Twisting and Turning the Sulfonamide Bond: A Synthetic, Quantum Chemical, and Crystallographic Study

Abstract

Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette’s sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]­hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S–N bond. Thus, going from the sp3-hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette’s sultam resulted in an increase in S–N bond length by ca. 0.06 Å. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.

Synthesis of Functionalized Bridged Bicyclic Sulfonamides with a Bridgehead Nitrogen Atom

“…As a result, products 17a–d were obtained in 70–81 % yield. Noteworthy, the yield of this reaction for bicyclic sultam 17a was significantly higher than the one previously reported for its non‐functionalized counterpart 18 (25 % from 19 ) . This observation can be attributed to the axial position of methylene sulfonyl fluoride moiety at azetidine ring required for cyclization, which is more favored for intermediate 20 with R = CN than for 20 with R = H (Scheme ).…”

“…Besides, presence of the SO 2 group adjacent to the N ‐atom completely eliminates basicity inherent to amines 4 and lowers compounds lipophilicity. Noteworthy, the confinement of sulfonamide moiety to the bridged bicyclic core results in abnormal structural characteristics, which were recently disclosed by our group . In particular, extremely high pyramidalization of N ‐atom was noticed for 3 with n=k = 0 and m = 1.…”

“…To access isomeric carboxylic acids 10 , we have turned to an alternative approach, namely lithiation–carboxylation of parent sultams 3 , which were obtained from substrates 21 (Table ) . In fact, lithiation of 3 with t BuLi was described by Paquette and co‐workers; the carbanion formed was used in the reaction with reactive alkylation reagents (i.e.…”

“…All starting materials were purchased from commercial sources. Compounds 3a – f were prepared by the same procedures reported in ref (see supporting info for additional details). Compounds 9b,d, 12b–17b, 12d–17d and 10a,c,d were obtained in racemic form.…”

“…cleavage of the sulfonamide bond. This approach was used by us recently for the preparation of the parent compounds 3 . In addition, we also report preparation of carboxylic acids 10a – d from non‐functionalized scaffolds 3 .…”