Birch Reduction of Aromatic Compounds

129 Pages·1972·3.19 MB·English

by  A. A. Akhrem

BIRCH REDUCTION
OF AROMATIC
COMPOUNDS
BIRCH REDUCTION
OFAROMATIC
COMPOUNDS
A. A. Akhrem, I. G. Reshetova, and Yu. A. Titov
Institute of Organic Chemistry
Academy of Sciences of the USSR
Moscow, USSR
Translated from Russian by
B. J. Hazzard
IFI/PLENUM • NEW YORK-WASHINGTON-LONDON • 1972
Afanasii Andreevich Akhrem was born in 1914. In 1934 he completed his studies
at the Minsk Polytechnic Institute. In 1949 he received the degree of Candidate
of Chemical Sciences and in 1959 that of Doctor of Chemical Sciences. He began
work in the Institute of Organic Chemistry of the Academy of Sciences of the
USSR in 1946, and in 1962 he became head of the Laboratory of Corticoid
Chemistry. Dr. Akhrem is a member of the Academy of Sciences of the Belo
russian SSR.
Irina Grigor'evna Reshetova was born in 1934. She completed her studies at the
Moscow Institute of Fine Chemical Technology, and since then has been work
ing at the Institute of Organic Chemistry of the Academy of Sciences of the
USSR in the field of modified steroids.
Yurii Andreevich Titov was born in 1932. In 1954 he completed his studies at the
Moscow Institute of Fine Chemical Technology, and since then has been work
ing at the Institute of Organic Chemistry of the Academy of Sciences of the
USSR, first as an assistant and, since 1965. as senior scientific researcher of the
Laboratory of Corticoid Chemistry.
The present work originally appeared as pages 7-128 in Reaktsii i Metody Issled
ovaniya Organicheskikh Soedinenii, Vyp. 20, published by Khimiya Press in
Moscow in 1969. This translation, revised and corrected by the authors, is pub
lished by special agreement with Mezhdunarodnaya Kniga, the Soviet book ex
port agency.
Library of Congress Catalog Card Number 70-183103
ISBN 978-1-4757-0431-0 ISBN 978-1-4757-0429-7 (eBook)
DOI 10.1007/978-1-4757-0429-7
© 1972 IFI/Plenum Data Corporation
Softcover reprint of the hardcover 1st edition 1972
A Subsidiary of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
United Kingdom edition published by Plenum Press, London
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Davis House (4th Floor), 8 Scrubs Lane, Harlesden, NWI0 6SE, London, England
All rights reserved
No part of this publication may be reproduced in any form without
written permission from the publisher
Contents
Introduction .......... . 1
Reaction Mechanism 2
Field of Application 4
Side Reactions .... 8
Methods and Examples of the Performance ot 'le Reaction. 15
2.5-Dihydroanisole ........ . 16
6-Alkylcyc1ohex-2-en-l-ones ..... . 16
Piperitone .................. . 17
3-Methoxyestra-2.5(10)-dien-17 8-01 . 17
Review of Literature Information .... 18
Index of Reagents .. 112
Literature Cited ... 116
v
Introduction
Birch reduction (see reviews [1-5]) is the name given to the reaction of
unsaturated organic compounds with alkali metals and alcohols in liquid am
monia. This method was first used for aromatic compounds in 1937 by Wooster
[6J, who showed that benzene and its derivatives are reduced by sodium in liq
uid ammonia in the presence of an alcohol, while this reaction does not take
place in the absence of an alcohol. However, the general recognition and broad
application of this reaction was achieved only after a series of investigations
by Birch published from 1944 onwards [7J.
Since the presence of an alcohol in the reaction medium is not indispen
sable for pOlycyclic aromatic systems, the present review includes only deriv
atives of the simplest aromatic compounds - benzene and naphthalene.
1
Reaction Mechanism
The most probable mechanism of Birch reduction, adopted by the major
ity of workers in this field [4, 8 -12] can be represented by the following stages:
i' v\ TI 1N H3 -+'-"- ",'.(+N Ha) , , ,e -(NHa)
3) + ROH ----+ (ll.. )
(NHa)
A
H H
4)
Q
')', H H
Q
~
5) ",,\\+ + +
RO" 110M,,,,,,
/ (NHa) . (NH:,)
H H Ii Ij
H H H H 0
X~.H~ 0 X/~H
6) >< H+ M,l<Utl•
V <~ ~J"H ~
lIT
H H
7)
2
REACTION MECHANISM 3
8)
When an alkali metal (M) is dissolved in liquid ammonia (stage 1) the
solvated cation and electron formed remain weakly attached to one another
in the form of an ion pair [13]. The reaction of the latter with the aromatic
nucleus is accompanied by electron transfer and the formation of a radical
anion which occupies the place of the electron on the ion pair (stage 2). The
radical anion of monobenzenoid systems is an extremely unstable particle
[14-16] because of the low electron affinity of the aryl nucleus. Consequently,
a shift of the equilibrium of stage 2 to the right is possible only if the radical
anion is constantly eliminated from the equilibrium mixture, which is achieved
by its irreversible protonation by means of the alcohol ROH (stage 3). Am
monia cannot provide the electron necessary for this in view of its low acidity
(pKa ~ 34), while the acidity of alcohols (pKa ~ 16 -18) is sufficient.
The intermediate radical obtained in stage 3 immediately adds a second
electron, being converted into an anion (stage 4). Protonation by the alcohol
again leads to a 1,4-dihydro derivative (stage 5).
If NHi ions are present in the reaction mixture, conditions are created
for the ionization of the 1,4-dihydro derivative, in consequence of which the
more thermodynamically stable 1,2-dihydro derivative accumulates in the
reaction mixture. The latter, being a conjugated diene, is reduced further to the
tetrahydro derivative <stage 6). However, in the majority of cases with an alcohol
present in the reaction mixture a strongly acid buffer (as compared with the acidi
ty of ammonia) is created, which prevents the accumulation of NH; ions.
The radical anion formed in stage 2 can react further with a second elec
tron, forming a dianion (stage 7) the subsequent double protonation of which
(stage 8) also leads to the 1,4-dihydro derivative. Because of the low electron
affinity of the aryl nucleus mentioned above, this possibility is apparently not
realized in the case of systems with a simple benzene nucleus. On the other
hand, naphthalene and its derivatives react in just this way [8, 9,17,18], i.e.,
via stages I, 2, 7, and 8.
Hiickel et a!. [19, 20] have proposed an alternative mechanism for Birch
reduction including in the first stage an attack of atomic hydrogen with the
formation of a radical. On the successive addition of an electron and a proton,
this radical is converted into the anion of a dihydro derivative, which then
reacts in the manner of stage 5.
Field of Application
The Birch reaction is used for the reduction of very diverse aromatic
compounds differing in their degree of substitution and in the nature of the
substituents. In the first stage of the reaction, l,4-dihydro derivatives are
always formed and through the further reactions of these are effected trans
formations to various compounds frequently difficult of access by other meth
ods of synthesis.
In the reduction of benzene and its derivatives, the corresponding cy
clohexadienes are obtained (yield up to 80-900/0). In this process the orienta
tion of the reduction is of prime importance. In accordance with the mech
anism illustra ted above. the structure of the products obtained is determined
by the direction of the addition of the protons to the radical anion in stage 3
and to the anion in stage 5. It is obvious that in both cases the protons will
a ttack the carbon atoms of the ring with the highest electron density. The
electron densities of all the carbon atoms of mono- and disubstituted benzenes
and also of the anion radicals formed from them ha ve been calculated by the
molecular orbitals method [18, 21j. When electron-donating substituents
(alkyl, alkoxyl, and amino groups) are present, the carbon atoms bearing the
substituents or those in the para position to them have the greatest tendency to
undergo protonation. Consequently. the Birch reduction of such compounds
leads to l,4-dihydro derivatives (I) containing the maximum number of sub
stituents on the remaining double bonds [8, 22]. This rule had previously been
deduced empirically by Birch [2, 7, 23, 24]:
A different distribution of electron densities is found when electron
accepting substituents are present; in this case the addition of protons takes
4
FIELD OF APPLICATION 5
place in the 1,4- positions with respect to the carbon atom bearing the sub
stituent, leading to compounds of type (II) [25-27J:
In the reduction of polycyclic derivatives of anisole (III), the addition
of protons in the 1,4- positions may take place in two directions with the
formation of compounds (IV) and (V). It is found, however, that the isomers
of type (V) always predominate in the mixture of reaction products [28J:
Examples are also known in which the reduction product originally
arising - the l,4-cyclohexadiene (VI) - then rearranges into the conjugated
1,3- derivative (VII) [8, 23, 29. 30J:
_ ()/CHa
(CHa)2N/'V
VI VII
When the reaction is carried out with alkoxy- and aminobenzenes,
the reduction products formed are ethers of the enolic forms (VIII) or are
enamines (IX) corresponding to the unsaturated ketones (X) into which they
can be converted by acid hydrolysis [22J:
0CH3 (yOCH:l
(Y
I
~II
,,?
V/II
6 FIELD OF APPLICATION
The Birch reduction of anisole derivatives is used particularly widely
in steroid chemistry to effect the passage from ethers of estrogens to 19-
norandrostanes. These compounds possess a high and diverse physiological
activity and are therefore of great value for medicine (see the reviews [31-
33J. The acid hydrolysis of the reduction products (XI) under severe condi
tions (hydrochloric acid) leads to b,4 -3-oxosteroids (XII), while milder hydrol
ysis using oxalic or acetic acid permits the double bond in the b,5(lO)_position
to be retained with the formation of (XIII):
The method of reduction under consideration has proved acceptable
in the total synthesis of various steroids [34J, alkaloids [35, 36J, resin acids
[37], and various terpenes [38-43J, including such complex ones as totarol
(XIV) [44J and cx-onocerin (XV) [45j:
Q6
I H
H3 CJ:?:' XO
CH(CH,),
H,C CH
3
XIV
Birch reduction has also found use for the synthesis of hydrogenated
naphthalene derivatives. Depending on the reaction conditions, naphthalene
itself forms the 1,4-dihydro derivative (XVI) or the 1,4,5, 8-tetrahydro
derivative (XVII) [46,47]:
(X)
CO~(X)
+
XVI XVII