One-pot synthesis of multisubstituted 2-aminoquinolines from annulation of 1-aryl tetrazoles with internal alkynes via double C-H activation and denitrogenation

Article abstract of DOI:10.1021/jo502192b

An efficient, one-pot synthesis of multisubstituted 2-aminoquinolines from 1-aryl tetrazoles and internal alkynes has been developed. The reaction involves cyclization of 1-aryl tetrazoles with internal alkynes via rhodium(III)-catalyzed double C-H activa

Full text of DOI:10.1021/jo502192b

Article
pubs.acs.org/joc
One-Pot Synthesis of Multisubstituted 2‑Aminoquinolines from
Annulation of 1‑Aryl Tetrazoles with Internal Alkynes via Double C−
H Activation and Denitrogenation
Lei Zhang, Liyao Zheng, Biao Guo, and Ruimao Hua*
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of
Education, Beijing 100084, China
S
* Supporting Information
ABSTRACT: An efficient, one-pot synthesis of multisubstituted 2-amino-
quinolines from 1-aryl tetrazoles and internal alkynes has been developed. The
reaction involves cyclization of 1-aryl tetrazoles with internal alkynes via
rhodium(III)-catalyzed double C−H activation and copper(II)-mediated
denitrogenation.
assisted C−H activation.11 However, the tetrazole moiety for
INTRODUCTION
■
C−H activation is only used as directing group without further
Quinolines are one of the most important classes of nitrogen-
containing heterocycles, which are ubiquitous in natural
transformation. Thus, we are specifically interested in
products with biological activities.1 They have also served as
privileged scaffolds in medicinal chemistry.2 Among them, 2-
aminoquinolines are particularly of interest due to their
pharmacological properties and have received much attention
in drug discovery.3 For example, C-3-substituted 2-amino-
quinoline derivatives can be served as an efficient BACE1 (beta-
site amyloid precursor protein cleaving enzyme 1) inhibitor for
the remedy of Alzheimer’s disease.4 Nowadays, the most
common approach to 2-aminoquinolines is based on the direct
amination of 2-chloroquinoline through aromatic nucleophilic
substitution.5 However, this method needs preactivated
substrates and the use of strong bases, which limit its scope.
Therefore, methods for modular assembly of multisubstituted
2-aminoquinolines from readily available substrates are still
needed to be developed.
integrating the tetrazole group involved in C−H activation
with its further transformation. Recently, Fu and co-workers12
reported copper-catalyzed cyclization reaction for the synthesis
of tetrazoloisoquinolines using substituted 5-(2-halophenyl)-
1H-tetrazoles and terminal alkynes through carbon−halogen
and nitrogen−hydrogen bond activation but also with
halogenous waste generation (Scheme 1a).
Scheme 1. Synthesis of Nitrogen-Containing Heterocycle via
Tetrazole and Alkyne
Transition-metal-catalyzed C−H bond activation and
functionalization has contributed greatly to the synthesis of
heterocycles.6 In particular, rhodium-catalyzed C−H activation
has emerged as a versatile tool in generating diverse
heterocyclic compounds through intermolecular cyclization
with alkynes, and among these works, heteroatom-containing
groups are widely used as directing groups for the C−H bond
cleavage and functionalization at their ortho position.7 More
recently, the direct C−H activation without the coordination
assistance coming from the directing group has received much
attention in the construction of various heterocycles through
dehydrogenation and cyclization with internal alkynes.8 For
example, Miura8b,f and Chen8c,d have developed Cp*Rh(III)-
catalyzed aza-fused polycyclic quinolines syntheses via double
C−H activation; however, the aza-fused rings cannot undergo
further transformation.
Inspired by these above attractive works and our continuing
efforts in Rh-catalyzed C−H activation and alkyne annulation,13
we envisioned that 1-aryl tetrazoles could couple with internal
alkynes via rhodium-catalyzed C−H activation to prepare
multisubstituted tetrazolo[1,5-a]quinolines or 2-aminoquino-
lins. To our delight, 1-phenyl-1H-tetrazole reacted with 1,2-
diphenylacetylene smoothly and afforded 3,4-diphenyl-2-
Tetrazoles are multinitrogen-containing compounds which
are widely used in synthetic organic chemistry.9−11 For
example, they can be served as a nitrogen source through
denitrogenation process10 and directing groups for chelating-
Received: September 23, 2014
© XXXX American Chemical Society
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aminoquinolin as a sole product. Herein, we wish to report this
efficient rhodium-catalyzed double C−H bond activation for
the synthesis of substituted aminoquinolines via the process of
denitrogenation (Scheme 1b).
not be improved by further variation of the amount of KOAc
and reaction temperature (Table 1, entries 18−21).
Under the optimized reaction condition (indicated in entry
11 of Table 1), we next examined the scope of the reaction. As
shown in Table 2, 1-aryl-1H-tetrazoles (1) with various
RESULTS AND DISCUSSION
■
a
Table 2. Substrate Scope of Aryltetrazoles
We initiated our investigation by employing 1-phenyl-1H-
tetrazole (1a, 0.5 mmol) and 1,2-diphenylacetylene (2a, 0.2
mmol) as model substrates in the presence of 2.5 mol % of
[Cp*RhCl2]2, Cu(OAc)2·H2O (2.0 equiv, 0.4 mmol) in 1,2-
dichloroethane (DCE) at 130 °C for 6 h. Unfortunately, no
product was detected (Table 1, entry 1). A variety of solvents
a
Table 1. Optimization of the Reaction Conditions
b
entry
additive (equiv)
solvent
yield (%)
1

DCE
NR
NR
NR
NR
NR
NR
trace
21
2

dioxane
THF
3

4

CH3CN
DMSO
toluene
CH3OH
o-xylene
DMF
5

6

7

8

9

43
10
11
12
13
14
15
16
17
18
19

DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
55
KOAc (2.0)
NaOAc (2.0)
K2CO3 (2.0)
Na2CO3 (2.0)
AgOAc (2.0)
HOAc (2.0)
PivOH (2.0)
KOAc (3.0)
KOAc (1.0)
KOAc (2.0)
KOAc (2.0)
68
60
37
29
trace
trace
trace
67
59
a
c
Unless otherwise noted, reactions were carried out using 1 (0.50
20
trace
69
mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H2O
d
21
(0.4 mmol), and KOAc (0.4 mmol) in 1.0 mL of DMAc at 130 °C
a
b
Unless otherwise noted, reactions were carried out using 1a (0.50
under N2 in a sealed tube for 6 h. For 8 h.
mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H2O
(0.4 mmol), additive (0.4 mmol) in 1.0 mL of DMAc at 130 °C under
b
N2 in a sealed tube for 6 h. Isolated yields based on the amount of 2a
c
d
used. At 100 °C. At 150 °C.
substitutes were employed to react with 1,2-diphenylacetylene
(2a). No significant steric effect was observed by using 1-aryl-
1H-tetrazoles with ortho-, meta-, or para-methyl on the phenyl
ring as substrates, and corresponding products 3b, 3c, and 3d
were obtained in similar yields. 1-Aryl-1H-tetrazoles with
electron-donating groups on the para-position of the phenyl
ring showed higher reactivity than those with electron-
withdrawing groups. Specifically, 1-aryl-1H-tetrazoles with
electron-donating groups, such as Me, OMe, Et, i-Pr, and t-
Bu on the para position of the phenyl ring reacted smoothly
with 1,2-diphenylacetylene (2a) to afford corresponding
products 3e−3h in improved yields (70−75%). Meanwhile,
1-aryl-1H-tetrazoles with an electron-withdrawing group, such
as F, Cl, CO2Me, and CF3O on the para position of the phenyl
ring gave corresponding products 3i−3l in declined yields (42−
58%). It should be noted that multisubstituted 1-aryl-1H-
were then examined, and the significant solvent effects were
observed. No desired product 3a was formed when the reaction
was performed in dioxane, THF, CH3CN, DMSO, toluene
(Table 1, entries 2−6). CH3OH was found to be ineffective for
this reaction (Table 1, entry 7). By using o-xylene, DMF, or
DMAc as solvents, 3a was formed in moderate yield (Table 1,
entries 8−10). For further optimization of the reaction system,
various additives were also screened. Improved yield (68%) was
obtained by using KOAc as additive (Table 1, entry 11). Other
bases, such as NaOAc, K2CO3, and Na2CO3 were less effective
and afforded inferior yields of 3a (Table 1, entries 12−14).
AgOAc and acids restrained the reaction and only a trace of the
product was detected (Table 1, entries 15−17). The yield could
B
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tetrazoles also reacted smoothly with 2a, giving the
corresponding products 3m−3o.
To test the applicability of our reaction, we also employed
various substituted alkynes under the standard reaction
conditions (Table 3). The substitution effect in the alkynes
Scheme 2. Control Experiments
a
Table 3. Substrate Scope of Alkynes
diphenyltetrazolo[1,5-a]quinoline (3a′) could be converted
into 3,4-diphenyl-2-aminoquinolin (3a) with 92% yield in the
presence of Cu(OAc)2·H2O (Scheme 2d), while other
conditions were proved to be invalid (Scheme 2, panels b, c,
and e). These results suggested that Cu(OAc)2 is involved in
the denitrogenative transannulation.
In addition, as shown in Scheme 2, we repeated the
denitrogenation reaction of 3a′ in the presence of Cu(OAc)2
(10 mol %) (f), Zn(OAc)2 (2.0 equiv) (g), or CuOAc (2.0
equiv) (h) to further understand the role of Cu(OAc)2. It was
found that the use of catalytic amount of Cu(OAc)2 resulted in
low yield of 3a (24%), Zn(OAc)2 showed no catalytic activity,
and the use of CuOAc gave 3a in low yield (32%). These
results indicate that the oxidative capability of Cu(OAc)2 may
be more relevant than its property as a Lewis acid to prompt
the denitrogenation of 3a′.
a
Unless otherwise noted, reactions were carried out using 1a (0.50
mmol), 2 (0.2 mmol), [Cp*RhCl2]2 (2.5 mol %), Cu(OAc)2·H2O (0.4
mmol), and KOAc (0.4 mmol) in 1.0 mL of DMAc at 130 °C under
N2 in a sealed tube for 6 h.
moiety also exists. Symmetrical diarylacetylenes containing
electron-donating group (Me) on the para position of the
phenyl ring reacted smoothly to afford the corresponding
product 3p in 65% yield, while diphenylacetylenes containing
electron-withdrawing groups (F and Br) gave corresponding
products 3q and 3r in declined yields. For asymmetrically
substituted alkynes, the desired products 3s−3w were obtained
with high regioselectivity. The structure of 3s was unambigu-
ously identified by single-crystal X-ray diffraction (see the
Supporting Information). Notably, alkyne with a free hydroxyl
group was also applicable for the reaction to afford the desired
product 3v in 52% yield. When 1-(5-chloropent-1-yn-1-yl)-4-
methoxybenzene was used, the chlorine group was substituted
by the acetate group in situ in the reaction system and afforded
3w with complete regioselectivity in 79% yield. Di(2-thienyl)-
acetylene also react smoothly to afford 3x in 57% yield.
To further probe the reaction mechanism, we continued our
investigation by using 1-(2,3,4-trimethoxyphenyl)-1H-tetrazole
(1o) for the H/D exchange experiment, which was carried out
in the mixture of DMAc/D2O (1:1, 1.0 mL) at 80 °C under a
N2 atmosphere for 40 min (Scheme 3). A significant D/H
exchange (>85%) at C(5) position indicated that the Rh(III)
insertion process occurred initially and a reversible C−H bond
rhodium process may be incorporated.
In the process of experimental condition optimization, 1-
phenyl-1H-tetrazole reacted with 1,2-diphenylacetylene gen-
erated another single product 4,5-diphenyltetrazolo[1,5-a]-
quinoline (3a′) in very low yield when the reaction temperature
was decreased to 80 °C (Scheme 2a). The structure of 3j′ (a
similar structure of 3a′) was identified by single-crystal X-ray
diffraction (see the Supporting Information). These results
implied that the temperature was vital for the denitrogenative
transannulation of the tetrazolo group. In addition, 4,5-
Scheme 3. Rhodium-Catalyzed H/D Exchange in DMA/D2O
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Scheme 4. Proposed Reaction Mechanism
a
On the basis of the above experiment results and known
rhodium-catalyzed C−H bond activation,8,9 a plausible reaction
mechanism is shown in Scheme 4. First, C(5)−H of 1-phenyl-
1H-tetrazole undergoes reversible C−H activation and Rh(III)
insertion to afford intermediate IM 1; the following C−H
activation occurs on the ortho position of tetrazole to afford the
five-membered ring rhodacycle intermediate IM 2. Diphenyla-
cetylene coordinates to Rh(III) to form intermediate IM 3.
Subsequently, Alkyne insertion of IM 3 affords a seven-
membered ring rhodacycle intermediate IM4. The reduction
elimination of IM 4 gives the isolated intermediate 3a′ and
regenerated the rhodium catalyst. After that, the tautomeriza-
tion of 3a′ occurs to give IM 5 in the presence of copper salt.
Finally, the reduction of IM 6 affords the final product 3a
through denitrogenative transannulation10 in the presence of
copper from intermediate IM 5.
On the basis of the proposed mechanism, it is found that
when the use of aryl-tetrazoles having an electron-rich group
may form a more stable five-membered rhodacycle intermediate
(IM 2), the use of diarylacetylenes bearing electron-donating
group in phenyl ring should lead to the easier formation of
alkyne-coordinated intermediate (IM 3). Therefore, we can
understand the reason why in most cases, the use of aryl-
tetrazoles or diarylacetylenes bearing electron-donating
group(s) resulted in the formation of 3 in relatively higher
yields as concluded in Tables 2 and 3.
Moreover, the further transformation of the 2-aminoquino-
lines into imidazo[1,2-a]quinolines was conducted (Scheme 5).
By following Hajra’s conditions14 with slight modification,
imidazo[1,2-a]quinolines (4a, 4c, 4e, 4h, 4p, and 4t) were
obtained by copper-catalyzed tandem oxidative cyclization of 3
in 52−72% yields.
In summary, we have developed a one-pot synthesis of
multisubstituted 2-aminoquinolines by the cyclization of 1-aryl
tetrazoles with internal alkynes through rhodium(III)-catalyzed
double C−H bond activation and Cu(II)-mediated denitroge-
nation in moderate to good yields. Further applications and
transformations of tetrazoles through Rh(III)-catalyzed C−H
activation are in progress in our lab.
Scheme 5. Derivatization of 2-Aminoquinolines
a
Reaction conditions: substituted aminouquinolines (3 0.3 mmol),
acetophenone (0.2 mmol). Cu(OAc)2·H2O (10%), 1, 10-phenanthro-
line (20%), ZnI2 (20%), 1,2-DCB (1.0 mL), air, 120 °C, 24 h, isolated
yields.
EXPERIMENTAL SECTION
■
General Methods. All organic starting materials are analytically
pure and used without further purification. All reactions were carried
out without any particular precautions to extrude moisture or oxygen.
Nuclear magnetic resonance (NMR) spectra were recorded using
1
CDCl3 as solvent at 298 K. H NMR (400 MHz) chemical shifts (δ)
were referenced to internal standard TMS (for 1H, δ = 0.00 ppm). 13
C
NMR (100 MHz) chemical shifts were referenced to internal solvent
CDCl3 (for 13C, δ = 77.16 ppm). HRMS spectra were obtained on a
high-resolution magnetic sector mass spectrometer with an electron
spray ionization (ESI) source. The melting points are uncorrected.
Rhodium catalyst [Cp*RhCl2]2 was prepared following a literature
procedure.15 1,2-Bis(4-methylphenyl)ethyne, 1,2-bis(4-fluorophenyl)-
ethyne, 1,2-bis(4-bromophenyl)ethyne, and 1,2-di(thiophen-2-yl)-
ethyne were prepared following a literature procedure16 with our
improvement.13a 4-Phenylbut-3-yn-1-ol and 1-(5-chloropent-1-yn-1-
yl)-4-methoxybenzene were prepared following a literature proce-
dure,17 and 1-aryl tetrazoles were prepared according to the literature
procedure.10a
Typical Procedure for the Synthesis of Substituted Quino-
line. 1-Aryltetrazole (1, 0.5 mmol), internal alkyne (2, 0.2 mmol),
[Cp*RhCl2]2 (3.1 mg, 0.005 mmol), Cu(OAc)2·H2O (80 mg, 0.4
mmol), KOAc (39.3 mg, 0.4 mmol) were added to a thick-walled
screw-capped Pyrex tube equipped with a magnetic stirrer. DMAc (1.0
mL) was added sequentially under N2 atmosphere. Then the tube was
sealed and stirred at 130 °C for 6 h. After the reaction was completed,
it was cooled to room temperature and extracted with ethyl acetate for
3 times. The organic phase was dried over MgSO4, filtered, and
D
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The Journal of Organic Chemistry
Article
concentrated under reduced pressure, further purification by flash
column chromatography on silica gel with petroleum ether/ethyl
acetate/triethylamine (3:1:0.05−1:1:0.05) to provide the correspond-
ing product (3).
6-Ethyl-3,4-diphenylquinolin-2-amine (3f). White solid (48.8 mg,
75%), mp 194−196 °C. 1H NMR (400 MHz, CDCl3): δ 7.66 (1H, d, J
= 8.4 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.16−7.06 (11H, m), 5.30 (2H,
br), 2.57 (2H, q, J = 7.6 Hz), 1.13 (3H, t, J = 7.6 Hz). 13C NMR (100
MHz, CDCl3): δ 155.2, 147.0, 145.6, 138.0, 136.8, 136.2, 130.2, 129.9,
129.8, 128.3, 127.4, 127.1, 126.9, 125.5, 124.4, 123.3, 123.2, 28.6, 15.7.
IR (KBr, cm−1): 3477, 3281, 3120, 3054, 2960, 2871, 1632, 1565,
1491, 1437, 1419, 830, 697. HRMS (ESI) calcd for C23H21N2 ([M +
H]+): 325.1699. Found: 325.1698.
Rhodium-Catalyzed H/D Exchange in DMAc/D2O.
[Cp*RhCl2]2 (3.1 mg, 0.005 mmol), 1-(2,3,4-trimethoxyphenyl)-1H-
tetrazole (1o, 0.2 mmol), Cu(OAc)2·H2O (80 mg, 0.4 mmol), KOAc
(39.4 mg, 0.4 mmol) were added to a thick-walled screw-called Pyrex
tube equipped with a magnetic stirrer. DMAc (0.5 mL) and D2O (0.50
mL) were added sequentially under a N2 atmosphere. The reaction
was performed at 80 °C in an oil bath for 40 min. Then it was cooled
to room temperature and extracted with ethyl acetate. The organic
phase was dried over MgSO4, filtered, and concentrated under reduced
pressure, and further purified by flash column chromatography on
silica gel with petroleum ether/ethyl acetate (3:1) to aford the product
1o-D. The deuterium incorporation was estimated by 1H NMR
spectroscopy (see the Supporting Information).
6-Isopropyl-3,4-diphenylquinolin-2-amine (3g). White solid (47.3
1
mg, 70%), mp 199−201 °C. H NMR (400 MHz, CDCl3): δ 7.68
(1H, d, J = 8.8 Hz), 7.46 (1H, dd, J1 = 8.4 Hz, J2 = 1.6 Hz), 7.24−7.09
(11H, m), 5.0 (2H, br), 2.57 (1H, m), 1.17 (6H, d, J = 6.8 Hz). 13C
NMR (100 MHz, CDCl3): δ 155.2, 147.3, 145.8, 142.7, 136.8, 136.3,
130.3, 129.9, 128.4, 128.3, 127.6, 127.3, 127.0, 125.7, 123.3, 123.2,
33.9, 23.9. IR (KBr, cm−1): 3478, 3460, 3284, 3124, 3056, 2955, 2870,
1635, 1565, 1494, 1437, 1420, 827, 698. HRMS (ESI) calcd for
C24H23N2 ([M + H]+): 339.1856. Found: 339.1853.
Characterization Data. 4,5-Diphenyltetrazolo[1,5-a]quinoline
1
(3a′). White solid (16.7 mg, 26%), mp 246−248 °C; H NMR (400
6-(Tert-butyl)-3,4-diphenylquinolin-2-amine (3h). White solid
1
MHz, CDCl3): δ 8.70 (1H, d, J = 8.0 Hz), 7.78−7.74 (1H, m), 7.61−
7.59 (1H, m), 7.53−7.49 (1H, m), 7.31−7.24 (5H, m), 7.21−7.13
(5H, m); 13C NMR (100 MHz, CDCl3): δ 148.0, 142.2, 135.1, 133.3,
130.6 (overlapped), 129.9, 128.6, 128.7, 128.4, 128.3, 128.2, 128.0,
127.8, 125.2, 125.0, 116.6; IR (KBr, cm−1): 3080, 3056, 2926, 2853,
1592, 1554, 1517, 1491, 1441, 1091, 773, 755, 704; HRMS (ESI) calcd
for C21H15N4 ([M + H]+): 323.1291. Found: 323.1294.
(49.8 mg, 71%), mp 215−217 °C. H NMR (400 MHz, CDCl3): δ
7.71−7.64 (2H, m), 7.30 (1H, d, J = 2.0 Hz), 7.26−7.10 (10H, m),
4.75 (2H, br), 1.24 (9H, s). 13C NMR (100 MHz, CDCl3): δ 155.1,
147.8, 145.4, 145.1, 136.8, 136.3, 130.4, 130.0, 128.6, 128.0, 127.6,
127.4, 127.1, 125.4, 123.2, 123.1, 121.9, 34.6, 31.2. IR (KBr, cm−1):
3482, 3285, 3145, 2955, 2867, 1631, 1565, 1492,1434, 1418, 1364,
1250, 890, 764, 698; HRMS (ESI) dalcd for C25H25N2 ([M + H]+):
353.2012. Found: 353.2013.
3,4-Diphenylquinolin-2-amine (3a). White solid (40.1 mg, 68%),
mp 241−243 °C; 1H NMR (400 MHz, CDCl3): δ 7.73 (1H, d, J = 8.4
Hz), 7.56−7.52 (1H, m), 7.34 (1H, d, J = 8.0 Hz), 7.25−7.10 (11H,
m), 4.93 (2H, br). 13C NMR (100 MHz, CDCl3): δ 155.6, 147.7,
147.2, 136.7, 136.1, 130.3, 130.0, 129.4, 128.6, 127.7, 127.5, 127.2,
126.7, 125.8, 123.7, 123.3, 122.4. IR (KBr, cm−1): 3481, 3281, 3121,
2924, 2851, 2742, 1634, 1608, 1565, 1490, 1464, 1442, 1249, 762, 704;
HRMS (ESI) calcd for C21H17N2 ([M + H]+): 297.1386. Found:
297.1386.
6-Fluoro-3,4-diphenylquinolin-2-amine (3i). White solid (35.8 mg,
1
57%), mp 217−219 °C. H NMR (400 MHz, CDCl3): δ 7.70−7.66
(1H, m), 7.32−7.16 (7H, m), 7.13 (2H, J = 6.8 Hz), 7.08−7.06 (2H,
m), 6.96 (1H, dd, J1 = 10.4 Hz, J2 = 2.8 Hz), 4.89 (2H, br). 13C NMR
(100 MHz, CDCl3): δ 158.2 (d, J = 240.1 Hz), 155.2, 147.1 (d, J = 4.6
Hz), 144.1, 136.3, 135.8, 130.2, 129.8, 128.6, 127.9, 127.7, 127.6,
127.4, 124.1, 124.0, 118.8 (d, J = 25.1 Hz), 110.4 (d, J = 22.9 Hz); IR
(KBr, cm−1): 3476, 3300, 3163, 3074, 3024, 1628, 1564, 1507, 1493,
1452, 1420, 1201, 834, 760. HRMS (ESI) calcd for C21H16FN2 ([M +
H]+): 315.1292. Found: 315.1296.
8-Methyl-3,4-diphenylquinolin-2-amine (3b). White solid (37.9
1
mg, 61%), mp 161−163 °C; H NMR (400 MHz, CDCl3): δ 7.42
(1H, d, J = 6.8 Hz), 7.26−7.02 (12H, m), 4.74 (2H, br), 2.72 (3H, s).
13C NMR (100 MHz, CDCl3): δ 154.6, 147.9, 146.2, 137.2, 136.4,
133.7, 130.3, 130.0, 129.6, 128.5, 127.6, 127.3, 127.0, 124.7, 123.5,
122.9, 122.0, 18.2. IR (KBr, cm−1): 3477, 3290, 3170, 2915, 1617,
1565, 1467, 1424, 1243, 1071, 1029, 746, 700. HRMS (ESI) calcd for
C22H19N2 ([M + H]+): 311.1543. Found: 311.1545.
6-Chloro-3,4-diphenylquinolin-2-amine (3j). White solid (35.5
1
mg, 54%), mp 226−228 °C. H NMR (400 MHz, CDCl3): δ 7.65
(1H, d, J = 8.8 Hz), 7.50−7.47 (1H, m), 7.30 (1H, d, J = 2.4 Hz),
7.28−7.20 (6H, m), 7.14−7.07 (4H, m), 4.90 (2H, br). 13C NMR
(100 MHz, CDCl3): δ 155.7, 147.0, 145.7, 136.0, 135.7, 130.2, 130.0,
129.9, 128.7, 127.9, 127.8, 127.7, 127.5, 127.4, 125.5, 124.5, 124.1. IR
(KBr, cm−1): 3475, 3284, 3140, 2850, 2812, 1630, 1583, 1565, 1484,
1436, 1420, 824, 699. HRMS (ESI) calcd for C21H16ClN2 ([M + H]+):
331.0997. Found: 331.0997.
7-Methyl-3,4-diphenylquinolin-2-amine (3c). White solid (42.2
1
mg, 68%), mp 220−222 °C. H NMR (400 MHz, CDCl3): δ 7.52
(1H, s), 7.23−7.08 (11H, m), 6.97 (1H, J = 8.4 Hz), 4.94 (2H, br),
2.48 (3H, s). 13C NMR (100 MHz, CDCl3): δ 155.6, 147.4, 147.3,
139.5, 136.9, 136.2, 130.4, 129.9, 128.5, 127.6, 127.3, 127.0, 126.4,
125.2, 124.4, 122.3, 121.6. 21.7. IR (KBr, cm−1): 3480, 3464, 3285,
3119, 3054, 2921, 1633, 1616, 1563, 1490, 1429, 1240, 869, 749, 699.
HRMS (ESI) calcd for C22H19N2 ([M + H]+): 311.1543. Found:
311.1546.
Methyl-2-amino-3,4-diphenylquinoline-6-carboxylate (3k). White
solid (29.8 mg, 42%), mp 244−246 °C. 1H NMR (400 MHz, CDCl3):
δ 8.17−8.11 (2H, m), 7.71 (1H, d, J = 8.8 Hz), 7.29−7.20 (6H, m),
7.15−7.09 (4H, m), 5.13 (2H, br), 3.84 (3H, s). 13C NMR (100 MHz,
CDCl3): δ 167.1, 155.6, 147.7, 147.2, 136.7, 136.1, 130.3, 130.0, 129.4,
128.6, 127.7, 127.5, 127.2, 126.7, 125.8, 123.7, 123.3, 122.4, 52.0. IR
(KBr, cm−1): 3483, 3408, 3292, 3151, 2946, 2738, 1707, 1610, 1424,
1273, 1238, 1110, 1020, 757, 700. HRMS (ESI) calcd for C23H19N2O2
([M + H]+): 355.1441. Found: 355.1446.
3,4-Diphenyl-6-(trifluoromethoxy)quinolin-2-amine (3l). White
solid (44.0 mg, 58%), mp 179−181 °C. 1H NMR (400 MHz,
CDCl3): δ 7.72 (1H, d, J = 9.2 Hz), 7.42−7.39 (1H, m), 7.27−7.07
(11H, m), 5.15 (2H, br). 13C NMR (100 MHz, CDCl3): δ 156.1,
147.4, 145.7, 143.9, 135.9, 135.6, 130.1, 129.8, 128.7, 127.9, 127.7,
127.6, 127.4, 124.3, 123.8, 123.2, 120.5 (q, J = 255.2 Hz), 118.2. IR
(KBr, cm−1): 3483, 3290, 3124, 2737, 1636, 1566, 1491, 1427, 1241,
1198, 1072, 1022, 832, 700. HRMS (ESI) calcd for C22H16F3N2O ([M
+ H]+): 381.1209. Found: 381.1211.
6-Methyl-3,4-diphenylquinolin-2-amine (3d). White solid (42.8
1
mg, 69%), mp 222−224 °C. H NMR (400 MHz, CDCl3): δ 7.57
(1H, d, J = 8.8 Hz), 7.31 (1H, dd, J 1= 8.4 Hz, J 2= 1.6 Hz), 7.18−7.00
(11H, m), 4.70 (2H, br), 2.25 (3H, s). 13C NMR (100 MHz, CDCl3):
δ 155.0, 147.1, 145.5, 136.9, 136.3, 131.9, 131.4, 130.3, 130.0, 128.5,
127.6, 127.4, 127.1, 125.7, 125.6, 123.6, 123.3, 21.4. IR (KBr, cm−1):
3480, 3467, 3284, 3134, 3056, 2696, 1631, 1565, 1492, 1432, 1419,
826, 786, 759, 699; HRMS (ESI) calcd for C22H19N2 ([M + H]+):
311.1543. Found: 311.1547.
6-Methoxy-3,4-diphenylquinolin-2-amine (3e). White solid (47.1
1
mg, 72%), mp 189−191 °C. H NMR (400 MHz, CDCl3): δ 7.67
(1H, d, J = 8.8 Hz), 7.25−7.09 (11H, m), 6.70 (1H, d, J = 2.8 Hz),
4.73 (2H, br), 3.65 (3H, s). 13C NMR (100 MHz, CDCl3): δ 154.9,
154.1, 146.8, 142.7, 136.9, 136.3, 130.3, 129.9, 128.5, 127.7, 127.4,
127.2, 127.1, 124.1, 123.5, 120.5, 106.2, 55.3. IR (KBr, cm−1): 3481,
3291, 3141, 3062, 2952, 2826, 1636, 1566, 1507, 1490, 1434, 1419,
1404, 1225, 1038, 828, 699; HRMS (ESI) calcd for C22H19N2O ([M +
H]+): 327.1492. Found: 327.1496.
6,7-Dimethyl-3,4-diphenylquinolin-2-amine (3m). White solid
1
(34.3 mg, 53%), mp 203−205 °C. H NMR (400 MHz, CDCl3): δ
7.52 (1H, s), 7.25−7.17 (6H, m), 7.15−7.06 (5H, m), 4.73 (2H, br),
2.40 (3H, s), 2.23 (3H, s). 13C NMR (100 MHz, CDCl3): δ 155.0,
146.9, 146.1, 139.3, 137.0, 136.4, 131.8, 130.4, 130.0, 128.5, 127.6,
127.3, 127.0, 126.0, 125.8, 122.4, 122.1, 20.3, 19.8. IR (KBr, cm−1):
E
dx.doi.org/10.1021/jo502192b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3482, 3469, 3283, 3147, 3053, 2917, 1629, 1620, 1559, 1490, 1429,
1405, 1245, 1018, 699. HRMS (ESI) calcd for C23H21N2 ([M + H]+):
325.1699. Found: 325.1700.
4-Butyl-3-phenylquinolin-2-amine (3u). White solid (36.5 mg,
66%), mp 128−130 °C. H NMR (400 MHz, CDCl3): δ 7.86−7.83
1
(1H, m), 7.69−7.66 (1H, m), 7.56−7.42 (4H, m), 7.31−7.27 (3H, m),
4.80 (2H, br), 2.73−2.67 (2H, m), 1.53−1.50 (2H, m), 1.30−1.23
(2H, m), 0.81−0.76 (3H, m). 13C NMR (100 MHz, CDCl3): δ 155.7,
147.3, 146.8, 136.6, 129.7, 129.2, 129.0, 128.0, 126.4, 124.1, 123.4,
122.9, 122.2, 32.6, 29.0, 22.9, 13.6. IR (KBr, cm−1): 3479, 3291, 3147,
3064, 2963, 2860, 1632, 1580, 1565, 1503, 1462, 1430, 1224, 1010,
757, 702. HRMS (ESI) calcd for C19H21N2 ([M + H]+): 277.1699.
Found: 277.1697.
6-Fluoro-8-methyl-3,4-diphenylquinolin-2-amine (3n). White
solid (33.4 mg, 51%), mp 212−214 °C. 1H NMR (400 MHz,
CDCl3): δ 7.26−7.19 (7H, m), 7.14−7.12 (2H, m), 7.08−7.06 (2H,
m), 6.82 (1H, dd, J1 = 10.4 Hz, J2 = 2.8 Hz), 4.72 (2H, br), 2.72 (3H,
s). 13C NMR (100 MHz, CDCl3): δ 157.6 (d, J = 239.3 Hz), 154.1,
147.4 (d, J = 5.7 Hz), 143.1, 136.7 (d, J = 8.6 Hz), 136.5, 136.2, 130.2,
129.9, 128.6, 127.8, 127.5, 127.3, 123.8 (d, J = 9.5 Hz), 123.7, 118.9
(d, J = 24.8 Hz), 107.9 (d, J = 21.9 Hz), 18.2. IR (KBr, cm−1): 3511,
3399, 3062, 3034, 2959, 2920, 1607, 1598, 1487, 1420, 1194, 1137,
875, 721, 701. HRMS (ESI) calcd for C22H18FN2 ([M + H]+):
329.1449. Found: 329.1449.
2-(2-Amino-3-phenylquinolin-4-yl)ethanol (3v). White solid (27.4
1
mg, 52%), mp 165−167 °C. H NMR (400 MHz, CDCl3): δ 7.88
(1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.53−7.37 (4H, m),
7.26−7.22 (3H, m), 4.60 (2H, br), 3.77 (2H, t, J = 7.6 Hz), 3.05 (2H,
t, J = 7.2 Hz), 2.95 (1H, br). 13C NMR (100 MHz, CDCl3): δ 155.5,
147.0, 142.5, 136.1, 129.7, 129.4, 129.3, 128.2, 126.2, 124.7, 124.2,
123.1, 122.6, 62.0, 32.8. IR (KBr, cm−1): 3469, 3369, 3181, 3050,
2981, 2870, 1623, 1607, 1569, 1506, 1430, 1319, 1050, 763, 707.
HRMS (ESI) calcd for C17H17N2O ([M + H]+): 265.1335. Found:
265.1334.
6,7,8-Trimethoxy-3,4-diphenylquinolin-2-amine (3o). White solid
1
(59.6 mg, 77%), mp 208−210 °C. H NMR (400 MHz, CDCl3): δ
7.19−7.15 (2H, m), 7.19−7.15 (3H, m), 7.05−7.03 (5H, m), 7.00
(1H, s), 4.65 (2H, br), 3.97 (3H, s), 3.81 (3H, s), 3.20 (3H, s). 13C
NMR (100 MHz, CDCl3): δ 155.4, 154.9, 149.7, 145.8, 145.4, 140.1,
139.2, 136.0, 130.4, 128.5, 128.1, 126.9, 126.3, 125.6, 122.4, 112.8,
102.1, 60.7, 60.4, 55.7. IR (KBr, cm−1): 3504, 3394, 3381, 3051, 3025,
2939, 2825, 1590, 1557, 1485, 1458, 1437, 1396, 1337, 1244, 1153,
1111, 1103, 1068, 993, 948, 834, 730, 705. HRMS (ESI) calcd for
C24H23N2O3 ([M + H]+): 387.1703. Found: 387.1701.
3-(2-Amino-3-(4-methoxyphenyl)quinolin-4-yl)propyl acetate
1
(3w). White solid (55.4 mg, 79%), mp 120−122 °C. H NMR (400
MHz, CDCl3): δ 7.83 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 8.0 Hz),
7.57−7.53 (1H, m), 7.31−7.27 (1H, m), 7.20 (2H, d, J = 8.8 Hz), 7.05
(2H, d, J = 8.4 Hz), 4.66 (2H, br), 3.98 (2H, t, J = 6.4 Hz), 3.88 (3H,
s), 2.83−2.79 (2H, m), 1.95 (3H, s), 1.90−1.83 (2H, m). 13C NMR
(100 MHz, CDCl3): δ 170.7, 159.3, 156.1, 147.2, 145.6, 130.8, 129.0,
128.1, 126.4, 123.7, 123.5, 122.7, 122.3, 114.7, 63.8, 55.2, 29.2, 25.6,
20.7. IR (KBr, cm−1): 3466, 3312, 3170, 2961, 1735, 1605, 1429, 1247,
1034, 761. HRMS (ESI) calcd for C21H23N2O3 ([M + H]+): 351.1703.
Found: 351.1706.
3,4-Di-p-tolylquinolin-2-amine (3p). White solid (42.2 mg, 65%),
mp 252−254 °C. 1H NMR (400 MHz, CDCl3): δ 7.70 (1H, d, J = 8.4
Hz), 7.53−7.50 (1H, m), 7.33 (1H, d, J = 8.4 Hz), 7.13−6.97 (9H, m),
4.91 (2H, br), 2.29 (3H, s), 2.27 (3H, s). 13C NMR (100 MHz,
CDCl3): δ 155.9, 147.7, 147.2, 137.0, 136.6, 133.8, 133.1, 130.1, 129.8,
129.3, 129.2, 128.4, 126.7, 125.7, 124.0, 123.3, 122.2, 21.2, 21.1. IR
(KBr, cm−1): 3467, 3284, 3116, 3060, 2917, 2859, 1636, 1606, 1565,
1496, 1430, 1339, 763. HRMS (ESI) calcd for C23H21N2 ([M + H]+):
325.1699. Found: 325.1703.
3,4-Di(thiophen-2-yl)quinolin-2-amine (3x). White solid (35.2 mg,
57%), mp 209−211 °C. 1H NMR (400 MHz, CDCl3): δ 7.71 (1H, d, J
= 8.0 Hz), 7.62−7.56 (2H, m), 7.36−7.32 (2H, m), 7.22−7.18 (1H,
m), 7.03−6.97 (4H, m), 5.10 (2H, br). 13C NMR (100 MHz, CDCl3):
δ 155.7, 147.5, 143.0, 136.5, 136.4, 130.2, 129.5, 129.1, 127.5, 127.1,
127.0, 126.7, 126.5, 125.9, 123.9, 122.9, 117.4. IR (KBr, cm−1): 3447,
3283, 3161, 3095, 2923, 1623, 1605, 1559, 1490, 1409, 1228, 844, 762,
711. HRMS (ESI) calcd for C17H13N2S2 ([M + H]+): 309.0515.
Found: 309.0516.
3,4-Bis(4-fluorophenyl)quinolin-2-amine (3q). White solid (33.8
1
mg, 52%), mp 269−271 °C. H NMR (400 MHz, CDCl3): δ 7.73
(1H, d, J = 8.4 Hz), 7.59−7.55 (1H, m), 7.30 (1H, d, J = 8.4 Hz),
7.19−6.95 (9H, m), 4.79 (2H, br). 13C NMR (100 MHz, CDCl3): δ
162.0 (d, J = 246.6 Hz), 161.9 (d, J = 245.9 Hz), 155.3, 147.3, 147.1,
132.5 (d, J = 3.4 Hz), 132.1 (d, J = 8.1 Hz), 131.8 (d, J = 3.1 Hz),
131.6 (d, J = 8.0 Hz), 129.7, 126.5, 126.0, 123.7, 122.8, 122.5, 115.9
(d, J = 21.4 Hz), 115.0 (d, J = 21.4 Hz). IR (KBr, cm−1): 3500, 3480,
3310, 3160, 3066, 2748, 1890, 1646, 1605, 1565, 1495, 1432, 1218,
1157, 1095, 1015, 828, 767, 741. HRMS (ESI) calcd for C21H15F2N2
([M + H]+): 333.1198. Found: 333.1201.
2,4,5-Triphenylimidazo[1,2-a]quinoline (4a). Yellow solid (40.9
1
mg, 52%), mp 152−153 °C. H NMR (400 MHz, CDCl3): δ 8.29
(1H, s), 7.92 (2H, d, J = 7.5 Hz), 7.83 (1H, d, J = 8.2 Hz), 7.50−7.46
(2H, m), 7.37−7.29 (4H, m), 7.24−7.13 (10H, m). 13C NMR (100
MHz, CDCl3): δ 145.0, 143.9, 136.9, 135.5, 135.3, 133.9, 131.7, 131.2,
131.1, 128.7, 128.5, 128.4, 128.2, 127.9, 127.4, 127.3, 127.1, 127.0,
125.9, 124.3, 124.1, 114.9, 106.9. IR (KBr, cm−1): 3361, 3059, 3023,
2923, 2854, 1595, 1518, 1454, 1421, 1319, 1249, 1163, 1073, 943, 751,
718, 707. HRMS (ESI) calcd for C29H21N2 ([M + H]+): 397.1699.
Found: 397.1699.
3,4-Bis(4-bromophenyl)quinolin-2-amine (3r). White solid (41.5
1
mg, 46%), mp 280−282 °C. H NMR (400 MHz, CDCl3): δ 7.73
(1H, d, J = 8.4 Hz), 7.60−7.56 (1H, m), 7.44−7.41 (4H, m), 7.29−
7.26 (1H, m), 7.19−7.16 (1H, m), 7.03−6.96 (4H, m), 4.71 (2H, br).
13C NMR (100 MHz, CDCl3): δ 154.9, 147.4, 146.6, 135.4, 134.7,
132.2, 132.0, 131.5, 131.3, 129.9, 126.4, 126.1, 123.3, 122.9, 122.1,
122.0, 121.8. IR (KBr, cm−1): 3475, 3291, 3118, 3056, 2740, 1637,
1607, 1568, 1486, 1430, 1387, 1068, 1012, 806, 757, 736. HRMS
(ESI) calcd for C21H15Br2N2 ([M + H]+): 452.9597. Found: 452.9598.
4-Methyl-3-phenylquinolin-2-amine (3s). White solid (29.0 mg,
8-Methyl-2,4,5-triphenylimidazo[1,2-a]quinoline (4c). Yellow
solid (51.8 mg, 63%), mp 141−143 °C. 1H NMR (400 MHz,
CDCl3): δ 8.37 (1H, s), 7.96 (2H, d, J = 8.0 Hz), 7.80 (1H, s), 7.43−
7.36 (5H, m), 7.30−7.13 (10H, m), 2.57 (3H, s). 13C NMR (100
MHz, CDCl3): δ 145.1, 144.3, 139.1, 137.2, 135.6, 135.4, 134.1, 131.9,
131.3, 131.1, 128.53, 128.49, 127.9 (overlapped), 127.5, 127.4, 127.1,
126.0, 125.9, 122.0, 115.0, 106.7, 21.8. IR (KBr, cm−1): 3057, 3026,
2920, 2851, 1685, 1654, 1591, 1559, 1448, 1319, 1071, 1027, 909, 818,
741, 695. HRMS (ESI) calcd for C30H23N2 ([M + H]+): 411.1856.
Found: 411.1855.
7-Methoxy-2,4,5-triphenylimidazo[1,2-a]quinoline (4e). Yellow
solid (49.3 mg, 58%), mp 195−197 °C. 1H NMR (400 MHz,
CDCl3): δ 8.35 (1H, s), 7.96−7.91 (3H, m), 7.40−7.36 (4H, m),
7.32−7.18 (10H, m), 6.96 (1H, d, J = 2.4 Hz), 3.71 (3H, s). 13C NMR
(100 MHz, CDCl3): δ 156.3, 145.0, 143.6, 137.0, 135.6, 135.0, 134.1,
131.3, 131.1, 129.3, 128.5, 128.0, 127.5, 127.4, 127.3, 127.1, 126.6,
126.0, 125.4, 116.9, 116.2, 110.6, 106.8, 21.8. IR (KBr, cm−1): 3122,
3056, 2960, 2853, 1614, 1539, 1514, 1479, 1377, 1293, 1237, 1159,
820, 737, 694. HRMS (ESI) calcd for C30H23N2O ([M + H]+):
427.1805. Found: 427.1807.
1
62%), mp 136−138 °C. H NMR (400 MHz, CDCl3): δ 7.84−7.82
(1H, m), 7.68−7.66 (1H, m), 7.57−7.48 (3H, m), 7.44−7.40 (1H, m),
7.30−7.25 (3H, m), 4.78 (2H, br), 2.32 (3H, s). 13C NMR (100 MHz,
CDCl3): δ 155.5, 146.8, 142.1, 136.8, 129.8, 129.3, 129.1, 128.0, 126.2,
124.1, 124.0, 123.9, 122.3, 15.8. IR (KBr, cm−1): 3462, 3288, 3106,
1636, 1607, 1559, 1424, 1226, 1020, 1002, 857, 756, 707. HRMS
(ESI) calcd for C16H15N2 ([M + H]+): 235.1230. Found: 235.1233.
4-Ethyl-3-phenylquinolin-2-amine (3t). White solid (31.1 mg,
63%), mp 157−159 °C. 1H NMR (400 MHz, CDCl3): δ 7.83 (1H, d, J
= 8.4 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.53−7.39 (4H, m), 7.29−7.23
(3H, m), 4.96 (2H, br), 2.72 (2H, q, J = 7.6 Hz), 1.12 (3H, t, J = 7.6
Hz). 13C NMR (100 MHz, CDCl3): δ 155.8, 147.8, 147.3, 136.5,
129.6, 129.2, 128.9, 127.9, 126.3, 124.0, 123.2, 122.5, 122.1, 22.4, 14.8;
IR (KBr, cm−1): 3468, 3289, 3144, 2971, 2872, 1632, 1583, 1570,
1505, 1424, 1218, 1133, 1006, 848, 757, 705. HRMS (ESI) calcd for
C17H17N2 ([M + H]+): 249.1386. Found: 249.1388.
F
dx.doi.org/10.1021/jo502192b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7-(Tert-butyl)-2,4,5-triphenylimidazo[1,2-a]quinoline (4h). Yellow
solid (53.9 mg, 60%), mp 204−206 °C. 1H NMR (400 MHz, CDCl3):
δ 8.39 (1H, s), 7.98−7.93 (3H, m), 7.69 (1H, dd, J1 = 8.4 Hz, J2 = 2.0
Hz), 7.55 (1H, s), 7.40−7.36 (4H, m), 7.32−7.19 (9H, m), 1.27 (9H,
s). 13C NMR (100 MHz, CDCl3): δ 147.4, 145.1, 144.1, 137.1, 135.7
(overlapped), 134.1, 131.3, 131.2, 130.0, 128.7, 128.5, 127.9, 127.5,
127.4, 127.2, 127.1, 126.3, 126.0, 124.8, 123.9, 114.7, 106.7, 34.7, 31.3.
IR (KBr, cm−1): 3060, 3032, 2955, 2868, 1594, 1558, 1423, 1364,
1314, 1072, 1021, 977, 816, 775, 703. HRMS (ESI) calcd for
C33H29N2 ([M + H]+): 453.2325. Found: 453.2326.
G.; Pyke, S. Org. Biomol. Chem. 2005, 3, 2543. (d) Inglis, S. R.; Jones,
R. K.; Booker, G. W.; Pyke, S. M. Bioorg. Med. Chem. Lett. 2006, 16,
387.
(4) Cheng, Y.; Judd, T. C.; Bartberger, M. D.; Brown, J.; Chen, K.;
Fremeau, R. T., Jr.; Hickman, D.; Hitchcock, 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.
(5) (a) Inglis, S. R.; Stojkoski, C.; Branson, K. M.; Cawthray, J. F.;
Fritz, D.; Wiadrowski, E.; Pyke, S. M.; Booker, G. W. J. Med. Chem.
2004, 47, 5405. (b) Jiang, J.; Hoang, M.; Young, J. 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.; DeVita, R. J. Bioorg. Med. Chem.
2006, 16, 5270. (c) Li, J.-S.; Chen, F.-X.; Shikiya, R.; Marky, L. A.;
Gold, B. J. Am. Chem. Soc. 2005, 127, 12657.
(6) For recent reviews on heterocycle syntheses via C−H activation:
(a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624. (b) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212.
(c) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(d) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta
2012, 45, 31. (e) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J.
A. Acc. Chem. Res. 2012, 45, 814. (f) Zhu, C.; Wang, R.; Falck, J. R.
Chem.Asian J. 2012, 7, 1502. (g) Ackermann, L. Acc. Chem. Res.
2014, 47, 281.
(7) For selected examples on rhodium-catalyzed C−H activation and
annulation with alkynes, see: (a) Umeda, N.; Tsurugi, H.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019. (b) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326.
(c) Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1977.
(d) Song, G.-Y.; Gong, X.; Li, X.-W. J. Org. Chem. 2011, 76, 7583.
(e) Jayakumar, J.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2012, 51, 197. (f) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew.
Chem., Int. Ed. 2013, 52, 5795. (g) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (h) Wang, Y.-F.; Toh,
K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed. 2011, 50, 5927.
(i) Pham, M. V.; Ye, B.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51,
10610. (j) Lee, H.; Sim, Y.-K.; Park, J.-W.; Jun, C.-H. Chem.Eur. J.
2014, 20, 323.
(8) For Pd, see: (a) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem.,
Int. Ed. 2009, 48, 7895. For Rh, see: (b) Umeda, N.; Hirano, K.;
Satoh, T.; Shibata, N.; Sato, H.; Miura, M. J. Org. Chem. 2011, 76, 13.
(c) Huang, J.-R.; Dong, L.; Han, B.; Peng, C.; Chen, Y.-C. Chem.
Eur. J. 2012, 18, 8896. (d) Huang, J.-R.; Zhang, Q.-R.; Qu, C.-H.; Sun,
X.-H.; Dong, L.; Chen, Y.-C. Org. Lett. 2013, 15, 1878. (e) Tan, X.;
Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang, B. J. Am. Chem. Soc.
2012, 134, 16163. (f) Iitsuka, T.; Hirano, K.; Satoh, T.; Miura, M.
2-Phenyl-4,5-di-p-tolylimidazo[1,2-a]quinoline (4p). Yellow solid
1
(65.1 mg, 77%), mp 251−253 °C. H NMR (400 MHz, CDCl3): δ
8.37 (1H, s), 7.99−7.94 (3H, m), 7.59−7.54 (2H, m), 7.40−7.25 (6H,
m), 7.13−7.04 (6H, m), 2.36 (3H, s), 2.31 (3H, s). 13C NMR (100
MHz, CDCl3): δ 145.0, 144.2, 136.7, 136.6, 135.2, 134.1, 132.6, 131.8,
131.2, 131.0, 128.8, 128.7 (overlapped), 128.4, 128.1 (overlapped),
127.4, 126.0, 124.5, 124.3, 114.9, 106.8, 21.30, 21.26. IR (KBr, cm−1):
3152, 3075, 3031, 2918, 1992, 1903, 1596, 1515, 1453, 1420, 1320,
1158, 1111, 1022, 858, 804, 769, 719. HRMS (ESI) calcd for
C31H25N2 ([M + H]+): 425.2012. Found: 425.2009.
5-Ethyl-2,4-diphenylimidazo[1,2-a]quinoline (4t). Yellow solid
1
(52.1 mg, 72%), mp 100−102 °C. H NMR (400 MHz, CDCl3): δ
8.26 (1H, s), 7.98 (1H, d, J = 8.0 Hz), 7.92−7.87 (3H, m), 7.60−7.56
(1H, m), 7.52−7.43 (6H, m), 7.34−7.30 (2H, m), 7.23−7.20 (1H, m),
2.85 (2H, q, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz). 13C NMR (100
MHz, CDCl3): δ 144.7, 144.5, 136.4, 135.4, 134.0, 132.2, 130.1, 128.7,
128.4, 128.1, 128.0, 127.6, 127.3, 126.2, 125.9, 124.5, 122.9, 115.4,
106.4, 22.1, 15.3. IR (KBr, cm−1): 3147, 3056, 2966, 2926, 2869, 1603,
1521, 1451, 1235, 1177, 1068, 1033, 904, 759, 732, 695. HRMS (ESI)
calcd for C25H21N2 ([M + H]+): 349.1699. Found: 349.1703.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all the products and X-
ray structural details of 3s and 3j′. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ruimao@mail.tsinghua.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This project was supported by National Natural Science
Foundation of China (Grants 21473097 and 21273125).
■
Chem.Eur. J. 2014, 20, 385. (g) Seoane, A.; Casanova, N.; Quinones,
̃
REFERENCES
N.; Mascarenas, J.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 7607.
̃
■
(h) Gandeepan, P.; Cheng, C.-H. Org. Lett. 2013, 15, 2084. For Ru,
see: (i) Chidipudi, S. R.; Khan, I.; Lam, H. W. Angew. Chem., Int. Ed.
2012, 51, 12115.
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (b) Barluenga, J.;
Rodriguez, F.; Fananas, F. J. Chem.Asian. J. 2009, 4, 1036.
(c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223.
(9) (a) Li, Y.; Gao, L.; Han, F. Chem. Commun. 2012, 48, 2719.
(2) (a) Andries, K.; Verhasselt, P.; Guillemont, J.; Gcļ mann, H. W.
̌
̌
(b) Spulak, M.; Lubojacky, R.; Senel, P.; Kunes, J.; Pour, M. J. Org.
́
̌
́
H.; Neefs, J.-M.; Winkler, H.; Gestel, J. V.; Timmerman, P.; Zhu, M.;
Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner, S.; Cambau,
E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V. Science 2005, 307, 223.
(b) Rouffet, M.; de Oliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.;
McCammon, J. A.; Cohen, S. M. J. Am. Chem. Soc. 2010, 132, 8232.
(c) Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry, D.
R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.;
Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.;
Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings, A.;
Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Nature
2010, 466, 935. (d) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011,
18, 1488.
Chem. 2010, 75, 241.
(10) Tetrazoles are served as nitrogen source, see: (a) Luo, K.; Meng,
L.; Zhang, Y.; Zhang, X.; Wang, L. Adv. Synth. Catal. 2013, 355, 765.
(b) Zhang, J.; Meng, L.; Li, P.; Wang, L. RSC Adv. 2013, 3, 6807.
(c) Shi, L.; Yang, H.; Jiang, Y.; Fu, H. Adv. Synth. Catal. 2013, 355,
1177.
(11) Tetrazoles are served as direction groups, see: (a) Seki, M. ACS
Catal. 2011, 1, 607. (b) Seki, M.; Nagahama, M. J. Org. Chem. 2011,
76, 10198. (c) Seki, M. Synthesis 2012, 3231. (d) Sadhu, P.; Alla, S. K.;
Punniyamurthy, T. J. Org. Chem. 2013, 78, 6104. (e) Sadhu, P.; Alla, S.
K.; Punniyamurthy, T. J. Org. Chem. 2014, 79, 8541. (f) Diers, E.;
Kumar, N. Y. P.; Mejuch, T.; Marek, I.; Ackermann, L. Tetrahedron
2013, 69, 4445. (g) Wang, L.; Wu, W.; Chen, Q.; He, M. Org. Biomol.
Chem. 2014, 12, 7923.
(3) (a) Alhaider, A. A.; Abdelkader, M. A.; Lien, E. J. J. Med. Chem.
1985, 28, 1394. (b) Campbell, S. F.; Hardstone, J. D.; Palmer, M. J. J.
Med. Chem. 1988, 31, 1031. (c) Inglis, S.; Jones, R.; Fritz, D.; Booker,
G
dx.doi.org/10.1021/jo502192b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(12) Shi, L.; Wang, R.; Yang, H.; Jiang, Y.; Fu, H. RSC Adv. 2013, 3,
6278.
(13) (a) Zheng, L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem. 2012, 77,
5794. (b) Zheng, L.; Hua, R. Chem.−Eur. J. 2014, 20, 2352. (c) Zheng,
L.; Hua, R. J. Org. Chem. 2014, 79, 3930.
(14) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv.
Synth. Catal. 2013, 355, 1741.
(15) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi,
R. Org. Lett. 2004, 6, 2785.
(16) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K.
L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4,
3199.
(17) Xu, X.; Liu, Y.; Park, C.-M. Angew. Chem., Int. Ed. 2012, 51,
9372.
H
dx.doi.org/10.1021/jo502192b | J. Org. Chem. XXXX, XXX, XXX−XXX