Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate

• conditions A and B (Table 6). The high selectivity observed for N-1 alkylation using NaH in THF (conditions A) was mainly effective using primary halide and tosylate compounds as electrophiles. Similar to the regiospecificity observed when employing n-pentyl bromide (ratio N-1 (10):N-2 (11) > 99:1, Table 1

• , entry 22), its tosylate counterpart gave the corresponding N-1 regioisomer 10 with a high degree of N-1 regioselectivity (ratio N-1 (10):N-2 (11) = 76:1) under conditions A (Table 6, entry 1). Furthermore, conditions A could be successfully applied to the synthesis of benzyl and alicyclic indazole

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• -hydroxy-4-furyl-tetralin 14af into the PAT analogue 22 (see Figure 1) [26]. The reaction of 14af with p-toluenesulfonyl chloride in pyridine afforded the tosylate 21 in 90% yield, which was then treated with 40% aqueous dimethylamine to produce the tertiary amine containing PAT analogue 22 (cis/trans

• basicity, the long reaction time of 20 hours may lead to an ion-pair species with 21 and hence erode the stereochemistry. To prove this idea, we performed the reaction with CH2Cl2 as the solvent in the presence of 5.0 equivalents of pyridine and 2.0 equivalents of TsCl. Under these conditions, the tosylate

• 21 was obtained with full retention of the expected stereochemistry (cis/trans =1:99) (see Supporting Information File 1 for details). The conversion of tosylate 21 to product 22 proceeded in a typical SN2 manner resulting in the expected inversion of the configuration. To unequivocally support the

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• tosylate under basic conditions affording 24 in a yield of 83%. The displacement of the tosyl group with an azide whilst heating the reaction at 80 °C allowed for the isolation of azide 25 in a good yield of 75%. Heating at higher temperatures resulted in product decomposition. Hydrogenation of the azide

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• an intramolecular nucleophilic substitution of the tosylate of the resulting primary alcohol (Scheme 15). This methodology was applicable to the synthesis of 1-phenyl-2-azaspiro[3.4]octane (45, n = 2, R = Ph) and 1-phenyl-2-azaspiro[3.5]nonane (45, n = 3, R = Ph). The structure and absolute

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

•  5) [38]. Tidwell et al. explored the influence of a CF3 group on the solvolysis reaction of various benzylic sulfonate derivatives [39][40]. They found a linear free-energy relationship between the solvolysis rate of sulfonate 13f in different solvents compared to the one of 2-adamantyl tosylate

• /kCD3 ratio of 1.54, highlighting an isotopic effect consistent with a solvolysis mechanism involving a carbenium ion (kCH3/kCD3 = 1.48 for 2-methyl-2-adamantyl tosylate). Also, kH/kCF3 = 2⋅105 was established, illustrating the retarding α-CF3 effect in the production of a carbenium ion [41]. In the

• group. Remarkably, they found that CF3 deactivates to such an extent that benzylic tosylate 13f was approximately 10 times less reactive than benzylic tosylate 17 (Figure 2, top). Similarly to the previous study, the Grunwald–Winstein plot [44] gave a linear free-energy relationship between the

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• in 105, which is associated with a difference in the regioselectivity of the C–C bond cleavage. The dissociation of the tosylate 104 to generate a cyclopropylmethyl carbocation A was accompanied by the cleavage of the proximal bond to form homoallylic products. The regioselectivity of the ring

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• , 1466, 1436, 1423, 1273, 1208, 1129, 1069 cm−1; HRESIMS (TOF) m/z: [M + H]+ calcd for C12H10BrN2O, 276.9971; found, 276.9974. Biologically active imidazo[1,5-a]pyridines. Activation of nitroalkanes towards nucleophilic attack by amines. Mechanistic rationale. Reaction of the N-tosylate 17 with

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• -methyl-3-buten-1-yl tosylate in the presence of Grubbs’ 2nd generation catalyst yielded 59, which, upon elimination with potassium tert-butoxide led to the diene 50. The reductive amination of 50 afforded an inseparable mixture of the C-14 amines (6:1 ratio). However, the amidation of this mixture with

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• available iodide 29. The formation of compound 30 proceeded in 21% yield, with alcohol 31 and dimer 32 also formed in 20% and 5% yield, respectively (Scheme 9). Indeed, when iodide 29 was replaced with bromide 33 and tosylate 34 no formation of compound 30 was observed, with alcohol 31 and dimer 32

• formation of dimer 28. Conditions: KOt-Bu, THF, 1 h, 68% yield. Alkylation of phosphoramidate 13 by iodide 29 to afford compound 30 and byproducts alcohol 31 and dimer 32. Use of bromide 33 or tosylate 34 afforded only compounds 31 and 32. Conditions: (i) s-BuLi (1.3 equiv), iodide 29, THF, −78 °C, 30 min

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• ring-opening followed by an intramolecular substitution to afford chiral thietane 175 [61]. 2.2.6 Synthesis via the nucleophilic ring-opening of three-membered heterocycles and subsequent displacement from aziridine-2-methyl tosylate: (1R,2S,6R)-6-Methyl-7-tosyl-7-azabicyclo[4.1.0]heptan-2-yl tosylate

• (179) is a derivative of aziridine-2-methyl tosylate. After the ring-opening with ammonium tetrathiomolybdate and subsequent intramolecular cyclization, the compound was converted into a bridged thietane 183 in 75% yield. The results indicated that, in the ring-opening step, tetrathiomolybdate

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• an attempt to determine the existence of radical behavior of PhMe2Si-MgMe (2), they studied the reaction of this Grignard reagent with dodecyl tosylate (1, X = OTs), which led to the formation of dodecyl silane 3 (20%) along with tridecane 4 (3%) and dodecane 5 (36%). Similarly, dodecyl bromide (1, X

• the Oestreich group in 2016 [27]. The reaction could be performed using CuCN as catalyst in the absence of a ligand. A wide variety of triflates 9, including some containing a remote tosylate, bromide, alkene, or alkyne functionality, afforded the desired alkylsilanes 10–16 in fair to good yields

Photophysics and photochemistry of NIR absorbers derived from cyanines: key to new technologies based on chemistry 4.0

• Bernd Strehmel,
• Christian Schmitz,
• Ceren Kütahya,
• Yulian Pang,
• Anke Drewitz and
• Heinz Mustroph

Beilstein J. Org. Chem. 2020, 16, 415–444, doi:10.3762/bjoc.16.40

• anions promoting the solubility in organic surroundings. Representative anions in the case of cationic absorbers relate to tosylate [5], [n-C12H25-Ph-SO3−] [5], FAP ([(C2F5)3PF3]−)[71], NTf2 ([(CF3SO2)2N]−) [5] or aluminates ([Al(t-C4F9O)4]−) [6] – just to count a few possible examples. Thus, replacement

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• chiral acetal ligands have been reported by Lyle et al. where the fluorine–metal exchange was achieved by treatment with potassium tert-butoxide for a relatively long period (24 h) (Scheme 4) [65]. Acid-catalyzed condensation of compound 20 with enantiomerically pure C2-symmetric 1,2-tosylate analogs 21

Oligomeric ricinoleic acid preparation promoted by an efficient and recoverable Brønsted acidic ionic liquid

• Fei You,
• Xing He,
• Song Gao,
• Hong-Ru Li and
• Liang-Nian He

Beilstein J. Org. Chem. 2020, 16, 351–361, doi:10.3762/bjoc.16.34

• designable structure, tunable properties as well as superior solubility [26][27]. Furthermore, the thermal stability and negligible vapor pressure of ILs can facilitate the product separation after reaction. To the best of our knowledge, the IL 1-butylsulfonic-3-methylimidazolium tosylate ([HSO3-BMim]TS) can

A chiral self-sorting photoresponsive coordination cage based on overcrowded alkenes

• Constantin Stuckhardt,
• Diederik Roke,
• Wojciech Danowski,
• Edwin Otten,
• Sander J. Wezenberg and
• Ben L. Feringa

Beilstein J. Org. Chem. 2019, 15, 2767–2773, doi:10.3762/bjoc.15.268

• formed revealing that a chiral self-sorting process takes place. In addition, two of the cage isomers can bind a tosylate anion in solution by formation of a host–guest complex. Results and Discussion Ligands Z-1 and E-1 (Scheme 1) were synthesized by a Suzuki cross-coupling reaction of 3

• -sorting. Next, we were interested in the guest binding abilities of cages Pd2(stable Z-1)4 and Pd2(stable E-1)4. The tosylate anion was chosen as it has the appropriate size to fit inside the cages. A Job plot analysis revealed a 1:1 binding stoichiometry between both cage isomers and OTs− (Figures S3–S5

• , Supporting Information File 1), which corresponds to the model in which OTs− serves as a guest molecule which is encapsulated inside the cages [55][56]. 1H NMR titrations with tetrabutylammonium tosylate revealed that both cages are able to bind OTs−, showing similar binding strengths (KB = 1604 ± 39 M−1 for

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• )-7 (Scheme 6) which was found to be an effective inhibitor of the mitotic kinesin. The biologically active enantiomer of mexiletine (R)-24 was efficiently synthesized from the alcohol (2R,1'R)-7 (Scheme 7) [45]. When the respective tosylate (2R,1'R)-25 was treated with 2,6-dimethylphenoxide two

• )-24 was obtained. On the other hand, alkylation of 2,6-dimethylphenol with the tosylate (2S,1'R)-25 proceeded regioselectively to give (2S,1'R)-26, a precursor to (S)-24. (−)-Cathinone ((S)-27) is an alkaloid acting as a central nervous system stimulant found in leaves of Catha edulis. It was

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• form alcohol 4 and further base-mediated alkylation with tosylate 5 affords phosphonate ester intermediate 6. Subsequent dealkylation of 6 using trimethylsilyl bromide (TMSBr) gives adefovir (1). The related analogue tenofovir, developed as an anti-HIV agent, may be prepared in a similar manner [37][38

• ]. The poor solubility of adenine and its derivatives in most organic solvents restricts the choice of solvent for this and subsequent reactions to polar aprotic solvents such as DMF, NMP and DMSO [38]. The choice of base for the alkylation of alcohol 4 with tosylate 5 has been the subject of recent

• tosylate 5 remained the superior alkylating agent under these conditions. The reaction of 4 with iodide 7 afforded only a trace amount of the phosphonate, with mostly unreacted starting material evident in the 1H and 31P NMR spectra of the crude reaction mixture. The reaction with triflate 8 resulted in a

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• synthesis may be partially explained by the fast mutarotation of 2′,3′-O-isopropylidene-D-ribofuranosylamine and its tosylate. This mutarotation is solvent-dependent. For example, according to 1H NMR data presented in the work of Cusack et al. [40], compound 23 exists essentially as the pure β-anomer in

• chloroform whereas in dimethyl sulfoxide and water solutions, mixtures of α- and β-anomers are observed, with α/β ratio being 1:1.7 and 1:1.5, respectively. Moreover, mutarotation of the tosylate 23 is very fast in aqueous basic solution, being almost instantaneous in aqueous 2 M Na2CO3 as emphasized by the

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• methyl tosylate (TsOCH3) as the methyl donor [72]. Kräutler et al. found an equilibrium methyl transfer between methylcobalamin and the methylated complex of 1 resulting in cob(II)alamin and β-methyl heptamethyl cob(III)yrinate. Such a thermal equilibration takes 16 days at room temperature [73]. Keese

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• tosylate in the presence of 18-crown-6 ether [15]. The synthesis of benzyl tosylate was accomplished using benzyl alcohol and freshly recrystallized p-toluenesulfonyl chloride in the presence of anhydrous trimethylamine and DMAP, in anhydrous dichloromethane [25]. At this stage, all attempts to obtain the

• key intermediate 13 removing the p-methoxybenzyl group [24][26][27][28] from 11 failed. Finally, compound 13 was successfully obtained by modifying the sequence of reactions. Deprotection of compound 10 with TFA [24], followed by selective alkylation with benzyl tosylate as previously described

• to rt, 1 h, 8a: 81%, 8b: 66%; e) dodecanoyl chloride, TEA, CHCl3, 0 °C to rt, 3 h, 90%; f) t-BuOK 1 M in THF, THF, reflux, 1.5 h, 65%; g) benzyl tosylate, KHMDS 0.5 M in toluene, crown ether 18-crown-6, THF, 0 °C to rt, 3 h, 35%; h) TFA, 60 °C, 2h; i) CAN, CH3CN/H2O (3:1), 0 °C to rt, 1h; j) benzyl

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• pyridine or TEA was sluggish. Subsequent substitution of the tosylate in 8 either with Super-hydride® (LiBHEt3) or with a cuprate generated in situ from MeMgBr and CuI afforded pyrrolidines 9 [31] and 12 in 68% and 44% yield, respectively (Scheme 1). In the course of tosylate substitution with the cuprate

• , 3-methylpiperidine 11 was isolated as a byproduct in 32% yield. A formation of the piperidine 11 proceeds via opening of aziridinium intermediate 10 (Scheme 1) [32]. Interestingly, a product of a ring expansion was not observed during the tosylate substitution with LiBHEt3. Simple acidic hydrolysis

Metal-free formal synthesis of phenoxazine

• Gabriella Kervefors,
• Antonia Becker,
• Chandan Dey and
• Berit Olofsson

Beilstein J. Org. Chem. 2018, 14, 1491–1497, doi:10.3762/bjoc.14.126

• of the desired aryl moiety, and the ortho-effect exerted by the 2-amido substituent was expected to improve the chemoselectivity further. Salt 5a was synthesized in good yield using our reported arylboronic acid methodology [33] (Scheme 3). Attempts to form the corresponding tosylate salt, either

Imide arylation with aryl(TMP)iodonium tosylates

• Souradeep Basu,
• Alexander H. Sandtorv and
• David R. Stuart

Beilstein J. Org. Chem. 2018, 14, 1034–1038, doi:10.3762/bjoc.14.90

• (TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the coupling reaction is compatible with electron

• reaction yield, using tosylate (OTs) produced the highest yield in both DCE and toluene as solvent (Table 1, entries 4–8). Given our ability to readily access aryl(TMP)iodonium tosylate salts [12] we continued our optimization with these reagents. We observed a very narrow operating temperature with a

• (via Mayr nucleophilicity constants) [16] may be useful in developing other coupling reactions with diaryliodonium electrophiles. Conclusion The coupling of both electron-deficient and sterically encumbered aryl groups with a phthalimide anion is achievable with aryl(TMP)iodonium tosylate salts. This

Cross-coupling of dissimilar ketone enolates via enolonium species to afford non-symmetrical 1,4-diketones

• Keshaba N. Parida,
• Gulab K. Pathe,
• Shimon Maksymenko and
• Alex M. Szpilman

Beilstein J. Org. Chem. 2018, 14, 992–997, doi:10.3762/bjoc.14.84

• competing side reaction was the nucleophilic attack by the tosylate on the enolonium species 4. Only in the rare cases mentioned below homocoupling did take place. The enolonium species 4 (R1 = Ph, R2 = H) reacts readily with both electron-rich and electron-poor TMS enol ethers 5 (Scheme 2). Thus, the cross

• enolonium species leads it to react faster with the less-hindered tosylate despite its poor electronic nucleophilicity. Thus, when the strategy of converting the least hindered enolate into the enolonium species 4 is used even highly hindered TMS enol ethers 5 may be used with formation of tertiary carbon