Copper-catalyzed oxidative esterification of unactivated C(sp³)–H bonds with carboxylic acids via cross dehydrogenative coupling

Abstract

An effective copper-catalyzed esterification of unactivated (non-benzylic and allylic) C(sp³)–H bonds of hydrocarbons with Selectfluor as an oxidant has been developed. This reaction could provide a direct, new and useful strategy for the synthesis of esters and alkyl alcohols by ester hydrolysis.

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Esterification is one of the most fundamental and important reactions widely employed in organic synthesis as well as in the synthesis of medicinal and natural products.¹ Traditional approaches for the formation of esters rely on prefunctionalized starting materials, such as alcohols, carboxylic acids and acyl chlorides. In recent years, the direct and catalytic activation of C(sp³)–H bonds adjacent to an oxygen atom, phenyl group or double bond, to form esters via coupling has attracted much attention (Scheme 1). Several transition-metal catalysts, such as Ru,² Rh,³ Pt,⁴ Pd,⁵ Cu,⁶ and Fe⁷ have been developed for this new cross dehydrogenative coupling reaction. The Wan group,⁸ Wang group,^9a and Patel group^9b,c have reported the use of Bu₄NI as a nonmetal catalyst for the activation of the C(sp³)–H bonds to form C–O bonds via coupling. However, direct esterification of the unactivated C(sp³)–H bonds has been rarely explored. Recently, the Han group^6e and Patel group^6h reported a Cu-catalyzed dehydrogenation–olefination and esterification of C(sp³)–H bonds of cycloalkanes with TBHP as an oxidant.

Scheme 1 Direct esterification of C(sp³)–H.

Selectfluor, a commercially available electrophilic fluorinating reagent, is widely employed for fluoro functionalization of organic compounds.¹⁰ Recently, a direct conversion of C(sp³)–H bonds to C(sp³)–F bonds with Selectfluor has been developed.¹¹ The Lectka group^11b unveiled C(sp³)–H fluorination employing a combination of Selectfluor, a copper(I) bisimine complex, an anionic phase-transfer catalyst and N-hydroxyphthalimide (NHPI). The Chen group^11e developed a photolytic method for direct benzylic fluorination in the presence of Selectfluor. Besides its fluorinating ability, the combination of Selectfluor with copper has shown a considerable oxidation ability that could facilitate C–H abstraction.¹² The Zhang group^12a,b reported a Selectfluor-mediated copper-catalyzed highly selective benzylic C–O cyclization. The Baran group^12c reported an intermolecular Ritter-type C–H amination of unactivated sp³ carbons with F-TEDA-PF₆ as an oxidant. Herein, we report an effective copper-catalyzed intermolecular C(sp³)–H esterification of unactivated (non-benzylic and allylic) hydrocarbons with a broad spectrum of carboxylic acids (Scheme 1).

Initially, a mixture of p-nitrobenzoic acid 1a (1.0 mmol, 1.0 equiv.), adamantane 2a (3.0 equiv.), Selectfluor (2.0 equiv.) and CuBr₂ (20 mol%) was stirred in acetonitrile at 60 °C for 4 h, and the reaction afforded only 20% yield of 1-adamantanol 4-nitrobenzoate 3a (Table 1, entry 1). According to the literature,^12c the intermolecular Ritter-type C–H amination of adamantane 2a with CH₃CN was inevitable. Other solvents such as DCE, acetone, THF, and CH₃NO₂ were screened in order to avoid the C–H amination. However, no reaction occurred in the above mentioned solvents. Further optimization of the C(sp³)–H esterification was carried out by screening on a range of additives. Compound 3a was obtained in 15% yield by adding 20 mol% of 1,10-phenanthroline in CH₃NO₂ at 60 °C (Table 1, entry 2). Other additives such as benzonitrile (1.0 equiv.), CH₂ClCN (1.0 equiv.), NH(Tf)₂ (1.0 equiv.), and 4-fluorobenzonitrile (1.0 equiv.), gave 3a in 55%, 25%, 32%, and 53% yield, respectively (Table 1, entries 3–6). In the presence of pentanenitrile (1.0 equiv.), the yield of 3a was improved to 60% (Table 1, entry 7). When the amount of pentanenitrile or Selectfluor was reduced by half, the yields dropped accordingly to 41% or 32% (Table 1, entries 8 and 9). To our delight, when CuBr₂ (30 mol%) and Selectfluor (2.5 equiv.) was used, the yield of 3a improved to 72% (Table 1, entry 10). Other copper salts such as CuBr, Cu(OTf)₂, CuCl, and CuI were less active (Table 1, entries 11–14). No reaction was observed when the copper catalyst or additive was absent (Table 1, entries 15–17). Switching the N–F reagent from Selectfluor to NFSI or F-TEDA-PF₆ gave 3a in 0% and 54% yield, respectively (Table 1, entries 18 and 19). No reaction was observed when additional base such as pyridine and Et₃N was added (Table 1, entry 20). The yield has no significant increase when K₂CO₃ was added (Table 1, entry 21).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Additive	Yield^b (%)
a Reaction conditions: 4-nitrobenzoic acid 1a (1.0 mmol, 1.0 equiv.), adamantane 2a (3.0 equiv.), catalyst, Selectfluor (2.0 equiv.), additive (1.0 equiv.), CH3NO2 (10.0 mL), N2, at 60 °C for 4 h, unless otherwise noted.b Isolated yields based on 1a.c Using CH3CN as solvent.d Using 1,10-phenanthroline (20 mol%) as the additive.e Using pentanenitrile (50 mol%) as the additive.f Selectfluor (1.0 equiv.) was used.g Selectfluor (2.5 equiv.) was used.h NFSI (2.0 equiv.) was used as the oxidant.i F-TEDA-PF6 (2.0 equiv.) was used as the oxidant.j Pyridine (2.0 equiv.) or Et3N (2.0 equiv.) was used as base.k K2CO3 (2.0 equiv.) was used as base.
1^c	CuBr2 (20)	—	20
2^d	CuBr2 (20)	1,10-Phenanthroline	15
3	CuBr2 (20)	Benzonitrile	55
4	CuBr2 (20)	CH2ClCN	25
5	CuBr2 (20)	NH(Tf)2	32
6	CuBr2 (20)	4-Fluorobenzonitrile	53
7	CuBr2 (20)	Pentanenitrile	60
8^e	CuBr2 (20)	Pentanenitrile	41
9^f	CuBr2 (20)	Pentanenitrile	32
10^g	CuBr2 (30)	Pentanenitrile	72
11	CuBr (20)	Pentanenitrile	34
12	Cu(OTf)2 (20)	Pentanenitrile	56
13	CuCl (20)	Pentanenitrile	18
14	CuI (20)	Pentanenitrile	0
15	AgNO3 (20)	Pentanenitrile	0
16	Bu4NBr (20)	Pentanenitrile	0
17	CuBr2 (20)	—	0
18^h	CuBr2 (20)	Pentanenitrile	0
19^i	CuBr2 (20)	Pentanenitrile	54
20^j	CuBr2 (20)	Pentanenitrile	0
21^k	CuBr2 (20)	Pentanenitrile	52

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With the optimized conditions established (Table 1, entry 10), we next screened different acids aiming to improve the esterification yield (Table 2). Using 4-nitrobenzoic acid (1.0 mmol) and CF₃COOH (1.0 mmol) as acids, gave esterification product in 30% and 24% yield, respectively (Table 2, entries 1 and 2). No desired product was obtained when CH₃COOH (1.0 mmol) was used (Table 2, entry 3). The reason might be that CH₃COOH was failed to deprotonated by F⁻ due to it's weak acidity. Gratifyingly, the application of CCl₃COOH (1.0 mmol) resulted in a significant increase in the yield of esterification (55%), along with 9% yield of 4 (Table 2, entry 4). Increasing the CCl₃COOH to 2.0 equiv. gave 3 in 60% yield, along with only 6% yield of 4 (Table 2, entry 5). Unexpectedly, replacing CCl₃COOH with CF₃SO₃H provided no esterification product 3, while the amination product 4 was obtained in 45% yield (Table 2, entry 6). When the amount of pentanenitrile was doubled, the yield of 4 improved to 76% (Table 2, entry 7). While the role of CF₃SO₃H remains unclear, it might be that the nucleophilicity of CF₃SO₃⁻ was not strong enough to undertake the esterification. On the other hand, the strong acidity of CF₃SO₃H would favor the amination, which might be similar to the role of Zn(OTf)₂ as was reported by Baran group.^12c

Table 2 Optimization of the acids^a

Entry	Acid 1	Yield^b (%)
		3	4
a Reaction conditions: acid 1 (1.0 mmol, 1.0 equiv.), cyclohexane 2b (10.0 equiv.), CuBr2 (30 mol%), Selectfluor (2.5 equiv.), pentanenitrile (1.0 equiv.), CH3NO2 (10.0 mL), N2, at 60 °C for 4 h, unless otherwise noted.b Yield was determined by ^1H NMR analysis of the crude mixture, based on 1.0 mmol of acid 1.c CCl3COOH (2.0 equiv.) was used.d Pentanenitrile (2.0 equiv.) was used.
1	4-Nitrobenzoic acid	30	10
2	CF3COOH	24	30
3	CH3COOH	0	0
4	CCl3COOH	55	9
5^c	CCl3COOH	60	6
6	CF3SO3H	0	45
7^d	CF3SO3H	0	76

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With the optimized conditions in hand, we subsequently explored the reaction scope by using a variety of carboxylic acids 1 and adamantane 2a (Table 3). Benzoic acids with electron-withdrawing and electron-donating substituents could be converted to the desired products (3a and 3i). Remarkably, the ortho-substituted benzoic acids (1b and 1c) with steric hindrance exhibited the similar activity as para-substituted benzoic acids (1a and 1f). Adamantane 2a reacted with CCl₃COOH and gave 3l in 80% yield. Compound 3m was obtained in 40% yield, along with some unidentified by-products. Surprisingly, the reaction showed a high regioselectivity which indicated that the esterification of the tertiary C–H was more accessible than secondary C–H, and the regioisomer was not found according to the ¹H NMR analysis of the crude mixture. The method tolerates various types of functional groups including nitro, tert-butyl, fluoro, chloro, bromo, iodo, and aldehyde group, and 3a–3k were obtained in 40%–78% yield. Notably, the aldehyde group was sensitive toward other different oxidants.^6c,e,8a However, p-methoxybenzoic acid was failed to converted to the desired products even if K₂CO₃, NaOH, or Cs₂CO₃ was added, due to acidity of p-methoxybenzoic acid was too weak.

Table 3 Substrate scope for the C(sp³)–H esterification^a

a Reaction conditions: acid (1.0 mmol, 1.0 equiv.), hydrocarbon (3.0 equiv.), CuBr₂ (30 mol%), Selectfluor (2.5 equiv.), pentanenitrile (1.0 equiv.), CH₃NO₂ (10.0 mL), N₂, at 60 °C for 4 h, isolated yield based on acid.b Hydrocarbon (10.0 equiv.) was used.c Isolated yield of the recovered acid.d 2-Methyl-6-nitrobenzoic acid (1.0 mmol) was used as substrate.

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After testing the coupling reaction of adamantane 2a with carboxylic acids, other target hydrocarbons were investigated under the similar reaction conditions (Table 3). Compounds 3o and 3p were obtained in 26% and 20% yield, respectively. Methylcyclohexane reacted with p-nitrobenzoic acid 1a, provided a mixture of unassigned regio- and diastereoisomers 3q in a total yield of 28%. Isooctane gave the corresponding product 3r in 17% yield. Attempts to perform the esterification of cyclododecane with CCl₃COOH using this method failed, due to the product 3s would further react with CCl₃COOH. Other cycloalkanes such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane, reacted with CCl₃COOH to give 3t, 3u, 3v and 3w in 35%, 55%, 50%, and 75% yield, respectively. Notably, this method was further expanded to the benzylic and allylic C(sp³)–H bonds, and providing the corresponding products 3x and 3y in 70% and 38% yield, respectively. Unfortunately, the activation of the C(sp³)–H bonds adjacent to an oxygen atom was failed.

The present esterification could be inhibited by the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), which is consistent with a radical based mechanism. Xu,^12d Zhang,^12a,b and Baran^12c have demonstrated that the copper(I) salt or copper(II) salt can be oxidized to generate a fluorinated copper(III) species by Selectfluor. Based on our experiments, no reaction was observed when pentanenitrile was absent. We inferred that pentanenitrile could improve the solubility of CuBr₂ in CH₃NO₂ by coordination. In addition, the coordination of pentanenitrile with copper(III) species might disperse copper(III) species' charge that would help to stabilize the copper(III) intermediate. The structure of a complex obtained by mixing copper(II) trifluoroacetylacetonate and F-TEDA-BF₄ has been previously characterized by X-ray crystallography.¹³ Crystalline H-TEDA-BF₄ has been isolated by Baran,^12c and the salt was characterized by X-ray crystallography. At the completion of the present esterification reaction, a white precipitate of H-TEDA-BF₄ could be collected by filtration. And the structure was validated by ¹H NMR and MS. Recently, the Lectka group^11a unveiled an unusual interplay between copper(I) and Selectfluor, the detailed reaction mechanism was revealed to be a radical chain mechanism in which copper acts as an initiator.

A plausible catalytic cycle has been proposed (Scheme 2). First, the copper(II) salt is oxidized to generate a fluorinated copper(III) species by Selectfluor. Next, the hydrocarbon R–H is oxidized to R˙ by A, followed by further oxidation of R˙ to the corresponding carbocation R⁺ by a copper(III) species in solution. At the same time, the carboxylic acid R₁COOH is deprotonated rapidly by F⁻ as a base, which gives the anion R₁COO⁻. Finally, capture of the carbocation R⁺ by R₁COO⁻ gives the desired ester.

Scheme 2 Postulated mechanism.

Conclusions

In summary, we have successfully developed a novel, effective, and direct method of copper-catalyzed esterification of unactivated (non-benzylic and allylic) C(sp³)–H bonds of hydrocarbons via a cross dehydrogenative coupling reaction. A variety of hydrocarbons could react smoothly with various carboxylic acids to give esters in 17–80% yields. Additionally, this reaction could also provide a direct, new and useful strategy for the synthesis of alkyl alcohols by esters hydrolysis. Based on the literatures and our experiments, a radical process was proposed in the catalytic cycle. Further studies to refine the mechanism and to expand the application scope of this reaction are currently underway in our laboratory.

Acknowledgements

We are grateful to Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals and National Natural Science Foundation of China (no. 21176222 and no. 21406200) for financial help.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, mechanism investigation and characterization data. See DOI: 10.1039/c4ra14586k

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