SELECTED REACTIONS of 4H-PYRIDO[1,2-A]PYRIMIDIN-4-ONES and an AZOXYQUINOXALINE

BUDAPESTI MŰSZAKI ÉS GAZDASÁGTUDOMÁNYI EGYETEM VEGYÉSZMÉRNÖKI ÉS BIOMÉRNÖKI KAR OLÁH GYÖRGY DOKTORI ISKOLA

SELECTED REACTIONS OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES AND AN AZOXYQUINOXALINE

Thesis

Written by Annamária Molnár Supervisors: Dr. István Hermecz Dr. Ferenc Faigl

External Pharmaceutical Department

2011 Acknowledgement

Acknowledgement

I would express my thanks to my supervisors, Dr. István Hermecz and Dr. Ferenc Faigl for their useful scientic advices, kindness and patience. I am grateful Dr. Zoltán Finta for the possibility performing my research at Chinoin Ltd. / Sanofi-aventis Preclinical Chemical Development and Dr. Csaba Gönczi for the useful advices and the scientific consultations. I express my thanks to Dr. Zoltán Novák and the Novák–Kele research group at ELTE Chemical Department for their kindness and support becoming familiar with the Buchwald– Hartwig amination methodology. I am grateful Dr. Ferenc Faigl and his research group for getting related to the Schlenk technique and lithiation reactions. I express my thanks to Dr. Zoltán Mucsi and Dr. Gábor Vlád for the DFT calculations. I am grateful for the analytical support for Dr. László Balázs, János Brlik, Sándor Boros, Dr. Anasztázia Hetényi, Dr. Benjámin Podányi, Dr. Kálmán Simon, Dr. László Párkányi, Ildikó Anton, Mária Juhász, Mária Kiss and Judit Halász. I express my thanks to Bálint Gyulai and Anita Kapros students, to Csilla Majláth and all my collages at Preclinical Chemical Development for their kindness and support in the preparative work. I am grateful David Durham for the linguistic improvement of the manuscripts of the pubblications and the Thesis. I express my thanks for support through a Chinoin Ltd. / Sanofi-aventis Fellowship and József Varga Foundation.

2 Table of contents

Table of contents

1. INTRODUCTION ...... 5 NEW DERIVATIVES OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE...... 7 2. LITERATURE ...... 7 2.1. SYNTHESES OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES ...... 7 2.1.1. Syntheses from diethyl malonic esters...... 7 2.1.2. Syntheses from Meldrum’s acid derivatives...... 9 2.1.3. Syntheses from (hemi)nitriles...... 9 2.2. PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS ...... 10 2.2.1. Suzuki–Miyaura cross-coupling reaction...... 11 2.2.1.1. Regioselectivity in palladium-catalyzed cross-coupling reactions...... 12 2.2.1.2. Cross-coupling reactions of halogenated 4H-pyrido[1,2-a]pyrimidon-4-ones...... 14 2.2.2. Hiyama cross-coupling reaction...... 17 3. RESULTS AND DISCUSSION ...... 19 3.1. SYNTHESES OF HALOGENATED 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES ...... 19 3.1.1. Role of repulsive electrostatic nonbonded interaction ...... 20 3.2. CROSS-COUPLING REACTIONS OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES ...... 26 3.2.1. Suzuki–Miyaura cross-coupling reaction...... 26 3.2.2. Hiyama cross-coupling reaction...... 30 UNEXPECTED TRANSFORMATIONS OF AN AZOXYQUINOXALINE ...... 32 4. LITERATURE ...... 32 4.1. WALLACH REARRANGEMENT ...... 32 4.1.1. Mechanism of the acid-catalyzed Wallach rearrangement...... 32 5. RESULTS AND DISCUSSION ...... 34 5.1. PROTON-CATALYZED TRANSFORMATION OF AZOXYQUINOXALINE 96 ...... 34 5.2. THERMAL TRANSFORMATION OF AZOXYQUINOXALINE 96...... 37 6. EXPERIMENTAL SECTION...... 40 6.1. SYNTHESIS OF HALOGENATED 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES...... 40 6.2. CROSS-COUPLING REACTIONS OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES ...... 43 6.3. UNEXPECTED TRANSFORMATIONS OF AZOXYQUINOXALINE 96...... 44 7. CONCLUSIONS ...... 45 8. SUMMARY OF THE NEW FINDINGS ...... 48 9. PUBLICATIONS ...... 49 10. REFERENCES ...... 50

3 Abbreviations

Abbreviations BDE Bond distortion enthalpy butylal Formaldehyde dibutyl acetal Compd. Compound Cy Cyclohexyl DCM Dichloromethane dba Dibenzylideneacetone DFT Density functional theory DMA N,N-Dimethylacetamide DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethylsulphoxide dppf 1,1’-Bis(diphenylphosphino)ferrocene eq Equivalent etylal Diethoxymethane FDA Food and Drug Administration FMO Frontier molecular orbital HOMO Highest occupied molecular orbital HRMS High-resolution mass spectroscopy IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene L1 1,3,5-Triaza-7-phosphaadamantane L2 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) L3 Bis(p-sulfonatophenyl)phenylphosphine L4 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl (BINAP) L5 Dibutyl-(2’,4’,6’-triisopropylbiphenyl-2-yl)phosphane LiTMP Lithium 2,2,6,6-tetramethylpiperidide MO Molecular orbital NMP N-Methylpiperidone NXS N-Halosuccinimide

Pd2dba3 Tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PEG Poly(ethylene glycol)

(PinB)2 Bis(pinacolato)diboron PPA Polyphosphoric acid XPhos Dicyclohexyl-(2’,4’,6’-triisopropylbiphenyl-2-yl)phosphane TASF Tris(diethylamino)sulfonium trimethyldifluorosilicate TBAF Tetrabutylammonium fluoride THF Tetrahydrofuran TMAF Tetramethylammonium fluoride TMP 2,2,6,6-Tetramethylpiperidine TMSOK Potassium trimethylsilanolate

4 Introduction

1. Introduction Certain types of pyridopyrimidines – e.g. 4H-pyrido[1,2-a]pyrimidin-4-ones – have aroused much interest owing to their valuable pharmacological properties. The pyrido[1,2-a]- pyrimidine skeleton is a privileged scaffold in medicinal chemistry for facile access to “drug- like” small molecules, 1 as the physical properties of their derivatives usually fulfil the requirements of the criteria of “rule of five” for developing orally active drugs.2 In particular, 4H-pyrido[1,2-a]pyrimidin-4-ones have attracted the attention of the pharmaceutical community, as they display diverse biological activities (Figure 1).

R CH3 CH3 + CH SO - N CH3 N N 3 4 N CH3

N F N N N N N N COOEt N - + O O NNK CH O O 3 O NO Risperidone 1 (R = H) Pemirolast 3 Rimazolium 4 Lusaperidone 5 Paliperidone 2 (R = OH) F

F R = O N CH3 R = N N N O N O R = R N N H F Pirenperone 6 Ramastine 7 Seganserin 8 Figure 1. Some biologically active 4H-pyrido[1,2-a]pyrimidin-4-ones

The best-known representative is the atypical neuroleptic Risperidone 1, which was one of the drugs most widely prescribed worldwide in 2007. 3 Its active, main metabolite, the antipsychotic Paliperidone 2, was registered by the FDA in 2007, and has been recently introduced into the human therapy for the treatment of bipolar disorders as oral atypical antipsychotic. Presently its palmitate ester prodrug is under the evaluation by FDA for treatment of schizophrenia injected monthly.4 The other outstanding members include the antiallergic Pemirolast 3,5 the nonnarcotic analgesic Rimazolium 4,6 the antidepressant Lusaperidone 5,7 the tranquillizer Pirenperone 6, 8 the antiallergic Ramastine 7 9 and the antihypertensive Seganserin 8. 10 Other representatives are also used as photographic sensitizers, catalysts for curing polyisocyanates, synthetic intermediates or as additives to photographic materials and dyes for acrylic nylon, polyester fibres.1 4H-Pyrido[1,2-a]pyrimidin-4-ones are usually synthesized from 2-aminopyridines, and the functionalization of this bicyclic ring system has not been widely explored, except in positions C(2) and C(3). 11 Direct synthesis from 2-aminopyridines sometimes give poor yields. For example, the potent glycogen synthase kinase 3β inhibitor 2-(4-pyridyl)-4H- pyrido[1,2-a]pyrimidin-4-ones could be prepared only in yields of 10-28% in the reaction of 2-aminopyridines and ethyl 3-(4-pyridyl)-3-oxopropionate in PPA at 140-150 oC for 12 h.12

5 Introduction

Nowadays, transition metal catalyzed carbon-carbon and carbon-heteroatom (N, S, O) bond formations of (het)aryl halides have become an indispensable tool for synthetic and medicinal chemists to explore the drugable part of the chemical space to obtain new derivatives with wide therapeutic potential. Their industrial importance is continuously growing.13 These reactions are fundamental techniques for the preparation of heterocycles, and also for the functionalization of (hetero)aromatic ring systems.14 The reactivity of the (pseudo)halo derivatives of wide range of heteroaromatics has been studied. One of the most widely used methods is the Suzuki–Miyaura cross-coupling reaction, which represents a powerful protocol for generation of C–C bonds via palladium catalyzed nucleophilic substitution with organoboranes.15 To date, systematic investigations have not been reported on cross-coupling reactions of 4H-pyrido[1,2-a]pyrimidin-4-ones; merely a few published examples of the carbon-carbon and carbon-nitrogen bond formation are to be found in the literature. Some examples could be found for introduction of an (het)aryl or alkenyl substituent into positions C(2), 16 C(3),17,18,19,20 C(7)21,22 and C(9)22,23,24,25 of the 4H-pyrido[1,2-a]pyrimidin-4-one nucleus by the Suzuki–Miyaura, the Stille or the Buchwald–Harwig cross-coupling reactions. We, therefore set out to investigate the reactivity of the 4H-pyrido[1,2-a]pyrimidin-4-one skeleton in cross-coupling reactions and to prove the scope and limitation of these transformations. This thesis reports on the synthesis of different halogen derivatives of 4H-pyrido[1,2-a]- pyrimidin-4-one, which seemed to be convenient and suitable substrates for cross-coupling reactions. The second part presents an account of investigations on the reactivity order of different positions of 4H-pyrido[1,2-a]pyrimidin-4-one skeleton, using its chloro, bromo and iodo derivatives, in the Suzuki–Miyaura and the Hiyama cross-coupling reactions. The second part of the thesis deals with two unexpected transformations of azoxyquinoxaline 96 (N,N’-diquinoxalin-2-yldiazene N-oxide; Figure 2). The conversion of azoxy arenes (e.g. azoxybenzene 87), on acid treatment, to hydroxy azo compounds is called the Wallach rearrangement. This transformation was discovered by Wallach and Belli in 1880.26 Since then, however, systematic investigations have not been reported on the scope and limitation of this reaction. Besides the benzene and naphthalene derivatives, only a few members of the hetaryl series, some phenylazoxypyridines have been investigated by Buncel and his co-workers.27 In order to broaden the scope of the previous studies, we set out to extend the generic Wallach rearrangement to the heterobicyclic ring systems, starting our investigations with 96. This revealed some interesting and surprising reactions and products, depending on the reaction media. These results and their discussion are also reported here.

N N + N N O N 96 Figure 2. Azoxyquinoxaline 96

6 Literature

NEW DERIVATIVES OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE

2. Literature 2.1. Syntheses of 4H-pyrido[1,2-a]pyrimidin-4-ones The synthetic method widely used for the preparation of 4H-pyrido[1,2-a]pyrimidin-4- ones 12 involves the condensation of 2-aminopyridines 9 with 1,3-bifunctional compounds 10 to yield intermediates 11, which are cyclized in a one-pot procedure or after isolation to furnish 12 (Scheme 1). The cyclization can be carried out through the action of heat, acid or basic reagents. Typical 1,3-bifunctional compounds 10 applied in these syntheses are  β-oxo esters and their congeners;  malonic esters and their congeners;  (2-alkoxymethylene)malonic esters, 3-alkoxyacrylic esters, 2-alkoxymethylene-β-oxo esters and their congeners.11

R R 21 R3 COOR42N R R + R R N NNH R3 COOR 4 N N R2 R3 2 H O 9 10 11 12 Scheme 1. Syntheses of 4H-pyrido[1,2-a]pyrimidin-4-ones 12

Compound 12 has also been prepared by reacting other pyridine derivatives and 1,3- bifunctional compounds [e.g. reaction of ketenes with N-(2-pyridyl)formimidates or Schiff bases], as well as by transformation of an appropriate ring system.11 From a synthetic aspect, the most simplest 1,3-bifunctional compounds 10 to deal with are 2-(alkoxymethylene)malonic esters 10 (R1 = H, R2 = OEt, R3 = COOEt, R4 = Et) and their derivatives. Therefore, the present thesis deals in details only with syntheses using 2- (alkoxymethylene)malonic esters and their congeners as starting materials. 2.1.1. Syntheses from diethyl malonic esters The first 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ester 16 (R3 = COOEt) was prepared by Lappin, who reacted 2-aminopyridines 9 with (2-ethoxymethylene)malonic ester 13 (R3 = COOEt) and cyclized the resulting condensed product 14 in boiling diphenyl ether (Scheme 2).28 The method was later extended by Hermecz and his co-workers, who cyclized 3 29 3 3 acrylic esters 14 (R = Me, Et, Ph), succinic (R = CH2COOEt) and glutaric esters 14 (R =

CH2CH2COOEt) to furnish various 3-substituted 4H-pyrido[1,2-a]pyrimidin-4-ones 16 in moderate to excellent yields.30 When the intermediates 14 were unsubstituted at position C(6) in the pyridine ring, the products were 4H-pyrido[1,2-a]pyrimidin-4-ones 16, whereas from the 6-substituted intermediates 14 1,8-naphthyridin-4(1H)-ones 17 were isolated. The special behaviour of 6- substituted derivatives 14 was ascribed by Lappin to the “ortho effect”: the steric hindrance of the substituent in position C(6) should completely prevent ring closure on the neighbouring

7 Literature ring nitrogen N(1). Cyclization, therefore, should occur at the activated C(3) position leading to formation of the naphthyridone skeleton 17.28 But there are some later, inconsistent results, which can not be explained just on the basis of Lappin’s “steric hindrance” concept.31

N R N R 3 6 O O EtO H R 3 COOEt R 3 C 3  16 R + R R O 3 6 - EtOH NNH R COOEt N N N N 3 2 H R 9 13 14 15 R N N H 17 Scheme 2. Syntheses from (2-alkoxymethylene)malonates 13 and their congeners

Hermecz and co-workers also studied the thermal cyclization of 6-substituted malonic esters 14 (R3 = COOEt) and acrylic esters 14 (R3 = Me, Et, Ph). They established that electrocyclization of the primarily formed iminoketene intermediates 15 takes place at N(1) position under kinetic control. Depending on the natures of R and R3, the first formed product 16 may be transformed into thermodynamic product 17 under the conditions of the ring closure. When position C(6) of the pyridine ring was unsubstituted, compounds 14 and 16 failed to give naphthyridones 17.29 Other research groups have also paid attention to the effect of the C(6) substituent on the course of ring transformation. X-ray diffraction studies on 18 led Wentrup et al. to draw attention to a weak attractive interaction between the C(6)–H and the oxygen of the C(4)=O group, as the C(4)=O group is tilted towards the ring nitrogen (Figure 3).* 32 On the other hand, while the ring transformation of 2-(het)aryl-4H-pyrido[1,2-a]pyrimidin-4-ones can be achieved in low yields at around 350-400 °C,33 their 6-methyl derivatives can be transformed in higher yields at lower temperature, 250-260 °C.34

H + N O

N 4 R 6 O 18 Figure 3. Compound 18

These experimental data indicate that the presence of a 6-substituent on the pyridopyrimidone skeleton enhances the ring transformation, as it generates tension through an unfavourable interaction between the 6-substituent and the oxygen of the C(4)=O group. In the ground state, the steric strain caused by a C(6)–R substituent can be relieved in several ways: extended N(5)–C(4) and C(6)–N(5) bond lengths; widened N(5)–C(4)=O and N(5)–

* Some characteristic data on 18: O=C(4)–N(5) angle: 115-118°, instead of 120°, and the amide-type N(5)–C(4) bonds are unusually long (144-149 pm), compared to a normal amide bond length (135 pm) showing no sign of amide-type conjugation.

8 Literature

C(6)–R bond angles, or a widened R–C(6)•••C(4)=O torsion angle. The driving force of the ring transformation is the release of the strain accumulated in the ground state between the C(4)=O group and the C(6) substituent. The cyclization of intermediate 14 can be carried out  through the action of heat in high-boiling indifferent solvents (e.g. diphenyl ether,28 Dowtherm A,35 diethylbenzene);36  under acidic conditions (e.g. PPA,37 mixture of phosphoryl chloride and PPA,29,30 glacial acetic acid);38  or applying basic regents (e.g. ethanolic sodium ethoxide).39 The intramolecular N(5)–C(4) amide bond is sensitive to basic reagents, therefore, on the action of ethanolic sodium ethoxide an equilibrium mixture of bicyclic product 16 and starting material 14 is formed (Scheme 2).39 2.1.2. Syntheses from Meldrum’s acid derivatives Meldrum’s acid (isopropylidene ester of malonic acid) derivative 19 was also subjected to the ring closure protocol.40 When the cyclization was performed under acidic conditions, in a mixture of phosphoryl chloride and PPA and the reaction mixture was treated with alcohol, carboxylic acid esters 20a (R1 = Me) were isolated. Treatment of the reaction mixture with water furnished carboxylic acids 20b (R1 = H).41 Thermal cyclization of 19 was accompanied by decarboxylation at position C(3) to furnish 21 (Scheme 3).42

N N POCl / PPA O  R R R N R1OH N COOR 1 NN O 3 H CH O 3 O O O 20a: R1 = Me 19 21 CH3 b: R1 = H Scheme 3. Syntheses from Meldrum’s acid derivatives 19

2.1.3. Syntheses from (hemi)nitriles Besides the malonic esters 14 (R3 = COOEt), heminitriles 22 (R1 = COOEt)43 and nitriles 22 (R1 = CN)44 were also subjected to cyclization. Depending on the natures of R, R1 and R2 substituents, reaction conditions and work-up protocols, various 3-substituted pyrido- 3 pyrimidines 23 (R = CN, CONH2, COOH, tetrazol-5-yl; X = O, NH) were synthesized (Scheme 4).

R 1 CN N R2 R R N N N R 2 R3 H X 22 23 (X = O, NH) Scheme 4. Syntheses from (hemi)nitriles 22

9 Literature

2.2. Palladium-catalyzed cross-coupling reactions Halogens, OH groups and O-bound leaving groups attached to a sp2-hybridized C atom of an alkene or an aromatic compound cannot be substituted by nucleophiles alone, but they can be detached from an sp2-hybridized C atom if organometallic reagents act as nucleophiles, or, if a transition metal is present in at least catalytic amounts. These latter SN reactions are designed as C,C-coupling / cross-coupling reactions, and often bear the name of their discoverer (Scheme 5). For the recognition of this principle and for the development of the topic to one of the key methods in modern synthetic organic chemistry, the Nobel Prize in Chemistry 2010 has been awarded jointly to Richard F. Heck (Mizoroki–Heck reaction), Ei- ichi Negishi (Negishi reaction) and Akira Suzuki (Suzuki–Miyaura reaction).45

ML + n RX R' M' R R' + X M'

(0) (0) MLn : Pd , Ni + X : Cl, Br, I, OTf, OSO2R, SOR, SR, N2

M' : B SuzukiMiyaura coupling Sn Stille coupling Mg KumadaCorriuTamao coupling Zn Negishi coupling (earliercalled Kharasch coupling) Si Hiyama coupling Cu SonogashiraHagihara coupling Scheme 5. Important C,C-coupling reactions

The most important substrates for cross-couplings and related reactions are alkenyl, alkynyl and aryl triflates, bromides and iodides. The most important organometallic compounds contain Al, B, Cu, Mg, Si, Sn, Zn or Zr. The metal-bound C atom can be sp3-, sp2- or sp-hybridized, and, in principle, each of these species is capable attacking unsaturated substrates. Organocopper compound (e.g. Gilman cuprates) most usually, but not always, substitute without the need for catalyst. Grignard compounds react in the presence of catalytic amounts of Ni complexes, while organoboron, organozinc and organosilicon compounds typically are reacted in the presence of Pd(0) complexes.45 Nowadays, all these reactions can be carried out in analogous fashion with chlorides in the presence of Pd(0)L complexes, where L is a monodentate bulky, electron rich P ligand of high 46 donicity [e.g. P(t-Bu)3, PCy3]. The development of catalytic systems, in addition, extended the range of the substrates: the adoption of N-, O- and S-nucleophiles led to new, powerful methodologies furnishing heteroaromatics. 47 Most notable is the important C–N bond formation, the Buchwald–Hartwig amination.48 A few other, mechanistically closely related C,C-coupling reactions of alkenyl, alkinyl and aryl triflates, bromides and chlorides are known. These substrates, however, react with metal-free alkenes or acetylenes, again, Pd complexes serve as catalysts. Acetylenes mainly, but not always, need the addition of Cu(I) salts as co-catalysts. The former reactions are summarized as Mizoroki–Heck reactions, 49 the latter is called Sonogashira–Hagihara coupling.50

10 Literature

Since their discovery in the 1970s, palladium-catalyzed cross-coupling reactions have become a long way hence it is possible to construct complex molecules efficiently in less steps than by traditional stoichiometric reactions for C–C bond formation (e.g. Grignard reaction, Wittig reaction, cycloaddition etc.). In the last two decades, these reactions become widely employed from a gram-scale synthesis in academic laboratories to a ton-scale production in the chemical industry.13 The present thesis deals only with the Suzuki–Miyaura and Hiyama reactions, which will be discussed in more details below. 2.2.1. Suzuki–Miyaura cross-coupling reaction In 1979, Miyaura and Suzuki reported the stereoselective synthesis of arylated (E)-alkenes by the reaction of 1-alkenylboronates with aryl halides in the presence of palladium catalyst.51 In honour, the palladium-catalyzed cross-coupling reactions making use of organoboron compounds containing a nucleophilic polarized α-carbon atom and organic halides or triflates providing a powerful and general method for the formation of C–C bonds are known as the Suzuki–Miyaura cross-coupling (Scheme 6).15

Pd(0) (catalytic) R X + R' B(R") R R' + X B(R") 2 base, ligand 2

R' = alkyl, allyl, alkenyl, alkynyl, aryl; R" = alkyl, OH, O-alkyl; R = alkenyl, aryl, alkyl

X = Cl, Br, I, OSO2R, OPO(OR)2 base: Na CO , Ba(OH) , K PO , Cs CO , K CO , TlOH, KF, CsF, Bu NF, NaOH, M+(-OR) 2 3 2 3 4 2 3 2 3 4 Scheme 6. Suzuki–Miyaura cross-coupling reaction

Nowadays, this reaction is probably the most important method for the synthesis of all kind of biaryl derivatives, because the required boronic acids or boronates can be easily synthesized from trialkyl boronates with Grignard or organolithium reagents. Furthermore,  boronic acids are stable towards air and moisture;  starting materials tolerate a wide variety of functional groups, and are unaffected by water;  boronic acids are environmentally safer and show much less toxicity than e.g. organostannes;  the reaction occurs under mild conditions, therefore, generally, the reaction is stereo- and regioselective;  many boronic acids / esters and trifluoroborates are commercial available;  inorganic by-products can be easily removed from the reaction mixture, making the reaction suitable for industrial process.13,45 Since the discovery, many research groups paid attention to the Suzuki–Miyaura cross- coupling. The main course of development focuses on the complex catalytic system (pre- catalysts and ligands), as the fine tuning of the chemical structure, electronic nature and donacity ability of the ligands may strongly influence the reactivity of the Pd complexes, therefore, would facilitate the rate-determining oxidative addition (or sometimes reductive

11 Literature elimination or transmetallation) step making use of new starting materials.46 Improvements may be summarized as follows:  sp3-hybridized alkyl boranes can also be coupled by the B-alkyl Suzuki–Miyaura coupling;52  the use of alkyl, alkenyl, aryl and alkynyl trilfuoroborates in place of boronic acids became general;52  high flexibility towards halides became well-known: less reactive aryl chlorides and alkyl halides, mainly iodides, might be coupled under mild conditions;53  new sulfonic acid derivatives were developed according to tendencies of the chemistry (e.g. fluorine chemistry – nanoflates;54 “green chemistry” – less harmful by-products due to imidazol-1-ylsulfonates).55 After this short summary indicating the utility of the Suzuki–Miyaura cross-coupling reaction, some disadvantages including side reactions should also be mentioned:  generally aryl halides react sluggishly, reactivity may be increased and reaction periods may be reduced by using sophisticated, but expensive ligands;  side products such as self-coupling products are formed because of solvent-dissolved oxygen;  coupling products of phosphine-bound aryls are often formed;  heteroaromatic boron acids are more reactive towards deboronation, this can be suppressed by in situ esterification, which may increase reaction period as boronic esters are less reactive than boronic acids;  since the reaction does not proceed in the absence of a base, side reactions such as racemisation of optically active compounds or aldol condensations may occur;  metal (palladium leaching) and other impurities derived from additives may contaminate the product.13,45 2.2.1.1. Regioselectivity in palladium-catalyzed cross-coupling reactions Wide range of important materials have complex structure containing a (hetero)aromatic core substituted with more than one (het)aryl groups. Syntheses of this type of molecules seem to be a clear limit for the cross-coupling reactions. The installation of e.g. three aryl groups necessitates the use of three sequential selective halogenation and cross-coupling sequence, insuring that the synthesis cannot have less than 6 steps. To overcome this synthetic problem one-pot regioselective polycoupling reactions have been developed to afford directly the polysubstituted product from polyhalogenated heterocycles.56 One source of selectivity is the nature of the halogen that is being displaced in decreasing sequence of I > Br > Cl. This originates from the significant differences in the carbon-halogen bond strengths.57 However, for heterocycles bearing multiple identical halogens, the bond strength should be very similar, and other factors might become important. Handy and Zhang achieved some success in predicting the preferred cross-coupling position in polyhaloheteroaromatics. They proposed a simple guide based upon the 1H NMR chemical shifts of the parent nonhalogenated heteroaromatics. Whilst there is a clear limit for the application, this is likely

12 Literature to be very useful in practice, in particular in the pharmaceutical industry. To explain the utility of this “rule”, some literature examples (e.g. 25b-30) and exceptions (e.g. 24, 25a) are depicted in Figure 4.58

I * 7.75 ppm 7.73 ppm 7.73 ppm 7.38 ppm OTf Br * Br

N Br MeOOC N Br * MeOOC N OTf N Br * 8.59 ppm 8.94 ppm 8.94 ppm 8.59 ppm 24 25a 25b 26

7.72 ppm 7.20 ppm 7.41 ppm 8.88 ppm Ar N COOMe * Br O CHO S Br * Br S Br * N Br Br * Br Br 6.43 ppm 6.93 ppm 6.61 ppm 6.96 ppm 27 28 29 30

* site of first coupling Figure 4. Reactivity of some selected polyhaloheteroaromatics

It is proved that the reactivity of palladium-catalyzed cross-coupling reactions is mainly determined by the relative ease of oxidative addition.59 Therefore, it is reasonable to assume, that the regioselectivity will be defined in this step. The electronic preference of the oxidative addition has been reported to parallel that of the degree of electron deficiency on carbon atom bearing the leaving group, i.e. halogen atom. Electron deficiency can be expressed in terms of 1H NMR chemical shifts if the instinct electronics of the (hetero)aromatic system dominates and the influence of the introduction of the halogens is comparatively modest.58 In order to understand factors that might govern regioselectivity, Garcia et al. carried out calculations on selected polychloroheteroaromatics at B3LYP/6-31G(d) level of theory to (0) determine the energetics for oxidative addition to Pd L2 active species. They found, that the reactivity is determined by both the energy to distort the C–Cl bond to the transition state (0) 60 geometry and to the interaction between the hetrocycle π* and Pd L2 HOMO (Figure 5).

Figure 5. Distortion/interaction model for oxidative addition

When two different halogens or identical halogens in very different chemical environments, are involved, BDEs are the selectivity-determining factors (e.g. 24). However, when the ease of carbon-halogen bond breaking is about the same, then the FMO interactions control the selectivity (e.g. 27).60 In the latter case, the relative rates of couplings at different positions might be influenced by the geometry and electronic nature of the catalytically active Pd(0) species. Extremely, highly electron rich ligands might led to reversed regioselectivity. E.g. various dihaloazoles can be monoarylated at a single carbon-halogen bond with high

13 Literature regioselectivity (Scheme 7). By changing ligand L2 or L3 to highly electron rich ligand L1, the selectivity can be switched for dihaloazoles 31-32, allowing Suzuki–Miyaura cross- coupling at the other, traditionally less reactive carbon–halogen bond. 61 Moreover, an α- nitrogen clearly facilitates carbon-halogen bond cleavage.60

O O O Pd, L1 Pd, L2 Ar I I Ar B(OH) Ar B(OH) I N 2 I N 2 Ar N 31 CH 3 CH3 CH3 Br N Br Ar N Pd, L1 N Pd, L3 Ar Br Br N Ar B(OH)2 N Ar B(OH)2 N 32 Scheme 7. Catalyst-controlled regioselective Suzuki–Miyaura cross-coupling of dihaloazoles 31-32

A more complex problem is the relative rate of breaking of C–O bonds, i.e. reactivity of triflates. Fu et al. described a regioselective Suzuki–Miyaura cross-coupling of 33 with 62 different ligands [P(t-Bu)3 vs. PCy3, Scheme 8]. This means that relative reactivities of triflates are dependent from reaction conditions.63

TfO CH3 CH CH3 3 mol% Pd(OAc)2 3 1.5 mol% Pd2(dba)3 6 mol% PCy3 3 mol% P(t-Bu)3 TfO Cl + (OH) B 3 eq KF 2 3 eq KF Cl THF, rt THF, rt 34a 33 34b 87% 95% Scheme 8. Regiocontrol by ligation state of Pd(0) species

Houk et al. gave a plausible interpretation of this phenomena based on the distortion/interaction model calculated at B3LYP/6-31+G(d) and LANL2DZ levels of theory. They showed that the ligation state of Pd(0) in the oxidative addition step is a key element for (0) regiocontrol. P(t-Bu)3 most likely reacts via monoligated Pd[P(t-Bu)3], and Pd L species favour chloride insertion over C–OTf bonds (33 → 34b). Predominantly due to the lack of distortion of Pd(0) species, the principal reason for preferential attack on the C–Cl bond is:

BDEC–Cl < BDEC–OTf. Therefore, regiselectivity is distortion-controlled. PCy3 is “not enough bulky” to elicit the initial dissociation of pre-catalyst to form Pd(0)L, and the catalytically (0) active species is bisligated Pd(PCy3)2. Pd L2 species are more nucleophilic than monoligated ones, exhibiting a higher HOMO, thus react at the C–OTf bond (33 → 34a). The principal reason for triflate insertion is having the lowest LUMO energy in its distorted TS geometry, and therefore greatest interaction. Thus, regioselectivity is interaction-controlled.64 2.2.1.2. Cross-coupling reactions of halogenated 4H-pyrido[1,2-a]pyrimidon-4-ones Several (pseudo)halo derivatives of the pyrido[1,2-a]pyrimidin-4-one skeleton were functionalized using cross-coupling reactions. A wide variety of substituents were introduced by the Suzuki–Miyaura technique, but a few examples for Stille cross-coupling and Buchwald-Hartwig amination are also reported. This chapter gives a general overview focused on the reaction conditions and introduced substituents.

14 Literature

The formation of biaryl compounds via Suzuki–Miyaura procedure utilizes usually potassium or sodium carbonate as base and 5 mol% Pd(PPh3)4 catalyst, leading selectively to the expected products in medium to excellent yields. Several (het)aromatic derivatives were successfully synthesized under these general conditions. Some typical examples are depicted in Scheme 9 and Scheme 10.

X O Ar O 9 NN N N 5 mol% Pd(PPh3)4 + ArB(OH)2 N K2CO3 N dioxane O Ar atm O 95 °C, 48 h 35 36 X = OTf, Br 20-88%

Ar = S

S O S

Scheme 9. Suzuki–Miyaura reaction in position C(9)

Barbeau et al. synthesized 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones 36 as potential inhibitors of DNA-dependent protein kinase (Scheme 9). They introduced several (het)aryl substituents from poor to excellent yields (20-88 %) employing a multiple- parallel Suzuki–Miyaura approach. As the synthesis of the 9-bromo starting material 35 was insufficient, triflate derivative 35 was utilized in the coupling reaction under simple conditions. Disadvantages are the need of inert atmosphere and low reactivity (48 h reaction period).23 To increase the productivity, reaction conditions were optimized. In the presence of (0) a stronger base (Cs2CO3) and a coordinativelly unsaturated Pd catalyst [5 mol% Pd(dppf)Cl2] even less reactive heterocyclic boronic acid esters could be coupled with 35 in excellent yield (92 %). Reaction periods dramatically decreased from 48 h to 30 min employing microwave heating at 180 °C).25 O’Mahony and co-inventors functionalized pyridopyrimidone 37 at position C(7) leading smoothly to compound 38 (Scheme 10).21

B(OH)2 N OBu N OBu Pd(PPh3)4 + N 2 M Na CO N Br 7 Ph 2 3 Ph toluene O Cl O reflux Cl 37 overnight 38 Scheme 10. Suzuki–Miyaura reaction in position C(7)

Knight et al. were interested in the synthesis of phosphatidylinositol 3-kinase inhibitors, and synthesized a wide range of 9-substituted 7-methyl-2-morpholin-4-yl-pyrido[1,2- a]pyrimidin-4-ones 40 from 9-bromo derivative 39. Two typical examples are depicted in Scheme 11. To decrease the reaction period in the Suzuki–Miyaura cross-coupling the more reactive Pd(dppf)Cl2 catalyst was used. To introduce N-bound substituents (e.g. benzylamine), Knight and co-workers also performed a successful Buchwald–Hartwig amination on compound 39.22

15 Literature

NH B(OH)2 2 Ar NH O Br O O 9 NN NN NH N N Ar NH2 2 N 5 mol% Pd(dppf)Cl N 5 mol% Pd(dppf)Cl N CH 2 CH 2 CH 3 KOt-Bu 3 Na CO 3 O O 2 3 O THF THF 40a 39 reflux, 24 h reflux, 24 h 40b 7-61% 58%

CH3

CH3 CH3 CH3 Ar = CH 3 CH3 OMe CH3

Scheme 11. Suzuki–Miyaura cross-coupling and Buchwald–Hartwig amination at position C(9)

The cheaper chloro derivatives were also subjected to cross-coupling protocols. Yoshida and co-workers synthesized potential MexAB-OprM specific efflux pump inhibitors from 2- chloro derivatives. By means of the Suzuki–Miyaura technique, mainly (het)aryl and alkenyl groups were introduced under simple and mild conditions [5 mol% Pd(PPh3)4, Na2CO3,

DME-H2O, 80 °C - reflux]. Disadvantages are the low reactivity (~ 48 h reaction period) and pure selectivity leading usually to an unseparable mixture of products. Utilizing Stille protocol, some vinyl derivatives were also generated in medium yields [5 mol% Pd2(dba)3, 16 P(t-Bu)3, CsF, dioxane, 80 °C]. Coupling reactions with B-alkyl boranes were also accomplished on 2-Cl and 3-Br derivatives in poor yields under more demanding conditions [5 mol% Pd(dppf)Cl2, K3PO4, DMF, 60 °C].16, 17 Polycouplings were also carried out on 4H-pyrido[1,2-a]pyrimidin-4-ones, e.g. compound 41. A typical procedure is depicted in Scheme 12. The substitution with commercially available boronic acids may be carried out in the presence of a Pd(II) catalyst under mild conditions. To introduce the second, more sophisticated heteroaromatic substituent Palani and co-inventors developed a reverse one-pot procedure. First, compound 42 is converted in situ to boronic acid pinacol ester in the presence of a Pd(0) catalyst, than in the second step heteroaromatic compound 43 and a base is added to the reaction mixture. The same Pd(0) complex deals as catalyst for the boronation and coupling steps.22

F F B(OH)2

1. (PinB)2, KOAc Br O O Pd(dppf)Cl2 O dioxane NN N N NN F 100 °C, 2 h N 10 mol% Pd(PPh ) Cl N 2. Na CO / H O N N Cl 3 2 2 Cl 2 3 2 Na CO Br N O 2 3 O O S DME / H O = 2:1 S 41 2 42 N 60 °C, 4 h N 58 % N N

N 43 N 100 °C, 8 h

Scheme 12. Polycoupling of pyridopyrimidone 41

16 Literature

2.2.2. Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling of organometallic reagents with organic (pseudo)- halides has become a powerful method for C–C bond formation. Organotin, organoboron and organozinc reagents are well established as competent precursors. But due to number of drawbacks, organosilicon reagents have emerged as competitive alternatives. The lack of toxicity, high chemical stability and low molecular weigh make them ideal for use as nucleophilic partners in cross-coupling reactions.65 Silicon-based reagents were originally considered to be insufficiently active toward transmetalation, but early work of Hiyama showed that organosilanes could be activated by a nucleophilic promoter to furnish pentacoordinated Si species, which smoothly undergo transmetalation.66 In honour, the palladium-catalyzed cross-coupling reactions making use of organosilicon compounds containing a nucleophilic polarized α-carbon atom and organic halides are known as the Hiyama cross-coupling (Scheme 13). Following this discovery, a multitude of organosilanes bearing a wide variety of substituents about the silicon center as well as an assortment of transferable groups have been identified.67

Pd(0) (catalytic) R X + R' SiY R R' + X SiY 3 activator, ligand 3

R' = alkyl, alkenyl, alkynyl, aryl, silyl; Y = F, alkyl, OH, O-alkyl; R = alkenyl, aryl, allyl

X = Cl, Br, I, OSO2R, OPO(OR)2, OCOOEt activator: TBAF, TMAF, TASF, KF, TMSOK, Ag O, Cs CO , NaOH, M+(-OR) 2 2 3 Scheme 13. Hiyama cross-coupling reaction

The coupling of organosilicon reagents has evolved to be comparable in scope to the other palladium-catalyzed methodologies. Generally, the reaction conditions are mild, but do require a strong nucleophilic promoter (e.g. KF, TBAF, TMAF, TASF, TMSOK, Ag2O,

Cs2CO3) to provide high yields of the desired products. The inorganic by-products are polysiloxanes, which can be removed by conventional methods such as chromatography or distillation.67 Hiyama and co-workers investigated theoretically the transmetalation between palladium(II)–vinyl complex 46 and vinylsilane 45 with the DFT and MP2 to MP4 methods to clarify the reaction mechanism and the reason why fluoride anion accelerates the palladium- catalyzed reaction between vinyl iodide 44 and vinylsilane 45. The energetics of the whole catalytic cycle was settled (Figure 6). They found that the transmetalation occurs with the largest activation barrier and with a very large endothermicity in the absence of fluoride anion, i.e. this is the rate-determining step. This is in harmony with the experimental facts that the reaction does not proceed well in absence of fluoride anion. The calculations indicated that the acceleration may proceed in two reaction courses;  an iodo ligand in 46 is substituted for fluoride anion, and the transmetalation occurs between the palladium(II)–fluoro–vinyl complex 48 and vinylsilane 45;  and fluoride anion attacks the Si center in the transition state of the transmetalation between the palladium(II)–iodo–vinyl complex 47 and vinylsilane 45.

17 Literature

Figure 6. Catalytic cycle of the Hiyama cross-coupling reaction of vinyl iodide 44 and vinylsilane 45

The acceleration is interpreted in terms of formation of a very strong Si–F bond and the stabilization of the transition state by a hypervalent Si center, which is induced by the fluoride anion.68 The fluoride promoter may be replaced by an alkoxy, hydroxy or any other heteroatom substituents as electronegative anions may also accelerate the transmetalation.68 Shi and Zhang developed mild conditions to achieve fluoride-free cross-coupling between aryl bromides 49 and aryl siloxanes 50 in good to high yields in aqueous medium. The success of the reactions requires the presence of PEG and 3 eq of sodium hydroxide (Scheme 14).69 Sore et al. performed coupling of vinylsilanolates formed in situ from vinyldisiloxanes 52 and (het)aryl iodides and bromides 51 under mild, fluoride-free conditions (Scheme 15).70

Br Si(OMe)3

1.8 mol% Pd(OAc)2 R 2 R 1 + R 2 3 eq NaOH R 1 H2O-PEG 2000 49 50 60 °C, 2-9 h Scheme 14. Fluoride-free Hiyama cross-coupling of arylsiloxanes 50

Hiyama cross-coupling can also be carried out with electron-deficient aryl chlorides using 71 electron rich ligands such as PCy3, P(o-tol)3 or IPr·HCl, aryl mesylates in the presence of 72 55 XPhos and imidazol-1-ylsulfonates applying electron rich Pd(dppf)Cl2 catalyst.

Me Me 1.5 mol% Pd2(dba)2 Ar X + Si R O Ar R 2 3 eq KOH MeOH 51 52 rt or 50 °C Scheme 15. Fluoride-free Hiyama cross-coupling of vinyldisiloxanes 52

18 Results and discussion

3. Results and discussion 3.1. Syntheses of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones As summarised in 2.1. Literature, several malonic acid derivatives can be used as starting material for the synthesis of the 4H-pyrido[1,2-a]pyrimidin-4-one skeleton, the alternative reaction sequences are depicted in Scheme 16. For the synthesis of pyridopyrimidones 21 [unsubstituted in position C(3)], Meldrum’s acid 55 was selected as starting material instead of dimethyl malonate 53, because 55 is a stronger CH acid (pKa = 7.32 in DMSO) and 73 therefore more reactive than 53 (pKa = 15.87 in DMSO). Another advantage is that 21 can be obtained from dimethyl malonates 51 in three reaction steps: cyclization, ester hydrolysis and then decarboxylation,74 whereas isopropylidene esters 19 give 21 directly in a one-pot reaction under thermal conditions where decarboxylation and cyclization occur during heating, at around 240-260 °C.35 Cyclization of isopropylidene malonates 19 can be elicited either on the action of acid or thermolytically. Application of acidic reagents at lower, 135-140 °C after alcoholic work-up leads to the formation of carboxylic acid esters 20, necessitating hydrolysis and decarboxylation again as separate steps.37, 41 For the syntheses of 21, therefore Meldrum’s acid 55 was selected as starting material and intermediates 19 were cyclized on the action of heat.

N COOMe R R N COOMe COOMe N N COOMe H O COOMe 20a 54 53 PPA / POCl 1. H O+ 3 3 MeOH 2. - CO2 O N O CH  O 3 R R N 3 N N O O CH3 H CH O 3 O O O CH 21 19 3 55 Scheme 16. Possible strategies for the synthesis of pyridopyrimidones 21

The detailed synthetic route for compounds 21a-k is shown in Scheme 17. The reaction between Meldrum’s acid 55 and trimethyl orthoformate smoothly yielded isopropylidene methoxymethylenemalonate 56. After the reaction mixture had been heated for 4 hours and then evaporated to dryness, the crystalline residue 56 was left to react with the appropriate 2- aminopyridine 9 in alcohol at ambient temperature overnight. The precipitated malonates 19 were filtered off and used, mainly, directly in the cyclization step without further purification (yields are shown in Table 1 and Table 3). The addition of 6-unsubstituted (2-pyridylamino)methylenemalonates 19a-k to preheated diphenyl ether at 260 oC afforded pyridopyrimidones 21a-k in medium to good 59-84% yields after dilution of the cold reaction mixture with hexane and extraction with aqueous hydrochloride acid, followed by adjustment of the pH of the aqueous extract to 8 with sodium hydroxide solution. The precipitated 21 were filtered off and recrystallized from EtOH. Our

19 Results and discussion work-up protocol provided 15-30% better yields for 21i-k (R = 7-Cl, Br, I) than in the earlier methods.42,75

R O O NNH 4 9 O CH O CH 2 5 3 8 N 3 HC(OCH3)3 3 9 O Ph2O R R N reflux EtOH, rt 6 ~ 260 °C 7 O CH3 MeO O CH NN O 4 h 3 overnight H CH 10 min O O 3 O O O 55 56 19 CH 21 61-99% 3 59-84% Scheme 17. Syntheses of pyridopyrimidones 21

Table 1. Synthesis of pyridopyrimidones 21 Compd. R Yield[a] [%] Compd. R Yield[b] [%] Mp.[b] [°C] 19a H7021a H 80 130-131 19b 3-F 87 21b 9-F 65 171 19c 3-Cl 85 21c 9-Cl 75 148 19d 3-Br 95 21d 9-Br 84 180-181 19e 3-I 75 21e 9-I 71 194-196 19f 4-Cl 79 21f 8-Cl 59 156-157 19g 4-Br 90 21g 8-Br 63 184-185 19h 5-F 81 21h 7-F 75 186 19i 5-Cl 84 21i 7-Cl 81 124 19j 5-Br 99 21j 7-Br 76 125-127 19k 5-I 69 21k 7-I 66 157-158 [a] if necessary, recrystallized from EtOH or precipitated with water from DMSO; [b] recrystallized from EtOH

3-Halopyridopyrimidones 57 were obtained from 21a (R = H) in medium to good 76-86% yields by reaction with the respective N-halosuccinimide in toluene (Scheme 18, Table 2).76

N N NXS N toluene N 30-120 min 3 X O O 21a 57 76-86% Scheme 18. Syntheses of 3-substituted pyridopyrimidones 57

Table 2. Syntheses of 3-substituted pyridopyrimidones 57 Compd. 3-X R. time [min] Yield[a] [%] Mp.[a] [°C] 57a 3-Cl 120 86 159-160 57b 3-Br 40 76 137-138 57c 3-I 30 86 142 [a] recrystallized from EtOH

3.1.1. Role of repulsive electrostatic nonbonded interaction 6-Substituted malonates 19m-p were also subjected to the thermal ring closure protocol (Scheme 19). Several authors reported on enhanced activity towards thermal ring transformation of 6-substituted pyridopyrimidones leading to the formation of the thermodynamically favoured naphthyridone skeleton.33, 77 From the 6-chloro and 6-bromo malonates 19n,o we expected to obtain 6-substituted pyridopyrimidones 21n,o or at least a

20 Results and discussion mixture of the two possible bicyclic products, 21 and 58, as the chlorine and bromine atoms exhibit similar bulkiness to that of the methyl group. For characterization of the size of the substituents, we selected Charton’s ν values derived from the van der Waals radii.78 A dilute solution of 19n,o in preheated diphenyl ether was stirred at boiling temperature for ~ 5 min and quickly cooled to ambient temperature. After dilution of the cold reaction mixture with n-hexane the precipitated crude product was filtered off. The mother liquid was treated with aqueous hydrochloride acid, but no pyridopyrimidones 21 could be isolated.†

O N O Ph2O 6 + + C H N O R ~ 260 °C N 16 10 4 2 2 R N N O R 7 N N H CH 5 min 6 H 3 R O O O CH3 C12H11N2O4R C8H5N2OR C8H5N2OR 19 (6-R) 21 (6-R) 58 59 Scheme 19. Thermal cyclization of 6-substituted malonates 19

Table 3. Synthesis and thermal cyclization of 6-substituted malonates 19 Compd. 6-R Yield[a] [%] 21 [%] 58 [%][b] 59 [%][b] 19m F99 – [c] 71 (mp 241 °C) 6 (mp > 300 °C) 19n Cl 61 – 75 (mp > 300 °C) 8 (mp > 300 °C) 19o Br 72 – 69 (mp > 300 °C) 6 (mp > 300 °C) 19p I9981 (mp 167 °C)[d] ++ 19q Ph 68 68 (mp 173) 18 (mp 286-287) + [a] if necessary, carefully recrystallized from EtOH and / or was purified by precipitating with water from DMSO; [b] fractional crystallization from EtOH; [c] + / – : detected / not detected by LC-MS; [d] recrystallized from THF

From the crude products besides the expected naphthyridones 58, we could isolate by- products, too. In both cases HRMS investigations have indicated a dimer formation with molecule formula C16H10N4O2R2. Naphthyridones 58 and dimers 59 could be separated by fractional crystallization from EtOH, as 59n,o exhibited lower solubility, than 58n,o. The structure of 59 was elucidated by detailed NMR studies. 1H and 13C NMR data are consistent with the dimer structure 59 proposed in Figure 7, and have indicated that the by-products are present as a Z / E ≈ 2:1 isomeric mixture in DMSO-d6. According to our knowledge, these are the first cases when dimeric products were detected and isolated in the case of the thermal cyclization of 6-substituted (2-pyridylamino)methylenemalonates.

A similar dimer formation was earlier described by Wentrup et al. in the case of 2- pyridylketene.79

† The two step work-up protocol was carried out in the expectation of being capable to separate the potentially formed two bicyclic products, 21 and 58, as naphthyridones exhibit a lower solubility than pyridopyrimidones.

21 Results and discussion

Cl 7.59* (d, 3J = 7.9 Hz) Cl 120.6 N 7.98 (d) 7.79** (d, 3J = 7.9 Hz) 142.3 5.89 (d, 3J = 7.4 Hz) N 7.91 (d) 8.05 (t) 150.5 120.6 141.6 N 108.2 8.07 (t) 150.5 141.4 3 5.87 (d, 3J = 8.3 Hz) 7.77* (d, J = 7.9 Hz) 141.4 N 123.4 163.9 183.6 7.61** (d, 3J = 7.9 Hz) 109.1 DMSO-d6 O105.2 O 123.4 164.3 180.7 O O 151.3 H E / Z = 1:2 105.2 3 151.3 9.23 (d) H N 13.53 (d, 3J = 12.3 Hz) 12.29 (d, J = 13.2 Hz) H 9.23 (d) 149.7 N H N 7.42 (d, 3J = 7.7 Hz) 149.7 121.6 N 7.41 (d, 3J = 7.7 Hz) 7.96 (dd) 121.6 Cl 7.64 (d, 3J = 8.1 Hz) Cl 7.96 (dd) 113.1 7.67 (d, 3J = 8.0 Hz) 113.1 (E)-59n (Z)-59n 1 13 Figure 7. Structure of 59n and some characteristic H (red) and C (blue) chemical shifts (DMSO-d6)

In Scheme 20 we present a possible interpretation of the formation of dimer 59. Intermediate 60 is formed quickly at 260 C from malonates 19. Different products, e.g. 21, 58 or 59 could be formed from this key intermediate. Dimer 59 would be formed in a head-to- tail [4+2]-cyclodimerization, which would probably take place in a pseudopericyclic manner, initiated by the attack of an imino lone pair on the carbonyl carbon of a second molecule of iminoketene 60. The initial dimer 61 thus formed, would tautomerise by [1,3]-hydrogen shift to the isolated product 59. From iminoketene 60, pyridopyrimidone 21 forms relatively easily. A C(6) substituent strongly influences the thermodynamic stability of 21, and iminoketene 60 may be regained in an equilibrium. This means that the concentration of 60 is higher for the 6- chloro, 6-bromo and 6-fluoro derivatives and a competing bimolecular [4+2]-cycloaddition can occur, leading to the formation of 59 even in dilute solution.

O H [4+2]-cyclo- O Ar Ar addition Ar Ar N N N N head-to-tail [1,3]-H- H Ar O O N O O shift 59  61 R N N O + H CH Ar 3 - aceton N O O - CO CH 2 3 O N O Ar [4+2]-cycloaddition 19 (6-R) 60 (6-R) 60 (6-R) NH O head-to-head Ar Ar = 6-halo-2-pyridyl 62 Scheme 20. A possible interpretation of formation of dimeric by-product 59

The [4+2]-cycloaddition may occur in a head-to-head (leading to 62) and a head-to-tail manner furnishing by-product 59. The DFT calculations indicate that the latter is ~ 30 kJ/mol more preferable than the former, which is in harmony with the experimental findings. The LC-MS and NMR analyses indicated an impurity in recrystallized 59 with identical molecule formula and “related chemical structure” which might be the head-to-head product 62. Although the thermal cyclization of 19n,o (R = 6-Cl, Br), in contrast with the 6-methyl derivative,31a, 35 failed to give 6-chloro and 6-bromopyridopyrimidones 21n,o, we became interested in the thermal ring closure accompanied by ring transformation of 6-substituted malonates 19. We set out to have a deeper look inside the driving force of these reactions, and extended our investigations to compounds 22m-q.

22 Results and discussion

Thermal cyclization was carried out as aforementioned. Surprisingly, while 6-fluoro derivative 19m gave a mixture of 58m and 59m, similarly to the 6-chloro derivative 19n in spite of containing a substituent roughly half of the size of the chlorine atom, 6-iodo derivative 19p afforded pyridopyrimidone 21p despite the sterically more demanding iodine atom. 6-Phenyl derivative 19q led to a mixture of 21q and 58q as expected (Table 3). To prove the structure, pyridopyrimidone 21p (R = 6-I) was also synthesized by an independent route via lithiation (Scheme 21). Lithiation of 21a (R = H) with LiTMP followed by treatment with solid iodine, furnished 21p in good ~ 80% HPLC yield. Besides the product ~ 20% starting material 21a was detected by HPLC and 1H NMR techniques. The crude product was purified by column chromatography, and compound 21p was isolated in poor, 27% yield. As far as we aware, this is the first example of the functionalization of the 4H- pyrido[1,2-a]pyrimidin-4-one skeleton at position C(6).‡

1. LiTMP N N THF, N2, -78 °C N N 2. I2 O I O 21a 21p HPLC yield: ~ 80% isolated yield: 27% Scheme 21. Lithiation of pyridopyrimidone 21a

As the surprising results of thermal ring closure of 19m-p could not be explained merely in terms of steric interactions between the C(6) substituent and the oxygen of the C(4)=O group, we carried out theoretical studies. Supporting the experimental observations, MO theory employing DFT method at the B3LYP6-311++G(2d,2p) level of theory has been used to discuss the potential geometry of pyridopyrimidones 21a,l-q in vacuum with respect to possible (de)stabilizing forces and interactions caused by C(6) substituent. The energetic profile of the reaction leading to the formation of 21 and 58, was settled, possible intermediates and transition states were also located. DFT calculations were carried out on the potential ground state geometry of 21a,l-q ( While all the atoms are situated in a plain in compound 21a (R = H), in the presence of a C(6) substituent (21l, R = Me / 21q, R = Ph), the methyl / phenyl group and the oxygen of the C(4)=O group are situated in opposite directions of outside this plane, creating a dihedral Table 4). The ground state structure of 6-methyl and 6-phenyl derivative 21l,q, respectively, could also be determined by means of single-crystal X-ray analyses. Fair agreement was achieved between the calculated and experimental data on 21l,q, considering that the theoretical calculations gave data relating to vacuum, while in the solid state the crystal packaging exerts some influence on the geometrical parameters.

‡ This method could not be extended for the preparation of the other 6-halopyridopyrimidones 21m-o. Experiments using electrophiles such as Br2, 1,2-dibromoethane, NBS, NCS, CO2, DMF, Me–S–S–Me, benzaldehyde were not successful, starting material 21a was recovered. Only D atom could be introduced at position C(6) reacting lithium derivative with D2O. In the case of Me–S–S–Me, a minor quantity of 6-tiomethyl- 2-aminopyridine was isolated.

23 Results and discussion

While all the atoms are situated in a plain in compound 21a (R = H), in the presence of a C(6) substituent (21l, R = Me / 21q, R = Ph), the methyl / phenyl group and the oxygen of the C(4)=O group are situated in opposite directions of outside this plane, creating a dihedral

Table 4. Calculated ground state geometry of pyridopyrimidones 21a,l-q Steric ν Bond length Bond length Distance Torsion angle Compd. 6-R param. N(5)–C(4) [pm] C(6)–R [pm] O···R[a] [pm] O=C(4)···C(6)-R [°] 21a H 0 146.5 107.8 222.4 0.01 21l Me 0.52 147.2 150.5 263.6 15.2 Me [b] 145.0(3) 150.4(3) 262.2 11.9 21m F 0.27 149.4 132.1 251.8 12.6 21n Cl 0.55 148.4 173.4 278.6 30 21o Br 0.65 148.2 190.2 287.1 30.8 21p I[c] 0.78 147.7-150.1 212.2-215.1 296.9-308.6 27.5-33.8 21q Ph 1.66[d] 147.3 148.5 267.7 28.2 Ph [b] 145.7(2) 148.6(2) 268.6(2) 31.0(2) [a] distance between the geometric centres; [b] italics indicate experimental data determined by single-crystal X- ray diffraction study; [c] calculations were carried out at the B3LYP/LANL2DZ, B3LYP/DGDZVP, B3LYP/CEP31G, B3LYP/CEP121G, MP2/LANL2DZ and MP2/DGDZVP levels, and the ranges are given; [d] average value, max.: 2.15, min.: 0.57 angle of 11.9° / 15.2° (21l) or 28.2° / 31.0° (21q), respectively. The phenyl group is characterized by a minimum and a maximum value, as its actual size depends on the interplanar angle (angle between the plane of phenyl group and the best plane of the bicycle), 80 which is cca. 55° / 54°. Intermolecular hydrogen bonding and π–π stacking stabilizes the crystal structure of 21q (R = 6-Ph). There is a nonclassical week hydrogen bonding [C(4)=O•••H–C = 255.0 pm, angle(O•••H–C) = 169°] between the oxygen of C(4)=O group and one of the hydrogen atom in meta position on the phenyl ring of an other molecule, and the perpendicular distance between pyrimidone rings of two bicycles is 352.8(6) pm (Figure 8).

a) b) c) d) Figure 8. Calculated ground state geometry (a, b, c) and molecular diagram (d) of compound 21q

In accordance with the Charton’s ν values, the calculations also indicated that the steric demand of 6-phenyl group is somewhat bigger than that of 6-methyl group, as the calculated torsion angle (28.2o) is almost twice as much as in 21l (15.2°; R = Me). And bigger torsion angle means less stability. This is in accordance with the experimental results. Thermal cyclization of malonate 19q (R = 6-Ph) resulted in 68% yield of 21q, which was accompanied by 17% yield of naphthyridone 58q. Under similar conditions 6-methyl derivative 19l afforded only a trace of 7-methylnaphthyridone 58l, beside the main product 21l.

24 Results and discussion

As the calculated dihedral angle in 21m (R = 6-F) is similar to that in 21l (R = 6-Me), and the size of the fluorine atom is only half that of the methyl group, it is postulated that, besides a steric interaction, there is also an unfavourable electrostatic interaction between the lone pair electrons of the fluorine and oxygen atoms. This results in a longer and, therefore, weaker N(5)–C(4) bond relative to that in the methyl derivative 21l. Furthermore, in spite of the similar size of the chlorine atom and the methyl group, the torsion angle in 21n (R = Cl) is twice as large as that in 21l (R = Me), which is probably also a consequence of the repulsion of the electron pairs of the neighbouring halo and oxygen atoms.81 The electrostatic interaction between the halo and oxygen atoms gradually decreases in the sequence F > Cl > Br > I derivatives as the distance between the halo atom and oxygen becomes longer, and the electrostatic interaction falls off exponentially with the distance. For the 6-chloro and 6-bromo derivatives 21n,o, containing sterically more demanding halo atoms, the steric effect plays a greater role than for the 6-fluoro derivative 21m, while the torsion angles are bigger, and the N(5)–C(4) bonds are somewhat shorter.

The decreased stability of 6-fluoro, 6-chloro and 6-bromo derivatives 21m-o is in harmony with the observation of Ferrarini et al. that the 6-fluoro, 6-chloro and 6-bromo derivatives of 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be transformed into naphthyridones only at 220 °C within 10 min.34

The 6-iodo derivative 21p is more stable than the other halo derivatives, even at the reaction temperature, as the electrostatic interaction is minimized in 21p by the longer distance between the oxygen and iodine atoms, the 6-iodo derivative containing the longest C(6)–halogen bond. The ready polarizability of the electron cloud of the iodine atom also decreases the repulsive interaction (if it exists at all in this case) between the neighbouring iodine and oxygen atoms. Furthermore, 6-iodo derivative 21p may be stabilized by a weak intramolecular halogen bonding.82 The electrostatic potential surfaces for pyridopyrimidones 21l-p support the above interpretation (Figure 9). For the 6-fluoro derivative 21m, electrostatic repulsion was indicated by the red areas on the fluorine and oxygen atoms. This gradually became smaller and smaller from the 6-chloro to the 6-iodo derivative.

Figure 9. Electrostatic potential surfaces for pyridopyrimidones 21a,l-p at the 0.02 electron/au3 density isocontour level. Blue is positive, red is negative potential, and green represents near zero potential.

25 Results and discussion

In summary, the DFT calculations in vacuum showed that in 21l (R = 6-Me), only the size of the methyl group influences the adopted conformation and its ring transformation capability, while for the 6-fluoro derivative 21m, mainly the electrostatic repulsion predominates. In 21n-o, both factors may play roles. At 260 oC, 21l,p are sufficiently stable during the short reaction period, but the 6-fluoro, 6-chloro and 6-bromo derivatives 21m-o are easily transformed to 58m-o via iminoketene 60. DFT method was also used to locate and discuss the energetics of the intermediates and transition states for the ring transformation in vacuum. From iminoketene 60, pyridopyrimidone 21 forms relatively easily by electrocyclization, while naphthyridone 58 is produced by aromatic electrophilic cyclization in a two-step mechanism involving a higher transition state. The final proton transfer is presumably a fast process.

3.2. Cross-coupling reactions of 4H-pyrido[1,2-a]pyrimidin-4-ones The functionalization of the 4H-pyrido[1,2-a]pyrimidin-4-one ring system is not a completely settled question, 11 and sometimes the direct synthesis from 2-aminopyridines gives poor yield.12 We wonder, whether cross-coupling processes might be an alternative method for the systematic functionalization of this bicycle. Accordingly, we set out to study the reactivity of the 4H-pyrido[1,2-a]pyrimidin-4-one ring system, to prove which position(s) might be adequate for introducing wide range of substituents. Because of the promising literature results, the commercial availability and the ease handling and of various boronic acids, we started our investigations with the Suzuki–Miyaura reaction. Since Hiyama reaction might be a useful alternative synthetic methodology to Suzuki– Miyaura coupling for the synthesis of biaryl compounds, a preliminary study on coupling with organosilicon compounds was carried out, and a short comparison was made of the two cross- couplings including productivity and selectivity using halo derivatives 21,57 and commercially available 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one 63 as substrates. 3.2.1. Suzuki–Miyaura cross-coupling reaction As explained in details in 2.2.1. Literature, Handy and Zhang proposed a simple guide for predicting the order of cross-coupling reaction in polyhalogenated heteroaromatics based upon the 1H NMR chemical shifts of the parent nonhalogenated heteroaromatics.58 There are exceptions if the chemical shift values vary in a narrow range (Δδ < 0.1-0.2 ppm). We wonder whether this practical rule is also applicable in the case of the 4H-pyrido[1,2-a]pyrimidin-4- one bicycle, as the 1H NMR chemical shifts of positions C(9), C(8), C(7) and C(2) are within 0.3-0.4 ppm (Figure 10). On this basis, the expected reaction sequence of chloro derivatives 21c,f,i, 57a,63, as follows:

Posn. C(2) > C(8) > C(9) > C(7) > C(3).

The chemical shift value of 6-H (8.96 ppm) could not be considered as it is influenced by the anisotropic effect of the neighbouring C(4)=O carbonyl group.

26 Results and discussion

7.70 ppm 9 N 7.97 ppm 8 2 8.31 ppm 7.30 ppm 7 N 3 6.34 ppm 6 O 21a 1 Figure 10. H NMR chemical shift values of 4H-pyrido[1,2-a]pyrimidin-4-one 21a (DMSO-d6)

First, preliminary investigations were made to settle the reaction conditions (catalyst, solvent, reaction temperature, base). As general, we used 1.05 eq of phenylboronic acid to 3- bromopyridopyrimidone 57b in the presence of 5 mol% of Pd-catalyst to yield 3-phenyl derivative 65. We applied an aqueous solution of a week base, NaHCO3, as the pyridopyrimidone skeleton is sensitive for nuchleophilic ring opening.39 Two equivalents of

NaHCO3 was used to boronic acid. For selection of a solvent and a catalyst we studied a few (0) (II) combinations of Pd - [freshly prepared Pd(PPh3)4] or Pd -complexes [PdCl2, Pd(PPh3)2Cl2,

Pd(OAc)2)] and solvents (e.g. ether type solvent – DME; alcohol type solvent – EtOH; ketone type solvent – NMP; acetal type solvents – butylal, DMA, etylal).

B(OH)2 N N N 5 mol% Pd(PPh3)4 X + + N DME N N 1 M NaHCO3 solution O ~ 80 °C, 4 h O O 21,57,63 64-68 21a Scheme 22. Investigation of the reactivity of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones

The reactions were monitored by HPLC. We experienced that hydrodehalogenation accompanied the coupling reactions in different extent to give 21a. Different catalyst-solvent combinations were characterized and compared by HPLC yield after a 24 h reaction period, which varied from almost no reaction (~ 5% HPLC yield) to excellent yield (96% HPLC yield). Hydrodebromination side reaction was significant in the presence of PdCl2 (5-11%).

As reaction periods and conversion were suitable, besides NaHCO3 no other base was studied in details. For more detailed experiments finally we chose Pd(PPh3)4 catalyst in DME as solvent. To prove the reactivity of the 4H-pyrido[1,2-a]pyrimidin-4-one skeleton and to decide whether the “rule of Handy and Zhang” is applicable we carried out coupling reactions on chloro derivatives 21c,f,i,57a,63 with phenylboronic acid. Conversion was measured by HPLC after a 4 h reaction period (Table 5). We found that the reactivity sequence for conditions depicted in Scheme 22 was reasonably well predicted by the “rule of Handy and Zhang”, as only the sequence for positions C(2) and C(8) seems to be reversed, as follows:

Posn. C(8) ≥ C(2) > C(9) > C(7) > C(3).

A plausible explanation might be that in the case 8-chloro derivative 21f the reaction

(oxidative addition) might have a higher SN1 character rather than an SN2 nature relative to the other chloro derivatives.

27 Results and discussion

Table 5. Relative reactivity of chloro derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones Compd. Posn. of Cl Product R. time [h] HPLC yield [%] Starting material [%] 63 2 64 4 (1) > 99 (87[a]) < 1 57a 3 65 45543 21i 7 66 46733 21f 8 67 4 (1) > 99 (94[a]) < 1 21c 9 68 47721 [a] after an 1 h reaction period

Next we have investigated the reactivity of the different halogens, using compounds 21,57,63 with phenylboronic acid (Table 6). Chosen reaction period was 4 h and conversion was again checked by HPLC. The relative reactivity of halogens was in harmony with the expected one,57 and it decreases in the order of I > Br > Cl derivatives. A preference was observed for the hydrodehalogenation side reaction in the slow-reacting positions C(3) and C(7), especially in the case of iodo derivatives 57c and 21k, respectively, leading to better isolated yields for chloro and bromo compounds. Therefore, for the syntheses of (het)aryl and vinyl derivatives depicted in Scheme 23 mainly the comparatively cheaper chloro derivatives were used to devoid side reactions.

Table 6. Relative reactivity of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones Starting material Product By-product 21a Compd. X HPLC yield [%][a] Compd. Posn. HPLC yield [%][a] HPLC yield [%][a] 63 2-Cl < 1 64 2-Ph > 99 < 1 57a 3-Cl 43 65 3-Ph 55 2 57b 3-Br 25 65 3-Ph 73 2 57c 3-I < 1 65 3-Ph 89 11 21i 7-Cl 33 66 7-Ph 67 < 1 21j 7-Br < 1 66 7-Ph > 99 < 1 21k 7-I < 1 66 7-Ph 91 9 21f 8-Cl < 1 67 8-Ph > 99 < 1 21g 8-Br < 1 67 8-Ph > 99 < 1 21c 9-Cl 21 68 9-Ph 77 2 21d 9-Br < 1 68 9-Ph 98 2 21e 9-I < 1 68 9-Ph 98 2 [a] after a 4 h reaction period

We demonstrate the general applicability for functionalization of the 4H-pyrido[1,2-a]- pyrimidin-4-one skeleton in Scheme 23. Conversion was checked in turns of 4 h, 24 h, 48 h and 96 h reaction periods; the applied reaction conditions and work-up protocol were not optimized. Crude products were purified by column or flash chromatography. Isolated yields vary from poor to excellent (38-99 %). The electronic nature of the substituent on the phenyl ring of arylboronic acids had a little effect on the reaction in the case of “slow reacting” derivatives. A sterically demanding substituent in ortho position to the B(OH)2 function made the reactions considerably slower; reaction of 3-chloro derivative 57c and 2-acetylphenyl boronic acid led to only ~45 % HPLC yield. The longest reaction period (96h) was necessary in the case of electron-deficient heteroaromatic boronic acids: reactions usually stopped before full conversion (typically 80-

28 Results and discussion

95 % HPLC yields.). Pentenylboronic acid also provided acceptable yield. In spite of the promising HPLC conversion using benzyl boronic acid pinacol ester ( > 99 % HPLC yield after a 96h reaction period), 2-benzyl derivative 75 could be isolated only in a poor yield (38 %), as we had to repeat the chromatographic step to obtain the compound in pure form. Reaction of iodo derivative 57c with isopropyl- and pentylboronic acids failed to give any coupled product even in the presence of electron rich Pd(dppf)Cl2 catalyst. In summary, the palladium catalyzed Suzuki–Miyaura cross-coupling reaction on halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with boronic acids allows easy access to (het)aryl, alkenyl and benzyl derivatives of this bicycle in poor to excellent yields (38-99 %), even from the comparatively cheaper chloro derivatives under simple conditions. There seems to be a clear limit as concerns applicable substrates: some alkylboronic acids yielded no expected products.

N N 5 mol% Pd(PPh3)4 X + R B(OH) R N 2 DME N 1 M NaHCO3 solution O ~ 80 °C, 4-96 h O 21,57,63 64-84

OMe CF3 S N N N N N N

N N N N N N O O O O O O O 64 69 70 71 72 73 91% (4 h)[a] 97% (4 h) 91% (4 h) 85% (24 h) 93% (4 h) 81% (24 h)

N N N N N N N N

N N N N N N

O O O O O O OMe 74 75 76 77 65 78 87% (96 h) 77% (96 h) 99% (24 h) 38% (96 h)[b] 98% (48 h; X = Cl) 92% (72 h) 70% (24 h; X = Br) 73% (24 h; X = I) N N N N N

N N N N N

O O O S O N O CF3 79 66 80 81 82 76% (96 h) 92% (24 h; X = Cl) 90% (24 h) 51% (96 h) 89% (96 h) 91% (4 h; X = Br) 87% (4 ;h X = I) MeO

N N N N

O O O O 67 83 84 68 97% (4 h; X = Cl) 81% (4 h; X = Br) 87% (24 h) 82% (24 h; X = Cl) 92% (4 h; X = Br) 95% (4 h; X = Br) 89% (4 h; X = I) [a] isolated yields (reaction period); if not indicated, X = Cl; [b] 5 mol% Pd(dppf)Cl , benzylboronic acid pinacol ester 2 Scheme 23. (Het)aryl and alkenyl derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one synthesized via Suzuki– Miyaura cross-coupling reactions

29 Results and discussion

3.2.2. Hiyama cross-coupling reaction The Hiyama cross-coupling of an organosilicon reagent is known as alternative methodology to the Suzuki–Miyaura reaction for the synthesis of biaryl compounds. Preliminary investigations of the coupling of 7-bromo derivative 21j with trimethoxyphenylsilane 85 were also performed (Scheme 24), and a comparison was made with the Suzuki– Miyaura reaction. Several palladium catalysts (Table 8), fluoride sources (Table 7) and solvents were tested; the most reasonable combination is depicted in Scheme 25. We found that 4H-pyrido[1,2-a]pyrimidin-4-one substrates are more sensitive to the Hiyama reaction conditions, yielding the expected 7-phenyl derivative 66 in only a medium isolated yield, as the N(5)–C(4) intramolecular amide bond undergoes hydrolysis under the reaction conditions.

Si(OMe)3 N N N Br Pd source (+ PPh ) + 3 ++ N solvent N N COOMe Br N N F source H O rt-100°C, 4-48 h O O 21j 85 66 21a 86 Scheme 24. Hiyama cross-coupling of 7-bromopyridopyrimidone 21j

Table 7. Influence of the fluoride source on the Hiyama cross-coupling of 21j F source 66 [%][a] 21j [%][a] 21a [%][a] 86 [%][a]

TBAF × 3 H2O 1.05 eq 77 6 6 12 1 M TBAF solution in THF 1.05 eq 79 8 4 9 KF 1.05 eq < 1 99 < 1 < 1 10 eq[b] 544473 NaOH 1.05 eq 15 22 8 55 KOH[c] 3 eq < 1 3 < 1 97

[a] HPLC yields after a 4 h reaction period; reaction conditions: 5 mol% Pd(PPh3)4, toluene, 100 °C; [b] HPLC yields after a 24 h reaction period; reaction conditions: 5 mol% Pd3(dba)3, 10 mol% PPh3; toluene, 100 °C; [c] HPLC yields after a 4 h reaction period; reaction conditions: 5 mol% Pd(PPh3)4, MeOH, rt

Table 8. Influence of the Pd catalyst on the Hiyama cross-coupling of 21j [a] [a] [a] [a] Pd source PPh3 66 [%] 21j [%] 21a [%] 86 [%]

Pd(PPh3)4 5 mol% - 77 6 6 12 Pd2dba3 5 mol% - 53 9 34 5 5 mol% 10 mol% 80 (89)[b] 11 (< 1) 2 (7) 5 2 mol% 4 mol% 58[b] 91123 Pd(PPh3)2Cl2 5 mol% - 76 18 5 < 1 PdCl2 5 mol% 10 mol% 72 < 1 8 20 PdOAc2 5 mol% 10 mol% 81 < 1 19 < 1 [a] HPLC yields after a 4 h reaction period; reaction conditions: 1.05 eq TBAF solution in THF, toluene, 100 °C; [b] HPLC yields after a 24 h reaction period

Other halo derivatives investigated furnished the expected phenyl derivatives 64-68,21q in poor to good HPLC yields (~ 15-85%) (Table 9).

30 Results and discussion

Si(OMe) 3 5 mol% Pd (dba) N 2 3 N 10 mol% PPh3 X + N toluene N 1 M TBAF solution in THF O ~ 100 °C, 4 h O 21,57,63 85 64-68,21q Scheme 25. Hiyama cross-coupling of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones 21,57,63

Table 9. Hiyama cross-coupling of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones 21,57,63 Starting material Product By-product 21a Compd. X HPLC yield [%][a] Compd. Posn. HPLC yield [%][a] HPLC yield [%][a] 63 2-Cl ~ 50% 64 2-Ph ~ 20% < 1% 57a 3-Cl ~ 35% 65 3-Ph ~ 55% < 1% 57b 3-Br ~ 10% 65 3-Ph ~ 75% ~ 10% 57c 3-I < 1% 65 3-Ph ~ 80% ~ 10% 21p 6-I ~ 5% 21q 6-Ph ~ 50% ~ 5% 21i 7-Cl ~ 20% 66 7-Ph ~ 55% < 1% 21j 7-Br 8% 66 7-Ph 82% 3% 21k 7-I < 1% 66 7-Ph ~ 75% ~ 25% 21f 8-Cl ~ 50% 67 8-Ph ~ 15% < 1% 21g 8-Br < 1% 67 8-Ph ~ 25% ~ 5% 21c 9-Cl ~ 35% 68 9-Ph ~ 40% < 1% 21d 9-Br ~ 10% 68 9-Ph ~ 80% ~ 5 % 21e 9-I < 1% 68 9-Ph ~ 85% ~ 15% [a] HPLC yields after a 4 h reaction period

The Suzuki–Miyaura reaction proved to be more efficient than the Hiyama cross-coupling, and the latter demands more optimization experiments to form the desired products in acceptable yields.

31 Literature

UNEXPECTED TRANSFORMATIONS OF AN AZOXYQUINOXALINE

4. Literature 4.1. Wallach rearrangement Treatment of azoxybenzene 87 and its derivatives with strong acids (e.g. sulfuric acid, chlorosulfonic acid, fluorosulfonic acid, para-toluenesulfonic acid) is known to result in the corresponding hydroxyazobenzene 88 (Scheme 26). The products of the rearrangement have been found to depend on the reaction conditions: at low acidities the hydroxy group generally appears in a para position and product 88 is obtained. Though blocking of both para positions may give rise to the ortho-hydroxy derivative being predominant over the para-isomer,83 but an ipso substitution at one of the para positions is also possible.84 At higher concentrations other products might be formed, azobenzene is a minor deoxygenation product,85 and, in addition, some polymeric materials of aniline and arylsulfonic acids are also formed in small amounts.83

4 OH H SO N + 2 4 N N 1 N O 4' 87 88 Scheme 26. Wallach rearrangement

The thermal,86,87 photochemical,87 and Lewis-acid88 induced Wallach rearrangements are also known, yielding ortho-hydroxy azo compounds as the sole hydroxylated product. In these rearrangements the hydroxy group is found in the more distant ring, and the mechanism proved to be intramolecular.89 4.1.1. Mechanism of the acid-catalyzed Wallach rearrangement Despite the experimental evidences, the mechanism90 has not been completely settled yet, and the proposed reactive intermediates and possible mechanisms are not known with great precision. Supporting the experimental observations and experiences, MO theory employing the semi-empirical AM1 method has been used to locate and discuss the energetics of the intermediates and transition states for the rearrangement in vacuum and also in solution.91 At any rate, the following facts are known: The phenolic oxygen atom in the product is not that in the azo compound but provided by the solvent, based on 18O isotopic scrambling experiments. Therefore the para rearrangement is known to proceed only intermolecularly, whereas the mechanism of the ortho orientation has been uncertain, with evidence presented for both intra- and intermolecular mechanisms.92 When the reaction was carried out with azoxybenzene 87 in which the N–O nitrogen was labelled with 15N, both nitrogens of the product carried the label equally, demonstrating that the oxygen did not have a preference for migration to either the more distant or to the less distant benzene ring.93 The employment of 14C isotopic tracer in position C(1) is in essential

32 Literature agreement with those mentioned before (Scheme 26).94 This indicates the appearance of a symmetrical intermediate since the unreacted azoxybenzene 87 does not undergo oxygen exchange or migration to the other nitrogen under reaction conditions.93 The primary kinetic isotope effect for the erstwhile 4- or 4’-arene protons is close to one excluding the corresponding C–H bond from breaking in the rate-determining step.95 Since the reaction rate continues to increase beyond the stage of complete monoprotonation of the substrate, kinetic studies point to the involvement of two protons in the reaction. Furthermore, other kinetic evidences identify the second proton-transfer to the oxygen of the protonated azoxy function as the rate-determining step occurring before the symmetric stage.96 These facts seem to provide a firmer basis for the dicationic intermediate mechanism (Scheme 27), however other mechanisms, involving an unsymmetrical quinonoid 97 or an N,N-oxide intermediate 98 with only one positive charge, have been proposed for certain substrates at low acidities. But only for those azoxy compounds in which the monoprotonated intermediate species can be stabilized in some way: for instance, by retention of full aromaticity in one of the aromatic rings of several azoxynaphthalenes.99

+ H+ N + + N N N NN O AH OH HO 87 89a 89b

H + N + N + N N N N + OH2 OH + OH 91 90 89c

b - H2O + + + + + N N + N N N N - H2O + - HO  - - A + HA 93a 93b 92 + + for clarity, only two possible (HA = H2SO4 or H3SO4 but not H3O ) - resonance forms are shown + HSO4

OSO H OH OSO3H 3 H N N N + N N N - H work-up + 94 95 88 (probably protonated) Scheme 27. Dicationic intermediate mechanism

33 Literature

The main feature of the dicationic intermediate mechanism is the postulate of the involvement of the symmetrical dicationic intermediate 93 (Scheme 27). This mechanism is followed at acidities greater than 80% sulfuric acid. The substrates are extensively monoprotonated in strong acidic media to give species 89 that is stable in the reaction media. It was argued that formation of dicationic intermediate 93 from the conjugate acid 89 of azoxybenzene might occur by two possible reaction pathways: (a) a possible second equilibrium protonation is followed by rate-determining heterolysis of the N–O bond, i.e. loss of water, to give resonance-stabilized dicationic intermediate 93; (b) conjugate acid 89 is attacked by a second molecule of acid on the oxygen function in the rate-determining step, only the strongest acids in the medium being capable of reacting in this general acid catalysis process. Then it is followed by a concerted loss of water and formation of dicationic intermediate 93 via transition state 92. The dicationic species 93 would then suffer a fast - nucleophilic attack by HSO4 to give para-sulfoazobenzene 95 as the reaction product after a proton-loss and rearomatization. 92 is known to hydrolyse rapidly to para-hydroxyazobenzene 88 as the reaction mixture is diluted.96 It has proved possible to obtain 89 and 93 as stable species in super acid solutions: dicationic intermediate 93 with an unusual Ar–N+≡N+–Ar motif has been detected by 1H NMR technique in a system of fluoroantimonic acid and azoxybenzene at -50 °C.100

5. Results and discussion We first applied the original Wallach rearrangement conditions, treating azoxy compound 96 with conc. sulfuric acid in the expectation of obtaining the corresponding 3-oxo 97a (ortho-like product) or 6-hydroxy 97b (para-like product) azo compound (Scheme 28).

N N N OH conc. H SO N N + 2 4 NN N N N N NN or N N O 6 N 3 N O N H 96 97a 97b Scheme 28. Expected reaction of azoxyquinoxaline 96 in conc. sulfuric acid

5.1. Proton-catalyzed transformation of azoxyquinoxaline 96

Buncel and his co-workers reported that the phenylazoxypyridines and their N-oxides react much more slowly than does azoxybenzene 87 itself, presumably because of the extra positive charge present in the substrates.27

We therefore decided to carry out the transformation of 96 at higher temperature. After azoxyquinoxaline 96 had been stirred in conc. sulfuric acid at 140 °C for 10 min, the isolated product was recrystallized and characterized by HRMS assay. Surprisingly, during the reaction we observed nitrous gas evolution and, consistently, HRMS assay did not contain any oxygen atom: instead of the Wallach rearrangement, formally HNO was eliminated from

34 Results and discussion

96. Compound 98, with the molecular formula C16H9N5, was obtained in 63% yield (Scheme 29). On the basis of 2D NMR measurements, a new pentacyclic system, imidazo[1,2-a:4,5- b’]diquinoxaline 98, is proposed for the structure.

N conc. H SO N N NN+ 2 4 N N 140 °C N O 10 min N N N

C16H10N6O - HNO C16H9N5 96 98 63% Scheme 29. Reaction of azoxyquinoxaline 96 in conc. sulfuric acid

Unfortunately we were not able to obtain single-crystals, so we decided to support the pentacyclic structure of compound 98 by an independent synthesis in the manner of establishing the imidazole ring via Buchwald–Hartwig amination (cross-coupling reaction for C–N bond formation).

Since the discovery of the Buchwald–Hartwig amination in 1995 the synthesis of several heterocyclic skeletons making use of it has been described in the literature.14a Loones et al. developed a new one-pot methodology for the synthesis of dipyrido[1,2-a:3’,2’-d]imidazole 101 and its aza-analogues. The tandem, consecutive inter- and intramolecular palladium- catalyzed amination of 2-chloro-3-iodopyridine 99 with amino(di)azines 100 in a regio- and chemoselective manner furnished the expected heterocycles in excellent yields (Scheme 30).101

Pd(OAc) I 2 L2 or L4 N + (N) Cs CO , toluene NCl NNH 2 3 N N (N) 2 reflux, 17 h 99 100 101 82-98% Scheme 30. Synthesis of dipyridoimidazole 101 and its analogues

The synthesis of compound 98 starting from 2,3-dichloroquinoxaline 102 and 2- aminoquinoxaline 103,102 was subjected to the protocol mentioned above (Scheme 31). We first carried out the reaction under typical Buchwald–Hartwig amination conditions: a mixture of chloride 102, amine 103, sodium tert-butoxide, palladium(0) source and a “Buchwald type” ligand (usually electron rich, bulky, sterically demanding biarylposhines) in tert-butanol was stirred under argon atmosphere at 75 °C for 24 h. The reaction has been examined with respect to the conversion applying palladium(0) sources and ligands in various combinations. The conditions depicted in Scheme 31 were found to be the most reasonable; imidazodiquinoxaline 98 was isolated in a yield of 43%. The synthesis was also carried out stepwise to increase the yield and to identify the intermediate after the first, intermolecular amination. The nucleophilic substitution of compound 102 with amine 103 in the presence of potassium tert-butoxide took place on ring

35 Results and discussion

N(1) nitrogen, but not on the amino function, to give 1-(3’-chloro-2’-quinoxalinyl)quinoxalin- 2(1H)-imine 104 in poor 29% yield.§ Imine 104 underwent a Buchwald–Hartwig cyclization under the same conditions as the one-pot procedure to furnish imidazole derivative 98 in good 79% yield. A better yield for 98 could not be achieved (overall yield for the two steps: 23%), but structure of 104 was settled. The product synthesized in the Buchwald-Hartwig amination was found to be identical with compound 98, supporting the pentacyclic structure, as well.

Pd2(dba)3 + L5 KOt-Bu N NH NaOt-Bu DMSO Cl t-BuOH rt, 24 h N Ar atm. N N N 75 °C, 24 h N Cl N NH2 + 104 N N N 29% N Cl N 102 98 103 Pd2(dba)3 + L5, NaOt-Bu, t-BuOH Ar atm., 75 °C, 24 h 2 step synth.: 79% (overal yield: 23%) one-pot synth.: 43% Scheme 31. Synthesis of imidazodiquinoxaline 98

After which the structure of product 98 was elucidated, we carried out some studies in order to evaluate the effect of the strength of the acid and temperature on the course of transformation. Stirring azoxyquinoxaline 96 at 140 °C for 10 min in various strong mineral and organic acids uniformly furnished 98 in moderate 56-67% yields. Yields and reaction conditions are listed in Table 10 (Entries 1-5). In the presence of sulfuric acid, a reduction of the temperature did not have a significant influence on the nature or quantity of the product, but the necessary reaction time increased considerably, from 10 min to 48 h (Entry 2).

Table 10. Influence of the nature of the medium and temperature on the transformation of 96 [a] [b] Entry Medium pKa Temp. [°C] Product Yield [%] 1 conc. H2SO4 -3.0 140 98 63 [c] 2 conc. H2SO4 -3.0 rt 98 67 3 CH3SO3H -2.6 140 98 56 [d] 4 CF3COOH -0.25 72 98 56 5HCOOH3.77 101[d] 98 67 6AcOH 4.76 118[d] 108[e] 85 [d] 7 Ac2O 140 108 87 8glycol 140 108 80 9 morpholine 8.36[f] 129[d] 112[g] 87 103 [a] pKa in water; [b] after 10 min; recrystallized yields; [c] after 48 h; [d] at boiling temperature; [e] 96 → 108 is shown in Scheme 33; [f] for conjugate acid; [g] 96 → 112 is shown in Scheme 35

§ The reaction was monitored by HPLC: 63% imine 104, 17% starting material 103, 6% pentacycle 98 and 14% others – not identified. The application of potassium tert-butoxide and / or chloride 102 in excess did not give significantly better yields. Compound 98 could not be achieved as the main product devoid of palladium catalyst. The crude product was two times recrystallized from acetonitrile to yield imine 104 in a yield of 29%.

36 Results and discussion

We present a possible interpretation of the formation of pentacyclic derivative 98 depicted in Scheme 32. In the protonated form 105 of the azoxy function, ** which is suitable to assume on the analogue of 89 (Scheme 27), [1,2]-aryl migration104 occurred on the diazo moiety, followed presumably by concerted loss of “HNO” to give resonance stabilized di(quinoxalin-2-yl)amino cation 106. Then pentacyclic skeleton of intermediate 107 was formed by [1,5]-electrocyclization of 106, and after a deprotonation and rearomatization compound 98 was obtained. The involvement of an electrocyclization step is suggested based on experimental observation: the reaction was not susceptible to influence neither by the value of pKa of the medium nor by increasing temperature.

N N + + H+ NN NN+ N N + N N N N N [1,2]-aryl N O OH migration N N N 96 105 - HNO 106a

N N N N N N + N N N N N N N - H+ H [1,5]-electrocyclization + :N N 98 107 106b

Scheme 32. Possible interpretation of the formation of imidazodiquinoxaline 98

5.2. Thermal transformation of azoxyquinoxaline 96

When the value of pKa was systematically increased, dramatic changes were observed above pKa = 3.77. Reaction in boiling acetic acid provided a yellow homogenous reaction mixture instead of the red pentacycle 98. After azoxyquinoxaline 96 had been stirred in boiling acetic acid for 10 min, the isolated product was recrystallized and characterized by

HRMS technique: the HRMS assay indicated the elimination of N2 from 96. Compound 108, †† 105 with the molecular formula C16H10N4O, was obtained in 85% yield. On the basis of 2D NMR measurements, 1-(quinoxalin-2-yl)quinoxalin-2(1H)-one 108 is proposed for the structure which was proved by single-crystal X-ray crystallography: the relative positions of the two planar quinoxaline rings are characterized by a C(12)–N(11)–C(3)–C(2) torsion angle of 63.2(2)° (Scheme 33). The question arose of the possibility of thermal reaction; the same product was obtained from neutral organic solvents, e.g. acetic anhydride and glycol, and even neat from 96. Yields and reaction conditions are listed in Table 10 (Entries 6-8). Accordingly, we carried out thermoanalytical studies (DSC, TG and DTG analyses). At 166 °C, at the melting point of azoxy compound 96, an intense exothermic reaction 96 → 108 (ΔH166°C = -84.6 kcal/mol)

** Not only azoxy moiety, but ring nitrogen(s) might be also protonated; to simplify this complex equilibrium system the quinoxaline rings in Scheme 32 are depicted in basic, nonprotonated form. †† Quinoxalone 108 was earlier isolated by Iijima as a by-product: heating of quinoxaline N-oxide with acetic anhydride resulted in formation of 108 in 4% yield among others.

37 Results and discussion

was detected, and the gravimetry demonstrated a relative loss of mass Δm172°C = 9.3%, which is consistent with N2 elimination (theoretical loss: Δm = 9.3%). When the same sample, now containing quinoxalone 96, was further heated to 220 °C, endothermic melting (ΔH220°C = 7.2 ‡‡ kcal/mol) ensued. One must state that in solvents, the N2 elimination proceeded even at much lower temperatures, indicating a very strong solvent effect (Entries 6-8).

N N NN + AcOH N N 118 °C N N O 10 min N O N C H N O C H N O 16 10 6 - N2 16 10 4 96 108 85% Scheme 33. Reaction of azoxyquinoxaline 96 in boiling acetic acid and structure of quinoxalone 108 with the crystallographic atomic numbering

This type of thermal transformation does not appear to have been widely described in the 106 literature: only one example of the thermolytic loss of N2 from azoxy compounds is known.

On the evidence of these studies and the literature data, we propose the mechanistic pathway depicted in Scheme 34. The first step involves ipso-attack by the oxygen of the azoxy moiety of 96 on the positively charged C(2) of the more distant quinoxaline ring to furnish spiro derivative 109. This is followed by a [2+2]-cycloreversion of intermediate 109 to give quinoxalone anion 110 and quinoxaline-3-diazonium ion 111 in a form of “intimate §§ ion pair”. Subsequent N2 loss occurred during recombination of cation 111 and anion 110 providing quinoxalone 108. However, devoid on detailed kinetic studies one can not determine the sequence of the two steps (recombination and N2 loss), product 108 also might be formed from the two ionic species 110 and 111 either by an SN2 or SN1 or concerted mechanism. To find support for the proposed cleavage of the C(1’)–N bond, we attempted to trap the cationic species formed in the reaction medium by a nucleophile. In view of the scope and limitation of the trapping reaction, we set out to catch cation 111 or – after N2 loss – the appropriate quinoxalinyl cation (SN2 versus SN1) in morpholine (Scheme 35). When 96 was heated for 10 min in boiling morpholine, 2-(morpholin-4-yl)quinoxaline 112 was obtained in good 87% yield; yield calculated for cation 111 (Table 10, Entry 9).*** 107

‡‡ Actually decomposition temperature of azoxyquinoxaline 96: Ton set = 164 °C (carefully recrystallized from butanol) - measured in open capillary tube with a Büchi 535 apparatus. Melting point of quinoxalone 108: mp. 222-223 °C (methanol). §§ “Intimate ion pair” should mean ions not solvated, but present together in one solvate cage. This type of intermediate was also proposed in the ortho-Wallach rearrangement.92 *** Similar treatment of quinoxalone 108 in morpholine resulted in no formation of 112 (HPLC yield after 10 min: < 1%).

38 Results and discussion

N N

NN +  N + N N N N N [1,4]-cyclization [2+2]-cycloreversion O O N N 96 109

+ NN N N 111 N N N O - N2 - O 110 N N 108 "intimate ion pair" Scheme 34. Possible interpretation of formation of quinoxalone 108

The reaction was monitored by LC-MS: in traces, quinoxalone 108 was also detected. This indicates, that anion 110 is also present in the reaction mixture, but this “other half “ of the molecule 96, i.e. other quinoxaline ring, was not dealt with. Since concentration of morpholine is much higher than those of 110, the formation of quinoxalone 108 only in small amounts is comprehensible. All these observations and results seem to support our proposal for the appearance of the cationic species 111.

N O NN + morpholine N N N N 129 °C O N 10 min N 96 112 87% (for cation 111) Scheme 35. Reaction of azoxyquinoxaline 96 in boiling morpholine

39 Experimental section

6. Experimental section The syntheses of the halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one were carried out on a 20 g scale; yields were not maximized. Cross-coupling reactions were performed on a 100 mg scale in commercially available 4 mL screw-cap vials. Reactions were monitored by

TLC (Silica gel 60 F254), HPLC (VWR AV Hitachi Elite LaChrom), LC-MS (Acquity UPLC, László Balázs) or GC (Shimadzu GC-2010) chromatography. Crude products were purified by crystallization, column chromatography (Silica gel 60) or flash chromatography (CombiFlash Retrieve). New compounds were characterized by means of NMR (Bruker Avance 200 or Bruker Avance-II 400, Sándor Boros), MS (Shimadzu GCMS-QP2010S), HRMS (Waters LCT Premier XE, László Balázs), UV (Agilent 8453 UV-Visible spectrometer, Mária Kiss), IR (KBr, VERTEX 70, Lászlóné Faragó). Melting points were determined in open capillary tubes with a Büchi 535 apparatus and are uncorrected. For detailed spectroscopic data, see [1], [2], [3] or [6]. Numbering in brackets with red, blue, gold and green refers [1], [2], [3] or [6], respectively. Compounds not listed below are commercially available and were used without further purification. MO theory employing the DFT method at the B3LYP6-311++G(2d,2p) level of theory was used to discuss the potential geometry of 6-substituted 4H-pyrido[1,2-a]pyrimidin-4-ones in vacuum (Gábor Vlád, Zoltán Mucsi). For compounds 21l,q, the calculated data are in fair agreement with those obtained from single-crystal X-ray diffraction studies (Rigaku R-AXIS Rapid IP, László Párkányi). Calculations on 6-iodo derivative 21p were carried out at the B3LYP/LANL2DZ, B3LYP/DGDZVP, B3LYP/CEP31G, B3LYP/CEP121G, MP2/LANL2DZ and MP2/DGDZVP levels, and the ranges are given. For characterization of the steric demand of C(6) substituents, we selected Charton’s ν values derived from the van der Waals radii.78 Electrostatic potential surfaces are depicted at the 0.02 electron/au3 density isocontour level (Figure 9). For computational details including geometries and electrostatic potential surfaces for compounds 21a,l-q, see Supporting Information of Appendix [2]. The material is available free of charge via the Internet at http://pubs.acs.org. CCDC-816421 and CCDC-749526 contain the supplementary crystallographic data for compounds 21q and 108, respectively These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 6.1. Synthesis of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones Synthesis of isopropylidene (2-pyridylamino)methylenemalonates 19 General method. A 1:2 mixture of Meldrum’s acid 55 (17.6 g, 0.12 mol) and trimethyl orthoformate (30 mL, 0.25 mol) was heated under reflux for 4 h, and the reaction mixture was then evaporated to dryness. The residue 56 was dissolved in EtOH (200 mL) and the appropriate 2-aminopyridine 9 (0.1 mol) was added, and the reaction mixture was stirred at ambient temperature overnight. The precipitated 19 was filtered off, washed with EtOH and was used in cyclization reaction – mainly – without further purification. If necessary, 19 was

40 Experimental section carefully recrystallized from EtOH and / or was purified by precipitating with water from DMSO. Yields are given in Table 1 and Table 3.

ISOPROPYLIDENE (2-PYRIDYLAMINO)METHYLENEMALONATE 19a [13a] ISOPROPYLIDENE (3-FLUOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19b [13b] ISOPROPYLIDENE (3-CHLOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19c [13c] ISOPROPYLIDENE (3-BROMOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19d [13d] ISOPROPYLIDENE (3-IODOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19e [13e] ISOPROPYLIDENE (4-CHLOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19f [13f] ISOPROPYLIDENE (4-BROMOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19g [13g] ISOPROPYLIDENE (5-FLUOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19h [13h] ISOPROPYLIDENE (5-CHLOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19i [13i] ISOPROPYLIDENE (5-BROMOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19j [13j] ISOPROPYLIDENE (5-IODOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19k [13k] ISOPROPYLIDENE (6-FLUOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19m [6c] ISOPROPYLIDENE (6-CHLOROPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19n [13l] ISOPROPYLIDENE (6-BROMOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19o [13m] ISOPROPYLIDENE (6-IODOPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19p [6f] ISOPROPYLIDENE (6-PHENYLPYRIDIN-2-YLAMINO)METHYLENEMALONATE 19q [46] Thermal cyclization of isopropylidene (2-pyridylamino)methylenemalonates 19 General Method. Isopropylidene (2-pyridylamino)methylenemalonate 19 (2 g) was added to o o Ph2O (40 g) preheated to 260 C. The reaction mixture was heated at 260 C for 2-10 min, then quickly cooled to room temperature, diluted with n-hexane (80 mL). The precipitated 6- iodo-4H-pyrido[1,2-a]pyrimidin-4-one 21p or a mixture of 7-halo-1,8-naphthyridin-4(1H)- one 58 and dimer 59 was filtered off and washed with n-hexane. 58 and 59 were separated by fractional crystallization from EtOH as 59 exhibited lower solubility. Yields and mp. are listed in Table 3. The mother liquid was extracted with 2 N HCl. The pH of the separated aqueous phase was adjusted to 8 with aqueous NaOH, and the precipitate was filtered off, washed with water, and recrystallized from EtOH to give 4H-pyrido[1,2-a]pyrimidin-4-ones 21. Yields and mp. are given in Table 1. 108 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21a [17a]

6-IODO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21p [8f] 6-METHYL-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21l [8b] 6-PHENYL-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21q [48] 7-FLUORO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21h [17h] 7-CHLORO -4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21i [17i] 7-BROMO -4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21j [17j] 7-IODO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21k [17k] 8-CHLORO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21f [17f] 8-BROMO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21g [17g] 9-FLUORO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21b [17b]

41 Experimental section

9-CHLORO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21c [17c] 9-BROMO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21d [17d] 9-IODO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 21e [17e] 7-FLUORO-1,8-NAPHTHYRIDIN-4(1H)-ONE 58m [9c] 42 7-CHLORO-1,8-NAPHTHYRIDIN-4(1H)-ONE 58n [27a] 42 7-BROMO-1,8-NAPHTHYRIDIN-4(1H)-ONE 58o [27b]

7-PHENYL-1,8-NAPHTHYRIDIN-4(1H)-ONE 58q [47] 1-(6-FLUORO-2-PYRIDYL)-3-[(6-FLUORO-2-PYRIDYLAMINO)METHYLENE]-1,2,3,4-TETRAHYDROPYRIDIN- 2,4-DIONE 59m [10c] 1-(6-CHLORO-2-PYRIDYL)-3-[(6-CHLORO-2-PYRIDYLAMINO)METHYLENE]-1,2,3,4-TETRAHYDROPYRIDIN- 2,4-DIONE 59n [29a] 1-(6-BROMO-2-PYRIDYL)-3-[(6-BROMO-2-PYRIDYLAMINO)METHYLENE]-1,2,3,4-TETRAHYDROPYRIDIN-2,4- DIONE 59o [29b] Synthesis of 3-halo-4H-pyrido[1,2-a]pyrimidin-4-ones 57 General Method. The respective N-halosuccinimide (0.11 mol) was added to a solution of 4H- pyrido[1,2-a]pyrimidin-4-one 21a (14.6 g, 0.1 mol) in toluene (200 mL), and the mixture was heated under reflux for 30-120 min, then filtered hot and evaporated to dryness. The residue was solved in DCM, extracted with NaOH solution and brine, dried over MgSO4, and was evaporated to dryness. The crude product was recrystallized from EtOH. Yields and mp. are listed in Table 2.

3-CHLORO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 57a [30a] 76 3-BROMO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 57b [30b]

3-IODO-4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONE 57c [30c] Synthesis of 6-iodo-4H-pyrido[1,2-a]pyrimidin-4-one 21p [8f] A solution of anhydrous TMP (1.27 mL, 7.54 mmol) in anhydrous THF (25 mL) was cooled to -78 °C, at this temperature a solution of n-butyllithium in hexane (4.3 mL, 6.85 mmol) was introduced dropwise under an atmosphere of dry nitrogen. The mixture was stirred for 10 min, after which 4H-pyrido[1,2-a]pyrimidin-4-one 21a (1.0 g, 6.85 mmol) was added to the solution. After 1 h stirring, solid iodine (1.71 g, 6.85 mmol) was introduced. After 1 h, the mixture was allowed to warm to rt, hydrolysis was carried out with water, the organic layer was removed under reduced pressure. The aqueous phase was extracted with DCM (3 × 20 mL), the combined organic extracts were dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel (Kieselgel 60 F254, toluene / methanol = 4 : 1), and was recrystallized from THF. Yellow crystals (0.51 g, 27 %; mp. 166- 167 °C).

42 Experimental section

6.2. Cross-coupling reactions of 4H-pyrido[1,2-a]pyrimidin-4-ones Palladium tetrakis(triphenylphosphine)109

Pd(PPh3)4 catalyst was prepared by reported procedure. 2-Chloro-4H-pyrido[1,2-a]pyrimidin-4-one 63 Compound 63 is commercially available. It was used after recrystallization from diisopropyl ether. Suzuki-Miyaura cross-coupling reaction General Method. To a solution of halogenated pyridopyrimidone 21,57,63 (0.25 mmol) and boronic acid (0.26 mmol) in DME (1.5 mL), 1 M NaHCO3 solution (0.6 mL, 0.53 mmol) was introduced. The mixture was heated to 80 °C, after which Pd(PPh3)4 catalyst (14 mg, 0.01 mmol) was added. After 1 h – 4 d stirring at 80 °C, the mixture was allowed to cool to RT, and was poured into water (3 mL), and was extracted with DCM (3 × 3 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by column or flash chromatography (RediSep®Rf 24 gram Flash Column, eluent: n- hexane / ethyl acetate = 1 : 1; for compounds 74,75,82: ethyl acetate). 110,111,112,113 2-PHENYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 64 [7] 33a,112,113 2-(4’-METHOXYPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 69 [29]

2-(4’-TRIFLUOROPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 70 [30] 2-(2’-ACETYLPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 71 [31] 33b 2-NAPHTHALEN-1-YLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 72 [32]

2-(THIOFEN-3-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 73 [33] 2-(PYRIDIN-3-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 74 [34] 12 2-(PYRIDIN-4-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 75 [35]

(E)-2-PENTENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 76 [36] 2-BENZYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 77 [37] 114 3-PHENYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 65 [8]

3-(4’-METHOXYPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 78 [38] 3-(4’-TRIFLUOROMETHYLPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 79 [39] 7-PHENYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 66 [9] 7-(NAPHTHALENE-1-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 80 [40] 7-(THIOFEN-3-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 81 [41] 7-(PYRIDINE-4-YL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 82 [42] 8-PHENYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 67 [10] 8-(4’-METHOXYPHENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 83 [43] (E)-8-PENTENYL)PYRIDO[1,2-a]PYRIMIDIN-4-ONE 84 [44] 9-PHENYLPYRIDO[1,2-a]PYRIMIDIN-4-ONE 68 [11]

43 Experimental section

Hiyama cross-coupling reaction A typical procedure. A solution of 7-bromopyridopyrimidone 21j (113 mg, 0.5 mmol), trimethoxyphenylsilane (100 μL, 0.525 mmol), 1M solution of TBAF in THF (525 μL, 0.525 mmol), Pd2dba3 (11 mg, 0.025mmol) catalyst and PPh3 (13 mg, 0.05 mmol) in toluene (1 mL) was heated at 100 °C for 4 h. After 4 h stirring at 100 °C, the mixture was allowed to cool to rt, and was poured into water (3 mL), and was extracted with DCM (3 × 3 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (RediSep®Rf 24 gram Flash Column, n-hexane : ethyl acetate = 1 : 1). Yellow crystals (87 mg, 78 %; mp. 216-217 °C). Isolated by-products:

(E)-3-(5-BROMO-PYRIDIN-2-YLAMINO)-ACRYLIC ACID METHYL ESTER 86a 1 3 White crystals (mp. 143-144 °C). H NMR (200 MHz, DMSO-d6, 27 °C): δ = 10.29 (br, 1 H, NH), 8.33 (d, JH,H = 13.7 Hz, 1 4 3 4 3 H, 3-H), 8.32 (d, JH,H = 2.2 Hz, 1 H, 6’-H), 7.85 (dd, JH,H = 8.8 Hz, JH,H = 2.2 Hz, 1 H, 4’-H), 6.79 (d, JH,H = 8.8 Hz, 1 H, 3’- 3 13 H), 5.29 (d, JH,H = 13.7 Hz, 1 H, 2-H), 3.60 (s, 3 H, OMe) ppm. - C NMR (50 MHz, DMSO-d6, 27°C): δ = 168.4 (1-C), 152.0 (2’-C), 148.9 (6’-C), 141.2 (2 C, 3-C and 4’-C), 112.8 (3’-C), 111.6 (5’-C), 94.3 (2-C), 51.0 (OMe) ppm. - MS(EI+): m/z = 256 [M+], 197, 156, 118, 76. (Z) -3-(5-BROMO-PYRIDIN-2-YLAMINO)-ACRYLIC ACID METHYL ESTER 86b 1 3 White crystals (mp. 111-112 °C). H NMR (200 MHz, DMSO-d6, 27 °C): δ = 10.13 (d, JH,H = 12.3 Hz, 1 H, NH), 8.31 (d, 4 3 4 3 3 JH,H = 2.3 Hz, 1 H, 6’-H), 7.89 (dd, JH,H = 8.7 Hz, JH,H = 2.3 Hz, 1 H, 4’-H), 7.88 (dd, JH,H = 12.3 Hz, JH,H = 8.8 Hz, 1 H, 3- 3 3 13 H), 7.24 (d, JH,H = 8.7 Hz, 1 H, 3’-H), 4.95 (d, JH,H = 8.8 Hz, 1 H, 2-H), 3.65 (s, 3 H, OMe) ppm. - C NMR (50 MHz,

DMSO-d6, 27°C): δ = 169.3 (1-C), 151.5 (2’-C), 148.7 (6’-C), 141.3 and 141.0 (3-C and 4’-C), 113.2 (3’-C), 112.5 (4’-C), 90.2 (2-C), 51.0 (OMe) ppm. - MS(EI+): m/z = 256 [M+], 197, 156, 118, 76.

6.3. Unexpected transformations of azoxyquinoxaline 96 N,N’-Di(quinoxalin-2-yl)diazene N-oxide 96115 Compound 96 was prepared and purified by reported procedure.115 Proton-catalyzed transformation of azoxyquinoxaline 96

IMIDAZO[1,2-a:4,5-b’]DIQUINOXALINE 98 [5] 2-AMINOQUINOXALINE 103 102 Compound 103 was prepared and purified by reported procedure.

1-(3’-CHLORO-2’-QUINOXALINYL)QUINOXALIN-2(1H)-IMINE 104 [8]

Compound 104 is present in DMSO-d6 as a mixture of geometric isomers (syn and anti) with coalescence point T ≈ 140°C. Thermal transformation of azoxyquinoxaline 96 105 1-(QUINOXALIN-2-YL)QUINOXALIN-2(1H)-ONE 108 [12] *** 2-(MORPHOLIN-4-YL)QUINOXALINE 112 [16]

44 Conclusions

7. Conclusions In conclusion, a productive one-pot synthesis was applied for the preparation of halogenated pyridopyrimidones 21 by the thermal cyclization and decarboxylation of malonates 19 (Scheme 36). For the synthesis of 21, Meldrum’s acid 55 was selected instead of dimethyl malonate, because 55 is a stronger CH acid, and thermal cyclization of 19 gives 22 directly in a one-pot reaction. The addition of 6-unsubstituted malonates 19a-k to preheated diphenyl ether afforded 21a-k in yields of 59-84%. Our work-up protocol provided 15-30% better yields for 21i-k (X = 7-Cl, 7-Br, 7-I) than those in the earlier methods. 10 halogenated pyridopyrimidones (seven new compounds; 21b-h) were synthesized.

OMe O R O N O O 6  R N N O R + H CH R N 4 N NH O O 3 2 O O N N 6

3CH CH3 CH3 O 9 56 19 60 21

6-R R = H NXS HC(OCH3)3 O O H O O N + O NR N N NR O H N R N N X 3CH CH3 H O O 55 58 (7-R) 59 (6-R) 57 Scheme 36. Summary of thermal cyclization of malonates 19

3-Halopyridopyrimidones 57 were obtained from 21a (X = H) in yields of 76-86% by reaction with the respective N-halosuccinimide (Scheme 36). Three halogenated pyridopyrimidones (two new compounds; 57a,c) were synthesized. 6-Substituted malonates 19 were also subjected to the ring-closure protocol. The thermal cyclization of the 6-fluoro, 6-chloro and 6-bromo derivatives 19m-o afforded not pyridopyrimidones 21m-o, but mixtures of 7-halonaphthyridones 58m-o and pyridine-2,4-diones 59m-o as by-products (Scheme 36). An explanation of the formation of the by-products 59m- o was proposed: the pyridin-2,4-dione structure results from a head-to-tail [4+2]- cyclodimerization from an iminoketene intermediate 60. Possible intermediates and transition states were determined by calculation, employing the DFT method at the B3LYP6- 311++G(2d,2p) level of theory. 6-Iodo derivative 19p surprisingly afforded 6-iodopyridopyrimidone 21p as the only isolated product. To prove the structure, 21p was also synthesized by an independent route, via lithiation from non-halogenated heterocycle 21a. As far as we aware, this is the first example of the functionalization of the 4H-pyrido[1,2-a]pyrimidin-4-one skeleton at position C(6). The method could not be extended to the other 6-halo derivates. Theoretical considerations were devoted to the explanation of these surprising results. We carried out calculations on the potential ground state geometry of selected 6-substituted

45 Conclusions pyridopyrimidones. The calculated geometry of 21a,l-p was analysed with respect to possible(de)stabilizing forces and the interactions caused by the C(6) substituent. In summary, the thermal ring transformation ability of 4H-pyrido[1,2-a]pyrimidin-4-ones is governed by both the steric and the electrostatic interactions between the oxygen of the carbonyl group and the substituent in the peri position. We demonstrated that for 6-subsituted pyridopyrimidones 21, when the C(6) substituent X has a lone pair(s) on the atom (e.g. X = F) connected to the ring, the lone pair electrons’ repulsion of substituent X and the oxygen of the C(4)=O group could play a particular role in the ring transformation. The electrostatic interaction gradually decreases in the sequence F > Cl > Br > I derivatives. The ready polarizability of the electron cloud of the iodine atom also decreases the repulsive interaction. Furthermore, 6-iodo derivative 21p may be stabilized by weak intramolecular halogen bonding. The 6-iodo derivative 21p is therefore more stable than the other 6-halo derivatives, even at the reaction temperature. In the second part of my thesis, two typical procedures for biaryl syntheses via palladium- catalyzed C–C bond formation were investigated. In 3.2.1. I reported on the Suzuki-Miyaura cross coupling of halogenated pyridopyrimidones 21,57,63, and in 3.2.2. preliminary result of reaction with trimethoxyphenylsiloxane was discussed and was compared to those aforementioned. First, we gave an account on investigation on the reactivity order of different positions of 4H-pyrido[1,2-a]pyrimidin-4-one skeleton in the Suzuki-Miyaura reaction (Scheme 37) using chloro derivatives 21c,f,i,57a,63. The reactivity order was settled on HPLC yields and was found to be decreasing in order of positions

C(8) ≥ C(2) > C(9) > C(7) > C(3).

This order was fairly predicted by the “rule of Handy and Zhang”, as only the order of positions C(2) and C(8) seems to be reversed. A plausible explanation might be that in the case 8-chloro derivative 21f the reaction (oxidative addition step) might have rather an SN1 than an SN2 characteristic compared to 2-chloro derivative 63.

9 N N 8 2 5 mol% Pd(PPh ) X + R B(OH) 3 4 R N 3 2 DME N 7 1 M NaHCO3 solution O ~ 80 °C, 4-96 h O 21,57,63 64-84 X = Cl, Br, I 51-99% R = aryl, hetaryl, vinyl, benzyl Scheme 37. Summary of Suzuki–Miyaura cross-couplings

The relative reactivity of different halo atoms was also investigated and was found to be in harmony with the expected decreasing order of I > Br > Cl. The enhanced reactivity towards cross-coupling reactions of iodo derivatives was accompanied by an enhanced reactivity towards hydrodehalogenation side reaction, especially in the case of “slow reacting” positions, derivatives 21k and 57c.

46 Conclusions

To prove the diversity of the reaction, several pyridopyrimidon derivatives were synthesized making use of various (het)aryl and alkenyl boronic acids. As coupling partner mainly chlorides were used under mild conditions. Products were isolated from medium to excellent (51-99 %) yields. In spite of the promising conversions 2-benzyl derivative 77 could be isolated only in poor yield (38 %), and other alkyl substituents could not be introduced. In conclusion, the Suzuki-Miyaura reaction was systematically investigated and 17 new pyridopyrimidones were synthesized under mild reaction conditions. Preliminary investigations of the Hiyama cross-coupling of 7-bromo derivative 21j with trimethoxyphenylsilane 85 were also performed, and a comparison was made with the Suzuki–Miyaura reaction. Several palladium catalysts, fluoride sources and solvents were tested; the most reasonable combination is depicted in Scheme 38. We found that 4H- pyrido[1,2-a]pyrimidin-4-one substrates are more sensitive to the Hiyama reaction conditions, yielding the expected 7-phenyl derivative 66 in only a medium isolated yield, as the N(5)–C(4) intramolecular amide bond undergoes hydrolysis under the harsh reaction conditions. Other halo derivatives investigated furnished the expected phenyl derivatives 64-68,21q in poor to good HPLC yields (~ 15-85%).

Si(OMe) 9 3 5 mol% Pd2(dba)3 8 N 2 N 10 mol% PPh3 X + R N 3 toluene N 7 1 M TBAF solution O ~ 100 °C, 4 h O 21,57,63 85 64-68,21q X = Cl, Br, I 15-85% HPLC yield Scheme 38. Summary of Hiyama cross-couplings

In conclusion, the main aim of the thesis, to present powerful and productive methods for the functionalization of 4H-pyrido[1,2-a]pyrimidin-4-one skeleton, was met. Functionalization could be done easily for wide range of substituent. The treatment of azoxy compound 96 with strong acids or thermally led to two different reaction pathways furnishing compound 98 and 108, respectively (Scheme 39). In summary, on the action of strong acids 96 did not give the expected Wallach-type hydroxylated product, but the first representative of the pentacyclic imidazo[1,2-a:4,5-b’]diquinoxaline system 98. Heating in a solvent (e.g. weak acid) or neat furnished 1-(quinoxalin-2-yl)quinoxalin-2(1H)- one 108. The structures of the products were supported by detailed NMR analysis, and confirmed by independent synthesis (for 98) and X-ray crystallography (for 108). Possible interpretations of the formation of products 98 and 108 are proposed.

N N N

+ N N N H N N +  N N N N - "HNO" - N2 N O N O N

C16H9N5 C16H10N6O C16H10N4O 98 96 108 Scheme 39. Unexpected transformations of azoxyquinoxaline 96

47 Summary of the new findings

8. Summary of the new findings 1. A productive one-pot synthesis was developed for the preparation of halogenated 4H- pyrido[1,2-a]pyrimidin-4-ones by the thermal cyclization and decarboxylation of isopropylidene (2-pyridylamino)methylenemalonates, prepared from 2-aminopyridines and isopropylidene methoxymethylenemalonate formed in situ from Meldrum’s acid and trimethyl orthoformate. Seven new derivatives were synthesized.[1]

2. The thermal cyclization of isopropylidene (6-fluoro-, 6-chloro- and 6-bromo-2- pyridylamino)methylenemalonates was found to afford a mixture of 7-halo-1,8-naphthyridin- 4(1H)-ones and 1-(6-halo-2-pyridyl)-3-[(6-halo-2-pyridylamino)methylene]-1,2,3,4-tetra- hydropyridine-2,4-diones as by-products. An explanation of the formation of the by-products was proposed: the pyridin-2,4-dione structure results from a head-to-tail [4+2]-cyclodimerization from an N-(2-pyridyl)iminoketene intermediate. Possible intermediates and transition-states were determined by calculation, employing the DFT method at the B3LYP6- 311++G(2d,2p) level of theory.[1],[2]

3. We reported the first example of the functionalization of the 4H-pyrido[1,2-a]pyrimidin- 4-one skeleton at position C(6): 6-iodo-4H-pyrido[1,2-a]pyrimidin-4-one was synthesized from 4H-pyrido[1,2-a]pyrimidin-4-one via lithiation. The method could not be extended to other 6-halo derivatives.[2]

4. DFT calculations were carried out on the potential ground-state geometry of 6-substituted- 4H-pyrido[1,2-a]pyrimidin-4-ones at the B3LYP6-311++G(2d,2p) level of theory to investigate possible (de)stabilizing forces and interactions caused by the C(6) substituent. We demonstrated that the thermal ring transformation ability is governed by both the steric and the electrostatic interactions between the oxygen of the carbonyl group and the substituent in the peri position. When the C(6) substituent has a lone pair(s) on the atom connected to the ring, the lone pair electrons’ repulsion of the substituent and the oxygen of the C(4)=O group could play a particular role in the ring transformation.[2]

5. The reactivity sequence in the Suzuki–Miyaura cross-coupling reactions of the different positions of the 4H-pyrido[1,2-a]pyrimidin-4-one skeleton was investigated, and was found to be: posn. C(8) ≥ C(2) > C(9) > C(7) > C(3). With the use of comparatively cheaper chloro derivatives under simple conditions, 17 new derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one were synthesized in good to excellent yields.[3]

48 Summary of the new findings

6. Preliminary investigations of the Hiyama cross-coupling of halogenated 4H-pyrido[1,2- a]pyrimidin-4-ones with trimethoxyphenylsilane were performed and in addition, a comparison with the Suzuki–Miyaura reaction was also made. We found that 4H-pyrido[1,2- a]pyrimidin-4-one substrates are more sensitive under the Hiyama reaction conditions, yielding the expected phenyl derivatives only in poor to good HPLC yields, as the N(5)–C(4) intramolecular amide bond undergoes hydrolysis under the harsh reaction conditions.[4]

7. I recognized that the treatment of N,N'-diquinoxalin-2-yldiazene N-oxide with strong acids or thermally led to two different reaction pathways, furnishing imidazo[1,2-a:4,5- b’]diquinoxaline and 1-(quinoxalin-2-yl)quinoxalin-2(1H)-one, respectively. Possible interpretations of the formation of the two different products are proposed.[5],[6]

9. Publications

[1] Molnár, A.; Faigl, F.; Podányi, B.; Finta, Z.; Balázs, L.; Hermecz, I.: SYNTHESIS OF HALOGENATED 4H- PYRIDO[1,2-a]PYRIMIDIN-4-ONES – Heterocycles 2009, 78, 2477-2488 (IF: 1.165). [2] Molnár, A.; Mucsi, Z.; Vlád, G.; Simon, K.; Holczbauer, T.; Podányi, B.; Faigl, F.; Hermecz, I.: RING TRANSFORMATION OF UNSATURATED N-BRIDGEHEAD FUSED PYRIMIDIN-4(3H)-ONES: ROLE OF REPULSIVE ELECTROSTATIC NONBONDED INTERACTION – J. Org. Chem. 2011, 76, 696-699 (IF: 4.219; 2009). [3] Molnár, A.; Kapros, A.; Párkányi, L.; Mucsi, Z.; Vlád, G.; Hermecz, I.: SUZUKI–MIYAURA CROSS-COUPLING REACTIONS OF HALO DERIVATIVES OF 4H-PYRIDO[1,2-a]PYRIMIDIN-4-ONES – submitted (Org. Biomol. Chem.). [4] Molnár, A.; Hermecz, I.: HIYAMA CROSS-COUPLING REACTIONS OF HALO DERIVATIVES OF 4H-PYRIDO[1,2-a]- PYRIMIDIN-4-ONES – under preparation. [5] Hermecz, I.; Molnár, A.; Boros, S.; Simon, K.; Gönczi, Cs.: UNEXPECTED RING TRANSFORMATIONS OF AN AZOXYQUINOXALINE – Eur. J. Pharm. Sci., Suppl. 2009, 38, S187-S189. [6] Molnár, A.; Boros, S.; Simon, K.; Hermecz, I.; Gönczi, Cs.: UNEXPECTED TRANSFORMATIONS OF AN AZOXYQUINOXALINE – ARKIVOC 2010, x, 199-207 (IF: 1.090, I: 1; 2009).

49 References

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53 Nyilatkozat

Nyilatkozat

Alulírott Molnár Annamária kijelentem, hogy ezt a doktori értekezést magam készítettem, és abban csak a megadott forrásokat használtam fel. Minden olyan részt, amelyet szó szerint, vagy azonos tartalomban, de átfogalmazva más forrásból átvettem, egyértelműen, a forrás megadásával megjelöltem.

Budapest, 2011. június 3.

54 Appendix

Appendix