ISSN 1349-4848

number147

Contr ibution :- Bifunctional Molecular Catalysts with

Cooperating Amine/Amido Ligands

Yoshihito Kayaki, Assistant Professor Takao Ikariya, Professor Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology

New Produc ts I nformation :- Air-Stable Phophine Oxide Ligand

- Allylic C–H Oxidation•Amination Catalyst “White Catalyst”

- Powerful and Easy Peptide Coupling Reagent

- Synthesis of Diazo Compounds

- Chemoselective Reduction of Aldehydes

2

10

CONTENTS

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1. Introduction

The chemistry of transition metal-based molecular catalysts has progressed with discoveries of novel catalytic transformations as well as understanding the reaction mechanisms. Particularly, significant efforts have been continuously paid to develop bifunctional molecular catalysts having the combination of two or more active sites working in concert, to attain highly efficient molecular transformation for organic synthesis. We have recently developed metal–ligand cooperating bifunctional catalysts (concerto catalysts), in which the non-innocent ligands directly participate in the substrate activation and the bond formation. The concept of bifunctional molecular catalysis is now an attractive and general strategy to realize effective molecular transformation.1 In 1995, Noyori and co-workers reported an unprecedented effect of diamine ligands on the enantioselective hydrogenation of simple aromatic ketones with BINAP-Ru(II) system [BINAP = 2,2’-bis(diphenylphosphino-1,1’-binaphthyl)].2 A combination of RuCl2[(S)-binap](dmf)n, chiral 1,2-diamine, and KOH showed an extremely high activity toward ketone hydrogenation than the classical BINAP–Ru catalyst. Subsequently, a prototype of a conceptually new phosphine-free Ru catalyst bearing N-sulfonylated 1,2-diamines as chiral ligands was developed for highly efficient asymmetric transfer hydrogenation of ketones.3 Detailed experimental and theoretical analyses of the real catalysts revealed that both an amidoruthenium complex having a square-planar geometry

and a coordinatively saturated hydrido(amine)ruthenium complex are involved in the catalytic cycle as depicted in Figure 1. The amido complex has sufficient Brønsted basicity to dehydrogenate readily secondary alcohols including 2-propanol to produce the hydrido(amine) complex. The NH unit bound to the metal center in the amine complex exhibits a sufficiently acidic character to activate ketonic substrates. During the interconversion between the amido and the amine complexes, the metal/NH moiety cooperatively assists the hydrogen delivery via a cyclic transition state where H– and H+ equivalents are transferred in a concerted manner from the hydrido(amine) complex to the C=O linkage or from 2-propanol to the amido complex without direct coordination to the metal center (outer-sphere mechanism). This unique concept of the bifunctional transition metal based-molecular catalysts leads to reactions with high rates and excellent stereoselectivies because the reactions proceed through a tight-fitting assembly of the reactants and chiral catalysts. Figure 2 lists some representative examples of well-defined bifunctional molecular catalysts recently developed in our group. The concept of the chiral bifunctional η6-arene–Ru complexes, RuH(Tsdpen)(η6-arene), [Tsdpen = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] has been successfully extended to analogous Cp*Rh and Ir complexes, Cp*MH(Tsdpen) [Cp* = η5-C(CH3)5, M = Rh, Ir].4 In addition to the N-sulfonylated diamine complexes, group 8 and 9 metal complexes with diamines (N–N),5 aminophosphines (P–N),6 aminoethanethiols (S–N),7 and o-aminomethylphenyl (C–N)8 ligands have been

Ru

NRu

N

TsR

R

NRu

N

H

TsR

R

δ–

δ+

H H

δ+

δ–

H

Rn

amido complex

amine hydrido complex

OH

O

Ar

Rn

O

OH

Ar H

N

N

O

H

H

CTs

A possible transition state

Rn

δ–

δ+

H H

　　　　 Figure 1. Concept of Concerto molecular catalysis: Interconversion of the amido and the amine hydrido Ru complex via a possible six-membered transition state.

Bifunctional Molecular Catalysts with Cooperating Amine/Amido Ligands

Yoshihito Kayaki and Takao Ikariya*

Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-E4-1 O-okayama, Meguro-ku, Tokyo, 152-8552, Japan

E-mail: tikariya@apc.titech.ac.jp

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extensively developed as the bifunctional molecular catalyst bearing the metal/NH effect.

As related bifunctional catalysts studied by other research groups, Figure 3 represents several group 8 and 9 metal complexes in which protic functional groups on the ancillary ligands works cooperatively with the metal center to catalyze hydrogenation, transfer hydrogenation, and so on. The Zhang’s (A)9 and Grützmacher’s catalysts (B)10 having tridentate protic amine ligands can help the H+/H– transfer in a similar manner to our bifunctional catalysts. The Shvo’s catalyst (C)11 can release the catalytically active species, cyclopentadienyl and cyclopentadienone complexes, and the OH group plays a vital role as a proton mediator to promote hydrogen transfer processes. Recently, Milstein developed new PNN pincer complexes (D)12 as highly active redox catalysts and found

their unique hydrogenation/dehydrogenation mechanism via dearomatization. Fujita and Yamaguchi have designed Cp*Ir complexes (E)13 having 2-hydroxypyridine and pyridonate ligands which efficiently promote dehydrogenation of secondary alcohols by the aid of the acidic OH function. Kitamura and Tanaka demonstrated that the acidic nature of 2-quinoline carboxylic acid on a CpRu fragment (F) effects a C–O bond activation of allyl alcohols to afford allyl ethers.14

This article focuses on the outline of our recent progress in the bifunctional molecular catalysts based on the metal/NH synergy, and their utilization to asymmetric redox transformations and related enantioselective C–C and C–N bond formation reactions.

NRu

N

Ts

C6H5

C6H5 HH H

Rn

RuH(Tsdpen)(η6-arene)

NRu

N

H

Cp*RuH(N–N)

NRu

P

HR

Cp*RuH(P–N)

H H H H

R2

Cp*MH(C–N)M = Rh, Ir

M

N

H H

RR

H

C6H5

C6H5N

MN

H

Ts

H H

Cp*MH(Tsdpen)M = Rh, Ir

RuH(S–N)(η6-arene)

NRu

N

Ts

HH H

Rn

RuH(Tscydn)(η6-arene)

NM

N

H

Ts

H H

Cp*MH(Tscydn)M = Rh, Ir

Rn

Ru

N

S

H

H

Ru

NHN

H

(A)

+

(B)

=N

HRh H

P(C6H5)3

(C)

Ph

Ph

Ph

O

PhH

OC

Ru

CO

Ph

Ph

Ph

O

Ph

CO

Ru

OC

H PhOHPh

Ph Ph

OCOC H

Ru

PhPhO

Ph Ph

OC CO

(D)

N Ru

PtBu2

NEt2

COH

HN Ru

PtBu2

NEt2

COH

–H2

H2

HH

HN Ru

N

N

LCl

Cl

O

OC6H5

C6H5

(E)

N

ClIr

ClHO

(F)

N

OH

Rusolv.O

+

Figure 2. Bifunctional catalysts bearing protic chelate amine ligands.

Figure 3. Related examples of metal-ligand cooperating catalysts having protic functional moiety.

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2. Asymmetric Transfer Hydrogenation Using Bifunctional Catalysts1c

In general, 2-propanol can be used as a safe, nontoxic, environmentally friendly hydrogen source. Although the asymmetric reduction in 2-propanol gives satisfactory results, an inherent drawback of the hydrogen transfer reaction is its reversibility, leading to limited conversion determined by thermodynamic factors of the system and the deterioration of enantiomeric purity of the products upon a long exposure of the reaction mixture to the catalyst. On the other hand, formic acid is amenable to the asymmetric reduction in an irreversible fashion leading to 100% conversion.15 Asymmetric reduction of simple aromatic ketones with a mixture of formic acid and triethylamine containing the bifunctional catalyst is characterized by high efficiency in terms of activity, selectivity, wide substrate scope, and practicability. The bifunctional hydrido(amine)-Ru complex is coordinatively saturated, and the catalyst system tolerates amino, ester, cyano,

nitro, azide, and chloro groups as well as heteroaromatic rings and the alkyne linkage,1c as summarized in Figure 4. Carbon–nitrogen double bonds are also reducible with a mixture of formic acid and triethylamine containing chiral Ru or Rh catalysts to the corresponding amines with a high level of enantiomeric excesses.16

A series of Cp*Ru(P–N) complexes bearing the protic phosphine-amine chelating ligands also serve as highly efficient catalysts for transfer hydrogenation as shown in Figure 5. Based on the reversible hydrogen transfer mechanism via interconversion between both the amido and amine complexes, the redox process can be successfully applied to rapid racemization of chiral alcohols17 as well as regioselective oxidative transformation of diols to lactones using acetone.18 A chiral Cp*Ru(P–N) complex accomplishes enantioselective isomerization of allylic alcohols to β-substituted ketones, and the following ring-closing metathesis affords (R)-muscone19 with a moderate ee.

Rn

C6H5

OH

C6H5

OH

X

C6H5

OH

N

OH

O

OH

C6H5

OH

O

C6H5

OH

OH

C6H5

OH

OH

C6H5

C6H5 OC2H5

OOH

C6H5Cl

OH

99% yield, 96% ee

>99% yield, 97% ee

X = CN, N3, NO2

67–100% yield, 95–98% ee

97% yield, 95% ee>99% yield, 98% ee

89% yield, 99% ee

78% yield, 95% ee

100% yielddl:meso = 98.6:1.4. 99% ee

n

n = 1, 94% yield, 93% een = 3, 99% yield, 95% ee

>99% yield, 98% ee

Cp*RhCl[(S,S)-Tsdpen]

HCOOH/N(C2H5)3or (CH3)2CHOH

NRu

N

H

TsR

RH H

Figure 4. Asymmetric transfer hydrogenation of ketones with chiral Ru and Rh catalysts.

Cp*RuCl(P–N)

OH

OH

OH OH

toluene

Cp*RuCl(P–N)

NH2

RuP

Cl

Ph2

ArCH2

ArCH2

O

O

ArCH2

ArCH2

toluene

Cp*RuCl(P–N)

OH

8toluene

Cp*RuCl(P–N)*O

8*

O

muscone

Cp*RuCl(P–N)*

NHRu

P

Cl

Ph2

*

74% ee

KOtBu

KOtBu

KOtBu

Figure 5. Hydrogen transfer reactions with Cp*Ru(P­–N) catalysts.

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5

3. Catalytic Hydrogenation of Polar Substrates with Bifunctional Catalysts6

Since we reported an effect of alcoholic solvent facilitating the heterolytic cleavage of H2 bound to the 16-electron [Cp*Ru{Me2N(CH2)2NH2}]+ (Cp*Ru(N–N)) fragment in 2001,20 we have systematically tested catalytic hydrogenation of polar substrates other than ketones, and found that the replacement of the tertiary amino group with a tertiary phosphino group has led to the expansion in the scope of the Ru/NH bifunctionality. For example, Cp*Ru(P–N) complex, [Cp*Ru{Ph2P(CH2)2NH2}]+, selectively delivers hydrogen to the non-substituted C–O bond in a variety of terminal epoxides, leading to the formation of the corresponding sec-alcohols, while Cp*Ru(N–N) complexes are totally inactive.21 The Cp*RuCl(P–N) catalyst allows the straightforward catalytic hydrogenation of N-acylcarbamates and carboxyimides to afford N-protected amines and alcohols selectively.22 Notably, the present hydrogenation is applicable to the reductive transformation. The deprotection of the primary amine from N-phthalimides with this bifunctional catalyst can be also applied to Gabriel amino acid synthesis. For instance, the HCl salt of L-Phe methyl ester with no loss of optical purity is obtainable from the hydrogenolysis of N-phthaloyl-L-Phe methyl followed by HCl treatment. Hydrogenolysis of chiral N-acyloxazolidiones, which are useful synthetic intermediates in the asymmetric synthesis developed by Evans gives chiral alcohol and the original chiral auxiliary without any loss in the optical purity as shown in Figure 6.23a The chiral version of the Cp*Ru(P–N) catalyst bearing the chiral P–N ligand derived from L-proline promotes the enantioselective hydrogenation of prochiral 4-arylglutarimides via desymmetrization to provide the corresponding δ-hydroxyamides with excellent ee values and in high yields. Further synthetic elaboration has furnished chiral piperidinone derivatives, which serve as important synthetic intermediates for a number of physiologically active chiral compounds including the antidepressant paroxetine.

The Cp*Ru(P–N) catalysts also promote the hydrogenation of esters and carboxamides to give alcohols or amines under more forcing conditions.23b This hydrogenation procedure will provide a powerful alternative method for classical reduction using stoichiometric amounts of metal hydride reagents.

4. Aerobic Oxidation with Bifunctional Catalysts24

When molecular oxygen can be used as a hydrogen acceptor for the dehydrogenative oxidation of alcohols with the bifunctional catalyst, aerobic oxidation becomes a simple and minimal organic waste process. Fortunately, we found a new family of isolable bifunctional amido-Ir complexes bearing a C–N chelating amine ligands, Cp*Ir[κ2(N,C)-(NHCR2-2-C6H4)] (R = C6H5 and CH3), and the corresponding hydrido(amine) complexes, Cp*IrH[κ2(N,C)-{NH2CR2-2-C6H4}], which serve as efficient catalysts for transfer hydrogenation of ketones, promote catalytic aerobic oxidation of alcohols.8a The catalytic reaction of 1-phenylethanol proceeds smoothly under atmospheric pressure of air containing amido-Ir complex, Cp*Ir[κ2(N,C)-{NHC(C6H5)2-2-C6H4}] (Figure 7).25 The hydrido(amine)-Ir complex, Cp*IrH[κ2(N,C)-{NH2C(C6H5)2-2-C6H4}], and binary catalyst systems, including the chloro(amine)-Rh and -Ru complexes and KOC(CH3)3, also provide the oxidation product acetophenone. The reaction of primary alcohols under identical conditions affords the oxidative dimerization product, esters. When a mixture of benzyl alcohols containing combined catalyst of the chloro complex, Cp*IrCl[κ2(N,C)-{NH2C(C6H5)2-2-C6H4}], with an equimolar amount of KOC(CH3)3 in THF is stirred under air at 30 °C, the corresponding benzyl benzoate derivatives are obtained. This aerobic oxidation of alcohols is more appealing when applied to the kinetic resolution of racemic secondary alcohols with chiral amido catalysts (Figure 7). A racemic 1-phenylethanol is efficiently resolved by the chiral Ir complex, Cp*Ir[(S,S)-Msdpen] (Ms = methanesulfonyl), under the aerobic

Figure 6. Hydrogenation of N-acylcarbamates and carboximides with Cp*Ru(P–N) catalysts.

N

O

O

CO2CH3

Bn

Cp*RuCl(P–N)KOtBu

2-propanol80 °C

H3N CO2CH3

Bn

>99% yield

HClO

O

+

Cl

+ H2

1.0 Mpa

Cp*RuCl(P–N)

NH2

RuP

Cl

Ph2

N

O

O

Ar O

O

HN

OH

O

Ar O

O

2-propanol

chiral Cp*RuCl(P–N)*

Ar = 4-FC6H4

99% yield98% ee

80 °C

chiral Cp*RuCl(P–N)*

NHRu

P

Cl

Ph2+ H2

NH

O

Ar

NH2ClAr

O

O

O

(–)-Paroxetine

2-propanol

Cp*RuCl(P–N)

80 °C

+ H2NO

O O

CH2C6H5

C6H5 CH33.0 MPa

3.0 MPa

+

OH

CH2C6H5

NHO

O

C6H5 CH3

90% yield>99% ee

89% yield

KOtBu

KOtBu

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condition to give (R)-1-phenylethanol with a 48% yield and 98% ee; the kf/ks ratio being up to 100.26 Similarly, the reactions of 1-indanol and 1-tetralol at ambient temperature provide the R-enantiomers with >99% ee and with 46–50%.

5. Extension to Dinuclear Bifunctional Catalysts Bearing Metal–Nitrogen Bond27

The metal–ligand bifunctional effect realized for the mononuclear half-sandwich amido complex is expected to be operative in imido-bridged dinuclear complexes with M–N bonds. Careful structural analysis and NMR studies revealed that the electron-withdrawing sulfonyl group stabilizes the imido-bridged dinuclear complexes,28 also has an acid/base bifunctional property originated from the M–N bond nature. A coordinatively unsaturtated bis(imido)-bridged di rhodium(II I ) complex, [ (Cp*Rh)2(μ -NTs)2] (Ts = SO2C6H4CH3-p) reacts smoothly with H2 (1 atm) in CH2Cl2 for 24 h at room temperature to afford the bis(amido)-bridged

dirhodium(II) complex, [(Cp*Rh)2(μ-NHTs)2], in 82% yield as shown in Figure 8. It should be noted that in this reaction, H2 is formally converted into two amido protons and two electrons for the reduction of the dirhodium(III) core in [(Cp*Rh)2(μ-NTs)2]. The bis(amido) complex was also obtained upon treatment of the bis(imido) complex with an excess of 2-propanol. The generation of two NH protons associated with two-electron reduction of the metal center is in sharp contrast with the dehydrogenation of primary and secondary alcohols by unsaturated mononuclear amido complexes, which leads to the formation of hydrido–amine complexes without formal reduction of the metal, as described above. The bis(amido)-bridged dirhodium(II) complex rapidly reacted with O2 to form the bis(imido)-bridged dirhodium(III) complex and water.29 Furthermore, the facile redox interconversion between the dinuclear imido and amido complexes can be applied to catalytic aerobic oxidation of H2 and alcohols.

Rh

N

N

Rh

Ts

Ts

H

H

Rh

N

N

Rh

Ts

Ts OH

H

IIII

1/2 O2H2O

or H2

IIIIII

N

Ir

HCH3 CH3

NH2

IrC6H5

C6H5H N

H

IrC6H5

C6H5

H2OO2C6H5

OH

C6H5

Ocat

THF30 °C, 3 h

++

(air)

cat:

S/C = 10

63% 72% 5%

cat, tBuOK

30 °C

+OH

O

O+

(air)

S/C = 10 64%

cat:

NH2

IrC6H5

C6H5Cl

H2OO2THF

H2OAr

OH

Ar

O

Ar

OH

N

Ms

NH

Ir

C6H5

C6H5

R++

THF, 30 °C+O2

(air)>99% eekf/ks = >100

Ir cat

Ir cat:

Figure 8. Interconversion between imido-bridged dirhodium(III) and amido-bridged dirhodium(II) complexes.

Figure 7. Aerobic oxidation of alcohols with bifunctional Ir catalysts.

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6. Asymmetr ic Conjugate Addi t ion wi th Bifunctional Catalysts30

The basic amido complexes can react with certain acidic organic compounds, leading to an amine complex bearing a metal bonded carbon nucleophile. For example, we have found that the purple-colored amido Ru complex, Ru[(R,R)-Tsdpen](η6-mesitylene), smoothly reacts with dimethyl malonate in toluene below –30 °C to give an yellow crystalline complex, Ru[CH(CO2CH3)2][(R,R)-Tsdpen](η6-mesitylene).31 If the amine complexes bearing a metal-bonded nucleophile generated from an amido metal complex with certain acidic compounds can attack to electron-deficient acceptors, the catalytic C–C bond formation could be achieved. In fact, a chiral Ru catalyst, Ru[(S,S)-Tsdpen](η6-arene) efficiently promots enantioselective Michael addition of dimethyl malonate to cyclic enones or nitro olefins to give the corresponding adducts with excellent ee's (Figure 9). NMR and DFT analyses of the Michael addition reaction of 1,3-dicarbonyl compounds to cyclic enones catalyzed by bifunctional Ru catalysts revealed that the enatioselective C–C bond formation proceeds through intermediate formation of chelating ion pairs that coordinate a molecule of enone via the Ru metal center producing a highly organized environment for the C−C bond formation, yielding selectively only one enantiomer of the product.31b The scope of the enantioselective conjugate addition with chiral amido catalysts is extensible to the Ir-catalyzed reaction of α-cyanoacetates with dialkyl azodicarboxylates that affords the direct amination products, the hydrazine adducts.32 When the acetylenic esters are used as electrophiles, enantioselective

and Z selective conjugate addition of α-cyanoacetate with bifunctional chiral catalysts proceeds smoothly to yield chiral adducts having a quaternary carbon center with an excellent ee.33

7. Summary

This article focuses on recent advances in chemistry of conceptually new the Concerto Catalysis with bifunctional transition metal-based molecular catalysts including the stereo-, regio- and chemoselective reductive or oxidative transformation as well as enantioselective C–C and C–N bond formations via Michael-type conjugate additions. The rational design of the cooperating amine ligand that adjust the balance of the electronic factors on the M/NH units in the bifunctional catalysts is crucial to exploit characteristic catalyst performance with a wide scope and high practicability. We believe the present bifunctional molecular catalysts offer a great opportunity to open up new fundamentals for selective molecular transformation including asymmetric synthesis.

This work was supported a Grant-in-Aid for Scientific Research (Priority Areas No. 18065007, “Chemistry of Concerto Catalysis” and (S) No. 22225004) from the Ministry of Education, Culture, Sports, Science and Technology, Japan and partly supported by GCOE program.

CO2R

CO2R

NM

N

Nu(H)

SO2R

R

N

NSO2

R

R

M

H H

Nu–H

amine complex

amido complexBrønsted base

deprotonation

C–C bond formationC–N bond formation

: arene–Ru, Cp*–Ir

H

N

NRO2C

CO2R

HN

N

CO2R

Nu CO2R

CO2R

Nu CO2R

H

O

OH

Nu

NO2

R

NO2

R Nu

R

R

Figure 9. Asymmetric 1,4-addition to enones and nitroalkenes with chiral bifunctional Ru or Ir catalysts.

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References

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22) a) M. Ito, A. Sakaguchi, C. Kobayashi, T. Ikariya, J. Am. Chem. Soc. 2007, 129, 290. b) M. Ito, C. Kobayashi, A. Himizu, T. Ikariya, J. Am. Chem. Soc. 2010, 132, 11414.

23) a) M. Ito, L. W. Koo, A. Himizu, C. Kobayashi, A. Sakaguchi, T. Ikariya, Angew. Chem. Int. Ed. 2009, 48, 1324.

b) M. Ito, T. Ootsuka, R. Watari, A. Shiibashi, A. Himizu, T. Ikariya, J. Am. Chem. Soc. 2011, 133, 4240.

24) T. Ikariya, S. Kuwata, Y. Kayaki, Pure Appl. Chem. 2010, 82, 1471.

25) S. Arita, T. Koike, Y. Kayaki, T. Ikariya, Chem. Asian J. 2008, 3, 1479.

26) S. Arita, T. Koike, Y. Kayaki, T. Ikariya, Angew. Chem. Int. Ed. 2008, 47, 2447.

27) S. Kuwata, T. Ikariya, Dalton Trans. 2010, 39, 2984.28) a) K. Ishiwata, S. Kuwata, T. Ikariya, Organometallics

2006, 25, 5847. b) H. Arita, K. Ishiwata, S. Kuwata, T. Ikariya, Organometallics 2008, 27, 493.

29) K. Ishiwata, S. Kuwata, T. Ikariya, J. Am. Chem. Soc. 2009, 113, 5001.

30) a) T. Ikariya, I. D. Gridnev, Chem. Rec. 2009, 9, 106. b) T. Ikariya, I. D. Gridnev, Top. Catal. 2010, 53, 894.

31) a) M. Watanabe, K. Murata, T. Ikariya, J. Am. Chem. Soc. 2003, 125, 7508. b) I. D. Gridnev, M. Watanabe, H. Wang, T. Ikariya, J. Am. Chem. Soc. 2010, 132, 16637.

32) Y. Hasegawa, M. Watanabe, I. D. Gridnev, T. Ikariya, J. Am. Chem. Soc. 2008, 130, 2158.

33) Y. Hasegawa, I. D. Gridnev, T. Ikariya, Angew. Chem. Int. Ed. 2010, 49, 8157.

(Received February 2012)

No.147 No.147

9

Introduction of the authors :

Yoshihito Kayaki Assistant Professor, Ph.D. Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology

Yoshihito Kayaki was born in Tokyo, Japan, in 1969. He recieved his Ph.D. from Waseda University in 1997 under the supervision of Prof. A. Yamamoto. While at Waseda, he was appointed to a research fellowship of the Japan Society for the Promotion of Science. He joined the research group of Prof. T. Ikariya in 1998 and served as the group leader of the PRESTO project of JST from 2001 to 2005. He is currently an assistant professor at Tokyo Institute of Technology. His research interests lie in the area of synthetic and mechanistic studies of organometallic compounds as well as reaction chemistry relevant to CO2 utilization.

Takao Ikariya Professor, Ph.D.Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology

Takao Ikariya completed his Ph.D. degree supervised by Prof. A. Yamamoto in 1976 at Tokyo Institute of Technology and then he was appointed as an assistant professor in the Department of Synthetic Chemistry at the University of Tokyo. He discovered a prototype of chiral Ru-BINAP complex and successfully developed asymmetric hydrogenation with the Ru-BINAP complexes. He spent Prof. R. H. Grubbs’ group at Caltech for one and a half years in 1979-1981 as a postdoctoral fellow. In 1985, he moved to the central research center of NKK Co. In 1991, he joined in the ERATO Molecular Catalysis Project of JST, which was directed by Prof. R. Noyori. Then Ikariya was promoted to professor at Tokyo Institute of Technology in 1997. He received the Chemical Society of Japan Award in 2009 and the Humboldt Research Award in 2011. His current research interests include powerful and practical molecular catalysis in both liquid solvents and supercritical fluids.

No.147

10

No.147

Air-Stable Phophine Oxide Ligand

T2645 4,4,5,5-Tetramethyl-1,3,2-dioxaphospholane 2-Oxide (1) 1g, 5g

4,4,5,5-Tetramethyl-1,3,2-dioxaphospholane 2-oxide (1) is an air-stable phosphine oxide ligand, which forms hydrogen-bond-stabilized bidentate complexes with transition metals to enhance cross-coupling reactions. In the Kumada cross-coupling reaction, for example, this ligand can be applied even to reactions with substrates having less reactivity, such as tosylates, especially electron-poor aryl or heteroaromatic tosylates, to give the corresponding coupling products in good yields.

Typical Procedure: Preparation of 4’-methoxy-3-(trifluoromethyl)biphenyl2)

A solution of Pd(dba)2 (2.9 mg, 0.005 mmol, 0.5 mol%) and 1 (1.6 mg, 0.010 mmol, 1.0 mol%) in dry dioxane (4.0 mL) is stirred under N2 for 5 min at ambient temperature, and then treated with (4-methoxyphenyl)magnesium bromide (0.5 M in THF, 3.0 mL, 1.50 mmol). The resulting mixture is stirred for 5 min at ambient temperature. Thereafter, 3-(trifluoromethyl)phenyl tosylate (317 mg, 1.00 mmol) is added, and the resulting suspension is stirred at 80 °C for 22 h. At ambient temperature, aqueous HCl (2.0 mL, 2.0 N), Et2O (50 mL), and H2O (30 mL) are added. The separated aqueous phase is extracted with Et2O (50 mL x 2 times). The combined organic layers are dried over MgSO4 and concentrated in vacuo. The remaining residue is purified by column chromatography on silica gel (pentane) to yield 4’-methoxy-3-(trifluoromethyl)biphenyl (237 mg, Y. 94%) as a colorless liquid.

References1) Nickel-catalyzed cross-coupling reaction of aryl fluorides and chlorides with Grignard reagents under nickel/magnesium

bimetallic cooperation N. Yoshikai, H. Mashima, E. Nakamura, J. Am. Chem. Soc. 2005, 127, 17978.2) Air-stable PinP(O)H as preligand for palladium-catalyzed Kumada couplings of unactivated tosylates L. Ackermann, A. Althammer, Org. Lett. 2006, 8, 3457.

Related CompoundsB3479 1,3-Bis(2,6-diisopropylphenyl)-1,3,2-diazaphospholidine 2-Oxide 200mg, 1gD3846 1,3-Di-tert-butyl-1,3,2-diazaphospholidine 2-Oxide 1g, 5gB1374 Bis(dibenzylideneacetone) Palladium(0) (Pd(dba)2) 1g, 5g

Pd(dba)2 (0.5–2.5 mol%), Dioxane, 80 °C, 22 h

1 (1.0–5.0 mol%)+Ar OTs

R1

MgBr

O

O

P

Me

Me

Me

Me

R1

Ar

O

H

OTs

CF3

N OTs

N

OMe

F3C

N

OMe

TsO

NOMe

ArOTs

94

99

98

R1 Product Yield (%)

4-MeO

4-MeO

2-MeO

PdH

2

OP

O OH

O

PPd

H

P

O

O

OO

O

Me

Me

Me

Me

Me

Me Me

Me Me

Me

Me Me

1

No.147 No.147

11

Figure 1. aaaaaa

Allylic C–H Oxidation•Amination Catalyst “White Catalyst”

B3292 1,2-Bis(phenylsulfinyl)ethane Palladium(II) Diacetate (1) 200mg, 1g

1,2-Bis(phenylsulfinyl)ethane palladium(II) diacetate (1) is a palladium catalyst, which was developed by M. C. White et al., and named “White catalyst” after the developer. For an example of its characteristic reactivity differing from other homogeneous palladium catalysts, the allylic C–H oxidation reaction has been reported, in which an acetoxy group is introduced regioselectively into the allylic position.1)

Moreover, White et al. have also reported the macrolactonization reaction of ortho-substituted salicylic acid substrates, applying the reaction into intramolecular allylic C–H oxidation, in which the corresponding 14-membered ring macrolides (6 and 7) are obtained in moderate yields.2)

In addition, White et al. have reported the allylic C–H amination reaction which transforms N-tosylcarbamate (8) into oxazolidinone (9). This reaction affords anti-isomer 9 with diastereoselectivity, which allows it to provide the syn-1,2-amino alcohol (10).3)

Typical Procedure: Synthesis of macrolactone 72)

A 1 dram vial is charged with 1 (10.1 mg, 0.02 mmol). Another 1 dram vial is charged with the benzoic acid (84.1 mg, 0.2 mmol). To a 100 mL round bottle flask is charged benzoquinone (43.2 mg, 0.4 mmol), 1 (transferred using 10 mL CH2Cl2), and the acid substrate (transferred using 10 mL CH2Cl2). The flask is charged with a stir bar, topped with a condenser, and allowed to heat at 45 °C with an empty balloon on the top of the flask. After 72 h, the reaction is quenched with saturated NH4Cl (5 mL) and extracted with CH2Cl2 (2 x 30 mL). The combined organic layers are washed with H2O (1 x 30 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. After lactonization, the amount of remaining starting material can not be determined by crude 1H-NMR due to overlap of the product and starting material peaks (a small amount of starting material does remain). Purification by SiO2 flash chromatography (10%EtOAc/hexanes) provides the desired product as a white solid (44.0 mg, Y. 54%).

References1) Serial ligand catalysis: a highly selective allylic C–H oxidation M. S. Chen, N. Prabagaran, N. A. Labenz, M. C. White, J. Am. Chem. Soc. 2005, 127, 6970.2) Macrolactonization via hydrocarbon oxidation K. J. Fraunhoffer, N. Prabagaran, L. E. Sirois, M. C. White, J. Am. Chem. Soc. 2006, 128, 9032.3) syn-1,2-Amino alcohols via diastereoselective allylic C–H amination a) K. J. Fraunhoffer, M. C. White, J. Am. Chem. Soc. 2007, 129, 7274. b) G. T. Rice, M. C. White, J. Am. Chem. Soc.

2009, 131, 11709.

R1

S SO O

Pd(OAc)2

1

AcOH, Dioxane, 43 °C R1

OAc

R1OAc

Benzoquinone (2 eq.)

2 Y. 73% (2 : 3 = 11 : 1)

+

PhPh

1)

R1 = C8H17 3

CH2Cl2, Air, 45 °C

1 (10 mol%)Benzoquinone (2 eq.)OH

O

O

O

O

O

O

O

OR2 OR2

6: R2 = MOM, Y. 57%

7: R2 = Bn, Y. 57%

2)

4: R2 = MOM

5: R2 = Bn

O NHTs

i-Pr

O

NTsO

O

i-Pr

THF, 45 °C, 72 h

1 (10 mol%)Phenylbenzoquinone (1.05 eq.)

i-PrCO2H

OH

NH2

9 Y. 76%8 10 (anti : syn = 6 : 1)

3)

No.147

12

No.147

Powerful and Easy Peptide Coupling Reagent

F0726 Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) (1) 1g, 5g

Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH, 1) is a useful peptide coupling reagent for solution and solid phase peptide synthesis.1,2) Moreover, 1 is an efficient reagent for the acylation of alcohols, thiols and dithiocarbamates.1-4) 1 is not hygroscopic and can be stored in a refrigerator, hence it is easy to handle under standard laboratory conditions.

Typical Procedure: Solution phase synthesis of protected leucine enkephalin2)

To a solution of Fmoc-Phe-OH (0.189 g) and H-Leu-OtBu·HCl (0.112 g) in CH2Cl2 (10 mL), 5% aqueous solution of Na2CO3 (5 mL) is added and stirred at room temperature. To the mixture, 1 (0.198 g) in CH2Cl2 (5 mL) is added. The reaction is stirred for 1 h. The organic layer is separated and washed with H2O and saturated NaCl solution, and then dried over MgSO4. The solvent is removed in vacuo to give a white solid which is dissolved in CH2Cl2 (10 mL). The solution is used directly for deblocking by adding tris(2-aminoethyl)-amine (TAEA) (7 mL) to give H-Phe-Leu-OtBu. Additional amino acids are added similarly until the protected leucine enkephalin [Fmoc-Tyr(tBu)-Gly-Gly-Phe-Leu-OtBu] is obtained as a white solid (0.265 g, Y. 60.7%).

Reference1) Review A. El-Faham, S. N. Khattab, Synlett 2009, 886.2) Peptide and acyl fluoride synthesis L. A. Carpino, A. El-Faham, J. Am. Chem. Soc. 1995, 117, 5401.3) Conversion of carboxylic acids to anilides, hydrazides and azides A. El-Faham, M. Abdul-Ghani, Org. Prep. Proced. Int. 2003, 35, 369.4) Acylation of alcohols, thiols and dithiocarbamates M. Pittelkow, F. S. Kamounah, U. Boas, B. Pedersen, J. B. Christensen, Synthesis 2004, 2485.

Related CompoundsL0197 Leu-OtBu·HCl 1g, 5gF0297 Fmoc-Phe-OH 5g, 25gF0293 Fmoc-Gly-OH 5g, 25gF0506 Fmoc-Tyr(tBu)-OH 1g, 5g, 25gT1243 Tris(2-aminoethyl)amine 25mL

Fmoc-Phe-OH

Fmoc-Tyr(tBu)-Gly-Gly-Phe-Leu-OtBu

(Total Y. 60.7%)

H-Leu-OtBu

1 (1.5 eq.)5% Na2CO3 / H2O, CH2Cl2rt, 1 h

TAEA, CH2Cl2rt, 15 min

ii)H-Phe-Leu-OtBu+

i)

N N

F

CH3

CH3

CH3

CH3

1

PF6

(1 eq.)

No.147 No.147

13

Synthesis of Diazo Compounds

S0816 N-Succinimidyl 3-(Diphenylphosphino)propionate (1) 1g, 5g

Diazo compounds are remarkably versatile intermediates in organic synthesis. Recently, Raines et al. have reported the conversion of azides into diazo compounds using N-succinimidyl 3-(diphenylphosphino)propionate (1). According to their results, azides react with 1 to give alkyl acyl triazenes in THF-H2O. Subsequent base-catalyzed fragmentation affords the corresponding diazo compounds in high yields. This is useful as a mild and convenient method for the synthesis of diazo compounds. Their broad future application is expected.

Typical Procedure: 2-Azido-N-benzylacetamide (57 mg, 0.300 mmol) is dissolved in THF/H2O (2 mL/300 μL). To this solution is added phosphine 1 (112 mg, 0.315 mmol), and the resulting solution is stirred for 4 h under Ar. Sat. aq. NaHCO3 (2 mL) is then added, and the mixture is stirred vigorously for 4 h. The mixture is then diluted with sat. aq. NaCl (15 mL) and extracted with CH2Cl2 (2 × 15 mL). The organic layers are combined, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue is purified by silica gel flash chromatography (hexane : EtOAc = 7 : 3), to give the diazo compound as a yellow solid (45 mg, 0.255 mmol, Y. 85%).

Reference1) A Phosphine-mediated conversion of azides into diazo compounds E. L. Myers, R. T. Raines, Angew. Chem. Int. Ed. 2009, 48, 2359.

1

P CH2CH2 C

O

O N

O

O

Yield (%)

85

Diazo Compounds

97

O

NHBnN2

ON2

O

OCH3N2

BnS

67

NH

O

NN

PPhPh

O

R2

R1

(1.05 eq.)

N3 R1

R2

N2 R1

R2sat. NaHCO3 aq.15 min-12 h

+ 1THF/H2O (20:3)

3-12 h

alkyl acyl triazene

+NH2

O

PPhPh

O

No.147

14

Chemoselective Reduction of Aldehydes

S0810 Sodium Tris(1,1,1,3,3,3-hexafluoroisopropoxy)borohydride (1) 5g

Sodium Tris(1,1,1,3,3,3-hexafluoroisopropoxy)borohydride (1) is a selective reducing agent developed by Toshima et al. Aldehydes are selectively reduced in the presence of ketones and other reducible functions using 1 to afford the corresponding primary alcohols in high yields. This is a useful method for reduction of aldehydes because it does not require the addition of other reagents and the reaction is very simple and convenient. As reduction reactions of carbonyl groups are very important steps in organic synthesis, this method should find wide application in both academia and industry.

Reference1) Chemoselective reduction of aldehydes over ketones Y. Kuroiwa, S. Matsumura, K. Toshima, Synlett 2008, 2523.

Y. 94%

CH3 CHO

O OTBS

CH3

O OTBS

Hexafluoroisopropanol, 25 °C, 1.5 h

1 /THF (3 eq.)OH

OCH(CF3)2

B

OCH(CF3)2

OCH(CF3)2H Na 1 :

No.147

15

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