Organocatalytic asymmetric intramolecular aza-Henry reaction: Facile synthesis of trans-2,3-disubstituted tetrahydroquinolines

Article abstract of DOI:10.1039/c5ob00795j

An enantio- and diastereoselective organocatalytic intramolecular aza-Henry (nitro-Mannich) reaction has been developed. The trans-2-aryl-3-nitro-tetrahydroquinoline products are obtained in high yields and in good enantioselectivities with a bifunctional

Full text of DOI:10.1039/c5ob00795j

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ARTICLE TYPE
Organocatalytic asymmetric intramolecular aza-Henry reaction: Facile
synthesis of trans-2,3-disubstituted tetrahydroquinolines
Rajendra Maity and Subhas Chandra Pan*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An
intramolecular aza-Henry (nitro-Mannich) reaction has been
developed. The trans-2-aryl-3-nitro-tetrahydroquinoline
products are obtained in high yields and in good
10 enantioselectivities with bifunctional tertiary amine-
enantio-
and
diastereoselective
organocatalytic
O
Previous reports:
O
Ar
NO2
(1)
X u etal.
Ar
+ CH3NO2
X
X
a
N
R
O
N
H
R
thiourea catalyst. Excellent enantioselectivities were obtained
after single recrystallization for some products.
O
W ang,
Kim and
Du etal.
The interest for the synthesis of nitrogen heterocycles is
persistent due to their importance in medicinal chemistry and
R
NO2
NO2
(2)
R
+
X
15 presence in
a
plethora of natural products. The
X
R1
tetrahydroquinoline system is one of the privileged scaffolds
present in drugs and natural products.1 Thus the development of
new strategies and protocols for the synthesis of
tetrahydroquinoline derivatives, particularly in enantiomerically
20 pure form, is an important task for synthetic chemists.2
Asymmetric Povarov reaction,3 reduction of quinolines,4 aza-
Michael additions5 and internal redox processes6 are the common
NHPG
N
R1
PG
NO2
(3)
R
NO2
R
Zhou etal.
X
Hantzsch
ester
X
+
N
H
N
cis
four
strategies
for
the
synthesis
of
enantiopure
This work:
X
tetrahydroquinolines.
25 Here in we wish to report an enantio and diastereoselective
synthesis of trans-2-aryl/alkyl-3-nitro-tetrahydroquinolines using
an alternate strategy namely intramolecular direct aza-Henry
reaction.7 Xu and co-workers earlier reported an asymmetric
tandem Michael/aza-Henry reaction for the synthesis of
30 trisubstituted terahydroquinolines having 2-aryl and 3-nitro
functionalities (Figure 1, eq. 1).8a Recently, similar types of
compounds with N-protections were synthesized by aza-Michael-
Michael strategies using nitroolefins (eq. 2).5 But a simple direct
aza-Henry reaction for the synthesis of disubstituted chiral
35 tetrahydroquinolines is still not known and importantly such
skeleton is present in Benzastatin D,9 a potent cholesteryl ester
transfer protein inhibitor and in P antagonist substance. Chiral 2-
aryl-3-nitro-1,2,3,4-tetrahydroquinolines have been previously
synthesized by chiral phosphoric acid catalyzed transfer
40 hydrogenation of 2-aryl-3-nitroquinolines but only cis
diastereoselectivity was observed (eq. 3).4j Here we demonstrate
an approach that provides trans-isomer as the predominant
product (eq. 4) and follows an intramolecular nitro-Mannich
reaction whose achiral version was previously reported by
45 Anderson and co-workers.10
NO2
(4)
R
NO2
X
+
RCHO
NH2
N
H
trans
50 Figure 1 Synthetic approaches to 2,(4)-(di)functionalized-3-nitro-
tetrahydroquinolines
desired intramolecular nitro-Mannich product 3a was isolated in
65% yield with 40% ee in perfect diastereoselectivity (Table 1,
55 entry 1). However, a racemic product was obtained with catalyst
II having pyrrolidine moiety (entry 2). Then bifunctional tertiary
amine-squaramide catalyst (III) was prepared. Surprisingly, with
this catalyst, no product was obtained. Then catalyst IV with an
extra chiral centre has been screened. Though desired product 3a
60 was obtained with catalyst IV, the enantioselectivity was poor
(entry 4). Gratifyingly, both yield and enantioselectivity was
improved with quinine derived bifunctional thiourea catalyst V
(entry 5).11 An enhancement in enantioselectivity (66% ee) was
observed by changing the solvent to chloroform (entry 6). Finally
65 the best solvent was found to be a mixture of pentane and
dichloromethane (5:1) that provided the product in 85% yield and
74%ee (entry 7, see supporting information for solvent
We started our experiments by treating a mixture of nitroalkane
1a and benzaldehyde (2a) with Takemoto catalyst (I) in toluene
at room temperature. After stirring for three days the
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Table 1 Catalyst screening and optimization of reaction condition
Table 2 Substrate scope for the intramolecular aza-Henry
15 reaction
CF3
CF3
O
O
R1
R1
catalyst V
(10 mol%)
S
NO2
+
NO2
R2
R2CHO
N
N
H
CF3
N
H
N
H
CF3
pentane: CH2Cl2
(5:1, 0.2 M)
RT, 3 d
H
NH2
N
H
2
NR2
NMe2
III
1
I: R = Me
II: R = -(CH2)4-
3a-3s
R1 = H, 4-Cl, 3-Cl,
R
5-NMe2, 4-CF3
H
N
entrya
1
R1
R2
Ph
3
yieldb
eec
S
iBu
NH
H
H
3a
85 74 (98)
90 67 (94)
78 61
N
N
Ar
N
H
N
H
O
2
4-MeC6H4
4-tBuC6H4
4-iPrC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
3b
3c
3d
3e
3f
iBu
S
N
H
3
H
NMe2
Ar = 3,5-(CF3)2C6H3
V: R = OMe
VI: R = H
IV
4
H
75 52
5
H
83 70 (96)
80 58 (94)
80 68 (99)
60 60
R
6
H
N
H
7
H
3g
3h
3i
8
H
4-OMeC6H4
4-PhC6H4
2-ClC6H4
3-BrC6H4
HN
9
H
95 61 (78)
75 40 (99)
85 47
Ar
N
10
11
12
13
14
15
16
17
18
19
H
3j
N
H
S
H
3k
Ar = 3,5-(CF3)2C6H3
VII: R = OMe
H
2,4-(Me)2C6H3 3l
91 70 (95)
75 28
H
Cinnamyl
nBu
nPr
3m
3n
3o
3p
3q
3r
VIII: R = H
H
82 68
H
81 63
NO2
catalyst
(10 mol%)
NO2
Ph
4-Cl
3-Cl
5-NMe2
4-CF3
Ph
70 75 (88)
72 62 (74)
80 64 (76)
69 76 (82)
Ph
+
PhCHO
solvent (0.2 M)
RT, 3 d
NH2
N
H
Ph
Ph
3s
1a
2a
3a
aReaction condition: 0.12 mmol of 1 with 0.16 mmol of 2 in 0.6
mL solvent using 10 mol% catalyst. bIsolated yield after silica gel
c
column chromatography. Determined by HPLC using stationary
entrya
catalyst
solvent
yieldb
65
eec
20 phase chiral column, ees in parenthesis are after recrystallization.
____________________________________________________
1
2
3
4
5
6
7
I
toluene
toluene
toluene
toluene
toluene
CHCl3
-40
0
II
50
III
IV
V
0
-
room temperature improved the enantioselectivity of product 3a
from 74% to 98% enantiomeric excess.
50
5
70
48
66
74
25 After the detection of optimized condition, we ventured in the
scope of the reaction. Initially, different aldehydes were reacted
with nitroalkane 1a and our reaction condition was found to be
suitable for a variety of aryl and aliphatic aldehydes affording
only trans-isomer (Table 2). In particular different para-
30 substituted benzaldeydes were found to provide the products in
high yields with good enantioselectivities (entries 1-9). 4-
Methylbenzaldehyde (2b) afforded the product 3b in 67% ee and
pleasingly it was improved to 94% ee after recrystallization
(entry 2). However other 4-alkyl substituted benzaldehyde
35 derived products are sticky liquids and did not crystallize under
various conditions (entries 3-4). Interestingly, solid crystalline
products (3e-3g) were obtained from 4-halo substituted
benzaldehydes in high yields with good optical purities (entries 5-
7). Excellent enantioselectivities could be attained after single
40 recrystallization for these products. Anisaldehyde delivered a
sticky liquid product in moderate yield with modest
enantioselectivity (entry 8). On the other hand a solid product 3i
was attained from biphenyl-4-carbaldehyde in excellent yield
(95%) with similar enantioselectivity which could be enhanced to
V
75
V
pentane/CH2Cl2
(5:1)
85
8
9
VI
VII
VIII
pentane/CH2Cl2
(5:1)
85
80
81
-60
-60
55
pentane/CH2Cl2
(5:1)
10
pentane/CH2Cl2
(5:1)
aReaction condition: 0.12 mmol of 1a with 0.16 mmol of 2a in
0.6 mL solvent using 10 mol% catalyst. bIsolated yield after silica
gel column chromatography. cDetermined by HPLC using
stationary phase chiral column.
5
____________________________________________________
screening). Under this condition other Cinchona alkaloid derived
thiourea catalysts VI-VIII were screened (entries 8-10).
10 Unfortunately, the enantioselectivity did not improve with these
catalysts. Lowering the temperature to 0 oC improves the
enantioselectivity to 80% ee but the diastereoselectivity was poor
(1:1). To our delight, a single recrystallization from ethanol at
2
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N
78% ee after recrystallization (entry 9). Decreased
CF3
enantioselectivities were obtained for the products derived from
ortho- and meta-substituted benzaldehydes (entries 10-11).
However, the enantioslectivity of product 3j could be improved
to excellent 99% ee after single crystallization (entry 10). 2,4-
Dimethylbenzaldehyde provided product 3l in 91% yield with
70% ee and here also the enantioselecitivity could be improved to
95% ee after recrystallization (entry 12). Cinnamaldehyde could
also be used in our reaction but poor enantioselectivity was
OMe
S
N
H
N
H
F3C
5
N
O
O
N
Ph
H
O
N
N
O
deprotonation
10 attained for the product 3m (entry 13). Aliphatic aldehydes are
challenging substrates for this kind of reaction due to imine-
enamine tautomerization. Gratifyingly, aliphatic aldehydes were
successfully enagaged in our reaction and moderate
enantioselectivities were obtained for the products 3m and 3o
15 (entries 14-15). Then different nitroalkanes having substitutions
on the aryl group were prepared and reacted with benzaldehyde
under the reaction condition (entries 16-19). 4-Chloro-substituted
nitroalkane 1b provided product 3p in 70% yield with 75% ee
which can be boosted upto 88% ee after crystallization (entry 16).
20 Similarly 3-chloro-substituted nitroalkane 1c resulted in the
formation of product 3q in 72% yield and with slightly lower
enantioselectivity (62% ee). The enantioselectivity can be
augmented to 74% ee after crystallization (entry 17). The chloro
functionalities in products 3p and 3q could be exploited in Pd
25 catalyzed cross-coupling reactions. Then nitroalkane 1d having
dimethylamino functionality was prepared and it was found to be
tolerant under the reaction condition providing product 3r in 80%
yield and 64% ee (entry 18). Here also crystallization helps to
improve the enantioselectivity (upto 76% ee). Finally CF3
30 substituted product 3s was obtained from nitroalkane 1e in
moderate yield (69%) and enantioselectivity (76% ee) that can be
increased to 82% ee after crystallization.
A
N
Ph
O
N
H
H
NO2
O
H
N
Ph
N
Ph
H
3a
B
Figure 3 Plausible TS and explanation for diastereoselectivity
50
Simultaneous activation of the imine by the protonated tertiary
amino group takes place from the Re face and the desired product
3a is formed. The extra stability of the trans-product could be
explained by the model (B) where the nitro group and amino
55 group are connected through intramolecular H-bond and the
phenyl group takes the equatorial position.10
Conclusions
In summary, we have developed asymmetric synthesis of trans-2-
aryl/alkyl-3-nitro-tetrahydroquinolines
60 intramolecular aza-Henry reaction. Easily available quinine
alkaloid derived bifunctional thiourea catalyst and
using
a
direct
straightforwardly synthesized amino nitroalkanes were utilized
for this purpose. Further applications of these catalysts in other
reactions are in progress in our laboratory.
65 Experimental
General
Chemicals and solvents were purchased from commercial
1
suppliers and used as received. H NMR spectra were recorded
on 400 MHz and 600 MHz spectrometer.13C NMR spectra were
70 recorded on 100MHz and 150MHz. Chemical shifts were
reported in parts per million (ppm), and the residual solvent peak
was used as an internal reference: proton (chloroform δ 7.26),
carbon (chloroform δ 77.23). Multiplicity was indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), m
75 (multiplet), dd (doublet of doublet), bs (broad singlet). Coupling
constants were reported in Hertz (Hz) HRMS spectra were
recorded using ESI mode. Melting points were measured using
BüCHI melting point B-540 apparatus. All melting points were
measured in open glass capillary and values are uncorrected.
80 Enantiomeric ratios were determined by HPLC analysis using
Dionex (Ultimate 3000) instrument with chiral columns in
comparison with authentic racemic materials. FT-IR spectra were
recorded using Perkin Elmer IR spectrometer. For single crystal
35 Figure 2 X-ray crystallographic structure of 3f
The absolute configuration of the product was determined to be
(2R, 3S) by X-ray crystallography12 (Figure 2) as well as by
40 comparison of the optical rotation with literature value4j (see
supporting information for details). On the basis of the absolute
configuration, a plausible transition state (A) has been drawn in
Figure 3. It dictates that the quinine derived thiourea catalyst
binds in bifunctional mode with the substrate.13 The thiourea
45 moiety presumably activates the nitronate moiety14 that is
generated from the niroalkane by deprotonation. Then the attack
of the nitronate group takes place from the Si face of the imine.
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X-ray analysis the intensity data we recollected using Bruker 60 calcd for C19H22N2O2 [M+H]+ 311.1754, found 311.1753; FT-
Smart Apex-II.
IR (KBr) 3374, 2964, 2924, 1607, 1546, 1370 cm-1. The ee value
All solvent were purified using standard procedure and store
under MS 4 Ao .Silica gel (60-120 mesh) was used for column
chromatography. Reactions were monitored by TLC on silica gel
60 F254 (0.25mm).
61% (τminor = 12.24 min, τmajor = 14.36 min) was determined by
HPLC analysis using Chiralpak IA column, 254 nm, 25 C, n-
o
5
Hexane/i-Propanol = 99.5:0.5, flow rate = 1 mL/min. The optical
65 rotation of 3c was [α]D23 = +20.0 (c 0.75, CHCl3).
Procedure for the intramolecular nitro-Mannich reaction
A solution of nitro-amine 1 (0.12 mmol, 1 equiv) and aldehyde 2
(0.156 mmol, 1.3 equiv) in pentane:n-hexane (5:1) was stirred at
(2R, 3S)-1,2,3,4-tetrahydro-2-(4-isopropylphenyl)-3-nitro-
quinoline (3d): Prepared according to the general procedure:
Yellow oil (26.7 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ
(ppm) 1.23 (d, J = 6.4 Hz, 6H), 2.86-2.93 (m, 1H), 3.26 (dd, J =
10 RT for 2-3h. Then 10 mol% organocatalyst was added to the
mixture and stirred for 3 days. After 3 days the crude reaction 70 5.2, 16.28 Hz, 1H), 3.56 (dd, J = 9.2, 16.2 Hz, 1H), 4.12 (bs, 1H),
mixture subjected to column chromatography on silica gel using
mixtures of hexanes and ethyl acetate as eluent to afford the
corresponding product. Recrystallization was done in ethanol at
15 room temperature.
4.83 (d, J = 8 Hz, 1H), 4.91-4.95 (m, 1H), 6.58 (d, J = 8 Hz, 1H),
6.74 (t, J = 7.2 Hz, 1H), 7.05-7.10 (m, 2H), 7.22 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 24.0, 24.1, 31.6, 34.0, 58.8, 85.3, 114.2, 116.7, 118.5,
75 127.3, 127.3, 128.1, 129.5, 135.9, 142.8, 150.0; ESI-MS m/z
calcd for C18H20N2O2 [M+H]+ 297.1598, found 297.1595; FT-IR
(KBr) 3427, 2965, 2928, 1726, 1607, 1550, 1493, 1370 cm-1. The
ee value 52% (τminor = 12.53 min, τmajor = 17.15 min) was
determined by HPLC analysis using Chiralpak IA column, 254
80 nm, 25 oC, n-Hexane/i-Propanol = 99.5:0.5, flow rate = 1
Characterization of the products
(2R, 3S)-1,2,3,4-tetrahydro-3-nitro-2-phenylquinoline (3a):
Prepared according to the general procedure: Yellow solid (26
o
1
1
mg, 85% yield), mp 100-101 C (lit. mp 98-99o C). H NMR
20 (400 MHz, CDCl3) δ (ppm) 3.25 (dd, J = 4.4, 15.2 Hz, 1H), 3.57
(dd, J = 8.6, 15.8 Hz, 1H), 4.14 (bs, 1H), 4.87 (d, J = 7.6 Hz, 1H),
4.90-4.96 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.75 (t, J = 7.4 Hz,
1H), 7.05-7.11 (m, 2H), 7.34-7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 31.4, 59.0, 85.3, 114.2, 116.7, 118.6, 127.3,
25 128.1, 129.2, 129.5, 138.7, 142.7; ESI-MS m/z calcd. for
C15H14N2O2 [M+H]+ 255.1128, found 255.1123; FT-IR (KBr) :
3407, 3030, 1604, 1547, 1493, 1371 cm-1. The ee value 74%
(τminor = 10.62 min, τmajor = 16.82 min), after recrystallization ee
value 98% (τminor = 10.05 min, τmajorr = 15.66 min) were
30 measured by HPLC analysis using a Chiralpak AS-H column,
254 nm, 25 oC, n-Hexane/i-propanol = 80:20, flow rate =
24
mL/min. The optical rotation of 3a was [α]D = +25.0 (c 0.27,
CHCl3).
(2R,3S)-2-(4-chlorophenyl)-1,2,3,4-tetrahydro-3-nitro-
quinoline (3e): Prepared according to the general procedure: Pale
1
85 yellow solid (28.7 mg, 83% yield), mp 119-120 oC. H NMR
(400 MHz, CDCl3) δ (ppm) 3.24 (dd, J = 4.8, 17 Hz, 1H), 3.57
(dd, J = 8.4, 16.4 Hz, 1H), 4.11 (bs, 1H), 4.85(d, J = 7.6 Hz, 1H),
4.88-4.91 (m, 1H), 6.61 (d, J = 8.8 Hz, 1H), 6.76 (t, J = 6.8 Hz,
1H), 7.06-7.12 (m, 2H), 7.32-7.35 (m, 4H); 13C NMR (100 MHz,
90 CDCl3) δ (ppm) 31.3, 58.4, 85.2, 114.4, 116.6, 119.0, 128.2,
128.8, 129.5, 129.5, 135.1, 137.2, 142.5; ESI-MS m/z calcd for
C15H13N2O2Cl [M+H]+ 289.0738, found 289.0736; FT-IR (KBr)
3398, 2924, 2850, 1607, 1548, 1484, 1370, 1337 cm-1. The ee
value 70% (τminor = 9.07 min, τmajor = 11.52 min) and after
95 recrystallization ee value 96% (τminor = 9.06 min, τmajor = 11.54
min) were determined by HPLC analysis using a chiralpak AS-H
column, 254 nm, 25 oC, n-Hexane/i-propanol = 70:30, flow rate =
23
1mL/min. The optical rotation of 3a was [α]D = +42.0 (c 0.17,
CHCl3).
(2R, 3S)-1,2,3,4-tetrahydro-3-nitro-2-p-tolylquinoline (3b):
35 Prepared according to the general procedure: White solid (29 mg,
90% yield), mp 105-106 oC (lit.1 mp 107-109o C). 1H NMR (400
MHz, CDCl3) δ (ppm) 3.25 (dd, J = 4.8, 16 Hz, 1H), 3.57 (dd, J
= 8.8, 16.2 Hz, 1H), 4.11 (bs, 1H), 4.81 (d, J = 8.8 Hz, 1H), 4.88-
4.93 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.74 (t, J = 8.4 Hz, 1H),
40 7.05-7.10 (m, 2H), 7.16-7.18 (m, 2H), 7.26-7.28 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 21.3, 31.6, 58.9, 85.5, 114.2,
116.7, 118.5, 127.2, 128.1, 129.5, 129.9, 135.5, 139.1, 142.8;
ESI-MS m/z calcd for C16H16N2O2 [M+H]+ 269.1285, found
269.1283; FT-IR (KBr) 3390, 2920, 2850, 1603, 1546, 1454,
25
1 mL/min. The optical rotation of 3e was [α]D = +44.0 (c 0.25,
CHCl3).
100 (2R, 3S)-2-(4-bromophenyl)-1,2,3,4-tetrahydro-3-nitro-
quinoline (3f): Prepared according to the general procedure:
Yellow solid (31.9 mg, 80% yield), mp 128-129 oC (lit.1 mp 125-
1
127o C). H NMR (400 MHz, CDCl3) δ (ppm) 3.24 (dd, J = 4.8,
45 1366, 1204 cm-1. The ee value 67% (τminor = 9.76 min, τmajor
=
16.4 Hz, 1H), 3.56 (dd, J = 8.4, 16 Hz, 1H), 4.12 (bs, 1H), 4.84-
105 4.91 (m, 2H), 6.61 (d, J = 8 Hz, 1H), 6.76(t, J = 7.6 Hz, 1H),
7.06-7.12 (m, 2H), 7.26-7.29(m, 2H), 7.50 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ (ppm) 31.2, 58.4, 85.1, 114.4,
116.6, 118.9, 123.2, 128.2, 129.0, 129.5, 132.4, 137.7, 142.4;
ESI-MS m/z calcd for C15H13N2O2Br [M+H]+ 333.0233, found
110 333.0231; FT-IR (KBr) 3398, 2924, 2854, 1607, 1550, 1488,
1374 cm-1. The ee value 58% (τminor = 20.09 min, τmajor = 25.19
min) and after recrystallization ee value 96% (τminor = 20.12 min,
τmajor = 25.25 min) were determined by HPLC analysis using a
13.14 min) and after recrystallization ee value 94% (τminor = 10.05
min, τmajor = 13.37 min) were determined by HPLC analysis using
Chiralpak AS-H column, 254 nm, 25 C, n-Hexane/i-Propanol =
o
80:20, flow rate = 1 mL/min. The optical rotation of 3b was
50 [α]D23 = +41.0 (c 0.15, CHCl3).
(2R,3S)-2-(4-tert-butylphenyl)-1,2,3,4-tetrahydro-3-nitro-
quinoline (3c): Prepared according to the general procedure:
Yellow oil (23.8 mg, 78% yield); 1H NMR (400 MHz, CDCl3) δ
(ppm) 1.30 (s, 9H), 3.26 (dd, J = 4.8, 16 Hz, 1H), 3.56 (dd, J =
55 9.2, 16 Hz, 1H), 4.12 (bs, 1H), 4.84 (d, J = 9.2 Hz, 1H), 4.90-4.96
(m, 1H), 6.58 (d, J = 8, 1H), 6.74 (t, J = 7.6 Hz, 1H), 7.06-7.11
(m, 2H), 7.31-7.32 (m, 2H), 7.37-7.39 (m, 2H); 13C NMR (100
MHz, CDCl3) δ (ppm) 31.4, 31.6, 58.7, 85.2, 114.2, 116.7, 118.5,
126.1, 127.1, 128.1, 129.5, 135.5, 142.8, 152.2; ESI-MS m/z
o
Chiralpak AS-H column, 254 nm, 25 C, n-Hexane/i-Propanol =
25
115 80:20, flow rate = 1 mL/min. The optical rotation of 3f was [α]D
= +14.0 (c 0.25, CHCl3).
(2R, 3S)-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-nitro-
4
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB00795J
quinoline (3g): Prepared according to the general procedure: Pale 128.3, 128.7, 129.6, 129.9, 130.2, 132.3, 137.7, 142.0; ESI-MS
o
yellow solid (26 mg, 80% yield), mp 130-131 C. 1H NMR (400 60 m/z calcd for C15H13N2O2Cl [M+H]+ 289.0738, found 289.0737;
MHz, CDCl3) δ (ppm) 3.26 (dd, J = 4.8, 16 Hz, 1H), 3.58 (dd, J
= 9.2, 16.2 Hz, 1H), 4.11 (bs, 1H), 4.82-4.91 (m, 2H), 6.61 (d, J =
7.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 7.04-7.11 (m, 4H), 7.37-
7.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm) 31.6, 58.5,
85.5, 114.4, 116.2 (d, J = 22 Hz), 116.7, 118.9, 128.2, 129.2 (d, J 65 Chiralpak AS-H column, 254 nm, 25 C, n-Hexane/i-Propanol =
30
= 9 Hz), 129.5, 134.5, 134.3, 142.6, 162.0, 164.4; ESI-MS m/z
calcd for C15H13N2O2F [M+H]+ 273.1034, found 273.1030; FT-
FT-IR (KBr) 3398, 2924, 2854, 1726, 1607, 1546, 1464, 1484,
1362, 1259 cm-1. The ee value 40% (τminor = 7.55 min, τmajor
10.05 min) and recrystallization ee value 99% (τminor = 7.55 min,
=
5
τmajor = 10.09 min) were determined by HPLC analysis using
o
80:20, flow rate = 1 mL/min. The optical rotation of 3j was [α]D
= +04.0 (c 0.15, CHCl3).
10 IR (KBr) 3407, 2920, 2850, 1730, 1546, 1370, 1337 cm-1. The
(2R, 3S)-2-(3-bromophenyl)-1,2,3,4-tetrahydro-3-nitro-
ee value 68% (τminor = 14.7 min, τmajor = 22.73 min) and after
recrystallization ee value 99% (τminor = 14.88 min, τmajor = 22.43 70 Yellow solid (33.8 mg, 85% yield), mp 108-110 C. H NMR
quinoline (3k): Prepared according to the general procedure:
o
1
min) were determined by HPLC analysis using chiralpak IA
(400 MHz, CDCl3) δ (ppm) 3.24 (d, J = 16 Hz, 1H), 3.56 (dd, J =
8.4, 17.2 Hz, 1H), 4.14 (bs, 1H), 4.88 (bs, 2H), 6.62 (d, J = 8 Hz,
1H), 6.77 (t, J = 7.6 Hz, 1H), 7.08(t, J = 8.4 Hz, 2H), 7.22-7.25
(m.1H), 7.32 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.57
75 (bs, 1H); 13C NMR (100 MHz,CDCl3) δ (ppm) 31.2, 58.3, 85.0,
114.4, 116.5, 119.0, 123.3, 126.2, 128.2, 129.5, 130.4, 130.8,
132.4, 141.1, 142.3; ESI-MS m/z calcd for C15H13N2O2Br
[M+H]+ 333.0233, found 333.0233; FT-IR (KBr) 3407, 2924,
o
column, 254 nm, 25 C, n-Hexane/i-Propanol = 95:5, flow rate =
26
15 1 mL/min. The optical rotation of 3g was [α]D = +57.0 (c 0.27,
CHCl3).
(2R, 3S)-1,2,3,4-tetrahydro-2-(4-methoxyphenyl)-3-nitro-
quinoline (3h): Prepared according to the general procedure:
1
brown oil (20.5 mg 60% yield), H NMR (400 MHz, CDCl3) δ
20 (ppm) 3.27 (dd, J = 4.8, 16 Hz, 1H), 3.57 (dd, J = 9.6, 16 Hz,
1H), 3.80 (s, 3H), 4.09 (bs, 1H), 4.77 (d, J = 8.4 Hz, 1H), 4.87-
2854, 1607, 1546, 1468, 1362 cm-1. The ee value 47% (τminor
=
4.92 (m, 1H), 6.59 (d, J = 8 Hz,1H), 6.74 (t, J = 7.6 Hz, 1H), 6.89 80 29.71 min, τmajor = 37.24 min) was determined by HPLC analysis
(d, J = 8.4 Hz, 2H), 7.06-7.10 (m, 2H),7.31 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ (ppm) 31.9, 55.5, 58.8, 85.7,
25 114.2, 114.6, 116.8, 118.6, 128.1, 128.6, 129.5, 130.3, 142.9,
160.3; ESI-MS m/z calcd for C16H16N2O2 [M+H]+ 285.1234,
using a Chiralpak AS-H column, 254 nm, 25 oC, n-Hexane/i-
Propanol = 95:5, flow rate = 1 mL/min. The optical rotation of 3k
was [α]D28 = +06.0 (c 0.28, CHCl3).
(2R, 3S)-1,2,3,4-tetrahydro-2-(2,4-dimethylphenyl)-3-nitro-
found 285.1237; FT-IR (KBr) 3382, 3345, 2924, 2854, 1730, 85 quinoline (3l): Prepared according to the general procedure:
o
1
1603, 1546, 1509, 1374, 1337 cm-1. The ee value 60% (τminor
=
White solid (31 mg, 91% yield), mp 126-128 C. H NMR (400
MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 2.39 (s, 3H), 3.25 (dd, J =
4.8, 16.4 Hz,1H), 3.56 (dd, J = 4.8, 16.4 Hz, 1H), 3.99 (bs, 1H),
4.92-4.97 (m, 1H), 5.14 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 8 Hz,
90 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.99-7.03 (m, 2H), 7.06-7.10 (m,
2H), 7.27-7.29 (m, 1H); 13C NMR (100 MHz,CDCl3) δ (ppm)
19.2, 21.2, 31.3, 54.8, 83.6, 114.1, 116.5, 118.4, 126.9, 127.7,
128.1, 129.5, 132.0, 133.8, 136.1, 138.6, 142.9; ESI-MS m/z
cacld for C17H18N2O2 [M+H]+ 283.1441, found 283.1443; FT-IR
26.31 min, τmajor = 31.05 min) was determined by HPLC analysis
30 using AS-H Chiralpak column, 254 nm, 25 oC, n-Hexane/i-
Propanol = 80:20, flow rate = 1 mL/min. The optical rotation of
3h was [α]D27 = +33.0 (c 0.15, CHCl3).
(2R, 3S)-2-(Biphenyl)-1,2,3,4-tetrahydro-3-nitroquinoline (3i):
Prepared according to the general procedure: Yellow solid (37.6
o
35 mg, 95% yield), mp 187-189 C. 1H NMR (400 MHz, CDCl3) δ
(ppm) 3.29 (dd, J = 4.8, 16 Hz, 1H), 3.59 (dd, J = 9.2, 16.2 Hz,
1H), 4.18 (bs,1H), 4.92-5.00 (m, 2H), 6.63 (d, J = 8 Hz,1H), 6.76 95 (KBr) 3374, 3345, 2924, 1607, 1546, 1337 cm-1. The ee value
(t, J = 7.2 Hz, 1H), 7.07-7.12 (m, 2H), 7.34-7.38 (m, 1H), 7.42-
7.48 (m, 4H), 7.56-7.60 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
40 31.4, 58.7, 85.2, 114.3, 116.7, 118.7, 127.3, 127.8, 127.9, 128.1,
129.0, 129.5, 137.6, 140.5, 142.1, 142.7; ESI-MS m/z calcd for
70% (τminor = 7.59 min, τmajor = 8.58 min) and recrystallization ee
value 95% (τminor = 7.82 min, τmajor = 8.52 min) were determined
by HPLC analysis using Chiralpak IA column, 254 nm, 25 oC, n-
Hexane/ i-Propanol = 98.5:1.5, flow rate = 1 mL/min. The optical
C21H18N2O2 [M+H]+ 331.1441, found 331.1441; FT-IR (KBr) 100 rotation of 3l was [α]D30 = +18.0 (c 0.05, CHCl3).
3411, 2924, 2854, 1734, 1611, 1546, 1480, 1370, 1333 cm-1. The
ee value 61% (τminor = 20.57 min, τmajor = 23.57 min) and
45 recrystallization ee 78% (τminor = 20.46 min, τmajor = 23.58 min)
were determined by HPLC analysis using Chiralpak IA column,
(2R, 3S)-1,2,3,4-tetrahydro-3-nitro-2-styrylquinoline (3m):
Prepared according to the general procedure: Yellow oil (25.2 mg
1
75% yield), H NMR (400 MHz, CDCl3) δ (ppm) 3.28 (dd, J =
5.2, 16.2 Hz, 1H), 3.54 (dd, J = 8.4, 16.2 Hz, 1H), 4.02 (bs, 1H),
254 nm, 25 oC, n-Hexane/i-Propanol = 98:2, flow rate = 1 105 4.46-4.50 (m ,1H), 4.76-4.81 (m, 1H), 6.16 (dd, J = 7.6, 15.6 Hz,
27
mL/min. The optical rotation of 3i was [α]D = +51.0 (c 0.30,
CHCl3).
1H), 6.59 (d, J = 9.2 Hz, 1H), 6.70-6.76 (m ,2H), 7.04-7.10 (m,
2H), 7.35-7.38 (m, 5H); 13C NMR (100 MHz,CDCl3) δ (ppm)
30.7, 57.4, 83.8, 114.5, 116.7, 118.7, 125.5, 126.9, 128.1, 128.6,
128.8, 129.5, 135.4, 135.7, 142.0; ESI-MS m/z calcd for
50 (2R, 3S)-2-(2-chlorophenyl)-1,2,3,4-tetrahydro-3-nitro-
quinoline (3j): Prepared according to the general procedure: Pale
o
yellow solid (25.9 mg, 75% yield), mp 129-130 C (lit.1 mp 126- 110 C17H16N2O2 [M+H]+ 281.1285, found 281.1276; FT-IR (KBr)
1
128o C). H NMR (400 MHz, CDCl3) δ (ppm) 2.99 (dd, J = 4.8,
17 Hz, 1H), 3.51 (dd, J = 4.6, 17.2 Hz, 1H), 4.27 (bs, 1H), 5.03-
55 5.06 (m, 1H), 5.64-5.66 (m, 1H), 6.68 (d, J = 8 Hz, 1H), 6.74 (t, J
= 7.8 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H),
3411, 2928, 2850, 1544, 1484, 1452, 1372 cm-1. The ee value
28% (τmajor = 18.04 min, τminor = 37.99 min) was determined by
HPLC analisis using Daicel Chiralpak OD-H column, 254 nm, 25
oC, n-Hexane/i-Propanol = 70:30, flow rate = 1 mL/min. The
7.22-7.29 (m, 2H), 7.38- 7.45 (m, 2H); 13C NMR (100 MHz, 115 optical rotation of 3m was [α]D28 = +16.0 (c 0.23, CHCl3).
CDCl3) δ (ppm) 28.1, 54.3, 80.5, 114.1, 115.6, 118.6, 127.8,
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C5OB00795J
(2R, 3S)-2-butyl-1,2,3,4-tetrahydro-3-nitroquinoline (3n):
were determined by HPLC analysis using Daicel Chiralpak OD-H
o
Prepared according to the general procedure: Yellow oil (23 mg, 60 column , 254 nm, 25 C, n-Hexane/i-propanol = 80:20, flow rate
29
= 1 mL/min. The optical rotation of 3q was [α]D = +31.0 (c
0.25, CHCl3).
82% yield), 1H NMR (400 MHz, CDCl3) δ (ppm) 0.92 (t, J = 7.2
Hz, 3H), 1.32-141 (m, 3H), 1.47-1.56 (m, 3H), 3.20 (dd, J = 5.2,
16.4 Hz, 1H), 3.49 (dd, J = 7.6, 16.4 Hz, 1H), 3.76-3.81 (m, 1H),
3.89 (bs, 1H), 4.63-4.68 (m, 1H), 6.55 (d, J = 8 Hz, 1H), 6.70 (t, J
5
(2R, 3S)-1,2,3,4-tetrahydro-N,N-dimethyl-3-nitro-2-phenyl-
quinolin-7-amine (3r): Prepared according to the general
1
= 7.2 Hz, 1H), 7.02-7.06 (m, 2H); 13C NMR (100 MHz, CDCl3) 65 procedure: Red solid (29 mg, 80% yield), mp 109-111 oC. H
δ (ppm) 14.1, 22.7, 27.4, 30.4, 32.7, 54.1, 83.6, 114.7, 116.9,
118.4, 127.9, 129.4, 142.2; ESI-MS m/z calcd for C13H18N2O2
10 [M+H]+ 235.1441, found 235.1443; FT-IR (KBr) 3415, 2957,
NMR (400 MHz, CDCl3) δ (ppm) 3.19 (dd, J = 4.8, 15.6 Hz,
1H), 3.48 (dd, J = 9.6, 15.6 Hz, 1H), 4.07 (bs, 1H), 4.82 (d, J =
7.2 Hz, 1H), 4.88-4.93 (m, 1H), 5.95 (d, J = 2.4 Hz, 1H), 6.23
(dd, J = 2.8, 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.33-7.41 (m,
2928, 1726, 1603, 1546, 1488, 1378, 1268 cm-1. The ee value
68% (τminor = 14.43 min, τmajor = 16.48 min) was determined by 70 5H); 13C NMR (100 MHz, CDCl3) δ (ppm) 31.0, 40.8, 59.2,
o
HPLC analysis using Chiralpak IA column, 254 nm, 25 C, n-
Hexane/i-Propanol = 99:1, flow rate = 1 mL/min. The optical
15 rotation of 3n was [α]D28 = +27.0 (c 0.78, CHCl3).
86.0, 97.8, 104.4, 105.3, 127.4, 129.1, 129.1, 129.9, 138.8, 143.3,
150.9; ESI-MS m/z calcd for C17H19N3O2 [M+H]+ 298.1550,
found 298.1551; FT-IR (KBr) 3316, 2871, 1579, 1619,
1553,1520, 1479, 1451, 1336, 1372 cm-1. The ee value 64%
(2R, 3S)-1,2,3,4-tetrahydro-3-nitro-2-propylquinoline (3o):
Prepared according to the general procedure: Yellow oil (21.4 75 (τminor = 33.56 min, τmajor = 40.16 min) and recrystallization 76%
1
mg, 81% yield), H NMR (400 MHz, CDCl3) δ (ppm) 0.87-0.98
(m, 5H), 1.56 (m, 2H), 3.22 (dd, J = 6.4, 17 Hz, 1H), 3.38 (dd, J
20 = 6.4, 17.4 Hz, 1H), 3.71 (bs, 1H), 3.92 (bs, 1H), 4.93-4.97 (m,
1H), 6.58 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 7.02-7.07
(τminor = 33.28 min, τmajor = 39.41 min.) were determined by
HPLC analysis using Chiralpak IA column, 254 nm, 25 C, n-
o
Hexane/i-propanol = 80:2, flow rate = 0.8 mL/min. The optical
rotation of 3r was [α]D29 = +04.0 (c 0.75, CHCl3).
(m , 2H); 13C NMR (150 MHz, CDCl3) δ (ppm) 14.0, 19.2, 29.1, 80 (2R,
3S)-6-(trifluoromethyl)-1,2,3,4-tetrahydro-3-nitro-2-
32.8, 53.3, 81.2, 115.1, 117.3, 118.9, 127.6, 129.5, 142.4; ESI-
MS m/z calcd for C12H16N2O2 [M+H]+ 221.1285, found
25 221.1283; FT-IR (KBr) 3415, 2957, 2928, 1726, 1603, 1546,
1488, 1378, 1268 cm-1. The ee value 63% (τmajor = 33.06 min,
phenylquinoline (3s): Prepared according to the general
o
1
procedure: White solid (27 mg, 69% yield), mp 125-127 C. H
NMR (600 MHz, CDCl3) δ (ppm) 3.22 (dd, J = 4.8, 16.8 Hz,
1H), 3.57 (dd, J = 8.4, 16.8 Hz, 1H), 4.38 (bs, 1H), 4.90-4.93 (m,
τminor = 55.86 min) was determined by HPLC analysis using 85 2H), 6.84 (bs, 1H), 6.97 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.8 Hz,
Daicel Chiralpak OD-H column, 254 nm, 25 oC, n-Hexane/i-
Propanol = 93:7, flow rate 1 mL/min. The optical rotation of 3o
30 was [α]D28 = +28.0 (c 1.05, CHCl3).
1H), 7.35-7.40 (m, 5H); 13C NMR (150 MHz, CDCl3) δ (ppm)
30.3, 56.5, 84.2, 110.7, 114.9, 115.0, 120.0, 123.3, 125.1, 127.0,
127.0, 129.4 (d, J = 36 Hz), 130.1, 138.5, 142.7; ESI-MS m/z
calcd for C16H13F3N2O2 [M+H]+ 323.1002, found 323.1005; FT-
(2R,
3S)-6-chloro-1,2,3,4-tetrahydro-3-nitro-2-phenyl-
quinoline (3p): Prepared according to the general procedure: 90 IR (KBr) 3401, 2923, 2853, 1622, 1595, 1563, 1549, 1487, 1369,
1
Yellow oil (24 mg, 70% yield), H NMR (600 MHz, CDCl3) δ
(ppm) 3.16 (dd, J = 4.8, 16.8 Hz, 1H), 3.51(dd, J = 7.8, 16.5 Hz,
35 1H), 4.18-4.22 (m, 1H), 4.88-4.94 (m, 2H), 6.53-6.55 (m, 1H),
7.03-7.39 (m, 5H); 13C NMR (150 MHz, CDCl3) δ (ppm) 32.1,
1337 cm-1.The ee value 76% (τmajor = 8.45 min, τminor = 9.91 min)
and recrystallization ee 82% (τmajor = 9.26 min, τminor = 10.78
min) were determined by HPLC analysis using Daicel Chiralpak
OD-H column, 254 nm, 25 oC, n-Hexane/i-propanol = 70:30,
29
58.7, 94.5, 115.2, 118.1, 123.2, 127.5, 128.1, 129.1, 129.3, 129.3, 95 flow rate = 1 ml/min. The optical rotation of 3s was [α]D
=
138.6, 141.2; ESI-MS m/z calcd for C15H13ClN2O2 [M+H]+
+25.0 (c 0.40, CHCl3).
289.0733, found 289.0737; FT-IR (KBr) 3398, 2924, 2850,
40 1607, 1548, 1484, 1370, 1337 cm-1. The ee value 75% (τmajor
=
Acknowledgements
13.43 min, τminor = 18.90 min) and recrystalliszation ee 88%
(τmajor = 13.42 min, τminor = 18.63 min) were determined by
HPLC analysis using Daicel Chiralpak OD-H column, 254 nm,
This work was supported by DST-MPI partner programme. We
thank CIF, Indian Institute of Technology Guwahati for the
100 instrumental facility.
o
25 C, n-Hexane/i-Propanol = 70:30, flow rate = 1 mL/min. The
45 optical rotation of 3p was [α]D28 = +46.0 (c 0.10, CHCl3).
(2R, 3S)-5-chloro-1,2,3,4-tetrahydro-3-nitro-2-phenyl-
quinoline (3q): Prepared according to the general procedure:
Notes and references
a Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati, 781039, India. Fax: 91-361-2582349; Tel: 91-361-2583304;
E-mail: span@iitg.ernet.in
o
1
Yellow solid (25mg, 72% yield), mp 165-166 C. H NMR (600
MHz, CDCl3) δ (ppm) 3.31 (dd, J = 5.8, 16.8 Hz, 1H), 3.52 (dd,
50 J = 7.8, 17.1 Hz, 1H), 4.27 (bs, 1H), 4.87 (d, J = 7.8 Hz, 1H),
4.93-4.96 (m, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 7.8 Hz,
1H), 7.02 (t, J = 7.8 Hz, 1H), 7.36-7.39 (m, 5H); 13C NMR (100
MHz, CDCl3) δ (ppm) 28.8, 58.3, 85.0, 112.6, 115.1, 119.2,
127.2, 128.5, 129.3, 134.8, 138.2, 144.2; ESI-MS m/z calcd for
55 C15H13ClN2O2 [M+H]+ 289.0733, found 289.0735; FT-IR (KBr)
3393, 2923, 1599, 1545, 1493, 1475, 1334, 1316 cm-1. The ee
value 62% (τmajor = 15.77 min, τminor = 22.52 min) and after
recrystallization 74% (τmajor = 14.75 min, τminor = 20.21 min )
105 † Electronic Supplementary Information (ESI) available: [Experimental
procedures and 1H, 13C NMR and HPLC data of all products]. See
DOI: 10.1039/b000000x/
1
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DOI: 10.1039/C5OB00795J
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