2

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NOCH2

OHOH

NH2

NN

N

A B

D CN

NH

N N

N

Co

N

H

H

CH3H

CH3

HH3C

H3C

H CH3

CH3

H

H2NOC

CH3

C

CONH2

CONH2CH3H2NOC

H2NOCL

CONH2

O

OH

H3C

P

O

O-O

O

H CH2OH

HN

CH3

CH3

HH

HO

L = CH3

L = Adenosylcobalamin

Methylcobalamin

L = CN Cyanocobalamin

Figure 1. Structure of vitamin B12 derivatives.

1. Introduction

It is widely known that vitamin B12 derivatives are unique coenzymes that possess cobalt–carbon (Co–C) bonds in vivo and are involved in a variety of catalytic functions in combination with various apoproteins.1 Vitamin B12 is a metal complex in which cobalt ions are coordinated to 4 ring nitrogen atoms in a corrin ring (Figure 1). It was originally developed as a magic bullet for the treatment of pernicious anemia, and its unique structure was elucidated by Hodgkin et al. by X-ray crystallography.2 The oxidation state of the central cobalt ions range from

+1 to +3; Co(I) imparts a gray-green color, Co(II) imparts a yellow-to-orange color, and Co(III), which is the most common form, imparts a red color to the B12 derivatives, and is known as the “red vitamin.” Methylcobalamin and adenosylcobalamin as the coenzyme forms are parts of in vivo enzymes that catalyze the biosynthesis of methionine and the isomerizations with carbon-skeleton rearrangements, respectively.3 Recent studies revealed that the complex of such corrin ring structures acts on the active center of the dechlorination reaction in anaerobic bacteria; this suggests a new function for the B12-dependent enzymes (Scheme 1).4

Contribution

Environmental-friendly Catalysts Learned from Vitamin B12-Dependent Enzymes

Hisashi Shimakoshi and Yoshio Hisaeda

Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, Fukuoka 819-0395, Japan

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The most remarkable feature of the B12-dependent enzyme reac t ion i s the fo rmat ion o f a un ique organometallic structure with a metal-carbon bond. This structure is mainly produced by the reactions of Co(I) with an organic halide and Co(III) with Grignard reagents, and it readily undergoes homolytic cleavage under mild exogenous stimuli such as visible light, heat, and redox treatment. Especially, when the former reaction occurs, formation of the Co–C bond involves dehalogenation of

the organic halide and produces organic radical species during cleavage of the Co–C bond (Scheme 2). By focusing on the above-mentioned features of the Co–C bond, we developed a molecular transformation utilizing the formation and cleavage of the Co–C bond with a B12 model complex that stimulates the active center of the B12 enzymes.5 In this article, we present our results on the synthesis of a vitamin B12 derivative and its catalytic application.

H S

NH3+

CO2-

HOOC

O

CoA

H H

C CCl

Cl

Cl

Cl

HOOC

O

CoAH

C CH

Cl

Cl

Cl

H3C S

NH3+

CO2-

Succinyl-CoA Methylmalonyl-CoA

Methylation

Isomerization

Homocysteine Methionine

Dehalogenation

Tetrachloroethylene Trichloroethylene

CoI RCl

Cl-

R

CoIII

R

CoII

+

PhotolysisThermolysisElectrolysis

Alkylated complex

Dechlorination

Radical type organic synthesis

Supernucleophile

+

Scheme 1.

Scheme 2.

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3. Electroorganic reaction using B12 complex

As described above, nucleophilic Co(I) species of the B12 derivative reacts with organic halides, which results in dehalogenation followed by the simultaneous production of an alkylated complex. Therefore, it may be important to develop a method to produce reactive Co(I) species to form the alkylated complex, which is a key intermediate of the B12-dependent enzyme reaction. The synthesized B12 complex can be reduced by chemical reductants, such as sodium borohydride, metallic zinc, and sodium amalgam, thus the mass use of these chemical reagents is not desirable in terms of synthetic as well as recent green chemistry. Consequently, an electrochemical technique

was used for generating Co(I) species of the B12 complex, in which the B12 complex works as a mediator for the electroorganic reaction (Figure 3).7 We developed various molecular transformations by controlled-potential electrolyses at the potentials of –1.4 or –1.5 V vs. Ag/AgCl using the hydrophobic vitamin B12 as a mediator (Scheme 3). For example, when bromoalkyl acrylate was used as a substrate, large-membered ring lactones were synthesized by intramolecular cyclization of organic radical species generated by the homolytic cleavage of the alkylated complex (Scheme 3, eq. 1).8 The formation of the alkylated complex as the intermediate was directly observed by monitoring the electrolysis solution using electrospray ionization

XCoN

NH

N

N

Me

MeMeHMe

H

H Me

MeH

MeMe

CO2Me

CO2MeCO2Me

CO2Me

MeO2C

MeO2C

CO2Me

CoN

NH

N

N

Me

MeMeHMe

H

H Me

MeH

MeMe

CO2Me

CO2MeCO2Me

CO2Me

MeO2C

MeO2C

CO NH R

CoN

NH

N

N

Me

MeMeHMe

H

H Me

MeH

MeMe

CO2R

CO2RCO2R

CO2R

RO2C

RO2C

CO2R(A) (B)

(C) (D)

CoN

NH

N

N

Me

MeMeHMe

H

H Me

MeH

MeMe

COOH

COOHCOOH

COOH

HOOC

HOOC

COOH

N O

O O

O

O OC

NH2

NH

R = CH3~C8H17

X = Cl, Br, NO2, NH2,

R = -(CH2)3Si(OMe)3,

-(CH2)3NH

2. Modeling of vitamin B12

Vitamin B12 is obtained on a large scale from cyanocobalamin-producing organisms for use as dietary supplements or livestock feed. Thus far, no problems have occurred with regards to the safety or economics of using natural vitamin B12 as a catalyst resource. However, natural vitamin B12 supplied from bacteria contains many vitamin B12-related substances, suggesting that it may have a poor chemical stability. This is not because of the instability of the corrin ring structure, but because of the deterioration of the side-chain substituents. As will be described later, the corrin ring structure has a high stability. To use the vitamin B12 derivative as a catalyst, the following conditions should be satisfied: (1) the corrin ring structure should be retained, (2) the central cobalt atoms should be intact, and (3) the modifiable side-chains should be maintained. In light of these 3 conditions, we temporarily removed the physiologically essential side-

chain substituents from cyanocobalamin for synthesizing the hydrophobic vitamin B12 (heptametyl cobyrinate) by chemical modification of all the peripheral side-chains into ester groups (Figure 2, Type A).6 About 80% of the hydrophobic vitamin B12 can be obtained using a single synthesis process by heating cyanocobalamin in alcohol in the presence of an acid catalyst, even when cyanocobalamin is used as the raw material, which is abundantly produced by microorganisms as mentioned above. Using the hydrophobic vitamin B12 as a starting material, it is possible to synthesize various B12 catalysts that can have wide applications (Figure 2, Type B-D). The corrin rings present in natural B12 are retained in the above-mentioned complexes, and hence, the redox potential and electronic property of the central cobalt ion of the synthetic B12 derivative are similar to those of natural B12, suggesting that the synthetic B12 derivative will show a high reactivity during molecular transformations like original enzymes.6

Figure 2. Modification of vitamin B12 derivatives.

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2e-e-

2e-e-

CoIII

Br-

CoI

CoIIICoII

R

Vitamin B12 complex

e-

Turnover

Products Substrate : RBr

or

Cathode

or

or

Alkylated complex

mass spectrometry (ESI-MS) and UV-vis spectra. The hydrophobic vitamin B12 can also effectively act as a dechlorination catalyst of environmental pollutants, such as dichlorodiphenyltrichloroethane (DDT) (Scheme 3, eq. 2).9 It is noteworthy that the B12 catalytic system does not generate toxic secondary pollutants such as chlorine gas and phosgene, because the chlorine atoms are dechlorinated to harmless chloride ions during the

reaction (Scheme 2). Furthermore, the B12 catalyst was not degraded after the reactions. Its high durability was confirmed by UV-vis and mass spectrum analyses after the reaction. When other cobalt complexes, such as the porphyrin complex, were used under the same conditions, the complexes were severely degraded during the electrolysis.

Figure 3. Electroorganic reactions mediated by vitamin B12 model complex.

+

CO2Et

C Ph

CO2Et

H2C

Br

CO2Et

C Ph

CO2Et

Me

CO2Et

CH

CO2Et

H2C

Ph

Br

CO2C2H5

O

n

O

CO2C2H5

CH3

n

O

CO2C2H5n

H2C

Br

C

CO2C2H5

CO2C2H5

CH3 H3C C

CO2C2H5

CO2C2H5

CH3 H2C CH

CO2C2H5

CO2C2H5

CH3

Br-(CH2)n O

O

ClCl

Cl

Cl ClDDT

O

O

ClH

Cl

Cl Cl

B12

B12

B12

B12

B12

Cl Cl

Cl Cl

+

(2)

(3)

+

+

(CH2)n

n = 2, 6,12

(1)

(4)

(5)

n = 1~4

-1.5 V vs. Ag/AgCl

-1.4 V vs. Ag/AgCl

-1.5 V vs. Ag/AgCl(AcOH)

-1.5 V vs. Ag/AgCl

-1.5 V vs. Ag/AgCl

Scheme 3.

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CoIIO Si

MeO

O

CoIO SiMeO

OCH2

CH2 BrCo

N

NH

N

N

Me

Me MeHMe

H

H Me

MeH

MeMe

CO2Me

CO2MeCO2Me

CO2Me

MeO2C

MeO2C

CO

NHSi(OMe)3

CoII Si(OMe)3

Br-Pt cathode

e-

e-Pt oxide

=

Turnover number 6,000 / h

-1.4 V vs. Ag/AgCl

+

Immobilization

Figure 4. B12 modified electrode for electroorganic reaction.

ClCl

Cl Cl

Cl

DDT

Et2O

NN

BF4-

H2O

Co

HH

Cl ClH

H

DDO

HCl

Cl Cl

H

DDMS

Conversion

of DDT (%)

75

82

Product

Ionic liquid

73

Run

1st

2nd

3rd

Vitamin B12 complex

Recycle use

Electrolysis

-1.5 V vs. Ag/AgCl+

etc...

To utilize repeatedly such a robust B12 catalyst, the B12 complex was immobilized on the electrodes or dissolved in an ionic liquid for recovering or recycling after the reaction. In the former case, the B12 complex could be immobilized on the platinum electrode surface at a coverage rate of approximately 1.6 × 10–10 mol/cm2 by introducing a trimethoxysilyl group into the side-chain (Figure 2, Type B). The reactivity was evaluated using phenethyl bromide as the model substrate, which demonstrated a high catalytic activity with 6,000 turnover number per hour (Figure 4).10 After the reaction, the product and the B12 catalyst could be easily separated as the B12 catalyst was immobilized on the electrode. Other examples of the B12-modified electrodes were also reported, such as a polymer-covered electrode, interface-polymerized electrode, and sol-gel film doped electrode.11-13

On the other hand, when an ionic liquid was used as the reaction solvent, the B12 complex was supported in an ionic liquid and showed the following various benefits. In general, an electroorganic reaction was carried out in a polar organic solvent containing supporting electrolytes. However, such a reaction using organic solvents containing many of the supporting electrolytes may not be desirable with regard to the recent regulated use of chemical reagents, even though this procedure is used to degrade chlorinated organic compounds. Recently, electroorganic reactions in an ionic liquid have been increasingly studied in order to address such issues. The ionic liquid is a room temperature liquid salt under ordinary pressure, which is characterized by its nonvolatility, fire retardance, and excellent electrical conductivity and is a superior solvent for the electroorganic reactions.14

When the electrolysis of DDT was carried out in an ionic liquid by using the B12 complex as a catalyst, the reaction proceeded effectively in the same manner as the dechlorination reaction in the polar organic solvent containing supporting electrolytes. Furthermore, during the extraction process after the reaction, the product and B12 complex could be separated in the organic solvent layer and the ionic liquid layer, respectively. The B12 complex dissolved in an ionic liquid can be recycled for the reaction (Figure 5).15 More interestingly, the reactivity of the B12 complex improved in the ionic liquid; i.e., the conversion efficiency of the substrate increased approximately 4-times that of the reaction performed in dimethylformamide (DMF). This enhanced reactivity in the ionic liquid over that in DMF could be explained by the application of the Hughes–Ingold predictions16 of solvent polarity effects on reaction rates. The reaction of electrochemically generated Co(I) with DDT is a ‘‘Menschutkin type of reaction’’ in which two neutral reactants, Co(I) and DDT, react to form charged products via a charge-separated activated complex in the polar ionic liquid, which ultimately decreases the activation energy, resulting in an increase in the reaction rate. A similar accelerating effect of the reaction in an ionic liquid has been closely examined by the reaction of methyl p-nitrobenzenesulfonate with tri-n-butylamine.17 Actually, the ETN value18 of the ionic liquid has been determined as a polarity index. For example, the value of 1-n-butyl-3-methylimidazolium tetrafluoroborate is 0.673, indicating it is highly polar compared to a polar organic solvent, such as DMF (ETN = 0.386).19

Figure 5. Reaction of vitamin B12 complex in ionic liquid.

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4. Photosensitized reaction of B12 complex We attempted to design a light-driven catalyzing system that could be used for the development of a clean molecular transformation using the B12 complex. Light is one of the abundant and cleanest energies on the earth and has been used in organic syntheses for a long time. Thus, we focused on a ruthenium(II) tris bipyridine complex ([RuII(bpy)3]Cl2), which has been widely used as a photosensitizer, and constructed the catalyzing system using a photo-induced electron transfer reaction for producing Co(I) species.20 The [RuII(bpy)3]Cl2 complex was excited under visible light irradiation and the [Ru(bpy)3]+ complex with high reduction potential (–1.35 V vs. Ag/AgCl) was produced due to reductive quenching by a sacrificial electron donor such as triethanolamine.21 Therefore, it is possible to generate the catalytically active B12 complex (E1/2(CoII/CoI) = – 0.6 V vs. Ag/AgCl)

by electron transfer from the ruthenium photosensitizer. Based on this strategy as shown in Figure 6, the dechlororination of DDT was carried out using the B12 complex in the presence of the ruthenium photosensitizer and sacrificial electron donor. Consequently, most of the DDT was converted to DDD, a mono-dechlorination product, within 3 hours. The reaction was hardly facilitated in the absence of the B12 complex or in the dark. Therefore, it is suggested that Co(I), which is produced by a photo-induced electron transfer reaction, might act as an active species to initiate the reaction. The ESR spectral change confirmed that the electron transfer reaction of the ruthenium photosensitizer reduces the B12 complex to Co(I) species. Characteristic ESR signals were detected for the paramagnetic Co(II) of B12, while the corresponding ESR signals for diamagnetic Co(I) were absent in the photoreaction (Figure 7).

N N

NNCoII

RO2C

CO2R CO2R

CO2RRO2C

RO2C CO2R

Visible light

ClCl

ClCl

Cl Cl

Cl Cl

Cl

DDT

CoI

N

N N

N

N N

RuIIVisible light

CoIIICl

Products

e

1.3 V vs. Ag/AgCl

[Ru(II)(bpy)3]2+

[Ru(II)(bpy)3]2+

[Ru(bpy)3]+Triethanol amine

E1/2 (CoII/CoI) = 0.5 V ~ 0.6 V vs. Ag/AgCl

+*

CoII

CoI

CoII

g = 2.00

g2 = 2.32

500 G

g3 = 2.00

A3Co = 139 G

g1 = 2.53(a)

(b)

(c)

(a) Before irradiation with visible light.(b) After irradiation with visible light.(c) After open to air (autooxidation).

Figure 6. Sterategy for photosensitized system for B12 catalysis.

Figure 7. ESR sepectral change of vitamin B12 derivative in the presence of [Ru(bpy)3]Cl2 and triethanolamine.

5. B12-TiO2 hybrid catalyst

Recently, hybrid catalysts composed of a metal complex and various semiconductors with photosensitizing ability have been reported.22,23 According to this technique, it is possible to develop a hybrid catalyst with concerted

effects of metal complexes and semiconductors. Thus, we focused on titanium oxide,24 which is an n-type semiconductor, to develop a light energy driven B12-TiO2 hybrid catalyst. The reduction power of the excited electrons in the titanium oxide (TiO2)-conduction band (–0.5 V vs. normal hydrogen electrode (NHE))25 enabled

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the reduction of the B12 complex to the catalytically active Co(I) species, and this indicated that a light energy-driven hybrid catalyst can be developed by immobilizing the B12 complex on TiO2. In this case, TiO2 not only played a role as a scaffold for the B12 complex, but also served as an electron source for the reduction of the B12 complex (Figure 8). Here, the B12 complex was immobilized on TiO2 by multiple interactions of the carboxyl groups of B12 (Figure 2, Type C) and surface hydroxyl groups of TiO2. Approximately 3–4 × 10–5 mol (40–50 mg) of the B12 complex (cobyrinic acid) was found to immobilize on 1 g of TiO2 and 70–80% of the TiO2 surface was covered with the B12 complex. The resulting B12 complex was firmly immobilized on the TiO2 surface, and the immobilization remained stable for more than 1 year even after being dispersed in various organic solvents, such as an alcohol, and was not separated by ultrasonic treatment. When a degradation reaction of a chlorinated organic compound, such as DDT, is performed using this hybrid catalyst, only a few milligrams of the catalyst can dechlorinate 100 times that of DDT in approximately 1 day.26 The hybrid catalyst was activated by light energy so that neither chemical reagents nor expensive reactors are required. Ultraviolet irradiation provided by black light (365 nm) is sufficient for the photoexcitation

of TiO2. Furthermore, both the B12 complex and TiO2 are non-toxic, thus the B12-TiO2 hybrid catalyst may be an environmental/human friendly catalyst. In addition, we investigated the use of the hybrid catalyst in radical reactions for organic synthesis. This result indicated that this hybrid catalyst could be applied to various molecular transformations, including the above-mentioned ring expansion reactions (Scheme 3, eq. 4) and 1,2-migration of the functional group (Scheme 3, eq. 5). Thus, the hybrid catalyst can be used as an alternative for the conventional radical organic synthetic reagent that uses a tin compound (Bu3SnH/AIBN system). TiO2 can also be immobilized on carriers, such as glass substrates and beads, when it is converted to slurry sol solutions. Thin films of TiO2 (with a thickness of a few hundred nanometers), which are prepared on glass substrates by dip-coating, can be hybridized with the B12 complex by only dipping into the B12 complex solution containing carboxyl groups. Thus the prepared B12-TiO2 hybrid catalyst on a glass plate also catalyzed the above-mentioned reactions (Figure 9). The immobilization of the B12-TiO2 hybrid catalyst on a glass plate can simplify the reaction process, and furthermore, facilitate the separation procedure of the product from the reaction mixture.

TiO2O

TiOTiTiO

TiO

O

O

O OO

O

OHHO

UV

CoII CoICoII

e-

DDT

N

N N

N

COOH

COOH

COOHHOOC

COOH

HOOC

HOOC

Co

Br

O

CH2C

Ph OEt

OOEt

Br

Cl

Cl Cl

Cl

Cl

OBr

CO2Et

CCl4

CHCl3

Cl

Cl

Cl

Cl

Products

Super-Nucleophilicity

Conduction band

Valance band

Vitamin B12 complex

=

Figure 8. Molecular transformations catalyzed by B12-TiO2 hybrid catalyst.

Cl

ClClCl

Cl

Cl

Cl

Cl

ClCl

ClCl

Cl

Cl

ClCl

Cl Cl

Cl

Glass plate

99 %

~100 %98 %

99 %

Dechlorination of various organic chloride catalyzed by B12-TiO2 coated glass plate.a

Substrate Conversion Substrate Conversion

aUnder irradiation with 365 nm black light.

300 nm

B12-TiO2 layer

Figure 9. Immobilization of B12-TiO2 hybrid catalyst onto glass plate.

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6. Vitamin B12-hyperbranched polymer hybrid catalyst

A hyperbranched polymer is one of the dendric polymers that are synthesized via a one-step polymerization reaction in an inexpensive and easy way, and it has various advantages when compared to dendrimers, which are synthesized via multiple-step polymerizations.27 Furthermore, as the polymer has a higher solubility and lower solution viscosity compared to linear polymers, it is expected to be used in a homogeneous solution.28 In fact, the hyperbranched polymers that have many terminal functional groups due to their highly branched structure are appropriate for carrying functionalized

molecules.29 Considering the nanospace provided by the hyperbranched polymers as a new catalyst reaction field, the B12-hyperbranched polymer hybrid catalyst was synthesized (Scheme 4).30 The amount of B12 complex used can be adjusted to somewhere between a few % and 70% per terminal functional groups of the hyperbranched polymers, and the density of the B12 complex can be readily controlled. When the B12 complex is densely immobil ized, a cooperative effect of the adjacent complex facilitates the dimerization reaction of phenethyl bromide.31 It is expected that the variable size and main chain polymer of the hyperbranched polymer will be able to produce various reaction characteristics.

7. Conclusions We have outlined the development of molecular transformations learned from the B12-dependent enzymes. The hybrid catalyst composed of synthesizing metal complexes, which are similar to the active center of the B12 enzyme, enabled various molecular transformations including environmatally-friendly organic synthesis reactions and degradation reactions of organic halides pollutants by an electroorganic reaction or a photochemical reaction. Combining the benefits of natural enzymes and engineering methods will allow the development of a new catalyst system that will exceed biological reactions. The

development of this bio-inspired chemistry introduced by us will play an important role in the next generation’s science and technology.

Acknowledgments - This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas (452 and 460) and Global COE Program “Science for Future Molecular Systems” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and an Industrial Technology Research Grant Program in 2005 from New Energy and Industrial Technology Development Organization (NEDO) of Japan.

N N

NNCo

RO2C

CO2RCO2R

CO2RHO2C

RO2CCO2R

X

X

Co

Co

Co Co

Co

Co=DC

DC

OH

HODC

OH

DCOH

HODC

OH

OHDC

DC

HO

OH

DC

S

S

NEt2

+

DC

DCHO

DC

DC DCOH

DC

DC

O

DC

O

O

OO

O

O

O

O O

CO2H

X=CN

in dry CH2Cl2

DC =

EDC

Modified yield : 72 %

Mw=12600, Mw/Mn=2.6

Scheme 4.

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20. (a) H. Shimakoshi, M. Tokunaga, T. Baba, Y. Hisaeda, Chem. Commun. 2004, 1806-1807; (b) H. Shimakoshi, S. Kudo, Y. Hisaeda, Chem. Lett. 2005, 34, 1806-1807.

21. A. Juris, V. Balzani, F. Barigelletti, S. Campagna, P. Belser, A. V. Zelewsky, Coord. Chem. Rev. 1988, 84, 85-277.

22. (a) S. O. Obare, T. Ito, G. J. Meyer, Environ. Sci. Technol. 2005, 39, 6266-6272; (b) Y. Astuti, E. Palomarse, S. A. Haque, J. R. Durrant, J. Am. Chem. Soc. 2005, 127, 15120-15126; (c) S. O. Obare, T. Ito, G. J. Meyer, J. Am. Chem. Soc. 2006, 128, 712-713; (d) B. I. Ipe and C. M. Niemeyer, Angew. Chem. Int. Ed. Engl. 2006, 45, 504-507.

23. R. J. Kuhler, G. A. Santo, T. R. Caudill, E. A. Betterton, R. G. Arnold, Environ. Sci. Technol. 1993, 27, 2104-2111.

24. (a) M. A. Fox, Acc. Chem. Res. 1983, 16, 314-321; (b) M. D. Ward, J. R. White, A. J. Bard, J. Am. Chem. Soc. 1983, 105, 27-31; (c) M. A. Fox and M. T. Dulay, Chem. Rev. 1993, 93, 341-357; (d) M. R. Hoffmann, S. T. Martin, W. Choi, D. W. Bahnemann, Chem. Rev. 1995, 95, 69-96.

25. A. Fujishima, T. N. Rao, D. A. Tryk, J. Photochem. Photobiol. C: Photochem. Rev. 2000, 1, 1-21.

26. H. Shimakoshi, E. Sakumori, K. Kaneko, Y. Hisaeda, Chem. Lett. 2009, 38, 468-469.

27. M. Jikei and M. Kakimoto, Prog. Polym. Sci. 2001, 26, 1233-1285.

28. P. H. Toy and K. D. Janda, Acc. Chem. Res. 2000, 33, 546-554.

29. (a) K. Ishizu and A. Mori, Polym. Int. 2001, 50, 906-910; (b) K. Ishizu, T. Shibuya, A. Mori, Polym. Int. 2002, 51, 424-428; (c) K. Ishizu, T. Shibuya, J. Park, S. Uchida, Polym. Int. 2004, 53, 259-265.

30. K. Tahara, H. Shimakoshi, A. Tanaka, Y. Hisaeda, Tetrahedron Lett. 2007, 48, 5065-5068.

31. K. Tahara, H. Shimakoshi, A. Tanaka, Y. Hisaeda, unpublished result.

(Received Jul. 2009)

11

number 138

Introduction of the authors

Hisashi Shimakoshi Assistant Professor, Graduate School of Engineering, Kyushu University

Education:B. S. and M. S., Doshisha UniversityPh. D., Kyushu UniversityProfessional Experiences:1996-present Assistant Professor, Kyushu UniversityHonors:2002 Synthetic Organic Chemistry Award for Young Scientists in Kyushu-Yamaguchi 2004 Electroorganic Chemistry Award for Young ScientistsExpertise and Speciality:Coordination chemistry, Bioinorganic chemistry

Yoshio Hisaeda Professor, Graduate School of Engineering, Kyushu University

Education:B. S., M. S., and Ph. D., Kyushu UniversityProfessional Experiences:1981-1988 Research Associate, Kyushu University1988-1995 Associate Professor, Kyushu University1993-1994 Visiting Professor, The University of Texas at Austin1995-present Professor, Kyushu UniversityHonors:1991 The Chemical Society of Japan Award for Young Chemists (The 40th Shinpo-sho)2008 BCSJ Award ArticleExpertise and Speciality:Biofunctional chemistry, Coordination chemistry, and Electroorganic chemistry

TCI Related Compound

Cyanocobalmin (vitamin B12) 100mg, 1g [C0449]

A B

D CN

NH

N N

N

Co

N

H

H

CH3H

CH3

HH3CH3C

H CH3

CH3

H

H2NOC

CH3

CCONH2

CONH2CH3H2NOC

H2NOCL

CONH2

O

OH

H3C

PO

O-O

O

H CH2OH

HN

CH3

CH3

HH

HO

12

number 138

D3683 Diphenylammonium Trifluoromethanesulfonate (1) 1g, 5g, 25gP1626 Pentafluoroanilinium Trifluoromethanesulfonate (2) 1g, 5g, 25g

DPAT (1) is a useful esterification catalyst developed by Tanabe et al. affording esters in high yeilds from equimolar amounts of carboxylic acids and alcohols under mild reaction condition1a-c). In this case, desired esters can be obtained by simple operation without addition of dehydrating agent and azeotropic water removal. There is also a report using fluorous solvent, in which 1 is useful for the substrate with high steric hindrance1d). PFPAT (2) shows higher activity than 1 and it can be applied widely to esterification and lactonization1b,c). Furthermore, 2 can be removed after work-up; washing with NaOH aqueous solution removed CF3SO3H, followed by distillation (C6F5NH2: bp 153 °C/ 760 mmHg). 2 is expected to be applied to various fields because it has high activity and it can be removed easily after the reaction.

References 1) Effective methods for the catalytic esterification using ammonium triflate catalyst a) K. Wakasugi, T. Misaki, K. Yamada, Y. Tanabe, Tetrahedron Lett. 2000, 41, 5249. b) Y. Tanabe, T. Misaki, A. Iida, Y. Nishii, Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.) 2004, 62, 1249. c) T. Funatomi, K. Wakasugi, T. Misaki, Y. Tanabe, Green Chemistry 2006, 8, 1022. d) B. Gacem, G. Jenner, Tetrahedron Lett. 2003, 44, 1391. 2) Other applications a) Selective N,N-dimethylation of primary aromatic amines with dimethyl carbonate Z. L. Shen, X. Z. Jiang, J. Mol. Catal. A: Chem. 2004, 213, 193. b) C-Acylation of enol silyl ethers or ketene silyl (thio)acetals with acid chlorides A. Iida, J. Osada, R. Nagase, T. Misaki, Y. Tanabe, Org. Lett. 2007, 9, 1859.

Useful Ammonium Triflate Catalysts for Esterification

NH3

FF

F

F F

OTfNH2 OTf

DPAT PFPAT1 2

R1 C OH

O

R2OH+(1.0 eq.) (1.0 eq.)

toluene, 80 °CR1 C OR2

O1 or 2 (1 mol%)

R2 Y. (%)

92

90

catalyst

1

1

2

PhCH2CH2 96CH(CH2)8H2C

2

tBu

96

time (h)

3

6

24

8

R1

tBu CH3(CH2)7

PhCH2CH2 CH(CH2)8H2C

CH3(CH2)7

13

number 138

Powerful Lewis Acid Catalyst

Intramolecular Cyclization

T2392 N-(Trimethylsilyl)bis(trifluoromethanesulfonyl)imide (1) 1g, 5g

N-(Trimethylsilyl)bis(trifluoromethanesulfonyl)imide (1) is an analogue of, TMSOTf and TMSN(SO2F)2, which has very low electron density on its silicon atom and acts as powerful Lewis acid catalyst in various reactions. For example, Mathieu et al. used 1 for Diels-Alder reaction using acrylates as dienophiles, to afford the corresponding addition products in high yields under mild conditions1). Furthermore, Mikami et al. and Ishihara et al. applied 1 to Friedel-Crafts alkylation2) and Mukaiyama aldol reactions3), respectively, and both groups reported the utility of 1 as an excellent Lewis acid catalyst.

References 1) Lewis acid catalyst of the Diels-Alder reaction B. Mathieu, L. Ghosez, Tetrahedron Lett. 1997, 38, 5497; B. Mathieu, L. Ghosez, Tetrahedron 2002, 58, 8219. 2) Effective catalyst for the Friedel-Crafts alkylation reaction A. Ishii, O. Kotera, T. Saeki, K. Mikami, Synlett 1997, 1145. 3 Lewis acid catalyst for Mukaiyama aldol reaction

K. Ishihara, Y. Hiraiwa, H. Yamamoto, Chem. Commun. 2002, 1564.

H1214 6-Heptynenitrile (1) 5g

6-Heptynenitrile (1) was treated with n-BuLi, chlorodiethylaminodimethylsilane, followed by reaction with propargyl alcohol to afford diynenitrile 2. Treatment of 2 with diethylcyclopentadienylcobalt catalyst afforded tetrahydroquinoline derivative 3 by intramolecular cyclisation. Subsequent treatment of this with KHCO3 and TBAF gave the desilylated tetrahydroquinoline 4. Alternatively, Tamao-Fleming oxidation of 3 with H2O2, KHCO3 and TBAF, gave diol 5 in high yield.

References 1) Cobalt-mediated regioselective synthesis of substituted tetrahydroquinolines U. Groth, T. Huhn, C. Kesenheimer, A. Kalogerakis, Synlett 2005, 1758. 2) Cobalt(I)-catalyzed cycloaddition J. A. Varela, L. Castedo, C. Saá, J. Org. Chem. 1997, 62, 4189.

CH2 OCH3

O

+1

toluene, 0 °C, 1 h

Y. 92% (endo : exo = 98 : 2)

CO2Me

1)

(3 eq.) (1 eq.)

(0.1 eq.)

Si

Me

Me

Me

NSO2CF3

SO2CF3

CNi) nBuLi

ii) ClMe2SiNEt2

iii)

N

Si O

N

N

OH

OH OH

CpCo(C2H4)(2.5 mol%)

i) H2O2ii) KHCO3iii) TBAF

i) KHCO3ii) TBAF1

3

4

5

Y. 83% Y. 52%2

Y. 71%

Y. 78%

Et2O

CN

Si O

CH2OH 1)

14

number 138

D3612 3,4-Dichlorothiophene 1,1-Dioxide (1) 1g

3,4-Dichlorothiophene 1,1-Dioxide (1) is useful as a synthetic starting material for the preparation of azulene derivatives. More specifically, the cycloaddition reaction of 1 with furan produce adducts 2 and 3, which can then be converted into 4 by treatment with triethylamine at room temperature. This compound 4 undergoes further cycloaddtion with 5 to give intermediate 6. Subsequent elimination of sulfur dioxide and dimethylamine affords 7 which can then be elaborated into azulene derivative 9 by treatment with tetrazine derivative 8, after denitrogenation and elimination of pyridazine derivative. Due to its instability, derivative 9 is isolated and identified as its Diels-Alder adduct with N-methylmaleimide.

References 1) The synthesis of some azuleno[c]furans A. D. Payne, D. Wege, Org. Biomol. Chem. 2003, 1, 2383. 2) The synthesis of 5,6-dichloroazulene D. Copland, D. Leaver, W. B. Menzies, Tetrahedron Lett. 1977, 639. 3) Diels-Alder reactions and addition-rearrangement reactions of halogenated thiophene dioxides a) H. Bluestone, R. Bimber, R. Berkey, Z. Mandel, J. Org. Chem. 1961, 26, 346; b) M. S. Raasch, J. Org. Chem. 1980, 45, 867.

Related CompoundD2785 6-(Dimethylamino)fulvene 1g

Synthesis of Azulene Derivatives

SO O

ClCl

Cl

OO

Cl

O+

SO2

O

NMe2

1 2 3

Et3N

4

5

6

7

8

9

2 + 3: Y. 75%

Y. 25% Y. 70%

- NHMe2

- SO2

O

Cl

Me2N

O2S

O

SO2

Cl

Cl

O

SO2Cl

Cl

- N2,

60 °C

i)

ii) N NN

N

N

N N

NN

N

-

Cl

15

number 138

Fluorinated Building Blocks

F0665 Fluoroacetonitrile (1) 5g, 25g

Fluoroacetonitrile (1) is known as a versatile fluorinated building block in organic synthesis. For example, reaction of (1) with Grignard reagent 2, followed by treatment with NaCN and NH4Cl affords 3, which can subsequently be converted into fluorinated ornithine decarboxylase inhibitor 4.1) Alternatively, 1 can be converted into α-fluoroacrylonitrile derivative 6 by Horner-Emmons reaction using diphenylphosphonic chloride (5)2) and also affords α-fluoroaldehyde derivative 9 by reaction with 2-methyl-1,3-pentanediol (7).3) In addition, fluoroacrylate cation equivalent 10 is useful as a synthetic material for the preparation of 2-fluoroalkenecarboxylic acid 11,4) allylic amines containing fluoromethyl group, α,β-unsaturated ketones,5) and fluorine-containing cytosine derivatives6) which are useful for the development of oncology drugs.

References 1) Grignard addition reaction on fluoroacetonitrile F. Gerhart, J.-P. François, M. Kolb, M. Laskovics, J.-F. Le Borgne, J. Fluorine Chem. 1990, 50, 243. 2) Synthesis of α-fluoroacrylonitriles by Horner-Wittig reaction J. H. van Steenis, A. M.C.H. van den Nieuwendijk, A. van der Gen, J. Fluorine Chem. 2004, 125, 107. 3) A new reagent for the preparation of α-fluoroaldehydes T. B. Patrick, S. Hosseini, S. Bains, Tetrahedron Lett. 1990, 31, 179. 4) Methods for the stereoselective synthesis of 2-fluoroalkenoates M. C. Pirrung, E. G. Rowley, C. P. Holmes, J. Org. Chem. 1993, 58, 5683. 5) A simple method for the preparation of fluoromethyl allylamines or α,β-unsaturated ketones F. Palacios, S. Pascual, J. Oyarzabal, A. M. Ochoa de Retana, Org. Lett. 2002, 4, 769. 6) A rapid and efficient synthesis of F containing cytosine derivatives J. L. Barkin, M. D. Faust Jr., W. C. Trenkle, Org. Lett. 2003, 5, 3333.

Related CompoundF0340 2-Fluoro-2-phosphonoacetic Acid Triethyl Ester 1g, 5g

H2SO4

i) nBuLi

ii) RX

i) NaBH4

7 8 9R=Allyl Y. 59%R=Allyl, X=Cl Y. 66%

Y. 35%

OH

OH 1

N

O

FN

O

F

R

H

O

R

F

ii) H+

3)

R1R2CO

2

3 4

R1=Ph, R2=H Y. 53% (E:Z=21:79)

6

15

p-TsOH

Y. 40%F CN

MgBr

i)

ii) NaCN,NH4Cliii) p-TsOH

NH2

CNF

NH2

CO2HF

H2N

P

O

Ph

LDA,THF

P

OPh

Ph

F

CNR1 CN

FR2

1)

2)Cl

Ph

HgCl2

1ii) H+

DIBAL-Hi) CS2, MeI

ii) LHMDS Y. 83% Y. 70%

Y. 83% Y. 86%

10

11

SCH3

CH3SCN

F

SCH3

CH3SCHO

F

i)

SCH3

CH3S

F

OH O

CH3S

4)

MgBr

F