CuBr₂-promoted cyclization and bromination of arene–alkynes: C–Br bond formation via reductive elimination of Cu(III) species

Abstract

A CuBr₂-promoted cyclization and bromination of arene–alkyne substrates has been developed, affording 9-bromophenanthrene derivatives highly efficiently. This reaction provides a novel and efficient protocol for C–Br bond formation from an inorganic bromine source via the reductive elimination of the Cu(III) species.

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Introduction

Halides are ubiquitous building blocks in organic synthesis, which can be used for lots of transformations.¹ They are also present in a large range of natural products,² pharmaceuticals,³ and agrochemicals.⁴ Therefore, highly efficient carbon–halogen bond construction methods have received continuous attention from chemists.⁵ Research studies on transition-metal-catalyzed carbon–halogen bond formation have a rich history. The halide exchange reaction is one of the most studied examples in this field, which has been applied in both academic and industrial processes.^5c,6 In such transformations, an initial organic halide is required (Scheme 1a). The carbon–halogen bond can also be formed by reductive elimination of the Pd(II) species, in which sterically hindered ligands are necessary⁷ (Scheme 1b). Recently, the Cu-catalyzed 1,3-bromine migration reaction in the presence of MOBu^t has been reported, which provides another route for the construction of the C–Br bond⁸ (Scheme 1c). Given the great importance of organic halides in modern chemistry, new protocols for preparing organic halides from inorganic halides are highly desired. Herein, we wish to report our recent observation on the CuBr₂-promoted transformation of arene–alkynes into 9-bromophenanthrenes, which presents a new way to build C–Br bonds via the reductive elimination of Cu(III) species using the inorganic bromide salt as the bromine source (Scheme 1d).

Scheme 1 Some carbon–halogen bond formation reactions.

Results and discussion

Initially, to optimize the reaction conditions, 2-((4-methoxyphenyl)ethynyl)-1,1′-biphenyl 1a was chosen as the model substrate and CuBr₂ was applied as the bromine source. In the first step, the solvent effect was examined carefully. No reaction occurred in triethylamine or ethyl acetate (entries 1 and 2, Table 1). Reactions in acetone, DCM, DCE, EtOH, THF, MeOH, DMF, or MeCN proceeded slowly to yield the desired product 2a in low yields (entries 3–10, Table 1). Encouragingly, when MeNO₂ was used as the solvent, a relatively higher reaction speed and yield were observed. However, the chemoselectivity was not satisfying, since the non-brominated byproduct 3a was also formed (entry 11, Table 1). Considering that the byproduct 3a might result from the in situ generated proton (vide infra), K₃PO₄ was added to neutralize the proton and therefore to improve the selectivity. In the presence of 0.2 equiv. of K₃PO₄, the yield increased, but the selectivity decreased slightly (entry 12, Table 1). When 0.5 equiv. of K₃PO₄ was added, the selectivity dramatically rose up to >99 : 1, however, the reaction speed was much slower (entry 13, Table 1). Next, more CuBr₂ was used (entries 14 and 15, Table 1). To our great delight, when 3 equiv. of CuBr₂ was applied, 2a was yielded quantitatively as the sole product (entry 15, Table 1). Thus, Condition A (CuBr₂ (3 equiv.), K₃PO₄ (0.5 equiv.), and CH₃NO₂) was applied for the following studies. At >99 : 1, however, the reaction speed was much slower (entry 13, Table 1). Then we tried to add more CuBr₂ (entries 14 and 15, Table 1). To our great delight, when 3 equiv. of CuBr₂ was applied, 2a was yielded quantitatively as the sole product (entry 15, Table 1). Attempts for a catalytical reaction were then carried out using CuBr₂ (10 mol%) and a cheap halogen source NaBr (6 equiv.) under argon (entry 16, Table 1) or oxygen (entry 17, Table 1) atmosphere. Disappointingly, no reaction took place at all. During the whole optimization process, we had been seeking the Cu(I) product/species for any possible information on the mechanism. However, all attempts failed. Thus, we finally conducted the reaction using CuBr instead of CuBr₂ under an argon (entry 18, Table 1) or oxygen (entry 19, Table 1) atmosphere. No reaction occurred under an argon atmosphere. A trace amount of the desired product was formed under an oxygen atmosphere. These results might indicate that CuBr cannot catalyze this reaction, however, when Cu(I) was oxidized by oxygen into Cu(II), the reaction could be initiated, although the efficiency was much lower than the standard conditions. Thus, Condition A (CuBr₂ (3 equiv.), K₃PO₄ (0.5 equiv.), and MeNO₂) was applied for the following studies.

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	CuBr2 (equiv.)	K3PO4 (equiv.)	Time (h)	2a ^b (%)	2a:3a ^b
a A solution of 1a (0.2 mmol) and CuBr2 in anhydrous solvent (3 mL) was stirred at rt under an argon atmosphere. b The results were determined by ^1H NMR (400 MHz) analysis of the crude reaction mixture with CH2Br2 (0.2 mmol) as an internal standard. c NMR recovery yield of 1a. d Isolated yield of 2a. e NaBr (1.2 mmol) was added. f The reaction was stirred under an O2 (1 atm) atmosphere. g CuBr was used instead of CuBr2.
1	Et3N	2	0	10	0 (98)^c	—
2	EA	2	0	10	0 (85)^c	—
3	Acetone	2	0	10	3 (68)^c	1.5 : 1
4	DCM	2	0	10	5 (75)^c	2.5 : 1
5	DCE	2	0	10	12 (88)^c	>99 : 1
6	EtOH	2	0	10	16 (84)^c	>99 : 1
7	THF	2	0	10	23 (63)^c	1.5 : 1
8	MeOH	2	0	10	27 (55)^c	2 : 1
9	DMF	2	0	10	31 (30)^c	>99 : 1
10	MeCN	2	0	10	38 (11)^c	1.5 : 1
11	MeNO2	2	0	10	71 (0)^c	4 : 1
12	MeNO2	2	0.2	12	77 (0)^c	3.5 : 1
13	MeNO2	2	0.5	96	78 (15)^c	>99 : 1
14	MeNO2	2.5	0.5	15	64 (0)^c	>99 : 1
15	MeNO2	3	0.5	5	100 (0)^c (100)^d	>99 : 1
16^e	MeNO2	0.1	0.5	10	0 (82)^c	—
17^e^,^f	MeNO2	0.1	0.5	10	0 (95)^c	—
18^g	MeNO2	CuBr (3)	0.5	10	0 (99)^c	—
19^f^,^g	MeNO2	CuBr (3)	0.5	10	Trace (95)^c	—

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After the above optimization, we paid attention to investigate the scope of this reaction. A series of mono-, di-, or tri-substituted arene–alkynes were applied under Condition A. Some typical results are summarized in Table 2. First, the electronic effect of Ar¹ was studied carefully. With strong electron-donating groups, such as methoxy and ethyoxy, the corresponding products were generated in excellent yields. The exact structure of product 2 was determined by the X-ray diffraction study of 2a.⁹ The reaction speed decreased, when this aryl ring turned to be electron-deficient. With strong electron-withdrawing groups, like the nitro group, a much higher temperature was required. Then the electronic effects of Ar² and Ar³ were examined. Similar results were observed. The reactions of highly electron-deficient substrates should be carried out under refluxing conditions. Next, some di- or tri-substituted arene–alkynes were applied under Condition A, which showed a very nice reactivity affording the corresponding 9-bromophenanthrenes in good to excellent yields. Notably, for highly electron-deficient substrates, a high reaction temperature was necessary. However for highly electron-rich reactants, a low reaction temperature was required. Most importantly, in all the tested cases, 2 was formed as the only product.

Table 2 Scope of this reaction^a

a A solution of 1 (0.2 mmol), K₃PO₄ (0.5 equiv.), and CuBr₂ (3 equiv.) in anhydrous MeNO₂ (3 mL) was stirred under an argon atmosphere. Isolated yield was reported.

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Further studies indicated that aliphatic substrates also showed very nice reactivities (Scheme 2). Notably, 9-bromo-10-trimethylsilylphenanthrene 5b was afforded in nearly quantitative yield. Given that TMS is another nice group for many transformations,¹⁰ some other more complicated phenanthrene derivatives might be easily prepared from this product. To gain more mechanistic insights, a competition reaction using [D]-1a was conducted (Scheme 3). The observed primary kinetic isotopic effect (k_H/k_D = 1.0) was low, which implied that the C–H bond cleavage was not the rate-limiting step. Thus, this reaction should not start from C–H bond activation.

Scheme 2 The reaction of aliphatic substrates.

Scheme 3 Kinetic isotopic effect experiment.

Next, the CuBr₂-promoted competitive reactions of some typical para-substituted substrates were carried out. The observed reactivity order for these reactions is as follows: p-OMe (k_X/k_H = 44.43) > p-OEt (28.00) > p-Me (3.54) > p-Et (2.38) > p-Br (0.46) > p-Cl (0.15).¹¹ As shown in Fig. 1, a linear correlation with a slope of −2.9 was obtained. This negative value indicated that the reaction might take place via a positively charged transition state.¹²

Fig. 1 Hammett plot.

Based on the above results and literature precedents,^13,14 a possible mechanism was proposed as shown in Scheme 4. First, CuBr₂ coordinated with the alkyne moiety of 1. Then the activated C–C triple bond was nucleophilically attacked by the intramolecular aryl ring as a molecule of MeNO₂ coordinated at the copper center to yield the cyclized alkenyl square planar Cu(II) anion 4. Subsequently, single electron transfer from 4 to a molecule of CuBr₂ afforded the Cu(III) species 6, CuBr, and the bromide ion. In this step, at least two equiv. of CuBr₂ were required to enable the whole transformation. This might be an explanation for why the excess amount of CuBr₂ is necessary. The following deprotonation resulted in the neutral aryl Cu(III) species 7 which could be protonated to give byproduct 3. In the presence of K₃PO₄, the in situ generated proton was neutralized. Therefore, only reductive elimination of the Cu(III)^13,14 species 7 took place to form the brominated product 2.

Scheme 4 Proposed mechanism.

Conclusions

In summary, a novel protocol for the construction of the C–Br bond from an inorganic bromine source via reductive elimination of the Cu(III) species has been developed. No organic ligand is required in this reaction. A series of 9-bromophenanthrenes have been synthesized from arene–alkynes, showing broad scope and high potential in organic synthesis.

Acknowledgements

We greatly acknowledge the financial support from the National Basic Research Program of China (973 Program, 2012CB720300), the International Science & Technology Cooperation Program of China (2014DFE40130), the Shanghai Rising-Star Program (14QA1400500), the medical guiding program of Shanghai Science Technology Commission (14411965200), and the Natural Science Foundation of Shanghai Science Technology Commission (12ZR1425600).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1438272. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00117c

‡ These authors contributed equally to this work.

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