Enantioselective synthesis of (R)-Sumanirole using organocatalytic asymmetric aziridination of an α,β-unsaturated aldehyde

Article abstract of DOI:10.1016/j.tetasy.2014.06.018

Herein we report an enantioselective synthesis of (R)-Sumanirole wherein an organocatalytic asymmetric aziridination of 2-nitrocinnamaldehyde was the key step.

Full text of DOI:10.1016/j.tetasy.2014.06.018

Tetrahedron: Asymmetry 25 (2014) 1133–1137
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of (R)-Sumanirole using organocatalytic
asymmetric aziridination of an a,b-unsaturated aldehyde
⇑
Tetsuhiro Nemoto, Minami Hayashi, Dashuang Xu, Akinari Hamajima, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2014
Accepted 19 June 2014
Herein we report an enantioselective synthesis of (R)-Sumanirole wherein an organocatalytic asymmetric
aziridination of 2-nitrocinnamaldehyde was the key step.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
have been developed6 based on nitrene-transfer catalysis,7 Brook-
hart–Templeton aziridinations8 using chiral Lewis acid catalysts9
Small organic molecules with a 3-amino tetrahydroquinoline
skeleton are attractive synthetic targets in medicinal chemistry
because of the ubiquity of this structural motif in various bioactive
molecules. A representative example of this class of compounds is
(R)-Sumanirole, which exhibits selective dopamine D2 receptor
agonist activity.1 A clinical trial for (R)-Sumanirole in the treatment
of Parkinson disease was performed based on this bioactivity until
the phase III study was terminated in 2004. Several enantioselec-
tive synthetic toward (R)-Sumanirole have been developed to date
using the chiral pool,2 a resolution,3 or a diastereoselective reaction
approach.4 Synthetic methods based on a catalytic asymmetric
reaction, however, are rarely reported on. The synthetic method
reported by Sudalai et al. is the only approach for the synthesis
or chiral Brønsted acid catalysts,10 phase-transfer catalysis,11 and
chiral amine organocatalysis.12 We recently reported on the asym-
metric aziridination of
a,b-unsaturated aldehydes using chiral
amine organocatalysts.12d Using 10 mol % of chiral prolinol deriva-
tive 113 as an organocatalyst, the asymmetric aziridination of
b-aryl
t-butyl p-toluenesulfonyloxy carbamate and sodium acetate, to
afford the corresponding trans- ,b-aziridine aldehydes with
a,b-unsaturated aldehydes proceeded in the presence of
a
excellent enantioselectivity (Scheme 1). We hypothesized that a
3-amino tetrahydroquinoline skeleton would be efficiently con-
structed by using the present catalytic asymmetric aziridination
and envisioned that the developed method would be applicable
to the enantioselective synthesis of (R)-Sumanirole. Herein we
report an enantioselective synthesis of (R)-Sumanirole using the
organocatalytic asymmetric aziridination of 2-nitrocinnamalde-
hyde as the key step.
of (R)-Sumanirole using a catalytic asymmetric
a-aminooxylation
of aldehydes.5
H
N
CH3
Ph
Ph
Boc
CHO
N
N
N
H
OTES
HN
CHO
O
X
(S)-1 (10 mol %)
+
(R)-Sumanirole
X
BocHN–OTs
NaOAc (3 equiv)
CH2Cl2 (0.2 M)
–20 °C
(1.2 equiv)
32–97% yield
94–99% ee
Optically active aziridines are versatile chiral building blocks in
organic synthesis. Selective modifications of the aziridine moiety
provide efficient access to a wide variety of useful chiral interme-
diates. Therefore, various catalytic asymmetric synthetic methods
Scheme 1. Organocatalytic asymmetric aziridination of b-aryl
aldehydes.
a,b-unsaturated
2. Results and discussion
⇑
Our plan for the enantioselective synthesis of (R)-Sumanirole is
outlined in Scheme 2. The cyclic urea structure can be constructed
Corresponding author. Tel./fax: +81 43 226 2920.
E-mail address: y-hamada@faculty.chiba-u.jp (Y. Hamada).
http://dx.doi.org/10.1016/j.tetasy.2014.06.018
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1134
T. Nemoto et al. / Tetrahedron: Asymmetry 25 (2014) 1133–1137
by an oxidative intramolecular CAN bond formation using an
N-methoxyurea derived from 3-N-Boc-amino tetrahydroquinoline
4 as a substrate.2 The key intermediate 4 can be prepared from a
chiral aziridine aldehyde derivative using a regioselective aziridine
opening reaction and a reductive cyclization process. Cinnamalde-
hyde derivatives with an electron-withdrawing group on the
aromatic ring are more effective substrates for our catalytic asym-
metric aziridination than those bearing an electron-donating
group. This led us to select chiral aziridine aldehyde 3 as a suitable
precursor for the synthesis of compound 4. Compound 3 could be
obtained in an optically active form via catalytic asymmetric azir-
idination of commercially available 2-nitrocinnamaldehyde 2.
We next examined the transformation of 3 into key intermedi-
ate 4. Nitrobenzene derivatives are generally converted into the
corresponding aniline derivatives in the presence of a Pd catalyst
under a hydrogen atmosphere. Benzylic CAN bonds are also
cleaved under the same reaction conditions. We thus hypothesized
that compound 3 could be converted into key intermediate 4 using
a one-pot sequential process involving the reduction of the nitro
group, hydrogenolysis of the benzylic CAN bond, and intramolecu-
lar reductive amination (Table 1). Studies were performed using
PdAC as a catalyst in MeOH under a hydrogen atmosphere. We
first examined the reaction using aziridine aldehyde 3 with 97%
ee in the presence of 1 equiv of acetic acid under 0.1 MPa hydrogen
pressure. Although the reaction was sluggish, the desired reaction
sequence proceeded under dilute conditions to give 3-amino tetra-
hydroquinoline derivative 4 in 29% yield (entry 2). The hydrogen
pressure significantly affected the reactivity and compound 4
was obtained in 88% yield when the reaction was performed under
0.4 MPa hydrogen pressure (entry 3). Chiral HPLC analysis was
used to determine the enantiomeric excess of 4 and revealed that
partial racemization occurred during this sequential process. The
optical purity decreased when the reaction was performed in the
absence of acetic acid (entry 4). These results led us to find an
alternative, racemization-free, synthetic route from 3 to 4.
H
N
CH3
aziridine opening
and
H
N
Boc
N
reductive
cyclization
process
HN
(R)-Sumanirole
Boc
N
H
O
4
catalytic asymmetric
aziridination
N
CHO
CHO
using (R)-1
We thought that the decrease in the enantiomeric excess was
due to partial enolization at the stage of an
a-N-Boc-amino alde-
NO2
NO2
hyde intermediate. Thus, compound 3 was first reacted with NaCN
and MnO2 in MeOH, to afford the corresponding methyl ester 5 in
81% yield (Scheme 4). We next transformed compound 5 into lac-
tam 6 in 79% yield via Pd-catalyzed hydrogenolysis of the benzylic
CAN bond, reduction of the nitro group, and a lactamization
3
2
Scheme 2. Retrosynthetic analysis.
Our synthesis started with the organocatalytic asymmetric
aziridination of 2-nitrocinnamaldehyde (Scheme 3). Using
10 mol % of (R)- -proline-derived chiral amine (R)-1, the asymmet-
cascade. Subsequent reduction of
6
using BH3ÁTHF at room
2
temperature afforded the key intermediate 4 in 82% yield. The
D
Boc
N
ric aziridination of 2 with 1.05 equiv of t-butyl p-toluenesulfonyl-
oxy carbamate proceeded smoothly at 0 °C to afford the
corresponding chiral aziridine aldehyde 3 in 94% yield and with
97% ee.
(i)
COOMe
(ii)
3
(97% ee)
81% yield
79% yield
NO2
5
Ph
Ph
CHO
NHBoc
NHBoc
Boc
N
(iii)
N
H
OTES
NO2
2
CHO
82% yield
N
H
N
H
O
1
(R)- (10 mol %)
3
NO2
4
(97% ee)
+
NaOAc (3 equiv)
CH2Cl2 (0.2 M)
0 °C, 12 h
6
BocHN–OTs
94%, 97% ee
(1.05 equiv)
Scheme 4. Racemization-free synthetic route. Reaction conditions: (i) NaCN
(2 equiv), MnO2 (500 w/w%), MeOH, 0 °C, 4 h. (ii) 5% Pd-C, H2 (0.4 MPa), AcOH
(1 equiv), MeOH, rt, 6.5 h. (iii) BH3ÁTHF (10 equiv), THF, rt, 2 h.
Scheme 3. Catalytic asymmetric aziridination of 2.
Table 1
One-pot transformation of 3 into tetrahydroquinoline derivative 4
Boc
5 % Pd-C
H
N
N
H
2 (x MPa)
CHO
Boc
AcOH (y equiv)
MeOH (conc.), rt
N
H
NO2
3 (97% ee)
4
a
Entry
H2 (MPa)
AcOH (equiv)
MeOH (M)
Time (h)
Yieldb (%)
Ee of 4c
1
2
3
4
0.1
0.1
0.4
0.4
1
1
1
0
0.06
24
24
7
24
29
88
73
N.D.
N.D.
77% ee
67% ee
0.016
0.016
0.016
17
a
b
c
1 MPa = 9.869 atm.
Isolated yield.
Determined by chiral HPLC analysis.

T. Nemoto et al. / Tetrahedron: Asymmetry 25 (2014) 1133–1137
1135
enantiomeric excess of 4 was determined to be 97% ee, thus indi-
cating that the enantiomeric purity did not erode over the course
of the reactions.
100 MHz for 13C NMR. Chemical shifts in CDCl3, are reported down-
field from TMS (=0 ppm) for 1H NMR. For 13C NMR, chemical shifts
are reported in a scale relative to the solvent signal [CHCl3
(77.0 ppm)] as an internal reference. Optical rotations were mea-
sured on a JASCO P-1020 polarimeter. ESI mass spectra were mea-
sured on JEOL AccuTOF LC-plus JMS-T100L. The enantiomeric
excess (ee) was determined by HPLC analysis. HPLC was performed
on JASCO HPLC systems consisting of the following: pump, PU-980;
detector, UV-970, measured at 254 nm; column DAICEL CHIR-
ALPAK AD-H, DAICEL CHIRALCEL OD-H, DAICEL CHIRALCEL OJ-H;
mobile phase, hexane–2-propanol. Reactions were carried out in
dry solvent under an argon atmosphere. Other reagents were
purified by the usual methods.
With the optically active intermediate 4 (97% ee) in hand, we
were thus able to complete the enantioselective synthesis of (R)-
Sumanirole (Scheme 5). After introducing a methoxyaminocarbon-
yl group on the aniline nitrogen (94% yield), the obtained product 7
was reacted with a hypervalent iodine reagent2,14 to give com-
pound 8 in 94% yield. N-methylation of compound 8, followed by
hydrogenolysis of the NAO bond in the presence of a Pd catalyst,
provided compound 10 in 89% yield over two steps. Finally, removal
of the Boc group afforded (R)-Sumanirole in 92% yield (35.8% overall
yield, 9 step from 1). The specific rotation of the synthetic sample
was measured after converting it into the corresponding HCl salt
{synthetic sample: [
a]
25 = À29.0 (c 0.43, MeOH) 97% ee, literature
4.2. tert-Butyl (2R,3S)-2-formyl-3-(2-nitrophenyl)aziridine-1-
carboxylate 3
D
data:3a
[
a]
D
25 = À30.3 (c 1.0, MeOH) 99% ee}.
NHBoc
To a stirred solution of (R)-1 (126.5 mg, 0.344 mmol), 2-nitro-
cinnamaldehyde
2 (610 mg, 3.44 mmol), and sodium acetate
(i)
94% yield
(ii)
4
N
(850 mg, 10.32 mmol) in CH2Cl2 (17 mL) at 0 °C was added tert-
butyl p-toluenesulfonyloxy carbamate (1.04 g, 3.61 mmol). After
being stirred for 12 h at 0 °C, the reaction mixture was diluted with
AcOEt, washed with satd aq NaHCO3, and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography (SiO2, hexane/AcOEt = 10:1) to give
3 (1.02 g, 94% yield, 97% ee) as a white solid. Mp. 73–75 °C; IR
94% yield
HN
O
7
OMe
Boc
N
NHBoc
(iii)
CH3
94% yield
N
N
(ATR)
m ;
1726, 1527, 1344, 1300, 1156 cmÀ1 1H NMR (CDCl3): d
N
N
1.53 (s, 9H), 3.19 (dd, J = 2.4 Hz, 3.6 Hz, 1H), 4.38 (d, J = 2.4 Hz,
1H), 7.55 (t, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H) 7.75 (d,
J = 7.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 9.55 (d, J = 3.6 Hz, 1H); 13C
NMR (CDCl3): d 27.8 (3C), 44.3, 48.6, 83.2, 125.0, 129.2, 129.4,
131.3, 134.3, 147.8, 158.1, 193.2; (+)-ESI-HRMS. Calcd for
MeO
(iv)
O
MeO
O
8
9
Boc
N
CH3
(v)
14H17N2O5+ (M+H+): 293.1137. Found: 293.1166; [ 20 = +59.7 (c
a]
(R)-Sumanirole
C
D
N
O
92% yield
95% yield
1.01, CHCl3) 97% ee. Enantiomeric excess was determined by using
chiral HPLC analysis after converting into the corresponding
methyl ester derivative 5 (DAICEL CHIRALCEL OD-H, hexane/2-pro-
panol = 95:5, flow rate: 1 mL/min, 254 nm, tR 8.8 min and 10.8 min,
detection at 254 nm).
HN
10
Scheme 5. Asymmetric synthesis of (R)-Sumanirole. Reaction conditions: (i)
triphosgene (0.35 equiv), MeONH2ÁHCl (1.1 equiv), NEt3 (3.2 equiv), THF, rt, 26 h.
(ii) PhI(OOCCF3)2 (1.3 equiv), CHCl3, rt, 2 h. (iii) NaH (2 equiv), MeI (2 equiv), DMF,
rt, 2 h. (iv) 5% Pd-C, H2 (0.4 MPa), EtOH, rt, 18 h. (v) TFA (26.5 equiv), CH2Cl2, rt, 12 h.
4.3. 1-(tert-Butyl) 2-methyl (2R,3S)-3-(2-nitrophenyl)aziridine-
1,2-dicarboxylate 5
3. Conclusion
To a stirred solution of 2 (2.54 g, 8.69 mmol) and sodium cyanide
(0.85 g, 17.38 mmol) in MeOH (43 mL) at 0 °C was added activated
manganese dioxide (12.70 g). After being stirred for 4 h at 0 °C, the
reaction mixture was diluted with ethyl acetate. The mixture was
washed with satd aq NH4Cl and brine, dried over Na2SO4, and then
concentrated in vacuo. The residue obtained was purified by flash
column chromatography (SiO2, hexane/AcOEt = 10:1) to give 5
In conclusion, we have achieved the enantioselective synthesis
of (R)-Sumanirole by using an organocatalytic asymmetric aziri-
dination of an
of 2-nitrocinnamaldehyde with t-butyl p-toluenesulfonyloxy car-
bamate proceeded by using 10 mol % of (R)- -proline-derived chi-
a,b-unsaturated aldehyde. Asymmetric aziridination
D
ral amine organocatalyst to afford the corresponding chiral
aziridine aldehyde in 94% yield and with 97% ee. The aziridine
obtained was converted into a 3-amino tetrahydroquinoline inter-
mediate via a Pd-catalyzed sequential process. The enantioselec-
tive synthesis of (R)-Sumanirole was achieved in nine steps with
an overall yield of 35.8%, which is the most efficient process com-
pared with the previously reported asymmetric synthesis. This
method could be applicable to the synthesis of other bioactive
molecules with a 3-amino tetrahydroquinoline skeleton. Further
studies are currently in progress.
(2.26 g, 81% yield) as a white solid. Mp. 67–69 °C; IR (ATR)
m 2979,
1726, 1525, 1440, 1341, 1234, 1204, 1149, 1083, 845, 753 cmÀ1
;
1H NMR (CDCl3): d 1.51 (s, 9H), 3.00 (dd, J = 0.8 Hz, 2.4 Hz, 1H),
3.87 (d, J = 0.8 Hz, 3H), 4.35 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 7.6 Hz,
8.0 Hz, 1H) 7.66 (dd, J = 7.6 Hz, 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H),
8.17 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3): d 27.9 (3C), 43.3, 43.5,
52.9, 82.6, 124.8, 129.2, 129.3, 131.7, 134.2, 147.9, 158.2, 167.3;
(+)-ESI-HRMS. Calcd for C15H18N2NaO+6 (M+Na+): 345.1057. Found:
345.1048; [a]
16 = +20.4 (c 0.95, CHCl3) 97% ee.
D
4. Experimental
4.1. General
4.4. tert-Butyl (R)-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)car-
bamate 6
Infrared (IR) spectra were recorded on a JASCO FT/IR 230 Fourier
transform infrared spectrophotometer, equipped with ATR (Smiths
Detection, DuraSample IR II). NMR spectra were recorded on a JEOL
ecp 400 spectrometer, operating at 400 MHz for 1H NMR, and
A suspension of 5 (342.0 mg, 1.06 mmol), Pd-C (5%, 65 mg), and
acetic acid (61 lL, 1.06 mmol) in MeOH (70 mL) was stirred at
room temperature under a hydrogen atmosphere (0.4 MPa). After
6.5 h, the reaction mixture was filtered through a short pad of

1136
T. Nemoto et al. / Tetrahedron: Asymmetry 25 (2014) 1133–1137
Celite and the filtrate was evaporated under reduced pressure. The
residue obtained was purified by flash column chromatography
(SiO2, hexane/AcOEt = 3:1) to give 6 (219.6 mg, 79% yield, 97% ee)
as a white solid. Enantiomeric excess was determined by using
chiral HPLC analysis (DAICEL CHIRALCEL OJ-H, hexane/2-
propanol = 95:5, flow rate: 1 mL/min, 254 nm, tR 10.6 min, and
solid. Mp. 54–57 °C; IR (ATR)
m 3321, 2979, 2933, 1684, 1492, 1455,
1365, 1164, 746 cmÀ1 1H NMR (CDCl3): d 1.43 (s, 9H), 2.69 (dd,
;
J = 5.6 Hz, 16.4 Hz, 1H), 3.08 (dd, J = 5.6 Hz, 16.4 Hz, 1H), 3.65–
3.85 (m, 2H), 3.74 (s, 3H), 4.07–4.13 (m, 1H), 4.88 (d, J = 7.2 Hz,
1H), 7.06–7.22 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H); 13C
NMR (CDCl3): d 28.3 (3C), 33.5, 46.0, 48.0, 64.2, 79.6, 122.9,
124.8, 126.9, 128.2, 129.7, 137.5, 155.2, 157.8; (+)-ESI-HRMS. Calcd
15.9 min, detection at 254 nm). Mp. 56–59 °C; IR (ATR)
m
3234,
2978, 1676, 1488, 1390, 1366, 1244, 1160, 753, 729 cmÀ1
;
1H
for C16H24N3O+4 (M+H+): 322.1761. Found: 322.1778; [ 25 = +21.9
a]
D
NMR (CDCl3): d 1.48 (s, 9H), 2.80–2.88 (m, 1H), 3.47–3.53 (m,
1H), 4.32–4.40 (m, 1H), 5.62 (broad peak: amide NH, 1H), 6.78
(d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 7.18–7.23 (m, 2H), 7.84
(broad peak: amide NH, 1H); 13C NMR (CDCl3): d 28.3 (3C), 32.4,
50.0, 79.9, 115.6, 122.8, 123.6, 127.9, 128.5, 136.2, 155.6, 170.2;
(+)-ESI-HRMS. Calcd for C14H19N2O+3 (M+H+): 263.1390. Found:
(c 0.50, CHCl3) 97% ee.
4.7. tert-Butyl (R)-(1-methoxy-2-oxo-1,2,5,6-tetrahydro-4H-
imidazo[4,5,1-ij]quinolin-5-yl)carbamate 8
To a stirred solution of 7 (51.8 mg, 0.16 mmol) in CHCl3 (2 mL)
at 0 °C was added PhI(OOCCF3)2 (89.8 mg, 0.208 mmol), and the
reaction was left to stir for 2 h at room temperature. The reaction
was quenched by the addition of satd aq NaHCO3 solution, and
the resulting mixture was extracted with Et2O (Â2). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo.
The residue obtained was purified by flash column chromatogra-
phy (SiO2, hexane/AcOEt = 5:1–1:1) to give 8 (47.8 mg, 94% yield)
263.1391; [
a]
25 = À2.0 (c 0.50, CHCl3) 97% ee.
D
4.5. tert-Butyl (R)-(1,2,3,4-tetrahydroquinolin-3-yl)carbamate 4
4.5.1. Synthesis of compound 4 using compound 3 as a substrate
(Table 1, entry 3)
A suspension of 3 (72.6 mg, 0.25 mmol), Pd-C (5%, 15 mg), and
acetic acid (17
l
L, 0.25 mmol) in MeOH (17 mL) was stirred at
as a pale orange solid. Mp. 64–67 °C; IR (ATR)
m
3321, 2979,
room temperature under a hydrogen atmosphere (0.4 MPa). After
7 h, the reaction mixture was filtered through a short pad of Celite
and the filtrate was evaporated under reduced pressure. The resi-
due obtained was purified by flash column chromatography
(SiO2, hexane/AcOEt = 3:1) to give 4 (54.6 mg, 88% yield, 77% ee)
as a white solid. The enantiomeric excess was determined by using
chiral HPLC analysis (DAICEL CHIRALPAK AD-H, hexane/2-propa-
nol = 80:20, flow rate: 1 mL/min, 254 nm, tR 4.7 min and 5.3 min,
detection at 254 nm).
1700, 1532, 1491, 1365, 1285, 1218, 1163, 1059, 747 cmÀ1
;
1H
NMR (CDCl3): d 1.43 (s, 9H), 2.88 (dd, J = 5.2 Hz, 16.0 Hz, 1H),
3.10 (dd, J = 4.0 Hz, 16.0 Hz, 1H), 3.80–3.95 (m, 2H), 4.09
(s, 3H), 4.40–4.50 (m, 1H), 4.70 (d, J = 6.0 Hz, 1H), 6.80 (d,
J = 8.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 7.6 Hz, 8.0 Hz,
1H); 13C NMR (CDCl3): d 28.3 (3C), 30.3, 43.5, 43.6, 64.8, 80.0,
105.1, 116.3, 120.8, 121.9, 122.1, 124.6, 150.2, 154.8; (+)-ESI-
HRMS. Calcd for
C
16H21N3NaO+4 (M+Na+): 324.1424. Found:
324.1436; [
a]
25 = +6.0 (c 0.50, CHCl3) 97% ee.
D
4.5.2. Synthesis of compound 4 using compound 6 as a substrate
To a stirred solution of 6 (20.0 mg, 0.08 mmol) in THF (0.3 mL)
at room temperature was added BH3ÁTHF (0.9 M, 0.85 mL,
0.76 mmol), and the mixture was left to stir for 22 h at 0 °C. The
reaction was quenched by the addition of MeOH, and the resulting
mixture was concentrated in vacuo. The residue obtained was puri-
fied by flash column chromatography (SiO2, hexane/AcOEt = 8:1) to
give 4 (15.5 mg, 82% yield) as a white solid. Mp. 91–92 °C; IR (ATR)
4.8. tert-Butyl (R)-(1-methoxy-2-oxo-1,2,5,6-tetrahydro-4H-
imidazo[4,5,1-ij]quinolin-5-yl)(methyl)carbamate 9
To a stirred solution of 8 (118.8 mg, 0.37 mmol) in DMF (2 mL)
at 0 °C was added NaH (60% oil, 30 mg, 0.74 mmol). After 30 min,
iodomethane (46.1 mL, 0.74 mmol) was added to the reaction at
0 °C, and the resulting mixture was stirred for 2 h at room temper-
ature. The reaction was quenched by the addition of water, and the
resulting mixture was extracted with Et2O (Â2). The combined
organic layers were washed with brine, dried over Na2SO4, and
then concentrated in vacuo. The residue obtained was purified by
flash column chromatography (SiO2, hexane/AcOEt = 5:1–2:1) to
give 9 (128.1 mg, 94% yield) as a white solid; Mp. 82–84 °C; IR
m
3394, 3006, 2977, 1693, 1495, 1364, 1280, 1237, 1163, 745 cmÀ1
;
1H NMR (CDCl3): d 1.43 (s, 9H), 1.46 (broad peak: amine NH, 1H),
2.67–2.75 (m, 1H), 3.04 (dd, J = 4.4 Hz, 16.0 Hz, 1H), 3.16–3.22
(m, 1H), 3.36 (dd, J = 2.0 Hz, 11.2 Hz, 1H), 4.14–4.20 (m, 1H), 5.00
(broad peak: amide NH, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.64–6.68
(m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.98–7.03 (m, 1H); 13C NMR
(CDCl3): d 28.4 (3C), 33.0, 43.0, 45.7, 79.3, 114.1, 117.8, 118.4,
127.1, 130.5, 143.7, 155.3; (+)-ESI-HRMS. Calcd for C14H21N2O2+
(ATR)
m
3229, 2980, 2931, 1666, 1492, 1455, 1391, 1363, 1290,
1242, 1148, 742 cmÀ1
;
1H NMR (CDCl3): d 1.48 (s, 9H), 2.87
(s, 3H), 2.92 (dd, J = 4.4 Hz, 15.6 Hz, 1H), 3.12 (dd, J = 11.2 Hz,
15.6 Hz, 1H), 3.64 (dd, J = 11.2 Hz, 11.2 Hz, 1H), 4.07 (s, 3H),
4.05–4.09 (m, 1H), 4.40–4.75 (m, 1H), 6.87 (d, J = 7.2 Hz, 1H),
6.94 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.2 Hz, 7.6 Hz, 1H); 13C NMR
(CDCl3): d 28.1 (3C), 28.1, 29.6, 40.3, 48.9, 64.4, 80.1, 104.4,
117.7, 119.8, 121.4, 121.7, 124.2, 149.6, 154.8; (+)-ESI-HRMS. Calcd
a]
(M+H+): 249.1598. Found: 249.1579; [ 24 = +7.92 (c 0.50, CHCl3,
D
97% ee).
4.6. tert-Butyl (R)-(1-(methoxycarbamoyl)-1,2,3,4-tetrahydro-
quinolin-3-yl)carbamate 7
for
C
17H23N3NaO+4 (M+Na+): 356.1581. Found: 356.1558;
[a]
25 = +37.9 (c 0.50, CHCl3) 97% ee.
D
To a stirred solution of 4 (200.0 mg, 0.81 mmol) and triethyl-
amine (0.18 mL, 1.30 mmol) in THF (2.7 mL) was added triphos-
gene (127.6 mg, 0.43 mmol) at 0 °C, and the resulting solution
was stirred at room temperature. After 22 h, methoxyamine hydro-
chloride (74.0 mg, 0.89 mmol) and triethylamine (0.18 mL,
1.30 mmol) were added to the reaction, and the resulting mixture
was stirred for 4 h at room temperature. The reaction was
quenched by the addition of water, and the mixture was extracted
with Et2O (Â2). The combined organic layers were washed with
brine, dried over Na2SO4, and then concentrated in vacuo. The res-
idue obtained was purified by flash column chromatography (SiO2,
hexane/AcOEt = 3:1–1:1) to give 7 (244.1 mg, 94% yield) as a white
4.9. tert-Butyl (R)-methyl(2-oxo-1,2,5,6-tetrahydro-4H-imidazo-
[4,5,1-ij]quinolin-5-yl)carbamate 10
A suspension of 9 (75.9 mg, 0.23 mmol), and Pd-C (5%, 15.2 mg)
in EtOH (2.3 mL) was stirred at room temperature under a hydro-
gen atmosphere (0.4 MPa). After 18 h, the reaction mixture was fil-
tered through
a short pad of Celite and the filtrate was
concentrated under reduced pressure. The residue obtained was
purified by flash column chromatography (SiO2, hexane/
AcOEt = 2:1) to give 10 (66.4 mg, 95% yield) as a white solid. IR

T. Nemoto et al. / Tetrahedron: Asymmetry 25 (2014) 1133–1137
1137
(ATR)
m ;
3014, 2931, 1485, 1493, 1393, 1365, 1216, 1146, 744 cmÀ1
References
1H NMR (CDCl3): d 1.48 (s, 9H), 2.88 (s, 3H), 2.93 (dd, J = 5.2 Hz,
15.6 Hz, 1H), 3.12 (dd, J = 11.6 Hz, 15.6 Hz, 1H), 3.68 (dd,
J = 11.2 Hz, 11.2 Hz, 1H), 4.11 (dd, J = 5.2 Hz, 11.2 Hz, 1H), 4.48–
4.68 (m, 1H), 6.86–7.01 (m, 3H), 10.24 (s, 1H); 13C NMR (CDCl3):
d 27.8, 28.4 (3C), 29.8, 40.7, 50.1, 80.5, 107.6, 117.6, 119.6, 121.6,
126.3, 126.8, 154.9, 155.2; (+)-ESI-HRMS. Calcd for C16H21N3NaO3+
1. McCall, R. B.; Lookingland, K. L.; Bédard, P. J.; Huff, R. M. J. Pharmacol. Exp. Ther.
2005, 314, 1248.
2. Romero, A. G.; Darlington, W. H.; McMillan, M. W. J. Org. Chem. 1997, 62, 6582.
3. (a) Heier, R. F.; Dolak, L. A.; Duncan, J. N.; Hyslop, D. K.; Lipton, M. F.; Martin, I.
J.; Mauragis, M. A.; Piercey, M. F.; Nichols, N. F.; Schreur, P. J. K. D.; Smith, M.
W.; Moon, M. W. J. Med. Chem. 1997, 40, 639; (b) Wuts, P. G.; Gu, R. L.; Northuis,
J. M.; Kwan, T. A.; Beck, D. M.; White, M. J. Pure Appl. Chem. 2002, 74, 1359.
4. (a) Jean-Gérard, L.; Macé, F.; Dentel, H.; Ngo, A. N.; Collet, S.; Guingant, A.;
Evain, M. Synlett 2010, 1473; (b) Jean-Gérard, L.; Macé, F.; Ngo, A. N.; Pauvert,
M.; Dentel, H.; Evain, M.; Collet, S.; Guingant, A. Eur. J. Org. Chem. 2012, 4240.
5. Rawat, V.; Kumar, B. S.; Sudalai, A. Org. Biomol. Chem. 2013, 11, 3608.
6. For a review, see: Pellissier, H. Adv. Synth. Catal. 2014, 356, 1899.
7. For representative examples, see: (a) Evans, D. A.; Woerpel, K. A.; Hinman, M.
M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726; (b) Li, Z.; Quan, R. W.; Jacobsen,
E. N. J. Am. Chem. Soc. 1995, 117, 5889; (c) Sanders, C. J.; Gillespie, K. M.; Bell, D.;
Scott, P. J. Am. Chem. Soc. 2000, 122, 7132; (d) Dauban, P.; Saniere, L.; Tarrade,
A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707; (e) Aggarwal, V. K.; Alonso, E.;
Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40,
1433; (f) Fukunaga, Y.; Uchida, T.; Ito, Y.; Matsumoto, K.; Katsuki, T. Org. Lett.
2012, 14, 4658; (g) Kim, C.; Uchida, T.; Katsuki, T. Chem. Commun. 2012, 7188.
and references cited therein.
(M+Na+): 326.1475. Found: 324.1465; [
97% ee.
a]
24 = +29.5 (c 0.25, CHCl3)
D
4.10. (R)-Sumanirole
To a stirred solution of 10 (77.7 mg, 0.26 mmol) in CH2Cl2
(13 mL) at 0 °C was added trifluoroacetic acid (0.51 mL,
6.89 mmol), and the resulting solution was stirred at room temper-
ature. After 12 h, the reaction mixture was poured into satd aq
NaHCO3 solution, and the mixture obtained was extracted with
CH2Cl2 (Â2). The combined organic layers were washed with brine,
dried over Na2SO4, and then concentrated in vacuo. The residue
obtained was purified by flash column chromatography (SiO2,
CHCl3/MeOH = 99:1–8:1) to give (R)-Sumanirole (48.8 mg, 92%
yield) as a white solid. [
ature data: [
obtained (16.6 mg, 0.08 mmol) was suspended in methanolic HCl
(2 M solution, 2 mL) and Et2O (2.5 mL), and stirred at 60 °C. After
2 h, the suspension was cooled to room temperature, filtered,
and washed with a mixture of MeOH/Et2O (1:1) to give (R)-
8. Caasarrubios, L.; Pérez, J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996,
61, 8358.
9. For representative examples, see: (a) Antilla, J. C.; Wullf, W. D. J. Am. Chem. Soc.
1999, 121, 5099; (b) Antilla, J. C.; Wullf, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518; (c) Patwardhan, A. P.; Pulgam, V. R.; Zhang, Y.; Wulff, W. D. Angew. Chem.,
Int. Ed. 2005, 44, 6169; (d) Desai, A.; Wullf, W. D. J. Am. Chem. Soc. 2010, 132,
13100; (e) Huang, L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892; (f) Larson,
S. E.; Li, G.; Rowland, G. B.; Junge, D.; Huang, R.; Woodcock, H. L.; Antilla, J. C.
Org. Lett. 2011, 13, 2188; (g) Gupta, A. K.; Mukherjee, M.; Wulff, W. D. Org. Lett.
2011, 13, 5866.
10. (a) Hashimoto, T.; Uchiyama, N.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
14380; (b) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445; (c) Zeng,
X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036; (d) Hashimoto,
T.; Nakatsu, H.; Yamamoto, K.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 9730;
(e) Hashimoto, T.; Nakatsu, H.; Yamamoto, K.; Watanabe, S.; Maruoka, K. Chem.
Asian J. 2011, 6, 607.
a]
25 = À21.6 (c 0.53, MeOH) 97% ee. Liter-
D
a]
D = À20.9 (c 1.00, MeOH) 100% ee.3a The product
SumaniroleÁHCl (19.0 mg, 97% yield) as a white solid. IR (ATR)
m
2923, 2852, 1695, 1463, 1404, 1170, 1036, 778, 732 cmÀ1 1H
;
NMR (D2O): d 2.63 (s, 3H), 3.01 (dd, J = 3.6 Hz, 17.2 Hz, 1H), 3.10
(dd, J = 3.6 Hz, 17.2 Hz, 1H), 3.77 (dd, J = 3.2 Hz, 13.6 Hz, 1H), 3.86
(m, 1H), 3.98 (dd, J = 3.2 Hz, 13.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H),
6.84 (d, J = 7.6 Hz, 1H), 6.94 (dd, J = 7.6 Hz, 7.6 Hz, 1H) (Amine
and amide protons could not be observed in this conditions.); 13C
NMR (D2O): d 26.6, 31.8, 40.0, 52.9, 109.2, 114.5, 121.1, 123.3,
126.3, 126.5, 155.5; (+)-ESI-HRMS. Calcd for C11H14N3O+ (M+H+):
11. Minakata, S.; Murakami, Y.; Tsuruoka, R.; Kitanaka, S.; Komatsu, M. Chem.
Commun. 2008, 6363.
12. (a) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew, Chem, Int. Ed. 2006, 45, 8005;
(b) Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Pape, A. R.; Wincewicz, R. Org.
Lett. 2007, 9, 351; (c) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni,
G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew, Chem., Int. Ed. 2008, 47, 8703;
(d) Arai, H.; Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.; Hamada, Y.
Tetrahedron Lett. 2009, 50, 3329; (e) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.;
Zhang, Q.; Leijonmarck, H.; Córdova, A. Adv. Synth. Catal. 2010, 352, 3201; (f)
Vincentiis, F.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Galzerano,
P.; Melchiorre, P. Chem. Asian J. 2010, 5, 1652; (g) Menjo, Y.; Hamajima, A.;
Sasaki, N.; Hamada, Y. Org. Lett. 2011, 13, 5744; (h) Deiana, L.; Dziedzic, P.;
Zhao, G.-L.; Vesely, J.; Ibrahem, I.; Rois, R.; Sun, J.; Córdova, A. Chem. Eur. J. 2011,
17, 7904; (i) Armstrong, A.; Pullin, R. D. C.; Jenner, C. R.; Foo, K.; White, A. J. P.;
Scutt, J. N. Tetrahedron: Asymmetry 2014, 25, 74.
204.1131. Found: 204.1135; [
Literature data: [
a]
25 = À29.0 (c 0.43, MeOH) 97% ee.
D
a]
D = À30.3 (c 1.0, MeOH) 100% ee.3a
Acknowledgement
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Advanced Molecular Transforma-
tions by Organocatalysts’ from The Ministry of Education, Culture,
Sports, Science and Technology, Japan.
13. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 794; (b) Hayashi, Y.; Gotoh, T.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212.
14. Romero, A. G.; Darlington, W. H.; Jacobsen, E. J.; Mickelson, J. W. Tetrahedron
Lett. 1996, 37, 2361.