Convenient synthesis of 5,6,7,8-tetrahydroquinolin-8-ylamine and 6,7-dihydro-5H-quinolin-8-one

Article abstract of DOI:10.1081/SCC-120024729

A novel two-step synthesis of 5,6,7,8-tetrahydroquinolin-8-ylamine, involving regioselective nitrosation of 5,6,7,8-tetrahydroquinoline followed by oxime reduction, is described. Oxime hydrolysis affords 6,7-dihydro-5H-quinolin-8-one.

Full text of DOI:10.1081/SCC-120024729

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Convenient Synthesis of 5,6,7,8-Tetrahydroquinolin-8-
ylamine and 6,7-Dihydro-5H-quinolin-8-one
Group Leader E. J. McEachern a , W. Yang a , G. Chen a , R. T. Skerlj a & G. J. Bridger a
a AnorMED Inc., Langley, British Columbia, Canada
Published online: 15 Aug 2006.
To cite this article: Group Leader E. J. McEachern , W. Yang , G. Chen , R. T. Skerlj & G. J. Bridger (2003): Convenient
Synthesis of 5,6,7,8-Tetrahydroquinolin-8-ylamine and 6,7-Dihydro-5H-quinolin-8-one, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:20, 3497-3502
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 20, pp. 3497–3502, 2003
Convenient Synthesis of
5,6,7,8-Tetrahydroquinolin-8-ylamine and
6,7-Dihydro-5H-quinolin-8-one
*
E. J. McEachern, W. Yang, G. Chen, R. T. Skerlj,
and G. J. Bridger
AnorMED Inc., Langley, British Columbia, Canada
ABSTRACT
A novel two-step synthesis of 5,6,7,8-tetrahydroquinolin-8-ylamine,
involving regioselective nitrosation of 5,6,7,8-tetrahydroquinoline
followed by oxime reduction, is described. Oxime hydrolysis affords
6,7-dihydro-5H-quinolin-8-one.
Key Words: Nitrosation; 5,6,7,8-Tetrahydroquinoline; Substituted
pyridines; Oxime reduction; Oxime hydrolysis.
*Correspondence: E. J. McEachern, Group Leader, Department of Chemistry,
AnorMED Inc., #200-20353 64th Ave, Langley, BC, Canada V2Y 1N5; Fax: 604-
530-0976; E-mail: emceachern@anormed.com.
3497
DOI: 10.1081/SCC-120024729
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3498
McEachern et al.
The 5,6,7,8-tetrahydroquinolin-8-ylamino moiety is found as a
subunit of numerous medicinally interesting compounds.[1] In the course
of our drug development program, we required a practical and cost-
effective method to prepare multigram quantities of the parent 5,6,7,8-
tetrahydroquinolin-8-ylamine 3.
Our original synthetic route[1a] relied on a Boekelheide rear-
rangement[2] of the N-oxide of 1 to install the requisite functionality,
while subsequent functional group manipulation provided the amine 3
(Sch. 1). This route suffers from the disadvantages of length, moderate
overall yield, multiple purifications, and a potentially unstable azide
intermediate; it was thus poorly suited to the large-scale preparation
of 3.[3,4]
Given the precedent for nitrosation of alkylpyridines and alkylisoqui-
nolines,[5] we attempted a regioselective nitrosation of 1 at the 8-position to
access the corresponding oxime. Employing the modified conditions
described by Lardenois et al.[6] for nitrosation of 5,6,7,8-tetrahydroisoqui-
noline at the 5-position (t-BuOK followed by t-BuONO) provided only a
6% yield of the desired oxime, with the remainder being recovered starting
material. After some optimization, it was found that a stronger base (such
as LDA or n-BuLi) was required to quantitatively metalate 1 at the
8-position; in practice, the lithiation was most efficiently accomplished
using 1.0 equiv. n-BuLi at low temperature. Since the initial adduct 4 con-
tains an acidic proton, it was necessary to employ two equivalents of base
to avoid quenching the anion of 1 (Sch. 2). However, as n-BuLi reacts
rapidly with t-butyl nitrite, the second equivalent of base was immediately
consumed upon addition of t-BuONO and the yield of the oxime under
these conditions was only 33%.
1. MsCl, Et N, CH Cl
2
1. H O , AcOH, 70˚C
3
2
2
2
2. Ac O, 90˚C
2. NaN , DMF, 70 ºC
2
3
N
N
N
3. K CO , MeOH
3. H , Pd/C, MeOH
2
3
2
OH
NH
2
3
2
1
38%
86%
Scheme 1.
1. n-BuLi
Base
2. t-BuONO
N
N
H
N
N
N
OLi
OLi
t-BuO
5
1
4
Scheme 2.

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5,6,7,8-Tetrahydroquinolin-8-ylamine Moiety
3499
Reasoning that a nonnucleophilic base (i.e., one that would not
react as quickly with t-BuONO) was required to effect the second
deprotonation, we repeated the nitrosation using 1.0 equiv. n-BuLi and
1.0 equiv. LDA with an inverse addition of the anion/LDA mixture to a
solution of the nitrite. The inverse addition was used to minimize for-
mation of N-nitrosodiisopropylamine, a side-product resulting from reac-
tion of LDA with the alkyl nitrite. The preferred nitrosating agent was
isoamyl nitrite, which gave similar results to t-butyl nitrite but is available
in higher purity and is more economical. Under these conditions, the
oxime 6 was isolated as a beige solid in 75% yield after crystallization
(Sch. 3). HPLC analysis revealed the purity of this material to be 98%.
Subsequent reduction of 6 using Zn/NH4OAc[7] followed by an extractive
workup provided the amine 3 in 84% yield and 93% HPLC purity.
Alternatively, 6 could be readily hydrolyzed to the ketone 7[8] by heating
with 6 N HCl in acetone. It should be noted that the synthesis of 3 by this
method has been carried out on scales up to 45 kg 1 with no appreciable
loss in yield.
In conclusion, we report an experimentally facile, two-step procedure
for the preparation of 5,6,7,8-tetrahydroquinolin-8-ylamine 3 in high yield
from 5,6,7,8-tetrahydroquinoline 1. The key step involves a regioselective
nitrosation of 1, and avoids the use of highly toxic and potentially
explosive reagents. The ketone 6,7-dihydro-5H-quinolin-8-one 7 can also
be obtained in excellent yield using this protocol.
EXPERIMENTAL
6,7-Dihydro-5H-quinolin-8-one oxime (6). A solution of 5,6,7,8-tetra-
hydroquinoline (10.0 g, 75.1 mmol) and diisopropylamine (10.5 mL,
75.1 mmol) in dry MTBE (50 mL) was stirred for 10 min while dry N2
1. n-BuLi/LDA
Zn, NH OAc
4
MTBE, -15 ºC
2. isoamyl nitrite
H O, 50 ºC
2
N
N
N
84%
NH
N
2
75%
HO
1
6
3
6 N HCl,
acetone, reflux
N
81%
O
7
Scheme 3.

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3500
McEachern et al.
was purged through the system. The solution was then cooled to ꢀ15ꢁC.
A 2.50 M solution of n-BuLi in hexanes (60.1 mL, 150 mmol) was then
added over a period of 5 min. The temperature of the cooling bath was
maintained below ꢀ15ꢁC throughout the addition. The thus obtained
orange/red mixture was then transferred via cannula to a pre-cooled so-
lution of isoamyl nitrite (30.2 mL, 225 mmol) in dry MTBE (30 mL) at
ꢀ15ꢁC; the transfer took about 10 min. The resulting mixture was stirred
at ꢀ15ꢁC for 1 h at which time water (2 mL, then 100 mL) was added. The
biphasic mixture was warmed to ambient temperature, and the layers
were separated. The aqueous layer was washed with MTBE
(2 ꢂ 70 mL), then the aqueous layer was concentrated to approximately
one-half volume (50 mL) under reduced pressure. The aqueous fraction
was then neutralized with 4 N HCl to pH 8–9 and the resulting slurry was
cooled to 0ꢁC. The precipitate was collected by filtration and the filter
cake was washed with cold water (15 mL) followed by heptane (20 mL).
The product was then dried at 50ꢁC under vacuum for 24 h to afford
9.13 g (75%) of the title compound as a beige solid, HPLC purity 98%.
1H NMR (CDCl3, 300 MHz) ꢀ 1.87–1.96 (m, 2H), 2.81 (t, 2H, J ¼ 6 Hz),
2.93 (t, 2H, J ¼ 8 Hz), 7.18 (dd, 1H, J ¼ 9, 6 Hz), 7.48 (dd, 1H, J ¼ 9,
1 Hz), 8.52 (dd, 1H, J ¼ 6, 1 Hz), 9.63 (br s, 1H). 13C NMR (CDCl3,
75 MHz) ꢀ 20.8, 23.8, 28.9, 123.4, 134.5, 136.7, 148.2, 148.9, 152.7.
ES-MS m/z 163 (M þ H).
5,6,7,8-Tetrahydroquinolin-8-ylamine (3). To a stirred mixture of 6,7-
dihydro-5H-quinolin-8-one oxime (9.60 g, 55.4 mmol) in water (40 mL)
was added concentrated NH4OH (22 mL), followed by ammonium acet-
ate (5.16 g, 67.0 mmol). The mixture was heated to 50ꢁC, then zinc dust
(14.4 g, 222 mmol) was added in five portions while maintaining a max-
imum temperature of 65ꢁC. After the addition was complete, the reaction
mixture was stirred for 16 h at 50ꢁC, then cooled to room temperature.
Solid NaCl (11 g) and toluene (80 mL) were added and the resulting
mixture was stirred vigorously for 1 h. At this time, the reaction mixture
was filtered through a Celite pad, which was rinsed with toluene
(2 ꢂ 10 mL). The layers were separated and the organic layer was set
aside. To the aqueous layer, NaCl (5 g) and toluene (80 mL) were
added and the reaction mixture was filtered once more through a Celite
pad. After separation of layers, the organic layer was set aside. The
combined organic layers were concentrated under reduced pressure,
then dissolved in dichloromethane (100 mL). The resulting solution was
washed with 2.5% aqueous NaOH solution (5 mL) then concentrated
NH4OH (30 mL). The organic layer was set aside, and the combined
aqueous layer was extracted with dichloromethane (2 ꢂ 30 mL). After
phase separation, the organic layers were combined, dried (MgSO4),

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5,6,7,8-Tetrahydroquinolin-8-ylamine Moiety
3501
and concentrated in vacuo to yield 6.90 g (84% yield) of the title com-
pound, HPLC purity 93%. 1H NMR (CDCl3, 300 MHz) ꢀ 1.52–1.62
(m, 2H), 1.78–1.85 (m, 1H), 1.91 (brs, 2H), 2.02–2.06 (m, 1H),
2.60–2.65 (m, 2H), 3.83–3.87 (m, 2H), 6.91 (dd, 1H, J ¼ 8, 5 Hz), 7.21
(dd, 1H, J ¼ 8, 1 Hz), 8.26 (d, 1H, J ¼ 5 Hz). 13C NMR (CDCl3, 75 MHz)
ꢀ 19.6, 28.7, 31.7, 51.0, 121.3, 131.2, 136.4, 146.7, 159.2. ES-MS m/z 149
(M þ H).
6,7-Dihydro-5H-quinolin-8-one(7).Toastirredsolutionof6,7-dihydro-
5H-quinolin-8-one oxime (220 mg, 1.36 mmol) in acetone (5.0 mL) was
added 6 N HCl (2.0 mL). The resulting mixture was heated to reflux for
16 h, then cooled to room temperature. The reaction mixture was rendered
basic with a minimum amount of 3 N NaOH, then extracted with CH2Cl2
(3 ꢂ 30 mL), and the combined organic extracts were dried (MgSO4), fil-
tered and concentrated in vacuo. Flash chromatography of the crude ma-
terial thus obtained (silica gel, 20:2:1 CH2Cl2-MeOH-NH4OH) afforded
161 mg (81%) of the title compound as a pale yellow solid, HPLC purity
98%. 1H NMR (CDCl3, 300 MHz) ꢀ 2.17–2.25 (m, 2H), 2.82 (t, 2H,
J ¼ 7 Hz), 3.04 (t, 2H, J ¼ 6 Hz), 7.37 (dd, 1H, J ¼ 9, 6 Hz), 7.66 (dd, 1H,
J ¼ 9, 1 Hz), 8.71 (dd, 1H, J ¼ 6, 1 Hz). 13C NMR (CDCl3, 75 MHz) ꢀ 22.2,
28.6, 39.2, 126.6, 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m/z 148
(M þ H).
ACKNOWLEDGMENT
We thank Roger Sun and Lucita Ramos for analytical support.
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Received in the USA April 17, 2003