meldrum acid history
TRANSCRIPT
Mol Divers (2009) 13:399–419DOI 10.1007/s11030-009-9136-x
REVIEW
One hundred years of Meldrum’s acid: advances in the synthesisof 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 therecent advances in the application of Meldrum’s acid reac-tivity for synthesis of diverse pyridine and pyrimidine deriv-atives, mostly small and drug-like molecules is presented.
Keywords Meldrum’s acid · Pyridine · Pyrimidine ·Azoloazines · Tandem reactions ·Multicomponent cyclocondensations
Introduction
One hundred years ago Scottish chemist Andrew NormanMeldrum synthesized a substance [1] that later obtained hisname. To date Meldrum’s acid is one of the most usefulreagents in the synthesis of heterocycles. In contrast to thegreat popularity of Meldrum’s acid, its discoverer remainsalmost 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 receivedhis B.Sc. with first-class honors (chemistry) from the
V. V. LipsonState Institution “V.Ya. Danilevsky Institute of EndocrinePathology Problems”, Academy of Medical Sciences of Ukraine,Artema St., 10, 61002 Kharkov, Ukrainee-mail: [email protected]
V. V. Lipson · N. Yu. Gorobets (B)Department of Chemistry of Heterocyclic Compounds,State Scientific Institution “Institute for Single Crystals”,National Academy of Sciences of Ukraine, Lenin Avenue, 60,61001 Kharkov, Ukrainee-mail: [email protected]
N. Yu. GorobetsAG Limbach, Institute for Organic Chemistry, Free University of Berlin,Takustr. 3, 14195 Berlin, Germany
University of Aberdeen, where he worked as a researchassistant with Francis Robert Japp [3]. Five years later hedefended his D.Sc. thesis, entitled Avogadro and Dalton:The Standing in Chemistry of their Hypotheses, and in 1907joined the laboratory of W. H. Perkin at the Victoria Univer-sity of Manchester [4], and ultimately in 1912 the IndianEducation Service. His first appointment was as chair ofchemistry at the Madhavlal Ranchodal Science Institute,Ahmedabad, and then in 1918 he proceeded to Bombay asprofessor of chemistry at the new Royal Institute of Science(University of Bombay), where he was also the principalfrom 1925 until his return to Edinburgh in 1931.
In his first independent publication [1], he studied the reac-tion between acetone and malonic acid and, following thesuggestion of Prof. Japp, employed a mixture of acetic anhy-dride and sulfuric acid as condensing agent. From elemen-tal analysis data, in conjunction with previous results andthe acidic properties of the final compound, he formulatedthe structure of the product to be β-lactone of β-hydrox-yisopropylmalonic acid 1 (Scheme 1).
Clearly, back then it was difficult to assign the correctchemical structure of product isolated from this reaction.For instance, the unusual C–H acidity of Meldrum’s acid(pKa 4.83 in water) continues to be the focus of attentionfor research [5,6]. However, it was not until 1948, whenmore experimental data on the chemistry of this productwere collected, that its correct structure was determined tobe 2,2-dimethyl-4,6-diketo-1,3-dioxane 2 [7]. Prof. Meldrumalso published several books regarding historical aspects ofchemical 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). Hewas the president of the chemical section of the Indian Sci-ence Congress (Lucknow, 1923) and editor of the Journalof Indian Chemical Society. In a detailed obituary his
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400 Mol Divers (2009) 13:399–419
O
OHO
HO
+Me Me
O
O
OMe
MeO
O
O
OHO
HO
Me
Me
O
HOMe
OO
Me
1
2
Scheme 1 Meldrum’s acid synthesis
contemporary [2] remembered him as a very good professorand teacher of research. His Indian students and colleaguesfounded in his honer the Meldrum Memorial Prize, and hislegacy is reflected in the thousands of publications where2,2-dimethyl-4,6-diketo-1,3-dioxane 2 is cited as Meldrum’sacid.
The first review on the chemistry of Meldrum’s acid byMcNab [8] describes mostly the synthesis of derivatives viafunctionalization of the methylene group, and only a fewreactions are mentioned where the 1,3-dioxane moeity is thereaction site. A more detailed literature survey [9] showsan enormous interest in Meldrum’s acid chemistry in the1980s that continues to this century. Thus, recent reviewsfocused on more specialized subjects such as the role ofMeldrum’s acid in multicomponent reactions [10], flash vac-uum pyrolysis (FVP) techniques [11,12], and more recentlyin synthesis of natural products [13].
The aim of this review is to cover the role and impactof Meldrum’s acid and its derivatives when they have beenused as building blocks for the construction of heterocyclicsystems. To clearly illustrate this, and due to the consider-able number of publications, we restricted the scope of thisreview to reactions leading to six-membered azoheterocy-cles, such as pyridine and pyrimidine derivatives, since thesecompound classes are of great importance in many fields,especially in pharmaceutical and drug discovery/medicinalchemistry [14–19]. Consequently, we will primarily focus onliterature concerning the synthesis of small drug-like mole-cules.
Meldrum’s acid as C1-synthon
In all cases where Meldrum’s acid acts as a C1-synthon,introducing one carbon into the target heterocycle, this atombelongs to CH2-group of the acid. Interestingly, in manycases the 1,3-benzodioxane ring survives the conditionsapplied for the heterocycle formation; for instance, aBiginelli-like three-component reaction with benzaldehydesand urea (Scheme 2) leads to spiro-pyrimidine compounds 6instead of the expected products 5.
This reaction proceeds smoothly with electron-with-drawing para-substituted benzaldehydes. In contrast, in the
presence of para-electron-donating groups, this leads tothe exclusive formation of Knoevenagel adducts 7. Suchdifference in the reactivity was rationalized by the proposedcascade mechanism, where the first stage can be a Knoeve-nagel condensation or a condensation of the aldehyde withurea (Scheme 2). In both cases, the electron-donating sub-stituents should decrease the reaction rate and even stop thereaction on the following stage of the Michael-type addition[20]. Different conditions and catalysts were also applied forthis kind of reaction [21,22].
An analogous known condensation is for β-keto-γ -lactams 8 [23,24], where Meldrum’s acid also works asone carbon atom supplier for the construction of the pyrimi-dine ring in the spirobicycle 9 (Scheme 3).
This reaction type has also been described with the use ofstarting polymer-supported β-keto-γ -lactams [23,24].
Formation of spiro-products was observed in the pyrroli-dine-catalyzed reaction between Meldrum’s acid 2 andN,N-disubstituted 2-aminobenzaldehydes 10 (Scheme 4).D’yachenko et al. proposed that the reaction mechanism goesthrough a tandem Knoevenagel condensation and tert-amino-effect cyclization, which leads to the formation of twonew C–C bonds in one stage, affording spiro-combined par-tially hydrogenated condensed quinolines 11 [25].
However, the Mátyus group described an analogous reac-tion between pyridazinecarbaldehyde 12 and Meldrum’s acid2 as a two-stage process giving first vinyl compounds 13in nonpolar solvents under pyrrolidine catalysis (Scheme 5).The conjugates 13 were then converted into spiro-compounds14 in polar solvents or in presence of Lewis acids [26,27].
These reaction types (Scheme 5) have also been reportedto afford higher yields when performed under solvent-freeconditions and microwave irradiation [28].
A literature survey indicates that similar condensation ofaldehydes with ethyl malonate, ethyl cyanoacetate ormalonodinitrile proceeds in the same two-stage manner viaKnoevenagel adducts in nonpolar solvents, and the tert-amino-effect cyclization occurs under heating in polar media[29,30]. In several recent publications devoted to this effect[31–36], authors have studied these tandem transformationsunder various conditions (temperature, solvents), with diversetertiary amine moieties, using hetero- and carbocyclic alde-hydes, e.g., 5-dialkylaminopyrazol-4-carbaldehyde 15(Scheme 6), and it can be concluded that these domino reac-tions are practically independent of the temperature and thepolarity of the solvents applied, tertiary amine nature, andcyclic methylene component. Electron-withdrawing groupsin the para-position to dialkylamino group in benzene ringdecrease the cyclization rate into the spiro-compounds andlead to the isolation of Knoevenagel conjugates. In this way,for instance for the heterocyclic aldehydes 15 with pyridine-like nitrogen atom, the reaction proceeds as a two-stage pro-cess (Scheme 6).
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Mol Divers (2009) 13:399–419 401
Scheme 2 Biginelli-likethree-component condensation
OOMeMe
OO
+ ArCHO +O
NH2H2N
HN
NH
O
O
O
Me
Me
Ar
O
O
O
NH
NHO
Me
Me
O
O
Ar
Ar
23 4
5
6
O
H2N N
Ar
OOMeMe
OO
Ar
O
O
Me
Me
O
O
HN
Ar
NH2
OO
O
Me
Me
O
O
HN
Ar
N
OAr
7
Scheme 3 Two-step one-carbontransfer in Biginelli-likecondensation
OOMeMe
OO
2
R OH
O
NH
O O
+1.DCC
2. ∆N
O
O
R
O
O
PhPh
Ar H
O
H2N NH2
O
HN NH
NR
O
O
Ph
O
OOAr Ar
8 9
Scheme 4 TandemKnoevenagel condensation andtert-amino-effect cyclization
X=CH2, (CH2)2, CHPh, NPh, NMe, O, SR=H, Me
O
N
X
R
R
2 +
10
i
N
X
O
O
O
O
Me
Me
RR
N
X
OO
MeMeO
O
R
R
11
i pyrrolidine, toluene, heat32-85 %
Scheme 5 Two-stepKnoevenagel condensation andtert-amino-effect cyclization i
53-76 %X=CH2, (CH2)2, CH2O
2 + NN
O
O
N
X
Me
12
NN
O
N
Me
13
O
OO
O
X
Alk
Alkii
NN
N
X
OMe
O
O
Alk
AlkO
O
14
i pyrrolidine, toluene, heat; ii AlCl3, xylene or DMF, heat
Scheme 6 Two-stepKnoevenagel condensation andtert-amino-effect cyclization i2 + ii
17
NN O
Me
NPh
15
NN
Me
NPh
16
O
O
O
OMe
Me NN
N
O
OO
O
Me
MeMe
Ph
i DMF, rt; ii 1-butanol, heat
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402 Mol Divers (2009) 13:399–419
Scheme 7 Meldrum’s acidderivative in aza Diels–Alderreaction
R2
R3
R4
R1
+
O O
NO
X
OO
Me Me
NOX
X = Ac, Ts18
OO
O
O
Me
Me
R1
R4R3
R2
N
CO2Me
R1
R4R3
R2
19 20
Scheme 8 Transformations ofspiro-cyclopropan derivative ofMeldrum’s acid
NPh
O
SMe + O O
Me Me
OOi
O O
Me Me
OO
NPh
OSMe
+
N
Ph
OSMe
O
O OMe
Me21 22 23 24
ii
iii
N
Ph
OSMe
O
O OHMe
Me
N
SMe
Ph
O O
O O
Me Me
N
SMe
Ph
O O
O O
Me Me
iv N
SMe
Ph
CO2Me
H+
24
i 1) NaH, DMF, 80 °C; 2) HCl, H 2O; ii 1) DIBALH, toluene, 0 °C; 2) HCl, H2O;
iii TsOH, toluene, MeOH, reflux, 50 h; iv TsOH, toluene, MeOH, reflux, 5 days
25 26
An elegant synthesis of highly substituted pyridines 20[37,38] based on the aza Diels–Alder reaction of Meldrum’sacid derived oxyamines 18 with different dienes [39] showsthe usage of such spiro-adducts 19 in heterocyclic synthesis(Scheme 7).
The first Diels–Alder addition step is accomplished bysimple heating in benzene, giving moderate yields of theadducts 19; however, much better yields were achieved inpresence of Me2AlCl as a Lewis acid promoter in dichloro-methane at −78 C. The next step is achieved by the addi-tion of sodium methylate and N-chlorosuccinimide to affordproducts 20 [37,38].
Another highly reactive Meldrum’s acid derivative 22(Scheme 8) was shown to undergo a sequence of transforma-tions, leading first to two compounds in comparable yields(about 40%): the desired chain-extension product 23 andunexpected medium-ring fused pyrrole derivative 24 [40].Since the anion 21 was generated by a great excess of sodiumhydride, and the reduction of the product 23 with diisobutyl-aluminium hydride (DIBALH) led to formation of themedium ring 24, authors believed that the reduction of thebenzoylpyrrol carbonyl function in 23 proceeded unusuallyby the action of the sodium hydride excess.
Acid-catalyzed rearrangement of the middle ring in 24leads to consequent formation of spiro-heterocycle 25 andpyrrolopyridine 26. Products 25 and 26 were obtained inmoderate yields after laborious and long procedure, whichdecrease the synthetic value of these transformations. Nev-
ertheless, such transformations clearly illustrate the unusualreactive properties of Meldrum’s acid derivatives.
Thus, one-carbon residue transfer of Meldrum’s acidinvolves formation of spiro-products or intermediates. Struc-ture of these molecules supposes their interesting reactiv-ity, which can probably be widely applied in the furthersynthesis of heterocycles. However, the chemical proper-ties of such complex systems, containing the spiro-combined1,3-dioxane and pyri(mi)dine fragments, are still not fullydisclosed so far.
Meldrum’s acid as C2-synthon
The utility of Meldrum’s acid reactivity as a C2-synthon isbased on the addition of electrophiles to the C–H acidic func-tion followed by intermolecular acylation with cleavage ofthe 1,3-benzodioxane ring and elimination of the acetoneand carbon dioxide molecules. This scheme is illustrated bya recent example of the three-stage synthesis of piperidine-2,4-dione 28 [41] (Scheme 9). Here, it is also possible toincrease the molecular diversity of building blocks 27 and28 by the selective 5-alkylation of tert-butyl 2,4-dioxopi-peridine-1-carboxylate 27 with lithium hexamethyldisilazide(LiHMDS) [42].
This sequence and the same coupling conditions(Scheme 9, i) was described earlier, including also a reduc-tion of the crude tri-carbonyl intermediates 30 into alkyl acids31, which were converted under decarboxylative ring closure
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Mol Divers (2009) 13:399–419 403
Scheme 9 Meldrum’s acid insynthesis of piperidin-2-onederivatives
NHBoc
COOHO
OO
O
Me
MeO
NHBoc
i ii N
O
O
Boc iii NH
O
O
i Meldrum’s 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
28
NHBoc
COOH
R1
O
OO
O
Me
MeOi
NHBoc
R1
29
iv O
OO
O
Me
Me
NHBoc
R1
30
vN O
31
R1
Boc
32
N OR2
OO O
R3
33 34
N
O
R1, R2, R3= Alk
27
Scheme 10 Two-carbon transferfor annellation of heterocyclicsystem
35 36
N NH
Cl
+N
N iN
N
HO H N
HN
37
ii
N
N
38
N
N
iii
O
N
N
H N
HN
OO
O
HO
MeMe
i NaOH, H2O, 5-25 °C; ii Meldrum's acid, EtOH, reflux; i ii DMF, reflux
conditions into the chiral lactams 32 in high yields. The over-all yields for this three-step reaction sequence from the Boc-protected amino acid 29 ranged between 59% and 94% [43].The same group recently described the application of thisstrategy [44] for synthesis of disubstituted chiral δ-lactams33 derived from aspartic acid. And the analogous protocol[45] was applied in the synthesis of tricycle 34 (Scheme 9).
The addition–acylation scheme may also be applied forthe annellation of the existing heterocycle with additionalsix-membered aza ring. Thus, Saczewski and Gdaniec [46]described two-carbon residue transfer in the reaction withpseudo base 37 obtained from 2-chloroimidazoline 35 andphthalazine 36 (Scheme 10).
Similarly to the pervious case (Scheme 9), the addi-tion occurs under rather mild conditions compared withdecarboxylative ring closure. This is one of the characteris-tic properties of Meldrum’s acid derivatives to give productscontaining the 1,3-dioxane ring under conditions of kineticcontrol and the decarboxylated product under tough condi-tions.
To accomplish pyrimidine ring closure in the case of con-formationally restricted anions 39 and 41 even higher tem-perature (Scheme 11) was required [47].
Dependent on the relative configuration of the reactioncenters, 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 fromMeldrum’s acid are alkylidene or arylidene derivatives. Theyare applied as an alternative for equivalent acyclic malon-ic ester derivatives and often formed as intermediates inthe multicomponent reactions with a use of aldehydes. Inthis way, a Knoevenagel reaction followed by intermolecu-lar cyclization is reported [48] to lead to a variety of uracilderived carboxylic acids 45 (Scheme 12).
There are also numerous reports that Knoevenagel adductscan act as dienes in hetero-Diels–Alder reactions. A power-ful methodology applying such interactions was proposedby Tietze et al. [49]. A multicomponent domino reaction(Scheme 13) between the aldehydes 46, Meldrum’s acid 2,and vinyl ethers in the presence of ethylenediammoni-um diacetate (EDDA) via cycloaddition of intermediatealkylidene Meldrum’s acid afforded a benzyl protected acetal47. Subsequent hydrogenolysis of the benzyl acetal and Cbzprotecting group with release of an amine and an aldehydefunction, after the ring closure led to the highly substitutedpiperidines 48.
Reliability of Meldrum’s acid in the two carbons transferinto azaheterocycles was repeatedly proven in total synthesisof alkaloids [13]. The listed examples show also that the
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404 Mol Divers (2009) 13:399–419
Scheme 11 Sterically controledpyrimidine ring closure
NO
O
HN O
PhO
O
Me
Me
NO
OHNO
PhO
O
Me
Me
Li
Li
N
NPh
Ph
Ph
O
PhO
i
N
NO
PhO
PhH
i N
NO
PhO
Ph
39 40
41 42 43
i vacuum pyrolysis 150-170 °C to 280 °C
N
N
O
OR1
R2 X
YH
O i N
N
O
OR1
R2 X
Y O
OH
O
i Meldrum's acid 2, piperidine, EtOH, reflux
R1, R2 = H, Me, Et; X = CH, N; Y = NH, O
4544
Scheme 12 Knoevenage reaction followed by intermolecular cycliza-tion
protected carboxylic function of the acid allows the nucle-ophilic addition of the methylene group under mild condi-tions, followed by intramolecular decarboxylative acylationat much higher temperature. It is an important feature that this1,3-dioxane ring protection tolerates such basic and reduc-tive condition as treatment with NaBH4. These properties ofthe Meldrum’s acid moiety are extremely valuable for thedesign of reaction schemes that include two carbons transferinto the heterocyclic skeleton.
Meldrum’s acid as C3-synthon
Looking at the structure of Meldrum’s acid, one would pre-dict that it can be easily applied as a 1,3-bisacylating agent
providing three carbon atoms into the product molecule;however, such reactions leading to pyri(mi)dine derivativesare unknown. Thus, different methylene derivatives of theacid play the role of the C3-synthons in the three carbontransfer process.
Thermal decomposition of (het)arylaminomethylenederivatives
Arylaminomethylene Meldrum’s acid derivatives 49 can beeasily obtained by a three-component reaction of the acid2, orthoformates, and anilines. This method was initiallyintroduced by the Polansky group [50], and these derivativesare most widely applied in the synthesis of quinolin-4-ones47 (Scheme 14). For recent examples of such synthesis see[51–57].
This transformation (Scheme 14) is performed by staticpyrolysis in diphenyloxide at 260 C or under FVP conditionsand proceeds via ketene intermediates 50. This mechanismis well described in reviews devoted to the FVP techniques[11]. However, this method works selectively for para-substituted aromatic ring in the starting material 49. In a casesof meta-substituted derivatives, two possible regioisomers ofthe product 51 are formed, and the use of ortho-substitutedones is reported to be accompanied also by replacement of
Scheme 13 TandemKnoevenagel and heteroDiels–Alder reaction
R2N H
Oii
n
R1
OBnR3
i
OO
OO
Me Me
OBnR3
R2N R1
+
46 47 48
OO
OR3
N
Me Me
O
R1
R2
OO
OO
Me Me
2
n n
n = 0, 1, 2
i EDDA, ultra sounds, toluene, 50 °C, 15 h; ii - Pd/C, H2, 1 bar, MeOH, rt, 24 h
CbzCbz
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Mol Divers (2009) 13:399–419 405
Scheme 14 General systhesis ofquinolin-4-ones
OO
O O
MeMe
NH
-CO2, -(CH3)2COC
N
ArC
NH
Ar NH
O
Ar
PyrolysisR
49 50 51
OCO
Scheme 15 Two directions ofpyrrolizis N
N
NH
NH
52
N
N
N
NH
54OO
O
O
OMe
Me
FVP N
N
N
NH
O
53
+ N N
NH
O
R
R = H, Me 55
Fig. 1 Fused heterocyclesobtained from heterocyclicaminomethylene Meldrum’sacids S
N
N
O
56
N
N
O
57
NN
N
O
59N
N
NH
O
60
NNH
O
61
N
N NH
O
58Ar
N
N
O
62
R4
R3
R2
R1N N
H
O
63
Me
Me N NH
O
64
Me
Me
SO2NHRi
ii
i HSO3Cl; ii RNH2
Scheme 16 Versatile synthesis of pyridones and pyrimidones derivedfrom 2-aminopyridine
N NH
O
N
O
N NH
65
O
O
O
OMe
Me
NH
O
O
O
OMe
Me66
Ph2O
250 °C
91 %
Scheme 17 Simple route to triazaphenantrenes
the ortho-substituent [58]. In a recent detailed study of thesetransformations [59], the authors succeeded in the separationof the isomers derived from some meta-substituted arenes.
Similar formation of two possible isomers is observed inthe presence of particular asymmetric heterocyclic moietiesin the amine fragment; for example, FVP of the aminomethyl-ene compound 52 yielded a mixture of two 1,2,4-triazolopyri-midinones 53 and 54 (Scheme 15). The ratio of the isomersdepended on the pyrolysis temperature. The major “thermo-dynamic” product 43 was obtained under 700 C and charac-terized as 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidin-7-oneusing 13C nuclear magnetic resonance (NMR). The kineticproduct 5,8-dihydro-1,2,4-triazolo[4,3-a]pyrimidin-5-one54 was observed when lower temperatures were used [60].At the same time in the case of pyrazole derivatives onlyformation of products 55 was observed [60,61].
The same thermal decomposition of aminomethyleneMeldrum’s acids derived from different 2-amino azahetero-
N
NH
O
67
N
NH
O
O
O
OMe
Me68
89 %
Dowtherm A
MeO
260 °C
MeO
NNH
O
69
MeO
NNH
O
70
N
NH
O
71
MeO
N
NH
O
72
Cl
Dowtherm A - the mixture of Ph2O and Ph2
Scheme 18 Pyridopyridones obtained from 3- and 4-aminopyridinederivatives
cycles was shown to lead to corresponding fused thiazole56 and pyridine 57 [62], pyrimidines 58 [63], pyrazine 59,benzimidazole 60, isomeric pyridine 61 [58], either in solu-tion 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 thatrelated 2-aminopyridine-derived Meldrum’s acids may beapplied for synthesis of diverse pyrido[1,2-a]pyrimidin-4-ones 62 [64–66] and 1,8-naphthyridinones 63 and 64 [67,68] depending on the substituents in the pyridine ring and themethod of thermal decomposition. The generated diversityof such products is represented in Scheme 16.
Interestingly, this combined formation of these two het-erocycles in one reaction proceeds in the case of bis-adduct65 (Scheme 17) that leads to formation of triazaphenantrenederivative 66 in very good yield [68].
Application of 3-amino-6-methoxypyridine in this schemegives only isomer 68 (Scheme 18); however, by applying dif-ferent blocking–deblocking strategies, the authors [69]developed synthetic routes to its regioisomer 69 and other der-ivatives 70–72, poorly accessible by the direct classical way.
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406 Mol Divers (2009) 13:399–419
73
SMe
OO
O O
Me Me
MeS
74
X
OO
O O
Me Me
ArHN
X = SMe, OEt, NH2
Ph2O
260 °C NH
X
OR
63-84%
75
Scheme 19 5-bis(methylthio)methylene derivative in synthesis ofquinolin-4-ones
Also, different aminopyridine derivatives with blocked α-position [59] were applied for synthesis of pyridopyridones,whose formation is not favorable in the course of classicalcyclization of this type (Scheme 18).
Application of 5-bis(methylthio)methylene derivative ofMeldrum’s acid 73 (Scheme 19) in this strategy has evengreater potential for diversity generation. This compoundeasily undergoes sequential nucleophilic displacement ofSMe groups when reacting with amines or EtOH, leading toderivatives of general formula 74. Heating these compoundsin Ph2O allows formation of 2-functionalized quinalones 75in very good yields [70].
Morpholine-derived 8-substituted quinolinones are use-ful as inhibitors of DNA-dependent protein kinase [71]. Therecent study of the thermal decomposition of the precur-sor 76 showed [72] that, beside the direct formation of thetarget quinolone 78 from 77, there is an alternative path-way via intermediate 79 formed by the cleavage of the 1,3-benzodioxane cycle with the second molecule of morpholine(Scheme 20).
This conclusion was made since heating 76 with 1 moleequivalent of morpholine in diphenyl ether at 100 C gave77, from which 78 was derived by raising the temperatureto 250 C. However, under these conditions a by-product 80was also formed. Monitoring the reaction by high-perfor-
82 R = SMe83 R = NH2
NH
O
OO
O
Me
Me
R
NN
O
HO
O
OMe
Me
NN
NH
O
R
O
HO
HO 84
HO R = SMe, NH2
Scheme 21 Annellation of pyrazole ring
mance liquid chromatography (HPLC) showed that 76 with2 mole equivalents of morpholine at 100 C gave exclusively77 after 1 h. Heating the mixture at 150 C for 16 h afforded79, which at 250 C gave 78.
An example where a heterocyclic moiety was annellat-ed by the 4-pyridone ring is represented by the synthesis ofpyrazolo[3,4-b]pyridine nucleosides 84 (Scheme 21) startingfrom disulfide 73. Its reaction with corresponding aminopyr-azole derivative followed by the substitution of the methylmercaptane (a sequential nucleophilic substitution similar toones outlined in Schemes 19 and 20) led to formation of thekey intermediate 83 (Scheme 21) that underwent cyclizationunder quite mild conditions (DMF, 120 C) [73].
One example of such reactions with application of linearfragment in the amino group is described [74]. Isothiose-micarbazone derivative 85 transforms into pyrimidines 86 indiphenyl ether with very good yields (Scheme 22).
In this work authors also postulated the formation of keteneintermediates, and this kind of molecules was isolated afterflash vacuum thermolysis of Meldrum’s acids 74 (Scheme 19,with X = SMe, NHR, NMe2, NEt2) at 700 C by collectionof the gas-phase products 87a–c (Scheme 23) in a cold trapat −50 C [75].
Having available the highly reactive cumulenes 87a–c,authors applied them in the synthesis of diverse nitrogen-containing heterocycles, including pyri(mi)dine derivatives
Scheme 20 Two pathways toformation of1,3-dioxane-4,6-dione thermalcleavage
76
SMe
OO
O O
Me Me
HN
NH
N
OBr
i
77
N
OO
O O
Me Me
HNBr O
Br
ii
O
78
N
Br
N
O
N
O
O
79
iii
v
NH
SMe
O
Br
NH
N
O
Ar O8180
iv
ii
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
123
Mol Divers (2009) 13:399–419 407
MeS
NN
N
O
8679-89 %
240 °C
R1
R2
NH
SMe
OO
MeMe
OPh2O
NR1
R2N
O
85
Scheme 22 Formation of pyrimidine ring using acyclic amino fragment
89–98, under mild conditions. The reaction begins from theattack of the ketene carbonyl function onto the morenucleophilic center of the corresponding 1,3-binucleophile,forming an intermediate 88, followed by its heterocyclizationon the remaining nitrogen. In the case of 8-aminoquinalone,the formation of the C-acylated product 94a was rationalizedby rearrangement of the initially formed intermediate of type88. When the nucleophilic centers have similar reactivity, theformation of two isomers (90a and 91a, 97a and 98a) wasobserved.
Thus, thermal decomposition of Meldrum’s acid deriv-atives 49 (Scheme 14) and 74 (Scheme 19) leads to highlyreactive ketene intermediates and affords synthesis of diversefused pyri(mi)dine derivatives under high-temperature con-ditions. Isolation of these intermediates provides even moreexiting perspectives for their application in synthesis ofheterocycles, using milder conditions.
The use of 5-acyl derivatives of Meldrum’s acid
Examples of the 5-acyl derivatives’ use for the C2-transferinto 2-pyridone heterocycle are illustrated in Scheme 9. Inthese transformations the carbonyl group of the 5-acyl frag-ment was not involved in the heterocyclization and optionally
OO
OHR2
OO
Me Me99
+N
S
R1
CO2Me101
iN
S
O
R2R1
CO2Me103
R2
O
CO
H
N
S
R1
CO2Me
+.. N
S
R1
CO2MeO
HO
R2
100i
102
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 functionacts as a reaction center, and the 5-acyl Meldrum’s acids 99introduce three carbon atoms into forming heterocyclic core.
Efficient enantioselective synthesis of thiazoline fusedhighly substituted 2-pyridinones 103 was suggested by theAlmqvist group [76]. The cycloaddition of imine 101 withacyl-ketene 100 one-pot generated from the correspondingMeldrum’s acid derivatives 99 under acidic conditions leadsto formation of the target products 102 in excellent yields(Scheme 24).
This reaction has been further performed in solid-phasecombinatorial format using polystyrene-supported thiazolineesters of type 101 [77]. Application of microwave-assistedorganic synthesis allowed decrease of the reaction time from2 days to a few minutes [78]. This reaction was used repeat-edly by the same research group as a key step for the
Scheme 23 Isolation ofintermediate cumulenes asstrategy for diverse fusedheterocycles
87a-cNC
CC
O
R
N
N
O
NMe
H
R89a-c
i 2-(methylamino)pyridine; ii 2-aminopyridines; iii 2-aminopyrimidines, iv 2-aminopyrazinev 8-aminoquinoline; vi 1-aminoisoquinoline; vii 2-aminothiazoline; viii 2-aminothiazole
i
N
N
O
NHR
R4
R3
R2
R1
N
N
R4
R3
R2
R191a-c
O
HNR
+
90a
N
NHMe
C
O
CNR
N
N N
O
NHR92a,b
R
NN
N
O
NHR93a,b
iiiii
NH
O
NHRN
94a
v
95a-c96a-c
vi
vi
S
vii97a-c 98a
+
S
88
viii
R =-BuCH2
mesityl-t-BuPh
a - tb -c - 2
N
N
O
NH
RN
N
O
NH
RN
N
O
NH
RSN
N O
HNR
123
408 Mol Divers (2009) 13:399–419
Scheme 25 5-acyl Meldrum’sacid 99 in synthesis ofpolicondensed 2-pyridones
N
O
Ph
N
+N
O
O
PhMe
99
104 105 106
106[4+2]
O
PhCO
+ 104-H2O
105
3 : 2
i
i MW, TFA, CH2Cl-CH2Cl
OMeOMe
OMeOMe
OMeOMe
Me
Scheme 26 Uracil derivativesfrom trifluoroacetyl Meldrum’sacid
N
N2 +
O CF3107
iOH
F3C
O
O
O
OMe
Me108
i iN
N
O
X
Me
Me
F3CF3C
HO
109X=S, O
i i iN
N
O
X
Me
Me110
i imidazole (1 equiv); ii N,N'-dimethyl(thio)urea; iii p-TsOH (cat.)
generation of diverse bioactive molecules from these thiazoloring-fused 2-pyridones [79–84]. Furthermore, this group hasrecently reported that dihydroisoquinoline 104 reacted withacyl Meldrum’s acids 99 under acidic, neutral, and basic con-ditions (Scheme 25) [85]. This study showed that the forma-tion of 2-pyridone 105 was clearly favored by acidic medium.Neutral conditions resulted in more complex product mix-tures, in which both 2-pyridone 105 and 1,3-oxazine-4-one106 were observed by NMR analysis. Basic conditions allowformation of 106 with high yield. However, in presence of thetrifluoroacetic acid, 1,3-oxazine-4-one 106 was converted toa mixture of the 2-pyridone 105 and the starting 3,4-dihydro-isoquinoline 104 in a 2:3 ratio. Thus, the role of the acid isnot only to facilitate the dehydration step in the frameworkof the 2-pyridone formation, but also to provide conversion(Scheme 24) of the formed 1,3-oxazine-4-one 106 into the2-pyridone 105.
6-Trifluoromethyl(thio)uracil derivatives 110 can be eas-ily obtained from trifluoroacetyl Meldrum’s acid 108(Scheme 26). The reaction with 1,3-dimethyl(thio)urea takesplace under mild conditions in THF at room temperatureduring 24 h and gives the dihydrouracil derivative 109 withexcellent yield [86]. Subsequent dehydration of 109 in tolu-ene under reflux with catalytic amounts of toluene-p-sulfonicacid affords 6-trifluoromethyl(thio)uracil 110.
The authors also referred trifluoroacetylketene to be anintermediate in formation of the pyrimidine 109 even at roomtemperature.
Thus, an easy solution-phase generation of highly reac-tive intermediate acylketenes as a result of decarboxylative
decomposition of the 5-acyl Meldrum’s acid derivativesopens impressive opportunities for their utilization inheterocyclic synthesis. Also, it should be pointed out thatthese intermediates are formed at rather low temperaturecompared with the corresponding aminomethylene deriva-tives (Scheme 14).
Combinations of Knoevenagel condensationwith Michael addition
We already mentioned the synthetic applications of Mel-drum’s acid in Knoevenagel-type condensations (Scheme 12)and the use of the Knoevenagel adducts as heterodienes(Scheme 13). Owing to their structures, however, they canalso be considered as Michael acceptors, and react with avariety of nucleophiles. At the same time, due to the C–Hacidity, Meldrum’s acid itself is one of the nucleophilesaffording Michael adducts with unsaturated compounds.Such addition is observed in the reaction with arylidene thio-acetomides 111 (Scheme 27). In the presence of organic base(piperidine or N-methylmorpholine) at room temperature thisreaction leads to formation of salts 112. Further cyclization ofthis intermediate in boiling EtOH affords tetrahydropyridinesalts 113 [87]. This reaction can be performed also in three-component format, starting directly from aromatic (hetero-cyclic or aliphatic) aldehydes 114, cyanothioacetamide 115or its seleno-analog and Meldrum’s acid 2 in ethanol in thepresence of excess N-methylmorpholine giving the same thi-olates or selenolates 113, respectively. A multicomponentreaction between 4-methoxybenzaldehyde 114, malononit-
123
Mol Divers (2009) 13:399–419 409
Scheme 27 Thio(seleno)cyanoacetamidederivatives inKnoevenagel–Michael reaction
H2N
R1
CN
S
i O
O
O
Me
Me
R1
CN
XH2NONH
R1
O
CN
X
73-90 %
R1CHO +
CN
XH2Ni
CN
CN+ + S
R1 = alk, Ar, Het;X = S, Se
61-77 %BH111 112
ii
BH
113
114 115
114 ii
i Meldrum's acid, EtOH, N-methylmorpholine, 25 °Cii Meldrum's acid, EtOH, N-methylmorpholine, reflux
NH
R1
O
R2
SAlk
116
NH
R1
O
CN
SAlk
117
NH
R1
O
118
S
NH2
R3
Scheme 28 Synthesis ofthieno[2,3-b]pyridin-6-ones viaphenylfminomethylideneMeldrum’s acid
CN
SH2N
O
O
O
Me
MeO
NH
Ph
+i
NH
HOOC
O
CN
SH64 %
i EtOH, KOH, rt, 24 h then HCl
119 111 120
NH
O
121
S
NH2
COR2R1O2C
Scheme 29 One-pot synthesisof ring-fusedtetrahydro-2-pyridones
NH
NH
2 +iO
R2114 122
+
NH
NH
O
R2
R1
OO
O
O
MeMe
N
HN
O
R1
O
R2n
123
n
n
124i Et3N, MeCN, reflux
83-93 %
R1CHO
rile, Meldrum’s acid 2, and sulfur under the aforementionedconditions also gives thiolates 113 [88]. Litvinov and co-workers [87–92] used the salts 113 as a key intermediate forthe synthesis of diversely alkylated tetrahydropyridine thi-ones 116, mercaptopyridones 117, and thienopyridones 118(Scheme 27).
Similarly, anilinomethylidene derivatives 119 react withthioamide 111 under more basic conditions (in the pres-ence 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 inhib-itors of the ubiquitin C-terminal hydrolase-L1 [93,94].
Among a variety of binucleophiles used in the tan-dem Knoevenagel condensation–Michael addition, enamineshave been recently studied. A one-pot three-componentreaction of heterocyclic ketene aminals 122, Meldrum’sacid 2, and aldehydes 114 resulted in formation of the
tetrahydropyridinone-fused 1,3-diazaheterocycles 124 invery good yields [95] (Scheme 29).
The reaction started from condensation of Meldrum’s acid2 and aldehyde 114. The resulting benzylidene derivativereacted with heterocyclic ketene aminal (probably in its imineform), giving the Michael adduct 123. Further cycloconden-sation and decarboxylation afforded the final product 124. Itwas found that the addition of triethylamine slightly improvedthe yield of the reaction, while the addition of the pyridineand ammonium acetate resulted in poorer yields. Aromaticaldehydes generally gave better yields then aliphatic ones.The substitution of the aromatic aldehydes also had someinfluence on the yields. The reaction proceeded smoothlywith electron-withdrawing para-substituted benzaldehydes.
Other representative reactions of the pyri(mi)dine for-mation from Meldrum’s acid derivatives used as C3-syn-thons can be roughly considered as analogues of Hantzsch orBiginelli multicomponent synthesis.
123
410 Mol Divers (2009) 13:399–419
2 + R1CHO+O
Alk
COR2
125
114 NH4OAc
i
NH
O
R1
COR2
Alk81-91 % 126
i AcOH, heat or MW or other
Scheme 30 Hantzsch reaction using Meldrum’s acid
2 + ArCHO+
127
114 AlkNH2
i
NO
Ar
82-96 % 128
i EtOH, MW R = H or Me
O
OR
R
R
R
O
Alk
Scheme 31 Hantzsch reaction applying Meldrum’s Acid, 1,3-cyclohexanedioned and alkylamides
Modified Hantzsch synthesis
Many examples of modified Hantzsch reactions with use ofMeldrum’s acid can be found in the literature. The four-component reaction between Meldrum’s acid 2 dicarbonylcompound 125 (alkyl acetoacetates, acetylacetone, and dime-done were commonly used), and appropriate aldehydes 114in presence of ammonium acetate leads to tetrahydropyridin-2-ones 126 (Scheme 30).
Such reactions were intensively studied because of thegeneral interest to the final dihydropyridines that attract atten-tion as calcium-channel blockers and have recently beenshown to be a new class of tumor drug-resistance revers-ers in cancer treatment [96]. This reaction (Scheme 30)consists of several steps with prior formation of two inter-mediates: the compound resulting from Knoevenagel con-densation between Meldrum’s acid and benzaldehyde andthe enamino ester produced from acetoacetate and ammo-nia. The key step of the overall cascade is the Michael-typeaddition of the enamino ester to the Knoevenagel product,followed by decarboxylative cleavage of the Meldrum’s acidring. This modified Hantzsch synthesis was reproduced ina wide range of conditions, such as solution-phase synthe-sis (mostly in AcOH) [97–101], microwave-assisted pro-cedures [102–104], including application of polymer-sup-ported β-ketoesters 125 [105] or using ionic liquid medium
2 + RCHO
114
H2CO3
+ i HN
N OH2N
R
132
133i DMF, heat or MW, 28-65%
NHH2N
NH2
Scheme 33 Biginelli-like reaction of Meldrum’s acid with guanidineand aldehydes
[106]. Application of microwaves also allowed introductionof an amine-derived diversity point into the dihydropyridinescaffold [107] (Scheme 31).
However, the first Hantzsch-like reaction involvingMeldrum’s acid was described by the Svetlik group in 1990[108]. Beside the use of usual aromatic aldehydes 114 inthe reactions with methyl acetoacetate as outlined on theScheme 30, they described the behavior of salicylaldehyde–acetone Knoevenagel adduct 129 in this type of transforma-tion (Scheme 32).
In spite of the obvious fact that compounds of type 131are of great interest as conformationally restricted analoguesof the dihydropyridine calcium-channel blockers, since firstdescribed this reaction has not been further developed.
Biginelli-type condensations
Typically, Biginelli synthesis involves the three-componentcondensation of aldehydes, β-ketoesters with urea, inprotic solvents under strongly acidic conditions, to producedihydropyrimidones with ester function in the 5-position.Amidines and compounds containing guanidine moiety asurea analogues were also applied as nucleophiles in this reac-tion; however, in this case the reaction has to be performed intwo-component format starting from arylidene β-ketoesters[109], probably due to the faster formation of the binary prod-uct between β-ketoester and guanidine [110]. In contrast,Meldrum’s acid 2 reacts with aldehydes 114 and guanidinecarbonate 132 (Scheme 33) under conventional or microwaveheating in DMF giving the aminopyrimidinones 133 in mod-erate to good yields after a simple workup [111].
The primary aminogroup in pyrimidine ring 133 can beeasily acylated by various electrophilic agents that can be uti-lized in synthesis of diverse heterocyclic compound libraries.
Scheme 32 Synthesisoxygen-bridged pyridones bymodified Hantzsch method
2 +
i NH4OAc, EtOH, reflux
HO
O
Me
129NH2
O
O
O
O
O
Me
Me
130
O
NH
O
i
131
27 %
123
Mol Divers (2009) 13:399–419 411
Scheme 34 Condensations ofarylmethylidene Meldrum’sacids with3-amino-1,2,4-triazole
O
OO
O
Ar Me
Me+
N
N
NH
NH2
iN
N
N
NH
O
Ar
134 135
137
47-71 %
ii
20-45 %
N
N
NH
NH
Ar O
NH
HN
N
N
138
+N
N
NH
NH
O
Me
139Ph
O
OO
O
O
OO
O
Me
Me
Me
Me136
+ 135 ii 138 139+
i PhNO2, reflux; ii DMF or MeOH, reflux
Scheme 35 Two directions inthree-component condensationof Meldrum’s acid,benzaldehydes, andmethylthioamino-1,2,4-triazole
N
N
N
NH
O
Ar
1412 +
114
+N
N
NH
NH2SMe
i SMe
140
40-65 %
ii141 +
N
N
N
NH
Ar
O
142
SMe
30-63 %
~ 35 %
ArCHO
i DMF, refux; ii EtOAc, Py, reflux
Scheme 36 Cyclocondansationof 3,5-diamino-1,2,4-triazolewith benzaldehydes andMeldrum’s acid
N
N
N
NH
Ar
O
144N
NH
N
NH2H2N
H2N
143
31-50 %
+N
N
N
NH
O
Ar
145
H2N
~ 50 %
20-24 %
N
NH
N
NH2N
R2
114
+ArCHO
i
ii 144
i
ii
2
146
i MeOH or iso-PrOH, reflux; ii DMF, reflux
Variants of the Biginelli-like cascade–Knoevenagel–Michael reactions involving the use of Meldrum’s acid, benz-aldehydes or ketones and α-aminoazoles as binucleophiliccomponent have also been intensively studied, mostly by theLipson group. The applied aminoazoles often have more thantwo different nucleophilic centers, and several types of prod-ucts may be expected. Usually, the product structure of suchmulticomponent reactions is strongly dependent on the azolenature and reaction conditions applied.
The condensation of arylmethylidene Meldrum’s acids134, or its precursors (Meldrum’s acid and aldehydes), orsynthetic equivalents (Michael adducts 136) with 3-amino-1,2,4-triazole 135 in nitrobenzene leads to tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5-ones 137. In DMF or in MeOHthe reaction proceeds with formation of ditriazole derivative138 and acetyltriazole 139 [112] (Scheme 34). The propiona-mides 138 were found to possess antidiabetic properties indifferent insulin-resistance states in the condition of func-tional impairment of pancreatic beta-cells [113,114].
Cyclocondensation of the same carbonyl compounds withmethylthio-amino-triazole 140 in DMF gives 2-methylthio-4, 5, 6, 7-tetrahydro-1, 2, 4-triazolo [1,5-a]pyrimidin-5-ones141. In EtOAc medium in the presence of catalytic amountsof pyridine, a mixture of 141 and its 7-oxo isomer 142 isformed, 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 andMeldrum’s acid or with Michael adducts of type 136 in alco-hol media, leading to aryl-substituted tetrahydro-1,2,4-triaz-olo[1,5-a]pyrimidin-7-ones 144 (Scheme 36). At the sametime, the mixture of isomers 144 and 145 was obtained whenthe reaction was carried out in DMF. Azomethynes 146reacted similarly [116].
In the case of 3,4,5-triamino-1,2,4-triazole this reactionappears to lead to both regioisomers 147 and 148 in moder-ate yields independently of the conditions applied (reflux inDMF or iso-PrOH, Fig. 2). It was shown also that diimine 149acted as a source of the corresponding benzaldehyde [117].
123
412 Mol Divers (2009) 13:399–419
Fig. 2 Products obtained from3,4,5-triamino-1,2,4-triazoleand 3-amino-1,2,4-triazoles N
N
N
N O
Ar
H2NN
N
N
N Ar
O
H2N
N
Ar
N
Ar
N
N
N
NH2N
N
147
Ar
Ar148 149
N
N
N
NH
O
R R2
R1
R = SMe, NH2; R1, R2 = Me or -(CH2)5-
150
O
OO
O
Me
Me
Ar
134
+N
NH
NH2
151
152
153
N
N
NH
N
N
NH
O
O
Ar
Ar
i
ii
i PhNO2, 1 h, reflux; ii DMF, 10 min, reflux
Scheme 37 Two regioisomers from reaction with 2-aminobenzimidazol
134 +N
N
NH2
Me
Ar1 154
i
NN
NH
Me
Ar1 155
O
Ar
42-65%i PhNO2, heat
Scheme 38 Synthesis of pyrazolo[3,4-b]pyridones
Selective formation of the 7-oxo isomer 150 was observedin the case of this type of three-component reaction withapplication of ketones instead of aldehydes. The reaction of2-aminobenzimidazole 151 with the arylmethylidene deriva-tives of Meldrum’s acid 134 in PhNO2 and DMF (Scheme 37)was also found to lead to two regioisomers 152 and 153correspondingly [118].
Summarizing these results, one could suggest thatformation of 1,2,4-triazolo[1,5-a]pyrimidine-5-ones in high-boiling-point solvents is a thermodynamically controlledprocess, and at the higher temperature the Michael additionoccurs by the endo-cyclic nitrogen, resulting in the isomers137, 141, 145, 147, and 152. At the same time, “kinetic”products 142, 144, 148, and 153 resulting from the additionby the exo-cyclic nitrogen are mainly formed under milderconditions.
When the aminoazole has a nucleophilic CH group, it canbe involved in the cascade reaction on the stage of the Michaeladdition. Such behavior of substituted 3(5)-aminopyrazoleswas discussed in several papers. When the endo-cyclic am-inogroup is blocked (Scheme 38, azoles 154), the formationof pyrazolopyridones 155 is only possible [119].
In the case of 3-amino-5-methylpyrazole 156 several alter-native routs for formation of partially hydrogenated azinering in such reactions can be expected, depending on theinitial step of the Michael addition and following hetero-
2 + +NH
N
NH2
Me
156114
i
157R = Me, Ar, Het
RCHON
HNNH
Me
O
R
i PhNO2, DMF, MeOH, reflux
Scheme 39 Three-component synthesis of pyrazolo[3,4-b]pyridones
NHN
NH
Me
158O
R1 R2N
N NH2
NH2
Ph
159
NN
NH
ArPh
H2NO
160
Fig. 3 Products obtained in works [120, 122]
cyclization. It was determined by the Lipson group that thisthree-component condensation (Scheme 39) in MeOH, DMF,or PhNO2 proceeds selectively and gives exclusively the3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones 157 [120].
Interestingly, in this reaction the arylmethylideneMeldrum’s acids cannot be considered as synthetic equiv-alents of similar malonic acid derivatives, since the reactionof benzylidene malonic acid with aminopyrazole 156 givesdifferent products [120]. Analogous reaction with ketonesinstead of aldehydes 114 is also selective, and allows syn-thesis of tetrahydropyrazolo[3,4-b]pyridine-6-ones 158 bothin MeOH and in DMF (Fig. 3). The secondary aminogroupin the pyrazole ring can be easily alkylated or acylated byvarious electrophilic agents, which might be employed insynthesis of diverse heterocyclic compounds libraries [121].
One could expect that application of diamine 159 in thereaction with aldehydes and Meldrum’s acid would lead toformation of corresponding fused pyrimidine or triazepinesystems. However, this reaction was shown recently to giveimidazo[5,1-b]pyridazin-2-one derivatives 160 (Fig. 3) ingood yields (52–60%) [122].
Application of Meldrum’s acid in cascade reactions com-bining Knoevenagel condensation with Michael additionis a powerful tool for fast generation of diverse pyridineand pyrimidine heterocyclic systems. The potential of theHantzsch- and Biginelli-like multicomponent synthesis is sogreat because of both the diversity of different available 1,3-binucleophiles and the possibility to control the direction of
123
Mol Divers (2009) 13:399–419 413
162
R
O
O Me
Me
O
O
99
HO Nu-H
R
O
Nu
O
Nu-H - alcohol, amine
R
O
CO
161
Scheme 40 General method for synthesis of β-ketocarbonylbuilding-blocks
the condensation by the reaction conditions. The last featureallows application of the same starting materials for the syn-thesis of different products, which is a significant advantagefor diversity-oriented research.
Indirect transfer
In this section, we will shortly review the use of Meldrum’sacid for synthesis of linear building blocks that can further beapplied for pyri(mi)dine synthesis. Thus, the carbon atoms ofthe acid are indirectly transferred into the heterocyclic core.This strategy is widely applied in combinatorial diversity-oriented synthesis. In this way, the trifluoroacetyl derivative108 (Scheme 26) was used also for synthesis of tret-butyl4-trifluoroethylacetoacetate (Scheme 40, 99, R = CF3, Nu =t-BuO) [86] which can be used, for example, in Biginelli orHantzsch multicomponent reactions for synthesis of hydro-genated pyrimidine or pyridine derivatives, correspondingly.Obviously, the cleavage of the 1,3-dioxane ring of such acylderivatives by the action of nucleophiles is a general route toβ-ketocarboxylic acid derivatives 162 (Scheme 40).
Many examples of application of this method using differ-ent N-nucleophiles [123–126], including polymer-supportedα-amino acid esters [127] and O-nucleophiles [128–131] aredescribed in the literature. The mechanism of this trans-formation was studied in details by use of online IR reac-tion monitoring for kinetic studies [132]. This work clearlyrevealed that formation of β-keto amides or esters from acylMeldrum’s adducts proceeded via the α-oxoketene interme-diate 161 under different conditions.
A versatile method for preparation of building blocks oftype 164 derived from N-Boc-α-amino acids 163 was pro-posed [133]. It applies one equivalent of 4-dimethylamino-pyridine (DMAP) and dicyclohexyl carbodiimide (DCC) forthe coupling of Boc-protected amino acid 163 withMeldrum’s acid 2, and the products are isolated as DMAPsalts 164 (Scheme 41). In contrast to the correspondingN-Boc-α-amino-5-acyl Meldrum’s acids (without DMAPcounterion), which slowly decomposed in the solid state,salts 164 were shown to be shelf-storage stable during atleast 6 months.
The DMAP salts 164 can be transformed into thecorresponding acetyl derivatives by treatment with an acidicpolystyrene sulfonic acid cation exchange resin. The cleav-
167R1
O
O
O
NN
R1
CO2HR2
R4
O
R3 N R1
CO2HR2
R4
O
R3
168 169
N
R2
R4
O
R3
172
NH
O
R1
N Me
CO2HR2
R4
O
R3
170
N Me
CO2HR2
N
O
N
171
R3
R3O
N
R2
R4
O
R3
173
NH
O
Fig. 4 Diversity of pyridines generated from polymer-supportedβ-ketoester building-block
age with benzylamine followed by Boc-deprotection andN-acylation with (R)-(−)-α-methoxy-α-trifluoromethylphe-nylacetic acid chloride allowed isolation of chiral diamides166, proving the stereochemical integrity of the acyl deriva-tives 164 formation.
To illustrate the application of this indirect transferstrategy for synthesis of pyri(mi)dines we will present sev-eral examples here. Polymersupported esters 167 (Fig. 4)were used intensively in sequential Hantzsch synthesis forthe combinatorial generation of highly substituted pyridinelibraries. Thus, resins 167 reacted with aldehydes (introduc-tion of the R2) to obtain their corresponding arylidene deriv-atives, which further condensed with β-ketoenomines (R3
and R4) to produce polymer-supported dihydropyridines, andthe latter were further oxidized with ceric ammonium nitrate(CAN) into the target 2,2’-bispyridines 168 and 169 afterrelease from the resin [134].
Earlier, pyridines 170 and pyrido[2,3-d]pyrimidines 171were obtained in this general way [135], and the same grouppublished the similar strategy, but with use of amino-acid-derived polymer-supported building blocks 167 andcyclactive cleavage at the final step [136] applied for thegeneration of diverse pyrrolo[3,4-b]pyridines 172 and relatedpyridine-fused heterocycles 173 (Fig. 4).
Also, such linear esters were used for the synthesis ofcompounds 172 (Scheme 42) that were in turn used for themodeling of DNA pyrimidine and protein aromatic aminoacids photo-cross-linking and elucidation of the mechanismof this process [137].
Pyrone derivatives obtained form Meldrum’s acid mayalso play a role of pyridine precursors. A novel and effi-cient method for metacyclophanes 179 synthesis was devel-oped by Sato and co-authors [138]. Mutual cycloaddition oftwo linked ketene moieties generated from bis (4, 6-dioxo-1,3-dioxane)s 176 provided the cyclophanes 177 that weretransformed into corresponding 2,6-dialkyl-4-pyrones 178
123
414 Mol Divers (2009) 13:399–419
Scheme 41 N-Boc-α-amino-5-acyl Meldrum’s acids asbuilding-blocks forcombinatorial synthesis
164163
i
R1, R2 -from diverse cyclic and lenear α–aminoacids
O
OMe
MeO
OOHN
R1Boc
R2
COOHN
R1Boc
R2
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.
* *DMAP
iiNH
OON
R1Boc
R2
*
Ph
ivNH
OON
R1
R2
*
Ph
O
MeOCF3
Phiii v
661561
Scheme 42 Modeling of DNApyrimidine and protein aromaticamino acids photo-cross-linking
99O
OEt
O
Ar
i
i EtOH, reflux; ii urea, DMSO, 155 °C; iii 254 nm, CD3OD
ii HN
NH
O
O
Ar
iii HN
NH
O
O R
D
R = H, OH
174 175
Scheme 43 Synthesis ofpyridine metacyclophanes
176
i
i PhCl, reflux; i i EtOH or conc HCl, heat ; ii i RNH2, EtOH,130 °C R = H, Me
O
O
O
O
O O
Me
MeO
O
O
OMe
Me
n
n = 8, 9, 10, 12, 18
O
C
O
OC
O
(CH2)n
O
OH O
O
(CH2)n
O
O
(CH2)n
i i
N
O
(CH2)n
R
177 178 179
i ii
followed by interaction with ammonia or methylamine undertough conditions (Scheme 43).
The indirect transfer strategy is not restricted to the pre-sented examples. There are other approaches known for thesynthesis of β-ketocarboxylic acid derivatives, but the factthat Meldrum’s acid is used for this purpose in modern pub-lications proves the advantage of this method over others.
Conclusion
Pyridines and pyrimidines, being among the simplestheterocycles, play a significant role in all basic vital functionsof living beings. Their core structure is present in nucleotidesand a great number of alkaloids. Consequently, it creates con-stant interest among scientists in synthetic approaches andhigh-throughput methods for diverse molecules belonging tothese privileged scaffolds. Meldrum’s acid and its derivativeshave been used in such syntheses for a long time, and the greatnumber of publications devoted to this subject is evidence ofits significant importance. Nevertheless, authors stronglybelieve that the synthetic potential of this reagent has not yetbeen fully uncovered, and we would consider the objectivesof this review to have been achieved if it would help in thesystematization and better understanding of the literature datacollected to date, and possibly bringing new ideas to the field.
Acknowledgements The authors would like to acknowledge DAAD(German Academic Exchange Service), Prof. H.-H. Limbach, andDr. Ilja G. Shenderovich for an opportunity to conduct research at theFree University of Berlin provided by the DAAD grant.
References
1. Meldrum AN (1908) A β-lactonic acid from acetone and malonicacid. J Chem Soc Trans 93:598–601. doi:10.1039/CT9089300598
2. Forster MO (1934) Obituary notices: Andrew Norman Meldrum,1876–1934. J Chem Soc 1476–1478. doi:10.1039/JR9340001468
3. Japp FR, Meldrum AN (1901) Homologues of anhydrace-tonebenzil. J Chem Soc Trans 79:1024–1042. doi:10.1039/CT9017901024
4. Meldrum AN, Perkin WH Jr (1908) The cis- and trans-modifi-cations of 1-methylcyclohexan-2-ol-4-carboxylic acid and theirconversion into 1 methyl-1-cyclohexane-4-carboxylic acid. JChem Soc Trans 93:1416–1428. doi:10.1039/CT9089301416
5. Byun K, Mo Y, Gao J (2001) New insight on the origin of theunusual acidity of Meldrum’s acid from ab initio and combinedQM/MM simulation study. J Am Chem Soc 123:3974–3979.doi:10.1021/ja001369r
6. Arnett EM, Harrelson JA Jr (1987) Ion pairing and reactivity ofenolate anions. 7. A spectacular example of the importance ofrotational barriers: the ionization of Meldrum’s acid. J Am ChemSoc 109:809–812. doi:10.1021/ja00237a028
7. Davidson D, Bernhard SA (1948) Structure of Meldrum’s sup-posed β-lactonic acid. J Am Chem Soc 70:3426–3428. doi:10.1021/ja01190a060
8. McNab H (1978) Meldrum’s acid. Chem Soc Rev 7:345–358.doi:10.1039/CS9780700345
123
Mol Divers (2009) 13:399–419 415
9. Chen BC (1991) Meldrum’s acid in organic synthesis. Heterocy-cles 32: 529–597
10. Gerencsér J, Dormán G, Darvas F (2006) Meldrum’s acid in multi-component reactions: applications to combinatorial and diversity-oriented synthesis. QSAR Comb Sci 25:439–448. doi:10.1002/qsar.200540212
11. McNab H (2004) Chemistry without reagents: synthetic appli-cations of flash vacuum pyrolysis. Aldrichim Acta 37:19–26.http://www.sigmaaldrich.com/etc/medialib/docs/Aldrich/Acta/al_acta_37_1.Par.0001.File.tmp/al_acta_37_1.pdf
12. Gaber AE-AM, McNab H (2001) Synthetic applications ofthe pyrolysis of Meldrum’s acid derivatives. Synthesis 14:2059–2074. doi:10.1055/s-2001-18057
13. Ivanov AS (2008) Meldrum’s acid and related compounds in thesynthesis of natural products and analogs. Chem Soc Rev 37:789–811. doi:10.1039/b716020h
14. Wang H, Tang Y, Wang L, Long C-L, Zhang Y-L (2007) ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butyl-amine derivatives. Curr Med Chem 14:133–155. doi:10.2174/092986707779313390
15. Connon SJ (2006) Catalytic asymmetric acyl-transfer mediatedby chiral pyridine derivatives. Lett Org Chem 3:333–338. doi:10.2174/157017806776611908
16. Saladino R, Ciambecchini U, Nencioni L, Palamara AT (2003)Recent advances in the chemistry of parainfluenza-1 (Sendai)virus inhibitors. Med Res Rev 23:427–455. doi:10.1002/med.10036
17. Baraldi PG, Cacciari B, Borea PA, Varani K, Pastorin G, Da RosT, Tabrizi MA, Fruttarolo F, Spalluto G (2002) Pyrazolo-triaz-olo-pyrimidine derivatives as adenosine receptor antagonists: apossible template for adenosine receptor subtypes. Curr PharmDes 8: 2299–2332
18. Gros P, Fort Y (2002) nBuLi/lithium aminoalkoxide aggregates:new and promising lithiating agents for pyridine derivatives. EurJ Org Chem 3375–3383. doi:10.1002/1099-0690(200210)2002:20<3375::AID-EJOC3375>3.0.CO;2-X
19. Rewcastle GW, Denny WA, Showalter HDH (2000) Synthesis of4-(phenylamino)pyrimidine derivatives as ATP-competitive pro-tein kinase inhibitors with potential for cancer chemotherapy. CurrOrg Chem 4: 679–706
20. Shaabani A, Bazgir A, Bijanzadeh HR (2004) A reexaminationof Biginelli-like multicomponent condensation reaction: one-potregioselective synthesis of spiro heterobicyclic rings. Mol Divers8:141–145. doi:10.1023/B:MODI.0000025613.35304.25
21. Amini MM, Shaabani A, Bazgir A (2006) Tungstophosphoricacid (H3PW12O40): an efficient and eco-friendly catalyst for theone-pot synthesis of dihydropyrimidin-2(1H)-ones. Catal Com-mun 7:843–847. doi:10.1016/j.catcom.2006.02.027
22. Shaabani A, Bazgir A (2004) A novel pseudo four-componentreaction: unexpected formation of densely functionalized pyr-roles. Tetrahedron Lett 45:2575–2577. doi:10.1016/j.tetlet.2004.01.154
23. Byk G, Kabha E (2004) Anomalous regioselective four-membermulticomponent Biginelli reaction II: one-pot parallel synthesisof spiro heterobicyclic aliphatic rings. J Comb Chem 6:596–603.doi:10.1021/cc049962i
24. Byk G, Kabha E (2006) A solid-supported stereoselective multi-component reaction: one-pot generation of three asymmetric car-bons. Synlett 747–748. doi:10.1055/s-2006-932498
25. D’yachenko EV, Glukhareva TV, Dyudya LV, Eltsov OV,Morzherin YY (2005) The tert-amino effect in heterocyclic chem-istry. Synthesis of spiro heterocycles. Molecules, 10:1101–1108.http://www.mdpi.org/molecules/papers/10091101.pdf
26. Schwartz A, Beke G, Kovári Z, Böcskey Z, Farkas Ö, MátyusP (2000) Applications of tert-amino effect and a nitrone-ole-fin 1,3-dipolar cycloaddition reaction: synthesis of novel angu-
larly annelated diazino heterocycles. J Mol Struct (Theochem)528:49–57. doi:10.1016/S0166-1280(99)00399-1
27. Beke G, Gergely A, Szasz G, Szentesi A, Nyitray J, BarabasO, Harmath V, Mátyus P (2002) Synthesis and stereochemis-try of dispiro substituted pyridazines: application of ellipticity-absorbance ratio spectra for proving enantiomeric relationshipby HPLC-CD/UV detection. Chirality 14: 365–371. doi:10.1002/chir.10096
28. Kaval N, Halasz-Dajka B, Vo-Thanh G, Dehaen W, Van derEycken J, Mátyus P, Loupy A, Van der Eycken E (2005) Anefficient microwave-assisted solvent-free synthesis of pyrido-fused ring systems applying the tert-amino effect. Tetrahedron61:9052–9057 doi:10.1016/j.tet.2005.07.046
29. Melh-Cohn O, Suschiizky H (1996). The t-amino effect: hetero-cycles formed by ring closure of ortho-substituted t-anilines AdvHeterocycl Chem 65:1. doi:10.1016/S0065-2725(08)60294-9
30. Ojea V, Muinelo I, Quintela JM (1998) Synthesis of fusedpyrido[2,3-d]pyrimidines by thermal isomerization of 4-amino-5-vinylpyrimidines. Tetrahedron 54:927–934. doi:10.1016/S0040-4020(97)10334-9
31. Glukhareva TV, D’yachenko EV, Morzherin YY (2002) Synthesisof spiro derivatives of pyrrolo[1,2-a]quinoline. Chem HeterocyclComp 1426–1427. doi:10.1023/A:1022107332320
32. D’yachenko EV, Glukhareva TV, Nikolaenko EF, Tkachev AV,Morzherin YY (2004) tert-Amino effect in heterocyclic chemis-try. Synthesis of hydrogenated spiro derivatives of quinolines.Russ Chem Bull Int Ed 53:1240–1247. doi:10.1023/B:RUCB.0000042280.71728.d0
33. Deeva EV, Glukhareva TV, Zybina NA, Morzherin YY (2005)Stereoselective synthesis of spiro derivatives of 2, 4-dimethyl-2,3,4,4a,5,6-hexahydro-6H-benzo[c]quinolizine. Russ Chem BullInt Ed 54:1537–1538. doi:10.1007/s11172-005-0444-8
34. Deeva EV, Glukhareva TV, Tkachev AV, MorzherinYY (2006) The stereo selective synthesis of spirofused 3-substituted 2,3,4,4a,5,6-hexahydro-6H -benzo[c]quinolizine bythe using tert-amino effect. Mendeleev Commun 16: 82–83
35. Paramonov IV, Belyaev NA, Glukhareva TV, Volkov AS, DeevaEV, Morzherin YY (2006) One-step synthesis of a novel heterocy-clic system: spiro 1,4-thiazino[4,3-a]quinoline-5,5′-pyrimidine].Chem Heterocycl Comp 42:127–128. doi:10.1007/s10593-006-0061-y
36. Vlaskina NM, Suzdalev KF, Babakova MN, Mezheritskii VV,Kartsev VG (2006) Use of the tert-amino effect in the synthesisof spirocyclic fused α-carbolines. Russ Chem Bull 55:384–386.doi:10.1007/s11172-006-0265-4
37. Renslo AR, Danheiser RL (1998) Synthesis of substitutedpyridines via regiocontrolled [4+2] cycloadditions of oximino-sulfonates. J Org Chem 63:7840–7850. doi:10.1021/jo981014e
38. Danheiser RL, Renslo AR, Amos DT, Wright GT (2003)Preparation of substituted pyridines via regiocontrolled [4+2]cycloadditions of oximinosulfonates: methyl 5-methylpyridine-2-carboxylate. Org Synth 80:133–143 http://www.orgsyn.org/orgsyn/pdfs/v80p0133.pdf
39. Katagiri N, Nochi H, Kurimoto A, Sato H, Kaneko C (1994)Synthesis of nucleosides and related compounds. XXXIV. Syn-thesis of 5-isonitroso-1,3-dioxane-4,6-diones and their reactions.Chem Pharm Bull 42:1251–1257 http://ci.nii.ac.jp/vol_issue/nels/AA00602100_en.html
40. Chou SY, Chang LS, Chen SF (1999) An anomalous prepar-ing of a tetrahydro-2H -oxocine fused pyrrole derivative and itsacid-catalyzed rearrangement. Heterocycles 51: 833–839
41. Vanotti E, Amici R, Bargiotti A, Berthelsen J, Bosotti R,Ciavolella A, Cirla A, Cristiani C, D’Alessio R, Forte B, Isac-chi A, Martina K, Menichincheri M, Molinari A, Montagnoli A,Orsini P, Pillan A, Roletto F, Scolaro A, Tibolla M, ValsasinaB,Varasi M, Volpi D, Santocanale C (2008) Cdc7 kinase inhibi-
123
416 Mol Divers (2009) 13:399–419
tors: pyrrolopyridinones as potential antitumor agents. 1. Synthe-sis and structure-activity relationships. J Med Chem 51:487–501.doi:10.1021/jm700956r
42. Orsini P, Maccario A, Colombo N (2007) Regioselectiveγ -alkylation of tert-butyl 2,4-dioxopiperidine-1-carboxylate.Synthesis 2007:3185–3190. doi:10.1055/s-2007-990792
43. Casimir JR, Didierjean C, Aubry A, Rodriguez M, BriandJ-P, Guichard G (2000) Stereoselective alkylation of N-Boc-pro-tected-5-substituted δ-lactams: synthesis of α, δ-disubstituted δ-amino acids. Org Lett 2:895–897. doi:10.1021/ol9913136
44. Marin J, Didierjean C, Aubry A, Briand J-P, Guichard G (2002)Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S, 5R)-5-hydroxylysine andrelated α-amino acids. J Org Chem 67:8440–8449 doi:10.1021/jo025950c
45. Tian X, Chen X, Gan L, Hayes JC, Switzer AG, Solinsky MG,Ebetino FH, Wos JA, Pinney BB, Farmer JA, Crossdoersen D,Sheldon R J. (2006) Synthesis of Tic-D-Phe [CH2 − CH2]isostere and its use in the development of melanocortin receptoragonists. Bioorg Med Chem Lett 16:1721–1725. doi:10.1016/j.bmcl.2005.12.005
46. Saczewski F, Gdaniec M (1996) Syntheses of novel fusedheterocyclic systems by reactions of 1,2-dihydro-2-(4,5-dihydroimidazol-2-yl)phtalazine-1-ol with active methy-lene compounds. Liebigs Ann 1996:1673–1677. doi:10.1002/jlac.199619961028
47. Benzing M, Vilsmaier E (1987) Reactions of diastereomericaminobicycloalkyl Meldrum’s acid derivatives—sterically con-trolled transformations at the [4.1.0]-bicyclic systems. Chem Ber120:1873–1880. doi:10.1002/cber.19871201116
48. Deb ML, Bhuyan PJ (2006) Synthesis of novel classesof pyrido[2,3-d]pyrimidines, pyrano[2,3-d]pyrimidines, andpteridines. Synth Commun 36: 3085–3090. doi:10.1080/00397910600775622
49. Tietze LF, Evers H, Enno T (2001) A novel concept in combi-natorial chemistry in solution with the advantages of solid-phasesynthesis: formation of N-betaines by multicomponent dominoreactions. Angew Chem Int Ed 40:903–905. doi:10.1002/1521-3773(20010302)40:5<903::AID-ANIE903>3.0.CO;2-7
50. Bihlmayer GA, Derflinger G, Derkosch J, Polansky OE (1967)Cyclic acylals. XVII. Hydroxy- and aminomethylene derivativesof Meldrum’s acid. Monatsh Chem 98:564–578. doi:10.1007/BF00901364
51. Feldman KS, Coca A (2008) Synthesis of the pentacyclic coreof lihouidine. Tetrahedron Lett 49:2136–2138 doi:10.1016/j.tet\discretionary-let.2008.01.118
52. Teague SJ, Barber S, King S, Linda S (2005) Synthesis ofbenzimidazole based JNK inhibitors. Tetrahedron Lett 46:4613–4616. doi:10.1016/j.tet\discretionary-let.2005.04.145
53. Kitahara Y, Mizuno T, Kubo A (2004) Synthetic studiesof benzo[b]pyrrolo[4,3,2-de][1,10]phenanthroline. Tetrahedron60:4283–4288. doi:10.1016/j.tet.2004.03.057
54. Watterson SH, Carlsen M, Dhar TGM, Shen Z, Pitts WJ, GuoJ, Gu HH, Norris D, Chorba J, Chen P, Cheney D, Witmer M,Fleener CA, Rouleau K, Townsend R, Hollenbaugh DL, Iwanow-icz EJ (2003) Novel inhibitors of IMPDH a highly potent andselective quinolone-based series. Bioorg Med Chem Lett 13:543–546. doi:10.1016/S0960-894X(02)00944-7
55. Beifuss U, Feder SG (2001) Efficient allylation of 4-silyloxy-quinolinium triflates and other positively charged heteroaromaticsystems. Tetrahedron 57:1005–1013. doi:10.1016/S0040-4020(00)01066-8
56. Delfourne E, Roubin C, Bastide J (2000) The first synthesis of thepentacyclic pyridoacridine marine alkaloids: arnoamines A andB. J Org Chem 65:5476–5479. doi:10.1021/jo000011a
57. Walz AJ, Sundberg RJ (2000) Synthesis of 8-methoxy-1-methyl-1H -benzo[de]1,6-naphthyridin-9-ol (isoaaptamine) andanalogues. J Org Chem 65:8001–8010. doi:10.1021/jo001080s
58. Al-Awadi NA, Abdelhamid IA, Al-Etaibi AM, Elnagdi MH(2007) Gas-phase pyrolysis in organic synthesis: rapid greensynthesis of 4-quinolinones. Synlett: 2205–2208. doi:10.1055/s-2007-985573
59. Morgentin R, Pasquet G, Boutron P, Jung F, Lamorlette M, Mau-det M, Ple P (2008) Strategic studies in the synthesies of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones. Tetrahedron 64:2772–2782. doi:10.1016/j.tet.2008.01.055
60. Blake AJ, McNab H, Morrow M, Rataj H (1993) Pyrazolo[1,2-a]-1,2,3-triazinium-4-olate. Chem Soc Chem Commun 840–842.doi:0.1039/C39930000840J
61. Quiroga J, Hormaza A, Insuasty B, Saitz C, Julian C, CaneteA (1998) Synthesis of pyrazolo[1,5-a]pyrimidines in the reactionof 5-amino-3-arylpyrazoles with methoxymethylene Meldrum’sacid derivative and thermolysis of their pyrazolylaminomethylen-ederivatives. J Heterocycl Chem 35: 61–64
62. Cassis R, Tapia J, Valderrama A (1985) Synthesis of 4(1H)-quinolones by thermolysis of arylaminomethylene Meldrum’sacid derivatives. Synth Commun 15:125–133. doi:10.1080/00397918508076818
63. Singh B, Laskowski SC, Lesher GY (1990) An efficient and fac-ile synthesis of novel 2-aryl-pyrido[2,3-d]pyrimidin-5(8H )-ones.Synlett 549–550 doi:10.1055/s-1990-21163
64. Ravina I, Zicane D, Petrova M, Gudriniece E, Kalejs U (2002)Exotic amino acids. Part 6. Synthesis of substituted 4-oxo-4H -pyrido[1,2-a]pyrimidines. Chem Heterocycl Comp 38:836–839.doi:10.1023/A:1020689805869
65. Dennin F, Blondeau D, Sliwa H (1989) Synthesis of newheterocyclic phenols: 9-hydroxypyrido[1,2-a]pyrimidin-4-oneand 9-hydroxypyrimido[1,6-a]pyrimidin-4-one. Tetrahedron Lett30:1529–1530. doi:10.1016/S0040-4039(00)99510-8
66. Horvath G, Hermecz I, Horvath A, Pongor-Csakvari M, PusztayL, Kiss AI, Czako L, Abdirizak OH (1985) Electronic structureof 4H -pyrido[1,2-a]pyrimidin-4-ones. J Heterocycl Chem 22:481–489
67. Everson da Silva L, Carlos JA, Nunes RJ, Navakoski deOliveira K (2008) Synthesis of tacrine analogs derived fromN-aryl-5-amino-4-cyanopyrazoles. Synth Commun 38:15–20.doi:10.1080/00397910701648744
68. Everson da Silva L, Joussef AC, Pacheco LK, Albino DBL, DuarteAMC, Steindel M, Rebelo RA (2007) Synthesis and antiparasiticactivity against Trypanosoma cruzi and Leishmania amazonensisof chlorinated 1,7- and 1,8-naphthyridines. Lett Drug Des Discov4:154–159. doi:10.2174/157018007779422550
69. Gomez L, Hack MD, Wu J, Wiener JJM, Venkatesan H, Santi-llan A, Pippel DJ, Mani N Morrow BJ, Motley ST, Shaw KJ,Wolin R, Grice CA, Jones TK (2007) Novel pyrazole derivativesas potent inhibitors of type II topoisomerases. Part 1: synthesisand preliminary SAR analysis. Bioorg Med Chem Lett 17:2723–2727. doi:10.1016/j.bmcl.2007.03.003
70. Ye F-C, Chen B-C, Huang X (1989) Synthesis of 7-substituted5-oxo-5H -thiazolo[3,2-a]pyrimidine-6-carboxylic acids, 2-substituted 4-oxo-4H -pyrido[1,2-a]pyrimidine-3-carboxylicacids, and 2,6-disubstituted 4-quinolones from Meldrum’s acidderivatives. Synthesis 4:317–320. doi:10.1055/s-1989-27241
71. Knight ZA, Chiang GG, Alaimo PJ, Kenski DM, Ho CB, Coan K,Abraham RT, Shokat KM (2004) Isoform-specific phosphoinosi-tide 3-kinase inhibitors from an arylmorpholine scaffold. BioorgMed Chem 12:4749–4759. doi:10.1016/j.bmc.2004.06.022
72. Barbeau OR, Cano-Soumillac C, Griffin RJ, Hardcastle IR,Smith GCM, Richardson C, Clegg W, Harrington RW, GoldingBT (2007) Quinolinone and pyridopyrimidinone inhibitors of
123
Mol Divers (2009) 13:399–419 417
DNA-dependent protein kinase. Org Biomol Chem 5:2670–2677.doi:10.1039/b705095j
73. Sanghvi YS, Larson SB, Robins RK, Revankar GR (1990) Aconvenient synthesis of pyrazolo[3,4-b]pyridine nucleosides byconvenient ring-closure procedures. X-ray crystal and molecularstructure of 4-amino-1-(β-D-ribofuranosyl)-1,7-dihydropyrazol-o[3,4-b]pyridin-6-one. J Chem Soc Perkin Trans 1 2943–2950.doi:10.1039/P19900002943
74. Huang X, Liu Zh (2003) Synthesis of 1-(N-alkylidene orbenzylideneamino)-1,6-dihydro-2-methylthio-6-oxo-pyrimidinefrom Meldrum’s acid derivatives. Synth Commun 33: 927–934
75. Bibas H, Moloney DWJ, Neumann R, Shtaiwi M, BernhardtPV, Wentrup C (2002) Chemistry of stable iminopropadie-nones, RN:C:C:C:O. J Org Chem 67:2619–2631. doi:10.1021/jo0110552
76. Emtenas H, Alderin L, Almqvist F (2001) An enantioselectiveketene-imine cycloaddition method for synthesis of substitutedring-fused 2-pyridinones. J Org Chem 66:6756–6761. doi:10.1021/jo015794u
77. Emtenas H, Ahlin K, Pinkner JS, Hultgren SJ, Almqvist F (2002)Design and parallel solid-phase synthesis of ring-fused 2-pyridi-nones that target pilus biogenesis in pathogenic bacteria. J CombChem 4:630–639. doi:10.1021/cc020032d
78. Emtenas H, Taflin C, Almqvist F (2003) Efficient microwaveassisted synthesis of optically active bicyclic 2-pyridinonesvia delta-2-thiazolines. Mol Divers 7:165–169. doi:10.1023/B:MODI.0000006800.46154.99
79. Sellstedt M, Almqvist F (2008) Synthesis of a novel tricyclicpeptidomimetic scaffold. Org Lett 10:4005–4007. doi:10.1021/ol801506y
80. Pemberton N, Pinkner JS, Edvinsson S, Hultgren SJ, Almq-vist F (2008) Synthesis and evaluation of dihydroimidazolo anddihydrooxazolo ring-fused 2-pyridones-targeting pilus biogene-sis in uropathogenic bacteria. Tetrahedron 64:9368–9376. doi:10.1016/j.tet.2008.07.015
81. Aberg V, Das P, Chorell E, Hedenstroem M, Pinkner JS,Hultgren SJ, Almqvist F (2008) Carboxylic acid isosteres improvethe activity of ring-fused 2-pyridones that inhibit pilus biogenesisin E. coli. Bioorg Med Chem Lett 18:3536–3540. doi:10.1016/j.bmcl.2008.05.020
82. Chorell E, Das P, Almqvist F (2007) Diverse functionalizationof thiazolo ring-fused 2-pyridones. J Org Chem 72:4917–4924.doi:10.1021/jo0704053
83. Pemberton N, Pinkner JS, Edvinsson S, Hultgren SJ, Almq-vist F (2008) Synthesis and evaluation of dihydroimidazolo anddihydrooxazolo ring-fused 2-pyridones-targeting pilus biogene-sis in uropathogenic bacteria. Tetrahedron 64:9368–9376. doi:10.1016/j.tet.2008.07.015
84. Aaberg V, Norman F, Chorell E, Westermark A, OlofssonA, Sauer-Eriksson AE, Almqvist F (2005) Microwave-assisteddecarboxylation of bicyclic 2-pyridone scaffolds and identifica-tion of Aβ-peptide aggregation inhibitors. Org Biomol Chem3:2817–2823. doi:10.1039/b503294f
85. Pemberton N, Jakobsson L, Almqvist F (2006) Synthesis of multiring-fused 2-pyridones via an acyl-ketene imine cyclocondensa-tion. Org Lett 8:935. doi:10.1021/ol052998e
86. Morita Y, Kamakura R, Takeda M, Yamamoto Y (1997) Conve-nient preparation of trifluoroacetyl Meldrum’s acid and its use as abuilding block for trifluoromethyl-containing compounds. ChemCommun 359–360. doi:10.1039/a608104e
87. Nesterov VN, Krivokolysko SG, Dyachenko VD, DotsenkoVV, Litvinov VP (1997) Synthesis, properties and structures ofammonium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. Russ Chem Bull 46:990–996. doi:10.1007/BF02496132
88. Krivokolysko SG, Dotsenko VV, Litvinov VP (2000) New mul-ticomponent condensation leading to sulfur-containing 1,2,3,
4-tetrahydro-2-pyridinones. Chem Heterocycl Comp 36:1108–1109. doi:10.1023/A:1002750402772
89. Dyachenko VD, Krivokolysko SG, Litvinov VP (1997) Anew method for the synthesis of N-methylmorpholinium4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates andtheir properties. Russ Chem Bull 46:1758–1762. doi:10.1007/BF02495131
90. Dyachenko VD, Krivokolysko SG, Litvinov VP (1997) Syn-thesis and some properties of 4-alkyl-5-cyano-6-mercapto-3,4-dihydropyridin-2(1H )-ones. Russ Chem Bull 46:1912–1915.doi:10.1007/BF02503785
91. Krivokolysko SG, Dyachenko VD, Litvinov VP (1999)Synthesis and alkylation of N-methylmorpholinium 5-cyano-4-(3- and 4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. Russ Chem Bull 48:2308–2311. doi:10.1007/BF02498278
92. Frolov KA, Dotsenko VV, Krivokolysko SG, Litvinov VP (2005)Three-component condensation in the synthesis of substitutedtetrahydropyrimidinethiolates. Russ Chem Bull 54:1335–1336.doi:10.1007/s11172-005-0404-3
93. Dotsenko VV, Krivokolysko SG, Chernega AN Litvinov VP(2002) Anilinomethylidene derivatives of cyclic 1,3-dicarbonylcompounds in the synthesis of new sulfur-containing pyridinesand quinolines. Russ Chem Bull 51:1556–1561. doi:10.1023/A:1020939712830
94. Mermerian AH, Case A, Stein RL, Cuny DG (2007) Structure-activity relationship, kinetic mechanism, and selectivity for newclass of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors.Bioorg Med Chem Lett 17:3729–3732. doi:10.1016/j.bmcl.2007.04.027
95. Yu C-Y, Yang P-H, Zhao M-X, Huang Z-T(2006) A novelone-pot reaction of heterocyclic ketene aminals: synthesis of asmall library of tetrahydropyrimidone-fused 1,3-diazaheterocy-cles. Synlett 12:1835–1840. doi:10.1055/s-2006-947343
96. Ramin M, Ahmadreza M (2008) Dihydropyridines and atyp-ical MDR: a novel perspective of designing general reversalagents for both typical and atypical MDR. Bioorg Med Chem 16:8329–8334. doi:10.1016/j.bmc.2008.07.025
97. Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL,Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W, Ye G,Semus SF, Evans CF, Harvey E, Jolivette LJ, Kirkpatrick RB, DulE, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, BehmDJ, Bentley R, Doe CP, Hu E, Lee D (2007) Development of dihy-dropyridone indazole amides as selective Rho-kinase inhibitors.J Med Chem 50:6–9. doi:10.1021/jm0609014
98. Suarez M, Verdecia Y, Ochoa E, Salfran E, Moran L, MartinN, Martinez R, Quinteiro M, Seoane C, Soto JL, Novoa H,Blaton N, Peeters OM, De Ranter C (2000) Synthesis andstructural study of 3,4-dihydro-2(1H )-pyridones and isoxazol-o[5,4-b]pyridin-6(7H )-ones. Eur J Org Chem 2079–2088. doi:10.1002/1099-0690(200006)2000:11<2079::AID-EJOC2079>3.0.CO;2-#
99. Surez M, Ochoa E, Verdecia Y, Pita B, Morin O, Martin N,Quinteiro M, Seoane C, Soto JL, Novoa H, Blaton N, Peters OM(1999) A joint experimental and theoretical structural study ofnovel substituted 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinolines.Tetrahedron 55:875–884. doi:10.1016/S0040-4020(98)01078-3
100. Morales A, Ochoa E, Suarez M, Verdecia Y, Gonzalez L,Martin N, Quinteiro M, Seoane C, Soto JL (1996) Novel hexa-hydrofuro[3,4-b]-2(1H )-pyridones from 4-aryl substituted 5-alk-oxycarbonyl-6-methyl-3,4-dihydropyridones. J Heterocycl Chem33: 103–107
101. Verdecia Y, Suarez M, Morales A, Rodriguez E, Ochoa E,Gonzalez L, Martin N, Quinteiro M, Seoane C, Soto JL (1996)Synthesis of methyl 4-aryl-6-methyl-4,7-dihydro-1H -pyrazol-o[3,4-b]pyridine-5-carboxylates from methyl 4-aryl-6-methyl-
123
418 Mol Divers (2009) 13:399–419
2-oxo-1,2,3,4-tetrahydropyridine-5-carboxylates. J Chem SocPerkin Trans 1 947–951. doi:10.1039/P1996000
102. Tu Sh, Fang F, Zhu S, Li T, Zhang X, Zhuang Q, Ji Sh,Zhang Y (2005) Microwave-assisted synthesis of phenylenedi(4′,4′′-tetrahydroquinoline) and di(4′,4′′-tetrahydropyridine) deriva-tives. J Heterocycl Chem 42: 29–32
103. Tu Sh, Miao Ch, Fang F, Feng Y, Li T, Zhuang Q, Zhang X, Zhu S,Shi D (2004) New potential calcium channel modulators: designand synthesis of compounds containing two pyridine, pyrimidine,pyridone, quinoline and acridine units under microwave irradia-tion. Bioorg Med Chem Lett 14:1533–1536. doi:10.1016/j.bmcl.2003.12.092
104. Rodriguez H, Suarez M, Perez R, Petit A, Loupy A (2003)Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones under microwave irradiation. Tetra-hedron Lett 44:3709–3712. doi:10.1016/S0040-4039(03)00625-7
105. Fu G-Y, Zhang X-L, Sheng S-R, Wei M-H, Liu X-L (2008) Rapidmicrowave-assisted liquid-phase synthesis of 4-substituted-5-methoxycarbonyl-6-methyl-3,4-dihydropyridones on poly(ethyl-eneglycol) support. Synth Comm 38:1249–1258. doi:10.1080/00397910701873144
106. Fan XS, Li YZ, Zhang XY, Qu GR, Wang JJ, Hu XY (2006) Anefficient and green synthesis of 1,4-dihydropyridine derivativesthrough multi-component reaction in ionic liquid. Heteroat Chem17:382–388. doi:10.1002/hc.2022
107. Tu S, Zhu X, Zhang J, Xu J, Zhang Y, Wang Q, Jia R, Jiang B,Zhang J, Yao C (2006) New potential biologically active com-pounds: design and an efficient synthesis of N-substituted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-diones under micro-wave irradiation. Bioorg Med Chem Lett 16:2925–2928. doi:10.1016/j.bmcl.2006.03.011
108. Svetlik J, Golijer I, Turecek F (1990) Oxygen-bridged tetrahy-dropyridines and dihydropyridones via a Hantzsch-like synthe-sis with 4-(2-hydroxyphenyl)but-3-en-2-one. J Chem Soc PerkinTrans 1:1315–1318. doi:10.1039/P19900001315
109. Cho H, Shima K, Hayashimatsu M, Ohnaka Y, Mizuno A,Takeuchi Y (1985) Synthesis of novel dihydropyrimidines andtetrahydropyrimidines. J Org Chem 50:4227–4230. doi:10.1021/jo00222a009
110. Katritzky AR, Yousaf TI (1986) A carbon-13 nuclear magneticresonance study of the pyrimidine synthesis by the reactions of1,3-dicarbonyl compounds with amidines and ureas. Can J Chem64:2087–2093. doi:10.1139/v86-34
111. Ostras KS, Gorobets NYu, Desenko SM, Musatov VI (2006) Aneasy access to 2-amino-5,6-dihydro-3H-pyridin-4-one buildingblocks: the reaction under conventional and microwave condi-tions. Mol Divers 10:483–489. doi:10.1007/s11030-006-9045-1
112. Lipson VV, Orlov VD, Desenko SM, Karnozhitskaya TM,Shirobokova MG (1999) Reaction of arylidene derivatives of Mel-drum’s acid with 3-amino-1,2,4-triazole. Chem Heterocycl Comp35:595–599. doi:10.1007/BF02324645
113. Ivanova O, Poltorak V, Gorbenko N, Lipson V (2001) Novelantioxidant L-2264 prevents insulin resistance development indexamethazone treated rats. Diabetologia 44(Suppl 1):A226
114. Ivanova O, Gorbenko N, Poltorak V, Gladkich A, LeshchenkoZ (2004) Antiaterogenic effect of new antioxidant L-2264 in dia-betic rabbits. Diabetologia 47(Suppl 1):A278
115. Lipson VV, Desenko SM, Borodina VV, Shirobokova MG,Karnozhitskaya TM, Musatov VI, Kravchenko SV (2005) 2-Methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5-and -7-ones. Chem Heterocycl Comp 41:216–220. doi:10.1007/s10593-005-0130-7
116. Lipson VV, Borodina VV, Shirobokova MG (2005) Cyclocon-densation of 3,5-diamino-1,2,4-triazole with benzaldehydes and
Meldrum’s acid. Ukrainskii Khimicheskii Zhurnal (Russian Edi-tion) 71:95–99. CAN 143:172828
117. Lipson VV, Borodina VV, Musatov VI (2006) Cyclocondensationof 3,4,5-triamino-1,2,4-triazole with para-substituted benzalde-hydes and Meldrum’s acid. Zh Org Farm Khim 4: 62–65. CAN147:235114
118. Lipson VV, Orlov VD, Desenko SM, Shishkina SV, ShishkinOV, Shirobokova MG (2001) 1,2,3,4-Tetrahydropyrimido[1,2-a]benzimidazol-2- and -4-ones. Chem Heterocycl Comp 36:1039–1043. doi:10.1023/A:1002777714158
119. Quiroga J, Hormaza A, Insuasty B, Marquez M (1998) Reactionof 5-amino-1-aryl-3-methylpyrazoles with benzylidene deriva-tives of Meldrum’s acid: synthesis and characterization of pyr-azolo[3,4-b]pyridinones. J Heterocycl Chem 35: 409–412
120. Lipson VV, Desenko SM, Shirobokova MG, Shishkin OV,Shishkina SV (2006) Heterocyclizations of 3-amino-5-methyl-pyrazole with unsaturated arylalyphatic acid derivatives. Russ JOrg Chem 42:1022–1027. doi:10.1134/S1070428006070153
121. Lipson VV, Shirobokova MG, Musatov VI (2005) Synthesisand chemical properties of partially hydrogenated 3-methyl-4-aryl(heteryl)pyrazolo[3,4-b]pyridin-6-ones. Zh Org Farm Khim3:64–69. CAN 145:249136
122. Lipson VV, Svetlichnaya NV, Shishkina SV, ShishkinOV (2008) Cascade cyclization of 1,2-diamino-4-phenylimida-zole with aromatic aldehydes and Meldrum’s acid. MendeleevCommun 18: 141–143
123. Hollick JJ, Rigoreau LJM, Cano-Soumillac C, Cockcroft X,Curtin NJ, Frigerio M, Golding BT, Guiard S, Hardcastle IR,Hickson I, Hummersone MG, Menear KA, Martin NMB, Mat-thews I, Newell DR, Ord R, Richardson CJ, Smith, GraemeCM, Griffin RJ (2007) Pyranone, thiopyranone, and pyridoneinhibitors of phosphatidylinositol 3-kinase related kinases. Struc-ture–activity relationships for DNA-dependent protein kinaseinhibition, and identification of the first potent and selective inhib-itor of the ataxia telangiectasia mutated kinase. J Med Chem50:1958–1972. doi:10.1021/jm061121y
124. Snider BB, Neubert, BJ (2004) A novel biomimetic route tothe 3-acyl-5-hydroxy-3-pyrrolin-2-one and 3-acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one ring systems. J Org Chem 69:8952–8955. doi:10.1021/jo048605r
125. Sorensen US, Falch E, Krogsgaard-Larsen P (2000) A novel routeto 5-substituted 3-isoxazolols. Cyclization of N,O-diBoc β-ketohydroxamic acids synthesized via acyl Meldrum’s acids. J OrgChem 65:1003–1007. doi:10.1021/jo991409d
126. Pak CS, Yang HC, Choi EB (1992) Aminolysis of 5-acyl-2,2-dimethyl-1,3-dioxan-4,6-diones (acyl Meldrum’s acids) as aversatile method for the synthesis of β-oxo carboxamides. Syn-thesis 12:1213–1214. doi:10.1055/s-1992-26338
127. Weber L, Iaiza P, Biringer G, Barbier P (1998) Solid-phasesynthesis of 3-acyltetramic acids. Synlett 10:1156–1158. doi:10.1055/s-1998-1862
128. Itoh T, Taguchi T, Kimberley MR, Booker-Milburn KI,Stephenson GR, Ebizuka Yu, Ichinose K (2007) Actinorhodin bio-synthesis: structural requirements for post-PKS tailoring interme-diates revealed by functional analysis of actVI-ORF1 reductase.Biochemistry 46:8181–8188. doi:10.1021/bi700190p
129. Venturi F, Venturi C, Liguori F, Cacciarini M, Montalbano M,Nativi C (2004) A new scaffold for the stereoselective synthesis ofα-O-linked glycopeptide mimetics. J Org Chem 69: 6153–6155.doi:10.1021/jo049441h
130. Kikuchi H, Sasaki K, Sekiya J, Maeda Y, Amagai A,Kubohara Y, Oshima Y (2004) Structural requirements of dicty-opyrones isolated from Dictyostelium spp. in the regulation ofDictyostelium development and in anti-leukemic activity. BioorgMed Chem 12:3203–3214. doi:10.1016/j.bmc.2004.04.001
123
Mol Divers (2009) 13:399–419 419
131. Bach T, Hoefer F (2001) Photochemical deconjugation ofchiral 3-methyl-2-butenoates derived from carbohydrate-basedalcohols: the influence of the sugar backbone on the facialdiastereoselectivity. J Org Chem 66:3427–3434. doi:10.1021/jo001740t
132. Xu F, Armstrong JD, Zhou GX, Simmons B, Hughes D, Ge Z,Grabowski EJJ (2004) Mechanistic evidence for an α-oxoketenepathway in the formation of β-ketoamides/esters via Meldrum’sacid adducts. J Am Chem Soc 126:13002–13009. doi:10.1021/ja046488b
133. Raillard SP, Weiwei Chen, Sullivan E, Bajjalieh W, Bhandari A,Baer TA (2002) Preparation and improved stability of N-Boc-α -amino-5-acyl Meldrum’s acids, a versatile class of buildingblocks for combinatorial chemistry. J Comb Chem 4:470–474.doi:10.1021/cc0200033
134. Tadesse S, Bhandari A, Gallop MA (1999) Solid-phase synthe-sis of highly functionalized 2,2′-bipyridines. J Comb Chem 1:184–187. doi:10.1021/cc980035j
135. Gordeev MF, Patel DV, Wu J, Gordon EM (1996) Approachesto combinatorial synthesis of heterocycles: solid phase synthesisof pyridines and pyrido[2,3-d]pyrimidines. Tetrahedron Lett37:4643–4646. doi:10.1016/0040-4039(96)00923-9
136. Bhandari A, Bei L, Gallop MA (1999) Solid-phase synthesis ofpyrrolo[3,4-b]pyridines and related pyridine-fused heterocycles.Synthesis 11:1951–1960. doi:10.1055/s-1999-3618
137. Sun G, Fecko CJ, Nicewonger RB, Webb WW, Begley TP (2006)DNA-protein cross-linking: model systems for pyrimidine-aromatic amino acid cross-linking. Org Lett 8:681–683. doi:10.1021/ol052876m
138. Sato M, Oda T, Iwamoto K, Murakami E (2003) Highly effi-cient methods for metacyclophane synthesis. Tetrahedron 59:2651–2655. doi:10.1016/S0040-4020(03)00326-0
123