Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• , Kashiwara, Osaka 582-8582, Japan 10.3762/bjoc.13.267 Abstract A series of aniline and m-phenylenediamine derivatives with electron-withdrawing 3,3,3-trifluoropropenyl substituents were synthesized as small and chemically stable fluorescent organic compounds. Their fluorescence performances were evaluated

• by converting 2,4-disubstituted aniline 1 to the non-fluorescent dipeptide analogue H-Gly-Pro-1 for the use as a fluorogenic substrate for dipeptidyl peptidase-4 (DPP-4). The progress of the enzymatic hydrolysis of H-Gly-Pro-1 with DPP-4 was monitored by fluorometric determination of 1 released into

• reactions of (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane and iodoanilines. This straightforward method is useful for TFPE introduction and a broad range of iodoanilines can be used without protection of the amino group. We used this approach to synthesize several aniline derivatives containing TFPE

One-pot syntheses of blue-luminescent 4-aryl-1H-benzo[f]isoindole-1,3(2H)-diones by T3P^® activation of 3-arylpropiolic acids

• Melanie Denißen,
• Alexander Kraus,
• Guido J. Reiss and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 2340–2351, doi:10.3762/bjoc.13.231

• aniline (3a) as model substrates (Scheme 3, Table 3). In dichloromethane at only slightly elevated temperatures imide 4a is not formed (Table 3, entry 1). Upon addition of N,N-dimethylformamide as a cosolvent at 80 °C the desired product 4a can be isolated in 15% yield (Table 3, entry 2). The yield of 4a

• can be increased to 47% upon raising the reaction temperature to 115 °C (Table 3, entry 3), however, higher temperatures, such as 160 °C, cause a significant drop in yield. Finally, at 115 °C with two equivalents of aniline the highest yield can be achieved (Table 3, entry 6). These imidation

• ]furan-1,3-diones 2 via in situ activation of arylpropiolic acids 1. Optimization of the synthesis of 2,4-diphenyl-1H-benzo[f]isoindole-1,3(2H)-dione (4a) by imidation of 4-phenylnaphtho[2,3-c]furan-1,3-dione (2a) with aniline (3a). Pseudo three-component synthesis of 4-aryl-1H-benzo[f]isoindole-1,3(2H

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• observed and the starting material was recovered intact. Therefore, in order to identify a suitable method converting 40a,b into 6a,b (Scheme 4), model studies was undertaken using the simplified substrate 41 (Table 2). Initially, attempts were made to reduce 41 into the corresponding aniline 42, with a

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

Beilstein J. Org. Chem. 2017, 13, 2068–2077, doi:10.3762/bjoc.13.204

• by condensation reactions between acenaphthoquinone and the corresponding aniline derivative under acidic conditions, involving the use of transition-metal templates [85]. The acid-catalysed ball-milling of acenaphthoquinone with aniline derivatives in the presence of an organic catalyst was able to

• completion. A rare example of a one-pot multistep ball milling reaction is the case of an electron-rich aniline derivative that produced 4 in good yield without the need for ligand isolation. Previously reported examples typically employ “preformed” ligands and metal complexes [68][86], raising the

Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al₂O₃/MeSO₃H

• Hashem Sharghi,
• Mahdi Aberi,
• Mohsen Khataminejad and
• Pezhman Shiri

Beilstein J. Org. Chem. 2017, 13, 1977–1981, doi:10.3762/bjoc.13.193

• MeSO3H has been previously used as an effective and mild reagent for organic transformations [14]. In continuation of our studies to develop new synthetic methods for heterocycles [15][16][17][18][19], herein, we disclose a novel route to the synthesis of 3-arylquinolines from aniline derivatives and

• . Column chromatography was carried out on short columns of silica gel 60 (70–230 mesh) in glass columns. General procedure for the synthesis of quinolines in the presence of Al2O3/MeSO3H Aniline (1.0 mmol) and styrene oxide (2.0 mmol) were added to a mixture of MeSO3H (0.3 mL) and Al2O3 (0.1 g). The

Synthesis of benzannelated sultams by intramolecular Pd-catalyzed arylation of tertiary sulfonamides

• Valentin A. Rassadin,
• Mirko Scholz,
• Anastasiia A. Klochkova,
• Armin de Meijere and
• Victor V. Sokolov

Beilstein J. Org. Chem. 2017, 13, 1932–1939, doi:10.3762/bjoc.13.187

• acetonitrile according to a previously published protocol (for more details see Supporting Information File 1) [40][41][42]. Surprisingly, the obtained 2-iodo-N-(4-methoxybenzyl)aniline (7a) turned out to be rather sluggish in its reaction with the sulfonyl chloride 2. Previously used conditions viz. carrying

• out the reaction in MeCN in the presence of pyridine at rt gave poor results [17][18][19][20]. Thus, in case of aniline 7a the desired sulfonamide 8a was obtained in only 7% yield. Employment of a stronger base such as triethylamine in various solvents (MeCN, DMF, CH2Cl2, THF) led to substantial

• sulfonyl chloride 2a should be performed in the presence of 2 equivalents of aniline without an additional base [21]. However, we figured out that the second equivalent of aniline could efficiently be replaced with an inexpensive weak base such as N,N-diethylaniline and under such conditions obtained the

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• mechanochemical Paal–Knorr pyrrole synthesis using a solid bio-sourced acid like citric acid. Using substituted aniline, benzyl or aliphatic amine and 1,4-diketo compounds in presence of 1 mol % citric acid under ball-milling afforded the desired N-substituted pyrrole with quantitative yield (Scheme 34) [142

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• aforementioned aims, we envisaged that the synthesis set out in Scheme 2 could deliver access to substrates for the PFB reaction such as 9. After an initial, unfruitful, attempt to obtain the aminoacetals 9 from sequential condensation of aniline and alkyl and aryl halides, a double reductive alkylation that

• attributed to the poor solubility of the intermediate benzylated aniline. In addition, the reaction of 3,4-dimethoxyaniline under the same conditions did not afford 9q and instead 11 was the sole isolable reaction product (62% yield (Scheme 3)). The reaction was reproducible and proceeded even in the absence

• solution of benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL, 12 mmol) in CHCl3 (60 mL) and the mixture was stirred at room temperature (rt) for one hour (h). 2,2-Dimethoxyacetaldehyde (30 mmol) was then introduced into the reaction mixture followed by NaBH(OAc)3 (3.3 g, 15.0 mmol) and the resultant

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• organocatalyst design was first introduced by reacting 3,5-di(trifluoromethyl)phenyl isothiocyanate with 3,5-di(trifluoromethyl)aniline and 4-chloroaniline in a 1:1 ratio under LAG conditions using methanol as the grinding liquid. This led to quantitative formation of the Schreiner's catalyst 5 and thiourea 17

• equiv) for 40 minutes, followed by the click-coupling reaction of the second equivalent of an aniline with the intermediate isothiocyanate. In this way, non-symmetrical thioureas 25a–d were synthesized and isolated in high 87–94% yields. Instead of using thiophosgene and CS2 as corrosive and hazardous

• by the addition of the second equivalent of aniline, led to non-symmetrical thioureas 28e–g in ≥97% yields (Scheme 9). Treating p-pda with two equivalents of 26 gave 99% of bis-thiocarbamoyl benzotriazole 29, a masked 1,4-phenylene diisothiocyanate equivalent. In contrast, the analogous reaction of o

Sulfamide chemistry applied to the functionalization of self-assembled monolayers on gold surfaces

• Loïc Pantaine,
• Vincent Humblot,
• Vincent Coeffard and
• Anne Vallée

Beilstein J. Org. Chem. 2017, 13, 648–658, doi:10.3762/bjoc.13.64

• Surface, UMR CNRS 7197, 4 place Jussieu, 75005 Paris, France Université de Nantes, CNRS, CEISAM, UMR 6230, Faculté des Sciences et des Techniques, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France 10.3762/bjoc.13.64 Abstract Aniline-terminated self-assembled monolayers (SAMs) on gold surfaces

• have successfully reacted with ArSO2NHOSO2Ar (Ar = 4-MeC6H4 or 4-FC6H4) resulting in monolayers with sulfamide moieties and different end groups. Moreover, the sulfamide groups on the SAMs can be hydrolyzed showing the partial regeneration of the aniline surface. SAMs were characterized by water

• elaboration of the aniline terminated surface (SAM 4-ATP) is the first step in creating SAMs bearing a sulfamide group, see Figure 1. For this purpose, 4-amino-thiophenol (4-ATP) was first adsorbed on gold surfaces. The aniline-terminated surface obtained can then react with ArSO2NHOSO2Ar (Ar = 4-MeC6H4 and 4

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• predominantly occurred at the position ortho to the aniline group. A mechanism investigation showed that the different regioselectivity was controlled by steric and electronic effects. In 2015, Hong and co-workers developed a C–H hydroxylation protocol for flavones; their work is of importance because the

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

• Nikolay V. Lukashev,
• Gennadii A. Grabovyi,
• Dmitry A. Erzunov,
• Alexey V. Kazantsev,
• Gennadij V. Latyshev,
• Alexei D. Averin and
• Irina P. Beletskaya.

Beilstein J. Org. Chem. 2017, 13, 564–570, doi:10.3762/bjoc.13.55

• ability, chromophoric properties, and antitumor activity as well [40]. We compared several CuI-based catalytic systems in the arylation of amine 3b with 4-iodotoluene as a model substrate. We found out that the CuI/L-proline combination with K2CO3 led to the target aniline 4 in excellent yield (Scheme 3

• derivatives from various dibromo- and dichloroarenes [42]. Thus, we adopted the well performing Pd(dba)2/BINAP catalytic system for the reaction of aminocholanols 3a–c with dibromo- and dichloroarenes (Scheme 4). The synthesis of aniline 5a was chosen to determine the viability of Pd-catalyzed amination

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• catalyst that is often overlooked and it is used merely as a support for other catalysts [39][40][41][42][43]. The use of γ-alumina for the methylation of aniline with dimethyl carbonate has been reported [44]. In this paper, we chose to study the intramolecular and intermolecular alkylation of amino

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• potential of a chemoselective synthesis as a continuous process. As bench mark, aniline and azepane were used as first and second reagent, respectively. After addition of the first reactant and completion of the reaction (followed by TLC) the second reactant was added. The chemoselectivity was determined by

• of sulfonylation. To improve the chemoselectivity when using secondary amines, an additional screening was performed with azepane and aniline as first and second reagent, respectively. Initially, we tried to increase the selectivity by decreasing the temperature. Unfortunately, the reaction mixtures

• performed, using azepane as the first and aniline as the second reactant. The concentrations used were 5 mM for F1 and F2 and 2.5 mM for F3. This leads to a final concentration of 1.25 mM. However, due to the increased flow rate, the second coupling step with aniline could not reach full conversion. Even by

The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction

• Erika Bálint,
• Ádám Tajti,
• Anna Ádám,
• István Csontos,
• Konstantin Karaghiosoff,
• Mátyás Czugler,
• Péter Ábrányi-Balogh and
• György Keglevich

Beilstein J. Org. Chem. 2017, 13, 76–86, doi:10.3762/bjoc.13.10

• aniline at room temperature under solvent-free conditions (Scheme 1). Then, the reaction of N-benzylidene(butyl)amine (1a) with four different dialkyl phosphites and diphenylphosphine oxide was investigated under MW-assisted solvent-free conditions searching for the optimum temperature and reaction time

• plates was dissected and used for X-ray measurement at low temperatures. There seems to be a slight disorder, which becomes evident in the ellipsoids of the aniline ring and one of the methyl carbon atoms (Figure 4). The crystal structure of compound 5b was published almost 40 years ago [61], and a

First DMAP-mediated direct conversion of Morita–Baylis–Hillman alcohols into γ-ketoallylphosphonates: Synthesis of γ-aminoallylphosphonates

• Marwa Ayadi,
• Haitham Elleuch,
• Emmanuel Vrancken and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2906–2915, doi:10.3762/bjoc.12.290

• -tosylaminoallylphosphonates 6. However, this reaction failed using primary, secondary amines or aniline as nucleophiles. Therefore, an alternative synthesis of γ-aminophosphonates 8 has been developed. Following our previous report [54], we have first converted the MBH alcohol 5 into its acetate 7 in 90% yields using a

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• mixture was analyzed by 1H NMR to determine the conversion. When the reaction reached a full conversion (>98%) no further purification step was required and the aniline was recovered as clean product after simple concentration of the organic phase and extraction with ethyl acetate. A screening of flow

• rates was initially performed and the results are reported in Table 1. As data show, the reaction is very fast and a complete conversion of nitroarene 1a to aniline 2a was achieved with very short residence times (10, 5 and 2.5 min, Table 1, entries 1–3). With a 1.2 minutes residence time, 91

• molecules of pharmaceutical interest. The reduction of nitro compound 3 afforded 2-(4'-chlorophenyl)aniline (4), the direct precursor of the fungicide boscalid (Scheme 4). Under the best reaction conditions in a 5 mL PTFE reactor (flow rate 0.1 mL/min, 50 min residence time), the desired amine 4 was

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

• Chao Yang,
• Kai Lin,
• Lan Huang,
• Wei-dong Pan and
• Sheng Liu

Beilstein J. Org. Chem. 2016, 12, 2490–2494, doi:10.3762/bjoc.12.243

• -dianilinobenzoate (2f–p) with various substituents at the aniline moieties. Given the ease with which methyl 2,4-dianilinobenzoates could be assembled, further efforts were focused on the optimization studies of the key bidirectional indole annulations using 2a as the model substrate. To maximize efficiency and

Construction of bis-, tris- and tetrahydrazones by addition of azoalkenes to amines and ammonia

• Artem N. Semakin,
• Aleksandr O. Kokuev,
• Yulia V. Nelyubina,
• Alexey Yu. Sukhorukov,
• Petr A. Zhmurov,
• Sema L. Ioffe and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2016, 12, 2471–2477, doi:10.3762/bjoc.12.241

• the reaction with two equivalents of chloroacetone hydrazone 1a provided the corresponding functionalized bishydrazones 3 and 4 in good yields (method A in Figure 2). On the other hand, an aromatic amine (aniline) under the aforementioned conditions led to monohydrazone 5 as a major product. Even when

• a 3-fold excess of 1a was used, a mixture of mono- and bisadducts was obtained. This may be attributed to the reduced nucleophility of the secondary amino group in the primarily formed adduct 5. The reaction of aniline with 1.0 equiv of chlorohydrazone 1a gave 5 in 84% yield (method B in Figure 2

TBHP-mediated highly efficient dehydrogenative cross-oxidative coupling of methylarenes with acetanilides

• Cui Chen,
• Weibing Liu and
• Peng Zhou

Beilstein J. Org. Chem. 2016, 12, 2250–2255, doi:10.3762/bjoc.12.217

• desired N-arylbenzamides in moderate yields, from 51% to 69% (Table 2, entries 12–14). It is noteworthy that the reactions did not result in the desired product when using aniline and diethylamine as the partners of acetanilide. In order to gain insight into the nature of this conversion, two experiments

Thiophene-forming one-pot synthesis of three thienyl-bridged oligophenothiazines and their electronic properties

• Dominik Urselmann,
• Konstantin Deilhof,
• Bernhard Mayer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2016, 12, 2055–2064, doi:10.3762/bjoc.12.194

• electronics [37][38][39][40]. In comparison to thiophene, phenothiazine, a tricyclic dibenzo-1,4-thiazine, possesses a significantly lower oxidation potential, similar to aniline. However, phenothiazine derivatives form stable deeply colored radical cations with perfect Nernstian reversibility [41][42][43][44

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• amines. Nonetheless they highlight the green benefits that they offer. For example Noroozi-Pesyan et al. synthesized azo dyes by grinding derivatives of aniline with solid sodium nitrite in the presence of p-toluenesulfonic acid [3]. It was found that the yield of isolated azo dyes obtained increased

Synthesis and NMR studies of malonyl-linked glycoconjugates of N-(2-aminoethyl)glycine. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger,
• Sven Hafner and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 1939–1948, doi:10.3762/bjoc.12.183

• )carbodiimide (EDCI) (Scheme 1, Table 1). In general, HBTU gave higher yields of malonamides 1a–d than EDCI. Previously, we used EDCI for coupling acids 6a–d to aniline derivatives because HBTU resulted in byproducts which were difficult to be removed [14]. Such byproducts were not observed here though. Next

Potent triazine-based dehydrocondensing reagents substituted by an amido group

• Munetaka Kunishima,
• Daiki Kato,
• Nobu Kimura,
• Masanori Kitamura,
• Kohei Yamada and
• Kazuhito Hioki

Beilstein J. Org. Chem. 2016, 12, 1897–1903, doi:10.3762/bjoc.12.179

• nucleophilic aniline 2b (Table 2, entry 2). To elucidate the reactivities of X and DMT-MM, time courses of amide-forming reactions using sterically hindered pivalic acid (1b) and 2-phenylethylamine (2a) in MeOH and THF were investigated by 1H NMR spectroscopy (Figure 2a,b, respectively). The steric hindrance

• materials such as aniline were used. This study contributes to the development of novel functionalized triazine-based dehydrocondensing reagents that are effective for aminolysis or alcoholysis shown in the second step of Scheme 1b. Structures of amido-substituted chlorotriazines. Time courses of the amide

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• para-position relative to nitrogen (the 6-position) was required for further functionalisation by typical cross-coupling reactions. THQ scaffolds similar to 1 are known in the literature, and have been typically prepared by two approaches. The first involves the alkylation of the starting aniline with

• iodination literature available [16][17]. Isopropylation of the inexpensive o-toluidine (5) can be conducted by simply adding NaOH and 2-iodopropane to a refluxing solution of the aniline (Scheme 2). While this straightforward procedure was well suited to larger scale, some bis-alkylation was difficult to

• vinyl ketone (MVK) indicated that only around 60% of the starting aniline had converted, particularly at larger scales (>1 g). Two equivalents of MVK were required to effect full conversion, however, under these conditions the bis-adduct was formed in around 6–10% and this was difficult to remove by