Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis

We describe a method for the synthesis of sulfonamides through the combination of an organometallic reagent, a sulfur dioxide equivalent, and an aqueous solution of an amine under oxidative conditions (bleach). This simple reaction protocol avoids the need to employ sulfonyl chloride substrates, thus removing the limitation imposed by the commercial availability of these reagents. The resultant method allows access to new chemical space, and is also tolerant of the polar functional groups needed to impart favorable physiochemical properties required for medicinal chemistry and agrochemistry. The developed chemistry is employed in the synthesis of a targeted 70 compound array, prepared using automated methods. The array achieved a 93 % success rate for compounds prepared. Calculated molecular weights, lipophilicities, and polar surface areas are presented, demonstrating the utility of the method for delivering sulfonamides with drug-like properties.


Array Synthesis
The array synthesis of sulfonamides was performed as a matrix using a Mettler-Toledo-Bohdan XT block equipped with an inert/purging manifold. The experiments were conducted in two runs using the same ten amines each time with 4 organometallic reagents in the first run and three in the second (1 × 40 combinations and 1 × 30 combinations). Non-commercially available organometallic reagents were prepared as stock solutions. 2,4-Dimethoxypyrimindin-5-ylmagnesium chloride was prepared from 5iodo-2,4-dimethoxy-pyrimidine and i PrMgCl.LiCl. 11 d 5 -Ethylmagnesium bromide was prepared from d 5 -bromoethane and Mg turnings. 12 3-Lithio-1-(triisopropysilyl)pyrrole was prepared from 3-bromo-1-(triisopropysilyl)pyrrole and t BuLi. 3-Acetoxypropylzinc iodide was prepared from 3-acetoxypropyl iodide and activated Zn dust. 13 3-Bromo-2,6-dimethoxypyridinyl-5-magnesium chloride was prepared from 3,5-dibromo-2,6-dimethoxypyridine and i PrMgCl.LiCl. 14 Typical Run: Oven-dried test tubes were placed in the block reactor which was connected to a manifold and the tubes were cooled by flushing with nitrogen gas. DABSO (36 mg, 0.15 mmol) was added to each of the tubes which were subsequently flushed with nitrogen for 2 mins. THF (0.5 mL) was added to the tubes which were then cooled to -40 °C followed by addition of the corresponding organometallic reagent (0.25 mmol). The resulting mixtures were stirred at this temp for 30 mins before being allowed to warm to room temp. To each of the tubes was added sequentially, H 2 O (1 mL), amine (1.25 mmol) and NaOCl (15.8% aqueous solution, 296 µL, 0.75 mmol). The resulting mixtures were stirred at room temp for 16 h before being transferred to glass vials containing sat. NaS 2 O 3 (aq) (10 mL) and stirred for a further 30 mins. EtOAc (10 mL) was added to each of the vials which were vigorously shaken (robotic assisted agitation) for 1 min before automated extraction of the organic layer via syringe. This process was repeated 3 times before removing the solvent by flushing with hot air (40 °C). The resulting crude reaction mixtures were purified using automated preparative liquid chromatography-mass spectrometry to deliver the desired sulfonamides as identified by LC-MS (retention times given in minutes). Purification of samples: Compounds were purified by mass directed prep HPLC using a mixed trigger of UV with ES+ on a Waters Fraction Lynx system comprising a 2767 injector/collector with a 2525 gradient pump, pump control module two 515 isocratic pumps, CFO, 2996 photodiode array, 2420 ELSD and Micromass S18 ZQ2000. A Waters XBridge dC18 5micron 19x10mm guard column was used with an XBridge dC18 5micron OBD 30x100mm prep column.
The preparative HPLC was conducted employing a generic 11.4 minute run time using H 2 O with 10mM ammonium acetate (solvent A) and CH 3        (1) 0.23 (7) 1.00 (7) 1.02      The compounds were also evaluated against several pathogens on leaf-piece assays at the rate of 100ppm for Uromyces viciae-fabae on bean and Zymoseptoria tritici on wheat, and at the rate of 200ppm for Phytophthora infestans on tomato. The compounds were applied prior to inoculation with the pathogens.

Time
Test species Host Rate (ppm)

Herbicide plate assays:
The compounds were tested for herbicidal activity against Arabidopsis thaliana at 10 ppm and Poa annua at 32ppm. Test plates were stored for seven days in a controlled environment cabinet. They were scored as 0 or 99, where 99 = herbicidal effect, and 0 = no effect.
Test species Treatment timing Rate (ppm)

Poa annua
Pre-emergence 32 Insecticide assays: The compound was tested for activity against an aphid species and Heliothis virescens at 1000ppm on a leaf-piece based assay, and against Plutella xylostella and Diabrotica balteata at 500ppm in artificial diet assays. Chemicals were applied to feeding aphids, or prior to infestation with P. xylostella, H. virescens and D. balteata larvae. Mortality was assessed relative to control wells using a 2 band system (0 or 99 where 99 = significant mortality, 0 = no effect), 3-6d after the treatments depending on the assay.