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

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second SNAr reaction with a sulfonamide-derived aniline affords pazopanib (Scheme 50) [76

C–C (alkynylation) vs C–O (ether) bond formation under Pd/C–Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines

• Dhilli Rao Gorja,
• K. Shiva Kumar,
• K. Mukkanti and
• Manojit Pal

Beilstein J. Org. Chem. 2011, 7, 338–345, doi:10.3762/bjoc.7.44

• -alkynylthieno[2,3- d]pyrimidines were prepared via alkynylation of 4-chlorothieno[2,3-d]pyrimidines in good to excellent yields. Some of the compounds synthesized were tested for cytotoxic activity in vitro. Keywords: catalysis; C–C bond; copper; palladium; thieno[2,3-d]pyrimidine; Introduction Alkynyl

• hand, the thiophene moiety is a common feature in many bioactive agents and drugs [4] and is considered as a bioisostere of the benzene ring [5]. Thus, one can anticipate that combining the pyrimidine ring of an alkynyl substituted pyrimidine moiety with a thiophene ring might afford compounds, i.e

• highly express these kinases [6]. In continuation of our research program into new drug discovery, we became interested in the generation of a small-molecule library A (Figure 1) based on thieno[2,3-d]pyrimidine for in-house pharmacological evaluation. Accordingly, we recently reported the synthesis of 4

Heavy atom effects in the Paternò–Büchi reaction of pyrimidine derivatives with 4,4’-disubstituted benzophenones

• Feng-Feng Kong,
• Jian-Bo Wang and
• Qin-Hua Song

Beilstein J. Org. Chem. 2011, 7, 113–118, doi:10.3762/bjoc.7.16

A new and facile synthetic approach to substituted 2-thioxoquinazolin-4-ones by the annulation of a pyrimidine derivative

• Nimalini D. Moirangthem and
• Warjeet S. Laitonjam

Beilstein J. Org. Chem. 2010, 6, 1056–1060, doi:10.3762/bjoc.6.120

• Nimalini D. Moirangthem Warjeet S. Laitonjam Department of Chemistry, Manipur University, Canchipur 795 003, Manipur, India 10.3762/bjoc.6.120 Abstract A new and facile synthesis of 2-thioxoquinazolin-4-ones by introducing a benzenoid system in the pyrimidine moiety by reacting ethoxymethylene

• derivatives of 1,3-diarylthiobarbituric acids (DTBA) with active methylene compounds, such as malononitrile and ethyl cyanoacetate, in presence of ZnCl2 has been developed. Keywords: benzenoid; ethylcyanoacetate; malononitrile; pyrimidine; 2-thioxoquinazolin-4-ones; Introduction Quinazolines and derivatives

• the pyrimidine ring. We have developed a new facile and convenient synthetic approach to 2-thioxoquinazolin-4-ones by constructing the benzene ring onto an existing pyrimidine moiety. As a part of our synthetic strategy, 1,3-diarylthiobarbituric acids (DTBA) were used as precursors for the synthesis

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

• without any problems, e.g., 2-mercapto-5-hydroxy-4,6-dimethyl pyrimidine [145]. In summary, heterocyclic thiols react with perfluoroalkyl iodides with considerably more difficultly than aromatic thiols. 4.1.3. Photochemical perfluoroalkylation in organic solvents under phase transfer conditions Liquid NH3

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• currently being evaluated in phase 3 clinical trials [8][9][10]. This compound was identified by replacing the quinazolinone moiety of another inhibitor B with a pyrimidine dione (Figure 1) [8]. All these inhibitors that belong to the non-peptidomimetic class contain an aminopiperidinyl moiety which

• target compound C as the TFA salt. The 1H NMR spectra of compound C indicated the presence of a spiro cyclopropyl ring: the four cyclopropyl protons appeared as a series of four multiplets in the region δ 0.15–0.25, 0.30–0.40, 0.50–0.60 and 0.65–0.75, the vinylic proton of pyrimidine-2,4-dione moiety

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• trifluoromethylated arenes by treatment with Umemoto reagents, 5a or 5b, in the presence of Pd(OAc)2 and Cu(OAc)2 at 110 °C in a mixture of dichloroethane (DCE) and 10 equiv of trifluoroacetic acid (TFA). Arenes having other heterocycles such as thiazole, imidazole, or pyrimidine also reacted under the same

Synthesis of some novel hydrazono acyclic nucleoside analogues

• Mohammad N. Soltani Rad,
• Ali Khalafi-Nezhad and
• Somayeh Behrouz

Beilstein J. Org. Chem. 2010, 6, No. 49, doi:10.3762/bjoc.6.49

• Abstract The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety

• different strategies were considered for the synthesis of the title compounds taking into account the differences in chemical behavior of purine and pyrimidine nucleobases compared to azoles. Because of their better solubility, reactivity and ease of separation of products, the reactions of the azole

• catalytic amount of acetic acid in ethanol, followed by heating at reflux (Scheme 1). For the synthesis of the purine and pyrimidine analogues of target compounds 2h–2o, we envisaged that there might be substantial problems in the synthesis of the desired ketones using similar method as outlined in Scheme 1

Molecular length distribution and the formation of smectic phases

• Nadia Kapernaum,
• C. Scott Hartley,
• Jeffrey C. Roberts,
• Robert P. Lemieux and
• Frank Giesselmann

Beilstein J. Org. Chem. 2009, 5, No. 65, doi:10.3762/bjoc.5.65

• -(tetradecyloxy)pyrimidine) [1], where the aromatic core is substituted symmetrically with two alkoxy chains each with 14 methylene units. It exhibits a molecular length of 45.5 Å. For the short compound we used either the phenylpyrimidine 2PhP (2-[4-(butyloxy)phenyl]-5-(octyloxy)pyrimidine) [1] or the

• occur. Therefore, the structure of bidisperse smectics is signified by extensive out-of-layer fluctuations. Experimental Compounds 2-[4-(tetradecyloxy)phenyl]-5-(tetradecyloxy)pyrimidine (PhP14) [1], 6-[4-(butyloxy)phenyl]-3-(octyloxy)pyridazine (6PhPz) [3] and (R,R)-2-[4-(octyloxy)phenyl]-5-(2,3

• -difluorohexyloxy)pyridine (MDW510) [7] were synthesized according to published procedures and shown to have the expected physical and spectral properties. The liquid crystal 2-[4-(butoxy)phenyl]-5-(octyloxy)pyrimidine (2PhP) was obtained from a commercial source. X-Ray scattering experiments were performed with Ni

Influence of spacer chain lengths and polar terminal groups on the mesomorphic properties of tethered 5-phenylpyrimidines

• Gundula F. Starkulla,
• Elisabeth Kapatsina,
• Angelika Baro,
• Frank Giesselmann,
• Stefan Tussetschläger,
• Martin Kaller and
• Sabine Laschat

Beilstein J. Org. Chem. 2009, 5, No. 63, doi:10.3762/bjoc.5.63

• hydrogen bonds seems to completely suppress the formation of mesophases. Furthermore, the polar pyrimidine ring seems to play an important role in promoting liquid crystalline properties. Experimental General Melting points were measured on a Mettler Toledo DSC822 and are uncorrected. NMR spectra were

Synthesis of 2-substituted 9-oxa-guanines {5-aminooxazolo[5,4-d]pyrimidin- 7(6H)-ones} and 9-oxa-2-thio- xanthines {5-mercaptooxazolo[5,4-d]pyrimidin- 7(6H)-ones}

• Subrata Mandal,
• Wen Tai Li,
• Yan Bai,
• Jon D. Robertus and
• Sean M. Kerwin

Beilstein J. Org. Chem. 2008, 4, No. 26, doi:10.3762/bjoc.4.26

• can be considered as 9-oxa-purine analogs of naturally occurring nucleic acid bases. Interest in this ring system has increased due to recent reports of biologically active derivatives. In particular, 5-aminooxazolo[5,4-d]pyrimidine-7(6H)-ones (9-oxa-guanines) have been shown to inhibit ricin. The

• to naturally occurring nucleic acid bases, this heterocyclic ring system continues to generate interest. Approaches to the oxazolo[5,4-d]pyrimidine ring system generally involve either cyclodehydration of an 5-(acylamino)-4-hydroxypyrimidine [6][7][8][9][10] or elaboration of a 4-cyano- or 4

• unsuccessful. An alternative route was sought in which the oxazole ring was formed first, followed by elaboration of the pyrimidine ring. Our previous work had demonstrated that in the case of ethyl 5-amino-2-methyloxazole-4-carboxylate 3a [20], direct annulation with chloroformamidine in DMSO at 120 °C or

Perhalogenated pyrimidine scaffolds. Reactions of 5-chloro- 2,4,6-trifluoropyrimidine with nitrogen centred nucleophiles

• Emma L. Parks,
• Graham Sandford,
• John A. Christopher and
• David D. Miller

Beilstein J. Org. Chem. 2008, 4, No. 22, doi:10.3762/bjoc.4.22

• functionalised pyrimidine derivatives are of great importance to the life-science industries and there exists a need for efficient synthetic methodology that allows the synthesis of polysubstituted pyrimidine derivatives that are regioselective in all stages to meet the demands of RAS techniques for applications

• in parallel synthesis. 5-Chloro-2,4,6-trifluoropyrimidine may be used as a scaffold for the synthesis of polyfunctional pyrimidine systems if sequential nucleophilic aromatic substitution processes are regioselective. Results Use of 5-chloro-2,4,6-trifluoropyrimidine as a core scaffold for the

• synthesis of functionalised pyrimidine systems is assessed in reactions with a small range of nitrogen centred nucleophiles. Mixtures of products arising from nucleophilic aromatic substitution processes are formed, reflecting the activating effect of ring nitrogen and the steric influences of the chlorine

Understanding the mechanism of Pd-catalyzed allylic substitution of the cyclic difluorinated carbonates

• Jun Xu,
• Xiao-Long Qiu and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2008, 4, No. 18, doi:10.3762/bjoc.4.18

• . Results and Discussion On installation of pyrimidine bases into the gem-difluorinated allylic carbonates 1 and 4, our group found that the γ-substitution products 2, 3 and 5 were surprisingly generated exclusively in good yields, respectively, when the compounds 1 and 4 reacted with suitably protected

An easy synthesis of 5-functionally substituted ethyl 4-amino- 1-aryl- pyrazolo- 3-carboxylates: interesting precursors to sildenafil analogues

• Said A. S. Ghozlan,
• Khadija O. Badahdah and
• Ismail A. Abdelhamid

Beilstein J. Org. Chem. 2007, 3, No. 15, doi:10.1186/1860-5397-3-15

• -arylhydrazononitriles 1a-c react readily with chloroacetonitrile, ethyl chloroacetate, and with phenacyl chloride to give 4-aminopyrazoles 4a-e. The pyrazolo[4,3-d]pyrimidine derivatives 7 and 10 are synthesized via reaction of the aminopyrazole 4b with phenylisothiocyanate and DMFDMA/NH4OAc respectively. Background

• Interest in the chemistry of 4-aminopyrazole carboxylic acid derivatives has recently been recognized as their derivatives are ideal precursors for the synthesis of biologically active pyrazolo[4,3-d]pyrimidine ring systems [1][2][3][4][5][6]. The reported synthetic approaches to these derivatives are also

• expected. Compound 9 could be readily converted into pyrazolo[4,3-d]pyrimidine 10 on treatment with AcOH/NH4OAc mixture. (cf. Scheme 3) Compound 1 reacted with hydroxylamine hydrochloride in ethanol/sodium acetate solution to yield amidooxime 11 as in the literature [10]. Trials to cyclize the amidooxime