An alicyclic 1,5,9-triketone 2,6-bis[(2-oxocyclohexyl)methyl]cyclohexanone, its cyclic form and reactions with N-nucleophiles

Article abstract of DOI:10.1016/j.tet.2008.07.069

The alicyclic 1,5,9-triketone 2,6-bis[(2-oxocyclohexyl)methyl]cyclohexanone, its cyclic form, and the product of its dehydration have been studied under Leuckart reaction conditions, with ammonium acetate in acetic acid and with hydroxylamine. The composi

Full text of DOI:10.1016/j.tet.2008.07.069

Tetrahedron 64 (2008) 9548–9554
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An alicyclic 1,5,9-triketone 2,6-bis[(2-oxocyclohexyl)methyl]cyclohexanone,
its cyclic form and reactions with N-nucleophiles
,
b
Taisia I. Akimova a, Natalia S. Kravchenko a , Vladimir A. Denisenko
*
a Department of Chemistry, Far Eastern National University, Oktyabrskaya St. 27, 690600 Vladivostok, Russia
b Pacific Institute of Bioorganic Chemistry, Russian Academy of Sciences, 690022 Vladivostok, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2008
Received in revised form 6 July 2008
Accepted 17 July 2008
Available online 23 July 2008
The alicyclic 1,5,9-triketone 2,6-bis[(2-oxocyclohexyl)methyl]cyclohexanone, its cyclic form, and the
product of its dehydration have been studied under Leuckart reaction conditions, with ammonium
acetate in acetic acid and with hydroxylamine. The composition of the melt of the cyclic form has been
determined. The obtained polycyclic products of N-heterocyclization confirm the existence of
intermediate forms of the cyclization of 1,5,9-triketone in the reaction mixture. The structure and ste-
reochemistry of the reaction products were determined using 1D selective COSY, NOE difference, and 2D
NMR experiments (1H–1H COSY, HSQC, HMBC, and NOESY).
Keywords:
NMR
Alicyclic 1,5,9-triketone
2,6-Bis[(2-oxocyclohexyl)-
methyl]cyclohexanone
Diastereomers
Ó 2008 Elsevier Ltd. All rights reserved.
Leuckart reaction
Perhydroacridines
Octahydroacridines
1,5-Diketone
1. Introduction
ring sizes (5-5-5, 5-6-5, 7-7-7, 5-7-5, 7-5-7, 7-6-7) do not form
similar cyclic products.10 Apparently, the driving force of this
The synthesis of alicyclic 1,5,9-triketones is conducted by the
same methods as used for the corresponding 1,5-diketones.1–7
These compounds are convenient starting materials for the syn-
thesis of heteropolycyclic structures, including analogues of natural
products. Using triketone 1 as a starting material, the analogue of
hexahydrojulolidine 10, the most carefully studied system in the
development of synthetic methods for some quinolizidine alka-
loids, was obtained by reductive amination (Scheme 4).8 Until now
it was known that 1,5,9-triketones in basic conditions can readily
undergo domino cyclization into frame structures b,5–7,9–10 while
the latter can be transformed back into the triketone form by
melting (Scheme 1).
cyclization is the high reactivity of the carbonyl group of
cyclohexanone.
The first step of the cyclization (Scheme 2, m¼n¼2) is intra-
molecular aldol condensation between the rings A and B occurring
by the same path as for the corresponding 1,5-diketones having
different rings:6,10 the six-membered ring A acts as the carbonyl
component and the methine group of the ring B (five- to seven-
membered) as the nucleophile, compound 2 is formed in this
reaction. The emergence of the quaternary carbon atom (not con-
nected with O-atoms) in structures b is only possible under the
same direction of aldol condensation; this was confirmed by 13C
NMR spectroscopic data. Furthermore, the hemiacetals 3 and 4 are
obtained in two subsequent stages. For the first time, the structure
of compounds b was determined by IR and NMR spectroscopy and
by isolation and characterization of the intermediate forms of the
cyclization:6,9 for 2,5-bis[(2-oxocyclohexyl)methyl]cyclopentanone
(triketone 6-5-6) the intermediate cyclic form similar to the form 2
and the dehydrated form similar to the form 6 were isolated and
analyzed. The configuration of 4 was also assigned by X-ray crystal
analysis.11,12 The latter allowed us to determine the mutual con-
figuration of nonsymmetrical centers of the molecule and showed
that five chiral atoms have S configuration and two have R
Previous research demonstrated7,10 that 1,5,9-triketones,
which can undergo this kind of cyclization, had at least two six-
membered rings in their structures (the number corresponds to
the ring size). In all cases ring A is six-membered, ring B has
between five and seven carbons and ring C consists of six or
seven carbon atoms. 1,5,9-Triketones with other combinations of
* Corresponding author. Tel./fax: þ7 4232429510.
E-mail address: natalysk@gmail.com (N.S. Kravchenko).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.069

T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
(CH2)m
9549
O
B
A
– B – C
OH
(CH2)m
(CH2)n
NaOH
(CH2)n
C
O
A
B
6 – 5 – 6
6 – 6 – 6
6 – 7 – 6
6 – 6 – 7
C
Δ
O
O
O
A
m=1-3, n=2-3
Scheme 1.
b
a
A
A
17
D
S
S
2
S
S
B
O
O
HO
O
C
S
4
R
C
S
9
1
B
OH
C
O
S
S
R
O
O
O
O
O
OH
1
2
3
4
A
O
3
8
1
D
14
B
10
9
12
O
O
O
6
5
Scheme 2.
configuration (for one enantiomer).11 The hydroxanthene rings in
cyclic structures b are in ‘boat’ conformations.
not detected. The IR spectrum of the melt showed the presence
of a carbonyl group at 1705 cmꢁ1 and the absence of an ab-
sorption band corresponding to an OH group. After 10 min,
hemiacetal 4 disappeared completely and the total content of the
prevailing diastereomers I and IV decreased to 50% with the ratio
1:2.1 while the share of the other diastereomers increased. The
decrease in content of the diastereomer I was remarkably large.
Its share drops from 27 to 7% during 30 min, while the share of
diastereomer IV changed only from 41 to 32% and still remained
prevalent in the mixture. The contents of diastereomers II, III, V
and VI increased 1.7–2.6 times. After 30 min, the achieved ratio of
isomers remained stable: I/II/III/IV/V/VI¼0.6:1.2:1.5:2.8:1:1. Ap-
proximately the same ratio was also achieved at 210 ꢀC after
5 min already with 5% of the initial hemiacetal 4 remaining in the
We continued studying the reactions of alicyclic 1,5,9-triketones
concentrating our research efforts on triketone 1. For the first time,
this compound in cyclic form 4 was obtained by Tilichenko as a by-
product of diketone condensation between cyclohexanone and
formaldehyde.1 He correctly determined its molecular formula
(unlike Plesek3) and the ability to transform into triketone 1 by
melting. The structure was confirmed by the IR spectrum and the
formation of its 2,4-dinitrophenylhydrazone.5 In the same work he
also first proposed a structure of its cyclic form 4, which had to be
revised later.6
2. Results and discussion
mixture. Hemiacetal
4 disappeared completely after 10 min.
These results indicate that the melt represents an equilibrium
diastereomeric mixture of triketone 1. The similar case of trans-
formation of stereoisomeric forms of 1,5-diketones was described
in the literature.4
2.1. Composition of the melt of hemiacetal 4
The melt of 4 was analyzed by GC–MS with the purpose to de-
termine its composition, number of diastereomers of triketone 1,
possibility of their transformation depending on the conditions
(temperature and time of heating), and also expecting to discover
the cyclization intermediates 2 and 3 in the melt besides the tri-
ketone form 1.
For this reason, the decyclization of 4 was carried out at the
melting temperature 194 ꢀC and also at 210 ꢀC, keeping the melt at
the indicated temperatures for 5, 10, 30 and 60 min. The experi-
ment demonstrated that after 5 min at 194 ꢀC the melt consisted of
a mixture of six diastereomers of triketone 1 (Table 1) with close
GC–MS retention times and the same decay pattern in the mass
spectra. Their ratio was I/II/III/IV/V/VI¼2.7:0.9:1:4.1:0.5:0.45. Two
of the diastereomers (I and IV) dominated and accounted for 67–
70% of the mixture in the ratio 1:1.5, respectively. Small amounts of
4 (3–5%) still remained in the mixture. Compounds 2 and 3 were
When the melt was treated with an ethanol solution of NaOH
(1 N) at room temperature, hemiacetal 4 crystallized from the
reaction mixture as a single diastereomer: 52%, 10 min; 97%, 24 h
(see Section4). This proves that the cyclization is stereoselective; all
six diastereomers 1 transformed into the same product 4.
Theoretically, triketone 1 can exist as four racemic and two
mesomeric forms, because it has four chiral centers. As it appears
from Scheme 2, three of the four chiral carbon atoms are not in-
volved in the cyclization of triketone 1. Therefore, these atoms re-
tain their configuration in structure 4. The configuration of these
centers in the structure 4 established with X-ray analysis can sug-
gest the configuration of the corresponding C-atoms in the initial
form of triketone 1. Apparently, the intramolecular cyclization oc-
curs on the basis of two diastereomersda meso form with config-
uration of nonsymmetrical centers SSSS and a racemate SRSS. These
diastereomers differ by the configuration of only those chiral cen-
ters, which participate in the intramolecular aldol condensation
and which, taking into account the mechanism of the reaction, form
the same enol intermediate. Probably, these two diastereomers
prevail in the melt just after decyclization of 4. Apparently, the
remaining four diastereomers are isomerized into the aforemen-
tioned diastereomers via keto–enol tautomerism in the course of
the cyclization. For that, any of them needs to change configuration
of only one chiral center.
Table 1
Change of contents of diastereomers of triketone 1 at 194 ꢀC by GC–MS
Heating time, Percentage of the stereoisomers in the melt (tR)a
min
I (23.55) II (23.66) III (23.82) IV (24.14) V (24.22) VI (24.92)
5
10
30
27
16
7
9
14
19
10
18
18
41
34
32
5
7
10
4.5
10
13
a
By peak area ratio (average values from several chromatograms were taken).

9550
T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
2.2. Dehydration of hemiacetal 4 in acetic acid
NH
O
When refluxed in acetic acid, hemiacetal 4 completely turned
into the dehydrated product 6. This compound was prevalent in
many reactions conducted with 4 in acid medium on heating. Its
formation is a result of transformation of 4 into 3 with subsequent
dehydration. The IR spectrum of 6 has an absorption band of car-
bonyl group at 1715 cmꢁ1. The 13C NMR spectrum has four qua-
ternary carbons (2 sp3 and 2 sp2), two tertiary, and the signal for the
carbonyl group carbon. Based on the 13C NMR spectroscopic data,
the alternative structure 5 with the same molecular weight, which
could be formed as the dehydration product of intermediate 2 has
been rejected. In the 1H NMR spectrum, the signals of protons at the
H2NCHO
HCO2H
1
N
10a-g
Scheme 4.
O
path a
4
3
tertiary carbon atoms were at low field. The multiplet signal of the
17
P
12
11
HO
11
HN
C
12-H at
d
2.48 has
Ji¼14.5 Hz, which confirms its equatorial
O
9
CHO
CHO
position. The multiplet signal of the
C14-H at d 2.37 has
4
P
N
1
Ji¼33.4 Hz, which confirms its axial position. These data speak
about preservation of stereochemistry of the rings A, B, and D in
comparison with the starting material 4. The protons of the sec-
2
H
H
OHC
H
13
path b
O
6
ondary C9 atom appear as two doublets at
d 2.13 and 1.40 with the
same coupling constant Jgem¼16.4 Hz (the signal form and coupling
HN
12
constant for the axial proton at
experiment).
d
1.40 were estimated from HSQC
Scheme 5.
2.3. Leuckart reaction
forms the N-formyl derivative 12 by analogy with ketone 8, which
later transforms into 13. It is likely that both paths take place in
the reaction process.
Compounds 1, 4, and 6 were introduced into a Leuckart reaction
(H2NCHO, HCO2H). It is known that the similar 1,5-diketone 2-
(2-oxocyclohexylmethyl)cyclohexanone 7 and its cyclic form 7a
under Leuckart reaction conditions give the same mixture of per-
hydro- (PHA) and octahydroacridines (OHA) in the ratio 2:1
(Scheme 3).13 The formation of the same products could be
explained by decyclization of 7a into diketone 7 under the reaction
conditions. Leuckart reaction runs differently with dehydration
product of form 7adketone 8 (n¼1): stereoisomers of N-formyl
derivatives with different configuration of the bridge carbon atom
are formed.14 Similar compounds were obtained from the homo-
logue of ketone 8 in the case of five-membered ring (n¼0).15
A mixture of eight diastereomers of 10 was obtained under
We suppose that formation of 15 and 18 from 6 occurs through
the intermediate 2 (Scheme 6). It is known that the formation of
PHA from 1,5-diketone 7 occurs through 1,4-dihydropyridine de-
rivative.16 For compound 2 containing the quaternary carbon, this
stage is accompanied by formation of the 3,4-dihydropyridine in-
termediate 14, which is reduced under Leuckart reaction conditions
into PHA derivative 15 or 18. We think the formation of 18 un-
dergoes predominantly via this route, but not through hydrolysis
of its N-formyl derivative 13. A control experiment showed that
when 13 was refluxed in 85% formic acid it was not transformed
into 18.
The IR spectrum of 13 has an absorption band at 1653 cmꢁ1
corresponding to an amide. The 1H NMR spectrum contains the
singlet signal of formyl proton at 8.38, the C2-H doublet, and
,
Leuckart reaction conditions with triketone
1 (Scheme 4).
Recently, we reported isolation and determination of their
stereochemistry.8
d
a multiplet signal of the equatorial proton C1-H (Table 2). The 13C
NMR spectrum contains the signal of the formyl group carbon, the
signals of three quaternary carbons and four tertiary carbons. For
this compound, as indicated by the spectroscopic data and ste-
reochemical models, the stereochemical character of starting
material 4 is retained and six-membered rings with N- and
O-heteroatoms are in ‘boat’ conformation.
The IR spectrum (CCl4) of 15 shows a broad absorption band at
3231 cmꢁ1 indicating the presence of a strong intramolecular hy-
drogen bond between OH and NH groups. When the solution was
diluted 10-fold the appearance of the absorption band did not
change. Such a strong intramolecular hydrogen bond can only exist
Three of these diastereomers (10a,b,e) as well as compounds 13
and 15 were obtained from hemiacetal 4 under Leuckart reaction
conditions. The N-formyl derivative 13 was a prevalent product
(Scheme 5), which crystallized from the reaction mixture on
cooling in 46% yield. The ratio of 10 and 15 in the residual solution
was 1:1 determined by GC–MS. Formation of 13 most likely occurs
from the intermediate 3 through the N-formyl derivative 11.
Leuckart reaction with ketone 6 gives 13 as the major product in
60% yield. Compounds 10, 15, and 18 are also present in the re-
action mixture. Two ways of converting 6 into 13 could be sug-
gested: (a) initially 6 undergoes hydration into hemiacetal 3 and
than according to Scheme 5; (b) it is also possible that 6 initially
+
N
H
N
O
OH
O
O
PHA
OHA
7a
7
(CH2)n
(CH2)n
NHCHO
O
n=1
8
9
Scheme 3.

T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
9551
2.4. Reaction with ammonium acetate in acetic acid
17
21
HO
11
9
10
Reaction with ammonium acetate in acetic acid is a traditional
chemical method to confirm the presence of 1,5-diketone moieties
in a molecule by converting them into the corresponding pyridine
derivative. 1,5-Diketone 7 and its cyclic derivative 7a form OHA17 in
about 70% yield under these conditions. Cupric acetate may be used
as an oxidant to boost the yield above 95%.12b,18
HO
4
2
3
N
1
4
H
2
H
H
H
N
15
14
6
Compounds 1, 4, and 6 were introduced into a reaction with
ammonium acetate in acetic acid (reflux 4–5 h). Triketone 1 formed
only the OHA derivative 17 according to GC–MS analysis. Therefore,
heterocyclization occurred only at the 1,5-diketone moiety of the
molecule. Hemiacetal 4 under these reaction conditions initially
transformed into 6 (after 1 h of refluxing the main product is 6 by
GC–MS). After refluxing for 4–4.5 h the products of N-hetero-
cyclization 18 as a mixture of two diastereomers (the ratio 1:1, 61%)
and 17 (30%) were obtained. When ketone 6 was used as a starting
material, the same products 17 (40%) and 18a,b (40%) were
obtained.
We suppose that the process of heterocyclization of 4 and 6
proceeds via cyclic form 2 (Scheme 6) through the same in-
termediate 14 as under Leuckart reaction conditions. Research of
the reaction pathway of the OHA formation from diketone 7 in the
reaction with ammonium acetate in acetic acid has shown that 1,4-
dihydropyridine derivative, 1,2,3,4,5,6,7,8,9,10-decahydroacridine,
is the intermediate compound. It can undergo further trans-
formation into OHA via two pathways18deither by oxidation or
by disproportioning into 1,2,3,4,4a,5,6,7,8,9,9a,10-dodecahy-
droacridine and OHA. Apparently, the transformation of the in-
termediate 14 into 18 occurs as a result of the realization of the
second pathway. At first 14 disproportionates into 17 and 16, and
the latter is cyclized into a mixture of diastereomers 18a,b. How-
ever, this does not exclude the possibility of formation of 17 by
another pathwaydoxidation of 14. Taking into account the high
yield of 17, this reaction pathway is more likely when the triketone
1 is used as a starting material.
The IR spectrum of 17 shows an absorption band of the carbonyl
group at 1709 cmꢁ1. The mass spectrum besides the molecular ion
peak has an ion peak at m/z 187 corresponding to OHA fragment.
The structure of 17 was also confirmed by NMR spectroscopy (see
Section4).
The NMR spectra of the diastereomers 18a,b are similar (Table
2). The only difference between them in the 1H NMR spectra is the
signal position and the coupling constant of the protons adjacent to
the secondary C10 carbon. This suggests that the distinction in the
structures of 18a,b is different ring fusions of the C4–C9 bond. As we
have noted before, the O- and N-heterocycles in both structures
18a,b are in ‘boat’ conformation. Therefore, the C9-H and one of the
HO
N
O
N
H
16
17
17
21
12
11
O
O
H
9
10
4
HN
HN
1
2
H
H
H
18a
H
H
18b
Scheme 6.
due to the spatial proximity of the OH and NH groups that corre-
lates well with the stereochemistry of 15 suggested in Scheme 6.
Besides the molecular ion peak the mass spectrum of 15 exhibits an
ion peak at m/z 193 corresponding to a PHA fragment.
The 13C NMR spectrum reveals the presence of two quaternary
carbons and five tertiary carbons. The 1H NMR spectrum of 15
shows a singlet signal of an NH group at
CD3OD). The C2-H proton appears like a doublet (Table 2), the C4-H
proton is a triplet of doublets at
d 6.85 (exchangeable with
d
2.22 (Jax,ax¼Jax,ax¼10.3 Hz,
Jax,eq¼3.4 Hz) proving its axial position. Multiplet signals of the
P
C9-H proton at
d
2.14 and the C17-H proton at
d
1.90 have Ji¼32 Hz
suggesting their axial position resulting from the trans-fusion of
the rings through the C4–C9 and C12–C17 bonds. This stereochem-
istry in the case of C4–C9 fusion is also confirmed by the position of
the C10-H2 protons signals and their coupling picture: the equato-
rial proton C10-H coupling with two axial C9-H and C10-H protons
gives a doublet of doublets at
and the axial C10-H proton gives a doublet of doublets at
d
2.07 (Jgem¼13.4 Hz, Jax,eq¼4.5 Hz),
d 0.5
(Jgem¼13.4 Hz, Jax,ax¼11.7 Hz).
The 2D NOESY spectrum showed NOEs of the C2-H proton with
the C4-H, C10-Hax, C21-Hax, and also with the protons of the region
d
1.71–1.86 where the C1-H and the C19-Hax protons are located. The
key HMBC correlations of 13 and 15 are given in Section4.
C10-H2 protons are in an eclipsed position. The C9-H hydrogen atom
Table 2
13C and 1H NMR data of the signals for characteristic atoms of 13, 15 and 18a,b
Position
13
15
18a
18b
d
13C
d
1H ()a
d
13C
d
1H ()a
d
13C
d
1H ()a
d
13C
d
1H ()a
P
1
2
4
9
28.5
60.4
82.6
41.7
36.7
2.56 (m, Ji¼22)
34.7
67.4
64.2
40.1
43.1
1.73–1.77 (m)
2.59 (d, 3.4)
33.7
59.3
80.3
39.8
37.4
1.70–1.74 (m)
2.82 (d, 2.9)
34.5
60.4
80.7
40.6
39.0
1.64–1.66 (m)
2.73 (d, 2.7)
3.59 (d, 3.4)
2.22 (td, 3.3, 10)b
P
P
1.65–1.72 (m, Ji¼33)
2.10–2.15 (m, Ji¼32)
2.07 (dd, 4.5, 13.4)
0.5 (dd, 11.7, 13.4)
1.76–1.82 (m)
1.68–1.74 (m)
2.0 (dd, 10.5, 13.2)
0.58 (dd, 6.6, 13.2)
10
1.47 (dd, 3.6, 14)b
1.36 (dd, 11.2, 14)
1.43 (dd, 4.1, 13.5)b
1.35 (dd, 11.4, 13.5)b
11
12
17
21
33.8
77.7
41.1
32.0
38.9
76.6
41.4
35.6
33.5
76.5
41.2
31.4
33.7
76.4
40.7
31.2
P
1.72–1.78 (m)
1.67–1.75 (m)
1.20 (ddd, 2.2, 5.5, 7.8)b
P
1.87–1.94 (m, Ji¼32)
1.66–1.69 (m)
1.62–1.68 (m)
1.05 (ddd, 7.3, 12.7, 14.7)
1.68–1.74 (m)
1.71–1.76 (m)
1.05 (ddd, 7.3, 12.5, 14.7)
1.79–1.82 (m)
1.05 (ddd, 7.3, 12.5, 14.5)
a
(Multiplicity, coupling constant or Ji).
The forms of proton signals and their coupling constants were determined from 1D selective COSY and NOE difference spectra.
b

9552
T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
is pseudoaxial in the structure 18a and pseudoequatorial in 18b. In
the isomer 18a the pseudoaxial C10-H atom is in an eclipsed posi-
tion with the pseudoaxial C9-H atom. As a result the C10-H proton in
melt reacted with N-nucleophiles it yielded the products of hetero-
cyclization of the open form with no traces of its isomerization into
the cyclic form. On the other hand, under the same conditions the
cyclic form 4 and the product of its dehydration 6 formed products
suggesting their initial isomerization into intermediate cyclic forms
2, 3, and a small amount of the open form of triketone 1.
the 1H NMR spectrum appears as a doublet of doublets at
d
1.35
with Jax,ax¼11.4 Hz and Jgem¼13.5 Hz. A doublet of doublet signal of
the pseudoequatorial C10-H proton at 1.43 has the following
d
coupling constants Jax,eq¼4.1 Hz and Jgem¼13.5 Hz. The pseudoe-
quatorial C9-H proton is in an eclipsed position with the pseudoe-
quatorial C10-H proton in the isomer 18b. As a result the C10-H
proton in the 1H NMR spectrum appears as a doublet of doublets at
4. Experimental
4.1. General
d
2.0 with Jeq,eq¼10.5 Hz and Jgem¼13.2 Hz. The pseudoaxial C10-H
proton gives a doublet of doublet signal at
and Jgem¼13.2 Hz.
d
0.58 with Jax,eq¼6.6 Hz
General methods have been described previously.8 GC–MS
conditions for Section4.3: Tinjector¼Tcolumn¼200 ꢀC.
The stereochemistry of the diastereomers 18a,b was confirmed
also by 2D NOESY experiment: NOE was observed in the case of 18a
between the C2-H and C9-H protons, indicating their spatial prox-
imity. In contrast, NOE was not observed between the same protons
in 18b. The key HMBC correlations of 18a,b are given in Section4.
It is noteworthy that the values of chemical shift and coupling
constants of the C10-H2 protons for 18a are similar to the corre-
sponding values for the analogous protons in 13 (Table 2). This fact
testifies to the same pattern of rings’ fusion through the C4–C9 bond
in these compounds.
4.2. Synthesis of 3,22-dioxahexacyclo[9.7.3.14,12.01,2.04,9.012,17]-
docosan-2-ol (4)
A 250 mL three-necked flask equipped with a dropping-funnel,
thermometer and backflow condenser was charged with cyclo-
hexanone (49 mL, 0.48 mol) and paraformaldehyde (5 g, 0.24 mol).
A solution of 2 N CH3ONa (0.74 g Na in 16 mL methanol) was added
dropwise for 30 min. The mixture was heated instantly to 80–85 ꢀC,
turned yellow and paraformaldehyde was dissolved. Once the ad-
dition was complete, the cloudy suspension was maintained at 60–
70 ꢀC for an additional 1 h. The mixture was neutralized with acetic
acid on cooling. White crystals of 4 were filtered after cooling to
0 ꢀC for 24 h, washed with water–ethanol solution (1:1).
We have to point out that hemiacetal 4 forms other products in
reactions with N-nucleophiles than triketone 1, unlike the cyclic
form of diketone 7a, which forms the same products as diketone 7.
This occurs due to the fact that in contrast with the one-step
transformation of 7a/7 the conversion 4/1 requires three steps
with formation of the reactive intermediates 3 and 2. They react
with the nucleophiles in the solution before they can undergo
decyclization into 1.
Yield 6.6 g (13%); mp 193–194 ꢀC; recrystallization from diethyl
ether of diethyleneglycol provided pure product, mp 195.5–196 ꢀC;
Rf 0.4 (10:1 hexane/ethyl acetate); tR 10.67; GC–MS (EI) m/z (%): 318
(Mþ, 2), 300 (MþꢁH2O, 100), 220 (57), 190 (37.5), 123 (21), 110 (52),
2.5. Reaction with hydroxylamine
98 (62.5), 79 (25), 67 (30), 55 (36); IR (KBr)
1460, 1443, 944 cmꢁ1 1H NMR
m); 13C NMR
n
3389 (OH), 2934, 2848,
;
d 2.31 (1H, s, OH), 2.04–1.10 (29H,
The reaction of triketone 1 with hydroxylamine hydrochloride
in refluxing ethanol furnished 20. We assume that this trans-
formation goes through 19 (Scheme 7). A similar tetracyclic com-
pound was obtained earlier from 1,5-diketone 7.19 Hemiacetal 4
does not react with hydroxylamine due to poor solubility in etha-
nol. Ketone 6 is transformed under these conditions into OHA 17 in
50% yield (see Section 4).
d
C-quaternary: 98.1 (C2), 95.9 (C4), 78.7 (C12), 37.5
(C11); C-tertiary: 40.8 (C9), 39.5 (C1), 39.3 (C17); C-secondary: 35.3,
33.6, 31.9, 31.3, 28.9, 28.6, 28.4, 27.6, 26.1, 25.4, 23.0, 21.2, 21.0.
4.3. Thermal decyclization of hemiacetal 4 into triketone 1
Four capillaries were charged by hemiacetal 4 (3 mg) and heated
in a melting point apparatus at 194 ꢀC for 5, 10, 30 and 60 min. The
same experiment was conducted at 210 ꢀC. After cooling the
resulting solid was analyzed by GC–MS (see Table 1).
In the reactions with nucleophiles triketone 1 was obtained by
heating hemiacetal 4 (0.5–1 g) in a flask at 193–195 ꢀC for 10 min.
7
9
NH2OH
B
A
N
1
13
22
2
O
C
N
Δ ,
EtOH
N
O
NH
15
O
OH
20
O
19
20
4.3.1. 2,6 Bis[(2-oxocyclohexyl)methyl]cyclohexanone (1)
Scheme 7.
Yellow oil; tR 23.55–24.92; GC–MS (EI) m/z (%): 300 (MþꢁH2O,
The IR spectrum of 20 reveals the absence of the absorption
bands for functional groups. The 13C NMR spectrum contains the
signals of three quaternary carbons and the signals of four tertiary
carbons. Stereochemical models demonstrated that the three rings
A, B, and C in 20 are rigidly bonded with two five-membered rings
and can exist only in one fusion typedtrans–syn–cis.
26), 220 (28), 208 (17.3), 202 (47.5), 190 (50), 123 (50), 110 (100), 98
(106), 67 (37), 55 (58); IR (CHCl3)
1449 cmꢁ1
n 3020, 2939, 2861, 1705 (C]O),
.
4.4. Cyclization of triketone 1 into hemiacetal (4)
3. Conclusion
Triketone 1 (0.5 g) was dissolved in ethanol (1 mL). Ethanol
solution of 1 N NaOH (1.5 mL) was added. In several minutes the
product crystallized from the reaction mixture. Then (after 10 min,
1 h, 2 h, 12 h and 24 h) the reaction mixture was neutralized by
adding 30% HCl solution. White crystals of 4 (identified by GC–MS
and mp) were filtered and washed with water–ethanol solution
(1:1). Depending on time of exposure yield of 4 varied: 10 min, 52%;
1 h, 77%; 2 h, 85%; 12 h, 94%; 24 h, 97%.
In conclusion, we have shown that the cyclic form of 1,5,9-tri-
ketone 2,6-bis[(2-oxocyclohexyl)methyl]cyclohexanone in the melt
transformed into a mixture of six diastereomers of triketone open
form 1. The composition of the diastereomers in the melt changes
with the heating time duration. Under basic conditions the di-
astereomers 1 stereoselectivity transformed back into 4. When the

T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
9553
4.5. Dehydration of hemiacetal 4 in acetic acid
4.7. Leukart reaction with ketone 6
A mixture of 4 (2 g) in acetic acid (10 mL) was refluxed for
30 min. Acetic acid was removed by distillation under reduced
pressure. The residue was neutralized with a saturated aqueous
NaOH solution on cooling. The obtained solid of 6 was filtered.
A mixture of 6 (0.3 g, 1 mmol) and formamide (1 mL, 25 mmol)
in 85% formic acid (2 mL) was heated for 1.5 h following the pro-
cedure described in Section4.6. White crystals of 13 (0.19 g, 60%)
were obtained when ethanol (3 mL) was added to the reaction
mixture in 24 h. The filtrate was diluted with water, basified with
a saturated aqueous Na2CO3 solution, and extracted with CH2Cl2.
The organic layer was washed with brine, dried over MgSO4, and
analyzed by GC–MS as a mixture of 13 (39%),15 (14.7%),18a,b (13%),
and 10 (31%, isomers 10a,b prevalent).
4.5.1. 2-Oxapentacyclo[8.8.0.310,12.03,8.01,14]heneicos-3(8)-
en-11-on (6)
Yield 1.58 g (84%); white crystals; mp 116–118 ꢀC (ethanol); Rf
0.65 (12:1 hexane/ethyl acetate); tR 10.60; GC–MS (EI) m/z (%): 300
(Mþ,100), 288 (20), 239 (37),173 (25), 91 (24); IR (KBr)
n
2945, 2851,
1715 (C]O), 1480, 1444, 1179, 1148, 1123, 958 cmꢁ1; for 1H NMR
4.8. Reaction of hemiacetal 4 with ammonium acetate in
acetic acid
data see the text; 13C NMR 217.2 (C]O); C-quaternary: 142.6 (C3),
d
103.8 (C8), 82.0 (C1), 51.7 (C10); C-tertiary: 46.3 (C12), 39.7 (C14); C-
secondary: 37.8, 36.3, 35.5, 32.0 (C9), 27.9, 27.7, 27.3, 26.9, 25.9, 23.1,
22.9, 21.5, 20.9. Anal. Calcd for C20H28O2: C, 79.96, H, 9.39. Found: C,
79.85; H, 9.50.
A mixture of 4 (1.908 g, 6 mmol) and ammonium acetate
(1.908 g, 24.7 mmol) in acetic acid (12 mL) was refluxed for 4–4.5 h.
The reaction was monitored by TLC. After completion of the re-
action acetic acid was removed by distillation under reduced
pressure. The residue was basified with a saturated aqueous
Na2CO3 solution on cooling and extracted with CH2Cl2 (3ꢂ20 mL).
The organic layer was washed with brine (2ꢂ20 mL) and dried over
MgSO4. The solvent was removed by distillation. The residue
(1.61 g) was analyzed by GC–MS as a mixture of two diastereomers
18a (29.4%) and 18b (32%), 17 (30%), and 6 (8.5%), which were
separated by column chromatography (Al2O3, light petroleum).
Yields: 18a (0.28 g, 17.4%), 18b (0.38 g, 24%), 6 (0.08 g, 5.2%), 17
(0.35 g, 21.5%).
4.6. Leukart reaction with hemiacetal 4
A 50 mL three-necked flask equipped with a dropping-funnel,
thermometer, and descending condenser, charged with formamide
(6 mL, 0.15 mol), was heated to 160 ꢀC. A suspension of 4 (3.5 g,
0.011 mol) in 85% formic acid (10 mL) was added for 60 min. The
temperature was maintained at 160–170 ꢀC for 2.5 h. The water
formed during reaction was removed by distillation. After com-
pletion of the reaction the resulting mixture was cooled to room
temperature. The obtained white solid of 13 was filtrated after 24 h
and washed with petroleum ether. The solvent was removed by
distillation under reduced pressure from filtrate. The residue was
diluted with water. The obtained white crystals of 15 were filtered
and washed with water. The filtrate was basified with a saturated
aqueous Na2CO3 solution and extracted with CH2Cl2 (2ꢂ15 mL). The
organic layer was washed with brine (1ꢂ20 mL), dried over MgSO4
and analyzed by GC–MS as a diastereomer mixture of 10 with three
prevalent isomers (10a,b,e, 67%) and 15.
4.8.1. 22-Oxa3-azahexacyclo[9.7.3.14,12.02,11.04,9.012,17]docosan (18)
The IR (CHCl3) spectra of 18a,b have the same characteristic
bands: n
3338, 2923, 2850, 1446, 1268, 1030, 970 cmꢁ1; GC–MS (EI)
data of 18a,b are the same, m/z (%): 301 (Mþ, 45), 191 (100), 258
(51); for 1H NMR data of 18a,b see Table 2; key HMBC correlations
(H to C) of 18a,b: C1-H/C2, C11, C2-H/C1, C4, C10, C11, C12, C21, C9-H/C4,
C10, C11, C12, C10-H2/C2, C4, C9, C11, C12, C21, C21-Hax/C2, C10, C11, C12
.
4.8.2. Isomer 18a
4.6.1. 22-Oxa-3-azahexacyclo[9.7.3.14,12.02,11.04,9.012,17]docasan-3-
carbaldegid (13)
White crystals; tR 10.52; mp 92–93 ꢀC; Rf 0.12 (2:1 hexane/ethyl
acetate); 13C NMR C-quaternary: 80.3 (C4), 76.5 (C12), 33.5 (C11); C-
d
Yield 1.66 g (46%); white crystals; mp 177–178 ꢀC (ethanol); Rf
0.54 (2:1 hexane/ethyl acetate); tR 13.42; GC–MS (EI) m/z (%): 329
(Mþ, 100), 300 (11.5), 219 (32), 204 (33), 191 (19), 174 (50), 91 (19),
tertiary: 59.3 (C2), 41.2 (C17), 39.8 (C9), 33.7 (C1); C-secondary: 37.4
(C10), 36.3, 31.8, 31.4 (C21), 31.0, 30.7, 29.9, 28.9, 26.4, 25.8, 22.5, 21.8,
20.9. Anal. Calcd for C20H31NO: C, 79.68; H, 10.36; N, 4.65. Found: C,
79.55; H, 10.22; N, 4.60.
55 (15); IR (KBr)
1322, 1188, 1097, 1005, 960, 776, 714, 503 cmꢁ1; for 1H NMR data
see Table 2; 13C NMR 159.1 (NCHO); C-quaternary: 82.6 (C4), 77.7
n 2932, 2850, 1653 (NCHO), 1454, 1378, 1360, 1342,
d
4.8.3. Isomer 18b
(C12), 33.8 (C11); C-tertiary: 60.4 (C2), 41.7 (C9), 41.1 (C17), 28.5 (C1);
C-secondary: 36.7 (C10), 33.2, 32.0 (C21), 31.4, 31.2, 30.2, 29.6, 28.7,
26.1, 25.2, 22.4, 21.3, 21.0; key HMBC correlations (H to C): C1-H/C2,
C11, C17, C2-H/C1, C4, C10, C11, C12, C21, NCHO, C9-H/C4, C10, C10-H2/C2,
C4, C9, C11, C12, C21, C21-Hax/C2, C10, C11, C12. Anal. Calcd for
Yellow oil; tR 10.48; Rf 0.63 (6:1 hexane/ethyl acetate); 13C NMR
d
C-quaternary: 80.7 (C4), 76.4 (C12), 33.7 (C11); C-tertiary: 60.4 (C2),
40.7 (C17), 40.6 (C9), 34.5 (C1); C-secondary: 39.0 (C10), 36.9, 32.7,
32.0, 31.2 (C21), 31.0, 30.1, 28.9, 26.2, 25.8, 23.3, 21.9, 21.2; HRMS
(ESI) calcd for C20H31NO, 301.4663; found, 301.4697.
C
21H31NO2: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.83; H, 9.58; N,
4.13.
4.9. Reaction of triketone 1 with ammonium acetate
in acetic acid
4.6.2. 3-Azapentacyclo[9.7.3.02,11.04,9.012,17]heneicosan-12-ol (15)
Yield 0.68 g (20.4%); white crystals; mp 199.5–200 ꢀC (ethanol);
Rf 0.49 (6:1, hexane/ethyl acetate); tR 11.55; GC–MS (EI) m/z (%): 303
Following the procedure described in Section4.8, the reaction of
1 (0.636 g, 2 mmol) and ammonium acetate (0.636 g, 8 mmol) in
acetic acid (5 mL) (refluxing 5 h) furnished 17 (100% by GC–MS),
which was purified by column chromatography (Al2O3, light pe-
troleum). Yield 0.4 g (68%).
(Mþ, 17.5), 193 (100), 150 (17.5); IR (KBr)
n
3254.5 (NH, OH), 2932,
C-
2849.6, 1448.2 cmꢁ1; for 1H NMR data see Table 2; 13C NMR
d
quaternary: 76.6 (C12), 38.9 (C11); C-tertiary: 67.4 (C2), 64.2 (C4),
41.4 (C17), 40.1 (C9), 34.7 (C1); C-secondary: 43.1 (C10), 35.6 (C21),
33.2, 33.1, 31.9, 31.7, 31.0, 29.2, 26.6, 25.9, 25.5, 22.1, 21.7; key HMBC
correlations (H to C): C1-H/C2, C11, C2-H/C1, C4, C10, C11, C12, C4-H/C2,
4.9.1. 4(2-Oxocyclohexylmethyl)1,2,3,4,5,6,7,8-octahydro-
acridine (17)
C9, C10, C9-H/C4, C10, C10-H2/C2, C4, C9, C11, C12, C21, C21-Hax/C2, C10
,
Yellow oil; Rf 0.47 (4:1 hexane/ethyl acetate); IR (thin film)
2931, 2857, 1709 (C]O), 1599, 1562, 1450 cmꢁ1; tR 12.08; GC–MS
(EI) m/z (%): 297 (Mþ, 3), 200 (100), 187 (81); 1H NMR
6.98 (1H, s,
n
C11, C12. Anal. Calcd for C20H33NO: C, 79.15; H, 10.96; N, 4.62. Found:
C, 78.96; H, 10.65; N, 4.52.
d

9554
T.I. Akimova et al. / Tetrahedron 64 (2008) 9548–9554
C9-H), 2.89–1.3 (26H, m); 13C NMR
d
213.8 (C]O); C-quaternary:
Acknowledgements
157.3, 153.9 (C4a, C5a), 129.1, 128.8 (C8a, C9a); C-tertiary: 137.2 (C9),
48.9, 37.7 (C4, C11); C-secondary: 42.1, 34.8, 33.9, 32.3, 29.2, 28.5,
28.3, 28.2, 27.7, 25.0, 23.4, 19.8. HRMS (ESI) calcd for C20H27NO,
297.4345; found, 297.4372.
We would like to thank A. Kostesha and D. Fischer for their as-
sistance in preparation of this manuscript. We also thank Research
and Educational Center ‘Marine biota’ and US Civilian Research and
Development Foundation for providing equipment for chemical
analyses.
4.10. Reaction of ketone 6 with ammonium acetate
in acetic acid
Following the procedure described in Section4.8, the reaction of
6 (0.15 g, 0.5 mmol) and ammonium acetate (0.15 g, 2 mmol) in
acetic acid (3 mL) furnished a mixture of 17 (40%), 18a,b (40%), and
starting material 6 (10%) (by GC–MS analysis).
References and notes
1. Tilichenko, M. N. Ezhegodnik Saratov Univ. 1954, 500–504.
2. Colonge, J.; Dreux, J.; Deplace, H. Bull. Soc. Chim. Fr. 1956, 1635–1640.
3. Plesek, J.; Munk, P. Collect. Czech. Chem. Commun. 1957, 22, 1596–1602.
4. Birkofer, L.; Kim, S. M.; Engels, H. D. Chem. Ber. 1962, 95, 1495–1504.
5. Tilichenko, M. N. J. Org. Chem. U.S.S.R. (Engl. Transl.) 1966, 2, 1593–1596.
6. Akimova, T. I.; Kosenko, S. V.; Tilichenko, M. N. Russ. J. Org. Chem. (Engl. Transl.)
1991, 27, 2271–2277.
7. Ivanenko, J. A.; Akimova, T. I.; Gerasimenko, A. V. Issledovano v Rossii. 2001, 130,
1510–1515; http://zhurnal.ape.relarn.ru/articles/2001/130.pdf.
8. Akimova, T. I.; Kravchenko, N. S.; Denisenko, V. A. Tetrahedron 2008, 64, 4204–
4208.
9. Akimova, T. I.; Kosenko, S. V.; Tilichenko, M. N. Zh. Org. Khim. 1990, 26, 2456–
2457.
10. Akimova, T. I.; Ivanenko, J. A.; Vysotskii, V. I. Russ. J. Org. Chem. (Eng. Transl.)
2001, 37, 1068–1073.
11. Newton, G. M.; Hill, R. K. Acta Crystallogr., Sect. C. 1994, 50, 1969–1971.
12. (a) Akimova, T. I.; Nesterov, V. V.; Antipin, M. Y.; Vysotskii, V. I. Chem. Heterocycl.
Compd. (Engl. Transl.) 1999, 35, 1299–1304; (b) Pilato, M. L.; Catalano, V. L.; Bell,
T. W. J. Org. Chem. 2001, 66, 1525–1526.
13. Tilichenko, M. N.; Vysotskii, V. I. Dokl. Chem. (Engl. Transl.) 1958, 118-123,
311–312.
14. (a) Barbulesku, N. S.; Vysotskii, V. I. Zh. Org. Khim. 1965, 1, 93–94; (b) Vysotskii,
V. I.; Patrusheva, O. V.; Vysotskaya, T. A.; Isakov, V. V. Zh. Org. Khim. 2002, 38,
1181–1186.
15. Akimova, T. I.; Ivanenko, Zh. A.; Gerasimenko, A. V.; Vysotskii, V. I. Zh. Org. Khim.
2001, 37, 1300–1305.
16. Kharchenko, V. G.; Markova, L. I.; Fedotova, O. V.; Pchelintseva, N. V. Chem.
Heterocycl. Compd. (Engl. Transl.) 2003, 39, 1121–1141.
17. Vysotskii, V. I.; Tilichenko, M. N. Khim. Geterotsikl. Soedin. 1969, 751–752.
18. Bell, T. W.; Rothenderger, S. D. Tetrahedron Lett. 1987, 28, 4817–4820.
19. Gamov, V. K.; Kaminskii, V. A.; Tilichenko, M. N. Khim. Geterosikl. Soedin. 1974,
1525–1526.
4.11. Reaction of triketone 1 with hydroxylamine
hydrochloride
Triketone 1 (0.5 g, 1.57 mmol) was dissolved in ethanol (5 mL)
and a solution of hydroxylamine hydrochloride (0.38 g, 5.5 mmol)
and sodium acetate (0.9 g) in water (2 mL) was added. The mixture
refluxed for 2.5 h furnished product 20, crystallizing from the re-
action mixture on cooling (0 ꢀC) for several days. The residual so-
lution was diluted with water and extracted with CH2Cl2
(2ꢂ25 mL). The organic layer was washed with brine (1ꢂ30 mL),
dried over MgSO4, and analyzed by TLC and GC–MS as product 17.
4.11.1. 1,23-Diaza-21,24-dioxaheptacyclo-
[11.8.1.12,23.120,22.02,7.09,22.015,20]tetracosan (20)
Yield 0.143 g (27.5%); colorless crystals; Rf 0.70 (10:1 hexane/
ethyl acetate); mp 156–157 ꢀC (ethanol); IR (KBr)
n
3007, 2994,
2.71 (2H, dd,
J¼3.4, 14.2 Hz, CH2), 2.15 (1H, ddd, J¼3.5, 6.7, 10.4 Hz, CH2), 1.92–
2925, 2858, 1449, 1424, 1153, 812 cmꢁ1
;
1H NMR
d
1.02 (27H, m); 13C NMR
d
C-quaternary: 104.6, 103.0 (C2, C20), 92.6
(C22); C-tertiary: 39.8, 39.8, 39.1, 37.5 (C7, C9, C13, C15); C-secondary:
34.2, 33.9, 33.5, 32.1, 31.0, 30.8, 29.5, 29.0, 25.9, 24.7 (2C), 23.3, 23.1;
HPLC–MS (ESI): m/z 331 [MþH]þ. Anal. Calcd for C20H30N2O2: C,
72.69; H, 9.15; N, 8.48. Found: C, 72.81; H, 9.07; N, 8.56.