Copper Catalyzed Oxidative C-C Bond Cleavage of 1,2-Diketones: A Divergent Approach to 1,8-Naphthalimides, Biphenyl-2,2′-dicarboxamides, and N-Heterocyclic Amides

Article abstract of DOI:10.1021/acs.joc.8b03114

We report here a simple and efficient copper catalyzed oxidative C-C bond cleavage of stable aromatic cyclic-fused and acyclic 1,2-diketones to deliver amides and imides in high yields. This newly developed protocol provides an excellent tool to transform structurally different 1,2-diketones into different products under the same reaction conditions. The key synthetic features of this methodology are the formation of 1,8-naphthalimides and biphenyl-2,2′-dicarboxamide motifs in high yields. The fluorescent studies of 1,8-naphthalimide derivatives were also carried out in order to show the potential application of these scaffolds.

Full text of DOI:10.1021/acs.joc.8b03114

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Article
Copper Catalyzed Oxidative C-C bond Cleavage of 1,2-
Diketones: A Divergent Approach to 1,8-Naphthalimides,
Biphenyl-2,2’- dicarboxamides and N-Heterocyclic amides
Priyanka R. Sakhare, Parthasarathi Subramanian, and Krishna Pillai Kaliappan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2019
Downloaded from http://pubs.acs.org on January 23, 2019
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Copper Catalyzed Oxidative C−C bond Cleavage of 1,2-Diketones:
A Divergent Approach to 1,8-Naphthalimides, Biphenyl-2,2’-
dicarboxamides and N‑Heterocyclic amides
Priyanka R. Sakhare, Parthasarathi Subramanian and Krishna P. Kaliappan*
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Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai – 400076,
India
Supporting Information
Abstract:
We report here a simple and efficient copper catalyzed oxidative C-C bond cleavage of
stable aromatic cyclic-fused and acyclic 1,2-diketones to deliver amides and imides in
high yields. This newly developed protocol provides an excellent tool to transform
structurally different 1,2-diketones into different products under the same reaction
conditions. The key synthetic features of this methodology are the formation of 1,8-
naphthalimides and biphenyl-2,2’-dicarboxamide motifs in high yields. The fluorescent
studies of 1,8-naphthalimide derivatives were also carried out in order to show potential
application of these scaffolds.
Introduction:
The selective cleavage of inherently inert C─C bond followed by their functionalization became
an attractive subject for chemists to reassemble molecular architecture into useful compounds.1,2
3
4
Remarkably, strategies developed by using noble transition metals such as iridium, rhodium,
5
6
ruthenium and palladium for C─C bond cleavage have made an immense contribution,
however, inexpensive 3d-transition metal catalysts has received attention only in recent years.7
Nonetheless, oxidative C─C bond cleavage by means of 3d-transition metal is a popular choice
8
to construct important scafolds. Recently our group has also disclosed a copper-catalyzed
9
oxidative C‒C bond cleavage of methyl ketones to form N-heterocyclic amides. Although, the
reports on selective C‒C bond cleavage of highly stable functionalities are increasing, to the best
of our knowledge cleavage of 1,2-diketone by means of copper catalysis is not known in the
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literature. The 1,2-diketone is a versatile motif, used as starting materials in various organic
transformations.11 Furthermore, the selective synthesis of different products from similar
substrates by using transition metal catalysis is often considered as an excellent tool to access
important motifs.8a,12 Therefore, we became interested in developing a divergent approach in
copper-catalyzed C─C bond functionalization of 1,2-diketones to useful compounds.
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Figure 1. Representative amides.
n-Bu
O
N
O
NHAr
NHAr
O
O
N
N
H
O
Br
3
O S O
NH
inhibitor for Kinetoplastid
Trypanosoma brucei
IC50 = 0.045 M
2
1
Chiral biphenyl-2,2'-
dicarboxamide
Probe for glutathione
detection in living cell
-
proligand
Further, amides are privileged feedstock present in many natural products, medicinally important
molecules, and agro-chemicals.13 The arene-fused cyclic-imides and biphenyl-2,2’-
dicarboxamides are special class of amides known for their signature applications (Figure 1). The
arene-fused cyclic imides are found in organic semiconductors, fungicides, organic
14
photovoltaics, polymers and pharmaceuticals. Among them, 1,8-naphthalimides are in huge
1
5
demand due to their inherent photo-physical properties. However, these 1,8-naphthalimides are
Scheme 1. Present work.
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R2
N
H
R
N
N
N
O
O
O
O
N
N
R
H
a
b
Cu/O2
O
Biphenyl-2,2'-dicarboxamide
O
R1
1
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Ar

Divergent strategy
using 1,2-diketones
 Also works with 1,3-diketones
 Broad substrate scope
1,8-Naphthalimides
Ar
+
2
-aminopyridine

43 examples
c
R2
O
O
OH
N
N
+
H
R1
R1
N-Heterocyclic
Carboxylic
Acids
amides
generally synthesized by following a traditional condensation reaction between carboxylic acid
derivatives with amines and mostly follow multiple reaction sequence.15,16 Biphenyl-2,2’-
dicarboxamides are another class of amides, having axial chirality, used as proligands and source
17
of chirality for the remote chiral induction in asymmetric catalysis. Despite these impressive
applications, sequential reactions such as acid-amine coupling followed by transition metal
catalyzed intramolecular aryl-aryl coupling are primarily relied upon for their
preparations.18 In order to overcome these multi-step sequential reactions, we intend to
design a divergent cascade approach to synthesize these molecules. Thus, herein, we
disclose a copper catalyzed oxidative C‒C bond cleavage of various 1,2-diketones with
2
-amino heterocycles towards the formation of cyclic-imides, biphenyl-2,2’-
dicarboxamides and N- heterocyclic amides. Our first strategy involves a copper
catalyzed oxidative C‒C bond functionalization between various acenaphthoquinones
and 2-aminopyridines to 1,8-naphthalimides (Scheme 1; a). The second strategy
discusses the synthesis of useful biphenyl-2,2’-dicarboxamides from 9,10-
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phenanthrenequinone and 2-aminopyridines (b). The third strategy deals with the
synthesis of N‑heterocyclic amides and carboxylic acids from acyclic 1,2-diketones (c).
Results and Discussion:
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Our investigation of proposed C─C bond cleavage strategy began with the exposure of
acenaphthoquinone 4a and 4-methyl-2-aminopyridine 5a to a series of copper catalytic reaction
conditions. When model substrates 4a and 5a were subjected in the presence of CuCl (20 mol%)
2
in DMF at 80 °C under O atmosphere, we were delighted to observe the formation of the N-
2
pyridyl 1,8-naphthalimide 6aa in 59% yield as sole product (Table 1, entry 1). Further addition
of additives was useful in order to improve the yield of the product. However, reaction was
sluggish when pyridine was used as an additive (refer Table 1, entry 7‒10). After the extensive
screening of reaction conditions, the desire product 6aa was isolated in 98% in the presence of
CuCl (20 mol%) and t-BuOH:m-xylene (1:2) solvent system along with 0.1 equiv. of pivalic
2
acid as an additive (Table 1, entry 15).
Table 1. Optimization for 1,8-naphthalimide
CH3
H C
3
5a (3 equiv.)
N
O
O
N
NH2
O
N
O
a
CuCl (20 mol%) , O
2
2
solvent (3 mL)
additive, 48 h
4a (1 equiv.)
6aa
Entry
Solvent
Additive
Isolated
Yield (%)
59
1
2
DMF
DMSO
-
-
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t-BuOH
-
66
4
5
6
m-Xylene
t-BuOH
m-Xylene
t-BuOH
DMF
m-Xylene
Isopropanol
-
61
81
71
87
72
84
91
94
74
42
70
98
Pivalic acid (0.1 equiv.)
Pivalic acid (0.1 equiv.)
Pyridine (1.0 equiv.)
Pyridine (1.0 equiv.)
Pyridine (1.0 equiv.)
Pyridine (1.0 equiv.)
Pyridine (1.0 equiv.)
Pyridine (1.0 equiv.)
-
b
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b
b
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0b
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CH CN
3
NMP: t-BuOH (1:2)
NMP: t-BuOH (1:2)
t-BuOH: m-Xylene (1:2)
t-BuOH: m-Xylene (1:2)
13
14
-
1
5
Pivalic acid (0.1 equiv.)
a- our earlier work on copper catalyzed C‒C bond cleavage route to amide synthesis was successful
using 20 mol% CuCl . b-reaction time is 72 h.
9
2
With optimized conditions in hand, the substrate scope for the synthesis of different 1,8-
naphthalimides were explored by using a range of 2-aminopyridines 5. We were pleased to
isolate the respective products 6aa‒6aj (Scheme 2) in good to excellent yields under the set
reaction condition. Both the electron-donating and -withdrawing substituents on 2-
aminopyridines were well tolerated under the reaction conditions. Remarkably, the halogen
substituents remain unaffected, proving its explicit selectivity towards the oxidative C─C bond
cleavage reaction. Further extension of this protocol with 5-bromoacenaphthylene-1,2-dione 4b
gave corresponding 1,8-napthalimdes under the optimized reaction conditions in good to
excellent yields (Scheme 2, 6ba-6bi). These 4-bromo-1,8-naphthalimides 6b further could be
easily elaborated to useful push-pull fluorescent dyes by using coupling reactions. Notably, the
oxidative C‒C bond functionalization of 5-bromoacenaphthylene-1,2-dione 4b took shorter
reaction time than the model compound 4a.
Scheme 2. Scope for 1,8-naphthalimide.
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R1
R1
O
R
O
N
5 (3 equiv.)
N
NH2
O
N
O
CuCl (20 mol%), O
2
2
t-BuOH:m-xylene (1:2)
pivalic acid (0.1 equiv.)
4
a or 4b (R = H/Br)
8
0-85 °C
6
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(1 equiv.)
R
-
------------------------------------------------------------------------------------------------------------
1
R
R1
R2
N
N
O
N
O
O
N
O
1
2
6
ae R = OMe, R = H, 86%, 48 h
1
6
aa R = Me, 98%, 48 h
1
2
6af R = Me, R = H, 91%, 48 h
X-ray crystal
1
6
6
6
ab R = Cl, 88%, 48 h
1
2
6ag R = CF , R = H, 79%. 48 h structure of 6ag
1
3
ac R = OMe, quant. 24 h
1
2
6ah R = Br, R = H, 64%, 72 h
1
ad R = H, 68%, 48 h
1
2
6ai R = Br, R = Me, 64%. 72 h
R1
R1
CH3
O
N
N
N
O
N
O
O
N
O
O
N
Br
Br
R
1
1
6ba R = Me, 87%, 6 h
6be R = CF , 71%, 12 h 6aj R = H, 94%, 48 h
3
1
1
6bb R = Cl, 74%,12 h
6bf R = Me, 69%, 6 h
6bi R = Br, 76%, 6 h
1
1
6bc R = OMe, 96%, 4 h
6bg R = I, 47%, 24 h
1
1
6bd R = H, 87%, 6 h
6bh R = Br, 39%, 24 h
To demonstrate the potential application of this method, we next employed six-membered cyclic
,2-diketones under the aforementioned conditions in Scheme 2. Interestingly, the reaction of
1
9,10-phenanthrenequinone 7 with 2-aminopyridine under these conditions offered biphenyl-2,2’-
dicarboxamide 8a in 66% instead of corresponding cyclic-imide along with recovery of some
starting material (Scheme 3). Nevertheless, biphenyl-2,2’-dicarboxamide 8a is a versatile
compound used for various purposes including in asymmetric catalysis. As well, to the best of
our knowledge, this method would be a shortest and single step protocol for accessing biphenyl-
2
,2’-dicarboxamides. Hence, we planned to optimize the reaction conditions further to improve
the yield of the product. After the solvent modification, we isolated 74% of the desired product
8a under CuCl (20 mol%) in a mixture of MeCN:t-BuOH:m-xylene (1:1:1). These revised
2
conditions were then applied to various 2-aminopyridines and the corresponding biphenyl -2,2’-
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dicarboxamides were isolated in excellent yields (Scheme 3). However, the strong electron
withdrawing substituents (-NO and –CN) on 2-aminopyridines have failed to provide the
2
,
expected products.
Scheme 3. Scope for biphenyl-2,2’-dicarboxyamide.
1
1
1
1
1
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1
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0
R
O
O
O
R
5
(4.5 equiv.)
NH2
CuCl (20 mol %), O
NH
R
N
N
HN
O
2
2
N
MeCN:t-BuOH:m-Xylene
pivalic acid (0.1 equiv.),
7
(1 equiv.)
8
80-85 °C, 48 h
-
------------------------------------------------------------------------------------------------------------
R
O
O
NH
N
R
NH
N
HN
O
N
HN
O
R
N
R
8a R = Me, 81%
8e, R = Br, 51%
8f, R = Cl, 66%
8g, R = Me, 83%
8b R = Cl, 88%
c R = OMe, 66%
8
O
NH
N
HN
O
N
X-ray structure of 8d
8d, 74%
After successfully developing a simple and efficient process for cleaving the cyclic 1,2-
diketones, we focused our attention to extend this strategy to acyclic 1,2-diketones (Scheme 4a).
Based on our earlier observations (Scheme 1 & 2) that 2 moles of amide formation was expected
from 1 mole of acyclic 1,2- diketones. However, the initial reaction of benzil 9a with 2-
aminopyridine 5d under optimized conditions (refer Table 2, entry 7) afforded corresponding N-
pyridyl amide 10aa in low yield (Scheme 4a). Although a further increase in the amine
Table 2: Optimization for N-Heterocyclic Amide
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NH2
O
O
O
N
N
N
OH
H
+
O
2
CuCl (20 mol%), O2
Solvent (3 mL)
9
a
10a (50%)
10b (50%)
8
0-85 °C
Isolated
Yield
for 50%
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2-
Entry aminopyridine
Time
h)
Solvent
Additive (equiv.)
(
(
equiv.)
1
2
3
4
5
6
7
8
9
10
3
DCE
DMSO
-
48
48
48
48
48
72
48
>72
48
48
48
72
48
72
72
72
>72
>72
48
48
-
20
10
-
3
-
3
DMF
-
3
n-hexanol
n-pentanol
i-PrOH
-
3
-
-
3
-
33
39
45
Trace
25
44
30
34
40
46
35
35
38
44
36
3
t-BuOH:m-xylene (1:2)
NMP:t-BuOH (1:2)
1,4-dioxane:MeCN (1:2)
NMP
-
3
-
3
-
3
3
pyridine (1.0)
pyridine (1.0)
pyridine (1.0)
pyridine (1.0)
pyridine (1.0)
pyridine (1.0)
pyridine (1.0)
pivalic acid (0.1)
pivalic acid (0.1)
formic acid (1.0)
AcOH (0.1)
1
1
1
1
t-BuOH
2a
3+1.5
3
t-BuOH
3
m-xylene
14
4.5
5
m-xylene
1
1
1
1
5
6
7
8
NMP:m-xylene (1:2)
t-BuOH:m-xylene (1:2)
t-BuOH
5
3
3
m-xylene
19
4.5
3
t-BuOH:m-xylene (1:2)
NMP:t-BuOH (1:2)
2
0
2
1
3
4.5
m-xylene
t-BuOH:m-xylene (1:2)
2,6-lutidine
48
48
14
50
b
2
2
pivalic acid (0.1)
a -1.5 equiv. of 2-aminopyridine was added after 24 h, b – benzoic acid isolated in 30% yield.
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equivalence slightly improved the yield, mass imbalance suggested the formation of side
product. After careful observations, corresponding benzoic acid 10ba was isolated from the
aqueous medium in good yield as another product of the reaction.
Scheme 4. Substrate scope with acyclic 1,2-diketones.
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
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
a) Symmetric 1,2-diketones
R2
5
(4.5 equiv.)
NH2
CuCl (20 mol %), O
R2
O
N
R1
O
O
R1
2
2
R1
N
N
+
R1 OH
O
t-BuOH:m-xylene (1:2)
pivalic acid (0.1 equiv.)
H
9 (1 equiv)
10a (50%)
10b (50%)
8
0-85 °C, 48 h
------------------------------------------------------------------------------------------------------------------------------------------------------------
-
R2
R2
O
O
O
R1
N
N
R3
N
N
N
N
H
H
H
R1
1
2
1
1
1
1
1
1
0aa, R = H, R = Me, 44%
1
c
2
3
10ag, R = F, 41% 10aj,
1
R = H, R = Me, 33%
1
2
0ab, R = H, R = Cl, 42%
1
2
3
c
0ah, R = Br, 48% 10ak
, R = Br, R = H, 31%
1
2
a
0ac, R = H, R = OMe, 50%
1
1
0ai, R = Me, 39%
1
2
a
0ad, R = H, R = H, 50%
Cl
O
1
2
0ae, R = OMe, R = H, 49%
O
1
2
0af, R = OMe, R = OMe, 47%
N
N
N
N
H
H
X
O
10ao, 39%b,c
1
0am, X = S, 30%
0an, X = O, 76%c
N
N
1
H
1
0al, 39%
-
------------------------------------------------------------------------------------------------------------------------------------------------------------
a. Reaction time is 24h , b. Reaction time 72h, c- brsm yield.
b) Unsymmetric 1,2-diketones
O
O
1
0ad
N
N
10ap
+
H
Cl
5
NH
2
d
O
3:2 ratio based on NMR
O
Cl
MeO
Br
11
N
Standard
Conditions
O
N
N
+
10ad
H
MeO
10aq, 29%
24%
1
2 O
O
O
5
d
CO2
OH
OH
+
N
N
Standard
Condition
H
Br
10ah, 68%
13
The reaction scope was examined further with a range of acyclic 1,2-diketones and 2-
aminopyridines. Subsequently, the corresponding products, amides 10a and acids 10b were
isolated in good to excellent yields (Scheme 4a, for acid refer SI). Further, a few unsymmetrical
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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
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4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
5
5
6
8
f
1
,2-diketones have also been subjected to oxidative C‒C bond cleavage reactions and the
results are described in Scheme 4b. Finally, the applicability of this catalytic system was tested
on other functionalities such as β-keto ester and 1,3-diketone. Thus, ethyl acetoacetate 14 with 2-
1
2
aminopyridine afforded acetamide 15 and N ,N -di(pyridin-2-yl)oxalamide 16 in good yields
Scheme 5, eq. 1), whereas, 1,3-diphenylpropane-1,3-dione 17 delivered the corresponding
(
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
amides (10ad & 10ab ) along with alpha-keto amides in low yields (Scheme 5, eq.2).8f,9
Scheme 5. Substrate scope with β-keto ester and 1,3-diketone.
O
1)
H
O
N
N
N
H
N
O
O
5d
+
H C
3
N
N
O
Standard
Condition
H
H C
3
OEt
16,
34%
1
5, 42%
14
O
H
N
O
2)
5d
Ph
Ph
N
N
+
O
N
H
O
O
10ad, 25%
1
8, 12%
Standard
Condition
Cl
Ph
Ph
O
H
N
17
O
Cl
+
5b
N
N
O
N
H
10ab, 38%
19, 15%
To gain insight into the reaction mechanism, several control experiments were carried out (refer
experimental section). When the standard reaction was carried out under an inert atmosphere,
only 1,8-naphthalimide 6aa was obtained in traces, suggesting the necessity of oxygen for the
formation of required product (Scheme 6, 1). Further, the reaction didn’t give the anticipated
9
product in the absence of copper catalyst. Following our earlier studies, we believed that the
mechanistic cycle commences with the formation of the copper-peroxy radical species. Thus, the
radical-trapping experiment was conducted using 2,4,6-tri(t-Bu)phenol as radical scavenger
under the standard conditions. The product formation was significantly inhibited, suggesting
radical processes being involved in this oxidative cleavage (Scheme 6). The in situ generation of
active catalytic species Cu(I) under the reaction medium was supported by XPS analysis (refer
SI).19
1
a
Based on the above control experiments and the literature reports a plausible mechanism for
this oxidative C‒C bond cleavage is outlined in Scheme 6, 2a. The catalytic cycle is initiated by
the in situ generation of active catalyst Cu(I) which upon reaction with molecular O to form
2
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copper-peroxy radical A. Subsequent chelation with substrate, 1,2-diketone to B followed by
20
SET oxidation to provide Cu(III)-intermediate C. It is speculated that the more electrophilic
chelation of Cu(III) in intermediate C facilitates the nucleophilic addition of 2-aminopyridine to
2
1
ketone to provide the reactive intermediate D. Further, the reductive cleavage of intermediate D
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
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
Scheme 6. 1) Control Experiments. 2) Possible Mechanism.
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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
1
) Control Experiments
H C
3
CH3
N
O
O
N
O
N
O
NH2
t-BuOH:m-xylene
6a
4a
pivalic acid, 80-85 °C
A = CuCl , under inert atm ...................trace
B = without CuCl , with O ....................No product
2 2
C = with 2,4,6-tri(t-Buphenol)................trace
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
-
--------------------------------------------------------------------------------------------------------
2) Possible Mechanism
LCu(II)
2a. Amide formation
benzil
O
O2
A
O
insitu
Cu(II)
reduction
Ph
Ph
O
(I)
O(II)
Cu O
Cu
O
O
B
t-BuOH
Ph
1
OH
0ba
O
O Cu(III)
Ph
Ph
O
OCu(I)
O
O
E
O
Ph
C
Ph
O
Cu(III)
O
Py
O
N
H
Ph
O
Py
2-aminopyridine
Ph
0ad
N
O
H
1
D
2b. 1,8-Naphthalimide formation
Py
Cu(III)
Py
NH
O
Py
O
HN
O
Ar
O
O
O
Cu(III)
O
N
Py
O
O
O
N
O
O
H
O
OCu(I)
Ar
D
F
6ad
2c. Biaryl dicarboxamide formation
Py
O
HN
Py
Ar
O
Cu(III)
HN
Py
Py
N
O
O
Cu(III)
O
N
O
O
H
O
H
O
Ar
O
O
O
(I)
D
Cu O
8d
G
O NH2Py
HN
Py
delivers the desired N-pyridyl amide and copper benzoyl peroxide E. Finally, the ligand
exchange or decomposition of copper benzoyl peroxide E in the presence of polar solvent
regenerate the active catalytic species Cu(I) and by-product, carboxylic acid 10ba. This
mechanism explains the oxidative C‒C bond cleavage of acyclic 1,2-diketones. The oxidative
C‒C bond cleavage of cyclic 1,2-diketone, acenaphthoquinone could be explained from the
reactive intermediate D (Scheme 6, 2b). The reductive cleavage of D offers the desired amide
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and copper peroxide moieties in the same compound. The proximity facilitated intramolecular
amidation of F affords the cyclic-imides and regenerates Cu(I)-species. However, 6-membered
cyclic ketone underwent for the intermolecular amidation reaction to obtain corresponding
biphenyl-2,2’-dicarboxamide 8d (Scheme 6, 2c).
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
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
In view of their impressive medicinal chemistry application of 1,8-naphthalimides including as
fluorescent probes, we envisioned to study the photo-physical properties of our newly
synthesized 1,8-naphthalimides. Thus, the chosen compounds were designed as push-pull
fluorophore system by attaching the electron donating motif on 4th position of 1,8-
naphthalimides (push-pull system) (Figure 2).. Subsequently, we studied extensively the photo-
physical properties our push-pull 1,8-naphthalimides by using various solvents. These
compounds showed high fluoresce even at 3µM concentration in non-polar solvent like
chloroform, dichloromethane whereas in polar solvents like methanol fluorescence is getting
quenched (Figure 2).. Also, substituents on pyridine ring did not affect much the absorption or
emission frequency in UV-vis and fluorescence spectra respectively (refer SI for details), Thus,
for further applications of these compounds as fluorescent dye or sensor, the fluoresces property
could be tuned by varying substitutions on naphthalimide core than on pyridyl ring.
Figure 2. Application of 1,8-naphthalimides
Conclusion:
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1
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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
In summary, an efficient strategy for oxidative cleavage of C-C bond of 1,2-diketones
has been successfully developed using inexpensive copper-catalyst. The reaction is
very mild, simple and a high yielding protocol to access 1,8-naphthalimides, biphenyl-
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
2,2’-dicarboxamides and N-heterocyclic amides which are important structural motifs.
Our work provides future scope for the utility of different acyclic and cyclic 1,2 or 1,3-
diketones towards the synthesis of diverse scaffolds under similar reaction conditions
which may find applications in synthetic, applied and material sciences.
Experimental Section:
General Information: All starting materials and reagents were obtained from commercial
suppliers and used after further purification as detailed below. The required solvents for isolation
of products and chromatography were reagent grade and glass distilled. Toluene and
tetrahydrofuran purified using solvent purification system by M-Braun (MB-SPS 5). The
reaction flasks were dried in an oven at 150 °C for 12 h. Air and moisture-sensitive reactions
were performed under UHP nitrogen atmosphere. Flash column chromatography was performed
using silica gel (230-400 mesh, Acma). Thin-layer chromatography (TLC) was conducted with
Merck silica gel 60 F254 percolated plates (0.25 mm) and visualized with UV. IR spectra were
recorded with Perkin Elmer Spectrum One and JASCO V-570 spectrophotometers. Mass spectra
1
were obtained with a Bruker ESI-QTOF spectrometer (maXIS impact 282001.00081). H NMR
spectra were recorded on a Bruker 400 MHz and a Bruker 500 MHz spectrometer and reported in
6
ppm using solvent as an internal standard (CDCl at 7.26 ppm, d -DMSO, at 2.50 ppm). Proton-
3
decoupled 13C NMR spectra were recorded on a Bruker 400 MHz and a Bruker 500 MHz
spectrometer and have been reported using solvent as an internal standard (CDCl at 77.2 ppm,
3
d6-DMSO at 39.51 ppm). The GC-MS analyses were done by an Agilent 7890A GC system
connected with a 5975C inert XL EI/CI MSD (with a triple axis detector). All the UV
experiments were carried out using Varian CARY 100 Bio UV-Visible Spectrophotometer. The
fluorescent studies were carried out by using Varian CARY Eclipse Fluorescence
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+
Spectrophotometer. The X-Ray studies were carried using Rigaku R-axis 724 single crystal x-
ray diffraction.
General Procedure A for Synthesis of 1,8-naphthalimide:
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
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
To a solution of 1,2-diketone (0.25 mmol/0.5 mmol, 1 equiv.) and 2-aminopyridine (0.75
mmol/1.5 mmol, 3 equiv.) in t-BuOH:m-xylene (1:2, 3 mL) in a reaction tube, anhydrous
CuCl (20 mol%) was added at r.t. along with pivalic acid (10 mol%). The reaction
2
mixture was stirred at 80-85 °C for 6-48 h under the oxygen atmosphere and then
quenched with H O after monitoring by TLC. The aqueous layer was extracted by
2
dichloromethane (DCM, 3 × 20 mL). The combined organic layer was washed with
water, dried over anhydrous Na SO and concentrated under vacuum to get the crude
2
4
product, which was further purified using flash column chromatography on silica gel
230-400 mesh) column (eluent ethyl acetate-petroleum ether).
(
2-(4-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6aa):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
0.5 mmol) and 4-methyl-2-aminopyridine (162 mg, 1.5 mmol) for 48 h provided
corresponding product 6aa as a pale yellow solid (141 mg, 98%). R = 0.1 (100% DCM);
f
1
m.p. = >260 °C; H NMR (500 MHz, CDCl ): δ 8.62 (d, J = 7.2 Hz, 2H), 8.57 (d, J = 4.9
3
Hz, 1H), 8.26 (d, J = 8.2 Hz, 2H), 7.77 (t, J = 7.6 Hz, 2H), 7.25 (s,1H), 7.22 (s, 1H), 2.46
1
(
s, 3H); 13C{ H} NMR (125 MHz, CDCl ): δ 164.4, 150.3, 149.7, 149.7, 134.6, 131.9,
3
-1
1
31.7, 128.8, 127.1, 125.3, 124.9, 122.8, 21.2; IR υ (KBr, cm ): 3429, 2921, 1713,
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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
1682, 1668, 1605, 1592, 1405, 1379, 1354, 1244, 781, 772; HRMS (ESI-QTOF): m/z
+
calcd. for C H N NaO [M+Na] 311.0791, found 311.0792.
18
12
2
2
2-(4-chloropyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ab):
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
Following the general procedure A, the reaction between acenaphthoquinone (91mg,
0.5 mmol) and 4-chloro-2-aminopyridine (192 mg, 1.5 mmol) for 48 h provided
corresponding product 6ab as a white solid (135 mg, 88%). R = 0.19 (20%
f
1
EtOAc/petroleum ether); m.p. = 257-260 °C; H NMR (400 MHz, CDCl ): δ 8.66–8.63
3
13
1
(m, 3H), 8.30 (d, J = 8.2 Hz, 2H), 7.81 (t, J = 8.0 Hz, 2H), 7.48–7.44 (m, 2H); C{ H}
NMR (125 MHz, CDCl ): δ 164.1, 150.7, 150.6, 146.1, 134.8, 131.9, 131.8, 128.7,
3
-1
1
27.2, 125.0, 124.7, 122.5; IR υ (KBr, cm ): 3438, 3064, 2922, 1706, 1666, 1574, 1556,
1392, 1374, 1351, 1239, 1197, 837, 775, 743, 720; HRMS (ESI-QTOF): m/z calcd. for
+
C H ClN NaO [M+Na] 331.0245, found 331.0247.
17
9
2
2
2-(4-methoxypyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ac):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
0.5 mmol) and 4-methoxy-2-aminopyridine (186 mg, 1.5 mmol) for 24 h provided
corresponding product 6ac as a yellow solid (152 mg, quantitative yield). R = 0.4 (100%
f
1
EtOAc); m.p. = 218-220 °C; H NMR (500 MHz, CDCl ): δ 8.62 (d, J = 10.0 Hz, 2H),
3
8.53 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 10.0 Hz, 2H), 7.77 (m, 2H), 6.96 (d, J = 5.0 Hz,
13
1
1
H), 6.93 (s, 1H), 3.90 (s, 3H); C{ H} NMR (125 MHz, CDCl ): δ 167.9, 164.2, 151.1,
3
-1
150.7, 134.6, 131.9, 131.7, 128.7, 127.1, 122.8, 110.9, 110.2, 55.7; IR υ (KBr, cm ):
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3363, 3069, 2921, 1708, 1681, 1665, 1600, 1567, 1376, 1357, 1242, 1226, 1195, 1035,
+
8
48, 782, 773; HRMS (ESI-QTOF): m/z calcd. for C H N NaO [M+Na] 327.0740,
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2
3
found 327.0741.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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2-(pyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ad):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
.5 mmol) and 2-aminopyridine (141 mg, 1.5 mmol) for 48 h provided corresponding
0
product 6ad as a yellow solid (125 mg, 68%). R = 0.35 (40% EtOAc/petroleum ether);
f
1
m.p. = 240-243 °C; H NMR (400 MHz, CDCl ): δ 8.74 (d, J = 4.0 Hz, 1H), 8.64 (d, J =
3
7
2
1
.6 Hz, 2H), 8.28 (d, J = 8.4 Hz, 2H), 7.95 (td, J = 7.6, 1.2 Hz, 1H), 7.79 (t, J = 7.6 Hz,
H), 7.47–7.44 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ
1
3
64.4, 150.2, 149.7, 138.7, 134.6, 131.9, 131.7, 128.8, 127.2, 124.3, 124.2, 122.8; IR υ
-1
(
KBr, cm ): 3433, 3079, 2922, 1704, 1664, 1631, 1589, 1464, 1436, 1375, 1291, 1240,
1198, 1116, 998, 845, 775, 742, 671; HRMS (ESI-QTOF): m/z calcd. for C H N NaO
17
10
2
2
+
[
M+Na] 297.0634, found 297.0633.
2-(5-methoxypyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ae):
Following the general procedure A, the reaction between acenaphthoquinone (45 mg,
0.25 mmol) and 5-methoxy-2-aminopyridine (93 mg, 0.75 mmol) for 48 h provided
corresponding product 6ae as a yellow solid (65 mg, 86%). R = 0.10 (40%
f
1
EtOAc/petroleum ether); m.p. = decomposed >260 °C; H NMR (500 MHz, CDCl ): δ
3
8.60 (d, J = 7.2 Hz, 2H), 8.38 (d, J = 2.7 Hz, 1H ), 8.25 (d, J = 8.1 Hz, 2H), 7.76 (t, J =
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7.7 Hz, 2H), 7.41 (dd, J = 8.6, 2.8 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H); C{ H}
NMR (125 MHz, CDCl ): δ 164.5, 156.0, 142.0, 137.2, 134.5, 131.8, 131.6, 128.7,
3
-1
1
27.1, 124.3, 123.1, 122.8, 56.0; IR υ (KBr, cm ): 3438, 3080, 1709, 1680, 1666, 1600,
0
1
2
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4
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6
7
8
9
0
1
2
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7
8
9
0
1
588, 1571, 1478, 1391, 1357, 1295, 1259, 1238, 1196, 1126, 1024, 850, 826, 785,
+
7
77; HRMS (ESI-QTOF): m/z calcd. for C H N NaO [M+Na] 327.0740, found
18
12
2
3
327.0737.
2-(5-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6af):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
.5 mmol) and 5-methyl-2-aminopyridine (162 mg, 1.5 mmol) for 48 h provided
0
corresponding product 6af as a yellow solid (132 mg, 91%). R = 0.12 (40%
f
1
EtOAc/petroleum ether); m.p. = decomposed >260 °C; H NMR (500 MHz, CDCl ): δ
3
8
.62 (d, J = 5.0 Hz, 2H), 8.55 (s, 1H), 8.26 (d, J = 10.0 Hz, 2H), 7.79–7.74 (m, 2H), 7.72
(d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 2.45 (s, 3H); 13C{ H} NMR (125 MHz,
1
CDCl ): δ 164.4, 150.5, 147.2, 139.2, 134.5, 134.0, 131.9, 131.6, 128.8, 127.1, 123.5,
3
-1
1
7
3
22.8, 18.3; IR υ (KBr, cm ): 3427, 1710, 1660, 1646, 1588, 1376, 1353, 1239, 1199,
+
75; HRMS (ESI-QTOF): m/z calcd. for C H N NaO [M+Na] 311.0791, found
18 12
2
2
11.0793.
2-(5-(trifloromethyl)pyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ag):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
0.5 mmol) and 5-(trifluoromethyl)-2-aminopyridine (243 mg, 1.5 mmol) for 48 h provided
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corresponding product 6ag as an off white solid (135 mg, 79%). R = 0.7 (100% DCM);
f
1
m.p. = 198-221 °C; H NMR (500 MHz, CDCl ): δ 9.01 (s, 1H), 8.64 (d, J = 7.1 Hz, 2H),
3
8
8
1
.30 (d, J = 8.1 Hz, 2H), 8.18 (d, J = 6.9 Hz, 1H), 7.80 (t, J = 7.6 Hz, 2H), 7.56 (d, J =
1
1
1
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5
6
0
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4
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7
8
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0
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7
8
9
0
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2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
3
.1 Hz, 1H); C{ H} NMR (100 MHz, CDCl ): δ 164.1, 152.8, 147.3 (q, J = 4.0 Hz),
3
C-F
36.0 (q, 3JC-F = 3.0 Hz), 134.9, 131.9, 128.8, 127.3 (q, 2JC-F = 33.0 Hz), 127.2,
124.6,123.5 (q, 1JC-F = 271.0 Hz), 122.4; F NMR (470 MHz, CDCl ) δ = -62.3 (s, 3F);
19
3
-1
IR υ (KBr, cm ): 3434, 1709, 1679, 1588, 1376, 1355, 1332, 1240, 1164, 1131, 1079,
+
7
79; HRMS (ESI-QTOF): m/z calcd. for C H F N NaO [M+Na] 365.0508, found
18
9
3
2
2
365.0500.
2-(5-bromopyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ah):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
.5 mmol) and 5-bromo-2-aminopyridine (258 mg, 1.5 mmol) for 72 h provided
0
corresponding product 6ah as a pale orange solid [91 mg, 52% (64% brsm)]. R = 0.66
f
1
(
100% DCM); m.p. = 234-237 °C; H NMR (400 MHz, CDCl ): δ 8.78 (d, J = 2.1 Hz, 1H),
3
8.63 (d, J = 7.2 Hz, 2H), 8.28 (d, J = 8.2 Hz, 2H), 8.03 (dd, J = 8.3, 2.3 Hz, 1H), 7.79 (t,
J = 7.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H); 13C{ H} NMR (125 MHz, CDCl ): δ 164.2,
1
3
151.3, 148.3, 141.3, 134.8, 131.9, 131.8, 128.8, 127.2, 125.6, 122.6, 121.2; IR υ (KBr,
-1
cm ): 3415, 2924, 1703, 1665, 1589, 1464, 1373, 1353, 1236, 1193, 1010, 826, 778;
+
HRMS (ESI-QTOF): m/z calcd. for C H BrN NaO [M+Na] 374.9740, found 374.9738.
17
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2-(5-bromo-4-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ai):
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Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
0.5 mmol) and 4-methyl-5-(trifluoromethyl)-2-aminopyridine (280 mg, 1.5 mmol) for 72 h
provided corresponding product 6ai as a off white solid [92 mg, 50% (64% brsm)]. R =
f
0
1
2
3
4
5
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7
8
9
0
1
2
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5
6
7
8
9
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9
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2
3
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8
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1
0
.65 (100% DCM); m.p. = 183-186 °C; H NMR (500 MHz, CDCl ): δ 8.74 (s, 1H), 8.64-
3
8.61 (m, 2H), 8.29-8.26 (m, 2H), 7.77 (dt, J = 8, 3, 2.3 Hz, 2H), 7.29 (s, 1H), 2.48 (s,
3H); 13C{ H} NMR (125 MHz, CDCl ): δ 164.3, 151.6, 149.9, 148.5, 134.8, 131.9,
1
3
-1
1
31.8, 128.7, 127.2, 126.3, 124.1, 122.6, 22.6; IR υ (KBr, cm ): 3432, 2924, 2169,
1714, 1682, 1669, 1588, 1457, 1376, 1369, 1343, 1239, 1032, 990, 781, 773; HRMS
+
(ESI-QTOF): m/z calcd. for C H BrN NaO [M+Na] 388.9896, found 388.9897.
18
11
2
2
2-(6-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6aj):
Following the general procedure A, the reaction between acenaphthoquinone (91 mg,
.5 mmol) and 6-methyl-2-aminopyridine (162 mg, 1.5 mmol) for 48 h provided
0
corresponding product 6aj as a pale yellow solid (135 mg, 94%). R = 0.5 (0.2% MeOH :
f
1
DCM); m.p. = 251-253 °C; H NMR (500 MHz, CDCl ): δ 8.61 (d, J = 7.2 Hz, 2H), 8.25
3
(d, J = 8.2 Hz, 2H), 7.81(t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.7 Hz,
1
1
H), 7.19 (d, J = 7.7 Hz, 1H), 2.64 (s, 3H); 13C{ H} NMR (125 MHz, CDCl ): δ 164.4,
3
159.5, 149.0, 138.8, 134.5, 131.8, 131.6, 128.8, 127.1, 123.9, 122.9, 121.0, 24.4; IR υ
-1
(KBr,cm ): 3432, 1714, 1679, 1659, 1591, 1461, 1376, 1355, 1243, 1201, 773, 760;
+
HRMS (ESI-QTOF): m/z calcd. for C H N NaO [M+Na] 311.0791, found 311.0798.
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12
2
2
6-bromo-2-(4-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6ba):
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Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(65 mg, 0.25 mmol) and 4-methyl-2-aminopyridine (81 mg, 0.75 mmol) for 6 h provided
corresponding product 6ba as a off white solid (80 mg, 87%). R = 0.25 (100% DCM);
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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6
0
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7
8
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5
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7
8
9
0
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2
3
4
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7
8
9
0
1
m.p. = 240-244 °C; H NMR (400 MHz, CDCl ): δ 8.70 (d, J = 4.0 Hz, 1H), 8.65 (d, J =
3
8.0 Hz, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H),
13
1
7.89 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 2.47 (s, 3H); C{ H} NMR (100 MHz,
CDCl ): δ 163.9, 163.8, 150.5, 149.8, 149.3, 133.9, 132.5, 131.6, 131.4, 131.0, 131.0,
3
-1
1
29.6, 128.3, 125.5, 124.9, 123.3, 122.4, 21.2; IR υ (KBr, cm ): 3434, 2922, 1710,
1669, 1605, 1588, 1570, 1399, 1359, 1346, 1242, 1193, 779, 773; HRMS (ESI-QTOF):
+
m/z calcd. for C H BrN O [M+H] 367.0077, found 367.0078.
18
12
2
2
6-bromo-2-(4-chloropyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bb):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(65 mg, 0.25 mmol) and 4-chloro-2-aminopyridine (96 mg, 0.75 mmol) for 12 h provided
corresponding product 6bb as a white solid (53 mg, 74%). R = 0.13 (20%
f
1
EtOAc/petroleum ether) ); m.p. = 252-256 °C; H NMR (400 MHz, CDCl ): δ 8.69 (qd, J
3
=
1
7.8, 1.0 Hz, 2H), 8.64 (d, J = 5.3 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz,
H), 7.90 (t, J = 7.3 Hz, 1H), 7.47 (dd, J = 5.3, 1.8 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H);
13
1
C{ H} NMR (125 MHz, CDCl ): δ 163.6, 163.5, 150.7, 150.3, 146.2, 134.2, 132.7,
3
-1
1
31.8, 131.4, 131.3, 131.0, 129.6, 128.4, 125.0, 124.9, 123.0, 122.1; IR υ (KBr, cm ):
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5
5
5
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5
5
5
6
2920, 1709, 1679, 1575, 1458, 1390, 1361, 1346, 1240, 1195, 1101, 1077, 778; HRMS
+
(
ESI-QTOF): m/z calcd. for C H BrClN NaO [M+Na] 408.9350, found 408.9349.
17
8
2
2
6-bromo-2-(4-methoxypyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bc):
0
1
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Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(32 mg, 0.125 mmol) and 4-methoxy-2-aminopyridine (46 mg, 0.375 mmol) for 4 h
provided corresponding product 6bc as a yellow solid (46 mg, 96%). R = 0.15 (100%
f
1
DCM); m.p. = 249-252 °C; H NMR (400 MHz, CDCl ): δ 8.70 (d, J = 7.8 Hz, 1H), 8.65
3
(d, J = 8.4 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8 Hz,
1
3
1
H), 7.89 (t, J = 7.5 Hz, 1H), 6.98 (dd, J = 5.7, 2.2 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H),
1
3
1
.91 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ 167.9, 163.7, 163.6, 150.9, 150..8,
3
33.9, 132.5, 131.6, 131.4, 131.0, 129.6, 128.6, 128.3, 123.3, 122.4, 111.0, 110.2, 55.7;
-1
IR υ (KBr, cm ): 3438, 2923, 1709, 1666, 1597, 1567, 1558, 1358, 1346, 1242, 1226,
1194, 1017, 994, 838, 778, 746; HRMS (ESI-QTOF): m/z calcd. for C H BrN O
18
12
2
3
+
[
M+H] 383.0026, found 383.0020.
6-bromo-2-(pyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bd):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(65 mg, 0.25 mmol) and 2-aminopyridine (70 mg, 0.75 mmol) for 6 h provided
corresponding product 6bd as a white solid (77 mg, 87%). R = 0.11 (20%
f
1
EtOAc/petroleum ether)); m.p. = 253-256 °C; H NMR (400 MHz, CDCl ): δ 8.74 (bs,
3
1H), 8.69 (t, J = 4.3 Hz, 1H), 8.64 (t, J = 8.2 Hz, 1H), 8.45 (t, J = 8.2 Hz, 1H), 8.08 (t, J
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= 8.0 Hz, 1H), 7.97 (t, J = 4.1 Hz, 1H), 7.94-7.86 (m, 1H), 7.47 (t, J = 4.1 Hz, 1H), 7.42
1
(
d, J = 8.0 Hz, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ 163.8, 163.7, 150.2, 149.3,
3
1
1
1
38.8, 134.0, 132.5, 131.7, 131.4, 131.1, 130.9, 129.6, 128.3, 124.3, 124.3, 123.2,
1
1
1
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1
1
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1
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2
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2
2
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4
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5
5
5
5
5
6
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
-1
22.3; IR υ (KBr, cm ): 3433, 2920, 1712, 1672, 1589, 1568, 1437, 1383, 1369, 1349,
244, 1197, 1045, 778, 743; HRMS (ESI-QTOF): m/z calcd. for C H BrN NaO
17
9
2
2
+
[M+Na] 374.9740, found 374.9735.
6-bromo-2-(5-(trifluoromethyl)pyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
(6be):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
65 mg, 0.25 mmol) and 5-(trifluoromethyl)-2-aminopyridine (121 mg, 0.75 mmol) for 12
(
h provided corresponding product 6be as a off white solid (74 mg, 71%). R = 0.7 (100%
f
1
DCM); m.p. = 219-222 °C; H NMR (400 MHz, CDCl ): 9.00 (s, 1H), 8.71 (d, J = 8.2 Hz,
3
1H), 8.67 (d, J = 8.2 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.10 (d,
13
1
J = 8.0 Hz, 1H), 7.91 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H); C{ H} NMR (100
MHz, CDCl ): δ 163.6, 163.5, 152.4, 147.3 (q, J = 4.0 Hz), 136.1 (q, 3JC-F = 3.0 Hz),
3
3
C-F
1
34.2, 132.7, 131.8, 131.4, 130.9, 129.5, 128.3, 127.3 (q, 2JC-F = 33.0 Hz), 124.5,123.5
(
q, 1JC-F = 271.0 Hz) 122.8, 121.9; 19F NMR (470 MHz, CDCl ): δ -62.3 (s, 3F); IR υ
3
-1
(KBr, cm ): 3088, 2921, 1712, 1680, 1587, 1363, 1349, 1331, 1244, 1162, 1124, 1087,
+
7
81; HRMS (ESI-QTOF): m/z calcd. for C H BrF N NaO [M+Na] 442.9613, found
18
8
3
2
2
442.9608.
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6-bromo-2-(5-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bf):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(65 mg, 0.25 mmol) and 5-methyl-2-aminopyridine (81 mg, 0.75 mmol) for 6 h provided
0
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2
3
4
5
6
7
8
9
0
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corresponding product 6bf as a pale yellow solid (63 mg, 69%). R = 0.13 (20%
f
1
EtOAc/petroleum ether)); m.p. = 230-234 °C; H NMR (400 MHz, CDCl ): δ 8.69 (d, J =
3
4.1 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.55 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H) 8.08 (d, J =
8.1 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H),
2.46 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ): δ 163.9, 163.9, 150.5, 146.8, 139.3,
1
3
134.3, 133.9, 132.5, 131.7, 131.4, 131.0, 131.0, 129.6, 128.3, 123.5, 123.3, 122.4, 18.4;
-1
IR υ (KBr, cm ): 3429, 2929, 1712, 1670, 1589, 1571, 1480, 1364, 1244, 1195, 1023,
+
779, 754; HRMS (ESI-QTOF): m/z calcd. for C H BrN O [M+H] 367.0077, found
18
12
2
2
367.0075.
6-bromo-2-(5-iodopyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bg):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
(32 mg, 0.125 mmol) and 5-iodo-2-aminopyridine (82 mg, 0.375 mmol) for 24 h provided
corresponding product 6bg as a off white solid (28 mg, 47%). R = 0.24 (20%
f
1
EtOAc/petroleum ether)); m.p. = 239-242 °C; H NMR (400 MHz, CDCl ): δ 8.93 (s, 1H),
3
8.70 (d, J = 8 Hz, 1H), 8.66 (d, J = 8 Hz, 1H), 8.46 (d, J = 8 Hz, 1H), 8.23 (dd, J = 8.2,
4.1 Hz, 1H), 8.09 (d, J = 8 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H);
13
1
C{ H} NMR (100 MHz, CDCl ): δ 163.6, 163.6, 156.4, 148.6, 147.0, 134.2, 132.7,
3
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131.8, 131.4, 131.3, 131.0, 129.6, 128.4, 126.0, 123.0, 122.1, 93.9; IR υ (KBr, cm ):
3
8
5
430, 2928, 1712, 1674, 1588, 1457, 1402, 1365, 1347, 1241, 1217, 1195, 1045, 971,
+
19; HRMS (ESI-QTOF): m/z calcd. for C H BrIN NaO [M+Na] 500.8706, found
17
8
2
2
1
1
1
1
1
1
1
1
1
1
2
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6
0
1
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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
00.8693.
6-bromo-2-(5-bromopyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bh):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
65 mg, 0.25 mmol) and 5-bromo-2-aminopyridine (129 mg, 0.75 mmol) for 24 h
(
provided corresponding product 6bh as a pale yellow solid (42 mg, 39%). R = 0.52
f
1
(
20% ethyl acetate/petroleum ether); m.p. = 232-235 °C; H NMR (500 MHz, CDCl ): δ
3
8
5
1
.78 (d, J = 5.2 Hz, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.45 (d, J =
.1 Hz, 1H), 8.09 (d, J = 5.0 Hz, 1H), 8.06 (dd, J = 9.8, 5.2 Hz, 1H), 7.89 (t, J = 10.1 Hz,
13
1
H), 7.31 (d, J = 5.0 Hz, 1H); C{ H} NMR (125 MHz, CDCl ): δ 163.6, 163.6, 151.4,
3
148..0, 141.4, 134.2, 132.8, 131.7, 131.4, 131.3, 131.0, 129.6, 128.4, 125.6, 123.0,
-1
1
1
4
22.1, 121.4; IR υ (KBr, cm ): 3434, 2928, 1714, 1674, 1597, 1588, 1573, 1460, 1367,
+
241, 1103, 1092, 779, 755; HRMS (ESI-QTOF): m/z calcd. for C H Br N O [M+H]
17
9
2
2
2,
30.9025 found 430.9029.
6-bromo-2-(6-methylpyridin-2-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (6bi):
Following the general procedure A, the reaction between 5-bromo-acenaphthoquinone
65 mg, 0.25 mmol) and 6-methyl-2-aminopyridine (81 mg, 0.75 mmol) for 6 h provided
(
corresponding product 6bi as a pale yellow solid (70 mg, 76%). R = 0.12 (20%
f
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EtOAc/petroleum ether)); m.p. = 239-243 °C; H NMR (500 MHz, CDCl ): δ 8.68 (d, J =
3
7
.2 Hz, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H),
7
.87 (t, J = 8 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.7
0
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2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 2.60 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ): δ 163.8, 163.8, 159.6, 148.6,
1
3
1
38.9, 133.9, 132.5, 131.6, 131.3, 131.0, 130.9, 129.6, 128.3, 124.1, 122.5, 123.3,
-1
121.0, 24.4; IR υ (KBr, cm ): 2935, 1711, 1672, 1588, 1567, 1456, 1363, 1244, 1046,
+
7
60; HRMS (ESI-QTOF): m/z calcd. for C H BrN NaO [M+Na] 388.9898, found
18
11
2
2
388.9896.
General Procedure B for biphenyl-2,2’-dicarboxamide synthesis:
To a solution of 1,2-diketone (0.25 mmol/0.5 mmol, 1 equiv.) and 2-aminopyridine
(
1.125 mmol/2.25 mmol, 4.5 equiv.) in t-BuOH:m-xylene (1:2, 3 mL) in a reaction tube,
anhydrous CuCl (20 mol%) was added at RT along with pivalic acid (10 mol%). The
2
°
reaction mixture was stirred at 80-85 C for 48-72 h under the oxygen atmosphere and
then quenched with H O after monitoring by TLC. The aqueous layer was extracted by
2
dichloromethane (3 × 20 mL). The combined organic layer was washed with water,
dried over anhydrous Na SO and concentrated under vacuum to get the crude product,
2
4
which was further purified using flash column chromatography on silica gel (230-400
mesh) column (eluent ethyl acetate-petroleum ether).
N2,N2'-bis(4-methylpyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide (8a):
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Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(52 mg, 0.25 mmol) and 4-methyl-2-aminopyridine (121 mg, 1.125 mmol) for 48 h
delivered the product 8a as a yellow solid (85 mg, 81%). R = 0.16 (40%
f
1
1
1
1
1
1
1
1
1
1
2
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2
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9
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2
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5
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9
0
1
EtOAc/petroleum ether); m.p.= 233-237 °C; H NMR (400 MHz, CDCl ): δ 10.18 (bs,
3
2H), 7.99 (s, 2H), 7.66 (d, J = 8.0 Hz, 4H), 7.39–7.31 (m, 4H), 7.19 (d, J = 8.0 Hz, 2H),
13
1
6.67 (t, J = 4.0 Hz, 2H), 2.25 (s, 6H); C{ H} NMR (125 MHz, CDCl ): δ 168.7, 151.7,
3
149.8, 147.3, 139.1, 136.1, 130.4, 129.8, 128.1, 127.8, 120.9, 115.0, 21.4; IR υ (KBr,
-1
cm ): 3493, 3238, 1659, 1609, 1539, 1411, 1350, 1301, 1278, 1278, 1238, 1167, 891,
+
828, 760, 710, 610; HRMS (ESI-QTOF): m/z calcd. for C H N NaO [M+Na]
26
22
4
2
445.1635, found 445.1633.
N2,N2'-bis(4-chloropyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide (8b):
Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(104 mg, 0.5 mmol) and 4-chloro-2-aminopyridine (288 mg, 2.25 mmol) for 48 h
delivered the product 8b as a off white solid (203 mg, 88%). R = 0.24 (40%
f
1
EtOAc/petroleum ether); m.p.= >260 °C; H NMR (400 MHz, CDCl ): δ 9.31 (s, 2H),
3
8.25 (s, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.73–7.70 (m, 2H), 7.46-7.44 (m, 4H), 7.24–7.22
1
(
m, 2H), 6.99–6.97 (m, 2H); 13C{ H} NMR (100 MHz, CDCl ): δ 168.6, 152.4, 148.6,
3
-1
145.8, 139.2, 135.5, 130.9, 130.1, 128.4, 127.6, 120.4, 114.0; IR υ (neat, cm ): 3440, ,
1696, 1572, 1519, 1402, 1383, 1291, 1093, 711; HRMS (ESI-QTOF): m/z calcd. for
+
C H Cl N O [M+H] 463.0723, found 463.0729.
24
17
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N2,N2'-bis(4-methoxypyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide (8c):
Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(52 mg, 0.25 mmol) and 4-methoxy-2-aminopyridine (139 mg, 1.125 mmol) for 48 h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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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
delivered the product 8c as a semi solid [62 mg, 66% (94% brsm)]. R = 0.62 (5% MeOH
f
1
in DCM); H NMR (500 MHz, CDCl ): δ 10.09 (s, 2H), 7.77 (s, 2H), 7.67–7.63 (m, 4H),
3
7.42–7.35 (m, 4H), 7.22 (dd, J = 7.4, 0.9 Hz, 2H), 6.41 (dd, J = 5.8, 2.3 Hz 2H), 3.78 (s,
13
1
6
H); C{ H} NMR (125 MHz, CDCl ): δ 168.8, 167.3, 153.4, 148.5, 139.1, 136.1, 130.5,
3
-1
130.1, 128.1, 127.7, 107.6, 99.2, 55.4; IR υ (neat, cm ): 3430, 3225, 2923, 1678, 1606,
1575, 1532, 1467, 1445, 1415, 1305, 1272, 1242, 1199, 1170,1038, 755; HRMS (ESI-
+
QTOF): m/z calcd. for C H N O [M+H] 455.1714, found 455.1712.
26
23
4
4
'
N2-phenyl-N2'-(pyridin-2-yl)-[1,1-biphenyl]-2,2'-dicaroxiamide (8d):
Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(52 mg, 0.25 mmol) and 2-aminopyridine (105 mg, 1.125 mmol) for 48 h delivered the
product 8d as a white solid (73 mg, 74%). R = 0.19 (40% EtOAc : pet ether); m.p.=
f
1
decomposed at 220 °C; H NMR (400 MHz, CDCl ): δ 9.74 (bs, 2H), 8.16 (d, J = 8.0 Hz,
3
2
H), 8.02 (s, 2H), 7.71 (d, J = 4.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 2H), 7.40–7.37 (m, 4H),
.23–7.21 (m, 2H), 6.93 (t, J = 5.6 Hz, 2H); 13C{ H} NMR (100 MHz, d -DMSO): δ
1
6
7
168.3, 151.4, 148.0, 138.7, 138.1, 135.6, 130.1, 129.1, 128.0, 127.7, 119.9, 113.7; IR υ
-1
(
KBr, cm ): 3456, 3224, 3066, 1665, 1591, 1531, 1467, 1429, 1353, 1307, 1272,
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1150,1042, 891, 779, 763, 751; HRMS (ESI-QTOF): m/z calcd. for C H N NaO
24
18
4
2
+
[
M+Na] 417.1322, found 417.1322.
N2,N2'-bis(5-bromopyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide (8e):
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
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4
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4
5
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5
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5
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5
5
5
6
0
1
2
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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
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2
3
4
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7
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0
1
2
3
4
5
6
7
8
9
0
Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(104 mg, 0.5 mmol) and 5-bromo-2-aminopyridine (387 mg, 2.25 mmol) for 72 h
delivered the product 8e as a yellow solid (140 mg, 51%). R = 0.45 (20%
f
1
EtOAc/petroleum ether); m.p.= 137-140 °C; H NMR (500 MHz, CDCl ): δ 9.48 (s, 2H),
3
8.11–8.07 (m, 4H), 7.71–7.68 (m, 4H), 7.44–7.42 (m, 4H), 7.22–7.20 (m, 2H); 13C{ H}
1
NMR (125 MHz, CDCl ): δ 168.5, 150.1, 148.8, 140.7, 139.2, 135.5, 130.9, 130.0,
3
-1
1
28.4, 127.5, 115.5, 114.9; IR υ (KBr, cm ): 3467, 3224, 1683, 1569, 1519, 1371, 1301,
1
222, 1132, 1092, 834, 755 HRMS (ESI-QTOF): m/z calcd. for C H Br N NaO
24 16
2
4
2
+
[
M+Na] 572.9527, found 572.9532.
N2,N2'-bis(5-chloropyridin-2-yl)-[1,1'-biphenyl]-2,2'-dicarboxamide (8f):
Following the general procedure B, the reaction between 9,10-phenanthrenequinone
(104 mg, 0.5 mmol) and 5-chloro-2-aminopyridine (288 mg, 2.25 mmol) for 72 h
delivered the product 8f as a off white solid (152 mg, 66%) ). R = 0.53 (20%
f
1
EtOAc/petroleum ether); m.p.= 252-255 °C; H NMR (500 MHz, CDCl ): δ = 9.66 (s,
3
2H), 8.15 (d, J = 10.0 Hz, 2H), 7.88 (d, J = 5.0 Hz, 2H), 7.69–7.67 (m, 2H), 7.55 (dd, J =
13
1
1
0, 5.0 Hz, 2H), 7.44–7.39 (m, 4H), 7.21–7.20 (m, 2H); C{ H} NMR (125 MHz, CDCl ):
3
δ = 168.5, 149.8, 146.6, 139.1, 137.9, 135.6, 130.8, 130.0, 128.3, 127.6, 126.9, 115.0;
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