Synthesis of new chiral 2-functionalized-1,2,3,4-tetrahydroquinoline derivatives via asymmetric hydrogenation of substituted quinolines

Article abstract of DOI:10.1016/j.tet.2013.07.090

The asymmetric hydrogenation of a series of quinolines substituted by a variety of functionalized groups linked to the C2 carbon atom is providing access to optically enriched 2-functionalized 1,2,3,4-tetrahydroquinolines in the presence of in situ generated catalysts from [Ir(cod)Cl]₂, a bisphosphine, and iodine. The enantioselectivity levels were as high as 96% ee.

Full text of DOI:10.1016/j.tet.2013.07.090

Tetrahedron 69 (2013) 9322e9328
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new chiral 2-functionalized-1,2,3,4-tetrahydroquinoline
derivatives via asymmetric hydrogenation of substituted quinolines
Anna M. Maj a, , Isabelle Suisse e, Christophe Hardouin d,
e
,
a,c,
*
a,b,e,
*
Francine Agbossou-Niedercorn
Universit ꢀe Lille Nord de France, F-59000 Lille, France
CNRS, UCCS UMR 8181, F-59655 Villeneuve d’Ascq, France
Universit ꢀe Lille 1, Sciences et Technologies, F-59655 Villeneuve d’Ascq, France
Oril Industrie, 13, rue Auguste Desgen ꢀe tais, 76210 Bolbec, France
a
b
c
d
e
ENSCL, UCCS e CCM e CCCF, Av. Mendeleïev, CS90108, F-59652 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2013
Received in revised form 23 July 2013
Accepted 29 July 2013
Available online 3 August 2013
The asymmetric hydrogenation of a series of quinolines substituted by a variety of functionalized groups
linked to the C2 carbon atom is providing access to optically enriched 2-functionalized 1,2,3,4-
tetrahydroquinolines in the presence of in situ generated catalysts from [Ir(cod)Cl]
and iodine. The enantioselectivity levels were as high as 96% ee.
2
, a bisphosphine,
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric hydrogenation
Heterocycles
Quinolines
Iridium
1
4
1
. Introduction
phosphine-phosphites, phosphinites,15 monodentate phospho-
16
17
18
rous ligands, phosphine-phosphoramidites, P,N-ligands, but
18
Chiral amines are ubiquitous building blocks found in many
bioactive compounds, such as pharmaceuticals and agrochemicals.
Because chiral heterocyclic compounds are structures of interest
present in natural and synthetic products with biological, agro-
chemical, and pharmaceutical properties, the asymmetric hydro-
genation of the parent heteroaromatic derivatives has been
extensively investigated. Actually, chiral heterocyclic compounds
obtained from efficient asymmetric hydrogenation of quinolines,
isoquinolines, quinoxalines, indoles, pyrroles, pyridines, oxa-
zoles, furans, benzofurans, and thiophenes have been re-
ported. The hydrogenation of quinolines was first described by
Zhou, who published, a decade ago, the highly efficient iridium-
catalyzed asymmetric hydrogenation of 2-substituted alkyl quino-
lines. The hydrogenation was performed with iridium catalysts
generated from [Ir(cod)Cl] and the atropisomeric diphosphine
MeOeBiphep. From this pioneering work, a variety of iridium cat-
also phosphine-free and organocatalytic systems, have been de-
veloped for this transformation. The substrate scope comprises es-
sentially 2-substituted quinolines bearing aryl, alkyl, or benzyl
residues. Quinolines bearing ketone, ester, amide, or benzene sul-
fonyl functionalities have also been considered. Nevertheless, the
additional functionality was generally connected to the N-hetero-
aromatic unit via a methylene spacer. Regardless the excellent re-
sults obtained with such type of derivatives, the substrate scope
deserves to be extended to other functionalized scaffolds eventually
directly connected to the C2 carbon atom in order to further increase
the potential of this methodology. As part of our ongoing research
toward the use of catalyzed asymmetric transformations for the
1
2
3
4
5
6
7
8
9
10
11
12
6
c,19
synthesis of biologically relevant targets,
and taking into account
3
a
the scarce examples of spacer free 2-functionalized tetrahy-
droquinolines, we thought to investigate valuable new 2-
functionalized quinoline substrates.
Herein, we report on our investigation based on Ir-catalyzed
hydrogenation of a series of quinolines, which have not been
studies yet (Fig. 1). Hydrogenations of quinoline carboxylates 2e5,
hydroxymethylene quinoline 7, bromoquinoline 8, and amino-
2
3
e,13
alysts bearing chiral ligands, such as, for example, diphosphines,
*
Corresponding authors. E-mail addresses: anna.maj@ensc-lille.fr (A.M. Maj),
19e
francine.agbossou@ensc-lille.fr (F. Agbossou-Niedercorn).
derivative 14 have been reported recently.
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.090

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
9323
8
1
2% yield into the 1,2,3,4-tetrahydroquinolic acid 16 (entry 1, Table
). An enantiomeric excess of 41% was determined on the corre-
sponding methyl ester 17 obtained after esterification of the hy-
drogenation product 16 (SOCl /MeOH) (entry 1). Under identical
2
conditions, ester 2 led to 17 in 88% yield and 66% ee (entry 2). On
this basis, a screening of ligands was then carried out specifically on
the hydrogenation of 2. Conversions were ranging from 7 to 100%,
selectivities into 17 from 2 to 98%, and ee’s from 0 to 74%. Among
the array of ligands employed, some iridium catalysts bearing
specific atropisomeric diphosphine led to the best results in terms
of conversion and enantioselectivity. Indeed, 66, 74, and 72% ee
were measured in the presence of MeOeBiphep L1, Difluorphos L7,
and P-Phos L8, respectively (entries 2, 8, and 9). However, Synphos
MeOeCleBiphep L2 and L5 led to only 36% and 25% ee, respectively
Fig. 1. 2-Functionalized quinoline substrates studied in this work.
(
entries 3 and 6). Low catalytic activities were noticed with Binap
L3, C -Tunephos L4, Me-Duphos L15, and the ferrocene based
Taniaphos SL-T002 L17 and SL-T001 L16 ligands (entries 4, 5,
4e16). On the other side, Et-FerroTANE L14 allowed a good yield
2
. Results and discussion
3
Five of the selected substrates were commercially available (1, 2,
, 10, and 11). The others were prepared easily by applying standard
transformations (Fig. 1, Scheme 1).
1
3
(
80%) but the ee remained low (11%) (entry 13). Finally, in the
Ò
presence of CatASium T3 L13, although the conversion and yield
are good, a poor ee was measured (11%, entry 12).
Next, we concentrated on the most appropriate ligands and
applied them in the hydrogenation of other substrates, i.e., esters
3e6, quinolin-2-ylmethanol 7, and halogenated 8 and 9 (Table 2).
Except for substrate 8 (entry 16), all quinolines could be hy-
drogenated selectively under the applied conditions. From the
complex reactions mixture obtained from 8, we could identify
the dehalogenated hydrogenated product 2-methyl-1,2,3,4-
tetrahydroquinoline. In the case of the ethyl ester 3, the best re-
sults are obtained with the Difluorphos L7 and P-Phos L8 ligands
reaching 94 and 88% ee, respectively (entries 4 and 7). These values
should be compared to the results obtained with methyl ester 2: 74
and 72% ee in the presence L7 and L8, respectively (entries 8 and 9,
Table 1). The much higher ee obtained with the ethyl ester shows
that a slight increase of the steric hindrance on the ester residue
could affect significantly the stereoselectivity outcome of the
transformation. Nonetheless, this was not a general trend as in the
presence of the MeOeBiphep ligand L1, the ee for the ethyl ester 18
hydrogenation was only 58% compared to 66% obtained for the
reduction of 17 (entry 2, Table 1 vs entry 1, Table 2). A further in-
crease of the steric hindrance of the ester group in going from ethyl
to propyl resulted in a small erosion of the enantioselectivity (entry
9). A high level of enantioselectivity was obtained again during the
hydrogenation of isobutyl ester 6 in the presence of P-Phos L8 li-
Scheme 1. Synthesis of the substrates.
The esters 4e6 were obtained by transesterification of the com-
mercial methyl-quinolone-2-carboxylate 2 in the presence of a cat-
alytic amount of cesium carbonate in the appropriate alcohol
80e90% yield). Alcohol 7 could be obtained by reduction of the ester
with sodium borohydride (73% yield). Chloro 8 and bromo 9
compounds were obtained from alcohol 7 by reaction with SOCl
and PBr , 76 and 83% yield, respectively. The synthesis of the diBoc
substrate 14 has been carried out by reaction of 2-(bromomethyl)
quinoline 9 with di-tert-butyliminodicarboxylate in the presence of
cesium carbonate (80% yield). The three substrates 12, 13, and 15
were obtained from 14. Thus, the cleavage of one Boc residue of 14
ꢀ
(
2
gand at 20 C (98% yield, 94% ee) (entry 11). By decreasing the re-
ꢀ
action temperature to 5 C, the enantioselectivity increased to 96%
2
ee (entry 12). In the case of the 2-hydroxymethylquinoline 7, be-
3
cause of the low solubility of this substrate in neat toluene, we used
i
a mixture of toluene/ PrOH as solvent. The stereoselectivity was
interesting with a maximum of 84% ee in the presence of Difluor-
phos ligand L7 (entry 14). Finally, 2-bromomethylquinoline 9 has
been studied. As in the case of the chloromethylquinoline 8, 2-
methyl-1,2,3,4-tetrahydroquinoline was observed as by-product
ꢀ
was performed in the presence of lithium bromide at 65 C for 1 h,
2
0
19e
furnishing 13 in 89% yield after purification. The complete depro-
tection of 14 into 15 was carried out in acidic ethanol with 90% yield.
Then, 2-aminomethylquinoline 12 was obtained in 82% yield from
reaction of 15 with sodium hydroxide. Substrate 15 could also be
obtained from nitrile 10 applying a hydrogenation over Pd/C fol-
(82e90% ee ). The higher ee obtained for this side product sug-
gests that the cleavage of the bromide is occurring most probably
prior to hydrogenation of the quinoline heterocycle. The best
compromise between yield and enantioselectivity was obtained in
the presence of the ligand L8 (100% yield, 81% ee, entry 19). Hy-
21
lowed by a protonation in 58% overall yield (Scheme 1).
For our initial hydrogenation experiments, we examined the
reduction of acid 1 and methyl ester 2. Hydrogenations were per-
drogenation of ethyl ester 3 has been performed on gram scale in
ꢀ
the same reaction conditions (50 bar H
2
and T¼20 C) and led after
17 h to 100% yield into the corresponding ester 18 and to the same
level of enantioselectivity (92% ee).
formed in the presence of [Ir(cod)Cl]
an additive, in toluene under 50 bar H
reported in Table 1.
2
, a diphosphine (Fig. 2), I
2
as
ꢀ
3a
2
at 20 C. The results are
In our preliminary communication, we reported on the hydro-
genation of the N,N-diBoc-2-yl-methanamine 14 providing up to
19e
When acid 1 was hydrogenated in the presence of ligand L1, the
91% ee.
We extended our study and examined the nitrogen
reaction proceeded smoothly with 90% conversion within 17 h and
functionalized substrates 10e15 in the presence of the best chiral

9324
A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
Fig. 2. Ligands investigated in the hydrogenation of quinoline substrates.
Table 2
Table 1
Asymmetric hydrogenation of 2-functionalized quinolines 3e9
a
a
Asymmetric hydrogenation of acid 1 and methyl ester 2
Entry
Substrate
Ligand
t (h)
Conv.b (%)
Yieldc (%)
eec (%)
41 (R)d
Entry
Substrate
Ligand
Conv.b (%)
Yieldc (%)
eec (%)
1
2
3
4
5
6
7
8
9
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
L1
L1
L2
L3
L4
L5
L6
L7
17
48
90
100
75
72
45
100
76
100
94
95
64
96
97
7
82
88
70
63
43
98
63
95
89
87
60
72
80
2
e
66 (R)
36 (S)
13 (S)
29 (S)
25 (S)
43 (S)
74 (S)
72 (S)
55 (S)
10 (S)
11 (S)
11 (R)
n.d.
1
2
3
4
5
3
L1
L5
L6
L7
L11
L12
L8
L10
L7
L7
L8
L7
L6
L7
L9
L8
L6
L7
L8
94
100
100
99
88
83
99
14
100
100
100
97
100
97
100
89
100
100
94
88
83
94
12
100
100
98
58
64
64
94
46
37
88
3
90
75
94
96
80
84
70
17
17
48
17
17
17
17
17
17
48
17
17
17
17
d
6
7
8
9
L8
L9
10
11
12
13
14
15
16
4
5
6
L10
L13
L14
L15
L16
L17
10
11
12
13
14
e
97
100
97
f
7
f
91
21
84
10
22 (S)
0
f
15
100
f,g
16
17
18
19
8
9
Mixture of products
a
All reactions were performed on
a
1
mmol scale; S/Ir/L/I¼100/1/1.1/10;
f,g
g
100
100
100
44
65
100
79
69
81
ꢀ
P
H2¼50 bar; 20 C; toluene 7 mL.
b
Conversion determined by GC and NMR.
Yield and ee of 17 determined by HPLC analysis on Chiralcel OJ-H column
c
i
a
(
hexane/ PrOH 70:30, 1 mL/min); configuration not determined. By-products have
All reactions were performed on
a
1
mmol scale; S/Ir/L/I¼100/1/1.1/10;
ꢀ
not been identified.
P
H2¼50 bar; 20 C; toluene 7 mL; 17 h.
d
b
Determined on the methyl ester 17 after esterification of the tetrahydroquinolic
Conversion determined by GC and NMR.
Yield and ee determined by HPLC analysis: 18e21: Chiralcel OJ-H column
c
acid 16.
e
i
i
Time not optimized.
(hexane/ PrOH 70:30, 1 mL/min); 22: Chiralcel OD column (hexane/ PrOH 90:10,
mL/min); 24 Chiralcel OD column (hexane/ PrOH 98:2, 1.5 mL/min); configuration
i
1
not determined.
ligands of the series explored in this work L6, L7, and L8. The results
are reported in Table 3.
We first examined the hydrogenation of the commercial sub-
strates 10 (Table 3, entry 1). The hydrogenation of 10 led to 50%
d
t¼3 days.
e
f
ꢀ
T¼5 C.
i
Solvent: toluene/ PrOH: 7/1: 8 mL.
g
2-Methyl-1,2,3,4-tetrahydroquinoline is observed as by-product.

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
9325
Table 3
Conv. (%)
100
ee (%)
a
Hydrogenation of quinoline derivatives 10e15
1
00
100
100
1
00
9
2
91
9
9
8
8
7
7
5
0
5
0
5
0
9
0
91
8
9
8
7
2
0
10
5
0
-5
Entry Substrate Ligand
P
H2 (bar) t (h) Conv.b (%) Yieldb (%) eec (%)
T ( C)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
10
11
L8
L8
L7
L8
L7
L8
L6
L7
L8
L6
L7
L8
L6
L6
L7
L8
L6
50
50
50
50
50
70
100
50
50
50
50
50
50
50
70
70
70
17
17
17
17
24
48
72
17
17
17
17
17
17
17
60
72
96
50
92
100
100
0
nd
92
100
100
d
d
54
62
62
d
Fig. 3. Asymmetric hydrogenation of 14: influence of the temperature.
d
d
12
13
14
20
0
0
d
d
totally hydrogenated with 89% ee whatever the temperature be-
d
ꢀ
tween 20 and ꢁ5 C in the presence of ligand L7. No reaction oc-
100
100
100
100
100
100
100
79
100
100
100
100
100
100
100
79
89
84
84
83
85
87
91
42
65
55
curred with the amine free substrate 12 (entry 5). When increasing
the pressure to 70 bar, the substrate was consumed partly, but the
hydrogenated compound could not be detected in the mixture of
otherwise unidentified products (entry 6).
0
1
2
3
4
5
6
7
d
e
e
e
When the corresponding bischlorohydrate substrate 15 was
reacted in the presence of Cs
only 79% conversion was obtained after 60 h at 20 C under 70 bar
of hydrogen and with a moderate enantioselectivity (42% ee) (entry
15). Results could be improved in terms of enantioselectivity in the
presence of L6 and L7 ligands (65 and 55% ee, entries 16 and 17).
f
CO
3
, product formed very slowly as
15
2
f
ꢀ
85
90
74
90
f
a
All reactions were performed on a 1 mmol substrate scale; S/Ir/L/I
2
¼100/1/1.1/
ꢀ
5
; 20 C; toluene 8 mL; 17 h.
b
Determined by GC and NMR.
c
i
Determined by HPLC: 26, Chiralcel OD (hexane/ PrOH 90:10,
1 mL/min),
ꢀ
i
ꢀ
3. Conclusion
T¼20 C; 27, Chiralcel OD (hexane/ PrOH 98:2, 0.2 mL/min), T¼22 C; 28: Chiralcel
i
ꢀ
i
OJ-H (hexane/ PrOH 90:10, 1 mL/min), 20 C; 30: Chiralcel AD-H (hexane/ PrOH/DEA
ꢀ
9
5:5:0.1, 1 mL/min), T¼7 C; Configuration not determined.
In summary, chiral 2-functionalized-1,2,3,4-tetrahydro-quino-
line derivatives could be obtained by catalytic asymmetric hydro-
genation of the corresponding quinoline precursors in the presence
d
e
f
ꢀ
T¼0 C.
i
Toluene/ PrOH: 8/1.
2 3
Cs CO (0.62 mmol); determined on the amine 27 after neutralization of the
chlorohydrate 30 with sodium hydroxide 1 N.
of in situ generated catalysts obtained from [Ir(cod)Cl]
2
, a bisphos-
phine, and iodine I . On one hand, the best results were obtained
2
with the two amine protected substrates bearing NHBoc 13 and
conversion, several products being formed. A LCeMS analysis
probed the presence of the double hydrogenation product (C]C
and CN reduction) and remaining substrate 10. However, the hy-
drogenated product was difficult to quantify. Two other products
could also be identified in the reaction mixture, i.e., the 2-
quinolinemethanamine, which results from the sole reduction of
the nitrile functionality and 2-methyl-1,2,3,4-tetrahydroquinoline,
which is produced by heteroaromatic ring hydrogenation and
cleavage of the amino residue. We varied some reaction conditions,
NBoc 14 groups. Selectivities up to 91% could then be achieved. On
2
the other hand, asymmetric hydrogenation of various quinoline
carboxylates has been successfully performed with levels of
enantioselectivity as high as 96%. High levels of reactivity and
enantioselectivity obtained on gram scale allow to display a high
potential of this transformation for an industrial application.
4
4
. Experimental
i.e., the ligand (L7 and L6), the pressure (from 50 to 100 bar), the
.1. General information
ꢀ
temperature (from 20 to 70 C), Cs
2
CO
3
as an additive. Un-
fortunately, results could not be improved.
All reactions were carried out under an inert nitrogen atmo-
We next studied the hydrogenation of the amide 11. This re-
action has already been reported in a racemic way over Adam’s
sphere using standard Schlenk techniques. Toluene and iso-
propanol were obtained from a solvent purification system MBraun
SPS-800. Methanol was distilled over magnesium. All solvents were
catalyst22 (PtO
, EtOH, HBraq, 20 C) but, to our knowledge, no
ꢀ
2
asymmetric version was reported. Under our reaction conditions,
i.e., toluene as the solvent and (R)-P-Phos L8 as the ligand, the
conversion of 11, after 17 h, was 92% with 54% ee (entry 2). The
incomplete conversion of the substrate can be attributed to the
relatively poor solubility of 11 in toluene. Indeed, when using
1
13
degassed prior to use. H (300 MHz) and C (75 MHz) NMR spectra
were recorded using a Bruker AC 300 spectrometer. Analytical thin
layer chromatography (TLC) was carried out using commercial sil-
ica gel plates (Merck 60 F 254), spots were determined with UV
light. Conversions were determined by gas chromatography on
a Varian 430-GC apparatus equipped with a CP Sil 5 CB column
i
a mixture of toluene/ PrOH, after 17 h, a complete transformation
was effectively observed with a slightly higher enantioselectivity
(
25 m, i.d.¼0.32 mm) and by NMR experiments. Enantiomeric ex-
(
62% ee) (entry 3). In the presence of ligand L8, no improvement of
the selectivity was observed (62% ee, entry 4).
In the case of the NHBoc and NBoc substrates (13 and 14), the
conversions were complete within 17 h. The ee values were in the
3e89% range (entries 8e13). We also examined the effect of the
temperature on the hydrogenation of 14 in the presence of the
cesses were determined by HPLC analyses with a Thermofinnigan
Spectra System at 254 nm or 304 nm. The analyses were performed
using Chiralpak OJ-H, AD-H, or OD columns. Melting points were
determined using a Barnstead Electrothermal (BI 9300) apparatus
and were uncorrected. Elemental analyses were performed at the
University Lille Nord de France on an Elementar, Vario Micro cube
apparatus. HRMS analyses were performed on an Exactive Thermo
Scientific spectrometer at CUMA-Pharm. Dept., University Lille
Nord de-France.
2
8
catalytic system [Ir(cod)Cl]
measured at 0 and ꢁ5 C (91% ee, entry 14). But at ꢁ5 C, the
conversion dropped to 92%. On the other side, substrate 13 was
2
/L6 (Fig. 3). The highest ee values were
ꢀ
ꢀ

9326
A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
4
.2. Synthesis of substrates
8.42 (1H, m, CHar); 13C NMR (75 MHz, DMSO) 47.77, 121.55, 127.49,
27.56, 128.37, 129.13, 130.52, 137.91, 147.33, 157.29.
1
Propyl quinoline 2-carboxylate 4, isopropyl quinoline 2-
carboxylate 5, and isobutyl quinoline 2-carboxylate 6 were ob-
tained by transesterification of methyl ester 2.
General procedure: The methyl ester 2 (1 g, 5.1 mmol) was stirred
in the selected alcohol (25 mL) in the presence of cesium carbonate
4.2.6. 2-(Bromomethyl)quinoline 9. Quinolin-2-ylmethanol 7 (6 g,
37.8 mmol) was dissolved in CH Cl (60 mL). PBr (2.14 mL,
22.6 mmol) was carefully added at 0 C to this solution. The mixture
was allowed to return at ambient temperature and was stirred for
30 min. Water (60 mL) was then added followed by a saturated
2
ꢀ
2
3
(
0.05 g, 0.15 mmol) for 24 h at ambient temperature. The progress
of the reaction was followed by TLC. At the end of the trans-
esterification, the solvent was evaporated, water (20 mL) was
added and the crude residue was extracted with ethyl acetate
aqueous solution of K
2
CO
3
(40 mL) to obtain a pH¼8. The organic
phase was washed with brine (2ꢂ30 mL), dried over magnesium
sulfate, and concentrated under reduced pressure. The crude resi-
due was purified through a silica gel column chromatography
(
5ꢂ25 mL). The solution was then dried over magnesium sulfate
ꢀ
1
and evaporated to dryness.
(AcOEt/MCH: 20/80). White solid; 83% yield; mp 55 C (dec);
H
NMR (300 MHz, DMSO) 4.86 (2H, s, CH ), 7.67 (2H, m, CHar), 7.78
2
13
4
.2.1. Propyl quinoline 2-carboxylate 4. Light yellow solid; 80%
(1H, m, CHar), 7.99 (2H, m, CHar), 8.40 (1H, m, CHar); C NMR
(75 MHz, DMSO) 35.67, 122.10, 127.46, 127.54, 128.34, 129.07,
ꢀ
1
yield; mp 45 C; H NMR (300 MHz, CDCl
.83 (2H, m, CH ), 4.38 (2H, m, CH ), 7.57 (1H, m, CHar), 7.72 (1H, m,
CHar), 7.81 (1H, m, CHar), 8.10 (1H, m, CHar), 8.25 (2H, m, CHar);
3 3
) 0.98 (3H, t, J 7.1 Hz, CH ),
1
2
2
130.53, 138.37, 147.36, 157.67; HRMS (ESI) m/z calculated for
13
þ
C
C
10
H
9
NBr [MþH] : 221.99129, found: 221.991.
NMR (75 MHz, CDCl
3
) 10.43, 22.11, 67.77, 121.09, 127.51, 128.56,
1
29.32, 130.28, 130.86, 137.27, 147.61, 148.28, 165.51; HRMS (ESI) m/
4.2.7. N,N-DiBoc-quinolin-2-ylmethanamine 14. HN(Boc)
2
(8.84 g,
þ
z calculated for C13
H14NO
2
[MþH] : 216.1019, found: 216.1018.
40.7 mmol) and K CO (8.45 g, 61.1 mmol) were added to a solution of
2
3
2
-(bromomethyl)quinoline 9 (9 g, 40.7 mmol) in acetonitrile (54 mL)
1
ꢀ
4
.2.2. Isopropyl quinoline 2-carboxylate 5. Yellow oil; 80% yield; H
NMR (300 MHz, CDCl ) 1.41 (6H, d, J 8.1 Hz, CH ), 5.34 (1H, m, CH),
.58 (1H, m, CHar), 7.71 (1H, m, CHar), 7.80 (1H, m, CHar), 8.09 (1H,
at 20 C. The mixture was then heated at reflux for 2 h. After cooling,
water (54 mL) and ethyl acetate (30 mL) were added successively. The
organic layer was washed with water (54 mL) and concentrated un-
der reduced pressure. The orange oily residue was purified through
a silica gel column chromatography (AcOEt/MCH: 97/3). White solid;
3
3
7
13
m, CHar), 8.24 (2H, m, CHar); C NMR (75 MHz, CDCl
3
) 21.91, 69.89,
121.02, 127.43, 128.48, 129.23, 130.10, 130.89, 137.18, 147.72, 148.63,
þ
ꢀ
1
164.86; HRMS (ESI) m/z calculated for
C
13
H
14
O
2
N
[MþH] :
80% yield; mp 96 C; H NMR (300 MHz, CDCl
(2H, s, CH ), 7.32 (1H, m, CHar), 7.52 (1H, m, CHar), 7.70 (1H, m, CHar),
.80 (1H, m, CHar), 8.04 (1H, m, CHar), 8.14 (1H, m, CHar); C NMR
(75 MHz, CDCl ) 28.04, 51.89, 81.98, 117.99, 126.05, 127.13, 127.54,
3 3
) 1.44 (18H, s, CH ), 5.11
216.1019, found: 216.1017.
2
13
7
1
4.2.3. Isobutyl quinoline 2-carboxylate 6. White solid; 90% yield; H
3
NMR (300 MHz, CDCl
.28 (2H, m, CH ), 7.65 (1H, m, CHar), 7.71 (1H, m, CHar), 7.80 (1H, m,
CHar), 8.09 (1H, m, CHar), 7.65 (1H, m, CHar), 7.80 (1H, m, CHar), 8.17
3
) 1.00 (6H, d, J 7.5 Hz, CH
3
), 2.21 (1H, m, CH),
129.08, 129.52, 136.65, 147.65, 152.48, 158.40; HRMS (ESI) m/z calcu-
þ
4
2
lated for C20H O N
27 4 2
[MþH] : 359.19653, found: 359.19614.
13
(
1H, m, CHar), 8.32 (1H, m, CHar); C NMR (75 MHz, CDCl
3
) 19.32,
4.2.8. tert-Butyl(quinolin-2-ylmethyl)carbamate 13. To a solution of
N,N-diBoc-quinolin-2-ylmethanamine 14 (4.7 g, 13.1 mmol) in
acetonitrile (50 mL), LiBr (3.41 g, 39.2 mmol) was added. The re-
2
7.94, 72.05, 120.95, 127.55, 129.30, 130.26, 130.85, 137.34, 147.66,
þ
148.25, 165.28; HRMS (ESI) m/z calculated for C14
H
16
O
2
N [MþH] :
ꢀ
2
30.11760 found: 230.11700.
action mixture was heated at 65 C for 1 h. After cooling at ambient
temperature, the mixture was evaporated to dryness and the yel-
low oil was dissolved in AcOEt (20 mL) then washed with water
(2ꢂ20 mL). The organic phase was dried over magnesium sulfate
and the crude yellow residue was purified through a silica gel
4
.2.4. Quinolin-2-ylmethanol 7. Methyl quinoline 2-carboxylate 2
(
5 g, 26.8 mmol) in solution in THF (30 mL) was added, at room
temperature, to a solution of NaBH (710 mg, 18.8 mmol) in THF
20 mL). The mixture was stirred at 35 C for 30 min. Then, at 35 C,
4
ꢀ
ꢀ
(
column chromatography (CH
2
Cl
) 1.52 (9H, s, CH
5.97 (1H, s, NH), 7.39 (1H, m, CHar), 7.55 (1H, m, CHar), 7.73 (1H, m,
2
/CH
3
OH: 98/2þ1% Et
3
N). 89%
1
methanol (2.5 mL) was added followed by warm water (30 mL), and
finally ethyl acetate (20 mL). The organic layer was washed with
water (2ꢂ30 mL). The organic phase was dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
crude yellow-blue residue was purified through a silica gel column
chromatography (AcOEt/MCH: 60/40). White solid; 73% yield; mp
yield; H NMR (300 MHz, CDCl
3
3
), 4.6 (2H, m, CH
2
),
13
CHar), 7.83 (1H, m, CHar), 8.15 (2H, m, CHar); C NMR (75 MHz,
CDCl ) 28.47, 46.20, 79.55, 119.85, 126.35, 127.33, 127.63, 128.85,
3
129.72, 136.82, 147.33, 156.07, 157.19; HRMS (ESI) m/z calculated for
þ
C
15
H
19
O
2
N
2
[MþH] : 259.1441, found: 259.14396.
ꢀ
1
1
35 C (dec); H NMR (300 MHz, CDCl
CH ), 7.31 (1H, m, CHar), 7.55 (1H, m, CHar), 7.71 (1H, m, CHar), 7.81
1H, m, CHar), 8.10 (2H, m, CHar); C NMR (75 MHz, CDCl
18.43, 126.35, 127.55, 127.69, 128.57, 129.81, 136.86, 146.72, 159.19;
Anal. Calcd for C10 NO C, 75.45; H, 5.70; N, 8.80. Found C, 75.13; H,
3
) 4.68 (1H, s, OH), 4.95 (2H, s,
2
4.2.9. Quinolin-2-ylmethanamine bischlorohydrate 15. First method:
To a solution of N,N-diBocquinolin-2-ylmethanamine 14 (5 g,
14 mmol) in EtOH (25 mL), a solution of EtOH$HCl 4 N (52.5 mL,
13
(
1
3
) 64.25,
ꢀ
H
9
210 mmol) was added at 0 C. The solution was allowed to return at
5
.56; N, 8.75.
ambient temperature and stirred for 3 h. Then, the mixture was
heated at 90 C up to the complete disappearance of the of N,N-
ꢀ
4
2
2
.2.5. 2-(Chloromethyl)quinoline 8. Quinolin-2-ylmethanol 7 (4 g,
diBoc-quinolin-2-ylmethanamine 14 (approxim. 30 min). The
mixture was evaporated to dryness to give a white solid, which was
5.1 mmol) was dissolved in CH
5.1 mmol) was carefully added at 0 C to this solution. The mixture
2
Cl
2
(40 mL). SOCl
2
(1.83 mL,
ꢀ
purified through a silica gel column chromatography (CH
2
Cl
) 4.47
), 7.71 (1H, m, CHar), 7.81 (1H, m, CHar), 7.94 (1H, m,
CHar), 8.10 (2H, m, CHar), 8.61 (1H, m, CHar), 8.88 (2H, s large, NH),
2
/
1
was allowed to return at ambient temperature and water (30 mL)
was added followed by a saturated aqueous solution of K CO
CH
(2H, m, CH
3
OH: 95/5þ1% Et
3 3
N). 90% yield; H NMR (300 MHz, CDCl
2
3
2
(
12 mL). The organic layer was washed with brine (2ꢂ30 mL) and
13
concentrated under reduced pressure. The crude residue was pu-
3
9.91 (1H, s large, NH); C NMR (75 MHz, CDCl ) 42.29, 120.62,
rified through a silica gel column chromatography (AcOEt/MCH:
126.78, 127.26, 128.22, 131.06, 139.06, 144.94, 149.37, 153.69.
Second method: Quinolin 2-carbonitrile 10 (1 g, 6.5 mmol) was
hydrogenated over Pd (10%) on activated carbon powder (standard,
1
3
0/70). White solid; 76% yield; H NMR (300 MHz, DMSO) 4.96 (2H,
2
s, CH ), 7.68 (2H, m, CHar), 7.79 (1H, m, CHar), 8.00 (2H, m, CHar),

A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
9327
reduced, nominally 50% water) (0.1 g) in MeOH/TFA (95/5: v/v)
100 mL) under 4 bar H at ambient temperature for 2 h. Then, the
solution was filtered and evaporated to dryness. HCl in PrOH 5 N
25 mL) was added to precipitate the pure chlorohydrate 15. 58%
yield.
3.98 (1H, m, CH), 5.12 (1H, m, NH), 6.65 (2H, m, CHar), 6.90 (2H, m,
CHar); C NMR (75 MHz, CDCl ) 21.83, 24.72, 25.85, 54.04, 68.95,
3
114.91, 117.91, 120.88, 127.07, 129.13, 142.66, 172.64.
13
(
2
i
(
4.3.5. Isobutyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 21. HPLC:
i
Chiralcel OJ-H Hexane/ PrOH 70/30, flow 1 mL/min,
l
¼254 nm; t
) 0.95 (6H, d, J
), 2.81 (2H, m, CH ),
3.78 (2H, m, CHeO), 3.98 (1H, m, CH), 5.12 (1H, m, NH), 6.64 (2H, m,
1
1
4.2.10. Quinolin-2-ylmethanamine 12. Quinolin-2-ylmethanamine
10.10 min, t
2
14.46 min; H NMR (300 MHz, CDCl
), 2.32 (1H, m, CH
3
bischlorohydrate 15 (0.5 g, 2.1 mmol) was neutralized drop by
drop with sodium hydroxide (1 M, 30 mL) up to pH¼10. The
7.5 Hz, CH ), 2.00 (1H, m, CH
3
2
2
2
13
aqueous phase was extracted by CH
2
Cl
2
(4ꢂ25 mL), then dried over
3
CHar), 6.99 (2H, m, CHar); C NMR (75 MHz, CDCl ) 17.20, 22.89,
magnesium sulfate, filtered, and evaporated to dryness affording
23.98, 25.89, 52.04, 69.48, 112.81, 115.81, 118.90, 125.16, 127.16,
140.97, 171.31.
1
the free amine 12. 82% yield; H NMR (300 MHz, CDCl
s, NH ), 4.16 (2H, s, CH ), 7.42 (1H, m, CHar), 7.49 (1H, m, CHar), 7.54
1H, m, CHar), 7.68 (1H, m, CHar), 7.80 (1H, m, CHar), 8.06 (2H, m,
3
) d 1.94 (2H,
2
2
(
4.3.6. 2-Hydroxymethyl-1,2,3,4-tetrahydroquinoline 22. HPLC: Chir-
13
i
CHar); C NMR (75 MHz, CDCl
3
) 30.72, 117.69, 123.87, 128.59,
alcel OD Hexane/ PrOH 90/10, flow 1 mL/min,
l
¼254 nm; t
) 1.67 (1H, m,
), 3.25 (1H, s, OH), 3.40
2
), 3.69 (1H, m, CH), 6.49 (1H, m,
1
1
129.08, 129.64, 131.54, 132.94, 138.50, 147.43.
12.90 min, t
CH ), 1.83 (1H, m, CH
(1H, m, CH ), 3.52 (1H, m, CH
CHar), 6.60 (1H, m, CHar), 6.91 (2H, m, CHar); C NMR (75 MHz,
CDCl ) 24.31, 25.35, 52.86, 66.65, 114.71, 117.60, 121.61, 126.91,
2
14.40 min; H NMR (300 MHz, CDCl
3
2
2
), 2.75 (2H, m, CH
2
4
.3. General procedure for the asymmetric hydrogenation
2
13
reactions
3
A 50 mL Schlenk flask, equipped with a magnetic stir bar, was
129.24, 144.00.
ꢁ3
charged with [Ir(cod)Cl]
2
(3.4 mg, 5ꢂ10 mmol) and the selected
ꢁ2
chiral ligand (1.1ꢂ10 mmol). Then, the mixture was conditioned
by three vacuum/nitrogen cycles and the degassed solvent (8 mL)
was added. The mixture with the precatalyst was stirred at room
temperature for 1 h before cannula transfer into a 50 mL double-
walled stainless steel autoclave containing the substrate (1 mmol)
and iodine (12.7 mg, 0.05 mmol). The autoclave was purged and
pressurized with molecular hydrogen and the reaction was per-
formed at the specified temperature during 17 h. At the end of the
reaction, the autoclave was cooled and depressurized. The mixture
was filtered through a small pad of silica gel and analyzed by GC or
NMR to determine the conversions. The enantiomeric excesses
were determined by HPLC.
4.3.7. 2-(Bromomethyl)-1,2,3,4-tetrahydroquinoline 24. HPLC: Chir-
alcel OD Hexane/ PrOH 98/2, flow 1.5 mL/min,
i
l
¼254 nm; t
1
),
1
6.54 min, t
2.16 (1H, m, CH
CH ), 6.41 (1H, m, CHar), 6.70 (2H, m, CHar), 7.04 (2H, m, CHar);
NMR (75 MHz, CDCl ) 25.56, 26.81, 38.16, 52.25, 114.62, 117.88,
2
7.55 min; H NMR (300 MHz, CDCl
3
) 1.84 (1H, m, CH
), 3.39 (1H, m, CH), 3.55 (2H, m,
2
2
), 2.84 (2H, m, CH
2
13
2
C
3
122.12, 127.02, 129.36, 143.65.
4.3.8. 1,2,3,4-Tetrahydroquinolin-2-carboxamide 26. HPLC: Chiralcel
i
OD Hexane/ PrOH 90/10, flow 1 mL/min,
l
¼254 nm; t
) 1.86 (1H, m, CH
), 3.93 (1H, m, CH), 5.78 (1H, s, NH), 6.56
1H, m, CHar), 6.63 (1H, m, CHar), 6.68 (2H, s, NH ), 7.00 (2H, m,
) 24.22, 24.75, 55.28, 114.88, 118.61,
1
30.16 min, t
2
1
36.42 min; H NMR (300 MHz, CDCl
m, CH ), 2.62 (2H, m, CH
3
2
), 2.24 (1H,
2
2
(
2
13
4
.3.1. Methyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 17. HPLC:
CHar); C NMR (75 MHz, CDCl
3
i
Chiralcel OJ-H Hexane/ PrOH 70/30, flow 1 mL/min,
l
¼254 nm; t
) 2.07 (1H, m,
), 3.81 (1H, s, CH ), 4.09
1
122.09, 127.18, 129.38, 141.62, 176.79. HRMS (ESI) m/z calculated for
1
þ
2
2.69 min, t
CH ), 2.29 (1H, m, CH
1H, m, CH), 6.67 (2H, m, CHar), 7.02 (2H, m, CHar); C NMR
75 MHz, CDCl ) 24.69, 25.82, 52.41, 53.89, 114.60, 117.69, 120.55,
2
29.43 min; H NMR (300 MHz, CDCl
3
C
10
H
13
N
2
O [MþH] : 177.10224 found: 177.10247.
2
2
), 2.81 (2H, m, CH
2
3
13
(
(
1
4.3.9. 1,2,3,4-Tetrahydroquinolin-2-ylmethanamine 27. HPLC: Chir-
i
ꢀ
3
alcel AD-H Hexane/ PrOH/DEA 95/5/0.1, flow 1 mL/min, T¼7 C,
1
27.07, 129.14, 142.92, 173.76.
l
¼304 nm; t
.19 (2H, s, NH
(4H, m), 3.17 (1H, m, CH
3
6.57 (1H, m, CHar), 6.90 (2H, m, CHar); C NMR (75 MHz; CDCl )
1
15.87 min, t
), 1.59 (1H, m, CH
), 4.25 (1H, s, NH), 6.43 (1H, m, CHar),
2
18.02 min; H NMR (300 MHz, CDCl
3
)
1
2
2
), 1.86 (1H, m, CH ), 2.55e2.84
2
4
.3.2. Ethyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 18. HPLC:
2
i
13
Chiralcel OJ-H Hexane/ PrOH 70/30, flow 1 mL/min,
l
¼254 nm; t
) 1.32 (3H, t, J
), 2.80 (2H, m, CH ),
), 4.44 (1H, s, NH), 6.66
) 14.41,
4.66, 25.79, 53.98, 61.44, 115.03, 118.12, 120.98, 127.10, 129.17,
42.42, 173.09.
1
1
1
6
4
(
2
8.18 min, t
2
29.18 min; H NMR (300 MHz, CDCl
), 2.02 (1H, m, CH ), 2.33 (1H, m, CH
.07 (1H, m, CH), 4.27 (2H, q, J 6.7 Hz, CH
3
25.97, 26.28, 47.44, 53.40, 114.44, 117.03, 121.46, 126.89, 129.26,
144.61.
.7 Hz, CH
3
2
2
2
2
13
2H, m, CHar), 6.99 (2H, m, CHar); C NMR (75 MHz, CDCl
3
4.3.10. tert-Butyl((1,2,3,4-tetrahydroquinolin-2yl)methyl)-carbamate
28. HPLC: Chiralcel OJ-H Hexane/ PrOH 90/10, flow 1 mL/min,
i
1
1
l
¼254 nm, t
1
13.94 min, t
), 1.64 (1H, m, CH
), 3.08 (1H, m, CH), 3.18 (1H, m, CH
2
20.17 min; H NMR (300 MHz, CDCl
3
)
1
CH
.38 (9H, s, CH
3
2
), 1.85 (1H, m, CH
2
), 2.71 (2H, m,
4
.3.3. Propyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 19. HPLC:
2
2
2
), 3.35 (1H, m, CH ), 4.85
i
Chiralcel OJ-H Hexane/ PrOH 70/30, flow 1 mL/min,
l
¼254 nm; t
) 0.96 (3H, t, J
), 2.33 (1H, m, CH ),
), 4.04 (1H, m, CH), 4.17 (2H, m, CH ), 6.63 (2H, m,
) 10.44, 22.09,
1
(1H, s, NH), 6.50 (1H, m, CHar), 6.59 (1H, m, CHar), 6.90 (2H, m,
1
13
1
7
2
3.36 min, t
.1 Hz, CH ), 1.64 (2H, m, CH
.79 (2H, m, CH
CHar), 7.01 (2H, m, CHar); C NMR (75 MHz, CDCl
2
20.18 min; H NMR (300 MHz, CDCl
3
3
CHar); C NMR (75 MHz, CDCl ) 25.20, 25.85, 28.39, 45.50, 51.69,
3
2
), 2.04 (1H, m, CH
2
2
79.73, 115.03, 118.14, 121.80, 126.94, 129.29, 143.13, 156.51; HRMS
(ESI) m/z calculated for C15
263.17508.
þ
2
2
H
23
N
2
O
2
[MþH] : 263.1754, found:
13
3
2
4.71, 25.81, 54.20, 66.95, 114.92, 118.00, 120.87, 127.08, 128.71,
þ
142.56, 173.22. HRMS (ESI) m/z calculated for C13
H18NO
2
[MþH] :
4.3.11. N,N-DiBoc methylene 1,2,3,4-tetrahydroquinoline 29. HPLC:
i
2
20.13321, found: 220.13291.
Chiralcel OD Hexane/ PrOH 98/2, flow 0.2 mL/min,
l
¼254 nm; t
) 1.43 (18H, s,
), 2.70 (2H, m, CH ), 3.47
1
1
3
4.00 min, t
CH ), 1.61 (1H, m, CH
(1H, m, CH), 3.67 (2H, m, CH
2
36.21 min; H NMR (300 MHz, CDCl
3
4
.3.4. Isopropyl 1,2,3,4-tetrahydroquinoline 2-carboxylate 20. HPLC:
3
2
), 1.87 (1H, m, CH
2
2
i
Chiralcel OJ-H Hexane/ PrOH 70/30, flow 1 mL/min,
l
¼254 nm; t
) 1.28 (6H, d, J
), 2.81 (2H, m, CH ),
1
2
), 6.41 (1H, m, CHar), 6.54 (1H, m, CHar),
1
13
10.75 min, t
2
14.08 min; H NMR (300 MHz, CDCl
), 2.31 (1H, m, CH
3
6.66 (1H, s, NH), 6.90 (2H, m, CHar); C NMR (75 MHz, CDCl
3
) 25.61,
7.5 Hz, CH ), 1.99 (1H, m, CH
3
2
2
2
25.85, 28.06, 50.95, 51.64, 82.76, 114.14, 116.89, 120.71, 126.82,

9328
A.M. Maj et al. / Tetrahedron 69 (2013) 9322e9328
1
29.16, 143.99, 153.17; HRMS (ESI) m/z calculated for C20
H
31
N
2
O
4
J., Eds.; Catalysts for Fine Chemical Synthesis; John Wiley & Sons: West Sussex,
UK, 2007; Vol. 5, pp 73e86; (i) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.;
Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614; (j) Kuwano, R.; Kaneda, K.; Ito, T.; Sato,
K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213; (k) Kuwano, R.; Kashiwabara, M.
Org. Lett. 2006, 8, 2653; (l) Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Ka-
neda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17, 521.
þ
[MþH] : 363.2278, found: 363.2274.
Acknowledgements
7
. (a) Wang, D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.; Fan, H.-J.; Duan, Y. J.
Am. Chem. Soc. 2011, 133, 8866; (b) Kuwano, R.; Kashiwabara, M.; Ohsumi, M.;
Kusano, H. J. Am. Chem. Soc. 2008, 130, 808; (c) Kuwano, R.; Kashiwabara, M.;
Ohsumi, M.; Kusano, H. J. Am. Chem. Soc. 2011, 133, 9136; (d) Kuwano, R. Het-
erocycles 2008, 76, 909.
This work was supported by Oril Industrie (A.M.M.). The authors
thank J.-P. Lecouv eꢀ , N. Pinault, L. Vaysse-Ludot for fruitful discus-
sions. Mrs. C. M eꢀ liet (UCCS CNRS) is thanked for helpful discussions
and elemental analyses. J. Lucet is thanked for some experiments.
8. (a) Blaser, H.-U.; Hornig, H.; Studer, M.; Wedemeyer-Exl, C. J. Mol. Catal. A:
Mrs. N. Duhal (CUMA, Universit eꢀ Lille Nord de France, Universit eꢀ
Lille 2 is thanked for HRMS and LC-MS analyses.
Chem. 1999, 139, 253; (b) Wang, X.-B.; Zeng, W.; Zhou, Y.-G. Tetrahedron Lett.
2008, 49, 4922; (c) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann,
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Supplementary data
4
343; (g) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966; (h)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.07.090.
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