A study about the synthesis of seven-membered-ring analogues of ketamine

Article abstract of DOI:10.1007/s11164-014-1790-7

Synthesis of seven-membered ring analogues of ketamine was studied with two strategies. In the first approach a sequence of five reactions was used which previously applied for ketamine synthesis. This strategy led to formation of 1-[(2-chlorophenyl)(methylimino)methyl]cyclohexan-1-ol as a precursor for the target molecule. In the second approach, we have designed and attempted to synthesize a new analogue of ketamine applying challenging reactions such as ring expansion and selective bromination. The result of this route is synthesis of some interesting compounds such as 6-phenyl-1-oxa-4-thiaspiro[4.6]undecane, 3-bromo-6-phenyl-1-oxa-4-thiaspiro[4.6]undecane and 2,7-dibromo-2-phenylcycloheptanone.

Full text of DOI:10.1007/s11164-014-1790-7

Res Chem Intermed
DOI 10.1007/s11164-014-1790-7
A study about the synthesis of seven-membered-ring
analogues of ketamine
•
Abolghasem Moghimi Mohammad Reza Shahdadi
•
•
Sajjad Keshipour Morteza Sadeghzadeh
Received: 22 April 2014 / Accepted: 11 August 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Synthesis of seven-membered ring analogues of ketamine was studied
with two strategies. In the first approach a sequence of five reactions was used which
previously applied for ketamine synthesis. This strategy led to formation of 1-[(2-
chlorophenyl)(methylimino)methyl]cyclohexan-1-ol as a precursor for the target
molecule. In the second approach, we have designed and attempted to synthesize a
new analogue of ketamine applying challenging reactions such as ring expansion
and selective bromination. The result of this route is synthesis of some interesting
compounds such as 6-phenyl-1-oxa-4-thiaspiro[4.6]undecane, 3-bromo-6-phenyl-1-
oxa-4-thiaspiro[4.6]undecane and 2,7-dibromo-2-phenylcycloheptanone.
Keywords Ketamine Á Phenylcycloheptanone Á Ring expansion Á Analgesia
Introduction
Ketamine is an arylcycloalkylamine prepared by Stevens by thermal isomerization
of 1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol [1]. This compound has
a wide range of effects on humans, including analgesia, anesthesia, hallucinations,
and elevated blood pressure. Although many drugs interact with the inflammatory
response in a positive, negative, or ‘‘dual’’ manner, among these drugs ketamine
seems to have a significant positive effect on regulation of inflammation [2–4].
Ketamine has applications as a sedative in intensive care, analgesia, and treatment
A. Moghimi (&) Á M. R. Shahdadi Á M. Sadeghzadeh
Department of Chemistry, Faculty of Science, Imam Hossein University, Tehran, Iran
e-mail: samoghimi@yahoo.com
S. Keshipour
Department of Nanochemistry, Nanotechnology Center, Urmia University, G. C.,
P. O. Box 165-5715944931, Urmia, Iran
123

A. Moghimi et al.
of bronchospasm [5–13]. Because some biologically active compounds, for example
eticyclidine [14], phencyclidine [15], rolicyclidine [16], and tiletamine [17], are
structurally related to ketamine (Fig. 1), synthesis of ketamine analogues is of
interest [18–21].
Synthesis of ketamine involves four steps, as depicted in Scheme 1 [1]. In this
strategy, 1-(2-chlorobenzoyl)cyclopentane, 3, prepared by reaction of 2-chloroben-
zonitrile, 1, and cyclopentylmagnesium bromide, 2, was brominated to give (1-
bromocyclopentyl)(2-chlorophenyl)methanone (4). Bromoketone 4, on reaction
with an aqueous solution of methylamine, yielded 1-((2-chlorophenyl)(methylimi-
no)methyl)cyclopentan-1-ol (5). On heating compound 5 in decalin, a ring-
expansion rearrangement occurs to produce ketamine, A.
Because of the wide range of applications of ketamine and its analogues, we
wished to extend the strategy of ketamine synthesis to preparation of 2-(2-
chlorophenyl)-2-(methylamino)cycloheptanone (10) as a new analogue of ketamine.
The preparation procedure is summarized in Scheme 2. This strategy has previously
been evaluated by our group [22], and led to synthesis of 9. Herein, we attempt to
optimize the reaction conditions of this approach and examine synthesis of 10 from
9. This is a new strategy for synthesis of 10.
Results and discussion
Synthesis of 10 was started by reaction of 2-chlorobenzonitrile, 1, and the
appropriate Grignard reagent, 6, [23] in tetrahydrofuran (THF) to give (2-
chlorophenyl)(cyclohexyl)methanone (7) in 78 % yield (Scheme 2). To improve
the reaction yield, different halogenated copper(I) compounds were used as
catalysts, and a high yield was obtained by use of 1 mol% CuI and 2 mol%
DABCO. It is important to note that reaction yield decreased in the presence of
larger and smaller amounts of CuI and in the absence of DABCO. The results of this
study are summarized in Table 1.
Bromination of 7 with HBr/H2O2 at 70 °C for 24 h furnished (1-bro-
mocyclohexyl)(2-chlorophenyl)methanone, 8, in 79 % yield. Compound 8 was
reacted with pure methylamine at low temperature in liquid nitrogen for 5 h and
then room temperature for 12 h. The 1-[(2-chlorophenyl)(methylimino)methyl]cy-
clohexan-1-ol (9) obtained was crystallized from the reaction mixture, in 88 %
yield, by use of n-hexane. This product is the result of two sequential reactions,
imination of the ketone group and nucleophilic substitution of bromide by hydroxyl.
The challenging step of this approach is the rearrangement reaction of 9 with ring
expansion. Ring expansion in the classic synthesis of ketamine (A) encouraged us in
the planning of this reaction. However, rearrangement product 10 was not obtained
even under harsh reaction conditions, for example reflux in decalin, o-xylene, or
toluene in the presence of a variety of catalysts, for example CuI, SnO2, and Al2O3.
This result proved 2,2-disubstituted cyclohexanone was more stable than 2,2-
disubstituted cycloheptanone, because ketamine as a 2,2-disubstituted cyclohexa-
none was synthesized via this route.
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Synthesis of seven-membered-ring analogues of ketamine
Fig. 1 Structures of some ketamine analogues
Scheme 1 Synthesis of ketamine
We therefore designed another approach to obtain the seven-membered ring
analogue of ketamine, as depicted in Scheme 3.
In this approach cyclohexanone 11 was reacted with the Grignard reagent 12 in
THF to give 1-benzylcyclohexanol (13) in 85 % yield [24]. Compound 13 was
brominated with NBS in CCl4 to produce 1-(bromo(phenyl)methyl)cyclohexanol
(14) which, on treatment with butylmagnesium bromide in benzene under reflux,
underwent rearrangement to 2-phenylcycloheptanone (15) [25, 26]. Because
compound 15 has two active sites for bromination, for regioselective bromination
the carbonyl group was protected by reaction with 2-mercaptoethanol in the
presence of BF3.OEt2. This reaction produced two diastereomeric compounds in
1
74:26 ratio (Scheme 4), as determined from the H NMR spectrum. Interestingly,
123

A. Moghimi et al.
Scheme 2 Synthesis of 2-(2-chlorophenyl)-2-(methylamino)cycloheptanone (10)
Table 1 Optimization of catalyst in the reaction of 2-chlorobenzonitrile 1 and Grignard reagent 6
Entry
Cux (mol %)
DABCO (mol %)
Yield (%)b
1
2
3
4
5
6
CuCl (1)
CuBr (1)
CuI (1)
2
2
2
0
1
4
78
83
93
75
80
86
CuI (1)
CuI (0.5)
CuI (2)
Reaction conditions: 2-Chlorobenzonitrile (1) (1.0 mmol), 6 (1.0 mmol), THF (10 mL), reflux, 4 h
Scheme 3 Attempts to synthesize the seven-membered ring analogue of ketamine
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Synthesis of seven-membered-ring analogues of ketamine
Scheme 4 Protection of 2-phenylcycloheptanone leading to two diastereoisomers, as confirmed by NMR
bromination of 6-phenyl-1-oxa-4-thiaspiro[4.6]undecane (16) proceeded with
bromination of the methylene group of SCH2 and led to the formation of
3-bromo-6-phenyl-1-oxa-4-thiaspiro[4.6]undecane (17) (Scheme 3), rather than the
desired product 18. The bromination reaction was therefore examined with other
reagents, HBr/H2O2 [22] and Br2 in CCl4, but the same product was obtained. To
prevent this unfavorable reaction we tried protecting the carbonyl group with 1,2-
ethanediol but this reaction did not proceed. This might be attributed to the low
activity of 1,2-ethanediol and hindrance by compound 15.
It is important to note that bromination of 15 by use of the above mentioned
approaches gave dibrominated product 19. This reaction was investigated with
control of the amount of bromine, with 0.5, 1, and 2 equivalents of bromine relative
to 2-phenylcycloheptanone (15) (Table 2). In all cases product 19, only, was
obtained.
In conclusion, attempts to synthesize the seven-membered ring analogue of
ketamine led to the formation of the new interesting compounds 1-[(2-chloro-
phenyl)(methylimino)methyl]cyclohexan-1-ol, 6-phenyl-1-oxa-4-thiaspiro[4.6]un-
decane, and 3-bromo-6-phenyl-1-oxa-4-thiaspiro[4.6]undecane and 2,7-dibromo-2-
123

A. Moghimi et al.
Yield (%)
Table 2 Effect of amount of bromine on bromination of 15
Entry
Br2 (mol %)
1
2
3
4
0.5
1
24
41
85
86
2
3
Reaction conditions: 15 (1.0 mmol), NBS, benzoyl peroxide (0.1 g), CCl4 (20 mL), under N2 atmosphere,
reflux, 4 h
phenylcycloheptanone. We hope these compounds may be of value to others
seeking novel synthetic fragments with ketamine properties.
Experimental
General remarks
All the reagents were purchased from Merck. IR spectra were recorded on Bruker
Tensor 27 and Perkin Elmer spectrophotometers.1H NMR spectra were recorded on
Bruker 250 MHz instrument.13C NMR spectra were recorded on Bruker 62.90 MHz
instrument.
Typical procedure for synthesis of cyclohexylmagnesium bromide
Cyclohexylmagnesium bromide was synthesized in THF in accordance with a
literature method [22] and used immediately after preparation.
Typical procedure for synthesis of cyclohexyl (2-chlorophenyl) ketone (7)
Toluene (40 mL) and CuI (0.32 mmol) were added to a stirred solution of
2-chlorobenzonitrile (32 mmol) and cyclohexylmagnesium bromide (37 mmol;
2 M in THF). The mixture was heated to remove the THF by distillation then heated
under reflux (under nitrogen) for 4 h. After cooling to 25 °C, H2O (5 mL) was
cautiously added, followed by 30 mL 15 % H2SO4. After stirring of the mixture for
5 h, 20 mL hexane was added. The organic layer was separated, and the aqueous
layer was extracted with diethyl ether (2 9 10 mL). The combined organic phase
was dried over MgSO4 and concentrated by rotary evaporation to afford a brown oil.
After chromatography (silica gel, hexane, 10:1 hexane: ethyl acetate) 6.6 g (93 %
yield) cyclohexyl (2-chlorophenyl) ketone was obtained as a white crystalline
1
compound. mp: 52 °C, IR (KBr), v(cm-1): 2,922, 2,852, 1,665, 1,578, 1,444. H
NMR (250 MHz, CDCl3) d: 1.21–1.53 (5H, m), 1.61–1.92 (5H, m), 3.06–3.14 (1H,
m), 7.23–7.42 (4H, m).; 13C NMR (62.90 MHz, CDCl3) d: 25.6 (CH2), 25.8 (CH2),
28.4 (CH2), 50.1 (CH), 126.7 (CH), 128.3 (CH), 130.2 (CH), 130.5 (quat-C), 131.8
(CH), 140.1 (quat-C), 207.4 (quat-C, C=O).
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Synthesis of seven-membered-ring analogues of ketamine
Typical procedure for synthesis of (1-bromocyclohexyl)(2-
chlorophenyl)methanone (8)
Cyclohexyl (2-chlorophenyl) ketone 7 (10 mmol) was placed in a flask covered with
aluminium foil. An aqueous solution (47 %) of HBr (1.2 mL, 1.1 mol equiv.) was
added to ketone. After stirring of the reaction mixture for 5 min at room
temperature, 10 mmol LiCl was added to the mixture and stirring was continued for
10 min. H2O2 (30 % aqueous solution, 2 mL, 2 mol equiv.) was then added slowly.
The reaction mixture was heated at 70 °C for 1 h then 5 mL H2O was cautiously
added, followed by 5 mL hexane. This mixture was stirred for 5 min. The organic
layer was separated and dried on MgSO4. The insoluble material was isolated by
filtration then the solvent was evaporated under reduced pressure to produce 2.4 g
(79 %) compound 8 as a yellow oil. 1H NMR (250 MHz, CDCl3) d: 1.23–1.27 (2H,
m), 1.64–1.84 (6H, m), 1.96–2.21 (4H, m), 7.25–7.82 (4H, m).; 13C NMR
(62.90 MHz, CDCl3) d: 22.5 (2CH2), 24.8 (CH2), 36.1 (2CH2), 70.6 (quat-C), 126.3
(CH), 129 (CH), 130 (CH), 130.3 (quat-C), 130.6 (CH), 137.8 (quat-C), 199.6 (quat-
C, C=O).
Typical procedure for synthesis of (1-[(2-
chlorophenyl)(methylimino)methyl]cyclohexanol (9)
(1-Bromocyclohexyl)(2-chlorophenyl)methanone (3.7 mmol) was slowly added to
4 mL methylamine in a sealed vitreous glass reactor cooled at -40 °C by liquid N2.
After stirring for 6 h, the temperature was increased to 25 °C and stirring was
continued for 12 h. Finally, 10 mL hexane was added, and the organic layer was
separated and concentrated by solvent removal under reduced pressure to afford
brown crystals. The crystals were washed with methanol (2 9 10 mL) to afford
shiny crystal in 88 % yield (0.8 g). Mp 79–81 °C.; IR (KBr) v: 3,209, 2,934, 2,855,
1,651, 1,410, 766 cm-1.; 1H NMR (250 MHz, CDCl3) d: 0.99–1.09 (1H, m),
1.31–1.35 (1H, m), 1.44–1.72 (8H, m), 3.02 (3H, S), 4.53 (1H, br s), 7.03–7.56 (4H,
m).; 13C NMR (62.90 MHz, CDCl3) d: 21.5 (CH2), 21.7 (CH2), 25.2 (CH2), 34.7
(CH2), 35.5 (CH2), 39.0 (CH3), 75.3 (quat-C), 126.5 (CH), 128.8 (CH), 129.8 (CH),
131.9 (quat-C), 134.1 (quat-C), 174.6 (quat-C).
Typical procedure for synthesis of 1-benzylcyclohexanol (13)
To a stirred solution of benzyl magnesium chloride (12 mmol) in THF (20 mL),
10 mmol cyclohexanone dissolved in 10 mL THF was added dropwise. The mixture
was heated to remove the THF by distillation, then heated under reflux (under
nitrogen) for 4 h. After cooling to room temperature, H2O (5 mL) was cautiously
added, followed by 30 mL 15 % H2SO4. The mixture was stirred for 1 then 20 mL
hexane was added. The organic layer was separated and the aqueous layer was
extracted with diethyl ether (2 9 10 mL). The combined organic phase was dried
over MgSO4 and concentrated by rotary evaporation to afford 1.9 g (85 % yield)
white crystals of 1-benzylcyclohexan-1-ol (13). Mp 41–43 °C.:1H NMR (250 MHz,
123

A. Moghimi et al.
CDCl3) d: 1.28–1.64 (10H, m), 2.70 (2H, s), 7.23–7.39 (5H, m).; 13C NMR
(62.90 MHz, CDCl3) d: 22.1, 25.7, 37.2, 48.65, 71.0, 126.3, 128.0, 130.6, 137.15.
Typical procedure for synthesis of 1-(bromo(phenyl)methyl)cyclohexanol (14)
1-Benzylcyclohexan-1-ol (13) (15 mmol) was added to a vessel containing 20 mL
anhydrous carbon tetrachloride, 1 equiv. N-bromosuccinimide, and benzoyl
peroxide (0.1 g). The mixture was brought to reflux for 2 h then cooled in an ice
bath. The succinimide was isolated by suction filtration. The carbon tetrachloride
was removed under vacuum by rotary evaporation to furnish 3.9 g light yellow oil
1
(96 % yield). H NMR (250 MHz, CDCl3) d: 1.28–1.63 (10H, m), 4.77 (1H, s),
7.22–7.36 (5H, m); 13C NMR (62.90 MHz, CDCl3) d: 22.0 (2CH2), 45.7 (CH2),
37.2 (CH2), 48.6 (CH), 71.0 (C), 126.2 (CH), 128.0 (CH), 130.6 (CH), 137.2 (C).
Typical procedure for synthesis of 2-phenylcycloheptanone (15)
Isopropylmagnesium bromide (11 mmol in 10 mL diethyl ether) was added
dropwise to an ice-cooled solution of 1-(bromo(phenyl)methyl)cyclohexan-1-ol
(14) (10 mmol) in 30 mL anhydrous benzene. The ice bath was then removed and
the resulting solution was heated under reflux for 3 h. The brown solution was then
cooled and added to a solution of ammonium chloride in water (6 mmol in 10 mL).
The benzene layer was separated and washed with 10 % sodium carbonate followed
by water. The benzene solution was then dried over magnesium sulfate and the
solvent was subsequently removed under vacuum. The residue was purified by
column chromatography on silica gel, with n-hexane then ethyl acetate as eluents,
furnishing 2-phenylcycloheptanone in 81 % yield (1.5 g). 1H NMR (250 MHz,
CDCl3) d: 1.40–1.61 (4H, m), 1.93–2.10(4H, m), 2.53–2.73 (2H, m), 3.71 (1H, dd,
3JH-H = 7.5 and 4 Hz), 7.20–7.33 (5H, m).; 13C NMR (62.90 MHz, CDCl3) d: 25.3
(CH2), 28.7 (CH2), 30 (CH2), 32 (CH2), 42 (CH2), – 58.0 (CH), 126.5 (CH), 127.5
(CH), 128.5 (CH), 140.0 (CH), 213.1 (CO).
Typical procedure for synthesis of 6-phenyl-1-oxa-4-thiaspiro[4.6]undecane
(16)
2-Phenylcycloheptanone (10 mmol), 2-mercaptoethanol (11 mmol), and dry diethyl
ether (20 mL) were heated under reflux in a three-necked, round-bottomed flask
purged with nitrogen gas and equipped with a reflux condenser. BF3.Et2O
(10 mmol) dissolved in diethyl ether (10 mL) was added dropwise to the mixture
over a period of 1 h, and heating under reflux was continued for 1 h. The mixture
was then cooled and washed with 20 mL NaHCO3 (1 M) and saturated NaCl. The
organic layer was separated and dried over MgSO4. After evaporation of the
solvent, purification by column chromatography gave 2.1 g (83 % yield) white
crystals of 6-phenyl-1-oxa-4-thiaspiro[4.6]undecane (16). Mp 28–30 °C.;1H NMR
for two diastereoisomers (250 MHz, CDCl3) d: 1.53–2.31 (20H, m, for two
diastereoisomers), 2.51(1H, m, diastereoisomer 1), 2.68 (1H, m, diastereoisomer 2),
3
3
2.98 (1H, d, JHH = 9.5 Hz, diastereoisomer 2), 3.13 (1H, d, JHH = 9.5 Hz,
123

Synthesis of seven-membered-ring analogues of ketamine
diastereoisomer 1), 3.51 (1H, m, diastereoisomer 2), 3.71–3.79 (5H, m, 2H for
diastereoisomer 2 and 3H for diastereoisomer 1), 7.15–7.35 (10H, m); 13C NMR
(62.90 MHz, CDCl3) d: 22.8, 23.0, 27.8, 28.1, 28.5, 28.8, 31.3, 33.4, 43.9, 44.6,
56.2, 57.4, 70.6, 71.9, 72.7, 93.3, 102.6, 125.8, 125.9, 126.8, 127.1, 130.2, 130.4,
137.5, 160.1.
Typical procedure for synthesis of 3-bromo-6-phenyl-1-oxa-4-
thiaspiro[4.6]undecane (17)
6-Phenyl-1-oxa-4-thiaspiro[4.6]undecane (16) (15 mmol) was added to a vessel
containing 20 mL anhydrous carbon tetrachloride, 1 equiv. N-bromosuccinimide,
and benzoyl peroxide (0.1 g). The mixture was brought to reflux for 4 h then cooled
in an ice bath and the succinimide was isolated by suction filtration. The carbon
tetrachloride was removed under vacuum by rotary evaporation to furnish 2.0 g
1
brown oil (61 % yield). H NMR (250 MHz, CDCl3) d: 1.43–2.65 (10H, m), 3.70
(1H, dd, 3JHH = 7.5 and 4.0 Hz), 4.21–4.27 (3H, m), 7.21–7.43 (5H, m).; 13C NMR
(62.90 MHz, CDCl3) d: 22.3 (CH2), 26.0 (CH2), 29.8 (CH2), 35.8 (CH2), 37.2
(CH2), 58.6 (CH2), 60.8 (CH), 70.3 (CH2), 75.1 (CSBr), 126.1 (CH), 127.9 (CH),
128.8 (CH), 130.4 (CH), 135.2 (C).
Typical procedure for synthesis of 2,6-dibromo-2-phenylcycloheptanone (19)
2-Phenylcycloheptanone (15) (5 mmol) was added to a vessel containing 20 mL
anhydrous carbon tetrachloride, 2 equiv. N-bromosuccinimide, and benzoyl
peroxide (0.1 g) under an N2 atmosphere. The mixture was brought to reflux for
4 h then cooled in an ice bath and the succinimide was isolated by suction filtration.
The carbon tetrachloride was removed under vacuum by rotary evaporation to
furnish 1.5 g light yellow oil (86 % yield). 1H NMR (250 MHz, CDCl3) d:
1.52–1.99 (6H, m), 2.35–2.62 (2H, m), 4.62 (1H, br), 7.17–7.66 (5H, m); 13C NMR
(62.90 MHz, CDCl3) d: 22.1 (CH2), 26.4 (CH2), 29.9 (CH2), 35.0 (CH2), 37.9
(CH2), 60.2 (C), 72.5 (C), 126.1 (CH), 127.2 (CH), 128.6 (CH), 130.9 (CH), 139.3
(C), 211.9 (C).
Acknowledgments We gratefully acknowledge financial support from the Research Council of Imam
Hossein University.
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