Three-component synthesis of C₂F₅-substituted pyrazoles from C₂F₅CH₂NH₂·HCl, NaNO₂ and electron-deficient alkynes

• Pavel K. Mykhailiuk

Beilstein J. Org. Chem. 2015, 11, 16–24, doi:10.3762/bjoc.11.3

• approach to CF3-pyrazoles by a three-component reaction between electron-deficient alkynes, sodium nitrite and trifluoroethylamine hydrochloride was developed [46]. This method worked for both the mono- and disubstituted alkynes. Because of similar electronic properties of CF3 and C2F5 groups [1], it was

• AS-136A [55]) (Scheme 3). Conclusion In summary, a novel approach to C2F5-substituted pyrazoles has been elaborated by a three-component reaction between C2F5CH2NH2·HCl, NaNO2 and electron-deficient alkynes. This method is highly practical: it does not require a) the pre-isolation of toxic diazo

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde

• Volodymyr V. Tkachenko,
• Elena A. Muravyova,
• Sergey M. Desenko,
• Oleg V. Shishkin,
• Svetlana V. Shishkina,
• Dmytro O. Sysoiev,
• Thomas J. J. Müller and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2014, 10, 3019–3030, doi:10.3762/bjoc.10.320

• at room temperature for 4 h without catalyst always led to the selective formation of the corresponding chroman-3-carboxamides 4a–h (Table 3, entries 1, 4, 7, 10, 13, 16, 19, 22). However, to our surprise, the ytterbium triflate-catalyzed three-component reaction of 5-amino-3-methylisoxazole (1

• . Some Biginelli-type three-component condensations with salicylaldehyde. Three-component heterocyclization of 5-amino-3-methylisoxazole (1), salicylaldehyde (2) and N-(2-methoxyphenyl)-3-oxobutanamide (3a). Possible pathways for the three-component reaction of 5-amino-3-methylisoxazole (1

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

New highlights of the syntheses of pyrrolo[1,2-a]quinoxalin-4-ones

• Emilian Georgescu,
• Alina Nicolescu,
• Florentina Georgescu,
• Florina Teodorescu,
• Daniela Marinescu,
• Ana-Maria Macsim and
• Calin Deleanu

Beilstein J. Org. Chem. 2014, 10, 2377–2387, doi:10.3762/bjoc.10.248

• from benzimidazoles unsubstituted at the five membered ring, alkyl bromoacetates and non-symmetrical electron-deficient alkynes in the molar ratio of 1:2:1, in 1,2-epoxybutane at reflux temperature, led directly to pyrrolo[1,2-a]quinoxalin-4-ones in fair yield by an one-pot three-component reaction

• ][9][10][11][12][13]. The development of more efficient synthetic methods towards these compounds is an active research area [14][15][16]. Recently, we reported on the formation of pyrrolo[1,2-a]benzimidazoles along with pyrrolo[1,2-a]quinoxalines in the one-pot three-component reaction of 1

• starting from benzimidazole derivatives unsubstituted at the five membered ring, alkyl bromoacetates and non-symmetrical electron-deficient alkynes in the molar ratio of 1:2:1, in 1,2-epoxybutane at reflux temperature. Results and Discussion The one-pot three-component reaction of 1-substituted

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• -aminoazoles, including thiazole [13][14] and 1,3,4-thiadiazole [15][16] derivatives, or 2-aminoazine-based heterocycles, such as pyridines [17][18][19], pyrimidines [20][21][22][23][24] and pyrazines [25][26][27], have recently been utilized as Groebke–Blackburn–Bienaymé three-component reaction (GBB-3CR

Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines

• Praveen Reddy Adiyala,
• D. Chandrasekhar,
• Jeevak Sopanrao Kapure,
• Chada Narsimha Reddy and
• Ram Awatar Maurya

Beilstein J. Org. Chem. 2014, 10, 2065–2070, doi:10.3762/bjoc.10.214

• amidines. However, it should be emphasized that our protocol with low catalyst loading (1 mol %) makes it a cleaner and lower environmental impact methodology to access α-amino amidines. Then, we tried the three-component reaction using heteroaromatic amines such as 2-aminopyridine, 3-aminopyridine and 4

• ]. Recently, catalytic iodine (10 mol %) was found to give good yields of imidazolopyridine in a three-component reaction of 2-amino-5-chloropyridine, isocyanide, and aldehydes under reflux conditions [28]. However, we found that the similar reaction using 2-amonopyridine could be performed at ambient

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 C-4-substituted 1,4-DHP nucleobase can be efficiently obtained from the three-component reaction between the sugar aldehyde 86, ethyl acetoacetate, and ethyl 3-aminocrotonate [108][109]. The course of the reaction in the presence of various additives was examined in detail. The best results were

Microwave-assisted Cu(I)-catalyzed, three-component synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles

• Yogesh Kumar,
• Vijay Bahadur,
• Anil K. Singh,
• Virinder S. Parmar,
• Erik V. Van der Eycken and
• Brajendra K. Singh

Beilstein J. Org. Chem. 2014, 10, 1413–1420, doi:10.3762/bjoc.10.145

• first, followed by the formation of triazole by CuAAC reaction to give the desired product 4a. Conclusion We developed a novel microwave-assisted, Cu(I)-catalyzed, three-component reaction for the synthesis of 2-(4-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazoles in good to

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• , Italy Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci 32, 20133 Milano, Italy 10.3762/bjoc.10.141 Abstract An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid

• examples with satisfactory selectivity were achieved to date [32][33][34][35][36]. Results and Discussion Relying on our previous experience, we selected chiral ketimine 1 as a suitable substrate and started to investigate the Ugi three-component reaction (3CR) with tert-butyl isocyanide (2a) and

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• works have discovered that some analogues of San A inhibit Hsp 90, a key protein that enables many proteins involved in tumor progression [35][36][37][38][39]. The Passerini three-component reaction (P-3CR) allows an easy access to depsipeptides using a convergent approach. It has become a powerful tool

Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates

• Michał Górny vel Górniak,
• Anna Czernicka,
• Piotr Młynarz,
• Waldemar Balcerzak and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 741–745, doi:10.3762/bjoc.10.68

• tissues. Thus, their libraries may serve for the construction of diagnostic tools. A similar approach has been recently patented as a mean to differentiate lipases and esterases [15]. The objective of this paper is to evaluate the utility of a popular three component reaction of triaryl phosphites with

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• efforts have established H-phosphinates R(H)P(O)(OR′) or appropriate P(III) acids R(H)P(O)(OH) as appropriate starting materials for the preparation of aminophosphinic acids. The most typical route involves the three-component reaction of an aldehyde, an amine and a P–H substrate in a one-pot Mannich type

• . This resulted in the preparation of the analogues of glycine 14a and phenylglycine 14b (Scheme 3). The three-component reaction with formaldehyde gave the best results and N-protected aminophosphinic acid 13a was isolated in a moderate yield, alongside phosphonic acid 10. The analogous reaction with

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• . the incorporation of bifunctional substrates or by activation of functionalized substrates in the initial MCR [19]. The Passerini reaction The first isocyanide-based MCR was described by Mario Passerini in 1921 and named after him. The Passerini reaction is a three-component reaction (3-CR) and

• -formation of the imine or the use of bifunctional inputs (e.g. amino acids) can reduce this Ugi-4CR to an Ugi-3CR. In particular, the Ugi reaction with bifunctional inputs is called an Ugi-four-center-three-component reaction (U-4C-3CR) and has been extensively applied in peptidomimetic synthesis [21][22

• , the group of Fülöp reported an efficient synthesis of bicyclic β-lactams from monocyclic β-amino acids via an Ugi four-center three-component reaction (U-4C-3R) [39]. Herein, the monocyclic β-amino acid acts as bifunctional moiety containing both an amino and carboxylic acid group. A variety of cyclic

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• ], phenylacetylene [73][74], and methyl acrylate [75]. Starting from these results, a MC approach to 1-(isoquinolin-1-yl)guanidines 55 was efficiently developed by a silver triflate-catalyzed three-component reaction of 2-alkynylbenzaldehydes 25, tosylhydrazide (41) and carbodiimides 54 (Scheme 29) [76]. The

• , aldehydes and alkenes in a three-component reaction based on the cascade imine formation, azomethine ylide generation and [3 + 2] cycloaddition reaction for the synthesis of pyrrolidines. However, the adopted method to induce chirality in the final products is rather dissimilar. Thus, in 2006 Garner’s group

• , which by loss of the tosyl group and base-catalyzed aromatization yields the H-pyrazolo[5,1-a]isoquinoline 48. Finally, a new series of fully aromatic pyrazolo[5,1-a]isoquinolines 53, bearing an amino group in position 2 can be synthesized under silver triflate catalysis by the usual three-component

A catalyst-free multicomponent domino sequence for the diastereoselective synthesis of (E)-3-[2-arylcarbonyl-3-(arylamino)allyl]chromen-4-ones

• Pitchaimani Prasanna,
• Pethaiah Gunasekaran,
• Subbu Perumal and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2014, 10, 459–465, doi:10.3762/bjoc.10.43

• ), (E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one (1 mmol) and 4-methoxyaniline (1 mmol). This three-component reaction was initially examined in solvents such as acetonitrile, dioxane, dimethyl sulfoxide, toluene and ethanol under heating. However, the only isolable product was compound 4d

A new manganese-mediated, cobalt-catalyzed three-component synthesis of (diarylmethyl)sulfonamides

• Antoine Pignon,
• Erwan Le Gall and
• Thierry Martens

Beilstein J. Org. Chem. 2014, 10, 425–431, doi:10.3762/bjoc.10.39

• related compounds by a new manganese-mediated, cobalt-catalyzed three-component reaction between sulfonamides, carbonyl compounds and organic bromides is described. This organometallic Mannich-like process allows the formation of the coupling products within minutes at room temperature. A possible

• and versatility of multicomponent procedures, we describe herein a new manganese-mediated, cobalt-catalyzed three-component reaction, which circumvents the above-mentioned limitations by allowing the synthesis of an extended range of (diarylmethyl)sulfonamides (and related compounds) within minutes at

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• extension of the substrate scope of the Flögel-three-component reaction of lithiated alkoxyallenes, nitriles and carboxylic acids is presented. The use of dicarboxylic acids allowed the preparation of symmetrical bis(β-ketoenamides) from simple starting materials in moderate yields. Cyclocondensations of

• – discovered and mechanistically elucidated by Oliver Flögel – features a three-component reaction that employs alkoxyallenes, nitriles and carboxylic acids: upon treatment with n-butyllithium the allene is lithiated in α-position to the alkoxy moiety; the addition of a nitrile as electrophile to this highly

• heteroaromatic systems containing up to six conjugated aryl and hetaryl groups. Complementary examples employing aromatic dinitriles in this Flögel-three-component reaction have previously been presented [39]. Results and Discussion As typical model substrates we chose to employ isophthalic acid (11) and

Additive-assisted regioselective 1,3-dipolar cycloaddition of azomethine ylides with benzylideneacetone

• Chuqin Peng,
• Jiwei Ren,
• Jun-An Xiao,
• Honggang Zhang,
• Hua Yang and
• Yiming Luo

Beilstein J. Org. Chem. 2014, 10, 352–360, doi:10.3762/bjoc.10.33

• our knowledge, the reversal of the regioselectivity in the 1,3-dipolar cycloaddition of azomethine ylide induced by the additive is reported for the first time. Results and Discussion Initially, a three-component reaction of isatin (1a), benzylamine (2) and benzylideneacetone (3a) was conducted in

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

• -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

• methylenenitriles to α,β-unsaturated ketones [8], 2-amino-4H-pyrans 1 (Scheme 1) have become the central focus of a number of chemical and biological investigations [9][10]. Perez et al. recently reported an interesting method for the synthesis of condensed pyridines 2 through a three-component reaction of

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• nucleus. The structure of compound 4a was determined by an X-ray diffraction study of a single crystal and supports the structure deduced from NMR spectroscopy (Figure 2). Dipolarophiles, such as aroylacrylic acids 5, can also be successfully used in this three-component reaction. The cycloaddition of

• aroylacrylic acids 5 were prepared according to the previously reported procedure [42]. General procedure for the synthesis of spirooxindoles 4a–4g from the three-component reaction of isatins, sarcosine or cyclic α-amino acids and acrylamides: A mixture of isatin (1.0 mmol), α-amino acid (1.0 mmol) and

• C13H14BrN3O2 (324.17): C 48.17, H 4.35, N 12.96; found: C 48.19, H 4.40, N 12.99. General procedure for the synthesis of spirooxindoles 6a–6h from the three-component reaction of isatins, sarcosine or proline and aroylacrylic acids: A mixture of isatin (1.0 mmol), α-amino acid (1.0 mmol) and aroylacrylic acid

Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate

• Hong Gao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 2934–2939, doi:10.3762/bjoc.9.330

• -toluenesulfonic acid-catalyzed three-component reaction of arylamine, aromatic aldehyde and acetylenedicarboxylate afforded 3-hydroxy-2-pyrrolidinone as main product [28]. In order to improve the reactivity of morpholine in this four-component reaction, p-toluenesulfonic acid was added in the four-component

Efficient synthesis of dihydropyrimidinones via a three-component Biginelli-type reaction of urea, alkylaldehyde and arylaldehyde

• Haijun Qu,
• Xuejian Li,
• Fan Mo and
• Xufeng Lin

Beilstein J. Org. Chem. 2013, 9, 2846–2851, doi:10.3762/bjoc.9.320

• ). The variation of the alkyl substituent of acetaldehydes 2 is well tolerated to provide the desired products 4o–4q in 48–55% isolated yields. Finally, N-ethylurea 1b was also investigated in the one-pot three-component reaction, and the reactions proceeded smoothly to give the corresponding

• catalyze the enantioselective three-component reaction of mono-substituted ureas 1, alkylaldehydes 2 and arylaldehydes 3 to generate enantioenriched dihydropyrimidinones 4 [32][33][34][35]. In our initial study, we examined the multicomponent model reaction between N-methylurea 1a, phenylacetaldehyde 2a

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

AgOTf-catalyzed one-pot reactions of 2-alkynylbenzaldoximes with α,β-unsaturated carbonyl compounds

• Qiuping Ding,
• Dan Wang,
• Puying Luo,
• Meiling Liu,
• Shouzhi Pu and
• Liyun Zhou

Beilstein J. Org. Chem. 2013, 9, 1949–1956, doi:10.3762/bjoc.9.231

• progress in this aspect. Wu and co-workers described an efficient three-component reaction of a 2-alkynylbenzaldoxime and an α,β-unsaturated carbonyl compound with bromine or iodine monochloride under mild conditions, which generates the 1-alkylated isoquinolines in good to excellent yields [36]. Wu and co

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• step involves the use of a β-amino acid-forming three-component reaction (3CR), the scope of which defines its role in the synthetic strategy. Keywords: β-amino acid; benzimidazole; multicomponent reaction; Introduction Library syntheses and high-throughput screening can often be combined to enable

• studies of this compound as a biological probe [14][15]. The synthesis of 1 emanates from a one-pot, three-component reaction (3CR) of an arylaldehyde, malonic acid (5), and ammonium acetate, which assembles the β-amino acid core (Figure 2) [14][15][18]. In the reported synthesis of 1, a protected β-amino