Methods of synthesis of alicyclic 1,5,9-triketones. Reaction of transaminomethylation

Article abstract of DOI:10.1134/S1070428017050128

Alicyclic 1,5,9-triketones with various combination of 5-, 6-, 7-membereded cycles in the molecule were obtained by methods of diketone condensation, Michael reaction, and proceeding from Mannich mono- and bisbases and cycloalkanones. The latter method wa

Full text of DOI:10.1134/S1070428017050128

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 5, pp. 720–728. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © Т.I. Akimova, О.А. Soldatkina, Zh.А. Ivanenko, V.G. Savchenko, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53,
No. 5, pp. 710–718.
Methods of Synthesis of Alicyclic 1,5,9-Triketones.
Reaction of Transaminomethylation
Т. I. Akimova,* О. А. Soldatkina, Zh. А. Ivanenko, and V. G. Savchenko
Far-Eastern Federal University, ul. Sukhanova 8, Vladivostok, 690091 Russia
*e-mail: akimova.ti@dvfu.ru
Received February 15, 2017
Abstract—Alicyclic 1,5,9-triketones with various combination of 5-, 6-, 7-membereded cycles in the molecule
were obtained by methods of diketone condensation, Michael reaction, and proceeding from Mannich mono-
and bisbases and cycloalkanones. The latter method was accompanied with a transaminomethylation, observed
for the first time at triketones preparation. The structures of cyclic forms of Michael reaction products were
refined.
DOI: 10.1134/S1070428017050128
First alicyclic 1,5,9-triketones were obtained in
nineteen fifties [1–3], however their reactions were
investigated only recently [4–7]. Initially the attention
of researchers was attracted by 1,5,9-triketone 1а,
consisting of six-membered rings А‒С that under the
effect of alkali easily underwent cyclization into
complex scaffold structure 2а (Scheme 1) and at
melting returned in the initial state. The intramolecular
cyclization is also typical of the other 1,5,9-triketones
containing cycles of various size (from five- to seven-
membered), but having in their structure no less than
two six-membered cycles [5, 8]. In reaction with N-
nucleophiles [4] triketone 1а forms a derivative of
quinolizidine base julolidine known for its bioactivity.
cycles of various sizes, to consider special features of
their formation, check and optimize the methods of
synthesis of known triketones. Methods of synthesis of
alicyclic 1,5,9-triketones containing cycles of various
size were unknown save those we had described in [9].
Therefore we ourselves developed methods of
synthesis of alicyclic 1,5,9-triketones 1 and 3‒11 with
five-, six- and seven-membered rings (Scheme 2).
Alicyclic 1,5,9-triketones, as a rule, are side
products in the synthesis of 1,5-diketones and are
obtained in small yields. At the synthesis of 1,5,9-
triketones it is necessary to create conditions that
reduce the yield of 1,5-diketones and to find methods
of separation of di- and triketones.
While investigating properties of alicyclic 1,5,9-
triketones we were obliged at the same time to develop
methods of synthesis of previously unknown
compounds of this type, particularly those containing
Main methods of synthesis of 1,5-diketones that
may be applied to the preparation of 1,5,9-triketones
are based on diketone condensation, on Michael
reaction, and Robinson annulation (a version of
Scheme 1.
R
O
B
R
R
O
O
B
OH
8
R
A
1
4
2
9
7
C
B
A
A
O
O
3
5
6
O
R
R
HO
OH
C
O
R
O
R
O
C
1a_1c
2a_2c
R = H (а), Ph (b), furan-2-yl (c).
720

METHODS OF SYNTHESIS OF ALICYCLIC 1,5,9-TRIKETONES
721
Scheme 2.
1,5-diketones in anhydrous conditions paraformalde-
hyde, sodium methylate, and methanol were applied in
a ratio ketone–aldehyde 3 : 1. The formation of 1,5,9-
triketones was not mentioned.
(CH2)m
(CH2)n
(CH2)m
O
O
O
We used this method to synthesize triketones 1а
and 3 and obtained them in 25 and 29% yields. All our
further attempts to increase the yield of 1,5,9-
triketones by changing reaction conditions did not
succeed.
1, 3_11
1, m = 2, n = 2 (6-6-6);1 3, m = 2, n = 2 (7-7-7); 4, m = 2,
n = 1 (6-5-6); 5, m = 3, n = 1 (7-5-7); 6, m = 1, n = 1 (5-5-5);
7, m = 1, n = 2 (5-6-5); 8, m = 1, n = 3 (5-7-5); 9, m = 2,
n = 3 (6-7-6); 10, m1 = 2, n = 2 , m2 = 3 (6-6-7); 11, m = 3,
n = 2 (7-6-7).
Triketone 1а was synthesized in cyclic form 2а,
and triketone 3, in an open ketone form. It should be
mentioned that triketone 3 obtained in anhydrous
conditions did not form in water-alcohol solution, and
diketone condensation of cycloheptanone with
formaldehyde is restricted to the formation of the
corresponding 1,5-diketone.
Scheme 3.
_
OH
1a_1c
+
RCHO
+
O
O
R
O
12a_12c
The reaction with aromatic aldehydes proceeds
more difficultly. By condensation of cyclohexanone
with benzaldehyde and furfural in conditions of
diketone condensation in water-alcohol environment
only 1,5,9-triketone 2c was obtained in 1.5% yield [1,
10, 12]. In anhydrous medium at excess of cyclo-
hexanone in the presence of sodium methylate the
yield of compound 2с practically did not increase.
R = H (а), Ph (b), furan-2-yl (c).
Michael reaction). By application of enamine method
one of the first alicyclic 1,5,9-triketones was obtained
consisting of five-membered cycles [3]. We used it
only as a version in addition to Robinson method.
Diketone condensation. First alicyclic 1,5,9-
triketone 1а was obtained in a yield not exceeding 14‒
16% as a side product of diketone condensation of
cyclohexanone with formaldehyde at the preparation of
1,5-diketone 12a (Scheme 3) (ratio ketone–aldehyde
2 : 1, catalyst 0.2 and 4N alcohol solutions of alkali
NaOH and KОН) [1, 2, 10]. In [11] for the synthesis of
Michael reaction. Whereas the conditions of
diketone condensation allow the preparation of
triketones with similar cycles, by Michael reaction it is
possible to obtain 1,5,9-triketones with diverse
combinations of cycles. Classic version of Michael
reaction applied to the synthesis of alicyclic 1,5,9-
Scheme 4.
R
R
O
O
13b, 13c
2b, 2c
R
O
2
R
R
OH
R
O
O
O
R
15b, 15c
14b, 14c
R = Ph (b), furan-2-yl (c).
1
Numbers in brackets show the ring size in di- and triketones.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

AKIMOVA et al.
Characteristic signals of carbon atoms in 13С NMR spectra (DEPT-135) of compounds 2а–2c
722
Quaternary carbon atoms
Tertiary carbon atoms
С2, С3, С4, С7, С8
Compound no.
С1, С6
С5
С9
2а
2b
2c
96.1, 98.2
95.8, 99.2
95.4, 98.3
79.0
80.8
80.2
37.8
41.6
41.8
39.6, 39.8, 41.1
44.8(С4), 45.3 (С7), 47.1 (С3), 47.8 (С8), 48.1 (С2)
40.8 (С8), 41.2 (С3) , 44.5 (С4), 44.7 (С7), 44.9 (С2)
triketones consists in cyclanones addition to diaryl-
ideneketones 13, or to dimers of monoarylideneketo-
nes 14 that are in an equilibrium with cyclic forms 15
[13, 14] (Scheme 4).
atom may appear only in the first aldol stage of
cyclization (Scheme 1) involving a methine and not a
methylene group, as it has been considered previously
[10]. In each structure there are also two C atoms
bound with two oxygen atoms (С1 and С6) and one
At heating 2,6-dibenzylidene- (13b) and 2,6-bis-
(furan-2-ylmethylidene)cyclohexan-1-one 13c with a
large excess of cyclohexanone in alkaline medium
triketones 1b and 1c are produced in cyclic forms 2b
and 2c in 3 and 14% yields respectively [10, 12]. At
the reaction of dimer 14c with cyclohexanone only
compound 2c was obtained in 16% yield. We repeated
these syntheses taking instead of alcohol solution of
NaOH a stronger base, sodium methylate, but there
was no significant increase in the yield of triketones.
The structure of these compounds was previously
established basing on IR spectra only, now we
registered the NMR spectra. The structure of
compound 2а, besides the 13С NMR spectrum [9], was
confirmed by X-ray diffraction analysis [15–17]. Two
hydroxanthene rings in the molecule of compound 2а
are in the boat conformation (see the figure).
13
(С5) linked to a single oxygen atom. С NMR spectra
confirmed the structure similarity of 2b, 2c, and 2а.
The obtained data allowed a correction of the structure
suggested previously [10] for cyclic forms 2b and 2c.
1Н NMR spectra 1D and 2D, and also 1Н-1Н
NOESY experiment made it possible to establish the
spatial position of phenyl and furyl substituents in
compounds 2b and 2c. In 1Н NMR spectrum of
compound 2b the benzyl proton at С8 appears as a
doublet, δ 2.98 ppm, J 8.5 Hz that evidences its pseudo
-equatorial position. Unlike that, the benzyl proton at
С3 takes the axial position, therefore it appears as a
doublet of doublets at δ 3.35 ppm, J1 4.8, J2 12.5 Hz.
1
In Н NMR spectrum of compound 2с the proton at С8
appears as a doublet at δ 3.03 ppm, J 8.5 Hz, and the
proton at С3 is observed as a doublet of doublets, δ
3.38 ppm, J1 4.8, J2 12.5 Hz. Consequently, the
substituent at С8 in the ring having a boat
conformation is in a pseudo-axial position, and at С3,
in an equatorial position (see the figure). It is
13С NMR spectra of compounds 2b and 2c have the
same characteristic signals as in the spectrum of
compound 2а (see the table), in particular, the signal of
quaternary atom С9 unbound to oxygen atoms. Such
1
confirmed by the presence in Н-1Н NOESY spectrum
of cross-peaks corresponding to the coupling of protons
at С7 and С4 atoms with оrtho-protons of the benzene
ring and with the proton at С3' atom of the furan ring.
For compound 2b the following cross-peaks are
O
H
4
5
O
H
3
Scheme 5.
(CH2)m
3'
H
H
(CH2)n
(CH2)m
6
8
7
9
4_6
a.
+
2
H
O
N(CH3)2
1
OH
H
O
O
O
O
H
3'
(CH2)n
b.
6_9, 11
+
(CH3)2N
N(CH3)2
Structure of 10,18-bis(furan-2-yl)-3,22-dioxahexacyclo-
[9.7.3.14,12.01,2.04,9.012,17]docosan-2-ol 2с and spatial
correlation 1Н-1Н in the NOESY experiment.
O
m, n = 1–3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

METHODS OF SYNTHESIS OF ALICYCLIC 1,5,9-TRIKETONES
723
Scheme 6.
O
O
12a
O
16
O
+
+
N(CH3)2
N(CH3)2
O
O
O
O
Transaminomethylation
O
O
O
O
O
17
N(CH3)2
11
O
O
O
O
O
O
O
9
10
observed: С3‒Ph (оrtho-protons)/C4Н at 7.23/2.2 ppm
and С8‒Ph (оrtho-protons)/C7Н at 7.48/2.49 ppm; for
compound 2с: С3‒Fur (C3'Н)/ С4Н at 6.05/2.21 and
С8‒Fur (C3'Н)/С7Н at 6.23/2.30 ppm.
reactivity of Mannich bases from cyclopentanone.
Using cyclopentanone as nucleophile in the reaction
with Mannich monobases obtained from cyclo-
hexanone and cycloheptanone we obtained 1,5,9-
triketones 4 (6-5-6) [9] and 5 (7-5-7) respectively.
Yield of compound 4 is 49%, triketone 5, 18%. We did
not succeed in preparation of triketones 7 (5-6-5) or 8
(5-7-5) at interaction with Mannich monobase obtained
from cyclopentanone with cyclohexanone or with
cycloheptanone, only diketones form in this reaction.
Robinson method that is a thermal option of
Michael reaction is widely used in the synthesis of 1,5-
diketones, and we applied it to the synthesis of 1,5,9-
triketones in three versions (а‒c). In the a version (classic
method [18]) Mannich monobase obtained from ketone
and cyclonone was used, 2.2 : 1 (Scheme 5, а).
The specific feature of reactions, where ketones
with almost similar nucleophilicity are involved (cyc-
lohexanone and cycloheptanone), is the appearance in
the reaction mixture of all possible 1,5-diketones and
1,5,9-triketones with these cycles because simul-
taneously with the main reaction the reaction of
transaminomethylation takes place that has been
previously observed in the synthesis of arylaliphatic
1,5-diketones [19, 20].
The method is sensitive to the reagent
nucleophilicity and to the reactivity of Mannich base
and not always gives positive results, stopping at the
stage of the formation of 1,5-diketone. Although the
nucleophilicity of 5- and 6-membered cyclic ketones
decreases with the increase in the cycle size, the
reactivity of Mannich bases obtained from
cyclohexanone is higher in this reaction than the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

AKIMOVA et al.
724
Scheme 7.
+
(H3C)2N
N(CH3)2
N(CH3)2
(H3C)2N
2
+
O
O
O
O
18
19
20
O
O
O
O
O
O
O
O
4, 11%
12a, 53%
21, 20%
At the attempt to synthesize triketone 9 (6-7-6)
from cycloheptanone and Mannich monobase obtained
from cyclohexanone (Scheme 6) we found in the reaction
products 37% of 1,5-diketones 12а (6-6), 16 (7-7), 17
(6-7), 0.3 : 1 : 1, and 17% of triketone fraction with
approximately equal ratio of triketones 9 + 10 and 11
(7-6-7 or 7-7-6) (GC/MS). The same reaction products
of were obtained at the attempt of synthesis of 11 (7-6-7)
from cyclohexanone and Mannich monobase from
cycloheptanone. In both cases the initially generated
diketone 17 (6-7) reacted with the Mannich bases
based on cyclohexanone or cycloheptanone. In the first
synthesis from triketone fraction after treating it with
alcohol solution of alkali triketone 10 was isolated in a
cyclic form.
triketones 7 (5-6-5) (70%) and 8 (5-7-5) (47%), which
failed to be obtained at the application of Mannich
monobase by method а. Triketone 2а is obtained in
equal amount with diketone 12а (6-6) (yield 50%).
However everything changes at application of
less reactive Mannich bisbase based on cyclopen-
tanone 18 (Scheme 7). At heating with 2 mol of
cyclohexanone aiming to prepare triketone 4 (6-5-6)
we obtained a mixture containing 53% of diketone 12а
(6-6), 20% of diketone 21 (5-6), and only 11% of
triketone 4. Evidently due to the low rate of the main
reaction the process of transaminomethylation
developes. As a result bisbase 18 turns into a mixture
of monobases from cyclopentanone 19 and cyclo-
hexanone 20. The latter enter into the reaction with
cyclohexanone and form the corresponding diketones
12а (6-6) and 21 (5-6). The prevailing formation of
particular six-membered 1,5-diketone 12а confirms the
higher reactivity of Mannich base based on cyclo-
hexanone comparing to Mannich basis based on
cyclopentanone.
If the formation of triketones 9, 10, and 17 is the
result of a normal reaction course, then the formation
of diketones 11, 12а, and 16 is the result of trans-
aminomethylation (Scheme 6). Transaminomethylation
is almost absent at the application of cyclopentanone
as nucleophile, and in the preparation of triketones 4
and 5 no transaminomethylation was detected.
The third version of triketones synthesis from
Mannich bases (method c) consists in the reaction of
Mannich bisbases with enamine of cyclanone. To
obtain 1,5,9-triketone 9 (6-7-6) we brought in the
reaction the Mannich bisbase based on cycloheptanone
and enamine of cyclohexanone (cyclohexenyl-
morpholine) [22] in a ratio 1 : 2. The yield of reaction
product in cyclic form was 69%, so for triketone 9 this
method was the most effective comparing to others.
Another approach to Robinson reaction (version b)
is the reaction of Mannich bisbases with cyclanone in
the ratio 1 : 2.2 (Scheme 5, b). By reaction of Mannich
bisbases prepared from cyclohexanone and cyclo-
heptanone triketones 11 (7-6-7) (47%) and 9 (6-7-6)
(66 %) were obtained respectively where the fraction
of products of transaminomethylation did not exceed
13%. By this method it was possible to synthesize also
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METHODS OF SYNTHESIS OF ALICYCLIC 1,5,9-TRIKETONES
725
Hence, it is possible to obtain triketones with 5-
membered cycle inside the molecule basing on
Mannich bases by method а [4 (6-5-6) and 5 (7-5-7)],
and with 6- and 7-membered cycles inside the
molecule, by method b [7 (5-6-5), 8 (5-7-5), 9 (6-7-6),
11 (7-6-7)]. Triketone 6 (5-5-5) forms both by methods
a and b, its yield does not exceed 45%. Method c is
evidently the most universal for the preparation of
triketones.
the composition of reaction mixture was monitored
with GC/MS. The chromatographic analysis was
realized on gas chromatograph Agilent GC 6890 Plus
with mass-selective detector 5973N at ionization with
electron impact (EI, 70 eV), quartz capillary column
HP-5MS (length 30 m, internal diameter 0.25 mm,
layer of the stationary phase 0.25 µm thick), carrier gas
helium. To record mass spectra EI of individual
compounds 2b and 2c a system of direct input of
sample HPP7 & ProbeDirect™ was applied in
combination with MSD HP 5973. Melting points were
determined on PTP (М) apparatus in capillaries.
It is characteristic that all 1,5,9-triketones are
present in the isolated reaction product as a mixture of
stereoisomers with a similar decay pattern in the mass
spectrum. The number of stereoisomers (GC/MS) is
varying from two to seven, and usually two-three
isomers are prevailing (70–80% of the mixture). The
ratio of stereoisomers in the equilibrium mixture may
vary due to mutual transformations [5]. We isolated
individually two isomers for each of triketones 4 [5]
and 6 [10] and one stereoisomer of triketone 9.
By the method of diketone condensation com-
pounds 2а, 3, 12a, and 16 were prepared.
3,22-Dioxahexacyclo[9.7.3.14,12.01,2.04,9.012,17]doco-
san-2-ol (2a). To a mixture of 49 mL (0.48 mol) of
cyclohexanone and 5 g (0.166 mol) of paraformalde-
hyde was added dropwise while stirring 2 mL of 2N
solution of CH3ONa, the mixture was boiled, parafor-
maldehyde dissolved. The rest 14 mL of 2N solution
of CH3ONa was added dropwise, maintaining weak
boiling of reaction mixture (30‒40 min). The mixture
was heated for 1 h more at 60‒70°C, cooled,
neutralized with acetic acid, left for 24 h at 5°C. The
precipitate was filtered off, washed with 12 mL of
aqueous ethanol, 1 : 1. Yield 6.6 g (25%), white
crystals, mp 193‒193.5°C, individual compound
according to GC-MS data. After recrystallization from
diethyl ether of diethyleneglycol mp 195.5‒196°C {mp
191‒193°C (from benzene or chloroform) [10]}.
In mass spectra obtained by electron impact the
molecular ion for most triketones was not found, and
in all cases an ion with the mass [М ‒ H2О]+ was present.
For all triketones, as well as for 1,5-diketones, the
characteristic fission of the molecule is by the retro-
Michael type, and in mass-spectra ions are present with
masses [М ‒ cyclanone]+, [М ‒ cyclanone ‒ CH2]+. This
type of fission is observed also at heating triketones
over 170°С, as well as at distillation in a vacuum that
leads to accumulation of the corresponding 1,5-
diketones and compounds with the mass [М ‒
cyclanone]+. Most easily the fission occurs in the
triketones with 6- and 7-membered cycles. Therefore
at the synthesis of, for example, triketone 11 (7-6-7) it
is necessary to keep the temperature no higher than
150°С, and vacuum distillation should be used only to
distill off the accompanying 1,5-diketone in a mode
conserving a short presence of reaction products in the
high temperature zone. As a result we obtained
triketone 11 of 98% purity.
From the filtrate at a reduced pressure a mixture of
alcohol and cyclohexanone was distilled off, the
residue was extracted with ether (3 × 30 mL), the
extract was washed with water, dried with MgSO4,
ether was distilled off. The residue (12.2 g), according
to GC-MS data, was a mixture of diketone 12а (6-6)
(35%) and its cyclic form (45%), triketone 1а (8%)
and its cyclic form 2а (12%). After distillation in a
vacuum we obtained 8.2 g (23.6%) of diketone 12а,
colorless oily liquid, bp 153‒156°C (3 mmHg) {bp
165‒170°C (12 mmHg) [11]}.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
Spectrum BX-II (Perkin Elmer). NMR spectra were
registered on a spectrometer Avance-400 Bruker at
working frequencies 400 (1H) and 125 (13С) МHz at
30°С, internal reference ТMS. The assignment of
2,7-Bis(2-oxocycloheptylmethyl)cycloheptan-1-
one (3) (7-7-7). To mixture of 5 g (0.0446 mol) of
cycloheptanone and 0.88 g (0.029 mol) of para-
formaldehyde was added dropwise at stirring 2 mL of
2N solution of CH3ONa. The mixture was heated at
30°C, paraformaldehyde dissolved, then the mixture
was heated on a boiling water bath for 1.5 h, cooled,
acidified with diluted (1 : 10) HCl, the reaction
1
signals was carried out using DEPT-135 and Н-1Н
NOESY experiments. Spectra of compounds 2b and 2c
were recorded in CDCl3. The progress of reaction and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

AKIMOVA et al.
726
products were extracted with ether (3 × 15 mL), the
extract was washed with water till рН 7, dried with
Na2SO4. In succession ether and cycloheptanone (at a
reduced pressure) were distilled off, the residue (5.3 g)
was distilled in a vacuum to obtain 1.5 g of diketone
16 (7-7) (21.9%), bp 148–152°C (3 mmHg) {bp 200–
203°C (11 mmHg [11]} and 2.95 g (28%) of triketone
3, bp 240–250°C (3 mmHg). According to GC-MS
data, triketone 3 was a mixture of 7 diasterometers, among
them three isomers dominated (66%), 27.7 : 19.8 : 18.9.
IR spectrum (СH2Cl2), ν, cm–1: 1698 s (C=O cyclohep-
tanone). Mass spectrum, m/z (Irel, %): 360 (1.6) [М]+,
342 (3.2) [М ‒ Н2О]+, 249 (19.4) [М ‒ С7Н11О]+, 236
(27.4) [М ‒ С7Н11О ‒ СН2]+, 207 (11.3), 112 (38.7)
[С7Н11О]+, 84 (32.3), 55 (100). Found, %: С 76.61; Н
9.96. [М]+ 360. С23Н36О3. Calculated, %: С 76.66; Н
10.00. М 360.
12]}. IR spectrum (KBr), ν, cm–1: 3392 s (ОН); 1589
m, 1503 m, 1011 s, 1066 s, 1082 s (furyl). 13C NMR
spectrum (CDCl3), δ, ppm (besides signals mentioned
in the table), secondary atoms С: 20.8, 21.90, 23.0,
23.1, 25.1, 25.8, 26.0, 26.9, 31.4, 32.0, 35.5 (11 СН2);
furan-2-yl: 106.0, 110.0, 110.1, 110.9 (=CH); 155.0,
157.7 (=C). Mass spectrum: m/z [М ‒ 18]+ 432. Found,
%: С 74.61; Н 7.51. С28Н34О5. Calculated, %: С 74.66;
Н 7.55. М 450.
Mannich monobase based on cycloalkanone. A
mixture of 0.1 mol of cycloalkanone, 0.1 mol of para-
formaldehyde, 0.1 mol of dimethylamine hydrochloride,
15 mL of isopropyl alcohol, and 0.3 mL of concentrated
HCl was heated while stirring for 1 h. Alcohol was
distilled off at a reduced pressure, the mixture was
cooled and kept for 12 h at 0°С. A fully crystallized
white mass of Mannich monobase hydrochloride was
obtained. To the obtained salt was added at shaking by
portions 20 mL of 2N solution of NaOH, Mannich
base was extracted with ether (3 × 15 mL), the extract
was dried with MgSO4, ether was distilled off. Yield
90–95%, light-yellow oily liquid.
By Michael reaction compounds 2b and 2c were
obtained.
1 0 , 1 8 - D i ph e n y l -3 , 2 2 - d io x a h ex a cy c l o -
[9.7.3.14,12.01,2.04,9.012,17]docosan-2-ol (2b). A mixture
of 30 g (0.3 mol) of cyclohexanone, 10 g (0.036 mol)
of 2,6-dibenzalcyclohexan-1-one, and 30 mL of 1N
alcoholic solution of NaOH was heated on a boiling
water bath for 6 h. The reaction mixture was left for
two days at 5°С, the separated yellow-brown amorphous
precipitate was filtered off (0.550 g), washed with
petroleum ether (20 mL) at 20°С, and then by portions
of boiling ethanol (10 mL in all). Yield 0.525 g (3%),
white amorphous powder, mp 330‒333°С (decomp.)
{mp 240°С (decomp.) [10]}. IR spectrum (KBr), ν,
cm–1: 3554 m, 3392 s (ОН); 1588 w, 1502 m (Ph). 13C
NMR spectrum (CDCl3), δ, ppm (besides signals
mentioned in the table), secondary atoms С: 21.3,
21.90, 22.1, 23.2, 25.3, 26.3, 26.5, 26.9, 31.7, 32.3,
35.8 (11 СН2); aromatic atoms С: 125.9, 126.3, 127.4,
128.3 (=СН); 141.7, 143.3 (=С). Mass spectrum: m/z
[М]+ 470. Found, %: С 81.65; Н 8.05. С32Н38О3.
Calculated, %: С 81.70; Н 8.08. М 470.
Mannich bisbases were obtained by same method
at molar ratio cycloalkanone‒paraformaldehyde‒
dimethylamine hydrochloride 0.05 : 0.1 : 0.1 in 25 mL
of 2-propanol.
Synthesis of triketones from Mannich bases.
General procedures. а. A mixture of Mannich mono-
base and cycloalkanone, 2.2 : 1, was heated for 5–7 h
on an oil bath first at 130°C, and gradually the
temperature was raised to 150‒170°С. The mixture
was cooled, acidified with diluted (1 : 5) HCl, the
reaction products were extracted with ether, the extract
was washed with water till рН 7, dried with MgSO4,
ether was distilled off. The residue was distilled in a
vacuum. Yield of triketones fraction 18–50%.
b. A mixture of Mannich bisbase with cyclopen-
tanone, cyclohexanone, or cycloheptanone was heated
for 1 h on an oil bath at 110°С and, at gradually raising
temperature to 165°С, for 4 h more. After cooling the
mixture was worked up as in procedure а. After
distilling off the ether the residue was distilled in a
vacuum or treated with 2N alcoholic solution of
NaOH.
10,18-Di(furan-2-yl)-3,22-dioxahexacyclo-
[9.7.3.14,12.01,2.04,9.012,17]docosan-2-ol (2c). A mixture
of 30 g (0.3 mol) of cyclohexanone, 10 g (0.039 mol)
of 2,6-bis[(furan-2-yl)methylidene]cyclohexan-1-one,
and 30 mL of 1N alcoholic solution of NaOH was heated
on a boiling water bath for 5 h, cooled, the precipitate
(4.6 g) was filtered off, washed with petroleum ether
(50 mL), then with ethyl acetate (15 mL) at 20°С.
Yield 2.4 g (14%), white amorphous powder, mp 258‒
261°С (decomp.) {mp 236‒237°С (decomp.) [10,
2,5-Bis(2-oxocyclohexylmethyl)cyclopentan-1-
one (4) (6-5-6) was obtained by method а [9]. By
method
b
from Mannich bisbase based on
cyclopentanone and cyclohexanone (1 : 2.2) 53% of
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METHODS OF SYNTHESIS OF ALICYCLIC 1,5,9-TRIKETONES
727
diketone 12а, 20% of diketone 17 and 11% of
triketone 4 were obtained.
(100) [С7Н11О]+, 97 (64.4) [С5Н7О ‒ СН2]+, 83 (95.5)
[С5Н7О]+, 55 (93.3). Found, %: С 74.96; Н 9.18.
С19Н28О3. Calculated, %: С 75.0; Н 9.21. М 304.
2,5-Bis(2-oxocycloheptylmethyl)cyclopentan-1-
one (5) (7-5-7). а. From 14 g (0.083 mol) of 2-
(dimethylaminomethyl)cycloheptane-1-one and 3.36 g
(0.04 mol) of cyclopentanone we obtained 12 g of semi-
solid mass. After vacuum distillation was extracted
4.45 g (54%) of diketone 16 (7-7), bp 146‒150°С
(4 mmHg) {128°C (0.1 mmHg) [11]} and 2.4 g (18%)
of triketone 5, bp 249‒255°С (4 mmHg), which
according to GC/MS data contained a mixture of five
main diasteromers, 3.0 : 2.1 : 1.8 : 0.9 : 0.6. IR
spectrum (CH2Cl2), ν, cm–1: 1729 (С=О cyclopen-
tanone), 1697 (С=О cycloheptanone). Mass spectrum,
m/z (Irel, %): 332 (1.0) [М]+, 314 (2.0) [М ‒ Н2О]+, 220
(27.8) [М ‒ С7Н11О]+, 207 (8.2) [М ‒ С7Н11О ‒ СН2]+,
125 (12.4) [С7Н11О ‒ СН2]+, 112 (25.8) [С7Н12О]+, 55
(100). Found, %: С 75.87; Н 9.59. С21Н32О3.
Calculated, %: С 75.90; Н 9.64. М 332.
2,7-Bis(2-oxocyclohexylmethyl)cycloheptan-1-
one (9) (6-7-6). b. From 11.0 g (0.048 mol) of 2,7-bis-
(dimethylaminomethyl)cycloheptane-1-one, 11 mL
(0.11 mol) of cyclohexanone we obtained 12.8 g of
oily residue containing 82.5% of triketone 9 (yield
66%), 3.5% of triketone 11 (7-6-7), and 13.5% of
diketones 12а (6-6) and 17 (6-7), 1 : 3. Triketone 9
contained a mixture of 6 stereoisomers, 31 : 21 : 11 :
9 : 7 : 5. Compound 9 was isolated by two methods.
(1) The residue (12.8 g) was mixed with 18 mL of
2N alcoholic solution of NaOH, left for 1 h at room
temperature and then in a refrigerator for a night. The
precipitate of cyclic form of triketone 9 was filtered
off, washed with ethanol. Yield 6.4 g (40%), white
crystals, mp 185‒187°С (ethanol) (185‒187°С [21]).
(2) The residue (11.2 g) was dissolved in alcohol
(20 mL) and cooled to ‒8°С. The precipitate formed
(0.75 g) was a mixture of prevailing 3 stereoisomers of
triketone 9. After recrystallization from ethanol we
obtained 0.11 g of individual stereoisomer of triketone
9, white crystals, mp 112.3‒113.0°С. IR spectrum
(KBr), ν, cm–1: 1705 (С=О cyclohexanone), 1696
(С=О cycloheptanone). Mass spectrum, m/z (Irel, %):
332 (2) [M]+, 314 (41) [М1 = М ‒ Н2О]+, 235 (61) [М ‒
С6Н9О]+, 221 (30.4) [М ‒ C6Н9О ‒ СН2]+, 216 (41)
[М1 ‒ С6Н9О]+, 204 (61) [М1 ‒ С6Н9О ‒ СН2]+, 137
(65) [М ‒ 2(С6Н9О)]+, 124 (69) [С7Н12О ‒ СН2]+, 112
(69) [С6Н9О ‒ СН2]+, 98 (100) [С6Н9О]+, 79 (35), 67
(60), 55 (70). Found, %: С 75.96; Н 9.58. С21Н32О3.
Calculated, %: С 75.90; Н 9.64. М 332.
2,6-Bis(2-oxocyclopentylmethyl)cyclohexan-1-
one (7) (5-6-5). b. From 6 g (0.028 mol) of 2,6-bis-
(dimethylaminomethyl)cyclohexan-1-one and 5.2 g
(0.062 mol) of cyclopentanone we obtained a mixture
containing 11% of diketone (5-6) and 84% of triketone
7. By distillation in a vacuum we isolated 0.43 g (8%)
of diketone (5-6), bp 139–143°С (3 mmHg) and 5.74 g
(70%) of triketone 7, bp 225–230°С (3 mmHg) as a
mixture of three diasteromers, 3 : 1 : 1. IR spectrum
(CH2Cl2), ν, cm–1: 1730 (С=О cyclopentanone), 1705
(С=О cyclohexanone). Mass spectrum, m/z (Irel, %):
272 (33.0) [М ‒ Н2О]+, 207 (18.0) [М ‒ С5Н7О]+, 198
(23.5) [М ‒ С5Н7О ‒ СН2]+, 176 (25.8), 123 (43.5) [М ‒
2(С5Н7О)]+, 110 (100) [С6Н8О ‒ СН2]+, 98 (72.9)
[С5Н7О ‒ СН2]+, 84 (55.3) [С5Н7О]+, 55 (47.1).
Found, %: С 74.45; Н 8.92. С18Н26О3. Calculated, %:
С 74.48; Н 8.96. М 290.
c. 4-(Cyclohex-1-en-1-yl)morpholine was obtained by
standard method [22]. A mixture of 2.9 g (0.0146 mol)
of Mannich bisbase prepared from cycloheptanone and
5 mL (0.03 mol) cyclohexenylmorpholine was heated
on an oil bath for 4 h, the temperature of reaction
mixture was gradually raised from 110 to 150°С. The
mixture was cooled, 5 mL of diluted (1 : 10) HCl
(рН 5) was added and the reaction mixture was
hydrolyzed while stirring for 40 min. Reaction
products were extracted with ether (3 × 15 mL), the
extract was washed with water to рН 7, dried with
MgSO4, ether was distilled off (traces of ether were
distilled in a vacuum) to obtain 3.6 g of residue as an
oily light-yellow liquid containing 96% of triketone 9
and 4% of diketone 17 (6-7). The residue was mixed
with 5 mL of 2N alcoholic solution of NaOH, left
2,7-Bis(2-oxocyclopentylmethyl)cycloheptan-1-
one (8) (5-7-5). b. From 8 g (0.035 mol) of 2,7-bis-
(dimethylaminomethyl)cycloheptan-1-one and 5.88 g
(0.07 mol) of cyclopentanone we obtained 7.4 g of
semi-solid mass, from which as a result of a vacuum
distillation were extracted 1.3 g (18%) of diketone (5-7),
bp 139–143°С (3 mmHg) and 5.0 g (47%) of triketone
8, bp 228–236°С (3 mmHg) as a mixture of four
diasteromers, 3 : 1.4 : 1 : 0.6. IR spectrum (CH2Cl2), ν,
cm–1: 1730 (С=О cyclopentanone), 1696 (С=О cyclo-
heptanone). Mass spectrum, m/z (Irel, %): 286 (35.5)
[М ‒ Н2О]+, 221 (93.3) [М ‒ С5Н7О]+, 208 (55.5) [М ‒
С5Н7О ‒ СН2]+, 137 (62.2) [М ‒ 2(С5Н7О)]+, 112
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 5 2017

AKIMOVA et al.
728
2. Plesek, J. and Munk, P., Coll. Czech. Chem. Commun.,
1957, vol. 22, p. 1596.
3. Birkofer, L., Kim, S.M., and Engels, H.D., Chem. Ber.,
1962, vol. 95, p. 1495.
4. Akimova, T.I., Kravchenko, N.S., and Denisenko, V.A.,
standing for 12 h at 20°С, the precipitate was filtered
off, washed with ethanol (3 mL). Yield 3.3 g (69%) of
cyclic form of triketone 9, white crystals, mp 185‒
187°С (ethanol) (mp 185–187°С [21]).
2-(2-Oxocyclohexylmethyl)-6-(2-oxocycloheptyl-
methyl)cyclohexan-1-one (10) (6-6-7) (cyclic form).
а. From 10.2 g (0.07 mol) of 2-(dimethylaminomethyl)-
cyclohexane-1-one and 3.43 g (0.035 mol) of cyclo-
heptanone we obtained 8.8 g of semi-solid mass, from
which by vacuum distillation was isolated 3.2 g of
diketones fraction, bp 152‒168°С (4 mmHg), (36%
from the mass of separated mixture) containing a mixture
of diketones 12а (6-6), 17 (6-7), and (7-7), 0.25 : 1 : 1,
and 1.5 g (17% of the mass of separated mixture) of
triketones fractions, bp 236‒248°С (4 mmHg). The
fraction of triketones, according to GC/MS data,
consisted of a mixture of compounds 9 (6-7-6), 10
(6-6-7), and 11 (7-6-7) approximately in equal amounts.
1 g of triketone fraction was dissolved in 2 mL of
ethanol, 5 mL of 1N alcohol solution of NaOH was
added, left for one day at room temperature. The
crystalline precipitate was filtered off, washed with
ethanol (2 mL). Yield of compound 10 0.12 g (12%),
colorless crystals, mp 195‒197°С (ethanol) (mp 195‒
197°С [21]). IR spectrum (KBr), ν, cm–1: 3381 (ОН).
Tetrahedron, 2008, vol. 64, p. 4204.
5. Akimova, T.I., Kravchenko, N.S., and Denisenko, V.A.,
Tetrahedron, 2008, vol. 64, p. 9548.
6. Kravchenko, N.S., Denisenko, V.A., and Akimova, T.I.,
Helv. Chim. Acta, 2009, vol. 92, p. 1282.
7. Akimova, T.I., Kravchenko, N.S., Gerasimenko, A.V.,
Denisenko, V.A., and Vysotskii, V.I., Tetrahedron Lett.,
2012, vol. 53, p. 5933.
8. Akimova, T.I., Ivanenko, Zh.A., and Vysotskii ,V.I.,
Russ. J. Org. Chem., 2001, vol. 37, p. 1068. doi
10.1023/A:1013115625249
9. Akimova, T.I., Kosenko, S.V., and Tilichenko, M.N.,
Zh. Org. Khim., 1991, vol. 27, p. 2553.
10. Tilichenko, M.N., Zh. Org. Khim., 1966, vol. 2, p. 1615.
11. Colonge, J., Dreux, J., and Deplace, H., Bull. Soc.
Chim., 1956, p. 1635.
12. Tilichenko, M.N. and Kharchenko, V.G., Doklady Akad.
Nauk, 1956, vol. 110, p. 226.
13. Vysotskii, V.I. and Tilichenko, M.N., Chem.
Heterocycl. Compd., 1971, vol. 7, p. 275. doi 10.1007/
BF00944402
14. Oszbach, Gy., Szabo, D., and Vitai, M.E., Acta Chim.
(Budapest), 1976, vol. 90, p. 51.
15. Newton, G.M. and Hill, R.K., Acta Crys., Sect. C, 1994,
2,7-Bis(cycloheptylmethyl)cyclohexan-1-one (11)
(7-6-7). b. A mixture of 9.65 g (0.046 mol) of 2,6-bis-
(dimethylaminomethyl)cyclohexan-1-one and 10.3 mL
(0.10 mol) of cycloheptanone was heated for 5 h on an
oil bath at temperature not exceeding 150°С. After
standard workup we obtained 9.58 g of residue con-
taining of 83% of triketone 11 and 17% of diketone 17
(6-7). Diketone 17 was quickly distilled off at 3 mmHg,
the residue in the flask was triketone 11 (7.5 g, 47%)
of purity 98%, mixture of 6 stereoisomers, 11 : 6 : 4 :
4 : 3 : 1. IR spectrum (KBr), ν, cm–1: 1705 (С=О cyclo-
hexanone), 1696 (С=О cycloheptanone). Mass spectrum,
m/z (Irel, %): 328 (42.6) [М1 = М ‒ Н2О]+, 217 (14.8)
[М1 ‒ С7Н11О]+, 204 (100) [М1 ‒ С7Н11О ‒ СН2]+, 105
(11.5) [М ‒ 2(С7Н11О)]+, 91 (42), 79 (37), 67 (30), 55
(40). Found, %: С 76.26; Н 9.78. С22Н34О3.
Calculated, %: С 76.30; Н 9.82. М 346.
vol. 50, p. 1969.
16. Akimova, T.I., Nesterov, B.B., Antipin, M.Yu., and
Vysotsky, V.I., Chem. Heterocycl. Compd., 1999, vol. 35,
p. 1299. doi 10.1007/BF02251997
17. Pilato, M.L., Catalano, V.L., and Bell, T.W., J. Org.
Chem., 2001, vol. 66, p. 1525.
18. Gill, N.S., James, K.B., Lions, F., and Potts, K.T.,
J. Am. Chem. Soc., 1952, vol. 74, p. 4923.
19. Brown, H.L., Buchanan, G.L., Curran, A.C.W., and
VcLay, G.W., Tetrahedron, 1968, vol. 24, p. 4565.
20. Austin, E.M., Braun, H.L., and Buchanan, G.L.,
Tetrahedron, 1969, vol. 25, p. 5509.
21. Ivanenko, Zh.A., Akimova, T.I., and Gerasimenko, A.V.,
Alitsiklicheskie 1,5,9-triketony: sintez i vnutrimolekulyar-
naya tsiklizatsiya (Alicyclic 1,5,9-Triketones: Synthesis and
Intramolecular Cyclization), Issledov. Rossii, 2001, p. 1510.
http://zhurnal.ape.relarn.ru/articles/2001/130
REFERENCES
22. Plate, A.F., Sintezy organicheskikh preparatov
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