The Au(III)-catalyzed coupling reactions between alcohols and N-heterocycles via C–H bond activation

Abstract

A novel and highly efficient dehydrogenative C–C coupling between sp³ C–H and sp² C–H bonds catalyzed by gold has been developed using environmentally benign tert-butyl hydroperoxide as oxidant. This new methodology provides a facile access to acylate N-heterocycles.

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The construction of the C–C bond is the most essential subject in chemistry since they can provide key steps in building more complex products from readily available materials. Lately, as C–H bonds are unique in organic molecules, the activation of the C–H bond for C–C coupling without substrate prefunctionalization has become a promising strategy.¹ More recently, homogeneous gold-catalyzed C–C bond formation has emerged as a very exciting area of research due to its powerful advantages for the synthesis of intricate scaffolds.² The groups of Tse and Nevado reported the gold-catalyzed oxidative homocoupling of simple arenes and oxidative ethynylation of arenes with terminal alkynes using PhI(OAc)₂ as an oxidant.³ During our group research, we also demonstrated a gold-catalyzed oxidative C–C coupling of Csp³–H bonds under TBHP or air conditions.⁴ However, all the above gold-catalyzed work focused on the sp³ C–H/sp³ C–H, sp C–H/sp² C–H and sp² C–H/sp² C–H oxidative coupling. To the best of our knowledge, the gold-catalyzed oxidative C–C coupling from sp³ C–H and sp² C–H bonds are rarely reported (Scheme 1). Moreover, activation of aromatic C–H bonds followed by generating a new C–C bond constitutes a conceptually promising methodology since it avoids the otherwise prefunctionalization of the aromatic counterpart.⁵

Scheme 1 Au-catalyzed oxidative coupling reactions from C–H bonds.

Recently, the activation of C–H bonds adjacent to oxygen has intrigued much attention because of the feasibility of formation a new C–C bond and the introduction of an oxygen-containing functional group into the organic molecule at the same time.⁶ However, the direct and selective activation of α C–H of alcohols remains a great challenge to chemists. Traditionally, alcohols are rarely employed as acylating agents since they are inclined to undergo energetically more favorable alkoxylation and dehydrogenative process followed by cleavage of the C–O bond (C–O bond dissociation energy = 85 to 91 kcal mol⁻¹).⁷ The pioneering research in this area about the hydroxymethylation and hydroxyethylation of N-heterocycles were explored by Minisci,⁸ in the presence of peroxides and equivalents of acid with moderate and low yields respectively. Recently, Li and co-workers reported a palladium-catalyzed C–C coupling reactions of alcohols and N-heterocycles using DCP as an oxidant.⁹ At the same time, Wang's group demonstrated C₂ alkylation of azoles with alcohols and ethers through dehydrogenative cross-coupling under metal-free conditions.¹⁰ Herein we became interested in the gold-catalyzed oxidative C–C coupling of N-heterocycles with various alcohols as Csp³–H coupling partners (Scheme 2).

Scheme 2 Au-catalyzed the dehydrogenative coupling between alcohols and isoquinoline.

In our initial study, the oxidative C–C coupling reaction of lepidine with ethanol was chosen as the model reaction. To our delight, the reaction could occur under the catalysis of 4a (5 mol%) at 120 °C under air with TBHP as oxidant, affording the product in 63% yield. Surprisingly, unlike the previous report, the acylation product of the lepidine rather than the alcohol was observed.^9,11 Then, different gold catalysts and other metal catalysts were tested. Among the Au(III) catalysts screened, 4c showed the best catalytic activity (Table 1, entries 1–3). Meanwhile, the utilization of Ph₃PAuCl or AuCl instead of Au(III) catalysts also resulted in a low yield (Table 1, entries 5,6). In addition, when other metal catalysts such as Cu^I, Fe^III and Ni^II were examined instead of 4c, the reaction proceeded very poorly (Table 1, entries 7–9). which indicated that gold catalyst 4c is necessary and plays an important role in the C–H activation process. Either trace amounts or no product was detected when the other oxidants were employed (Table 1, entries 11–13). Notably, the yields decreased under oxidative reaction conditions when the amount of oxidant (TBHP) and catalyst 4c loading was reduced (Table 1, entries 14–16). Consequently, the optimal reaction conditions included catalysis by 5 mol% of 4c at 120 °C under air in the presence of TBHP as oxidant.¹²

Table 1 Optimization of the C–H activation reaction conditions^a

Entry	Cat (mol%)	Oxidant	Yield (%)^b
a Conditions: 1a (0.5 mmol), ethanol 2a (2 mL), catalyst 4 (5 mol%), oxidant (4.5 equiv), 120 °C, 24 h; b isolated yield.
1	4a(5)	TBHP(4.5)	63
2	4b(5)	TBHP(4.5)	46
3	4c(5)	TBHP(4.5)	73
4	4d(5)	TBHP(4.5)	65
5	4e(5)	TBHP(4.5)	59
6	4f(5)	TBHP(4.5)	58
7	FeCl3(5)	TBHP(4.5	n.d
8	CuI(5)	TBHP(4.5)	n.d
9	NiCl2(5)	TBHP(4.5)	23
10	none	TBHP(4.5)	0
11	4c(5)	NaClO(4.5)	0
12	4c(5)	TEMPO(4.5)	0
13	4c(5)	mCPBA(4.5)	trace
14	4c(5)	TBHP(3.5)	53
15	4c(5)	TBHP(2.0)	26
16	4c(2.5)	TBHP(4.5)	65

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Under the optimized reaction conditions, the scope of the alcohols in the direct oxidative coupling of lepidine (1a) was investigated. The results are shown in Table 2. As can be seen from Table 2, the reactions of lepidine with aliphatic alcohols, such as ethanol, n-propanol, n-butanol, n-pentanol and n-heptanol, produced the corresponding dehydrogenative cross-coupling products (3a–f) in moderate to good yields. It is important to point out that increasing the chain length of the aliphatic primary alcohols showed a little influence on the yield of the corresponding products. Furthermore, a variety of nitrogen containing heterocycles were also investigated. It was found that quinolines and isoquinolines were effective substrates for the reaction, affording the desired product with satisfactory yields. Significantly, the electron-withdrawing groups on the aromatic rings usually gave the products (3i–l) in higher yields (53–73%), than those with electron-donating groups (3h and 3o). It should be noted that the acylation reactions proceeded with high regioselectivity. For example, only one isomer can be isolated when the N-heterocycles had alternative sp² C–H bonds adjacent to an N-heteroatom (3g, 3k).

Table 2 The reaction scope of C–H activations between alcohols and N-heterocycles^a,b

a Conditions: 1 (0.5 mmol), alcohol (2 mL), catalyst 4c (5 mol%), TBHP (4.5 equiv), 120 °C, 24 h; b Isolated yields.

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To gain insight into the reaction mechanism, the ESI-MS was employed to determine whether the final product 3a was transferred from the alcohol intermediate 5 (Fig. 1). Intriguingly, the intermediate 5 was detected by ESI-MS when the reaction proceeded for three hours, and no acylation product 3a was observed. Six hours later, both the alcohol intermediate 5 and the final product 3a could be found. Moreover, only the desired product 3a was obtained when the reaction finished, and the alcohol intermediate 5 disappeared completely.¹³ These results indicated that the reaction proceeded through the activation of α sp³ C–H of alcohols. When the radical inhibitors such as BHT (2,6-di-tert-butyl-4-methylphenol) and TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) were added into the reaction of ethanol 1a and lepidine 2a, no acylation product was detected.

Fig. 1 The monitored results of the reaction of 1a and 2a by ESI-Ms.

From these results we believe that the reaction proceeded through the activation α C–H of alcohols by a radical mechanism¹⁴ similar to Minisci reaction.⁸ Initially, a hydroxyl radical and an alkoxyl radical are generated under heating from a homolytic cleavage of tert-butyl hydroperoxide (Scheme 3). The generated free radicals 6 subsequently undergo a hydrogen atom abstraction from the α-position sp³ C–H of ethanol 2a, forming the corresponding free radical 7. It is probable that this radical 7 reacts with the gold-activated lepidine 1a to form radical 9, which is rearomatized by radical initiator, delivering the detected alcohol intermediate 5. Then, the alcohol intermediate 5 is further turned into the acylation product 3a through a gold-catalyzed oxidation process with TBHP.¹⁵ Although the role of gold in the reaction is not very clear, we believe it plays a very important role in the process, as a trace amount of desired product or no product 3a could be isolated when other metal catalysts was used instead of 4c (Table 1, entries 14–16). It is possible that gold may be participating in the generation of the radical intermediate 7 and oxidized the alcohol intermediate 5 into the final product 3a.

In summary, the first gold-catalyzed C–C bond formation based on the direct oxidative Csp³–H/Csp²–H coupling reactions involving N-heterocycles and alcohols has been developed. This novel methodology provides a facile access to direct acylation of the N-heterocycles. A detailed mechanistic study and further investigation on the application of this kind of oxidant under gold are currently underway in our laboratory.

Scheme 3 The possible reaction mechanism.

This work is supportrd by National Natural Science Foundation of China (20832001, 20972065, 21074054, 21172106) and National Basic Research Program of China (2010CB923303) for their financial support.

References

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Footnote

† Electronic supplementary information (ESI) available: The experimental details and the characterization data for the products. See DOI: 10.1039/c2ra22120a

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