δ-Regioselective heteroarylation of free alcohols through 1,5-hydrogen-atom transfer

Abstract

An efficient silver-catalyzed δ-regioselective C(sp³)–H heteroarylation of free alcohols has been developed. Various alcohols reacted with quinolines, isoquinoline, pyridines, pyrimidine, phthalazine, 4-hydroxyquinazoline, acridine, quinoxaline and pyrazine to give the corresponding C(sp²)–H alkylation products in 31–89% yields. Notably, all types (1°, 2°, and 3°) of δ-C(sp³)–H bonds in the alcohols could be regioselectively activated. This protocol provides a platform to access divergent functionalizations of alcohols and heteroaryls by forming the challenging δ-selective C(sp³)–C(sp²) bond.

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Introduction

Alcohols and their derivatives serve as significant building block compounds in chemistry and pharmaceutical science.¹ Many groups have developed direct C–O etherification,² α-oxy C(sp³)–H heteroarylation,³ α-C(sp³)–H alkylation or arylation of alcohols⁴ and other types of functionalizations of α-oxy C(sp³)–H bonds.⁵ According to the bond dissociation energy,⁶ the C–H bonds distal to the hydroxyl group have much lower reactivity than the proximal ones. In 1960, Barton discovered that alkoxyl radicals could lead to 1,5-hydrogen atom transfer (1,5-HAT) to activate the remote C–H bond.⁷ However, the HAT process triggered by alkoxy radicals is still a formidable challenge, due to the strong dissociation energy of the alcoholic O–H bond (∼105 kcal mol⁻¹) and high oxidation potential of alcoholic O–H bonds.⁸

Although significant challenges lie ahead,⁹ functionalizing remote unactivated C(sp³)–H bonds of free aliphatic alcohols has been attractive to chemists in the past few decades. A series of functionalization reactions such as amination,¹⁰ oxime cyanation,¹¹ and mono-/di-halogenation¹² have been realized on the organic synthesis stage in recent years.

Electron-deficient N-heteroaromatics play an important role in the field of bioactive molecules and drugs.¹³ Notably, a major breakthrough has been achieved by the Zhu group, who disclosed remote C(sp³)–H heteroarylation of free alcohols using the PhI(OTFA)₂ system under visible-light catalysis (Scheme 1A).¹⁴ Chen further developed the Ru(bpy)₃Cl₂/PFBI-OH catalyzed δ-C(sp³)–H heteroarylation of free aliphatic alcohols (Scheme 1B).¹⁵

Scheme 1 Remote C(sp³)–H heteroarylation of free alcohols.

Herein, we describe a silver-catalyzed remote C(sp³)–H (primary, secondary, and tertiary) heteroarylation of free alcohols (Scheme 1C).

Results and discussion

We initiated our research by exploring the reaction conditions for the δ-selective C(sp³)–H heteroarylation of 4-methyl quinoline (1a) with n-pentanol (2a) (Table 1). After considerable experimentation, we were pleased to obtain the heteroarylated product 3a in 79% yield with AgNO₃ as the catalyst, K₂S₂O₈ as the oxidant, and TFA as the acid in acetone/H₂O (1 mL/1 mL) under a nitrogen atmosphere at 50 °C for 24 h (Table 1, entry 1). A lower yield was obtained without the application of TFA or using 1.0 equiv. of TFA (Table 1, entries 2 and 3). In order to improve the electrophilicity of 1a, other acids including TfOH, TCA, HCl, and H₂SO₄ were screened, but the yields showed no significant improvement (Table 1, entry 4). Furthermore, varieties of mixed solvents, such as CH₃CN/H₂O, DMSO/H₂O, DCM/H₂O, DMF/H₂O and 1,4-dioxane/H₂O, were examined, and acetone/H₂O was found to be the best solvent (Table 1, entries 5–9). Water was vital to dissolve AgNO₃ and K₂S₂O₈ (Table 1, entry 10). Other kinds of silver salts such as Ag₂CO₃ and AgCOOCF₃ gave 3a in moderate yields; AgCl and CuCl₂ had no efficiency (Table 1, entry 11). The stoichiometries of AgNO₃ and K₂S₂O₈ also had a major influence on this reaction (Table 1, entries 12–15). Further temperature screening showed that 50 °C was the most suitable temperature for the reaction (Table 1, entry 16).

Table 1 Optimization of reaction conditions^a

Entry	Deviation from the standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), AgNO3 (20 mol%), K2S2O8 (2.0 equiv.), TFA (2.0 equiv.), acetone/H2O (1 mL/1 mL), stirred at 50 °C under N2 (1 atm) for 24 h. b Isolated yields based on 1a.
1	None	79
2	Without TFA	59
3	1.0 equiv. of TFA	67
4	TfOH, TCA, HCl, or H2SO4 as the acid	73, 67, trace, 67
5	CH3CN/H2O as the solvent	45
6	DMSO/H2O as the solvent	49
7	DCM/H2O as the solvent	64
8	DMF/H2O as the solvent	44
9	1,4-Dioxane/H2O as the solvent	47
10	Acetone as the solvent	N.R.
11	AgCl, Ag2CO3, AgCOOCF3, or CuCl2 as the catalyst	N.R., 67, 75, N.R.
12	Without AgNO3	N.R.
13	Without K2S2O8	N.R.
14	1.5 equiv. of K2S2O8	60
15	10 mol% of AgNO3	61
16	25 °C, 70 °C	50, 70

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With the optimized reaction conditions established, we began to investigate the generality of the protocol (Scheme 2). At first, diverse electron-deficient N-heteroaromatics were tested under the standard conditions. Quinolines with para-substituents such as an electron-donating group (Me) or electron-withdrawing groups (Br, Cl) gave the desired alkylation products 3a, 3b, 3c and 3d in 51–79% yields. Pleasingly, the aldehyde group was tolerated in this oxidant system (3e). Quinolines with ortho-substitutions such as Me, OMe, Cl and CO₂Et gave 3f, 3g, 3h and 3i in 57–86% yields. Unsubstituted quinoline could react with alcohols, giving a mixture of ortho and para substitution products (3j, o/p = 1 : 1). Isoquinoline reacted with n-pentanol to give a 1-alkylated product (3k). Moreover, 4-CH₃ and 4-CN substituted pyridine, 2-chloropyrimidine and phthalazine only afforded mono-functionalization products in moderate yields, along with some unreacted materials (3l, 3m, 3n and 3o). Other N-heteroaromatics such as 4-hydroxyquinazoline and acridine gave a 2-substituted product (3p) and a 9-substituted product (3q), respectively. Additionally, 2-chloroquinoxaline and 2,3,5-trimethylpyrazine could be converted into the corresponding products both in 81% yields (3r, 3s). Unfortunately, when 4-hydroxyquinoline, benzothiazole and benzoxazole were used, we failed to obtain the corresponding Minisci-type products (3t, 3u, and 3v). In general, this protocol indicated a broad scope of heteroaryls.

Scheme 2 Scope of N-heteroarenes. Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), AgNO₃ (20 mol%), K₂S₂O₈ (2.0 equiv.), TFA (2.0 equiv.), acetone/H₂O (1 mL/1 mL), stirred at 50 °C under N₂ (1 atm) for 24 h, isolated yields.

In addition, diverse classes of alcohols were investigated (Scheme 3). In most cases, alcohols reacted with 2-methylquinoline well to afford the Minisci-type products in moderate to excellent yields. The unactivated primary C(sp³)–H bond in 1-butanol was readily transformed, delivering the product 3w in 61% yield. Other simple aliphatic primary alcohols containing secondary δ-C(sp³)–H bonds were suitable substrates, and the corresponding products were obtained in 73–89% yields (3x, 3y, 3z). Notably, the tertiary δ-C(sp³)–H bond with significant steric hindrance could also be regioselectively activated to obtain the product (3aa). Besides, secondary alcohols were applicable to generate alkoxy radicals to obtain the heteroaryl products (3ab, 3ac, 3ad). The reaction with cyclic C(sp³)–H bonds proceeded smoothly (3ae). Remarkably, the 1,5-HAT exclusively occurred even in the presence of the more reactive allylic and benzylic C–H bonds (3af and 3ag), showing excellent regioselective control. 4-Phenyl-1-butanol, containing the benzylic C–H bond, was oxidized to 4-hydroxy-1-phenylbutan-1-one in this oxidation system. Additionally, the substrates containing ester and amide groups did not degrade the activity (3ag and 3ah). The C(sp³)–H bonds adjacent to the oxygen atom were also readily functionalized, giving 3ai in 45% yield. Unfortunately, when tertiary alcohol 2-methylpentan-2-ol was used, only 4-methylquinoline was recovered.

Scheme 3 Scope of alcohols. Reaction conditions: 1a (0.3 mmol), 2 (0.9 mmol), AgNO₃ (20 mol%), K₂S₂O₈ (2.0 equiv.), TFA (2.0 equiv.), acetone/H₂O (1 mL/1 mL), stirred at 50 °C under N₂ (1 atm) for 24 h, isolated yields.

Then we explored the reaction efficiency on a larger scale using 1.15 g of 1f, and 3f was isolated in 80% yield (Scheme 4).

Scheme 4 Scale-up of the reaction.

A series of control experiments were conducted to investigate the preliminary mechanism. No desired product 3a was detected when the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the reaction mixture under the standard conditions (Scheme 5a and b). Then, we replaced 1-butanol with di-n-butyl ether and discovered that the transformation was entirely inhibited (Scheme 5c). The above experiments indicated that this kind of silver-catalyzed reaction might start from an oxygen radical.

Scheme 5 Control experiment.

We thus postulated a plausible mechanism based on the results of our group and others¹⁶ (Scheme 6). At first, alcohol 2 coordinated with Ag^II, which was oxidized from Ag^I by K₂S₂O₈, to form intermediate 4. Then, intermediate 4 was activated to form alkoxyl radical 5, generating Ag^I. Subsequently, the N-heteroaromatic salt 6 trapped 7, which was triggered by 5 through 1,5-HAT, generating the radical cation 8. After a sulfate radical anion obtained a hydrogen atom from 8, the alkylated product 3 was ultimately formed.

Scheme 6 Postulated mechanism.

Conclusions

In summary, a general protocol for direct silver-catalyzed δ-regioselective C(sp³)–H heteroarylation of free alcohols through 1,5-hydrogen atom transfer has been developed. This simple catalytic system is suitable for a diverse range of N-heteroarenes and alcohols under mild reaction conditions. In particular, activated and unactivated (1°, 2°, and 3°) δ-C(sp³)–H bonds of alcohols can be regioselectively converted into heteroarylated adducts. Furthermore, it may be worthwhile to provide a reasonable method for medicinal synthesis in the near future.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

We are grateful to the Natural Science Foundation of China (No. 21776254) and Natural Science Foundation of Zhejiang Province (No. LQ 20B060006) for financial help.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, NMR spectra. See DOI: 10.1039/d0qo01238f

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