Synthesis of Spirocyclic β‐ and γ‐Sultams by One‐Pot Reductive Cyclization of Cyanoalkylsulfonyl Fluorides

Abstract

One‐pot intramolecular cyclization of novel sp3‐enriched cyanoalkylsulfonyl fluorides into spirocyclic β‐ or γ‐sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH4, NiCl2·6H2O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48–84 %, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S‐nucleophilic substitution in β‐functionalized alkanenitriles or double alkylation of α‐alkylthioacetonitrile, followed by oxidative chlorination with Cl2 and further reaction with KHF2. The title mono‐ and bifunctional sultams are advanced sp3‐enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[175][176][177][178] A related approach to spirocyclic sultams 21 relied on the intramolecular reductive sulfonylation of cyanoalkyl sulfonyl fluorides 22 via the formation of aminoalkyl sulfonyl fluorides 23 (Scheme 15, C). [179] Another example relied on annulative SuFEx reaction of arylsubstituted ethenesulfonyl fluorides 24 as bis-electrophiles with ketones bearing an activated methylene group [180][181][182] or pyrazolones [181][182][183] for the synthesis of 6-membered δ-sultones 25 (Scheme 15D).…”

“…Many of the methods described for (hetero)aromatic sulfonyl fluorides in section 3.2 are also commonly used for the synthesis of their saturated counterparts (Scheme 30). In particular, AlkSO 2 F 59 can be obtained from sulfonyl chlorides 60 via the common ClÀ F exchange using KF (KHF 2 ), [159,179,289,290,318,319] which in some cases was performed in the presence of 18-crown-6 (A). [139,176,287,320] Other F À sources included NH 4 F, [321,322] NaF, [323] as well as TBAF.…”

A practical fluorosulfonylating platform via photocatalytic imidazolium-based SO2F radical reagent

“…Sulfonyl fluorides as the most widely used connective hubs of SuFEx click reaction have attracted enormous attention and find widespread applications in the fields of chemical biology 2 – 6 , drug discovery 7 – 11 and materials science 12 – 16 . Methods have been developed for rapid construction of sulfonyl fluoride moiety, including the chloride-fluoride exchange of sulfonyl chlorides 17 – 19 , SO 2 insertion/fluorination 20 – 23 , electrophilic fluorination of thiols and anodic oxidative fluorination 24 – 27 . Compared with the above mentioned S-F bond formation, direct fluorosulfonylation would provide a concise and redox economic approach for C-SO 2 F bond formation.…”

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

“…Attributing to the frequent recurrence of spirocycles in biologically active molecules and natural products, the asymmetric preparation of spirocyclic compounds and their biological evaluation has been an important research area for organic chemists [1–10] . Being essential constituents of natural products, drugs, living organisms and other products of utility to mankind in all walks of life, azetidin‐2‐one (β‐lactam) heterocycles have been recognized as a significant contribution of science to humanity [11] .…”