Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl-N-methylimidazole Michael Acceptors: Scope, Limitations and Iterative Reactions

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DOI: 10.1002/adsc.201600458

Copper-Catalyzed Asymmetric Conjugate Addition of Dimethyl-

zinc to Acyl-N-methylimidazole Michael Acceptors: Scope,

Limitations and Iterative Reactions

Sammy Drissi-Amraoui,^aThibault E. Schmid,^bJimmy Lauberteaux,^b

Christophe Crꢀvisy,^bOlivier Baslꢀ,^bRenata Marcia de Figueiredo,^a

Stꢀphanie Halbert,^cHꢀlꢁne Gꢀrard,^c,* Marc Mauduit,^b,*

and Jean-Marc Campagne^a,*

a

Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM-ENSCM, Ecole Nationale Supꢀrieure de Chimie de

Montpellier, 8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France

E-mail: jean-marc.campagne@enscm.fr

Ecole Nationale Supꢀrieure de Chimie de Rennes, UMR CNRS 6226, 11 Allꢀe de Beaulieu, CS 50837, 35708 Rennes

b

Cedex 7, France

E-mail: marc.mauduit@ensc-rennes.fr

Sorbonne Universitꢀs, UPMC Universitꢀ Paris 06, CNRS, Laboratoire de Chimie Thꢀorique CC 137-4, place Jussieu

c

75252 Paris Cedex 05, France

E-mail: helene@lct.jussieu.fr

Received: April 29, 2016; Revised: June 8, 2016; Published online: && &&, 0000

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600458.

Abstract: An efficient copper-catalyzed enantioselec- ring. Thanks to the development of efficient proto-

tive conjugate addition of dimethylzinc to unsaturat- cols to regenerate the unsaturated 2-acyl-N-methyli-

ed 2-acyl-N-methylimidazoles has been achieved midazole moiety, an iterative process has been devel-

using a chiral bidentate hydroxyalkyl-NHC ligand. oped ultimately leading to 3,5,7 all-syn or anti-anti

The reactions proceed with excellent regioselectivity polydeoxypropionate stereodiads.

(1,4 vs. 1,6 and 1,8) in extended conjugated systems

to afford the 1,4-adducts in high enantioselectivities. Keywords: acyl-N-methylimidazole; asymmetric con-

This regioselectivity could be ascertained by DFT jugate addition; copper; 1,3-deoxypropionates; itera-

studies highlighting the crucial role of the imidazole tive process

Introduction

mone of Antitrogus parvulus, presents an anti,anti,anti

triad.^[5]Thus, the development of efficient and con-

À

Among the myriad of asymmetric C C bond forma- venient methodologies allowing the selective con-

tion reactions mediated by transition metal com- struction of all these various types of 1,3-stereogenic

plexes, the enantioselective introduction of a methyl units with high enantio- and diastereoselectivities is of

group to form all-carbon stereogenic centers repre- high demand.

sents one of the most important challenges in modern

In the last few decades, intensive researches have

organic chemistry.^[1]Indeed, this highly valuable chiral been conducted in this direction.^[1,6]Particular atten-

methyl-substituted pattern is found in a broad range tion has been given to metal-catalyzed asymmetric

of natural products (Figure 1).^[2]Particularly, the syn- conjugate addition (ACA) of organometallic reagents

thesis of (poly)deoxypropionate motifs, which are to electron-deficient unsaturated acyclic systems.^[7]

prevalent subunits in many biologically relevant mole- Among the wide range of metals and the plethora of

cules^[3]such as insect pheromones, lipopeptides and chiral ligands studied, copper-based catalytic systems

mycobacterial glycolipids, remains challenging. For in- appeared to be quite efficient to selectively transfer

stance, (À)-lardolure, a pheromone of the acarid mite alkylated organometallic reagents on various acyclic

Lardoglyphus konoi, contains all-syn units^[4]whereas Michael acceptors,^[7,8]including notably methylated

[9]

4,6,8,10,16,18-hexamethyldocosane, a sexual phero- hard nucleophiles (i.e., AlMe_3,MeMgBr_,^[10]and

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Figure 2. Synthetic strategies previously reported for the

construction of 1,3-alkylated units via sequential 1,6/1,4

copper-catalyzed asymmetric conjugate additions.

linear dienic Michael acceptors (Figure 2).^[12]Advan-

tageously, the resulting enantioenriched 1,6-adduct

can be isomerized to a new electron-deficient a,b-un-

saturated pattern, which can undergo subsequent 1,4-

conjugate addition. This strategy, developed by Ferin-

ga, Minnaard and co-workers^[13]and by our group,^[14]

represents an efficient and straightforward route to

Figure 1. Selected natural products featuring poly-deoxypro-

pionate subunits.

Me₂Zn^[11]). Important breakthroughs have recently the enantioenriched 1,3-alkylated subunit. Additional-

emerged through the enantioselective 1,6-addition to ly, iterative 1,4 ACA or 1,6/1,4 ACA processes lead-

Figure 3. a) Copper-catalyzed enantioselective conjugate addition of dimethylzinc to unsaturated acyl-N-methyl-imidazoles

and subsequent post-functionalization. b) New targeted objectives and related synthetic applications.

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ing to poly-deoxypropionate moieties were also stud-

ied.^[15]Such methodologies were successfully imple-

mented in formal or total syntheses of complex mole-

cules, involving Michael acceptors bearing ester^[16]or

thioester^[13]electron-withdrawing groups (EWG).

Nonetheless, examples of such strategies are scarce

and there is still a great interest in exploring the reac-

tivity of new EWG as versatile synthetic platforms.

In this context, we have recently described an un-

precedented and efficient copper-catalyzed enantiose-

lective 1,4-addition of dimethylzinc reagent to various

unsaturated 2-acyl-N-methylimidazoles 1.^[17]By using

a chiral hydroxyalkyl N-heterocyclic carbene (NHC)

ligand L1,^[18]expected 1,4-adducts were exclusively

formed in good yields and excellent enantio-induc-

tions (typically 87–95% ee), even in the case of ex-

tended unsaturated substrates (Figure 3). Thanks to

the facile post-transformation of the N-acylimidazole

moiety into useful functional groups such as alde-

hydes, ketones, esters,^[19]or amines,^[17]this methodolo-

gy was successfully applied in the synthesis of natural

products. Iterative 1,4-ACA was also achieved leading

to a syn 1,3-deoxypropionate fragment with excellent

diastereoselectivity (94% de).

With the objective to extend the scope of this meth-

odology and enable applications in the synthesis of

more complex molecules, we decided, through this

study, to focus our attention on several points: (i) to

find shorter access to a new potent chiral ligand, (ii)

to explore the influence of different N-acyl functions,

(iii) to scale-up the catalytic transformation, (iv) to

determine the absolute configurations of the newly

Scheme 1. Synthesis of unsaturated analogue ligand L2 and

its evaluation in Cu(OTf)₂-catalyzed ACA of dimethylzinc

to a,b-unsaturated 2-acyl-N-methylimidazole 1a.

created stereogenic centers, (v) to evaluate the regio- Gratifyingly, using a slightly modified procedure con-

and enantioselectivity outcomes in the case of extend- sisting in an imidazole formation/alkylation sequence,

ed conjugated systems (1,4 vs. 1,6 vs. 1,8), in combina- analytically pure L2 was obtained in an overall 32%

tion with DFT calculations and (vi) to set up an itera- yield (Scheme 1). In contrast with the less straightfor-

tive process that would ultimately lead to the forma- ward L1 synthesis, L2 could thus be obtained in

tion of syn/syn and anti/anti 3,5,7 deoxypropionate a single day. We then investigated the catalytic effi-

units.

ciency of this new ligand precursor in the model con-

jugate addition of Me₂Zn onto 1a. Under the standard

conditions described in our initial report [i.e., the use

of Cu(OTf)₂as the copper source with a loading of

2 mol%, and in situ deprotonation of the imidazolium

ligand (3 mol%) using 8 mol% of n-BuLi], the cata-

lytic system based on the new unsaturated ligand L2

enabled the complete conjugate addition of Me₂Zn

Results and Discussion

Investigation of the Catalytic Potency of an

Unsaturated NHC Ligand

In our previous study,^[17]the bidentate ligand L1, com- onto 1a and the isolation of the desired product 2a in

bining the bulky tert-leucinol chelating side arm and high yield (79%) and enantioselectivity (87% ee).

a flexible benzylic fragment, afforded the best results,

Despite this good result, tert-leucinol-based species

providing product 2a in high yield (85%) and excel- L1 still appeared to be the best ligand for this trans-

lent ee (95%) (Scheme 1). Nevertheless, and despite formation, as the desired adduct 2a was obtained with

its high potency as a chiral ligand, this imidazolinium 95% ee. The difference in selectivity between these

salt may suffer from its demanding 4-steps synthesis. analogous catalytic systems could be explained by the

We have recently developed a highly practical multi- higher steric pressure usually associated with saturat-

component procedure leading to unsymmetrical imi- ed NHCs in comparison to their unsaturated counter-

dazolium salts,^[20]which we decided to implement to parts,^[21]enhancing the enantioselectivity of this trans-

produce L2 (i.e., the unsaturated analogue of L1). formation. Despite the good performance displayed

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by the easily accessed ligand precursor L2, the contin-

uation of this study was carried out using the most

potent imidazolinium L1.

Variation of the Imidazole Moiety in the Michael

Acceptor

In order to gain a better understanding of the param-

eters governing the outcomes of this highly valuable

transformation, we decided to survey a variety of Mi-

chael acceptors bearing modified acylimidazole moi-

eties. Using our typical synthetic route from commer-

cially available trans-decenal, consisting in the addi-

tion of various deprotonated heteroaryl reagents fol-

lowed by an oxidation step, new substrates 1b–1e, fea-

turing various heteroaryl moieties, could be readily

produced in moderate to good isolated yields

(Scheme 2). It should also be noted that contrary to

the procedure used for the synthesis of 1a, com-

pounds 1b–1e have been synthesized without purifica-

tion of the sensitive alcohol intermediates 3.

Under the standard conditions, no significant

change in reactivity and selectivity was observed after

modification of the N-substitution of the imidazole

core (1a–1c), which demonstrated that the nature of

the acylimidazole does not affect the efficiency of the

ACA (Scheme 3). On the other hand, replacement of

the acylimidazole fragment by a different heterocycle

such as N-methylbenzimidazole (1d) or 2-pyridine

(1e) resulted in a slight decrease of the reaction yield

(74–70%) and selectivity (86% ee). Overall, the ACA

Scheme 3. Effect of the acyl-heteroaryl moiety on the

copper-catalyzed conjugate addition of dimethylzinc cata-

lyzed by L1/Cu(OTf)₂.

of Me₂Zn onto such mono-unsaturated substrates

proved to be highly tolerant with regard to the nature

of the heterocycle, therefore broadening the applica-

bility of this methodology in synthesis.

Benchmark Reaction Scale-Up

To further validate this protocol for its implementa-

tion in total synthesis strategies, we decided to at-

tempt our model reaction with lower catalyst loadings

on the one hand, and in a larger scale on the other

hand. Results are combined in Table 1.

At a 0.5 mmol scale, the catalyst loading was gradu-

ally reduced from 2 to 0.1 mol%. While excellent re-

action rate (99% conversion in 3 h) and enantioselec-

tivity (93% ee) could be maintained with 1 mol% of

copper (compare Table 1, entries 1 and 2), a further

ten-fold decrease of catalyst loading dramatically im-

pacted both selectivity (79% ee) and reaction rate

(99% conversion in 16 h). On a larger scale, with

1 and 5 mmoles (Table 1, entries 4–6), excellent isolat-

ed yields have been obtained with slightly diminished

enantioselectivities (91% vs. 95%). These new results

further prove the applicability and robustness of this

Scheme 2. Synthesis of a,b-unsaturated 2-acyl-N-heteroaryl

substrates 1a–e.

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Table 1. Effect of the catalyst loading and the scale for

copper-catalyzed ACA of Me₂Zn to a,b-unsaturated 2-acyl-

N-methylimidazole 1a.

Entry Scale

(mmol)

Loading

(mol%)

Time Conversion/

[h]

ee^[c]

Yield [%]^[a,b]

1

2

3

4

5

6

0.5

2

1

0.1

2

3

16

2

99/85

99/89

99/91

99/85

99/92

99/89

95

93

79

91

89

0.5

1

5

1

2

Scheme 4. Post-functionalization of enantioenriched adducts

2 onto corresponding aldehydes 4 enabling the determina-

tion of absolute configurations of newly created stereogenic

centers.

[a]

[b]

[c]

1

Determined by H NMR spectroscopy.

Isolated yield.

Enantiomeric excesses were determined by HPLC on

a chiral stationary phase (see the Supporting Information

for details).

termination of the (R) absolute configuration of 4a,^[23]

whereas 4f^[24]and 4g^[25]are (S) compounds; which in

methodology, as it could be performed on a larger turn gives access undoubtedly to the absolute configu-

scale as well as with a slightly lower catalyst loading ration of their precursors, namely 2a, 2f and 2g.

without having a significant negative impact on the

reaction yield and selectivity.

To illustrate further the usefulness of our ACA/

post-functionalization sequence in the synthesis of

molecules of interest, we decided to conduct the syn-

thesis of (+)-(S)-3-(3-isopropylphenyl)butanal 4h,

a highly desirable synthetic fragrance commercialized

by Givaudan in the racemic form as Florhydral^ꢃ

(Scheme 5).^[26]Based on the determination of the ab-

Aldehyde Formation for Absolute Configuration

Determination and Florhydral^ꢀSynthesis

As previously mentioned, the acylimidazole moiety is solute configuration of the previously produced alde-

a highly attractive synthetic platform, since it can be hydes, we expected to obtain 4h with the correct ste-

readily converted into

a

variety of functional reochemistry.^[27]Starting from the commercially avail-

groups.^[19]For instance, compound 1a can be easily able 3-bromobenzaldehyde, the Negishi coupling cata-

converted into the aldehyde 4a in 85% overall yield lyzed by Pd-PEPPSI-IPent complex^[28]followed by

following a 3-step procedure consisting of reduction the Horner–Wadsworth–Emmons reaction provided

to the corresponding alcohol with NaBH₄, followed the unsaturated derivative 5h in a 64% yield over two

by N-methylation of the imidazole ring and elimina- steps. Subsequent reaction with the deprotonated N-

tion under basic in the presence of glycine methylimidazole afforded the expected unsaturated

(Scheme 4).^[19a]The use of glycine proved to be essen- acylimidazole 1h in 86% yield. Cu/L1-catalyzed ACA

tial to prevent extensive formation of cross-aldol of dimethylzinc onto the latter compound yielded at

products.^[22]Such compounds are valuable targets as room temperature the corresponding 1,4-product 2h

a number of enantiomeric enriched aldehydes are re- in excellent yield and enantioselectivity (91% and

ported in the literature, therefore enabling the deter- 93%, respectively). Interestingly, when the addition

mination of the absolute configuration of the chiral was performed at 08C, the enantioselectivity was

centers generated in the ACA reaction. In addition to slightly increased to 95%. Finally, the post-functional-

compound 4a, aldehydes 4f and 4g were produced in ization of the acylimidazole moiety afforded 4h in an

a similar manner from the corresponding acylimida- overall 44% yield over 7 steps. A polarimetry mea-

zoles, (Scheme 4). Specific rotations of the latter surement confirmed that the (+)-(S) enantiomer of

products were determined by polarimetry measure- Florhydral^ꢃwas obtained.

ments and all three compounds proved to be dextro-

rotary. Comparison with literature values allowed de-

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Scheme 5. Application of the ACA/post-functionalization sequence involving a,b-unsaturated 2-acyl-N-methylimidazole 1h

to the synthesis of (+)-(S)-Florhydral^ꢃ.

Extension of the 1,4-ACA to Polyunsaturated

Systems

of Me₂Zn to dienic acylimidazole substrate 1i oc-

curred with very high 1,4-selectivity. To confirm this

trend, extended Michael acceptors 1j–m were synthe-

Controlling the regioselectivity of copper-catalyzed sized in order to be tested under the optimized cata-

ACA reactions on extended conjugated systems while lytic conditions (Scheme 6). Various substrates were

maintaining high enantioselectivities is a highly chal- quickly accessed in low to good yields following

lenging issue, which proved to be dependent upon the a two-steps route consisting in the formation of Wein-

nature of the electrophile and nucleophile as well as reb amides via a Horner–Wadsworth–Emmons reac-

the catalytic system.^[12a]In the initial screen, the ACA tion followed by the insertion of the N-methylimida-

zole moiety.

These novel Michael acceptors were tested in the

ACA of Me₂Zn using a Cu(OTf)₂/L1. The results are

combined in Scheme 7.

Similarly to what had been observed with mono-un-

saturated substrates, a 2 mol% catalyst loading with

regard to Cu(OTf)₂proved sufficient to achieve

a total conversion of aliphatic substrates (2i, 2j and

2n), whilst aromatic Michael acceptors 2k–2m re-

quired a copper charge of 4 mol%. Gratifyingly, 1,4-

addition products were consistently obtained with ex-

cellent regioselectivities (>96:4) and enantioselectivi-

ties (86 to 95% ee), demonstrating the generality of

this unusual but nonetheless highly attractive reactivi-

ty.^[29]The unsaturated chiral acylimidazoles 2i–2n

indeed constitute versatile synthetic platforms, as

chemical modification could be envisioned by trans-

formation of the imidazole moiety as well as the unsa-

À

turated C C bond.

DFT Studies – Mechanistic Origin of the 1,4-

Regioselectivity of the ACA

In light of the remarkable 1,4-regioselectivity reached

with our L1/Cu(OTf)₂catalytic system, we decided to

investigate, through DFT calculation, the C C bond

Scheme 6. Synthesis of unsaturated di- and trienic 2-acyl-N-

methylimidazole subtrates 1i–n.

À

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adduct where the reactant is bound to both copper

and zinc. Coordination to Zn takes place at the car-

bonyl group and plays the role of an electrophilic acti-

vation. Coordination to copper can take place on

either of the two C=C bond, forming a p-complex

À

(I₁). Subsequent formation of the C C bond can take

place at the position 6 (I_1-6) or at the position 4 (I_1-4).

The energy profiles for these two reaction pathways,

in the case of S1 are given in the Scheme 8b, using I_1-4

as a reference following the previous studies.^[31]This

profile clearly suggests that the most favorable path-

way is the 1,4 conjugate addition from both thermo-

dynamic (as the enolate product P_1-4is more stable

than P_1-6by 4.4 kcalmol^À1) and kinetic (as TS_1-4is

lower than TS_1-6by more than 7 kcalmol^À1) points of

view. This result is different from the previous theo-

retical studies with a cuprate aggregate model, since

the authors propose that the addition takes place at

the terminal alkene terminal (C-5=C-6) of penta-2,4-

dienal because of an accessible reductive elimination

with very low activation energy.^[32]We thus decided to

compare the conjugate addition involving S1 to its an-

alogue S2, featuring an aromatic ketone moiety. In

this case, the opposite feature is obtained

(Scheme 8c). The 1,4 adduct (I_2-4) is less stable than

I_2-6by 1.7 kcalmol^À1. Moreover, TS_2-4is higher than

TS_2-6by 4.4 kcalmol^À1(since they are respectively

20.5 and 16.1 kcalmol^À1above the 1,4 adduct). Finally,

product P_2-4is disfavored compared to P_2-6by 7.6 kcal

mol^À1(since they are respectively À21.4 and

À29.0 kcalmol^À1above the 1,4 adduct). Understand-

ing of the reverse preference in the case of N-methyli-

midazole can be partially answered by looking at

TS_1-4. The lone pair of the nitrogen in the N-methyli-

midazole moiety is pointing towards the Cu center

À

Scheme 7. Substrate scope for the 1,4-regioselective ACA of

dimethylzinc to poly-unsaturated 2-acyl-N-methylimidazoles

1i–n catalyzed by L1/Cu(OTf)₂.

and is associated with a Cu N short distance of

2.553 ꢄ. The second order perturbation energy by

NBO analysis indicates two stabilizing contributions

(8.87 and 15.57 kcalmol^À1) from donor-acceptor inter-

formation step in the conjugate addition of dimethyl- action between the lone pair of the N and the Cu

À

zinc to a,b,g,d-unsaturated 2-acyl-N-methylimidazole center (p orbital). The Cu N interaction can thus be

substrates. As depicted in Scheme 8, a simplified S1 described as a donation of electronic density from the

substrate was chosen as a model and compared to 1- lone pair of the nitrogen to the Cu orbital. We can

phenylpentadienone S2 to properly evaluate the thus propose that this interaction could facilitate the

effect of the imidazole group on the regioselectivity methyl migration from Cu to the carbon of the unsa-

(see computational details in the Supporting Informa- turated bond associated with a decrease of the activa-

tion). Furthermore, a model complex C involving tion barrier.

a simplified NHC scaffold was used as no electronic

effect is expected from the CH₂Mes or t-Bu side

chains and since the enantioselectivity will not be dis- Iterative Strategies for the Synthesis of

cussed.

Following a previously proposed mechanism by Na-

Deoxypropionate Moieties

kamura and co-workers,^[30]the NHC ligand plays the Having validated the methodology enabling access to

role of a bridge between the two metal centers, since aldehydes from enantioenriched acylimidazoles

Cu is coordinated to the carbene carbon and Zn(CH₃) (Scheme 4), and verified the generality of the 1,4-re-

interacts with the alkoxide arm of the NHC model. gioselectivity of the ACA reaction, iterative processes

The reaction goes through the formation of an initial to access deoxypropionate moieties were then envi-

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Scheme 8. DFT calculation concerning the regioselectivity of the copper-catalyzed addition of dimethylzinc to a,b,g,d-unsa-

À

turated 2-acyl-N-methylimidazoles. a) The studied model transformation. b) Gibbs energy profile of the C C bond forma-

À1

À

tion step to S1 relative to the 1,4-adduct I_1-4(Gibbs rnergy in kcalmol ). c) Gibbs energy profile of the C C bond formation

step to S2 relative to the 1,4-adduct I_2-4(Gibbs energy in kcalmol^À1).

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Scheme 8. (Continued).

sioned. The strategy for the synthesis of such motifs trated in Figure 4, the 4 stereoisomers of 2o could be

consists in performing a Horner–Wadsworth–Emmons synthesized and efficiently separated by chiral HPLC

homologation on chiral aldehydes previously obtained (see the Supporting Information for full details). Con-

by 1,4-ACA, followed by the addition of deprotonat- verting (R)-1o using catalytic systems based on L1

ed N-methylimidazole. This approach would lead to and (ent)- L1, both syn and anti diastereoisomers 3-

a new Michael acceptor, which could then undergo an (R),5-(R)-2o and 3-(S),5-(R)-2o were obtained in high

additional ACA of Me₂Zn and afford the desired de- yields, excellent diastereo- and enantioselectivities

oxypropionate moiety. In order to validate the feasi- (85%, 98:2 dr and 84%, 96:4 dr, respectively). Nota-

bility of such a methodology, citronellal was selected bly, no significant mismatch effect could be observed,

as a model compound, and both enantiomers were which is in sharp contrast with previously described

readily transformed into the corresponding unsaturat- related reactions on citronellal-derived substrates,^[33]

ed acylimidazoles (R)-1o and (S)-1o in 85% and 81% further illustrating the efficiency of the catalytic

yields respectively (Scheme 9).

system. Similar behavior was also observed with the

As illustrated in Scheme 10, these new substrates (S)-citronellal-based substrate (S)-1o, which was con-

[(R)-1o and (S)-1o] were submitted to the typical cat- verted to the enantioenriched samples of the two re-

alytic conditions in both the presence of ligand L1 maining diastereoisomers 3-(R),5-(S)-2o (86%, 95:5

and its enantiomer (ent)- L1, in order to selectively dr) and 3-(S),5-(S)-2o (86%, 97:3 dr).

obtain all four possible configurations of the target

molecule 2o.

The ACA of Me₂Zn to compounds 1o in the pres-

ence of ligand L1 consistently afforded (R) configura-

Chiral HPLC analyses were undertaken to access tions, according to those assessed in Scheme 4, whilst

the stereoisomeric purities of the four different iso- (S) centers were produced with ligand (ent)- L1, ena-

mers resulting from these transformations. As illus- bling the full control of the stereochemistry of the de-

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oxypropionate thus produced. It should also be noted

that these syn and anti 1,3 deoxypropionate units do

not follow Breitꢅs rule.^[34]According to this empirical

1

rule, via the H NMR diastereotopic signals of the

geminal methylene protons of a 1,3,n-methyl-substi-

tuted carbon chain, the relative configuration can be

assigned as follows: for anti derivatives: Dd=0.00–

0.1 ppm and for syn derivatives Dd>0.4 ppm. In our

case (see the Supporting Information), both syn and

anti derivatives have very similar Dd values, around

0.14 ppm.

From compounds 2o, the introduction of a third

methyl unit was next considered. The syn 3-(R),5-(R)-

2o derivative was converted into aldehyde syn 3-

(R),5-(R)-4o in 83% yield and subsequently trans-

formed into unsaturated acylimidazole 3-(R),5-(R)-1p

(Scheme 11). The introduction of the third methyl

unit was then accomplished using the previously de-

veloped conditions leading to compound 3-(R),5-

(R),7-(R)-2p in 77% yield and excellent diastereose-

lectivity (>95:5 dr).

Similarly, the anti,anti 3-(S),5-(R),7-(S)-2p, was ob-

tained from 3-(R),5-(S)-2o using a similar pathway

with again minimal impact of the mismatched pairs

on yields (68% yield) and diastereoselectivity (>

90:10 dr) (Scheme 12).

Scheme 9. Synthesis of a,b-unsaturated acyl-imidazoles 1o

derived from (R)- and (S)-citronellal.

Scheme 10. Copper-catalyzed conjugate addition of dimethylzinc to enantiopure citronellal-derived acyl-N-methylimidazole

1o catalyzed by L1/Cu(OTf)₂or (ent)-L1/Cu(OTf)₂.

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Figure 4. Chiral HPLC of the four isomers of 2o adduct.

Conclusions

formed stereogenic centers, allowing us to consider

the enantioselective synthesis of a highly desirable

Through this study, we have successfully extended the fragrance such as the (+)-(S)-Florhydral^ꢃ, which was

scope of the enantioselective copper/hydroxyal- reached with up to 95% ee and 44% overall yield (7

kylNHC L1-catalyzed conjugate addition of dimethyl- steps). Lastly but not the least, taking the advantage

zinc to various (poly)unsaturated acyl-N-methylimida- of the efficient post-derivatization of the acyl-N-meth-

zoles with excellent 1,4-selectivities and relatively ylimidazole into aldehydes, powerful iterative process-

good ees. Interestingly, DFT calculations revealed es were described by involving both enantiomers of

a significant participation of the N-imidazole hetero- the hydroxyalkyl-NHC ligand L1. Therefore, the syn-

cycle towards the 1,4-regioselectivity when extended theses of 3,5,7 all-syn or anti-anti stereodiads were ac-

substrates are involved. Nevertheless, structural modi- complished in good yields and high diastereoselectivi-

fications of both the acyl function and chiral NHC ties (up to >95:5). We believe that this versatile

ligand did not allow for an improvement of the level methodology could pave the way to the total synthesis

of the enantioinduction. Furthermore, we have clearly of more complex molecules of interest.

identified the absolute configuration of the new

Scheme 11. Synthesis of all-syn 3-(R),5-(R),7-(R) acyl-N-methylimidazole 2p.

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Scheme 12. Synthesis of anti,anti 3-(S),5-(R),7-(S) acyl-N-methylimidazole 2p.

ADP 440 Polarimeter or a Perkin–Elmer^ꢃ341 Polarimeter

Experimental Section

with a sodium lamp at 589 nm. Low resolution mass spectra

were recorded on a Waters QTof-I spectrometer using elec-

trospray ionization. High resolution mass spectra were ob-

tained using the mass spectrometers operated by the Labo-

ratoire de Mesures Physiques of the University of Montpel-

lier. THF was dried by distillation over sodium and benzo-

phenone under argon.

General Considerations

Unless otherwise specified, all commercial products and re-

agents were used as purchased, without further purification.

Substrates 1a and 1i were prepared according to our previ-

ous study.^[17]Reactions were carried out in round-bottom

flasks and Schlenk tubes equipped with a magnetic stirring

bar under an argon atmosphere. Analytical thin-layer chro-

matography (TLC) of all reactions was performed on silica

gel 60 F254 TLC plates. Visualization of the developed chro-

matogram was performed by UV absorbance (254 nm) and/

or using potassium permanganate. Flash chromatography

was carried out on silica gel 60 ꢄ (35–70 nm). FT-IR spectra

were recorded with a Perkin–Elmer Spectrum 1000 and

Thermo scientific iD7 ATR spectrometer; absorptions are

given in wave numbers (cm^À1). ¹H (400 MHz), ¹³C

(100 MHz), ¹⁹F (376 MHz) and ³¹P (162 MHz) NMR spectra

were recorded with a Bruker Ultra Shield 400 Plus and

General Procedure A: Addition of NMI to

Aldehydes/Oxidation Sequence

In

a

flame-dried round-bottom flask, n-butyllithium

(11.0 mmol, 1.10 equiv.) was added dropwise at À788C to

a solution of heteroarene (10.0 mmol, 1.00 equiv.) in 20 mL

of dry THF. The resulting solution was stirred 10 min at

À788C then was allowed to warm up to room temperature

and stirred for additional 10 min. The reaction was then

cooled to À788C before the addition of the aldehyde

(11.0 mmol, 1.10 equiv.). The mixture was stirred 1 hour at

À788C then water (10 mL) was added to quench the reac-

tion. The aqueous phase was separated and the organic

phase was further washed with a saturated aqueous solution

of NaHCO₃and brine. The organic layer was dried over

magnesium sulfate (MgSO₄) and concentrated under

vacuum. The resulting oil was transferred to a flame-dried

round-bottom flask and dissolved in THF (c=0.1M). The

solution was cooled down to 08C, manganese(IV) oxide

(10.0 equiv.) was added in one portion and the mixture was

stirred for up to 2 h at this temperature. After reaction com-

pletion (monitored by TLC), the mixture was allowed to

warm to room temperature, filtered through a celite^ꢃpad,

washed with ethyl acetate and evaporated under vacuum.

Purification was performed by column chromatography to

afford the desired compound.

1

Bruker ARX400. H and ¹³C chemical shifts are reported in

parts per million with the solvent resonance as the internal

standard (CDCl₃, ¹H: d=7.26 ppm, ¹³C: d=77.16 ppm;

CD₂Cl₂, ¹H: d=5.31, ¹³C: d=53.8 ppm; CD₃OD, ¹H: d=

3.31, ¹³C: d=49.0 ppm). Splitting patterns are designated as

s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet;

sept, septuplet; m, multiplet; br, broad and combinations

thereof. All coupling constants (J values) are reported in

Hertz (Hz). Data are reported as follows: chemical shift (d

in ppm), multiplicity, coupling constants (Hz), integration

and attribution. Enantiomeric and diastereoisomeric excess-

es were measured on a Shimadzu^ꢃLC 20 A HPLC with

a UV/visible detector at 254 nm or any wavelength specified

and an enantiomeric on an Alliance e2695 Watersꢃ HPLC

with a UV/visible detector 2489 Watersꢃ at 254 nm. Optical

rotations were measured with a Bellingham + Stanley^ꢃ

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and concentrated under vacuum. The residue was purified

by column chromatography to afford the title compound.

Notably, when multiple parallel reactions were conducted,

a stock solution of the catalyst could be prepared and used

without loss of catalytic efficiency. In that case, Cu(OTf)₂

and the NHC precursor were dissolved in THF in a flame-

dried Schlenk flask under argon and stirred for 10 min

([Cu(OTf)₂]=2 to 4.10^À2M for a loading of 2 to 4 mol%, re-

spectively). A titrated solution of n-butyllithium was added

dropwise and the mixture was stirred 10 min [Cu(OTf)₂/

NHC.HPF₆/n-BuLi=1/1.5/4]. Portions of this stock solution

were then distributed between several flame-dried Schlenk

flasks under argon prior to the addition of Me₂Zn. The pro-

cedure is then continued similarly to the procedure de-

scribed above.

General Procedure B: Horner–Wadsworth–Emmons

Homologation of Aldehydes

In a flame-dried round-bottom flask, diethyl 2-[methoxy-

ACHTUNGTRENNUNG(methyl)amino]-2-oxoethylphosphonate (2.87 g, 12.0 mmol,

1.20 equiv.) was dissolved in THF (25 mL) and sodium hy-

dride (powder, 95%, 288 mg, 12.0 mmol, 1.20 equiv) was

added portionwise at room temperature until bubbling has

stopped. The mixture was then cooled down to À788C

before the addition of the aldehyde (10.0 mmol, 1 equiv.)

dissolved in THF (5.8 mL). The reaction medium was stirred

at À788C for 1 hour, then allowed to warm up to room tem-

perature and stirred overnight (³¹P NMR monitoring).

Water was added, the layers were separated and the organic

layer was washed with a saturated aqueous solution of

NaHCO₃, brine, dried over magnesium sulfate and concen-

trated under vacuum. The residue was purified by column

chromatography to afford the desired Weinreb amide.

General Procedure E: Transformation of the Chiral

Acylimidazole into Aldehyde

In a round-bottom flask, sodium borohydride (2.50 equiv.)

was added portionwise to a solution of the substrate

(1.00 equiv.) in freshly distilled methanol (c=0.125M). The

reaction was stirred at room temperature for 2 h and its

completion was checked by TLC. Water was then added and

the mixture was extracted three times with ethyl acetate.

The organic layers were combined, washed with brine, dried

over magnesium sulfate, filtered and concentrated under

vacuum. The intermediate thus obtained was dissolved with

ethyl acetate (c=0.05M) and treated with methyl iodide

(7.00 equiv,). The mixture was heated at 608C for 16 h,

cooled down to room temperature and concentrated to dry-

ness. The crude residue was taken up in toluene (c=

0.17M). Then, glycine (4.00 equiv.) and 2M NaOH solution

(9.00 equiv.) were added and the mixture was heated at

808C for 5 h. At 808C, 1M HCl solution (9.00 equiv.) was

added and the mixture was stirred until the observation of

a clear aqueous phase. Then, the mixture was cooled down

to room temperature and the mixture was extracted with

ethyl acetate. The aqueous layer was extracted two more

times with ethyl acetate. The organic layers were combined,

washed with an aqueous solution of 1M HCl, brine, dried

over magnesium sulfate, filtered and concentrated under

vacuum. The residue was purified by column chromatogra-

phy to afford the title compound

General Procedure C: Addition of NMI to Weinreb

Amide

In

a

flame-dried round-bottom flask, n-butyllithium

(1.10 equiv.) was added dropwise at À788C to a solution of

distilled 1-methyl-1H-imidazole (1.10 equiv.) in THF (c=

0.33M). The resulting mixture was stirred 20 min at À788C

then was allowed to warm up to room temperature and

stirred for additional 10 min. The reaction was cooled down

to À788C before the addition of the Weinreb amide

(1.00 equiv.) in THF (c=1M). The mixture was stirred

30 min at À788C then at room temperature until completion

(TLC monitoring). The reaction was quenched with a satu-

rated NH₄Cl aqueous solution. Ethyl acetate was added and

the organic phase was separated and further washed with

a saturated aqueous solution of NaHCO₃and brine. The or-

ganic layer was dried over magnesium sulfate (MgSO₄) and

evaporated. Purification was performed by column chroma-

tography or recrystallization afforded the desired com-

pound.

General Procedure D: Copper-Catalyzed ACA of

Me₂Zn on a Typical 0.5-mmol Scale

In a flame-dried Schlenk flask, Cu(OTf)₂(0.01–0.02 mmol,

2–4 mol%) and the NHC ligand precursor (0.015–

0.03 mmol, 3–6 mol%) were dissolved in freshly distilled

THF (0.5 mL). The mixture was stirred 10 min at room tem-

Unsaturated NHC Precursor L2

The reaction was performed in an open vessel under air at-

mosphere. In a round-bottomed flask were placed ammoni-

um acetate (175 mg, 2.26 mmol, 1.0 equiv.), (S)-tert-leucinol

(265 mg, 2.26 mmol, 1.0 equiv.), acetic acid (0.66 mL,

11.5 mmol, 5 equiv.) and distilled H₂O (0.3 mL) then the

mixture was heated at 708C until a homogeneous solution is

obtained (mixture A). In another round-bottomed flask

were placed glyoxal (0.26 mL, 2.26 mmol, 1.0 equiv., 40 wt%

in aqueous solution), formaldehyde (0.17 mL, 2.26 mmol,

1.0 equiv., 37 wt% in aqueous solution) and acetic acid

(0.66 mL, 11.5 mmol, 5 equiv.) then the mixture was heated

at 708C for 10 min (mixture B). At 708C mixture B was

added to mixture A and the resulting mixture was stirred at

708C for 1 h, during which it turned to deep orange.

perature.

A titrated solution of n-butyllithium (0.04–

0.08 mmol, 8–16 mol%) was added dropwise and the mix-

ture was stirred 10 min, during which it turned to brown-

green (Cu/NHC/n-BuLi ratio=1/1.5/4). Dimethylzinc

(3.00 equiv.) was then added dropwise to the solution, which

gradually turned yellow and was stirred at room tempera-

ture for 10 min. The substrate (0.5 mmol, 1.0 equiv.) in THF

(0.5 mL) was finally added dropwise. The reaction was

stirred at the desired temperature and monitored by TLC

until completion then quenched with 3 mL of 1M HCl.

Ethyl acetate was added and layers were separated. 6 mL of

a saturated aqueous solution of NaHCO₃were added to the

aqueous layer and the aqueous layer was extracted with

ethyl acetate (2ꢆ10 mL). The combined organic layers were

washed with brine (10 mL), dried over magnesium sulfate

The reaction mixture was then evaporated to dryness

under high vacuum and the resulting oil was dissolved in

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10 mL THF, the resulting suspension was then filtered on

a plug of celite^ꢃand rinsed with 10 mL THF. 2-(Bromo-

general procedure A from trans-decenal (1.08 mL) and 1-

phenylimidazole (632 mL, 5 mmol); yield: 342.1 mg (23%).

¹H NMR (400 MHz, CDCl₃): d=7.50–7.42 (m, 3H, 3 CH_ar),

7.39 (m, 1H, CH_imid), 7.33–7.27 (m, 3H, CH=CHCO+2

CH_ar), 7.19 (s, 1H, CH_imid), 7.11–7.01 (m, 1H, CH=CHCO),

2.33–2.24 (m, 2H, CH₂CH=CH), 1.54–1.44 (m, 2H,

CH₂CH₂CH=CH), 1.36–1.16 [m, 8H, CH₃(CH₂)₄], 0.87 [t,

J=6.8 Hz, 3H, CH₃(CH₂)₄]; ¹³C NMR (100 MHz, CDCl₃):

d=179.4 (CO), 149.6 (CH=CHCO), 143.8 (C_IV,imid), 138.6

(C_IV,ar), 129.6 (CH=CHCO), 128.9 (2 CH_ortho), 128.6 (CH_para),

127.0 (CH_imid), 126.0 (CH_imid), 125.9 (2 CH_meta), 32.7 (CH₂),

31.7 (CH₂), 29.2 (CH₂), 29.0 (CH₂), 28.1 (CH₂), 22.6 (CH₂),

14.1 (CH₃); IR: n=2926.0, 2854.6, 1673.0, 1623.0,

methyl)-1,3,5-trimethylbenzene

(573 mg,

2.70 mmol,

1.2 equiv.) was added to the filtrate and the solution was

heated to reflux for 1.5 h, during which a white precipitate

appeared. The reaction was left to cool down to room tem-

perature and was filtered on a sintered glass filter, the white

solid was washed with 10 mL Et₂O, dried under high

vacuum and dissolved in 10 mL CH₂Cl₂. To the CH₂Cl₂

phase was added 10 mL distilled H₂O and KPF₆(497 mg,

2.70 mmol, 1.2 equiv.), the resulting biphasic mixture is

stirred vigorously for 1 h, after which the phases are separat-

ed. The aqueous layer was extracted with CH₂Cl₂(10 mL),

the organic phases were combined, dried (MgSO₄), filtered

and evaporated to dryness, affording analytically pure 3-

[(S)-2N-4,4-dimethylpropanol]-1-(2,4,6-trimethylbenzyl) imi-

dazolium hexafluorophosphate (L2) as a white powder;

1405.0 cm^À1

;

MS (ESI⁺): m/z=297.20 (100, [M+H]⁺);

HRMS (ESI⁺): m/z=297.1966, calcd. for C₁₉H₂₅N₂O [M+

H]⁺: 297.1967 (0.3 ppm); R_f=0.60 (pentane/Et₂O 70:30,

KMnO₄).

(E)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)dec-2-en-1-one

(1d): The title compound was isolated by column chroma-

tography (eluent: pentane/Et₂O 70:30) as a light yellow oil

1

yield: 323 mg (32%). H NMR (400 MHz, CD₂Cl₂): d=8.41

(s, 1H, NCHN), 7.33 (t, J_H,H=1.9 Hz, 1H, NCHCHN), 7.01

(t, J_H,H=1.9 Hz, 1H, NCHCHN), 6.99 (s, 2H, 2 CH_ar), 5.41

(d,

J

_H,H=2.4 Hz, 2H, ArCH₂N), 4.22–4.10 (m, 2H,

following the general procedure A from trans-decenal

CHCH₂OH), 4.06–4.01 (m, 1H, CHCH₂OH), 2.31 (s, 3H,

Ar-CH₃) 2.26 (s, 6H, Ar-CH₃), 0.98 (s, 9H, C(CH₃)₃);

¹³C NMR (100 MHz, CD₂Cl₂): d=140.9 (C_IV,Ar), 138.6

(C_IV,Ar, 2C), 135.8 (NCHN), 130.6 (CH_Ar, 2 C), 125.4 (C_IV,Ar),

123.4 (CH_Ar), 121.4 (CH_Ar), 73.2 (CHCH₂OH), 60.3

(CHCH₂OH), 48.5 (ArCH₂N), 34.3 (C(CH₃)₃), 27.1

(C(CH₃)₃), 21.3 (Ar-CH₃), 19.8 (Ar-CH₃, 2H); ³¹P NMR

(162 MHz, CD₂Cl₂): d=144.3 (sept, J_{P, F}=712 Hz); ¹⁹F NMR

(376 MHz, CD₂Cl₂): d=À72.30 (d, J_{P, F}=712 Hz); IR: n=

3593, 3158, 2970, 1707, 1613, 1553, 1470, 1374, 1152, 1055,

(2.02 mL) and 1-methylbenzimidazole (1.32 g, 10 mmol);

yield: 185.4 mg (13%) mp=34–358C;. H NMR (400 MHz,

1

CDCl₃): d=7.90 (dt, J=8.1, 0.9 Hz, 1H, CH_ar), 7.58 (dt, J=

15.6, 1.5 Hz, 1H, CH_ar), 7.48–7.42 (m, 2H, 2 CH_ar), 7.41–

7.34 (m, 1H, CH=CHCO), 7.31–7.20 (m, 1H, CH=CHCO),

4.19 (s, 3H, NCH₃), 2.43–2.20 (m, 2H, CH₂CH=CH), 1.62–

1.48 (m, 2H, CH₂CH₂CH=CH), 1.39–1.22 [m, 8H,

CH₃(CH₂)₄], 0.96–0.83 [m, 3H, CH₃(CH₂)₄]; ¹³C NMR

(100 MHz, CDCl₃): d=183.1 (CO), 150.6 (CH=CHCO),

146.9 [N=C_IVN(CH₃)], 141.7 (C_IVN=C_IVN), 137.0 [N=

C_IVN(CH₃)C_IV], 126.5 (CH=CHCO), 125.8 (CH_ar), 123.6

(CH_ar), 121.8 (CH_ar), 110.4 (CH_ar), 32.8 (CH₂CH=CH), 32.3

(CH₂), 31.7 (NCH₃), 29.3 (CH₂), 29.1 (CH₂), 28.2 (CH₂),

22.6 (CH₂), 14.1 (CH₃); IR: n=2925.6, 2854.6, 1670.6,

1621.1, 1456.3 cm^À1; MS (ESI⁺): m/z=285.20 (100, [M+

H]⁺); HR-MS (ESI⁺): m/z285.1967, calcd. for C₁₈H₂₅N₂O

[M+H]⁺: 285.1967 (0 ppm); R_f=0.55 (pentane/Et₂O 40:60,

KMnO₄).

825 cm^À1

;

HR-MS (ESI⁺): m/z=301.2276, calcd. for

C₁₉H₂₉N₂O [M+H]⁺: 301.22744 (0 ppm); [a]²_D⁰: +7.0 (c=1,

MeOH).

Preparation and Analytical Data of Monounsaturated

Substrates 1b–e

(E)-1-(1-Butyl-1H-imidazol-2-yl)dec-2-en-1-one (1b): The

title compound was isolated by column chromatography

(eluent: pentane/Et₂O 80:20) as a light yellow oil following

the general procedure A from trans-decenal (2.01 mL) and

1-butylimidazole (1.31 mL, 10 mmol); yield: 1.20 g (43%).

¹H NMR (400 MHz, CDCl₃): d=7.43 (d, J=15.6 Hz, 1H,

CH=CHCO), 7.18 (s, 1H, CH_imid), 7.16–7.06 (m, 1H, CH=

CHCO), 7.08 (s, 1H, CH_imid), 4.47–4.39 (m, 2H, NCH₂), 2.30

(dt, J=8.0, 4.1 Hz, 2H, CH₂CH=CH), 1.85–1.71 (m, 2H,

NCH₂), 1.51 (dt, J=14.8, 7.4 Hz, 2H, NCH₂CH₂), 1.42–1.21

[m, 10H, NCH₂CH₂CH₂+CH₃(CH₂)₅], 0.94 [t, J=7.4 Hz,

3H, N(CH₂)₃CH₃], 0.87 [t, J=6.8 Hz, 3H, CH₃(CH₂)₅];

¹³C NMR (100 MHz, CDCl₃): d=180.5 (CO), 148.8 (CH=

CHCO), 143.2 (CHCOC_IV), 129.1 (CH=CHCO), 126.3

(CH_imid), 126.0 (CH_imid), 48.6 (NCH₂), 33.2 (CH₂), 32.7

(CH₂), 31.7 (CH₂), 29.2 (CH₂), 29.1 (CH₂), 28.2 (CH₂), 22.6

(CH₂), 19.7 (CH₂), 14.0 (N(CH₂)₃CH₃), 13.6 (CH₂CH₃); IR:

n=2957.0, 2926.3, 2856.0, 1665.9, 1618.9, 1470.4 cm^À1; MS

(ESI⁺): m/z=277.23 (100, [M+H]⁺); HR-MS (ESI⁺): m/z=

277.2282, calcd. for C₁₇H₂₉N₂O [M+H]⁺: 277.2280

(0.7 ppm); R_f=0.19 (pentane/Et₂O 80:20, KMnO₄).

(E)-1-(Pyridin-2-yl)dec-2-en-1-one (1e): The title com-

pound was isolated by column chromatography (eluent:

pentane/Et₂O 90:10) as a yellow oil following the general

procedure A from trans-decenal (2.75 mL) and 2-bromopyri-

dine (1.31 mL, 13.7 mmol); yield: 917 mg (27%). ¹H NMR

(400 MHz, CDCl₃): d=8.71 (ddd, J=4.8, 1.7, 0.9 Hz, 1H,

CH_ar), 8.12 (dt, J=7.9, 1.0 Hz, 1H, CH_ar), 7.85 (td, J=7.7,

1.7 Hz, 1H, CH_ar), 7.59 (dt, J=15.7, 1.5 Hz, 1H, CH_ar), 7.46

(ddd, J=7.5, 4.8, 1.2 Hz, 1H, CH=CHCO), 7.25 (dt, J=15.7,

7.0 Hz, 1H, CH=CHCO), 2.41–2.29 (m, 2H, CH₂CH=CH),

1.60–1.48 (m, 2H, CH₂CH₂CH=CH), 1.44–1.16 [m, 8H,

CH₃(CH₂)₄], 0.88 [t, J=6.9 Hz, 3H, CH₃(CH₂)₄]; ¹³C NMR

(100 MHz, CDCl₃): d=189.5 (CO), 154.2 (C_IV,ar), 150.6

(CH_ar), 148.7 (CH_ar), 136.9 (CH_ar), 126.7 (CH_imid), 124.3

(CH_ar), 122.9 (CH_imid), 33.0 (CH₂), 31.7 (CH₂), 29.2 (CH₂),

29.1 (CH₂), 28.2 (CH₂), 22.6 (CH₂), 14.1 (CH₃); IR: n=

2925.2, 2854.9, 1677.6, 1621.9, 1329.7 cm^À1; MS (ESI⁺): m/

z=232.17 (81, [M+H]⁺); HR-MS (ESI⁺): m/z=232.1703,

calcd. for C₁₅H₂₂NO [M+H]⁺: 232.1701 (0.9 ppm); R_f=0.25

(pentane/Et₂O 90:10, UV).

(E)-1-(1-Phenyl-1H-imidazol-2-yl)dec-2-en-1-one

(1c):

The title compound was isolated by column chromatography

(eluent: pentane/Et₂O 70:30) as a yellow oil following the

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lowing the general procedure B from the 2-nitrocinnamalde-

hyde (1.62 g); yield: 1.85 g (71%). ¹H NMR (400 MHz,

CDCl₃): d=7.99–7.91 (m, 1H, CH_ar), 7.67 (m, 1H, CH_ar),

7.58 (m, 1H, CH_ar), 7.55–7.30 (m, 3H, 1 CH_ar+ 2 CH_sp2),

6.94–6.86 (m, 1H, CH=CH), 6.66 (d, J=15.2 Hz, 1H,

CH_sp2), 3.72 (s, 3H, NOCH₃), 3.26 (s, 3H, NCH₃); ¹³C NMR

(100 MHz, CDCl₃): d=166.4 (CO), 147.8 (C_IVNO₂), 142.1

(CH_ar), 133.6 (CH_ar), 133.0 (CH_ar), 131.7 (C_IV,ar), 131.5

(CH_ar), 128.8 (CH_sp2), 128.1 (CH_sp2), 124.7 (CH_sp2), 121.5

(CH_sp2), 61.8 (OCH₃), 32.3 (NCH₃); IR: n=2937.3, 1649.2,

1519.36, 1343.1, 997.3 cm^À1; MS (ESI⁺): m/z=263.10 (100,

[M+H]⁺); HR-MS (ESI⁺): m/z=263.1033, calcd. for

C₁₃H₁₅N₂O₄[M+H]⁺: 263.1032 (0.4 ppm); R_f=0.28 (Et₂O,

UV).

Preparation and Analytical Data of Weinreb Amides

5j–n and a,b,g,d-Unsaturated Acylimidazoles 1j–n

(2E,4E)-N-Methoxy-N-methylhexa-2,4-dienamide (5j):^[35]In

a

round-bottom flask, sorbic acid (1.12 g, 10 mmol,

1.00 equiv.) was dissolved in dichloromethane (20 mL) and

1,1-dicarbonylimidazole (CDI, 1.78 g, 11 mmol, 1.10 equiv.)

was added portionwise (quick and strong carbon dioxide for-

mation). The mixture was stirred until the bubbling stopped

before the addition of (N,O)-dimethylhydroxylamine hydro-

chloride salt (1.07 g, 11 mmol, 1.10 equiv.). The resulting

mixture was stirred at room temperature for 16 h. Water

was added and the aqueous layer was extracted with di-

chloromethane. The combined organic layers were washed

with water twice and were concentrated under vacuum. The

title compound was isolated by column chromatography

(eluent: Et₂O) as a yellow oil; yield: 820.2 mg (53%).

¹H NMR (400 MHz, CDCl₃): d=7.30 (dd, J=15.2, 10.8 Hz,

1H, CH=CHCO), 6.36 (d, J=15.2 Hz, 1H, CH=CHCO),

6.30–6.20 (m, 1H, CH=CHCH=CHCO), 6.19–6.08 (m, 1H,

CH=CHCH=CHCO), 3.70 (s, 3H, OCH₃), 3.25 (s, 3H,

NCH₃), 1.85 (d, J=6.4 Hz, 3H, CH₃CH); ¹³C NMR

(100 MHz, CDCl₃): d=167.4 (CO), 143.7 (CH=CHCO),

138.4 (CH=CHCH=CHCO), 130.2 (CH=CHCH=CHCO),

116.6 (CH=CHCO), 61.7 (OCH₃), 32.4 (NCH₃), 18.6

(CH₃CH).

(2E,4E)-N-Methoxy-N-methyl-5-phenylpenta-2,4-diena-

mide (5k):^[36]The title compound was isolated by column

chromatography (eluent: pentane/Et₂O, from 50:50 to

0:100) as a white solid following the general procedure B

from cinnamaldehyde (1.26 mL); yield: 1.93 g (89%).

¹H NMR (400 MHz, CDCl₃): d=7.50 (dd, J=13.8, 8.7 Hz,

1H, CH=CHCO), 7.46 (m, 2H, CH=CHCH=CH), 7.38–7.32

(m, 2H, CH_ortho), 7.32–7.26 (m, 1H, CH_para), 7.00–6.85 (m,

2H, CH_meta), 6.60 (d, J=15.1 Hz, 1H, CH=CHCO), 3.73 (s,

3H, OCH₃), 3.28 (s, 3H, NCH₃); ¹³C NMR (100 MHz,

CDCl₃): d=167.0 (CO), 143.3 (CH_sp2), 139.6 (CH_sp2), 136.2

(C_IV,Ph), 128.7 (CH_sp2), 128.7 (CH_ortho, 2 C), 127.0 (CH_para),

126.8 (CH_meta, 2 C), 119.0 (CH_sp2), 61.7 (OCH₃), 32.4

(NCH₃); R_f=0.5 (Et₂O, UV).

(2E,4E,6E)-N-Methoxy-N-methyldodeca-2,4,6-trienamide

(5n): The title compound was isolated by column chroma-

tography (eluent: pentane/Et₂O 40:60) as a colorless oil fol-

lowing the general procedure B from (2E,4E)-decadienal

1

(1.75 mL); yield: 1.79 g (75%). H NMR (400 MHz, CDCl₃):

d=7.35 (dd, J=15.0, 11.3 Hz, 1H, CH_sp2), 6.53 (dd, J=14.9,

10.7 Hz, 1H, CH_sp2), 6.43 (d, J=15.1 Hz, 1H, CH_sp2), 6.27

(dd, J=14.9, 11.3 Hz, 1H, CH_sp2), 6.13 (dd, J=15.1, 10.7 Hz,

1H, CH_sp2), 5.96–5.86 (m, 1H, CH_sp2), 3.70 (s, 3H, OCH₃),

3.25 (s, 3H, NCH₃), 2.13 (q, J=7.3 Hz, 2H, CH₂CH=CH),

1.41 (dt, J=14.2, 7.2 Hz, 2H, CH₂CH₂CH=CH), 1.37–1.24

(m, 4H, CH₃CH₂CH₂), 0.89 (t, J=6.9 Hz, 3H, CH₃CH₂);

¹³C NMR (100 MHz, CDCl₃): d=167.3 (CO), 143.6 (CH_sp2),

140.6 (CH_sp2), 140.0 (CH_sp2), 129.9 (CH_sp2), 128.3 (CH_sp2),

117.7 (CH_sp2), 61.7 (OCH₃), 32.9 (CH₂CH=CH), 32.4

(NCH₃), 31.3 (CH₂), 28.7 (CH₂), 22.4 (CH₂), 14.0 (CH₃); IR:

n=2957.3, 2931.9, 1859.7, 1658.7, 1380.8, 1000.8 cm^À1; HR-

MS (ESI⁺): m/z=238.1806, calcd. for C₁₄H₂₄N₂O [M+H]⁺:

228.1807 (0.4 ppm); R_f=0.25 (pentane/Et₂O 40:60, UV).

(2E,4E)-1-(1-Methyl-1H-imidazol-2-yl)deca-2,4-dien-1-

one (1j): The title compound (772 mg, 76%) was isolated by

column chromatography (eluent: pentane/Et₂O 60:40) as

a yellow oil following the general procedure C from the cor-

responding intermediate 5j (815 mg). ¹H NMR (400 MHz,

CDCl₃): d 7.48–7.32 (m, 2H, CH_sp2), 7.16 (d, J=0.9 Hz, 1H,

CH_imid), 7.03 (s, 1H, CH_imid), 6.39–6.30 (m, 1H, CH_sp2), 6.30–

6.20 (m, 1H, CH_sp2), 4.05 (s, 3H, NCH₃), 1.89 (d, J=5.7 Hz,

3H, CH₃CH) ppm; ¹³C NMR (100 MHz, CDCl₃): d 181.0

(CO), 143.9 (C_IV,imid), 143.8 (CH_sp2), 140.9 (CH_sp2), 130.7

(CH_sp2), 129.0 (CH_imid), 126.9 (CH_sp2), 124.1 (CH_imid), 36.2

(NCH₃), 18.8 (CH₃CH) ppm; IR (cm^À1): 3098.1, 1657.0,

1627.7, 1593.3, 1408.1, 1019.9, 999.1; MS (ESI+): m/z 177.10

(100, [M+H]⁺); HRMS (ESI+) m/z: Calcd for C₁₀H₁₃N₂O

[M+H]⁺: 177.1028 found 177.1029 (0.6 ppm); R_f=0.38

(pentane/Et₂O 40:60, UV).

(2E,4E)-1-(1-Methyl-1H-imidazol-2-yl)-5-phenylpenta-2,4-

dien-1-one (1k): The title compound was isolated by column

chromatography (eluent: toluene/Et₂O 90:10) as a yellow oil

following the general procedure C from the corresponding

intermediate 5k (1.93 g); yield: 2.01 g (89%). ¹H NMR

(400 MHz, CDCl₃): d=7.60 (dd, J=9.2, 5.5 Hz, 1H, CH_sp2),

7.49 (d, J=7.6 Hz, 2H, CH_sp2), 7.42–7.28 (m, 3H, CH_sp2),

7.19 (s, 1H, CH_imid), 7.10–6.97 (m, 3H, CH_sp2), 4.08 (s, 3H,

NCH₃); ¹³C NMR (100 MHz, CDCl₃): d=180.6 (CO), 144.0

(C_IV,imid), 143.3 (CH_sp2), 141.6 (CH_sp2), 136.2 (C_IV,Ar), 129.2

(CH_imid), 129.1 (CH_sp2), 128.8 (CH_sp2, 2 C), 127.2 (CH_sp2, 2

C), 127.2 (CH_sp2), 127.0 (CH_imid), 126.5 (CH_sp2), 36.2

(NCH₃); IR: n=3025.6, 1650.4, 1579.4, 1402.5, 1286.5,

(2E,4E)-N-Methoxy-5-(4-methoxyphenyl)-N-methylpenta-

2,4-dienamide (5l): The title compound was isolated by re-

crystallization (DCM/pentane) as a white solid following the

general procedure

B

from 4-methoxycinnamaldehyde

(1.62 g); yield: 1.08 g (44%). ¹H NMR (400 MHz, CDCl₃):

d=7.48 (ddd, J=15.1, 8.7, 1.6 Hz, 1H, CH=CHCO), 7.44–

7.38 [m, 2H, C(OCH₃)CH_ar], 6.93–6.81 [m, 4H,

C(OCH₃)CHCH_ar

+ CH=CHCH=CHCO], 6.54 (d, J=

15.0 Hz, 1H, CH=CHCO), 3.82 (s, 3H, C_arOCH₃), 3.73 (s,

3H, NOCH₃), 3.27 (s, 3H, NCH₃); ¹³C NMR (100 MHz,

CDCl₃): d=167.3 (CO), 160.1 (C_IVOMe), 143.7 (CH=

CHCO), 139.4 (CH=CHCH=CHCO), 129.1 (C_IV,ar), 128.4

[C(OCH₃)CH_ar, 2 C], 124.8 (CH=CHCH=CHCO), 117.8

(CH=CHCO), 114.2 [C(OCH₃)CHCH_ar,

2

C], 61.7

(NOCH₃), 55.3 (C_IV,arOCH₃), 32.4 (NCH₃); IR: n=2935.4,

1645.5, 1509.7, 1375.1, 1249.3 cm^À1; MS (ESI⁺): m/z=248.13

(100, [M+H]⁺); HR-MS (ESI⁺): m/z=247.1289 calcd. for

C₁₄H₁₈NO₃[M+H]⁺: 248.1287 (0.8 ppm); mp 75–77; R_f=

0.41 (Et₂O, UV).

(2E,4E)-N-Methoxy-N-methyl-5-(2-nitrophenyl)penta-2,4-

dienamide (5m): The title compound was isolated by

column chromatography (eluent: Et₂O) as a yellow solid fol-

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1016.0, 998.8 cm^À1; MS (ESI⁺): m/z=239.12 (100, [M+H]⁺);

HR-MS (ESI⁺): m/z=239.1185, calcd. for C₁₅H₁₅N₂O [M+

H]⁺: 239.1184 (0.4 ppm); mp 125–1278C; R_f=0.31 (toluene/

Et₂O 90:10, UV).

Preparation and Analytical Data of Catalysis

Products

(R)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)decan-1-one

(2a):^[17]Following the general procedure D with copper

loadings of 0.1–2 mol%, ligands L1 or L2 for the appropri-

ate time, the title compound was isolated by column chro-

matography (eluent: pentane/Et₂O 40:60) as a yellow oil

from the corresponding substrate 1a (0.5–5 mmol), and was

(2E,4E)-5-(4-Methoxyphenyl)-1-(1-methyl-1H-imidazol-2-

yl)penta-2,4-dien-1-one (1l): The title compound was isolat-

ed by column chromatography (eluent: toluene/Et₂O 85:15)

as a yellow solid following the general procedure C from

the corresponding intermediate 5l (1.08 g); yield: 471 mg,

in accordance with our previously reported analytical data;

1

(37%). H NMR (400 MHz, CDCl₃): d=7.66–7.51 (m, 2H,

[17]

.

The ees were determined with a Chiralcel OJ-H column,

CH_sp2), 7.48–7.39 (m, 2H, CH_sp2), 7.18 (d, J=0.9 Hz, 1H,

CH_imid), 7.04 (s, 1H, CH_imid), 7.01–6.87 (m, 4H, CH_sp2), 4.07

(s, 3H, NCH₃), 3.83 (s, 3H, OCH₃); ¹³C NMR (100 MHz,

CDCl₃): d=180.7 (CO), 160.5 (C_IV,OMe), 144.1 (C_IV,imid), 143.9

(CH_sp2), 141.5 (CH_sp2), 129.1 (CH_,imid), 129.1 (C_IV,ar), 128.8

(CH_ar, 2 C), 126.9 (CH_,imid), 125.4 (CH_sp2), 125.1 (CH_sp2),

114.3 (CH_ar, 2 C), 55.3 (OCH₃), 36.3 (NCH₃); IR: n=3099.7,

1651.8, 1571.3, 1411.3, 1260.9, 1022.6 cm^À1; MS (ESI⁺): m/

z=269.13 (100, [M+H]⁺); HR-MS (ESI⁺): m/z=269.1290,

calcd. for C₁₆H₁₇N₂O₂[M+H]⁺: 269.1290 (0 ppm); mp 136–

1388C; R_f=0.18 (toluene/Et₂O 90:10, UV)

(2E,4E)-1-(1-Methyl-1H-imidazol-2-yl)-5-(2-nitrophenyl)-

penta-2,4-dien-1-one (1m): The title compound was isolated

by column chromatography (eluent: chloroform/Et₂O 20:80)

as a yellow solid following the general procedure C from

the corresponding intermediate 5m (1.84 g); yield: 327 mg

(16%). ¹H NMR (400 MHz, CDCl₃): d=7.98 (dd, J=8.2,

1.1 Hz, 1H, CH_sp2), 7.70 (dd, J=7.9, 1.3 Hz, 1H, CH_sp2),

7.68–7.57 (m, 3H, CH_sp2), 7.53–7.42 (m, 2H, CH_sp2), 7.20 (t,

J=2.2 Hz, 1H, CH_imid), 7.07 (s, 1H, CH_imid), 6.99 (dd, J=

15.4, 10.0 Hz, 1H, CH_sp2), 4.08 (s, 3H, NCH₃); ¹³C NMR

(100 MHz, CDCl₃): d=180.3 (CO), 144.1 (C_IV,imid), 143.4

(C_nitro), 142.1 (CH_sp2), 135.4 (CH_sp2), 133.2 (CH_sp2), 131.9

(CH_sp2), 131.8 (C_IV,Ar), 129.4 (CH_sp2), 129.1 (CH_imid), 128.7

(CH_sp2), 128.3 (CH_sp2), 127.3 (CH_imid), 124.9 (CH_sp2), 36.3

(NCH₃); IR: n=1651.7, 1587.5, 1516.2, 1405.1, 1345.7,

1018.3 cm^À1; MS (ESI⁺): m/z=284.10 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=284.1035, calcd. for C₁₅H₁₄N₃O₃[M+H]⁺:

284.1035 (0.4 ppm); mp 86–888C; R_f=0.18 (chloroform/

Et₂O 20:80, UV).

(2E,4E,6E)-1-(1-Methyl-1H-imidazol-2-yl)dodeca-2,4,6-

trien-1-one (1n): The title compound was isolated by recrys-

tallization (DCM/pentane) as a brown solid following the

general procedure C from the corresponding intermediate

5n (1.73 g); yield: 167.1 mg (9%). ¹H NMR (400 MHz,

CDCl₃): d=7.54–7.40 (m, 2H, 2 CH_sp2), 7.17 (s, 1H, CH_imid),

7.04 (s, 1H, CH_imid), 6.65 (dd, J=14.8, 10.7 Hz, 1H, CH_sp2),

6.37 (ddd, J=14.9, 6.9, 3.6 Hz, 1H, CH_sp2), 6.20 (dd, J=15.1,

10.7 Hz, 1H, CH_sp2), 6.04–5.93 (m, 1H, CH_sp2), 4.06 (s, 3H,

NCH₃), 2.15 (q, J=7.0 Hz, 2H, CH₂CH=CH), 1.48–1.36 (m,

2H, CH₂), 1.37–1.23 (m, 4H, CH₂), 0.89 (t, J=6.9 Hz, 3H,

CH₃); ¹³C NMR (100 MHz, CDCl₃): d=180.6 (CO), 144.1

(C_IV,imid), 143.7 (CH_sp2), 142.7 (CH_sp2), 141.2 (CH_sp2), 130.1

(CH_sp2), 129.0 (CH_sp2), 128.8 (CH_sp2), 126.9 (CH_imid), 125.2

(CH_imid), 36.2 (NCH₃), 33.0 (CH₂), 31.4 (CH₂), 28.6 (CH₂),

22.4 (CH₂), 14.0 (CH₃); IR: n=2951.4, 2924.2, 1738.3,

1573.5, 1407.0, 1000.0 cm^À1; MS (ESI⁺): m/z =259.18 (100,

[M+H]⁺); HR-MS (ESI⁺): m/z=259.1812, calcd. for

C₁₆H₂₃N₂O [M+H]⁺: 259.1810 (0.8 ppm); mp 72–738C; R_f=

0.35 (toluene/Et₂O 90:10, UV).

n-hexane/i-PrOH 99.5:0.5, 1 mLmin^À1: major 7.0 min, minor

10.1 min.

(R)-3-Methyl-1-(1-butyl-1H-imidazol-2-yl)decan-1-one

(2b): Following the general procedure D with a copper load-

ing of 2 mol% and L1, for 4 h, the title compound was iso-

lated by column chromatography (eluent: pentane/Et₂O

60:40) as a yellow oil, from the corresponding substrate 1b

(138.1 mg); yield: 129.9 mg (85%, 95% ee). ¹H NMR

(400 MHz, CDCl₃): d=7.16 (d, J=0.9 Hz, 1H, CH_imid), 7.08

(d, J=0.9 Hz, 1H, CH_imid), 4.45–4.37 (m, 2H, NCH₂), 3.10

(dd, J=15.9, 5.9 Hz, 1H, CHCH’CO), 3.01 (dd, J=15.9,

8.0 Hz, 1H, CHCH’CO), 2.25–2.07 (m, 1H, CHCH₃), 1.85–

1.69 (m, 2H, NCH₂CH₂), 1.46–1.17 [m, 14H, CH₃(CH₂)₆+

N(CH₂)₂CH₂], 1.02–0.92 [m, 6H, CHCH₃+ N(CH₂)₃CH₃],

0.90 [t, J=6.9 Hz, 3H, CH₃(CH₂)₅]; ¹³C NMR (100 MHz,

CDCl₃): d=193.1 (CO), 142.9 (C_IV,imid), 128.8 (CH_imid), 125.8

(CH_imid), 48.5 (NCH₂), 46.5 (CH₂CO), 37.0 (CH₂), 33.2

(CH₂), 31.8 (CH₂), 29.8 (CH₂), 29.7 (CHCH₃), 29.3 (CH₂),

27.0 (CH₂), 22.6 (CH₂), 19.9 (CHCH₃), 19.7 (CH₂), 14.1

[N(CH₂)₃CH₃], 13.6 [CH₃(CH₂)₅]; IR: n=2957.3, 2925.7,

2855.4, 1673.7, 1465.3, 1408.2 cm^À1; MS (ESI⁺): m/z=293.26

(100, [M+H]⁺); HR-MS (ESI⁺): m/z= 293.2594 calcd. for

C₁₈H₃₃N₂O [M+H]⁺: 293.2593 (0.3 ppm); chiral HPLC

(Chiralcel IC column, n-hexane/i-PrOH 98:2, 1.0 mLmin^À1):

major 8.2 min, minor 7.2 min; [a]²_D¹: À2.9 (c 1.0M, CHCl₃)=

; R_f=0.48 (pentane/Et₂O 60:40, KMnO₄).

(R)-3-Methyl-1-(1-phenyl-1H-imidazol-2-yl)decan-1-one

(2c): Following the general procedure D with a copper load-

ing of 2 mol% and L1, for 4 h, the title compound was iso-

lated by column chromatography (eluent: pentane/Et₂O

60:40) as a colorless oil from the corresponding substrate 1c

(148.2 mg); yield: 126.0 mg (81%, 95% ee). ¹H NMR

(400 MHz, CDCl₃): d=7.51–7.45 (m, 3H, 2 CH_ortho

+

CH_para), 7.32–7.26 (m, 3H, 2 CH_meta+ CH_imid), 7.18 (d, J=

1.0 Hz, 1H, CH_imid), 3.11 (dd, J=16.2, 5.8 Hz, 1H,

CHCH’CO), 3.01 (dd, J=16.1, 8.0 Hz, 1H, CHCH’CO),

2.19–2.07 (m, 1H, CHCH₃), 1.40–1.18 [m, 12H, CH₃(CH₂)₆],

0.94 (d, J=6.7 Hz, 3H, CHCH₃), 0.89 [t, J=6.9 Hz, 3H,

CH₃(CH₂)₅]; ¹³C NMR (100 MHz, CDCl₃): d=191.5 (CO),

143.4 (C_IV,imid), 138.5 (C_IV,Ph), 129.3 (CH_para), 128.9 (CH_imid),

128.7 (2 CH_ortho), 126.9 (CH_imid), 125.8 (2 CH_meta), 46.4

(CH₂CO), 37.0 (CH₂), 31.8 (CH₂), 29.7 (CH₂), 29.4

(CHCH₃), 29.3 (CH₂), 27.0 (CH₂), 22.6 (CH₂), 19.9

(CHCH₃), 14.1 [CH₃(CH₂)₅]; IR: n=2924.5, 2853.8, 1687.8,

1493.1, 1404.3 cm^À1; MS (ESI⁺): m/z=313.23 (100, [M+

H]⁺); HR-MS (ESI⁺): m/z=313.2282, calcd. for C₂₀H₂₉N₂O

[M+H]⁺: 313.2280 (0.6 ppm); chiral HPLC (Chiralcel IC

column, n-hexane/i-PrOH 98:2, 1.0 mLmin^À1): major

13.8 min, minor 13.0 min; [a]²_D¹: +1.9 (c 1.1M, CHCl₃); R_f=

0.51 (pentane/Et₂O 60:40, KMnO₄).

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(R)-3-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)de-

can-1-one (2d): Following the general procedure D with

a copper loading of 2 mol% and L1, for 4 h, the title com-

pound was isolated by column chromatography (eluent:

pentane/Et₂O 90:10) as a yellow oil from the corresponding

substrate 1d (142.2 mg, 0.5 mmol); yield: 111.0 mg (74%,

CH₃(CH₂)₄], 1.05 (d, J=6.8 Hz, 3H, CH₃CH), 0.85 [t, J=

7.1 Hz, 3H, CH₃(CH₂)₄]; ¹³C NMR (100 MHz, CDCl₃): d=

192.4 (CO), 143.4 (C_IV,imid), 134.5 (CH_sp2), 129.1 (CH_sp2),

128.8 (CH_imid), 126.7 (CH_imid), 46.1 (CH₂CO), 36.1 (NCH₃),

33.1 (CHCH₃), 32.4 (CH₂), 31.2 (CH₂), 29.1 (CH₂), 22.5

(CH₂), 20.7 (CH₃CH), 14.0 [CH₃(CH₂)₄]; IR: n=2957.1,

2924.8, 2855.5, 1672.7, 1405.2 cm^À1; MS (ESI⁺): m/z=249.20

(100, [M+H]⁺); HR-MS (ESI⁺): m/z=249.1967, calcd. for

C₁₅H₂₅N₂O [M+H]⁺: 249.1967 (0 ppm); chiral HPLC (Chir-

alcel OJ-H column, n-hexane/i-PrOH 99.5:0.5, 1 mLmin^À1):

major 13.9 min, minor 17.6 min; [a]²_D⁰: À7.5 (c 1.1M,

CHCl₃); R_f=0.47 (pentane/Et₂O 40:60, KMnO₄).

(S,E)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)hex-4-en-1-

one (2j): Following the general procedure D with a copper

loading of 2 mol% and L1, for 2 h, the title compound was

isolated by column chromatography (eluent: pentane/Et₂O

40:60) as a yellow oil from the corresponding substrate 1j

(88.1 mg); yield: 48.8 mg (51%, 88% ee, >95:5 1,4/1,6 mix-

ture). ¹H NMR (400 MHz, CDCl₃): d=7.13 (d, J=0.9 Hz,

1H, CH_imid), 7.01 (s, 1H, CH_imid), 5.49–5.37 (m, 2H, CH=

CH), 3.99 (s, 3H, NCH₃), 3.15 (dd, J=15.7, 7.4 Hz, 1H,

CHCH’CO), 3.03 (dd, J=15.7, 6.9 Hz, 1H, CHCH’CO),

2.89–2.77 [m, 1H, CH(CH₃)CH₂CO], 1.62–1.57 (m, 3H,

CH₃CH=CH), 1.05 (d, J=6.8 Hz, 3H, CH₃CH); ¹³C NMR

(100 MHz, CDCl₃): d=192.4 (CO), 143.3 (C_IV,imid), 135.8

(CH_sp2), 128.8 (CH_imid), 126.8 (CH_imid), 123.4 (CH_sp2), 46.0

(CH₂CO), 36.2 (NCH₃), 32.9 (CHCH₃), 20.6 (CH₃CH), 17.9

1

86% ee). H NMR (400 MHz, CDCl₃): d=7.89 (dt, J=8.1,

0.9 Hz, 1H, CH_ar), 7.45–7.42 (m, 2H, CH_ar), 7.37 (td, J=8.4,

4.5 Hz, 1H, CH_ar), 4.14 (s, 3H, NCH₃), 3.28 (dd, J=16.6,

5.9 Hz, 1H, CHCH’CO), 3.18 (dd, J=16.6, 7.9 Hz, 1H,

CHCH’CO), 2.29–2.14 (m, 1H, CHCH₃), 1.39 [ddd, J=15.3,

10.7, 5.5 Hz, 2H, CH₃(CH₂)₅CH₂], 1.28 [d, J=18.2 Hz, 10H,

CH₃(CH₂)₅CH₂], 0.99 (d, J=6.7 Hz, 3H, CHCH₃), 0.87 [t,

J=6.9 Hz, 3H, CH₃(CH₂)₅CH₂]; ¹³C NMR (100 MHz,

CDCl₃): d=196.0 (CO), 146.4 (NC_IVN), 141.5 (C=NC_IV),

136.9 [CN(CH₃)C_IV], 125.8 (CH_ar), 123.7 (CH_ar), 121.9

(CH_ar), 110.5 (CH_ar), 47.1 (CH₂CO), 37.0 (CH₂), 32.4

(NCH₃), 31.9 (CH₂), 29.8 (CH₂), 29.5 (CHCH₃), 29.4 (CH₂),

27.1 (CH₂), 22.7 (CH₂), 20.0 (CHCH₃), 14.2 [CH₃(CH₂)₆];

IR: n=2923.8, 2853.5, 1682.8, 1458.7 cm^À1; MS (ESI⁺): m/z

301.23 (100, [M+H]⁺); HR-MS (ESI⁺): m/z=301.2281,

calcd. for C₁₉H₂₉N₂O [M+H]⁺: 301.2280 (0.3 ppm); chiral

HPLC (Chiralcel OJ-H column, n-hexane/i-PrOH 99.5:0.5,

1.0 mLmin^À1): major 8.8 min, minor 9.8 min; [a]²_D¹: À11.7 (c

1.2M, CHCl₃)=; R_f=0.24 (pentane/Et₂O 90:10, KMnO₄).

(R)-3-Methyl-1-(pyridin-2-yl)decan-1-one (2e): Following

the general procedure D with a copper loading of 2 mol%

and L1, for 4 h, the title compound was isolated by column

chromatography (eluent: pentane/Et₂O 90:10) as a yellow

oil from the corresponding substrate 1e (115.7 mg); yield:

86.6 mg (70%, 90% ee). ¹H NMR (400 MHz, CDCl₃): d=

8.68 (ddd, J=4.8, 1.7, 0.9 Hz, 1H, NCH_ar), 8.07–8.01 (m,

1H, NCHCHCH_ar), 7.83 (td, J=7.7, 1.7 Hz, 1H,

NCHCHCH_ar), 7.45 (ddd, J=7.5, 4.8, 1.3 Hz, 1H,

CH_arC_IVN), 3.19 (dd, J=16.4, 5.7 Hz, 1H, CHCH’CO), 3.05

(dd, J=16.4, 8.0 Hz, 1H, CHCH’CO), 2.26–2.10 (m, 1H,

CHCH₃), 1.43–1.32 [m, 2H, CH₃(CH₂)₅CH₂], 1.32–1.17 [m,

10H, CH₃(CH₂)₅CH₂], 0.95 (d, J=6.7 Hz, 3H, CH₃CH),

0.87 [t, J=6.9 Hz, 3H, CH₃(CH₂)₅CH₂]; ¹³C NMR

(100 MHz, CDCl₃): d=202.0 (CO), 153.8 (C_IV,ar), 148.8

(NCH_ar), 136.8 (NCHCHCH_ar), 126.9, 121.7 (NCHCH_ar),

44.8 (CH₂CO), 37.1 (CH₂), 31.9 (CH₂), 29.8 (CH₂), 29.3

(CH₂), 29.3 (CHCH₃), 27.0 (CH₂), 22.7 (CH₂), 20.0

(CHCH₃), 14.1 [CH₃(CH₂)₆]; IR: n=2955.9, 2924.8, 2854.4,

1698.2 cm^À1; MS (ESI⁺): m/z=248.20 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=248.2016, calcd. for C₁₆H₂₆N₂O [M+H]⁺:

248.2014 (0.8 ppm); chiral HPLC (Chiralcel IC column, n-

hexane/i-PrOH 99.5:0.5, 1.0 mLmin^À1): major 7.9 min, minor

8.6 min; [a]²⁰: À5.4(c 1.0m, CHCl₃); R_f=0.24 (pentane/Et₂O

90:10, KMn^DO₄).

(CH₃CH=CH); IR: n=2960.4, 1671.1, 1404.5, 966.5 cm^À1

;

MS (ESI⁺): m/z=193.13 (100, [M+H]⁺); HR-MS (ESI⁺):

m/z=193.1343, calcd. for C₁₁H₁₇N₂O [M+H]⁺: 193.1341

(1.0 ppm); chiral HPLC (Chiralcel OJ-H column, n-hexane/

i-PrOH 99.5:0.5, 1.0 mLmin^À1): major 18.7 min, minor

23.1 min; [a]²_D¹: +5.2 (c 1.0M, CHCl₃); R_f=0.38 (pentane/

Et₂O 40:60, KMnO₄).

(S,E)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)-5-phenyl-

pent-4-en-1-one (2k): Following the general procedure D

with a copper loading of 4 mol% and L1, for 24 h, the title

compound was isolated by column chromatography (eluent:

pentane/Et₂O 40:60) as a yellow oil from the corresponding

substrate 1k (119.1 mg); yield: 75.2 mg (59%, 86% ee, 95:5

1

1,4/1,6 mixture). H NMR (400 MHz, CDCl₃): d=7.37–7.27

(m, 4H, CH_ortho+meta), 7.24–7.18 (m, 1H, CH_para), 7.17 (d, J=

0.9 Hz, 1H, CH_imid), 7.04 (s, 1H, CH_imid), 6.43 (d, J=

15.9 Hz, 1H, PhCH=CH), 6.24 (dd, J=15.9, 7.4 Hz, 1H,

PhCH=CH), 4.01 (s, 3H, NCH₃), 3.34 (dd, J=15.6, 7.3 Hz,

1H, CHCH’CO), 3.18 (dd, J=15.6, 6.8 Hz, 1H, CHCH’CO),

3.10 (dt, J=13.5, 6.6 Hz, 1H, CHCH₃), 1.22 (d, J=6.7 Hz,

3H, CHCH₃); ¹³C NMR (100 MHz, CDCl₃): d=191.9 (CO),

143.3 (C_IV,imid), 137.6 (C_IV,Ph), 135.0 (CH_sp2), 128.9 (CH_sp2),

128.4 (CH_sp2), 128.4 (2 CH_ortho), 126.9 (CH_sp2), 126.9 (CH_sp2),

126.1 (2 CH_meta), 45.7 (CH₂CO), 36.2 (NCH₃), 33.4

(CHCH₃), 20.5 (CH₃CH); IR: n=2961.1, 1673.5, 1455.8,

1406.8 cm^À1; MS (ESI⁺): m/z=255.15 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=255.1498, calcd. for C₁₆H₁₉N₂O [M+H]⁺:

255.1497 (0.4 ppm); chiral HPLC (Chiralcel OJ-H column,

n-hexane/i-PrOH 80:20, 1.0 mLmin^À1): major 9.8 min, minor

11.4 min; [a]²_D¹: +43.1 (c 1.2M, CHCl₃); R_f=0.25 (pentane/

(S,E)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)dec-4-en-1-

one (2i):^[17]Following the general procedure

D with

a copper loading of 2 mol% and L1, for 2 h, the title com-

pound was isolated by column chromatography (eluent:

pentane/Et₂O 60:40) as a yellow oil from the corresponding

substrate 1i (116.2 mg); yield: 67.6 mg (54%, 95% ee, 96:4

1,4/1,6 mixture). ¹H NMR (400 MHz, CDCl₃): d=7.12 (s,

1H, CH_imid), 7.00 (s, 1H, CH_imid), 5.46–5.32 (m, 2H, CH= Et₂O 40:60, KMnO₄).

CH), 3.98 (s, 3H, NCH₃), 3.15 (dd, J=15.5, 7.4 Hz, 1H,

CHCH’CO), 3.02 (dd, J=15.5, 7.0 Hz, 1H, CHCH’CO),

2.83 [dt, J=12.4, 6.3 Hz, 1H, CH(CH₃)CH₂CO], 1.92 (dd,

J=12.2, 7.0 Hz, 2H, CH₂CO), 1.32–1.15 [m, 8H,

(S,E)-5-(4-Methoxyphenyl)-3-methyl-1-(1-methyl-1H-imi-

dazol-2-yl)pent-4-en-1-one (2l): Following the general proce-

dure D with a copper loading of 4 mol% and L1, for 24 h,

the title compound was isolated by column chromatography

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(eluent: pentane/Et₂O 40:60) as a yellow oil from the corre-

sponding substrate 1l (134.2 mg, with 1 mL of THF); yield:

79 mg (59%, 87% ee, >98/2 1,4/1,6 mixture). ¹H NMR

(400 MHz, CDCl₃): d=7.26–7.21 [m, 2H, (CH₃)OCH_ar],

7.14 (d, J=0.9 Hz, 1H, CH_imid), 7.01 (d, J=0.5 Hz, 1H,

CH_imid), 6.83–6.79 [m, 2H, (CH₃)OCHCH_ar], 6.33 (d, J=

15.9 Hz, 1H, ArCH=CH), 6.06 (dd, J=15.9, 7.5 Hz, 1H,

ArCH=CH), 3.97 (s, 3H, NCH₃), 3.79 (s, 3H, OCH₃), 3.29

(dd, J=15.6, 7.4 Hz, 1H, CHCH’CO), 3.13 (dd, J=15.6,

6.8 Hz, 1H, CHCH’CO), 3.09–2.98 (m, 1H, CHCH₃), 1.17

(d, J=6.7 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz, CDCl₃):

d=192.0 (CO), 158.7 (C_IV,Ph), 143.3 (C_IV,imid), 132.8

(C_IV,PhCH), 130.3 (CH₃OC_IV), 128.9 (CH_imid), 127.7

CH₃(CH₂)₃CH₂]; ¹³C NMR (100 MHz, CDCl₃): d=192.1

(CO), 143.3 (C_IV,imid), 136.1 (CH_sp2), 133.3 (CH_sp2), 130.1

(CH_sp2), 129.0 (CH_sp2), 128.9 (CH_imid), 126.8 (CH_imid), 45.8

(CH₂CO), 36.1 (NCH₃), 32.9 (CHCH₃), 32.5 (CH₂), 31.4

(CH₂), 29.0 (CH₂), 22.5 (CH₂), 20.5 (CH₃CH), 14.0

(CH₃CH₂); IR: n=2925.7, 2957.3, 2855.0, 1673.5, 1047.4,

988.7 cm^À1; MS (ESI⁺): m/z=275.21 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=275.2123, calcd. for C₁₅H₂₇N₂O [M+H]⁺:

275.2123 (0 ppm); chiral HPLC (Chiralcel OJ-H column, n-

hexane/i-PrOH 98:2, 1.0 mLmin^À1): major diastereoisomer

10.0 min, minor 16.9 min; [a]²_D¹: À14.3 (c 1.1M, CHCl₃); R_f=

0.25 (pentane/Et₂O 20:80, KMnO₄).

(C_IV,PhCH=CH), 127.1 (CH₃OC_IVCHCH,

2

C), 126.9

Post-Functionalization of Chiral Acylimidazoles onto

Aldehydes

(CH_imid), 113.8 (CH₃OC_IVCH, 2 C), 55.2 (OCH₃), 45.8

(CH₂CO), 36.1 (NCH₃), 33.4 (CHCH₃), 20.6 (CH₃CH); IR:

n=2958.1, 1670.0, 1606.9, 1509.8, 1403.2, 1244.3,

1174.7 cm^À1; MS (ESI⁺): m/z=285.16 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=285.1604, calcd. for C₁₇H₂₁N₂O₂[M+H]⁺:

285.1603 (0.4 ppm); chiral HPLC (Chiralcel OJ-H column,

n-hexane/i-PrOH 80:20, 1 mLmin^À1): major 19.8 min, minor

21.4 min; [a]²_D⁰: +47.8 (c 1.0M, CHCl₃); R_f=0.19 (pentane/

Et₂O 40:60, KMnO₄).

(R)-3-Methyldecanal (4a): The title compound was synthe-

sized in our previous study.^[17]Its analytical data were in full

accordance with the bibliographic data: [a]²_D¹: +2.3 (c 0.7M,

CHCl₃, 83% ee), lit: [a]²_D¹: + 3.5.^[23](c 1.2M, CHCl₃, 81%

ee).

(S)-3-Cyclohexylbutanal (4f): The title compound was iso-

lated by column chromatography (pentane/Et₂0 98:2) as

a yellow oil following the procedure E from the correspond-

ing substrate 2f^[17](30 mg, 91% ee); yield: 18 mg (37%). Its

analytical data was in full accordance with the bibliographic

data: [a]²_D¹: +2.3 (c 0.26, EtOH), lit: [a]²_D¹: +8.3^[24](c 1.0M,

EtOH, 91% ee).

(S)-3-Phenylbutanal (4g): The title compound was isolat-

ed by column chromatography (pentane/Et₂0 95:5) as

a yellow oil following the procedure E from the correspond-

ing substrate 2g^[17](23.4 mg, 91% ee); yield: 20 mg (42%).

Its analytical data was in full accordance with the biblio-

graphic data: [a]_D²¹: +17.5 (c 0.4m, CHCl₃), lit: [a]²_D¹:

+18.4^[25](c 1.0m, CHCl₃, 72% ee).

(S,E)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)-5-(2-nitro-

phenyl)pent-4-en-1-one (2m): Following the general proce-

dure D with a copper loading of 4 mol% and L1, for 24 h,

the title compound was isolated by column chromatography

(eluent: pentane/Et₂O 20:80) as an orange oil following

from the corresponding substrate 1m (141.6 mg, with 2.5 mL

of THF); yield: 42.5 mg (28%, 90% ee, 97:3 1,4/1,6 mixture).

¹H NMR (400 MHz, CDCl₃): d=7.92–7.86 (m, 1H, CH_ar),

7.56–7.49 (m, 1H, CH_ar), 7.39–7.32 (m, 2H, CH_ar), 7.17 (d,

J=0.9 Hz, 1H, CH_imid), 7.06 (d, J=0.4 Hz, 1H, CH_imid), 6.84

(dd, J=15.7, 1.0 Hz, 1H, C_IVCH=CH), 6.22 (dd, J=15.7,

7.4 Hz, 1H, C_IVCH=CH), 4.03 (s, 3H, NCH₃), 3.36–3.20 (m,

2H, CH₂CO), 3.21–3.12 (m, 1H, CHCH₃), 1.26 (d, J=

6.6 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz, CDCl₃): d=

191.5 (CO), 147.6 (C_IV,Ph), 143.2 (C_IV,imid), 140.5 (CH_sp2),

133.3 (O₂NC_IV), 132.8 (CH_sp2), 129.0 (CH_sp2), 128.7 (CH_imid),

127.5 (CH_sp2), 127.1 (CH_imid), 124.3 (CH_sp2), 124.0 (CH_sp2),

45.6 (CH₂CO), 36.2 (NCH₃), 33.9 (CHCH₃), 20.3 (CH₃CH);

Florhydral^ꢀSynthesis

(E)-3-(3-Isopropylphenyl)-N-methoxy-N-methylacrylamide

(5h): The title compound was isolated by column chroma-

tography (eluent: pentane Et₂O 40:60) as a yellow oil fol-

lowing the general procedure B from the 3-isopropylbenzal-

dehyde produced according to the literature procedure^[28]

(480 mg); yield: 523.8 mg (70%). ¹H NMR (400 MHz,

CDCl₃): d=7.73 (d, J=15.8 Hz, 1H, CH_sp2), 7.44–7.37 (m,

2H, CH_ar), 7.35–7.28 (m, 1H, CH_ar), 7.26–7.21 (m, 1H,

CH_ar), 7.02 (d, J=15.8 Hz, 1H, CH_sp2), 3.77 (s, 3H, OCH₃),

3.32 (s, 3H, NCH₃), 3.00–2.86 [m, 1H, CH(CH₃)₂], 1.27 [d,

J=6.9 Hz, 6H, CH(CH₃)₂]; ¹³C NMR (100 MHz, CDCl₃):

d=167.2 (CO), 149.6 (C_IVar), 144.0 (C_IVar), 135.3 (CH_sp2),

128.9 (CH_ar), 128.2 (CH_ar), 126.6 (CH_ar), 125.6 (CH_ar),

115.58 (CH_sp2), 62.0 (OCH₃), 34.2 (NCH₃) ppm, 32.7

[CH(CH₃)₂], 24.1 [CH(CH₃)₂]; IR: n=2960, 1654, 1616,

1375, 1177, 1096, 995 cm^À1; HR-MS (ESI⁺): m/z=256.1308,

calcd. for C₁₄H₁₉NO₂Na [M+Na]⁺: 256.1308 (0 ppm); R_f=

0.36 (pentane/Et₂O 60:40, UV).

IR: n=2960.3, 2925.3, 1673.3, 1522.0, 1407.5, 1345.2 cm^À1

;

MS (ESI⁺): m/z=300.13 (100, [M+H]⁺); HR-MS (ESI⁺):

m/z=300.1349, calcd. for C₁₆H₁₈N₃O₃[M+H]⁺: 300.1348

(0.3 ppm); chiral HPLC (Chiralcel IA column, n-hexane/i-

PrOH 90:10, 1 mLmin^À1): major 23.9 min, minor 27.6 min;

[a]²_D¹: +21.8 (c 0.7M, CHCl₃); R_f=0.25 (pentane/Et₂O 20:80,

KMnO₄).

(S,4E,6E)-3-Methyl-1-(1-methyl-1H-imidazol-2-yl)dodeca-

4,6-dien-1-one (2n): Following the general procedure D with

a copper loading of 4 mol% and L1, for 24 h, the title com-

pound was isolated by column chromatography (eluent:

pentane/Et₂O 20:80) as an orange oil from the correspond-

ing substrate 1n (129.2 mg); yield: 80.1 mg (58%, 91% ee,

1

96:4:0 1,4/1,6/1,8 mixture). H NMR (400 MHz, CDCl₃): d=

7.13 (d, J=0.9 Hz, 1H, CH_imid), 7.01 (d, J=0.5 Hz, 1H,

CH_imid), 6.06–5.90 (m, 2H, CH_sp2), 5.61–5.50 (m, 2H, CH_sp2),

3.98 (s, 3H, NCH₃), 3.17 (dd, J=15.9, 7.4 Hz, 1H,

CHCH’CO), 3.08 (dd, J=15.9, 6.9 Hz, 1H, CHCH’CO),

2.97–2.84 (m, 1H, CHCH₃), 2.02 [q, J=7.0 Hz, 2H,

CH₃(CH₂)₃CH₂], 1.40–1.21 [m, 6H, CH₃(CH₂)₃CH₂], 1.08 (t,

J=6.0 Hz, 3H, CHCH₃), 0.87 [t, J=6.9 Hz, 3H,

(E)-3-(3-Isopropylphenyl)-1-(1-methyl-1H-imidazol-2-

yl)prop-2-en-1-one (1h): The title compound was isolated by

column chromatography (eluent: pentane/Et₂O 60:40) as

a slightly colored solid following the general procedure C

from the corresponding intermediate 5h (474.4 mg); yield:

439.5 mg (86%). ¹H NMR (400 MHz, CDCl₃): d=8.09 (d,

J=15.9 Hz, 1H, CH_sp2), 7.84 (d, J=16 Hz, 1H, CH_sp2), 7.58

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(s, 1H, CH_ar), 7.56–7.46 (m, 1H, CH_ar), 7.33 (t, J=7.6 Hz,

1H, CH_ar), 7.30–7.28 (m, 1H, CH_ar), 7.25 (s, 1H CH_imid), 7.09

(s, 1H, CH_imid), 4.11 (s, 3H, NCH₃), 2.94 [sept, J=6.9 Hz,

1H, CH(CH₃)₂], 1.28 [d, J=6.9 Hz, 6H, CH(CH₃)₂];

¹³C NMR (100 MHz, CDCl₃): d=180.7 (CO), 149.7 (C_IVar),

144.2 (C_IVimid), 144.0 (C_IVar), 135.0 (CH_sp2), 129.4 (CH_imid),

128.96 (CH_ar), 128.91 (CH_imid), 127.4 (CH_ar), 126.8 (CH_ar),

122.5 (CH_sp2), 36.5 (NCH₃), 34.2 [CH(CH₃)₂], 24.1

CH₃cis), 1.60 (s, 3H, (CH₃)₂C=CH, CH₃trans), 1.57–1.48

(m, 1H, CHCH₃), 1.41–1.28 [m, 2H,

(CH₃)CHCH₂CH(CH₃)], 1.15–1.03 [m, 2H, (CH₃)₂C=

CHCH₂CH₂], 0.94 (d, J=6.6 Hz, 3H, CHCH₃), 0.88 (d, J=

6.6 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz, CDCl₃): d=

193.2 (CO), 143.5 (C_IV,imid), 130.9 [(CH₃)₂C=CH], 128.8

(CH_imid), 126.7 (CH_imid), 124.9 [(CH₃)₂C=CH], 46.0

(CH₂CO), 44.9 [CH₂CH(CH₃)CH₂CO], 36.8 (CH₂), 36.2

(NCH₃), 29.8 (CH₃CH), 27.1 (CH₃CH), 25.7 [(CH₃)₂C=CH,

CH₃trans], 25.3 (CH₂), 20.6 (CHCH₃), 19.9 (CHCH₃), 17.6

[(CH₃)₂C=CH, CH₃cis); IR: n=2958.7, 2913.4, 1738.5,

1671.6, 1405.5 cm^À1; MS (ESI⁺): m/z=277.23 (100, [M+

H]⁺); HR-MS (ESI⁺): m/z=277.2277, calcd. for C₁₇H₂₉N₂O

[M+H]⁺: 277.2280 (1.1 ppm); chiral HPLC (Chiralcel OJ-H

column, n-hexane/i-PrOH 99.5:0.5, 0.5 mLmin^À1): major dia-

stereoisomer 13.6 min, minors 14.3, 17.2, 19.0 min; [a]²_D⁰:

À14.0 (c 1.1M, CHCl₃); R_f=0.35 (pentane/Et₂O 60:40,

KMnO₄). See the Supporting Information S2 for more de-

tails.

[CH(CH₃)₂]; IR: n=2957, 1656, 1604, 1401, 1054, 1021 cm^À1

;

HR-MS (ESI⁺): m/z=277.1311, calcd. for C₁₆H₁₈N₂ONa

[M+Na]⁺: 277.13113 (0 ppm); R_f=0.33 (pentane/Et₂O

60:40, UV).

(S)-3-(3-Isopropylphenyl)-1-(1-methyl-1H-imidazol-2-yl)-

butan-1-one (2h): Reaction was run for 3 h. The title com-

pound was isolated by column chromatography (eluent:

pentane/Et₂O 60:40) as a slightly yellow oil following the

catalytic procedure D from the corresponding substrate 1h

1

(128 mg); yield: 110 mg (81%, 95% ee). H NMR (400 MHz,

CDCl₃): d=7.20 (td, J=7.5, 0.5 Hz, 1H, CH_ar), 7.13–7.12

(m, 2H, CH_ar+ CH_imid), 7.10 (dt, J=7.6, 1.6 Hz, 1H, CH_ar),

7.06–7.01 (m, 1H, CH_ar), 6.99 (d, J=1.1 Hz, 1H, CH_imid),

3.95 (s, 3H, NCH₃), 3.54–3.44 [m, 1H, ArCH(CH₃)], 3.44–

3.40 (m, 2H, CH₂CO), 2.86 [sept, J=6.9 Hz, 1H,

CH(CH₃)₂], 1.31 [d, J=6.6 Hz, 3H, ArCH(CH₃)], 1.22 [d,

J=6.9 Hz, 6H, CH(CH₃)₂]; ¹³C NMR (100 MHz, CDCl₃):

d=192.1 (CO), 149.0 (C_IVar), 146.5 (C_IVar), 143.5 (C_IVimid),

129.1 (CH_imid), 128.4 (CH_imid), 126.9 (CH_ar), 125.4 (CH_ar),

124.5 (CH_ar), 124.2 (CH_ar), 47.1 (CH₂CO), 36.3 (NCH₃), 35.9

[ArCH(CH₃)], 34.3 [CH(CH₃)₂], 24.2 [CH(CH₃)₂], 22.5

[ArCH(CH₃)]; IR: n=2959, 2360, 1674, 1410 cm^À1; HR-MS

(ESI⁺): m/z=293.1624, calcd. for C₁₇H₂₂N₂ONa [M+Na]⁺:

293.16243 (0 ppm); chiral HPLC (Chiralcel OJ-H column,

n-hexane/i-PrOH 99.5:0.5, 1.0 mLmin^À1): major 21.5 min,

minor 19.1 min; [a]²_D¹: +4.5 (c 1.0M, CHCl₃); R_f=0.29 (pen-

tane/Et₂O 60:40, UV or KMnO₄).

(+)-(S)-Florhydralꢀ (4h): The title compound was isolat-

ed by column chromatography (eluent: pentane/Et₂O 99:1)

as a muguet-smelling slightly yellow oil following the proce-

dure E from the corresponding substrate 2h (100 mg); yield:

70 mg (99%). Its analytical data were in full accordance

with the bibliographic data: [a]²_D⁰: +28.5 (c 1.0M, CHCl₃),

lit: [a]²_D¹: +30.7^[26](c 1.39M, CHCl₃).

(3R,5S)-3,5,9-Trimethyl-1-(1-methyl-1H-imidazol-2-

yl)dec-8-en-1-one [3-(R),5-(S)-2o]: Following the general

procedure D with a copper loading of 2 mol% and L1, for

16 h, the title compound was isolated by column chromatog-

raphy (eluent: pentane/Et₂O 40:60) as a yellow oil from the

corresponding substrate (S)-1o (130.2 mg); yield: 119 mg

(86%, 95:5 dr, 90% ee). ¹H NMR (400 MHz, CDCl₃): d=

7.12 (d, J=0.8 Hz, 1H, CH_imid), 7.01 (s, 1H, CH_imid), 5.13–

5.05 [m, 1H, (CH₃)₂C=CH], 4.00 (s, 3H, NCH₃), 3.07–2.95

(m, 2H, CH₂CO), 2.33–2.19 (m, 1H, CHCH₃), 2.05–1.87 (m,

2H, CH₂), 1.67 [d, J=0.9 Hz, 3H, (CH₃)₂C=CH, CH₃cis],

1.59 [s, 3H, (CH₃)₂C=CH, CH₃trans], 1.36–1.19 (m, 3H,

CHCH₃+ CH₂), 1.19–1.09 (m, 2H, CH₂), 0.92 (d, J=6.6 Hz,

3H, CHCH₃), 0.87 (d, J=6.6 Hz, 3H, CHCH₃); ¹³C NMR

(100 MHz, CDCl₃): d=193.1 (CO), 143.5 (C_IV,imid), 130.9

(CH₃)₂C=CH), 128.8 (CH_imid), 126.7 (CH_imid), 124.9

[(CH₃)₂C=CH], 46.9 (CH₂CO), 44.5 [CH₂CH(CH₃)CH₂CO],

37.7 (CH₂), 36.2 (NCH₃), 29.7 (CH₃CH), 27.0 (CH₃CH),

25.7 [(CH₃)₂C=CH, CH₃trans], 25.5 (CH₂), 19.6 (CH₃CH),

19.3 (CH₃CH), 17.6 [(CH₃)₂C=CH, CH₃cis]; chiral HPLC

(Chiralcel OJ-H column, n-hexane/i-PrOH 99.5:0.5,

0.5 mLmin^À1): major diastereoisomer 14.3 min, minors 13.6,

17.2, 19.0 min; [a]²_D⁰: +19.4 (c 1.3M, CHCl₃); R_f=0.35 (pen-

tane/Et₂O 60:40, KMnO₄). See the Supporting Information

S2 for more details.

Preparation and Analytical Data of Compounds

Resulting from the Iterative Strategy Applied to

Citronellal Derivatives 1o: 1p, 2o–2p, 4o

(3S,55)-3,5,9-Trimethyl-1-(1-methyl-1H-imidazol-2-yl)dec-

8-en-1-one [3-(S),5-(R)-2o]: Following the general proce-

dure D with a copper loading of 2 mol% and (ent)-L1, for

16 h, the title compound was isolated by column chromatog-

raphy (eluent: pentane/Et₂O 40:60) as a yellow oil from the

corresponding substrate (R)-1o (130.2 mg); yield: 116.5 mg

Compounds (R)-1o and (S)-1o were synthesized in two steps

from (R)- and (S)-citronellal following the procedure de-

scribed in our previous study.^[17]

1

(84%, 96.5:3.5 dr, 93% ee). H NMR (400 MHz, CDCl₃): d=

(3R,5R)-3,5,9-Trimethyl-1-(1-methyl-1H-imidazol-2-

yl)dec-8-en-1-one [3-(R),5-(R)-2o]: Following the general

procedure D with a copper loading of 2 mol% and L1, for

16 h, the title compound was isolated by column chromatog-

raphy (eluent: pentane/Et₂O 40:60) as a yellow oil from the

corresponding substrate (R)-1o (130.2 mg); yield: (117.9 mg,

7.12 (d, J=0.9 Hz, 1H, CH_imid), 7.01 (d, J=0.4 Hz, 1H,

CH_imid), 5.08 [dddd, J=7.1, 5.7, 2.8, 1.4 Hz, 1H, (CH₃)₂C=

CH], 4.00 (s, 3H, NCH₃), 3.03–2.97 (m, 2H, CH₂CO), 2.32–

2.19 (m, 1H, CHCH₃), 2.06–1.86 [m, 2H, (CH₃)₂C=CHCH₂],

1.67 [d, J=1.0 Hz, 3H, (CH₃)₂C=CH, CH₃cis], 1.59 [s, 3H,

(CH₃)₂C=CH, CH₃trans], 1.58–1.46 (m, 1H, CHCH₃), 1.36–

1

85%, 98:2 dr, 94% ee). H NMR (400 MHz, CDCl₃): d=7.12

1.10

[m,

4H,

(CH₃)₂C=CHCH₂CH₂

+

(d, J=0.8 Hz, 1H, CH_imid), 7.00 (s, 1H, CH_imid), 5.12–5.06

(m, 1H, (CH₃)₂C=CH), 4.00 (s, 3H, NCH₃), 3.03 (dd, J=

16.0, 5.4 Hz, 1H, CHCH’CO), 2.95 (dd, J=16.0, 8.3 Hz, 1H,

CHCH’CO), 2.35–2.19 (m, 1H, CHCH₃), 2.08–1.85 (m, 2H,

(CH₃)₂C=CHCH₂), 1.67 (d, J=0.9 Hz, 3H, (CH₃)₂C=CH,

(CH₃)CHCH₂CH(CH₃)], 0.92 (d, J=6.6 Hz, 3H, CHCH₃),

0.86 (d, J=6.6 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz,

CDCl₃): d=193.1 (CO), 143.4 (C_IV,imid), 131.0 [(CH₃)₂C=

CH], 128.8 (CH_imid), 126.8 (CH_imid), 124.9 [(CH₃)₂C=CH],

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46.9 (CH₂CO), 44.4 [CH₂CH(CH₃)CH₂CO], 37.8 (CH₂),

and L1, for 16 h, the title compound was isolated by column

36.2 (NCH₃), 29.7 (CH₃CH), 27.0 (CH₃CH), 25.7 [(CH₃)₂C= chromatography (eluent: pentane/Et₂O 40:60) as a yellow

oil from the corresponding substrate 5-(R),7-(R)-1p

(46.4 mg, 0.153 mmol); yield: 37.5 mg (77%, 95:5 dr, 99%

ee). H NMR (400 MHz, CDCl₃): d=7.13 (d, J=0.9 Hz, 1H,

CH, CH₃trans], 25.5 (CH₂), 19.6 (CHCH₃), 19.2 (CHCH₃),

17.6 [(CH₃)₂C=CH, CH₃cis]; IR: n=2958.7, 2913.4, 1738.5,

1671.6, 1405.5 cm^À1; chiral HPLC (Chiralcel OJ-H column,

n-hexane/i-PrOH 99.5:0.5, 0.5 mLmin^À1): major diastereo-

isomer 17.1 min, minors 13.6, 14.3, 19.0 min; [a]²_D¹: +4.0 (c

1.1M, CHCl₃); R_f=0.35 (pentane/Et₂O 60:40, KMnO₄). See

the Supporting Information S2 for more details.

1

CH_imid), 7.01 (s, 1H, CH_imid), 5.12–5.05 [m, 1H, (CH₃)₂C=

CH], 4.00 (s, 3H, NCH₃), 3.02 (dd, J=18.0, 7.5 Hz, 1H,

CHCH’CO), 2.96 (dd, J=18.0, 10.4 Hz, 1H, CHCH’CO),

2.33–2.21 (m, 1H, CHCH₃), 2.06–1.81 (m, 2H, CH₂), 1.68 [d,

J=1.0 Hz, 3H, (CH₃)₂C=CH, CH₃cis], 1.60 [s, 3H,

(CH₃)₂C=CH, CH₃trans], 1.65–1.53 (m, 1H, CHCH₃), 1.53–

1.43 (m, 1H, CHCH₃), 1.37–1.17 (m, 4H, CH₂), 1.08–0.97

(m, 2H, CH₂), 0.93 (d, J=6.6 Hz, 3H, CHCH₃), 0.86 (d, J=

6.3 Hz, 3H, CHCH₃), 0.84 (d, J=6.4 Hz, 3H, CHCH₃);

¹³C NMR (100 MHz, CDCl₃): d=193.3 (CO), 143.5 (C_IV,imid),

130.9 [(CH₃)₂C=CH], 128.8 (CH_imid), 126.8 (CH_imid), 125.0

[(CH₃)₂C=CH], 45.7 (CH₂CO), 45.1 (CH₂), 45.0 (CH₂), 36.5

(CH₂), 36.2 (NCH₃), 29.6 (CH₃CH), 27.5 (CH₃CH), 27.1

(CH₃CH), 25.7 [(CH₃)₂C=CH, CH₃trans], 25.4 (CH₂), 20.8

(CH₃CH), 20.5 (CH₃CH), 20.4 (CH₃CH), 17.6 [(CH₃)₂C=

CH, CH₃cis]; IR: n=2956.0, 2914.4, 1672.9, 1459.6,

1406.9 cm^À1; MS (ESI⁺): m/z=319.27 (100, [M+H]⁺); HR-

MS (ESI⁺): m/z=319.2750, calcd. for C₁₇H₂₉N₂O [M+H]⁺:

319.2749 (0.3 ppm); [a]²_D¹: À3.9 (c 1.1M, CHCl₃); R_f=0.35

(pentane/Et₂O 60:40, KMnO₄).

(3S,5S)-3,5,9-Trimethyl-1-(1-methyl-1H-imidazol-2-yl)dec-

8-en-1-one [3-(S),5-(S)-2o]: Following the general procedure

D with a copper loading of 2 mol% and (ent)-L1, for 16 h,

the title compound was isolated by column chromatography

(eluent: pentane/Et₂O 40:60) as a yellow oil from the corre-

sponding substrate (S)-1o (130.2 mg); yield: 119 mg (86%,

1

96.5:3.5 dr, 93% ee). H NMR (400 MHz, CDCl₃): d=7.13

(s, 1H, CH_imid), 7.01 (s, 1H, CH_imid), 5.13–5.05 [m, 1H,

(CH₃)₂C=CH], 4.00 (s, 3H, NCH₃), 3.04 (dd, J=16.1,

5.5 Hz, 1H, CHCH’CO), 2.96 (dd, J=15.9, 8.3 Hz, 1H,

CHCH’CO), 2.32–2.21 (m, 1H, CHCH₃), 1.93 [ddd, J=21.5,

15.2, 6.8 Hz, 2H, (CH₃)₂C=CHCH₂], 1.67 [d, J=0.8 Hz, 3H,

(CH₃)₂C=CH, CH₃cis], 1.60 [s, 3H, (CH₃)₂C=CH, CH₃

trans], 1.57–1.47 (m, 1H, CHCH₃), 1.41–1.28 [m, 2H,

(CH₃)CHCH₂CH(CH₃)], 1.15–1.03 [m, 2H, (CH₃)₂C=

CHCH₂CH₂], 0.94 (d, J=6.6 Hz, 3H, CHCH₃), 0.88 (d, J=

6.6 Hz, 3H, CHCH₃); ¹³C NMR (100 MHz, CDCl₃): d=

193.2 (CO), 143.4 (C_IV,imid), 131.0 [(CH₃)₂C=CH], 128.8

(CH_imid), 126.8 (CH_imid), 124.9 [(CH₃)₂C=CH], 46.0

(CH₂CO), 44.8 [CH₂CH(CH₃)CH₂CO], 36.8 (CH₂), 36.2

(NCH₃), 29.8 (CH₃CH), 27.1 (CH₃CH), 25.7 [(CH₃)₂C=CH,

CH₃trans], 25.4 (CH₂), 20.6 (CH₃CH), 19.9 (CH₃CH), 17.6

[(CH₃)₂C=CH, CH₃cis]; chiral HPLC (Chiralcel OJ-H

column, n-hexane/i-PrOH 99.5:0.5, 0.5 mLmin^À1): major dia-

stereoisomer 18.9 min, minors 13.6, 14.3, 17.2 min; [a]²_D¹:

+4.9 (c 0.6M, CHCl₃); R_f=0.35 (pentane/Et₂O 60:40,

KMnO₄). See the Supporting Information S2 for more de-

tails.

(3R,5R)-3,5,9-Trimethyldec-8-enal [3-(R),5-(R)-4o]: The

title compound (66 mg, 86%) was isolated by column chro-

matography (pentane/Et₂O 98:2) as a yellow oil following

the procedure E from the corresponding substrate 3-(R),5-

(R)-2o (109 mg); yield: 66 mg (86%).

(3R,5R)-3,5,9-Trimethyldec-8-enal [3-(R),5-(S)-4o]: The

title compound was isolated by column chromatography

(pentane/Et₂O 98:2) as a yellow oil following the procedure

E from the corresponding substrate 3-(R),5-(S)-2o (108 mg);

yield: 63.6 mg (83%).

(3S,5R,7S)-3,5,7,11-tetramethyl-1-(1-methyl-1H-imidazol-

2-yl)dodec-10-en-1-one [3-(S),5-(R),7-(S)-2p]: Following the

general procedure D with a copper loading of 2 mol% and

(ent)-L1, for 16 h, the title compound was isolated by

column chromatography (eluent: pentane/Et₂O 40:60) as

a yellow oil from the corresponding substrate 5-(R),7-(S)-1p

(44.8 mg, 0.148 mmol); yield: 31.9 mg (68%, 90:10 dr, 99%

1

ee). H NMR (400 MHz, CDCl₃): d=7.12 (d, J=0.6 Hz, 1H,

CH_imid), 7.00 (s, 1H, CH_imid), 5.09 [t, J=7.1 Hz, 1H,

(CH₃)₂C=CH], 4.00 (s, 3H, NCH₃), 3.07–2.95 (m, 2H,

CH₂CO), 2.34–2.20 (m, 1H, CHCH₃), 2.08–1.85 (m, 2H,

CH₂), 1.67 [s, 3H, (CH₃)₂C=CH, CH₃cis], 1.59 [s, 3H,

(CH₃)₂C=CH, CH₃trans], 1.65–1.53 (m, 1H, CHCH₃), 1.53–

1.44 (m, 1H, CHCH₃), 1.33–1.20 (m, 2H, CH₂), 1.20–0.97

(m, 4H, CH₂), 0.93 (d, J=6.6 Hz, 3H, CHCH₃), 0.82 (d, J=

6.5 Hz, 6H, 2 CHCH₃); ¹³C NMR (100 MHz, CDCl₃): d=

193.1 (CO), 143.5 (C_IV,imid), 131.0 [(CH₃)₂C=CH], 128.8

(CH_imid), 126.8 (CH_imid), 125.0 [(CH₃)₂C=CH], 46.9

(CH₂CO), 45.4 (CH₂), 45.3 (CH₂), 37.8 (CH₂), 36.2 (NCH₃),

29.6 (CH₃CH), 27.4 (CH₃CH), 27.1 (CH₃CH), 25.7

[(CH₃)₂C=CH, CH₃trans], 25.5 (CH₂), 19.7 (CH₃CH), 19.5

(CH₃CH), 19.2 (CH₃CH), 17.6 [(CH₃)₂C=CH, CH₃cis]; IR:

n=2958.4, 2922.1, 1673.5, 1462.6, 1407.5, 1378.1 cm^À1; [a]_D²¹:

À1.4 (c 1.0M, CHCl₃); R_f=0.35 (pentane/Et₂O 60:40,

KMnO₄).

(5R,7R,E)-5,7,11-Trimethyl-1-(1-methyl-1H-imidazol-2-

yl)dodeca-2,10-dien-1-one [5-(R),7-(R)-1p]: The title com-

pound was isolated by column chromatography (pentane/

Et₂O 60:40) as a colorless oil following the procedure B fol-

lowed by C from the corresponding substrate 3-(R),5-(R)-4o

(66 mg); yield: 46.4 mg (49% over two steps).

(5R,7S,E)-5,7,11-trimethyl-1-(1-methyl-1H-imidazol-2-yl)-

dodeca-2,10-dien-1-one [5-(R),7-(S)-1p]: The title compound

was isolated by column chromatography (pentane/Et₂O

60:40) as a colorless oil following the procedure B followed

Acknowledgements

This work was supported by the Agence Nationale de la Re-

cherche (project SCATE, no. ANR-12-B507-0009-01 grant to

SDA). RMF, MM and OB also thank the CNRS. MM thanks

the ENSCR for its financial support concerning the synthesis

of (+)-(S)-Florhydral through Practical Training with under-

graduate students (A. Furet, H. Kranemburg, E. Grousson).

Special thanks to Takasago Company for a generous gift of

by

C from the corresponding substrate 3-(R),5-(S)-4o

(63.6 mg); yield: 44.8 mg (48% over two steps).

(3R,5R,7R)-3,5,7,11-tetramethyl-1-(1-methyl-1H-imidazol-

2-yl)dodec-10-en-1-one [3-(R),5-(R),7-(R)-2p]: Following

the general procedure D with a copper loading of 2 mol%

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citronellal. RMF, JMC and SDA kindly thank P. Guiffrey for

her help in chiral HPLC analyses.

Synlett 1999, 1811; b) R. R. Cesati, J. De Armas, A. H.

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[12] For recent reviews, see: a) T. E. Schmid, S. Drissi-Am-

raoui, C. Crꢀvisy, O. Baslꢀ, M. Mauduit, Beilstein J.

Org. Chem. 2015, 11, 2418; b) A. G. Csaky, G. de La

Herran, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080;

c) E. M. P. Silva, A. M. S. Silva, Synthesis 2012, 44,

3109.

[13] T. den Hartog, D. J. van Dijken, A. J. Minnaard, B. L.

Feringa, Tetrahedron: Asymmetry 2010, 21, 1574.

[14] M. Magrez-Chiquet, M. S. T. Morin, J. Wencel-Delord,

S. Drissi Amraoui, O. Baslꢀ, A. Alexakis, C. Crꢀvisy,

M. Mauduit, Chem. Eur. J. 2013, 19, 13663.

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Copper-Catalyzed Asymmetric Conjugate Addition of

Dimethylzinc to Acyl-N-methylimidazole Michael

Acceptors: Scope, Limitations and Iterative Reactions

23

Adv. Synth. Catal. 2016, 358, 1 – 23

Sammy Drissi-Amraoui, Thibault E. Schmid,

Jimmy Lauberteaux, Christophe Crꢀvisy, Olivier Baslꢀ,

Renata Marcia de Figueiredo, Stꢀphanie Halbert,

Hꢀlꢁne Gꢀrard,* Marc Mauduit,* Jean-Marc Campagne*

Adv. Synth. Catal. 0000, 000, 0 – 0

23

ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÞÞ

These are not the final page numbers!

Article Doi

Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl-N-methylimidazole Michael Acceptors: Scope, Limitations and Iterative Reactions

DOI: 10.1002/adsc.201600458

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Full text of DOI:10.1002/adsc.201600458

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