Synthesis of New Propargylated 1-Pyrindane Derivatives as Rasagiline Analogues

Article abstract of DOI:10.1055/s-0032-1318492

Rasagiline is a compound with important neuroprotective activity applicable to the treatment of neurodegenerative diseases. This work describes an easy and straightforward methodology to the synthesis of new propargylated rasagiline analogues derived from commercially available 6,7-dihydro-5H-cyclopenta[b] pyridine. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318492

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Supporting Information
for DOI: 10.1055/s-0032-1318492
©
Georg Thieme Verlag KG Stuttgart · New York 2013
Thieme

Synthesis of New Propargylated 1-Pyrindane
Derivatives as Rasagiline Analogues
a
a
a
b
Cidália Silva Pereira, Sofia Salgado, Fabio Rizzo-Aguiar, Xerardo Garcia-Mera,
a
and José E. Rodríguez-Borges *
a
Centro de Investigação em Química, Department of Chemistry and Biochemistry,
Faculty of Science, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto,
Portugal
b
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago
de Compostela, E-15782 Santiago de Compostela, Spain
jrborges@fc.up.pt
Supplementary Data
Table of contents
1
13
Experimental Procedure, H, C-NMR, ESI-MS and R data for the synthesized
f
compounds
2
7
1
13
H and C NMR spectra
HR-ESI-FIA-TOF spectra
14

6
,7-dihydro-5H-cyclopentapyridine-N-oxide (5). 3-chloroperbenzoic acid (3.84 g;
17.1 mmol) was slowly added to a solution of 4 (2.04 g, 17.1 mmol) in DCM. The
mixture was stirred at room temp. for 2 hours. The solvent was evaporated under
reduced pressure and the crude purified by chromatographic column (ethyl acetate)
1
giving 2.30 g of a white solid (K=99%). H NMR (CDCl , 400 MHz,), G(ppm): 2.12
3
(
2H, q, J=7.6 Hz, CH ); 2.96 (2H, t, J=7.6 Hz, CH ); 3.11 (2H, t, J=8.0 Hz, CH ), 6.99-
2 2 2
1
3
7
.06 (2H, m, Harom), 7.98 (1H, d, J=7.2 Hz, Harom). C NMR (CDCl , 100 MHz) δ
3
(
ppm): 22.84 (CH ), 30.34 (CH ) 32.40 (CH ), 123.45 (Cpara), 124.71 (Cmeta), 138.04
2 2 2
+
(
Cortho), 143.10 (Cipso) e 153.89 (Cipso). ESI-MS: calculated for [C H NO + H] (M
8 9
+
+
H ) 136.07, obtained 136.27; Rf = 0.05 (ethyl acetate); m.p. = 121-123 ºC
6
,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6). A solutiom of 5 (1.66 g, 12.3
mmol) in acetic anhydride (15.0 mL) was heated to 100ºC for 2 hours. The anhydride
excess was evaporated under reduced pressure. Column chromatography purification
1
using ethyl acetate as eluent gave 1.57 g of an orange oil (K=72%). H NMR (CDCl ,
3
4
2
5
00 MHz), G(ppm): 2.03-2.10 (1H, m), 2.12 (3H, s, OC(O)CH ), 2.60-2.69 (1H, m),
3
.85-2.93 (1H, m), 3.07 (1H, ddd, J =5.1 Hz, J =8.9 Hz, J =14.6 Hz), 6.13 (1H, dd, J =
1
2
3
1
.0 Hz, J =7.4 Hz), 7.19 (1H, dd, J =4.9 Hz, J =7.7 Hz, Harom), 7.60 (1H, dd, J =1.1
2
1
2
1
1
3
Hz, J =7.7 Hz, Harom), 8.55 (1H, d, J=4.9 Hz, Harom). C NMR (CDCl , 100 MHz)
2
3
δ (ppm): 22.11 (OCOCH ), 28.64 (CH ), 31.66 (CH ), 78.08 (CH), 124.27 (Cmeta),
3
2
2
1
34.10 (Cipso), 138.35 (Cpara), 149.68 (Corto), 161.30 (Cipso), 171.72 (OCOCH3).
+
+
ESI-MS: calculated for [C H NO + H] (M + H ) 178.08, obtained 178.10; Rf = 0.44
10
11
2
(ethyl acetate).
2

6
,7-dihydro-5H-ciclopenta[b]pyridin-7-ol (7). A solution of KOH (0.25, 4.54 mmol)
in ethanol (5.00 mL) was added to a solution of 6 (0.80 g, 4.54 mmol) in ethanol (2.00
mL). After stirring for 1 hour at r.t., the mixture was extracted with DCM and the
organic layer washed with brine. The combined organic layers were dried over
anhydrous Na SO . The solvent was evaporated and the crude purified by column
2
4
1
chromatography (ethyl acetate) to afford 0.55 g (K=90%) of a light brown solid. H
NMR (CDCl , 400 MHz), G(ppm): 2.05-2.14 (1H, m), 2.52-2.61 (1H, m), 2.80-2.88
3
(
(
1H, m), 3.07 (1H, ddd, J =4.3 Hz, J =8.9 Hz, J =13.2 Hz), 4.76 (1H, bs, -OH), 5.28
1 2 3
1H, app t, J= 6.00 Hz), 7.16 (1H, dd, J =5.0 Hz, J =7.6 Hz, Harom), 7.59 (1H, dd,
1
2
13
J =0.6 Hz, J =7.6 Hz, Harom), 8.43 (1H, d, J=4.9 Hz, Harom). C NMR (CDCl , 100
1
2
3
MHz) δ (ppm): 28.41 (CH ), 33.65 (CH ), 74.83 (CH-OH), 123.57 (Cmeta), 134.44
2
2
(Cipso), 137.54 (Cpara), 148.45 (Cortho) e 166.04 (Cipso). ESI-MS: calculated for
+
+
[
C H NO + H] (M + H ) 136.07, obtained 136.07; Rf = 0.16 (ethyl acetate); m.p. = 80-
8 9
8
3 ºC
7-(prop-2-yn-1-yloxy)-6,7-dihydro-5H-cyclopena[b]pyridine (±1). To a solution of 7
(1.22 g; 9.03 mmol) in DCM, potassium terc-butoxide (1.01 g; 9.03 mmol) in DMF and
propargyl chloride (0.98 mL; 13.50 mmol) were added. The system was stirred under
argon atmosphere overnight and at r.t.. A saturated solution of NaHCO was added and
3
the organic layer separated. The aqueous phase was extracted with DCM and the
organic layers washed with brine and dried over anhydrous Na SO . After solvent
2
4
1
evaporation, chromatographic purification yielded 0.80 g (K=50%) of a dark oil. H
NMR (CDCl , 400 MHz), G(ppm): 2.09-2.16 (1H, m), 2.32-2.39 (1H, m), 2.42 (1H, t,
3
J=2.4 Hz, OCH CCH), 2.77 (1H, ddd, J =4.6 Hz, J =8.7 Hz, J =13.3 Hz), 3.00-3.08
2
1
2
3
(
1H, m), 4.38 (1H, dd, J =2.4 Hz, J =15.6 Hz, OCHHCCH), 4.46 (1H, dd, J =2.4 Hz,
1 2 1
J =15.7 Hz OCHHCCH) 4.98 (1H, dd, J = 3.7 Hz, J = 7.0), 7.10 (1H, dd, J =4.9 Hz,
2
1
2
1
3

J =7.6 Hz, Harom), 7.51 (1H, dd, J =0.6 Hz, J =7.6 Hz, Harom), 8.39 (1H, d, J=4.9 Hz.
2
1
2
1
3
Harom). C NMR (CDCl , 100 MHz), G(ppm): 28.78 (CH ), 31.66 (CH ), 57.45
3
2
2
(
OCH CCH), 75.14 (OCH CCH), 81.08 (OCH CCH), 81.84 (CH), 124.01 (Cmeta),
2 2 2
1
33.97 (Cpara), 138.21 (Cipso), 148.94 (Cortho), 163.40 (Cipso). HR-ESI-MS:
+
+
calculated for [C H NO + H] (M + H ) 174.0913, obtained 174.0917; Rf = 0.65
1
1
11
(ethyl acetate).
5
H-cyclopenta[b]pyridin-7(6H)-one (9). A solution of DMSO (1.28 mL; 18.0 mmol)
anhydrous DCM was added dropwise to a cooled solution (-78 °C) of (COCl) (0.79
2
mL; 9.01 mmol) in anhydrous DCM. 15 minutes later, a solution of 7 (1.22 g; 9.01
mmol) and Et N (5mL, 36.0 mmol) were added dropwise. The system was stirred under
3
argon atmosphere for 24 hours. After addition of 40.0 mL of water, the organic layer
was separated. The aqueous phase was extracted with DCM and the organic layers
washed with NaHCO3 and brine, and dried over anhydrous Na SO . The
2
4
1
chromatographically purified crude gave 0.84 g (K=70%) of a greenish solid. H NMR
CDCl , 400 MHz), G(ppm): 2.76-2.79 (2H, m); 3.19 (2H, tapp, J =6,0 Hz); 7.46 (1H,
(
3
dd, J =4.5 Hz, J = 7.8 Hz, Harom), 7.90 (1H, dd, J =1.4 Hz, J =7.9 Hz, Harom), 8.78
1
2
1
2
1
3
(
(
(
1H, d, J=4.5 Hz, Harom). C NMR (CDCl , 100 MHz), G(ppm): 24.41 (CH ), 35.81
3
2
CH ), 128.24 (Cmeta), 136.27 (Cpara), 150.41 (Cipso), 151.66 (Cortho) 155.01
2
+
+
Cipso), 206.20 (C=O). ESI-MS: calculated for [C H NO + H] (M + H ) 134.06,
8
7
obtained 134.07; Rf = 0.30 (ethyl acetate); m.p.= 98-101 ºC.
N-(prop-2-yn-1-yl)-6,7-dihydro-5H-cyclopena[b]pyridin-7-amine (2). Method A –
To an ice bath cooled solution of 7 (0.11 g, 0.81 mmol) and Et N (0.25 mL, 1.80 mmol)
3
in dry DCM, methanesulfonyl chloride (0.15 mL, 1.90 mmol) was added under argon
atmosphere. After 3 hours, saturated aqueous solution of NaHCO was added, and the
3
4

organic layers washed with brine and dried over anhydrous Na SO . The removal of
2
4
solvent affords a dark brown crude which was used in the next step without further
purification. To a solution of this crude (0.08 g; 0.46 mmol) in anhydrous DCM,
propargylamine (0.04 mL; 0.58 mmol) and DMAP (catalytic amount) were added under
argon atmosphere. After 2 hours, the solvent was removed under reduced pressure and
the obtained crude was purified by column chromatography. The joined aliquots
afforded 0.01 g (η = 14%) of a dark oil. Method B – To a solution of 9 (0.17 g; 1.26
mmol) and NaBH(OAc) (0.54 g; 2.52 mmol) in DCE propargylamine (0.12 mL; 1.89
3
mmol) was added at r.t. under argon atmosphere. 24 hours after, TLC control
determined the end of the reaction and the mixture was extracted with DCM, washed
with brine and dried with anhydrous Na SO . The crude purification by
2
4
1
chromatographic column gave 0.16 g (K=72%) of a dark oil. H NMR (CDCl , 400
3
MHz) G(ppm): 1.87-2.03 (m + bs, 1H + NH); 2.26 (1H, t, J=2.4 Hz, NHCHHCCH),
2
.45-2.53 (1H, m); 2.84-2.92 (1H, m); 2.91 (1H, ddd, J =3.8 Hz, J =8.8 Hz, J =12.7
1 2 3
Hz); 3.58 (1H, dd, J =2.3 Hz, J =17.0 Hz, NHCHHCCH); 3.72 (1H, dd, J =2.4 Hz,
1
2
1
J =17.0 Hz, NHCHHCCH), 4.42 (1H, t, J=7.0 Hz); 7.12 (1H, dd, J = 5.0 Hz, J =6.9 Hz,
2
1
2
1
3
Harom); 7.55 (1H, d, J=7.6 Hz, Harom); 8.42 (1H, d, J=4.9 Hz, Harom). C NMR
(
CDCl , 100 MHz), G(ppm): 28.16 (CH ), 31.29 (CH ), 36.53 (NHCH CCH), 61.15
3
2
2
2
(
CH), 71.53 (NHCH CCH), 82.07 (NHCH CCH), 122.29 (Cmeta), 132.71 (Cipso),
2 2
136.62 (Cpara), 147.82 (Cortho) e 164.49 (Cipso). HR-ESI-MS: calculated for
+
+
[
C H N + H] (M + H ) 173.1073, obtained 173.1072; Rf = 0.22 (DCM/MeOH –
11 12 2
19:1).
N,N-di(prop-2-yn-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine (±3). To a
solution of 2 (0.12g; 0.72 mmol) in anhydrous DCM, propargyl chloride (52.0 PL; 0.72
mmol) and DMAP as catalyst were added. The system reacted for 24 hours at r.t.. After
addition of water, the mixture was extracted with DCM and the organic layers washed
5

with brine and dried over anhydrous Na SO . After purification by flash
2
4
1
chromatography, 0.10 g (K=57%) of a dark brown oil was obtained. H NMR (CDCl ,
3
4
00 MHz) G(ppm): 2.22 (2H, t, J=2.4 Hz, 2 x NHCHHCCH) 2.23-2.40 (2H, m), 2.77-
2
.85 (1H, m); 3.01 (1H, ddd, J =5.1 Hz, J =8.6 Hz, J =13.7 Hz); 3.70 (2H, dd, J =2.4
1
2i
3
1
Hz, J =16.9 Hz, 2 x NHCHHCCH); 3.83 (2H, dd, J =2.4 Hz, J =16.9 Hz, 2 x
2
1
2
NHCHHCCH), 4.44 (1H, t, J=6.7 Hz); 7.11 (1H, dd, J = 4.9 Hz, J =7.6 Hz, Harom);
1
2
1
3
7
.52 (1H, dd, J =1.3 Hz, J =7.6, Harom); 8.45 (1H, d, J=4.2 Hz, Harom). C NMR
1 2
(
CDCl , 100 MHz), G(ppm): 28.05 (CH ), 29.01 (CH ), 40.71 (2 x NHCH CCH), 66.83
3
2
2
2
(
CH), 73.60 (NHCH CCH), 80.94 (NHCH CCH), 123.21 (Cmeta), 133.52 (Cpara),
2 2
1
38.21 (Cipso), 148.79 (Cortho) 164.17 (Cipso). HR-ESI-MS: calculated for
+
+
[
C H N + H] (M + H ) 211.1230, obtained 211.1224; Rf = 0.75 (DCM/MeOH –
14 14 2
9:1).
6

1
13
H and C NMR spectra
N
O
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
ppm (t1)
1
Figure 1: H-NMR spectrum of compound 5.
1
50
100
50
ppm (t1)
1
3
Figure 2: C-NMR spectrum of compound 5.

N
O
O
8.0
7.0
6.0
5.0
4.0
3.0
2.0
ppm (t1)
1
Figure 3: H-NMR spectrum of compound 6.
78.50
78.00
77.50
ppm (t1)
150
100
50
ppm (t1)
1
3
Figure 4: C-NMR spectrum of compound 6.
8

N
OH
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
ppm (t1)
1
Figure 5: H-NMR spectrum of compound 7.
1
50
100
50
ppm (t1)
1
3
Figure 6: C-NMR spectrum of compound 7.
9

N
O
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
ppm (t1)
1
Figure 7: H-NMR spectrum of compound 1.
1
50
100
50
ppm (t1)
1
3
Figure 8: C-NMR spectrum of compound 1.
1
0

N
O
8
.0
7.0
6.0
5.0
4.0
3.0
ppm (t1)
1
Figure 9: H-NMR spectrum of compound 9.
2
00
150
100
50
ppm (t1)
1
3
Figure 10: C-NMR spectrum of compound 9.
1
1

N
NH
8
.0
7.0
6.0
5.0
4.0
3.0
2.0
ppm (t1)
1
Figure 11: H-NMR spectrum of compound 2.
1
50
100
50
ppm (t1)
1
3
Figure 12: C-NMR spectrum of compound 2.
1
2

N
N
8
.0
7.0
6.0
5.0
4.0
3.0
ppm (t1)
1
Figure 13: H-NMR spectrum of compound 3.
150
100
50
ppm (t1)
1
3
Figure 14: C-NMR spectrum of compound 3.
1
3

HR-ESI-FIA-TOF spectra
Figure 15: HR-ESI-FIA-TOF spectrum of compound 1.
1
4

Figure 16: HR-ESI-FIA-TOF spectrum of compound 2.
1
5

Figure 17: HR-ESI-FIA-TOF spectrum of compound 3.
1
6