Chapter 3 Diels–Alder Reaction Using Pyrroles or Thiophenes and Ring-opening Aromatization ...

102 Pages·2017·1.84 MB·English

Studies on One-pot Synthesis of Polysubstituted Benzoate Derivatives vi
Title
a Diels-Alder Reaction
Author(s) 篠原, 広幸
Editor(s)
Citation
Issue Date 2015-02
URL http://hdl.handle.net/10466/14543
Rights
http://repository.osakafu-u.ac.jp/dspace/
Studies on One-pot Synthesis of Polysubstituted
Benzoate Derivatives via Diels–Alder Reaction

Hiroyuki Shinohara

February 2015

Doctoral Thesis at Osaka Prefecture University

Preface

This thesis deals with the studies conducted during April 2012 to March 2015 under the
guidance of Professor Akiya Ogawa at the Department of Applied Chemistry, Graduate School of
Engineering, Osaka Prefecture University and Associate professor Motohiro Sonoda at the
Department of Bioscience and Informatics, Graduate School of Life and Environmental Science,
Osaka Prefecture University.
This thesis is concerned with convenient synthesis of polysubstituted benzoate
derivatives via Diels–Alder reaction.

Department of Applied Chemistry
Graduate School of Engineering
Osaka Prefecture University
Hiroyuki Shinohara
February 2015
i
List of Abbreviations
Functional Groups
Me methyl Et ethyl
iPr isopropyl nBu normal-butyl
tBu tert-butyl (tertiary butyl) Ph phenyl
Ac acetyl Boc tert-butoxycarbonyl
Ar aryl Cy cyclohexyl
Bn benzyl MOM methoxymethyl
Tf trifluoromethanesulfonyl Bz benzoyl
X halide
Organic Compounds
THF tetrahydrofuran
dba dibenzylideneacetone
Technical Terms
EI electron impact ionization method
FAB fast atom bombardment ionization method
ESI electrospray ionization method
IR infrared spectroscopy
GC gas chromatography (gas-liquid chromatography)
GPC gel permeation chromatography
HRMS high resolution mass spectrometry
MS mass spectrometry
ND not detected
NMR nuclear magnetic resonance
rt room temperature
TLC thin layer chromatography
PTLC preparative thin layer chromatography
DFT density functional theory
ii
Contents
Chapter 1 General Introduction ・・・1

Chapter 2 IrCl or FeCl -catalyzed Direct Synthesis
3 3
of 3-Hydroxyphthalate derivatives ・・・6

Chapter 3 Diels–Alder Reaction Using Pyrroles or Thiophenes and
Ring-opening Aromatization Reaction of
7-Azanorbornadiene Derivative ・・・22

Chapter 4 Silica Gel-promoted Convenient Synthesis of
2-Bromo-3-hydroxybenzoate Derivatives and
Following Transformations ・・・32

Chapter 5 Synthesis of Amino- or Thio-substituted 3-Hydroxybenzoate
Derivatives Using Furan, Bromoalkyne, and Nucleophiles ・・・69

Chapter 6 Conclusion ・・・91

List of Publications ・・・93

Acknowledgement ・・・95
iii

Chapter 1. General Introduction
Chapter 1

General Introduction

Numerous and ubiquitous organic compounds such as organic functional materials,
polymers, and various bioactive agents including pharmaceuticals, agrichemicals, and natural
products have been created by the aid of synthetic organic chemistry. For the purpose of the
development of more convenient and effective synthesis methods for useful organic compounds,
novel organic reactions are going to be developed with all organic chemists’ might.
Hydroxybenzoate derivatives have been well known as one of the most important key
units found in various bioactive agents1 containing pharmaceuticals and functional materials2 as
represented by aspirin and phthalic acid resin. Therefore, a development of convenient and
efficient synthetic method for hydroxybenzoates has been strongly demanded. In general,
polysubstituted hydroxybenzoates were synthesized from cheap and easily available aromatic
compounds via multi-step reactions. However, this traditional methods have some problems with
wastes caused by solvents, catalysts, additives, or byproducts generated by the course of the
multi-step reaction. On the other hand, development of efficient synthetic methods, i.e. highly
atom-economic, low waste, energy-saving, and highly regioselective reactions, have been
strongly demanded in these decades because of upsurge of intention for environmental
conservation. From these viewpoints, the author aimed to develop an efficient, selective, and
direct synthetic method for polysubstituted benzoate derivatives.
In order to achieve the aim, the author focused on the use of 7-oxanorbornadiene
derivatives, which has non-planar structure and the same degrees of unsaturation with benzene
ring, as a starting material instead of planar aromatic compounds. This is because (i) it could be
synthesized easily by a Diels–Alder reaction using furans and alkynes,3 (ii) non-planar structure
-1-
Chapter 1. General Introduction
would be expected to reduce the magnitude of steric repulsion between substituents, and (iii) it
could easily take place ring-opening reaction associated with cleavage of C–O bond.4
Furthermore, the Diels–Alder cycloaddition reaction is superior from viewpoint of eco-friendly
organic synthesis because of its functional group compatibility and relatively low yields of
byproducts. On the basis of these considerations, the author examined to develop a convenient
synthetic method for polysubstituted benzoate derivatives started by the Diels–Alder reaction of
furans with alkynyl esters. Additionally, further transformations using obtained products were
also examined. In the author’s strategy, by using ring-opening aromatization as a powerful
driving force, polysubstituted benzene ring was constructed momentum from polysubstituted
non-planar 7-oxanorbornadienes with relatively less steric hindrance. Therefore, it is expected
that this reaction has advantages in reaction efficiencies, reaction steps, organic and/or inorganic
wastes, and experimental operations.
This thesis summarizes the studies on convenient one-pot synthesis of various
polysubstituted benzoate derivatives via Diels–Alder reaction using five-membered
heteroaromatics with electron-deficient alkynes, and this thesis consists of six chapters.
Chapter 1 is general introduction for this thesis.
Chapter 2 describes the convenient synthesis of 3-hydroxyphthalate derivatives
catalyzed by IrCl ·3H O or FeCl in one-pot method. Hydroxyphthalate derivatives are found in
3 2 3
various bioactive agents, functional materials, and their important synthetic intermediates.
Therefore, the development of convenient and selective synthetic method of polysubstituted
hydroxyphthalates is one of the most important research areas in synthetic organic chemistry and
more efficient and eco-friendly synthetic method was strongly desired. Thus, the author examined
the synthetic method of polysubstituted 3-hydroxyphthalate via Diels–Alder reaction of furans
with dimethyl acetylenedicarboxylate (DMAD) and the following ring-opening aromatization
reaction. By employment of IrCl ·3H O or FeCl as a Lewis acid catalyst, the desired one-pot
3 2 3
reactions for various phthalate derivatives have been developed.
-2-
Chapter 1. General Introduction
Chapter 3 explains the results of the Diels–Alder reaction using pyrrole or thiophene
derivatives and ring-opening aromatization reaction of 7-azanorbornadiene derivative. Pyrroles
and thiophenes are five-membered heteroaromatics including diene structure, same as furans, and
are applicable for Diels–Alder reaction. However, according to the relevant literatures, examples
of Diels–Alder reaction using pyrroles or thiophenes are fewer than the reaction of furans because
of their high aromaticity. In general, the reactions required high pressure and high temperature,
and the Diels–Alder reaction of pyrroles or thiophenes showed substrate specific. Therefore, a
development of versatile Diels–Alder reaction of five-membered heteroaromatics except for
furans in mild condition remains an attractive challenge. From this point of view, the author
examined Diels–Alder reaction using pyrroles and thiophenes in various conditions and found
that N-Bocpyrrole was applicable as a conjugate diene to form 7-azanorbornadiene derivative.
Furthermore, ring-opening aromatization of this Diels–Alder adduct proceeded to give
3-aminophthalate when Pd(OAc) was employed as a catalyst. Unfortunately, development of
2
Diels–Alder reactions using thiophenes under various conditions could not be successful.
Chapter 4 presents convenient synthesis of 2-bromo-3-hydroxybenzoate derivatives via
the Diels–Alder reaction of furans with methyl 3-bromopropiolate and the following ring-opening
aromatization. In addition, further transformation reactions using obtained products were
performed. Polysubstituted hydroxybenzoates are one of the most important key units for
synthetic organic chemistry often found in various bioactive agents, pharmaceuticals, functional
materials, and their synthetic intermediates. Therefore, its methodology for convenient synthesis
and transformation reaction is strongly demanded. In this chapter, the author examined
convenient synthesis of 2-bromo-3-hydroxybenzoates and further transformation reactions at
bromo group, hydroxy group, and/or ester group of aromatic ring of the products. As a result, it
was revealed that ring-opening aromatization of Diels–Alder adducts derived from furans and
methyl 3-bromopropiolate was proceeded in one-pot when FeCl was employed as a catalyst.
3
Furthermore, silica gel was also found to be a good additive for the one-pot reaction, surprisingly.
-3-