Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols

Abstract

New small ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron donating aromatics are successful, proceeding via an azetidine carbocation. The N-Cbz group is a requirement for good reactivity, and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs. New chemical motifs with appropriate physicochemical properties offer valuable opportunities in drug design. 1,2 As a result, there has been significant recent attention on the synthesis of new modules that may be readily incorporated in medicinal chemistry, as fragments, building blocks or isosteres. 3 Small heterocyclic rings are attractive in this context due to low molecular weight and defined exit vectors. 4,5 Small rings readily access new chemical and IP space, particularly when combined with medicinally relevant substituents, which is partly due to their limited synthetic accessibility preventing their investigation. Sulfur functional groups are prevalent in pharmaceuticals and agrochemicals, 6 with thioethers being important in their own right and as intermediates to access sulfoxide, sulfone and sulfoximine moieties. There are examples of azetidine thioethers in biologically active compounds in the literature with the majority 3-monosubstituted, including compounds having RBP4-lowering activity and antibacterial activity (Figure 1A). 7,8 3,3-Disubstituted azetidine sulfides, without additional C2 or C4 1 2a 5 a Isolated yields quoted. Alternative 3-aryl-azetidin-3-ol substrates (3-8) were prepared by the addition of Grignard reagents to commercially available N-Cbz azetidine-3-one (Scheme 2). 16 Preinstalled benzyl-and TIPS-protected phenols were tolerated under the reaction conditions producing 9 and 10 in excellent yield. Increasing the steric demands of the azetidinol with ortho-substituted aromatics gave azetidine 11 in 92% yield. Benzodioxole and trimethoxybenzene azetidinols reacted similarly well giving products 12 to 14 in good yield using benzylic, aryl or alkyl thiols respectively as nucleophiles. Importantly, indole containing sulfanylazetidine 15 was formed in 97% yield. As such, a range of 3-sulfanyl azetidines can be readily prepared with appealing functionalities of interest to medicinal chemists, varying both the thiol and preinstalled aryl group. 3-Phenylazetidin-3-ol returned starting material, even increasing the temperature to 80 °C, indicating the need for electron-rich aromatics to stabilize the postulated azetidine carbocation intermediate. The reaction could be extended to the 5 and 6-membered N-heterocycles giving piperidine 16 and pyrrolidine 17 in 95% and 93% yield respectively using benzylmercaptan. 6 Scheme 2. Scope of azetidinols. a a Isolated yields quoted. The derivatization of various 3-sulfanyl azetidi...

Catalytic Friedel‐Crafts Reactions on Saturated Heterocycles and Small Rings for sp3‐sp2 Coupling of Medicinally Relevant Fragments

“…These Lewis acid catalysts were also those previously shown to be reactive with oxetane and azetidine substrates. [23][24][25][26] Cyclic tertiary alcohol substrates 1-7 were prepared from the corresponding commercially available ketones by the addition of the aryllithium or Grignard regents. [27] To compare the effect of the electronic properties of the aromatic stabilizing group substrates were prepared with 4-chlorophenyl (a), phenyl (b), and 4-methoxyphenyl (c, PMP) substituents.…”

“…We examined Li, Ca and Fe catalysts, chosen to represent different Lewis acidic metals considered to be relatively environmentally benign and sustainable. These Lewis acid catalysts were also those previously shown to be reactive with oxetane and azetidine substrates . Cyclic tertiary alcohol substrates 1 – 7 were prepared from the corresponding commercially available ketones by the addition of the aryllithium or Grignard regents .…”

“…We also reported 3,3‐diarylazetidines by Friedel–Crafts alkylation of electron rich aromatics with azetidinols, where a calcium triflimide catalyst was optimal (Figure b) . On the other hand, very recently we have shown that thiol alkylation with azetidinols proceeds most efficiently with an FeCl 3 catalyzed procedure …”

“…In our prior studies on azetidines, the NCbz-group was uniquely reactive, with no reaction occurring on the NBoc derivative. [25,26] We proposed a π-cation stabilizing interaction between the phenyl group of the Cbz group and the azetidine carbocation. Preliminary results for the NBoc pyrrolidinol and piperidinol derivatives were also significantly less reactive than the Cbz derivatives, with increased elimination, especially in the 6-membered ring (see later).…”

“…[25] On the other hand, very recently we have shown that thiol alkylation with azetidinols proceeds most efficiently with an FeCl 3 catalyzed procedure. [26] Figure 2. Previous work on the catalytic preparation of diaryloxetanes and diarylazetidines, and this work on catalytic Friedel-Crafts reactions on heterocycles.…”