Three‐Dimensional Heterocycles by Iron‐Catalyzed Ring‐Closing Sulfoxide Imidation

Abstract

A general and atom‐economical method for the synthesis of cyclic sulfoximines by intramolecular imidations of azido‐containing sulfoxides using a commercially available FeII phthalocyanine (FeIIPc) as catalyst has been developed. The method conveys a broad functional group tolerance and the resulting three‐dimensional heterocycles can be modified by cross‐coupling reactions.

Increasing Complexity: A Practical Synthetic Approach to Three‐Dimensional, Cyclic Sulfoximines and First Insights into Their in Vitro Properties

“…The synthetic applicability of bromo-substituted products such as 3ah for metal-catalyzed cross-coupling reactions has already been demonstrated by Bolm and co-workers. [11] ortho-Iodo derivative 3ai was envisaged to allow access to P, Nl igands [20] by cross-coupling with suitable phosphanes. [21] Prepa-ration of the matched pyridyl analogueso fp henyl derivative 3ab provedt ob ed ifficult due to very high polarity and solubility of the corresponding products, which hampered preparative isolation.H owever,t he feasibility of heterocyclic substituents R 1 is displayed in products 3al and 3am.M oreover,s tarting from 3-sulfanylestra-1(10),2,4-trien-17-one, [22] the applicability of the three-step procedure for complex, drug-like molecules is demonstrated by the formation of 3an (1:1 mixture of diastereomers) in high overall yield.…”

“…Finally,t reatment with tBuOK/nBuLi afforded cyclized product 3ab.The six-membered cyclic homologue 3bb (see Ta ble 1) was prepared in as imilar manner.R ecently,B olm and co-workers reported an approach, with broad functional-group tolerance, to five-and six-memberedc yclic sulfoximines 3 by intramolecular imidation of azido-containing sulfoxides with ac ommerciallya vailable iron(II) phthalocyanine as catalyst. [11] Moreover,M aruoka andc o-workersh ave outlined ap rocedure for the synthesis of unsaturated five-membered cyclic sulfoximinesf rom N-propargylsulfinamides through sulfur-carbon bond formation. [12] The development of significantly improved methodologies for the synthesis of sulfoximines 2 has been an important trigger for the increased interesti nt his functional group by the drug-discovery community in recenty ears.…”

Recent Advances in the Synthesis and Reactivity of Isothiazoles

“…More recently, Bolm and co‐workers reported the synthesis of novel isothiazole derivatives by an iron‐catalyzed sulfoxide imidation (Scheme ) . Thus, azido‐substituted sulfoxides upon treatment with Fe(II)Pc (Pc=phthalocyanine) as the catalyst underwent ring‐closing sulfur imidation reactions delivering directly 4,5‐dihydro‐3 H ‐isothiazole 1‐oxides (Scheme , top ) and benzofused 3 H ‐1λ 4 ‐isothiazole 1‐oxides (Scheme , bottom ) in high to excellent yields.…”

“… Synthesis 4,5‐dihydro‐3 H ‐isothiazole 1‐oxides and 3 H ‐1λ 4 ‐arylo[ d ]isothiazole 1‐oxides via iron‐catalyzed sulfoxide imidation by Bolm …”

“… Synthesis of simple five‐membered isothiazole oxides by Bolm. A: intramolecular halocyclization; B: Hofmann–Löffler–Freytag reaction …”