Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Asymmetric

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Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Asymmetric C(sp2)-H Borylation of Diarylmethylamines Xiaoliang Zou, Haonan Zhao, Yinwu Li, Qian Gao, Zhuofeng Ke, and Senmiao Xu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13756 • Publication Date (Web): 10 Mar 2019 Downloaded from http://pubs.acs.org on March 10, 2019

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Journal of the American Chemical Society

Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Asymmetric C(sp2)-H Borylation of Diarylmethylamines Xiaoliang Zou,a,† Haonan Zhao,a,† Yinwu Li,b,† Qian Gao,a Zhuofeng Keb,*and Senmiao Xua,c* aState

Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute, Lanzhou Institute of Chemical Physics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lanzhou 73000, China bSchool of Materials Science & Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275, China cKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 311121, P. R. China ABSTRACT: Optically active organoboronic acids and their derivatives are an important family of target compounds in organic chemistry, catalysis, and medicinal chemistry. Yet there are rare asymmetric catalytic examples reported for the synthesis of these compounds via atom and step economic ways. Herein, we report a chelate-directed iridium-catalyzed asymmetric C(sp2)-H borylation of aromatic C-H bonds directed by free amine groups and DFT calculation of mechanisms. The success of these transformations relies on a novel family of chiral bidentate boryl ligands L. They can be synthesized straightforwardly in three steps starting from readily available (S,S)-1,2-diphenyl-1,2-ethanediamie ((S,S)-DPEN). The Ir-catalyzed C(sp2)-H borylation comprises two parts. The first part is desymmetrization of prochiral diarylmethylamines 7. In the presence of L3/Ir, a vast array of corresponding borylated products were obtained with high regioselectivity and good to excellent to enantioselectivities (26 examples, up to 96% ee). The second part is kinetic resolution of racemic diarylmethylamines 9 was also conducted. Good selectivity values (up to 68, 11 examples) were obtained when L8 was used. We also demonstrated the synthetic utility of current method on gram-scale reaction for several transformations. The C-B bond of product 8l could be converted to a variety of functionalities including C-O (11 and 12), C-C (13), C-C (14), C-Br (15) and C-P (16) bonds. Notably, 11, 12 and 16 could be potentially used as ligands in asymmetric catalysis. Finally, we performed DFT calculations of desymmetrization to understand its reaction pathways.

Introduction Optically active organoboron compounds are of great importance in synthetic chemistry,1 drug discovery,2 and catalysis.3 Accordingly, a number of synthetic methods for these compounds have been developed during past decades. Early methods usually rely on chiral reagents and auxiliaries, including lithiation-borylation and Matteson homologation.4 Some of these suffered from harsh reaction conditions. Transition-metal-catalyzed asymmetric carbon-boron coupling of carbon-halogen bonds,5 asymmetric hydroboration of unsaturated substrates, carbene insertion into B-H bonds,6 and C-C coupling of gem-diboron compounds7 have been developed under mild conditions. These methods are also compatible with a wide range of functional groups. However, substrates for these reactions need to be pre-functionalized, which will cost extra reaction steps, purifications, and other reagents. Transition-metal-catalyzed enantioselective functionalization of prochiral C-H bonds has recently emerged as a new avenue for developing asymmetric catalysis.8 Despite significant advances made over the past decade,8,9 enantioselective C-H activation still suffers from limitations such as reaction scope and efficiency.8 To overcome drawbacks,

novel chiral ligands are continuously in demand in this area.8 The state-of-art Ir-catalyzed borylation of aromatic C-H bonds with bis(pinacolato)diboron (B2pin2) or pinacolborane (HBpin) has become a powerful tool to provide a number of arylboronates with atom and step economy.10 However, in stark contrast, there is only one example of their highly enantioselective variants has been realized, which relies on a relay-directed strategy that involves the formation of Ir-Si bond (Scheme 1, A).11 The use of coordinating directing groups to achieve such transformations remains a great challenge,9x however, it will undoubtedly extend the breadth of substrates and provide products with diverse functionalities. We believe the deficiency is probably due to the lack of adequate chiral ligands. Mechanistically, the active catalyst in 4,4’-tBu2-2,2’-bipyridine (dtbpy) system is the 16-electron Ir(III) complex, in which only a single vacant coordination site is available for the cleavage of C-H bond.12 In general, a second vacant or weakly coordinating site is a necessity to perform coordination directed enantioselective C-H functionalization.8a Indeed, a number of catalyst-controlled Ircatalyzed ortho-borylation reactions of aromatic C-H bonds have been developed.13 Active catalysts containing two available coordination sites are responsible for the observed regioselectivities.13l Among these, elegant work independently

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developed by groups of Smith13m and Li13n, in which Ir complexes were ligated by elaborate bidentate silyl and boryl ligands, respectively, inspired us to design suitable chiral ligands for asymmetric C-H borylation. For example, incorporation of a pendant chiral silyl or boryl moiety will assist in creation of the desired chiral ligand. In view of appealing attributes of optically active organoboron compounds, catalytic asymmetric C-H functionalization, and iridium-catalyzed regioselective C-H borylation, we herein report the first example of chelatedirected Ir-catalyzed regioselective asymmetric C(sp2)-H borylation of diarylmethylamines, including desymmetrization and kinetic resolution (Scheme 1, B). Key to the success of these transformations relies on a novel class of chiral (S,S)DPEN-derived bidentate boryl ligand (L) (Scheme 1, B). Their synthetic routes are also described here. Notably, it represents the first example using chiral boryl group as supporting ligand in asymmetric catalysis.14

Meanwhile, we synthesized 1,2-aminoalcohol derived chiral boryl ligand L10. C-N coupling of readily available carbamate 5 with 2-bromopyridine in the presence of a Pd catalyst followed by hydrolysis using LiOH afforded ligand precursor 6 in 72% yield over two steps. Direct condensation of 6 with PhMe2SiB(NiPr2)2 resulted in L10 in almost quantitative 1H NMR yield. Unfortunately, we were not able to purify it due to its sensitivity to acid. The crude L10 was then subjected to undergo complexation with [IrCl(COD)]2 in n-hexane at 80 º C for 12 h, furnishing Ir(III) complex L10-Ir in 60% yield over two steps. The single crystal structure of L10-Ir containing iridium-boron bond unambiguously confirmed the structural assignment.15 Scheme 2. Catalytic Asymmetric Synthesis of Chiral Organoboron Compounds Ph

Ph NH2

R'

R'

Ir, B2pin2

R''

R'

*

N

R'

NR2

R''

desymmetrization

R''

kinetic resolution

Ph

N

Ph

B SiMe2Ph

Ar

Chiral Boryl Ligand (L)

iridium B2pin2

B N

Ph Ar

5

R'

LiOH, EtOH/H2O

Br

N

Pd2dba3 (2.5 mol%) Xantphos (5 mol%) NaOtBu, toluene reflux, 16 h

O

2.

Bpin Bpin

Proposed Active Catalyst Speceis

Ligand Synthesis

The preparation of ligand L is fairly straightforward as illustrated in Scheme 2. Arylations of commercially available (S,S)-DPEN 1 with aryl halides 2 in the presence of catalytic amount of Pd2dba3 and rac-BINAP in toluene at 110 ˚C for 18 hours afforded corresponding diamine 3 in 55-80% yields. Subsequent coupling of 3 and 2-pyridyl bromide in the presence of Pd2dba3 and XantPhos in toluene at 110 ˚C for 18 hours furnished optically active 2-pyridyl diamine 4 in 52-88% yields. The reaction of 4 with BH3 resulted in unidentified mixtures under a variety of conditions. Although transamination of diamine 4 with PhMe2Si-B(NiPr2)2 was not successful even at 180 º C,13n complete conversion was observed when a catalytic amount of HCl (20 mol%) was used. Presumably, the acid could protonate nitrogen atom of PhMe2Si-B(NiPr2)2, thus promoting leaving ability of NiPr2 groups. The corresponding chiral BN ligand L1-L9 could be obtained in 50-72% yield.

iPr Ph Ph HO

PhMe2SiB(NiPr2)2 toluene, 160 C

6 iPr

1/2 [Ir(COD)Cl]2

iPr Ph Ph

hexane, 80 C 12 h, 60% over 2 steps

N B O

Ph H N N Si B O Ph Cl Ir Si: PhMe2SiL10-Ir

L10

Ir

N H

N

reflux, 16 h 77% yield over 2 steps

R''

Results and Discussion 1.

N B SiMe2 L

O

Bpin NR2

N

N

Ph

50-72% yield

iPr Ph Ph

PhMe2Si

N N

N

L1: Ar = Ph L2: Ar =4-Me-C6H4 L3: Ar = 3,5-Me2C6H3 L4: Ar = 3,5-(CF3)2C6H3 L5: Ar = 3,5-(MeO)2C6H3 L6: Ar = 3,5-Et2C6H3 L7: Ar = 3,5-iPr2C6H3 L8: Ar = 3,5-tBu2-C6H3 L9: Ar = 3,5-Ph2-C6H3

Ph Ar

B = Bpin

N

Ph

Pd2dba3 (2.5 mol%) Xantphos (5.0 mol%) NaOtBu, toluene, reflux, 18 h

Ar

B

R'  R'' L/Ir, B2pin2

R'

N

HCl (10 mol%), toluene 160 C, 16 - 48 h

Ar

4

HN

R' = R'' L/Ir, B2pin2

PhMe2Si-B(Ni-Pr2)2

52-88% yield

B: Ir-catalyzed C(sp2)-H Borylation Using Chiral Boryl Ligand (This Work): Chelate-directed

Bpin NR2

Ph

NH HN

Ph

3

Ph

N

Si B N Ir

NaOtBu, toluene reflux, 18 h

N

HN

55-80% yield

Ph

via:

Bpin SiMe2H

X = Br, I

1

Ph

chiral dinitrogen ligand

Ar

Br

Ph

H2N

2

H Borylation A: Asymmetric C(sp2)-H Activation Borylation (Shi, Hartwig): Relay-directed

Ph

Pd2dba3 (2.5 mol%) rac-BINAP (5.0 mol%)

X

+ H2N

Scheme 1. Strategies Developed for Ir-Catalyzed Asymmetric C(sp2)-

SiMe2H

Page 2 of 10

Regioselective Asymmetric Diarylmethylamines.

C-H

Borylation

of

Optically active diarylmethylamines are key constituents in bioactive compounds such as Certirizine hydrochloride, Solifenacin, and SNC80(Figure 1).16 Therefore, a variety of catalytic asymmetric methods have been developed to synthesizing these structures,17 including the addition of arylmetal reagents to aldimines18 and hydrogenation of diarylketimines.19 These methods require either prefunctionalized substrates imines and arylmetals, or high pressure of H2 gas. On the other hand, asymmetric palladiumcatalyzed C-H iodination of prochiral diarylmethylamines by the Yu group delivered these structures in atom and step economic ways.20 However, this protocol is mainly restricted to ortho-substituted substrates in order to avoid diiodination. Therefore, highly selective C-H functionalization remains a great challenge. OH

O N

O N

Me

N

O

2HCl N

O

N N

Me OMe

Et2NOC

Cl Certirizine hydrochloride

Solifenacin

SNC-80

Figure 1. Optically active bioactive diarylmethylamines

a)

Desymmetrization of Prochiral Diarylmethylamines


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With chiral BN ligand L in hand, we began with testing their use in Ir-catalyzed enantioselective C-H borylation reactions of prochiral diarylmethylamines. In order to identify reaction conditions, we chose N,N-dimethyl diphenylmethylamine 7a as our model substrate. Initial attempt using ligand L1 and [IrCl(COD)]2 in tetrahydrofuran (THF) at 80 ºC for 12 hours resulted in desired product 8a as a single regioisomer in 58% NMR yield and with meaningful enantioselectivity (19% ee) (table 1, entry 1). Notably, an only trace amount of product was observed when the reaction was carried out without a ligand under otherwise identical reaction conditions (Table 1, entry 2). In addition, no desired product was observed when a reported ligand dtbpy was used (Table 1, entry 3). This proof-of-principle result encouraged us to further investigate the correlation between chiral induction and Aryl (Ar) group of L. The Ar group of L significantly affected the ee value of the product. For example, when the ligand containing Ar = p-MeC6H4 (L2) was applied, a reduction in chiral induction was observed (Table 1, entry 4, 13% ee). Gratifyingly, when ligand L3 bearing Ar = 3,5Me2C6H3 was used, the corresponding product was obtained with excellent enantioselectivity (90% ee) in 95% 1H NMR yield (Table 1, entry 5). Increasing the alkyl size of 3,5substituents of Ar (L6-L8) gave inferior results (Table 1, entries 8-10, 77-87% ee). Substituents at 3,5-positions other than alkyl such as CF3 (L4), MeO (L5), and Ph (L9) also had negative effects on chiral induction (Table 1, entries 6, 7, and 11, 47-85% ee). In stark contrast, iridium complex L10-Ir showed almost no reactivity (Table 1, entry 12)

aUnless

otherwise noted, all the reactions were carried out with 7a (0.1 mmol), [IrCl(COD)]2 (0.005 mmol), L (0.01 mol), B2pin2 (0.1 mmol) in THF (1.0 mL) at 80 ˚C for 12 h. bYield of 8aa was determined by 1H NMR using CH Br as 2 2 internal standard. Numbers in parentheses refer to isolated yields. cThe enantiomeric excess was determined by HPLC on a chiral AD-H column. dThe reaction was carried out in 1,4-dioxane. eThe reaction was carried out in n-hexane. fThe reaction temperature was 70 ˚C. g[IrOMe(COD)]2 was used.

With optimal ligand L3 in hand, we then further investigated other reaction conditions. THF was the optimal solvent in terms of reactivity and enantioselectivity (Table 1, entries 5, 13 and 14). When the reaction was carried out at 70 ˚C in THF for 12 hours, the product 8a was obtained in 98% 1H NMR yield (88% isolated yield) with an elevated ee value (94%) (Table 1, entry 15). The use of [IrOMe(COD)]2 instead of [IrCl(COD)]2 resulted in inferior yield (72%) and enantioselectivity (90%) (Table 1, entry 16 vs. entry 15). Of note, only trace amount of diborylated product was observed (mono: di>20:1) probably due to the presence of coordination between the amine nitrogen and boron atom ( 13.7 ppm of 11B NMR of 8a). This interaction could suppress further borylation by preventing the coordination between the nitrogen atom and the iridium center. Table 2. Substrate Generality of Enantioselective C-H Borylation of Prochiral Diarylmethylamines 7.a NMe2

Table 1. Optimization of Reaction Conditions of Ir-catalyzed Enantioselective C-H Borylation of N,NDimethyldiphenylmethylamine 7a.a NMe2

L(10 mol%) [IrCl(COD)]2 (5 mol%)

entry

L

Bpin NMe2

8

Me 8a 88% yield, 94% ee

Cl

F 8e 82% yield, 90% ee

L1

58

19

2

none

trace

--

3

dtbpy

--

--

4

L2

67

13

5

L3

95

90

F

6

L4

90

85

7

L5

90

47

F 8m+8mk' (ratio of regioisomers: 4: 1)b 77% yield, 94% ee/89% ee

8

L6

99

77

9

L7

93

Bpin NMe2

L8

81

87

11

L9

88

56

12

L10-Ir

trace

n.d.

13d

L3

90

74

14e

L3

87

74

15f

L3

98 (88)

94

16f,g

L3

72

90

Br

F3C

Bpin NMe2

Bpin NMe2

Bpin NMe2

CF3 8h 65% yield, 95% ee

8g 66% yield, 82% ee

Cl

Me F3CO

Ph

OCF3

8i 86% yield, 82% ee

Ph

8l 74% yield, 95% ee

Bpin NMe2

Bpin NMe2 F

Cl

Me 8k 70% yield, 81% ee

8j 79% yield, 90% ee

Bpin NMe2

Bpin NMe2 Br

F

CF3

+

Bpin NMe2

Br 8n 65% yield, 92% ee

Ph

OMe OMe

8p 80% yield, 92% ee

Bpin NMe2 Cl O

O

OMe

Br

F

Me

Br

OMe

F MeO

F 8x+8x' (ratio of regioisomers: 4: 1)b 86% yield, 89% ee/82% ee


Me Br

F

F Me

Bpin NMe2

Bpin NMe2 F

Me F 8w 77% yield, 85% ee

8v 60% yield, 89% ee

Bpin NMe2 +

Bpin NMe2 Br

OMe 8u 71% yield, 79% ee

Bpin NMe2

8s 83% yield, 88% ee

Bpin NMe2 OMe

OMe 8t 76% yield, 86% ee

Cl Cl

8r 61% yield, 82% ee

Bpin NMe2 Cl

Cl

O

O

8q 70% yield, 87% ee

Bpin NMe2

MeO

Bpin NMe2

OMe MeO

Cl

CF3 8o 90% yield, 96% ee

Bpin NMe2

Ph

83

10

Bpin NMe2

Br

Cl 8f 95% yield, 88% ee

1

OMe

6d 76% yield, 85% ee

Bpin NMe2

Bpin NMe2

F

MeO

Me 8c 70% yield, 88% ee

8b 60% yield, 86% ee

Bpin NMe2

ee (%)c

Bpin NMe2

Bpin NMe2

Bpin N

Bpin NMe2

8a

yield (%)b

R

R

7

B2pin2, THF, 80 °C 7a

B2pin2, THF, 70 °C 12-36 h

R

R

Bpin NMe2

L3 (10 mol%) [IrCl(COD)]2 (5 mol%)

F

OMe Cl Cl 8y 90% yield, 85% ee

8z 89% yield, 91% ee


With optimized conditions identified, we then turned our attention to the asymmetric C-H borylation of other substrates as shown in Table 2. Substituents at the nitrogen atom other than the methyl groups showed a negative influence on stereoselectivity (8b: 86% ee). Most of N,Ndimethyldiarylmethylamines underwent reactions smoothly under optimized reaction conditions to provide corresponding products with good to excellent enantioselectivity. Generally, electron-withdrawing group substituted substrates gave products with superior ee values compared to substrates with electron-donating groups. For example, the reactions of substrates bearing para-fluoro (7e), trifluoromethyl (7h), and phenyl (7j) afforded borylated product with excellent level of enantioselectivity, ranging from 90% to 95% ee, while those containing para-methyl (7c), methoxyl (7d), chloro (7f), bromo (7g), and trifluoromethoxyl (7i) were shown good ee values (82-88%). Substrates bearing electron-withdrawing groups at the meta-position of phenyl rings gave products with uniformly excellent enantioselectivity (8l-8p, 90-96% ee). Notably, meta-fluoro substituted substrate 8m produced two regioisomers (4:1) with 95% ee (major isomer) and 89% ee (minor one). Disubstituted substrates were also compatible with the reaction, giving products with good enantioselectivity (8q-8y, 79-89% ee). The reaction of naphth-2-yl substituted 7z gave the borylated product with excellent enantioselectivity (91% ee). The absolute configuration of product 8n was confirmed as S by X-ray diffraction analysis. The configurations of the other products were assigned the same tentatively by analogy.15 Unfortunately, The reactivity of substrates bearing other bulky amine groups (Figure 2) was very low probably due to steric hindrance preventing coordination of nitrogen atom with iridium center.

To avoid borylation of both aromatic rings of a single enantiomer, we chose racemic diarylmethylamine 9a containing one aromatic ring of 3,5-(CF3)2C6H3 as our model substrate for the kinetic resolution. Initial experiment with L3 (5 mol%), [IrOMe(COD)]2 (2.5 mol%), a racemic mixture of diarylmethylamine 9a, and 0.60 equivalent of B2pin2 in THF at 70 ˚C (Table 4, entry 1) for 48 h offered good selectivity (s = 28). Notably, only a single regioisomer was observed according to 1H NMR of the crude reaction. Further investigation of ligand effect revealed that L8 bearing bulky tbutyl groups was optimal in terms of selectivity (s = 68), conversion (30%) and ee value (94%) of the product (Table 4, entry 5). Table 3. Optimization of Reaction Conditions of Kinetic Resolution of Ir-catalyzed C-H Borylation of Racemic N,NDimethyldiphenylmetanamine 9a.a NMe2 CF3

N

N

N

7aa

7ab

7ac

7ad

NR2 H''

Bpin NR2 H'' f ast

NR2 H

R''

R' H'

R' R' good dif f erentiation 2 of two identical C(sp )-H bonds

R''

R'

NR2 H''

H' slow

R'

R''

CF3 10a

entry

L

conv.(%)b

ee10a (%)c

ee9a (%)c

sd

1

L3

35

89

48

28

2

L4

26

85

30

17

3

L6

19

96

22

39

4

L7

26

93

33

44

5

L8

30

94

41

68

aUnless

otherwise noted, all the reactions were carried out with 9a (0.1 mmol), [IrCl(COD)]2 (0.0025 mmol), L (0.005 mol), B2pin2 (0.06 mmol) in THF (1.0 mL) at 70 ˚C for 48 h. bConversion was calculated by [ee /(ee c 9a 10a + ee9a)]. ee9a was determined by chiral GC on a chiral B-DA column ; ee10a was determined by HPLC on a chiral AD-H column after oxidation with NaBO3. ds = kfast/kslow = ln[(1-conv./100)(1ee9a/100)]/ln[(1-conv./100)(1+ee9a/100)]

NMe2

Recognizing the excellent ability of differentiation of two identical aromatic C-H bonds of the ligands, we believe that our catalyst is able to differentiate two enantiomers of racemic diarylmethylamines. And if one of two aryl rings of the substrate does not have an available reaction site, the reaction of one enantiomer should be faster than the other and kinetic resolution will take place (Figure 3). Such a process will undoubtedly broaden the generality of the protocol as well as provide more opportunities for the application of optically active diarylmethylamines.

H

CF3

B2pin2 (0.6 equiv) THF, 70 C, 48 h

CF3

Kinetic Resolution of Racemic Diarylmethylamines

H'

Bpin NMe2

Table 4. Substrate Generality of Kinetic Resolution of C-H Borylation of Racemic Diarylmethylamines 9.a

Figure 2. Substrates that did not work well.

b)

L (5 mol%) [IrCl(COD)]2 (2.5 mol%)

9a

O N

Page 4 of 10

NR2 Bpin

R'

dif f f erntiation of enantiomers : kinetic resolution

Figure 3. From desymmetrization to kinetic resolution.

R''

R3

R1

R2

L (5 mol%) [IrCl(COD)]2 (2.5 mol%)

Bpin NMe2

B2pin2 (0.6 equiv) THF, 70 C, 24 - 48 h

R3

9

R1

R2

10

entry

R1, R2, R3

conv.(%)b

ee10 (%)c

ee9 (%)c

sd

1

CF3, CF3, H

30

94

41

68

2

CF3, CF3, 3-Me

30

90

40

25

3

OMe, Me, 3-Cl

28

90

35

27

4

OMe, OMe, H

33

85

42

19

5e

Me, Cl, 3-Ph

39

87

55

23

6e

OMe, Cl, 3-Ph

37

87

51

24

7e

CF3, CF3, 3-Ph

27

93

34

33

8f

Br, Br, H

24

90

28

22

9g

OMe, CF3, 3-Cl

50

88

88

45

10f

CF3, Cl, 3-Ph

47

83

75

27

11

CF3, CF3, 4-Cl

54

72

62

9

aUnless

otherwise noted, all the reactions were carried out with 9 (0.1 mmol), [IrCl(COD)]2 (0.0025 mmol), L (0.005 mol),


Synthetic Application

To demonstrate the synthetic utility of the current enantioselective C(sp3)-H borylation reaction, we conducted gram-scale reactions and several transformations of C(sp2)-B bond as shown in Scheme 3. The reaction of 7l in the presence of reduced catalyst loading (2 mol%) for 40 h afforded 8l in 62% isolated yield without erosion of stereoselectivity. Optically pure 8l were obtained after recrystallization (>99% ee). Oxidation of 8a and 8l with excessive NaBO3 in THF/H2O at room temperature afforded corresponding hydroxylated product 11 and 12 in 99% yields. A Suzuki-Miyaura reaction of 8l with p-bromotoluene provided arylated product 13 in 78% yield.21 Amination of 8l with morpholine in the presence stoichiometric amout of Cu(OAc)2 furnished 14 in 60% yield.22 In addition, the C(sp2)-B bond of 8l could also be converted into a C-Br bond using CuBr2, producing 15 in 62% yield.23 This compound could be further converted a chiral phosphine 16 by treatment of nBuLi followed by ClPPh2 in 95% yield. Notably, 11, 12, and 16 could potentially be used as ligands in asymmetric catalysis. Scheme 3. Synthetic Desymmetrization.

Bpin NMe2 Cl

8l THF/H2O rt, 12 h 99% yield NaBO3

OH

NMe2 R

B

from

Ir

H N B N

Ph

N

on ati

Ar

Ar Ph B N Ir B B N Ph N

Cl

Cl 13

Cu(OAc)2 morpholine

B

O

CH3CN, 4Å MS 80 C, 12 h 60% yield

N

B NMe2 Cl

Ph

N H2

H N Ir B N N

NMe2 Cl

nBuLi, Ph2PCl

PPh2 NMe2 Cl

THF, -78 C 95% yield

Cl 15

Ar Ph Ph

CBf

14

B2pin2

B Ir Ph

N H2

N

N N

orm ati on

IrV/III pathway IrIII/I pathway

Ph

Ar Ph

B

N H2

17

Ph

s co ubs or tra din te ati on 18

B Ph

Cl

Br

N H2

Ph

B N B N

18

NMe2

62%, 92% ee (>99% ee after recrystallization) CuBr2 MeOH/H2O 80 C, 1 h 62% yield

Ph

18

R 11: R = H 12: R = Cl

3.

r ne ge re

Ar Ph

Me

p-CH3C6H4Br Pd(OAc)2 (5 mol%) SPhos (5 mol%) THF/H2O (4:1) NaOH, 80 C, 16 h 78% yield

Cl

(1.0 gram) 7l

8l

B2pin2

Ir

B

B2pin2, THF, 70 °C 40 h Cl

Product

B HBpin

N

L3 (2 mol%) [IrCl(COD)]2 (1 mol%)

Cl

of

In order to further understand the reaction mechanism for this Ir-catalyzed C-H borylation reaction, density functional theory (DFT) studies were carried out with the simplified Irboyl (Cat-s) as the catalyst model (Figure S1). In the mechanism study, diphenylmethanamine (17) were employed as the model substrate. As shown in Figure 4, the proposed catalytic cycle should consist of three major steps: (1) C-H oxidative addition, (2) C-B bond formation, (3) regeneration of the active species.

N H2

B

H

B2pin2

Ir Ph

N H2

N

Ar Ph N Ir N

B N

B N B N

Ph

H HBpin

Ph

Ar B Ph H N Ir B N Ph N B

B Ir

Ph

Ar Ph Ph

C-H activation

NMe2

Application

Where the Ggas is the gas-phase free energy, Gsolv is the solvation free energy. The final term accounts for the free energy change from an ideal gas of 1 atm (24.5 L, 298.15 K) to 1M solution. All the calculations were performed with the Gaussian 09 program.29 The 3D optimized structures were displayed by CYLview visualization program.30

n itio add B-B

c)

𝐺(sol) = 𝐺gas + ∆𝐺solv + 𝑅𝑇ln(24.5) (1)

fo rm ati on

With optimized reaction conditions identified, the Ircatalyzed kinetic resolution of additional racemic diarylmethylamines was explored as shown in Table 4. The reactions gave selectivity values ranging from 9-68 depending on the electronic nature and position of phenyl ring substituents. Substituents at meta-positions of left phenyl rings showed selectivity ranging from 19-45 (Table 1, entries 2-7, 9 and 10). The substituent position of right ring affected the reaction substantially. Significantly diminished selectivity (s = 9) was observed with the substrate bearing a para-Cl (Table 1, entry 11) of the left phenyl ring.

M06-L functional25 with basis sets I (BSI, lanl2dz26 for metal atom and 6-31G (d, p) for nonmetal atoms) in the gas phase. Frequency analysis calculations of optimized structures were performed at the same level of theory (M06-L/BSI) to characterize the structures to be minima (no imaginary frequency) or transition states (one imaginary frequency). Intrinsic reaction coordinate (IRC) calculations were performed to confirm the connection between two correct minima for a transition state. Based on the M06-L/BSI optimized geometries, the energy results were further refined by calculating the single point energy at the M06-L/BSII level of theory (BSII designates SDD27 for metal atom and 6311++G**28 for nonmetal atoms). The bulky solvation effect of THF (= 7.4) was simulated by SMD26 continuum solvent mode at the M06-L/BSII level of theory. The standard Gibbs free energy in solution is calculated by equation (1),

CB

mmol) in THF (1.0 mL) at 70 ˚C for 24-48 h. was calculated by [ee9/(ee10 + ee9)]. cee9 was determined using GC or HPLC on chiral stationary phase; ee10 was determined by Chiral HPLC after oxidation with NaBO3. ds = kfast/kslow = ln[(1-conv./100)(1-ee9/100)]/ln[(1conv./100)(1+ee9/100)]. e0.80 equiv of B2pin2 was used. f1.2 equiv of B2pin2 was used. g0.5 equiv of B2pin2 was used.

fo rm at io n

B2pin2 (0.06 bConversion

n tio era en reg

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CB

Page 5 of 10

N H2

N

B N B N

Ar Ph Ph

n tio iza er m iso

B-B addition pathway Cl 16

Figure 4 Proposed catalytic cycle for the C-H borylation by Irboryl catalyst (B = Bpin).

Mechanistic Investigation

Computational Details. All reported structures were optimized by the density functional theory (DFT)24 with the

C-H activation. As shown in Figure 5, starting from 14electron two-vacant-site IrIII active species Cat-S,12,13m substrate



Page 6 of 10

diphenylmethylamine binds to the metal center, resulting in intermediate RC (0.2 kcal/mol). In RC, the C-H bond of phenyl ring is pre-activated by an agostic interaction with the IrIII center (C-H = 1.056 Å, as shown in Figure 6). Remarkably, this catalyst undergoes the C-H oxidative addition via transition state TS1 (22.4 kcal/mol) involving the synergetic assista nce of the Ir-B bond,12,31 leading to a seven-coordinated IrV intermediate IM1 (17.8 kcal/mol). Due to the assistance of the Ir-B bond, the hydride is stabilized by the empty p orbital of boron in TS1 (C-H = 1.650 Å; Ir-H = 1.632 Å; B1-H = 1.869 Å, of the C-H bond.12,31,32 Furthermore, the hydride locates bridgΔ G/Δ H (kcal/mol)

B B N B B Ir N N N H2 Ph

IrV/III pathway IrIII/I pathway

B H N B B Ir N N N H2 Ph

B-B addition pathway

H N B B Ir N N N H2 Ph

TS4

22.4/5.1 TS1 B H N B B Ir N N N H2 Ph

N B B Ir N N 17

0.0/0.0 Cat-s

N

45.2/27.7

B

B

N

17.8/-1.0 IM1

N

N N H2 Ph

53.2/30.8

Ph N N H2

42.0/39.1

B-B

H-B

N

B B Ir

TS5

31.3/28.0 IM4

B B

N B B Ir N N N H2 Ph

TS7

B B N B B Ir N N N H2 Ph

19.5/1.9 16.5/-3.4

TS2

TS3

13.8/-4.4 H B NB B Ir N N N H2 Ph

0.2/-14.4 RC

B B Ir

B H N B B Ir N N N H2 Ph

7.2/-10.2

IM3

8.8/-12.0

H B

NB B Ir N N N H2 Ph

14.2/-5.2

TS6

PC3

IM5

IM2

H B

11.8/-9.8

H B NB B Ir N N N H2 Ph

NB B Ir N N N H2 Ph

Ph N N

H 2N B Ir

B

N

-0.8/-16.7 -0.8/-22.6 PC1 PC2 H

NB B B Ir N N N Ph H2

B N B B B Ir N N N H Ph 2

Figure 5. The free energy profiles for the Ir-catalyzed C-H borylation reaction (B = 1,3,2-dioxaborolan-2-yl). The free energies (in kcal/mol) are calculated at the M06-L/BSII/SMD(THF)//M06-L/BSI level of theory.

of the C-H bond.12,31,32 Furthermore, the hydride locates bridging to both the boron atom and the iridium atom in IM1 (B1-H = 1.607 Å; Ir-B1 = 2.062 Å; B-Ir-H = 49o, as shown in Figure 6). Then, the bridging hydride transfers to the other IrBpin bond via TS2 (19.5 kcal/mol), resulting in the IrV intermediate IM2 (7.2 kcal/mol; B2-H = 1.593 Å; Ir-B2 = 2.096 Å; B2-Ir-H = 49o, as shown in Figure S2) which can reduce the congestion of the seven-coordinated Ir(V) intermediate. B1 H Ir

H

C

Ir

IM1

H C

Ir-H: 1.607 Ir-B1: 2.062 B1-H: 1.579 B1-Ir-H:49

Ir-H: 2.299 Ir-C: 2.843 C-H: 1.056

RC

B1 Ir

Ir-H: 1.632 B1-H:1.869 C-H: 1.650

TS1

Figure 6. Key transition state structures for the Ir-catalyzed CH borylation reaction. Bond lengths are shown in Ångstrom. C-B bond formation via IrV/III pathway. After the oxidative addition of the C-H bond, the subsequent step is the C–B

bond formation via reductive elimination. Our DFT results suggest that the IrV/III reductive elimination pathway is the most plausible mechanism for the C-B bond formation (as shown in Figure 5).31,33 In the IrV/III reductive elimination pathway, firstly, the bridging hydride flips out of the Ir-Bpin bond (IM3), and then the C-B reductive elimination occurs via transition state TS3 (16.5 kcal/mol, Ir-B1 = 2.134 Å; Ir-C = 2.068 Å; B1-C = 2.251 Å, as shown in Figure S3) to form the borylation product in IrIII species PC1 (-0.8 kcal/mol). As expected, this IrV/III reductive elimination is facile, as compared with the C-H activation step (TS1, 22.0 kcal/mol), owing to the driving force of the high oxidation state and congested environment of the IrV intermediate IM3. Similar facile IrV/III C-B reductive elimination was also suggested in the literature.31b,33,34 C-B bond formation via IrIII/I pathway. Another possible mechanism is the IrIII/I pathway, in which the C-N bond formation occurs from an IrIII intermediate, which is reduced to an IrI intermediate, as shown in Figure 5. After the C-H activation, the yielded IrV intermediate IM1 first goes through


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


an H-Bpin elimination via transition state (TS4) to form the IrIII intermediate IM2. This process, however, is less feasible due to its high activation free energy of 45.2 kcal/mol. The subsequent C-B reductive elimination from IrIII intermediate IM3 also has to overcome an activation free energy as high as 42.0 kcal/mol, indicating that the low oxidation state IrIII intermediate is lack of driving force to promote the C-B reductive elimination, as compared with the IrV intermediate IM1 in the IrV/III pathway. C-B bond formation after the B-B addition. Theoretically, the oxidative addition of B2pin2 could re-oxidize the IrIII intermediate IM2 to another IrIV state, which may have a high tendency to drive the C-B reductive elimination. Indeed, the C-B reductive elimination from IM5 to PC2 via TS6, only needs to overcome an activation free energy of 3.0 kcal/mol (Figure 5). However, since the H-Bpin elimination step is already very difficult (G‡ = 45.2 kcal/mol), the oxidative addition of B2pin2 to the IrIII center in IM2 has an activation free energy as high as 53.2 kcal/mol (TS5). Transition state TS5 well reflects an early transition state feature, with the calculated Ir-B1 and Ir-B2 distances to be 2.902 and 2.755 Å, respectively. Overall, the IrV/III reductive elimination pathway, rather than the IrV/III or the B-B addition pathway is the most plausible mechanism With the support of both our KIE observation (KIE value of2.1 is similar to that observed in literature reported Ir-catalyzed CH borylation35see Supporting Information for more details) and DFT results, the C-H bond activation is the ratedetermining step of the whole catalytic cycle, which also leads to the enantioselectivity of this reaction. Conclusion We have developed a new class of bidentate chiral boryl ligands, which enable chelate-directed irdium-catalyzed asymmetric C(sp2)-H borylation using free amines as directing groups.36 With this protocol, we realized Ir-catalyzed desymmetrization of prochiral diarylmethylamines, kinetic resolution racemic diarylmethylamines for the first time. This protocol provides a vast range of optically active diarylmethylamines with excellent enantioselectivities. We also demonstrated the borylated products can be used as versatile precursors in preparation of a variety of functionalized chiral diarylmethylamines, including potent ligands. Further applications of chiral boryl ligands in other catalytic asymmetric transformations are currently underway in our laboratory.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxx. Experimental procedures, spectroscopic data. (PDF) Crystallographic data of L10-Ir, 8n, and 11 (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] Author Contributions

†X.Z., H.Z., and Y.L. contributed equally.

Notes The authors declare no competing financial interests..

ACKNOWLEDGMENT We thank National Natural Science Foundation of China (21573262, 21673301, 21801246 and 21473261), Natural Science Foundation of Jiangsu Province (BK20161259, BK20170422), the Guangdong Natural Science Funds for Distinguished Young Scholar (No. 2015A030306027), a Start-up Grant from Lanzhou Institute of Chemical Physics, and the Fundamental Research Funds for the Central Universities, for generous financial support.

REFERENCES 1. Leonori, D.; Aggarwal, V. K., Reagent-Controlled Lithiation– Borylation. In Synthesis and Application of Organoboron Compounds, Fernández, E.; Whiting, A., Eds. Springer International Publishing: Cham, 2015; pp 271-295. 2. a) Andres, P.; Ballano, G.; Calaza, M. I.; Cativiela, C., Synthesis of -aminoboronic acids. Chem. Soc. Rev. 2016, 45, 2291-2307. b) Gorovoy, A. S.; Gozhina, O. V.; Svendsen, J. S.; Domorad, A. A.; Tetz, G. V.; Tetz, V. V.; Lejon, T., Boron-Containing Peptidomimetics – A Novel Class of Selective Anti-tubercular Drugs. 2013, 81, 408. c) Smoum, R.; Rubinstein, A.; Dembitsky, V. M.; Srebnik, M. Boron Containing Compounds as Protease Inhibitors. Chem. Rev. 2012, 112, 4156. 3. Corey, E. J.; Helal, C. J., Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angew. Chem., Int. Ed. 1998, 37, 1986. 4. a) Leonori, D.; Aggarwal, V. K., Lithiation–Borylation Methodology and Its Application in Synthesis. Acc. Chem. Res. 2014, 47, 3174. b) Matteson, D. S., .alpha.-Halo boronic esters: intermediates for stereodirected synthesis. Chem. Rev. 1989, 89, 1535. c)Brown, H. C.; Veeraraghavan Ramachandran, P., Versatile αpinene-based borane reagents for asymmetric syntheses. J. Organomet. Chem. 1995, 500, 1. 5. Wang, Z.; Bachman, S.; Dudnik, A. S.; Fu, G. C., Nickel-Catalyzed Enantioconvergent Borylation of Racemic Secondary Benzylic Electrophiles. Angew. Chem., Int. Ed. 2018, 57, 1. 6. a) Cheng, Q.-Q.; Zhu, S.-F.; Zhang, Y.-Z.; Xie, X.-L.; Zhou, Q.-L., Copper-Catalyzed B–H Bond Insertion Reaction: A Highly Efficient and Enantioselective C–B Bond-Forming Reaction with Amine– Borane and Phosphine–Borane Adducts. J. Am. Chem. Soc. 2013, 135, 14094. b) Pang, Y.; He, Q.; Li, Z.-Q.; Yang, J.-M.; Yu, J.-H.; Zhu, S.F.; Zhou, Q.-L., Rhodium-Catalyzed B–H Bond Insertion Reactions of Unstabilized Diazo Compounds Generated in Situ from Tosylhydrazones. J. Am. Chem. Soc. 2018, 140, 10663. c) Chen, D.; Zhang, X.; Qi, W.-Y.; Xu, B.; Xu, M.-H., Rhodium(I)-Catalyzed Asymmetric Carbene Insertion into B–H Bonds: Highly Enantioselective Access to Functionalized Organoboranes. J. Am. Chem. Soc. 2015, 137, 5268-5271. d) Yang, J.-M.; Li, Z.-Q.; Li, M.-L.; He, Q.; Zhu, S.-F.; Zhou, Q.-L., Catalytic B–H Bond Insertion Reactions Using Alkynes as Carbene Precursors. J. Am. Chem. Soc. 2017, 139, 3784. e) Kan, S. B. J.; Huang, X.; Gumulya, Y.; Chen, K.; Arnold, F. H., Genetically programmed chiral organoborane synthesis. Nature 2017, 552, 132. 7. a) Potter, B.; Edelstein, E. K.; Morken, J. P., Modular, Catalytic Enantioselective Construction of Quaternary Carbon Stereocenters by Sequential Cross-Coupling Reactions. Org. Lett. 2016, 18, 3286. b)Potter, B.; Szymaniak, A. A.; Edelstein, E. K.; Morken, J. P., Nonracemic Allylic Boronates through Enantiotopic-Group-Selective Cross-Coupling of Geminal Bis(boronates) and Vinyl Halides. J. Am. Chem. Soc. 2014, 136, 17918. c) Sun, C.; Potter, B.; Morken, J. P., A Catalytic Enantiotopic-Group-Selective Suzuki Reaction for the



Construction of Chiral Organoboronates. J. Am. Chem. Soc. 2014, 136, 6534. d) Zhan, M.; Li, R.-Z.; Mou, Z.-D.; Cao, C.-G.; Liu, J.; Chen, Y.-W.; Niu, D., Silver-Assisted, Iridium-Catalyzed Allylation of Bis[(pinacolato)boryl]methane Allows the Synthesis of Enantioenriched Homoallylic Organoboronic Esters. ACS Catal. 2016, 6, 3381. e) Joannou, M. V.; Moyer, B. S.; Meek, S. J., Enantioand Diastereoselective Synthesis of 1,2-Hydroxyboronates through Cu-Catalyzed Additions of Alkylboronates to Aldehydes. J. Am. Chem. Soc. 2015, 137, 6176. 8. a) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q., Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts. Science 2018, 359, 759. b) Wang, Y.; Shi, Z.-J., Enantioselective CH Activation and Ligand Acceleration with Newly Designed APAQ Ligands. Chem 2016, 1, 528. 9. For selected reviews, see: a) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q., Transition metal-catalyzed C-H activation reactions: diastereoselectivity and enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242. b) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N., Catalytic Enantioselective Transformations Involving C– H Bond Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117, 8908. For selected examples, see: c) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q., PdII-Catalyzed Enantioselective Activation of C(sp2)-H and C(sp3)-H Bonds Using Monoprotected Amino Acids as Chiral Ligands. Angew. Chem., Int. Ed. 2008, 47, 4882. d) Deng, R.; Huang, Y.; Ma, X.; Li, G.; Zhu, R.; Wang, B.; Kang, Y.-B.; Gu, Z., Palladium-Catalyzed Intramolecular Asymmetric C-H Functionalization/Cyclization Reaction of Metallocenes: An Efficient Approach toward the Synthesis of Planar Chiral Metallocene Compounds. J. Am. Chem. Soc. 2014, 136, 4472. e) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L., Enantioselective Synthesis of Planar Chiral Ferrocenes via Palladium-Catalyzed Direct Coupling with Arylboronic Acids. J. Am. Chem. Soc. 2013, 135, 86. f) Saget, T.; Cramer, N., Palladium(0)-Catalyzed Enantioselective C-H Arylation of Cyclopropanes: Efficient Access to Functionalized Tetrahydroquinolines. Angew. Chem., Int. Ed. 2012, 51, 12842. g) Katayev, D.; Nakanishi, M.; Buergi, T.; Kuendig, E. P., Asymmetric C(sp3)-H/C(Ar) coupling reactions. Highly enantio-enriched indolines via regiodivergent reaction of a racemic mixture. Chem. Sci. 2012, 3, 1422. g) Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J., Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands. J. Am. Chem. Soc. 2017, 139, 1412. h) Kim, J. H.; Gressies, S.; BoultadakisArapinis, M.; Daniliuc, C.; Glorius, F., Rh(I)/NHC*-Catalyzed Siteand Enantioselective Functionalization of C(sp3)-H Bonds Toward Chiral Triarylmethanes. ACS Catal. 2016, 6, 7652. i) Hao, W.; Hua‐ Rong, T.; Gang, H.; Gong, C., An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand. Angew. Chem., Int. Ed. 2016, 55, 15387. j) Anas, S.; Cordi, A.; Kagan, H. B., Enantioselective synthesis of 2-methylindolines by palladium catalyzed asymmetric C(sp3)-H activation/cyclization. Chem. Commun. 2011, 47, 11483. k) Yang, L.; Melot, R.; Neuburger, M.; Baudoin, O., Palladium(0)catalyzed asymmetric C(sp3)-H arylation using a chiral binol-derived phosphate and an achiral ligand. Chem. Sci. 2017, 8, 1344. l) Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.F.; Liu, T.; Houk, K. N.; Yu, J.-Q., Ligand-accelerated enantioselective methylene C(sp3)–H bond activation. Science 2016, 353, 1023. m) Su, B.; Zhou, T.-G.; Li, X.-W.; Shao, X.-R.; Xu, P.-L.; Wu, W.-L.; Hartwig, J. F.; Shi, Z.-J., A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C−H Bonds. Angew. Chem., Int. Ed. 2017, 56, 1092. n) J.; Shao, Q.; Wu, Q.; Yu, J.-Q., Pd(II)-Catalyzed Enantioselective C(sp3)–H Borylation. J. Am. Chem. Soc. 2017, 139, 3344. o) Lee, T.; Wilson, T. W.; Berg, R.; Ryberg, P.; Hartwig, J. F., Rhodium-Catalyzed Enantioselective Silylation of Arene C-H Bonds: Desymmetrization of Diarylmethanols. J. Am. Chem. Soc. 2015, 137, 6742. p) Taegyo, L.; F., H. J., Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C−H Bonds. Angew. Chem., Int. Ed. 2016, 55, 8723. q) Zhang, Q.-W.;

Page 8 of 10

An, K.; Liu, L.-C.; Yue, Y.; He, W., Rhodium-catalyzed enantioselective intramolecular C-H silylation for the syntheses of planar-chiral metallocene siloles. Angew. Chem., Int. Ed. 2015, 54, 6918. r) Su, B.; Hartwig, J. F., Ir-Catalyzed Enantioselective, Intramolecular Silylation of Methyl C-H Bonds. J. Am. Chem. Soc. 2017, 139, 12137. s) Pan, S.; Endo, K.; Shibata, T., Ir(I)-Catalyzed Enantioselective Secondary sp3 C–H Bond Activation of 2(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692. t) Shibata, T.; Shizuno, T., Iridium-Catalyzed Enantioselective C-H Alkylation of Ferrocenes with Alkenes Using Chiral Diene Ligands. Angew. Chem., Int. Ed. 2014, 53, 5410-5413. u) Su, B.; Hartwig, J. F., Ir-Catalyzed Enantioselective, Intramolecular Silylation of Methyl C– H Bonds. J. Am. Chem. Soc. 2017, 139, 12137. 10. For a review, see: a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F., C−H Activation for the Construction of C−B Bonds. Chem. Rev. 2010, 110, 890. For pioneering work, see: b) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R., Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305. c) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F., Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390. 11. a) Su, B.; Zhou, T.-G.; Xu, P.-L.; Shi, Z.-J.; Hartwig, J. F., Enantioselective Borylation of Aromatic C−H Bonds with Chiral Dinitrogen Ligands. Angew. Chem., Int. Ed. 2017, 56, 7205. 12. Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F., Mechanism of the Mild Functionalization of Arenes by Diboron Reagents Catalyzed by Iridium Complexes. Intermediacy and Chemistry of Bipyridine-Ligated Iridium Trisboryl Complexes. J. Am. Chem. Soc. 2005, 127, 14263. 13. For selected reviews, see: a) Xu, L.; Wang, G.; Zhang, S.; Wang, H.; Wang, L.; Liu, L.; Jiao, J.; Li, P., Recent advances in catalytic C-H borylation reactions. Tetrahedron 2017, 73, 7123. b) Ros, A.; Fernandez, R.; Lassaletta, J. M., Functional group directed C-H borylation. Chem. Soc. Rev. 2014, 43, 3229. c) Hartwig, J. F., Regioselectivity of the borylation of alkanes and arenes. Chem. Soc. Rev. 2011, 40, 1992. For selected examples, see: d) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N., Ortho-C-H borylation of benzoate esters with bis(pinacolato)diboron catalyzed by iridium-phosphine complexes. Chem. Commun. 2010, 46, 159. e) Sasaki, I.; Taguchi, J.; Hiraki, S.; Ito, H.; Ishiyama, T., Catalyst-controlled regiodivergent CH borylation of multifunctionalized heteroarenes by using iridium complexes. Chem. - Eur. J. 2015, 21, 9236. f) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M., Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine−Iridium System. J. Am. Chem. Soc. 2009, 131, 5058. g). Kawamorita, S.; Ohmiya, H.; Sawamura, M., Ester-Directed Regioselective Borylation of Heteroarenes Catalyzed by a SilicaSupported Iridium Complex. J. Org. Chem. 2010, 75, 3855. h) Yamazaki, K.; Kawamorita, S.; Ohmiya, H.; Sawamura, M., Directed Ortho Borylation of Phenol Derivatives Catalyzed by a SilicaSupported Iridium Complex. Org. Lett. 2010, 12, 3978-3981. i) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B., Phosphine-directed C-H borylation reactions: facile and selective access to ambiphilic phosphine boronate esters. Angew. Chem., Int. Ed. 2014, 53, 7589. j) Roering, A. J.; Hale, L. V. A.; Squier, P. A.; Ringgold, M. A.; Wiederspan, E. R.; Clark, T. B., Iridium-Catalyzed, Substrate-Directed C–H Borylation Reactions of Benzylic Amines. Org. Lett. 2012, 14, 3558. k) Hale, L. V. A.; McGarry, K. A.; Ringgold, M. A.; Clark, T. B., Role of Hemilabile Diamine Ligands in the Amine-Directed C–H Borylation of Arenes. Organometallics 2015, 34, 51. l) Ros, A.; Estepa, B.; López-Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M., Use of Hemilabile N,N Ligands in Nitrogen-Directed Iridium-Catalyzed Borylations of Arenes. Angew. Chem., Int. Ed. 2011, 50, 11724. m) Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.; Fernández, R.; Lassaletta, J. M., Hydrazone as the Directing Group for Ir-Catalyzed Arene Diborylations and


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Sequential Functionalizations. J. Am. Chem. Soc. 2012, 134, 4573. n) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Smith, M. R., Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis. J. Am. Chem. Soc. 2014, 136, 14345. o) Wang, G.; Liu, L.; Wang, H.; Ding, Y.-S.; Zhou, J.; Mao, S.; Li, P., N,B-Bidentate Boryl Ligand-Supported Iridium Catalyst for Efficient Functional-GroupDirected C–H Borylation. J. Am. Chem. Soc. 2017, 139, 91. 14 For pioneering work of boron as chiral Lewis-acid catalysts, see: a) Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H., Asymmetric Diels-Alder reaction directed toward chiral anthracycline intermediates. Tetrahedron Letters 1986, 27, 4895. b) Ikeda, N.; Arai, I.; Yamamoto, H., Chiral allenylboronic esters as practical reagents for enantioselective carbon-carbon bond formation. Facile synthesis of (-)ipsenol. J. Am. Chem. Soc. 1986, 108, 483. c) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B., Practical enantioselective Diels-Alder and aldol reactions using a new chiral controller system. J. Am. Chem. Soc. 1989, 111, 5493. For a review, see: d) Deloux, L.; Srebnik, M., Asymmetric boron-catalyzed reactions. Chem. Rev. 1993, 93, 763. 15. Crystallographic data for L10-Ir, 8n, and 11 could be found in the Supporting Information. CCDC 1850297 (L10-Ir), CCDC 1850296 (8n), and CCDC 1850295 (11) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. 16. a) Ameen, D.; Snape, T. J., Chiral 1,1-diaryl compounds as important pharmacophores. MedChemComm 2013, 4, 893. b) Chen, C., Physicochemical, Pharmacological and Pharmacokinetic Properties of the Zwitterionic Antihistamines Cetirizine and Levocetirizine. Curr. Med. Chem. 2008, 15, 2173. c) Basra, R.; Kelleher, C., A review of solifenacin in the treatment of urinary incontinence. Ther. Clin. Risk Manag. 2008, 4, 117. d) Metcalf, M. D.; Yekkirala, A. S.; Powers, M. D.; Kitto, K. F.; Fairbanks, C. A.; Wilcox, G. L.; Portoghese, P. S., The δ Opioid Receptor Agonist SNC80 Selectively Activates Heteromeric μ–δ Opioid Receptors. ACS Chem. Neurosci. 2012, 3, 505. 17. Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C., Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines. Chem. Soc. Rev. 2006, 35 (5), 454-470. 18. (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M., Catalytic Enantioselective Formation of C−C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update. Chem. Rev. 2011, 111 (4), 26262704. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P., N-tertButanesulfinyl Imines: Versatile Intermediates for the Asymmetric Synthesis of Amines. Acc. Chem. Res. 2002, 35 (11), 984-995. 19. Hou, G.; Tao, R.; Sun, Y.; Zhang, X.; Gosselin, F., Iridium−Monodentate Phosphoramidite-Catalyzed Asymmetric Hydrogenation of Substituted Benzophenone N−H Imines. J. Am. Chem. Soc. 2010, 132, 2124. 20. Chu, L.; Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q., Pd-Catalyzed Enantioselective C–H Iodination: Asymmetric Synthesis of Chiral Diarylmethylamines. J. Am. Chem. Soc. 2013, 135, 16344. 21. Meng, F.; McGrath, K. P.; Hoveyda, A. H., Multifunctional organoboron compounds for scalable natural product synthesis. Nature 2014, 513, 367. 22. Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F., Arenes to Anilines and Aryl Ethers by Sequential Iridium-Catalyzed Borylation and Copper-Catalyzed Coupling. Org. Lett. 2007, 9, 761. 23. Murphy, J. M.; Liao, X.; Hartwig, J. F., Meta Halogenation of 1,3Disubstituted Arenes via Iridium-Catalyzed Arene Borylation. J. Am. Chem. Soc. 2007, 129, 15434. 24. Hohenberg, P.; Kohn, W., Inhomogeneous Electron Gas. Phys. Rev. 1964, 136, B864. 19 25. Zhao, Y.; Truhlar, D. G., The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent

interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215. 26. Hay, P. J.; Wadt, W. R., Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys. 1985, 82, 299. 27. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G., Performance of SM6, SM8, and SMD on the SAMPL1 Test Set for the Prediction of Small-Molecule Solvation Free Energies. J. Phys. Chem. B 2009, 113, 4538. 28. Rassolov, V. A.; Pople, J. A.; Ratner, M. A.; Windus, T. L., 6-31G* basis set for atoms K through Zn. J. Chem. Phys. 1998, 109, 1223-1229. 29. M. J. G. Frisch 2009, G., Revision D.01, Gaussian, Inc. Wallingford CT, 2009. 30. Legault, C. Y., CYLview, 1.0b; Université de Sherbrooke 2009, http://www.cylview.org. 31. a) Huang, G.; Kalek, M.; Liao, R.-Z.; Himo, F., Mechanism, reactivity, and selectivity of the iridium-catalyzed C(sp3)–H borylation of chlorosilanes. Chem. Sci. 2015, 6, 1735. b) Jover, J.; Maseras, F., Mechanistic Investigation of Iridium-Catalyzed C–H Borylation of Methyl Benzoate: Ligand Effects in Regioselectivity and Activity. Organometallics 2016, 35, 3221. 32. Webster, C. E.; Fan, Y.; Hall, M. B.; Kunz, D.; Hartwig, J. F., Experimental and Computational Evidence for a Boron-Assisted, σBond Metathesis Pathway for Alkane Borylation. J. Am. Chem. Soc. 2003, 125, 858. 33. Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S., Iridium-Catalyzed Borylation of Benzene with Diboron. Theoretical Elucidation of Catalytic Cycle Including Unusual Iridium(V) Intermediate. J. Am. Chem. Soc. 2003, 125, 16114.. 34. Li, Q.; Liskey, C. W.; Hartwig, J. F., Regioselective Borylation of the C–H Bonds in Alkylamines and Alkyl Ethers. Observation and Origin of High Reactivity of Primary C–H Bonds Beta to Nitrogen and Oxygen. J. Am. Chem. Soc. 2014, 136, 8755. 35. Larsen, M. A.; Wilson, C. V.; Hartwig, J. F., Iridium-Catalyzed Borylation of Primary Benzylic C–H Bonds without a Directing Group: Scope, Mechanism, and Origins of Selectivity. J. Am. Chem. Soc. 2015, 137, 8633. 36. For a recent example of Ir-catalyzed enantioselective borylation of C(sp3)-H bonds, see: Reyes, R. L.; Harada, T.; Taniguchi, T.; Monde, K.; Iwai, T.; Sawamura, M., Enantioselective Rh- or Ir-catalyzed Directed C(sp3)–H Borylation with Phosphoramidite Chiral Ligands. Chem. Lett. 2017, 46, 1747.



Page 10 of 10

B = Bpin Chiral diamine controls stereoselectivity

Ph Ph

NR2

Ar B N B B Ir N N

B2Pin2 R'

R''

Two vacant or weekly coordinated sites control regioselectivity

Bpin NR2

Bpin NR2

R' R' = R'' Desymmetrization R'

26 exmples 79-96% ee


R'

R'

R' = R'' Kinetic Resolution 11 exmples up to 94% ee s up to 68

10

Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Asymmetric

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