Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• phenanthridines via silver-catalyzed radical sulfonylation–cyclization of 2-isocyanobiphenyls (Scheme 25) [98]. Wang et al. reported a radical borylative cyclization of 2-isocyanobiaryls with N-heterocyclic carbene borane (Scheme 26) [99]. The boryl radical generated via hydrogen abstraction in the presence of di

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• -Methylene spirolactones at C-3 11a and 11b derived from dihydrocholesterol and stanolone were also obtained in 41% and 52% yields, respectively (dr > 20:1) (Scheme 3). More recently, a functionalized spiro-β-lactone was obtained via a metal-free procedure involving photoinduced carbene C–H insertion in a

• diazo precursor. To achieve this, cholesterol was first esterificated using 2-(4-methoxyphenyl)acetic acid and DCC. The resulting arylacetic ester 12 was then reacted with 4-acetamidobenzenesulfonyl azide (p-ABSA) and DBU in anhydrous acetonitrile to yield the diazo compound 13 in 22% yield. The carbene

• C–H insertion to produce the spiro-β-lactone was accomplished by simply exposing the diazo derivative to 440 nm blue LEDs (Kessil lamp) at 50 °C, that favored the formation of a singlet carbene that reacted selectively by insertion into the C(3)–H bond. Spiro-lactones 14 were obtained in 80% yield

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• fractionated cell cultures of M. alba with 49 was followed by irradiation with 365 nm light to generate reactive carbene from diazirine. This sequence allowed the formation of covalent bonds between the synthetic probe and binding proteins. The resulting mixture was subjected to a copper-catalyzed click

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• reaction. AlCl3-mediated Cannizzaro disproportionation of aldehydes. Ru–N-heterocyclic carbene catalyzed dehydrogenative synthesis of carboxylic acids. Intramolecular desymmetrization of tetraethylene glycol. Desymmetrization of oligoethylene glycol dialdehydes. Intramolecular Cannizzaro reaction of calix

Two-fold addition reaction of silylene to C₆₀: structural and electronic properties of a bis-adduct

• Masahiro Kako,
• Masato Kai,
• Masanori Yasui,
• Michio Yamada,
• Yutaka Maeda and
• Takeshi Akasaka

Beilstein J. Org. Chem. 2024, 20, 1179–1188, doi:10.3762/bjoc.20.100

• 305-8577, Japan 10.3762/bjoc.20.100 Abstract The addition reaction of C60 with silylene 1, a silicon analog of carbene, yielded the corresponding bis-adduct 3. The structure of 3 was determined by single-crystal X-ray structure analysis, representing the first example of a crystal structure of a

• silicon analog of carbene, were described as providing silirane (silacyclopropane)-type 6,6-mono-adducts Dip2SiC60 (2, Scheme 1) and Dip2SiC70 [15][16]. Furthermore, bis-adducts (Dip2Si)2C60 and (Dip2Si)2C70 were obtained as byproducts, but no details of these bis-adducts have been clarified [15][16]. The

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• mechanism suggested that dearomatization–aromatization pathways operated for the dehydrogenation of the alcohol and C–C bond formations. After the successful attempt of bidentate N-heterocyclic carbene-manganese complex-catalyzed N-alkylation of amines with alcohols at room temperature [41], Liu and Ke's

• ]. Under optimized conditions (2 mol % Mn(CO)5Br, 10 mol % t-BuOK, t-AmOH, argon atmosphere), various quinoline derivatives were successfully synthesized with this protocol (Scheme 71). In 2019, Liu et al. used a bis-N-heterocyclic carbene-supported manganese complex for quinoline synthesis by coupling

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• vinyl propargylic esters could be employed as five-carbon atom building blocks in [5 + 2] cycloadditions with alkynes or alkenes by carbene intermediates. Starting from those results they envisaged the benzannulation of heteroaryl propargylic esters favored by CO [44]. The process led to the desired

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• carbene insertion into bicyclobutane was reported in 2022 by Bychek and Mykhailiuk [74]. Previously the same group had also reported the synthesis of BCPs containing a difluorinated bridge by CF2 carbene insertion into bicyclobutanes [75]. More recently Davies and co-worker reported the one-pot synthesis

• of bridge difluorinated BCPs from α-allyldiazoacetates. In their reaction sequence, intramolecular cyclopropanation first forms the bicyclobutane which is then subjected to CF2 carbene insertion to yield the BCP [76]. Another useful pathway to 1,2,3-BCPs is strain release functionalisation as was

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• a highly emerging area of research and exhibit complementary reactivity to those well-developed carbene-mediated MCRs [30][31][32][33][34][35][36][37][38][39][40][41][42]. In the radical-mediated difunctionalization of alkenes, the carbon-centered radical species from a diazo compound can add to

• -catalyzed carboamination of 1,3-dienes (Scheme 5, lower left) or allenes (Scheme 5, lower right) with diazo esters. There are two possible paths to generate the hybrid α-ester alkylpalladium radical I. Path a undergoes an oxidative addition of HX with Pd(0)Ln, followed by the formation of Pd–carbene species

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• -step ynamide annulation and imidazolium ring-formation sequence. Metalation with Au(I), Cu(I) and Ir(I) at the C2 position provides an L-shaped NHC ligand scaffold that has been validated in gold-catalysed alkyne hydration and arylative cyclisation reactions. Keywords: annulation; carbene; gold

• contrast to the most widely used ‘umbrella-like’ NHCs (Figure 1) [2][3]. An extended π-system influences the donor and acceptor properties of the carbene whilst substitution on the polycycle can position groups adjacent to the active centre. The imidazo[1,5-a]pyridin-3-ylidene motif (ImPy), independently

• fused imidazolium core (Scheme 2). No reaction was observed between 6a and [Ir(cod)Cl]2 in the presence of NEt3. A solution of the free carbene was prepared from 6 and reacted with [Ir(cod)Cl]2 and then CO to afford the AImOxIr(CO)Cl complex 15. A minor side-product with a strong red colour was formed

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• alcohols, followed by base-promoted cyclization to afford the target spirocyclic compounds in good to high yields. Keywords: diazoarylidene succinimides; intramolecular cyclization; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocyclic motifs have emerged as auspicious frameworks for

• this protocol for spirocyclization and spiroheterocycle formation. The first step of the synthesis, the insertion of rhodium carbene into the O–H bond of 3-bromopropanol, was carried out under standard conditions in the presence of 0.05 mol % Rh2(esp)2 in dry DCM. 1H NMR spectroscopy was used to

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• carbene (NHC)-catalyzed radical relay, and (iv) mechanisms under electrochemical activation. By discussing selected literature examples, we illustrate how the activation mode of NHPI esters, and the reactivity of the resulting radical species, can vary depending upon the choice of catalytic or

• , accompanied by the formation of cyano-B(pin) 142. Importantly, in the absence of ZnCl2, intermediate 140 could be detected by HRMS and 11B NMR, highlighting the pivotal role of ZnCl2 in promoting rearomatization. N-Heterocyclic carbene (NHC) catalysis In 2019, Nagao and Ohmiya reported the decarboxylative

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• organic synthesis, as they can be used as diazo intermediates or carbene precursors for the rapid construction of complex molecules along with the introduction of fluoroalkyl groups [14][15][16]. Although the reaction of trifluorodiazoethane [17][18][19][20][21][22][23][24][25][26][27] as well as α-diazo

• reacts with the copper catalyst generating the Cu-carbene intermediate B, which undergoes nucleophilic attack by acetonitrile to form the intermediate C. Subsequently, nucleophilic addition of benzoic acid to intermediate C affords the acetimidic anhydride D with the release of CuI catalyst for the next

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes

• Nedra Touj,
• François Mazars,
• Guillermo Zaragoza and
• Lionel Delaude

Beilstein J. Org. Chem. 2023, 19, 1947–1956, doi:10.3762/bjoc.19.145

• ][19]. These mesoionic carbenes (MICs), together with their pyrazolin-4-ylidene [20] and 1,2-isoxazol-4-ylidene cousins [21], are the strongest donors among the various types of carbene ligands known thus far [22]. A distinct class of mesoionic or abnormal carbenes based on the 1,2,3-triazole ring

• report described the preparation of a CAAC·CS2 zwitterion. Thus, in 2009 Bertrand et al. obtained the betaine 2 by reacting the free carbene 1 with a slight excess of CS2 in THF at room temperature (Scheme 1) [62]. The starting material that featured a bulky and rigid spirocyclic alkyl group derived from

• free carbene [39][41][42][58]. Hence, we decided to probe the feasibility of this approach for the synthesis of CAAC·CS2 and MIC·CS2 betaines from readily available aldiminium or 1,2,3-triazolium salts. Synthesis of CAAC·CS2 zwitterions To begin our study, we investigated the synthesis of CAAC·CS2

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• acknowledged to be effective in introducing substituents to the nitrogen atoms of NH-heterocycles by means of carbene insertion into the N–H bond upon catalytic or photolytic decomposition of diazo compounds [25]. Furthermore, the reaction of N-heterocycles containing multiple non-equivalent nitrogen atoms

• will be reported in the following works. Conclusion In summary, a new diazo reagent for the convenient incorporation of heterocyclic substituents at the alpha-position of glutarimide by Rh(II)-catalyzed insertion of carbene into the N–H bond of nitrogen heterocycles has been proposed. The method allows

Active-metal template clipping synthesis of novel [2]rotaxanes

• Cătălin C. Anghel,
• Teodor A. Cucuiet,
• Niculina D. Hădade and
• Ion Grosu

Beilstein J. Org. Chem. 2023, 19, 1776–1784, doi:10.3762/bjoc.19.130

• molecule which catalyzes the macrocyclization reaction around the axle (Figure 1b). Results and Discussion In order to access the target [2]rotaxanes we made use of the CuAAC reaction, performed in the presence of a copper(I) N-heterocyclic carbene, a very stable and efficient class of catalysts used in

• active-metal template and clipping methods to yield the target interlocked molecules via [1 + 1] or intramolecular macrocyclizations, realized through CuAAC reactions catalyzed by axle-copper(I) N-heterocyclic carbene complexes. The [2]rotaxane obtained by [1 + 1] clipping (R1) could be only observed by

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• traditional heating methods. In the meanwhile, Qiu and Xu et al. reported the coupling reaction between diazo compounds 163 and N-sulfenylsuccinimides 1 under catalyst-, base-, and additive-free conditions (Scheme 71) [101]. The reaction proceeded via a radical pathway, in which a free carbene was generated

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• Nosheen Beig Varsha Goyal Raj K. Bansal Department of Chemistry, The IIS (deemed to be University), Jaipur, 302 020, India 10.3762/bjoc.19.102 Abstract N-Heterocyclic carbenes (NHCs) are a special type of carbenes in which the carbene carbon atom is part of the nitrogen heterocyclic ring. Due to

• addition; [3 + 2] cycloaddition reaction; hydrosilylation reaction; N-heterocyclic carbenes; NHC–Cu complexes; NHC–Cu complexes as catalyst; Introduction N-Heterocyclic carbenes (NHCs) are a neutral species having the carbene carbon atom as a part of the nitrogen heterocyclic ring. The transient

• ) reported by Arduengo et al. [3], turned out to be a watershed in this regard as it initiated intense research activity in this field. Compound 6 is stable in the absence of oxygen and air. The first air-stable carbene, namely 1,3-dimesityl-4,5-dichloroimidazol-2-ylidene (7b) [4] was obtained from the

Organic thermally activated delayed fluorescence material with strained benzoguanidine donor

• Alexander C. Brannan,
• Elvie F. P. Beaumont,
• Nguyen Le Phuoc,
• George F. S. Whitehead,
• Mikko Linnolahti and
• Alexander S. Romanov

Beilstein J. Org. Chem. 2023, 19, 1289–1298, doi:10.3762/bjoc.19.95

•  1. Benzoguanidine has an extended π-conjugation compared with carbazole and is more nitrogen-rich (three N-atoms vs one in carbazole). Thompson et al. recently reported a series of carbene–metal–amide (CMA) (metal = Cu, Ag, Au) emitters employing a benzoguanidine ligand [10]. The extended π

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• ]. However, numerous inconsistencies have been observed when comparing the outcomes of diazo- and iodonium ylide-based metallocarbene reactions, especially during metal-free control experiments, which led researchers to propose alternative, carbene-free reaction pathways for iodonium ylides. This was first

• , where the byproducts typically associated with free carbene formation (e.g., dimerization or rearrangement) were not observed (Scheme 2). In 1988, Hadjiarapoglou was investigating transition metal- and photocatalyzed intermolecular cyclopropanations between ylide 8 and norbornene, and found indane 9 was

• produced in 74% yield after six days at room temperature in the absence of catalyst (Scheme 2a) [107]. At that time, the authors did not articulate any theory as to how the reaction might initiate under such mild conditions, though they recognized that the decomposition of 8 into a free carbene would not

Copper-catalyzed N-arylation of amines with aryliodonium ylides in water

• Kasturi U. Nabar,
• Bhalchandra M. Bhanage and
• Sudam G. Dawande

Beilstein J. Org. Chem. 2023, 19, 1008–1014, doi:10.3762/bjoc.19.76

• generation of carbene as a reactive intermediate [36][37]. Also, spirocyclic iodonium ylides have been used for radiolabeling techniques [38]. In 2013, Shibata’s research group reported a novel trifluoromethanesulfonyl iodonium ylide for trifluoromethylthiolation of enamines, indoles, and ketoesters

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• significantly affect the C–H alkylation reaction and the reaction also proceeded well with hydrazones 13 obtained from aliphatic aldehydes or ketones. Based on mechanistic experiments and DFT calculations, the reaction presumably proceeds via a Cu–carbene migratory insertion (Scheme 4b). In the presence of CuI

• and the base the initial direct C–H activation of the ylide 12 gives the copper pyridinium ylide 15. The latter reacts with the diazo compound formed through reaction of hydrazone 13 with the base to give the copper–carbene species 16. Then, the intermediate 16 undergoes a Cu–carbene migratory

• with a bulky N-heterocyclic carbene ligand and (2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD) as the Lewis acid which allowed the direct C-4 alkylation of pyridines 1 (Scheme 12a). With the optimized reaction conditions in hand the group also screened the alkene and pyridine substrate scope which resulted C4

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• to the PBTA scaffold is an annulation of benzothiazoles with a pyrrole moiety (Scheme 1). It includes intramolecular cyclizations of benzothiazoles bearing a 3'-chloro substituent at C2 position (Scheme 1, entries 1 and 2) [5][6][7], intramolecular catalytic carbene cascade reactions of propargyl 1,3

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• ring, while flavylium triflate and 2,4,6-triphenylpyrylium tetrafluoroborate were not compatible with our reaction conditions. Heterodonor ferrocenyl phosphane–carbene ligands efficiently promote the conjugate addition of Grignard reagents to α,β-unsaturated lactones [58]. Building on this knowledge

• the trapping of metal enolates by Michael reactions with nitroalkenes 122 and disulfonyl ethylenes 124 (Scheme 31) [67]. The conjugate additions of dialkylzinc, Grignard, and trialkylaluminum reagents to cyclic enones 121 were realized using previously established chiral phosphoramidite, carbene or

• , which begins with a Cu-catalyzed enantioselective conjugate addition/enolate alkylation tandem reaction sequence utilizing the N-heterocyclic carbene ligand L40 [112]. Ketone 232 was isolated in 61% yield and 81% ee. Hereafter, the authors were able to synthesize the complex tetracyclic structure within

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• -Innovation Center of Efficient Processing and Utilization of Forest Resources College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China 10.3762/bjoc.19.39 Abstract A synthetic route to the bench-stable fluorinated masked carbene reagent diethyl 2-diazo-1,1,3,3,3

• fluorinated diazo compounds might be rationalized by their low accessibility and high volatility [44]. As a part of our continuing investigations in fluorinated carbene chemistry [45][46][47][48][49], we hypothesized that the synthesis of cyclopropanes with geminal trifluoromethyl and

• difluoromethylphosphonate groups at the ring might be possible by using our newly developed bench-stable diazo reagent CF3C(N2)CF2P(O)(OEt)2. Therefore, we report herein our preliminary results toward this goal via copper iodide-catalyzed cyclopropanation reaction of an acceptor carbene precursor with selected terminal