Asymmetric Catalytic Halofunctionalization of Î±,Î²-Unsaturated

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Asymmetric Catalytic Halofunctionalization of #,#-Unsaturated Carbonyl Compounds Yunfei Cai, Xiaohua Liu, Pengfei Zhou, and Xiaoming Feng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01951 • Publication Date (Web): 19 Oct 2018 Downloaded from http://pubs.acs.org on October 19, 2018

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The Journal of Organic Chemistry

Asymmetric Catalytic Halofunctionalization of α,β-Unsaturated Carbonyl Compounds Yunfei Cai,†,‡ Xiaohua Liu,† Pengfei Zhou,† and Xiaoming Feng*,† †Key

Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China ‡School

of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing 400030,

China ABSTRACT: Halofunctionalization methods enable the vicinal difunctionalization of alkenes with hetero-atom nucleophiles and halogen moieties. As a fundamental transformation in organic synthesis, the catalytic asymmetric variants have only recently been reported. In sharp contrast to the asymmetric halocyclization of simple alkenes which involves a nucleophile assisted alkene activation process, the asymmetric halofunctionalization of enones developed by our laboratory feature an electrophile assisted 1,4-addition pathway. Our work in this area has resulted in the development of several different types of regio-, diastereo- and enantioselective processes, including inter- and intramolecular haloaminations, haloetherifications and haloazidations. The scope, updated mechanism, limitations and future perspective of these reactions are discussed.

1.

INTRODUCTION The halofunctionalization of carbon-carbon double bond (Scheme 1, eqs 1 and 2) is a useful and widely studied reaction in organic chemistry.1 The process enables concomitant formation of stereocontrolled vicinal halocarbon and heteroatom-carbon bond. The resulting halogenated compounds are versatile motifs of many biologically active compounds and also key intermediates in organic synthesis as the halo group can be readily transformed into other functional groups.2 Mechanistically, early in 1937 Kimball3 proposed a stepwise pathway involving initial formation of a bridged halonium ion instead of cationic intermediate and subsequent nucleophilic bond formation by its anti opening of a nucleophile to rationalize the observed exclusive formation of anti-products. This overgeneralized textbook scheme of stepwise mechanism was also widely used and invoked in many recent publications.4,5 However, an alternative concerted addition mechanism was also provided to elucidate the observation that reaction rates were accelerated by proximity of the nucleophilic component to the alkene during the past few decades by many groups (Shilov and Staninets, Williams, Cambie, and others).6 Very recently, Jackson, Borhan and Denmark reaffirmed this concerted AdE-3 type mechanism where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack, namely a nucleophile-assisted alkene activation (NAAA) process.7 Scheme 1. Halofunctionalizations of Alkenes

X R

1

R2

+ Nu

+ X

R

Nu R2

1

or

Nu

X = F, Cl, Br, I

NuH

+ X

or

R

R2

(1)

X

Nu R

R

1

Nu (2)

R X

X Nu: COO, Halolactonization (Type I) A X A X 2 O, Haloetherification (Type II) R NTs, Haloaminocyclization (Type III) R1 R X, Dihalogenation (Type IV) Nu Nu C, Halocarbocyclization (Type V) concerted AdE3 mechanism

n

Despite alkene halofunctionalization has been extensively studied with a history of over 100 years,8 but the catalytic enantioselective variants only recently began to appear in the literature9 and significant advances in the field of catalytic asymmetric halocyclization reactions (eq 2) have also been achieved since 2010 as evidenced by various reviews.5,9 The most successful strategy is based on chiral Lewis base activation via the strong interaction between chiral Lewis base and halogenating agent (Figure 1).10 In many cases, hydrogen bonding to O- or Nnucleophiles or other functional group embellished in the olefins is also involved. Several chiral Lewis base catalysts containing basic N-, O-, S-, and Se-heteroatoms have been developed and applied to the enantioselective halofunctionalization of styrene derivatives. Representative examples have been listed in Figure 1, including BINOL-derived phosphine or phosphoramide (or thiophosphoramide, selenophosphoramide),11 diaminocyclohexane-derived urea,12 cinchonine- or prolinol-derived thiocarbamate,13,14 mannitol-derived

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cyclic sulfide or selenide,15 (DHQD)2PHAL,16-20 phosphate21, and trisimidazolinylbenzene23 etc. For instance, Borhan and coworkers discovered the first example of catalytic asymmetric chlorolactonization to yield chlorolactones (Type I) with biscinchonine alkaloid (DHQD)2PHAL catalyst (Scheme 2, eq 1).16a Two reactive complexes were proposed: a hydrogen bonding of the chlorine source with the protonated catalyst or tight ion pair between the chlorinated catalyst and the monochloro anion of the chlorine source. Later on, this catalyst system has been expanded to chlorocyclization of unsaturated amides, bromolactonization of alkynes, haloetherification and haloesterfication of allyl amides, dichlorination of allylic alcohols (Type VI), even fluorocyclization and others.16-20 Another distinct ion-pair modes using a chiral phase-transfer catalyst is demonstrated by Toste and coworkers.22 Enantioselective fluorocyclization of olefins (Type II) proceeded through the chiral anion directed catalysis: a chiral anionic phosphate catalyst brings a cationic fluorinating agent into solution (Scheme 2, eq 2). 22

R

R

O P YR' O

O Y P NHR' O

N H

N H

N H

H

N

(Type I, III, V)

Taguchi (Type V)

O

O NH HN

MeO

H

N N O

O

N

H

N

OMe

(DHQD)2PHAL Borhan, Nicolaou, Gouverneur, Hennecke, You (Type I, II, III, IV, polyene cyclization)

Ph

Ph

NH HN Ar Sc(OTf)3 Shi (Type III)

Shi (Type III) Bn N

Bn N

N HN NH Ni(OAc)2 Arai (Type I)

Ph

Ph

O

DCDPH (1.1 equiv) benzoic acid (1.0 equiv)

cat*

O

H

N Cl DCDPH

N H

R

Cl N

Ph Ph

HA

HA

Ph

N H

R

N Cl R'

NH

O O P O OY Y = H, Na, Li R

(1)

O

R' R'

R'

F

X

Phosphoric acid (10 mol%)

O

Selectfluor (1.5 equiv) Na2CO3 (1.25 equiv)

R

O

N Cl

O

Ar

O

N Cl N

H

or

O

O X

O

Cl Et

Cl N

Ph

N

Fujioka (Type I)

R

(DHQD)2PHAL (10 mol%)

OH

Et

N H

HA H N N

O

Ph2P

Sc(OTf)3

O

Ph

Ph N

M = Co, CrCl

O O

PPh2

(Type I, III)

N

tBu

Kang (Type I, II)

Ph2P

R

Et

N

tBu

O

tBu

Yeung Et

O

2

Scheme 2. Asymmetric Halocyclization of Alkenes

S OAr (Se) OAr

(Type II, III)

N M

tBu

Ph

Ph

N

Ti

O

O

R N S CH3 CONHAr

N

O

Figure 2. Representative Lewis Acid Catalysts

Jacobsen (Type I)

H

O

O

O

R

S Ar

O

Ph

N

R

Ishihara, Denmark, Yamamoto (Type I, II, polyene cyclization)

Ph

Ph

Ph

R Y = O, S, Se

R Y = O, NH Ishihara (polyene cyclization)

oxide32 complexes and others (Figure 2). These catalysts could activate the nucleophile and/or the halogen electrophile. As shown in Scheme 2, eq 3, chiral Cr(III)salen complex could control the enantioselectivity in the iodocyclization to form tetrahydrofurans. The slow release of ICl from NCS and iodine anion is critical, which performs as a zwitterion-like species for the enantioselective iodocyclization after interaction with the metal complex.

O Ar

Page 2 of 15

N

Ar

(2)

Ar Cl Ar O O O O P P N O O O N O Ar Ar F chiral ion pair

Denmark, Shi (Type II, III)

HO

Figure 1. Representative Chiral Organocatalysts In addition to chiral organocatalyst-mediated approach, actually, application of chiral Lewis acids in enantioselective iodolactonization reaction emerged early in 1992.24 Later on, highly efficient asymmetric iodocarbocyclization (Type V) could be accomplished by the use of chiral titanium-taddolate catalyst and a base (Figure 2).25 Significant breakthroughs have been accomplished recently using Co(II)/Cr(III)-salen,26,27 Ni(II)-pybidine,28 Zn(II)-imidazolidine,29 Cu(II)iminoamino,30 Sc(III)-phosphine31 and Sc(III)-phosphine

R

I

Salen-Cr(III) R

I2 (1.2 equiv) NCS (0.7-0.75 equiv)

- + H Cl I H N O

N

O

(3)

OH R H

Cr O Cl

In the halofunctionalization of carbon-carbon double bond of alkenes bearing an electron-withdrawing carbonyl group, the halo-agent (Figure 3), the nucleophile, and electronic nature of the substituent on the alkenes, and the


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catalyst as well have remarkable effect on reactivity, regio-, diastereo- and enantioselectivity. In comparison with the halocyclization of simple alkenes, the halofunctionalization of enones proceeded successfully even in an intermolecular three-component manner. Our laboratory has mainly developed asymmetric halofunctionalization of enones by the use of Lewis acid catalysts based on chiral N,N'-dioxide ligands (Figure 4).33 In this Perspective, we primarily focus on these developments from our laboratory, including haloamination, haloetherification, and haloazidation. Related reports from others are briefly introduced. The discussion includes the research discovery, scope, mechanism and limitation of these reactions. The background references were summarized which highlighted the difficulties lied in the halofunctionalization of enones, involving substrate- or Lewis acid-directed regioselectivity, and the stereogenicity forged in the first addition step. Our efforts on the development of chiral Lewis acid catalysis lead to highly diastereo- and enantioselective generation of βnucleophilic addition α-halo substituted ketone derivatives. O

O Cl S N O Cl

R

N X O NBS: X = Br NCS: X = Cl NIS: X = I

TsNCl2: R = Me p-NsNCl2: R = NO2

R

O Br S N O Br

O I N N O I DIH

TsNBr2: R = Me BsNBr2: R = H CbsNBr2: R = Cl p-NsNBr2: R = NO2

O Br Ph S N O Me BsNMeBr

Figure 3. Structures of Relevant Halogen Sources O R

N N

H

O

O

N O

N H

R

L-PrPr2: R = 2,6-iPr2C6H2

N O

O R

N H

N O H N

O R

L-PiPh: R = Ph L-PiPhEt: R = CH2CH2Ph L-PiAd: R = 1-adamantyl L-PiPr2: R = 2,6-iPr2C6H2

O

N O

N H

N O H N

O

Ar Ar L-RaPr2: Ar = 2,6-iPr2C6H3

α,β-unsaturated esters and chalcones providing antisubstituted α-amino-β-halo-esters and ketones (Scheme 3).36-38 Alliphatic substrates were found to favor formation of α-halo-β-amino adducts.39 Scheme 3. Diastereoselective Aminochlorination of α,β-Unsaturated Carbonyl Compounds

Ar

OMe

O Ar

+

R

2.

ASYMMETRIC CATALYTIC HALOAMINATIONS OF ENONES State of the Field ca. 2009. The haloamination (or aminohalogenation) of olefins with the simultaneous formation of C–N and C–X (X = Cl, Br, I) bonds is one of the most powerful methods for the preparation of the vicinal haloamines.34 This reaction has long been recognized; the addition of N,N-dihalobenzenesulfonamide to cyclohexene, for example, was recorded in 1967.35 In regard to haloaminations of electron-deficient alkenes, Li and coworkers in 1999 described copper(I) triflate (CuOTf) catalyzed highly diastereoselective aminochlorination of



NHTs

2-NsNCl2

1) CuOTf (10 mol %) CH3CN

2-NsNHNa

2) aq. Na2SO3

Cl

O

Ar



R HN

SO2Ar (Ar = 2-NO2C6H4)

In the presence of CuI, MnSO4 or V2O5, the regioselectivity of the reaction among α,β-unsaturated carbonyl compound, N-bromosuccinimide (NBS) and ptoluenesulfonamide (TsNH2) was found to depend on the electronic property of the substituent on the β-aryl group, as reported by Sudalai and co-workers in 2003 (Scheme 4).40 Generally, the amine functionality is introduced at the α-position to the carbonyl group except for aromatic substituent with a para-OMe group, which delivered the corresponding β-amino products. Likewise, the reversal of regioselectivity in the reaction of α,β-unsaturated carbonyl compounds with TsNH2/NBS was also found by the use of the catalyst, such as hypervalent iodine, copper, aluminum or elemental silicon powder.41 To rationalize the observed regiochemistry, both bromonium- and aziridinium-based mechanism was proposed. However, it’s contentious since there is no unambiguous evidence to support these hypotheses. An alternative concerted AdE-3 mechanism as reaffirmed by Borhan and Denmark based on their recent studies might be more possible.7 Scheme 4. Regioselective Bromoamination of α,βUnsaturated Carbonyl Compounds

R

Br

[L-RaAd-Sc(OTf)2]+

Figure 4. Structures of N,N’-dioxide ligands and crystal structures of relevant metal complexes

OMe

Ar

2) aq. Na2SO3

41-82% yield 5/1-30/1 anti/syn

Ar

[L-RaPr2-Sc(OTf)(H2O)]2+

TsNCl2

66-91% yield

O

[L-PrPr2-Sc(OTf)(H2O)]2+

+

O

Cl

1) CuOTf or ZnCl2 (cat) 4 Å MS, CH3CN

O

Ph

+

TsNH2 NBS

O R NHTs

75-82% yield (R = OMe) 68-88% yield (R = Ph)

CuI, MnSO4, or V2O5 (5 mol %) CH2Cl2 >99:1 anti/syn Br

O R NHTs

Cl 63-78% yield (R = OEt) 70-72%yield (R = Ph)

TsHN

Br

O R + Ar

Ar Br (±)

TsHN

O

R NHTs (±) O

R Br MeO 75-82% yield (R = OEt) 78-88% yield (R = Ph)

In terms of asymmetric halofunctionalization of α,βunsaturated carbonyl compounds, very limited examples existed before 2009, which using substrate- and reagentcontrolled methods. As early as 1977, a chiral substrate induced asymmetric bromolactonization of (S)-N-(α,βunsaturated) carbonylprolines readily prepared from α,βunsaturated acids and (S)-proline, was first reported by Terashima.42a Using NBS as bromine source, halolactonization reaction proceeds almost stereospecifically, giving a mixture of the diastereomeric halolactones with up to 94.5:4.5 dr (Scheme 5). In 2004, Li and co-workers developed chiral substrate controlled



asymmetric aminochlorination of optically active α,βunsaturated N-acyl-4-phenyl oxazolidinones with TsNCl2 as both chlorine and nitrogen sources.42b α-Amino-βchloro-substituted products were obtained in good yield and moderate diastereoselectivity (Scheme 6). Scheme 5. Substrate-Controlled Asymmetric Bromolactonization of α,β-Unsaturated Amide COOH

N O

N

t-BuOK

Me

DMF

O

Ph

COOK Me

DMF

Ph

O

N

NBS

O

O Br

N

Me

+

Br

Ph N

O

+ TsNCl2 O

1) CuOTf (8 mol %) 4 Å MS, [Bmim][BF4] 2) aq. Na2SO3

Cl

Me Ph

:

1

Scheme 6. Chiral Auxiliary Group Diastereoselective Aminochlorination O

O

O

Ph 99

Ar

O

Induced O

Ph N

Ar TsHN

O

O

60-72% yield up to 75% de

Work in the Field Since 2009. When our group realized the powerful coordination ability of chiral N,N'-dioxides with metal salts,33 we are interested in chiral Lewis acidpromoted enantioselective haloamination of enones.43 Initially, bromoamination reaction of chalcone with TsNH2 and NBS was tested by the use of the metal complexes of chiral ligand L-PiPh (Scheme 7). Interesting information was derived from this early study. These reactions take place to provide racemic anti-α-amino-β-bromo ketone adduct with low to moderate yield by the use of a series of metal salts, including CuOTf, Cu(OTf)2, Zn(OTf)2, Fe(OAc)2, Fe(OTf)3, Ni(ClO4)2, Co(ClO4)2, Mg(OTf)2, InBr3, CrCl3, Cd(OAc)2.2H2O and SnCl2. Nevertheless, study using Sc(OTf)3 as the metal salt revealed a different regioselectivity, yielding anti-α-bromo-β-amino ketone adduct in good ee value. Although N,N'-dioxides act as tetradentate ligands that securely bind a metal ion forming similar crystal structures of distorted octahedral complexes, the malleability inherent in these metal complexes strongly impacts the reaction.33 During

investigation of the effect of metal ions on the reaction, other L-PiPh-metal complexes except L-PiPh-Sc(III) complex exhibited no reactivity on the regioselective bromoamination reaction to afford α-Br product and the observation of low to moderate yield of β-Br adduct might be due to the background reaction of chalcone with TsNBr2 generated from the Lewis acid catalyzed-reaction of NBS and TsNH2. Scheme 7. Influence of metal salts on the reaction of chalcone with TsNH2 and NBS

O Ph

Ph

+ TsNH2 NBS

Page 4 of 15

L-PiPh-metal salt (10 mol %) CH2Cl2, 35 °C 24 h

Br Ph

TsHN

O Ph NHTs -Br

0-50% yield, 0% ee

or

O

Ph

Ph Br -Br

34% yield, 85% ee

metal ions: Cu(I), Cu(II), Zn(II), Fe(II), Fe(III), Ni(II), Co(II), Mg(II), In(III), Cr(III), Cd(II), Sn(II)

metal salt: Sc(OTf)3

Given this set of circumstances, we next explored chiral N,N'-dioxide-Sc(OTf)3 complex catalyzed asymmetric bromoamination reaction. After further optimization of reaction parameters including chiral ligand (L-PiEPh), additive (4 Å MS), and reaction temperature (0 oC), excellent yield with high enantioselectivity and diastereoselectivity was achieved. A wide range of substrates with various β-aryl or benzoyl groups was examined and selected substituent variation was shown in Scheme 8. The electronic nature of the substituents had a little effect on the regio-, diastereo-, and enantioselectivity of the reaction. It was noteworthy that only 0.05 mol % of catalyst loading is enough for the reaction. Besides using TsNH2 as the nucleophile, other aryl-substituted sulfonamides and methanesulfonamide were also suitable nitrogen-sources for this reaction, and the corresponding anti-α-bromo-β-amino ketones were given with excellent enantioselectivities and diastereoselectivities. Furthermore, this reaction was readily scalable, and the vicinal bromoamine product is readily transformed into chiral aziridine. Actually, α-bromo-β-amino substituted ketones were observed as the sole adducts in our studies by the use of chiral N, N'-dioxide-Sc(III) catalyst, regardless of the electronic nature of the substituent on the substrates or the halo/nitrogen sources. Explanations for the regio- and stereoselective lability of the catalytic bromoamination reaction of enone are difficult. Initially, a bromoniumbased mechanism was proposed mainly based on the observed regioselectivity of the reaction and previous literature reports.40,41 Our controlled experimentation also showed that primary sulfonamide was a weak nucleophile and 1,4-addition product was not observed in the absence of halogen source under the optimal reaction conditions. However, our recent studies on other halofunctionalization reactions of enones (see section 3 and 4) strongly support the synergistic Michael addition/halogenation pathway. The β-Re-face was blocked by the amide unit of N,N'dioxide, thus the β-Si-face attack of sulfonamide anion generated from the reaction of NBS and TsNH2 to C=C bond of enone, following by α-bromination of the resulted corresponding enolate intermediate from the opposite face affords the (1R, 2R)-configuration product (Scheme 8, below). Scheme 8. Asymmetric Bromoamination of α,βUnsaturated Ketones


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O Ar1

Ar2

+

NBS TsHN Ar

TsHN

O

1

Ar

L-PiEPh-Sc(OTf)3 (1:1, 0.05-0.5 mol %)

O R3 S NH2 O

2

Ph

4 Å MS, CH2Cl2 0 °C, 24 h

O

Br N

S

N

H

L* O Sc S O NBr O H

NBS

O

Ph

TsNBr +

Ar

O N Sc O

O

Br

Ar

O

HN

Ph

Ph

95% yield, 95% yield 96% ee, >95:5 dr 92% ee, >95:5 dr

TsNHBr + Succinimide

O

O

MsHN Ph

Br

NBS + TsNH2

R2 Br

F3C

68% yield 97% ee, >95:5 dr

90-99% yield 90-99% ee, >95:5 dr

O

R1

O

TsHN

Br

Br

R3 O S O NH

NH

O O

Br N

widely used in the aminochloronation reaction. When it was employed in the reaction, the yield of chloroaminated product slightly increased. When TsNH2 integrated with TsNCl2, the transformation became highly efficient, allowing the generation of anti-α-chloro-β-amino ketone in the presence of the optimal L-PiAd-Sc(OTf)3 catalyst (Scheme 10, eq 2). Again, the products were obtained with generally high diastereo- and enantioselectivity at low catalyst loading (0.05 mol %). The same facial selectivity of chalcones in chloroamination reaction comparing with that in bromoamination reaction was obtained, affording the corresponding (1R, 2R)-configuration product. The observation that the reaction rate could be accelerated by use more reactive halogen source indicates that the synergistic effect of 1,4-addition and halogenations might be existed. A typical haloamination dependency was observed, with reactivity decreasing in the order NBS> NIS > NCS.

O

Scheme 10. Asymmetric Chloroamination of Chalcones O Ph

The process depicted in Scheme 9 represent our later encouraging progress on a catalytic iodoamination of α,βunsaturated carbonyl compounds.44 The reactions were carried out under strictly anhydrous conditions with freshly dried molecular sieves (4 Å MS) in dark using 0.5 mol % of L-PiEPh-Sc(OTf)3 complex as the catalyst. Niodosuccinimide (NIS) and TsNH2 could be used as the iodo and nitrogen sources, respectively. The substituent at βposition could be aryl, ester, methyl, trifluoromethyl, and hydrogen, and the outcomes remained excellent. The existence of I2 can strongly switch the diastereoselectivity of the reaction, which enabled the transformation of antiα-iodo-β-amino ketone into syn-α-iodo-β-amino ketone due to the epimerization and crystallization-induced resolution. As a result, both cis- and trans-aziridine derivatives are available. Scheme 9. Asymmetric Iodoamination of Chalcones and 4-Aryl-4-oxobut-2-enoates L-PiEPh-Sc(OTf)3 (1:1, 0.5 mol %)

O R

1

R

TsHN

2

O

Ar

+ TsNH2 + NIS

TsHN Ar

I 85-98% yield 96-98% ee

O

RO2C

TsHN Ar

I 83-97% yield 95-98% ee

TsHN

O

R1

4 Å MS, CH2Cl2 0 °C, dark

R2

I >95:5 dr O

R1

Ph I R1 = Me, 86% yield, 94% ee R1 = CF3, 93% yield, 98% ee R1 = H, 90% yield, 90% ee

However, with N-chlorosuccinimide (NCS) and TsNH2 as chlorine and nitrogen sources, chalcone was chloroaminated with very low conversion (< 5%), even the catalyst loading was increased to 5 mol % and the reaction temperature raised to 35 oC (Scheme 10, eq 1).45 The low reactivity promoted us to examine other active chlorine and nitrogen sources. As both chlorine and nitrogen source, N,N-dichloro-4-methylbenzenesulfonamide (TsNCl2) was

Ph

+

O R

Ar

TsHN

+

L-PiEPh-Sc(OTf)3 (1:1, 5 mol %)

TsNH2 NCS

TsHN

O

Ph

4 Å MS, CH2Cl2 35 °C

R

O

TsHN

Ar

1

Cl full conversion 61% yield 21% ee, >95:5 dr

Ar (2)

TsHN Ar

2

O

F3C

Ar

Cl 96% yield 96% ee 97:3 dr L-PiAd

Cl 83-97% yield 95-99% ee >95:5 dr

O Sc S O O NX H

Ar Ph

O

Cl O

TsHN Ar

Cl 65-99% yield 93-99% ee 83:17->95:5 dr

Cl 99% yield 98% ee >95:5 dr

MeO

TsHN

O

Ph RO2C

Cl 19:1 dr Ar Cl

N Bn

O Sc O N O

O S

NHTs

Cl

O

N Bn

N Bn 86% yield 96% ee

65-90% yield 97-99% ee L-PiEPh-Fe(acac)3 (1:1, 0.2-5 mol %)

ArO2SHN

O

Ar1

4 Å MS CH2Cl2, 25 °C

Ar

O N O

NHTs O

O

O N Bn 91-99% yield 94-99% ee O

Ar1

R1

OR

Ar

R

NHTs

X


TsNH2

N Bn

O Br

L-PiEPh-Fe(acac)3 (1:1, 3-5 mol %)

TsNX2

+

Ar2

X 92-98% yield 97-99% ee, >19:1 dr

L-PiEPh O Sc S O O NX H

Ar

NH

TsNCl2

Cl

O

Cl N

NBn Ts

X = H or Cl

Notably, we later demonstrated ArSO2NH2/ArSO2NBr2 combination is highly effective bromine and nitrogen sources in aminobromination of chalcones even in the absence of Lewis acid catalysts.47 As shown in Scheme 12, electron-rich chalcones exhibited higher reactivity and were in favor of the formation of α-Br products; however, for the electron-deficient ones, the β-Br products were observed as the major products. Similar tendency was also observed in the chloroamination reaction by the use of ArSO2NH2/ArSO2NCl2 combination. These results reveal that the reaction has the electrophilic addition feature and might undergo a concerted AdE-3 reaction7 like styrene halofunctionalization in the absence of Lewis acid. The reason of the observed low enantioselectivity in chloroand bromoamination reaction of 3-(4-methoxyphenyl)-1phenylprop-2-enone, bearing a relatively electron-rich carbon-carbon double bond, might ascribe to the strong background reaction. Scheme 12. Catalyst-free Aminohalogenation Chalcones with TsNX2/TsNH2 Combinations

of

Ph

Ar

+


TsNX2 TsNH2

(X = Br, Cl) Ar 4-CF3C6H4 4-ClC6H4 Ph 4-MeC6H4 4-MeOC6H4

Asymmetric R2

Page 6 of 15

4h >19:1 dr

yield

-Br : -Br

46% 85% 92% 95% 99%

>19:1 >19:1 15:1 1:1 19:1 dr

Y = NTs 85% yield 40% ee 93:7 dr

97% yield 95% ee 96:4 dr

93% yield 77% ee 88:12 dr

R2

NH S O O 6/1->19/1 syn/anti 92-96% ee

O

O

O

X

R

90% yield 89% ee >99:1 dr

Ph

R1

NH S O O O 5/1-17/1 anti/syn 92-99% ee

CATALYTIC ASYMMETRIC HALOETHERIFICATION OF ENONES

Besides nitrogen nucleophiles, oxygen-containing nucleophile was also proven effective in the enantioselective halofunctionalizations.51a By judicious selection of aryl sulfonamide or succinimide derived halogen sources and chiral N,N'-dioxide/metal complex catalysts, we realized intramolecular haloetherification of enones. This type of reaction enables the diastereo- and enantioselective synthesis of oxa-heterocycles, including six-membered and seven-membered ones (Scheme 15). Three types of halogen atoms could be easily installed into the α-position of the ketones in good to excellent yields and stereoselectivity. The use of iron(III) salt as the catalyst precursor could promote the formation of tetrahydropyran derivatives. The chiral Ce(III) complex was efficient for the generation of oxepane derivatives, nevertheless the diastereoselectivity was poor which was in sharp contrast to bromoamination reaction and the formation of six-membered oxa-heterocyclic adducts. High enantioselectivity was observed after the two

Cl 1) L-PiPr2-Ce(OTf)3 (1:1, 5 mol %) m-CPBA (5 mol %)

O HO

2

86% yield 90% ee 80:20 dr

O

O Ph

I

O

O 1

L-PiEPh-Sc(OTf)3 (1:1,10 mol %)

Y

R X

O

O

O R1

X = Cl, p-NsNCl2 X = Br, BsNMeBr X = I, NIS

O

O

o-xylene, 0 C

X

R2 NH S O O O

L-PiPr2-Fe(acac)3 (1:1, 5 mol %)

X+ source

Ar

O

O

+

Intramolecular

R

BsNMeBr o-xylene 0 C or 35 °C

O

O

2) Et3N BnSH

R

CH2Cl2, rt

Br 50:50-66:34 dr

Scheme 16. Asymmetric Haloetherification of Enones

R1

R3

R O

2

L-RaPr2-Sc(OTf)3 (1:1; 0.5-5 mol %)

MeOH

toluene, 35 C

O

OMe Ar2

Ar1

O

OMe

70% yield 75% ee > 19:1 dr

Ph

R3

O

Ph

R1

OMe Br

67% yield 60% ee/60% ee 75:25 dr

MeOH (10.0 equiv) toluene, 35 C

OMe

Br R2

Br CN

L-RaPr2-Sc(OTf)3 (1:1; 5 mol %) p-NsNCl2 (0.75 equiv)

O

R = Aryl or Alkyl 73-86% yield 95-98% ee

O

OMe

Ph

Ph Br

Br 81-99% yield 92-96% ee > 19:1 dr

Ph

+

O

Intermolecular

CbsNBr2

O

O R

Ph

64% yield 96% ee > 19:1 dr O

OMe

Ph Cl 64% yield 88% ee, > 19:1 dr Ph

In addition, the resulted chiral α-Br ketone products can be readily transformed into various optically enriched derivatives (Scheme 17). For example, syn-α-azideketone could be yielded with maintained enantioselectivity via an SN2 substitution of the anti-α-Br ketone (eq 1). Removal of the bromo-substituent gave a β-methoxyl ketone



derivative. Reduction and intramolecular substitution afforded epoxide (eq 2). The excellent performance of chiral L-PiPr2-Fe(acac)3 was also highlighted in the kinetic resolution of racemic secondary alcohol via the enantioselective bromoetherification (Scheme 19, eq 3). The synthetic utility of this bromoetherification reaction was further demonstrated by the synthesis of (−)Centrolobine. Scheme 17. Transformation of the Products O

O

O NaN3

O

DMSO, rt

Br

O

49% yield, 90% ee > 19:1 dr O

OMe

Et3N, BnSH CH2Cl2, rt

Ph

Ph

95% yield 94% ee

OMe

1) LiBH4, 0 C Ph 2) KOH, 0 C

Ph Br

OH 3

Ar2

(1

HO

O L-PiPr2-Fe(acac)3 1 Ar2 O BsNMeBr, o-xylene Ar Br 0 °C, 20 min > 93% ee Ar1 = 4-OBnC6H4 Ar2 = 4-BrC6H4 Et3N BnSH three steps

2

Ar3

O

Ar3 = 4-MeOC6H4 ()-Centrolobine 99% ee

O

OMe

+

()-1

Ph

O

(3)

99% ee TfOH ()-2 38% yield for two steps 97.5% ee

O

O Ar2 ()-2 50% yield for two steps 95% ee, > 19:1 dr (recrystallization: 77% yield, >99% ee)

79% overall yield

Ar1

Scheme 18. Working Mechanistic Models Asymmetric Haloetherification Reactions

H

(2)

Ph

Ph

53% yield, 94% ee >19:1 dr

94% ee >19:1 dr

O Ar1

(1) N3

O

93% ee, 96:4 dr

O

O

O

H

O

Ph

O

in

Me

Page 8 of 15

pendent hydroxyl group and promote the 1,4-addition from the dominat face of enones. 4. CATALYTIC ASYMMETRIC HALOAZIDATION OF α,βUNSATURATED KETONES An advance related to enantioselective haloazidation of α,β-unsaturated ketones was realized by the exploration of L-RaPr2-Fe(OTf)2 catalyst system. Azide52 as the nucleophile and similar halo-reagents to these used in haloetherification were used for this purpose.53 Although the related azide 1,4-addition to α,β-unsaturated compounds have been achieved by several groups. The substrates are still limited to α,β-unsaturated imides/ketones and nitro alkenes and the enantiomeric excess are not unsatisfactory in many examples.54 In this haloazidation reaction, a broad range of enones is identified, including both aryl- and alkyl substituted ones (Scheme 19). Bromoazidation performed better than chloro- and iodo-azidation in terms of diastereoselectivity. Noteworthily, the introduction of the halo-reagent accelerated the nucleophilic addition of azide due to the fact that no conjugate addition adduct of azide was detected in the absence of halogen source under optimal catalyst system. We further conducted some kinetic studies with the help of in suit IR to get better understanding of the reaction process. A clear first order dependence on chiral catalyst, enone substrate and TMSN3, but zero order on bromine reagent were presented. This rate equation strongly supports the 1,4-addition/bromination pathway (Scheme 20). We proposed that the azide ion coordinate with iron ion based on recent publication55 and the coordinated azide ion attack the β-position of enone from Si-face since the Re-face was shied by amine moiety. Scheme 19. Catalytic Asymmetric Haloazidation of α,βUnsaturated Ketones

O

R

1

R

2

R3 Note: Catalytic model is based on the X-ray structure of L-RaPr2-Sc(OTf)3

When the identified chiral catalysts were used for either intermolecular or intramolecular oxa-Michael addition reaction in the absence of the halo-reagents, the reactions were sluggish, and only the tetrahydropyran-type of Michael adduct was isolated in moderate yield with extremely low enantioselectivity. None of the oxa-Michael addition products underwent α-bromination in the catalytic reaction conditions. The observation of low diastereoselectivity in some examples and the low reactivity of the substrate with electron-donating substituent on benzoyl group support a stepwise Michael addition/α-halogenation process. Our recent research51b showed that methanol could occupy one position of the N,N'-dioxide complexed Lewis acid, thus we thought that chiral iron catalyst could coordinated methanol or the

O R

1

L-RaPr2 or L-PiPr2 (0.5-5 mol %) Fe(OTf)2 (0.5-5 mol %)

TMSN3

R4

O

+

X+ Source

X = Br, BsNMeBr X = Cl, p-NsNCl2 X = I, NIS

N3

Br R1 = aryl or alkyl 1 R = aryl or alkyl 65-97% yield 85->99% ee 10:1-> 19:1 dr

Ph

Ph

R

CHCl2CHCl2, 0 C

O N3 Me R2

O

N3

Ph Me Br

82% yield 93% ee 11:1 dr

52% yield 97% ee >19:1 dr

X R3

O Ph

Br

O N3 R4 1

R2

N3 Ph

Ph X

X = Cl, 69% yield 95% ee, 2.5:1 dr X = I, 95% yield 92% ee, 3:1 dr

Scheme 20. Proposed Mechanism of Bromoazidation of Enone


Fe2+L*

O Me

O

nPr

O

L* Fe2+

TMSN3

Fe2+

2+L*

Fe

Br

1

1

nPr

O

E

N

N E

Nu-H

O

*

OMe H Me S

O Me

N

Me

*

Me

AcO

Cl Cl NFSI

E

NBn

Cl

Nu

-H+ Me

*

Cl

Cl

N

O

Ph

O X

Me

O

X = Cl, 70% yield 99% ee, 8:1 dr 75% yield, 99% ee 82% yield, >99% ee 77% yield, 99% ee X = F, 60% yield 12:1 dr 11:1 dr 11:1 dr 99% ee, 3:1 dr Cl

Ph

O

Nu

Me

N N

Cl

R

Nucleophile (Nu) Electrophile (E)

N

0

E= O

Nu

N H

Bn

R

nPr

Reaction rate = k [L-RaPr2/Fe(OTf)2] [A] [TMSN3] [BsNMeBr]

N

tBu

N3

N3

1

Me N

O

O

BsNMeBr O-

Ph O Me O S N Br Me

nPr

L* Fe

Me

nPr

Me

N3

Me

2+

*

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


*

Page 9 of 15

O

Cl

Cl

Scheme 22. Reversal of Diastereoselectivity in Hydrofluorination of α,β-Unsaturated Aldehyde Note: Catalytic model is based on the X-ray structure of L-RaPr2-Sc(OTf)3

5.

O

OTHER MISCELLANEOUS DIFUNCTIONALIZATION OF α,β-UNSATURATED COMPOUNDS

Me N

Scheme 21. Halofunctionalization of α,β-Unsaturated Aldehyde

tBu

O

NH (7.5 mol %)

Me

In the case of difunctionalization reaction of α,βunsaturated aldehydes, the relay iminium and enamine activation catalysis played an important role.56 Catalytic asymmetric cascade difunctionalization by the use of electron-rich arene nucleophiles (such as indole, furan and thiophene, butenolides, and tertiary amino lactone equivalents) and halogen electrophiles has been welldesigned by MacMillan and coworkers (Scheme 21). It was noteworthy that syn-diastereoselectivity in all cases was directed by the chiral amine catalyst rather than the stereogenicity forged in the first nucleophilic addition step. This organo-cascade catalysis strategy is also presented in transfer hydrogenation in conjunction with halogenation of (E)-3-phenylbut-2-enal. The hydro-chlorination process provided higher diastereoselectivity than hydrofluorination in the presence one chiral imidazolidinone catalyst. More importantly, the diastereoselectivity of the hydro-fluorination could be improved and modulated by merging two different amine catalysts and judicious selection of the imidazolidinone enantiomer involved in the second catalytic cycle (Scheme 22).

Bn

Ph

O tBuO2C

Hantzsch esters

H

H

Me

H Me Ph

O F 16:1 anti:syn 99% ee, 81% yield

NFSI

OO O CO2tBu O S S N Ph Ph F Me

N H Hantzsch ester nucleophile

NMe Me N Me H (30 mol %)

NFSI electrophile

H Me O

Ph

NMe Me Me N Bn H (30 mol %)

O F 9:1 syn:anti 99% ee, 62% yield

Merging amine-based relay iminium and enamine activation catalyst has also been demonstrated by Cόrdova and co-workers in aminosulfenylation of α,β-unsaturated aldehydes.57 Although neither the separate conjugate transformation nor α-sulfenylation reaction of aldehydes is productive, the domino process involving the two catalytic cycles pushed the equilibrium towards bifunctionalization products (Scheme 23). N-benzylthiosuccinimide acts as the electrophile and a masked nucleophilic component, and the β-amino-α-mercaptoaldehydes were available in good yield and enantioselectivity in the presence of the protected chiral diarylprolinol organocatalyst. The low diastereoselectivity observed in this transformation was attributed to the epimerization of the α-carbon of the product by the chiral amine catalyst. Scheme 23. Aminosulphenylation of α,β-Unsaturated Aldehyde O R

O

N SBn O

Ph Ph N OTMS H (20 mol %) succinimide (10 mol %) CHCl3 60-83% yield

O

N

O

R

O SBn 94->99% ee 49:51-77:23 syn:anti

Chiral metal complex-promoted trifluromethylthiolation of acyclic enones was recently realized by Wang and coworkers. The tandem 1,4-addition of diethylzinc and



Page 10 of 15

electrophilic trifluoromethylthiolation enabled the formation of α-SCF3-β-substituted carbonyl compounds in moderate to good yield and stereoselection (Scheme 24).58 Unlike amine-cascade process, the induction of the second step in this case was closely related to the stereogenicity forged in the first catalytic step as evidenced from the racemic product from the reaction of 1-phenylpropenone.

selection of combination of F+ electrophile and other stronger nucleophile might pave the way to address this issue in future.

Scheme 24. Tandem Addition/Trifluoromethylthiolation of Chalcone

ORCID

O R1

R2

Et2Zn "SCF3"

(R)-Binol-phos PPh2 OH OH PPh2

6.

(R)-Binol-phos/Cu(II) (1.05:1, 10 mol%) THF, -20 oC 50-92% yield

Et

O

R2

R1 SCF3

2:1-20:1 syn:anti 68-96% ee

"SCF3" O2N

1,4-

O N SCF3 O

O

Et

AUTHOR INFORMATION Corresponding Author *[email protected] Yunfei Cai: 0000-0003-4823-8221 Xiaohua Liu: 0000-0001-9555-0555 Pengfei Zhou: 0000-0003-0077-8739 Xiaoming Feng: 0000-0003-4507-0478

Notes The authors declare no competing financial interest.

Biography

Ph SCF3 82% yield, racemic

CONCLUSION AND OUTLOOK

Halofunctionalization of α,β-unsaturated carbonyl compounds is a powerful approach to the synthesis of chiral β-nucleophile substituted α-halo carbonyl compounds in organic chemistry. As summarized in sections 2-4, we have developed Lewis acid catalyzed regio-, diastereo- and enantioselective haloamination, haloetherification, and haloazidation of a broad range of enones with nitrogen-, oxygen- and azide heteroatom nucleophiles, respectively. In sharp contrast to simple olefin halogenations involving a nucleophile assisted alkene activation (NAAA) process, these reactions feature a halogen electrophile assisted 1,4-addition pathway. The synergic α-electrophilic halogenation step controlled by chiral Lewis acid catalyst accelerates the β-nucleophilic addition of these weak hetero-atom nucleophiles. An alternative and also traditional method to this vicinal halofunctionalized products is through stepwise asymmetric conjugate addition of α,β-unsaturated carbonyl compounds to generate chiral β-nucleophilic addition adducts, following by α-halogenation reaction. However, the direct asymmetric conjugate addition of these hetero-atom nucleophiles to electron-deficient olefins has been still a significant challenge in organic synthesis, owing to its low reactivity and the reversibility of the reaction. Despite recent advances in this field of three-component halofunctionalization of α,β-unsaturated carbonyl compounds, many challenges remain: (1) the current substrate scope is extremely limited to enones. A wide range of other electron-deficient α,β-unsaturated compounds such as nitro alkenes, α,β-unsaturated esters and amides need to be explored further. (2) The compatibility between nucleophile and electrophile is another issue due to the possible direct reaction of strong nucleophiles (widely used in conjugate additions such as enolates, phenols, indoles) with halogen electrophiles. (3) F+ based electrophile is still not tolerated and judicious

Xiaoming Feng was born in 1964. He received his B.S. in 1985 and M.S. in 1988 from Lanzhou University. Then he worked at Southwest Normal University from 1988 to 1993, becoming an associate professor in 1991. In 1996, he received his Ph.D. from the Chinese Academy of Sciences (CAS) under the supervision of Professors Zhitang Huang and Yaozhong Jiang. He went to the Chengdu Institute of Organic Chemistry, CAS, from 1996 to 2000 and was appointed a professor in 1997. He did postdoctoral research at Colorado State University in 1998−1999 with Professor Yian Shi. In 2000, he moved to Sichuan University as a professor. He was selected as an Academician of the Chinese Academy of Sciences in 2013. He focuses on the design of chiral catalysts, development of new synthetic methods, and synthesis of bioactive compounds.

ACKNOWLEDGMENT We appreciate the National Natural Science Foundation of China (Nos. 21432006, 21290182, 21625205) for financial support.

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R2

O

1 3

low reactivity reversibility Nu R2 O 1

R + NuH Heteroatom Nucleophile halogenation

4

R

R4

R

yst atal ral C Chi

R R3

Low Yield, Poor ee Conjugate Addition

N ,N

' -D iox ide -M eta l + X Source

X = Cl, Br, I Nu R2 O

R4 R1 dehalogenation R3 X no erosion of ee Good yield, High ee and dr Electrophile Assisted Halofunctionalization


Asymmetric Catalytic Halofunctionalization of Î±,Î²-Unsaturated

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