ISSN 1349-4848

number156

Chemistr y Chat –Focusing on the Elements-- Heavy Hydrogen

Kentaro Sato

S cience “ Winter ” S eminar - Carbonyl Ole�nation (1)

Takeshi Takeda Professor of Department of Applied Chemistry, Tokyo University of Agriculture and Technology

Shor t Topic : M ore ways to use reagents - Mitsunobu Reaction Using Acetone Cyanohydrin

Haruhiko Taguchi Tokyo Chemical Industry Co., Ltd.

New Produc ts I nformation :- Useful Asymmetric Organoligands for [3+2] Cycloaddition- 2'-O-Methylribonucleosides: Basic Reagents for RNA Biochemistry and Bioscience- Cross-linkers Containing Photoreactive Diazirine Group- New Palladacycle Precatalyst - Nitric Oxide Donor Activated by Two-Photon Excitation- Bone Resorption Inhibitors- Pirfenidone: A Unique Anti�brotic and Anti-In�ammatory Agent

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CONTENTS

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No.156

Chemistry Chat -Focusing on the Elements-

Isotope with Its Own Symbol

Discovering and naming a new element are one of scientists’ biggest dreams. The name of an element that you coined would be used for generations to come, so it might be a greater honor than receiving a Nobel Prize. In the history of chemical elements, which we know a few more than a hundred today, there have been many disputes and confusions over claiming that honor. In fact, the number of the “phantom elements” – elements that were given a name once but removed from the periodic table after their identities were proven false - is said to equal that of the “real” elements.

Quite a few cases are known where an isotope of the same element was mistaken as a distinct element and given its own name. For example, thorium 227 and 230 were initially named radioactinium and ionium, respectively, and had their own atomic symbols. This kind of confusions were gradually sorted out, but there remain two isotopes of the same element which maintain own names and symbols. Of course, they are deuterium (atomic symbol D) and tritium (atomic symbol T).

The reason why these two names are still being used is because these isotopes have somewhat different physico-chemical properties from common “light hydrogen” (atomic symbol H) and their properties have useful applications. As you know, the properties of the isotopes of the same element are essentially equivalent. But for the smallest element in the periodic table, the difference in the number of neutron by just one has such a big relative impact to the whole elemental character that the differences in the properties between isotopes become tangible.

Deuterium was discovered in 1932. Harold Urey (who is also famous for the Urey-Miller experiment demonstrating the synthesis of amino acids in pre-biotic atmosphere) succeeded in concentrating deuterium by slowly distilling liquid hydrogen, relying on the small difference in boiling point. Urey was given the Nobel Prize in Chemistry just two years later, a testament to how highly his discovery was recognized.

Atomic Energy and Deuterium

An important application of newly isolated deuterium was in the development of nuclear energy. In order to sustain nuclear chain reactions of radioactive substances such as uranium, it was necessary to slow down the speed of released neutrons. In this purpose, deuterium had just the right property as a “neutron moderator.” Even today, heavy water (also known as deuterium oxide) is used as a neutron moderator in nuclear reactors in countries such as Canada.

Deuterium was also used as a component of nuclear fusion and therefore in the development of hydrogen bombs. Deuterium and tritium are a combination which brings about nuclear fusion at the lowest temperature (which is still 100 million degrees Kelvin), so they are considered as the most promising “fuels” for nuclear fusion reactors. However, there are all too many issues to overcome before realizing practical implementation of the technology. Even after a few decades of research, nuclear fusion remains as a “potential future energy source.”

Heavy Hydrogen

Kentaro Sato

No.156

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In 1989, a report of “cold fusion” generated a controversy. The report was that anomalously high levels of heat and small amounts of nuclear radiation were detected in the electrolysis of heavy water using the electrodes made of palladium. It was claimed that the cause was the nuclear fusion of deuterium at room temperature! Nuclear fusion requires a huge plant and ultrahigh temperature otherwise, so if the finding were true it would revolutionize energy use. This experiment, known as the Fleischmann-Pons experiment after the names of the discoverers, became not only a scientific, but also an industrial and a political sensation.

Unfortunately though, the Fleischmann-Pons result could not be reproduced despite the replication experiments by many other scientists. The radiation levels measured in these experiments were minimally different from the background and far from sufficient to support the claim that nuclear fusion reaction was taking place. The research on cold fusion is still ongoing today, but few reports appear on reliable peer-reviewed scientific journals. Even with most optimistic perspective, it does not seem to become a hopeful energy source anytime soon.

Deuterated Solvents

For organic chemists, the most common application of deuterium is probably NMR solvent. Deuterated solvents such as d-chloroform, d6-DMSO, and D2O are routinely used by chemists to prepare sample solutions for NMR measurements. Deuterated solvents are undoubtedly an essential part of chemistry research.

So how are these deuterated solvents synthesized? In electrolysis of water, H2O reacts more easily than D2O, releasing more of gaseous H2 than D2. As a result, this process increases the concentration of D2O and this is currently the main way of how heavy water is produced.

According to an old literature, deuterium can be synthesized by reacting hexachloroacetone with D2O. Also reported is the synthesis of deuterated acetone by stirring acetone in alkaline heavy water. Deuterated DMSO can be made probably under similar conditions. It would be nice to know how deuterated solvents are produced commercially in these days, but most of it seems to be kept as corporate secrets. Nonetheless, we should be grateful to have an access to high quality deuterated solvents which once had to be prepared in our laboratories.

Deuterium and Life

How does deuterium behave in terms of biology? For instance, what biological effects would it have if you raise an animal with heavy water alone? Would it produce an animal with the same appearance but with 10% heavier weight? According to a report, if you give an animal heavy water, health defects such as muscle weakness start to show after 10–20% of the body fluids are replaced with heavy water and death is reached at 30–40%. As mentioned earlier, deuterium has different reactivities from common hydrogen. For example, carbon-deuterium (C-D) bond is famously known to be 6–10 times less reactive compared to carbon-hydrogen (C-H) bond. This deuterium isotope effect most likely disrupts important biological reactions and causes toxic effects.

The application of deuterium has been growing broader in recent years. The compounds which are “isotopically labeled” with deuterium are suited for detection by mass spectroscopy, making them useful in areas such as the study of biosynthetic pathway of natural molecules and the tracing of drug molecules inside the body. Though the detection sensitivity of deuterium is lower than tritium, deuterium is less expensive and easier to handle (not requiring any special facilities for handling of a radioactive isotope) therefore is a more popular choice.

O

CD3

ND3C CD3

OH

Example of Deuterated Drugs “Venlafaxine-d6”

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But the isotope effect of deuterium mentioned earlier has to be considered carefully. Pharmaceutical drug molecules are often metabolized in the liver through oxidative cleavage of their C-H bonds. Therefore, labeled compounds containing deuteriums in place of hydrogens may not necessarily behave the same as non-labeled counterparts do.

Then there came an idea that the isotope effect could be something positive if looked at from an opposite angle; if the incorporation of deuterium into a drug molecule increases its stability in vivo, it could increase the efficacy of existing drugs. There was a venture company which rattled the pharmaceutical industry by doing exactly that and starting to file new patent applications for one existing drug after another. If all these get approved as new patents, the venture would potentially take away the huge profits of major drug makers.

However, it seems that most of them have not been approved because simple deuteration of existing drug molecules has been judged insufficient to qualify as “inventiveness”, which is an essential quality of new patents. Still, this idea has become one of standard means of drug design. The number of drug candidate molecules containing deuteriums for the aim of slowing down metabolism is increasing. Also in recent years, there have been cases in the field of materials science where deuterium was used in the light emitting layer of OLED (organic light-emitting diode) to improve emission efficiency and durability. The cost of using deuterium is of course a concern, but this kind of high value added products may be able to counterbalance it. Being hydrogen but not exactly hydrogen at the same time, this interesting “element” deuterium has been kind of in the blind spot of scientists. It could very well have many more possibilities.

Introduction of the author :

Kentaro Sato

[Brief career history] He was born in Ibaraki, Japan, in 1970. 1995 M. Sc. Graduate School of Science and Engineering, Tokyo Institute of Technology. 1995-2007 Researcher in a pharmaceutical company. 2007- Present Freelance science writer. 2009-2012 Project assinstant professor of the graduate school of Science, the University of Tokyo.[Specialty] Organic chemistry[Website] The Museum of Organic Chemistry

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Deuterium and Tritiump.2 “Heavy Hydrogen”

Deuterium is one of isotope of hydrogen and has a nucleus consisting of one proton and one neutron, and one electron out of the nucleus. Tritium is one of isotope of hydrogen and has a nucleus consisting of one proton and two neutrons, and one electron out of the nucleus.

Nuclear Fusionp.2 “Heavy Hydrogen”

Nuclear fusion is a phenomenon in which two light nuclei fuse with each other to form a single heavier nucleus. As a typical example, one deuterium and one tritium transform into one helium and one neutron by nuclear fusion.

One actual example of nuclear fusion in our life is the sun. At the center of the sun, four hydrogen atoms fuse to form a helium atom. Enormous energy is generated in the nuclear fusion. How much energy would be produced by nuclear fusion? The atomic weights of hydrogen and helium are 1.008 and 4.003 respectively. The total atomic weight of four atoms of hydrogen is calculated at 4.032. In fact, the actual atomic weight of helium is 4.003. It is suggested that the atomic weight of helium becomes lighter by 0.029 amu. As a matter of fact, the decreased amount of weight is transformed into energy. To calculate the energy we use Einstein’s equation (i.e. E = mc2). In the case of 1kg of hydrogen atom, 7.2 g of the weight will be decreased by nuclear fusion. So the amount of energy can be calculated by the following (shown below in an equation):

Wefindanenormousamountofenergyisreleasedbynuclearfusion.Itseemslikegreatenergy,butthereare many problems to be solved for the technical and safety aspects. To be available to use that energy for our benefit,itwilltakemoretime.

Hydrogen(Light Hydrogen)

Deuterium(Heavy Hydrogen) Tritium

Proton

Electron

Neutron

Neutron

Deuterium

Tritium

Nuclear Fusion

Helium

Four Hydrogen Atoms

nn

Helium

1.008 x 4 = 4.032

4.003-0.029

How energy is produced from 1kg of hydrogen?

E = mc2 = 7.2 x 10-3 x ( 3.0 x 108 )2 ≒ 6.48 x 1014 J

Nuclear Fusion

Technical Glossary

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No.156

1. Introduction

In 1953, Wittig and Geissler reported that olefins were produced by the reaction of phosphonium ylides with carbonyl compounds.1) This reaction, now known as the Wittig reaction,2) enjoys a great advantage in that no ambiguity exists as to the location of the double bond in the product. Since the discovery of the Wittig reaction, the transformation of a C=O double bond of the carbonyl compound into a C=C double bond, often called as carbonyl olefination, has been extensively studied as one of the most important methods for the construction of carbon skeletons. Thus a variety of reactions, such as the

Horner–Wadworth–Emmons reaction using organophosphorous compounds,3) two Julia reactions (the Julia-Lythgoe and Julia-Kocienski reactions, see the column on the next page) using organosulfur compounds,4) and the Peterson reaction using organosilicon compounds,5) have been developed for this transformation (Scheme 1). Depending on their characteristic reactivity and selectivity, these reactions are employed for the synthesis of various organic molecules. Despite these extensive studies, many problems still remain unsolved in carbonyl olefination. In this article, some of these problems are discussed along with our results of the study on this issue.

2. Tetrasubstituted Olefins

One of the serious drawbacks remaining in the Wittig and Horner–Wadsworth–Emmons reactions is that they cannot be employed for the transformation of ketones into tetrasubstituted olefins. In 1972, Barton reported the multistep synthesis of

tetrasubstituted olefins via azines (Scheme 2),6) in which he described that “the Wittig reaction has been widely used in the preparation of disubstituted olefins, but yields are lower in the case of trisubstituted olefins, and generally very low (often not reported) in case of tetrasubstituted olefins.”

R3 PR3

R4

R2

R1 R4

R3R1 R2

O

R3 SiR3

R4

R3 SO2Ar

R4

(Na/Hg)

R3 POR2

R4

Wittig reaction

Horner-Wadsworth-Emmons reaction

Julia reaction

Peterson reaction

1

Scheme 1

Science "Winter" SeminarScience "Winter" Seminar

Carbonyl Olefination (1)

Takeshi Takeda

Department of Applied Chemistry, Tokyo University of Agriculture and Technology

No.156

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The transformation of ketones into trisubstituted olefins is also recognized to be difficult under the standard conditions of the Julia-Lythgoe reaction, and it can only be achieved by the modification using SmI2 instead of Na(Hg) for the reduction of β-acyloxy sulfones (Scheme 3).7) Furthermore, there seems to be no report on the preparation of tetrasubstituted olefins by the

Julia reactions. As for the Peterson reaction, preparations of certain tetrasubstituted olefins containing a carbo- or heterocycle have been reported. However the yields are generally low as compared with the formation of corresponding trisubstituted olefins (Scheme 4).8)

OH2N NH2

N

NH2S

HNS

HN

NS

N P(OEt)3Pb(OAc)42

74% 100% 99% 75%

Scheme 2

Two “Julia” Reactions

Although the names and reagents used are similar to each other, their reaction pathways are completely different. In 1973, Marc Julia and Jean-Marc Paris reported the carbonyl olefination using a-lithio sulfones 1.1) Later on, this “Julia” reaction was extensively studied by Lythgoe and Kocienski, and hence it is also called the Julia-Lythgoe reaction. The reaction was carried out in a same reaction vessel, but the reaction essentially consists of two steps, the addition of 1 to carbonyl compounds followed by acetylation and the reductive elimination of the resulting β-acetoxy sulfones 2. Another “Julia” reaction named the Julia-Kocienski reaction was first reported by Sylvestre Julia in 19912) and extensively studied by Kocienski and co-workers. The reaction proceeds through the addition of a-lithio sulfones 1 to carbonyl compounds, the subsequent Smiles rearrangement, and elimination of sulfur dioxide and aryloxide.

1) M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 4833.2) J. B. Baudin, G. Hareau, S. A. Julia, O. Ruel, Tetrahedron Lett. 1991, 32, 1175.

O

O

SiMe3 / LDA

Ph R

O

O

O

Ph

RR = H 89%

R = Me 50%

Hex SO2Ph / BuLi

Ph

O 1)

2) PhCOCl

Ph

OCOPhHex

SO2Ph81%

SmI2

PhHex

72% E:Z = ca. 2:1

Scheme 4

Scheme 3

R3 R4

O

PhO2S

O

R3R4

R1R2

R4R2

R3R1

PhSO2

R1

R2

AcCl Na(Hg)PhO2S

OAc

R3R4

R1R2

1 2

ArO2S

O

R3R4

R1

R2

Smiles rearrangement

- SO2, ArO-Ar =

S

N

N

NN N

N

R, ,

-O2S

OAr

R3R4

R1

R2

3

Julia-Lythgoe reaction

Julia-Kocienski reaction

R3 R4

O

ArSO2

R1

R2

1

R4R2

R3R1

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The most powerful tool to synthesize highly sterically-congested tetrasubstituted olefins would be the low-valent titanium mediated reductive coupling of ketones (the McMurry coupling).9) Although the preparation of ethylene bearing four tert-butyl groups has not appeared yet, highly sterically crowded olefins such as those shown in Schemes 510) and 611) were prepared by the McMurry coupling. The reaction,

however, suffers several limitations. For example, the selective preparation of unsymmetrical olefins by the cross-coupling of two distinct ketones is generally difficult even though one of the coupling components is employed in large excess (Scheme 7). Therefore, a new efficient method for the transformation of ketones into highly substituted olefins is still required.

3. Olefination of Carboxylic Acid Derivatives

Although numerous efforts have been devoted to develop the methods for the transformation of carboxylic acid derivatives into heteroatom-substituted olefins, this transformation still remains problematic. Unlike the carbonyl olefination of aldehydes and ketones, it is recognized that the Wittig reaction cannot be employed for the olefination of carboxylic acid derivatives such as esters due to the preferential acylation of ylides. However, as shown in Schemes 8 and 9, whether the acylation (Scheme 8)13) or carbonyl olefination (Scheme 9)14) is preferred is largely dependent on the structure of substrates and, in certain cases, the process is synthetically useful for the preparation of heteroatom-substituted olefins in reasonable

yields. The preferential carbonyl olefination shown in Scheme 9 is attributable to the conformation of starting material favorable to the formation of cyclic structure and a conjugated system stabilizing the olefination product.

Some additional examples are depicted in Schemes 10,15) 11,16) 12,17) and 13.18) The carbonyl compounds employed in these reactions are restricted to formats and carboxylic acid derivatives bearing an electron withdrawing group such as perfluoroalkyl and acyl groups. These reactions are referred to as the non-classical Wittig reaction19) and often employed for the synthesis of heterocyclic compounds as indicated in the last example.

O

O

(4 equiv)

+ +TiCl3 / Li

50% 26%

O2

TiCl3(DME)1.5-Zn/Cu

87%

Ph3P OEt

O O

PPh384%

O O

OAc

AcO OAc

O PPh3

OO O

OAc

AcO OAcO

65%

N

SPhOCH2CONH

OCO2Bn

CO2MePh3P

67%N

SPhOCH2CONH

CO2BnMeO2C

E:Z = 1:1

O213%

TiCl3-LiAlH4

O

O

O

O

O

PPh3

OMeOMe

O

O60%

O O

CF3

Ph PPh3 O

CF3

Ph65%

PPh3

S

O

NHOBn S

NHOBn

86%

Scheme 7

Scheme 5

Scheme 8

Scheme 10

Scheme 12

Scheme 6

Scheme 9

Scheme 11

Scheme 13

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The McMurry coupling is generally applied to the reductive coupling of aldehydes and ketones, but in certain cases, the reaction is also effective for the cross-coupling of esters and amides with ketones or aldehydes. Although the preparation of enol ethers and enamines by the intermolecular McMurry coupling were reported (Schemes 1420) and 1521)), these reactions should be considered as exceptional. In contrast, the intramolecular McMurry coupling is useful for the preparation of benzofurans (Scheme 16)22) and indoles (Scheme 17)23) and

often employed for the synthesis of natural products such as alkaloids.

Several other reagents have also been developed for the olefination of carboxylic acid derivatives24) which include the organometallic species generated from the gem-dibromides- TiCl4-Zn-TMEDA system (Scheme 18)25) and gem-dizinc compounds (Scheme 19).26)

As described above, various reagents can be employed to perform the carbonyl olefination of carboxylic acid derivatives, but the most promising reagent for this transformation would be titanium-carbene complexes. Since methylidenetitanocene 2 generated from the Tebbe reagent 3 was found to methylidenate carbonyl compounds in 1978,27) Pine, Grubbs, Petasis, and many other researchers studied the carbonyl olefination using titanium carbene complexes.28) The carbene complex 2 is the most frequently employed reagent for the methylidenation of carboxylic acid derivatives, and numerous applications have appeared as exemplified in Scheme 20.29) Titanium-alkylidene complexes such as 4 generated from bis(trimethylsilylmethyl)

titanocene 5 (Scheme 21)30) are also powerful tools for the preparation of heteroatom substituted olefins from carboxylic acid derivatives. The formation of such alkylidene complexes by a-elimination of dialkyltitanocenes, however, still remains a serious problem in that it cannot be applied for the preparation of alkylidene complexes bearing a β-hydrogen. In order to overcome all these drawbacks of conventional reactions, we have studied a new carbonyl olefination utilizing a wide variety of titanium carbene complexes generated by the desulfurizative titanation of thioacetals. The details of our results on this study will be discussed next.

+

O OEt

t-BuS

OOEt

SBu-tTiCl3-LiAlH4, Et3N

60%

O

NEt2 +

MeO NEt2

Ph

PhMeO

Ph Ph

O Sm-SmI2

75%

Scheme 14

Scheme 15

Ph OMe

O

Ph

MeOBr

Br

/ Zn / TiCl4

TMEDA

61% E:Z = 10:90

OPr-i

O

OPr-iβ-TiCl3 / TMEDA90%

CH2(ZnI)2

Scheme 18

Scheme 19

NH

O

O NH

TiCl3-C8K

86%

MeO

MeO

OMe

OMe

OMe

OMe

MeO

MeO

H

O

O

PhO

OPh

TiCl3-C8K

89%

Scheme 17Scheme 16

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No.156

References

1) G. Wittig, G. Geissler, Liebigs Ann. 1953, 580, 44.2) A. Maercker, Org. React. 1965, 14, 270.3) W. S. Wadsworth, Jr., Org. React. 1977, 25, 73.4) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1 2002, 2565.5) D. J. Ager, Org. React. 1990, 38, 1.6) D. H. R. Barton, B. Willis, J. Chem. Soc., Perkin Trans. 1

1972, 305.7) I. Marko, F. Murphy, S. Dolan, Tetrahedron Lett. 1996, 37,

2089.8) G. L. Larson, R. M. Betancourt de Perez, J. Org. Chem.

1985, 50, 5257.9) J. E. McMurry, Chem. Rev. 1989, 89, 1513; M. Ephritikhine,

C. Villiers, in Modern Carbonyl Olefination, ed. by T. Takeda, Wiley-VCH, Weinheim, 2004, p. 223.

10) J. E. McMurry, T. Lectka, J. G. Rico, J. Org. Chem. 1989, 54, 3748.

11) G. Böhrer, R. Knorr, Tetrahedron Lett. 1984, 25, 3675.12) J. E. McMurry, L. R. Krepski, J. Org. Chem. 1976, 41,

3929.13) H. O. House, H. Babad, J. Org. Chem. 1963, 28, 90.14) H. J. Bestmann, D. Roth, Angew. Chem., Int. Ed. 1990, 29,

99.15) B. Beagley, D. S. Larsen, R. G. Pritchard, R. J. Stoodley, J.

Chem. Soc., Perkin Trans. 1 1990, 3113.16) J. P. Bégué, D. Bonnet-Delpon, S. W. Wu, A. M’Bida, T.

Shintani, T. Nakai, Tetrahedron Lett. 1994, 35, 2907.

17) M. L. Gilpin, J. B. Harbridge, T. T. Howarth, J. Chem. Soc., Perkin Trans. 1 1987, 1369.

18) C. N. Hsiao, T. Kolasa, Tetrahedron Lett. 1992, 33, 2629.19) P. J. Murphy, S. E. Lee, J. Chem. Soc., Perkin Trans. 1

1999, 3049.20) S. Sabelle, J. Hydrio, E. Leclevc, C. Mioskowski, P.-Y.

Renardo, Tetrahedron Lett. 2002, 43, 3645.21) X. Xu ,Y. Zhang, Tetrahedron 2002, 58, 503.22) A. Fürsner, D. N. Jumbam, Tetrahedron 1992, 48, 5991.23) A. Fürsner, D. N. Jumbam, G. Seidel, Chem. Ber. 1994,

127, 1125.24) T. Okazoe, K. Takai, K. Oshima, K. Utimoto, J. Org. Chem.

1985, 52, 4410.25) S. Matsubara, K. Ukai, T. Mizuno, K. Utimoto, Chem. Lett.

1999, 825.26) S. Matsubara, K. Oshima, in Modern Carbonyl Olefination,

ed. by T. Takeda, Wiley-VCH, Weinheim, 2004, p. 200.27) F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem.

Soc. 1978, 100, 3611.28) S. H.Pine, Org. React. 1993, 43, 1; N. A. Petasis, in

Transition Metals for Organic Synthesis, eds. by M. Beller, C. Bolm, Wiley-VCH, Weinheim, 1999, p. 361; T. Takeda, A.Tsubouchi, in Modern Carbonyl Olefination, ed. by T. Takeda, Wiley-VCH, Weinheim, 2004, p. 151.

29) S. H. Pine, R. Zahler, D. A. Evans, R. H. Grubbs, J. Am. Chem. Soc. 1980, 102, 3270.

30) N. A. Petasis, I. Akiritopoulou, Synlett 1992, 665.

Introduction of the authors :

Takeshi Takeda Professor, Department of Applied Chemistry, Tokyo University of Agriculture and Technology

Takeshi Takeda obtained his Ph.D. (1977) in chemistry from Tokyo Institute of Technology. He joined the University of Tokyo as an Assistant Professor in 1977. After a half year of postdoctoral work at University of California, Los Angeles, he moved to Tokyo University of Agriculture and Technology as an Associate Professor in 1981. He was appointed to a Professorship in 1994.He received an Incentive Award in Synthetic Organic Chemistry, Japan (1987) and a Chemical Society of Japan Award for Creative Work (2003).His current research interests include organic chemistry, organometallic chemistry, and organic synthesis.

OEt

O

O

OEtTiCp2 CH2

3 81%

2

TiCp2Cl

AlMe2

O OCp2Ti

SiMe3

SiMe3

Cp2TiSiMe3

OSiMe3

67% E:Z = 2.5:15

4

Scheme 20

Scheme 21

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More ways to use reagents

Mitsunobu Reaction Using Acetone Cyanohydrin

Haruhiko Taguchi

Tokyo Chemical Industry, Co. Ltd.

Organic Synthesis Using Acetone Cyanohydrin This chat for introduction of another usage of reagents has started since issue #155 of TCIMAIL. In this issue, we pick acetone cyanohydrin. Acetone cyanohydrin has been used since the early 20th century, so various usages of it have been developed.1) As typical usages, cyanohydrynations of aldehydes and ketones, chemical synthesis of a-amino acids by the Strecker reaction and 1,4-additions of a,β-unsaturated carbonyl compounds have been performed by using acetone cyanohydrin. Acetone cyanohydrin can be also used as a source of the cyano anion and which reacts with alkyl halides to afford corresponding products. Furthermore, in industrial usage, it has been used for the intermediate in the production of poly(methyl methacrylate) resin.

As described above, acetone cyanohydrin has a number of usages. However, it is considered that acetone cyanohydrin is a minor item compared with other cyanation reagents such as sodium cyanide and potassium cyanide because most chemists will chose them at the beginning of trying a cyanation. At first, I will describe the synthetic properties of alkanenitriles by using such cyanation reagents.

Efficient Synthetic Methods of Secondary Alkanenitriles The synthesis of alkanenitriles is commonly seen in various textbooks of organic chemistry. This process seemed to be easy for us. I had thought the synthesis of alkanenitriles was very easy only being careful of treatment of the cyanide ion in graduate studies. But actually I had tried to synthesize alkanenitriles. The synthesis of them was very tough and much liquid waste containing cyanide ion had been produced. In general, alkanenitriles will be synthesized by the reaction of alkyl halides with cyanide ion. It is true that such a reaction is widely suited when primary alkyl halides are employed, but when secondary alkyl halides are employed, the yields decreased in some cases depending on these structures. It is considered that the nucleophilic and basic characters of a cyano ion are present at the same time when using secondary alkyl halides, so nucleophilic substitution of a cyano ion wouldn’t proceed preferentially. Of course, when tertiary alkyl halides are used, the cyanation isn’t successful. These alkylations using cyano ion are good examples for study of the nucleophilic and basic characters of the cyano ion from actual chemical experiments. Well, how can secondary alkanenitriles be synthesized effectively? One successful method is shown in technical books of organic synthesis, in which generation of the a-anion of primary alkanenitriles by the action of sodium amide in liquid ammonia followed by using it for the synthesis of secondary alkanenitriles. This synthetic method is excellent but many special tools are needed to prepare liquid ammonia and more, it is hard work. If there are other synthetic methods, most chemists will select another one.

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No.156

Another method focuses on the a-proton of alkanenitriles with a pKa value commonly of 25. This result suggests that an a-proton of alkanenitriles can be removed by the action of a strong base such as LDA. Consequent treatment with alkyl halides will form secondary alkanenitriles. So when I actually tried according to such a synthetic manner, it gave only a tertiary alkanenitrile. There was no observation of any secondary alkanenitriles. I considered that in this synthetic method, the pKa value of monoalkylated alkanenitriles increases compared to non-alkylated alkanenitriles, so the second deprotonation of mono-alkylated alkanenitriles occurs more rapidly forming products with a second alkylation; that is, a tertiary alkanenitrile is formed as a sole product. I think that this synthetic method is excellent because it can be used for the synthesis of tertiary alkanenitriles. Thus, for the conventional method for the synthesis of secondary alkanenitriles, I think alkylation of cyanoacetate esters is better. After alkylation, hydrolysis of the ester group and consequent decarboxylation, the desired secondary alkanenitriles will be given. If the hydrolysis of alkylated cyanoacetate esters is performed under alkaline conditions, the cyano group will be partially hydrolyzed. Of course, after work up, the desired alkanenitriles are obtained but the yields would be a little decreased. To optimize the above synthetic manner, after alkylation, decarboxylation is performed by Krapcho’s decarboxylation2) instead of an alkaline hydrolysis consequent decarboxylation. I believe this method would be one of the most effective synthetic methods of secondary alkanenitriles. Alkanenitriles are well used for organic synthesis because the cyano group can be easily exchanged to other functional groups. But their chemical synthesis is not simple and the development of an efficient synthetic route to them is very hard.

To Use Acetone cyanhydrin for the Mitsunobu Reaction Well, let's get back to the subject, as a remarkable character of acetone cyanohydrin, which shows formally the same reactivities as hydrogen cyanide. Here, focusing on the pKa value of hydrogen cyanide, it is about 9.1. It is suggested that hydrogen cyanide can be used as a reactant in the Mitsunobu reaction. Hydrogen cyanide is in the liquid or gas state at ambient temperature making it difficult to use it for the Mitsunobu reaction. For such a usage, acetone cyanohydrin should be used instead of hydrogen cyanide. Tsunoda and his coworkers searched a cyanation of alcohols by the Mitsunobu reaction using an acetone cyanohydrin and found primary and secondary alcohols are successfully transformed to the corresponding alkanenitriles in good to moderate yield with an inversion of stereochemistry.3)

Further searching of references about the Mitsunobu reaction using acetone cyanohydrin, which is well used by pharmaceutical companies in syntheses of drug substances, is warranted. It seems that the Mitsunobu reaction is a useful synthetic method for such a purpose because it has wide range of applications and the reactions proceed under mild conditions. These synthetic advantages would be fit for the synthesis of drug substances. TCI has various reagents which can be used for the Mitsunobu reaction. Especially, the Tsunoda reagent is widely suited for various Brønsted acids because the low pKa value can be employed. So, the Mitsunobu reaction using acetone cyanohydrin is a very attractive synthetic method for introducing a cyano group. All of reagents are available from TCI.

References1) S. A. Haroutounian, in Encyclopedia of Reagents for Organic Synthesis, ‘Acetone Cyanohydrin’ 2001, 28.2) a) A. P. Krapcho, Synthesis 1982, 805. b) A. P. Krapcho, Synthesis 1982, 893.3) T. Tsunoda, K. Uemoto, C. Nagino, M. Kawamura, H. Kaku, S. Ito, Tetrahedron Lett. 1999, 40, 7355.

Related CompoundsM0361 Acetone Cyanohydrin 25mL 500mLC1500 Cyanomethylenetri-n-butylphosphorane 1g 5g 25gA0705 Diethyl Azodicarboxylate (40% in Toluene, ca. 2.2 mol/L) 25g 250gA1458 1,1'-Azobis(N,N-dimethylformamide) 1g 5gT0519 Triphenylphosphine 25g 500gT0361 Tributylphosphine 25mL 500mL

R1 R2

OH

HO

CH3

CH3

CN

Mitsunobu Reagent R1 R2

CN

No.156 No.156

13

Strecker Reactionp.11 “Mitsunobu Reaction Using Acetone Cyanohydrin”

The Strecker reaction is one of the methods for the synthesis of a-amino acids and which has been conventionally used since the middle of the 19th century. The Strecker reaction is performed by the following: Aldehydes or ketones are reacted with hydrogen cyanide in the presence of ammonia or ammonium chloride to afford the corresponding a-aminonitriles, which are directly transformed to a-amino acids by alkaline- or acid-hydrolysis. Acetone cyanohydrin, potassium cyanide, sodium cyanide and trimethylsilyl cyanide are used as a cyanide source instead of hydrogen cyanide.

Krapcho Reaction (Krapcho’s Decarboxylation)p.12 “Mitsunobu Reaction Using Acetone Cyanohydrin”

The Krapcho reaction is the method for the decarboxylation of carboxylic acid esters having an electron-withdrawing group at the β-position without hydrolysis of the ester group. In this synthetic manner, DMSO or DMSO-water is used as a solvent and the decarboxylation proceeds more rapidly by addition of salts such as sodium chloride, lithium chloride, potassium cyanide, or sodium cyanide. The detail of this reaction and a number of experimental data are collected in “Synthesis” by Krapcho.1)

1) a) A. P. Krapcho, Synthesis 1982, 805. b) A. P. Krapcho, Synthesis 1982, 893.

R1 R2

O NH3 or NH4Cl

R1 R2

OHH2N

R1 R2

CNH2NCN source

CN source : HCN, (CH3)2C(OH)(CN), NaCN, KCN, TMSCN

α-aminonitrile

Strecker Reaction

H+ or OH- H2NOH

O

R1 R2

α-amino acid

hydrolysis

Krapcho Reaction (Krapcho's Decarboxylation)

EWGO

O

R1 R2

R3 MX

DMSO-H2O

EWG : ester, acyl, cyano

EWGO

O

R1 R2

R3

R2

R1

EWG CO2

MX

MX : NaCl, LiCl, KCN, NaCN etc.

M+ X-

+ + R3 X

Technical Glossary

No.156

14

No.156

Useful Asymmetric Organoligands for [3+2] Cycloaddition

D4168 IAP (= 2,4-Dibromo-6-[[[[(4S,5S)-4,5-dihydro-4,5-diphenyl-1-tosyl-1H-imidazol- 2-yl]methyl][(S)-1-phenylethyl]amino]methyl]phenol) (1) 50mgB3934 PyBidine (=2,6-Bis[(2R,4S,5S)-1-benzyl-4,5-diphenylimidazolidin-2-yl]pyridine) (2) 50mg

IAP (1) and PyBidine (2) are asymmetric organoligands developed by Arai et al. The asymmetric organoligand 1 is found by using a novel high-throughput screening system1) for analyzing the asymmetric induction with circular dichroism as a detector.2) 2 is an asymmetric organoligand having two chiral imidazolidine moieties.3) The structure of an imidazoline, which is usually used as a N-heterocyclic ligand, is nearly planar, while 2 has imidazolidine moieties as ligands instead of imidazoline moieties, which affords a chiral asymmetrical field because of steric hindrance of sp3 carbon on the chiral imidazoline ligand.

A copper(I) complex of 1 is highly effective in asymmetric Henry reactions and asymmetric Friedel–Crafts alkylations and the desired products are given in high enantiomeric excess.2) On the other hand, a complex of 2 and copper(II) acts as a catalyst of an asymmetric Mannich reaction.4) Furthermore, asymmetric [3+2] cycloaddition of iminoesters with alkenes can be performed by using the nickel(II) complex of 1, 5) or copper(II) complex of 23) and pyrrolidine cycles are formed with high enantioselectivities. In a case using 1 as a ligand, exo' product is formed, and in a case of 2, the endo one is formed each with high enantioselectivities.

References1) Direct monitoring of the asymmetric induction of solid-phase catalysis using circular dichroism: diamine–CuI-catalyzed

asymmetric Henry reaction T. Arai, M. Watanabe, A. Fujiwara, N. Yokoyama, A. Yanagisawa, Angew. Chem. Int. Ed. 2006, 45, 5978.2) A library of chiral imidazoline–aminophenol ligands: discovery of an efficient reaction sphere T. Arai, N. Yokoyama, A. Yanagisawa, Chem. Eur. J. 2008, 14, 2052.3) Chiral bis(imidazolidine)pyridine−Cu(OTf)2: catalytic asymmetric endo-selective [3+2] cycloaddition of imino esters with

nitroalkenes T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki, H. Sato, J. Am. Chem. Soc. 2010, 132, 5338.4) syn-Selective asymmetric Mannich reaction of sulfonyl imines with iminoesters catalyzed by the N,N,N-tridentate

bis(imidazolidine)pyridine (PyBidine)–Cu(OTf)2 complex T. Arai, A. Mishiro, E. Matsumura, A. Awata, M. Shirasugi, Chem. Eur. J. 2012, 18, 11219.5) Catalytic asymmetric exo'-selective [3+2] cycloaddition of iminoesters with nitroalkenes T. Arai, N. Yokoyama, A. Mishiro, H. Sato, Angew. Chem. Int. Ed. 2010, 49, 7895.

OH

Br

BrN

CH3

N NS

CH3

O

O

N

NH

N

HN

N

IAP (1) PyBidine (2)

O2NR1

R2 N COOCH3

1 [D4168] (11 mol%)Ni(OAc)2 (10 mol%)

K2CO3acetonitrile

−10 °C

NH

R1O2N

COOCH3R2

highly exo'-selective

O2NR4

R3

R5 N COOCH3

R62 [D3934] (5.5 mol%)Cu(OTf)2 (5 mol%)

Cs2CO3dioxane

rt

NH

R3R4

COOCH3R5

highly endo-selective

O2NR6

+

+

No.156 No.156

15

2’-O-Methylribonucleosides: Basic Reagents for RNA Biochemistry and Bioscience

M2290 2'-O-Methyluridine (1) 1g, 5gM2291 2'-O-Methyladenosine (2) 1gM2317 2'-O-Methylcytidine (3) 200mg, 1gM2318 2'-O-Methylguanosine Hydrate (4) 200mg, 1g

2'-O-Methylribonucleosides are minor components of RNAs, and oligoribonucleotides containing these nucleosides have been synthesized to study their chemical, structural, and molecular biological behaviors. In the 1980s, oligo-2'-O-methylribonucleotide-RNA duplexes were noted for their high thermodynamic stability and resistance to degradation by nucleases.1)

In the 2000s, synthetic 2'-O-methyl-modified small interfering RNA (siRNA) duplexes were reported to have high resistance to degradation by nucleases without significant loss of RNA interference activity.2) In addition, 2'-O-methyl-modified- single stranded RNA (ssRNA) and siRNA duplexes were reported as abrogators of immune activation.3) In addition, 2'-O-methylcytidine (3) showed as an inhibitor of RNA polymerase from the hepatitis C virus (HCV).4)

References1) Synthesis and evaluations of 2'-O-methylribonucleotide-RNA duplexes a) H. Inoue, Y. Hayase, A. Imura, S. Iwai, K. Miura, E. Ohtsuka, Nucleic Acids Res. 1987, 15, 6131. b) B. S. Sproat, A. I. Lamond, B. Beijer, P. Neuner, U. Ryder, Nucleic Acids Res. 1989, 17, 3373. c) E. A. Lesnik, C. J. Guinosso, A. M. Kawasaki, H. Sasmor, M. Zounes, L. L. Cummins, D. J. Ecker, P. D. Cook, S. M.

Freier, Biochemistry 1993, 32, 7832.2) Resistance of 2'-O-modified siRNA to degradation by nucleases F. Czauderna, M. Fechtner, S. Dames, H. Aygün, A. Klippel, G. J. Pronk, K. Giese, J. Kaufmann, Nucleic Acids Res.

2003, 31, 2705.3) Abrogation of immune activation by 2'-O-methyl-modified ssRNA and siRNA a) A. D. Judge, G. Bola, A. C. H. Lee, I. MacLachlan, Mol. Ther. 2006, 13, 494. b) M. Robbins, A. Judge, L. Liang, K. McClintock, E. Yaworski, I. MacLachlan, Mol. Ther. 2007, 15, 1663. c) M. Sioud, Eur. J. Immunol. 2006, 36, 1222.4) Inhibition of hepatitis C virus (HCV) RNA replication by 2'-O-metylcytidine S. S. Carroll, J. E. Tomassini, M. Bosserman, K. Getty, M. W. Stahlhut, A. B. Eldrup, B. Bhat, D. Hall, A. L. Simcoe, R.

LaFemina, C. A. Rutkowski, B. Wolanski, Z. Yang, G. Migliaccio, R. De Francesco, L. C. Kuo, M. MacCoss, D. B. Olsen, J. Biol. Chem. 2003, 278, 11979.

Related CompoundsProtective reagent for 5'-hydroxy group of nucleosides D1612 4,4'-Dimethoxytrityl Chloride 5g, 25gPhosphitylation reagent of nucleosides C2228 2-Cyanoethyl N,N,N',N'-Tetraisopropylphosphordiamidite 1g, 5g

O

OH

NHO

N

N

N

NH2

OCH3

O

OH

NHO

HN

O

O

OCH3

O

OH

NHO

N

O

NH2

OCH3

O

OH

NHO

N

N

NH

O

OCH3

NH2

1 2 3 4

xH2O.

No.156

16

No.156

Cross-linkers Containing Photoreactive Diazirine Group

T2818 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzyl Alcohol (1) 200mg, 1gT2819 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzyl Bromide (2) 200mg, 1gT2820 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzoic Acid (3) 200mg, 1g

Diazirine changes to a high-reactive carbene by absorbing light near 360 nm, which forms a covalent bond to a nearby molecule. The covalent bond is more stable than one formed by nitrene derived from a photoreactive azide. Phenyldiazirine derivatives 1–3 have a functional group at the para position. For example, after the functional group attaches to a ligand, the diazirine group reacts with the acceptor molecule under photoexcitation. It has been reported in research of the photoaffinity labelings which include the crosslinker with peptides or sugars,2) and the photoaffinity microarrays.3)

References1) Reviews a) T. Tomohiro, M. Hashimoto, Y. Hatanaka, Chem. Record 2005, 5, 385. b) M. Hashimoto, Y. Hatanaka, Eur. J. Org. Chem. 2008, 2513. c) Y. Sadakane, YAKUGAKU ZASSHI 2007, 127, 1693.2) Photoaffinity labeling a) Y. Kashiwayama, T. Tomohiro, K. Narita, M. Suzumura, T. Glumoff, J. K. Hiltunen, P. P. van Veldhoven, Y. Hatanaka, T.

Imanaka, J. Biol. Chem. 2010, 285, 26315. b) E. W. S. Chan, S. Chattopadhaya, R. C. Panicker, X. Huang, S. Q. Yao, J. Am. Chem. Soc. 2004, 126, 14435. c) K. Matsuda, M. Ihara, K. Nishimura, D. B. Sattelle, K. Komai, Biosci. Biotechnol. Biochem. 2001, 65, 1534. d) M. Wiegand, T. K. Lindhorst, Eur. J. Org. Chem. 2006, 4841.3) Photoaffinity microarray a) D. M. Dankbar, G. Gauglitz, Anal. Bioanal. Chem. 2006, 386, 1967. b) S. Wei, J. Wang, D.-J. Guo, Y.-Q. Chen, S.-J. Xiao, Chem. Lett. 2006, 35, 1172. c) N. Kanoh, S. Kumashiro, S. Simizu, Y. Kondoh, S. Hatakeyama, H. Tashiro, H. Osada, Angew. Chem. Int. Ed. 2003,

42, 5584.4) Phenyldiazirine synthesis H. Nakashima, M. Hashimoto, Y. Sadakane, T. Tomohiro, Y. Hatanaka, J. Am. Chem. Soc. 2006, 128, 15092.

N N

CF3

CH2OH

1

N N

CF3

CH2Br

N N

CF3

C

O

OH

2 3

X

CF3 N

N

CF3 N

NLigand

Ligand

UV Light

CF3

Ligand

CF3

Ligand

Acceptor

Acceptor

No.156 No.156

17

New Palladacycle Precatalyst

D4191 Di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)dipalladium(II) (1) 1g

Di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)dipalladium(II) (1) is a palladacycle dimer formed from two aminobiphenyl-palladacycle units structurally bridged by two chlorine atoms.1) 1 is a palladacycle precatalyst and by the use of 1 with various phosphine ligands, which can be used as a catalyst for Suzuki–Miyaura cross-coupling.2) As an example, when a catalyst prepared from 1 and 1,1'-bis(diisopropylphosphino)ferrocene (dippf) is employed, couplings of benzyloxymethyltrifluoroborate with aromatic mesyl esters successfully proceed to afford the desired coupling products.2a)

References1) The cyclopalladation reaction of 2-phenylaniline revisited J. Albert, J. Granell, J. Zafrilla, M. Font-Bardia, X. Solans, J. Organomet. Chem. 2005, 690, 422.2) Suzuki–Miyaura cross-coupling using 1 as a palladacycle precatalyst a) G. A. Molander, F. Beaumard, Org. Lett. 2011, 13, 3948. b) G. A. Molander, S. L. J. Trice, S. M. Kennedy, S. D. Dreher, M. T. Tudge, J. Am. Chem. Soc. 2012, 134, 11667. c) G. A. Molander, S. R. Wisniewski, J. Am. Chem. Soc. 2012, 134, 16856.

Cl

ClPd

H2N

Pd

NH2

O

BF3KR = Aryl, Heteroaryl

O

R

dippf (6–10 mol%)K3PO4 (4 eq.)

tert-BuOH/H2O (1:1, v/v)110 °C 46–92% (R = Aryl)

46–81% (R = Heteroaryl)

R OMs +

1 [D4191] (3–5 mol%)

No.156

18

No.156

Nitric Oxide Donor Activated by Two-Photon Excitation

Bone Resorption Inhibitors

D3959 Flu-DNB Monohydrate (= 5-[4-(3,5-Dimethyl-4-nitrostyryl)benzamido]-2-(6-hydroxy- 3-oxo-3H-xanthene-9-yl)benzoic Acid Monohydrate) (1) 5mg

A2456 Alendronate Sodium Trihydrate (1) 5g, 25gD4159 Disodium Etidronate Hydrate (2) 5g, 25gM2289 Monosodium Risedronate Hemipentahydrate (3) 100mg, 1gS0877 Sodium Ibandronate (4) 1g, 5g

Flu-DNB (1), which was developed by Nakagawa et al., is a nitric oxide (NO) donor activated by two-photon excitation (TPE). 1 has the fluorescein structure as a two-photon absorbing moiety and the 2,6-dimethylnitrobenzene structure as an NO release moiety, which is activated by two-photon excitation upon 720 nm pulse laser irradiation to release NO. Since 1 does not contain any transition metal complexes and biocompatible long-wavelength lights can be applied, 1 would be highly advantageous for biological applications.

References1) Nitric oxide donors activated by two-photon excitation a) K. Hishikawa, H. Nakagawa, T. Furuta, K. Fukuhara, H. Tsumoto, T. Suzuki, N. Miyata, J. Am. Chem. Soc. 2009, 131,

7488. b) K. Hishikawa, H. Nakagawa, N. Miyata, YAKUGAKU ZASSHI 2011, 131, 317.

Bisphosphonates (1~4) are known as anti-bone resorptive agent.1) Alendronate, ibandronate, and risedronate strongly inhibit farnesyl diphosphate synthase.1a) Ibandronate has been investigated for in vitro anti-tumor effects and its in vivo role.2)

This product is for research purpose only.

References1) Anti-bone resorption a) J. E. Dunford, K. Thompson, F. P. Coxon, S. P. Luckman, F. M. Hahn, C. D. Poulter, F. H. Ebetino, M. J. Rogers., J.

Pharmacol. Exp. Ther. 2001, 296, 235. b) E. Hiroi-Furuya, T. Kameda, K. Hiura, H. Mano, K. Miyazawa, Y. Nakamaru, M. Watanabe-Mano, N. Okuda, J.

Shimada, Y. Yamamoto, Y. Hakeda, M. Kumegawa, Calcif. Tissue Int. 1999, 64, 219.2) In vitro anti-tumor effects and its in vivo role P. Fournier, S. Boissier, S. Filleur, J. Guglielmi, F. Cabon, M. Colombel, P. Clézardin, Cancer Res. 2002, 62, 6538.

O OHO

C

O

OH

NH C

O

CH CH NO2

CH3

CH3Flu-DNB (1)

xH2O.

N CH2CH2 C

P

P

OH

O

HO ONa

O

HO OH

42

CH3(CH2)4

CH3C

P

P

OH

O

HO ONa

O

HO ONa

CH3

3H2O.1

C

P

P

OH

O

HO OH

O

HO ONa

H2N(CH2)3

2 1/2H2O.3

C

P

P

OH

O

HO OH

O

HO ONa

CH2N

No.156 No.156

19

Pirfenidone: A Unique Antifibrotic and Anti-Inflammatory Agent

P1871 Pirfenidone (1) 100mg, 1g

Pirfenidone (1) is a bioactive small molecule, and was first reported as an anti-inflammatory agent in the 1970s.1) Recently, Oku et al. have reported its unique anti-inflammatory properties.2) Additionally in the 1990s, Margolin et al. discovered that 1 had an antifibrotic action.3) Here, they showed that 1 was an inhibitor of collagen production and fibroblast proliferation in the lungs of rats and hamsters. The study of antifibrotic activity in various organs has been developed by using a variety of animal models.4)

This product is for reseach purpose only.

References1) The first reports of pirfenidone as an anti-inflammatory agent a) S. M. Gadekar, U.S. Patent 3839346, 1974. b) S. M. Gadekar, U.S. Patent 3974281,1976. c) S. M. Gadekar, Jpn.

Kokai Tokkyo Koho S49-87677, 1974. d) S. M. Gadekar, Jpn. Kokai Tokkyo Koho S51-128437, 1976.2) Unique anti-inflammatory properties of pirfenidone H. Oku, H. Nakazato, T. Horikawa, Y. Tsuruta, R. Suzuki, Eur. J. Pharmacol. 2002, 446, 167.3) The first reports of pirfenidone as an antifibrotic agent a) H. Suga, S. Teraoka, K. Ota, S. Komemushi, S. Furutani, S. Yamauchi, S. B. Margolin, Exp. Toxic. Pathol. 1995, 47,

287. b) S. N. Iyer, J. S. Wild, M. J. Schiedt, D. M. Hyde, S. B. Margolin, S. N. Giri, J. Lab. Clin. Med. 1995, 125, 779.4) The antifibrotic activity of pirfenidone in various organs a) S. N. Iyer, G. Gurujeyalakshmi, S. N. Giri, J. Pharmacol. Exp. Ther. 1999, 291, 367. b) G. Miric, C. Dallemagne, Z. Endre, S. Margolin, S. M. Taylor, L. Brown, Br. J. Pharmacol. 2001, 133, 687. c) C. J. Schaefer, D. W. Ruhrmund, L. Pan, S. D. Seiwert, K. Kossen, Eur. Respir. Rev. 2011, 20, 85.

N

CH3

O 1

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CONTENTSChemistry ChatHeavy Hydrogen / Kentaro Sato

Science "Winter" SeminarCarbonyl Olefination (1) / Takeshi Takeda

Short TopicMitsunobu Reaction Using Acetone Cyanohydrin / Haruhiko Taguchi

New Products InformationUseful Asymmetric Organoligands for [3+2] Cycloaddition2'-O-Methylribonucleosides: Basic Reagents for RNA Biochemistry and BioscienceCross-linkers Containing Photoreactive Diazirine GroupNew Palladacycle PrecatalystNitric Oxide Donor Activated by Two-Photon ExcitationBone Resorption InhibitorsPirfenidone: A Unique Antifibrotic and Anti-Inflammatory Agent