Synthesis of dihydroisoindole derivatives

185 Pages·2013·1.53 MB·English

University of Wollongong
Research Online
University of Wollongong Thesis Collection University of Wollongong Thesis Collections
1981
Synthesis of dihydroisoindole derivatives
Onn Choon Wong
University of Wollongong
Recommended Citation
Wong, Onn Choon, Synthesis of dihydroisoindole derivatives, Doctor of Philosophy thesis, , University of Wollongong, 1981.
http://ro.uow.edu.au/theses/2110
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Synthesis of Dihydroisoindole
Derivatives
A THESIS
Submitted in fulfilment of the
requirements for admittance to
the degree of
DOCTOR OF PHILOSOPHY
of the
UNIVERSITY OF WOLLONGONG
by
WONG ONN CHOON
SUMMARY
A series of isotryptamine and hydroxyisotryptamine
derivatives were synthesized because of their potential
pharmacological activities.
The following results were achieved:
(1) A new synthetic route was developed for the
preparation of isotryptamine and its N-alkyl
derivatives from isoindolin-1-one-3-ethanoic
acid.
(2) A modified synthetic route was developed first
for the preparation of 1-nitrosodihydroxynaph-
thalenes, then for that of hydroxyisoindolin-1-
one-3-ethanoic acids and finally, for hydroxy-
isotryptamines and their N-alkyl derivatives.
(3) It was shown that isoindolin-1-one-3-ethanamide,
hydroxyisoindolin-1-one-3-ethanamide and their N-
alkylated derivatives can be synthesized in good
yield from the corresponding acids and urea
derivatives.
(4) As standard reduction methods gave only very low
yields of isotryptamine derivatives the require
ments of reducing lactamamide groupings were
reinvestigated. Contrary to published reports
it was shown that boron trifluoride plays a
catalytic role in the reaction and it was
established that
(a) the nature of the solvent used
(b) the order in which the reagents are
added and
(c) the generation of diborane j_n si tu
determine the yield of the amine.
(5) A new tricyclic compound, isocarboline, was
synthesized by ring closure, via a methylene
bridge, between the two nitrogen atoms of
isotryptamine.
TABLE OF CONTENTS
Page
SUMMARY (i
INTRODUCTION
A. PHYSIOLOGICAL ACTIVITY OF DIHYDROISOINDOLE
2
AND INDOLE DERIVATIVES.
B. STRUCTURE-ACTIVITY RELATIONSHIP 11
C. DIHYDROISONDOLE SYNTHESIS via RING
CLOSURE REACTIONS.
D. SYNTHESIS OF ISOINDOLES AND THEIR DERIVATIVES
via RING CLOSURE REACTIONS. 34
DISCUSSION
A. AIM AND PROPOSED SYNTHESIS. 44
B. DIRECT NITROSATION OF NAPHTHOLS. 51
C. BECKMANN FRAGMENTATION OF 1-NITR0S0-2-
54
NAPHTHOL DERIVATIVES.
D. FORMATION OF THE ACID AMIDE IN THE SIDE 61
CHAIN.
E. PREPARATION OF THE AMINES. 83
F. DISCUSSION OF N.M.R. SPECTRA. 104
EXPERIMENTAL 109
REFERENCES 154
ACKNOWLEDGEMENTS 178
I N T R O D U C T I ON
- 2 -
A. PHYSIOLOGICAL ACTIVITY OF DIHYDROISOINDOLE
AND INDOLE DERIVATIVES
Several compounds containing the "basic" isoindole
nucleus have been found to be physiologically active. In
the field of non-steroidal anti-inf1ammatory agents
Nannini et. al. [1] investigated the effects of 4-(l-oxo-2
isoindolinyl)-phenylacetic acid derivatives (1) and found
that several were highly active both as analgesics and
anti-inflammatory agents in live animal tests.
R:
COOH
(1)
R1- H; 0CH ; CH ; Cl.
3 3
R2- H; CH ; Cl; 0CH .
3 3
R3 = H; CH .
3
R4 = H; alkyl; OH; 0CH ; CH 0l
3 2
The products suspended in 0.5% methocal were
"loo
administered orally to rats. Compounds with R = R = R
= H; R4 = H,alkyl up to C.H showed marked activity in rats
g
4
in both of the above test systems. However if R was
-CHpOH, OH, -0CH , the resulting compound showed no
3
- 3 -
analgesic activity. By studying the relationship between
the partition coefficient values, pK, of the compounds and
the size of the substituent groups, Nannini [1] pointed out
that the decrease in pharmacological activity with
4
increasing chain length of R > CH substituents was due to
3
their increasing lipophilic character, which favours their
metabolism and prevents their coming into contact with the
active site for sufficient length of time to act.
Another biologically active compound, 2-(3,4-dimethoxy-
phenyl ethyl)-5-6-dimethoxydihydroiso indole (2) , synthesized
by Casagrande et. al. [2], exhibited a fair degree of oc-
adrenergic activity.
N CH, CH OCH.
»-A\ /
CH,0
OCH.
(1)
This activity was evaluated iji vitro by measuring its
antagonist effect on the contraction induced by adrenalin
in guinea pig seminal vesicles.
Within a known series of dihydroisoindole analogues
(table 1.), Casagrande et. al. [2] found that the presence
of a carbonyl group in the heterocyclic ring system e.g.
(3), and the lack of an aromatic system attached to the
- 4 -
nitrogen atom, e.g. (4), (5J , (6) and (7j , eroded the
activity.
TABLE 1.
Dihydroisoindole Derivatives
N — R2
Compound Activity*
R1 R3 R2
3 CH O 0 ; -CH -CH Ph(m-0CH )(£-0CH ) 7.5
3 2 2 3 3
4 CH O H -CH«-CH«-CH -CH« 10.0
3 2 0
5 CH O H -CH -CH -N-(C H ) 50.0
3 2 2 2 2 5 2
6 cH o H -CH -CH -l/~^0 50.0
3 2 2 2
7 CH O 0 -CH -CH -N(C H ) 20.0
3 2 2 2 5 2
8 CH O H -CH -Ph(m-0CH )(£-0CH ) 1.0
3 2 2 5 3
9 CH O H -CH -CH -Ph 5.0
3 2 2 2
10 CH O H -CH(CH )CH -Ph 1.5
3 2 3 2
11 CH 0 H -CH -CH -Ph-(p_-0CH ) 2.5
3 2 2 2 3
12 CH 0 H -CH -CH -Ph(m-0CH )(£-0CH ) 0.5
3 2 2 2 3 3
13 CH3O H -(CH ) -Ph 0.5
2 3 3
14 CH 0 H -CH -CH -0-Ph-(o-OCH ) 0.025
3 2 2 2 3
*a-adrenergic blocking activity, EC™ (ug/mL).
Furthermore, modification in the aromatic ring which is
linked to the nitrogen atom by one or more methylene groups
e.g. (8), (9), (10) and (JJJ, decreased the activity of the