Synthesis of substituted tricyclo[5.3.1.04,9]undecan-2,6-dione from 4,4-disubstituted cyclohexanone enamines and methacryloyl chloride

Article abstract of DOI:10.1080/00397910500516381

Morpholine enamines 4-acetyl-4-methyl-1-morpholinocyclohexene 4a, 4-acetyl-4-phenyl-1-morpholinocyclohexene 4b, and 4-acetyl-4-isopropenyl-1- morpholinocyclohexene 4c react with methacryloyl chloride to give 1,7-dimethyl-4(N-morpholino) tricyclo[5.3.1.0

Full text of DOI:10.1080/00397910500516381

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Synthesis of Substituted
Tricyclo[5.3.1.04,9]undecan‐2,6‐dione from
4,4‐Disubstituted Cyclohexanone Enamines
and Methacryloyl Chloride
Syeda Asghari Ahmed a , Kawsari Akhter a , Yoshisuke Tsuda b , M. Mahmun
Hossain c , F. Holger Forsterling c & M. Giasuddin Ahmed a
a Department of Chemistry , University of Dhaka , Dhaka, Bangladesh
b Faculty of Pharmaceutical Sciences , Kanazawa University , Kanazawa,
Japan
c Department of Chemistry , University of Wisconsin—Milwaukee ,
Milwaukee, Wisconsin, USA
Published online: 24 Feb 2007.
To cite this article: Syeda Asghari Ahmed , Kawsari Akhter , Yoshisuke Tsuda , M. Mahmun Hossain , F. Holger
Forsterling & M. Giasuddin Ahmed (2006) Synthesis of Substituted Tricyclo[5.3.1.04,9]undecan‐2,6‐dione
from 4,4‐Disubstituted Cyclohexanone Enamines and Methacryloyl Chloride, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:9, 1273-1283
To link to this article: http://dx.doi.org/10.1080/00397910500516381
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Synthetic Communicationsw, 36: 1273–1283, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500516381
Synthesis of Substituted
Tricyclo[5.3.1.04,9]undecan-2,6-dione from
4,4-Disubstituted Cyclohexanone Enamines
and Methacryloyl Chloride
M. Giasuddin Ahmed, Syeda Asghari Ahmed,
and Kawsari Akhter
Department of Chemistry, University of Dhaka, Dhaka, Bangladesh
Yoshisuke Tsuda
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa,
Japan
M. Mahmun Hossain and F. Holger Forsterling
Department of Chemistry, University of Wisconsin—Milwaukee,
Milwaukee, Wisconsin, USA
Abstract: Morpholine enamines 4-acetyl-4-methyl-1-morpholinocyclohexene 4a,
4-acetyl-4-phenyl-1-morpholinocyclohexene 4b, and 4-acetyl-4-isopropenyl-1-
morpholinocyclohexene 4c react with methacryloyl chloride to give 1,7-dimethyl-
4(N-morpholino) tricyclo[5.3.1.04,9]undecan-2,6-dione 9a, 1-phenyl-7-methyl-4(N-
morpholino) tricyclo[5.3.1.04,9]undecan-2,6-dione 9b, and 1-ispropenyl-7-methyl-
4(N-morpholino) tricyclo[5.3.1.04,9]undecan-2,6-dione 9c respectively, along with
the corresponding substituted adamandane-2,4-diones.
Keywords: Methacryloyl chloride, morpholine enamines, tricycloundecanediones
Received September 9, 2005
Address correspondence to M. Giasuddin Ahmed, Department of Chemistry,
University of Dhaka, Dhaka 1000, Bangladesh. Fax: 880-2-8615583; E-mail:
mgahmed1@yahoo.com
1273

1274
M. G. Ahmed et al.
In continuation of our previous work[1–4] on the synthesis of the substituted
tricyclo[5.3.1.04,9]undecan-2,6-diones we now herein report the synthesis of
three new substituted tricyclo[5.3.1.04,9]undecan-2,6-diones 9a, 9b, and 9c.
The synthesis is based on a general reaction of 4,4-disubstituted cyclohexa-
none enamines with methacryloyl chloride. We first prepared 4,4-disubstituted
cyclohexanones 3a–c following literature methods[5,6] in which one of the
substituents is an acetyl group (Scheme 1). The morpholine enamines 4a–c
were prepared (Scheme 1) in accordance with the general procedure
reported earlier[3,4] without using any catalyst.
Methacryloyl chloride underwent reaction with the morpholine enamines
4a–c to produce the compounds 9a (25%), 9b (25%), and 9c (10%) respect-
ively, in addition to the corresponding substituted isomeric adamantane-2,4-
diones.[7]
RESULTS AND DISCUSSION
The general reaction between a,b-unsaturated acid chlorides and 4,4-
disubstituted cyclohexanone enamines is shown to follow the mechanistic
pathways (Scheme 2) reported earlier,[1] yielding substituted adamantane-
2,4-diones and substituted tricycloundecan-2,6-diones. The formation of sub-
stituted adamantane-2,4-diones has been explained through the formation of
the intermediate enolate anion 12, which cyclizes eventually onto the
Scheme 1.

Substituted Tricyclo[5.3.1.04,9]undecan-2,6-dione
1275
Scheme 2.

1276
M. G. Ahmed et al.
axially orientated acetyl group. When the acetyl group is in equatorial confor-
mation it may give rise to an alternative enolate anion 8 (preferably twist
form), which would lead to the formation of the tricycloundecan-2, 6-dione
structures by cyclization onto the iminium carbon.
In our previous studies we found that the reactions of 4a, 4b, and 4c with
methacryloyl chloride yielded the corresponding adamantanediones[7] 13a,
13b, and 13c and the respective tricycloundecanediones 9a, 9b, and 9c. It is
evident that the substituent X is equatorial in the enolate anion 12,
producing the adamantanediones, and is axial in the enolate anion 8,
producing the tricycloundecanediones. The reactions of the same enamines
also yielded a mixture of adamantanediones and tricycloundecanediones
with acryloyl chloride, as reported[1] earlier. The explanation for the
formation of both such types of tricyclic compounds in reactions with
Scheme 3.

Substituted Tricyclo[5.3.1.04,9]undecan-2,6-dione
1277
acryloyl chloride may be attributed to the steric interaction resulting from the
axially orientated substituent X, or Y would be a minimum in the ketene or
enolate anion where R0 and R00 both are H (Scheme 3). A similar explanation
may be put forward for similar results, which we obtained from such reactions
with methacryloyl chloride, showing that the resulting steric interactions are
still at a minimum when R0 is H and R00 is CH3.
The structures of the compounds 9a, 9b, and 9c were fully established
1
1
from its elemental analysis, IR spectra, H and 13C NMR, H–1H NMR
COSY, 13C–1H NMR COSY, DEPT, HMBC, and mass spectral data.
The coupling sites of all the protons of the compounds were located
1
clearly from H–1H NMR COSY, and their coupling constants were deter-
1
1
mined from one-dimensional H NMR spectrum. In the H NMR spectra
(Table 1) the equivalent CH2 –O–CH2 methylene protons of the morpho-
line moiety of the compounds 9a–c appeared as a triplet at d 3.58–3.60
(30 and 50 protons) at the lowest field. On the other hand 20 and 60
protons, which are a to the N-atom, appeared as a multiplet, and the none-
quivalence of these protons arises probably because of different spatial
arrangements next to the cage structure. The methylene protons at
position 3 gave two doublets (18.60–18.75 Hz) in the form of ABq,
which characterizes their structural environment. The axial proton at
position 3 is more deshielded than the equatorial protons because of the
Table 1. 1H NMR spectral data of the tricycloundecandiones 9a, 9b, and 9c (chemical
shift in d and coupling constants J in Hz)
Protons
9a
9b
9c
3-Ha
2.24
2.32
2.91
2.85
1.87
1.74
2.38
1.77
2.03
1.63
1.85
2.42
2.50
3.08
2.85
1.92
1.81
2.56
2.17
2.66
2.03
2.48
2.26
2.34
2.96
2.81
1.86
1.76
2.43
1.84
2.41
1.71
2.24
3-He
5-H
7-H
8-Ha
8-He
9-H
10-Ha
10-He
11-Ha
11-He
20, 60-H2
30, 50-H2
1-CH3
7- CH3
1-C6H5
1-C-CH3
1-C-C-Hc
1-C-C-Ht
2.43–2.56 (m)
2.50–2.63 (m)
3.63
2.42–2.55 (m)
3.60
1.02
1.11
—
3.58
—
—
1.10
1.08
—
7.16–7.36 (m)
—
—
—
—
—
1.75
4.72
5.00
—

1278
M. G. Ahmed et al.
adjacent carbonyl group. But at position 3, the axial proton also receives
steric shielding from the adjacent morpholine group (position 4), which
is equatorial. The overall effect is that 3-Ha is more upfield by 0.08 ppm
than 3-He. Of the alicyclic part, the most downfield proton was at bridge-
head position 5 as it is flanked by a carbonyl group and a morpholino
group. 8-Ha is more deshielded than 8-He because of the anisotropic
effect of carbonyl group at position 6.
At both the positions 10 and 11 the axial protons came more upfield than
the equatorial protons, 0.26–0.57 ppm in the case of 10-Ha and 0.22–0.53 ppm
in the case of 11-Ha, probably because of the anisotropic effect of the X group
at position 1. 7-CH3 resonated at d 1.08–1.11 as a doublet. The chemical shift
value of 7-H at d 2.81–2.85 is comparable to that of the axial proton at the
7-position in the reported[1] similar tricyclo compound, 1-methyl-4-(N-
morpholino)tricyclo[5.3.1.04,9]undecan-2,6-dione. This indicates the equator-
ial conformation of the methyl group in the compounds 9a, 9b, and 9c, which is
also expected for its bulky nature.
The coupling constants are shown in Table 2. The geminal couplings
between 8-Ha and 8-He, 10-Ha and 10-He, and11-Ha and11-He showed the J
values as 12.80–13.80, 11.9–13.9, and 14.5–14.75 respectively. The large
J values of 11.9–12.15 Hz were observed for vicinal coupling between 5-H
and 11-He. The vicinal coupling between 9-H and10-He also showed a large
coupling constant of 11.90–12.00 Hz (Table 3).
The 13C NMR of tricyclic compounds 9a, 9b, and 9c were analyzed by
means of 13C–1H NMR COSY, DEPT, and HMBC. The two carbonyl
groups at positions 2 and 6 resonated at the lowest field (Table 2). The
Table 2. Coupling constants (J in Hz) of the tricycloundecan-
diones 9a, 9b, and 9c
Protons
9a
9b
9c
3-Ha, 3-He
5-H, 11-Ha
5-H, 11-He
9-H, 10-Ha
9-H, 10-He
7-H, 8-Ha
18.75
3.5
18.60
3.65
11.9
3.25
11.90
4.84
2.75
3.65
2.75
12.8
13.9
14.75
3.65
6.4
18.66
3.67
12.15
4.18
—
12.0
3.5
12.0
4.5
4.94
—
7-H, 8-He
2.5
4.0
9-H, 8-Ha
9-H, 8-He
8-Ha, 8-He
10-Ha, 10-He
11-He, 11-Ha
11-He, 10-He
7-CH3, 7-H
3.13
—
3.0
13.25
11.5
14.5
4.0
13.80
12.04
14.50
2.99
6.41
6.38

Substituted Tricyclo[5.3.1.04,9]undecan-2,6-dione
1279
Table 3. 13C NMR spectral data of the tricycloundecandiones 9a,
9b, and 9c (chemical shift in d)
Carbons
9a
9b
9c
1-C
2-C
41.53
213.15
38.63
48.71
49.54
210.80
39.42
63.06
47.46
213.30
33.07
34.89
30.37
33.03
30.46
44.85
67.41
—
210.42
39.53
63.01
3-C
4-C
6316
5-C
6-C
47.75
213.58
33.12
34.91
30.46
36.34
33.59
44.83
67.43
19.18
14.27
—
41.86
213.06
33.16
34.99
7-C
8-C
9-C
30.79
35.05
10-C
11-C
20, 60,-C2
30, 50,-C2
1-CH3
7-CH3
1-C6H5
32.45
44.95
67.47
—
14.26
14.23
—
138.95 (C1)
128.27(C2)
127.34(C2)
127.12 (C1)
—
1-C-C(CH3)55CH2
1-C-C(CH3)55CH2
1-C-C(CH3)55CH2
—
—
—
144.40
112.90
20.66
—
—
signal at d 213.06–213.58 was assigned to 6-C and at d 210.42–213.15 for
2C. 6-C of the 6-carbonyl group shifted downfield in comparison with
2-carbonyl carbon because 6-C is flanked by the a-substituent 7-CH3 and
the bridgehead carbon at position 5. In the present work, the two resonating
values (for 6-C and 2-C) were confirmed with the help of HMBC.
6-Carbonyl carbon and 2-carbonyl carbon were correlated to 7-CH3 and
substitutions at the adjacent carbon’s position 1, by three-bond coupling
(HMBC). The methyl carbon in the case 9a at position 1 and at position
7 resonated at the highest field (d 19.18 and d 14.27 respectively). 1-CH3
is more deshielded than 7-CH3 because of the fully substituted 1-C. The
quarternary 1-C and 4-C gave less intense peaks. 4-C was deshielded tre-
mendously because of the electron-withdrawing morpholino group. 7-C
of 9a, 9b, and 9c were deshielded by 2.57–2.66 ppm in comparison to
that in the reported[1] compound. This can be explained by CH3 substitution
at 7-C. The chemical shift for 8-C (d 34.89–34.99) was also deshielded by
about 9.55–9.65 ppm in the same reported[1] tricyclic compound. This may
be accounted for by the b–SCS effect because of the methyl group at the
7-position.

1280
M. G. Ahmed et al.
The d values of 9-C and 11-C agreed very well with the reported[1]
compound. Of 7-C, 8-C, 9-C, 10-C, and 11-C, carbon at the 10-position is
the most deshielded (d 33.03–36.34). Besides other factors, the reason
may be attributed to g-anti-effect,[8] which indicates that Ca (11-position),
Cb (1-position), and Cg (2-position doubly substituted by O) are compressed
in the same plane.[8] 3-C gave the expected downfield shift because of the
adjacent (2-position) carbonyl group and fully substituted 4-position.
The 5-C is more deshielded than 3-C by 8.04–9.12 ppm because of more
substitution at the bridgehead. In the case of compound 9b, because of
phenyl substitution at position 1, 1-C was more deshielded (d 48.71) in
comparison to that in 9a (d 41.53).
Synthesis of substituted tricyclo[5.3.1.04,9]undecan-2,6-dione
EXPERIMENTAL
1
The H NMR and 13C NMR spectra were recorded on Bruker 500-MHz and
300-MHz instruments at the University of Wisconsin—Milwaukee, Depart-
ment of Chemistry, USA. A number of NMR spectra were also recorded on
JEOL 500-MHz and 400-MHz instruments, at the Kyoto, Kanazawa, and
Showa Pharmaceutical Universities in Japan. Some of NMR and mass
spectra were also recorded at the H. E. J. Laboratory of Karachi University,
Pakistan, and mass spectra were also recorded in the Department of
Chemistry, George Mason University, USA. The infrared spectra were
recorded on a IR 470 infrared spectrometer (Shimadzu) in the Department
of Chemistry, University of Dhaka, Bangladesh. All 1H and 13C NMR
spectra were recorded in CDCl3 if not otherwise mentioned. IR spectra
were run as KBr pellets in the case of solids and solution in the case of
liquids; absorptions are expressed in centimeters21. For column chromato-
graphy, silica gel 100 (supplied by E Mark) and light petroleum (60–808C):
chloroform ¼ 10 : 1 were used.
Preparation of 4,4-Disubstituted Cyclohexanones
4-Acetyl-4-methyl cyclohexanone 3a,[6] 4-acetyl-4-phenylcyclohexanone
3b,[5] and 4-acetyl-4-isopropenylcyclohexanone 3c,[6], and their precursors
1a,[5] 2a,[5] 1b,[5] 2b,[5] 1c,[9] and 2c[10] were prepared by essentially
following the literature methods.
Preparation of Enamines: General Method
A mixture of the 4,4-disubstituted cyclohexanone (17.47–32.2 mmol) and a
slight excess of morpholine (17.47–32.2 mmol) in toluene (75–80 ml) was

Substituted Tricyclo[5.3.1.04,9]undecan-2,6-dione
1281
heated to reflux under a Dean and Stark head for 12 h. On cooling, the solvent
and the excess of morpholine were removed under reduced pressure, and crude
enamine was used without further purification because extensive decompo-
sition occurred on distillation. In this way the following enamines were
obtained:
4-Acetyl-4-methyl-1-morpholinocyclohexene (4a) gmax in cm21: 1700
(C55O), 1638 (C55C).
4-Acetyl-4-phenyl-1-morpholinocyclohexene, (4b), gmax in cm21: 1700
(C55O), 1638 (C55C).
4-Acetyl-4-isopropesiyl-1-morpholinocychohexene (4c), gmax in cm21: 1700
(C55O) 1655, 1638 (C55C).
Synthesis of 1,7-Dimethyl-4(N-morpholino)
Tricyclo[5.3.1.04,9]undecan-2,6-dione 9a, 1-Phenyl-7-methyl-4(N-
morpholino) Tricyclo[5.3.1.04,9]undecan-2,6-dione 9b, and
1-Ispropenyl-7-methyl-4(N-morpholino)
Tricyclo[5.3.1.04,9]undecan-2,6-dione 9c: General Method
The methacryloyl chloride (21.72–35.40 mmol) in dry toluene (40–45 ml)
was added dropwise to a boiling solution of the enamine (21.5–
35.45 mmol) in dry toluene (130–160 ml) during 2 h. During the addition
a solid was slowly precipitated from the reaction mixture. The mixture
was then heated under reflux with stirring for 5 h and cooled, and the pre-
cipitated iminium salt was filtered off, washed with dry toluene, and hydro-
lyzed by stirring with ice-cold water (50 ml) for 10 h. The crude solid were
isolated by extraction with ether (5 ꢀ 25 ml). The separated aqueous layer
was further extracted with chloroform (5 ꢀ 25 ml). The crude tricyclic
compound was isolated from the extracts and purified by separation from
adamantanediones with the help of column chromatography (silica-gel
column) and was eluted initially with light petroleum (60–808C)
followed by gradual addition of chloroform. The following results were
obtained:
Methacryloyl chloride reacting with (4a) gave a 25% yield of 9a, which
was further purified by recrystallization from chloroform and light petroleum
(40–608C) and obtained as white crystals, mp 149–508C; Rf in TLC 0.37
(chloroform and ethyl acetate, 5 : 1); IR gmax 1700 (C55O), 1665, 1595
(C55C); MS m/z 291 (Mþ), 263, 248, 222, 195, 166, 119, 91, 79, 41, 27.
Anal. calcd. for C17H25NO3: C, 70.10%; H, 8.59%; N, 4.81%. Found: C,
70.05%; H, 8.62%; N, 4.78%.
Methacryloyl chloride reacting with (4b) gave a 25% yield of 9b, which
was further purified by recrystallization from chloroform and light petroleum
(40–608C) and obtained as white needles, mp 197–988C; Rf in TLC 0.36
(chloroform and ethyl acetate, 5 : 1); IR gmax 1705 (broad C55O), 1680

1282
M. G. Ahmed et al.
(C55C), 760, 740, 700, 670, 620, 545, 560 (C–H bending of phenyl); MS m/z
353 (Mþ), 236, 311, 270, 257, 207, 193, 165,139, 91, 86, 40, 18. Anal. calcd.
for C22H27NO3: C, 74.78%; H, 7.64%; N, 3.96%. Found: C, 74.34%; H,
7.64%; N, 3.81%.
Methacryloyl chloride reacting with (4c) gave a 10% yield of 9c, which
was further purified by recrystallization from chloroform and light
petroleum (40–608C) and obtained as white needles, mp 150–518C; Rf in
TLC 0.40 (chloroform and ethyl acetate, 5 : 1); IR gmax 1710 (broad C55O),
1630 (C55C). MS m/z 317 (Mþ), 289, 274, 260, 246, 234, 218, 208, 193,
180, 166, 152, 134, 131, 117, 105. Anal. calcd. for C19H27NO3: C, 71.92%;
H, 8.52%; N, 4.42%. Found: C, 70.64%; H, 8.42%; N, 4.31%.
ACKNOWLEDGMENT
Dr. Kudrat-e-Khoda Doctoral Fellowship (October 1999–March 2003)
to Kawsari Akhter by BCSIR Laboratories, Dhaka, Bangladesh, is
acknowledged.
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