5.9 Oxidation: C–X Bond Formation (X=Halogen, S, Se)

5.9 Oxidation: CX Bond Formation (X¼Halogen, S, Se) N Shibata, X-H Xu, and S Suzuki, Nagoya Institute of Technology, Nagoya, Japan D Cahard, CNRS, Mont Saint Aignan, France r 2012 Elsevier Ltd. All rights reserved.

5.9.1 5.9.2 5.9.2.1 5.9.2.2 5.9.2.3 5.9.3 5.9.3.1 5.9.3.2 5.9.3.3 5.9.4 5.9.5 5.9.6 5.9.6.1 5.9.6.2 5.9.6.3 5.9.6.4 5.9.7 5.9.7.1 5.9.7.2 5.9.8 References

Introduction Enantioselective Electrophilic Fluorination Chiral Fluorinating Agents Chiral Base-mediated Enantioselective Fluorination Transition-metal Catalysis Enantioselective Electrophilic Chlorination Chiral Chlorinating Agents Transition-metal Catalysis Chlorination of an Olefin Enantioselective Electrophilic Bromination Enantioselective Electrophilic Iodination Enantioselective Electrophilic Sulfenylation Chiral Sulfenylating Reagents Chiral Auxiliary Transition-metal Catalysis Organocatalytic Sulfenylation Enantioselective Electrophilic Selenenylation Chiral Selenenylating Reagents Organocatalytic Selenenylation Conclusion and Outlook

Glossary Chiral auxillary Optically active parts temporarily incorporated into the substrates to induce asymmetric center(s) in the products and they should be removed in the final step. C2-symmetric compounds Molecules which exist in the same geometry as the starting geometry of the molecules after being rotated 1801 around an axis of the molecule

5.9.1

218 219 219 222 222 231 231 232 236 236 238 239 239 240 241 243 243 243 244 244 244

Electrophilic reagents Reactants act as electron-pair acceptors in the covalent bond formation reaction. Enantiomer One of a pair of compounds having a mirror image relationship. Enantioselectivity The selectivity of a reaction towards one of a pair of enantiomers. Ionic liquid A class of purely ionic, salt-like materials that are liquid at unusually low temperatures.

Introduction

The formation of CX bonds (X ¼ halogen, S, Se, etc.), particularly those categorized as oxidation, is one of the fundamental parts of many chemical reactions. Therefore, innovations in enantioselective variants of these types of reactions is tremendously important in organic synthesis, enriching this science. This chapter focuses on the direct enantioselective carbon–X bond formation reactions based on electrophilic reactions via the functionalization of CH bonds or sp2 carbon. The chapter basically covers the reactions in chronological order of their discovery. The first part of the chapter describes the electrophilic enantioselective halogenation reactions including fluorination, bromination, chlorination, and iodination by both stoichiometric and catalytic pathways. In the next parts, we discuss the carbon–sulfur and carbon–selenium bond formation reactions via the enantioselective electrophilic pathway. The synthesis of stereodefined halogenated molecules is an important challenge in organic chemistry. This topic has received considerable attention because of the utility of chiral halogenated compounds in a wide variety of disciplines. There are two types of oxidation processes for CHal bond formation depending on whether the halogen atom is radical or cationic. Diatomic halides are the simplest reagents to generate halogen radicals but are of little synthetic use because of the difficulties in controlling their reactivity, often leading to nonselective radical processes. Nevertheless, there are a few examples that use chlorine or iodine as sources of positive halogens. Therefore, stable, selective, and safe reagents are crucial to the development of electrophilic halogenation. A halogen acts as an electrophile when it is polarized in a positive sense by combination with a group containing electronegative elements. A considerable number of electrophilic halogenating agents have been reported. The popularity of these reagents comes from the fact that they possess a long shelf life; several are commercially available, and they can be handled safely

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Oxidation: CX Bond Formation (X¼Halogen, S, Se)

219

in glassware. In this chapter, only the enantioselective halogenations conducted with chiral reagents and organometallic catalytic approaches are covered. Diastereoselective reactions are mentioned in Volume 3 whereas organocatalytic a-halogenation of aldehydes and ketones are presented in Volume 7. In the second half on this chapter, we treat the preparation of CX bonds where X is S or Se. Chiral organosulfur- and organoselenium-containing compounds are synthetic targets attracting much recent interest in view of both their ambiguous synthetic utilities as chiral building blocks and chiral ligands, as well as compounds with unique biological activities. Among various strategies that have been available for this purpose, enantioselective electrophilic sulfenylation and selenylation of carbonyl compounds, including aldehydes, ketones, 1,3-dicarbonyl compounds, or their equivalents with various electrophilic reagents, which allows the direct conversion of racemic or achiral carbonyl compounds to chiral a-sulfenyl or selenyl carbonyl compounds in a single operation, are important processes in organic synthesis. In addition to the halogenation reactions mentioned above, here, the enantioselective CS and CSe bond formation reactions conducted with stoichiometric chiral reagents and organometallic catalytic approaches, as well as organocatalytic approaches, are described. The related reactions are also mentioned in Chapters 6.19 and 7.20.

5.9.2

Enantioselective Electrophilic Fluorination

There are several methods for conducting enantioselective electrophilic fluorination.1 The use of chiral, nonracemic N–F or [N–F] þ reagents is quite a general approach since a wide variety of substrates can be fluorinated. With the aid of a stoichiometric, chiral fluorinating agent, a prochiral substrate is transformed into a chiral product with the concomitant creation of a fluorinebearing stereogenic center. Another approach involves transition-metal catalysis of the fluorination of essentially 1,3-dicarbonyl compounds and b-keto phosphonates. Since enolization of 1,3-dicarbonyl compounds is promoted by Lewis acids, chiral transition-metal catalysts have been investigated, and are found to produce enantioenriched a-fluorinated 1,3-dicarbonyl compounds. More recently, enantioselective organocatalytic a-fluorination of aldehydes and ketones has demonstrated a high level of enantioselectivity and is reported in Volume 7.

5.9.2.1

Chiral Fluorinating Agents

The first enantioselective fluorinating agents were the camphor-derived N-fluorocamphorsultams 1a–d (Figure 1). They are prepared by passing a mixture of 10% (v/v) molecular fluorine in nitrogen through a solution of the corresponding camphorsultam in CHCl3/CFCl3 at –401 in the presence of powdered NaF as the HF-scavenger.

R2 R2 N F 1 SO2 R

1a: R1 = H, R2 = H 1b: R1 = Me, R2 = H 1c: R1 = H, R2 = Cl 1d: R1 = H, R2 = OMe

Figure 1 Camphor-derived N-fluorosultams. Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

The fluorination of various prochiral metal enolates of ketones, esters, and b-keto esters affords a-fluoro carbonyl compounds in modest yields and with up to 75% ee (equation 1). However, most of the ee values are in the range of 10–40%.

O

(i) NaHMDS, THF, −78 to 0 °C (ii) (–) -1c (0.8 equivalent), inverse addition

O

F Yield = 40% ee = 75%

ð1Þ

Other examples of chiral fluorinating agents include the nonracemic, acyclic N-fluorosulfonamides 2 and 3a,b (Figure 2) synthesized from phenylglycine and a-phenethylamine as chiral starting materials. Their preparations utilize either diluted molecular fluoride or perchloryl fluoride. However, they display poor reactivity toward metalated enolates and are not very stable under the reaction conditions. Poor yields (r53%) and only moderate ee values of up to 54% are obtained. Several enantiopure, cyclic N-fluorosulfonamides 4–6 (Figure 2) have been designed and tested for electrophilic fluorination of aryl ketone enolates. Although the synthesis of N-fluorosulfonamide 4 requires several steps, this reagent exhibits excellent enantioselectivity in the case of 2-benzyl-1-tetralone, producing ee values as high as 88%, and affords good chemical yields (equation 2).

220

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

Ts

F N

OAc

Ts

F N

Ms

Ph

F N

Ph

2

Ph

3a

O2 S N F

O2 S

O2N

3b

N

O2 S

F

F N

i-Pr

t-Bu 4

5

6

Figure 2 Chiral N–F fluorinating agents. Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

O

O (i) LDA, THF, –40 °C

Bn

Bn

Yield = 79% ee = 88%

F

(ii) 4 (1.1 equivalent)

ð2Þ

Although satisfactory enantiomeric excesses (ees) of up to 88% are attained in the fluorination of metal enolates, the N–F reagents present two sizeable drawbacks: their arduous multi-step syntheses, and the necessity of handling molecular fluorine or perchloryl fluoride. A major breakthrough in the field of enantioselective electrophilic fluorination came from the development of a different class of reagents: the [N–F] þ ammonium salts of cinchona alkaloids (Figure 3). These fluorinating agents are easily obtained in a one-step transfer-fluorination of cinchona alkaloids with the aid of Selectfluor [1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)], or can be generated in situ from the same reagents. Advantageously, cinchona alkaloids are readily available in diastereomeric forms [cinchonidine (CD)/cinchonine (CN) and quinidine (QD)/quinine (QN)], known to behave as pseudoenantiomers in asymmetric synthesis. In addition, such reagents benefit from the commercial availability of both Selectfluor and the cinchona alkaloids. Several achiral fluorinating agents (Selectfluor, NFTh (1-fluoro-4hydroxy-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate)), NFSI (N-fluorobenzenesulfonimide), and 2,6-Cl2FP-BF4 (N-fluoro-2,6-dichloropyridinium tetrafluoroborate) are efficient fluorine-transfer reagents.

+ N R1O

F

X

–

F

R

+ N OR1

R2

X– R2

N Cinchonine (CN) and quinidine (QD) derivatives

N Cinchonidine (CD) and quinine (QN) derivatives

R1 = H, Ac, Bz, 4-ClBz, 4-MeOC6H4CO, 4-O2NC6H4CO, 1-naphthoyl, 2-naphthoyl, 9-phenanthryl, 4-methyl-2-quinolyl R2 =H, OMe X = BF4, OTf, (PhSO2)2N

+ N

R

N

N N O

O

F

BF4–

MeO

OMe N

N

Example of a bis-alkaloid [N–F]+ reagent F-(DHQD)2PHAL-BF4

Figure 3 [N–F] þ Reagents from cinchona alkaloids.

Unlike the chiral, neutral N–F reagents, the [N–F] þ ammonium salts of cinchona alkaloids are employed for the fluorination of a number of substrates: ketone and ester enolates, b-keto esters, a-cyano esters, a-nitro esters, a-amino esters, silyl enol ethers, enol acetates, nitrile anions, and oxindoles. These reagents possess stronger fluorinating power than the neutral N–F reagents, allowing the fluorination of enol derivatives such as silyl enol ethers (equation 3). OTMS (i) or (ii) Bn

O F Bn

(i) (4-ClC6H4CO)DHQN/Selectfluor, MeCN, 3 Å MS, –20 °C, 12 h, yield = 86%, ee = 91% (ii) F-(2-naphthoyl)QN-BF4, MeCN, –40 °C, 20 h, yield = 98%, ee = 84%

ð3Þ

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

221

These charged [N–F] þ reagents are appropriate for fluorinations conducted in ionic liquids on the principle that ‘like dissolves like’, allowing the recovery and reuse of the cinchona alkaloids. Grafting cinchona alkaloids onto a polystyrene support or using a fluorousphase soluble cinchona alkaloid constitute other approaches to recycling the source of chirality in the enantioselective electrophilic fluorination. Applications of these [N–F] þ reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (equation 4), BMS-204352, a potent opener of maxi-K channels (equation 5), and 20-deoxy-20-fluorocamptothecin (equation 6).

O

(i) LiHMDS, THF, –78 °C

O

N

CN or CO2Et

(ii) F-(4-MeOC6H4CO)QN-BF4, –78 °C, 12 h

H N

F3C

O

N *

O

Yield = 56−86% ee = 76−94%

ð4Þ

CN F or CO2Et

H N

F3C O

O (i) or (ii)

OMe

F OMe

ð5Þ Cl BMS-204352

Cl

ee >99% after a single crystallisation

(i) (DHQN)2AQN/Selectfluor, MeCN, CH2Cl2, –80 °C, 12 h, yield = 94%, ee = 84% (ii) F-(2-naphthoyl)QN-BF4, DABCO, THF, MeCN, CH2Cl2, – 78 °C, 12 h, yield = 96%, ee = 88% O

O

N

N

N

(DHQD)2PHAL/Selectfluor O

N O

CH2Cl2, r.t., 1−2 days

ð6Þ

O

F

O

20-deoxy-20-fluoro camptothecin Yield = 87% ee = 88%

The ease of preparation and generality of fluorination make the [N–F] þ class of reagents an excellent choice for enantioselective electrophilic fluorination. However, a stoichiometric amount of cinchona alkaloid has to be used. An attempt to render the electrophilic fluorination catalytic in cinchona alkaloids initially failed because fluorination by a stoichiometric achiral reagent is faster than fluorine transfer, thus leading to racemic fluorinated products. Nevertheless, enantioselective electrophilic fluorination was recently successfully achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of biscinchona alkaloids and NFSI in the presence of excess base (equations 7 and 8).2 OTMS R

K2CO3 (6 equivalent) –40 °C, CH3CN, 8 days

n n = 1 or 2 R = CH2Ar, Et Ar

NFSI (1.2 equivalent) (DHQD)2AQN (5 mol%)

R O N Boc

O

NFSI (1.2 equivalent) (DHQ)2PHAL (10 mol%)

CsOH.H2O (6 equivalent) –80 °C, CH3CN/CH2Cl2, 5 days

R = H, Me, OMe Ar = p-Tol, Ph, p-F-C6H4

F R

ð7Þ

Yield = 74−95% ee = 67−86%

R

Ar F O N Boc

ð8Þ

Yield = 77−99% ee = 35−87%

a-Fluorocarbonyl compounds are the targets in most enantioselective electrophilic fluorination. Interestingly, allylic fluorides were synthesized through a regio- and enantioselective electrophilic fluorodesilylation of allylsilanes. The in situ generation of fluorinated

222

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

cinchona alkaloids was preferred in this reaction, leading to allylic fluorides with excellent enantioselectivity of up to 96% and a high conversion (equation 9). The steric bulk of the silyl group was important with regard to enantioselectivity, with the triphenylsilyl group being responsible for higher enantioselectivities. As for silyl enol ethers and oxindoles, a catalytic version of this reaction has been recently developed using 10 mol% of a bis-cinchona alkaloid and NFSI in the presence of excess base.2 SiMe3 R

(DHQ)2PYR F+ donor

R

CH3CN, –20 °C

n

F n

ð9Þ

(i) Stoichiometric version, R = CH2C6H5, (DHQ)2PYR (1.2 equivalent), Selectfluor (1.2 equivalent), 24 h, conversion >95%, ee = 96% (ii) Catalytic version, R = CH2C6H4-p-Me, (DHQ)2PYR (0.1 equivalent), NFSI (1.2 equivalent), K2CO3 (6 equivalent), 12 h, yield = 75%, ee = 95%

5.9.2.2

Chiral Base-mediated Enantioselective Fluorination

A different approach to a-fluorocarbonyl compounds consists in the desymmetrization of a ketone via in situ generation of an intermediate silyl enol ether with the aid of a chiral lithium amide base followed by electrophilic fluorination with Selectfluor. In the desymmetrization of N-carbethoxytropinone, the enantiodiscriminating step is the deprotonation by a chiral base, which is followed by a face-selective fluorination of the silyl enol ether, affording the enantiomerically enriched chiral a-fluoro-Ncarbethoxytropinone in 55% yield and 60% ee (equation 10). CO2Et CO2Et N chiral base (1 equivalent), n-BuLi (2 equivalent) N F Me3SiCl (5 equivalent), LiCl (1 equivalent), then Selectfluor (2 equivalent) O

Ph

O Yield = 55% ee = 60%

Ph

Ph

Ph NH HN

ð10Þ

chiral base Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

5.9.2.3

Transition-metal Catalysis

At the same time the work on cinchona alkaloid N-fluoroammonium salts was reported, the first transition-metal-catalyzed fluorination had been achieved. For this purpose, it was anticipated that catalytic transition-metal complexes would accelerate enolization of b-keto esters due to the relatively high acidity of their a-protons. The fluorination of various acyclic b-keto esters, with Selectfluor in the presence of 5 mol % of [TiCl2((R,R)-TADDOLato)] catalyst 7, was reported to give high yields (Z80%), and up to 90% ee (equation 11). Computational and experimental studies strongly support a single-electron-transfer mechanism as a pathway for the fluorination. Noteworthy, a one-pot enantioselective heterodihalogenation of a simple b-keto ester with N-chlorosuccinimide and Selectfluor was conducted by sequential addition leading to an a-chloro-a-fluoro-b-keto ester, albeit in a moderate (65%) ee. The more sterically hindered catalyst 7 gives rise to higher enantioselectivities than catalyst 8; 7 is also a more effective catalyst. O

O

R1

O

O

R2

F

catalyst 7 (5 mol%)

OR3

R1

Selectfluor, MeCN, r.t.

R2

R1 = Ph, Et, Me R2 = Me, Cl R3 = Et, Bn, CHPh2, 1-Naphth, CH2C6H2-2,4,6-i-Pr3

O

O

Yield = 53−89% ee = 33−90%

1-napht 1-napht

1-napht

O Cl O 1-napht Ti MeCN NCMe Cl Catalyst 7

OR3

O

O

Ph

Ph O Cl O Ph Ti Me O O Me

Ph

Cl Catalyst 8

ð11Þ

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

223

The efficiency of chiral transition-metal catalyst 7 was clearly demonstrated by the high ee values of the fluorinated products. The reaction was extended to a-acyl-g-lactams as substrates. Catalytic asymmetric fluorination was performed with NFSI in toluene at 0 1C, with 5 mol % of the Ti(TADDOLato) catalyst 7. All substrates were successfully fluorinated in good yields with scarce to good enantioselectivities (equation 12).3 O

O

O

O

R1

R2

N

Catalyst 7 (5 mol%)

R1

N

R2

F

NFSI, toluene, 0 °C

ð12Þ

R1 = Me, Ph, Cy, t-Bu R2 = Me, Bn, Cy

Yield = 40−78% ee = 6−87%

Reproduced from Perseghini, M.; Massaccesi, M.; Liu, Y.; Togni, A. Tetrahedron 2006, 62, 7180.

Relatively soft late transition-metal Lewis acids are also suitable catalysts for electrophilic fluorination. Indeed, cationic chiral ruthenium(II)-PNNP complex 9 (PNNP is (1S,2S)-N,N0 -bis(o-(diphenylphosphino)benzylidene)cyclohexane-1,2-diamine) is a powerful catalyst for the enantioselective fluorination of b-keto esters (equation 13).4 O

O

O

O

Catalyst 9 (10 mol%) Ot-Bu

Ot-Bu

F

NFSI, CH2Cl2/Et2O (1/1), r.t.

Yield = 94% ee = 93%

PF6– N

Cl N Ru + P L P Ph2 Ph2

ð13Þ

L = OEt2

Catalyst 9 Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

All these reactions involve 1,3-dicarbonyl compounds as ideal substrates; interestingly, a single example of transition-metal catalyzed enantioselective a-fluorination of aldehydes has been reported. The substrate scope is limited to secondary benzylic aldehydes and the reaction proceeds through a mechanistically distinct pathway. The aldehyde undergoes a two-electron oxidation to an a-carbonyl cation in the presence of two equivalents of silver (I) salt followed by a nucleophilic attack by fluoride from silver bifluoride. Unfortunately, this unprecedented reaction was achieved in both low yields and ees (equation 14).5 O

O

Catalyst 10 (5 mol%), AgHF2 (2.4 equivalent) H

R

H

1,2-C2H4Cl2, 60 °C, 24 h

R = Me, Et, i-Pr, t-Bu

R F Yield = 13−35% ee = 27%

SbF6– N

Cl N Ru + P P Ph2 Ph2 Catalyst 10

O Ph

H

[RuII] O Ph

ð14Þ 2 Ag+

2 Ag

Ph

H

R

R

[RuIV] O H R

[RuII]

+

O Ph

O Ph

R F

[RuII] H

O F–

Ph +

[RuII] H

R

H

R F

Other chiral complexes combining a transition metal and a chiral ligand were further reported. In particular, efficient enantioselective fluorinations of various b-keto esters were conducted with chiral 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl

224

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

(BINAP)–palladium complexes (equation 15). In this case, NFSI was preferred to Selectfluor and the reactions were performed either in ethanol or in ionic liquids in which the palladium complexes can be immobilized and reused with excellent reproducibility even after 10 consecutive cycles. For example, the enantioselective electrophilic fluorination of 2-methyl-3-oxo-3phenylpropionic acid tert-butyl ester with 11b in [hmim][BF4] gives the corresponding fluorinated product in 93% yield with 92% ee, and still in 67% yield with 91% ee after 10 cycles. O

O

R1

Ot-Bu R2

Catalyst 11a−c (2.5 mol%) O or Catalyst 12a (5 mol%) R1 R2 –20 to 20 °C, NFSI, EtOH

O Ot-Bu F

R1, R2 = −(CH2)3−, −(CH2)4−, indanyl Yield = 49−92% ee = 83−94% R1 = Ph, Me R2 = Me, Et O O Ar2 Ar2 H Ar2 Ar2 H O + P O P +O + P P + O Pd Pd Pd Pd O O P P P P O O Ar2 Ar2 H Ar2 H Ar2 O O 2 TfO– 2 X– Ar = Ph, 3,5-dimethylphenyl

Ar = 3,5-di(t-butyl)-4-MeOC6H4

O O O

ð15Þ

2

O

2 TfO–

Ar = 3,5-di(t-butyl)-4-MeOC6H4

11c

11a: X=BF4 11b: X=OTf

Ar2 + P 2 Pd OH2 P Ar OH2

12a

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Application of these chiral BINAP–palladium complexes was further extended to the highly efficient catalytic enantioselective fluorination of oxindoles by using catalyst 11b. The reaction proceeded well without exclusion of air and moisture to give the corresponding fluorinated oxindoles in good yields with high to excellent enantioselectivities (equation 16).6 This catalytic asymmetric reaction was applied to the synthesis of BMS-204352 in 90% yield with 71% ee and 499% ee after recrystallization (see Section 5.9.2.1). R1 O N Boc

R2

R1

Catalyst 11b (2.5 mol%) NFSI (1.5 equivalent)

O N Boc

0 °C to r.t., 2−18 h, i-PrOH R2

R1 = Ph, 4-MeC6H4, 4-FC6H4, 2-MeOC6H4, Me, Et, CH2C(O)Me, Bn, i-Bu R2 = H, CF3

F

ð16Þ Yield = 72−96% ee = 75−96%

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

The fluorinated oxindoles could be treated with sodium methoxide in methanol to give the corresponding optically active a-fluoro-a-arylacetate derivatives. In addition, tandem asymmetric fluorination-methanolysis of an N-Boc-protected oxindole afforded a chiral monofluorinated aryl acetate in 53% yield with 93% ee (equation 17). F O N Boc

Catalyst 11b (2.5 mol%) NFSI (1.5 equivalent) ClCH2CH2Cl / MeOH (1/1)

CO2Me * NHBoc

ð17Þ Yield = 53% ee = 93%

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Other substrates include tert-butoxycarbonyl lactones and lactams. Reactions with lactones proceeded smoothly in an alcoholic solvent with 2.5 mol% catalyst. In the case of the less acidic lactam substrates, concurrent use of the Pd complex and 2,6-lutidine as a co-catalyst was effective. Under the reaction conditions, the fluorinated lactones and lactams were obtained in good yields with excellent enantioselectivities (up to 99% ee) (equation 18).7

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O

O

O Ot-Bu

X

Catalyst 11–13 (2.5−5 mol%)

X

NFSI, base, alcohol, r.t.

( )n X = O, NH, NR n = 1, 2

225

O *

( )n F

Ot-Bu

Yield = 35−96% ee = 77−99%

O Ar2 P 2+ OH2 Pd OH2 P Ar2

O O

Ar2 P 2+ OH2 Pd OH2 P Ar2

O 2 TfO– Ar = 3,5-dimethylphenyl

ð18Þ

2 TfO– Ar = 3,5-dimethylphenyl

12b

13

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

b-Keto phosphonates are similar to 1,3-dicarbonyl compounds with respect to the relatively high acidity of the a-proton. The synthesis of a-fluoroalkylphosphonates is of great interest since they are better mimics of natural phosphates than phosphonates with very similar second pKa values. In addition, the stereochemistry of the carbon–fluorine center does affect enzyme binding. Consequently, the enantioselective electrophilic fluorination of several cyclic and acyclic b-keto phosphonates was reported using diverse catalytic systems. For example, the synthesis of a-fluoro-b-keto phosphonates can be realized in high ees (87–98% ee) using chiral palladium complexes 12b, 13, or 14 and NFSI (equation 19). Alternatively, a combination of the chiral tridentate ligand 15 (R,R)-Ph-DBFOX and Zn(ClO4)2 or Zn(SbF6)2 afforded a-fluoro-b-keto phosphonates in moderate to good yields with up to 91% ee (equation 19).9 O

O P(OR3)2

R1

O

Catalyst 12b–15 R1

NFSI

R2

O

3 * P(OR )2 2 F R

Ph2 P 2+ OH 2 Pd NCMe P Ph2

O O

2 X–

N Ph

Ar = Ph, 3,5-dimethylphenyl, 4-methylphenyl X = BF4, OTf, SbF6, PF6

N

O

ð19Þ

Ph

15 (R,R)-Ph-DBFOX

14 Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Concerning the synthesis of a-fluoro-a-cyano-a-aryl phosphonates, two catalytic systems involving chiral Pd(II) complexes in the presence of an organic base such as pyridine derivatives have been developed. The Pd(II) complexes activate the substrates through coordination of the nitrile group, and pyridine derivatives abstract an acidic proton, thereby affording the desired fluorinated products in good yields with good to high enantioselectivities (equation 20). Unfortunately, the reaction is not applicable to a-alkyl-a-cyano phosphonates. O CN + NFSI

(EtO)2P Ar

(i) or (ii) EtOH

O (EtO)2P Ar

CN F

Ar = Ph, 4-MeC6H4, 4-ClC6H4, 1-naphthyl (i) Catalyst 11b (Ar = Ph, 2.5 mol%), 2,6-lutidine (1 equivalent), –20 °C, yield = 92−96%, ee = 24−78% (ii) Catalyst 14 (Ar = 3,5-Me2C6H3, X = OTf, 5 mol%), 2,6-t-Bu2-4-MePyridine (2 equivalent), r.t., yield = 73−98%, ee = 80−91%

ð20Þ

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

The catalytic enantioselective fluorination of a-cyano acetates was also catalyzed by the chiral palladium complex 14 (Ar ¼ Ph, X ¼ PF6), leading to a-cyano-a-fluoro acetates with excellent ees (equation 21).

226

Oxidation: CX Bond Formation (X¼Halogen, S, Se) CO2R CN F

CO2R Catalyst 14 (Ar = Ph, X = PF6, 5 mol%) Ar

Ar

NFSI, MeOH, 0 °C, 17−60 h

CN

ð21Þ

Yield = 56−94% ee = 67−99%

Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 2-naphthyl, 9-anthryl R = Me, Et, Bn, t-Bu

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Another remarkable advance in the catalytic enantioselective fluorination of acyclic (2-aryl acetyl)thia- and oxazolidin-2-ones has been reported with the unique combination system of Ni(II)-BINAP/R3SiOTf/2,6-ludidine (equation 22). Such a reaction allows the preparation of a-fluorocarboxylic acid derivatives that have not been as thoroughly explored as activated b-keto esters due to the difficulty to generate metal enolates in situ under catalytic conditions. In this reaction, a substoichiometric amount of Et3SiOTf and a stoichiometric amount of the base were required for a high chemical yield. NFSI has to be strongly activated by a Lewis acid, Et3SiOTf, in order for fluorination to take place. Therefore, cooperative activation by a cationic metal complex and an organic base could promote the formation of a metal enolate from the two-point binding substrates. The monofluorinated compounds were formed in excellent yield with high enantioselectivity (up to 88% ee). Unfortunately, the reaction with (2-alkyl acetyl)thiazolidin-2-ones failed to provide good results.10

Ar

Catalyst 16 (5−10 mol%) NFSI (1.5 equivalent)

O

O

S

N

Et3SiOTf (0.75−1.5 equivalent) toluene, –20 °C, 10 min

2,6-lutidine (1 equivalent)

O

O Ar

S

N

– 20 °C, 24 h

F

Ar = Ph, 4-FC6H4, 4-MeOC6H4, 3-MeOC6H4, 2-MeOC6H4, 2-Naphthyl, 1-Naphthyl

Yield = 87−99% ee = 78−88%

ð22Þ

Ph Ph P Cl Ni Cl P Ph Ph Catalyst 16 Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

The enantioselective fluorination of aryl acetylthiazolidinones was highly improved by the use of a catalyst combination Ni(II)/(R,R)-Ph-DBFOX 15/HFIP/2,6-lutidine. Excellent enantioselectivities and high yields were obtained although the reaction times are rather long. The strong Lewis acid, Et3SiOTf, also used in the previous case, was replaced by the relatively strong Brønsted acid, 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP; pKa ¼ 9.3). The beneficial effect of HFIP is probably due to an improved turnover of catalysts thanks to a faster release of the fluorinated product in the transition state (equation 23). The utility of this catalytic system was further demonstrated in the enantioselective fluorination of nonconjugated enone substrates such as 3-butenoyl derivatives (equation 24) and 3-heteroaryl substrates (equation 25), which have no precedent in the literature.11

Ar

Catalyst 15 (11 mol%) Ni(ClO4)2·6H2O (10 mol%) NFSI (1.2 equivalent)

O

O N

S

HFIP (30 mol%) 2,6-lutidine (2 equivalent) CH2Cl2, MS, –60 °C, 2−7 days

Ar = Ph, 4-FC6H4, 4-BrC6H4, 4-CF3C6H4, 4MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 3-MeC6H4, 4-MeC6H4, 2-Naphthyl, 1-Naphthyl O

O Ar

N R

S

O

O Ar

N

S

F

ð23Þ

Yield = 70−96% ee = 92−99%

Catalyst 15 (11 mol%) Ni(ClO4)2·6H2O (10 mol%) Ar NFSI (1.2 equivalent)

O

O N R

HFIP (30 mol%) 2,6-lutidine (2 equivalent), CH2Cl2 MS, –60 to –80 °C, 8−92 h Yield = 50−99% Ar = Ph, 4-BrC6H4, 4-ClC6H4, ee = 78−91% 4-MeC6H4, 2-Naphthyl R = H, Me, Ph

S

F

ð24Þ

Oxidation: CX Bond Formation (X¼Halogen, S, Se) Boc N

N

Boc N

Catalyst 15 (11 mol%) Ni(ClO4)2·6H2O (10 mol%) NFSI (1.2 equivalent)

O

O

S

R R = H, OMe, Me, Br

O

O N

S

F

HFIP (30 mol%) 2,6-lutidine (2 equivalent), CH2Cl2 R MS, –60 °C, 2−4 days

227

ð25Þ

Yield = 64−99% ee = 97−99%

Bidentate bisoxazoline–copper (II) complexes are also efficient for the catalytic fluorination of both acyclic and cyclic b-keto esters using NFSI as the achiral fluorinating agent. These nitrogen-containing ligands are complementary to the oxygen- and phosphorus-containing ligands previously investigated. Ligand 17 ((R,R)-Ph-BOX) with various Lewis acids did not lead to enantioselectivities as high as those observed with catalysts 7, 8, or 11 (equation 26). However, as little as 0.1 mol% of catalyst made of 17 and copper triflate can be used; the addition of HFIP was crucial for achieving high enantioselectivity. Selectfluor and N-fluoropyridinium triflate produced ee values ca. 10% lower than those obtained with NFSI. Importantly, a simple change of the metal salt allows the preparation of either of the two enantiomers (equation 27). Indeed, the use of (S,S)-Ph-BOX-Cu(II) and (S,S)-Ph-BOXNi(II) complexes as catalysts in the enantioselective electrophilic fluorination of b-keto esters provided the fluorinated products with opposite configuration. The origin of the reversed sense of stereoinduction could be a consequence of a change in the metal-center geometry from distorted square–planar (Cu complex) to square–pyramidal (Ni complex) in the reactive intermediates. O

O

R1

Cu(OTf)2 (1 mol%) (R,R)-17 (1 mol%)

OR3 R2

R1

HFIP (1 equivalent) NFSI, Et2O, 20 °C, 0.5−96 h

O

O

R2

F

OR3

Yield = 72−96% ee = 35−85%

R1, R2 = −(CH2)3−, −(CH2)4−, indanyl, tetralonyl, Ph, Me R3 = t-Bu, Bn, Naphth, CHPh2

ð26Þ O

O N

N

(R,R)-Ph-BOX Ph

Ph Catalyst 17

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

O

(S,S)-17 (10 mol%) Cu(OTf)2 (10 mol%)

O OR F

O

O

O

O N

OR + NFSI Ph R = t-Bu, 1-adamantyl

Up to 84% ee

N Ph

O

(S,S)-17

ð27Þ

O OR

(S,S)-17 (10 mol%) Ni(ClO4)2.6H2O (10 mol%)

F Up to 93% ee

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

The chiral bidentate bisoxazoline–copper (II) complex 17/Cu(OTf)2 was exploited in a catalytic enantioselective tandem transformation via Nazarov cyclization/electrophilic fluorination. This sequence is efficiently promoted to afford fluorinecontaining 1-indanone derivatives featuring two new adjacent carbon- and fluorine-substituted tertiary and quaternary stereocenters with high diastereoselectivity (trans/cis up to 49/1) and high enantioselectivity (up to 95.5% ee) (equation 28). O

O

R

O OR1

+ NFSI

Catalyst 17 (10 mol%) Cu(OTf)2 (10 mol%)

R

F

O OR1

ClCH2CH2Cl, 80 °C, 8 h R2

R2 Yield = 60−80% ee = 43−95.5%

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

ð28Þ

228

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

As already demonstrated in the fluorination of a-keto phosphonates and aryl acetylthiazolidinones, a combination of the chiral tridentate ligand (R,R)-Ph-DBFOX 15 and Ni(ClO4)2  6H2O efficiently catalyzed the enantioselective electrophilic fluorination of cyclic carbonyl compounds that are also capable of two-point binding. The fluorination reaction of a series of b-keto esters and oxindoles with Boc-protecting groups was carried out to afford the desired products in high yields with high to excellent enantioselectivities (equation 29). One of the fluorinated oxindoles was converted into BMS-204352 by cleavage of the Boc group; this example provides another catalytic enantioselective preparation of BMS-204352. In addition, it was noted that a positive nonlinear effect of chiral amplification was observed in the fluorination of b-keto esters.12 O

(R,R)-Ph-DBFOX 15 (11 mol%) Ni(ClO4)2·6H2O (10 mol%) NFSI (1.2 equivalent)

BS

R1 R2

R3

CH2Cl2, MS, r.t., 2−35 h

BS: binding site O

O

O

L* Ni

R1

BS

R1

( )n

Et Me

CO2t-Bu

n =1, yield = 84%, ee = 93% n = 2, yield = 86%, ee = 99%

n =1, R = t-Bu, Ad, L-Men n = 2, R = Ad Yield = 66−88% ee = 95−99%

R1

R3

F R2

BS

O

R3

O F

( )n

BS

R3

O CO2R

F

or R2

R2

F

F

L*

CO2CHPh2 F

ð29Þ

Yield = 75% ee = 83%

MeO F

R

O N Boc R = Me, yield = 73%, ee = 93% R = Ph, yield = 72%, ee = 96%

O

Cl

N

F3C

Boc

Yield = 71% ee = 93%

The (R,R)-Ph-DBFOX 15/Zn(OAc)2 combination proved to be an effective catalyst to give optically pure 2-fluorinated malonates in a process similar to desymmetrization (equation 30). Although the malonates are nearly symmetrical and less acidic, the enantioselectivities observed in the desymmetrization-like fluorination reaction are very high and superior to the corresponding enzymatic methods. This synthetically useful method was applied to the synthesis of pharmaceutically attractive compounds.13

H MeO2C

R CO2t-Bu

(R,R)-Ph-DBFOX 15 (11 mol%) Zn(OAc)2 (10 mol%) NFSI (1.2 equivalent)

F

CH2Cl2, reflux, MS, 15−36 h

Racemic

R

MeO2C

R = Me, Et, Bu, Ph, Bn, OPh, SPh, NPhth

CO2t-Bu

ð30Þ

Yield = 81−95% ee = 93−99%

The optically active N,N,N-tridentate ligand 18 having both axial chirality on the binaphthyl backbone and carbon-centered chirality on the oxazoline ring was synthesized and utilized in enantioselective direct fluorination of b-keto esters in excellent yields and enantioselectivities (equation 31).14 Ni(ClO4)2 gave satisfactory results whereas Mg(ClO4)2 provided slightly lower ees. Such a catalyst is highly efficient but its synthesis requires seven steps. It is interesting to note that the use of ligands that have the opposite absolute configuration on the axial chiral binaphthyl backbone showed poor enantioselectivity. Catalyst 18 (5 mol%) Ni(ClO4)2 or Mg(ClO4)2 (5 mol%)

O CO2R

NFSI (1.1 equivalent) CH2Cl2, r.t., MS 4 Å, 1−24 h

n n = 1,2 R = t-Bu, Bn

N

R1

CO2R F n Yield = 65−99% ee = 35−99%

O

N R1

O

ð31Þ

N R2

Catalyst 18 R1 = H, Ph 2 R = i-Pr, Bn, Ph, t-Bu

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

229

Other polydentate ligands, (S,S)-ip-Pybox 19 and (R,R)-Jacobsen’s salen ligand 20, in combination with cobalt salts, Co(ClO4)2  6H2O or Co(acac)2, have been recently exploited in the electrophilic enantioselective fluorination of both aliphatic cyclic and acyclic b-keto esters (equation 32). The highly enantioselective fluorination of ethyl-2-oxocyclopentanecarboxylate is reported to be difficult; however, the use of 20/Co(acac)2 catalyst allowed a good 89% ee to be obtained.15

O

Catalyst 19 or 20 (10 mol%) Co(acac)2 (10 mol%)

O OR

R = Me, Et, t-Bu n = 1, 2, 3

OR

Yield = 65−75% ee = 75−90%

O

O

with 20

O

OEt yield = 64% ee = 71%

O

O F n

NFSI (1.4 equivalent) Et2O, −20 °C to r.t.,12 h

n

O

O

OEt

N

O

N N

t-Bu

N

N HO

OH

i-Pr

i-Pr

ð32Þ

F

t-Bu

t-Bu

t-Bu

Catalyst 20 (R,R)-Jacobsen's salen

Catalyst 19 (S,S)-ip-Pybox

A series of chiral rare earth metal complexes 21 (M ¼ Sc, La, Gd, Yb, In) bearing polyfluorinated binaphthyl phosphate ligand F8BNP (5,50 ,6,60 ,7,70 ,8,80 -octafluoro-1,10 -binaphthyl-2,20 -diyl phosphate) were used as catalysts for the enantioselective electrophilic fluorination reaction of b-keto esters. The use of Sc[(R)-F8BNP]3 catalyst in combination with N-fluoro pyridinium triflate (NFPY-OTf) as a fluorinating agent was found to give the desired fluorinated products in high yields with good enantioselectivities under mild conditions (equation 33).16 The priviledged 1,10 -bi-2-naphthol (BINOL) ligand has also been introduced in the Al–Li–BINOL complex 22 and evaluated in the fluorination of alicyclic b-keto esters allowing the preparation of a-fluoro-b-keto esters with only moderate enantiomeric excesses (equation 34).

O

O 10 mol% 21

R1 R2

OR3 NFPY-OTf (1.2 equivalent) toluene, r.t.

R1, R2 = −(CH2)3−, −(CH2)4− R1 = Ph R2 = Me R3 = Me, Et, i-Pr, t-Bu, Bn

O

O

F

R2

R1

OR3

Yield = 16−97% ee = 47−84%

ð33Þ

F F O

F F F

F

O M P O O

Catalyst 21 M= Sc; Sc[(R)-F8BNP]3

F F 3

Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

230

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O

O

O

O

25 mol% 22

Ot-Bu

NFPY-BF4, THF HFIP, r.t.

O

Ot-Bu F Yield = 58% ee = 67%

ð34Þ

O Al

O

O Li

Catalyst 22 Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

C1-symmetric amino sulfoximine-copper complex 23 has been used as chiral catalyst in halogenation reactions of b-keto esters in the presence of NFSI as a source of electrophilic fluorine (equation 35).17 Other electrophilic fluorine donors, Selectfluor and pyridinium salts, are inadequate in this reaction. O

23 (10 mol%) Cu(OTf)2 (10 mol%)

O

R1

OR3 R2

NFSI (1.2 equivalent) Et2O, −78 °C to r.t.,16 h

R1, R2 = −(CH2)3−, −(CH2)4−, −(CH2)6− R1 = Me R2 = Me, Et, Ph, Bn R3 = Me, Et R2, R3 = −(CH2)2− O HN Ph S N Me i-Pr Catalyst 23

O

O

F

R2

R1

OR3

Yield = 49−99% ee = 39−74%

ð35Þ

i-Pr

i-Pr

The preparation of a-fluorobenzyl sulfones has been investigated in a single report in order to obtain a-fluorinated sulfur compounds as useful synthetic intermediates for the synthesis of bioactive compounds. Fluorination of a lithiated trifluoromethyl benzyl sulfone with NFSI in the presence of (S,S)-Ph-BOX 17 afforded the R enantiomer exclusively in 50% yield (equation 36).18

O F3C

O S

(i) n-BuLi (1.2 equivalent) (S,S)-Ph-BOX 17(1.25 equivalent) Ph (ii) NFSI (1.5 equivalent) toluene, –30 °C

O F3C

O S

F Ph

ð36Þ

Yield = 50% ee = 99% Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Finally, DNA-mediated enantioselective electrophilic fluorination was conducted with a catalytic system comprising of DNA, an achiral ligand, 4,40 -dimethyl-2,20 -bipyridine (dmbipy), and a Cu(II) salt. The catalytic system demonstrated its ability in biocatalysis by forming a chiral C–F quaternary carbon center in b-keto esters. Enantioselectivities with ee values up to 74% were achieved for the fluorine transfer from Selectfluor to substrates in water (equation 37). Selectfluor, salmon testes-DNA [Cu(dmbipy)(NO3)2]

O CO2t-Bu

MES buffer (Ph = 5.5), 5 °C, 6 h

O F CO2t-Bu

ð37Þ Yield = 75% ee = 74% Reproduced from Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1, with permission from American Chemical Society.

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

231

Organocatalysis is an alternative approach to induce high to very high enantioselectivities. The use of the cinchonine-derived or binaphthyl-scaffolded quaternary ammonium salts as chiral phase-transfer catalysts with an achiral fluorinating agent allows the enantioselective fluorination of b-keto esters and a-cyano esters. Direct organocatalytic enantioselective a-fluorination of aldehydes and ketones that employs proline derivatives or imidazolidinones is presented in Volume 7. In this latter case, ees are very high, often 498%, in particular for aldehydes; however, a-fluoroaldehydes must be reduced into alcohols in order to avoid racemization.

5.9.3

Enantioselective Electrophilic Chlorination

The field of enantioselective electrophilic fluorination has experienced a very fast development during the past decade and the catalysts and methods that are successful in fluorination reactions were also applied to other halogenations, mainly in chlorination. Chiral nonracemic chlorinating agents are not well developed unlike chiral fluorinating agents. Silyl enol ethers are the main targets in this approach, which requires the stoichiometric use of a chiral chlorinating agent. In another approach, the concomitant formation of a C–Cl bond and stereoselective generation of a new stereogenic center have received a great deal of attention through the use of chiral organometallic catalysts in the presence of various sources of electrophilic chlorine. b-Keto esters, b-keto phosphonates, and oxindoles are essentially the targets of enantioselective electrophilic chlorination.

5.9.3.1

Chiral Chlorinating Agents

Chiral C2-symmetric a,a-dichloromalonates 24 and 25 have been designed, synthesized and utilized as efficient chlorinating agents in the reaction with silyl enolates. Although these reagents are weak chlorinating agents, the stoichiometric addition of a Lewis acid, in particular zirconium tetrachloride, substantially increases the electrophilic power of positive chlorine for the reaction with weak nucleophilic silyl enolates. All reaction yields are superior to 90% with the best ees obtained with a,a-dichloromalonate 25 featuring a bulky aromatic moiety on the cyclohexane rings, in particular, the 9-phenanthryl group. The steric hindrance of the silyl group is also important to attain high enantioselectivities, with dimethylthexylsilyl providing up to 98% ee for the chlorination of the silyl enolate of 2-methyl-1-tetralone (equation 38).19

R1

OSi(alkyl)3 ZrCl4 (1 equivalent) R3 chiral reagents 24−25 (1 equivalent)

O R1

CH2Cl2, –78 °C, 1−5 h

R2

Cl R3

R2

Yield > 90% ee = 31−98% R1, R2 = indanyl, tetralonyl, benzosuberonyl, −(CH2)4− R3 = H, Me, Ph R1,2 = Ph, t-Bu, n-pent, Et

ð38Þ

Chiral chlorinating agents

O

O

O

O Cl Cl

O

O

Cl

Cl

O Ar

O Ar

Ar = Ph, 1-naphthalyl, 9-phenanthryl 24

25

Similarly, other chiral C2-symmetric chlorinating agents 26 possessing a N-chloroimidodicarbonate motif were prepared and applied in the enantioselective chlorination of silyl enol ethers (equation 39).20 Samarium(III) triflate was found to be the Lewis acid of choice, at least for conversion, to activate the chlorinating agent through coordination with the two carbonyl groups of the imidodicarbonate moiety. Unfortunately, these reagents only provided modest enantioselectivities not exceeding 40%. Non C2-symmetric chlorinating agents were also evaluated; however, poor results were obtained (eeo16%).

232

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

R1

O

OSi(alkyl)3 Sm(OTf)3 (1.1 equivalent) chiral reagent (1 equivalent) R3

R1

THF/CH2Cl2, –78 °C, 10 min

R2

Cl R2

R3

Yield = 81−91% ee = 4−40%

R1, R2 = tetralonyl; R3 = H R1 = Ph, 4-ClC6H4, 4-MeOC6H4 R2,3 = H, Me, Pr Chiral chlorinating agents 26

ð39Þ O O

O N Cl

O O

N

O

Cl

O O

O

O

O N Cl

O

No catalytic version was reported on a similar model to catalytic electrophilic fluorination by cinchona alkaloid derivatives.

5.9.3.2

Transition-metal Catalysis

With rare exceptions, all the catalysts used in chlorination reactions were previously developed for fluorination reactions. Most of the substrates were b-keto esters but we have also seen chlorination of a b-diketone, oxindoles, imides, and some b-keto phosphonates. Various chlorine donors were evaluated (Figure 4) and the results of enantioselective electrophilic chlorination on b-keto esters are listed in Table 1. Already described catalysts and ligands as well as new ones are depicted in Figure 5. O

O

N Cl

O

N Cl Cl

O NCS

N Cl

N

O

O A O

B Cl

Cl

Cl

Cl

Cl Cl

O Cl

I

Cl

O

N

N N Cl

Cl O

C CF3SO2Cl

Cl D Figure 4 Electrophilic chlorine donors.

Pioneering work on transition-metal catalysed enantioselective electrophilic chlorination was conducted after observing the incorporation of chlorine ligand into b-keto esters during asymmetric fluorination in the presence of [TiCl2((R,R)-TADDOLato)] catalysts. Thus, initial chlorination reactions mediated by a transition-metal catalyst were performed on b-keto esters in the presence of 5 mol % of [TiCl2((R,R)-TADDOLato)] catalysts 7 or 8 with N-chlorosuccinimide (NCS) in analogy to electrophilic fluorination reactions. The bulkier catalyst 7 tended to give higher ee values in shorter reaction times with the best result being obtained in the chlorination of a bulky diphenylmethyl acyclic b-keto ester (entry 1, Table 1).21 Dichloro(4-methylphenyl)iodine is also a suitable chlorinating agent in the chlorination of b-keto esters albeit with slightly lower yields and ee values (entry 2, Table 1).22 Chiral bisoxazoline copper(II) complexes such as (S,S)-t-Bu BOX 27 / Cu(OTf)2 gave optically active a-chloro-b-keto esters in high yields and moderate enantioselectivities (entry 3, Table 1).23 In this case, the evaluation of other chlorinating agents A–D (see Figure 4) resulted in lower enantioselectivities relative to NCS whereas additives such as bases or HFIP did not improve the ee. Much higher enantioselectivities were attained with the aid of Ni(II)/(R,R)-Ph-DBFOX 15 for chlorination of cyclic b-keto esters derived from indanone and tetralone (entry 4, Table 1).12 Importantly, the use of CF3SO2Cl as a chlorinating agent is essential to achieve high enantioselectivity, since NCS provided a significant drop in ee. A single example of chlorination was reported with the chiral tridentate ligand 18/Ni(ClO4)2 combination leading to a high ee only by slow addition of the

Table 1 Entry

Enantioselective electrophilic chlorination on b-keto esters catalyzed by transition-metal complexes Substrates

O

1

O

R1

OR2

Conditions

Cl-donor

Yield (%)

ee (%)

Ref.

Catalyst 7 or 8 (5 mol%) MeCN, r.t., 30 min–15 h

NCS

85–97

11–88

2000 HCA 2425

Catalyst 7 (5 mol%) Pyridine (1.2 equivalent) Toluene, 50 1C, 20 min

Cl

37–83

o10–71

2001 HCA 605

(S, S)-t-Bu-Box 27 (10 mol%) Cu(OTf)2 (10 mol%) Et2O, r.t., 1 h

NCS

88–99

48–77

2001 CEJ 2133

(R, R)-Ph-DBFOX 15 (0.11 equivalent) Ni(ClO4)2  6H2O (0.1 equivalent) CH2Cl2, MS, r.t., 3–45 h

CF3SO2Cl

66–85

94–98

2005 ACIE 4204

99

92

2008 CL 1098

R1 = Ph, Et, Me, 2-Naphth R2 = Et, Bn, CHPh2, C6H22,6-t-Bu2-4-Me O

2

O OR3

R1

I Cl

R2 R1

= Ph, Me R2 = Me, Bn, allyl R3 = Et, Bn, Ph, AnthCH2 O

3

O

R1

OEt

R1 = Me, Et, i -Pr, Ph R2 = Me, Et, Bn R1,2 = −(CH2)n− (n = 3,4,5)

4

O CO2R n n = 1,2 R = t-Bu, Ad, L-men

5

O CO2t-Bu

Ligand 18 (5 mol%) Ni(ClO4)2 (5 mol%) CH2Cl2, MS, r.t., 2 h

O Cl

Cl

Cl

Cl Cl Cl

233

(Continued )

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

R2

Entry

234

Table 1

Continued Substrates

R1

O OR3

Cl-donor

Yield (%)

ee (%)

Ref.

Ligand 23 (10 mol%) Cu(OTf)2 (10 mol%) Et2O,  78 1C to r.t., 16 h

NCS

88–99

24–91

2009 EJOC 4085

Ligand 20 (10 mol%) Co(acac)2 (10 mol%) Toluene, r.t., MS, 12 h

CF3SO2Cl

62

88

2010 CL 466

Ligand 28 (5 mol%) CuOTf.1/2 C6H6 (5 mol%) CH2Cl2, 0 1C, 2 h

NCS

95–99

47–83

2010 TA 247

R2 R1 = Me1 R2 = Me, Et, Bn, Ph R1,2 = −(CH2)n − (n = 3,4,6) R3 = Me, Et; R2,3 = −(CH2)2− O

7

CO2t-Bu

8

R1

O CO2R2

n n = 1, 2 R1 = H, 5,6-OMe, 5-Cl, 5-Br R2 = Me, i-Pr, t-Bu, Bn

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O

6

Conditions

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O

O

1-napht

napht-1 O Cl O 1-napht Ti MeCN NCMe Cl

Ph O Cl O Ph Ti Me O O Me

1-napht

Ph

O

N

N

O O

N

Ph

Ph

27 (S, S)-t-Bu-BOX

O

N

N

t-Bu

t-Bu

Catalyst 8

O Ph S N Me

N

O

O

Cl

Catalyst 7

N

Ph

O

O

235

15 (R, R)-Ph-DBFOX

O HN

N

i-Pr t-Bu

i-Pr

OH

N HO

t-Bu

Ph

N

N HO

t-Bu

t-Bu

i-Pr Ligand 18

Ligand (S)-23

Ligand 20 (R,R)-Jacobsen's salen

Ligand 28

Figure 5 Catalysts and ligands used in chlorination reactions.

chlorinating agent, perchloro-2,4-cyclohexadien-1-one D, to the reaction mixture containing the substrate and the catalyst; changing the operation sequence led to the racemic chlorinated product (entry 5, Table 1).14 C1-symmetric amino sulfoximine–copper complex 23 has been used as chiral catalyst in chlorination reactions of b-keto esters in the presence of NCS as a source of electrophilic chlorine (entry 6, Table 1).17 The best result (91% ee) was obtained in the chlorination of ethylcyclohexanone-2-carboxylate, a substrate that regularly gives poor stereodifferentiation; however, the analog substrate having a cyclopentanone ring only gave 39% ee. t-Butylcyclopentanone-2-carboxylate was chlorinated in up to 88% ee with CF3SO2Cl in the presence of (R,R)-Jacobsen’s salen ligand 20 in combination with Co(acac)2 (entry 7, Table 1). Molecular sieves were required to increase both the yield and enantioselectivity.15 Finally, the chiral oxazoline-Schiff base ligand 28 was developed only for chorination. Over the metal employed, copper(I) triflate. ½ C6H6 provided high catalytic activity for the chlorination conducted with NCS (entry 8, Table 1).24 It is evident that the choice of the ligand/metal combination as well as the source of chlorine donor is essential for achieving high enantioselectivities. The type of substrate (acylic, cyclic, with or without fused aromatic ring, bulkiness of the ester moiety) is obviously also important. Nevertheless, the availability or simplicity to prepare the chiral ligand will certainly orientate the choice when such chlorination is required in a synthetic plan. Apart from b-keto esters, one case of chlorination of a 1,3-diketone was reported with the aid of (S,S)-t-Bu BOX 27/Cu(OTf)2 giving optically active a-chloro derivative in 99% yield with only 32% ee (equation 40).23 Oxindoles have been chlorinated with CF3SO2Cl and the Ni(II)/(R,R)-Ph-DBFOX 15 combination with up to 96% ee; one of them was converted into BMS-225113, a pharmaceutically active chlorooxindole (equation 41).12 In addition, the enantioselective chlorination of phenyl acetylthiazolidinone was achieved with the Ni(II)/(R,R)-Ph-DBFOX 15/HFIP/2,6-lutidine combination in high yield and excellent enantioselectivity (equation 42).11 O

(S,S)-t-Bu-BOX 27 (10 mol%) Cu(OTf)2 (10 mol%)

O

O

O Ph

Ph NCS, Et2O, r.t., 1 h

ð40Þ

Cl Yield = 99% ee = 32%

Boc N

F3C

O

H N

(i) (R,R)-Ph-DBFOX 15 (0.11 equivalent) F3C Ni(ClO4)2·6H2O (0.1 equivalent)

OMe

O Cl OMe

CF3SO2Cl, CH2Cl2, MS, r.t., 14 h (ii) deprotection

Cl

BMS-225113

Cl Yield = 71% ee = 93%

ð41Þ

236

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

Ph

(R,R)-Ph-DBFOX 15 (11 mol%) Ni(ClO4)2·6H2O (10 mol%) CF3SO2Cl (1.2 equivalent)

O

O N

S

O

O Ph *

HFIP (30 mol%) 2,6-lutidine (2 equivalent) CH2Cl2, MS, –60 °C, 3 days

S

N

Cl

ð42Þ

Yield = 97% ee = 93%

Reproduced from Reddy, D. S.; Shibata, N.; Horikawa, T.; et al. Chem. Asian J. 2009, 4, 1411, with permission from Wiley.

Acyclic and cyclic b-keto phosphonates were readily chlorinated to a-chloroalkylphosphonates in a similar way to fluorination. In a comparison of the two halogenations, chlorination versus fluorination, the use of NCS allowed slightly better ee values than NFSI. The best combination was Zn(SbF6)2/(R,R)-Ph-DBFOX 15 in dichloromethane at room temperature (equation 43).9 O

O P(OR3)2

R1

(R,R)-Ph-DBFOX 15 (10 mol%) Zn(SbF6)2 (10 mol%) NCS(1.2 equivalent)

R2

CH2Cl2, r.t., 20 h

O

3 * P(OR )2 2 Cl R

ð43Þ

Yield = 40−98% ee = 72−94%

R1 = Me, Ph, 2-naphth R2 = Me, Allyl R1,2 = −(CH2)3− R3 = Me, Et

5.9.3.3

O R1

Chlorination of an Olefin

The enantioselective chlorination of an olefin moiety is rare. A few examples of alkene chlorination with measurable enantioselectivities, typically below 25% ee, are known but only one example gave satisfactory ee.25 Napyradiomycin A1 is a halogenated natural product isolated from terrestrial strains of Streptomyces bacteria that features a chlorinated stereogenic carbon center. Toward the total enantioselective synthesis of (–)-napyradiomycin A1, enantioselective alkene chlorination has been performed in the presence of (S)-1,10 -biphenanthryl-2,20 -diol 29 and the borane tetrahydrofuran complex (4 equivalent of each) with diatomic chlorine (equation 44). The dichlorinated product was obtained with 1,2-trans-stereochemistry in 93% yield with 87% ee that was improved to 95% after crystallization.25 OH

O

OH

O

Cl Cl

.THF,

MOMO

O

BH3 (S)-29 Cl2, THF, –78 °C

O

MOMO

O O

Yield = 93% ee = 87% (95% after crystallization)

ð44Þ

OH OH

(S)-29

5.9.4

Enantioselective Electrophilic Bromination

Transition-metal catalysed enantioselective bromination of b-keto esters was studied with N-bromosuccinimide (NBS), as an electrophilic source of bromine under conditions analogous to chlorination and fluorination in the presence of a Ti(TADDOLato) catalyst 7 or 8. High yields were obtained for bromination of b-keto esters, but a dramatic drop in enantioselectivity was observed (eeo23%) compared to the corresponding halogenation with smaller halogens.21 C1-symmetric amino sulfoximine-copper complex 23 has also been used as a chiral catalyst in bromination reactions of b-keto esters with NBS that are in many respects parallel to the chlorination reactions, but NBS was less stereodiscriminating than NCS since ee values were at best 73% versus 91% in chlorination (equation 45).17

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O

Ligand (S)-23 (10 mol%) Cu(OTf)2 (10 mol%)

O

R1

OR3 R2

R1 = Me R2 = Me, Et, Bn, Ph R1,2 = −(CH2)n − (n = 3,4,6) R3 = Me, Et; R2,3 = −(CH2)2−

O

O

Br

R2

R1

NBS (1.2 equivalent) Et2O, −78 °C to r.t.,16 h

237

OEt

ð45Þ Yield = 90−99% ee < 73%

Improved enantioselectivities in bromination of acyclic and cyclic b-keto esters were achieved by means of chiral bisoxazoline copper (II) complex (S,S)-t-Bu BOX 27/Cu(OTf)2 providing optically active a-bromo-b-keto esters in high yields with ee values up to 82%, slightly higher than analogous chlorination (equation 46).23 O

O

R1

(S,S)-t-Bu-BOX 27 (10 mol%) Cu(OTf)2 (10 mol%)

OEt R2

O

O

Br

R2

R1

NBS (1.1 equivalent), Et2O, r.t., 1 h

OEt

ð46Þ

R1 = Me, Et, i-Pr, Ph R2 = Me, Et, Bn R1,2 = −(CH2)5−

Yield = 70−99% ee = 41−82%

The halogenation of mono-carbonyl compounds has been less developed and proved to be more challenging. For the purpose of enantioselective bromination, simple ketones were oxidized by monometallic catalysts 30 or 31 and reacted with bromide anions from copper(II) bromide in the presence of methanesulfonic acid to accelerate the enolization (equation 47).26

O R1

R2

Catalyst 30 or 31 (1 mol%) CuBr2 (1.3 equivalent) LiBr (35 mol%) CH3SO3H (47 mol%)

O R1

H2O/THF, r.t., O2(1 atm), 12 h Cyclopentanone, cyclohexanone, cycloheptanone, 3-pentanone, 4-heptanone, 1-tetralone, 2-butanone 2+ Ph2 P NCMe Pd NCMe P Ph2

Br Yield = 70−90% ee = 68−89%

N t-Bu

N 2 BF4–

t-Bu

Pd

MeCN

Catalyst 30

ð47Þ

2+

O

O

2 BF4–

2 * R

NCMe Catalyst 31

The enantioselective halogenation of olefins is a rare process with two noteworthy examples: (i) the synthesis of allylic fluorides by a regio and enantioselective electrophilic fluoro-desilylation of allylsilanes (see Section 5.9.2.1), and (ii) the enantioselective chlorination of an isolated olefin toward the synthesis of ()-napyradiomycin (see Section 5.9.3.3). In addition, chiral 1,2-dibromides were obtained by oxidation of olefins by chiral monometallic and bimetallic Pd(II)-Cu(II) catalyts in bromidecontaining aqueous tetrahydrofuran (THF) reaction mixtures. Co-bromination of terminal olefins gave up to 97% ee whereas internal alkenes gave lower enantioselectivities up to 80% (equation 48).27

[Pd2(triketone)(L*−L*)] or [PdBr2(L*−L*)]

O Ar Ar = 4-MeOC6H4, 4CNC6H4, Ph, 2,6−(i−Pr)2−C6H3

CuBr2, LiBr, O2, H2O/THF

L = (S)-BINAP, (S)-Tol-BINAP

O

* Br

Ar Br

Yield = 95% ee = 94−97%

ð48Þ

238

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

5.9.5

Enantioselective Electrophilic Iodination

Iodination reactions that include iodolactonisation and iodoetherification represent a class of widely used alkene oxidation reactions. Several substrate-controlled diastereoselective reactions have been reported in the literature but only few examples of reagent-controlled and enantioselective approaches were developed. In iodolactonisation and iodoetherification reactions, terminal alkenes do not give rise to a stereogenic center featuring the halogen atom; only cis- or trans-substituted alkenes have the possibility to furnish lactones or cyclic ethers having two adjacent stereogenic centers, one endocyclic and one exocyclic bearing the iodine atom. Only these latter examples are described in this section. A reagent-controlled asymmetric iodolactonisation was achieved with complexes of electrophilic iodine with dihydroquinidine O-protected derivatives. The bis-dihydroquinidine derivative–iodine complex 32 promoted the iodolactonisation of prochiral g,d-unsaturated carboxylic acids in reasonable yields albeit in quite low enantioselectivity, at best 15% (equation 49).28 In this study, three other substrates and six different cinchona alkaloid derivatives were evaluated but no improvement in enantioselectivity was observed.

32 (1 equivalent, c = 27 mM) HO2C

CH2Cl2, –78 °C to r.t., 1 h

O

O I Yield = 90% ee = 15%

N

ð49Þ

I+ BF4–

BzO MeO

32 2

N

More recent investigations were conducted on catalytic enantioselective iodoetherification of g-hydroxyalkenes in the presence of (R,R)-Salen-metal-complexes and iodine. Among several metal complexes, Salen–Co(II) and Salen–Cr(III)Cl complexes were found to drive the reaction to completion whereas the effect of additives, in particular NCS, considerably enhanced the enantioselectivity (equation 50). Because of high loading amount (30 mol%) of the Salen–Co complex, the more effective Salen–CrCl catalyst (7 mol%) was preferred and the protocol was applied to the synthesis of swainsonine. It has to be noted that only cis-alkenes provide good results since iodoetherification of trans-alkenes proceeded with poor enantioselectivity and moderate conversion (11% ee, 50% yield).29

N

N

(i) NCS (0.7 equivalent), K2CO3 (0.5 equivalent), toluene, r.t.

t-Bu

O

O

t-Bu

t-Bu

I

OH

M t-Bu

M = Co (30 mol%), CrCl (7 mol%)

R (ii) I2, –78 °C, 20 h R = Me, Et, Pr, i-Pr, Bn, (CH2)2Ph, (CH2)3Ph, (CH2)3OTr, (CH2)4N3

R

O

ð50Þ

Yield = 83−96% ee = 67−93%

The chiral environment around the iodonium cation was also created through the use of the [(R)-BINOL]2–Ti(IV) complex for iodoetherification using N-iodosuccinimide (NIS) as the activator. The same substrates reacted to give the corresponding cyclic ethers with lower ees than for Salen–metal complexes, at best 68%.30 Electrophilic halocyclisation of polyprenoids is an interesting reaction to understand the biosynthesis of these natural products. In this reaction, a new CHal bond is formed concomitantly with a C–C bond followed by a cascade of polycyclisation. The enantioselective version was recently described using phosphoramidite such as 33 as the chiral nucleophilic promoter and NIS to give iodinated polycyclic products up to 99% ee (equation 51).31

Oxidation: CX Bond Formation (X¼Halogen, S, Se) R

(i) NIS (1.1 equivalent) chiral promoter 33 (100 mol%) toluene, –40 °C, 24 h

R

(ii) ClSO3H, i-PrNO2, –78 °C, 4 h

n

I

O P N O

H Yield = 52% ee = 99%

SiPh3 33

239

ð51Þ

Pr H

SiPh3

5.9.6

Enantioselective Electrophilic Sulfenylation

Optically active sulfur-containing compounds constitute an important class of chiral ligands, auxiliaries, and synthetic intermediates in organic chemistry. Carbon–sulfur bond-forming reactions and simultaneous generation of a stereogenic center were based on different strategies. However, reports related to the direct asymmetric introduction of sulfur were mainly limited to nucleophilic approaches, such as conjugative addition of thiols to alkenes bearing electron-withdrawing substituents. Relatively few examples of enantioselective electrophilic sulfenylation have been reported. Optically active sulfenylating reagents and chiral auxiliaries have rarely been employed. However, catalytic enantioselective electrophilic sulfenylation involving metal-catalyzed and organocatalytic approaches have been developed by several groups in recent years.

5.9.6.1

Chiral Sulfenylating Reagents

The asymmetric sulfenylation of ketones with several kinds of chiral sulfenamides was reported in the late seventies.32 The acyclic reagents 34a–d and cyclic reagents 35a–c were prepared from optically active primary or secondary amines and phenylsulfenyl chloride with triethylamine in THF, respectively, in good yields (Figure 6).

R2 PhS

N H

R N SPh

R1

34a: R1 = Ph, R2 = Me 34b: R1 = 1-naphthyl, R2 = Me 34c: R1 = CO2 Et, R2 = Me 34d: R1 = CO2 Et, R2 = Bn

35a: R3 = CO2Me 35b: R3 = CO2Et 35c: R3 = CO2t-Bu

Figure 6 Chiral sulfenylating reagents.

The asymmetric sulfenylation of 4-alkylcyclohexanones with these chiral sulfenamides was attempted. Among all the sulfenamides, sulfenamide 34b was the most effective. Sulfenylation of 4-t-butylcyclohexanone was carried out with sulfenamide 34b in the presence of a catalytic amount of triethylamine hydrochloride in benzene to give diastereomeric mixtures of a-phenylthio ketone, which were then transformed into the corresponding phenylthiocyclohexene with 64% ee (equation 52). O

O 34b, Et3N • HCl, benzene

t-Bu

65 °C 62%

SPh * * t-Bu

SPh 3 steps

ð52Þ

67% t-Bu ee = 64%

Another chiral sulfenylating reagent, (S)-4-diphenylmethyl-3-phenylsulfenyl-2-(N-cyanoimino)thiazolidine 36, was developed for sulfenylation of b-diketones and b-keto esters (equation 53).33 In this reagent, the 2-(N-cyanoimino)thiazolidine (NCT) group can function as a leaving group whereas the asymmetric center in NCT induces the chirality in the products. The reactions of

240

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

cyclohexanone sodium enolate derivatives and reagent 36 in THF gave a-phenylthio products in good yields. Among them, the reaction of 2-methoxycarbonylcyclohexanone resulted in up to 96% ee. Ph2HC PhS N

O

S

R 36

O

NCN

SPh R

*

ð53Þ

NaH, THF, −78 °C Up to 93% yield Up to 96% ee

R = CO2Me, CO2Et, CO2i-Pr, CO2Ph, COMe, COt-Bu, COPh, CN

The influence of the ring size of cyclic b-keto methyl esters on asymmetric a-phenylsulfenylation was investigated (equation 54). The ee values for 5- and 7-membered rings were not as high as the 6-membered ring compound, and no selectivity was observed with the 8-membered ring compound. O

O CO2Me

SPh

NaH, 36

* CO2Me (CH2)n

THF, −78 °C

(CH2)n n (ring size)

Yield (%)

ee (%)

1 (5) 2 (6)

79 90

65 96

3 (7) 4 (8)

76 87

22 0

ð54Þ

Reproduced from Tanaka, T.; Azuma, T.; Fang, X.; et al. Synlett 2000, 33, with permission from Georg Thieme Verlag KG.

5.9.6.2

Chiral Auxiliary

The enantioselective electrophilic sulfenylation of ketones or 3-acyl-2-oxazolidones via divalent tin enolates, generated from ketones or 3-acyl-2-oxazolidones and stannous trifluoromethanesulfonate, was reported (equation 55).34 Initially, the reactants were treated with stannous trifluoromethanesulfonate in the presence of N-ethylpiperidine as a base in CH2Cl2, then a chiral diamine 37 was added as a ligand (stoichiometric), followed by sulfenylating reagents 38a or 38b. The corresponding a-keto sulfides were obtained in good yields (up to 93%) and good ees (up to 85%). In this reaction, the auxiliary was not covalently bound to the reactants. The enantioselectivity was induced by the effective coordination of chiral diamine with the divalent tin enolates.

N O R1

Sn(OTf)2 N-ethylpiperidine

R2

N

Ph

37 chiral diamine

O O S S R

38a: R = 1-naphthyl 38b: R = phenyl

CH2Cl2, −78 °C

O R2

R1 O O

R2

R1

SPh Reagent

Yield (%)

ee (%)

R1 = Ph, R2 = Me R1 = Ph, R2 = Et R1 = i-Pr, R2 = Me R1 = t-Bu, R2 = Me

38a 38a 38a 38a

78 80 72 52

85 75 50 70

R2 = Me R2 = Bn

38b 38b

93 91

81 82

Reactant

O

O N

R2

Reproduced from Yura, T.; Iwasawa, N.; Clark, R.; Mukaiyama, T. Chem. Lett. 1986, 15, 1809, with permission from Chemical Society of Japan.

ð55Þ

Oxidation: CX Bond Formation (X¼Halogen, S, Se) 5.9.6.3

241

Transition-metal Catalysis

The first metal-catalyzed enantioselective electrophilic sulfenylation of b-keto esters was developed using chiral Ti(TADDOLato) complex 7 (equation 56).35 Reactions were carried out using phenylsulfenyl chloride as the source of electrophilic sulfur in toluene at room temperature, and without the need to add any base to neutralize the hydrogen chloride formed during the reaction. The corresponding products were obtained in good yields (up to 95%) and good ees (up to 88%). O

O

O Catalyst 7 (1.2~5 mol%)

R1

OR3

R1

PhSCl, toluene, r.t.

R2 R1, R2 = alkyl R3 = alkyl, Ar

O

OR3 R2 SPh

ð56Þ

Up to 95% yield Up to 88% ee

Reproduced from Jereb, M.; Togni, A. Org. Lett. 2005, 7, 4041, with permission from American Chemical Society.

Trying to extend the scope of this new [Ti(TADDOLato)]-catalyzed asymmetric sulfenylation reaction, the influence of the structure of b-keto esters on enantioselectivity was further studied (Table 2).36 Compared to t-butyl ester 39a, the enantioselectivity of 39b dropped from 88% to 52%, which was caused by a single methylene spacer. For similar compounds 39c–f, moderate ees were obtained. So, it was concluded that the vicinity of the bulky group to the reaction center was of prime importance for high enantioselectivity. On the other hand, for substrates 39f and 39g having a bulky ester group, no high enantioselectivity of the products was obtained, which showed that the steric effect on enantioselectivity was not only a matter of size, but mainly of shape and position of corresponding substituents. Three isomeric b-keto esters 39h, 39i, and 39j were converted to their corresponding products with 90%, 92%, and 97% ees, respectively. A closer examination of the structure of these three esters revealed that the branching of the ester group was crucial for enantioselectivity. On the basis of the above

Table 2

Enantioselective electrophilic sulfenylation on b-keto esters catalyzed by 7

O

O

O

Catalyst 7 (5 mol%), PhSCl, toluene, r.t.

OR

OR SPh 40a−n

39a−n R=

( )6 39a

39b

O

Ph

39c

C6F5

39d

39e

t-Bu Ph Ph

t-Bu

39f O

39g

O

Et

O OPh

39k

39h

39i O

O

Ph

O

O

OEt

O 39l

O

39j

39m

Ot-Bu F 39n

Reactant

Yield (%)

ee (%)

Reactant

Yield (%)

ee (%)

39a 39b 39c 39d 39e 39f 39g

86 75 73 60 57 71 78

88 52 53 62 73 49 63

39h 39i 39j 39k 39l 39m 39n

85 86 82 93 75 75 60

90 92 97 72 86 66 89

242

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

findings, the positive steric effect of the ester group on enantioselectivity was a matter of it being a bulky, rigid and compact aliphatic group. The role of the structure of the group attached to the ketone carbonyl moiety was also examined by comparing 39k, 39l, and 39m. The ees of the corresponding products showed that the structure of keto group functionality possessed a considerable lower impact on enantioselectivity than the ester group. Meanwhile, the catalytic asymmetric sulfenylation of fluorine-containing analogue 39n was tested. The desired compound was obtained in moderate yield and high ee. This method to prepare chiral a-fluoro-a-sulfenylated b-keto ester could lead to interesting fluorine- and sulfur-containing molecules with potential biological activity. Cyclic b-keto esters were also evaluated in the Ti-catalyzed asymmetric sulfenylation with phthalimide-N-sulfenyl chloride as the source of electrophilic sulfur (equation 57).37 For different substrates, the products were obtained in high yields with a maximum of 60% ee (for 41). The enantioselectivities were lower than those of a corresponding reaction with phenylsulfenyl chloride.

O

O

CO2Et

SCl N

+

O O

CO2Et O

catalyst 7 (2 mol%)

S N

toluene, r.t.

ð57Þ

O Yield = 94% ee = 60%

41

Enantioselective electrophilic sulfenylation was further investigated using the DBFOX–Ph/Ni(II) complex (equation 58).38 The reaction of a-fluoro-b-keto esters 42a–c and phenylsulfenyl chloride catalyzed by the DBFOX–Ph/Ni(II) complex in CH2Cl2 gave the corresponding a-fluoro-a-sulfenyl-b-keto esters 43a–c in moderate to good yields with up to 93% ee. Notably, the addition of molecular sieves was essential for this reaction. Treatment of compound 43a with DAST gave tri-fluorinated a-sulfenylcarboxylate 44 in good yield, which should be a useful intermediate for the synthesis of the nonracemizing fluoro-isosteric analogue of pharmaceutically attractive SM32.

O

O

R

Ot-Bu F 42a: R = Me 42b: R = Et 42c: R = Ph

O Catalyst 15 (11 mol%) Ni(ClO4)2 6H2O (10 mol%) PhSCl, CH2Cl2, MS, r.t.

O

R

Ot-Bu F SPh 43a: R = Me, 70% yield, 86% ee 43b: R = Et, 80% yield, 87% ee 43c: R = Ph, 80% yield, 93% ee from 43a DAST, CH2Cl2, r.t. 89% yield

X X Me

O

O X SPh

X = H; (R)-SM32 X = F, Fluoro-SM32

F F N Me

Me

ð58Þ

O

Ot-Bu F SPh 44

The enantioselective a-phenylsulfenylation as well as a-pentafluoro-phenylsulfenylation of nonfluorinated b-keto esters were also carried out under the same catalyst conditions affording products 45a–h in high yields with high ees (equation 59). The acyclic b-keto esters were converted to the corresponding a-sulfenyl-b-keto esters 45a–d with up to 95% ee, whereas sulfenylation of cyclic b-keto esters gave products 45e and 45f with somewhat lower ees. On the other hand, a-pentafluoro-phenylsulfenylation with C6F5SCl as an electrophile was attempted. The desired products 45g and 45h were obtained in good yields and high ees, which showed that this method could be used to prepare various classes of molecules containing a quaternary stereogenic carbon atom bearing a perfluoroaryl thioether functionality.

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

O R1

O Me

Catalyst 15 (11 mol%)

O OR2

O Me

45a 96% Yield, 88% ee

O

OAdm SPh

O

O

O

O

O

Et

O

Ot-Bu SPh 45c 88% Yield, 88% ee

Ot-Bu SPh 45d 95% Yield, 95% ee

O

Ph

O

O

Me S

OAdm SPh

45e 78% Yield, 45% ee

OR2 SAr 45a-h

O

45b 84% Yield, 90% ee

Ot-Bu SPh

5.9.6.4

O

O

R1

ArSCl, CH2Cl2, MS, r.t.,

O Ot-Bu SPh

O

Ni(ClO4)2 6H2O (10 mol%)

t-Bu O F

ð59Þ

O

Et S

t-Bu O F F

F F

F

F 45h F 73% Yield, 89% ee

F 45g F 90% Yield, 80% ee

45f 57% Yield, 25% ee

243

Organocatalytic Sulfenylation

Organocatalysis is an alternative approach that can induce high enantioselectivities on asymmetric sulfenylation. This part is discussed in detail in Volume 7. Only selected examples are shown in equations 60–62 to give a brief introduction of organocatalytic asymmetric electrophilic sulfenylation. Chiral pyrrolidine derivatives 46, 47, and 48 were reported to catalyse the a-sulfenylation of aldehydes (equation 60),39 the a-sulfenylation of b-keto esters (equation 61),40 and the aminosulfenylation of a,b-unsaturated aldehydes (equation 62).41 In these three types of reactions, different electrophilic sulfur sources were used and the desired compounds were all obtained with very high ees. Ar Ar N OTMS H 46 (10 mol%)

O N +

N SBn

O CO2R (CH2)n

N SAr

+

O

O

O R

N SBn

H +

5.9.7.1

O

X N OH H 47 (20 mol%)

* CO2R SAr (CH2)n

X = 3,5-(CH3)2C6H3

Ph Ph N H OTMS 48 (20 mol%)

O

5.9.7

R Up to 98% ee

X

O

N

O R

ð60Þ

SBn

Ar = 3,5-(CF3)2C6H3

N

R

O

ð61Þ

Up to 97% ee

O O

N

O H

SBn Up to 98% ee

+

O O

ð62Þ R

H

SBn Up to >99% ee

Enantioselective Electrophilic Selenenylation Chiral Selenenylating Reagents

The asymmetric selenenylation of cyclohexanones using chiral selenenamides as selenenylating reagents was reported (equation 63).42 The best result was obtained when 4-tert-butylcyclohexanone was treated with chiral selenenamide 49, prepared in situ from

244

Oxidation: CX Bond Formation (X¼Halogen, S, Se)

(S)-1-naphthylehtylamine and phenylselenenyl chloride, followed by oxidative elimination to give the highest ee (26%) of 4-tertbutyl-2-cyclohexenone.

PhSe

O

SePh

49

*

THF, 55 °C 44%

t-Bu

O

O

N H

30% aqueous H2O2, THF, r.t., 2.5−5 h

ð63Þ

quant.

* t-Bu

t-Bu ee = 26%

An example of enantioselective a-selenenylation of 2-phenylpropanal was reported in 1988.43 The optically active seleneamides were formed in situ by reaction of secondary amines and phenylselenenyl bromide in the presence of triethylamine (equation 64). 2-Phenylpropanal was then added to the reaction mixture to prepare the a-selenenylated aldehyde with up to 60% ee. Notably, as the reactions were carried out in one pot, it could not be excluded that the chiral enamine intermediates were generated in situ from 2-phenylpropanal and chiral proline derivatives. O

N H

ArSeBr, Et3N, CH2Cl2/HMPA

R

H N SeAr

−30 °C

Ph

O

R

H CH2Cl2/HMPA −30 °C

*

Ph

SePh Up to 60% ee

ð64Þ

R = CH2OMe, CO2Me; Ar = Ph, p-chlorophenyl Reproduced from Tiecco, M.; Carlone, A.; Sternativo, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 6882, with permission from Wiley.

5.9.7.2

Organocatalytic Selenenylation

The initial examples of highly enantioselective a-selenenylation of aldehydes were reported in 2007.44,45 In both cases, N-(phenylseleno)phthalimide was used as the selenenylating reagent and diarylprolinol silyl ether derivatives were used as organocatalysts for a-selenenylation of aldehydes (equation 65). Very high enantioselectivities of a-selenenylated aldehydes were obtained, most of them ranging from 95 to 99% ee. Ar

O

O +

N SePh

N H

R O

5.9.8

Ar OTMS

O SePh

ð65Þ

R 95−99% ee

Conclusion and Outlook

We have discussed the enantioselective CX bond formation reactions including halogenation, sulfenylation, and selenylation, particularly based on the electrophilic-type reaction. Although the initial protocols for these reactions involved stoichiometric amounts of chiral reagents or chiral auxiliaries on the substrates, recent advances in asymmetric synthesis have significantly improved towards catalytic enantioselective process. Metal-catalyzed enantioselective CX bond formation reactions as well as CX bond formation by the use of chiral organocatalysts enable catalytic highly enantioselective CX bond formation reactions, and today more than 90% enantioselectivity is routinely achieved in these fields. However, there are still a lot of challenges and issues to be solved, the direct enantioselective replacement of unactivated hydrogen by X atom, for example. It is the hope of the authors that this chapter will stimulate chemists to further place efforts in catalyst and reagent modifications to achieve this goal.

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Oxidation: CX Bond Formation (X¼Halogen, S, Se)

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