Synthesis of biaryls

349 Pages·2004·10.398 MB·English

by  Ivica Cepanec

Synthesis of Biaryls
Elsevier, 2004

Author: Ivica Cepanec
ISBN: 978-0-08-044412-3

Preface, Pages v-vi

Abbreviations, Pages xi-xiii

Chapter 1 - Introduction, Pages 1-6

Chapter 2 - Classical methods for synthesis of biaryls, Pages 7-41

Chapter 3 - Coupling reactions of aryl halides and sulfonates with metal
complexes and active metals, Pages 43-81

Chapter 4 - Cross-coupling reactions of arylmetallic reagents with aryl halides
and sulfonates, Pages 83-137

Chapter 5 - The Suzuki-Miyaura reaction, Pages 139-207

Chapter 6 - Synthesis of biaryls and polyaryls by oxidative couplings of arenes,
Pages 209-239

Chapter 7 - Miscellaneous methods for synthesis of biaryls, Pages 241-291

Chapter 8 - Synthesis of axially chiral biaryls, Pages 293-320

Subject index, Pages 321-349
PREFACE
Organic chemistry is one of the most rapidly growing sciences. There is a wide
variety of applications of organic compounds, for instance, pharmaceutical active
substances, agrochemicals, optoelectronics, etc. Within this group there are hundereds
and thousands of new compounds synthesized or isolated from natural sources. Such
important organic chemistry developments are accompanied by the profound break-
through of new reactions, increasingly efficient methodologies, reagents and catalysts.
The chemistry of biaryls is one of the most interesting fields in organic chemistry. The
aryl-aryl, C-C bond forming reactions are not only of academic interest, but also play
an important role in a number of industrial processes, fine chemical industry, natural
products synthesis, chiral catalyst chemistry, chiral stationary phases chemistry,
environmental pollutant chemistry, electronic devices production, etc. The synthesis of
biaryls has been impressively developed during the last century, starting from the
classical Ullmann and Gomberg-Bachmann-Hey, generally known as high-temperature
or low yielding reactions, to the modern Suzuki-Miyaura cross-coupling reactions, as
well as various recent reactions involving diaryliodonium salts or miscellaneous
organometallics, which cleanly proceed even at room temperature or below, tolerating
several sensitive functional groups. Whereas the synthesis of complicated biaryl
structures several decades ago was realized with aryl-aryl, C-C bond forming reaction
in very early steps of synthesis, very powerful modern reactions allow to build the
biaryl structure from highly functionalized substrates in the last step.
The book is organized through eight Chapters. In the first Chapter, a short
introduction to the topic, and elementary structure facts are given. The old methods
with newer improvements are presented in the second Chapter, whereas in Chapters 3-
7 all important reactions of biaryl chemistry are described. The Suzuki-Miyaura, as
probably the most important general reaction for the synthesis of biaryls, is described
in particular detail. Not less interestingly, the Chapter 7, includes several specific
approaches to biaryl synthesis, e.g. Meyers, Motherwell synthesis or palladium
catalysed arylations of arenes with aryl halides. In the last, Chapter 8, the most
relevant methods for the synthesis of axially chiral biaryls are included. The material is
presented from both a synthetic and mechanistic point of view, whilst the
representative synthetic procedures may be helpful for understanding the methodology
of the given reaction. I hope that readers, advanced undergraduate and post-graduate
students, research and industrial chemists and engineers, will find the book interesting
vi
and useful. In addition, lecturers may find it a helpful support to improve their
presentations. The knowledge has been taken from numerous literature references,
from early 1900's till the end of 2003, with appreciable additional experiences from the
Belupo Pharmaceuticals Research Department.
It is now my pleasure to express profound gratitude to my coworkers and friends,
especially Dr. Mladen Litvi6, Mrs Stefica Vr~ak for type-writting, Mrs Mihaela
Farquhar, her husband Graeme, and Miss Lana Donaldson for English language
editing, as well as to the persons who, each of them in different times, helped me to
realize the beauty of chemistry - many thanks to: Dr. Franjo Kajfe~, Dr. Zvonimira
MikoticS-Mihun, Dr. Vladimir Vinkovi6 and Prof. Dr. Vitomir Sunji6.
Finally, I want to thank my wife Katarina and children Ivan and Jelena, who with
love and understanding endured me for many days, whilst I spent hours in the library
and on the computer. I dedicate this work to them.
Zagreb, Croatia, 2004.
Dr. Ivica Cepanec
xi
ABBREVIATIONS
cA Acetyl
acac Acetylacetonate
NB1A Azobisisobutyronitrile
.qa Aqueous
3hPsA Triphenylarsine
BHT 2,6-Di-t-butyl-4-methylphenol
Bn Benzyl
BOC t-Butoxycarbonyl
bpy 2,2'-Bipyridine
n-Bu lytuB-lamron
s-Bu lytuB-yradnoces
t-Bu lytuB-yraitret
n-BuLl n-Butyllithium
s-BuLl s-Butyllithium
t-BuLl t-Butyllithium
Bz Benzoyl
o C Degrees Celsius
CAN Ammonium cerium(IV) nitrate
.tac Catalytic
CBz Carbobenzyloxy
CDI ,1 l'-Carbonyldiimidazole
COD 1,5-Cyclooctadienyl
Cp Cyclopentadienyl
CTAB Cetyltrimethylammonium bromide
Cy Cyclohexyl
% d.e. % Diastereomeric excess
DABCO -4,1 Di azobi cyclo 2.2.2 octane
DDQ 2,3-Dichloro-5,6-dicyano- 1,4-benzoquinone
H1ABID Diisobutylaluminum hydride
Xll oo
DMAc Dimethylacetamide
DME 1,2-Dimethoxyethane
DMF -N,N Di methyl formami de
DMI N,N-Dimeth ylimi daz o li d inone
DMPU N,N'- Di meth ylpropyleneurea
DMSO Dimethylsulfoxide
dppb 1,4- B is( di phen ylphosphin o)butane
dppe 1,2-Bis(diphenylphosphino)ethane
dppf B is( di phen yl phosphi no) ferrocene
dppp 1,3-Bis(diphenylphosphino)propane
EDTA Ethylenediaminetetraacetic acid
%e.e. % Enantiomeric excess
Et Ethyl
eq. Molar equivalent
h Hour, hours
HMPA Hexamethylphosphoramide
hv Irradiation with light
i-Pr lsopropyl
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
LHMDS Lithium hexamethyldisilazide
LIC-KOR super base KOt-Bu / n-BuLi
LTA Lead(IV) acetate
Me Methyl
MeCN Acetonitrile
MIBK Methyl isobutylketone
rain Minute, minutes
m.p. Melting point
Ms (OMs) Mcthancsulfonyl
MS Molecular sieves (3 or 4 *)
NCS N-Chlorosuccinimidc
NMP 1 -Methyl-2-pyrrol idinone
OCA oxidative coupling of arenes
~.uBP Tri-n- but ly ph osph ine
Pt-Bu3 Tri-t-butylphosphine
~.yCP Tricyclohexylphosphine
PEG Polyethylene glycol
3tEP Triethylphosphine
PFu3 Tri (2- furyl )p hosphi ne
Ph Phenyl
xiii
PIDA Iodosobenzene diacetate
PIFA lodosobenzene bis(trifluoroacetate)
3hPP Triphenylphosphine
PS Polystyrene backbone
PTC Phase transfer catalyst
3loTP Tri(2-tolyl)phosphine
Py Pyridine
SM Suzuki-Miyaura reaction
TBAB Tetra-n-butylammonium bromide
TBAF Tetra-n-butylammonium fluoride
TDAE Tetraki s ( dimeth yl amino)eth yl ene
TFA Trifluoroacetic acid
Tf (OTf) Triflate
THF Tetrahydrofuran
TMS Trimethylsilyl
TMU 1,1,3,3-Tetramethylurea
Tr Trityl
Ts (OTs) Tosylate
TTFA Thallium(Ill) trifluoroacetate
CHAPTER
1
1. INTRODUCTION
1.1. Aryl-aryl bond forming reactions
The formation of an aryl-aryl bond is one of the most important goals in the field
of organic chemistry. The methodology for performing the synthesis of biaryls has
been a challenging focus for over a century. Since Ullmann's first reports about the
coupling reactions of aryl halides to biaryls with copper bronze, a number of valuable
reactions and methods have been published. The main reason for such a different
approach to the aryl-aryl bond forming reactions from alkyl-alkyl bond are the
distinguished properties of electrophilic aryl-compounds. Thus ordinarily aryl halides,
in contrary to alkyl halides, are not suitable counterparts for classical nucleophilic
substitution reactions. Exceptions are the aryl halides bearing an electron-withdrawing
substituent in ortho and/or para-positions. The latter readily undergo nucleophilic
aromatic substitutions (SNAr), however, these reactions are rarely useful in the
generation of aryl-aryl bonds, since several common electron-withdrawing
substituents, e.g. nitro, cyano, or alkoxycarbonyl, are not well tolerated with aryl-
carbanion donors, e.g. aryllithiums or aryl Grignard reagents. Alternatives to the
nucleophilic substitution approach to the aryl-aryl bond formation are the free-radical
arylation, or reductive elimination of various diarylmetallics such as diarylnickel,
diarylpalladium or diarylcopper complexes. Whereas the former process, involving
free-radicals, is the basis of classical Gomberg-Bachmann-Hey reaction and several
older or modern alternative arylations, the latter reaction proceeds within the
coordinative sphere of nickel, palladium or copper. This organometallic process is
crucial for a number of reactions whose only difference is in the pathway of obtaining
the unstable diaryl-nickel, -copper, or-palladium species. Some reactions involve the
formation of transient diarylmetallic species, e.g. diarylcoppers in the Ullmann, or
diarylnickel compounds in the homo-coupling reactions of aryl halides with nickel(0)
complexes, whereas some other certain reactions include the separate preparation of an
arylmetallic reagent, e.g. arylboronic acids in the Suzuki-Miyaura, arylzincs in the
Negishi, aryl Grignard reagents in the Kharasch reaction, etc., which, upon
SYNTHESIS OF BIARYLS
transmetallation to arylpalladium(II) complexes, give the desired diarylpalladium
species. The unstable diaryl-nickel, -copper or -palladium complexes are the crucial
species which, by reductive elimination of the metallic compounds in lower oxidation
state, generate the new aryl-aryl bond. Beside these, diaryl compounds of various
metals were given the reductive elimination reaction to produce biaryls, however, only
with nickel, copper, and palladium, the process can be accomplished catalytically.
Synthesis of biaryls have been the theme of a great number of papers during more than
a hundered years. Apart from the several recent successful general reactions which are
very important and valuable alternatives to the older, classical reactions for synthesis
of biaryls, a number of basic problems is still waiting for efficient solutions.
.2.1 ehT ecnatropmi fo slyraib
Biaryl structures are wide-spread in many of naturally occuring products
including alkaloids, lignans, terpenes, flavonoids, tannins, as well as polyketides,
coumarins, peptides, glycopeptides, etc. For example, vancomycin (1) is a basic
structure of several related glycopeptide antibiotics 1: balhimycin, actinoidin A,
ristocetin A, teicoplanin A2-2, complestatin, etc which are important in medicinal
chemistry or as a HPLC chiral stationary phases (vancomycin) 2.
OH
\ ~"/"'OH
HO
lC
, ' ~ C HO
.nrOH ~ I 1 7 6 0 H
CH 3
H O O C V ~ HN 2
1
.o ~
A lot of natural pigments are biaryls; as gossypol (2), a major constituent of cottonseed
pigment, is a binaphthyl structured polyphenol, having also a male antifertility action
INTR OD UCTION 3
3. Among lignans, an illustrative example is steganacin (3), a constituent of
Steganotaenia araliacea, the respective synthetic target of several scientific papers,
which possesses a significant antileukemic activity 4.
H O ~ o H
H3CO--~
HO CH 3
H3CO OCH 3
2
Unfortunately, some of the biphenyls such as polychlorobiphenyls (PCB's) are
important environmental pollutants as a result of their practical uses. Their general
stability to air and environmental conditions, similarly to DDT, is the reason for
extremely slow degradation process to nontoxic substances, and will be matter of
ecological and health debates for years. The biaryl structure is the basis of several
successful chiral separations by crown ethers, inclusion complexes or by preparative
chromatography on the chiral stationary phases. Chiral binaphthols and related chiral
auxiliaries are widely employed chemicals in some impressive industrial processes.
The simplest and still the most important chiral biaryl molecule is 1,1'-binaphthyl-
2,2'-diol (4) which is used as a chiral ligand or starting material in the production of
several valuable catalysts for certain enantioselective reactions. A few heterobiaryls
are important ligands in the coordinative chemistry and in certain useful catalysts. For
instance, 2,2'-bipyridine (5) is a widely employed ligand for nickel(II) salts acting as
the oxidation catalysts, e.g. toluenes to benzoic acids with sodium hypochlorite as
cheap terminal oxidant, or as aryl halide homo-coupling reaction catalyst, see Chapter
3. 2,2':6',2"-Terpyridine (6) is a versatile tridentate ligand which forms several
important metal complexes, e.g. Ru(IV), acting as the oxidation catalysts, bleaching
agents, oxygen-binding molecules, as well as having miscellaneous interesting
applications 5.
H O (cid:127) (
5 6
SYNTHESIS OF BIAR YLS
Recently, in the medicinal chemistry, biphenyl motif became an important "spacer"
within the structure of several modern antihypertenzive agents, so-called sartanes. For
example, losartan (7) is one of the most prescribed block-buster drugs of today.
H
1C OH N"N"
U3C--- ~
The aryl-aryl bond formation is the most important reaction in the synthesis of various
polyaryl materials which possess valuable conducting properties. The polyaryls such
as poly-p-phenylene (PPP), which by various doping procedures reach a conductive
state, are in locus as a potential for use as electrode materials in light-weight
rechargeable batteries, electrochemical cells, semi-conductor devices, solar cells, and
in the several other possible electrochemical uses. Very comprehensive polyarene-
chemistry and its practical applications are excellently rewieved by Takakazu
Yamamoto 6.
1.3. Structure of biaryls. Atropisomerism
The structure tbrmula of biphenyl (8) is usually written as two phenyl-rings
connected by single C-C bond as a planar structure. However, a rotation about the
aryl-aryl bond is normal, at room temperature this is a readily occuring process
involving a planar and axial conformer (as well as all intermediate conformers). The
first conformer is coplanar, all twelve carbon atoms lay ni a single plane, whereas in
the latter two planes which contain two phenyl-rings are axial, mutually under the
angle of 90 ~ (interplanar angle). Observing this two planes from the left- (or right-)
oo r-
side, a cross can be seen, Figure I.
8 8
Fig. 1