A concise enantioselective synthesis of 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxyquinolin-1(2H)-yl]propan-1-one, (S)-903

Article abstract of DOI:10.1016/j.tetasy.2009.01.019

A concise enantioselective synthesis of (S)-903, an inotropic agent, is described in nine linear steps and 95% ee based on asymmetric dihydroxylation of cinnamate ester and Co-catalyzed multifunctional reduction of several functional groups leading to the

Full text of DOI:10.1016/j.tetasy.2009.01.019

Tetrahedron: Asymmetry 20 (2009) 335–339
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A concise enantioselective synthesis of 1-[(S)-3-(dimethylamino)-3,4
dihydro-6,7-dimethoxyquinolin-1(2H)-yl]propan-1-one, (S)-903
*
Arun R. Jagdale, R. Santhosh Reddy, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise enantioselective synthesis of (S)-903, an inotropic agent, is described in nine linear steps and
95% ee based on asymmetric dihydroxylation of cinnamate ester and Co-catalyzed multifunctional reduc-
tion of several functional groups leading to the construction of core tetrahydroquinolin-3-ol, as the key
steps.
Received 2 December 2008
Accepted 21 January 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
NHMe
H
1. Introduction
HO
HO
N
Peptide
Substituted tetrahydroquinoline derivatives bearing various
simple and complex substituents are of medicinal and industrial
importance due to their pronounced activity in many physiological
processes.1,2 These core structures are present in numerous other
pharmacological agents such as Sumanirole maleate (PNU9566 E)
1, an anti-depressant agent for the treatment of Parkinson’s dis-
ease,3 Anachelin H 2, a secondary metabolite recently isolated from
the cyanobacterium Anabaena cylindrica, which serves as a ligand
for iron (siderophores) mediating iron uptake,4 and Vesnarinone
N
N
HN
H3C CH3
O
1
2
PNU 95666 E
Anachelin H chromophore
R
N
MeO
NMe2
N
3,
a
positive inotropic agent.5 1-[(S)-3-(Dimethylamino)-6,7-
dimethoxytetrahydroquinoline propanone 4 has been identified
as potentially interesting positive inotropic agent6 (Fig. 1). Also,
tetrahydroquinoline-based inhibitors have also been found to be
the most potent among several structural classes of protein far-
nesyl transferase inhibitors.7 Among the diverse strategies that
have been devised for the synthesis of tetrahydroquinolines,1b,8
the partial reduction of the heteroaromatic ring system has
emerged as one of the most useful routes.9 In contrast, only few
methods currently exist in the literature for the asymmetric syn-
thesis of 3-substituted tetrahydroquinolines. Prominent strategies
include the oxidative aza-annulation of chiral amino acids;10 the
MeO
N
N
H
O
O
R = 3, 4-dimethoxybenzoyl
4
3
, Vesnarinone
(S)-903
Figure 1. Structures of tetrahydroquinoline derivatives.
which proceeds via the multifunctional reduction of several func-
tional groups in a single step (Scheme 1).14 We proposed that the
simultaneous reduction of both nitro and cyclic sulfite groups
takes place to give the unstable species A, which underwent cycli-
zation to afford hydroxylactam B. Finally, the reduction of lactam
Rh-catalyzed reduction of
a
-amino cinnamates11 and asymmetric
dihydroxylation;12 and the epoxidation10 of olefins followed by
cyclization with aromatic amino group. Notably, the reported syn-
thesis of (S)-903 has been achieved by making use of chiral starting
materials involving lengthy reaction sequences.5
carbonyl in B assisted by a-hydroxyl group resulted in the forma-
tion of tetrahydroquinoline 6.
Herein, we report the application of this simple procedure for
the asymmetric synthesis of 1-[(S)-3-(dimethylamino)-6,7-
dimethoxytetrahydroquinoline-propanone, (S)-903 4.
In continuation with our studies on simultaneous reduction of
multifunctional moieties,13 we have recently reported a process
involving a Co-catalyzed one-step reduction of nitro cyclic sulfite
5 to give the corresponding 3-hydroxytetrahydroquinoline 6,
2. Results and discussion
The asymmetric synthesis of (S)-903 4 was carried out starting
from commercially available 3,4-dimethoxybenzaldehyde, which
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.019

336
A. R. Jagdale et al. / Tetrahedron: Asymmetry 20 (2009) 335–339
in 11 was then protected as its amide 12 [(EtCO)2O), Et3N, CH2Cl2].
O
The enantiomeric purity of 12 was determined to be 95% ee by
HPLC analysis. The free hydroxyl group in 12 was then activated
as its mesylate 13 followed by its SN2 displacement with NaN3
gave the azidoamide 14 in 91% yield over two steps with complete
S
O
O
OH
a
CO2Et
N
NO2
inversion {½a 2D5
ꢀ
¼ þ38:2 (c 2, CHCl3)}. The reduction of azide 14
H
5
6, 94% ee
[10% Pd/C, H2 (1 atm), MeOH)] followed by dimethylation of the
resulting amine (HCHO, HCO2H, reflux) gave 4 in 73% yield and
Scheme 1. Reagents and conditions: (a) CoCl2ꢂ6H2O (1 mol %), NaBH4 (4 equiv),
EtOH, 0–25 °C, 12 h.
95% ee {½a 2D5
ꢀ
¼ ꢁ3:2 (c 1, EtOH), lit.6
½
a 2D5
ꢀ
¼ ꢁ3:3 (c 1, EtOH)}.
3. Conclusion
on Wittig olefination produced (E)-ethyl 3-(3,4-dimethoxy-
phenyl)acrylate 7 in 95% yield. The Os-catalyzed asymmetric
dihydroxylation15 of (E)-ethyl 3-(3,4-dimethoxyphenyl)acrylate 7
was carried out using (DHQ)2-PHAL as the chiral ligand to provide
the chiral diol 8 in 95% yield. Initially, the regioselective nitration
of the aromatic nucleus with concentrated HNO3 was achieved,
although in lower yields, when the reaction was carried out in ace-
tic acid as solvent. However, the nitration with concentrated HNO3
in CH2Cl2 as solvent proceeded smoothly to give nitro diol 9 as a
single regioisomer in 70% yield. Nitro diol 9 was then treated with
thionyl chloride to produce nitro cyclic sulfite 10 in quantitative
yield.16 When 10 was subjected to Co-catalyzed multifunctional
reduction with NaBH4, tetrahydroquinolin-3-ol 11 was obtained
in 78% yield (Scheme 2). During this reduction process, we ob-
served that the simultaneous reduction of the nitro, the reductive
opening of cyclic sulfite, the reduction of ester moiety, and the
cyclization, all had occurred in a single step to produce tetrahydro-
quinolin-3-ol 11 in high yields.14 Mechanistically, we propose that
simultaneous reduction of both nitro and cyclic sulfite groups in 10
takes place to give the unstable species A, which undergoes cycli-
zation to afford hydroxylactam B. Finally, the reduction of lactum
In conclusion, we have achieved the concise synthesis of (S)-903
4 in nine linear steps with an overall yield of 24% and 95% ee by
employing the asymmetric dihydroxylation of cinnamate ester
coupled with a novel Co-catalyzed multifunctional reduction of
several functional groups that led to the construction of tetrahy-
droquinoline core as the key steps.
4. Experimental
4.1. General experimental
All melting points were measured on a Büchi 535 melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were re-
corded on Bruker AV200 MHz digital NMR spectrometer in CDCl3
or CD3OD. The solvents were purified and dried by the standard
procedures prior to use; petroleum ether of the boiling range 60–
80 °C was used for column chromatography. Optical rotations were
measured using sodium D line on a JASCO-P-1020-polarimeter.
Infrared spectra were recorded on Perkin–Elmer FT-IR spectrome-
ter. Elemental analyses were carried out with a Carlo Erba CHNS-O
analyzer. Enantiomeric excess of the products was determined by
Mosher’s ester analysis, Chiral HPLC [Column: Cromasil 5-Cellu-
carbonyl in B assisted by a-hydroxyl group resulted in the forma-
tion of tetrahydroquinoline 11 (Scheme 3). The amine functionality
O
S
O
O
OH
O
O
MeO
MeO
MeO
MeO
MeO
MeO
a
c
OEt
OEt
CO2Et
OH
R
NO2
8, R = H
10
7
b
9, R = NO2
MeO
MeO
N3
MeO
MeO
OMs
MeO
MeO
OH
d
g
f
N
N
N
R
O
O
11, R = H
12, R = COEt, 95.5 % ee
14
13
e
MeO
MeO
NMe2
h-i
N
O
4
95% ee
Scheme 2. Reagents and conditions: (a) K2OsO4 (0.1 mol %), (DHQ)2-PHAL (0.5 mol %), K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), MeSO2NH2 (1 equiv), tert-BuOH/H2O (1:1), 25 °C,
24 h, 95%; (b) concd HNO3, CH2Cl2, 0–25 °C, 30 min 70%; (c) SOCl2, Et3N, CH2Cl2, 0 °C, 30 min; (d) CoCl2ꢂ6H2O (1 mol %), NaBH4 (4 equiv), EtOH, 0–25 °C, 12 h, 78% over two
steps; (e) (EtCO)2O, Et3N, CH2Cl2, 0 °C, 6 h, 82%; (f) MsCl, Et3N, CH2Cl2, 0 °C, 10 min; (g) NaN3, DMF, 80 °C, 12 h, 91% over two steps; (h) H2 (1 atm), 10% Pd/C, MeOH, 25 °C,
12 h; (i) HCHO, HCO2H, 80 °C, 3 h, 73% over two steps.

A. R. Jagdale et al. / Tetrahedron: Asymmetry 20 (2009) 335–339
337
O
H-
S
O
CoCl2/
NaBH4
OH
MeO
MeO
O
MeO
MeO
CO2Et
CO2Et
NO2
NH2
EtOH
A
10
CoCl2/
NaBH4
OH
O
OH
MeO
MeO
MeO
MeO
N
N
H
H
11
B
Scheme 3. Mechanistic pathway for the Co-catalyzed reduction of nitro cyclic sulfite.
Coat, Length 250 mm, i.d. 4.6 mm, wavelength: 220 nm], or com-
paring the specific rotation of the known compounds. All evapora-
tions were performed under reduced pressure. For column
chromatography, silica gel (230–400 mesh) was employed.
was monitored by TLC. After completion, 50 mL of water was
added. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (2 ꢃ 50 mL). The combined organic lay-
ers were washed with brine (50 mL), dried over anhyd Na2SO4, and
concentrated under reduced pressure to give the crude product
that was purified by column chromatography [silica gel (230–400
mesh) and petroleum ether/EtOAc (60:40) as an eluent] to give
2.2 g of 9 in pure form. Yield: 70%; yellow solid, mp: 131 °C;
4.2. (E)-Ethyl 3-(3,4-dimethoxyphenyl)acrylate 7
To a stirred solution of 3,4-dimethoxybenzaldehyde (4.72 g,
20 mmol) in benzene (50 mL), Ph3P@CHCO2Et (8.70 g, 25 mmol)
was added. It was then refluxed for 4 h under a N2 atmosphere.
After completion of reaction, benzene was distilled out to give
the crude product. Chromatographic purification of the crude prod-
uct [silica gel (230–400 mesh) and petroleum ether/ethyl acetate
(90:10) as eluent] afforded cinnamate 7 (4.5 g). Yield: 95%, gum;
1H NMR (200 MHz, CDCl3): d 1.34 (t, J = 7.1 Hz, 3H), 3.91 (s, 6H)
4.25 (q, J = 7.1 Hz, 2H), 6.29 (d, J = 15.9 Hz, 1H), 6.85 (d, J = 8.2 Hz,
1H), 7.04–7.14 (m, 2H), 7.61 (d, J = 15.9 Hz, 1H); 13C NMR (CDCl3):
d 14.1, 55.4, 55.5, 59.9, 109.3, 110.7, 115.6, 122.2, 127.1, 144.1,
148.9, 150.8, 166.6. Anal. Calcd for C13H16O4: C, 66.09; H, 6.83.
Found: C, 66.01; H, 6.77.
½
a 2D5
ꢀ
¼ þ105:2 (c 1, CHCl3); IR (CHCl3): 787, 848, 937, 1049, 1240,
1371, 1747, 2985, 3460, 3640 cmꢁ1 1H NMR (200 MHz, CDCl3): d
;
1.34 (t, J = 7.1 Hz, 3H), 3.95 (s, 3H), 4.01 (s, 3H), 4.33 (q,
J = 7.1 Hz, 2H), 4.51(d, J = 2.2 Hz, 1H), 5.85 (d, J = 2.2 Hz, 1H), 7.33
(s, 1H), 7.65 (s, 1H); 13C NMR (50 MHz, CDCl3): d 13.3, 55.1, 55.3,
60.1, 69.0, 72.7, 106.1, 111.0, 132.3, 138.3, 146.6, 152.1, 171.6.
Anal. Calcd for C13H17NO8: C, 49.52; H, 5.43; N, 4.44. Found: C,
49.65; H, 5.23; N, 4.55.
4.5. Nitro cyclic sulfite 10
To a stirred solution of nitro diol 9 (1.90 g, 6.0 mmol) and trieth-
ylamine (3.00 mL, 18 mmol) in CH2Cl2 (20 mL), was added freshly
distilled thionyl chloride (0.5 mL, 7 mmol) dropwise under a nitro-
gen atmosphere at 0 °C and allowed to stir at 0 °C for 30–45 min
(monitored by TLC). The reaction mixture was quenched by the
addition of cold water (20 mL) and a saturated solution of NaHCO3
(20 mL). The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (2 ꢃ 30 mL). The combined organic ex-
tracts were washed with brine, dried over anhyd Na2SO4, and con-
centrated under reduced pressure to give crude nitro cyclic sulfite
10. Nitro cyclic sulfite was found to be very labile and air sensitive,
which was then subjected to Co-catalyzed reduction without puri-
fication. Yield: 92%; Gum; IR (CHCl3): 648, 771, 914, 1066, 1278,
4.3. (2R,3S)-Ethyl 2,3-dihydroxy-3-(3,4-
dimethoxyphenyl)propanoate 8
A 500-mL RB flask was charged with K3Fe(CN)6 (14.8 g mmol),
K2CO3 (6.21 g, 45 mmol), MeSO2NH2 (1.42 g, 15 mmol), tert-BuOH
(75 mL), and H2O (75 mL). The reaction mixture was stirred for
10 min after which (DHQ)2-PHAL (1 mol %) and K2OsO4 (0.2 mol %)
were addedand stirred foran additional30 min. Tothereactionmix-
ture, ester 7 was added and allowed to stir for 24 h at 25 °C. After the
completion of the reaction, sodium bisulfite (5 g) was slowly added
at 0 °C. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (3 ꢃ 100 mL). The combined organic
layer was washed with brine (200 mL), dried over sodium sulfate,
and concentratedunder reduced pressureto yield thecrude product.
Flash column chromatographic purification [silica gel (230–400
mesh) and petroleum ether/EtOAc (60:40) as an eluent] afforded 8
1340, 1525, 1585, 1748, 2976, 3028 cmꢁ1 1H NMR (200 MHz,
;
CDCl3): d 1.35 (t, J = 7.2 Hz, 3H), 3.09 (s, 6H), 4.30–3.41 (q,
J = 7.2 Hz, 2H), 6.12 (d, J = 5.9 Hz, 1H), 6.50 (d, J = 5.9 Hz, 1H),
7.28 (s, 1H), 7.68 (s, 1H); 13C NMR (50 MHz, CDCl3): d 13.54,
56.09, 56.27, 62.58, 83.58, 105.95, 109.60, 125.96, 139.36, 148.69,
153.77, 166.10.
in pure form. Yield: 95%; Gum, ½a D25
¼ þ3:5 (c 1.5, CHCl3); IR (CHCl3):
ꢀ
848, 939, 1047, 1240, 1373, 1446, 1517, 1737, 2983, 3500 cmꢁ1; 1H
NMR (200 MHz, CDCl3): d 1.28 (t, J = 7.1 Hz, 3H), 3.88 (s, 3H), 3.90 (s,
3H), 4.27 (q, J = 7.1 Hz, 2H), 4.35 (d, J = 3.1 Hz, 1H), 4.95 (d, J = 3.1 Hz,
1H), 6.84–6.98 (m, 3H); 13C NMR (50 MHz, CDCl3): d 13.8, 55.6, 55.7,
61.7, 74.2, 74.8, 109.4, 110.6, 118.4, 132.4, 148.4, 148.6, 172.6. Anal.
Calcd for C13H18O6: C, 57.77; H, 6.71. Found: C, 57.47; H, 6.63.
4.6. (R)-1,2,3,4-Tetrahydro-6,7-methoxyquinolin-3-ol 11
To a stirred solution of nitro cyclic sulfite 10 (6 mmol) and
CoCl2ꢂ6H2O (14 mg, 1 mol %) in 95% ethanol (30 mL), NaBH4
(0.91 g, 24 mmol) was added at 0 °C and allowed to stir at 25 °C
for 12 h. After completion of reaction, it was poured into ice cold
water to form a black precipitate. To the aqueous layer, 100 mL
of ethyl acetate was added, and the combined mixture was passed
through Celite. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (2 ꢃ 50 mL). The combined
organic layers were washed with brine (2 ꢃ 50 mL), dried over an-
hyd Na2SO4, and concentrated under reduced pressure to give the
4.4. (2R,3S)-Ethyl 2,3-dihydroxy-3-(4,5-dimethoxy-2-
nitrophenyl)propanoate 9
To a stirred solution of diol 8 (2.70 g, 10 mmol) in CH2Cl2
(40 mL), concd HNO3 (2 mL, d = 1.4) was added dropwise at 0 °C.
The mixture was stirred for 30 min and progress of the reaction

338
A. R. Jagdale et al. / Tetrahedron: Asymmetry 20 (2009) 335–339
crude product. Chromatographic purification of the crude product
[flash silica gel (230–400 mesh) and petroleum ether/ethyl ace-
tate/Et3N (60:38:2)] gave 1.02 g of pure (R)-1,2,3,4-tetrahydro-
4.9. 1-[(R)-3-Azido-3,4-dihydro-6,7-dimethoxyquinolin-1(2H)-
yl]propan-1-one 14
6,7-methoxyquinolin-3-ol 11. Yield: 78%; gum; ½a D25
ꢀ
¼ þ25:4 (c
To a stirred solution of mesylate 13 in dry DMF (10 mL), was
added NaN3 (1.30 g, 20 mmol). It was then stirred for 16 h at
80 °C. After completion of the reaction (monitored by TLC), it was
poured into 50 mL of ice cold water and extracted with ethyl ace-
tate (3 ꢃ 50 mL). The combined organic layers were washed with
brine (2 ꢃ 25 mL), dried over anhyd Na2SO4, and concentrated un-
der reduced pressure to give the crude product. Chromatographic
purification of the crude product [silica gel (230–400 mesh) and
petroleum ether/ethyl acetate (70:30)] gave azide 14 in pure form.
1.26, CHCl3); IR (CHCl3): 769, 1215, 1423, 1647, 3456 cmꢁ1
;
1H
NMR (200 MHz, CDCl3): d 2.63–2.73 (dd, J = 3.9, 16.5 Hz, 1H),
2.85 (br s, 2H), 2.92–3.02 (dd, J = 4.3, 16.5 Hz, 1H), 3.20–3.22 (m,
2H), 3.78 (s, 3H), 3.79 (s, 3H), 4.13–4.22 (m, 1H), 6.12 (s, 1H),
6.50 (s, 1H); 13C NMR (50 MHz, CDCl3): d 34.2, 47.6, 55.5, 56.3,
63.3, 99.3, 110.1, 113.9, 137.2, 141.6, 148.0; MS: 209, 194, 176,
166, 148, 133, 120, 103, 91, 77, 65, 44. Anal. Calcd for
C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.09; H, 7.17;
N, 6.61.
Yield: 91%; Gum; ½a D25
ꢀ
¼ þ38:2 (c 2, CHCl3); IR (CHCl3): 757, 1043,
1217, 1514, 1650, 1735, 2110, 3018 cmꢁ1
;
1H NMR (200 MHz,
CDCl3): d 1.22 (t, J = 7.3 Hz, 3H), 2.57 (q, J = 7.3 Hz, 2H), 2.78–2.88
(dd, J = 5.5, 16.0 Hz, 1H), 3.04–3.15 (dd, J = 5.4, 16.6 Hz, 1H),
3.72–3.82 (m, 1H) 3.89 (s, 3H), 3.90 (s, 3H), 3.99–4.13 (m, 2H),
6.68 (br s, 2H); 13C NMR (50 MHz, CDCl3): d 9.5, 27.4, 31.7, 46.5,
55.7, 55.8, 56.1, 108.1, 110.9, 119.8, 130.8, 146.8,146.9, 173.3. Anal.
Calcd for C14H18N4O3: C, 57.92; H, 6.25; N, 19.30. Found: C, 57.88;
H, 6.20; N, 19.33.
4.7. 1-[(R)-3, 4-Dihydro-3-hydroxy-6,7-dimethoxyquinolin-
1(2H)-yl]propan-1-one 12
To a stirred solution of tetrahydroquinolin-3-ol 11 (4 mmol)
and Et3N (1.4 mL, 10 mmol) in 20 mL of CH2Cl2, propionic anhy-
dride (6.5 mL, 5 mmol) was added at 25 °C, and was stirred for
3 h. The progress of the reaction was monitored by TLC and after
completion of reaction, saturated aq NaHCO3 (30 mL) was added.
The organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2 (2 ꢃ 50 mL). The combined organic layers were
washed with brine (2 ꢃ 25 mL), dried over anhyd Na2SO4, and con-
centrated under reduced pressure to give the crude product. Chro-
matographic purification [silica gel (230–400 mesh) and petroleum
ether/ethyl acetate (60:40)] of the crude product gave amido alco-
hol 12 in pure form. Yield: 82%; Gum; Chiral Column: Cromasil 5-
CelluCoat column, length 250 mm, i.d. 4.6 mm, wavelength:
220 nm, flow rate 0.8 mL per min. Mobile phase: 10% isopropyl
alcohol in hexane. Retention time: 27.608 (97.7%) and 30.850
4.10. 1-[(R)-3-(Dimethylamino)-3,4-dihydro-6,7-
dimethoxyquinolin-1(2H)-yl]-propan-1-one 4
To a solution of azide 14 (2 mmol) in methanol (10 mL), was
added 10% Pd/C (40 mg). It was stirred under H2 (1 atmosphere,
balloon pressure) for 12 h. After completion of reaction (monitored
by TLC), it was passed through column packed with Celite and con-
centrated under reduced pressure to afford the crude amine. To the
crude amine, 40% aq solution HCHO (1 mL) and HCO2H (2 mL) were
added, and the resulting mixture was refluxed for 3 h. After com-
pletion of the reaction, a saturated aq NaHCO3 solution (10 mL)
was added, and the mixture was extracted with ethyl acetate
(3 ꢃ 20 mL). The combined organic layer was washed with brine
(2 ꢃ 20 mL), dried over anhyd Na2SO4, and concentrated under re-
duced pressure. Chromatographic purification of the crude product
[silica gel (230–400 mesh) and petroleum ether/ethyl acetate/tri-
ethyl amine (60:38:2) as eluent] gave pure (S)-903 4. Yield: 73%;
(2.2%). Ee = 95.5%; ½a D25
ꢀ
¼ þ8:7 (c 1.15, CHCl3); IR (CHCl3): 846,
937, 1240, 1388, 1514, 1660, 1751, 2983, 3529 cmꢁ1
;
1H NMR
(200 MHz, CDCl3): d 1.18 (t, J = 7.3 Hz, 3H), 2.56 (q, J = 7.3 Hz,
2H), 2.67–2.78 (dd, J = 4.6, 16.5 Hz, 1H), 2.98–3.09 (dd, J = 5.4,
16.5 Hz, 1H), 3.86 (s, 6H), 3.74–3.95 (m, 2H), 4.32 (m, 1H), 6.63
(br s, 2H); 13C NMR (50 MHz, CDCl3): d 8.6, 27.4, 35.0, 49.7, 55.6,
65.0, 108.0, 111.1, 122.4, 130.7, 146.3, 174.3; MS: 265, 209, 194,
176, 166, 148, 133, 120, 104, 91, 77, 57, 44. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.43; H, 7.19;
N, 5.22.
mp 136 °C [lit.5 135–137 °C];
½
a 2D5
ꢀ
¼ ꢁ3:2 (c 1, EtOH) {lit.
½
a 2D5
ꢀ
¼ ꢁ3:3 (c 1, EtOH)};5 IR (CHCl3): 760, 1049, 1211, 1511,
1647, 1743, 3018, 3450 cmꢁ1 1H NMR (200 MHz, CDCl3): d 1.12
;
(t, J = 7.3 Hz, 3H), 2.35 (s, 6H), 2.46 (q, J = 7.3 Hz, 2H), 2.80–2.91
(m, 2H), 3.23–3.54 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 6.64 (br s,
2H); 13C NMR (50 MHz, CDCl3): d 9.8, 27.5, 29.5, 41.3, 41.4, 55.9,
55.9, 61.4, 61.8, 108.2, 111.1, 128.6, 131.8, 146.9, 173.0. Anal. Calcd
for C15H21N2O3: C, 64.96; H, 7.63; N, 10.10. Found C, 64.82; H, 7.60;
N, 10.27.
4.8. (R)-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-
propionylquinolin-3-yl methane-sulfonate 13
To a stirred solution of amide 12 (4 mmol) and triethyl amine
(1.4 mL, 10 mmol) in 20 mL of CH2Cl2, methane sulfonyl chloride
(5 mmol, 0.5 mL) was added at 0 °C. It was then stirred for
15 min. After completion of the reaction (monitored by TLC), a
saturated aq solution of NaHCO3 (30 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 ꢃ 50 mL). The combined organic layers were washed
with brine (2 ꢃ 25 mL), dried over anhyd Na2SO4, and concen-
trated under reduced pressure to give crude mesylate. An attempt
to purify mesylate was unsuccessful as they undergo elimination
readily. Since the mesylate was difficult to purify, it was con-
verted to the corresponding azide without purification. However,
the formation of mesylate 13 was confirmed by its TLC, 1H and
Acknowledgments
A.R.J. and R.S.R. are grateful to CSIR, New Delhi for the award of
research fellowship. The authors are also thankful to Dr. B. D. Kulk-
arni, Head, CEPD, for his constant support and encouragement.
References
1. For reviews see: (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A.
Chem. Rev. 1997, 97, 787–828; (b) Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031–15070.
2. (a) Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa, T.; Takahashi,
K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull. 1995, 43, 378–391; (b) Konishi, M.;
Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, I. J. Am. Chem. Soc. 1990,
112, 3715–3716; (c) Ogawa, T.; Ichimura, M.; Katsumata, S.; Morimoto, M.;
Takahashi, K. J. Antibiot. 1989, 42, 1299–1301; (d) Omura, S.; Nakagawa, A.
Tetrahedron Lett. 1981, 22, 2199–2202.
13C NMR spectra. 1H NMR (200 MHz, CDCl3):
d 1.18 (t,
J = 7.3 Hz, 3H), 2.52 (q, J = 7.3 Hz, 2H), 3.04 (s, 3H), 2.95–3.22
(m, 2H), 3.72–3.82 (m, 1H) 3.86 (s, 6H), 3.81–3.92 (m, 1H),
4.06–4.33 (m, 1H), 5.22 (m, 1H), 6.63 (br s, 2H); 13C NMR
(50 MHz, CDCl3): d 9.6, 27.4, 33.0, 38.3, 46.4, 55.8, 74.3, 108.2,
11.0, 128.5, 130.9, 147.1, 173.6.
3. (a) Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P. Org. Process Res. Dev.
2005, 9, 997–1002; (b) Hulin, B.; Lopaze, M. G. Tetrahedron: Asymmetry 2004,

A. R. Jagdale et al. / Tetrahedron: Asymmetry 20 (2009) 335–339
339
15, 1957–1958; (c) Jian, Z. J. Label. Compd. Radiopharm. 2004, 47, 609–614; (d)
Wuts, P. G. M.; Gu, R. L.; Northuis, J. M.; Kwan, T. A.; Beck, D. M.; White, M. J.
Pure Appl. Chem. 2002, 74, 1359–1368; (e) Wuts, P. G. M. Curr. Opin. Drug Discov.
Dev. 1999, 2, 557–564; (f) Romero, A. G.; Darlington, W. H.; McMillan, M. W. J.
Org. Chem. 1997, 62, 6582–6587; (g) 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–
646; (h) Moon, M. W.; Morris, J. K.; Heier, R. F.; Chidester, C. G.; Hoffmann, W.
E.; Piercey, M. F.; Althaus, J. S.; VonVoigtlander, P. F.; Evans, D. L.; Figur, L. M.;
Lahtis, R. A. J. Med. Chem. 1992, 35, 1076–1092.
8. (a) Zhu, G.; Pang, K.; Parkin, G. J. Am. Chem. Soc. 2008, 130, 1564–1565; (b)
Kinney, W. A.; Teleha, C. A.; Thompson, A. S.; Newport, M.; Hansen, R.;
Ballentine, S.; Ghosh, S.; Mahan, A.; Grasa, G.; Zanotti-Gerosa, A.; Dingenen, J.;
Schubert, C.; Zhou, Y.; Leo, G. C.; McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E.
J. Org. Chem. 2008, 73, 2302–2310; (c) Fujita, K.; Kitatsuji, C.; Furukawa, S.;
Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215–3217; (d) Bouyssou, P.; Le Goff,
C.; Chenault, J. J. Heterocycl. Chem. 1992, 29, 895–898; (e) Schaus, J. M.; Huser,
D. L.; Titus, R. D. Synth. Commun. 1990, 20, 3553–3562; (f) Gracheva, I. N.;
Tochilkin, A. I. Chem. Heterocycl. Comp. (Eng. Trans.) 1988, 65–67; (g)
Murahashi, S.-I.; Imada, Y.; Hirai, Y. Tetrahedron Lett. 1987, 28, 77–80.
9. (a) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 7357–7360; (b)
Steinhagen, H.; Corey, E. J. Org. Lett. 1999, 1, 823–824; (c) Katritzky, A. R.;
Rachwal, B.; Rachwal, S. J. Org. Chem. 1995, 60, 2588–2596; (d) Katritzky, A. R.;
Rachwal, B.; Rachwal, S. J. Org. Chem. 1995, 60, 7631–7640; (e) Fujita, K.;
Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 4, 2691–2694; (f) Fujita, K.;
Yamamoto, K.; Yamaguchi, R. Org. Lett. 2001, 3, 2053–2056; (g) Tokes, A. L.;
Litkei, G.; Szilagyi, L. Synth. Commun. 1992, 22, 2433–2445.
4. (a) Gademann, K.; Bethuel, Y.; Locher, H. H.; Hubschwerlen, C. J. Org. Chem.
2007, 72, 8361–8370; (b) Zurcher, S.; Wackerlin, D.; Bethuel, Y.; Malisova, B.;
Textor, M.; Tosatti, S.; Gademann, K. J. Am. Chem. Soc. 2006, 128, 1064–1065; (c)
Bethuel, Y.; Gademann, K. J. Org. Chem. 2005, 70, 6258–6264; (d) Gademann, K.;
Bethuel, Y. Org. Lett. 2004, 6, 4707–4710; (e) Gademann, K.; Bethuel, Y. Angew.
Chem., Int. Ed. 2004, 43, 3327–3329; (f) Ito, Y.; Ishida, K.; Okada, S.; Murakami,
M. Tetrahedron 2004, 60, 9075–9080; (g) Gademann, K.; Budzikiewicz, H.
Chimia 2004, 58, 212–214.
10. For review, see: Lawrence, A. K.; Gademann, K. Synthesis 2008, 331–351.
11. Gallou-Dagommer, I.; Gastaud, P.; RajanBabu, T. V. Org. Lett. 2001, 3, 2053–
2056.
5. Santangelo, F.; Casagrande, C.; Miragoli, G.; Vecchietti, V. Eur. J. Med. Chem.
1994, 29, 877–882.
6. (a) Wang, T.; Zhang, Z.; Meanwell, N. A. J. Org. Chem. 1999, 64, 7661–7662; (b)
Fujioka, T.; Teramoto, S.; Mori, T.; Hosokawa, T.; Sumida, T.; Tominaga, M.;
Yabuuchi, Y. J. Med. Chem. 1992, 35, 3607–3612.
7. Van Voorhis, W. C.; Rivas, K. L.; Bendale, P.; Nallan, L.; Hornéy, C.; Barrett, L. K.;
Bauer, K. D.; Smart, B. P.; Ankala, S.; Hucke, O.; Verlinde, C. L. M. J.; Chakrabarti,
D.; Strickland, C.; Yokoyama, K.; Buckner, F. K.; Hamilton, A. D.; Williams, D. K.;
Lombardo, L. J.; Floyd, D.; Gelb, M. H. Antimicrob. Agents Chemother. 2007,
3659–3671.
12. Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1997, 119, 311–325.
13. (a) Jagdale, A. R.; Sudalai, A. Tetrahedron Lett. 2008, 49, 3790–3793; (b) Jagdale,
A. R.; Paraskar, A. S.; Sudalai, A. Synthesis, in press.; (c) Paraskar, A. S.; Sudalai,
A. Tetrahedron 2006, 2, 5756–5762.
14. Jagdale, A. R.; Reddy, R. S.; Sudalai, A. Org. Lett. 2009, doi:10.1021/o18028109.
15. For review, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547.
16. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–7539.