ars.els-cdn.com · Web viewTo a solution of the crude mesylate (1.3 g, 4.58 mmol) in dry MeCN (40...

Substituted pyrazolones require N2 hydrogen bond donating ability to protect

against cytotoxicity from protein aggregation of mutant superoxide dismutase 1

Paul C. Trippiera, Radhia Benmohammedb, Donald R. Kirschb, and Richard B.

Silverman*a,c

a Department of Chemistry, Northwestern University, Evanston, Illinois, USA.

b Cambria Pharmaceuticals, Cambridge, Massachusetts, USA.

c Department of Molecular Biosciences, Center for Molecular Innovation and Drug

Discovery, Chemistry of Life Process Institute, Northwestern University, Evanston,

IL, USA.

* Corresponding author. Department of Chemistry, Northwestern University, 2145

Sheridan Road, Evanston, IL 60208-3113. Phone: 1-847-491-5653. Fax: 1-847-491-

7713. E-mail: [email protected].

Supporting Information

1

Contents:

3. Mutant SOD1-induced cytotoxicity protection bioassay procedure.

4. General experimental procedures.

5. Synthetic details and characterization for compounds 5a-w, 7-9, 11-13,

15-18, 20-22.

2

Mutant SOD1-Induced Cytotoxicity Protection Assay.

Viability and EC50 values of 5a-w were determined according to the previously

reported assay procedure (Ref. 13 of the manuscript). PC12 cells expressing

fluorescent protein fused mutant G93A SOD1 were seeded at 15,000

cells/well in 96-well plates and incubated for 24 h prior to compound addition.

DMSO was utilized as a negative control and 700 nM radiciol as positive

control. Compounds (in DMSO) were assayed in 12-point dose−response

experiments to determine potency and efficacy. The highest compound

concentration tested was 32 μM, which was decreased by one-half with each

subsequent dose to the lowest concentration of 0.0156 μM. After 24h of

incubation with the compounds, MG132 was added at a final concentration of

100 nM. MG132 is a well-characterized proteasome inhibitor, which increases

the appearance of G93A SOD1 protein aggregates by blocking the

proteosomal clearance of aggregated proteins. G93A mutant SOD1

aggregates are toxic in this cellular model and thus cell viability was

measured 48 h later using a fluorescent viability probe, Calcein-AM

(Molecular Probes). Briefly, cells were washed twice with PBS, Calcein-AM

was added at a final concentration of 1 μM for 20 min at room temperature,

and fluorescence intensity was read in a POLARstar fluorescence plate

reader (BMG). Fluorescence data were coupled with compound structural

data, then stored and analyzed using the CambridgeSoft Chemoffice

Enterprise Ultra software package.

3

General Experimental Procedures

All reactions were carried out in oven- or flame-dried glassware open to the

air unless otherwise noted. All reactions were monitored by analytical thin

layer chromatography using Whatman precoated silica gel glass plates.

Visualization was accomplished by UV light (256 nm) or by potassium

permanganate and/or phosphomolybdic acid solution as indicator. Flash

column chromatography was performed using silica gel 60 (mesh 230-400)

supplied by E. Merck. Commercial grade solvents and reagents were

obtained from Sigma Aldrich, Pierce Biotechnology, or Alfa Aesar and used

without further purification except as indicated. Tetrahydrofuran was distilled

from sodium benzophenone ketyl under an atmosphere of dry argon. 1H, 13C, COSY, HMQC and DEPT NMR spectra were recorded on a Bruker

Advance III (500 MHz 1H, 125.77 MHz 13C) equipped with a DCH Cryo-Probe.

Multiplicities are indicated by s (single), d (doublet), dd (doublet of doublets) t

(triplet), q (quartet), m (multiplet), br (broad). Chemical shifts are reported in

parts per million (ppm, δ) using CDCl3 (1H 7.26 ppm, 13C 77.36 ppm) and

MeOH-d4 (1H 3.31 ppm, 13C 49.00 ppm) as internal standards. N.O.e

experiments were performed on a Varian Inova (500 MHz) or Varian Inova

(400 MHz) spectrometer. High resolution mass spectrometry was performed

on a VG70-250SE mass spectrometer. High pressure liquid chromatography

was performed on a Beckman System Gold chromatograph (Model 125P

solvent module and Model 166 detector) with a Vydac (C18, 5μm, 90Å,

4.6mm x 250mm) column (Grace, Deerfield, IL), all samples were assessed to

possess >92% purity.

4

General method for the preparation of substituted pyrazolones (5a-w)

To a solution of β-keto ester 4 (100 mg, 0.38 mmol) in EtOH (10 mL) was

added the substituted hydrazine (2 equiv. 0.76 mmol) and the solution stirred

at room temperature over night. The solvent was removed in vacuo and the

residue purified by column chromatography (20:1 DCM:MeOH) to provide the

title compound. NMR data is reported for the major tautomer observed.

For detailed synthesis of compounds 2-4 and 5a-c see Ref 15 in the main

article.

5

(3aS,4S,6aR)-4-(5-(3-((3,5-dichlorophenoxy)methyl)-5-oxo-2,5-dihydro-1H-

pyrazol-1-yl)-5-oxopentyl)tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one (5d): To a solution of ethyl 4-(3,5-dichlorophenoxy)-3-oxobutanoate (92.6 mg, 0.35

mmol) in DMSO-d6 was added (+)-biotin hydrazide (100 mg, 0.39 mmol), and

the solution was stirred at room temperature for 4 days. The solvent was

removed in vacuo to provide the title compound as a yellow powder.1H NMR (500 MHz; DMSO-d6): δH: 1.24-1.41 (2H, m, CH2), 1.42-1.67 (4H, m,

2 x CH2), 2.58 (2H, d, J = 12.83 Hz, CH2S), 2.82 (1H, d, J = 10.90 Hz, CHS),

2.51 (2H, m, CH2), 4.14 (1H, m, CH bridge), 4.31 (1H, t, J = 5.50 Hz, CH

bridge), 4.74 (2H, s, CH2O pyrazolone), 5.03 (1H, s, CH pyrazolone), 6.40

(1H, br. s, NH), 6.47 (1H, br. s, NH), 7.04 (2H, s, ArCH), 7.15 (1H, d, J = 7.0

Hz, ArCH), 10.61 (1H, br. s, NH).13C NMR (125.77 MHz; CDCl3): δC: 24.15 (CH2), 28.06 (CH2), 31.96 (CH2),

38.88 (CH2C(O)), 39.95 (CH2S), 59.29 (CH bridge), 61.16 (CH bridge), 70.88

(CH2O), 72.15 (CH pyrazolone), 114.2 (ArCH), 120.5 (ArCH), 134.40 (ArC-Cl),

162.7 (NHC(O)NH), 167.6 (C(O)), 169.4 (ArC-O), 175.13 (C(O) pyrazolone).

6

N-(15-(3-((3,5-dichlorophenoxy)methyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-

15-oxo-3,6,9,12-tetraoxapentadecyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-

thieno[3,4-d]imidazol-4-yl)pentanamide (5e): To a solution of 4 (26 mg, 0.10

mmol) in DMSO-d6 (4 mL) was added Biotin-PEG4-Hydrazide (50 mg, 0.10

mmol) and the solution stirred at room temperature for 7 days. The orange

solution was concentrated to provide 5e and analyzed immediately.1H NMR (500 MHz; DMSO-d6): δH: 1.30 (2H, m, CH2), 1.49 (2H, m, CH2),

1.60 (2H, m, CH2), 2.07 (2H, t, J = 7.48Hz, CH2C(O)), 2.25 (2H, t, J = 6.52Hz

CH2C(O)), 2.82 (1H, dd, J = 5.00 and 7.67Hz, SCHH’), 3.09 (1H, m, SCHH’),

3.18 (2H, q, J = 6.33 and 12.00Hz, CH2NH), 3.36 (1H, m, SCH), 3.42 (14H, s,

OCH2CH2O), 3.49 (2H, m, OCH2CH2O), 3.59 (2H, t, J = 6.39Hz,

OCH2CH2NH), 4.13 (1H, m, CHbridging), 4.19 (2H, s, CH2(pyrazolone)), 4.31 (1H, t, J

= 7.25Hz, CHbridging), 5.05 (1H, s, CHpyrazolone), 6.40 (2H, d, J = 32.10Hz, NHbiotin),

7.06 (2H, s, ArCH), 7.19 (1H, s, ArCH), 7.87 (1H, t, J = 5.48Hz, CH2NHC(O)),

9.00 (1H, br. s, NHpyrazolone).13C NMR (125.77 MHz; DMSO-d6): δC: 13.95 (CH2), 25.23 (CH2), 27.99

(CH2), 28.17 (CH2), 34.21 (CH2C(O)), 35.04 (CH2C(O)), 38.39 (CH2NH), 45.19

(CH2S), 55.40 (CHS), 59.14 CHbridging), 60.80 (CHbridging), 66.60 (CH2CH2O),

69.11, 69.46, 69.52, 69.62, 69.66, 69.73 (CH2O), 72.32 (CH2OAr), 94.40

(CHpyrazolone), 113.88 (ArCH), 120.21 (ArCH), 134.50 (ArC-Cl), 162.69

(C(O)pyrazolone), 167.00 (ArC-O), 169.48 (C(O)biotin), 172.14 (CHC(O)).

7

5-((3,5-dichlorophenoxy)methyl)-2-(2-hydroxyethyl)-1H-pyrazol-3(2H)-one

(5f): Following the general method 2-hydroxyethylhydrazine was utilized to

afford 5f as a red oil (17 mg, 38%).

Rf: 0.20 (20:1 DCM:MeOH).1H NMR (500 12MHz; CDCl3): δH: 3.72 (2H, s, CH2C(O)), 3.92 (2H, q, J =

4.54Hz,CH2CH2OH), 4.04 (2H, t, J = 4.46Hz, CH2CH2OH), 4.87 (2H, s, OCH2),

6.71 (2H, d, J = 1.62Hz, ArCH), 6.96 (1H, t, J = 1.70Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 50.85 (CH2CH2OH), 53.46 (CH), 59.96

(CH2CH2OH), 63.69 (OCH2), 113.48 (ArCH), 122.20 (ArCH), 135.68 (ArC-Cl),

141.35 (C), 158.76 (ArC-O), 171.31 (C(O)).

m/z (ESI): 301.38 [M-H] (100%), 249.20 (25), 227.14 (70)

HRMS: C12H12Cl2N2O3 requires 302.0225, Found 302.0227.

5-((3,5-dichlorophenoxy)methyl)-2-(3-hydroxypropyl)-1H-pyrazol-3(2H)-one

(5g): Following the general method 3-hydrazinylpropan-1-ol was utilized to

afford 5f as a yellow powder (100 mg, 61%).

Rf: 0.05 (20:1 DCM:MeOH).1H NMR (500 12MHz; CDCl3): δH: 1.77 (2H, m, CH2), 2.92 (2H, t, J =

6.86Hz,CH2), 3.66 (2H, t, J = 6.92Hz, CH2), 4.70 (1H, s, CH), 4.94 (2H, s,

OCH2), 6.68 (2H, d, J = 1.79Hz, ArCH), 6.85 (1H, t, J = 1.69Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 22.49 (CH2), 31.59 (CH2), 50.83 (CH2),

77.60 (OCH2), 82.96 (CH), 113.61 (ArCH), 120.84 (ArCH), 135.59 (ArC-Cl),

157.12 (ArC-O), 158.66 (C), 171.91 (C(O)).

m/z (ESI): 259.26 [MH-PrOH] (100%), 261.27 (65), 260.27 (10).

8

5-((3,5-dichlorophenoxy)methyl)-2-phenyl-1H-pyrazol-3(2H)-one (5h): Following the general method phenylhydrazine was utilized and the solution

heated at 50 oC for 48 hrs to afford 5h as an orange oil (60 mg, 53%).

Rf: 0.90 (10:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.71 (2H, s, OCH2), 5.30 (1H, s CH), 6.91

(2H, d, J = 1.77Hz, ArCH), 7.04 (1H, t, J = 1.77Hz, ArCH), 7.10 (1H, d, J =

1.64Hz, ArCH), 7.19-7.32 (2H, m, ArCH), 7.35-7.55 (2H, m, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 34.33 (CH2C(O)), 71.90 (OCH2), 113.20

(ArCH), 119.69 (ArCH), 121.49 (ArCH), 126.04 (ArCH), 128.96 (ArCH),

135.29 (ArC-Cl), 141.49 ( ArC-O), 151.46 (C), 159.29 (ArC-N), 169.68 (C(O)).

m/z (ESI): 333.27 [M-H] (70%), 335.23 (35), 336.21 (10).

HRMS: C16H11Cl2N2O2 requires: 334.0276, Found: 334.0264.

2-(4-chlorophenyl)-5-((3,5-dichlorophenoxy)methyl)-1H-pyrazol-3(2H)-one

(5i): Following the general method 4-chlorophenylhydrazine hydrochloride and

TEA (2 equiv) were utilized to afford 5i as an orange oil (60 mg, 43%).

Rf: 0.80 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 2.91 (1H, d, J = 5.03Hz, CH), 4.47 (2H, s

CH2O), 6.83 (2H, d, J = 1.72Hz, ArCH), 6.91 (2H, d, J = 8.79Hz, ArCH), 7.05

(1H, t, J = 1.59Hz, ArCH), 7.21 (2H, d, J = 8.79Hz, ArCH).

9

13C NMR (125.77 MHz; CDCl3): δC: 58.26 (OCH2), 67.43 (CH), 113.57

(ArCH), 122.51 (ArCH), 124.24 (ArCH), 129.03 (ArCH), 128.52 (ArC-Cl),

135.83 (ArC-N), 137.79 (ArC-Cl), 143.93 (ArC-O), 157.91 (C), 167.61 (C(O)).

m/z (ESI): 369.21 [MH+] (100%), 368.21 (95).


2-(2,6-dichloro-4-(trifluoromethyl)phenyl)-5-((3,5-dichlorophenoxy)methyl)-1H-

pyrazol-3(2H)-one (5j): Following the general method [2,6-dichloro-4-

(trifluoromethyl)phenyl]hydrazine was utilized to afford 5j as a yellow oil (85

mg, 48%).

Rf: 0.99 (10:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.72 (2H, s CH2O), 4.91 (1H, s, CH), 6.93

(2H, d, J = 1.89Hz, ArCH), 6.98 (1H, t, J = 1.76Hz, ArCH), 7.52 (2H, s, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 62.31 (OCH2), 70.71 (CH), 114.00 (ArCH),

121.68 (ArCH), 121.78 (CF3), 126.25 (ArC-CF3), 135.34 (ArC-Cl), 135.85

(ArC-Cl), 144.30 (ArC-N), 158.92 (C), 168.42 (ArC-O), 171.19 (C(O)).

5-((3,5-dichlorophenoxy)methyl)-2-(2,4-dinitrophenyl)-1H-pyrazol-3(2H)-one

(5k): Following the general procedure 2,4-dinitrophenylhydrazine was utilized

to afford 5k as a yellow powder (85 mg, 53%).

10

Rf: 0.99 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.82 (1H, s CH), 4.96 (2H, s CH2O), 6.96

(2H, d, J = 1.78Hz, ArCH), 7.09 (1H, t, J = 1.68Hz, ArCH), 7.97 (1H, t, J =

9.51Hz, ArCH), 8.31-8.40 (1H, m, ArCH), 9.15 (1H, dd, J = 2.58 and 4.70Hz

ArCH).13C NMR (125.77 MHz; CDCl3): δC: 71.00 (OCH2), 99.91 (CH), 113.87


135.62 (ArC-Cl), 145.54 (ArC-NO2), 158.43 (ArC-O), 166.52 (C), 169.08

(C(O)).

m/z (GCMS): 446 [M-H+Na] (100%).

5-((3,5-dichlorophenoxy)methyl)-2-(4-phenylthiazol-2-yl)-1H-pyrazol-3(2H)-

one (5l): Following the general method 2-hydrazino-4-phenylthiazole was

utilized to afford 5l as a red oil (100 mg, 63%).

Rf: 0.80 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.65 (1H, s, CH), 4.72 (2H, s CH2O), 6.89

(2H, d, J = 1.76Hz, ArCH), 6.99 (1H, t, J = 1.76Hz, ArCH), 7.30 (1H, t, J =

7.40Hz, ArCH), 7.37 (2H, m, ArCH), 7.39 (1H, s, SCH), 7.79 (2H, d, J =

7.40Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 64.89 (OCH2), 70.93 (CH), 104.25 (SCH),

113.97 (ArCH), 121.68 (ArCH), 125.87 (ArCH), 127.73 (ArCH), 128.57

(ArCH), 134.50 (ArC-C), 135.39 (ArC-Cl), 151.23 (NC-Ph), 167.69 (ArC-O),

168.51 (C), 169.46 (C(O)), 169.63 (NCS(N)).

m/z (ESI): 486.37 [M+Na+EtOH] (100%), 950.85 [2M+2EtOH+Na] (99).

HRMS: C21H19Cl2N3O3S requires 463.0524, Found: 463.0536.

11

2-benzyl-5-((3,5-dichlorophenoxy)methyl)-1H-pyrazol-3(2H)-one (5m): Following the general method benzylhydrazine dihydrochloride and TEA (4

equiv.) were utilized to afford 5m as a yellow oil (45 mg, 34%).

Rf: 0.80 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 3.75 (1H, s, CH), 4.75 (2H, s, CH2Ph), 4.85

(2H, s CH2O), 6.82 (2H, d, J = 1.80Hz, ArCH), 7.01 (1H, t, J = 1.74Hz, ArCH),

7.27-7.40 (5H, m, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 38.72 (CH2Ph), 65.71 (OCH2), 113.73


135.66 (ArC-Cl), 136.10 (ArC-N), 153.18 (C), 158.47 (ArC-O), 171.67 (C(O)).

m/z (ESI): 349.37 [MH] (75%)

HRMS: C17H14O2N2Cl2 requires: 348.0432, Found: 348.0431

5-((3,5-dichlorophenoxy)methyl)-2-(3-hydroxybenzyl)-1H-pyrazol-3(2H)-one

(5n): Following the general method 3-hydroxybenzylhydrazine dihydrochloride

and TEA (2 equiv) was utilized to afford 5n as a yellow oil (45 mg, 32%).

Rf: 0.00 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.47 (2H, s, CH2Ph), 4.73 (1H, s, CH), 4.78

(2H, s CH2O), 6.78 (2H, m, ArCH), 6.82 (2H, d, J = 1.77Hz, ArCH), 6.87 (1H,

d, J = 8.43Hz, ArCH), 7.04 (1H, t, J = 1.76Hz, ArCH), 7.20 (1H, t, J = 8.24Hz,

ArCH).

12

13C NMR (125.77 MHz; CDCl3): δC: 53.72 (CH2Ph), 60.80 (OCH2), 67.44 (CH),


(ArCH), 129.95 (ArCH), 135.78 (ArC-Cl), 143.72 (ArC-CH2), 153.51 (ArC-OH),

158.49 (ArC-O), 167.74 (C), 171.79 (C(O)).

m/z (ESI): 365.04 [MH+] (100%), 366.93 (50), 368.23 (25).


5-((3,5-dichlorophenoxy)methyl)-2-(4-methoxybenzyl)-1H-pyrazol-3(2H)-one

(5o): Following the general method 4-methoxybenzhydride was utilized to

afford 5o as a colorless oil (140 mg, 97%).

Rf: 0.10 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 3.58 (3H, s, OCH3), 4.45 (2H, s, CH2Ph), 4.78

(3H, m, CH and CH2O), 6.82 (2H, d, J = 1.85Hz, ArCH), 6.97 (2H, d, J =

8.80Hz, ArCH), 7.02 (1H, t, J = 1.70Hz, ArCH), 7.92 (2H, d, J = 8.59Hz,

ArCH).13C NMR (125.77 MHz; CDCl3): δC: 53.36 (OCH3), 55.37 (CH2Ph), 60.59

(OCH2), 67.23 (CH), 114.06 (ArCH), 122.11 (ArCH), 124.79 (ArC-C), 128.75

(ArCH), 135.53 (ArC-Cl), 158.08 (ArC-OMe), 162.37 (C), 168.10 (C(O)).

3-((3,5-dichlorophenoxy)methyl)-5-oxo-2,5-dihydro-1H-pyrazole-1-

carbaldehyde (5p). Following the general method formic hydrazide was

utilized to afford 5p as a white powder (71 mg, 66%).

Rf: 0.30 (20:1 DCM:MeOH).

13

1H NMR (500 MHz; CDCl3): δH: 4.46 (2H, s, CH2), 4.66 (1H, s, CH), 6.84 (2H,

d, J = 1.63Hz, ArCH), 7.04 (1H, t, J = 1.63Hz, ArCH), 8.68 (1H, d, br. s, CHO).13C NMR (125.77 MHz; CDCl3): δC: 67.46 (OCH2), 71.04 (CH), 113.79

(ArCH), 122.45 (ArCH), 135.73 (ArC-Cl), 157.94 (CHO), 166.13 (ArC-O),

167.22 (C(O)), 167.61 (C).

m/z (ESI): 285.51 [M-H] (100%), 287.51 (64).


2-acetyl-5-((3,5-dichlorophenoxy)methyl)-1H-pyrazol-3(2H)-one (5q): Following the general method acetylhydrazide was utilized to afford 5q as a

white powder (60 mg, 99%).

Rf: 0.80 (10:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 2.30 (3H, s, C(O)CH3), 4.67 (1H, s, CH), 4.77

(2H, s, CH2), 6.85 (2H, d, J = 1.44Hz, ArCH), 6.99 (1H, t, J = 1.44Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 20.39 (CH3), 65.40 (CH), 72.21 (OCH2),

113.79 (ArCH), 123.87 (ArCH), 135.73 (ArC-Cl), 167.07 (C), 169.64

(C(O)CH3), 173.69 (C(O)), 174.18 (ArC-O).

m/z (ESI): 299.47 [M-H] (70%), 301.41 (50), 302.41 (5).

HRMS: C14H16Cl2N2O4 [M+EtOH] requires: 346.0487, Found: 346.0501.

3-(3-((3,5-dichlorophenoxy)methyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-3-

oxopropanenitrile (5r): Following the general method 2-cyanoacetohydrazide

was utilized to afford 5r as white powder (71 mg, 57%).

14

Rf: 0.30 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 2.92 (2H, dd, J = 2.09Hz, CH2CN), 4.47 (2H,

s, CH2), 4.66 (1H, s, CH), 6.83 (2H, d, J = 1.78Hz, ArCH), 7.04 (1H, t, J =

1.82Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 25.72 (CH2CN), 67.43 (OCH2), 70.94

(CH), 113.59 (ArCH), 121.91 (CN), 122.32 (ArCH), 135.74 (ArC-Cl), 157.92

(ArC-O), 158.61 (C(O)), 167.03 (C), 167.63 (C(O)CH2CN).

m/z (ESI): 394.29 [M+EtOH+Na] (100%), 396.53 (66).


5-((3,5-dichlorophenoxy)methyl)-2-(thiophene-2-carbonyl)-1H-pyrazol-3(2H)-

one (5s): Following the general method 2-thiophenecarboxcylic acid

hydrazine was heated at reflux for 2 days to afford 5s as a white powder (27

mg, 25%).

Rf: 0.30 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 3.54 (1H, s, CH), 4.80 (2H, s, CH2), 6.91 (2H,

d, J = 1.55Hz, ArCH), 7.00 (2H, t, J = 1.88Hz, ArCH x2), 7.15 (2H, dd, J =

3.71 and 1.05Hz, SCH and SC-CH).13C NMR (125.77 MHz; CDCl3): δC: 78.17 (CH2), 95.54 (CH), 113.81 (ArCH),


(ArCH), 135.36 (ArC-Cl), 135.92 (ArC-C(O)), 158.55 (C), 162.53 (ArC-O),

169.29 (C(O)), 169.45 (C(O)).

m/z (ESI): 437.44 [M+EtOH+Na] (100%), 439.34 (65), 441.34 (15).

15

5-((3,5-dichlorophenoxy)methyl)-2-(4-isothiocyanatobenzoyl)-1H-pyrazol-

3(2H)-one (5t): Following the general procedure 4-

isothiocyanatobenzohydrazide was utilized to afford 5t as a yellow gum (41

mg, 26%).

Rf: 0.30 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 4.91 (2H, s, OCH2), 5.62 (1H, s, CH), 6.70

(2H, d, J = 1.75Hz, ArCH), 6.74 (1H, t, J = 1.75Hz, ArCH), 6.79 (2H, d, J =

1.85Hz, ArCH), 6.82 (2H, d, J = 1.85Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 70.14 (OCH2), 85.65 (CH), 113.87 (ArCH),

121.78 (ArCH), 122.04 (ArCH), 131.18 (ArCH), 135.18 (ArC-NCS), 135.31

(ArC-NCS), 135.45 (ArC-Cl), 158.97 (ArC-O), 167.86 (C), 168.96 (C(O)).

m/z (ESI): 870.70 [2M+S] (80%), 446.09 [MH+CN] (40).

5-((3,5-dichlorophenoxy)methyl)-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-

pyrazol-3(2H)-one (5u): Following the general method 4-methyl-1,2,3-

thiadiazole-5-carboxylic acid hydrazide was utilized to afford 5u as a white

powder (60 mg 41%).

Rf: 0.10 (20:1 DCM:MeOH).1H NMR (500 MHz; CDCl3): δH: 2.19 (3H, s, CH3), 4.47 (2H, s, OCH2), 4.83

(1H, s, CH), 6.83 (2H, d, J = 1.74Hz, ArCH), 7.04 (1H, t, J = 1.74Hz, ArCH).

16

13C NMR (125.77 MHz; CDCl3): δC: 13.75 (CH3), 67.40 (OCH2), 70.08 (CH),

113.76 (ArCH), 122.51 (CN), 135.41 (ArC-CH3), 135.76 (ArC-Cl), 152.60 (SC-

C(O)), 159.56 (ArC-O), 160.54 (C(O)), 161.86 (C), 164.05 (NC(O)S).

m/z (ESI): 453.40 [M+Na+EtOH] (100%), 385.37 [MH+] (10).

HRMS: C16H16Cl2N4O4S [M+EtOH] requires: 430.0269, Found: 430.0274.

2-(4-aminobenzoyl)-5-((3,5-dichlorophenoxy)methyl)-1H-pyrazol-3(2H)-one

(5v): Following the general method 4-aminobenzoic hydrazide was utilized to

afford 5v as a white powder (138 mg, 96%).


(2H, d, J = 8.56Hz, ArCH), 6.83 (2H, d, J = 1.76Hz, ArCH), 7.05 (1H, t, J =

1.76Hz, ArCH), 7.80 (2H, d, J = 8.47Hz, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 58.00 (OCH2), 65.27 (CH), 111.74 (ArCH),

119.94 (ArCH), 120.62 (ArCH), 133.55 (ArCH), 133.84 (ArC-Cl), 148.41 (ArC-

NH2), 156.02 (ArC-O), 156.91 (C(O)N), 165.59 (C), 169.24 (C(O)).

m/z (ESI): 446.38 [M+Na+EtOH] (100%), 448.39 (70), 449.44 (15).

HRMS: C18H17Cl2N3O4 [M+EtOH] requires: 409.0596, Found: 409.0611.

17

5-((3,5-dichlorophenoxy)methyl)-2-nicotinoyl-1H-pyrazol-3(2H)-one (5w): Following the general method nicotinic hydrazine was utilized to afford 5w as

a colorless oil (54 mg, 35%).


(2H, d, J = 1.79Hz, ArCH), 7.05 (1H, t, J = 1.69Hz, ArCH), 7.46 (1H, br. s,

ArCH), 8.29 (1H, d, J = 6.90Hz, ArCH), 8.80 (1H, s, ArCH), 9.19 (1H, s,

ArCH).13C NMR (125.77 MHz; CDCl3): δC: 61.62 (CH), 67.43 (OCH2), 113.59 (ArCH),

122.05 (ArCH), 122.32 (ArCH), 135.59 (ArCH), 135.74 (ArC-Cl), 153.21 (C),

157.88 (ArC-O), 158.72 (C(O)), 167.43 (C(O)).

m/z (ESI): 842.94 [2M+2EtOH+Na] (100%), 432.43 [M+EtOH+Na] (25).


4-Bromo-3-(bromomethyl)but-2-enoic acid (7): To a stirred solution of 3,3-

dimethylacrylic acid (1.0 g, 10 mmol) in CCl4 (40 mL) was added NBS (3.93 g,

22 mmol). The solution was heated at reflux for 3 hrs, during which time

benzoyl peroxide (30 mg) was added portionwise at hourly intervals. Reflux

was continued for a further 1 h and the reaction allowed to cool. The yellow

precipitate was removed and the filtrate evaporated in vacuo. Purification by

column chromatography (4 : 1 hexane : EtOAc) provided 7 as a yellow oil.

Rf: 0.03 (4:1 hexane : EtOAc).1H NMR (500 MHz; CDCl3) δH: 3.96 (2H, s CH2), 4.58 (2H, s, CH2), 5.99 (1H,

s, CH), 11.00 (1H, br. s, CO2H).

18

13C NMR (125.77 MHz; CDCl3) δC: 29.24 (CH2), 37.96 (CH2), 118.46 (CH),

155.47 (C), 170.68 (C(O)).

4-(Bromomethyl)furan-2(5H)-one (8): 5% NaOH (100 mL) and 7 (1.98 g, 7.68

mmol) were stirred overnight at room temperature. The reaction was

extracted into DCM (3 x 150 mL), washed with aqueous NaHCO3 and water,

dried (Na2SO4), filtered and concentrated in vacuo. Purification by column

chromatography (4:1 hexane : EtOAc) provided 8 as a mixture of enol – keto

tautomers as a yellow oil (150 mg, 11%).

Rf: 0.00 (4:1 hexane : EtOAc).

Keto tautomer:1H NMR (500 MHz; CDCl3) δH: 4.24 (2H, s, CH2Br), 4.98 (2H, s, CH2), 6.16

(1H, s, CH).13C NMR (125.77 MHz; CDCl3) δC: 41.33 (CH2Br), 74.05 (CH2), 121.09 (CH),

155.42 (C), 178.32 (C(O)).

Enol tautomer:1H NMR (500 MHz; CDCl3) δH: 2.30 (1H, m, CH2CH), 4.20 (2H, m, CH2Br),

4.74 (2H, m, CH2), 6.09 (1H, s, CH), 9.10 (1H, br. s, OH).

m/z (EI): 149 [M-CO-] (100%), 96 (40), 68 (50), 39 (70).

GC: Rf: 6.57 min.

4-((3,5-Dichlorophenoxy)methyl)furan-2(5H)-one (9): To a solution of 3,5-

dichlorophenol (137 mg, 0.84 mmol) in EtOH (10 mL) was added NaOEt (0.32

mL, 0.85 mmol of a 21% wt solution in EtOH) and stirring continued for 10

19

min. A solution of 35 (150 mg, 0.84 mmol) in EtOH (5 mL) was added

dropwise and the reaction mixture heated at 70 oC overnight. The reaction

was allowed to cool, 1M HCl added and extracted with EtOAc, dried (Na2SO4),

filtered and concentrated in vacuo. Purification by column chromatography

(4:1 hexane : EtOAc) provided 9 as a largely insoluble white powder (31 mg,

14%).

Rf: 0.00 (EtOAc).1H NMR (500 MHz; CDCl3) δH: 2.28 (1H, t, J = 6.62 Hz, CH), 2.40 (3H, m,

OCH2CH & CHH’OAr), 3.73 (1H, q, J = 7.06 & 7.29 Hz, CHH’OAr), 6.79 (2H,

s, ArH), 7.31 (1H, s, ArH), 11.11 (1H, br. s, OH).13C NMR (125.77 MHz; CDCl3) δC: 52.75 (CH2), 61.05 (CH2), 109.83 (ArCH),

116.39 (CH), 126.16 (ArCH), 134.44 (ArC-Cl), 172.77 (ArC-O), 173.81 (C),

179.40 (C(O)).

m/z (GCMS): 264.58 [M+Li] (100%).

Bicyclo[3.1.0]hexan-2-one (11): To a three-necked round bottomed flask fitted

with a constant flow of nitrogen, a thermometer and an addition funnel was

added anhydrous DMSO (40 mL) and cooled to 0 oC. NaH (800 mg, 20.13

mmol of a 60% dispersion in mineral oil) was added portionwise so as to

maintain the temperature between 20-35 oC. Trimethylsulfoxonium iodide

(4.43 g, 20.13 mmol) was added portionwise over 30 min so as to keep the

reaction temperature < 30 oC, stirring was continued for 1 h in the ice bath.

Cyclopent-1-ene (1.53 mL, 18.3 mmmol) was added dropwise, the white

solution turning orange and was stirred in the ice bath for 30 min and at 50 oC

for 2 h. The reaction was allowed to cool and poured onto ice. The resulting

suspension was filtered and the filtrate extracted with Et2O, dried (Na2SO4),

filtered and concentrated in vacuo (bath temperature < 30 oC) to provide 11 as

a yellow oil (580 mg, 33%).

20

1H NMR (500 MHz; CDCl3) δH: 0.45 (1H, m, C-3a), 0.95 (1H, m, C-2), 1.30

(2H, m, C-3b & C-4), 2.05 (4H, m, C-5 & C-6).13C NMR (125.77 MHz; CDCl3) δC: 13.61 (C-4), 21.78 (C-3), 22.67 (C-5),

27.52 (C-2), 31.46 (C-6), 216.00 (C(O)).

3-(Iodomethyl)cyclopentanone (12): To a mixture of NaI (902 mg, 12.02

mmol) and 11 (580 mg, 6.03 mmol) in dry MeCN (20 mL) under a nitrogen

atmosphere was added chloro-trimethylsilane (1.53 mL, 12.04 mmol) and the

reaction stirred at room temperature for 44 h. The solution was poured onto

5% Na2SO3 saturated with KF and extracted into Et2O, the combined organic

layers were washed with brine and water, dried (Na2SO4), filtered and

concentrated in vacuo to provide 12 as a dark orange oil (530 mg, 39%).1H NMR (500 MHz; CDCl3) δH: 1.62 (2H, m, C-1a & C-4a), 2.00 (1H, m, C-

5a), 2.29 (1H, m, C-4a), 2.45 (3H, m, C-2 & C-1b & C-5b), 3.29 (2H, m, CH2I).13C NMR (125.77 MHz; CDCl3) δC: 11.25 (CH2I), 30.12 (C-4), 36.20 (C-5),

39.05 (C-1), 46.97 (C-2), 220.01 (C(O)).

3-((3,5-dichlorophenoxy)methyl)cyclopentanone (13): To a solution of 3,5-

dichlorophenol 184 mg, 1.13 mmol) in EtOH (20 mL) at 0 oC was added

NaOEt (0.46 mL, 1.14 mmol of a 21%wt solution in EtOH) and stirring was

continued for 10 mins. A solution of 12 (200 mg, 1.13 mmol) in EtOH (10 mL)

was added dropwise at 0 oC and the solution heated at 90 oC overnight. 1M

HCl was added and the organic layer separated, the aqueous layer was

extracted with EtOAc and the combined organic layers dried (Na2SO4), filtered

and concentrated in vacuo. The residue was purified by column

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chromatography (3:1 hexane:EtOAc) to provide 13 as a yellow oil (90 mg,

27%).

Rf: 0.33 (3:1 hexane:EtOAc).1H NMR (500 MHz; CDCl3) δH: 1.70-2.12 (6H, m, 3x CH2), 2.42 (1H, m, CH),

3.40 (1H, m, CHH’O), 3.48 (1H, m, CHH’O), 6.74 (2H, d, J = 1.72Hz, ArCH),

ArCH), 6.79 (1H, t, J = 1.72Hz, ArCH).13C NMR (125.77 MHz; CDCl3) δC: 25.42 (CH2), 28.90 (CH), 37.35 (CH2),

48.27 (CH2), 58.54 (CH2), 114.80 (ArCH), 120.30 (ArCH), 135.20 (ArC-Cl),

158.33 (ArC-O), 204.83 (C(O)).

m/z (ESI): 277.18 [M+NH4+] (100%), 257.26 [MH] (80), 255.24 (45), 251.04

(25).

ethyl 4-bromobut-2-ynoate (15): To a solution of propargyl bromide (1 mL,

11.22 mmol) in dry Et2O (30 mL) at -40 oC was added nBuLi (1.26 mL, 13.46

mmol of a 1.6M solution in hexanes) under N2 and stirring continued for 1 h.

A solution of ethyl chloroformate (2.14 mL, 22.44 mmol) in dry Et2O (10 mL)

was added dropwise and stirring continued at -40 oC for 1 h. The yellow

solution was allowed to warm to room temperature, aqueous NaHCO3 was

added and the aqueous layer extracted with Et2O, the combined organic

layers were dried (Na2SO4), filtered, and concentrated. Purification by column

chromatography (4:1 hexane:EtOAc) provided 15 as a colorless oil (225 mg,

1.18 mmol).

Rf: 0.75 (4:1 hexane:EtOAc).1H NMR (500 MHz; CDCl3) δH: 1.34 (3H, t, J = 6.98 Hz, CH2CH3), 3.98 (2H, s,

CH2), 4.28 (2H, q, J = 7.03 Hz, CH2CH3).13C NMR (125.77 MHz; CDCl3) δC: 11.30 (CH2Br), 13.77 (OCH2CH3), 62.23

(OCH2CH3), 69.91 (C(O)CC), 81.32 (CC-CH2), 152.76 (C(O)).

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5-(bromomethyl)isoxazol-3(2H)-one (16): To a solution of 15 (225 mg, 1.18

mmol) in MeOH (15 mL) at -40 oC was added aqueous hydroxylamine (0.5

mL) and stirring continued for 15 mins. The solution was adjusted to pH 8.5 –

9.0 by addition of 1M NaOH, allowed to warm to room temperature and stirred

overnight. EtOAc was added and the solution extracted, dried (Na2SO4),

filtered, and concentrated. Recrystallization from hexanes provided 16 as

yellow crystals (98 mg, 0.55 mmol).1H NMR (500 MHz; d4-MeOH) δH: 4.37 (2H, s, CH2), 5.91 (1H, s, CH), 8.00

(1H, br. s, NH).13C NMR (125.77 MHz; d4-MeOH) δC: 31.36 (CH2), 94.97 (CH), 155.70

(C(O)), 159.52 (C).

5-((3,5-dichlorophenoxy)methyl)isoxazol-3(2H)-one (17): To a solution of 3,5-

dichlorophenol (90 mg, 0.5 mmol) in EtOH (25 mL) was added NaOEt (0.22

mL of a 21%wt solution in EtOH) and the reaction stirred at room temperature

for 10 mins. A solution of 16 (98 mg, 0.55 mmol) in EtOH (5 mL) was added

dropwise and the solution heated at 70 oC overnight. The yellow solution was

allowed to cool, 1M HCl added and extracted with EtOAc, dried (Na2SO4),

filtered, and concentrated. Purification by column chromatography (10:1

DCM:MeOH) provided 17 as a yellow oil (28 mg, 0.11 mmol).

Rf:0.10 (10:1 DCM:MeOH).1H NMR (500 MHz; CDCl3) δH: 3.53 (2H, s, CH2), 6.23 (1H, s, CH), 6.78 (2H,

d, J = 1.79 Hz, ArCH), 6.97 (1H, t, J = 1.74 Hz, ArCH), 8.04 (1H, br, s. NH).13C NMR (125.77 MHz; CDCl3) δC: 95.16 (CH2), 99.17 (CH), 114.66 (ArCH),

121.07 (ArCH), 135.39 (ArC-Cl), 156.49 (ArC-O), 173.71 (C(O)), 185.81 (C).

23

m/z (ESI): 161.25 [Cl2C6H3OH] (100%), 327.25 [M-H+Na+EtOH] (20).

1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one (19): To a solution of methyl-1-

benzyl-5-oxo-3-pyrrolidinecarboxylate (1.5 g, 6.4 mmol) in dry THF (50 mL)

under nitrogen was added LiBH4 (280 mg, 12.85 mmol), and the solution was

stirred at room temp overnight. The reaction was quenched with 1M HCl and

extracted with Et2O. The combined organic layers were dried (Na2SO4),

filtered, and concentrated in vacuo to provide 19 as a colorless oil, which

crystallized upon standing (1.30 g, 99%).1H NMR (500 MHz; CDCl3): δH: 2.20 (1H, m, CH), 2.45 (2H, m, CH2C(O)),

3.04 (1H, m, CHH’N), 3.28 (1H, m, CHH’OH), 3.48 (2H, m, CHH’OH and

CHH’N), 4.35 (2H, m, CH2Ar), 7.24 (5H, m, ArCH), 16.90 (1H, br. s, OH).13C NMR (125.77 MHz; CDCl3): δC: 27.10 (CH), 33.16 (CH2C(O)), 46.60

(NCH2), 49.34 (CH2Ar), 64.50 (CH2OH), 127.66, 127.84, 129.12, 129.94,

130.38 (all ArCH), 136.21 (ArC-CH2), 174.27 (C(O)).

m/z (ESI): 228.19 [MNa+] (65%), 206.27 [MH+] (100).

HRMS: C12H15NO2 requires: 205.1107, Found: 205.1103.

Synthesis of 1-benzyl-4-(bromomethyl)pyrrolidin-2-one (20): To a solution of

19 (1.23 g, 6.0 mmol) in DCM (30 mL) at 0 oC was added NEt3 (1.04 mL, 7.5

mmol) and methanesufonylchloride (0.48 mL, 6.2 mmol). Stirring was

continued at 0 oC for 1 h. Water was added to the cloudy solution, and the

aqueous layer that separated was extracted with DCM. The combined

organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to

provide the crude mesylate as an orange oil (1.30 g, 4.58 mmol), which was

taken forward without further purification.

To a solution of the crude mesylate (1.3 g, 4.58 mmol) in dry MeCN (40 mL)

was added LiBr (478 mg, 5.5 mmol), and the yellow solution was heated at

reflux under nitrogen overnight. The reaction was allowed to cool, 1M HCl

24

was added and the mixture was extracted with EtOAc. The combined organic

layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification

by column chromatography (EtOAc) provided 20 as a colorless oil (520 mg,

32%).

Rf: 0.42 (2:1 DCM:EtOAc)1H NMR (500 MHz; CDCl3): δH: 2.35 (1H, dd, J = 8.41 and 10.09 Hz, CHH’-3),

2.68 (1H, dd, J = 8.08 and 10.09 Hz, CHH’-3), 2.79 (1H, m, CH-4), 3.11 (1H,

dd, J = 5.89 and 4.31 Hz, CH), 3.37 (1H, m, CH), 3.44 (2H, m, 2 x CH), 4.47

(2H, m, CH2Ph), 7.32 (5H, m, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 29.78 (CH), 33.53 (CH2C(O)), 35.80

(CH2Br), 46.60 (CH2Ar), 51.08 (CH2N), 127.77, 128.19, 128.32, 128.39,

128.63 (all ArCH), 136.07 (ArC), 172.94 (C(O)).

m/z (ESI): 268.02 (100%) [MH+], 270.37 (100) [MH+]

HRMS: C12H14BrNO requires: 267.0259, Found: 267.0258.

1-benzyl-4-((3,5-dichlorophenoxy)methyl)pyrrolidin-2-one (21): To a solution

of 3,5-dichlorophenol (211 mg, 1.31 mmol) in dry DMF (10 mL) was added

NaOEt (0.52 mL, 1.21 mmol of a 21%wt solution in EtOH), and stirring was

continued for 30 min. A solution of 20 (350 mg, 1.3 mmol) in dry THF (10 mL)

was added dropwise, and the solution was heated at reflux for 24 h. The

orange solution was allowed to cool, 1M HCl added, and the mixture was

extracted with EtOAc. The combined organic layers were washed with water

and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by

column chromatography (4:1 hexane : EtOAc) provided (21) as a dark orange

oil (123 mg, 28%).

Rf: 0.05 (4:1 hexane:EtOAc)1H NMR (500 MHz; CDCl3): δH: 2.36 (1H, dd, J = 6.05 and 17.02 Hz, CHH’-3),

2.68 (1H, dd, J = 9.06 and 16.82 Hz, CHH’-3), 2.84-2.77 (1H, m, CH-4), 3.16

25

(1H, dd, J = 5.39 and 10.37 Hz, CHH’-5), 3.46 (1H, dd, J = 8.06 and 10.14 Hz,

CHH’-5), 3.83 (1H, dd, J = 7.22 and 8.89 Hz, CHH’O), 3.90 (1H, dd, J = 5.70

and 9.03 Hz, CHH’O), 4.47 (2H, s, CH2Ar), 6.73 (2H, d, J = 1.75 Hz, ArCH),

6.96 (1H, t, J = 1.75 Hz, ArCH), 7.24-7.39 (5H, m, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 30.68 (C-4), 33.96 (C-3), 46.63 (CH2Ar),

49.24 (C-5), 70.23 (CH2O), 113.55 (ArCH), 121.55 (ArCH), 127.78, 128.20,

128.79 (all ArC), 135.48 (ArC-Cl), 146.3 (ArC-O), 173.68 (C(O)).

m/z (ESI): 372.27 [MNa+], (35%), 350.37 [MH+], (100), 352.33 (70), 353 (10).

HRMS: C18H17Cl2NNaO2 requires: 349.0636, Found: 349.0633.

1-benzyl-4-((3,5-dichlorophenoxy)methyl)-1H-pyrrol-2(5H)-one (22): To a

solution of dry diisopropylamine (40 μL, 0.29 mmol) in dry THF (8 mL) at -

78oC under N2 was added nBuLi (0.14 mL of a 2.0M solution in hexanes) and

stirring continued for 15 mins. A solution of 21 (84 mg, 0.24 mmol) in dry THF

(2 mL) was added dropwise and stirring continued for 15 mins. A solution of

PhSeBr (113 mg, 0.48 mmol) in dry THF (2 mL) was added rapidly and the

cold solution poured onto HCl:Et2O (1:1, 25 mL), the organic layer was

separated, washed with water, NaHCO3, brine, dried (Na2SO4), filtered and

concentrated. The crude orange oil (150 mg, 0.29 mmol) was dissolved in

DCM and the solution cooled to 0oC. Pyridine (0.12 mL, 0.6 mmol) and H2O2

(2 mL, of a 30% solution in water) was added dropwise and the solution

allowed to warm to room temperature over 2 h. The orange solution was

poured onto DCM:NaHCO3 (1:1 25 mL) and the aqueous layer separated and

extracted with DCM. The combined organic layers were washed with HCl,

brine, dried (Na2SO4), filtered and concentrated. Purification by column

chromatography (4:1 hexane:EtOAc) provided 22 as an orange oil (25.5 mg,

27%).

Rf: 0.1 (4:1 hexane:EtOAc)

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1H NMR (500 MHz; CDCl3): δH: 3.52 (2H, s, CH2NBn), 4.31 (2H, s, OCH2),

4.95 (2H, s, CH2Ph), 6.20 (1H, s, CH), 6.84 (2H, d, J = 1.60Hz, ArCH), 7.03

(1H, t, J = 1.60Hz, ArCH), 7.30-7.40 (5H, m, ArCH).13C NMR (125.77 MHz; CDCl3): δC: 43.00 (CH2NBn), 63.87 (CH2Ph), 81.92

(OCH2), 113.73 (ArCH), 115.06 (CH), 122.05 (ArCH), 127.82 (ArCH), 128.27

(ArCH), 128.90 (ArCH), 135.64 (ArC-Cl), 142.84 (ArC-CH2), 154.78 (C),

158.75 (ArC-O), 168.47 (C(O)).

m/z (ESI): 348.42 [MH+] (100%), 350.44 (80), 352.30 (20).

HRMS: C18H15Cl2NNaO2 requires: 347.0480, Found: 347.0496.

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