An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• , pyrimidine-derived analogues (1,3-diazines) are the most common. Pyridazines (1,2-diazines) and pyrazines (1,4-diazines) are less prominent. The main reasons are most probably that pyrimidines are highly abundant in important biogenic molecules such as the ribonucleotides and that this heterocycle can be

• readily obtained through well-established condensation chemistries. In the next sections the most common syntheses of a number of drugs containing the pyrimidine as well as pyridazine and pyrazine scaffolds are presented. Furthermore, some non-aromatic derivatives including bicyclic analogues of these

• structures will be introduced. The additional nitrogen atom in pyrimidine leads to a significantly reduced basicity when compared to simple pyridine (pKa[pyrimidine] = 1.1; pKa[pyridine] = 5.3) as well as a much more electron-deficient ring system. However, owing to the presence of two nitrogen atoms

Synthesis, characterization and luminescence studies of gold(I)–NHC amide complexes

• Adrián Gómez-Suárez,
• David J. Nelson,
• David G. Thompson,
• David B. Cordes,
• Duncan Graham,
• Alexandra M. Z. Slawin and
• Steven P. Nolan

Beilstein J. Org. Chem. 2013, 9, 2216–2223, doi:10.3762/bjoc.9.260

• ) with each (hetero)aromatic amine in THF at room temperature for 20 h. A range of aromatic amines were employed, including aniline, diphenylamine, pyridines, a pyrimidine and one isoquinoline. The corresponding complexes were obtained in analytically pure form and in good yields as yellow or white

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• and coworkers then applied the same strategy to prepare two other types of heterocycles, isoquino[2,1-a][3,1]oxazine and isoquino[2,1-a]pyrimidine (75, Scheme 19) [87]. The use of [Ir(ppy)2(dtbbpy)](PF6) with air as the external oxidant was found to be optimal for catalyzing the reaction. Later, the

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• favourably with microwave-heated batch experiments. For dihydropyrimidinone 8, a flow rate of 2 mL min–1 delivered a very respectable processing rate of 25 g h–1. Following the success of this reactor design in delivering pyridine and pyrimidine heterocycles, albeit from very different processes, and the

Damage of polyesters by the atmospheric free radical oxidant NO₃^•: a product study involving model systems

• Catrin Goeschen and
• Uta Wille

Beilstein J. Org. Chem. 2013, 9, 1907–1916, doi:10.3762/bjoc.9.225

• the strongest free-radical oxidants known [E(NO3•/NO3−) = 2.3–2.5 V vs NHE] [9], and recent product studies by us revealed that NO3• readily damages aromatic amino acids and pyrimidine nucleosides through an oxidative pathway [10][11][12][13]. Thus, the ease by which model compounds of biologically

Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives

• Aleksandra Jankowiak,
• Emilia Obijalska and
• Piotr Kaszynski

Beilstein J. Org. Chem. 2013, 9, 1873–1880, doi:10.3762/bjoc.9.219

• with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4-cyanopyridine, pyrazine and pyrimidine, presumably due to their instability under the reaction conditions. The experimental results and mechanism are discussed with the aid of DFT

• reactivity of the azines, and CH2OH to provide a potential synthetic handle for the incorporation into more complex structures. Here we present the synthesis of four substituted derivatives of 1a and investigate the preparation of cations derived from pyrazine 2 and pyrimidine 3 shown in Figure 2. Our

• the pyrazine derivative 5-Z (ΔG298 = 2.7 kcal/mol), which also has the lowest TS energy (ΔG‡298 = 18.7 kcal/mol, Table 2). On the other hand, the cyclization of pyrimidine 6-Z is most endergonic and has the highest TS energy among all azoazines considered in this work. These significant differences

The first example of the Fischer–Hepp type rearrangement in pyrimidines

• Inga Cikotiene,
• Mantas Jonusis and
• Virginija Jakubkiene

Beilstein J. Org. Chem. 2013, 9, 1819–1825, doi:10.3762/bjoc.9.212

• -pyrimidinediamines. It was found that the outcome of the reaction strongly depends on the structure of the pyrimidines. Activation of the pyrimidine ring by three groups with a positive mesomeric effect is crucial for the intramolecular nitroso group migration. Keywords: Fischer–Hepp rearrangement; nitrosation; 5

• -nitrosopyrimidines; nucleophilic substitution; pyrimidinediamines; Introduction The pyrimidine moiety is an important structural motif in natural products and therefore frequently used as a building block for pharmaceutical agents [1][2]. It is well-known that chemical properties of pyrimidines depend on the π

• -defficient character of this heterocycle. An electrophilic aromatic substitution at the C-5 of a pyrimidine is usually difficult [1][3][4][5]. However, the presence of two or three activating groups leads to the successful introduction of an electrophile (Scheme 1) [1][6][7][8]. On the other hand

An organocatalytic route to 2-heteroarylmethylene decorated N-arylpyrroles

• Alexandre Jean,
• Jérôme Blanchet,
• Jacques Rouden,
• Jacques Maddaluno and
• Michaël De Paolis

Beilstein J. Org. Chem. 2013, 9, 1480–1486, doi:10.3762/bjoc.9.168

• electronically deficient pyridyl residue was also converted into 5e (80%) while pyrrolidine 4f bearing a pyrazine core underwent aromatization with high efficiency to give 5f (97%). The C2-symmetric scaffold 4g was efficiently converted into 5g (86%) and similar treatment of pyrimidine 4h provided pyrrole 5h in

• heteroaryl substituents, with yields ranging from 64–87%. Oxidation under the same conditions was found to be more troublesome with pyrazine 5f since alcohol 9f was isolated in only 20% yield. Similar treatment of pyrazine 5g and pyrimidine 5h gave a complex mixture of products. While the oxidation of the

3-Pyridylnitrene, 2- and 4-pyrimidinylcarbenes, 3-quinolylnitrenes, and 4-quinazolinylcarbenes. Interconversion, ring expansion to diazacycloheptatetraenes, ring opening to nitrile ylides, and ring contraction to cyanopyrroles and cyanoindoles

• Curt Wentrup,
• Nguyen Mong Lan,
• Adelheid Lukosch,
• Pawel Bednarek and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 743–753, doi:10.3762/bjoc.9.84

• -diazoethoxycarbonylmethylene)-2-(α-hydroxybenzyl)pyrimidin-4-(2H)-one, have been reported [27]. We find that FVT of the 4- and 2-(5-tetrazolyl)pyrimidines 22–24 also affords cyanopyrroles (Scheme 8). FVT of 2-(5-tetrazolyl)pyrimidine (22) affords a ca. 1:1 ratio of 2- and 3-cyanopyrroles (Scheme 8). The results of FVT of

• -tetrazolyl)pyrimidine (22) [36][37], 2-phenyl-4-(5-tetrazolyl)quinazoline (52) [23], and 5-phenyl-1,2,3-triazolo[1,5-a]quinazoline (53) [23] were prepared according to literature procedures. 4,6-Dimethyl-2-(5-tetrazolyl)pyrimidine (24) and 2,4-dimethyl-6-(5-tetrazolylpyrimidine) (23) were prepared from the

• dimethylpyrimidine-carbonitriles [38][39] by adaptation of the literature method [36][37]. 4,6-Dimethyl-2-(5-tetrazolyl)pyrimidine (24): From 3.0 g (22.5 mmol) of 4.6-dimethylpyrimidine-2-carbonitrile was obtained 2.8 g (71%); mp 209–210 °C (dec); 1H NMR (CDCl3) 12.0 (very broad), 7.37 (s, 1H), 2.50 (s, 6H); MS m/z

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• , allowed the researchers to identify three distinct chemical series that were selected for optimization based on their ability to reduce both cellular toxicity and mutant SOD1 protein aggregation: arylsulfanyl pyrazolones (ASP, 10), cyclohexane-1,3-diones (CHD, 11), and pyrimidine 2,4,6-triones (PYT, 12

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• –cyclisation leading to indoline 97 with an intramolecular Friedel–Crafts reaction to afford a tricyclic derivative 98 substituted by a trifluoromethyl group [44]. The second exploits the presence of both a protected primary amine and an easily substitutable chlorine on the pyrimidine ring in 99a,b to afford

Spin state switching in iron coordination compounds

• Philipp Gütlich,
• Ana B. Gaspar and
• Yann Garcia

Beilstein J. Org. Chem. 2013, 9, 342–391, doi:10.3762/bjoc.9.39

Dipyrazolo[1,5-a:4',3'-c]pyridines – a new heterocyclic system accessed via multicomponent reaction

• Wolfgang Holzer,
• Gytė Vilkauskaitė,
• Eglė Arbačiauskienė and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2012, 8, 2223–2229, doi:10.3762/bjoc.8.251

• ; Introduction Condensed pyrazole scaffolds are important substructures of compounds with biological activity and can be found in some well-known drug molecules, such as, for example, Sildenafil (a pyrazolo[4,3-d]pyrimidine) [1][2], Allopurinol (a pyrazolo[3,4-d]pyrimidin-4-one) [3], Zaleplon (a pyrazolo[1,5-a

• ]pyrimidine) [4], and Zolazepam (a pyrazolo[3,4-e][1,4]diazepine derivative, used in veterinary medicine) [5]. Particularly pyrazolopyrimidines are a very frequently accessed class of compounds [6] with the particular importance of the pyrazolo[3,4-d]pyrimidine core, which can closely mimic the purine system

Features of the behavior of 4-amino-5-carboxamido-1,2,3-triazole in multicomponent heterocyclizations with carbonyl compounds

• Eugene S. Gladkov,
• Katerina A. Gura,
• Svetlana M. Sirko,
• Sergey M. Desenko,
• Ulrich Groth and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2012, 8, 2100–2105, doi:10.3762/bjoc.8.236

• . However, MS data obtained for the reaction product isolated from the MCR between aminoazole 1 and cycloalkanone 2 may correspond to both structure 3 and 4. Moreover, 1H and 13C NMR spectra of these compounds should contain very similar signals, and we thus used the position of the signal of pyrimidine NH

• contain cross-peaks between pyrimidine NH and spiro-carbon, which is also in good correlation with structure 4. Analogous elucidations allowed the structures of compounds 7 and 9 to be established. Conclusion In summary, two types of heterocyclization reactions involving 4-amino-5-carboxamido-1,2,3

• -triazole and cyclic ketones were studied under conventional thermal heating, and microwave and ultrasonic irradiation. ABB’-type MCR proceeding with chemodifferentiation of cyclopentanone or cyclohexanone molecules yields 4,5,6,7-tetrahydrospiro{cyclopenta[d][1,2,3]triazolo[1,5-a]pyrimidine-8,1

Engineering of indole-based tethered biheterocyclic alkaloid meridianin into β-carboline-derived tetracyclic polyheterocycles via amino functionalization/6-endo cationic π-cyclization

• Piyush K. Agarwal,
• Meena D. Dathi,
• Mohammad Saifuddin and
• Bijoy Kundu

Beilstein J. Org. Chem. 2012, 8, 1901–1908, doi:10.3762/bjoc.8.220

• developed for the construction of a functionalized natural product, meridianin, and its post conversion to pyrimido-β-carboline by cationic π- cyclization. The strategy involves the introduction of an amino group at the C-5 of the pyrimidine ring and utilizing the nucleophilictiy of the C-2 in the indole

• nortopsentins [21][22][23]), dihydroimidazole (discodermindole [24]), oxadiazine (alboinon [25]), piperazine (dragmacidon [26]), maleimide (didemidines [25]), and pyrimidine (meridianins) [27][28][29]. Among these, meridianins (Figure 1), the tethered biheterocycles isolated from the south Atlantic tunicate

• inhibition [48] to inhibition of cGMP-dependent processes [49][50]. In this communication, we report engineering of naturally occurring tethered indole-based biheterocyclic alkaloid meridianins into β-carboline-derived tetracyclic polyheterocycles by amino functionalization of the pyrimidine ring followed by

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

• on alternatives to the phenyl ring to improve aqueous solubility. As illustrated in Figure 2, we replaced the phenyl ring with a variety of structurally diverse heteroaryl groups, including pyridine, pyrimidine and imidazole rings. In order to investigate the effect of the N-position in the

• heteroaryl ring, different pyridine and pyrimidine substituents were also incorporated. Generally, the compounds 10a–g were synthesized following the general route in Scheme 1, by using aldehydes 11a–g as key intermediates. As described in Scheme 5, 11a–d were prepared through Pd-catalyzed Suzuki coupling of

• reaction conditions, we found that the reaction proceeded well in 1,4-dioxane at 100 °C for 8 h with Na2CO3 as base in the presence of Pd(OAc)2 as catalyst, and PPh3 as ligand, providing the products in 73–85% yield. Different from the synthetic strategy of 11a–d, the pyrimidine nucleus in biaryl aldehydes

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• -deficient heteroaromatic azadienes are well-established for the synthesis of heterocyclic compounds, and have been previously applied to the synthesis of α-carbolines. Intramolecular IEDDA chemistry to prepare α-carbolines employing 2-N-(o-alkynylanilino)pyrimidine systems have been successful in a limited

Chemistry of polyhalogenated nitrobutadienes, 10: Synthesis of highly functionalized heterocycles with a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Armin de Meijere and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2012, 8, 621–628, doi:10.3762/bjoc.8.69

• chlorides result in the formation of the enamines 11, 12, 13, 16, 25, the amidine 6, and the amides 20, 21, respectively. In the following, cyclization to the highly functionalized pyrazoles 27, 28, pyrimidine 26 and pyridopyrimidine 24 succeeded. Deprotection of 21, 12 and 28 proved to be only partially

• feasible. Keywords: isothiazole; nitrochlorobutadiene; nitropyrazole; nucleophilic substitution; pyrimidine; small rings; Introduction Nitropolychlorobutadienes are potent precursors for a variety of highly functionalized acyclic and (hetero)cyclic compounds. The readily accessible 2-nitroperchloro-1,3

• have tautomerized to a pyridin-2(1H)-imine derivative, which then underwent cyclization by a formal nucleophilic substitution leading to the 4H-pyrido[1,2-a]pyrimidine 23. The remaining benzotriazole group in 23, which is activated by the adjacent nitro substituent allows for a further nucleophilic

Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system

• Caterina Fraschetti,
• Matthias C. Letzel,
• Antonello Filippi,
• Maurizio Speranza and
• Jochen Mattay

Beilstein J. Org. Chem. 2012, 8, 539–550, doi:10.3762/bjoc.8.62

• are the elementary units of the RNA and DNA biomacromolecules, and their physiological importance at many different levels [52][53][54] makes them potential candidates as anticancer drugs. The gas-phase study of the intimate interactions between the resorcin[4]arene V and several pyrimidine

• nucleosides can be an inspiration for both the design of new drug carriers, characterized by high solubility and selectivity, and a better understanding of the selective uptake of nucleosides by their respective membrane receptors [55]. The selected pyrimidine nucleosides are reported in Figure 8, i.e., 2

Synthesis, solid-state fluorescence properties, and computational analysis of novel 2-aminobenzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides

• Kenichirou Yokota,
• Masayori Hagimori,
• Naoko Mizuyama,
• Yasuhisa Nishimura,
• Hiroshi Fujito,
• Yasuhiro Shigemitsu and
• Yoshinori Tominaga

Beilstein J. Org. Chem. 2012, 8, 266–274, doi:10.3762/bjoc.8.28

• , 2825-7, Huis Ten Bosch, Sasebo 859-3298, Japan Department of Pharmacy, Saga University Hospital, 5-1-1, Nabeshima, Saga 849-8521, Japan Industrial Technology Center of Nagasaki, Omura, Nagasaki, 856-0026, Japan 10.3762/bjoc.8.28 Abstract New fluorescent compounds, benzo[4,5]thieno[3,2-d]pyrimidine 5,5

• -dioxides (3a–g), 2-amino-4-methylsulfanylbenzo[4,5]thieno[3,2-d]pyrimidine (6), and 2-amino-4-methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-d]pyrimidine (7), were synthesized in good yields from heterocyclic ketene dithioacetals (1a–c) and guanidine carbonate (2a) or (S)-methylisothiourea sulfate (2b) in

• pyridine under reflux. Among the fused pyrimidine derivatives, compound 3c, which has an amino group at the 2-position and a benzylamino group at the 4-position of the pyrimidine ring, showed the strongest solid-state fluorescence. The absorption and emission properties of the compounds were quantitatively

Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

• Bruno Piqani and
• Wei Zhang

Beilstein J. Org. Chem. 2011, 7, 1294–1298, doi:10.3762/bjoc.7.150

• Initiator microwave synthesizer at 140 °C for 30 min. The resulting mixture was purified by flash chromatography to give 5a (24 mg) in 67% yield. Typical procedure for cyclocondensation of 4e,f. Synthesis of methyl 3,7-dimethyl-5-(3-(perfluorooctylsulfonyloxy)phenyl)-5H-thiazolo[3,2-a]pyrimidine-6

Functionalization of heterocyclic compounds using polyfunctional magnesium and zinc reagents

• Paul Knochel,
• Matthias A. Schade,
• Sebastian Bernhardt,
• Georg Manolikakes,
• Albrecht Metzger,
• Fabian M. Piller,
• Christoph J. Rohbogner and
• Marc Mosrin

Beilstein J. Org. Chem. 2011, 7, 1261–1277, doi:10.3762/bjoc.7.147

• -coupling (Negishi reaction) affords the 5-arylated furan 15 in 89% yield. Interestingly, a high chemoselectivity is observed with several heterocyclic dihalides [8][9]. Thus, the tribromopyrimidine 16 provides only the 4-zincated pyrimidine 17. After allylation, the expected allylated pyrimidine 18 is

• addition reactions at temperatures above −30 °C. Quenching of the 4-magnesiated pyrimidine 109 with MeSO2SMe provides the thiomethyl derivative 110 in 81% yield (Scheme 18 and Supporting Information File 1, Procedure 7) [46]. The presence of a thiomethyl substituent considerably increases the electron

• density of this pyrimidine and the addition of a Grignard reagent to this heterocycle can no longer occur. Therefore, a subsequent magnesiation of 110 with TMPMgCl·LiCl (1.0 equiv) can be performed at 25 °C. After 5 min reaction time at this temperature, the resulting 6-magnesiated pyrimidine 111 is

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• formation by base catalysis, by metal catalysis or by fluorination of appropriate pre-formed enol derivatives, such as trimethylsilyl enols or enol acetate derivatives [13][14]. Dicarbonyl systems are, of course, widely used for the construction of heterocyclic ring systems such a pyrimidine, pyridazine and

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

• Christian Eidamshaus,
• Roopender Kumar,
• Mrinal K. Bera and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2011, 7, 962–975, doi:10.3762/bjoc.7.108

• pyridine but also pyrimidine derivatives with lactic acid based side chains should be accessible. O-TBS-protected lactic nitrile 63 was prepared following a literature procedure in four steps starting from enantiopure methyl lactate [48]. The scope of the multicomponent reaction with respect to lactic acid

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

• Lucie Brulikova and
• Jan Hlavac

Beilstein J. Org. Chem. 2011, 7, 678–698, doi:10.3762/bjoc.7.80

• instance, was one of the first [1] and most investigated anticancer drugs, either chemically or biologically, and triggered the research of 5-substituted pyrimidine analogues. The elucidation of the life cycle of a virus is crucial in antiviral chemotherapy. Several 5-substituted pyrimidine analogues

• specific and much less toxic for organisms. One of those groups of investigated derivatives is a group of uracil analogues modified at the 5 position by an ether or ester moiety. Since a vast number of C-5 modified pyrimidine analogues are known, this review is focused on a group of selected compounds with

• efficient synthetic route for the preparation of ethoxy-substituted 5-(perfluoroalkyl)pyrimidines (Scheme 10) and investigated their regioselective transformations [18]. Some of these fluorine-containing pyrimidine analogues are potent antitumor and antiviral agents. The reported synthesis started with the