Synthesis of 2-aminoquinolines via palladium-catalyzed intermolecular oxidative cyclization of 2-vinylanilines with isocyanides

Article abstract of DOI:10.1016/j.tet.2015.12.060

An efficient palladium-catalyzed intermolecular oxidative cyclization of 2-vinylanilines with isocyanides to the synthesis of 2-aminoquinolines is achieved. This transformation is applicable to a broad range of 2-vinylanilines and isocyanides.

Full text of DOI:10.1016/j.tet.2015.12.060

Tetrahedron 72 (2016) 952e958
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Synthesis of 2-aminoquinolines via palladium-catalyzed
intermolecular oxidative cyclization of 2-vinylanilines with
isocyanides
*
*
Qiang Zheng, Qiuping Ding , Cong Wang, Wenfan Chen, Yiyuan Peng
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering, Jiangxi Normal
University, Nanchang, Jiangxi 330022, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient palladium-catalyzed intermolecular oxidative cyclization of 2-vinylanilines with isocyanides
to the synthesis of 2-aminoquinolines is achieved. This transformation is applicable to a broad range of 2-
vinylanilines and isocyanides.
Received 1 November 2015
Received in revised form 8 December 2015
Accepted 23 December 2015
Available online 29 December 2015
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminoquinoline
2-Vinylaniline
Isocyanide
Oxidative cyclization
1. Introduction
Isocyanides and CO represent two kinds of versatile C1 synthons
which have been extensively applied in organic synthesis chemis-
Quinoline nucleus is prevalent in a broad range of natural and
synthetic compounds which possesses different biological and
pharmacological activities.1 Among them, the significant 2-
aminoquinoline derivatives are widely used as potential pre-
cursors because they often exhibit many biological and medicinal
activities such as antidepressant, antiprotozoal, anthelmintic, and
antihypertensive activities.2 Recently, Cheng and Judd reported that
2-aminoquinoline compound A (Fig. 1) is a potent inhibitor of beta-
site amyloid precursor protein cleaving enzyme 1 (BACE1).3 Com-
pound B was prepared and evaluated by DeVita in melanin-
concentrating hormone receptor 1 (MCH1R) binding and func-
tional antagonist assays as a potential target for obesity (Fig. 1).4
Helical chiral 2-aminopyridinium ion (compound C) was found as
an obviously more practicable dual hydrogen-bonding catalyst than
commonly used (thio)urea-based systems (Fig. 1).5 Despite the
importance of 2-aminoquinoline derivatives, only limited efficient
synthetic methods were reported.6 Therefore, the development of
more direct and economical approaches for the efficient synthesis
of such compounds is highly desirable.
try, especially in the synthesis of natural and drug-like products or
their intermediates.7,8 Impressive progress has been made in
transition metal-catalyzed carbonylation reactions since the be-
ginning of the 20th century because CO is an inexpensive and easily
available C1 source.8 Though isocyanides as C1 synthons are rela-
tively new, transition-metal-catalyzed isocyanide insertion re-
action is an attractive area for the construction of various
heterocycles.9,10 Recently, Alper reported the palladium-catalyzed
oxidative
cyclocarbonylation
of
N-monosubstituted-2-
vinylanilines for the synthesis of 2(1H)-quinolines (Scheme 1, Eq.
1).11 In view of the importance of 2-aminoquinoline compounds
and our previous work on the synthesis of 4-aminoquinoline de-
rivatives based on Pd-catalyzed isocyanide insertion (Scheme 1, Eq.
2),10j,k we envisioned that Pd-catalyzed intermolecular oxidative
cyclization of 2-vinylanilines with isocyanides may offer a new
efficient route to 2-aminoquinoline derivatives (Scheme 1, Eq. 3).
2. Results and discussion
Based on our recent work,10j,k we began the investigation with
2-vinylaniline 1a and tert-butyl isocyanide 2a as model substrates
in CH3CN catalyzed by Pd(OAc)2 (10 mol %) in the presence of 1,10-
phen (20 mol %), Cu(OAc)2 (2.0 equiv), and Cs2CO3 (2.0 equiv). To
our disappointment, we failed to observe the desired product
* Corresponding authors. Tel./fax: þ86 791 88120388; e-mail addresses:
dqpjxnu@gmail.com (Q. Ding), yypeng@jxnu.edc.cn (Y. Peng).
http://dx.doi.org/10.1016/j.tet.2015.12.060
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
953
Fig. 1. Representative examples of 2-aminoquinoline-based active molecules and chiral catalyst.
Scheme 1. Pd-catalyzed intermolecular oxidative cyclization.
(Table 1, entry 1). However this reaction proceeded smoothly when
ethylenediamine was used as ligand, and the product 3a could be
obtained in moderate isolated yield (50%) (Table 1, entry 2). Ligand
screening revealed that commercially available bidentate P-ligand
(dppe) was the best one, affording 65% yield (Table 1, entries 3e7).
Only 45% yield of product 3a was obtained under ligand-free con-
ditions, which indicated the presence of ligand is critical to the
success of the reaction (Table 1, entry 8). Subsequently, screening
various bases revealed that the base also played an important role
in this transformation, and DBU provided the best yield of 73%
(Table 1, entries 9e19). A control reaction showed that no desired
product was observed in the absence of base (Table 1, entry 20).
Further investigation revealed that Cu(OAc)2 was superior to other
oxidants such as Cu(OAc)2$H2O, CuCl2, O2, and Ag2CO3 (Table 1,
entries 21e24). Replacing the catalyst Pd(OAc)2 with other Pd(II)
and Pd(0) sources failed to increase the reaction activity (Table 1,
entries 26e31). Finally, no better results were obtained when the
reaction was carried out in other solvents (see SI).
With the optimized conditions in hands, we started to explore
the scope of substrates. Electron-donating groups on the aryl ring of
2-vinylaniline are compatible with this reaction (3bee), although
the 4-methoxy group offers a lower yield (3e, 41%). Various
electron-withdrawing groups such as fluoro and chloro are well-
tolerated in general, providing the desired products (3fek) in
63e90% yields. In the cases of bromo-substituted substrates gave
the lower yields due to the formation of by-products via Pd-
catalyzed isocyanide insertion into CeBr bond. Various 2-(1-
arylvinyl)anilines also could proceed well, resulting in the corre-
sponding products (3neq) in good yields. For instance, substrate 2-
(1-(p-tolyl)vinyl)aniline reacted with tert-butyl isocyanide 2a giv-
ing the desired product 3o in 83% yield. Fortunately, the substrate
2-(1-(thiophen-2-yl)vinyl)aniline was also compatible affording
the product 3r in 48% yield (see Table 2).
We further investigated the reaction of several other isocyanides
with substrate 1a under standard conditions. Notably, when other
tertiary, secondary, or primary aliphatic isocyanides 2bee were
applied in this process as coupling partners, the reactions pro-
ceeded smoothly to afford the desired products 3sev in moderate
yields (48e66%, Table 3, entries 1e4). The results (3a, 3sev) show
that the reactivity of tertiary isocyanides (2a and 2b) is a little
better than that of secondary and primary isocyanides (2cee)
(Table 3, entries 2e4). Unfortunately, when aromatic isocyanides
(2feg) were employed, it was found that only traces of desired
products (3wex) were observed (Table 3, entries 5 and 6). It is
worth noting that when we finished our experiments, we noticed
a related but independent work reported by Zeng and co-workers
via palladium-catalyzed direct coupling of 2-vinylanilines and
isocyanides using expensive Ag2CO3 as oxidant.11 The results of aryl
isocyanides also show poor reactivity.
Based on the previous studies,12 a plausible mechanism for this
intermolecular oxidative cyclization is proposed in Scheme 2.
Firstly, the addition of nitrogen atom of the aniline to Pd(II) species
leads to the formation of a PdeN bond. Secondly, the coordination
and insertion of isocyanide 2a result in the palladium intermediate
III. Thirdly, alkene insertion into the PdeC bond of Pd(II) species III
could give an alkyl palladium intermediate IV. Then,
b-hydride
elimination of IV could generate the products 3a0, 3a00, and Pd(0)
species. Finally, 2-aminoquinoline 3a is formed from 3a0 via [1,3]-H-

954
Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
Table 1
Optimization of reaction conditionsa
Entry
[Pd]
Ligand
Oxidant
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
1,10-phen
Cu(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
DBU
DABCO
tBuONa
Pyridine
Et3N
CsOAc
CsF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NR
50
46
d
Ethylenediamine
DMEDA
TMEDA
PPh3
dppp
dppe
d
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2$H2O
CuCl2
20
35
65
45
30
35
73
61
20
45
40
49
56
47
Trace
Trace
65
Trace
25
15
NR
62
40
38
50
35
9
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
NaHCO3
NaOAc
d
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
O2
Ag2CO3
d
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Pd(PhCN)2Cl2
Pd(PPh3)2Cl2
Pd(TFA)2
Pd(PPh3)4
Pd2(dba)3
DBU
DBU
DBU
36
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), [Pd] catalyst: 10 mol %, ligand: 20 mol %, oxidant: 2.0 equiv, base: 2.0 equiv, solvent: 2 mL, 100 ꢀC.
NR: no reaction.
shift and aromatization. Pd(II) is regenerated by Cu(OAc)2 to finish
chromatography using petroleum ether/ethyl acetate (20:1 to 10:1)
the catalytic cycle.
as eluent to provide the desired products 3.
3. Conclusion
4.1.1. N-(tert-Butyl)-4-methylquinolin-2-amine
(Rf¼0.4, EtOAcepetroleum ether¼1:10) as a yellow oil (73% yield);
1H NMR (400 MHz, CDCl3)
7.73 (d, J¼8.0 Hz, 1H), 7.66 (d, J¼8.4 Hz,
1H), 7.49 (t, J¼7.6 Hz, 1H), 7.20 (t, J¼7.4 Hz, 1H), 6.46 (s, 1H), 4.58 (s,
1H), 2.53 (s, 3H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3)
156.4,
147.9, 144.1, 129.0, 126.8, 123.5, 123.3, 121.6, 113.0, 51.3, 29.6, 18.8.
HRMS (ESI): m/z [MþH]þ calcd for C14H19N2; 215.1548; found:
215.1536.
(3a). Isolated
In conclusion, we have developed an efficient palladium-
catalyzed intermolecular oxidative cyclization of 2-vinylanilines
with isocyanides to the synthesis of 2-aminoquinolines in moder-
ate to good yields. The presence of oxidant and base are very crucial
for this reaction. Various aliphatic isocyanides (including tertiary,
secondary, and primary isocyanides) are compatible in the process.
d
d
4. Experimental
4.1. General
4.1.2. N-(tert-Butyl)-4,6-dimethylquinolin-2-amine
(Rf¼0.5, EtOAcepetroleum ether¼1:10) as a yellow solid (78%
yield), mp: 105e107 ꢀC. 1H NMR (400 MHz, CDCl3)
7.56 (d,
(3b). Isolated
d
J¼8.4 Hz, 1H), 7.49 (s, 1H), 7.32 (d, J¼6.0 Hz, 1H), 6.43 (s, 1H), 4.48 (s,
General procedure for the palladium-catalyzed intermolecular
oxidative cyclization of 2-vinylanilines with isocyanides to the
synthesis of 2-aminoquinolines: A mixture of 2-vinylaniline 1
(0.2 mmol) and isocyanide 2 (0.4 mmol, 2.0 equiv), Pd(OAc)2
(10 mol %), dppe (20 mol %), Cu(OAc)2 (0.4 mmol, 2.0 equiv), DBU
(0.4 mmol, 2.0 equiv), and CH3CN (2 mL) were added into a sealed
tube. The mixture was stirred at 100 ꢀC or about 24 h (monitored by
TLC). After being cooling to room temperature, evaporation of the
solvent under reduced pressure followed purification by silica gel
1H), 2.50 (s, 3H), 2.45 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d 156.1, 146.3, 143.5, 130.9, 130.8, 126.8, 123.2, 122.7, 112.9,
51.2, 29.7, 21.4, 18.8. HRMS (ESI): m/z [MþH]þ calcd for C15H21N2;
229.1705; found: 229.1704.
4.1.3. N-(tert-Butyl)-4,7-dimethylquinolin-2-amine
(Rf¼0.3, EtOAcepetroleum ether¼1:10) as a yellow oil (65% yield);
1H NMR (400 MHz, CDCl3)
7.61 (d, J¼8.4 Hz, 1H), 7.47 (s, 1H),
7.02 (d, J¼8.4 Hz, 1H), 6.37 (s, 1H), 4.54 (s, 1H), 2.48 (s, 3H), 2.45 (s,
(3c). Isolated
d

Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
955
Table 2
Palladium-catalyzed insertion reactions of tert-butyl isocyanides 2a with substituted 2-vinylanilines 1
3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
156.6, 148.2, 143.9,
(ESI): m/z [MþH]þ calcd for C15H21N2O; 245.1654; found:
139.0, 126.4, 123.5, 123.2, 121.2, 112.2, 51.3, 29.6, 21.6, 18.7. HRMS
245.1640.
(ESI): m/z [MþH]þ calcd for C15H21N2; 229.1705; found: 229.1701.
4.1.6. N-(tert-Butyl)-6-fluoro-4-methylquinolin-2-amine
(3f). Isolated (Rf¼0.5, EtOAcepetroleum ether¼1:20) as a yellow
4.1.4. N-(tert-Butyl)-4,8-dimethylquinolin-2-amine
(Rf¼0.7, EtOAcepetroleum ether¼1:20) as a yellow solid (89%
yield), mp: 132e135 ꢀC; 1H NMR (400 MHz, CDCl3)
7.58 (d,
(3d). Isolated
solid (66% yield), mp: 108e110 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.63
d
(dd, J¼9.2, 5.6 Hz, 1H), 7.33 (dd, J¼10.0, 2.8 Hz, 1H), 7.26e7.22 (m,
J¼8.0 Hz, 1H), 7.37 (d, J¼7.2 Hz, 1H), 7.08 (t, J¼8.0 Hz, 1H), 6.33 (s,
1H), 6.44 (s, 1H), 4.47 (s, 1H), 2.46 (s, 3H), 1.51 (s, 9H); 13C NMR
1H), 4.37 (s, 1H), 2.66 (s, 3H), 2.48 (s, 3H), 1.55 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d
157.9 (d, JCeF¼238.6 Hz), 155.9, 144.9, 143.3,
1
3
3
(100 MHz, CDCl3)
d
155.1, 146.9, 144.1, 134.8, 129.2, 122.9, 121.3,
128.8 (d, JCeF¼8.4 Hz), 123.5 (d, JCeF¼8.6 Hz), 117.9 (d,
2JCeF¼24.4 Hz), 113.9, 107.4 (d, 2JCeF¼22.0 Hz), 51.4, 29.5,18.7. HRMS
(ESI): m/z [MþH]þ calcd for C14H18N2F; 233.1454; found: 233.1452.
121.0, 113.1, 51.4, 29.1, 18.9, 18.8. HRMS (ESI): m/z [MþH]þ calcd for
C
15H21N2; 229.1705; found: 229.1707.
4.1.5. N-(tert-Butyl)-6-methoxy-4-methylquinolin-2-amine
4.1.7. N-(tert-Butyl)-7-fluoro-4-methylquinolin-2-amine
(3g). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow oil
(3e). Isolated (Rf¼0.4, EtOAcepetroleum ether¼1:10) as a yellow
oil (41% yield); 1H NMR (400 MHz, CDCl3)
7.19 (d, J¼9.2 Hz, 1H), 7.06 (s, 1H), 6.49 (s, 1H), 3.88 (s, 3H), 2.50 (s,
3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3)
154.9, 154.8, 143.9,
142.2, 123.3, 120.0, 117.2, 113.0, 113.7, 55.6, 51.3, 2.7, 19.0. HRMS
d
7.61 (d, J¼8.8 Hz, 1H),
(63% yield); 1H NMR (400 MHz, CDCl3)
d
7.65 (dd, J¼8.9, 6.4 Hz, 1H),
7.28 (dd, J¼11.2, 2.4 Hz, 1H), 6.95e6.91 (m, 1H), 6.35 (s, 1H), 4.57 (s,
1H), 2.47 (s, 3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3)
163.4 (d,
J¼244.6 Hz), 157.1, 149.6 (d, J¼12.9 Hz), 143.8, 125.2 (d, J¼10.3 Hz),
d
d

956
Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
Table 3
Palladium-catalyzed insertion reactions of various isocyanides 2beg with 2-(prop-1-en-2-yl)aniline 1a
Entry
2
3
Yield (%)
Entry
2
3
Yield (%)
1
AdNC
66
4
BnNC
50
2b
2e
3v
3s
3t
2
3
CyNC
2c
61
48
5
6
Trace
Trace
2f
3w
nBuNC
2d
3x
3u
2g
Scheme 2. Proposed catalytic cycle.

Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
957
120.2,112.3,111.0,110.7 (d, J¼24.3 Hz), 51.5, 29.5,18.8. HRMS (ESI): m/
z [MþH]þ calcd for C14H18N2F; 233.1454; found: 233.1450.
1H NMR (400 MHz, CDCl3)
d
7.72 (d, J¼8.4 Hz, 1H), 7.61 (d, J¼7.2 Hz,
1H), 7.49 (t, J¼7.6 Hz, 1H), 7.34 (d, J¼8.0 Hz, 2H), 7.27 (d, J¼7.8 Hz,
2H), 7.10 (t, J¼8.0 Hz, 1H), 6.51 (s, 1H), 4.65 (s, 1H), 2.43 (s, 3H), 1.54
4.1.8. N-(tert-Butyl)-8-fluoro-4-methylquinolin-2-amine
(3h). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow
(s, 9H); 13C NMR (100 MHz, CDCl3)
d 156.2, 148.9, 148.7, 137.9, 135.8,
129.2, 129.1, 126.9, 125.6, 122.1, 121.7, 112.8, 100.0, 51.5, 29.6, 21.3.
HRMS (ESI): m/z [MþH]þ calcd for C20H23N2; 291.861; found:
291.1870.
oil (71% yield); 1H NMR (400 MHz, CDCl3)
d
7.47 (d, J¼8.0 Hz, 1H),
7.22e7.17 (m, 1H), 7.09e7.04 (m, 1H), 6.48 (s, 1H), 4.73 (s, 1H), 2.50
(s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 157.0 (d,
3
1JCeF¼249.2 Hz), 156.2, 144.0, 138.1 (d, JCeF¼10.6 Hz), 125.3, 120.5
4.1.16. N-(tert-Butyl)-4-(4-fluorophenyl)quinolin-2-amine
(3p). Isolated (Rf¼0.7, EtOAcepetroleum ether¼1:20) as a yellow
3
2
(d, JCeF¼7.9 Hz), 119.0, 113.6, 113.4 (d, JCeF¼19.1 Hz), 51.4, 29.4,
19.1. HRMS (ESI): m/z [MþH]þ calcd for C14H18N2F; 233.1454;
found: 233.1445.
oil (68% yield); 1H NMR (400 MHz, CDCl3)
d
7.73 (d, J¼8.0 Hz, 1H),
7.54e7.48 (m, 2H), 7.42e7.39 (m, 2H), 7.19e7.07 (m, 3H), 6.48 (s,
1H), 4.65 (s, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
162.7 (d,
4.1.9. N-(tert-Butyl)-6-chloro-4-methylquinolin-2-amine
JCeF¼247.2 Hz), 156.0, 148.7, 147.8, 134.7, 131.0 (d, JCeF¼8.0 Hz),
129.3, 127.1, 125.3, 121.9, 121.9, 115.5 (d, JCeF¼21.0 Hz), 113.1, 51.5,
29.5. HRMS (ESI): m/z [MþH]þ calcd for C19H20N2F; 295.1611;
found: 295.1618.
(3i). Isolated (Rf¼0.4, EtOAcepetroleum ether¼1:20) as a yellow
solid (61% yield), mp: 102e104 ꢀC; 1H NMR (400 MHz, CDCl3)
d 7.66
(d, J¼2.4 Hz, 1H), 7.58 (d, J¼8.8 Hz, 1H), 7.41 (dd, J¼8.8, 2.4 Hz, 1H),
6.41 (s, 1H), 4.54 (s, 1H), 2.46 (s, 3H), 1.51 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d
156.4, 146.6, 143.1, 129.4, 128.5, 126.7, 124.1,
4.1.17. N-(tert-Butyl)-4-(4-chlorophenyl)quinolin-2-amine
122.6, 113.9, 51.5, 29.5, 18.6. HRMS (ESI): m/z [MþH]þ calcd for
(3q). Isolated (Rf¼0.5, EtOAcepetroleum ether¼1:20) as a yellow
C
14H18N2Cl; 249.1159; found: 249.1158.
oil (70% yield); 1H NMR (400 MHz, CDCl3)
d
7.73 (d, J¼8.0 Hz, 1H),
7.53 (d, J¼8.4 Hz, 1H), 7.49 (d, J¼7.6 Hz, 1H), 7.42e7.39 (m, 2H),
4.1.10. N-(tert-Butyl)-7-chloro-4-methylquinolin-2-amine
7.18e7.11 (m, 3H), 6.47 (s, 1H), 4.64 (s, 1H), 1.55 (s, 9H); 13C NMR
(3j). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow oil
(100 MHz, CDCl3) d 163.9, 161.5, 156.0, 148.7, 147.8, 134.7, 131.0,
(76% yield); 1H NMR (400 MHz, CDCl3)
d
7.65 (s, 1H), 7.61 (d,
130.9, 129.3, 127.1, 125.3, 121.9, 115.5, 115.3, 113.1, 51.5, 29.5. HRMS
J¼8.8 Hz, 1H), 7.12 (d, J¼8.8 Hz, 1H), 6.36 (s, 1H), 4.55 (s, 1H), 2.47 (s,
(ESI): m/z [MþH]þ calcd for C19H20N2Cl; 311.1315; found: 311.1318.
3H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
156.9, 148.9, 143.7,
134.6, 126.0, 124.7, 122.0, 121.8, 113.3, 51.5, 29.4, 18.6. HRMS (ESI):
4.1.18. N-(tert-Butyl)-4-(thiophen-2-yl)quinolin-2-amine
m/z [MþH]þ calcd for C14H18N2Cl; 249.1159; found: 249.1164.
(3r). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow
oil (48% yield); 1H NMR (400 MHz, CDCl3)
d
7.96 (d, J¼8.4 Hz, 1H),
4.1.11. N-(tert-Butyl)-8-chloro-4-methylquinolin-2-amine
(3k). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow
solid (90% yield), mp: 103e105 ꢀC; 1H NMR (400 MHz, CDCl3)
7.73 (d, J¼8.4 Hz, 1H), 7.52 (t, J¼8.4 Hz, 1H), 7.44 (d, J¼5.2 Hz, 1H),
7.30 (d, J¼3.2 Hz, 1H), 7.20e7.17 (m, 2H), 6.65 (s, 1H), 4.66 (s, 1H),
1.55 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 155.9, 148.8, 141.1, 139.5,
d
7.62e7.60 (m, 2H), 7.06 (t, J¼7.8 Hz, 1H), 6.40 (s, 1H), 4.61 (s, 1H),
129.4, 127.8, 127.5, 127.1, 126.2, 125.2, 122.1, 121.6, 113.5, 51.6, 29.5.
HRMS (ESI): m/z [MþH]þ calcd for C17H19N2S; 283.1269; found:
283.1277.
2.48 (s, 3H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
156.1, 144.5,
144.2, 131.1, 129.1, 124.5, 122.3, 121.0, 113.8, 51.7, 29.0, 18.9. HRMS
(ESI): m/z [MþH]þ calcd for C14H18N2Cl; 249.1159; found: 249.1156.
4.1.19. N-(((3R,5R,7R)-Adamantan-1-yl)methyl)-4-methylquinolin-
2-amine (3s). Isolated (Rf¼0.4, EtOAcepetroleum ether¼1:10) as
a yellow solid (66% yield), mp: 139e142 ꢀC; 1H NMR (400 MHz,
4.1.12. 6-Bromo-N-(tert-butyl)-4-methylquinolin-2-amine
(3l). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:30) as a yellow
solid (40% yield), mp: 165e168 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.83
CDCl3)
d
7.72 (d, J¼8.4 Hz, 1H), 7.64 (d, J¼8.4 Hz, 1H), 7.48 (t,
(s, 1H), 7.57e7.50 (m, 2H), 6.42 (s, 1H), 4.55 (s, 1H), 2.47 (s, 3H), 1.51
J¼7.8 Hz, 1H), 7.19 (t, J¼7.8 Hz, 1H), 6.49 (s, 1H), 4.55 (s, 1H), 2.52 (s,
(s, 9H); 13C NMR (100 MHz, CDCl3)
d 156.5, 146.9, 143.1, 132.0, 128.8,
3H), 2.33e2.05 (m, 9H), 1.80e1.66 (m, 6H); 13C NMR (100 MHz,
125.8, 124.7, 114.5, 113.8, 51.5, 29.5, 18.6. HRMS (ESI): m/z [MþH]þ
CDCl3) d 156.4, 148.0, 144.1, 129.0, 126.8, 123.4, 123.3, 121.5, 113.2,
calcd for C14H18N2Br; 293.0653; found: 293.0660.
51.9, 42.5, 36.7, 29.8, 18.8. HRMS (ESI): m/z [MþH]þ calcd for
C20H25N2; 293.2018; found: 293.2021.
4.1.13. 7-Bromo-N-(tert-butyl)-4-methylquinolin-2-amine
(3m). Isolated (Rf¼0.6, EtOAcepetroleum ether¼1:20) as a yellow
4.1.20. N-Cyclohexyl-4-methylquinolin-2-amine
(Rf¼0.2, EtOAcepetroleum ether¼1:10) as a yellow oil (61% yield);
1H NMR (400 MHz, CDCl3)
(3t). Isolated
oil (41% yield); 1H NMR (400 MHz, CDCl3)
d 7.84 (s, 1H), 7.55 (d,
J¼8.4 Hz, 1H), 7.26 (d, J¼8.4 Hz, 1H), 6.38 (s, 1H), 4.55 (s, 1H), 2.47 (s,
d
7.73 (d, J¼8.0 Hz, 1H), 7.64 (d, J¼8.8 Hz,
3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
156.8, 149.2, 143.8,
1H), 7.49 (t, J¼8.0 Hz, 1H), 7.19 (t, J¼7.8 Hz, 1H), 6.47 (s, 1H), 4.62 (s,
129.3, 124.8, 124.6, 122.9, 122.0, 113.5, 51.6, 29.4, 18.6. HRMS (ESI):
1H), 3.85e3.79 (m, 1H), 2.55 (s, 3H), 2.11e2.07 (m, 2H), 1.79e1.74
m/z [MþH]þ calcd for C14H18N2Br; 293.0653; found: 293.0658.
(m, 2H),1.70e1.62 (m,1H),1.50e1.39 (m, 2H),1.32e1.16 (m, 3H); 13
C
NMR (100 MHz, CDCl3)
d 156.3, 148.3, 144.9, 129.2, 126.4, 123.7,
4.1.14. N-(tert-Butyl)-4-phenylquinolin-2-amine
(3n). Isolated
123.5, 121.5, 111.1, 49.8, 33.6, 25.8, 25.0, 18.9. HRMS (ESI): m/z
(Rf¼0.7, EtOAcepetroleum ether¼1:10) as a yellow oil (78% yield); 1H
[MþH]þ calcd for C16H21N2; 241.1705; found: 241.1697.
NMR (400 MHz, CDCl3)
d
7.73 (d, J¼8.0 Hz,1H), 7.59 (d, J¼8.4 Hz,1H),
7.54e7.41 (m, 6H), 7.11 (t, J¼7.6 Hz,1H), 6.52 (s, 1H), 4.65 (s, 1H), 1.55
4.1.21. N-Butyl-4-methylquinolin-2-amine (3u). Isolated (Rf¼0.6,
EtOAcepetroleum ether¼1:3) as a yellow oil (48% yield); 1H NMR
(s, 9H); 13C NMR (100 MHz, CDCl3)
d
156.1, 148.9, 148.6, 138.7, 129.3,
129.2, 128.4, 128.0, 126.9, 125.6, 121.9, 121.8, 112.9, 51.5, 29.5. HRMS
(400 MHz, CDCl3)
d
7.75 (d, J¼8.4 Hz, 1H), 7.67 (d, J¼8.4 Hz, 1H), 7.52
(ESI): m/z [MþH]þ calcd for C19H21N2; 277.1705; found: 277.1702.
(t, J¼7.6 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H), 6.50 (s, 1H), 4.83 (s, 1H),
3.48e3.43 (m, 2H), 2.57 (s, 3H), 1.70e1.58 (m, 2H), 1.49e1.43 (m,
4.1.15. N-(tert-Butyl)-4-(p-tolyl)quinolin-2-amine
(Rf¼0.4, EtOAcepetroleum ether¼1:20) as a yellow oil (83% yield);
(3o). Isolated
2H), 0.97 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 156.9147.8,
145.2, 129.4, 126.3, 123.7, 123.6, 121.7, 110.9, 41.6, 31.9, 20.2, 18.9,

958
Q. Zheng et al. / Tetrahedron 72 (2016) 952e958
13.9. HRMS (ESI): m/z [MþH]þ calcd for C14H19N2; 215.1548; found:
Chem. 2004, 47, 5405; (f) Inglis, S.; Jones, R.; Fritz, D.; Booker, G.; Pyke, S. Org.
Biomol. Chem. 2005, 3, 2543; (g) Inglis, S. R.; Jones, R.; K. G.; Booker, W.; Pyke, S.
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215.1554.
3. Cheng, Y.; Judd, T. C.; Bartberger, M. D.; Brown, J.; Chen, K.; Fremeau, R. T.;
Hickman, J.; Hitchcock, D. S. A.; Jordan, B.; Li, V.; Lopez, P.; Louie, S. W.; Luo, Y.;
Michelsen, K.; Nixey, T.; Powers, T. S.; Rattan, C.; Sickmier, E. A.; Jean, D. J. St., Jr.;
Wahl, R. C.; Wen, P. H.; Wood, S. J. Med. Chem. 2011, 54, 5836.
4. Jiang, J.; Hoang, M.; Young, Jo. R.; Chaung, D.; Eid, R.; Turner, C.; Lin, P.; Tong, X.;
Wang, J.; Tan, C.; Feighner, S.; Palyha, O.; Hreniuk, D. L.; Pan, J.; Sailer, A. W.;
MacNeil, D. J.; Howard, A.; Shearman, L.; Stribling, S.; Camacho, R.; Strack, A.;
Van der Ploeg, L. H. T.; Gouleta, M. T.; DeVitaBioorg, R. J. Med.Chem. Lett. 2006,
16, 5270.
4.1.22. N-Benzyl-4-methylquinolin-2-amine (3v). Isolated (Rf¼0.4,
EtOAcepetroleum ether¼1:5) as a yellow oil (50% yield); 1H NMR
(400 MHz, CDCl3)
d
7.77 (d, J¼8.0 Hz, 1H), 7.71 (d, J¼8.4 Hz, 1H), 7.54
(t, J¼7.6 Hz, 1H), 7.41 (d, J¼7.4 Hz, 2H), 7.34 (t, J¼7.2 Hz, 2H), 7.28 (d,
J¼7.2 Hz, 1H), 7.24 (d, J¼7.2 Hz, 1H), 6.50 (s, 1H), 5.08 (s, 1H), 4.72 (d,
J¼5.2 Hz, 2H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 156.6,145.3,
139.5, 129.4, 128.6, 127.7, 127.3, 123.9, 123.6, 122.0, 111.3, 45.8, 18.8.
HRMS (ESI): m/z [MþH]þ calcd for C17H17N2; 249.1392; found:
249.1396.
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Acknowledgments
Financial Supported from China Postdoctoral Science Founda-
tion (2013M531556, 2014T70617), the Project of Jiangxi Youth
Scientist (20122BCB23012), and Natural Science Foundation of
Jiangxi Province of China (20133ACB20008, 20132BAB203006) is
gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.12.060.
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