The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• ). After exiting the cold reactor zone, this stream passes through a coil maintained at 30 °C in order to ensure the complete consumption of the ketone 134. The resulting solution of lithium alkoxide 135 is combined with a further stream containing trifluoroacetic anhydride (TFAA) before being mixed with a

Highly selective palladium–benzothiazole carbene-catalyzed allylation of active methylene compounds under neutral conditions

• Antonio Monopoli,
• Pietro Cotugno,
• Carlo G. Zambonin,
• Francesco Ciminale and
• Angelo Nacci

Beilstein J. Org. Chem. 2015, 11, 994–999, doi:10.3762/bjoc.11.111

• methylene deprotonation, the alkoxide anion (RO−), can in fact originate (in situ) from the degradation of the allylic carbonate by the Pd catalyst [2]. Optimisation of the reaction conditions was carried out on the model substrate diethyl malonate by varying several parameters such as ligands, Pd sources

CO₂ Chemistry

• Thomas E. Müller and
• Walter Leitner

Beilstein J. Org. Chem. 2015, 11, 675–677, doi:10.3762/bjoc.11.76

• ]. Activation of carbon dioxide by inserting it into metal-alkoxide bonds allows for subsequent applications in polymer synthesis such as the copolymerisation of carbon dioxide with epoxides and other co-monomers [11]. Here, the catalysis with cobalt complexes still presents surprising effects [12]. More

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• ). Interestingly, when the oxygen in (S,S)-(+)-pseudoephedrine was protected, a reversal in diastereoselectivity was observed [54]. The authors attributed the difference in diastereoselectivity to the fact that when unmodified (S,S)-(+)-pseudoephedrine is used, a lithium alkoxide is produced in the presence of the

• lithium amide nucleophile. This alkoxide is believed to direct the addition of the lithium amide through coordination (Figure 4). On the other hand, when the oxygen in pseudoephedrine is TBS-protected (OTBS-15), this group sterically blocks one side of the double bond, thus the nucleophile attacks the

• method to synthesize protected syn-1,3-diols by performing intramolecular conjugate additions to a series of α,β-unsaturated esters and amides [71] (Scheme 8). Upon treatment of 24 with KHMDS and benzyaldehyde, a hemiacetal forms which provides the alkoxide nucleophile for the DCA reaction. These

Anionic sigmatropic-electrocyclic-Chugaev cascades: accessing 12-aryl-5-(methylthiocarbonylthio)tetracenes and a related anthra[2,3-b]thiophene

• Laurence Burroughs,
• John Ritchie,
• Mkhethwa Ngwenya,
• Dilfaraz Khan,
• William Lewis and
• Simon Woodward

Beilstein J. Org. Chem. 2015, 11, 273–279, doi:10.3762/bjoc.11.31

• either the rac or meso diastereomer could be realised. The meso enriched diastereomer of 8a could be realised by treating rac/meso mixtures of bis-lithium alkoxide of 8a with freshly prepared anhydrous NBu4F (2 equivalents) [23] (Scheme 3). Acid quench of the resultant purple dianion leads to ca. 5:1

Switching the reaction pathways of electrochemically generated β-haloalkoxysulfonium ions – synthesis of halohydrins and epoxides

• Akihiro Shimizu,
• Ryutaro Hayashi,
• Yosuke Ashikari,
• Toshiki Nokami and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2015, 11, 242–248, doi:10.3762/bjoc.11.27

• alkoxide ion, which is protonated by water to give bromohydrin 5a-Br (Scheme 2). The stereochemistry determined by NMR (5a-Br was synthesized using NBS according to the literature; see Supporting Information File 1) indicated that the addition of Br+ and DMSO across the C–C double bond was anti-selective

• , which is consistent with the results reported previously [22]. Treatment of 3a-Br with NaOMe resulted in a different product, namely epoxide 6a in 95% yield. In this case, the methoxide ion attacks the sulfur atom and cleaves the S–O bond under formation of an alkoxide ion. The latter intramolecularly

• attacks the carbon atom bearing the bromine substituent to give epoxide 6a (Scheme 2). Presumably, the protonation of the alkoxide ion with MeOH is slower than the intramolecular nucleophilic attack. We could not exclude the possibility that a protonated DMSO molecule presumably generated by the reaction

Copper-catalyzed cascade reactions of α,β-unsaturated esters with keto esters

• Zhengning Li,
• Chongnian Wang and
• Zengchang Li

Beilstein J. Org. Chem. 2015, 11, 213–218, doi:10.3762/bjoc.11.23

• conjugate reduction of the α,β-unsaturated diester with newly generated copper hydride, followed by aldol reaction to yield the key intermediate alkoxide A, which is subjected to further lactonization to form the lactone. Lam’s group has furnished a cobalt-catalyzed conjugate reductive aldolization

• with a γ-keto ester (instead of simple ketone) would yield an intermediate B as described in Figure 2. Intermediate B possesses a γ-alkoxide unit and an ester unit as that in intermediate A, and therefore, it is expected to afford a γ-carboxymethyl lactone as the final product. Furthermore, change of

• condensation [20]. Therefore, it is rationalized that an α,β-unsaturated monoester-derived enolate should react preferentially with the keto group in the keto ester to yield the alkoxide, which further lactonizes with an intramolecular ester group to form the lactone. It should provide a novel three-step

New highlights of the syntheses of pyrrolo[1,2-a]quinoxalin-4-ones

• Emilian Georgescu,
• Alina Nicolescu,
• Florentina Georgescu,
• Florina Teodorescu,
• Daniela Marinescu,
• Ana-Maria Macsim and
• Calin Deleanu

Beilstein J. Org. Chem. 2014, 10, 2377–2387, doi:10.3762/bjoc.10.248

• opening and generation of the benzimidazolium N-ylide 7 by the action of the alkoxide. The benzimidazolium N-ylide 7 reacts with the activated alkynes 3 to give the corresponding primary cycloadduct dihydropyrrolo[1,2-a]benzimidazoles 8. The formation of pyrrolo[1,2-a]quinoxalin-4-ones 4 involves the

Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: benzyl versus o-tolyl rearrangement

• Maroš Bella,
• Bohumil Steiner,
• Vratislav Langer and
• Miroslav Koóš

Beilstein J. Org. Chem. 2014, 10, 1942–1950, doi:10.3762/bjoc.10.202

• unambiguously confirmed by single-crystal X-ray analysis. The formation of o-tolyl isomers 4 and 5 can be explained by the possible reaction sequence (path 1) depicted in Scheme 2. The first step involves an addition of the Grignard reagent to the saccharide aldehyde, producing a trienic magnesium alkoxide

• ][25] for the reaction of 1-naphthylmethylmagnesium chloride (10) with some aldehydes and ketones (Scheme 3). However, in this case, a trienic magnesium alkoxide intermediate E (magnesium salt of 2-hydroxymethyl-1-methylene-1,2-dihydronaphthalene, an analogue of intermediate A in Scheme 2, path 1

• ), produced by an addition of the Grignard reagent 10 to the monomeric formaldehyde (11, R1 = R2 = H), was unstable and decomposed by a reversible process into the Grignard reagent and aldehyde. The latter underwent a Prins-type reaction with the magnesium alkoxide intermediate E in the presence of MgCl2, to

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• , entry 16), indicating the potential use of this reagent as a tosylating agent for phenols. The outcome in the phenol reaction may be linked to the potential reaction pathway, an aspect that is described below. However, because phenoxide is a softer nucleophile as compared to alkoxide, we had to consider

Copolymerization and terpolymerization of carbon dioxide/propylene oxide/phthalic anhydride using a (salen)Co(III) complex tethering four quaternary ammonium salts

• Jong Yeob Jeon,
• Seong Chan Eo,
• Jobi Kodiyan Varghese and
• Bun Yeoul Lee

Beilstein J. Org. Chem. 2014, 10, 1787–1795, doi:10.3762/bjoc.10.187

• signals were observed at 25 °C and ca. 70 °C (entries 1, 5, 8–10). In the polymerization reaction, the nitrate and acetate anions in 1 became chain-growing carbonate or alkoxide anions [14][17]. In the presence of protic compounds such as water (present as an impurity) or alcohols (deliberately added

• incorporation process in the PO/CO2/PA terpolymerizations. In addition to the direct attack of the alkoxide anion on PA, another PA consumption process might operate in the presence of the chain transfer agent such as deliberated added ethanol or impurity water. In this process, PA directly reacted with the

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• complex 1. The reaction begins with the addition of NH3 to the carbonyl carbon of acetaldehyde to form a Mulliken charge-transfer complex 2. This complex was firstly proposed here. In 2, the C–O bond is elongated to1.345 Å, which has an alkoxide character and the complex is not stable in the gas phase

• . However, it is more stable than the precursor complex by 3.5 kcal/mol when ten specific water molecules are considered; see Figure 2. This result indicates that the consideration of water molecules in the reaction is necessary to describe the step 1 → 2. Then, the alkoxide oxygen atom captures a proton

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• alkoxide after formation of the bisphosphonate would face the strong possibility of phosphonate–phosphate rearrangement [15][16][17]. However, diethyl hydroxymethylphosphonate (7, Scheme 1) is known to react with a base and geranyl bromide to afford the ether 8 in good yield [18]. With compound 8 in hand

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• (Scheme 2). The benzoate scrambling was completely suppressed by avoiding highly nucleophilic alkoxide intermediates, which was achieved with acidic deprotection conditions. Thus, treating the mixture of 11 and 12 with trifluoroacetic acid in dichloromethane at ambient temperature resulted in desilylation

Carbenoid-mediated nucleophilic “hydrolysis” of 2-(dichloromethylidene)-1,1,3,3-tetramethylindane with DMSO participation, affording access to one-sidedly overcrowded ketone and bromoalkene descendants^§

• Rudolf Knorr,
• Thomas Menke,
• Johannes Freudenreich and
• Claudio Pires

Beilstein J. Org. Chem. 2014, 10, 307–315, doi:10.3762/bjoc.10.28

• in static and dynamic model systems for several reasons. (i) With respect to repulsive strain, an attempted protonation of the alkoxide 2 immediately after its generation [2] at −70 °C failed to provide 1, because 2 cyclized too rapidly with formation of the chlorooxirane 3. On the other hand, the

• somewhat alleviated internal repulsion in alkoxide 4 allowed it to be trapped by protonation below −10 °C before the cyclization could interfere [3], so that the resultant alcohol 5 could be isolated (crude yield 90% from 1,1,3,3-tetramethylindan-2-one) and dehydrated to give 2-(dichloromethylidene

Substrate dependent reaction channels of the Wolff–Kishner reduction reaction: A theoretical study

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 259–270, doi:10.3762/bjoc.10.21

• reaction to convert an aldehyde or ketone to an alkane by the use of hydrazine (H2N–NH2) and a base (OH− or alkoxide RO−) [1][2]. The reaction is illustrated in Scheme 1. It is described as a "homogeneous" reaction [3] because the platinum catalyst used initially is not included. The formal change of the W

Bidirectional cross metathesis and ring-closing metathesis/ring opening of a C₂-symmetric building block: a strategy for the synthesis of decanolide natural products

• Bernd Schmidt and
• Oliver Kunz

Beilstein J. Org. Chem. 2013, 9, 2544–2555, doi:10.3762/bjoc.9.289

• co-solvent, together with toluene. Under these conditions, reproducible yields in the range between 67% and 78% were obtained (Table 2, entries 1–3). The alcohol is believed to protonate the Cu-enolate formed upon conjugate addition, resulting in the ketone and a Cu-alkoxide, which is then reduced

Oxidative 3,3,3-trifluoropropylation of arylaldehydes

• Akari Ikeda,
• Masaaki Omote,
• Shiho Nomura,
• Miyuu Tanaka,
• Atsushi Tarui,
• Kazuyuki Sato and
• Akira Ando

Beilstein J. Org. Chem. 2013, 9, 2417–2421, doi:10.3762/bjoc.9.279

• )silane (1) and arylaldehydes 2 was triggered by fluoride anions to afford aryl 3,3,3-trifluoropropyl ketones 3 in moderate to good yield. A mechanistic study of this reaction indicated that it occurred via an allyl alkoxide (4). A subsequent 1,3-proton shift of the benzylic proton of 4 forms 3. This

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

• 1.80 is then hydrolysed to reveal once again the amino acid functionality, which upon diazotisation in the presence of hydrobromic acid selectively forms the α-bromo ester 1.82. A more direct SNAr approach utilising 4-fluorobenzonitrile as the acceptor and the sodium alkoxide of hydroxyethylpyridine

A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand

• Hideki Shimizu,
• Jeffrey C. Holder and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2013, 9, 1637–1642, doi:10.3762/bjoc.9.187

• adventitious moisture for more than one week. Furthermore, chloride 11 proved to be a superior cyclization substrate. A series of bases were screened. Organic amine bases (Table 2, entries 4,5) and sodium hydride (Table 2, entry 6) provided inadequate conversion and low yields, whereas hydroxide and alkoxide

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

• titanium-mediated, alkoxide-directed fragment coupling reaction between vinylcylopropanes and vinyldimethylchlorosilane (Scheme 3, reaction 4) in which the stereochemical outcome of the rearrangement is orchestrated by the adjacent alkoxide, which is believed to direct formation of a tricyclic

Re₂O₇-catalyzed reaction of hemiacetals and aldehydes with O-, S-, and C-nucleophiles

• Wantanee Sittiwong,
• Michael W. Richardson,
• Charles E. Schiaffo,
• Thomas J. Fisher and
• Patrick H. Dussault

Beilstein J. Org. Chem. 2013, 9, 1526–1532, doi:10.3762/bjoc.9.174

• dithioacetals. Reactions of hemiacetals with nitrogen nucleophiles are unsuccessful. 1,2-Dioxolan-3-ols (peroxyhemiacetals) undergo Re(VII)-promoted etherification but not allylation. Hydroperoxyacetals (1-alkoxyhydroperoxides) undergo selective exchange of the alkoxide group in the presence of either Re2O7 or

• were curious about the interactions of Re(VII) oxides with hydroperoxyacetals (1-alkoxyhydroperoxides), versatile intermediates available from ozonolysis of alkenes in alcoholic solvents [23][24]. As can be seen in Table 8, Re2O7, Me3SiOReO3 and PTSA all catalyze alkoxide metathesis to furnish a

• moderate yield of a new hydroperoxyacetal. The exchange reaction was observed in several solvents (e.g., CH2Cl2, 1,2-dichloroethane) but was most efficient in acetonitrile. The alkoxide exchange was accompanied by much slower exchange of the peroxide; for example, prolonged reaction (>24 h) of acetal 26 in

Anionic cascade reactions. One-pot assembly of (Z)-chloro-exo-methylenetetrahydrofurans from β-hydroxyketones

• István E. Markó and
• Florian T. Schevenels

Beilstein J. Org. Chem. 2013, 9, 1319–1325, doi:10.3762/bjoc.9.148

• sole base (Scheme 4). In stark contrast, applying this procedure to the keto-alcohol 14 resulted in a mediocre 13% yield of 6, probably due to a rapid retro-aldol reaction of the derived, rather hindered, potassium alkoxide. Applying the LDA/KOt-Bu protocol improved the yield to 41%. It thus transpires

1-n-Butyl-3-methylimidazolium-2-carboxylate: a versatile precatalyst for the ring-opening polymerization of ε-caprolactone and rac-lactide under solvent-free conditions

• Astrid Hoppe,
• Faten Sadaka,
• Claire-Hélène Brachais,
• Gilles Boni,
• Jean-Pierre Couvercelle and
• Laurent Plasseraud

Beilstein J. Org. Chem. 2013, 9, 647–654, doi:10.3762/bjoc.9.73

•  2). The protonation of the formed zwitterionic acylimidazole intermediate by the alcohol initiator followed by the attack of the thereby obtained alkoxide regenerates the carbene species. The chain propagation is by the attack of the newly formed hydroxy-terminated monomer (I) on another

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• in the radical sense by converting it into a fluoropyridineoxy derivative by reaction of the alkoxide anion with inexpensive 2,6-difluoropyridine [61][62][63][64][65]. In this manner, any allylic alcohol becomes a potential radical allylating agent. This has proved to be a powerful route to complex