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InPursuitofFluorinatedSigmaReceptorLigandCandidatesRelatedto[18F]-FPS SupplementaryMaterial …page1of95

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In Pursuit of Fluorinated Sigma Receptor Ligand

Candidates Related to [18F]-FPS

Rasha S. Jwad,a,b Alan H. C. Pang,a Luke Hunter,a Roger W. Reada*

a School of Chemistry, The University of New South Wales, UNSW Sydney NSW 2052, Australia. b Department of Chemistry, College of Science, Al-Nahrain University, Al-Jadriya,

Baghdad, Iraq *Corresponding author. Email: [email protected]

Supplementary Material

Table of Contents General Information Table S1. Selected 13C NMR Data Experimental Procedures Reaction of 4-hydroxybenzyl alcohol 8 with KF under Appel reaction conditions

Reductive N-methoxybenzylation of 4-hydroxymethylpiperidine 14 Treatment of (1-(4-methoxybenzyl)piperidin-4-yl)methanol 20 with (CF3SO2)2O Treatment of (1-(3-methoxybenzyl)piperidin-4-yl)methanol 19 with (CH3SO2)2O Treatment of aminotriflate 31/32 with sodium 4-(hydroxymethyl)phenolate Methoxybenzoylation of ethyl isonipecotate 21 Treatment of amidoesters 25-27 with NaBH4 Treatment of amidoester 27 with LiAlH4 Reaction of amidoalcohols 28-30 with CH3SO2Cl Reaction of amidoalcohol mesylates 36-38 with 4-hydroxybenzaldehyde 39 Reduction of aldehydes 40-42 with NaBH4 Reaction of mesylate 38 with 4-hydroxybenzyl alcohol 8 and 4-methylphenol (p-cresol) 46 Treatment of amidoalcohols 43-45 with CH3SO2Cl Treatment of amidochlorides 51, 52 and 49 with n-Bu4NF (TBAF) Free radical fluorination of ibuprofen methyl ester and of compound 47 Treatment of amidofluoride 53 with LiAlH4 References Copies of 1H and 13C NMR Spectra

tan13r

Typewritten Text

10.1071/CH18510_AC ©CSIRO 2019 Australian Journal of Chemistry 2019, 72(3), 213-225

InPursuitofFluorinatedSigmaReceptorLigandCandidatesRelatedto[18F]-FPS SupplementaryInformation …page2of95

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EXPERIMENTAL

General Information

All chemicals used were purchased from either Sigma Aldrich or Alfa Aesar and used

without purification.

Nuclear magnetic resonance (1H, 19F and 13C NMR) experiments were carried out using a

Bruker DPX 300 (1H, 300.2 MHz; 19F, 282.4 MHz; 13C, 75.5 MHz), a Bruker Avance III 400

MHz (1H, 400.1 MHz; 13C, 100.6 MHz), or Bruker Avance III Cryo 600 MHz (1H, 600.2

MHz; 13C, 150.9 MHz) instrument. Samples were dissolved in the stated deuterated solvents

and the spectra referenced against residual non-deuterated solvent peaks: δH 7.26 and δC

77.16 for CDCl3.[1] Concern has been raised over the widespread irreproducibility of 19F

NMR data.[2] In the current work, the data were indirectly calibrated to the chemical shift of

Me4Si by reference to the residual non-deuterated solvent signal in CDCl3 for each sample

and multiplying the 1H SF value by 0.94094011 to obtain the SF value for the 19F spectrum,

according to IUPAC Recommendations 2008.[3] The resulting data were within 5 decimal

places of those obtained following the absolute method described at

https://www.chem.wisc.edu/~cic/nmr/Guides/Other/Xi_chem_shift_scale.pdf. In all cases,

NMR multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), broad (br),

multiplet (m), and based on first order analyses. Data are reported as chemical shifts

measured in parts per million (ppm) downfield from TMS (δ), multiplicity, observed

coupling constant (J) in Hertz (Hz), proton count, and assignment.

NOTES:

1. Systematic nomenclature has been used throughout the Experimental Section for all new

compounds. However, in order to simplify comparisons and ensure accuracy of assignments,


3

the 1H, 19F and 13C NMR spectra have been assigned according to a different, uniform

positional numbering scheme with the piperidine ring as core, as represented throughout the

text and in generic structures 57 and 58 (see Table S1). In accordance with the literature,[4 and

references therein] position 2 in the piperidine ring of amide derivatives (X = O) has been assigned

to the position anti to the X group. Analysis of multiplicities has been based on first order

principles and assignment of signals has been assisted or confirmed by COSY, HSQC and/or

HMBC experiments.

2. The assignment of quaternary carbon signals in the 13C NMR spectra was also supported

by the observation of consistent trends in the chemical shifts, as recorded in Table S1.

Low-resolution electrospray ionisation (ESI) mass spectra were carried out on a Waters

Micromass ZQ2000 electrospray instrument. High resolution ESI-MS were carried out by Dr

Sarowar Chowdhury, Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical

Centre, UNSW.

Infrared spectra were recorded on a Nicolet Avatar 320 FTIR spectrometer over the range of

4000 to 400 cm-1. Spectra are reported in wavenumbers (cm-1).

Column chromatography was carried out on Merck Kieselgel 60 silica gel (0.040-0.063 mm).

Thin layer chromatography (TLC) was performed using Merck Kieselgel 60 F-254 precoated

aluminium sheets (0.2 mm). Ratios of solvents used for chromatography were expressed as

volume/volume as specified.

Elemental microanalyses were performed by staff in the Microanalytical Unit, Research

School of Chemistry, The Australian National University.


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Table S1. Correlation trends in the chemical shift values of selected quaternary signals that were helpful in the assignment of 13C NMR spectra for compounds 25–30, 36–38, 40–45, 47, 49, 51–54, and 5–7. 13C NMR chemical shifts were referenced to literature residual solvent signal shifts.[1]

Str Base X R Y Z δC (ppm) (major/minor isomer) C1' C4''-Z C'-OMe C1''-O 25 57 O 2'-OMe CO2Et na 125.7/125.8 na 155.2/155.1 na 26 57 O 3'-OMe CO2Et na 137.4 na 159.8 na 27 57 O 4'-OMe CO2Et na 127.7 na 160.5 na 28 57 O 2'-OMe CH2OH na 125.7/125.9 na 155.1 na 29 57 O 3'-OMe CH2OH na 137.6 na 159.7 na 30 57 O 4'-OMe CH2OH na 128.5 na 160.7 na 36 57 O 2'-OMe CH2OMs na 125.8/126.0 na 155.3 na 37 57 O 3'-OMe CH2OMs na 137.3 na 159.6 na 38 57 O 4'-OMe CH2OMs na 128.1 na 160.8 na 40 58 O 2'-OMe na CHO 126.1/126.3 130.0 155.4 164.0 41 58 O 3'-OMe na CHO 137.5 130.1 159.7 163.9 42 58 O 4'-OMe na CHO 128.3 130.1 160.8 164.0 43 58 O 2'-OMe na CH2OH 126.1/126.2 133.6 155.3 158.4 44 58 O 3'-OMe na CH2OH 137.5 133.6 159.7 158.4 45 58 O 4'-OMe na CH2OH 128.3 133.5 160.8 158.5 47 58 O 4'-OMe na CH3 128.5 130.1 160.7 156.9 53 58 O 3'-OMe na CH2)2-O 136.9 130.7 159.8 158.6 54 58 H2 4'-OMe na CH2OH 130.2 133.2 158.93 158.85 51 58 O 2'-OMe na CH2Cl 126.2/126.4 129.9 155.4 159.2 52 58 O 3'-OMe na CH2Cl 137.7 130.0 159.8 159.1 49 58 O 4'-OMe na CH2Cl 128.3 130.0 160.8 159.1 5 58 O 2'-OMe na CH2F 126.3/126.4 128.5 155.5 159.6 6 58 O 3'-OMe na CH2F 137.7 128.6 159.8 159.6 7 58 O 4'-OMe na CH2F 128.4 128.6 160.8 159.9

NO

Z

X

R

2'3'

4'

65

4

2''3''4''

N

Y

X

R

2'3'

4'

65

4

57 58

23

23


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Reaction of 4-hydroxybenzyl alcohol 8 with KF under Appel reaction conditions[5]

Following the method of Bandgar et al.,[5] 4-hydroxybenzyl alcohol 8 (0.64 g, 5.2 mmol) was

added to a mixture of KF (0.61 g, 10.5 mmol), PPh3 (3.38 g, 12.9 mmol) in a solution of CCl4

(1 mL) and DMF (4 mL). The mixture was stirred at r.t. for 30 min, then the mixture

extracted with pentane (2 × 5 mL). The combined organic layers were dried over Na2SO4 and

the solvent evaporated in vacuo to yield the crude product (0.60 g, 93% mass recovery). The

crude material was analysed by ESI mass spectrometry and 1H and 18F NMR spectroscopy.

Reductive N-methoxybenzylation of 4-hydroxymethylpiperidine 14

General procedure: 4-Hydroxymethylpiperidine 14 (~9 mmol; 1.0 mol equiv.) was dissolved

in CH2Cl2 (25 mL) and methoxybenzaldehyde (1.1 mol equiv.) was added. Solid

NaBH(OAc)3 (~10 mmol, 1.1 mol equiv.) was added in one portion, and the mixture was

stirred at ambient temperature for 19 h. The mixture was then quenched with 1 M aq. NaOH

(50 mL), the organic layer separated and dried over Na2SO4, and the solvent evaporated

under reduced pressure. The crude material was column chromatographed or dissolved in

CH2Cl2 (50 mL) and the solution extracted with 10% aq. HCl (100 mL), the extracts basified

using NaOH pellets, and the solution reextracted with CH2Cl2 (3 × 25 mL), to give combined

extracts that were dried over Na2SO4 and evaporated to dryness.

(i) 4-Hydroxymethylpiperidine 14 (1.12 g, 9.7 mmol) and 2-methoxybenzaldehyde 17 (1.3

mL, 1.46 g, 10.7 mmol) with NaBH(OAc)3 (2.30 g, 10.8 mmol) gave a yellow oil that was

chromatographed on silica gel (MeOH:EtOAc, 1:20) to yield (1-(2-methoxybenzyl)piperidin-

4-yl)methanol 18 as a yellow oil (1.02 g, 51%). 1H NMR (400 MHz, CDCl3; dfr-180311 at

25 °C; 110318-dfr 3 1): δ 7.37 (dd, J = 7.4, 1.5 Hz, 1H, H6'), 7.24 (td, J = 7.9, 1.7 Hz, 1H,

H4'), 6.94 (td, J = 7.4, 0.6 Hz, 1H, H5'), 6.87 (d, J = 8.2 Hz, 1H, H3'), 3.82 (s, 3H, 2'-OCH3),

3.60 (s, 2H, 1'-CH2N), 3.45 (d, J = 6.3, 2H, 4-CH2OH), 2.98 (d, J = 11.7 Hz, 2H, Heq2 and


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Heq6), 2.07 (ddd, J = 11.8, 11.7, 2.2 Hz, 2H, Hax2 and Hax6), 1.71 (br d, J = 12.7 Hz, 2H, Heq3

and Heq5), 1.49 (m, 1H, H4), 1.34 (dddd, J = 12.7, 12.2, 11.8, 3.6 Hz, 2H, Hax3 and Hax5). 13C

NMR (100.1 MHz, CDCl3; dfr-180311 at 25 °C; 110318-dfr 4 1): δ 159.3 (C2'), 132.4 (C6'),

129.6 (C4'), 127.1 (C1'), 121.7 (C5'), 111.9 (C3'), 69.0 (4-CH2O), 57.6 (1'-CH2N), 56.8 (2'-

OCH3), 54.7 (C2 and C6), 39.8 (C4), 30.0 (C3 and C5). HRMS (ESI) m/z: 493.3029

([2M+Na]+, 13%), 356.2213 ([M+MeO-benzyl]+, 25), 258.1459 ([M+Na+H]+, 38), 236.1640

([M+H]+, 100%).

(ii) 4-Hydroxymethylpiperidine 14 (1.00 g, 8.7 mmol) and 3-methoxybenzaldehyde 17 (1.3

mL, 1.45 g, 10.7 mmol) were treated with NaBH(OAc)3 (2.2 g, 10.4 mmol) gave a yellow oil

that was chromatographed on silica gel (MeOH:EtOAc, 1:20) to yield (1-(3-

methoxybenzyl)piperidin-4-yl)methanol 19[6] as a yellow oil (1.14 g, 56 %) (Found: C, 71.20;

H, 9.11; N, 6.08%. C14H21NO2 requires C, 71.46; H, 8.99; N, 5.95%).1H NMR (400 MHz,

CDCl3; dfr-210211 at 25 °C; 110221-dfr 3 1): δ 7.22 (dd, J = 8.4, 7.7 Hz, 1H, H5'), 6.91 (dd,

J = 8.0, 1.7 Hz, 1H, H2'), 6.90 (d, J = 7.7 Hz, 1H, H6'), 6.79 (dd, J = 8.4, 1.7 Hz, 1H, H4'),

3.80 (s, 3H, 3'-OCH3), 3.49 (s, 2H, 1'-CH2N), 3.47 (d, J = 6.4 Hz, 2H, 4-CH2OH), 2.92 (br d,

J = 11.6 Hz, 2H, Heq2 and Heq6), 2.45 (br s, 1H, OH), 1.98 (ddd, J = 11.8, 11.6, 2.2 Hz, 2H,

Hax2 and Hax6), 1.70 (br d, J = 12.7 Hz, 2H, Heq3 and Heq5), 1.49 (m, 1H, H4), 1.31 (dddd, J

= 12.7, ~12.0, 11.8, 3.8 Hz, 2H, Hax3' and Hax5'). 13C NMR (100.1 MHz, CDCl3; dfr-210211

at 25 °C; 110221-dfr 4 1): δ 161.0 (C3'), 141.0 (C1'), 130.6 (C5'), 123.1 (C6'), 116.2 (C2'),

114.0 (C4'), 69.1 (4-CH2O), 64.7 (1'-CH2N), 56.6 (3'-OCH3), 54.8 (C2 and C6), 39.9 (C4),

30.0 (C3 and C5). MS (ESI) m/z: 547.22 ([2M+2K]+, 3%), 471.31 ([2M+H]+, 6), 258.30

([M+Na+H]+, 4), 237.24 ([M+2H]+, 16), 236.34 ([M+H]+, 100).

(iii) 4-Hydroxymethylpiperidine 14 (1.12 g, 9.7 mmol) and 4-methoxybenzaldehyde 17 (1.3

mL, 10.7 mmol) with NaBH(OAc)3 (2.30 g, 10.8 mmol) gave a yellow oil (1.93 g) that


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contained aldehyde, and after acid/base extraction yielded (1-(4-methoxybenzyl)piperidin-4-

yl)methanol 20[7,8] as white needles (1.65 g, 74%) m.p. 52-55 °C (Found: C, 71.51; H, 8.99;

N, 5.72%. C14H21NO2 requires C, 71.46; H, 9.12; N, 5.95%). IR (Nujol): 3110, 1609, 1515,

1299, 1183, 1074, 1039, 970, 851, 723 cm-1.1H NMR (400 MHz, CDCl3; dfr-161110 at 25

°C; 101116-dfr 5 1): δ 7.21 (d, J 8.4 Hz, 2H, H2' and H6'), 6.83 (d, J = 8.4 Hz, 2H, H3' and

H5'), 3.77 (s, 3H, 4'-OCH3), 3.43 (s, 2H, 1'-CH2N), 3.41 (d, J 6.8 Hz, 2H, 4-CH2OH), 3.15

(br s, 1H, OH), 2.88 (br d, J 11.2 Hz, 2H, Heq2 and Heq6), 1.92 (ddd, J 12.0, 11.2, 2.0 Hz, 2H,

Hax2 and Hax6), 1.68 (br d, J 11.2 Hz, 2H, Heq3 and Heq5), 1.44 (m, 1H, H4), 1.25 (dddd, J =

12.4, 12.0, 11.6, 3.6 Hz, 2H, Hax3' and Hax5'). 13C NMR (100.1 MHz, CDCl3; dfr-161110 at

25 °C; 101116-dfr 6 1): δ 158.7 (C4'), 130.7 (C2' and C6'), 129.8 (C1'), 113.6 (C3' and C5'),

67.4 (4-CH2OH), 62.7 (1'-CH2N), 55.2 (4'-OCH3), 53.2 (C2 and C6), 38.5 (C4), 28.7 (C3 and

C5). MS (ESI) m/z: 493.56 ([2M+Na]+, 7%), 258.50 ([M+Na]+, 20), 236.47 ([M+H]+, 100).

Treatment of (1-(4-methoxybenzyl)piperidin-4-yl)methanol 20 with (CF3SO2)2O

(i) In pyridine. Following the method of Lee et al.,[9] aminoalcohol 20 (0.21 g, 0.89 mmol)

was dissolved in pyridine (5.0 mL) and the solution stirred in ice for 15 min, then

trifluoromethanesulfonic anhydride (0.22 mL, 1.31 mmol) added dropwise. The temperature

of the mixture was raised to r.t. and the mixture stirred for 1 h. The mixture was diluted with

water, and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed

sequentially with water (3 × 15 mL), sat. aq. NaHCO3 solution (3 × 20 mL), and brine (3 × 20

mL). The organic layers were then dried over Na2SO4, filtered, and evaporated to dryness in

vacuo to yield a brown oil (0.33 g, 60% based on the expected triflate 31 or 32). The mixture

was analysed by 1H NMR spectroscopy (AP 110314-ahp 1 1) and the main features described

in the Results and Discussion.


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(ii) In dichloromethane with no added base. Aminoalcohol 20 (0.40, 1.71 mmol) was

dissolved in CH2Cl2 (10 mL) and stirred at 0 °C for 15 min before trifluoromethanesulfonic

anhydride (0.60 mL, 3.57 mmol) was added dropwise. The temperature of the mixture was

then raised to r.t., and stirring continued for 1 h. The mixture was then quenched with water,

and the organic layer washed with sat. aq. NaHCO3 solution (3 × 10 mL) and brine (3 × 20

mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to yield a brown oil

(0.59 g, 94% based on the expected triflate 31 or 32). The mixture was analysed by 1H (AP

110328-ahp 1 2) and 19F (AP 110328-ahp 3 2) NMR spectroscopy, and subsequently after

further D2O exchange (AP 110404-ahp 1 2), then the main features described in the Results

and Discussion.

(iii) In dichloromethane with Hunig's base. Aminoalcohol 20 (0.47 g, 2.00 mmol) and N,N-

diisopropylethylamine (0.67 mL, 4.00 mmol) were dissolved together in CH2Cl2 (10 mL) and

stirred at 0°C for 15 min. Trifluoromethanesulfonic anhydride (0.67 mL, 4.15 mmol) was

added dropwise and the temperature of the mixture was raised to r.t., and the mixture stirred

for a further 1 h. The mixture was then quenched in water, and the organic layer washed with

sat. aq. NaHCO3 solution (3 × 10 mL) and brine (3 × 20 mL). The organic layer was dried

over Na2SO4 and evaporated to dryness in vacuo to yield an oil (0.71 g, 96 % based on the

expected triflate 31 or 32). The product was analysed by 1H NMR spectroscopy (AP 110520-

ahp 1 2) and the main features described in the Results and Discussion.

Treatment of (1-(3-methoxybenzyl)piperidin-4-yl)methanol 19 with (CH3SO2)2O

4-Hydroxymethyl-1-(3-methoxybenzyl)piperidine 33 (0.40, 1.71 mmol) was dissolved in

CH2Cl2 (10 mL), and the solution stirred at 0°C for 15 min. Methanesulfonic anhydride (0.60

mL, 3.57 mmol) in CH2Cl2 (10 mL) was added dropwise and the temperature of the mixture

raised to r.t. and stirring continued for another 1 h. The mixture was quenched with water,


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and the organic layer washed with sat. aq. NaHCO3 solution (3 × 10 mL) and brine (3 × 20

mL). The organic layer was then dried over Na2SO4 and evaporated to dryness in vacuo to

yield a brown oil (0.59 g, 94 %, based on the anticipated norbornanium methanesulfonate

35). The mixture was analysed by NMR spectroscopy (AP 110526-ahp 1 2) and mass

spectrometry and the outcome described in the Results and Discussion.

Treatment of aminotriflate 31/32 with sodium 4-(hydroxymethyl)phenolate

A solution of aq. NaOH (0.1 M, 100 mL) was titrated into an aq. solution of 4-

hydroxymethylphenol (0.12 g, 1.0 mmol) in water (20 mL) containing phenolphthalein

indicator until the endpoint (colour change from clear to pink; ~100 mL). The slightly basic

solution was then added to a portion of the supposed triflate 31 or 32 (0.37 g, 1.0 mmol) from

the preparation above and the mixture stirred at reflux for 24 h. The mixture was then

extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na2SO4 and

the solvent removed in vacuo to yield the crude mixture as a brown oil (0.29 g). The 1H NMR

spectrum of the crude product was then analysed to show aminoalcohol 20 as the only

piperidine-derived material admixed with other purely aromatic residues.

Methoxybenzoylation of ethyl isonipecotate 21

General procedure: Triethylamine (1.74 mL, 1.26 g, 12.5 mmol) was added in one portion to

a solution of ethyl isonipecotate 21 (1.73 mL, 1.76 g, 11.2 mmol) in dry CH2Cl2 (10 mL) and

the mixture stirred at 0 ºC for 10 min under nitrogen. The appropriate acid chloride (1.35 mL,

1.55 g, 9.1 mmol) was introduced dropwise via syringe. The reaction mixture was stirred for

30 min, allowed to warm to r.t. and then stirred overnight. The mixture was diluted with

CH2Cl2 (50 mL) and washed with 1 N HCl (2 × 25 mL) and water (25 mL). The organic layer

was dried over Na2SO4, evaporated to dryness under reduced pressure, and the residue flash


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chromatographed on silica gel (MeOH/CH2Cl2, 1:25) and the major component isolated and

characterised.

(i) Ethyl 1-(2-methoxybenzoyl)piperidine-4-carboxylate 25

Yellow oil (1.60 g, 60%). Rf 0.71 (EtOAc). FTIR (neat) νmax 2930, 2857, 1722, 1622, 1432,

1372, 1311, 1263, 1248, 1177, 1112, 1038, 860 cm–1. 1H NMR (300 MHz, CDCl3; RJ-01-43

at 25 °C; 140605-rsj 1 2; 52:48 mixture of isomers): δ (major) 7.338 (ddd, J 8.4, 7.5, 1.7 Hz,

1H, H4'), 7.199 (ddd, J 7.5, 1.7 Hz, 1H, H6'), 6.974 (dd, J 7.5, 7.5 Hz, 1H, H5'), 6.915 (dd, J

8.4, 0.8 Hz, 1H, H3'), 4.587 (ddd, J 13.4, 4.1, 4.1 Hz, 1H, Heq6), 4.142 (q, J 7.1 Hz, 2H, 4-

CO2CH2CH3), 3.817 (s, 3H, 2'-OCH3), 3.489 (dm, J 13.5 Hz, 1H, Heq2), 3.064 (ddd, J 13.5,

11.4, 3.1 Hz, 1H, Hax2), 3.016 (ddd, J 13.3, 10.8, 2.9 Hz, 1H, Hax6), 2.554 (tt, J 10.8, 4.1 Hz,

1H, H4), 2.017 (dm, J 13.1 Hz, 1H, Heq5), 1.182 (dm, J 13.4 Hz, 1H, Heq3), 1.710 (dddd, J

13.1, 10.8, 10.8, 4.1 Hz, 1H, Hax5), 1.566 (dddd, J 13.1, 11.4, 10.8, 4.2 Hz, 1H, Hax3), 1.252

(t, J 7.1 Hz, 3H, 4-CO2CH2CH3). δ (minor) 7.338 (ddd, J 8.4, 7.5, 1.7 Hz, 1H, H4'), 7.229

(ddd, J 7.5, 1.7 Hz, 1H, H6'), 6.974 (dd, J 7.5, 7.5 Hz, 1H, H5'), 6.915 (dd, J 8.4, 0.8 Hz, 1H,

H3'), 4.592 (ddd, J 13.6, 4.1, 4.1 Hz, 1H, Heq6), 4.154 (q, J 7.1 Hz, 2H, 4-CO2CH2CH3),

3.829 (s, 3H, 2'-OCH3), 3.489 (dm, J 13.5 Hz, 1H, Heq2), 2.992 (ddd, J 13.6, 11.0, 3.7 Hz,

1H, Hax6), 2.970 (ddd, J 13.5, 10.4, 3.7 Hz, 1H, Hax6), 2.538 (tt, J 10.7, 4.4 Hz, 1H, H4),

2.017 (dm, J 13.1 Hz, 1H, Heq5), 1.182 (dm, J 13.4 Hz, 1H, Heq3), 1.781 (dddd, J 13.1, 11.0,

10.7, 4.1 Hz, 1H, Hax5), 1.566 (dddd, J 13.1, 11.0, 10.8, 4.2 Hz, 1H, Hax3), 1.263 (t, J 7.1 Hz,

3H, 4-CO2CH2CH3). 13C NMR (75 MHz, CDCl3; RJ-01-43 at 25 °C; 140605-rsj 2 2; 52:48

mixture of isomers): δ (major) 174.11 (4-CO2CH2CH3), 167.68 (1'-C(O)N), 155.15 (C2'),

130.22 (C4'), 127.54 (C6'), 125.70 (C1'), 120.76 (C5'), 110.81 (C3'), 60.425 (4-CO2CH2CH3),

55.42 (2'-OCH3), 46.31 (C2), 40.94 (C4), 40.73 (C6), 28.28 (C3), 27.76 (C5), 14.06 (4-

CO2CH2CH3). δ (minor) 174.19 (4-CO2CH2CH3), 167.52 (1'-C(O)N), 155.13 (C2'), 130.16


11

(C4'), 127.68 (C6'), 125.82 (C1'), 120.72 (C5'), 110.73 (C3'), 60.420 (4-CO2CH2CH3), 55.35

(2'-OCH3), 45.79 (C2), 40.94 (C4), 40.66 (C6), 28.28 (C3), 27.82 (C5), 14.06 (4-

CO2CH2CH3). HRMS (ESI, +ve) m/z: 314.1356 [M + Na]+. C16H21O4Na requires 314.1363.

(ii) Ethyl 1-(3-methoxybenzoyl)piperidine-4-carboxylate 26

White solid (2.56 g, 97%) mp 57–59 °C, Rf 0.77 (EtOAc). FTIR (neat) νmax: 3066, 2989,

2863, 1721, 1625, 1581, 1425, 1311, 1264, 1248, 1175, 1037, 946, 860, 814 cm–1. 1H NMR

(300 MHz, CDCl3; RJ-01-45-m at 25 °C; 140609-rsj 1 2): δ 7.29 (m, 1H, H5'), 6.92 (m, 2H,

H4' and H6'), 6.91 (m, H2'), 4.50 (4.35-4.65) (br s, 1H, Heq6), 4.14 (q, J 7.1, 2H, 4-

CO2CH2CH3), 3.80 (s, 3H, 3'-OCH3), 3.74 (3.60-3.90) (br s, 1H, Heq2), 3.02 (m, 2H, Hax2 and

Hax6), 2.55 (tt, J 10.8, 4.1 Hz, 1H, H4), 1.98 (1.88-2.13) (br s, 1H, Heq5), 1.85 (1.73-1.96) (br

s, 1H, Heq3), 1.71 (1.50-1.85) (br s, 2H, Hax3 and Hax5), 1.24 (t, J 7.1, 3H, 4-CO2CH2CH3).

13C NMR (75 MHz, CDCl3; RJ-01-45-m at 25 °C; 140609-rsj 2 2): δ 174.3 (4-CO2CH2CH3),

170.2 (1'-C(O)N), 159.8 (C3'), 137.4 (C1'), 129.7 (C5'), 118.9 (C6'), 115.6 (C4'), 112.3 (C2'),

60.8 (4-CO2CH2CH3), 55.5 (2'-OCH3), 47.0 (br, C2), 41.6 (br, C6), 41.2 (C4), 28.4 (br, C3),

28.0 (br, C5), 14.3 (4-CO2CH2CH3). HRMS (ESI, +ve) m/z: 314.1353 [M + Na]+.

C16H21O4Na requires 314.1363 [M + Na]+.

(iii) Ethyl 1-(4-methoxybenzoyl)piperidine-4-carboxylate 27

Yellow oil (1.89 g, 71%), Rf 0.74 (EtOAc). FTIR (neat) νmax: 3262, 2933, 2857, 2008, 1879,

1832, 1758, 1722, 1624, 1509, 1485, 1424, 1300, 1241, 1170, 1107, 1027, 935, 838, 684 cm–

1. 1H NMR (400 MHz, CDCl3; RJ-01-08 at –20 °C): δ 7.36 (d, J 8.8 Hz, 2H, H2' and H6'),

6.89 (d, J 8.9 Hz, 2H, H3' and H5'), 4.56 (ddd, J 13.3, 4.0, 3.2 Hz, 1H, Heq6), 4.12 (q, J 7.2

Hz, 2H, 4-CO2CH2CH3), 3.84 (ddd, J 13.3, 4.1, 3.4 Hz, 1H, Heq2), 3.82 (s, 3H, 4'-OCH3),

3.06 (ddd, J 13.3, 11.2, 2.7 Hz, 1H, Hax2), 2.90 (ddd, J 13.3, 11.4, 2.6 Hz, 1H, Hax6), 2.56 (tt,

J 11.2, 3.9 Hz, 1H, H4), 2.03 (dddd, J 13.6, 3.9, 3.2, 2.6 Hz, 1H, Heq5), 1.86 (dddd, J 13.4,


12

3.9, 3.4, 2.7 Hz, 1H, Heq3), 1.72 (dddd, J 13.6, 11.4, 11.2, 4.0 Hz, 1H, Hax5), 1.65 (dddd, J

13.4, 11.2, 11.2, 4.1 Hz, 1H, Hax3), 1.24 (t, J 7.2 Hz, 3H, 4-CO2CH2CH3). 13C NMR (100

MHz, CDCl3; RJ-01-08 at –20 °C): δ 174.5 (4-CO2CH2CH3), 170.5 (1'-C(O)N), 160.5 (C4'),

129.0 (C2' and C6'), 127.7 (C1'), 113.6 (C3' and C5'), 60.9 (4-CO2CH2CH3), 55.4 (4'-OCH3),

47.3 (C2), 41.7 (C6), 41.1 (C4), 28.5 (C3), 27.9 (C5), 14.2 (4-CO2CH2CH3). HRMS (ESI,

+ve) m/z: 314.1363 [M + Na]+. C16H21O4Na requires 314.1363 [M + Na]+.

Treatment of amidoesters 25-27 with NaBH4

General procedure: Sodium borohydride (0.39 g, 10.3 mmol) was added to a solution of the

amidoester (0.50 g, 1.7 mmol) in dry THF (4 mL) under nitrogen and the reaction mixture

warmed to reflux. MeOH (1 mL) was added dropwise and the reaction mixture was refluxed

overnight. Upon cooling to r.t., the mixture was quenched with 1N HCl and concentrated

under reduced pressure. The residue was extracted with CH2Cl2 (3 x 10 mL). The combined

organic layers were washed with brine (2 x 10 mL), dried over Na2SO4 and the solvent was

removed under reduced pressure. The oily residue was flash chromatographed on silica gel

using a gradient of MeOH/CH2Cl2 (1:25 to 1:15) to yield amidoalcohols 28-30.

(i) 4-(Hydroxymethyl)piperidin-1-yl)(2-methoxyphenyl)methanone 28


2847, 1591, 1438, 1365, 1186, 878, 767 cm–1. 1H NMR (600 MHz, CDCl3; RJ-01-61 at 10

°C; 170607-rsj 2 2; 54:46 mixture of isomers): δ (major isomer) 7.296 (ddd, J 8.3, 7.4, 1.7

Hz, 1H, H4'), 7.164 (dd, J 7.4, 1.7 Hz, 1H, H6'), 6.925 (ddd, J 7.4, 7.4, 0.8 Hz, 1H, H5'),

6.857 (d, J 8.3 Hz, 1H, H3'), 4.698 (ddd, J 13.1, 4.4, 2.2 Hz, 1H, Heq6), 3.763 (s, 3H, 2'-

OCH3), 3.414 (ddd, J 13.4, 4.4, ~2 Hz, 1H, Heq2), 3.352 (dd, J 14.0, 10.7 Hz, 1H, 4-

CHaHbOH), 3.342 (dd, J 14.0, 10.7 Hz, 1H, 4-CHaHbOH), 3.19 (br s, 1H, 4-CH2OH), 2.923

(ddd, J 13.2, 12.8, 2.6 Hz, 1H, Hax2), 2.682 (ddd, J 13.1, 12.7, 2.9 Hz, 1H, Hax6), 1.731 (dm,


13

J 13.4 Hz, 1H, Heq5), 1.61 (br m, 1H, H4), 1.551 (dm, J 13.1 Hz, 1H, Heq3), 1.110 (dddd, J

13.4, 12.7, 12.2, 4.4 Hz, 1H, Hax5), 0.937 (dddd, J 13.1, 12.8, 12.2, 4.4 Hz, 1H, Hax3). δ

(minor isomer) 7.287 (ddd, J 8.3, 7.4, 1.7 Hz, 1H, H4'), 7.130 (dd, J 7.4, 1.7 Hz, 1H, H6'),

6.921 (ddd, J 7.4, 7.4, 0.8 Hz, 1H, H5'), 6.857 (d, J 8.3 Hz, 1H, H3'), 4.698 (ddd, J 13.1, 4.4,

2.2 Hz, 1H, Heq6), 3.758 (s, 3H, 2'-OCH3), 3.414 (ddd, J 13.4, 4.4, ~2 Hz, 1H, Heq2), 3.324

(dd, J 13.4, 10.7 Hz, 1H, 4-CHaHbOH), 3.314 (dd, J 13.4, 10.7 Hz, 1H, 4-CHaHbOH), 3.19

(br s, 1H, 4-CH2OH), 2.816 (ddd, J 13.2, 12.7, 2.5 Hz, 1H, Hax2), 2.650 (ddd, J 13.1, 12.6,

3.0 Hz, 1H, Hax6), 1.731 (dm, J 13.4 Hz, 1H, Heq5), 1.61 (br m, 1H, H4), 1.594 (dm, J 13.1

Hz, 1H, Heq3), 1.163 (dddd, J 13.4, 12.7, 12.2, 4.3 Hz, 1H, Hax5), 0.937 (m, 1H, Hax3). 13C

NMR (150 MHz, CDCl3; RJ-01-61 at 10 °C; 170607-rsj 8 2; 54:46 mixture of isomers): δ

(major) 167.86 (1'-C(O)N), 155.09 (C2'), 130.31 (C4'), 127.51 (C6'), 125.72 (C1'), 120.77

(C5'), 110.75 (C3'), 66.81 (4-CH2OH), 55.49 (2'-OCH3), 46.66 (C2), 41.52 (C6), 38.72 (C4),

29.14 (C3), 28.43 (C5). δ (minor) 167.69 (1'-C(O)N), 155.11 (C2'), 130.20 (C4'), 127.70

(C6'), 125.87 (C1'), 120.75 (C5'), 110.63 (C3'), 66.91 (4-CH2OH), 55.35 (2'-OCH3), 47.33

(C2), 41.57 (C6), 38.72 (C4), 29.21 (C3), 28.37 (C5). HRMS (ESI, +ve) m/z: 272.1250

[M+Na]+. C14H19NO3Na requires 272.1257 [M + Na]+.

(ii) 4–(Hydroxymethyl)piperidin–1–yl)(3–methoxyphenyl)methanone 29


3009, 2912, 2907, 2859, 2306, 1598, 1451, 1298, 1255, 1110, 1037, 854, 790, 725 cm–1. 1H

NMR (300 MHz, CDCl3; single isomer at 25 °C; RJ-01-59-2 140619-rsj 4 2): δ 7.28 (dddd, J

8.1, 7.1, 1.0, 0.8 Hz, 1H, H5'), 6.92 (m, 1H, H4'), 6.91 (m, 1H, H6'), 6.90 (m, 1H, H2'), 4.69

(very br d, J 9.9 Hz, 1H, Heq6), 3.79 (s, 3H, OCH3), 3.75 (very br d, J 10.4 Hz, 1H, Heq2),

3.45 (br d, J 5.5 Hz, 2H, 4-CH2OH), 2.95 (br dd, J 10.4, 9.8 Hz, 1H, Hax2), 2.73 (br dd, J

9.9, 9.4 Hz, 1H, Hax6), 2.30 (2.05-2.55) (br s, 1H, 4-CH2OH), 1.80 (1.65-1.90) (br s, 1H,


14

Heq5), 1.74 (1.60-1.82) (br s, 1H, Heq3), 1.72 (m, 1H, H4), 1.18 (1.10-1.35) (br s, 1H,

Hax5), 1.15 (1.00-1.25) (br s, 1H, Hax3). 1H NMR (300 MHz, CDCl3; RJ-01-59-2 at –10 °C;

140701-rsj 2 2): δ 7.27 (dddd, J 8.1, 7.3, 0.6, 0.4 Hz, 1H, H5'), 6.90 (m, 1H, H4'), 6.89 (m,

1H, H6'), 6.86 (m, 1H, H2'), 4.66 (dm, JHeq,Hax 13.2 Hz, 1H, Heq6), 3.77 (s, 3H, OCH3), 3.71

(dm, JHeq,Hax 13.4 Hz, 1H, Heq2), 3.37 (m, 2H, 4-CH2OH), 3.17 (t, J 4.4 Hz, 1H, 4-CH2OH),

2.92 (ddd, JHax2,Heq2 13.4, JHax2,Hax3 12.8, JHax2,Heq3 3.0 Hz, 1H, Hax2), 2.68 (ddd, JHax6,Heq6

13.2, JHax6,Hax5 12.6, JHax6,Heq5 3.1 Hz, 1H, Hax6), 1.77 (dm, JHeq,Hax 13.2 Hz, 1H, Heq5), 1.65

(m, 1H, H4), 1.63 (dm, JHeq,Hax 12.4 Hz, 1H, Heq3), 1.17 (ddd, JHax5,Heq5 13.2, JHax5,Hax6 12.6,

JHax5,H4 11.9, JHax5,Heq6 3.1 Hz, 1H, Hax5), 1.06 (ddd, JHax3,Hax2 12.8, JHax3,H4 12.8, JHax3,Heq3

12.4, JHax3,Heq2 3.0 Hz, 1H, Hax3). 13C NMR (75 MHz, CDCl3; RJ-01-59-2 at 25 °C; 140619-

rsj 2 2): δ 170.2 (1'-C(O)N), 159.7 (C3'), 137.6 (C1'), 129.6 (C5'), 118.9 (C6'), 115.4 (C4'),

112.3 (C2'), 67.1 (4-CH2OH), 55.4 (3'-OCH3), 47.8 (br, C2), 42.2 (br, C6), 38.9 (C4), 29.5

(br, C3), 28.5 (br, C5). HRMS (ESI, +ve) m/z: 272.1256 [M+Na]+. C14H19NO3Na requires

272.1257 [M + Na]+.

(iii) 4–(Hydroxymethyl)piperidin–1–yl)(4–methoxyphenyl)methanone 30


2907, 2907, 2321, 2090, 1601, 1438, 1301, 1249, 1167, 1112, 1028, 956, 931 cm–1. 1H NMR

(300 MHz, CDCl3; RJ-01-22 at 25 °C; 140506-rsj 1 2): δ 7.35 (d, J 8.7 Hz, 2H, H2' and H6'),

6.89 (d, J 8.7 Hz, 2H, H3' and H5'), 4.2-4.9 (very br s, 1H, Heq6), 3.7-4.2 (very br s, 1H,

Heq2), 3.81 (s, 3H, 4'-OCH3), 3.25 (d, J 5.9 Hz, 2H, 4-CH2OH), 1.9-2.2 (br s, 1H, 4-CH2OH),

2.6-3.2 (br s, 2H, Hax2 and Hax6), 1.77 (m, 1H, Heq5), 1.75 (m, 1H, H4), 1.72 (m, 1H, Heq3),

1.24 (m, 1H, Hax5), 1.20 (m, 1H, Hax3). 1H NMR (400 MHz, CDCl3; RJ-01-22 at –20 °C;

170412-rsj 3 2): δ 7.34 (d, J 8.7 Hz, 2H, H2' and H6'), 6.88 (d, J 8.7 Hz, 2H, H3' and H5'),

4.67 (br d, J 13.0 Hz, 1H, Heq6), 3.85 (br d, J 13.0 Hz, 1H, Heq2), 3.81 (s, 3H, 4'-OCH3), 3.42


15

(br s, 2H, 4-CH2OH), 3.10 (br s, 1H, 4-CH2OH), 2.97 (ddd, J 13.2, 13.0, 2.2 Hz, 1H, Hax2),

2.70 (ddd, J 13.0, 12.9, 2.6 Hz, 1H, Hax6), 1.80 (br d, J 13.0 Hz, 1H, Heq5), 1.70 (m, 1H, H4),

1.68 (br d, J 13.2 Hz, 1H, Heq3), 1.20 (dddd, J 13.0, 13.0, 12.5, 4.4 Hz, 1H, Hax5), 1.11

(dddd, J 13.2, 13.0, 12.5, 3.8 Hz, 1H, Hax3). 13C NMR (75 MHz, CDCl3; RJ-01-22 at 25 °C;

140506-rsj 2 2): δ 170.5 (1'-C(O)N), 160.7 (C4'), 129.0 (C2' and C6'), 128.5 (C1'), 113.8 (C3'

and C5'), 67.3 (4-CH2OH), 55.4 (4'-OCH3), ~47.8 (very br, C2), ~43.3 (very br, C6), 39.0

(C4), 29.1 (br, C3), 29.0 (br, C5). HRMS (ESI, +ve) m/z: 272.1256 [M+Na]+. C14H19NO3Na

requires 272.1257 [M + Na]+.

Treatment of amidoester 27 with LiAlH4

(i) Lithium aluminiumhydride (0.12 g, 3.2 mmol) was added in one portion to a stirred

solution of amidoester 27 (0.15 g, 0.52 mmol) in dry THF (10 mL) under nitrogen at –20 °C.

Stirring was continued at the same temperature for 45 min then the mixture quenched with

sat. aq. NH4Cl (10 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and the

combined extracts washed with water (2 x 10 mL), dried over Na2SO4 and evaporated to

dryness under reduced pressure. The oily residue was flash chromatographed over silica gel

using a gradient of 2:1 EtOAc/n-hexane to pure EtOAc to yield 4–(hydroxymethyl)piperidin–

1–yl)(4–methoxyphenyl)methanone 30 (0.11 g, 88%) with identical spectroscopic properties

to those of the product derived through reduction with NaBH4.

(ii) Treatment of amidoester 27 (0.94 g) under the same conditions as in (i) except that

reaction time was increased to 2 h gave (1-(4-methoxybenzyl)piperidin-4-yl)methanol 20 as a

white solid (0.56 g, 74%) mp 44–45 °C, Rf 0.15 (EtOAc) with identical spectroscopic

properties to those of the product derived through reductive alkylation of 4-

hydroxymethylpiperidine 14, namely FTIR (neat) νmax: 3106, 2806, 1607, 1511, 1438, 1326,

1298, 1240, 1180, 1102, 1035, 967, 819 cm–1. 1H NMR (300 MHz, CDCl3; RJ-01-75 at 25


16

°C; 150120-rsj 13 2): δ 7.21 (d, J 8.4 Hz, 2H, H2' and H6'), 6.83 (d, J 8.4 Hz, 2H, H3' and

H5'), 3.78 (s, 3H, 4'-OCH3), 3.44 (d, J 6.5 Hz, 2H, 4-CH2OH), 3.43 (s, 2H, 1'-CH2N), 2.88

(br d, J 11.2 Hz, 2H, Heq2 and Heq6), 2.47 (br s, 1H, OH), 1.92 (ddd, J 12.0, 11.2, 2.0 Hz, 2H,

Hax2 and Hax6), 1.68 (br d, J 11.2 Hz, 2H, Heq3 and Heq5), 1.44 (m, 1H, H4), 1.25 (dddd, J

12.4, 12.0, 11.6, 3.6 Hz, 2H, Hax3' and Hax5'). 13C NMR (100.1 MHz, CDCl3): δ 158.7 (C4'),

130.7 (C2' and C6'), 129.8 (C1'), 115.6 (C3' and C5'), 67.4 (4-CH2OH), 62.7 (1'-CH2N), 55.2

(4'-OCH3), 53.2 (C2 and C6), 38.55 (C4), 28.7 (C3 and C5). 13C NMR (75 MHz, CDCl3; RJ-

01-75 at 25 °C; 150120-rsj 14 2): δ 158.7 (C4'), 130.6 (C2' and C6'), 130.2 (C1'), 113.6 (C3'

and C5'), 67.7 (4-CH2OH), 62.9 (1'-CH2N), 55.3 (4'-OCH3), 53.3 (C2 and C6), 38.6 (C4),

28.8 (C3 and C5). HRMS (ESI, +ve) m/z: 236.1629 [M+H]+. C14H22NO2 requires 236.1645

[M + H]+.

Reaction of amidoalcohols 28-30 with CH3SO2Cl

General procedure: Methanesulfonyl chloride (0.23 mL, 0.34 g, 3.0 mmol) was added to a

solution of alcohol 28-30 (0.50 g, 2.0 mmol) in pyridine (5 mL). The mixture was stirred

overnight at r.t. and then concentrated under reduced pressure. The residue was dissolved in

CH2Cl2 (25 mL) and the solution washed successively with 15% aq. HCl (2 x 10 mL) and

distilled water (10 mL), dried over MgSO4 and evaporated to dryness. The crude product was

column chromatographed on silica gel using MeOH/CH2Cl2 as eluent to give amido mesylate

esters 36-38.

(i) (1-(2-Methoxybenzoyl)piperidin-4-yl)methyl methanesulfonate 36


1616, 1467, 1327, 1244, 1167, 1017, 904, 850 cm–1. 1H NMR (300 MHz, CDCl3; 52:48

mixture at 25 °C; RJ-01-70; 150120-rsj 2 2): δ (major) 7.310 (ddd, J 8.4, 7.4, 1.7 Hz, 1H,

H4'), 7.199 (dd, J 7.5, 1.7 Hz, 1H, H6'), 6.982 (dd, J 7.5, 7.4 Hz, 1H, H5'), 6.883 (dd, J 8.4


17

Hz, 1H, H6'), 4.798 (dm, J 13.1 Hz, 1H, Heq6), 4.069 (dd, J 10.6, 6.4 Hz, 1H, 4–

CHaHbOSO2CH3), 4.037 (dd, J 10.6, 6.5 Hz, 1H, 4–CHaHbOSO2CH3), 3.788 (s, 3H, OCH3),

3.498 (dm, J 13.6 Hz, 1H, Heq2), 2.996 (ddd, JHax2,Heq2 13.6, JHax2,Hax3 12.4, JHax2,Heq3 2.8 Hz,

1H, Hax2), 2.973 (s, 3H, 4–CHaHbOSO2CH3), 2.756 (ddd, JHax6,Heq6 13.1, JHax6,Hax5 12.9,

JHax6,Heq5 2.9 Hz, 1H, Hax6), 1.977 (m, 1H, H4), 1.833 (br d, JHeq5,Hax5 12.9 Hz, 1H, Heq5),

1.658 (br d, JHeq3,Hax3 12.9 Hz, 1H, Heq3), 1.349 (dddd, JHax5,Heq5 12.9, JHax5,Hax6 12.9,

JHax5,Hax4 12.4, JHax5,Heq6 4.5 Hz, 1H, Hax5), 1.111 (dddd, JHax3,Heq3 12.9, JHax3,Hax2 12.4,

JHax3,Hax4 12.2, JHax3,Heq2 4.1 Hz, 1H, Hax3). δ (minor) 7.316 (ddd, J 8.4, 7.4, 1.7 Hz, 1H, H4'),

7.159 (dd, J 7.5, 1.7 Hz, 1H, H6'), 6.982 (dd, J 7.5, 7.4 Hz, 1H, H5'), 6.883 (d, J 8.4 Hz, 1H,

H6'), 4.798 (dm, J 13.1 Hz, 1H, Heq6), 4.076 (dd, J 10.6, 6.4 Hz, 1H, 4–CHaHbOSO2CH3),

4.034 (dd, J 10.6, 6.5 Hz, 1H, 4–CHaHbOSO2CH3), 3.798 (s, 3H, OCH3), 3.498 (dm,

JHeq2,Hax2 13.6 Hz, 1H, Heq2), 2.981 (s, 3H, 4–CHaHbOSO2CH3), 2.844 (ddd, JHax2,Heq2 13.6,

JHax2,Hax3 12.3, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.713 (ddd, JHax6,Heq6 13.1, JHax6,Hax5 12.8,


1.658 (br d, JHeq3,Hax3 12.9 Hz, 1H, Heq3), 1.314 (m, 1H, Hax3), 1.298 (m, 1H, Hax5). 13C

NMR (75 MHz, CDCl3; 52:48 mixture at 25 °C; RJ-01-70; 150120-rsj 2 2): δ (major) 167.86

(1'-C(O)N), 155.29 (C2'), 130.44 (C4'), 127.69 (C6'), 125.82 (C1'), 120.94 (C5'), 110.97

(C3'), 73.21 (4-CH2OAr), 55.59 (OCH3), 46.77 (C2), 41.08 (C6), 37.34 (4-CH2OSO2CH3),

36.13 (C4), 28.85 (C3), 28.03 (C5). δ (minor) 167.66 (1'-C(O)N), 155.29 (C2'), 130.31 (C4'),

127.84 (C6'), 126.00 (C1'), 120.94 (C5'), 110.90 (C3'), 73.30 (4-CH2OAr), 55.50 (OCH3),

46.07 (C2), 40.99 (C6), 37.34 (4-CH2OSO2CH3), 36.13 (C4), 28.85 (C3), 28.03 (C5). HRMS

(ESI, +ve) m/z: 350.1028 [M+Na]+. C15H21NO5SNa requires 350.1033 [M + Na]+.

(ii) (1-(3-Methoxybenzoyl)piperidin-4-yl)methyl methanesulfonate 37


18


2857, 2320, 1616, 1454, 1339, 1290, 1258, 1169, 1107, 973 cm–1. 1H NMR (300 MHz,

CDCl3; near equal isomers at 25 °C; RJ-01-72; 150120-rsj 5 1): δ 7.29 (dddd, J 7.4, 6.9, 1.7,

0.8 Hz, 1H, H5'), 6.892 (m, 1H, H4'), 6.891 (m, 1H, H6'), 6.87 (m, 1H, H2'), 4.69 (4.40-4.85)

(br s, 1H, Heq6), 4.04 (d, J 6.4 Hz, 2H, 4-CH2OSO2CH3), 3.79 (3.52-4.00) (br s, 1H, Heq2),

3.771(minor) / 3.770(major) (2xs, 3H total, OCH3), 2.968(major) / 2.966(minor) (2xs, 3H

total, 4-CH2OSO2CH3), 2.95 (2.83-3.10) (br s, 1H, Hax2), 2.76 (2.60-2.90) (br s, 1H, Hax6),

2.00 (m, 1H, H4), 1.76 (1.57-1.85) (br s, 2H, Heq3 and Heq5), 1.26 (1.07-1.42) (br s, 2H,

Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; apparent single isomer at 25 °C; RJ-01-72;

150120-rsj 6 2): δ 170.06 (1'-C(O)N), 159.61 (C3'), 137.27 (C1'), 129.60 (C5'), 118.78 (C6'),

115.37 (C4'), 112.23 (C2'), 73.10 (4-CH2OSO2CH3), 55.33 (OCH3), 47.12 (br, C2), 41.61 (br,

C6), 37.27 (4-CH2OSO2CH3), 36.05 (C4), 29.91 (br, C3), 28.00 (br, C5). HRMS (ESI, +ve)

m/z: 350.1033 [M+Na]+. C15H21NO5SNa requires 350.1033 [M + Na]+.

(iii) (1-(4-Methoxybenzoyl)piperidin-4-yl)methyl methanesulfonate 38


2863, 2307, 1607, 1514, 1436, 1335, 1296, 1249, 1167, 1121, 1110, 949 cm–1. 1H NMR (300

MHz, CDCl3; single isomer at 25 °C; RJ-01-29-1; 140516-rsj 1 2): δ 7.34 (d, J 8.8 Hz, 2H,

H2' and H6'), 6.88 (d, J 8.8 Hz, 2H, H3' and H5'), 4.48 (4.00-5.00) (br s, 1H, Heq6), 4.07 (d,

J 6.4 Hz, 2H, 4-CH2OSO2CH3), 3.80 (s, 3H, OCH3), 3.72 (3.20-4.30) (br s, 1H, Heq2), 2.99

(s, 3H, 4-CH2OSO2CH3), 2.87 (2.70-3.05) (br s, 2H, Hax2 and Hax6), 2.02 (m, 1H, H4), 1.78

(br d, J 12.5 Hz, 2H, Heq3 and Heq5), 1.28 (dddd, J 12.5, 12.0, 10.5, 4.1 Hz, 2H, Hax3 or

Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-01-29/2; 140516-rsj 2 2): δ

170.5 (1'-C(O)N), 160.8 (C4'), 129.0 (C2' and C6'), 128.1 (C1'), 113.8 (C3' and C5'), 73.2 (4-

CH2OSO2CH3), 55.4 (OCH3), 46.6 (very br and weak, C2), 42.4 (very br and weak, C6), 37.4


19

(4-CH2OSO2CH3), 36.2 (C4), 28.5 (br, C3 and C5). HRMS (ESI, +ve) m/z: 350.1030

[M+Na]+. C15H21NO5SNa requires 350.1033 [M + Na]+.

Reaction of amidoalcohol mesylates 36-38 with 4-hydroxybenzaldehyde 39

General procedure: Mesylate ester (1.25 g, 3.82 mmol) was added with stirring to a mixture

of 4-hydroxybenzaldehyde 7 (0.50 g, 4.10 mmol) and K2CO3 (2.30 g, 16.7 mmol) in dry

DMF (40 mL) under nitrogen. The reaction mixture was heated to 70 oC overnight, after

which time it was cooled to r.t., poured into distilled water (100 mL) and extracted with

CH2Cl2 (3 x 100 mL). The combined extracts were washed with distilled water (3 x 100 mL),

dried over Na2SO4 and the solvent removed under reduced pressure to give a white solid that

was flash chromatographed over silica gel using a gradient of 1:2 EtOAc/n–hexane to 100%

EtOAc.

(i) 4-((1-(2-Methoxybenzoyl)piperidin-4-yl)methoxy)benzaldehyde 40

Colourless gum (0.90 g, 67%), Rf 0.57 (EtOAc). FTIR (neat) νmax: 2996, 2933, 2861, 1672,

1594, 1508, 1431, 1292, 1245, 1155, 1121, 1015, 985, 832, 753 cm–1. 1H NMR (300 MHz,

CDCl3; 52:48 mixture at 25 °C; RJ-02-41; 150323-rsj 1 2): δ (major) 9.855 (s, 1H, 4"-CHO),

7.806 (dd, J 8.8, 2.1 Hz, 1H, H3'' and H5''), 7.325 (ddd, J 8.1, 7.7, 1.8 Hz, 1H, H4'), 7.235

(dd, J 7.4, 1.7 Hz, 1H, H6'), 6.964 (dd, J 8.8, 2.1 Hz, 2H, H2'' and H6''), 6.962 (ddd, J 7.4,

7.4, 1.0 Hz, 1H, H5'), 6.894 (dd, J 8.4, 0.9 Hz, 1H, H3'), 4.846 (dddd, JHeq6,Hax6 13.3,

JHeq6,Hax5 4.2, JHeq6,Heq2 2.5, JHeq6,Heq5 2.0 Hz, 1H, Heq6), 3.928 (dd, JHa,Hb 9.2 Hz, JHa,H4 6.1

Hz, 1H, 4–CHaHbOAr), 3.867 (dd, JHb,Ha 9.2 Hz, JHb,H4 6.5 Hz, 1H, 4–CHaHbOAr), 3.807 (s,

3H, OCH3), 3.538 (dddd, JHeq2,Hax2 13.6, JHeq2,Hax3 4.5, JHeq2,Heq3 2.8, JHeq2,Heq6 2.5 Hz, 1H,

Heq2), 3.055 (dddd, JHax2,Heq2 13.6, JHax2,Hax3 12.5, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.816 (ddd,

JHax6,Heq6 13.3, JHax6,Hax5 12.4, JHax6,Heq5 3.0 Hz, 1H, Hax6), 2.079 (m, 1H, H4), 1.932 (dm,

JHeq5,Hax5 13.0, 1H, Heq5), 1.746 (dm, JHeq3,Hax3 13.0, 1H, Heq3), 1.385 (m, 1H, Hax5),


20

1.197 (dddd, JHax5,Heq5 13.0, JHax3,Hax2 12.5, JHax3,Hax4 12.4, JHax3,Heq2 4.3 Hz, 1H, Hax3). δ

(minor) 9.855 (s, 1H, 4"-CHO), 7.806 (dd, J 8.8, 2.1 Hz, 1H, H3'' and H5''), 7.319 (ddd, J 8.1,

7.7, 1.8 Hz, 1H, H4'), 7.191 (dd, J 7.4, 1.7 Hz, 1H, H6'), 6.964 (dd, J 8.8, 2.1 Hz, 2H, H2''

and H6''), 6.962 (ddd, J 7.4, 7.4, 1.0 Hz, 1H, H5'), 6.894 (dd, J 8.4, 0.9 Hz, 1H, H3'), 4.846

(dddd, JHeq6,Hax6 13.3, JHeq6,Hax5 4.2, JHeq6,Heq2 2.5, JHeq6,Heq5 2.0 Hz, 1H, Heq6), 3.928 (dd,

JHa,Hb 9.2 Hz, JHa,H4 6.1 Hz, 1H, 4–CHaHbOAr), 3.858 (dd, JHa,Hb 9.2 Hz, JHb,H4 6.2 Hz, 1H,

4–CHaHbOAr), 3.811 (s, 3H, OCH3), 3.538 (dddd, JHeq2,Hax2 13.6, JHeq2,Hax3 4.5, JHeq2,Heq3 2.8,

JHeq2,Heq6 2.5 Hz, 1H, Heq2), 2.945 (ddd, JHax2,Heq2 13.6, JHax2,Hax3 12.5, JHax2,Heq3 2.8 Hz, 1H,

Hax2), 2.773 (ddd, JHax6,Heq6 13.3, JHax6,Hax5 12.4, JHax6,Heq5 3.0 Hz, 1H, Hax6), 2.079 (m, 1H,

H4), 1.932 (m, 1H, Heq5), 1.778 (dm, JHeq3,Hax3 13.0 Hz, 1H, Heq3), 1.428 (m, 1H, Hax5),

1.385 (m, 1H, Hax3). 13C NMR (75 MHz, CDCl3; 52:48 mixture at 25 °C; RJ-02-41; 150323-

rsj 2 2): δ (major) 190.81 (4''-CHO), 167.91 (1'-C(O)N), 163.97 (C1''), 155.36 (C2'), 132.05

(C3'' and C5''), 130.39 (C4'), 130.04 (C4''), 127.72 (C6'), 126.07 (C1'), 120.94 (C5'), 114.77

(C2'' and C6''), 111.01 (C3'), 72.42 (4-CH2OAr), 64.76 (4''-CH2OH), 55.64 (OCH3), 46.45

(C2), 41.36 (C6), 36.30 (C4), 29.47 (C3), 28.59 (C5). δ (minor) 190.81 (4''-CHO), 167.69 (1'-

C(O)N), 164.00 (C1''), 155.36 (C2'), 132.05 (C3'' and C5''), 130.26 (C4'), 130.04 (C4''),

128.62 (C3'' and C5''), 127.92 (C6'), 126.25 (C1'), 120.99 (C5'), 114.77 (C2'' and C6''),

110.91 (C3'), 72.48 (4-CH2OAr), 64.76 (4''-CH2OH), 55.54 (OCH3), 47.14 (C2), 41.43 (C6),

36.30 (C4), 29.52 (C3), 28.66 (C5). HRMS (ESI, +ve) m/z: 376.1513 [M+Na]+.

C21H23NO4Na requires 376.1519 [M + Na]+.

(ii) 4-((1-(3-Methoxybenzoyl)piperidin-4-yl)methoxy)benzaldehyde 41

Colourless gum (0.93 g, 69%), Rf 0.63 (EtOAc). FTIR (neat) νmax: 2933, 2858, 2730, 1692, 1600,

1437, 1293, 1249, 1162, 1106, 979, 829, 813, 749 cm–1. 1H NMR (300 MHz, CDCl3; single

isomer at 25 °C; RJ-02-42; 150323-rsj 6 2): δ 9.86 (s, 4''-CHO), 7.81 (d, J 8.7 Hz, 1H, H3''

and H5''), 7.28 (dd, J 8.9, 7.2 Hz, 1H, H5'), 6.97 (d, J 8.7 Hz, 2H, H2'' and H6''), 6.94 (d, J


21

8.9 Hz, 1H, H6'), 6.92 (d, J 7.2 Hz, 1H, H4'), 6.92 (m, 1H, H2'), 4.76 (4.65-4.85) (br s, 1H,

Heq6), 3.90 (br d, J 4.6 Hz, 2H, 4–CH2OAr), 3.82 (3.70-3.95) (br s, 1H, Heq2), 3.80 (s, 3H,

OCH3), 3.01 (2.85-3.20) (br s, 1H, Hax2), 2.81 (2.60-3.10) (br s, 1H, Hax6), 2.10 (m, 1H,

H4), 1.87 (1.65-2.10) (br, 2H, Heq3 and Heq5), 1.36 (1.15-1.60) (br s, 2H, Hax3 and Hax5).

13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-02-42; 150323-rsj 7 2): δ 190.798

(4''-CHO), 170.2 (1'-C(O)N), 163.9 (C1''), 159.7 (C3'), 137.5 (C1'), 132.0 (C3'' and C5''),

130.1 (C4''), 129.6 (C5'), 118.9 (C6'), 115.4 (C4'), 114.8 (C2'' and C6''), 112.3 (C2'), 72.3 (4-

CH2OAr), 55.4 (OCH3), 47.6 (br, C2), 42.0 (br, C6), 36.3 (C4), 29.6 (br, C3), 28.6 (br, C5).

HRMS (ESI, +ve) m/z: 376.1513 [M+Na]+. C21H23NO4Na requires 376.1519 [M + Na]+.

(iii) 4-((1-(4-Methoxybenzoyl)piperidin-4-yl)methoxy)benzaldehyde 42


1674, 1593, 1508, 1428, 1293, 1253, 1156, 1110, 1014, 822 cm–1. 1H NMR (300 MHz,

CDCl3; single isomer at 25 °C; RJ-01-47-1; 140604-rsj 12 2): δ 9.87 (s, 4''-CHO), 7.82 (d, J

8.8 Hz, 1H, H3'' and H5''), 7.38 (m, 2H, H2' and H6'), 6.98 (d, J 8.8 Hz, 2H, H2'' and H6''),

6.90 (d, J 8.8 Hz, 2H, H3' and H5'), 4.62 (4.28-5.10) (br s, 1H, Heq6), 3.91 (d, J 6.2 Hz, 2H,

4–CH2OAr), 3.86 (3.50-4.40) (br s, 1H, Heq2), 3.82 (s, 3H, OCH3), 2.94 (2.76-3.10) (br s,

2H, Hax2 and Hax6), 2.12 (m, 1H, H4), 1.89 (br d, J 12.0 Hz, 2H, Heq3 and Heq5), 1.38 (br

ddd, J 12.0, 11.7, 10.7 Hz, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at

25 °C; RJ-01-47-1; 140604-rsj 13 2): δ 190.9 (4''-CHO), 170.5 (1'-C(O)N), 164.0 (C1''),

160.8 (C4'), 132.1 (C3'' and C5''), 130.1 (C4''), 129.1 (C2' and C6'), 128.3 (C1'), 114.8 (C2''

and C6''), 113.8 (C3' and C5'), 72.5 (4-CH2OAr), 55.5 (OCH3), 47.8 (very br and weak, C2),

43.4 (very br and weak, C6), 36.4 (C4), 29.2 (br, C3 and C5). HRMS (ESI, +ve) m/z:

376.1512 [M+Na]+. C21H23NO4Na requires 376.1519 [M + Na]+.


22

Reduction of aldehydes 40-42 with NaBH4

General procedure: A cold solution of NaBH4 (0.16 g, 4.23 mmol) in dry MeOH (3 mL) was

added to a solution of the aldehyde (0.28 g, 0.79 mmol) in dry MeOH (3 mL). The reaction

mixture was refluxed for 2h under nitrogen then cooled to r.t., quenched with 1N HCl (5 mL)

and extracted with CH2Cl2 (3 x 10 mL). The combined extracts were washed with distilled

water (2 x 10 mL), dried over Na2SO4 and the solvent removed under reduced pressure. The

residue was flash chromatographed over silica gel using a gradient of 1:1 EtOAc/n–hexane to

100% EtOAc.

(i) (4-((4-(Hydroxymethyl)phenoxy)methyl)piperidine-1-yl)(2-methoxyphenyl)methanone 43

White solid (0.18 g, 65%) mp 122–124°C, Rf 0.56 (EtOAc). FTIR (neat) νmax: 3372, 2941,

2857, 1602, 1491, 1472, 1287, 1237, 1171, 1117, 1023, 985, 825, 750 cm–1. 1H NMR (300

MHz, CDCl3; 52:48 mixture at 25 °C; RJ-02-43; 150323-rsj 11 2): δ (major) 7.331 (ddd, J

8.4, 7.7, 1.7 Hz, 1H, H4'), 7.242 (d, J 8.6 Hz, 1H, H3'' and H5''), 7.229 (dd, J 7.4, 1.7 Hz, 1H,

H6'), 6.966 (ddd, J 7.7, 7.4, 0.8 Hz, 1H, H5'), 6.895 (dd, J 8.4, 0.8 Hz, 1H, H6'), 6.834 (d, J

8.6 Hz, 2H, H2'' and H6''), 4.813 (dm, J 13.3 Hz, 1H, Heq6), 4.554 (s, 2H, 4''-CH2OH), 3.843

(dd, JHa,Hb 9.2, JHa,H4 6.2 Hz, 1H, 4–CHaHbOAr), 3.807 (s, 3H, OCH3), 3.774 (dd, JHb,Ha 9.2,

JHb,H4 6.2 Hz, 1H, 4–CHaHbOAr), 3.522 (dm, J 13.5 Hz, 1H, Heq2), 3.041 (ddd, JHax2,Heq2

13.5, JHax2,Hax3 12.9, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.764 (ddd, JHax6,Heq6 13.3, JHax6,Hax5 12.6,

JHax6,Heq5 3.0 Hz, 1H, Hax6), 2.372 (br s, 1H, OH), 2.032 (m, 1H, H4), 1.925 (m, 1H, Heq5),

1.744 (m, 1H, Heq3), 1.420 (m, 1H, Hax5), 1.196 (dddd, JHax3,Heq3 ~12.8 (ex COSY),

JHax3,Hax2 12.6, JHax3,Hax4 12.3, JHax3,Heq2 4.2 Hz, 1H, Hax3). δ (minor) 7.322 (ddd, J 8.4, 7.7,

1.7 Hz, 1H, H4'), 7.249 (d, J 8.6 Hz, 1H, H3'' and H5''), 7.186 (dd, J 7.4, 1.7 Hz, 1H, H6'),

6.966 (ddd, J 7.7, 7.4, 0.8 Hz, 1H, H5'), 6.895 (dd, J 8.4, 0.8 Hz, 1H, H6'), 6.845 (d, J 8.6 Hz,

2H, H2'' and H6''), 4.813 (dm, JHeq6,Hax6 13.3 Hz, 1H, Heq6), 4.554 (s, 2H, 4''-CH2OH), 3.843


23

(dd, JHa,Hb 9.2, JHa,H4 6.2 Hz, 1H, 4–CHaHbOAr), 3.807 (s, 3H, OCH3), 3.768 (dd, JHb,Ha 9.2,

JHb,H4 6.6 Hz, 1H, 4–CHaHbOAr), 3.522 (dm, JHeq2,Hax2 13.5 Hz, 1H, Heq2), 2.930 (ddd,

JHax2,Heq2 13.5, JHax2,Hax3 12.9, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.802 (ddd, JHax6,Heq6 13.3,

JHax6,Hax5 12.6, JHax6,Heq5 3.0 Hz, 1H, Hax6), 2.372 (br s, 1H, OH), 2.032 (m, 1H, H4), 1.925

(m, 1H, Heq5), 1.781 (m, 1H, Heq3), 1.420 (m, 1H, Hax5), 1.370 (m, 1H, Hax3). 13C NMR

(75 MHz, CDCl3; 52:48 mixture at 25 °C; RJ-02-43; 150323-rsj 12 2): δ (major) 167.96 (1'-

C(O)N), 158.43 (C1''), 155.34 (C2'), 133.56 (C4''), 130.36 (C4'), 128.62 (C3'' and C5''),

127.73 (C6'), 126.06 (C1'), 120.92 (C5'), 114.46 (C2'' and C6''), 111.00 (C3'), 72.21 (4-

CH2OAr), 64.76 (4''-CH2OH), 55.63 (OCH3), 47.57 (C2), 41.48 (C6), 36.37 (C4), 29.56 (C3),

28.74 (C5). δ (minor) 167.75 (1'-C(O)N), 158.43 (C1''), 155.34 (C2'), 133.56 (C4''), 130.24

(C4'), 128.62 (C3'' and C5''), 127.91 (C6'), 126.23 (C1'), 120.92 (C5'), 114.46 (C2'' and C6''),

110.88 (C3'), 72.21 (4-CH2OAr), 64.76 (4''-CH2OH), 55.51 (OCH3), 47.25 (C2), 41.55 (C6),

36.37 (C4), 29.60 (C3), 28.66 (C5). HRMS (ESI, +ve) m/z: 378.1674 [M+Na]+.


(ii) (4-((4-(Hydroxymethyl)phenoxy)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone 44


3002, 2914, 2862, 1603, 1510, 1452, 1286, 1240, 1172, 1106, 1017, 970, 916, 823 cm–1. 1H

NMR (300 MHz, CDCl3; single isomer at 25 °C; RJ-02-44; 150323-rsj 16 1): δ 7.29 (m, 1H,

H5'), 7.25 (d, J 8.7 Hz, 1H, H3'' and H5''), 6.93 (m, 2H, H4' and H6'), 6.92 (m, 1H, H2'), 6.84

(d, J 8.7 Hz, 2H, H2'' and H6''), 4.65-4.82 (br s, 1H, Heq6), 4.56 (s, 2H, 4''-CH2OH), 3.70-

4.00 (m, 3H, 4–CH2OAr and Heq2), 3.80 (s, 3H, OCH3), 2.90-3.12 (m, 1H, Hax2), 2.70-2.90

(m, 1H, Hax6), 2.3-2.5 (br m, 1H, OH), 2.08 (br m, 1H, H4), 1.75-2.00 (m, 2H, Heq3 and

Heq5), 1.28-1.50 (m, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25

°C; RJ-02-44; 150323-rsj 17 1): δ 170.2 (1'-C(O)N), 159.7 (C3'), 158.4 (C1''), 137.5 (C1'),


24

133.6 (C4''), 129.6 (C5'), 128.6 (C3'' and C5''), 118.9 (C6'), 115.4 (C4'), 114.5 (C2'' and C6''),

112.6 (C2'), 72.1 (4-CH2OAr), 64.8 (4''-CH2OH), 55.4 (OCH3), 47.7 (br, C2), 42.1 (br, C6),

36.4 (C4), 29.7 (br, C3), 28.7 (br, C5). HRMS (ESI, +ve) m/z: 378.1673 [M+Na]+.


(iii) (4-((4-(Hydroxymethyl)phenoxy)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone 45


2857, 1590, 1508, 1440, 1392, 1300, 1238, 1170, 1112, 1030, 988, 834 cm–1. 1H NMR (300

MHz, CDCl3; single isomer at 25 °C; RJ-01-86-1; 140819-rsj 5 2): δ 7.37 (d, J 8.8 Hz, 2H,

H2' and H6'), 7.27 (d, J 8.7 Hz, 2H, H3'' and H5''), 6.90 (d, J 8.8 Hz, 2H, H3' and H5'), 6.86

(d, J 8.7 Hz, 2H, H2'' and H6''), 4.59 (s, 2H, –CH2OH), 3.3-5.3 (br s, 2H, Heq2 and Heq6),

3.82 (d, J 6.2 Hz, 2H, 4–CH2OAr), 3.82 (s, 3H, OCH3), 2.92 (br t, J ~10.3 Hz, 2H, Hax2 and

Hax6), 2.08 (br m, 1H, H4), 2.06 (br m, 1H, OH), 1.88 (br d, J 12.7 Hz, 2H, Heq3 and Heq5),

1.35 (br m, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-01-

86-1; 140819-rsj 6 2): δ 170.5 (1'-C(O)N), 160.8 (C4'), 158.6 (C1''), 133.5 (C4''), 129.1 (C2'

and C6'), 128.7 (C3'' and C5''), 128.3 (C1'), 114.6 (C2'' and C6''), 113.8 (C3' and C5'), 72.2

(4-CH2OAr), 65.0 (4''-CH2OH), 55.5 (OCH3), 41.7-43.5 (very br, C2 and C6), 36.5 (C4),

29.4 (br, C3 and C5). HRMS (ESI, +ve) m/z: 378.1676 [M+Na]+. C21H25NO4Na requires

378.1676 [M + Na]+.

Reaction of mesylate 38 with 4-hydroxybenzyl alcohol 8 and 4-methylphenol (p-cresol)

46

General procedure: Mesylate 38 (0.33 g, 1.01 mmol) was added with stirring to a mixture of

p-hydroxybenzyl alcohol 8 (0.19 g, 1.53 mmol) or p-cresol 46 (0.19 g, 1.76 mmol) and KOH

(0.34 g, 6.0 mmol) in dry DMF (10 mL) under nitrogen. The reaction mixture was heated to

70 oC overnight then cooled to r.t., poured into distilled water (25 mL) and the mixture


25

extracted with CH2Cl2 (3 x 25 mL). The combined extracts were washed with distilled water

(2 x 25 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to give

a white solid that was flash chromatographed over silica gel using 1:1 EtOAc/n–hexane to

afforded the desired product.

(i) (4-((4-(Hydroxymethyl)phenoxy)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone 45

White solid (0.23 g, 60%) with identical spectroscopic properties to those of the product from

reduction of aldehyde 42.

(ii) (4-Methoxyphenyl)(4-((4-tolyloxy)methyl)piperidin-1-yl)methanone 47

p-Cresol yielded the product as a white solid (0.28 g, 82%) mp 122–123 °C, Rf 0.66 (EtOAc).

FTIR (neat) νmax: 3017, 2910, 2863, 1608, 1507, 1429, 1394, 1286, 1240, 1172, 1108, 1026,

917, 826 cm–1. 1H NMR (300 MHz, CDCl3; single isomer at 25 °C; RJ-01-105; 141011-rsj 7

2): δ 7.39 (d, J 8.8 Hz, 2H, H2' and H6'), 7.08 (d, J 8.6 Hz, 2H, H3'' and H5''), 6.91 (d, J 8.8

Hz, 2H, H3' and H5'), 6.79 (d, J 8.6 Hz, 2H, H2'' and H6''), 4.62 (4.20-5.20) (br s, 2H, Heq6),

3.99 (3.40-4.50) (br s, 2H, Heq2), 3.83 (s, 3H, OCH3), 3.81 (d, J 6.3 Hz, 2H, 4–CH2OAr),

2.93 (2.80-3.07) (br s, 2H, Hax2 and Hax6), 2.28 (s, 3H, 4''-CH3), 2.07 (m, 1H, H4), 1.89 (br

d, J 12.4 Hz, 2H, Heq3 and Heq5), 1.36 (br ddd, J 12.4, 12.1, 11.8 Hz, 2H, Hax3 and Hax5).

13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-01-105; 141011-rsj 8 2): δ 170.5 (1'-

C(O)N), 160.7 (C4'), 156.9 (C1''), 130.1 (C4''), 130.0 (C3'' and C5''), 129.0 (C2' and C6'),

128.5 (C1'), 114.4 (C2'' and C6''), 113.8 (C3' and C5'), 72.3 (4-CH2OAr), 55.4 (OCH3), 46.8

(br and very weak, C2), 42.7 (br and very weak, C6), 36.6 (C4), 29.3 (br, C3 and C5), 20.6

(4''-CH3). HRMS (ESI, +ve) m/z: 362.2743 [M+Na]+. C21H25NO3Na requires 362.2717 [M +

Na]+.


26

Treatment of amidoalcohols 43–45 with CH3SO2Cl

General procedure: The amidoalcohols 43-45 (0.50 g, 2 mmol) were dissolved separately

with Et3N (3.1 mmol) in dry CH2Cl2 (5 mL) and the solution cooled in a bath at –20 oC.

Methanesulfonyl chloride (0.23 mL, 3 mmol) was added dropwise and the mixture allowed to

warm to r.t. then stirred overnight. The reaction mixture was concentrated under reduced

pressure, the residue dissolved in CH2Cl2 (25 mL), and the solution washed with 15% aq.

HCl (2 x 10 mL) and distilled water (10 mL), dried over anhydrous Na2SO4 and evaporated

to dryness. Flash chromatography on a silica gel column packed in 10:90 EtOAc/n-hexane

containing 0.5% v/v Et3N and eluted with 1:2 EtOAc/n-hexane afforded the unexpected

amidochlorides 51, 52 and 49, respectively.

(i) (4-((4-(Chloromethyl)phenoxy)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone 51

White gum (0.39 g, 74%), Rf 0.82 (EtOAc). FTIR (neat) νmax: 2932, 2856, 1627, 1511, 1466,

1294, 1245, 1176, 1099, 1025, 833 cm–1. 1H NMR (300 MHz, CDCl3; 52:48 mixture at 25

°C; RJ-02-88-1; 150714-rsj 1 2): δ (major) 7.344 (ddd, J 8.4, 7.6, 1.7 Hz, 1H, H4'), 7.297 (d,

J 8.7 Hz, 1H, H3'' and H5''), 7.252 (dd, J 7.4, 1.7 Hz, 1H, H6'), 6.982 (ddd, J 7.6, 7.4, 0.9 Hz,

1H, H5'), 6.910 (dd, J 8.4, 0.9 Hz, 1H, H3'), 6.850 (d, J 8.7 Hz, 2H, H2'' and H6''), 4.842 (dm,

JHeq6,Hax6 13.3 Hz, 1H, Heq6), 4.560 (s, 2H, 4''-CH2Cl), 3.867 (dd, JHa,Hb 9.2, JHa,H4 6.4 Hz,

1H, 4–CHaHbOAr), 3.828 (s, 3H, OCH3), 3.793 (dd, JHb,Ha 9.2, JHb,H4 6.4 Hz, 1H, 4–

CHaHbOAr), 3.541 (dm, JHeq2,Hax2 13.0 Hz, 1H, Heq2), 3.056 (ddd, JHax2,Heq2 13.0, JHax2,Hax3

12.9, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.786 (ddd, JHax6,Heq6 13.3, JHax6,Hax5 12.6, JHax6,Heq5 3.0

Hz, 1H, Hax6), 2.053 (m, 1H, H4), 1.954 (m, 1H, Heq5), 1.755 (m, 1H, Heq3), 1.447 (m, 1H,

Hax5), 1.194 (dddd, JHax3,Heq3 ~12.8 (ex COSY), JHax3,Hax2 12.6, JHax3,Hax4 12.3, JHax3,Heq2 4.2

Hz, 1H, Hax3). δ (minor) 7.337 (ddd, J 8.4, 7.6, 1.7 Hz, 1H, H4'), 7.303 (d, J 8.7 Hz, 1H, H3''

and H5''), 7.210 (dd, J 7.4, 1.7 Hz, 1H, H6'), 6.982 (ddd, J 7.6, 7.4, 0.9 Hz, 1H, H5'), 6.910


27

(dd, J 8.4, 0.9 Hz, 1H, H3'), 6.860 (d, J 8.7 Hz, 2H, H2'' and H6''), 4.842 (dm, JHeq6,Hax6 13.3

Hz, 1H, Heq6), 4.560 (s, 2H, 4''-CH2Cl), 3.867 (dd, JHa,Hb 9.2, JHa,H4 6.4 Hz, 1H, 4–

CHaHbOAr), 3.828 (s, 3H, OCH3), 3.787 (dd, JHb,Ha 9.2, JHb,H4 6.5 Hz, 1H, 4–CHaHbOAr),

3.541 (dm, JHeq2,Hax2 13.0 Hz, 1H, Heq2), 2.948 (ddd, JHax2,Heq2 13.0, JHax2,Hax3 12.9, JHax2,Heq3

2.8 Hz, 1H, Hax2), 2.826 (ddd, JHax6,Heq6 13.3, JHax6,Hax5 12.6, JHax6,Heq5 3.0 Hz, 1H, Hax6),

2.053 (m, 1H, H4), 1.925 (m, 1H, Heq5), 1.800 (m, 1H, Heq3), 1.447 (m, 1H, Hax5), 1.378

(m, 1H, Hax3). 13C NMR (75 MHz, CDCl3; 52:48 mixture at 25 °C; RJ-02-88-1; 150714-rsj

2 2): δ (major) 167.98 (1'-C(O)N), 159.16 (C1''), 155.44 (C2'), 130.28 (C4'), 130.21 (C3'' and

C5''), 129.95 (C4''), 127.82 (C6'), 126.39 (C1'), 121.04 (C5'), 114.75 (C2'' and C6''), 111.07

(C3'), 72.29 (4-CH2OAr), 55.71 (OCH3), 47.60 (C2), 46.38 (4''-CH2Cl), 41.51 (C6), 36.46

(C4), 29.71 (C3), 28.72 (C5). δ (minor) 167.76 (1'-C(O)N), 159.14 (C1''), 155.44 (C2'),

130.40 (C4'), 130.21 (C3'' and C5''), 129.95 (C4''), 128.00 (C6'), 126.23 (C1'), 121.02 (C5'),

114.75 (C2'' and C6''), 110.94 (C3'), 72.32 (4-CH2OAr), 55.59 (OCH3), 47.29 (C2), 46.38

(4''-CH2Cl), 41.59 (C6), 36.46 (C4), 29.65 (C3), 28.82 (C5). HRMS (ESI, +ve) m/z: 396.1328

[M+Na]+ C21H24ClNO3Na requires 396.1337.

(ii) (4-((4-(Chloromethyl)phenoxy)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone 52

White gum (0.43 g, 82%), Rf 0.78 (EtOAc). FTIR (neat) νmax: 3014, 2911, 2864, 1621, 1511,

1429, 1290, 1239, 1169, 1110, 1033, 973, 931, 827 cm–1. 1H NMR (300 MHz, CDCl3; single

isomer at 25 °C; RJ-02-95-1; 150714-rsj 5 2): δ 7.31 (dd, J 9.1, 7.2 Hz, 1H, H5'), 7.302 (d, J

8.8 Hz, 1H, H3'' and H5''), 6.95 (m, 1H, H6'), 6.938 (m, 1H, H2'), 6.937 (m, 1H, H4'), 6.87

(d, J 8.8 Hz, 2H, H2'' and H6''), 4.64-4.92 (br s, 1H, Heq6), 4.56 (s, 2H, 4''-CH2Cl), 3.83 (d, J

5.9 Hz, 2H, 4–CH2OAr), 3.70-3.95 (br s, Heq2), 3.82 (s, 3H, OCH3), 2.38-3.18 (br s, 1H,

Hax2), 2.65-3.00 (br s, 1H, Hax6), 2.09 (m, 1H, H4), 1.72-2.01 (br s, 2H, Heq3 and Heq5),

1.12-1.57 (br s, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-


28

02-95-1; 150714-rsj 6 2): δ 170.2 (1'-C(O)N), 159.8 (C3'), 159.1 (C1''), 137.7 (C1'), 130.2

(C3'' and C5''), 130.0 (C4''), 129.7 (C5'), 119.0 (C6'), 115.5 (C4'), 114.8 (C2'' and C6''), 112.4

(C2'), 72.2 (4-CH2OAr), 55.5 (OCH3), 47.7 (br, C2), 46.4 (4''-CH2Cl), 42.3 (br, C6), 36.5

(C4), 29.9 (br, C3), 28.8 (br, C5). HRMS (ESI, +ve) m/z: 396.1331 [M+Na]+.

C21H24ClNO3Na requires 396.1337 [M + Na]+.

On one occasion, attempted chromatography of a crude sample of amidochloride 52 (0.28 g)

on silica gel gave (((((oxybis(methylene))bis(4,1-

phenylene))bis(oxy))bis(methylene))bis(piperidine-4,1-diyl))bis((3-

methoxyphenyl)methanone) 56 as a yellow gum (0.23 g, 83% mass recovery). Rf 0.46

(EtOAc). FTIR (neat) νmax: 3344, 2915, 2854, 1607, 1508, 1430, 1319, 1272, 1237, 1172,

1108, 1033, 987, 958, 788 cm–1. 1H NMR (300 MHz, CDCl3; single isomer at 25 °C; RJ-02-

96-1-2; 150714-rsj 21 2): δ 7.32 (dd, J 8.2, 8.1 Hz, 1H, H5'), 7.27 (d, J 8.7 Hz, 2H, H3'' and

H5''), 6.95 (dm, J 8.2 Hz, 1H, H4'), 6.94 (dm, J 8.1 Hz, 1H, H6'), 6.93 (m, 1H, H2'), 6.86 (d,

J 8.7 Hz, 2H, H2'' and H6''), 4.72 (4.60-4.86) (br s, 1H, Heq6), 4.45 (s, 2H, 4''-CH2O), 3.82

(3.70-3.95) (m, 3H, 4–CH2OAr and Heq2), 3.82 (s, 3H, OCH3), 3.05 (2.90-3.15) (br s, 1H,

Hax2), 2.85 (2.70-2.98) (br s, 1H, Hax6), 2.08 (m, 1H, H4), 1.89 (1.70-2.02) (br s, 2H, Heq3

and Heq5), 1.36 (1.15-1.57) (br s, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single

isomer at 25 °C; RJ-02-96-1-2; 150714-rsj 22 2): δ 170.5 (1'-C(O)N), 159.8 (C3'), 158.6

(C1''), 136.9 (C1'), 130.7 (C4''), 129.8 (C5'), 129.6 (C3'' and C5''), 119.0 (C6'), 115.8 (C4'),

114.5 (C2'' and C6''), 112.3 (C2'), 72.1 (4-CH2OAr), 71.6 (4''-CH2O), 55.5 (OCH3), 47.9 (br,

C2), 42.4 (br, C6), 36.4 (C4), 29.8 (br, C3), 28.7 (br, C5). HRMS (ESI, +ve) m/z: 715.3347

[M+Na]+. C42H48N2O7Na requires 715.3354 [M + Na]+.


29

(iii) (4-((4-(Chloromethyl)phenoxy)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone 49

White solid (0.40 g, 76 %) m.p. 118-120 °C, Rf 0.82 (EtOAc). FTIR (neat) νmax: 3010, 2917,

2865, 1606, 1509, 1429, 1396, 1290, 1241, 1173, 1109, 1024, 973, 829 cm–1. 1H NMR (300

MHz, CDCl3; single isomer at 25 °C; RJ-01-chloride; 150120-rsj 17 2): δ 7.39 (d, J 8.68 Hz,

2H, H2' and H6'), 7.30 (d, J 8.71 Hz, 2H, H3'' and H5''), 6.91 (d, J 8.68 Hz, 2H, H3' and H5'),

6.86 (d, J 8.71 Hz, 2H, H2'' and H6''), 4.56 (s, 2H, –CH2Cl), 4.00-4.65 (br s, 2H, Heq2 and

Heq6), 3.834 (d, J 6.1 Hz, 2H, 4–CH2OAr), 3.830 (s, 3H, OCH3), 2.94 (br t, J 11.6 Hz, 2H,

Hax2 and Hax6), 2.09 (m, 1H, H4), 1.89 (br d, J 12.4 Hz, 2H, Heq3 and Heq5), 1.37 (dddd, J

12.6, 12.4, 11.6, 3.8 Hz, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at

25 °C; RJ-01-chloride; 150120-rsj 18 2): δ 170.6 (1'-C(O)N), 160.8 (C4'), 159.1 (C1''), 130.2

(C3'' and C5''), 130.0 (C4''), 129.1 (C2' and C6'), 128.3 (C1'), 114.8 (C2'' and C6''), 113.8 (C3'

and C5'), 72.2 (4-CH2OAr), 55.5 (OCH3), 42-49 (br, C2 and C6), 46.4 (4''-CH2Cl), 36.5 (C4),

29.3 (br, C3 and C5). HRMS (ESI, +ve) m/z: 374.1510 [M+H]+. C21H25ClNO3 requires

374.1517 [M + Na]+.

Treatment of amidochlorides 51, 52 and 49 with n-Bu4NF (TBAF)

A solution of tetra-n-butylammonium fluoride (TBAF) in THF (1.5 mL of 1.0 M; 0.36 g, 1.5

mmol,) was added a stirred solution of amidochloride (0.100 g, 0.27 mmol) in dry THF ( 5.0

mL) under N2. The reaction mixture was heated to reflux for 30 min and then cooled to r.t.

and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc (10

mL), the solution washed with distilled water (3 × 5 mL) then dried over Na2SO4 and

evaporated to dryness under reduced pressure to give a white residue. The residue was flash

chromatographed on a silica gel column packed in using 0.5% TEA in 10:90 EtOAc/n-

hexane containing 0.5% v/v Et3N and eluted with 1:2 EtOAc/n-hexane to afford the desired

amidofluoride.


30

(i) 4-((4-(Fluoromethyl)phenoxy)methyl)piperidin-1-yl)(2-methoxyphenyl)methanone 5

White gum (0.092 g, 90%), Rf 0.82 (EtOAc). FTIR (neat) νmax: 2938, 2359, 1628, 1513,

1467, 1372, 1294, 1247, 1176, 1123, 1025, 967, 765 cm–1. 1H NMR (300 MHz, CDCl3;

53:47 mixture at 25 °C; RJ-02-93-1; 150714-rsj 9 2): δ (major) 7.338 (ddd, J 9.0, 8.6, 1.8 Hz,

1H, H4'), 7.319 (dd, JH,H 9.2 Hz, JH,F 2.2 Hz, 2H, H3'' and H5''), 7.248 (dd, J 7.5, 1.7 Hz, 1H,

H6'), 6.982 (ddd, J 7.5, 7.4, 1.0 Hz, 1H, H5'), 6.911 (dd, J 8.3, 0.8 Hz, 1H, H3'), 6.892 (dd,

JH,H 8.8 Hz, JH,F 2.4 Hz, 2H, H2'' and H6''), 5.291 (d, JH,F 48.6 Hz, 2H, 4''-CH2F), 4.856 (dm,

JHeq6,Hax6 13.0 Hz, 1H, Heq6), 3.877 (dd, JHa,Hb 9.2, JHa,H4 6.4 Hz, 1H, 4–CHaHbOAr), 3.830

(s, 3H, OCH3), 3.810 (dd, JHb,Ha 9.2, JHb,H4 6.4 Hz, 1H, 4–CHaHbOAr), 3.544 (dddd, JHeq2,Hax2

13.2, JHeq2,Hax3 4.5, JHeq2,Heq6 2.5, JHeq2,Heq3 2.0 Hz, 1H, Heq2), 3.058 (ddd, JHax2,Heq2 13.2,

JHax2,Hax3 12.7, JHax2,Heq3 2.8 Hz, 1H, Hax2), 2.830 (ddd, JHax6,Heq6 13.1, JHax6,Hax5 12.2,


1.763 (br d, JHeq3,Hax3 11.6 Hz, 1H, Heq3), 1.387 (m, 1H, Hax5), 1.200 (dddd, JHax3,Heq3 12.2,

JHax3,Hax2 12.0, JHax3,Hax4 11.5, JHax3,Heq2 4.2 Hz, 1H, Hax3). δ (minor) 7.338 (ddd, J 9.0, 8.6,

1.8 Hz, 1H, H4'), 7.319 (dd, JH,H 9.2 Hz, JH,F 2.2 Hz, 2H, H3'' and H5''), 7.211 (dd, J 7.4, 1.7

Hz, 1H, H6'), 6.982 (ddd, J 7.5, 7.4, 1.0 Hz, 1H, H5'), 6.911 (dd, J 8.3, 0.8 Hz, 1H, H3'),

6.892 (dd, JH,H 8.8 Hz, JH,F 2.4 Hz, 2H, H2'' and H6''), 5.291 (d, JH,F 48.6 Hz, 2H, 4''-CH2F),

4.856 (dm, JHeq6,Hax6 13.0 Hz, 1H, Heq6), 3.877 (dd, JHa,Hb 9.2, JHa,H4 6.4 Hz, 1H, 4–

CHaHbOAr), 3.830 (s, 3H, OCH3), 3.804 (dd, JHb,Ha 9.2, JHb,H4 6.4 Hz, 1H, 4–CHaHbOAr),

3.544 (dddd, JHeq2,Hax2 13.2, JHeq2,Hax3 4.5, JHeq2,Heq6 2.5, JHeq2,Heq3 2.0 Hz, 1H, Heq2), 2.954

(ddd, JHax2,Heq2 12.5, JHax2,Hax3 12.2, JHax2,Heq3 3.1 Hz, 1H, Hax2), 2.789 (ddd, JHax6,Heq6 13.1,

JHax6,Hax5 12.6, JHax6,Heq5 3.1 Hz, 1H, Hax6), 2.061 (m, 1H, H4), 1.954 (br d, J 12.0 Hz, 1H,

Heq5), 1.800 (br d, J 12.1 Hz, 1H, Heq3), 1.454 (dddd, JHax5,Heq5 12.2, JHax5,Hax6 12.0,

JHax5,Hax4 11.5, JHax5,Heq6 4.2 Hz, 1H, Hax5), 1.387 (m, 1H, Hax3). 13C NMR (75 MHz,

CDCl3; 53:47 mixture at 25 °C; RJ-02-93-1; 150714-rsj 10 2): δ (major) 167.76 (1'-C(O)N),


31

159.63 (d, JC,F 3.5 Hz, C1''), 155.45 (C2'), 130.40 (C4'), 130.00 (d, JC,F 5.0 Hz, C3'' and C5''),

128.54 (d, JC,F 17.4 Hz, C4''), 127.82 (C6'), 126.25 (C1'), 121.01 (C5'), 114.63 (d, JC,F 1.9 Hz,

C2'' and C6''), 110.95 (C3'), 84.62 (d, JC,F 164.5 Hz, 4''-CH2F), 72.28 (4-CH2OAr), 55.71

(OCH3), 46.60 (C2), 41.58 (C6), 36.48 (C4), 29.72 (C3), 28.74 (C5). δ (minor) 168.00 (1'-

C(O)N), 159.63 (d, JC,F 3.5 Hz, C1''), 155.45 (C2'), 130.28 (C4'), 130.00 (d, JC,F 5.0 Hz, C3''

and C5''), 128.54 (d, JC,F 17.4 Hz, C4''), 128.01 (C6'), 126.43 (C1'), 121.06 (C5'), 114.63 (d,

JC,F 1.9 Hz, C2'' and C6''), 111.08 (C3'), 84.62 (d, JC,F 164.5 Hz, 4''-CH2F), 72.32 (4-

CH2OAr), 55.60 (OCH3), 47.28 (C2), 41.53 (C6), 36.48 (C4), 29.66 (C3), 28.82 (C5). 19F

NMR (282 MHz, CDCl3; 52:48 mixture by integration at 25 °C; RJ-02-93-1; 150714-rsj

13/14 2): δ (minor) −199.30 (t, 2JF,H 48.6 Hz, 1F, –CH2F); δ (major) −199.36 (t, 2JF,H 48.6

Hz, 1F, –CH2F). HRMS (ESI, +ve) m/z: 380.1624 [M+Na]+. C21H24FNO3Na requires

380.1632 [M + Na]+.

(ii) 4-((4-(Fluoromethyl)phenoxy)methyl)piperidin-1-yl)(3-methoxyphenyl)methanone 6

White gum (0.075 g, 74%), Rf 0.82 (EtOAc). FTIR (neat) νmax: 3049, 2994, 2933, 1626,

1599, 1512, 1319, 1290, 1245, 1176, 1115, 1029, 973, 958, 821, 794 cm–1. 1H NMR (300

MHz, CDCl3; single isomer at 25 °C; RJ-02-96-1; 150714-rsj 15 2): δ 7.32 (dd, JH,H 8.8 Hz,

JH,F 2.3 Hz, 2H, H3'' and H5''), 7.31 (dd, J 9.1, 7.4 Hz, 1H, H5'), 6.96 (dd, J 8.3, 1.0 Hz, 1H,

H6'), 6.940 (dd, J 7.7, 2.1 Hz, 1H, H4'), 6.939 (m, 1H, H2'), 6.89 (dd, JH,H 8.8 Hz, JH,F 1.0

Hz, 2H, H2'' and H6''), 5.29 (d, JH,F 48.6 Hz, 2H, 4''–CH2F), 4.78 (4.65-4.90) (br s, 1H,

Heq6), 3.84 (3.78-3.94) (m, 2H, 4–CH2OAr), 3.82 (s, 3H, OCH3), 3.80 (3.67-3.07) (br s, 1H,

Heq2), 3.03 (2.90-3.15) (br s, 1H, Hax2), 2.83 (2.65-3.00) (br s, 1H, Hax6), 2.10 (m, 1H,

H4), 1.92 (1.74-1.94) (br s, 1H, Heq3), 1.87 (1.74-1.94) (br s, 1H, Heq5), 1.37 (1.15-1.55) (br

s, 2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-02-96-1;

150714-rsj 16 2): δ 170.2 (1'-C(O)N), 159.8 (C3'), 159.6 (d, JC,F 3.3 Hz, C1''), 137.7 (C1'),


32

130.0 (d, JC,F 4.9 Hz, C3'' and C5''), 129.7 (C5'), 128.6 (d, JC,F 17.4 Hz, C4''), 119.0 (C6'),

115.5 (C4'), 114.6 (d, JC,F 1.9 Hz, C2'' and C6''), 112.4 (C2'), 84.6 (d, JC,F 164.5 Hz, 4''-

CH2F), 72.2 (4-CH2OAr), 55.5 (OCH3), 47.8 (very br, C2), 42.2 (very br, C6), 36.5 (C4),

29.8 (br, C3), 28.7 (br, C5). 19F NMR (282 MHz, CDCl3; single isomer at 25 °C; RJ-02-96-1;

150714-rsj 19/20 2): δ −199.39 (t, 2JF,H 48.8 Hz, 1F, –CH2F). HRMS (ESI, +ve) m/z:

380.1625 [M+Na]+. C21H24FNO3Na requires 380.1632 [M + Na]+.

(iii) 4-((4-(Fluoromethyl)phenoxy)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone 7

White solid (0.076 g, 75%) mp 115–117°C, Rf 0.81 (EtOAc). FTIR (neat) νmax: 3020, 2915,

2865, 1609, 1510, 1430, 1373, 1290, 1243 1117, 1109, 1025, 966, 834, 704 cm–1. 1H NMR

(300 MHz, CDCl3; single isomer at 25 °C; RJ-02-38-1; 150309-rsj 1 2): δ 7.39 (d, J 8.8 Hz,

2H, H2' and H6'), 7.32 (dd, JH,H 8.7 Hz, JH,F 2.2 Hz, 2H, H3'' and H5''), 6.91 (d, J 8.8 Hz, 2H,

H3' and H5'), 6.90 (dd, JH,H 8.7 Hz, JH,F 1.0 Hz, 2H, H2'' and H6''), 5.29 (d, JH,F 48.6 Hz, 2H,

4''–CH2F), 4.65 (4.35-5.00) (br s, 2H, Heq6), 4.08 (3.80-4.35) (br s, 2H, Heq2), 3.85 (d, J 6.4

Hz, 2H, 4–CH2OAr), 3.83 (s, 3H, OCH3), 2.93 (2.80-3.10) (br s, 2H, Hax2 and Hax6), 2.09

(m, 1H, H4), 1.89 (br d, J 12.8 Hz, 2H, Heq3 and Heq5), 1.39 (br ddd, J 12.4, 10.8, 10.3 Hz,

2H, Hax3 and Hax5). 13C NMR (75 MHz, CDCl3; single isomer at 25 °C; RJ-02-38-1;

150309-rsj 2 2): δ 170.5 (1'-C(O)N), 160.8 (C4'), 159.9 (d, JC,F 3.4 Hz, C1''), 130.0 (d, JC,F

4.9 Hz, C3'' and C5''), 129.1 (C2' and C6'), 128.6 (d, JC,F 17.3 Hz, C4''), 128.4 (C1'), 114.6 (d,

JC,F 2.0 Hz, C2'' and C6''), 113.8 (C3' and C5'), 84.6 (d, JC,F 164.5 Hz, 4''-CH2F), 72.3 (4-

CH2OAr), 55.5 (OCH3), 45.6 (very br, C2), 40.8 (very br, C6), 36.5 (C4), 29.3 (br, C3), 28.3

(br, C5). 19F NMR (282 MHz, CDCl3; single isomer at 25 °C; RJ-02-38-1; 150309-rsj 3/6 2):

δ −199.36 (t, 2JF,H 48.6 Hz, 1F, –CH2F). HRMS (ESI, +ve) m/z: 380.1624 [M+Na]+

C21H24FNO3Na requires 380.1632 [M + Na]+.


33

Free radical fluorination[10] of ibuprofen methyl ester and of compound 47

(i) Following the method of Groves et al.,[10] ibuprofen methyl ester (35 mg, 0.16 mmol) and

AgF (62 mg, 0.5 mmol) were added to an oven-dried Schlenk flask containing Mn(Salen)Cl

(20 mg, 0.3 mmol). The flask was capped with a rubber septum and the flask connected to the

Schlenk line to evacuate and refill with nitrogen, a cycle that was replicated three times.

Degassed MeCN (2.0 mL) was then added via syringe through the septum followed by

adding of Et3N•3HF (12 µL). The flask was placed in a pre-heated oil bath at 60 °C, PhIO (32

mg, 0.15 mmol) was added in portions over 3 h to the stirred mixture at the same temperature

and the mixture left for a further 30 min. The reaction mixture was allowed to cool to r.t.,

diluted with CH2Cl2 (2 mL), the solution filtered, and the residue washed with fresh CH2Cl2

(3 × 2 mL). The combined solution and washings were evaporated to dryness to give the

crude product as a pale-yellow syrup. Analysis of the syrup by 1H NMR spectroscopy

revealed a 94:6 mixture (based on integration of signals at δ 2.45 (d, J 7.2 Hz, 2H) and 5.09

(dd, 2JH,F 47.0, 2JH,F 6.8 Hz, 1H)) of unreacted ibuprofen methyl ester and of its monofluoro

derivative, respectively. The latter was observed, particularly in the 19F NMR spectrum, as an

equimolar mixture of diastereomers with the following diagnostic signals: 1H NMR (300

MHz, CDCl3; RJ-02-107 crude; 150803-rsj 5 2): δ 7.30 (d, J 8.3 Hz, 2H), 7.25 (d, J 8.3 Hz,

2H), 5.09 (dd, 2JH,F 47.0, 2JH,F 6.8 Hz, 1H), 3.74 (q, J 7.2 Hz, 1H), 3.67 (s, 3H), 2.10 (ddh,

3JH,F 16.8, 3JH,H 6.8, 3JH,H 6.8 Hz, 1H), 1.51 (d, J 7.2 Hz, 3H), 1.028/1.025 (2xd, J 6.6/6.7 Hz,

total 3H), 0.86 (d, J 6.8 Hz, 3H). 19F NMR (282 MHz, CDCl3; RJ-02-107 crude; 150803-rsj

6/7 2) δ −179.64 (dd, 2JF,H 47.0, 3JF,H 16.9 Hz), −179.62 (dd, 2JF,H 46.9, 3JF,H 17.0 Hz). The

observation of diastereoisomers was not mentioned in the report by Groves et al.,[10] but was

supported by data and tangentially mentioned in Supporting Information in an earlier

reported synthesis of the same compound by Fasan et al..[11]


34

(ii) Identical treatment of compound 47 to that described for ibuprofen methyl ester in part

(i), gave, with identical workup and chromatography on silica gel, a fraction with largely

unreacted tolylamido compound 47, admixed with ~4% of the desired amidofluoride 7, as

evidenced by NMR signals at (300 MHz, CDCl3; RJ-02-40-2; 150306-rsj 4 2) δH 5.30 (d,

2JF,H 48.5 Hz, 2H, 4''-CH2F), δH 7.32 (dd, 3JH,H 8.86 Hz, 4JH,F 2.10 Hz, 2H, H3'' and H5''), and

(282 MHz, CDCl3; RJ-02-40-2; 150306-rsj 6 2) δF –199.4 (tt, 2JF,H 49.5 Hz, 4JF,H 2.7 Hz, 4'-

CH2F).

Treatment of amidofluoride 7 with LiAlH4

(i) A solution of amidofluoride 7 (0.025 g, 0.07 mmol) in dry THF (3 mL) was added

dropwise to a stirred solution of lithium aluminiumhydride (0.20 mL of 1.0 M THF solution,

0.20 mmol) under nitrogen in a bath at –20 °C. The reaction mixture was stirred at bath

temperature for 30 min, warmed to 0 °C then sat. aq. NH4Cl solution (5 mL) added. The

mixture was extracted with EtOAc (3 x 10 mL), the combined extracts washed with water (3

x 5 mL), dried over Na2SO4, and evaporated under reduced pressure. The oily residue was

analysed by NMR spectroscopy to reveal complete consumption of compound 7 and 54%

yield of an 11:50:39 mixture of what appeared by 1H NMR spectroscopy to be 4-

methoxybenzaldehyde, 4-methoxybenzyl alcohol and 4-((4''-

fluoromethylphenoxy)methyl)piperidine 54, respectively; spectra were described in Section

2.3 of the main text.

(ii) The reaction in part (i) was repeated but with addition of the lithium aluminiumhydride

solution to the amidofluoride 7 solution and the reaction prolonged at –20 °C for 50 min.

Reaction workup gave by 1H NMR spectroscopic analysis a 3:15:11:71 mixture of what

appeared to be 4-methoxybenzaldehyde, 4-methoxybenzyl alcohol, aminofluoride 54 and the

desired aminoalcohol 56, respectively, in 77% yield; spectra are discussed in the main text.


35

The crude product was flash chromatographed on a column packed with silica gel in 10:90

EtOAc/n-hexane containing 0.5% Et3N. Elution with a 1:2 EtOAc/n-hexane to 100% EtOAc

gradient eventually afforded only (4-((1-(4-methoxybenzyl)piperidin-4-

yl)methoxy)phenyl)methanol 56 as a white solid (0.23 g) m.p. 76–78 °C, Rf 0.14 (EtOAc).

FTIR (neat) νmax: 2916, 2854, 2359, 1610, 1509, 1463, 1240, 1172, 1100, 1032, 814, 754 cm–

1. 1H NMR (300 MHz, CDCl3; RJ-03-06-1; 150929-rsj 13 2): δ 7.27 (d, J 8.7 Hz, 2H, H3''

and H5''), 7.24 (d, J 8.6 Hz, 2H, H2' and H6'), 6.859 (d, J 8.6 Hz, 2H, H2'' and H6''), 6.856 (d,

J 8.8 Hz, 2H, H3' and H5'), 4.61 (s, 2H, 4''–CH2OH), 3.90 (s, 3H, OCH3), 3.79 (d, J 6.2 Hz,

2H, 4–CH2OAr), 3.47 (s, 2H, 1'-CH2N), 2.93 (dm, J 11.5 Hz, 2H, Heq2 and Heq6), 1.99 (dd,

J 11.5, 11.0 Hz, 2H, Hax2 and Hax6), 1.81 (br d, J 12.1 Hz, 2H, Heq3 and Heq5), 1.80 (m,

1H, H4), 1.71 (1.55-1.80) (br s, 1H, OH), 1.40 (m, 2H, Hax3 and Hax5). 13C NMR (75 MHz,

CDCl3; RJ-03-06-1 at 25 °C; 150930-rsj 13 2): δ 158.9 (C4'), 158.9 (C1''), 133.2 (C4''), 130.6

(C2' and C6'), 130.2 (br, C1'), 128.8 (C3'' and C5''), 114.7 (C2'' and C6''), 113.7 (C3' and C5'),

72.9 (4-CH2OAr), 65.2 (4''-CH2OH), 62.9 (1'-CH2N), 55.4 (OCH3), 53.3 (C2 and C6), 36.0

(C4), 29.1 (C3 and C5). HRMS (ESI, +ve) m/z: 342.2060 [M+H]+. C21H28NO3 requires

342.2064 [M + H]+.

References

[1.] G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M.

Stoltz, J. E. Bercaw, K. I. Goldberg, Organometallics, 2010, 29, 2176.

[2.] C. P. Rosenau, B.J. Jelier, A. D. Gossert, A. Togni, Angew. Chem. Int. Ed., 2018, 57,

9528.

[3.] R. K. Harris, E. D. Becker, S. M. Cabral De Menezes, P. Granger, R. E. Hoffman, K.

Zilm, Pure Appl. Chem., 2008, 80, 59.


36

[4.] M. Tafazzoli, A. Ziyaei–Halimjani, M. Ghiasi, M. Fattahi, M. R. Saidi, J. Mol. Struct.,

2008, 886, 24.

[5.] B. P. Bandgar, V. T. Kamble, A. V. Biradar, Monatsh. Chem. 2005, 136, 1579.

[6.] J. Bertin, P. R. Bovy, G. Courtemanche, O. Crespin, G. Defosse, E. Fett, PCT Int. Appl.

(2000), WO 2000046220 A1 20000810.

[7.] C. Lecoutey, C. Rochais, D. Genest, S. Butt-Gueulle, C. Ballandonne, S. Corvaisier, F.

Dulin, A. Lepailleur, J. Sopkova-de Oliviera Santos, P. Dallemagne, Med. Chem.

Commun., 2012, 3, 627.

[8.] K. S. T. Dias, C. T. de Paula, T. dos Santos, I. N. O. Souza, M. S. Boni, M. J. R.

Guimaraes, F. M. R. da Silva, N. G. Casstro, G. A. Neves, C. C. Veloso, M. M. Coelho,

IS. F. de Melo, F. C. V. Giusti, A. Giusti-Paiva, M. L. da Silva, L. E. Dardenne, I. A.

Guedes, L. Pruccoli, F. Morroni, A. Tarozzi, C. Viegas Jr., Eur. J. Med. Chem., 2017,

130, 440.

[9.] M. Y. Lee, D. J. Baek, S. Lee, D. Kim, S. Kim, J. Org. Chem. 2011, 76, 408.

[10.] W. Liu, J. T. Groves, Angew. Chem. Int. Ed., 2013, 52, 6024.

[11.] A. Rentmeister, F. H. Arnold, R. Fasan, Nat. Chem. Biol., 2009, 5, 26.

Copies of 1H and 13C NMR Spectra (see following)

SupplementaryInformation–NMRspectra …pageof95

37

Ethyl 1-(2-methoxybenzoyl)piperidine-4-carboxylate 25 1H NMR at 25 °C

[ppm

] 8

6

4

2

7.36767.36207.34527.34077.33817.33567.31517.30957.24577.24007.22087.21517.20957.19027.18456.99896.97416.94926.93026.92776.90246.89984.62814.62314.61434.60934.60054.59554.58364.57864.56984.56484.55604.55114.18984.17714.16614.15344.14864.14234.12964.12464.11864.10594.10083.82903.81683.51543.5066M 3.47473.47063.46163.06353.05393.02763.01613.00322.99452.99232.98122.96962.95812.55352.53872.51752.50322.04512.04292.03492.0110M 2.00411.99691.98431.84461.83971.83231.82811.81391.80881.80011.79601.78741.78321.77661.77001.75651.74331.72091.71281.70811.28641.27581.26281.25201.2390

0.9340.905

0.9730.915

0.906

1.943

2.833

0.970

1.933

1.000

0.279

1.079

2.446

0.567

3.029

RJ-01-43-o HNMR of 2-MeO CO2Et in CDCl3 (calibrated to 1.2562 then 7.2600 ppm)

140605-rsj 1 3 (300 MHz)

140605-rsj 1 3 /Users/rogerwread/NMR/Rasha

N

CO2Et

CH3O25

O


3813C NMR at 25 °C

[ppm

] 1

50

100

5

0

174.1917174.1114

167.6797167.5202

155.1537155.1317

130.2232130.1584127.6770127.5375125.8237125.7013120.7555120.7246

110.8140110.7266

60.425460.201455.420855.3453

46.308045.785040.936840.728140.6621

28.280627.816727.7603

20.8803

14.0567

RJ-01-43-O CNMR in CDCl3 (calibrated to 77.16 ppm)

140605-rsj 2 2 (75 MHz)



39

Ethyl 1-(3-methoxybenzoyl)piperidine-4-carboxylate 26 1H NMR at 25 °C

[ppm

] 6

4

2

7.31087.30667.28727.28447.28217.26007.25646.93986.93856.93246.91066.90726.9036

M 4.5040

4.17304.14924.12554.10173.79973.74003.72853.7245

M 3.05673.0205M 2.98422.59842.58492.57142.56262.54912.53562.52682.51332.4998

1.9773M 1.8528M 1.77581.7094

1.26771.24391.2202

1.000

2.604

0.849

1.891

0.330 2.7720.519

1.857

0.938

3.919

2.780

RJ-01-45-m HNMR of 3-MeO CO2Et in CDCl3 (calibrated to 7.2600 ppm)

140609-rsj 1 2 (300 MHz)


N

CO2Et

26CH3OO


4013C NMR at 25 °C

[ppm

] 1

50

100

5

0

174.2687170.2407

159.7520

137.4257

129.7000

118.9420115.5954112.2495

77.582077.158376.7346

60.7596

55.4491

M 47.0403

M 41.640541.1802

M 28.4254M 28.0166

14.2983

RJ-01-45-m CNMR of 3-MeO CO2Et in CDCl3 at 25 °C (calibrated to 77.16 ppm)

140609-rsj 2 2 (75 MHz)



41

Ethyl 1-(4-methoxybenzoyl)piperidine-4-carboxylate 27 1H NMR at –20 °C

[ppm

] 8

6

4

2

7.36847.34657.2599

6.90306.8811

5.29714.57184.53864.14754.12964.11174.09393.86753.86003.84833.83973.83343.82663.82163.81463.80573.09943.09273.06413.03603.02952.93672.92992.90252.87412.86752.59222.58252.57272.56422.55452.54482.53612.52642.51672.17992.16382.05152.04612.01752.0118M 1.87401.86841.8414M 1.83491.77231.76221.74311.73311.70961.70041.69101.68041.67141.66251.63881.62971.61031.60011.26061.24271.2249

2.062

2.078

0.780

1.000

2.063

0.818 3.282

1.0351.041

1.044

0.4211.0561.0452.088

3.132

RJ-01-08 HNMR of 4-MeO CO2Et in CDCl3 at -20 °C (calibrated to 7.2600 ppm)

140415-rsj 7 2 (400 MHz)


N

CO2Et

27

CH3O

O


4213C NMR at –20 °C

[ppm

] 1

50

100

5

0

174.5464170.4961

160.4821

128.9573127.6694

113.5966

77.475377.157376.8390

60.8683

55.437053.7048

47.3048

41.744441.0969

28.478027.8953

14.2437

RJ-01-08 CNMR of 4-MeO CO2Et in CDCl3 at -20 °C (calibrated to 77.16 ppm)

140415-rsj 8 2 (100 MHz)



43

4-(Hydroxymethyl)piperidin-1-yl)(2-methoxyphenyl)methanone 28 1H NMR (600 MHz) at 10 °C

[ppm

] 7

6

5

4

3

2

1

7.31087.30797.30147.29847.29697.29567.29417.28907.28757.28627.28467.28167.27517.27237.26007.17197.16917.15957.15677.13707.13427.12467.12186.93866.93726.93446.93306.92626.92486.92206.92066.91396.91246.90966.90826.86366.84964.71194.70864.70514.70124.69384.69014.68674.68353.76263.75763.43043.42713.42373.42053.40823.40483.40113.39803.35793.35213.34753.34213.33433.33193.32403.32013.31393.30923.30233.29153.18952.94212.92472.92062.81662.81372.70142.68482.67992.66342.65212.64721.74651.74281.73821.72451.72051.71641.62341.61351.60431.60031.58681.58311.13671.12321.12071.1162

0.505 0.4950.545 0.461

1.0021.009

0.993

3.013

1.0032.0131.053

0.5460.4681.007

1.0062.025

1.482

0.543

RJ-01-61 HNMR of 2-MeO CH2OH at 10 degC (calibrated to 7.26 ppm)

170607-rsj 2 2 (600 MHz) (enhanced LB-1.00 GB 0.80)


NOH

CH3O28

O


4413C NMR (150 MHz) at 10 °C

[ppm

] 1

50

100

5

0

167.8619167.6955

155.1105155.0917

130.3173130.2046127.7004127.5107125.8763125.7253120.7703120.7511

110.7566110.6358

66.908866.8086

55.493555.3550

47.334046.662741.567741.521638.7213

29.210329.145928.435128.3731

RJ-01-61 CNMR of 2-MeO CH2OH in CDCl3 at 10 degC (calibrated to 77.16 ppm)

170607-rsj 8 2 (150 MHz )



45

4-(Hydroxymethyl)piperidin-1-yl)(3-methoxyphenyl)methanone 29 1H NMR at 25 °C

[ppm

] 6

4

2

7.30327.29987.27947.27607.27427.26007.25177.24926.93356.93016.92486.92196.91956.90666.89546.88906.8832

4.69254.68614.6690

3.7910

3.45883.44043.26023.25353.21393.20812.9489

2.7343

2.3020

1.71611.70431.69561.6879

1.19471.18301.1544

0.996

2.820

1.001

3.955

1.957

0.111

1.005

0.974

1.132

2.937

2.024

RJ-01-59-2 HNMR of 3-MeO CH2OH in CDCl3 at 25 °C (calibrated to H7.26 ppm)

140619-rsj 1 2 (300 Hz)


NOH

29CH3OO


461H NMR at –10 °C

[ppm

] 6

4

2

7.26007.24197.24066.91736.91396.90886.90546.90096.89596.89256.88976.88616.88156.87766.87166.86736.86506.86196.85906.85716.8533

4.68594.67964.67304.64224.63574.62953.77113.75083.74253.73603.72963.69793.69123.68513.39493.37813.36443.35103.31613.18863.17412.96482.95622.92092.91362.87772.87032.72902.71972.68632.67682.64332.63382.47731.79071.74681.73921.71801.70931.69701.68021.65981.65021.63871.63071.61841.61051.24311.22871.21921.20101.18671.16111.14731.12681.11961.11271.10641.08451.07101.03951.02850.99900.9858

1.048

2.994

1.000

3.0630.931

2.011

1.039

1.021

1.025

0.148

1.0242.005

1.053

1.010

RJ-01-59-2 HNMR of 3-MeO CH2OH in CDCl3 at 25 °C (calibrated to 7.26 ppm)

140701-rsj 2 2 (300 MHz)



4713C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.2142

159.6588

137.6149

129.6406129.5543

119.1227118.9042115.3520113.1533112.2906

67.132566.840965.0568

55.418755.283152.9619

47.8433

42.208438.902236.9256

29.454828.5408

RJ-01-59-2 CNMR of 3-MeO CH2OH in CDCl3 (calibrated to C77.1600 ppm)

140619-rsj 2 2 (75 MHz) at 25 °C



48

4-(Hydroxymethyl)piperidin-1-yl)(4-methoxyphenyl)methanone 30 1H NMR (300 MHz) at 25 °C

[ppm

] 8

6

4

2

7.36567.35897.34327.33657.25996.90296.89616.88046.8737

4.5903

3.8140

3.49803.47833.26263.2414

2.8725

2.03032.00321.77391.76591.74691.73741.70601.26831.24391.24181.22121.1952

1.000

0.997

0.560

2.065

1.082

1.051

0.744

1.559

1.131

RJ-01-22-2 HNMR of 4-MeO CH2OH in CDCl3 (calibrated to H7.2600 ppm)

140506-rsj 1 2 (300 MHz) at 25 °C


NOH

30

CH3O

O


491H NMR (400 MHz) at –20 °C

[ppm

] 8

6

4

2

7.35787.35147.34627.32987.32277.26006.90176.89516.89006.87346.8663

5.2487

M 4.68574.68184.65294.6492

3.86203.82753.81863.80793.42273.09543.00893.00332.9759M 2.97212.9434M 2.93942.73132.72492.69912.69282.66692.66062.51301.81161.77921.69511.66871.24761.23671.21591.20631.18491.17521.15451.14651.12541.11601.09371.08441.06211.0526

1.992

1.987

0.237

1.000

3.966

2.008

0.9401.038

1.024

0.429

1.0701.929

2.099

RJ-01-22 HNMR of 4-MeO CH2OH in CDCl3 at -20 °C (calibrated to 7.2600 ppm)

170412-rsj 3 2 (400 MHz) F:\\ rsj 2



5013C NMR (75 MHz) at 25 °C

[ppm

] 1

50

100

5

0

170.5260

160.7315

129.0044128.4564

113.7716

77.582577.158776.7350

67.3242

55.4485

M 48.0806M 47.7617M 47.3231M 45.3696M 43.3363M 42.618739.0298

M 29.331729.1250M 28.9961

RJ-01-22-2 CNMR of 4-MeO CH2OH in CDCl3 (calibrated to C77.1600 ppm

140506-rsj 2 2 (75 MHz) at 25 °C



51

(1-(2-Methoxybenzoyl)piperidin-4-yl)methyl methanesulfonate 36 1H NMR at 25 °C

[ppm

] 6

4

2

7.33947.31307.29257.28697.28137.25997.21407.20857.18927.18367.17397.16847.14907.14356.97296.94826.92336.89716.86934.82014.77644.07564.06934.05544.04794.03653.53513.52733.52063.51363.50573.49013.48213.47533.46853.46063.04363.0344M 3.0000M 2.99162.98132.97312.95622.94732.93452.9254M 2.89202.88462.84872.83952.80392.79412.76082.75082.71782.70822.67482.66502.12572.06452.02532.01442.00852.00381.99351.97651.96491.95551.94401.90441.85471.81161.67911.63631.41881.40371.37571.36061.33421.31901.30411.29431.27671.25881.25441.22551.21631.20061.17901.16461.13781.12371.09731.08231.0548

0.9650.484 0.493

0.997 1.004

1.000

2.021

3.044

1.040

4.040

1.039

1.0811.0281.021

1.620

0.509

RJ-01-70 HNMR of 2-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150120-rsj 1 2 (300 MHz)


N

CH3O36

O

OMs


5213C NMR at 25 °C

[ppm

] 1

50

100

5

0

167.8599167.6612

155.2888

130.4362130.3080127.8429127.6906125.9951125.8165120.9356

110.9708110.8951

77.579677.155576.731073.297773.2124

55.594055.5014

46.772346.070441.084440.990437.336636.1275

28.847728.0274

RJ-01-70 CNMR or 2-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to C77.16000 ppm)

150120-rsj 2 2 (75 MHz)



53


[ppm

] 6

4

2

7.28377.26547.25997.23516.91896.91576.91046.90736.90546.90276.89936.89426.89086.88536.87936.87476.86936.86636.8642

4.6922

4.05504.03383.80123.78513.77103.77003.75162.98212.97662.96792.96642.9480M 2.75452.07032.05772.04812.03662.03082.02392.01832.00911.99751.99031.98551.97701.97031.96411.95841.94681.93701.92491.84181.83261.80331.79331.75991.29041.25661.25421.23971.23191.21131.1845

0.936

2.666

0.813

1.954

0.3812.9480.456

0.1832.986 0.6110.695 0.1440.450

0.1751.000

2.090

2.171

RJ-01-72 HNMR of 3-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150120-rsj 5 2 (300 MHz)


N37CH3O

O

OMs


5413C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.0627

159.6087

137.2729

129.5990

118.7833115.3659112.2335

77.584277.158776.733973.0970

55.3303

47.122045.387741.6143

37.267736.0519

28.9132M 27.999527.8768

RJ-01-72 CNMR of 3-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150120-rsj 6 2 (75 MHz)



55


[ppm

] 6

4

2

7.35527.34837.33297.32597.31677.25996.89506.88816.87266.8657

5.2730

M 4.4761

4.07904.0577

3.8016

2.98922.87352.06882.05722.05212.03922.03032.01822.00601.99761.99181.97931.96731.95791.94521.91061.80101.75941.33331.30291.29331.26261.25201.2276

1.000

1.018

0.559

1.0970.1321.575

0.144

0.029 1.5280.992

0.5250.1541.027

1.041

RJ-01-29/2 HNMR of 4-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

140516-rsj 1 2 (300 MHz)


N38

CH3O

O

OMs


5613C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.4704

160.7933

128.9933128.0539

113.7666

77.582777.158276.734273.1846

55.402853.5332

M 46.6142M 46.0339M 43.5582M 43.2487M 42.4363M 42.088237.379836.2132

28.5340

RJ-01-29/2 CNMR of 4-MeO-COpipCH2-OMs in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

140516-rsj 2 2 (75 MHz)



57

4-((1-(2-Methoxybenzoyl)piperidin-4-yl)methoxy)benzaldehyde 40 1H NMR at 25 °C

[ppm

] 1

0 8

6

4

2

9.85517.82447.81747.81097.80167.79517.78817.35457.34867.34257.32157.30197.29607.29017.25997.25027.24467.22547.21987.20617.20057.18127.17576.98876.98546.98296.97336.96396.96066.95426.94426.93916.93586.90946.90646.88156.87854.87214.86474.85804.82794.82073.93363.92343.91283.90313.89313.88303.87123.86223.84073.83133.81113.80703.57533.56703.56053.55373.54543.53023.52203.51533.50883.50063.05963.05092.94962.94102.82022.81112.77762.77312.76882.10542.08562.07272.05952.05262.01681.95381.94661.91811.91061.76441.73551.72791.45831.43911.41341.39881.37191.35761.25591.23211.2083

1.000

2.083

1.0521.127

3.166 1.058

1.061

2.253 3.097

1.081

0.5890.5170.563 0.522

1.2141.2381.109

1.6120.644

RJ-02-41 HNMR of 2-MeO-COpip-OC6H4-CHO in CDCl3 at 25°C (calibrated to H7.26ppm)

150323-rsj 1 2 (300 MHz)


NO

CH3O40

O

CHO


5813C NMR at 25 °C

[ppm

] 1

50

100

5

0

190.8087

167.9136167.6923M 163.9960163.9726

155.3558

132.0455130.3875130.2643130.0373127.9192127.7236126.2458126.0701120.9932120.9385114.7672111.0143110.9101

77.583477.159476.735272.480872.4179

55.634755.5377

47.140546.449141.431141.363936.2970M 29.520029.466728.656728.5882

RJ-02-41 CNM R of 2-MeO-COpip-OC6H4-CHO in CDCl3 at 25 °C (calibrated to C77.1600ppm)

150323-rsj 2 2 (75 MHz)



59


[ppm

] 1

0 8

6

4

2

9.85489.8416

7.82067.81527.79807.79167.31367.28397.27557.25996.97906.95016.93486.92736.9206

4.7611

M 3.90313.88793.79543.7829

3.01252.99452.8095

2.10702.09562.08832.06951.8972

1.3587

0.999

2.015

1.087

5.047

0.936

2.3084.033

1.009

1.212

1.216

2.415

2.273

RJ-02-42 HNMR of 3-MeO-COpip-OC6H4-CHO in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150323-rsj 6 2 (300 MHz) NB: poorly shimmed


NO

41CH3OO

CHO


6013C NMR at 25 °C

[ppm

] 1

50

100

5

0

190.7981

170.1626

163.9305159.6789

137.5219

132.0391130.0624129.6407

118.9029115.3898114.7650112.3348

77.582277.158876.734272.3321

55.3909

47.6232

41.9667

36.2826

29.554028.6257

RJ-02-42 CNMR of 3-MeO-COpip-OC6H4-CHO in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150323-rsj 7 2 (75 MHz)



61


[ppm

] 1

0 8

6

4

2

9.8728

7.84597.83727.83067.81447.80787.79917.40467.39547.38857.37317.36607.35697.25997.00266.99406.98806.97116.96506.95646.92586.91666.90976.89426.88736.8781

4.05843.92343.90273.86843.82072.93702.19112.17842.16902.15742.1519M 2.14532.13912.13092.11882.10662.0988M 2.09282.08562.08022.06802.05942.04681.90811.86811.39791.3645

1.000

2.039

2.038

2.0912.049

1.062

0.788

2.1383.296

0.330

2.186

1.121

2.709

2.242

RJ-01-47-1 HNMR of 4-MeO-COpipCH2-OC6H4-CHO in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

140604-rsj 12 2 (300 MHz)


NO

42

CH3O

O

CHO


6213C NMR at 25 °C

[ppm

] 1

50

100

5

0

190.8643

170.5289

164.0058160.8055

132.1100130.1291129.0551128.3245

114.8165113.8030

77.580177.156676.733172.4498

55.4495

36.4146

29.2447

RJ-01-47-1 CNMR of 4-MeO-COpipCH2-OC6H4-CHO in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

140604-rsj 13 2 (75 MHz)



63

(4-((4-(Hydroxymethyl)phenoxy)methyl)piperidin-1-yl) (2-methoxyphenyl)methanone 43 1H NMR at 25 °C

[ppm

] 8

6

4

2

7.36047.35437.34797.32757.30797.30187.29547.26387.25997.25617.24437.23487.22737.21997.21447.20167.19597.17687.17116.99206.98896.96726.96416.94246.93936.91036.90766.88256.87976.85926.84816.84096.83066.81944.83774.83164.79344.78734.55363.86963.84823.83913.81693.80723.80113.79513.79093.77893.76933.74853.55933.55083.54453.53803.52953.51443.50603.49953.49323.48473.04533.03662.93272.92642.80722.80182.79862.76862.76022.37172.06492.05312.04472.03182.02412.01862.00731.93951.93091.91691.90311.89571.76311.75781.73211.72561.43491.41081.39311.38231.36971.35181.34091.33051.2423

1.0002.533 0.446

1.020 1.015 1.949

0.993

1.967

4.969

1.022

0.5250.4971.012

0.892

1.3231.0231.030

1.527

0.625

RJ-02-43 HNMR of 2-MeO-COpip-OC6H4-CH2OH in CDCl3 at rt (calibrated to H7.2600 ppm)

150323-rj 11 2 (300 MHz) (enhanced gfp -1.00 0.30)


NO

CH3O43

O

OH


6413C NMR at 25 °C

[ppm

] 1

50

100

5

0

167.9563167.7471

158.4341155.3409

133.5589130.3594130.2416128.6150127.9085127.7259126.2291126.0610120.9239

114.4635111.0044110.8804

77.581877.157776.733672.2055

64.7556

55.627655.5129

47.245746.566241.551041.4825

36.3676

29.599429.562328.739028.6546

RJ-02-43 CNMR of 2-MeO-COpip-OC6H4-CH2OH in CDCl3 at rt (calibrated to C77.1600 ppm)

150323-rsj 12 2 (75 MHz) (slightly enhanced in SI 65536)



65

(4-((4-(Hydroxymethyl)phenoxy)methy)piperidin-4-1-yl) (3-methoxyphenyl)methanone 44 1H NMR at 25 °C

[ppm

] 6

4

2

7.29057.28327.26697.25997.25777.25277.23066.94566.94206.93616.93276.92166.91736.91416.90986.85426.84716.83226.8251

4.72174.5566

3.81003.80483.7948

3.0051

2.7939

2.34252.08282.07422.04982.04162.03621.89841.88811.8373

1.34671.3054

0.924 2.690

3.4262.323

1.073

2.464

6.992

1.210

1.295

1.179

1.642

2.386

2.443

RJ-02-44 HNMR of 3-MeO-COpipCH2-OC6H4-CH2OH in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150323-rsj 16 2


NO

44CH3OO

OH


66

13C NMR at 25 °C

[ppm

] 1

60

140

1

20

100

8

0 6

0 4

0

170.2014

159.6452158.4195

137.5204

133.5773

129.6230128.6217

118.9239115.4201114.4786112.2801

77.579377.155676.7312

72.1187

64.7851

55.3897

47.6609

42.1167

36.3712

29.738428.7005

RJ-02-44 CNMR of 3-MeO-COpip-OC6H4-CH2OH in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150323-rsj 17 2 (75 MHz)



67

(4-((4-(Hydroxymethyl)phenoxy)methyl)piperidin-1-yl) (4-methoxyphenyl)methanone 45 1H NMR at 25 °C

[ppm

] 6

4

2

7.38667.37967.36437.35727.27987.25997.25076.91266.90566.89026.88326.87176.86466.84976.8427

4.5860

M 4.3814M 4.3186

3.83343.81993.8124

3.00482.94392.93682.92472.86592.86402.13492.12472.11392.09772.07542.06152.05482.04892.04192.03662.02472.01552.00531.89941.85781.42071.40801.37971.36721.33831.32601.29681.28361.2509

1.0001.053

1.022 0.996

0.111

1.024

0.748

2.541

0.149

1.001

1.169

0.998

1.044

RJ-01-86-1 HNMR of 4-MeO-COpip-OC6H4-CH2OH in CDCl3 at 25 °C (calibrated tp H7.2600 ppm)

140819-rsj 5 2 (300 MHz)


NO

45

CH3O

O

OH


6813C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.5354

160.7606158.5459

133.5394129.0449128.7078128.3283

114.5595113.7765

77.580077.156576.732972.2233

64.9500

55.4351

M 47.5831M 45.7111M 45.2717M 42.5210

36.4870

29.2722

RJ-01-86-1 CNMR on 3-MeO-COpip-OC6H4CH2OH in CDCl3 at rt (calibrated to C77.1600 ppm)

140819-rsj 6 2 (75 MHz) seeking signals at 40-50 ppm



69

(4-Methoxyphenyl)(4-((4-tolyloxy)methyl)piperidin-1-ylmethanone 47 1H NMR at 25 °C

[ppm

] 6

4

2

7.40147.39457.37917.37217.26007.08947.06216.92226.91536.89976.89296.79936.79246.77746.7707

4.6176

3.99063.98183.82773.81693.7958

2.93032.28322.14342.13132.12152.11022.09252.08372.07172.05942.05152.03342.02112.01251.99981.90801.8667M 1.41601.37661.3416M 1.3013

1.582

1.5521.6341.655

0.862

0.758

2.591 1.532

0.256

1.747

2.455

1.000

1.697

1.583

RJ-01-105 HNMR of 4-MeO-COpipCH2-OC6H4-CH3 in CDCl3 at 25 °C (calibrated to 7.2600 ppm)

141011-rsj 7 2 (300 MHz)


NO

47

CH3O

O

CH3


7013C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.4843

160.7384156.8960

130.1074130.0131129.0375128.4835

114.4144113.7723

77.582877.158976.735272.2820

55.4359

M 46.7913M 42.7155M 41.3232

36.5534

29.2858

20.5583

RJ-01-105 CNMR of 4-MeO-COpipCH2-OC6H4-CH3 in CDCl3 (calibrated to C77.1600 ppm)

141011-rsj 8 2 (75 MHz)



71

(4-((4-(Chloromethyl)phenoxy)methyl)piperidin-1-yl) (2-methoxyphenyl)methanone 51 1H NMR at 25 °C

[ppm

] 6

4

2

7.37257.36667.3605M 7.34147.33957.31747.31147.28897.28237.26767.25997.24297.23717.22527.21967.20057.19487.00837.00516.98356.98036.95876.95556.92516.92226.89736.89436.87476.86426.84576.83524.87774.87124.86384.83354.82674.55923.87213.86293.8421M 3.8399M 3.83593.82813.81773.81233.79533.78993.76553.57793.56943.56333.55673.54813.53303.52483.51813.51153.50313.05993.05122.95172.94382.82912.8237M 2.79132.78162.08742.07552.06922.06532.05312.04222.03351.95421.93481.92531.92031.91271.80701.79671.77331.76881.73641.46201.44691.43341.41941.40671.39291.36621.35191.25681.25421.22091.2061

2.889 0.515 0.272 0.465

0.988 1.009 1.961

1.000

1.935

0.842 3.111 0.983

1.005

0.5390.4980.5160.489

1.0311.057

1.454

1.592

0.714

RJ-02-88-1 HNMR of 2-MeO-COpip-OC6H4-CH2Cl in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150714-rsj 1 2 (300 MHz)


NO

CH3O51

O

Cl


7213C NMR at 25 °C

[ppm

] 1

50

100

5

0

M 167.8457

159.1624155.4441

130.3983130.2817130.2083129.9481127.9983127.8145126.3949121.0441

114.7535111.0684110.9443

77.580077.156876.733472.2876

55.709455.5939

47.285546.598246.379141.5129

36.4554

29.711429.649428.817928.7156

RJ-02-88-1 CNMR for 2-MeO-COpip-OC6H4-CH2Cl in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150714-rsj 2 2 (75 MHz)



73


[ppm

] 6

4

2

7.30347.29557.28797.27917.26006.97416.97026.96606.96326.95446.95086.94636.94176.93846.93306.92876.87246.86526.85036.8432

4.80974.7759

4.5604

3.84103.82123.01432.84172.83362.78782.74312.73592.70272.69422.66202.65362.14892.14092.12842.12292.11582.11032.10172.08952.07732.06952.06312.05672.05102.04192.03812.03022.01741.88231.70191.28041.25661.2328

1.000 0.087

0.9920.676

0.274

0.677

0.5021.284 0.170

0.352

0.384

0.362

0.684

0.186

0.791

RJ-02-95-1 HNMR of 3-MeO-COpip-OC6H4-CH2Cl in CDCl3 at rt (calibrated to H7.2600)

150714-rsj 5 2 (300 MHz)


NO

52CH3OO

Cl


7413C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.2414

159.7561159.1041

137.6743

130.2152129.9967129.6946

119.0060115.5004114.7609112.3573

77.577377.153976.730472.2053

55.4769

M 47.711246.3664M 42.2859

36.4607

M 29.8520M 28.8396

RJ-02-95-1 CNMR of 3-MeO-COpip-OC6H4-CH2Cl

150714-rsj 6 2 (75 MHz)



75

(((((Oxybis(methylene))bis(4,1-phenylene))bis(oxy))bis(methylene)) bis(piperidine-4,1-diyl))bis((3-methoxyphenyl)methanone) 53 1H NMR at 25 °C

[ppm

] 6

4

2

7.26007.25647.25067.24116.97706.97386.96866.96546.96076.95596.95216.95036.94546.94236.93806.93176.92646.87336.86636.85126.8443

4.73594.7221

4.4516

3.84913.83933.83473.83043.82333.81413.80183.7818

3.07373.06253.05103.01302.8459

2.10862.09662.08431.97281.93521.93231.8940

1.35671.34591.3419

2.083

0.488

3.943

1.000

0.1950.837 0.164

5.013

0.774

0.866

0.854

1.630

1.965

RJ-02-96-1-2 HNMR of (3-MeO-COpipCH2-OC6H4CH2)2-O in CDCl3 T 25 °C (calibrated to H7.26 ppm0

150714-rsj 21 2 (300 MHz)


NO

O

O

53CH3O

2


7613C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.5152

159.7760158.5955

136.8858130.7450M 130.2490130.1861M 129.8755129.8002129.5608

119.0152115.7941M 114.6266M 114.5436114.4786112.3493M 111.9917

72.100871.5801

55.5120

M 47.9441M 47.7888M 45.5637M 42.6399M 42.4071

36.3732

M 29.8066M 29.1597M 28.7199M 28.4094

RJ-02-96-1-2 CNMR of (3-MeO-COpipCH2-OC6H4CH2)2-O in CDCl3 at 25 °C (calibrated to C77.16 ppm)

150714-rsj 22 2 (300 MHz)



77


[ppm

] 6

4

2

7.40187.37297.31617.30937.29407.28717.25996.92416.89526.87346.86656.85126.8444

4.5598

M 4.3313

3.84413.82983.8237

3.12742.97602.93662.89802.12632.10832.09982.08792.07612.06922.04982.03742.02861.99731.90781.86661.43491.42231.39281.38151.35221.34051.31131.29841.2538

1.0000.950

1.0280.928

0.957

0.872

2.523

0.962

0.5660.4100.946

1.007

RJ-01-chloride HNMR of 4-MeO-COpip-OC6H4-CH2Cl in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150120-rsj 17 2 (300 MHz)


NO

49

CH3O

O

Cl


7813C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.5582

160.8152159.1219

130.2110129.9774129.0932128.3348

114.7649113.8205

77.580077.156776.733472.2434

55.4731

M 48.354046.3732M 42.5466M 41.8012M 40.962736.4963

29.3294M 28.2609

RJ-01-chloride CNMR of 4-MeO-COpip-OC6H4-CH2Cl in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150120-rsj 18 2(75 MHz)



79

(4-((4-(Fluoromethyl)phenoxy)methyl)piperidin-1-yl) (2-methoxyphenyl)methanone 5 1H NMR at 25 °C

[ppm

] 6

4

2

7.37297.36697.36087.33817.32977.32177.31447.30797.30077.29377.26867.26377.25997.24387.23817.22647.22087.20167.19607.00897.00566.98416.98086.95936.95606.92596.92316.91096.90286.89836.89536.88176.87365.37225.21024.88094.87454.83754.83033.88603.87663.85483.83483.82983.81013.80383.78053.58163.57303.56663.55993.55163.53673.52863.52173.51503.50673.06243.05382.95672.94802.83252.79412.78552.09552.08242.07422.06142.04872.04231.96341.95281.94241.93361.92231.78211.77641.75201.74341.66061.48211.46781.43971.42621.41441.39981.37171.35921.33391.28411.25471.23321.22601.21371.1862

2.9011.234

1.0062.926

1.968

1.000

4.952

1.031

0.5330.5040.5220.504

1.0781.0401.0700.526

1.725

1.060

RJ-02-93-1 HNMR of 2-MeO-COpip-OC6H4-CH2F in CDCl3 at 25 °C (calibrated to 7.2600 ppm)

150714-rsj 9 2 (300 MHz)


NO

CH3O5

O

F


8013C NMR at 25 °C

[ppm

] 1

50

100

5

0

M 170.4462M 170.3514M 167.9967M 167.7605

M 161.5351M 159.6506M 159.6047155.4507

130.3969130.2810130.0292129.9630128.6547128.4246128.0111127.8161M 126.4306M 126.2468M 126.0697M 125.5579M 121.0568121.0123114.6377114.6121111.0746110.9500

85.709083.5298

77.580977.157376.7340M 72.319172.2827

55.712755.5966

47.282946.602641.5794M 41.5268

36.4777

29.7155M 29.663828.820828.7346

RJ-02-93-1 CNMR of 2-MeO-COpip-OC6H4-CH2F in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150714-rsj 10 2 (75 MHz)



8119F NMR at 25 °C

[ppm

]- 5

0 - 1

00

- 150

- 2

00

- 250

-199.1299-199.1870-199.3019-199.3589-199.4740-199.5313

6.335

79.327

8.815

5.523

RJ-02-93-1 19FNMR of 2-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal to ref H7.2600)

150714-rsj 13 2 (282.44 MHz) F:\\ rsj 14



8219F NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.1299

-199.1870

-199.3019

-199.3589

-199.4740

-199.5313

8.815

RJ-02-93-1 19FNMR of 2-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal to ref H7.2600)

150714-rsj 13 2 (282.44 MHz) F:\\ rsj 14



8319F{1H} NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.3032

-199.3608

80.623

0.505

4.024

4.243

0.308

RJ-02-93-1 19F{1H}NMR of 2-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal to ref H7.2600)

150714-rsj 14 2 (282.44 MHz) F:\\ rsj 14



84


[ppm

] 6

4

2

7.30937.30557.30357.29797.27897.25996.97116.96706.95436.95086.94736.94276.93946.93286.92856.91056.90726.88136.8779

5.37245.2105

4.7774

3.85283.84183.83773.83373.8204

3.02933.02652.82952.16862.15622.14762.13542.12992.12302.11722.10882.09652.08422.07602.06992.06332.05772.04582.04102.03642.02421.93471.92421.86601.68601.3672

1.578

2.421

1.000

0.431

2.919

0.493

0.582

0.5350.4790.5460.218

1.122

RJ-02-96-1 HNMR of 3-MeO-COpip-OC6H4-CH2F in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150714-rsj 15 2 (300 MHz)


NO

6CH3OO

F


8513C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.2419

159.7581159.5800159.5364

137.6816

130.0262129.9608129.6939128.6972128.4661

119.0031115.4925114.6391114.6134112.3578

85.694383.5152

77.582177.158576.735072.1934

55.4706

M 47.8110

M 42.2102

36.4681

29.823428.8532M 28.6638

RJ-02-96-1 CNMR of 3-MeO-COpip-OC6H4-CH2F in CDCl3 at 25°C (calibrated to C77.1600 ppm)

150714-rsj 16 2 (75 MHz)



8619F NMR at 25 °C

[ppm

]- 5

0 - 1

00

- 150

- 2

00

- 250

-199.2178-199.3905-199.5618

5.499

77.210

12.549

4.742

RJ-02-96-1 19FNMR of 3-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal in ref to H7.2600)

150714-rsj 19 2 (282.44 MHz) F:\\ rsj 15



8719F NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.2178

-199.3905

-199.5618

77.210

12.549

RJ-02-96-1 19FNMR of 3-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal in ref to H7.2600)

150714-rsj 19 2 (282.44 MHz) F:\\ rsj 15



8819F{1H} NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.2055

-199.3914

-199.4974

-199.7877

12.803

RJ-02-96-1 19F{1H}NMR of 3-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal in ref to H7.2600)

15-714-rsj 20 2 (282.44 MHz) F:\\ rsj 15



89


[ppm

] 6

4

2

7.37157.36247.33427.32687.31977.31237.30517.29767.25996.93226.92306.91606.91186.90866.90086.89366.88286.8794

5.37235.2104

M 4.6524

M 4.08113.85753.83633.8291

M 2.93412.16572.15342.14482.13272.12722.12022.11442.10632.09392.08162.07342.06902.06092.05512.04262.03412.02161.91171.86921.70111.42921.42471.38871.35431.34731.33321.30411.2529

2.0351.958

4.014

1.0000.989

1.117

0.767

1.562 3.497

2.118

1.055

2.048

1.202

2.1900.437

RJ-02-38-1 HNMR of 4-MeO-COpip-OC6H4-CH2F in CDCl3 at 25°C (calibrated to H7.2600 ppm)

150309-rsj 1 2 (300 MHz)


NO

7

CH3O

O

F


9013C NMR at 25 °C

[ppm

] 1

50

100

5

0

170.5400

160.7927159.6103159.5658

130.0284129.9629129.0668128.6838128.4486

114.6522114.6254113.8127

85.706983.5272

77.580577.157176.733572.2500

55.4665

M 45.6127

M 40.7925

36.5206

29.3474M 28.3406

RJ-02-38-1 CNMR of 4-MeO-COpip-OC6H4-CH2F in CDCl3 at 25 °C (calibrated to C77.1600ppm)

150309-rsj 2 2 (75 MHz)



9119F NMR at 25 °C

[ppm

]- 5

0 - 1

00

- 150

- 2

00

- 250

-199.1876-199.3587-199.5316

5.889

0.993

78.410

9.340

5.368

RJ-02-38-1 19FNMR of 4-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (calibrated with ref to H7.2600)

150309-rsj 3 2 (282.44 MHz) F:\\ rsj 33



9219F NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.1876

-199.3587

-199.5316

78.410

9.340

RJ-02-38-1 19FNMR of 4-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (calibrated with ref to H7.2600)

150309-rsj 3 2 (282.44 MHz) F:\\ rsj 33



9319F{1H} NMR at 25 °C (–200 to –198 ppm)

[ppm

]- 1

98.5

- 1

99.0

- 1

99.5

-199.3612

13.963

RJ-02-38-1 19F{1H}NMR of 4-MeO-COpipCH2-OC6H4-CH2F in CDCl3 at 25 °C (cal in ref to H7.2600)

150309-rsj 6 2 (282.44 MHz) F:\\ rsj 33



94

(4-((1-(4-Methoxybenzyl)piperidin-4-yl)methoxy)phenyl)methanol 56

1H NMR at 25 °C

[ppm

] 6

4

2

7.27647.26197.25997.24337.22896.87126.86786.86336.86006.85686.85236.8489

4.6059

3.80133.79183.7817

3.4647

2.93832.9192

2.00491.98631.96801.81871.81481.80861.79951.79471.78461.77751.77151.76661.70911.43541.43041.42761.41121.39461.39011.38111.3730

1.322 0.966

0.987 0.959

0.043 0.9880.037

1.577 0.935

0.995

1.000

1.025

1.7111.063

1.0700.558

RJ-03-06-1 HNMR for 4-MeO-CH2pipCH2-OC6H4-CH2OH in CDCl3 at 25 °C (calibrated to H7.2600 ppm)

150929-rsj 13 2 (600 MHz) (from LAH reduction of fluoromethylamide)


NO

56

CH3OOH


9513C NMR at 25 °C

[ppm

] 1

50

100

5

0

158.9260158.8515

133.1733130.6288M 130.2199128.7663

114.6821113.6933

77.368877.157276.945572.8539

65.202362.9039

55.391253.3205

36.0174

29.837829.1297

RJ-03-06.1 CNMR of 4-MeO-CH2pipCH2-OC6H4-CH2OH in CDCl3 at 25 °C (calibrated to C77.1600 ppm)

150930-rsj 13 2 (150 MHz) (from LAH reduction of fluoromethylamide)


in pursuit of fluorinated sigma receptor ligand · in pursuit of fluorinated sigma receptor ligand...

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