Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• . Naturally occurring amino acids, e.g., glycine, are often used in medicinal chemistry as linkers, structural components of scaffolds or even as precursors to useful building blocks. Wallentin and co-workers have described a method for the reductive decarboxylation of amino acids, using bis(4-chlorophenyl

• such a mild and selective oxidation. MacMillan and co-workers have recently developed a method for the bioconjugation of peptides by radical decarboxylation of the C-terminus of peptides and subsequent Giese-type addition to Michael acceptors. This is performed under blue light irradiation, using

Synthesis of pyrimido[1,6-a]quinoxalines via intermolecular trapping of thermally generated acyl(quinoxalin-2-yl)ketenes by Schiff bases

• Svetlana O. Kasatkina,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Ivan G. Mokrushin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2018, 14, 1734–1742, doi:10.3762/bjoc.14.147

• reaction (Table 1) was not detected. The most likely way of the formation of quinoxalinone 4a is hydration of the ketene with subsequent decarboxylation (Scheme 2); more careful drying the reaction vials and solvents easily reduced the amount of compound 4a. The formation of pyrido[1,2-a]quinoxaline 5a can

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• = COOEt); di-tert-butyl, R3 = COOt-Bu etc.) act as the most common dipolarophiles because of their high reactivity. Moreover, one or both carboxylate groups in position 3 and 4 in the final pyrazole are easily removable using a hydrolysis/decarboxylation protocol [5][16] thus giving pyrazole-4-carboxylic

• decarboxylation [16][95][96]. A novel strategy (Scheme 8) was recently developed by Harrity et al. (see entries 73, 74, 94, 117, 136, 137, 145–150 [32][33][34][82][89][91] in Table 4) who used trimethylsilyl acetylene as a dipolarophile. After regioselective cycloaddition giving 3-trimethylsilylpyrazole (cf. also

• example phenylpropiolic acid (R3: COOH) gives only minor a yield of the cycloaddition/decarboxylation product with 5,6-dihydro-3-hydroxy-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium [97][98] (Scheme 9). The Table 5 again summarizes all the examples found, including reaction conditions from which we have come

An unusual thionyl chloride-promoted C−C bond formation to obtain 4,4'-bipyrazolones

• Gernot A. Eller,
• Gytė Vilkauskaitė,
• Algirdas Šačkus,
• Vytas Martynaitis,
• Ashenafi Damtew Mamuye,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2018, 14, 1287–1292, doi:10.3762/bjoc.14.110

• of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products

• upon alkaline hydrolysis and subsequent decarboxylation (Scheme 7). According to the NMR spectra, compounds 10 are obviously present as 5-hydroxypyrazoles due to the absence of a proton attached to pyrazole C4. NMR spectroscopic investigation In Supporting Information File 1 the NMR spectroscopic data

Rapid transformation of sulfinate salts into sulfonates promoted by a hypervalent iodine(III) reagent

• Elsa Deruer,
• Vincent Hamel,
• Samuel Blais and
• Sylvain Canesi

Beilstein J. Org. Chem. 2018, 14, 1203–1207, doi:10.3762/bjoc.14.101

• , decarboxylation, and fragmentation [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The sulfonate group is a useful functionality frequently employed as a leaving group in substitution reactions. Production of sulfonates [28] from alcohols generally involves reaction with a

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• involves the condensation of o-phthalaldehyde (27) with diethyl 1,3-acetonedicarboxylate (28), followed by hydrolysis and decarboxylation steps [46][47] (Scheme 5). Similar syntheses were made by Cook’s [48] and Föhlisch’s [49] groups. Nevertheless, for performing large-scale synthesis, the cost of 27 make

• structure of 86 was confirmed by the spectroscopic data. The formation of the heptafulvalenes could be explained via an intermolecular [2 + 2] cycloaddition product such as 87 between the carbonyl group of tropones and the ketene C=C double bond of 8-oxoheptafulvene (85) followed by decarboxylation. In a

• dehydrogenation using N-bromosuccinimide, and its properties were compared with those of benzotropolone 241A (Scheme 50) [178]. The benzotropolone 174 could also be prepared from diester 301 in a similar way (Scheme 50) [179]. The simultaneous hydrolysis and decarboxylation of benzotropolone-diester 304 to 174

Selective carboxylation of reactive benzylic C–H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system

• Toshifumi Dohi,
• Shohei Ueda,
• Kosuke Iwasaki,
• Yusuke Tsunoda,
• Koji Morimoto and
• Yasuyuki Kita

Beilstein J. Org. Chem. 2018, 14, 1087–1094, doi:10.3762/bjoc.14.94

• electrophilic aromatic rings, non-acidic carbonyl groups, and suitable oxygen, nitrogen, and sulfur functionalities. Carbonyloxy radicals derived from typical hypervalent iodine(III) carboxylates by photolysis and other conditions [65][66][67][68] are known to undergo irreversible decarboxylation [69][70

• oxidation forming aryl ketones [52]. Note that the successful coupling of a range of secondary and tertiary carboxylic acids now supports the direct and selective C–H bond activation at the benzyl position by avoiding the formation of carbonyloxy radicals, which are susceptible to decarboxylation. In

Hypervalent iodine(III)-mediated decarboxylative acetoxylation at tertiary and benzylic carbon centers

• Kensuke Kiyokawa,
• Daichi Okumatsu and
• Satoshi Minakata

Beilstein J. Org. Chem. 2018, 14, 1046–1050, doi:10.3762/bjoc.14.92

• . Keywords: acetoxylation; carboxylic acids; decarboxylation; hypervalent iodine; iodine; Introduction The decarboxylative functionalization of carboxylic acids and the derivatives thereof is an important transformation in organic synthesis. In recent years, increasing efforts have been devoted to the

• development of decarboxylative transformations [1][2][3][4][5][6][7][8][9][10][11][12][13], especially through radical decarboxylation processes, allowing an easy access to valuable compounds from readily available carboxylic acids. However, despite these advances, the oxidative decarboxylation coupled with C

• most of the starting material was recovered (Table 1, entry 14). This result is consistent with a reaction proceeding via a light-induced radical decarboxylation process [21][25]. We next explored the scope of the decarboxylative acetoxylation reaction (Scheme 2). A variety of carboxylic acids

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• -methylbutyl acetate (29) and 2-methylbutyl acetate (32). The alcohol portion of these esters likely originates from leucine and isoleucine through transamination to the corresponding α-ketocarboxylic acid, oxidative decarboxylation and reduction. For the pentanoate and heptanoate esters not only the

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• ). However, it was found that the generation of the trifluoromethyl anion proceeds faster than the subsequent transfer of CF3 to the aromatic halide. Subsequently, the problem was solved by using a slow addition mode that adjusted the rate of decarboxylation step to the rate of the consumption of CF3 in the

• aromatic trifluoromethylation step. The attractive prospect of trifluoroacetate as the trifluoromethyl source for the preparation of trifluoromethylarenes prompted the investigation of the mechanism of this reaction. A mechanistic study indicated that CuCF3 was formed by decarboxylation of the

• as the CF3 source (Scheme 7). High temperature was required to accelerate the rate of the decarboxylation of CF3CO2K and the increased pressure occurred during the process, which brought problems under batch conditions. Buchwald and co-worker deal with it through combining flow chemistry. Under flow

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• are already defined. A third extension with malonyl-SCoA and methylation gives rise to intermediate C that can be released, e.g., by a thioesterase to the β-keto acid D, followed by spontaneous decarboxylation to 11a. Two structurally related molecules to 11a have been reported from endophytic

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

From dipivaloylketene to tetraoxaadamantanes

• Gert Kollenz and
• Curt Wentrup

Beilstein J. Org. Chem. 2018, 14, 1–10, doi:10.3762/bjoc.14.1

• ]nonadienes (bisdioxines) 4. When arylamines are used as the nucleophiles under neutral conditions, decarboxylation occurs during the formation of bisdioxines 8. However, when water or alcohols are added to 3 under acidic conditions, bisdioxine-carboxylic acids and esters 10 and 11 are obtained. Acid

• in isolable enol intermediates of type 9 [18]. The carboxylate cannot form in the presence of an acid and therefore decarboxylation does not take place (17 → 18 → 10). The mono- and dicarboxylic acids 10 and 11 are stable and do not decarboxylate easily. However, aromatic amines carrying strongly

• decarboxylated tetraoxaadamantane can be obtained. It is noteworthy that, when a free carboxylic acid moiety is present in the bisdioxine, it is invariably lost during the tetraoxaadamantane formation. The decarboxylation is likely to take place in the acrylic acid moieties in the trioxanonadienes during the

Quinone-catalyzed oxidative deformylation: synthesis of imines from amino alcohols

• Xinyun Liu,
• Johnny H. Phan,
• Benjamin J. Haugeberg,
• Shrikant S. Londhe and
• Michael D. Clift

Beilstein J. Org. Chem. 2017, 13, 2895–2901, doi:10.3762/bjoc.13.282

• deformylation of 2-phenylglycinol (1a) to deliver N-PMP imine 7a (Table 1). We selected quinone catalysts (2a−c) that have previously been utilized in amine oxidation reactions [21][32][40][41], and began with reaction conditions similar to those developed for our quinone-catalyzed oxidative decarboxylation

The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

• Ommid Anamimoghadam,
• Saira Mumtaz,
• Anke Nietsch,
• Gaetano Saya,
• Cherie A. Motti,
• Jun Wang,
• Peter C. Junk,
• Ashfaq Mahmood Qureshi and
• Michael Oelgemöller

Beilstein J. Org. Chem. 2017, 13, 2833–2841, doi:10.3762/bjoc.13.275

• excess amounts to suppress competing ‘simple’ decarboxylation (-CO2− ↔ -H exchange) reactions to the corresponding toluene derivatives [25]. Following the established protocol and utilizing a 1:1 acetone/water mixture as reaction medium [27][30], irradiations with UVB light (300 ± 30 nm) for 4 hours

• one of the N-ethyl groups of the side chain. The mechanism of the photodecarboxylation is well established (Scheme 7) and involves triplet sensitization by acetone and electron transfer between the phenylacetate and the excited phthalimide [55][56][57]. Subsequent decarboxylation, radical combination

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• CF3SO2Na (Scheme 56) [81]. The authors used basically the same protocol as Sanford and Molander but observed that a more diluted reaction medium gave improved reaction yields. Trifluoromethylation of alkenes by decarboxylation: Liu and co-workers were the first to describe the copper-catalysed

A Brønsted base-promoted diastereoselective dimerization of azlactones

• Danielle L. J. Pinheiro,
• Gabriel M. F. Batista,
• Pedro P. de Castro,
• Leonã S. Flores,
• Gustavo F. S. Andrade and
• Giovanni W. Amarante

Beilstein J. Org. Chem. 2017, 13, 2663–2670, doi:10.3762/bjoc.13.264

• affording 2a after protonation and thus regenerating the catalyst intermediate 3. 1H NMR analysis using CD3CN showed high levels of HCCl3, which could be form after decarboxylation of the basic species. In an attempt to obtain a better understanding at this dimerization reaction and to give new insights

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• (thermodynamically controlled) Mannich-type adduct B, followed by rapid irreversible decarboxylation of B into compound 4a. Contrastingly, in a high-polar solvent, the intermediate A is so labile that it undergoes decarboxylation to product 5a rather than rearrangement to B. The proposed reaction mechanism is

• supported by the known effect of solvent polarity on the decarboxylation rate of malonic acid derivatives which was claimed to be faster in polar media [40]. To study the substrate scope of the regioselective additions of malonic acid, we introduced substituted pyrimidones 2b–m in the reaction and performed

• the Michael-type adduct, phenyl 2-(3-methyl-2-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-4-yl)acetate (6a). The presence of DBU caused substantial decarboxylation of starting reagent 1a (Table 3, entry 3). This unwanted process necessitated using of up to 6 equivalents of 1a to reach a

Comparative profiling of well-defined copper reagents and precursors for the trifluoromethylation of aryl iodides

• Peter T. Kaplan,
• Jessica A. Lloyd,
• Mason T. Chin and
• David A. Vicic

Beilstein J. Org. Chem. 2017, 13, 2297–2303, doi:10.3762/bjoc.13.225

• trifluoromethylation ‘catalysis’ using copper have been observed [4][5][6][7][8][9], but these reactions typically only work for aryl iodides and have a low substrate scope, low turn-over values, and/or involve decarboxylation reactions at high temperatures. Stoichiometric trifluoromethylating agents are therefore

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• developed to provide the enhanced facial selectivity for the acceptor attack [38][39][40][41]. Beyond early intramolecular glycosylations achieved via the orthoester rearrangement by Lindberg [42] and Kochetkov [43], as well as the decarboxylation of glycosyl carbonates by Ishido [44], Barresi and Hindsgaul

• glycosylation was based on the 1,2-orthoester rearrangement by Lindberg [42] and Kochetkov [43], as well as the decarboxylation of glycosyl carbonates by Ishido [44]. Intramolecular glycosylations where the glycosyl acceptor was purposefully attached directly to the leaving group of the glycosyl donor have been

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

• Somaia Kamouka and
• Wesley J. Moran

Beilstein J. Org. Chem. 2017, 13, 1823–1827, doi:10.3762/bjoc.13.177

• 2-oxazoline formation through the iodoarene-catalyzed cyclization of β-amidoketones 5. These are readily prepared by alkylation of the corresponding β-ketoester followed by decarboxylation (Scheme 4) [40][41]. The cyclization of β-amidoketones 5 was successful with the same conditions as

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• tryptophan derivatives with appropriate aldehydes. A hypervalent iodine reagent, iodobenzene diacetate was used in stoichiometric quantities to facilitate both oxidative decarboxylation/dehydrogenation of 108–110 to afford the desired natural products 111–113 (Scheme 42). Conclusion Substantial amount of

Synthesis and metal binding properties of N-alkylcarboxyspiropyrans

• Alexis Perry and
• Christina J. Kousseff

Beilstein J. Org. Chem. 2017, 13, 1542–1550, doi:10.3762/bjoc.13.154

• yields from 60–82% (Table 1, entries 3, 7, and 9–11). This protocol was ineffective for the synthesis of C2SP (n = 1) and C4SP (n = 3). In the former case, the intermediate N-ethanoate indolium salt 3a underwent thermal decarboxylation to give N-methylindolium salt 7, in a similar manner to that

• previously reported [28]. Presumably, this reaction proceeds via azomethine ylid 6 (Scheme 3); analogous indolium ylids have been used synthetically in 1,3-dipolar cycloadditions [29] and mechanistic studies have been published on the related decarboxylation of pyridinium 2-carboxylates [30]. Fortunately, α

• , it is ineffective with bromoacetic acid and bromobutyric acid, where decarboxylation and intramolecular lactonisation respectively compete with N-alkylation. In these cases, we have developed alternative, though lower-yielding procedures. N-Alkylcarboxyspiropyrans can function as colourimetric

Sustainable synthesis of 3-substituted phthalides via a catalytic one-pot cascade strategy from 2-formylbenzoic acid with β-keto acids in glycerol

• Lina Jia and
• Fuzhong Han

Beilstein J. Org. Chem. 2017, 13, 1425–1429, doi:10.3762/bjoc.13.139

• phthalides in good to excellent yields. Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a catalytic one-pot cascade reaction in glycerol has been accomplished. Keywords: β-keto acid; decarboxylation; glycerol; one-pot cascade

• -formylbenzoic acid (1a) is attacked preferably by benzoylacetic acid (2a) in the presence of a base to afford the aldol intermediate A. Next, the subsequent facile decarboxylation and lactonization of intermediate A leads to 3-phenacylphthalide (3a). Conclusion In summary, we have accomplished a sustainable and

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

• Olga Bakulina,
• Alexander Ivanov,
• Vitalii Suslonov,
• Dmitry Dar’in and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2017, 13, 1413–1424, doi:10.3762/bjoc.13.138

• formation of HPA dimer 11 and product of its decarboxylation 12 (Scheme 1). The formation of these two products (observed by 1H NMR) was recently reported by Knapp et al. [35] as a result from the treatment of HPA with a strong base (which was absent in our case). The failure to activate sterically hindered

• fate of Mannich adduct 13e. Mechanistic rationale for the 13e→ syn/anti-10e conversion. Decarboxylation of anti/syn-10h. Indolo[1,2-b]isoquinolonic acids 10 obtained via the CCR of indolenines 9. Supporting Information Supporting Information File 338: Detailed experimental procedures, analytical data