ISSN 1 3 4 9 - 4 8 4 8
num ber
156
CO N T E N T S
2
Chem is tr y Chat –Focu s i ng on t he E l ements- Heavy Hydrogen
Kentaro Sato
6
S cience “ Winter ” S em inar
- Carbonyl Olefination (1)
Takeshi Takeda
Professor of Department of Applied Chemistry,
Tokyo University of Agriculture and Technology
11
Sho r t To pic: M o re ways to us e reagent s
- Mitsunobu Reaction Using Acetone Cyanohydrin
Haruhiko Taguchi
Tokyo Chemical Industry Co., Ltd.
14
N ew Pro d uc ts I nfo rm atio n :
- 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 Antifibrotic and Anti-Inflammatory Agent
No.156
Chemistry Chat
-Focusing on the Elements-
Heavy Hydrogen
Kentaro Sato
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 physicochemical 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.
2
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.”
No.156
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.
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.
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.
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 carbonhydrogen (C-H) bond. This deuterium isotope effect most
likely disrupts important biological reactions and causes
toxic effects.
Deuterated Solvents
For organic chemists, the most common application of
deuterium is probably NMR solvent. Deuterated solvents
such as d-chloroform, d6-DMSO, and D 2O 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, H 2O reacts more easily than D2O,
releasing more of gaseous H 2 than D 2. As a result, this
process increases the concentration of D 2O and this is
currently the main way of how heavy water is produced.
Deuterium and Life
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.
CD3
O
D3C
N
CD3
OH
Example of Deuterated Drugs “Venlafaxine-d6”
3
No.156
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. 2007Present 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 <http://www.org-chem.org/yuuki/MOC.html>
4
No.156
Technical Glossary
Deuterium and Tritium
p.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.
Proton
Electron
Neutron
Hydrogen
(Light Hydrogen)
Deuterium
(Heavy Hydrogen)
Tritium
Nuclear Fusion
p.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.
Deuterium
Helium
Nuclear Fusion
Neutron
Tritium
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):
n
n
Nuclear Fusion
Helium
Four Hydrogen Atoms
1.008 x 4 = 4.032
-0.029
4.003
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
We find an enormous amount of energy is released by nuclear fusion. It seems like great energy, but there
are many problems to be solved for the technical and safety aspects. To be available to use that energy for our
benefit, it will take more time.
5
No.156
Science "Winter" Seminar
Carbonyl Olefination (1)
Takeshi Takeda
Department of Applied Chemistry, Tokyo University of Agriculture and Technology
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 JuliaKocienski 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.
R4
R3
PR3 1
Wittig reaction
R4
R3
O
R1
POR2
Horner-Wadsworth-Emmons reaction
R4
R2
R3
SO2Ar
R1
R4
R2
R3
Julia reaction
(Na/Hg)
R4
R3
SiR3
Peterson reaction
Scheme 1
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
6
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.”
No.156
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
O
H2N NH2
2
H2S
N
N
74%
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)
HN
HN
100%
Pb(OAc)4
S
N
N
99%
P(OEt)3
S
75%
Scheme 2
1) Hex
O
OCOPh
Hex
SO2Ph / BuLi
Ph
Ph
2) PhCOCl
81%
SmI2
Hex
Ph
SO2Ph
72% E:Z = ca. 2:1
Scheme 3
O
Ph
SiMe3 / LDA
O
O
O
R
R = H 89%
O
R
Ph
R = Me 50%
Scheme 4
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 b-acetoxy sulfones 2. Another “Julia” reaction named
the Julia-Kocienski reaction was first reported by Sylvestre Julia in 1991 2) and extensively studied by Kocienski and coworkers. 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.
Julia-Lythgoe reaction
O
R1
PhSO2
3
R4
R
R1
R2
R3
PhO2S
AcCl
R3
PhO2S
R1
O
R2
1
R4
2
R2
Na(Hg)
R4
OAc
R1
R3
R2
R4
Julia-Kocienski reaction
O
R1
ArSO2
R3
R4
R3
ArO2S
R
2
R
R2
1
-
O2S
R3
R4
1
R
R2
R4
Smiles rearrangement
1
OAr
-
- SO2, ArO
O
3
R1
R3
2
4
R
R
Ar =
N
N
,
S ,
N N
N N
R
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.
7
No.156
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.
The most powerful tool to synthesize highly stericallycongested 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 5 10) and
611) were prepared by the McMurry coupling. The reaction,
TiCl3-LiAlH4
TiCl3(DME)1.5-Zn/Cu
O
2
O
2
87%
13%
Scheme 5
Scheme 6
O
O
TiCl3 / Li
+
+
(4 equiv)
50%
26%
Scheme 7
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.
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
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
O
Ph3P
OEt
PPh3
84%
O
PPh3
O
O
O
O
60%
Scheme 8
O
AcO
Scheme 9
O
O
O
O
PPh3
OAc
AcO
65%
OAc
CF3
O
OAc
O
O
CF3
Ph
O
O
S
Ph3P
CO2Me
N
CO2Bn
67%
8
O
Ph
Scheme 11
PhOCH2CONH
MeO2C
S
PPh3
NHOBn
O
N
E:Z = 1:1
Scheme 12
PPh3
65%
OAc
Scheme 10
PhOCH2CONH
OMe
O
OMe
CO2Bn
S
NHOBn
86%
Scheme 13
S
No.156
often employed for the synthesis of natural products such as
alkaloids.
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 14 20) and 15 21) ), 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
O
OEt
O
Several other reagents have also been developed for the
olefination of carboxylic acid derivatives24) which include the
organometallic species generated from the gem-dibromidesTiCl 4 -Zn-TMEDA system (Scheme 18) 25) and gem-dizinc
compounds (Scheme 19).26)
OEt
TiCl3-LiAlH4, Et3N
+
SBu-t
60%
t-BuS
Scheme 14
O
NEt2
+
MeO
Ph
Ph
Sm-SmI2
Ph
Ph
75%
NEt2
Scheme 15
O
O
MeO
H
O
O
MeO
O
TiCl3-C8K
89%
Ph
MeO
NH
O
OMe
O
Ph
OMe
Scheme 16
TiCl3-C8K
MeO
86%
MeO
OMe
N
H
OMe
Scheme 17
Br
O
Ph
Br
OMe
/ Zn / TiCl 4
MeO
Ph
TMEDA
Scheme 18
61% E:Z = 10:90
CH2(ZnI)2
O
OPr-i
β-TiCl3 / TMEDA
OPr-i
90%
Scheme 19
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 α-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.
9
No.156
O
TiCp2 CH2 2
OEt
O
TiCp2
Cl
AlMe2
OEt
81%
3
Scheme 20
Cp2Ti
O
O
SiMe3
4
O
SiMe3
Cp2Ti
SiMe3 5
SiMe3
67% E:Z = 2.5:1
Scheme 21
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.
10
No.156
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,b-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.
11
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)
CH3
HO
OH
R1
R2
CN
CH3
Mitsunobu Reagent
CN
R1
R2
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.
References
1)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 Compounds
M0361
C1500
A0705
A1458
T0519
T0361
12
Acetone Cyanohydrin
Cyanomethylenetri-n-butylphosphorane
Diethyl Azodicarboxylate (40% in Toluene, ca. 2.2 mol/L)
1,1'-Azobis(N,N-dimethylformamide)
Triphenylphosphine
Tributylphosphine
1g
25mL 500mL
5g
25g
25g 250g
1g
5g
25g 500g
25mL 500mL
No.156
Technical Glossary
Strecker Reaction
p.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 acidhydrolysis. Acetone cyanohydrin, potassium cyanide, sodium cyanide and trimethylsilyl cyanide are used as a
cyanide source instead of hydrogen cyanide.
Strecker Reaction
O
R1
O
H2N OH
NH3 or NH4Cl
R1
R2
H2N CN
CN source
R1
R2
R2
H+
or
OH-
H2N
hydrolysis
α-aminonitrile
OH
R1 R 2
α-amino acid
CN source : HCN, (CH3)2C(OH)(CN), NaCN, KCN, TMSCN
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 electronwithdrawing group at the b-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)
Krapcho Reaction (Krapcho's Decarboxylation)
O
EWG
O
R1
MX
R3
EWG
DMSO-H2O
R1 R2
M+
MX
+
CO2
+
R3 X
X-
O
EWG
R2
EWG : ester, acyl, cyano
O
R3
MX : NaCl, LiCl, KCN, NaCN etc.
R 1 R2
1) a) A. P. Krapcho, Synthesis 1982, 805. b) A. P. Krapcho, Synthesis 1982, 893.
13
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)
B3934 PyBidine (=2,6-Bis[(2R,4S,5S)-1-benzyl-4,5-diphenylimidazolidin-2-yl]pyridine)
(2)
50mg
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.
O
N
S
N
O
Br
N
CH3
N
OH
N
N
HN
NH
CH3
Br
IAP (1)
PyBidine (2)
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.
1 [D4168] (11 mol%)
R
O2N
1
+
R2
N
R4
+
R5
N
K2CO3
acetonitrile
−10 °C
2 [D3934] (5.5 mol%)
R6
R3
O2N
COOCH3
Cu(OTf) 2 (5 mol%)
COOCH3
R1
O2N
Ni(OAc)2 (10 mol%)
Cs2CO3
dioxane
rt
R2
N
H
COOCH3
highly exo'-selective
R4
R3
O2N
R5
R6
N
H
COOCH3
highly endo-selective
References
1)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.
14
No.156
2’-O-Methylribonucleosides:
Basic Reagents for RNA Biochemistry and Bioscience
M2290
M2291
M2317
M2318
2'-O-Methyluridine (1)
2'-O-Methyladenosine (2)
2'-O-Methylcytidine (3)
2'-O-Methylguanosine Hydrate (4)
NH2
O
N
HN
HO
N
O
N
N
HO
N
OCH3
1
OH
O
NH2
N
N
HO
O
O
OH
1g, 5g
1g
200mg, 1g
200mg, 1g
N
O
2
OH
OCH3
3
N
HO
N
NH2
O
O
OCH3
NH
OH
OCH3
. xH2O
4
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)
References
1)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 Compounds
Protective reagent for 5'-hydroxy group of nucleosides
D1612 4,4'-Dimethoxytrityl Chloride
Phosphitylation reagent of nucleosides
C2228 2-Cyanoethyl N,N,N',N'-Tetraisopropylphosphordiamidite
5g, 25g
1g,
5g
15
No.156
Cross-linkers Containing Photoreactive Diazirine Group
T2818 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzyl Alcohol (1)
T2819 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzyl Bromide (2)
T2820 4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzoic Acid (3)
N N
N N
CF3
N N
CF3
CF3
CH2OH
N
N
2
CF3
Ligand
N
N
O
CH2Br
1
CF3
200mg, 1g
200mg, 1g
200mg, 1g
C OH
3
CF3
CF3
Acceptor
Acceptor
UV Light
X
Ligand
Ligand
Ligand
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)
References
1)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.
16
No.156
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 crosscoupling.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)
NH2
Pd
Cl
Cl
Pd
H2N
1 [D4191]
(3–5 mol%)
O
R OMs
+
R = Aryl, Heteroaryl
BF3K
dippf (6–10 mol%)
K3PO4 (4 eq.)
tert-BuOH/H2O (1:1, v/v)
110 °C
O
R
46–92% (R = Aryl)
46–81% (R = Heteroaryl)
References
1)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.
17
No.156
Nitric Oxide Donor Activated by Two-Photon Excitation
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)
HO
O
5mg
O
C OH
O
O
NH
CH3
C
CH
CH
NO2
CH3
Flu-DNB (1)
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.
References
1)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.
Bone Resorption Inhibitors
A2456
D4159
M2289
S0877
Alendronate Sodium Trihydrate (1)
Disodium Etidronate Hydrate (2)
Monosodium Risedronate Hemipentahydrate (3)
Sodium Ibandronate (4)
5g, 25g
5g, 25g
100mg, 1g
1g, 5g
O
O
O
O
HO P OH
HO P ONa
HO P OH
HO P ONa
H2N(CH2)3 C OH
CH3
C OH
HO P ONa
HO P ONa
O
O
1
. 3H2O
2
. xH2O
CH2 C OH
N
HO P ONa
O
CH3(CH2)4
CH3
N CH2CH2 C OH
HO P OH
. 2 1/2H2O
3
O
4
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.
References
1)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.
18
No.156
Pirfenidone: A Unique Antifibrotic and Anti-Inflammatory Agent
P1871 Pirfenidone (1)
100mg, 1g
CH3
N
O
1
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.
References
1)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.
19
TCI AMERICA
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Fax
E-mail
Address
:
:
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888-520-1075 • +1-503-283-1987
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9211 N. Harborgate Street, Portland, OR 97203, U.S.A.
Boston Office
www.TCIchemicals.com
TCI EUROPE N.V.
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Address
:
:
:
:
+32 (0)3 735 07 00
+32 (0)3 735 07 01
[email protected]
Boerenveldseweg 6 - Haven 1063, 2070 Zwijndrecht
Belgium
TCI Deutschland GmbH
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:
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+49 6196 64053-00
+49 6196 64053-01
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Mergenthalerallee 79-81, D-65760, Eschborn, Germany
Tokyo Chemical Industry UK Ltd.
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:
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+44 1865 78 45 60
+44 1865 78 45 61
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The Magdalen Centre, Robert Robinson Avenue
The Oxford Science Park, Oxford OX4 4GA
United Kingdom
Tel
: 781-239-7515
Fax
: 781-239-7514
Address : 303 Wyman Street, Suite 300, Waltham, MA 02451
Philadelphia Office
Tel
: 800-423-8616
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: 888-520-1075
Address : 121 Domorah Drive, Montgomeryville, PA 18936
TOKYO CHEMICAL INDUSTRY CO., LTD.
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+81-3-5640-8878
+81-3-5640-8902
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4-10-2 Nihonbashi-honcho, Chuo-ku, Tokyo 103-0023
Japan
梯希爱(上海)化成工业发展有限公司
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800-988-0390 • +86 (0)21-6712-1386
+86 (0)21-6712-1385
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上海化学工业区普工路96号, 邮编201507
TCI Chemicals (India) Pvt. Ltd.
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Address
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+91-(0)44-2262 0909
+91-(0)44-2262 8902
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Plot No. B-28, Phase II, 5th Cross Street, MEPZ-SEZ,
Tambaram, Chennai, Tamilnadu-600045, India