Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions

Activated aromatic ketones could be also used as nucleophiles for Brønsted base catalyzed reactions, while much more efforts were donated to -cyano ketones.6 This chapter reviews the pr

Chapter 1

Fluorocarbon Nucleophiles in Organocatalysis

2

1.1 Introduction

The emergence of asymmetric organocatalysis as a reliable strategy for the

development of asymmetric reactions represents a remarkable advance in

synthetic organic chemistry For enamine catalysis, iminium catalysis, general

acid/base catalysis, nucleophilic catalysis and phase-transfer catalysis, most of

these orgnic catalysis systems are electrophile-nucleophile reactions The

nucleophiles in such reactions are very important for the asymmetric

transformation by the interaction between the hydrogen bond donor catalyst and

substrates Generally, a chiral acid or a chiral base catalyst can promote an

enantioselective nucleophile-electrophile reaction However, the development of a

broadly useful platform for the activation of nucleophiles via base catalysis

represented a major challenge in asymmetric catalysis

Recent research efforts have mainly focused on di-carbonyl compounds, which

are easily activated and widely used in many asymmetric conjugated addition

reactions Most aliphatic ketone and acetophenone nucleophiles used in

organocatalytic asymmetric transformations rely on the formation of highly

reactive enamine intermediates.1 On the other hand, Brønsted basesare seldom

used as catalysts in reactions of simple carbonyls due to the relatively lower

basicity of most organobases, thus its inability to activate the carbonyl through

enolization Successful examples typically employ strategies to increase the

acidity of the -proton For example, activated esters, such as trifluoroethyl

thioesters,2 -cyanothioacetates,3 -substituted cyanoacetates,4 and

-nitroacetate5 are valuable nucleophiles for organic base-catalyzed reactions because of their enhanced acidity Activated aromatic ketones could be also used

as nucleophiles for Brønsted base catalyzed reactions, while much more efforts

were donated to -cyano ketones.6

This chapter reviews the progress on fluorocarbon nucleophiles used in

organocatalysis, and some related transitional metal catalyzed asymmetric

reaction of fluorocarbons are also included

1.2 Fluorocarbon nucleophiles in organocatalysis

1.2.1 Fluoroacetone as nucleophile

Using fluoroacetone as the most promising fluorocarbon nucleophile in

asymmetric aldol reaction, the methodology provides a useful route for the

synthesis of optically active -fluoro-β-hydroxy ketones Barbas and his coworkers7 reported the first amino alcohol catalyzed direct asymmetric aldol

reactions of fluoroacetone 1 with aldehydes 2 using chiral prolinol 3 as catalyst

The formation of more reactive enamine of fluoroactone 1 with L-prolinol made

the reaction proceed, although a long reaction time was required in presence of 35

mol% catalyst In most cases, both aromatic aldehydes and aliphatic aldehydes

were tolerated, and the products were formed with high regioselectivities The

anti--fluoroaldol products 4 were obtained in unsatisfactory yields with

OH R

1 2

4/5 = 1:4-43:3 yield: 29-82%

ee: 79-87%

Scheme 1.1 Aldol reaction of aldehydes with fluoroacetone catalyzed by prolinol

Direct asymmetric aldol reaction between aldehydes and fluoroacetone

provides convenient access to chiral -fluoro-β-hydroxy ketones However, it is not easy to control the selectivity and generate a single isomer because six

isomers were produced in this reaction Recently, Gong’s group8a has developed a

highly enantioselective aldol reaction with fluoroacetone catalyzed by L-proline

amide 6 The reaction predominantly afforded 4 with regiomeric ratios of 4/5

ranging from 83/17 to 98/2 and excellent enantioselectivities ranging from 94% to

98%, although the aromatic aldehydes with strong electron-withdrawing group

were required as the aldol acceptor (Scheme 1.2 Eq 1) Similarly, Guillena et al.9

also reported a solvent-free asymmetric direct aldol reaction between

fluoroacetone and 4-nitrobenzaldehyde catalyzed by (S)-binam-L-prolinamide 8

The anti aldol product was obtained with 80% ee

The anti diastereomers were provided predominantly by the second

amine-based organocatalysts, so the highly enantioselective syn-direct aldol

reaction remained an important challenge.10 Gong and his coworkers8b designed a

new organocatalyst 7, which was easily synthesized from primary amino acids

and β-amino alcohols The nitro substituted aromatic aldehydes were used as aldol

acceptors, and the highly enantioselective syn aldol adducts 4 (up to 99% ee) were

achieved with good yields (Scheme 1.2 Eq 2)

20 mol% 6

THF, 0 o C

OH Ar

1 2

CO2Et

CO2Et OH

20 mol% 7

m-xylene, rt

OH Ar

O

F

4 1

(S)-Binam-L-prolinamide

8

Scheme 1.2 Aldol reaction of aldehydes with fluoroacetone

1.2.2 Fluorinated 1,3-dicarbonyl compounds as nucleophile

Fluorinated 1,3-dicarbonyl compounds are much more reactive fluorocarbon

nucleophiles for some asymmetric transformations in the presence of chiral metal

complexes or organocatalysts

O OBn

O BnO + 0.5 mol% [Cu((S,S)-Ph-Box)](OTf)211

DCM, RT

O

R1F

O

R2N HN COOBn COOBn

10b

Boc +

O

R1F

O OEt N HN Boc Boc

R

Ni HN HN R

R

X X

Togni and co-workers11 reported the first asymmetric amination of β-keto esters

9a-9e and β-keto amide 9f with azodicarboxylates 10a catalyzed by a

copper-bisoxzoline catalyst 11 -Fluoro--hydrazino β-keto esters 12, which are

also potential precursors for -fluoro--amino acids, could be obtained in good

yield with ee up to 94% However, the preliminary experiments dealing with the

cleavage of the N-N bond failed Subsequently, NMR studies about the N-CO and

N-N bonds rotation were examined in their research (Scheme 1.3 Eq 1.) Similar

work has also been reported by Kim and his co-worker.12 The air and moisture

stable chiral nickel complex 14 was used as a catalyst for the amination reaction

between -fluoro-β-ketoesters 9 and azodicarboxylates 10b The desired products

13 were obtained with good yields, but the enantioselectivities were moderate (up

to 78% ee) (Scheme 1.3 Eq 2) Maruoka et al.13 reported one single entry about

asymmetric amination of -fluoro-β-ketoester by the binaphthyl-modified

quaternary phosphonium salts, with 73% ee obtained

In contrast to the chiral metal complexes, such fluorinated methane

nucleophiles were more efficient under chiral organic base catalyzed conditions

More recently, Lu and his co-workers14a documented the enatioselective

amination reactions of β-keto esters 9 and azodicarboxylates 10b catalyzed by a

chiral guanidines derived from cinchona alkaloids (G-C-a and G-C-b) The ee

values of adducts 13 (up to 92% ee) were higher than the results from Kim’s work

(Scheme 1.4)

Scheme 1.4 Asymmetric amination of β-keto esters with azodicarboxylates

Recently, Lu14b and Wang15a reported highly enantioselective Michael reaction

of -fluoro-β-ketoesters and nitroalkenes catalyzed by cinchona alkaloid-derived

8

organocatalysts, respectively Lu and co-workers examined -fluoro-β-ketoesters

9 with a wide range of aryl and alkyl nitroolefins 16 catalyzed by cinchona

alkaloid-based thiourea bifunctional organocatalyst QD-1 Quantitative yields and

excellent enantioselectivities were achieved, although the diastereoselectivities

were moderate in most of the cases (Scheme 1.5) The Michael adducts containing

fluorinated quaternary carbons can be converted into useful chiral structural

scaffolds with three contiguous stereogenic centers 19 and 20 after one or two

steps from adduct 18 (Scheme 1.6)

Scheme 1.5 Asymmetric Michael reaction of -fluoro-β-ketoesters and nitroalkenes

Pioneering work was reported by Wang and his co-workers.15a The alkyl

-fluoro-β-ketoesters 9 used as Michael donor reacted with various nitroolefins

16 catalyzed by cinchona alkaloid derivative QD-2 with a low catalyst loading (1

mol%) The reaction afforded the Michael adducts with moderate

diastereoselectivities and excellent enantioselectivities The adduct 21 was

converted to synthetically useful chiral ∆1-pyrrolidine 22 by a simple

hydrogenation reaction (Scheme 1.6)

O

Ph

O

OEt F

NO2

OH Ph

O OEt F

OH F

21

Ph3SiH, AlCl3DCM, 86%

NiCl2/NaBH4

CH3OH 91%

NO2Cl

N

CO2Et F

Cl

22

Raney Ni

1 atm H 2 EtOH, 12h 80%

ee: 98%, 95%

dr: 2.5/1

Scheme 1.6 Modification of Michael adducts 18 and 21

Another similar work in this area was also done by them.15b They discovered

an efficient Michael addition of nitroolefins using commercially available

-fluoromalonate as nucleophile Highly enantioselective Michael adducts 23 (up

to 98% ee) were obtained with high yields in presence of QD-2 (Scheme 1.7)

Scheme 1.7 Asymmetric Michael reaction of -fluoromalonate and nitroalkenes

10

Inspired by previous work, Kim and co-workers16 reported this kind of Michael

reaction using bifunctional thiourea-type organocatalyst bearing both central and

axial chiral elements 17 The Michael adducts were obtained in high yields with

moderate diastereoselectivities and excellent enantioselectivities (up to >99% ee)

(Scheme 1.5)

Scheme 1.8 Asymmetric Michael reaction between -fluoro-β-ketoesters and

N-alkyl maleimides

Our group17 also developed a highly enantioselective and diastereoselective

Michael addition reaction of -fluoro-β-ketoesters 9 (R1 = Ar) with N-alkyl

maleimides 24 catalyzed by chiral guanidine 25 Aryl -fluoro-β-ketoesters 9

performed as nucleophiles in this Michael reaction in presence of 5 mol% chial

guanidine catalyst The adducts 26 were afforded with high yields, excellent

diastereoselectivities (dr: >99/1) and ee values up to 99% (Scheme 1.8 Eq 1) Aryl

-fluoro-β-ketoesters 9 were also found to be good nucleophiles for Michael addition with linear Michael acceptors such as trans-4-oxo-4-arylbutenamides 27

With 10 equivalents triethylamine as an additive and 20 mol% catalyst loading,

the adducts 28 were obtained in excellent eantioselectivities (up to 96%),

diastereoselectivities (99:1) (Scheme 1.8 Eq 2)

Figure 1.1 Optimized (B3LYP/6-31G*) geometries of the four transition states

leading to the (S,R)-, (S,S)-, (R,S)-, and (R,R)-products Calculated related

energies were given in square brackets in KJmol-1 and the bond lengthsare given

in Ǻ Side view of the calculated face-on pre-transition state complex was also given

To understand the mechanism, density functional theory (DFT) calculations at

the B3LYP/6-31* level were performed An ion-pair complex between

guanidinium cation and -fluoro-β-ketoester was formed, before the maleimide approaches the complex to form a pretransition-state complex Two possible

structures for the pretransition-state complex were hypothesized: face-on or

side-on The side-on TS was strongly preferred over the face-on TS because of the

stronger hydrogen bond association with the maleimide carbonyl group For the

12

four plausible side-on transition states, the calculated preference for the

(S,R)-stereoisomer was in agreement with the observed high enantioselectivity

and diasteroselectivity (Figure 1.1)

dr: 6/1->99:1 yield: 44-80%

O

R1

R3

CO2R2F

33

+ OH

N H

NH2NHR'

32a: R' = CH2CH2CH3

32b: R' = C(CH3)3O

F

R3

R1

CO2R2O

intramolucular aldol reaction

Scheme 1.9 Asymmetric Robinson annulations of -fluoro-β-ketoesters 29

Most recently, Zhao and co-workers18 reported asymmetric Robinson

annulation reaction of -fluoro-β-ketoesters 29 catalyzed by primary-secondary

diamine catalysts 32 The multiply substituted fluorinated chiral cyclohexenones

trans-31 and 33 were synthesized by the combination of Michael addition,

intramolecular aldol reaction and dehydration The highly enantioselective

products trans-31 (up to >99% ee) were achieved with good yields by the diamine

catalyst 32a in presence of 10 mol% p-nitrobenzoic acid as additive (Scheme 1.9)

Besides the major products, there was also undehydrated product 33 obtained in

the reaction The ratio of trans-31/33 ranged from 1/1 to 6/1 They proposed a

probable mechanism for the observed transformation Intermediates I and II were

achieved by Michael reaction between -fluoro-β-ketoesters 29 and

,β-unsaturated ketones 30 This was followed by intramolecular aldol reaction which gave I’ and 33 respectively The intermediate I’ underwent the dehydration

step quickly to deliver the product trans-31, while dehydration of 33 was very

slow due to the intramolecular hydrogen bond interaction between the hydroxyl

group and the ester’s carbonyl group (Scheme 1.9)

R'

R' = 3,4,5-F3C6H2

(S,S)-35

Scheme 1.10 Asymmetric alkylation of -fluoro-β-ketoesters

Maruoka and co-workers19 reported asymmetric alkylation of

-fluoro-β-ketoesters 9 and alkyl halide 34 with N-spiro chiral quaternary

14

ammonium bromide (S,S)-35 Under phase-transfer conditions, fluorocarbon

nucleophiles exhibited good reactivity towards various alkyl halides such as

allylic and simple alkyl halides The best enantioselectivity achieved was 89% ee

R1= Ph

R 2 = Et

O Ph

O OEt Cl

NHBoc

O Ph

O OEt NHBoc

dr: 6/1 yield: 92%

ee: 82%

dr: 1/1 yield: 95%

ee: 97%/92%

Scheme 1.11 Asymmetric Mannich reaction of -fluoro-β-ketoesters

Fluorocarbon nucleophile are also excellent nucleophiles for Mannich reaction

under chiral organic base catalysts Lu and co-workers20 reported asymmetric

Mannich reaction of -fluoro-β-ketoesters 9 and N-Boc imine 36 with a

tryptophan-derived bifunctional thiourea catalyst Trp-a High enantioselective

Mannich products 37 were observed with a wide range of aromatic and alkyl

-fluoro-β-ketoesters in good diastereoselectivities -Fluoro-β-lactam 38 and

-fluoro-β-lactone 39 were prepared by three steps from the Mannich products 37 The Mannich product 40 was achieved using -chloro-β-ketoester as nucleophile,

but slightly lower enantioselectivity was obtained (82% ee, 17% ee lower than the

fluorinated one) For the nonfluorinated β-ketoester, the product 41 was obtained

with high enantioselectivities for both diastereomers although the dr value was

one to one (Scheme 1.11)

ee: 95->99%

N

R2O O

42: R1= Ar, alkyl

O OCEt3

DCM, RT 24-36h

N N N H

O R1

Et3OC O

O O

44

R1= Me

R2= p-BrC6H4

K2CO3(2.0 equiv) EtOH, -20oC

50% (w/w) NaOH (aq.) toluene, H2O,RT

NH F

O

Et3OC O

H Br

NH H

O

Et3OC O

F Br

Scheme 1.12 Asymmetric Mannich reaction of β-keto acetyloxazolidinones

Pioneering work was also reported by our group.21 β-Keto acetyloxazolidinones

were used as fluorocarbon nucleophiles in asymmetric Mannich reaction with

N-Eoc imines 43 catalyzed by our chiral guanidine catalyst 25 Excellent

diastereoselectivities (up to 99/1) and enantioselectivities (up to 99% ee) were

16

achieved for the Mannich adducts 44 When the Mannich product was treated

with two equivalents potassium carbonate, the -fluoro-β-amino ester 45 was obtained after deacylation, protonation and transesterification steps When it was

treated with sodium hydroxide, -fluoro-β-amino ketone 46a and 46b were generated by decarboxylation and protonation steps (Scheme 1.12)

1.2.3 FBSM and FSM derivatives as nucleophile

1-Fluoro-bis(phenylsulfonyl)methane (FBSM) and fluoro(phenylsulfonyl)

methane (FSM) derivatives are effective synthetic equivalent of

monofluoromethide species in asymmetric catalysis With electron withdrawing

sulfonyl or nitro functionalities in the molecule, the fluorocarbon is much more

FBSM

L1 or L2 (5 mol%)

[{Pd(C3H5)Cl}2] (2.5 mol%)

Cs2CO3(1.1-1.5 equiv) DCM, 0oC