Download PDF
Synthesis 2022; 54(21): 4646-4660
DOI: 10.1055/a-1892-5473
short review

Recent Advances in Transition-Metal-Catalyzed Asymmetric Functionalization of Enamides

Yang Xi
,
Yifeng Chen  ∗

This work was supported by NSFC/China (22171079), Natural Science Foundation of Shanghai (21ZR1480400), Shanghai Rising-Star Program (20QA1402300), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX03), the Program of Introducing Talents of Discipline to Universities (B16017), the Fundamental Research Funds for the Central Universities (222201717003).
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Enamides, as prefunctionalized electron-rich heteroatom-substituted alkenes represent a powerful platform to synthesize useful nitrogen-containing natural products and bioactive molecules. This review discloses recent progress in the transition-metal-catalyzed enantioselective functionalization of enamides, including the Heck reaction, hydrofunctionalization, and difunctionalization, with a focus on the general scope, current limitations, stereochemical reaction control, and mechanistic aspects.

1 Introduction

2 Asymmetric Heck Reaction of Enamides

3 Asymmetric Hydrofunctionalization of Enamides

3.1 Nickel Catalysis

3.2 Copper Catalysis

3.3 Rhodium Catalysis

3.4 Iridium Catalysis

4 Asymmetric Difunctionalization of Enamides

4.1 Palladium Catalysis

4.2 Nickel Catalysis

4.3 Copper Catalysis

5 Summary and Outlook


#

Key words

enamides - asymmetric catalysis - Heck reaction - hydrofunctionalization - difunctionalization
1

Introduction

Chiral amines are powerful pharmacophores for defining new pharmaceutical drugs[1] [2] due to their high density of structural information and inherent ability for hydrogen bonding.[2] Several exciting strides have been developed to access optically pure amines enabled by asymmetric catalysis, including hydrogenation of imines,[3] C–H amination,[4] Mannich reaction,[5] and hydroamination of alkenes.[6] Additionally, enamides as prefunctionalized electron-rich heteroatom-substituted alkenes have been broadly applied for nitrogen-containing complex synthesis due to two key advantages.[7] Firstly, their stability relative to enamines allows them to be readily handled and tailors their reactivity through alteration of the electron-withdrawing group upon the nitrogen. Secondly, the change of hybridization of the carbon center bonded to the enamide carbon allows for controlled increase in complexity without the requirement of introducing nitrogen directly during key reactions.

Zoom Image
Yang Xi was born in Jiangsu Province, China. She received her B.Sc. degree from Nanjing Xiaozhuang University in 2015, and her M.Sc. (2018) in organic chemistry from Nanjing Tech University. Currently, she is pursuing her Ph.D. studies at East China University of Science and Technology (ECUST) under the direction of Prof. Yifeng Chen. Yifeng Chen was born in Anhui Province, China. He received his BA in Chemistry from Soochow University in 2007 and completed his Ph.D. under the supervision of Prof. Yuanhong Liu at the Shanghai Institute of Organic Chemistry in 2012. After completing postdoctoral research with Stephen Buchwald (MIT) and Timothy Newhouse (Yale University), he started his independent group at East China University of Science and Technology in 2017. His main research interests include Organometallic Catalysis Directed Towards Organic Synthesis (OMCOS), particularly in asymmetric catalysis.

There has been significant progress towards the enantioselective transformation of enamides. In this review, our goal is to focus on the transition-metal-catalyzed asymmetric functionalization of enamides with regio-, diastereo-, and enantioselectivity based on three aspects: Heck reaction, hydrofunctionalization, and difunctionalization (Scheme [1]). Thereby, the asymmetric hydrogenation of enamides,[8] [9] as well as the organocatalyzed reactions of enamides,[10] are omitted.

Zoom Image
Scheme 1 Outline of transition-metal-catalyzed asymmetric functionalization of enamides

# 2

Asymmetric Heck Reaction of Enamides

The palladium-catalyzed Heck reaction has revolutionized organic synthesis, and it is broadly recognized as the most efficient route for synthesis of alkene derivatives. Particularly, the asymmetric Pd-catalyzed Heck reaction proceeds through regioselective β-H elimination of an alkylated palladium(II) reactive intermediate, thus leading to the alkene isomerization product with the construction of stereogenic centers.[11] Among these reactions, the Pd-catalyzed asymmetric Heck reaction of enamides provides a straightforward access to optically active nitrogen-containing compounds. The asymmetric Heck reaction of the alkenyl iodide tethered enamides 1 to give the indolizidine skeleton 2 was reported in 1993 by Shibasaki and co-workers (Scheme [2]).[12] Performing the asymmetric intramolecular Heck reaction in the presence of BPPFOH {(R)-α-[(S)-1′,2-bis(diphenylphosphino)ferrocenyl]ethyl alcohol} gave a mixture of 2 and 3 (94% yield, 86% ee); Ag-exchanged zeolite was the most effective silver salt in this conversion. The alkene isomerization of 3 to 2 was realized by treatment with Pd/C. The method was successfully applied to the synthesis of the natural products lentiginosine (4) and gephyrotoxin 209D (5).[13]

Zoom Image
Scheme 2 Palladium-catalyzed intramolecular asymmetric Heck reaction of alkenyl iodide tethered enamides
Zoom Image
Scheme 3 Palladium-catalyzed intramolecular asymmetric Heck reaction of the aryl triflate tethered enamides
Zoom Image
Scheme 4 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamide with triflates

In 1997, Ripa and Hallberg successfully extended the intramolecular asymmetric Heck reaction of aryl triflate tethered cyclic enamides 6 to provide spiro compounds as a 6:1 mixture of isomers, (R)-7 (87% ee) and (R)-8 (>99% ee), in 71% overall yield with the (S)- t BuPhOX as chiral ligand (Scheme [3]).[14] The use of (R)-BINAP or addition of silver additives led to low yields and moderate to high enantioselectivities. The utilization of an aryl triflate was crucial for the high enantioselectivity of the spirobicycles, while the enantiomeric excess significantly dropped with the corresponding aryl iodide as the starting material.

Besides the intramolecular asymmetric Heck reaction, the intermolecular asymmetric Heck reaction of enamides, particularly N-protected 2,3-dihydropyrrole or enelactams is also a research hotspot. In 1992, Hayashi reported the Pd-catalyzed the intermolecular Heck reaction using the combination of N-substituted 2-pyrroline 9 and aryl triflates 10 in the presence of the chiral ligand (R)-BINAP (Scheme [4a]).[15] In this reaction system, the 2-aryl-dihydropyrroles were obtained as a mixture of 2-aryl-2,3-dihydropyrroles 11 (up to 74% ee) and 2-aryl-2,5-dihydropyrroles 12.

It should be noted that the enantioselectivity dropped when the Heck reaction was performed under neutral conditions using an aryl iodide as the electrophile. The employment of an alkenyl triflate as electrophile led to the asymmetric Heck reaction with excellent yield (95%) and enantiomeric excess (>99% ee) (Scheme [4b]).[16] In 2000, the Tietze group disclosed that the (S)-BITIANP ligand could improve the ee up to 95% (Scheme [4c]).[17] Recent progress by the Zhou group used the bisphosphine monoxide ligand [(R)-Xyl-SDP(O)] as the chiral ligand to provide the expected major product 17 with 99% ee, obviating the formation of the undesired regioisomer (Scheme [4d]).[18] This method was utilized in the formal synthesis of BMS-394136.

Zoom Image
Scheme 5 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamide with benzyl trifluoroacetate and aryl halides

In 2012, the Zhou group disclosed that the phosphoramidite ligand L1 was the optimal chiral ligand in the enantioselective Heck benzylation reaction employing benzyl trifluoroacetates 20 as the electrophile, affording the desired products 21 in excellent yields and satisfactory enantiomeric excess (Scheme [5a]).[19] The same group employed aryl halides as electrophiles which smoothly coupled to generate Heck products 24 in reasonably good yields, excellent enantioselectivities, and moderate stereoselectivity by using the chiral (R)-Xyl-SDP(O) ligand (Scheme [5b]).[20] The alcohol solvent was crucial for this reaction, as the hydrogen bond between the alcohol and the bromide facilitates the formation of a cationic Pd(II) species as evidenced by the control experiments. The acidic additives further improved the reactivity and enantioselectivity.

In addition to five-membered enamides, the Sigman group successfully achieved the intermolecular asymmetric relay Heck reaction of six- and seven-membered enamides using PyrOx L2 as the chiral ligand (Scheme [6]).[21] Both electron-deficient electrophiles alkenyl triflates 27 and electron-rich electrophiles alkenyl iodonium salts 30 were both suitable in the reaction. The investigation of seven-membered-ring systems found that the enantioselectivity was maintained, albeit only 3 examples were performed, but the yield was generally lower. The synthetic application was demonstrated by the formal synthesis of (+)-calvine and (+)-2-epicalvine (Scheme [6b]).

Zoom Image
Scheme 6 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamides with alkenyl electrophiles

Sigman and co-workers developed the palladium-catalyzed relay oxidative Heck reaction under an oxygen atmosphere to synthesize enantiomerically enriched 6-arylated α,β-unsaturated δ-lactams bearing a tetrasubstituted chiral carbon center with the PyrOx ligand L3 in good yields (up to 94% yield) and excellent enantiomeric ratios (up to >99:1 er) (Scheme [7]).[22] A plausible mechanism is shown in Scheme [7]: transmetalation of the boronic acid with Pd(II) catalyst yields the aryl-Pd(II) species. The cyclic enamide presents a polarized alkene, which should preclude issues associated regioselectivity (which occur with other cyclic substrates). Thus the enantiodetermining migratory insertion into the cyclic enelactam 34 should afford intermediate 37 with subsequent β-hydride elimination to yield 38. The Pd–H species undergoes reinsertion to generate the Pd-alkyl intermediate 39, then β-hydride elimination of Hb selectively occurs to produce the thermodynamically more stable α,β-unsaturated δ-lactam product 36.

Zoom Image
Scheme 7 Palladium-catalyzed intermolecular asymmetric oxidative Heck reaction of cyclic enamides with arylboronic acid
Zoom Image
Scheme 8 Palladium-catalyzed intermolecular asymmetric Heck–Matsuda­ Reaction of cyclic enamides with arenediazonium salts

Arenediazonium salts have also been applied as arylation reagents in enantioselective Heck reaction. Ding, Hou, and co-workers disclosed the asymmetric Heck–Matsuda reaction for cyclic enamides such as N-Boc-1,4-dihydroquinolines 40 with arenediazonium tetrafluoroborates 41 by employing a chiral bisoxazoline ligand L4 that afforded 2-aryl-dihydroquinolines 42 in moderate to good yields and enantioselectivities (Scheme [8]).[23]

In addition to palladium catalysis, in 2021 the Zhou group reported the Ni-catalyzed asymmetric intermolecular Heck reaction of N-Cbz-2,3-dihydropyrrole 43 with aryl triflates. The utilization of the nickel chloride complex of QuinoxP* allows the synthesis of 2-arylated 3,4-dihydropyrroles 44 (Scheme [9]).[24] The more congested N-Boc derivative reacted very sluggishly.

Zoom Image
Scheme 9 Nickel-catalyzed intermolecular asymmetric Heck reaction of 2,3-dihydropyrrole with aryl triflates

# 3

Asymmetric Hydrofunctionalization of Enamides

Hydrofunctionalization of unsaturated hydrocarbons presents an atom-economic and straightforward conversion for the synthesis of functionalized molecules.[25] It has been proven that transition metal catalysts can govern the chemo-, regio-, and enantioselectivity hydrofunctionalization of enamides by the formation of C–C or C–X (X = O, N, B, Si, etc.) bonds. The field has been dominated by transition metals based on nickel, copper, rhodium, and iridium. Several typical examples in the asymmetric hydrofunctionalization of enamides are described in this section.

3.1

Nickel Catalysis

The NiH-catalyzed reductive hydrofunctionalization of alkenes with aryl or alkyl halides has become a promising alternative for traditional asymmetric C–C cross-coupling reaction to construct saturated stereogenic carbon centers. The use of readily available and bench-stable alkenes as masked nucleophiles in the presence of silane circumvents the use of stoichiometric and often sensitive organometallic reagents.

In 2021, the Nevado group demonstrated the competence of the nickel-catalyzed asymmetric reductive hydroarylation of linear enamides 45 to produce chiral α-arylbenzamides (R)-47 (Scheme [10a]).[26] A bisimidazoline ligand, BIm L5, was employed in the hydroarylation reaction to obtain a range of chiral α-arylbenzamides in good enantiomeric excess, it should be noted that a series of bisoxazoline, pyridine-oxazoline, and isoquinoline-oxazoline ligands were not suitable for this protocol. A variety of readily available aryl halides were utilized and gave the corresponding enamides in a highly regio- and enantioselective manner, including 1,3-diiodobenzene that delivered (R)-47a with excellent yield and diastereomeric ratio. Additionally, β-bromostyrene and benzyl bromide could also be used in the reaction to afford the amides (R)-47b and (R)-47c in 70% and 90% yields, respectively albeit with moderate enantioselectivity. Interestingly, the internal 1,2-disubstituted enamides of different configurations displayed markedly different efficiency, but similar enantioselectivity and the product configuration was also consistent. For example, (Z)-45d delivered the desired product in higher yield than (E)-45d with the same enantioselectivity (94% ee). In addition, they found that the reactions of α,α-disubstituted enamide 45f and β-substituted enamide 45g were unsuccessful, probably due to steric hindrance that inhibited enantiodetermining Ni–H insertion.

Zoom Image
Scheme 10 NiH-catalyzed asymmetric reductive hydroarylation of enamides to chiral benzylamines

Zhu and co-workers explored a similar protocol for chiral benzylamine synthesis (Scheme [10b]),[27] which was limited to β-alkyl-substituted enamides and aryl iodides. Optimization studies revealed excellent enantioselectivity by using chiral bis-imidazoline ligand L6. This enantioselective hydroarylation protocol tolerated sensitive functional groups such as a halogen or triflate substituent in the aryl iodide with high yields and excellent enantioselectivities. Notably, the less sterically hindered N-pivaloyl enamide 45h also underwent asymmetric hydroarylation smoothly with high enantioselectivity. It was found that the configuration of the enamide did not affect the reaction efficiency and enantioselectivity in this protocol.

Control experiments and DFT calculations by the Nevado group[26] show that the Ni–H species is generated from a ligated Ni(I) precursor in the presence of silane and base (Scheme [11]). Ni–H underwent regio- and enantioselective migratory insertion to enamides 45 to give Csp3–Ni(I) intermediate 48, which is stabilized by chelation from the amide group, obviating the formation of the arylNiIII side intermediate 49. Intermediate 48 oxidizes the aryl halide to form Ni(III) intermediate 50, followed by reductive elimination to afford the α-arylbenzamide 47 and regenerate Ni(I) catalyst.

Zoom Image
Scheme 11 Mechanism for NiH-catalyzed asymmetric hydroarylation of enamides

In parallel to asymmetric hydroarylation, NiH-catalyzed asymmetric hydroalkylation of enamides was also demonstrated by the groups of Hu,[28] Fu,[29] and Shu[30] to access useful α-branched chiral alkylamine derivatives (Scheme [12]). Different from the NiH-catalyzed asymmetric hydroarylation, chiral bis(oxazoline) ligands including PhBiOX (L7), Box (L8, L10, and L11), and PyrOx (L9) were effective in this asymmetric hydroalkylation process. A variety of activated halides, such as benzylic bromides, as well as unactivated alkyl halides, including primary and sterically hindered secondary alkyl iodides, were suitable for this protocol to afford the corresponding chiral dialkyl amines 53 (Scheme [12]). Even a sterically demanding the β,β′-disubstituted enamide gave the corresponding chiral alkylamine 53a, although the enantioselectivity was only 88% ee with 48% yield.[28] However, using Fu’s catalytic system, a α-substituted enamide gave the corresponding product 53c with complete loss of enantioselectivity.[29] Moreover, the α-alkylated trisubstituted enamides 51b failed to furnish the desired products. In contrast to previous work on NiH-catalyzed hydrofunctionalization of secondary enamides, a tertiary enamide worked well using the chiral nickel/bisoxazoline L8 catalyst. The scope of Shu’s method was further expanded to tertiary enamide 51f, leading to corresponding product 53f with a good yield, albeit with mediocre enantioselectivity.[30] This asymmetric hydroalkylation protocol tolerated installation of both steric and electronic properties in the N-substitution in high yields and excellent enantioselectivities. The configuration of the tertiary enamide influenced the enantioselectivities, the (E)-substrate afforded a much higher level of enantioselectivity.

Zoom Image
Scheme 12 NiH-catalyzed asymmetric hydroalkylation of enamides with alkyl halides

Two tentative mechanistic pathways are proposed for the present enantioselective hydroalkylation of enamides (Scheme [13]).[31] The key difference between the two catalytic cycles is the oxidation state of NiH species to initiate the catalytic cycle, with both the possibility of both Ni(I)H and Ni(II)H intermediates. In the former, the Ni(I)H 55 species is generated from ligated Ni(I)–X precursor 54 in the presence of silane and base, which regioselective inserts into the enamide generating the alkyl nickel intermediate 57 stabilized by the chelation of amide group. The resulting Ni(I)–alkyl species 57 is oxidized by an alkyl halide to give a Ni(III)–bis(alkyl) intermediate 58, which undergoes reductive elimination to give the final product 53 and regenerate Ni(I) catalyst 54. In the second mechanism, the Ni(I)–X species first undergoes single electron transfer with an alkyl halide to generate an alkyl radical and Ni(II)–X 59. The resulting Ni(II)–H 60 species, generated by the transmetalation with silane, undergoes migratory insertion into the enamide to form alkyl Ni intermediate 61, which recombines with the alkyl radical to give Ni(III) complex 58. After the reductive elimination of 58, the chiral amine 53 is generated with the regeneration of Ni(I) catalyst 54. It should be pointed out that Fu and co-authors favored the second possible mechanism according to their experiment and DFT calculation.

Zoom Image
Scheme 13 Mechanism for the NiH-catalyzed asymmetric hydroalkylation of enamides

# 3.2

Copper Catalysis

Copper-catalyzed asymmetric hydroboration of α,β-unsaturated compounds has provided a vital access to enantioenriched α-boronate esters.[32] In 2017, two groups simultaneously reported a highly efficient Cu(I)-catalyzed asymmetric hydroboration of electron-withdrawing group substituted activated enamides (Scheme [14]). The leverage of a chiral bidentate phosphine ligand, either BIPHEP- or SEGPHOS-based, was crucial for maintaining high reactivity and enantioselectivity. Intriguingly, Xu and co-workers disclosed that the enantioselectivity was significantly lower when an unprotected N–H group containing trans-enamide 63a was used, and 88% ee was obtained with the (Z)-enamide 63b as starting material (Scheme [14a]).[33] The isoindoline-protected enamide 63c did not work under these conditions. The approach of Parra, Tortosa and co-workers used CuCl/(R)-SEGPHOS-catalyzed conditions for the hydroboration of a variety of functionalized β-ester-substituted enamides 63 to give β-boryl β-amino esters 65 with high stereoselectivity.[34] In this transformation, the configuration of the enamide did not adversely affect the reactivity, and the DFT computation revealed migratory insertion as the rate-limiting step as well as the enantiodetermining step.

Zoom Image
Scheme 14 Copper-catalyzed asymmetric hydroboration of enamides

Following this, Zhang, Xu, and co-workers achieved another enantioselective chiral NHC-copper-catalyzed conjugate hydrosilylation of β-ester- and cyano-substituted enamides (Scheme [15]).[35] The reaction was applicable to substrates bearing lactams and a free N–H group at the β-position, giving α-silylamines 67 in superior yields with excellent levels of stereoselectivity.

Zoom Image
Scheme 15 Copper-catalyzed asymmetric hydrosilylation of enamides
Zoom Image
Scheme 16 Rhodium-catalyzed asymmetric hydroboration of enamides

# 3.3

Rhodium Catalysis

The rhodium-catalyzed hydroboration of enamides was developed earlier than the copper-catalyzed reaction. As early as 2015, the Tang group reported the rhodium-catalyzed asymmetric hydroboration of α-aryl-trisubstituted enamides 68 with chiral ligand BI-DIME developed in their group, affording a series of α-amino tertiary boronic esters 69 in good yields and excellent enantioselectivities (Scheme [16]).[36] The configuration of the enamide has no effect on the reactivity and enantioselectivity. An α-(2-furyl)-substituent enamide 69c worked well under these mild conditions, albeit with a slightly low ee. Mechanistic studies have shown that the reaction proceeds via a key boryl Rh(III) hydride 71 instead of 72, which is followed by olefin insertion into the Rh hydride bond, then reductive elimination to provide product 74 and regenerate the Rh(I)-(R)-BI-DIME species.

The Li group further exploited the rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides 75 to access both α- 76/77 and β-aminoboronic esters 78 (Scheme [17]).[37] The regioselectivity of the hydroboration was controlled by the chiral ligand. Duanphos was employed in the asymmetric hydroboration reaction of (Z)-secondary enamides to obtain a range of chiral α-aminoboronic esters 76 in high enantiomeric excess. The α-aminoboronic ester 76b with two vicinal chiral centers can also be obtained by using β,β-disubstituted enamides in high diastereoselectivity and enantioselectivity. Enantioenriched α-borated products 77 with a tetrasubstituted stereocenter could be obtained exclusively in high yield and enantioselectivity from α,β-disubstituted enamides in the presence of Duanphos. Furthermore, a regioselectivity variation of this hydroboration was achieved using a Walphos ligand, delivering the β-hydroboration product 78 in good yields, but lower enantioselectivities. DFT calculations show that the repulsion between the ligand and the substrate during the migration insertion is the key to controlling the regioselectivity of the hydroboration.

Zoom Image
Scheme 17 Rhodium-catalyzed regiodivergent asymmetric hydroboration of enamides

The Li group developed the Rh-catalyzed asymmetric hydroalkynylation of enamides for the synthesis of α-alkyl propargyl amides 81 (Scheme [18]).[38] The utilization of i Pr-MeOBIPhep allowed complete α-selectivity and high enantioselectivity. However, (E)-enamides produced the product in significantly lower yields and enantioselectivity, and trisubstituted enamides were not successful in this reaction. Characterization of the resting state Rh complex and kinetic isotope effect studies showed that migratory insertion of the enamide to the rhodium hydride is the turnover limiting step. Computational studies suggest that migratory insertion of the enamide is an irreversible process which also is the enantioselectivity determination step. In the transition state of the main enantiomers, the repulsion between ligand and enamide is smaller, and the C–H···O interaction between ligand and enamides is stronger.

Zoom Image
Scheme 18 Rhodium-catalyzed asymmetric hydroalkynylation of enamides

# 3.4

Iridium Catalysis

In 2016, the Li group reported the first example of enantioselective hydroalkynylation of enamides by a preformed [Ir(COD)(Ph-BPE)]OTf complex as the catalyst producing chiral β-alkynyl-substituted homopropargyl amides 88 with complete regiocontrol and good to high enantioselectivity (Scheme [19]).[39] The reaction features broad (Z)-substrate scope under mild conditions.

Zoom Image
Scheme 19 Iridium-catalyzed asymmetric hydroalkynylation of enamides

The proposed catalytic cycle commences with the generation of the Ir(III)–H species 90 via the oxidative addition of the silylacetylene to the iridium(I) complex 89. Ir(III)–H 90 then reacts with the enamide to give a Ir(III)–alkyl species 92 through migratory insertion to the double bond. Finally, product 88 is formed with the regeneration of Ir(I) complex 89 by sequential reductive elimination of 92.[40]

Zoom Image
Scheme 20 Iridium-catalyzed enantioselective hydroalkynylation of β,β-disubstituted enamides

The Li group further explored the reactivity of β,β-disubstituted enamides and developed two new catalytic systems to regiodivergently realize the Ir-catalyzed asymmetric hydroalkynylation of β,β-disubstituted enamides. With the phosphoramidite ligand L13 and L13-H8, propargylamides 94 (Scheme [20])[41] with vicinal stereocenters were obtained in good yields (up to 99%) with excellent levels of enantioselectivity (up to 99% ee) and diastereoselectivity (>20:1). Using a combination of enamide geometry and ligand configuration, the stereodiversity synthesis of four stereoisomers could be realized with high diastereoselectivity and high enantioselectivity. In contrast, in the presence of electron-rich ligand L14, homopropargyl amides 95 with a β all-carbon quaternary center were obtained in both high yield and high enantioselectivity, albeit with a small amount of α-alkynylation products (Scheme [20]).[42] Computational studies indicated that the ligand is crucial for controlling the regioselectivity of the hydroalkynylation of β,β-disubstituted enamides. The phosphoramidite ligand is less electron-donating than a bisphosphine ligand, so the electron density at the metal center is reduced, which is conducive to the reductive elimination of the iridium center, leading to the formation of the α-hydroalkynylation product. The rate-limiting step of β-hydroalkynylation is migratory insertion of the enamides into the metal–carbon bond, electron-rich ligand L14 favors this behavior.


#
# 4

Asymmetric Difunctionalization of Enamides

In addition to asymmetric hydrofunctionalization, enamides have outstanding performance in asymmetric difunctionalization, which represents a straightforward route to provide more nitrogen-containing complexes with one or multiple new chiral carbon centers. By using this strategy, a range of simple, readily available electrophiles and nucleophiles are incorporated into a molecule to form two new enantioselective chemical bonds with high atom- and step-economic efficiency. It is the powerful potential for generating one or multiple new chiral carbon centers with simultaneous control of both the regio-, diastereo-, and enantioselectivity, which is still a long-standing challenging in organic synthesis. In this perspective, we summarize recent transition-metal-catalyzed asymmetric difunctionalization of enamides.

4.1

Palladium Catalysis

In 2013, the Zhou group realized an asymmetric domino cyclization of a cyclic enamide with o-vinylphenyl triflate (96) in the presence of bisphosphine monoxide ligand [(R)-Xyl-SDP(O)]. The reaction proceeded via two sequential Heck reaction to access a fused carbo- and heterocycle 97 in good yield with excellent diastereo- and enantioselectivity (Scheme [21]).[43] Heterocycle 97 was used in an asymmetric synthesis of (–)-martinellic acid, which is a chiral diamine route to a primary ingredient in folk eye medicine in South America.

Zoom Image
Scheme 21 Palladium-catalyzed asymmetric domino cyclization of a cyclic enamide with o-vinylphenyl triflate

Then, the Zhou group continued to perform elegant studies on intermolecular asymmetric difunctionalization with propargylic acetates, leading to exclusive trans-oxyallenylation[44] and carboallenylation[45] in excellent enantioselectivity, depending on the nature of the cyclic enamide (Scheme [22]). A palladium catalyst with furyl-MeOBIPHEP L15 showed high activity and stereoselectivity in the asymmetric coupling reaction. In addition to using alcohols and arylamines as the nucleophilic reagent, the Zhou group extend the enantioselective three-component difunctionalization of cyclic enamides to nucleophilic heteroarenes including indoles, pyrroles, and some activated furans and thiophenes, as well as some anilines without the aid of a directing group. In addition, it is worth mentioning that two methyl groups on the propargyl fragment were necessary, which dramatically affected the reactivity.

Zoom Image
Scheme 22 Palladium-catalyzed asymmetric difunctionalization of cyclic enamides

In another line of research, the palladium catalyst ligated by chiral bis(oxazoline) ligand i PrBiOX L16 was found to promote Heck-type three-component couplings of acyclic enamides by the Chen group. In 2021, they developed the first palladium-catalyzed enantioselective 1,2-arylfluorination of internal enamides to afford β-fluoro-α-aryl-substituted amide derivatives bearing two vicinal tertiary carbons with excellent regio- and diastereoselectivity (Scheme [23]).[46]

Mechanistically, Pd(II) complex transmetalation with the boronic acid and thereafter coordination and insertion with the enamide yields a β-arylated benzylic Pd(II) species 103, which is stabilized by the removable carbonyl functionality of the lactam group that retards the undesired β-hydride elimination process thereby promoting oxidation by Selectfluor. Ultimately, the desired β-fluoroamine derivatives 102 are obtained by reductive elimination from the Pd(IV) intermediate 104. The oxazolidinone successfully allows selective ring-opening with TMSI to give various β-fluoroaminated­ derivatives, like β-fluoro-primary amine derivatives 106 maintaining the high ee.

Zoom Image
Scheme 23 Palladium-catalyzed asymmetric 1,2-arylfluorination of internal­ enamides

In continuation of these advances, other asymmetric difunctionalization approaches were recently developed by the Chen group, employing the carbonyl coordination-assisted­ transient palladacycles strategy for the diarylation of enamides. The Chen group reported a Pd-catalyzed multicomponent regiodivergent Heck-type diarylation of internal enamides with arylboronic acids and arenediazonium salts (Scheme [24]).[47] A wide range of coupling components and internal enamides bearing different functional groups were coupled to give various chiral 1,2,2-triarylethylamine and 1,3,3-triarylpropylamine derivatives with high regio-, diastereo-, and enantioselectivity. Intuitively, the choice of aryl on the enamide is crucial to stabilized benzylic palladium intermediate, allowing for facile 1,2-diarylation. Interestingly, when benzyl-substituted enamides were used in the three-component coupling, the reaction tended to furnish 1,3-diarylated products by a carbonyl coordination-assisted­ extension of six-membered transient palladacycles 111 to seven-membered palladacycles 113. Mechanistically, it was proposed that the transformation involves oxidative addition of the arenediazonium salt with Pd(0) to form a palladium(II) complex that can undergo migratory insertion into enamides. The migratory insertion intermediate tends to form a benzylic Pd(II) species, via a β-hydride elimination/Pd–H reinsertion sequence. The stable benzyl palladium species 113 is intercepted by the arylboronic acid. Ultimately, reductive elimination yields a single 1,3-diarylated product with single diastereoselectivity and regioselectivity.

Zoom Image
Scheme 24 Palladium-catalyzed asymmetric 1,2-diarylation and 1,3-diarylation of internal enamides

An intramolecular Heck/Suzuki cascade reaction to access isoindolinone scaffolds was also described by the Chen group in 2021 via a Pd-catalyzed dicarbofunctionalization of 1,1-disubstituted enamides (Scheme [25]).[48] Notably, this reaction exhibits excellent functional group tolerance in the presence of i Pr-AntPhos L17. By replacing the arylboronic acid with an alkenylboronic acid, including trisubstituted alkenylboronic acids, a range of quaternary 3-allyl-substituted amide derivatives were also generated in good yield with excellent enantioselectivities. The tandem Heck/Suzuki coupling provided expeditious syntheses of the precursor of PI3K-delta inhibitor 117 with 95% ee.

Zoom Image
Scheme 25 Palladium-catalyzed intramolecular asymmetric Heck/Suzuki coupling reaction of 1,1-disubstituted enamides

# 4.2

Nickel Catalysis

Recently, Ni-catalyzed asymmetric reductive difunctionalization of alkenes have been especially of great research interest. The Chen group realized a Ni-catalyzed aryl­alkylation of 1,1-disubstituted enamides by a tandem cyclization/reductive cross-coupling strategy, providing an efficient protocol to the amide derivatives 119 containing a tetrasubstituted carbon center (Scheme [26]).[49] A broad range of primary/secondary alkyl and aryl iodides were well tolerated in this reaction with a chiral bis-oxazoline ligand BnBiOx. Mechanistically, it is postulated that the annulation is initiated by oxidative addition of the aryl bromide in enamide 115 to Ni(0) followed by intramolecular enantioselective migratory insertion to furnish the alkyl-nickel intermediate 121, which proceeds with Zn reduction to generate intermediate 122. Then, Ni(I) intermediate 122 reacts with alkyl iodide via a single electron transfer (SET) pathway to form the intermediate 124, which subsequently furnishes the desired product 119 following reductive elimination.

Zoom Image
Scheme 26 Nickel-catalyzed intramolecular asymmetric reductive dicarbofunctionalization of 1,1-disubstituted enamides

In 2020, the Nevado group introduced the enantioconvergent radical relayed reductive coupling reaction of terminal enamides via a Ni-catalyzed SET process with a chiral bis(2-oxazoline) ligand (S)-sec-Bu-BiOx to give chiral amines 127 with high levels of enantiocontrol (Scheme [27]).[50] The method relied on the combination of a nickel catalyst with tetrakis(dimethylamino)ethylene (TDAE) as an organic sacrificial reductant, and a computational study showed that TDAE-mediated one-electron reductions to form Ni(I) species are highly favorable processes. Mechanistically, Ni(I) undergoes oxidative addition with aryl or alkenyl electrophiles to generate C(sp2)–Ni species, which are reduced to Ni(I) with TDAE. The C(sp2)–Ni species reduces the tertiary alkyl iodide to generate a tertiary alkyl radical and a new C(sp2)–Ni(II) species is released. Subsequently, the tertiary alkyl radical is trapped by the enamide, which combines with the C(sp2)–Ni(II) species to produce a C(sp2)–Ni(III) species followed by reductive elimination to yield the product and the Ni(I) species.

Zoom Image
Scheme 27 Ni-catalyzed asymmetric three-component reductive coupling of terminal enamides

# 4.3

Copper Catalysis

In addition to palladium catalysis and nickel catalysis, a Cu(I)/bis(oxazoline) system was utilized by Liu and co-workers for the three-component asymmetric cyanation and etherification reactions of terminal enamides (Scheme [28]).[51] Under the optimized conditions, the Box ligand L18 formed α-cyano amides 129 in 70–98% yields and excellent levels of enantioselectivity (86–98% ee) and the chiral Box ligand L19 led to chiral α-hemiaminals 130 with moderate to excellent enantioselectivities. From a mechanistic perspective, the coordination of the carbonyl group in the enamide is crucial in the asymmetric radical coupling step. During the reaction, a CF3 radical and Cu(II) are generated from Togni’s reagent [CF3 +] and Cu(I) via SET. Then the CF3 radical is captured by an enamide to form radical 132, which subsequent undergoes highly enantioselective capture of CRAN (a carbon radical adjacent to a nitrogen atom) by chiral (Box)Cu(II) species to yield a Cu(III) intermediate 133. Finally, the Cu(III) species 133 undergoes reductive elimination to furnish the final product and Cu(I) species.

Zoom Image
Scheme 28 Copper-catalyzed three-component asymmetric cyanation and etherification reactions of enamides

In the presence of a chiral bis-oxazoline ligand, the Tang group realized a chiral copper-catalyzed asymmetric cyclopropanation–rearrangement (CPRA) reaction of exocyclic vinyl enamides that directly provided (R)-spiroaminals 136 and fused bicyclic N,O-acetals 138 with excellent enantioselectivity (Scheme [29]).[52] The strategy was applied to a 2-methylene-1,2,3,4-tetrahydropyridine, which contains both exocyclic and endocyclic C=C bonds, yielding the corresponding product 139 in 48% yield with 99% ee and 90:10 dr.

Zoom Image
Scheme 29 Copper-catalyzed cyclization reaction of enamides with α-diazo ketones via a cyclopropanation–rearrangement approach

#
# 5

Summary and Outlook

In summary, many successful examples presented in this short review convincingly demonstrate the great potential of the transition-metal-catalyzed functionalization of enamides in asymmetric synthesis. The progress covers the synthesis of chiral amines not only bearing one chiral center but also multiple chiral centers. Despite the significant strategies presented in this fast-growing research field over the past few years, numerous challenges persist in this research arena and there are many opportunities for further development. These include the following: (1) The current scope of enamides is rather restricted. Most functionalization reactions are performed on terminal enamides and disubstituted enamide. Although the reactivity of tri- and tetrasubstituted enamide is intuitively lower, trisubstituted enamides also provide possibilities for the development of chiral quaternary carbon centers. (2) There are only a few examples of multicomponent intermolecular enantioselective difunctionalization using internal enamides, so progress in this area will be welcome with high regio, diastereo-, and enantioselectivities. (3) Only carbon radicals, but no heteroatom radicals, have been used to initiate the reaction. With the emergence of photocatalysts harboring distinct redox potentials and triplet state energies, additional studies are needed to explore the implementation of novel radical precursors in the functionalization of enamides, especially heteroatom-centered species.

As the area is continuously evolving, we anticipate this review may contribute to the continuous development and applicative potential of enamides chemistry to access more complex chiral nitrogen frameworks.


#
#

Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Yifeng Chen
Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science & Technology
130 Meilong Road, Shanghai, 200237
P. R. of China   

Publication History

Received: 04 June 2022

Accepted after revision: 05 July 2022

Accepted Manuscript online:
05 July 2022

Article published online:
18 August 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Yang Xi was born in Jiangsu Province, China. She received her B.Sc. degree from Nanjing Xiaozhuang University in 2015, and her M.Sc. (2018) in organic chemistry from Nanjing Tech University. Currently, she is pursuing her Ph.D. studies at East China University of Science and Technology (ECUST) under the direction of Prof. Yifeng Chen. Yifeng Chen was born in Anhui Province, China. He received his BA in Chemistry from Soochow University in 2007 and completed his Ph.D. under the supervision of Prof. Yuanhong Liu at the Shanghai Institute of Organic Chemistry in 2012. After completing postdoctoral research with Stephen Buchwald (MIT) and Timothy Newhouse (Yale University), he started his independent group at East China University of Science and Technology in 2017. His main research interests include Organometallic Catalysis Directed Towards Organic Synthesis (OMCOS), particularly in asymmetric catalysis.
Zoom Image
Scheme 1 Outline of transition-metal-catalyzed asymmetric functionalization of enamides
Zoom Image
Scheme 2 Palladium-catalyzed intramolecular asymmetric Heck reaction of alkenyl iodide tethered enamides
Zoom Image
Scheme 3 Palladium-catalyzed intramolecular asymmetric Heck reaction of the aryl triflate tethered enamides
Zoom Image
Scheme 4 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamide with triflates
Zoom Image
Scheme 5 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamide with benzyl trifluoroacetate and aryl halides
Zoom Image
Scheme 6 Palladium-catalyzed intermolecular asymmetric Heck reaction of cyclic enamides with alkenyl electrophiles
Zoom Image
Scheme 7 Palladium-catalyzed intermolecular asymmetric oxidative Heck reaction of cyclic enamides with arylboronic acid
Zoom Image
Scheme 8 Palladium-catalyzed intermolecular asymmetric Heck–Matsuda­ Reaction of cyclic enamides with arenediazonium salts
Zoom Image
Scheme 9 Nickel-catalyzed intermolecular asymmetric Heck reaction of 2,3-dihydropyrrole with aryl triflates
Zoom Image
Scheme 10 NiH-catalyzed asymmetric reductive hydroarylation of enamides to chiral benzylamines
Zoom Image
Scheme 11 Mechanism for NiH-catalyzed asymmetric hydroarylation of enamides
Zoom Image
Scheme 12 NiH-catalyzed asymmetric hydroalkylation of enamides with alkyl halides
Zoom Image
Scheme 13 Mechanism for the NiH-catalyzed asymmetric hydroalkylation of enamides
Zoom Image
Scheme 14 Copper-catalyzed asymmetric hydroboration of enamides
Zoom Image
Scheme 15 Copper-catalyzed asymmetric hydrosilylation of enamides
Zoom Image
Scheme 16 Rhodium-catalyzed asymmetric hydroboration of enamides
Zoom Image
Scheme 17 Rhodium-catalyzed regiodivergent asymmetric hydroboration of enamides
Zoom Image
Scheme 18 Rhodium-catalyzed asymmetric hydroalkynylation of enamides
Zoom Image
Scheme 19 Iridium-catalyzed asymmetric hydroalkynylation of enamides
Zoom Image
Scheme 20 Iridium-catalyzed enantioselective hydroalkynylation of β,β-disubstituted enamides
Zoom Image
Scheme 21 Palladium-catalyzed asymmetric domino cyclization of a cyclic enamide with o-vinylphenyl triflate
Zoom Image
Scheme 22 Palladium-catalyzed asymmetric difunctionalization of cyclic enamides
Zoom Image
Scheme 23 Palladium-catalyzed asymmetric 1,2-arylfluorination of internal­ enamides
Zoom Image
Scheme 24 Palladium-catalyzed asymmetric 1,2-diarylation and 1,3-diarylation of internal enamides
Zoom Image
Scheme 25 Palladium-catalyzed intramolecular asymmetric Heck/Suzuki coupling reaction of 1,1-disubstituted enamides
Zoom Image
Scheme 26 Nickel-catalyzed intramolecular asymmetric reductive dicarbofunctionalization of 1,1-disubstituted enamides
Zoom Image
Scheme 27 Ni-catalyzed asymmetric three-component reductive coupling of terminal enamides
Zoom Image
Scheme 28 Copper-catalyzed three-component asymmetric cyanation and etherification reactions of enamides
Zoom Image
Scheme 29 Copper-catalyzed cyclization reaction of enamides with α-diazo ketones via a cyclopropanation–rearrangement approach