Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• functionalization of triazoles under metal-free conditions has been reported. These include the Broensted acid-catalysed N2 alkylation [27], organocatalytic N1 alkylation [28][29], N2-arylation using hypervalent iodine (Scheme 1c) [30], N2-alkylation involving radical intermediate [31], pyridine-N-oxide-mediated N1

• -arylation [32], NIS-mediated N2-arylation [33], etc. Although these are significant advances towards metal-free functionalization of triazoles, many of them suffer from poor regioselectivity. Therefore, a new method for N1-selective alkylation of the triazole moiety under simple, mild and metal-free

Metal-free visible-light-enabled vicinal trifluoromethyl dithiolation of unactivated alkenes

• Xiaojuan Li,
• Qiang Zhang,
• Weigang Zhang,
• Jinzhu Ma,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2021, 17, 551–557, doi:10.3762/bjoc.17.49

• approaches for the trifluoromethylthio (SCF3) difunctionalization of alkenes, such as cyanation [23], etherification [24][25][26][27], amination [28][29][30], chlorination [31][32], hydrogenation [33], trifluoromethylation [34], phosphonization [35], arylation [36][37][38], trifluoromethylthiolation [39

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

• < T < −40 °C in the presence of aromatic nucleophiles, thiophenes 72-Cl and 72-Br could be converted into 74-Cl and 74-Br derivatives via a side-chain arylation reaction. When the reaction was conducted at −40 °C, the reactivity was shown to be governed by the nature of the halogen atom. For the

• brominated derivatives 72-Br, the corresponding side-chain arylation reaction occurred at −60 °C, but a further hydrodehalogenation led to the bromine-free derivatives 75. For the chlorinated derivatives 72-Cl, a similar side-chain arylation−hydrodehalogenation sequence occurred, but an additional Friedel

• –Crafts arylation at the C4-position led to derivatives 76. In this latter case, a two-step one-pot process was developed in order to access derivatives bearing two different aromatic rings. Mechanistic investigations were then undertaken by in situ low-temperature NMR experiments, allowing the

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

• Daria I. Tonkoglazova,
• Anna V. Gulevskaya,
• Konstantin A. Chistyakov and
• Olga I. Askalepova

Beilstein J. Org. Chem. 2021, 17, 11–21, doi:10.3762/bjoc.17.2

• catalytic systems Pd(PPh3)4/K3PO4/THF (method A) and Pd(PPh3)4/K3PO4/1,4-dioxane (method B) were less effective. 3-Alkynyl-2-carbazolylazines can also be prepared using an alternative synthetic sequence, i.e., the Suzuki–Miyaura arylation–Sonogashira reaction. It should be noted that in the case of 2,3

• corresponding carbazolyl derivative 4a in 15% yield only (Table 2). The Pd(PPh3)4/K2CO3/1,4-dioxane/H2O catalytic system (method B) was more effective producing 4a in 63% yield. Thus, it was not the way for the synthesis of compounds 2a,b. Arylation of 2,3-dibromopyridine using the Pd(PPh3)4/K2CO3/1,4-dioxane

Metal-free synthesis of biarenes via photoextrusion in di(tri)aryl phosphates

• Hisham Qrareya,
• Lorenzo Meazza,
• Stefano Protti and
• Maurizio Fagnoni

Beilstein J. Org. Chem. 2020, 16, 3008–3014, doi:10.3762/bjoc.16.250

• dependence on the nature of the aromatic substituents G was apparent, since arylation took place (in variable yields) with electron-rich aromatic substituents, while it was completely inhibited in the presence of electron-withdrawing groups (path (b’), in Scheme 3). In the case of the triaryl phosphates

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

• enantioselectivities (20 examples, up to >99:1 er), with a quantum yield of 0.013. While there has been significant progress using bifunctional catalysts, dual catalytic systems can offer other modes of reactivity. For instance, Jiang et al. developed a urea-catalysed formal arylation of benzofuranones 215, using

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• products, in contrast to the 4-methyl and 4-unsubstituted substrates which do not undergo N1-arylation under similar reaction conditions. Keywords: C–N cross-coupling; Chan–Evans–Lam reaction; pyrimidin-2(1Н)-ones; fluoroalkyl group; boronic acids; Introduction The catalytic formation of C–N bonds in the

• arylation of the nucleophilic nitrogen atom, known as the Ullmann [6][7] reaction, and its modification by Chan and Lam [8] are favored due to the several advantages they offer versus the Pd counterpart (i.e., the Buchwald–Hartwig reaction) such as the lower cost and lower toxicity of the metal as well as

• their tolerance of aerobic conditions [2][9]. The efficiency of the Ullmann arylation has recently been greatly improved through extensive mechanistic investigation, ligand/precatalyst design and optimization studies [10][11][12][13]. As a result, the reaction has become feasible under milder conditions

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• intermediate 29 (Scheme 9) [14]. In 2012, Wu’s team have employed the Pd-catalyzed arylation reaction of sumanene with chlorobenzene and 2-bromo-1,3-dimethylbenzene to afford the aryl-substituted sumanenes 49a (Scheme 10). On the other hand, Higashibayashi et al. has revealed the synthesis of three different

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• economic and abundant source of energy to promote these transformations is in agreement with sustainable and eco-friendly chemistry. Directed C–H activation Pd-catalyzed arylation The first example of dual catalysis merging C–H activation and photoredox catalysis was published in 2011 by Sanford [80]. The

• transformation concerned the direct arylation of various aromatic compounds bearing different DGs with aryldiazonium salts (Figure 20). In her initial study in 2005, Sanford reported a similar arylation and diazonium salts were already identified as appropriate coupling partners. However, harsh reaction

• , pyrimidines, and oximes (Figure 20). The mild arylation proceeded in good to excellent yields over 20 examples and worked with electron-deficient, electron-rich as well as relatively sterically hindered arylating reagents. The mechanism proposed by the authors is presented in Figure 21. First, the DG-assisted

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• - and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels–Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels–Alder cycloaddition with maleimides to furnish octahydropyrrolo

• [3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative

• in governing the endo stereocontrol. Keywords: endo-Diels–Alder stereocontrol; 2-formylpyrrole; intramolecular Heck arylation reaction; non-covalent interactions; pyrroloindoles; pyrroloisoindoles; Introduction Pyrrolizines [1][2] and pyrrolizidines [3][4], abundant in nature [4][5], are among the

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

• trapping of the ensuing C(sp3) radical with the deuterated or tritiated thiol results in the incorporation of deuterium or tritium in multiple positions within the product 9.3. C(sp2) radicals Aryl radicals Considering the importance of arylation reactions in organic synthesis [61], aryl radicals are

• important intermediates to develop new synthetic methods [62]. Their reactivity was first explored in the Meerwein arylation as well as the Gomberg–Bachman and the Sandmeyer reaction [63][64][65]. Similar to C(sp3) radicals, aryl radicals add to unsaturated systems, such as (hetero)arenes, alkenes, or

• visible-light irradiation. The key aryl radical was trapped with heteroarenes, such as 11.2, to give the arylation products 11.3. Recently, similar methodologies for aryl radical generations have been developed exploiting flow techniques [74] and different organophotocatalysts, such as a metal-free

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• Quentin Lefebvre Christophe Salome Thomas C. Fessard SpiroChem AG, Rosental area, WRO-1047-3, Mattenstrasse 24, 4058 Basel, Switzerland 10.3762/bjoc.16.87 Abstract Herein we report a workflow coupling photoredox-nickel dual-catalyzed N-arylation reactions to benchtop analysis for the efficient

• thus be rapidly accessed, identifying privileged or challenging scaffolds and paving the way for further exploration. Keywords: benchtop analytics; fragment-based library; heterocyclic sp2–sp3 fragments; N-arylation; photoredox-nickel dual catalysis; Introduction Heterocyclic sp2–sp3 fragments are

• often exhibit different reactivity from unstrained substrates [8]. N-Arylation of spirocyclic amines would be a very efficient strategy for the modular synthesis of heterocyclic sp2–sp3 fragments, but their lack of stability to strongly basic conditions and heating might be an issue in palladium

Synthesis and properties of tetrathiafulvalenes bearing 6-aryl-1,4-dithiafulvenes

• Aya Yoshimura,
• Hitoshi Kimura,
• Kohei Kagawa,
• Mayuka Yoshioka,
• Toshiki Itou,
• Dhananjayan Vasu,
• Takashi Shirahata,
• Hideki Yorimitsu and
• Yohji Misaki

Beilstein J. Org. Chem. 2020, 16, 974–981, doi:10.3762/bjoc.16.86

• Abstract Novel multistage redox tetrathiafulvalenes (TTFs) bearing 6-aryl-1,4-dithiafulvene moieties were synthesized by palladium-catalyzed direct C–H arylation. In the presence of a catalytic amount of Pd(OAc)2, P(t-Bu3)·HBF4, and an excess of Cs2CO3, the C–H arylation of TTF with several aryl bromides

• direct C–H arylation was reported, and the structural and electrochemical properties of the products were clarified [30]. This motivated us to synthesize novel multistage redox-TTFs bearing 1,3-dithiole rings on aromatic rings, 1–3 (Figure 1). In addition, we focused on cross-conjugated systems with 1,3

• -dithiole rings, which are of interest as novel multistage redox systems as well as donor components for organic conductors [1][31][32][33][34][35][36][37][38][39][40][41]. The palladium-catalyzed C–H arylation might offer access to new cross-conjugated molecules bearing vinyl-extended TTF moieties (EBDTs

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

• applications of these compounds in photomedicine [23][25][26][27]. Recently we reported a porphyrin-photocatalyzed protocol for the arylation of enol acetates and elucidated the mechanism explaining why the electron-deficient porphyrin TPFPP is more efficient than TPP in the whole process (Scheme 4A). Briefly

• for the alkylation of aldehydes with diazo acetates in the presence of TPP. Arylation of heteroarenes with aryldiazonium salts using TPFPP as photocatalyst, and corresponding mechanism. A) Scope with different aryldiazonium salts and enol acetates. B) Photocatalytic cycles and comparison between TPP

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• reported a selective photoredox merger C(sp3)–H alkylation/arylation of ethers using benzaldehyde as the photoorganocatalyst and nickel as the transition metal catalyst [57]. For the coupling between (3-bromopropyl)benzene (132) and THF (131), presented in Scheme 28, NiBr2·glyme (134) was employed as the

• good yields of 145h–l (Scheme 32). Additionally, products derived from ureas (i.e., 146), N,N-dimethylaniline (i.e., 147), amides (i.e., 148), and lactams (i.e., 149a) were obtained. Moreover, for N-methylpyrrolidinone, α-arylation was achieved in a good yield and regioselectivity for the substitution

• the aldehyde 161 could afford the acyl radical 168 through a HAT process, which then could add to diethyl maleate (154) and afford the desired product 162 through a propagation mechanism. In 2019, König and co-workers presented a catalytic arylation of aromatic aldehydes 170 by aryl bromides 171 using

Copper-catalyzed O-alkenylation of phosphonates

• Nuria Vázquez-Galiñanes,
• Mariña Andón-Rodríguez,
• Patricia Gómez-Roibás and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2020, 16, 611–615, doi:10.3762/bjoc.16.56

• (alkenyl)iodonium salts, which are air- and moisture-stable, nontoxic and easy to prepare compounds, have become efficient reagents for mild and selective arylation and alkenylation reactions in organic synthesis [16][17][18]. In particular, the use of these hypervalent iodine reagents in copper catalysis

• Feringa recently reported a catalytic method for the synthesis of mixed alkyl aryl phosphonates based on a copper-catalyzed arylation of phosphonates with diaryliodonium salts [32]. Encouraged by this work, in the context of an electrophilic alkenylation of phosphonates, we reasoned that the action of a

• , Table 1). We first run the reaction under the conditions reported for the copper-catalyzed O-arylation of phosphonates (CuCl as catalyst, 2,6-di-tert-butylpyridine (dtbpy) as additive in dichloromethane at 40 °C) [32]. Under those conditions, enol phosphonate 3a was the only product of the reaction

Regioselectively α- and β-alkynylated BODIPY dyes via gold(I)-catalyzed direct C–H functionalization and their photophysical properties

• Takahide Shimada,
• Shigeki Mori,
• Masatoshi Ishida and
• Hiroyuki Furuta

Beilstein J. Org. Chem. 2020, 16, 587–595, doi:10.3762/bjoc.16.53

• extensively developed to tune the optoelectronic properties [21]. Therefore, the development of more efficient and shorter step synthetic methods for the BODIPY derivatives, such as direct C–H functionalizations (e.g., arylation [22][23][24][25][26][27][28], annulation [29], olefination [30], styrylation [31

Efficient synthesis of 3,6,13,16-tetrasubstituted-tetrabenzo[a,d,j,m]coronenes by selective C–H/C–O arylations of anthraquinone derivatives

• Seiya Terai,
• Yuki Sato,
• Takuya Kochi and
• Fumitoshi Kakiuchi

Beilstein J. Org. Chem. 2020, 16, 544–550, doi:10.3762/bjoc.16.51

• alkyl and alkoxy substituents at the 3, 6, 13, and 16-positions was achieved based on the ruthenium-catalyzed coupling reactions of anthraquinone derivatives with arylboronates via C–H and C–O bond cleavage. The reaction sequence involving the arylation, carbonyl methylenation, and oxidative cyclization

• effectively provided various tetrabenzo[a,d,j,m]coronenes in short steps from readily available starting materials. Tetrabenzo[a,d,j,m]coronenes possessing two different types of substituents were obtained selectively by sequential chemoselective C–O arylation and C–H arylation. The 1H NMR spectra of the

• tetrabenzo[a,d,j,m]coronene product indicated its self-assembling behavior in CDCl3. Keywords: C–H arylation; C–O arylation; oxidative cyclization; polycyclic aromatic hydrocarbons; ruthenium catalyst; Introduction Polycyclic aromatic hydrocarbons (PAHs) and their derivatives have attracted much attention

Copper-catalyzed remote C–H arylation of polycyclic aromatic hydrocarbons (PAHs)

• Anping Luo,
• Min Zhang,
• Zhangyi Fu,
• Jingbo Lan,
• Di Wu and
• Jingsong You

Beilstein J. Org. Chem. 2020, 16, 530–536, doi:10.3762/bjoc.16.49

• Anping Luo Min Zhang Zhangyi Fu Jingbo Lan Di Wu Jingsong You Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P.R. China 10.3762/bjoc.16.49 Abstract The regioselective C–H arylation of

• substituted polycyclic aromatic hydrocarbons (PAHs) is a desired but challenging task. A copper-catalyzed C7–H arylation of 1-naphthamides has been developed by using aryliodonium salts as arylating reagents. This protocol does not need to use precious metal catalysts and tolerates wide variety of functional

• groups. Under standard conditions, the remote C–H arylation of other PAHs including phenanthrene-9-carboxamide, pyrene-1-carboxamide and fluoranthene-3-carboxamide has also accomplished, which provides an opportunity for the development of diverse organic optoelectronic materials. Keywords: C–H

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• excellent yields. Finally, a Meerwein arylation reaction was developed through the copper photocatalyzed formation of an aryl radical according to a reductive process. A large panel of aryl iodides was added to various pyrroles and electron-rich aromatic derivatives. The arylated products were obtained in

• aryl radical on ynamides or cyanamides, followed by a final cyclization. Using similar reaction conditions as those used for the Meerwein arylation, the three alkaloids were synthesized in good to excellent yield in a straightforward manner. In 2017, Fu, Peters, and co-workers reported the copper

• )(xantphos)]PF6. Chlorosulfonylation of styrene and alkyne derivatives by ATRA reactions. Reduction of aryl and alkyl halides with the complex [Cu(I)(bcp)(DPEPhos)]PF6. aIrradiation was carried out at 420 nm. All redox potential are reported vs SCE. Meerwein arylation of electron-rich aromatic derivatives

Room-temperature Pd/Ag direct arylation enabled by a radical pathway

• Amy L. Mayhugh and
• Christine K. Luscombe

Beilstein J. Org. Chem. 2020, 16, 384–390, doi:10.3762/bjoc.16.36

• Amy L. Mayhugh Christine K. Luscombe Department of Chemistry, University of Washington, Seattle, WA 98195, USA Department of Materials Science & Engineering, University of Washington, Seattle, WA 98195, USA 10.3762/bjoc.16.36 Abstract Direct arylation is an appealing method for preparing π

• -conjugated materials, avoiding the prefunctionalization required for traditional cross-coupling methods. A major effort in organic electronic materials development is improving the environmental and economic impact of production; direct arylation polymerization (DArP) is an effective method to achieve these

• goals. Room-temperature polymerization would further improve the cost and energy efficiencies required to prepare these materials. Reported herein is new mechanistic work studying the underlying mechanism of room temperature direct arylation between iodobenzene and indole. Results indicate that room

Synthesis and circularly polarized luminescence properties of BINOL-derived bisbenzofuro[2,3-b:3’,2’-e]pyridines (BBZFPys)

• Ryo Takishima,
• Yuji Nishii,
• Tomoaki Hinoue,
• Yoshitane Imai and
• Masahiro Miura

Beilstein J. Org. Chem. 2020, 16, 325–336, doi:10.3762/bjoc.16.32

• through the arylation of 1 utilizing Ph2IOTf as arylating reagent [43][44]. Some copper-mediated arylation protocols using bromobenzene or iodobenzene [45][46] were also applicable to the preparation of 5, but significant loss of optical purity was inevitable. After the Pd-catalyzed cyclization under the

• the solid state [50][51][52][53][54]. Conclusion In summary, we have achieved the synthesis of a series of CPL-active polyheteroaromatic compounds from readily available chiral BINOLs via the O-arylation and subsequent palladium-catalyzed C–H/C–H coupling reaction. The substitution pattern on the

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• shown in Figure 12. Likewise, no result was obtained in the absence of light and photocatalyst. Aryl C–H arylation With the idea of introducing dual photoredox catalysis, in 2011, Sanford’s group reported the preparation of arylated compounds [115], important structural components of many natural

• previously reported methods required high temperatures [118][119][120]. A library of compounds was reported by that group using this approach, and a plausible mechanism is shown in Figure 13. Arylation of purines: Purine bases and purine nucleosides, which are common structural motifs in DNA and RNA, have an

• enormous range of applications in biology [121][122][123]. Inspired by other C–H arylation methods for N-heterocycles [124][125][126], recently, Guo and co-workers reported a dual photoredox-catalyzed C–H arylation of 6-arylpurine using photoredox catalyst 12a in the presence of a Pd cocatalyst [127]. With

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• , there are few reports. For example, the supported Ru-catalysed regiospecific C(sp2)–H arylation of benzo[h]quinolines and the addition of vinylsilanes to the C–H bonds of α-tetralones were reported by Inoue and co-workers [41][42]. Pieters et al. reported the Ru nanoparticle-catalysed C–H deuteration

Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki–Heck reaction

• Damian Kusy,
• Agata Wojciechowska,
• Joanna Małolepsza and
• Katarzyna M. Błażewska

Beilstein J. Org. Chem. 2020, 16, 15–21, doi:10.3762/bjoc.16.3

• substrates, a mixture of regioisomers, resulting from α- and β-arylation, was formed (see Supporting Information File 1, Figures S16 and S17, S32 and S33) [21]. In case of the reaction with allyl alcohol, the generated products isomerized in situ to give the saturated aldehydes, compounds 12, 21, and 22, a