doi.org/10.26434/chemrxiv.11830935.v3

Regio-, Stereo- and Enantioselective α-Addition of CarbonylNucleophiles to Allenamides Catalyzed by a Synergistic Copper/EnamineSystemRémi Blieck, Sebastien Lemouzy, Marc Taillefer, Florian Monnier

Submitted date: 13/04/2020 • Posted date: 15/04/2020Licence: CC BY-NC-ND 4.0Citation information: Blieck, Rémi; Lemouzy, Sebastien; Taillefer, Marc; Monnier, Florian (2020): Regio-,Stereo- and Enantioselective α-Addition of Carbonyl Nucleophiles to Allenamides Catalyzed by a SynergisticCopper/Enamine System. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.11830935.v3

A dual copper/enamine catalytic system is found to enable an intermolecular enantioselective α-addition ofvarious carbonyl nucleophiles to allenamides. Secondary amine catalysts allowed the highly enantioselectiveaddition of aldehydes, while using primary amine catalysts led to the enantioselective addition of ketoesternucleophiles. The process was found to be highly regio-, stereo- and enantio-selective and represented thefirst allene hydrofunctionalization using an synergistic catalysis involving copper

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Regio-, Stereo- and Enantioselective α-Addition of Carbonyl Nucleo-philes to Allenamides Catalyzed by a Synergistic Copper/Enamine System

Rémi Blieck,†,# Sébastien Lemouzy,†,# Marc Taillefer,†,* and Florian Monnier†, ‡,* #Both authors equally contributed to this work. †Ecole Nationale Supérieure de Chimie de Montpellier, Institut Charles Gerhardt Montpellier UMR 5253 CNRS,

AM2N, 8 rue de l’Ecole Normale, Montpellier 34296 Cedex 5, France. ‡Institut Universitaire de France, IUF, 1 rue Descartes, 75231 Paris cedex 5, France.

Supporting Information Placeholder

ABSTRACT: A dual copper/enamine catalytic system is found to enable an intermolecular enantioselective α-addition of various carbonyl nucleophiles to allenamides. Secondary amine catalysts allowed the highly enantioselective addition of aldehydes, while using primary amine catalysts led to the enantioselective addition of ketoester nucleophiles. The process was found to be highly regio-, stereo- and enantio-selective and represented the first allene hydrofunctionalization using an synergistic catalysis in-volving copper.

Synergistic catalysis has recently emerged as a powerful tool in organic synthesis, by combining the divergent reactivity of two distinct catalytic systems in a single reaction mixture.1 In particu-lar, the combination of transition-metal catalysis with amine organocatalysts through imine or enamine species has recently been exploited to develop new efficient synthetic methods for the formation of useful building blocks.2-3 Recently, the combination of chiral amine catalyst and chiral iridium catalyst has shown impressive results in the context of enantioselective allylic substi-tution of aldehydes (scheme 1a).4 One of the particular features of this reaction is the very high diastereo-divergence of the process, which has been successfully applied to the synthesis of several diastereomer of tetrahydrocannabinols.4c

Scheme 1. Representative examples of synergistic catalysis and of hydrofunctionnalization of allenes.

In order to address the atom economy issues in allylation pro-cesses, the hydrofunctionalization has recently emerged as a powerful strategy. A representative example is the work per-formed by the Breit research group, developping a range of enan-

tioselective branched-selective reaction based on rhodium-catalyzed additions of various nucleophiles to terminal allenes (scheme 1b).5 In parallel, our research group also reported the addition of nitrogen, oxygen and carbon nucleophiles to terminal allenes using a copper catalyst (scheme 1c).6 In our conditions, exclusive regioselectivity for the linear product was observed, owing to the addition of the nucleophile in the distal C=C bond. In our quest for the development of enantioselective copper-catalyzed transformations, we envisioned the possibility of using carbonyl pronucleophiles in the presence of a chiral amine cata-lyst to perform the addition to terminal allenamides in a synergis-tic catalytic process (scheme 2).

Scheme 2. This work: synergistic Cu-enamine catalyzed anti-Markovnikov addition of aldehydes

Indeed, such synergistic catalysis-based enantioselective func-tionalization of allenes has been reported only by the use of pre-cious transition-metal catalysts such as palladium7 or gold8 and thus represents a challenging area of research. More specifically, functionalization of allenamide derivatives via distal addition is of high importance, as enamine products are intermediates of high synthetic value9.

To test our hypothesis, we reacted allene 1a with aldehyde 2a in THF in the presence Cu(MeCN)4BF4 and Hayashi-Jorgensen type amine catalysts C2-C5 (Table 1). When 1a was heated at 70°C in THF in the presence of diphenylprolinol trimethylsilyl ether C2 as chiral amine catalyst, the desired product was obtained in good yield but with very modest enantioselectivity (Table 1, entry 1). Switching the solvent to toluene increased the enantiose-lectivity, although the reactivity of the catalytic system was de-creased (Table 1, entry 2). The reaction temperature was lowered to 60°C, leading to a low yield of 16%, but the enantioselectivity was largely improved (Table 1, entry 3). In order to increase the catalyst turn-over, we hypothesized that the addition of external nitrogen—based ligand (as 2,2’-bipyridine) would prevent the potential formation of (prolinol)copper (I) complex.10 We thought that this stable specie would sequestrate the organocatalyst and thus would be responsible for the drop of catalytic activity in such non-polar, weakly coordinating solvent as toluene. Furthermore,

Carreira[4]: Catalyst-controlled synergistic Ir / enamine catalysis

Breit[5]: Rhodium catalyzed enantioselective Markovnikov addition to allenes

Our group[6]: Copper catalyzed anti-markovnikov addition to allenes

OR2

R1

R3

OHcat. [Ir(cod)Cl]2

L*

chiral amineacidic promoter

O

R2 R1

R3

H

R + NuHcat. [Rh(cod)Cl]2

L* R

Nu

High dr and erEnantio / diastero-divergent

High erWide array of NuH

R + NuHcat. [Cu]

R

Mild conditionsRegio- and stereo- selective

Nu

a)

b)

c)

FGO

R

R

O

FGCu En

Ar

ArCu/enamine catalysisAldehyde & ketoester nucleophilesMild conditionsRegio-, Stereo-, Enantioselective

we thought that the use of a catalytic amount of weak acid (RCOOH) could enhance the organocatalyst activity by accelerat-ing the enamine formation, without any risk of hydrocarboxyla-tion of the allenamides at 60°C in the absence of a base.6f When 20 mol% of p-methylbenzoic acid A1 was added as the sole addi-tive, the yield and enantioselectivity were slightly improved (Ta-ble 1, entry 4). When a combination of 20 mol% of A1 and 2,2’-bipyridine L1 acting as copper ligand, the yield and enantioselec-tivity were further improved to 46% and 88:12 er, respectively (Table 1, entry 5). With these new conditions in hand, we tried to find the most suitable organocatalyst, using a range of commer-cially-available amine catalysts. Although, L-proline C1 gave essentially racemic mixture (entry 6), prolinol based organocata-lysts (C2-C5) gave the best enantioselectivity, with C5 giving an excellent enantiomeric ratio of 95.5:4.5, although giving 3aa in somewhat lower yield (Table 1, entry 9). McMillan-type catalysts (C6-C7) and Cinchona Alkaloids-derived amine catalyst C8 gave lower enantioselectivity (Table 1, entry 10-12).

Table 1. Preliminary catalyst screening

With catalyst C5 in hand, we then tried to find the best combi-nation of solvent, ligand and acid additive (Table 2). When, 4,4’-ditert-butyl-2,2’bipyridine L2 was used, the yield could be in-creased up to 65% (58% isolated yield) without affecting the enantioselectivity (Table 2, entry 2). Overall, although the nature of L ligand on copper did not affect the enantioselectivity, large reactivity differences were observed, with bipyridines L1-L2 and diamines (Table 2, entries 1-2, 5) giving moderate to good catalyt-ic activity, unlike phenanthroline-based ligands L3-L4 (Table 2, entries 3-4). Next we screened the solvents, and we were pleased to note that the use of aromatic solvents yielded the desired prod-uct 3aa in similar enantioselectivities ranging from 95:5 to 97:3 er (Table 2, entries 6-8). Among these solvents, reaction in α,α,α-trifluorotoluene afforded 3aa in very high isolated yield (86%, Table 2, entry 7). When THF was used as the solvent, the product

was isolated in similar yield as with α,α,α-trifluorotoluene, but the enantioselectivity was decreased to 87:13 er (Table 2, entry 9). Finally, we screened the influence of the acid additive over both reactivity and enantioselectivity, using 10 mol% of Cu(MeCN)4BF4 as the metal catalyst. An almost linear pKa / reactivity correlation was observed using various carboxylic acids and p-toluenesulfonic acid as additives. While A1 gave 30% of yield (Table 2, entry 10), stronger acids gave higher yields (39-72%) in the same conditions (Table 2, entries 12-14). However, in the case of strong acid (PTSA A5, Table 2, entries 14-15) this enhancement of catalytic activity was accompanied with a sub-stantial loss of enantioselectivity. Rate enhancement of the back-ground enol addition to the unsaturated substrate under strong Brønsted acid conditions might account for this result.11

Table 2. Ligand, solvent and acid additive screening

Using our optimized conditions (Table 2, entry 7), we evaluated the scope of the reaction, with a range of allenamides starting materials (scheme 3). When N-allenyl oxazolidinone 1b was used as the substrate, similar enantioselectivity was obtained, although the yield of 3ba decreased if we compared with 3aa. We then evaluated the influence of the substitution pattern on the nitrogen atom, obtaining moderate to good yield with N-allenyl sulfona-mide derivatives 3da, 3ea and 3ha. In order to study catalyst-control versus substrate-control in aldehyde face discriminated, we used two enantiomeric substrates based on N-allenyl 4-benzyloxazolidinone 1f. When the substrate bearing (R) configu-ration at the carbon center (1f) was reacted, moderate yield and good 5.5: 1 diastereomeric ratio (assessed by 1H NMR on the crude mixture) were observed (3fa). The (S) substrate (1g) gave the same-opposite diastereomer, in a lower-good-excellent xx:1 dr, thus confirming a catalyst-substrate-control with slight-

Entry

123456789

101112

yield%b

623216284648351039273367

erc

45.5 : 54.537 : 63

20.5 : 79.515.5 : 84.5

12 : 8850 : 5015 : 85

nd4.5 : 95.549 : 51

27.5 : 72.524.5 : 75.5

Solvent

THFTolueneTolueneTolueneTolueneTolueneTolueneTolueneTolueneTolueneTolueneToluene

x

000

202020202020202020

T

707060606060606060606060

y

0000

2020202020202020

C

C2 (20)C2 (20)C2 (20)C2 (20)C2 (20)C1 (20)C3 (20)C4 (20)C5 (20)C6 (20)C7 (20)C8 (20)

NH OR

PhPh

= TMS= TBS= H

RC2C3C4

NH

NO

Bn

C6

N

MeOH2N

N

NH

CO2H

C1

NH

NO

BnC7 C8

aReaction conditions: 1a (0.25 mmol), 2a (0.5 mmol) in 0.5 mL of solvent, 18h. bAssessed by 1H NMR using 1,3,5 trimethoxybenzene as the internal standard cAssessed by chiral HPLC (Chiralcel OD-H, 95:5 Hex:IPrOH, 1.5ml/min) on isolated product.

NH OTMS

CF3CF3

F3C

CF3C5

Organocatalysts

N

O

O Ph

O

N

O

1a 2a 3aa

Cu(MeCN)4BF4 20 mol%C 20 mol%

A1 x mol%bipyridine y mol%

Solvent, T(°C), 18h

N N

RR

R = H L1 R = H L3 DMEDA L5 tBu L2 = Me L4

N NR R

NH HN

Bidentates N,N ligands

Carboxylic acids (RCOOH)

A1 R = p-Me-C6H4 A2 R = n-pent

A3 R = o-Me-C6H4

A4 R = o-I-C6H4A5 PTSA-H2O

Entry

123456789

101112131415

A (pKa)

A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A1 (4.4)A2 (4.9)A3 (3.9)A4 (3.0)A5 (-6)A5 (-6)

yield%a

3965(58)

12224163

88(86)47

87(81)302539607276

erb

4.5 : 95.54 : 96

nd7.5 : 92.5

4 : 964 : 965 : 953 : 97

13 : 878 : 92

nd5 : 958 : 92

15 : 8511.5 : 88.5

Solvent

TolueneTolueneTolueneTolueneToluene

PhClPhCF3

MesityleneTHF

PhCF3PhCF3PhCF3PhCF3PhCF3PhCF3

L

L1L2L3L4L5L2L2L2L2L2L2L2L2L2L2

x

202020202020202020101010101020

aReaction conditions: 1a (0.25 mmol), 2a (0.5 mmol) in 0.5 mL of solvent, 60°C, 18h. bAssessed by 1H NMR using 1,3,5 trimethoxybenzene as the internal standard cAssessed by chiral HPLC (Chiralcel OD-H, 95:5 Hex:IPrOH, 1.5ml/min) on isolated product.

N

O

O Ph

O

N

O

1a 2a 3aa

Cu(MeCN)4BF4 x mol%C5 20 mol%

A 20 mol%L 20 mol%

Solvent, 60°C, 18h

moderate-high matching-mismatching effect. Product 3ha was obtained with good yields and high enantiomeric ratio. Finally, we evaluated the substituents on the aldehyde partner. Changing from phenyl to propyl resulted in an important drop of the reactivity, even though the enantioselectivity was maintained.

Scheme 3. Scope of allenamide substrates and aldehydes nucleophiles

In a next set of experiments, we wonder to see if our efficient catalytic system was able to perform the addition of keto-esters to allenamides (Table 3). We took allenamide 1a and ketoester 2g as substrate models for the development of the reaction. Starting with previous optimized conditions in table 2, we obtained the targeted compound 3ag in moderate yield with poor selectivity (Table 3, entry 1). As shown by Luo and coworkers, the reactivity of ketoesters is better with primary amine organocatalyst.7 So we decided to test several primary amine catalyst C8-C13 in order to boost the reactivity. In classical conditions, C10 catalyst exhibits excellent reactivity in term of yield but with poor enantiomeric ratio (Table 3, entry 10). To date, diamino catalyst C12 showed moderate conversion but an interesting er of 73:27 (Table 3, entry 12). At the present stage of the studies, we are still preforming the reaction development of the reaction of ketoesters.

Table 3. Reaction conditions developpement for the addi-tion of ketoesters.

To conclude, we are developing a copper/enamine synergistic system able to perform the addition of aldehydes and ketoesters nucleophiles on allenamides. Studies are still on progress for the development of this unprecedented reaction catalyzed by copper with a large scope of carbonyl nucleophiles.

ASSOCIATED CONTENT

Supporting Information

Detailed experimental procedures and characterization data for all new compounds are provided.

AUTHOR INFORMATION

Corresponding Author *Email: florian.monnier@enscm.fr , marc.taillefer@enscm.fr

Author Contributions #These authors contributed equally. The manuscript was written through contributions of all authors. All authors have given ap-proval to the final version of the manuscript. Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT

Financial support provided by Région Languedoc-Roussillon (PhD fellowship for RB), ENSCM (Postdoctoral fellowship for SL), IUF (Institut Universitaire de France to FM), ANR CD2I (Agence Nationale de la Recherche) and CNRS are warmly acknowledged with thanks.

R1 R2

O

[N]

31 2

Cu(MeCN)4 BF4 20 mol%C5 20 mol%a

L2 20 mol%A1 20 mol%

PhCF3, 60°C, 18h

H[N] R1

R2

O

H

N

O

CHO

Me Ph

3aa, 86%, 95:5 er

N CHO

Me PhTs

ON

O

CHO

Me Ph

Bn3fa, 49%, 5.5:1 dr

N

O

CHO

Me

3ab, 19%, er = nd

3da, 46%, 91:9 er

3ac, 75%, 94.5:5.5 er

3ha, 82%, 91.5:8.5 er

N CHO

Me PhMs

MeO

N

O

CHO

Me

OMe

NPh CHO

Me PhBoc

3ka, 36%, er tbd

ON

O

CHO

Me Ph

3ba, 53%, 94:6 er

3ea, 82%, 92:8 er

N CHO

Me PhTs

N

O

N

OCO2Et

O

Cu(MeCN)4 BF4 20 mol%A1 20 mol%

Amine 20 mol%L2 20 mol%

Solvent, 60°C, 18h1a

OEtO2C

2g

Entry

123456789

10111213

Amine

C5C8 C10C12C9C9C9C9C9C10C11C12C13

yield%a

53212124383336470

90303455

erb

48 : 5268 : 3260 : 4060 : 4046 : 5443 : 5727 : 73

48.5 : 51.5nd

50 : 5071 : 2973 : 2753 : 47

Solvent

PhCF3PhCF3PhCF3PhCF3PhCF3THF

MeCNTolueneDMSOMeCNMeCNMeCNMeCN

aReaction conditions: 1a (0.25 mmol), 2g (0.5 mmol) in 0.5 mL of solvent, 60°C, 18h. bAssessed by 1H NMR using 1,3,5 trimethoxybenzene as the internal standard cAssessed by chiral HPLC (Chiralcel OD-H, 95:5 Hex:IPrOH, 1.5ml/min) on isolated product.

HN

NH2

GTFA C11Boc C12Bz C13

=NEt2

X

NH2

X = O C9 H2 C10

G

3ag

REFERENCES

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Breit, B. Rhodium-catalyzed regio- and enantioselective addition of N-hydroxyphtalimide to allenes: a strategy to synthesize allylic alcohols. Org. Lett., 2018, 20, 300-03. (e) Grugel, C.P.; Breit, B. Rhodium-catalyzed enantioselective decarboylative alkynylation of allenes with arylpropiolic acids. Org. Lett., 2018, 20, 1066-69. 6. (a) Blieck, R.; Bahri, J.; Taillefer, M.; Monnier, F. Copper-catalyzed hydroamination of terminal allenes. Org. Lett., 2016, 18, 1482-85. (b) Perego, L.A.; Blieck, R.; Groué, A.; Monnier, F.; Taillefer, M.; Ciofini, I.; Grimaud, L. Copper-catalyzed hydroamination of allenes: from mechanis-tic understanding to methodology development. ACS Catal., 2017, 7, 4253-64. (c) Perego, L.A.; Blieck, R.; Michel, J.; Ciofini, I.; Grimaud, L.; Taillefer, M.; Monnier, F. Copper-catalyzed hydroamination of N-allenylazoles: access to amino-substituted N-vinylazoles. Adv. Synth. Catal., 2017, 359, 4388-92. (d) Blieck, R.; Abed Ali Abdine, R.; Taillefer, M.; Monnier, F. Regio- and stereoselective copper-catalyzed allylation of 1,3-dicarbonyl compounds with terminal allenes. Org. Lett., 2018, 20, 2232-35. (e) Blieck, R.; Perego, L.A.; Ciofini, I.; Grimaud, L.; Taillefer, M.; Monnier, F. Copper-catalysed hydroamination of N-allenylsulfonamides: the key role of ancillary coordinating groups. Synthe-sis, 2019, 51, 1225-34. (f) Blieck, R.; Taillefer, M.; Monnier, F. Copper-catalyzed hydrocarboxylation of N-allenyl derivatives. J. Org. Chem., 2019, 84, 11247-52. 7. (a) Zhou, H.; Wang, Y.; Zhang, L.; Cai, M.; Luo, S. Enantioselective terminal addition to allenes by dual chiral primary amine / palladium catalysis. J. Am. Chem. Soc., 2017, 139, 3631-34. For an intramolecular version of the reaction: (b) Li, M.; Datta, S.; Barber, D.M.; Dixon, D.J. Dual amine and palladium catalysis in diastereo- and enantioselective allene carbocyclization reactions. Org. Lett., 2012, 14, 6350-53. 8. (a) Ballesteros, A.; Moran-Poladura, P.; Gonzalez, J.M. Gold(I) opera-tional in synergistic catalysis for the intermolecular α-addition reaction of aldehydes across allenamides. Chem. Commun., 2016, 52, 2905-08. (b) Fernandez-Casado, J.; Nelson, R.; Mascareñas, J.L.; Lopez, F. Synergistic gold and enamine catalysis: intermolecular α-alkylation of aldehydes with allenamides. Chem. Commun., 2016, 52, 2909-12. 9. (a) Enamines: Synthesis, Structure and Reactions, ed A. G. Cook, Marcel Dekker, New York, 2nd edn., 1987; (b) The Chemistry of Enamines, ed. Z. Rappaport, J. Wiley, Chichester, UK, 1994. (c) Mukher-jee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Cataly-sis. Chem.Rev. 2007, 107, 5471-569. 10. For some recent examples on the synthesis and characterization of amino-alcohols copper complexes, see: (a) Kirillova, M.V.; Tomé de Paiva, P.; Carvalho, W.A.; Mandelli, D.; Kirillov, A.M. Mixed-ligand aminoalcohol-dicarboxylate copper(II) coordination polymers as catalysts for the oxidative of cyclic alkanes and alkenes, Pure Appl. Chem., 2017, 89, 61-74. (b) Fernandes, T.A.; André, V.; Kirillov, A.M.; Kirillova, M.V. Mild homogeneous oxidation and hydrocarbocylation of cycloalkanes catalyzed by novel dicopper(II) aminoalcohol-driven cores, J. Mol. Cat. A: Chem., 2017, 426, 357-67. (c) Fernandes, T.A.; Kirillova, M.V.; André, V.; Kirillov, A.M. Interplay between H-bonding and interpenetration in an aqueous copper(II) aminoalcohol pyromellitic acid system: self-assembly synthesis, structural features and catalysis, Dalton Trans., 2018, 47, 16674-83. 11. For an example of Bronsted acid catalyzed addition to allenes: Dion, I.; Bauchemin, A.M. Asymmetric Bronsted acid catalysis enabling hy-droaminations of dienes and allenes. Angew. Chem. Int. Ed., 2011, 50, 8233-35. 12. For an account on primary amine organocatalysis: Zhang, L.; Fu, N.; Luo, S. Pushing the limits of aminocatalysis: enantioselective transfor-mations of α-branched β-ketocarbonyls and vinyl ketones by chiral prima-ry amines. Acc. Chem. Res., 2015, 48, 986-97.

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FGO

R

R

O

FGCu En

Ar

ArCu/enamine catalysisAldehyde & ketoester nucleophilesMild conditionsRegio-, Stereo-, Enantioselective

 

download fileview on ChemRxivTOC Monnier et al.pdf (67.96 KiB)

Experimental Section

Regio-, Stereo- and Enantioselective α-Addition of Carbonyl Nucleophiles to Allenamides Catalyzed by a Synergistic Copper/Enamine System

Rémi Blieck,†,# Sébastien Lemouzy,†,# Marc Taillefer,†,* and Florian Monnier†, ‡,* #Both authors equally contributed to this work. †Ecole Nationale Supérieure de Chimie de Montpellier, Institut Charles Gerhardt Montpellier UMR

5253 CNRS, AM2N, 8 rue de l’Ecole Normale, Montpellier 34296 Cedex 5, France. ‡Institut Universitaire de France, IUF, 1 rue Descartes, 75231 Paris cedex 5, France.

1. General Considerations

All reactions were performed in schlenk tube closed with a Rodaviss® screw cap and PTFE liner (approx 25mL), using a freshly anhydrous solvents obtained from a Mbraun Pure Solv® solvent purification system. Copper salts were purchased from either Sigma-Aldrich®, Strem®, Alfa Aesar® or Acros Organic®, used as received, stored in a dessicator cabinet and weighed to air. [Cu(NCMe)4]PF6 was synthesized according to a previously reported method.1 1Other reagents were purchased from either Sigma-Aldrich® or Alfa Aesar® or Acros Organic® and used as received. 1H and 13C NMR spectra were recorded with a Bruker AC-400 MHz spectrometer in CDCl3 For 1H NMR (400 MHz), CHCl3 and TMS served as internal standards (δ = 7.27, 2.50 and 0 ppm) and data are reported as follows: chemical shift (in ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (in Hz), and integration. For 13C NMR (100 MHz), CHCl3 was used as internal standards (δ = 77.2) and spectra were obtained with complete proton decoupling. Gas chromatography–mass spectra (GC-MS) were recorded on a Shimadzu QP2012-SE with a Zebron ZB-5MS (20m × 0,18mm), capillary apolar column (Stationary phase: 0.18µm film). GC-MS method: Initial temperature: 50 oC; Initial time: 2 min; Ramp: 22 oC/min; Final Temperature: 280 oC; Final time: 15 min or 23min. Melting point were measured with a Stuart SMP50 Automatic Melting Point apparatus.

All allenes were synthesized according to previously described methods and analysis were in accordance with the literature.2

2. General procedure

In a flame-dried, argon filled 4 ml vial were charged the copper complex (20 mol%), the amine (20 mol%) and the additives. The vial was then purged three times (vacuum-argon) and dry solvent (0.5 ml) was added. Then, allene (0.25 mmol, 1 equiv, 31 mg) and aldehyde (0.5 mmol, 67 mg, 67µl) were added and the reaction was stirred for 18 hours at the given temperature (oil bath was used if necessary). After cooling down to room temperature, the internal standard (trimethoxybenzene, 0.33 equiv, 14 mg) was added and the reaction was diluted in DCM (4 ml) and the organic was washed with distilled water (2 ml). The product was isolated by column chromatography on silica gel using either a mixture of DCM : Et2O or a mixture of Hexane : AcOEt as the solvent system.

3. Characterization Data

According to the general procedure, (E)-2-methyl-5-(2-oxopyrrolidin-1-yl)-2-phenylpent-4-enal 3aa was isolated as a light-yellow oil (55 mg, 86% yield). 1H NMR 400MHz CDCl3 : δ 9.51 (s, 1H, CHO), 7.42 – 7.35 (m, 2H), 7.33 – 7.26 (m, 1H), 7.25 – 7.21 (m, 2H), 6.88 (d, J = 14.4 Hz, 1H, N-CH=CH), 4.62 (dt, J = 14.6, 7.6 Hz, 1H, N-CH=CH), 3.40 – 3.35 (m, 2H, NCH2), 2.66 (dd, J = 7.6, 1.1 Hz, 2H, CH=CH-CH2), 2.45 (t, J = 8.2 Hz, 2H,

N-CO-CH2), 2.09 – 2.00 (m, 2H, N-CH2-CH2), 1.43 (s, 3H, CH3); These data are consistent with those of the literature.3 Rf (DCM:Et2O 10:1) = 0.4; HPLC separation (Chiralpak OD-H, hexane / isopropanol (95:5), 1.5 mL / min, 220 and 235 nm, rt first eluted 22.6 min, rt second eluted 25.5 min) e.r = 95:5; [α]D25= + 17 (c=0.19, CH2Cl2)

According to the general procedure, ((E)-2-methyl-5-(2-oxooxazolidin-3-yl)-2-phenylpent-4-enal 3ba was isolated as a light-yellow oil (34 mg, 53% yield). 1H NMR 400MHz CDCl3 : 9.52 (s, 1H, CHO), 7.42 – 7.36 (m, 2H), 7.33 – 7.28 (m, 1H), 7.25 – 7.21 (m, 2H), 6.66 (d, J = 14.3 Hz, 1H, N-CH=CH), 4.51 (dt, J = 14.3, 7.6 Hz, 1H, N-CH=CH), 4.43 – 4.33 (m, 2H, OCH2), 3.61 – 3.54 (m, 2H, NCH2), 2.66 (dd, J = 7.6, 1.2 Hz, 2H,

CH=CH-CH2), 1.44 (s, 3H, CH3).; These data are consistent with those of the literature1. Rf (DCM:Et2O 10:1) = 0.2; HPLC separation (Chiralpak OD-H, hexane / isopropanol (95:5), 1.5 mL / min, 220 and 235 nm, rt first eluted 22.6 min, rt second eluted 25.5 min) e.r = 95:5; [α]D25= + 17 (c=0.19, CH2Cl2)

According to the general procedure, (E)-N-allyl-4-methyl-N-(4-methyl-5-oxo-4-phenylpent-1-en-1-yl)benzenesulfonamide 3da was isolated as a light-yellow oil (44 mg, 46% yield). 1H NMR 400MHz CDCl3 : δ 9.48 (s, 1H, CHO), 7.49 – 7.44 (m, 2H), 7.38 – 7.25 (m, 8H), 7.16 – 7.11 (m, 2H), 6.91 (dt, J = 13.9, 1.1 Hz, 1H, NCH=CH), 6.88 – 6.81 (m, 2H), 4.15 (dt, J = 13.9, 7.7 Hz, 1H, NCH=CH), 2.57

(dd, J = 7.8, 1.1 Hz, 2H, NCH=CH-CH2), 2.48 (s, 3H, CH3ArSO2), 1.34 (s, 3H, C-CH3). 13C NMR 101 MHz CDCl3 δ 202.1 (CHO), 143.8, 139.4, 136.2, 131.6, 129.9, 128.9, 128.5, 127.5, 127.3, 127.0, 118.0,

106.5, 54.3 (N-CH2), 48.1, 37.6, 31.1, 21.7. Rf (Hex:AcOEt 5:1) = 0.33; HRMS (ESI+) Calc. for [M+H]+ 384.1628, found 384.1636; HPLC separation (Chiralpak OD-H, hexane / isopropanol (99:1), 0.8 mL / min, 300 nm, rt first eluted 49.8 min, rt second eluted 55.6 min) e.r = 91:9; [α]D25= + 17 (c=0.19, CH2Cl2)

According to the general procedure, (E)-4-methyl-N-(4-methyl-5-oxo-4-phenylpent-1-en-1-yl)-N-phenylbenzenesulfonamide 3ea was isolated as a light-yellow oil (85 mg, 82% yield). 1H NMR 400MHz CDCl3 : δ 9.48 (s, 1H, CHO), 7.49 – 7.44 (m, 2H), 7.38 – 7.25 (m, 8H), 7.16 – 7.11 (m, 2H), 6.91 (dt, J = 13.9, 1.1 Hz, 1H, NCH=CH), 6.88 – 6.81 (m, 2H), 4.15 (dt, J = 13.9, 7.7 Hz, 1H, NCH=CH), 2.57 (dd, J = 7.8, 1.1 Hz, 2H,

NCH=CH-CH2), 2.48 (s, 3H, CH3ArSO2), 1.34 (s, 3H, C-CH3). 13C NMR 101 MHz CDCl3 δ 202.1, 143.9, 139.5, 136.7, 135.8, 131.8, 130.0, 129.7, 129.5, 129.0, 128.9, 127.5, 127.4, 127.1, 106.7, 54.4, 37.1, 21.8, 18.8. Rf (Hex:AcOEt 5:1) = 0.39; HRMS (ESI+) Calc. for [M+H]+ 420.1628, found 420.1648; HPLC separation (Chiralpak OD-H, hexane / isopropanol (99:1), 1 mL / min, 220 and 235 nm, rt first eluted 42.8 min, rt second eluted 56.2 min) e.r = 92:8; [α]D25= + 17 (c=0.19, CH2Cl2)

According to the general procedure, (E)-N-(4-methoxyphenyl)-N-(4-methyl-5-oxo-4-phenylpent-1-en-1-yl)methanesulfonamide

3ha was isolated as a light-yellow oil (85 mg, 82% yield). 1H NMR 400MHz CDCl3 : δ 9.49 (s, 1H, CHO), 7.39 – 7.33 (m, 2H), 7.30 – 7.26 (m, 1H), 7.18 – 7.13 (m, 2H), 7.10 – 7.04 (m, 2H), 6.94 –

6.89 (m, 2H), 6.67 (dt, J = 13.7, 1.1 Hz, 1H, N-CH=CH), 4.25 (dt, J = 13.9, 7.8 Hz, 1H, N-CH=CH), 3.82 (s, 3H, OMe), 2.84 (s, 3H), 2.54 (dd, J = 7.8, 1.1 Hz, 2H, CH=CH-CH2), 1.36 (s, 3H, CH3). 13C NMR 101 MHz CDCl3 δ 202.1, 143.9, 139.5, 136.7, 135.8, 131.8, 130.0, 129.7, 129.5, 129.0, 128.9, 127.5, 127.4, 127.1, 106.7, 54.4, 37.1, 21.8, 18.8. Rf (Hex:AcOEt 3:1) = 0.35; HRMS (ESI+) Calc. for [M+H]+ 374.1421, found 374.1433; HPLC separation (Chiralpak OD-H, hexane / isopropanol (95:5), 0.8 mL / min, 220 and 235 nm, rt first eluted 63.8 min, rt second eluted 72.3 min) e.r = 91.5:8.5; [α]D25= + 17 (c=0.19, CH2Cl2).

According to the general procedure, (E)-2-(4-methoxyphenyl)-2-methyl-5-(2-oxopyrrolidin-1-yl)pent-4-enal 3ac was isolated as a light-yellow oil (54 mg, 75% yield). 1H NMR 400MHz CDCl3 : δ 9.45 (s, 1H, CHO), 7.18 – 7.07 (m, 2H), 6.97 – 6.77 (m, 3H, 2H Ar + N-CH-CH2), 4.62 (dt, J = 14.7, 7.6 Hz, 1H, N-CH-CH2), 3.81 (s, 3H, O-CH3), 3.38 (t, J = 7.4 Hz, 2H, N-CH2), 2.63 (dd, J = 7.8, 1.3 Hz, 2H), 2.45 (t, J = 8.1 Hz, 2H), 2.05 (p, J = 7.8 Hz, 2H), 1.40 (s, 3H, C-CH3); 13C

NMR 101 MHz CDCl3 δ 202.0, 173.0, 158.8, 131.1, 128.3, 126.3 114.3, 106.3, 55.3, 53.4, 45.2, 37.2, 31.2, 18.9, 17.3. Rf (DCM:Et2O 10:1) = 0.37; HRMS (ESI+) Calc. for [M+H]+ 288.1594, found 288.1604; HPLC separation (Chiralpak IA, hexane / isopropanol (95:5), 1.4 mL / min, 235 and 254 nm, rt first eluted 26.9 min, rt second eluted 42.2 min) e.r = 94.5:5.5; [α]D25= + 17 (c=0.19, CH2Cl2)

According to the general procedure, ethyl (E)-2-oxo-1-(3-(2-oxopyrrolidin-1-yl)allyl)cyclopentane-1-carboxylate 4a was isolated as a colorless oil (24 mg, 34% yield). 1H NMR 400MHz CDCl3 : δ 6.92 (d, J = 14.4 Hz, 1H, N-CH=CH), 4.83 (dt, J = 14.5, 7.6 Hz, 1H, N-CH=CH), 4.17 (qd, J = 7.1, 0.9 Hz, 2H, O-CH2), 3.53 – 3.39 (t, J = 7.3 Hz, 2H, , N-CH2), 2.66 (ddd, J = 14.1, 7.4, 1.3 Hz, 1H, N-CH=CH-CH2), 2.48 (t, J = 7.9 Hz, 2H), 2.44 – 2.38 (m,

2H), 2.35 (ddd, J = 14.1, 7.9, 1.1 Hz, 1H, N-CH=CH-CH2), 2.29 – 2.19 (m, 1H), 2.13 – 2.04 (m, 2H), 2.03 – 1.86 (m, 3H), 1.25 (t, J = 7.1 Hz, 3H).13C NMR 101 MHz CDCl3: δ 214.7 (C=O ketone), 173.2 (C=O ester), 171.1 (C=O lactam), 127.0 (N-C=C), 106.1 (N-C=C), 61.6 (O-C ester), 60.6 (C-N lactam), 45.4, 38.2, 34.4, 32.4, 31.3, 19.6, 17.5, 14.3; HRMS (ESI+) Calc. for [M+H]+ 280.1543, found 280.1553; Rf (DCM:Et2O 10:1) = 0.38 HPLC separation (Chiralpak OD-H, hexane / isopropanol (95:5), 1.5 mL / min, 220 and 235 nm, rt first eluted 25.0 min, rt second eluted 29.1 min) e.r = 73 : 27; [α]D25= + 17 (c=0.19, CH2Cl2)

4. NMR spectra of new compounds

1 G. J. Kubas, B. Monzyk and A. L. Crumblis, Inorg. Synth. 1990, 28, 68 2 (a) R. Blieck, J. Bahri, M. Taillefer and F. Monnier, Org. Lett., 2016, 18, 1482; (b) L. Perego, R. Blieck, A. Groué, F. Monnier, M.Taillefer, I. Ciofini and L. Grimaud, ACS Catal., 2017, 7, 4253; (c) L. A. Perego, R. Blieck, J. Michel, I. Ciofini, L. Grimaud, M. Taillefer and F. Monnier, Adv. Sytnh. Catal., 2017, 359, 4388; (d) R. Blieck, R. Abed Ali Abdine, M. Taillefer and F. Monnier, Org. Lett., 2018, 20, 2232. (e) R. Blieck, L. A. Perego, I. Ciofini, L. Grimaud, M. Taillefer and F. Monnier, Synthesis, 2019, 51, 1225. 3 Fernandez-Casado, J.; Nelson, R.; Mascareñas, J.L.; Lopez, F. Synergistic gold and enamine catalysis: intermolecular α-alkylation of aldehydes with allenamides. Chem. Commun., 2016, 52, 2909-12.

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