Copper(I)-catalyzed homo-coupling of terminal alkynes at room temperature under solvent and base free conditions using O₂ as an oxidant

Abstract

The homo-coupling of various terminal alkynes were realized in the presence of 0.5 mol% CuI and 5 mol% benzylamine. This transformation proceeded at room temperature under solvent and base free conditions using O₂ as an oxidant. The TON was up to 1760.

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The structural motif of 1,3-diynes exists widely in pharmaceuticals and natural products with a variety of bioactivities.¹ For example, phosphoiodyns A (Fig. 1), isolated from a Korean marine sponge Placospongia, displays potential hPPARδ (human peroxisome proliferator-activated receptor delta) activity (EC₅₀ = 23.7 nM).^1f Debilisone C, isolated from the roots of Polyalthia debilis, exhibits antimycobacterial activity against Mycobacterium tuberculosis (MIC = 12.5 μg mL⁻¹).^1c,g Moreover, 1,3-diynes are also important building blocks in organic synthesis² and functional materials.³ Consequently, establishing efficient and mild access to 1,3-diynes is of great significance.

Fig. 1 Bioactive natural products with 1,3-diyne structure.

The direct Csp–Csp coupling reactions have been proved to be powerful and straightforward to access 1,3-diynes, including Glaser coupling,⁴ Hay coupling,⁵ and Cadiot–Chodkiewicz coupling.⁶ In recent years, a great progress has been made in this field. A number of metal catalytic systems for the Csp–Csp coupling have been reported,^7–15 such as Cu(II),⁸ Cu(I),⁹ Cu supported heterogeneous catalysts,¹¹ Cu substituted homogeneous catalysts,¹² and the combination Cu with Pd,¹⁰ Ni,¹³ Ag¹⁴ or Fe.¹⁵ However, some challenges still exist, such as requirement of complicate ligands, excess bases, external oxidants, organic solvents, and hash reaction conditions, and accompaniment with the byproduct of enynes when Pd catalysts are involved in the reaction.¹⁶ Moreover, the procedures reported suffer from low TON (turnover number). In the view point of green chemistry, development of aerobic oxidative homo-coupling of terminal alkynes under solvent and base free conditions at room temperature with high TON is of great significance.^17–19 Herein, we disclose the combination of CuI/benzylamine as an effective catalytic system for the oxidative homo-coupling of various terminal alkynes. Both of CuI and benzylamine are cheap and commercial available. This transformation features with low catalyst loading, environmental friendliness, mild reaction conditions, and a general substrate scope.

Phenylacetylene 1a and CuI were initially chosen as a substrate and catalyst to screen the reaction parameters. As shown in Table 1, the ligands were examined first (entries 1–13). No desired product was observed in the absence of ligand (entry 1). Pyridine gave the corresponding product 2a (entry 2) in 12% yield. While, a trace amount of product 2a was detected by using aqueous ammonia or triethylamine as ligand (entries 3 and 4). TMEDA (N, N, N′, N′-tetra-methylethylenediamine) could provide 2a in 31% yield (entry 5). Phen (1,10-phenanthroline), a commonly used ligand in copper catalyzed reactions, afforded 2a in 12% yield (entry 6). Interestingly, CuI powder could be resolved in 5 equiv. (equivalent) of benzylamine quickly, and affording a brown clear solution immediately. After stirred at RT (room temperature) for 12 h, the product 2a was precipitated as a white solid and was isolated in 98% yield (entry 7). Then, several benzylamine derivatives were next examined for this transformation. Electron-rich benzylamines (entries 8 and 9) gave better results than electron-deficient benzylamines (entries 10–12), probably because CuI is more likely to form the Cu complex with electron-rich amines. However, N-methylbenzylamine only gave 2a in 55% yield (entries 13). Considering its low cost and convenient availability, benzylamine was chosen as a ligand in the next examination. A variety of Cu salts, including Cu(II) and Cu(I) salts, were screened. No better result was obtained than CuI (entries 14–20). Further investigation showed that 1 mol% CuI with 5 mol% benzylamine under air gave the best result (entries 7, 21–23). It is worth noting that 0.5 mol% CuI was efficient enough for this transformation by using 1 atm O₂ as an oxidant (entry 24).

Table 1 Screening the reaction parameters for the homo-coupling of phenylacetylene 1a^a

Entry	Catalyst	Ligand	Time (h)	Yield^b (%)
a Reactions conditions: phenylacetylene 1a (3.0 mmol), 1 mol% copper salts, 5 mol% ligand, room temperature, under air. b Isolated yield based on 1a. c 3 mol% benzylamine. d 7 mol% benzylamine. e 0.5 mol% CuI. f Under 1 atm O2. BZA = benzylamine.
1	CuI	—	12	0
2	CuI	Pyridine	12	12
3	CuI	NH3 (aq)	12	Trace
4	CuI	Et3N	12	Trace
5	CuI	TMEDA	12	31
6	CuI	Phen	12	12
7	CuI	BZA	12	98
8	CuI	4-tBuBZA	10	98
9	CuI	4-MeOBZA	11	98
10	CuI	3-ClBZA	24	89
11	CuI	4-ClBZA	24	86
12	CuI	2-FBZA	12	90
13	CuI	N-MeBZA	12	55
14	CuSO4	BZA	12	26
15	Cu(OAc)2	BZA	12	14
16	CuCl2	BZA	12	35
17	CuO	BZA	12	Trace
18	Cu2O	BZA	12	32
19	CuCl	BZA	12	36
20	CuBr	BZA	12	58
21^c	CuI	BZA	48	55
22^d	CuI	BZA	12	97
23^e	CuI	BZA	24	95
24^e^,^f	CuI	BZA	12	98

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The substrate generality and scope of this transformation were explored. The results were listed in Table 2. The terminal alkynes with electron-donating as well as electron-withdrawing substituents proceeded homo-coupling reactions smoothly and afforded the corresponding symmetrical aromatic 1,3-diyne derivatives 2a–i in good to excellent yields (entries 1–9). However, the alkyne 1j with amino group only gave the corresponding product 2j in 63% yield under the optimal reaction conditions (entry 10). The heteroaromatic alkyne 1k was also a suitable substrate and gave the desired 1,3-diyne 2k in 74% yield under the optimal reaction conditions (entry 11). Moreover, this catalytic system was applied to aliphatic terminal alkynes. For instance, the symmetrical aliphatic 1,3-diynes 2l–n were obtained in 83%, 94%, and 99% yields, respectively (entries 12–14).

Table 2 Copper(I)-catalyzed oxidative homo-coupling of terminal alkynes^a

Entry	R	Product	Time (h)	Yield^b (%)
a Reactions conditions: alkynes 1 (3.0 mmol), 0.5 mol% CuI, 5 mol% benzylamine, room temperature under O2. b Isolated yield based on 1.
1	Ph	2a	12	98
2	2-MeC6H4–	2b	12	81
3	3-MeC6H4–	2c	12	99
4	4-MeC6H4–	2d	12	99
5	4-n-PentylC6H4–	2e	17	99
6	4-n-ButylC6H4–	2f	12	99
7	4-OMeC6H4–	2g	14	92
8	3-ClC6H4–	2h	14	87
9	4-FC6H4–	2i	12	90
10	3-NH2C6H4–	2j	48	63
11	Thienyl-2–	2k	22	74
12	n-Butyl	2l	36	83
13	n-Hexyl	2m	36	94
14	t-Butyl	2n	24	97

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This approach is also capable for solid terminal alkynes, however organic solvent is required. THF was found to be a suitable solvent for this transformation and aromatic product 2o was generated in 95% yield (Scheme 1). Aliphatic product 2p bearing a L-proline scaffold was isolated in 96% yield as a single diastereomer which might be applied in life science.

Scheme 1 Transformation for solid terminal alkynes. Reaction conditions: terminal alkynes (3.0 mmol), CuI (0.5 mol%), benzylamine (5 mol%) in THF (3 mL) was stirred at room temperature under 1 atm O₂.

Finally, a gram experiment with 20 mmol (2.04 g) 1a and CuI (0.05 mol% 1.9 mg) was employed (Scheme 2). The TON reached 1340 and 1760 under air or 1 atm O₂, which are the highest TONs for the Cu-catalyzed homo-coupling reaction reported to date (see the ESI†).

Scheme 2 Gram scale experiment. Reaction conditions: 1a (20 mmol) in the presence of CuI (0.05 mol%), benzylamine (5 mol%) was stirred at room temperature under air (condition 1) or under 1 atm O₂ (condition 2).

In summary, we have developed a practical, economical and green approach for the CuI catalyzed oxidative homo-coupling of terminal alkynes under solvent and base free conditions. The transformation is general and can involve aromatic, heteroaromatic, and aliphatic alkynes. The desired symmetrical 1,3-diynes were provided in good to excellent yields. The TON was up to 1760.

This work was supported by National Natural Science Foundation of China (21202048), Program for Minjiang Scholar (10BS216), Science Research Item of Science and Technology of Xiamen City (3502z201014) and the Natural Science Foundation of Fujian Province, China (2013J01050).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra43873b

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