Enantioselective transfer hydrogenation, a key step for the synthesis of 3-aminotetrahydroquinolines

Article abstract of DOI:10.1039/c6nj02249a

An enantioselective transfer hydrogenation has been successfully achieved to furnish 3-aminotetrahydroquinolines. The reaction was conducted in the presence of Hantzsch dihydropyridine and a catalytic amount of chiral phosphoric acid under mild conditions.

Full text of DOI:10.1039/c6nj02249a

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Enantioselective transfer hydrogenation, a key step
for the synthesis of 3-aminotetrahydroquinolines†
Cite this:DOI: 10.1039/c6nj02249a
Alexandre Aillerie, Vincent Lemau de Talence, Clement Dumont, Sylvain Pellegrini,
´
´
Received (in Montpellier, France)
19th July 2016,
Frederic Capet, Till Bousquet* and Lydie Pelinski*
´ ´
´
Accepted 21st September 2016
DOI: 10.1039/c6nj02249a
www.rsc.org/njc
An enantioselective transfer hydrogenation has been successfully
achieved to furnish 3-aminotetrahydroquinolines. The reaction was
conducted in the presence of Hantzsch dihydropyridine and a
catalytic amount of chiral phosphoric acid under mild conditions.
1,2,3,4-Tetrahydroquinoline (THQ) scaffolds are found in many
biologically active molecules including natural and unnatural
products. In addition, they are widely used as building blocks
for organic synthesis. Among the synthetic pathways to access
enantioenriched THQs, the reduction of their parent quinoline
derivatives represents one of the most common and powerful
strategies.1
Since the first report on chiral phosphoric acid-catalyzed
asymmetric transfer hydrogenation (ATH) of CQN bonds,2
efforts have been made to significantly extend the scope of this
reaction.3 Although a broad range of quinolines were success-
fully reduced in this way,4 only recently were heterosubstituted
derivatives studied affording 3-nitro and 3-amino THQs with
excellent enantio- and diastereoselectivities.5
As part of our ongoing interest in the synthesis of relevant
therapeutic agents,6 we were interested in the formation of
enantiopure 2-unsubstituted-3-aminotetrahydroquinolines. These
privileged structures are in particular identified in Anachelin H,
an antimicrobial siderophore isolated from the cyanobacterium
Anabaena cylindrica,7 but also in Sumanirole, a highly selective
agonist for the dopamine D2 receptor and a potential anti-
Parkinson agent8 or in the 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-
dimethoxyquinolin-1(2H)-yl]propanone (S)-903, recently identified
as a potentially attractive positive inotropic agent (Fig. 1).9
Among the strategies developed to access these molecules or
their precursors, most are based on the use of the chiral pool10
Fig. 1 Biologically relevant 3-aminotetrahydroquinolines.
and few examples are related to asymmetric catalysis11 including
organocatalysis.12
Following our research in the field of organocatalysis,13 we
decided to reduce enantioselectively in this fashion the model
substrate 1a. For this purpose, we first investigated the conditions
previously described by Zhou and coworkers for the synthesis
of 3-amino-2-substituted-tetrahydroquinolines.5 Unfortunately,
although the product was obtained with a good (88%) yield, a
40% enantiomeric excess (ee) was observed.
This disappointing result prompted us to investigate a more
appropriate reductive system for the transfer hydrogenation of
such unsubstituted 3-aminoquinolines.
Hence, our initial investigations were focused on finding
both the best nitrogen-substituted quinoline and organocatalyst.
For this study, three quinolines 1a–c possessing a tosylamide, a
carbamate or an acetamide group, respectively, in position 3
were considered (Fig. 2). To promote the asymmetric transfer
hydrogenation transformation, we restricted our attention to the
phosphoric acid derivatives of (S)-BINOL 3a–e and (S)-VAPOL 3f.
The reactions on quinoline derivative 1 were performed in
toluene for 24 h in the presence of Hantzsch dihydropyridine 4
and 5 mol% of catalyst 3. When the reduction was carried out
on N-tosylquinoline 1a, despite lower reactivity, the highest
enantioselectivity was achieved with MacMillan phosphoric
acid 3e (44% yield and 90% ee, Table 1, entry 5).
´
Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 – UCCS – Unite de
Catalyse et Chimie du Solide, F-59000 Lille, France. E-mail: till.bousquet@univ-lille1.fr,
lydie.pelinski@univ-lille1.fr
Although the yield was improved to 90% by increasing the
temperature to 70 1C, the ee decreased to 83% ee (Table 1, entry 6).
Finally, the best conditions in terms of reactivity and enantio-
selectivity were found when the reaction was conducted at 50 1C
† Electronic supplementary information (ESI) available. CCDC 1484089. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c6nj02249a
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Scheme 1 Zhou’s conditions applied to the transfer hydrogenation of
3-tosylaminoquinoline 1a.
Fig. 2 Quinolines and catalysts evaluated for the optimization.
was used, increasing the temperature to 70 1C improved the
reactivity of the transformation but was detrimental to the
selectivity (96% yield, 61% ee, entry 16).
Table 1 Identification of the best 3-aminoquinoline derivative 1 and
catalyst 3 for the transfer hydrogenationa
Furthermore, it is worth noting that N-acetyl quinoline 1c in
the presence of the best catalysts 3d and 3e did not furnish the
transfer hydrogenation product in good yields and/or selectivities
(entries 17–19).
Following this survey, we decided to continue the optimizations
with quinoline 1a in combination with the triphenylsilyl BINOL
derivative 3e. Our attention then turned to the solvent effect on
the transfer hydrogenation (Table 2). The results revealed that
the nature of the solvent had much less impact on the enantio-
selectivity than on the reactivity. Among the solvents screened
in this scope, benzene exhibited the highest activity with a good
enantioselectivity (96% yield and 90% ee, Table 2, entry 2).
Decreasing the temperature or the catalyst loading resulted in a
lower efficiency for the reaction (Table 2, entries 8–10). Chlorinated
solvents maintained the yields to a satisfying level but resulted
in a slightly lower selectivity (Table 2, entries 3 and 4). The use
of ethereal solvents such as THF or methyl-tert-butyl ether has a
dramatic impact on the yield even though the tetrahydroadduct
was obtained with 91% and 89% ee respectively (Table 2,
entries 5 and 6).
Entry
Reagent
Catalyst
Product
Yieldb (%)
eec (%)
1
2
3
4
1a
1a
1a
1a
1a
1a
1a
1a
3a
3b
3c
3d
3e
3e
3e
3f
2a
2a
2a
2a
2a
2a
2a
2a
82
80
82
74
44
83
78
81
9
39
17
36
90
83
88
0
5
6d
7e
8
9
1b
1b
1b
1b
1b
1b
1b
1b
3f
2b
2b
2b
2b
2b
2b
2b
2b
75
96
98
98
98
79
40
96
22
25
2
27
49
73
73
61
10
11
12
13
14 f
15
16d
3a
3b
3c
3d
3d
3e
3e
17
1c
1c
1c
3d
3e
3e
2c
2c
2c
82
Trace
30
48
From this preliminary study, it was therefore decided to
extend the scope of asymmetric transfer hydrogenation to diversely
substituted N-tosylquinolines, in the presence of 5 mol% of catalyst
3e, in benzene at 50 1C for 48 h.
18
Ndg
78
19d
a
Reaction conditions: 1 (1 equiv.), 4 (2.4 equiv.), 3 (5 mol%), toluene,
b
c
50 1C, 24 h. Isolated yields. Determined by chiral stationary phase
d
e
HPLC. Reaction performed at 70 1C. Reaction performed for 48 h.
f
g
Reaction performed at 20 1C. Not determined.
Table 2 Screening of solvents and catalyst loading for the transfer
hydrogenation of 1aa
for 48 h (78% yield and 88% ee, Table 1, entry 7). Interestingly,
when the reaction was performed on 1a with catalyst 3b, the
enantioselectivity of product 2a was comparable to the one observed
in our preliminary trial (Table 1, entry 2, vs. Scheme 1). Thus it
appears, afterwards, that the disappointing ee of 2a under Zhou’s
conditions was mainly due to an inappropriate catalyst.
To improve these conditions, we next performed the reaction
on N-carbamate quinoline 1b. As observed with 1a, the 3,30-
triphenylsilyl-substituted catalyst 3e appeared to be more selective
but less reactive than the 9-anthracenyl derivative 3d (40% yield
and 73% ee vs. 98% yield and 49% ee, Table 1, entries 15 vs. 13).
With catalyst 3d, the enantioselectivity was improved to 73% by
decreasing the temperature to 20 1C, but only 79% yield was
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
Toluene
Benzene
CHCl3
CH2Cl2
THF
78
96
87
95
38
20
35
38
84
89
88
90
86
87
91
89
70
91
85
43
MTBE
CH3CN
Benzene
Benzene
Benzene
8d
9e
10 f
a
Reaction conditions: 1a (1 equiv.), 4 (2.4 equiv.), 3e (5 mol%), solvent,
b
c
50 1C, 48 h. Isolated yields. Determined by chiral stationary phase
HPLC. Reaction performed at 30 1C. Reaction performed using 2 mol%
of the catalyst. Reaction performed using 1 mol% of the catalyst. THF:
d
e
f
achieved (entry 14). Besides this, in the case where catalyst 3e tetrahydrofuran, MTBE: methyl-tert-butyl ether.
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Table 3 Scope of the transfer hydrogenationa
Scheme 2 Synthesis of Sumanirole from 2a.
Entry
Reagent
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1d
1e
1f
1g
1h
1i
1j
1k
1l
H
6-Cl
6-Br
7-Br
7-CF3
5-NO2
6,7-OCH2O
7-OMe
6-OMe
7-Ph
2a
2d
2e
2f
2g
2h
2i
2j
2k
2l
96
98
88
87
69
43
0
90
30
0
90
85
60
87
75
56
—
84
87
—
85
In conclusion, we have achieved an effective and enantio-
selective transfer hydrogenation of 3-tosylaminoquinolines.
The tetrahydroadducts accessible in this way could therefore
be considered for the synthesis of biologically interesting
scaffolds. In particular, product 2a, following a five-step synthetic
pathway developed in the literature, could lead to (R)-Sumanirole
(Scheme 2).13b
9
10
11
1m
6-Ph
2m
75
a
Reaction conditions: 1 (1 equiv.), 4 (2.4 equiv.), 3e (5 mol%), benzene,
Experimental
50 1C, 48 h. b Isolated yields. Determined by chiral stationary phase HPLC.
c
In a typical procedure, the 3-aminoquinolines (1 mmol, 1 equiv.),
4-toluenesulfonyl chloride (1 mmol, 1 equiv.) and DMAP
(0.15 mmol, 0.15 equiv.) were suspended in pyridine (10 mL
mmolꢀ1) in a Schlenk tube under a nitrogen atmosphere. The
reaction mixture was stirred at room temperature and the
progress of the reaction was monitored by TLC. After comple-
tion, the mixture was diluted in water (30 mL), extracted with
DCM (5 ꢁ 10 mL) and the combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography to give the
desired product 2.
Among the quinolines evaluated, none of them furnished
the corresponding product with a better ee than 2a. The first
experiments proved that the presence of electron withdrawing
groups in position 6 or 7 was compatible with the transfer
hydrogenation reaction (Table 3, entries 2–5). However, a nitro
substituent in position 5 resulted in a lower yield and reactivity
(Table 3, entry 6). The enantioselectivity dropped down when a
chloride in position 6 was replaced by a bromo substituent
(Table 3, entries 2 vs. 3). Our first trial with electron donating
group derivatives was performed on the 6,7-methylenedioxy quino-
line 1i and unfortunately did not furnish any traces of compound
2i (Table 3, entry 7). Therefore we decided to evaluate separately
the 6 and the 7-methoxy quinoline derivatives. Although the
selectivity was comparable, these experiments clearly demon-
strated that the presence of a methoxy group in position 6 was
detrimental to the reactivity (Table 3, entries 8 vs. 9). Besides this,
surprisingly no conversion was observed when the transfer hydro-
genation was attempted on the 7-phenyl-3-aminoquinoline 1l.
Therefore the reaction was attempted on the 6-phenyl substituted
substrate 1m. The adduct was obtained with a satisfying yield and
85% ee. Such a difference in reactivity between substitution on
position 6 and position 7 with an electron donating group or an
aryl group is intriguing and still remains to be clarified.
Description of product 2a: a white solid with 96% yield. Rf:
0.47 (petroleum ether/ethyl acetate: 1/1). 1H-NMR (300 MHz,
CDCl3): d = 7.75 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.02–
6.97 (m, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.64 (td, J = 7.4, 1.1 Hz,
1H), 6.50 (dd, J = 8.0, 0.9 Hz, 1H), 4.99 (d, J = 8.7 Hz, 1H), 3.90–
3.81 (m, 1H), 3.30–3.25 (m, 1H), 3.11–3.05 (m, 1H), 2.93–2.87
(m, 1H), 2.60–2.53 (m, 1H), 2.44 (s, 3H); 13C-NMR (75 MHz,
CDCl3): d = 143.5, 143.3, 138.4, 130.5, 129.9, 127.6, 127.1, 118.4,
117.6, 114.5, 46.4, 46.2, 33.6, 29.8, 21.7. [a]2D0 ꢀ15.2 (c 0.3;
CHCl3). HPLC conditions: Chiracels OJ-H (Hex/EtOH = 70/30,
0.9 mL minꢀ1), major enantiomer: tR = 72.67 min, minor
enantiomer: tR = 64.10 min, 90% ee. HRMS m/z (ESI) calcd for
C
16H19O2N2S [M + H]+ 303.1162, found 303.1146.
The absolute configuration of adduct 2a was unambiguously
determined to be (R) by X-ray diffraction analysis (Fig. 3) and
those of other products were assigned by analogy.
Acknowledgements
´
We are grateful to the ‘‘Conseil Regional Nord-Pas de Calais’’
´
(program PRIM, grant for AA) and the ‘‘Comite Nord de la Ligue
contre le Cancer’’ for financial support. The Chevreul Institute
`
´
(FR no. 2638), Ministere de l’Enseignement Superieur et de la
´
Recherche, Region Nord-Pas de Calais and FEDER are acknowl-
edged for funding of X-ray diffractometers.
Notes and references
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Fig. 3 X-ray crystal structure of (R)-2a.
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