Cu Catalysis Enables

Publication Date (Web): September 18, 2018. Copyright © 2018 American Chemical Society. *E-mail: [email protected]. Cite this:Org. Lett. XXXX...
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2‑Azaadamantane N‑oxyl (AZADO)/Cu Catalysis Enables Chemoselective Aerobic Oxidation of Alcohols Containing ElectronRich Divalent Sulfur Functionalities Yusuke Sasano, Naoki Kogure, Shota Nagasawa,† Koki Kasabata, and Yoshiharu Iwabuchi* Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan Org. Lett. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/18/18. For personal use only.

S Supporting Information *

ABSTRACT: The chemoselective oxidation of alcohols containing electron-rich sulfur functionalities (e.g., 1,3-dithianes and sulfides) into their corresponding carbonyl compounds with the sulfur groups can sometimes be a demanding task in modern organic chemistry. A reliable method for this transformation, which features azaadamantane-type nitroxyl radical/ copper catalysis using ambient air as the terminal oxidant is reported. The superiority of the developed method was demonstrated by comparing it with various conventional alcohol oxidation methods.

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lcohols are ubiquitous functional groups embedded in numerous organic molecules. Therefore, a chemoselective method for their selective modification will provide chemists with opportunities to design and synthesize valuable new molecules. Among the various types of modification methods for alcohols, the oxidation of the primary and secondary alcohols to give the corresponding carbonyl compounds plays indispensable roles in organic synthesis, because of their versatile uses. Thus, a diverse range of methods to efficiently conduct this particular transformation have been developed.1 However, increases in functional group diversity and molecular complexity pose significant challenges, with regard to the chemoselectivity issue, which requires the development of breakthrough methods that enable selective alcohol oxidation in the presence of oxidation-labile, electron-rich functional groups. Some sulfur-containing functional groups, such as dithianes and sulfides, are examples of the oxidation-labile functional groups.2 Thus, in the synthesis of organosulfur compounds, sulfur-containing functional groups are often introduced at a late stage.3 Considering the great importance of organosulfur compounds as pharmaceuticals, agrichemicals, flavors/fragrances, materials, and synthetic intermediates, among others,4 it would be highly rewarding to develop a reliable method for the chemoselective oxidation of sulfurcontaining alcohols into the corresponding carbonyl compounds, as this would expand the diversity of the synthetic strategy for organosulfur compounds. We previously demonstrated a highly chemoselective aerobic oxidation of unprotected amino alcohols into amino carbonyl compounds, based on combination catalysis of a less-hindered nitroxyl radical [2-azaadamantane N-oxyl (AZADO)] and a copper salt (see Figure 1).5 Such combination catalysis can impart unprecedented chemoselectivity upon an alcohol oxidation at room temperature, employing ambient molecular oxygen as the terminal oxidant. We envisaged that AZADO/ copper catalysis could be applicable to the oxidation of © XXXX American Chemical Society

Figure 1. Nitroxyl radicals.

alcohols with oxidation-labile sulfur-containing functional groups if we could identify an appropriate combination of nitroxyl radical/copper salt/ligand/additives. Although several combination catalysts of nitroxyl radicals and copper for aerobic alcohol oxidation have been reported,6 their applicability to electron-rich sulfur-containing alcohols has rarely been reported.7 The main issues that must be overcome in nitroxyl radical/copper catalysis are as follows: (i) the oxidatively active species must be orthogonal to the sulfurcontaining moiety, (ii) the active catalytic copper complex must not be deactivated by coordination to the sulfur group, and (iii) H2O2 generated in situ after alcohol oxidation must be dismutated before it reacts with the sulfur moiety. Here, we report a highly chemoselective aerobic oxidation of oxidationlabile sulfur-containing alcohols into the corresponding carbonyl compounds. In this study, we first optimized the reaction conditions using 1,3-dithiane-containing alcohol 1a as a substrate model (see Table 1). Considering our previous optimization study,5a we first compared the activities of CuOTf in a concentrated solution and CuCl in a diluted solution (entries 1 and 2).8 As a result, CuCl in a diluted solution showed higher activity to afford ketone 2a in 43% conversion. No other products were observed in the gas chromatography (GC), thin-layer chromatography (TLC), and 1H nuclear magnetic resonance (NMR) analysis of crude products. The combination of Received: August 7, 2018

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DOI: 10.1021/acs.orglett.8b02528 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Substrate Scopea

Table 1. Optimization of the Reaction Conditions

entry 1 2 3c 4 5 6c 7 8 9 10 11 12

nitroxyl radical

Cu salt (mol %)

MeCN (M)

time (h)

conversiona (%)

AZADO AZADO AZADO AZADO AZADO AZADO Nor-AZADO ABNO 1-MeAZADO TEMPO ketoABNO AZADOL

CuOTf (3)b CuCl (3) CuOTf (3)b CuCl (6) CuOTf (6)b CuOTf (6)b CuCl (6) CuCl (6) CuCl (6)

1 0.2 1 0.2 0.2 0.2 0.2 0.2 0.2

1 3 1 1 2 3 1 1 1

15 43 38 100 (94d) 51 89 100 (97d) 100 (94d) 100 (96d)

CuCl (6) CuCl (6) CuCl (6)

0.2 0.2 0.2

3 1 1

trace 100 (94d) 100 (95d)

a

Determined by GC. Conversion did not increase after an extended reaction time. b(CuOTf)2·benzene was used as the CuOTf source. c 4,4′-Dimethoxy-2,2′-bipyridyl and N-methylimidazole were used instead of bpy and DMAP, respectively. dYield determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard.

CuOTf, 4,4′-dimethoxy-2,2′-bipyridyl, and N-methylimidazole, which is reported by Stahl,7a resulted in only a 38% conversion (Table 1, entry 3). Increasing the amount of CuCl from 3 mol % to 6 mol % achieved complete conversion of the oxidation in 1 h (Table 1, entry 4). The same amount (6 mol %) of CuOTf gave lower conversion (Table 1, entries 5 and 6). Next, we compared the catalytic activities of nitroxyl radicals (Table 1, entries 7−11). Nitroxyl radicals of a less-hindered class, namely, Nor-AZADO,9 ABNO,10 and 1-Me-AZADO, 11 induced complete conversion, although highly hindered TEMPO did not promote any reactions (Table 1, entries 7− 10). An electron-deficient nitroxyl radical, ketoABNO,12 also showed good reactivity (Table 1, entry 11). AZADOL, the commercially available hydroxylamine variant of AZADO, showed the same reactivity as AZADO (Table 1, entry 12). Considering both reactivity and availability, we chose AZADO as the nitroxyl radical for evaluation of the substrate scope.11a With the optimum conditions determined, we evaluated their substrate scope (see Table 2). 1,3-Dithiane-containing cyclohexanol 1a, acyclic alcohol 1b, and even highly oxygenated alcohol 1c were chemoselectively oxidized to afford ketones 2a−2c in high yields. We then examined the oxidation of sulfide-containing alcohols 1d−1k. Both benzylic alcohol 1d and aliphatic alcohol 1e with phenylsulfide groups were efficiently oxidized to ketones 2d and 2e, respectively. The alcohol oxidation smoothly proceeded in the presence of other functional groups such as a silyl ether (1f), a tertiary amine, a nitrile (1g), a secondary benzylic amine (1h), and an ester (1i). The AZADO/copper-catalyzed oxidation of 1i gave a higher yield (79%) than the previously reported Swern oxidation (61%).2a The primary alcohols 1j and 1k (a biotin derivative) were respectively oxidized into aldehydes 2j and 2k in good yields.13 The oxidation of alcohols 1l−1o with protected/unprotected thiols were also examined. Alcohols 1l−1n, which contain thiols protected by PMB, Tr, and Fm groups, were oxidized into ketones 2l−2n efficiently without

a

Yields are for the isolated product. bThe reaction was performed at 0 °C. c0.1 M MeCN was used. d1-Me-AZADO was used instead of AZADO (see ref 5a). e0.1 M MeCN/DMF (1:1) was used as the solvent, and the product was isolated as the corresponding 2,4dinitrophenylhydrazone.

any deprotection, although CuCl is known to catalyze the deprotection of Tr groups on thiols.14 Application of AZADO/ copper oxidation to alcohol 1o with an unprotected thiol group B

DOI: 10.1021/acs.orglett.8b02528 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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promoted not alcohol oxidation, but disulfide formation to give only dihydroxydisulfide 1p as a detectable product even after an extended reaction time. In contrast, the alcohol-selective oxidation of isolated 1p smoothly proceeded to afford diketone 2p in high yield. To demonstrate the usefulness of the developed method, we compared its reaction efficiency with those of conventional methods, namely, PCC,15 Swern oxidation,16 DMP,17 TPAP,18 and PhI(OAc)2 with AZADO catalyst,11 using 1a and 1l as the model substrates (see Table 3). Although Swern, TPAP, and

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02528. Preparation of the substrates, procedure of alcohol oxidation, characterization data, and copies of spectra (PDF)

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Table 3. Comparison of Oxidation Methodsa

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yoshiharu Iwabuchi: 0000-0002-0679-939X Present Address † Department of Chemistry, University of California, Berkeley, CA 94720, USA.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by JSPS KAKENHI Grant Nos. 16H00998, 18H04232 (Precisely Designed Catalysts with Customized Scaffolding), 16H05072, and 15K07848, by Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under Grant No. JP18am0101100, and by Core to Core Program “Advanced Research Network for Asian Cutting-Edge Organic Chemistry” from JSPS.

a

Reaction conditions for PCC: PCC (1.5 equiv), MS4A (500 mg/1 mmol substrate), CH2Cl2 (0.2 M), rt. Reaction conditions for Swern: (COCl)2 (0.2 equiv), DMSO (4 equiv), Et3N (6 equiv), CH2Cl2 (0.2 M), − 78 °C to rt. Reaction conditions for DMP: Dess−Martin periodinane (1.5 equiv), CH2Cl2 (0.2 M), rt. Reaction conditions for TPAP: TPAP (5 mol %), NMO (1.5 equiv), MS4A (500 mg/1 mmol substrate), CH2Cl2 (0.1 M), rt. Reaction conditions for AZADO/ PhI(OAc)2: AZADO (3 mol %), PhI(OAc)2 (1.5 equiv), CH2Cl2 (1 M), rt; AZADO/Cu/air: AZADO (3 mol %), CuCl (6 mol %), bpy (3 mol %), DMAP (6 mol %), MeCN (0.2 M), air (open), rt. Yields in terms of product/time (remaining substrate) are shown. Yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal standard.

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REFERENCES

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AZADO/PhI(OAc)2 oxidations of 1a gave good to high yields of the corresponding ketone, PCC and DMP oxidations of 1a gave modest to low yields. All of these conventional oxidation methods did not efficiently oxidize alcohol 1l with an electronrich sulfide to afford the corresponding ketone, proceeding in only modest to low yields. Note that little or no substrate remained under these conditions. In contrast, AZADO/copper catalysis oxidized both alcohols in nearly quantitative yields. In summary, we have developed a convenient method for chemoselective oxidation of alcohols with oxidation-labile sulfur-containing functional groups into their corresponding carbonyl compounds. The combination catalysis of AZADO and CuCl oxidizes alcohols with dithianes, sulfides, and even a disulfide in good to high yields, employing ambient molecular oxygen as the terminal oxidant at room temperature. Comparison of the reaction efficiency of the developed method with conventional methods indicates the exceptional chemoselectivity of the newly developed protocol. We believe that the AZADO/copper-catalyzed aerobic alcohol oxidation will be applicable to the synthesis of many organosulfur compounds and will expand the diversity of the synthetic approaches to such compounds. C

DOI: 10.1021/acs.orglett.8b02528 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.8b02528 Org. Lett. XXXX, XXX, XXX−XXX