An efficient method for the preparation of tert-butyl esters from benzyl cyanide and tert-butyl hydroperoxide under the metal free condition

Abstract

A novel protocol to synthesize tert-butyl esters from benzyl cyanides and tert-butyl hydroperoxide has been successfully achieved. In the presence of tert-butyl hydroperoxide, Csp³–H bond oxidation, C–CN bond cleavage and C–O bond formation proceeded smoothly in one pot under the metal-free condition.

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tert-Butyl ester moiety is an important functional group that has found wide occurrences in polymers, pharmaceutical agents, biologically relevant natural products, and is also a favorable protecting group which can be readily converted to the corresponding acid.¹ Conventional synthetic procedures for the preparation of tert-butyl esters relied on the reaction of carboxylic acid or its derivatives with tert-butyl alcohol.^2,3 However, these reactions are based on the excess loading of strong acid activators, excess reagents, high catalyst loadings, and require preactivation, prefunctionalization.^2,3 Recently, several protocols for the preparation of tert-butyl esters was reported such as intramolecular rearrangement of α-azidoperoxides, alkoxycarbonylation of aryl halides, and many attractive processes have been developed.^4,5 However the approaches are far from ideal due to the use of a crucial raw material, the toxic carbon monoxide, less common metals. Despite numerous protocols reported in the literature, the formation of tert-butyl esters remains a persistent challenge under friendly conditions.

Since C–C bond cleavage was reported, which has become more and more attractive topic and given great opportunity to utilization of inert starting materials to construct new chemical bonds.^6,7 As the substrate of a powerful building blocks, benzyl cyanide reagents represent a kind of stable and easily obtained structures.^8–11 While C–CN bond is relatively stronger and stable because of the higher bond dissociation energy.¹² Thus, the cleavage of C–CN bonds is a challengeable topic and transition metal catalysts are generally required.^6–12 Moreover, through transition metal catalyzed C–CN bond activation, benzyl nitriles can be utilized in the reactions of cyanofunctionalization, while only CN unit is presented in product.¹³ However, to date, using aromatic unit to construct new C–C or C-hetero bond has been rarely reported.^14–17 In 2014, Li et al. developed the copper-catalyzed amidation benzyl cyanides with DMF for the synthesis of formamides.¹⁴ We have reported copper-catalyzed aerobic oxidative benzyl cyanides and tertiary amines to tertiary amides.¹⁵ However, the protocol to synthesize tert-butyl esters from benzyl cyanides under friendly conditions has not been reported.

tert-Butyl hydroperoxide was widely known as stoichiometric oxidant for C–H bond oxidation, and transition-metal salts, such as Fe, Co, Cu salts could be used as the active catalysts.¹⁸ There has limited report of using TBHP as oxidant for C–H bond oxidation and functionalization under metal-free condition.¹⁹ And, to date, metal-free TBHP-mediated esterification reaction has only met with limited success.^5a Herein, we report an efficient TBHP oxidative esterification benzyl cyanides to develop tert-butyl esters under metal-free conditions (eqn (1)). In the presence of tert-butyl hydroperoxide, Csp³–H bond oxidation, C–CN bond cleavage and C–O bond formation proceeded smoothly in one pot under the metal-free condition.

Initially, the reaction of 2-phenylacetonitrile with tert-butyl hydroperoxide (TBHP) was chosen as a model reaction for optimization of the reaction conditions including the catalyst type, solvent, temperature, additive, and the results were compiled in Table 1. Using 5 mol% of CuCl as catalyst, various solvents were examined, the results showed that the solvent considerably affected the reaction efficiency (Table 1, entries 1–6), and CH₃CN was the best solvent, resulted 2a in 45% yield (Table 1, entry 6). After further optimization as shown in entries 7–10, MnCl₂, MnCO₃, FeCl₃, AgNO₃ were also effective catalysts for this reaction. So, we deduced that external catalyst was not necessary for the reaction. Gratifyingly, in the absence of other catalysts, the yield of 2a was obtained in 46% yield (Table 1, entry 11). To promote the reaction, an additional additive 4 Å molecular sieve was added to the reaction mixture for 16 h, the substrate 2-phenylacetonitrile was consumed, and the yield of 2a was increased to 89% (Table 1, entry 12). Increasing the reaction temperature to 80 °C did not improve the yield of 2a evidently (Table 1, entry 13), while increasing the reaction temperature to 100 °C resulted in a low yield (Table 1, entry 14). Decreasing the reaction temperature to 40 °C resulted in the formation of 2a in lower yields (Table 1, entry 15). When DTBP (di-tert-butyl peroxide) was used as oxidant in CH₃CN at 60 °C, this reaction did not take place at all (Table 1, entry 16). On the basis of these results, entry 12 represents the best conditions.

Table 1 Optimization of the reaction conditions^a

Entry	Cat	Ms^b 4 Å	Solvent	Yield^c (2a%)
a Reaction conditions: 2-phenylacetonitrile 1a (0.2 mmol), TBHP (340 μL, 1.2 mmol, 70% solution in water), cat (5 mol%), Ms 4 Å (110 mg, 3.0–5.0 mm, and was dried before use), solvent (2 mL), in 25 mL Schlenk tube, 60 °C, N2, 16 h.b Abbreviation: + or − shows the presence or absence of 4 Å molecular sieves.c GC yields based on 1a using n-hexadecane as internal standard.d 80 °C.e 100 °C.f 40 °C.g Di-t-butyl peroxide (DTBP) was employed as oxidant under N2 atmosphere.
1	CuCl	−	Acetone	34
2	CuCl	−	DCE	35
3	CuCl	−	1,4-Dioxane	40
4	CuCl	−	Toluene	37
5	CuCl	−	DMSO	27
6	CuCl	−	CH3CN	45
7	MnCl2	−	CH3CN	41
8	MnCO3	−	CH3CN	20
9	FeCl3	−	CH3CN	18
10	AgNO3	−	CH3CN	41
11	—	−	CH3CN	46
12	—	+	CH3CN	89
13^d	—	+	CH3CN	86
14^e	—	+	CH3CN	60
15^f	—	+	CH3CN	29
16^g	—	+	CH3CN	—

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Under the optimized conditions, we then turned our attention to explore the generality of the current procedure by testing various electron-rich or electron-deficient group substituted 2-phenylacetonitrile to synthesize tert-butyl esters. As compiled in Table 2, substituted 2-phenylacetonitrile could undergo C–CN bond cleavage and be esterified by TBHP to give the corresponding ester products in high yields. Phenylacetonitrile with electron-rich substituents like methyl (–CH₃), methoxy (–OCH₃), and hydroxy (–OH) reacted smoothly with TBHP to provide the corresponding esters 2a–2d (Table 2, entries 1–4). Phenylacetonitrile containing electron-withdrawing groups like fluoro (–F), chloro (–Cl), bromo (–Br), iodine (–I), trifluoromethy (–CF₃) or phenyl (–Ph) were used as substrates, could also be esterified by TBHP to give the corresponding ester products 2e–2j through C–C bond activation under the optimal reaction conditions (Table 2, entries 5–10). Reaction of 2-(4-NO₂-phenyl) acetonitrile, a strong electron-deficient group substituted substrate, with TBHP also took place to provide the desired product 2k in 90% yield (Table 2, entry 11). However, amino (–NH₂) was not compatible, and amino was oxidized to the corresponding nitro, giving tert-butyl 4-nitrobenzoate 2k in 58% yield (Table 2, entry 12). In addition, two tertiary butyl groups can easily produce from double benzyl cyanide 1m with TBHP (Table 2, entry 13). Esterification of 2-(thiophen-2-yl)acetonitrile was equally effective for the current process (Table 2, entry 14). 1-(Naphthalen-2-yl) or 2-(naphthalen-2-yl)acetonitrile was also served as an efficient substrate and could react with TBHP, furnishing the esters (2n–2o) in 85% and 84% yield respectively through C–C bond cleavage (Table 2, entries 15 and 16). Besides TBHP, 2-hydroperoxy-2-methylbutane was also an effective oxidant for the present reaction condition. Substrates with electron-rich or electron-deficient group substituted 2-phenylacetonitrile could undergo C–C bond cleavage with 2-hydroperoxy-2-methylbutane, giving the corresponding esters 2p–2r in high yield (Table 2, entries 17–19).

Table 2 TBHP-mediated oxidative formation of esters from substituted-benzyl cyanide^a

Entry	Benzyl cyanides	Products	Yield^b
a Reaction conditions: substrate 1a–1p (0.2 mmol), TBHP (1.2 mmol), 4 Å Ms (110 mg), CH3CN (2 mL), N2 in 25 mL Schlenk tube at 60 °C, 16 h.b Isolated yield.c TBHP (2.4 mmol), 4 Å Ms (220 mg).d 2-Hydroperoxy-2-methylbutane (1.2 mmol, 85% solution in water) was used as oxidant.
1	1a		2a, 82%
2	1b		2b, 81%
3	1c		2c, 82%
4	1d		2d, 72%
5	1e		2e, 81%
6	1f		2f, 78%
7	1g		2g, 83%
8	1h		2h, 69%
9	1i		2i, 78%
10	1j		2j, 73%
11	1k		2k, 90%
12	1l		2k, 58%
13^c	1m		2l, 72%
14	1n		2m, 72%
15	1o		2n, 80%
16	1p		2o, 84%
17^d	1c		2p, 82%
18^d	1g		2q, 88%
19^d	1k		2r, 83%

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To get some information of the reaction mechanism, several control experiments were carried out as shown below. When benzaldehyde 1q or phenylacetic acid 1r was used as substrate under the standard reaction condition, 2a was not detected at all, showing that aldehyde or acid was not the efficient intermediate (eqn (2) and (3)). The reaction of benzoyl cyanide 1s with tert-butyl alcohol was used as substrate, ester 2a was obtained in 85% yield (eqn (4)). The results indicated that benzoyl cyanide 1s was the efficient intermediate for this transformation. When radical scavenger TEMPO was loaded under the standard reaction conditions, the yield of 2a was sharply reduced to 11%, indicating that a free radical perhaps was involved in the present reaction process (eqn (5)).

Based on the present results and the reported literatures,^5a,20–22 a plausible mechanism is shown in Scheme 1. The tert-butoxyl and tert-butylperoxy radicals were generated from the present system.¹⁹ The tert-butoxyl radical allows benzyl cyanide 1 to generate a key intermediate radical M, which was then trapped by the tert-butylperoxy radical to give α-benzylperoxides M-I.^20,21 After an elimination, M-I converted to M-II. Followed with the attack of tert-butyl alcohol to M-II, the desired ester 2 was obtained.

Scheme 1 Plausible reaction pathway for the synthesis of tert-butyl esters.

Conclusions

In summary, the novel metal-free oxidative esterification of inter C–CN bond with TBHP for the synthesis of tert-butyl esters has been presented. In the present system, we achieved metal-free oxidation of sp³C–H bonds, C–C bond cleavage and C–O bond formation in one pot.

Acknowledgements

Financial support by National Natural Science Foundation of China (21603068), Science and Technology Innovation Team Project of Hubei Provincial Department of Education (T201419) and research fund for the doctoral program of Hubei University of Science and Technology is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data for the products. See DOI: 10.1039/c6ra20966a

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