B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

• Filip Meger,
• Alexander C. W. Kwok,
• Franziska Gilch,
• Dominic R. Willcox,
• Alex J. Hendy,
• Kieran Nicholson,
• Andrew D. Bage,
• Thomas Langer,
• Thomas A. Hunt and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2022, 18, 1332–1337, doi:10.3762/bjoc.18.138

• , Chemical Development U.K., AstraZeneca, Macclesfield, SK10 2NA, United Kingdom Medicinal Chemistry, Early Oncology, AstraZeneca, Cambridge, CB4 0WG, United Kingdom 10.3762/bjoc.18.138 Abstract The reduction of nitriles to primary amines is a useful transformation in organic synthesis, however, it often

• relies upon stoichiometric reagents or transition-metal catalysis. Herein, a borane-catalysed hydroboration of nitriles to give primary amines is reported. Good yields (48–95%) and chemoselectivity (e.g., ester, nitro, sulfone) were observed. DFT calculations and mechanistic studies support the proposal

• of a double B–N/B–H transborylation mechanism. Keywords: boron; catalysis; hydroboration; nitrile; transborylation; Introduction Primary amines are prevalent throughout organic synthesis, finding regular application in materials chemistry, pharmaceuticals, and agrochemicals (Scheme 1a) [1][2][3

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• outstanding results were achieved in the N-formylation of indoline (Scheme 1, formamide 10). The present methodology could also be effectively applied to the synthesis of N-formylmorpholine (Scheme 1, product 11). Aliphatic primary amines can be more challenging substrates [22]. In fact, when the reaction was

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• monomethylamines by reduction of N-substituted carbonylimidazoles with NaBH4/I2 in THF at reflux temperature is described. This method used no special catalyst and various monomethylamines can be easily obtained in moderate to good yields from a wide range of raw materials including amines (primary amines and

• ][31] and carbon dioxide (CO2) [32][33][34][35][36][37][38][39] have been developed for the N-methylation of amines. However, these N-alkylation methods often require the employment of expensive catalysts, and the N-alkylation of primary amines generally does not stop with monomethylation as expected

• N-substituted carbonylimidazoles. By employing inexpensive and commercially available reagents, a variety of aliphatic and aromatic monomethylamines were obtained in moderate to good yields from a broad substrate scope including not only amines (both primary amines and secondary amines) but also

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• synthetic method showed very limited substrate scope. Only less bulky primary amines underwent the first aza-Michael addition and then intramolecular nucleophilic substitution. However, aromatic amines, aniline, 2,3-dihydro-1H-inden-4-amine, and the bulky aliphatic primary amine adamantylamine did not

• -dimethylhydrazine. Synthesis of ethyl 2-ethoxy-1,2-azaphospholidine-4-carboxylate 2-oxides from ethyl 2-((chloro(ethoxy)phosphoryl)methyl)acrylate (202) and primary amines. Synthesis of (1S,3R)-2-(tert-butyldiphenylsilyl)-3-methyl-1-phenyl-2,3-dihydrobenzo[c][1,2]azaphosphole 1-oxide via double displacement of

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• strongly varying yields (5–72%) and dual orientation (either 3,5- or 5,3-positions) of an amino and dichloromethyl unit in the pyrazole (Scheme 3). We suggest that dienes 4a,l–o, obtained from 2c and primary amines are stabilized by formation of intramolecular hydrogen bonds between the NH and the NO2

Trichloroacetic acid fueled practical amine purifications

• Aleena Thomas,
• Baptiste Gasch,
• Enzo Olivieri and
• Adrien Quintard

Beilstein J. Org. Chem. 2022, 18, 225–231, doi:10.3762/bjoc.18.26

• dicyclohexylamine (Table 3, entry 1), a broad range of primary amines could also be separated from the aromatic impurities (Table 3, entries 2–10). As for other purification techniques, the challenge lies in the identification of the appropriate solvent to dissolve well the initial mixture and induce the amine–TCA

• complex precipitation. For such purpose, EtOAc, pentane, CH3CN or Et2O have been used in this table depending on the solubility observed (see Supporting Information File 1 for details). Depending on the TCA–amine salt solubility in the solvent used, the purified primary amines could be isolated in 40–94

Green synthesis of C5–C6-unsubstituted 1,4-DHP scaffolds using an efficient Ni–chitosan nanocatalyst under ultrasonic conditions

• Soumyadip Basu,
• Sauvik Chatterjee,
• Suman Ray,
• Suvendu Maity,
• Prasanta Ghosh,
• Asim Bhaumik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 133–142, doi:10.3762/bjoc.18.14

• same time, namely that of an aldehyde and that of one multiple bond. Generally, aldehydes and multiple bonds are very reactive in the presence of primary amines. However, since we used cinnamaldehyde derivatives 3, which are conjugated systems of a double bond and an aldehyde, the reactivity was rather

• The substrate scope and the generality of the reaction under the optimized conditions were explored through the synthesis of various products using differently substituted primary amines 1, cinnamaldehydes 3, and dialkyl but-2-ynedioates 2. Aromatic, aliphatic, benzylic, and various other types of

• primary amines 1 afford an excellent yield. Ortho-, meta-, and para-substituted aromatic amines with both electron-donating and -withdrawing groups were used in this protocol. Aromatic amines with electron-donating groups offered a slightly higher yield compared to those with electron-withdrawing groups

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• possible to identify three alternatives for the functionalization of β-NQS with amines: a) substitution of sulfonate by secondary amines; b) substitution of sulfonate by primary amines, followed by isomerization; and c) double addition of primary amines. In addition, other nucleophiles can also be used

• , secondary or primary, by substituting the sulfonic acid group at position C4. These reactions are dependent on the structures of the aliphatic amino reagents. In the case of secondary aliphatic amines, 4-alkyl- (or aryl-) amino-1,2-naphthoquinones 21 are formed (Scheme 3A), but using primary amines forms a

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• reduction of the intermediate nitrostyrenes and N-ethoxycarbonylation of the resulting primary amines [15]. For the synthesis of the alkaloids rac-reticuline (2e) and rac-orientaline (2f) we used a carbamate building block A3 without protection of the phenolic group, since our previous work [10

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• (Scheme 5 and Scheme 6). First, the three primary amines 15a–c with the same substitution patterns as reported for the secondary amines 9a–c (Scheme 4) were reacted under the standard conditions. While the yield for fluorenone 10b starting from primary amine 15b1 (40%) is slightly higher compared to its

• counterpart starting from secondary amine 9b (34%), the trend of electron-donating groups at the aminomethyl carrying arene adversely affecting the yield was also observed for primary amines. The negligible difference in yields for fluorenone 10b starting from amine 15b1 (34%) and 15b2 (38%) respectively

• whether primary or secondary benzylic amines are more suited for this cyclization. Nevertheless, we decided to further characterize the TBHP-mediated cyclization using primary amines, as these typically are more readily accessible. Comparing the yields for methoxyfluorenones 10e (52%) and 10b (obtained

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• carbenes (NHC) In recent years, NHCs have been used as organocatalysts for a wide variety of reactions [62]. Wang et al. investigated the use of several 1,2,4-triazolo-annelated chiral NHCs as organocatalysts to catalyze enantioselective aza-MR between primary amines (100) and β-trifluoromethyl-β

• chiral N-triflylphosphoramide. Aza-Michael addition of primary amines to β-trifluromethyl-β-phenylnitroolefin catalyzed nitrogen heterocyclic carbene. Asymmetric aza-Michael additions of pyrroles to protected (E)-4-hydroxybut-2-enals. Asymmetric aza-Michael addition of purine bases to aliphatic α,β

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• %), largely due to the poison of copper catalyst by thioether. Acyclic amines were also tested and the amination products were obtained in low yields (4n, 18%; 4o, 15%). Unfortunately, primary amines and anilines were completely inert. Encouraged by the above results, we further tried to synthesize ferrocene

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• tandem reaction of 2-trifluoromethyl-1,3-enynes 36 with primary amines, affording various trifluoromethyl-substituted 3-pyrrolines [56]. Subsequently, they also developed a novel route for the synthesis of halogenated trifluoromethylated pyrroles 37 and 38 by sequential intermolecular hydroamination

• reaction of 2-trifluoromethyl-1,3-enynes 36 with aliphatic primary amines and the following NXS-mediated oxidative cyclization (Scheme 13) [57]. The method tolerated various substituted benzylamines, 2-phenylethanamines, isopropylamine, and other aliphatic chain-like amines. Furthermore, both furan-2

• and Gandhi reported an Ag-catalyzed cascade cyclization of 6-hydroxyhex-2-en-4-ynals 42 and primary amines to give the 2-(α-hydroxyacyl)pyrroles 43 in moderate to good yield (Scheme 17) [62]. The proposed mechanism involves the condensation of amine and aldehyde to give the imine 44 and the AgNO3

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• product 17 was obtained in 15 steps with 6% overall yield. Although chiral secondary amines have proved to be particularly useful catalysts, primary amines as organocatalysts in asymmetric synthesis have also played a significant role [36]. For instance, Kim et al. described the enantioselective Michael

• described by Herrera et al. for the first time using primary aromatic diamines 31 as organocatalysts. The application of this class of catalysts for the Michael asymmetric addition of 4-hydroxycoumarins 1 to enones 2 is interesting from the point of view of organocatalysis, since the presence of two primary

• amines enables both the formation of an imine ion with the enone and activation of the hydroxycoumarin by hydrogen bonding [41]. Despite the long reaction time (3 days), the desired products 3 were obtained with good to excellent yields and moderate enantiomeric excesses (Scheme 9). A new organocatalyst

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• research. This has been explored utilizing the reactivity between primary amines and the aldehyde moiety of a 2’-O-(2-oxoethyl)uridine nucleotide, incorporated centrally in an 11-mer TFO, to form a Schiff base (monomers 41–45) [80]. All aminoalkylated moieties improved the triplex stability. Notably, a

• carrying the dimethylamino groups had a higher effect on the cellular uptake for 5’-FAM-labelled ASOs relative to the oligomers carrying BCNS being primary amines. However, both modifications demonstrated an improved cellular uptake relative to the unmodified 5’-end FAM-labelled 2’-OMe ASO [115]. Another

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• aniline (Scheme 5) [40]. A one-pot and multicomponent route to 1,4,5-trisubstituted 1,2,3-triazoles 11 containing a carboxylic ester group on the triazole ring was reported by Zhao et al. This strategy generates desired products from the reaction of readily available primary amines 10, 1,3-dicarbonyl

• the faster hydrolysis of the in situ generated imine intermediates, aromatic aldehydes containing electron-withdrawing substituents afforded no product in the reaction. It was proved that a variety of aliphatic primary amines can efficiently produce the triazole products (Scheme 14) [45]. This one-pot

• , amine 118, and CO were reacted in the presence of a catalytic amount of Pd(PPh3)4 as well as KOH in (CH3O)2CO as solvent to obtain 1,2,3-triazole-5-carboxamides 119. The reaction with several aliphatic primary amines led almost exclusively to the corresponding products. However, no product was obtained

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• amines (from few minutes to 24 h), with secondary amines reacting much faster than primary amines (Scheme 14). In this way, a large series of mono-, di-, tri-, and tetrasubstituted biguanides in positions N1 and N5 was synthesized. Interestingly, the application of strong Lewis acids such as FeCl3 or

• demonstrated by Schenker and Hasspacher for the synthesis of potential blood sugar-lowering biguanides, derived from cyclic secondary amines (Scheme 32) [66]. Besides, Bernatowicz et al. showed in a methodological study that primary amines are more reactive toward N-amidinopyrazole than N-amidino

• first reacted with an ammoniacal solution of CuSO4 in a sealed tube at 110 °C to produce unsubstituted biguanide in the 1880s. In 1962, this method was revisited by Hokfelt and Jonsson to prepare four N1-monoalkylbiguanides with antihyperglycemic activity [16]. The conditions included reacting primary

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• introduces primary amines for 1,3-dipolar cycloaddition which is less explored due to the probability of competitive Strecker degradation over decarboxylation of azomethine ylides. The protocol reveals the efficiency of MW assisted reaction with reduced reaction time from 18 h to 12 min and enhanced the

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• -amine (5f, 80%), cyclohexylamine (5d, 85%), and also with the 4-CF3 and 4-OMe-benzylamines (5g, 85%; 5h, 65%). Additionally, when using primary amines in the reaction the formation of polysubstituted products was not observed. On the other hand, N-phenylpyridin-2-amine afforded the appropriate compound

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• , aliphatic primary amines and ammonia, such as benzylamine and N-butylamine, were also examined as nitrogen donors; however, no desired product was detected. Then, we attempted to synthesize pharmaceutically active N-heterocyclic pyrrole derivatives with the aid of this three-component reaction. To our great

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

• Giovanna Bosica,
• Kaylie Demanuele,
• José M. Padrón and
• Adrián Puerta

Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235

• source of nitrogen has also been varied from the classical use of ammonia. The most common nitrogen source reported in literature is ammonium acetate (3). Others include the use of oxahydrazines, primary amines, and urea. The oxidation of dihydropyridines to pyridines has been achieved using mild

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

Tuneable access to indole, indolone, and cinnoline derivatives from a common 1,4-diketone Michael acceptor

• Dalel El-Marrouki,
• Sabrina Touchet,
• Abderrahmen Abdelli,
• Hédi M’Rabet,
• Mohamed Lotfi Efrit and
• Philippe C. Gros

Beilstein J. Org. Chem. 2020, 16, 1722–1731, doi:10.3762/bjoc.16.144

• construction of nitrogen-containing heterocycles from common substrates: 1,4-diketones and primary amines. Indeed, by just varying the substrates, the substituents, or the heating mode, it is possible to selectively synthesize indole, indolone (1,5,6,7-tetrahydroindol-4-one), or cinnoline (5,6,7,8

• indole, indolone, or cinnoline derivatives from the same starting material is not yet available. To reach this goal, the Michael reaction between 1,4-diketones and primary amines seems particularly attractive because of its straightforward and metal-free properties, and because they can be performed

• ; indoles 6, indolones 7, and cinnolines 8, starting from common substrates 1,4-diketones 5 and primary amines. The protocols developed here used mild conditions, were functional-group tolerant, transition-metal-free, proceeded in moderate to good yield, and could therefore easily be used in medicinal

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• oxidation of amines to imines was also described using heterogeneous catalysis. Zhang and co-workers demonstrated that the MOF (SnIV)porphyrin-containing photocatalyst (UNLPF-12) can be used for the oxidation of primary amines to imines in 88–99% yields under visible light irradiation (Scheme 53) [40]. In

• this case, the authors observed the oxidative coupling between the primary amines and their respective imines to produce the secondary imines. Wang and co-workers reported the synthesis, characterization, and application of interesting metal-free heterogeneous photocatalysts, 2D porphyrin-COFs (Por-COF

• methodology (conditions A). However, when primary amines were used, the authors observed an oxidative coupling between the amines and their respective N-substituted imines, which were trapped with TMSCN to afford the corresponding nitriles. The authors solved this problem by cooling the reaction to −50 °C and

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts

• David Schönbauer,
• Carlo Sambiagio,
• Timothy Noël and
• Michael Schnürch

Beilstein J. Org. Chem. 2020, 16, 809–817, doi:10.3762/bjoc.16.74

• from amino acids gave a complex reaction mixture, and the desired products could not be isolated. Additionally, alkyl salts derived from primary amines were unreactive. For the more stable allyl radicals, our initially optimized conditions with [Ru(bpy)3]Cl2 in DMA/ACN were again applicable and the