Condensation of isophorone and isophorone oxime with amines and aldehydes

Article abstract of DOI:10.1134/S1070428010070055

Mannich condensations of isophorone (3,5,5-trimethylcyclohex-2-en-1-one) with paraformaldehyde and dimethylamine, benzylamine, and piperidine hydrochlorides were studied. The reactions were not selective, and they involved both activated methylene group a

Full text of DOI:10.1134/S1070428010070055

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 987–997. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © S.S. Koval’skaya, N.G. Kozlov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 7, pp. 991–1001.
Condensation of Isophorone and Isophorone Oxime
with Amines and Aldehydes
S. S. Koval’skaya and N. G. Kozlov
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: loc@ifoch.bas-net.by
Received May 13, 2009
Abstract—Mannich condensations of isophorone (3,5,5-trimethylcyclohex-2-en-1-one) with paraformaldehyde
and dimethylamine, benzylamine, and piperidine hydrochlorides were studied. The reactions were not selective,
and they involved both activated methylene group and vinylic carbon atom, as well the exocyclic methyl group
at the double bond. The corresponding isomeric amino ketones were formed in comparable amounts (42, 30,
and 28%). The E and Z isomers of isophorone oxime reacted with paraformaldehyde and dimethylamine
hydrochlride to give mixtures of analogous Mannich condensation products, but the fraction of the addition
product at the carbon atom spatially close to the oxime hydroxy group was larger. Under analogous conditions,
the reaction of isophorone with aromatic amines and aromatic aldehydes gave products of two-component
condensation of isophorone with aldehydes, and the reactions involved exclusively the activated methylene
group in the initial enone with formation of the corresponding trans,trans-isomeric 7-arylmethylidene
derivatives.
DOI: 10.1134/S1070428010070055
α-Aminomethylation of carbonyl compounds with
iminium intermediates generated from amines and al-
dehydes, which is known as Mannich condensation
[1], is widely used in organic synthesis. The signifi-
cance of this reaction is determined primarily by the
fact that the resulting β-amino ketones or their quater-
nary salts readily undergo deamination with formation
of α,β-unsaturated carbonyl compounds; high reac-
tivity of the latter underlies their application in the
synthesis of a broad series of derivatives. Using as
an example 3-methylideneisocamphanone prepared by
deamination of the corresponding Mannich base, we
demonstrated the possibility for synthesizing a number
of terpene derivatives with various functional groups,
heterocyclic compounds, and carbocyclic analogs of
prostaglandin endoperoxides [2–4]. The behavior of
α,β-unsaturated ketones under the Mannich condensa-
tion conditions was studied very poorly. A probable
reason is high lability of such compounds, especially
under acid catalysis necessary for the Mannich
reaction.
as well as cyclic structure and high degree of substitu-
tion in the enone fragment, which make it relatively
stable and weakly prone to undergo polymerization
(tarring). The isophorone molecule possesses an enol-
izable CH2C=O fragment, which is a classical reaction
center for Mannich condensation. Therefore, the
formation of 6-aminomethylisophorone derivatives II
might be expected.
In fact, β-amino ketones like II were formed as
a result of Mannich condensation of I with paraformal-
dehyde and amines, but they were not the only prod-
ucts (42% in the product mixture). Simultaneously,
α-aminomethylation occurred at both C2 vinylic carbon
atom and methyl carbon atom (C7) at the double bond
(γ-aminomethylation). The fractions of 2- and
7-aminomethyl derivatives III and IV in the product
mixtures (30 and 28%, respectively) were slightly
smaller than that of the classical condensation product
II, but the ratio of regioisomers II–IV was the same in
the reactions with dimethylamine, benzylamine, and
piperidine hydrochlorides.
We examined transformations of isophorone (I,
3,5,5-trimethylcyclohex-2-en-1-one) in the Mannich
reaction. This α,β-unsaturated ketone was selected as
substrate taking into account primarily its accessibility,
Mixtures of regioisomeric amino ketones II–IV
were separated by fractional crystallization. The most
difficult was isolation of N,N-dimethylamino deriva-
tives IIa–IVa, for these hydrochlorides are relatively
987

KOVAL’SKAYA, KOZLOV
988
Scheme 1.
O
O
Cl–
Me
Me
Me
Me
Me
Me
CH2NHRR'
I
V
OH
OH
OH
Me
Me
Me
Me
Me
Me
Me
CH2
Me
A
B
C
H
H
H
O
O
O
RR'N CH2
H2C NRR'
Me
Me
Me
Me
Me
Me
Me
CH2
H2C NRR'
Me
R
R
H
H
·
·
·
·
·
·
R'
N
O
O
N
R'
O
Cl–
Cl–
NHRR'
Cl–
Me
Me
Me
Me
Me
Me
Me
Me
IIa–IIc
IIIa–IIIc
IVa–IVc
R = R′ = Me (a); R = H, R′ = PhCH2 (b); RR′ = (CH2)5 (c).
low-melting substances and are extremely hygro-
scopic. Therefore, our attempt to isolate compounds
IIa–IVa according to the procedure reported previ-
ously [5] (precipitation with diethyl ether or acetone
from a solution in alcohol), instead of separation of the
corresponding hydrochloride, resulted in formation of
two layers, one of which contained all three com-
ponents of the reaction mixture, initial solvents, and
a small amount of water. Samples enriched in each
regioisomer (no less than 80%) were obtained by
repeated precipitation with anhydrous tetrahydrofuran
from anhydrous acetone. Amino ketone hydrochlorides
obtained from benzylamine and piperidine were
separated using mixtures of anhydrous diethyl ether,
chloroform, and/or acetone.
The stucture of the isolated compounds was deter-
1
mined on the basis of their IR, H NMR, and mass
spectra. The IR spectrum of 6-(dimethylaminomethyl)-
isophorone hydrochloride (IIa) contained absorption
bands typical of stretching vibrations of conjugated
carbonyl group (1665 cm–1) and N–H bond
(3400 cm–1) and a series of bands in the region 2400–
2700 cm–1, corresponding to vibrations of protonated
amines. In the mass spectrum of IIa the molecular ion
peak had an m/z value of 196 (protonated form) and
a relative intensity of 7%. Reliable proofs for the struc-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

CONDENSATION OF ISOPHORONE AND ISOPHORONE OXIME
989
ture of IIa as 6-aminomethyl derivative were obtained
negativity of the carbonyl oxygen atom, the above
interaction becomes possible.
1
by H NMR spectroscopy. Compound IIa displayed in
1
the H NMR spectrum signals from methyl groups at
The structure of the minor component of the
product mixture (28%) was even more surprising. Its
IR spectrum was similar to the spectra of regioisomers
IIa and IIIa. The mass spectrum of this compound
also contained the molecular ion peak with m/z 196,
but the fragmentation pattern was essentially different,
indicating considerable differences in the structure.
δ 1.02 (6H, 5-CH3) and 1.98 ppm (d, 3H, 3-CH3,
4J = 1.4 Hz), a quartet from the olefinic proton at
δ 5.97 ppm (4J = 1.4 Hz), and a broadened two-proton
singlet at δ 2.26 ppm due to methylene protons on
C4. The 6-H signal was a doublet of doublets at
δ 3.32 ppm with vicinal coupling constants of 8 and
2
6 Hz. Protons on C10 resonated at δ 3.64 (d.d, J = 11,
1
Analysis of the H NMR data showed that compound
2
3
3J = 6 Hz) and 3.54 ppm (d, J = 11, J = 8 Hz).
Nonequivalence of the geminal protons on C10 [as in
saturated analog, 2-(dimethylaminomethyl)dihydroiso-
phorone] indicates formation of a strong intramolec-
ular hydrogen bond between the amino and carbonyl
groups, which restricts rotation of the aminomethyl
substituent [5]. The differences in the chemical shifts
of protons on C10 and in the vicinal coupling constants
are smaller than those observed for the saturated
analog, which may be due to distortion of bond angles
caused by the presence of a planar enone fragment in
molecule IIa.
IVa is the condensation product at the methyl group
attached to the double-bonded carbon atom, 3-[2-(di-
methylamino)ethyl]-5,5-dimethylcyclohex-2-en-1-one
1
hydrochloride. The H NMR spectrum of IVa lacked
signal typical of 3-methyl group at about δ 2 ppm,
whereas a two-proton multiplet appeared as
δ 2.36 ppm, and the olefinic 2-H proton resonated as
a triplet at δ 5.98 ppm (4J = 1.4 Hz), indicating the
presence of only two protons in the cis-allylic position.
The C10H2 protons gave a triplet at δ 3.06 ppm (2H)
with a coupling constant 3J of 7 Hz due to vicinal inter-
action with protons of the neighboring methylene
group. The fact that protons on C10 are magnetically
equivalent suggests conformational mobility of the
aminomethyl fragment and its remoteness from the
carbonyl group; therefore, intramolecular hydrogen
bonding is impossible.
The IR and mass spectra of the second product
(32%) were analogous to those of compound IIa. This
product was assigned the structure of 2-(dimethyl-
aminomethyl)isophorone hydrochloride (IIIa) on the
1
1
basis of the H NMR data. The H NMR spectrum of
IIIa lacked signal from olefinic proton but contained
two broadened two-proton singlets at δ 2.20 and
2.64 ppm, corresponding to the C4H2 and C6H2 methyl-
ene groups, respectively. These findings indicate that
the dimethylaminomethyl group is attached to the
double-bonded carbon atom (C2). Signals from protons
on C10 appear as two doublets at δ 3.08 and 3.12 ppm
with a distinct “roof” effect and a geminal coupling
1
Likewise, the IR, H NMR, and mass spectra of
benzylaminomethyl and piperidinomethyl derivatives
IIb–IVb and IIc–IVc confirmed the assumed struc-
tures (see Experimental).
Thus, the molecule of 3,5,5-trimethylcyclohex-2-
en-1-one (I) was found to possess three reaction
centers capable of being involved in Mannich con-
densation. Apart from the classical reaction path, i.e.,
aminomethylation at the activated α-methylene group,
the reaction also occurred at the α-olefinic and γ-allylic
carbon atoms. Isophorone molecule possesses one
more γ-allylic carbon atom (C4), but no aminomethyla-
tion products at C4 (V) were detected in the reaction
mixtures. Presumably, the presence of three methyl
groups in the α-positions to C4 hampers reaction at that
center for steric reasons.
2
constant J of 12 Hz (AB system). The multiplicity of
these signals indicates the absence of proton in the
vicinal position, in keeping with the proposed struc-
ture. The same follows from the presence of a singlet
at δ 1.99 ppm, which belongs to the methyl group on
C3 (no allylic coupling typical of compound IIa was
observed).
Aminomethylation at the double-bonded carbon
atom in the α-position with respect to the carbonyl
group in molecule I was unexpected; this reaction path
is not consistent with the classical scheme of alkylation
of enolates. In keeping with the generally accepted
views on the mechanism of Mannich condensation, the
reaction center should possess an effective negative
charge. Taking into account that the double C=C bond
in the enone fragment is polarized due to high electro-
It is commonly believed that the α-methylene group
in ketones is activated during the Mannich condensa-
tion as a result of enolization of the carbonyl group [6].
Such enolization of isophorone should give rise to
hydroxy diene A. It may be presumed that compound I
may be converted into both normal dienol A and
analogous intermediates B and C, in which the activat-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KOVAL’SKAYA, KOZLOV
990
ed atoms are C2 and C4 or C2 and C7, respectively. The
product ratio is determined by the probability for
formation of the corresponding dienols and spatial
accessibility of the reaction centers therein. Therefore,
the reaction of intermediate B with methylidene-
iminium cation should lead to 2-aminomethyl deriva-
tive III, while intermediate C should be converted
mainly into compound IV (Scheme 1).
siderable tarring. The major product obtained from
E isomer VI was 6-(dimethylaminomethyl)isophorone
oxime hydrochloride (VIII, 55%), while the fractions
of 2- and 7-dimethylaminomethyl derivatives IX and
X were 24 and 21%, respectively. Under similar con-
ditions, Z-oxime VII gave rise to a mixture of products
consisting of 34% of 6-(dimethylaminomethyl) deriva-
tive XI, 43% of 2-(dimethylaminomethyl) isomer XII,
and 23% of 7-aminomethyl analog XIII (Scheme 2).
The products were separated by the same procedure as
that described above for the separation of analogous
amino ketones.
The reaction mechanism involving the correspond-
ing enols is not the only possible, for compounds that
could not give rise to enols are also capable of reacting
with aldehydes and amines according to Mannich;
such compounds are, e.g., ketone oximes [5, 7, 8]. We
synthesized isophorone oxime as a mixture of E and
Z isomers VI and VII whose ratio depended on the
oximation conditions. The reaction at room tempera-
ture gave a mixture of E and Z isomers at a ratio of
1:3, whereas at elevated temperature the VI:VII ratio
The structure of amino oximes VIII–XIII was con-
firmed by their IR, 1H NMR, and mass spectra. The IR
spectra of VIII–XIII contained an absorption band at
1650 cm–1, corresponding to stretching vibrations of
C=N bond in α,β-unsaturated oximes, and a band at
3400 cm–1, which is typical of vibrations of oxime
hydroxy group. In the mass spectra of VIII–XIII, the
molecular ion peaks (m/z 211) had a relative intensity
of 5–6%. The products were assigned the structure of
particular regioisomers on the basis of the same con-
siderations as in the structure assignment of the amino
ketone analogs. Amino oximes VIII and XI displayed
1
was 8:11 (according to the H NMR data; see below).
Separation of isomeric oximes is difficult; both iso-
mers are very readily soluble in most organic solvents,
and they crystallized jointly from strongly concentrat-
ed solutions even in the cold. We succeeded in obtain-
ing a sample slightly enriched in the major Z isomer
(VII) by crystallization from aqueous acetone (ace-
tone–water ratio 6:1). By repeated dissolution–crys-
tallization we isolated a sample containing no less than
92% of isomer VII. A sample consisting mainly of the
E isomer (VI) was obtained by repeated crystallization
from aqueous methanol of the substance isolated from
the mother liquor (see Experimental).
1
in the H NMR spectra signals from both olefinic
proton and methyl group at the double bond, as well as
a downfield signal from 6-H; therefore, these com-
pounds were assigned the structure of 6-dimethyl-
aminomethyl derivatives. The spectra of IX and XII
lacked olefinic proton signal, which is consistent with
the structure of 2-(dimethylaminomethyl)isophorone
oxime hydrochlorides, while in the spectra of minor
products X and XIII we observed no signal assignable
to methyl group at the double bond (δ 2 ppm), which
indicated that aminomethylation occurred at the C7
atom of the initial oxime.
The structure of E and Z stereoisomers was as-
signed to compounds VI and VII on the basis of their
1H NMR spectra. It is known [9] that proton located in
the vicinity of the oxime hydroxy group gives a signal
in a weaker field due to deshielding effect of the
hydroxy group. In our case, the signal from the olefinic
proton in the major isomer appears at δ 6.64 ppm, and
that from the minor isomer, at δ 5.92 ppm; therefore,
the former was assigned Z configuration where the
hydroxy group on the nitrogen is oriented toward the
C2 atom. By contrast, the signal from methylene
protons on C6 in the E isomer is located in a weaker
field (δ 2.37 ppm) relative to the corresponding signal
of the Z isomer (δ 2.08 ppm).
Unlike amino ketones II and III, strong intramolec-
ular hydrogen bond is formed only in amino oximes
IX and XI where the hydroxy group on the oxime
nitrogen atom is oriented in the opposite direction to
the amino group, so that there are no steric hindrances
for hydrogen bonding between the NH proton and
oxime nitrogen atom. As a result of intramolecular
hydrogen bonding, protons in the methylene group
neighboring to the amino nitrogen atom become non-
1
equivalent, and they appear in the H NMR spectra as
Oximes VI and VII were used as substrates in the
Mannich condensation with paraformaldehyde and
dimethylamine hydrochloride. These reactions also
afforded mixtures of aminomethylation products at C2,
C6, and C7, though in a smaller yield because of con-
two doublets of doublets with the same coupling
constants as in the spectra of analogous amino ketones
(see Experimental). Signals from the corresponding
protons in the spectra of regioisomeric amino oximes
VIII and XII were two-proton doublets with a vicinal
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

CONDENSATION OF ISOPHORONE AND ISOPHORONE OXIME
991
Scheme 2.
OH
HO
O
N
N
+
Me
Me
Me
Me
Me
Me
Me
Me
Me
I
VI
VII
Me
OH
H
OH
OH
Me
·
·
·
N
N
N
N
Me
Cl–
Cl–
CH2O, Me2NH·HCl
NHMe2
Cl–
VI
+
+
Me
Me
VIII
Me
Me
Me2NH
Me
Me
Me
IX
X
Me
HO
HO
H
HO
·
·
·
Cl–
Me2NH
N
N
N
N
Me
Cl–
Cl–
CH2O, Me2NH·HCl
VII
+
+
Me
Me
Me
Me
Me2NH
Me
Me
Me
Me
XI
XII
XIII
3
coupling constant J of 7 Hz. These protons in mole-
cules VIII and XII are magnetically equivalent due to
conformational mobility of the aminomethyl fragment.
hyde. This process was strictly regio- and stereoselec-
tive, and the corresponding trans,trans-7-(arylmethyli-
dene)isophorones XIV were isolated in good yields
(Scheme 3). Analogous compounds were not obtained
in the condensation with salicylaldehyde and m- and
p-nitrobenzaldehydes; in these cases, only the corre-
sponding Schiff bases were isolated from the reaction
mixture. Probable reasons are discussed below. The
expected Mannich bases were detected but only as
minor components (no more than 5%).
Thus the transformations of oximes VI and VII in
the Mannich reaction are generally similar to those
occurring with isopohorone. The only difference is
slightly increased fraction of the aminomethylation
product at the carbon atom neighboring to the oxime
fragment (compounds VIII and XII for the E and
Z isomers, respectively). As we noted previously [5],
this may be due to association of intermediate iminium
carbocation with the hydroxy group at the stage
preceding its addition. As concerns other aspects, the
mechanism of Mannich condensation of non-enoliz-
able ketone oximes remains unclear.
The structure of dienones XIV was determined by
1
IR and H NMR spectroscopy. The IR spectra of these
compounds contained an absorption band at 1630–
1650 cm–1, which is typical of stretching vibrations of
carbonyl group in conjugated systems, and bands be-
longing to vibrations of conjugated and aromatic C=C
We also made an attempt to perform Mannich con-
densation of isophorone (I) with paraformaldehyde and
aromatic amines. However, the reactions with aromatic
amines (p-toluidine, p-chloroaniline, p-methoxyani-
line, and methyl p-aminobenzoate) as both free bases
and hydrochlorides were accompanied by fast tarring,
and we failed to isolate appreciable amounts of the
target Mannich bases from the reaction mixtures.
Tarring also occurred in the reactions of isophorone (I)
with aromatic aldehydes and aromatic amine hydro-
chlorides. When aromatic amines were taken as free
bases, we isolated products of two-component con-
densation of isophorone with the corresponding alde-
1
bonds. In the H NMR spectra we observed signals
from protons in the aromatic fragment, a singlet from
methyl protons (6H, δ ~1.1 ppm), and broadened
singlets due to methylene protons on C4 and C6 (2H
each, δ ~2.30 and 2.45 ppm). The 2-H olefinic proton
resonated as an unresolved multiplet. Its chemical shift
(δ ~6 ppm) insignificantly differed from that of initial
isophorone, indicating the absence of shielding by the
arylvinyl fragment and hence s-trans orientation of the
latter with respect to the endocyclic C=C bond. Signals
from protons at the C7=C8 double bond were two
doublets with a clearly pronounced “roof” effect (AB
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KOVAL’SKAYA, KOZLOV
992
Scheme 3.
O
Ar
Ar
Ar
O
HN
O
HN
HN
Me
ArNH2, RC6H4CHO
I
+
+
Me
Me
Me
XV
Me
Me
Me
Me
R
R
R
XVI
XVII
–ArNH2
Me
–ArNH2
O
O
R
O
1
7
R
+
Me
Me
XVIII
8
Me
Me
Me
Me
R
Me
XIX
XIVa–XIVh
R = 4-F (a), 4-Br (b), 4-HO (c), 4-MeO (d), 4-Me2N (e), 3-EtO-4-HO (f), 3-MeO-4-HO (g), 3,4-(MeO)2 (h);
Ar = 4-MeC6H4, 4-MeOC6H4, 1-naphthyl, 2-naphthyl, etc.
system, δ ~6.8 and ~6.9 ppm). An exception was
7-(p-bromobenzylidene) derivative XIVb; the 7-H and
8-H protons resonated in the spectrum of XIVb as one
two-proton singlet (the protons turned out to be acci-
dentally equivalent). The vicinal coupling constant for
7-H and 8-H in all other compounds XIV was 16 Hz,
which corresponds to trans configuration of the double
bond and hence trans arrangement of the isophorone
and aromatic fragments.
dimethyl group is possible in both these structures. By
contrast, deamination of β-enamino ketone XVII
seems to be quite advantageous, for it could lead to the
formation of linear conjugated double bond system in
thermodynamically favorable trans,trans configura-
tion. As follows from the NMR data, just dienones
having structure XIV were obtained.
Taking into account that the formation of amino
ketones XV and XVI is reversible and that compound
XIV is chemically inert (it does not undergo further
transformations), just the latter accumulates as product
under the given conditions. Furthermore, it is very
probable that the formation of Mannich bases XV–
XVII is characterized by different regioselectivity than
in the synthesis of analogs II–IV, for the intermediate
Schiff base has a much larger size than iminium inter-
mediate generated from formaldehyde; therefore, the
C7 atom (methyl group) in isophorone is the most
accessible for the addition of Schiff base molecule.
A probable mechanism for formation of compounds
XIV is as follows. It is known that aromatic amines
readily react with aldehydes to give the corresponding
Schiff bases. Addition of CH acid at the activated C=N
bond in Schiff bases could lead to β-arylamino
ketones. Insofar as the addition step is reversible,
Mannich base always exists in equilibrium with initial
isophorone and Schiff base. Another possible decom-
position path typical of Mannich bases is their de-
amination (Hofmann elimination). Compound XVI
cannot undergo elimination according to Hofmann, for
it lacks proton in the β-position with respect to the
amino group. Deamination of the addition product at
C6 (XV) is possible; however, this process is not favor-
able for thermodynamic and steric reasons: as a result,
compounds XVIII and XIX would be formed with
cross-conjugated system of double bonds, one of
which is strained and oriented cis with respect to the
carbonyl group; moreover, van der Waals repulsion be-
tween the aryl substituents and the carbonyl or geminal
The assumed formation of aryldienone XIV
through intermediate Mannich base XVII rather than
direct condensation is supported by the following. First
of all, the corresponding Schiff bases were isolated as
by-products from all reaction mixtures, and in some
cases traces of compounds XV–XVII were detected.
Second, we found that isophorone does not react with
aromatic aldehydes in the presence of tertiary amines
(e.g., N,N-dimethylaniline) despite their higher acidity,
other conditions being equal. Third, as we already
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

CONDENSATION OF ISOPHORONE AND ISOPHORONE OXIME
993
noted, neither salicylaldehyde nor m- and p-nitrobenz-
aldehydes reacted with isophorone and aromatic
amines, and only the corresponding Schiff bases were
isolated from the reaction mixtures. Obviously, com-
pounds XX formed from aromatic amines and salicyl-
aldehyde are stabilized by intramolecular hydrogen
bond which prevents them from being involved in sub-
sequent Michael addition process.
phase Apiezon L on Chromaton N-AW-DMCS, 0.16–
0.20 mm).
Isophorone oximes were synthesized according to
the procedure described in [10]. Prolonged stirring of
the reaction mixture at room temperature resulted in
the formation of a mixture of E and Z isomers VI and
VII at a ratio of 1:3. Crystallization of the isomer mix-
ture from acetone–water (6:1) increased the fraction of
the major isomer, (Z)-VII. After five crystallizations,
the product contained no less than 92% of Z isomer
VII. When the reaction was carried out at elevated tem-
perature (under reflux), the ratio of E- and Z-isomeric
isophorone oximes VI and VII was 8:11. The product
was recrystallized from acetone–water (6:1), and the
mother liquor enriched in minor component VI was
evaporated. The residue was a semicrystalline material
which was dissolved in methanol, water was added to
the solution until it turned turbid, the mixture was
evaporated, and the precipitate enriched in E isomer
VI was filtered off. After six recrystallizations we ob-
tained a sample containing ~93% of E isomer VI.
Ar
N
H
O
XX
In the case of Schiff bases derived from nitrobenz-
aldehydes, electronic factors are likely to be crucial. It
is generally accepted that the addition involves cyclic
transition state XXI which is converted into Mannich
base XXII via bond migration (Scheme 4). The pres-
ence of a strong electron-withdrawing substituent
(nitro group) in the benzene ring reduces the electron
density on the double C=N bond, so that its reactivity
weakens. If dienones XIV were formed according to
a different scheme, i.e., that not involving formation
and subsequent addition of Schiff bases, chemical re-
activity of the latter would not affect the condensation
of isophorone with aldehydes.
(E)-3,5,5-Trimethylcyclohex-2-en-1-one oxime
(VI). mp 90–92°C. IR spectrum, ν, cm–1: 3400 br, v.s
(OH), 3050 v.w (=C–H), 2965 s, 2930 m (C–Haliph),
1
1650 s (C=N), 960 m (N–O). H NMR spectrum, δ,
4
ppm: 0.96 s (6H, 5-CH3), 1.83 d (3H, 3-CH3, J =
1.4 Hz), 1.98 br.s (2H, 4-H), 2.08 br.s (2H, 6-H),
6.64 q (1H, 2-H, 4J = 1.4 Hz), 9.60 br.s (1H, OH).
Scheme 4.
Ar
(Z)-3,5,5-Trimethylcyclohex-2-en-1-one oxime
(VII). mp 99–101°C. IR spectrum, ν, cm–1: 3420 br, v.s
(OH), 3050 v.w (=C–H), 2960 s, 2930 m (C–Haliph),
Ar
H
Ar'
N
H
N
1
HO
Ar'
O
1650 s (C=N), 950 m (N–O). H NMR spectrum, δ,
4
XXI
XXII
ppm: 1.00 s (6H, 5-CH3), 1.80 d (3H, 3-CH3, J =
1.4 Hz), 1.94 br.s (2H, 4-H), 2.37 br.s (2H, 6-H),
5.92 q (1H, 2-H, 4J = 1.4 Hz), 9.80 br.s (1H, OH).
Our attempts to obtain compounds analogous to
dienones XIV from E- and Z-isomeric isophorone
oximes VI and VII were unsuccessful: in all cases,
complete tarring occurred.
Mannich condensations of isophorone (I) and its
oximes VI and VII were carried out according to the
procedure described in [5]. After addition of diethyl
ether to the solution in ethanol obtained by reaction
with dimethylamine hydrochloride, the mixture divid-
ed into layers. The bottom layer containing the target
products was separated and evaporated on a rotary
evaporator. Compounds obtained in the reactions with
benzylamine and piperidine hydrochlorides were
isolated by evaporation of the reaction mixture to 1/5
of the initial volume and subsequent precipitation with
excess anhydrous acetone.
EXPERIMENTAL
The IR spectra were recorded on a Nicolet Protégé-
460 spectrometer with Fourier transform. The 1H NMR
spectra were measured on a Bruker Avance instrument
(500 MHz) from solutions in CDCl3 using tetramethyl-
silane as internal reference. The mass spectra were
obtained on a Hewlett–Packard 5890/5972 GC–MS
system (HP-5MS column; electron impact, 70 eV).
The progress of reactions was monitored, and the reac-
tion mixtures were analyzed, by GLC on a Chrom-5
chromatograph (glass column, 2000×2 mm, stationary
Dimethylaminomethyl ketone hydrochlorides
IIa–IVa were isolated as a dark thick oily substance
(overall yield 60%). The isomers were separated as
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KOVAL’SKAYA, KOZLOV
994
follows. The product mixture was dissolved in anhy-
drous acetone, anhydrous tetrahydrofuran was added
until the solution turned turbid, and the mixture was
placed in a refrigerator with protection from atmos-
pheric moisture (the obtained hydrochlorides are very
hygroscopic). The precipitate was filtered off, THF
was added to the filtrate until it turned turbid and so
on. Following this procedure, first crystallization frac-
tions were enriched in compound IIa, last crystalliza-
tion fractions were enriched in IIIa, and the mother
liquor was enriched in isomer IVa.
Benzylaminomethyl ketone hydrochlorides IIb–
IVb were isolated as a light yellow semicrystalline
material with an overall yield of 64%. To isolate
particular regioisomers, the mixture was dissolved in
chloroform, and the products were fractionally precip-
itated with diethyl ether. The first fractions were
enriched in compound IVb, the last fractions were
enriched in IIIb, and the mother liquor was enriched in
isomer IIb.
6-(Benzylaminomethyl)-3,5,5-trimethylcyclohex-
2-en-1-one hydrochloride (IIb) was isolated by four-
fold dissolution in acetone and precipitation with di-
ethyl ether of the product isolated from the mother
liquor, purity ≥90%. IR spectrum, ν, cm–1: 3400 br.s
(NH), 3060 m (C–Harom), 2960 s, 2930 m (C–Haliph),
2730–2400 (several bands, NH+), 1665 s (C=O), 1620
(C=C), 1590 s (C=Carom), 745 s, 695 m (δC–Harom).
1H NMR spectrum, δ, ppm: 1.05 s (6H, 5-CH3), 1.97 d
(3H, 3-CH3, 4J = 1.4 Hz), 2.27 br.s (2H, 4-H), 3.28 d.d
6-(Dimethylaminomethyl)-3,5,5-trimethylcyclo-
hex-2-en-1-one hydrochloride (IIa) was isolated after
four dissolution–precipitation cycles, purity ≥87%. IR
spectrum, ν, cm–1: 3400 br.s (NH), 3050 v.w (=C–H),
2960 s, 2930 m (C–Haliph), 2730–2350 (several bands,
1
NH+), 1665 s (C=O), 1620 (C=C). H NMR spectrum,
4
δ, ppm: 1.03 s (6H, 5-CH3), 1.98 d (3H, 3-CH3, J =
1.4 Hz), 2.30 br.s (2H, 4-H), 2.95 s (6H, NCH3),
3.32 d.d (1H, 6-H, 3J = 6, 8 Hz), 3.54 d.d (1H, 10-H,
(1H, 6-H, J = 6, 8 Hz), 3.57 d.d (1H, 10-H, J = 10,
3
2
3
2
3
2
3
2J = 11, J = 8 Hz), 3.64 d.d (1H, 10-H, J = 11, J =
3J = 8 Hz), 3.62 d.d (1H, 10-H, J = 10, J = 6 Hz),
4
2
6 Hz), 5.97 q (1H, 2-H, J = 1.4 Hz), 9.80 br.s
4.08 d and 4.16 d (1H each, PhCH2, J = 13.2 Hz),
(1H, NH). Mass spectrum, m/z (Irel, %): 196 (7) [M]+,
150 [M – Me2NH2]+, 135, 121, 118, 108, 96, 93,
67 (100), 52, 41.
5.93 q (1H, 2-H, 4J = 1.4 Hz), 7.38 m (3H) and 7.66 m
(2H) (Ph), 8.60 br.s (1H, NH, free), 10.2 br.s (1H, NH,
chelated). Mass spectrum, m/z (Irel, %): 258 (5) [M]+,
150 [M – PhCH2NH2]+, 135, 121, 118, 108, 107 (100),
96, 93, 67, 52, 41.
2-(Dimethylaminomethyl)-3,5,5-trimethylcyclo-
hex-2-en-1-one hydrochloride (IIIa) was isolated
after five recrystallization from dioxane of a fraction
enriched in this isomer, purity ≥83%. IR spectrum, ν,
cm–1: 3410 br.s (NH), 2960 s, 2930 m (C–Haliph),
2730–2350 (several bands, NH+), 1665 s (C=O), 1620
(C=C). 1H NMR spectrum, δ, ppm: 0.82 s (6H, 5-CH3),
2-(Benzylaminomethyl)-3,5,5-trimethylcyclohex-
2-en-1-one hydrochloride (IIIb) was isolated by five-
fold recrystallization from acetone of a fraction en-
riched in this isomer, purity ≥88%. IR spectrum, ν,
cm–1: 3410 br.s (NH), 3060 m (C–Harom), 2960 s,
2930 m (C–Haliph), 2730–2400 (several bands, NH+),
1665 s (C=O), 1620 (C=C), 1590 s (C=Carom), 750 s,
4
1.99 d (3H, 3-CH3, J = 1.4 Hz), 2.20 br.s (2H, 4-H),
2.64 br.s (2H, 6-H), 2.88 s (6H, NCH3), 3.08 d (1H,
2
2
1
10-H, J = 12 Hz), 3.16 d (1H, 10-H, J = 12 Hz),
9.60 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 196
(9) [M]+, 150 [M – Me2NH2]+, 135, 121, 118, 108, 96,
93, 67 (100), 52, 41.
700 m (δC–Harom). H NMR spectrum, δ, ppm: 0.84 s
(6H, 5-CH3), 1.96 d (3H, 3-CH3, 4J = 1.4 Hz), 2.18 br.s
2
(2H, 4-H), 2.58 br.s (2H, 6-H), 3.12 d (1H, 10-H, J =
2
12 Hz), 3.18 d (1H, 10-H, J = 12 Hz), 4.12 d and
2
4.18 d (1H each, PhCH2, J = 13.2 Hz), 7.32 m (3H)
3-[2-(Dimethylamino)ethyl]-5,5-dimethylcyclo-
hex-2-en-1-one hydrochloride (IVa) with a purity of
≥80% was isolated after four recrystallizations from
anhydrous acetone of the product isolated from the
mother liquor. IR spectrum, ν, cm–1: 3350 br.s (NH),
3050 v.w (=C–H), 2960 s, 2930 m (C–Haliph), 2730–
2350 (several bands, NH+), 1670 s (C=O), 1620
and 7.60 m (2H, Ph), 8.80 br.s (1H, NH, free), 10.4 br.s
(1H, NH, chelated). Mass spectrum, m/z (Irel, %): 258
(6) [M]+, 150 [M – PhCH2NH2]+, 135, 121, 118, 108,
107 (100), 96, 93, 67, 52, 41.
3-[2-(Benzylamino)ethyl]-5,5-dimethylcyclohex-
2-en-1-one hydrochloride (IVb) was isolated by four-
fold precipitation with diethyl ether from chloroform,
purity ≥85%. IR spectrum, ν, cm–1: 3350 br.s (NH),
3060 m (C–Harom), 2960 s, 2930 m (C–Haliph), 2730–
2380 (several bands, NH+), 1670 s (C=O), 1620
(C=C), 1580 s (C=Carom), 760 s, 690 m (δC–Harom).
1H NMR spectrum, δ, ppm: 1.37 s (6H, 5-CH3),
1
(C=C). NMR spectrum, δ, ppm: 1.34 s (6H, 5-CH3),
2.24 br.s (2H, 4-H), 2.36 m (2H, 7-H), 2.58 br.s (2H,
6-H), 2.90 s (6H, NCH3), 3.06 t (2H, 10-H, 3J = 7 Hz),
4
5.98 t (1H, 2-H, J 1.4 Hz), 8.40 br.s (1H, NH). Mass
spectrum, m/z (Irel, %): 196 (5) [M]+, 150 [M –
Me2NH2]+, 136, 123, 108, 92, 83, 67 (100), 55, 41.
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CONDENSATION OF ISOPHORONE AND ISOPHORONE OXIME
995
2.27 br.s (2H, 4-H), 2.34 m (2H, 7-H), 2.56 br.s (2H,
3050 v.w (=C–H), 2960 s, 2930 m (C–Haliph), 2760–
2390 (several bands, NH+), 1670 s (C=O), 1620
(C=C). 1H NMR spectrum, δ, ppm: 1.32 s (6H, 5-CH3),
1.87 m (6H, 3′-H, 4′-H, 5′-H), 2.22 br.s (2H, 4-H),
2.37 m (2H, 7-H), 2.61 br.s (2H, 6-H), 2.88 m (6H,
3
6-H), 3.05 t (2H, 10-H, J = 7 Hz), 4.09 d and 4.17 d
2
4
(1H each, PhCH2, J = 13.2 Hz), 5.96 t (1H, 2-H, J =
1.4 Hz), 7.37 m (3H) and 7.64 m (2H) (Ph), 8.70 br.s
(2H, NH). Mass spectrum, m/z (Irel, %): 258 (3) [M]+,
150 [M – PhCH2NH2]+, 136, 123, 108, 107 (100), 92,
83, 67, 55, 41.
4
2′-H, 6′-H, 10-H), 5.87 t (1H, 2-H, J = 1.4 Hz),
8.50 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 236
(3) [M]+, 150 [M – (CH2)5NH]+, 136, 123, 108, 92, 85
(100), 83, 67, 55, 41.
Piperidinomethyl ketone hydrochlorides IIc–IVc
were isolated as a light brown semicrystalline material
in an overall yield of 55%. Particular regioisomers
were isolated by dissolution of their mixture in anhy-
drous acetone and fractional precipitation with diethyl
ether. The first fractions were enriched in compound
IVc, the subsequent fractions were enriched in com-
pound IIIc, and the mother liquor was enriched in
isomer IIc.
Mannich base hydrochlorides VIII–XIII were
synthesized from the E and Z isomers of isophorone
oxime according to the standard procedure (see above).
Insofar as the reaction mixtures underwent consider-
able tarring, excess diethyl ether was added to the
resulting alcoholic solution, and the upper (diethyl
ether) layer was separated. The remaining ethanol
solution contained mush less polymeric products. If
necessary, a fresh portion of ethanol was added to
the solution, and treatment with diethyl ether was
repeated.
3,5,5-Trimethyl-6-(piperidinomethyl)cyclohex-2-
en-1-one hydrochloride (IIc) was isolated by fourfold
dissolution in chloroform and precipitation with di-
ethyl ether of the product isolated from the mother
liquor, purity ≥90%. IR spectrum, ν, cm–1: 3420 br.s
(NH), 3050 v.w (=C–H), 2960 s, 2930 m (C–Haliph),
2750–2380 (several bands, NH+), 1665 s (C=O), 1620
(C=C). 1H NMR spectrum, δ, ppm: 0.98 s (6H, 5-CH3),
1.90 m (6H, 3′-H, 4′-H, 5′-H), 2.08 d (3H, 3-CH3, 4J =
1.4 Hz), 2.23 br.s (2H, 4-H), 2.90 m (4H, 2′-H, 6′-H),
Compounds VIII–X (overall yield 49%) were
obtained from E isomer VI by removal of the solvent
by distillation. Particular isomers were isolated accord-
ing to the same procedure as in the isolation of analo-
gous amino ketone hydrochlorides.
2
3
(E)-6-(Dimethylaminomethyl)-3,5,5-trimethyl-
cyclohex-2-en-1-one oxime hydrochloride (VIII)
was isolated by fivefold recrystallization from aceto-
nitrile of a fraction enriched in this isomer, purity
≥81%. IR spectrum, ν, cm–1: 3400 br.s (NOH), 3260
(NH), 3060 w (=C–H), 2960 s, 2900 m, 2870 m
(C–Haliph), 2690–2440 (several bands, NH+), 1650 s
3.20 d.d (1H, 10-H, J = 11, J = 8 Hz), 3.49 d.d (1H,
2
3
3
10-H, J = 11, J = 6 Hz), 3.54 d.d (1H, 6-H, J = 6,
4
8 Hz), 5.84 q (1H, 2-H, J = 1.4 Hz), 10.00 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 236 (4) [M]+, 150
[M – (CH2)5NH]+, 135, 121, 118, 108, 96, 93, 85 (100),
67, 52, 41.
3,5,5-Trimethyl-2-(piperidinomethyl)cyclohex-2-
en-1-one hydrochloride (IIIc) was isolated by five-
fold recrystallization from butanol of a fraction en-
riched in this isomer, purity ≥82%. IR spectrum, ν,
cm–1: 3430 br.s (NH), 2960 s, 2930 m (C–Haliph),
2750–2390 (several bands, NH+), 1665 s (C=O), 1620
(C=C). 1H NMR spectrum, δ, ppm: 0.78 s (6H, 5-CH3),
1.90 m (6H, 3′-H, 4′-H, 5′-H), 2.06 d (3H, 3-CH3, 4J =
1.4 Hz), 2.21 br.s (2H, 4-H), 2.56 br.s (2H, 6-H),
2.90 m (4H, 2′-H, 6′-H), 2.99 d (1H, 10-H, 2J = 12 Hz),
1
(C=N), 1620 m (C=C), 950 (NOH). H NMR spec-
trum, δ, ppm: 1.02 s (6H, 5-CH3), 1.87 d (3H, 3-CH3,
4J = 1.4 Hz), 1.97 br.s (2H, 4-H, 2.98 s (6H, NCH3),
3
3
3.28 t (2H, 10-H, J = 7 Hz), 3.65 t (1H, 6-H, J =
4
7 Hz), 5.98 q (1H, 2-H, J = 1.4 Hz), 8.40 br.s (1H,
NH), 9.60 br.s (1H, NOH). Mass spectrum, m/z
(Irel, %): 211 (3) [M]+, 195 [M – OH]+, 165 [M –
Me2NH2]+, 148 [M – Me2NH2 – OH]+, 133, 120, 117,
107, 96, 93, 67 (100), 52, 41.
2
3.07 d (1H, 10-H, J = 12 Hz), 10.20 br.s (1H, NH).
(E)-2-(Dimethylaminomethyl)-3,5,5-trimethyl-
cyclohex-2-en-1-one oxime hydrochloride (IX) was
isolated by triple reprecipitation with anhydrous
acetone from a chloroform solution, purity ≥80%. IR
spectrum, ν, cm–1: 3390 br.s (NOH), 3280 (NH), 2960 s,
2910 m, 2880 m (C–Haliph), 2670–2440 (several bands,
NH+), 1650 s (C=N), 1620 m (C=C), 950 (NOH).
1H NMR spectrum, δ, ppm: 0.88 s (6H, 5-CH3), 1.89 d
Mass spectrum, m/z (Irel, %): 236 (5) [M]+, 150
[M – (CH2)5NH]+, 135, 121, 118, 108, 96, 93, 85
(100), 67, 52, 41.
5,5-Dimethyl-3-(2-piperidinoethyl)cyclohex-2-
en-1-one hydrochloride (IVc) was isolated by four-
fold crystallization from anhydrous acetone of the
product isolated from the first fractions (see above),
purity ≥84%. IR spectrum, ν, cm–1: 3340 br.s (NH),
4
(3H, 3-CH3, J = 1.4 Hz), 2.00 br.s (2H, 4-H), 2.77 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

KOVAL’SKAYA, KOZLOV
996
2
(6H, NCH3), 2.87 d (1H, 10-H, J = 12 Hz), 2.91 br.s
(2H, 6-H), 3.02 d (1H, 10-H, 2J = 12 Hz), 9.6 br.s (2H,
NH, NOH). Mass spectrum, m/z (Irel, %): 211 (3)
[M]+, 195 [M – OH]+, 165 [M – Me2NH2]+, 148
[M – Me2NH2 – OH]+, 133, 121, 117, 108, 96, 93,
67 (100), 52, 41.
(C–Haliph), 2680–2440 (several bands, NH+), 1650 s
(C=N), 1620 m (C=C), 950 (NOH). H NMR spec-
1
trum, δ, ppm: 0.90 s (6H, 5-CH3), 1.87 d (3H, 3-CH3,
4J = 1.4 Hz), 1.98 br.s (2H, 4-H), 2.40 br.s (2H, 6-H),
2.72 s (6H, NCH3), 3.05 br.s (2H, 10-H), 8.40 br.s (1H,
NH), 9.60 br.s (1H, NOH). Mass spectrum, m/z
(Irel, %): 211 (3) [M]+, 195 [M – OH]+, 165 [M –
Me2NH2]+, 148 [M – Me2NH2 – OH]+, 133, 121, 117,
108, 96, 93, 67 (100), 52, 41.
3-[2-(Dimethylamino)ethyl]-5,5-dimethylcyclo-
hex-2-en-1-one hydrochloride (X) was isolated by
fourfold crystallization from anhydrous acetone of the
product isolated from fractions enriched with this
isomer, purity ≥80%. IR spectrum, ν, cm–1: 3350 br.s
(NOH, NH), 3050 v.w (=C–H), 2960 s, 2920 m,
2850 w (C–Haliph), 2680–2420 (several bands, NH+),
1650 s (C=N), 1620 (C=C), 960 (NOH). H NMR
spectrum, δ, ppm: 1.13 s (6H, 5-CH3), 2.10 br.s (2H,
4-H), 2.22 m (2H, 7-H), 2.82 br.s (2H, 6-H), 2.81 s
(6H, NCH3), 2.92 t (2H, 10-H, J = 7 Hz), 5.97 t (1H,
(Z)-3-[2-(Dimethylamino)ethyl]-5,5-dimethyl-
cyclohex-2-en-1-one oxime hydrochloride (XIII)
was isolated by fourfold crystallization from anhy-
drous acetone of the product isolated from the mother
liquor, purity ≥80%. IR spectrum, ν, cm–1: 3370 br.s
(NOH + NH), 3050 v.w (=C–H), 2960 s, 2920 m,
2850 m (C–Haliph), 2680–2420 (several bands, NH+),
1
3
1
1650 s (C=N), 1620 (C=C), 960 (NOH). H NMR
4
2-H, J = 1.4 Hz), 8.40 br.s (1H, NH), 9.60 br.s (1H,
spectrum, δ, ppm: 1.12 s (6H, 5-CH3), 2.11 br.s (2H,
NOH). Mass spectrum, m/z (Irel, %): 211 (2) [M]+, 195
[M – OH]+, 165 [M – Me2NH2]+, 148 [M – Me2NH2 –
OH]+, 135, 122, 108, 92, 83, 67 (100), 55, 41.
4-H), 2.19 m (2H, 7-H), 2.36 br.s (2H, 6-H), 2.73 s
3
(6H, NCH3), 2.96 t (2H, 10-H, J = 7 Hz), 6.64 t (1H,
4
2-H, J = 1.4 Hz), 8.50 br.s (1H, NH), 9.50 br.s (1H,
NOH). Mass spectrum, m/z (Irel, %): 211 (2) [M]+, 195
[M – OH]+, 165 [M – Me2NH2]+, 148 [M – Me2NH2 –
OH]+, 135, 122, 108, 92, 83, 81, 67 (100), 55, 41.
Compounds XI–XIII were obtained in an overall
yield of 47% from Z isomer VII by washing with
diethyl ether (see above) and removal of the solvent by
distillation. Particular regioisomers were isolated ac-
cording to the same procedure as in the isolation of
analogous amino ketone hydrochlorides.
3-[(Z)-2-Arylethenyl]-5,5-dimethylcyclohex-2-en-
1-ones XIVa–XIVh (general procedure). As noted
above, compounds XIV were obtained in most cases
instead of expected Mannich bases by heating a solu-
tion of equimolar amounts of isophorone, aromatic
amine, and aromatic aldehyde in ethanol under reflux.
The best yields of XIVa–XIVh were obtained in the
reactions with p-toluidine as amine component; reduc-
tion of the amount of the latter to 0.3 equiv decreased
tarring and impurity of the corresponding Schiff base.
(Z)-6-(Dimethylaminomethyl)-3,5,5-trimethyl-
cyclohex-2-en-1-one oxime hydrochloride (XI) was
isolated by fivefold crystallization from acetonitrile of
a fraction enriched in this isomer, purity ≥83%. IR
spectrum, ν, cm–1: 3400 br.s (NOH), 3280 (NH),
3060 w (=C–H), 2960 s, 2900 m, 2870 m (C–Haliph),
2660–2440 (several bands, NH+), 1650 s (C=N),
1620 m (C=C), 950 (NOH). H NMR spectrum, δ,
ppm: 1.01 s (6H, 5-CH3), 1.88 d (3H, 3-CH3, J =
1.4 Hz), 1.98 br.s (2H, 4-H), 3.00 s (6H, NCH3),
3.20 d.d (1H, 10-H, J = 11, J = 8 Hz), 3.29 d.d (1H,
6-H, J = 6, 8 Hz), 3.37 d.d (1H, 10-H, J = 11, J =
6 Hz), 6.62 q (1H, 2-H, J = 1.4 Hz), 9.50 br.s (1H,
NH), 9.80 br.s (1H, NOH). Mass spectrum, m/z
(Irel, %): 211 (3) [M]+, 195 [M – OH]+, 165 [M –
Me2NH2]+, 148 [M – Me2NH2 – OH]+, 133, 120, 117,
107, 96, 93, 67 (100), 52, 41.
1
3-[(Z)-2-(4-Fluorophenyl)ethenyl]-5,5-dimethyl-
cyclohex-2-en-1-one (XIVa). Yield 64%, mp 116–
117°C. IR spectrum, ν, cm–1: 3070, 3050, 3030 (=C–H,
C–Harom), 2950, 2920, 2865 (C–Haliph), 1655 (C=O),
1615 (C=C), 1590, 1580, 1505 (C=Carom), 1155 (C–F),
4
2
3
3
2
3
4
1
840 (δC–Harom). H NMR spectrum, δ, ppm: 1.09 s
(6H, 5-CH3), 2.29 br.s (2H, 6-H), 2.43 d (2H, 4-H, 4J =
1.2 Hz), 6.05 t (1H, 2-H, 4J = 1.2 Hz), 6.84 d (1H, 7-H,
3
3J = 16.0 Hz), 6.89 d (1H, 8-H, J = 16.0 Hz), 7.04 t
3
3
(2H, 3′-H, 5′-H, JHH = JHF = 8.6 Hz), 7.46 d.d (2H,
2′-H, 6′-H, 3JHH = 8.6, 4JHF = 5.5 Hz).
(Z)-2-(Dimethylaminomethyl)-3,5,5-trimethyl-
cyclohex-2-en-1-one oxime hydrochloride (XII) was
isolated by fourfold precipitation with anhydrous
acetone from chloroform of fractions enriched in this
isomer, purity ≥81%. IR spectrum, ν, cm–1: 3380 br.s
(NOH), 3300 (NH), 2960 s, 2910 m, 2880 m
3-[(Z)-2-(4-Bromophenyl)ethenyl]-5,5-dimethyl-
cyclohex-2-en-1-one (XIVb). Yield 67%, mp 121–
122°C. IR spectrum, ν, cm–1: 3060, 3040, 3030 (=C–H,
C–Harom), 2950, 2920, 2865 (C–Haliph), 1655 (C=O),
1615 (C=C), 1575, 1485 (C=Carom), 835 (δC–Harom),
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CONDENSATION OF ISOPHORONE AND ISOPHORONE OXIME
997
1
540 (C–Br). H NMR spectrum, δ, ppm: 1.13 s (6H,
3-[(Z)-2-(4-Hydroxy-3-methoxyphenyl)ethenyl]-
5,5-dimethylcyclohex-2-en-1-one (XIVg). Yield 81%,
mp 158–159°C. IR spectrum, ν, cm–1: 3135 (OH),
3070, 3050 (=C–H, C–Harom), 2950, 2935, 2925
(C–Haliph), 1630 (C=O), 1610 (C=C), 1585, 1570, 1525
(C=Carom), 1285 (C–O), 1260, 1235 (C–O–C), 850
4
5-CH3), 2.32 br.s (2H, 6-H), 2.46 d (2H, 4-H, J =
1.2 Hz), 6.08 t (1H, 2-H, 4J = 1.2 Hz), 6.91 s (2H, 7-H,
8-H), 7.37 d (2H, 3′-H, 5′-H, 3J = 8.5 Hz), 7.47 d (2H,
2′-H, 6′-H, 3J = 8.5 Hz).
3-[(Z)-2-(4-Hydroxyphenyl)ethenyl]-5,5-dimeth-
ylcyclohex-2-en-1-one (XIVc). Yield 72%, mp 192–
194°C. IR spectrum, ν, cm–1: 3200 br.s (OH), 3060,
3045 (=C–H, C–Harom), 2950, 2920, 2865 (C–Haliph),
1645 (C=O), 1615 (C=C), 1600, 1515 (C=Carom), 1285
1
(δC–Harom). H NMR spectrum, δ, ppm: 1.11 s (6H,
4
5-CH3), 2.31 br.s (2H, 6-H), 2.47 d (2H, 4-H, J =
4
1.2 Hz), 3.95 s (3H, OCH3), 6.06 t (1H, 2-H, J =
3
1.2 Hz), 6.80 d (1H, 7-H, J = 16.0 Hz), 6.86 d (1H,
3
3
1
5-H, J = 8.5 Hz), 6.90 d (1H, 8-H, J = 16.0 Hz),
(C–O), 835 (δC–Harom). H NMR spectrum, δ, ppm:
3
6.96 s (1H, 2′-H), 7.05 d (1H, 6′-H, J = 8.5 Hz),
1.11 s (6H, 5-CH3), 2.32 br.s (2H, 6-H), 2.48 d (2H,
4-H, 4J = 1.2 Hz), 6.07 t (1H, 2-H, 4J = 1.2 Hz), 6.84 d
10.0 (1H, OH).
3
3
3-[(Z)-2-(3,4-Dimethoxyphenyl)ethenyl]-5,5-di-
methylcyclohex-2-en-1-one (XIVh). Yield 76%,
mp 139–141°C. IR spectrum, ν, cm–1: 3060, 3035
(=C–H, C–Harom), 2960, 2930, 2855 (C–Haliph), 1630
(C=O), 1610 (C=C), 1595, 1575, 1515 (C=Carom),
(1H, 7-H, J = 16.0 Hz), 6.90 d (1H, 8-H, J =
3
16.0 Hz), 6.96 d (2H, 3′-H, 5′-H, J = 8.5 Hz), 7.80 d
(2H, 2′-H, 6′-H, 3J = 8.5 Hz), 9.87 (1H, OH).
3-[(Z)-2-(4-Methoxyphenyl)ethenyl]-5,5-dimeth-
ylcyclohex-2-en-1-one (XIVd). Yield 75%, mp 135–
136°C. IR spectrum, ν, cm–1: 3080, 3050, 3020 (=C–H,
C–Harom), 2970, 2935, 2870 (C–Haliph), 1635 (C=O),
1610 (C=C), 1600, 1510 (C=Carom), 1250 (C–O–C),
1
1275, 1240 (C–O–C), 860 (δC–Harom). H NMR spec-
trum, δ, ppm: 1.12 s (6H, 5-CH3), 2.31 br.s (2H, 6-H),
4
2.47 d (2H, 4-H, J = 1.2 Hz), 3.94 s and 3.97 s (3H
each, OCH3), 6.07 t (1H, 2-H, 4J = 1.2 Hz), 6.79 d (1H,
1
840 (δC–Harom). H NMR spectrum, δ, ppm: 1.11 s
3
3
(6H, 5-CH3), 2.31 br.s (2H, 6-H), 2.47 d (2H, 4-H, 4J =
7-H, J = 16.0 Hz), 6.88 d (1H, 5′-H, J = 8.5 Hz),
3
4
6.90 d (1H, 8-H, J = 16.0 Hz), 6.96 s (1H, 2′-H),
1.2 Hz), 3.88 s (3H, OCH3), 6.07 t (1H, 2-H, J =
1.2 Hz), 6.84 d (1H, 7-H, J = 16.0 Hz), 6.90 d (1H,
8-H, J = 16.0 Hz), 6.98 d (2H, 3′-H, 5′-H, J =
8.5 Hz), 7.85 d (2H, 2′-H, 6′-H, 3J = 8.5 Hz).
7.08 d (1H, 6′-H, 3J = 8.5 Hz).
3
3
3
REFERENCES
3-[(Z)-2-(4-Dimethylaminophenyl)ethenyl]-5,5-
dimethylcyclohex-2-en-1-one (XIVe). Yield 55%,
mp 138–140°C. IR spectrum, ν, cm–1: 3080, 3050,
3020 (=C–H, C–Harom), 2970, 2935, 2870 (C–Haliph),
1645 (C=O), 1615 (C=C), 1590, 1505 (C=Carom), 1175
1. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 1.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1982, vol. 2, pp. 585, 643.
2. Koval’skaya, S.S. and Kozlov, N.G., Russ. J. Org.
Chem., 1998, vol. 34, p. 1131.
3. Koval’skaya, S.S. and Kozlov, N.G., Russ. J. Org.
Chem., 2001, vol. 37, p. 499.
4. Pashkovskii, F.S., Lakhvich, F.A., Koval’skaya, S.S.,
and Kozlov, N.G., Russ. J. Org. Chem., 2001, vol. 37,
p. 375.
1
(C–N), 830 (δC–Harom). H NMR spectrum, δ, ppm:
1.10 s (6H, 5-CH3), 2.31 br.s (2H, 6-H), 2.46 d (2H,
4-H, 4J = 1.2 Hz), 3.03 s (6H, NCH3), 6.07 t (1H, 2-H,
3
4J = 1.2 Hz), 6.78 d (2H, 3′-H, 5′-H, J = 8.5 Hz),
3
3
6.84 d (1H, 7-H, J = 16.0 Hz), 6.89 d (1H, 8-H, J =
16.0 Hz), 7.74 d (2H, 2′-H, 6′-H, 3J = 8.5 Hz).
5. Koval’skaya, S.S., Kozlov, N.G., and Tkachev, A.V.,
3-[(Z)-2-(3-Ethoxy-4-hydroxyphenyl)ethenyl]-
5,5-dimethylcyclohex-2-en-1-one (XIVf). Yield 88%,
mp 146–148°C. IR spectrum, ν, cm–1: 3135 (OH),
3060, 3040 (=C–H, C–Harom), 2960, 2930, 2870
(C–Haliph), 1635 (C=O), 1610 (C=C), 1590, 1570, 1520
(C=Carom), 1280 (C–O), 1260 and 1240 (C–O–C), 840
Russ. J. Org. Chem., 2005, vol. 41, p. 1836.
6. Carey, F.A. and Sundberg, R.J., Advanced Organic
Chemistry, New York: Plenum, 1977. Translated under
the title Uglublennyi kurs organicheskoi khimii,
Moscow: Khimiya, 1981, vol. 2, p. 48.
7. Koval’skaya, S.S. and Kozlov, N.G., Russ. J. Org.
Chem., 1997, vol. 33, p. 177.
8. Koval’skaya, S.S. and Kozlov, N.G., Russ. J. Org.
Chem., 2000, vol. 36, p. 785.
9. Daniel, A. and Pavia, A.A., Tetrahedron Lett., 1967,
1
(δC–Harom). H NMR spectrum, δ, ppm: 1.12 s (6H,
5-CH3), 1.50 t (3H, CH2CH3, 3J = 7 Hz), 2.32 br.s (2H,
6-H), 2.47 d (2H, 4-H, 4J = 1.2 Hz), 4.19 q (2H, OCH2,
4
3J = 7 Hz), 6.07 t (1H, 2-H, J = 1.2 Hz), 6.79 d (1H,
3
3
7-H, J = 16.0 Hz), 6.86 d (1H, 5′-H, J = 8.5 Hz),
vol. 8, p. 1145.
3
6.90 d (1H, 8-H, J = 16.0 Hz), 6.96 s (1H, 2′-H),
10. Soloducho, J. and Zabza, A., Pol. J. Chem., 1979,
7.05 d (1H, 6′-H, 3J = 8.5 Hz), 10.0 (1H, OH).
vol. 53, p. 1497.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010