Chiral N-Heterocyclic Carbene Ligands Enable Asymmetric C-H Bond Functionalization

Ligands Enable Asymmetric C- H Bond Functionalization.

Jompol Thongpaen, Romane Manguin, and Olivier Baslé*

N N

..

R R

R ^*

C H R ^*

TM

R R

* R C C

Accepted Manuscript

Abstract: The asymmetric functionalization of C-H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N-Heterocyclic Carbene (NHC) ligands have become ubiquitous in enantioselective transition-metal catalysis. Conversely, the use of chiral NHC ligands in metal-catalyzed asymmetric C-H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.

1. Introduction

Chiral molecules play an important role in the chemistry of life, medicine and material science. Pioneered by H. B. Kagan, ^[1] W.

S. Knowles, ^[2] R. Noyori ^[3] and K. B. Sharpless, ^[4] the field of catalytic asymmetric synthesis has grown exponentially, resulting in innovative methods and processes for the efficient production of enantiomerically pure substances. ^[5] Among those contemporary methodologies, transition-metal-catalyzed asymmetric cross-coupling reaction has appeared in the past decades as one of the most powerful synthetic tools to construct C-C and C-heteroatom bonds. ^[6] Despite of the tremendous success of these transformations, cross-coupling reactions require the use of prefunctionalized substrates such as organohalides and organometallic reagents, forcing synthetic chemists to pursue multistep manipulations. On the other hand, the transition metal-catalyzed direct functionalization of inert C-H bonds has emerged over the past two decades as an increasingly important synthetic tool opening new avenues in the construction of chiral molecules from readily available materials. ^[7] As for other asymmetric catalytic processes, chiral ligand engineering has been the key to the success of TM-catalyzed C-H functionalization. Thanks to their manifold application possibilities, phosphorus-based chiral ligands have been central to numerous breakthroughs in asymmetric C-H functionalization. ^{[7c] [8]} On the other hand, In 2009 Yu and co-workers demonstrated that monoprotected a-amino acids are effective chiral ligands for Pd(II)-catalyzed enantioselective alkylation of Csp ² -H and Csp ³ -H bonds. ^[9] This discovery has led in the past decade to significant advances in the development of efficient asymmetric C-H transformations. ^[10] Meanwhile, Cramer and co-workers developed a new class of chiral ligands based on C 2 -symmetrical cyclopentadienyl derivatives that have proven to be efficient in asymmetric C-H functionalization catalyzed by rhodium, ^[11] while offering promising potential in a variety of other catalytic processes using TM-based Cp * complexes. ^[12]

Amongst alternative chiral ligands, ^[13] N-Heterocyclic Carbenes (NHCs) are unambiguously those offering the greatest perspectives in TM-catalyzed asymmetric C-H functionalization. ^[14] During the past two decades, NHCs have become ubiquitous ligands in coordination chemistry and catalysis. Their unique properties, including strong σ-donation, are responsible for forming robust TM catalysts that allow for the development of more efficient synthetic procedures. ^[15] Moreover, straightforward synthetic methods give access to a large variety of NHC structures with diverse chiral architectures. ^[16]

Nevertheless, and despite the recent success of chiral NHC ligands in asymmetric homogeneous catalysis, ^[17] including intramolecular a-arylation of amides, ^[18-24] the use of such ligands in TM-catalyzed asymmetric C-H bond functionalization is still in its infancy. This minireview highlights all the developments and the new advances in this burgeoning and promising field of research.

Jompol Thongpaen was born in Yala Province, Thailand, in 1992. He received his Bachelor’s degree in Chemistry in 2014 from Mahidol University, Thailand. Then, he was granted a Franco-Thai scholarship from the French Embassy to pursue and complete his International Master Degree at the University of Rennes 1, France. He performed his master’s research in Dr. M. Mauduit group at ENSC- Rennes, France. Initiated at ENSC-Rennes, he is

now pursuing his PhD work under the supervision of Dr. Olivier. Baslé at Laboratoire de Chimie de Coordination (LCC), Toulouse. His research mainly focuses on C-H bond functionalization catalyzed by NHC - Metal complexes.

Romane Manguin was born in Chartres in 1993.

She completed her bachelor degree in Brest under the supervision of Prof. M. Berchel. Then she received her master degree from the University of Rennes 1, and performed her master research on diyne metathesis in Dr. M.

Mauduit group. Now, she is PhD student within the same group under the supervision of Dr.

Olivier Baslé and work on the design of new NHC - Metal catalysts for asymmetric C-H functionalization.

Olivier Baslé completed his Master degree under the supervision of Prof. P. H. Dixneuf at the university of Rennes in 2006 and obtained his PhD degree in 2009 at McGill University under the guidance of Prof. C.-J. Li. After postdoctoral studies with Prof. J. Rodriguez and T.

Constantieux in Marseille and Dr. D. Bourissou in Toulouse, he was appointed CNRS researcher in 2011 at ENSC-Rennes. In 2018, he joined the CNRS Laboratory of Coordination Chemistry in

Toulouse. His research program focuses on the development of selective catalytic transformations using N-heterocyclic carbene-Metal complexes.

[a] J. Thongpaen, Dr. O. Baslé

LCC-CNRS, Université de Toulouse, CNRS, Toulouse, France E-mail : olivier.basle@lcc-toulouse.fr

J. Thongpaen, R. Manguin

Univ Rennes, Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR – UMR 6226, F-35000 Rennes, France.

Accepted Manuscript

2. Functionalization of C(sp ³ )-H Bonds

2.1. Intramolecular Arylation of Unactivated C(sp ³ )-H Bonds In 2011, Kündig and coworkers reported the first example of the use of chiral NHC ligands in enantioselective functionalization of unactivated C-H bonds (Scheme 1). ^[25] In a continuing effort to demonstrate the potential of their unsaturated C 2 -symmetrical NHC ligands based on ortho-substituted a-tert- butylbenzylamines, ^[23] high efficiency could be achieved using the naphthyl-based L1 ligand in palladium-catalyzed intramolecular arylation of unactivated C(sp ³ )-H bonds at high temperature (140-160°C). The great robustness of the catalytic system allowed the synthesis of a variety of fused indolines (2 and 4) with very high enantioselectivity (up to 99% ee). ^[26] Mechanistic studies revealed that the reaction proceeds first via oxidative addition of the C-Br bond giving palladium(II) complex 5, followed by the enantiodetermining C-H bond cleavage by means of Concerted- Metalation Deprotonation (CMD) process (see transition state 6). ^[27] When the (S,S)-L1 is employed, reductive elimination from the chiral cyclopalladated intermediate 7 affords preferentially the enantioenriched product with (R) configuration.

Scheme 1. Asymmetric intramolecular arylation of unactivated C(sp

³

)-H bonds for the synthesis of fused-indolines.

Later, the same group reported a regiodivergent synthetic approach to indolines using a similar catalytic system (Scheme

2). ^{[28], [29]} The asymmetric C-H annulation of racemic carbamate

substrates led to the formation of two different indolines with high enantio-induction. Enantiomers interacted with the chiral catalyst differently, providing for each a regioselective product accordingly (Scheme 2). The observed behavior of this parallel kinetic resolution methodology was in a good agreement with computational studies based on calculated activation barriers of the CMD enantiopic-determining step. In the case of substrate (S)-8a, the C-H bond cleavage of CH 3 is more favored than of CH 2 (with a large ΔΔG ^‡ = 14.0 kJ.mol ^-1 ) affording the 2-substituted indoline 9a exclusively. On the other hand, CH 2 bond cleavage of (R)-8a is more favored (ΔΔG ^‡ = 19.2 kJ.mol ^-1 ) leading selectively to the 2,3-substituted product 10a.

Scheme 2. Regiodivergent synthesis of indolines.

Baudoin and co-workers described in 2012 the Pd-catalyzed intramolecular asymmetric annulation of aryl bromides bearing unactivated C(sp ³ )-H bonds. ^[30] While the highest enantioselectivity in the synthesis of indanes 12 was achieved with chiral phosphines, interesting enantio-discrimination could also be obtained applying the conditions previously described by Kündig and coworkers using the NHC ligand (S,S)-L2 (Scheme 3).

Scheme 3. Enantioselectivity in the synthesis of indanes.

Very recently, the same group extended this methodology towards the enantioselective synthesis of indane 17, precursors of (nor)illudalane sesquiterpenes. ^[31] The strategy involved the intramolecular enantioselective arylation of a C(sp ³ )–H bond to generate a quaternary stereocenter at the adjacent position (Scheme 4). Among several NHC ligands that were surveyed, the (S,S)-L1, developed by Kündig and coworkers afforded the highest enantioinduction (80:20 e.r.) in the desymmetrization of the gem-dimethyl group of the morpholinamide substrate 13. By employing (L)-proline derived substrate 15, the desired product 16 could be obtained with good 87% isolated yield and satisfactory 85:15 d.r. (matched case). The sequential treatments including hydrolysis of the amide group and recrystallization furnished the highly enantioenriched compound 17, the parent substance of the key intermediate 18 in the synthesis of (nor)illudalane sesquiterpenes.

O

N OMe

PdBr NHC*

N MeO2C

Pd NHC* O

O tBu

H

N CO2Me PdO NHC*

OH tBu

Concerted-Metallation Deprotonation (CMD) via

CsOPiv

Ar Ar Ar

5 6 7

N CO2Me Br

Cs2CO3, CsOPiv mesitylene, 140-160 ^oC

N CO2Me H

( )n H

( )n

N CO2Me

Br Z

N CO2Me H Z

H n = 1,2

Ar² = phenyl, pyridine Z = C, O, S, NBoc, NCbz

32-92% yield 78-99% ee 13-94% yield

10-95% ee

N N

(S,S)-L1

N N

(R,R)-L1

Ar¹ Ar¹

[Pd(π-cinnamyl)Cl]₂ (2.5-5 mol%) (S,S)-L1.HI (5-10 mol%)

Ar²

Cs₂CO_3, CsOPiv mesitylene, 160 ^oC [Pd(π-cinnamyl)Cl]2 (2.5 mol%)

(R,R)-L1.HI (5 mol%) Ar² Ar¹ = phenyl

Proposed key reaction intermediates based on a model substrate:

1 2

3 4

N CO

2

Me

Br [Pd(π-cinnamyl)Cl]

₂ (S,S)-L1.HI

Cs

2

CO

3,

CsOPiv

xylenes, 140

^o

C

N CO

₂

Me

Ph H Ph

N CO

2

Me H Ph

H 96 % yield

>99% ee

97 % yield

>99% ee N

MeO

2

C Pd

O

NHC* O

tBu

H Ph

favored for (S)-8a via

[Pd(π-cinnamyl)Cl]

₂ (S,S)-L1.HI

Cs

2

CO

3,

CsOPiv xylenes, 140

^o

C N

CO

2

Me Br

Ph N

MeO

2

C Pd NHC* O O

tBu

H Ph

via

favored for (R)-8a (R)-8a

(S)-8a

+ / or

Cs

₂

CO

_3,

CsOPiv xylenes, 140

^o

C [Pd(π-cinnamyl)Cl]

2

(5 mol%)

(S,S)-L1.HI (10 mol%) N

CO

2

Me Br

N CO

2

Me R

¹

H R

¹

R

²

R

²

H N

CO

2

Me R

²

H

R

¹

+ H

“racemic mixture” up to 99% ee up to 99% ee

R

¹

= Aryl, heteroaryl, Alkyl, ether, ester, thioether R

²

= H, Me, Ph

Proposed key reaction intermediates based on a model substrate 10a:

8 9 10

9a

10a

up to 99% yield

Br

NC iPr

NC iPr

39% yield (d.r. = 11.1) 38% ee

N N

..

tBu tBu

(S,S)-L2 Cs₂CO_3, CsOPiv

mesitylene, 160 ^oC [Pd(π-cinnamyl)Cl]₂ (10 mol%)

(S,S)-L2.HI (10 mol%)

11 12

Accepted Manuscript

Scheme 4. Regiodivergent synthesis of indolines.

2.2. Intermolecular Arylation of Benzylic C-H Bonds.

In 2016, Glorius and coworkers reported the first example of rhodium(I)-catalyzed intermolecular functionalization of C(sp ³ )-H bonds (Scheme 5). ^[32] The use of NHC ligands afforded high selectivity in favor of the benzylic C-H arylation and the mesityl substituent on the NHC appeared crucial for the activity (no catalytic activity with Dipp-based ligand such as L10). The authors postulated that cyclometalation at the o-tolyl substituent of the NHC enabled the generation of the catalytically active species (21). Thanks to a multicomponent procedure affording a simple and rapid access to unsymmetrical imidazolium salts, ^[33] a large variety of chiral NHC precursors was screened and the best results were obtained with L9 that afforded in a model reaction the desired product 20a in high 85% isolated yield and 78%

enantiomeric excess. The direct arylation reaction of 8-benzyl quinolones 19 with aryl bromides was only slightly influenced by the electronic and steric nature of the substituents on both substrates, affording the desired products 20 in high yields and good enantiomeric ratios. In the proposed mechanism, the authors postulated that the catalytically active cyclometalated species 21 undergoes successive oxidative addition of the aryl bromide and diastereoselective transmetalation with the deprotonated 8-benzyl quinolone substrate 22 to form the Rh(III)- intermediate 23.

Scheme 5. Rhodium-catalyzed intermolecular enantioselective C(sp

³

)-H bond arylation.

2.3. Intermolecular C-H Alkenylation of Alcohols

Very recently, Shi and coworkers described the first example of enantioselective C-H alkenylation of alcohols with alkynes (Scheme 6). ^[34] In order to achieve high stereoselectivity in this redox-neutral coupling catalyzed by nickel(0)-system, the authors investigated a new class of bulky chiral NHCs, that was initially introduced by Gawley in 2011, ^[35] and concomitantly developed by the Shi ^[36] and the Cramer ^[37] groups (vide infra, section 3.1). The catalytic system made in situ from the deprotonation of the imidazolinium salt (L11.HCl; analogue of SiPr) by NaHMDS in the presence of Ni(cod) 2 and in combination with the electron deficient phosphite ligand P(OPh) 3 delivered the desired chiral allylic alcohols with high E/Z ratios (up to 99:1) and high enantioselectivities (up to 92% ee). Similar result could be obtained with the isolated Ni(0)-NHC complex C1 and control experiment in the absence of P(OPh) 3 evidenced only an erosion in E/Z ratio confirming the important role of the additive to suppress the product isomerization. It is also important to note that a range of chiral NHC ligands was tested during the optimization of the model reaction between benzyl alcohol (24a) and 4-octyne (25a) showing the strong impact of NHC structure on the reaction outcome. In fact, the commonly used C 2

symmetrical NHC ligands L12 and L13 proved to be inoperative.

On the other hand, a noticeable decreased of the catalytic efficiency was observed in the presence of ligands L14 and L15, unsaturated analogues of L11. The proposed mechanism involves dehydrogenation of alcohol 24 to generate the corresponding aldehyde 27, which undergoes oxidative cyclization with alkyne 25 and Ni(0) to produce the enantioenriched oxanickelacycle 28 as a key intermediate.

Br O OMe

N

O Cs2CO3, CsOPiv

mesitylene, 160 ^oC [Pd(π-cinnamyl)Cl]2 (5 mol%)

L.HX (10 mol%)

amido auxiliary

OMe O

* N

N N

(S,S)-L1 100% yield, 80:20 e.r.

N N

..

tBu

L3 22% yield, 66.5:33.5 e.r.

iPr

iPr N N

..

O O

L4 100% yield, 66:34 e.r.

(GC yield)

N N

..

O O

L5 11% yield, 62:38 e.r.

N N

..

O O

L6 56% yield, 61:39 e.r.

Cs2CO3, CsOPiv

mesitylene, 160 ^oC 87% yield

85:15 d.r.

[Pd(π-cinnamyl)Cl]₂ (5 mol%) (S,S)-L1.HI (10 mol%) Br

O N

CO2iPr

L-proline-derived chiral auxiliary

OMe OMe

O R

*

*

OH CO₂H

57% yield 96:4 e.r.

15 16

17 a) Selected examples from the optimization studies:

OH CO2H

18 66% yield common key intermediate

2 steps

amide hydrolysis then recrystallization b) Applications towards synthesis of (Nor)illudalane sesquiterpenes:

O

13 14

Postulated intermediates:

N N ^tBu

Rh PPh3

PPh₃

Ar Ar² Br

21 N

Ar¹ Rh PPh3 1)

2) N

Ar¹ Na

Ar² NHC*

N Ar¹

+ Ar² Br

RhCl(PPh3)3 (5 mol%) L9.HCl (5 mol %) NaOtBu (3 equiv.) dioxane, 80 °C, 12h

N Ar¹ Ar²

L9 Ar = 4-F-C6H5 Ar¹ = Ph, electron rich and poor aryl

Ar² = Ph, electron rich and poor aryl, benzofurane.

19 examples up to 85% yield up to 78% ee Selected examples from the reaction optimization:

L8 80% yield, 64% ee

N +

Br

RhCl(PPh₃)₃ (5 mol%) L.HCl (5 mol %) NaOtBu (3 equiv.) toluene, 100 °C, 4h

N F F

N N

..

tBu Ar

N N

..

tBu

L9 90% yield, 74% ee

(Ar = 4-F-C6H5)

N N

..

tBu Ar

L7 25% yield, 40% ee

N N

..

iPr (3 equiv.)

L10 0% yield, 0% ee

N N

..

tBu iPr

iPr

(OA) (RE)

20

ent-22 22

19 20

19a 20a

23

Accepted Manuscript

Scheme 6. Nickel-catalyzed enantioselective C-H alkenylation of alcohols with alkynes.

3. Functionalization of C(sp ² )-H Bonds

3.1. Intramolecular Hydroarylation of Olefins

In 2014, Cramer and coworkers reported a nickel-catalyzed C-H functionalization of 2-pyridones by selective intramolecular olefin hydroarylation (Scheme 7). ^[38] The regioselectivity of the cyclization was fully controlled by the ligand and unsymmetrical chiral NHC L16 based on the isoquinoline framework delivered selectively the endo-cyclization product with promising enantioselectivity.

Scheme 7. Ligand controlled nickel-catalyzed annulation of pyridones.

More recently, the same group further investigated this transformation and among the chiral NHCs that were surveyed, the sterically demanding monodentate ligand L17 allowed for highly enantioselective C-H functionalization of 2- and 4- pyridones (Scheme 8). ^[37] While unsatisfactory results were obtained with common chiral carbene ligands (L4, L1, L18), interesting catalytic activities could be obtained using L14. ^[35],[36]

Introduction of the acenaphthene fragment on the backbone of L15 improved the selectivity and authors evidenced that this flexible ligand displays an improved C 2 -symmetric binding pocket.

The enantioselectivity could be further increased with the introduction of bulky aromatic side arms, i.e. 3,5-di-methyl phenyl groups (L17). Then, in the presence of MAD (methylaluminium bis(2,6-di-tert-butyl-4-methylphenolate), the desired endo- cyclized annulated pyridines were obtained with high yields (up to 91% yield) and enantioselectivities (up to 98% ee) under mild reaction conditions. The endo-cyclization selectivity is in accordance with theoretical and mechanistic studies of Ni- catalyzed hydroarylations, in which a mechanism involving direct ligand to ligand hydrogen transfer (LLHT) is proposed. ^[39]

Scheme 8. Nickel-catalyzed enantioselective pyridone C-H functionalizations.

MAD = methylaluminium bis(2,6-di-tert-butyl-4-methylphenoxide).

The intramolecular regio- and enantioseletive C-H cyclization of pyridines with olefins was very recently reported by Shi and coworkers (Scheme 9). ^[40] Among several chiral NHC ligands that were investigated, the bulky chiral saturated L11, ^[34] the analogue of SiPr, provided excellent catalytic activities and furnished the targeted tetrahydroquinolines and tetrahydroisoquinolines with excellent enantioinduction (up to 99% ee). During the optimization of the reaction conditions, pronounced ligand effect could be observed in the cyclization of substrate 33a. Notably, while L11 performed with high reactivity and selectivity (99% yield and 93%

ee), its replacement by the unsaturated analogue L14 dramatically decreased the yield and enantioselectivity (77% yield and 60% ee). It should be noted that 34a could be obtained with up to 96% ee using the bulkier ligand L21, but with slightly lower reactivity. The proposed mechanism involves coordination of the bulky MAD to the pyridine nitrogen, which favors the

OH

+

[Ni(cod)

2

] (2 to 20 mol%)

NaHMDS (4 to 40 mol%)

cyclohexane, RT, 24 h

Ar = Electron rich and poor aryl group

R

¹

, R

²

= Me, Et, nPr, nBu, nHex, (CH

₂₎₂

OPG, Ph

OH

R¹

up to 92 % yield up to E/Z = 99:1 up to 92% ee

Ar Ar

N N

..

Ph Ph Ph

Ph

(R,R,R,R)-L11

L11.HCl (2 to 20 mol%)

P(OPh)3 (2 to 20 mol%) R²

R¹ R²

(1 example with phenylpropanol)

OH

+

[Ni(cod)

2

] (2 mol%)

NaHMDS (4 mol%)

cyclohexane, RT, 24 h

OH

nPr L.HCl (2 mol%)

without P(OPh)3 nPr

nPr

nPr

N N

..

(R,R,R,R)-L15 Ph

Ph

Ph

Ph

N N

..

Ph Ph Ph

Ph

(R,R,R,R)-L14

N N

N N ..

..

N N

..

Ph Ph Ph

Ph

(R,R,R,R)-L11 (R,R)-L12 (R,R)-L13

(1.5 equiv.)

<2% yield, E/Z ratio and ee (nd)

68% yield, 88/12 E/Z, 85% ee <2% yield, E/Z ratio and ee (nd)

42% yield, 88/12 E/Z, 83% ee 84% yield, 94/6 E/Z, 91% ee

Selected examples from the reaction optimization:

N N

Ph Ph Ph

Ph

Ni

Ph Ph

(R,R,R,R)-Ni-C1 92% yield, 92/8 E/Z, 90% ee

24 25 26

24a 25a 26a

Proposed mechanism:

Ni(0)

dehydrogenation

24

Ni(0)

25 O

Ar H

O Ar

Ni^II H R¹

R² 24 26

27 28

N

O [Ni(cod)2] (10 mol%)

15 mol% L16 40 mol% AlMe3 toluene, 80 °C, 24 h

N O

H

H N N

Ph

..

L16

2 examples up to 70% yield iPr

up to 57% ee

29 30

H

(R,R,R,R)-L17

N N

..

O O

L4 20% yield, 58% ee Selected examples from the reaction optimization:

N O

[Ni(cod)2] (10 mol%) 11 mol% L17 40 mol% MAD Toluene, 40 °C, 24 h

N O

H

R² R¹ H H

up to 91% yield up to 98% ee R¹

R²

N H

R³ or

O

N R¹

H O

or N N

..

Ar Ar Ar

Ar

R¹ = Me, Ph, 2-Naphthyl, 1-furyl, PMP

R² = H, Me, Ph;R³ = Me, Ph, Naphthyl Ar = 3,5-Xyl

23 examples :

N

O [Ni(cod)2] (10 mol%) 11 mol% L 40 mol% AlMe3 Toluene, 80 °C, 24 h

N O

H Me

N N

(R,R)-L1 4% yield, 46% ee

N N

..

Ph Ph Ph

Ph

N N

..

Ph Ph Ph

Ph Me Me

L14 95% yield, 64% ee MAD instead of AlMe3 at 40 °C:

95% yield, 76% ee

L19 MAD instead of AlMe3 at 40 °C:

71% yield, 68% ee

N N

Ph Ph

..

L18 72% yield, 2% ee

N N

..

Ph Ph Ph

Ph L15 MAD instead of AlMe3 at 40 °C:

74% yield, 80% ee

29 30

31 32

29a 30b

iPr iPr

Accepted Manuscript

regioselective oxidative C-H bond addition on Ni(0), which is potentially the rate determining step (KIE = 2.5). The following anti-Markovnikov hydronickelation of the alkene and subsequent reductive elimination afford the desired endo-annulation product 36. The electronic and steric properties of the NHC ligands are apparently critical to every elementary steps of this catalytic cycle.

Scheme 9. Nickel-catalyzed enantioselective C-H functionalization of pyridines.

In 2019, Cramer and coworkers introduced new members of this ligands family to achieve high enantioselectivity in Ni-catalyzed C- H functionalization of indoles and pyrroles (Scheme 10). ^[41] The authors demonstrated that both the reactivity and selectivity of the cyclization reaction was impacted by the NHC ligand structure.

While poor yield and enantiocontrol could be obtained using the imidazole-2-ylidene L14, an increase of the bulk on the aryl side- arms (L22) improved the catalytic activity and reversed the enantioselectivity to afford 61% yield of the cyclized product 38a with 40% ee in favor of the (S)-enantiomer. Pleasantly, the use of a dihydroimidazole-2-ylidene ligand with sterically more demanding 3,5-di-tert-butyl phenyl groups on the side arms (L23) ^[42] resulted in complete conversion of 37a, 93% yield of 38a with 88% ee. Finally, a decrease of the reaction temperature to 60 °C and by replacing the solvent to trifluorotoluene improved the enantiocontrol of the endo-cyclisation to obtain 38a with 90%

ee. The optimized conditions were then applied with high

efficiency to the enantioselective cyclization of pyrroles, indoles and related aza-heterocycles with a variety of substituted alkenes.

The regioselectivity of the cyclization and results obtained from deuterium transfer experiments support a mechanism involving direct ligand to ligand hydrogen transfer. ^[39]

Scheme 10. Nickel-catalyzed enantioselective C-H functionalization of indoles and pyrroles.

In their continuing effort to develop asymmetric C-H cyclization reactions with alkenes, Shi and coworkers recently reported the first example of catalytic enantioselective functionalization of polyfluoroarenes. ^[43] The reaction achieved by the use of bulky NHC ligands (L11 or L17) for Ni(0)-based catalysts afforded a large variety of cyclized products in high efficiency and excellent levels of chemo-, regio-, and enantioselectivity (Scheme 11).

Initial attempts to cyclized the styrene-based substrate 39a with a catalytic system generated in situ involving commonly used C 2 - symmetrical chiral NHC ligands such as L12 were unsuccessful.

Under the same reaction conditions, the saturated ligand L11 was inapplicable as predominant alkene isomerization occurred. On the other hand, its unsaturated ligand analogue L14 could prevent alkene isomerization ^[44] and afforded the desired product 40a in good 52% yield and enantioselectivity (76% ee). Further ligand screening evidenced the bulky acenaphthene-based NHC L17 as the most efficient ligand affording 40a in nearly quantitative yield and high 97 % enantiomeric excess. While the catalytic system based on L17 was also applicable to 1,1-dialkyl alkene substrates, L11 demonstrated higher efficiency with such substrates that are less prone to isomerize under the reaction conditions. With the optimized conditions in hand, a variety of chiral fluorotetralins 40 were synthesized with excellent enantiocontrol from tetrafluoro, trifluoro and diflurorobenzenes tethered alkenes 39. Importantly no competitive C-F bond cleavage was observed with the catalytic systems based on L11 and L17. The authors reasoned that the bulky NHCs favor the formation of monomeric active Ni-NHC

(R,R,R,R)-L11

Selected examples from the reaction optimization:

[Ni(cod)

2

] (5 mol%) 5 mol% L11.HCl 10 mol% NaOtBu MAD (1.2 equiv.) CPME, 80 °C, 24 h

up to 99% yield up to 99% ee

or N N

..

Ph Ph

Ph

Ph

R

²

= H, gem-Me, spirocyclohexyl R

³

= H, Me, tBu, Aryl, Heteroaryl

R

¹

= H, Me, Ph 33 examples :

L15

99% yield, 72% ee

N N

..

Ph Ph

Ph

Ph L11

99% yield, 93% ee

N N

..

Ar Ar

Ar

Ar N

R⁴ N

R³ R² R¹

R

⁴

= Me, tBu, n-pentyl, Cy, Ph

or

N R⁴ N

R³ R² R¹

[Ni(cod)

2

] (5 mol%) 5 mol% L.HCl 10 mol% NaOtBu

MAD (1.2 equiv.) CPME, 80 °C, 24 h

N N

OMe OMe

N N

..

Ph Ph

Ph

Ph

N N

R

..

Ph Ph

Ph

Ph R

R = CH(Ph)

2 L20

99% yield, 76% ee

Ar = 3,5-Xyl

L17

99% yield, 86% ee

N N

..

Ar

Ar

Ar

Ar

N N

..

Ph Ph

Ph

Ph L14

77% yield, 60% ee Ar = 3,5-Xyl

L21

80% yield, 96% ee

Proposed mechanism:

N

R

MAD Ni

⁰

L

Al

N

Ni

H

Ni Al

N

R Al

N

R Ni

⁰

L L L

H

R RE insertion

OA Al = MAD; L = NHC

N R

33 34

35 36

33a 34a

35 36

H

(R,R,R,R)-L23 Ar

N X

Ar N X

R¹ R¹

Selected examples from the reaction optimization:

L15 25% yield, 4% ee (R)

N N

..

Ph Ph Ph

Ph

L11 47% yield, 24% ee (S)

N N

..

Ph Ph Ph

Ph

N N

..

Ar Ar Ar

Ar Ar = 3,5-Xyl

L21 57% yield, 70% ee (S) [Ni(cod)2] (5 mol%)

5.5 mol% L23.HCl 25 mol% NaOtBu PhCF3, 60 °C, 24 h

R¹ = alkyl, SiMe3

X = C, N Ar = aryl, heteroaryl

n n

R² R²

R² = H, Me

up to 93% yield up to 95% ee 22 examples (n = 1) :

N N

Me Me

[Ni(cod)2] (10 mol%) 11 mol% L.HCl 50 mol% NaOtBu PhMe, 80 °C, 24 h

N N

..

Ar Ar Ar

Ar Ar = 3,5-tBu-C₆H₃

N N

..

Ph Ph Ph

Ph

L14 49% yield, 24% ee (R)

N N

..

L23 Ar

Ar Ar

Ar Ar = 3,5-tBu-C₆H₃ 93% yield, 86% ee (S)

N N

..

Ar Ar Ar

Ar Ar = 3,5-Xyl

L22 61% yield, 40% ee (S)

37a 38a

37 38

Accepted Manuscript

catalysts which favor C-H activation. In the same way as for the C-H cyclization of pyridines with olefins (vide supra, scheme 9), the electron-donating and sterically demanding properties of the NHC ligands are apparently critical to every elementary steps of the catalytic cycle. However, while a mechanism involving C-H oxidative addition of Ni(0) and alkene insertion is not excluded, deuterium transfer experiments indicate that direct ligand to ligand hydrogen transfer (LLHT) is likely the favored pathway. ^[39]

Scheme 11. Nickel-catalyzed enantioselective C-H alkylation of fluoroarenes with alkenes.

3.2. Intermolecular Hydroarylation of Olefins

Catalytic systems based on chiral NHC ligand and Ni(0) have also demonstrated high potential in the asymmetric synthesis of indanol derivatives with the direct generation of four stereocenters (Scheme 12). The reductive three components coupling involving ortho-C-H functionalization of an aromatic aldehyde in the presence of a silane and a norbornene substrate was achieved by a Ni(0) catalyst bearing the chiral C 2 -symmetric NHC ligand L24. ^[45] The originality of ligand L24 resided in the 1,2- di(naphthalene-1-yl)ethylene diamine backbone that strongly influenced the reaction outcome to allow accessing the desired annulated products 43 as single diastereoisomer in high enantioselectivity. In the proposed mechanism, the enantiodetermining step is the formation of the oxanickelacycle which subsequently reacts with silane leading to a nickel-hydride intermediate able to perform C(sp ² )-H activation in the presence of another equivalent of norbonene.

Scheme 12. Nickel-catalyzed enantioselective three-component coupling to access indanol derivatives.

In a program to develop first-row transition metal-based systems for C-H functionalization, ^[46] Ackermann and coworkers described in 2017, the first enantioselective iron-catalyzed C-H alkylation using NHC ligand (Scheme 13). ^[47] In this study, the authors clearly demonstrated the critical role of the newly designed meta- decorated NHC ligands in the stereoinduction. Detailed mechanistic insights and additional experiments with isotopically labelled substrates strongly support an inner-sphere C-H activation mechanism. ^[48] The reaction is initiated by the formation of active species iron complex 47, followed by the coordination of olefin. Then the enantio-determining step is believed to proceed

Scheme 13. Iron-catalyzed intermolecular asymmetric C-H Alkylation of indoles.

(R,R,R,R)-L17 Selected examples from the reaction optimization:

L15 89% yield, 91% ee

N N

..

Ph Ph Ph

Ph L11 9% yield, ee (nd)

N N

..

Ph Ph Ph

Ph Ni(cod)2 (5 mol%) 5 mol% L11.HCl or L17.HCl

NaOtBu (0.5 equiv.) MTBE, 40 °C, 24 h (with L11)

R = alkyl, aryl, akenyl, N-aryl n = 2, 3 or 4

up to 99% yield up to 99% ee 37 examples

N N

..

(R,R,R,R) L11 Ph

Ph Ph

Ph

N N

..

Ph Ph Ph

Ph L14 52% yield, 76% ee ArF_n

H R

R ArF_n

[Ni(cod)2] (5 mol%) 5 mol% L.HCl NaOtBu (0.5 equiv.) c-hexane, 80 °C, 24 h H

Ph

Ph F

F F F

F F

N N

..

Ar Ar Ar

Ar Ar = 3,5-Xyl L11 for R = alkyl

L17 for R different than alkyl

c-hex., 80 °C, 24 h (with L17)

N N

(R,R)-L12

>2% yield, ee (nd)

N N

..

Ar Ar Ar

Ar

L17 95% yield, 97% ee

Ar = 3,5-Xyl

39 40

39a 40a

Proposed mechanism:

Ni

R Ni⁰

L*

L*

Ph H

reductive elimination

40a Ph F F F

F F

F

H direct LLHT

enantiodetermining step

F F

F

39a Ni(0)L*

L = NHC

Proposed mechanism:

Ni(0)

N N

Ph Ph

iPr iPr

..

N N

..

O O

L18 53% yield, 72% ee L4

0% yield, 0% ee

L3 41% yield, 22% ee

N N

..

tBu

L1 5% yield, 48% ee

iPr

iPr Selected examples from the reaction optimization:

+

N N iPr

..

[Ni(cod)2] (10 mol%) L24 (10 mol%)

THF, 23 °C

Ar = phenyl, electron rich and poor aryl R¹ = R² = CH2OMe, Ph

up to 99 % yield up to 91 % ee

L24 R¹

R²

SiO R

’R

Si = TIPS, TES, TBS, TBDPS 18 examples

SiH

iPr

O

Ar H

H

Ar

+

[Ni(cod)2] (10 mol%) L (10 mol%)

THF, 23 °C

SiO

(iPr)

3

SiH

O

H H

(2 equiv.)

41 42 43

41a 42a

43a

41a

42a Ni

O L*

Ph R3SiH

Ni R₃SiO

L*

enantiodetermining step

+ - norbornane

42a Ni

H Ph R3SiO

L*

N N

Ar

49

Selected examples from the reaction optimization:

N N

Ph Ph

i

Pr

i

Pr ..

L18 3% yield, 8% ee

X N

R

²

NPMP

H +

Ar

Fe(acac)

3

(10 mol%)

L25.HBF4 (20 mol %)

CyMgCl (1.1 equiv.) THF, 45 °C, 16h, then H

⁺

TMEDA (2 equiv.) N

R

²

R

¹

O

Ar R

¹

= H, Ome, F; X = C, N

R

²

= Bn, Me, PMB, pFCH

2

C

6

H

4

, (CH

2

)

2

Ph, MOM, CH

2

CHF

2

Ar = 12 examples R

¹

> 35 examples up to 96% yield up to 94% ee

N N

Ph Ph

Me

L25

Ad Ad

Me BF

₄

N Bn

NPMP

H +

Fc

Fe(acac)

3

(10 mol%)

L.HBF4 (20 mol %)

CyMgCl (1.1 equiv.) THF, 45 °C, 16h, then H

⁺

TMEDA (2 equiv.)

N R

²

R

¹

O

Fc = ferrocene

Fc

N N

Ph Ph

Me Me ..

L26 5% yield, 50% ee

N N

Ph Ph

Me

Me Me

Me

L27 69% yield, 78% ee

..

^{N N}

Ph Ph

Me

t

Bu

t

Bu

Me

L28 53% yield, 90% ee

..

Mechanistic rationale:

48

Ar N

R

² N Fe PMP

Ar N

R

² 47

Fe N

PMP

NHC*

N R

²

Fe N

PMP

NHC*

N R

² N PMP

H

N

R

²

N

PMP

H

NHC*

44 45 46

44a

45a

46a

Accepted Manuscript

during migratory insertion induced by secondary interaction in the transition state which is promoted by the addition of the second molecule of substrate to form the key intermediate 49 involved in the C-H activation step.

In 2016, Ohmiya, Sawamura and coworkers reported a copper- catalyzed enantioselective alkylations of electron-deficient azoles with g,g-disubstituted allylic phosphates (Scheme 14). ^[49] The reaction is believed to proceed through an inner-sphere mechanism involving the base assisted C-H cupration of heterocycles to form [ArCuL(OtBu) ^- ] active species. ^[50] The structure of NHC ligand was found critical to form a controlled all- carbon quaternary stereogenic center. In the model reaction between benzothiazole (50a) and the E-allylic phosphate (51a), the unsymmetrical chiral NHC ligand L29 bearing a phenoxy group at the ortho position afforded low catalytic activity and low enantioselectivity. However, by changing the phenol group to a naphtol group, dramatic increases in product yield and enantioselectivity were obtained using L30. The enantioselectivity could be further increased to 81% ee using ligand L31 bearing the N-2,4-dicyclohexyl-6-methylphenylgroup, but at the expense of product yield. Under the optimized conditions using L31 in the presence of [Cu(CH 3 CN) 4 ]PF 6 in a solvent mixture of THF/CH 3 CN, the reaction between various azoles 50 and allylic phosphates 51 afforded a variety of quaternary stereogenic carbon centers with high enantioselectivity.

Scheme 14. Copper-catalyzed enantioselective C-H alkylation of azoles.

3.3. intermolecular Hydroalkenylation of Olefins

Transition metal-catalyzed 1,2-hydrovinylation of two terminal alkenes via C-H functionalization can lead to a number of products with high degree of functional density. ^[51] The use of chiral NHC ligand in asymmetric nickel-catalyzed cross- hydrovinylation was reported by Ho and coworkers in 2015 (Scheme 15). ^[52] The intermolecular tail-to-tail hydroalkenylation

of vinylarenes 53 with terminal olefins 54 was catalyzed by in situ generated NiH ^[53] complexes bearing C 1 -symmetrical NHC L36 and afforded the chiral gem-disubstituted olefin products 55 with high enantioselectivity. While both N-aryl groups of the NHC were substituted with a bulky cyclohexyl substituent at position 2, a steric discrimination at the ortho-positions was beneficial to the enantioselectivity of the reaction. Moreover, the reaction involving electron rich styrene substrates was found to be optimal when the electronics of one N-aryl group was modified by a fluoro substituent in the para-position.

Scheme 15. Nickel-catalyzed asymmetric cross-hydrovinylation.

4. Summary and Outlook

In this minireview, we highlighted all the development and the recent advances in the field of TM-catalyzed enantioselective C- H functionalization using chiral NHC ligands. During the past two decades, NHCs have become ubiquitous ligands in coordination chemistry and catalysis. Concomitantly, enantioselective C-H functionalization has experienced an exponential growth.

Nevertheless, and despite the success of chiral NHC ligands in asymmetric homogeneous catalysis, the use of such ligands in TM-catalyzed asymmetric C-H bond functionalization has remained, until recently, relatively limited. The unique properties of NHC ligands, including their strong s-donation, allow for the development of highly stable TM-catalyst that can efficiently prevent undesired background reactions. This advantage was evidenced in the seminal work published by Kündig in 2011 which described the spectacular highly enantioselective functionalization of unactivated C(sp ³ )-H bonds at up to 160 °C.

Moreover, the numerous existing synthetic methodologies to construct NHCs offer a large diversity of chiral structures to be surveyed in a given asymmetric C-H transformation. This approach has played a significant role in the multiple recent successes encountered in enantioselective C-H functionalization with nickel-based catalysts and will certainly contribute to the exponential use of abundant 3d TM-catalysts in this rapidly evolving research area. ^[54] Overall, chiral NHCs, including yet underexplored multifunctional NHCs, ^[55] are promising ligands for a variety of TM-catalyzed C-H functionalization reactions and we

Ar X N

Selected examples from the reaction optimization:

[Cu(CH₃CN)₄]PF₆ (10 mol%) L31.HBF4 (10 mol%)

LiOtBu (2.2 equiv.) THF/MeCN, 25 °C, 36 h

X = S, O Ar = aryl, heteroaryl

R = alkyl up to 87% yield

up to 92% ee 13 examples

S N

L31

50a 52a

R OPO(OEt)₂

S N Ph

+ R OPO(OEt)₂

+ N N

Ph Ph

Cy

..

OH Cy

R

X N Ar

CuCl (10 mol%) L.HBF4 (10 mol%) LiOtBu (2.2 equiv.) 1,4-dioxane, 25 °C, 24 h

..

..

N N

Ph Ph

..

OH

L31 57% yield, 81% ee

L32 29% yield, 76% ee

L30 77% yield, 68% ee

..

L33 0% yield, -% ee

N N

Ph Ph

..

L29 35% yield, 15% ee

R = (CH₂)₂Ph 51a

OH

N N

Ph Ph

OH Cy Cy

N N

Ph Ph

Cy Cy

N N

Ph Ph

OMe Cy Cy

50 51 52

via

S N

[Cu] NHC*

+ N N

Ph Ph

Cy Me

F Cy

..

[Ni(cod)2] / L36 (10 mol%) TESOTf / NEt3 4-MeOC₆H₄CHO Toluene, RT, 40 h R

H

Ar = electron rich aryl group R = Bn, nHex, iBu, CH₂C₆H₁₁, CH₂C₅H₉

R

up to 87% yield up to 94% ee

L36

Ar Ar

+

[Ni(cod)2] / L (10 mol%) TESOTf / NEt₃ 4-MeOC6H4CHO Toluene, RT, 40 h nHex

H nHex

Selected examples from the reaction optimization:

N N

Ph Ph

Cy Cy Me

..

L35

Cy

Cy 82% yield, 73% ee

N N

Ph Ph

Cy Cy Me

..

L36 Cy 81% yield, 75% ee F

N N

Ph Ph

Cy Cy Me

..

L34 Cy 11% yield, 13% ee Cy Me

with vinylanisole:

84% yield, 82% ee with vinylanisole:

80% yield, 77% ee

53 54 55

53a 54a 55a

NHC*

NiH H via

Accepted Manuscript

expect that the recent enthusiasm for their use in fine catalyst engineering will lead to an increasing pace of discovery in this exciting research field.

Acknowledgements

We acknowledge the Centre National de la Recherche Scientifique (CNRS); the Ecole Nationale Supérieure de Chimie de Rennes (ENSCR) and the Ministère de l’Enseignement Supérieure, de la Recherche et de l’Innovation (MESRI, grant to RM). This work was supported by the Agence Nationale de la Recherche (ANR-15-CE07-0012-01 “CHADOC” grant to OB, JT), Keywords: chiral NHC • C-H bond functionalization • transition metals • catalysis • asymmetric reaction

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Accepted Manuscript

REVIEW

The asymmetric functionalization of C- H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral NHC ligands have become ubiquitous in enantioselective transition-metal catalysis. Conversely, the use of chiral NHC ligands in metal- catalyzed asymmetric C-H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.

J. Thongpaen, R. Manguin, O. Baslé*

Page No. – Page No.

Chiral N-Heterocyclic Carbene Ligands Enable Asymmetric C-H Bond Functionalization

N N

..

R R

R ^*

R ¹ R ³

R ²

*

C H C

C R ^*

TM

Accepted Manuscript