key: cord-0761553-e1hbd5no
authors: Hussain, Ibrar; Yawer, Mirza Arfan; Lalk, Michael; Lindequist, Ulrike; Villinger, Alexander; Fischer, Christine; Langer, Peter
title: Hetero-Diels–Alder reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with arylsulfonylcyanides. Synthesis and antimicrobial activity of 4-hydroxy-2-(arylsulfonyl)pyridines
date: 2008-12-01
journal: Bioorg Med Chem
DOI: 10.1016/j.bmc.2008.10.033
sha: a055ce10127f2cdd2e4ef0f320b96fb41c8f7339
doc_id: 761553
cord_uid: e1hbd5no

Hetero-Diels–Alder reactions of 1,3-bis(silyloxy)-1,3-butadienes with arylsulfonylcyanides afforded a variety of 4-hydroxy-2-(arylsulfonyl)pyridines. Several derivatives show antimicrobial activity against Gram-positive bacteria.

Hetero-Diels-Alder reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with arylsulfonylcyanides. Synthesis and antimicrobial activity of 4-hydroxy-2-(arylsulfonyl)pyridines

Nitriles represent versatile electrophilic building blocks in basemediated cyclization reactions with nucleophiles. 1,2 In contrast, cycloaddition reactions of nitriles are more rare. 1 Known examples include, for example, transition metal-catalyzed [2 + 2 + 2] cycloaddition of nitriles with two molecules of alkynes. 3 The photochemical [2 + 2] cycloaddition of aryl nitriles with electron rich alkenes has been reported to give azetines. 4a-c A 1,3-azetin-2-one has been prepared by [2 + 2] cycloaddition of trichloroacetylisocyanate with trichloroacetonitrile. 4d The [3 + 2] cycloaddition of nitriles with azides has been reported to give 1H-tetrazoles. 5 The best yields were generally obtained for nitriles containing an electron deficient substituent. Sharpless et al. studied the synthesis of tetrazoles by Cu-catalyzed 'click reaction' of nitriles with azides. 6 For example, 1-substituted-5-tosyltetrazoles were prepared from tosyl cyanide (TsCN); the tosyl group was subsequently elaborated by nucleophilic substitution reactions. The 1,3-dipolar cycloaddition of diazomethane with TsCN has been reported to give 1,2,3triazines. 7 The [4 + 2] cycloaddition of nitriles with 1,3-dienes (hetero-Diels-Alder reaction) has been reported to give dihydropyridines which often undergo elimination or oxidation reactions to the corresponding pyridine derivatives. Noteworthy, intermolecular reactions of this type are relatively rare and highly activated nitriles, such as arylsulfonylnitriles and cyanoformates, have to be employed. 8 Breitmaier and Rüffer reported 8f an efficient synthesis of functionalized pyridines by cyclization of 1,3-butadienes, including 2-silyloxy-1,3-butadienes, with tosylcyanide 9 (TsCN). Pyridines have been prepared also by cyclization of pyran-2-ones with TsCN with extrusion of carbon dioxide. 10 Recently, the synthesis of 1azabicyclo[2.2.2]oct-1-enes by cyclization of 2-silyloxycyclohexa-1,3-diene with TsCN has been reported. 11 Recently, we reported, 12 based on the work of Breitmaier, the hetero-Diels-Alder reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes 13 with TsCN. Herein, we report full details of these studies and a considerable extension of the scope. The reactions reported herein allow a convenient synthesis of a variety of functionalized 4-hydroxy-2-(arylsulfonyl)pyridines which are not readily available by other methods.

In recent years, it has been shown that 2-(arylsulfonyl)pyridines and related molecules are of considerable pharmacological relevance. 10-Oxa-9-thia-1-aza-anthracene-9,9-dioxide possesses in vitro (rat brain homogenate) inhibitory activity against monoamine oxidase (MAO). 14 6-(Benzenesulfonyl)-pyrido [3,2-d] pyrimidine-2,4-diamine shows parenteral antimalarial effects against Plasmodium Berghi in mice. 15 1-(10,10-Dioxo-5k 9 -dihydro-10,6thiochromeno [2,3-b] pyridin-5-yl)-1,3-dimethyl-urea shows gas- activity. 16 2-Benzenesulfonyl-4-methylbenzo[h]quinolines show antibiotic activity against various pathogens. 17 6-(Benzenesulfonyl)-pyrido [3,2-d] pyrimidine-2,4-diamines have been reported to inhibit Pneumocystis carinii dihydrofolate reductase and Toxoplasma gondii dihydrofolate reductase. 18 3-[5-(Phenylcarbamoyl)-pyridine-2-sulfonyl]-benzoic acids show binding activity to Sf9 cell membranes. 19 2,4-Diamino-10,10-dioxo-5,10-dihydro-10k 6 -thiochromeno[2,3-b]pyridine-3-carbonitrile and related derivatives inhibit recombinant MAP kinase-activated protein kinase 2. 20 2-(Benzenesulfonyl)-5-nitropyridines and related compounds show inhibitory activity of recombinant SARS coronavirus main protease 2. 21 2-(4-Fluoro-benzenesulfonyl)-5-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyridine binds to the human 5-HT2A receptor. 22 Other derivatives have been shown to bind to the human cannabinoid CB2 receptor. 23 Other effects have also been reported. 24 Herein, we report the antimicrobial activity of several 2-(arylsulfonyl)-4-hydroxypyridines prepared by our new synthetic methodology.

The reaction of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (1a), readily available from methyl acetoacetate, 25 with ptoluenesulfonyl cyanide (TsCN, 2a) afforded the 4-hydroxy-2tosylpyridine 3a in 43% yield (Scheme 1, Table 1 ). The best yields were obtained when a neat mixture of the starting materials was allowed to slowly warm from -78°C to ambient temperature. A complex mixture was obtained when the reaction was carried out at elevated temperatures or when a solvent was added. An aqueous work-up using NH 4 Cl or HCl was necessary. The formation of 3a can be explained by [4 + 2] cycloaddition to give intermediate A and subsequent acid-mediated cleavage of the silyloxy group and aromatization.

The cyclization of 1,3-bis(silyloxy)-1,3-butadienes 1a-p with arylsulfonyl cyanides 2a,b afforded the 4-hydroxy-2-sulfonylpyridines 3a-v (Table 1 ). The reaction conditions were optimized. The reactions of dienes 1a,b,e,f, prepared from unsubstituted bketoesters, were carried out at 20°C (the starting materials were added at -78°C and the mixture was subsequently warmed to 20°C during 30 min. The reaction time was in the range of 24-28 h. A considerable extension of the reaction time was necessary for the less reactive dienes 1c and 1d derived from pentane-2,4dione and 1-methoxy-pentane-2,4-dione, respectively. In these cases, the starting materials were added at 0 rather than -78°C. The reactions were carried out at 20°C. An increase of the temper-ature resulted in partial decomposition. The reactions of dienes 1g-i and 1m-o were carried out at 45°C (48 h). The arylthiosubstituted dienes 1j-l,p solidify at 20°C. Since all reactions reported herein had to be carried out without solvent (neat) it proved to be advantageous to carry out the reactions of 1j-l,p at 60°C (96 h).

Noteworthy, the yields of pyridines 3i-v were considerably higher than those of 3a-h. This can be explained by the cisoid conformation of 1,3-bis(silyloxy)-1,3-butadienes 1g-s, due to the presence of the substituent located at the central carbon atom. The reaction of 2a with 1,3-bis(silyloxy)-1,3-butadienes containing a substituent located at the terminal carbon atom proved to be unsuccessful, presumably due to steric reasons. The reaction of 1a with ethoxycarbonyl cyanide was also unsuccessful, due to the low reactivity of the latter compared to 2a. No conversion was observed when the reaction was carried out at 20 and 60°C. Forcing conditions (neat, 120°C) resulted in decomposition and 1,5 O ? C TMS shift of the 1,3-bis(silyl enol ether) to give a 3-silyloxy-4-silylcrotonate. 26 The structures of the products were elucidated by spectroscopic methods (2D NMR). The structures of 3l and 3r were independently confirmed by X-ray crystal structure analyses (Figs. 1 and 2). 27 All arylsulfonyl-pyridines were tested towards their antimicrobial activity. The agar diffusion test method was used to evaluate the influence on the growth of the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis as well as the Gram-negative Escherichia coli and the yeast Candida maltosa. The results of that screening are summarized in Table 2 . Some of the compounds showed considerable activities against S. aureus and B. subtilis. In this screening no activity against the Gram-negative E. coli was observed. Only 3o showed a weak activity against the yeast C. maltosa. Compound 3o is also among the most active derivatives in this study. To evaluate the antimicrobial potential of the most active compounds minimal inhibitory concentrations were determined. The results of these investigations are summarized in Table 3 . Derivatives 3i,j,o, containing a halogen atom located at the pyridine moiety, show the best activities. A good activity was also observed for derivative 3n containing a tolylthio moiety.

The chloro derivatives 3i and 3o show a good antibiotic activity against the tested Gram-positive pathogenes. Interestingly, the R 2 thio-substituted sulfonyl-pyridines 3l-n and 3u-v are also active, but at a lower level in the agar diffusion assay. In contrast to this observation, the MIC of 3n, 3u and 3v are lower compared to the chlorinated compounds 3i and 3o. A possible explanation would be a better bioavailability in case of the non-chlorinated derivatives in the dilution assay. All compounds show much lower activity compared to Ampicillin in this study. In future studies, the influence of a halogenation at position R 2 or R 3 in the thioaryl derivatives could be of interest to get better insight into the structure-activity relationships.

In conclusion, the hetero-Diels-Alder reaction of 1,3-bis(silyloxy)-1,3-butadienes with arylsulfonylcyanides afforded a variety of 4-hydroxy-2-(arylsulfonyl)pyridines. The products, which are not readily available by other methods, show a considerable antimicrobial activity against Gram-positive bacteria.

All solvents were dried by standard methods and all reactions were carried out under an inert atmosphere. For 1 H and 13 C NMR spectra the deuterated solvents indicated were used. Mass spectro- 

To the arylsulfonyl cyanide 2 (1.0 equiv) was added dropwise the 1,3-bis(silyl enol ether) 1 (2.0-2.5 equiv) at À78°C. The neat reaction mixture was allowed to warm 45À60°C during 48À96 h with stirring. To the mixture was added a saturated aqueous solution of NH 4 Cl (20 mL) and the organic and the aqueous layer were separated. The latter was extracted with CH 2 Cl 2 (3 Â 20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, n-heptane/EtOAc) to give 3a-v. The synthesis of 3a-h has been previously reported in our preliminary communication. 13 

Starting with 2a (0.167 g, 1.0 mmol) and 1 g (0.617 g, 2.0 mmol), 3i was isolated as a yellow viscous oil (0.175 g, 56%). 

Starting with 2b (0.167 g, 1.0 mmol) and 1 k (0.746 g, 2.0 mmol), 3m was isolated as a yellow solid (0.210 g, 56% 13 

The bacterial cultures were obtained from the ATCC. Assay for antimicrobial activity: a modified disc diffusion method was used to determine the antimicrobial activity. A sterile filter disc of 6 mm diameter (B & D research) was impregnated with the test compounds. The amount of the compounds tested in these experiments was 1 lmol per paper disc. The paper disc was placed on the agar plate seeded with respective microorganisms. The plates were kept in the refrigerator at 4°C for 4 h. The plates were then turned over to incubate overnight at 37°C (at 25°C in case of C. maltosa) in an inverted position. At the end of the incubation period the clear zones of inhibition around the paper disc were measured. Negative control experiments were performed by using paper discs loaded with an equivalent volume of solvent, and positive control experiments were performed by the use of an equivalent amount of Ampicillin (in the case of S. aureus, B. subtilis and E. coli) and Nystatin (C. maltosa). All experiments were done in triplicate.

HRMS (EI): Calcd for C 19 H 17 NO 3 S 2

Starting with 2a (0.094 g, 1.0 mmol) and 1 g (0.617 g, 2.0 mmol), 3o was isolated as a red viscous oil (0.156 g, 48%)

42 (s(br), 1 H, OH Heterl ), 7.84 (d, 3 J = 8.2 Hz, 2 H, CH Tol ). 13 C NMR (75 MHz

840 (s), 676 (s), 589 (s). MS (CI, Positive, 70 eV): m/z (%) = 330

HRMS (ESI, Positive): Calcd for C 14 H 14 FNO 4 S

1319 (s), 1267 (s), 1146 (s), 1083 (s), 904 (w), 812 (m)

HRMS (ESI, Positive): Calcd for C 14 H 15 NO 4 S

18 (s, 3 H, CH 3Tol ), 2.32 (s, 3 H, CH 3Heter ), 6.47 (m, 1 H, CH Tol ), 6.53 (s, 1 H, CH Heter ), 6.75 (d, 3 J = 7.3 Hz, 1 H, CH Tol ), 7.00À7.06 (m, 2 H, CH Tol ), 7.21 (d, 3 J = 8.2 Hz, 2 H, CH Tol ), 7.62 (s(br

86 (d, 3 J = 8.2 Hz, 2 H, CH Tol ). 13 C NMR (75 MHz

0 mmol) and 1i (0.757 g, 2.0 mmol), 3t was isolated as a red viscous oil (0.253 g, 62%)

29 (s, 6 H, CH 3Xyl ), 2.52 (s, 3 H, CH 3Tol

2C Xyl ), 149.6 (C Tol ), 158.4 (C Heter ), 159.7 (C Xyl ), 159.9, 160.4 (C Heter )

HRMS (EI): Calcd for C 19 H 17 NO 3 S 2 : 371.06444; found: 371.06400. References and notes 1. For a review of applications of nitriles as reagents for organic synthesis with loss of the nitrile functionality (including cycloaddition reactions), see Collier

Sulfonylcyanides have been used as electrophilic cyanation reagents

For a review of 1,3-bis(trimethylsilyloxy)-1,3-butadienes, see Langer, P. Synthesis

Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-686724 (3l) and CCDC-686725 (3r). Copies of this data can be obtained, free of charge

Cambridge CB2 1EZ, UK; fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk) or via www

Financial support by the state of Pakistan (HEC scholarships for I.H. and for M.A.Y.) is gratefully acknowledged.