Highly Efficient Synthesis of N1-Substituted 1H-Indazoles by DBU-Catalyzed Aza-Michael Reaction of Indazole with Enones

Article abstract of DOI:10.1055/s-0035-1561334

1H-Indazoles are important heterocycles as they are a substantial part in many drugs. Here, a DBU-catalyzed aza-Michael reaction of indazole with enones is described. A variety of aromatic and aliphatic enones are well tolerated and afford the correspondi

Full text of DOI:10.1055/s-0035-1561334

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
J. Yang et al.
Paper
Synthesis
Highly Efficient Synthesis of N1-Substituted 1H-Indazoles by DBU-
Catalyzed Aza-Michael Reaction of Indazole with Enones
Jingya Yang*a
X
Yunfen Baoa
Hongyan Zhoub
X
O
N
DBU (10 mol%)
MeCN, 40 °C
N
Tianyuan Lia
Nana Lia
Zheng Lia
+
N
O
R1
R2
N
H
R1
R2
X = H, NO2
R1, R2 = aryl, heteroaryl, alkyl
22 examples
up to 93% yield
• metal-free catalyst • good substrate tolerance
• high atom-economy • mild reaction conditions
• exclusive N1-regioselectivity
a College of Chemistry and Chemical Engineering, Northwest
Normal University, Lanzhou 730070, P. R. of China
yangjy@nwnu.edu.cn
b College of Science, Gansu Agricultural University, Lanzhou
730070, P. R. of China
Received: 18.11.2015
Accepted after revision: 30.12.2015
Published online: 04.02.2016
gies remain scarce in the literature. In this respect, addi-
tions of indazole, 5-chloroindazole, and 5-nitroindazole to
acrylamide9 and of 4-bromoindazole to ethyl acrylate10 un-
der basic conditions have been demonstrated. Therein,
moderate yields were obtained. Moreover, addition of 5-ni-
troindazole and 6-nitroindazole to Ludartin, a bioactive
natural product, at the exocyclic double bond of the α-
methylene-γ-lactone motif was handily achieved.7c During
the preparation of this manuscript, a microwave-assisted
aza-Michael addition of indazole to tetraethyl ethylidene-
1,1-bisphosphonate was also developed.11 With respect to
enones, however, no systematic work has been described
except for an example with cyclohept-2-enone.12
DOI: 10.1055/s-0035-1561334; Art ID: ss-2015-h0669-op
Abstract 1H-Indazoles are important heterocycles as they are a sub-
stantial part in many drugs. Here, a DBU-catalyzed aza-Michael reaction
of indazole with enones is described. A variety of aromatic and aliphatic
enones are well tolerated and afford the corresponding N1-substituted
1H-indazoles in high to excellent yields with exclusive N1-regioselectivi-
ty. The use of a metal-free catalyst, good substrate tolerance, mild re-
action conditions, and high atom economy make this procedure a di-
rect and facile method for the preparation of N1-substituted 1H-
indazoles.
Key words Michael addition, indazoles, enones, catalysis, regioselec-
tivity
NO2
N
N
N
The atom-economical aza-Michael reaction has shown
great potential for constructing C–N bonds. The products,
β-amino carbonyl compounds, represent versatile building
blocks for the synthesis of β-amino acids, β-lactams, natu-
ral products, and pharmaceuticals.1 While this reaction has
been widely explored,2 the catalytic addition of aromatic N-
heterocycles with decreased nucleophilicity still presents a
significant challenge in organic synthesis.3
N
O
N
O
O
O
O
N
OH
Cl
O
O
N
antimicrobial
OH
anticancer
CRTH2 antagonist
Indazole and its derivatives, a typical class of aromatic
N-heterocycles, have sparked significant concern in syn-
thetic and medicinal chemistry due to their diverse biologi-
cal activities.4,5 Furthermore, diverse heterocyclic struc-
tures could be accessed from indazole-derived N-heterocy-
clic carbenes.6 Among indazoles, N1-substituted 1H-
indazoles are widely used as anticancer, anti-inflammatory,
anti-HIV, and antimicrobial drugs (Figure 1).4,7
Figure 1 Representative examples of pharmacologically active 1H-in-
dazoles
In addition, redox–isomerization of alkynols followed
by aza-Michael reaction with indazole can be seen as a vari-
ant of the direct aza-Michael reaction of indazole with
enones. Han reported the reaction of ethyl 4-hydroxy-4-
phenylbut-2-ynoate with four substituted 1H-indazoles in
CH2Cl2 to afford the desired products in 60–76% yield, yet
more than 1 equivalent of DBU was needed.13 When these
conditions were employed in the reaction of propargyl al-
cohols with N-heterocycles, however, only 49% yield was
Generally, the synthesis of N1-substituted 1H-indazoles
involves a cyclization procedure from miscellaneous start-
ing materials.4a,b,8 Beyond that, the aza-Michael reaction of
1H-indazoles is undoubtedly a potential and alternative
strategy to this target. Unfortunately, general methodolo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
J. Yang et al.
Paper
Synthesis
obtained.14 Recently, the Sahoo group demonstrated a con-
venient approach to 3-(1H-indazol-1-yl)-1,3-diphenylpro-
pan-1-one (2a) from 1,3-diphenylprop-2-yn-1-ol and 1H-
indazole in the presence of 1 equivalent of Cs2CO3 in tolu-
ene at 70 °C (Scheme 1, top).14 Although 92% yield was ob-
tained, the high cost of Cs2CO3 and the very large amounts
of metal-contaminated waste limit the application of such a
method. In addition, only one example aimed at N1-substi-
tuted indazoles was investigated. Therefore, further devel-
opment of a novel protocol with metal-free, direct, and effi-
cient features under mild conditions is still in demand.
Herein, we disclose a metal-free aza-Michael reaction of
indazole with a wide range of enones under mild condi-
tions (Scheme 1, bottom). Only 10 mol% of DBU is required
to obtain the target products in good to excellent isolated
yields. This investigation opens up the possibility of the di-
rect synthesis of N1-substituted 1H-indazole derivatives.
three hours with no influence on the yield (Table 1, entry
22). However, further increasing the reaction temperature
resulted in an inferior result (Table 1, entry 23). When the
catalyst loading was decreased to 5 mol%, the product was
also achieved in unfavorable yield (Table 1, entry 24). Thus,
the best conditions for this reaction had been established,
10 mol% of DBU as catalyst in acetonitrile at 40 °C.
Table 1 Optimization of the Reaction Conditionsa
O
N
catalyst
N
+
N
O
solvent
N
Ph
Ph
temp, time
H
Ph
Ph
1a
2a
Entry Catalyst
(mol%)
Solvent
Temp
(°C)
Time (h) Isolated
yield (%)
Sahoo's work
1
2
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhMe
hexane
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
20
24
24
6
0
0
OH
Na2CO3 (10)
K2CO3 (10)
Cs2CO3 (10)
KOAc (10)
LiCl (10)
Cs2CO3 (1 equiv)
N
N
+
3
trace
80
0
Ph
N
O
N
toluene, 70 °C
H
4
Ph
Ph
Ph
• redox–isomerization conjugate addition
• stoichiometric Cs2CO3
5
(only 1 example)
6
0
This work
7
DBU (10)
DMAP (10)
TBAF (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (10)
DBU (5)
90
0
8
24
24
6
O
N
N
DBU (10 mol%)
R2
MeCN, 40 °C
9
0
N
O
+
R1
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
trace
48
0
R1
(21 examples)
R2
R1 = aryl, heteroaryl, alkyl
2 = aryl, heteroaryl, alkyl
6
R
• aza-Michael reaction
• metal-free catalyst
• catalytic amount of DBU
1,4-dioxane
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
60
40
6
6
13
50
70
37
0
CH2Cl2
CHCl3
DCE
6
Scheme 1 Strategies for the synthesis of β-(1H-indazol-1-yl) ketones
6
6
Initially, chalcone (1a) was used as a model substrate to
optimize the reaction conditions (Table 1). In the absence of
catalyst, none of the desired product 2a was obtained (Ta-
ble 1, entry 1). Then, we screened several alkali metal salts,
but only Cs2CO3 showed effective activity and gave the
product in 80% yield after 20 hours (Table 1, entries 2–6).
Considering the high cost of Cs2CO3, metal waste, and still
unsatisfactory results, we turned our attention to commer-
cial organic bases (Table 1, entries 7–9). While DMAP and
TBAF did not show catalytic activity, DBU promoted the re-
action efficiently to furnish the desired product 2a in excel-
lent yield after six hours (Table 1, entry 7). DBU appears to
be a superior catalyst than Cs2CO3 in this reaction. Encour-
aged by these results, we further optimized the reaction
conditions. Then, the effect of solvent on the reaction was
investigated (Table 1, entries 10–21). Unfortunately, all of
the tested solvents afforded the product 2a in less-than-
desirable yields. In addition, increasing the reaction tem-
perature to 40 °C notably shortened the reaction time to
DMF
6
DMSO
MeOH
EtOH
6
44
trace
0
6
6
Et2O
6
55
90
80
80
MeCN
MeCN
MeCN
3
2
3
a Reaction conditions: 1a (0.1 mmol), 1H-indazole (0.12 mmol), solvent (1.5
mL).
With the optimized reaction conditions in hand, the
substrate scope of enones was examined (Table 2). A variety
of chalcone derivatives with different substituents were
subjected to the optimal reaction conditions, and afforded
the corresponding N1-substituted 1H-indazoles 2a–2q in
good to excellent yields (Table 2, entries 1–17). In detail,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
J. Yang et al.
Paper
Synthesis
when R1 was 4-nitrophenyl or benzo[d][1,3]dioxol-5-yl, the
desired compounds 2i and 2q were obtained in slightly
lower yields than those of other substituted phenyl deriva-
tives (Table 2, entries 9 and 17). Furthermore, the het-
eroaryl-substituted enones were well tolerated under the
optimal conditions (products 2r, 2s). To our delight, aliphat-
ic enones were viable and gave the target products 2t, 2u in
acceptable yields (Table 2, entries 20 and 21). In addition,
the structure of product 2s was confirmed by X-ray crystal-
lographic analysis (Figure 2),15 which further established
the N1-regioselectivity of this reaction. It should be noted
that no N2-adducts were observed in all cases.
Table 2 DBU-Catalyzed Aza-Michael Reaction of Indazole with Enonesa
O
DBU (10 mol%)
MeCN, 40 °C
N
N
N
O
+
Figure 2 X-ray crystal structure of 2s
R1
R2
N
H
R1
R2
1
2
troindazole could be successfully transformed into the cor-
responding N1-substituted 5-nitro-1H-indazole 3a in 87%
yield (Scheme 2).
Entry R1
R2
Time Product Isolated
(h)
yield (%)
1
2
Ph
4-MeC6H4
Ph
4
4
5
4
4
4
3
5
3
4
3
4
4
5
4
3
4
5
4
3
3
2a
2b
2c
2d
2e
2f
90
89
80
88
85
83
80
89
66
90
90
81
93
88
80
90
76
70
89
75
73
O2N
Ph
O2N
+
O
3
4-MeOC6H4
2-MeOC6H4
2-ClC6H4
4-FC6H4
4-ClC6H4
4-F3CC6H4
4-O2NC6H4
Ph
Ph
DBU (10 mol%)
N
N
O
4
Ph
MeCN, 40 °C, 5 h
N
Ph
Ph
N
5
Ph
1a
H
Ph
3a, 87%
Ph
6
Ph
7
Ph
2g
2h
2i
Scheme 2 Aza-Michael addition of 5-nitroindazole to chalcone
8
Ph
9
Ph
In summary, we have developed an efficient and conve-
nient method for the aza-Michael reaction of indazole with
enones using 10 mol% of DBU as catalyst. The approach
shows good functional group tolerance, in which aryl, het-
eroaryl, and alkyl enones, as well as 5-nitroindazole, are
suitable substrates. Other merits of this strategy include
use of a metal-free catalyst, high atom economy, high yield,
and exclusive N1-regioselectivity. The presented reaction
provides a direct, complementary, and more attractive
pathway than previous methods for the synthesis of N1-
substituted 1H-indazoles. The development of asymmetric
variants of the current reaction is now under investigation.
10
11
12
13
14
15
16
17
18
19
20
21
4-MeC6H4
4-ClC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-MeOC6H4
2j
Ph
2k
2l
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
2,4-Cl2C6H3
2m
2n
2o
2p
2q
2r
benzo[d][1,3]dioxol-5-yl Ph
furan-2-yl
Ph
Ph
thiophen-2-yl
2s
2t
n-butyl
n-pentyl
Me
Me
2u
1H NMR and 13C NMR spectra were recorded on a Varian Mercury-400
Plus or Agilent Technologies DD2 (600 MHz) spectrometer. IR spectra
were recorded on an Alpha Centauri FTIR spectrometer. High-resolu-
tion mass spectra (HRMS) were performed on a Thermo Orbitrap
Elite instrument with an ESI source. The X-ray single-crystal diffrac-
tion was performed on a Bruker APEX II CCD instrument. Melting
points were measured on an XT4A apparatus (uncorrected). Reagents
and solvents were commercially available, and were used without
a Reaction conditions: enone 1 (1.0 mmol), 1H-indazole (1.2 mmol), DBU
(10 mol%), MeCN (3 mL), 40 °C.
To further explore the substrate scope, the reaction be-
tween 5-nitroindazole and chalcone (1a) was also exam-
ined. Under the standard conditions, chalcone and 5-ni-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
J. Yang et al.
Paper
Synthesis
further purification. The reaction mixtures were purified by column
chromatography over silica gel (PE–EtOAc).
3-(1H-Indazol-1-yl)-3-(2-methoxyphenyl)-1-phenylpropan-1-one
(2d)
White solid; yield: 314 mg (88%); mp 148–150 °C.
N1-Substituted 1H-Indazoles 2, 3a; General Procedure
IR (KBr): 3064, 2941, 2844, 1682, 1597, 1495, 1458, 1368, 1247, 1022,
749, 684 cm–1
.
Enone 1 (1.0 mmol), 1H-indazole or 5-nitro-1H-indazole (1.2 mmol),
DBU (15.2 mg, 0.1 mmol), and MeCN (3.0 mL) were sequentially
charged into a dry Schlenk tube. The reaction mixture was stirred at
40 °C until reaction completion (monitored by TLC), then cooled to
r.t., diluted with EtOAc (3 mL), and washed with brine (3 × 4 mL). The
aqueous phase was extracted with EtOAc (4 mL). The organic layer
was combined, dried with anhydrous Na2SO4, then concentrated un-
der reduced pressure. The residue was purified by flash column chro-
matography on silica gel (PE–EtOAc, 20:1, unless otherwise noted) to
afford the pure products 2 and 3a.
1H NMR (600 MHz, CDCl3): δ = 8.00–7.97 (m, 3 H), 7.67 (d, J = 8.4 Hz, 1
H), 7.57–7.52 (m, 2 H), 7.45–7.41 (m, 2 H), 7.34–7.31 (m, 1 H), 7.23–
7.20 (m, 1 H), 7.11–7.08 (m, 1 H), 7.04–7.02 (m, 1 H), 6.93–6.89 (m, 2
H), 6.84–6.81 (m, 1 H), 4.65 (dd, J = 17.4, 10.2 Hz, 1 H), 3.91 (s, 3 H),
3.63 (dd, J = 17.4, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 196.8, 155.7, 139.7, 136.7, 133.0,
132.8, 129.2, 128.7, 128.4 (2 C), 128.1 (2 C), 127.2, 126.0, 124.0, 120.8,
120.6, 120.5, 110.3, 109.8, 55.4, 50.9, 42.7.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2O2: 357.1598; found:
3-(1H-Indazol-1-yl)-1,3-diphenylpropan-1-one (2a)14
White solid; yield: 294 mg (90%); mp 105–107 °C.
357.1610.
3-(2-Chlorophenyl)-3-(1H-indazol-1-yl)-1-phenylpropan-1-one
(2e)
IR (KBr): 3057, 2920, 2851, 1686, 1608, 1494, 1449, 1359, 1204, 750,
695 cm–1
.
Pale yellow solid; yield: 307 mg (85%); mp 109–110 °C.
1H NMR (600 MHz, CDCl3): δ = 8.00–7.99 (m, 3 H), 7.68 (d, J = 7.8 Hz, 1
H), 7.55–7.51 (m, 2 H), 7.46–7.42 (m, 2 H), 7.35–7.33 (m, 3 H), 7.30–
7.27 (m, 2 H), 7.25–7.21 (m, 1 H), 7.13–7.10 (m, 1 H), 6.47 (dd, J = 8.4,
4.8 Hz, 1 H), 4.68 (dd, J = 17.4, 8.4 Hz, 1 H), 3.76 (dd, J = 17.4, 4.8 Hz, 1
H).
13C NMR (150 MHz, CDCl3): δ = 196.7, 140.9, 139.7, 136.6, 133.3,
133.1, 128.8 (2 C), 128.6 (2 C), 128.2 (2 C), 127.8, 126.6 (2 C), 126.4,
124.3, 120.9, 120.8, 109.6, 57.5, 44.4.
IR (KBr): 3063, 2926, 2854, 1679, 1595, 1465, 1402, 1361, 1262, 1212,
1018, 833, 756, 619 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.00–7.99 (m, 3 H), 7.68 (d, J = 7.8 Hz, 1
H), 7.57–7.53 (m, 2 H), 7.46–7.43 (m, 2 H), 7.40 (d, J = 7.8 Hz, 1 H),
7.37–7.34 (m, 1 H), 7.20–7.17 (m, 2 H), 7.15–7.11 (m, 2 H), 6.94 (dd,
J = 9.6, 3.6 Hz, 1 H), 4.72 (dd, J = 17.4, 9.6 Hz, 1 H), 3.61 (dd, J = 17.4,
3.6 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 196.1, 139.8, 138.6, 136.5, 133.30,
133.27, 131.9, 129.6, 129.0, 128.6 (2 C), 128.3, 128.2 (2 C), 127.5,
126.5, 124.3, 121.0, 120.9, 109.7, 54.0, 42.9.
3-(1H-Indazol-1-yl)-1-phenyl-3-(p-tolyl)propan-1-one (2b)
Pale yellow solid; yield: 303 mg (89%); mp 109–110 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H18ClN2O: 361.1102; found:
361.1113.
IR (KBr): 3051, 2982, 2942, 2923, 2859, 1678, 1595, 1498, 1448, 1374,
1205, 824, 744, 687 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.00–7.97 (m, 3 H), 7.67 (d, J = 7.8 Hz, 1
H), 7.57–7.51 (m, 2 H), 7.46–7.43 (m, 2 H), 7.35–7.32 (m, 1 H), 7.25 (d,
J = 9.0 Hz, 2 H), 7.12–7.08 (m, 3 H), 6.43 (dd, J = 8.4, 4.8 Hz, 1 H), 4.64
(dd, J = 17.4, 8.4 Hz, 1 H), 3.75 (dd, J = 17.4, 4.8 Hz, 1 H), 2.28 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 196.8, 139.6, 137.8, 137.5, 136.6,
133.3, 133.0, 129.4 (2 C), 128.6 (2 C), 128.2 (2 C), 126.6 (2 C), 126.3,
124.3, 120.9, 120.7, 109.6, 57.3, 44.3, 21.0.
3-(4-Fluorophenyl)-3-(1H-indazol-1-yl)-1-phenylpropan-1-one
(2f)
Eluent: PE–EtOAc, 15:1; white solid; yield: 286 mg (83%); mp 115–
117 °C.
IR (KBr): 3055, 2924, 2868, 1683, 1602, 1508, 1448, 1405, 1223, 1164,
832, 746, 689 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.00–7.98 (m, 3 H), 7.68 (d, J = 8.4 Hz, 1
H), 7.57–7.54 (m, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.45 (m, 2 H), 7.37–
7.33 (m, 3 H), 7.13 (m, 1 H), 6.98–6.95 (m, 2 H), 6.44 (dd, J = 8.4, 5.4
Hz, 1 H), 4.60 (dd, J = 17.4, 8.4 Hz, 1 H), 3.78 (dd, J = 17.4, 5.4 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 196.5, 163.0, 161.4, 139.6, 136.6 (d, J =
3.2 Hz), 136.5, 133.4 (d, J = 15.6 Hz), 128.6 (2 C), 128.4 (d, J = 8.1 Hz, 2
C), 128.2 (2 C), 126.5, 124.3, 120.9 (d, J = 12.3 Hz, 2 C), 115.7, 115.5,
109.4, 56.8, 44.4.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2O: 341.1648; found:
341.1649.
3-(1H-Indazol-1-yl)-3-(4-methoxyphenyl)-1-phenylpropan-1-one
(2c)
Yellow solid; yield: 285 mg (80%); mp 121–123 °C.
IR (KBr): 3061, 2996, 2908, 2834, 1686, 1610, 1512, 1458, 1367, 1303,
1246, 1021, 829, 758, 689 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C22H18FN2O: 345.1398; found:
345.1398.
1H NMR (600 MHz, CDCl3): δ = 8.01–7.97 (m, 3 H), 7.67 (d, J = 7.8 Hz, 1
H), 7.56–7.51 (m, 2 H), 7.45–7.42 (m, 2 H), 7.35–7.32 (m, 1 H), 7.30 (d,
J = 8.4 Hz, 2 H), 7.12–7.09 (m, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.41 (dd,
J = 8.4, 5.4 Hz, 1 H), 4.60 (dd, J = 17.4, 8.4 Hz, 1 H), 3.76 (dd, J = 17.4,
5.4 Hz, 1 H), 3.74 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 196.8, 159.1, 139.5, 136.7, 133.3,
133.0, 132.9, 128.6 (2 C), 128.2 (2 C), 127.9 (2 C), 126.3, 124.3, 120.9,
120.8, 114.1 (2 C), 109.6, 57.0, 55.2, 44.4.
3-(4-Chlorophenyl)-3-(1H-indazol-1-yl)-1-phenylpropan-1-one
(2g)
White solid; yield: 289 mg (80%); mp 100–102 °C.
IR (KBr): 3054, 2919, 2856, 1682, 1589, 1491, 1447, 1406, 1364, 1205,
828, 743, 690 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2O2: 357.1598; found:
357.1610.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
J. Yang et al.
Paper
Synthesis
1H NMR (600 MHz, CDCl3): δ = 8.00–7.98 (m, 3 H), 7.69 (d, J = 7.8 Hz, 1
H), 7.57–7.54 (m, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.47–7.43 (m, 2 H),
7.37–7.34 (m, 1 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H),
7.14–7.11 (m, 1 H), 6.43 (dd, J = 7.8, 6.0 Hz, 1 H), 4.60 (dd, J = 17.4, 7.8
Hz, 1 H), 3.77 (dd, J = 17.4, 6.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 195.6, 140.7, 139.8, 139.7, 134.9,
133.1, 129.7 (2 C), 128.9 (2 C), 128.8 (2 C), 127.9, 126.6 (2 C), 126.4,
124.3, 121.0, 120.9, 109.5, 57.6, 44.3.
1-(4-Chlorophenyl)-3-(1H-indazol-1-yl)-3-phenylpropan-1-one
(2k)
White solid; yield: 325 mg (90%); mp 106–108 °C.
IR (KBr): 3057, 2920, 2852, 1684, 1585, 1491, 1400, 1205, 829, 739,
700 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2 H),
7.68 (d, J = 7.8 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 2 H),
7.35–7.32 (m, 3 H), 7.30–7.27 (m, 2 H), 7.25–7.22 (m, 1 H), 7.13–7.09
(m, 1 H), 6.43 (dd, J = 9.0, 4.8 Hz, 1 H), 4.65 (dd, J = 17.4, 9.0 Hz, 1 H),
3.67 (dd, J = 17.4, 4.8 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H18ClN2O: 361.1102; found:
361.1113.
13C NMR (150 MHz, CDCl3): δ = 195.6, 140.8, 139.8, 139.7, 134.9,
133.1, 129.7 (2 C), 128.9 (2 C), 128.8 (2 C), 127.9, 126.6 (2 C), 126.4,
124.4, 121.0, 120.9, 109.5, 57.6, 44.3.
3-(1H-Indazol-1-yl)-1-phenyl-3-(4-(trifluoromethyl)phenyl)pro-
pan-1-one (2h)
White solid; yield: 351 mg (89%); mp 134–136 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H18ClN2O: 361.1102; found:
IR (KBr): 3062, 2914, 2865, 1682, 1452, 1321, 1164, 1114, 835, 766,
361.1113.
738, 690, 610 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.02–7.99 (m, 3 H), 7.70 (d, J = 7.8 Hz, 1
H), 7.58–7.53 (m, 3 H), 7.50–7.44 (m, 5 H), 7.38–7.35 (m, 1 H), 7.16–
7.12 (m, 1 H), 6.52 (dd, J = 7.8, 6.0 Hz, 1 H), 4.64 (dd, J = 17.4, 7.8 Hz, 1
H), 3.81 (dd, J = 17.4, 6.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 196.4, 139.6, 139.4, 136.5, 133.7,
133.4 (d, J = 6.2 Hz), 128.9 (2 C), 128.7 (2 C), 128.2 (d, J = 10.4 Hz, 2 C),
126.6, 124.4, 121.1 (d, J = 7.4 Hz, 2 C), 109.4, 56.9, 44.3.
3-(1H-Indazol-1-yl)-1-(4-nitrophenyl)-3-phenylpropan-1-one (2l)
Pale yellow solid; yield: 301 mg (81%); mp 158–160 °C.
IR (KBr): 3072, 2915, 2862, 1693, 1604, 1518, 1460, 1408, 1347, 1209,
854, 748, 702 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.25 (d, J = 8.4 Hz, 2 H), 8.11 (d, J = 9.0
Hz, 2 H), 7.92 (s, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 9.0 Hz, 1 H),
7.31–7.25 (m, 5 H), 7.25–7.22 (m, 1 H), 7.10–7.07 (m, 1 H), 6.38 (dd,
J = 9.0, 4.2 Hz, 1 H), 4.73 (dd, J = 17.4, 9.0 Hz, 1 H), 3.62 (dd, J = 17.4,
4.2 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C23H18F3N2O: 395.1366; found:
395.1369.
13C NMR (150 MHz, CDCl3): δ = 195.6, 150.4, 141.1, 140.4, 139.6,
133.1, 129.3 (2 C), 128.9 (2 C), 128.1 (2 C), 126.5, 126.4, 124.4, 123.8
(2 C), 121.0, 120.9, 109.5, 57.7, 44.9.
3-(1H-Indazol-1-yl)-3-(4-nitrophenyl)-1-phenylpropan-1-one (2i)
Yellow solid; yield: 245 mg (66%); mp 149–151 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H18N3O3: 372.1343; found:
372.1358.
IR (KBr): 3063, 2920, 2851, 1681, 1601, 1520, 1347, 1219, 855, 746,
694 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.14 (d, J = 9.0 Hz, 2 H), 8.04 (s, 1 H),
8.00–7.98 (m, 2 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.59–7.56 (m, 1 H), 7.53
(d, J = 9.0 Hz, 2 H), 7.49–7.45 (m, 3 H), 7.39–7.36 (m, 1 H), 7.17–7.14
(m, 1 H), 6.56 (dd, J = 7.2, 6.0 Hz, 1 H), 4.62 (dd, J = 18.0, 7.2 Hz, 1 H),
3.86 (dd, J = 18.0, 6.0 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 195.9, 147.9, 147.5, 139.7, 136.2,
133.9, 133.7, 128.7 (2 C), 128.2 (2 C), 127.8 (2 C), 126.8, 124.4, 124.0
(2 C), 121.3, 121.2, 109.1, 56.7, 44.1.
3-(1H-Indazol-1-yl)-1,3-di(p-tolyl)propan-1-one (2m)
Pale yellow solid; yield: 330 mg (93%); mp 101–103 °C.
IR (KBr): 3054, 2919, 2862, 1674, 1605, 1460, 1408, 1362, 1262, 813,
752 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.90 (d, J = 8.4 Hz, 2 H),
7.68–7.64 (m, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.35–7.32 (m, 1 H), 7.27–
7.23 (m, 4 H), 7.11–7.08 (m, 3 H), 6.43 (dd, J = 8.4, 4.8 Hz, 1 H), 4.60
(dd, J = 18.0, 8.4 Hz, 1 H), 3.73 (dd, J = 18.0, 4.8 Hz, 1 H), 2.39 (s, 3 H),
2.27 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H18N3O3: 372.1343; found:
372.1358.
13C NMR (150 MHz, CDCl3): δ = 196.4, 144.1, 139.6, 137.9, 137.5,
134.2, 133.0, 129.4 (2 C), 129.3 (2 C), 128.4 (2 C), 126.6 (2 C), 126.3,
124.3, 120.9, 120.7, 109.6, 57.3, 44.2, 21.6, 21.0.
3-(1H-Indazol-1-yl)-3-phenyl-1-(p-tolyl)propan-1-one (2j)
Pale yellow solid; yield: 307 mg (90%); mp 124–126 °C.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O: 355.1805; found:
355.1805.
IR (KBr): 3032, 2917, 2849, 1676, 1607, 1494, 1456, 1403, 1360, 1267,
1174, 823, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.90 (d, J = 7.8 Hz, 2 H),
7.68 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.36–7.32 (m, 3 H),
7.30–7.27 (m, 2 H), 7.25–7.21 (m, 3 H), 7.12–7.09 (m, 1 H), 6.46 (dd,
J = 8.4, 4.8 Hz, 1 H), 4.63 (dd, J = 17.4, 8.4 Hz, 1 H), 3.74 (dd, J = 17.4,
4.8 Hz, 1 H), 2.40 (s, 3 H).
3-(1H-Indazol-1-yl)-1-(4-methoxyphenyl)-3-(p-tolyl)propan-1-
one (2n)
Eluent: PE–EtOAc, 15:1; white solid; yield: 326 mg (88%); mp 126–
128 °C.
13C NMR (150 MHz, CDCl3): δ = 196.8, 139.6, 137.8, 137.5, 136.7,
133.3, 133.0, 129.4 (2 C), 128.6 (2 C), 128.2 (2 C), 126.6 (2 C), 126.3,
124.3, 120.9, 120.7, 109.6, 57.3, 44.3, 21.0.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2O: 341.1648; found:
341.1649.
IR (KBr): 3028, 2968, 2927, 2841, 1672, 1596, 1509, 1456, 1368, 1255,
1167, 1020, 837, 748 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.98–7.95 (m, 3 H), 7.68–7.63 (m, 1 H),
7.52–7.50 (m, 1 H), 7.34–7.30 (m, 1 H), 7.23 (d, J = 7.2 Hz, 2 H), 7.10–
7.06 (m, 3 H), 6.90–6.88 (m, 2 H), 6.41 (dd, J = 8.4, 5.4 Hz, 1 H), 4.56
(dd, J = 17.4, 8.4 Hz, 1 H), 3.84 (s, 3 H), 3.70 (dd, J = 17.4, 5.4 Hz, 1 H),
2.26 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. Yang et al.
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13C NMR (150 MHz, CDCl3): δ = 195.2, 163.7, 139.6, 138.0, 137.4,
132.9, 130.5 (2 C), 129.8, 129.4 (2 C), 126.6 (2 C), 126.3, 124.3, 120.9,
120.7, 113.7 (2 C), 109.6, 57.4, 55.4, 43.9, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O2: 371.1754; found:
371.1767.
IR (KBr): 3059, 2907, 1682, 1597, 1446, 1417, 1357, 1301, 1222, 1173,
831, 753, 717, 687 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.98–7.94 (m, 3 H), 7.66–7.60 (m, 2 H),
7.54–7.51 (m, 1 H), 7.42–7.36 (m, 3 H), 7.13–7.09 (m, 2 H), 6.98–6.96
(m, 1 H), 6.86–6.84 (m, 1 H), 6.71 (dd, J = 8.4, 4.8 Hz, 1 H), 4.56 (dd, J =
18.0, 8.4 Hz, 1 H), 3.88 (dd, J = 18.0, 4.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 196.3, 143.7, 139.6, 136.4, 133.8,
133.5, 128.7 (2 C), 128.3 (2 C), 126.7, 126.6, 125.2, 125.1, 124.2, 121.1,
121.0, 109.5, 53.2, 45.0.
1-(4-Chlorophenyl)-3-(1H-indazol-1-yl)-3-(p-tolyl)propan-1-one
(2o)
Eluent: PE–EtOAc, 15:1; white solid; yield: 300 mg (80%); mp 147–
148 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2O2: 317.1285; found:
317.1289.
IR (KBr): 3054, 2918, 2862, 1683, 1587, 1463, 1401, 1207, 1089, 830,
742 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.95–7.91 (m, 3 H), 7.66 (d, J = 8.4 Hz, 1
H), 7.48 (d, J = 9.0 Hz, 1 H), 7.41–7.40 (m, 2 H), 7.33–7.30 (m, 1 H),
7.22 (d, J = 8.4 Hz, 2 H), 7.11–7.07 (m, 3 H), 6.38 (dd, J = 8.4, 4.8 Hz, 1
H), 4.61 (dd, J = 17.4, 8.4 Hz, 1 H), 3.65 (dd, J = 17.4, 4.8 Hz, 1 H), 2.27
(s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 195.7, 139.7, 139.6, 137.7, 137.6,
135.0, 133.0, 129.7 (2 C), 129.4 (2 C), 128.9 (2 C), 126.5 (2 C), 126.3,
124.3, 120.9, 120.8, 109.5, 57.3, 44.3, 21.0.
3-(1H-Indazol-1-yl)-3-phenyl-1-(thiophen-2-yl)propan-1-one (2s)
White solid; yield: 296 mg (89%); mp 131–133 °C.
IR (KBr): 3082, 2922, 1657, 1613, 1494, 1452, 1410, 1357, 1274, 1214,
850, 744, 698 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.80 (d, J = 4.8 Hz, 1 H),
7.66 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 4.8 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H),
7.32–7.19 (m, 6 H), 7.10–7.07 (m, 2 H), 6.41 (dd, J = 8.4, 4.8 Hz, 1 H),
4.54 (dd, J = 16.8, 8.4 Hz, 1 H), 3.71 (dd, J = 16.8, 4.8 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 189.4, 143.8, 140.5, 139.6, 134.0,
133.2, 132.4, 128.7 (2 C), 128.1, 127.8, 126.6 (2 C), 126.3, 124.2, 120.9,
120.8, 109.5, 57.4, 44.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H20ClN2O: 375.1259; found:
375.1271.
3-(2,4-Dichlorophenyl)-3-(1H-indazol-1-yl)-1-(3-methoxyphe-
nyl)propan-1-one (2p)
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2OS: 333.1056; found:
333.1057.
White solid; yield: 383 mg (90%); mp 104–106 °C.
IR (KBr): 3072, 2940, 2840, 1686, 1580, 1468, 1362, 1260, 1020, 785,
4-(1H-Indazol-1-yl)octan-2-one (2t)
742, 686 cm–1
.
Yellow liquid; yield: 183 mg (75%).
1H NMR (600 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H),
7.58 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 1 H), 7.46–7.44 (m, 1 H),
7.41 (d, J = 2.4 Hz, 1 H), 7.38–7.33 (m, 2 H), 7.16–7.08 (m, 4 H), 6.86
(dd, J = 9.6, 3.6 Hz, 1 H), 4.63 (dd, J = 18.0, 9.6 Hz, 1 H), 3.80 (s, 3 H),
3.58 (dd, J = 18.0, 3.6 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 195.6, 159.8, 139.7, 137.7, 137.1,
134.2, 133.6, 132.7, 129.6, 129.4, 129.2, 127.8, 126.7, 124.3, 121.1,
120.9, 120.8, 120.1, 112.2, 109.4, 55.4, 53.5, 42.9.
IR (neat): 3059, 2957, 2930, 2862, 1716, 1615, 1497, 1462, 1423,
1363, 1166, 1012 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H),
7.52 (d, J = 7.2 Hz, 1 H), 7.39–7.35 (m, 1 H), 7.13–7.10 (m, 1 H), 5.07–
5.02 (m, 1 H), 3.35 (dd, J = 17.4, 7.8 Hz, 1 H), 2.94 (dd, J = 17.4, 5.4 Hz,
1 H), 2.09–2.03 (m, 1 H), 2.02 (s, 3 H), 1.84–1.78 (m, 1 H), 1.29–1.18
(m, 2 H), 1.14–1.07 (m, 1 H), 0.95–0.87 (m, 1 H), 0.77 (t, J = 7.4 Hz, 3
H).
HRMS (ESI): m/z [M + H]+ calcd for C23H19Cl2N2O2: 425.0818; found:
425.0837.
13C NMR (150 MHz, CDCl3): δ = 206.3, 140.1, 133.4, 126.2, 123.4,
120.8, 120.5, 109.3, 53.9, 48.4, 35.1, 30.5, 28.2, 22.2, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N2O: 245.1648; found:
245.1657.
3-(Benzo[d][1,3]dioxol-5-yl)-3-(1H-indazol-1-yl)-1-phenylpropan-
1-one (2q)
Yellow solid; yield: 282 mg (76%); mp 159–161 °C.
4-(1H-Indazol-1-yl)nonan-2-one (2u)
IR (KBr): 3054, 2920, 2862, 1728, 1689, 1586, 1489, 1402, 1240, 1092,
Yellow liquid; yield: 189 mg (73%).
1032, 809, 769, 746 cm–1
.
IR (neat): 3059, 2952, 2929, 2859, 1716, 1615, 1462, 1423, 1364,
1H NMR (600 MHz, CDCl3): δ = 7.96–7.92 (m, 3 H), 7.67 (d, J = 7.8 Hz, 1
H), 7.49 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.36–7.32 (m, 1 H),
7.13–7.09 (m, 1 H), 6.86–6.82 (m, 2 H), 6.71 (d, J = 8.4 Hz, 1 H), 6.32
(dd, J = 8.4, 4.8 Hz, 1 H), 5.92–5.86 (m, 3 H), 4.57 (dd, J = 17.4, 8.4 Hz, 1
H), 3.66 (dd, J = 17.4, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 195.5, 147.9, 147.2, 139.8, 139.5,
134.9, 134.5, 133.1, 129.6 (2 C), 128.9 (2 C), 126.4, 124.3, 120.9, 120.8,
120.0, 109.4, 108.2, 107.1, 101.1, 57.3, 44.3.
1165, 1014 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1 H),
7.52 (d, J = 8.4 Hz, 1 H), 7.38–7.36 (m, 1 H), 7.13–7.10 (m, 1 H), 5.08–
5.02 (m, 1 H), 3.35 (dd, J = 17.4, 8.4 Hz, 1 H), 2.94 (dd, J = 17.4, 5.4 Hz,
1 H), 2.08–2.03 (m, 1 H), 2.02 (s, 3 H), 1.83–1.76 (m, 1 H), 1.23–1.07
(m, 5 H), 0.98–0.89 (m, 1 H), 0.77 (t, J = 6.9 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 206.3, 140.0, 133.4, 126.2, 123.4,
120.8, 120.5, 109.3, 53.9, 48.4, 35.3, 31.3, 30.6, 25.7, 22.3, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N2O3: 371.1390; found:
371.1397.
HRMS (ESI): m/z [M + H]+ calcd for C16H23N2O: 259.1805; found:
259.1814.
3-(Furan-2-yl)-3-(1H-indazol-1-yl)-1-phenylpropan-1-one (2r)
3-(5-Nitro-1H-indazol-1-yl)-1,3-diphenylpropan-1-one (3a)
Yellow solid; yield: 222 mg (70%); mp 129–131 °C.
Yellow solid; yield: 323 mg (87%); mp 70–72 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. Yang et al.
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IR (KBr): 3064, 2980, 2924, 2854, 1864, 1733, 1519, 1450, 1339, 1071,
812, 785, 750, 691 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.67 (s, 1 H), 8.23 (d, J = 9.6 Hz, 1 H),
8.17 (s, 1 H), 7.98 (d, J = 7.2 Hz, 2 H), 7.63–7.53 (m, 2 H), 7.48–7.44 (m,
2 H), 7.37–7.27 (m, 5 H), 6.46 (dd, J = 9.6, 3.6 Hz, 1 H), 4.74 (dd, J =
18.0, 9.6 Hz, 1 H), 3.68 (dd, J = 18.0, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 196.5, 142.7, 141.6, 140.0, 136.5,
135.9, 133.8, 129.3 (2 C), 128.9 (2 C), 128.6, 128.4 (2 C), 126.8 (2 C),
123.6, 121.7, 119.1, 110.2, 58.5, 44.4.
Wang, Y. Adv. Synth. Catal. 2012, 354, 2977. (r) Wang, J.; Li, P.-F.;
Chan, S. H.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron Lett. 2012,
53, 2887. (s) Wu, Y.; Wang, J.; Li, P.; Kwong, F. Y. Synlett 2012,
23, 788. (t) Xie, S.-L.; Hui, Y.-H.; Long, X.-J.; Wang, C.-C.; Xie, Z.-
F. Chin. Chem. Lett. 2013, 24, 28. (u) Lee, S.-J.; Ahn, J.-G.; Cho, C.-
W. Tetrahedron: Asymmetry 2014, 25, 1383. (v) Li, P.; Fang, F.;
Chen, J.; Wang, J. Tetrahedron: Asymmetry 2014, 25, 98.
(w) Zhang, J.; Zhang, Y.; Liu, X.; Guo, J.; Cao, W.; Lin, L.; Feng, X.
Adv. Synth. Catal. 2014, 356, 3545. (x) Yang, J.; Ma, B.; Zhou, H.;
Zhan, B.; Li, Z. Chin. J. Org. Chem. 2015, 35, 121. (y) Chen, S.-W.;
Zhang, G.-C.; Lou, Q.-X.; Cui, W.; Zhang, S.-S.; Hu, W.-H.; Zhao,
J.-L. ChemCatChem 2015, 7, 1935.
.
HRMS (ESI): m/z [M + H]+ calcd for C22H18N3O3: 372.1343; found:
372.1358.
(4) For reviews, see: (a) Gaikwad, D. D.; Chapolikar, A. D.; Devkate,
C. G.; Warad, K. D.; Tayade, A. P.; Pawar, R. P.; Domb, A. J. Eur. J.
Med. Chem. 2015, 90, 707. (b) Schmidt, A.; Beutler, A.;
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Speisky, H. Future Med. Chem. 2013, 5, 1843. (e) Thangadurai,
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Chem. Res. 2012, 21, 1509. (f) Cerecetto, H.; Gerpe, A.; Gonzalez,
M.; Aran, V. J.; de Ocariz, C. O. Mini-Rev. Med. Chem. 2005, 5,
869.
Acknowledgment
The authors thank the National Natural Science Foundation of China
(21362034 and 21462038), the Research Fund for the Doctoral Pro-
gram of Higher Education of China (20136203120005), and the Gansu
Educational Committee (2013B-003) for financial support.
Supporting Information
(5) For recent examples, see: (a) Wang, H.-L.; Cee, V. J.; Chavez, F.
Jr.; Lanman, B. A.; Reed, A. B.; Wu, B.; Guerrero, N.; Lipford, J. R.;
Sastri, C.; Winston, J.; Andrews, K. L.; Huang, X.; Lee, M. R.;
Mohr, C.; Xu, Y.; Zhou, Y.; Tasker, A. S. Bioorg. Med. Chem. Lett.
2015, 25, 834. (b) Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa,
M.; Nakano, S.; Morimoto, A.; Kasahara, K.-i.; Tanaka, E.; Takada,
Y.; Ohashi, S.; Mori, M.; Shuto, S. J. Med. Chem. 2015, 58, 6048.
(c) Liu, Y.; Lang, Y.; Patel, N. K.; Ng, G.; Laufer, R.; Li, S.-W.;
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561334.
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