| Advances
in Organic Synthesis:
Modern Organofluorine Chemistry-Synthetic Aspects
ISBN: 90-77527-08-7
Advances in Organic Synthesis:
Modern Organofluorine Chemistry-Synthetic Aspects
Volume 2, 2006
Contents
Foreword Pp. iv-vi
Editorial Pp.
1
Electrophilic Fluorination with Elemental Fluorine
and Reagents Derived from it Pp. 3
Shlomo Rozen
[Abstract]
The Chemistry of Interhalogen Monofluorides
Pp. 43
Dale F. Shellhamer and Victor L. Heasley
[Abstract]
Fluorination Using Hypervalent Halogen Fluorides Pp.
49
Shoji Hara
[Abstract]
Application of Xenon Difluoride in Synthesis Pp.
61-
Barbara Zajc
[Abstract]
N-Fluoropyridinium Salts, Synthesis and Fluorination
Chemistry Pp. 159
Teruo Umemoto
[Abstract]
Onium-Poly Hydrogen Fluorides as Acid Catalysts, Ionic
Liquids and Fluorinating Agents in Organic Reactions
Pp. 183
V. Prakash Reddy, G.K. Surya Prakash and George A. Olah
[Abstract]
N-Fluoro-1,4-Diazoniabicyclo[2.2.2]octane Dication
Salts; Efficient Fluorinating Agents and Functionalization
Mediators for Organic Compounds Pp. 213
Stojan Stavber and Marko Zupan
[Abstract]
α,α-Fluoroalkyl(Alkenyl)
Amino Reagents (FAR) - Recent Development Pp. 269
Viacheslav A. Petrov
[Abstract]
DAST and Deoxofluor Mediated Nucleophilic Fluorination
Reactions of Organic Compounds Pp. 291
Rajendra P. Singh, Dayal T. Meshri and Jean’ne M.
Shreeve
[Abstract]
Synthetic Approaches to gem-Difluoromethylene
Compounds Pp. 327
V. Prakash Reddy, Meher Perambuduru and Ramesh Alleti
[Abstract]
Fluorinated Polycyclic Aromatic Hydrocarbons(PAHs)
and Heterocyclic Aromatic Hydrocarbons (Hetero-PAHs); Synthesis
and Utility Pp. 353
Takao Okazaki and Kenneth K. Laali
[Abstract]
Fluorinated Carbohydrates Pp. 381
Martin Hein and Ralf Miethchen
[Abstract]
Enantioselective Electrophilic Fluorination: The Complete
Story Pp. 431
C. Audouard, J.-A. Ma and D. Cahard
[Abstract]
Synthesis of Chiral Fluorinated Materials via
Biotransformation Pp. 463
Tomoya Kitazume, Tomoko Matsuda and Kaoru Nakamura
[Abstract]
Recent Advances in the Chemistry of Fluorine- Containing
π-Allylmetal
and Allenylmetal Complexes Pp.491
Tsutomu Konno and Takashi Ishihara
[Abstract]
Synthetic Utility of Fluorinated β-Keto-Phosphonium
Salts, -Phosphonates and Related Compounds Pp. 523
Yanchang Shen
[Abstract]
Abstracts
[Back to top]
Foreward
Academic and industrial fluorine chemistry has experienced
over the past decade or so a shift in emphasis from research
on highly fluorinated materials to research on lightly fluorinated
compounds. This in large part is because of the significant
commercial impact of new fluorine-containing pharmaceuticals
and agrochemicals coupled with the overall optimism about
opportunities for sustained growth of fluorinated biologically
active materials. More recently, a growing concern about the
environmental fate of some highly fluorinated materials also
has been a contributing factor. A consequence of this change
in emphasis is that many of the centers of specialized excellence
in traditional fluorine chemistry are much less prominent
today, or they have disappeared altogether. Witness, for example,
the dramatic change in industrial and academic fluorine chemistry
in the UK over the past couple decades, and the same trend
is evident in the US and Russia/CIS. It should come as no
surprise, therefore, that synthetic fluorine chemistry is
increasingly being practiced by chemists who would not consider
themselves to be fluorine chemists. These chemists are mainly
interested in useful, practical methods for introducing one
or two fluorines, or a trifluoromethyl group, at specific
sites in a molecule. Commercially available fluorinating agents
or fluorinated starting materials and methods that do not
require specialized laboratory equipment or handling procedures
are of prime importance to these practitioners. This new volume
for the Advances in Organic Synthesis series edited
by Professor Kenneth Laali admirably fulfills most of these
needs.
An obvious strength of this volume is that its sixteen chapters
were written by experts who either invented the various fluorinating
agents and methods or helped scope the chemistry and applications.
The coverage is intentionally not historical but rather contemporary
where most of the literature citations are less than ten years
old. This captures the modern developments and applications,
but the non-expert may find the need to refer to earlier literature
for a more comprehensive perspective.
The volume is a tour de force on electrophilic fluorinating
agents and their chemistry, leading off with selective fluorinations
using elemental fluorine and mainly acetyl hypofluorite, which
is easily and inexpensively generated from sodium acetate
and fluorine. This methodology more than any other covered
in this volume does require special care and equipment for
handling elemental fluorine, but this should not be a deterrent
since reliably safe procedures have been developed and published,
for example, in Organic Syntheses. The next two chapters
cover the use of interhalogen monofluorides, mainly BrF and
IF generated in situ from the halogen and elemental
fluorine, and their hypervalent halogen fluoride counterparts
BrF3 and IF5, plus ArIF2,
which is the most stable class of hypervalent halogen fluorides.
The following chapter, the longest one with 97 pages and 262
references, is an Organic Reactions style survey
of contemporary reactions of xenon difluoride. The diverse
applications of XeF2 in synthesis are truly remarkable,
although in most cases alternative less-expensive fluorinating
agents do as well or better. An exception and an underutilized
method is the “fluoro-Hunsdiecker” reaction where
XeF2 cleanly converts primary or tertiary alkyl
carboxylic acids to alkyl fluorides in good to excellent yields.
Olah’s pyridinium and dimethyl ether polyhydrogen fluorides,
Umemoto’s N-fluoropyridinium salts, and the N-fluoro-1,4-diazoniabicyclo[2.2.2]octane
dication salts (SelectfluorTM, AccufluorTM),
which are among today’s most popular and versatile reagents
for selective electrophilic fluorinations, are thoroughly
reviewed in the last three chapters on electrophilic agents.
A particular highlight of this volume is the complementary
Chapter 13 that reviews enantioselective electrophilic fluorinations
employing various optically active N-F sulfonamides and sultams,
and N-fluoroamine salts of cinchona alkaloids (generated by
transfer fluorination of the alkaloids with SelectfluorTM).
Enantioselective fluorinations with achiral N-F reagents catalyzed
by chiral organometallic complexes also are described. This
is state-of-the art methodology for direct chiral fluorinations,
and although there remains room for improvement in the observed
ee’s, its importance to the increasing demand for optically
pure pharmaceuticals and agrochemicals cannot be overemphasized.
Recent developments in nucleophilic fluorinations of primarily
alcohols and carbonyl compounds and their derivatives mediated
by the classical FAR (fluoroalkyl or –alkenyl-amino
reagents) and DAST (diethylaminosulfur trifluoride) reagent
and its modern analog Deoxofluor®, are nicely reviewed
in Chapters 8 and 9. The former updates the use of the familiar
Yarovenko-Raksha reagent, CFHClCF2N(C2H5)2,
and Ishikawa’s reagent, CF3CFH CF2N(C2H5)2/CF3CF=CFN(C2H5)2,
and introduces a new, relatively inexpensive reagent CF2HCF2N(CH3)2
that is easily made from tetrafluoroethylene and dimethylamine.
Altho-ugh it is not commercially available yet, it promises
to be superior to the traditional FAR offerings.
The following chapters on the synthesis of gem-difluoromethylene
compounds, lightly fluorinated polycyclic aromatic hydrocarbons,
and fluorinated carbohydrates illustrate many useful applications
for several of the electrophilic and nucleophilic reagents
from the preceding chapters. These reviews describe and sometimes
critically compare the available options for introducing fluorine,
but the reader likely will have to consult the primary literature
cited to decide on the best choice to accomplish the desired
transformation.
The chapter on synthesis of chiral fluorinated materials
via biotransformations is thematically rather out
of place with the rest of the volume since it does not deal
with fluorination reactions per se but rather covers
enantioselective or diastereoselective reactions of fluorinated
molecules promoted by biocatalysts, including lipase-catalyzed
hydrolyses (kinetic resolutions) of fluorinated esters to
chiral alcohols, enantioselective acetylations of trifluoromethyl-containing
alcohols, and dead-cell promoted asymmetric reductions of
trifluoromethylated ketones. Nonetheless, these green processes
represent very useful methods for synthesizing chiral building
blocks and products that should be part of the modern chemist’s
arsenal of synthetic methods.
It is unrealistic to expect that this single volume can cover
all of the significant advances in synthetic fluorine chemistry.
Although Rupert’s reagent, (CH3)3SiCF3,
is briefly described in a couple of chapters, it along with
other nucleophilic trifluoromethylating reagents warrant more
extensive coverage. Absent are modern sources of truly anhydrous
fluoride ion, as well as the new mild reagents and procedures
to generate difluorcarbene for the synthesis of fluorinated
cyclopropanes and difluoromethyl ethers, for example. One
would hope that Professor Laali or an equally competent editor
has plans for a second volume that will include these omissions
and update other advances in synthetic organofluorine chemistry.
In summary, this book is a valuable addition to the repertoire
of modern synthetic organofluorine chemistry and an excellent
source of information for synthetic chemists interested in
selective fluorination methods and fluorinated building blocks.
Bruce E. Smart
Regional Editor
Journal of Fluorine Chemistry
DuPont Central Research & Development
Wilmington, DE
USA
[Back to top]
Editorial
I was first introduced to fluorine chemistry over 30 years
ago as a PhD student at Manchester University (with Robert
Hazseldine). My involvement and interest in organofluorine
chemistry grew during my postdoctoral years, in particular
while in George Olah’s laboratory. Over the years, my
research activities and interests branched out into other
areas of mechanistic and synthetic chemistry, but I continued
to maintain serious interest in fluorine chemistry and managed
to keep some research activity going in the field whenever
possible. Today’s synthetic organofluorine chemists
have at their disposal a wide range of both electrophilic
and nucleophilic fluorinating agents whose reactivities/ selectivites
may be tuned to the task at hand. Further exciting new developments
include the synthesis and utility of chiral electrophilic
fluorinating agents, application of transition metal catalysis
to enantioselective electrophilic fluorination, biotransformations
for synthesis of chiral fluorinated materials, and the emergence
of “tamed” fluorination under “green”
conditions. Whether by improving on the more traditional reagents
or by developing newer, more task-specific agents, the repertoire
of synthetic organofluorine chemistry has greatly expanded
during the last decade; and these advances are bound to create
greater diversity in terms of structural, physical, and biological
properties.
Early in 2004 I received an invitation from Dr. Atta-ur-Rahman,
Editor for “Advances in Organic Synthesis”,
to act as Executive Guest Editor for a volume within this
series, on a topic of my own choice. I had contemplated for
some time to edit and/or co-write a volume focusing on selected
aspects of organofluorine chemistry, with an emphasis on recent
advances. The invitation signaled an opportunity and created
the impetus for me to begin the task of getting the project
off the ground. I have been most fortunate that a large group
of active scientists and leading researchers in the field
expressed interest in this project and agreed to contribute.
As editor, my goal has been to oversee the creation of a series
of focused and self-contained chapters that summarize and
put into perspective (preferably in a comparative fashion)
the more recent advances in the field. The collection should
serve as a valuable guiding source on the reactivity trends,
efficacy, and scope which are illustrated via examples. It
is gratifying to see that the final outcome far exceeded my
initial expectations.
Comment on the Order of Chapters
In organizing this multi-authored volume, I felt it would
be most appropriate that the first four chapters deal with
recent developments involving the well established, older,
reagents (such as elemental fluorine, interhalogen monofluorides,
hypervalent halogen mono-fluorides, and xenon difluoride).
The ensuing nine chapters delineate/describe/outline the progress
in synthetic fluorination chemistry involving the more recently
developed electrophilic and nucleophilic reagents (such as
N-fluoropyridinium, onium polyhydrogen fluorides, Selecfluor,
the chiral NF compounds, DAST and Deoxofluor), while the last
three chapters focus on enzymatic synthesis and the organometallic/heteroatom
chemistry aspects.+
Chapter Summaries:
The volume brings together sixteen contributions by experts
from seven countries:
Chapter 1. (by S. Rozen) describes the regio- and stereospecific
electrophilic fluorination of tertiary centers and double
bonds employing tamed F2, while also illustrating some new
chemistry involving acetyl hypofluorite.
Chapter 2. (by D. Shellhammer and V. Heasley) focuses on
in situ generation and the scope of fluorination involving
interhalogen monofluorides XF (X = Cl, Br, I).
Chapter 3. (by S. Hara) deals with the characteristic features
and representative reactions involving hypervalent halogen
fluorides BrF3, IF5 and ArIF2.
Chapter 4. (by B. Zajc) provides a comprehensive coverage
of the organofluorine chemistry of XeF2 with emphasis on the
more recent studies.
Chapter 5. (by T. Umemoto) summarizes the synthetic routes
to a variety of N-Fluoropyridinium salts with variable fluorinating
power, illustrating their synthetic scope.
Chapter 6. (by V.P. Reddy, G.K.S. Prakash and G.A. Olah)
is devoted to onium polyhydrogen fluorides and their fluorination
chemistry.
Chapter 7. (by S. Stavber and M. Zupan) focuses on NF dication
salts as efficient electrophilic fluorinating agents as well
as functionalization mediators.
Chapter 8. (by V.A. Petrov) reviews the synthetic methods
and utility of “FAR” reagents.
Chapter 9. (by R.P. Singh, D.T. Meshri and J.M. Shreeve)
is devoted to nucleophilic fluorination with DAST and Deoxofluor.
Chapter 10. (by V.P. Reddy, M. Perambuduru and R. Alleti)
reviews the available methods for synthesis of gem-difluoromethylene
compounds.
Chapter 11. (by T. Okazaki and K.K. Laali) focuses on the
synthesis and utility of fluorinated PAHs.
Chapter 12 (by M. Hein and R. Miethchen) provides a review
of the methods that have so far been used in carbohydrate
chemistry to synthesize fluorinated sugars and examines the
utility of glycosyl fluorides in chemical and enzymatic glycosylations.
Chapter 13. (by C. Audouard, J.-M. Ma and D. Cahard) reviews
and evaluates recent progress in enantioselective electrophilic
fluorination.
Chapter 14. (by T. Kitazume, T. Matsuda and K. Nakamura)
demonstrates how chiral fluorinated compounds can by prepared
enzymatically.
Chapter 15. (by T. Konno and T. Ishihara) is devoted to fluorinated
pi-allyl and pi-allenyl metal complexes and their chemistry.
Chapter 16. (by Y. Shen) concentrates on fluorinated beta-keto-phosphonium
salts and –phosphonates and their efficacy in synthesis.
Kenneth K. Laali (Executive Guest Editor)
Department of Chemistry
Kent State University
Kent
OH 44242
USA
E-mail: Klaali@kent.edu
[Back to top]
Electrophilic Fluorination with Elemental Fluorine
and Reagents Derived from it
Shlomo Rozen
Elemental fluorine is a highly reactive reagent which could
destroy almost any organic compound or perfluorinate it under
controlled conditions. However, under the right set of conditions,
it may act as an electrophile and as such, it can be a powerful
electrophile indeed. This chapter describes some regio- and
stereospecific electrophilic fluorination at saturated tertiary
sp3 centers, which are usually very unreactive
and cannot participate in specific organic reactions. It was
concluded that the higher the hybridization on p
of these centers, the better is the outcome of the reaction.
In many cases, the substitution of such tertiary hydrogen
takes place in yields of 70% and more. Such fluorinations,
which were carried out on a wide variety of organic compounds,
provide an excellent opportunity for dehydrofluorination reactions
to form double bonds and hence are considered to enable functionalization
of “impossible sites” in organic molecules. Elemental
fluorine was also used for fluorination of double bonds, in
a syn mode, replacing the old and inefficient method
of reacting olefins with Pb(OAc)4 and HF. Acetyl
hypofluorite is easily and readily made from sodium acetate
and F2. It proved to be a very useful reagent for
fluorination of activated aromatic compounds, for addition
across double bonds, in order to synthesize biologically important
fluorine containing derivatives, for constructing α-fluoro
carbonyl and ether derivatives and for use in Positron Emitting
Tomography (PET).
[Back to top]
The Chemistry of Interhalogen Monofluorides
Dale F. Shellhamer and Victor L. Heasley
Interhalogen monofluorides (XF; X=Cl, Br or I) generated
in situ from hypohalites or N-halosuccinimides and
a source of fluoride ion are “sluggish” electrophiles.
XF reagents formed from F2 gas and a halogen source
(ie: ClF3, Br2, I2,) are
very reactive electrophiles. This wide range of reactivity
allows the synthetic chemist to carry out reactions on electron-rich
or electron-deficient substrates. Halofluorinations of alkenes,
alkynes and electrophilic aromatic substitution without catalyst
are reviewed. Synthesis of geminal difluorides from hydrazones
is also presented.
[Back to top]
Fluorination Using Hypervalent Halogen Fluorides
Shoji Hara
Among various hypervalent halogen fluorides, BrF3,
IF5, and ArIF2 have been successfully
used to introduce fluorine atoms into molecules selectively.
Characteristic features and representative fluorination reactions
involving these reagents are shown.
[Back to top]
Application of Xenon Difluoride in Synthesis
Barbara Zajc
Reactions of xenon difluoride (XeF2) with alkanes,
carbanions, alkenes and alkynes, aromatic and heteroaromatic
compounds, carbonyl derivatives, benzyl alcohols, organic
iodo compounds, organosulfur, selenium, tellurium, phosphorus,
antimony, bismuth, silicon and tin compounds are reviewed.
Greater emphasis has been placed on the synthetic details
and utility. For each functional group, the most recent papers
describing the reactivity of XeF2 are discussed
in more detail. Research progress achieved during the period
1999-2004 is reviewed rather comprehensively. Also included
are the syntheses of compounds containing C-Xe(II) bond employing
xenon difluoride and its derivatives.
[Back to top]
N-Fluoropyridinium Salts, Synthesis and Fluorination
Chemistry
Teruo Umemoto
Synthesis of N-fluoropyridinium salts and their
synthetic application are discussed. Various types of stable
N-fluoropyridinium salts are synthesized from unsubstituted
and substituted pyridines and acids, their salts, silyl esters
or Lewis acids by reaction with F2 diluted with
N2. The N-fluoropyridinium salts are particularly
useful as electrophilic fluorinating agents toward organic
compounds in terms of easy handling and variability of fluorinating
power and selectivity. This variability makes selective fluorination
of a wide range of organic compounds differing in reactivity
possible. Three classes of power- and selectivity-variable
fluorinating agents, non-counterion-bound N-fluoropyridinium
salt series, counterion-bound N-fluoropyridinium-sulfonate
series, and dimeric N,N’-difluorobipyridinium
salt series, were developed and successfully utilized for
selective fluorinations of various substrates. As another
synthetic application, a novel base-initiated reaction of
N-fluoropyridinium salts producing α-fluoropyridines
is discussed.
[Back to top]
Onium-Poly Hydrogen Fluorides as Acid Catalysts, Ionic
Liquids and Fluorinating Agents in Organic Reactions
V. Prakash Reddy, G.K. Surya Prakash and George A. Olah
Onium-poly hydrogen fluorides, the amine or ether complexes
of hydrogen fluoride, have been widely used as fluorinating
agents in organic synthesis. A variety of fluorination reactions
involving electrophilic additions to unsaturated compounds,
nucleophilic substitutions, desulfurative fluorinations, strained
ring-opening fluorinations, and deprotection of acetal, ketal
and O-silyl ethers could be achieved with these onium-poly
hydrogen fluorides. Fluorination of alcohols could be achieved
under either SN1 or SN2 conditions,
depending on the reagent choice and reaction conditions. Deaminative
fluorinations using these reagents provide convenient access
to chiral α-fluoro
acids. As strong Bronsted acids they can be used to catalyze
the electrophilic alkylation of alkanes with alkenes to give
high-octane gasoline-range hydrocarbons. They also serve as
high dielectric constant ionic liquid media. In addition,
polymer-supported onium polyhydrogen fluorides such as polyvinylpyridinium
polyhydrogen fluoride (PVPHF) have been developed as convenient
alternative reagents, which could be recovered and recycled
for further use.
[Back to top]
N-Fluoro-1,4-Diazoniabicyclo[2.2.2]octane Dication
Salts; Efficient Fluorinating Agents and Functionalization
Mediators for Organic Compounds
Stojan Stavber and Marko Zupan
Fluorination of organic compounds using the most representative
reagents from the group of N-fluoro-1,4-diazoniabicyclo[2.2.2]octane
dication salts is reviewed. Data dealing with selective fluorofunctionalization
of aro-matics, alkenes, alkynes, saturated hydrocarbons, organometallics,
and organic molecules bearing nitrogen, sulfur, phosphorus,
silicon or carbonyl containing functional groups with SelectfluorTM
F-TEDA-BF4 1 (1-chloro-methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetra-fluoroborate)), Ac-cufluorTM NFTh
2 (1-fluoro-4-hydroxy-1,4-diazoniabicyclo
[2.2.2]octane bis(tetrafluoroborate)) or bis(NF)-TEDA-BF4
3 (1,4-difluoro-1,4-diazoniabi-cyclo[2.2.2]octane
bis (tetrafluoroborate)) are systematically collected and
comparatively evaluated. Fluorination of potentially bioactive
organic mole-cules (steroids, pyrimidine bases, glycols …)
with the above mentioned reagents is particularly emphasized.
Functionalization of organic compounds mediated by SelectfluorTMF-TEDA-BF4
is briefly reviewed.
[Back to top]
α,α-Fluoroalkyl(Alkenyl)
Amino Reagents (FAR) - Recent Development
Viacheslav A. Petrov
The review provides an update on the synthesis α-Fluoroalkyl
(alkenyl)Amino Reagents (FAR) and their application for conversion
of hydroxy- and carbonyl compounds into the corresponding
fluorides.
The first part of the review contains data on the synthesis
of FAR by addition of secondary amines to fluoroolefins, halogen
exchange reactions, fluorination of carbonyl and thiocarbonyl
compounds, as well as via electron transfer reactions
of polyfluorinated bromoalkanes. The second section summarizes
data on the physical properties, handling and storage of FAR.
The third section of the review discusses the reactions of
FAR with primary, secondary, tertiary, and cyclic alcohols,
as well as sugars, carbonyl and thiocarbonyl compounds, and
acids, which have been developed during the past decade. Recent
results on the chemical transformations of FAR other than
fluorination reactions are collected in the final section
of the review.
[Back to top]
DAST and Deoxofluor Mediated Nucleophilic Fluorination
Reactions of Organic Compounds
Rajendra P. Singh, Dayal T. Meshri and Jean’ne M.
Shreeve
Organofluorine compounds have had a marked impact on medicinal
and agrochemical fields and the number of applications continues
to grow. These significant contributions arise from the unique
changes that occur in the physical and chemical properties
of ordinary organic compounds wrought by the presence of fluorine
or a fluorine-containing group. Among a large number of methods
available to introduce fluorine into organic compounds, the
nucleophilic replacement of oxygen with fluorine is one of
the most practical ways. Although there are numerous fluorinating
reagents available, diethylaminosulfur trifluoride (DAST)
and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor)
often are the reagents of choice. Organic compounds containing
oxygen in hydroxyl and carbonyl groups are readily converted
into their corresponding fluorinated analogues by the introduction
of one or two fluorine atoms, respectively, through the use
of these reagents. In some cases, depending upon the compound
and the reaction conditions, a very useful nonfluorinated
product can also be produced. Our interest in applying various
synthetic methods to incorporate fluorine or a fluorinated
group into a large variety of organic compounds encouraged
us to summarize the recent chemistry of DAST and Deoxofluor.
[Back to top]
Synthetic Approaches to gem-Difluoromethylene
Compounds
V. Prakash Reddy, Meher Perambuduru and Ramesh Alleti
Organic compounds containing a gem-difluoromethylene group
are useful for a variety of applications in biological, pharmaceutical
and materials chemistry. Over the years a variety of synthetic
protocols for this class of compounds have been developed.
They can be prepared from their corresponding carbonyl compounds
or through various derivatives such as oximes and dithiolanes,
electrophilic fluorinations of unsaturated compounds and enolates,
free-radical additions of halodifluoroalkanes to olefins,
and nucleophilic difluoromethylations of aldehydes and ketones.
Other approaches involve methods that utilize fluorinated
compounds as synthons. Enantioselective gem-difluorination
reactions have emerged employing chiral auxiliaries such as
sulfinimines, and chiral Lewis acid catalysts. This review
focuses on the recent developments in this area, emphasizing
the synthetic methods that can be conveniently carried out
and are potentially broadly applicable.
[Back to top]
Fluorinated Polycyclic Aromatic Hydrocarbons(PAHs)
and Heterocyclic Aromatic Hydrocarbons (Hetero-PAHs); Synthesis
and Utility
Takao Okazaki and Kenneth K. Laali
Fluorinated aromatic compounds are in high demand in a number
of fields including synthetic chemistry, molecular recognition/host-guest
chemistry, materials chemistry, as well in biology and pharmaceuticals.
Recent progress in the synthesis of fluorinated polycyclic
hydrocarbons and heterocyclic hydrocarbons is reviewed.
[Back to top]
Fluorinated Carbohydrates
Martin Hein and Ralf Miethchen
The review demonstrates how carbohydrate chemists exploit
the two fundamental strategies of organofluorine chemistry;
(a) direct introduction of fluorine atom(s) or fluorinated
groups by appropriate reagents in a late synthetic step, or
(b) linking of fluorine-containing “building blocks“
with various reactants (including enantioselective approaches),
in order to synthesize a wide variety of fluorinated sugars.
Numerous representative examples of these strategies are provided
and discussed. Also included are a number of recommended experimental
procedures (provided at the end of sections 1-3). In addition
to reviewing various convenient fluorinating reagents that
have so far been applied to carbohydrate chemistry, the utility
of glycosyl fluorides in chemical and enzymatic glycosylations
are also examined.
[Back to top]
Enantioselective Electrophilic Fluorination: The Complete
Story
C. Audouard, J.-A. Ma and D. Cahard
Progress in the field of enantioselective electrophilic fluorination
during the past eighteen years resulting from fascinating
research conducted by twelve international groups is reviewed.
Two complementary strategies for the synthesis of enantiopure
fluorine-containing molecules currently define state-of-the-art
in this area. The use of chiral, non-racemic fluorinating
agents is the most general approach while catalytic methods
using either transition-metal catalysts or organocatalysts
apply to specific substrates.
[Back to top]
Synthesis of Chiral Fluorinated Materials via
Biotransformation
Tomoya Kitazume, Tomoko Matsuda and Kaoru Nakamura
Biotransformation of organofluorine materials into the optically
active functionalized fluorinated materials along with the
discussion on the effect of fluorine atom(s) during the enantioselective
and/or diastereoselective transformations is described. The
ability of microorganism to discriminate between enantiomers
is very important for the purpose of resolution and asymmetric
synthesis. Also included are discussions on recent developments
in methodologies to control enantioselectivities of catalytic
reactions. Examples of practical applications that involve
reduction of various types of ketones are also included.
[Back to top]
Recent Advances in the Chemistry of Fluorine- Containing
π-Allylmetal
and Allenylmetal Complexes
Tsutomu Konno and Takashi Ishihara
π-Allylmetal
complexes derived from α-fluoroalkylated
allyl mesylates react smoothly with various nucleophiles such
as stabilized carbanions, carboxylates, and amines at the
carbon distal to a fluoroalkyl group in a highly regioselective
manner to give the corresponding γ-products
in high to excellent yields. Treatment of the above fluorine-containing
π-allylmetal
complexes with hydride nucleophile gives the adducts derived
from the hydride attacking on the carbon attached to a fluoroalkyl
group. The γ-adducts,
obtained by the reaction of π-allylpalladium
complex with α-methoxy
acetate or N-protected glycine, undergo smooth Ireland-Claisen
rearrangement to give the corresponding multi-functionalized
molecules in high yields. On the other hand, the reaction
of α-fluoroalkylated
propargylic mesylates with zinc reagents or stabilized carbanions
in the presence of palladium catalyst affords fluorine-containing
allene or furan derivatives respectively, in high yields,
via allenylpalladium complex.
[Back to top]
Synthetic Utility of Fluorinated β-Keto-Phosphonium
Salts, -Phosphonates and Related Compounds
Yanchang Shen
Sequential transformations have attracted much interest in
recent years because they provide simple and efficient entry
into complex compounds by including two or more steps in a
single operation to increase the complexity of the substrate,
starting from commercially available, relatively simple precursors.
The new methodologies discussed in this review chapter are
based on sequential transformations and possess high stereoselectivity.
They include the synthetic utility of fluorinated β-keto-phosphonium
salts, “one-pot” carbon-carbon double bond formation,
ylide-ion formation resulting from nucleophilic addition,
stereocontrolled olefination method, alkenylation based on
elimination of triphenylarsine, reductive olefination mediated
by Ti(O-i-Pr)4 and Ph3P and sequential transformation
of organophosphorus compounds in organic synthesis. The newly
discussed methodologies are, therefore, potentially useful
in organic synthesis particularly in the medicinal and agricultural
chemistry for the synthesis of biologically active compounds.
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