Iridium/chiral phosphoramidite–olefin complex-catalysed enantioselective [3+2] annulation of ortho-ketoarylboron compounds with conjugated dienes

Abstract

The iridium-catalysed enantioselective [3+2] annulation of ortho-ketoarylboron compounds with conjugated dienes proceeded to give chiral indanol derivatives bearing an all-carbon quaternary stereogenic center in high yields with high enantioselectivity. Chiral phosphoramidite–olefin ligands were effective for the high reactivity and enantioselectivity.

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Indane derivatives, which have a fused structure of benzene ring and five-membered ring, are important structural motifs in several chiral drugs and natural products.¹ Transition-metal-catalysed stereoselective [3+2] annulation is one of the useful methods for the synthesis of indane derivatives, and ortho-functionalized arylboron reagents have often been used with unsaturated hydrocarbons such as allenes, alkynes and conjugated dienes for the [3+2] annulation.² In this respect, we reported iridium-catalyzed [3+2] annulation of ortho-carbonylated arylboronic acids with 1,3-dienes giving indanol derivatives with high regio- and diastereoselectivity (Scheme 1a).³ The reaction proceeded via an ortho-carbonylaryliridium(I) species, which is generated from a hydroxoiridium complex and the corresponding arylboronic acids. The enantioselective annulation was also achieved by use of a chiral diene ligand (Scheme 1b).^4,5 However, the successful reaction was limited to ortho-formylarylboron compounds, and ortho-ketoarylboron reagents could not be applied to the annulation because of the low reactivity. In addition, high reaction temperature to promote the reaction can probably cause ligand exchange between the chiral diene ligand and the 1,3-diene, which exists in excess to the Ir catalyst. Unfortunately, the use of chiral diphosphine ligands, which strongly coordinate to the iridium, inhibited the reaction. It follows that new ligands bearing appropriate coordination ability are required for the realization of the iridium-catalyzed asymmetric annulation. In this context, we focused on chiral phosphine–olefin hybrid ligands,^6,7 which have stronger coordination ability than diene ligands, and are unique ligands that combine the coordination properties of both phosphines and olefins.^7,8 Here we report that iridium/chiral phosphine–olefin complexes are effective in catalysing asymmetric [3+2] annulation of ortho-keto arylboron compounds with 1,3-dienes.

Scheme 1 Ir-catalysed [3+2] annulation.

In the first set of experiments, annulation of ortho-acetylphenylboron compound 1a with isoprene (2a) was examined under several reaction conditions (Table 1). Treatment of 1a with 2a (3.0 equiv.) in toluene/H₂O (1 : 1) at 80 °C for 24 h in the presence of [IrCl(coe)₂]₂ (5 mol% of Ir, coe = cyclooctene), (rac)-L1 (6 mol%), and Et₃N (1.3 equiv.) gave the corresponding product cis-3aa exclusively as a single isomer in 58% yield (entry 1).⁹ The reaction in 1,4-dioxane or 1,2-dichloroethane instead of toluene decreased the yield of 3aa (entries 2 and 3). The lower diastereoselectivity (cis : trans = 73 : 27) was observed in the reaction without triethylamine, which was added to inhibit the hydrolysis reaction of 1a by the iridium catalysis (entry 4).¹⁰ Water was necessary for the reaction (entry 5). The reaction without ligand (rac)-L1, where Ir(I)/isoprene complex is formed, did not procced (entry 6). Fortunately, the use of (R)-L1^7a gave 3aa with good enantioselectivity (85% ee, entry 7). It was found that a rhodium complex with (rac)-L1 also promoted the present reaction albeit with low yield (20%, entry 8). Boron functional groups influenced the yield and enantioselectivity (entries 9–11). Commercially available ortho-acetylboronic acid (4a) showed slightly lower reactivity compared with potassium aryltrifluoroborate 1a (entry 9). Boron esters can also be applied to the present reaction (entries 10 and 11), and, in particular, pinacol ester 6a displayed excellent reactivity, thus giving 3aa in 79% yield with 86% ee (entry 11). The absolute configuration of 3aa obtained using (R)-L1 was determined to be (1R,3R) by HPLC analysis of a separately synthesized (1R,3R)-3aa (see the ESI† for details).

Table 1 Ir-catalyzed annulation of 1a with isoprene (2a)^a

Entry	Changes from standard conditions	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a or 4a–6a (0.20 mmol), 2a (0.60 mmol, 3.0 equiv.), [IrCl(coe)2]2 (0.0050 mmol, 5 mol% of Ir), L1 (0.012 mmol, 6 mol%) and Et3N (0.26 mmol, 1.3 equiv.) in toluene (0.8 mL) and H2O (0.8 mL) at 80 °C for 24 h under N2 atmosphere. Unless otherwise stated, the ratio of diastereomers is >99 : 1. b Determined by ^1H NMR. c Determined by chiral HPLC analysis. d The product was obtained as a mixture of diastereomers (cis/trans = 73 : 27).
1	No changes	58	—
2	1,4-Dioxane instead of toluene	43	—
3	ClCH2CH2Cl instead of toluene	31	—
4	Without Et3N	43^d	—
5	Without H2O	15	—
6	Without (rac)-L1	<1	—
7	(R)-L1 instead of (rac)-L1	66	85
8	[RhCl(coe)2]2 instead of [IrCl(coe)2]2	20	—
9	4a instead of 1a with (R)-L1	55	87
10	5a instead of 1a with (R)-L1	31	86
11	6a instead of 1a with (R)-L1	79	86

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Screening results of chiral phosphoramidite–olefin ligands using 1a as the substrate are shown in Scheme 2. We took an approach to revise the binaphthyl moiety due to easy synthesis and availability. The use of phosphoramidite–olefin ligands with a 3,3′-disubstituted binaphthyl moiety (L2–L5) gave 3aa with excellent enantioselectivity (98–99% ee). In particular, L3 substituted with a 3,3′-dibromo-substituted binaphthyl showed the best reactivity and enantioselectivity (66%, 99% ee). As the steric hindrance of the 3,3′-substituents further increased, the product yield decreased (L4 and L5). H8-Binol backbone in L6 did not improve the enantioselectivity. The phosphoramidite–olefin ligand derived from (R,R)-TADDOL (L7)^7b or L-prolinol (L8)^7b did not induce the catalytic activity. Phosphite–olefin ligand L9,⁸ which is used for Rh-catalyzed asymmetric 1,4-additions, could not be applied to the present annulation.

Scheme 2 Screening of chiral phosphoramidite–olefin ligands. ^a Reaction conditions: 1a (0.20 mmol), 2a (0.60 mmol, 3.0 equiv.), [IrCl(coe)₂]₂ (0.0050 mmol, 5 mol% of Ir), ligand (0.012 mmol, 6 mol%) and Et₃N (0.26 mmol, 1.3 equiv.) in toluene (0.8 mL) and H₂O (0.8 mL) at 80 °C for 24 h under N₂ atmosphere. The ratio of diastereomers is >99 : 1. ^b Determined by ¹H NMR. ^c Determined by chiral HPLC analysis.

The scope of ortho-ketoarylboron esters 6, some of which are readily available by C–H borylation,¹¹ is shown in Scheme 3.¹² The reaction of 6a with isoprene (2a) gave 3aa in 53% yield with 98% ee. Para-substituted acetophenone derivatives 6b and 6c underwent the annulation to give the corresponding products 3ba and 3ca, respectively, with high enantioselectivity (99% ee). Arylboron esters 6d and 6e substituted with ethyl and isopropyl groups reacted efficiently to give the corresponding products 3da and 3ea in 76 and 55% yields, respectively, with complete enantioselectivity. The reaction of α-tetralone derivative 6f gave tricyclic product 3fa in 72% yield with 95% ee. Boron ester 6g bearing a benzoyl group is also a good substrate to give the corresponding indanol 3ga in 85% yield with 99% ee. Para-, meta-, and ortho-substituted benzoylphenylboron esters 6h–6l efficiently participated in the reaction to give the corresponding products 3ha–3la in good yields (56–85%) with excellent selectivity (95–99% ee). The reaction using 1.0 mmol of 6l gave 3la in 60% yield with 99% ee. In the reaction of arylboron ester 6m, which has a 6-methoxynaphthyl group, the use of L4 was effective in displaying the high enantioselectivity (99% ee) of the product 3ma. Unfortunately, the use of o-formylphenylboron ester 6n resulted in the formation of unidentified complex mixtures.

Scheme 3 Ir-catalyzed asymmetric annulation of 6 with isoprene (2a).^{a a} Reaction conditions: 6 (0.20 mmol), 2a (0.60 mmol, 3.0 equiv.), [IrCl(coe)₂]₂ (0.0050 mmol, 5 mol% of Ir), L3 (0.012 mmol, 6 mol%), and Et₃N (0.20 mmol, 1.0 equiv.) in toluene (0.8 mL) and H₂O (0.8 mL) at 80 °C for 24 h under N₂ atmosphere. The ratio of diastereomers is >99 : 1. ^b 1.0 mmol scale reaction.

The results obtained for the reaction of several 1,3-dienes with 6g are shown in Scheme 4. 2-Substituted 1,3-dienes such as myrcene (2b), myrcenol (2c), and acetylated myrcenol 2d could be applied to the reaction of 6g to give the corresponding products 3gb–3gd with high enantioselectivity. The reactions of 3-methyl-1,3-pentadiene (2e) and 2,3-dimethyl-1,3-butadiene (2f) also displayed high enantioselectivity, albeit with the somewhat low yields. Unfortunately, however, dienes 2g–2j were not applicable to the present reaction.

Scheme 4 Ir-catalyzed asymmetric annulation of 6g with dienes 2.^{a a} Reaction conditions: 6g (0.20 mmol), 2 (0.60 mmol, 3.0 equiv.), [IrCl(coe)₂]₂ (0.0050 mmol, 5 mol% of Ir), L3 or L4 (0.012 mmol, 6 mol%) and Et₃N (0.20 mmol, 1.0 equiv.) in toluene (0.8 mL) and H₂O (0.8 mL) at 80 °C for 24 h under N₂ atmosphere. The ratio of diastereomers is >99 : 1.

Indanol 3ga was converted into several compounds while maintaining the stereochemistry (Scheme 5). Dehydration of 3ga with trimethylsilyl chloride (TMSCl) in CHCl₃ gave indene 7 in 88% yield.¹³ Rh(I)-catalysed hydrogenation of 3ga gave indanol 8 in 70% yield.¹⁴ Mizoroki–Heck reaction of indanol 3ga with p-iodotoluene gave 9 in 80% yield.¹⁵

Scheme 5 Transformation of 3ga.

In summary, we have developed the asymmetric [3+2] annulation of ortho-ketoarylboron compounds with 1,3-dienes catalysed by the iridium/chiral phosphoramidite–olefin complex. The use of a new chiral phosphoramidite–olefin ligand with a 3,3′-bromo-substituted binaphthyl structure showed almost complete enantioselectivity of the annulation products bearing an all-carbon quaternary center.

This work was supported by JSPS KAKENHI Grant Number JP19H02721 and JP24K08416.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

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9. The mechanism of the present reaction has been proposed in previous work (ref. 3) from the observed regio- and stereoselectivity.
10. It is not clear why the bases affect the diastereoselectivity. See also ESI† for the results using other bases.
11. H. Itoh, T. Kikuchi, T. Ishiyama and N. Miyaura, Chem. Lett., 2011, 40, 1007.
12. The corresponding ketones formed by hydrolysis of 6 were also observed.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, and compound characterization data. See DOI: https://doi.org/10.1039/d4cc04238g

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