Mild and efficient cyanuric chloride catalyzed Pictet–Spengler reaction

• Ashish Sharma,
• Mrityunjay Singh,
• Nitya Nand Rai and
• Devesh Sawant

Beilstein J. Org. Chem. 2013, 9, 1235–1242, doi:10.3762/bjoc.9.140

• driving force of the reaction [1]. The Pictet–Spengler reaction is catalyzed by Brønsted acids, as they convert the intermediate imine to the corresponding iminium ion, thus making it more electrophilic [18][19][20][21][22]. Conventionally, TFA [18], HCl [20], H2SO4 [21] and p-TsOH [22] are employed as

• a 6-endo intramolecular cyclization of the imine to produce the cyclized product. The second step is the rate-limiting step and the electrophilicity of the imine is the driving force of the cyclization. HCl generated in situ from TCT protonated the imine intermediate to an iminium ion, which

Selective copper(II) acetate and potassium iodide catalyzed oxidation of aminals to dihydroquinazoline and quinazolinone alkaloids

• Matthew T. Richers,
• Chenfei Zhao and
• Daniel Seidel

Beilstein J. Org. Chem. 2013, 9, 1194–1201, doi:10.3762/bjoc.9.135

• , which contains two tertiary amines and is readily obtainable by an acid-promoted hydride shift process [52][53][54], was also exposed to oxidative conditions (Scheme 1, reaction 2). We had hypothesized that quinazolinone 32 might be formed in this reaction by the debenzylation of an intermediate iminium

• ion. However, the major product from this reaction was identified to be 31, the apparent product of iminium hydrolysis. Conclusion We have demonstrated that quinazoline alkaloids and their analogues can be synthesized from aminals by using Cu(OAc)2/O2/AcOH and KI/TBHP catalyst systems. The use of

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• trifluoroacetate and camphorsulfonic acid salts, as compared to the chloride and acetate salts, can be attributed to the rate at which they promote vinyl iminium ion formation through a “balanced act” [12]. The difference in reactivity is related to the dissociation capacity of the respective amine salts. Since

• both “free amine” and “free acid” are needed in a synergistic manner to generate the vinyl iminium ion from the corresponding enone, the ability of the amine salt to dissociate to its “free amine” and “free acid” can exert an impact on the rate of the iminium formation. The low reactivity of the

• chloride salt can be attributed to its higher resistance toward dissociation, or is simply a tighter ion-pair compared to the CSA and the trifluoroacetate salt. At the same time, the formation of vinyl iminium ion from carbonyl systems and the “free amine” is also promoted by protonation of the carbonyl

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• applying a dendritic analogue in a dialysis device we were able to successfully drive the aqueous reductive amination of an unprotected amino acid to completion, despite the unfavorable equilibria for iminium ion formation in water. Since the dendrimer remains inside the dialysis bag due to its size, the

• the aromatic bipyridine peaks. The reactivity of macromolecular catalysts 16 and 17 was examined in the aqueous reductive amination of valine (18, Scheme 4). This reaction is in fact a multistep process, in which the equilibria unfavorable in water for the formation of hemiaminal 20 and iminium ion 21

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• 60. However, the reaction suffered from very poor yields (15–21%). The reaction is thought to proceed through the condensation of aldehyde 60 and prolinol 61 to give a chiral iminium-ion intermediate. This intermediate then undergoes a domino reaction involving a Michael reaction with salicylaldehyde

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• 2006, using diarylprolinolether as an effective organocatalyst. This method involved an oxa-Michael attack of salicylaldehydes 1 on the α,β-unsaturated aldehydes 2 activated through an iminium ion formation with the catalyst Ib, followed by an intramolecular aldol reaction and the subsequent water

• , Córdova et al. [42][43] and subsequently Wang et al. [44] independently reported similar oxa-Michael/aldol reactions by means of the same iminium-ion activation strategies but with improved yields and enantioselectivities. Córdova et al. reported the tandem reaction of salicylaldehydes 1 and α,β

Arylglycine-derivative synthesis via oxidative sp³ C–H functionalization of α-amino esters

• Zhanwei Xu,
• Xiaoqiang Yu,
• Xiujuan Feng and
• Ming Bao

Beilstein J. Org. Chem. 2012, 8, 1564–1568, doi:10.3762/bjoc.8.178

• with ethyl 2-aminoacetate derivatives is shown in Scheme 3 [16][17][18][19]. mCPBA oxidized 2a to amine N-oxide 4 before being transformed into 3-chlorobenzoic acid. The interaction of 4 with 3-chlorobenzoic acid led to the generation of the iminium ion 5 and 3-chlorobenzoate anion. The Mannich-type

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• iminium ion (3), which can be treated by Equation 1 as indicated in the bottom right of Figure 2 [23][24][25][26][27][28]. In order to predict which nucleophiles 4 are suitable reagents for such transformations because they are strong enough to react with iminium ions 3, but weak enough not to react with

• hold for reactions with iminium ions 3. Analogous experiments showed that the cinnamaldehyde-derived iminium ions 3a–i cover a reactivity range of five orders of magnitude; the iminium ion 3b, derived from MacMillan’s generation II catalyst, turned out to be by far the most reactive one of this series

• – demonstrated that CF3CO2– acted as a general base to deprotonate the Wheland intermediate 13a+ and thus suppresses its retroaddition with regeneration of the pyrrole 12a and the iminium ion 3a. Rate constants observed at variable concentrations of CF3CO2– allowed us to calculate the second-order rate constants

Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels–Alder reactions

• Stefan Bräse,
• Nicole Volz,
• Franziska Gläser and
• Martin Nieger

Beilstein J. Org. Chem. 2012, 8, 1385–1392, doi:10.3762/bjoc.8.160

• enantioselective organocatalytic Diels–Alder reaction was reported by MacMillan in his pioneering work in 2000 [17]. The activated iminium ion, formed through condensation of imidazolidinone and an α,β-unsaturated aldehyde, underwent reactions with various dienes to yield [4 + 2]-cycloadducts in excellent yields

• contrast to the thioureas with a cyclopropyl- and m-halophenyl-moiety (Table 2, entries 7–9), the corresponding bis(trifluoromethyl)thioureas (Table 2, entries 16–18) provide a higher conversion. Next to the previously described thiourea catalysts, we also analyzed iminium-ion catalysts according to

• ). An assortment of natural products synthesized by Diels–Alder reactions. Intermediates towards the total synthesis of (−)-Δ9-tetrahydrocannabinol (4). Formation of the iminium-ion. Crystal structure of the side product from the reaction of 13. Confirmation of the relative configuration with NOESY

Organocatalytic C–H activation reactions

• Subhas Chandra Pan

Beilstein J. Org. Chem. 2012, 8, 1374–1384, doi:10.3762/bjoc.8.159

• generate iminium ion 6. Finally, ring closure and proton loss provides the formation of the product 3. Redox alkylation In 2009, Tunge and co-workers demonstrated the synthesis of N-alkyl-pyrroles by redox isomerisation from the reaction of 3-pyrroline and aldehydes or ketones (Scheme 6) [17]. A series of

• ) groups. Recently, Xue, Cheng and co-workers carried out detailed DFT and MP2 computational studies for the reaction of 3-pyrroline and 2-phenylpropanal using acetic acid as the catalyst [21]. Interestingly, the authors could not find the existence of free iminium ion 12 in the rearrangement. They

• transformation is shown in Scheme 11. At first, the secondary amine catalyst reacts with the α,β-unsaturated aldehyde to generate an iminium ion. Subsequent 1,5-hydride shift generates the corresponding enamine. Finally, Mannich-type cyclization provides the product 14, and the secondary amine catalyst is

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• targets has led to considerable interest from the synthetic community [12][13][14][15][16][17][18][19]. Common synthetic approaches to incorporate this motif include nucleophilic additions to pyridine rings and further manipulation [20][21][22][23][24][25], intramolecular iminium ion cyclisation [26][27

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

• Iain Coldham,
• Adam J. M. Burrell,
• Hélène D. S. Guerrand,
• Luke Watson,
• Nathaniel G. Martin and
• Niall Oram

Beilstein J. Org. Chem. 2012, 8, 107–111, doi:10.3762/bjoc.8.11

• (R = Et) with glycine ethyl ester to give the tricyclic product 2 [19][20] (Scheme 1). In this chemistry, the intermediate imine undergoes cyclization onto the tethered alkyl chloride to give an iminium ion which deprotonates to give an azomethine ylide that undergoes dipolar cycloaddition with the

• formation, then cyclization with displacement of chloride to give an iminium ion. Deprotonation of this iminium ion would give the azomethine ylide that undergoes intramolecular cycloaddition. The preference for the all-cis isomer 13a arises from a preference for cycloaddition from the conformation shown in

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• novel strategy, dedicated to the synthesis of indenamines 14, involves addition of an electron-rich palladium/phosphine complex to a triple bond, followed by nucleophilic addition to an iminium ion generated in situ by addition of a secondary amine to an aldehyde. Transmetallation of the resulting

Reductive amination with zinc powder in aqueous media

• Giovanni B. Giovenzana,
• Daniela Imperio,
• Andrea Penoni and
• Giovanni Palmisano

Beilstein J. Org. Chem. 2011, 7, 1095–1099, doi:10.3762/bjoc.7.125

• dehydrative condensation to give an imine or an iminium ion, the latter being formally hydrogenated to the final amine product. The selectivity of the reducing agent is crucial as it should efficiently reduce the C=N bond of the intermediate while leaving unaffected the potentially reducible carbonyl compound

Recent developments in gold-catalyzed cycloaddition reactions

• Fernando López and
• José L. Mascareñas

Beilstein J. Org. Chem. 2011, 7, 1075–1094, doi:10.3762/bjoc.7.124

• furanyl intermediate featuring an iminium ion (XI). This species undergoes an intramolecular cyclization to yield the observed azepine product, and regenerates the gold catalyst. Very recently, the same group reported a related gold-triggered formal (4 + 3) cycloaddition between nitrones and 1-(1-alkynyl

Intramolecular hydroamination of alkynic sulfonamides catalyzed by a gold–triethynylphosphine complex: Construction of azepine frameworks by 7-exo-dig cyclization

• Hideto Ito,
• Tomoya Harada,
• Hirohisa Ohmiya and
• Masaya Sawamura

Beilstein J. Org. Chem. 2011, 7, 951–959, doi:10.3762/bjoc.7.106

• cationic gold center coordinates with 4a to form the gold–alkyne complex A. Intramolecular nucleophilic attack of the nitrogen atom affords the 7-exo-dig cyclization product B with an exocyclic C–C double bond. The protonated N-sulfonylenamide B tautomerizes to iminium ion C through 1,3-proton shift, or

When gold can do what iodine cannot do: A critical comparison

• Sara Hummel and
• Stefan F. Kirsch

Beilstein J. Org. Chem. 2011, 7, 847–859, doi:10.3762/bjoc.7.97

• majority of gold-catalyzed cyclization modes have involved initial carbon-heteroatom bond formation [7][10]. As a general rule, the nucleophilic attack of a carbonyl (or imine) group onto an alkyne activated by gold-complexation generates first an oxonium (iminium) ion species, the cationic character of

An efficient and practical entry to 2-amido-dienes and 3-amido-trienes from allenamides through stereoselective 1,3-hydrogen shifts

• Ryuji Hayashi,
• John B. Feltenberger,
• Andrew G. Lohse,
• Mary C. Walton and
• Richard P. Hsung

Beilstein J. Org. Chem. 2011, 7, 410–420, doi:10.3762/bjoc.7.53

• state through increasing negative charge density at the β-carbon. This action would lead to an N-acyl iminium ion-like character with the migrating hydrogen being proton-like with the α-position being favoured. This polarized transition state should also have a lower thermal activation barrier for the

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• substitution for improved activity and selectivity. Pyrrolidine 35 (Figure 9) is a highly selective catalyst for the epoxidation of α,β-unsaturated aldehydes (e.g. 36) [33]. In the first step of the reaction, aldehyde 36 and pyrrolidine 35 react together to form the iminium ion 37. This has a LUMO-lowering

• . The proposed bioactive conformation is shown in Newman projections. Capsaicin (33) and fluorinated analogues (R)-34 and (S)-34. Asymmetric epoxidation reaction catalysed by pyrrolidine 35. Inset: the geometry of the activated iminium ion intermediate 37 is stabilised by a gauche F–C–C–N+ alignment

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

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

• hoped for alcohol 8. A similar outcome was observed under both Sakurai-type conditions and treatment with potassium cyanide. It seems probable that these failures reflect a combination of the inability of the N-lone pair to stabilise the developing α-carbocation (the resultant N-sulfonyl iminium ion

Mitomycins syntheses: a recent update

• Jean-Christophe Andrez

Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33

• assisting deprotonation at C9a through a seven-membered ring and thereby accelerating the formation of the desired iminium ion. The authors found that changing the carbobenzyloxy protecting group to less basic groups such as a silyloxy ether or a methoxymethyl ether gave virtually no selectivity between C9a

• desired isomer. Presumably, allylstannane 185 approached the iminium ion by a synclinal transition state 192 as shown in Scheme 52. The pro-S face of the iminium being less hindered and possessing a lower LUMO energy than the pro-R face, the approach occurred accordingly from the face opposite the alkoxy

• substituent. When the allylation reaction was done with the iminium derived from pyrrolidine 186, no diastereoselectivity for the formation of 188 was observed. The bulkiness of the benzyl carbamate now proximal to the iminium ion was responsible for this poor result. The pyrrolidine 187 was synthesized from

The role of an aromatic group in remote chiral induction during conjugate addition of α-sulfonylallylic carbanions to ethyl crotonate

• Shlomo Levinger,
• Ranjeet Nair and
• Alfred Hassner

Beilstein J. Org. Chem. 2008, 4, No. 32, doi:10.3762/bjoc.4.32

• -carbonitrile was indicated by formation of a 10-tert-butyl derivative on reaction with tert-butylmagnesium chloride [9]. However, since iminium ion intermediates are much more reactive than ketones [7], imines 8h and 8j were successfully reduced to the primary amines 6 upon treatment with sodium

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• summarized in Table 2. 4-Nitroaniline (3c) is known to be inactive in Ugi reaction due to the reduced nucleophilicity of the nitrogen and the low basicity of the resulting imine leading consequently to a low concentration of the iminium ion. However, by performing the reaction in trifluoroethanol (TFE) [35

Facile synthesis of two diastereomeric indolizidines corresponding to the postulated structure of alkaloid 5,9E- 259B from a Bufonid toad (Melanophryniscus)

• Angela Nelson,
• H. Martin Garraffo,
• Thomas F. Spande,
• John W. Daly and
• Paul J. Stevenson

Beilstein J. Org. Chem. 2008, 4, No. 6, doi:10.1186/1860-5397-4-6

• the product 3 in 68% yield. The alternate diastereoisomer could not be detected by NMR spectroscopy in the crude reaction mixture. Product 3 formally arises by attack of trimethylallyl silane from the least hindered face of the thermodynamically less stable Z-iminium ion and the mechanistic details of