Structural conditions required for the bridge lithiation and substitution of a basic calix[4]arene

• Conrad Fischer,
• Wilhelm Seichter and
• Edwin Weber

Beilstein J. Org. Chem. 2011, 7, 1602–1608, doi:10.3762/bjoc.7.188

• Conrad Fischer Wilhelm Seichter Edwin Weber Institut für Organische Chemie, TU Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany 10.3762/bjoc.7.188 Abstract Lithiation and subsequent reaction with CO2 was applied to calix[4]arenes with different, equal or mixed, ether functions at

• new monobridge-substituted calix[4]arenes were characterized with respect to their conformational behaviour in solution and the X-ray crystal structure of one key intermediate is taken into consideration. Keywords: calixarene; lithiation; methylene bridge; supramolecular chemistry; X-ray structure

• ], whereas we follow a route involving the formation of a methylene carbanion through lithiation, which by nucleophilic substitution forms the desired bridge-substituted calixarenes [4][5]. While the number of substituted methylene atoms in the first protocol depends clearly on the amount of N

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

• regioselective functionalization. Ortho-lithiation by means of alkyllithium and lithium amides bases has been extensively developed as lithiated species display a high reactivity towards many electrophiles, leading to various substitutions (e.g., halogenation, carboxylation, acylation, hydroxymethylation

• favours the formation of the 2-stannyloxazole, which is isolated as the major product and then successfully engaged in Stille cross-coupling reactions with various (hetero)aryliodides and bromides [28][29][30]. The subsequent transmetalation reaction following lithiation with zinc dichloride also favours

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

• Elizabeth P. Jones,
• Peter Jones,
• Andrew J. P. White and
• Anthony G. M. Barrett

Beilstein J. Org. Chem. 2011, 7, 1570–1576, doi:10.3762/bjoc.7.185

• reactions: The benzyne precursor 2a and Schöllkopf’s bislactim ether 1 were allowed to react with 2.5 equivalents of sec-butyllithium at –95 °C to carry out the required ortho-lithiation for benzyne formation from 2a and the deprotonation of bislactim 1. During warming to room temperature, fragmentation to

• publication, we demonstrated the scope of the methodology over a range of ortho-lithiation benzyne precursors. To establish that any one of these precursors could be used to form quaternary adducts, we subjected the benzylation conditions to precursor 2b and the allylation conditions to precursor 2c

Directed aromatic functionalization in natural-product synthesis: Fredericamycin A, nothapodytine B, and topopyrones B and D

• Charles Dylan Turner and
• Marco A. Ciufolini

Beilstein J. Org. Chem. 2011, 7, 1475–1485, doi:10.3762/bjoc.7.171

• activity: Fredericamycin A, nothapodytine B, and topopyrones B and D. In each case, directed aromatic functionalization methodology greatly facilitated the assembly of the key molecular subunits. Keywords: alkaloids; directed aromatic functionalization; fredericamycin; heterocyclic compounds; lithiation

• regard, we elected to prepare 42 by Suzuki coupling [85] between a furylboronic acid and a 2-chloroquinoline [86]. The (relative) acidity of the C-2 position of furan is such that n-BuLi without added TMEDA suffices to induce lithiation. Accordingly, treatment of commercial 2-ethylfuran with n-BuLi in

• . arrows in 65). An MM+ conformational study [105] of a simplified analog of 63 estimated an energy barrier for internal rotation equal to about 17 kcal/mol [106]. As seen in Scheme 13, DAF technology came into the picture at the stage of the union of aldehyde 65 with amide 56. Thus, lithiation of

Carbamate-directed benzylic lithiation for the diastereo- and enantioselective synthesis of diaryl ether atropisomers

• Abigail Page and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1327–1333, doi:10.3762/bjoc.7.156

• ; diastereoselective; enantioselective; lateral lithiation; metallation; Introduction One of the first uses of the chiral diamine (−)-sparteine (1) in its now familiar role of controlling asymmetric deprotonation/electrophilic quench reactions [1] was an enantioselective benzylic deprotonation of bis(2,6

• -dimethylbenzene) with the aim of generating an atropisomeric product in enantiomerically enriched form (Scheme 1) [2]. Enantioselective lithiation has since then commonly been used to generate axial or planar chirality [3], in many cases by desymmetrising deprotonation of a functionalised aromatic system. The

• rotation [19]. Several of the classes of atropisomers we have studied contain functional groups which are excellent directors of lithiation [20], and indeed our original interest in lithiation stemmed from the need to build these atropisomeric structures rapidly and efficiently [21]. We recently reported

Directed ortho,ortho'-dimetalation of hydrobenzoin: Rapid access to hydrobenzoin derivatives useful for asymmetric synthesis

• Inhee Cho,
• Labros Meimetis,
• Lee Belding,
• Michael J. Katz,
• Travis Dudding and
• Robert Britton

Beilstein J. Org. Chem. 2011, 7, 1315–1322, doi:10.3762/bjoc.7.154

• undergo ortho-lithiation [30], reaction of the tetralithio intermediate 8 with dimethyldichlorosilane led to the formation of the bis(siloxane) 19 (not the 5-membered ring bis(siloxane) isomer), whose structure was unambiguously confirmed by X-ray crystallographic analysis (see Scheme 2, inset). As

Bromine–lithium exchange: An efficient tool in the modular construction of biaryl ligands

• Laurence Bonnafoux,
• Frédéric R. Leroux and
• Françoise Colobert

Beilstein J. Org. Chem. 2011, 7, 1278–1287, doi:10.3762/bjoc.7.148

• analogues. So far, such a process, based on the effective discrimination between bromine atoms as a function of their chemical environment, has been observed only sporadically. Keywords: biaryl; bromine–lithium exchange; ligand; lithiation; phosphine; Introduction Atropisomeric biaryls are important

• -Dimethylamino-2',6-dibromobiphenyl (1c) was obtained in an overall yield of 79% in 3 steps (Scheme 1). To introduce the methoxy group, 2,2',6-tribromobiphenyl (1a) was successively subjected to lithiation, borylation with fluorodimethoxyborane·diethyl ether, followed by oxidation with hydrogen peroxide and O

• throughout the synthesis. Mixed dialkyl(diaryl)phosphinobiphenyls: Path B In order to synthesize mixed diphosphines, we took advantage of the non-equivalence of the two phenyl rings towards lithiation. We started from the same dibromobiaryls 1 as before, but submitted them now to just one equivalent of

Combined directed ortho-zincation and palladium-catalyzed strategies: Synthesis of 4,n-dimethoxy-substituted benzo[b]furans

• Verónica Guilarte,
• M. Pilar Castroviejo,
• Estela Álvarez and
• Roberto Sanz

Beilstein J. Org. Chem. 2011, 7, 1255–1260, doi:10.3762/bjoc.7.146

• ]. The DoM strategy, when linked with different cross-coupling Pd-catalyzed reactions, could provide a superior approach for the construction of polysubstituted aromatic and heteroaromatic compounds [33][34][35][36][37][38]. In this context, we studied the o-lithiation of 3-halophenols and the resulting

Meta-metallation of N,N-dimethylaniline: Contrasting direct sodium-mediated zincation with indirect sodiation-dialkylzinc co-complexation

• David R. Armstrong,
• Liam Balloch,
• Eva Hevia,
• Alan R. Kennedy,
• Robert E. Mulvey,
• Charles T. O'Hara and
• Stuart D. Robertson

Beilstein J. Org. Chem. 2011, 7, 1234–1248, doi:10.3762/bjoc.7.144

• that replaces the departing hydrogen atom, prompting metallations of this type to be best regarded as “Alkali-Metal-Mediated Zincations (AMMZn)” [17]. Directed ortho-metallation (DoM) is a special sub-category of deprotonative metallation. Defined as a metallation (nearly always lithiation) of an

• -dimethylaniline with Cr(CO)3 leads to a mixture of ortho-, meta- and para-deprotonation upon lithiation [21], other situations of meta-deprotonation require a special combination of substituents on the aromatic ring. Such situations, which because of the multiple substitution limit the number of sites available

Selectivity in C-alkylation of dianions of protected 6-methyluridine

• Ngoc Hoa Nguyen,
• Christophe Len,
• Anne-Sophie Castanet and
• Jacques Mortier

Beilstein J. Org. Chem. 2011, 7, 1228–1233, doi:10.3762/bjoc.7.143

• report herein that sequential ring lithiation/methylation of the simple protected uridine 1 leading to 2 followed by lateral lithiation/alkylation with ω-alkenyl bromides provides a useful regioselective chain-extension procedure and an efficient route to 3. Results and Discussion Most methods for the

• construction of C-substituted nucleosides are based on ring lithiation of nucleoside derivatives followed by their reaction with appropriate electrophiles. Thus, sequential lithiation of 2',3'-O-isopropylideneuridine (6) with LDA in THF (Figure 1) and electrophilic quenching with n-bromobutane was reported to

• Li2CuCl4 [16][17][18] to 11 followed by quenching with 4-bromobut-1-ene failed to produce 3a. Consequently, lateral lithiations were examined. Lateral lithiation of benzenoid aromatics requires a stabilizing group capable of either delocalizing negative charge or stabilizing an organolithium by

A simple and convenient one-pot synthesis of substituted isoindolin-1-ones via lithiation, substitution and cyclization of N'-benzyl-N,N-dimethylureas

• Keith Smith,
• Gamal A. El-Hiti,
• Amany S. Hegazy and
• Benson Kariuki

Beilstein J. Org. Chem. 2011, 7, 1219–1227, doi:10.3762/bjoc.7.142

• 10.3762/bjoc.7.142 Abstract Lithiation of N'-benzyl-N,N-dimethylurea and its substituted derivatives with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C followed by reaction with various electrophiles afforded a range of 3-substituted isoindolin-1-ones in high yields. Keywords: N'-benzyl-N,N-dimethylureas

• ; isoindolin-1-ones; directed lithiation; electrophiles; substitution; synthesis; Introduction In recent years there has been a great deal of interest in compounds possessing an isoindolinone ring system since it represents the core unit of numerous naturally occurring substances [1][2][3][4][5][6][7][8

• for the synthesis of substituted isoindolines, of which the most generally useful involve palladium-catalysed reactions [34][35][36][37][38][39][40][41][42] or lithiation procedures [43][44][45][46][47][48][49][50][51][52][53][54]. In particular, among the various lithiation methods two useful

Directed aromatic functionalization

• Victor Snieckus

Beilstein J. Org. Chem. 2011, 7, 1215–1218, doi:10.3762/bjoc.7.141

• , representative of the subject areas described above, demonstrates the current activity in aromatic chemistry. For example, the DoM reaction as applied to the construction of molecules of value for asymmetric synthesis is nicely presented by Rob Britton; lithiation chemistry in service of heterocyclic synthesis

Lithium phosphonate umpolung catalysts: Do fluoro substituents increase the catalytic activity?

• Anca Gliga,
• Bernd Goldfuss and
• Jörg M. Neudörfl

Beilstein J. Org. Chem. 2011, 7, 1189–1197, doi:10.3762/bjoc.7.138

• ). The synthesis of diol 1 was conducted by an ortho lithiation of 1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol and subsequent addition of the in situ generated carbanion to formaldehyde. For comparison, a nonfluorinated diol precursor 2 was synthesized. Diol 3 was used as the precursor to investigate the

• nine ring phosphonates. The synthesis of these diols was realized by a double ortho lithiation of biphenyl and subsequent addition to the corresponding carbonyl compound. By this procedure, two asymmetric carbon centres and a chiral axis, which is fixed by intramolecular hydrogen bonds (6

Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl₃ promoted homocoupling

• Aiichiro Nagaki,
• Yuki Uesugi,
• Yutaka Tomida and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2011, 7, 1064–1069, doi:10.3762/bjoc.7.122

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• used to govern the enantioselectivity of the reaction pathway [56]. Tertiary organosulfur compounds can be made in this way by lithiation of a chiral secondary thiol derivative (Scheme 24). Three conditions must be met if this method is to be used for preparation of enantiomerically pure tertiary thiol

• greater steric bulk in the chalcogen substituent. 2.2.2 Lithiation and alkylation of thiocarbamates Hoppe and co-workers applied the observations of Hoffmann and Reich in comprehensive studies on configurationally stable α-lithiothiocarbamates. Stereoselective deprotonations of thiocarbamate 73 in the

• which they undergo electrophilic substitution [56], and 82 is remarkable in that all electrophiles, except protonating agents, react with complete inversion of configuration. Enantiopure cyclohexenyl thiocarbamates also form configurationally stable α-thioallyllithium species [68][69][70]. Lithiation of

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

• up. Alternative routes to such trisubstituted benzenes include directed ortho-lithiation of 1,3-disubstituted benzenes followed by trapping of the anion with a nitrogen electrophile [63]. As a result a new route to access the key building block has been proposed which makes use of a less widely

Redox-active tetrathiafulvalene and dithiolene compounds derived from allylic 1,4-diol rearrangement products of disubstituted 1,3-dithiole derivatives

• Filipe Vilela,
• Peter J. Skabara,
• Christopher R. Mason,
• Thomas D. J. Westgate,
• Asun Luquin,
• Simon J. Coles and
• Michael B. Hursthouse

Beilstein J. Org. Chem. 2010, 6, 1002–1014, doi:10.3762/bjoc.6.113

• -dithiole-2-thione and TTF derivatives, postulate a likely reaction mechanism and comment on substituent effects. Results and Discussion Synthesis Scheme 1 summarises the overall procedure that leads to the 1,4-aryl rearrangements. The lithiation of compound 1 with LDA and subsequent reaction with aryl

α,β-Aziridinylphosphonates by lithium amide-induced phosphonyl migration from nitrogen to carbon in terminal aziridines

• David. M. Hodgson and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2010, 6, 978–983, doi:10.3762/bjoc.6.110

• acids; aziridines; lithiation; migration; synthetic methods; Introduction The synthesis of aminophosphonic acids and their derivatives has attracted considerable attention, since the presence of such functionality, typically as amino acid surrogates, leads to interesting bioactivity in, for example

• our investigations [9][10][11][12][13] on the generation and subsequent chemistry of α-lithiated terminal aziridines [14], we considered whether α,β-aziridinylphosphonates 3 could be accessed by α-lithiation of N-phosphonate terminal aziridines 1, followed by N- to C-[1,2]-anionic phosphonyl group

• ]. More recently, Modro et al. reported a similar ortho-lithiation followed by [1,3]-shift of a phosphonyl group (6→7, Scheme 2) [18]; related processes have been observed with diazaphospholidine oxides [19] and bicyclic phosphoric triamides [20]. Benzylic lithiation-induced N- to C-[1,2]-anionic

Addition of lithiated enol ethers to nitrones and subsequent Lewis acid induced cyclizations to enantiopure 3,6-dihydro-2H-pyrans – an approach to carbohydrate mimetics

• Fabian Pfrengle and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2010, 6, No. 75, doi:10.3762/bjoc.6.75

• ether, dihydropyran, and dihydrofuran, all added smoothly to glyceraldehyde-derived nitrones 2a or 2b after lithiation with tert-butyllithium. Whereas in the reaction with uncomplexed nitrones, 1.5 equivalents of the respective lithiated enol ether were sufficient to obtain the desired syn-products with

A perfluorocyclopentene based diarylethene bearing two terpyridine moieties – synthesis, photochemical properties and influence of transition metal ions

• Falk Wehmeier and
• Jochen Mattay

Beilstein J. Org. Chem. 2010, 6, No. 53, doi:10.3762/bjoc.6.53

• diarylethene unit (3) can be obtained by lithiation of 3-bromo-2-methylbenzo[b]thiophene (1) followed by quenching with perfluorocyclopentene (2), according to the method described by Irie [12]. Electrophilic iodination leads to the diiodo photoswitch 4 (Scheme 1) [13][14]. We decided to use the diiodo switch

Synthesis of bis(3-{[2-(allyloxy)ethoxy]methyl}-2,4,6-trimethylbenzoyl)(phenyl)phosphine oxide – a tailor-made photoinitiator for dental adhesives

• Norbert Moszner,
• Iris Lamparth,
• Jörg Angermann,
• Urs Karl Fischer,
• Frank Zeuner,
• Thorsten Bock,
• Robert Liska and
• Volker Rheinberger

Beilstein J. Org. Chem. 2010, 6, No. 26, doi:10.3762/bjoc.6.26

• under analogous conditions. The lithiation step was carried out in the presence of different model compounds for the reactive sites of the [2-(allyloxy)ethoxy]methyl substituent, such as benzyl methyl ether, allyl ethyl ether or diethylene glycol dimethyl ether. In the case of benzyl methyl ether and

• allyl ethyl ether, BAPO was formed in a lower yield showing that benzyl and allyl groups had a negative effect on the yield of BAPO. Probably, these groups initiate side reactions during the lithiation step. Furthermore, it was found that the temperature of the phosphine oxidation significantly

• WBAPO was synthesized via the dichlorophosphine route in a satisfactory yield. Benzyl and allyl groups of the introduced [2-(allyloxy)ethoxy]methyl substituent probably initiate side reactions during the lithiation step and have a negative effect on the yield of the synthesis. WBAPO, a yellow liquid

Diastereoselective functionalisation of benzo-annulated bicyclic sultams: Application for the synthesis of cis-2,4-diarylpyrrolidines

• Susan Kelleher,
• Pierre-Yves Quesne and
• Paul Evans

Beilstein J. Org. Chem. 2009, 5, No. 69, doi:10.3762/bjoc.5.69

• vinyl bromide 24a in lithiation and Pd-coupling chemistry is described. In the case of the latter, hydrogenation of the styryl products afforded a single diastereoisomer. These compounds were then studied under dissolved metal reduction conditions, in which the cleavage of both N–S and C–S bonds takes

• vinyl bromides 24a and 24b in good yields, respectively (Scheme 7). Vinyl bromide 24a was then subjected to lithiation with t-BuLi, followed by a CO2 quench. The desired carboxylic acid recovered from this reaction was only formed in low yields possibly due to issues with competing directed ortho

• -lithiation [25]. Notwithstanding, this acid was transformed into the corresponding methyl ester 25 using a Steglich-type esterification. Alkenyl reduction of the α,β-unsaturated ester under standard conditions gave the product of hydrogenation as an undetermined 3:1 mixture of diastereoisomers. The likely

Synthesis of unsymmetrically substituted biaryls via sequential lithiation of dibromobiaryls using integrated microflow systems

• Aiichiro Nagaki,
• Naofumi Takabayashi,
• Yutaka Tomida and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2009, 5, No. 16, doi:10.3762/bjoc.5.16

• micromixers and four microtube reactors to obtain unsymmetrically substituted biaryl compounds. Keywords: dibromobiaryls; fast mixing; integrated microflow system; selective lithiation; unsymmetrically substituted biaryls; Introduction Unsymmetrical biaryls have received significant research interest

• lithiation of dibromobiaryls using an integrated microflow system. These observations may open a new aspect of the synthesis of unsymmetrically substituted biaryls (Scheme 1), and herein we report full details of this study. Results and Discussion Br-Li Exchange Reaction of 2,2′-Dibromobiphenyl First, we

Convenient methods for preparing π-conjugated linkers as building blocks for modular chemistry

• Jiří Kulhánek,
• Filip Bureš and
• Miroslav Ludwig

Beilstein J. Org. Chem. 2009, 5, No. 11, doi:10.3762/bjoc.5.11

• ′-bromobiphenyl intermediates necessary for the preparation of 4a–c were synthesized by the Suzuki–Miyaura cross-coupling of 1-bromo-4-iodobenzene with the corresponding boronic acids/esters 1a–c in the yields of 82, 84, and 91%, respectively. A routine procedure involving a lithiation and reaction with

• % yield). Since the Sonogashira reaction between bromo derivatives and trimethylsilylacetylene proved to be sluggish and low yielding (even with a large excess of acetylene and elevated temperature), the bromo derivatives were converted to the corresponding iodo derivatives by lithiation and quenched with

• . Overall 12 extended π-linkers have been easily synthesized (8 of them are new compounds) utilizing procedures such as a lithiation/reaction with triisopropyl borate/esterification with pinacol, Mizoroki–Heck coupling with vinylboronate pinacol ester, borylation with bis(pinacolato)diboron or Sonogashira

Enantiospecific synthesis of [2.2]paracyclophane- 4-thiol and derivatives

• Gareth J. Rowlands and
• Richard J. Seacome

Beilstein J. Org. Chem. 2009, 5, No. 9, doi:10.3762/bjoc.5.9

• by sulfinyl-directed ortho lithiation with n-butyllithium followed by reaction with tosyl azide. The resulting azo[2.2]paracyclophane was reduced in situ to give the amine (Rp,RS)-8 in good yield for the two steps (Scheme 2). Trichlorosilane-mediated deoxygenation proceeded uneventfully to furnished