Oxidative C–N Bond Formation of Isochromans Using an Electronically Tuned Nitroxyl Radical as Catalyst

Abstract

The cross-dehydrogenative coupling between isochromans and nucleophiles using an electronically tuned nitroxyl radical catalyst, which effectively promotes the oxidation of benzylic ethers, has been investigated. Using sulfonamides as a nucleophile, modification of isochromans via oxidative C–N bond formation has been achieved at ambient temperature.

Keywords

isochroman - cross-dehydrogenative coupling - nitroxyl radical - C–N bond formation - organocatalyst - oxidation

Owing to their attractive properties, isochromans, which are cyclic benzyl ethers that are frequently found in natural and synthesized bioactive compounds, have attracted considerable research attention (Figure [1]).[1] To date, numerous synthetic methods have been reported for the modification of isochromans. The oxidative transformation of the benzylic carbon of isochromans has been widely reported as one of the most effective ways to synthesize isochromans functionalized at the α-position with respect to the oxygen atom. Indeed, a variety of transition-metal-catalyzed[2] [3] and organocatalytic[4,5] methods have already been reported to achieve this transformation. Nitroxyl-type catalysts such as 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO),[6] 2-azaadamantane N-oxyl (AZADO),[7] and their derivatives have frequently been employed as organocatalysts for the oxidation of alcohols. Due to their high level of safety and environmentally benign nature, these catalysts are even used in process chemistry.[8] Although examples of the use of nitroxyl-type catalysts for the oxidation of other functional groups are still scarce,[9] the oxidation of isochromans under acidic conditions using TEMPO sulfonate derivative 1 has recently been reported.[4a] In addition, Foss and co-workers have reported the oxidation of cyclic ethers with TEMPO in the presence of flavin and nitromethane,[4c] while Muramatsu and co-workers have developed oxidative C–C, C–N, and C–S bond-formation reactions using AZADOL, which is a reduced form of AZADO (Scheme [1a]).[5b] Unfortunately, these catalytic transformations using TEMPO and AZADO require elevated temperatures,[4c] [5b] and further improvement is required to realize practical applications.

Figure 1 Natural products and bioactive agents that contain an isochroman moiety functionalized on the benzylic carbon

We have previously developed a highly reactive nitroxyl-radical catalyst 2 (Scheme [1]), whose reactivity can be electronically tuned by introducing electron-withdrawing ester groups adjacent to the nitroxyl group.[10] [11] This catalyst oxidizes acyclic benzylic ethers such as p-methoxybenzyl and benzyl ethers at room temperature, thus achieving the deprotection of benzyl-type protecting groups for alcohols.[12] We also applied the electronically tuned catalyst 2 to the oxidation of isochromans to synthesize isochromanones (Scheme [1b]).[4d] The oxidative transformations of these benzylic ethers proceed rapidly at room temperature. In this paper, we report the modification of isochromans via oxidative C–N bond formation using nitroxyl-radical catalyst 2 at ambient temperature (Scheme [1c]).

Scheme 1 Natural products and bioactive agents that contain an isochroman moiety functionalized on the benzylic carbon

As part of our efforts to develop a catalytic cross-dehydrogenative coupling using isochromans as substrates, we first investigated the optimal reaction conditions in terms of base and solvent (Table [1]). Treatment of isochroman with 1.2 equivalents of phenyliodine bis(trifluoroacetate) (PIFA), 4 equivalents of potassium carbonate, and 2 equivalents of p-toluenesulfonamide in the presence of 10 mol% of racemic 2 in CH₂Cl₂ at room temperature resulted in the rapid formation of 3, which contains a C–N bond, in 85% yield (entry 1).[13] [14] While the yield was slightly reduced when no base was used (entry 2), the use of sodium bicarbonate had a similar effect on the improvement of yield as the use of potassium carbonate (entry 3). Pyridine was also tested as an organic base, which is soluble in dichloromethane, but the reaction did not proceed (entry 4).[15] Next, we tried to identify the optimal co-oxidant. Although [hydroxy(tosyloxy)iodo]benzene (HTIB) furnished 3 in 72% yield (entry 5), iodobenzenediacetate (PIDA) and trichloroisocyanuric acid (TCCA), which have been used for the oxidation of nitroxyl radicals,[16] produced hardly any of the coupling product 3 (entries 6 and 7) due to their relatively low reactivity. A screening of solvents revealed that 1,2-dichloroethane afforded results similar to those obtained using dichloromethane (entry 8), whereas more polar solvents such as THF and MeCN resulted in lower yields and recovery of starting material (entries 9 and 10). Meanwhile, attempts to use diethyl malonate, TMSCN, and 2-methylbenzenethiol as nucleophiles for the oxidative coupling to achieve C–C or C–S bond formation did not afford the desired products.

Table 1 Optimization of the Reaction Conditions

Entry	Variation from the ‘standard’ conditions	Yield (%)a
1	none	85
2	no K2CO3	73
3	NaHCO3 instead of K2CO3	79
4	pyridine instead of K2CO3	<5
5	HTIB instead of PIFA	72
6	PIDA instead of PIFA	<5
7	TCCA instead of PIFA	<5
8	ClCH2CH2Cl instead of CH2Cl2	85
9	THF instead of CH2Cl2	<5
10	MeCN instead of CH2Cl2	<5

^a Yield determined by ¹H NMR analysis of the crude reaction residue using methyl 3,5-dinitrobenzoate as an internal standard.

As compound 3 was obtained via the oxidative coupling of isochroman and p-toluenesulfonamide, we subsequently investigated the substrate scope of this reaction (Table [2]). First, the effect of the substituent on the benzene ring was studied. An electron-donating methyl group at the ortho-, meta-, or para-position and a methoxy group at the para-position successfully afforded the corresponding coupling products 3–6 in good to high yield (63–87%). Although benzenesulfonamides without substituents and with a chloro group at the para-position gave 7 and 8 in moderate yield (49% and 46%, respectively). A sulfonamide with a nitro group at the meta-position, that was less nucleophilic than above, afforded 9 in low yield (35%). Then, alkylsulfonamides were investigated as nucleophiles, which revealed that methyl sulfonamide afforded 10 in 53% yield, whereas trifluoromethyl sulfonamide did not furnish the corresponding product 11, probably due to the instability of 11 in the presence of the highly electron-withdrawing trifluoromethanesulfonyl group. Next, several N-methylsulfonamides 12–14 were synthesized, although the yields of the products 12 and 13 were lower than the corresponding protonated sulfonamides 3 and 10, possibly due to the steric hindrance of the nucleophiles. We also tested dibenzenesulfonimide as a nucleophile; unfortunately, the desired product 15 was not obtained, probably due to the high leaving-group properties of the sulfonimide. The effect of the presence of substituents on the phenyl ring of the isochromans was then investigated. An electron-rich arene bearing a methyl substituent yielded the corresponding product 16 in low yield, possibly because 16 is unstable due to the good stability of the oxocarbenium cation produced from 7-methylisochroman. In contrast, the electron-deficient fluorine-containing derivative afforded 17 in good yield (62%). We also tested a substrate with a naphthalene ring; however, the corresponding coupling product 19 was obtained only in low yield (26%).

Table 2 Substrate Scope

^a Isolated yield.

A plausible mechanism for the oxidation of isochromans induced by 2 is shown in Scheme [2]. First, oxoammonium A is formed via the oxidation of nitroxyl radical 2 by PIFA. The rate-determining hydride transfer from the benzylic C–H bond of the isochromans to the oxygen of oxoammonium A affords hydroxyamine B and oxocarbenium cation C.[4d] [17] Subsequent addition of the sulfonamide to C then leads to hemiaminal ether D.

Scheme 2 Plausible mechanism for the oxidation of isochromans promoted by nitroxyl radical 2

In conclusion, we have investigated the efficacy of the 2/PIFA system for the cross-dehydrogenative coupling of isochromans.[18] [19] Although it is generally not effective for several C–C bond formations, this system enables the fast formation of C–N bonds using sulfonamides as a nucleophile at room temperature. Further studies on the derivatization of the coupling products by taking advantage of the reactivity of sulfonamides are in progress in our laboratories.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1a Grove JF, Pople J. J. Chem. Soc., Perkin Trans. 1 1979; 2048
• 1b Papillon JP. N, Adams CM, Hu Q-Y, Lou C, Singh AK, Zhang C, Carvalho J, Rajan S, Amaral A, Beil ME, Fu F, Gangl E, Hu C.-W, Jeng AY, LaSala D, Liang G, Logman M, Maniara WM, Rigel DF, Smith SA, Ksander GM. J. Med. Chem. 2015; 58: 4749
• 1c Zhang H, Matsuda H, Kumahara A, Ito Y, Nakamura S, Yoshikawa M. Bioorg. Med. Chem. Lett. 2007; 17: 4972

For examples of the oxidation of isochromans using transition-metal catalysts, see
• 2a Catino AJ, Nichols JM, Choi H, Gottipamula S, Doyle MP. Org. Lett. 2005; 7: 5167
• 2b Gonzalez de Castro A, Robertson CM, Xiao J. J. Am. Chem. Soc. 2014; 136: 8350
• 2c Wang Y, Kuang Y, Wang Y. Chem. Commun. 2015; 51: 5852
• 2d Yang Y, Ma H. Tetrahedron Lett. 2016; 57: 5278
• 2e Tanaka H, Oisaki K, Kanai M. Synlett 2017; 28: 1576
• 2f Hong C, Ma J, Li M, Jin L, Hu X, Mo W, Hu B, Sun N, Shen Z. Tetrahedron 2017; 73: 3002

For examples of cross-dehydrogenative coupling reactions using transition-metal catalysts, see:
• 3a Zhang Y, Li C.-J. Angew. Chem. Int. Ed. 2006; 45: 1949
• 3b Richter H, Rohlmann R, Mancheño OG. Chem. Eur. J. 2011; 17: 11622
• 3c Zhang Z, Tu Y.-Q, Zhang X.-M, Zhang F.-M, Wang S.-H. Org. Chem. Front. 2019; 6: 2275

For examples of the oxidation of isochromans using organocatalysts, see:
• 4a Zhang Z, Gao Y, Liu Y, Li J, Xie H, Li H, Wang W. Org. Lett. 2015; 17: 5492
• 4b Thatikonda T, Deepake SK, Kumar P, Das U. Org. Biomol. Chem. 2020; 18: 4046
• 4c Thapa P, Hazoor S, Chouhan B, Vuong TT, Foss FW. Jr. J. Org. Chem. 2020; 85: 9096
• 4d Hamada S, Yano K, Kobayashi Y, Kawabata T, Furuta T. Tetrahedron Lett. 2021; 83: 153404

For examples of the cross-dehydrogenative coupling of isochromans using organocatalysts, see:
• 5a Muramatsu W, Nakano K, Li C.-J. Org. Lett. 2013; 15: 3650
• 5b Muramatsu W, Nakano K. Org. Lett. 2015; 17: 1549
• 5c Mao Y, Cao M, Pan X, Huang J, Li J, Xu L, Liu L. Org. Chem. Front. 2019; 6: 2028
• 6a de Nooy AE. J, Basemer AC, van Bekkum H. Synthesis 1996; 1153
• 6b Tebben L, Studer A. Angew. Chem. Int. Ed. 2011; 50: 5034
• 6c Leifert D, Studer A. Chem. Rev. 2023; 123: 10302
• 7a Iwabüchi Y. Chem. Pharm. Bull. 2013; 61: 1197
• 7b Shibuya M. Tetrahedron Lett. 2020; 61: 151515
• 8a Ciriminna R, Pagliaro M. Org. Process Res. Dev. 2010; 14: 245
• 8b Sasano Y, Sato H, Tadokoro S, Kozawa M, Iwabüchi Y. Org. Process Res. Dev. 2019; 23: 571
• 9 Nagasawa S, Sasano Y, Iwabüchi Y. Heterocycles 2022; 105: 61
• 10 Hamada S, Furuta T, Wada Y, Kawabata T. Angew. Chem. Int. Ed. 2013; 52: 8093
• 11 Catalyst 2 can be used in the oxidation of isochroman on a gram scale; for details, see ref. 4d
• 12a Hamada S, Sugimoto K, Elboray EE, Kawabata T, Furuta T. Org. Lett. 2020; 22: 5486
• 12b Hamada S, Sumida M, Yamazaki R, Kobayashi Y, Furuta T. J. Org. Chem. 2023; 88: 12464
• 13 A small amount of 1-isochromanone was also produced as a byproduct.
• 14 In the absence of 1, no product was obtained

Weak inorganic bases probably neutralize trifluoroacetic acid derived from PIFA slowly in dichloromethane, whereas organic bases are much faster. The differences in solution acidity may affect the reactivity and selectivity of the oxidation catalyzed by 2. For examples of the acidity affecting the reactivity of the oxidation mediated by nitroxyl-radical catalysts or oxoammonium salts, see:
• 15a Bailey WF, Bobbitt JM, Wiberg KB. J. Org. Chem. 2007; 72: 4504
• 15b Hamada S, Sakamoto K, Miyazaki E, Elboray EE, Kobayashi Y, Furuta T. ACS Catal. 2023; 13: 8031
• 16a De Mico A, Margarita R, Parlanti L, Vescovi A, Piancatelli G. J. Org. Chem. 1997; 62: 6974
• 16b De Luca L, Giacomelli G, Porcheddu A. Org. Lett. 2001; 3: 3041
• 17 The hydride-transfer step has already been proposed as the rate-determining step in the oxidation of isochromans to the corresponding oxocarbenium cations; for details, see ref. 4d.
• 18 General Procedure PIFA (103 mg, 0.240 mmol) was added to a mixture of isochroman (26.8 mg, 200 mmol), 2 (4.6 mg, 20 μmol), K₂CO₃ (111 mg, 0.800 mmol), and sulfonamide (0.400 mmol) in DCM (2.0 mL). The resulting mixture was stirred under N₂ atmosphere for 2 h at room temperature. Then, the reaction was quenched with saturated aq. Na₂S₂O₃ and extracted with CHCl₃. Subsequently, the organic layer was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography.
• 19 Representative Spectral Data N-(Isochroman-1-yl)-4-methyl­benzenesulfonamide (3)1 The title compound 3 (38.0 mg, 63%) was synthesized from isochroman (26.8 mg, 0.200 mmol) and 4-methylbenzenesulfonamide (68.5 mg, 0.400 mmol). Colorless solid; mp 178–181 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 7.26–7.18 (m, 3 H), 7.08 (d, J = 7.2 Hz, 1 H), 6.10 (d, J = 8.6 Hz, 1 H), 5.40 (d, J = 8.6 Hz, 1 H), 3.73–3.57 (m, 2 H), 2.85 (ddd, J = 15.9, 9.7, 6.0 Hz, 1 H), 2.61 (dt, J = 16.7, 4.0 Hz, 1 H), 2.44 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.40, 138.79, 134.54, 132.82, 129.52, 128.87, 128.47, 127.25, 126.84, 126.76, 79.91, 58.76, 27.58, 21.63. IR (ATR) 3202, 1328, 1157, 748 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₇NNaO₃S: 326.0827; found: 326.0829.

Publication History

Received: 31 March 2024

Accepted after revision: 24 April 2024

Article published online:
13 May 2024