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

Structure of 1,5-benzodiazepinones in the solid state and in solution: Effect of the fluorination in the six-membered ring

• Marta Pérez-Torralba,
• Rosa M. Claramunt,
• M. Ángeles García,
• Concepción López,
• M. Carmen Torralba,
• M. Rosario Torres,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2013, 9, 2156–2167, doi:10.3762/bjoc.9.253

• , (tautomer a in Figure 7). The molecule is not planar due to the folding of the seven-membered ring with C1, C2 and C3 out of the plane defined by the aromatic ring and the nitrogen atoms. The dihedral angles between this plane and those formed by the C1N1O1 and N2C3C8 atoms are 35.4(2)º and 41.7(2)º

• space group containing one molecule per asymmetric unit (Figure 5). As for compound 1, the molecular geometry corresponds to tautomer a. The seven-membered ring is also folded with dihedral angles between the aromatic ring and C1N1O1 of 44.1(3)º and with N2C3C8 of 43.2(3)º. This higher values compared

• tautomers are possible (Figure 7). Mannschreck et al. already concluded in 1967 that 3 has the structure 3a based on a methylene signal at 3.14 ppm [11]. This is also compatible with tautomer 3d but considering that amides never exist as imidic acids, Mannschreck's conclusion is certainly right. Varma et al

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• (1) rather than the functionalities on the 3-acyl and C(5) positions. Thus, the dominant tautomer of N-unsubstituted and N-alkyltetramates is D, while N-acyltetramates exist as a mixture of external tautomers AB and D in approximately equal ratio [23]. By contrast, it was found that the

• tautomerisation of 3-carboxamides and 3-alkoxycarbonyls was not affected by substitution on N(1). Therefore, the dominant tautomer of 3-carboxamide tetramates is tautomer A (over 80%) with a minor contribution of tautomer D, while 3-alkoxycarbonyltetramates exist as only tautomer A (>99%). In order to understand

• -acyltetramate 10a, the ground-state energies of tautomers B and D, which shows preference for tautomer D, is considerably lower than those of tautomers A and C. This outcome supports experimental NMR observations (>80% of tautomer D and <20% of tautomer B, Table 1, entry 1). On the other hand, the ground state

Mechanistic studies on the CAN-mediated intramolecular cyclization of δ-aryl-β-dicarbonyl compounds

• Brian M. Casey,
• Dhandapani V. Sadasivam and
• Robert A. Flowers II

Beilstein J. Org. Chem. 2013, 9, 1472–1479, doi:10.3762/bjoc.9.167

• obtain a better understanding of the impact of arene substitution on the intramolecular cyclization, DFT calculations were performed at UB3LYP/6-31G(d) level by using Gaussian 03/09 [28]. Previous research from our group has shown that the oxidation of the enol tautomer of a diketone initially forms a

• proposed for the oxidation of δ-aryl-β-dicarbonyl compounds in MeOH with CAN. Initial oxidation of the enol tautomer (4’) by CAN produces protonated radical 5. Intermediate 5 is deprotonated by MeOH to radical species 6. When the radical contains a δ-aryl group with an appropriate substitution at the meta

Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach

• Sandeep Kumar,
• Ramendra Pratap,
• Abhinav Kumar,
• Brijesh Kumar,
• Vishnu K. Tandon and
• Vishnu Ji Ram

Beilstein J. Org. Chem. 2013, 9, 809–817, doi:10.3762/bjoc.9.92

• interaction. Hence, density functional theory (DFT) calculations also indicate that the tautomer 8y is relatively more stable than 8x and 8z (Figure 2). Further, in order to generalize the reaction, attempts were made for the alkenylation of indolin-2-one with 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles

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

• becomes the energetically most favourable mechanism of formation of 3-cyanopyrrole (8) via the 3H tautomer 18 with a barrier of only 10 kcal/mol above the S1 nitrene or 16 kcal/mol above the nitrile ylide (Scheme 4 and Figure 1). This explains why 3-cyanopyrrole (8) is the predominant isomer, in contrast

• 21 → 20, with free energies of activation of 18–22 kcal/mol in solution, has been demonstrated for 1,2,3-triazolo[1,5-a]pyrimidines [24] but not for 1,2,3-triazolo[1,5-c]pyrimidines [25][26]. However, 7-benzyl-3-ethoxycarbonyl-1,2,3-triazolo[1,5-c]pyrimidin-5-ol and its diazo valence tautomer, 6-(2

A computational study of base-catalyzed reactions of cyclic 1,2-diones: cyclobutane-1,2-dione

• Nargis Sultana and
• Walter M. F. Fabian

Beilstein J. Org. Chem. 2013, 9, 594–601, doi:10.3762/bjoc.9.64

• tautomerism [32][33]. Product P3a essentially is the ion-dipole complex between the ring tautomer of neutral γ-oxobutanoic acid with [OH(H2O)5]– , and hence, its formation is completely reasonable. The actual pathway C obtained by the calculations is indicated in Scheme 5. In fact, Int4 is barely stable if

Cyclodextrin-induced host–guest effects of classically prepared poly(NIPAM) bearing azo-dye end groups

• Gero Maatz,
• Arkadius Maciollek and
• Helmut Ritter

Beilstein J. Org. Chem. 2012, 8, 1929–1935, doi:10.3762/bjoc.8.224

• , a large bathochromic (red) shift takes place, due to the protonation of the azo dye of 6 [17]. As illustrated in Figure 1A this red shift corresponds to an increase of the absorption up to 500–550 nm, whereas the band at 420 nm decreases. Thus, the protonated azonium tautomer is considered to be the

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• ]) of the corresponding carbenes 49a–c (in kJ mol–1, MP2/6-31+G(2d,p)//B98/6-31G(d)), and the NICS(1) values of 47–49 (B3LYP/6-311+G(d)) (from [107]). Berkessel’s synthesis of a Breslow intermediate (51, keto tautomer) from carbene 43 [112]. Synthesis of O-methylated Breslow intermediates [114

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• -5, giving trans-14 in 91% yield, compared to 38% for the cis-isomer. In both cases the 1H NMR suggested that these compounds exist as the usually disfavoured enol tautomer. These reactions, along with the reactions of 1, clearly illustrate the power of this two-directional approach to DOS. Using

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

• the reactivity of the 2-lithio-oxazoles resulting from the ready deprotonation, with n-BuLi at low temperature, of the most acidic C2-proton (pKa = 20–22 was suggested), which is complicated by the coexistence of a ring-open isonitrile tautomer. In particular, the treatment by trimethylstannylchloride

• direct arylation of oxazole was further improved for scale-up (Scheme 2) [34]. The C2-magnesation of oxazole was first performed with lithium tributylmagnesate at room temperature, and rapid evolution of the C2-magnesated oxazole to a ring-open isonitrile tautomer was evidenced by 1H NMR spectroscopy

• -metallated oxazole with its ring-open tautomer [67]. Using Pd(0)/Cu(I) catalysis, the C2-cuprated oxazole may act as a transmetallating agent through a standard cross-coupling reaction (Scheme 18, route B) [67]. Under Pd(0)- and Cu(I)-free catalysis, Zhuralev identified a cross-coupling-type mechanism for

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• equilibirum mixture is halogenated quickly, leaving behind the keto tautomer [63]. Further halogenation is then limited by the rate of enolization. This effect forms the basis of Meyer’s famous enol-titration experiments for determining the degree of enolization in activated carbonyl compounds (Scheme 2a) [63

• (Figure 2). Freshly dissolved ethyl benzoylpropionate 1 contained some enol tautomer in CDCl3. In CD3CN, the value decreased to below 0.5% on standing (Figure 2). Fluorination of 1 in a saturated solution of F–TEDA in acetonitrile was negligible (<1%) after two weeks at ambient temperature, assuring us

• solvent. Presumably, the enol tautomer reacts uncatalyzed with F–TEDA, followed by a slow, Lewis acid catalyzed fluorination of the remaining ketone. The catalytic effects of other Lewis acids in the fluorination of 1 were semiquantitatively studied by TLC experiments and found as presented in Scheme 3

Gold(I)-catalyzed synthesis of γ-vinylbutyrolactones by intramolecular oxaallylic alkylation with alcohols

• Michel Chiarucci,
• Mirko Locritani,
• Gianpiero Cera and
• Marco Bandini

Beilstein J. Org. Chem. 2011, 7, 1198–1204, doi:10.3762/bjoc.7.139

• [52] and entry 15 in Table 1). Regeneration of the active cationic gold species or assistance in the formation of the reactive allylic carbocation intermediate II are key steps in which the Brønsted cocatalysis could be exerted [52]. Finally, the mandatory role of enol tautomer (or gold–enolate

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

• pyridines in Table 1 are depicted in their predominant tautomeric form as found in CDCl3 at ambient temperature. Interestingly, the pyridone/pyridinol equilibrium seems to depend on the substituents at the C-2 or C-6 side chains. In general, a hydrogen bond-acceptor seems to stabilize the pyridone tautomer

• , whereas the pyridinol tautomer is favored when a hydrogen bond-donor is present. Compound 37 exists exclusively as pyridone tautomer, but after desilylation the resulting product, with a free hydroxy group in the side chain, strongly prefers the pyridinol tautomer. It seems reasonable to assume that the

• pyridone tautomer is stabilized through an internal hydrogen bond between a silyl ether or a tertiary amine moiety of the side chain as observed for compounds 22 and 24. Moreover, we found that the equilibrium is strongly influenced by the solvent. In CDCl3 pyridine 40 exclusively exists in its pyridone

Preparation of pyridine-3,4-diols, their crystal packing and their use as precursors for palladium-catalyzed cross-coupling reactions

• Tilman Lechel,
• Irene Brüdgam and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2010, 6, No. 42, doi:10.3762/bjoc.6.42

• pyridine-3,4-diol side by a polar protic solvent such as methanol. Surprisingly, the X-ray crystal structure measurement of compound 2c [24] revealed that in the solid state a 1:1 ratio of diol and its pyridinone tautomer 2c′ is preferred. Figure 1 shows that two pyridine-3,4-diol molecules are in one

Synthesis of 3-(phenylazo)-1,2,4-triazoles by a nucleophilic reaction of primary amines with 5-chloro- 2,3-diphenyltetrazolium salt via mesoionic 2,3-diphenyltetrazolium- 5-aminides

• Shuki Araki,
• Satoshi Hirose,
• Yoshikazu Konishi,
• Masatoshi Nogura and
• Tsunehisa Hirashita

Beilstein J. Org. Chem. 2009, 5, No. 8, doi:10.3762/bjoc.5.8

• salt 4. Deprotonation of 4 affords tetazolium-5-aminide A, which is in the equilibrium with the acyclic tautomer B. Further deprotonation from B followed by an intramolecular ring-closure gives C, which is oxidized by air to furnish triazole 3. The sterically demanding primary amines (isopropylamine

• from 4 proceeds readily to give tetrazolium-5-aminides A. Contrary to the stable type A mesoionic tetrazolium-5-aminides [6][7], type B mesoionic aminide A undergoes further transformations from its acyclic tautomer B to furnish 1,2,4-triazoles 3. Experimental General Melting points were measured with

Diastereoselective and enantioselective reduction of tetralin- 1,4-dione

• E. Peter Kündig and
• Alvaro Enriquez-Garcia

Beilstein J. Org. Chem. 2008, 4, No. 37, doi:10.3762/bjoc.4.37

• E. Peter Kundig Alvaro Enriquez-Garcia Department of Organic Chemistry, University of Geneva, 1211 Geneva 4, Switzerland 10.3762/bjoc.4.37 Abstract Background The chemistry of tetralin-1,4-dione, the stable tautomer of 1,4-dihydroxynaphthalene, has not been explored previously. It is readily

• (81%, 95% ee). Conclusion Diastereoselective and enantioselective reductions of the unexplored tetralin-1,4-dione provides a very convenient entry into a number of synthetically highly attractive 1,4-tetralindiols and 4-hydroxy-1-tetralone. Keywords: asymmetric; catalysis; ketone; reduction; tautomer

• ; Introduction In this article, we briefly review synthetic approaches to 2,3-dihydro-1,4-naphthoquinone, more simply named tetralin-1,4-dione (2). This symmetric diketone is the stable tautomer of 1,4-dihydroxynaphthalene (1). Although known for many years, it has never been used in synthesis. The reactions of

Inversion symmetry and local vs. dispersive interactions in the nucleation of hydrogen bonded cyclic n-mer and tape of imidazolecarboxamidines

• Sihui Long,
• Venkatraj Muthusamy,
• Peter G. Willis,
• Sean Parkin and
• Arthur Cammers

Beilstein J. Org. Chem. 2008, 4, No. 23, doi:10.3762/bjoc.4.23

• weaker electron donor, agrees with previous studies of competitive solid state hydrogen bonding [19]. Rotamer/tautomer 4 was not observed in the crystalline phases, providing further control and predictability. Crystallization requires non-equilibrium conditions to progress [20][21]; however, predictions

• and hydrogen bond molecularity. 2: The amidine and imidazole moieties are not coplanar due to steric interactions; the CN–CN dihedral angle (50–90°) directs hydrogen bond vectors (dashed arrows). 3: Imidazole prefers the tape. 4: This tautomer/rotamer is not observed. Facile syntheses of imidazole

The Elbs and Boyland- Sims peroxydisulfate oxidations

• E. J. Behrman

Beilstein J. Org. Chem. 2006, 2, No. 22, doi:10.1186/1860-5397-2-22

• : Both of these reactions, last reviewed in 1988 [1], are nucleophilic displacements on a peroxide oxygen of the peroxydisulfate ion. In the Elbs oxidation, the nucleophile is a phenolate anion (or a tautomer) and in the Boyland-Sims oxidation, it is a neutral aromatic amine. There is no radical

• -carbanion tautomer of the phenolate anion, 5, rather than through the intermediate 3 (Scheme 4). This experimental finding was confirmed and expanded by calculations of the energies of the two pathways for phenol itself. Other recent developments Among recent developments is the observation that the

Efficient synthesis of 5-substituted 2-aryl- 6-cyanoindolizines via nucleophilic substitution reactions

• Eugene V. Babaev,
• Natalya I. Vasilevich and
• Anna S. Ivushkina

Beilstein J. Org. Chem. 2005, 1, No. 9, doi:10.1186/1860-5397-1-9

• the structure A for indolizinones 1, we assumed the existence of tautomerism between forms A and B involving hydrogen interchange between oxygen and C-3 carbon (Scheme 1). Although the amount of tautomer B is negligibly small, one would expect that treatment of 1 a – d with phosphorous oxychloride may