Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synergistic Catalysis-Enabled Thia-Aza-Prins Cyclization with DMSO and Disulfides: Entry to Sulfenylated 1,3-Oxazinanes and Oxazolidines Yang Ni, Honghua Zuo, Huaibin Yu, Yuzhou Wu, and Fangrui Zhong* Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, China Org. Lett. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/10/18. For personal use only.
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ABSTRACT: A novel synergistically catalyzed thia-aza-Prins cyclization of alkenylamines with disulfides is reported, rendering the first synthesis of sulfenylated 1,3-oxazinanes and oxazolidines in good to high yields. Importantly, DMSO serves simultaneously as a reaction medium and a surrogate for formaldehyde. Mechanistic studies provide evidence that actions of CuBr2 and in situ formed sulfinic acids as a Lewis acid and Brønsted acid catalyst, respectively, synergistically catalyze these cyclization processes.
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epoxides and acetals as carbonyl equivalents have been realized as well.3 Despite broad applications of Prins cyclization in constructing core skeletons for many natural product syntheses,4 their structure diversity is largely restricted to 1,3-dioxanes, tetrahydropyrans, and piperidines. Another substantial drawback lies in the challenge of optimizing the product distribution from diverse reaction pathways; thus, an accurate control of the experimental conditions is often required.1 As a part of our research interest in developing efficient C− N bond formation reactions,5 we recently reported that Lewis acid activation of disulfides triggers an electrophilic sulfenoamination of alkenes and enables the preparation of various sulfenyl N-heterocycles.5a Based on this disclosure, we envisaged that capture of the carbocation arising from the electrophilic addition of disulfides to alkenes by formaldehyde and ring closure with a pendant nitrogen nucleophile would result in a novel thia-aza-Prins cyclization to access sulfenylated 1,3-oxazinanes (Scheme 1, eq 4). Oxazinanes are interesting skeletons of considerable synthetic and pharmacological utility.6 This class of heterocycles can be routinely obtained by condensing amino alcohols with aldehydes under general acid−base catalysis. Other isolated cases of synthesis via azaWacker reaction,7 chain-walking reaction,8 and cycloadditions9 have also been documented. Notably, oxazinanes provided by these protocols generally have only simple alkyl- or arylsubstituted frameworks with limited molecular complexity. Pharmaceutically, incorporation of a sulfenyl group to such frameworks appears to be fascinating,10 as demonstrated by the unique bioactivity profile of molecules such as cysteine, biotin, glutathione, and penicillin. Unfortunately, to date, synthetic methods to produce sulfenyl 1,3-oxazinanes have not yet
he Prins cyclization represents a fundamental method for the construction of oxygen-containing heterocycles.1 This classical reaction has different pathways that give rise to distinct adducts. A typical one involves an electrophilic addition of oxocarbenium species to the olefin group of homoallylic alcohol substrates, followed by capture of the in situ formed carbocation with a nucleophile to assemble tetrahydropyrans (Scheme 1, eq 1). Alternatively, when the Scheme 1. Different Pathways Relevant to Prins Cyclization
carbocation is attacked by an additional carbonyl reactant, exclusively formaldehyde so far, a dioxane skeleton is constructed (Scheme 1, eq 2). Development of the Prins cyclization has led to the successful extension to its azacounterpart,2 although this is much less explored, rendering the conversion of homoallylic amines to various valuable Nheterocycles (Scheme 1, eq 3). Synthetic variations using © XXXX American Chemical Society
Received: August 10, 2018
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DOI: 10.1021/acs.orglett.8b02551 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
TiCl4, and no reaction took place in the absence of a catalyst (Table 1, entries 13−15). We moved on to examine the substrate generality of this CuBr2-catalyzed thia-aza-Prins cyclization by employing different alkenylamines and disulfides (Scheme 2). Pleasingly,
become available. In this report, we show our discovery in the first synthesis of the titled compounds via a copper-catalyzed thia-aza-Prins cyclization of homoallylic amines with readily available disulfides and dimethyl sulfoxide (DMSO) as a formaldehyde surrogate. To test our hypothesis of the modified Prins cyclization, we set out to examine the reaction of N-tosyl-homoallylic amine 1a and phenyl disulfide 2a with paraformaldehyde. CuBr2 (10 mol %) as a proven suitable activator5a of disulfide was first selected, and the reaction was conducted at elevated temperature. To our delight, the anticipated sulfenylated 1,3oxazinane 3a was smoothly furnished in DMF in appreciable yield (34%) (Table 1, entry 2). Surprisingly, among various
Scheme 2. Scope of Copper-Catalyzed Thia-Aza-Prins Cyclization of N-Tosylalkenylamine 1 with DMSO and Disulfide 2ab
Table 1. Optimization of Conditions for the Thia-Aza-Prins Cyclization Reactiona
entry
cat.
solvent
temp (°C)
x
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 Cu(OTf)2 CuCl2 FeBr3 AlBr3 ZnBr2 LiBr TiCl4 BF3·Et2O
toluene DMF DCE 1,4-dioxane DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO
reflux 100 reflux 100 100 100c 100 100 100 100 100 100 100 100 100
10 10 10 10 10 0 0 0 0 0 0 0 0 0 0
5 34 0 16 85 91 NR 9 66 71 58 34 12
