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

• hydrolysis of the phosphoramidate directing group the resulting pyridone 1.93 is subjected to a sequence of chlorinations rendering a suitably functionalised coupling partner for a final Stille coupling to yield etoricoxib. Although the synthesis of etoricoxib as depicted in Scheme 17 very efficiently forms

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

• ][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. Inspired by their works, we reported a direct arylation of ferrrocene with arylboronic acid to introduce planar chirality into the ferrocene backbone using N,N-dimethylaminomethyl as the directing group and Boc-L-Val-OH as the ligand

Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C–H functionalization

• Ryan Pearson,
• Shuyu Zhang,
• Gang He,
• Nicola Edwards and
• Gong Chen

Beilstein J. Org. Chem. 2013, 9, 891–899, doi:10.3762/bjoc.9.102

• excellent directing group for a range of Pd-catalyzed C–H functionalization reactions [26][27][28][29][30][31][32][33][34][35]. In 2005, the Daugulis laboratory first reported that the ortho-C(sp2)−H bond of benzylpicolinamides could be arylated with aryl iodides under Ag-promoted Pd-catalyzed conditions

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 before they decompose [22][23][24][25]. Thus, Yoshida [26] demonstrated that the addition of aryllithiums, generated by halogen–lithium exchange, to conjugated enynes bearing an appropriate directing group occurs with complete regioselectivity and in good yields. More recently, they applied this

• resulting organolithiums can be trapped with different electrophiles to afford allenes 24 with complete regioselectivity and good yields. The best ee is obtained when there is a carbamoyloxy group (CbO) as directing group in the substrate with (−)-sparteine (L1) as the chiral ligand (Scheme 8) [27]. Despite

Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation

• Kei Murakami and
• Hideki Yorimitsu

Beilstein J. Org. Chem. 2013, 9, 278–302, doi:10.3762/bjoc.9.34

• group; (2) alkynes bearing a directing group; (3) strained cyclopropenes; (4) unactivated alkynes or alkenes; and (5) substrates that have two carbon–carbon unsaturated bonds (allenes, dienes, enynes, or diynes). Keywords: alkene; alkyne; carbomagnesiation; carbometalation; carbozincation; transition

• bearing a directing group; (3) cyclopropenes; (4) unactivated alkynes or alkenes; and (5) substrates that have two carbon–carbon unsaturated bonds (allenes, dienes, enynes, or diynes). Review Carbomagnesiation and carbozincation of electron-deficient alkynes Since conjugate addition reactions of

• reacts with allyl bromide to give 1i in 60% yield. Carbomagnesiation and carbozincation of alkynes bearing a directing group Directing groups have been utilized in successful carbometalation with high regio- and stereoselectivity. Classically, hydroxy groups on propargylic alcohols are used in

Alternaric acid: formal synthesis and related studies

• Michael C. Slade and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2013, 9, 166–172, doi:10.3762/bjoc.9.19

• involved; and (2) one or more additional steps for the removal of the directing group would be required. Thus, we developed a synthesis of a nucleophile that would allow the vast majority of the alternaric acid carbon skeleton to be installed through the three-component coupling reaction (Scheme 8). It

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

• Gianluigi Broggini,
• Egle M. Beccalli,
• Andrea Fasana and
• Silvia Gazzola

Beilstein J. Org. Chem. 2012, 8, 1730–1746, doi:10.3762/bjoc.8.198

• -rich heterocycles. Regioselective alkenylation of the unprotected indole. Plausible mechanism of the selective indole alkenylation, adapted from [49]. Directing-group control in intermolecular indole alkenylation. Direct C–H alkenylation of N-(2-pyridyl)sulfonylindole. N-Prenylation of indoles with 2

Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

• Esteban P. Urriolabeitia,
• Eduardo Laga and
• Carlos Cativiela

Beilstein J. Org. Chem. 2012, 8, 1569–1575, doi:10.3762/bjoc.8.179

• activating and breaking C–H bonds and, thus, transforming the inert C–H unit into the reactive C–M group (M = transition metal) [1][2][3]. In addition, the introduction of the concept of a "directing group" enables the attack of the metal on a unique position [4], therefore affording highly selective

C–H Functionalization

• Huw M. L. Davies

Beilstein J. Org. Chem. 2012, 8, 1552–1553, doi:10.3762/bjoc.8.176

• several instances the substrates have a natural preference for functionalization at specific C–H bonds. Alternatively, selective functionalization is achieved by using a directing group to orient the catalyst in a defined position. These types of synthetic strategies are already having a significant

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

• pyrimidyl group functions as a readily removable directing group [34]. We also reported an ortho-alkylation reaction of aromatic imines with vinylsilanes and simple olefins using a cobalt–phenanthroline catalyst (Scheme 1b) [35]. Building on these studies, we have developed a cobalt–bathocuproine catalyst

• present alkylation reaction, although it was a good substrate for the C2-alkenylation reaction. A pyridyl group served as an alternative directing group to the pyrimidyl group, affording the alkylation product 3ka in 80% yield. On the other hand, an N,N-dimethylcarbamoyl group, which was previously used

• as a directing group for rhodium-catalyzed C2-alkenylation [36], was entirely ineffective. Vinylsilanes bearing dimethylphenylsilyl and triphenylsilyl groups were amenable to the addition reaction with 1a, affording the adduct 3ab and 3ac in modest yields. Vinyltriethoxysilane also reacted with 1a in

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

• , the amide directing group and the PMDTA additive work together to abstract the metal ion from the deprotonated α-C of the propyl group (4.107(4) Å). A short distance of 1.376(3) Å is observed between the deprotonated carbon centre and a planar aromatic system that shows a pattern of bond lengths which

• ; 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

Use of mixed Li/K metal TMP amide (LiNK chemistry) for the synthesis of [2.2]metacyclophanes

• Marco Blangetti,
• Patricia Fleming and
• Donal F. O'Shea

Beilstein J. Org. Chem. 2011, 7, 1249–1254, doi:10.3762/bjoc.7.145

• reaction. Examples of such challenges include the selective aryl metalation of arenes containing more than one directing group (DG), arene metalation in positions not ortho to the directing group, or the identification of reaction conditions to achieve selective benzylic metalation of substituted toluenes

• sites and an ortho-aryl position primed for metalation by a strong directing group. Sequential treatment of 4a–d with BuLi, KOt-Bu and TMP(H) at −78 °C followed by the oxidant 1,2-dibromoethane [25] gave good to excellent yields of the targeted homo-dimer products 6a–d (Table 1, entries 1–4). It was

• for 6f. 2H NMR spectrum in CH2Cl2. *CD2Cl2. X-Ray structure of 8c with thermal ellipsoids drawn at 50% probability level. Selective benzylic metalation with LiNK conditions. DG = directing group. Iterative LiNK/oxidative coupling synthesis of [2.2]metacyclophanes. Oxidative coupling of benzylic

Brønsted acid-promoted azide–olefin [3 + 2] cycloadditions for the preparation of contiguous aminopolyols: The importance of disiloxane ring size to a diastereoselective, bidirectional approach to zwittermicin A

• Hubert Muchalski,
• Ki Bum Hong and
• Jeffrey N. Johnston

Beilstein J. Org. Chem. 2010, 6, 1206–1210, doi:10.3762/bjoc.6.138

• directing group [23][24][25]. After 45 min at 100 °C under microwave irradiation in neat benzyl azide [26], all three possible stereoisomers formed non-selectively (1:2:1 ratio). The desired 2,3-anti diastereomer 10a was separated and the relative stereochemistry was assigned through a spectroscopic study

Recent advances in carbocupration of α-heterosubstituted alkynes

• Ahmad Basheer and
• Ilan Marek

Beilstein J. Org. Chem. 2010, 6, No. 77, doi:10.3762/bjoc.6.77

• conditions. In all cases, no carbomagnesiation occurred, which proves that the directing group assistance is essential for both reactivity and regioselectivity (Scheme 23). During these investigations, it was found that the amount of CuI employed has a significant influence on the efficiency of

Benzyne arylation of oxathiane glycosyl donors

• Martin A. Fascione and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2010, 6, No. 19, doi:10.3762/bjoc.6.19

• inbuilt α-directing group (Scheme 1b) [13]. The principal objective of our approach was to develop a thioglycoside donor that could mimic the key trans-decalin intermediate 2 by using the sulfur-containing auxiliary as both the anomeric leaving group and α-directing participating group. An efficient

• then already pre-organised to give a 1,2-cis directing group upon activation, and afford 1,2-cis-glycosides 7 on alcohol addition. Following the synthesis of the oxathiane ketal glycosyl donors 5, activation of the β-thioglycoside linkage was necessary to form the key trans-decalin sulfonium ion 6, and

The oxanorbornene approach to 3-hydroxy, 3,4-dihydroxy and 3,4,5-trihydroxy derivatives of 2-aminocyclohexanecarboxylic acid

• Ishmael B. Masesane,
• Andrei S. Batsanov,
• Judith A. K. Howard,
• Raju Mondal and
• Patrick G. Steel

Beilstein J. Org. Chem. 2006, 2, No. 9, doi:10.1186/1860-5397-2-9

• -aminocyclohexanecarboxylic acid. The principal feature of this approach is the reliance on simple reactions exploiting substrate-controlled selectivity. In this respect, the ability of the carbamate group as a directing group is particularly noteworthy. The use of these hydroxylated cyclohexyl β-amino acids in the synthesis