Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to α,β-unsaturated trifluoromethyl ketones

Abstract

The conjugate diynylation of α,β-unsaturated trifluoromethyl ketones is carried out in the presence of a low catalytic load (2.5 mol%) of a copper(I)–MeOBIPHEP complex, triethylamine and a terminal 1,3-diyne. Pre-metalation of the terminal 1,3-diyne with stoichiometric or higher amounts of dialkylzinc reagent is not required. The corresponding internal diynes bearing a propargylic stereogenic center are obtained with good yields and excellent enantioselectivities.

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The 1,3-diyne moiety is present in a large number of natural and artificial molecules.¹ Naturally occurring diynes are found as metabolites in a variety of fungi, higher plants and marine organisms, and many of them have important biological and pharmacological properties ranging from antifungal to anticancer activities.² Diynes and oligoynes are also of interest as probes of extended π-conjugation and can serve as active components in optoelectronic devices.³ Furthermore, conjugate diynes are intriguing building blocks due to the unique behavior of alkynes, especially in transition metal-catalyzed processes.⁴

In recent years the nucleophilic addition of terminal alkynes to prochiral electrophiles has emerged as one of the most efficient procedures for the synthesis of internal alkynes bearing a propargylic stereogenic center. Thus considerable success has been made in the enantioselective alkynylation of carbonyl compounds⁵ and imines,⁶ and, more recently, in the conjugate alkynylation of electrophilic double bonds.⁷ However, studies on enantioselective addition of 1,3-diynes are more limited, and all the examples reported in the literature involve the activation of terminal 1,3-diynes as diynylzinc reagents, which requires in most of the cases the use of stoichiometric or larger amounts of expensive dialkylzinc reagents. Thus, after the pioneering work of Carreira in 2003,⁸ on the use of 4 equivalents of Zn(OTf)₂/N-methylephedrine to achieve the addition of a terminal 1,3-diyne to an aliphatic aldehyde, Trost⁹ reported in 2010 a catalytic enantioselective addition of 1,3-diynes to aldehydes using a dinuclear ProPhenol/zinc catalyst. Later on, Pu,¹⁰ Tykwinski¹¹ and Wang¹² developed their own versions of the asymmetric zinc-catalyzed addition of 1,3-diynes to aldehydes by using combinations of dialkylzinc with amino alcohol^11,12 or binaphthol-type¹⁰ ligands. In 2011, Ma described the enantioselective addition of 1,3-diynylzinc reagents, generated in situ from Me₂Zn and terminal diynes, to aromatic ketones in the presence of a Cu(II)–hydroxycamphor–sulfonamide complex and Me₂Zn.¹³ On the other hand, the diynylation of different kinds of aldimines¹⁴ and fluorinated ketimines¹⁵ has been reported by the same group using terminal diynes, Me₂Zn and binaphthol-type ligands. However, a procedure for the enantioselective addition of 1,3-diynes to electrophilic C–C double bonds, i.e. enones, has not been reported so far.

Following our research interest in the conjugate alkynylation reaction,^7d,e,i,j we report in this communication our results on the enantioselective copper-catalyzed conjugate addition of terminal 1,3-diynes to enones, a reaction without any precedent in the literature. In our study, we have chosen α,β-unsaturated trifluoromethyl ketones (Scheme 1) as electrophiles because of the significance of fluorinated compounds in medicinal chemistry.¹⁵ Trifluoromethyl enones^16,17 are a particularly challenging class of substrates for conjugate asymmetric transformations since the presence of the strongly electron-withdrawing trifluoromethyl group not only activates the alkene but also renders the ketone functionality highly reactive making the control over regioselectivity difficult. In fact, only two examples of alkynylation of trifluoromethyl enones have been reported so far, both taking place regioselectively on the carbonyl group.^17a,18

Scheme 1 Conjugate diynylation of α,β-unsaturated trifluoromethyl ketones and ligands used in this study.

In the onset of our investigation we studied the addition of phenyl-1,3-butadiyne (1a, R¹ = Ph) to enone 2a (R² = Ph) catalyzed by 20 mol% of [Cu(CH₃CN)₄]BF₄ and (R)-MeOBIPHEP 2 (L1) in toluene (Scheme 1, Table 1, entry 1). Pleasantly, compound 3aa was obtained in 82% yield and 93% ee under these reaction conditions. No products arising from 1,2-addition to the carbonyl group were observed. Further studies with this catalytic system (Table 1, entries 2–6) showed that the catalyst load could be reduced to as low as 2.5 mol% and the amount of base decreased to sub-stoichiometric 0.1 equiv. without a significant effect on the reaction outcome. Furthermore, the amount of diyne was also reduced to only 1.3 equivalents with respect to enone. Other phosphine ligands L2–L6 were also tested (Table 1, entries 7–11). Surprisingly, from all the studied ligands, only biarylphosphine L1 provided a catalytic complex sufficiently active to promote the reaction with this low catalytic load. The use of copper(I) triflate (Table 1, entry 12) provided similar results to [Cu(CH₃CN)₄]BF₄, whereas other solvents such as THF or CH₂Cl₂ decreased the reaction rate, compound 3aa being obtained in lower yields than in toluene, although still with good enantioselectivities (Table 1, entries 13 and 14). Diethyl ether performed better than THF, but with lower yield and ee than toluene (Table 1, entry 15). The use of other bases such as DIPEA did not improve the results obtained with Et₃N (Table 1, entry 16).

Table 1 Conjugate addition of phenylbuta-1,3-diyne (1a) to enone 2a. Screening of ligands and reaction conditions

Entry	L	L-Cu (mol%)	1a (equiv.)	Et3N (equiv.)	Solvent	t (h)	Yield (%)	ee^a (%)
a Determined by HPLC using chiral stationary phases. b CuOTf 0.5 Tol was used instead of [Cu(CH3CN)4]BF4. c DIPEA was used instead of Et3N.
1	L1	20	7.4	1.0	Toluene	18	82	93
2	L1	10	5	1.0	Toluene	18	70	93
3	L1	5	3	1.0	Toluene	18	73	93
4	L1	5	3	0.1	Toluene	18	75	93
5	L1	2.5	1.3	0.1	Toluene	18	73	93
6	L1	2.5	1.3	0	Toluene	18	n.r.	—
7	L2	2.5	1.3	0.1	Toluene	18	n.r.	—
8	L3	2.5	1.3	0.1	Toluene	18	n.r.	—
9	L4	2.5	1.3	0.1	Toluene	18	n.r.	—
10	L5	2.5	1.3	0.1	Toluene	18	Trace	—
11	L6	2.5	1.3	0.1	Toluene	18	Trace	—
12^b	L1	2.5	1.3	0.1	Toluene	18	65	93
13	L1	2.5	1.3	0.1	THF	48	34	94
14	L1	2.5	1.3	0.1	CH2Cl2	48	17	90
15	L1	2.5	1.3	0.1	Et2O	48	58	90
16	L1	2.5	1.3	0.1^c	Toluene	18	65	91

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Under the best reaction conditions available (Table 1, entry 5) we studied the scope of the reaction with various enones 1 and diynes 2.‡ First, we conducted the addition of diyne 2a with several trifluoromethyl enones bearing different substituents at the β position of the double bond. The results are gathered in Table 2. Good results were obtained with a variety of enones bearing a substituted aromatic ring at this position. Good enantiomeric excesses were obtained for enones bearing an aromatic ring substituted at either the ortho, meta or para positions (Table 2, entries 2–4). Aromatic rings bearing electron-withdrawing (Table 2, entries 5 and 6) or electron-donating (Table 2, entries 7 and 8) substituents were also tolerated yielding the expected products with enantiomeric excesses above 90%. Enone 1i bearing a bulky 2-naphthyl group also reacted under the optimized conditions to give the diynylated product 3ia with good yield and high ee. Remarkably, the reaction could also be carried out with enones, featuring aliphatic groups on the β-carbon, providing the corresponding products 3ja–3la with moderate yields but high enantiomeric excesses (84–88%, Table 2, entries 10–12), although a higher catalytic load (10 mol%) was required in these cases.

Table 2 Enantioselective conjugate addition of terminal 1,3-diynes 2 to enones 1. Scope of the reaction^a

Entry	1	R^1	2	R^2	3	Yield (%)	ee^b (%)
a 1 (0.14 mmol), 2 (1.3 equiv.), Et3N (0.1 equiv.), [Cu(CH3CN)4]BF4 (2.5 mol%), L6 (2.5 mol%), toluene, rt. b Determined by HPLC using chiral stationary phases. c Reaction carried out with 10 mol% of catalyst. d Reaction carried out with 0.6 mmol of 1a.
1	1a	Ph	2a	Ph	3aa	73	93
2	1b	2-MeC6H4	2a	Ph	3ba	94	94
3	1c	3-MeC6H4	2a	Ph	3ca	55	93
4	1d	4-MeC6H4	2a	Ph	3da	56	92
5	1e	2-BrC6H4	2a	Ph	3ea	76	94
6	1f	4-BrC6H4	2a	Ph	3fa	55	92
7	1g	2-MeOC6H4	2a	Ph	3ga	69	94
8	1h	4-MeOC6H4	2a	Ph	3ha	41	92
9	1i	2-Naphthyl	2a	Ph	3ia	59	92
10^c	1j	PhCH2CH2	2a	Ph	3ja	50	84
11^c	1k	CH3(CH2)3	2a	Ph	3ka	53	87
12^c	1l	(CH3)2CHCH2	2a	Ph	3la	50	88
13	1a	Ph	2b	3-FC6H4	3ab	50	90
14	1a	Ph	2c	4-FC6H4	3ac	68	92
15	1a	Ph	2d	2-MeOC6H4	3ad	89	92
16	1a	Ph	2e	4-MeOC6H4	3ae	65	91
17	1a	Ph	2f	3-Thienyl	3af	72	94
18	1a	Ph	2g	PhCH2CH2	3ag	41	93
19	1b	2-MeC6H4	2g	PhCH2CH2	3bg	50	95
20	1a	Ph	2h	6-ClC4H8	3ah	61	93
21	1a	Ph	2i	TIPS	3ai	50	85
22^d	1a	Ph	2a	Ph	3aa	62	92

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Next, we tested the diyne scope (Table 2, entries 13–21). Substituted phenyl-1,3-butadiynes bearing electron-donating (MeO) or electron-withdrawing (F) groups on the phenyl group reacted with compound 1a with variable yields but excellent enantioselectivities (Table 2, entries 13–16). The heterocyclic 3-thienyl-1,3-butadiyne (2f) reacted with 1a to give compound 3af with 72% yield and 94% ee (Table 2, entry 17). Next, we examined the reaction with aliphatic diynes, which reacted similarly to aromatic diynes. 6-Phenyl-1,3-hexadiyne reacted with enones 1a and 1b to give the corresponding chiral diynes 3ag and 3bg, respectively, with moderate yield but high enantioselectivity (Table 2, entries 18 and 19). 8-Chloro-1,3-octadiyne (2h) reacted in a similar way to give compound 3ah in 61% yield and 93% ee (Table 2, entry 20). These results are in contrast to those observed in the copper-catalyzed conjugate alkynylation of β-trifluoromethyl enones with terminal monoynes where aliphatic alkynes reacted with lower yields and enantioselectivities than aromatic and heteroaromatic ones.^7d Finally, silyldiyne 2i, which is an equivalent of 1,3-butadiyne, could be reacted with enone 1a to give the diynylated product 3ai with 85% ee (Table 2, entry 21), showing the broad scope of the reaction regarding the diyne nucleophile. The reaction between enone 1a and diyne 2a was also carried out at a fourfold scale with a small decrease of yield but without a noticeable effect on the enantioselectivity (Table 2, entry 22).

The absolute stereochemistry of compound 3af (Table 2, entry 15) was elucidated by X-ray crystallographic analysis (see Fig. S2 in the ESI†),¹⁹ and for the rest of the products it was assigned on the assumption of a uniform reaction mechanism.

Some synthetic modifications of diynes 3 are presented in Scheme 2. Thus, full hydrogenation of both triple bonds in 3aa could be carried out over 10% Pd/C in ethyl acetate to give trifluoromethyl ketone 4 without any loss of optical purity. On the other hand, a chiral tetrahydrofuran 6 bearing a trifluoromethylated quaternary stereocenter could be obtained after diastereoselective addition of methylmagnesium chloride to compound 3aa followed by silver-catalyzed cyclization. We have also performed the desilylation of compound 3ai (70% yield) to give the chiral terminal diyne 7 upon treatment with TBAF and acetic acid in THF.

Scheme 2 Examples of chemical transformations carried out on diynes 3.

In summary, we have reported the first example of enantioselective conjugate diynylation of enones. The reaction requires only a small excess (1.3 equiv.) of a terminal diyne and is carried out in the presence of a low catalytic load of a copper(I)–biphosphine complex (0.025 equiv.) and an amine (0.1 equiv.) to provide the corresponding internal diynes bearing a propargylic stereogenic center with excellent enantioselectivities. The reaction is broad in scope for a wide range of trifluoromethyl ketones²⁰ allowing variation of substituents on the enone β-carbon as well as on the diyne. It should be remarked that, unlike in other enantioselective diynylation reactions of carbonyl compounds and imines previously reported in the literature, pre-metalation of the terminal diyne with stoichiometric amounts of a dialkylzinc reagent is not required. Our results show that the transient diynyl-copper species formed from the terminal diyne and the copper(I) complex in the presence of an amine are sufficiently nucleophilic to react even with weak electrophiles. This may anticipate the possibility of other enantioselective diynylation reactions not requiring pre-metalation of terminal diynes with stoichiometric amounts of organometallic reagents in the future.

Financial support from the Ministerio de Economía y Competitividad (MINECO-Gobierno de España) and FEDER (EU) (CTQ2013-47494-P) and from Generalitat Valenciana (ISIC2012/001) is gratefully acknowledged. A. S.-M. thanks the MINECO for a predoctoral grant (FPI program). Access to NMR and MS facilities from the Servei Central de Suport a la Investigació Experimental (SCSIE)-UV is also acknowledged.

Notes and references

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19. CCDC 1046444.
20. Other non-fluorinated enones such as 2-cyclohexenone, chalcone or 4-phenyl-3-buten-2-one did not react under the optimized conditions.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for new compounds, and X-ray data and ORTEP plot for compound 3af. CCDC 1046444. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc01676b

‡ General procedure for the enantioselective conjugate diynylation reaction: [Cu(CH₃CN)₄]BF₄ (1.1 mg, 0.0034 mmol) and (R)-L1 (4.1 mg, 0.0034 mmol) were added to a dried round bottom flask which was purged with nitrogen. Toluene (0.2 mL) was added via a syringe and the mixture was stirred for 1.5 h at room temperature under a nitrogen atmosphere. Then, a solution of α,β-unsaturated trifluoromethyl ketone 1 (0.144 mmol) in toluene (1.0 mL) was added via a syringe, followed by triethylamine (2 μL, 0.0144 mmol). The solution was stirred for 10 min at room temperature. Then a solution of 1,3-diyne 2 (0.188 mmol) in toluene (1.0 mL) was added via a syringe and the solution was stirred at room temperature until the reaction was complete (TLC). The reaction mixture was quenched with 20% aqueous NH₄Cl (1.0 mL), extracted with CH₂Cl₂ (2 × 15 mL), washed with brine (15 mL), dried over MgSO₄ and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexane:ethyl acetate mixtures afforded compound 3.

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