Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain

Graphical Abstract

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Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu

opioid receptor agonists for treating neuropathic pain

a

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Jiaying Xiong , Jian Jin , Lanchang Gao , Chao Hao , Xin Liu , Bi-Feng Liu , Yin Chen

b,

a,b,

*, Guisen Zhang

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Systems Biology Theme, Department of Biomedical Engineering, College of Life Science

and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

b

Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key

Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu

Ocean University, Lianyungang 222005, China

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* Author to whom correspondence should be addressed.

*Phone: +86-27-87792235. Fax: +86-27-87792170.

*E-Mail: gszhang@mail.hust.edu.cn. E-Mail: 2019000015@jou.edu.cn

Keywords

Piperidine propionamide; Sigma-1 receptor antagonists; Mu receptor agonists; Analgesic

Abstract

We designed and synthesized a novel series of piperidine propionamide derivatives as

potent sigma-1 (σ ) receptor antagonists and mu (µ) opioid receptor agonists, and measured

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their affinity for σ and µ receptors in vitro through binding assays. The basic scaffold of

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the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide.

Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl)

propionamide, showed the highest affinity for σ receptor (K σ = 1.86 nM) and µ receptor

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(K µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED = 15.1 ±

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1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ antagonist) in a CCI model.

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Therefore, Compound 44, which has mixed σ /µ receptor profiles, may be a potential

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candidate for treating neuropathic pain.

1. Introduction

Neuropathic pain is an expensive and debilitating condition that affects 7%–10% of

the general population, with the prevalence increasing with age [1]. First-line treatments for

neuropathic

pain

include

anticonvulsants,

tricyclic

antidepressants,

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serotonin-norepinephrine reuptake inhibitor antidepressants. In addition, opioids provide

second-line treatment. Unfortunately, these drugs are limited in their efficacy and have side

effects, in particular with chronic use [2, 3]. Opioids, one category of analgesics, can

rapidly reduce symptoms in patients with severe neuropathic pain [4]; however, long-term

use can lead to respiratory depression, constipation, tolerance, and physical dependence [5].

Thus, there is a need to explore novel analgesic mechanisms that improve the efficacy of

existing therapies while reducing their adverse effects.

In 1976, Martin discovered sigma receptors, which were initially thought to be a new

subtype of opioid receptor [6]. Six years later, Su and colleagues demonstrated that sigma

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receptors differ from opioid receptors [7]. σ receptor, a subtype of sigma receptor, is a

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chaperone protein that modulates the activity of the NMDA receptor; opioid receptors; and

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several ion channels, including the K and Ca channels [8, 9]. Many studies have

validated the involvement of σ receptor in moderating pain. Cendán found that σ receptor

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knockout mice exhibited reduced pain sensitivity in the formalin test [10]. Haloperidol (1),

nonselective σ₁receptor antagonist, inhibits capsaicin-induced mechanical

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hypersensitivity [11, 12]. S1RA (2), a highly active and selective σ receptor antagonist,

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exhibits analgesic activity in neuropathic pain models [13] and is currently in Phase II

clinical trials for treating neuropathic pain. Moreover, ligands of σ receptor antagonists

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with heterocyclic rings of pyrimidine (3), pyridazinone (4), and 1,2,4-oxadiazole (5)

scaffolds have been designed and tested. Each ligand exhibits dose-dependent analgesic

effects in pain models (Fig. 1) [14-16]. Despite these findings, there are currently no

selective σ receptor antagonists analgesics on the market.

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σ₁receptor was originally being used for analgesia when Chien and Pasternak

identified its role in the endogenous anti-opioid system. σ receptor agonists counteract

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opioid receptor-mediated analgesic effects, whereas σ receptor antagonists, such as

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haloperidol, have potentiating effects [17, 18]. A series of experiments were conducted with

the highly selective σ antagonist S1RA and σ R-KO mice to investigate the potentiation of

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opioid analgesia through inhibiting σ receptor. The results were consistent with those of

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nonselective σ antagonists [19-21], which suggests that the analgesic mechanism of

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opioids is related to σ receptor. Therefore, synergistic administration of σ antagonists with

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opioid analgesics may enhance the analgesic potency of opioids. Nevertheless, few

analgesics with the dual targets of σ and µ receptors have been reported, and none has

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entered clinical trials to date.

Carroll and colleagues evaluated the biological activity of phenazocine enantiomers in

vitro and showed that both (-)-phenazocine (6a) and (+)-phenazocine (6b) bind to σ and µ

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receptors (Fig. 2) [22]. In addition, phenazocine enantiomers have demonstrated affinity for

other opioid receptors [23, 24]. In regard to analgesic potency, the analgesic effects of

(+)-phenazocine (ED = 6.7 mg/Kg) were comparable to those of morphine (ED = 2.1

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mg/Kg) in the hot plate test, whereas (-)-phenazocine was nearly 20 times more potent than

morphine (ED = 0.11 mg/Kg) [25, 26]. Prezzavento found that phenazocine enantiomers

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acted as strong analgesics in mechanical pain models, which have mixed σ receptor

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antagonist and µ receptor agonist profiles [24]. Recently, Mónica García proposed using a

merging strategy to design a new series of 1-oxa-4,9-diazaspiro [5.5] undecane derivatives

(7) (Fig. 2) as potential dual ligands for σ and µ receptors [27], given its balanced dual

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profile and fit to the pharmacophore model. In the mice paw pressure test, Compound 7

(ED = 15 mg/kg) showed analgesic activity comparable to that of oxycodone (ED = 4.3

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mg/kg) and induced less constipation than oxycodone at equal doses. Thus, these novel

compounds with dual pharmacology of σ₁and µ receptors, such as phenazocine

enantiomers and Compound 7 are potential candidates for novel analgesic treatments.

In this study, novel ligands with dual σ and µ receptor pharmacology were explored.

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N-phenylpropionamide is an important pharmacophore of fentanyl (8) and its derivatives,

with the piperidine ring acting as the essential group [28, 29]. Rui et al. reported that

RC-106 (9), which contains 4-benzylpiperidine, exhibits good affinity for both σ and σ₂

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receptors (K σ = 12 nM, K σ = 22 nM) and thus has promise as a novel anticancer drug

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targeting σ receptors [30]. Here we developed piperidamide derivatives (10) using

molecular hybridization to link the N-arylpropionamide of fentanyl with the

4-benzylpiperidine of RC-106 (Fig. 3). As a σ receptor antagonist and µ receptor agonist,

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compound 44 exhibits basic pharmacophore features, including hydrogen bond acceptors

(green), hydrophobic groups (blue), positively ionizable groups (red), and hydrophobic

aromatic rings (orange-blue; Fig. 4). Which is consistent with the pharmacophore model

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proposed by Mónica García [27].

In this study, we synthesized a series of novel compounds of piperidamide derivatives,

which were used in structure–activity relationship (SAR) studies evaluating their

pharmacological efficacy and in competitive receptor binding assays to determine their

relative affinity for σ and µ opioid receptors in vitro. These analyses revealed that

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Compound 44 exhibited high affinity for σ and µ receptors and displayed dose-dependent

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anti-nociceptive effects in the formalin test and potent analgesic activity in a CCI model.

Therefore, Compound 44 is a hit compound with a mixed σ /µ receptor ligand that may be

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useful for treating neuropathic pain.

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2. Chemistry

The reaction pathways for the synthesis of the novel compounds studied are outlined

in Schemes 1. We synthesized 2-chloro-N-phenylacetamide derivatives 12a–12k by

substituting different aromatic amines 11a–11k with chloroacetyl chloride (Scheme 1).

Subsequently, a substitution reaction with 4-benzylpiperidine was used to prepare

intermediates 13a–13k. The reduction reaction with intermediates 13a–13k using LiAlH as

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a reducing agent in anhydrous tetrahydrofuran generated intermediates 14a–14k. We

prepared Compounds 15–25 (Scheme 1, Table 1) by reacting 14a–14k with propionyl

chloride, using triethylamine as a base in dichloromethane (DCM) under an ice bath. We

synthesized Compounds 31–36 (Scheme 1, Table 2) by reacting 4-methoxyaniline (11b)

with 3-chloropropionyl chloride (4-chlorobutyryl chloride or 5-chlorovalerylchloride) and

then coupling it with 4-substituted piperidine following the same reaction pathway.

Intermediates 12b–12d reacted with 4-(4-methylbenzyl) piperidine or 4-(4-fluorobenzyl)

piperidine to obtain the target Compounds 43–48 (Scheme 1, Tables 3–5). Finally, to reduce

the oiliness of the compounds, we converted all target products into oxalate for more

convenient pharmacological experiments. The free base was dissolved in ethyl acetate, 1.05

equivalents of oxalic acid dihydrate were added, and the mixture was stirred at room

temperature for 4 hours to generate oxalate of target compounds.

3. Results and discussion

3.1 Receptor affinity and SAR analyses

The novel series of 4-benzyl piperidamide derivatives were designed according to the

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pharmacophoric characteristics of σ receptor and µ receptor ligands. The parent structure

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of the compounds (Fig. 3) were devised to ensure that the 4-substituted piperidine ring and

propionamide acted as the primary scaffolds and to maintain the effects of different

arylamines. We investigated all synthesized compounds with radioligand binding assay to

analyze their affinity for σ and µ receptors. Some of the tested compounds had mixed

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nanomolar affinity for σ and µ receptors in vitro (Tables 1–5).

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We investigated the influence of phenylamino and other various arylamines on affinity

for σ and µ receptors (Table 1, Compounds 15–25). Phenylamino group (Compound 15)

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showed high µ receptor affinity (K µ = 3.7 nM) and moderate σ affinity (K σ = 38.6 nM).

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These results may be attributed to the presence of N-phenylpropionamide, a common group

of fentanyl and its derivatives. It is interesting that Compounds 16–18, with methoxyl,

methyl, or fluorine substituted at the 4-position of phenylamino group, all bound to σ₁

receptor with high affinity, but had slightly decreased affinity for µ receptor, which suggests

that the changes to phenylamino group are negligible (Compound 16: K σ = 1.5 nM, K µ

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= 20.4 nM; Compound 17: K σ = 1.6 nM, K µ = 16.7 nM; Compound 18: K σ = 4.1 nM,

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K µ = 19.4 nM). Compound 19, which contained 3,4,5-trifluoro-phenylamino group, had

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weakened σ receptor binding affinity and did not bind to µ receptor. Compound 20 (K σ =

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402 nM, K µ = 238 nM), which contained a pyridine ring in place of the benzene ring in

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Compound 15, had attenuated affinity for the two types of receptor. We used

3-fluoropyridin-2-amine and 6-(trifluoromethyl) pyridin-2-amine to synthesize Compounds

21 and 22 to investigate reduced activity of the pyridine ring. Compound 21 (K σ = 506

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nM, K µ = 253 nM) had similar affinity for both σ and µ receptors as Compound 20,

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whereas Compound 22 had no affinity for either receptor. Compounds 23 and 24, which

included additional carbon atoms between the benzene ring and the amino group, each

bound moderately to σ receptor (Compound 23: K σ = 17.4 nM, Compound 24: K σ =

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18.7 nM) and had low affinity for µ receptor. In Compound 25, 2-phenylethylamino group

replaced the phenylamino group, resulting in lower σ receptor binding affinity (K σ = 269

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nM) and no affinity for µ receptor, likely because of the length of the benzene ring and the

amino group linker.

These findings indicate that the N-phenylpropionamide derivatives have the strongest

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affinity for σ and µ receptors, with Compound 16 showing the highest σ receptor binding

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affinity (K σ = 1.5 nM) and moderate µ receptor affinity (K µ = 20.4 nM; Table 1). These

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analyses indicate that the spatial distance between phenylpropanamide and the piperidine

ring has mildly weakened the binding affinity for σ receptor, and significantly decrease the

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affinity for µ receptor (Compound 31: K σ = 2.2 nM, K µ = 43 nM; Compound 32: K σ

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= 18 nM, K µ = 78 nM; Compound 33: K σ = 42 nM, K µ = 165 nM; Table 2). The

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effects of linker length between phenyl and the piperidine ring were explored. Compound

34 (K σ = 39 nM, K µ = 26 nM), which substituted 4-benzylpiperidine with

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4-phenylpiperidine, bound with moderate affinity to both receptors. Compound 35 (K σ =

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372 nM, K µ = 82 nM) and Compound 36 (K σ = 893 nM, K µ = 74 nM), σ activity was

i i 1 i 1

significantly reduced and bound with moderate affinity to µ receptor as the carbon chain

grew. We found that 4-phenylpiperidine group was the optimal parent structure, and two

carbon atoms between the piperidine ring and amide group was the optimal linker length.

Because 4-benzylpiperidine and phenylpropanamide were linked by two carbon atoms

and showed strong affinity for both σ and µ receptors. Analogs with different substituents

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at the para position of the benzene ring were synthesized. The 4-benzylpiperidine of

Compound 16 was substituted with 4-(4-methylbenzyl) piperidine or 4-(4-fluorobenzyl) to

produce Compounds 43 and 44 (Table 3). Compound 43 (K σ = 35 nM, K µ = 77 nM) had

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slightly weakened affinity for σ and µ receptors, whereas Compound 44 (K σ = 1.86 nM,

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K µ = 2.1 nM) maintained high affinity for σ receptor and bound strongly to µ receptor,

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which suggests that the electron-withdrawing fluorine atoms may have yielded improved

activity. Similarly, Compounds 45 and 46 were derived from Compound 17 (Table 4) and

Compounds 47 and 48 were derived from Compound 18 (Table 5). The in vitro affinity of

Compound 45 (K σ = 29 nM, K µ = 82 nM) reduced mildly from that of Compound 17.

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Moreover, Compound 46 (K σ = 2.4 nM, K µ = 27.9 nM) varied marginally for both

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receptors. Compound 47 (K σ₁= 47 nM, K µ = 148 nM), which contained

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4-(4-methylbenzyl) piperidine, exhibited reduced affinity compared to Compound 18.

However, Compound 48 (K σ₁= 1.3 nM, K µ = 5.6 nM), which contained

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4-(4-fluorobenzyl) piperidine and 4-fluorophenyl propenamide, exhibited high affinity for

both receptors.

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3.2 Selectivity profile

Because Compounds 44 and 48 possessed high affinity for σ and µ, their selectivity

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with other receptors related to pain (e.g., σ , serotoninergic-1A, serotoninergic-2A, H , CB ,

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CB ) was investigated with an in vitro binding assay (summarized in the supporting

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information). Compounds 44 and 48 bound weakly to all other receptors (inhibition at 1

µM < 50%; Table 6).

3.3 Acute toxicity

Compounds 44 and 48 bound to σ and µ receptors with high affinity and

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demonstrated high selectivity compared to other receptors. An acute toxicity test was

performed subcutaneously (s.c.) to assess the safety profiles (median lethal dose, LD ) of

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these compounds (Table 7). Compounds 44 (LD₅₀= 396.7 mg/kg) and 48 (LD = 415.8

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mg/kg) yielded a higher LD value than S1RA (LD = 357.4 mg/kg).

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3.4 Formalin test

The antiallodynic activity of Compounds 44 and 48 was investigated with the formalin

test. Formalin-induced nociceptive behavior in mice is characterized by a typical acute

chemical nociceptive pain response (Phase I) and subsequent persistent pain response

(Phase II). The acute pain response results from the stimulation of subcutaneous

chemoreceptors and Group C nerve fibers that transmit the pain signal. The secondary pain

response is the combined result of central sensitization of the pain stimulus and a peripheral

inflammatory response. We assessed the pain response in mice by measuring the time spent

licking or biting the injected paw after injection[31, 32].

Mice were pretreated with Compounds 44 and 48 or S1RA at a dose of 50 mg/kg (s.c.)

30 min before the formalin injection. The S1RA (50 mg/kg s.c.) treatment group showed a

negligible decline in licking/biting time in Phase I and 273 ± 12.15 s spent licking/biting in

Phase II. Compound 44 inhibited the formalin-induced nociceptive behavior more

effectively, reducing licking/biting time to 21 ± 3.25 s in Phase I and 63 ± 4.53 s in Phase II.

Compound 48 reduced licking/biting time to 36 ± 3.54 s and 110 ± 9.47 s in Phase I and

Phase II, respectively (Fig. 5).

The analgesic effects of Compound 44 were further investigated at different doses

(12.5–100 mg/kg). In Phase II, licking/biting time decreased significantly as the dose

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increased (201 ± 12.86 s, 108 ± 7.61 s, 63 ± 4.53 s, and 41 ± 2.31 s at 12.5, 25, 50, and 100

mg/kg s.c., respectively), demonstrating dose-dependent analgesic effects (Fig. 6). The

ED value was 15.1 ± 1.67 mg/kg for Phase II in the formalin test. The therapeutic index

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(TI = LD50/ED50) of Compound 44 in the formalin test was 26.27, which indicates

improved safety compared to S1RA (TI = 11.98, in previous studies).

3.5 CCI model

The chronic constriction injury (CCI) model is the most widely used tool for studying

neuropathic pain [33], as it allows investigators to study the main characteristics of

neuropathic pain, including spontaneous pain, hyperalgesia, and allodynia [34]. The CCI

model involves mechanical hyperalgesia and is relatively stable. The mechanical

withdrawal threshold (MWT) was measured as an indicator of mechanical allodynia.

Compound 44 (25 mg/kg) was evaluated in a rat CCI model of neuropathic pain and

yielded an analgesic effect equivalent to that of S1RA (50 mg/kg; Fig. 7). At day 15,

Compound 44 showed dose-dependent inhibition of mechanical allodynia with a

single-dose treatment, with an ED value of 44.14 ± 3.25 mg/kg.

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4. Conclusion

This report details the synthesis of and structure–activity relationships among a novel

series of piperidine propionamide derivatives. Several factors affected the binding affinity

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for σ and µ receptors in this family of compounds. The results showed that phenylamino

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group or para-substituted phenylamino group were the optimal scaffold and two carbon

units was the most suitable linker length between phenylpropanamide and the piperidine

ring. In addition, the 4-(4-fluorobenzyl) piperidine showed the most potent σ /µ receptor

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affinity. Of all compounds studied, Compound 44 exhibited the highest affinity for σ and µ

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receptors and an excellent selectivity profile. Compound 44 showed dose-dependent

analgesic effects in Phase II of the formalin test and exhibited anti-neuropathic pain effects

consistent with S1RA in the CCI model. These findings suggest that Compound 44 may be

a potential candidate drug for treating neuropathic pain.

5. Experimental

5.1 Chemistry experimental

All commercially available chemicals and reagents were used without further

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purification. Reagents were all of analytical grade (>99%) or of chemical purity (>95%).

Melting points were determined on a Mel-TEMP II meltingpoint apparatus and are

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uncorrected. H and C NMR spectra were recorded on a Bruker Avance III 400

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spectrometer at 400 MHz ( H) and 101 MHz ( C) or Bruker Avance III 600 spectrometer at

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600 MHz ( H) and 151 MHz ( C) using CDCl as solvent. Chemical shifts were given in δ

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values (ppm), using tetramethylsilane (TMS) as the internal standard; coupling constants (J)

were given in Hz. Signal multiplicities were characterized as s (singlet), d (doublet), t

(triplet), q (quartet), m (multiplet), br (broad signal). Analytical thin layer chromatography

(TLC) was performed on silica gel GF254. Column chromatographic purification was

carried out using silica gel. Compound purity is determined by high performance liquid

chromatography (HPLC), and all final test compounds were >95% purity.

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HPLC methods used the following: Agilent 1260 Infinity II spectrometer; column, Inert

Sustain C18 5.0 mm × 150 mm × 4.6 mm i.d. (SHIMADZU, Japan); mobile phase, 30

mmol NH COOH (ROE SCIENTIFIC INC, USA) aq/acetonitrile (Merck Company,

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Germany) 45/55; flow rate, 1.0 mL/min; column temperature, 40 °C. Compounds 12a-12d

[35], 12f [36], 12i [37], 12j-12k [38], 26a [39], 26b [40] were prepared according to the

reported procedures.

5.1.1 General method for preparation of compounds 12e, 12g, and 12h [35].

10.0 mmol of 3, 4, 5-trifluoroaniline, (or 3-fluoropyridin-2-amine or 6-(trifluoromethyl)

pyridin-2- amine), and potassium carbonate (20mmol) was dissolved in 50 mL acetone, and

stirred in an ice bath to 0 °C. Chloroacetyl chloride (12.0mmol) was slowly added dropwise

and stirred at room temperature for 4 hours. The reaction mixture was quenched with water

and extracted with ethyl acetate. The organic layer was washed with water and brine

successively, dried over anhydrous sodium sulfate, and concentrated in vacuum. The

resulting residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1)

to give the desired product 12e, 12g and 12h.

5.1.1.1 2-chloro-N-(3, 4, 5-trifluorophenyl) acetamide (12e).

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Yield: 86%.Beige solid, m. p. 115-119 °C. H NMR (400 MHz, CDCl ) δ 8.33 (s, 1H), 7.43

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– 7.21 (m, 2H), 4.19 (s, 2H). C NMR (101 MHz, CDCl ) δ 164.10, 152.43, 152.38, 152.33,

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152.28, 149.96, 149.91, 149.86, 149.81, 138.25, 135.77, 132.29, 132.24, 104.70, 104.45,

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42.66. MS (ESI) m/z 224.2 (calcd 224.0 for C H ClF NO [M + H] ).

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5.1.1.2 2-chloro-N-(3-fluoropyridin-2-yl) acetamide (12g).

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Yield: 79%. White solid, m. p. 129-132 °C. H NMR (400 MHz, CDCl ) δ 8.27 (s, 1H),

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7.80 (d, J = 4.7 Hz, 1H), 7.37 – 7.31 (m, 1H), 6.72 – 6.67 (m, 1H), 3.68 (s, 2H). C NMR

(101 MHz, CDCl ) δ 168.53, 148.31, 145.81, 139.17, 139.12, 122.98, 122.83, 113.35,

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+

113.32, 29.69. MS (ESI) m/z 189.2 (calcd 189.0 for C H ClFN O [M + H] ).

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5.1.1.3 2-chloro-N-(6-(trifluoromethyl) pyridin-2-yl) acetamide (12h)

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Yield: 81%. Pale yellow solid, m. p. 123-126 °C. H NMR (400 MHz, CDCl ) δ 8.95 (s,

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1H), 8.42 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.24 (s,

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2H). C NMR (101 MHz, CDCl ) δ 164.90, 150.55, 146.72, 146.37, 139.96, 122.35, 119.62,

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+

116.89, 116.86, 116.77, 42.65.MS (ESI) m/z 239.2 (calcd 239.0 for C H ClF N O [M +

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+

H] ).

5.1.2 General method for preparation of compounds 13a-13k.

A mixture of intermediate 12a (10mmol) (12b-12k) and 4-benzyl piperidine

(11.0mmol) in 100 mL acetone was stirred at room temperature for 8 hours in the presence

of potassium carbonate (30mmol). After the reaction was completed, it was quenched with

water, and extracted with ethyl acetate; the mixture was washed three times with saturated

brine and dried over anhydrous sodium sulfate. Distilling solvent under reduced pressure,

the crude product was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1)

to yield corresponding intermediates 13a-13k.

5.1.2.1 2-(4-benzylpiperidin-1-yl)-N-phenylacetamide (13a).

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Yield: 91%. White solid, m. p. 133-135 °C. H NMR (600 MHz, CDCl ) δ 9.20 (s, 1H),

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7.57 (d, J = 7.6 Hz, 2H), 7.34 – 7.31 (m, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.4 Hz,

1H), 7.14 (d, J = 7.1 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 3.07 (s, 2H), 2.87 (d, J = 11.7 Hz,

2H), 2.57 (d, J = 7.2 Hz, 2H), 2.18 (td, J = 11.8, 2.2 Hz, 2H), 1.69 (d, J = 12.7 Hz, 2H),

1

3

1.61 – 1.52 (m, 1H), 1.37 – 1.29 (m, 2H). C NMR (151 MHz, CDCl ) δ 168.77, 140.23,

3

137.64, 129.00, 128.93, 128.19, 125.88, 124.01, 119.34, 62.31, 54.23, 43.00, 37.20,

+

32.47.MS (ESI) m/z 309.2 (calcd 309.2 for C H N O [M + H] ).

2

0

25

2

5.1.2.2 2-(4-benzylpiperidin-1-yl)-N-(4-methoxyphenyl) acetamide (13b)

1

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

Yield: 84%. Brown solid, m. p. 141-143 °C. H NMR (600 MHz, CDCl ) δ 9.07 (s, 1H),

3

7.50 – 7.45 (m, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 7.0 Hz,

2H), 6.89 – 6.85 (m, 2H), 3.79 (s, 3H), 3.06 (s, 2H), 2.87 (d, J = 11.7 Hz, 2H), 2.57 (d, J =

7.2 Hz, 2H), 2.18 (td, J = 11.8, 2.2 Hz, 2H), 1.69 (d, J = 13.3 Hz, 2H), 1.61 – 1.52 (m, 1H),

1

3

1.33 (qd, J = 12.3, 3.8 Hz, 2H). C NMR (151 MHz, CDCl ) δ 168.50, 156.19, 140.27,

3

130.91, 129.02, 128.20, 125.90, 121.06, 114.11, 62.24, 55.45, 54.27, 43.02, 37.22, 32.48.

+

2

+

MS (ESI) m/z 339.2 (calcd 339.2 for C H N O [M + H] ).

2

1

27

2

5.1.2.3 2-(4-benzylpiperidin-1-yl)-N-(p-tolyl) acetamide (13c)

1

Yield: 89%. Yellow solid, m. p. 130-131 °C. H NMR (600 MHz, CDCl ) δ 9.12 (s, 1H),

3

1

2

3

7.45 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.16 – 7.10 (m,

4H), 3.06 (s, 2H), 2.87 (d, J = 11.7 Hz, 2H), 2.56 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.18 (td,

J = 11.8, 2.2 Hz, 2H), 1.69 (d, J = 13.3 Hz, 2H), 1.60 – 1.51 (m, 1H), 1.33 (qd, J = 12.3, 3.8

1

3

Hz, 2H). C NMR (151 MHz, CDCl ) δ 168.61, 140.27, 135.14, 133.58, 129.42, 129.02,

3

128.20, 125.89, 119.39, 62.31, 54.24, 43.01, 37.22, 32.48, 20.82. MS (ESI) m/z 323.2

+

(calcd 323.2 for C H N O [M + H] ).

2

1

27

2

5.1.2.4 2-(4-benzylpiperidin-1-yl)-N-(4-fluorophenyl) acetamide (13d)

1

Yield: 82%. Brown solid, m. p. 122-124 °C. H NMR (600 MHz, CDCl ) δ 9.19 (s, 1H),

3

7.56 – 7.50 (m, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.1 Hz,

2H), 7.04 – 6.99 (m, 2H), 3.07 (s, 2H), 2.87 (d, J = 11.7 Hz, 2H), 2.57 (d, J = 7.2 Hz, 2H),

2.19 (td, J = 11.8, 2.2 Hz, 2H), 1.70 (d, J = 13.3 Hz, 2H), 1.61 – 1.53 (m, 1H), 1.33 (qd, J =

1

3

12.3, 3.8 Hz, 2H). C NMR (151 MHz, CDCl ) δ 168.72, 159.96, 158.35, 140.20, 133.75,

3

133.73, 129.01, 128.20, 125.91, 121.04, 120.99, 115.61, 115.46, 62.18, 54.26, 42.99, 37.17,

+

32.46. MS (ESI) m/z 327.2 (calcd 327.2 for C H FN O [M + H] ).

2

0

24

2

5.1.2.5 2-(4-benzylpiperidin-1-yl)-N-(3, 4, 5-trifluorophenyl) acetamide (13e)

1

Yield: 95%. White solid, m. p. 135-137 °C. H NMR (400 MHz, CDCl ) δ 9.29 (s, 1H),

3

7.32 – 7.27 (m, 4H), 7.20 (dd, J = 8.3, 6.3 Hz, 1H), 7.15 (d, J = 7.0 Hz, 2H), 3.07 (s, 2H),

2.85 (d, J = 11.7 Hz, 2H), 2.58 (d, J = 7.1 Hz, 2H), 2.21 (td, J = 11.8, 2.2 Hz, 2H), 1.71 (d,

13

J = 13.1 Hz, 2H), 1.64 – 1.52 (m, 1H), 1.38 – 1.23 (m, 2H). C NMR (101 MHz, CDCl ) δ

3

169.11, 152.46, 152.35, 150.00, 149.89, 140.13, 133.33, 129.04, 128.25, 125.98, 103.75,

103.49, 99.95, 62.08, 54.30, 42.96, 37.14, 32.43.MS (ESI) m/z 363.3 (calcd 363.2 for

1

+

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

C H F N O [M + H] ).

20 22 3 2

5.1.2.6 2-(4-benzylpiperidin-1-yl)-N-(pyridin-2-yl) acetamide (13f)

1

Yield: 89%. Brown solid, m. p. 121-123 °C. H NMR (400 MHz, CDCl ) δ 9.67 (s, 1H),

3

8.33 – 8.29 (m, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 11.2, 4.5 Hz, 1H), 7.27 (t, J =

7.4 Hz, 2H), 7.20 – 7.11 (m, 3H), 7.04 – 6.99 (m, 1H), 3.09 (s, 2H), 2.86 (d, J = 11.5 Hz,

2H), 2.54 (d, J = 7.0 Hz, 2H), 2.16 (t, J = 11.4 Hz, 2H), 1.65 (d, J = 12.6 Hz, 2H), 1.60 –

1

3

1.47 (m, 1H), 1.45 – 1.38 (m, 2H). C NMR (101 MHz, CDCl ) δ 169.49, 150.92, 147.78,

3

140.22, 138.07, 128.88, 128.04, 125.71, 119.53, 113.61, 62.33, 54.16, 42.84, 37.10, 32.10.

+

MS (ESI) m/z 310.2 (calcd 310.2 for C H N O [M + H] ).

1

9

24

3

1

2

3

5.1.2.7 2-(4-benzylpiperidin-1-yl)-N-(3-fluoropyridin-2-yl) acetamide (13g)

1

Yield: 83%. Purple solid, m. p. 129-131 °C. H NMR (400 MHz, CDCl ) δ 9.77 (s, 1H),

3

8.28 (d, J = 4.6 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.31 – 7.26 (m, 2H), 7.20 (dd, J = 8.4, 6.3 Hz,

1H), 7.17 – 7.09 (m, 3H), 3.16 (s, 2H), 2.93 (d, J = 11.7 Hz, 2H), 2.56 (d, J = 7.1 Hz, 2H),

2.23 (td, J = 11.7, 2.2 Hz, 2H), 1.70 (d, J = 13.4 Hz, 2H), 1.63 – 1.48 (m, 1H), 1.40 – 1.31

1

3

(m, 2H). C NMR (101 MHz, CDCl ) δ 168.68, 151.57, 148.99, 143.92, 143.87, 140.29,

3

140.12, 140.01, 129.01, 128.18, 125.87, 123.79, 123.62, 121.02, 120.99, 62.24, 54.25,

+

42.98, 37.17, 32.42. MS (ESI) m/z 328.2 (calcd 328.2 for C H FN O [M + H] ).

1

9

23

3

5.1.2.8 2-(4-benzylpiperidin-1-yl)-N-(6-(trifluoromethyl) pyridin-2-yl) acetamide (13h)

1

Yield: 75%. White solid, m. p. 109-111 °C. H NMR (400 MHz, CDCl ) δ 9.73 (s, 1H),

3

8.46 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.28 (dd, J =

13.8, 6.3 Hz, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 7.1 Hz, 2H), 3.12 (s, 2H), 2.87 (d, J

= 11.6 Hz, 2H), 2.59 (d, J = 7.0 Hz, 2H), 2.19 (td, J = 11.7, 1.8 Hz, 2H), 1.68 (d, J = 13.4

1

3

Hz, 2H), 1.62 – 1.51 (m, 1H), 1.48 – 1.40 (m, 2H). C NMR (101 MHz, CDCl ) δ 170.20,

3

151.33, 146.57, 146.22, 140.42, 139.51, 129.07, 128.21, 125.89, 122.56, 119.84, 116.74,

115.97, 115.94, 62.55, 54.40, 42.95, 37.32, 32.12. MS (ESI) m/z 378.3 (calcd 378.2 for

+

C H F N O [M + H] ).

20

23

3

5.1.2.9 2-(4-benzylpiperidin-1-yl)-N-(1-phenylethyl) acetamide (13i)

1

Yield: 67%. Yellow solid, m. p. 122-124 °C. H NMR (400 MHz, CDCl ) δ 7.52 (d, J = 8.4

3

Hz, 1H), 7.36 – 7.22 (m, 7H), 7.18 (t, J = 7.3 Hz, 1H), 7.14 – 7.10 (m, 2H), 5.19 – 5.10 (m,

1H), 3.00 – 2.89 (m, 2H), 2.84 – 2.77 (m, 1H), 2.75 – 2.69 (m, 1H), 2.52 (d, J = 7.1 Hz,

1

2

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2H), 2.06 (qd, J = 11.7, 2.3 Hz, 2H), 1.66 – 1.57 (m, 2H), 1.56 – 1.50 (m, 1H), 1.49 (d, J =

1

3

6.9 Hz, 3H), 1.32 – 1.16 (m, 2H). C NMR (101 MHz, CDCl ) δ 169.60, 143.30, 140.24,

3

128.91, 128.51, 128.08, 127.08, 125.82, 125.76, 61.79, 54.13, 47.79, 42.89, 37.14, 32.23,

+

32.17, 22.02.MS (ESI) m/z 337.2 (calcd 337.2 for C H N O [M + H] ).

22

29

2

5.1.2.10 N-benzyl-2-(4-benzylpiperidin-1-yl) acetamide (13j)

1

Yield: 88%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.57 (s, 1H), 7.33 – 7.28 (m, 2H),

3

7.26 – 7.21 (m, 5H), 7.15 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 4.45 (d, J = 6.1 Hz,

2H), 2.98 (s, 2H), 2.76 (d, J = 11.6 Hz, 2H), 2.47 (d, J = 7.1 Hz, 2H), 2.05 (td, J = 11.7, 2.0

1

3

Hz, 2H), 1.58 (d, J = 13.0 Hz, 2H), 1.53 – 1.44 (m, 1H), 1.20 (qd, J = 12.4, 3.7 Hz, 2H). C

1

2

3

NMR (101 MHz, CDCl ) δ 170.29, 140.02, 138.32, 128.72, 128.33, 127.88, 127.13, 126.98,

3

125.55, 61.66, 54.02, 42.68, 42.48, 36.89, 31.94. MS (ESI) m/z 323.2 (calcd 323.2 for

+

C H N O [M + H] ).

21

27

2

5.1.2.11 2-(4-benzylpiperidin-1-yl)-N-phenethylacetamide (13k)

1

Yield: 82%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.25 – 7.21 (m, 6H), 7.17 – 7.12 (m,

3

3H), 7.07 (t, J = 7.4 Hz, 2H), 3.50 (q, J = 6.6 Hz, 2H), 2.83 (s, 2H), 2.76 (t, J = 6.8 Hz, 2H),

2.57 (d, J = 11.4 Hz, 2H), 2.44 (d, J = 6.9 Hz, 2H), 1.91 (t, J = 10.9 Hz, 2H), 1.47 (d, J =

1

3

13.2 Hz, 2H), 1.43 – 1.34 (m, 1H), 1.04 (qd, J = 12.5, 3.6 Hz, 2H). C NMR (101 MHz,

CDCl ) δ 169.73, 139.64, 138.24, 138.08, 128.40, 128.07, 127.91, 127.52, 126.76, 126.57,

3

125.75, 125.21, 61.19, 53.60, 53.48, 42.38, 38.99, 36.42, 34.91, 31.59, 31.54. MS (ESI)

+

m/z 337.2 (calcd 337.2 for C H N O [M + H] ).

2

29

2

5.1.3 General method for preparation of compounds 14a-14k.

The intermediate 13a (10mmol) (13b-13k) was dissolved in 100 mL of anhydrous THF

and stirred for 15 min in an ice bath. Then, LiAlH (20mmol) was added slowly, the

4

°

mixture was t refluxed at 65 C for 4 h. The reaction mixture was quenched with ethanol

°

under 0 C conditions, and extracted with ethyl acetate. The organic layer was washed with

5% NaOH solution, water and brine successively, and then dried over anhydrous Na SO₄

2

and concentrated in vacuum. The resulting residue was purified by silica gel

chromatography (petroleum ether/EtOAc = 1/2) to give the desired product 14a-14k.

5.1.3.1 N-(2-(4-benzylpiperidin-1-yl) ethyl) aniline (14a)

1

Yield: 80%. Brown oil. H NMR (600 MHz, CDCl ) δ 7.24 (t, J = 7.5 Hz, 2H), 7.17 – 7.13

3

1

3

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

(m, 3H), 7.11 (d, J = 7.0 Hz, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.59 (dd, J = 8.5, 0.9 Hz, 2H),

4.27 (s, 1H), 3.09 (t, J = 5.7 Hz, 2H), 2.83 (d, J = 11.6 Hz, 2H), 2.51 (dd, J = 12.7, 6.7 Hz,

4H), 1.87 (td, J = 11.8, 2.1 Hz, 2H), 1.59 (d, J = 13.2 Hz, 2H), 1.54 – 1.46 (m, 1H), 1.30 –

1

3

1.22 (m, 2H). C NMR (151 MHz, CDCl ) δ 148.47, 140.49, 129.01, 128.94, 128.00,

3

125.63, 116.98, 112.73, 56.88, 53.53, 43.05, 40.38, 37.83, 32.07. MS (ESI) m/z 295.2

+

(calcd 295.2 for C H N [M + H] ).

2

0

27

2

5.1.3.2 N-(2-(4-benzylpiperidin-1-yl) ethyl)-4-methoxyaniline (14b)

1

Yield: 71%. Colorless oil. H NMR (600 MHz, CDCl ) δ 7.26 – 7.22 (m, 2H), 7.17 – 7.13

3

(m, 1H), 7.10 (d, J = 6.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 9.2 Hz, 1H), 6.60 –

6.56 (m, 1H), 3.70 (s, 3H), 3.67 (s, 1H), 3.50 – 3.45 (m, 1H), 3.07 (t, J = 6.0 Hz, 1H), 2.85

(d, J = 11.5 Hz, 2H), 2.54 (tt, J = 18.0, 7.5 Hz, 4H), 1.94 – 1.86 (m, 2H), 1.60 (d, J = 11.5

1

2

3

13

Hz, 2H), 1.55 – 1.45 (m, 1H), 1.28 (qd, J = 12.4, 3.6 Hz, 2H). C NMR (151 MHz, CDCl )

3

δ 151.83, 142.80, 140.46, 128.92, 127.98, 125.60, 114.68, 113.99, 57.00, 55.59, 53.56,

+

43.01, 41.40, 37.79, 32.02. MS (ESI) m/z 325.2 (calcd 325.2 for C H N O [M + H] ).

2

1

29

2

5.1.3.3 N-(2-(4-benzylpiperidin-1-yl) ethyl)-4-methylaniline (14c)

1

Yield: 68%. Colorless oil. H NMR (600 MHz, CDCl ) δ 7.24 (td, J = 7.6, 3.5 Hz, 2H), 7.15

3

(dd, J = 12.0, 4.6 Hz, 1H), 7.11 (t, J = 6.4 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.57 – 6.51 (m,

2H), 4.09 (s, 1H), 3.09 (t, J = 6.1 Hz, 2H), 2.84 (d, J = 11.6 Hz, 2H), 2.56 – 2.49 (m, 4H),

2.22 (s, 3H), 1.88 (td, J = 11.8, 2.0 Hz, 2H), 1.60 (d, J = 12.9 Hz, 2H), 1.53 – 1.48 (m, 1H),

1

3

1.31 – 1.24 (m, 2H). C NMR (151 MHz, CDCl ) δ 146.31, 140.53, 129.54, 128.97,

3

128.03, 126.19, 125.65, 112.99, 56.99, 53.58, 43.08, 40.87, 37.86, 32.09, 20.28. MS (ESI)

+

m/z 309.2 (calcd 309.2 for C H N [M + H] ).

2

1

29

2

5.1.3.4 N-(2-(4-benzylpiperidin-1-yl) ethyl)-4-fluoroaniline (14d)

1

Yield: 65%. Brown oil. H NMR (600 MHz, CDCl ) δ 7.25 (t, J = 7.5 Hz, 2H), 7.15 (td, J =

3

7.1, 4.8 Hz, 2H), 7.11 (t, J = 6.5 Hz, 2H), 6.88 – 6.84 (m, 1H), 6.60 (d, J = 7.7 Hz, 1H),

6.53 – 6.48 (m, 1H), 4.17 (s, 1H), 3.10 (t, J = 6.0 Hz, 1H), 3.04 (t, J = 6.0 Hz, 1H), 2.87 –

2.81 (m, 2H), 2.54 – 2.49 (m, 4H), 1.91 – 1.85 (m, 2H), 1.60 (d, J = 12.3 Hz, 2H), 1.52 –

1

3

1.48 (m, 1H), 1.27 (td, J = 14.9, 4.1 Hz, 2H). C NMR (151 MHz, CDCl ) δ 148.51,

3

144.92, 140.53, 140.49, 128.97, 128.03, 125.66, 125.65, 116.99, 115.47, 115.32, 113.50,

113.45, 112.75, 56.90, 56.86, 53.56, 43.07, 41.08, 40.40, 37.85, 37.84, 32.10. MS (ESI) m/z

1

4

+

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

313.2 (calcd 313.2 for C H FN [M + H] ).

20 26 2

5.1.3.5 N-(2-(4-benzylpiperidin-1-yl) ethyl)-3, 4, 5-trifluoroaniline (14e)

1

Yield: 72%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.27 (t, J = 7.4 Hz, 2H), 7.21 – 7.11

3

(m, 3H), 6.18 – 6.09 (m, 2H), 4.46 (s, 1H), 3.00 (dd, J = 11.3, 5.4 Hz, 2H), 2.83 (d, J = 11.5

Hz, 2H), 2.53 (dd, J = 6.4, 3.7 Hz, 4H), 1.90 (td, J = 11.8, 2.1 Hz, 2H), 1.63 (d, J = 13.2 Hz,

1

3

2H), 1.53 – 1.47 (m, 1H), 1.27 (qd, J = 12.5, 3.7 Hz, 2H). C NMR (101 MHz, CDCl ) δ

3

153.17, 153.11, 153.07, 153.00, 150.74, 150.67, 150.63, 150.57, 144.63, 144.51, 144.49,

144.40, 140.55, 133.32, 133.17, 130.95, 130.80, 129.07, 128.13, 125.78, 96.16, 95.92,

+

56.37, 53.54, 43.12, 40.41, 37.90, 32.15. MS (ESI) m/z 349.2 (calcd 349.2 for C H F N

2

0

24

3

+

1

2

3

[M + H] ).

5.1.3.6 N-(2-(4-benzylpiperidin-1-yl) ethyl) pyridin-2-amine (14f)

1

Yield: 80%. Brown oil. H NMR (400 MHz, CDCl ) δ 8.07 (dd, J = 5.0, 1.1 Hz, 1H), 7.41 –

3

7.35 (m, 1H), 7.27 (dd, J = 10.4, 4.3 Hz, 2H), 7.20 – 7.11 (m, 3H), 6.55 – 6.50 (m, 1H),

6.38 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 3.31 (dd, J = 11.5, 5.6 Hz, 2H), 2.88 (d, J = 11.6 Hz,

2H), 2.57 – 2.51 (m, 4H), 1.92 (td, J = 11.7, 2.1 Hz, 2H), 1.65 – 1.58 (m, 2H), 1.57 – 1.46

1

3

(m, 1H), 1.34 – 1.25 (m, 2H). C NMR (101 MHz, CDCl ) δ 158.78, 148.04, 140.61,

3

137.19, 129.03, 128.08, 125.70, 112.47, 106.97, 56.94, 53.61, 43.13, 38.72, 37.90, 32.10.

+

MS (ESI) m/z 296.2 (calcd 296.2 for C H N [M + H] ).

1

9

26

3

5.1.3.7 N-(2-(4-benzylpiperidin-1-yl) ethyl)-3-fluoropyridin-2-amine (14g)

1

Yield: 69%. Colorless oil. H NMR (400 MHz, CDCl ) δ 7.87 (d, J = 5.0 Hz, 1H), 7.30 –

3

7.25 (m, 2H), 7.19 (dd, J = 7.8, 1.6 Hz, 1H), 7.17 – 7.12 (m, 2H), 7.11 – 7.07 (m, 1H), 6.50

– 6.46 (m, 1H), 5.27 (s, 1H), 3.51 (dd, J = 11.4, 5.8 Hz, 2H), 2.91 (d, J = 11.6 Hz, 2H), 2.59

(t, J = 6.1 Hz, 2H), 2.54 (d, J = 7.1 Hz, 2H), 1.94 (td, J = 11.7, 2.1 Hz, 2H), 1.63 (d, J =

1

3

13.5 Hz, 2H), 1.59 – 1.48 (m, 1H), 1.36 – 1.26 (m, 2H). C NMR (101 MHz, CDCl ) δ

3

148.89, 148.78, 148.51, 146.01, 142.70, 142.64, 140.71, 129.07, 128.13, 125.75, 119.82,

119.67, 111.43, 111.41, 57.00, 53.64, 43.17, 37.99, 37.70, 32.19. MS (ESI) m/z 314.2

+

(calcd 314.2 for C H FN [M + H] ).

1

9

25

3

5.1.3.8 N-(2-(4-benzylpiperidin-1-yl) ethyl)-6-(trifluoromethyl) pyridin-2-amine (14h)

1

Yield: 58%. Colorless oil. H NMR (400 MHz, CDCl ) δ 7.49 (t, J = 7.9 Hz, 1H), 7.27 (dd,

3

J = 12.5, 5.0 Hz, 2H), 7.21 – 7.12 (m, 3H), 6.89 (d, J = 7.3 Hz, 1H), 6.52 (d, J = 8.5 Hz,

1

5

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1H), 5.37 (s, 1H), 3.35 (dd, J = 11.6, 5.4 Hz, 2H), 2.88 (d, J = 11.6 Hz, 2H), 2.54 (dd, J =

9.8, 4.5 Hz, 4H), 1.92 (td, J = 11.7, 2.1 Hz, 2H), 1.63 (d, J = 13.1 Hz, 2H), 1.58 – 1.51 (m,

1

3

1H), 1.36 – 1.25 (m, 2H). C NMR (101 MHz, CDCl ) δ 158.59, 146.69, 146.36, 140.64,

3

137.83, 129.09, 128.14, 125.77, 123.05, 120.33, 110.02, 108.55, 108.51, 56.82, 53.67,

+

43.17, 38.58, 37.95, 32.12. MS (ESI) m/z 364.2 (calcd 364.2 for C H F N [M + H] ).

2

0

25

3

5.1.3.9 2-(4-benzylpiperidin-1-yl)-N-(1-phenylethyl) ethanamine (14i)

1

Yield: 73%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.36 – 7.27 (m, 4H), 7.27 – 7.14 (m,

3

4H), 7.12 (d, J = 7.9 Hz, 2H), 3.74 (q, J = 6.6 Hz, 1H), 2.92 (dd, J = 15.3, 5.9 Hz, 2H), 2.84

– 2.76 (m, 2H), 2.51 (dd, J = 6.9, 4.0 Hz, 2H), 2.47 – 2.34 (m, 2H), 2.25 (s, 1H), 1.89 –

1

3

1

2

3

1.74 (m, 2H), 1.66 – 1.51 (m, 3H), 1.37 (d, J = 6.6 Hz, 3H), 1.34 – 1.16 (m, 2H). C NMR

(101 MHz, CDCl ) δ143.24, 140.48, 128.89, 128.22, 128.03, 127.04, 126.73, 125.57, 61.74,

3

57.72, 47.75, 44.09, 42.98, 37.72, 32.18, 23.97. MS (ESI) m/z 323.2 (calcd 239.0 for

+

C H N [M + H] ).

2

31

2

5.1.3.10 N-benzyl-2-(4-benzylpiperidin-1-yl) ethanamine (14j)

1

Yield: 84%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.28 (d, J = 4.4 Hz, 4H), 7.26 – 7.18

3

(m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.0 Hz, 2H), 3.75 (s, 2H), 2.79 (d, J = 11.5 Hz,

2H), 2.65 (t, J = 6.2 Hz, 2H), 2.49 (d, J = 7.0 Hz, 2H), 2.42 (t, J = 6.2 Hz, 3H), 1.82 (td, J =

11.7, 1.7 Hz, 2H), 1.57 (d, J = 12.8 Hz, 2H), 1.49 – 1.42 (m, 1H), 1.25 (qd, J = 12.4, 3.6 Hz,

1

3

2H). C NMR (101 MHz, CDCl ) δ 140.35, 140.07, 128.78, 128.03, 127.83, 127.80,

3

126.55, 125.45, 57.78, 53.70, 53.64, 45.62, 42.91, 37.64, 31.91. MS (ESI) m/z 309.2 (calcd

+

309.2 for C H N [M + H] ).

2

1

29

2

5.1.3.11 2-(4-benzylpiperidin-1-yl)-N-phenethylethanamine (14k)

1

Yield: 70%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.32 – 7.23 (m, 5H), 7.22 – 7.16 (m,

3

3H), 7.12 (d, J = 7.0 Hz, 2H), 2.90 – 2.84 (m, 2H), 2.81 (dd, J = 12.9, 6.8 Hz, 4H), 2.72 –

2.64 (m, 2H), 2.50 (t, J = 6.0 Hz, 2H), 2.46 – 2.37 (m, 2H), 2.20 (s, 1H), 1.84 (td, J = 11.8,

1

3

1.9 Hz, 2H), 1.58 (dd, J = 16.9, 6.9 Hz, 2H), 1.50 – 1.40 (m, 1H), 1.31 – 1.14 (m, 2H). C

NMR (101 MHz, CDCl ) δ 140.59, 139.94, 128.98, 128.59, 128.33, 128.01, 125.99, 125.63,

3

57.89, 53.89, 51.11, 46.50, 43.10, 37.80, 36.18, 32.06. MS (ESI) m/z 323.2 (calcd 323.2 for

+

C H N [M + H] ).

2

31

2

5.1.4 General method for preparation of compounds 15-25.

1

6

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

Propionyl chloride (9.0mmol) was added slowly to the solution of 14a (3.0mmol)

(14b-14k) and Et N (18.0mmol) in DCM (30mL) under ice-cooled, and the mixture was

3

°

stirred at 0 C for 3h. The mixture was diluted with saturated aqueous NaHCO , and

3

extracted with DCM, and the organic layer was washed with saturated aqueous NaHCO₃

and brine, and then dried over anhydrous Na SO concentrated in vacuo. The residue was

2

4,

purified by column chromatography on silica gel (petroleum ether/EtOAc = 1/1) to afford

the free base of compounds 15-25.

5.1.4.1 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-phenylpropionamide (15)

1

Yield: 65%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 7.44 – 7.34 (m, 2H), 7.31 (t, J =

3

1

2

3

7.3 Hz, 1H), 7.25 (dd, J = 10.4, 4.2 Hz, 2H), 7.21 – 7.14 (m, 3H), 7.14 – 7.07 (m, 2H), 3.88

– 3.78 (m, 2H), 2.84 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 7.1 Hz, 2H), 2.48 – 2.42 (m, 2H),

2.02 (q, J = 7.3 Hz, 2H), 1.96 – 1.83 (m, 2H), 1.58 (d, J = 12.9 Hz, 2H), 1.54 – 1.42 (m,

1

3

1H), 1.29 – 1.19 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.44,

3

142.68, 140.51, 129.35, 128.94, 128.28, 127.96, 127.60, 125.58, 55.62, 53.79, 46.40, 43.06,

+

37.68, 32.04, 27.64, 9.48. MS (ESI) m/z 351.2 (calcd 351.2 for C H N O [M + H] ).

2

3

31

2

5.1.4.2 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(4-methoxyphenyl) propionamide (16)

1

Yield: 72%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 7.26 (dd, J = 8.0, 6.8 Hz, 2H),

3

7.17 (t, J = 7.4 Hz, 1H), 7.15 – 7.05 (m, 4H), 6.88 (t, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.81 –

3.76 (m, 2H), 2.85 (d, J = 11.3 Hz, 2H), 2.51 (d, J = 7.0 Hz, 2H), 2.47 – 2.42 (m, 2H), 2.01

(q, J = 7.5 Hz, 2H), 1.90 (t, J = 10.9 Hz, 2H), 1.59 (d, J = 12.8 Hz, 2H), 1.54 – 1.42 (m,

1

3

1H), 1.35 – 1.13 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.97,

3

158.78, 140.64, 135.45, 129.39, 129.05, 128.07, 125.68, 114.53, 55.68, 55.40, 53.90, 46.47,

+

43.16, 37.79, 32.13, 27.66, 9.57. MS (ESI) m/z 381.2 (calcd 381.3 for C H N O [M + H]

2

4

33

2

+

).

5.1.4.3 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(p-tolyl) propionamide (17)

1

Yield: 83%. Colorless oil. H NMR (400 MHz, CDCl ) δ 7.26 (t, J = 7.3 Hz, 2H), 7.20 –

3

7.11 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H), 3.83 – 3.77 (m, 2H), 2.85 (d, J = 11.4 Hz, 2H), 2.50

(d, J = 7.1 Hz, 2H), 2.47 – 2.42 (m, 2H), 2.37 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 1.90 (t, J =

10.8 Hz, 2H), 1.58 (d, J = 13.0 Hz, 2H), 1.55 – 1.42 (m, 1H), 1.32 – 1.18 (m, 2H), 1.02 (t, J

1

3

= 7.4 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.72, 140.63, 140.11, 137.56, 130.05,

3

17

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

129.04, 128.05, 125.67, 113.05, 55.69, 53.90, 46.46, 43.16, 37.78, 32.13, 27.68, 21.02, 9.58.

+

MS (ESI) m/z 365.2 (calcd 365.3 for Chemical Formula: C H N O [M + H] ).

24

33

2

5.1.4.4 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(4-fluorophenyl) propionamide (18)

1

Yield: 78%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 7.30 – 7.23 (m, 2H), 7.22 –

3

7.15 (m, 3H), 7.14 – 7.11 (m, 2H),7.10 – 7.04 (m, 2H), 3.79 (t, J = 7.1 Hz, 2H), 2.83 (d, J =

11.5 Hz, 2H), 2.51 (d, J = 7.1 Hz, 2H), 2.46 – 2.41 (m, 2H), 2.05 – 1.96 (m, 2H), 1.94 –

1.84 (m, 2H), 1.59 (d, J = 12.9 Hz, 2H), 1.55 – 1.43 (m, 1H), 1.28 – 1.16 (m, 2H), 1.03 (t, J

1

3

= 7.4 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.58, 162.91, 160.44, 140.57, 138.77,

3

138.74, 130.18, 130.09, 129.04, 128.06, 125.69, 116.41, 116.19, 55.68, 53.85, 46.45, 43.13,

+

1

2

3

37.77, 32.11, 27.74, 9.51. MS (ESI) m/z 369.2 (calcd 369.2 for C H FN O [M + H] ).

23 30 2

5.1.4.5 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(3, 4, 5-trifluorophenyl) propionamide (19)

1

Yield: 60%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 7.27 (t, J = 7.4 Hz, 2H), 7.20 –

3

7.10 (m, 3H), 7.01 – 6.95 (m, 2H), 3.78 (t, J = 6.7 Hz, 2H), 2.89 (d, J = 11.4 Hz, 2H), 2.57

– 2.48 (m, 4H), 2.06 (d, J = 6.7 Hz, 2H), 1.99 – 1.92 (m, 2H), 1.62 (d, J = 12.9 Hz, 2H),

1

3

1.53 – 1.47 (m, 1H), 1.30 – 1.22 (m, 2H), 1.09 – 1.03 (m, 3H). C NMR (101 MHz, CDCl )

3

δ 173.13, 152.40, 152.35, 152.30, 152.25, 149.89, 149.84, 149.79, 149.74, 140.38, 140.10,

138.16, 128.99, 128.09, 125.75, 113.54, 113.32, 55.42, 53.56, 46.20, 42.98, 37.60, 31.67,

+

27.73, 9.36. MS (ESI) m/z 405.2 (calcd 405.2 for C H F N O [M + H] ).

23

28

3

2

5.1.4.6 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(pyridin-2-yl) propionamide (20)

1

Yield: 65%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 8.53 – 8.45(m, 1H), 7.73 (td, J

3

= 7.8, 2.0 Hz, 1H), 7.29 – 7.23 (m, 3H), 7.22 – 7.14 (m, 2H), 7.13 – 7.08 (m, 2H), 3.99 –

3.93 (m, 2H), 2.82 (d, J = 11.6 Hz, 2H), 2.55 – 2.46 (m, 4H), 2.21 (q, J = 7.3 Hz, 2H), 1.90

(td, J = 11.7, 2.1 Hz, 2H), 1.56 (d, J = 13.4 Hz, 2H), 1.46 – 1.35 (m, 1H), 1.21 – 1.13 (m,

1

3

2H), 1.08 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.54, 155.60, 149.02,

3

140.50, 138.00, 128.99, 128.00, 125.63, 122.13, 121.99, 56.26, 53.82, 45.38, 43.05, 37.62,

+

31.97, 27.99, 9.44. MS (ESI) m/z 352.2 (calcd 352.2 for C H N O [M + H] ).

2

30

3

5.1.4.7 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(3-fluoropyridin-2-yl) propionamide (21)

1

Yield: 79%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 8.30 (d, J = 4.3 Hz, 1H), 7.47 –

3

7.39 (m, 1H), 7.30 – 7.22 (m, 3H), 7.21 – 7.14 (m, 1H), 7.12 – 7.05 (m, 2H), 3.94 (t, J = 6.8

Hz, 2H), 2.73 (d, J = 11.4 Hz, 2H), 2.52 (t, J = 6.8 Hz, 2H), 2.44 (d, J = 6.8 Hz, 2H), 2.13 (s,

1

8

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2H), 1.85 (t, J = 10.8 Hz, 2H),1.48 (d, J = 13.0 Hz, 2H), 1.42 –1.36 (m, 1H), 1.08 (t, J = 7.4

13

Hz, 3H), 1.02 – 0.89 (m, 2H). C NMR (101 MHz, CDCl ) δ 173.28, 155.72, 153.14,

3

144.68, 144.55, 144.29, 144.23, 140.39, 129.04, 127.97, 125.62, 124.62, 124.43, 124.03,

56.60, 53.61, 44.78, 42.98, 37.46, 31.78, 27.07, 27.05, 9.16. MS (ESI) m/z 370.2 (calcd

+

370.2 for C H FN O [M + H] ).

2

29

3

5.1.4.8

N-(2-(4-benzylpiperidin-1-yl)

ethyl)-N-(6-(trifluoromethyl)

pyridin-2-yl)

propionamide (22)

1

Yield: 65%. Yellow oil. H NMR (600 MHz, CDCl ) δ 7.80 (t, J = 7.9 Hz, 1H), 7.67 (d, J =

3

6.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.5 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.09

(d, J = 7.1 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 2.80 (d, J = 11.5 Hz, 2H), 2.55 (t, J = 6.8 Hz,

2H), 2.46 (d, J = 7.0 Hz, 2H), 2.41 (dd, J = 14.5, 7.2 Hz, 2H), 1.93 – 1.88 (m, 2H), 1.53 (d,

1

2

3

1

3

J = 12.7 Hz, 2H), 1.50 – 1.42 (m, 1H), 1.15 (t, J = 7.4 Hz, 3H), 1.09 – 1.02 (m, 2H). C

NMR (151 MHz, CDCl ) δ 173.78, 155.34, 140.14, 138.58, 128.79, 127.78, 125.42, 123.54,

3

121.77, 119.96, 117.00, 56.55, 53.54, 44.74, 42.75, 37.28, 31.66, 28.16, 9.21. MS (ESI) m/z

+

420.2 (calcd 420.2 for C H F N O [M + H] ).

2

3

29

3

5.1.4.9 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-(1-phenylethyl) propionamide (23)

Yield: 63%. Pale yellow oil. Spectroscopic data of amide 23 were obtained as a mixture of

1

two rotational isomers. H NMR (400 MHz, CDCl ) δ 7.35 – 7.28 (m, 3H), 7.25 (td, J = 7.5,

3

3.9 Hz, 4H), 7.21 – 7.13 (m, 1H), 7.12 – 7.06 (m, 2H), 3.23 – 3.07 (m, 2H), 2.69 – 2.60 (m,

2H), 2.47 (dd, J = 9.8, 4.9 Hz, 3H), 2.38 (dd, J = 14.8, 7.3 Hz, 2H), 2.30 – 2.12 (m, 1H),

1.96 – 1.77 (m, 2H), 1.71 (td, J = 11.7, 2.0 Hz, 1H), 1.60 (d, J = 6.9 Hz, 1H), 1.58 – 1.51 (m,

13

2H), 1.50 – 1.47 (m, 2H), 1.42 – 1.34 (m, 1H), 1.29 – 1.13 (m, 5H). C NMR (101 MHz,

CDCl ) δ 174.12, 173.69, 141.18, 140.75, 140.67, 140.57, 129.18, 129.16, 128.73, 128.47,

3

128.25, 128.21, 127.84, 127.66, 127.47, 126.91, 125.91, 125.82, 58.60, 56.75, 55.02, 54.41,

54.17, 53.79, 51.00, 43.25, 43.19, 41.49, 40.81, 37.79, 37.76, 32.08, 26.99, 26.85, 18.45,

+

16.80, 9.98, 9.69. MS (ESI) m/z 379.2 (calcd 379.3 for C H N O [M + H] ).

2

5

35

2

5.1.4.10 N-benzyl-N-(2-(4-benzylpiperidin-1-yl) ethyl) propionamide (24)

Yield: 55%. Pale yellow oil. Spectroscopic data of amide 24 were obtained as a mixture of

1

two rotational isomers. H NMR (400 MHz, CDCl ) δ 7.33 – 7.21 (m, 6H), 7.17 – 7.09 (m,

3

4H), 4.61 and 4.55 (pair of s, due to rotamers, 2H), 3.53 (t, J = 6.6 Hz, 1H), 3.33 (s, 1H),

1

9

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

3.02 and 2.83 (pair of d, due to rotamers, J = 10.7 Hz, J = 10.5 Hz, 2H), 2.63 (d, J = 6.3 Hz,

1H), 2.50 (d, J = 3.2 Hz, 2H), 2.45 – 2.39 (m, 2H), 2.36 – 2.30 (m, 1H), 2.05 (t, J = 11.4 Hz,

1H), 1.97 – 1.89 (m, 1H), 1.61 (d, J = 12.2 Hz, 2H), 1.50 (s, 1H), 1.39 – 1.24 (m, 2H), 1.19

1

3

and 1.10 (pair of t, due to rotamers, J = 7.1 Hz, J = 7.3 Hz, 3H). C NMR (101 MHz,

CDCl ) δ 173.99, 173.64, 140.04, 139.96, 137.61, 136.64, 128.73, 128.52, 128.20, 127.87,

3

127.69, 127.18, 126.93, 125.97, 125.55, 56.24, 54.69, 53.74, 53.07, 51.16, 48.49, 43.96,

42.66, 42.61, 42.54, 37.29, 37.09, 31.42, 30.86, 28.46, 26.05, 25.84, 9.49, 9.42, 9.11. MS

+

(ESI) m/z 365.2 (calcd 365.3 for C H N O [M + H] ).

2

4

33

2

5.1.4.11 N-(2-(4-benzylpiperidin-1-yl) ethyl)-N-phenethylpropionamide (25)

1

2

3

Yield: 51%. Pale yellow oil. Spectroscopic data of amide 25 were obtained as a mixture of

1

two rotational isomers. H NMR (400 MHz, CDCl ) δ 7.32 – 7.24 (m, 4H), 7.23 – 7.18 (m,

3

2H), 7.18 – 7.11 (m, 4H), 3.54 – 3.46 (m, 3H), 3.26 – 3.21 (m, 1H), 2.91 (d, J = 11.6 Hz,

1H), 2.88 – 2.77 (m, 3H), 2.51 (d, J = 7.1 Hz, 2H), 2.50 – 2.45 (m, 1H), 2.39 – 2.30 (m,

2H), 2.14 (q, J = 7.4 Hz, 1H), 1.99 – 1.87 (m, 2H), 1.62 (d, J = 12.7 Hz, 2H), 1.55 – 1.48

(m, 1H), 1.33 – 1.20 (m, 2H), 1.15 and 1.04 (pair of t, due to rotamers, J = 7.4 Hz, J = 7.4

1

3

Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.46, 173.44, 140.48, 140.34, 139.29, 138.15,

3

128.96, 128.95, 128.73, 128.59, 128.31, 128.04, 128.01, 126.55, 126.11, 125.70, 125.64,

57.11, 56.00, 54.26, 54.01, 49.93, 48.62, 46.14, 43.50, 43.04, 42.96, 37.65, 37.59, 35.26,

34.01, 32.03, 31.97, 26.15, 25.88, 9.46, 9.30. MS (ESI) m/z 379.2 (calcd 379.3 for

+

C H N O [M + H] ).

25

35

2

5.1.5 General method for preparation of 5-chloro-N-(4-methoxyphenyl) pentanamide

(26c).

4-chlorobutyryl chloride (15.0 mmol) was added dropwise to a mixture of the

4-methoxyaniline (10.0 mmol) in 50 mL acetone under ice bath conditions. After the

addition is completed, stirring for 4 h at room temperature, the reaction mixture was

quenched with water and extracted with ethyl acetate. The organic layer was washed with

water and brine successively, dried over anhydrous sodium sulfate, and concentrated in

vacuum. The resulting residue was purified by silica gel chromatography (petroleum

ether/EtOAc = 10/1) to give the intermediate 26c.

1

Yield: 67%. Pale yellow oil. H NMR (400 MHz, CDCl ) δ 8.01 (s, 1H), 7.39 (d, J = 8.9 Hz,

3

2

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2H), 6.81 (d, J = 8.9 Hz, 2H), 3.76 (s, 3H), 3.52 (t, J = 5.8 Hz, 2H), 2.34 (t, J = 6.8 Hz, 2H),

1

3

1.83 – 1.78 (m, 4H). C NMR (101 MHz, CDCl ) δ 171.01, 156.28, 130.92, 121.99,

3

113.93, 55.35, 44.52, 36.16, 31.82, 22.84. MS (ESI) m/z 242.2 (calcd 242.1 for

+

C H ClNO [M + H] ).

12

17

2

5.1.6 General method for preparation of compounds 27a-27c.

A mixture of intermediate 26a (10mmol) (26b-26c) and 4-benzyl piperidine (11.0mmol)

in 100 mL acetone was stirred at room temperature for 8 hours in the presence of potassium

carbonate (30mmol). After the reaction was completed, it was quenched with water, and

extracted with ethyl acetate; the mixture was washed three times with saturated brine and

dried over anhydrous sodium sulfate. Distilling solvent under reduced pressure, the crude

product was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to yield

corresponding intermediates 27a-27c.

1

2

3

5.1.6.1 3-(4-benzylpiperidin-1-yl)-N-(4-methoxyphenyl) propanamide (27a)

1

Yield: 90%. Brown solid, m. p. 139-141 °C. H NMR (400 MHz, CDCl ) δ 10.80 (s, 1H),

3

7.48 – 7.42 (m, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.0 Hz,

2H), 6.87 – 6.79 (m, 2H), 3.75 (s, 3H), 3.11 (d, J = 11.7 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H),

2.61 (t, J = 6.1 Hz, 2H), 2.56 (d, J = 7.0 Hz, 2H), 2.14 (t, J = 11.1 Hz, 2H), 1.74 (d, J = 12.9

1

3

Hz, 2H), 1.69 – 1.58 (m, 1H), 1.48 – 1.35 (m, 2H). C NMR (101 MHz, CDCl ) δ 169.71,

3

155.68, 139.69, 131.80, 128.90, 128.09, 125.86, 120.95, 113.89, 55.25, 53.52, 52.78, 42.45,

+

37.10, 32.19, 31.33. MS (ESI) m/z 353.2 (calcd 353.2 for C H N O [M + H] ).

2

29

2

5.1.6.2 4-(4-benzylpiperidin-1-yl)-N-(4-methoxyphenyl) butanamide (27b)

1

Yield: 85%. Brown solid, m. p. 138-139 °C. H NMR (400 MHz, CDCl ) δ 9.20 (s, 1H),

3

7.43 (t, J = 6.1 Hz, 2H), 7.30 – 7.23 (m, 2H), 7.18 (q, J = 6.9 Hz, 1H), 7.13 – 7.08 (m, 2H),

6.82 (t, J = 6.1 Hz, 2H), 3.74 (s, 3H), 2.88 (d, J = 11.4 Hz, 2H), 2.50 (d, J = 7.0 Hz, 2H),

2.40 – 2.31 (m, 4H), 1.91 – 1.80 (m, 4H), 1.67 – 1.58 (m, 2H), 1.57 – 1.50 (m, 1H), 1.33 –

1

3

1.21 (m, 2H). C NMR (101 MHz, CDCl ) δ 171.41, 155.84, 140.24, 131.46, 128.84,

3

127.97, 125.62, 121.61, 113.77, 57.35, 55.20, 53.44, 42.87, 37.58, 35.34, 31.77, 22.28. MS

+

(ESI) m/z 367.3 (calcd 367.2 for C H N O [M + H] ).

2

3

31

2

5.1.6.3 5-(4-benzylpiperidin-1-yl)-N-(4-methoxyphenyl) pentanamide (27c)

1

Yield: 75%. Brown solid, m. p. 116-118 °C. H NMR (400 MHz, CDCl ) δ 8.36 (s, 1H),

3

2

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

7.42 (d, J = 9.0 Hz, 2H), 7.26 (dd, J = 8.4, 6.4 Hz, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.11 (d, J =

7.1 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 3.74 (s, 3H), 2.89 (d, J = 11.5 Hz, 2H), 2.50 (d, J =

7.0 Hz, 2H), 2.32 (t, J = 7.3 Hz, 4H), 1.86 (t, J = 11.1 Hz, 2H), 1.68 (dt, J = 14.9, 7.4 Hz,

2H), 1.61 (d, J = 14.7 Hz, 2H), 1.57 – 1.52 (m, 2H), 1.51 – 1.46 (m, 1H), 1.35 – 1.24 (m,

1

3

2H). C NMR (101 MHz, CDCl ) δ 171.51, 156.05, 140.36, 131.25, 128.94, 128.03,

3

125.68, 121.87, 113.84, 58.05, 55.29, 53.68, 42.90, 37.61, 36.84, 31.63, 26.02, 23.58. MS

+

(ESI) m/z 381.2 (calcd 381.2 for C H N O [M + H] ).

2

4

33

2

5.1.7 General method for preparation of compounds 28a-28c.

A mixture of intermediate 12b (10mmol) and 4-Phenylpiperidine (11.0mmol)

( 4-phenethyl- piperidine or 4-(3-phenylpropyl) piperidine) in 100 mL acetone was stirred

at room temperature for 8 hours in the presence of potassium carbonate (30mmol). After the

reaction was completed, it was quenched with water, and extracted with ethyl acetate; the

mixture was washed three times with saturated brine and dried over anhydrous sodium

sulfate. Distilling solvent under reduced pressure, the crude product was purified by silica

gel chromatography (petroleum ether/EtOAc = 1/1) to yield corresponding intermediates

28a-28c.

1

2

3

5.1.7.1 N-(4-methoxyphenyl)-2-(4-phenylpiperidin-1-yl) acetamide (28a)

1

Yield: 72%. Brown solid, m. p. 115-117 °C. H NMR (400 MHz, CDCl ) δ 9.10 (s, 1H),

3

7.53 – 7.48 (m, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.23 (dd, J = 15.3, 7.0 Hz, 3H), 6.90 – 6.85

(m, 2H), 3.78 (s, 3H), 3.14 (s, 2H), 3.02 (d, J = 11.6 Hz, 2H), 2.55 (tt, J = 11.9, 3.8 Hz, 1H),

1

3

2.38 (td, J = 11.7, 2.4 Hz, 2H), 1.91 (d, J = 10.7 Hz, 2H), 1.86 – 1.76 (m, 2H). C NMR

(101 MHz, CDCl ) δ 168.48, 156.32, 145.74, 130.95, 128.55, 126.81, 126.39, 121.23,

3

116.42, 114.21, 62.40, 55.52, 54.79, 41.81, 33.71. MS (ESI) m/z 325.2 (calcd 325.2for

+

C H N O [M + H] ).

20

25

2

5.1.7.2 N-(4-methoxyphenyl)-2-(4-phenethylpiperidin-1-yl) acetamide (28b)

1

Yield: 84%. Brown solid, m. p. 125-126 °C. H NMR (400 MHz, CDCl ) δ 9.28 (s, 1H),

3

7.50 (d, J = 8.9 Hz, 2H), 7.28 (dd, J = 13.7, 6.6 Hz, 2H), 7.19 (t, J = 7.7 Hz, 3H), 6.90 –

6.84 (m, 2H), 3.79 (s, 3H), 3.16 (s, 2H), 2.96 (d, J = 10.5 Hz, 2H), 2.67 – 2.60 (m, 2H),

2.31 (s, 2H), 1.81 (d, J = 9.5 Hz, 2H), 1.60 (dt, J = 7.7, 5.8 Hz, 2H), 1.41 – 1.27 (m, 3H).

1

3

C NMR (101 MHz, CDCl ) δ 168.82, 156.23, 142.35, 130.88, 128.33, 128.24, 125.73,

3

2

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

121.11, 116.37, 114.09, 61.96, 55.44, 54.14, 50.48, 38.10, 34.43, 32.98. MS (ESI) m/z

+

353.2 (calcd 353.2 for C H N O [M + H] ).

2

29

2

5.1.7.3 N-(4-methoxyphenyl)-2-(4-(3-phenylpropyl) piperidin-1-yl) acetamide (28c)

1

Yield: 87%. Brown solid, m. p. 119-122 °C. H NMR (400 MHz, CDCl ) δ 9.09 (s, 1H),

3

7.50 – 7.44 (m, 2H), 7.29 – 7.23 (m, 2H), 7.19 – 7.13 (m, 3H), 6.87 – 6.81 (m, 2H), 3.74 (s,

3H), 3.03 (s, 2H), 2.84 (d, J = 11.5 Hz, 2H), 2.62 – 2.56 (m, 2H), 2.17 (t, J = 11.1 Hz, 2H),

1

3

1.72 – 1.66 (m, 2H), 1.61 (dd, J = 15.2, 7.6 Hz, 2H), 1.32 – 1.19 (m, 5H). C NMR (101

MHz, CDCl ) δ 168.37, 155.95, 142.31, 130.76, 128.13, 128.04, 125.45, 120.82, 116.09,

3

113.87, 62.11, 55.42, 55.18, 54.15, 35.87, 35.83, 34.78, 32.45, 28.41. MS (ESI) m/z 367.2

+

1

2

3

(calcd 367.2 for C H N O [M + H] ).

23 31 2 2

5.1.8 General method for preparation of compounds 29a-29c, 30a-30c.

The intermediate 27a (10mmol) (27b-27c, 28a-28c) was dissolved in 100 mL of

anhydrous THF and stirred for 15 min in an ice bath. Then, LiAlH (20mmol) was added

4

°

slowly, the mixture was t refluxed at 65 C for 4 h. The reaction mixture was quenched with

°

ethanol under 0 C conditions, and extracted with ethyl acetate. The organic layer was

washed with 5% NaOH solution, water and brine successively, and then dried over

anhydrous Na SO and concentrated in vacuum. The resulting residue was purified by silica

2

4

gel chromatography (petroleum ether/EtOAc = 1/2) to give the desired product 29a-29c,

30a-30c.

5.1.8.1 N-(3-(4-benzylpiperidin-1-yl) propyl)-4-methoxyaniline (29a)

1

Yield: 72%. Yellow oil. H NMR (400 MHz, CDCl ) δ 7.30 – 7.23 (m, 2H), 7.21 – 7.11 (m,

3

3H), 6.80 – 6.74 (m, 2H), 6.57 – 6.51 (m, 2H), 3.89 (s, 1H), 3.72 (s, 3H), 3.09 (t, J = 6.4 Hz,

2H), 2.91 (d, J = 11.6 Hz, 2H), 2.54 (d, J = 7.0 Hz, 2H), 2.41 (t, J = 6.8 Hz, 2H), 1.88 –

1.80 (m, 2H), 1.80 – 1.71 (m, 2H), 1.64 (d, J = 13.1 Hz, 2H), 1.54 – 1.46 (m, 1H), 1.38 –

1

3

1.24 (m, 2H). C NMR (101 MHz, CDCl ) δ 151.67, 142.97, 140.44, 128.97, 128.93,

3

127.99, 125.62, 114.73, 113.79, 57.43, 55.63, 53.84, 44.32, 43.01, 37.77, 32.12, 25.99. MS

+

(ESI) m/z 339.2 (calcd 339.2 for C H N O [M + H] ).

2

31

2

5.1.8.2 N-(4-(4-benzylpiperidin-1-yl) butyl)-4-methoxyaniline (29b)

1

Yield: 67%. Yellow oil. H NMR (400 MHz, CDCl ) δ 7.31 – 7.24 (m, 3H), 7.21 – 7.11 (m,

3

3H), 6.81 – 6.74 (m, 2H), 6.59 – 6.54 (m, 1H), 3.91 (s, 1H), 3.74 (s, 3H), 3.07 (t, J = 6.3 Hz,

2

3

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2H), 2.94 – 2.80 (m, 2H), 2.52 (t, J = 5.5 Hz, 2H), 2.29 (dt, J = 15.2, 7.4 Hz, 2H), 1.89 –

1

3

1.74 (m, 2H), 1.63 – 1.58 (m, 4H), 1.56 – 1.45 (m, 3H), 1.38 – 1.27 (m, 2H). C NMR

(101 MHz, CDCl ) δ 151.86, 142.75, 140.67, 129.07, 128.11, 125.72, 114.85, 113.92, 58.54,

3

55.79, 53.89, 44.77, 43.18, 37.94, 32.12, 27.55, 24.76. MS (ESI) m/z 353.2 (calcd 353.3 for

+

C H N O [M + H] ).

23

33

2

5.1.8.3 N-(5-(4-benzylpiperidin-1-yl) pentyl)-4-methoxyaniline (29c)

1

Yield: 62%. Yellow oil. H NMR (400 MHz, CDCl ) δ 7.27 (dd, J = 10.1, 4.6 Hz, 2H), 7.21

3

– 7.12 (m, 4H), 6.80 – 6.74 (m, 2H), 6.59 – 6.53 (m, 1H), 3.85 (s, 1H), 3.74 (s, 3H), 3.05 (t,

J = 7.1 Hz, 2H), 2.88 (t, J = 12.1 Hz, 2H), 2.52 (dd, J = 6.9, 3.2 Hz, 2H), 2.33 – 2.23 (m,

2H), 1.82 (dd, J = 21.3, 11.2 Hz, 2H), 1.62 (dd, J = 14.4, 7.1 Hz, 4H), 1.55 – 1.44 (m, 3H),

1

2

3

1

3

1.38 (dt, J = 11.7, 5.7 Hz, 2H), 1.33 – 1.22 (m, 2H). C NMR (101 MHz, CDCl ) δ 151.93,

3

142.74, 140.69, 129.08, 128.10, 125.71, 114.85, 113.98, 58.95, 55.79, 53.96, 44.86, 43.18,

+

37.94, 32.11, 29.54, 26.84, 25.23. MS (ESI) m/z 367.2 (calcd 367.3 for C H N O [M + H]

2

4

35

2

+

).

5.1.8.4 4-methoxy-N-(2-(4-phenylpiperidin-1-yl) ethyl) aniline (30a)

1

Yield: 75%. Brown oil. H NMR (600 MHz, CDCl ) δ 7.31 – 7.27 (m, 2H), 7.24 – 7.17 (m,

3

3H), 6.81 – 6.77 (m, 2H), 6.63 – 6.60 (m, 2H), 3.73 (s, 1H), 3.71 (s, 3H), 3.14 (t, J = 6.0 Hz,

2H), 3.02 (d, J = 11.5 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.50 (tt, J = 11.8, 4.1 Hz, 1H), 2.09

1

3

(td, J = 11.6, 2.6 Hz, 2H), 1.82 (d, J = 12.2 Hz, 2H), 1.80 – 1.74 (m, 2H). C NMR (151

MHz, CDCl ) δ 151.96, 146.21, 142.87, 128.30, 126.72, 126.03, 114.80, 114.12, 57.15,

3

+

55.71, 54.10, 42.55, 41.52, 33.38. MS (ESI) m/z 311.2 (calcd 311.2 for C H N O [M + H]

2

0

27

2

+

).

5.1.8.5 4-methoxy-N-(2-(4-phenethylpiperidin-1-yl) ethyl) aniline (30b)

1

Yield: 69%. Brown oil. H NMR (600 MHz, CDCl ) δ 7.30 – 7.25 (m, 2H), 7.17 (dt, J = 9.0,

3

3.8 Hz, 3H), 6.80 – 6.76 (m, 2H), 6.62 – 6.59 (m, 2H), 3.75 (s,1H), 3.74 (s, 3H), 3.11 (t, J =

6.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 2.62 (dd, J = 9.1, 7.0 Hz, 2H), 2.58 (dd, J = 11.3,

5.2 Hz, 2H), 1.95 (t, J = 10.4 Hz, 2H), 1.72 (d, J = 9.1 Hz, 2H), 1.59 – 1.54 (m, 2H), 1.30 –

1

3

1.25 (m, 3H). C NMR (151 MHz, CDCl ) δ 152.01, 142.98, 142.73, 128.28, 128.27,

3

125.60, 114.86, 114.18, 57.21, 55.82, 53.75, 41.58, 38.37, 35.37, 33.08, 32.31. MS (ESI)

+

m/z 339.2 (calcd 339.2 for C H N O [M + H] ).

2

31

2

4

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

5.1.8.6 4-methoxy-N-(2-(4-(3-phenylpropyl) piperidin-1-yl) ethyl) aniline (30c)

1

Yield: 82%. Brown oil. H NMR (400 MHz, CDCl ) δ 7.24 (dd, J = 9.3, 5.5 Hz, 2H), 7.17 –

3

7.11 (m, 3H), 6.77 – 6.74 (m, 2H), 6.59 – 6.54 (m, 2H), 3.87 (s, 1H), 3.69 (s, 3H), 3.07 (t, J

= 6.0 Hz, 2H), 2.84 (d, J = 11.3 Hz, 2H), 2.54 (dt, J = 12.3, 6.8 Hz, 4H), 1.90 (t, J = 11.0

1

3

Hz, 2H), 1.63 (d, J = 10.6 Hz, 2H), 1.61 – 1.55 (m, 1H), 1.29 – 1.15 (m, 6H). C NMR

(101 MHz, CDCl ) δ 151.76, 142.79, 142.44, 128.14, 128.03, 125.42, 116.12, 114.63,

3

113.94, 57.05, 55.53, 53.66, 41.37, 36.02, 35.95, 35.54, 32.20, 28.50. MS (ESI) m/z 353.2

+

(calcd 353.3 for C H N O [M + H] ).

2

3

33

2

5.1.9 General method for preparation of compounds 31-36.

1

2

3

Propionyl chloride (9.0mmol) was added slowly to the solution of 29a (3.0mmol)

(29b-29c, 30a-30c) and Et N (18.0mmol) in DCM (30mL) under ice-cooled, and the

3

°

mixture was stirred at 0 C for 3h. The mixture was diluted with saturated aqueous NaHCO ,

3

and extracted with DCM, and the organic layer was washed with saturated aqueous

NaHCO and brine, and then dried over anhydrous Na SO concentrated in vacuo. The

3

2

4,

residue was purified by column chromatography on silica gel to (petroleum ether/EtOAc =

1/1) afford the free base of compounds 31-36.

5.1.9.1 N-(3-(4-benzylpiperidin-1-yl) propyl)-N-(4-methoxyphenyl) propionamide (31)

1

Yield: 58%. Yellow oil. H NMR (400 MHz, CDCl ) δ 7.25 (t, J = 7.3 Hz, 2H), 7.16 (t, J =

3

7.3 Hz, 2H), 7.13 – 7.05 (m, 3H), 6.91 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.67 (t, J = 7.1 Hz,

2H), 3.16 (d, J = 11.6 Hz, 2H), 2.62 – 2.56 (m, 2H), 2.52 (d, J = 6.7 Hz, 2H), 2.14 (t, J =

11.1 Hz, 2H), 2.02 (q, J = 7.4 Hz, 2H), 1.82 (dt, J = 14.9, 7.4 Hz, 2H), 1.66 (d, J = 12.9 Hz,

1

3

2H), 1.60 – 1.54 (m, 1H), 1.51 – 1.45 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). C NMR (101

MHz, CDCl ) δ 173.84, 158.57, 139.60, 134.47, 128.81, 128.58, 127.79, 125.51, 114.43,

3

54.98, 54.68, 52.50, 46.70, 42.20, 36.70, 34.92, 30.03, 28.86, 27.23, 23.54, 9.16. MS (ESI)

+

2

+

m/z 395.2 (calcd 395.3 for C H N O [M + H] ).

2

5

35

2

5.1.9.2 N-(4-(4-benzylpiperidin-1-yl) butyl)-N-(4-methoxyphenyl) propionamide (32)

1

Yield: 52%. Beige oil. H NMR (400 MHz, CDCl ) δ 7.27 (dd, J = 12.2, 5.0 Hz, 2H), 7.20 –

3

7.11 (m, 3H), 7.05 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.65 (t, J =

6.9 Hz, 2H), 2.94 (d, J = 11.4 Hz, 2H), 2.52 (d, J = 7.0 Hz, 2H), 2.39 – 2.33 (m, 2H), 2.01

(q, J = 7.5 Hz, 2H), 1.91 (t, J = 11.2 Hz, 2H), 1.63 (d, J = 12.5 Hz, 2H), 1.55 – 1.46 (m, 5H),

2

5

1

3

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1.43 – 1.31 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). C NMR (101 MHz, CDCl ) δ 173.92,

3

158.76, 140.39, 135.11, 129.15, 128.94, 128.03, 125.66, 114.62, 58.27, 55.32, 53.58, 48.64,

42.89, 37.60, 31.51, 29.54, 27.60, 25.57, 23.55, 9.53. MS (ESI) m/z 409.2 (calcd 409.3 for

+

C H N O [M + H] ).

26

37

2

5.1.9.3 N-(5-(4-benzylpiperidin-1-yl) pentyl)-N-(4-methoxyphenyl) propionamide (33)

1

Yield: 61%. Beige oil. H NMR (400 MHz, CDCl ) δ 7.26 (t, J = 7.8 Hz, 2H), 7.18 (d, J =

3

7.2 Hz, 1H), 7.13 (t, J = 6.6 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H),

3.82 (s, 3H), 3.66 – 3.61 (m, 2H), 2.88 (d, J = 11.5 Hz, 2H), 2.52 (d, J = 7.0 Hz, 2H), 2.28 –

2.23 (m, 2H), 2.01 (q, J = 7.4 Hz, 2H), 1.83 (t, J = 10.9 Hz, 2H), 1.61 (d, J = 12.6 Hz, 2H),

1

3

1

2

3

1.53 – 1.45 (m, 5H), 1.36 – 1.25 (m, 4H), 1.02 (t, J = 7.5 Hz, 3H). C NMR (101 MHz,

CDCl ) δ 173.83, 158.73, 140.57, 135.28, 129.18, 128.98, 128.01, 125.62, 114.60, 58.69,

3

55.33, 53.71, 48.97, 43.05, 37.80, 31.88, 27.64, 27.51, 26.48, 24.74, 9.57. MS (ESI) m/z

+

423.2 (calcd 423.3 for C H N O [M + H] ).

2

7

39

2

5.1.9.4 N-(4-methoxyphenyl)-N-(2-(4-phenylpiperidin-1-yl) ethyl) propionamide (34)

1

Yield: 43%. Colorless oil. H NMR (600 MHz, CDCl ) δ 7.28 (dd, J = 10.0, 5.2 Hz, 2H),

3

7.20 (d, J = 7.1 Hz, 2H), 7.17 (dd, J = 10.2, 4.3 Hz, 1H), 7.15 – 7.11 (m, 2H), 6.93 – 6.89

(m, 2H), 3.86 – 3.83 (m, 2H), 3.81 (s, 3H), 3.00 (d, J = 11.5 Hz, 2H), 2.54 – 2.51 (m, 2H),

2.46 (tt, J = 11.8, 3.8 Hz, 1H), 2.09 (td, J = 11.7, 2.3 Hz, 2H), 2.04 (q, J = 7.5 Hz, 2H), 1.79

1

3

(d, J = 10.9 Hz, 2H), 1.72 (qd, J = 12.5, 3.6 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H). C NMR

(151 MHz, CDCl ) δ 173.85, 158.69, 146.19, 135.34, 129.25, 128.16, 126.61, 125.86,

3

114.44, 55.66, 55.25, 54.19, 46.35, 42.35, 33.27, 27.54, 9.48. MS (ESI) m/z 367.2 (calcd

+

367.2 for C H N O [M + H] ).

2

3

31

2

5.1.9.5 N-(4-methoxyphenyl)-N-(2-(4-phenethylpiperidin-1-yl) ethyl) propionamide (35)

1

Yield: 49%. Colorless oil. H NMR (600 MHz, CDCl ) δ 7.25 (dd, J = 8.9, 5.9 Hz, 2H),

3

7.18 – 7.14 (m, 3H), 7.12 – 7.08 (m, 2H), 6.91 – 6.88 (m, 2H), 3.81 (s, 3H), 3.79 (d, J = 7.3

Hz, 2H), 2.87 (d, J = 11.5 Hz, 2H), 2.60 (dd, J = 9.1, 7.1 Hz, 2H), 2.47 – 2.43 (m, 2H), 2.02

(q, J = 7.5 Hz, 2H), 1.93 (t, J = 10.9 Hz, 2H), 1.68 (d, J = 9.6 Hz, 2H), 1.56 – 1.51 (m, 2H),

1

3

1.27 – 1.17 (m, 3H), 1.02 (t, J = 7.5 Hz, 3H). C NMR (151 MHz, CDCl ) δ 173.88,

3

158.73, 142.66, 135.43, 129.32, 128.17, 128.14, 125.47, 114.47, 55.73, 55.32, 53.87, 46.44,

+

38.35, 35.19, 32.98, 32.24, 27.60, 9.53. MS (ESI) m/z 395.2 (calcd 395.3 for C H N O

2

5

35

2

6

+

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

[M + H] ).

5.1.9.6 N-(4-methoxyphenyl)-N-(2-(4-(3-phenylpropyl) piperidin-1-yl) ethyl) propionamide

(36)

1

Yield: 66%. Beige oil. H NMR (400 MHz, CDCl ) δ 7.28 – 7.22 (m, 2H), 7.15 (dd, J = 6.9,

3

4.0 Hz, 3H), 7.08 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 3.87 – 3.81 (m, 2H), 3.80 (s,

3H), 3.00 (d, J = 10.6 Hz, 2H), 2.62 – 2.54 (m, 4H), 2.10 – 1.98 (m, 4H), 1.65 (d, J = 8.7

1

3

Hz, 2H), 1.61 – 1.53 (m, 1H), 1.31 – 1.19 (m, 6H), 1.05 – 0.98 (m, 3H). C NMR (101

MHz, CDCl ) δ 173.89, 158.66, 142.27, 135.01, 128.99, 128.04, 127.94, 125.34, 114.43,

3

55.13, 54.83, 53.24, 45.73, 35.81, 35.68, 34.96, 31.24, 28.46, 28.35, 27.37, 9.31. MS (ESI)

+

1

2

3

m/z 409.2 (calcd 409.3 for C H N O [M + H] ).

26 37 2 2

5.1.10 General method for preparation of compounds 37a-37b, 38a-38b, 39a-39b.

A mixture of intermediate 12b (10mmol)(12c, 12d) and 4-(4-methylbenzyl) piperidine

or (11.0 mmol) (4-(4-fluorobenzyl) piperidine) in 100 mL acetone was stirred at room

temperature for 8 hours in the presence of potassium carbonate (30mmol). After the

reaction was completed, it was quenched with water, and extracted with ethyl acetate; the

mixture was washed three times with saturated brine and dried over anhydrous sodium

sulfate. Distilling solvent under reduced pressure, the crude product was purified by silica

gel chromatography (petroleum ether/EtOAc = 1/1) to yield corresponding intermediates

37a-37b, 38a-38b, and 39a-39b.

5.1.10.1 N-(4-methoxyphenyl)-2-(4-(4-methylbenzyl) piperidin-1-yl) acetamide (37a)

1

Yield: 92%. Beige solid, m. p. 120-121 °C. H NMR (400 MHz, CDCl ) δ 9.08 (s, 1H),

3

7.48 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 8.9

Hz, 2H), 3.73 (s, 3H), 3.03 (s, 2H), 2.83 (d, J = 11.5 Hz, 2H), 2.49 (d, J = 7.1 Hz, 2H), 2.30

(s, 3H), 2.13 (t, J = 11.0 Hz, 2H), 1.65 (d, J = 12.4 Hz, 2H), 1.56 – 1.48 (m, 1H), 1.30 (qd, J

13

= 12.5, 3.6 Hz, 2H). C NMR (101 MHz, CDCl ) δ 168.23, 155.90, 136.92, 134.98, 130.72,

3

128.67, 128.64, 120.79, 113.82, 62.01, 55.11, 54.00, 42.31, 37.01, 32.19, 20.75. MS (ESI)

+

2

+

m/z 353.2 (calcd 353.2 for C H N O [M + H] ).

2

29

2

5.1.10.2 2-(4-(4-fluorobenzyl) piperidin-1-yl)-N-(4-methoxyphenyl) acetamide (37b)

1

Yield: 90%. Beige solid, m. p. 133-135 °C. H NMR (400 MHz, CDCl ) δ 9.07 (s, 1H),

3

7.51 – 7.44 (m, 2H), 7.13 – 7.06 (m, 2H), 7.01 – 6.93 (m, 2H), 6.91 – 6.84 (m, 2H), 3.79 (s,

27

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

3H), 3.07 (s, 2H), 2.88 (d, J = 11.7 Hz, 2H), 2.54 (d, J = 7.1 Hz, 2H), 2.19 (td, J = 11.7, 2.0

1

3

Hz, 2H), 1.67 (d, J = 13.0 Hz, 2H), 1.59 – 1.46 (m, 1H), 1.37 – 1.22 (m, 2H). C NMR

(101 MHz, CDCl ) δ 168.47, 162.50, 160.08, 156.20, 135.85, 135.82, 130.86, 130.33,

3

130.25, 121.07, 115.06, 114.85, 114.10, 62.21, 55.44, 54.21, 42.13, 37.28, 32.35. MS (ESI)

+

m/z 357.2 (calcd 357.2 for C H FN O [M + H] ).

2

1

26

2

5.1.10.3 2-(4-(4-methylbenzyl) piperidin-1-yl)-N-(p-tolyl) acetamide (38a)

1

Yield: 88%. White solid, m. p. 126-128 °C. H NMR (400 MHz, CDCl ) δ 9.14 (s, 1H),

3

7.45 (d, J = 8.3 Hz, 2H), 7.11 (dd, J = 12.9, 8.1 Hz, 4H), 7.03 (d, J = 7.9 Hz, 2H), 3.05 (s,

2H), 2.86 (d, J = 11.6 Hz, 2H), 2.52 (d, J = 7.1 Hz, 2H), 2.31 (d, J = 3.0 Hz, 6H), 2.16 (td, J

= 11.7, 2.0 Hz, 2H), 1.68 (d, J = 12.8 Hz, 2H), 1.59 – 1.46 (m, 1H), 1.37 – 1.24 (m, 2H).

1

2

3

1

3

C NMR (101 MHz, CDCl ) δ 168.59, 137.11, 135.25, 135.08, 133.51, 129.36, 128.84,

3

128.83, 119.34, 62.26, 54.20, 42.50, 37.22, 32.42, 20.91, 20.77. MS (ESI) m/z 337.2 (calcd

+

337.2 for C H N O [M + H] ).

2

29

2

5.1.10.4 2-(4-(4-fluorobenzyl) piperidin-1-yl)-N-(p-tolyl) acetamide (38b)

1

Yield: 94%. Beige solid, m. p. 119-121 °C. H NMR (400 MHz, CDCl ) δ 9.16 (s, 1H),

3

7.45 (d, J = 8.4 Hz, 2H), 7.15 – 7.07 (m, 4H), 7.00 – 6.93 (m, 2H), 3.08 (s, 2H), 2.89 (d, J =

11.7 Hz, 2H), 2.54 (d, J = 7.1 Hz, 2H), 2.31 (s, 3H), 2.25 – 2.16 (m, 2H), 1.67 (d, J = 13.1

1

3

Hz, 2H), 1.58 – 1.46 (m, 1H), 1.38 – 1.24 (m, 2H). C NMR (101 MHz, CDCl ) δ 168.48,

3

162.49, 160.07, 135.81, 135.78, 135.04, 133.67, 130.31, 130.24, 129.42, 119.43, 115.05,

114.84, 62.19, 54.14, 42.08, 37.23, 32.26, 20.81. MS (ESI) m/z 341.2 (calcd 341.2 for

+

C H FN O [M + H] ).

21

26

2

5.1.10.5 N-(4-fluorophenyl)-2-(4-(4-methylbenzyl) piperidin-1-yl) acetamide (39a)

1

Yield: 89%. White solid, m. p. 130-132 °C. H NMR (400 MHz, CDCl ) δ 9.21 (s, 1H),

3

7.56 – 7.51 (m, 2H), 7.08 (d, J = 7.8 Hz, 2H), 7.04 – 6.95 (m, 4H), 3.03 (s, 2H), 2.83 (d, J =

11.6 Hz, 2H), 2.50 (d, J = 7.1 Hz, 2H), 2.30 (s, 3H), 2.14 (dd, J = 11.5, 10.2 Hz, 2H), 1.66

1

3

(d, J = 12.2 Hz, 2H), 1.60 – 1.44 (m, 1H), 1.36 – 1.26 (m, 2H). C NMR (101 MHz, CDCl )

3

δ 168.53, 160.09, 157.67, 136.89, 135.04, 133.62, 128.68, 120.86, 120.78, 115.38, 115.16,

61.98, 54.02, 42.31, 37.00, 32.20, 20.75. MS (ESI) m/z 341.2 (calcd 341.2 for

+

C H FN O [M + H] ).

21

26

2

5.1.10.6 2-(4-(4-fluorobenzyl) piperidin-1-yl)-N-(4-fluorophenyl) acetamide (39b)

2

8

Article Doi

Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain

DOI: 10.1016/j.ejmech.2020.112144

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Article abstract of DOI:10.1016/j.ejmech.2020.112144

Full text of DOI:10.1016/j.ejmech.2020.112144

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