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Limonene
A. F. Thomas
Firmenich SA, Research Laboratories, 12 I I Geneva 8, Switzerland
Y. Bessiere
126I Borex, Switzerland
is over 95 % pure, there is sometimes doubt in the literature as
to whether the limonene that was used in any experiment was
further purified or not. The major impurity in the material from
orange oil is myrcene (3); this can be removed by clathration
with tetrakis(4-methy1pyridine)di thiocyanatonickel. l 1 About
1 YOof aldehydes (mainly octanal) is also present, and there are
traces of other monoterpenes. The aldehydes can be removed
by distillation over 0.5 YOsodium hydroxide.
The presence of these impurities has led to widely different
values being determined for the flavour threshold concentration
in water. This has been given as 0.21 p.p.m., and the effect of
non-volatiles on this value has been measured,12 but the
limonene was only 96.5 YOpure, and was probably only distilled
orange oil, so the figures are meaningless. Values of 0.01
p.p.m.13 and 229 p.p.b. (also for 96% pure limonene)" have
been published, but in these papers we are not even informed
which enantiomer was tested, and it is known that the
organoleptic properties of the ( + ) - and the (-)-isomer are
different.I5 Again, the promotion of mouse skin tumours by
orange oil was long assumed to be caused by ( + )-limonene, but
pure ( + )-limonene does not exert this effect.16The toxicology of
limonene is well known;" its metabolism is mostly by allylic
oxidation or formation of an epoxide.lx One of the major
metabolites, uroterpenol glycoside (4), was isolated from urine,
especially of subjects with adrenal hyperplasia or in pregnancy;
this does not occur as an optically pure enantiomer, presumably
because of the variety of enantiomers in dietary limonene.19
(Uroterpenol will be discussed later.) Other metabolites are
known,')" and the conversion of (+)-limonene ( I ) into (+)perillic acid ( 5 ) by Pseudonioncrs incognita has been described .zl
Limonene is reportedly insecticidal ; B B . ' ) B it is toxic to cat fleas
(Ctmocephalidesj e l i ~ ) , ~for
' example, and may play a part in
conferring resistance to trees against attack by insects.'" There
is a simple school experiment to demonstrate the insecticidal
properties of ( + )-limonene."'
1 Introduction
2 Hydrogen Shifts and Disproportionation ; the Action
of Acids and Bases
3 Addition of Water, Alcohols, and other HX-type
Molecules
4 Addition of Halogens, Sulphur, etc.
5 Hydrogenation of Limonene
6 Hydroboration and Related Reactions
7 Oxidation (except Epoxide Formation)
8 The Limonene Epoxides
9 Addition of a C, Unit to Limonene
10 Addition of C, or More to Limonene
1 1 Pyrolysis and Miscellaneous Reactions
12 Biological Reactions of Limonene
13 References
1 Introduction
The production of (+)-limonene ( I ) in Brazil is about 12500
tonnes per year from orange stripper oil, 15000 tonnes per year
from cold-pressed orange oil [over 90% of which is (+)limonene], and about 11000 tonnes per year from other
sections of the citrus industry (orange-essence recovery water,
ete.),' making the annual world production of ( + )-limonene
about 50000 tonnes. Smaller amounts of more or less racemic
limonene (dipentene) are produced as a by-product from the
hydration of turpentine; distillation of turpentine is a source of
(-)-limonene, which can also be distilled from oil of Eucalyptus
s f q y r i a n a , although the purity is not as high as that of the (+)enantiomer. (+)-Limonene is one of the cheapest chiral starting
materials suitable for organic synthesis, and this review is
intended to survey its chemistry.
Until 1877, when Tilden distinguished between terpenes of
the 'turpentine group' and the 'orange group' by the
characterization of crystalline nitroso-derivatives,' there was
considerable confusion regarding the hydrocarbons obtained
from essential oils. Wallach pointed out that hesperidene,
citrene, carvene, di-isoprene, terpilene, kautschine, cynene,
cajeputene, and isoterebentine were all identical to (+)limonene.3 The discovery of ( -)-limonene (from Pinus silvrstrisJ)came a little later, making clear the constitution of the
racemate, dipentene, which had been obtained from the
distillation of rubber." The correct formula was given by
Wagner in 1894,6and the first rational synthesis was by Perkin
in 1905.' Racemic limonene is one of the products of the
pyrolysis of (-)-(S)-a-pinene (2),8 and the conversion of
turpentine into limonene over catalysts such as sodium sulphide
on alumina at 350 "C has been patented.'
We shall use the name 'limonene' for both the racemate and
optically active forms.
The major uses for limonene are in the flavour and fragrance
industries, as a solvent, and in the manufacture of polymers
and adhesives. Its uses as a solvent will not be discussed further
but there are patents, and such use has been increasing on
account of the low toxicity, pleasant odour. and biodegradability of (+)-limonene
Because ( + )-limonene that has been distilled from orange oil
Q
(3)
COOH
(4)
29 1
(5)
NATURAL PRODUCT REPORTS. 1989
292
the situation is complex: this fragment does not arise in the
field-free zone directly from the molecular ion that is formed by
collision-induced fragmentation.:''
+
2 Hydrogen Shifts and Disproportionation ;
the Action of Acids and Bases
(7)
Published on 01 January 1989 on http://pubs.rsc.org | doi:10.1039/NP9890600291
Q
+
Scheme 1
An interesting recent application of limonene is in the
purification of cyclodextrins from gelatinized starch, with some
of which it forms filtrable solid^.^'
The variation of optical activity of limonene with temperature
is known.28Nuclear magnetic resonance spectrometry in the
presence of Ag' and an optically active lanthanide complex has
been used to measure the chirality,29 and the
n.m.r.
spectrum of limonene, based on 13C-'3Ccouplings, has been
reported three times"" with somewhat different figures. Naturalabundance deuterium n.m.r. spectroscopy provides a rapid
means of locating the positions from which protons are lost
during its biosynthesis; these positions will have excess
deuterium, on account of the isotope effect. By this means,
Epstein et al. have shown that C-9 and C-I0 are not equivalent
during the bio~ynthesis.~'
This result was suggested by feeding
experiments, but difficult to prove because of the low
incorporation of precursors.32
The mass spectrum of limonene appears to consist of two
fragments of isoprene, one of which is charged ( m / z 68),3'3but
The carbenium ion (a) that is derived from limonene by the
action of acids rearranges as shown i n Scheme 1 . 3 3 Formation
of the ion (a) is also the initiation step in the Friedel-Craftscatalysed and acid-promoted polymerization of Iim~nene,:'~
the
chemistry of this ion going back to 1789, when turpentine [i.cl.
r-pinene (2)] was treated with sulphuric acid."' When (+)limonene ( I ) is homopolymerized by Ziegler-Natta catalysts,
the resulting polymer is optically inactive, and consists of both
the monocyclic structure (6) and the bicyclic structure (7)."x
The properties of such dipentene resins, which are used as
tackifiers mainly in hot-melt adhesives (packaging materials),
have been summarized by Ruckel et
Although, in principle, all of the hydrogen shifts of Scheme
1 are reversible, in practice (a) > ( I ) . does not occur much,
because the formation of terpinolene (8) is preferred, followed
Other
by further shifts to CL- (9) and y-terpinene
menthadienes are also formed [particularly isoterpinolene ( 1 1),
which is better prepared from car-3-ene (12)"], but careful
distillation of the products is necessary for preparative
purposes. There is always some disproportionation (Scheme 1 ),
leading to the menthenes and p-cymene (1 3), and ref. 35 notes
how to avoid this.
Much work has been invested in studying the differences
between various acids effecting hydrogen transfers and disprop~rtionation,~'
and the kinetics have been studied using
trifluoroacetic
The results vary somewhat with the
strength of the
Acid forms of ion-exchange resins effect
the same transformation^.“^ The chirality of limonene is lost in
all of these products [ion (b) is already achiral] and the
recovered limonene gradually loses optical activity because of
the reaction (a) >(1). Heating limonene in dipolar aprotic
solvents also causes slow rearrangement of double bonds and
disprop~rtionation.~~
These hydrogen shifts are encountered in
many other reactions of limonene, and can significantly lower
the yields of the desired products (e.g. in the hydration of
limonene to a-terpineol, or in catalytic hydrogenation).
Three isomeric dimethylbicyclo[3 . 2 . Iloctenes (14) were
mentioned after the action on limonene of phosphoric acid on
a silica support had been investigated, first in 1947 (with a
different
and then in 1974.47 The latter paper
includes an identification of the n.m.r. spectrometer that was
used, but not a single n.m.r. spectrum; one of us (AFT)
repeated this work but found only the usual hydrogen shifts
and disproportionations. Many years earlier, phosphoric acid
had been reported to give an unidentified compounddxwhich
was dehydrogenated over sulphur to 2,6,9-trimethylphena n t h ~ e n e , "the
~ structure of which was confirmed by an
independent synthesis.jn The unlikely compound ( I 5 ) is also
reputed to be formed by the action of phosphoric acids5'
Other reactions that have led to the isolation of dimers from
limonene or its disproportionation products are treatment with
chloranil for 2 hours at 130-170 "C [to form (16)l" and the
reaction of limonene with p-cymene (13), which has been
reported to give the tetracyclic compound (17) in 20-25 YO
NATURAL PRODUCT REPORTS, 1989-A.
293
F. THOMAS A N D Y. BESSIERE
D
conversion of p-cymene and in over 40% selectivity.j3 The
action of BF;OEt, in CCI, or toluene apparently also gives
dimerS..54.j.5 The formula in ref. 54 would be the result of the
cycloaddition of the two methylene groups, to form a
cyclobutane, which seems unlikely. There are a vast number of
patents and publications dealing with the copolymerization of
limonene with ethylene and propyIene,jfiwith norbornadiene,j7
and with other alkenes, as well as on the influence of limonene
as a chain-transfer agent in the styrenation of vinyl ether
polymers.j8and the polymerization of vinyl monomers (styrene,
vinyl acetate, etc.)."'
Double-bond rearrangement of limonene also occurs in the
presence of bases3*5.fio
such as potassium t-butoxide in dimethyl
sulphoxide61 or calcium oxide at 290-380 oC.6' Disproportionation to p-cymene (1 3) is readily carried out with potassium
hydride in pyrrolidine or ethylenediamine,'? a reaction which
led to the suggestion that limonene could be used to measure
the proton-removing power of 'superbases '. The formation of
the limonene anion (c) by metallation with butyl-lithium and
N,N,N',N'- tetramethyle thylenediamine was described by
. anion
~ ~ can be transformed into menthaErman et ~ 1 This
1,8( IO)-dien-9-01(18)6.5and was used in several syntheses which
will be referred to in later sections. Katzenellenbogen and
Crumrine also converted the anion (c) into the alcohol ( I 8) and
then into the corresponding bromide for further synthesis.""
Other derivatives (including some sulphides) have been made
~ ~ tin and silicon derivatives have been
by Suemune et U I . ,and
prepared from the anion (c).~' In all of these reactions, the
chirality of limonene is retained.
The dianion (d) of limonene can be formed by treatment with
butyl-lithium and potassium t-butoxide (Lochmann's base) or
potassium t-amyloxidc at reflux; quenching this dianion with
deuterium oxide yielded 7,IO-dideuteriated limonene ( 1 9) and
some dideuteriated dimethylstyrene (20).69
3 Addition of Water, Alcohols, and other
HX-type Molecules
The carbo-cations that are formed by the action of acids on
limonene (see Scheme I ) can lead to addition products. Thus aterpineol (21 ; R = H) can be formed by the addition of watcr;
this is generally accompanied by some /j- (22) and y-tcrpineol
(23) from addition of water to the endocyclic double bond. The
reaction was first described by Bouchardat and Lafont in
1886,"' and it is surprising that the addition of methanol was
only described 50 years later,7' although the product, a-terpinyl
f
D
!?
X
OR
methyl ether (21 ; R = Me), had been made [by etherification of
a-terpineol (21 ; R = H)j2] and its odour described:" in 1883.
Actually, a-terpineol was known before Bouchardat's
experiment, having been made by the hydration of turpentine
with acid catalysts,j4 but the structure was only established in
1 895.75a-Terpineol was also known from dehydration of 1,8terpin (24; X = OH),7(ithis also being obtained from turpentine.
The a-terpineol that is obtained from limonene is generally
(though not invariably; see below) racemic because of the
isomerizations in Scheme 1 , and the racemate was one of the
first substances to be purified (m. pt 35 "C) by low-temperature
crystallization. i i
Some of these early experiments were conducted in glacial
acetic acid, when the main product is terpenyl acetate (21 ; R =
Ac), from which the alcohol was obtained by
Sulphuric acid in acetic anhydride also yields a- and /j-terpenyl
acetate^.^" The terpineols are themselves hydrated under acid
conditions, 5 OO/ aqueous sulphuric acid hydrating z-terpineol,
with /)- and y-terpineols reacting more slowly, while Iimonene
is unchanged under these conditions.x0This further hydration
was well known to the early workers,70.i'~''who believed that
a-terpineol (21 ; R = H) gave only cis-terpin [cis-(24; X = H).
'cis' referring to the hydroxyl and the hydroxypropyl groups]
while the y-isomer (23) gave both isomers of (24; R = H).'?
More recently it was shown that cis-terpin is the major, but not
cxclusivc, product of hydration of all of the terpineols.':'
Consequently, many hydration processes of limonene produce
large amounts of the diols (24; R = H) besides the terpineols,
but these diols may be dehydrated to the terpineols. Surprisingly, 1,4-cineole ( 2 5 ) , but not 1,8-cineole (26), is said to be
NATURAL PRODUCT REPORTS, 1989
294
(35) R=Me R'=iPr
d
c1
(31)
(33)
(34)
(36) R=iPr R'=Me
Br
(32)
formed in a d d i t i ~ n , ' ~
although 1,8-cineole (26) is a major
component of the products resulting from treatment of aterpineol (21 ; R = H) with an acid.84 Surprises here are,
however, common ; for example, terpin of unspecified stereochemistry is dehydrated by aluminium phosphate and aluminium oxide to give limonene (l), p-cymene (13), and
unidentified p r ~ d u c t s .The
~ ~ authors of this paper were
surprised by the p-cymene, but we are surprised by the
limonene, since we would have expected terpinolene (8) !
Innumerable different conditions have been described for the
preparation of a-terpineol (21 ; R = H) from terpene hydrocarbons, mostly from turpentine. The most efficient way from
limonene seems to be by using chloroacetic acids and a cationexchange resin ; this gives optically active a-terpineol in 85 O/O
conversion and 99 O/O selectivity ;*' alternatively, formic acid in
the presence of zeolites gives 87-100% conversion and high
selectivity.8i From limonene and acetic acid, with ferric sulphate
as a catalyst, a 6:4 mixture of a- and /3-terpinyl acetates is
efficiently made.8HOxymercuration of limonene followed by
reduction with sodium borohydride gives a-terpineol (21 ;
R = H) [70%], the rest being the diol (24; X = OH) and 1,8cineole (26).89 In fact it has long been known that if this
If
procedure is applied to a-terpineol it leads to 1,8-~ineole.~~)
the mercuration of limonene is carried out in the presence of
sodium lauryl sulphate, the formation of micelles causes the
ionized part of the molecule to be exposed to attack by water
on the periphery, and monohydration raises the yield of
terpineol to 97
The addition of methanol to limonene in the presence of an
acid could not be repeated by Treibs,92who reported that there
was mainly dimerization with a small amount of double
addition. The reaction was taken up again in 1949, when
Royals showed the reaction to be reversible by the fall in the
optical activity of the product (21 ; R = Me) with increasing
reaction time. Royals prepared other terpenyl ethers.93 (See
also refs. 54 and 71). By-products from this reaction would be
expected; although they have not been described, those from
the very similar reaction of pinene and methanol have,94
notably the ethers (27), (28), and (29). Bicyclic systems arising
from the reaction of pinene would, of course, be absent from
the products from limonene. Diol monoethers are known,
being made, for example, from limonene and ethylene glycol in
the presence of an ion-exchange resin.g"(See also ref. 96). The
light-induced addition of methanol to limonene takes a different
course from the acid-catalysed reaction, yielding 52 '/o of the
ethers (27) and (28) with about 13 YOof mentha-1(7),8-diene
(30).9i
The microbiological addition of water to limonene is
mentioned later.
The addition of hydrogen chloride to limonene to give its
monohydrochloride (31)98works well only in the absence of
SR
(37) (-)-(38) R=H
(39)
(40) R=Ph
NCHO
moisture and in a solvent, e.g. carbon disulphide,99petroleum
ether,'OO or dichloromethane. lnl Hydrogen bromide reacts
similarly, and the halides are converted into a-terpineol by the
action of magnesium and air,'"O or with 2 % potassium
hydroxide (a stronger base yields hydrocarbons, mostly
dipentene).lo2Zinc oxide (in 80 YOacetone for a-terpineol, or in
acetic acid for the acetate) has also been recommended.103
Because the chloride that is made in this way is optically active,
so is the terpineo1.lo2The di-addition products (24; X = C1)
and (24; X = Br) have also been known for a long time;'"' they
are best made by the action of concentrated halogen acids in
methanol"" or acetic acid o n limonene and can be converted
into the terpineols by adding a base.ln5The safest route from
limonene to y-terpineol (23) is still the original one from
Baeyer,lo6consisting in brominating the dihydrobromide (24;
X = Br), to obtain 1,4,8-tribromomenthane (32),loi and then
reducing this with zinc in acetic acid to the acetate of (23), with
overall yields of 50-60 YO.''' A method that is said to produce
72% of y-terpineol (23) consists in dehydrating terpin (24;
X = OH) in isopropyl alcohol and 95 Yo sulphuric acid at room
temperature for 80
The reaction of limonene with phenols dates from 1922,""
and the products have been patented as resins and lacquers."'
These products could arise either by aromatic substitution or
by formation of a phenol ether,112 further reaction giving
polymers.l13 The reactions are more complex than those of
camphene or pinene (cf: the vague description of the reaction of
limonene with 2,4-dimethylphenol compared with the precision
of the same reaction with camphene in 1960114)and while two
products [(33) and (34)] have been described from the reaction
of phenol and limonene in the presence of boron trifluoride,'l"
this cannot be the whole story. In the presence of a cationic ionexchange resin, for instance, limonene reacts with cresols, ocresol yielding the ethers (35) and (36)11' [another surprise,
since these products require a carbenium ion that is derived
295
NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE
from a-terpinene (9)]. Dimethylphenols with one free orthoposition"' and sesamol (3,4-methylenedioxyphenol)'18 give
similar compounds. The reaction of limonene with phenol has
also been studied in the USSR,"' but the publication was not
available to us.
Addition of nitric acid to limonene has been
The ester that was obtained was reduced (by zinc dust) to aterpineol. 120 The racemization of ( +)-limonene in sulphur
dioxide occurs via the addition complex (37).122Menth- I-ene
also racemizes in liquid
The addition of hydrogen sulphide to limonene was shown to
give menth-1-ene-8-thiol (38) in 1979,124this compound also
being obtainable by the EtAlCIBr- or AlBr,-catalysed addition
of H,S to pinenes.12j This compound is characteristic of
grapefruit flavour, in which it occurs naturally, and has the
lowest recorded flavour threshold of any naturally occurring
substance.126 It is converted into 2,8-epithio-cis-p-menthane
(39) by radical cyclization.126The acid-catalysed addition of
thiophenol to limonene yields 40 YOof 8-phenylthiomenth- I ene (40), but it is difficult to purify the latter above 82%, and
Fourneron et al. preferred to protect the double bond at C-1 of
(+)-limonene by treating it with N-bromosuccinimide in
methanol [which yielded (41)] before acid-catalysed addition of
thiophenol and removal of the protecting groups (using zinc
and acetic acid) to obtain ( -)-(40),12' which they required for
a synthesis of car-2-ene (42).
Di(p-toly1)methyl chloride adds to one double bond of
limonene in the presence of zinc chloride (to the double bonds
at C-8 and C-1 in the ratio of 2.5: 1).12R
In three hours, at 55 "C, hydrogen cyanide in 55 YOsulphuric
acid also adds to both double bonds of limonene. From the
product (43), 1,8-di-isocyanomenthane was prepared by using
phosgene, rearrangement of the isocyano-compounds to 1 3 dicyanomenthane taking place with o-dichlorobenzene at
250 "C. The stereochemistry of the products was not discussed.'29 The addition of isocyanic acid in the presence of
BF, OEt, gave only a-terpinyl isocyanate.130
(47) X=Br
(48) x=€1
&Cl
SPh
&SPh
c1
*
4 Addition of Halogens, Sulphur, etc.
The addition of halogens to limonene has been known since the
time of Walla~h.'~'
Addition of chlorine is not clean because of
the intervention of free-radical substitution. The matter was reinvestigated by Carman and Venzke, who have given a method
(using iodobenzene dichloride) to achieve clean formation of a
tetrachloro-compound (44). They have also described the
photochemical chlorination of limonene dihydrochloride (24 ;
X = Cl), which leads to the 1,2,4,8-tetrachloride (45).'"2
Addition of bromine to limonene is a two-stage process,133
but the rate slows well before the first mole has been added, and
a mixture of the dibromide (46), two tetrabromides, and some
other compounds were identified, but no dibromide arising
from addition only to the C(7tC(8) double bond.',' ' Limonene
tetrabromide' had long been used as a crystalline derivative of
limonene (cf. Mosher13*),and Carman and Venzke showed that
the crude bromination mixture consisted of 70 YOof a crystalline
tetrabromide and 30 YOof another tetrabromide which was oily
if (+)-limonene was used but crystalline if the racemate was
used. At first, they considered the crystalline tetrabromide from
( + )-limonene to have the (8S)-~onfiguration,'~~
but X-ray
crystallography showed it to be the (8R)-isomer (47).136A
related dichlorodibromide (48), which was made135by partial
debromination of racemic limonene tetrabromide followed by
chlorination of the double bond, was shown similarly to have
the same ~ 0 n f i g u r a t i o n . l ~ ~
Somewhat similar to halogenation is the addition of iodine
azide to both double bonds of (+)-lim~nene.'~'
Addition of benzenesulphenyl chloride to limonene also
occurs across both double bonds ;138 one mole adds 70 YOto the
C(8)-C(9) double bond and the main isomers of the double
addition are (49) and (50).139
The formation of volatile sulphides from the reaction of
(54)
sulphur with limonene was noted by Nakatsuchi in 1930,'J0 but
it was only in 1959 that Weitkamp deduced the formulae
(51)-(54)
and discussed the possible mechanism of their
f ~ r r n a t i o n . Weitkamp's
'~~
major product (54) is isomeric with
one of the compounds (39) that were described by Demole and
Enggist (see above).126Actually, Weitkamp had also obtained
this isomer (39), mixed with (54), by catalytic reduction of
(53).14'These products must have been the main components of
a mixture that had earlier been patented as a flotation agent.lJ2
More recently, refluxing limonene with sulphur for two hours
was shown to give a complex mixture consisting of ten
hydrocarbons and 22 sulphur-containing aromatic and terpenyl
compounds. The mass spectra of these substances were taken,
and proposals of several new structures were made, including
the trisulphide (55),ld3but it would be desirable to have further
proof. Sulphurized limonene has been patented by oil companies as an additive in lubricating and oxidation-resistant
The reaction of diphenyl diselenide with hydrogen peroxide
gives phenylseleninic acid, ' PhSeOH ', which adds to limonene
to yield oxabicyclic selenium compounds (56), reduction of
which (by tributyltin hydride) leads to 1,8-cineole (26) in high
yield. 145
5 Hydrogenation of Limonene
The first catalytic hydrogenations of limonene, which were
carried out by Sabatier and Senderens at the turn of the
296
NATURAL PRODUCT REPORTS, 1989
Published on 01 January 1989 on http://pubs.rsc.org | doi:10.1039/NP9890600291
QOH
H
p.
H
OH
OH
H
(67) R a e
century, yielded menth-l-ene (57) over copper"" and the
menthanes (58) over nickel."' These results were rapidly
followed by others, e.g. the use of platinum black, which caused
addition of hydrogen in two stages,"$ and the use of pressure.""
It was soon recognized that many catalysts effccted not only
hydrogenation but disproportionation ( c ) . g . copper'"'!' and
platinum on charcoal'j'). Some catalytic supports favour
hydrogenation more than dehydrogenation (ZrO, and Tho,)
while some favour dehydrogenation (MgO, CaO, and La20:3).'.i'
The occurrence of undesired disproportionation reactions has
led to the discovery of many methods that give high yields of
menth- 1-ene, for example sodium borohydride and platinum
salts (98 YOyield)'"" or nickel chloride and polyvinylpyrrolidone
with hydrogen.'.j4 A catalyst that contained neodymium and a
silane gave menthene after 1.5 hours'jj and a complex that
contained rhodium trichloride and triphenylphosphine and
which was used as a catalyst in water give menthene after 32
hours and menthane after 76
For preparative
purposes, Newhall has confirmed'"' the utility of Vavon's
platinum catalystlA8rather than palladium or copper for
menth-l-ene, and we have found that a small amount of Raney
nickel is adequate to give over 90 YOof (57).ljXThe configuration
of the fully reduced menthanes (58) has been well established,'"!'
and catalytic reduction generally gives preferentially the tramisomer, but catalytic amounts of cob(1)alamin in aqueous acetic
acid give nearly 70% of the cis-isomer.'"' The readiness of
double-bond rearrangement in limonene during reduction has
been exploited by using hydrogenation over a deactivated
palladium catalyst; this yielded a mixture from which menth-3ene (59) could be isolated, the unchanged limonene being
recycled (racemization was not mentioned, but we can suppose
it to have occurred).161 The reason for this rearrangement-hydrogenation was to make menthone [( +)-(60)] from
the epoxide of (59).162
Most of the catalytic reductions that have been mentioned
yield optically active menthene, but reducing conditions
involving isomerization are known. Thus menth- 1-ene slowly
racemizes when heated in toluene with sodium and ochlorotoluene because of the reversible reaction that occurs
between menth- 1-ene (57) and menth-3-ene (59), the equilibrium
mixture containing 63% of the latter [together with 5 % of
menth-4(8)-ene (6 I )].lfi3
Dehydrogenation of limonene to p-cymene is reported to
occur best over a catalyst of PdO and sulphur on active
charcoal at 220-230 "C,giving 97 YOyield of p-cymene (1 3) in
96% purity.164 On a small scale, iodine yields 65% of pcymene.165
The disproportionation of limonene to p-cymene ( I 3) and
menthane (58) has been known since 1924, with palladium151or
platinum on charcoal166 as catalyst. The dehydrogenation
occurs in two stages; initially 52-53 YOof p-cymene is formed,
OO
/
of menth-8-enes (62). Longer reaction
together with 4-2
(68) R=CMe2CHMe2
(71) R=H
"p
(72) X=OH
( 7 3 ) X=I
(74)
times lead to the menthanes; with mesityl oxide as the hydrogen
acceptor, yields of up to 94% of p-cymene can be obtained.lfii
The hydrogen that is available from limonene has also been
used in the hydrogenation of double bondslfiH
and of nitriles to
methyl groups1"!' (both with palladium on charcoal as catalyst)
and, by adding ferric chloride to the same catalyst, of carbonyl
groups to hydrocarbons.""
Reductions of limonene other than catalytic ones have not
been used; Semmler showed in 1904 that sodium in alcohol was
without action."' Reduction of limonene vici hydroboration is
mentioned below.
6 Hydroboration and Related Reactions
The first attempted monoaddition of diborane to limonene
resulted in a statistical mixture of the diols (63).li2 Using
disiamylborane, Brown showed how menth- 1 -en-9-01 (64) was
obtained in 79 % yield after oxidation,"" similar results having
been obtained with aluminium alkyls."' Brown did not mention
the stereoisomerism at C-8 of (64), which was pointed out by
Albaiges et ci1.li5 Using the addition of di-isobutylaluminium
hydride to (+)-limonene followed by aerial oxidation, Ohloff et
al. described the stereochemistry of the isomers of (64) and the
corresponding aldehydes (65), a diastereoisomeric mixture of
which occurs in Bulgarian rose oil."" X-Ray crystallography of
the (lR,3R,4S,8R)-isomer of the diols (66)l" and of the
(4R,8R)-isomer of menth- I-en-9-01 (64)liX established the
stereochemistry of each of them. More recently it was
reported"" that boron dihydrogen chloride gave 81 o/' of the
alcohols, although thexylboron hydrogen chloride seems to be
more stereoselective, and oxidation of the menth- 1 -en-9-ylborane that was obtained with the latter gave 68% of menth1 -en-9-als directly.1H"Direct reductive alumination of limonene
with aluminium and hydrogen in hexane at 160 "C and then
aerial oxidation leads to (64).I8l Some methods of reduction of
limonene, involving boron and cobalt compounds and then an
acid, have been described,"' but treatment of the adduct of
View Online
NATURAL PRODUCT REPORTS. 1989-A.
Q
F. THOMAS AND Y. BESSIERE
QOl1OQ
/
2' 9'9
or1
(79)
HO #*a,
OOH HO +,,
OH
RO.*,
\
/
0
(83)
(81 1
(80)
(84)
(85)
disiamylborane and limonene with acetic acid at 100 "C gives
completely racemized menth- 1 -ene.lH3
A preliminary note by Brown and Pfaffenberger in 1967IH4
was followed by a rather different full paper in 1975l"j in which
the preparation of the cyclic boron compounds (67) and (68) is
described. The diols (69) were obtained from (67) (the
stereochemistry at C-8 again not being specified) while 83 YOof
D-( -)-( 1 R,2R,4R)-carvornenthol (70) was obtained from (68),
this being the most efficient way of making a single carvomenthol from limonene. Hydroboration of ( + )-limonene with
BH,Cl .OEt, and then reduction with lithium aluminium
hydride gives a borane (71) that is said to be useful for
asymmetric induction in the hydroboration of alkenes.1N6
Acetoxyborohydride is made from NaBH, and Hg(OAc), in
tetrahydrof~ran.'~'?
This reagent hydroborates limonene on the
double bond at C-1, then treatment with hydrogen peroxide
yields dihydrocarveol (72) (stereochemistry unspecified) and
iodine yields 2-iodomenth-8-ene (73).l H H
Hydroboration can be used on functionalized limonenes
such as the epoxides,lxg and the alcohol (64) can be converted
into the corresponding chloride with CCI, and Ph3P,190leading
to a wide variety of synthetic routes.
(+)-Limonene has been silylated to (74) with triethoxysilane
at 80 "C and a catalytic amount of platinum on charcoal. The
product was patented as a waterproofing agent for concrete. lB1
7 Oxidation (except Epoxide Formation)
Since 1914 it has been knownlg2that limonene is very sensitive
to air or oxygen, rapidly acquiring a high peroxide number, and
it has been used as an a n t i 0 ~ i d a n t .The
l ~ ~ peroxides are slowly
converted into other substances under various conditions (this
oxidation is partly responsible for the 'off-flavour' of aged
citrus oils). A full explanation has been given by Schenck et
~ 1 . ' ~The
' ' effect of an acid on the hydroperoxides was noticed
by Bain,1g5.196
and we have noticed that the rise in temperature
that often occurs when limonene is hydrated under mild
conditions (weak aqueous acid in organic solvent) is due to the
presence of hydroperoxides. Ig7 Autoxidation is not stereospecific, racemic alcohols being formed after reduction of the
297
hydroperoxides (cis:trans = ca. 1 : 1) and racemized through
the intermediacy of the radical (e). Decomposition of the
hydroperoxides with heavy-metal catalysts can alter the
distribution of the products (after reduction) between carvone
[( +)-(75)] and the menthadienol(76), which has predominantly
cis hydroxyl and isopropenyl
There are many patents
and papers concerning such reactions (with Co, Mn, and Ni
The products that were formed by leaving a
drum of limonene open in Australian sunlight included a trace
of perilla alcohol (77),lg9and heating a solution of limonene in
dimethyl sulphoxide at 100 "C in air for 48 hours is reported to
give 95 OO/ of 4-methylacetophenone, via dimethylstyrene (78),'0°
whereas, in dimethylformamide or hexamethylphosphoric
triamide as the solvent, cymenol (79) is the main product.'"
Autoxidation in the presence of ammonia (' ammonoxidation ')
yields a complex mixture of terpene hydrocarbons, pulegone
(SO), and, more interestingly, some trimethylpyridines, including the 2,3,6-i~omer.~~*
Dye-sensitized photo-oxygenation (by '0,)of limonene leads
to hydroperoxides, the stereoisomers of which have been
separated and chara~terized.'~~
The reduction products of the
laiter are stereoisomers of the menthadienols -(76), (8 I), and
(82), but, in contrast to the autoxidation, the alcohols with cis
hydroxyl and isopropenyl groups are predominant, particularly
(76), and they are optically active.204Improvements (of the
lamp or by supporting the Rose Bengal catalyst on magnesium
oxide) have been claimed.*05 Reaction rates have been
determined.206Uranyl-acetate-catalysed photochemical oxidation of limonene leads to a hydroperoxide (83), hydrogenation
of which (over Pd) gives the tvans-menthane-trans- 1,2-diol
(84).'07 Catalysis of the photo-oxidation of menth- 1-ene with
ferric chloride, which has not been reported with limonene,
gives 38 YOof ring-opened products.'08
Oxidations that are supposed to permit greater selectivity,
especially for avoiding racemization via the radical (e), include
the use of t-butyl peracetate or perbenzoate in the presence of
cuprous bromide. The cis-carveol (82) and the trans-carveol
(85; R = H), which are obtainable from (+)-limonene, were
then converted into (-)-carvone (75).'09 Wacker conditions of
oxidation (air and copper chloride, with a catalytic amount of
palladium chloride in acetic acid) give a highly stereoselective
oxidation to trans-carveyl acetate (85 ; R = Ac) in 63 YOyield,210
PdCl(NO,)(MeCN), being without catalytic action.'"
The oldest method of converting limonene into carvone is
through the nitroso-chlorides (86), which were first made by
Tilden from gaseous nitrosyl chloride,212this preparation being
improved by Wallach by using an alkyl nitrite and HCl."'" The
action of base then gave carvone oxime,214from which carvone
was obtained by the action of an acid. This route is both
industrialz1" and academic, there being an undergraduate
experiment for making carvone from orange
There are
variants, using nitrosylsulphuric acid,"'? dinitrogen tetroxide in
formic acid,'18 and so forth.
Direct allylic oxidation has been carried out with t-butyl
chromate, this giving 21 YO of carvone (75) and 13 YO of
isopiperitenone (87),'l9 with the Cr0,-pyridine complex, to
give 36 YOof (75) and 31 YOof (87),220with t-butyl hydroperoxide
and hexacarbonylchromium, to give net yields of 39% of (75)
and 28.5% of (87) (with 47.7% of the limonene being
recovered),221and with pyridinium chlorochromate, to give
(75) and (87) in the ratio of 2 : 1 . 2 2 2 Pyridinium dichromate and
298
NATURAL PRODUCT REPORTS, 1989
OH
(92)
OMe
(93)
t-butyl hydroperoxide in the presence of Celite is reported to
give a 48 YOconversion and 23 YOyield of piperitenone (88), but
the 'H n.m.r. figures that are given223correspond neither to
piperitenone (88) nor to isopiperitenone (87). It should be
noted that (88) is readily prepared by oxidation by dichromate
ion of the major product (76) from the photo-oxidation of
limonene.2n4
The first experiments on the electrochemical oxidation of
limonene concerned the experimental technique, but no
products were isolated.224Later it was suggested that, in an
aqueous medium, hydration occurred before oxidation."5 In
methanol, a mixture was obtained, mostly of ally1 methyl
ethers;226a-terpineol (21 ; R = H) and trans-carveol ( 8 5 ; R =
H) have also been reported."' On a graphite electrode, in
NaCIO,, the major products from (+)-limonene are (-)dihydrocarvone (89) and the trans-diol (90); both antipodes of
limonene were examined.22H
The cis-hydroxylating oxidant potassium permanganate
yields the tetraol 'limonite' (91) (m. pt 192 0C),"9 which was
also obtained with hydrogen peroxide and catalytic amounts
of osmium tetroxide.'"" The 1,2-diol that is obtained by the
reaction of limonene in acetic acid2"' arises by a different
mechanism from ring-opening of the epoxide (see below).
The first work on the oxidation of limonene by selenium
dioxide contained no spectral data,*"' and Sakuda'"" and one of
showed that the main product from the reaction in
ethanol is racemic mcntha- 1,8-dien-4-01 (92), together with a
certain amount of mentha- 1,8( 1 O)-dien-9-01( 1 8) and optically
active truns-carveol ( 8 5 ; R = H). The isolation of supposedly
optically active mentha- 1,8-dien-4-01 has been described in
later papers, one using the same method,':'" the other using
H 2 0 2and catalytic SeO,,':'" this reaction also being described
el~ewhcrc.~"'
Sharpless confirmed our work, and showed that
the spurious optical activity was due to
The
reaction is indeed complex (Sharpless mentions 27 products,
and the carbonyl-containing products have been analysed'"!'),
but the main product is always (92). Oxidation by selenium
dioxide in acetic acid takes a different course, leading mainly to
carveyl acetate [truns (85; R = Ac)/cis = 4 : 1 ; 40%], the
acetate of ( 1 8) [30 %I, and trans-mentha- 1(7),8-dien-2-yl acetate
(93) [ 10 Yo].
Oxidation of limonene by lead tetra-acetate is useful for
making optically active derivatives of mentha- 1,8(1 O)-dien-9-01
(18) from the initial product (94) of the rea~tion'~'(cf: the
preparation of lanceo124'),although it was first carried out on
the ra~emate.'~"
Although the limonene anion (c) makes this
reaction apparently redundant, it was still used to make the
aldehydes (65) in 1979.244
Oxidation by manganese(rr1) acetate is discussed in Section
10.
The oxidation of limonene by mercuric acetate in acetic acid
He -
R
(99) R=CHO
0
$CHO
(100)
ODmEt
(1011
fcHo
(102)
(104) R=CH20H
leads to a small amount of hydrocarbons (including mentha1,4,8-triene and p-cymene) and to mentha- 1,4(8)-dien-9-y1
acetate (95) and trans-carveyl acetate ( 8 5 ; R = Ac).'~, Under
different conditions (and after reduction with NaBH,), zterpineol (21 ; R = H) and P-terpineol (22) were obtained, the
terpins (24; X = H) also having been reported'lj (although the
authors did not seem to appreciate the instability of these on
gas chromatography).
Oxidation of limonene by thallium(III) nitrate is one of the
few routes from it to the bicyclo[3.2. Iloctane structure (another
is mentioned in Section 8, under the 8,9-epoxide). In methanol,
81 YO of the limonene was converted into a mixture of
stereoisomers of (96) and (97) (1 : 4), 19 YOof the products being
unidentified. 246
Early work on the oxidation of limonene by chromyl
but later work led
chloride mentioned a number of product~,'~'
only to a small amount of dihydrocarvone (89).'48
When passed over vanadium pentoxide on pumice at 425 O C ,
limonene yields maleic anhydride.249
The action of N-bromosuccinimide on limonene should lead
to allylic bromination ; the first study reported unstable
brominated products, which were converted in 80 YOyield into
p-cymene (13) by KOH in MeOH.'"" It is likely that the major
brominated product is indeed the expected one (98; X = Br),
Taher and Retamar having converted limonene into carvone by
this route; they used aqueous KOH in dioxane for the
hydrolysis.251The action of t-butyl hypochlorite appears to be
cleaner; the production of (-)-trans-carveyl chloride (98; X =
C1) has been optimized'"' and the latter converted into carveyl
esters with zinc carboxylates. 23:j
View Online
NATURAL PRODUCT REPORTS, 1989-A.
(107)
(108)
299
F. THOMAS AND Y. BESSIERE
(109) X = S e ( O ) P h
Y=OH
(110) X=OH Y = S e ( O ) P h
6
Br
(111) X&1
Y=OH
(112) X=OH Y=C1
(114) X=NMe2 Y=OH
(115) X=OH Y=NMe2
Early work on the ozonolysis of limonene was restricted to
the possible identification of some (methyloxocyclohexenyl)
acetic acids;'j4 a diozonide was also reported.255The reaction
occurs very rapidly."j" The study of partial ozonolysis seems to
date only from 1956, the aldehyde (99) and the corresponding
acid being identified after oxidative decomposition (by CrO,)
of the ozonide (with a small amount of 4-methylcyclohex-3enyl methyl ketone, from ozonolysis of the isopropenyl
group)."j' The aldehyde (100) was mentioned (without its
properties), but it was only compared with a degradation
product from cembrene.'" The isolation of the C, acid, after
reduction and then esterification to ( I O I ) , rather than a C, acid
of the early work'j4 was also claimed.259The cyclization of the
aldehyde (99) to an aldehyde (102)260or a ketone (103)''' was
studied by Wolinsky [who made (99) from limonene epoxide]."'
The optical activity of saturated (99) has been used in further
syntheses."? Mono-ozonolysis has been exploited by a Polish
group,?"3
who have also shown that electrochemical reduction
of the ozonide of (+)-limonene leads to the optically active
alcohol (104), the latter cyclizing to the tetrahydrofuran (105)
in acid.?6J.?6.5See also the description of the cyclization of (99)
to a cyclopentanone (106) with a rhodium chloride catalyst."6
$0.
-\
OH
OH
chlorohydrins ( 1 11) and ( 1 12) with HCI in ether; only (1 12)
[from the truns-epoxide (108)l gives a crystalline p-nitrobenzoate, After separation, KOH in MeOH enabled the pure
epoxides to be recovered.280The greater reactivity of the cisepoxide towards acids means that this isomer will give transdi hydrocarvone (89) before the trans-epoxide begins to react,
and the latter can then be isolated by fractional distillation.281
The cis-isomer (107) also reacts more rapidly with bromine;
treatment of the bromides ( 1 13) that were obtained from the
epoxide mixture by its reaction with tributyltin hydride gives
The products
1,8-cineole (26) and the trans-epoxide ( 108).2H2
from treatment of the epoxide mixture with dimethylamine,
which were the amino-alcohols (1 14) and ( 1 15), can be readily
separated, and the methiodides then yield the pure epoxides
with potassium hydroxide. 283
The presence of the limonene 8,9-epoxides ( I 16) and ( 1 17)
among the epoxidation products was suspected as early as
1926,284but they were in fact only described in 1961 as arising
from the oxidation of limonene by air.lg6 They were later
prepared285by using the Payne epoxidation (H,02 and PhCN),
40-50 YOof the epoxidation then occurring in the isopropenyl
8 The Limonene Epoxides
group, although the conversion is very low. An alternative
synthesis from methyl 4-methylcyclohex-3-enyl ketone and
Direct oxidation of limonene with perbenzoic acid was first
described by Prileshajew ; p f i 7 peracetic acid was later used on
dimethylsulphonium methylideZ8'has been preferred. 12j" Methyl
(-)-limonene,'68 but only in 1957 on the ( +)-isomer.26gThese
4-methylcyclohex-3-enyl ketone is usually made from isoprene
and methyl vinyl ketone, and is racemic, but it can also be
and other oxidations with peracids lead to nearly 1 : 1 mixtures
prepared from limonene in optically active form (by ozonolysis
of the cis- and trans- I ,2-epoxides ( I 07) and ( I 08) or (in an early
case, when H , 0 2 in acetic acid was used) to the menth-8-eneof limonene 1,2-epoxides and removal of the epoxides after
1,2-di0ls.'"~The cis-oxide (1 07) was prepared stereospecifically
separation of the isomers).288The two 8,9-epoxides can be
by Polish workers, who used the monotosylate of the 1,2separated by careful distillation, and they were assigned
diol,"O and a full investigation of the two isomers was made by
configuration by Horeau's method and correlated with the
uroterpenols (limonene metabolites) ( I 18) and ( I 19) by KergoNewhall."' Oxidation by a peracid gives about 10 YOof the 8,9epoxides (see be lo^),"^ and various other methods slightly
mard and Veschambre. 289 Kergomard also converted the
alter this proportion. For example, epoxidation of limonene
uroterpenols into the optically active a-bisabolols [u.g. (120)
with sodium hypochlorite in the presence of a manganese(1rr)
but there was a discrepancy between
from (+ )-1im0nene],~~~
porphyrin gives a ratio of 7 : 1 of l12-epoxidesto 8,9-epo~ides,~'~ the stereochemistry of these and the stereochemistry of
and iodosobenzene with an iron porphyrin (which is more
bisabolols that had been made in another way,290and an X-ray
electrophilic than manganese) gives a ratio of nearly 20: 1 . 2 7 8
study showed that the configuration of the bisabolol was not
Molybdenum-hexacarbonyl-catalysed t-amyl hydroperoxide
that attributed to it by K e r g ~ m a r d . ~ A
" careful study by
yielded 70 YOof the cis-isomer ( 107),274this work having been
Carman has now shown that Kergomard's assignments of
repeated in order to prepare the menthadienol (76) and the
stereochemistries for the uroterpenols ( 1 18) and ( 1 19) are
(the
trans-isomer of (81) via the selenoxides (109) and ( I
correct (as are, therefore, the stereochemistries of the epoxides).
latter had been briefly mentioned independently elsewhere2").
The mixture of uroterpenols is not separable, and neither are
A 1 : 1 mixture of (107) and (108) can be obtained from
the dibromides of the uroterpenols. Finally, the p-nitrobenzoates of the uroterpenol dibromides were separable, and
limonene, in 60 Yo yield, with pertungstate-catalysed hydrogen
peroxide2" and in 87 % yield by the action of superoxide anion
X-ray crystallography of the recovered uroterpenols showed
clearly that the lower-melting isomer has the stereochemistry
(potassium superoxide and 0- or p-nitrobenzenesulphonyl
( 1 1 8).292Carman also showed that the higher-boiling (4R,8R)chloride) on limonene."'
isomer of the epoxide (1 16) was converted into ( 1 18) by
Although the isomers (107) and (108) can be separated by
tetramethylammonium hydroxide in dimethyl sulphoxide in 36
careful distillati~n,"~
details of several chemical methods have
hours at 3 5 - 4 0 "C,the other epoxide ( I 17) yielding ( 1 19) under
been published. One involved their conversion into the
c
300
NATURAL PRODUCT REPORTS, 1989
p..kme
the same conditions.293 The bisabolol discrepancy remains
unexplained.
The 8,9-epoxides have been used as intermediates in the
conversion of limonene into the bicyclo[3.2. Iloctane system.
Thermal rearrangement of the 8,9-epoxides to the menth- 1-en9-als (65) was described in 1961,294and this reaction also occurs
with acid ion-exchange resins, the reaction going further to
yield optically active 2,6-exo-dimethylbicyclo[3 .2.l]oct-2-en7-endo-01 (121) as the major product together with a little of the
6-endo-methyl isomer.295The racemate of (1 2 1 ) had already
been prepared from geranyl acetate.29'
The mixture of the four possible diepoxides has been known
as long as the 1,2-epo~ides.~~'
Little work was carried out until
1955, when it was again described,297and from 1956 onwards
there are many patents describing the polymerization of
' limonene diepoxide ' with Friedel-Crafts catalysts298or photosensitized cationic polymerization. 299 Although this is a major
use of limonene, there exists no description of the individual
isomers of the diepoxides (122) and they have only one
Chemical Abstracts Service Registry Number. The 1,2-epoxide
group is more reactive towards acid than the 8,9-epoxide
group, and the epoxides of (1 1 1) and (1 12) have been obtained
by treating the mixture of the diepoxides ( 1 22) with hydrochloric
acid under mild conditions.300When the diepoxides are used in
synthesis, the mixture is employed without comment (e.g. the
synthesis of hernandulcin by Mori and Kato301).
The epoxides have been used to protect a double bond in
limonene. Thus Ohloff et al. prepared optically active mentha1,8-dien-4-01 (92) by selenium-dioxide-catalysed oxidation of
( + )-limonene cis-1,2-epoxide ( 1 07), followed by removal of the
epoxide group by treatment with zinc and acetic acid and
sodium iodide,302but the yield was not good. An alternative
suggestion is to reflux the epoxide with lithium and 1 mol % of
biphenyl in ethylene glycol dimethyl ether.303
Limonene diepoxide (122) has been examined for cytotoxic
activity .,04
CIC1
The episulphides of limonene have been prepared indirectly
from the epoxides by treating these with thiourea followed by
ab a ~ e . ~ ~ ~ . ~ ~ ~
9 Addition of a C, Unit to Limonene
After an early study in which no compounds were identified,"06
Prins suggested structure (123) for a compound that was
formed by the acid-catalysed reaction of formaldehyde and
limonene.,07 In 1953, Lombard re-examined the reaction ; he
used a zinc chloride catalyst, and suggested that the main
product was the homo-alcohol (124; R = H),8n8this structure
being well established by Ohloff (who used an uncatalysed
reaction in acetic acid)309and by Blomquist et al."" This work
was soon followed by o t h e r ~ , ~ ~ . ~
the
~ ~dioxanes
."'"
(125) and
(126) also being identified from a perchloric-acid-catalysed
reaction.313The n.m.r. spectra of the products [including the aterpenyl ether of (124; R = H)] were measured by Blomquist,
who obtained 80 O h of the acetate (124; R = Ac) by using BF,
and acetic anhydride.,l4
The alcohol (124; R = H) was oxidized by Suga and
Watanabe.315 The corresponding dihydrogenated aldehyde
(127) is the main product from hydroformylation of limonene,
which was first carried out over Raney
In methanol
(using octacarbonylcobalt as catalyst), the main product is
the saturated methyl ether (128), and the aldehydes (129)
were reported from the reaction in acetone,317 although we
question this structure. Later, rhodium catalysts, notably
RhH(CO)(PPh,)3,31*were used, and the rate of reaction of
limonene was shown to be rather low compared to those of
other a l k e n e ~ although
, ~ ~ ~ the yields were
After the
initial patenting of ( 1 2 7 ) y other patents followed.321
Phosphite-modified rhodium catalysts increase the rate of
hydroformylation of l i m ~ n e n e .Esters
~ ~ ~ of the acid corresponding to (1 27)323and a Mannich product ( I 30)324have
been made.
30 1
NATURAL PRODUCT REPORTS, 1989-A. F. THOMAS AND Y. BESSIERE
&.
kOH
(145)
Although the Vilsmeier reaction of [CICH=NMe,]+[CI,PO,]with (+)-limonene gives a yield of only 40 % after 6 days, it is
very useful in that the ( E ) / ( Z ) ratio of the aldehydes (131 ;
R = H) that are formed is 98 :2; this fact led Dauphin to a rapid
synthesis of (E)-atlantone (1 32).325An earlier synthesis of (1 3 1 ;
R = H) was a multi-step one from methyl vinyl ketone.'s26The
isomers of (131: R = H) have been patented as flavour
material^."^
Delay and Ohloff used the anion (c) for adding one carbon
atom to (+)- or to (-)-limonene. Carbonation gives the /j'y
unsaturated acid (1 33 ; R = OH).32H
The corresponding ester is
isomerized (by MeONa in MeOH) to the thermodynamic
mixture of the conjugated esters (131 ; R = OMe) [ ( E ) / ( Z )=
82: 181. After separation, these were used in the synthesis of
or-bisabolenes (1 34) of known stereochemistry.32'H
Carbon tetrachloride reacts with limonene either in the
presence of a
or under the influence of ultraviolet
light33nto yield an addition product (135), hydrolysis of which
(by ethanolic KOH) leads to the optically active acid (131 ;
R = OH),330.331which was also used331for synthesizing (R,E)atlantone from (+)-limonene. Distillation of ( 1 35) in ethylene
glycol (at 200-2 10 "C) gives methyl 4-methylcyclohex-3-enyl
ketone. 33
Carbon oxysulphide reacts with limonene in a dimethyl- or
diethyl-aluminium-catalysed ene reaction to give ( I 33 ; R =
SH).332
The Simmons-Smith reaction of limonene was reported in
1958 to yield exclusively the product (136) of addition to the
isopropenyl double bond, the recovered limonene having
undergone 'little or no racemization' despite a fall by 5 0 %
being recorded in the rotation.333The structure was established
by infrared spectrometry.""4 The same compound ( 1 36) was
obtained by the palladium(n)-acetate-catalysed addition of
diazomethane.335Kropp et al. prepared all of the possible
addition products by irradiation of methylene iodide and
limonene in chloroethane; the yields were, after three hours,
7 % of (136), 47% of (137), and 14% of (l38).""" The
bicyclo[4.1. Olheptane (1 37) has also been prepared by the
reaction of the readily accessible dichlorocarbene addition
but in none of these
product ( I 39) with naphthalenelithi~m,:~:~~
papers were the spectral properties of (137) described; a paper
in which the 13Cn.m.r. spectra of the cyclopropanes ( 1 37) are
given does not say how they were prepared and separated.:':''
One of us has confirmed that the major addition product from
the Simmons-Smith reaction is indeed (136), but that the two
isomers of (137) are also formed (the ratio is about 3: l), and
the reason that the earlier papers missed this was probably that
(137) distilled with the limonene that was recovered, thereby
lowering the observed optical
This preference for
reaction on the exocyclic double bond is the contrary of that
found in 4-vinylcyclohexene, where 8 1 % of the monoaddition
takes place on the endocyclic double bond.310
Addition of dihalocarbenes is difficult to stop at the stage of
monoaddition3-'1 unless phase-transfer conditions are employed."-', The products vary with the catalyst: PhCH,NEt,+
C1- gives the diaddition products (l40), as does Me,,NC,,H,,+
Br-,"l" the more hydrophilic Me,"
CI- yielding specifically
monoaddition products, ( 1 39) being obtained in 68 YOyield."J-'
1,4-Diazabicyclo[2.2.2]octane leads to 100 O h of monoaddition .:IJ5
10 Addition of C, or More t o Limonene
Acetylation of limonene with acetyl chloride in the presence of
stannic chloride at - 100 "C was examined by Cookson et ctl. in
1974. After dehydrochlorination of the product (using LiF and
Li,CO:,) they obtained about 30% of the product (141) from
reaction at the isopropenyl double bond, with 22% of the
unconjugated ketone (142) and 28 O/' of the conjugated ketone
(143) that had been formed by reaction with the trisubstituted
double bond."-', With senecioyl chloride (3-methylbut-2-enoyl
chloride), the same group synthesized a-atlantone ( 1 32) after
dehydrochlorination, about 60 YOof the reaction occurring in
the isopropenyl group against 29% in the ring."li The
acetylation was confirmed by Hoffmann, who did not, however,
mention Cookson.:34H
Acetylation on C-I0 can be effected by
trapping the limonene anion ( c ) ~ ' with trimethyltin. The
stannane (144) will then react with acetyl chloride to yield (133;
R = Me) or with senecioyl chloride to give a ratio of 25 : 75 of
a-atlantone and the direct coupling product (/j-atlantone).:"!'
Erman et al. converted the anion (c) into the alcohol (145) by
allowing it to react with ethylene oxide, and into a variety of
sesquiterpenes (146) by its reaction with the appropriate alkyl
The anion (c) was again used for the synthesis of
halides RX."-'
sesquiterpenes; its reaction with a functionalized isoprene (147)
added a C, unit, giving (148), which is an intermediate in the
synthesis of lanceol (146; R = CH,CH=CMeCH,OH)."""
Oxidation of limonene by manganese(ri1) acetate in acetic
acid results in radical addition, giving the acid (149), in 38%
yield,""' and the lactone ( I 50).352Despite this relatively good
yield, the reported overall yield of the alcohol (145) was only
8
Gardrat converted (149) into (150) directly by the
action of formic acid, in 43% isolated yield from limonene."""
The isopropenyl group of limonene reacts in an ene reaction
View Online
302
NATURAL PRODUCT REPORTS. 1989
(154)
4
COOEt
COOEt
&. ph9
(159)
(157)
QI.
R".
OH
Ph
I
OYNYO
R=
yN"xH
with methyl acrylate if aluminium chloride is present as a
catalyst; the major product is the ester (151), with a small
amount of double-bond-rearranged material (1 52). This work
described the preparation of P-bisabolene ( 1 53) from ( 1 5
A similar reaction, using methyl vinyl ketone, yielded the
ketone ( 1 54), which was also converted into P-bisabolene
( 1 53),355 but this reaction is difficult to reproduce and
unsatisfactory in its application.356The corresponding reaction
with propargylates is more successful, methyl propargylate in
the presence of aluminium chloride giving 39% of the ester
(155) with smaller amounts of the two esters (156).357Snider
has also described the Me,AICl-catalysed addition of aldeh y d e ~ . In
~ ~place
*
of a carbon-carbon double bond, a carbonoxygen double bond has been used; thus diethyl oxomalonate
reacts with limonene in the presence of zinc chloride to give the
diester (157) in one week.358
Benzyne reacts with limonene in an ene reaction to give the
phenyl-substituted menthadienes (1 58) and ( I 59) ; these might
be optically active, because the symmetrical radical is probably
not involved, but, while a very small optical activity was
determined in the corresponding reaction with menth- I-ene, it
was not measured in the case of l i r n ~ n e n e The
. ~ ~ reaction
~
of
1,2,4-triazoline-3,5-dionewith limonene leads to a double
adduct, the structure of which was reported as (160); this
supposedly arises in a type of ene reaction, the initial attack on
the isopropenyl double bond and transfer of the proton at C4 being followed by a second addition on the C(4tC(8) double
bond.360Unfortunately, the published n.m.r. spectrum does not
include the signals for the vinyl protons, and it is not clear why
a mechanism like that proposed by Mehta and Singh for the
benzyne reaction361 was not considered; this would lead to
(161).
This type of reaction is always complicated by the tendency
of limonene to polymerize in the presence of Lewis acids or
Ziegler catalysts (see above), which is the reason for using low
temperatures in the reactions. The ene reaction between
limonene and chloral (or bromal) nevertheless gives mostly
unrearranged product ( 1 62) in the presence of aluminium
chloride, although the yield is rather
In the presence of
acids, the tendency to rearrangement of the double bond has to
be considered, as well as the addition of water in aqueous
milieu.
Despite these problems, Julia and co-workers realized the
extremely simple addition of dimethylvinylcarbinol to limonene
in formic acid and methylene chloride. They prepared the four
isomers of a-bisabolol ( I 20) [( + )-(4R,8R)-a-bisabolol from
( + )-limonene], and isomers of the ring-substituted alcohol
(163).363
The Ritter reaction of ( +)-limonene with acetonitrile and
dilute perchloric acid gives the chiral iminium salt (164). The
racemate of (164) is similarly obtained from terpinolene (8),
while (-)-P-pinene (165) yields the e n a n t i ~ m e r . The
~ ' ~ same
reaction, if carried out on a-terpineol (21; R = H) with
propionitrile, is said to yield a product with the enantiomeric
stereochemistry at what was C-1 of the menthene
Cycloaddition of acetonitrile to limonene occurs exclusively on
the isopropenyl double bond to give the isoxazoline ( 1 66).:"'
An interesting photochemical addition of acetylacetone to
(+)-limonene has been described by a Brazilian group. The
major product (167) (for which full spectral data were given)
was used to prepare octalones. [It would appear that they were
hoping to prepare the eudesmane skeleton; although it was
formed, the major isomers that were produced were the cis- and
the trans-isomer of ( 168).]367
A reaction that has given rise to some discussion is that
between limonene and maleic anhydride. Hultzsch reported in
1939 that, with maleic acid, limonene underwent rearrangement
to a-terpinene (9), which then gave a Diels-Alder product. He
also reported a different reaction with maleic anhydride, which
NATURAL PRODUCT REPORTS, 1989-A.
303
F. THOMAS A N D Y. BESSIERE
S02Me
S0,Me
SOZCHZAc
Scheme 2
t
starting material.3i9 The reaction of limonene(tricarbony1)iron
with aryl-lithium derivatives has been described.'38o
A new method for the addition of alkyl groups to the
terminal isopropenyl group of limonene consists in the radical
addition of methanesulphonyl iodide and elimination, to form
the methyl sulphone (1 73). Deprotonation (by butyl-lithium)
and alkylation, for example with prenyl bromide, leads to the
C-C-coupled product ( I 74). The sulphonyl group is removed
from (1 74) by acylating the anion to the /?-oxosulphone (1 7 3 ,
which is reduced by aluminium amalgam to the allylic sulphinic
acid. This loses SO, in situ, giving a regiospecifically defined
alkene product. The (0-and (2)-a-bisabolenes ( 1 34) were
made in this
12 Biological Reactions of Limonene
Scheme 3
yielded an anhydride of uncertain structure.368 Alder and
Schmitz re-investigated the reaction, but apparently did not
obtain the same anhydride.36Y Further re-investigation by
Eschinazi and Pines led to the conclusion that limonene did not
react with maleic anhydride under the conditions that were
used by Hultzsch (i.e., simple heating)."7u Radical cyclocopolymerization of limonene with maleic anhydride is well
known, and probable intermediates are shown in Scheme 2;3i1
conceivably, the product that Hultzsch obtained was an
anhydride, derived from one of these.
11 Pyrolysis and Miscellaneous Reactions
The pyrolysis of limonene ( I ) has been known since 1884 to
yield primarily isoprene at 'just below red heat ' ; 3 i 2 indeed, this
was the best way of preparing isoprene for many years."7"Pines
and Ryer made the first serious mechanistic study, and correctly
deduced that the main reaction pathway was via allo-ocimene
( 1 69), which, at somewhat lower temperatures than those that
were required for a good yield of isoprene, then yielded a
mixture of products similar to those obtained after the pyrolysis
of a-pinenc (2) (Scheme 3)."i'3 The whole problem was rcinvestigated by Cocker et ul., who characterized a vast number
in a mixture that was very similar to that
of sub~tances"~"
obtained from the pyrolysis of pin~ne.'~'"
The pyronenes ( 1 70)
and ( 1 71) are present, and, under the conditions that were used,
the Irish group found up to 25 YOof compound ( 172).:j7,j
There are descriptions of a number of addition reactions with
metals scattcrcd about thc oldcr litcraturc, but mostly nothing
definite was identified. We might, however, mention the reaction
with antimony tri~hloride'~'~
and somc colour reactions with
phosphomolybdic acid (pink or rcd-orange, dcpcnding on the
co nd i ti o n s) .''''
With pcntacarbonyliron, limonene forms mixtures of
diene-Fe(CO),, compounds, the dienes being isomers of the
It is not the intention of this article to discuss the biogenesis of
limonene (leading references are given in a note about the use
of natural-abundance deuterium n.m.r. spectrometry to establish the difference between C-9 and C-10 during biogenesis"82),nor do we deal in detail with its metabolic fate
[although the uroterpenols ( 1 18) and ( 1 19), which are the
products of its mammalian metabolism, are mentioned above,
and are known to play a central role in the biogenesis of other
monoterpenoids, notably the 7-oxygenated menthanes of
Perilla j,rut~scens"~].Nevertheless, certain microbial reactions
lead to possibly useful routes to optically active oxygenated
menthanes.
Pioneering work on the transformation of limonene by
Aspergillus niger was made by Bhattacharyya et
who
obtained (+)-cis-carveol (82), carvone (75), a-terpineol (2 1 ;
R = H), and p-mentha-2,s-dien-1-01 (76). Later, Dhavalikar
isolated a strain of a member of the Enterobacteriaceae which
oxidized (+)-limonene to perillic acid ( 5 ) and a dihydroacid.38.5 This led to the definition of three pathways for the
metabolism of limonene: these are ally1 oxidation, leading to
carveol or to the perilla series (the latter is the main pathway),
epoxidation, and rearrangement to dihydrocarvone.:IX6Complete degradation by Pseudonionas PL-strain in the presence of
arsenite gave a variety of ring-opened products, and ultimately
2-methylpropionic acid, for which a mechanism was proposed."8' A patent"" covers the efficient conversion of limonenc
which was
into carvone by Corynehac.tcv-iumh)~dr.occrrboc,lustus,
isolated from soil.
Limonene undergoes microbial hydroxylation with
Corynespora cusiicolr, giving 80 YOof the trans- 1,2-diol from
(+)-limonene and 76 YO of (90) from (-)-li~onene."~!'Other
micro-organisms (members of the genera Fusarium, Cihberella,
Aspergillus, Streptomyw, and others are mentioned) also
work, and the diols can be dehydrated to mentha-2,s-dien-1-01
(76).'3X9
The same workers have shown that (k)-limonene is
converted into (+):a-terpineol (21 ; R = H ) with Penicillium
digitutum .'M
13 References
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Published on 01 January 1989 on http://pubs.rsc.org | doi:10.1039/NP9890600291
304
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NATURAL PRODUCT REPORTS. 1989
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View Online
NATURAL PRODUCT REPORTS, 1989-A.
F. THOMAS A N D Y. BESSIERE
69 D. Wilhelm, T. Clark, T. Friedl, and P. von R. Schleyer, Chem.
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3, 1939 (Chem. Abstr., 1939, 33, 5007'); Hercules Powder Co., Br.
P. 494504 and 494506, Oct. 10, 1938 (Chem. Absrr., 1939, 33,
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alcohols) with dipentene, protecting the product as a solvent and
softener.
72 A. Baeyer, Ber. Dtsch. Chem. Ges., 1893, 26, 820.
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1887, 104, 996 carried out the first crystallization. 0. Wallach,
Liebigs Ann. Chem., 1893, 275, 104 is credited with it in Beilsrein.
but Wallach only raised the m.pt. The method has recently been
patented by Z . P. Golovina, A. I. Bibicheva, and G . P.
Kudryatseva (Kaluga Perfume), USSR P. 1066981, Dec. 30, 1981
(Chenz. Abstr., 1984, 100, 192 113).
78 J. Bertram, D. R. P. 67255 (Friedl., 1892,3,892) patented what he
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the error in the second name probably arose from mis-reading
handwritten Frakturschrift.
79 R. Luft, J . Org. Chem., 1979,44,523. This paper also describes the
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80 0. Wallach, Liebigs Ann. Cheni., 1908, 360, 82.
81 W. A. Tilden, J . Chem. Soc., 1879, 35, 287.
82 W. H. Perkin, J . Chem. Soc., 1907, 91, 372.
83 R. Lombard and E. Geiger, Bull. SOC.Chim. Fr., 1956, 1564.
84 E. von Rudloff, Can. J . Chem., 1961, 39, 1, and references cited
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85 A. Costa and J. M. Riego, Synth. Commun., 1987, 17, 1373.
86 Y. Matsubara, K. Tanaka, M. Urata, T. Fukunaga, M. Kuwata,
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Kuwata (Yasuhara Yushi Kogyo Co. Ltd), Jpn. Kokai 50131946, Oct. 18, 1975 [Appl. 49-39117, April 5 , 19741 (Chem.
Abstr., 1976, 84, 150791); M. Nomura and Y. Fujihara, Nippon
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87 M. Nomura and Y. Fujihara, Kinki Daigaku Kogakubu Kenkyu
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88 T. Yamanaka (Takasago Perfumery Co. Ltd), Jpn. Kokai 51127044, Nov. 5, 1976 [Appl. 50-48595, April 23, 19751 (Chem.
Abstr., 1977, 86, 190275).
89 H. C. Brown, P. L. Geohegan, G. J. Lynch, and J. T. Kurek, J.
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91).
90 J. Sand and F. Singer, Ber. Dtsch. Chem. Ges., 1902, 35, 3170;
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91 C. M. Link, D. K. Jansen, and C. N. Sukenik, J. Am. Chem. Soc.,
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92 W. Treibs, Ber. Drsch. Chem. Ges., B, 1937, 70, 589.
93 E. E. Royals, J . Am. Chem. Soc., 1949,71,2568. Some of Royals'
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94 B. Burczyk, Rocz. Chem., 1970, 44, 1381.
95 Y. Matsubara, J. Kimura, and M. Noguchi, Yukagaku, 1975,24,
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96 D. H. Sheffield (Hercules Powder Co.), U S . P. 2220462, Nov. 5,
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97 P. J. Kropp, J . Am. Chem. Soc., 1969, 91, 5783; F. P. Tise and
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98 J. Riban, C . R. Hebd. Seances Acad. Sci., 1874,79,223; Bull. Soc.
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99 0.Wallach, Liebigs Ann. Chem., 1888, 245, 244; 0. Wallach and
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100 R. F. Bacon, Philipp. J. Sci., Sect. A , 1909, 4, 93 (Chem. Abstr.,
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of petroleum ether as a solvent, J. N. Borglin (Hercules Powder
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the chloride as late as 1946 (Beilstein, 4th edn., Vol. 5, p. 236);
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101 V. 1. Lysenkov, T. I. Pekhk, and G . N. Bazhina, Vesrsi Akud.
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102 0. Wallach, Liebigs Ann. Cheni.. 1906. 350, 141 ; F. W. Semmler,
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103 S. Andaraman, K. N. Gurudutt, C. P. Natarajan, and B. Ravindranath, Tetrahedron Lerr., 1980, 21, 2189.
104 F. Flawitzky, Ber. Drsch. Chem. Ges., 1879, 12. 2354.
105 R. Lombard and E. Geiger, Bull. Soc. Chin?. Fr., 1953, 927.
106 A. Baeyer, Ber. Drsch. Chem. Ges.. 1894, 27, 441.
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108 This figure is taken from J. Verghese. Indian Perfuni., 1972, 16, 35;
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109 G . W. Gladden, F. Johnson, and G. Watson (Cocker Chemical
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110 H . Wuyts, Br. P. 204754, June 29, 1922 (Cheni. Zenrralbl., 1923,
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11 1 J. Verghese, Perfum. Essenr. Oil Rec.. 1969, 60, 271, lists several.
112 K. Hultzsch, Angew. Cliem., 1938, 51, 920.
113 A. L. Remmelsburg (Hercules Powder Co.), U.S. P. 2471455,
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114 L. J. Kitchen, J . A m . Chem. Soc., 1948, 70, 3608.
11 5 Y. Watanabe, Kogyo Kagaku Zasshi, 1960, 63, 153 (CIieni. Absri-.,
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I16 E. Pottier and L. Savidan, Bull. Soc. Chim. Fr., Parr. 2, 1977. 557.
I17 E. Pottier, Bull. Soc. Chim. Fr., Part. 2. 1981, 335.
118 K. L. Stevens, L. Jurd, and G. Manners, Tetraheilron, 1974, 30,
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119 A. I. Sedel'nikov, T. S. Tikhonova, N. P. Polyakova, and V. P.
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120 L. Kuczynski and H. Kuczinski, Roc:. Chem., 1951, 25, 432
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121 R. M. Carman and B. N. Venzke, Ausr. J . Clieni., 1974. 27, 383.
122 D. Masilamani, E. H. Manahan, J. Vitrone, and M. M. Rogic. J.
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123 M. M. Rogid and D. Masilamani, J . Am. CIiem. Soc.. 1977, 99,
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124 G. A. Tolstikov, F. Ya. Kanzafarov, Yu. A. Sangalov, and U. M .
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125 G . A. Tolstikov, F. Ya. Kanzafarov, U. M . Dzhemilev, R . G.
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126 E. Demole, P. Enggist, and G. Ohloff, HeIv. Chini. Actu, 1982, 65,
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127 J. D. Fourneron, L. M. Harwood, and M. Julia, Tetruheclron,
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128 H. Mayr and R. Pock, Chem. Ber., 1986, 119, 2473.
129 G. Klein, D . Arlt, and M. Jautelat (Bayer A.-G.), Ger. Offen.
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130 T. Lesiak and W. Forys, Poi. J . Chem., 1978, 52, 927.
131 0. Wallach, Liebigs Ann. Chem., 1884, 225, 304; 1885, 230, 262.
132 R. M. Carman and B. N. Venzke, Aust. J . Chem., 1971, 24,
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133 J. Verghese, Perfum. Essenr. Oil Rec., 1968, 444.
134 W. A. Mosher, J. Am. Chem. Soc., 1947, 69, 2139.
135 R. M. Carman and B. N. Venzke, Aust. J . Chem., 1971,24, 1727.
136 R. M. Carman, C. H. L. Kennard, W. T. Robinson, G. Smith,
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137 B. Bochwic, J. Kapukinski, and B. Olejniczak, R o c . Chem., 1971,
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138 N. Kharasch and C. M. Buess, J . Am. Chem. Soc., 1949,71,2724.
139 G. A. Jones, C. J. M. Stirling, and N. G. Bromby, J . Chem. Soc.,
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140 A. Nakatsuchi, J . Soc. Chem. Ind. Jpn. (Suppl. Binding), 1930,33,
408; 1932, 35, 376.
141 A. W. Weitkamp, J. Am. Chem. Soc., 1959, 81, 3430, 3434, 3437.
See also C. G. Moore and M. Porter, Tetrahedron, 1959, 6, 10,
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142 J. H. Werntz (E. 1. du Pont de Nemours, Inc.), U S . P. 2402698
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143 C. Bertaina, F. Cozzolino, R. Fellous, G. George, and E. Rouvier,
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306
144 For example: W. H. Reiland, Jr. (Sun Oil Co.), U S . P. 3274 113,
Sept. 20, 1966 [Appl. Aug. 28, 19631 (Chem. Ahstr., 1966, 65,
184074.
145 R. M. Scarborough, Jr., A. B. Smith, 111, W. E. Barnette, and
K. C . Nicolaou, J . Org. Chem., 1979, 44, 1742.
146 P. Sabatier and J. B. Senderens, C . R . Hebd. Seances Acad. Sci.,
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147 P. Sabatier and J. B. Senderens, C . R . Hehd. Seunces Acad. Sci.,
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148 G. Vavon, Bull. Soc. Chim. Fr.. 1914, 15, 282.
149 W. Ipatiev, Ber. Dtsch. Cliem. Ges., 1910, 43, 3547.
150 P. Sabatier and G. Gaudion, C . R . Hebd. Seances Acad. Sci., 1919,
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151 N. Zelinsky, Ber. Dtsch. Chem. Ges., 1924, 57, 2058.
152 Y. Tanaka, H . Hattori. and K. Tanabe, Bull. Chem. Soc. Jpn.,
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153 C. A. Brown and H. C. Brown, J. Org. Chem.. 1966, 31, 3989.
154 H. C. Brown, Agency of Ind. Sci. Tech. 557014537, taken from
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155 G. Jeske, H. Lauke. H. Mauermann, H. Schumann. and T. J.
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156 C. Larpent. R. Dabard, and H. Patin, Tetrtrhedron Lett., 1987, 28,
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157 W. F. Newhall, J . Org. Chem., 1958. 23, 1274.
158 W. Schenk and A. F. Thomas, unpublished work.
159 H. van Bekkum. D. Medema. P. E. Verkade, and B. M. Wepster.
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160 A. Fischli and P. M. Muller, Hell?. Chim. Actu, 1980. 63, 1619.
161 H. Nagashima, T. Ogura, K. Takayama, T. Sato, and T. Matsui
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Ahstr.. 1979, 91. 20802).
162 H. Nagashima. T. Ogura. K. Takayama. T. Sato. and T. Matsui
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163 H. Pines and H. E. Eschinazi, J . Am. Cliem.Soc., 1956, 78, I 178.
164 R. Martin and W. Gramlich (BASF), Ger. Offen. 3607448. Sept.
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165 T.-L. Ho, Chem I d . (London), 1987, 295.
166 R. P. Linstead, K. 0. A. Michaelis, and S. L. S. Thomas, J . Clwni.
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167 H. E. Eschinazi and E. D. Bergmann, J . Ani. Chcni.Soc., 1950.
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168 K. Kindler and K. Luhrs, Liebigs Ann. C h ~ m .1965,
,
685, 36.
169 K. Kindler and K. Luhrs, Chem. Ber.. 1966, 99, 227. There are a
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170 G . Brieger and T.-H. Fu, J . Chuw. Soc., Chrm. Commun., 1976,
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171 F. W. Semmler. Liehigs Ann. Chem., 1904, 34, 3125.
172 R. Dulou and Y. Chretien-Bessiere, C.R . Hrhrl. Secrncc~.~
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173 H. C. Brown and G. Zweifel, J . Am. Chem. Soc., 1961, 83,
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174 K. Ziegler, F. Krupp, and K. Zosel, Angcw~.Cliem., 1955, 67, 425;
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92, 336.
175 J. Albaiges, J. Castello, and J. Pascual, J . Org. Chmi., 1966. 31,
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176 G . Ohloff, W. Giersch, K.-H. Schulte-Elte, and E. sz. Kovlits,
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177 K.-H. Schulte-Elte and G. Ohloff, Helv. Chin?. Actcr, 1967, 50,
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178 J. F. Blount, B. A. Pawson, and G. Saucy, Chcw. Commun., 1969,
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179 1. Uzarewicz and A. Uzarewicz, Pol. J . Chem., 1979, 53, 1989; see
also ref. 189.
180 H. C. Brown, S. U. Kulkarni, C. Gundu Rao, and V. D. Patil,
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181 A. V. Kuchin, G. A. Tolstikov, V. P. Yur'ev, V. I. Ponomarenko,
G. N. Kurilenko, R. A. Nurushev, and L. I. Akhmetov, Zh.
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182 N. Satyanarayana and M. Periasamy, Tetrahedron Lett., 1984.25,
2501 ; P. Le Maux and G. Simonneaux, J . Mol. Cutal., 1984, 26,
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183 H. C. Brown and K. J. Murray, Tetrahedron, 1986, 42, 5497.
NATURAL PRODUCT REPORTS. 1989
184 H. C . Brown and C. D. Pfaffenberger, J . Am. Chem. Soc., 1967.
89, 5475.
185 H. C. Brown and C . D. Pfaffenberger, Tetrahedron, 1975,31,925.
186 P. K. Jadhav and S. U. Kulkarni, Heterocycles, 1982, 18, 169.
187 C . Narayana and M. Periasamy, Tetrahedron Lett., 1985, 26,
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188 V. K. Gautam, J. Singh, and R. S. Dhillon, J . Org. Chem., 1988,
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89 M. Zaidlewicz and R. Sarnowski, Heterocycles. 1982, 18, 281.
90 B. D. McKenzie, M. M. Angelo, and J. Wolinsky, J. Org. Chem.,
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91 R. J. De Pasquale and P. W. Kremer (SCM Corp.), U.S. P.
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1987, 106, 5274).
92 A. Blumann and 0. Zeitschel, Ber. Dtsch. Chem. Ges., 1914, 47.
2623.
93 N. Duffaut, Bull. Mens. lnf. ITERG, 1950, 4, 251 (Chem. Ahstr.,
1950, 44, 7571a).
94 G . 0. Schenck, 0.-A. Neumuller, G . Ohloff, and S. Schroeter,
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195 J. P. Bain, A. B. Booth, and E. A. Klein (Glidden Co.), U.S. P.
2863882, Dec. 9, 1958 (Chem. Ahstr., 1959, 53, 8194~).
196 J. P. Bain, W. Y. Gary, and E. A . Klein (Glidden Co.), U.S. P.
3014047, Dec. 19, 1961 [Appl. Aug. 27, 19531(Chem. Ahstr., 1962,
57, 12557~).
197 F. Ferregutti and A. F. Thomas, unpublished work.
198 F. Matsubara and T. Kurota. Jpn. Kokai 50-149648, Nov. 29,
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199 A. Blumann, H. Farnow, and F. Porsch. J . Cliem. Soc., 1965,
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200 Y. Matsubara, M. Kaneko, and H. lwamuro (Takasago Perfumery Co. Ltd), Jpn. Kokai Tokkyo Koho 54-1 15326, Sept. 7,
1979 [Appl. 53-22041, March I , 19781 (Chem. Ahstr., 1980, 92,
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201 H. Iwamuro, T. Ohshio, and Y. Matsubara, Nippon Kuguku
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202 S. R. Dolhyj and L. J. Velenyi, I n d . Eng. Cliem.,Prod. Res. Dev.,
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203 B. 8 . Jones, B. C. Clark, Jr., a n d G . A. lacobucci, J . Cliromutogr.,
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204 S. Schroeter, Diss., Gottingen, 1962; G. 0. Schenck, K. Gollnick.
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205 Kuraray Co. Ltd, Jpn. Kokai Tokkyo Koho 56-34779, April 7.
1981 [Appl. 54-1 1 1 309. Aug. 28, 19791 (Cheni. Ahstr., 1981, 95,
133 193); Toray Industries Inc., Jpn. Kokai Tokkyo Koho 551 18421, Sept. 1 1 , 1980 [Appl. 54-25649, March 7, 19791 (Chcw.
Ahstr.. 1981, 94, 139315).
206 G . 0. Ubiergo, G . Malinskas, and H. A. Taher, €.s.sen:e Deriv.
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207 E. Murayama and T. Sato. Totrtiheeiro~iLett., 1977, 4079; Biill.
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208 A. Kohda and T. Sato, J . C I w i . Soc., Cheni.Coiiimiin., 198 I , 95 I ;
T. Sato, K. Maemoto, and A. Kohda. ;hid.. p. 1 116.
209 C. W. Wilson, 111, and P. E. Shaw (U.S. Dept. of Agriculture).
U.S. Pat. Appl. 665741, March 1 I . 1976 (Chcwi. Ahstr., 1977. 87.
136045).
210 A. Heumann, M. Reglier, and B. Waegell. Angeii.. Cheni..I n t . Ed.
Etigl., 1982, 21, 366.
21 I A. Heumann, F. Chauvet. and B. Waegell. Tclruhcdroti Lctt..
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CIicwi., 1987, 52, 1916.
212 W. A. Tilden, J . Chcwi. Soc., 1877, 31, 554.
213 0. Wallach. Lic4ig.s Ann. Clwni.. 1888. 245, 2 5 5 ; 1889, 252. I LO;
1904, 336, 43.
2 14 A. Baeyer, Ber. Dtsch. Chem. Ges., 1896. 29, 8.
215 C. Bordenca and R. K. Allison. I t i d . Eng. Chwi., 1951. 43, 1196;
R. K. Allison (Food Machinery and Chemical Corp.), U.S. P.
2485 180, Oct. 18, 1949 (Clieni.Ahstr., 1950, 44, 5291.0; A. Sattar.
R. Ahmad, and S. A. Khan. Puk. J . Sci. / r i d Rcs.. 1980. 23. 177
(Chcwi. Ahstr., 1981, 95, 49 182) report 90% of the nitrosochloride, from which carvone oxime is obtained i n 92 o/' yield : see
also A. Nuiiez Selles and R. Tapanes Peraza. RPV.Cicwc. Quini..
1981, 12, 165 (Chcni. Ahstr., 1983,98, 89672). and the 74.7% yield
of (-)-carvone by M. T. Magalhaes. M. Koketsu, and V. C .
Wilberg (EMBRAPA). Braz. Pedido 83-00508, Sept. 27, 1983
[Appl. 82-508, Jan. 29, 19821 (Chcw. Ahsrr. 1984. 100. 139397).
N A T U R A L PRODUCT REPORTS. 1989-A. F. THOMAS A N D Y. BESSIERE
216 0. S. Rothcnburpcr. S. B. Krasnoff. and R. B. Rollins. J . C l i c w i .
Etlirc.., 1981. 57. 741.
217 A. J. Mulder and R. V ~ I I I Heldcn (Shell Intern~ItionilleRcSciIrCh
Maatschappij B.V.), Br. P. 2008573. Junc 6. 1979 [Appl. 7743499. Oct. 19. 19773 (Chcvii. Ah.~lr..1980, 92, 76734).
218 M. Nakai. K. H>trdii. and M. Nishiniura (Ube Industries Ltd).
Jpn. Kokai Tokkyo Koho 53-1 1 1 038. Sept. 8. 1978 [Appl. 5224741. March 9, 19773 (Chwi. Ahsrr., 1979. 90.72366).
219 K. Fujita. Nippon Krrgrikii Zmdii. 1960. 81. 676 (Chern. Ahstr ..
196 I , 55. 65 16c.); J . Sci. Hiroshitiirr L / n i ~ .Scr.
.
'4 Math.. Plij*s..
Clrcwi., 1960. 24. 691 (Clicvii. A h t i . . . 1962. 56. 47991).
220 W. G. Dauben. M. Lorber. and D. S. Fullcrton, J . Org. Chcni.,
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221 A. J. Pearson. Y.-S. Chcn. G . R. Han. S.-Y. Hsu. and T. Ray. J .
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222 V. Niiriisimhiin. R. Rathore. and S. Chandrasekaran, S j ~ / h .
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223 N. Chidambaram and S. Chandrasekaran. J. Org. Clieni., 1987,
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224 S. Glasstone and H. E. Stanley. Truns. Ekt~~rroc~hmi.
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225 M. Y. Duarte. H. A. Landerreche. C. M. Marschoff, and M. E.
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226 T. Shono. A. Ikeda. J. Hayashi. and S. Hakozaki, J . Am. Clicwi.
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227 M. Kasano. Y. Sakai, K. Yokoi, Y. Matsubara, and C. Yoshimura, Kink; Daiguku Rikogakuhri Keiikjw Hokoku, 1977, 12, 93
(Chcwi. Ahsrr.. 1977, 87, 184699).
228 V. Montiel. M. Lopez-Segura. A. Aldaz, M. Grande. and F.
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229 G. Wagner. Ber. Dtsch. Chem. Ges., 1890, 23, 2307.
230 N. A. Milas and S. Sussman, J . Am. Chem. Soc., 1937, 59, 2345.
231 J. Sword. J. Cheni. Soc., 1925, 127, 1682.
232 Y. Sebe. J . Clieni. Soc. Jpn.. 1941, 62, 16 (Chem. Abstr., 1943, 37,
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233 Y. Sakuda, Bull. Chem. Soc. Jpn., 1969, 42, 3348. A residual
optical rotation of (92) was ascribed in this paper to impurities.
234 A. F. Thomas and W. Bucher, Helv. Chim. Acta, 1970, 53,
770.
235 E. N. Trachtenberg and J. R. Carver, J . Org. Chem., 1970, 35,
1646. report [a],+ 13.6" for (92).
236 C. W. Wilson, 111, and P. E. Shaw, J . Org. Chem., 1973,38, 1684,
report [a],-43" for (92).
237 M. Sumimoto, T. Suzuki, and T. Kondo, Agric. Biol. Chem.,
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238 H. P. Jensen and K. B. Sharpless, J . Org. Chem., 1975, 40, 264.
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240 Y. Kita, Y. Nakatani. and T. Yamanishi, Agric. Biol. Chem.,
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241 T. Aratani, Nippon Kaguku Zasshi, 1959, 80, 528 (Chem. Abstr.,
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242 R. Ruegg. A. Pfiffner, and M. Montavon, Recherches, 1966, 3.
243 Y. Ogata and Y. Matsubara, J . Chem. Soc. Jpn., Ind. Chem. Sect.,
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244 M. Nomura, Y. Fujihara, and Y. Matsubara, Nippon Kugaku
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255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
307
This work seems to be based on a thesis of H. Neresheimer; cf.
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C. C. Spencer, W. I. Weaver, E. A. Oberright, H. J. Sykes, A. L.
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292 R. M. Carman, K. L. Greenfield, and W. T. Robinson, Aust. J .
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293 R. M. Carman, J. J. De Voss, and K. L. Greenfield, Aust. J .
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294 J. P. Bain, W. Y. Gary, and E. A. Klein (Glidden C o . ) , U.S. P.
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298 G. A. Trigaux, Mod. Plust., 1960, 38, 147, gives a list of useful
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299 J. V. Crivello and J. L. Lee, Macromolecules, 1981, 14, 1141.
300 L. A. Mukhamedova,
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304 J. A. Hendry, R. F. Homer, F. L. Rose, and A. L. Walpole, Br. J .
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309 G . Ohloff, Arch. Phurm. Ber. Dtsch. Phurni. Ges., 1954, 287, 258.
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312 J. Colonge and J. Crabalona, Bull. Soc. Cliini. Fr., 1960, 98.
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316 C. Bordenca and W. A. Lazier (Food Machinery and Chemical
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317 W. H. Clement and M. Orchin, Ind. Eng. Chem., Prod. R m . Dev.,
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318 D. Evans, J. A. Osborn, and G. Wilkinson, J . Chcm. Soc., A ,
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324 J . Weber, W. Bernhagen, and H. Springer (Ruhrchemie A. G.),
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325 G . Dauphin, Synthesis, 1979, 799.
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327 B. D. Mookherjee, R. A. Wilson. M. H. Vock, and M. H. Zam-
NATURAL PRODUCT REPORTS, 1989
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328 F. Delay and G. Ohloff, Helv. Chim. A m , 1979, 62, 369.
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330 G. Dupont, R. Dulou, and G . Clement, C . R . Hebd. Seances Acud.
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331 J. Alexander and G. S. Krishna Rao, Indian J . Chem., 1973, 11,
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332 B. B. Snider, D. J. Rodini, T. C. Kirk, and R. Cordova, J . Am.
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338 T. I. Pehk, H. E. Kooskora, E. T. Lippmaa, V. I. Lysenkov,
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340 S. D. Koch, R. M. Kliss, D. V. Lopiekes, and R. J. Wineman, J .
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351 M. Okano, Client. I d . (London), 1972, 423.
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372 W. A. Tilden, J . Chem. Soc., 1884, 45, 410.
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376 K. J. Crowley and S. G. Traynor, Tetrahedron, 1978, 34, 2783.
377 H. von Euler and L. Ahlstrom, Ark. Kemi, 1932, 11A, No. 2
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378 V. E. Levine and E. Richman, Biochem. J . , 1933, 27, 2051, also
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379 J. E. Arnet and R. Pettit, J . Am. Chem. Soc., 1961, 83, 2954.
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384 G . K. Swamy, K. L. Khanchandani, and P. K. Bhattacharyya,
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386 R. S. Dhavalikar, P. N. Rangachari, and P. K. Bhattacharyya,
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387 B. L. Hungund, P. K. Bhattacharyya, and P. N. Rangachari,
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389 W. R. Abraham, B. Stumpf, and K. Kieslich (Ges. Biotechnol.
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390 B. Stumpf, W. R. Abraham, and K. Kieslich (Ges. Biotechnol.
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