Divergent copper-mediated dimerization and hydroxylation of benzamides involving C-H bond functionalization

Article abstract of DOI:10.1039/c6ob00392c

Convenient methods were developed for copper-mediated oxidative C-H activation of aminoquinoline benzamides. The reaction conditions can be tuned to give either hydroxylation or dimerization compounds as the major products efficiently. Preliminary mechanistic studies suggested that different coordination states of copper may lead to different reaction outcomes.

Full text of DOI:10.1039/c6ob00392c

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Divergent Copper-mediated dimerization and hydroxylation of
benzamides involving C-H bond functionalization
Mingliang Wang,a Yimin Hu,*b Zhe Jiang,a Hong C. Shenb and Xun Sun *a, c
Received 00th January 20xx,
Accepted 00th January 20xx
Convenient methods were developed for copper-mediated oxidative C-H activation of aminoquinoline
benzamides. The reaction conditions can be tuned to give either hydroxylation or dimerization compounds
as the major products effiecntly. Preliminary mechanistic studies suggested that different coordination states
of copper may lead to different reaction outcomes.
DOI: 10.1039/x0xx00000x
www.rsc.org/
hydroxylation of arenes through aerobic copper-mediated C-H
functionalization. We found that small variations of additives
Introduction
Directed C-H bond functionalizations mediated by transition
metals have attracted extensive research interests recently
and have led to practical applications in natural product
synthesis and pharmaceutical research.1 Copper-mediated
oxidative C−H funcꢀonalizaꢀon is an important research
direction,2 as copper salts are generally inexpensive and
abundant. Such transformations can be facilitated by either
monodentate (represented by the C-H functionalization of 2-
arylpyridines reported independently by Yu3 and Chatani4 in
2006) or bidentate ligands (showcased by the 8-
aminoquinoline-derived auxiliary5 first developed by Daugulis).
A variety of other directing groups have been developed since
then, including the the 2-(pyridine-2-yl)isopropyl (PIP) group
reported by Shi6 and co-workers. The PIP group can promote
ortho-selective hydroxylation and methoxylation using Ag2CO3
as the oxidant.7 During the preparation of our manuscript, a
simple method of copper-mediated ortho-selective
hydroxylation of arenes using molecular oxygen as the oxidant
was reported by Yu and co-workers with oxazol-2-yl as the
directing group8. Besides copper-mediated hydroxylation,
there were only limited reports exploring dimerization of
arenes through a directed C-H functionalization. In 2014,
Miura et al. reported aminoquinoline-directed homocoupling
of thiophenes mediated by copper.9 Very recently, the
Daugulis group reported a novel Co- and Mn-promoted
dimerization of aminoquinoline benzamides.10 Herein we
could direct the reaction toward different pathways. These
easy-to-operate and robust protocols may facilitate the
preparation of important building blocks in medicinal
chemistry.
Previous work:
1) Hydroxyaltion:
DG
H
DG
OH
1.0 equiv Cu(OAc)2
1 atm O2 or Ag2CO3
R
R
Ref: 3, 7, 8
O
O
DG =
N
H
N
N
H
N
N
O
O
2) Dimerization
S
O
R
O
S
Q
HN
R
Q
2.0 equiv Cu(OAc)2
Q = 8-aminoquinolinyl
o-Xylene, 165o
C
N
H
R
Ref: 9
H
S
NH
Q
O
O
H
Q
N
H
Q
R
0.5 equiv Co(acac)2
N
H
Ref: 10
R
R
1 equiv Mn(OAc)2
O2
H
N
Q
O
Divergent approach in this work:
1.0-1.2 eq Cu(OAc)2
(nBu)4NI, DMSO
90oC, 1h
NHQ
0.5 eq Cu(OAc)2
DMSO, 108oC, 1h
O
report
a divergent approach for both dimerization and
O
H
OH
NHQ
Quench with base, H2O
Quench with HCl
Ar
Cu-mediated
No Ag2CO3 is needed
QHN
O
NHQ
O
a.Department of Natural Products Chemistry, Fudan University, 826 Zhangheng
Road, Shanghai 201203, China. E-mail: sunxunf@shmu.edu.cn; Fax: +86 21
51980003
Scheme
benzamides
1 Cu-mediated dimerization and hydroxylation of
b.Roche Pharmaceutical Research and Early Development, Roche Innovation Center
Shanghai, Shanghai 201203, China. E-mail: yimin.hu@roche.com
c.
Results and discussion
Shanghai Key Laboratory of Clinical Geriatric Medicine, 221 West Yanan Road,
Shanghai 200040, China.
In our efforts for the hydroxylation of 4-fluoro benzamide, following
a slightly modified procedure from the report by Shi and co-
workers,7 with aminoquinoline instead of PIP as the directing group,
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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a Reaction conditions: 1a (0.2 mmol), Cu salt, base (0.2 mmol), solvent (2
mL), 100 oC, air, 1h. b Isolated yield. c 108 oC for 1hr d under Ar atmosphere.
e 90 oC for 1hr;
we found that hydroxylation product (3a) could be obtained in 56%
yield, with a 19% isolated yield of the dimerization product (2a). To
our surprise, applying similar condition without Ag2CO3 afforded a
60% yield of the dimerization product 2a, along with a 30% yield of
the hydroxylation product 3a (Table 1, entry 1-2). The different
preference toward either reaction pathway spurred our further
interest in investigating the detail and identifying a divergent
approach to either dimerization or hydroxylation. In the presence
of 1 equivalent of K2CO3 at 100 °C with reaction mixture simply
opened to air, the yield of dimerization product 2a was improved to
76% (Table 1, entry 3). The loading of Cu(OAc)2 could be lowered to
0.5 equivalent without affecting the outcome of the reaction.
Further reduction of Cu(OAc)2 loading reduced the reaction
conversion significantly (Table 1, entry 4-6). Thus we used 0.5
equivalent Cu(OAc)2 in our standard condition for dimerization. It
should be noted that in the report by Miura et al,9 the dimerization
With the optimized conditions in hand, we then examined the
scope of benzamide substrates for both dimerization and
hydroxylation (Table 2).
Table 2 The scope of substratesa, b, c
Ar
1-1.2 equiv Cu(OAc)2
2 equiv TBAI
NHQ
0.5 equiv Cu(OAc)2
1 equiv K2CO3
O
O
Ar
Ar
DMSO, 90 oC, 1h
NHQ
NHQ
NHQ
DMSO, 108 oC, 1h
Ar
Q = 8-aminoquinolinyl
Q = 8-aminoquinolinyl
H
O
OH
O
2
1
3
O
O
3b, R = H, 81%
2b, R = H, 61%
NHQ
3c, R = Me, 76%
3d, R = n-Bu, 78%
3e, R = OMe, 72%
3f, R = Cl, 62 %
2c, R = Me, 68 %
2d, R = n-Bu, 63%
2e, R = OMe, 71%
2f, R = Cl, 82%
NHQ
OH
R
R
R
NHQ
o
reaction proceeded at a higher temperature (165 C) and longer
O
O
O
time (3 hr), which is likely due to the use of non-polar solvents such
as o-xylene, and the absence of a base. In contrast, we postulated
that basic conditions and a polar solvent such as DMSO may
O
O
O
3g, R = Br, 58%
3h, R = CO2Me, 69%
3i, R = Ph, 73%
3j, R = CF3, 58%
3k, R = CN, 56%
2g, R = Br, 83%
NHQ
2h, R = CO2Me, 78%
2i
NHQ
R
R
, R = Ph, 76%
R
OH
2j, R = CF3, 87%
2k, R = CN, 81%
NHQ
F
promote
a more facile formation of copper complex via
deprotonation of the amide, which was reflected in our screening of
different solvents (Table 1, entry 7-9). These combined factors may
account for generally higher yields and milder conditions with our
procedures.
O
NHQ
O
F
O
NHQ
NO2
NO2
NHQ
OH
NHQ
OH
NO2
NHQ
NHQ
F
Hydroxylation was favored when TBAI was added as an additive
(Table 1, entry 10). After optimization of reaction temperature, and
the loading of Cu(OAc)2 and TBAI, a 66% yield of the hydroxylation
product (3a) was obtained using 1.1 equivalents of Cu(OAc)2 and 2
equivalents of TBAI. The reaction proceeded at 90 °C for 1 h with
the reaction mixture open to air (Table 1, entry 16). More detailed
reaction discovery and optimization process can be found in the
supporting information.
O
3l, 63%
3m, 61% d
2l, 79%
O
2m, 82%
O
NHQ
O
NHQ
O
N
N
NHQ
OH
N
NHQ
N
N
N
NHQ
OH
NHQ
O
O
2n, 78%
3o, 63%
3n, 61%
2o, 73%
O
O
NHQ
S
O
S
NHQ
O
Table 1 Optimization of the reaction conditionsa
S
NHQ
S
NHQ
S
NHQ
NHQ
OH
3q, 57%
S
OH
3p, 62%
O
O
2p, 72%
2q, 68%
aDimerization reaction conditions: Amide (1 mmol), Cu(OAc)2 (0.5 mmol),
K2CO3 (1 mmol), DMSO (5 mL), 108 oC, air, 1 h. bHydroxylation reaction
conditions: Amide (1 mmol), Cu(OAc)2 (0.5 mmol), TBAI (1 mmol), DMSO
(10 mL), 90 oC, air, 1 h. cYield of isolated product.
performed at 65 oC
d
Reaction was
Entry Cu(OAc)2 Base/Additive
Solvent
Yield b
2a 3a %)
.
(equiv)
1.0
1.0
1.0
0.5
0.5
0.2
0.5
0.5
0.5
1.0
1.0
0.5
1.1
2.0
1.1
1.1
1.0
2.0
2.0
(equiv)
Ag2CO3 (1.0)
None
(
/
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
dioxane
DMF
19 / 56
58 / 21
76 / 8
2
As shown in Table 2, both electron-rich and -deficient
substituents such as alkyl, methoxy, trifluoromethyl, fluoro,
and bromo are well-tolerated under the reaction conditions,
thus generating the corresponding dimerization and
hydroxylation products in moderate to excellent yields. Nitro
group, a strong electron withdrawing substituent (1m), and
hetero arenes, such as pyridines (1n and 1o) and thiophenes
3
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
TBAI (2.0)
TBAI (1.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
TBAI (2.0)
K2CO3 (1.0)
K2CO3 (1.0)
TBAI(2.0)
4
5c
78 / <5
84 / <5
34 / <5
9 / <5
6
7
8
11 / <5
72 / 12
9 / 73
9
(
1p and 1q), were tolerated as well, demonstrating a wide
10
11
12
13
14
15d
16e
17d
18d
19d
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
range of-functional group compatibility of our robust protocols
for both reaction pathways. No significant difference was
observed between 3- and 4-pyridylcarboxyamides (1o and 1n).
In the case of 1o, the reaction favored the formation of the C-C
bond para to the nitrogen atom of the pyridyl group.
To demonstrate the utility of this hydroxylation reaction, we
conducted deprotection of the directing group with dimerization
and hydroxylation products. The aminoquinoline directing group
was smoothly removed bytreating product 2i and 3b with
11 / 68
<5 / 48
<5 / 75
9 / 75
<5 / 42
<5 / 78
8/32
38/41
<5/63
2 | J. Name., 2012, 00, 1-3
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KOH/EtOH at 120 °C for 48 h, and the corresponding acids were
obtained in 71% and 73% yield, respectively (Scheme 2).
Scheme 2. Removal of the Directing Group
addition of the commonly used radical quencher 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO) had negligible effect on
the yield, indicating that the reaction did not significantly
involve a radical reaction pathway. Thirdly, LC/MS analysis of
the reaction mixture suggested that major intermediates
before quenching were 6a and 7a, corresponding to the
molarity requirements of Cu(OAc)2 in earlier optimization
efforts for dimerization and hydroxylation, respectively (0.5
equivalent of Cu(OAc)2 was needed for dimerization and 1.0
equivalent was needed for hydroxylation (see supporting
information for details).
Combining the above results, we proposed that the
hydroxylation reaction involved a copper-mediated C−H
cleavage step rather than an electrophilic aromatic
substitution (SEAr) or a radical pathway, which is consistent
with previous reports.7, 8 The reaction may start from the
complexation of 1a with copper to give Cu(II)-complex
acetate ligand-enabled C−H acꢀvaꢀon affords the Cu(III)-aryl
species . The C-H activation step from to could go through
8. An
9
8
9
either a one step disproportionative C−H acꢀvaꢀon directly11
or a two step process, which is acetate-enabled, concerted-
metalation-deprotonation C−H acꢀvaꢀon to a Cu(II)-aryl
species, followed by disproportionation or oxidation to afford
To probe the mechanism of this reaction, we performed a series
of experiments as shown in Table 1. Under inert atmosphere, the
reaction of benzamide 1a stopped at around 50% conversion with 1
equivalent of Cu(OAc)2 (Table 1, Entry 17). Applying similar
conditions with 2 equivalents of Cu(OAc)2 gave almost full
conversion with about 1:1 ratio of dimerization (2a) and
hydroxyaltion (3a) products (Table 1, Entry 18) . Such observation
suggests that oxygen helps the turnover of copper with less than 2
equivalents of Cu(OAc)2 under the dimerization conditions. In
addition, excess Cu(OAc)2 favored the formation of hydroxylation
product 3a. Under hydroxylation conditions in the presence of TBAI
and 2 equivelents of Cu(OAc)2, the reaction gave almost full
conversion with similar yield of 3a isolated as under our standard
condition for hydroxylation in table 1, entry 19.
Cu(III)-aryl intermediate 9 7
(K2CO3) could deprotonate excess benzamide 1a and promote
two ligand coordination on the copper to give intermediate 10
.
Subsequently, additional base
.
Following reductive elimination gives intermediate 6a, which
leads to the formation of dimerization product 2a after work-
up. In the case of reactions using TBAI as an additive,
presumably iodide serves as a ligand for copper and prevents
dimerization, , which leads to the C-O bond formation pathway
and form intermediate 7a, as suggested previously.7 The final
work-up of intermediate 7a then gives hydroxylation product
Scheme 3. Further experiments to probe reaction mechanism
3a.
Scheme 4. Plausible reaction mechanism.
O
NHQ
F
1 a
Cu(OAc)2
O
N
Cu
O
N
F
H
O
8
Cu(II)
Cu(I)
disproportionation
or oxidation
Ref. 7,11
O
O
O
K2CO3
TBAI
N
N
CuIII
N
Cu
L
Cu
N
N
N
1 a
F
F
F
OAc
L= I -, OAc-
10
9
11
Two ligand coordination
Ref 7, 8
F
F
O
O
N
N
N
N
2 a
(ll)Cu
In the subsequent mechanistic studies (Scheme 3),
significant kinetic isotope effects were observed for the
hydroxlation of 1b. However, Kinetic isotope experiment for
the dimmerization is not conclusive due to very fast reaction
under standard conditions. Next, it was found that the
3 a
Cu
O
N
N
F
O
7 a
6 a
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5, 5’-Dimethyl-N2, N2’-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
Conclusions
dicarboxamide (2c). White solid, 68% yield, mp 227-229 °C. 1H NMR
(400 MHz, CDCl3) δ 10.27 (s, 2H), 8.65 (dd, J = 7.4, 1.4 Hz, 2H), 8.44
(dd, J = 4.2, 1.6 Hz, 2H), 7.90 (dd, J = 8.3, 1.6 Hz, 2H), 7.74 (d, J = 7.8
Hz, 2H), 7.27-7.14 (m, 10H), 2.38 (s, 6H); 13C NMR (101 MHz, CDCl3):
δ 167.59, 147.67, 140.79, 140.20, 138.27, 135.76, 134.87, 133.72,
131.71, 128.59, 128.05, 127.45, 127.06, 121.27, 121.14, 116.52,
21.57; HRMS (ESI-TOF) calcd for C34H27N4O2 [M + H] +: 523.2129,
found: 523.2133.
In conclusion, we developed a divergent approach for the copper-
mediated dimerization and hydroxylation of bezamides through C-H
bond functionalization, directed by a removable bidentate auxiliary.
The reaction conditions tolerated various functional groups and
thus can be applied to heterocycles such as pyridines and
thiophenes. Preliminary mechanistic studies revealed more details
in this copper-mediated C-H bond functionalization process and
may guide future efforts to improve the process.
5, 5’-Dibutyl-N2, N2’-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
dicarboxamide (2d). White solid, 63% yield, mp 147-148 °C. 1H NMR
(400 MHz, CDCl3) δ 10.32 (s, 2H), 8.73 (d, J = 6.7 Hz, 2H), 8.45 (dd, J
Experimental
All reagents and metal catalysts were obtained from = 4.1, 1.4 Hz, 2H), 7.96 (dd, J = 8.2, 1.3 Hz, 2H), 7.81 (d, J = 7.9 Hz,
commercial sources and used without further purification.
NMR spectra were obtained on a Bruker AV II-400 MHz
spectrometer (1H NMR at 400 MHz, 13C NMR at 100 MHz, and
19F NMR at 375 MHz). The 1H NMR chemical shifts were
measured relative to CDCl3 or DMSO-d6 as the internal
reference (CDCl3: δ= 7.26 ppm; DMSO-d6: δ= 2.50 ppm). The
13C NMR chemical shifts were given using CDCl3 or DMSO-d6 as
the internal standard (CDCl3: δ= 77.16 ppm; DMSO-d6: δ=
39.52 ppm). Mass spectroscopy data were collected on an
HRMS-ESI instrument.
2H), 7.35-7.15 (m, 10H), 2.54 (t, J = 7.6 Hz, 4H), 1.46 – 1.30 (m, 4H),
1.17 – 1.03 (m, 4H), 0.71 (t, J = 7.3 Hz, 6H); 13C NMR (101 MHz,
CDCl3): δ 167.74, 147.75, 145.61, 139.66, 138.50, 135.85, 134.93,
134.07, 131.13, 128.52, 127.98, 127.63, 127.20, 121.31, 121.29,
116.59, 35.49, 33.32, 22.13, 13.92; HRMS (ESI-TOF) calcd for
C40H39N4O2 [M + H] +: 607.3068, found: 607.3077.
5, 5’-Dimethoxy-N2, N2’-di (quinolin-8-yl)-[1, 1’-biphenyl]-2, 2’-
dicarboxamide (2e). White solid, 71% yield, mp 184-185 °C. 1H NMR
(400 MHz, CDCl3) δ 10.26 (s, 1H), 8.70 (dd, J = 7.4, 1.4 Hz, 1H), 8.48
(dd, J = 4.2, 1.6 Hz, 1H), 7.96 (dd, J = 8.3, 1.5 Hz, 1H), 7.85 (d, J = 8.5
Hz, 1H), 7.32 – 7.23 (m, 4H), 6.96 (d, J = 2.5 Hz, 1H), 6.92 (dd, J = 8.5,
2.6 Hz, 1H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 167.03,
161.10, 147.65, 141.82, 138.38, 135.99, 134.98, 130.26, 128.99,
127.64, 127.25, 121.33, 121.24, 116.70, 115.93, 113.73, 55.60;
HRMS (ESI-TOF) calcd for C34H27N4O4 [M + H] +: 555.2027, found:
555.2025.
General Procedure for the Dimerization
A solution of amide 1 (1 mmol, 1.0 equiv), K2CO3 (138 mg, 1 mmol,
1.0 equiv), Cu(OAc)2 (91 mg, 0.5 mmol, 0.5 equiv) in DMSO (5 mL)
was stirred at room temperature for 5 min and the mixture was
then heated at 108 oC for 1h under air. After completion of the
reaction as detected by TLC, the reaction mixture was cooled to
room temperature. Then Na2S·xH2O (500 mg), CH2Cl2 (50 mL) and
H2O (50 mL) were added, resulting biphasic solution was stirred 10
min at room temperature and filtered through a pad of celite,
organic layer was separated and aqueous layer was extracted with
CH2Cl2 (2 x 50 mL). Combined organic phase was dried with
anhydrous magnesium sulfate. After concentration, product was
purified using column chromatography on silica gel with DCM-
MeOH (100: 1 to 10:1) as the eluent togive the desired product 2.
5, 5’-Dichloro-N2, N2’-di (quinolin-8-yl)-[1, 1’-biphenyl]-2, 2’-
dicarboxamide (2f). White solid, 82% yield, mp 246-248 °C. 1H NMR
(400 MHz, CDCl3) δ 10.24 (s, 2H), 8.59 (dd, J = 5.9, 2.9 Hz, 2H), 8.49
(d, J = 2.8 Hz, 2H), 7.93 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H),
7.49 (d, J = 1.8 Hz, 2H), 7.43 (dd, J = 8.2, 1.9 Hz, 2H), 7.32 – 7.25 (m,
4H), 7.22-7.17 (m, 4H); 13C NMR (101 MHz, CDCl3): δ 166.04, 147.80,
140.58, 138.05, 136.85, 136.08, 134.81, 134.28, 130.84, 129.41,
128.60, 127.51, 127.12, 121.70, 121.44, 116.90; HRMS (ESI-TOF)
calcd for C32H21Cl2N4O2 [M + H] +: 563.1036, found: 563.1035.
5,5'-Dibromo-N2,N2'-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
dicarboxamide （2g）. White solid, 83% yield, mp 246-248 °C. 1H
NMR (400 MHz, CDCl3) δ 10.25 (s, 2H), 8.59 (dd, J = 5.7, 3.2 Hz, 2H),
8.50 (dd, J = 4.1, 1.4 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2
Hz, 2H), 7.66 (d, J = 1.8 Hz, 2H), 7.59 (dd, J = 8.2, 1.9 Hz, 2H), 7.30
(dd, J = 8.2, 4.3 Hz, 2H), 7.23 – 7.18 (m, 4H); 13C NMR (100 MHz,
CDCl3): δ 166.14, 147.73, 140.59, 137.90, 136.29, 135.23, 134.12,
133.70, 131.58, 129.54, 127.55, 127.20, 125.21, 121.76, 121.43,
117.13; HRMS (ESI-TOF) calcd for C32H21Br2N4O2 [M + H] +:
651.0026, found: 651.0025.
5, 5’-Difluoro-N2, N2’-di (quinolin-8-yl)-[1, 1’-biphenyl]-2, 2’-
dicarboxamide (2a). White solid, 83% yield, mp 247-249 °C. 1H NMR
(400 MHz, CDCl3) δ 10.27 (s, 2H), 8.63 (dd, J = 6.8, 2.1 Hz, 2H), 8.48
(dd, J = 4.2, 1.6 Hz, 2H), 7.94 (dd, J = 8.3, 1.6 Hz, 2H), 7.84 (dd, J =
8.5, 5.6 Hz, 2H), 7.29-7.11 (m, 10H); 13C NMR (101 MHz, CDCl3) δ
166.14, 163.59 (d, J = 250.8 Hz), 147.87, 141.56 (d, J = 7.2 Hz),
138.29, 135.91, 134.49, 132.74 (d, J = 3.3 Hz), 130.31 (d, J = 9.1 Hz),
127.54, 127.11, 121.65, 121.46, 117.90 (d, J = 22.4 Hz), 116.69 (s),
115.37 (d, J = 21.2 Hz); 19F NMR(375 MHz, CDCl3) δ −109.73 to
−109.80 (m, 2F); HRMS (ESI-TOF) calcd for C32H21F2N4O2 [M + H] +:
531.1627, found: 531.1633.
Dimethyl 6, 6’-bis (quinolin-8-ylcarbamoyl)-[1, 1’-biphenyl]-3,
3’-dicarboxylate (2h). White solid, 78% yield, mp 252-254 °C. 1H
NMR (400 MHz, CDCl3) δ 10.36 (s, 2H), 8.58 (dd, J = 4.9, 4.1 Hz, 2H),
8.46 (dd, J = 4.2, 1.6 Hz, 2H), 8.19 – 8.09 (m, 4H), 7.95 – 7.86 (m,
4H), 7.29-7.25 (m, 2H), 7.19-7.14 (m, 4H), 3.92 (s, 6H); 13C NMR (101
MHz, CDCl3): δ 166.21, 147.88, 140.08, 139.65, 138.15, 135.84,
134.25, 132.11, 132.03, 129.58, 128.00, 127.42, 126.94, 121.75,
121.45, 116.72, 52.51; HRMS (ESI-TOF) calcd for C36H27N4O6 [M + H]
+: 611.1925, found: 611.1915.
N2, N2’-Di (quinolin-8-yl)-[1, 1’-biphenyl]-2, 2’-dicarboxamide
(2b). White solid, 61% yield, mp 215-217 °C. 1H NMR (400 MHz,
CDCl3) δ 10.36 (s, 2H), 8.69 (d, J = 7.3 Hz, 2H), 8.46 (dd, J = 4.0, 1.2
Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 7.4 Hz, 2H), 7.50 – 7.37
(m, 6H), 7.32 – 7.22 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 167.55,
147.79, 139.83, 138.42, 136.52, 135.86, 134.76, 130.97, 130.55,
128.08, 127.99, 127.58, 127.13, 121.47, 121.36, 116.72; HRMS (ESI-
TOF) calcd for C32H23N4O2 [M + H] +: 495.1816, found: 495.1818.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00392C
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N4', N6’’-di (quinolin-8-yl)-[1, 1’:3’, 1’’:3’’, 1’’’-quaterphenyl]-4',
6’’-dicarboxamide (2i). White solid in 76% yield, mp 201-203 °C. 1H
NMR (400 MHz, CDCl3) δ 10.37 (s, 2H), 8.70 (dd, J = 7.0, 1.8 Hz, 2H),
8.45 (dd, J = 4.1, 1.4 Hz, 2H), 7.95 (dd, J = 8.2, 1.8 Hz, 4H), 7.79 (d, J
= 1.7 Hz, 2H), 7.66 (dd, J = 8.0, 1.8 Hz, 2H), 7.64 – 7.57 (m, 4H), 7.41
(t, J = 7.3 Hz, 4H), 7.38 – 7.32 (m, 2H), 7.29 – 7.20 (m, 6H); 13C NMR
DMSO): δ 164.24, 150.86, 150.37, 148.63, 142.70, 137.54, 136.34,
133.26, 130.30, 127.30, 126.42, 122.57, 122.09, 121.24, 116.43;
HRMS (ESI-TOF) calcd for C30H21N6O2 [M + H] +: 497.1721, found:
497.1720.
N3,N3'-di(quinolin-8-yl)-[4,4'-bipyridine]-3,3'-dicarboxamide
(2o). White solid, 73% yield, mp 205-207 °C. 1H NMR (400 MHz,
(100 MHz, CDCl3): δ 167.19, 147.81, 143.46, 140.32, 140.01, 138.36, CDCl3) δ 10.44 (s, 2H), 9.13 (s, 2H), 8.78 (d, J = 4.9 Hz, 2H), 8.57 (dd,
135.93, 135.31, 134.72, 129.88, 128.95, 128.86, 128.03 (s), 127.58,
127.46, 127.14, 126.68, 121.44, 121.36, 116.73 (s); HRMS (ESI-TOF)
calcd for C44H31N4O2 [M + H] +: 647.2442, found: 647.2434.
N2, N2’-di (quinolin-8-yl)-5, 5’-bis (trifluoromethyl)-[1, 1’-
biphenyl]-2, 2’-dicarboxamide (2j). White solid in 87% yield, mp
231-233 °C. 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 2H), 8.56 (dd, J =
5.8, 3.1 Hz, 2H), 8.50 (dd, J = 4.2, 1.6 Hz, 2H), 7.97 – 7.91 (m, 4H),
7.83 – 7.75 (m, 4H), 7.31 (dd, J = 8.3, 4.2 Hz, 2H), 7.19 – 7.13 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 165.65, 147.97, 139.65, 138.05,
135.90, 132.82 (q, JC-F = 32.8 Hz), 128.37, 127.92, 127.88, 127.40,
126.92, 126.60 (q, JC-F = 3.7 Hz), 123.65 (q, JC-F = 271.2 Hz), 121.89,
121.52, 116.70; 19F NMR (375MHz, CDCl3, ppm) δ -61.29; HRMS
(ESI-TOF) calcd for C34H21F6N4O2 [M + H] +: 631.1563, found:
631.1567.
J = 6.9, 2.0 Hz, 2H), 8.52 (dd, J = 4.2, 1.6 Hz, 2H), 7.95 (dd, J = 8.3,
1.6 Hz, 2H), 7.39 (d, J = 5.0 Hz, 2H), 7.30 (dd, J = 8.3, 4.2 Hz, 2H),
7.24 – 7.17 (m, 4H); 13C NMR (101 MHz, CDCl3): δ 164.45, 151.72,
148.58, 148.11, 145.80, 138.21, 136.05, 133.93, 131.62, 127.55,
126.92, 124.37, 122.21, 121.66, 116.96; HRMS (ESI-TOF) calcd for
C30H21N6O2 [M + H] +: 497.1721, found: 497.1717.
N2, N2’-di (quinolin-8-yl)-[3, 3’-bithiophene]-2, 2’-
dicarboxamide (2p). White yellow solid, 72% yield, mp 196-198 °C.
1H NMR (400 MHz, CDCl, ppm) δ 10.33 (s, 2H), 8.77 (dd, J = 7.4, 1.5
Hz, 2H), 8.68 (dd, J = 4.2, 1.7 Hz, 2H), 8.01 (dd, J = 8.3, 1.6 Hz, 2H),
7.65 (d, J = 5.0 Hz, 2H), 7.47 – 7.38 (m, 4H), 7.33 (dd, J = 8.3, 4.2 Hz,
2H), 7.16 (d, J = 5.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 159.89,
148.34, 139.90, 138.74, 136.04, 134.46, 134.38, 131.44, 131.05,
127.85, 127.24, 121.86, 121.64, 116.80; HRMS (ESI-TOF) calcd for
C28H19N4O2S2 [M + H] +: 507.0944, found: 507.0937.
5, 5’-Dicyano-N2,N2'-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
dicarboxamide (2k). White solid, 81% yield, mp 212-214 °C. 1H NMR
(400 MHz, CDCl3) δ 10.35 (s, 2H), 8.51 (ddd, J = 5.8, 5.3, 2.1 Hz, 4H),
7.97 – 7.89 (m, 4H), 7.82 – 7.75 (m, 4H), 7.31 (dd, J = 8.3, 4.2 Hz,
2H), 7.24 – 7.16 (m, 4H); 13C NMR (101 MHz, CDCl3): δ 164.97,
148.07, 140.15, 139.32, 138.05, 136.07, 134.03, 133.75, 132.53,
128.61, 127.50, 126.98, 122.31, 121.65, 117.71, 116.97, 114.88;
HRMS (ESI-TOF) calcd for C34H21N6O2 [M + H] +: 545.1721, found:
545.1723.
N2, N2’-di(quinolin-8-yl)-[3,3'-bibenzo[b]thiophene]-2,2'-
dicarboxamide (2q). White yellow solid, 68% yield, mp 273-275 °C.
1H NMR (400 MHz, CDCl3): δ 10.54 (s, 2H), 8.73 (dd, J = 7.4, 1.6 Hz,
2H), 8.58 (dd, J = 4.3, 1.6 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 7.95 (dd, J
= 8.3, 1.6 Hz, 2H), 7.47 – 7.42 (m, 2H), 7.41 – 7.32 (m, 6H), 7.31 –
7.24 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 160.04, 148.38, 141.98,
141.06, 140.56, 138.63, 135.93, 134.20, 127.79, 127.74, 127.34,
127.07, 125.57, 124.66, 122.54, 122.06, 121.68, 116.89; HRMS (ESI-
TOF) calcd for C36H23N4O2S2 [M + H] +: 607.1257, found: 607.1250.
3, 3’-Difluoro-N2, N2’-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
dicarboxamide (2l).White solid in 79% yield, mp 215-217 °C. 1H
NMR (400 MHz, CDCl3) δ 10.90 (s, 2H), 8.65 (dd, J = 7.3, 1.4 Hz, 2H),
8.50 (dd, J = 4.2, 1.5 Hz, 2H), 7.98 (dd, J = 8.3, 1.5 Hz, 2H), 7.45 –
7.35 (m, 4H), 7.31 – 7.20 (m, 6H), 7.05 – 6.97 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 163.07, 159.61 (d, J = 247.7 Hz), 148.07, 140.12,
138.93, 136.14, 134.13, 131.03 (d, J = 9.1 Hz), 127.88, 127.13,
126.08 (d, J = 3.1 Hz), 125.38 (d, J = 17.5 Hz), 122.58, 121.47,
118.77, 115.58(d, J = 22.1 Hz); 19F NMR(375 MHz, CDCl3) δ−115.25
to−115.29 (m, 2F); HRMS (ESI-TOF) calcd for C32H21F2N4O2 [M + H] +:
531.1627, found: 531.1632.
General Procedure for the Hydroxylation
To a 25 mL Schlenk tube were added amide 1 (1 mmol, 1.0 equiv),
TBAI (738 mg, 2 mmol, 2.0 equiv), Cu (OAc) 2(200 mg, 1.1 mmol, 1.1
equiv), DMSO (10 mL). The reaction tube was stirred at room
temperature for 5 min and the mixture was then heated at 90 oC for
1h under air. LCMS show the reaction was completed, the reaction
mixture was cooled to room temperature, Na2S·xH2O (500 mg),
CH2Cl2 (50 mL) and H2O (50 mL) were added. Resulting biphasic
solution was stirred 10 min at room temperature and filtered
through a pad of celite. Organic layer was separated and aqueous
layer was extracted with CH2Cl2 (2 x 50 mL). Combined organic
phase was dried with anhydrous MgSO4. After concentration,
product was purified using column chromatography on silica gel
using appropriate eluent.
5, 5’-Dinitro-N2,N2'-di(quinolin-8-yl)-[1,1'-biphenyl]-2,2'-
dicarboxamide (2m). White solid in 82% yield, mp 153-155 °C. 1H
NMR (400 MHz, CDCl3) δ 10.42 (s, 2H), 8.54 – 8.46 (m, 4H), 8.38 (dt,
J = 8.3, 2.1 Hz, 4H), 8.00 (d, J = 8.3 Hz, 2H), 7.94 (dd, J = 8.3, 1.4 Hz,
2H), 7.31 (dd, J = 8.3, 4.2 Hz, 2H), 7.20 – 7.12 (m, 4H); 13C NMR (101
MHz, CDCl3): δ 164.77, 148.90, 147.97, 141.63, 139.93, 137.80,
136.23, 133.58, 129.00, 127.46, 126.97, 125.74, 123.94, 122.37,
121.66, 117.13; 19F NMR(375 MHz, CDCl3) δ−115.25 to−125.29 (m,
1F); HRMS (ESI-TOF) calcd for C32H21N6O6 [M + H] +: 585.1517,
found: 585.1512.
4-Fluoro-2-hydroxy-N-(quinolin-8-yl)benzamide （3a）. White
solid, 78.5% yield, mp 163-164 °C. 1H NMR (400 MHz, CDCl3) δ 12.64
(s, 1H), 10.87 (s, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.78 (dd, J = 5.2,
3.8 Hz, 1H), 8.20 (dd, J = 8.3, 1.6 Hz, 1H), 7.83 (dd, J = 8.7, 6.1 Hz,
1H), 7.61 – 7.55 (m, 2H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 6.77 – 6.68
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 167.94, 166.60 (d, J = 252.0
Hz), 164.49 (d, J = 13.8 Hz), 148.67, 138.89, 136.66, 133.57, 128.18,
128.07, 127.48, 122.51, 122.05, 117.12, 112.01, 107.16 (d, J = 22.8
N4, N4’-di (quinolin-8-yl)-[3, 3’-bipyridine]-4, 4’-dicarboxamide
(2n). White yellow solid, 78% yield, mp 252-254 °C. 1H NMR (400
MHz, DMSO) δ 10.35 (s, 2H), 8.81 (d, J = 5.0 Hz, 2H), 8.77 (s, 2H),
8.63 (dd, J = 4.1, 1.4 Hz, 2H), 8.37 (d, J = 7.5 Hz, 2H), 8.25 (dd, J =
8.3, 1.3 Hz, 2H), 7.89 (d, J = 5.0 Hz, 2H), 7.52 (dd, J = 8.3, 4.2 Hz, 2H), Hz), 105.57 (d, J = 23.5 Hz); 19F NMR(375 MHz, CDCl3) δ −103.04 to
7.45 (d, J = 7.9 Hz, 2H), 7.27 (t, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
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−103.11 (m, 1F); HRMS (ESI-TOF) calcd for C16H12FN2O2 [M + H] +:
283.0877, found: 283.0881.
127.21, 122.67, 122.55, 122.11, 122.04, 117.24, 114.31; HRMS (ESI-
TOF) calcd for C16H12BrN2O2 [M + H] +: 343.0077, found: 343.0080.
Methyl 3-hydroxy-4-(quinolin-8-ylcarbamoyl)benzoate (3h).
White solid in 69% yield, mp 181-183 °C. 1H NMR (400 MHz, CDCl3)
δ 12.29 (s, 1H), 11.01 (s, 1H), 8.88 (dt, J = 6.7, 3.4 Hz, 1H), 8.83 –
8.76 (m, 1H), 8.22 – 8.18 (m, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.69 (d, J =
1.6 Hz, 1H), 7.63 (dd, J = 8.3, 1.6 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.50
2-Hydroxy-N-(quinolin-8-yl)benzamide (3b). White solid in 81%
yield, mp 131-132 °C. 1H NMR (400 MHz, CDCl3): δ 12.31 (s, 1H),
10.98 (s, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.83 (dd, J = 6.3, 2.6 Hz,
1H), 8.20 (dd, J = 8.3, 1.6 Hz, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.60
– 7.57 (m, 2H), 7.52-7.46 (m, 2H), 7.06 (dd, J = 8.4, 1.0 Hz, 1H), 7.03
– 6.99 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.63, 162.27, 148.65, (dt, J = 7.6, 3.8 Hz, 1H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
138.98, 136.62, 134.75, 133.76, 128.16, 127.50, 126.22, 122.42,
122.02, 119.18, 118.96, 117.11, 115.36; HRMS (ESI-TOF) calcd for
C16H13N2O2 [M + H] +: 265.0972, found: 265.0973.
167.69, 166.17, 161.97, 148.76, 138.88, 136.64, 135.51, 133.39,
128.11, 127.43, 126.26, 122.79, 122.10, 120.20, 119.75, 118.67,
117.28, 52.62; HRMS (ESI-TOF) calcd for C18H15N2O4 [M + H] +:
323.1026, found: 323.1028.
2-Hydroxy-4-methyl-N-(quinolin-8-yl)benzamide (3c). White
solid in 76% yield, mp 158-160 °C. 1H NMR (400 MHz, CDCl3) δ 12.29
(s, 1H), 10.89 (s, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.81 (dd, J = 6.8,
2.1 Hz, 1H), 8.19 (dd, J = 8.3, 1.6 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H),
7.61 – 7.54 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 6.87 (s, 1H), 6.81
3-Hydroxy-N-(quinolin-8-yl)-[1,1'-biphenyl]-4-carboxamide (3i).
White solid, 73% yield, mp 167-169 °C. 1H NMR (400 MHz, CDCl3): δ
12.40 (s, 2H), 11.00 (s, 2H), 8.90 (dd, J = 4.2, 1.6 Hz, 2H), 8.84 (dd, J
= 6.6, 2.3 Hz, 2H), 8.21 (dd, J = 8.3, 1.6 Hz, 2H), 7.92 (d, J = 8.3 Hz,
(d, J = 8.1 Hz, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.66, 2H), 7.69 – 7.64 (m, 4H), 7.63 – 7.57 (m, 4H), 7.54 – 7.46 (m, 6H),
162.26, 148.58, 145.90, 138.94, 136.57, 133.86, 128.14, 127.49,
126.03, 122.21, 121.95, 120.36, 119.05, 116.98, 112.72, 21.87;
HRMS (ESI-TOF) calcd for C17H15N2O2 [M + H] +: 279.1128, found:
279.1127.
7.44 – 7.39 (m, 2H), 7.30 (d, J = 1.7 Hz, 2H), 7.27 – 7.23 (m, 3H); 13C
NMR (100 MHz, CDCl3): δ 168.47, 162.52, 148.62, 147.53, 139.78,
138.92, 136.70, 133.76, 129.06, 128.49, 128.18, 127.53, 127.30,
126.69, 122.42, 122.01, 118.09, 117.20, 117.04, 114.10; HRMS (ESI-
TOF) calcd for C22H17N2O2 [M + H] +: 341.1285, found: 341.1284.
2-Hydroxy-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide (3j).
White solid in 58% yield, mp 150-152 °C. 1H NMR (400 MHz, CDCl3)
4-Butyl-2-hydroxy-N-(quinolin-8-yl)benzamide (3d). White solid,
78% yield, mp 91-93 °C. 1H NMR (400 MHz, CDCl3) δ 12.29 (s, 1H),
10.90 (s, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.81 (dd, J = 6.8, 2.1 Hz,
1H), 8.19 (dd, J = 8.4, 1.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.61 – 7.54 δ 12.45 (s, 1H), 11.05 (s, 1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.84 –
(m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.82
(dd, J = 8.0, 1.6 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 1.68 – 1.59 (m, 2H),
1.43 – 1.34 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.67, 162.28, 150.83, 148.58, 138.96, 136.58, 133.89,
128.15, 127.49, 126.05, 122.20, 121.95, 119.74, 118.39, 116.98,
112.91, 35.82, 33.03, 22.44, 14.06; HRMS (ESI-TOF) calcd for
C20H21N2O2 [M + H] +: 321.1598, found: 321.1597.
8.78 (m, 1H), 8.22 (dd, J = 8.3, 1.5 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H),
7.64 – 7.56 (m, 2H), 7.53 (dd, J = 8.3, 4.2 Hz, 1H), 7.31 (s, 1H), 7.23
(d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 167.46, 162.23,
148.82, 138.90, 136.72, 136.04 (q, JC-F = 32.5 Hz), 133.29, 128.16,
127.47, 126.95, 123.40 (q, JC-F = 271.3 Hz), 122.95, 122.17, 118.02,
117.36, 116.30 (q, JC-F = 4.0 Hz), 115.51 (q, JC-F = 3.7 Hz); 19
NMR(375 MHz, CDCl3) δ −63.63; HRMS (ESI-TOF) calcd for
C17H12F3N2O2 [M + H] +: 333.0845, found: 333.0849.
F
2-Hydroxy-4-methoxy-N-(quinolin-8-yl)benzamide (3e). White
solid, 72% yield, mp 145-147 °C. 1H NMR (400 MHz, CDCl3): δ 12.66
(s, 1H), 10.80 (s, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.79 (dd, J = 7.1,
1.7 Hz, 1H), 8.19 (dd, J = 8.3, 1.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H),
7.62 – 7.53 (m, 2H), 7.49 (dd, J = 8.3, 4.2 Hz, 1H), 6.59 – 6.50 (m,
2H), 3.86 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 168.53, 164.83,
164.58, 148.55, 138.93, 136.59, 133.96, 128.16, 127.54, 127.52,
122.05, 121.94, 116.87, 108.32, 107.59, 101.82, 55.63; HRMS (ESI-
TOF) calcd for C17H15N2O3 [M + H] +: 295.1077, found: 295.1076.
4-Chloro-2-hydroxy-N-(quinolin-8-yl) benzamide (3f). White
solid, 62% yield, mp 179-181 °C. 1H NMR (400 MHz, CDCl3) δ 12.49
(s, 1H), 10.92 (s, 1H), 8.91 – 8.85 (m, 1H), 8.83 – 8.76 (m, 1H), 8.21
(dd, J = 8.3, 1.5 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.62 – 7.57 (m, 2H),
7.52 (dd, J = 8.3, 4.3 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.98 (dd, J =
8.5, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 167.85, 162.94,
148.69, 140.28, 138.85, 136.65, 133.45, 128.12, 127.45, 127.14,
122.62, 122.07, 119.65, 118.98, 117.17, 113.87; HRMS (ESI-TOF)
calcd for C16H12ClN2O2 [M + H] +: 299.0582, found: 299.0586.
4-Bromo-2-hydroxy-N-(quinolin-8-yl)benzamide (3g).White
solid, 58% yield, mp 182-184 °C. 1H NMR (400 MHz, CDCl3) δ 12.46
(s, 1H), 10.94 (s, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.83 – 8.77 (m,
1H), 8.22 (dd, J = 8.3, 1.6 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.63 – 7.56
(m, 2H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.14
(dd, J = 8.5, 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 168.01,
162.86, 148.74, 138.91, 136.70, 133.49, 128.68, 128.17, 127.50,
4-Cyano-2-hydroxy-N-(quinolin-8-yl)benzamide (3k), White solid
in 56% yield, mp 247-248 °C. 1H NMR (400 MHz, CDCl3) δ 12.52 (s,
1H), 11.07 (s, 1H), 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.81 (dd, J = 6.8, 2.2
Hz, 1H), 8.24 (dd, J = 8.3, 1.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.67 –
7.58 (m, 2H), 7.54 (dd, J = 8.3, 4.3 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H),
7.27 (q, J = 1.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 167.06, 162.09,
148.89, 138.87, 136.79, 133.09, 128.17, 127.48, 127.09, 123.20,
122.89, 122.25, 122.07, 119.03, 117.86, 117.55, 117.51;HRMS (ESI-
TOF) calcd for C17H12N3O2 [M + H] +: 290.0924, found: 290.0922.
2-Fluoro-N-(quinolin-8-yl)benzamide (3l). White solid, 63% yield,
mp 171-173 °C. 1H NMR (400 MHz, CDCl3): δ 13.19 (s, 1H), 11.53 (d,
J = 19.3 Hz, 1H), 8.92 – 8.83 (m, 2H), 8.18 (d, J = 8.3 Hz, 1H), 7.61 –
7.55 (m, 2H), 7.48 (dd, J = 8.2, 4.2 Hz, 1H), 7.37 (dd, J = 15.1, 8.3 Hz,
1H), 6.86 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 12.6, 8.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3)：δ 166.63 (d, J = 3.6 Hz), 164.15 (d, J = 4.4 Hz),
161.39 (d, J = 246.8 Hz), 160.15, 148.87, 139.07, 136.43, 134.13 (d, J
= 13.3 Hz), 128.13, 127.37, 122.91, 121.97, 118.16, 114.86 (d, J = 2.9
Hz), 106.07(d, J = 25.5 Hz), 104.73 (d, J = 12.1 Hz); 19F NMR(375
MHz, CDCl3) δ−109.88 to−109.99 (m, 1F); HRMS (ESI-TOF) calcd for
C16H12FN2O2 [M + H] +: 283.0877, found: 283.0878.
2-Hydroxy-4-nitro-N-(quinolin-8-yl)benzamide (3m). The
reaction temperature was at 65oC. White solid, 61% yield, mp 251-
253 °C. 1H NMR (400 MHz, DMSO): δ 12.82 (s, 1H), 12.36 (s, 1H),
8.94 (dd, J = 6.1, 4.1 Hz, 2H), 8.44 (dd, J = 8.3, 1.4 Hz, 1H), 8.30 (d, J
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB00392C
Journal Name
ARTICLE
2011, 40, 5068. (f) K. Gao and N. Yoshikai, Acc. Chem. Res.,
2014, 47, 1208. For a recent example in natural product
synthesis, see: Z. Meng, et al. Nat. Commun. 2015, 6, 6096.
= 8.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.7, 2.2 Hz, 1H),
7.72 (d, J = 8.2 Hz, 1H), 7.65 (dt, J = 11.3, 6.1 Hz, 2H); 13C NMR (100
MHz, DMSO): δ 161.62, 156.44, 149.89, 149.15, 138.31, 136.69,
134.85, 132.82, 127.92, 127.15, 124.98, 122.48, 122.26, 117.05,
113.95, 111.51; HRMS (ESI-TOF) calcd for C16H12N3O4 [M+H] +:
310.0822, found: 310.0821.
2
(a) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew.
Chem., Int. Ed., 2011, 50, 11062; (b) L. D. Tran, J. Roane and
O. Daugulis, Angew. Chem., Int. Ed., 2013, 52, 6043; (c) M.
Nishino, K. Hirano, T. Satoh and M. Miura, Angew. Chem.,Int.
Ed., 2013, 52, 4457; (d) M. Shang, S.-Z. Sun, H.-L. Wang, B. N.
Laforteza, H.-X. Dai and J.-Q. Yu, Angew. Chem., Int. Ed.,
2014, 53, 10439; (e) M. Shang, H.-L. Wang, S.-Z. Sun, H.-X.
Dai and J.-Q. Yu, J. Am. Chem. Soc., 2014,136, 11590; (f) Y.-J.
Liu, Y.-H. Liu, X.-S. Yin, W.-J. Gu and B.-F. Shi, Chem. – Eur. J.,
2015, 21, 205; (g) X.-Q. Hao, L.-J. Chen, B. Ren, L.-Y. Li, X.-Y.
Yang, J.-F. Gong, J.-L. Niu and M.-P. Song, Org. Lett., 2014, 16
1104; (h) W. Zhu, D. Zhang, N. Yang and H. Liu, Chem.
Commun., 2014, 50, 10634; (i) J. Dong, F. Wang and J. You,
Org. Lett., 2014, 16, 2884; (j) Z. Wang, J. Ni, Y. Kuninobu and
3-Hydroxy-N-(quinolin-8-yl)isonicotinamide (3n). White solid,
61% yield, mp 263-265 °C. 1H NMR (400 MHz, DMSO) δ 12.31 (s,
2H), 8.95 (dd, J = 4.5, 1.7 Hz, 2H), 8.45 (dd, J = 8.2, 1.4 Hz, 2H), 8.24
(s, 1H), 7.93 (d, J = 5.0 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.66 (dt, J =
10.7, 6.1 Hz, 2H); 13C NMR (100 MHz, DMSO): δ 161.90, 149.19,
140.15, 138.36, 138.31, 136.78, 136.68, 134.86, 127.93, 127.15,
123.51, 122.51, 122.29, 121.07, 117.05; HRMS (ESI-TOF) calcd for
C15H12N3O2 [M + H] +: 266.0924, found: 266.0922.
,
4-Hydroxy-N-(quinolin-8-yl)nicotinamide (3o). White solid, 63%
yield, mp 262-264 °C. 1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H),
12.21 (s, 1H), 8.97 – 8.90 (m, 2H), 8.62 (d, J = 4.0 Hz, 1H), 8.38 (dd, J
= 8.3, 1.6 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.69 – 7.55 (m, 3H), 6.50 (d, J
= 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO): δ 177.27, 163.06, 149.00,
142.30, 138.76, 138.08, 136.29, 135.73, 127.95, 126.99, 122.00,
121.90, 119.64, 118.55, 117.42; HRMS (ESI-TOF) calcd for
C15H12N3O2 [M + H] +: 266.0924, found: 266.0927.
M. Kanai, Angew. Chem., Int. Ed., 2014, 53, 3496; (k) X. Wu, Y.
Zhao, G. Zhang and H. Ge, Angew.Chem., Int. Ed., 2014, 53
,
3706; (l) Z. Wang, Y. Kuninobu and M. Kanai, Org. Lett., 2014,
16, 4790; (m) D. Katayev, K. F. Pfister, T. Wendling and L. J.
Gooßen, Chem. – Eur. J., 2014, 20, 9902; (n) J. Liu, S. Zhuang,
Q. Gui, X. Chen, Z. Yang and Z. Tan, Adv. Synth. Catal., 2015,
357, 732; (o) M. Iwasaki, W. Kaneshika, Y. Tsuchiya,K.
Nakajima and Y. Nishihara, J. Org. Chem., 2014, 79, 11330.
X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem.
Soc., 2006, 128, 6790.
3
4
5
6
3-Hydroxy-N-(quinolin-8-yl)thiophene-2-carboxamide (3p).
White solid, 62% yield, mp 174-175 °C. 1H NMR (400 MHz, CDCl3): δ
11.17 (s, 1H), 10.12 (s, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (dd, J
= 6.8, 2.1 Hz, 1H), 8.19 (dd, J = 8.3, 1.5 Hz, 1H), 7.62 – 7.53 (m, 2H),
7.49 (dd, J = 8.3, 4.2 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 6.84 (d, J = 5.4
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 165.01, 164.77, 148.64,
138.60, 136.52, 134.02, 128.14, 128.09, 127.45, 122.05, 121.97,
120.46, 116.86, 106.00; HRMS (ESI-TOF) calcd for C15H10N2O2S [M +
H] +:271.0536, found: 271.0533.
T. Uemura, S. Imoto and N. Chatani, Chem. Lett., 2006, 35
842.
,
For a recent review, see: J. Roane, L. D. Tran and O. Daugulis,
Acc. Chem. Res., 2015, 48, 1053.
(a) F.-J. Chen, S. Zhao, F. Hu, K. Chen, Q. Zhang, S.-Q.
Zhang and B.-F. Shi, Chem. Sci. 2013, 4, 4187. (b) Q. Zhang,
K. Chen, W.-H. Rao, Y.-J. Zhang, F.-J. Chen and B.-F. Shi,
Angew. Chem., Int. Ed. 2013, 52, 13588.
X. Li, Y.-H. Liu, W.-J. Gu, B. Li, F.-J. Chen and B.-F. Shi, Org.
Lett., 2014, 16, 3904.
S.-Z. Sun, M. Shang, H.-L. Wang, H.-X. Lin, H.-X. Dai and J.-Q.
Yu, J. Org. Chem., 2015, 80, 8843.
7
8
9
3-hydroxy-N-(quinolin-8-yl)benzo[b]thiophene-2-carboxamide
(3q). White solid, 57% yield, mp 208-210 °C. 1H NMR (400 MHz,
CDCl3): δ 11.77 (s, 1H), 10.25 (s, 1H), 8.91 (dd, J = 4.3, 1.6 Hz, 1H),
8.79 (dd, J = 6.7, 2.2 Hz, 1H), 8.24 (dd, J = 8.3, 1.5 Hz, 1H), 7.99 (d, J
= 7.9 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.66 – 7.57 (m, 2H), 7.55 –
7.49 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
165.54, 159.83, 148.58, 138.43, 137.01, 136.79, 133.83, 131.46,
128.85, 128.19, 127.52, 124.82, 123.21, 123.13, 122.35, 121.99,
117.38, 103.77; HRMS (ESI-TOF) calcd for C19H12N2O2S [M + H]
+:321.0692, found: 321.0694.
O. Riko, N. Mayuko, H. Koji, S. Tetsuya and M. Masahiro,
Heterocycles., 2014, 88, 595.
10 L. Grigorjeva and O. Daugulis, Org. Lett., 2015, 17, 1204.
11 (a) A. E. King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas
and S. S. Stahl, J. Am. Chem. Soc. 2010, 132, 12068; (b) Z.-L.
Wang, L. Zhao and M.-X. Wang, Org. Lett. 2011, 13, 6560.
Acknowledgements
We thank the NSFC (no.81373276) and the Shanghai Municipal
Committee of Science and Technology (14XD1400300) for
financial support. We also thank Professor Ang Li (Shanghai
Institute of Organic Chemistry, CAS) for helpful discussions.
Notes and references
1
For recent reviews, see: (a) D. Alberico, M. E. Scott and M.
Lautens, Chem. Rev., 2007, 107,174; (b) C. J. Li, Acc. Chem.
Res., 2009, 42, 335; (c) X. Chen, K. M. Engle, D. H. Wang and
J. Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (d) T. W.
Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (e) S.
H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev.,
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J. Name., 2013, 00, 1-3 | 7
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