Tetrahedron Letters 55 (2014) 6147–6155

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Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

Digest Paper

Recent advances in asymmetric fluorination and fluoroalkylationreactions via organocatalysis

http://dx.doi.org/10.1016/j.tetlet.2014.09.0310040-4039/� 2014 Published by Elsevier Ltd.

⇑ Corresponding author. Tel.: +86 21 5492 5340; fax: +86 21 6416 6128.E-mail address: jchxiao@sioc.ac.cn (J.-C. Xiao).

Jin-Hong Lin, Ji-Chang Xiao ⇑Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

a r t i c l e i n f o

Article history:Received 22 July 2014Revised 19 August 2014Accepted 7 September 2014Available online 28 September 2014

Keywords:AsymmetricFluorinationMonofluoroalkylationgem-DifluoroalkylationTrifluoromethylationOrganocatalysis

a b s t r a c t

The past decade has witnessed the significant advances of asymmetric organocatalytic fluorination,monofluoroalkylation, gem-difluoroalkylation, and trifluoromethylation. This digest summarizes the lat-est progress of these reactions. In the research area of asymmetric organocatalytic fluorination, a newcatalysis concept, chiral anion phase-transfer catalysis strategy, has emerged and has proved to be highlyefficient. Asymmetric organocatalytic monofluoroalkylation and gem-difluoroalkylation have been muchless explored and the Lewis base/acid catalysis has been the most used strategy. Compared with electro-philic trifluoromethylation, nucleophilic trifluoromethylation has been intensively studied in theresearch field of asymmetric organocatalytic trifluoromethylation.

� 2014 Published by Elsevier Ltd.

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6147Asymmetric organocatalytic fluorination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6148

Phase-transfer catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6148

Chiral anion phase-transfer catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6148Chiral cation phase-transfer catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6149

Enamine catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6150Brønsted base/acid catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6150

Asymmetric organocatalytic monofluoroalkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6151

Chiral phase-transfer catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6151Brønsted base/acid catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6152

Asymmetric organocatalytic gem-difluoroalkylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6153Asymmetric organocatalytic trifluoromethylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6154Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6154Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6155References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6155

Introduction

Fluorine element has so many unique properties such as smallatomic radius, extremely low polarizability, and highest electro-negativity among all elements that the effect of this atom has beendescribed in various terms, including ‘a small atom with a big ego’,1

‘fabulous fluorine’,2 ‘magic effect’,3 as well as ‘flustrates’ referringto fluorine-containing substrates.4 The incorporation of fluorineor a fluoroalkyl group into a molecule usually modifies its physicaland chemical properties through steric, electronic, and stereoelec-tronic effects. The deep understanding of fluorine effects has led tothe widespread application of organic fluorochemicals in a varietyof research areas, such as medical and agricultural chemistry andmaterials science.1,5 Since the first F-containing drug wasdeveloped in 1957, over 150 fluorinated drugs have been approved

XR2

R1Ar2

NH

O

Ar1

CPA 4, Selectfluor, Na3PO4

CF3Ph, rtX

N

R2

R1O

Ar1Ar2

F

Up to 91% yield> 20/1 dr96% ee

3 5

Phase-transfer catalysisX= C, O

PO

O

OAr

Ar

N N+

F Cl

O H

NR

PhCPA 4:

OO

PO

OH

Cy

Cy

Cy

Cy

Cy

Cy

N+N+

F

PO

O

O

O-* PO

O-O

O*

Soluble fluorinating reagent

Cl

In2X = C, R1 = R2 = H, Ar2 = Ph

Scheme 2. Enantioselective 1,4-aminofluorocyclization of 1,3-dienes.

OR1

CPA 7, Selectfluor, Na2CO3

OR1Amine catalyst

O

Me

F

F

MeHO

H

H

MeO S

F

OCOEt

Fluticasone Propionate Gemcitabine Efavirenz

OHO

HO FF

N

NONH2

Cl

NH

O

O

F3C

Figure 1. Chiral fluorinated drugs.

6148 J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155

by FDA (Food and Drug Administration) in the United Statesfor treating different diseases.6 A survey in 2006 showed thatapproximately 20% of pharmaceuticals and 30–40% of agrochemi-cals on the market contain a fluorine substituent.2 These figuresclearly demonstrate the exceptional importance of fluorinatedcompounds.

As it is well known, one enantiomer of a chiral drug may exhibitdesired beneficial biological and pharmacological effects while theother may result in harmful side effects, or sometimes even bene-ficial but completely different effects. ‘In 2006, 80% of small-mole-cule drugs approved by FDA were chiral and 75% were singleenantiomers’.7 It was estimated that around 200 chiral compoundscould enter the development process each year,7 indicating thestrong demand for the chiral drugs to cure diseases. To date, over15 chiral drugs containing fluorinated or fluoroalkylated stereo-genic centers are commercially available, including FluticasonePropionate, Gemcitabine, Efavirenz, and so on (Fig. 1).8 The pres-ence of fluorine atom(s) is critical to enhance the pharmacologicalproperties of these molecules.

The above facts serve to emphasize that the asymmetric fluori-nation and fluoroalkylation are fascinating research areas inorganofluorine chemistry. Considerable efforts have been directedtoward the development of broadly applicable catalyst system topromote asymmetric fluorination and fluoroalkylation.9 Bothasymmetric transition metal catalysis and organocatalysis haveproved to be quite efficient, but the methods involving transitionmetal catalyst10 are not included here. The asymmetric organocat-alytic fluorination and fluoroalkylation have been intensively stud-ied and the material appearing in the literature prior to 2011 hasbeen reviewed.9f,g Asymmetric catalytic (including transition metalcatalytic) difluoromethylation was reviewed by the group of Zhou

NH

OR1

R2

Ar CPA, Selectfluor, baseC6H5F (or C6H5F + hexane)

O

NR2

R1F

Ar

R3

R3

R4

R4

OO

PO

OH

N+N+

F

ClP

O

O

O

O-* PO

O-O

O*

CPA: Chiral phosphoric acid

baseP

O

O

O

O-*M+

N+N+

F

Cl

2BF4-

SelectfluorInsoluble fluorinating reagent

Soluble fluorinating reagent

1 2up to 95% yield

> 20 / 1 dr97% ee

In1

Scheme 1. Chiral anion phase-transfer catalysis.

in 2013.9i Very recently, Ma and co-workers have summarized theprogress in asymmetric fluorination and trifluoromethylationreactions.9j In this digest we only discuss the latest advances inasymmetric organocatalytic fluorination, monofluoroalkylation,gem-difluoroalkylation, and trifluoromethylation which are notcovered in the reported reviews,9 and introduce some previouspapers as background when necessary.

Asymmetric organocatalytic fluorination

Phase-transfer catalysis

Chiral anion phase-transfer catalysisIn 2011, Toste and co-workers took advantage of a largely

overlooked concept of phase-transfer catalysis that a chiral anioniccatalyst brings a cationic species into solution to achieve the

XX = CR2

2, NBoc, OR1 = aryl, alkenyl, alkynyl

Toluene, rt

Phase-transfer catalysisX

F

6 8

H2O

X

NHR4

R1

X

NR1

R3OMe

O

NH3+

Cl-

CO2Me

R3

H H

PO

O-O

O*

"F+"

X

NR4

FR1

N+N+

F

PO

O

O

O-* PO

O-O

O*

Soluble fluorinating reagent

Cl

H2O

R3 = CH2Ph, CH2-9-Anthryl orCH2-1-Naphthyl

OO

PO

OH

R5

R5

R6

R6

R5 = C8H17, R6 = 2,4,6-( iPr)3-C6H2

CPA:

Up to 61% yield, 94% ee

In4

CPA 7

In3 In5

Scheme 3. Asymmetric fluorination of ketones.

OR1

R2

OCat. 14, NFSI

Toluene (0.33 M)50% aq. K2HPO4

OR1 O

F R2

P

R3

R3

Br-

R3 = 3,5-(3,4,5-F3C6H2)2C6H3

Cat. 14

Up to 96% yield, 56% ee13 15

Scheme 5. Asymmetric fluorination of esters.

ONFSI, Cat. 18, Na2CO3

THF

N H

+H3NNCCl3CO2

-

Catalyst library

up to 88% yield, 99% ee16 17

OMe

Cat. 18

X

O

X

F

Scheme 6. Enantioselective a-fluorination of ketones.

N

Et

FN

Ar H

+

In7

Scheme 7. Transition state for a-fluorination of ketones.

J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155 6149

enantioselective fluorocyclization of olefins 1 with insolubleSelectfluor in the presence of a BINOL-derived chiral phosphoricacid (CPA) catalyst (Scheme 1).11 The important step to achieveexcellent enantio- and diastereoselectivity in the catalytic cycleis the dissolution of insoluble fluorinating reagent (Selectfluor) intothe nonpolar organic liquid phase by counter anion exchange fromtetrafluoroborate (BF4

�) to the chiral phosphate anion (intermedi-ate In1). This strategy for catalytic enantioselective fluorinationreactions is highly valuable due to the following reasons. Firstly,the two stereogenic centers generated in the desired products can-not be easily constructed by alternative methods. Secondly, theapproach is applicable to not only electron-rich olefins, but alsoun-activated olefin. Thirdly, this asymmetric organocatalytic reac-tion represents an efficient chiral anion phase-transfer catalysistactic, which might find application in other asymmetric transfor-mations involving cationic electrophiles.

The group of Toste found this strategy could be extended to var-ious asymmetric fluorination reactions.12 Recently, they describedan efficient method for 1,4-aminofluorocyclization of 1,3-dienes 3with Selectfluor by utilizing phase-transfer catalysis strategy(Scheme 2).13 Surprisingly, although far from the reactive center,substitution on the benzamide arene shows a strong influence onselectivity. 4-tert-Butylbenzamide group was found to be the bestnucleophile after the investigation of other substituted benzamidegroups. The mechanism study suggests that the observed diaste-reoselectivity arises from a concerted anti-1,4-addition (In2).

On the basis of the good results for enantioselective fluorinationof enamides via phase-transfer catalysis,12b Toste and co-workersmade further attempts at the asymmetric fluorination of a-branched cyclohexanones 6 by a combination of chiral anionphase-transfer catalysis and enamine catalysis (Scheme 3).14 Inthe presence of amine catalyst, the substrate ketone would be con-verted to enamine intermediate In3, the fluorination of which andsubsequent hydrolysis gives the final product. The strategy hasproved to be very successful to give the desired fluorinated prod-ucts with high ee. A hydrogen-bonded transition state In4 possess-ing two matched elements of chirality should be able to account forthe observed enantioselectivity.

Akiyama and co-workers reported the enantioselective fluori-nation of b-ketoesters 9 with NFSI (N-fluorobenzenesulfonimide)catalyzed by chiral sodium phosphate with a slightly differentreaction mechanism (Scheme 4).15 In contrast to the strategydeveloped by the group of Toste, the utilization of Selectfluor asfluorination reagent leads to a dramatic loss of enantioselectivi-ty and a decrease in reaction yield. Therefore, Akiyama andco-workers propose that the transition state of this reaction shouldinvolve NFSI. In their proposed transition state (In6), sodium phos-

R1

O

OR2

ONFSI, CPA 11, Na2CO3

BenzeneR1

O

OR2

O

F R3R3

Up to 85% yield, 92% ee

R1O

OR2

O

R3

Na+

POO

O-O

*

Na+

OS

S

Ph

Ph

O

OO

NF

OO

PO

OH

R4

CPA 11:

MeMe

R4

R4 = 9-anthryl

9 10

In6

NSO2PhPhO2S

FNFSI12

Scheme 4. Enantioselective fluorination of b-ketoesters.

phate acts as bifunctional catalyst, Lewis basic activation of sodiumenolate moiety by phosphoryl oxygen, and Lewis acidic activationof sulfonyl group of NFSI by sodium atom of phosphate moiety.

Chiral cation phase-transfer catalysisChiral cation phase-transfer catalysis for asymmetric fluorina-

tion usually employs chiral quaternary ammonium salt as cata-lyst.9f The group of Ma employed chiral quaternary phosphoniumsalt as catalyst to promote fluorination of 3-substituted benzofu-ran-2(3H)-ones 13 with NFSI (Scheme 5).16 The products wereobtained with low enantioselectivity, albeit in high yields. It shouldbe noted that low catalyst loading (2 mol %) is effective, and the

CHOR

Cl

NFSI, Cat. 21 CHOR

Cl F

H

N X

RH

Cl

N X

Cl

BnH

NFSI

19 20

In8 (Z)-In9

NH

ArAr

OTMSCat. 21

Ar = 3,5-(CF3)2-C6H3

Conditions A: 19/NFSI = 3/1, high eeConditions B: 19/NFSI = 1/2, low ee

Scheme 8. Asymmetric fluorination of chloroaldehyde.

6150 J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155

initial concentration of the substrate is important to accelerate thereaction.

Enamine catalysis

In continuation of their efforts to realize enantioselective organ-ocatalytic a-fluorination of carbonyl group,17 Macmillan andcoworkers recently investigated a-fluorination of cyclic ketones16 (Scheme 6).18 They developed a robotic platform to automatethe parallel execution of �400 small-scale reactions to determinethe utility of a library of 250 novel and known organocatalysts inthis reaction by utilizing NFSI as fluorinating reagent. After care-fully screening the reaction conditions, they found that the primaryamine catalyst 18 was quite efficient for this conversion. The reac-tion is applicable to a variety of ketone substrates and enableschemo-, regio-, and diastereoselective fluorination of some com-plex substrates.

Although Macmillan suggested that the reaction may proceedby dual activation of the ketone and the fluorine source, they didnot propose a detailed mechanism (Scheme 6). Recently, the groupof Houk utilized the density functional calculations to elucidate thereaction mechanism and determine the origin of selectivity(Scheme 7).19 Simplified model catalysts were used to computethe enamine transition states (In7) for this reaction. It was con-cluded that the high facial selectivity of fluorination stems fromtwo factors: (1) the preferred chair conformation of the fluorinetransfer ring, and (2) the equatorial site of the bulky quinolinegroup (‘Ar’ in the transition state) on the organocatalyst in theseven-membered fluorine transfer ring.

In a previous study, the group of Shibatomi found that asym-metric fluorination of chloroaldehyde rac-19 with NFSI could give

NO

Boc

R1

R2

SN

S

FR3 R3

O O O O

NO

Boc

R1 F

R2

(DHQD)2PHAL, K2CO3

N

ONN

MeO

N

H

Et

O

N

OMe

N

H

Et(DHQD)2PHAL:

(DHQD)2PHAL

CH2Cl2/CH3CN

NO- K+

Ar1

Boc

R1

23

23

N

Et

F

+N(SO2Ar)2-

In10

K2CO3

N

Et

F

+ KCO3-

KN(SO2Ar)2

NO

Ar1

Boc

R1

N

Et

F

+ HCO3-

In11

In12

23 or In10

KN(SO2Ar)2 or KHCO3

In13

Up to 49% yield, 94% ee22 24

Cat. 25

+24

Scheme 9. Asymmetric fluorination of b-ketoesters.

the fluorinated product 20 in high ee when substrate 19 was usedin excess. Interestingly, the alcohol obtained from the remainingsubstrate by reduction with NaBH4 was obtained with 37% ee.20

If substrate 19 was used as limiting reagent and NFSI was usedin excess, low ee was observed. They collect more experimentalinformation to put forward a mechanism which could explainthe phenomena (Scheme 8).21 They propose that (R)-19 could beconverted to intermediate (Z)-In9 faster than to the thermodynam-ically unfavorable intermediate (E)-In9, suggesting that fluorina-tion of (R)-19 would give the desired product in high ee. Theconversion of (S)-19 to intermediate (Z)- or (E)-In9 is kineticallyand thermodynamically unfavorable, respectively. Thus, fluorina-tion of (S)-19 goes slower than fluorination of (R)-19, and it is dif-ficult to control the enantioselectivity of the fluorination of (S)-19,indicating that if NFSI is used as limiting reagent in the reaction ofrac-19 with NFSI, kinetic resolution of the aldehyde rac-19 wouldbe observed and the fluorination reaction would afford the product20 with high enantioselectivity.

Brønsted base/acid catalysis

On the basis of the results of a previous study that the combina-tion of (DHQD)2PHAL and NFSI is effective for enantioselectivefluorination,22 Yang and co-workers investigated the (DHQD)2-

PHAL-catalyzed fluorination of oxindoles 22 with modified NFSI23 (Scheme 9).23 The modified NFSI are benzenesulfonimides bear-ing different substituents such as F, t-Bu, OMe, CF3, and OCF3 on thepara-position of the symmetric phenyl ring. The fluorinating effi-ciency of these reagents was compared with that of NFSI in thecontext of the enantioselective fluorination of various oxindolesubstrates. It was found that the p-t-Bu substituted NFSI can con-siderably increase the enantioselectivity in most cases, albeitexhibiting lower fluorinating reactivity. In their proposed mecha-nism, the anion metathesis of K2CO3 with intermediate In10 gener-ated from the reaction of catalyst and NFSI gives intermediateIn11. The deprotonation of substrate by In11 produces intermedi-ate In12 and In13. The fluorination of In13 with modified NFSI orintermediate In10 affords the final product.

Recently, Yi et al. described a one-pot approach for the con-struction of fluorinated stereogenic center via fluorination of b-ketoesters 26, followed by Michael addition (Scheme 10).24 Themechanism study suggested that fluorination of b-ketoesters givesracemic product 29, and the Michael addition constructs two stere-ogenic centers in the final product 27. The bifunctional fluoroalky-lated catalyst 28 could be recycled by fluorous solid-phaseextraction in high purity and without significant loss of mass.The reused catalyst can catalyze the reaction almost withoutchange of product yield and selectivity.

R1

O

OR2

O Selectfluor, Cat. 28,R3 R4

CH3CN/PhMe

R1

O

OR2

O

FR4

R3

26 27Up to 96% yield

> 20/1 dr, 94% eeSelectfluor

C8F17

NH

HN

SN

OMe

NEt

R1

O

OR2

O

Frac -29 R3 R4

Cat. 28

Cat. 28

Scheme 10. One-pot fluorination and Michael addition.

NN

R1

R2

O1) Cat. 32, , TolueneR3 NO2

2) NFSI

NN

R1

R2

O

R3 NO2F

O

OAcAcO

AcO N

OAc

N

S

H H

Ph Ph

NHMe2PhCO2

-

Cat. 32

30 31Up to 88% yield, > 99/1 dr, 94% ee

R3 NO2

NN

R1

R2

O

R3 NO2

NN

R1

R2

OH

R3 NO2

Cat. 32

NN

R1

R2

OH

-OBz

R4 N N

S

H H

Ph Ph

NMe2

PhCO2-

H

NO O

HR3

+

NFSI

NSO2PhPhO2S

H

Cat. 32

33 34

In14

Scheme 11. One-pot 1,4-addition/dearomative-fluorination.

ON

Ar1 O1) Cat. 38, , Et2OAr2 NO2

2) NFSI, Na2CO3

ON

Ar1 O

Ar2NO2

F

O

OAcAcO

AcO N

OAc

N

S

H H

Ph Ph

N

Cat. 38

35 36Up to 94% yield, > 99/1 dr

Ar2 NO2

ON

Ar1 OH

Ar2NO2

39

92% ee

Cat. 38Na2CO3

NO

R N N

S

H H

Ph Ph

N

NO O

HAr2

+NaO

Ar1

NFSI

In15

37

Scheme 12. One-pot sequential conjugate addition/dearomative fluorination.

NH

Ar

RSO2Tol

Cs2CO3, (PhSO2)2CHF

NH

Ar

R

SO2Ph

FSO2Ph

up to 92% yield, 97% ee

Cat. 42, Toluene (0.04 M)

Cs2CO3

NAr

R

N

OH

N

R'

+

Br-

R' = 3,5-(tBu)2C6H3Cat. 42

40 41

(PhSO2)2CHF43and

In16

NH

Ph

Ph

SO2Ph

FSO2Ph

MgMeOH/THF

NH

Ph

PhCH2F

(R)-41a (R)-44a90% ee 61% yield, 89% ee

Scheme 13. Asymmetric monofluoromethylation of indoles.

F

R1PhO2S+ I

O

O

SiR23

Cat. 48toluene

∗F

R1PhO2S

Up to 91% yield, 61% ee

N

O NH

H

+

Br-45 46 47

Cat. 48

Scheme 14. Asymmetric monofluoromethylation of alkynes.

J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155 6151

The group of Ma developed a one-pot sequential 1,4-addition/dearomative-fluorination transformation of pyrazolones 30 withnitroolefins and NFSI (Scheme 11).25 The reaction could be appliedto aromatic, hetero-aromatic, and alkylated nitroolefins. All ofthese products could be obtained with excellent levels of enanti-oselectivity, albeit with lower diastereoselectivity for hetero-aro-matic olefin and in lower yields for alkylated olefins. In order toelucidate the reaction mechanism, they collected much experi-mental information. They proved that the keto substrate 30 couldreadily tautomerize to enol form and the hydroxyl group in theenol form is important to promote the reaction, suggesting thattautomerization of both substrate 30 and Michael addition product33 to their corresponding enol forms is very important for this con-version. Interestingly, fluorination of some isolated Michael addi-tion products 33 can give the desired products in high ee withthe use of Et3N instead of the catalyst 32, but lower diastereoselec-tivity was observed, indicating that the chiral catalyst controls thestereoselectivity of both steps, Michael addition and fluorination.

Soon afterward, the group of Ma further extended their strategyto one-pot sequential conjugate addition/dearomative fluorinationtransformation of isoxazol-5(4H)-ones 35 with nitroolefins andNFSI (Scheme 12).26 This conversion could only be applied to aro-matic and hetero-aromatic nitroolefins. No product was observedfor the cases of alkylated nitroolefins. They made an attempt atthe fluorination of one Michael addition product 39 with NFSIand Na2CO3 without the presence of the catalyst 38. It was foundthat this reaction can afford the final product 36 in excellent yield,but with lower ee, suggesting that the chiral catalyst controls thestereoselectivity of both steps.

Asymmetric organocatalytic monofluoroalkylation

Chiral phase-transfer catalysis

In the examination of asymmetric catalytic monofluoromethy-lation of C2-arylindoles 40 with FBSM (1-fluoro-1,1-bis(phenylsul-fonyl)methane) 43, Shibata and co-workers found that a chiralquaternary ammonium salt (42) was very efficient to convert thesubstrates into desired products in high yields and high ee(Scheme 13).27 The initial concentration of substrate shows animportant effect on ee value, and excellent enantioselectivity wasobserved in toluene with the concentration at 0.04 M. The C2-aryl

F

SO2PhPhO2S+

COOMeOBoc

R

N

O

MeO

N

H

Et

O

N

OMe

N

H

Et

O O

(DHQD)2AQN:

Toluene, 50 oC CO2MeRH

F SO2PhPhO2S

49 43 50

Cat. 51

Up to 72% yield

(DHQD)2AQN

> 99.9% ee for all cases

Scheme 15. Asymmetric monofluoromethylation of MBH carbonates using Huang’sprocedure.

ArCOOR2

OBoc+ EtO OEt

O O

F

Cat. 53

Up to 90% yield, 90% ee

ArCOOR2OEt

OO

EtOF

Toluene or Xylene

49 52 54

N

OH

N

Et

O

Cat. 53

Scheme 17. Asymmetric monofluoromethylation of MBH carbonates.

Ar1COOMe

OBoc+ Ar2 OEt

O O

F

(DHQD)2PHAL

Up to 75% yield, 3/1 dr, 96% ee

Ar1COOMeOEt

OO

Ar2F

Mesitylene

49 55 56

Scheme 18. Asymmetric monofluoromethylation of MBH carbonates.

R

O CO2Et

F

O2N Cat. 59 / PNBAToluene

EtO2CR O

F NO257 58 60

Up to 95% yield, 1.8/1.0 dr,Up to 99% ee for both diastereomers

N

N

NH2

Cat. 59

PNBA: p-Niitrobenzoic acid

Scheme 19. Asymmetric monofluoroalkylation of a,b-unsaturated ketones.

O

R1

F

SO2Ph+R2 NO2

Cat. 63m-Xylene, rt

O

R1

R2

NO2

F SO2Ph

Up to 85% yield, 20/1 dr, 92% ee

O

ONN

HN

Bn

HN

S CF3

F3CCat. 63

61 62 64

N

O

NR

H

H

O-N

O

NH

R' R''

R1O-

F SO2Ph

H+

HR2

In17

Scheme 20. Asymmetric monofluoroalkylation of nitroolefins.

6152 J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155

group of indoles also plays an important role for the asymmetricinduction. The reactions of substrates possessing either methyl orhydrogen at the C2 position afforded an almost racemic mixtureof 41, albeit in high yields. A simple one-step reduction of thetwo phenylsulfonyl groups in substrate 40a can be realized underconventional Mg/MeOH conditions to furnish the correspondingmonofluoromethylated product 44a with only slight loss ofenantioselectivity.

The group of Vesely demonstrated the monofluoromethylationof hypervalent iodine substituted silyl alkynes 46 with monoflu-orosubstituted compound 45 catalyzed by cinchona-basedammonium salt 48 to give fluoro-propargyl compounds 47(Scheme 14).28 The R1 group in the substrate 45 can be differentelectron-withdrawing groups, including nitro, nitrile, and carbonylgroups. In contrast to the results obtained by Shibata,27 FBSM(R1 = PhSO2) is not a suitable monofluoromethylation reagent.The reaction of alkyne with FBSM afforded the desired product ina moderate yield without any enantioselectivity. The best enanti-oselectivity was observed when R1 was a nitro group. The silylgroup in substrate 46 was found to be important for both the reac-tion yield and ee value. Bulky silyl group such as tert-butyldiphen-ylsilyl or tri-isopropylsilyl group results in no reaction. A smallersilyl group such as TMS or TES is in favor of the reaction.

Brønsted base/acid catalysis

In 2011, Huang and co-workers achieved the monofluorome-thylation of Morita–Baylis–Hillman carbonates (MBH carbonates)49 with FBSM 43 catalyzed by (DHQD)2AQN (Scheme 15).29 Inter-estingly, a convenient work-up procedure can give the desiredproduct as a pure enantiomer. A simple filtration and the subse-quent washing of the residue with cold toluene/petroleum ethergive the product with >99.9% ee. They compared the reactivity ofBSM [bis(phenylsulfonyl)methane, (PhSO2)2CH2] with FBSM andfound that the reactivity of FBSM was lower than BSM in thisconversion.

Almost at the same time, the group of Shibata reported thesame reaction with the utilization of the same catalyst(Scheme 16).30 The slightly different reaction conditions include

F

SO2PhPhO2S+

COOMeOBoc

R Cat. 51

CO2MeRH

F SO2PhPhO2S

49 43 50Up to 92% yield, 97% ee

PhCF3, 40 oC

Scheme 16. Asymmetric monofluoromethylation of MBH carbonates using Shiba-ta’s procedure.

reaction solvent and temperature. Shibata and co-workers used adifferent work-up procedure, resulting in higher yields and loweree. After the reaction was completed, the reaction mixture wassubjected to flash column chromatography to give the desiredproduct. But in Huang’s case,29 the crude product was washed withcold solvent so that the minor enantiomer was washed away,meaning that the reaction yield would be lowered and the ee valuewould be increased.

Rios and co-workers described the monofluoroalkylation ofMBH carbonates 49 with 2-fluoromalonate 52 catalyzed by b-isoc-upreidine (Cat. 53) (Scheme 17).31 The electronic effect of the sub-stituent on the phenyl group (Ar group) in the substrates 49 shows

NH

R1Br

R2 O + R3

O HO OH

CF3F

Cat. 67

DIPEA (2.5 equiv)MTBE, rt

65 66 68

NH

R1

R2 O

F

O

R3

NNH

O

NH

CF3

CF3

Cat. 67

Up to 60% yield, >20:1 dr, 99% ee

NH

O

F

O

PhN3

PPh3

THF/H2ONH

O

N

F

Ph

> 20/1 dr, 94% ee 3.5/1 dr, 92% ee68a 69a

Scheme 21. Asymmetric monofluoroalkylation of 3-bromooxindoles.

R

NBoc F

F Ar

OTMSCat. 11, 3A MS

THF R

NH

F FAr

OBoc

75 76 77Up to 83% yield, 92% ee

Ph

NBoc F

F Ph

OTMS Cat. 11THF, , 3A MS Ph

NH

F FPh

OBoc

H

H Ph

OTMS

1.0 equiv 1.5 equiv 1.5 equiv 50% yield, 94% ee 26% yield, 72% ee

Ph

NH

Ph

OBoc

75a 76a 78 77a 79

Ph

NH

F FPh

OBoc

MCPBA

Ph

NH

F FOPh

OBoc

1) TFA, CH2Cl22) iPrMgCl, THF

HN

Ph

O

FF

77a (> 99% ee) 80 81 (99% ee)

+ (1)

(2)

Scheme 23. Asymmetric gem-difluoroalkylation of N-Boc imine.

N

O

O

2

R1

Cat. 72THF N

O

R1 HOF

F Ar

OTMS Ar

OFF

J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155 6153

an important effect on the enantioselectivity. The electron-donat-ing group results in a good yield and good ee, but the electron-withdrawing group leads to lower ee.

Monofluoroalkylation of MBH carbonates 49 with a-fluoro-b-keto esters 55 catalyzed by (DHQD)2PHAL was recently reportedby Tan and co-workers (Scheme 18).32 Even though the diastere-oselectivity was low (3/1 to 4/1 dr), the enantioselectivity wasexcellent in many cases.

Zhao and co-workers demonstrated the monofluoroalkylationof a,b-unsaturated ketones 57 with a-fluoro-a-nitro esters 58 viaMichael addition (Scheme 19).33 The reaction can construct twostereogenic centers, but the diastereoselectivity was quite low.The two diastereomers in each reaction could be separated by flashcolumn chromatography and both of them were obtained in excel-lent enantioselectivity.

Soon afterward, the group of Zhao further extended the Michaeladdition strategy to achieve the monofluoroalkylation of nitroole-fins 61 with a-fluoro-a-phenylsulfonyl ketones 62 (Scheme 20).34

In this conversion, the diastereoselectivity and enantioselectivitywere excellent in most cases. On the basis of the absolute configu-ration of one of the major products determined by X-ray crystallo-graphic analysis, they propose a possible transition state In17 toaccount for the stereochemical results.

Trifluoromethyl a-fluorinated b-keto gem-diol (66) can be usedas an efficient monofluoroalkylating reagent to achieve asymmetricmonofluoroalkylation of 3-bromooxindoles (65) catalyzed by Take-moto’s catalyst (Cat. 67) (Scheme 21).35 This conversion affords thedesired products in excellent diastereoselectivity and excellentenantioselectivity starting from two racemic substrates under mildconditions. The synthetic utility of this methodology was furtherillustrated by the conversion of one of the monofluoroalkylation

R1 OTMS

FNH

O

O

R2

Cat. 72 or 73MeCN

NH

O

R2

n

nR1HO

FO

70 71 74Up to 95% yield, 15/1 dr, 94% ee

N

NH

N

R5R3

XNHR4

Cat. 72: R3 = OMe, R4 = 3,5-(CF3)2C6H3, X = O, R5 = EtCat. 73: R3 = H, R4 = t -Bu, X = S, R5 = CH2CH

Scheme 22. Asymmetric monofluoroalkylation of isatins.

products (68a) into 50-fluorinated 3,40-piperidyl spirooxindole(69a), a derivative which shows potential in clinical efficiency innervous system diseases.

Very recently, Zhou et al. disclosed the monofluoroalkylation ofisatins 71 with monofluorinated silyl enol ethers 70 via an organ-ocatalytic Mukaiyama–Aldol reaction (Scheme 22).36 The reactionsproceeded slowly to afford the expected products in moderate tohigh yields and with good to high stereoselectivity. Both the yieldand stereoselectivity were dramatically decreased for the case ofN-methyl protected substrate, suggesting that the free N–H in sub-strate 71 is essential for good results. The acyclic fluorinated silylenol ether is not suitable for this reaction under standard condi-tions, as the corresponding product was obtained in a much loweryield and diastereoselectivity.

Asymmetric organocatalytic gem-difluoroalkylation

The studies on asymmetric organocatalytic gem-difluoroalkyla-tion remained largely unexplored. In 2011, Akiyama and coworkersreported the chiral phosphoric acid catalyzed gem-difluoroalkyla-tion of N-Boc imine 75 with difluoroenol silyl ethers 76 via Man-nich-type reaction (Scheme 23).37 The reaction is applicable toaromatic and heteroaromatic aldimines (75), but not suitable foraliphatic aldimine. The effect of fluorine substituent was disclosedby comparing the reactivity of 76a with non-fluorinated analogue78. Although it was expected that 76a would be less reactive than

R R2

71 76 82Up to 90% yield, 95% ee

CF3

F3C N

O

N

Ar'

NEt

N

O O

H H

R2R1

F

FAr

OSi

CF3

F3C N

O

N

Ar'

NEtH H

FAr

OSi

N

OO

R2

R1

F

In18 In19Favored Disfavored

Scheme 24. Asymmetric gem-difluoroalkylation of isatins.

R1O2CAr

OR2

TMSCF3(DHQD)2PHAL

R1O2C Ar

CF3

49 83Up to 52% yield, 94% ee

Scheme 25. Asymmetric trifluoromethylation of MBH carbonates.

R2O2CF

R1TMSCF3

(DHQD)2PHALR2O2C

F

R1 R2O2CCF3

R1

rac-84 (R)-84 (S)-83

Up to 41% yield97% ee

Up to 50% yield96% ee

R2O2C

FR1

MeSi

Me MeF3C

R2O2C

FR1

MeSi

Me MeF3C

NR

R'R''

(2) Kinetic resolution

fast

slow

(1) C-F bond activation

-Me3SiFR2O2C

R1

NR

R'R''

R2O2CF

R1

(R)-84

CF3-

+ +In20 In22

In21

(3) Enantioselectivetrifluoromethylation

Scheme 26. Kinetic resolution of allyl fluorides by an enantioselective allylictrifluoromethylation.

Cl

NO2

O1) TMSCF3, Cat. 86

toluene/CH2Cl2

N

OMe

OnBu

N+

R

R

R = 3,5-(CF3)2C6H3

85 (S)-87

2) TBAF

Cl

NO2

F3C

OH

74% yield, 80% ee

Fe/AcOH

THF/MeOH

Cl

NH2

F3C

OHKHCO3, MTBE/H2O

4-nitrophenyl chloroformate Cl

NH

F3C

O

O

88 Efavirenz

Cat. 86

98%

64%

80% ee

Recrystallization

99% ee

26%

Scheme 27. Asymmetric synthesis of Efavirenz.

6154 J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155

78 due to the �I effect and +Ip effect of fluorine, competitiveexperiments with 76a and 78 revealed that 76a is much more reac-tive than 78 (Eq. 1, Scheme 23). The synthetic utility of this gem-difluoroalkylation reaction was demonstrated by converting oneof the products 77a into 3,3-difluoroazetidin-2-one 81, a derivativewhich might be used as a pharmaceutically important target aswell as a synthetic building block (Eq. 2, Scheme 23).

Zhou et al. also used difluoroenol silyl ethers 76 as gem-dif-luoroalkylating reagent to achieve gem-difluoroalkylation of isatins71 catalyzed by Brønsted base 72 (Scheme 24).38 The reaction isquite effective for a-aromatic group substituted difluoroenol silylethers (76), but not suitable for a-aliphatic group substituted diflu-oroenol silyl ethers because aliphatic ether cannot be prepared aspure compounds and can only be isolated as mixture with DMF,a solvent which was found to have a negative effect on both thereactivity and enantioselectivity of the gem-difluoroalkylationreaction. In contrast to their results for monofluoroalkylation ofisatines 71 (Scheme 22),36 the free N–H in substrate 71 is notessential in this work. N-Methyl protected isatines 71 can also beconverted into the desired products in good yields with highenantioselectivity. They propose a possible transition state In18to account for the absolute configuration of products. Transitionstate In19 is disfavored due to steric effect.

Asymmetric organocatalytic trifluoromethylation

In 2011, the groups of Shibata and Jiang independently dis-closed the trifluoromethylation of MBH carbonates 49 with Rup-pert–Prakash reagent TMSCF3 catalyzed by (DHQD)2PHAL withhigh enantioselectivity (Scheme 25).39 On the basis of these results,Shibata and co-workers further developed a ‘kill two birds by onestone’ strategy to realize kinetic resolution of allyl fluorides by anenantioselective allylic trifluoromethylation of racemic MBH-typeallyl fluorides 84 via organocatalysis (Scheme 26).40 They proposethat the kinetic resolution/trifluoromethylation proceeds via threesteps, starting from CAF bond activation of rac-84 by coordination

to the silicon atom of TMSCF3. The subsequent SN20 processthrough the addition of (DHQD)2PHAL to the alkene moiety ofIn20 or In21 is the rate-determining step. Kinetic resolution ofrac-84 occurs because the catalyst (DHQD)2PHAL prefers to attackIn20 to release Me3SiF and produce intermediate In22 while In21remains intact. A second SN20 substitution of In22 with CF3

� affordsthe final trifluoromethylation product (S)-83.

Recently, the group of Shibata reported the asymmetric synthe-sis of Efavirenz, which was approved by the FDA in 1998 to be usedas a potent non-nucleoside reverse transcriptase inhibitor of HIV-1and has been used in combination with other antiretrovirals for thetreatment of HIV infection, beginning with the organocatalyzedenantioselective trifluoromethylation of ketone 85 (Scheme 27).41

The following reduction of the nitro group in trifluoromethylationproduct (S)-87 and cyclization reaction give Efavirenz with 80% ee.A single recrystallization easily increased the ee value from 80% eeto 99% ee.

Conclusions and perspectives

The past decade has witnessed the significant advances ofasymmetric organocatalytic fluorination and fluoroalkylation.Among these reactions, fluorination and trifluoromethylation havebeen intensively studied, whereas monofluoroalkylation and gem-difluoroalkylation have been much less explored and remainedchallenging. Even though a variety of electrophilic and nucleophilicfluorinating reagents are commercially available, electrophilicfluorination, usually employing Selectfluor or NFSI as fluorinesource, has been the most used methods for asymmetric organo-catalytic fluorination. In contrast, asymmetric organocatalytictrifluoromethylation usually utilizes nucleophilic trifluoromethy-lating reagents. Asymmetric trifluoromethylation of carbonyl com-pounds, imines, and MBH carbonates has been the subject ofintense research.9j The development of efficient and generallyapplicable monofluoroalkylating and gem-difluoroalkylatingreagents, especially monofluoromethylating and difluoromethylat-ing reagents, are the main issues that remain to be addressedfor the asymmetric organocatalytic monofluoroalkylation andgem-difluoroalkylation.

So far, the asymmetric organocatalytic fluorination and fluor-oalkylation usually construct only one or two stereogenic centers.More efforts should be directed toward the construction of

J.-H. Lin, J.-C. Xiao / Tetrahedron Letters 55 (2014) 6147–6155 6155

multi-stereogenic centers and multi-membered ring(s) via tandemreactions. More importantly, the exploration of new organocataly-sis concepts is also highly desirable.

Acknowledgments

We thank the National Natural Science Foundation (21032006and 21172240), the 973 Program of China (2012CBA01200), andthe Chinese Academy of Sciences, Science and Technology Com-mission of Shanghai Municipality (14ZR1448800).

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