An Isolable and Bench-Stable Epoxidizing Reagent Based on Triazine

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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An Isolable and Bench-Stable Epoxidizing Reagent Based on Triazine: Triazox Kohei Yamada,† Yuki Igarashi,† Tatsuki Betsuyaku,† Masanori Kitamura,† Koki Hirata,† Kazuhito Hioki,‡ and Munetaka Kunishima*,† †

Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan ‡ Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 655-8586, Japan S Supporting Information *

ABSTRACT: A new triazine-based oxidizing reagent, 2-hydroperoxy-4,6diphenyl-1,3,5-triazine (Triazox), has been developed. The reagent can be synthesized from inexpensive starting materials and is a bench-stable solid that is isolable in pure form. Epoxidation of alkenes possessing acid-sensitive functionalities using Triazox proceeded in good to excellent yields. The accompanying nonacidic triazinone coproduct can be easily removed by filtration. These features indicate that Triazox is a practically useful oxidizing reagent.

T

1).9 The condensation of a carboxylic acid and an amine using DMT-MM consists of two steps: the formation of the acyloxytriazine intermediate followed by aminolysis. Computational study of tautomerization of 2,4-bis(benzyloxy)-6hydroxy-1,3,5-triazine indicated that the amide form is more stable than the imidate form by 9.69−11.18 kcal/mol.10 Thus,

he epoxidation of alkenes using a stoichiometric amount of nonmetal organic oxidant is a fundamental reaction for organic synthesis. 3-Chloroperbenzoic acid (m-CPBA) is a widely used reagent for this transformation because it is a convenient and relatively stable oxidant that is commercially available as a hydrate in approximately 80% purity.1 Because an acidic coproduct, 3-chlorobenzoic acid, is generated in the course of the reaction, a proton scavenger such as NaHCO3 must be added to successfully transform acid-sensitive starting materials to products. Dimethyldioxirane (DMDO) is an alternative milder oxidant for alkene epoxidation under neutral conditions and results in acetone as the coproduct.2 Therefore, DMDO is used for the epoxidation of glycals, of which the corresponding epoxides are unstable under acidic conditions.3 However, DMDO is inherently unstable and must be prepared immediately prior to use. Triphenylsilyl hydroperoxide was reported as an epoxidizing reagent that can be synthesized and isolated in pure form.4 In this case, an excess amount of the reagent (2 equiv) and long reaction time (1 day) were needed to obtain epoxides in a moderate yield, perhaps due to its low reactivity. The in situ generation of oxidants prepared from aqueous hydrogen peroxide and activating reagents, such as nitriles,5 carbodiimides,6 and other condensing reagents,7 has also been reported. However, the epoxidation reactions using these reagents must be conducted in an organic solvent miscible with water, such as MeOH, with specific attention to the pH, depending on the activating reagent. Therefore, an easy to use, bench-stable, and storable reagent for alkene epoxidation under mild conditions is still required. We have developed several triazine-based solid reagents that are bench-stable, low-cost, and easy to use: 4-(4,6-dimethoxy1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as a condensing reagent8 and 2,4,6-tris(alkoxy)-1,3,5triazine (TriAT) as acid-catalyzed alkylating reagents (Figure © XXXX American Chemical Society

Figure 1. Concept and design of a new oxidizing reagent based on triazine chemistry. Received: February 15, 2018

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DOI: 10.1021/acs.orglett.8b00560 Org. Lett. XXXX, XXX, XXX−XXX

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that Triazox did not contain a water molecule of hydration. Thus, Triazox can be accurately weighed and used under nonaqueous conditions. Differential scanning calorimetry measurements of Triazox revealed that the exothermic onset temperature (To) and the heat of decomposition (Q), which can be a measure of sensitivity and severity for potentially explosive materials, were 110 °C and 213 cal/g, respectively. Considering that the average To and Q of nine organic peroxides measured are 117 °C and 362 cal/g, respectively,12 and To and Q of m-CPBA are 88 °C and 472 cal/g, respectively, Triazox seems to be a relatively mild reagent. Moreover, by analogy with the data that the pKa of 4,6-dimethoxy-1,3,5triazin-2(1H)-one is determined to be 6.88 (Figure S1), 4,6diphenyl-1,3,5-triazin-2(1H)-one (3, see Table 2), which is the coproduct of epoxidation with Triazox, is considered to be less acidic than 3-chlorobenzoic acid (pKa: 3.83), the coproduct of m-CPBA, because the electron-withdrawing ability of the phenyl goup is less than that of methoxy group (Hammett’s substituent constant (σm), phenyl: 0.06, methoxy: 0.12).13,14 Therefore, the reaction could be carried out under nearly neutral conditions. These results indicate that Triazox is a more user-friendly oxidant than m-CPBA and DMDO (Table 1).15 Upon treatment with Triazox in dichloromethane (CH2Cl2) at room temperature for 1 h, 1-phenylcyclohexene (1a) underwent epoxidation to give the desired epoxide 2a in 95% yield (Table 2, entry 1). Further screening of the epoxidation in

the aminolysis step is considered favorable because a more stable triazinone structure is formed from the acyloxytriazine structure (Figure 1A). Similarly, the acid-catalyzed alkylation of an alcohol with TriATs can be also promoted by the formation of triazinone structure (Figure 1B).9,9a−c On the basis of these works, we envisioned that a triazinyl hydroperoxide would work as an oxidizing reagent and also have the aforementioned desirable features (Figure 1C). Herein, we report the development of a new oxidizing reagent based on triazine chemistry. When 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was treated with a peroxide anion prepared from hydrogen peroxide and NaOH, thin-layer chromatography indicated that CDMT disappeared. However, the desired triazinyl hydroperoxide was not obtained after the acidic workup, perhaps because of the high solubility of the product in water and an unwanted substitution side reaction at the methoxy groups (Scheme 1A). Scheme 1. Synthesis of Triazox

Table 2. Solvent Screening for Epoxidation Using Triazox

entry 1 2 3 4 5 6 7 a

Therefore, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDPT) was used as a starting material to decrease water solubility and to prevent undesired substitution.11 After optimization of conditions, 2-hydroperoxy-4,6-diphenyl-1,3,5-triazine (Triazox) could be obtained in 78% yield (Scheme 1B). Triazox is an airstable, non-hygroscopic solid that can be stored in a freezer for at least six months without any decomposition. Irritating or allergenic properties were not observed in our laboratory. The structure of Triazox was confirmed by X-ray crystal structure analysis (Scheme 1C). Moreover, elemental analysis indicated

solvent CH2Cl2 toluene AcOEt MeOH MeCN DME DMF

time (h)

yielda (%)

1 1 1 3 3 5 8

95 (92) 96 94 60 94 90 80

b

DNc 1 0.1 17.1 19 14 24 26.6

NMR yield. bIsolated yield. cSee ref 20a.

different solvents was conducted. The reactions in toluene and ethyl acetate proceeded smoothly to afford 2a in excellent yields (entries 2 and 3). The yield of product decreased in MeOH (60%, entry 4). When acetonitrile and dimethoxyethane (DME) were used, longer reaction times (3 and 5 h, respectively) were necessary to obtain good yields (entries 5 and 6). Epoxidation in DMF led to inferior results (8 h, 80%, entry 7).

Table 1. Comparison of Triazox with m-CPBA and DMDO m-CPBA availability coproduct stock form exothermic onset temp (To) (°C) heat of decomposition (Q) (cal/g)

commercially available 3-chlorobenzoic acid (pKa: 3.83) in refrigerator solid containing coproduct and water (purity: 80%) 88 472 B

DMDO

Triazox

freshly prepared before use acetone (neutral) difficult to store over long periods of time acetone solution (∼10 mM)

easily synthesized at a low cost triazinone (pKa: >6.59) in refrigerator crystalline solid 110 213 DOI: 10.1021/acs.orglett.8b00560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Triazinone 3 was generated as the coproduct and could be easily removed by filtration, owing to its low solubility toward both water and nonpolar organic solvents (81% in the case of Table 2, entry 1). Reuse of the coproduct is desired from the viewpoint of economy. Conversion of recovered 3 to CDPT was accomplished through chlorination using POCl3 (Scheme 2).16

The substrate scope for epoxidation with Triazox was investigated (Table 3). The reactions of trans-stilbene (1b) and cis-stilbene (1c) proceeded stereospecifically to provide the corresponding epoxides 2b and 2c in excellent yields (93%, 92%, respectively, entries 1 and 2). Monosubstituted alkenes 1d and 1e also gave good yields (92%, 87%, respectively, entries 3 and 4), although a prolonged reaction time (48 h) was required in the case of allyl ether 1e. Oxidation of electron-deficient cinnamate 1f resulted in a moderate yield (64%) after a prolonged reaction time (entry 5). Dihydronaphthalene (1g) afforded the epoxide 2g without the production of naphthalene (entry 6). Alkenes possessing a hydroxy group provided excellent yields (entries 7 and 8). Similar to epoxidation using m-CPBA,17 cyclohexenol (1j) underwent stereoselective epoxidation to yield 2j (cis/trans = 81:19, entry 9), owing to neighboring group participation. The initial screening of

Scheme 2. Conversion of 3 to CDPT

Table 3. Scope and Limitations of Epoxidation Using Triazox

a Isolated yield. bGC yield. cLiClO4 (1.0 equiv) was added. dThe reaction was conducted at −20 °C. eMgCl2 (1.0 equiv) was added. fCaBr2 (1.0 equiv) was added. gZnF2 (1.0 equiv) was added. hReaction was conducted at 40 °C. iThe reaction was conducted in toluene at 0 °C. jNMR yield.

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respectively). (4) It was reported that the reaction mechanisms of epoxidation using perimidic acids, which can be considered as a partial structure of Triazox, are similar to those using peracids.21 By analogy to the mechanisms of epoxidation using peracids and perimidic acids,22 the epoxidation using Triazox would proceed through a “spiro transition state” involving an intramolecular hydrogen bonding between the hydroperoxy proton and the nitrogen and a nucleophilic attack by the πbond of alkenes to σ* of the O−O bond (Scheme 4).

additives for improving stereoselectivity indicated that addition of 1.0 equiv of LiClO4 was beneficial (cis/trans = 85:15, entry 10). Moreover, when the reaction was conducted at −20 °C, the stereoselectivity increased to 94:6 (94%, entry 11). Other metals, such as Mg, Ca, and Zn, did not improve the yield or selectivity (entries 12−14, see also Table S1). In the case of a cyclohexane possessing an exomethylene moiety (1k), products 2k were obtained as a 66:34 mixture (entry 15). 18 Tetraphenylethene 1l underwent epoxidation at 40 °C for 30 h to give 2l in 89% yield (entry 16). High yields could be obtained when versatile protecting groups of the hydroxy group, such as tert-butyldimethylsilyl (TBS) and acetyl (Ac) groups, were present in the alkenes (entries 17 and 18). pMethoxybenzyl (PMB)-protected cinnamyl alcohol (1o), which is prone to undergo deprotection under oxidative or acidic conditions, was successfully epoxidized (entry 19). It is worth noting that the epoxidation of glycal 1p was achieved, and the corresponding epoxide 2p was obtained in 73% yield (entry 20). Triazox was also tested for Baeyer−Villiger oxidation reactivity using aromatic aldehyde 4 and ketone 8. The reaction of naphthylaldehyde (4) with Triazox in the presence of NaHCO3 proceeded to give formate 5, which was isolated as 2-naphthol (7) after subsequent hydrolysis and 2-naphthoic acid 6 (78% and 12% yield, respectively, Scheme 3A). On the

Scheme 4. Plausible Reaction Mechanisms for Epoxidation Using Triazox

In conclusion, we developed a practically useful triazinebased oxidizing reagent, Triazox. It is a non-hygroscopic, stable, anhydrous solid that can be weighed accurately. Moreover, the epoxidation of alkenes possessing acid- or base-labile functionalities proceeds in good to excellent yields. The userfriendly nature and mild reactivity make Triazox suitable for application in many fields, such as natural product synthesis and medicinal chemistry.

Scheme 3. Baeyer−Villiger Oxidation Using Triazox

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00560. General experimental procedure and characterization data of the compounds (PDF) Accession Codes

CCDC 1815627 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

other hand, when benzophenone 8 was used as a substrate, only a trace amount of the corresponding ester 9 was obtained (Scheme 3B). These results suggest that Triazox has mild reactivity. The epoxidation using Triazox is considered to proceed through reaction mechanisms similar to that using peracids for the following reasons: (1) Epoxidation with peracids occurred at slower rates in the solvent with basic oxygen than in nonbasic solvents due to disruption of the intramolecular hydrogen bond between the hydroperoxy proton and the carbonyl oxygen.19 This internal hydrogen bond is important for the epoxidation to proceed. In the case of Triazox, the reactions in solvents with low donor number (DN),20 which is a quantitative measure of Lewis basicity, were completed faster than those in solvents with relatively high donor number (Table 2). (2) trans- and cisstilbene underwent stereospecific epoxidation, which indicates that the reaction would proceed through concerted mechanisms, but not stepwise mechanisms. (3) As is the case with the reaction with peracids,1 the reaction rate of electron-rich alkenes, such as 1a and 1p (1 h), were faster than that of electron-poor alkenes, such as 1e and 1f (48 h, 72 h,

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kohei Yamada: 0000-0002-7857-1474 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Hidetoshi Miura for useful discussions. This work was partially supported by JSPS KAKENHI Grant Nos. 17H03970 and 16K08160 and a Grant-in-Aid for Young Scientists from the Hokuriku Bank, Ltd. D

DOI: 10.1021/acs.orglett.8b00560 Org. Lett. XXXX, XXX, XXX−XXX

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(22) (a) Bach, R. D.; Owensby, A. L.; Gonzalez, C.; Schlegel, H. B.; McDouall, J. J. W. J. Am. Chem. Soc. 1991, 113, 2338. (b) Bach, R. D.; Dmitrenko, O. J. Phys. Chem. A 2003, 107, 4300.

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DOI: 10.1021/acs.orglett.8b00560 Org. Lett. XXXX, XXX, XXX−XXX