Novel enantioselective synthesis of (S)-ketamine using chiral auxiliary and precursor Mannich base

Article abstract of DOI:10.1139/cjc-2017-0731

Ketamine has been extensively used as an anesthetic drug. Chiral auxiliaries such as tert-butanesulfinamide (TBSA) can be used for the asymmetric synthesis of (S)-ketamine. Condensation of TBSA with ketones provides tert-butanesulfinylimines in consistently high yields. The tert-butanesulfinyl group actuates the imine for nucleophilic addition, is a potent chiral directing group, and after nucleophilic addition is easily dissociated by intervention with acid solution. To prepare 2-(N-piperidinomethyl)-1-phenylcyclohexylamine (1), we started with the cyclohexanone and using Mannich reaction achieved an aminoketone. Then, we made the sulfiniylamin (2) by the condensation of TBSA with aminoketone. By using salts such as Ti(OEt)₄, we obtained N-tert-butanesulfinylketimine in 85% yield. Next, we provided a new chiral center (3) using Grignard reagent as nucleophile at -78 °C (80% yield). Finally, after many steps, the (S)-ketamine synthesized under ozonolysis conditions, with good yield and enantioselectivity (75% yield and 75% ee).

Full text of DOI:10.1139/cjc-2017-0731

Page 1 of 21
Novel enantioselective synthesis of (S)-ketamine using chiral
auxiliary and precursor Mannich base
Seyed Jamal addin Gohari,1* Abdollah Javidan,2 Abolghasem Moghimi,3
Mohammad Javad Taghizadeh,4 Maryam Iman5
1Department of Chemistry, Faculty of Science, Imam Hossein comprehensive University, Tehran – Iran
E-mail: gohari_129@yahoo.com
2 Department of Medicine Chemistry, Faculty of Science Pharmaceutical Sciences Branch, Islamic Azad University,
Tehran, Iran.
E-mail: abdollah.javidan@gmail.com
3Department of Chemistry, Faculty of Science, Islamic Azad University, Tehran North Branch, Tehran – Iran
E-mail: samoghimi@yahoo.com
4Department of Chemistry, Faculty of Science, Imam Hossein comprehensive University, Tehran – Iran
E-mail: mohammadjavadtaghizadeh31@yahoo.com
5Department of Chemical Injuries Research Center, System Biology and Poisonings Institute, Baqiyatallah
University of Medical Sciences, Tehran, Iran.
E-mail: iman1359@yahoo.com
*Corresponding author: Seyed Jamal addin Gohari, Phone: 9127235678 Fax: +2177104569
E-mail: gohari_129@yahoo.com
1

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Abstract
Ketamine has been extensiely used as an anesthetic drug. For the asymmetric synthesis of (S)-ketamine,
can be use to chiral auxiliaries such as tert-butanesulfinamide (TBSA). Condensation of TBSA with
ketones provides tert-butanesulfinylimines in consistently high yields. The tert-butanesulfinyl group
actuates the imine groups for the attack of some different groups of nucleophiles, prepare as a potent
chiral directing group, and after nucleophilic addition is easily dissociated by intervention with acid
solution. In this work, for reach to the 2- (N-piperidino methyl)-1-phenylcyclohexylamine (1), we started
with the cyclohexanone and using Mannich reaction achived to an aminoketone (Scheme 1). Then, we
made the sulfiniylamin (2) by the condensation of TBSA with aminoketone. In addition, Ti(OEt)4 is
effective for reach to N-tert-butanesulfinylketimine in 85% yield. At next, we provided a new chiral
center (3) using Grignard reagent as nucleophile at −78 °C (80% yield). At after multistep, finally, the
(S)-ketamine synthesized under ozonolize condition and gave the good yield and enantioselectivity (75%
yield and 75% ee).
Keywords: (S)-ketamine, asymmetric synthesis, enantioselective synthesis, aminoketone, chiral
auxiliary, tert-butanesulfinamide.
2

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1. Introduction
Ketamine induces its anesthetic actuates by blocking the N-methyl-D-aspartate receptor
(NMDAR) in the central nervous system (CNS). Ketamine hampers the NMDAR by binding
both in the open channel and at an allosteric site.1 The commercial ketamine is a racemic mixture
of their enantiomers. The racemic ketamine was produced by Stevens through rearrangement of
1-[(2-chlorophenyl)(methylimino)methyl]cyclopentanol.2-5 The (S)-ketamine is display to be
more powerful with an about 3–4 fold anesthetic potency compared to (R)-ketamine. This relates
to the higher binding attraction for the PCP-site of the NMDAR.6
Then, the synthesis of chiral amines is of great interest due to their prevalence in biologically
active molecules. Therefore, development of an asymmetric synthesis for the (S)-ketamine is
highly desirable. One of routes of asymmetric synthesis for preparation of chiral molecules is
using chiral auxiliaries.7 At present, many routes of asymmetric synthesis of (S)-ketamine were
reported. Recently, Kiyooka et al. were presented two procedures for this propose.8 At first
procedure, the phenyllithium was reacted to chiral α-ketoketal bearing chiral auxiliary on a
ketone group with 83% yield and 82% de. However, the reaction of 2-chlorophenyllithium did
not perform in which this procedure was unfavorable for the (S)-ketamine. At second procedure,
a different strategy was designed, which the chiral carbon of ketamine with a reduction step by
(S)-BINAL-H catalyst, was obtained (>99% ee). Beside, Biermann et al. were presented a new
method, the chirality induction prepared using Sharpless dihydroxylation and followed with
Ritter reaction (Scheme 2). Finally, the obtained alcoholamine was converted to (S)-norketamine
by Jones oxidation (=99% ee).9
3

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As part of our ongoing research to find a new dependable procedure to (S)-ketamine, we applied
a simple methodology, using nucleophilic 1,2-addition to obtained chiral imine from β-
aminoketone. Mannich reaction represents easily obtainable intermediates for the synthesis of β-
aminoketone compounds.10 Mannich bases are very reactive; in fact, the reactivity of the bases
accounts for several interesting properties. β-Aminoketones demonstrate an eminent group of
compounds in pharmaceutical chemistry because of their various biological properties.11 Also,
they are useful building blocks for the synthesis of various medicinal. They can present as chiral
ligands for asymmetric synthesis.12 Herein, we reported, an auxiliary-based process for the
asymmetric synthesis of chiral nitrogen-substituted carbon center in the cyclohexane ring, which
proceeds through the addition of Grignard reagent to obtained imine of N-tert-butylsulfinylimine
with good yields and diastereoselectivities (Scheme 3). During the past few years, one of main
research lines has focused on the use of N-(tert-butylsulfinyl)imines in asymmetric synthesis.13-15
N-tert-butanesulfinamides have been established to be highly effective chiral auxiliaries in the
synthesis of various chiral amines by the virtue of their good diastereocontrol and readily
cleavage.16,17 We report here on the preparation of quaternary carbon by the addition of Grignard
reagent to N-sulfinylimine derived from cyclic Mannich base. Tertiary carbinamine was obtained
by addition of Grignard reagents to N-sulfinylketimines in high yields (80%) and with high
diastereoselectivities (89:11 dr).16,17 The N-tert-butylsulfinyl group can prepare as not only an
efficient chiral auxiliary for the asymmetric synthesis of ketamine, but also an amine protecting
group.18-20 Generally, the ketones with the electron-donating substituent on the aromatic ring
could participate better in the reaction, resulting in the obtained products with better yields
(75%–80%) and diastereoselectivities (>95 : 5 dr).13-16 The sulfinyl group is eliminated from the
Grignard addition product by treatment with HCl in protic solvents such as methanol to present
4

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the amine salt in good yields.13-20 Enantiomerically pure material may be provided by first
chromatographing or recrystallizing the Grignard addition product prior to sulfinyl group
removal or by either crystallizing the amine hydrochloride salt.14-20 Amine (6) was obtained in
the high isolated yield of 92%. The resulting chirality of the carbon center was proved again to
be (S) by comparison of the optical rotation with the literature value.21 In this procedure, for
reach to (S)-ketamine further provides the nucleophilic addition upon N-sulfinyl cyclic imine
where both conditions of ring and the sulfinyl group have the potential to control reaction
diastereoselectivity.
2. Experimental
General
All the chemicals were used as purchased (Merck) for the reaction without further purification.
All the organic solvents were purchased from commercial suppliers and were purified according
to standard procedures. Lewis acids were also obtained from commercial suppliers. All reactions
were carried out in oven-dried glassware under nitrogen atmosphere. Infrared spectra were
recorded using a Perkin–Elmer Spectrom-100 FT-IR spectrometer. IR spectra of liquids were
recorded as thin films on NaCl plates, and IR spectra of solids were recorded as KBr pellets. The
1H NMR spectra were determined using TMS as an internal reference with an Avance FT NMR
13
spectrometer operating at 250 MHz. The C NMR spectra were determined using TMS as an
internal reference with an Avance FT NMR spectrometer operating at 60 MHz. Mass spectra
analyses were recorded on an Agilent Technologies, Model: 5975C VL MSD by EI mass
spectrometry on a Q-TOF instrument. Preparative normal phase HPLC were performed on a
5

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Waters HPLC prep 4000 system equipped with a 4000-controller pump by using column
DAICEL CHIRALCEL OD-H; Detection: UV 254 nm, Mobile phases were 5% 2-propanol/n-
hexane, Flow: 0.5 mL/min. Flash chromatography was performed using silica gel 60 (200–300
mesh). Thin layer chromatography was carried out on silica gel 60 F-254 TLC plates of 20 cm ×
20 cm. Column chromatography was performed using Merck Silica gel 60 (0.063–0.200 mm).
Elemental analysis on C, H and N were performed using a HN Heraeuse Elemental Analyser.
Synthesis of Intermediates:
2.1. Preparations of 2-(N-piperidin-1-methyl)cyclohexan-1-one (1):
Compound (1) was synthesized according to classical Mannich reaction, Mannich and
Lammering, 1922.22 A mixture of the cyclohexanone, paraformaldehyde, piperidine
hydrochloride were heated under reflux in 20 mL acetic acid 95% v/v. Only for formation of
piperidine hydrochloride, hydrochloric acid 37% v/v, 3 mL was added in to 10 mL piperidine.
The mol ratios of cyclohexanone, paraformaldehyde, piperidine hydrochloride and duration of
heating were as follows: 0.02, 0.01, 0.01, 2 h. The acetic acid was evaporated in vacuo to give
compound (1) as solid crystals. After evaporation, compound was heated in 20 mL dry acetone
under 45 °C at 30 min and were recrystalized from ethanol. The white crystals were dried in oven
(mp. 101-105 °C). Then crystals were dissolved to water and on cooling were treated with
sodium hydroxide 30% (pH=14) to give base. The mixture was extracted with ether. Finally, the
mannich base, yellow liquid, was separated.
yellow liquid, (88%), Isolated yield = 0.078 g. IR (KBr): 2933, 2733, 1720, 1447, 1090, 1222,
865, 500 cm-1; 1H NMR (250 MHz, CDCl3, TMS) δ: 2.78 (dd, 1H, J= 12.75, 5.5), 2.51-2.70 (m,
1H), 2.25-2.48 (m, 5H), 2.15-2.25 (m, 2H), 2.00-2.15 (m, 1H), 1.80-2.00 (m, 1H), 1.70-1.81 (m,
6

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13
2H), 1.47-1.65 (m, 4H), 1.20-1.51 (m, 2H) ppm.; C NMR (62.5 MHz, CDCl3) δ: 211.3, 64.9,
57.5, 54.1, 47.7, 41.1, 32.1, 28.1, 25.0, 23.9, 23.6 ppm.; Mass spectrum (EI, 70 eV), m/z (Irel,
%): [М]+ 195 (13), 181 (8), 149 (8), 111 (13), 98 (10), 84 (8), 71 (13), 57 (100), 41 (51);
Elemental analysis for C12H21NO: Calculated C 73.85, H 10.77, N 7.18, Found C 73.98, H 10.79,
N 7.20%.
2.2. Preparations of (S)-2-methyl-N-((E)-2-(piperidine-1-methyl)cyclohexyliden)propane-2-
sulfonamide (2):
A 0.5 M solution of Ti(OEt)4 (11.72 g, 51.4 mmol) and ketone (1) (5.01 g, 25.7 mmol) in THF
was prepared under a N2 atmosphere. Then, (S)-tert-butanesulfunamine (3.11 g, 25.7 mmol) was
added and the flask was heated. Conversion was followed by TLC, and the mixture cooled
immediately upon completion. Once at room temperature, the mixture was poured into an equal
volume of brine while rapidly stirring. The resulting suspension was filtered through a plug of
Celite, and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory
funnel where the organic layer was washed with brine. The brine layer was extracted once with a
small volume of EtOAc, and the combined organic portions were dried (Na2SO4), filtered, and
concentrated. The sulfinylimine (2) were purified either by flash chromatography.
red liquid (85%), Isolated yield = 0.101 g. IR (KBr): 3300, 2950, 2933, 2733, 1668, 1620, 1030,
800 cm-1; 1H NMR (250 MHz, CDCl3, TMS) δ: 2.76 (dd, 1H, J= 12.75, 5.5), 2.45-2.64 (m, 2H),
2.20-2.45 (m, 6H), 2.09-2.22 (m, 2H), 1.85-2.07 (m, 2H), 1.70-1.82(m, 2H), 1.57-1.69 (m, 2H),
1.42-1.57 (m, 3H), 1.27-1.42 (m, 2H), 1.15 (s, 9H) ppm.; 13C NMR (62.5 MHz, CDCl3) δ: 168.5,
20
훼
[ ]
:
+42 (c
56.7, 53.6, 53.4, 47.0, 40.6, 32.0, 31.5, 27.0, 26.8, 24.2, 23.4, 23.2, 22.8, 20.9 ppm.;
퐷
1.2, CHCl3) Mass spectrum (EI, 70 eV), m/z (Irel, %): [М]+ 298 (10), 280 (4), 267 (5), 250 (3),
7

Page 8 of 21
214 (13), 186 (20), 149 (20), 127 (20), 111 (30), 98 (65), 84 (37), 57 (100), 41 (40); Elemental
analysis for C16H30N2SO: Calculated C 64.42, H 10.06, N 9.39, Found C 64.45, H 10.12, N
9.43%.
2.3. Preparations of (S)-N-((1R)-1-(2-chlorophenyl)-2-(piperidin-1-methyl)cyclohexyl)-2-
methylpropane-2-sulfinamide (3):
To a solution of containing 4.00 g (13.4 mmol) of product (2) in dry THF (25 mL) at −78 °C
under N2 was added dropwise a solution of 2-cholorophenylmagnesium bromid (8.60 g (40.2
mmol) in 50 mL ether) The mixture was stirred at −78 °C and then was warmed to room
temperature with stirring overnight. The reaction mixture was quenched by the addition of
saturated aqueous Na2SO4. The organic layer was removed, and the aqueous layer was extracted
twice with ether. The combined organic layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The products obtained 3 were purified either by silica gel
chromatography.
yellow liquid, (80%), Isolated yield = 0.104 g. IR (KBr): 3500, 3300, 3026, 2950, 2933, 2733,
1600, 1620, 1445, 1351, 1030, 984, 800, 780, 710, 500 cm-1.; 1H NMR (250 MHz, CDCl3, TMS)
δ: 7.53-7.56 (m, 1H), 7.37-7.40 (m, 1H), 7.16-7.19 (m, 1H), 7.06-7.11 (m, 1H), 5.48-5.49 (NH),
2.88 (dd, 1H, J= 12.75, 5.5), 2.54-2.76 (m, 2H), 2.36-2.54 (m, 2H), 2.28-2.36 (m, 1H), 2.13-2.28
(m, 2H), 1.91-2.13 (m, 3H), 1.71-1.90 (m, 4H), 1.43-1.70 (m, 4H), 1.29 -1.43 (m, 2H), 1.19-1.29
13
(m, 2H), 1.16 (s, 9H) ppm.; C NMR (62.5 MHz, CDCl3) δ: 133.0, 129.7, 128.0, 127.8, 127.3,
20
훼
[ ]
:
−53
121.6, 66.1, 57.1, 54.0, 47.4, 46.1, 41.2, 32.6, 27.4, 24.5, 24.0, 22.9, 22.3, 21.5 ppm.
퐷
(c 1.2, CHCl3) Mass spectrum (EI, 70 eV), m/z (Irel, %): [М]+ 410 (6), 377 (5), 363 (3), 341 (3),
326 (5), 289 (4), 238 (6), 180 (12), 139 (100), 120 (19), 111 (22), 105 (34), 69 (28), 55 (22);
8

Page 9 of 21
Elemental analysis for C22H35N2SOCl: Calculated C 64.39, H 8.53, N 6.83, Found C 64.56, H
8.71, N 6.91%.
2.4. Preparations of 1-(((2R)-2-(((S)-tert-butylsulfinyl)(methyl)amino)-2-(2-chlorophenyl)
cyclohexyl)methyl)-1-methylpiperidin-1-ium (4):
2.00 g (4.9 mmol) of product (3) in 20 mL acetone was homogenized at room temperature. Then,
K2CO3 (2.00 g (14.4 mmol)) was added and the flask was refluxed for 2 h. The solution was
stirred, and methyl iodide (1.5 g (10.5 mmol)) was added dropwise over 30 min. After the
addition was completed, the mixture was stirred for 1.5 h. The mixture was filtered and
concentrated under reduced pressure. The oil obtained was extracted twice with 25 mL n-hexane.
The combined organic layers were washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The product obtained was purified either by silica gel chromatography.
yellow oil, (70%), Isolated yield = 0.129 g. IR (KBr): 3300, 2900, 2800, 2750, 1620, 1600, 1490,
1
1351, 1030, 984, 800, 780, 710, 500 cm-1.; H NMR (250 MHz, CDCl3, TMS) δ: 7.67-7.7 (m,
1H), 7.53-7.58 (m, 1H), 7.35-7.41 (m, 1H), 3.40 (s, 3H), 2.76 (dd, 1H, J= 12.75, 5.5), 2.44-2.64
(m, 2H), 2.17 (s, 3H), 2.07-2.15 (m, 2H), 1.96-2.07 (m, 2H), 1.51-1.96 (m, 12H), 1.37-1.53 (m,
2H), 1.24 (s, 9H) ppm.; 13C NMR (62.5 MHz, CDCl3) δ: 133.7, 130.3, 128.3, 127.8, 122.3, 68.0,
20
훼
[ ]
:
−64 (c 1.2,
67.2, 66.9, 63.0, 52.2, 38.6, 33.1, 30.2, 29.6, 28.8, 23.3, 22.8, 22.0, 20.3 ppm.
퐷
CHCl3) Mass spectrum (EI, 70 eV), m/z (Irel, %): [М]+ 439 (3), 424 (4), 410 (5), 393 (4), 377
(6), 341 (4), 326 (3), 305 (5), 205 (3), 139 (100), 111 (22), 105 (34), 69 (22), 55 (20); Elemental
analysis for C24H40N2SOCl: Calculated C 65.6, H 9.11, N 6.38, Found C 65.74, H 9.23, N
6.42%.
9

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2.5. Preparations of (S)-N-((R)-1-(2-chlorophenyl)-2-methylenecyclohexyl)-N, 2-
dimethylpropane-2-sulfinamide (5):
1.50 g (3.4 mmol) of quaternary salt (4) was dissolved in 25 mL mixture of water and methanol.
The volume ratio was as follows: 1 to 9 respectively. Next, the NaHCO3 (0.70 g (8.3 mmol))
was added and then was stirred for 15 min. Then solution was refluxed for 3h at 80 °C. The oil
obtained was extracted twice with 25 mL n-hexane. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated under reduced pressure. The product obtained
was purified either by silica gel chromatography.
Yellow liquid, (90%). Isolated yield = 0.052 g. IR (KBr): 3350, 3100, 2900, 2820, 1620, 1600,
1406, 1175, 760, 680, 500 cm-1.; 1H NMR (250 MHz, CDCl3, TMS) δ: 7.68-7.70 (m, 1H), 7.53-
7.58 (m, 1H) 7.36-7.41 (m, 1H), 4.84 (s, 1H), 4.78 (s, 1 H), 2.20-2.61 (m, 1H), 2.47 (m, 3H),
13
2.09 (s, 3H), 1.82-2.04 (m, 2H), 1.49-1.81 (m, 3H), 1.31-1.57 (m, 2H), 1.23 (s, 9H) ppm.; C
NMR (125.75 MHz, CDCl3) δ: 156.7, 130.0, 129.6, 129.2, 128.9, 127.7, 126.0, 107.9, 67.6, 56.3,
20
훼
[ ]
:
−55 (c 1.2, CHCl3) Mass spectrum (EI, 70
34.3, 31.3, 28.8, 29.1, 23.9, 22.9, 22.2 ppm.
퐷
eV), m/z (Irel, %): [М]+ 339 (7), 324 (4), 309 (3), 293 (15), 279 (9), 256 (6), 277 (9), 222 (27),
209 (12), 186 (24), 167 (30), 149 (100), 139 (45), 127 (30), 111 (45), 85 (76), 57 (67); Elemental
analysis for C18H26NSOCl: Calculated C 49.20, H 5.92, N 3.19, Found C 49.63, H 6.03, N
3.32%.
2.6. Preparations of (R)-1-(2-chlorophenyl)-N-methyl-2-methylenecyclohexan-1-amine (6):
1.00 g (2.9 mmol) of alkene obtained (5) and MeOH (20 mL) were mixtured and aq HCl 36%
(3.5 mL) was added. The reaction was stirred at 70 °C for 5 h, during which the cleavage was
monitored by TLC. Volatiles were removed under reduced pressure. Then, reaction mixture was
10

Page 11 of 21
cooled to 25 °C and was added 10 mL saturated aqueous Na2SO4. Next, the many drop NH3 was
added (to pH= 6). The amine obtained was extracted twice with 25 mL EtOAc and concentrated
to pale liquid. The combined organic layers were washed with brine and dried (Na2SO4).
Concentration under reduced pressure gave a residue, which was purified by flash
chromatography to afford the corresponding amine.
Colorless liquid (80%), Isolated yield = 0.034 g. IR (KBr): 3500, 2750, 1920, 1700, 1600, 1406,
1
1195, 680 cm-1.; H NMR (250 MHz, CDCl3, TMS) δ: 7.16-7.52 (m, 4H), 4.86 (s, 1H), 4.61 (s,
1H), 3.27 (NH), 2.46-2.67 (m, 3H), 2.37 (s, 3H), 1.90-2.2 (m, 2H), 1.60-1.87 (m, 3H) ppm.; 13C
NMR (125.75 MHz, CDCl3) δ: 157.1, 132.8, 130.7, 129.9, 128.1, 127.2, 126.3, 108.2, 63.8, 40.8,
20
훼
[ ]
:
−49 (c 1.2, CHCl3) Mass spectrum (EI, 70 eV), m/z (Irel, %):
32.2, 29.8, 28.4, 18.0 ppm.
퐷
[М]+ 235 (6), 220 (12), 206 (18), 193 (15), 175 (18), 164 (12), 152 (9), 140 (15), 124 (18), 111
(21), 98 (100), 94 (15), 84 (24), 67 (18), 55 (21), 41 (15); Elemental analysis for C14H18NCl:
Calculated C 71.48, H 7.65, N 5.95, Found C 71.56, H 7.74, N 6.01%.
2.7. Preparations of (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone ((S)-ketamine)
(7):
Amine (6) (0.30 g (1.3 mmol)) was dissolved in 10% HCl solution (8 mL). Concentration under
reduced pressure gave the corresponding amine HCl salt. Ozone was passed into a solution of the
amine HCl salt in MeOH (20 mL) at −78 °C, terminating the ozonolysis upon observing the
distinctive blue color of ozone. After purging with nitrogen, dimethyl sulfide (1600 μL) was
added at −78 °C. The solution was allowed to warm up to room temperature and concentrated
under reduced pressure to give the crude material, which was dissolved in EtOH (6 mL). When
n-hexane was added, the HCl salt of (S)-ketamine was immediately crystallized. Finally, the salt
11

Page 12 of 21
was again dissolved in a 10% NaOH solution (12 mL) and the corresponding amine was
extracted with ether (30 mL). After evaporation of solvent, the amine was purified by flash
chromatography (50% EtOAc/n-hexane) to afford (S)-ketamine. The enantiomeric excess was
determined by HPLC analysis (DAICEL CHIRALCEL OD-H column).
Colorless crystals; (75%), Isolated yield = 0.032 g. Mp 122 °C. IR (KBr): 2960, 2500, 2420,
1728, 1560, 1440, 1380, 1100, 960, 775, 700, 580 cm-1.; 1H NMR (CDCl3) δ: 7.62-7.82 (1H, m),
7.41-7.62 (1H, m), 7.32-7.41 (1H, m), 7.21-7.32 (1H, m), 2.76–2.84 (1H, m), 2.44–2.55 (2H, m),
2.11 (3H, s), 2.06–2.15 (1H, m), 1.96–2.05 (1H, m), 1.82–1.90 (1H, m), 1.72–1.78 (3H, m) ppm.;
13C NMR (CDCl3) δ: 209.0, 137.5, 133.8, 131.2, 129.5, 128.8, 126.7, 70.2, 39.4, 38.6, 29.1, 28.1,
20
ο
21
훼
:
−43.2 (c 1.2, EtOH); ee = 75% by HPLC analysis (DAICEL
[ ] 퐷
21.8 ppm.; Mp: 122 C;
CHIRALCEL OD-H column). Mass spectrum (EI, 70 eV), m/z (Irel, %): [М]+ 237 (12), 222 (27),
186 (23), 167 (29), 149 (100); Elemental analysis for C13H16NOCl: Calculated C 65.82, H 6.75,
N 5.90, Found C 65.98, H 6.86, N 5.99%.
3. Results and Discussion
In the present study, we prepared 2-(N-piperidino methyl) cyclohexanone (1) by the reaction of
cyclohexanone with formaldehyde and piperidine hydrochloride. In the classical Mannich
procedures to β-aminoketones, yields are sometimes low because observed side reactions, such
as deamination, occur under the reaction conditions. The rate of deamination should be inversely
proportional to the basicity of the amine leaving group.22,23 It was provided from the amine
tertiary (3) by reaction with methyl iodide according to the procedure of Edwards et al.24 On the
other hand, the reaction condition was focused on the using of N-tert-butylsulfonamide with
12

Page 13 of 21
Mannich base to afford sulfinylimine (2) in the presence of Ti(OEt)4 with THF as solvent at 60
◦C. The reaction emerged smoothly, giving the obtained sulfinyliminein 85% yield after 3 h
(Table 1, entry 1). Also, in this investigation, some titanium-(IV) salts were searched, mainly to
effect the condensation of sulfinamide with the ketone. Due to their Lewis acidity and excellent
water-scavenging ability, Ti(IV) salts such as Ti(OEt)4 and Ti(O-i-Pr)4 have been used to
condense amines with ketones.19 At experiments, Ti(O-i-Pr)4 was moderately effective (Table 1,
entries 5-7). Fortunately, Ti(OEt)4 was found to be more efficient than Ti(O-i-Pr)4 without
promotion of the aldol condensation side reaction. An 85% yield was provided.
Based on prior studies on the synthesis of imines,25,26 the thermal stability of the sulfinylketimine
products appears to be correlated to the steric demand about the ketones that require more
compelling conditions to condense deliver imine products that do not hydrolyze observably
under these conditions. Although some tert-butanesulfinylimines decompose very slowly in air,
they were stored dry at low temperatures (−4 °C) for extended periods of time. But, sulfinylimine
(2) (derived from cyclohexanone) will fully hydrolyze over the course of 3 days in air. The
relative stabilities of the tert-butanesulfinylimines to silica chromatography relate to the rates of
hydrolysis in air. However, the sulfinylimine (2) not could be quickly chromatographed with n-
hexane/Et2O as eluent. Also, steric effects control the E/Z isomer ratios observed for
sulfinylimines. The E isomer is only observed by NMR (250 MHz) in CDCl3. Optimizing the
reaction conditions was then carried out to ameliorate the yield of the reaction. The investigation
of various solvents was shown in Table 1, and THF was found to be the best choice. The
showing of the reaction time displayed that this transformation could complete in 3 h (entry 1),
and extending reaction time resulted in a decrease in both yield (entries 3 and 7). Next, we
evaluated Grignard reagent addition to N-sulfinylimine derived from Mannich base. In order,
13

Page 14 of 21
optimizing the reaction conditions was then carried out to ameliorate both the yields and the
diastereoselectivities of the reaction (Table 2).
The temperature was found to be important for this reaction. Elevating reaction temperature
caused a significant improve in the yields (up to 90%), but brought dramatic decrease in
diastereoselectivities (entries 3, 4). As shown in Scheme 3, a six-membered cyclic transition state
with Mg coordinated to the oxygen of the sulfinyl group is consistent with the sense of
induction.26
In this model, Grignard reagent ideally added to the imine from the less hindered face to afford
(Ss , R) as major diastereomer (Scheme 3). Also, the proposed cyclic transition state is consistent
with the reaction proceeding with highest selectivities in noncoordinating solvents. Notably, the
best diastereoselectivity (95 : 5 dr) was obtained with CH2Cl2 as noncoordinating solvent, but
along with really lower yield (65%, entry 6). The selectivity observed for Grignard reagent is
also noteworthy, considering that transformation is performed in the coordinating solvent THF.
Therefore, the best conditions for the Grignard reaction was obtained in THF as solvent (entry 1,
Table 2). In this model, Grignard reagent ideally added to the imine from the less hampered face
to afford (Ss , S) as major diastereomer (Scheme 3). The N-tert-butylsulfinyl group can present as
not only an effective chiral auxiliary for the asymmetric synthesis of ketamine, but also an amine
protecting group. The diastereoselectivity of the reaction should be determined by both
equatorial attack upon the low-energy chair conformation and the stereochemistry of the sulfinyl
group. However, the selectivity for additions to our cyclic imine should be dependent on the
steric properties of the ring substituent located C2 and the aryl substituent. In this procedure,
after three steps (methylation, deamination and deprotection), we was obtained the chiral
14

Page 15 of 21
compound (6). Finally, by oxidation step was provided a nitrogen-substituted quaternary carbon
bearing α-carbonyl group ((S)-ketamine).
4. Conclusions
In summary, the asymmetric synthesis of anesthetic (S)-ketamine was a very difficult challenge.
We have presented a novel procedure for the synthesis of (S)-ketamine as antagonist of blocking
the NMDA receptor. In this paper, we have proved a straightforward procedure for the
construction of a chiral nitrogen-substituted carbon using an enantioselective 1,2-addition
reaction of 2-cholorophenyl magnesium bromide to chiral α- N-sulfinylimine-Mannich base, 2,
having α-chiral sulfinylimine auxiliary. We have confirmed that use of (S)-tert-
butanesulfinamide is advantageous in strategy because the tert-butanesulfinyl group actuates the
imine for nucleophilic addition and provides as a potent chiral directing group. We speculate that
the diastereoselectivity of the reaction may be determined by both equatorial attack upon the
low-energy chair conformation and the stereochemistry of the sulfinyl group. After deprotection,
the approach served the chiral compound with a nitrogen-substituted quaternary carbon bearing
α-carbonyl group. Thus, the asymmetric synthesis of (S)-ketamine, was accomplished with good
selectivity (>75% ee).
5. Acknowledgements
The authors would like to thank the kind referee(s) for the positive suggestions which have
greatly improved the present text. And the author gratefully acknowledges the financial support
of this work by the Research Affairs Office of the Imam Hossein University, Babaee Branch,
Tehran, I. R. Iran.
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Page 16 of 21
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Table 1. Condensations of TBSA with compound (1) mediated by Ti(IV) compounds
Entry
Lewis acida
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Ti(OEt)4
Ti(OEt)4
THF
THF
3
12
24
3
85
85
70
75
65
65
60
60
Ti(OEt)4
THF
Ti(OEt)4
THF
Ti(OEt)4
Toluene
THF
3
Ti(O-i-Pr)4
Ti(O-i-Pr)4
Ti(O-i-Pr)4
12
24
3
THF
Toluene
a) Mol ratio of Lewis acid to monoketal, 2 to 1 b) Yield determined by NMR analysis.
Table 2. Optimization of addition of Grignard reagent to N-tert-butanesulfinylimine (2)
Solvent
Entry
T/°C
Time (h)
Yield (%)a
dr (S: R) b
1
2
3
4
5
6
7
8
9
THF
THF
15
15
15
15
24
24
15
24
15
80
87
90
94
85
65
67
67
75
90:10
80:20
75:25
68:32
90:10
95:5
−78
−50
0
THF
THF
25
THF
−78
−78
−78
−78
−50
CH2Cl2
Toluene
Toluene
Toluene
80:20
73:27
70:30
Isolated yield of diastereomerically and analytically pure material after chromatography. a) Yield determined by NMR analysis. b) Diastereomeric
ratio was determined by chiral HPLC assay.
19

Page 20 of 21
O
Cl
S
NH2
S
O
O
N
O
MgBr
S
CH2O
HN
Cl
N
O
N
H
N
N
Ti(OEt)4
CH3COOH
-78 C
3
1
2
K2CO3
MeI
Cl
Cl
Cl
Cl
O
S
N
O
S
H
H
NaHCO3
HCl
N
N
N
O3, Me2S
-78C
O
N
6
7
4
5
Scheme 1. Asymmetric synthesis of (S)-ketamine
Cl
MgBr
HO
O
Cl
H+ (Conc)
Cl
Ether
H2 / Raney Ni
K2OsO4 (DHQD)PHAL
K2Fe(CN)6 , t-BuOH
(Sharpless Ox.)
Cl
Cl
Cl
H2N
HO
H2N
HO
O
HO
PCC
(Jonse Ox.)
MeCN
(Ritter Rea.)
Scheme 2. Asymmetric synthesis of (S)-norketamine
20

Page 21 of 21
PhMgBr
THF
R
S
S
S
t-Bu
N
N
N
M
H
R
O
Ph
O
Ph
O
R
Scheme 3. Intermediates of nucleophilic addition to N-sulfinylimine
21