Recent advances in copper-catalyzed C–H bond amidation

• Jie-Ping Wan and
• Yanfeng Jing

Beilstein J. Org. Chem. 2015, 11, 2209–2222, doi:10.3762/bjoc.11.240

• of o-halobenzamides 82 and (benzo)imidazoles 87 for the one-pot synthesis of (benzo)imidazoquinazolinones 88 under the catalysis of CuI and assistance of L-proline. A subsequent oxidation using molecular oxygen was required for the final formation of products. According to the results, the mechanism

• were disclosed by Wang et al. [80]. The synthesis using 92 and benzimidazoles 87 provided benzimidazole-fused cyclic sulfonamides 93. The reaction allowed the synthesis of various products with fair to high yields with the assistance of L-proline as ligand. The expected conversion took place also in

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

• Sundaravel Vivek Kumar,
• Shanmugam Muthusubramanian,
• J. Carlos Menéndez and
• Subbu Perumal

Beilstein J. Org. Chem. 2015, 11, 1707–1712, doi:10.3762/bjoc.11.185

• , entry 5), pyridine (Table 1, entry 6), N,N-dimethylaminopyridine (DMAP, Table 1, entry 7), piperidine (Table 1, entry 8), L-proline (Table 1, entry 9), potassium carbonate (Table 1, entry 10), sodium carbonate (Table 1, entry 11) and caesium carbonate (Table 1, entry 12). After identifying potassium

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• -acetylhydroxyamino acids. They were in fact the first researchers to at all investigate compounds belonging to this class of amino acid derivatives. Under the mantra «acidity favors O-acylation, while alkalinity favors N-acylation», they accomplished this feat by treatment of hydroxy-L-proline, DL-serine, DL

• employed by others, as for example in the preparation of O-acetyl-DL-serine reported by Frankel, Cordova and Breuer in 1953 [11], and O-acetylhydroxy-L-proline by Kurtz, Fasman, Berger and Katchalski in 1958 [12]. However, other and perhaps more ad hoc procedures for the preparation of O-acetylhydroxyamino

• -L-proline, L-serine, DL-serine and L-threonine were all obtained directly in excellent purity in over 90% yield at >10 g scale. Early O-acylation of hydroxyamino acids in trifluoroacetic acid As narrated in the previous section, developments taking place from the early 1940s into the early 1960s had

A simple copper-catalyzed two-step one-pot synthesis of indolo[1,2-a]quinazoline

• Chunpu Li,
• Lei Zhang,
• Shuangjie Shu and
• Hong Liu

Beilstein J. Org. Chem. 2014, 10, 2441–2447, doi:10.3762/bjoc.10.254

• 201203, P. R. China 10.3762/bjoc.10.254 Abstract A convenient CuI/L-proline-catalyzed, two-step one-pot method has been developed for the preparation of indolo[1,2-a]quinazoline derivatives using a sequential Ullmann-type C–C and C–N coupling. This protocol provides an operationally simple and rapid

• convenient method for the synthesis of 2-(trifluoromethyl)indoles by introducing the trifluoroacetyl group to activate the CuI/L-proline-catalyzed system [21]. Zhao [22] and Kobayashi [23] reported the synthesis of 2-amino-1H-indole derivatives using the same kind of copper-catalyzed system. Meanwhile, the

• copper catalysts were screened at 80 °C using L-proline as ligand, and K2CO3 as base in a mixed solvent of DMSO and H2O (volume ratio 1:1) (Table 1, entries 1–4). To our delight, the desired product 4a was obtained in 36% yield using CuI as catalyst and 50% yield with Cu2O (Table 1, entries 1 and 4

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• -deoxyaldoses were treated with triethylamine (TEA) to yield α,β-unsaturated aldehydes 3a–c quantitatively. The aldehydes 3a–c were stereoselectively epoxidized by applying the conditions developed by Jørgenson et al [23][24][25]. The required amine catalyst was synthesized starting from L-proline following a

• the use of a chiral L-proline derived epoxidation catalyst. The introduction of nitrogen was achieved via a Tsuji–Trost-like azide opening of allylic epoxides. Although global deprotection proved to be cumbersome, we were able to develop a versatile reaction sequence to overcome this problem. The

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds

• Miroslav Palík,
• Jozef Kožíšek,
• Peter Koóš and
• Tibor Gracza

Beilstein J. Org. Chem. 2014, 10, 2077–2086, doi:10.3762/bjoc.10.216

• 2 steps starting from the aldehyde 31 using the Yamamoto’s [33] sequential O-nitrosoaldol and Grignard addition process using different reagents (Scheme 4). Thus, L-proline-catalysed oxidation of 31 with 2-nitrosotoluene gave the optically pure O-selective nitrosoaldol product 32, which underwent a

• ; f) MeLi, Et2O, −78 °C, 1 h. TBDPSCl = tert-butyldiphenylsilyl chloride. Synthesis of substrates 33–35, 37. Reagents and conditions: a) lit. [33] L-proline (0.25 equiv), 2-nitrosotoluene, CHCl3, −18 °C; b) RMgCl, CeCl3·2LiCl, THF, −78 °C to rt, overnight; c) acetone, PTSA, 3 h, rt; d) OsO4 (0.01

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• J. Alexander Willms Rita Beel Martin L. Schmidt Christian Mundt Marianne Engeser University of Bonn, Kekulé-Institute of Organic Chemistry and Biochemistry, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany 10.3762/bjoc.10.211 Abstract A new 4-hydroxy-L-proline derivative with a charged 1

• , mechanistic studies on organocatalytic reactions [31][32][33][34][35][36][37][38] using ESI mass spectrometry [20][39][40][41][42][43][44][45][46][47][48][49] have been reported. The pioneering studies of List and Barbas [50] revealed that the amino acid L-proline is an effective catalyst for a great variety

• in the catalytic cycle or just serves as an rate limiting parasitic off-cycle equilibrium [31][33][35][52]. Thus, we aimed to synthesize a charge-tagged L-proline-based organocatalyst for mechanistic studies by ESIMS. Few proline derivatives carrying a covalently fixed charge have been reported by

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• the reaction was performed with an excess (1.5 equiv) of methyl acetoacetate and methyl 3-aminocrotonate under L-proline-catalyzed conditions. In contrast to other catalysts tested (ytterbium triflate, D-proline, (S)-5-(pyrrolidin-2-yl)-1H-tetrazole, or (S)-1-(pyrrolidin-2-ylmethyl)pyrrolidine/TFA

• system), the catalytic effect of L-proline resulted in an increase in the reaction yield. Moreover, epimerization on the C-1 carbon atom of the starting aldehyde 88 was also suppressed. The latter effect was attributed to the preferential activation of methyl 3-aminocrotonate by L-proline via the

• formation of compounds 91 (Scheme 36) [110]. Regardless of the catalyst used, aldehyde 90 gave product 91 with a very high diastereomeric excess. Analogously to the reaction performed with aldehyde 90 in the presence of L-proline, aldehyde ent-90 gave compound ent-91 with the same diastereomeric excess

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• by using a chiral auxiliary (>95% de in the case of an L-proline-derived diene). Diversification on the different units, diene, dienophile and aldehyde, has been described. Concerning the maleimide material, substituent R3 did not exert any significant effect on the process. Other dienophiles have

Organobase-catalyzed three-component reactions for the synthesis of 4H-2-aminopyrans, condensed pyrans and polysubstituted benzenes

• Moustafa Sherief Moustafa,
• Saleh Mohammed Al-Mousawi,
• Maghraby Ali Selim,
• Ahmed Mohamed Mosallam and
• Mohamed Hilmy Elnagdi

Beilstein J. Org. Chem. 2014, 10, 141–149, doi:10.3762/bjoc.10.11

• -3,5-dicyanophthalic acid ester derivatives 37a–c were developed. The synthetic methods utilize one-pot reactions of acetylene carboxylic acid esters, α,β-unsaturated nitriles and/or active methylenenitriles in the presence of L-proline or DABCO. Plausible mechanisms are suggested for the formation of

• -oxo-5-phenyl-3H-isoindole-4-carboxylate (40). Keywords: aminopyranes; arylbenzoic acid; DABCO; L-proline; multicomponent; tetrahydronaphthalene; three-component reaction; Introduction The reaction of arylidenemalononitriles with active methyl and methylene compounds was extensively utilized for the

• generated using a one-pot reaction involving condensation of ethyl propiolate (4a) with benzylidenemalononitrile (7a) in the presence of L-proline (5) (Scheme 4) [4]. It is believed that the pathway followed in this process involves conjugate addition of proline to the propiolate to yield adduct 6 which

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• triazolium salts 5 and 6 [18][22]. The route to target 7 began by treating N-Boc-trans-4-hydroxy-L-proline methyl ester (11) with diethylaminosulfur trifluoride (DAST) in CH2Cl2 to install the first fluoro substituent (12) with clean configurational inversion (88%, Scheme 1). Oxidation of the pyrrolidine to

• have been omitted for clarity. An overview of the molecular editing approach to catalyst development. Synthesis of the difluorinated triazolium salt 7 starting from commercially available N-Boc-trans-4-hydroxy-L-proline methyl ester (11). Synthesis of the monofluorinated triazolium salt 8. Synthesis of

Microwave-assisted synthesis of 5,6-dihydroindolo[1,2-a]quinoxaline derivatives through copper-catalyzed intramolecular N-arylation

• Fei Zhao,
• Lei Zhang,
• Hailong Liu,
• Shengbin Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2013, 9, 2463–2469, doi:10.3762/bjoc.9.285

• temperature to 90 °C, and a slightly higher yield was obtained (Table 1, entry 8). With L-proline as the best ligand, a further screening of the solvents revealed that increasing the polarity of the solvent had a positive effect on the reaction yield, and DMSO displayed as the best choice to promote the

• system of CuI/L-proline/K2CO3 in DMSO under microwave irradiation for 45 minutes. After determining the optimal reaction conditions, we then examined the general applicability of the process. First, the substituents of the indole moiety were explored (Table 2). Halogens (F, Cl, Br) were tolerated well

• equiv), L-proline (0.05 mmol, 5.8 mg, 0.2 equiv), and the base indicated (0.5 mmol, 2.0 equiv) in DMSO (2 mL). The vessel was degassed, refilled with argon, and sealed. The mixture was heated to the temperature indicated for the indicated time under microwave irradiation (fixed power, 30 W). After

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• ][31], among them L-proline and its derivative were used as popular precursors from the pool of chiral compounds [13][14][15][18][19][20][21][22]. Herein, we report a concise diastereoselective synthesis of (8S,8aS)-5 starting from (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14, a versatile building

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• -aziridines are plentiful and can be found in a diverse set of privileged structures, including cinchona alkaloids-based PTCs, L-proline-derived amino alcohols, chiral phosphorous acids, chiral thioureas, chiral guanidines, and chiral 1,2,3-triazolium chlorides. But for the desymmetrization of meso-epoxides

• . Cinchona alkaloid-derived catalysts OC-12 to OC-19. The chiral phosphoric acids catalysts OC-20 and OC-21. The proposed mechanism for chiral phosphorous acid-induced enantioselctive desymmetrization of meso-aziridines (chiral PA = OC-21). L-Proline and its derivatives OC-22 to OC-27. Proposed bifunctional

Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

• Carsten S. Kramer and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 1414–1418, doi:10.3762/bjoc.9.158

• ). At first, the use of MacMillan's imidazolidinone organocatalyst 6 [12] was examined, but no catalytic effect was observed (Table 2, entry 2). The usage of L-proline as a bifunctional catalyst only gave a slight improvement compared to the uncatalyzed reaction (Table 2, entry 3). Whereas the addition

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

• Martina Bonsignore,
• Maurizio Benaglia,
• Laura Raimondi,
• Manuel Orlandi and
• Giuseppe Celentano

Beilstein J. Org. Chem. 2013, 9, 633–640, doi:10.3762/bjoc.9.71

• testing the commercially available N-Boc-L-proline (1) as catalyst in the reduction of ketimines with trichlorosilane. The imines were typically prepared with a microwave-promoted reaction between acetophenone and the aromatic amine in toluene in the presence of K10 clay as activator. The first screening

• modest to good yields. The N-formyl-L-proline (2) led to a racemic product in 21% yield, suggesting the importance of having a bulky group on the nitrogen atom. In order to validate our hypothesis, we also tested the N-Boc-L-proline methyl ester (3): the enantiomeric excess was 19% and the yield was 49

A one-pot catalyst-free synthesis of functionalized pyrrolo[1,2-a]quinoxaline derivatives from benzene-1,2-diamine, acetylenedicarboxylates and ethyl bromopyruvate

• Mohammad Piltan,
• Loghman Moradi,
• Golaleh Abasi and
• Seyed Amir Zarei

Beilstein J. Org. Chem. 2013, 9, 510–515, doi:10.3762/bjoc.9.55

• ][26]. Ma and Yuan have reported the synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones by CuI/L-proline-catalyzed coupling of N-trifluoroacetyl-2-haloanilines with methyl pyrrole-2-carboxylates [27]. The development of more efficient methods for the preparation of these compounds is still an active

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• under different protocols in which the stereoselectivity of the reaction can be introduced through the use of a chiral catalyst [9][10] (Lewis acid, Brønsted acids, L-proline, Cinchona alkaloids derivatives, thioureas, etc.), or by the addition of chiral amines to α,β-unsaturated esters [11][12] or the

Efficient Cu-catalyzed base-free C–S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides

• Silvia M. Soria-Castro and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2013, 9, 467–475, doi:10.3762/bjoc.9.50

• reaction did not occur under air or in the absence of the ligand and was improved to 96% yield by using 10 and 20 mol % of CuI salt and ligand, respectively, (Table 1, entries 6–9). Similarly, a series of ligands usually employed in copper-catalyzed cross-coupling reactions was also screened, such as L

• -proline, benzotriazole, tetramethylethylenediamine (TMEDA), dimethylethylenediamine (DMEDA), and acetylacetone, under the optimized reaction conditions with 1,10-phenanthroline (Table 1, entry 9). These ligands, with different coordinating and structural properties, gave no positive results, and PhI was

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• a type II β-turn. The synthetic approach to the novel highly constrained spiro-bicyclic turn mimics found in PLG peptidomimetics 27–29 relied on α-alkylaldehyde proline derivatives (34, Scheme 1) as key starting materials [44][46]. These aldehyde intermediates were obtained from L-proline via the

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

• 24 in 94% yield (Scheme 9) [22]. In 2009, Shanthi and co-workers reported the use of the amino acid L-proline as a catalyst in a three component reaction of salicylaldehyde, malononitrile and indole for the synthesis of 2-aminochromene 27 in 90% yield (Scheme 10) [23] The synthesis proceeds through a

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• -milling conditions using L-proline (I) as catalyst (Scheme 1) [29][30]. Various five and six-membered cyclic ketones 1 were reacted with aromatic aldehydes 2 to provide anti-aldol products 3 in good to excellent yield (42–99%) and poor to high diastereoselectivity (50:50 to 99:1 dr) and moderate to

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• yield of the product in 3 h (Table 6, entry 4). The catalytic system developed by us for the coupling of amino acid esters with N-protected 7-azaindoles was ineffective for L-proline (6f), L-serine (6g), and L-glutamic acid (6h) (Table 6, entries 8–10). This may be ascribed to the fact that these amino

Asymmetric desymmetrization of meso-diols by C₂-symmetric chiral 4-pyrrolidinopyridines

• Hartmut Schedel,
• Keizo Kan,
• Yoshihiro Ueda,
• Kenji Mishiro,
• Keisuke Yoshida,
• Takumi Furuta and
• Takeo Kawabata

Beilstein J. Org. Chem. 2012, 8, 1778–1787, doi:10.3762/bjoc.8.203

• racemic diols (s: up to 12) [8] and amino alcohol derivatives (s: up to 54) [9]. Catalyst 2, readily prepared from L-proline, could be employed for the kinetic resolution of amino alcohol derivatives (s: up to 11) [10]. Chiral PPY catalysts with dual functional side chains at C(2) and C(4) of the

• pyrrolidine ring such as 3 were prepared from trans-4-hydroxy-L-proline. These catalysts were found to be moderately effective for the asymmetric desymmetrization of meso-diols [11]. C2-Symmetric PPY-catalyst 4 was found to be effective for the chemo- and regioselective acylation of carbohydrates [12][14][16

Enantioselective total synthesis of (R)-(−)-complanine

• Krystal A. D. Kamanos and
• Jonathan M. Withey

Beilstein J. Org. Chem. 2012, 8, 1695–1699, doi:10.3762/bjoc.8.192

• owing to N–O bond lability. Recent reports suggest that this O-nitrosoaldol reaction proceeds much more cleanly with 2-nitrosotoluene than with nitrosobenzene, probably owing to the suppression of N–O bond cleavage [10]. Thus, treatment of aldehyde 3 with 2-nitrosotoluene in the presence of L-proline as

• mg, 3.33 mmol) and L-proline (115 mg, 1.00 mmol) in CHCl3 (20 mL) at 0 °C was added a solution of (5Z,8Z)-undeca-5,8-dienal (3, 1.66 g, 10.0 mmol) in CHCl3 (20 mL). Following stirring at 0 °C for 3 h, a solution of NaBH4 (570 mg, 15.0 mmol) in EtOH (30 mL) was added and the reaction mixture was

• . Reagents and conditions: (a) 2-Nitrosotoluene, L-proline (10 mol %), CHCl3, 0 °C, 3 h; (b) NaBH4, EtOH, 0 °C, 30 min, 78% from 3; (c) Cu(OAc)2, EtOH, rt, 16 h, 72%; (d) MsCl, pyridine, CH2Cl2, 0 °C, 3 h; (e) NaN3, DMF, 80 °C, 16 h, 84% from 8; (f) PPh3, THF, H2O, rt, 12 h, 88%; (g) N-[4-(trimethylammonio