A facile synthesis for novel loperamide analogs as potential μ opioid receptor agonists

Article abstract of DOI:10.3390/molecules171214288

A facile synthesis for novel loperamide analogs as potential μ opioid receptors is described. The synthetic procedure for compound 5, which contains two 4-phenyl piperidine scaffolds, was optimized, and this compound was synthesized in excellent yield. We

Full text of DOI:10.3390/molecules171214288

Molecules 2012, 17, 14288-14297; doi:10.3390/molecules171214288
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Facile Synthesis for Novel Loperamide Analogs as Potential μ
Opioid Receptor Agonists
Xiaofeng Bao †,*, Duliang Liu †, Yanyan Jin and Yao Yang
Department of Biochemical Engineering, Nanjing University Science & Technology,
Chemical Engineering Building B302, 200 Xiaolinwei, Nanjing 210094, China;
E-Mails: ldl12358@hotmail.com (D.L.); j.yy.1002c@163.com (Y.J.); bxfeng11@hotmail.com (Y.Y.)
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: baoxiaofeng@njust.edu.cn;
Tel./Fax: +86-25-8431-5945.
Received: 6 November 2012; in revised form: 27 November 2012 / Accepted: 28 November 2012 /
Published: 3 December 2012
Abstract: A facile synthesis for novel loperamide analogs as potential μ opioid receptors
is described. The synthetic procedure for compound 5, which contains two 4-phenyl
piperidine scaffolds, was optimized, and this compound was synthesized in excellent yield.
We also describe a mild and highly efficient protocol for the synthesis of compounds 6 and 7.
Keywords: loperamide analogs; μ opioid receptor agonist; morphine; opioid ligand receptors
1. Introduction
Opioid ligand receptors are involved in various physiological activities, including analgesia, miosis,
bradycardia, general sedation, hypothermia, insensitivity and depression of the flexor reflexes and have
been widely used in medicine, most prominently in the treatment of pain [1,2]. Three separate
receptors—μ (mu), δ (delta), and κ (kappa)—were proven to be the basis of the pharmacologic
responses using in vitro radioligand binding affinity assays and in vivo localization of labeled drug in
tissue homogenates or sections [3,4]. These reports indicate that μ opioid receptor (MOR) agonists are
useful analgesics in the periphery, especially for inflamed tissues [5,6]. Phenylpiperidine structures,
such as loperamide (1) [7,8], N-desmethylloperamide (2) [9], diphenoxylate (3) [10], and 4 (Figure 1) [11],
are typical representatives of these compounds. Although diphenoxylate and loperamide are MOR

Molecules 2012, 17
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agonists and show affinity and selectivity for the cloned μ human opioid receptor, they do not easily
pass through the blood–brain barrier (BBB) [12], therefore, they are currently mainly used as
antidiarrheal drugs.
Figure 1. Structures of representative MOR agonists.
Cl
Cl
Cl
O
O
OH
OH
N
N
N
R N
O
NC
4, 4-(4-chlorophenyl)-1-(3,3-
diphenylpropyl)piperidin-4-ol
Diphenoxylate
3,
1, R=Me, Loperamide
2, R=H, N-desmethylloperamide
More recently, MOR agonists based on the 4-phenylpiperidine scaffold have been reported and
have shown promising results [13,14]. The therapeutic potential of loperamide and other compounds
based on 4-phenylpiperidine scaffolds may also be of interest to the scientific community in light of
the recent discovery of DiPOA, a novel, systemically available and peripherally restricted MOR
agonist with antihyperalgesic activity [15].
Therefore, the compounds 1,4-bis(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutan-
1-one (5, Figure 2), 4-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (6, Figure 2)
and (Z)-2-(2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl) ethyl)-3-methylene-2-phenylhex-4-enamide
(7, Figure 2), which are based on loperamide and diphenoxylate, were designed and synthesized as
potential MOR agonists. The novel analog 5 contains two 4-phenylpiperidine scaffolds, and analogs
6 and 7 each contain one 4-phenylpiperidine scaffold. We consider these analogs to be promising
MOR agonists.
Figure 2. Structures of novel loperamide analogs.
Cl
R
Cl
HO
OH
HO
N
N
N
O
H2N
O
6, R=F
7, R=Br
1,4-bis(4-(4-chlorophenyl)-4-hydroxy
piperidin-1-yl)-2,2-diphenylbutan-1-one
5,

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2. Results and Discussion
As a consequence of our interest in MORs containing 4-phenylpiperidine scaffolds, we developed a
mild and highly efficient protocol for the synthesis of compounds 5, 6 and 7. We initiated our studies
by preparing the key intermediate 10b by coupling commercially available compounds 8 and 9b to
achieve product 10b under different reaction conditions, as shown in Table 1. The reaction using
conditions based on those of a similar reaction that was previously reported in the literature was not
successful for an unknown reason [16]. When the reaction time was prolonged to 30 h with 3 eq. of
DIPEA at 105 °C, we successfully isolated compound 10b in a disappointing 6% yield. The possible
reasons for failure may be that the hydroxyl group on compound 9b was affected. This group is also a
strong nucleophile under basic conditions, as observed in our previously published study [17], and the
carboxylates present under basic conditions may also compete with the secondary amine in the
nucleophilic substitution reaction. Because the overall yield of 10b using this approach was poor, an
alternate strategy was adopted for synthesizing a high yield of 10b.
Table 1. Synthesis of the intermediate compound 10b.
Cl
HO
N
Br
Cl
Base,Heat
Solvent
O
OH
OH
OH
10b
HN
O
8
9b
Entry
Ratio 8:9b:DIPEA
Reaction conditions
THF, reflux, 2 days
THF, reflux, 2 days
CH3CN, 70 °C, 30 h
CH3CN, 85 °C, 30 h
CH3CN, 105 °C, 30 h
Yield *10b
1
2
3
4
5
1:1.5:0
1:1:3
1:1:3
1:1:3
1:1:3
-
-
-
Trace
6%
* Isolated yield.
Subsequently, we designed another approach to prepare the intermediate 10b involving the
alkylation of 4-(4-chlorophenyl)-4-hydroxylpiperidine with 4-bromo-2,2-diphenylbutyronitrile in the
t
presence of DIPEA, followed by the hydrolysis of 12b with KOH in BuOH to afford compound 13b
(Scheme 1) [18]. We also prepared analogs 6 and 7 using a similar procedure for the future
radiolabeling study. The slow hydrolysis of amide precursor 13b in 40% H2SO4 aq. at reflux gave a
trace amount of 10b. The hydrolysis of nitrile compound 12b under different reaction conditions was
also investigated (Table 2). Compound 10b was obtained in 7% yield when the reaction was catalyzed
with H2O2/NaOH in H2O at 80 °C for 20 h [19,20]. A trace amount of 10b was obtained when an
inorganic base (2 M sodium hydroxide) was used as a catalyst [21]. We isolated two byproducts, 14b
(20%~23% yield) and 15b (66%~72% yield), when the reaction was performed under acidic
conditions (37% HCl or 40% H2SO4) [22]. The principal reason was that the tertiary hydroxyl group
on 13b was very easily eliminated under acidic conditions to form an alkene [17].

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Scheme 1. Synthesis of the amides 6, 13b and 7.
R
HO
R
N
Br
DIPEA, CH3CN
NC
OH
HN
NC
80oC, 35-66%
9a, R=F
9b, R=Cl
9c, R=Br
12a, R=F
12b, R=Cl
12c, R=Br
11
R
Cl
HO
HO
N
N
KOH, t-BuOH
40%H2SO4aq
100oC
O
O
Reflux, 40-57%
H2N
HO
6, R=F
13b, R=Cl
, R=Br
10b
7
Table 2. Hydrolysis of the nitrile 12b.
Cl
Cl
Cl
HO
N
N
N
12b
O
O
NC
HO
HO
15b
14b
10b
Yield (%) *
Entry
Catalyst
Reaction conditions
10b
15b
-
14b
1
2
3
4
5
NaOH a
NaOH a
HCl b
CH3OH/H2O, Reflux, 30 h
H2O, Reflux, 30 h
trace
-
-
trace
-
1,4-Dioxane, Reflux, 16 h
H2O, 100 °C, 16 h
-
-
20
23
-
66
72
-
c
H2SO4
H2O2 /NaOH a
H2O, 80 h, 20 h
7
d
Catalyst concentration: a 2 M; b 37%; c 40%; d 30%. * Isolated yield.
The desired product 5 was obtained in low yield by coupling 10b with the amine 9b in a reaction
catalyzed by TiCl4 in toluene refluxing for 20 h (Scheme 2) [23]. Unfortunately, this second approach
was not feasible for use in the rest of the study.

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Scheme 2. Synthesis of compound 5.
Cl
Cl
HO
HO
Cl
N
OH
N
9b, TiCl4
N
O
toluene, reflux
O
HO
5
10b
When the first approach was analyzed in detail, it was determined that the formation of a substantial
amount of salt at the start of reaction may be responsible for the low yield of 12b. Thus, a new method
involving the protection of the carboxyl group of 8 with a methyl group to form an ester precursor
before coupling with 9b was developed (Scheme 3). A mixture of 4-bromo-2,2-diphenylbutyric acid 8,
thionyl chloride and catalytic DMF in dichloromethane was stirred and refluxed for 3 h. After
concentration under reduced pressure, crude 4-bromo-2,2-diphenylbutyric acid chloride (17) was
achieved as a pale yellow oil. Compound 17 was converted into the ester 18 in excellent yield (82%)
by reaction with methanol at 50 °C for 4 h. The desired product, 5, was obtained as a white solid in
71% yield by condensing 18 with 9b in the presence of DIPEA in CH3CN at 80 °C for 15 h (Scheme 3).
The side product 19 was also obtained as a pale orange solid in 8% yield.
Scheme 3. The Synthesis of the ester 19 and 5.
Br
Br
MeOH, 50oC
82%
Br
SOCl2, catalytic DMF
reflux
O
OH
Cl
O
O
8
O
17
18
Cl
Cl
HO
HO
N
9b, DIPEA
Cl
OH
N
80oC
O
N
O
O
19
5
3. Experimental
3.1. General
All reagents and organic solvents were ACS grade or higher and used without further purification.
Unless otherwise noted, all chemicals were purchased from J&K Scientific (Shanghai, China).
Reactions were performed under argon atmosphere with standard Schlenk techniques. Thin layer
chromatography was performed on HAIYANG silica gel F254 plate, and compounds were visualized
under UV light (λ = 254 nm). Column chromatography was carried out using HAIYANG silica gel
(type: 200–300 mesh ZCX-2). 1H (500 MHz), 13C-NMR (126 MHz) and 19F-NMR (470 MHz) spectra
were recorded on an Avance 500 spectrometer (Bruker; Billerica, MA, USA). Chemical shifts are
reported in δ units (ppm) downfield relative to the chemical shift for tetramethylsilane.

Molecules 2012, 17
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4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (10b). Entry 2. The
4-bromo-2,2-diphenylbutanoic acid 8 (200 mg, 0.6266 mmol) was dissolved in THF (10 mL),
followed by addition of 4-(4-chlorophenyl)-piperidin-4-ol (133 mg, 0.6266 mmol, 1 eq.) and DIPEA
(0.242 mL, 1.8798 mmol, 3 eq.) to the solution. The mixture was refluxed for 2 days. No new product
was found via TLC. Entry 5. The 4-bromo-2,2-diphenylbutanoic acid 8 (400 mg, 1.253 mmol) was
suspended in acetonitrile (10 mL) and DIPEA (0.675 mL, 3.75 mmol) was added. The mixture was
stirred at 105 °C for 30 h. After the solvent was removed under vacuum, the crude was dissolved in
CH2Cl2 and was introduced onto a silica gel column. The product was eluted with 3% MeOH in
dichloromethane to give 10b as a pale-orange solid (20 mg, 6% yield). TLC (silica gel; MeOH–CH2Cl2
(5:95 v:v); Rf = 0.40). LC-MS (M++1): found 449.88; calcd for C27H29ClNO3, 450.18.
4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12b). 4-(4-Chlorophenyl)-
4-hydroxypiperidine (2.1 g, 10.0 mmol) was suspended in acetonitrile (15 mL) and DIPEA (3.5 mL,
30 mmol) was added. 4-Bromo-2,2-diphenylbutanenitrile (3.00 g, 10 mmol) in acetonitrile (15 mL)
was then added. The reaction mixture was stirred at 70 °C for 30 h. After the solvent was removed
under vacuum, the crude material was redissolved in CH2Cl2 and introduced onto a silica gel column.
The product was eluted with 5% MeOH in dichloromethane to yield 12b as a pale-orange solid (2.8 g,
1
66% yield). TLC (silica gel; MeOH–CH2Cl2 (5:95 v:v); Rf = 0.50). H-NMR (CDCl3): δ 7.37 (m,
14H), 2.80 (d, 2H, J = 11.25 Hz), 2.67 (m, 2H), 2.55 (m, 2H), 2.47 (t, 2H, J = 11.3 Hz), 2.105 (m, 2H),
13
1.73 (d, 2H, J = 11.9 Hz). C-NMR (CDCl3): δ 140.16, 132.95, 129.09, 128.57, 128.10, 126.95,
126.23, 122.27, 71.11, 54.93, 50.17, 49.71, 38.52, 36.80ppm. LC-MS (M++1) found 431.20; calcd for
C27H28ClN2O, 431.19.
4-(4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12a). Compound 12a was
synthesized using the same procedure that was followed the synthesis of the compound 12b, and was
obtained in 35% yield as a pale-orange solid. 1H-NMR (CDCl3): δ 7.45 (m, 2H), 7.39 (d, 4H, J = 10 Hz),
7.35 (t, 4H, J = 5Hz ), 7.29 (t, 2H, J = 10 Hz ), 7.00 (t, 2H, J = 10 Hz), 2.75 (d, 2H, J = 10 Hz), 2.63
(m, 2H), 2.52 (m, 2H), 2.47 (t, 2H, J = 10 Hz), 2.08 (m, 2H), 1.71 (d, 2H, J = 15 Hz).13C-NMR: δ
162.89, 160.93, 144.27, 140.16, 129.03, 128.05, 126.91, 126.45, 126.39, 122.23, 115.18, 115.01,
19
70.91, 54.88, 50.19, 49.72, 38.56, 36.74. F-NMR: δ 116.12. LC-MS (M++1): Found: 415.06; Calcd:
C27H28FN2O: 415.22.
4-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (12c). Compound 12c was
synthesized using the same procedure that was followed the synthesis of the compound 12b, and was
obtained in 58% yield as a pale-orange solid. 1H-NMR (CDCl3): δ 7.48 (d, 2H, J = 10 Hz), 7.41 (d, 4H,
J = 10 Hz), 7.37 (m, 6H), 7.31 (t, 2H, J = 5 Hz), 2.76 (d, 2H, J = 10 Hz), 2.65 (m, 2H), 2.54 (m, 2H),
13
2.45 (t, 2H, J = 10 Hz), 2.08 (m, 2H), 1.68 (m, 3H). C-NMR: δ 147.64, 140.11, 131.47, 129.07,
128.09, 126.91, 126.66, 122.25, 121.00, 70.97, 54.90, 50.18, 49.64, 38.35, 36.67. LC-MS (M++1):
Found: 476.92; Calcd: C27H28BrN2O: 477.13.
4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide
(13b).
4-(4-(4-Chloro-
phenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (2.5 g, 6.0 mmol) was dissolved in BuOH
(40 mL) and potassium hydroxide (1.2 g, 21.3 mmol) was added. The reaction mixture was stirred at

Molecules 2012, 17
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100 °C for 3d. After concentration under vacuum, the crude material was redissolved in
dichloromethane and filtered through a pad of Celite. Chromatography of the sample on a silica gel
column eluted with ammonium hydroxide (2 M) solution in MeOH-CH2Cl2 (5:95 v/v) gave 13b as a
pale-yellow solid (1.58 g, 55% yield). TLC (silica gel; MeOH–CH2Cl2 (5:95 v:v); Rf = 0.40). 1H-NMR
(CDCl3): δ 7.36 (m, 14H), 6.58 (s, 1H), 5.46 (s, 1H), 3.91 (s, 1H), 2.83 (m, 2H), 2.69 (s, 2H), 2.39 (m,
13
3H), 2.10 (m, 2H), 1.74 (d, 2H, J = 12.85 Hz). C-NMR: 176.56, 167.25, 158.96, 146.67, 143.26,
132.82, 128.69, 128.41, 127.06, 126.10, 59.91, 54.92, 49.48, 38.28, 35.87. LC-MS (M++1): Found:
449.3; Calcd: C27H30ClN2O2: 449.20.
4-(4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (6). Compound 6 was
synthesized using the same procedure that was followed the synthesis of the compound 13b, and was
1
obtained in 40% yield as a pale-orange solid. H-NMR (CDCl3): δ 7.45 (m, 2H), 7.31 (m, 10H), 6.99
(t, 2H, J = 10 Hz), 5.07 (s, 1H), 2.89 (m, 2H), 2.64 (m, 2H), 2.35 (m, 2H), 2.04 (m, 2H), 1.59 (d, 2H,
J = 5 Hz), 6.22 (s, 1H), 5.82 (s, 1H), 3.02 (m, 2H), 2.82 (m, 4H), 2.63 (m, 2H), 2.36 (m, 2H), 1.76 (d,
2H, J = 10 Hz). 13C-NMR: δ 175.53, 162.43, 160.51, 145.88, 143.83, 129.27, 128.46, 127.29, 127.24,
127.07, 115.15, 114.98, 69.28, 59.54, 54.73, 49.44, 37.33, 29.55. 19F-NMR: δ 117.01.
4-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide (7). Compound 7 was
synthesized using the same procedure that was followed the synthesis of the compound 13b, and was
obtained in 57% yield as a pale-orange solid.1H-NMR (CDCl3): δ 7.41 (t, 2H, J = 5 Hz), 7.31 (m,
12H), 6.45 (s, 1H), 5.87 (s, 1H), 2.82 (m, 12H), 2.31 (m, 12H), 2.50 (m, 12H), 2.42 (m, 12H), 2.11 (m,
13
12H), 1.69 (m, 12H). C-NMR: δ 176.79, 147.17, 143.14, 131.46, 128.75, 128.57, 127.26, 126.64,
121.06, 70.67, 59.88, 55.00, 49.48, 37.79, 35.46. LC-MS (M++1): Found: 494.93; Calcd:
+
C27H30BrN2O2 : 495.14.
4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (10b). 4-(4-(4-Chloro-
phenyl)-4-hydroxycyclohexyl)-2,2-diphenylbutanamide (1.2 g, 2.6 mmol) was added to 40%H2SO4
(50 mL) and the mixture was stirred at 100 °C for 2 days. The crude material was extracted with ethyl
acetate (60 mL×3). The ethyl acetate was removed by reduced pressure distillation. After drying with
MgSO4 and dissolving in CH2Cl2 (2 mL), the product was introduced onto a silica gel and eluted with
5% MeOH in CH2Cl2 to give trance amount of 10b. TLC (silica gel; MeOH–CH2Cl2 (5:95 v:v); Rf = 0.30).
1H-NMR (CDCl3): δ 7.3096(m, 14H), 5.9319 (s, 1H), 3.29 (m, 2H), 2.94 (m, 2H), 2.80 (m, 2H), 2.72
+
(m, 2H), 2.67 (m, 4H), 2.10 (m, 2H). LC-MS (M++1): found: 449.88; Calcd for C27H28ClNO3 , 450.18.
Procedure for Preparing 10b from 12b
Entry 3. 4-(4-(4-Chlorophenyl)-4-hydroxypiperidine-1-yl)-2,2-diphenylbutanenitrile (400 mg, 0.928 mmol)
was dissolved in 1,4-dioxane (10 mL) and 37% hydrochloric acid (5 mL) was then added. The reaction
mixture was refluxed for 16 h. After concentration under vacuum, the crude was dissolved in
trichloromethane (10 mL) and extracted with H2O (20 mL × 3). After the organic layer was dried by
MgSO4, the solvent was removed under vacuum and redissolved in CH2Cl2. The mixture was
introduced onto a silica gel column and the product was eluted with 50% EtOAc in hexane first and
5% MeOH in CH2Cl2 later to give the product 14b as a yellow solid (250 mg, 66%). TLC (silica gel;

Molecules 2012, 17
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1
EtOAc–hexane (1:1 v:v); Rf = 0.70). Compound 14b: H-NMR (CDCl3): δ 7.36 (m, 14H), 6.04 (m,
13
1H), 3.16 (m, 2H), 2.74 (m, 2H), 2.62 (m, 4H), 2.53 (m, 2H) ppm. C-NMR (CDCl3): δ 141.44,
140.57, 135.56, 134.26, 130.53, 129.92, 129.55, 128.27, 127.72, 123.52, 55.96, 54.81, 51.93, 51.57,
+
38.48, 29.44 ppm. MS (M++1): found 412.99; Calcd C27H25ClN2 , 412.95.
1,4-bis(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutan-1-one
(5).
4-(4-Chloro-
phenyl)-4-hydroxypiperidinorophenyl)-4-hydroxypiperidine (28 mg, 0.12 mmol, 2 eq.) was dissolved
in toluene (5 mL) and 4-(4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid (30 mg,
0.067 mmol) and TiCl4 (1.5 mL) was then added. The mixture was refluxed for 20 h. After the solvent
was removed under vacuum, the crude material was dissolved in CH2Cl2 (10 mL). After the mixture
was filtered and CH2Cl2 was then removed to 2 mL, the product was introduced onto a silica gel with
5% MeOH in CH2Cl2 to give 5 as a pale-orange solid (trace amount). TLC (silica gel column;
MeOH–CH2Cl2 (5:95 v:v); Rf = 0.40).
Methyl 4-bromo-2,2-diphenylbutanoate (18). 4-Bromo-2,2-diphenylbutanoic acid (2.0 g, 6.266 mmol)
was dissolved in dry CH2Cl2 (20 mL) and thionyl chloride (2.27 mL, 31.33 mmol, 5 eq.) was then
added slowly. A trace amount of DMF was added later. The reaction mixture was refluxed at N2 for 3 h.
Methyl alcohol (2 mL, excess) was added slowly and the mixture was stirred at 50 °C for 3 h. After the
solvent was removed under vacuum, the crude material was redissolved in CH2Cl2 and introduced onto
a silica gel column. The product was eluted with 10% EA in hexane to give a pale-orange oil (900 mg,
43% yield).TLC (silica gel; EtAc–hexane (10:90 v:v); Rf = 0.80). 1H-NMR (CDCl3): δ 7.31 (m, 10H),
3.74 (s, 1H), 3.13 (m, 2H), 3.00 (m, 2H).13C-NMR (CDCl3): δ 174.05, 141.70, 128.70, 128.42, 127.46,
60.84, 52.78, 42.0447, 29.18 ppm. GC-MS: found: 331.99; Calcd for C17H17BrO2, 332.04.
Methyl4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoate (19) and 1,4-bis(4-(4-
chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenyl -butan-1-one (5). Methyl 4-bromo-2,2-
diphenylbutanoate (800 mg, 2.4 mmol) was dissolved in CH3CN (15 mL) and 4-(4-chlorophenyl)-4-
hydroxypiperidine (406 mg, 1.92 mmol, 0.8 eq.) was then added. The reaction mixture was stirred at 50 °C
for 30 h. After concentration under vacuum, the crude material was redissolved in CH2Cl2 and
introduced onto a silica gel column. The product was eluted with 3% MeOH in CH2Cl2 first and 5%
MeOH in CH2Cl2 later to get 19 as a pale-orange solid (70 mmg, 8% yield) and 20 as a pale-orange solid
1
(437 mg, 71%). Compound 19: TLC (silica gel; MeOH-CH2Cl2 (10:90 v:v); Rf = 0.40). H-NMR
(CDCl3): δ 7.34 (m, 14H), 3.74 (s, 3H), 3.28 (2H, m), 3.13 (2H, m), 3.12 (2H, m), 3.10 (4H, m), 2.60
13
(1H, s), 2.06 (2H, d, J = 14.0 Hz). C-NMR (CDCl3): δ 173.06, 143.62, 140.18, 132.54, 127.72,
127.52, 127.28, 126.62, 126.32, 125.04, 68.58, 58.02, 51.81, 48.22, 34.51, 31.73, 30.93, 28.36, 21.69.
+
MS: found: 463.92; calcd for C28H31ClNO3 , 464.20. Compound 5: TLC (silica gel; MeOH–CH2Cl2
1
(10:90 v:v); Rf = 0.40). H-NMR (CDCl3): δ 7.3094 (m, 18H), 4.5945 (d, 1H, J = 11.4 Hz), 3.31 (m,
13
10H), 2.73 (m, 2H), 2.55 (m, 2H), 2.28 (m, 2H), 1.87 (m, 4H), 1.65 (m, 2H). C-NMR (CDCl3):
171.38, 146.46, 145.29, 141.45, 136.64, 133.00, 132.68, 129.45, 125.03, 128.89, 128.45, 128.31,
128.17, 127.57, 126.54, 126.08, 71.10, 69.06, 60.03, 54.44, 44.25, 42.68, 39.65, 39.21, 37.91, 35.95,
+
35.30, 29.77 ppm. MS: found: 644.88; Calcd for C38H42Cl2N2O3 , 644.25.

Molecules 2012, 17
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4. Conclusions
In summary, compound 5 was synthesized in excellent yield. Analogs 6 and 7 were obtained
through the hydrolysis of the nitrile group in good yield. These methods have the advantages of high
yields, convenient procedures, and mild reaction conditions.
Supplementary Material
Supplementary data associated with this article can be found in the online version (1H-NMR,
13C-NMR, and LC-MS for all compounds), which can be accessed at: http://www.mdpi.com/1420-
3049/17/12/14288/s1.
Acknowledgments
This research was supported by Jiangsu Science Foundation BK2011704 and NJUST Research
Funding (NO. 2011ZDJH08).We thank Wei Jiang for helpful experimental suggestions.
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Sample Availability: Samples of the compounds 5–7, 10b, 12a–c, 13b, 14b, 18 and 19 are available
from the authors.
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