4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

• Michael J. Burns,
• Thomas O. Ronson,
• Richard J. K. Taylor and
• Ian J. S. Fairlamb

Beilstein J. Org. Chem. 2014, 10, 1159–1165, doi:10.3762/bjoc.10.116

• 2-pyrones 3b–e were synthesised according to the method of Hsung and co-workers [18], in order to further explore the scope of the Mitsunobu process. This involves a one-pot silyl-protection of the hydroxy group of 6-methyl-4-hydroxy-2-pyrone 3a with HMDS, followed by lithiation and alkylation

Molecular recognition of isomeric protonated amino acid esters monitored by ESI-mass spectrometry

• Andrea Liesenfeld and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 825–831, doi:10.3762/bjoc.10.78

• started from 1-bromo-4-methoxybenzene which was transferred into 2-bromo-4’-methoxybiphenyl (3) in 92% yield via lithiation with t-BuLi, transmetallation with zinc(II) bromide, and subsequent Negishi cross-coupling reaction with 1-bromo-2-iodobenzene [14][15]. 3 was then transformed into the corresponding

Towards allosteric receptors – synthesis of β-cyclodextrin-functionalised 2,2’-bipyridines and their metal complexes

• Christopher Kremer,
• Gregor Schnakenburg and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 814–824, doi:10.3762/bjoc.10.77

• 1,3-dimethoxybenzene via lithiation and borylation [39] afforded 22 in very good yield [40][41][42]. 22 forms the 1:1 complex [Cu(22)([H3CCN)2]BF4 upon coordination to copper(I) ions. Zinc(II) ions were found to form the dimeric complex [Zn(22)2](OTf)2 with an excess of 22 if no other ligand is

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles

• Antonio Arcadi,
• Emanuela Pietropaolo,
• Antonello Alvino and
• Véronique Michelet

Beilstein J. Org. Chem. 2014, 10, 449–458, doi:10.3762/bjoc.10.42

• -fluoroserotonin and 4-fluoromelatonin was accomplished by means of a lithiation/fluorination sequence [16]. The validity of this latter strategy was also demonstrated for the fluorination at the 2-position of N-protected indoles by electrophilic fluorinating agents. Our literature search revealed that the access

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• enantioselective lithiation and subsequent hydroxyalkylation. 4. Recently, Pansare [40] reported the synthesis of L-733,060, CP-99,994 and a hydroxypipecolic acid through asymmetric organocatalytic vinylogous aldol addition as the key step. While the syntheses by Charette [38] and Pansare [40] are restricted to

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• followed by reductive epoxide opening furnished the desired alcohol 73 [72]. Alcohol-directed 1,4-reduction using LiAlH4 [73] followed by ether formation gave methyl ether 74. Reduction of the remaining ketone moiety gave the equatorial alcohol exclusively. Ortho-lithiation followed by the addition of

Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis

• Tao Wang,
• Patrick Rabe,
• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2767–2777, doi:10.3762/bjoc.9.311

• Scheme 1. Surprisingly, no satisfying synthetic procedure for compound 4a was available from literature, but ortho-lithiation of veratrole (5) followed by treatment with trifluorosulfonyl chloride and triethylamine gave acceptable yields (47%). Conversion of 4-aminoveratrole (6) into the corresponding

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C₃-building block

• Volker M. Schmiedel,
• Stefano Stefani and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2013, 9, 2564–2569, doi:10.3762/bjoc.9.291

• scale in two steps, starting from propargyl bromide (Scheme 5) [43]. Lithiation of 11 with n-BuLi and subsequent addition to pentadecanal (6) in analogous fashion to the synthesis of allenyl alcohol 7 led after column chromatography to a 57:43 mixture of the diastereomeric allenyl alcohols 12 and 13 in

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

• recently reported an approach to forming the first aryl–aryl C–C bond by a directed lithiation of a pyridine 1.91 followed by conversion to its organozinc derivative. This intermediate then undergoes a high-yielding Negishi cross-coupling reaction with an arylbromide (Scheme 17) [52]. After acidic

Regioselective carbon–carbon bond formation of 5,5,5-trifluoro-1-phenylpent-3-en-1-yne

• Motoki Naka,
• Tomoko Kawasaki-Takasuka and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2013, 9, 2182–2188, doi:10.3762/bjoc.9.256

• clear that the Ha region also contains a couple of peaks (■) with the 3JH-F coupling constant of 6.6 Hz basically identical to the one of 4, which anticipated us the simultaneous formation of the regioisomeric 4-d1 on the basis of the similar consideration. Thus, lithiation of 4 and the following quench

• substrate 4, we have reached to a conclusion that its initial lithiation would occur at both vinylic sites and the following reactions with appropriate electrophiles would proceed under kinetic control where equilibration of the resultant lithiated species might be effective if the capture of electrophiles

• 4. Lithiation of 4 and the following electrophilic reactions. Alternative reaction mechanism between 1 and MeLi. Investigation of reaction conditions. Scope and limitation of the present reactions. Supporting Information Supporting Information File 436: Experimental.

Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed annulation with diarylethynes

• Yan-Chao Shi,
• Rong-Fei Yang,
• De-Wei Gao and
• Shu-Li You

Beilstein J. Org. Chem. 2013, 9, 1891–1896, doi:10.3762/bjoc.9.222

• and our previous study [51][67][68]. Next, to test our original hypothesis, planar chiral P,N-ligand (Sp)-L1 was prepared from (Sp)-3ca. Starting from (Sp)-3ca (96% ee), lithiation with n-BuLi followed by quenching with Ph2PCl gave the planar chiral P,N-ligand (Sp)-L1 in 43% yield and 97% ee (Scheme 2

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• an oxygenated epoxide fragment under a variety of conditions reported by Smith for lithiation and electrophilic trapping [51] were unsuccessful. We suspected that the lithiated dithiane was not being generated and decided to investigate this step of the reaction independently of reaction with the

• epoxide electrophile. To this end, 41 was treated with tert-butyllithium at –78 °C in a 90:10 THF/HMPA mixture, referred to as the method of first choice for lithiation of complex dithianes (Scheme 11). Following warming to –42 °C, the reaction was quenched with deuterated methanol. Analysis of the

Incorporation of perfluorohexyl-functionalised thiophenes into oligofluorene-truxenes: synthesis and physical properties

• Neil Thomson,
• Alexander L. Kanibolotsky,
• Joseph Cameron,
• Tell Tuttle,
• Neil J. Findlay and
• Peter J. Skabara

Beilstein J. Org. Chem. 2013, 9, 1243–1251, doi:10.3762/bjoc.9.141

• underwent a copper-mediated coupling reaction with perfluorohexyl iodide (Scheme 1). Lithiation of 3 and treatment with perfluorohexyl iodide gave the product 2-iodo-3-perfluorohexylthiophene (4). The regioselectivity of this reaction was poor, and the product was obtained as a mixture with its isomer, 2

• /ethanol solution. Lithiation and treatment with perfluorohexyliodide afforded 12, which was deprotected with tetrabutylammonium fluoride to afford 13. The boronic ester 16 was then synthesised by the same steps applied to obtain compound 8 (see Scheme 1). T1-3FTh and T1-4FTh were then synthesised by

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• intermediates that can be converted into various types of chiral ferrocene derivatives through diastereoselective ortho-lithiation [21]. Some years ago, the concept of flash chemistry was proposed, involving fast chemical synthesis by using flow microreactors, which enabled the use of highly reactive

• , such as halogen–lithium exchange, tin–lithium exchange, selenium–lithium exchange or reductive lithiation [1][2][3][4][5][6][7][8]. Once the organolithium has been generated, the intramolecular carbolithiation reaction usually takes place with high stereochemical control, as a consequence of a rigid

Polar reactions of acyclic conjugated bisallenes

• Reiner Stamm and
• Henning Hopf

Beilstein J. Org. Chem. 2013, 9, 36–48, doi:10.3762/bjoc.9.5

• involving polar intermediates and/or transition states has been investigated on a broad scale for the first time. The reactions studied include lithiation, reaction of the thus formed organolithium salts with various electrophiles (among others, allyl bromide, DMF and acetone), oxidation to cyclopentenones

• lithiation/quenching process, the asymmetric bisallene 3 was subjected to the above conditions, employing a three-fold excess of the metalation reagent. Compared to the tetramethylderivative 2, this hydrocarbon possesses five different allenic C–H bonds, which could in principle be replaced by a

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

• Wafa Gati,
• Mohamed M. Rammah,
• Mohamed B. Rammah and
• Gwilherm Evano

Beilstein J. Org. Chem. 2012, 8, 2214–2222, doi:10.3762/bjoc.8.250

• 10.3762/bjoc.8.250 Abstract We have developed a general synthesis of polysubstituted 1,4-dihydropyridines and pyridines based on a highly regioselective lithiation/6-endo-dig intramolecular carbolithiation from readily available N-allyl-ynamides. This reaction, which has been successfully applied to the

• assumptions: According to the remarkable work of the Beak group on the α-lithiation of Boc-protected amines [34][35][36][37][38], N-allyl-ynamides 1 should be readily deprotonated to afford a transient chelation-stabilized allyllithium 2 and, provided that a metallotropic equilibrium exists between this

• formal synthesis of the anti-dyskinesia agent sarizotan. Results and Discussion Feasibility of the deprotonation/intramolecular carbolithiation To first evaluate the compatibility of the ynamide moiety with the lithiation step and address potential problems associated with competitive carbolithiation of

Alkenes from β-lithiooxyphosphonium ylides generated by trapping α-lithiated terminal epoxides with triphenylphosphine

• David. M. Hodgson and
• Rosanne S. D. Persaud

Beilstein J. Org. Chem. 2012, 8, 1896–1900, doi:10.3762/bjoc.8.219

• David. M. Hodgson Rosanne S. D. Persaud Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK 10.3762/bjoc.8.219 Abstract Terminal epoxides undergo lithium 2,2,6,6-tetramethylpiperidide-induced α-lithiation and subsequent interception

• deuterated terminal alkene, respectively, in modest yields. Keywords: alkenes; epoxides; lithiation; synthetic methods; ylide; Introduction β-Lithiooxyphosphonium ylides 4 are useful intermediates in synthesis as they react with a variety of electrophiles to provide a convergent entry to alkenes, often

• epoxides began with studies to produce allylic ester 6 under LTMP-based conditions for α-lithiation of terminal epoxides [20][21][22] but with Ph3P also present (Scheme 3). Encouragingly, a red-orange colour, which is characteristic of a β-lithiooxyphosphonium ylide [8][9], gradually developed (mixing only

Rh(III)-catalyzed directed C–H bond amidation of ferrocenes with isocyanates

• Satoshi Takebayashi,
• Tsubasa Shizuno,
• Takashi Otani and
• Takanori Shibata

Beilstein J. Org. Chem. 2012, 8, 1844–1848, doi:10.3762/bjoc.8.212

• ]. Planar chiral 1,2-disubstituted ferrocene derivatives are usually synthesized by using diastereoselective ortho-lithiation of monosubstituted ferrocenes with an appropriate chiral ortho-directing substituent such as chiral amines, sulfoxides, and oxazolines [3]. However, this method suffers from low atom

• reactivity. The absolute configuration of planar chirality in 3c was determined to be S by X-ray crystallography (Figure 1). The absolute configuration is consistent with the previous report of diastereoselective ortho-lithiation of 1b [27]. Conclusion In conclusion, a Cp*Rh(III)-catalyzed reaction between

C2-Alkylation of N-pyrimidylindole with vinylsilane via cobalt-catalyzed C–H bond activation

• Zhenhua Ding and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2012, 8, 1536–1542, doi:10.3762/bjoc.8.174

• C2-lithiation with a stoichiometric lithium base or indol-2-yl radicals generated from 2-halogenated indoles [12][13][14][15][16][17]. Examples of direct C2-alkylation via transition-metal-catalyzed C–H activation are still limited [18][19][20], while Jiao and Bach recently reported an elegant

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• synthesis started with the saponification of 15, followed by the protection of O-4 and O-6 by using di-tert-butylsilyl bis(trifluoromethanesulfonate). Subsequent protection of O-3 with TES-Cl, gave the fully protected glucal 18. According to Denmark et al. [31], lithiation and silylation of 18 should give

• 20, but in our hands a more complicated mixture resulted. We concluded that under our conditions deprotonation of the protecting group (protons α to silicon) may be competitive with the desired α-lithiation next to oxygen. Use of the more substituted TIPS silyl protecting group in 19 indeed solved

• this problem and yielded 21 in almost quantitative yield. Additional test reactions confirmed this trend as the corresponding 3,4,6-tri-O-(triisopropylsilyl)-D-glucal (52) yielded a single product after lithiation (Supporting Information File 1) and the 3,4,6-tri-O-(tert-butyldimethylsilyl)-D-glucal

Sonogashira–Hagihara reactions of halogenated glycals

• Dennis C. Koester and
• Daniel B. Werz

Beilstein J. Org. Chem. 2012, 8, 675–682, doi:10.3762/bjoc.8.75

• preparation of internal alkynes [24]. We started our investigations with the persilylated 1-iodoglucal 7, which is easily available by a sequence of lithiation and iodination from the parent, fully TIPS-protected congener [25]. The Sonogashira reaction was carried out under standard conditions. Pd(PPh3)2Cl2

Synthesis of oleophilic electron-rich phenylhydrazines

• Aleksandra Jankowiak and
• Piotr Kaszyński

Beilstein J. Org. Chem. 2012, 8, 275–282, doi:10.3762/bjoc.8.29

• lithiation of aryl bromides 5 with t-BuLi to avoid the formation of n-BuBr with n-BuLi and N-butylation of hydrazide 2. Hydrazide 2a was also obtained by the Cu2+-catalyzed addition [18] of arylboronic acid 6a [28] to DTBAD. The yields of both syntheses of 2a were comparable. The trichloroethyl hydrazide 3a

Fluorescent hexaaryl- and hexa-heteroaryl[3]radialenes: Synthesis, structures, and properties

• Antonio Avellaneda,
• Courtney A. Hollis,
• Xin He and
• Christopher J. Sumby

Beilstein J. Org. Chem. 2012, 8, 71–80, doi:10.3762/bjoc.8.7

• , undergoes non-specific lithiation with n-butyllithium [27]. As selective lithiation at the methane position is required, bis(3,5-dimethylpyrazol-1-yl)methane [28] – where the 3- and 5-positions are blocked with methyl groups – was used to give hexakis(3,5-dimethylpyrazol-1-yl)[3]radialene (1) via Fukunaga’s

On the control of secondary carbanion structure utilising ligand effects during directed metallation

• Andrew E. H. Wheatley,
• Jonathan Clayden,
• Ian H. Hillier,
• Alison Campbell Smith,
• Mark A. Vincent,
• Laurence J. Taylor and
• Joanna Haywood

Beilstein J. Org. Chem. 2012, 8, 50–60, doi:10.3762/bjoc.8.5

• ; Introduction Directed deprotonative lithiation – where the directing group generally combines inductive electron withdrawal with the presence of an electron-rich metal-coordinating atom [1] – has established itself as an enormously powerful tool for the elaboration of aromatic and heteroaromatic compounds [2

• approaches the reactive position (“ortho lithiation” when deprotonation occurs adjacent to the directing group [2][3], “directed remote metallation” when reaction is non-adjacent [12][13][14][15]). However, the presence of substituents at the ortho position of the aromatic ring introduces the possibility of

• deprotonating the substituent at the benzylic (or α-) position (“lateral lithiation”) through the directing group coordinating the incoming organometallic substrate whilst conjugatively withdrawing electrons from the benzylic group [2]. In the case of lateral reaction, stabilisation of the resulting anion is

Sexithiophenes as efficient luminescence quenchers of quantum dots

• Christopher R. Mason,
• Yang Li,
• Paul O’Brien,
• Neil J. Findlay and
• Peter J. Skabara

Beilstein J. Org. Chem. 2011, 7, 1722–1731, doi:10.3762/bjoc.7.202

• %, respectively). In parallel, dibrominated terthiophene 6 was prepared in an analogous fashion to 4a and 4b with 2.2 equiv of NBS. Subsequent Negishi coupling of compound 6 with organozinc intermediates of 4a and 4b, which were prepared by lithiation followed by reaction with zinc chloride, led to the isolation