PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Med Chem. Author manuscript; available in PMC 2010 April 9.
Published in final edited form as:
PMCID: PMC2832311
NIHMSID: NIHMS103371

Selective 5-Hydroxytrytamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine – Identification of Drugs with Antidepressant-Like Action

Abstract

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37 with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10–60 mg/kg) decreased immobility time in the mouse forced swim test.

Introduction

Serotonin (5-HTa) (1) mediates or regulates a wide variety of behaviors including cognition, emotion, attention, and appetite among others.1,2 The diverse effects of this neurotransmitter are related to the extensive projections of serotonergic neurons throughout the brain and to the presence of at least 14 different receptor subtypes in humans.35 The 5-HT2 subtype family includes the 5-HT2A, 5-HT2B, and 5-HT2C receptors. The 5-HT2A receptor mediates the hallucinogenic activity of drugs such as lysergic acid diethylamide (LSD) and is a major target for treating schizophrenia as well as insomnia.6 The 5-HT2B receptor mediates the potentially lethal valvulopathic side effects of several compounds that were used as prescription drugs.79 Two decades after its initial identification, the 5-HT2C receptor has only recently emerged as a promising target in the treatment of depression, anxiety, eating disorders, obsessive-compulsive disorder, chronic pain conditions, obesity, epilepsy, and erectile dysfunction.1019 The 5-HT2C receptor is abundantly expressed throughout the central nervous system (CNS) and displays high-affinity interactions with a wide variety of psychiatric medications.2023 Due to the serious side effects caused by the activation of the pharmacologically and structurally closely related subtypes,24 it is essential that 5-HT2C agonists developed for clinical use have a high specificity and subtype selectivity. To date, a number of designed synthetic compounds have been identified that show 5-HT2C receptor agonistic activity (Figure 1).18,2531 Several compounds have shown efficacy in preclinical animal models and are currently being tested in clinical trials.32

Figure 1
The classical 5-HT2C receptor agonist m-CPP and several more recently developed 5-HT2C ligands.

Despite recent progress in obtaining crystal structures of G protein-coupled receptors,3335 information about the structure and function of 5-HT receptors is still restricted to homology modeling using rhodopsin or beta-adrenergic receptors as a starting template. However, it is well known that there are inherent limitations in the use of such homology models for drug design purposes36 and they still lack sufficient predictive power for drug discovery.37 Therefore, we based our search for selective 5-HT2C receptor agonists on high-throughput chemical library screening to identify a suitable lead structure followed by stepwise activity-guided chemical modification. Using this approach, we have identified the reversible monoamine oxidase (MAO) inhibitor tranylcypromine 938,39 as a lead compound from screening the Prestwick drug library of 800 compounds (Figure 2).40

Figure 2
Structures of 9 and its analogs.

In initial experiments, we then examined the effects of side chain homologation, stereochemistry, and amine substitution in 5-HT2A, 5-HT2B, and 5-HT2C functional calcium flux assays (Figure 2). The trans-2-phenylcyclopropylmethylamine hydrochloride 14a turned out to be a potent (EC50 = 13 nM), moderately selective and fully efficacious (Emax = 96%) agonist at the 5-HT2C receptor. Thus, this core structure was selected for substitution screening in all of the subsequent SAR studies. Several ring-unsubstituted N-alkyl derivatives of trans-aminomethyl-2-phenylcyclopropane (14a) have previously been found to have sympathomimetic activity in animal tests, but these effects were probably mediated by a 5-HT2C independent mechanism.41,42

Chemistry

Both the trans- and cis-(2-phenylcyclopropyl)methylamine hydrochlorides were prepared as structurally more flexible analogs of the lead compound 9 starting from styrene 10 (Scheme 1). Cyclopropanation was carried out using ethyl diazoacetate in the presence of Cu(acac)2 as a catalyst.43 The ester product was obtained as a 2:1 racemic mixture of the trans and cis isomers. After separation of the configurational isomers on silica gel, the resulting ester isomers trans-11a and cis-11b were converted to the corresponding amine hydrochlorides 14a and 14b, respectively, employing a standard sequence of reactions involving amide formation, followed by borane reduction.

Scheme 1a
a Reagents and conditions: (a) N2CHCO2Et, Cu(acac)2, CH2Cl2, reflux, 5 h; (b) 2 N KOH, MeOH; (c) (i) SOCl2, toluene, 80 °C, 3 h; (ii) NH3 (liquid), toluene/CH2Cl2; (d) (i) BH3/THF, reflux, 20 h; (ii) 1 M HCl, 0 °C.

N-Monomethylation of the amino group in compound 9 (Figure 2, n = 0) and of the elongated cyclopropylmethylamine derivative (Figure 2, n = 1) was carried out by reduction of the corresponding N-formyl derivatives. Formylation of the amine with acetic formic anhydride followed by in situ borane-dimethyl sulfide reduction afforded the corresponding N-methylamines.44 The products 15 and 16 obtained in this way were free of any contamination by the dialkylation product. The N,N-dimethylamine derivative 17 of compound 9 was prepared by reductive N-alkylation using an excess of 37% aqueous formaldehyde and NaBH3CN according to a literature procedure.45,46 The mono-isopropyl and mono-benzylamine analogs 18–20 were prepared by similar reductive N-alkylation protocols47,48 (Scheme 2).

Scheme 2a
a Reagents and conditions: (a) acetic formic anhydride, BH3·SMe2/THF; (b) HCHO (excess), NaBH3CN, acetonitrile/H2O; (c) acetone or benzaldehyde, NaBH3CN, MeOH.

Next, we explored the activity of derivatives bearing various substituents on the aromatic ring, or having the aromatic ring replaced by the larger naphthyl ring or by a biphenyl structure (Figure 3). The substituted phenyl and naphthyl derivatives 26–61 were synthesized from the corresponding styrenes 22, followed by application of the same chemistry used in the preparation of 14a and 14b. Some of styrenes were prepared from the corresponding aldehydes 21 by Wittig chemistry (Scheme 3).

Figure 3
Aromatic substitution screening of trans-(2-phenylcyclopropyl)methylamine hydrochloride analogs.
Scheme 3a
a Reagents and conditions: (a) methyltriphenylphosphonium bromide, NaH, THF, 20 h; (b) N2CHCO2Et, Cu(acac)2, CH2Cl2, reflux, 5 h; (c) 2 N KOH, MeOH; (d) (i) SOCl2, toluene, 80 °C, 3 h; (ii) NH3 (liquid), toluene/CH2Cl2; (e) (i) BH3/THF, reflux, ...

The N-Boc protected aminomethylcyclopropane derivatives 62–64 were very useful intermediates for the preparation of other analogs. The bromophenyl derivatives 29, 36, or 43 were thus used as convenient starting materials to generate a limited number of biphenyl and heteroarylphenyl derivatives 66–74 by means of the Suzuki coupling reaction.49 Some of amide and amine substituted phenyl derivatives 78 and 80–84 were prepared through Pd catalyzed conversion of the bromo group to an amine. These amines were reacted in turn with acid chlorides or aryl- and alkylisocyanates to afford the corresponding amides and urethanes. An alkynyl group was also successfully introduced as a side chain appendage into the arylcyclopropane by the Sonogashira coupling reaction (86–90)50 (Scheme 4).

Scheme 4aScheme 4a
a Reagents and conditions: (a) Boc2O, triethylamine, CH2Cl2; (b) Ar-B(OH)2, Pd(PPh3)4, K2CO3, dimethoxyethane, 80 °C, 20 h; (c) TFA, CH2Cl2, rt; (d) (i) benzophenone imine, Pd(OAc)2, BINAP, Cs2CO3, toluene, 80 °C; (ii) NaOAc, NH2OH·HCl, ...

In order to prepare the pure enantiomers of 14a (Scheme 5), we first converted the intermediate carboxylic acid formed in the cyclopropanation step into its diastereomeric amides. This was brought about by coupling the racemic carboxylic acid 12a with (R)-phenylglycinol.46 The resulting diastereomeric pair was then separated by silica gel column chromatography. The choice of (R)-phenylglycinol as the alcohol component was based on its successful use in the resolution of other racemic carboxylic acids and the ease of cleavage of the resulting diastereomers under acidic conditions that involves an N,O-acyl transfer. The carboxylic acids (+)-12a and (−)-12a, whose optical rotations were compared with the known compounds in the literature,51 were then converted individually to (+)-and (−)-trans-(2-phenylcyclopropyl)methylamine hydrochloride ((+)-14a and (−)-14a) using the same method as described above.52

Scheme 5a
a Reagents and conditions: (a) (R)-phenylglycinol, EDCI, HOBT, CH2Cl2; (b) H2SO4, 100 °C.

Biological Results and Discussion

In vitro SAR studies

The functional activity of the compounds was determined by measuring Gq mediated transient intracellular calcium mobilization in HEK-293 cells stably expressing the human 5-HT2A, human 5-HT2B, and human 5-HT2C (INI) receptors.53 The results are summarized in Table 1, ,2,2, and and3.3. Throughout the course of the project, different batches of cell lines or passages were used. In contrast to binding affinities, the potencies in functional assays can vary strongly depending on cell type, receptor expression level, and passage number. Direct comparisons of the potencies and efficacies are only valid within the bounds of each particular table section. In over-expressing cell lines such as those utilized in the current screening it is common to observe EC50 potency concentrations much lower than the Ki binding constant, particularly when 3H-antagonist radioligands are used for competition binding studies.54

Table 1
Functional activity and selectivity of the lead compound 9 and its initial analogs 14–20, and 26 at human 5-HT2A, 5-HT2B, and 5-HT2C receptors in a calcium flux assays using stably transfected HEK-293 cells.
Table 2
Functional activity of compounds 27–61 in calcium flux assays using HEK-293 cells stably expressing the human 5-HT2A, 5-HT2B, or 5-HT2C receptor.
Table 3
Radioligand binding data of selected compounds at the human 5-HT2A, human 5-HT2B, and 5-HT2C receptors as well as the neurotransmitter reuptake transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). For 5-HT2B the agonist radioligand ...

The trans isomer 14a with its side chain elongated by one methylene group was much more potent (EC50 = 13 nM) at the 5-HT2C receptor as compared to its parent compound 9 and the cis isomer 14b was much less active than the trans isomer 14a (Table 1). The trans-aminomethyl-2-phenylcyclopropane 14a and several of its N-mono- and N-dialkyl analogs have previously been described as centrally active sympathomimetic compounds that cause hyperlocomotion, reverse reserpine-induced depressant effects in a model of antidepressant activity, and cause anorexia similar to compound 941 while the fully unsubstituted compound 14a was devoid of MAO inhibitory activity in a tryptamine potentiation model.42 This behavioral and biochemical profile and the different structure-activity relationships suggest a non-5-HT2C-mediated mechanism for these early ring-unsubstituted compounds, perhaps through inhibition of monoamine reuptake.

Assay of the two enantiomers revealed that the (S,S)-stereoisomer (+)-14a was significantly more potent than its (R,R)-isomer (−)-14a. We have observed the same stereochemical preference for the corresponding 2-bromo-substituted enantiomeric pair (+)-29 and (−)-29 (Table 2).

Alkylation of the amine nitrogen in analogs 15–20 led to sharply decreased 5-HT2C receptor potency in comparison to the parent compounds 9 or 14a. Compound 9 and its potent analogs 14a (racemic) and (+)-14a were full agonists at the 5-HT2C receptor and displayed a high selectivity over the 5-HT2A receptor and a three to seven-fold selectivity over the 5-HT2B receptor.

As a preliminary summary, the initial SAR studies established the following essential features responsible for high 5-HT2C receptor potency: a cyclopropyl ring attached to a phenyl group carrying a primary aminomethyl group in trans orientation. Based upon these preliminary observations, our further work focused on variations in the phenyl ring of this core structure.

In the following four rounds of structural exploration and functional screening, we systematically tested the effects of mono- and disubstitutions at the phenyl ring (Table 2). Selected compounds from previous optimization rounds, the known 5-HT2C agonist WAY 629 (1,2,3,4,8,9,10,11-octahydro-[1,4]diazepino[6,7,1-jk]carbazole) (6)29 and lorcaserin ((1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine) (7)30 as well as 1 were included as reference compounds for comparison purposes.

All tested compounds were highly efficacious 5-HT2C agonists. Mono- and disubstituted analogs carrying chloro and bromo substitutions in the 2-position were consistently more potent than their respective fluoro, trifluoromethyl, methyl, methoxy, or hydroxy analogs.

In the 3-position, potency was less strongly influenced by the tested substituents and tended to decrease with molecular size from fluoro, methyl, and hydroxy over chloro to bromo and trifluoromethyl.

In the 4-position, the optimal substitution was a fluoro group. Any replacement by other halogens, methyl, trifluoromethyl, methoxy, or hydroxy groups resulted in a sharp decrease in 5-HT2C potency and selectivity over 5-HT2B activity.

Qualitatively similar trends of these substituent effects on potency and selectivity were observed between mono- and disubstituted compounds. However, the tested disubstitutions did not result in additive effects on potency or selectivity.

At the 5-HT2B receptor, the 3-hydroxy analog 40 has about a ten-fold higher potency than the corresponding 3-methyl analog 37 while both compounds were essentially equipotent at the 5-HT2C receptor. This made compound 37 one of the most selective compounds and might indicate a hydrogen bond interaction between compound 40 and the 5-HT2B receptor that is absent in the 5-HT2C-40-complex.

5-HT2A potencies of most tested compounds were above or around 0.5 µM, resulting in a generally good 5-HT2A over 5-HT2C selectivity. Additionally, most compounds were partial agonists at the 5-HT2A receptor, but full agonists at the 5-HT2C receptor. 2-Chloro and 2-bromo substitutions resulted in increased 5-HT2A potency, a trend also seen at the other two receptors.

We also prepared and tested the biphenyl and heteroaryl-phenyl derivatives 66–74, the 2- and 3-acetamido, 2- and 3-benzamido, 2-benzylamino, and 2-(4-chlorophenyl)urea analogs 78, 80–84, and a series of extended alkynyl derivatives 86–90 (Table S1). Most of these compounds were inactive or had potencies above 1 µM at all tested receptors. None of these compounds had a 5-HT2C potency below 100 nM.

The basic ring-monosubstituted derivatives presented in this publication do not reach the same level of selectivity as the 5-HT2C agonists that are currently in clinical trials; in our hands the potent compound (+)-29 displayed about five-fold less 5-HT2C over 5-HT2B selectivity as compared to 7.

A molecular overlay of several of the new selective 5-HT2C agonists prepared by other research groups with one of our more selective compounds 37 reveals the molecular features common to all these compounds, which include a similarly aligned positively charged nitrogen atom (blue) positioned above the plane of an aromatic ring which is substituted with hydrophobic group(s), such as chloro, methyl, ethyl, or trifluoromethyl (Figure 4).

Figure 4
Overlay of the 3-methyl bearing analog 37 (orange) with 7 (purple) and the BMS pyrazinoisoindoline (8)31 (light blue) show the expected similarities in structure. See Figure 1 for structures.

A selection of compounds was then subjected to binding experiments together with 7 as a reference compound (Table 3). 37 (3-Me), 41 (4-F), and 53 (2-Cl, 4-F) had comparable 5-HT2C binding affinities. Compound 41 was as 5-HT2C-selective as 7 while 29, (+)-29, and 37 where less selective. Since earlier data suggested sympathomimetic effects for the unsubstituted parent compound 14a,41,42 we also tested these compounds on all three monoamine reuptake transporters. None of the compounds had sub-micromolar binding affinities at SERT (5-HT transporter), NET (norepinephrine transporter), and DAT (dopamine transporter).

In vivo studies: evaluation of a 5-HT2C agonist for antidepressant potential

5-HT2C agonists have been reported to have antidepressant-like properties in multiple animal models, indicating that the 5HT2C receptor may be a desired target for CNS therapeutic effects. Compound 37 is one of the most potent and selective ligands for the 5HT2C receptor in the current series (120-fold selectivity over 2A and 14-fold selectivity over 2B, EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively, see Table 2). Based on this in-vitro profile, compound 37 was chosen for an initial in vivo profiling in the mouse forced swim test, which is a commonly used assay to validate antidepressant-like properties of compounds.

In the mouse forced swim test, compound 37 (10–60 mg/kg) produced a dose-dependent decrease in immobility time compared to vehicle (F(4,45) = 8.865, p < 0.001). Post-hoc analysis indicated that compound 37 produced a significant decrease in immobility at all 3 doses tested (28%, 38%, and 38% decrease in the 10, 30, and 60 mg/kg groups, respectively, (p < 0.05). In comparison, the reference selective serotonin reuptake inhibitor sertraline (92) (10 mg/kg) was used as a positive control in the same study. Both 92 (p < 0.001) and compound 37 significantly reduced the immobility time, indicative of an antidepressant-like effect (Figure 5). The results also demonstrate that compound 37 possesses drug-like properties in-vivo and that it is centrally active. The antidepressant-like effects together with the absence of monoamine reuptake transporter binding are in agreement with previous studies which demonstrated that 5HT2C agonists have antidepressant-like properties in both acute and chronic preclinical models used to predict antidepressant efficacy.20,22

Figure 5
The effects of compound 37 or 92 in the mouse forced swim test. Compound 37 (10–60 mg/kg, ip) or the reference compound 92 (10 mg/kg, ip) was administered 30 minute prior to testing. Both compounds 92 and 37 produced a significant decrease in ...

Conclusions

5-HT2C agonists have demonstrated efficacy in preclinical models of depression, obesity, and psychosis.23,55 The present work reports the chemical synthesis of 67 new side-chain analogs of the monoamine oxidase inhibitor 9, which were identified as a new class of 5-HT2C agonists. Starting from compound 9, a selective but only moderately potent 5-HT2C agonist, we have undertaken a structural optimization campaign that has led to a potent and moderately selective agonist that demonstrates antidepressant-like effects in a commonly used behavioral assay. Moreover, preliminary results based on the work presented in this article suggest the possibility of compounds with improved selectivity profiles comparable to drugs currently in clinical trials. This study therefore presents a new scaffold for 5-HT2C drug discovery, which may in turn lead to novel therapeutics for use in a variety of CNS related disorders.

Experimental Section

Chemistry

1H and 13C NMR spectra were obtained with a Bruker Avance spectrometer at 300 and 75 MHz, or a Bruker Avance spectrometer at 400 and 100 MHz, respectively. 1H chemical shifts (δ) were reported in ppm downfield from internal Me4Si. Mass spectra were measured in positive mode electrospray ionization (ESI). The HRMS data were obtained on a Micromass Q-TOF-2TM, ThermoFinnigan LTQFT and Shimadzu LCMSITTOF instruments. Optical rotations were measured with an AUTOPOL IV (Rudolph Research Analytical) instrument. TLC was performed on silica gel 60F254 glass plates; column chromatography was performed using Merck silica gel (230–400 mesh). Analytical HPLC was performed using a Shimadzu LC-10AD system equipped with the following columns: Column 1: ACE 5 AQ C18 UltraInert column (4.6 × 250 mm; 5 µm). Column 2: Waters μ-Bondapak C18 column (3.9 × 300 mm; 5 µm). Column 3: ACE 3 AQ C18 UltraInert column (4.6 × 100 mm; 3.5 µm). Chiralcel OJ (4.6 × 250 mm, DAICEL) and Chiralpak AD (10.0 × 250 mm, DAICEL) were used for Chiral HPLC analysis. HPLC data were recorded using following methods. Method A: H2O/MeCN (0.1% TFA), 90/10 → 0/100 in 18 min, + 2 min isocratic, flow rate of 1.6 mL/min, λ = 254, 280 nm. Method B: H2O/MeCN (0.1% TFA), 100/0 → 0/100 in 20 min, + 2 min isocratic, flow rate of 1.6 mL/min, λ = 254, 280 nm. Method C: H2O/MeCN (0.1% TFA), 70/30 → 0/100 in 21 min, + 7 min isocratic, flow rate of 1.3 mL/min, λ = 254, 280 nm. Method D: H2O/MeCN (0.1% TFA), 90/10 → 0/100 in 20 min, + 7 min isocratic, flow rate of 1mL/min, λ = 254, 280 nm. Method E: H2O/MeCN (0.1% TFA), 100/0 → 0/100 in 30 min, + 3 min isocratic, flow rate of 1.3 mL/min, λ = 254, 280 nm. Starting materials were obtained from Aldrich, Alfa Aesar, or Acros. Solvents were obtained from Fisher Scientific or Aldrich and were used without further purification unless noted otherwise.

General Procedure for the Synthesis of trans- and cis-(2-Phenylcyclopropyl)methylamine Hydrochloride (14a and 14b). Step A. trans- and cis-2-Phenylcyclopropanecarboxylic Acid Ethyl Ester (11a and 11b)

Under dry conditions, Cu(acac)2 (78 mg, 0.3 mmol) was dissolved in anhydrous CH2Cl2 (20 mL). After the solution was stirred for 5 min, a few drops of phenylhydrazine were added and stirring was continued. To this solution was added styrene (1.15 mL, 10 mmol). The mixture was stirred at 40 °C for 5 min, and a solution of ethyl diazoacetate (1.56 mL, 15 mmol) in CH2Cl2 (20 mL) was added via syringe pump over 5 h at 40 °C. After stirring for one more hour followed by the addition of CH2Cl2 (50 mL), the mixture was washed successively with satd. aq. NaHCO3 (×2) and H2O (×2). The organic portion was dried over Na2SO4 and all volatiles were removed in vacuo. The isomers were separated by silica gel chromatography (hexane/Et2O 20:1) to afford the title compounds as colorless oils (trans-isomer 11a: 1.19 g, 67% yield) and (cis-isomer 11b: 490 mg, 27% yield). 11a: 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 2 H), 7.24 (m, 1 H), 7.13 (d, J = 7.1 Hz, 2 H), 4.20 (q, J = 7.1 Hz, 2 H), 2.54 (m, 1 H), 1.93 (m, 1 H), 1.63 (m, 1 H), 1.37-1.29 (m, 4 H). 13C NMR (75 MHz, CDCl3) δ 173.3, 140.0, 128.4, 126.4, 126.1, 60.6, 26.1, 24.1, 17.0, 14.2. 11b: 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 5 H), 3.90 (q, J = 7.1 Hz, 2 H), 2.60 (m, 1 H), 2.10 (m, 1 H), 1.74 (m, 1 H), 1.35 (m, 1 H), 0.99 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 170.1, 136.5, 129.2, 127.8, 126.6, 60.1, 25.4, 21.7, 14.0, 11.0.

Step B. trans-2-Phenylcyclopropanecarboxylic Acid (12a)

A solution of 11a (128 mg, 0.726 mmol) in MeOH (1 mL) was added to KOH (406 mg, 7.26 mmol) in MeOH (3 mL) at 0 °C. The mixture was stirred at rt overnight, and then poured into water and extracted with CH2Cl2. The organic layer was discarded, and the aqueous phase was acidified with 10% HCl and extracted with CH2Cl2 (×2). The combined organic phases were dried over Na2SO4 and all volatiles were removed in vacuo. The acid was isolated as white powders and further purified by recrystallization from hexane (80 mg, 68% yield). 1H NMR (300 MHz, CDCl3) δ 10.3 (br s, 1 H), 7.34-7.22 (m, 3 H), 7.14 (d, J = 7.0 Hz, 2 H), 2.64 (m, 1 H), 1.93 (m, 1 H), 1.70 (m, 1 H), 1.44 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 180.2, 139.9, 128.9, 127.1, 126.7, 27.5, 24.4, 17.9.

cis-2-Phenylcyclopropanecarboxylic Acid (12b)

Prepared by the same procedure as described for 12a (233 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.29-7.20 (m, 5 H), 2.65 (m, 1 H), 2.05 (m, 1 H), 1.68 (m, 1 H), 1.40 (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 177.2, 135.8, 129.2, 127.9, 126.8, 26.6, 21.4, 12.0.

Step C. trans-2-Phenylcyclopropanecarboxylic Acid Amide (13a)

Several drops of dimethylformamide and thionyl chloride (13.5 mL, 185 mmol) were added dropwise to a solution of 12a (2.0 g, 12.3 mmol) in toluene (40 mL). After stirring at 80 °C for 3 h, the reaction mixture was concentrated under vacuum. The resulting residue was dissolved in toluene (10 mL), and the resulting solution was added to liquid ammonia at -78 °C. After stirring at -78 °C for 30 min and then at rt for 30 min, CH2Cl2 (25 ml) was added to the mixture at -78 °C and the resulting mixture was stirred at rt overnight. After addition of EtOAc, the mixture was washed with satd. aqueous NH4Cl (×2), dried over Na2SO4, and all volatiles were removed in vacuo. The title compound was isolated as a pearly yellow powder and further purified by recrystallization from hexane/EtOAc (1.72 g, 87% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (br s, 1 H), 7.29-7.10 (m, 5 H), 6.91 (br s, 1 H), 2.21 (m, 1 H), 1.82 (m, 1 H), 1.32 (m, 1 H), 1.18 (m, 1 H). 13C NMR (75 MHz, DMSO-d6) δ 173.8, 142.1, 129.2, 126.8, 126.6, 26.4, 24.8, 16.1.

cis-2-Phenylcyclopropanecarboxylic Acid Amide (13b)

Prepared by the same procedure as described for 13a (128 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.40 (br s, 1 H), 7.21-7.20 (m, 4 H), 7.13 (m, 1 H), 6.59 (br s, 1 H), 2.36 (m, 1 H), 1.97 (m, 1 H), 1.45 (m, 1 H), 1.13 (m, 1 H). 13C NMR (100 MHz, DMSO-d6) δ 170.9, 138.2, 129.4, 127.9, 126.2, 24.3, 23.4, 9.9.

Step D. trans-(2-Phenylcyclopropyl)methylamine Hydrochloride (14a)

To a solution of 13a (1.6 g, 9.93 mmol) in anhydrous THF (40 mL) was added dropwise 1 M borane/THF solution (39.7 mL) at 0 °C. The mixture was heated under reflux at 70 °C overnight, then was quenched by the careful addition of 10% aqueous HCl. After stirring at rt for 1 h, the THF was removed by evaporation and the residual aqueous solution was washed with Et2O (×2), neutralized with 10% NaOH, and then extracted with Et2O (×4). The combined organic layers were dried over Na2SO4 and concentrated until the volume was reduced to about 20 mL. To the solution was added 1 M HCl in Et2O (20 mL, 20 mmol) at 0 °C. After stirring at 0 °C for 15 min and at rt for 1 h, the mixture was concentrated under vacuum. The resulting residue was purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (1.54 g, 86% yield). HPLC purity: 11.9 min, 95.4% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.29-7.24 (m, 2 H), 7.18-7.13 (m, 3 H), 3.01 (d, J = 7.4 Hz, 2 H), 2.03 (m, 1 H), 1.41 (m, 1 H), 1.14-1.05 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 141.6, 128.4, 126.0, 125.9, 43.9, 22.2, 19.8, 14.0. MS (ESI) m/z 148.1 [MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.1127.

cis-(2-Phenylcyclopropyl)methylamine Hydrochloride (14b)

Prepared by the same procedure as described for 14a (26.8 mg, 47% yield). HPLC purity: 12.4 min, 95.5% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.35-7.24 (m, 5 H), 2.99-2.94 (m, 1 H), 2.20 (m, 1 H), 1.49 (m, 1 H), 1.25-1.18 (m, 1 H), 1.08 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 137.3, 129.1, 128.5, 126.8, 40.5, 21.1, 15.5, 8.3. MS (ESI) m/z 148.1 [MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.1123.

General Procedure for the Preparation of Optically Pure Ligand ((+)- and (−)-14a). Step A. (+)- and (−)-trans-2-Phenylcyclopropanecarboxylic Acid (2-Hydroxy-1-phenylethyl)amide ((+)- and (−)-91)

To a stirred solution of 12a (1.62 g, 10.0 mmol) in CH2Cl2 (20 mL) were added (R)-(−)-2-phenylglycinol (2.06 g, 15.0 mmol), HOBT (1.35 g, 10.0 mmol) and EDC·HCl (2.88 g, 15.0 mmol). The mixture was stirred at 0 °C for 1 h followed at rt overnight. The reaction mixture was washed with 5% aqueous citric acid, satd. aqueous NaHCO3 and satd. NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/Et2O 1:2) to afford the (−)-isomer with a higher Rf value (650 mg, 23% yield) and the (+)-isomer with a lower Rf value (703 mg, 25% yield) as colorless solids. (+)-91: 1H NMR (300 MHz, MeOD-d4) δ 7.35-7.10 (m, 9 H), 5.02 (t, J = 6.3 Hz, 1 H), 3.75 (m, 2 H), 2.34 (m, 1 H), 2.03 (m, 1 H), 1.53 (m, 1 H), 1.27 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 173.6, 141.2, 140.4, 128.5, 128.4, 127.4, 127.0, 126.3, 126.1, 65.3, 56.4, 25.8, 24.8, 15.2. (−)-91: 1H NMR (300 MHz, MeOD-d4) δ 7.36-7.13 (m, 9 H), 5.03 (t, J = 6.3 Hz, 1 H), 3.75 (m, 2 H), 2.42 (m, 1 H), 2.03 (m, 1 H), 1.46 (m, 1 H), 1.24 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 173.6, 141.2, 140.4, 128.5, 128.4, 127.4, 127.0, 126.2, 126.0, 65.2, 56.3, 25.7, 24.8, 15.4.

Step B. (+)-trans-2-Phenylcyclopropanecarboxylic Acid ((+)-12a)

A solution of (+)-91 (150 mg, 0.534 mmol) in dioxane (5 mL) was added to 3 N H2SO4 (5 mL). The mixture was stirred at 100 °C for 24 h and then poured into water and extracted with CH2Cl2 (×3). The combined organic phases were dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/hexane 1:2) to afford the title compound as a colorless solid (73 mg, 84% yield). 1H NMR (300 MHz, CDCl3) δ 10.3 (br s, 1 H), 7.34-7.22 (m, 3 H), 7.14 (d, J = 7.0 Hz, 2 H), 2.64 (m, 1 H), 1.93 (m, 1 H), 1.70 (m, 1 H), 1.44 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 180.2, 139.9, 128.9, 127.1, 126.7, 27.5, 24.4, 17.9. [α]D +389° (c 0.61, CHCl3) [lit. 405° (c 1.0, CHCl3), Macromolecules, 1971, 4, 718-722]

(−)-trans-2-Phenylcyclopropanecarboxylic Acid ((−)-12a)

Prepared by the same procedure as described for (+)-12a. 1H NMR (300 MHz, CDCl3) δ 9.76 (br s, 1 H), 7.34-7.22 (m, 3 H), 7.14 (d, J = 7.0 Hz, 2 H), 2.64 (m, 1 H), 1.93 (m, 1 H), 1.70 (m, 1 H), 1.44 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 180.2, 139.9, 128.9, 127.1, 126.7, 27.5, 24.4, 17.9, [α]D -396° (c 0.72, CHCl3) [lit. -410° (c 1.0, CHCl3), Macromolecules, 1971, 4, 718-722]

Step C. (+)-trans-(S,S)-(2-Phenylcyclopropyl)methylamine Hydrochloride ((+)-14a)

Refer to the general procedure for the synthesis of 14a described above with substituting (+)-trans-2-phenyl-cyclopropanecarboxylic acid (+)-12a for (±)-12a in Step C. HPLC purity: 12.8 min, 97.9% (column 1, method C). 1H NMR (MeOD-d4) δ 7.29-7.24 (m, 2 H), 7.18-7.13 (m, 3 H), 3.01 (d, J = 7.4 Hz, 2 H), 2.02 (m, 1 H), 1.41 (m, 1 H), 1.14-1.06 (m, 2 H). 13C NMR (MeOD-d4) δ 141.6, 128.4, 126.0, 125.9, 43.9, 22.2, 19.8, 14.0. MS (ESI) m/z 148.2 [MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.11202. [α]D +72.9° (c 0.45, MeOH).

(−)-trans-(R,R)-(2-Phenylcyclopropyl)methylamine Hydrochloride ((−)-14a)

Prepared by the same procedure as described for (+)-14a. HPLC purity: 12.6 min, 98.1% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.29-7.24 (m, 2 H), 7.18-7.13 (m, 3 H), 3.01 (d, J = 7.4 Hz, 2 H), 2.06-2.02 (m, 1 H), 1.42 (m, 1 H), 1.13-1.05 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 141.6, 128.4, 126.0, 125.9, 43.9, 22.2, 19.8, 14.0. MS (ESI) m/z 148.2 [MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.11200. [α]D -71.3° (c 0.45, MeOH).

trans-N-Methyl-(2-phenylcyclopropyl)amine (15)

Acetic formic anhydride was generated by dropwise addition of formic acid (0.36 mL, 9.6 mmol) to acetic anhydride (0.73 mL, 7.8 mmol). The mixture was kept on ice and then heated at 50 °C for 2 h. The mixture was cooled to rt, and THF (5 mL) was added. This mixture (0.6 mL, 0.3 mmol) was added to a solution of 9 (50 mg, 0.3 mmol) in THF (1 mL) at -15 °C followed by addition of N-methylmorpholine (45 µL, 0.3 mmol). The resulting mixture was stirred at -15 °C for 30 min and at rt for 1 h, insoluble materials were filtered out, and the solution was concentrated in vacuo. The crude residue (65 mg) was dissolved in THF (1.2 mL), and to the solution was added 1.0 M solution of borane dimethylsulfide complex in THF (0.75 mL). After the mixture was stirred at 65 °C overnight, the reaction was quenched by 10% aqueous HCl. The mixture was concentrated under reduced pressure to remove THF, and the residual aqueous solution was washed with Et2O (×1), neutralized with 10% aqueous NaOH, and then extracted with Et2O (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc/Et3N/MeOH 8:1:1) to afford the title compound as a colorless oil (21 mg, 47% yield). HPLC purity: 24.8 min, 95.2% (column 2, method C). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2 H), 7.20-7.16 (m, 1 H), 7.09-7.06 (m, 2 H), 2.54 (br s, 3 H), 2.34 (m, 1 H), 1.92 (m, 1 H), 1.76 (br s, 1 H), 1.12-1.06 (m, 1 H), 1.02-0.98 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 142.8, 128.6, 126.3, 125.9, 43.7, 36.2, 25.3, 17.5. MS (ESI) m/z 148.1 [MH+]. HRMS (ESI) calculated for C10H14N+ [MH+] 148.1126, found 148.1124.

trans-N-Methyl-(2-phenylcyclopropylmethyl)amine (16)

Acetic formic anhydride was generated as described above for 15 from formic acid (0.18 mL, 4.8 mmol) and acetic anhydride (0.365 mL, 3.9 mmol), and THF (4.5 mL). This mixture (0.53 mL, 0.408 mmol) was added to a solution of 14a (30 mg, 0.163 mmol) in THF (1 mL) at -15 °C followed by addition of N-methylmorpholine (17.9 µL, 0.163 mmol). The resulting mixture was stirred at -15 °C for 30 min and at rt for 1 h, insoluble materials were filtered out, and the mixture was concentrated in vacuo. The crude residue (42 mg) was dissolved in THF (1.2 mL), and to the solution was added 1.0 M borane dimethylsulfide complex in THF (0.41 mL). After the mixture was stirred at 65 °C overnight, the reaction was quenched by 10% aqueous HCl. The mixture was concentrated in vacuo to remove THF, and the residual aqueous solution was washed with Et2O (×1), neutralized with 10% aqueous NaOH, and then extracted with Et2O (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc/Et3N/MeOH 8:1:1) to afford the title compound as a colorless oil (14.0 mg, 53% yield). HPLC purity: 21.0 min, 96.8% (column 2, method C). 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2 H), 7.18-7.15 (m, 1 H), 7.10-7.07 (m, 2 H), 2.66 (br d, 2 H), 2.49 (br s, 3 H), 2.37 (br s, 1 H), 1.77 (m, 1 H), 1.38-1.32 (m, 1 H), 0.99-0.85 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 143.3, 128.7, 126.2, 125.9, 56.5, 36.5, 23.3, 22.5, 15.1. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 162.1283, found 162.1285.

trans-N,N-Dimethyl-(2-phenylcyclopropyl)amine (17)

To a stirred solution of 9 (34 mg, 0.2 mmol) in acetonitril/H2O (1:1, v/v) (5 mL) were added N-methylmorpholine (45 µL, 0.4 mmol), 37% aqueous formaldehyde (0.16 mL, 2.0 mmol), and sodium cyanoborohydride (40 mg, 0.6 mmol). Glacial acetic acid (40 µL) was added to the mixture over 10 min and the reaction was stirred at rt for 30 min. To the reaction mixture was added crushed ice, and the acetonitrile was removed in vacuo. The aqueous residue was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc/Et3N 95:5) to afford the title compound as a colorless oil (19.7 mg, 61% yield). HPLC purity: 19.8 min, 94.8% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 2 H), 7.18 (t, J = 7.3 Hz, 1 H), 7.09 (d, J = 7.2 Hz, 2 H), 2.74 (d, J = 3.6 Hz, 2 H), 2.42 (s, 6 H), 2.00 (m, 1 H), 1.83 (m, 1 H), 1.13 (m, 1 H), 0.99 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 142.5, 128.6, 126.5, 126.0, 50.6, 45.4, 25.7, 17.6. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 162.1283, found 162.1279.

trans-N-Isopropyl-(2-phenylcyclopropyl)amine (18)

To a stirred solution of 9 (50 mg, 0.295 mmol) in MeOH (1 mL) were added acetone (21.7 µL, 0.295 mmol) and sodium cyanoborohydride (22 mg, 0.354 mmol). The mixture was stirred at 0 °C for 1 h and at rt overnight. Crushed ice was added to the reaction mixture and the MeOH was removed in vacuo. The aqueous residue was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (EtOAc/Et3N 95:5) to afford the title compound as a colorless oil (16.7 mg, 32% yield). HPLC purity: 8.6 min, 97.4% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2 H), 7.19-7.14 (m, 1 H), 7.06 (d, J = 7.3 Hz, 2 H), 3.01 (m, 1 H), 2.31 (m, 1 H), 1.90 (m, 1 H), 1.87 (br s, 1 H), 1.12 (d, J = 6.3 Hz, 6 H), 1.07 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 142.8, 128.6, 126.1, 125.8, 49.7, 40.7, 25.9, 23.7, 23.6, 17.2. MS (ESI) m/z 176.1 [MH+]. HRMS (ESI) calculated for C12H18N+ [MH+] 176.1439, found 176.1437.

trans-N-Benzyl-(2-phenylcyclopropyl)amine (19)

Prepared by the same procedure as described for 18 with benzaldehyde (27 µL, 0.266 mmol) as the starting material (15.4 mg, 23% yield). HPLC purity: 14.6 min, 96.8% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 9 H), 7.18 (m, 1 H), 7.03 (d, J = 7.3 Hz, 2 H), 3.92 (s, 2 H), 2.42 (m, 1 H), 2.25 (m, br s, 1 H), 1.97 (m, 1 H), 1.14 (m, 1 H), 1.01 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 142.7, 140.7, 128.8, 128.7, 128.6, 127.4, 126.3, 125.9, 54.0, 41.6, 25.8, 17.5. MS (ESI) m/z 224.1 [MH+]. HRMS, (ESI) calculated for C16H18N+ [MH+] 224.1439, found 224.1440.

trans-N-Benzyl-(2-phenylcyclopropylmethyl)amine (20)

Prepared by the same procedure as described for 18 with 14a (30 mg, 0.163 mmol) and benzaldehyde (14.9 µL, 0.147 mmol) as the starting materials (20.8 mg, 54% yield). HPLC purity: 15.7 min, 95.1% (column 1, method C). 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 7 H), 7.19-7.16 (m, 1 H), 7.10-7.07 (m, 2 H), 3.87 (s, 2 H), 2.71 (m, 1 H), 1.73 (m, 1 H), 1.69 (br s, 1 H), 0.95 (m, 1 H), 0.85 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 143.4, 140.8, 128.8, 128.7, 128.5, 127.4, 126.1, 125.9, 54.1, 54.0, 23.8, 22.5, 15.3. MS (ESI) m/z 238.1 [MH+]. HRMS (ESI) calculated for C17H20N+ [MH+] 238.1596, found 238.1589.

General Procedure for the Synthesis of Substituted Styrene (22)

To a stirred suspension of benzaldehyde 21 (10 mmol) and methyltriphenylphosphonium bromide (4.28 g, 12 mmol) in THF (50 mL) was added sodium hydride (1.08 g, 45.10 mmol) under argon purge at 0 °C. After the mixture was stirred at rt overnight, the organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (hexane/Et2O 20:1) to afford the title compound as a colorless oil (90-99% yield).

trans-(2-Naphthalen-2-ylcyclopropyl)methylamine Hydrochloride (26)

Refer to the general procedure for the synthesis of 14a described above by using 2-vinylnaphthalene as the starting material. HPLC purity: 14.8 min, 97.7% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.81-7.77 (m, 3 H), 7.63 (s, 1 H), 7.48-7.38 (m, 2 H), 7.28 (m, 1 H), 3.06 (d, J = 7.4 Hz, 2 H), 2.20 (m, 1 H), 1.55 (m, 1 H), 1.24 (m, 1 H), 1.15 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 139.1, 134.0, 132.7, 128.1, 127.6, 127.4, 126.2, 125.3, 124.7, 124.3, 43.9, 22.4, 19.9, 14.1. MS (ESI) m/z 198.1 [MH+]. HRMS (ESI) calculated for C14H16N+ [MH+] 198.1283, found 198.1290.

trans-[2-(2-Fluorophenyl)cyclopropyl]methylamine Hydrochloride (27)

Refer to the general procedure for the synthesis of 14a described above by using 2-fluorostyrene as the starting material. HPLC purity: 12.3 min, 95.8% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.21 (m, 1 H), 7.13-7.02 (m, 3 H), 3.07-3.03 (m, 2 H), 2.16 (m, 1 H), 1.49 (m, 1 H), 1.17-1.09 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 162.1 (d, 1JCF = 243.9 Hz), 128.3 (d, 2JCF = 14.2 Hz), 127.81 (d, 3JCF = 8.3 Hz), 127.2 (d, 3JCF = 3.9 Hz), 124.4 (d, 4JCF = 3.5 Hz), 115.0 (d, 2JCF = 22.1 Hz), 43.8, 18.3, 15.7, 12.7. MS (ESI) m/z 166.1 [MH+]. HRMS (ESI) calculated for C10H13NF+ [MH+] 166.1032, found 166.1029.

trans-[2-(2-Chlorophenyl)cyclopropyl]methylamine Hydrochloride (28)

Refer to the general procedure for the synthesis of 14a described above by using 2-chlorostyrene as the starting material. HPLC purity: 6.8 min, 96.2% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.38 (dd, J = 7.4, 1.2 Hz, 1 H), 7.26-7.11 (m, 3 H), 3.25 (m, 1 H), 2.93 (m, 1 H), 2.22 (m, 1 H), 1.37 (m, 1 H), 1.12 (t, J = 6.8 Hz, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 139.8, 136.4, 130.4, 129.0, 128.7, 128.4, 44.9, 21.6, 19.7, 14.9. MS (ESI) m/z 182.1 [MH+]. HRMS (ESI) calculated for C10H13NCl+ [MH+] 182.0731, found 182.0738.

trans-[2-(2-Bromophenyl)cyclopropyl]methylamine Hydrochloride (29)

Refer to the general procedure for the synthesis of 14a described above by using 2-bromostyrene as the starting material. HPLC purity: 14.8 min, 96.1% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.57 (d, J = 8.1 Hz, 1 H), 7.29 (t, J = 7.0 Hz, 1 H), 7.13 (m, 2 H), 3.33 (m, 1 H), 2.89 (m, 1 H), 2.17 (m, 1 H), 1.39 (m, 1 H), 1.13 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 140.3, 132.5, 128.2, 127.9, 127.8, 125.8, 43.8, 23.3, 18.7, 12.9. MS (ESI) m/z 226.0 [MH+]. HRMS (ESI) calculated for C10H13NBr+ [MH+] 226.0231, found 226.0228.

trans-[2-(2-Methylphenyl)cyclopropyl]methylamine Hydrochloride (30)

Refer to the general procedure for the synthesis of 14a described above by using 2-methylstyrene as the starting material. HPLC purity: 9.4 min, 98.5% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.13 (t, J = 7.8 Hz, 1 H), 6.96-6.91 (m, 3 H), 7.13 (m, 2 H), 3.00 (m, 1 H), 2.28 (s, 3 H), 2.89 (m, 1 H), 2.01-1.96 (m, 1 H), 1.44 (m, 1 H), 1.05 (t, J = 6.7 Hz, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 142.6, 139.0, 129.4, 127.8, 127.7, 124.1, 45.1, 23.2, 21.6, 20.8, 15.2. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 161.1277, found 162.1270.

trans-[2-(2-Trifluoromethylphenyl)cyclopropyl]methylamine Hydrochloride (31)

Refer to the general procedure for the synthesis of 14a described above by using 2-trifluoromethylstyrene as the starting material. HPLC purity: 7.9 min, 99.3% (column 3, method A). 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 3 H), 7.67 (d, J = 6.4 Hz, 1 H), 7.58 (m, 1 H), 7.40 (m, 1 H), 7.29 (d, J = 5.8 Hz, 1 H), 3.00 (m, 1 H), 2.75 (m, 1 H), 2.15 (m, 1 H), 1.50 (m, 1 H), 1.09 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 140.0, 133.2, 128.6 (q, 2JCF = 30.0 Hz), 128.0, 127.0, 126.1 (q, 3JCF = 5.5 Hz), 125.1 (q, 1JCF = 273.7 Hz), 42.7, 19.3, 19.2, 14.3. MS (ESI) m/z 216.1 [MH+]. HRMS (ESI) calculated for C11H13NF3 + [MH+] 216.0995, found 216.0990.

trans-[2-(2-Methoxyphenyl)cyclopropyl]methylamine Hydrochloride (32)

Refer to the general procedure for the synthesis of 14a described above by using 2-methoxystyrene as the starting material. HPLC purity: 7.3 min, 97.7% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.17-7.13 (m, 1 H), 6.94-6.82 (m, 3 H), 3.86 (s, 3 H), 2.79 (m, 2 H), 2.07-2.02 (m, 1 H), 1.29-1.25 (m, 1 H), 1.09-1.02 (m, 1 H), 0.97-0.90 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 159.8, 130.7, 128.5, 127.3, 121.7, 111.4, 56.1, 45.8, 20.8, 18.2, 13.3. MS (ESI) m/z 178.1 [MH+]. HRMS (ESI) calculated for C11H16NO+ [MH+] 178.1226, found 178.1228.

trans-[2-(2-Hydroxyphenyl)cyclopropyl]methylamine Hydrochloride (33)

To a solution of 32 (80 mg, 0.451 mmol) in dry CH2Cl2 (2 mL) under a nitrogen atmosphere at -78 °C was slowly added a solution of boron tribromide (1.0 M in CH2Cl2, 1 mL). The reaction mixture was allowed to warm to rt and stirred for 4 h. The brown solution was cooled with an ice bath, and to the solution was slowly added water (2 mL). The organic layer was separated, and the water layer was extracted with EtOAc (×4). The combined organic layers were dried over Na2SO4 and concentrated until the volume was reduced to about 1 mL. To the solution was added 1 M HCl in Et2O (1 mL, 1 mmol) at 0 °C. After stirring at 0 °C for 15 min and at rt for 1 h, the mixture was concentrated in vacuo. The resulting residue was purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (50 mg, 68% yield). HPLC purity: 7.7 min, 97.7% (column 3, method B). 1H NMR (400 MHz, MeOD-d4) δ 7.03-6.99 (m, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 6.79-6.73 (m, 2 H), 3.15-3.10 (m, 1 H), 2.91-2.86 (m, 1 H), 2.07-2.02 (m, 1 H), 1.24-1.20 (m, 1 H), 1.75-1.11 (m, 1 H), 1.00-0.95 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 157.3, 128.4, 128.4, 127.8, 120.8, 115.7, 45.5, 19.5, 18.4, 12.6. MS (ESI) m/z 164.1 [MH+]. HRMS (ESI) calculated for C10H14NO+ [MH+] 164.1070, found 164.1068.

trans-[2-(3-Fluorophenyl)cyclopropyl]methylamine Hydrochloride (34)

Refer to the general procedure for the synthesis of 14a described above by using 3-fluorostyrene as the starting material. HPLC purity: 12.6 min, 95.9% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.27 (m, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 6.90 (m, 2 H), 3.01 (m, 2 H), 2.06 (m, 1 H), 1.44 (m, 1 H), 1.12 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 163.5 (d, 1JCF = 243.0 Hz), 144.8 (d, 3JCF = 6.0 Hz), 130.1 (d, 3JCF = 8.8 Hz), 122.0, 112.7 (d, 2JCF = 22.0 Hz), 43.7, 22.0, 20.3, 14.4. MS (ESI) m/z 166.0 [MH+]. HRMS (ESI) calculated for C10H13NF+ [MH+] 166.1032, found 166.1032.

trans-[2-(3-Chlorophenyl)cyclopropyl]methylamine Hydrochloride (35)

Refer to the general procedure for the synthesis of 14a described above by using 3-chlorostyrene as the starting material. HPLC purity: 7.4 min, 98.6% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.27-7.05 (m, 4 H), 3.00 (d, J = 4.1 Hz, 2 H), 2.03 (m, 1 H), 1.43 (m, 1 H), 1.11 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 145.4, 135.4, 131.1, 127.3, 127.2, 125.6, 44.9, 23.0, 21.3, 15.4. MS (ESI) m/z 182.1 [MH+]. HRMS (ESI) calculated for C10H13NCl+ [MH+] 182.0731, found 182.0732.

trans-[2-(3-Bromophenyl)cyclopropyl]methylamine Hydrochloride (36)

Refer to the general procedure for the synthesis of 14a described above by using 3-bromostyrene as the starting material. HPLC purity: 16.3 min, 95.9% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.33 (d, J = 7.8 Hz, 2 H), 7.26-7.11 (m, 2 H), 3.08-2.95 (m, 2 H), 2.07-2.01 (m, 1 H), 1.50-1.39 (m, 1 H), 1.17-1.07 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 144.5, 130.2, 129.2, 129.1, 124.8, 122.4, 43.7, 21.8, 20.2, 14.2. MS (ESI) m/z 226.0 [MH+]. HRMS (ESI) calculated for C10H13NBr+ [MH+] 226.0231, found 226.0235.

trans-[2-(3-Methylphenyl)cyclopropyl]methylamine Hydrochloride (37)

Refer to the general procedure for the synthesis of 14a described above by using 3-methylstyrene as the starting material. HPLC purity: 9.5 min, 99.2% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.13-7.05 (m, 3 H), 7.02-7.00 (m, 1 H), 3.25-3.21 (m, 1 H), 2.94-2.88 (m, 1 H), 2.40 (s, 3 H), 2.04-1.99 (m, 1 H), 1.46-1.41 (m, 1 H), 1.09-1.04 (m, 1 H), 0.97-0.93 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 140.2, 138.8, 130.8, 127.5, 127.1, 126.8, 45.1, 21.6, 20.0, 18.7, 13.9. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 161.1277, found 162.1270.

trans-[2-(3-Trifluoromethylphenyl)cyclopropyl]methylamine Hydrochloride (38)

Refer to the general procedure for the synthesis of 14a described above by using 3-trifluorostyrene as the starting material. HPLC purity: 8.4 min, 98.3% (column 3, method A). 1H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 3 H), 7.50-7.39 (m, 4 H), 2.96 (m, 1 H), 2.74 (m, 1 H), 2.12 (m, 1 H), 1.34 (m, 1 H), 1.15-1.05 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 143.2, 129.6, 129.3, 129.0 (q, 2JCF = 31.0 Hz), 124.2 (q, 1JCF = 272.6 Hz), 122.6 (q, 3JCF = 3.5 Hz), 122.4 (q, 3JCF = 3.5 Hz), 42.7, 21.3, 20.4, 14.4. MS (ESI) m/z 216.1 [MH+]. HRMS (ESI) calculated for C11H13NF3 + [MH+] 216.0995, found 216.0991.

trans-[2-(3-Methoxyphenyl)cyclopropyl]methylamine Hydrochloride (39)

Refer to the general procedure for the synthesis of 14a described above by using 3-methoxystyrene as the starting material. HPLC purity: 6.9 min, 98.5% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.18-7.13 (m, 1 H), 6.72-6.69 (m, 3 H), 3.76 (s, 3 H), 2.99 (d, J = 7.3 Hz, 2 H), 2.03-1.97 (m, 1 H), 1.44-1.39 (m, 1 H), 1.11-1.01 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 161.4, 144.5, 130.5, 119.3, 113.1, 112.5, 55.8, 45.0, 23.4, 21.0, 15.2. MS (ESI) m/z 178.1 [MH+]. HRMS (ESI) calculated for C11H16NO+ [MH+] 178.1226, found 178.1226.

trans-[2-(3-Hydroxyphenyl)cyclopropyl]methylamine Hydrochloride (40)

Prepared by the same procedure as described for 33 with 39 as the starting material (45 mg, 70% yield). HPLC purity: 7.5 min, 97.2% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 6.95 (t, J = 7.7 Hz, 1 H), 6.51-6.45 (m, 3 H), 2.87 (m, 2 H), 1.83 (m, 1 H), 1.28 (m, 1 H), 0.96-0.91 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 158.6, 144.4, 130.5, 118.4, 114.1, 113.8, 45.1, 23.3, 20.9, 15.2. MS (ESI) m/z 164.1 [MH+]. HRMS (ESI) calculated for C10H14NO+ [MH+] 164.1070, found 164.1073.

trans-[2-(4-Fluorophenyl)cyclopropyl]methylamine Hydrochloride (41)

Refer to the general procedure for the synthesis of 14a described above by using 4-fluorostyrene as the starting material. HPLC purity: 12.7 min, 95.4% (column 1, method C). 1H NMR (300 MHz, MeOD-d4) δ 7.16 (m, 2 H), 7.00 (m, 2 H), 3.01 (d, J = 7.4 Hz, 2 H), 2.04 (m, 1 H), 1.39 (m, 1 H), 1.08 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 161.8 (d, 1JCF = 243.0 Hz), 137.6, 127.8 (d, 3JCF = 7.9 Hz), 115.0 (d, 2JCF = 21.7 Hz), 43.8, 21.5, 19.7, 13.9. MS (ESI) m/z 166.1 [MH+]. HRMS (ESI) calculated for C10H13NF+ [MH+] 166.1032, found 166.1034.

trans-[2-(4-Chlorophenyl)cyclopropyl]methylamine Hydrochloride (42)

Refer to the general procedure for the synthesis of 14a described above by using 4-chlorostyrene as the starting material. HPLC purity: 7.4 min, 98.2% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.25 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 2 H), 3.00 (d, J = 7.2 Hz, 2 H), 2.05-1.99 (m, 1 H), 1.44-1.38 (m, 1 H), 1.09 (t, J = 6.9 Hz, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 141.7, 132.8, 129.6, 128.8, 44.9, 22.8, 21.2, 15.3. MS (ESI) m/z 182.1 [MH+]. HRMS (ESI) calculated for C10H13NCl+ [MH+] 182.0731, found 182.0736.

trans-[2-(4-Bromophenyl)cyclopropyl]methylamine Hydrochloride (43)

Refer to the general procedure for the synthesis of 14a described above by using 4-bromostyrene as the starting material. HPLC purity: 14.3 min, 97.4% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.41 (d, J = 8.5 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H), 3.05-2.96 (m, 2 H), 2.04-1.99 (m, 1 H), 1.44-1.39 (m, 1 H), 1.14-1.07 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 140.6, 131.0, 127.6, 119.1, 21.3, 19.6, 13.7. MS (ESI) m/z 225.9 [MH+]. HRMS (ESI) calculated for C10H13NBr+ [MH+] 226.0231, found 226.0233.

trans-[2-(4-Methylphenyl)cyclopropyl]methylamine Hydrochloride (44)

Refer to the general procedure for the synthesis of 14a described above by using 4-methylstyrene as the starting material. HPLC purity: 6.5 min, 98.8% (column 1, method D). 1H NMR (400 MHz, MeOD-d4) δ 6.92 (d, J = 7.9 Hz, 2 H), 6.86 (d, J = 7.9 Hz, 2 H), 2.78 (d, J = 7.4 Hz, 2 H), 2.13 (s, 3 H), 1.81-1.76 (m, 1 H), 1.22-1.18 (m, 1 H), 0.90-0.82 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 139.9, 136.6, 130.1, 127.0, 45.4, 23.0, 21.7, 21.1, 15.0. MS (ESI) m/z 162.1 [MH+]. HRMS (ESI) calculated for C11H16N+ [MH+] 161.1277, found 162.1272.

trans-[2-(4-Trifluoromethylphenyl)cyclopropyl]methylamine Hydrochloride (45)

Refer to the general procedure for the synthesis of 14a described above by using 4-trifluorostyrene as the starting material. HPLC purity: 8.4 min, 99.3% (column 3, method A). 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 3 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 2.96 (m, 1 H), 2.75 (m, 1 H), 2.14 (m, 1 H), 1.40 (m, 1 H), 1.12 (t, J = 7.0 Hz, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 147.6, 129.0 (q, 2JCF = 32.3 Hz), 127.7, 126.2 (q, 3JCF = 3.3 Hz), 125.7 (q, 1JCF = 270.8 Hz), 45.1, 23.2, 21.7, 16.1. MS (ESI) m/z 216.1 [MH+]. HRMS (ESI) calculated for C11H13NF3 + [MH+] 216.0995, found 216.0989.

trans-[2-(4-Methoxyphenyl)cyclopropyl]methylamine Hydrochloride (46)

Refer to the general procedure for the synthesis of 14a described above by using 4-methoxystyrene as the starting material. HPLC purity: 5.7 min, 99.1% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.05 (d, J = 8.3 Hz, 2 H), 6.81 (d, J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 2.98 (d, J = 6.8 Hz, 2 H), 1.95 (m, 1 H), 1.31 (m, 1 H), 1.01 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 159.7, 134.6, 128.3, 115.0, 55.8, 45.1, 22.7, 20.5, 14.7. MS (ESI) m/z 178.1 [MH+]. HRMS (ESI) calculated for C11H16NO+ [MH+] 178.1226, found 178.1226.

trans-[2-(4-Hydroxyphenyl)cyclopropyl]methylamine Hydrochloride (47)

Prepared by the same procedure as described for 33 with 46 as the starting material (38 mg, 72% yield). HPLC purity: 6.1 min, 99.2% (column 3, method B). 1H NMR (300 MHz, MeOD-d4) δ 6.96 (d, J = 8.4 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 2.96 (d, J = 7.3 Hz, 2 H), 1.95-1.89 (m, 1 H), 1.29 (m, 1 H), 1.03-0.92 (m, 2 H). 13C NMR (75 MHz, MeOD-d4) δ 157.0, 133.3, 128.4, 116.3, 45.2, 22.7, 20.4, 14.5. MS (ESI) m/z 164.1 [MH+]. HRMS (ESI) calculated for C10H14NO+ [MH+] 164.1070, found 164.1069.

trans-[2-(2,3-Difluorophenyl)cyclopropyl]methylamine Hydrochloride (48)

Refer to the general procedure for the synthesis of substituted styrene 14a described above by using 2,3-difluorobenzaldehyde as the starting material. HPLC purity: 8.7 min, 95.1% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.08-7.05 (m, 2 H), 6.87-6.86 (m, 1 H), 3.08-3.02 (m, 2 H), 2.21-2.16 (m, 1 H), 1.58-1.51 (m, 1 H), 1.16 (t, J = 6.9 Hz, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 151.9 (dd, 1JCF = 246.0, 2JCF = 13.0 Hz), 150.9 (dd, 1JCF = 245.4, 2JCF = 13.0 Hz), 132.3 (d, 2JCF = 10.9 Hz), 125.6 (dd, 2JCF = 7.2, 3JCF = 4.8 Hz), 123.2 (m), 116.0 (d, 2JCF = 17.3 Hz), 44.7, 19.8, 16.7, 14.3. MS (ESI) m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2 + [MH+] 184.0932, found 184.0931.

trans-[2-(2,4-Difluorophenyl)cyclopropyl]methylamine Hydrochloride (49)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 2,4-difluorobenzaldehyde as the starting material. HPLC purity: 8.5 min, 95.5% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.11 (dd, J = 15.4, 8.4 Hz, 1 H), 6.93-6.86 (m, 2 H), 3.02 (m, 2 H), 2.11-2.06 (m, 1 H), 1.43-1.40 (m, 1 H), 1.14-1.05 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 163.1 (d, 1JCF = 258 Hz), 163.0 (d, 1JCF = 258 Hz), 129.7 (dd, 3JCF = 9.5, 3JCF = 5.4 Hz), 112.3 (dd, 2JCF = 21.4, 3JCF = 3.7 Hz), 104.5 (dd, 2JCF = 26.1, 2JCF = 26.1 Hz), 44.8, 19.3, 16.5, 13.5. MS (ESI) m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2 + [MH+] 184.0932, found 184.0930.

trans-[2-(2,6-Difluorophenyl)cyclopropyl]methylamine Hydrochloride (50)

Refer to the general procedure for the synthesis of substituted styrene 14a described above by using 2,6-difluorobenzaldehyde as the starting material. HPLC purity: 5.4 min, 96.5% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.31-7.21 (m, 1 H), 6.98-6.89 (m, 2 H), 3.06-3.03 (m, 2 H), 1.93 (m, 1 H), 1.64 (m, 1 H), 1.26 (m, 1 H), 1.13 (m, 1 H). 13C NMR (75 MHz, MeOD-d4) δ 162.5 (d, 1JCF = 246.5 Hz), 128.5 (d, 3JCF = 10.7 Hz), 116.5, 111.4 (d, 2JCF = 26.1 Hz), 43.9, 17.0, 11.7, 11.6. MS (ESI) m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2 + [MH+] 184.09323; found 184.09316.

trans-[2-(3,4-Difluorophenyl)cyclopropyl]methylamine Hydrochloride (51)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 3,4-difluorobenzaldehyde as the starting material. HPLC purity: 8.6 min, 96.4% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.17-7.05 (m, 2 H), 6.98-5.97 (m, 1 H), 2.98 (m, 2 H), 2.10-2.06 (m, 1 H), 1.44 (m, 1 H), 1.12-1.09 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 151.6 (dd, 1JCF = 245.7, 2JCF = 12.8 Hz), 150.0 (dd, 1JCF = 244.1, 2JCF = 12.7 Hz), 140.6 (dd, 3JCF = 5.9, 4JCF = 3.6 Hz), 123.7 (dd, 3JCF = 6.1, 4JCF = 3.3 Hz), 118.2 (d, 2JCF = 17.3 Hz), 116.1 (d, 2JCF = 17.9 Hz), 44.9, 22.6, 21.3, 15.3. MS (ESI) m/z 184.1 [MH+]. HRMS (ESI) calculated for C10H12NF2 + [MH+] 184.0932, found 184.0930.

trans-[2-(4-Chloro-2-fluorophenyl)cyclopropyl]methylamine Hydrochloride (52)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 4-chloro-2-fluorobenzaldehyde as the starting material. HPLC purity: 7.4 min, 94.4% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.13-7.07 (m, 3 H), 3.13-3.00 (m, 2 H), 2.16-2.12 (m, 1 H), 1.57-1.52 (m, 1 H), 1.17-1.11 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 162.8 (d, 1JCF = 247.9 Hz), 133.4 (d, 3JCF = 10.4 Hz), 129.6 (d, 3JCF = 4.9 Hz), 128.6 (d, 2JCF = 14.4 Hz), 125.7 (d, 4JCF = 3.6 Hz), 116.7 (d, 2JCF = 25.9 Hz), 44.7, 19.5, 16.6, 14.1. MS (ESI) m/z 200.1 [MH+]. HRMS (ESI) calculated for C10H12NFCl+ [MH+] 200.0637, found 200.0639.

trans-[2-(2-Chloro-4-fluorophenyl)cyclopropyl]methylamine Hydrochloride (53)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 2-chloro-4-fluorobenzaldehyde as the starting material. HPLC purity: 7.2 min, 98.2% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.20-7.17 (m, 2 H), 7.03-6.99 (m, 1 H), 3.27-3.22 (m, 1 H), 2.96-2.91 (m, 1 H), 2.19-2.14 (m, 1 H), 1.44-1.39 (m, 1 H), 1.17-1.07 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 162.6 (d, 1JCF = 247.0 Hz), 137.0 (d, 3JCF = 10.3 Hz), 136.0, 130.3 (d, 3JCF = 8.8 Hz), 117.4 (d, 2JCF = 25.2 Hz), 115.2 (d, 2JCF = 21.2 Hz), 44.8, 21.1, 19.5, 13.8. MS (ESI) m/z 200.1 [MH+]. HRMS (ESI) calculated for C10H12NFCl+ [MH+] 200.0637, found 200.0633.

trans-[2-(2,3-Dichlorophenyl)cyclopropyl]methylamine Hydrochloride (54)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 2,3-dichlorobenzaldehyde as the starting material. HPLC purity: 8.7 min, 98.7% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.37 (d, J = 6.9 Hz, 1 H), 7.22 (dd, J = 7.9, 7.9 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 3.32-3.25 (m, 1 H), 2.98-2.93 (m, 1 H), 2.29-2.24 (m, 1 H), 1.49-1.45 (m, 1 H), 1.21-1.10 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 142.4, 134.5, 133.9, 129.7, 128.9, 127.2, 44.8, 22.5, 19.8, 14.2. MS (ESI) m/z 216.0 [MH+]. HRMS (ESI) calculated for C10H12NCl2 + [MH+] 216.0341, found 216.0338.

trans-[2-(2,4-Dichlorophenyl)cyclopropyl]methylamine Hydrochloride (55)

Refer to the general procedure for the synthesis of substituted styrene and 14a described above by using 2,4-dichlorobenzaldehyde as the starting material. HPLC purity: 8.3 min, 93.7% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.43 (d, J = 1.9 Hz, 1 H), 7.26 (dd, J = 8.3, 1.9 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 3.25-3.20 (m, 1 H), 2.96-2.91 (m, 1 H), 2.22-2.17 (m, 1 H), 1.45-1.40 (m, 1 H), 1.18-1.09 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 138.9, 137.1, 133.8, 130.0, 129.9, 128.5, 44.7, 21.1, 19.7, 14.0. MS (ESI) m/z 216.0 [MH+]. HRMS (ESI) calculated for C10H12NCl2 + [MH+] 216.0341, found 216.0338.

trans-[2-(4-Fluoro-3-methylphenyl)cyclopropyl]methylamine Hydrochloride (56)

Refer to the general procedure for the synthesis of 14a described above by using 1-fluoro-2-methyl-4-vinylbenzene as the starting material. HPLC purity: 11.69 min, 99.6% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.08-6.84 (m, 3 H), 3.07-2.91 (m, 1 H), 2.22 (s, 3 H), 2.04-1.92 (m, 1 H), 1.42-1.28 (m, 1 H), 1.12-0.96 (m, 2 H).13C NMR (100 MHz, MeOD-d4) δ 161.0 (d, 1JCF = 241.4 Hz), 136.7 , 128.8, 124.6 (d, 3JCF = 7.9 Hz), 124.2, 114.2 (d, 2JCF = 25.5 Hz), 43.4, 21.1, 19.2, 13.3, 13.0. MS (ESI) m/z 163.0 [MH+]. HRMS (ESI) calculated for C11H15NF+ [MH+] 180.1183, found 180.1187.

trans-[2-(2-Chloro-6-methylphenyl)cyclopropyl]methylamine Hydrochloride (57)

Refer to the general procedure for the synthesis of 14a described above by using 1-chloro-3-methyl-2-vinylbenzene as the starting material. HPLC purity: 13.76 min, 96.7% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.24-7.18 (m, 1 H), 7.14-7.09 (m, 2 H), 3.56-3.45 (m, 1H), 2.81-2.70 (m, 1H), 2.44 (s, 3H), 1.86-1.77 (m, 1H), 1.48-1.35 (m, 1 H), 1.27-1.17 (m, 1 H), 1.02-0.92 (m, 1H). 13C NMR (100 MHz, MeOD-d4) δ 140.8, 135.7, 135.6, 128.7, 127.5, 127.0, 43.6, 19.3, 18.9, 18.8, 14.2. MS (ESI) m/z 179.1 [MH+]. HRMS (ESI) calculated for C11H15NCl+ [MH+] 196.0888, found 196.0892.

trans-[2-(2-Bromo-4-methylphenyl)cyclopropyl]methylamine Hydrochloride (58)

Refer to the general procedure for the synthesis of 14a described above by using 2-bromo-4-methyl-1-vinylbenzene as the starting material. HPLC purity: 16.41 min, 96.8% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.41 (s, 1 H), 7.09 (d, J = 7.9 Hz, 1 H), 7.0 (d, J = 7.9 Hz, 1 H), 3.37-3.24 (m, 1 H), 2.92-2.81 (m, 1 H), 2.29 (s, 3 H), 2.17-2.06 (m, 1 H), 1.40-1.26 (m, 1 H), 1.13-1.02 (m, 2H). 13C NMR (100 MHz, MeOD-d4) δ 136.5, 135.1, 130.9, 126.5, 125.3, 123.6, 41.9, 20.9, 17.6, 16.6, 10.8. MS (ESI) m/z 224.0 [MH+]. HRMS (ESI) calculated for C11H15NBr+ [MH+] 240.0382, found 240.0388.

trans-[2-(2,3-Dimethylphenyl)cyclopropyl]methylamine Hydrochloride (59)

Refer to the general procedure for the synthesis of 14a described above by using 1,2-dimethyl-3-vinylbenzene as the starting material. HPLC purity: 12.92 min, 98.4% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.03-6.80 (m, 3 H), 3.27-3.15 (m, 1H), 2.97-2.83 (m, 1 H), 2.33 (s, 3H), 2.27 (s, 3 H), 2.08-1.94 (m, 1H), 1.46-1.32 (m, 1 H), 1.11-1.0 (m, 1H), 0.95-0.88 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 138.4, 136.0, 135.7, 127.7, 125.0, 123.9, 43.6, 20.8, 19.1, 17.1, 14.0, 12.2. MS (ESI) m/z 159.1 [MH+]. HRMS (ESI) calculated for C12H18N+ [MH+] 176.1434, found 176.1436.

trans-[2-(3,4-Dimethylphenyl)cyclopropyl]methylamine Hydrochloride (60)

Refer to the general procedure for the synthesis of 14a described above by using 1,2-dimethyl-4-vinylbenzene as the starting material. HPLC purity: 13.03 min, 99.2% (column 1, method E). 1H NMR (400 MHz, MeOD-d4) δ 7.0 (d, J = 7.8 Hz, 1 H), 6.89 (s, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 3.02 (m, 2 H), 2.25 (s, 3 H), 2.21 (s, 3 H), 1.97-1.89 (m, 1 H), 1.40-1.29 (m, 1H), 1.08-0.95 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 138.4, 136.0, 133.7, 129.11, 126.8, 122.8, 43.5, 21.4, 19.1, 18.3, 17.9, 13.2. MS (ESI) m/z 159.1[MH+]. HRMS (ESI) calculated for C12H18N+ [MH+] 176.1434, found 176.1433.

trans-[2-(6-Chloro-2-fluoro-3-methylphenyl)cyclopropyl]methylamine Hydrochloride (61)

Refer to the general procedure for the synthesis of 14a described above by using 1-chloro-3-fluoro-4-methyl-2-vinylbenzene (1g, 5.8 mmol) as the starting material. HPLC purity: 13.03 min, 95.6% (column 1, method D). 1H NMR (400 MHz, MeOD-d4) δ 7.16-7.04 (m, 2 H), 3.22-3.11 (m, 1 H), 3.0-2.91 (m, 1 H), 2.22 (s, 3 H), 1.88-181 (m, 1 H), 1.56-1.45 (m, 1 H), 1.21-1.11 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 161.6 (d, 1JCF = 245.4 Hz), 133.5, 129.8, 125.8 (d, 2JCF = 16.4 Hz), 125.2, 123.8, 43.5, 17.5, 15.2, 12.9, 12.5. MS (ESI) m/z 214.1[MH+]. HRMS (ESI) calculated for C11H14NFCl+ [MH+] 214.0793, found 214.0786.

trans-[2-(2-Bromophenyl)cyclopropylmethyl]carbamic Acid tert-Butyl Ester (62)

To a solution of 29 (1.63 g, 6.21 mmol) and Boc2O (1.35 g, 8.07 mmol) in Et2O (75 mL) was added 10% aqueous NaOH (14.9 mL, 37.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min and then at rt for 7 h. To the resulting mixture were added crushed ice and Et2O. The organic layer was further washed with water (×1), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc 10:1) to afford the title compounds as colorless oils (1.71 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 2 H), 7.40 (d, J = 8.5 Hz, 2 H), 7.30-7.19 (m, 3 H), 7.00 (d, J = 7.2 H, 1 Hz), 4.45 (br s, 1 H), 3.05-2.95 (m, 2 H), 1.76 (m, 1 H), 1.46 (s, 9 H), 1.26 (m, 1 H), 0.94 (m, 1 H), 0.77 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 156.2, 141.6, 140.5, 139.6, 133.4, 131.2, 130.0, 128.8, 128.2, 126.1, 125.3, 79.6, 44.9, 28.8, 23.3, 20.6, 14.3.

trans-[2-(3-Bromophenyl)cyclopropylmethyl]carbamic Acid tert-Butyl Ester (63)

Prepared by the same procedure as described for 62 (1.59 g, 99% yield). 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 6.8 Hz, 1 H), 7.20 (s, 1 H), 7.12 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 4.70 (br s, 1 H), 3.22-3.11 (m, 2 H), 1.80-1.76 (m, 1 H), 1.47 (s, 9 H), 1.33-1.27 (m, 1 H), 0.94 (t, J = 6.9 Hz, 2 H). 13C NMR (75 MHz, CDCl3) δ 156.5, 145.5, 130.2, 129.3, 129.1, 124.9, 122.9, 28.8, 23.8, 22.0, 14.8.

trans-[2-(4-Bromophenyl)cyclopropylmethyl]carbamic Acid tert-Butyl Ester (64)

Prepared by the same procedure as described for 62 (356 mg, 82% yield). 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 8.3 Hz, 2 H), 6.93 (d, J = 8.3 Hz, 2 H), 4.69 (br s, 1 H), 3.18-3.11 (m, 2 H), 1.79-1.76 (m, 2 H), 1.47 (s, 9 H), 1.28 (m, 2 H), 0.94-0.90 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 156.0, 142.0, 131.7, 128.0, 127.0, 79.9, 45.0, 28.8, 23.7, 21.9, 14.8.

trans-[2-(4'-Fluorobiphenyl-2-yl)cyclopropyl]methylamine Hydrochloride (66). Step A

62 (30 mg, 0.092 mmol), Pd(PPh3)4 (10.4 mg, 0.009 mmol), and 4-fluorophenylboronic acid (32.2 mg, 0.23 mmol) were dissolved in dimethoxyethane (DME) (4 mL), and the mixture was degassed for 1 min and stirred for 10 min at rt. To the mixture was added 2 M aqueous K2CO3 (0.115 mL, 0.23 mmol). The mixture was degassed again for 1 min, and stirred at 85 °C overnight. The resulting mixture was cooled to ambient temperature and poured into a mixture of 0.1 N HCl/EtOAc (15 mL/15 mL). After partition, the organic layer was washed with water, filtered, and concentrated. The residue was purified by preparative TLC (hexane/EtOAc 4:1) to afford the title compound as a colorless oil (31 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 7.38 (dd, J = 8.6, 5.5 Hz, 2 H), 7.32-7.12 (m, 5 H), 7.01 (d, J = 7.7 Hz, 1 H), 4.38 (br s, 1 H), 3.07 (m, 1 H), 2.92 (m, 1 H), 1.77 (m, 1 H), 1.46 (s, 9 H), 1.20 (m, 1 H), 0.95 (m, 1 H), 0.76 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 162.4 (d, 1JCF = 246 Hz), 156.2, 142.0, 139.7, 138.0 (d, 4JCF = 3.3 Hz), 131.4 (d, 3JCF = 7.9 Hz), 130.2, 128.1, 126.1, 125.6, 115.6 (d, 2JCF = 21.3 Hz), 79.6, 45.0, 28.8, 23.1, 20.8, 14.0.

Step B

To a solution of trans-[2-(4'-fluorobiphenyl-4-yl)cyclopropylmethyl]carbamic acid tert-butyl ester (30 mg) in CH2Cl2 (1 mL) was added TFA (0.1 mL) at 0 °C. After standing at 0 °C for 30 min and at rt for 1 h, the mixture was concentrated. The residue was dissolved in CH2Cl2 (1 mL), and 1 M HCl in Et2O (0.3 mL) was added to the solution. The mixture was let stand at 0 °C for 30 min, and concentrated. The resulting white solid was purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (16 mg, 66% yield). HPLC purity: 7.8 min, 97.7% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.43-7.39 (m, 2 H), 7.33-7.24 (m, 2 H), 7.22-7.13 (m, 4 H), 2.96 (m, 1 H), 2.54 (m, 1 H), 1.96 (m, 1 H), 1.31 (m, 1 H), 1.00 (m, 1 H), 0.93 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 163.6 (d, 1JCF = 245 Hz), 143.3, 139.6, 139.3 (d, 4JCF = 3.4 Hz), 132.4 (d, 3JCF = 8.0 Hz), 130.9, 129.0, 127.5, 127.2, 116.1 (d, 2JCF = 21.5 Hz), 44.8, 22.3, 20.3, 15.2. MS (ESI) m/z 242.2 [MH+]. HRMS (ESI) calculated for C16H17NF+ [MH+] 242.13395, found 242.13373.

trans-C-[2-(2-Benzofuran-2-ylphenyl)cyclopropyl]methylamine Hydrochloride (67)

Prepared by the same procedure as described for 66 with 2-benzofuranboronic acid (37.3 mg, 0.23 mmol) as the starting material (22 mg, 111% and 76% yields). HPLC purity: 10.5 min, 98.9% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.77 (d, J = 7.2 Hz, 1 H), 7.66 (d, J = 7.5 H, 1 Hz), 7.55 (d, J = 8.0 Hz, 1 H), 7.39-7.25 (m, 5 H), 7.14 (s, 1 H), 3.21 (m, 1 H), 2.84 (m, 1 H), 2.42 (m, 1 H), 1.50 (m, 1 H), 1.15 (m, 1 H), 1.05 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 157.0, 156.2, 139.9, 132.5, 130.6, 130.2, 129.8, 128.7, 127.9, 125.7, 124.2, 122.3, 112.0, 106.8, 45.1, 23.1, 19.8, 14.8. MS (ESI) m/z 264.1 [MH+]. HRMS (ESI) calculated for C18H18NO+ [MH+] 264.13829, found 264.13814.

trans-[2-(4'-Fluorobiphenyl-3-yl)cyclopropyl]methylamine Hydrochloride (68)

Prepared by the same procedure as described for 66 with 63 (30 mg, 0.092 mmol) and 4-fluorophenylboronic acid (32.2 mg, 0.23 mmol) as the starting materials (18 mg, 115% and 63% yields). HPLC purity: 18.2 min, 97.3% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.63-7.60 (m, 1 H), 7.40-7.33 (m, 3 H), 7.17 (t, J = 8.8 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H), 3.09-3.00 (m, 2 H), 2.14-2.09 (m, 1 H), 1.52-1.47 (m, 1 H), 1.21-1.16 (m, 1 H), 1.14-1.09 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 164.0 (d, 1JCF = 245 Hz), 143.5, 141.7, 138.8 (d, 4JCF = 3.2 Hz), 130.2, 130.0 (d, 3JCF = 8.1 Hz), 126.0, 125.9, 125.8, 116.6 (d, 2JCF = 21.7 Hz), 45.0, 23.4, 21.1, 15.2. MS (ESI) m/z 242.1 [MH+]. HRMS (ESI) calculated for C16H17NF+ [MH+] 242.13395, found 242.13373.

trans-[2-(4'-Chlorobiphenyl-3-yl)cyclopropyl]methylamine Hydrochloride (69)

Prepared by the same procedure as described for 68 with 4-chlorophenylboronic acid (36.0 mg, 0.23 mmol) as the starting material (17 mg, 82% and 83% yields). HPLC purity: 17.9 min, 97.7% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.58 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.40-7.33 (m, 3 H), 7.12 (d, J = 7.5 Hz, 2 H), 3.02 (m, 2 H), 2.09 (m, 2 H), 1.46 (m, 1 H), 1.18 (m, 1 H), 1.10 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 143.6, 141.5, 141.2, 134.6, 130.3, 130.1, 129.7, 126.3, 126.0, 125.9, 45.0, 23.4, 21.1, 15.2. MS (ESI) m/z 258.2 [MH+]. HRMS (ESI) calculated for C16H17NCl+ [MH+] 258.10440, found 258.10422.

trans-[2-(4'-Trifluoromethybiphenyl-3-yl)cyclopropyl]methylamine Hydrochloride (70)

Prepared by the same procedure as described for 68 with 4-trifluoromethylphenylboronic acid (43.7 mg, 0.23 mmol) as the starting material (15 mg, 66% and 81% yields). HPLC purity: 17.6 min, 95.6% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.81 (d, J = 8.2 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.51-7.47 (m, 2 H), 7.41 (t, J = 7.7 Hz, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 3.07-3.00 (m, 2 H), 2.16-2.11 (m, 1 H), 1.52-1.48 (m, 1 H), 1.24-1.20 (m, 1 H), 1.16-1.11 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 144.4, 141.8, 139.2, 128.4, 126.8, 125.0, 124.9, 124.9, 124.4, 124.3, 43.1, 21.5, 19.2, 13.3. MS (ESI) m/z 292.2 [MH+]. HRMS (ESI) calculated for C17H17NF3 + [MH+] 292.13076, found 292.13050.

trans-[2-(4'-Cyanobiphenyl-3-yl)cyclopropyl]methylamine Hydrochloride (71)

Prepared by the same procedure as described for 68 with 4-cyanophenylboronic acid (33.8 mg, 0.23 mmol) as the starting material (20 mg, 94% and 75% yields). HPLC purity: 13.6 min, 97.9% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.81 (s, 4 H), 7.49 (m, 1 H), 7.48 (s, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 3.10-3.01 (m, 2 H), 2.17-2.12 (m, 1 H), 1.55-1.47 (m, 1 H), 1.24-1.19 (m, 1 H), 1.16-1.11 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 147.2, 144.0, 140.7, 133.9, 130.5, 129.1, 127.3, 126.3, 126.2, 119.9, 112.0, 45.0, 23.4, 21.2, 15.3. MS (ESI) m/z 249.2 [MH+]. HRMS (ESI) calculated for C17H17N2+ [MH+] 249.13863, found 249.13861.

trans-C-[2-(3-Benzofuran-2-ylphenyl)cyclopropyl]methylamine Hydrochloride (72)

Prepared by the same procedure as described for 68 with 2-benzofuranboronic acid (37.3 mg, 0.23 mmol) as the starting material (21 mg, 101% and 85% yields). HPLC purity: 12.5 min, 98.4% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.71 (d, J = 6.5 Hz, 2 H), 7.61 (d, J = 7.5 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.29 (d, J = 7.3 Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.19 (br s, 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 3.05 (m, 2 H), 2.13 (m, 1 H), 1.51 (m, 1 H), 1.21 (m, 1 H), 1.14 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 157.2, 156.4, 143.6, 132.0, 130.7, 130.2, 127.4, 125.7, 124.3, 123.8, 123.7, 122.2, 112.0, 102.7, 79.3, 45.0, 23.4, 21.1, 15.2. MS (ESI) m/z 264.2 [MH+]. HRMS (ESI) calculated for C18H18NO+ [MH+] 264.13829, found 264.13811.

trans-[2-(4'-Fluorobiphenyl-4-yl)cyclopropyl]methylamine Hydrochloride (73)

Prepared by the same procedure as described for 66 with 64 (34 mg, 0.104 mmol) and 4-fluorophenylboronic acid (36.5 mg, 0.261 mmol) as the starting materials (14 mg, 62% and 86% yields). HPLC purity: 18.0 min, 96.4% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.70 (m, 2 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.16 (m, 2 H), 3.03 (d, J = 7.4 Hz, 2 H), 2.06 (m, 1 H), 1.49 (m, 1 H), 1.13 (m, 2 H) (ppm). 13C NMR δ 157.0, 140.9, 138.2, 137.5, 128.6, 128.5, 126.9, 126.5, 115.6, 115.3, 43.9, 21.9, 20.0, 14.1. MS (ESI) m/z 242.1 [MH+]. HRMS (ESI) calculated for C16H17NF+ [MH+] 242.1345, found 242.1344.

trans-[2-(4-Furan-2-ylphenyl)cyclopropyl]methylamine Hydrochloride (74)

Prepared by the same procedure as described for 66 with 64 (30 mg, 0.092 mmol) and 2-furanboronic acid (25.7 mg, 0.23 mmol) as the starting materials (18 mg, 98% and 82% yields). HPLC purity: 13.6 min, 96.5% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.60 (d, J = 8.2 Hz, 2 H), 7.53 (s, 1 H), 7.17 (d, J = 8.1 Hz, 2 H), 6.70 (m, 1 H), 6.50 (s, 1 H), 3.02 (d, J = 7.4 Hz, 2 H), 2.07-2.01 (m, 1 H), 1.44 (m, 1 H), 1.18-1.08 (m, 2 H). 13C NMR δ 154.2, 142.1, 140.9, 129.3, 126.3, 123.8, 111.7, 104.6, 43.8, 22.0, 20.0, 14.1. MS (ESI) m/z 214.1 [MH+]. HRMS (ESI) calculated for C14H16NO+ [MH+] 214.1232, found 214.1228.

trans-[2-(2-Aminophenyl)cyclopropylmethyl]carbamic Acid tert-Butyl Ester (75). Step A

To a mixture of Pd(OAc)2 (3.4 mg, 0.015 mmol), BINAP (19.1 mg, 0.031 mmol), and 62 (50 mg, 0.153 mmol) in toluene (3 mL) were added benzophenone imine (0.051 mL, 0.306 mmol) and Cs2CO3 (125 mg, 0.383 mmol) under nitrogen. The resulting mixture was stirred at 100 °C overnight, diluted with EtOAc, filtered, and concentrated. The residue was purified by preparative TLC (hexane/EtOAc 3:1) to afford the corresponding diphenyl ketimine compound as a colorless oil (51.9 mg, a mixture of starting material and the product). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 6.9 Hz, 2 H), 7.46 (m, 3 H), 7.28 (m, 3 H), 7.16 (m ,2 H), 6.86 (m, 2 H), 6.79 (m, 1 H), 6.39 (m, 1 H), 4.88 (br s, 1 H), 3.34-3.23 (m, 2 H), 1.87 (m, 1 H), 1.45 (s, 9 H), 1.28 (m, 1 H), 0.93 (m, 1 H), 0.85 (m, 1 H). 13C NMR (75MHz, CDCl3) δ 168.3, 156.2, 150.9, 139.9, 136.7, 131.1, 129.8, 129.5, 129.1, 128.7, 128.3, 127.8, 126.1, 123.8, 119.8, 79.4, 45.4, 28.9, 22.9, 18.8, 12.9.

Step B

To a solution of the ketimine adduct (35 mg, 0.188 mmol) in MeOH (0.8 mL) at rt were added NaOAc (16.2 mg, 0.197 mmol) and NH2OH·HCl (10.3 mg, 0.148 mmol). The mixture was stirred at rt for 2 h, diluted with CH2Cl2, and purified by preparative TLC (hexane/EtOAc 2:1) to afford the title compound as a colorless oil (20.5 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 6.69 (m, 2 H), 4.89 (br s, 1 H), 3.42-3.36 (m, 1 H), 3.16-3.11 (m, 1 H), 1.65 (m, 1 H), 1.48 (s, 9 H), 1.14 (m, 1 H), 0.94 (m, 1 H), 0.80 (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 156.3, 146.3, 127.8, 127.2, 125.5, 117.9, 114.6, 79.4, 44.2, 28.4, 20.2, 14.1, 9.7.

trans-[2-(3-Aminophenyl)cyclopropylmethyl]carbamic Acid tert-Butyl Ester (76)

Prepared by the same procedure as described for 75 with 63 (120 mg, 0.368 mmol) as the starting material (33 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.8 Hz, 1 H), 6.56 (dd, J = 1.4Hz, 7.9 Hz, 1 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.46 (s, 1 H), 4.70 (br s, 1 H), 3.22 (m, 1 H), 3.10 (m, 1 H), 1.73 (m, 1 H), 1.47 (s, 9 H), 1.28 (m, 1 H), 0.91 (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 155.5, 144.9, 143.6, 128.9, 116.4, 112.7, 44.4, 28.0, 22.4, 21.5, 13.8.

trans-[3-(2-Aminomethylcyclopropyl)phenyl]benzylamine Hydrochloride (78). Step A

76 (15 mg, 0.0572 mmol) was dissolved in MeOH (0.5 mL) containing benzaldehyde (0.0052 mL, 0.0512 mmol) at 0 °C. To the mixture was added NaCNBH3 (4.3 mg, 0.0686 mmol). The resulting mixture was stirred at 0 °C for 1 h and at rt overnight and directly purified by preparative TLC (hexane/EtOAc 1:1) to afford the title compound as a colorless oil (9.9 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 7.38-7.35 (m, 4 H), 7.32-7.28 (m, 1 H), 7.08 (t, J = 7.8 Hz, 1 H), 6.47-6.42 (m, 2 H), 6.37 (s, 1 H), 4.68 (br s, 1 H), 4.33 (s, 2 H), 4.07 (br s, 1 H), 3.26-3.23 (m, 1 H), 3.12-3.05 (m, 1 H), 1.72 (m, 1 H), 1.47 (s, 9 H), 1.28 (m, 1 H), 0.89 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 155.8, 148.2, 143.7, 139.4, 129.2, 128.6, 127.5, 127.2, 114.9, 110.4, 110.2, 79.1, 48.3, 44.8, 28.4, 22.7, 22.1, 14.2.

Step B

Prepared by the same deprotection procedure as described for 66 (5.6 mg, 76% yield). HPLC purity: 4.4 min, 94.4% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.45-7.41 (m, 6 H), 7.28 (d, J = 8.0 Hz, 1 H), 7.20-7.18 (m, 2 H), 4.60 (s, 2 H), 3.03 (m, 2 H), 2.11 (m, 1 H), 1.48 (m, 1 H), 1.17-1.12 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 146.0, 132.4, 131.6, 131.4, 130.9, 130.3, 128.3, 121.7, 121.5, 56.8, 44.7, 23.1, 21.6, 15.6. MS (ESI) m/z 253.2 [MH+]. HRMS (ESI) calculated for C17H21N2 + [MH+] 253.16993, found 253.16979.

trans-N-[2-(2-Aminomethylcyclopropyl)phenyl]acetamide Hydrochloride (80). Step A

75 (7.0 mg, 0.0267 mmol) and DMAP (3.3 mg, 0.0267 mmol) in CH2Cl2 (0.3 mL) was added acetic anhydride (0.004 mL, 0.0423 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and rt overnight, and directly purified by preparative TLC (hexane/EtOAc 1:1) to afford the title compound as a colorless oil (7.2 mg, 89% yield). 1H NMR (300 MHz, CDCl3) δ 8.63 (br. s, 1 H), 8.09 (d, J = 7.9 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.06-6.96 (m, 2 H), 4.89 (br s, 1 H), 3.58 (m, 1 H), 3.05 (m, 1 H), 1.84 (m, 1 H), 1.46 (s, 9 H), 1.27 (m, 1 H), 1.24 (m, 1 H), 0.83 (m, 1 H). 13C NMR (75 MHz, CDCl3) δ 169.7, 157.4, 138.0, 131.5, 127.1, 126.5, 124.4, 122.5, 80.4, 43.7, 30.1, 28.8, 24.8, 22.4, 18.1.

Step B

Prepared by the same deprotection procedure as described for 66 (3.6 mg, 77% yield). HPLC purity: 4.8 min, 97.0% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.22-7.20 (m, 3 H), 6.99 ((m, 3 H), 3.08 (m, 1 H), 2.94 (m, 1 H), 1.96 (m, 1 H), 1.32 (m, 1 H), 1.16 (m, 1 H), 1.08 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 172.6, 138.1, 137.2, 128.1, 127.6, 127.2, 126.0, 45.0, 23.1, 21.2, 19.8, 14.0. MS (ESI) m/z 205.2 [MH+]. HRMS (ESI) calculated for C12H17N2O+ [MH+] 205.13354, found 205.13345.

trans-N-[2-(2-Aminomethylcyclopropyl)phenyl]benzamide Hydrochloride (81)

Prepared by the same procedure as described for 80 with 75 (5.8 mg, 0.0221 mmol) and benzoyl chloride (0.0039 mL, 0.0332 mmol) as the starting materials (3.5 mg, 100% and 53% yields). HPLC purity: 6.48 min, 99.2% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 8.05 (d, J = 7.3 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 7.56 (t, J = 7.4 Hz, 2 H), 7.33-7.27 (m, 3 H), 7.07 (m, 1 H), 3.01 (m, 1 H), 2.86 (m, 1 H), 2.01 (m, 1 H), 1.38 (m, 1 H), 1.21 (m, 1 H), 1.05 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 169.4, 138.7, 137.5, 135.3, 133.3, 129.8, 128.8, 128.4, 127.7, 127.6, 126.3, 45.0, 21.2, 20.2, 13.7. MS (ESI) m/z 267.1 [MH+]. HRMS (ESI) calculated for C17H19N2O+ [MH+] 267.14919, found 267.14900.

trans-1-[2-(2-Aminomethylcyclopropyl)phenyl]-3-(4-chlorophenyl)urea Hydrochloride (82). Step A

To a solution of 75 (30.0 mg, 0.114 mmol) in THF (5 mL) were added DMAP (2.8 mg, 0.023 mmol) and 4-chlorophenyl isocyanate (0.022 mL, 0.172 mmol) at rt. The mixture was stirred at 50 °C overnight and directly purified by preparative TLC (hexane/EtOAc 1:1) to afford the title compound as a colorless oil (29.1 mg, 61% yield). 1H NMR (300 MHz, CDCl3) δ 8.42 (br s, 1 H), 8.32 (d, J = 8.2 Hz, 1 H), 8.08 (br s, 1 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.29-7.22 (m, 3 H), 7.04 (t, J = 6.9 Hz, 1 H), 6.90 (d, J = 6.9 Hz, 1 H), 6.95 (t, J = 7.2 Hz, 1 H), 4.98 (br t, J = 6.2 Hz, 1 H), 3.93 (m, 1 H), 3.23 (m, 1 H), 1.61 (m, 1 H), 1.50 (s, 9 H), 1.19 (m, 1 H), 0.83-0.72 (m, 2 H). 13C NMR (75 MHz, CDCl3) δ 158.5, 153.3, 139.7, 138.8, 129.2, 128.9, 127.6, 127.4, 127.1, 122.3, 120.2, 119.3, 81.5, 40.6, 28.8, 21.2, 16.2, 6.5.

Step B

Prepared by the same deprotection procedure as described for 66 (18 mg, 79% yield). HPLC purity: 8.1 min, 99.5% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.48 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.9 Hz, 2 H), 7.24-7.12 (m, 2 H), 7.03 (d, J = 7.6 Hz, 1 H), 3.11-2.95 (m, 2 H), 2.12-2.05 (m, 1 H), 1.44-1.38 (m, 1 H), 1.14-1.09 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 155.1, 138.5, 137.1, 135.0, 128.8, 127.6, 126.7, 125.6, 125.5, 124.8, 120.5, 44.0, 19.3, 18.7, 13.0. MS (ESI) m/z 316.2 [MH+]. HRMS (ESI) calculated for C17H19N3OCl+ [MH+] 316.12112, found 316.12080.

trans-N-[3-(2-Aminomethylcyclopropyl)phenyl]acetamide Hydrochloride (83)

Prepared by the same procedure as described for 80 with 75 (5.8 mg, 0.0221 mmol) and benzoyl chloride (0.0039 mL, 0.0332 mmol) as the starting materials (3.3 mg, 94% and 60% yields). 1H NMR (300 MHz, MeOD-d4) δ 7.47 (s, 1 H), 7.25-7.19 (m, 2 H), 6.90 (d, J = 6.4 Hz, 1 H), 3.01 (d, J = 7.4 Hz, 2 H), 2.13 (s, 3 H), 2.01 (m, 1 H), 1.42 (m, 1 H), 1.10 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 171.9, 143.6, 140.2, 130.0, 123.0, 119.0, 118.9, 45.0, 24.0, 23.4, 21.1, 15.2. MS (ESI) m/z 205.2 [MH+]. HRMS (ESI) calculated for C12H17N2O+ [MH+] 205.13354, found 205.13341.

trans-N-[3-(2-Aminomethylcyclopropyl)phenyl]benzamide Hydrochloride (84)

Prepared by the same procedure as described for 80 with 76 (7.0 mg, 0.0234 mmol) and benzoyl chloride (0.0047 mL, 0.040 mmol) as the starting materials (4.3 mg, 97% and 74% yields). HPLC purity: 4.8 min, 99.6% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.94 (d, J = 7.2 Hz, 2 H), 7.62-7.51 (m, 4 H), 7.13-7.09 (m, 2 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 3.02 (d, J = 7.4 Hz, 2 H), 2.06 (m, 1 H), 1.46 (m, 1 H), 1.17 (m, 1 H), 1.10 (m, 1 H). 13C NMR (100 MHz, MeOD-d4) δ 169.1, 143.6, 140.1, 136.4, 133.1, 130.0, 129.8, 128.7, 123.6, 120.2, 120.0, 45.0, 23.4, 21.1, 15.2. MS (ESI) m/z 267.1 [MH+]. HRMS (ESI) calculated for C17H19N2O+ [MH+] 267.14919, found 267.14899.

General Procedure for t-Boc Deprotection

The protected amine was dissolved in a 2 N HCl solution in diethyl ether, and the reaction mixture was stirred at ambient temperature for 12-24 h. A white precipitate formed after several minutes to hours. The mixture was stirred until the reaction was complete by TLC and worked up as described below.

trans-{2-[2-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylamine Hydrochloride (86). Step A

62 (50 mg, 0.153 mmol), Pd(PPh3)2Cl2 (8.6 mg, 0.012 mmol), PPh3 (6.4 mg, 0.024 mmol), CuI (4.7 mg, 0.024 mmol), and 5-hexyn-1-ol (0.037 ml, 0.337 mmol) were dissolved in triethylamine (TEA) (1.4 mL), and the mixture was degassed for 1 min and stirred at 85 °C overnight. The resulting mixture was cooled to ambient temperature and poured into a mixture of 0.1 N HCl/EtOAc (3 mL/3 mL). After partition, the organic layer was washed with water, filtered, and concentrated. The residue was purified by silica gel chromatography (hexane/Et2O 4:1) to afford the title compound as colorless oil (30 mg, 57% yield).

Step B

Refer to the general procedure for t-Boc deprotection described above. The mixture was concentrated, and washed with ethanol/Et2O to afford the title compound as a brown oil (22 mg, 90% yield). HPLC purity: 7.9 min, 94.7% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.24-7.08 (m, 3 H), 6.94 (d, J = 7.6 Hz, 1 H), 5.74 (t, J = 7.1 Hz, 1 H), 3.52 (t, J = 6.1 Hz, 2 H), 2.62 (m, 1 H), 2.38-2.33 (m, 1 H), 2.09-2.06 (m, 1 H), 1.57-1.50 (m, 4 H), 1.29 (m, 1 H), 1.02-0.95 (m, 3 H). 13C NMR (100 MHz, MeOD-d4) δ 143.3, 140.8, 132.3, 130.8, 127.5, 126.7, 90.5, 81.2, 62.8, 45.1, 33.4, 30.0, 26.1, 21.7, 20.3, 12.3. MS (ESI) m/z 244.2 [MH+]. HRMS (ESI) calculated for C16H22NO+ [MH+] 244.1696, found 244.1688.

trans-[2-(3-Ethynylphenyl)cyclopropyl]methylamine Hydrochloride (87)

Pd(PhCN)2Cl2 (1.8 mg, 0.0045 mmol) and CuI (0.6 mg, 0.003 mmol) were added to a dry vial, which was then sparged with argon and charged with dioxane (0.3 mL). P(t-Bu)3 (1.0 M in dioxane, 9.2 µL, 0.009 mmol), HN(i-Pr)2 (13.3 µL, 0.184 mol), 63 (50 mg, 0.153 mmol), and ethynyltrimethylsilane (26 µL, 0.184 mmol) were added to the stirred reaction mixture. During the reaction, precipitation of [H2N(i-Pr)2]Br was observed. After stirring at 50 °C overnight, the reaction mixture was diluted with EtOAc (5 mL), filtered through a small pad of silica gel, concentrated, and purified by silica gel chromatography (hexane/Et2O 4:1) to afford the title compound as brown powder (58 mg, 57% yield). To a stirred solution of trans-[2-(3-trimethylsilanylethynylphenyl)cyclopropylmethyl]carbamic acid tert-butyl ester (58 mg, 0.17 mmol) in THF (1.5 mL) was added TBAF solution (1.0 M in THF, 0.255 mL, 0.255 mmol) slowly under argon purge to give a deep dark solution. After 1 h, the reaction mixture was diluted with EtOAc (5 mL). The organic layer was washed with water, filtered and concentrated, and purified by silica gel chromatography (hexane/Et2O 4:1) to afford the title compound as brown powder (58 mg, 57% yield). Refer to the general procedure for t-Boc deprotection described above. The crude precipitate was filtered and purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (22 mg, 90% yield). HPLC purity: 9.3 min, 99.4% (column 1, method D). 1H NMR (400 MHz, MeOD-d4) δ 7.28-7.22 (m, 3 H), -7.13 (d, J = 6.8 Hz, 1 H), 3.45 (s, 1 H), 3.04-2.93 (m, 2 H), 2.02-1.97 (m, 1 H), 1.42-1.38 (m, 1 H), 1.33-1.04 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 143.3, 130.8, 130.7, 129.7, 127.6, 124.0, 78.7, 44.9, 23.0, 21.1, 15.2. MS (ESI) m/z 272.1 [MH+]. HRMS (ESI) calculated for C12H14N+ [MH+] 172.1121, found 172.1122.

trans-{2-[3-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylamine Hydrochloride (88)

Refer to the general procedure for the synthesis of 86 described above with substitution of 63 for 62. The crude precipitate was filtered and purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (21 mg, 86% yield). HPLC purity: 5.8 min, 94.8% (column 1, method C). 1H NMR (400 MHz, MeOD-d4) δ 7.19-7.05 (m, 3 H), 6.97 (d, J = 7.2 Hz, 1 H), 3.51 (t, J = 5.9 Hz, 2 H), 2.90 (m, 2 H), 2.34 (t, J = 6.7 Hz, 2 H), 1.93-1.88 (m, 1 H), 1.63-1.55 (m, 4 H), 1.34-1.29 (m, 1 H), 1.02-0.96 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 143.1, 130.3, 130.1, 129.5, 126.6, 125.6, 90.7, 81.9, 62.6, 44.9, 32.9, 26.4, 23.1, 21.7, 19.9, 15.2. MS (ESI) m/z 244.2 [MH+]. HRMS (ESI) calculated for C16H22NO+ [MH+] 244.1696, found 244.1688.

trans-{2-[3-(3-Hydroxy-3-methylbut-1-ynyl)phenyl]cyclopropyl}methylamine Hydrochloride (89)

Refer to the general procedure for the synthesis of 86 described above with substitution of 63 for 62 and 2-methylbut-3-yn-2-ol for 5-hexyn-1-ol (17 mg, 98% and 85% yields). HPLC purity: 8.5 min, 95.4% (column 3, method A). 1H NMR (400 MHz, MeOD-d4) δ 7.26-7.16 (m, 3 H), 7.12-7.10 (m, 1 H), 3.04-2.95 (m, 2 H), 2.01-1.98 (m, 1 H), 1.51-1.38 (m, 7 H), 1.13-1.05 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 143.3, 130.4, 130.3, 129.7, 127.4, 124.2, 91.6, 85.6, 65.9, 44.9, 31.5, 28.9, 23.0, 21.1, 15.1. MS (ESI) m/z 230.1 [MH+]. HRMS (ESI) calculated for C15H20NO+ [MH+] 230.1539, found 230.1537.

trans-{2-[4-(6-Hydroxyhex-1-ynyl)phenyl]cyclopropyl}methylamine Hydrochloride (90)

Refer to the general procedure for the synthesis of 76 described above with substitution of 64 for 62. The crude precipitate was filtered and purified by recrystallization from ethanol/Et2O to afford the title compound as a white solid (21 mg, 86% yield). HPLC purity: 7.7 min, 99.0% (column 3, method A). 1H NMR (300 MHz, MeOD-d4) δ 7.25 (d, J = 8.2 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 2 H), 3.60 (t, J = 6.1 Hz, 2 H), 2.98 (m, 2 H), 2.47-2.40 (m, 2 H), 2.00-1.95 (m, 1 H), 1.71-1.63 (m, 4 H), 1.39 (m, 1 H), 1.11-1.04 (m, 2 H). 13C NMR (100 MHz, MeOD-d4) δ 142.5, 132.7, 127.0, 123.2, 90.5, 81.8, 62.6, 44.9, 33.0, 26.5, 23.2, 21.3, 19.9, 15.4. MS (ESI) m/z 244.2 [MH+]. HRMS (ESI) calculated for C16H22NO+ [MH+] 244.1696, found 244.1689.

Biological Methods. Calcium Flux Assays

Calcium flux assays were performed essentially as described earlier.44 HEK 293 cells stably expressing the human 5-HT2A, 5-HT2B, or 5-HT2C (INI) receptor were seeded and incubated for 20 h in serum-free DMEM containing 50 U/mL penicillin and 50 µg/mL streptomycin sulfate in tissue culture-treated black clear-bottom 384-well plates (Greiner, Germany); plates were coated with 20 µL/well of 50 mg/L poly-l-lysine (Sigma, P-1524) in PBS. The cells were preincubated for 75 min at 37 °C in a humidified incubator with 20 µL of reconstituted fura-4 based calcium dye (Calcium Plus Assay Kit, Molecular Devices) in assay buffer (Hanks' balanced salt solution containing calcium and magnesium (Invitrogen, 14065-056), 50 mM HEPES, 2.5 mM probenecid, 100 mg/L ascorbic acid, pH 7.4). The plates were allowed to cool to rt over 10 min and were transferred to a FLIPR Tetra fluorescence image plate reader (Molecular Devices). The test compounds in 15 µL assay buffer were automatically added and fluorescence (excitation: 470–495 nm, emission: 515–575 nm) was measured every second for 3 min. The baseline was averaged from ten data points immediately before the additions and results were exported as the maximal response over baseline during 60 s after addition. Compounds were measured at seven concentrations from 10 µM to 10 pM in triplicate. EC50 values and Emax values were obtained from nonlinear curve fitting against a sigmoidal dose-response model using Prism (Graphpad).

Behavior. Animals

C57BL/6J male mice (9 weeks of age at testing) were obtained from Jackson Laboratory (Bar Harbor, ME). Mice were housed 4 to a cage in a colony room maintained at 22 °C on a 12 h light-dark cycle. All animal experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the PsychoGenics Animal Care and Use Committee.

Mouse Forced Swim Test

Procedures were based on those previously described.48 Mice were individually placed into clear glass cylinders (i.e., 15 cm tall × 10 cm wide, 1 L beakers) containing 23 ± 1 °C water 12 cm deep (approximately 800 mL). The time the animal spent immobile was recorded every 1 min over a 6 min trial. Immobility was described as the postural position of floating in the water. After testing, mice were dried and returned to their home cage.

Drugs

Sertraline was purchased from a commercial vendor (Sigma, St. Louis, MO). All compounds were dissolved in 10% DMSO vehicle in saline, 30 minutes prior to testing. All compounds were administered i.p., 1 ml/kg dosing volume.

Statistics

ANOVA was performed to determine the effects of test treatment, followed by post-hoc analysis using Fisher’s PLSC.

Supplementary Material

1_si_001

Supporting Information Available:

Functional activity of compounds 66–74, 78, 80–84, and 86–90. Copy of original Spectroscopic data and purity assessment of key compounds 29 and 37. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENT

This work was supported in part by NIH grant (R01 DA022317, Grantee Alan P. Kozikowski), (RO1MH61887, NO1MH80032 and U19MH82441, Grantee Bryan L. Roth) and NIDA fellowship (2006–2007). This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2007-357-C00071). The authors wish to thank Dr. Rong He for help with the preparative of the manuscript and Dr. Arsen Gaysin for help with generating the data reported. S. J. Cho expresses appreciation to Dr. Suresh Tipparaju, Dr. Annamaria Lilienkampf, Dr. Sophie Gaudrel-Grosay, and Dr. Ki Duk Park for helpful discussions.

Footnotes

aAbbreviations: 5-HT, 5-hydroxytrytamine (serotonin); LSD, lysergic acid diethylamide; CNS, central nervous system; MAO, monoamine oxidase; SAR, structure activity relationship; SERT, serotonin 5-HT transporter; NET, norepinephrine transporter; DAT, dopamine transporter.

References

1. Hoyer D, Martin G. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology. 1997;36:419–428. [PubMed]
2. Roth BL. Multiple serotonin receptors: clinical and experimental aspects. Ann. Clin. Psychiatry. 1994;6:67–78. [PubMed]
3. Kroeze WK, Roth BL. The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis. Biol. Psychiatry. 1998;44:1128–1142. [PubMed]
4. Kroeze WK, Sheffler DJ, Roth BL. G-protein-coupled receptors at a glance. J. Cell Sci. 2003;116:4867–4869. [PubMed]
5. Kroeze WK, Kristiansen K, Roth BL. Molecular biology of serotonin receptors structure and function at the molecular level. Curr. Top. Med. Chem. 2002;2:507–528. [PubMed]
6. Nichols DE. Hallucinogens. Pharmacol. Ther. 2004;101:131–181. [PubMed]
7. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–2841. [PubMed]
8. Roth BL. Drugs and valvular heart disease. N. Engl. J. Med. 2007;356:6–9. [PubMed]
9. Loke YK, Derry S, Pritchard-Copley A. Appetite suppressants and valvular heart disease - a systematic review. BMC Clin. Pharmacol. 2002;2:6. [PMC free article] [PubMed]
10. Rocha BA, Goulding EH, O'Dell LE, Mead AN, Coufal NG, Parsons LH, Tecott LH. Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice. J. Neurosci. 2002;22:10039–10045. [PubMed]
11. Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature. 1995;374:542–546. [PubMed]
12. Chou-Green JM, Holscher TD, Dallman MF, Akana SF. Compulsive behavior in the 5-HT2C receptor knockout mouse. Physiol. Behav. 2003;78:641–649. [PubMed]
13. Delgado PL, Moreno FA. Hallucinogens, serotonin and obsessive-compulsive disorder. J. Psychoactive Drugs. 1998;30:359–366. [PubMed]
14. Martin JR, Bos M, Jenck F, Moreau J, Mutel V, Sleight AJ, Wichmann J, Andrews JS, Berendsen HH, Broekkamp CL, Ruigt GS, Kohler C, Delft A. M. 5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential. J. Pharmacol. Exp. Ther. 1998;286:913–924. [PubMed]
15. Roth BL, Shapiro DA. Insights into the structure and function of 5-HT2 family serotonin receptors reveal novel strategies for therapeutic target development. Expert. Opin. Ther. Targets. 2001;5:685–695. [PubMed]
16. Miller KJ. Serotonin 5-HT2C receptor agonists: potential for the treatment of obesity. Mol. Interv. 2005;5:282–291. [PubMed]
17. Roth BL, Lopez E, Patel S, Kroeze WK. The multiplicity of serotonin receptors: Uselessly diverse molecules or an embarrassment of riches? Neuroscientist. 2000;6:252–262.
18. Isaac M. Serotonergic 5-HT2C receptors as a potential therapeutic target for the design antiepileptic drugs. Curr. Top. Med. Chem. 2005;5:59–67. [PubMed]
19. Millan MJ, Peglion JL, Lavielle G, Perrin-Monneyron S. 5-HT2C receptors mediate penile erections in rats: actions of novel and selective agonists and antagonists. Eur. J. Pharmacol. 1997;325:9–12. [PubMed]
20. Cryan JF, Lucki I. Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine2C receptors. J. Pharmacol. Exp. Ther. 2000;295:1120–1126. [PubMed]
21. Giorgetti M, Tecott LH. Contributions of 5-HT2C receptors to multiple actions of central serotonin systems. Eur. J. Pharmacol. 2004;488:1–9. [PubMed]
22. Rosenzweig-Lipson S, Sabb A, Stack G, Mitchell P, Lucki I, Malberg JE, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo SJ, Dunlop J, Barrett JE, Marquis KL. Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology (Berl) 2007;192:159–170. [PubMed]
23. Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR, Jr, Nguyen HQ, Dawson LA, Barrett JE, Stack G, Meltzer HY, Harrison BL, Rosenzweig-Lipson S. WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J. Pharmacol. Exp. Ther. 2007;320:486–496. [PubMed]
24. Berger M, Gray JA, Roth BL. The Expanded Biology of Serotonin. Annu. Rev. Med. 2009;60:355–366. [PubMed]
25. Lacivita E, Leopoldo M. Selective agents for serotonin2C (5-HT2C) receptor. Curr. Top. Med. Chem. 2006;6:1927–1970. [PubMed]
26. Nilsson BM. 5-Hydroxytryptamine 2C (5-HT2C) receptor agonists as potential antiobesity agents. J. Med. Chem. 2006;49:4023–4034. [PubMed]
27. Siuciak JA, Chapin DS, McCarthy SA, Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour PA, Swick A, Iredale PA. CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. Neuropharmacology. 2007;52:279–290. [PubMed]
28. Welmaker GS, Nelson JA, Sabalski JE, Sabb AL, Potoski JR, Graziano D, Kagan M, Coupet J, Dunlop J, Mazandarani H, Rosenzweig-Lipson S, Sukoff S, Zhang Y. Synthesis and 5-hydroxytryptamine (5-HT) activity of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines. Bioorg. Med. Chem. Lett. 2000;10:1991–1994. [PubMed]
29. Sabb AL, Vogel RL, Welmaker GS, Sabalski JE, Coupet J, Dunlop J, Rosenzweig-Lipson S, Harrison B. Cycloalkyl[b][1,4]benzodiazepinoindoles are agonists at the human 5-HT2C receptor. Bioorg. Med. Chem. Lett. 2004;14:2603–2607. [PubMed]
30. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Dosa PI, Covel JA, Ren A, Webb RR, Beeley NR, Martin M, Morgan M, Espitia S, Saldana HR, Bjenning C, Whelan KT, Grottick AJ, Menzaghi F, Thomsen WJ. Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J. Med. Chem. 2008;51:305–313. [PubMed]
31. Wacker DA, Varnes JG, Malmstrom SE, Cao X, Hung CP, Ung T, Wu G, Zhang G, Zuvich E, Thomas MA, Keim WJ, Cullen MJ, Rohrbach KW, Qu Q, Narayanan R, Rossi K, Janovitz E, Lehman-McKeeman L, Malley MF, Devenny J, Pelleymounter MA, Miller KJ, Robl JA. Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT2C receptor. J. Med. Chem. 2007;50:1365–1379. [PubMed]
32. Wacker DA, Miller KJ. Agonists of the serotonin 5-HT2C receptor: preclinical and clinical progression in multiple diseases. Curr. Opin. Drug. Discov. Devel. 2008;11:438–445. [PubMed]
33. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science. 2007;318:1258–1265. [PMC free article] [PubMed]
34. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature. 2007;450:383–387. [PubMed]
35. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science. 2007;318:1266–1273. [PubMed]
36. Rohl CA, Strauss CE, Chivian D, Baker D. Modeling structurally variable regions in homologous proteins with rosetta. Proteins. 2004;55:656–677. [PubMed]
37. Ferrara P, Gohlke H, Price DJ, Klebe G, Brooks CL., 3rd Assessing scoring functions for protein-ligand interactions. J. Med. Chem. 2004;47:3032–3047. [PubMed]
38. Burger A, Walter CR, Jr, Bennet WB, Turnbull LB. Arylcycloalkylamines. Science. 1950;112:306. [PubMed]
39. Burger A, Yost WL. Arylcycloalkylamines. I. 2-Phenylcyclopropylamine. J. Am. Chem. Soc. 1948;70:2198–2201.
41. Teotino UM, Bella DD, Gandini A, Benelli G. Chemical and biological properties of some aminomethyl-2-phenylcyclopropane derivatives. Pharmacological comparison with tranylcypromine. J. Med. Chem. 1967;10:1091–1096. [PubMed]
42. Zirkle CL, Kaiser C, Tedeschi DH, Tedeschi RE, Burger A. 2-Substituted Cyclopropylamines. Ii. Effect of Structure Upon Monoamine Oxidase-Inhibitory Activity as Measured in Vivo by Potentiation of Tryptamine Convulsions. J. Med. Pharm. Chem. 1962;5:1265–1284. [PubMed]
43. Yoshida S, Meyer OG, Rosen TC, Haufe G, Ye S, Sloan MJ, Kirk KL. Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine substitution at the cyclopropane ring on inhibition of microbial tyramine oxidase. J. Med. Chem. 2004;47:1796–1806. [PubMed]
44. Krishnamurthy S. A highly efficient and general N-monomethylation of functionalized primary amines via formylation--borane:methyl sulfide reduction. Tetrahedron Lett. 1982;23:3315–3318.
45. Balboni G, Salvadori S, Guerrini R, Negri L, Giannini E, Bryant SD, Jinsmaa Y, Lazarus LH. Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R' analogues: acquisition of potent δ antagonism. Bioorg. Med. Chem. 2003;11:5435–5441. [PubMed]
46. Arvidsson LE, Johansson AM, Hacksell U, Nilsson JL, Svensson K, Hjorth S, Magnusson T, Carlsson A, Lindberg P, Andersson B. N,N-Dialkylated monophenolic trans-2-phenylcyclopropylamines: novel central 5-hydroxytryptamine receptor agonists. J. Med. Chem. 1988;31:92–99. [PubMed]
47. Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, Kato T, Ohta H, Iwasawa Y. Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) J. Med. Chem. 1999;42:5061–5063. [PubMed]
48. Chandrasekhar S, Reddy CR, Ahmed M. A single step reductive amination of carbonyl compounds with polymethylhydrosiloxane-Ti((OPr)-Pr-i)(4) Synlett. 2000:1655–1657.
49. Miyaura N, Suzuki A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995;95:2457–2483.
50. DeVasher RB, Moore LR, Shaughnessy KH. Aqueous-phase, palladium-catalyzed cross-coupling of aryl bromides under mild conditions, using water-soluble, sterically demanding alkylphosphines. J. Org. Chem. 2004;69:7919–7927. [PubMed]
51. Overberger CG, Shimokawa Y. Synthesis and Optical Properties of Asymmetric Polyamides Derived from Optically Active Cyclic Dicarboxylic Acids. Macromolecules. 1971;4:718–725.
52. Zhang X, Hodgetts K, Rachwal S, Zhao H, Wasley JW, Craven K, Brodbeck R, Kieltyka A, Hoffman D, Bacolod MD, Girard B, Tran J, Thurkauf A. trans-1-[(2-Phenylcyclopropyl)methyl]-4-arylpiperazines: mixed dopamine D2/D4 receptor antagonists as potential antipsychotic agents. J. Med. Chem. 2000;43:3923–3932. [PubMed]
53. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL. N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity. Neuropsychopharmacology. 2007;33:2303–2312. [PubMed]
54. Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K. Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors. Synapse. 2000;35:144–150. [PubMed]
55. Dunlop J, Marquis KL, Lim HK, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S. Pharmacological profile of the 5-HT2C receptor agonist WAY-163909; therapeutic potential in multiple indications. CNS Drug Rev. 2006;12:167–177. [PubMed]