One-pot synthesis of 2-aminoquinoline-based alkaloids from acetonitrile

Article abstract of DOI:10.1039/c2ob25709b

α-Diaminoboryl carbanions, readily prepared from acetonitrile, stereoselectively convert 2-nitrobenzaldehydes into nitrophenyl (Z)-acrylonitriles. Subsequent reductive cyclization leads to a series of 2-aminoquinoline derivatives. The entire procedure is practically operated in a single flask.

Full text of DOI:10.1039/c2ob25709b

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PAPER
One-pot synthesis of 2-aminoquinoline-based alkaloids from acetonitrile†
Takashi Tomioka,* Yusuke Takahashi and Toshihide Maejima
Received 10th April 2012, Accepted 6th May 2012
DOI: 10.1039/c2ob25709b
α-Diaminoboryl carbanions, readily prepared from acetonitrile, stereoselectively convert
2-nitrobenzaldehydes into nitrophenyl (Z)-acrylonitriles. Subsequent reductive cyclization leads to a
series of 2-aminoquinoline derivatives. The entire procedure is practically operated in a single flask.
Introduction
2-Aminoquinoline1 and related natural/unnatural congeners are
pharmaceutically important alkaloids. Many of these exhibit
various biological activities such as anthelmintic,1 antiprotozoal,2
antidepressant,3 and antihypertensive4 activities etc.5 A recent
study also revealed that 2-aminoquinolines possess subnano-
molar potency for BACE1 (beta-site amyloid precursor protein
cleaving enzyme 1) and may serve as a small BACE inhibitor for
Alzheimer’s disease therapeutics.6 Therefore, these compounds
Scheme 2 Z-selective one-pot olefination.
continue to be an attractive study target and are anticipated as
potent leads in the medicinal chemistry community.
Such a 2-aminoquinoline framework 1 (Scheme 1) is syntheti-
method is consistently Z-stereoselective (E : Z = ∼1 : 4) for aro-
cally often prepared by means of a simple reductive cyclization
matic aldehydes and also the entire procedure, including reagent
of a nitrophenyl acrylonitrile 2, through a presumed aminocyano
preparation as well as further modification, can be achieved in a
olefin 3, in the presence of an appropriate reducing metal (e.g.,
single flask. Besides, since the olefination is normally worked up
with an aqueous NH4Cl solution, such an acidic quenched reac-
tion mixture could be directly utilized for the next reductive
cyclization by simply adding a proper reducing agent without
isolation/purification of acrylonitrile 2. Therefore, our protocol
seemed to be highly advantageous for application to the syn-
thesis of 2-aminoquinoline-based alkaloids.
Herein, we describe a one-pot, divergent approach leading to a
[M] = Fe,7 Zn,7c Sn,8 Sm9 and In,7c etc.10), typically under
acidic conditions.11 For mild and effective cyclization, the pre-
sence of a Z-acrylonitrile moiety in 2 is highly essential unless
photochemical isomerization (E → Z) is applied.8 Even though
the starting acrylonitrile 2 can be obtained from 2-nitrobenzalde-
hyde using Horner–Emmons reagents, the reported Z-selectivity
is low (E : Z = ∼1 : 2).8,12
Recently, we developed a facile stereoselective olefination for
series of 2-aminoquinoline derivatives from acetonitrile in a
highly effective manner.
the synthesis of a series of β-monosubstituted acrylonitriles 513
and α,β-disubstituted acrylonitriles 714 with the assistance of a
presumed α-diaminoboryl carbanion species 4 (Scheme 2). This
Results and discussion
Our preliminary study demonstrated that the carbanion 4 was
well compatible with a nitro-group functionality and underwent
Z-olefination with 2-nitrobenzaldehyde (E : Z = 19 : 81). Sub-
sequent reductive cyclization conditions (i.e., sources of acid and
Scheme 1 Reductive cyclization of 2 into 1.
reducing agent, reaction temperature, etc.) were accordingly
investigated (Table 1). To begin, following the olefination, the
reaction mixture was quenched with a saturated NH4Cl solution
Department of Chemistry and Biochemistry, University of Mississippi,
as usual and then directly exposed to zinc powder (entries 1
University, MS 38677, USA. E-mail: tomioka@olemiss.edu;
and 2). These initial attempts readily provided the desired
Fax: +1-662-915-7300; Tel: +1-662-915-5332
†Electronic supplementary information (ESI) available: 1H and 13C
2-aminoquinoline 1a in 65–68% yield. Even though NH4Cl is a
NMR spectra. See DOI: 10.1039/c2ob25709b
mild and convenient inorganic acid, the reaction in biphasic
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Table 1 Condition optimization for one-pot reductive cyclizationa
Table 2 One-pot synthesis of 2-aminoquinolines 1b–1ga
Entry ArCHO
1
Product
1 (%)
1b 67
Entry
H+ source (mL)
[M] (equiv.)
Temp.
1a (%)
1
2
3
4
5
6
7
8
sat. NH4Cl (5)
sat. NH4Cl (5)
sat. NH4Cl (5)
AcOH (1)
AcOH (1)
AcOH (1)
Zn (5)
Zn (5)
Fe (5)
Zn (5)
Zn (5)
Zn (3)
Fe (5)
Zn (5)
r.t.
Reflux
r.t.
r.t.
Reflux
r.t.
68
65
38
76
76
37
16
28
2
1c
55
AcOH (1)
MeOH (10)
r.t.
Reflux
3b
4b
5b
6b
1d 77
a Reaction conditions: 2-nitrobenzaldehyde (1.0 mmol), 4 (1.1 mmol),
THF (6.0 mL).
1e
1f
67
71
41
media (THF/aq·NH4Cl) seemed to be slightly inefficient. Thus, a
miscible organic acid, acetic acid, was alternatively employed
(entries 4–6). The use of acetic acid successfully improved the
overall yield of 1a to 76%, which should be close enough to the
theoretical yield based on the E : Z ratio of the prior olefination.
[Note: the E-isomer does not undergo cyclization under the con-
ditions.] Another reducing metal, iron, was also tested; however,
iron powder did not work well in this reaction system (entries 3
and 7). The use of methanol as a H+ source also gave an inferior
result (entry 8).
1g
a 1.0 mmol reaction scale. b Reflux conditions.
Table 2 illustrates various 2-nitrobenzaldehydes examined
under the optimized conditions, i.e., AcOH–Zn system. The ex-
pected functionalized 2-aminoquinolines 1b–1g were smoothly
obtained in 41–77% yield. Since the α-boryl carbanion protocol
can also lead to α,β-disubstituted Z-acrylonitriles 7 via an inter-
mediate 6 (see Scheme 2), one-pot synthesis of 3-substituted-2-
aminoquinolines 8 was accordingly investigated (Table 3). After
treating the carbanion 4 with an alkyl halide (R1X), the obtained
crude intermediate 6 was directly exposed to a base and then an
aldehyde. Subsequent reductive cyclization at room temperature
cleanly provided 8a–8i in 55–73% yield.
Conclusions
The use of a readily-accessible α-diaminoboryl carbanion
species generated from acetonitrile enabled facile one-pot syn-
thesis of a variety of substituted 2-aminoquinoline derivatives.
Experimental section
Materials and methods
To further test the generality of this one-pot protocol, 4-substi-
tuted-2-aminoquinoline synthesis was also attempted. 2′-Nitro-
acetophenone smoothly underwent olefination with the
carbanion species 4 and provided desired (Z)-acrylonitrile with
decent stereoselectivity (Z : E = 83 : 17). Subsequent cyclization
of the acrylonitrile was slow and not very effective; however, the
expected product 9 was still obtained in 35% yield (Scheme 3).
Elevation of the reaction temperature (i.e., reflux conditions) did
not help to improve the yield of 9.15
All experiments were performed in flame-dried glassware fitted
with rubber septa under an argon atmosphere. Tetrahydrofuran
(THF) was distilled over sodium/benzophenone ketyl. Tetra-
methylethylenediamine (TMEDA) was distilled over calcium
hydride. Bis(diisopropylamino)chloroborane was prepared in
accordance with a literature procedure.18 Unless otherwise noted,
all other reagents were obtained from commercial sources and
used as received. 1H Nuclear Magnetic Resonance (NMR)
spectra were recorded at 300 or 500 MHz. Data are presented as
follows: chemical shift (in ppm on the δ scale relative to δH
7.26 for the residual protons in CDCl3), multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),
coupling constant (J/Hz), integration. Coupling constants were
taken directly from the spectra and are uncorrected. 13C NMR
spectra were recorded at 75 or 125 MHz, and all chemical shift
values are reported in ppm on the δ scale, with an internal refer-
ence of δC 77.0 for CDCl3. Analytical TLC was performed on
silica gel plates using UV light and/or potassium permanganate
Reductive N-alkylation of aminoarenes16 as well as nitro-
arenes17 with an aldehyde in the presence of Zn–AcOH reagents
is well-demonstrated. Due to the similar reaction conditions, our
one-pot protocol seemed further applicable to the preparation of
N-alkylated 2-aminoquinoline derivatives directly from aceto-
nitrile. Following reductive cyclization to 1a and 8a (Scheme 4),
propanal (5 equiv.) was simply added into the reaction mixture
without isolation of the aminoquinolines. The desired N-alky-
lation products, N-1a and N-8a, were successfully afforded in
good yields (∼60%).
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Table 3 One-pot synthesis of 3-substituted-2-aminoquinolines 8a–8ia
Entry
1
R1X
MeI
ArCHO
Product
8 (%)
8a
8b
8c
8d
8e
8f
66
2
3
4
5
6
7
8
9
BnBr
73
72
66
62
59
64
55
64
p-Xylyl bromide
Allyl bromide
BnBr
EtI
BnBr
8g
8h
8i
p-Xylyl bromide
p-F-BnBr
a 1.0 mmol reaction scale.
Scheme 3 One-pot synthesis of 4-substituted-2-aminoquinoline.
Scheme 4 One-pot synthesis of N-alkylated-2-aminoquinolines.
stirring at −78 °C and stirred for another hour. The reaction was
then quenched with acetic acid (1.0 mL, 17.5 mmol) and
allowed to warm up to room temperature. The reaction mixture
was treated with zinc powder (0.33 g, 5.0 mmol) and stirred
overnight at room temperature (for entries 1 and 2) or refluxed
overnight (for entries 3–6). The mixture was basified with
excess ammonium hydroxide (∼15 mL) to pH 9–10. After stir-
ring 30 min, the aqueous layer was extracted three times with
EtOAc (5 mL each). The combined organic extracts were dried
over MgSO4, concentrated, and chromatographed (CHCl3–
MeOH eluent system) to give a 2-aminoquinoline derivative 1.
stain followed by heating. Flash column chromatography was
performed on silica gel 60A (32–63D).
Synthesis of 2-aminoquinolines 1 (1a–1g)
Into a solution of nBuLi (2.5 M in hexanes; 0.88 mL, 2.2 mmol)
in THF (6 mL) at −78 °C was added acetonitrile (172 μL,
3.3 mmol) dropwise with stirring. After 20 min, (i-Pr2N)2BCl
(301 μL, 1.1 mmol) was added dropwise with stirring at −78 °C.
After 1 h, an aldehyde (1.0 mmol) was added slowly with
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(d, J = 8.4 Hz, 1H), 5.17 (brs, 2H), 3.02 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 157.2, 151.8, 148.1, 137.9, 128.1, 115.5,
111.6, 107.0, 103.9, 40.4; HRMS (TOF MS ES+) calcd for
C11H14N3 188.1159 [M + H]+, found 188.1188.
2-Aminoquinoline (1a)
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1a
1
(110 mg, 76%). H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.7
Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H),
7.60–7.54 (m, 1H), 7.30–7.24 (m, 1H) 6.72 (d, J = 8.7 Hz, 1H),
4.73 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 156.9, 147.4,
138.2, 129.8, 127.5, 125.8, 123.5, 122.7, 111.7; HRMS
(TOF MS ES+) calcd for C9H9N2 145.0766 [M + H]+, found
145.0740. This product spectroscopically matched that of the
known compound.8
Benzo[h]quinolin-2-amine (1g)
Column chromatography (CHCl3–MeOH = 9.8 : 0.2) yielded 1g
1
(80 mg, 41%). H NMR (300 MHz, CDCl3) δ 9.18–9.10 (m,
1H), 7.95–7.81 (m, 2H), 7.69–7.51 (m, 4H), 6.77 (d, J = 8.4 Hz,
1H), 4.88 (brs, 2 h); 13C NMR (75 MHz, CDCl3) δ 156.8,
145.6, 138.0, 134.1, 130.3, 127.59, 127.55, 126.0, 125.2, 124.2,
123.3, 120.3, 110.3; HRMS (TOF MS ES+) calcd for C13H11N2
195.0922 [M + H]+, found 195.0917.
6-Chloroquinolin-2-amine (1b)
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1b
1
(120 mg, 67%). H NMR (300 MHz, CDCl3) δ 7.77 (d, J =
Synthesis of 3-substituted-2-aminoquinolines 8 (8a–8i)
8.7 Hz, 1H), 7.68–7.42 (m, 3H), 6.72 (d, J = 8.7 Hz, 1H), 5.01
(brs, 2H); 13C NMR (75 MHz, CDCl3) δ 157.1, 146.0, 137.1,
130.3, 127.8, 127.3, 126.2, 124.1, 112.6; HRMS (TOF MS ES+)
calcd for C9H8ClN2 179.0376 [M + H]+, found 179.0383.
Into a solution of nBuLi (2.5 M in hexanes; 0.88 mL, 2.2 mmol)
in THF (6 mL) at −78 °C was added acetonitrile (172 μL,
3.3 mmol) dropwise with stirring. After 20 min, (i-Pr2N)2BCl
(301 μL, 1.1 mmol) was added dropwise with stirring at −78 °C.
After 1 h, an alkylhalide (1.1 mmol) was added slowly with stir-
ring at −78 °C and stirred for another hour. After the reaction
mixture was allowed to warm up to room temperature, THF and
acetonitrile were rotary evaporated. Another portion of THF
(6.0 mL) was added to the reaction pot and cooled to −78 °C.
TMEDA (165 μL, 1.1 mmol) and n-BuLi in hexanes (2.5 M;
0.44 mL, 1.1 mmol) were then added dropwise with stirring in
this order at −78 °C. After 1 h, an aldehyde (1 mmol) was
added slowly at −78 °C and stirred for another hour. The reac-
tion was quenched with acetic acid (1 mL, 17.5 mmol) and
allowed to warm up to room temperature. The reaction mixture
was treated with a zinc powder (0.33 g, 5.0 mmol) and stirred
overnight at room temperature. The mixture was basified with
excess ammonium hydroxide (∼15 mL) to pH 9–10. After stir-
ring 30 min, the aqueous layer was extracted three times with
EtOAc (5 mL each). The combined organic extracts were dried
(MgSO4), concentrated, and chromatographed to give a 3-substi-
tuted-2-aminoquinoline 8.
6,7-Dimethoxyquinolin-2-amine (1c)
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1c
1
(112 mg, 55%). H NMR (300 MHz, CDCl3) δ 7.70 (d, J =
8.7 Hz, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 6.57 (d, J = 8.7 Hz, 1H),
4.85 (brs, 2H), 3.94 (s, 3H), 3.91 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 155.9, 152.4, 146.7, 143.3, 136.8, 117.7, 109.1, 106.0,
105.4, 55.9, 55.8; HRMS (TOF MS ES+) calcd for C11H13N2O2
205.0977 [M + H]+, found 205.0976.
[1,3]dioxolo[4,5-g]quinolin-6-amine (1d)
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1d
1
(145 mg, 77%). H NMR (300 MHz, CDCl3) δ 7.71 (d, J =
8.7 Hz, 1H), 7.04 (s, 1H), 6.92 (s, 1H), 6.58 (d, J = 8.7 Hz, 1H),
6.02 (s, 2H), 4.67 (brs, 1H); 13C NMR (75 MHz, CDCl3)
δ 155.9, 150.7, 145.3, 144.9, 137.1, 119.1, 109.0, 103.7, 103.4,
101.3; HRMS (TOF MS ES+) calcd for C10H9N2O2 189.0664
[M + H]+, found 189.0643.
3-Methylquinolin-2-amine (8a)
6-Fluoroquinolin-2-amine (1e)
Column chromatography (CHCl3–MeOH = 5 : 1) yielded 8a
(105 mg, 66%). H NMR (300 MHz, CDCl3) δ 7.69–7.45 (m,
1
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1e
1
(108 mg, 67%). H NMR (300 MHz, CDCl3) δ 7.80 (d, J =
4H), 7.22 (apparent t, J = 7.5 Hz, 1H), 5.28 (brs, 2H), 2.24 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 156.6, 145.5, 136.9, 129.0,
126.8, 124.6, 124.1, 122.7, 119.6, 17.5; HRMS (TOF MS ES+)
calcd for C10H11N2 159.0922 [M + H]+, found 159.0901.
This product spectroscopically matched that of the known
compound.8
8.7 Hz, 1H), 7.67–7.57 (m, 1H), 7.36–7.20 (m, 2H), 6.73 (d, J =
8.7 Hz, 1H), 4.87 (brs, 2H); 13C NMR (75 MHz, CDCl3)
1
4
δ 158.2 (d, JCF = 240.9 Hz), 156.4, 144.3, 137.4 (d, JCF
=
3
3
4.5 Hz), 127.7 (d, JCF = 8.5 Hz), 123.7 (d, JCF = 9.4 Hz),
2
2
119.1 (d, JCF = 24.8 Hz), 112.6, 110.9 (d, JCF = 21.5 Hz);
HRMS (TOF MS ES+) calcd for C9H8FN2 163.0672 [M + H]+,
found 163.0659.
3-Benzylquinolin-2-amine (8b)
Column chromatography (EtOAc–MeOH = 5 : 1) yielded 8b
N7,N7-dimethylquinoline-2,7-diamine (1f)
1
(172 mg, 73%). H NMR (300 MHz, CDCl3) δ 7.79–7.50 (m,
Column chromatography (CHCl3–MeOH = 9 : 1) yielded 1f
4H), 7.50–7.15 (m, 6H), 4.84 (brs, 2H), 4.00 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 156.3, 146.7, 137.5, 137.4, 129.1, 128.9,
128.6, 127.1, 127.0, 125.5, 124.2, 122.7, 122.1, 37.9; HRMS
1
(133 mg, 71%). H NMR (300 MHz, CDCl3) δ 7.67 (d, J =
8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.87–6.75 (m, 2H), 6.42
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(TOF MS ES+) calcd for C16H15N2 235.1235 [M + H]+, found
235.1227.
6,7-Dimethoxy-3-(4-methylbenzyl)quinolin-2-amine (8h)
Column chromatography (CHCl3–MeOH = 5 : 1) yielded 8h
1
(170 mg, 55%). H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H),
7.28 (s, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H),
7.00 (s, 1H), 5.89 (brs, 2H), 4.06 (s, 3H), 3.98 (s, 2H), 3.95 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 152.8, 147.9, 146.3, 136.8,
134.7, 133.5, 129.7, 128.4, 126.7, 119.5, 117.1, 106.2, 98.1,
56.4, 56.0, 37.1, 21.0; HRMS (TOF MS ES+) calcd for
C19H21N2O2 309.1603 [M + H]+, found 309.1612.
3-(4-Methylbenzyl)quinolin-2-amine (8c)
Column chromatography (Benzene–Acetone = 1 : 1) yielded 8c
1
(178 mg, 72%). H NMR (300 MHz, CDCl3) δ 7.72–7.64 (m,
2H), 7.64–7.49 (m, 2H), 7.26 (apparent t, J = 7.5 Hz, 1H),
7.18–7.06 (m, 4H), 4.85 (brs, 2H), 3.95 (s, 2H) 2.35 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 156.4, 146.8, 137.3, 136.7,
134.4, 129.7, 129.1, 128.5, 127.1, 125.6, 124.4, 122.7, 122.3,
37.7, 21.0; HRMS (TOF MS ES+) calcd for C17H17N2 249.1392
[M + H]+, found 249.1383.
7-(4-Fluorobenzyl)-[1,3]dioxolo[4,5-g]quinolin-6-amine (8i)
Column chromatography (Hex–EtOAc–MeOH
=
5 : 5 : 1)
1
yielded 8i (190 mg, 64%). H NMR (300 MHz, CDCl3) δ 7.50
(s, 1H), 7.20–7.12 (m, 2H), 7.05–6.90 (m, 3H), 6.90 (s, 1H),
6.02 (s, 2H), 4.53 (brs, 2H), 3.91 (s, 2H); 13C NMR (75 MHz,
3-Allylquinolin-2-amine (8d)
1
CDCl3) δ 161.8 (d, JCF = 243.9 Hz), 155.0, 150.2, 145.0,
Column chromatography (Benzene–Acetone = 1 : 1) yielded 8d
144.5, 136.6, 133.5 (d, 4JCF = 3.2 Hz), 130.0 (d, 3JCF = 7.9 Hz),
1
(122 mg, 66%). H NMR (300 MHz, CDCl3) δ 7.72–7.63 (m,
2
119.9, 119.3, 115.8 (d, JCF = 3.2 Hz), 103.5, 102.9, 101.2,
2H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (apparent t, J = 7.5 Hz, 1H),
7.25 (apparent t, J = 7.5 Hz, 1H), 6.03–5.91 (m, 1H), 5.28–5.06
(m, 4H), 3.38 (d, J = 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 156.5, 146.4, 136.7, 134.5, 129.1, 127.0, 125.2, 124.2, 122.6,
121.2, 117.8, 36.0; HRMS (TOF MS ES+) calcd for C12H13N2
185.1058 [M + H]+, found 185.1079.
36.9; HRMS (TOF MS ES+) calcd for C17H14FN2O2 297.1039
[M + H]+, found 297.1038.
Synthesis of 4-methylquinolin-2-amine (9)
Into a solution of nBuLi (2.5 M in hexanes; 0.88 mL, 2.2 mmol)
in THF (6 mL) at −78 °C was added acetonitrile (172 μL,
3.3 mmol) dropwise with stirring. After 20 min, (i-Pr2N)2BCl
(301 μL, 1.1 mmol) was added dropwise with stirring at −78 °C.
After 1 h, 2-nitroacetophenone (107 μL, 1.0 mmol) was added
slowly with stirring at −78 °C and stirred for another hour. The
reaction was then quenched with acetic acid (1 mL, 17.5 mmol)
and allowed to warm up to room temperature. The reaction
mixture was treated with zinc powder (0.33 g, 5.0 mmol) and
stirred for 2 days at room temperature. The mixture was basified
with excess ammonium hydroxide (∼15 mL) to pH 9–10. After
stirring 30 min, the aqueous layer was extracted three times with
EtOAc (5 mL each). The combined organic extracts were
dried (MgSO4), rotary evaporated, and chromatographed
(EtOAc–MeOH = 1 : 1) to give 9 (55 mg, 35%). 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 1H), 7.67 (d, J =
8.4 Hz, 1H), 7.55 (td, J = 8.4 Hz, 1.2 Hz, 1H), 7.33–7.24
(m, 1H), 6.57 (s, 1H), 5.00 (brs, 2H), 2.57 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 156.7, 147.1, 146.2, 129.6, 126.0, 123.8,
123.6, 122.5, 111.9, 18.7; HRMS (TOF MS ES+) calcd for
C10H11N2 159.0922 [M + H]+, found 159.0915.
3-Benzyl-6-chloroquinolin-2-amine (8e)
Column chromatography (CHCl3–MeOH = 5 : 1) yielded 8e
1
(166 mg, 62%). H NMR (300 MHz, CDCl3) δ 7.60–7.51 (m,
3H), 7.43 (dd, J = 2.1 Hz, 9.0 Hz, 1H), 7.36–7.24 (m, 3H),
7.21–7.15 (m, 2H), 5.14 (brs, 2H), 3.94 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 156.5, 144.6, 136.9, 136.4, 129.7, 129.0,
128.6, 127.8, 127.1, 126.5, 125.8, 124.6, 123.3, 37.7; HRMS
(TOF MS ES+) calcd for C16H14ClN2 269.0846 [M + H]+, found
269.0832.
6-Chloro-3-ethylquinolin-2-amine (8f)
Column chromatography (CHCl3–MeOH = 10 : 1) yielded 8f
1
(121 mg, 59%). H NMR (300 MHz, CDCl3) δ 7.63–7.53 (m,
3H), 7.43 (dd, J = 2.4 Hz, 8.7 Hz, 1H), 5.04 (brs, 2H), 2.59 (q,
J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.2, 144.4, 133.3, 129.3, 127.6, 126.7, 125.8, 125.7,
124.9, 23.7, 11.9; HRMS (TOF MS ES+) calcd for C11H12ClN2
207.0689 [M + H]+, found 207.0687.
Synthesis of N-alkylated-2-aminoquinolines (N-1a and N-8a)
3-Benzyl-6,7-dimethoxyquinolin-2-amine (8g)
The reaction mixture of 1a/8a prepared as described in the
general procedure above was quenched with acetic acid (1 mL,
17.5 mmol) and allowed to warm up to room temperature. The
resulting mixture was then treated with zinc powder (0.523 g,
8.0 mmol) and stirred overnight at room temperature. Sub-
sequently, propanal (364 μL, 5.0 mmol) was added and stirred
for 4 days at room temperature. The mixture was basified with
excess ammonium hydroxide (∼15 mL) to pH 9–10. After stir-
ring 30 min, the aqueous layer was extracted three times with
Column chromatography (CHCl3–MeOH = 5 : 1) yielded 8g
1
(188 mg, 64%). H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H),
7.39–7.15 (m, 6H), 6.95 (s, 1H), 5.97 (brs, 2H), 4.05 (s, 3H),
4.01 (s, 2H), 3.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.8,
147.9, 146.3, 136.7, 134.6, 128.9, 128.6, 127.1, 126.9,
119.3, 117.0, 106.2, 98.0, 56.3, 56.0, 37.4; HRMS (TOF
MS ES+) calcd for C18H19N2O2 295.1447 [M + H]+, found
295.1467.
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EtOAc (5 mL each). The combined organic extracts were dried
(MgSO4), concentrated in vacuo, and chromatographed to give
the final products, N-1a/N-8a.
Notes and references
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N-Propylquinolin-2-amine (N-1a)
4 S. F. Campbell, J. D. Hardstone and M. J. Palmer, J. Med. Chem., 1988,
31, 1031.
5 (a) S. R. Inglis, C. Stojkoski, K. M. Branson, J. F. Cawthray, D. Fritz,
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11 Reductive cyclization under acidic conditions, see: ref. 7 and 8.
12 Some examples are even E-stereoselective, see: (a) L. Garanti and
G. Zecchi, J. Org. Chem., 1980, 45, 4767; (b) M. L. Kantam,
H. Kochkar, J.-M. Clacens, B. Veldurthy, A. Garcia-Ruiz and F. Figueras,
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14 T. Tomioka, R. Sankranti, T. G. Vaughan, T. Maejima and T. Yanase,
J. Org. Chem., 2011, 76, 8053.
Column chromatography (Hex–EtOAc–MeOH
=
5 : 5 : 1)
yielded N-1a (114 mg, 61%). 1H NMR (300 MHz, CDCl3)
δ 7.80 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.60–7.47
(m, 2H), 7.19 (m, 1H), 6.63 (d, J = 9.0 Hz, 1H), 4.86 (brs, 1H),
3.48–3.40 (m, 2H), 1.68 (dq, J = 7.2, 7.2 Hz, 2H), 1.02 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.1, 148.0, 137.3,
129.5, 127.4, 125.9, 123.3, 121.8, 110.9, 43.6, 22.9, 11.5;
HRMS (TOF MS ES+) calcd for C12H15N2 187.1235 [M + H]+,
found 187.1245.
3-Methyl-N-propylquinolin-2-amine (N-8a)
Column chromatography (EtOAc–MeOH = 95 : 5) yielded N-8a
1
(120 mg, 60%). H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.4
Hz, 1H), 7.60 (s, 1H), 7.56–7.43 (m, 2H), 7.18 (td, J = 7.4 Hz,
0.9 Hz, 1H), 4.49 (brs, 1H), 3.60 (dt, J = 5.4, 7.2 Hz, 2H),
2.24 (s, 3H), 1.74 (tq, J = 7.2, 7.2 Hz, 2H), 1.05 (t, J = 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 155.9, 147.2, 135.3, 128.3,
126.6, 126.0, 123.6, 121.7, 119.5, 43.3, 22.9, 17.4, 11.7; HRMS
(TOF MS ES+) calcd for C13H17N2 201.1392 [M + H]+, found
201.1390.
15 16% isolated yield of product 9 under reflux conditions.
16 A. Da Settimo, G. Primofiore, P. L. Ferrarini, M. Ferretti, P. L. Barili,
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Acknowledgements
We thank Dr Amal Dass, Mr. Nuwan Kothalawala, and
Mr. Vijay Jupally for their analytical assistance. The University
of Mississippi supported this research.
5118 | Org. Biomol. Chem., 2012, 10, 5113–5118
This journal is © The Royal Society of Chemistry 2012