Cationic gold(I)-catalyzed enantioselective hydroalkylation of unactivated alkenes: influence of the chloride scavenger on the stereoselectivity

Abstract

Enantioselective intramolecular additions of β-ketoamides to unactivated alkenes have been accomplished by means of gold catalysis. Chiral LAuCl complexes have been activated by various Lewis acids (Cu, Ag, Ga, In, Si, Bi etc.). The influence of these activators on the stereoselectivity has been studied.

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Catalytic C–C bond forming reactions enjoy a pre-eminent place in organic chemistry. Among them, addition of carbon nucleophiles (or pronucleophiles¹) to alkynes, allenes, or alkenes, has become an essential synthetic tool.² Whereas catalytic asymmetric hydroalkylation and hydroarylation of alkynes³ and allenes^4,5 have been well-studied (Scheme 1, eqn (1) and (2)), the case of simple olefins has received little attention (eqn (3)).⁶

Scheme 1 Prototypical hydrocarbonations of alkynes, allenes, and alkenes, leading to chiral products (Y, Z = COR, CO₂R, CN, SO₂Ph, Meldrum acid etc.).

In contrast with catalytic asymmetric additions to activated alkenes (Michael type reactions) which can be achieved in a variety of ways, including with pronucleophiles,⁷ the corresponding transformations of readily available unactivated substrates are still scarce⁸ and mostly rely on stoichiometric carbometallation.⁹ Only a few catalytic enantioselective hydroarylations of unactivated alkenes have been reported.¹⁰ Widenhoefer et al. notably described platinum-catalyzed intramolecular additions of indoles to alkenes (Scheme 2).^10a,b

Scheme 2 Example of enantioselective metal-catalyzed hydroarylation of an unactivated alkene.

To the best of our knowledge, no catalytic asymmetric hydroalkylation of an unactivated alkene had been reported until we described¹¹ the cyclization of ene-β-ketoamide 1a in the presence of (R)-DTBM-SEGPHOS(AuCl)₂A1 and Cu(OTf)₂ (Scheme 3).^12–14 This reaction led to a mixture of the separable enantioenriched diastereomers 2a and 2a′.¹⁵

Scheme 3 Enantioselective hydroalkylation of ene-β-ketoamide 1a.

In our previous study, our aim was to show that not only silver salts could serve as scavengers to generate active cationic gold complexes from the corresponding chlorides,¹⁶ but also Cu(I) and Cu(II) complexes such as Cu(OTf)₂. The interest of using a copper salt is to gradually deliver the fragile cationic gold species from the very stable gold chloride. Among various reactions, we have carried out the one shown in Scheme 3 as a proof that the cyclization was not merely attributable to the formation of triflic acid or molecular Au(0) clusters in the reaction medium.^17,18 No attempt to improve the stereoselectivity was made. The possible influence of the activator on the stereoselectivity was not studied either. Since two contiguous stereogenic sp³ carbons are formed, this case seems more challenging than the related Conia-ene reaction on alkynes.³ Nevertheless, considering its innovative ground and its inherent synthetic interest,¹⁹ we decided to study in detail the experimental factors governing the asymmetric hydroalkylation of ene-β-ketoamides.

Contrary to the previously studied substrates under Au/Cu catalysis,^11a Cu(OTf)₂ alone proved able to promote the cyclization of 1a, albeit at a slower pace (Table 1, entry 1, 32% conversion without gold),^20,21 which possibly hampers the enantioinduction. Lowering the temperature to 50 °C dramatically decreased the conversion to 9% (entry 2), even after raising the proportion of Cu(OTf)₂ to 25 mol% (entry 3). The use of 10 mol% of (MeCN)₅Cu(SbF₆)₂ increased the conversion to 29% at 50 °C (entry 4). It reached 51% with 25 mol% of the Cu(II) salt (entry 5). Finally, the Cu(I) salt CuOTf·0.5C₆H₆ allowed 92% conversion at 50 °C provided 25 mol% were engaged (entries 6 and 7). In the context of the development of silver-free two-component catalytic mixtures in gold catalysis, the higher activity of CuOTf compared to Cu(OTf)₂ under smooth conditions is an interesting feature. However, there is no positive effect of lowering the temperature on the stereoselectivity.

Table 1 Enantioselective hydroalkylation of ene-β-ketoamide 1a using the chiral gold complex A and copper salts

Entry	[Cu]	x	T (°C)	Conv^a^,^b (%)	dr^a	ee^a^,^c (%)
a Estimated by chiral SFC; diastereomeric ratios shown are 2a/2a′. b Conversion without gold is indicated in parentheses. c Corresponding to 2a/2a′. d The dr without gold is 64/36.
1	Cu(OTf)2	10	110	100 (32)	68/32^d	59/35
2	Cu(OTf)2	10	50	9 (6)	84/16	49/22
3	Cu(OTf)2	25	50	9 (7)	85/15	44/44
4	(MeCN)5Cu(SbF6)2	10	50	29 (6)	77/23	52/14
5	(MeCN)5Cu(SbF6)2	25	50	51 (11)	71/29	45/13
6	CuOTf·0.5C6H6	10	50	34 (16)	78/22	52/28
7	CuOTf·0.5C6H6	25	50	92 (18)	65/35	51/25

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Since the diastereoselectivity with Cu(OTf)₂ alone was similar to that obtained with the Au/Cu catalytic system (64/36 vs. 68/32 respectively, see Table 1, entry 1), the question of a possible chiral ligand exchange was raised. However, the addition of (R)-DTBM-SEGPHOS (10 mol%) to Cu(OTf)₂ (10 mol%) shut down the reactivity. It is therefore obvious that the enantioselectivity of the reaction stems from the gold catalyst. Nevertheless, the unexpected activity of copper in this reaction encouraged us to briefly examine the case of chiral ligands located at copper instead of gold, however, the enantioselectivity did not exceed 38% (see Table S1 in the ESI†). We also checked whether a matched pair of chiral complexes could be formed, but this was not the case (see Table S2 of the ESI†).

Since the ee did not exceed 59% with the Au/Cu system, we next investigated the Au–AgOTf catalytic mixture (Table 2). With complex A1 in toluene at 110 °C, the two diastereomers were obtained with 63% and 67% ees (entry 1). As opposed to copper, lowering the temperature to 50 °C improved the ee of the major product which reached 71% (entry 2). A similar enantioselectivity for the major diastereomer was observed in THF or dioxane, although the dr was lower than in toluene (entries 3 and 4). The use of nitromethane as more-polar solvent led to low selectivities (entry 5), which indicates that the proximity of the counterion to the cationic gold center is an important factor in the enantioinduction.²²

Table 2 Solvent and gold catalyst screening in the enantioselective hydroalkylation of ene-β-ketoamide 1a using AgOTf

Entry	[Au]	Solvent	T (°C)	Time (h)	Conv^a (%)	dr^a	ee^a^,^b (%)
a Estimated by chiral SFC; diastereomeric ratios shown are 2a/2a′. b Corresponding to 2a/2a′. c 91% isolated yield.
1	A1	Toluene	110	24	100	66/34	63/67
2	A1	Toluene	50	24	100	78/22	71/62
3	A1	THF	50	24	100	66/34	72/25
4	A1	Dioxane	50	24	99	72/28	73/49
5	A1	MeNO2	50	24	49	59/41	5/18
6	A2	Toluene	50	2	98	79/21	71/59
7	B1	Toluene	50	0.5	100	80/20	24/31
8	B2	Toluene	50	2	100	82/18	44/38
9	C1	Toluene	50	24	100^c	43/57	82/96
10	C2	Toluene	50	2	100	74/26	65/80
11	D	Toluene	50	2	100	74/26	32/33
12	E	Toluene	50	23	53	67/33	4/5
13	F	Toluene	50	5	100	71/29	4/18
15	G	Toluene	50	4	98	75/25	31/35
16	H	Toluene	50	4	97	79/21	41/3
17	I	Toluene	50	8	98	79/21	16/7
18	J	Toluene	50	2	100	74/26	3/12
19	K	Toluene	50	23	80	22/78	8/5

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Various chiral mono- and digold complexes were next evaluated (entries 6–19). The chiral gold complexes used in this study are shown in Fig. 1. Compounds A1, A1′,²³A2,²⁴B1,²⁵B2,²⁶C1,²⁷C2,²⁸D,²⁹E,^23,30G,³¹H,³²I,³³ and K³⁴ have been previously described. Complexes F^33,35 and J³⁶ are new but structurally close to other reported gold catalyst. With C1, although the diastereoselectivity was low, 2a and 2a′ were obtained with high enantioselectivities of 82 and 96% respectively (entry 9).

Fig. 1 Chiral gold complexes used in this study.

Using the digold complex C1, additional silver salts and other activators were scrutinized (Table 3, the result with AgOTf is reminded in entry 1 for clarity).‡ The conversion reached in the absence of gold is indicated in parentheses. It remained very modest if any.³⁷ A very good dr of 91/9 was achieved with AgBF₄ (entry 2). The major diastereomer was obtained in 83% ee in this case. The use of AgPF₆, AgSbF₆, and AgNTf₂ led to lower induction levels (entries 3–5). Pertaining to our research program aimed at developing silver-free two-component approaches in gold catalysis,¹¹ various Lewis acids were tested next. With Cu(OTf)₂, 2a was formed in 66% ee and 2a′ in 93% ee (entry 6). Similarly to AgOTf, 2a and 2a′ were formed with low diastereoselectivity but in high ees with In(OTf)₃ and Bi(OTf)₃ (entries 7 and 8). With TMSOTf, the stereoselectivity was comparable to other metal triflates but full conversion was not reached (entry 9). Other activators such as Zn(OTf)₂, Ga(OTf)₃, and In(NTf₂)₃ have also been tested towards the chiral gold complex A1 (see Table S3 of the ESI†), yet none outperformed silver salts.

Table 3 Screening of activators in the enantioselective hydroalkylation of ene-β-ketoamide 1a

Entry	[LA]	Conv^a^,^b (%)	dr^a	ee^a^,^c (%)
a Estimated by chiral SFC; diastereomeric ratios shown are 2a/2a′. b Conversion without gold is indicated in parentheses. c Corresponding to 2a/2a′.
1	AgOTf	100 (3)	43/57	82/96
2	AgBF4	100 (3)	91/9	83/2
3	AgPF6	100 (4)	74/26	78/66
4	AgSbF6	100 (5)	84/16	66/14
5	AgNTf2	100 (4)	88/12	68/33
6	Cu(OTf)2	12 (6)	53/47	66/93
7	In(OTf)3	100 (5)	48/52	80/85
8	Bi(OTf)3	100 (9)	43/57	82/92
9	TMSOTf	59 (5)	47/53	83/95

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Table 4 Gold(I)-catalyzed enantioselective hydroalkylation of ene-β-ketoamides 1b–g

Entry	Substrate	T (°C)	Conv^a (%)	Yield^b (%)	dr^a	ee^a (%)
a Estimated by chiral SFC. b Isolated product. c The two diastereomers were separated. d With AgBF4: dr 26/74, ee 55/66, 92% yield. e The two diastereomers were separated, the two methyl groups have a trans relationship in the major one (see ESI).
1	1b	50	100	90	70/30	98/72
2	1c	50	87		45/55	88/96
3	1c	110	100	89	46/54^c	83/95
4	1d	50	94		46/54	93/82
5^d	1d	110	100	94	49/51^e	90/81
6	1e	50	9		52/48	73/62
7	1e	110	88	74	59/41	79/86
8	1f	50	25		68/32	81/87
9	1f	110	95	80	69/31	78/83
10	1g	50	29		55/45	90/95
11	1g	110	98	86	53/47	85/91

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Thus, the nature of the major product greatly varies as a function of the Lewis acid. Nevertheless, as far as the enantioselectivity is concerned, it is with AgOTf that the best result was obtained. Focusing on our objective to show that catalytic asymmetric hydroalkylation of unactivated alkenes can be achieved, the C1–AgOTf mixture was used with the ene-β-ketoamides 1b–g (Table 4). We selected malonates displaying a tertiary α-carbon to avoid epimerization of the final product.^11a Gratifyingly, 1b transformed into the expected spiro derivative 2b with an excellent ee of 98% for the major diastereomer (entry 1). With 1c, which is the benzo-fused analog of 1a, high ees were also obtained but full conversion was not reached at 50 °C (entry 2). Raising the temperature to 110 °C allowed full conversion without significantly affecting the stereoselectivity (entry 3). The transformation of the acyclic substrates 1d–g furnished the desired products with good to high ees, even at 110 °C which was a required temperature to achieve high conversions (entries 4–11). In each case, the products could be isolated in good to high yields. As for the transformation of 1a, the diastereoselectivity remained moderate to low. It could be improved from 49/51 to 26/74 by using AgBF₄ instead of AgOTf (entry 5), but this was at the expense of the enantioselectivity which became 55/66 instead of 90/81.

Even though it is now well-established that both the ligand and the counterion influence the selectivity in Au(I)-catalysis, it is not yet possible to establish a clear structure–activity relationship.³⁸ Nevertheless, a plausible mechanism can be summarized as follows (Scheme 4). According to our study in the Au/Cu catalytic system,^11a we suppose that all of the activators used in this study are able to promote chloride abstraction from the gold precatalyst. The C–C bond formation likely involves the coordination of the alkene by the cationic gold π-acid catalyst,³⁹ triggering an anti or syn nucleophilic attack⁴⁰ of the malonate activated in the form of a metal enolate or an enol ether.^41,42 The 5-exo trig cyclization gives rise to a σ-gold complex that would finally undergo protodemetallation with YH. As shown above, the aptitude of the counterion Y⁻ to remain close to the “spectator” gold atom and serve as proton shuttle⁴³ is a likely determining factor.

Scheme 4 Mechanistic rationale (Y = counterion).

Conclusions

This study has shown for the first time the feasibility of asymmetric hydroalkylation of unactivated alkenes, a synthetic approach which avoids the use of activating groups and their subsequent removal. Enantioselective transformations of ene-β-ketoamides into 2-azaspirodiones and 3-acetylpyrrolidin-2-ones have been accomplished by means of gold catalysis. High enantioselectivities have been reached by using (R)-DTBM-MeOBIPHEP-(AuCl)₂ and various triflates such as AgOTf, In(OTf)₃, and Bi(OTf)₃.

We are grateful for the financial support from ANR JCJC HAONA, UPS, CNRS, the Chinese Scholarship Council, and IUF. We are also thankful to Arnaud Voituriez and Angela Marinetti (ICSN) for a gift of a chiral gold complex. Dedicated to Prof. Max Malacria on the occasion of his 65^th birthday.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details and characterizations. See DOI: 10.1039/c4qo00112e

‡ General procedure pertaining to Table 3, entry 1, and Table 4: A 10 mL oven-dried tube equipped with a Teflon-coated magnetic stir bar was charged with C1 (8.2 mg, 0.005 mmol), silver(I) triflate (2.6 mg, 0.010 mmol), and toluene (0.5 mL) and the mixture was stirred at room temperature for 1 min. The substrate (0.10 mmol) in toluene (0.5 mL) was added and the tube was sealed with a plastic stopper. The tube was covered by aluminum foil and immersed and stirred in a preheated oil bath at the indicated temperature for 24 h. Then, the reaction mixture was filtered through a short pad of silica gel which was rinsed with diethyl ether. After evaporation, the residue was purified by chromatography on silica gel to afford the desired product.

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