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Synthesis 2022; 54(21): 4764-4772
DOI: 10.1055/a-1683-9455
special topic
Asymmetric C–H Functionalization

Cationic Iridium/Chiral Bidentate Phosphoramidite Catalyzed Asymmetric Hydroarylation

Tomohiko Shirai 
a   Department of Materials Science and Engineering, National Institute of Technology, Kochi College Otsu, Monobe, Nangoku, Kochi 783-8508, Japan
,
Yasunori Yamamoto  ∗
b   Division of Chemical Process Engineering and Frontier Chemistry Center (FCC), Faculty of Engineering, Hokkaido University, Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628, Japan
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Abstract

In this personal account, we summarize our investigations on the asymmetric direct addition of C(sp2)–H bonds to unsaturated bonds, such as C=O and C=C, using cationic iridium/chiral O-linked bidentate phosphoramidite (Me-BIPAM) and S-linked bidentate phosphoramidite (S-Me-BIPAM) catalyst systems.

1 Introduction

2 Highly Enantioselective Intramolecular Hydroarylation of α-Keto Amides

3 Highly Enantioselective Intermolecular Hydroarylation of Bicyclo­alkenes

4 Conclusion


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Key words

asymmetric synthesis - C–H functionalization - hydroaryl­ation - iridium catalysts - chiral bidentate phosphoramidites
1

Introduction

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Yasunori Yamamotowas born in Hokkaido, Japan in 1968. He received his B. Eng. (1991) and M. Eng. (1993) from Hokkaido University under the direction of Professor Akira Suzuki. He worked at Mitsubishi Chemical Corporation as Researcher from 1993 to 1995. In 1995, he then moved to Hokkaido University as an Assistant Professor of the Miyaura research group and received his Ph. D. degree in 2003 from Hokkaido University. In 2012, he was promoted to a Specially Appointed Associate Professor at Hokkaido University. His research interests are in the development of new methods for the organic syntheses using the transition-metal-catalyzed cross-coupling and addition reactions of organoboron compounds, and asymmetric synthesis by using transition-metal-catalyzed C–H activation.

Transition-metal-catalyzed C–C bond-forming reactions via C–H bond activation are the ultimate atom-economical processes. In particular, direct additions of arenes to double bonds such as C=O, C=N and C=C, called hydroarylation reactions, are completely atom-economical.[1] [2] Furthermore, enantioselective transformations by C–H activation constitute an ideal tool for the synthesis of chiral building blocks.[2] Our group has already demonstrated that cationic iridium (I)/chiral bidentate phosphoramidite (Me-BIPAM) complexes can catalyze the asymmetric direct addition of C(sp2)–H bonds to unsaturated bonds, such as C=O and C=C.[3] On the other hand, we have developed moderate π-acidic chiral bidentate phosphoramidite ligands[4] for the transition-metal-catalyzed asymmetric nucleophilic addition reactions of organoboronic acid derivatives for 15 years (Figure [1]).[5] We previously showed that a chiral bidentate phosphoramidite ligand achieved high enantioselectivities for arylation reactions of C=C,[6] C=N[7] and C=O[8] bonds. These chiral bidentate phosphoramidite ligands can be easily prepared from the corresponding linked BINOL.[3c] [6a] [7a] [8] [9] In this account, we summarize our recently developed cationic iridium/ Me-BIPAM­-catalyzed asymmetric hydroarylation of unsaturated bonds with activation of sp2 carbon–hydrogen bonds. As a result of various investigations, we found that the newly developed cationic iridium/Me-BIPAM complex has excellent catalytic activity for the asymmetric intramolecular hydroarylation of ketones with the activation of sp2 carbon–hydrogen bonds (see Scheme [1]).[3a] At the same time, mechanistic studies revealed the rate-limiting step in the estimated catalytic cycle.[3b] Furthermore, in the process of tuning the catalyst, we found that the newly developed catalytic system consisting of a novel sulfur-bridged bidentate phosphoramidite ligand (S-Me-BIPAM) and cationic iridium is effective for the asymmetric intermolecular hydroarylation of bicycloalkenes via activation of sp2 carbon–hydrogen bonds (see Schemes 7 and 13).[3c] [d]

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Figure 1 Chiral bidentate phosphoramidite ligands

# 2

Highly Enantioselective Intramolecular Hydroarylation of α-Keto Amides[3a] [b]

Intramolecular cyclizations by C–H bond activation have been reported for the efficient synthesis of oxindole derivatives.[10] In 2009, Shibata and co-workers reported cationic Ir/(S)-H8-BINAP-catalyzed enantioselective synthesis of a chiral 4-acetyl-3-hydroxy-3-methyl-2-oxindole with 72% ee using the methodology of direct C–H bond functionalization.[11] During study on Me-BIPAM for enantioselective bond-forming reactions, we achieved direct synthesis of chiral 3-substituted 3-hydroxy-2-oxindoles from α-keto amides using cationic iridium and (R,R)-Me-BIPAM (Scheme [1]).[3a]

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Scheme 1 Iridium-catalyzed intramolecular hydroarylation

We examined the enantioselective hydroarylation using α-keto amide 3 in the presence of a cationic iridium/(R,R)-Me-BIPAM catalyst (Table [1]).[3a] All reactions selectively gave 4-acetyl-3-hydroxy-3-phenyl-2-oxindole (4) with complete regioselectivity.[12] BArF 4 anion was more suitable than other counteranions (entries 1–6), and the yield and enantio­selectivity were moderate (62%, 71% ee). In the further optimization of solvent, 1,2-dimethoxyethane (DME) was the best one (90%, 88% ee; entry 8).

Table 1 Optimization of the Reaction Conditions for Intramolecular Hydroarylationa

Entry

Catalyst (mol%)

Solvent

Yield (%) of 4/5

ee (%) of 4

1

[Ir(cod)2](BArF 4) (5)

PhCl

62/trace

71

2

[Ir(cod)2](BF4) (5)

PhCl

37/trace

53

3

[Ir(cod)2](SbF6) (5)

PhCl

12/trace

38

4

[Ir(cod)2](OTf) (5)

PhCl

15/trace

29

5

[Ir(cod)2](ClO4) (5)

PhCl

3/trace

29

6

[Ir(cod)2]Cl (5)

PhCl

n.r.

n.r.

7

[Ir(cod)2](BArF 4) (5)

THF

94/trace

66

8

[Ir(cod)2](BArF 4) (5)

DME

90/trace

88

9

[Ir(cod)2](BArF 4) (5)

dioxane

28/trace

77

a Reaction conditions: α-keto amide (0.25 mmol), iridium catalyst (5 mol%), (R,R)-Me-BIPAM (1.1 equiv to Ir), solvent (1 mL), stirred, 135 °C, 24 h.

We also examined other directing groups (Table [2]).[3a] The dimethylaminocarbonyl group was most effective and the enantioselectivity improved to 98% ee (entry 4). The enantioselectivity was not impaired even when the reaction time was 16 hours or when the catalyst amount was 3 mol% (entries 5 and 6). The directing group was essential in this reaction (entry 8). The absolute configuration of the product was assigned as the S enantiomer from X-ray crystallographic analysis of compound 2a.[13]

Table 2 Optimization of the Directing Group for Intramolecular Hydroarylationa

Entry

DG

Ligand

Yield (%)

ee (%)b

1

Ac

(R,R)-Me-BIPAM

90

88

2

Bz

(R,R)-Me-BIPAM

90

88

3

CO2Me

(R,R)-Me-BIPAM

37

95

4

CONMe2

(R,R)-Me-BIPAM

>99

98 (S)

5c

CONMe2

(R,R)-Me-BIPAM

>99

98 (S)

6d

CONMe2

(R,R)-Me-BIPAM

96

97 (S)

7

NHAc

(R,R)-Me-BIPAM

63

82

8

H

(R,R)-Me-BIPAM

n.r.

–

a Reaction conditions: α-keto amide (0.25 mmol), iridium catalyst (5 mol%), (R,R)-Me-BIPAM (1.1 equiv to Ir), DME (1 mL), stirred, 135 °C, 24 h.

b The absolute configuration of the chiral center within the product is given in parentheses.

c Reaction mixture was stirred at 135 °C, 16 h.

d Iridium catalyst (3 mol%) was used.

The cationic Ir/Me-BIPAM catalyst achieved highly enantioselective hydroarylation of various α-keto amides (Scheme [2]). In some cases, the enantioselectivity was raised by using the preformed [Ir(cod)((R,R)-Me-BIPAM)](BArF 4) complex. A variety of aliphatic α-keto amides also gave 3-alkyl-3-hydroxy-2-oxindoles in excellent selectivities (90–94% ee). A methyl group on the nitrogen atom also resulted in good yields and enantioselectivities (70–92% ee).

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Scheme 2 Enantioselective intramolecular hydroarylation of α-keto amides
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Figure 2 Formation of iridium hydride species

In an NMR study,[3b] some signals for iridium hydride species were observed over 100 °C (Figure [2]). Although iridium hydride was detected at 100 °C, the yield was low under catalytic reaction (Scheme [3]). These results showed that addition to the carbonyl group proceeded at 135 °C. As result of the reaction of substrate 1b in the presence of D2O (6 equiv), the unreacted substrate 1b-D (30%) and product 2b-D (68%) were observed (Scheme [4]). Deuterium was observed at the ortho position of the keto amide group (11%-D at Hb and 44%-D at Hd) and the ortho position of the N,N-dimethyl carbamoyl group (10%-D at Ha) in the substrate, and the 5- and 7-positions of the product (11%-D at Ha and Hd). These results showed that the C–H bond cleavage occurs in a fast and reversible manner prior to the carbonyl insertion.[11] [14] Deuterium was also observed at the N,N-dimethyl carbamoyl group in both the substrate 1b-D and product 2b-D. The intermolecular kinetic isotope effect (KIE) of the reaction employing substrates 1a and 1a-D was found to be 1.85 at the early stage of the reaction (Scheme [5]).[14] These experimental observations for the C–H bond cleavage step showed that C–H bond cleavage occurs before the turnover-limiting step in the catalytic cycle, and a secondary isotope effect was observed.[15]

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Scheme 3 Effect of temperature
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Scheme 4 Deuterium labeling experiment
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Scheme 5 Kinetic isotope effect

To determine the turnover-limiting step of this reaction, Hammett plot analysis for substituent (X) at the para position to the reactive C–H bond indicated a linear correlation (ρ = –0.99) (Figure [3]).[3b] This result showed that the nucleophilicity of aryliridium accelerated the addition to carbonyl group. Next, the Hammett plot for substituents (Y) at the para position to the ketone group was also attempted to confirm the hypothesis as mentioned above (Figure [4]). The results showed a small linear relationship (ρ = –0.099 and –0.34).

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Figure 3 Hammett plot using α-keto amides
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Figure 4 Hammett plot using α-keto amides

These experimental and kinetic data suggested that the turnover-limiting step in this reaction is the insertion of a carbonyl group into the aryliridium intermediate rather than the C–H bond cleavage step.[14b] The catalytic cycle begins with the reaction of Ir/Me-BIPAM with substrate 1 to give aryliridium intermediate b. Hydroarylation of the carbonyl group gives iridium alkoxide species d through intermediate c. Finally, reductive elimination occurs, yielding product 2 and regenerating the catalyst (Scheme [6]).

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Scheme 6 Proposed catalytic cycle

To further investigate the carbonyl insertion process (intermediate c in Scheme [6]), DFT calculations were performed with B3LYP/LANL2DZ level of theory (Figure [5]).[3b] At first, the two minimum energy modes of Ar-[Ir((R,R)-Me-BIPAM)]-H (b1 and b2) were calculated (ΔEb1–b2 = 2.64 kcal/mol). Next, the turnover-limiting and stereodetermining step, which is coordinated with the two carbonyl groups (aryliridium intermediate c in Scheme [6]), were calculated. Conformation c2 giving the experimentally observed S product has a lower energy for reaction from the intermediate in which the carbonyl oxygen is coordinated to the iridium center at the Si-face after the C–H bond cleavage process. Conversely, coordination at the Re-face of the carbonyl group (c1) has a higher energy than Si-face coordination (c2) (ΔEc1–c2 = 3.10 kcal/mol). Thus, enantio­selective insertion at the Si-face of the carbonyl group occurs through less sterically congested intermediate c2.

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Figure 5 DFT calculations of enantioselection models

# 3

Highly Enantioselective Intermolecular Hydroarylation of Bicycloalkenes (Scheme [7])[3c] [d]

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Scheme 7 Iridium-catalyzed intermolecular hydroarylation

Although some effort has been made to develop efficient catalytic systems for direct asymmetric intermolecular additions of arenes to alkenes, there have been no reports showing high levels of enantioselectivity, catalytic activity and generality.[16] [17] [18] [19] In 2000, Togni and co-workers reported [CpIr((R)-MeO-BIPHEP)]-catalyzed asymmetric hydroarylation of 2-norbornene with benzamide.[20] For asymmetric hydroarylation of 2-norbornene (7a) using 2′-methoxyacetophenone (6a) giving ortho-alkylated product 8a, we considered the reaction conditions including the iridium precursor, chiral ligand and solvent (Table [3]).[3c] Because our previously developed asymmetric hydroarylation of ketones was effectively catalyzed by an [Ir(cod)2](BArF 4)/ bidentate bis(phosphoramidite) (Me-BIPAM) complex, we examined several chiral BIPAM ligands (entries 1–3). The use of (R,R)-Me-BIPAM as the ligand gave 8a in 93% yield with 52% ee, and higher ee was achieved by changing the linker atom of the linked BINOL unit from oxygen to nitrogen [(R,R)-N-Me-BIPAM, 35% yield, 73% ee; entry 2]. The use of a sulfur-linked bis(phosphoramidite) ligand [(R,R)-S-Me-BIPAM­] achieved highest enantioselectivity (82% yield, 88% ee; entry 3).

Table 3 Optimization of Precursors and Ligandsa

Entry

Ligand

Yield (%)

ee (%)

1

(R,R)-Me-BIPAM

93

52

2

(R,R)-N-Me-BIPAM

35

73

3

(R,R)-S-Me-BIPAM

82

88

a Reaction conditions: arene (0.25 mmol), iridium catalyst (5 mol%), ligand (1.1 equiv to Ir), solvent (1 mL), stirred, 135 °C, 24 h.

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Scheme 8 Substrate scope of intermolecular asymmetric hydroaryl­ation

Under the optimized catalytic conditions, we examined the substrate scope for enantioselective hydroarylation of 2-norbornene (Scheme [8]).[3c] For hydroarylation using a ketone directing group, various substituents such as OMe, F and Me resulted in high enantioselectivities. In the hydroarylation of acetophenone as substrate, a mixture of mono- and di-ortho-alkylated products was formed (Scheme [9]). The hydroarylation reactions of 2-norbornene with various benzamides were examined (Scheme [8]). A range of amide-based directing groups, such as diethyl-, diisopropyl- and Weinreb amides, was also tolerated and gave the hydroaryl­ated product. Pyrrolidine- and piperidine-derived amides also gave the respective desired products. Substituents at the para position were tolerated and potentially reactive functional groups such as aryl ester and bromide showed good results. The amide-directed hydroarylations only gave mono-ortho-alkylated product. X-ray diffraction analysis of a single crystal of 8b showed that the absolute configuration is R at C1 and S at C8 and C9.[21] The acetyl group of 8b is also orthogonal to the phenyl ring for steric hindrance. Amide directing groups show a limited bond rotation in the congested environment. So, hydroarylation with benz­amides could give only mono-ortho-alkylated products (Scheme [10]).[22]

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Scheme 9 Hydroarylation of 2-norbornene with unfunctionalized acetophenone­
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Scheme 10 Hydroarylation of 2-norbornene with benzamide

For the reaction mechanism, we carried out an asymmetric hydroarylation of substrate 9 in the presence of D2O (10 equiv) under the optimized conditions [(A) in Scheme [11]].[3c] The reaction gave 35% of unreacted substrate 9-D and 64% of product 10-D. Deuterium incorporation was not seen at the ortho position of the amide group in the substrate. This result showed that the C–H bond cleavage occurs in a nonreversible manner before the insertion of alkene. In addition, comparison of the initial rate constants for the addition of normal and deuterated 1-benzoylpiperidine (11 and 11-D) to 2-norbornene in separate vessels revealed a KIE of 2.08 [(B) in Scheme [11]]. These results showed that the turnover-limiting step in our developed asymmetric hydroarylation includes the C–H bond cleavage step.[14] [15] A catalytic cycle is shown in Scheme [12]. We propose a catalytic cycle involving chelation-assisted C–H bond cleavage, migratory insertion of bicycloalkene into the Ir–C bond, and C–H bond-forming reductive elimination of the resulting organoiridium species.[15]

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Scheme 11 Deuterium labeling experiments
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Scheme 12 Proposed catalytic cycle

The amide-based directing group showed the best performance in our developed reaction compared with the ketone. But, in general, it is difficult to convert tertiary amides into other functional groups.[23] Because aniline derivatives such as acetanilides can be easily transformed to other functional groups compared with amides, we examined an iridium/(R,R)-S-Me-BIPAM-catalyzed direct asymmetric alkylation of acetanilides with 2-norbornene (Scheme [13]).[3d] In 2017, Shibata and co-workers reported cationic iridium/chiral bis(phosphine) catalyzed enantioselective C–H addition of acetanilide to α,β-unsaturated carbonyl compounds in moderate yield with good enantioselectivity.[24]

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Scheme 13 Enantioselective hydroarylation of 2-norbornene with acetanilides­

We examined reaction conditions in the hydroarylation of 2-norbornene with 2-methylacetanilide (13a) (Table [4]).[3d] When [Ir(cod)2](BArF 4) was used in 1,2-dichloroethane (DCE), the reaction proceeds in high yield with excellent enantioselectivity (89%, 97% ee; entry 1). The use of 1,4-dioxane gave the best result (entry 5). (R,R)-SO2-Me-BIPAM also showed good yield with high enantioselectivity. The use of (R,R)-Me-BIPAM or (R,R)-CH2-Me-BIPAM gave unsatisfactory results.

Table 4 Optimization of the Reaction Conditionsa

Entry

Ligand

Solvent

Yield (%)

ee (%)

1

(R,R)-S-Me-BIPAM

DCE

89

97

2

(R,R)-S-Me-BIPAM

toluene

90

93

3

(R,R)-S-Me-BIPAM

DME

69

97

4

(R,R)-S-Me-BIPAM

THF

71

99

5

(R,R)-S-Me-BIPAM

dioxane

92

97

6

(R,R)-Me-BIPAM

DCE

52

73

7

(R,R)-SO2-Me-BIPAM

DCE

85

96

8

(R,R)-CH2-Me-BIPAM

DCE

75

16

a Reaction conditions: 13a (0.25 mmol), iridium catalyst (5 mol%), ligand (1.1 equiv to Ir), solvent (1 mL), stirred, 135 °C, 21 h.

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Scheme 14 Enantioselective hydroarylation of 2-norbornene with anilides

A range of aniline derivatives gave the desired products in good yield with high enantioselectivity (Scheme [14]). Alkyl substituents such as ethyl, isopropyl and tert-butyl on the amide group showed good results. Furthermore, a broad range of substituents on the benzene ring was tolerated. The reaction of 2,3- or 2,4-disubstituted acetanilides with 2-norbornene also gave the products in good yields with high enantioselectivities. In contrast to the reaction of benzamide derivatives (see Scheme [10]), the use of acetanilide gave only the dialkylation product (Scheme [15]). Thus, the selectivity of mono- or dialkylation was found to depend on the ease of bond rotation of the directing group. To gain insight into the reaction mechanism, we examined the reaction of 2-norbornene with 3′-methylacetanilide in the presence of D2O. There was 67% deuterium incorporation at the C6 position of recovered substrate, as shown in Scheme [16]. This H/D scrambling showed that the C–H activation is reversible. We propose a similar catalytic cycle for the hydroarylation with acetanilide derivatives (Scheme [17]) as for the benzamide derivatives.

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Scheme 15 Hydroarylation with acetanilide
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Scheme 16 Deuterium labeling experiment
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Scheme 17 Proposed catalytic cycle

# 4

Conclusion

In this account, we have summarized our recent efforts to use chiral bidentate phosphoramidites for enantioselective hydroarylation. Using the cationic iridium complex [Ir(cod)2](BArF 4) and the chiral O-linked bidentate phosphoramidite (R,R)-Me-BIPAM, enantioselective intramolecular hydroarylation of α-keto amides gave various types of optically active 3-substituted 3-hydroxy-2-oxindoles in high yields with complete regioselectivity and high enantio­selectivities. In the mechanistic studies, all the data showed that carbonyl insertion into aryliridium is included in the turnover-limiting step of the catalytic cycle. On the other hand, highly enantioselective cationic iridium-catalyzed hydroarylation of bicycloalkenes was achieved using a newly synthesized sulfur-linked bis(phosphoramidite) ligand (S-Me-BIPAM). The hydroarylation reactions of 2-norbornene with N,N-dialkylbenzamides gave the mono-ortho­-alkylation products with excellent enantioselectivities. We also developed the highly enantioselective direct hydroarylation of 2-norbornene using aniline derivatives with the cationic Ir/(R,R)-S-Me-BIPAM complex.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Yasunori Yamamoto
Division of Chemical Process Engineering and Frontier Chemistry Center (FCC), Faculty of Engineering, Hokkaido University
Kita 13, Nishi 8, Kita-ku, Sapporo, Hokkaido 060-8628
Japan   

Publikationsverlauf

Eingereicht: 05. Oktober 2021

Angenommen nach Revision: 01. November 2021

Accepted Manuscript online:
01. November 2021

Artikel online veröffentlicht:
14. Dezember 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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Yasunori Yamamotowas born in Hokkaido, Japan in 1968. He received his B. Eng. (1991) and M. Eng. (1993) from Hokkaido University under the direction of Professor Akira Suzuki. He worked at Mitsubishi Chemical Corporation as Researcher from 1993 to 1995. In 1995, he then moved to Hokkaido University as an Assistant Professor of the Miyaura research group and received his Ph. D. degree in 2003 from Hokkaido University. In 2012, he was promoted to a Specially Appointed Associate Professor at Hokkaido University. His research interests are in the development of new methods for the organic syntheses using the transition-metal-catalyzed cross-coupling and addition reactions of organoboron compounds, and asymmetric synthesis by using transition-metal-catalyzed C–H activation.
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Figure 1 Chiral bidentate phosphoramidite ligands
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Scheme 1 Iridium-catalyzed intramolecular hydroarylation
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Scheme 2 Enantioselective intramolecular hydroarylation of α-keto amides
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Figure 2 Formation of iridium hydride species
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Scheme 3 Effect of temperature
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Scheme 4 Deuterium labeling experiment
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Scheme 5 Kinetic isotope effect
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Figure 3 Hammett plot using α-keto amides
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Figure 4 Hammett plot using α-keto amides
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Scheme 6 Proposed catalytic cycle
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Figure 5 DFT calculations of enantioselection models
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Scheme 7 Iridium-catalyzed intermolecular hydroarylation
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Scheme 8 Substrate scope of intermolecular asymmetric hydroaryl­ation
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Scheme 9 Hydroarylation of 2-norbornene with unfunctionalized acetophenone­
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Scheme 10 Hydroarylation of 2-norbornene with benzamide
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Scheme 11 Deuterium labeling experiments
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Scheme 12 Proposed catalytic cycle
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Scheme 13 Enantioselective hydroarylation of 2-norbornene with acetanilides­
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Scheme 14 Enantioselective hydroarylation of 2-norbornene with anilides
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Scheme 15 Hydroarylation with acetanilide
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Scheme 16 Deuterium labeling experiment
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Scheme 17 Proposed catalytic cycle