Copper(II)-Mediated Intermolecular C(sp2)-H Amination of Benzamides with Electron-Rich Anilines

Article abstract of DOI:10.1021/acs.joc.6b00659

Despite significant progress, copper-catalyzed/mediated C-H amination reactions with electron-rich anilines remain an unsolved problem due to catalyst deactivation and deleterious side reactions. Herein, we report a copper(II)-mediated C(sp²)-H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory drugs.

Full text of DOI:10.1021/acs.joc.6b00659

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Article
Copper(II)-mediated Intermolecular C(sp2)-H
Amination of Benzamides with Electron-Rich Anilines
Bijaya Kumar Singh, Arghya Polley, and Ranjan Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00659 • Publication Date (Web): 05 May 2016
Downloaded from http://pubs.acs.org on May 5, 2016
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Copper(II)-mediated Intermolecular C(sp )-H Amination of Benzamides
with Electron-rich Anilines
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Bijaya Kumar Singh, Arghya Polley, and Ranjan Jana*
Organic and Medicinal Chemistry Division, CSIRꢀIndian Institute of Chemical Biology,
4
Raja S. C. Mullick Road, Jadavpur, Kolkataꢀ700032, West Bengal, India
Fax: (+91) 33 2473 5197; Eꢀmail: rjana@iicb.res.in
ABSTRACT: Despite significant progress, copperꢀcatalyzed/mediated CꢀH amination reactions with
electronꢀrich anilines remains an unsolved problem due to catalyst deactivation and deleterious side
2
reactions. Herein we report, a copper(II)ꢀmediated C(sp )ꢀH amination of benzamides with
electronically neutral or electronꢀrich anilines. A dramatic influence of silver(I) and
tetrabutylammonium bromide (TBAB), was observed on the reaction outcome. The present protocol
also demonstrates the synthesis of a number of nonꢀsteroidal antiꢀinflammatory drugs (NSAID’s).
INTRODUCTION
Diarylamines are ubiquitously found in numerous biologically active natural products, medicinally
1
relevant scaffolds, pharmaceuticals, agrochemicals, dyes, and functionalized materials (Figure 1).
Conventionally, they are synthesized through a palladiumꢀ or copperꢀcatalyzed Goldberg crossꢀcoupling
2
between aryl halides and amines. In recent years, metal catalyzed CꢀH activation strategy provides a
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direct access to the functionalized amines obviating the need for aryl halides. In this vein, Pd, Ir, Rh
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catalysis have been explored with amines and highly energetic azides. To circumvent the metal
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poisoning issues with amines, the use of inexpensive first row transition metals such as manganese,
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iron, cobalt, nickel, and copper is emerging. A seminal report on copperꢀmediated sp CꢀH
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amidation using nonꢀremovable 2ꢀpyridine moiety was disclosed by the Yu group. Subsequently, they
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accomplished a bidentate auxiliaryꢀdirected C(sp )ꢀH amination with electronꢀpoor anilines. The
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Daugulis group also reported a 8ꢀaminoquinolineꢀdirected Cu(II)/Ag(I) catalyzed C(sp )ꢀH amination
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with aliphatic amines. However, sp CꢀH amination with readily available and inexpensive anilines to
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4b
afford diarylamines is extremely rare.
Notably, the Chang group also reported iridium ꢀ and
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rhodiumꢀcatalyzed CꢀH amination with electronꢀdeficient anilines and aryl azides respectively. This
could be attributed due to the deleterious side reactions especially azoarene formation and catalyst
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deactivation with nucleophilic amine derivatives.
Figure 1. Biologically-active diarylamines
Very recently, the Daugulis group reported an examples of copperꢀmediated CꢀH amination with
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2,4,6ꢀtrimethylanilne. However, other electronꢀrich anilines such as 4ꢀmethoxy aniline etc. are not
stable under this condition, which clearly demonstrates the challenges associated with this
2
transformation. Therefore, development of a general C(sp )ꢀH amination reaction conditions for
electronꢀrich anilines is in high demand. We report herein, a general copperꢀmediated CꢀH amination of
benzamides with electronically neutral and electronꢀrich anilines (Scheme 1) to afford diarylamines in
good to high yields. This methodology will enable direct access to a plethora of biologically active
compounds (Figure 1).
Scheme 1. C-H Amination of Benzamides with Aromatic Amines and Azides
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RESULTS AND DISCUSSION
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Under the Yu’s conditions, the 8ꢀaminoquinolineꢀprotected benzamide 1 afforded amination product
with pꢀnitroaniline (3ab, Scheme 2) in 60% yield. Gratifyingly, changing the base from
sodiumcarbonate to lithum tertꢀbutoxide and purging the reaction vessel with oxygen the yield was
increased to 96%. Unfortunately, electronꢀrich pꢀmethoxy aniline, 2 did not furnish any amination
1
8
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product under these conditions but a mixture of CꢀH hydroxylation (20%) and azoarene 5 (9%) was
isolated as side products. Gratifyingly, 30% amination product along with azoarene 5 (45%) was
isolated with the addition of 1.0 equiv of silver(I) acetate under nitrogen atmosphere (entry 1, Table 1).
Remarkably, the hydroxylation and azoarene formation was suppressed substantially with the addition
of tetrabutylammonium bromide (TBAB) (entry 2, Table 1). Increasing the amount of TBAB (3.0 equiv)
the azoarene and hydroxylation formation were completely diminished (entry 10, Table 1). However,
the role of TBAB is not clear at this moment. TBAB may form a soluble TBA(OAc) in situ leading a
rapid precipitation of silver(I)bromide. To test this the reaction was performed with 3.0 equiv
TBA(OAc) in lieu of TBAB. We isolated 52% and 22% of amination product along with azo
compounds in the presence and absence of silver(I)acetate respectively (entry 14 and 15, Table 1).
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TBAB may involve in the OAc/Br ion exchange on the copper salt. However, no amination product was
formed using 1.0 equiv of copper(II)bromide leaving a doubt on the exact role of TBAB. In fact, the
Daugulis group also found that TBAI was useful for CꢀH amination reaction which was proved inferior
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in this case (entry 5, Table 1). The yield of the desired amination product was further increased to 65%
80% based on recovered starting material) with 2.0 equiv of copper(II) acetate (entry 11, Table 1).
(
From control experiment it was confirmed that catalytic amount of copper(II) acetate is not effective for
this transformation. During optimization it was also observed that depending upon the electronic nature
of the anilines; judicious choice of oxidant is crucial for the reaction outcome. For example, in case of
electronꢀdeficient anilines, oxygen promotes amination reaction and no external oxidant is required.
However, in case of electronically neutral or electronꢀrich anilines even a trace amount of oxygen was
proved to be detrimental and silver(I) acetate was found to be optimal (entry 13, Table 1). Therefore, the
amination reaction with electronꢀrich anilines was performed under nitrogen atmosphere with 1.0 equiv
of silver(I) acetate.
a
Table 1. Optimization of the Reaction Conditions
c
entry
catalyst
additive
yield (%)
of 3
3:4:5
15:0:23
21:4:8
15:0:0
16:0:0
9:0:10
b
1
2
3
4
5
Cu(OAc)
1 equiv)
2
2
2
2
.H
2
2
2
2
O
O
O
O
ꢀ
30
42
15
16
18
(
Cu(OAc)
(1 equiv)
.H
.H
.H
TBAB
(1 equiv)
Cu(OAc)
(1 equiv)
TBAF
(1 equiv)
Cu(OAc)
TBACl
(1 equiv)
(
1 equiv)
Cu(OAc) .H O TBAI
2
2
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(1 equiv)
Cu(OAc)
(1 equiv)
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2
.H
2
O
K
2
S
2
O
8
5
5:0:12
(1 equiv)
(1 equiv)
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CuBr
2
(1 equiv) TBAB
0
ꢀ
(1 equiv)
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8
CuCl
2
(1 equiv) TBAB
0
ꢀ
(1 equiv)
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CuSO
4
.5H
2
O
TBAB
0
ꢀ
(1 equiv)
(1 equiv)
10
11
Cu(OAc) .H O TBAB
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51:0:0
65:0:0
ꢀ
2
2
(1 equiv)
(3 equiv)
d
Cu(OAc) .H O TBAB
65(80)
0
2
2
(2 equiv)
(3 equiv)
1
1
1
2
3
4
5
ꢀ
TBAB
(3 equiv)
e
Cu(OAc)
(3 equiv)
2
.H
.H
.H
2
O
O
O
TBAB
(3 equiv)
10
10:0:0
13:0:3
11:0:8
Cu(OAc)
(2 equiv)
2
2
2
TBA(OAc) 52
(3 equiv)
f
1
Cu(OAc)
2
TBA(OAc) 22
(3 equiv)
(2 equiv)
a
b
c
All reactions were carried out in 0.1 mmol scale. Yields refer to here are isolated yields. product
1
d
distribution was measured by H NMR. yield in the parenthesis is based on the starting material
e
f
2 2
recovery. Purged with O instead of N . without silver(I)acetate.
Under the optimized reaction conditions, the substrate scope of the CꢀH amination reaction was
explored. A wide range of benzamides containing functional groups were found to be amenable for CꢀH
amination. Besides alkyl and alkoxyl groups, trifluoromethyl, aryl, cyano groups remained intact under
these reaction conditions. More interestingly, an acetyl group containing benzamide afforded the
corresponding amination product in high yields which prefers facile imine formation with anilines under
slightly acidic conditions (3e, Scheme 2). Halogen substituents such as fluoro, chloro, bromo even iodo
on the benzamide or anilines remained intact which is useful for further crossꢀcoupling reactions to
achieve molecular complexity. A number of amide protected nonꢀsteroidal antiꢀinflammatory drug
(NSAID’s) such as mefenamic acid, 3o, tolfenamic acid, 3p, flufenamic acid, 3w were synthesized in
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good to high yields. Heteroaromatic benzamide and aniline also provided CꢀH amination product in
moderate to good yields (3yꢀ3aa, Scheme 2). Most of the cases with electronꢀrich anilines the unreacted
benzamides were isolated. It was not consumed completely even after the addition of anilines in excess.
Prolonged heating also did not improve the yield rather product decomposition was observed. As
discussed earlier, contrary to the electronꢀrich anilines electronꢀdeficient anilines such as pꢀnitro, pꢀ
cyano, or 3,5ꢀditrifluoromethyl anilines provided the corresponding amination products in excellent
yields using oxygen as terminal oxidant (3abꢀ3ad, Scheme 2).
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Scheme 2. Substrate Scope
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O
O
NH2
Cu(OAc)2 H2O (2.0 equiv)
NHQ
AgOAc (1.0 equiv)
TBAB (3.0 equiv)
NHQ
NH
+
H
t
R
BuOLi (2.0 equiv)
R
R1
1.5 equiv
DMSO (0.066 M)
N2, 100 oC, 6 h
1
.0 equiv
R1
O
O
10
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O
CF3
O
R
NHQ
NH
NHQ
NHQ
NHQ
R
NH
NH
NH
O
3
a: R = H, 70%
3f
3g: R = CF3, 52%
3h: R = p-tol, 55%
:
59%
OMe
3b: R = CF , 58%
3i: 75%
3
3
3
3
c: R = Br, 54%
d: R = Et, 63%
e: R = Ac, 66%
O
O
O
NHQ
NHQ
NHQ
NH
NH
NH
R
Me
R
R
R
3
m: R = OMe, 46%
3n: R = Me, 48%
3j: R = OMe, 65%
3o: R = Me, 62%
3p: R = Cl, 57%
3q: R = CF , 61%
3k: R = Me, 64%
t
3l: R = Bu, 59%
3
O
O
O
O
Br
NHQ
NH
NHQ
NHQ
NHQ
NH
F
NH
Me
NH
MeO
OMe
F
Br
I
3
r: 63%
3s: 63%
3t: 61%
3u: 60%
O
O
O
O
NHQ
NHQ
NH npentO
NHQ
NHQ
NH
N
NC
NH
NH
NO2
F3C
MeO
OMe
OMe
3
v: 54%
3w: 72%
3x: 73%
3y: 35%
O
O
O
O
N
NHQ
NH
NHQ
NH
NHQ
NHQ
NH
NH
N
Me
F3C
c
CF3
3ad: 80%c
OMe
3aa: 44%
R
3
z: 62%
3ab: R = NO , 96%
2
ac: R = CN, 67%c
3
a
b
All reactions were carried out in 0.2 mmol scale. Yields refer to the average of isolated yields of at
c
t
o
least two experiments. Reaction conditions: 0.2 mmol Cu(OAc)
2 2 2
.H O, 0.4 mmol BuOLi, O , 110 C, 3
h.
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Substituted diarylamines are useful synthetic precursor to a range of Nꢀheterocycles such as 9Hꢀ
2
0
carbazoles, quinazolinone, indazolol, acridone, acridine etc. The oꢀcarboxylic acid substituted
diarylamines also constitute a various biologically active compounds such as SIRT1inhibitor, MEK
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inhibitor, nonꢀsteroidal antiꢀinflammatory drugs (NSAID’s) etc. As an illustrative example the present
protocol was applied for the gramꢀscale synthesis of mefenamic acid. Under the standard conditions, the
amination reaction between benzamide 1 and 2,3ꢀdimethyl aniline was performed in 1.2 g scale and
almost identical yield (60%) of the corresponding amination product was isolated. Refluxing the
amination product in alkaline ethanol furnished the mefenamic acid in 90% yield (Scheme 3).
Scheme 3. Gram-Scale Synthesis of Mefenamic Acid
INVESTIGATION OF THE RECTION MECHANISM
Several control experiments were performed to understand the underlying mechanism of this
amination reaction. The kinetics of the amination reaction with benzamide 1 and d ꢀ1 was observed as
5
H D
k /k = 4.3 suggesting that the amination reaction may involve a concertedꢀmetalation deprotonation
(CMD) in the rate limiting step (Scheme 4a). The Nꢀmethylated benzamide did not furnish any
amination product which indicates that coordination of the copper center in bidentate fashion is crucial
for the reaction to occur (Scheme 4b). A competition reaction between equimolar amount of electronꢀ
rich pꢀmethoxyaniline and electronꢀdeficient pꢀnitroaniline afforded the corresponding amination
products in 30% and 55% yields respectively (Scheme 4c). Whereas, the respective reactions afforded
higher yields 65% (3j) and 98% (3ab) yields individually. This result suggests that not only the
electronꢀrich anilines are difficult substrates for amination also there may have catalyst inhibition by the
amination products. For further clarification, the amination reaction was performed in the presence of
an amination product, 3k (Scheme 4d). Only 15% of the amination product 3j was isolated suggesting
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that the catalyst is deactivated presumably via chelation with the amination product. This also explains
the requirement of stoichiometric copper salt for the present transformation. These control experiments
II
III
suggest that Cu complex may undergo a chelationꢀassisted CꢀH insertion to generate arylꢀCu
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species which reacts with Nꢀnucleophiles to provide the amination products.
Scheme 4. Control Expeiments
CONCLUSION
2
In conclusion, we have developed a copper(II)ꢀmediated C(sp )ꢀH amination of benzamides with
electronically neutral or electronꢀrich anilines. The present transformation is extremely challenging due
to the formation of deleterious side reactions and catalyst inhibition by the amination product. This
protocol provides direct access to the nonꢀsteroidal antiꢀinflammatory drugs (NSAID’s).
EXPERIMENTAL SECTION
General Information
Melting points were determined in open endꢀcapillary tubes and are uncorrected. TLC was performed
on silica gel plates (Merck silica gel 60, f254), and the spots were visualized with UV light (254 and
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365 nm) and KMnO
4
stain. H and C NMR spectra were recorded in CDCl
3
using TMS as the internal
standard. HRMS (m/z) were measured using EI (magnetic sector, positive ion) and ESI (QꢀTOF,
positive ion) techniques. Infrared (IR) spectra were recorded on Fourier transform infrared
spectroscopy; only intense peaks were reported.
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7
8
9
0
General Experimental Procedure for Benzamide Formation
The benzamides were synthesized according to the literature procedure, and the spectral data are
18
consistent with the reported values.
General Experimental Procedure for C-H Amination Reaction with Electron-rich
Anilines
2 2
In a 15 mL sealed tube, the substrates (0.2 mmol), Cu(OAc) .H O (80 mg, 0.4 mmol, 2 equiv), AgOAc
t
(
33.5 mg, 0.2 mmol, 1 equiv), BuOLi (32 mg, 0.4 mmol, 2 equiv), TBAB (196.7 mg, 0.6 mmol, 3
equiv) and anilines (0.3 mmol, 1.5 equiv) was added followed by DMSO (3 mL). The nitrogen gas was
passed to the reaction mixture for 1 minute. Then, the tube was charged with preheated oil bath at 100
O
C for 6 h. The reaction mixture was diluted with 10 mL ethyl acetate and quenched with 20 ml aq.
ammonium solution. Then, it was filtered through celiteꢀ545 and aqueous phase was extracted with
ethyl acetate (2x20). The combined organic phase was washed with 20 mL saturated sodium hydroxide
solution and collected, dried over Na
column chromatography on silica gel with gradient of elution of pet ether and ethyl acetate to give the
desired amination product
2 4
SO and concentrated under vacuum. The crude was purified by
.
Note: Aerial oxygen is detrimental to the amination reaction with electronꢀrich anilines.
2
-(Phenylamino)-N-(quinolin-8-yl)benzamide, 3a, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
2
o
1
3
white solid (48 mg, 70 %): mp 144 – 146 C; H NMR (600 MHz, CDCl ) δ 10.74 (s,1H), 9.57 (s,
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1H),8.88ꢀ8.86 (m, 2H),8.21 (dd, J = 8.2, 1.8 Hz, 1H), 7.89 (dd, J = 7.8, 1.2 Hz, 1H), 7.61 (t, J = 7.8 Hz,
1H), 7.57 (dd, J = 8.4, 1.8 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.44ꢀ7.42 (m, 1H), 7.38ꢀ7.32 (m,
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
3
1
1
H), 7.29ꢀ7.27 (m, 2H), 7.06ꢀ7.03 (m, 1H), 6.95ꢀ6.92 (m, 1H); C NMR (150 MHz, CDCl
3
) δ 167.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
48.3, 146.2, 141.4, 138.8, 136.4, 134.6, 132.6, 129.3, 128.04, 128.02, 127.4, 122.6, 121.69, 121.66,
21.2, 118.5, 118.0, 116.4, 115.6; IR (neat) υmax 3345, 2923, 1644, 1583, 1520, 1261; HRMS (ESI, m/z)
+
calcd for C22
H
18
N
3
O [M + H] 340.1450, found 340.1473.
2
-(Phenylamino)-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide, 3b, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (47 mg, 58 %): mp 156 – 158 C; H NMR (300 MHz, CDCl ) δ 10.75 (s, 1H), 9.66 (s, 1H),
3
8.86ꢀ8.83 (m, 2H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.63ꢀ7.56 (m, 3H), 7.50 (dd,
13
J = 8.4, 4.2 Hz, 1H), 7.40ꢀ7.35 (m, 2H), 7.28ꢀ7.24 (m, 2H), 7.14ꢀ7.09 (m, 2H); C NMR (75 MHz,
CDCl ) δ 166.8, 148.4, 146.7, 140.3, 138.7, 136.4, 134.16, 134.19 (q, J =33.80 Hz), 129.6, 128.8,
28.6, 128.0, 127.3, 123.8, 123.7 (q, J =275.3), 122.1, 121.8, 120.5, 116.6, 113.9 (q, J =3.7 Hz), 111.7
3
1
(
q, J =3.7 Hz); IR (neat) υmax 3351, 3046, 1655, 1589, 1536, 1428, 1335, 1175, 1119; HRMS (EI, m/z)
+
calcd for C23
H
16
F
3
N
3
O [M] 407.1245, found 407.1248.
4
-Bromo-2-(phenylamino)-N-(quinolin-8-yl)benzamide, 3c, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
white solid (45 mg, 54 %): mp 168 – 170 C; H NMR (600 MHz, CDCl
8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.84 (dd, J = 7.8, 1.8 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (d, J
2
o
1
3
) δ 10.70 (s, 1H), 9.71 (s, 1H),
=
8.4 Hz, 1H), 7.62ꢀ7.57 (m, 2H), 7.52ꢀ7.50 (m, 2H),7.40ꢀ7.37 (m, 2H), 7.28ꢀ7.27 (m, 2H), 7.12 (t, J =
13
7
.8, 1H), 7.02 (dd, J = 8.4, 1.8 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 167.3, 148.4, 147.7, 140.3,
1
38.8, 136.4, 134.3, 129.5, 129.2, 128.0, 127.4, 127.3, 123.7, 122.2, 121.9, 121.8, 120.7, 117.5, 116.5,
116.4; IR (neat) υmax 3445, 3356, 2924, 2854, 1648, 1586, 1530, 1413; HRMS (ESI, m/z) calcd for
+
C H BrN ONa [M + Na] 440.0374, found 440.0377.
22
16
3
4
-Ethyl-2-(phenylamino)-N-(quinolin-8-yl)benzamide, 3d, Scheme 2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
Column chromatography (SiO
2
, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
o
1
white solid (46 mg, 63 %): mp 82 – 85 C; H NMR (300 MHz, CDCl
.87ꢀ8.83 (m, 2H), 8.17 (dd, J = 8.1, 1.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62ꢀ7.51 (m, 3H), 7.47 (dd,
J = 8.4, 4.2 Hz, 1H), 7.38ꢀ7.33 (m, 2H), 7.31ꢀ7.27 (m, 2H), 7.08ꢀ7.02 (m, 1H), 6.78 (dd, J = 8.1, 1.8 Hz,
3
) δ 10.71 (s, 1H), 9.68 (s, 1H),
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1H), 2.62 (q, J =7.5 Hz, 2H), 1.28 (t, J =7.5 Hz, 3H); C NMR (75 MHz, CDCl
3
) δ 167.9, 149.5, 148.2,
146.4, 141.6, 138.8, 136.3, 134.7, 129.3, 128.2, 128.0, 127.4, 122.4, 121.7, 121.5, 121.1, 118.1, 116.3,
116.0, 114.7, 29.1, 15.2; IR (neat) υmax 3351, 3046, 2963, 2926, 1727, 1650, 1528, 1262; HRMS (ESI,
+
m/z) calcd for C24
H
21
N
3
ONa [M + Na] 390.1582, found 390.1562.
4
-Acetyl-2-(phenylamino)-N-(quinolin-8-yl)benzamide, 3e, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
yellow solid (50 mg, 66 %): mp 144 – 146 C; H NMR (600 MHz, CDCl
H), 8.88ꢀ8.86 (m, 2H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.97ꢀ7.94 (m, 2H), 7.63ꢀ7.58 (m, 2H), 7.51 (dd,
J = 8.4, 4.2 Hz, 1H), 7.46 (dd, J = 8.4, 1.8 Hz, 1H), 7.39ꢀ7.36 (m, 2H), 7.30ꢀ7.28 (m, 2H), 7.10 (t, J =
2
o
1
3
) δ 10.78 (s, 1H), 9.58 (s,
1
13
7
.2 Hz, 1H), 2.58 (s, 3H); C NMR (150 MHz, CDCl ) δ 197.8, 167.0, 148.4, 146.4, 140.8, 140.1,
3
138.7, 136.4, 134.2, 129.5, 128.4, 128.0, 127.3, 123.3, 122.1, 121.8,121.7, 121.3,117.3, 116.6, 115.1,
26.9; IR (neat) υmax 3357, 2923, 1688, 1652, 1527, 1381, 1307; HRMS (ESI, m/z) calcd for
+
C
24
H
19
N
3
O
2
Na [M + Na] 404.1375, found 404.1371.
2-(Phenylamino)-N-(quinolin-8-yl)-6-(trifluoromethyl)benzamide, 3f, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (48 mg, 59%): mp 169 – 171 C; H NMR (300 MHz, CDCl
.4, 3.3 Hz, 1H), 8.78 (dd, J = 4.2, 1.5 Hz, 1H), 8.18 (dd, J = 8.4, 1.8 Hz, 1H), 7.62ꢀ7.55 (m, 3H), 7.46
dd, J = 8.4, 4.2 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7..32ꢀ7.24 (m, 3H), 7.15ꢀ7.11 (m, 2H), 7.04ꢀ6.98 (m,
3
) δ 10.31 (s, 1H), 8.96 (dd, J =
8
(
13
3
2H); C NMR (75 MHz, CDCl ) δ 165.4, 148.4, 143.3, 141.1, 138.5, 136.3, 134.1, 130.3 (q, J =4.5
Hz), 130.25, 129.8, 129.4, 128.3(q, J =30.8 Hz), 128.0, 127.2, 123.8 (q, J =272.3 Hz), 123.2, 122.8,
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122.7, 121.8, 120.3, 119.4, 117.2 (q, J =5.3 Hz), 117.1; IR (neat) υmax 3337, 3040, 2926, 1665, 1591,
+
1
527, 1326, 1126; HRMS (EI, m/z) calcd for C23
H
16
F
3
N
3
O [M ] 407.1245, found 407.1241.
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(Phenylamino)-N-(quinolin-8-yl)-5-(trifluoromethyl)benzamide, 3g, Scheme 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
yellow solid (42 mg, 52 %): mp 171 – 172 C; H NMR (600 MHz, CDCl
3
) δ 10.74 (s, 1H), 9.86 (s,
1H), 8.90 (dd, J = 4.2, 1.8 Hz, 1H), 8.83 (dd, J = 7.2, 2.4 Hz, 1H), 8.23 (dd, J = 8.4, 1.8 Hz, 1H), 8.09
(d, J = 1.8 Hz, 1H), 7.64ꢀ7.59 (m, 2H), 7.55ꢀ7.52 (m, 2H), 7.41ꢀ7.37 (m, 3H), 7.30ꢀ7.29 (m, 2H), 7.16
13
(t, J = 7.2 Hz, 1H); C NMR (150 MHz, CDCl
3
) δ 167.0, 149.3, 148.6, 139.9, 138.8, 136.4, 134.2,
1
29.51, 129.3 (q, J = 3.0 Hz), 128.0, 127.2, 125.4 (q, J = 3.0 Hz), 124.2 (q, J = 270.0), 124.3, 122.8,
122.1, 121.9, 119.0 (q, J = 33.0), 117.0, 116.6, 114.6; IR (neat) υmax 3348, 3216, 2923, 2853, 1654,
+
1534; HRMS (EI, m/z) calcd for C23
H
16
F
3
N
3
O [M] 407.1245, found 407.1248.
4'-Methyl-4-(phenylamino)-N-(quinolin-8-yl)-[1,1'-biphenyl]-3-carboxamide, 3h, Scheme 2
Column chromatography (SiO
2
, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
o
1
yellow solid (47 mg, 55 %): mp 286 – 288 C; H NMR (600 MHz, CDCl ) δ 10.77 (s, 1H), 9.47 (s,
3
1H), 8.89 (dd, J = 7.8, 1.8 Hz, 1H), 8.85 (dd, J = 4.2, 1.8 Hz, 1H), 8.21(dd, J = 8.4 Hz, 1.8 Hz, 1H),
8
7
1
.08 (d, J = 2.4 Hz, 1H), 7.64ꢀ7.56 (m, 5H), 7.52ꢀ7.48 (m, 2H), 7.37ꢀ7.34 (m, 2H), 7.31ꢀ7.29 (m, 4H),
13
.06 (t, J = 7.2 Hz, 1H), 2.44 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 168.0, 148.4, 145.0, 141.4, 138.8,
37.5, 136.6, 136.3, 134.6, 131.10, 131.06, 129.6, 129.3, 128.0, 127.3, 126.3, 126.2, 122.6, 121.8,
121.7, 121.0, 119.3, 116.5, 116.1, 21.1; IR (neat) υmax 3358, 3294, 2922, 1657, 1597, 1533, 1328;
+
HRMS (ESI, m/z) calcd for C29
H
24
N
3
O [M + H] 430.1919, found 430.1906.
4-Acetyl-2-((4-methoxyphenyl)amino)-N-(quinolin-8-yl)benzamide, 3i, Scheme 2
2
Column chromatography (SiO , eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a
o
1
yellow solid (62 mg, 75 %): mp 138 – 140 C; H NMR (300 MHz, CDCl
3
) δ 10.77 (s, 1H), 9.44 (s,
1H), 8.88ꢀ8.84 (m, 2H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H),7.92 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 1.5 Hz,
1H), 7.60ꢀ7.56 (m, 2H),7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.36 (dd, J = 8.1, 1.5 Hz, 1H), 7.23ꢀ7.19 (m,
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1
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
6
1
3
2H), 6.94ꢀ6.91 (m, 2H), 3.83 (s, 3H), 2.53 (s,3H); C NMR (150 MHz, CDCl
3
) δ 198.0, 167.2, 156.5,
1
1
48.4, 148.2, 140.2, 138.7, 136.4, 134.3, 133.4, 128.3, 128.0, 127.3, 124.9, 122.0, 121.8, 120.0, 116.5,
16.1, 114.8, 114.0, 55.5, 26.9; IR (neat) υmax 3345, 2924, 2853, 1685, 1653, 1517, 1242; ; HRMS (ESI,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
m/z) calcd for C H N O Na [M + Na] 434.1481, found 434.1456.
25
21
3
3
2-((4-Methoxyphenyl)amino)-N-(quinolin-8-yl)benzamide, 3j, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
yellow solid (48 mg, 65 %): mp 120 – 122 C; H NMR (300 MHz, CDCl
2
o
1
3
) δ 10.73 (s, 1H), 9.44 (s,
H), 8.88ꢀ8.86 (m, 1H), 8.86ꢀ8.85 (m, 1H), 8.20 (dd, J = 8.1, 1.5 Hz, 1H), 7.86 (dd, J = 8.1, 1.8 Hz,
H), 7.62ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.33ꢀ7.27 (m, 1H), 7.23ꢀ7.11 (m, 3H), 6.93ꢀ6.81
1
1
13
(m, 3H), 3.82 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 168.0, 156.2, 148.3, 148.2, 138.6, 136.4, 134.7,
1
34.0, 132.7, 128.0, 127.9, 127.4, 125.0, 121.7, 121.5, 116.84, 116.77, 116.3, 114.6, 114.4, 55.5; IR
+
(
neat) υmax 3348, 2923, 1648, 1580, 1515, 1242; HRMS (ESI, m/z) calcd for C23
92.1375, found 392.1380.
N-(Quinolin-8-yl)-2-(p-tolylamino)benzamide, 3k, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
yellow solid (45 mg, 64 %): mp 146 – 148 C; H NMR (300 MHz, CDCl
.88ꢀ8.83 (m, 2H), 8.18 (dd, J = 8.4, 1.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.62ꢀ7.52 (m, 2H), 7.48 (dd,
19 3 2
H N O Na [M + Na]
3
2
o
1
3
) δ 10.7 (s, 1H), 9.5 (s, 1H),
8
1
3
J = 8.1, 4.2 Hz, 1H), 7.33ꢀ7.30 (m, 2H),7.19ꢀ7.12 (m, 4H), 6.90ꢀ6.84 (m, 1H), 2.34 (s, 3H); C NMR
(75 MHz, CDCl ) δ 167.9, 148.3, 147.1, 138.8, 138.6, 136.4, 134.6, 132.63, 132.57, 129.8, 128.0,
3
1
1
3
27.3, 122.1, 121.7, 121.6, 117.7, 117.4, 116.3, 115.0, 20.8; IR (neat) υmax 3350, 3025, 2923, 2859,
+
726, 1650, 1519, 1262; HRMS (ESI, m/z) calcd for C23
76.1419.
H
19
N
3
ONa [M + Na] 376.1426, found
2-((4-(tert-Butyl)phenyl)amino)-N-(quinolin-8-yl)benzamide, 3l, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
2
o
1
3
organge solid (47 mg, 59 %): mp 280 – 284 C; H NMR (600 MHz, CDCl ) δ 10.72 (s, 1H), 9.54 (s,
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1H), 8.88ꢀ8.87 (m, 1H), 8.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.88 (dd, J = 7.8,
1.8 Hz, 1H), 7.62ꢀ7.60 (m, 1H), 7.57ꢀ7.55 (m, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.40ꢀ7.34 (m, 4H),
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
7
1
1
.24ꢀ7.21 (m, 2H),6.91ꢀ6.86 (m, 1H), 1.35 (s, 9H); C NMR (150 MHz, CDCl
3
) δ 167.9, 148.3, 146.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
45.8, 138.8, 138.6, 136.4, 134.6, 132.6, 128.01, 127.99, 127.4,126.1, 121.7, 121.8,121.3, 117.9,
17.5,116.4,115.3, 34.3, 31.4; IR (neat) υmax 3351, 2959, 2926, 1651, 1590, 1520, 1324; HRMS (EI,
+
m/z) calcd for C26
H
25
N
3
O [M] 395.1998, found 395.2007.
2
-((2,4-Dimethoxyphenyl)amino)-N-(quinolin-8-yl)benzamide, 3m, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (37 mg, 46 %): mp 252 – 254 C; H NMR (600 MHz, CDCl ) δ 10.72 (s, 1H), 9.24 (s, 1H),
3
8.92 (dd, J = 7.2, 1.2 Hz, 1H), 8.86ꢀ8.85 (m, 1H), 8.20ꢀ8.18 (m, 1H), 7.87 (dd, J = 7.8, 1.2 Hz, 1H),
7
.61ꢀ7.59 (m, 1H), 7.55ꢀ7.54 (m, 1H), 7.50ꢀ7.47 (m, 1H), 7.33ꢀ7.28 (m, 2H), 7.12ꢀ7.10 (m, 1H),
6
.86ꢀ6.84 (m, 1H), 6.58( d, J = 3.0 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H);
1
3
C NMR (150 MHz, CDCl
3
) δ 167.9, 156.8, 153.8, 148.2, 147.8, 138.8, 136.3, 134.8, 132.5, 127.99,
1
υ
27.96, 127.4, 123.7, 123.4, 121.6, 121.4, 117.6, 116.9, 116.4, 114.6, 103.8, 99.5, 55.8, 55.5; IR (neat)
22 3 3
max 3337, 3313, 2949, 2830, 1643, 1540, 1511, 1211, 1159; HRMS (ESI, m/z) calcd for C24H N O
+
[
M + H] 400.1661, found 400.1651.
2
-((2,4-Dimethylphenyl)amino)-N-(quinolin-8-yl)benzamide, 3n, Scheme 2
2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
o
1
white solid (35 mg, 48 %): mp 134 – 136 C; H NMR (600 MHz, CDCl ) δ 10.76 (s, 1H), 9.37 (s, 1H),
3
8
.90 (dd, J = 7.8, 1.2 Hz, 1H), 8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.89 (dd, J
7.8, 1.2 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 7.57ꢀ7.55 (m, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.32ꢀ7.29
m, 1H), 7.25ꢀ7.24 (m, 1H), 7.11ꢀ7.10 (m, 1H), 7.03ꢀ7.02 (m, 1H), 6.97ꢀ6.96 (m, 1H), 6.86ꢀ6.84 (m,
=
(
13
3
1H), 2.35 (s, 3H), 2.32 (s, 3H); C NMR (150 MHz, CDCl ) δ 168.0, 148.2, 148.1, 138.8, 136.8, 136.4,
134.7, 133.8, 132.71, 132.68, 131.7, 128.0, 127.9, 127.4, 127.1, 123.8, 121.7, 121.5, 116.8, 116.7,
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116.3, 114.7, 20.9, 18.0; IR (neat) υmax 3358, 3286, 1642, 1520, 1483, 1322; HRMS (ESI, m/z) calcd for
+
C
24
H
21
N
3
ONa [M + Na] 390.1582, found 390.1565.
2-((2,3-Dimethylphenyl)amino)-N-(quinolin-8-yl)benzamide, 3o, Scheme 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
2
o
1
3
white solid (46 mg, 62 %): mp 139 – 141 C; H NMR (300 MHz, CDCl ) δ 10.77 (s, 1H), 9.45 (s, 1H),
8.92ꢀ8.91 (m, 1H), 8.89 (dd, J = 4.2, 1.8 Hz, 1H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.90 (dd, J = 8.1, 1.5
Hz, 1H), 7.65ꢀ7.55 (m, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.34ꢀ7.28 (m, 1H), 7.24ꢀ7.22 (m, 1H), 7.12
13
(
t, J = 7.5 Hz, 1H), 7.02ꢀ6.94 (m, 2H), 6.89ꢀ6.84 (m, 1H), 2.36 (s, 3H), 2.27 (s, 3H); C NMR (75
MHz, CDCl ) δ 168.0, 148.2, 148.0, 139.3, 138.8, 138.0, 136.4, 134.7, 132.7, 131.5, 128.0, 127.9,
3
127.4, 126.0, 125.8, 121.8, 121.7, 121.5, 116.9, 116.9, 116.3, 114.9, 20.6, 14.0; IR (neat) υmax 3343,
+
2
3
2
923, 1647, 1578, 1520, 1320; HRMS (ESI, m/z) calcd for C24
H
21
N
3
ONa [M + Na] 390.1582, found
90.1566.
-((3-Chloro-2-methylphenyl)amino)-N-(quinolin-8-yl)benzamide, 3p, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (44 mg, 57 %): mp 130 – 132 C; H NMR (600 MHz, CDCl
3
) δ 10.77 (s, 1H), 9.53 (s, 1H),
8.89 (dd, J = 7.8, 1.8 Hz, 1H), 8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 7.91 (dd, J
=
7.8, 1.8 Hz, 1H), 7.63ꢀ7.60 (m, 1H), 7.58ꢀ7.56 (m, 1H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H) 7.36ꢀ7.33 (m,
1H), 7.30ꢀ7.28 (m, 1H), 7.17 (dd, J = 7.8, 1.8 Hz, 1H), 7.13ꢀ7.10 (m, 1H), 7.03 (dd, J = 8.4, 1.2 Hz, 1
13
H), 6.94ꢀ6.91 (m, 1H), 2.43 (s, 3H); C NMR (150 MHz, CDCl ) δ 167.8, 148.3, 146.9, 141.1, 138.8,
3
136.4, 135.4, 134.5, 132.7, 130.4, 128.02, 127.98, 127.4, 126.7, 124.6, 121.71, 121.70 121.1, 117.9,
117.8, 116.4, 115.4, 15.0; IR (neat) υmax 3435, 3358, 2921, 1657, 1590, 1528, 1324; HRMS (EI, m/z)
+
calcd for C23
H
18ClN
3
O [M] 387.1138, found 387.1132.
2-((2-Methyl-3-(trifluoromethyl)phenyl)amino)-N-(quinolin-8-yl)benzamide, 3q, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (51 mg, 61 %): mp 142 – 144 C; H NMR (600 MHz, CDCl
3
) δ 10.79 (s, 1H), 9.56 (s, 1H),
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8.90ꢀ8.89 (m, 1H), 8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.93 (dd, J = 7.8, 1.8
Hz, 1H), 7.63ꢀ7.60 (m, 1H), 7.58ꢀ7.56 (m, 2H), 7.51(dd, J = 8.4, 4.2 Hz, 1H), 7.42ꢀ7.41 (m, 1H),7.38ꢀ
13
7
.35 (m, 1H) 7.28ꢀ7.26 (m, 1H), 7.04(dd, J = 8.4, 1.8 Hz, 1H), 6.97ꢀ6.94 (m, 1H), 2.48(s, 3H); C
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
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4
4
4
4
4
4
4
4
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0
1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (150 MHz, CDCl ) δ 167.8, 148.3, 146.7, 141.4, 138.8, 136.4, 134.5, 130.52 (q, J = 30.0 Hz),
3
130.51, 128.1, 128.0, 127.4, 126.1, 125.7, 124.48 (q, J = 271.5 Hz), 121.76, 121.73, 121.10 (q, J = 3.0
Hz), 118.18, 118.16, 116.4,115.4, 13.8 (d, J = 3.0 Hz); IR (neat) υmax 3432, 3352, 2923, 1652, 1583,
+
1325; HRMS (EI, m/z) calcd for C24
H
18
F
3
N
3
O [M] 421.1402, found 421.1400
2-((3,5-Dimethoxyphenyl)amino)-N-(quinolin-8-yl)benzamide, 3r, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (50 mg, 63 %): mp 124 – 126 C; H NMR (600 MHz, CDCl
3
) δ 10.72 (s, 1H), 9.55 (s, 1H),
.87ꢀ8.86 (m, 2H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.88 (dd, J = 7.8, 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz,
H), 7.57ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.40ꢀ7.38 (m, 1H), 6.97ꢀ6.94 (m, 1H), 6.46ꢀ6.45
8
1
13
(
m, 2H), 6.18 (t, J = 1.8 Hz, 1H), 3.80(s, 6H); C NMR (150 MHz, CDCl
3
) δ 167.8, 161.4, 148.3,
145.6, 143.4, , 138.8, 136.4, 134.5, 132.5, 128.0, 127.3, 121.74, 121.71, 119.1, 118.5, 116.6, 116.4,
98.8, 94.9, 55.3; IR (neat) υmax 3347, 2928, 1650, 1597, 1521, 1155; HRMS (ESI, m/z) calcd for
+
C
24
H
22
N
3
O
3
[M + H] 400.1661, found 400.1647.
5
-Bromo-2-((4-fluorophenyl)amino)-N-(quinolin-8-yl)benzamide, 3s, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
yellow solid (55 mg, 63 %): mp 190 – 192 C; H NMR (300 MHz, CDCl ) δ 10.62 (s, 1H), 9.38 (s,
2
o
1
3
1H), 8.88 (dd, J = 8.4, 1.5 Hz, 1H), 8.80 (dd, J = 6.0, 3.0 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.92
(d, J = 2.4 Hz, 1H), 7.59ꢀ7.55 (m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.40ꢀ7.36 (m, 1H), 7.20ꢀ7.16 (m,
13
2
3
H), 7.09ꢀ7.01 (m, 3H); C NMR (75 MHz, CDCl ) δ 166.5, 159.2 (d, J =241.5 Hz), 148.5, 146.1,
138.7, 136.7 (d, J = 2.3 Hz), 136.4, 135.4, 134.2, 130.4, 128.0, 127.2, 124.3, 124.2, 122.0, 121.8, 119.3,
116.6, 116.4, 116.1(d, J = 22.5 Hz), 108.9; IR (neat) υmax 3443, 3343, 2923, 1653, 1541, 1511, 1390,
+
1206; HRMS (ESI, m/z) calcd for C22
H
16
N
3
BrFO [M + H] 436.0461, found 436.0476.
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2-((4-Bromophenyl)amino)-4-fluoro-N-(quinolin-8-yl)benzamide, 3t, Scheme 2
Column chromatography (SiO
white solid (53 mg, 61 %): mp 278 – 280 C; H NMR (300 MHz, CDCl
.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.79 (dd, J = 6.9, 2.4 Hz, 1H), 8.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.88ꢀ7.83
m, 1H), 7.61ꢀ7.53 (m, 2H), 7.49 (dd, J = 8.4, 4.2 Hz, 1H), 7.46ꢀ7.42 (m, 2H), 7.15ꢀ7.10 (m, 2H), 6.98ꢀ
2
, eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
o
1
3
): δ 10.64 (s, 1H), 9.86 (s, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
(
1
3
6.93 (m, 1H), 6.63ꢀ6.56 (m, 1H); C NMR (75 MHz, CDCl
3
): δ 167.1, 165.6 (d, J = 248.2 Hz), 148.5,
1
1
48.3, 139.5, 138.7, 136.4, 134.3, 132.4, 130.3, 130.2, 128.0, 127.3, 123.5, 121.8 (d, J = 5.2 Hz),
16.4, 115.9, 114.3 (d, J = 1.5 Hz) , 114.26, 105.5 (d, J = 22.5 Hz), 101.2 (d, J = 26.2 Hz); IR (neat)
+
υmax 3350, 3310, 1649, 1592, 1534, 1486; HRMS (ESI, m/z) calcd for C H N BrFONa [M + Na]
22 15
3
458.0280, found 458.0271.
-((4-Iodophenyl)amino)-4-methyl-N-(quinolin-8-yl)benzamide, 3u, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
yellow solid (58 mg, 60 %): mp 158 – 160 C; H NMR (600 MHz, CDCl
H), 8.86 (dd, J = 3.6, 1.8 Hz, 1H), 8.85ꢀ8.83 (m, 1H), 8.20ꢀ8.19 (m, 1H), 7.79 (dd, J = 7.8, 1.8 Hz,
1H), 7.62ꢀ7.54 (m, 3H), 7.50ꢀ7.48 (m, 1H), 7.44ꢀ7.28 (m, 1H), 7.21ꢀ7.15 (m, 1H), 7.05ꢀ7.04 (m, 2H),
2
2
o
1
3
) δ 10.71 (s, 1H), 9.65 (s,
1
1
3
6
1
1
3
.78 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H); C NMR (150 MHz, CDCl ) δ 167.7, 148.3, 145.5, 143.4, 141.4,
38.8, 138.1, 136.4, 134.6, 132.2, 128.1, 128.0, 127.3, 122.8, 122.7, 121.7, 121.6, 119.9, 116.33,
16.30, 115.9, 84.5, 21.9; IR (neat) υmax 3449, 3334, 1646, 1526, 1482, 1256; HRMS (ESI, m/z) calcd
+
for C H N IONa [M + Na] 502.0392, found 502.0369.
23
18
3
4
-Cyano-2-((4-methoxyphenyl)amino)-N-(quinolin-8-yl)benzamide, 3v, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
yellow solid (43 mg, 54 %): mp 154 – 156 C; H NMR (300 MHz, CDCl
2
o
1
3
) δ 10.74 (s, 1H), 9.48 (s,
1H), 8.86 (dd, J = 4.5, 1.5 Hz, 1H), 8.82 (dd, J = 5.7, 3.6 Hz, 1H), 8.21 (dd, J = 8.4, 1.8 Hz,1H), 7.86
(d, J = 8.1 Hz, 1H), 7.60ꢀ7.56 (m, 2H), 7.51 (dd, J = 8.4, 4.2 Hz, 1H), 7.26 (s, 1H), 7.19ꢀ7.16 (m, 2H),
13
7
.02 (dd, J = 8.1, 1.5 Hz, 1H), 6.96ꢀ6.93 (m, 2H), 3.84 (s, 3H); C NMR (75 MHz, CDCl
3
) δ 166.5,
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157.2, 148.6, 148.5, 138.7, 136.5, 134.0, 132.2, 128.6, 128.0, 127.3, 125.9, 122.2, 121.9, 119.5, 119.0,
118.5, 117.4, 116.6, 115.8, 115.0, 55.5; IR (neat) υmax 3420, 3320, 2910, 2229, 1659; HRMS (ESI, m/z)
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
calcd for C24
H
18
N
4
O
2
Na [M + Na] 417.1327, found 417.1335.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(Quinolin-8-yl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide, 3w, Scheme 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired product as a
white solid (59 mg, 72 %): mp 140 – 142 C; H NMR (300 MHz, CDCl
2
o
1
3
) δ 10.77 (s, 1H), 9.73 (s, 1H),
8
7
.88ꢀ8.85 (m, 2H), 8.22 (dd, J = 8.1, 1.8 Hz, 1H), 7.91 (dd, J = 7.2, 1.5 Hz, 1H), 7.65ꢀ7.55 (m, 2H),
13
.53ꢀ7.48 (m, 2H), 7.46ꢀ7.39 (m, 4H), 7.28ꢀ7.23 (m, 1H), 7.06ꢀ7.00 (m, 1H); C NMR (75 MHz,
CDCl ) δ 167.6, 148.4, 144.8, 142.2, 138.6, 136.4, 134.4, 132.7, 131.7 (q, J = 31.5 Hz), 129.8, 128.2,
3
128.0, 127.3, 124.02 (q, J = 270.0 Hz), 123.1, 121.9, 121.8, 119.6, 119.3, 118.5 (q, J = 3.7 Hz), 116.5
(
q, J = 3.7 Hz), 116.4, 116.0; IR (neat) υmax 3356, 3219, 1659, 1595, 1532, 1333; HRMS (EI, m/z) calcd
+
for C23
H
16
F
3
N
3
O [M] 407.1245, found 407.1242.
2
-((4-Methoxy-2-nitrophenyl)amino)-4-(pentyloxy)-N-(quinolin-8-yl)benzamide, 3x, Scheme 2
Column chromatography (SiO , eluting with 7:3 hexane/ethyl acetate) afforded the desired product as a
2
o
1
red solid (73 mg, 73 %): mp 110 – 112 C; H NMR (600 MHz, CDCl
3
) δ 10.95 (s, 1H), 10.76 (s, 1H),
8
9
6
.90 (dd, J = 7.8, 1.8 Hz, 1H), 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.26 (dd, J = 8.4, 1.8 Hz, 1H), 7.95 (d, J =
.0 Hz, 1H), 7.63ꢀ7.61(m, 2H), 7.58ꢀ7.56 (m, 1H), 7.52ꢀ7.50 (m, 2H), 7.11(dd, J = 9.6, 3.0 Hz, 1H),
.91 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 9.0, 2.4 Hz, 1H), 3.98 (t, J = 6.6 Hz, 2H), 3.83(s, 3H), 1.81ꢀ1.79
13
(m, 2H), 1.46ꢀ1.39 (m, 4H), 0.95 (t, J =7.2 Hz, 3H); C NMR (150 MHz, CDCl ) δ 166.3, 162.4,
3
1
1
1
52.7, 147.5, 143.4, 137.9, 137.7, 137.4, 134.0, 133.9, 130.6, 128.1, 127.9, 124.0, 121.9, 121.5, 121.0,
18.6, 116.8, 108.6, 107.9, 105.5, 68.3, 55.8, 28.8, 28.1, 22.4, 14.0; IR (neat) υmax 3350, 2928, 2859,
+
655, 1514, 1254, 1148; HRMS (ESI, m/z) calcd for C28
H
29
N
4
O
5
[M + H] 501.2138, found 501.2133.
3-((3-Methoxyphenyl)amino)-N-(quinolin-8-yl)isonicotinamide, 3y, Scheme 2
Column chromatography (SiO , eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a
2
o
1
3
yellow solid (26 mg, 35 %): mp 128 – 130 C; H NMR (600 MHz, CDCl ) δ 10.85 (s, 1H), 9.16 (s,
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1H), 8.90 (dd, J = 7.2, 1.8 Hz, 1H), 8.87 (dd, J = 4.2, 1.8 Hz, 1H), 8.77 (s, 1H), 8.23ꢀ8.21 (m, 2H), 7.67
(d, J = 5.4, 1H), 7.63ꢀ7.59 (m, 2H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.43 (dd, J = 7.2, 1.2 Hz, 1H), 7.09ꢀ
13
7
1
1
.06 (m, 1H), 6.99ꢀ6.94 (m, 2H), 3.94 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 165.8, 151.3,148.5,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
40.6, 139.9, 139.0, 138.7, 136.4, 134.0, 129.5, 128.0, 127.4, 124.1, 123.7, 122.2, 121.8, 120.6, 120.4,
20.0, 116.8, 111.3, 55.7; IR (neat) υmax 3367, 3344, 2921, 2852, 1669, 1598, 1562, 1534, 1025; HRMS
+
(ESI, m/z) calcd for C22
H
18
N
4
O
2
Na [M + Na] 393.1327, found 393.1334.
N-(Quinolin-8-yl)-4-(m-tolylamino)nicotinamide, 3z, Scheme 2
Column chromatography (SiO , eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a
2
o
1
yellow solid (44 mg, 62 %): mp 160 – 162 C; H NMR (600 MHz, CDCl ) δ 10.87 (s, 1H), 10.11 (s,
3
1H), 9.04 (s, 1H), 8.88 (dd, J = 4.2, 1.8 Hz, 1H), 8.83 (dd, J = 7.2, 1.8 Hz, 1H), 8.29 (d, J = 6.0
Hz,1H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.62ꢀ7.58 (m, 2H),7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.32ꢀ7.29 (m,
13
1
H), 7.12ꢀ7.11 (m, 2H), 7.08 (d, J = 6.0 Hz,1H), 7.04 (d, J = 7.8 Hz,1H), 2.39 (s,3H); C NMR (150
3
MHz, CDCl ) δ 166.6, 152.6, 151.9, 149.1, 148.5, 139.6, 138.7, 138.5, 136.4, 134.2, 129.3, 128.0,
127.2, 126.1, 124.4, 122.0, 121.9, 120.7, 116.5, 113.0, 108.0, 21.4; IR (neat) υmax 3370, 3353, 3045,
+
19 4
1648, 1603, 1535, 1326, 1195; HRMS (ESI, m/z) calcd for C22H N O [M + H] 355.1559, found
3
55.1566.
-((6-Methoxypyridin-3-yl)amino)-N-(quinolin-8-yl)benzamide, 3aa, Scheme 2
, eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a
2
Column chromatography (SiO
white solid (33 mg, 44 %): mp 108 – 110 C; H NMR (600 MHz, CDCl ) δ 10.77 (s, 1H), 9.46 (s, 1H),
2
o
1
3
8
.88ꢀ8.86 (m, 2H), 8.21 (dd, J = 8.4, 1.8 Hz, 1H), 8.15 (d, J = 3.0 Hz, 1H), 7.89 (dd, J = 7.8, 1.8 Hz,
H), 7.61 (t, J = 7.8 Hz, 1H), 7.57ꢀ7.54 (m, 2H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.34ꢀ7.31 (m, 1H), 7.03
1
13
(
dd, J = 8.4, 1.2 Hz, 1H), 6.90ꢀ6.88 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H); C NMR (150
MHz, CDCl ) δ 167.9, 161.0, 148.3, 148.1, 142.4, 138.8, 136.4, 135.6, 134.5, 132.9, 131.3, 128.02,
3
127.99, 127.3, 121.72, 121.69, 117.4, 117.0, 116.4, 114.1, 111.1, 53.6; IR (neat) υmax 3352, 3290, 2922,
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+
1651, 1583, 1534, 1486, 1273; HRMS (ESI, m/z) calcd for C22
93.1344.
18 4 2
H N O Na [M + Na] 393.1327, found
3
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
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3
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3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
General Experimental Procedure for C-H Amination Reaction with Electron-
deficient Anilines
0
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4
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6
7
8
9
0
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2
3
4
5
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7
8
9
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2
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7
8
9
0
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
In a 15 mL sealed tube, the substrate 1 (0.2 mmol), Cu(OAc)
2 2
.H O (40 mg, 0.2 mmol, 1 equiv), BuOLi
(32 mg, 0.4 mmol, 2 equiv), and anilines 2 (0.3 mmol, 1.5 equiv) was added followed by DMSO (3
mL). The oxygen gas was passed to the reaction mixture for 1 minute. Then, the tube was charged with
O
preheated oil bath at 100 C for 3 h. The reaction mixture was diluted with 10 mL ethyl acetate and
quenched with 20 ml aq. ammonium solution. Then, it was filtered through celiteꢀ545 and aqueous
phase was extracted with ethyl acetate (2x20). The combined organic phase was collected, dried over
2 4
Na SO and concentrated under vacuum. The crude was purified by column chromatography on silica
gel with gradient of elution of pet ether and ethyl acetate to give the desired amination product
.
2-((4-Nitrophenyl)amino)-N-(quinolin-8-yl)benzamide, 3ab, Scheme 2
Column chromatography (SiO
2
, eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
o
1
yellow solid (74 mg, 96 %): mp 204 – 206 C; H NMR (600 MHz, CDCl
3
) δ 10.76 (s, 1H), 9.98 (s,
1H), 8.87ꢀ8.84 (m, 2H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 8.17 (d, J = 9.0 Hz, 2H), 7.95 (dd, J = 8.4, 1.8
13
Hz, 1H), 7.63ꢀ7.59 (m, 3H), 7.53ꢀ7.50 (m, 2H), 7.24ꢀ7.22 (m, 2H), 7.20ꢀ7.17 (m, 1H); C NMR (150
MHz, CDCl
3
) δ 167.1, 148.5, 148.3, 142.2, 140.7, 138.7, 136.5, 134.1, 132.5, 128.3, 128.0, 127.3,
125.9, 122.4, 122.3, 121.9, 121.8, 118.7, 116.6, 116.4; IR (neat) υmax 3347, 1655, 1595, 1528, 1329,
+
1
16 4 3
111; HRMS (ESI, m/z) calcd for C22H N O Na [M + Na] 407.1120, found 407.1117.
2-((4-Cyanophenyl)amino)-N-(quinolin-8-yl)benzamide, 3ac, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
2
o
1
white solid (49 mg, 67 %): mp 192 – 194 C; H NMR (300 MHz, CDCl ) δ 10.74 (s, 1H), 9.80 (s, 1H),
3
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2
2
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2
2
2
2
2
2
2
3
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3
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5
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6
8.86ꢀ8.81 (m, 2H), 8.21 (dd, J = 8.1, 1.5 Hz, 1H), 7.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.61ꢀ7.44 (m, 7H),
1
3
7
1
1
3
.25ꢀ7.22 (m, 2H), 7.14ꢀ7.09 (m, 1H); C NMR (75 MHz, CDCl ) δ 167.3, 148.4, 146.2, 142.7, 138.7,
36.5, 134.2, 133.6, 132.5, 128.3, 128.0, 127.3, 122.2 121.8, 121.8, 121.7, 121.1, 119.7, 118.0, 117.7,
0
1
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8
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2
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7
8
9
0
1
2
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16.6, 103.1; IR (neat) υmax 3357, 2214, 1653, 1587, 1514, 1326, 1171; HRMS (EI, m/z) calcd. for
+
C
23
H
16
N
4
O [M] 364.1324, found 364.1313.
2-((3,5-Bis(trifluoromethyl)phenyl)amino)-N-(quinolin-8-yl)benzamide, 3ad, Scheme 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired product as a
white solid (76 mg, 80 %): mp 168 – 170 C; H NMR (300 MHz, CDCl
.87ꢀ8.82 (m, 2H), 8.20 (dd, J = 6.9, 1.5 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.63 (s, 2H), 7.61ꢀ7.56 (m,
2
o
1
3
) δ 10.77 (s, 1H), 9.92 (s, 1H),
8
1
3
2H), 7.52ꢀ7.46 (m, 3H), 7.42 (s, 1H), 7.14ꢀ7.09 (m, 1H); C NMR (75 MHz, CDCl
3
) δ 167.3, 148.4,
1
1
1
43.4, 143.3, 138.7, 136.4, 134.1, 132.8, 132.4, 128.3, 128.0, 127.2, 123.2, (q, J =270.8 Hz), 122.1,
21.8, 120.9, 120.7, 118.2 (q, J =3.8 Hz), 116.7, 116.5, 114.4 (q, J = 3.8 Hz); IR (neat) υmax 3351, 3205,
+
648, 1530, 1387, 1279; HRMS (EI, m/z) calcd. for C24
H
15
F
6
N
3
O [M] 475.1119, found 475.1121.
Gram-Scale Synthesis of Compound 3o
The compound Nꢀ(quinolinꢀ8ꢀyl)benzamide (1.24 gm, 5 mmol) was taken in an oven dried two way 250
mL round bottom flask which was connected through condenser under N ballon and dissolved with 60
2
mL DMSO, then it was degased two times followed by Cu(OAc)
2
.H
2
O (1.99 gm, 10 mmol, 2 equiv),
t
AgOAc (0.83 gm, 5 mmol, 1 equiv), TBAB (4.83 gm, 15 mmol, 3 equiv), LiO Bu (.80 gm, 10 mmol, 2
equiv), and 2,3ꢀdimethylaniline (0.9 ml, 7.5 mmol, 1.5 equiv) was added in it. Then it was degassed
o
three times and stirred for 6 h at 100 C. The reaction mixture was diluted with 80 mL ethyl acetate and
quenched with 200 mL aq. ammonium solution. Then, it was filtered through celiteꢀ545 and aqueous
phase was extracted with ethyl acetate (4x50). The combined organic phase was collected and dried
2 4
over Na SO and concentrated under vacuum. The crude was purified by column chromatography on
silica gel with gradient of elution of pet ether and ethyl acetate to give the desired white amination
product 3o with 1.1 gm 60% yield.
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Synthesis of Mefenamic Acid, Scheme 3
In a 15 mL sealed tube, the substrate 3o (73.4 mg, 0.2 mmol), KOH (448 mg, 40 equiv) was added
O
followed by ethanol (2 mL). Then, the tube was charged with preheated oil bath at 110 C for 18 h.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
After completion of reaction, the solvent was evaporated by vacuum and added EtOAc (25 mL x 4) to
extract. The organic phased was dried over Na SO and purified by column chromatography on silica
2
4
gel with a gradient elute of 7:3 hexane/ethyl acetate to give the directing group with 26 mg, yield 91%.
Next, the water fraction was acidified with 1N HCl to PH 3ꢀ4, and extracted with ethyl acetate followed
by organic fraction was dried over Na
elute of 6:4 hexane/ethyl acetate to give Mefenamic acid with 43 mg, 90% yield.
-((2,3-Dimethylphenyl)amino)benzoic acid
Column chromatography (SiO , eluting with 6:4 hexane/ethyl acetate) afforded the desired product as a
white solid (43 mg, 90 %): mp 228 – 230 C; H NMR (600 MHz, CDCl
.4, 1.8 Hz, 1H), 7.31ꢀ7.29 (m, 1H), 7.18ꢀ7.13 (m, 2H), 7.07 (d, J = 7.2 Hz, 1H), 6.73ꢀ6.69 (m, 2H),
2 4
SO and purified by chromatography on silica gel with a gradient
2
2
o
1
3
) δ 9.14 (s, 1H), 8.04 (dd, J =
8
13
2.36 (s, 3H), 2.20 (s, 3H); C NMR (150 MHz, CDCl
3
) δ 173.0, 150.3, 138.33, 138.28, 135.2, 132.9,
132.4, 127.2, 126.0, 123.7, 116.1, 113.7, 109.2, 20.6, 14.0; IR (neat) υmax 3341, 3311, 2860, 1650, 1575,
+
1506, 1445, 1254; HRMS (EI, m/z) calcd. for C15
H
2
15NO [M] 241.1103, found 241.1097.
Control Experiments, Scheme 4
Intermolecular Molecular Kinetic Isotopic effect, Scheme 4a
In a 15 mL sealed tube, the Compound 1 (24.8mg, 0.1 mmol), d
5
2 2
ꢀ1 (25.3 mg, 0.1 mmol) Cu(OAc) .H O
t
(
79.7 mg, 0.4 mmol, 2 equiv), AgOAc (33.3 mg, 0.2 mmol, 1 equiv), BuOLi (32 mg, 0.4 mmol, 2
equiv), TBAB (193.4 mg, 0.6 mmol, 3 equiv) and aniline (27µL, 0.3 mmol, 1.5 equiv) was added
followed by DMSO (3 mL). The nitrogen gas was passed to the reaction mixture for 1 minute. Then, the
O
tube was charged with preheated oil bath at 100 C for 45 minutes. The reaction mixture was diluted
with 10 mL ethyl acetate and quenched with 20 ml aq. ammonium solution. Then, it was filtered
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
6
through celiteꢀ545 and aqueous phase was extracted with ethyl acetate (2x20). The combined organic
2 4
phase was washed with 20 mL saturated sodium hydroxide solution and collected, dried over Na SO
and concentrated under vacuum. The crude was purified by column chromatography on silica gel with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gradient of elution of pet ether and ethyl acetate to give the desired amination product, The product was
1
analyzed by H NMR (300 MHz, CDCl
3
).
Coordination Effect, Scheme 4b
2 2
In a 15 mL sealed tube, the NꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (26.3 mg, 0.1 mmol), Cu(OAc) .H O
t
(
40 mg, 0.2 mmol, 2 equiv), AgOAc (17 mg, 0.1 mmol, 1 equiv), BuOLi (16 mg, 0.2 mmol, 2 equiv),
TBAB (98 mg, 0.3 mmol, 3 equiv) and aniline (13.5 µL, 0.15 mmol, 1.5 equiv) was added followed by
DMSO (2 mL). The nitrogen gas was passed to the reaction mixture for 1 minute. Then, the tube was
O
charged with preheated oil bath at 100 C for 6 h. The reaction mixture was diluted with 10 mL ethyl
acetate and quenched with 20 ml aq. ammonium solution. Then, it was filtered through celiteꢀ545 and
aqueous phase was extracted with ethyl acetate (2x20). The combined organic phase was washed with
2 4
20 mL saturated sodium hydroxide solution and collected, dried over Na SO and concentrated under
vacuum. The crude was purified by column chromatography on silica gel with gradient of elution of pet
1
ether and ethyl acetate and from H NMR analysis, it was found that no reaction occurred and starting
material was recovered.
Competition Reaction, Scheme 4c
In a 15 mL sealed tube, the Nꢀ(quinolinꢀ8ꢀyl)benzamide (24.8 mg, 0.1 mmol), Cu(OAc) .H O (40 mg,
2
2
t
0
.2 mmol, 2 equiv), AgOAc (17 mg, 0.1 mmol, 1 equiv), BuOLi (16 mg, 0.2 mmol, 2 equiv), TBAB
(98 mg, 0.3 mmol, 3 equiv) and 4ꢀmethoxyaniline (18.4 mg, 0.15 mmol, 1.5 equiv), 4ꢀnitroaniline (20.7
mg, 0.15 mmol, 1.5 equiv) was added followed by DMSO (3 mL). The nitrogen gas was passed to the
O
reaction mixture for 1 minute. Then, the tube was charged with preheated oil bath at 100 C for 6 h. The
reaction mixture was diluted with 10 mL ethyl acetate and quenched with 20 ml aq. ammonium
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solution. Then, it was filtered through celiteꢀ545 and aqueous phase was extracted with ethyl acetate
(2x20). The combined organic phase was washed with 20 mL saturated sodium hydroxide solution and
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
collected, dried over Na SO and concentrated under vacuum. The crude was purified by column
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatography on silica gel with gradient of elution of pet ether and ethyl acetate to give the desired
amination products.
Catalyst Inhibition Experiment, Scheme 4d
In a 15 mL sealed tube, the Nꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀ(pꢀtolylamino)benzamide (35.2 mg, 0.1 mmol), Nꢀ
2 2
(quinolinꢀ8ꢀyl)benzamide (24.8 mg, 0.1 mmol), Cu(OAc) .H O (40 mg, 0.2 mmol, 2 equiv), AgOAc
t
(
17 mg, 0.1 mmol, 1 equiv), BuOLi (16 mg, 0.2 mmol, 2 equiv), TBAB (98 mg, 0.3 mmol, 3 equiv)
and 4ꢀmethoxyaniline (18.4 mg, 0.15 mmol, 1.5 equiv), was added followed by DMSO (3 mL). The
nitrogen gas was passed to the reaction mixture for 1 minute. Then, the tube was charged with preheated
O
oil bath at 100 C for 6 h. The reaction mixture was diluted with 10 mL ethyl acetate and quenched with
20 ml aq. ammonium solution. Then, it was filtered through celiteꢀ545 and aqueous phase was extracted
with ethyl acetate (2x20). The combined organic phase was washed with 20 mL saturated sodium
hydroxide solution and collected, dried over Na SO and concentrated under vacuum. The crude was
2
4
purified by column chromatography on silica gel with gradient of elution of pet ether and ethyl acetate
to give the desired amination product 6 mg, 15% yield.
ASSOCIATED CONTENT
Supporting Information
1
13
1
H, C NMR, and kinetic isotope study H NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rjana@iicb.res.in
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ACKNOWLEDGMENT
This work was supported by DST, SERB, Govt. of India; grant no. EMR/2014/000469 & Ramanujan
Fellowship, award no. SR/S2/RJNꢀ97/2012. BKS and AP thank UGC, and CSIR respectively for their
fellowships.
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REFERENCES
(1) (a) Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences; WileyꢀVCH: Weinheim,
Germany, 2008. (b) Lawrence, S. A. Amines: Synthesis Properties and Applications; Cambridge
University Press, Cambridge, UK, 2004.
(2) (a) Okano, K.; Tokuyama, H.; Fukuyama, T. Chem. Commun. 2014, 50, 13650ꢀ13663. (b) Surry, D.
S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338ꢀ6361. (c) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534ꢀ1544.
(3) For recent reviews, see: (a) Kim, H.; Chang, S. ACS Catal. 2016, 6, 2341ꢀ2351. (b) Jiao J.;
Murakami, K.; Itami. K. ACS Catal. 2016, 6, 610ꢀ633. (c) Louillat, M.ꢀL.; Patureau, F. W. Chem. Soc.
Rev. 2014, 43, 901ꢀ910. (d) Armstrong, A.; Collins, J. C. Angew. Chem. Int. Ed. 2010, 49, 2282ꢀ2285.
(4) For selective examples, see: (a) Zhu, D.; Yang, G.; He, J.; Chu, L.; Chen, G.; Gong, W.; Chen, K.;
Eastgate, M. D.; Yu, J.ꢀQ. Angew. Chem. Int. Ed. 2015, 54, 2497ꢀ2500. (b) Kim, H.; Shin, K.; Chang, S.
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