Organoselenium chemistry synthesis and reactions

Edited by
Thomas Wirth
Organoselenium
Chemistry


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Edited by Thomas Wirth

Organoselenium Chemistry

Synthesis and Reactions


The Editor
Prof. Dr. Thomas Wirth
Cardiff University
School of Chemistry
Park Place Main Building
Cardiff CF10 3AT
United Kingdom

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V

Contents
Preface XI
List of Contributor XIII

1
1.1
1.1.1
1.1.2
1.2
1.2.1
1.2.2
1.2.3
1.2.4
1.3
1.3.1
1.3.2
1.3.3
1.3.4
1.3.5

2
2.1
2.1.1
2.1.2
2.2
2.2.1
2.2.2
2.2.3
2.3
2.3.1

Electrophilic Selenium 1
Claudio Santi and Stefano Santoro
General Introduction 1

Synthesis of Electrophilic Selenium Reagents 3
Reactivity and Properties 7
Addition Reactions to Double Bonds 11
Addition Reaction Involving Oxygen-Centered Nucleophiles 11
Addition Reaction Involving Nitrogen-Centered Nucleophiles 22
Addition Reactions Involving Carbon-Centered Nucleophiles 26
Addition Reaction Involving Chiral Nucleophiles or Chiral
Substrates 28
Selenocyclizations 30
Oxygen Nucleophiles 31
Nitrogen Nucleophiles 35
Competition between Oxygen and Nitrogen Nucleophiles 40
Carbon Nucleophiles 42
Double Cyclization Reactions 44
References 45
Nucleophilic Selenium 53
Michio Iwaoka
Introduction 53
Development of Nucleophilic Selenium Reagents
Examples of Recent Applications 54
Properties of Selenols and Selenolates 56
Electronegativity of Selenium 56
Tautomerism of Selenols 57
Nucleophilicity of Selenolates 58
Inorganic Nucleophilic Selenium Reagents 59
Conventional Reagents 59

53

VI

Contents

2.3.2
2.4
2.4.1
2.4.2
2.4.3
2.4.4
2.4.5
2.4.6
2.4.7
2.4.8
2.4.9
2.4.10
2.4.11
2.4.12
2.4.13
2.4.14
2.4.15
2.4.16
2.4.17
2.4.18

New Reagents 61
Organic Nucleophilic Selenium Reagents 65
Preparation 65
Structure 66
Ammonium Selenolates (NH4+) 67

Selenolates of Group 1 Elements (Li, Na, K, and Cs) 67
Selenolates of Group 2 Elements (Mg, Ca, and Ba) 70
Selenolates of Group 3 Elements (Sm, Ce, Pr, Nb, and U) 71
Selenolates of Group 4 Elements (Ti, Zr, and Hf) 73
Selenolates of Group 5 Elements (V, Nb, and Ta) 74
Selenolates of Group 6 Elements (Mo and W) 75
Selenolates of Group 7 Elements (Mn and Re) 76
Selenolates of Group 8 Elements (Fe, Ru, and Os) 78
Selenolates of Group 9 Elements (Co, Rh, and Ir) 81
Selenolates of Group 10 Elements (Ni, Pd, and Pt) 84
Selenolates of Group 11 Elements (Cu, Ag, and Au) 90
Selenolates of Group 12 Elements (Zn, Cd, and Hg) 92
Selenolates of Group 13 Elements (B, Al, Ga, and In) 95
Selenolates of Group 14 Elements (Si, Ge, Sn, and Pb) 97
Selenolates of Group 15 Elements (P, As, Sb, and Bi) 100
References 102

3

Selenium Compounds in Radical Reactions 111
W. Russell Bowman
Homolytic Substitution at Selenium to Generate Radical
Precursors 111
Bimolecular SH2 Reactions: Synthetic Considerations 112
Radical Reagents 115
Alkyl Radicals from Selenide Precursors 115
Acyl Radicals from Acyl Selenide Precursors 119
Imidoyl Radicals from Imidoyl Selenides 123
Other Radicals from Selenide Precursors 125
Selenide Building Blocks 126

Solid-Phase Synthesis 128
Selenide Precursors in Radical Domino Reactions 130
Homolytic Substitution at Selenium for the Synthesis of
Se-Containing Products 132
Intermolecular SH2 onto Se 132
Intramolecular SH2: Cyclization onto Se 132
Seleno Group Transfer onto Alkenes and Alkynes 134
Seleno-Selenation 135
Seleno-Sulfonation 136
Seleno-Alkylation 137
PhSeH in Radical Reactions 138
Radical Clock Reactions 138

3.1
3.1.1
3.1.1.1
3.1.2
3.1.3
3.1.4
3.1.5
3.2
3.3
3.4
3.5
3.5.1
3.5.2
3.6
3.6.1
3.6.2
3.6.3

3.7
3.7.1


Contents

138

3.7.2
3.7.3
3.8

Problem of Unwanted Trapping of Intermediate Radicals
Catalysis of Stannane-Mediated Reactions 139
Selenium Radical Anions, SRN1 Substitutions 141
References 143

4

Selenium-Stabilized Carbanions 147
João V. Comasseto, Alcindo A. Dos Santos, and Edison P. Wendler
Introduction 147
Preparation of Selenium-Stabilized Carbanions 149
Deprotonation of Selenides 149
Element-Lithium Exchange 154
Conjugate Addition of Organometallics to Vinyl- and
Alkynylselenides 158
Reactivity of the Selenium-Stabilized Carbanions with Electrophiles
and Synthetic Transformations of the Products 161
Reaction of Selenium-Stabilized Carbanions with Electrophiles 166

Selenium-Based Transformations on the Reaction Products of
Selenium-Stabilized Carbanions with Electrophiles 167
Stereochemical Aspects 168
Cyclic Selenium-Stabilized Carbanions 173
Acyclic Selenium-Stabilized Carbanions 176
Application of Selenium-Stabilized Carbanions in Total Synthesis 176
Examples Using Alkylation Reactions of Selenium-Stabilized
Carbanions 177
Examples Using the Addition of Selenium-Stabilized Carbanions to
Carbonyl Compounds 180
Examples Using 1,4-Addition of Selenium-Stabilized Carbanions to
α,β-Unsaturated Carbonyl Compounds 184
Conclusion 186
References 187

4.1
4.2
4.2.1
4.2.2
4.2.3
4.3
4.3.1
4.3.2
4.4
4.4.1
4.4.2
4.5
4.5.1
4.5.2
4.5.3

4.6
5
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.8.1
5.8.2
5.8.3

Selenium Compounds with Valency Higher than Two 191
Józef Drabowicz, Jarosław Lewkowski, and Jacek S´cianowski
Introduction 191
Trivalent, Dicoordinated Selenonium Salts 192
Trivalent, Tricoordinated Derivatives 194
Tetravalent, Dicoordinated Derivatives 211
Tetravalent, Tricoordinated Derivatives 225
Pentavalent Derivatives 239
Hexavalent, Tetracoordinated Derivatives 240
Hypervalent Derivatives 244
Selenuranes 244
Selenurane Oxides 249
Perselenuranes 250
Acknowledgment 251
References 251

VII


VIII

Contents

6
6.1
6.2
6.3
6.4
6.5
6.6
6.7

7
7.1
7.2
7.3
7.3.1
7.3.2
7.4
7.4.1
7.4.2
7.5
7.5.1
7.5.2
7.5.3
7.6

7.6.1
7.6.2
7.6.3
7.7

8
8.1
8.2
8.2.1

Selenocarbonyls 257
Toshiaki Murai
Overview 257
Theoretical Aspects of Selenocarbonyls 259
Molecular Structure of Selenocarbonyls 261
Synthetic Procedures of Selenocarbonyls 261
Manipulation of Selenocarbonyls 270
Metal Complexes of Selenocarbonyls 278
Future Aspects 280
References 281
Selenoxide Elimination and [2,3]-Sigmatropic Rearrangement 287
Yoshiaki Nishibayashi and Sakae Uemura
Introduction 287
Preparation and Properties of Chiral Selenoxides 288
Selenoxide Elimination 292
Enantioselective Selenoxide Elimination Producing Chiral Allenes and
α,β-Unsaturated Ketones 293
Diastereoselective Selenoxide Elimination Producing Chiral
Allenecarboxylic Esters 295
[2,3]-Sigmatropic Rearrangement via Allylic Selenoxides 297

Enantioselective [2,3]-Sigmatropic Rearrangement Producing Chiral
Allylic Alcohols 297
Diastereoselective [2,3]-Sigmatropic Rearrangement Producing Chiral
Allylic Alcohols 299
[2,3]-Sigmatropic Rearrangement via Allylic Selenimides 305
Preparation and Properties of Chiral Selenimides 307
Enantioselective [2,3]-Sigmatropic Rearrangement Producing Chiral
Allylic Amines 309
Diastereoselective [2,3]-Sigmatropic Rearrangements Producing Chiral
Allylic Amines 310
[2,3]-Sigmatropic Rearrangement via Allylic Selenium Ylides 311
Preparation and Properties of Optically Active Selenium Ylides 312
Enantioselective [2,3]-Sigmatropic Rearrangements via Allylic
Selenium Ylides 313
Diastereoselective [2,3]-Sigmatropic Rearrangement via Allylic
Selenium Ylides 315
Summary 317
References 317
Selenium Compounds as Ligands and Catalysts 321
Fateh V. Singh and Thomas Wirth
Introduction 321
Selenium-Catalyzed Reactions 321
Stereoselective Addition of Diorganozinc Reagents to Aldehydes

322


Contents

Diethylzinc Addition 322

Diphenylzinc Addition 323
Selenium-Ligated Transition Metal-Catalyzed Reactions 324
Selenium-Ligated Stereoselective Hydrosilylation of Ketones 324
Selenium-Ligated Copper-Catalyzed Addition of Organometallic
Reagents to Enones 325
8.2.2.3
Selenium-Ligated Palladium-Catalyzed Asymmetric Allylic
Alkylation 326
8.2.2.4
Selenium-Ligands in Palladium-Catalyzed Mizoroki–Heck
Reactions 328
8.2.2.5
Selenium-Ligands in Palladium-Catalyzed Phenylselenenylation
of Organohalides 330
8.2.2.6
Selenium-Ligands in Palladium-Catalyzed Substitution
Reactions 331
8.2.2.7
Selenium-Ligands in the Palladium-Catalyzed Allylation of
Aldehydes 331
8.2.2.8
Selenium-Ligands in Palladium-Catalyzed Condensation
Reactions 332
8.2.2.9
Ruthenium-Catalyzed Substitution Reactions 333
8.2.2.10 Selenium-Ligands in Zinc-Catalyzed Intramolecular
Hydroaminations 334
8.2.3
Selenium-Ligands in Organocatalytic Asymmetric Aldol
Reactions 334

8.2.4
Selenium-Ligands in Stereoselective Darzens Reactions 334
8.2.5
Selenium-Catalyzed Carbonylation Reactions 335
8.2.6
Selective Reduction of α,β-Unsaturated Carbonyl Compounds 336
8.2.7
Selenium-Catalyzed Halogenations and Halocyclizations 336
8.2.8
Selenium-Catalyzed Staudinger–Vilarrasa Reaction 337
8.2.9
Selenium-Catalyzed Elimination Reactions of Diols 338
8.2.10
Selenium-Catalyzed Hydrostannylation of Alkenes 339
8.2.11
Selenium-Catalyzed Radical Chain Reactions 340
8.2.12
Selenium-Catalyzed Oxidation Reactions 342
8.2.12.1 Selenium-Catalyzed Epoxidation of Alkenes 342
8.2.12.2 Selenium-Catalyzed Dihydroxylation of Alkenes 344
8.2.12.3 Selenium-Catalyzed Oxidation of Alcohols 346
8.2.12.4 Baeyer–Villiger Oxidation 347
8.2.12.5 Selenium-Catalyzed Allylic Oxidation of Alkenes 349
8.2.12.6 Selenium-Catalyzed Oxidation of Aryl Alkyl Ketones 350
8.2.12.7 Selenium-Catalyzed Oxidation of Primary Aromatic Amines 350
8.2.12.8 Selenium-Catalyzed Oxidation of Alkynes 351
8.2.12.9 Selenium-Catalyzed Oxidation of Halide Anions 352
8.2.13
Stereoselective Catalytic Selenenylation–Elimination
Reactions 353

8.2.14
Selenium-Catalyzed Diels–Alder Reactions 355
8.2.15
Selenium-Catalyzed Synthesis of Thioacetals 355
8.2.1.1
8.2.1.2
8.2.2
8.2.2.1
8.2.2.2

IX


X

Contents

8.2.16

Selenium-Catalyzed Baylis–Hillman Reaction 356
References 356

9

Biological and Biochemical Aspects of Selenium Compounds 361
Bhaskar J. Bhuyan and Govindasamy Mugesh
Introduction 361
Biological Importance of Selenium 361
Selenocysteine: The 21st Amino Acid 362
Biosynthesis of Selenocysteine 363

Chemical Synthesis of Selenocysteine 366
Chemical Synthesis of Sec-Containing Proteins and Peptides 367
Selenoenzymes 369
Glutathione Peroxidases 369
Iodothyronine Deiodinase 379
Synthetic Mimics of IDs 384
Thioredoxin Reductase 387
Summary 389
References 392

9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.7.1
9.7.2
9.7.3
9.7.4
9.8

77

Se NMR Values

Index

435

397


XI

Preface
Selenium was discovered in 1818 – almost 200 years ago – by the Swedish chemist
Jöns Jacob Berzelius. Selenium is a common companion of sulfur, but was named
after the goddess of the moon Selene. This indicates the chemical relation to tellurium, named after the Greek word for earth, tellus. Berzelius studied the element
selenium and its inorganic compounds in detail. Nowadays, selenium is obtained
in the electrolytic refining of copper and its production reaches several thousand
tons per year. The first organoselenium derivative (ethyl selenol) was published in
1847 by Wöhler and Siemens. The use of selenium dioxide as an oxidant was
described in a patent in 1929. Since that time, selenium and its derivatives have
appeared as reagents in organic synthesis. Organoselenium chemistry started
blossoming in the early seventies with the discovery of the selenoxide elimination
for the introduction of double bonds under mild reaction conditions. Since 1971,
the chemistry of selenium and tellurium is also regularly promoted in a conference
series (ICCST, International Conference on the Chemistry of Selenium and Tellurium). Several monographs and many review articles have appeared during the
last decades. This book summarizes the latest developments with a strong emphasis on the last decade providing an updated picture of the many facets of organoselenium chemistry.
I am very grateful to all the distinguished scientists who have contributed to this
book with their time, knowledge, and expertise. I hope that all chapters will not
only be a rich source of information, but also a source of inspiration to students
and colleagues.
Cardiff, July 2011

Thomas Wirth

XIII

List of Contributors
Bhaskar J. Bhuyan
Indian Institute of Science
Department of Inorganic and Physical
Chemistry
Bangalore 560 012
India
W. Russell Bowman
Loughborough University
Department of Chemistry
Loughborough, Leics LE11 3TU
UK
João V. Comasseto
Universidade de São Paulo
Instituto de Química
Av. Prof. Lineu Prestes, 748
05508-000 São Paulo-SP
Brazil
Alcindo A. Dos Santos
Universidade de São Paulo
Instituto de Química
Av. Prof. Lineu Prestes, 748
05508-000 São Paulo-SP
Brazil

Józef Drabowicz
Polish Academy of Sciences
Department of Heteroorganic

Chemistry
Center of Molecular and
Macromolecular Studies
Sienkiewicza 112
Łódz´ 90–363
Poland
and
Jan Długosz University
Institute of Chemistry and
Environmental Protection
Armii Krajowej 13/15
Cze˛stochowa 42–200
Poland
Michio Iwaoka
Tokai University
School of Science
Department of Chemistry
Kanagawa 259-1292
Japan
Jarosław Lewkowski
University of Łódz´
Faculty of Chemistry
Department of Organic Chemistry
Tamka 12; 91-403 Łódz´
Poland


XIV

List of Contributors

Toshiaki Murai
Gifu University
Faculty of Engineering
Department of Chemistry
Yanagido, Gifu 501-1193
Japan
Govindasamy Mugesh
Indian Institute of Science
Department of Inorganic and Physical
Chemistry
Bangalore 560 012
India

Jacek S´cianowski
Nicolaus Copernicus University
Faculty of Chemistry
Department of Organic Chemistry
Gagarina 7
Torun´ 87–100
Poland
Fateh V. Singh
Cardiff University
School of Chemistry
Park Place
Cardiff CF10 3AT
UK

Yoshiaki Nishibayashi
The University of Tokyo

School of Engineering
Bunkyo-ku
Tokyo 113-8656
Japan

Sakae Uemura
Okayama University of Science
Faculty of Engineering
Okayama 700-0803
Japan

Claudio Santi
University of Perugia
Dipartimento di Chimica e Tecnologia
del Farmaco
Perugia 06123
Italy

Edison P. Wendler
Universidade de São Paulo
Instituto de Química
Av. Prof. Lineu Prestes, 748
05508-000 São Paulo-SP
Brazil

Stefano Santoro
University of Perugia
Dipartimento di Chimica e Tecnologia
del Farmaco
Perugia 06123

Italy

Thomas Wirth
Cardiff University
School of Chemistry
Park Place
Cardiff CF10 3AT
UK


1

1
Electrophilic Selenium
Claudio Santi and Stefano Santoro
1.1
General Introduction

During the last few decades, organoselenium compounds have emerged as important reagents and intermediates in organic synthesis.
Selenium can be introduced as an electrophile, as a nucleophile, or as a radical
and generally it combines chemo-, regio-, and stereoselectivity with mild experimental conditions. Once incorporated, it can be directly converted into different
functional groups or it can be employed for further manipulation of the molecule.
Since the discovery in the late 1950s that species of type RSeX add stereospecifically to simple alkenes [1], electrophilic organoselenium compounds provided the
synthetic chemist with useful and powerful reagents and the selenofunctionalization of olefins represents an important method for the rapid introduction of vicinal
functional groups, often with concomitant formation of rings and stereocenters
(Scheme 1.1a and b).

O
*

R1

R2

SeR
O

(c)

R1

R2

R-SeX
(a)

(b)
H-Nu

Nu *
R1
Scheme 1.1

SeR

R1
Nu-H

*

Nu
R1

*
R1

SeR

The reactivity of electrophilic selenium reagents.

Organoselenium Chemistry: Synthesis and Reactions, First Edition. Edited by Thomas Wirth.
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.


2

1 Electrophilic Selenium

In addition, electrophilic selenium reagents can be also used for the α-selenenylation
of carbonyl compounds (Scheme 1.1c) affording useful intermediates for the
synthesis of α,β-unsaturated [2] derivatives or 1,2-diketones through a selenoPummerer reaction [3].
Oxidation of selenides to the corresponding selenoxide for the synthesis of α,βunsaturated compounds represents a current topic in organic chemistry and has
been used successfully also in structurally complex product synthesis. An example
has been very recently reported in which the electrophilic selenenylation followed
by an oxidative elimination represent a crucial step in the total synthesis of heptemerone G, a diterpenoid fungi-derived with interesting antibacterial activity
(Scheme 1.2) [4].

O

OH

O

1. LDA
Me3SiCl
–78°C

O

OH

2. PhSeCl
Pyr

H

SePh
O

O

O
heptemerone G

mCPBA
NaHCO3

H

1

O

H

2

3

Scheme 1.2 Electrophilic selenium reagent in the total synthesis of heptemerone G.

The kinetic lithium enolate 1, trapped as trimethysilyl derivatives, reacts with
PhSeCl affording the selenide 2 that, after oxidation with metachloroperbenzoic
acid, is converted into the enone 3 from which the heptemerone G can be prepared
in some additional steps.
The treatment of selenides with tin hydrides, in the presence of AIBN, produces
the homolytic cleavage of the carbon–selenium bond generating a carbon radical
and opening the way for interesting radical reactions.
An elegant application was reported for the total synthesis of (+)-Samin (Scheme
1.3). The selenide 4 was subjected to radical deselenenylation conditions affording
the tetrahydrofurane derivative 5 following a 5-exo-trig radical cyclization mechanism. From 5, (+)-Samin was obtained through a few classical steps [5].
OTBDMS

OTBDMS
RO

Ar
HO

TBDMSO

Ar*Se+

O
O

Ph3SnH

O

AIBN

(+)-Samin

O

O

O
4

5

Scheme 1.3 Electrophilic selenium reagent in the total synthesis of (+)-Samin.

The main aspects of organoselenium chemistry have been described in a series of
books [6] and review articles and, in recent times, the synthesis of chiral selenium


1.1 General Introduction

electrophiles as well as their applications in asymmetric synthesis represents a
very interesting field of interests for many research groups [7].
In this chapter, we take in consideration some general aspects of the chemistry
promoted by electrophilic selenium reagents by reporting selected examples and
some more recent and innovative applications.
1.1.1
Synthesis of Electrophilic Selenium Reagents

Some phenylselenenyl derivatives such as chloride, bromide, and Nphenylselenophthalimide [8] are nowadays commercially available and represent
the most common electrophilic reagents used to introduce selenium into organic
molecules. Otherwise, in a more general procedure, very versatile precursors for
the preparation of various electrophilic selenium species are the corresponding
diselenides 6. They can be easily converted into selenenyl halides 7, 8 by treatment
with sulfuryl chloride or chlorine in hexane and bromine in tetrahydrofuran,
respectively (Scheme 1.4).
R-Se-Cl
R-Se-Se-R
6

7

R-Se-Br
8

AgY

R-Se-Y

9 Y = PF6

10 Y = SbF6
11 Y = OTs
12 Y = OTf
13 Y =

O
N
S
O

Scheme 1.4

O

Electrophilic selenium reagents.

The use of halides in synthesis often gives rise to side processes due to the nucleophilicity of the halide anions. For this reason, a series of new selenenylating
agents with nonhalide counterions have been reported.
Some of them were directly prepared starting from the appropriate selenenyl
halide with silver salts such as hexafluorophosphate 9 [9], hexafluoroantimoniate
10 [10], tolylsulfonate 11 [11], and triflate 12 [12].
This latter is probably the most commonly used electrophilic selenium reagent
even if, in many cases, the stoichiometric amount of trifluoromethanesulfonic acid
formed is not compatible with the stability of the substrates and/or of the products.
More recently, Tingoli reported a similar procedure to prepare the N-saccharin
derivatives 13 containing a sulfonamide anion that is scarcely nucleophilic and
generating saccharin that is a very weak acidic species [13].
In other cases, the electrophilic reagent can be more conveniently produced by
the in situ oxidation of 6 with several inorganic reagents: KNO3 [14], CuSO4 [15],
Ce(NH4)2(NO2)6 [16], Mn(OAc) [17], or nitrogen dioxide [18]. Among these, starting

from diphenyl diselenide, (NH4)2S2O8 [19] produces the strongly electrophilic
phenylselenenyl sulfate (PSS) 14 through a mechanism that reasonably involves
an electron transfer or an SN2 reaction. A product derived from a single electron

3


4

1 Electrophilic Selenium

transfer has been proposed also as an intermediate in the reaction of diphenyl
diselenide with 1,2-dicyanonaphthalene [20] that leads to the formation of the
phenylselenenyl cation 15 as depicted in Scheme 1.5.
R
R

Se
Se

OSO3
SO4

2

OSO3

2 R-Se-OSO3

OSO3

14

R

Se OSO3
Se SO4 2
R
R
R

Se
Se
6

CN

CN
R
R
CN

Se
+
Se

R-Se + R-Se
15

CN

Scheme 1.5 Electrophilic selenium reagents through a single electron transfer mechanism.

Some other organic oxidizing agents such as m-nitrobenzenesulfonyl peroxide
[21], (bis[trifluoroacetoxy] iodo)benzene [22], (diacethoxy iodo)benzene [23], and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [24] have been also used in
some cases. The choice of the best reagent strongly depends on the chemical
susceptibility of the substrate and its functional groups and is mainly dictated by
the requirements of the addition reaction to be carried out.
In recent years, polymer-supported reagents have also attracted interest because
they can provide attractive and practical methods for combinatorial chemistry and
solid-phase synthesis.
Polymer-supported selenium reagents represent an interesting improvement
for synthetic organic chemists because of their facile handling without the formation of toxic and odorous by-products. Some electrophilic selenium-based
approaches for solid-phase chemistry have been reported by different groups and
the use of these reagents allows easy purification and recycling of the reagent for
a next reaction. In addition, it represents useful strategies especially for constructing libraries of heterocyclic derivatives [25]. Wirth and coworkers compared the
efficiency of polystyrene, TentaGel, and mesopouros silica as a solid support for
enantioselective electrophilic addition reactions [26].


1.1 General Introduction

In a recent application, polystyrene-supported selenenylbromide was reacted
with methyl acrylate and a primary amine to afford in a one-pot procedure a resin
that has been used to prepare libraries of 2-pyridones, 1,4-diazepines, 1,4 oxazepines
[27], and other nitrogen heterocycles [28].
Even if the mild reaction conditions usually required for the selenenylation of
unsatured substrates represent an attractive aspect for this chemistry, some of
these conversions suffer the drawback that the selenium reagent must be used in

stoichiometric amounts. However, addition–elimination sequences using catalytic
amount of diselenides in the presence of an excess of oxidizing reagent have been
reported using peroxydisulfates [29] as well as hypervalent iodine compounds [30].
An electrochemical procedure to generate a selenium electrophile starting from
diphenyl diselenide involves the use of tetraethylammonium bromide as redox
catalyst and as electrolyte. The anodic oxidation of bromide to bromine initiates
the reaction producing the electrophilic phenylselenenyl bromide from the diselenide [31].
During the last 10 years, several research groups devoted their efforts to the
preparation of different optically active diselenides that have been used as electrophilic selenenylating agents precursors [32].
Since the first binaphthyl-based diselenides developed by Tomoda and Iwaoka
[33], a series of interesting chiral scaffolds have been proposed and evaluated as
chiral sources in asymmetric electrophilic addition and cyclofunctionalization
reactions. Selected examples are collected in Scheme 1.6.
R
X
R'
Se)2
16

Ph

N

NMe2
Se)2
R
17 R = H
18 R = OMe

OH

R

N

Se)2

Se)2

19

SMe

Se)2

N

Se)2

20

O

R

Scheme 1.6

23 R = H
24 R = OMe

Aromatic chiral diselenides.

i-Pr

i-Pr
S

25

i-Pr
S

tBu

Se)2
21 R = H
22 R = OMe

Ph

O
Se)2

MeO
26

5


6

1 Electrophilic Selenium

Wirth and coworkers reported that easily accessible diselenides having the general
structure 10 can be conveniently used to prepare electrophilic selenium reagents
and promote asymmetric electrophilic addition reactions [34].
Starting from readily available chiral precursors, diselenides 17–24 can be prepared in one-step syntheses consisting of ortho-lithiation, reaction with elemental
selenium and air oxidation in generally good overall yields. All these compounds
have as common characteristic the presence of heteroatom able to interact with
the nearby electrophilic selenium forcing the chiral moiety to come close to the
reaction center and leading, at the same time, to a more rigid transition state. Both
these conditions have been proposed to play an important role in the enantioselective addition to double bonds and we demonstrated that the substitution of the
heteroatom with a methylene group determines a complete lost of diastereoselectivity [35].
The existence of nonbonding interaction like that depicted in structure 27 has
been demonstrated by several authors for a large number of organochalcogen
systems using a combination of techniques such as X-ray crystallography, NMR,
DFT calculations, and has been object of a recent review [36].
The major factor contributing toward nonbonding interactions in these compounds is identified as arising from the orbital interaction.
We first described a Se. . .S interaction in the selenenyl halides 28 [37] and 29
[38] prepared starting from diselenide 23. For these reagents, we reported spectroscopic and chemical evidences for the existence of this interaction. X-ray analysis
evidenced a T-shaped coordination geometry around the selenium atom with a
distance between Se and S (2.497[7] Å for 29 and 2.344[2] Å for 28) that is significantly shorter than the sum of the van der Waals radii (3.7 Å) [35].
The shorter distance observed in 28 compared to 29 seems to indicate a stronger
interaction when the counterion is a chloride.
Comparison of nuclear Overhauser effect (n.O.e.) of arylselenyl halides 28 and
29 to the corresponding aryl methylselenide 30 proves a greater conformational
rigidity reasonably deriving from the Se...S interaction atom, which is not only
present in the crystal form but also in CDCl3 solution (Scheme 1.7).

n.O.e.

Me H

Me H

Se

Se

27

H Me H

S

Y
X

Me

n.O.e.

X

δ

δ

28 X = Cl
29 X = Br

Scheme 1.7 Selenium–heteroatom nonbonding interaction.

S
Se
Me

30

Me


1.1 General Introduction

Organoselenium compounds exhibiting intramolecular Se...N and Se...O interactions are particularly interesting since these interactions are expected to modulate
the biological activity of the selenium compounds. Selenocyanates are commonly
used as intermediates in the synthesis of diorganoselenates and are investigated
as antitumor drugs. Jones, Mugesh, and du-Mont determined the X-ray structure
of methyl-2-selenocyanatobenzoate in which the Se...O contact is sensibly shorter
in comparison with the Se...N one [39].
More recently starting from (S)-ethyllactate and (−)-(1R)-para-toluensulfinate,
Wirth and coworkers reported the syntheses of two new optically active sulfoxide
containing diselenides 25 and 26 [40]. These were used to prepare new selenium
electrophiles that have been successfully used for stereoselective functionalization
of alkenes.
X-ray comparison between diselenides 25 and 22 evidences that the oxygen
attached to the chiral center in compound 25 has no interaction with the selenium
atom in the solid state.
Convenient methods for the synthesis of optically active nonfunctionalized or
functionalized selenium reagents from mono- and bicyclic terpenes have also been

developed in the recent period; Scheme 1.8 summarizes some of the most representative structures (31–37) [41].

OH

OC6F5

SeOTf

SeOTf
SeX

SeOTf

O

31 X = Cl
32 X = Br
33 X = OTf
34 X = OSO3H
Scheme 1.8

35

36

37

Terpene-based electrophilc selenium reagents.

In some of these cases, X-ray analysis and DFT calculations showed the existence

of an intramolecular heteroatom-selenium interaction, which seems to be an
important factor for the chirality transfer in the transition state of the addition
reactions.
Concerning this class of diselenides, it is possible to generalize that the facial
selectivity produced by the aliphatic electrophilic selenium reagent is usually lower
in respect to those obtained using an aromatic core.
1.1.2
Reactivity and Properties

In many aspects, the properties of organoselenium compounds are similar to
those of the better-known sulfur analogues. However, the introduction of the

7


8

1 Electrophilic Selenium

heteroatom, the manipulation of the resulting molecules, and, in particular,
the removal of the selenium-containing functions occurs under much simpler
and milder conditions than those required for the corresponding sulfur
compounds.
The reaction of selenium electrophiles with alkenes consists in a stereospecific
anti-addition that involves the initial formation of a seleniranium ion intermediate.
This is rapidly opened in the presence of a nucleophile that can be external,
leading to the addition products, or internal, giving the corresponding cyclized
derivative.
The intermediate seleniranium ion can be ring-opened to afford two different
regioisomers. The regiochemistry usually follows the thermodynamically favored

Markovnikov orientation even if examples of anti-Markovnikov addition were
reported, as a consequence of the coordinating effect of a hydroxyl group in the
allylic position.
When the reagent is chiral, a differentiation between the two faces of unsymmetrically substituted alkenes can be observed (Scheme 1.9). Depending on the
reaction conditions, the formation of the seleniranium ion can be reversible and
at low temperatures the reaction is under kinetic control.

*R
Se
H

H

H
R
*R Se X

H

R
38

39

H
R

H
H
Se

*R

H
H

40

H
R
MeO
NuH

SeR*

41
MeO
H
R

SeR*
42

Scheme 1.9 Stereoselective addition.

Steric and electronic effects control the formation of the diastereoisomeric intermediates 39 and 40 and the ratio reflects the different stability between them.
Subsequent reaction with a nucleophile affords the diastereoisomers 41 and 42
derived from the stereospecific ring opening of 39 and 40, respectively.
The presence of an equilibrium between the starting materials and the
seleniranium intermediates has been chemically demonstrated starting from

the hydroxyselenides 43 and 44, easily obtained by the nucleophilic ring
opening of the corresponding optically pure (R)- and (S)-styrene epoxide (Scheme
1.10) [42].


1.1 General Introduction

H
O
SeAr*

Ph
H

CF3SO3H

OH

Ph
H

43

Se

MeOH

H
H

SeAr*

Ph
H
OMe

45

Ph

47

+ Ar*Se+

OH

Ar* =

H
O
Ar*Se

Ph
H
OH
44

Scheme 1.10

CF3SO3H

H
H

Se

Ph
H

MeOH

46

Ar*Se

Ph
H
OMe
48

Mechanism of the enantioselective addition reactions.

Treatment of 43 and 44 with trifluoromethane sulfonic acid generates selectively
the corresponding seleniranium ions 45 and 46 according to an intramolecular
SN2 displacement of a molecule of water. In the case of 43, only the seleniranium
ion 45 is formed and the subsequent treatment with methanol affords the adduct
47 corresponding to the Re-attack of the selenium electrophile to the styrene
double bond. Ab initio calculations on the stability of the intermediates indicated
that 45 is more stable than 46.
Under the same experimental conditions, the hydroxyselenide 44 produces the

less-stable seleniranium ion 46. After reaction with methanol, the formation of
both isomers 47 and 48 in a 3 : 1 ratio clearly indicates a decomplexation–
complexation mechanism that is involved in the above-mentioned equilibrium [43].
Even if the central tenet of this class of reaction is the formation of the high
reactive seleniranium ions, only few examples were reported in which they have
been independently synthesized and analyzed. Many studies have been performed
with the assumption that the putative intermediate seleniranium ions are responsible for the observed products.

9


10

1 Electrophilic Selenium

After seminal computational studies in which the enthalpic activation barrier
for direct, intramolecular thiiranium–olefin and seleniranium–olefin transfer were
compared for alkylthiiranium, arylthiiranium, and arylseleniranium ions [44]
Denmark et al. reported a crossover experiment as the first direct observation of
the transfer of a selenonium cation from one olefin to another [45].
On the basis of these observations, the authors suggest that the rapid olefin-toolefin transfer represents one of the most likely pathways for racemization of the
enantiomerically enriched seleniranium ions (Scheme 1.11).

SbF6
H
R

Ph
Se

Ph
SbF6
Se
R
H

R
R

Scheme 1.11 Crossover experiment.

Our recent NMR investigations on the haloselenenylation of styrene derivatives
[46], according to other evidence previously reported by Garrat [47], demonstrate
the presence of a more complicated equilibrium when the nucleophile is chlorine
or a bromine. The initial formation of the Markovnicov’s adduct is very fast and
rapidly reaches the equilibrium with the anti-Markovnicov regioisomer. NMR
analysis of the equilibrium mixture, combined with kinetic investigation, evidenced the presence of two different intermediates in the formation of the
Markovnicov and anti-Markovnicov product that were assigned to the episelenurane 49 and seleniranium ion 50, respectively (Scheme 1.12).

δ 6.80 ppm

δ 5.10 ppm

δ 6.05 ppm

δ 4.65 ppm

δ 5.85 ppm

Cl

H

H

Ph + H
PhSeCl

Cl
H
Ph

Ph
Se

H
H

SePh

H
Ph
Cl

fast

M

49

ROH

Ph

SePh

RO

Scheme 1.12 Mechanism of the chloroselenenylation reaction.

H
Ph

Ph
Se

50

H
H

H

Cl

Ph
slow

SePh
aM

1.2 Addition Reactions to Double Bonds

When the anion is chloride, the treatment of the above-described equilibrium
mixture with an oxygen-containing nucleophile such as methanol affords quantitatively the Markovnikov alkoxyselenide.
After 60 years since the first stereospecific selenoaddition reaction, some mechanistic aspects are still under investigation and a clear explanation of the species
involved in these reactions should represent an important aspect in the development of more efficient and selective reactions.
Electrophilic selenenylation of dienes has not been extensively used and investigated. The first example of conjugated diene selenenylation reported that the
reaction with PhSeCl gives either an allylic alcohol or an enone depending on the
experimental procedure [48].
More recently, treatment of dienes with aryl selenenamides in the presence of
phosphorus(V)oxyhalides has been proposed as a useful method to effect
the 1,4-haloselenenylation of conjugated dienes. Similar experimental conditions applied to nonconjugated dienes afforded only mono-haloselenides (Scheme
1.13) [49].

PhSeNEt2
POX3

X

SePh
X = Br, Cl

Scheme 1.13

Conjugated electrophilic addition to dienes.

Furthermore, the reaction of divinylsulfide with selenium dibromide prepared
from selenium and bromine in carbon tetrachloride gives, in near quantitative
yield, the six-membered heterocyclic compound 2,6-dibromo-1,4-thiaselano that
underwent spontaneous rearrangement to a five-membered thioselenolanderivative [50].

1.2
Addition Reactions to Double Bonds
1.2.1
Addition Reaction Involving Oxygen-Centered Nucleophiles

Addition reactions to double bonds promoted by electrophilic selenium reagents
are usually carried out in the presence of a solvent that acts as external nucleophile.
Simple and efficient procedures to introduce oxygen and nitrogen nucleophiles
have been reported and are currently employed in the functionalization of olefins.
In the first case, the process is named oxyselenenylation and leads to the introduction of hydroxy-, alkoxy-, or acetoxy groups.
PhSeBr and acetic acid in the presence of acetic anhydride and KNO3 promote
the acetoxyselenenylation of alkenes, but this methodology suffers of considerably

11


12

1 Electrophilic Selenium

low regioselectivity in the case of terminal olefins [51]. An alternative and more
efficient procedure involves the oxidation of diphenyl diselenide with (diacetoxy
iodo) benzene in acetonitrile [23].
Currently the most relevant developments in this field of research concern
the use of optically pure electrophilic reagents in the asymmetric synthesis of
alkoxy- and hydroxy derivatives. Methoxyselenenylation of styrene has been
used by several groups as a test reaction to compare the diastereoselectivity
induced by different chiral selenenylating reagents and to compare the effect of
the different experimental conditions as well as the structural features of the

reagents.
Selected examples are collected in Table 1.1 and, even if in all the cases the
diastereoselectivity is usually good, some general considerations on the ability of
various electrophilic reagents to transfer the chirality to the newly generated center
can be attempted.
Considering the above-mentioned role of the heteroatom on coordinating to the
electrophilic selenium atom, from the data reported in Table 1.1, sulfur atom
(entries 10–11), in respect to oxygen and nitrogen atom (entries 1,2,8,9), seems to
be more effective, leading to higher diasteromeric excesses at higher reaction
temperatures. The results reported in entries 3–7 also suggest that the presence
of a second chiral center could produce a positive effect in terms of diastereoselectivity. Using the electrophilic reagent derived from the oxidation of diselenide
20, a match/mismatch effect related to the relative configuration of the two chiral
centers has been described [52].
As shown in entries 8–9 and 10–11 reagents, with a methoxy group in the orthoposition to the selenium electrophile shows higher selectivities than unsubstituted
one. Probably this arises from a different coordination of the side chain, even if
detailed calculations [53] showed that the strength of coordination does not correlate with the trend of the experimentally observed selectivities. Probably the situation is different when the chiral moiety is a sulfoxide. In this case in fact, as
already reported, no selenium heteroatom interaction was observed and the
methoxy selenenylation of styrene proceeds with moderate diasteroselectivity (d.r.
6 : 1). For this reagent, the introduction of a substituent (MeO-) in the orthoposition to the electrophilic selenium atom dramatically reduces the yield (24%)
as well as the diasteromeric excess (2 : 1).
The information gained from these experiments can be used as preliminary
indications even if a strong dependence on the alkene structure as well as on the
nucleophile and the solvent must be taken in consideration.
As an illustrative example when the conditions reported on entry 12 were applied
to effect the methoxyselenenylation of 2-chlorostyrene or β-methyl styrene,
the selectivity increases affording a diasteromeric ratios of 11 : 1 in dichloromethane. Other solvents such as THF, diethyl ether, and chloroform give considerably
lower selectivity. Concerning the nucleophile, slight differences in selectivity
have been observed using different alcohols, and this suggests that probably
different nucleophiles coordinate in different ways to the selenium electrophile.
Using the selenenyl triflates generated from oxygen-containing diselenides (21,