6-Nitro-1,2,3,4-tetrahydroquinolines by a tandem reductive amination-S NAr reaction

Article abstract of DOI:10.1002/jhet.5570450433

(Chemical Equation Presented) A tandem reductive amination-S_NAr reaction has been developed for the synthesis of 6-nitro-1,2,3,4- tetrahydroquinolines. Treatment of 4-(2-fluoro-5-nitrophenyl)-2-butanone or 3-(2-fluoro-5-nitrophenyl)-propanal with primary amines and sodium cyanoborohydride in methanol at room temperature provided good to excellent yields of the substituted tetrahydroquinolines. The reaction proceeded best with the ketone substrate using primary amines that were unbranched at the α-carbon. The aldehyde also produced the target heterocycles, but these were accompanied by 10-15% of the uncyclized side chain reductive amination products.

Full text of DOI:10.1002/jhet.5570450433

Jul-Aug 2008
6-Nitro-1,2,3,4-tetrahydroquinolines by a Tandem
Reductive Amination-SNAr Reaction
1155
Richard A. Bunce* and Takahiro Nago [1]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA
E-mail: rab@okstate.edu
Received December 11, 2007
O2N
O2N
RNH2, NaBH3CN
CH3OH, 22 o
58-98%
C
O
CH3
N
R
CH3
F
A tandem reductive amination-SNAr reaction has been developed for the synthesis of 6-nitro-1,2,3,4-
tetrahydroquinolines. Treatment of 4-(2-fluoro-5-nitrophenyl)-2-butanone or 3-(2-fluoro-5-nitrophenyl)-
propanal with primary amines and sodium cyanoborohydride in methanol at room temperature provided
good to excellent yields of the substituted tetrahydroquinolines. The reaction proceeded best with the
ketone substrate using primary amines that were unbranched at the ꢀ-carbon. The aldehyde also produced
the target heterocycles, but these were accompanied by 10-15% of the uncyclized side chain reductive
amination products.
J. Heterocyclic Chem., 45, 1155 (2008).
INTRODUCTION
[7] and heating the resulting ꢁ-keto acid at 150 °C then
gave 4 in 64% yield. Aldehyde 6 was prepared in 68%
yield by oxidation of 3-(2-fluoro-5-nitrophenyl)propanol
(5) [2f] with sodium acetate-buffered pyridinium
chlorochromate [8] (see Scheme 1).
Over the past several years, our work has led to a
number of reductive cyclizations that yield 1,2,3,4-tetra-
hydroquinolines [2]. These earlier procedures focused on
the production of derivatives with specific substitution
patterns on the saturated carbons. A recent report has
revealed that certain 2-substituted-6-nitro-1,2,3,4-tetra-
hydroquinolines promote increased bone mineral density
in rats and may, thus, have use in the treatment of
osteoporosis [3]. Tetrahydroquinolines bearing a nitro
group at C6 would not be accessible using our previous
methods, but could potentially be prepared using an SNAr
reaction coupled with an SN2 displacement of halide [2f]
or a reductive amination reaction [4]. Since the target
heterocycles are substituted at C2 and therefore sterically
hindered, it is unlikely that a process involving the SN2
reaction would be successful. Thus, we sought to design
systems to explore the feasibility of a tandem reductive
amination-SNAr sequence.
Scheme 1 [a]
CO2-t-C4H9
O2N
a
Br
+
54%
O
CH3
F
1
2
O2N
CO2-t-C4H9
O2N
b
64%
O
CH3
O
CH3
F
F
3
4
O2N
O2N
c
68%
OH
O
H
F
F
5
6
[a] Key (a) 1,8-diazabicyclo[5.4.0]undec-7-ene, C6H6, 22 oC; (b) i. CF3CO2H,
(C2H5)3SiH, CH2Cl2, 22 oC; ii. 150o, neat; (c) C5H5NH+ CrO3Clꢀ, NaO2CCH3,
CH2Cl2, 22 oC.
RESULTS AND DISCUSSION
We prepared 4-(2-fluoro-5-nitrophenyl)-2-butanone (4)
and 3-(2-fluoro-5-nitrophenyl)propanal (6) to evaluate the
reductive amination-SNAr sequence as an approach to 6-
nitro-1,2,3,4-tetrahydroquinolines. Ketone 4 was pre-
pared in three steps starting from tert-butyl acetoacetate
(1) and 2-fluoro-5-nitrobenzyl bromide (2) [5].
Monoalkylation of 1 with 2 proved difficult under
standard conditions [5], but was accomplished by treating
2 with 1,8-diazabicyclo[5.4.0]undec-7-ene in benzene
followed by addition of 1 [6]. This afforded a 54% yield
The results of our reductive amination-SNAr cyclization
studies are summarized in Tables 1 and 2. Ketone 4
reacted with simple primary amines to give 6-nitro-
1,2,3,4-tetrahydroquinolines in high yields. It was also
possible to neutralize amine salts such as ethyl glycinate
hydrochloride [9] or ammonium acetate [10] to provide
amines for the reaction. Problems arose, however, in
cases where branching at the ꢀ-carbon of the amine
hindered its approach to the ketone. Thus, benzylamine
cyclized to 7a in 98% yield while cyclohexylamine
furnished 7h in only 12% yield and tert-butylamine gave
no reaction at all. Aldehyde 6 afforded somewhat lower
of the desired monoalkylation product
3
after
chromatography. Cleavage of the tert-butyl ester in 3
using trifluoroacetic acid in the presence of triethylsilane

1156
R. A. Bunce and T. Nago
Vol 45
Table 1
Isolation of the simple reductive amination product
from the reaction of 6 with tert-butylamine suggests that
the chronology of the sequence involves initial reductive
amination of the side chain carbonyl followed by
nucleophilic aromatic substitution of the resulting amine
at the activated fluorine on the aromatic ring. This is
further supported by the observation that the reaction does
not develop the deep yellow color of the cyclized 4-
nitroaniline moiety until the reducing agent is added. The
final ring closure likely proceeds through a chair-like
conformation that permits alignment of the side chain
nucleophile for addition from above (or below) the plane
of the aromatic ring [2f].
O2N
NaBH3CN
4
+
RNH2
CH3OH, 22 o
C
N
CH3
R
7
R
Yield (%)
Unbranched
98
96
a
b
c
d
e
f
C6H5CH2
C6H5CH2CH2
n-C6H13
i-C4H9
98
90
88
76 [a]
58 [b]
i-C3H7OCH2CH2CH2
CH3CH2O2CCH2
H
g
The ketone substrate reacts cleanly to give high yields
of the 6-nitrotetrahydroquinoline products; the aldehyde
gives more side reactions, but the yields are still
synthetically useful. The greater proportion of cyclized
products from the ketone is puzzling, but may derive from
steric interactions in a chair-like conformation possible for
ring closure. The ꢀ-methyl group in the amine produced
from the ketone would be expected to adopt a pseudo-
equatorial orientation (Figure 1), which should orient the
ꢀ-Branched
h
i
c-C6H11
t-C4H9
12 [c]
0 [c]
[a] Ethyl glycinate hydrochloride was neutralized with sodium ethoxide prior to
reaction. [b] Ammonium acetate was neutralized with potassium hydroxide
prior to reaction. This reaction also gave 19% of (±)-4-(2-fluoro-5-nitro-
phenyl)-2-butanol. [c] The major product was recovered starting material.
Table 2
NaBH3CN
6
+
RNH2
CH3OH, 22 o
C
ꢁꢂꢃ
ꢆ
O2N
O2N
ꢅꢆꢇ
ꢄꢃ
+
ꢀ
N
R
F
NHR
8
9
Figure 1. Possible conformation for ring closure from the ketone
Yield (%)
R
8
9
reactive centers close together and promote efficient ring
formation. The lack of this alkyl substituent in the
aldehyde-derived amine would result in a more random
orientation of the side chain that should make cyclization
less favorable.
Unbranched
75
72
70
76
a
b
c
C6H5CH2
13
C6H5CH2CH2
n-C6H13
13
12
15
d
i-C4H9
ꢀ-Branched
e
f
c-C6H11
t-C4H9
42
0
11 [a]
28 [a]
CONCLUSION
We have developed a new approach to the synthesis of
6-nitro-1,2,3,4-tetrahydroquinolines based on a novel
tandem reductive amination-SNAr reaction. The sequence
gave excellent yields of the target ring system from a
ketone and good yields from an aldehyde substrate. The
superior results from the ketone may arise from its greater
stability to the reaction conditions and from steric effects
in a chair-like conformation leading to ring closure. We
are pursuing further studies of this reaction in systems
bearing other electron-withdrawing groups at C6 and C8
of the tetrahydroquinoline system.
[a] In addition to 8 and/or 9, these reactions gave complex and largely insepar-
able mixtures of products.
yields of the cyclized products accompanied by 10-15%
of the uncyclized side chain reductive amination products
[11]. The less hindered aldehyde gave higher yields of
tetrahydroquinolines from the ꢀ-branched amine
cyclohexylamine (42%), but again, failed to produce any
of the target heterocycle from tert-butylamine. Instead,
the latter gave a modest yield of 9f (28%) along with an
inseparable mixture containing the alcohol reduction
product and several unidentified compounds. Finally, the
aldehyde substrate was too labile to permit reaction with
amine salts requiring treatment with base prior to
condensation (entries f and g, Table 1) and yielded only
complex mixtures of products.
EXPERIMENTAL
All reactions were run under dry nitrogen. Methanol was used
from a freshly opened bottle. Reactions were monitored by thin
layer chromatography on silica gel GF plates (Analtech 21521)

Jul-Aug 2008
6-Nitro-1,2,3,4-tetrahydroquinolines
1157
with ultraviolet detection. Preparative separations were
performed by one of the following methods: (1) flash column
chromatography [12] on silica gel (grade 62, 60-200 mesh)
containing ultraviolet-active phosphor (Sorbent Technologies
UV-5) packed into quartz columns or (2) preparative thin layer
chromatography on 20-cm x 20-cm silica gel GF plates
by thin layer chromatography until the alcohol was consumed,
then diluted with 35 mL of hexanes and filtered through a pad of
Celiteꢁ. The chromium salts remaining in the flask were washed
(three times) by adding 10 mL of dichloromethane, stirring for 5
minutes, adding 10 mL of hexanes and filtering through the
same Celiteꢁ pad. Concentration under vacuum and purification
on a 30 cm x 2 cm silica gel column eluted with 5% ether in
hexanes gave 682 mg (68%) of 6 as a light yellow oil that
crystallized on standing at room temperature, mp 33.5-35.5 °C.
(Analtech 02015).
Band elution for both methods was
monitored using a hand-held ultraviolet lamp. Hexanes used in
chromatography had a boiling range of 65-70 °C. Melting
points were uncorrected. Infrared spectra were run as thin films
on sodium chloride disks and referenced to polystyrene. 1H and
13C Nuclear magnetic resonance spectra were measured in
deuteriochloroform at 300 MHz and 75 MHz, respectively,
using tetramethylsilane as the internal standard; coupling
constants (J) are given in Hertz. Mass spectra (electron
impact/direct probe) were obtained at 70 electron volts.
1
ir: 2830, 2731, 1727, 1525, 1348, 1243 cm-1; H nmr: ꢀ 9.84 (s,
1H), 8.17 (dd, 1H, J = 6.2, 2.7), 8.13 (ddd, 1H, J = 9.0, 4.4, 2.7),
7.18 (t, 1H, J = 9.0), 3.06 (t, 2H, J = 7.3), 2.88 (t, 2H, J = 7.3);
13C nmr: ꢀ 199.8, 164.5 (d, J = 256.8), 144.2, 129.1 (d, J = 18.0),
126.5 (d, J = 6.9), 124.2 (d, J = 10.0), 116.3 (d, J = 24.9), 43.0,
21.5 (d, J = 2.3); ms: m/z 196 (M+-H). Anal. Calcd. for
C9H8FNO3: C, 54.82; H, 4.06; N, 7.11. Found: C, 54.85; H, 4.10;
N, 7.03.
tert-Butyl (±)-2-(2-Fluoro-5-nitrobenzyl)acetoacetate (3).
To a solution of 2.37 g (15.0 mmoles) of 1 in 75 mL of benzene
was added 2.28 g (15.0 mmoles) of 1,8-diazabicyclo[5.4.0]-
undec-7-ene [6]. The mixture was stirred for 5 minutes and a
solution of 3.50 g (15.0 mmoles) of 2 [5] in 10 mL of benzene
was added dropwise. The mixture was stirred at room
temperature for 15 hours, then poured into saturated aqueous
ammonium chloride and extracted with ether (three times). The
combined ether extracts were washed with saturated aqueous
sodium chloride, dried (magnesium sulfate) and concentrated
under vacuum. The resulting brown oil was flash
chromatographed on a 50 cm x 2 cm silica gel column eluted
with 5-10% ether in hexanes to give 2.48 g (54%) of pure 3 as a
light yellow oil. ir: 1734, 1715, 1529, 1350 cm-1; 1H nmr: ꢀ 8.15
(m, 2H), 7.18 (t, 1H, J = 8.7), 3.76 (dd, 1H, J = 9.0, 6.3), 3.26
(dd, 1H, J = 14.7, 6.3), 3.17 (dd, 1H, J = 14.7, 9.0), 2.28 (s, 3H),
1.41 (s, 9H); 13C nmr: ꢀ 201.2, 167.4, 164.7 (d, J = 257.1),
144.0, 127.4 (d, J = 18.0), 127.2 (d, J = 6.9), 124.5 (d, J = 10.3),
116.3 (d, J = 24.6), 82.8, 60.0, 29.0, 28.1 (3C), 27.7. Anal.
Calcd. for C15H18FNO5: C, 57.88; H, 5.79; N, 4.50. Found: C,
57.91; H, 5.83; N, 4.44.
Representative Procedure for Ring Closures with Ketone
4: (±)-1-Benzyl-2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline
(7a). To a solution of 105 mg (0.50 mmoles) of 4 in 5 mL of
methanol was added 64 mg (0.065 mL, 0.60 mmoles) of
benzylamine. The mixture was stirred for 5 minutes and 40 mg
(0.64 mmoles) of sodium cyanoborohydride was added. The
mixture was stirred at room temperature for 48 hours, added to
saturated sodium chloride and extracted with ether (three times).
The combined ether extracts were dried (magnesium sulfate),
concentrated under vacuum and purified by preparative thin
layer chromatography using 20% ether in hexanes. The bright
yellow band contained 138 mg (98%) of 5 as a yellow solid, mp
104-106 °C. ir: 1512, 1330 cm-1; 1H nmr: ꢀ 7.91 (d, 1H, J = 2.7),
7.81 (dd, 1H, J = 9.3, 2.7), 7.36-7.22 (complex, 3H), 7.16 (d,
2H, J = 7.3), 6.33 (d, 1H, J = 9.3), 4.68 (d, 1H, J = 17.4), 4.59 (d,
1H, J = 17.4), 3.72 (m, 1H), 2.88 (ddd, 1H, J = 17.0, 12.5, 5.2),
2.80 (dt, 1H, J = 16.1, 4.1), 2.02 (m, 1H), 1.94 (m, 1H), 1.26 (d,
3H, J = 6.5); 13C nmr: ꢀ 149.8, 136.8, 136.3, 128.8, 127.2, 125.9,
125.0, 124.4, 120.9, 109.9, 53.7, 53.1, 26.9, 23.3, 19.1; ms: m/z
191 (M+-C7H7). Anal. Calcd. for C17H18N2O2: C, 72.34; H, 6.38;
N, 9.93. Found: C, 72.32; H, 6.38; N, 9.94.
4-(2-Fluoro-5-nitrophenyl)-2-butanone (4). To a solution of
2.46 g (7.91 mmoles) of 3 in 20 mL of dichloromethane was
added 9.02 g (5.88 mL, 79.1 mmoles) of trifluoroacetic acid and
4.58 g (6.30 mL, 39.5 mmoles) of triethylsilane [7]. The mixture
(±)-2-Methyl-6-nitro-1-(2-phenylethyl)-1,2,3,4-tetrahydro-
quinoline (7b). This compound (142 mg, 96%) was isolated as a
1
yellow oil. ir: 1511, 1328 cm-1; H nmr: ꢀ 8.01 (dd, 1H, J = 9.3,
was stirred at room temperature for
5 hours and then
2.7), 7.91 (d, 1H, J = 2.7), 7.36-7.17 (complex, 5H), 6.57 (d, 1H,
J = 9.3), 3.76 (ddd, 1H, J = 15.0, 8.0, 5.2), 3.46 (apparent dt, 1H,
J = 16.2, 8.0), 3.35 (m, 1H), 3.02-2.78 (complex, 3H), 2.70 (dt,
1H, J = 16.1, 4.0), 1.72 (m, 2H), 1.15 (d, 3H, J = 6.4); 13C nmr: ꢀ
149.0, 138.6, 136.0, 128.7 (2C), 126.7, 125.3, 124.6, 120.7,
108.8, 53.6, 51.5, 33.2, 26.4, 23.1, 18.9; ms: m/z 205 (M+-C7H7).
Anal. Calcd. for C18H20N2O2: C, 72.97; H, 6.76; N, 9.46. Found:
C, 73.02; H, 6.79; N, 9.40.
concentrated under vacuum to give a brown oil. This oil was
gradually heated to 150 °C (oil bath) and maintained at this
temperature until gas evolution ceased. The reaction was cooled
and the product was flash chromatographed on a 35 cm x 2 cm
silica gel column using 5% ether in hexanes to give 1.08 g
(64%) of 4 as a light yellow oil that crystallized at 0 °C, mp 28-
1
29 °C. ir: 1718, 1529, 1350 cm-1; H nmr: ꢀ 8.16 (dd, 1H, J =
6.5, 2.7), 8.11 (ddd, 1H, J = 9.0, 4.4, 2.7), 7.16 (t, 1H, J = 9.0),
3.00 (t, 2H, J = 7.4), 2.83 (t, 2H, J = 7.4), 2.19 (s, 3H); 13C
NMR: ꢀ 206.3, 164.6 (d, J = 256.8), 144.2, 129.7 (d, J = 18.0),
126.5 (d, J = 6.9), 124.0 (d, J = 10.0), 116.2 (d, J = 24.9), 42.5
(d, J = 1.1), 29.1, 22.9 (d, J = 2.3); ms: m/z 211 (M+). Anal.
Calcd. for C10H10FNO3: C, 56.87; H, 4.74; N, 6.64. Found: C,
56.93; H, 4.79; N, 6.56.
3-(2-Fluoro-5-nitrophenyl)propanal (6). To a stirred
suspension of 2.40 g (11.1 mmoles) of pyridinium chloro-
chromate [8] and 0.18 g (2.20 mmoles) of anhydrous sodium
acetate in 25 mL of dichloromethane at room temperature was
added (dropwise) a solution of 1.00 g (5.02 mmoles) of 5 [2e] in
10 mL of dichloromethane. The reaction mixture was monitored
(±)-1-Hexyl-2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline
(7c). This compound (138 mg, 94%) was isolated as a yellow
1
oil. ir: 1512, 1328 cm-1; H nmr: ꢀ 7.96 (dd, 1H, J = 9.3, 2.7),
7.88 (m, 1H), 6.44 (d, 1H, J = 9.3), 3.61 (m, 1H), 3.44 (ddd, 1H,
J = 14.7, 8.7, 6.0), 3.22 (ddd, 1H, J = 15.0, 9.3, 7.1), 2.87
(apparent dt, 1H, J = 16.4, 9.3), 2.71 (dt 1H, J = 16.4, 4.1), 1.84
(m, 2H), 1.62 (m, 2H), 1.34 (m, 6H), 1.20 (d, 3H, J = 6.5), 0.91
(t, 3H, J = 7.0); 13C nmr: ꢀ 149.3, 135.7, 125.2, 124.6, 120.5,
108.8, 53.3, 49.9, 31.6, 26.9, 26.7, 26.6, 23.2, 22.6, 19.1, 14.0;
ms: m/z 205 (M+-C5H11). Anal. Calcd. for C16H24N2O2: C, 69.57;
H, 8.70; N, 10.14. Found: C, 69.66; H, 8.74; N, 10.05.
(±)-1-Isobutyl-2-methyl-6-nitro-1, 2, 3, 4-tetrahydroquin-
oline (7d). This compound (111 mg, 90%) was isolated as a dark

1158
R. A. Bunce and T. Nago
Vol 45
yellow oil that crystallized on standing at 0 °C, mp 71-72.5 °C.
1
(±)-2-Methyl-6-nitro-1,2,3,4-tetrahydroquinoline (7g). To a
solution of 193 mg (2.50 mmoles) of ammonium acetate in 5 mL
of methanol was added 2.40 mL of 1 M aqueous potassium
hydroxide (2.40 mmoles) and the mixture was stirred for 5
minutes. To the colorless solution was added 105 mg (0.50
mmoles) of 4 and stirring was continued for 5 minutes to give a
light yellow solution. To this solution was added 40 mg (0.64
mmoles) of sodium cyanoborohydride and the reaction was
stirred at room temperature for 5 days, during which time the
yellow color intensified. The reaction was quenched with
saturated aqueous sodium chloride and extracted with ether
(three times). The combined extracts were dried (magnesium
sulfate), concentrated under vacuum and purified by preparative
thin layer chromatography using 25% ether in hexanes to give
two major bands. Band 1 gave 56 mg (58%) of 7g as a yellow
ir: 1511, 1326 cm-1; H nmr: ꢀ 7.94 (dd, 1H, J = 9.3, 2.7), 7.89
(m, 1H), 6.44 (d, 1H, J = 9.3), 3.62 (m, 1H), 3.46 (dd, 1H, J =
14.7, 4.9), 2.92 (ddd, 1H, J = 16.5, 13.4, 5.7), 2.83 (dd, 1H, J =
14.7, 9.7), 2.74 (dm, 1H, J = 16.5), 2.13 (m, 1H), 1.95 (tt, 1H, J
= 13.4, 4.9), 1.85 (m, 1H), 1.16 (d, 3H, J = 6.6), 0.96 (d, 6H, J =
6.8); 13C nmr: ꢀ 149.6, 135.6, 125.4, 124.3, 120.1, 109.3, 57.3,
54.1, 26.7, 26.1, 22.9, 20.2, 20.1, 17.9; ms: m/z 205 (M+-C3H7).
Anal. Calcd. for C14H20N2O2: C, 67.74; H, 8.06; N, 11.29.
Found: C, 67.75; H, 8.04; N, 11.27.
(±)-1-(3-Isopropyloxypropyl)-2- methyl-6- nitro-1, 2, 3, 4-
tetrahydroquinoline (7e). This compound (128 mg, 88%) was
isolated as a yellow oil. ir: 1516, 1328 cm-1; 1H nmr: ꢀ 7.96 (dd,
1H, J = 9.2, 2.6), 7.89 (d, 1H, J = 2.6), 6.56 (d, 1H, J = 9.2), 3.65
(m, 1H), 3.57 (m, 2H), 3.45 (t, 2H, J = 5.8), 3.42 (m, 1H), 2.89
(ddd, 1H, J = 17.7, 11.2, 7.5), 2.73 (dt, 1H, J = 16.3, 3.7), 1.87
(m, 4H), 1.20 (d, 3H, J = 6.6), 1.18 (d, 3H, J = 6.1), 1.17 (d, 3H,
J = 6.1); 13C nmr: ꢀ 149.4, 135.7, 125.2, 124.5, 120.4, 109.1,
71.7, 64.9, 53.1, 46.7, 27.7, 26.6, 23.1, 22.1, 22.0, 18.9; ms: m/z
205 (M+-C5H11O). Anal. Calcd. for C16H24N2O3: C, 65.75; H,
8.22; N, 9.59. Found: C, 65.79; H, 8.26; N, 9.53.
1
solid, mp 135-137 °C. ir: 3352, 1528, 1322 cm-1; H nmr: ꢀ
7.87 (m, 2H), 6.37 (d, 1H, J = 9.5), 4.66 (br s, 1H), 3.55 (m, 1H),
2.80 (m, 2H), 2.00 (m, 1H), 1.57 (m, 1H), 1.27 (d, 3H, J = 6.5);
13C nmr: ꢀ 150.4, 137.2, 125.8, 124.3, 119.6, 112.1, 47.4, 28.7,
26.1, 22.2; ms: m/z 177 (M+-CH3). Anal. Calcd. for C10H12N2O2:
C, 62.50; H, 6.25; N, 14.58. Found: C, 62.57; H, 6.26; N, 14.51.
Band 2 gave 20 mg (19%) of (±)-4-(2-fluoro-5-nitrophenyl)-
(±)-1-Cyclohexyl-2- methyl-6- nitro-1, 2, 3, 4-tetrahydro-
quinoline (7h). This compound (16 mg, 12%) was isolated as a
yellow oil that slowly crystallized on standing, mp 71-73 °C. ir:
1
2-butanol as a colorless oil. ir: 3369, 1527, 1350, 1245 cm-1; H
nmr: ꢀ 8.17 (dd, 1H, J = 6.3, 2.7), 8.10 (ddd, 1H, J = 9.0, 4.4,
2.7), 7.16 (t, 1H, J = 9.0), 3.85 (sextet, 1H, J = 6.3), 2.85 (m,
2H), 1.79 (m, 2H), 1.50 (br s, 1H), 1.27 (d, 3H, J = 6.3); 13C
nmr: ꢀ 164.7 (d, J = 256.2), 144.3, 130.8 (d, J = 18.3), 126.4 (d,
J = 7.2), 123.7 (d, J = 10.3), 116.1 (d, J = 25.2), 67.1, 38.7, 25.2,
23.7. Anal. Calcd. for C10H12FNO3: C, 56.34; H, 5.63; N, 6.57.
Found: C, 56.47; H, 5.66; N, 6.49.
Representative Procedure for Ring Closures with
Aldehyde 6. To a solution of 98.5 mg (0.50 mmoles) of 6 in 5
mL of methanol was added 0.60 mmoles of the amine. The
mixture was stirred for 2 hours and 8 mg (0.13 mmoles) of
sodium cyanoborohydride was added. This was followed by
three more 8 mg-portions of sodium cyanoborohydride at 4-hour
intervals. The mixture was stirred at room temperature for 24-48
hours, added to saturated sodium chloride and extracted with
ether (three times). The combined ether extracts were dried
(magnesium sulfate) concentrated under vacuum and purified by
preparative thin layer chromatography using 20% ether in
1
1503, 1323 cm-1; H nmr: ꢀ 7.95 (dd, 1H, J = 9.3, 2.7), 7.91 (d,
1H, J = 2.7), 6.63 (d, 1H, J = 9.3), 3.88 (m, 1H), 3.70 (tt, 1H, J =
11.4, 3.4), 2.93 (ddd, 1H, J = 16.5, 14.0, 6.1), 2.73 (ddm, 1H, J =
16.5, 4.3), 2.07-1.20 (complex, 12H), 1.14 (d, 3H, J = 6.4); 13C
nmr: ꢀ 149.6, 135.7, 125.9, 124.3, 120.7, 110.1, 58.2, 46.0, 31.3,
30.4, 26.9, 26.2 (2C), 25.7, 23.0, 20.5; ms: m/z 274 (M+). Anal.
Calcd. for C16H22N2O2: C, 70.07; H, 8.03; N, 10.22. Found: C,
70.14; H, 8.08; N, 10.13.
Attempted Preparation of (±)-1-tert-Butyl-2-methyl-6-
nitro-1,2,3,4-tetrahydroquinoline (7i). Using the procedure
above, reaction of 4 with tert-butylamine led to a 98% recovery
of the starting ketone.
Ethyl (±)-2-Methyl-6-nitro-1,2,3,4-tetrahydroquinoline-1-
acetate (7f). In a 50-mL round-bottomed flask, 23 mg (1.00
mmole) of sodium metal was dissolved in 5 mL of absolute
ethanol. To the resulting solution was added 145 mg (1.04
mmole) of ethyl glycinate hydrochloride and the mixture was
stirred for 5 minutes to give a white suspension. To this
suspension was added 105 mg (0.50 mmoles) of 4 followed by
50 mg (0.79 mmoles) of sodium cyanoborohydride. To increase
the solubility of the reactants, 1 mL of anhydrous tetrahydro-
furan was added to the mixture. The reaction was stirred at room
temperature for 5 days and the mixture turned a bright yellow
color. The reaction was quenched with saturated aqueous
sodium chloride and extracted with ether (three times). The
combined extracts were dried (magnesium sulfate), concentrated
under vacuum and purified by preparative thin layer
chromatography using 30% ether in hexanes to give 105 mg
(76%) of 7f as a yellow oil that gradually crystallized at 0 °C to
a waxy solid, mp 45-47 °C. ir: 1743, 1511, 1333 cm-1; 1H nmr: ꢀ
7.95 (dd, 1H, J = 9.0, 2.7), 7.91 (d, 1H, J = 2.7), 6.31 (d, 1H, J =
9.2), 4.22 (q, 2H, J = 7.0), 4.11 (s, 2H), 3.65 (m, 1H), 2.89 (ddd,
1H, J = 16.5, 12.2, 4.9), 2.76 (dt, 1H, J = 16.2, 4.3), 1.98 (m,
hexanes to give two bands. Band
1 (yellow) gave the
tetrahydroquinoline; band 2 (observed under ultraviolet light)
gave the unclosed amine resulting from simple reductive
amination.
1-Benzyl-6-nitro-1,2,3,4-tetrahydroquinoline (8a). This
compound (100 mg, 75%) was isolated as a dark yellow oil. ir:
1
1520, 1345 cm-1; H nmr: ꢀ 7.89 (s, 1H), 7.87 (dd, 1H, J = 9.2,
2.7), 7.38-7.27 (complex, 4H), 7.18 (d, 1H, J = 8.2), 6.42 (d, 1H,
J = 9.2), 4.60 (s, 2H), 3.51 (t, 2H, J = 5.8), 2.86 (t, 2H, J = 6.2),
2.04 (quintet, 2H, J = 6.0); 13C nmr: ꢀ 150.6, 136.6, 136.4,
128.9, 127.4, 126.2, 125.0, 124.7, 121.4, 109.4, 54.9, 50.2, 27.9,
21.4; ms: m/z 177 (M+-C7H7). Anal. Calcd. for C16H16N2O2: C,
71.64; H, 5.97; N, 10.45. Found: C, 71.68; H, 5.99; N, 10.40.
N-Benzyl-3-(2-fluoro-5-nitrophenyl)propanamine (9a).
This compound (18 mg, 13%) was isolated as a light yellow oil.
1
ir: 3330, 1526, 1349, 1243 cm-1; H nmr: ꢀ 8.13 (m, 2H), 7.38-
1H), 1.89 (m, 1H), 1.50 (t, 3H, J = 7.0), 1.23 (d, 3H, J = 6.4); 13
C
7.27 (complex, 5H), 7.18 (t, 1H, J = 9.1), 4.09 (d, 1H, J = 12.7),
3.83 (d, 1H, J = 12.7), 3.50 (t, 1H, J = 7.1), 2.95 (m, 3H), 2.15
(m, 2H), 1.57 (br s, 1H); 13C nmr: ꢀ 164.6 (J = 257.1), 144.4,
137.9, 128.5 (overlapping s and d, J = 18.3), 127.7, 126.4 (d, J =
6.9), 124.4 (d, J = 10.3), 119.5, 116.4 (d, J = 24.9), 51.6, 48.7,
nmr: ꢀ 169.6, 149.4, 137.1, 124.9, 124.3, 121.6, 109.0, 61.5,
54.5, 51.4, 26.8, 23.4, 19.2, 14.1; ms: m/z 205 (M+-C3H5O2).
Anal. Calcd. for C14H18N2O4: C, 60.43; H, 6.47; N, 10.07.
Found: C, 60.48; H, 6.51; N, 9.99.

Jul-Aug 2008
6-Nitro-1,2,3,4-tetrahydroquinolines
1159
33.1, 25.4 (d, J = 2.0); ms: m/z 197 (M+-C7H7). Anal. Calcd. for
C16H17FN2O2: C, 66.67; H, 5.90; N, 9.72. Found: C, 66.64; H,
5.91; N, 9.73.
m/z 211 (M+-C3H7). Anal. Calcd. for C13H19FN2O2: C, 61.42; H,
7.48; N, 11.02. Found: C, 61.47; H, 7.52; N, 10.97.
1-Cyclohexyl-6-nitro-1,2,3,4-tetrahydroquinoline (8e).
This compound (55 mg, 42%) was isolated as a dark yellow oil.
1-(2-Phenylethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (8b).
This compound (102 mg, 72%) was isolated as a dark yellow oil.
1
ir: 1511, 1344 cm-1; H nmr: ꢀ 7.95 (dd, 1H, J = 9.3, 2.7), 7.83
1
ir: 1519, 1335 cm-1; H nmr: ꢀ 7.97 (dd, 1H, J = 9.2, 2.6), 7.85
(d, 1H, J = 2.7), 6.54 (d, 1H, J = 9.3), 3.68 (tt, 1H, J = 11.2, 3.3),
3.32 (t, 2H, J = 5.8), 2.74 (t, 2H, J = 6.2), 2.02-1.69 (complex,
6H), 1.65-1.32 (complex, 4H), 1.30-1.08 (complex, 2H); 13C
nmr: ꢀ 150.6, 135.5, 125.1, 124.7, 122.1, 108.6, 57.3, 42.4, 29.5,
28.3, 25.8, 25.6, 21.5; ms: m/z 260 (M+). Anal. Calcd. for
C15H20N2O2: C, 69.23; H, 7.69; N, 10.77. Found: C, 69.25; H,
7.65; N, 10.71.
N-Cyclohexyl-3-(2-fluoro-5-nitrophenyl)propanamine (9e).
This compound (15 mg, 11%) was isolated as a light yellow oil.
ir: 3322, 1529, 1348, 1242 cm-1; 1H nmr: ꢀ 8.15 (m, 2H), 7.19 (t,
1H, J = 8.9), 3.59 (t, 1H, J = 7.1), 2.96 (m, 2H), 2.75 (tt, 1H, J =
10.1, 3.5), 2.11 (m, 2H), 1.90-1.46 (complex, 6H), 1.38-1.16
(complex, 5H), 1.02 (m, 1H); 13C nmr: ꢀ 164.5 (d, J = 256.7),
144.1, 128.9 (d, J = 18.3), 126.6 (d, J = 6.9), 124.4 (d, J = 10.0),
116.4 (d, J = 24.9), 54.9, 46.6, 34.1, 33.7, 31.9, 25.9, 25.4, 24.7,
24.2; ms: m/z 280 (M+). Anal. Calcd. for C15H21FN2O2: C, 64.29;
H, 7.50; N, 10.00. Found: C, 64.37; H, 7.54; N, 9.93.
N-tert-Butyl-3-(2-fluoro-5-nitrophenyl)propanamine (9f).
This compound (35 mg, 28%) was isolated as a light yellow oil.
ir: 3312, 1529, 1348, 1243 cm-1; 1H nmr: ꢀ 8.16 (dd, 1H, J = 6.4,
2.9), 8.09 (ddd, 1H, J = 9.0, 4.4, 2.9), 7.15 (t, 1H, J = 9.0), 2.79
(t, 2H, J = 7.7), 2.61 (t, 2H, J = 7.3), 1.81 (quintet, 2H, J = 7.5),
1.10 (2s, 10H); 13C nmr: ꢀ 164.6 (d, J = 256.2), 144.2, 130.9 (d,
J = 18.6), 126.4 (d, J = 7.2), 123.6 (d, J = 10.0), 116.0 (d, J =
25.2), 50.3, 41.7, 31.0, 29.1, 26.7 (3C); ms: m/z 239 (M+-CH3).
Anal. Calcd. for C13H19FN2O2: C, 61.42; H, 7.48; N, 11.02.
Found: C, 61.49; H, 7.51; N, 10.97.
(dt, 1H, J = 2.7, 1.1), 7.36-7.14 (complex, 5H), 6.52 (d, 1H, J =
9.2), 3.60 (t, 2H, J = 7.4), 3.22 (t, 2H, J = 5.8), 2.91 (t, 2H, J =
7.4), 2.74 (t, 2H, J = 6.2), 1.86 (quintet, 2H, J = 6.2); 13C nmr: ꢀ
150.0, 138.6, 136.2, 128.8, 128.7, 126.7, 125.2, 124.7, 121.4,
108.6, 53.3, 50.2, 32.7, 27.9, 21.1; ms: m/z 191 (M+-C7H7). Anal.
Calcd. for C17H18N2O2: C, 72.34; H, 6.38; N, 9.93. Found: C,
72.29; H, 6.36; N, 9.91.
N-(2-Phenylethyl)-3-(2-fluoro-5-nitrophenyl)propanamine
(9b). This compound (21 mg, 13%) was isolated as a light
1
yellow oil. ir: 3321, 1525, 1348, 1243 cm-1; H nmr: ꢀ 8.14 (m,
2H), 7.36-7.14 (complex, 6H), 3.51 (t, 1H, J = 7.3), 3.16 (m,
1H), 3.10-2.76 (complex, 6H), 2.05 (m, 2H), 1.58 (br s, 1H); 13
C
nmr: ꢀ 164.6 (d, J = 257.1), 144.2, 138.9, 128.9 (d, J = 18.2),
128.6, 126.5 (overlapping s and d, J = 7.0), 124.4 (d, J = 10.3),
119.5, 116.5 (d, J = 24.9), 49.6, 48.4, 36.0, 32.9, 25.3; ms: m/z
211 (M+-C7H7). Anal. Calcd. for C17H19FN2O2: C, 67.55; H,
6.29; N, 9.27. Found: C, 67.61; H, 6.32; N, 9.22.
1-Hexyl-6-nitro-1,2,3,4-tetrahydroquinoline (8c). This
compound (92 mg, 70%), was isolated as a dark yellow oil. ir:
1
1520, 1338 cm-1; H nmr: ꢀ 7.95 (dd, 1H, J = 9.2, 2.7), 7.83 (dt,
1H, J = 2.7, 1.1), 6.45 (d, 1H, J = 9.2), 3.41 (t, 2H, J = 5.8), 3.33
(t, 2H, J = 7.7), 2.77 (t, 2H, J = 6.2), 1.95 (quintet, 2H, J = 6.2),
1.62 (quintet, 2H, J = 7.0), 1.33 (m, 6H), 0.90 (t, 3H, J = 6.6);
13C nmr: ꢀ 150.3, 135.9, 125.1, 124.7, 121.1, 108.5, 51.6, 49.7,
31.6, 27.9, 26.7, 26.2, 22.6, 21.2, 14.0; ms: m/z 191 (M+-C5H11).
Anal. Calcd for C15H22N2O2: C, 68.70; H, 8.40; N, 10.69. Found:
C, 68.77; H, 8.43; N, 10.64.
Acknowledgment. T. N. thanks Oklahoma State University
for a Niblack Scholarship and the Department of Chemistry for a
Skinner Scholarship. Funding for the 300 MHz NMR
spectrometer of the Oklahoma Statewide Shared NMR Facility
was provided by NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Finally, the authors wish to thank the OSU College
of Arts and Sciences for funds to upgrade our departmental
FTIR and GC-MS instruments.
N-Hexyl-3-(2-fluoro-5-nitrophenyl)propanamine (9c). This
compound (17 mg, 12%) was isolated as a light yellow oil. ir:
1
3321, 1529, 1349, 1243 cm-1; H nmr: ꢀ 8.15 (m, 2H), 7.19 (t,
1H, J = 9.0), 3.50 (t, 1H, J = 7.2), 2.96 (m, 1H), 2.89 (m, 1H),
2.61 (m, 1H), 2.11 (m, 2H), 1.62-1.42 (complex, 3H), 1.40-1.18
(complex, 8H), 0.90 (t, 3H, J = 6.8); 13C nmr: ꢀ 164.6 (d, J =
256.8), 144.3, 128.8 (d, J = 18.3), 126.5 (d, J = 6.9), 124.4 (d, J
= 10.0), 116.4 (d, J = 24.9), 49.8, 47.7, 33.1, 31.6, 29.7, 26.8,
25.4, 22.6, 14.0; ms: m/z 211 (M+-C5H11). Anal. Calcd.
C15H23FN2O2: C, 63.83; H, 8.16; N, 9.92. Found: C, 63.86; H,
8.18; N, 9.86.
REFERENCES AND NOTES
[1] Undergraduate research participant, 2006-present.
[2a] Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org. Chem.
2000, 65, 2847. [b] Bunce, R. A.; Herron, D. M.; Johnson, L. B.;
Kotturi, S. V. J. Org. Chem. 2001, 66, 2822. [c] Bunce, R. A.;
Schammerhorn, J. E.; Slaughter, L. M. J. Heterocyclic Chem. 2006, 43,
1505. [d] Bunce, R. A.; Schammerhorn, J. E.; Slaughter, L. M. J.
Heterocyclic Chem. 2007, 44, 1051. [e] Bunce, R. A.; Nago, T.; Sonobe,
N. J. Heterocyclic Chem. 2007, 44, 1059. [f] Bunce, R.; Nago, T.;
Sonobe, N.; Slaughter, L. M. J. Heterocyclic Chem. 2008, 45, 551.
[3] Hanada, K.; Furuya, K.; Yamamoto, Y.; Nejishima, H.;
Ichikawa, K.; Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita,
Y.; Oguro, N. Biol. Pharm. Bull. 2003, 26, 1563.
1-Isobutyl-6-nitro-1,2,3,4-tetrahydroquinoline (8d). This
compound (89 mg, 76%) was isolated as a dark yellow oil. ir:
1
1520, 1335 cm-1; H nmr: ꢀ 7.93 (dd, 1H, J = 9.2, 2.7), 7.84 (dt,
1H, J = 2.7, 1.1), 6.45 (d, 1H, J = 9.2), 3.43 (t, 2H, J = 5.8), 3.15
(d, 2H, J = 7.5), 2.79 (t, 2H, J = 6.2), 2.12 (nonet, 1H, J = 6.6),
1.96 (m, 2H), 0.96 (d, 6H, J = 6.6); 13C nmr: ꢀ 150.7, 135.9,
125.2, 124.5, 121.0, 109.0, 59.5, 51.1, 28.0, 26.8, 21.2, 20.3
(2C); ms: m/z 191 (M+-C3H7). Anal. Calcd. for C13H18N2O2: C,
66.67; H, 7.69; N, 11.97. Found: C, 66.73; H, 7.72; N, 11.89.
N-Isobutyl-3-(2-fluoro-5-nitrophenyl)propanamine (9d).
This compound (19 mg, 15%) was isolated as a light yellow oil.
ir: 3321, 1529, 1348, 1243 cm-1; 1H nmr: ꢀ 8.15 (m, 2H), 7.20 (t,
1H, J = 9.0), 3.49 (t, 1H, J = 7.3), 2.97 (m, 3H), 2.70 (dd, 1H, J
= 11.1, 7.0), 2.42 (dd, 1H, J = 11.1, 6.6), 2.12 (m, 2H), 1.73
(nonet, 1H, J = 6.8), 1.52 (br s, 1H), 0.96 (d, 3H, J = 6.8), 0.95
(d, 3H, J = 6.8); 13C nmr: ꢀ 164.6 (d, J = 257.1), 144.2, 128.9 (d,
J = 18.5), 126.5 (d, J = 6.9), 124.4 (d, J = 10.0), 116.5 (d, J =
24.9), 55.4, 49.9, 33.1, 28.5, 25.3 (d, J = 2.0), 20.6, 20.4; ms:
[4] Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
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[5] Attempts to alkylate using K2CO3 as the base in acetone
resulted in deprotonation of tert-butyl acetoacetate and C-alkylation
followed by a second deprotonation and intramolecular SNAr reaction of
the enolate oxygen at the fluorine-bearing aromatic carbon, see Bunce,
R. A; Rogers, D.; Nago, T.; Bryant, S. A. J. Heterocyclic Chem. 2008,
45,547.

1160
R. A. Bunce and T. Nago
Vol 45
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[8] Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
[9] Alkyl glycinates and their hydrochloride salts have been used
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Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
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