presence of particular asymmetric heterocyclic moieties in the amine fragment; for example, FVP of the aminomethylene compound 52 yielded a mixture of two 1,2,4-triazolopyrimidinones 53 and 54 (Scheme 15). The ratio of the isomers depended on the pyrolysis temperature. The major thermodynamic product 43 was obtained under 700 C and characterized as 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidin-7-one using 13 C nuclear magnetic resonance (NMR). The kinetic product 5,8-dihydro-1,2,4-triazolo[4,3-a]pyrimidin-5-one 54 was observed when lower temperatures were used [60]. At the same time in the case of pyrazole derivatives only formation of products 55 was observed [60,61]. The same thermal decomposition of aminomethylene Meldrums acids derived from different 2-amino azahetero-

cycles was shown to lead to corresponding fused thiazole 56 and pyridine 57 [62], pyrimidines 58 [63], pyrazine 59, benzimidazole 60, isomeric pyridine 61 [58], either in solution or in gas phase (Fig. 1). The two last products mentioned, however, were obtained only in quite small yield. Generally, it can be concluded from literature data that related 2-aminopyridine-derived Meldrums acids may be applied for synthesis of diverse pyrido[1,2-a]pyrimidin4-ones 62 [6466] and 1,8-naphthyridinones 63 and 64 [67, 68] depending on the substituents in the pyridine ring and the method of thermal decomposition. The generated diversity of such products is represented in Scheme 16. Interestingly, this combined formation of these two heterocycles in one reaction proceeds in the case of bis-adduct 65 (Scheme 17) that leads to formation of triazaphenantrene derivative 66 in very good yield [68]. Application of 3-amino-6-methoxypyridine in this scheme gives only isomer 68 (Scheme 18); however, by applying different blockingdeblocking strategies, the authors [69] developed synthetic routes to its regioisomer 69 and other derivatives 7072, poorly accessible by the direct classical way.

123

406
MeS O O O SMe O ArHN O O O X O Ph2O 260 C R N H 75 63-84% X
Me Me O O HO R N N O N H O O O O Me Me

Mol Divers (2009) 13:399419

O N N HO O HO HO 84 R = SMe, NH2 N H R

Me Me 73

Me Me 74 X = SMe, OEt, NH2

82 R = SMe 83 R = NH2

Scheme 19 5-bis(methylthio)methylene derivative in synthesis of quinolin-4-ones

Scheme 21 Annellation of pyrazole ring

Also, different aminopyridine derivatives with blocked position [59] were applied for synthesis of pyridopyridones, whose formation is not favorable in the course of classical cyclization of this type (Scheme 18). Application of 5-bis(methylthio)methylene derivative of Meldrums acid 73 (Scheme 19) in this strategy has even greater potential for diversity generation. This compound easily undergoes sequential nucleophilic displacement of SMe groups when reacting with amines or EtOH, leading to derivatives of general formula 74. Heating these compounds in Ph2 O allows formation of 2-functionalized quinalones 75 in very good yields [70]. Morpholine-derived 8-substituted quinolinones are useful as inhibitors of DNA-dependent protein kinase [71]. The recent study of the thermal decomposition of the precursor 76 showed [72] that, beside the direct formation of the target quinolone 78 from 77, there is an alternative pathway via intermediate 79 formed by the cleavage of the 1,3benzodioxane cycle with the second molecule of morpholine (Scheme 20). This conclusion was made since heating 76 with 1 mole equivalent of morpholine in diphenyl ether at 100 C gave 77, from which 78 was derived by raising the temperature to 250 C. However, under these conditions a by-product 80 was also formed. Monitoring the reaction by high-perforScheme 20 Two pathways to formation of 1,3-dioxane-4,6-dione thermal cleavage

mance liquid chromatography (HPLC) showed that 76 with 2 mole equivalents of morpholine at 100 C gave exclusively 77 after 1 h. Heating the mixture at 150 C for 16 h afforded 79, which at 250 C gave 78. An example where a heterocyclic moiety was annellated by the 4-pyridone ring is represented by the synthesis of pyrazolo[3,4-b]pyridine nucleosides 84 (Scheme 21) starting from disulde 73. Its reaction with corresponding aminopyrazole derivative followed by the substitution of the methyl mercaptane (a sequential nucleophilic substitution similar to ones outlined in Schemes 19 and 20) led to formation of the key intermediate 83 (Scheme 21) that underwent cyclization under quite mild conditions (DMF, 120 C) [73]. One example of such reactions with application of linear fragment in the amino group is described [74]. Isothiosemicarbazone derivative 85 transforms into pyrimidines 86 in diphenyl ether with very good yields (Scheme 22). In this work authors also postulated the formation of ketene intermediates, and this kind of molecules was isolated after ash vacuum thermolysis of Meldrums acids 74 (Scheme 19, with X = SMe, NHR, NMe2 , NEt2 ) at 700 C by collection of the gas-phase products 87ac (Scheme 23) in a cold trap at 50 C [75]. Having available the highly reactive cumulenes 87ac, authors applied them in the synthesis of diverse nitrogencontaining heterocycles, including pyri(mi)dine derivatives

Br HN O O O SMe O

Br HN N O O O

ii
Br N H 78 O N O

Me Me 76

iii
O

Me Me 77 N N N Br 79

ii

iv
O

v
O

O N H SMe 80

Ar

N H 81

N O

Br

i morpholine (2 equiv.), Ph2O, 90 C; ii Ph2O, 260 C; iii morpholine (2 equiv.), Ph2O, 200 C; iv polyphosphoric acid, 130 C; v cat. Pd(PPh3)4, K2CO3, ArB(OH)2, dioxane, 90 C

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Mol Divers (2009) 13:399419

407

R1 N N R2

SMe NH O O 85 O Me O Me R Ph2O 240 C 79-89 % R2 MeS

1

R2

OH O O Me +

R1 S N 101 CO2Me 103 R i

2

R1 S N O CO2Me

O N N N 86

O O Me

99

Scheme 22 Formation of pyrimidine ring using acyclic amino fragment

O R2

R1 S C + O N .. HO R
2

R1 S N CO2Me

8998, under mild conditions. The reaction begins from the attack of the ketene carbonyl function onto the more nucleophilic center of the corresponding 1,3-binucleophile, forming an intermediate 88, followed by its heterocyclization on the remaining nitrogen. In the case of 8-aminoquinalone, the formation of the C-acylated product 94a was rationalized by rearrangement of the initially formed intermediate of type 88. When the nucleophilic centers have similar reactivity, the formation of two isomers (90a and 91a, 97a and 98a) was observed. Thus, thermal decomposition of Meldrums acid derivatives 49 (Scheme 14) and 74 (Scheme 19) leads to highly reactive ketene intermediates and affords synthesis of diverse fused pyri(mi)dine derivatives under high-temperature conditions. Isolation of these intermediates provides even more exiting perspectives for their application in synthesis of heterocycles, using milder conditions. The use of 5-acyl derivatives of Meldrums acid Examples of the 5-acyl derivatives use for the C2 -transfer into 2-pyridone heterocycle are illustrated in Scheme 9. In these transformations the carbonyl group of the 5-acyl fragment was not involved in the heterocyclization and optionally
Scheme 23 Isolation of intermediate cumulenes as strategy for diverse fused heterocycles
O N N 95a-c O

H CO2Me O 102 100 i HCl (gas), ClCH2-CH2Cl

Scheme 24 Enantioselective synthesis of thiazoline-fused 2-pyridones

could be removed, if necessary, by reduction with NaBH4 . Here, we discuss the reactions where this carbonyl function acts as a reaction center, and the 5-acyl Meldrums acids 99 introduce three carbon atoms into forming heterocyclic core. Efcient enantioselective synthesis of thiazoline fused highly substituted 2-pyridinones 103 was suggested by the Almqvist group [76]. The cycloaddition of imine 101 with acyl-ketene 100 one-pot generated from the corresponding Meldrums acid derivatives 99 under acidic conditions leads to formation of the target products 102 in excellent yields (Scheme 24). This reaction has been further performed in solid-phase combinatorial format using polystyrene-supported thiazoline esters of type 101 [77]. Application of microwave-assisted organic synthesis allowed decrease of the reaction time from 2 days to a few minutes [78]. This reaction was used repeatedly by the same research group as a key step for the
O N N H R vi S N 96a-c vii O v C C C R N vi 87a-c iii O N NH R R N N 92a,b NH R R2 ii R4 R
3

O N N H R S N 97a-c O i N C NH Me C 88 N H R +

HN N S N 98a

O O N H N R

viii

NR

N H

NH R

N 89a-c Me

94a R= a - t -BuCH2 b - mesityl c - 2-t-BuPh N

O N N 93a,b

O N R + R2
3

R4 HN N N R1 90a

NH N R1 91a-c R

i 2-(methylamino)pyridine; ii 2-aminopyridines; iii 2-aminopyrimidines, iv 2-aminopyrazine v 8-aminoquinoline; vi 1-aminoisoquinoline; vii 2-aminothiazoline; viii 2-aminothiazole

123

408 Scheme 25 5-acyl Meldrums acid 99 in synthesis of policondensed 2-pyridones

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OMe OMe Me N 104 [4+2] Ph

i

OMe OMe 99 Ph + N O O 105 -H2O : O N Ph O Me

OMe OMe

106

106

+ C O

104 3

105 2

i MW, TFA, CH2Cl-CH2Cl

Scheme 26 Uracil derivatives from triuoroacetyl Meldrums acid
N 2 + O N CF3 107 OH i F3C O O 108 O ii O Me Me O N F3 C N HO Me Me X 109 iii F3C O N N Me Me X

i imidazole (1 equiv); ii N,N'-dimethyl(thio)urea; iii p-TsOH (cat.)

110 X=S, O

generation of diverse bioactive molecules from these thiazolo ring-fused 2-pyridones [7984]. Furthermore, this group has recently reported that dihydroisoquinoline 104 reacted with acyl Meldrums acids 99 under acidic, neutral, and basic conditions (Scheme 25) [85]. This study showed that the formation of 2-pyridone 105 was clearly favored by acidic medium. Neutral conditions resulted in more complex product mixtures, in which both 2-pyridone 105 and 1,3-oxazine-4-one 106 were observed by NMR analysis. Basic conditions allow formation of 106 with high yield. However, in presence of the triuoroacetic acid, 1,3-oxazine-4-one 106 was converted to a mixture of the 2-pyridone 105 and the starting 3,4-dihydroisoquinoline 104 in a 2:3 ratio. Thus, the role of the acid is not only to facilitate the dehydration step in the framework of the 2-pyridone formation, but also to provide conversion (Scheme 24) of the formed 1,3-oxazine-4-one 106 into the 2-pyridone 105. 6-Triuoromethyl(thio)uracil derivatives 110 can be easily obtained from triuoroacetyl Meldrums acid 108 (Scheme 26). The reaction with 1,3-dimethyl(thio)urea takes place under mild conditions in THF at room temperature during 24 h and gives the dihydrouracil derivative 109 with excellent yield [86]. Subsequent dehydration of 109 in toluene under reux with catalytic amounts of toluene- p-sulfonic acid affords 6-triuoromethyl(thio)uracil 110. The authors also referred trifluoroacetylketene to be an intermediate in formation of the pyrimidine 109 even at room temperature. Thus, an easy solution-phase generation of highly reactive intermediate acylketenes as a result of decarboxylative

decomposition of the 5-acyl Meldrums acid derivatives opens impressive opportunities for their utilization in heterocyclic synthesis. Also, it should be pointed out that these intermediates are formed at rather low temperature compared with the corresponding aminomethylene derivatives (Scheme 14). Combinations of Knoevenagel condensation with Michael addition We already mentioned the synthetic applications of Meldrums acid in Knoevenagel-type condensations (Scheme 12) and the use of the Knoevenagel adducts as heterodienes (Scheme 13). Owing to their structures, however, they can also be considered as Michael acceptors, and react with a variety of nucleophiles. At the same time, due to the CH acidity, Meldrums acid itself is one of the nucleophiles affording Michael adducts with unsaturated compounds. Such addition is observed in the reaction with arylidene thioacetomides 111 (Scheme 27). In the presence of organic base (piperidine or N-methylmorpholine) at room temperature this reaction leads to formation of salts 112. Further cyclization of this intermediate in boiling EtOH affords tetrahydropyridine salts 113 [87]. This reaction can be performed also in threecomponent format, starting directly from aromatic (heterocyclic or aliphatic) aldehydes 114, cyanothioacetamide 115 or its seleno-analog and Meldrums acid 2 in ethanol in the presence of excess N-methylmorpholine giving the same thiolates or selenolates 113, respectively. A multicomponent reaction between 4-methoxybenzaldehyde 114, malononit-

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Mol Divers (2009) 13:399419 Scheme 27 Thio(seleno)cyanoacetamide derivatives in KnoevenagelMichael reaction

409

R1 CN H2N 111 S Me 73-90 % CN R1CHO 114 + i Me O

R1 CN ii O 61-77 % CN 114 + CN R1 R1 CN N H SAlk O 117 N H NH2 R3 + S

R1 CN N H X 113 ii BH

O BH

O H2N 112 i

H2N X 115 R2

R1

N H

SAlk O 116

S 118 R1 = alk, Ar, Het; X = S, Se

i Meldrum's acid, EtOH, N-methylmorpholine, 25 C ii Meldrum's acid, EtOH, N-methylmorpholine, reflux

Scheme 28 Synthesis of thieno[2,3-b]pyridin-6-ones via phenylfminomethylidene Meldrums acid
O O Me Me O 119 O N H Ph + H 2N 111 S CN HOOC i 64 % O N H SH 120 CN

R 1O 2C O N H

NH2 COR2 S 121

i EtOH, KOH, rt, 24 h then HCl

Scheme 29 One-pot synthesis of ring-fused tetrahydro-2-pyridones

2 + R CHO + 114 i Et3N, MeCN, reflux
1

O n n NH N H O 122 R2 O Me O O 123 Me i NH R2 R
1

N H O

H N n N 83-93 % O

O R2 R1 124

rile, Meldrums acid 2, and sulfur under the aforementioned conditions also gives thiolates 113 [88]. Litvinov and coworkers [8792] used the salts 113 as a key intermediate for the synthesis of diversely alkylated tetrahydropyridine thiones 116, mercaptopyridones 117, and thienopyridones 118 (Scheme 27). Similarly, anilinomethylidene derivatives 119 react with thioamide 111 under more basic conditions (in the presence of KOH) and give acid 120 in good yield; however, decarboxylation in this case does not proceed (Scheme 28). Acid 120 is a substrate for synthesis of 7-H -thieno[2,3-b] pyridin-6-one derivatives 121, which are of interest as inhibitors of the ubiquitin C-terminal hydrolase-L1 [93,94]. Among a variety of binucleophiles used in the tandem Knoevenagel condensationMichael addition, enamines have been recently studied. A one-pot three-component reaction of heterocyclic ketene aminals 122, Meldrums acid 2, and aldehydes 114 resulted in formation of the

tetrahydropyridinone-fused 1,3-diazaheterocycles 124 in very good yields [95] (Scheme 29). The reaction started from condensation of Meldrums acid 2 and aldehyde 114. The resulting benzylidene derivative reacted with heterocyclic ketene aminal (probably in its imine form), giving the Michael adduct 123. Further cyclocondensation and decarboxylation afforded the nal product 124. It was found that the addition of triethylamine slightly improved the yield of the reaction, while the addition of the pyridine and ammonium acetate resulted in poorer yields. Aromatic aldehydes generally gave better yields then aliphatic ones. The substitution of the aromatic aldehydes also had some inuence on the yields. The reaction proceeded smoothly with electron-withdrawing para-substituted benzaldehydes. Other representative reactions of the pyri(mi)dine formation from Meldrums acid derivatives used as C3 -synthons can be roughly considered as analogues of Hantzsch or Biginelli multicomponent synthesis.

123

410

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Alk 2 + O COR2 125 + R1CHO 114 i NH4OAc 81-91 % O

R1 COR N H Alk 126

2

NH2 H 2 CO3 2 + RCHO + 114 H 2N NH 132 i HN H2 N

i DMF, heat or MW, 28-65%

N 133

i AcOH, heat or MW or other

Scheme 30 Hantzsch reaction using Meldrums acid
O 2 + O + ArCHO R AlkNH2 114 R 82-96 % 127 i Ar O R O N R Alk 128

Scheme 33 Biginelli-like reaction of Meldrums acid with guanidine and aldehydes

i EtOH, MW

R = H or Me

Scheme 31 Hantzsch reaction applying Meldrums Acid, 1,3cyclohexanedioned and alkylamides

Modied Hantzsch synthesis Many examples of modied Hantzsch reactions with use of Meldrums acid can be found in the literature. The fourcomponent reaction between Meldrums acid 2 dicarbonyl compound 125 (alkyl acetoacetates, acetylacetone, and dimedone were commonly used), and appropriate aldehydes 114 in presence of ammonium acetate leads to tetrahydropyridin2-ones 126 (Scheme 30). Such reactions were intensively studied because of the general interest to the nal dihydropyridines that attract attention as calcium-channel blockers and have recently been shown to be a new class of tumor drug-resistance reversers in cancer treatment [96]. This reaction (Scheme 30) consists of several steps with prior formation of two intermediates: the compound resulting from Knoevenagel condensation between Meldrums acid and benzaldehyde and the enamino ester produced from acetoacetate and ammonia. The key step of the overall cascade is the Michael-type addition of the enamino ester to the Knoevenagel product, followed by decarboxylative cleavage of the Meldrums acid ring. This modied Hantzsch synthesis was reproduced in a wide range of conditions, such as solution-phase synthesis (mostly in AcOH) [97101], microwave-assisted procedures [102104], including application of polymer-supported -ketoesters 125 [105] or using ionic liquid medium
Scheme 32 Synthesis oxygen-bridged pyridones by modied Hantzsch method

[106]. Application of microwaves also allowed introduction of an amine-derived diversity point into the dihydropyridine scaffold [107] (Scheme 31). However, the rst Hantzsch-like reaction involving Meldrums acid was described by the Svetlik group in 1990 [108]. Beside the use of usual aromatic aldehydes 114 in the reactions with methyl acetoacetate as outlined on the Scheme 30, they described the behavior of salicylaldehyde acetone Knoevenagel adduct 129 in this type of transformation (Scheme 32). In spite of the obvious fact that compounds of type 131 are of great interest as conformationally restricted analogues of the dihydropyridine calcium-channel blockers, since rst described this reaction has not been further developed.

Biginelli-type condensations Typically, Biginelli synthesis involves the three-component condensation of aldehydes, -ketoesters with urea, in protic solvents under strongly acidic conditions, to produce dihydropyrimidones with ester function in the 5-position. Amidines and compounds containing guanidine moiety as urea analogues were also applied as nucleophiles in this reaction; however, in this case the reaction has to be performed in two-component format starting from arylidene -ketoesters [109], probably due to the faster formation of the binary product between -ketoester and guanidine [110]. In contrast, Meldrums acid 2 reacts with aldehydes 114 and guanidine carbonate 132 (Scheme 33) under conventional or microwave heating in DMF giving the aminopyrimidinones 133 in moderate to good yields after a simple workup [111]. The primary aminogroup in pyrimidine ring 133 can be easily acylated by various electrophilic agents that can be utilized in synthesis of diverse heterocyclic compound libraries.

O 2 + Me HO 129 i NH4OAc, EtOH, reflux NH 2 O i O O O O 130 Me Me 27 % N O H 131 O

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Mol Divers (2009) 13:399419 Scheme 34 Condensations of arylmethylidene Meldrums acids with 3-amino-1,2,4-triazole
Ar O Ar O O Me + O Me 134 N 135 N NH NH2 ii i 47-71 % N N N N 137 H O HN N N H 20-45 % 139 N N NH + N 139 O N H

411

N NH N N H

Ar

Me

O O Me O Me

Ph

O O Me + 135 O Me ii

138

138

O O 136

i PhNO2, reflux; ii DMF or MeOH, reflux

Scheme 35 Two directions in three-component condensation of Meldrums acid, benzaldehydes, and methylthioamino-1,2,4-triazole
2 + ArCHO 114 + Me N NH S N 140 NH 2

Ar i Me S N N N 141 ii 141 ~ 35 % 142 + Me S N N N N H 30-63 % Ar N H O O 40-65 %

i DMF, refux; ii EtOAc, Py, reflux

Scheme 36 Cyclocondansation of 3,5-diamino-1,2,4-triazole with benzaldehydes and Meldrums acid

ArCHO 114 + H2N

O i N N N H 143 NH2 ii 144 + 20-24 % i MeOH or iso-PrOH, reflux; ii DMF, reflux H2N N N N 145 N H O ~ 50 % 2 H2N N N Ar Ar ii 2 H2N i N N N H 146 R N

N N 31-50 % 144 H

Variants of the Biginelli-like cascadeKnoevenagel Michael reactions involving the use of Meldrums acid, benzaldehydes or ketones and -aminoazoles as binucleophilic component have also been intensively studied, mostly by the Lipson group. The applied aminoazoles often have more than two different nucleophilic centers, and several types of products may be expected. Usually, the product structure of such multicomponent reactions is strongly dependent on the azole nature and reaction conditions applied. The condensation of arylmethylidene Meldrums acids 134, or its precursors (Meldrums acid and aldehydes), or synthetic equivalents (Michael adducts 136) with 3-amino1,2,4-triazole 135 in nitrobenzene leads to tetrahydro-1,2, 4-triazolo[1,5-a]pyrimidin-5-ones 137. In DMF or in MeOH the reaction proceeds with formation of ditriazole derivative 138 and acetyltriazole 139 [112] (Scheme 34). The propionamides 138 were found to possess antidiabetic properties in different insulin-resistance states in the condition of functional impairment of pancreatic beta-cells [113,114].

Cyclocondensation of the same carbonyl compounds with methylthio-amino-triazole 140 in DMF gives 2-methylthio4, 5, 6, 7-tetrahydro-1, 2, 4-triazolo [1,5-a]pyrimidin-5-ones 141. In EtOAc medium in the presence of catalytic amounts of pyridine, a mixture of 141 and its 7-oxo isomer 142 is formed, the latter product predominating (Scheme 35) [115]. Analogous behavior was observed for 3,5-diamino-1,2, 4-triazole 143. This triazole reacted with benzaldehydes and Meldrums acid or with Michael adducts of type 136 in alcohol media, leading to aryl-substituted tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones 144 (Scheme 36). At the same time, the mixture of isomers 144 and 145 was obtained when the reaction was carried out in DMF. Azomethynes 146 reacted similarly [116]. In the case of 3,4,5-triamino-1,2,4-triazole this reaction appears to lead to both regioisomers 147 and 148 in moderate yields independently of the conditions applied (reux in DMF or iso-PrOH, Fig. 2). It was shown also that diimine 149 acted as a source of the corresponding benzaldehyde [117].

123

412 Fig. 2 Products obtained from 3,4,5-triamino-1,2,4-triazole and 3-amino-1,2,4-triazoles

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Ar H2N N N N N Ar
Ar i

O H2N N N N N Ar N 148 Ar N N H2N N N

Ar N R N N N

O R2 N H R
1

N 147

Ar 149

150

R = SMe, NH2; R1, R2 = Me or -(CH2)5Me Me i N H NH2 156 HN N 157 N H O R

O NH N 151 NH2 + O O Me 134 ii Ar O Me

N N 152 N H O O

2 + RCHO + N 114

N N N 153 H Ar

R = Me, Ar, Het i PhNO2, DMF, MeOH, reflux

i PhNO2, 1 h, reflux; ii DMF, 10 min, reflux

Scheme 39 Three-component synthesis of pyrazolo[3,4-b]pyridones

Scheme 37 Two regioisomers from reaction with 2-aminobenzimidazol

Me

R1 R2

Ph N O NH2 N NH2 159

Ph N H2N N

Ar

Me 134 + N 154 i PhNO2, heat N Ar1 NH2 i

Me N N Ar1

Ar
HN N N 158 H

N H

O
Fig. 3 Products obtained in works [120, 122]

O N H 160

155 42-65%

Scheme 38 Synthesis of pyrazolo[3,4-b]pyridones

Selective formation of the 7-oxo isomer 150 was observed in the case of this type of three-component reaction with application of ketones instead of aldehydes. The reaction of 2-aminobenzimidazole 151 with the arylmethylidene derivatives of Meldrums acid 134 in PhNO2 and DMF (Scheme 37) was also found to lead to two regioisomers 152 and 153 correspondingly [118]. Summarizing these results, one could suggest that formation of 1,2,4-triazolo[1,5-a]pyrimidine-5-ones in highboiling-point solvents is a thermodynamically controlled process, and at the higher temperature the Michael addition occurs by the endo-cyclic nitrogen, resulting in the isomers 137, 141, 145, 147, and 152. At the same time, kinetic products 142, 144, 148, and 153 resulting from the addition by the exo-cyclic nitrogen are mainly formed under milder conditions. When the aminoazole has a nucleophilic CH group, it can be involved in the cascade reaction on the stage of the Michael addition. Such behavior of substituted 3(5)-aminopyrazoles was discussed in several papers. When the endo-cyclic aminogroup is blocked (Scheme 38, azoles 154), the formation of pyrazolopyridones 155 is only possible [119]. In the case of 3-amino-5-methylpyrazole 156 several alternative routs for formation of partially hydrogenated azine ring in such reactions can be expected, depending on the initial step of the Michael addition and following hetero-

cyclization. It was determined by the Lipson group that this three-component condensation (Scheme 39) in MeOH, DMF, or PhNO2 proceeds selectively and gives exclusively the 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine6-ones 157 [120]. Interestingly, in this reaction the arylmethylidene Meldrums acids cannot be considered as synthetic equivalents of similar malonic acid derivatives, since the reaction of benzylidene malonic acid with aminopyrazole 156 gives different products [120]. Analogous reaction with ketones instead of aldehydes 114 is also selective, and allows synthesis of tetrahydropyrazolo[3,4-b]pyridine-6-ones 158 both in MeOH and in DMF (Fig. 3). The secondary aminogroup in the pyrazole ring can be easily alkylated or acylated by various electrophilic agents, which might be employed in synthesis of diverse heterocyclic compounds libraries [121]. One could expect that application of diamine 159 in the reaction with aldehydes and Meldrums acid would lead to formation of corresponding fused pyrimidine or triazepine systems. However, this reaction was shown recently to give imidazo[5,1-b]pyridazin-2-one derivatives 160 (Fig. 3) in good yields (5260%) [122]. Application of Meldrums acid in cascade reactions combining Knoevenagel condensation with Michael addition is a powerful tool for fast generation of diverse pyridine and pyrimidine heterocyclic systems. The potential of the Hantzsch- and Biginelli-like multicomponent synthesis is so great because of both the diversity of different available 1,3binucleophiles and the possibility to control the direction of

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Mol Divers (2009) 13:399419

O HO R O O Me Nu-H O Me 99 O R C O R 162

413
O
O O

R2 CO2H R4 R1 R3 O R1 167 O NH R3 N 172 R1 O O O

R2 CO2H N 169 O R4 R3 N 170 CO2H R1 R2 CO2H Me

R4
Nu

161 Nu-H - alcohol, amine

R3

N 168 O NH

Scheme 40 General method for synthesis of -ketocarbonyl building-blocks

O R4 R3

R2

N 173 R
4

the condensation by the reaction conditions. The last feature allows application of the same starting materials for the synthesis of different products, which is a significant advantage for diversity-oriented research. Indirect transfer In this section, we will shortly review the use of Meldrums acid for synthesis of linear building blocks that can further be applied for pyri(mi)dine synthesis. Thus, the carbon atoms of the acid are indirectly transferred into the heterocyclic core. This strategy is widely applied in combinatorial diversityoriented synthesis. In this way, the triuoroacetyl derivative 108 (Scheme 26) was used also for synthesis of tret-butyl 4-triuoroethylacetoacetate (Scheme 40, 99, R = CF3 , Nu = t-BuO) [86] which can be used, for example, in Biginelli or Hantzsch multicomponent reactions for synthesis of hydrogenated pyrimidine or pyridine derivatives, correspondingly. Obviously, the cleavage of the 1,3-dioxane ring of such acyl derivatives by the action of nucleophiles is a general route to -ketocarboxylic acid derivatives 162 (Scheme 40). Many examples of application of this method using different N-nucleophiles [123126], including polymer-supported -amino acid esters [127] and O-nucleophiles [128131] are described in the literature. The mechanism of this transformation was studied in details by use of online IR reaction monitoring for kinetic studies [132]. This work clearly revealed that formation of -keto amides or esters from acyl Meldrums adducts proceeded via the -oxoketene intermediate 161 under different conditions. A versatile method for preparation of building blocks of type 164 derived from N-Boc--amino acids 163 was proposed [133]. It applies one equivalent of 4-dimethylaminopyridine (DMAP) and dicyclohexyl carbodiimide (DCC) for the coupling of Boc-protected amino acid 163 with Meldrums acid 2, and the products are isolated as DMAP salts 164 (Scheme 41). In contrast to the corresponding N-Boc--amino-5-acyl Meldrums acids (without DMAP counterion), which slowly decomposed in the solid state, salts 164 were shown to be shelf-storage stable during at least 6 months. The DMAP salts 164 can be transformed into the corresponding acetyl derivatives by treatment with an acidic polystyrene sulfonic acid cation exchange resin. The cleav-

R2

O R3 N N R3

N 171

Me

Fig. 4 Diversity of pyridines generated from polymer-supported -ketoester building-block

age with benzylamine followed by Boc-deprotection and N-acylation with (R)-()--methoxy--triuoromethylphenylacetic acid chloride allowed isolation of chiral diamides 166, proving the stereochemical integrity of the acyl derivatives 164 formation. To illustrate the application of this indirect transfer strategy for synthesis of pyri(mi)dines we will present several examples here. Polymersupported esters 167 (Fig. 4) were used intensively in sequential Hantzsch synthesis for the combinatorial generation of highly substituted pyridine libraries. Thus, resins 167 reacted with aldehydes (introduction of the R2 ) to obtain their corresponding arylidene derivatives, which further condensed with -ketoenomines (R3 and R4 ) to produce polymer-supported dihydropyridines, and the latter were further oxidized with ceric ammonium nitrate (CAN) into the target 2,2-bispyridines 168 and 169 after release from the resin [134]. Earlier, pyridines 170 and pyrido[2,3-d]pyrimidines 171 were obtained in this general way [135], and the same group published the similar strategy, but with use of amino-acidderived polymer-supported building blocks 167 and cyclactive cleavage at the nal step [136] applied for the generation of diverse pyrrolo[3,4-b]pyridines 172 and related pyridine-fused heterocycles 173 (Fig. 4). Also, such linear esters were used for the synthesis of compounds 172 (Scheme 42) that were in turn used for the modeling of DNA pyrimidine and protein aromatic amino acids photo-cross-linking and elucidation of the mechanism of this process [137]. Pyrone derivatives obtained form Meldrums acid may also play a role of pyridine precursors. A novel and efcient method for metacyclophanes 179 synthesis was developed by Sato and co-authors [138]. Mutual cycloaddition of two linked ketene moieties generated from bis (4, 6-dioxo1,3-dioxane)s 176 provided the cyclophanes 177 that were transformed into corresponding 2,6-dialkyl-4-pyrones 178

123

414 Scheme 41 N-Boc--amino-5acyl Meldrums acids as building-blocks for combinatorial synthesis

R2 N * COOH R1 163
1 2

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R2 OH O N * R1 O O

DMAP O Me Me ii iii Boc

Boc

Boc

R2 O N * R1

O iv NH v MeO O

R2 O N *

O NH

Ph 165 164 R , R -from diverse cyclic and lenear aminoacids i DCC, DMAP, CH2Cl2, 0 oC to rt; ii CH2Cl2 ion exchange, H+; iii PhCH2NH2, toluene, 70 C; iv TFA, CH2Cl2; v (R)-C6H5C(OCH3)(CF3)COCl, DIEA.

R1 Ph Ph CF3 166

Scheme 42 Modeling of DNA pyrimidine and protein aromatic amino acids photo-cross-linking

O i 99 Ar O O OEt ii HN O N H Ar 174 iii O HN

N H D

175

i EtOH, reflux; ii urea, DMSO, 155 C; iii 254 nm, CD3OD

R = H, OH

Scheme 43 Synthesis of pyridine metacyclophanes

O Me

O
n

O O Me O Me i

C O

O C O

OH O ii O O

O iii O (CH 2) n 178 R = H, Me

O Me

176 n = 8, 9, 10, 12, 18

(CH 2) n

(CH2 )n 177

N R (CH2 )n 179

i PhCl, reflux; ii EtOH or conc HCl, heat ; iii RNH2, EtOH,130 C

followed by interaction with ammonia or methylamine under tough conditions (Scheme 43). The indirect transfer strategy is not restricted to the presented examples. There are other approaches known for the synthesis of -ketocarboxylic acid derivatives, but the fact that Meldrums acid is used for this purpose in modern publications proves the advantage of this method over others.

Acknowledgements The authors would like to acknowledge DAAD (German Academic Exchange Service), Prof. H.-H. Limbach, and Dr. Ilja G. Shenderovich for an opportunity to conduct research at the Free University of Berlin provided by the DAAD grant.

References
1. Meldrum AN (1908) A -lactonic acid from acetone and malonic acid. J Chem Soc Trans 93:598601. doi:10.1039/CT9089300598 2. Forster MO (1934) Obituary notices: Andrew Norman Meldrum, 18761934. J Chem Soc 14761478. doi:10.1039/JR9340001468 3. Japp FR, Meldrum AN (1901) Homologues of anhydracetonebenzil. J Chem Soc Trans 79:10241042. doi:10.1039/ CT9017901024 4. Meldrum AN, Perkin WH Jr (1908) The cis- and trans-modications of 1-methylcyclohexan-2-ol-4-carboxylic acid and their conversion into 1 methyl- 1-cyclohexane-4-carboxylic acid. J Chem Soc Trans 93:14161428. doi:10.1039/CT9089301416 5. Byun K, Mo Y, Gao J (2001) New insight on the origin of the unusual acidity of Meldrums acid from ab initio and combined QM/MM simulation study. J Am Chem Soc 123:39743979. doi:10.1021/ja001369r 6. Arnett EM, Harrelson JA Jr (1987) Ion pairing and reactivity of enolate anions. 7. A spectacular example of the importance of rotational barriers: the ionization of Meldrums acid. J Am Chem Soc 109:809812. doi:10.1021/ja00237a028 7. Davidson D, Bernhard SA (1948) Structure of Meldrums supposed -lactonic acid. J Am Chem Soc 70:34263428. doi:10. 1021/ja01190a060 8. McNab H (1978) Meldrums acid. Chem Soc Rev 7:345358. doi:10.1039/CS9780700345

Conclusion Pyridines and pyrimidines, being among the simplest heterocycles, play a significant role in all basic vital functions of living beings. Their core structure is present in nucleotides and a great number of alkaloids. Consequently, it creates constant interest among scientists in synthetic approaches and high-throughput methods for diverse molecules belonging to these privileged scaffolds. Meldrums acid and its derivatives have been used in such syntheses for a long time, and the great number of publications devoted to this subject is evidence of its significant importance. Nevertheless, authors strongly believe that the synthetic potential of this reagent has not yet been fully uncovered, and we would consider the objectives of this review to have been achieved if it would help in the systematization and better understanding of the literature data collected to date, and possibly bringing new ideas to the eld.

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