Efficient synthesis of a new series of piperidine ring-modified alcohol and methyl ether analogs of (±)-threomethyl phenyl(piperidin-2-yl)acetate

Article abstract of DOI:10.1080/00397911.2011.569681

(Chemical Equation Presented) A series of novel piperidine ring-modified alcohol and methyl ether analogs of (±)-threo-methyl phenyl(piperidin-2- yl)acetate was synthesized. This series of methyl phenyl(piperidin-2-yl)acetate analogs was developed by piperidine ring alkylation and/or acylation followed by lithium aluminum hydride reduction to give alcohol derivatives. Methylation of the alcohol analogs by extension of standard literature procedures gave the corresponding methyl ether derivatives. The chemical structure of these compounds was established based on mass and ¹H NMR spectral data and CHN elemental analysis data. Several significant modifications to the literature methodologies made the reaction more efficient, and good yields were generally obtained. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.569681

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Efficient Synthesis of a New Series of
Piperidine Ring–Modified Alcohol and
Methyl Ether Analogs of (±)-threo-Methyl
Phenyl(piperidin-2-yl)acetate
Babatunde Ojo a
a Department of Chemistry, Fort Valley State University, Fort Valley,
Georgia, USA
Available online: 17 Nov 2011
To cite this article: Babatunde Ojo (2012): Efficient Synthesis of a New Series of Piperidine
Ring–Modified Alcohol and Methyl Ether Analogs of (±)-threo-Methyl Phenyl(piperidin-2-yl)acetate,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:19, 2818-2830
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Synthetic Communications1, 42: 2818–2830, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.569681
EFFICIENT SYNTHESIS OF A NEW SERIES OF
PIPERIDINE RING–MODIFIED ALCOHOL AND
METHYL ETHER ANALOGS OF (ꢀ)-THREO-
METHYL PHENYL(PIPERIDIN-2-YL)ACETATE
Babatunde Ojo
Department of Chemistry, Fort Valley State University, Fort Valley,
Georgia, USA
GRAPHICAL ABSTRACT
Abstract A series of novel piperidine ring–modified alcohol and methyl ether analogs of
(ꢀ)-threo-methyl phenyl(piperidin-2-yl)acetate was synthesized. This series of methyl
phenyl(piperidin-2-yl)acetate analogs was developed by piperidine ring alkylation and/or
acylation followed by lithium aluminum hydride reduction to give alcohol derivatives.
Methylation of the alcohol analogs by extension of standard literature procedures gave
the corresponding methyl ether derivatives. The chemical structure of these compounds
was established based on mass and 1H NMR spectral data and CHN elemental analysis
data. Several significant modifications to the literature methodologies made the reaction
more efficient, and good yields were generally obtained.
Keywords Lithium aluminum hydride reduction; methylation; methyl phenyl(piperidin-
2-yl)acetate; ritalinol
Received December 14, 2010.
Address correspondence to Babatunde Ojo, Department of Chemistry, Fort Valley State
University, 1005 State University Drive, Fort Valley, GA 31030, USA. E-mail: ojob@fvsu.edu
2818

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2819
INTRODUCTION
Methyl phenyl(piperidine-2-yl)acetate (ritalin) has high potential for abuse and
addiction because of its pharmacological similarity to cocaine and amphetamines.
Cocaine-like effects can occur with very large doses taken orally. In both animals
and humans, cocaine is one of the most reinforcing drugs known; hence it has great
abuse potential. The abuse of cocaine (and other stimulant drugs) is of greatest
concern to society today and has therefore become a focus of medical, social, and
political leaders. Methyl phenyl(piperidin-2-yl)acetate was first synthesized in 1944
by Panizzon[1] and was identified as a stimulant in 1954.[2] A review of the synthesis
of commercially pure (‘‘R, 2’R)-(þ)-threo-methyl phenyl(piperidin-2-yl)acetate
hydrochloride has been published.[3] The original method of Pannizzon[1] for the syn-
thesis of methyl phenyl(piperidin-2-yl)acetate often gave mixtures of products that
may require tedious chromatographic separations, resulting generally in a very poor
yield. A detailed review of piperidine analogs of cocaine, tropanes, and GBR 12935
compounds has been reported in the literature.[4,5] Furthermore, the synthesis of
piperidine ring–modified analogs of methylphenidate has been reported in the litera-
ture.[5,6] These analogs basically involve the replacement of the piperidine ring with
other secondary amines with five-, seven-, ꢀ and eight-membered rings.
Over the past several years, the chemical synthesis of a series of (ꢀ)-threo-
methyl phenyl(piperidin-2-yl)acetate analogs has been reported,[4–14] but there are
not many reports on piperidine ring–modified analogs synthesis with methyl phenyl
(piperidine-2-yl)acetate as the starting point for the syntheses. In continuation of
our drug development program, we have recently reported the chemical synthesis
of a new series of piperidine ring–modified (ꢀ)-threo-methyl phenyl(piperidin-2-yl)
acetate analogs from methyl phenyl(piperidine-2-yl)acetate.[15] In continuation of
our drug development efforts, we embarked on bioisosteric modification of the
methyl ester moiety of methyl phenyl (piperidine-2-yl) acetate. The rationale for this
study is to synthesize a new series of piperidine ring–modified alcohol and methyl
ether analogs of (ꢀ)-threo-methyl phenyl(piperidin-2-yl)acetate by making several
significant modifications to existing literature methodologies[16] to make the reaction
more efficient and hence produce compounds with improved yields. Compounds 1a
(99%), 1c (93%), 1d (100%), 2a (99.4%), and 2d (86%) previously have been reported
in the literature.[14b] In our laboratory, the syntheses of these analogs were carried by
an extension of literature procedure to complete the series of compounds for SAR stu-
dies of the effect of both ester moiety and piperidine ring modifications on biological
activity of these classes of compounds. In particular, compounds 1a and 1c were
synthesized in our laboratory in better yields (100% and 98%, respectively), whereas
compound 1d (100%) was obtained in a comparable yield to that described in the lit-
erature.[14b] For the ritalinol methyl ether series, a different synthetic strategy was uti-
lized in our laboratory that resulted in a slightly better yield for compounds 2a (100%)
and 2d (93%) than those reported in the literature.[14b] Furthermore, these compounds
should be useful in the synthesis of novel ligands for testing as pharmaceutical agents.
We report the efficient synthesis of several new piperidine ring–modified alcohol and
methyl ether analogs of methyl phenyl(piperidin-2-yl)acetate.
The synthesis of methyl phenyl(piperidin-2-yl)acetate has previously been
described in the literature, based on the alkylation of 2-bromopyridine with various

2820
B. OJO
phenylacetonitrile anions. The original method developed by Panizzon[1] was
modified in a previous report.[14] The chemical synthesis of several piperidine ring–
modified analogs of methyl phenyl(piperidin-2-yl)acetate has recently been
reported.[15] Acylation of amine with acid chloride produced the amide, which upon
reduction with lithium aluminum hydride in anhydrous solvents gave the corre-
sponding alcohols generally in excellent yield. The effect of reaction solvents is a very
important factor in regulating the reactivity. Methylation was not observed in tolu-
ene, tetrahydrofuran, and dioxane alone but proceeded efficiently in a mixture of
polar aprotic solvents with nonpolar solvents. In this study, the aprotic polar sol-
vents were dimethyl formanide (DMF), dimethyl sulfoxide (DMSO), or a mixture
of these and nonpolar solvents, such as hexane. Also, it was observed that the
optimum condition was a 1:1 mixture of polar aprotic solvents with nonpolar
solvents in the presence of methyl iodide as the alkylating agent and powdered
potassium hydroxide as the base at a temperature of 0–5 ꢁC. A summary of this
method is described in Scheme 1.
Scheme 1. General scheme for synthesis of ritalinol and ritalinol methyl ether analogs.

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2821
Reagents and conditions: (a) sodium carbonate, methylene chloride; (b) pow-
dered potassium carbonate, benzyl bromide, acetone, potassium iodide, room tem-
perature, overnight; (c) lithium aluminum hydride (LAH), anhydrous diethyl
ether; and (d) DMSO–DMF (1:1), hexane, powdered potassium hydroxide, methyl
iodide, room temperature, 12 h.
Table 1. Physical and analytical data of alcohol and methyl ether analogs of methyl phenyl(piperidin-2-
yl)acetate
Molecular
formula
(M)
Elemental analysis (%) (calc.=found)
Yield
(%)
Compound
n
R
Mp (ꢁC)
108–110
C
H
N
1a
—
H
H
100
98
C13H19NO
(205.286)
76.06
75.83
76.67
76.98
77.21
76.89
81.32
81.52
81.51
81.64
81.69
81.49
81.86
81.61
76.67
76.58
77.21
77.30
77.69
77.50
81.51
81.20
81.69
81.36
81.86
81.73
82.01
82.21
9.33
9.53
9.65
9.81
9.93
9.74
8.53
8.63
8.79
8.67
9.04
9.13
9.26
9.41
9.65
9.62
9.93
9.86
10.19
10.28
8.79
8.89
9.04
9.19
9.26
9.17
9.46
9.32
6.82
6.65
6.39
6.22
6.00
6.18
4.74
4.58
4.53
4.64
4.33
4.25
4.15
4.06
6.39
6.44
6.00
6.12
5.66
5.44
4.53
4.62
4.33
4.53
4.15
4.28
3.98
4.01
1b
1c
1d
1e
1f
—
—
1
115–117
113–114
105–106
121–122
124–125
130–132
154–155
159–160
162–164
227–229
232–234
239–241
244–245
C
14H21NO
(219.312)
C15H23NO
(233.338)
Ethyl
Phenyl
Phenyl
Phenyl
Phenyl
H
98
100
83
C20H25NO
(295.406)
C21H27NO
(309.432)
2
3
89
C22H29NO
(323.458)
C23H31NO
(337.484)
1g
2a
2b
2c
2d
2e
2f
4
88
—
—
—
1
100
89
C14H21NO
(219.312)
C15H23NO
(233.338)
H
Ethyl
Phenyl
Phenyl
Phenyl
Phenyl
89
C16H25NO
(247.364)
C21H27NO
(309.432)
C22H29NO
(323.458)
93
2
91
3
89
C23H31NO
(337.484)
2g
4
88
C24H33NO
(351.51)

2822
B. OJO
RESULTS AND DISCUSSION
The results of piperidine ring acylation followed by lithium aluminum
hydride reduction and subsequent methylation of methyl phenyl(piperidin-2-yl)
acetate in suitable solvents to give the corresponding alcohol and methyl ether ana-
logs are summarized in Table 1. These compounds were synthesized in good yields
(80% and above), and pure crystals of each compound were obtained. Several sol-
vents were attempted for the alkylation process. When solvents such as DMF and
hexamethylphosphoramide (HMPA) were utilized in the alkylation process under a
nitrogen atmosphere, there was no trace of alkylation. Also, DMSO and ethanol
(EtOH) were employed under a nitrogen atmosphere, but both of these solvents
gave little traces of alkylation and the 1H NMR data was not consistent with
the expected structures for the alkylated product. Furthermore, when ethanol
was used as the solvent for the alkylation reaction, it resulted in a trans-esterifi-
cation product with little trace of alkylation. In general, acetone, methanol, and
methylene chloride were found to be the best solvents because the products were
obtained in relatively pure form (single spot on TLC). Furthermore, it was
observed that methylation of the alcohol with methyl iodide proceeded efficiently
in a mixture of polar aprotic solvents with nonpolar solvents (hexane). Several sol-
vent systems were attempted for the recrystallization process, but a mixture of
ethyl acetate and hexane was found to give the purest form of these compounds,
supported by spectral data. The chemical structure of these compounds was estab-
1
lished based on the mass and, H NMR spectral data. All compounds synthesized
in this study gave satisfactory elemental analysis data and were within ꢀ 0.4 of
calculated values.
Compounds synthesized and reported in this study are dl-threo-methyl
phenyl(piperidin-2-yl)acetate analogs, consistent with previous literature reports.
In continuation of our drug development efforts, we have recently embarked on
the resolution of this racemic mixture into individual pure d- and l-enantiomers
for pharmacological evaluation of biological activity; based on a previous report[17]
that only the d-enantiomers significantly potentiated the pressor responses to intra-
venous norepinephrine. An article based on the synthesis and biological activity of
these pure enantiomers is currently in progress.
CONCLUSION
In conclusion, a mixture of methyl phenyl(piperidin-2-yl)acetate, appropriate
acid chloride, and sodium carbonate in methylene chloride gave the amide intermedi-
ate, which upon reduction with lithium aluminum hydride (LAH) in anhydrous
diethyl ether gave the corresponding alcohol derivatives. The alcohol was reacted
with methyl iodide and powdered potassium hydroxide in a mixture of polar aprotic
solvents (DMSO–DMF in a 1:1 ratio) with nonpolar solvent (hexane) at a tempera-
ture of 0–5 ꢁC to provide the corresponding methyl ether analogs. An aqueous
workup procedure gave the desired target compounds in good yield. This may serve
as an excellent synthetic methodology for efficient syntheses of several new piperi-
dine ring–modified alcohol and methyl ether analogs of methyl phenyl(piperidin-2-
yl)acetate in good yields.

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2823
EXPERIMENTAL
Compounds were synthesized utilizing reagents commercially available from
Aldrich Chemical Co. and Fisher Scientific without further purification. Melting
points were determined in open capillary tubes on a Meltemp melting-point appar-
1
atus and are uncorrected. H NMR spectra were recorded with a Bruker Avance
(AV) 400 spectrometer at 400 MHz. Chemical shifts are quoted in parts per million
from internal standard tetramethylsilane (TMS). All solvents and chemicals were of
research grade and were obtained from Merck and Lancaster. The progress of the
reaction was monitored by thin-layer chromatography (TLC). Mass spectra were
obtained using a Micromass LCT mass spectrometer operating at 20 eV. Elemental
analyses were performed on a Perkin-Elmer 2400 CHN analyzer instrument and
were within ꢀ0.4 of calculated values.
General Methods for the Synthesis of Amide Intermediates
Method A. A solution of (ꢀ)-threo methyl phenyl(piperidine-2-yl)acetate
(0.30 g, 0.13 mmol) in dry CH2Cl2 (15 mL) was charged with anhydrous MgSO4
(2 g) and anhydrous Na2CO3 (2 g). The suspension was vigorously stirred for
15 min before a solution of appropriate aromatic acid chloride (0.32 mL, 0.24 mol)
in dry CH2Cl2 (10 mL) was added drop by drop over 5 min at room temperature.
The suspension was stirred for 30 min and filtered. A standard acid–base workup
procedure was employed in the isolation of the crude product: The organic layer
was washed successively with 1.5 M HCl (100 mL) and (25% brine (100 mL) and dried
over anhydrous MgSO4. The residue obtained after removal of solvents was recrystal-
lized in a minimum amount of hot methanol provided 0.58 g (91.5%) of the corre-
sponding amide derivatives as a white solid.
Method B. A mixture of (ꢀ)-threo methyl phenyl(piperidine-2-yl)acetate
(1.0 g, 4.29 mmol), acetic anhydride (1.38 mL, 14.58 mmol), and anhydrous potassium
acetate (0.421 g, 4.29 mmol) in methylene chloride (20 mL) was stirred at room tem-
perature for 22 h and filtered through a small bed of silica inside a pipette. A standard
aqueous dilute hydrochloric acid workup procedure was employed to quench this
reaction at the end of reaction (based on TLC examination), followed by the addition
of ethyl acetate (10 mL). The resulting mixture was rinsed with a minimum volume of
water, and the organic layer was separated and dried (MgSO4). Removal of solvents
in vacuo provided 1.20 g (91%) of the crude amide as a white solid.
(ꢀ)-threo-N-Methyl Methyl Phenyl(piperidine-2-yl)acetate[15]
A
solution of (ꢀ)-threo methyl phenyl(piperidine-2-yl)acetate (230 mg,
0.99 mmol) in methanol (20 mL) was treated with 0.37% formaldehyde solution
(0.095 mL, 1.28 mmol) and allowed to stand at room temperature for 20 min. Meth-
anol (5 mL), acetic acid (0.03 mL), and 5% Pd=C (45 mg) were then added. The result-
ing mixture was treated with hydrogen gas at 35 psi for 1.5 h at room temperature.
The mixture was filtered, and the filtrate and the washings were evaporated in vacuo.
The residue was mixed with water (5 mL), made basic with 15% NaOH solution, and
extracted with EtOAc (3 ꢂ 100 mL). The extracts were combined, washed with water,

2824
B. OJO
dried with magnesium sulfate, and evaporated in vacuo. The residue was chromato-
graphed on 5 g of silica gel using 5% MeOH in chloroform to give a yellow residue.
The hydrochloride salt was obtained by addition of 1 M HCl in ether to a methanol
solution of the residue, evaporation of solvents to dryness in vacuo, and recrystalliza-
1
tion (EtOAc–Hexane), providing 190 mg (80%) of 1 as a yellow viscous liquid; H
NMR (CDCl3): d 1.1–1.6 (m, 6H), 2.40 (s, 3H, CH2), 2.90–2.98 (m, 1H), 2.42–2.59
(m, 1H), 3.08–3.10 (m, 1H), 3.62 (s, 3H, OCH3), 3.88 (d, 1H), 7.2–7.4 (m, 5H, aro-
matic) ppm; MS-CI m=z 248.160 calcd. for C15H22NO2 (MHþ) 248.165. Anal. calcd.
for C15H21NO2: C, 72.87; H, 8.56; N, 5.67. Found: C, 72.85; H, 8.55; N, 5.68.
(ꢀ)-threo-N-Benzyl Methyl Phenyl(piperidine-2-yl)acetate[15]
A
mixture of (ꢀ)-threo methyl phenyl(piperidine-2-yl)acetate (100 mg,
0.40 mmol), powered potassium carbonate (250 mg), and benzyl bromide (70 mg,
0.46 mmol) in acetone (20 mL) was stirred overnight at room temperature. The mix-
ture was filtered, and the filtrate and the washings were evaporated in vacuo. The
residue was chromatographed on 5 g of silica gel using 5% MeOH in chloroform
to give pure (TLC, one spot RF ¼ 0.42) 115 mg (85%) of 1 as a white solid: mp
69–71 ꢁC. The hydrochloride salt was obtained by addition of 1 M HCl in ether to
a methanol solution of the residue, evaporation of solvents to dryness in vacuo,
and recrystallization (EtOAc–hexane), providing 128 mg (87%) of 1 as white solid:
1
mp 169–170 ꢁC; H NMR (CDCl3), d 1.1–1.6 (m, 6H, J ¼ 13.4 Hz), 3.97 (d, 1H,
J ¼ 13.2), 4.2 (d, 1H, J ¼ 10.4 Hz), 7.2–7.4 (m, 10H, aromatic-H) ppm; MS-CI m=z
324.20 calcd. for C21H26NO2 (MHþ). Anal. calcd. for C21H26NO2: C, 78.03; H,
7.80; N, 4.32. Found: C, 78.01; H, 7.81; N, 4.31.
(ꢀ)-threo-Ritalinol (1a)
Methyl phenyl(piperidine-2-yl)acetate (1.0 g, 4.29 mmol) was dissolved in anhy-
drous Et2O (15 mL) and cooled in an icebath for 15 min. A solution of LiAlH4 in ether
(1 M), 0.325 g, 8.57 mmol) was added via syringe under a nitrogen atmosphere and the
mixture was stirred in an icebath for an additional 5 min. The resulting mixture was
heated under reflux for 2 h, and then cooled in an icebath. Unreacted LiAlH4 was
quenched by careful drop by drop addition of water until gas evolution ceased.
The reaction flask was subsequently rinsed with water and ether. The ether layer
was separated, and the aqueous layer extracted with ethyl acetate (3 ꢂ 50 mL). The
ether=ethyl acetate extracts were combined, washed with water (2 ꢂ 50 mL), dried
(MgSO4), and evaporated in vacuo to give a residue (alternative standard quenching
method is by careful addition of base, e.g., 10% NaOH). The resulting solution was
filtered, and the residue was washed repeatedly with excess EtOAc. The ethyl acetate
extract was dried (Na2SO4), and removal of solvents in vacuo provided 0.635 g (98%)
of the free base, mp 96–98 ꢁC (lit.[14b] mp 95–97 ꢁC). The hydrochloride salt was
obtained by addition of 1 M HCl in ether to a methanol solution of the residue, evap-
oration of solvents to dryness in vacuo, and recrystallization (EtOAc–hexane), pro-
1
viding 0.792 g (100%) of 1a as a white crystal: mp 108–110 ꢁC; H NMR (CDCl3):
d 1.24–1.50 (m, 3H), 1.52–1.62 (m, 1H), 1.74–1.85 (m, 1H), 2.57–2.66 (m, 2H), 2.98
(q, 1H), 3.08–3.15 (m, 1H), 3.90 (dd, 1H), 4.0 (dd, 1H), 7.2–7.4 (m, 5H, aromatic-H)

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2825
ppm. MS-CI m=z 206.18; calcd. for C13H20NO (MHþ). Anal. calcd. for C13H19NO:
C, 76.06; H, 9.33; N, 6.82. Found: C, 75.83; H, 9.53; N, 6.65.
(ꢀ)-threo-N-Methyl Ritalinol (1b)
N-Methyl methyl phenyl(piperidine-2-yl)acetate (1.0 g, 4.04 mmol) was dis-
solved in anhydrous Et2O (15 mL) and cooled in an icebath for 15 min. The mixture
was reduced with LiAlH4 in ether (1 M, 0.306 g, 8.09 mmol) by a method virtually
identical to that used to synthesize 1a. The ether layer was dried (MgSO4), and evap-
oration of solvents in vacuo provided 0.635 g (96%) of 1b as a white solid, mp
100–101 ꢁC. The hydrochloride salt was obtained by addition of 1 M HCl in ether
to a methanol solution of the residue, and evaporation of solvents to dryness in
vacuo and recrystallization (EtOAc–hexane) provided 0.680 g (98%) of 1b as a white
crystal: mp 115–117 ꢁC; 1H NMR (CDCl3): d 1.25–1.50 (m, 3H), 1.52–1.65 (m, 1H),
1.74ꢃ1.85 (m, 1H), 2.40 (s, 3H, CH3), 2.57–2.66 (m, 2H), 2.98 (q, 1H), 3.08–3.15 (m,
1H), 3.90 (dd, 1H), 4.0 (dd, 1H), 7.2–7.4 (m, 5H, aromatic-H) ppm; MS-CI m=z
221.20, calcd. for C14H22NO (MHþ). Anal. calcd. for C14H21NO: C, 76.67; H,
9.65; N, 6.39. Found: C, 76.98; H, 9.81; N, 6.22.
(ꢀ)-threo-N-Ethyl Ritalinol (1c)
Methyl phenyl(piperidine-2-yl)acetate (0.60 g, 2.57 mmol) was reacted with
acetic anhydride (0.82 mL, 8.74 mmol) and potassium acetate (0.252 g, 2.57 mmol),
utilizing general method B to provide 0.75 g (90.5%) of the crude amide as white solid.
The amide (0.50 g, 1.82 mmol) was dissolved in anhydrous THF (15 mL), and the
resulting mixture was reduced with LiAlH4 (0.138 g, 3.65 mmol) by a method virtually
identical to that used to synthesize 1a. The ether layer was dried (MgSO4), and evap-
oration of solvents in vacuo provided 0.85 g (98%) of 1c as a yellow viscous liquid.
The hydrochloride salt was obtained by addition of 1 M HCl in ether to a methanol
solution of the residue, and evaporation of solvents to dryness in vacuo and recrys-
tallization (EtOAc–hexane) provided 0.964 g (98%) of 1c as a white solid: mp
1
113–114 ꢁC; H NMR (CDCl3): d 0.86–0.92 (m, 1H), 1.2 (t, 3H, J ¼ 7.25 Hz, CH3),
1.22–1.65 (m, 6H), 2.77 (d, 1H, J ¼ 13.78 Hz), 2.86 (q, 2H, J ¼ 7.22 Hz), 3.15–3.30
(m 2H), 3.43 (d, 1H, J ¼ 10.78, 3.35 Hz), 3.74 (dd, 1H, J ¼ 10.4, 3.35 Hz), 4.0 (t,
1H, J ¼ 10.4 Hz), 7.12–7.35 (m, 5H, aromatic-H) ppm; MS-EI m=z 234.20, calcd.
for C15H24NO (MHþ). Anal. calcd. for C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found:
C, 76.89; H, 9.74; N, 6.18.
(ꢀ)-threo-N-Benzyl Ritalinol (1d)
N-Benzyl methyl phenyl(piperidine-2-yl)acetate (1.0 g, 3.90 mmol) was dis-
solved in anhydrous Et2O (15 mL) and cooled in an ice bath for 15 min. The mixture
was reduced with LiAlH4 in ether (1 M) (0.235 g, 6.19 mmol) by a method virtually
identical to that used to synthesize 1a. The ether layer was dried (MgSO4), and evap-
oration of solvents in vacuo provided 0.932 g (99.9%) of 1d as a white solid, mp
77–78 ꢁC (lit.[14b] mp 76–77 ꢁC). The hydrochloride salt was obtained by addition
of 1 M HCl in ether to a methanol solution of the residue, and evaporation of

2826
B. OJO
solvents to dryness in vacuo and recrystallization (EtOAc-Hexane) provided 0.952 g
1
(100%) of 1d as a white solid: mp 105–106 ꢁC; H NMR (CDCl3): d 0.99–1.73 (m,
6H), 2.76 (m, 1H), 3.19–3.35 (m, 2H), 3.42–3.54 (m, 1H), 3.72 (dd, 1H, J ¼ 3.25,
11.02 Hz), 3.85 (t, 1H, J ¼ 11.02 Hz), 4.04 (s, 2H), 7.08 (d, 2H, J ¼ 8.15 Hz,
aromatic-H), 7.16–7.42 (m, 8H, aromatic-H) ppm; MS-CI m=z 296.19, calcd. for
C20H26NO (MHþ). Anal. calcd. for C20H25NO: C, 81.32; H, 8.53; N, 4.76. Found:
C, 81.52; H, 8.63; N, 4.58.
(ꢀ)-threo-N-Phenylethyl Ritalinol (1e)
The amide (0.50 g, 1.423 mmol) was reduced with LiAlH4 (0.108 g, 2.85 mmol)
by a method virtually identical to that used to synthesize 1a, with the exception that
the reaction was first carried out at room temperature for a period of 1 h and then
refluxed for an additional 3 h. In addition, an aqueous workup procedure was used
in the purification step. The hydrochloride salt was obtained by addition of 1 M HCl
in ether to a methanol solution of the residue, and evaporation of solvents to dryness
in vacuo and recrystallization (EtOAc–hexane) provided 0.142 g (83%) of 1e as a
1
white solid: mp 121–122 ꢁC; H NMR (CDCl3): 0.99–1.61 (m, 6H), 2.98 (t, 3H),
3.15 (t, 2H, N-CH2), 3.2 (d, 1H), 3.38 (t, 1H), 3.41 (t, 1H), 3.80 (dd, 1H), 4.0 (t,
1H), 7.10–7.38 (m, 10H, aromatic-H) ppm; MS-CI m=z 310.20, calcd. for
C21H28NO (MHþ). Anal. calcd. for C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found:
C, 81.64; H, 8.67; N, 4.64.
(ꢀ)-threo-N-Phenylpropyl Ritalinol (1f)
The amide (0.50 g, 1.368 mmol) was reduced with LiAlH4 (0.104 g, 2.74 mmol)
employing a method virtually identical to that use to synthesize 1a. The hydrochlor-
ide salt was obtained by addition of 1 M HCl in ether to a methanol solution of the
residue, and evaporation of solvents to dryness in vacuo and recrystallization
1
(EtOAc-hexane) provided 0.162 g (89%) of 1f as a white solid: mp 124–125 ꢁC; H
NMR (CDCl3): 0.99–1.62 (m, 6H), 1.08–1.81 (m, 2H), 2.75 (t, 3H), 2.81 (t, 2H,
N-CH2), 3.2 (d, 1H), 3.38 (t, 1H), 3.41 (t, 1H), 3.80 (dd, 1H) H), 4.0 (t, 1H),
7.12–7.38 (m, 10H, aromatic-H) ppm; MS-CI m=z 324.20, calcd. For C22H30NO
(MHþ). Anal. calcd. for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.49;
H, 9.13; N, 4.25.
(ꢀ)-threo-N-Phenylbutyl Ritalinol (1g)
The amide (0.50 g, 1.318 mmol) was reduced with LiAlH4 (0.100 g, 2.64 mmol)
by a method virtually identical to that used to synthesize 1a. The hydrochloride salt
was obtained by addition of 1 M HCl in ether to a methanol solution of the residue,
and evaporation of solvents to dryness in vacuo and recrystallization (EtOAc–
1
hexane) provided 0.176 g (88%) of 1g as a white solid: mp 130–132 ꢁC; H NMR
(CDCl3): 0.99–1.60 (m, 6H), 1.60–1.79 (m, 4H), 2.75 (t, 1H), 3.41 (t, 1H), 3.80
(dd, 1H), H), 4.0 (t, 1H), 7.11–7.37 (m, 10H, aromatic-H) ppm; MS-CI m=z
338.20, calcd. for C23H32NO (MHþ). Anal. calcd for C23H31NO: C, 81.86; H,
9.26; N, 4.15. Found: C, 81.61; H, 9.41; N, 4.06.

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2827
(ꢀ)-threo-Ritalinol Methyl Ether (2a)
(ꢀ)-threo-Ritalinol (0.250 g, 1.22 mmol) was dissolved in a mixture of DMSO,
DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to 0–5 ꢁC, powdered
potassium hydroxide (0.102 g, 1.83 mmol) and methyl iodide (0.242 g, 0.106 ml,
1.70 mmol) were added, and the reaction mixture was stirred for 12 h. The progress
of the reaction was monitored by TLC and high-performance liquid chromatography
(HPLC), which showed that up to 98–99% of the methylated product was formed.
After 12.0 h the organic hexane layer separated out, and the DMSO–DMF layer
was extracted with hexane (3 ꢂ 20 ml). Both hexane layers were combined and washed
with water to remove the inorganic salts. Removal of solvents in vacuo provided
0.258 g (HPLC purity 96%). The hydrochloride salt was obtained by addition of
anhydrous 1 M HCl in ether to a methanol solution of the residue, and evaporation
of solvents to dryness in vacuo and recrystallization (EtOAc–hexane) provided
1
0.280 g (100%) of 2a as a white crystal: mp 155–156 ꢁC (lit.[14b] mp 154–155 ꢁC); H
NMR (CDCl3): d 1.24–1.50 (m, 3H), 1.52–1.65 (m, 1H), 1.74–1.85 (m, 1H), 2.57–
2.66 (m, 2H), 2.98 (q, 1H), 3.08–3.15 (m, 1H), 3.24 (s, 3H, OCH3), 3.93–4.00 (m,
2H), 7.2–7.4 (m, 5H, aromatic-H) ppm; MS-CI m=z 220.18, calcd. for C14H22NO
(MHþ). Anal. calcd. for C14H21NO: C, 76.67; H, 9.65; N, 6.39. Found: C, 76.58;
H, 9.62; N, 6.44.
(ꢀ)-threo-N-Methyl Ritalinol Methyl Ether (2b)
(ꢀ)-threo-N-Methyl ritalinol (0.250 g, 1.14 mmol) was dissolved in a mixture of
DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to 0–5 ꢁC,
powdered potassium hydroxide (0.096 g, 1.71 mmol) and methyl iodide (0.227 g,
0.099 ml, and 1.59 mmol) were added, and the reaction mixture was methylated by
a method virtually identical to that used to synthesize 2a. The hydrochloride salt
was obtained by addition of 1 M HCl in ether to a methanol solution of the residue,
and evaporation of solvents to dryness in vacuo and recrystallization (EtOAc–
1
hexane) provided 0.272 g (89%) of 2b as a white crystal: mp 159–160 ꢁC; H NMR
(CDCl3): d 1.5–1.24 (m, 3H), 1.65–1.52 (m, 1H), 1.85–1.74 (m, 1H), 2.40 (s, 3H,
CH3), 2.66–2.57 (m, 2H), 2.98–2.91 (q, 1H), 3.15–3.08 (m, 1H), 3.27 (s, 3H,
OCH3), 4.0–3.93 (m, 2H), 7.4–7.2 (m, 5H, aromatic-H) ppm; MS-CI m=z 234.34,
calcd. for C15H24NO (MHþ). Anal. calcd. for C15H23NO: C, 77.21; H, 9.93; N,
6.00. Found: C, 77.30; H, 9.86; N, 6.12.
(ꢀ)-threo-N-Ethyl Ritalinol Methyl Ether (2c)
(ꢀ)-threo-N-Ethyl ritalinol (0.250 g, 1.07 mmol) was dissolved in a mixture of
DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to 0–5 ꢁC,
powdered potassium hydroxide (0.090 g, 1.61 mmol) and methyl iodide (0.213 g,
0.093 ml, and 1.49 mmol) were added, and the reaction mixture was methylated by
a method virtually identical to that used to synthesize 2a. The hydrochloride salt
was obtained by addition of 1 M HCl in ether to a methanol solution of the residue,
and evaporation of solvents to dryness in vacuo, and recrystallization (EtOAc–
1
hexane) provided 0.261 g (89%) of 2c as a white solid: mp 162–164 ꢁC; H NMR

2828
B. OJO
(CDCl3): d 0.86–0.92 (m, 1H), 1.2 (t, 3H, J ¼ 7.25 Hz, CH3), 1.22–1.65 (m, 6H), 2.77
(d, 1H, J ¼ 13.78 Hz), 2.86 (q, 2H, J ¼ 7.22 Hz), 3.16–3.30 (m 2H), 3.43 (d, 1H,
J ¼ 10.78, 3.35 Hz), 3.24 (s, 3H, OCH3), 4.0 (m, 2H), 7.12–7.35 (m, 5H, aromatic-H)
ppm; MS-EI m=z 248.36, calcd. for C16H26NO (MHþ). Anal. calcd. for C16H25NO:
C, 77.69; H, 10.19; N, 5.66. Found: C, 77.50; H, 10.28; N, 5.44.
(ꢀ)-threo-N-Benzylritalinol Methyl Ether (2d)
(ꢀ)-threo-N-Benzyl ritalinol (0.300 g, 1.02 mmol) was dissolved in a mixture of
DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to 0–5 ꢁC,
powdered potassium hydroxide (0.085 g, 1.52 mmol) and methyl iodide (0.202 g,
0.088 ml, and 1.42 mmol) were added, and the reaction mixture was methylated by
a method virtually identical to that used to synthesize 2a. The hydrochloride salt
was obtained by addition of 1 M HCl in ether to a methanol solution of the residue,
and evaporation of solvents to dryness in vacuo and recrystallization (EtOAc–
hexane) provided 0.310 g (93%) of 2d as a white solid: mp 227–229 ꢁC (lit.[14b] mp
1
228–229 ꢁC); H NMR (CDCl3) d 1.05–1.17 (m, 6H), 2.47–2.53 (M, 1H), 2.92–3.01
(m, 1H), 3.27 (s, 3H, OCH3, 3.37–3.45 (m, 1H), 3.65 (t, 1H, J ¼ 9.3 Hz), 3.77 (d,
1H, J ¼ 13.2 Hz), 3.97–4.01 (m, 2H), 7.18–7.38 (m, 10H) ppm; MS-CI m=z 310.43,
calcd. for C21H28NO (MHþ). Anal. calcd. for C21H27NO: C, 81.51; H, 8.79; N,
4.53. Found: C, 81.20; H, 8.89; N, 4.62.
(ꢀ)-threo-N-Phenylethyl Ritalinol Ether (2e)
(ꢀ)-threo-N-Phenylethyl ritalinol (0.300 g, 0.97 mmol) was dissolved in a mix-
ture of DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to
0–5 ꢁC, powdered potassium hydroxide (0.082 g, 1.45 mmol) and methyl iodide
(0.193 g, 0.084 ml, and 1.36 mmol) were added, and the reaction mixture was meth-
ylated by a method virtually identical to that used to synthesize 2a. The hydrochlor-
ide salt was obtained by addition of 1 M HCl in ether to a methanol solution of the
residue, and evaporation of solvents to dryness in vacuo and recrystallization
1
(EtOAc–hexane) provided 0.318 g (91%) of 2e as a white solid: mp 232–234 ꢁC; H
NMR (CDCl3): 0.99–1.61 (m, 6H), 2.98 (t, 3H), 3.15 (t, 2H, N-CH2), 3.2 (d, 1H),
3.38 (t, 1H), 3.41 (t, 1H), 3.28 (s, 3H, OCH3), 4.0 (m, 2H), 7.10–7.38 (m, 10H,
aromatic-H) ppm; MS-CI m=z 324.46, calcd. for C22H30NO (MHþ). Anal. calcd.
for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.36; H, 9.19; N, 4.53.
(ꢀ)-threo-N-Phenylpropyl Ritalinol Methyl Ether (2f)
(ꢀ)-threo-N-Phenylpropyl ritalinol (0.300 g, 0.93 mmol) was dissolved in a mix-
ture of DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to
0–5 ꢁC, powdered potassium hydroxide (0.078 g, 1.39 mmol) and methyl iodide
(0.184 g, 0.081 ml, and 1.29 mmol) were added, and the reaction mixture was meth-
ylated by a method virtually identical to that used to synthesize 2a. The hydrochlor-
ide salt was obtained by addition of 1 M HCl in ether to a methanol solution of the
residue, and evaporation of solvents to dryness in vacuo and recrystallization
(EtOAc–hexane) provided 0.310 g (89%) of 2f as a white solid: mp 239–241 ꢁC;

RITALINOL AND RITALINOL METHYL ETHER ANALOGS
2829
1H NMR (CDCl3): 0.99–1.62 (m, 6H), 1.08–1.18 (m, 2H), 2.75 (t, 3H), 2.81 (t, 2H,
N-CH2), 3.2 (d, 1H), 3.38 (t, 1H), 3.41 (t, 1H), 3.26 (s, 3H, OCH3), 4.0 (m, 2H),
7.11–7.38 (m, 10H, aromatic-H) ppm; MS-CI m=z 338.48, calcd. for C23H32NO
(MHþ). Anal. calcd. for C23H31NO: C, 81.86; H, 9.26; N, 4.15. Found: C, 81.73;
H, 9.17; N, 4.28.
(ꢀ)-threo-N-Phenylbutyl Ritalinol Methyl Ether (2g)
(ꢀ)-threo-N-Phenylbutyl ritalinol (0.300 g, 0.89 mmol) was dissolved in a mix-
ture of DMSO, DMF, and hexane (6, 4, and 10 ml, respectively). After cooling to
0–5 ꢁC, powdered potassium hydroxide (0.075 g, 1.33 mmol) and methyl iodide
(0.177 g, 0.077 ml, and 1.24 mmol) were added, and the reaction mixture was methyl-
ated by a method virtually identical to that used to synthesize 2a. The hydrochloride
salt was obtained by addition of 1 M HCl in ether to a methanol solution of the
residue, and evaporation of solvents to dryness in vacuo and recrystallization
1
(EtOAc–hexane) provided 0.315 g (88%) of 2g as a white solid: mp 244–245 ꢁC; H
NMR (CDCl3): 0.99–1.61 (m, 6H), 1.60–1.79(m, 4H), 2.75 (t, 1H), 3.41 (t, 1H),
3.27 (s, 3H, OCH3), 4.0 (m, 2H), 7.10–7.38 (m, 10H, aromatic-H) ppm; MS-CI m=z
352.51, calcd. for C24H34NO (MHþ). Anal. calcd. for C24H33NO: C, 82.01; H,
9.46; N, 3.98. Found: C, 82.21; H, 9.32; N, 4.01.
ACKNOWLEDGMENTS
The author thanks Gabrielle Jones, Shanet Goodwin, Robersy Matute, and
Olabimpe Olafuyi for their assistance during the preparation of this article, and
the National Institutes of Health (NIH=NIGMS) for support of this work.
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