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Research Feature “Micro Review”

Introduction: Unit Reactions in Synthetic Organic Chemistry

Large amounts of various organic compounds such as pharmaceuticals, agricultural chemicals, dyes, food additives, aroma chemicals, and functional materials are produced and utilized everyday. Such essential organic compounds in modern society are created based on synthetic organic chemistry. Namely, “easily available (inexpensive) organic compounds A” can be converted to “more valuable organic compounds X” by using a variety of organic transformation reactions.

Scheme1

For examples, compounds A are typified by hydrocarbon compounds such as acetylene, ethylene, and benzene, which can be abundantly and inexpensively obtained from carbon resources such as coal and petroleum, and compounds X are typified by pharmaceuticals such as taxol and tamiflu, which have complicated molecular structures (Scheme 1). In most cases, compounds A cannot be directly transformed to compounds X in one step. Therefore, “multi-step

Development of Addition-type Ozone Oxidation and Its Application

Kazunobu Igawa1, Yuuya Kawasaki2, Katsuhiko Tomooka1

1Institute for Materials Chemistry and Engineering, Kyushu University2Interdisciplinary Graduate School of Engineering Sciences, Kyushu University

Ozone is a simple, economical, clean, and efficient oxidation agent. Thus, it is widely utilized in many aspects of industry. Moreover, in organic synthesis, ozone is commonly used for oxidative cleavage of a carbon-carbon double bond which is a well known “textbook reaction”. On the other hand, addition-type oxidation of an alkene is also an important transformation in organic synthesis; however, the usage of ozone in this transformational is severely limited. We recently found that the reaction of ozone and an alkenyl silane provides an α-silylperoxy aldehyde or ketone by the addition-type oxidation reaction. The thus obtained silyl peroxides can serve as a versatile precursor for polyol derivatives and acyloin compounds.

synthesis” is commonly used for synthesis of valuable organic compounds, i.e., a compound A is converted to compound B with slight modification of structure by a proper reaction; the obtained compound B are again converted to compounds C, and compounds X are obtained after such repetitions. In order to effectively synthesize organic compounds with various structures, it is necessary to line up various reactions (called “unit reactions”) and properly utilize them depending on the purpose. In order words, the “unit reactions” are essential “tools” for molecular conversion and construction.

Addition-type Oxidation of Unsaturated Hydrocarbons

Addition-type oxidation of unsaturated hydrocarbons is an important fundamental reaction of synthetic organic chemistry. This type of reactions transform unsaturated hydrocarbons such as acetylene and ethylene, which are poor in functionality, to “more valuable organic compounds” such as ketones, alcohols, and epoxides by introduction of oxy-functional groups. The ideal reagent (oxidizing agent) to carry out such an addition-type oxidation reaction is oxygen (O2), which is ubiquitous on Earth. For example, the simplest alkene, ethylene, reacts with oxygen in the presence of a palladium catalyst to give acetaldehyde (Scheme 2).

Scheme 2

This reaction is known as Wacker oxidation, and it is an excellent industrial synthesis process of acetaldehyde.1) However, the applicable substrates are very limited, and it is often not suitable for the oxidation of multi-substituted alkenes. In synthetic organic

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chemistry, it is common to perform epoxidation, hydroxylation, and dihydroxylation using highly reactive compounds such as meta-chloroperbenzoic acid (mCPBA), boranes (BH3, R2BH) with hydrogen peroxide, and osmium tetroxide (OsO4), respectively, as the reagents for the addition-type oxidation of alkenes (Scheme 3).2) The applicable range of these reactions is wide, and they are frequently used as “absolutely necessary tools”. However, there are issues on the explosive nature, cost, toxicity of the reagents, and the generation of by-products. Thus, the development of more efficient reactions and reagents is required.

Scheme 3

Ozone Oxidation of Alkenes Ozone (O3) is one of the most conceivable oxidizing

agents as alternative of oxygen. It can be easily prepared by silent discharge treatment or ultraviolet irradiation of oxygen. Moreover, ozone easily reverts back to nontoxic oxygen by self-decomposition. Therefore, ozone is an attractive oxidizing agent (Scheme 4).3)

Scheme 4

If the “addition-type oxidation of an alkene” is possible with ozone, the issues of the conventional method would be solved at once. However, there have been no examples of the addition-type oxidation of an alkene using ozone. The reason for this is described in textbook of organic chemistry. When ozone is reacted with an alkene, an oxidative cleavage reaction takes place rather than the addition-type oxidation reaction (Scheme 5).4)

Scheme 5

That is, when ozone is reacted with an alkene, a [3+2] cycloaddition reaction proceeds and molozonide i is formed. Molozonide i is rearranged (called “ozonide rearrangement”) and the carbon-carbon bond is cleaved; thus, two carbonyl compounds are formed with reductive work-up. (Scheme 5, 1→i→ii→2+3). This reaction is very useful as the “oxidative cleavage reaction” in synthetic organic chemistry. However it is meaning that “addition-type oxidation products cannot be obtained by ozone oxidation”, which has been commonly known in synthetic organic chemistry. How can we change the reaction type? We considered that an addition-type oxidation product would be obtained if molozonide i is converted to a more stable structure before rearrangement to ozonide ii. Indeed, by introduction of a silyl group (SiR3) on the alkene carbon, we succeeded in obtaining the α-silylperoxy carbonyl compound 5, which is an addition-type oxidation product, in an excellent yield (Scheme 6).5)

Scheme 6

The results indicate that the silyl group migrated to the oxygen of the molozonide generated from the reaction of the alkene and ozone, before the rearrangement (Scheme 6, 4→i→iii→5). This reaction has numerous advantages such as (1) different oxygen functional groups (silylperoxy group, carbonyl group) can be regiospecifically introduced to the two carbons of the alkene, (2) all three oxygen atoms of ozone are incorporated into the product; thus, a reductive work-up is not necessary, and (3) no residual wastes from reagents is generated; thus, the work-up procedure is simple.

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Research Feature “Micro Review”

Synthesis of Alkenyl SilanesThe silyl substituted alkene (called an “alkenyl

silane”) 4, which is the substrate of the present ozone oxidation reaction, can be easily prepared from propargyl alcohols, alkynes, ketones, and so on using prevalent synthetic methods (Scheme 7).

Scheme 7

Accordingly, we prepared various alkenyl silanes 4 by the (1) hydroalumination reaction of a γ-silyl propargylic alcohol, (2) hydrosilylation reaction of an alkyne, (3) Shapiro reaction of a ketone and silylation, and (4) reaction of silylvinyl anion species and a carbon electrophile.6, 7)

Generality and Application Examples of the Addition-type Ozone Oxidation Reaction

In the present addition-type ozone oxidation reaction, an aldehyde or a ketone having a silylperoxy group at the α-position can be obtained depending on the substitution pattern of alkenyl silanes (Scheme 8). For example, α-silylperoxy aldehyde 5a can be obtained from alkenyl silane 4a having a substituent only at the 2-position, and α-silylperoxy ketone 5b can be obtained from 1, 2-disubstituted alkenyl silane 4b. The experimental procedure of the present addition-type ozone oxidation reaction is very simple. The substrate alkenyl silane is dissolved in ethyl acetate at –78 ºC, and then only treated with bubbling ozone gas. After completion of the reaction, the remaining excess ozone is removed with bubbling argon gas. Then, the solvent is removed with a rotary evaporator to obtain the desired product. As the solvent, ethyl acetate is the most suitable, while the yields of similar reactions with commonly used methanol or methylene chloride for ozone oxidation are substantially lowered.The obtained α-silylperoxy carbonyl compounds have sufficient chemical stability, no significant decomposition is observed in typical experimental handling and purification process. Also, we have observed the thermal stability of α-silylperoxy ketone 5b by thermogravimetry and differential thermal analysis (TG / DTA). It shows no decrease in weight

around room temperature, and gradual decomposition over 150 °C (Figure 1).

Scheme 8

Figure 1

Analysis of the Reaction MechanismIn order to clarify the detailed reaction mechanism

of the addition-type ozone oxidation reaction, the reaction of the simple vinyltrimethylsilane 4c and ozone was analyzed by calculation with density functional theory. As shown in scheme 9, the reaction proceeds by, 1) the formation of molozonide iv, 2) the silyl group migrates to the adjacent 2-position oxygen at the 2-position, and 3) the generated 3-position oxygen anion attacks the silicon atom to form the α−silylperoxy carbonyl compound 5c.

Scheme 9

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Transformation of the α-Silylperoxy Carbonyl Compound

The silylperoxy group and carbonyl group introduced on the alkene carbons by the present addition-type ozone oxidation reaction can be transformed to other oxygen functional groups (Scheme 10).5c) For example, α-siloxy ketone 6 can be obtained by the reaction with a phosphite ester, and diketone 7 can be obtained by the reaction with an amine base. Moreover, the reductive cleavage of the oxygen-oxygen bond proceeds under 1 atm of hydrogen in the presence of Pd/C, giving α-hydroxy ketone 8. On the other hand, a reaction with an organic lithium reagent provides nucleophilic addition to the carbonyl group product with the preservation of the silylperoxy group and thus, α-silylperoxy alcohol 9 can be obtained. These results clearly shows that the α-silylperoxy carbonyl compound is useful as the precursor for a variety of oxygen-functionalized compounds.

Scheme 10

ConclusionsIn this manuscript, we described the newly

developed addition-type oxidation reaction of alkenes using ozone. This reaction allows obtaining highly valuable multi-oxygen-functionalized compounds from easily available carbon resources. Currently, we are investigating on the development of efficient hydrosilylation method of acetylenes, which are simple carbon resources, and on the development of the method for recovery and reuse of silyl groups after the addition-type oxidation reaction. We expect to achieve the development of sequential conversion, acetylene → alkenyl silane → multi-oxygen-

functionalized, as an efficient synthetic methodology (Scheme 11).

Scheme 11

AcknowledgmentsThe authors thank Dr. Masahiro Murakami and

Mr. Kyohei Sakita (Tokyo Institute of Technology), who developed the fundamental work of this study. The authors are also thankful for the research fund from the G-COE program “Novel Carbon Resource Sciences” and for the Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology, “Organic Synthesis Based on Reaction Integration, Development of New Methods and Creation of New Substances”.

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R. Sieber, R. Rüttinger, H. Kojer, Angew. Chem., 71, 176 (1959). (b) J. Smidt, W. Hafner, R. Jira, R. Sieber, S. Sedlmeier, A. Sabel, Angew. Chem. Int. Ed., 1, 80 (1962).

2) Review: Comprehensive Organic Synthesis, Vol. 7: Oxi-dation, ed. by B. M. Trost, I. Fleming, Pergamon Press, Oxford (1991).

3) History of study of ozone: Rubin, M. B. Bull. Hist. Chem., 27, 81 (2002).

4) Reviews: (a) P. S. Bailey, Ozonation in Organic Chem-istry, Vol. 1: Olefinic Compounds, Academic Press, Lon-don (1978). (b) P. S. Bailey, Ozonation in Organic Chem-istry, Vol. 2: Nonolefinic Compounds, Academic Press, London (1982).

5) (a) M. Murakami, K. Sakita, K. Igawa, K. Tomooka, Org. Lett., 8, 4023 (2006). (b) K. Igawa, K. Sakita, M. Mura-kami, K. Tomooka, Synthesis, 1641 (2008). (c) K. Igawa, Y. Kawasaki, K. Tomooka, Chem. Lett., 40, 233 (2011).

6) Review: E. Colvin, Silicon in Organic Synthesis, Aca-demic Press, New York, pp 44−60 (1988).

7) Recently, we have developed regioselective hydrosilylation of unsymmetric alkynes, which allows efficiently obtaining a variety of alkenyl silanes, see: Y. Kawasaki, Y. Ishikawa, K. Igawa, K. Tomooka, J. Am. Chem. Soc., 133, 20712 (2011).