Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
DOI: 10.1039/C5OB01739D
ARTICLE
Journal Name
4H), 0.96 (t, J = 7.3 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ = 136.0 (C), 127.7 (C),
127.0 (C), 124.9 (CH), 122.0 (CH), 119.6 (CH), 110.6 (CH), 99.8 (CH), 53.9 (2 × CH2), 52.7
(CH2), 27.9 (CH2), 16.8 (2 × CH2), 11.1 (2 × CH3) ppm; IR (neat): ν 3241, 2971, 2939,
2882, 2531, 1673, 1462, 1344, 1177, 1130, 758; MS (ESI+) m/z (%): 245 ([MH]+, 100%);
HRMS (ES+): m/z calcd for C16H25N2 [MH]+: 245.2012; found: 245.2014; these data being
in accord with literature values.11
tert-Butyl 2-hydroxy-4-(2-oxoethyl)-2,3-dihydro-1H-indole-1-carboxylate (9). Through
a solution of carbamate 7 (1.00 g, 4.08 mmol) in EtOAc (15 mL) at –78 °C was bubbled a
stream of O3 (1–5% in O2). On disappearance of the pale yellow colour, the solution
was purged with O2 for 10 min then PPh3 (3.00 g, 11.4 mmol) was added. The solution
was warmed to RT and after 16 h was concentrated in vacuo. Purification by column
chromatography (50–66% Et2O in petrol) afforded the title compound as a gummy
yellow oil (756 mg, 2.73 mmol, 66%) 1H NMR (400 MHz, CDCl3): δ = 9.69 (t, J = 2.0 Hz,
1H), 7.38 (br s, 1H), 7.21 (app t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.01 (br s, 1H),
3.65 (d, J = 1.5 Hz, 2H), 3.23 (dd, J = 17.2, 7.6 Hz, 1H), 2.88 (d, J = 17.2 Hz, 1H), 1.62 (s,
9H) ppm with some broadening of resonances due to romaters; 13C NMR
(100 MHz, CDCl3): δ = 198.1 (CH), 153.2 (C), 140.8 (C), 128.4 (CH), 128.0 (C), 124.0 (CH),
113.7 (CH), 83.1 (CH), 82.7 (C), 48.0 (CH2), 34.4 (CH2), 28.4 (3 × CH3) ppm with one C not
observed; IR (neat): ν 3434, 2970, 2926, 2852, 1677, 1598, 1461, 1367, 1159, 934, 770;
MS (ESI+) m/z (%): 577 ([2M+Na]+, 100%); HRMS (ES+): m/z calcd for C15H18NNaO4
[M+Na]+: 300.1206; found: 300.1206.
Ropinirole (13). To a solution of indole 12 (205 mg, 0.84 mmol) in tBuOH (8 mL) was
added NBS (166 mg, 0.93 mmol). After 1h, sat. NaHCO3 (2 mL) was added and the
reaction mixture was extracted with EtOAc (3 × 20 mL). The organic phases were
combined and concentrated in vacuo to a dark oil which was dissolved in THF (8 mL)
and 1 M HCl (1 mL) was added. The solution was heated at reflux for 2 h then cooled to
RT, basified with sat. K2CO3 (0.5 mL) and extracted with EtOAc (3 × 30 mL). The organic
phases were combined, dried (MgSO4), concentrated in vacuo and purified by column
chromatography (0–10% MeOH in CH2Cl2) to afford ropinirole 13 as an orange oil (133
mg, 0.51 mmol, 61%), 1H NMR (400 MHz, CDCl3): δ = 8.32 (br s, 1H), 7.08 (t, J = 7.7 Hz,
1H), 6.78 (d, J = 7.7 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 3.42 (s, 2H), 2.65 (br s, 4H), 2.53–
2.36 (m, 4H), 1.44 (app sxt, J = 7.5 Hz, 4H), 0.83 (t, J = 7.3 Hz, 6H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 177.1 (C), 142.2 (C), 137.4 (C), 128.0 (CH), 124.0 (C), 122.9 (CH),
107.3 (CH), 56.2 (2 × CH2), 54.3 (CH2), 35.0 (CH2), 30.9 (CH2), 20.4 (2 × CH2), 11.9 (2 ×
CH3) ppm; IR (neat): ν 3194, 2957, 2933, 2804, 1702, 1618, 1606, 1458, 1247, 775; MS
(ESI+) m/z (%): 261 ([MH]+, 100%); HRMS (ES+): m/z calcd for C16H25N2O [MH]+:
261.1961; found: 261.1963; these data being in accord with literature values.11
Also prepared by adapting the procedure of Gavriilidis et al. 24 Thus, a stock solution of
carbamate 7 (0.2 M in EtOAc, 0.85 mL/min) was ozonised (1.5 equiv., 202 g/Nm3, 62.5
mL/min) under continuous flow at –7 °C using using a Vapourtec R2+ device and a PPh3
quench (2.25 equiv., 0.3 M in EtOAc, 1.28 mL/min). An aliquot (4.6 mL) was collected,
concentrated in vacuo and purified by column chromatography (30% EtOAc in
cyclohexane) to afford aldehyde 9 as a gummy yellow oil (77 mg, 0.28 mmol, 75%);
data as reported above.
A Lemieux-Johnson type oxidation procedure was also examined. Thus, to a solution of
8-Acetamidonaphthalen-2-yl acetate (17). Adapting the procedure of Vermeulen et
al.26 To a suspension of 8-amino-2-naphthol 16 (4.38 g, 27.5 mmol) in CH2Cl2 (80 mL)
were added Ac2O (5.7 mL, 60.3 mmol) and Et3N (8.4 mL, 60.2 mmol). After 4 h, the
carbamate 7 (907 mg, 3.70 mmol) in H2O/tBuOH/MeOH (1:1:1, 100 mL) were added
t
citric acid monohydrate (590 mg, 2.81 mmol), OsO4 (2.5% w/w in BuOH, 50 μl, 5 μmol)
and NMO (658 mg, 5.62 mmol). After 16 h, the reaction mixture was extracted with
EtOAc (4 × 100 mL) then the organic phases were combined, dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography (1:1 EtOAc/Et2O)
afforded tert-butyl rel-6R,7S-(6,7-dihydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbam-
ate as a white solid (801 mg, 2.87 mmol, 78%) MP 174–175 °C (aq. EtOH); 1H NMR
(300 MHz, CD3OD): δ = 7.18 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 7.7 Hz,
1H), 4.08–3.98 (m, 2H), 3.07–2.92 (m, 2H), 2.92–2.76 (m, 2H), 1.51 (s, 9H) ppm; 13C
NMR (100 MHz, CD3OD): δ = 156.6 (C), 137.4 (C), 136.1 (C), 129.9 (C), 127.5 (CH), 127.2
(CH), 124.2 (CH), 81.0 (C), 70.2 (CH), 70.1 (CH), 35.7 (CH2), 31.4 (CH2), 28.9 (3 × CH3)
ppm; IR (neat): ν 3344, 2971, 2920, 1392, 1246, 1161, 1008, 623; MS (ESI+) m/z (%):
343 ([M+CH3CN+Na]+, 51%), 302 ([M+Na]+, 100%); HRMS (ES+): m/z calcd for
C15H21NNaO4 [M+Na]+: 302.1376; found: 302.1370. The aforementioned diol (38 mg,
0.14 mmol) was disolved in aq. THF (1:1, 2 mL) and a solution of NaIO4 (51 mg, 0.24
mmol) in H2O (2 mL) was added. After 18 h, the reaction mixture was extracted with
CH2Cl2 (3 × 50 mL), the organic phases were combined, dried (MgSO4), concentrated in
vacuo and purified by column chromatography (2:1 Et2O/petroleum ether) to afford
aldehyde 9 as a gummy yellow oil (24 mg, 0.09 mmol, 62%); data as reported above.
reaction mixture was washed with H2O (3
× 50 mL), then dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography (EtOAc) afforded with
title compound as a pink solid (6.59 g, 27.1 mol, 99%) MP 192–195 °C (MeOH) [Lit. 184
°C];29 1H NMR (400 MHz, d6-DMSO): δ = 9.90 (br s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.82–
7.77 (m, 3H), 7.49 (app t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 2.35 (s, 3H), 2.20 (s,
3H) ppm; 13C NMR (100 MHz, d6-DMSO): δ = 169.5 (C), 169.0 (C), 148.3 (C), 133.6 (C),
131.7 (C), 129.7 (CH), 128.0 (C), 125.4 (CH), 124.8 (CH), 122.0 (CH), 121.8 (CH), 114.0
(CH), 23.5 (CH3), 20.9 (CH3) ppm; IR (neat): ν 3256, 3025, 2160, 1758, 1663, 1539,
1503, 1209, 1186; MS (ESI+) m/z (%): 266 ([M+Na]+, 100%); HRMS (ES+): m/z calcd for
C
14H14NO3 [MH]+: 244.0968; found: 244.0966; these data being in accord with literature
values. 29
N-(7-Hydroxynaphthalen-1-yl)acetamide (18). Adapting the procedure of Vermeulen
et al.,26 to a suspension of naphthol 17 (4.00 g, 16.4 mmol) in MeOH (40 mL) was added
sat. NaHCO3 (20 mL). The mixture was heated at reflux for 1 h then cooled to RT,
acidified with 1 M HCl (10 mL) and concentrated in vacuo. Purification flash column
chromatography (50% EtOAc in hexane) afforded the title compound as a pink solid
(3.20 g, 15.8 mmol, 96%) MP 200 °C decomp. (H2O) [Lit. 191 °C decomp.];30 1H NMR
(300 MHz, d6-DMSO): δ = 9.80 (s, 1H), 9.77 (s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.62 (d, J =
7.9 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.23 (app t, J = 7.9 Hz, 1H),
7.11 (dd, J = 8.8, 2.4 Hz, 1H), 2.16 (s, 3H) ppm; 13C NMR (75 MHz, d6-DMSO): δ = 168.7
(C), 155.4 (C), 132.1 (C), 129.9 (C), 129.7 (CH), 128.4 (C), 125.2 (CH), 122.5 (CH), 122.0
(CH), 118.5 (CH), 104.4 (CH), 23.3 (CH3) ppm; IR (neat): ν 3150, 3051, 1618, 1546, 1505,
1442, 1379, 1272, 741; MS (ESI+) m/z (%): 265 ([M+CH3CN+Na]+, 100%); these data
being in accord with literature values.31
tert-Butyl 4-(2-(dipropylamino)ethyl)-2-hydroxyindoline-1-carboxylate (11). To
a
solution of aldehyde 9 (5.13 g, 18.5 mmol) in CH2Cl2 (250 mL) were added nPr2NH2 (5.8
mL, 42.3 mmol) and AcOH (1.1 mL, 19.2 mmol). After 45 min, NaCNBH3 (2.67 g, 42.4
mmol) was added. After a further 2 h the reaction mixture was concentrated in vacuo
and purified by column chromatography (gradient elution, 0–3% MeOH in CH2Cl2) to
afford the title compound as a pale yellow oil (6.70 g, 18.5 mmol, 100%) 1H NMR
(300 MHz, CDCl3): δ = 7.57 (br s, 1H), 7.08 (app t, J = 7.9 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H),
5.93 (br s, 1H), 5.74 (br s, 1H), 3.24 (dd, J = 17.1, 7.6 Hz, 1H), 2.91 (d, J = 17.4 Hz, 1H),
2.82 (s, 4H), 2.72–2.58 (m, 4H), 1.67–1.56 (m, 4H), 1.55 (s, 9H), 0.89 (t, J = 7.4 Hz, 6H)
ppm with some broadening of resonances due to rotamers; 13C NMR (75 MHz, CDCl3): δ
= 140.4 (C), 134.8 (C), 127.9 (CH), 127.0 (C), 122.8 (CH), 112.7 (CH), 82.9 (CH), 82.2 (C),
54.7 (2 × CH2), 53.1 (CH2), 34.3 (CH2), 28.6 (CH2), 28.2 (3 × CH3), 18.3 (2 × CH2), 11.4 (2 ×
CH3) ppm with one C not observed; IR (neat): ν 3367, 2970, 2936, 1694, 1597, 1462,
1369, 1136, 907, 725, 645; MS (ESI+) m/z (%): 363 ([MH]+, 100%); HRMS (ES+): m/z
calcd for C21H35N2O3 [MH]+: 363.2642; found: 363.2642.
N-(7-Methoxynaphthalen-1-yl)acetamide (20). Adapting the procedure of Mewshaw et
al.31 To a suspension of phenol 18 (1.00 g, 4.97 mmol) in acetone (20 mL) was added
K2CO3 (1.72 g, 12.4 mmol) and MeI (620 μL, 9.96 mmol). The mixture was heated at
reflux for 1 h then cooled to RT and purified by column chromatography (EtOAc) to
afforded the title compound as a pale brown powder (962 mg, 4.47 mmol, 90%) MP
178–180 °C (EtOH) [Lit. 175–176 °C (EtOH)];32 1H NMR (300 MHz, d6-DMSO): δ = 9.82
(s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.38 (d, J
= 1.9 Hz, 1H), 7.31 (app t, J = 7.9 Hz, 1H), 7.19 (dd, J = 9.0, 2.3 Hz, 1H), 3.90 (s, 3H), 2.19
(s, 3H) ppm; 13C NMR (75 MHz, d6-DMSO): δ = 168.8 (C), 157.3 (C), 132.6 (C), 129.8
(CH), 129.2 (C), 128.8 (C), 124.8 (CH), 123.0 (CH), 122.1 (CH), 118.2 (CH), 101.6 (CH),
55.2 (CH3), 23.6 (CH3) ppm; IR (neat): ν 3270, 2928, 2830, 1632, 1536, 1251; MS (ESI+)
m/z (%): 279 ([MH+CH3CN]+, 100%); these data being in accord with literature values.31
4-[2-(N,N-dipropylamino)ethyl]indole (12). To a solution of hemiaminal 11 (62 mg,
0.20 mmol) in CH2Cl2 (2 mL) was added TFA (12 mL). After 3 h, 2M NaOH (5 mL) was
added. The aqueous phase was separated and extracted with CH2Cl2 (3 × 30 mL). The
organic phases were then combined, dried (MgSO4) and concentrated in vacuo.
Purification by column chromatography (4% MeOH in CH2Cl2) afforded the title
compund as a yellow oil (40 mg, 0.20 mmol, 96%) 1H NMR (300 MHz, CDCl3): δ = 8.94
(br s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.21 (app t, J = 2.9 Hz, 1H), 7.09 (dd, J = 8.1, 7.3 Hz,
1H), 6.89 (d, J = 7.3 Hz, 1H), 6.57 (m, 1H), 3.31 (s, 4H), 3.10–2.96 (m, 4H), 1.89–1.67 (m,
N-(7-Methoxy-5,8-dihydronaphthalen-1-yl)acetamide (22). To
naphthylamide 20 (87 mg, 0.40 mmol) in THF (10 mL) were added tBuOH (50 µL) and
a suspension of
NH3 (10 mL). Na (20 mg, 0.87 mg-atom) was added portionwise to the refluxing
4 | Org. Biomol. Chem., 2013, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins