Vanadium-Catalyzed Oxidative C(CO)-C(CO) Bond Cleavage for C-N Bond Formation: One-Pot Domino Transformation of 1,2-Diketones and Amidines into Imides and Amides

Article abstract of DOI:10.1021/acs.joc.7b00950

A novel vanadium-catalyzed one-pot domino reaction of 1,2-diketones with amidines has been identified that enables their transformation into imides and amides. The reaction proceeds by dual acylation of amidines via oxidative C(CO)-C(CO) bond cleavage of 1,2-diketones to afford N,N′-diaroyl-N-arylbenzamidine intermediates. In the reaction, these intermediates are easily hydrolyzed into imides and amides through vanadium catalysis. This method provides a practical, simple, and mild synthetic approach to access a variety of imides as well as amides in high yields. Moreover, one-step construction of imide and amide bonds with a long-chain alkyl group is an attractive feature of this protocol.

Full text of DOI:10.1021/acs.joc.7b00950

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Article
Vanadium–Catalyzed Oxidative C(CO)–C(CO) Bond Cleavage
for C–N Bond Formation: One Pot Domino Transformation
of 1,2-Diketones and Amidines into Imides and Amides
Chander Singh Digwal, Upasana Yadav, P. V. Sri Ramya,
Sravani Sana, Baijayantimala Swain, and Ahmed Kamal
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Jun 2017
Downloaded from http://pubs.acs.org on June 27, 2017
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Vanadium–Catalyzed Oxidative C(CO)–C(CO) Bond Cleavage for C–N Bond
Formation: One Pot Domino Transformation of 1,2-Diketones and Amidines
into Imides and Amides
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Chander Singh Digwal, Upasana Yadav, P. V. Sri Ramya, Sravani Sana, Baijayantimala Swain,
and Ahmed Kamal*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Balanagar, Hyderabad 500037, India.
Email: ahmedkamal@iict.res.in
Abstract:
A novel vanadiumꢀcatalyzed one pot domino reaction of 1,2ꢀdiketones with amidines has been
identified that enables their transformation into imides and amides. The reaction proceeds by
dual acylation of amidines via oxidative C(CO)–C(CO) bond cleavage of 1,2ꢀdiketones to afford
N,N'ꢀdiaroylꢀNꢀarylbenzamidine intermediates. In the reaction, these intermediates are easily
hydrolyzed into imides and amides through vanadium catalysis. This method provides a
practical, simple and mild synthetic approach to access a variety of imides as well as amides in
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high yields. Moreover, one step construction of imide and amide bond with long chain alkyl
group is an attractive feature of this protocol.
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Introduction:
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Imides are the key structural motifs in many natural products as well as pharmaceutical
agents,1 and also appear as important precursors in a variety of reactions.2 Accordingly, imide
synthesis was explored extensively and many improved methods were developed in the past few
decades.3 However, use of sophisticated reagents, low yield of imides, limited substrate
availability and product diversity are some limitations for most of them. The efficient routes for
the synthesis of imides rely on direct oxidation of Nꢀalkylbenzamides4 (Figure 1a) and cerric
ammonium nitrate (CAN) promoted oxidation of 4,5ꢀdiphenyloxazoles (Figure 1b).5 In addition,
Fe/Cuꢀcatalyzed direct coupling of amides with thioesters6 and aldehydes7 also provided access
to a variety of imides. Moreover, Guan and coꢀworkers reported the Pdꢀcatalyzed
aminocarbonylation of aryl iodides with amides for the rapid synthesis of imides (Figure 1c).8 It
is noteworthy that in most of these methods, stoichiometric or excess amount of oxidants,
sometimes additives or special preparation of the substrates are required for the synthesis of
imides. Hence, development of simple, inexpensive, greener and high yielding methods for the
preparation of imides from easily accessible starting materials are of considerable importance,
especially which could be operative under oxidant and additive free conditions.
Over the past years, the prominence of C–C bond cleavage has grown increasingly, because
these reactions provide multifarious molecular transformations that are otherwise hard to
achieve.9,10 Among them, the C(CO)–C(α) bond cleavage of ketones has evolved as a powerful
tool for the construction of many organic functional groups such as acids,11 aldehydes,12 esters,13
and αꢀketoesters14 etc. Moreover, some remarkable approaches on Cuꢀcatalyzed direct aerobic
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oxidative C–N bond formation utilizing C(CO)–C(α) bond cleavage of ketones have also been
reported.15
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a) Oxidation of Nꢀalkylbenzamides
b) Oxidation of oxazoles
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c) Aminocarbonylation of aryl iodide with amides
d) This Work:
Figure 1. Comparison of previous approaches with the present method developed for the
synthesis of Imides
Vanadium is nontoxic, inexpensive, readily available, and also present in various bacterial
enzymes.16 Several research groups have explored the potential utility of vanadium based
catalysts to afford oxidative C–C bond cleavage of ditertiary glycols,17 αꢀhydroxyketones or
ketones,18 and catechols19 etc. Although, the synthetic utility of C(CO)–C(CO) bond cleavage of
1,2ꢀdiketones for their transformation into acids and/or esters is also well documented in the
literature,20 but a metal catalytic system for direct C–N bond formation through C(CO)–C(CO)
bond cleavage has not been realized till to date. Herein, we report a novel vanadium catalyzed
oxidative C(CO)–C(CO) bond cleavage reaction of 1,2ꢀdiketones (1) with Nꢀarylamidines (2) for
C–N bond formation, which allows their transformation into imides (4) and amides (5) through
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hydrolysis of inꢀsitu generated N,N'ꢀdiaroylꢀNꢀarylbenzamidines (3) in a one pot manner (Figure
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1d).
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Results and Discussion:
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In 1952, Peak reported that the acidic hydrolysis of N,N'ꢀdibenzoylꢀNꢀphenylbenzamidine (3a)
provided N-benzoylbenzamide (4aa) and benzanilide (5a) by the reaction at the amidino carbon
center (Figure 2a).21 Moreover, a photosensitized autoꢀoxidation of tetraꢀphenylimidazole into
3a, probably via ring opening of dioxetane intermediate, was described by the group of
Wasserman (Figure 2b).22 These investigations led us to question whether 1) the C(CO)–C(CO)
bond of 1,2ꢀdiketones could be activated with Nꢀarylamidines in presence of appropriate metal
catalyst to provide the corresponding N,N'ꢀdiaroylꢀNꢀarylbenzamidines (3); 2) the hydrolysis of 3
could be secured under mild conditions by employing Lewis acid metal catalyst to activate N'ꢀ
carbonyl group, as it might promote electron deficiency at amidino carbon atom due to ketoꢀ
imine conjugation.
a) Acidic hydrolysis of N,N'ꢀdibenzoylꢀNꢀphenylbenzamidine (3a)
b) Photooxidation of tetraphenylimidazole
Figure 2. Previous reports on N,N'ꢀdibenzoylꢀN'ꢀphenylbenzamidine (3a)
To test this concept, we commenced our research with the screening of 20 mol% of various
metal catalysts for the model reaction of benzil (1a), Nꢀphenylbenzimidamide (2aa) and H2O
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using dry N,Nꢀdimethylformamide (DMF) as solvent under air atmosphere (Supporting
information (SI), Table S1). These experiments disclosed that the frequently used copper sources
(Cu(OAc)2, CuCl2, CuBr, CuI and Cu(OTf)2) could activate the C(CO)–C(CO) bond to afford 3a
in 26ꢀ55% yields after 48 h at room temperature. Interestingly, in presence of more acidic
Cu(OTf)2, the hydrolyzed products 4aa and 5a were also obtained in 21% and 22% yields,
respectively. However, further modification in the reaction conditions using Cu(OTf)2 did not
give satisfying results and other tested metal catalysts such as silver based catalysts, In(OTf)3,
Zn(OTf)2, Sc(OTf)3, FeCl3 were found ineffective for this transformation.
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Very recently, we reported that an inexpensive and less toxic vanadium salt, vanadyl sulphate
(VOSO4), is a highly efficient catalyst for the transformation of 1a and oꢀphenylenediamines into
quinaoxalines.23 With this knowledge base, the model reaction was carried out in the presence of
20 mol% of VOSO4 at room temperature. Gratifyingly, 3a was obtained in 96% yield after 8 h
(entry 1, Table 1). The reaction did not show improvements with varying amount of water (entry
2 and 3, Table 1). The hydrolysis of 3a was very slow at room temperature and 3a remain unꢀ
reacted even after a week (entry 4, Table 1). However, heating the reaction mixture at 70 ºC for a
period of 20 h afforded 4aa and 5a in 97% and 96% yields respectively, with complete
consumption of 3a (entry 5, Table 1). Furthermore, the variation in the reaction temperature did
not give superior results in terms of reaction time or yield of the products (entry 6 and 7, Table
1). The subsequent exploration of the effect of catalyst loading proved that 20 mol% of VOSO4
was optimal for the reaction (entry 8 and 9, Table 1). Among various tested common solvents,
DMF appeared to be the best solvent in terms of yield and reaction time (SI, Table S2). Thus, 20
mol% VOSO4, 70 ºC and DMF are the optimal conditions to obtain 4aa and 5a in excellent
yields (entry 5, Table 1).
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Optimization of the reaction conditions using VOSO4 in DMF. a
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Table 1
:
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Yield of products (%)b
VOSO4·xH2O
(y mol %)
Entry
H2O (equiv.)
T [ºC]
Time (h)
3a
96
94
85
n.d.
0
4aa
trace
trace
trace
n.d.
97
5a
trace
trace
trace
n.d.
96
1c
2c
3c
4c
5
20
20
20
20
20
20
20
30
10
20
20
20
H2O (5)
H2O (10)
H2O (2.5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
H2O (5)
rt
rt
8
8
rt
rt
8
168
20
32
18
20
30
20
17
17
70
60
80
70
70
70
70
70
6
7
0
0
92
87
91
92
8
9
10d
11e
12f
0
0
94
89
95
92
47
0
50
87
52
90
19
trace
trace
aReaction conditions: 0.5 mmol of 1a and 0.6 mmol of 2a in presence of VOSO4·xH2O in
dry DMF (3 mL) under air. bIsolated yields of pure products based on 1a. cThe reaction was
d
e
run at room temperature. The reaction was run under N2 balloon. The reaction was run
f
under O2 balloon. The reaction was run in dry DMF under O2 balloon with 4 Å molecular
sieves; 74% of 1a was recovered. n.d. : not determined.
To investigate the role of VOSO4 on the hydrolysis of 3a, two control experiments with and
without VOSO4 were carried out. The results revealed that the hydrolysis of 3a did certainly
occur only in the presence of VOSO4 (SI, control experiments, eqs S1 and S2). Next, to shed light
on the role of dioxygen in this one pot process, the reaction was performed under nitrogen
atmosphere. After 20 h, 4aa and 5a were obtained with lower conversion of 3a (entry 10, Table
1). Likewise, the hydrolysis of 3a was also slow under anaerobic conditions (SI, control
experiments, eq S3). These results indicate that oxygen is not required for C(CO)–C(CO) bond
cleavage as well as catalyst turnover, although it does increase the rate of reaction (entry 11,
Table 1). Furthermore, when the model reaction was performed in anhydrous conditions under
O2 atmosphere, 74 % of 1a, 19 % of 3a, and traces of 4aa and 5a were obtained (entry 12, Table
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1). These results strongly suggests that water is the crucial component for this one pot
transformation.
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After adopting the optimal reaction conditions, various amidines (2) were investigated with 1a
for the synthesis of imides considering Nꢀphenylbenzamide (5a) as a byꢀproduct (Table 2). To
our delight, both electronꢀrich (2ab and 2ah) and electronꢀdeficient (2acꢀ2ag) substituents
arylamidines provided excellent yields of the corresponding imide products (4abꢀ4ah, Table 2).
Notably, haloꢀsubstituents at metaꢀ and orthoꢀpositions on the aryl ring affected only the reaction
times but not the yields (4ad, 4ae and 4ag, Table 2). It was observed that electronꢀdonating
substituents arylamidines react faster with 1a than electronꢀdeficient ones and favor formation of
the corresponding intermediates (3). On the other hand, hydrolysis of the intermediates to their
corresponding imides and 5a was faster with electronꢀdeficient substituents arylamidines than
electronꢀdonating ones. This could be due to the fact that electronꢀdeficient group decreases the
nucleophilicity of nitrogen atom to attack carbonyl groups but increases electron deficiency at
amidino carbon atom for water attack. Steric effects could be observed in the case of 2ꢀmethylꢀ
Nꢀphenylbenzmidamide (2ai) and the reaction afforded imide product (4ai, Table 2) in 42%
yield. In addition, orthoꢀ and metaꢀ diꢀsubstituted arylamidines (2aj and 2ak) also provided good
yields of corresponding imide products (4aj and 4ak, Table 2). Heterocycleꢀderived amidines
such as Nꢀphenylthiopheneꢀ2ꢀcarboximidamide (2al), Nꢀphenylfuranꢀ2ꢀcarboximidamide (2am),
2ꢀchloroꢀNꢀphenylnicotinimidamide (2an) and Nꢀphenylisonicotinimidamide (2ao) reacted
smoothly to yield the corresponding imide products (4alꢀ4ao, Table 2) in 84ꢀ94% yields.
Moreover, the reaction of amidines bearing cyclopropylꢀ (2ap) and 1ꢀpropylꢀ (2aq) groups do
not affect the efficiency of the method and the corresponding imides (4ap and 4aq, Table 2)
were obtained in 88% and 80% yields, respectively.
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Table 2: One pot synthesis of imides: Substrate scope of amidines.a
3
4
5
6
7
8
9
Yield of products (%)b
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Entry
Amidine (2)
Time (h)
Imide (4)
97 (4aa)
91 (4ab)
98 (4ac)
96 (4ad)
96 (4ae)
92 (4af)
92 (4ag)
95 (4ah)
42 (4ai)
Amide (5a)
1
2
3
4
5
6
7
8
9c
R = H (2aa)
4ꢀOMe (2ab)
20
18
18
24
36
18
22
22
96
96
96
95
98
94
96
91
98
45
4ꢀCl (2ac)
3ꢀCl (2ad)
2ꢀCl (2ae)
4ꢀBr (2af)
3ꢀBr (2ag)
4ꢀMe (2ah)
2ꢀMe (2ai)
10
11
24
32
82 (4aj)
90 (4ak)
78
92
(2aj)
(2ak)
(2al)
12
13
24
18
89 (4al)
93
98
94 (4am)
(2am)
14
15
36
24
92 (4an)
84 (4ao)
91
92
(2an)
(2ao)
16
17
18
28
88 (4ap)
80 (4aq)
93
84
(2ap)
(2aq)
aStandard reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), H2O (2.5
mmol, 45 µL) and VOSO4·xH2O (0.1 mmol) in dry DMF (3 mL), at 70
ºC, under air. Isolated yields. Accompanied by 35% of unreacted
corresponding intermediate
b
c
Next, the reactivity of symmetrical 1,2ꢀdiketones (1b and 1c) towards various amidines was
studied (Table 3). Comparable results with regard to yields were obtained, when 1,2ꢀbis(4ꢀ
chlorophenyl)ethaneꢀ1,2ꢀdione (1b) was reacted with amidines containing aromatic (2aa, 2ad
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and 2af), heterocyclic (2alꢀ2an), aliphatic (2ap and 2aq) partners, affording the corresponding
imides (4ac, 4arꢀ4ay, Table 3) in 82ꢀ96% yields within 24 h. Notably, 2ai also underwent
smooth conversion to furnish imide product (4at, Table 3) in 91% yield. This effect
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Table 3: One pot synthesis of imides: Substrate scope of 1,2ꢀdiketones.a
Yield of products (%)b
Entry
1,2ꢀDiketone (1)
Amidine (2)
2aa
Time (h)
16
Imide (4)
96 (4ac)
Amide (5)
97 (5b)
1
2
3
4
5
6
7
8
9
2ad
18
95 (4ar)
89 (4as)
91 (4at)
90 (4au)
91 (4av)
90 (4aw)
84 (4ax)
82 (4ay)
97 (5b)
93 (5b)
94 (5b)
93 (5b)
94 (5b)
92 (5b)
88 (5b)
85 (5b)
2af
16
2ai
16
2al
18
2am
2an
18
24
2ap
18
2aq
18
72
72
96
72
85 (4ab)
82 (4az)
77 (4ba)
86 (4bb)
88 (5c)
10c
11c
2aa
2ac
2ah
2ap
83 (5c)
80 (5c)
87 (5c)
12c,d
13c
aStandard reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), H2O (2.5
mmol, 45 µL) and VOSO4·xH2cO (0.1 mmol) in dry DMF (3 mL), at 70
b
ºC, under air. Isolated yields. Accompanied by unreacted 1c: 5% with
2aa, 10% with 2ac, 8% with 2ah, 6% with 2ap. dAccompanied by 10% of
the corresponding intermediate.
can be allied to increased reactivity of carbonyl groups of 1b due to chloroꢀsubstituents, and
thereby amidines react faster with 1b than 1a. Moreover, chloroꢀsubstituents on aryl ring of 1b
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also facilitates the hydrolysis of the corresponding intermediate. As expected, 1,2ꢀbis(4ꢀ
methoxyphenyl)ethaneꢀ1,2ꢀdione (1c) reacted very slowly with amidines due to decreased
electrophilicity of carbonyl groups and required much longer reaction times (72ꢀ96 h) to obtain
good yields (77ꢀ86%) of the corresponding imide products (4ab, 4azꢀ4bb, Table 3). The effect
of electronꢀwithdrawing groups on the aryl ring of amidines for the hydrolysis of intermediates is
more obvious when we compare the reactions of 1c with 2ac and 2ah in the generation of imides
(4az and 4ba, Table 3). In the case of 4ꢀchloroꢀNꢀphenylbenzimidamide (2ac), the corresponding
intermediate was not obtained after 72 h, whereas 10% of corresponding intermediate was
observed with 4ꢀmethylꢀNꢀphenylbenzimidamide (2ah) even after 96 h.
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In the present protocol, it could be expected that unsymmetrical 1,2ꢀdiketone can give two
corresponding intermediates with amidine, and as a result of their hydrolysis, four products (two
imides and two amides) will exist in the reaction mixture. As evident from Table 4, the reaction
of 1ꢀ(4ꢀnitrophenyl)ꢀ2ꢀphenylethaneꢀ1,2ꢀdione (1d) with 2aa certainly provided two imides
(42% 4aa and 44% 4bc, Table 4) and two amides (45% 5a and 42% 5d, Table 4), however it was
somewhat disappointing as no selectivity was observed in the formation of these products. A
comparable result was also obtained with 1e and the products (4bc, 4ab, 5b and 5d, Table 4)
were isolated in 38ꢀ41% yields. It is noteworthy that in all the above reactions, the amide
derivatives were also obtained in high yields.
Amides, as one of the most important classes of Nꢀcontaining organic compounds, are known
to be present in proteins, natural products, bioactive compounds and agrochemicals.24 In recent
years, constant efforts targeted efficient catalytic methods for the construction of omnipresent
amide bond.25 Despite significant advancement in this area, there is still continuing need for
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Table 4: One pot reaction of unsymmetrical 1,2ꢀdiketones with 2aa.a
3
4
5
6
7
8
9
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Yield of the productsb
Entry
1,2ꢀDiketones (1)
Imides (4)
Amides (5)
1
(1d)
(1e)
44% (4bc)
40% (4bc)
42% (4aa)
41% (4ab)
45% (5a)
38% (5d)
42% (5d)
40% (5b)
2
aStandard reaction conditions: 1 (0.5 mmol), 2aa (0.6 mmol), H2O (2.5 mmol, 45
µL) and VOSO4·xH2O (0.1 mmol) in dry DMF (3 mL), at 70 ºC, under air for 12
h.
development of new synthetic methods for amide bond synthesis. Therefore, we turned to
explore the scope and limitation of present protocol for the amide synthesis (Table 5). In general,
amidines containing electronꢀdonating groups such as methoxyꢀ (2ar), trimethoxyꢀ (2as),
methylꢀ (2aw) and iꢀpropylꢀ (2ax) as well as halogen substituents (2atꢀ2av) reacted efficiently
with 1a and afforded the corresponding amide derivatives (5eꢀ5k, Table 5) in 92ꢀ98% yields.
However, the position of chloroꢀsubstituent (para- and meta-) has obvious effect on the reaction
time (8 h for 5g and 6 h for 5h, Table 5). This effect of chloroꢀsubstituents present on the
amidines is probably due to the reduction of electronꢀdonor capacity of the nitrogen atom and
thereby promoting electron deficiency at the amidino carbon atom for facilitating attack by water
molecule. Moreover, this method becomes valuable for Nꢀbenzoylation of heat sensitive
electronꢀrich anilines (5e and 5f) and electron deficient anilines (5gꢀ5i). In the case of Nꢀ
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Table 5: Substrate scope for one pot synthesis of amides.a
3
4
5
6
7
8
9
Yield of products (%)b
Amide (5) Imide (4aa)
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Entry
Amidine (2)
R= 4ꢀOMe (2ar)
Time (h)
1
2
3
4
5
6
7
8
18
24
8
97 (5e)
95 (5f)
98 (5g)
98 (5h)
94 (5i)
97 (5j)
92 (5k)
76 (5l)
96
93
96
95
92
94
89
74
3,4,5ꢀOMe (2as)
4ꢀCl (2at)
3ꢀCl (2au)
6
4ꢀF (2av)
24
18
24
96
4ꢀMe (2aw)
4ꢀiꢀpropyl (2ax)
2,4,6ꢀMe (2ay)
9
48
96
12
74 (5m)
52 (5n)
n.r.
76
58
(2az)
(2ba)
10
11
n.r.
(2bb)
(2bc)
12
13
24
18
95 (5o)
97 (5p)
95
94
(2bd)
(2be)
(2bf)
14
15
24
18
86 (5q)
83 (5r)
28
15
5s: 18 h, 93 %
4ac: 91 %
5t: 96 h, 80 %
4ab: 74 %
aStandard reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), H2O (2.5 mmol, 45
µL) and VOSO4·xH2O (0.1 mmol) in dry DMF (3 mL), at 70 ºC, under air.
bIsolated yields. n.r. : no reaction
mesitylbenzamide (2ay), only 76% yield of amide product (5l, Table 5) was obtained due to
considerable steric hindrance of methyl groups. The aliphatic partners such as cyclopropylꢀ(2az)
and 2ꢀpentylꢀ(2ba) of amidines provided moderate yields of corresponding amide products (5m
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and 5n, Table 5). Disappointingly, the reaction did not proceed, when Nꢀ(tertꢀ
butyl)benzimidamide (2bb) was employed in the reaction. Furthermore, pyridineꢀderived
amidines (2bc and 2bd) transformed smoothly under optimal conditions and provided amides
(5o and 5p, Table 5) in 95% and 97% yields, respectively. Although, the reaction of Nꢀ(pyridinꢀ
2ꢀyl)benzimidamide (2be) and Nꢀ(5ꢀbromopyridinꢀ2ꢀ yl)benzimidamide (2bf) also afforded good
yields of the corresponding amide products (5q and 5r, Table 5), surprisingly their
corresponding imide product (4aa) was obtained in 28 and 15% yields, respectively with some
amount of unidentified products. These results indicate that alternative reactivity of these
amidines (2be and 2bf) is involved in the generation of corresponding amide products. These
reactions are our focus for future development of new synthetic methods. Furthermore, a similar
scope was observed for the synthesis of amides (5s and 5t, Table 5), when the reaction of 1b and
1c was carried out with 2aw and 2ar, respectively.
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Overall, the present method displayed high functional group tolerance and the synthesis of two
most important Nꢀcontaining class of compounds i.e. imides and amides in moderate to high
yields. Moreover, the scope of 1,2ꢀdiketones could also be extended to cyclohexaneꢀ1,2ꢀdione
(1f), but we ended up with low yields (33ꢀ41%) of the target products (6aꢀ6c, Table 6) and many
byꢀproducts. However, the reaction of biacetyl (1g) with 2ar provided corresponding imide
(4bd, Table 6) and amide (5u) products in 74 % and 78 % yields, respectively. It may be noted
that in the case of 1f, the corresponding intermediates were not observed during the reaction by
TLC analysis, which could be attributed to the rapid hydrolysis of the intermediates into 6aꢀ6c.
The lower yields of these products might be correlated with increased side reactions due to
enolic form of 1f or by the decomposition of the product formed. In spite of the low yield of
these products, this approach represents an interesting research area for future catalyst
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development, by which imide and amide bond construction with long chain alkyl group can be
achieved in one step.
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Table 6: Reaction of aliphatic 1,2ꢀdiketones with amidines.a
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Entry
1c
1,2ꢀDiketone (1)
Amidine (2)
Time (h)
8
Yield of productsb
2aa
6a: 33 %
6b: 38 %
2c
3c
2ar
2ap
6
8
6c: 41 %
4
2ar
24
4bd: 74%
5u: 78 %
aStandard reaction conditions: 1 (1 mmol), 2 (1.2 mmol), H2O (5 mmol, 90
µL) and VOSO4·xH2O (0.2 mmol) in dry DMF (3 mL), at 70 ºC, under air;
bIsolated yield. The reaction was monitored until complete consumption of
c
1f.
Next, in order to elucidate the reaction mechanism of C(CO)–C(CO) bond cleavage of 1,2ꢀ
diketones, some control experiments were carried out. It was found that benzil (1a) does not
undergo C(CO)–C(CO) bond cleavage to afford benzoic acid under standard conditions at room
temperature (SI, control experiments, eq S4). In addition, the reaction of benzaldehyde and 1,2ꢀ
diphenylethanone with Nꢀphenylbenzimidamide (2aa) exclude the possibility of imine formation
(SI, control experiments, eqs S5 and S6). The reaction proceeds through direct nucleophilic
addition of amidine to 1,2ꢀdiketone to produce tertiary vicinal diol intermediate, which rapidly
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undergo C–C bond cleavage in the presence of VOSO4. The vanadium catalyst is not likely to
produce the cyclic intermediates as in the case of C–C bond cleavage of 1,2ꢀdiols with higher
valence inorganic oxidants, such as periodates and lead tetracarboxylates. In the case of lead
tetracarboxylates oxidation, cisꢀglycols react much faster than transꢀglycols,26 whereas, cyclic
transꢀglycols are usually inactive in the case of oxidation by periodates, probably due to
difficulty in the formation of cyclic intermediates.27 It was reported that both cyclic cisꢀ and
transꢀditertiary glycols similarly undergo oxidative cleavage in the presence of vanadium
oxytrichloride (VOCl3).17
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Further, in the absence of 1a and 2aa, a mixture of 16 mg of VOSO4 and H2O (45 µL) in dry
DMF (3 mL) was stirred at room temperature under air. A dark violet homogenous reaction
mixture was observed after 2 h (SI, page S6). The dark violet color has been proven for
vanadium (V) species for the aerobic oxidation of alcohols with VOSO4/TEMPO catalytic
system.28 The dark violet color turns black on addition of 1a and 2aa, which then turned green
after stirring the reaction mixture for 8 h at room temperature. The green color of the reaction
mixture is suggested for the presence of vanadium (IV) species.29 A similar color change was
also observed, when 3a was added to the dark violet mixture of VOSO4 in DMF. Interestingly,
the reaction mixture did not produce dark violet color, when a mixture of VOSO4 and H2O in dry
DMF was stirred for 2 h under nitrogen atmosphere. These results indicate that a VVꢀVIV
catalytic cycle in water may participate in the present one pot process. Molecular oxygen
probably shows its effect by accelerating the oxidation of VIV to VV species. However, the role of
DMF in the oxidation of vanadium is not clear at this stage. Recently, Wang and coꢀworkers
demonstrated the VOSO4 catalyzed transformation of cellulose and its derived carbohydrates
+
into formic and lactic acids in water.30 The redox conversion between VO2 and VO2+ species
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participated in the transformation of glucose into formic acid under oxygen atmosphere. An
electronꢀtransfer and oxygenꢀtransfer (ETꢀOT) mechanism was proposed for oxidative C–C bond
cleavage of intermediary glyceraldehyde to produce formic acid on the basis of the
polyoxometalate H5PV2Mo10O40ꢀcatalyzed transformation.31 In this mechanism, two VV species
are required to accept two electrons from the substrate at the same time to be reduced to VIV and
donate one O atom at the same time.
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On the basis of the aforementioned results and the literature reports, we speculate that the C–C
bond cleavage of 1,2ꢀdiketones may also follow the ETꢀOT mechanism. A plausible mechanism
following the redox conversion of VO2 /VO2+ is proposed in Figure 3. The reaction is initiated
+
+
+
by the activation of 1,2ꢀdiketone by two VO2 species or its hydrolyzed form (H2VO3 ) in
water,32 in the next step, the nucleophilic addition of amidines produce a binuclear VV
Figure 3. Mechanistic proposal
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intermediate coordinated by tetraꢀsubstituted imidazolyl ring. Each VV center reduces to VIV by
accepting one electron from the V–O bond connected to the C–O bond. This leads to the
formation of two C=O bonds and the simultaneous cleavage of the C–C bond to produce 3. The
3
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+
+
reduced VO2+ reoxidized into VO2 in our aerobic reaction conditions. The VO2 cation may act
as a Lewis acid33 to catalyze the hydrolysis of 3. The VO2 cation activates carbonyl group of 3
+
and promotes electron deficiency at amidino carbon atom. The water attacks at amidino carbon
atom to afford 5 and VV intermediate coordinated by 4. This VV intermediate produces 4 and
hydrolyzed form of vanadium (IV) species (H2VO2 ) in the presence of water.34 The H2VO2
2+
2+
form gets converted to VO2+ cation after elimination of water.
In conclusion, a new facile and efficient one pot domino route for the synthesis of imides and
amides from easily accessible 1,2ꢀdiketones and amidines via oxidative C(CO)–C(CO) bond
cleavage has been developed. The reaction employs an inexpensive, less toxic and water soluble
vanadium catalyst. A series of imide as well as amide derivatives could be easily synthesized
under oxidant and additive free conditions. One step construction of imide and amide bond with
long chain alkyl group is another important feature of this protocol. This transformation is
proposed to proceed through redox conversion between VO2 and VO2+ cation, and further
+
mechanistic investigation including the interaction of VOSO4 with 1,2ꢀdiketones, amidines and
DMF at molecular level are underway.
Experimental Section:
General information: Unless otherwise specified, all reagents and solvents were purchased
from commercial sources and were used as received. Vanadium (IV) sulfate oxide hydrate
(VOSO4·xH2O, 99.9%) was purchased from AlfaꢀAesar. MERCK precoated silica gel 60Fꢀ254
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(0.5 mm) aluminum plates were used for thin layer chromatography (TLC) and visualization of
the spots on TLC plates was achieved by UV light. Melting points were measured on a StuartTM
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1
13
melting point apparatus SMP3. H and C NMR spectra were recorded on a Bruker 500 MHz
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1
instrument using tetramethyl silane (TMS) as the internal standard. Chemical shifts for H and
13C are expressed in parts per million (ppm) relative to resonance in TMS at δ 0.00 or DMSOꢀd6
at 2.50 for 1H NMR and δ 39.9 for C NMR. Coupling constant (J) values are reported in hertz
13
(Hz). HRMS were determined with Agilent QTOF mass spectrometer 6540 series instrument.
General procedures for the synthesis of 1,2-diketones (1b-1e):
General procedure for the preparation of deoxybenzoins35: To a solution of substituted
phenylacetic acid (50 mmol) in dichloromethane (50 mL) was added thionyl chloride (75.0
mmol) and dimethylformamide (0.05 mmol) and the reaction mixture stirred at room temperature
for 1 hour. The solvent was removed under vacuum to provide arylacetyl chlorides in
quantitative yield, which was used without further purification. The arylacetyl chloride was
stirred with appropriate benzene derivatives (500 mmol) at 0 ºC. Anhydrous aluminium chloride
(62.5 mmol) was added slowly portionꢀwise maintaining the internal temperature below 5 ºC.
The solution was allowed to warm to room temperature and stirred until acid chloride was
completely consumed as indicated by TLC. The reaction mixture was then poured onto iceꢀ
water. The organic layer was separated, washed with brine, and dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified over silica gel (60–120
mesh) using hexane:ethylacetate (19:1) as the eluent to give the corresponding deoxybenzoin
derivatives.
General procedure for the oxidation of deoxybenzoins36: To a solution of deoxybenzoin
derivatives (5 mmol) in DMSO (50 mL) was added selenium dioxide (7.5 mmol) and irradiated
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in the microwave oven (domestic household oven 650 W) for 5 min at 40 ºC. The reaction
mixture was filtered while hot to remove the selenium metal and was poured onto iceꢀwater
mixture to precipitate the crude product. The crude product was collected, dried and purified
over silica gel using hexane:ethylacetate (19:1) as the eluent to provide corresponding 1,2ꢀ
diketones (1bꢀ1e).
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General procedures for the synthesis of amidines (2)37:
Method A: A round bottom flask (100 mL in volume) was charged with NaH (60% in mineral
oil) (15 mmol, 1.5 equiv), sealed with a rubber septum, evacuated and backfilled with nitrogen
using balloon. DMSO (5 ml) was added and the resulting suspension cooled with an iceꢀwater
bath prior to the addition of carbonitrile (10.0 mmol) and aniline (12.0 mmol, 1.2 equiv). The
mixture was kept at 0 ºC for 30 min and stirred at room temperature until the starting material
was consumed as indicated by TLC analysis. After completion of reaction, iceꢀwater (50 mL)
was added to quench the reaction mixture while maintaining vigorous stirring. In the cases when
the amidine precipitated upon addition of water, the solid was filtered off and dissolved in
EtOAc. In all other cases, the aqueous layer was extracted with EtOAc (3 × 50 mL). The extracts
were combined and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified either by silica gel
chromatography or upon recrystallization (solvent: DCM/Hexane) to provide corresponding
amidine derivatives (2aaꢀ2ac, 2ae, 2af, 2ah, 2ai, 2al, 2am, 2ao, 2arꢀ2at, 2av, 2aw, 2bcꢀ2bf).
Method B: A sealed tube (15 mL in volume) equipped with a stirrer bar was charged with the
carbonitrile (10.0 mmol) and the aniline (11.0 mmol, 1.1 equiv) under air. AlCl3 (10.0 mmol, 1.0
equiv) was added portion wise. The tube was tightly sealed with a cap and lowered into a
preheated oil bath at 140 ºC. The reaction mixture was stirred for about an hour. The hot mixture
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was poured into a solution of concentrated NaOH solution (40 mL) in mixed water and ice (100
mL) and stirred for about 15 minutes. Then the mixture was extracted with EtOAc or DCM (50
mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over
anhydrous Na2SO4, and evaporated under vacuum. The residue was purified either by silica gel
chromatography or upon recrystallization (solvent: DCM/Hexane) to provide corresponding
amidine derivatives (2ad, 2ag, 2aj, 2ak, 2an, 2ap, 2aq, 2axꢀ2bb).
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General procedure for the synthesis of imides (4) and amides (5) : To an oven dried test tube
(27 mL in volume) equipped with a stir bar, the 1,2ꢀdiketone (1, 0.5 mmol, 1 equiv.), amidine (2,
1.2 equiv.), H2O (5 equiv.), 20 mol% VOSO4·xH2O and dry DMF (3 mL) were added. The
reaction mixture was lowered into a preheated oil bath at 70 °C and stirred for the specified time
under air. After completion of the reaction, the reaction mixture was allowed to cool to room
temperature. The reaction mixture was added into water (50 mL), and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by
column chromatography on silica gel (60–120 mesh). The amide products (5) were purified
using hexane:ethylacetate (9:1) as the eluent. The imide products (4) were purified using
hexane:ethylacetate (7:3) as the eluent.
N,N'-Dibenzoyl-N-phenylbenzamidine (3a)21: According to general procedure, 1a (105 mg, 0.5
mmol), 2aa (117 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) at room temperature
1
afforded 3a (194 mg, 96%) as a white solid. eluent (hexane:ethylacetate = 9:1); H NMR
(DMSOꢀd6, 500 MHz): δ 7.76–7.70 (m, 2H), 7.68–7.61 (m, 4H), 7.57–7.51 (m, 1H), 7.45–7.29
(m, 10H), 7.28–7.23 (m, 2H), 7.15–7.10 (m, 1H); 13C NMR (DMSOꢀd6, 125 MHz): δ 176.4,
171.6, 158.2, 140.7, 135.1, 134.6, 133.6, 133.1, 132.2, 132.1, 129.7, 129.4, 129.3, 129.2, 129.0,
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128.9, 128.8, 128.7, 127.9; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C27H21N2O2 405.1603;
3
4
5
6
found 405.1603.
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9
N-Benzoylbenzamide (4aa)4c: According to general procedure, 1a (105 mg, 0.5 mmol), 2aa (117
mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4aa (109 mg, 97%) as a white
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1
solid. H NMR (DMSOꢀd6, 500 MHz): δ 11.34 (s, 1H), 7.94–7.90 (m, 4H), 7.68–7.60 (m, 2H),
7.56–7.51 (m, 4H); 13C NMR (DMSOꢀd6, 125 MHz): δ 168.2, 134.3, 133.1, 129.1, 128.9;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H11NNaO2 248.0687; found 248.0691.
N-Benzoyl-4-methoxybenzamide (4ab)4a: According to general procedure, 1a (105 mg, 0.5
mmol), 2ab (136 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ab (116 mg,
91%) as a white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.18 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H),
7.89 (d, J = 7.9 Hz, 2H), 7.65–7.61 (m, 1H), 7.54–7.50 (m, 2H), 7.07–7.04 (m, 2H), 3.85 (s, 3H);
13C NMR (DMSOꢀd6, 125 MHz): δ 168.4, 167.2, 163.3, 134.6, 132.9, 131.4, 129.0, 128.8,
126.21, 114.1, 56.0; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H13NNaO3 278.0793;
found 278.0796.
N-Benzoyl-4-chlorobenzamide (4ac)4c: According to general procedure, 1a (105 mg, 0.5 mmol),
2ac (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ac (127 mg, 98%) as a
white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.40 (s, 1H), 7.95–7.89 (m, 4H), 7.67–7.62 (m,
1H), 7.60 (d, J = 8.6 Hz, 2H), 7.53 (t, J = 7.7 Hz, 2H); 13C NMR (DMSOꢀd6, 125 MHz): δ
168.1, 167.3, 137.8, 134.1, 133.16, 133.13, 131.0, 129.1, 128.9, 128.8; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C14H10ClNNaO2 282.0298; found 282.0299.
N-Benzoyl-3-chlorobenzamide (4ad)7a: According to general procedure, 1a (105 mg, 0.5 mmol),
2ad (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ad (124 mg, 96%) as a
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white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.42 (s, 1H), 7.99–7.95 (m, 1H), 7.95–7.90 (m,
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2H), 7.87–7.84 (m, 1H), 7.72–7.69 (m, 1H), 7.67–7.62 (m, 1H), 7.58–7.51 (m, 3H); C NMR
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(DMSOꢀd6, 125 MHz): δ 168.0, 166.8, 136.3, 134.1, 133.5, 133.1, 132.7, 130.8, 129.1, 128.8,
128.7, 127.7; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H10ClNNaO2 282.0298; found
282.0299.
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N-Benzoyl-2-chlorobenzamide (4ae): According to general procedure, 1a (105 mg, 0.5 mmol),
2ae (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ae (124 mg, 96%) as a
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white solid. mp 139–141 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.74 (s, 1H), 7.93 (d, J = 7.4
13
Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.58–7.47 (m, 5H), 7.43 (td, J = 7.3, 1.4 Hz, 1H); C NMR
(DMSOꢀd6, 125 MHz): δ 168.4, 166.7, 136.8, 133.5, 133.1, 131.6, 129.83, 129.81, 129.1, 129.0,
128.9, 127.6; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H10ClNNaO2 282.0298; found
282.0299.
N-Benzoyl-4-bromobenzamide (4af)7a: According to general procedure, 1a (105 mg, 0.5 mmol),
2af (165 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4af (140 mg, 92%) as a
white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.40 (s, 1H), 7.94–7.90 (m, 2H), 7.85 (d, J = 8.6
Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.67–7.62 (m, 1H), 7.53 (t, J = 7.7 Hz, 2H); 13C NMR
(DMSOꢀd6, 125 MHz): δ 168.0, 167.5, 134.1, 133.5, 133.1, 131.8, 131.1, 129.1, 128.8, 126.9;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H10BrNNaO2 325.9793; found 325.9794.
N-Benzoyl-3-bromobenzamide (4ag): According to general procedure, 1a (105 mg, 0.5 mmol),
2ag (165 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ag (140 mg, 92%) as a
white solid. mp 122–124 ºC; 1H NMR (DMSOꢀd6, 500 MHz): δ 11.43 (s, 1H), 8.12–8.10 (m,
1H), 7.94–7.98 (m, 3H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.57–7.47 (m, 3H);
13C NMR (DMSOꢀd6, 125 MHz): δ 168.0, 166.7, 136.5, 135.6, 134.1, 133.1, 131.5, 131.0,
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129.1, 128.8, 128.1, 122.0; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H10BrNNaO2
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325.9793; found 325.9793.
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N-Benzoyl-4-methylbenzamide (4ah)4c: According to general procedure, 1a (105 mg, 0.5
mmol), 2ah (126 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ah (112 mg,
95%) as a white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.25 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H),
7.83 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 8.0 Hz,
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2H), 2.39 (s, 3H); C NMR (DMSOꢀd6, 125 MHz): δ 168.2, 167.8, 143.4, 134.4, 133.0, 131.4,
129.4, 129.3, 129.0, 128.8, 21.5; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H13NNaO2
262.0844; found 262.0844.
N-Benzoyl-2-methylbenzamide (4ai)7a: According to general procedure, 1a (105 mg, 0.5 mmol),
2ai (126 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ai (50 mg, 42%) as a
white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.50 (s, 1H), 8.00–7.96 (m, 2H), 7.71–7.66 (m,
1H), 7.57 (t, J = 7.8 Hz, 2H), 7.54–7.51 (m, 1H), 7.45 (td, J = 7.5, 1.3 Hz, 1H), 7.37–7.30 (m,
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2H), 2.43 (s, 3H); C NMR (DMSOꢀd6, 125 MHz): δ 170.7, 167.2, 136.4, 135.9, 133.6, 133.2,
130.9, 130.6, 129.0, 128.8, 127.9, 126.0, 19.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H13NNaO2 262.0844; found 262.0846.
N-Benzoyl-5-bromo-2-methoxybenzamide (4aj): According to general procedure, 1a (105 mg,
0.5 mmol), 2aj (183 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4aj (137 mg,
82%) as a white solid. mp 168–170 ºC; 1H NMR (DMSOꢀd6, 500 MHz): δ 11.42 (s, 1H), 7.93–
13
7.88 (m, 2H), 7.71–7.63 (m, 3H), 7.56 (t, J = 7.7 Hz, 2H), 7.16– 7.10 (m, 1H), 3.82 (s, 3H); C
NMR (DMSOꢀd6, 125 MHz): δ 166.3, 165.8, 156.3, 135.3, 133.5, 133.4, 132.1, 129.1, 128.7,
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127.0, 114.9, 112.3, 56.9; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H12BrNNaO3
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355.9898; found 355.9901.
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N-Benzoyl-2,5-dichlorobenzamide (4ak): According to general procedure, 1a (105 mg, 0.5
mmol), 2ak (160 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ak (132 mg,
90%) as a white solid using silica gel (100ꢀ200 mesh) and hexane:ethylacetate (19:1) as the
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eluent. mp 153–155 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.84 (s, 1H), 7.94 (d, J = 7.6 Hz,
2H), 7.72 (s, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.57–7.51 (m, 4H). 13C NMR (DMSOꢀd6, 125 MHz):
δ 167.1, 166.7, 138.4, 133.6, 132.8, 132.2, 131.5, 131.2, 129.1, 129.0, 128.5, 128.4; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C14H9Cl2NNaO2 315.9908; found 315.9912.
N-Benzoylthiophene-2-carboxamide (4al)8a: According to general procedure, 1a (105 mg, 0.5
mmol), 2al (122 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4al (103 mg,
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89%) as a white solid. H NMR (DMSOꢀd6, 500 MHz): δ 11.28 (s, 1H), 8.16 (dd, J = 3.8, 1.1
Hz, 1H), 8.00 (dd, J = 5.0, 1.1 Hz, 1H), 7.90–7.84 (m, 2H), 7.68–7.60 (m, 1H), 7.57–7.50 (m,
2H), 7.25 (dd, J = 5.0, 3.8 Hz, 1H); 13C NMR (DMSOꢀd6, 125 MHz): δ 168.1, 161.3, 138.8,
134.8, 134.5, 133.0, 132.6, 129.1, 128.9, 128.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C12H9NNaO2S 254.0252; found 254.0259.
N-Benzoylfuran-2-carboxamide (4am)8a: According to general procedure, 1a (105 mg, 0.5
mmol), 2am (114 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4am (101 mg,
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94%) as a light yellow solid. eluent (hexane:ethylacetate = 1:1); H NMR (DMSOꢀd6, 500
MHz): δ 11.11 (s, 1H), 8.03 – 8.00 (m, 1H), 7.89–7.84 (m, 2H), 7.67– 7.62 (m, 1H), 7.60 (d, J =
13
3.6 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 6.74 (dd, J = 3.6, 1.7 Hz, 1H); C NMR (DMSOꢀd6, 125
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MHz): δ 167.7, 157.2, 147.9, 146.7, 134.3, 133.1, 129.0, 128.8, 118.2, 112.8; HRMS (ESIꢀTOF)
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m/z: [M + Na]+ Calcd for C12H9NNaO3 238.0480; found 238.0485.
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N-Benzoyl-2-chloronicotinamide (4an): According to general procedure, 1a (105 mg, 0.5
mmol), 2an (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4an (120 mg,
92%) as a white solid. mp 148–150 ºC; 1H NMR (DMSOꢀd6, 500 MHz): δ 11.91 (s, 1H), 8.52
(dd, J = 4.8, 1.9 Hz, 1H), 8.05 (dd, J = 7.6, 1.9 Hz, 1H), 7.97–7.92 (m, 2H), 7.69–7.64 (m, 1H),
7.57–7.52 (m, 3H); 13C NMR (DMSOꢀd6, 125 MHz): δ 167.4, 166.7, 150.7, 145.9, 138.1, 133.7,
133.5, 132.7, 129.1, 129.0, 123.5; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H9ClN2NaO2
283.0250; found 283.0251.
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N-Benzoylisonicotinamide (4ao): According to general procedure, 1a (105 mg, 0.5 mmol), 2ao
(118 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ao (83 mg, 84%) as a light
yellow solid. eluent (hexane:ethylacetate = 3:7); mp 188–190 ºC; 1H NMR (DMSOꢀd6, 500
MHz): δ 11.60 (s, 1H), 8.81–8.74 (m, 2H), 7.98–7.90 (m, 2H), 7.78 (d, J = 5.8 Hz, 2H), 7.66 (t, J
= 7.4 Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H); 13C NMR (DMSOꢀd6, 125 MHz): δ 167.8, 167.5, 150.6,
141.8, 133.7, 133.4, 129.2, 128.9, 122.4; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C13H10N2NaO2 249.0640; found 249.0644.
N-(Cyclopropanecarbonyl)benzamide (4ap)4c: According to general procedure, 1a (105 mg, 0.5
mmol), 2ap (96 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ap (83 mg,
88%) as a white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.15 (s, 1H), 7.93– 7.88 (m, 2H),
7.66–7.60 (m, 1H), 7.55– 7.49 (m, 2H), 2.50–2.44 (m, 1H), 1.03–0.79 (m, 4H); 13C NMR
(DMSOꢀd6, 125 MHz): δ 175.3, 166.7, 134.0, 133.0, 128.9, 128.8, 15.0, 9.8; HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C11H11NNaO2 212.0687; found 212.0690.
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N-Butyrylbenzamide (4aq)4b: According to general procedure, 1a (105 mg, 0.5 mmol), 2aq (97
mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4aq (76 mg, 80%) as a white
solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 10.93 (s, 1H), 7.91–7.88 (m, 2H), 7.65–7.58 (m, 1H),
7.51 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 1.64–1.55 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C
NMR (DMSOꢀd6, 125 MHz): δ 174.9, 166.8, 133.8, 133.0, 128.8, 128.7, 39.4, 17.9, 14.0;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C11H13NNaO2 214.0844; found 214.0850.
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3-Chloro-N-(4-chlorobenzoyl)benzamide (4ar): According to general procedure, 1b (139 mg,
0.5 mmol), 2ad (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ar (140
1
mg, 95%) as a white solid. mp 155–157 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.53 (s, 1H),
8.04–8.01 (m, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 8.0, 1.1 Hz,
1H), 7.66 (d, J = 8.5 Hz, 2H), 7.61 (t, J = 7.9 Hz, 1H); 13C NMR (DMSOꢀd6, 125 MHz): δ
167.1, 166.8, 138.0, 136.2, 133.6, 132.9, 132.8, 131.1, 130.8, 128.9, 128.7, 127.8; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C14H9Cl2NNaO2 315.9908; found 315.9910.
4-Bromo-N-(4-chlorobenzoyl)benzamide (4as): According to general procedure, 1b (139 mg,
0.5 mmol), 2af (165 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4as (151
mg, 89%) as a white solid. mp 190–192 ºC; 1H NMR (DMSOꢀd6, 500 MHz): δ 11.45 (s, 1H),
7.95–7.91 (m, 2H), 7.87–7.83 (m, 2H), 7.77–7.73 (m, 2H), 7.63–7.59 (m, 2H); 13C NMR
(DMSOꢀd6, 125 MHz): δ 167.4, 167.2, 138.0, 133.3, 132.9, 131.8, 131.1, 131.0, 128.9, 127.0;
HRMS (ESIꢀTOF) m/z: [M + Na,81Br]+ Calcd for C14H9BrClNNaO2 361.9383; found 361.9384.
N-(4-Chlorobenzoyl)-2-methylbenzamide (4at): According to general procedure, 1b (139 mg,
0.5 mmol), 2ai (126 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4at (125 mg,
91%) as a white solid. mp 167–169 ºC; 1H NMR (DMSOꢀd6, 500 MHz): δ 11.50 (s, 1H), 7.93 (d,
J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.31–
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7.24 (m, 2H), 2.37 (s, 3H); 13C NMR (DMSOꢀd6, 125 MHz): δ 170.4, 166.3, 138.0, 136.2,
136.0, 132.5, 131.0, 130.7, 128.9, 128.0, 126.0, 19.82; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C15H12ClNNaO2 296.0454; found 296.0455.
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N-(4-Chlorobenzoyl)thiophene-2-carboxamide (4au): According to general procedure, 1b (139
mg, 0.5 mmol), 2al (122 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4au
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(119 mg, 90%) as a white solid. mp 162–164 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.35 (s,
1H), 8.16–8.12 (m, 1H), 8.01 (dd, J = 5.0, 1.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5
Hz, 2H), 7.25 (dd, J = 4.9, 3.9 Hz, 1H); 13C NMR (DMSOꢀd6, 125 MHz): δ 167.3, 161.2, 138.6,
137.7, 135.0, 133.3, 132.8, 131.0, 128.9, 128.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C12H8ClNNaO2S 287.9862; found 287.9863.
N-(4-Chlorobenzoyl)furan-2-carboxamide (4av): According to general procedure, 1b (139 mg,
0.5 mmol), 2am (114 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4av (113
1
mg, 91%) as a yellow solid. eluent (hexane:ethylacetate = 1:1); mp 126–128 ºC; H NMR
(DMSOꢀd6, 500 MHz): δ 11.20 (s, 1H), 8.02 (dd, J = 1.6, 0.6 Hz, 1H), 7.91–7.85 (m, 2H), 7.64–
13
7.53 (m, 3H), 6.74 (dd, J = 3.6, 1.7 Hz, 1H); C NMR (DMSOꢀd6, 125 MHz): δ 166.9, 157.1,
148.0, 146.6, 137.8, 133.1, 130.9, 128.9, 118.4, 112.8; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C12H8ClNNaO3 272.0090; found 272.0094.
2-Chloro-N-(4-chlorobenzoyl)nicotinamide (4aw): According to general procedure, 1b (139
mg, 0.5 mmol), 2an (139 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4aw
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(132 mg, 90%) as a white solid. mp 166–168 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.97 (s,
1H), 8.52 (dd, J = 4.8, 1.9 Hz, 1H), 8.06 (dd, J = 7.6, 1.9 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.63
13
(d, J = 8.7 Hz, 2H), 7.55 (dd, J = 7.6, 4.9 Hz, 1H); C NMR (DMSOꢀd6, 125 MHz): δ 167.3,
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165.8, 150.8, 146.0, 138.6, 138.2, 133.3, 131.5, 131.0, 129.2, 123.5; HRMS (ESIꢀTOF) m/z: [M
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+ Na]+ Calcd for C13H8Cl2N2NaO2 316.9861; found 316.9862.
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4-Chloro-N-(cyclopropanecarbonyl)benzamide (4ax): According to general procedure, 1b (139
mg, 0.5 mmol), 2ap (96 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ax (94
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mg, 84%) as a white solid. mp 173–175 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 11.19 (s, 1H),
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7.92 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 2.47–2.41 (m, 1H), 1.11–0.43 (m, 4H); C
NMR (DMSOꢀd6, 125 MHz): δ 175.2, 165.8, 137.9, 132.8, 130.8, 129.0, 15.0, 9.9; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C11H10ClNNaO2 246.0298; found 246.0298.
N-Butyryl-4-chlorobenzamide (4ay)7c: According to general procedure, 1b (139 mg, 0.5 mmol),
2aq (97 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ay (92 mg, 82%) as a
white solid. 1H NMR (DMSOꢀd6, 500 MHz): δ 11.00 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.59 (d, J
= 8.6 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 1.66 – 1.49 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR
(DMSOꢀd6, 125 MHz): δ 174.9, 165.9, 137.9, 132.6, 130.7, 128.9, 39.3, 17.8, 14.0; HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C11H12ClNNaO2 248.0454; found 248.0455.
4-Chloro-N-(4-methoxybenzoyl)benzamide (4az)4a: According to general procedure, 1c (135
mg, 0.5 mmol), 2ac (115 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4az
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(119 mg, 82%) as a white solid. H NMR (DMSOꢀd6, 500 MHz): δ 11.24 (s, 1H), 7.92 (d, J =
8.9 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 3.85 (s,
3H); 13C NMR (DMSOꢀd6, 125 MHz): δ 167.5, 167.1, 163.4, 137.6, 133.3, 131.4, 130.9, 128.8,
126.0, 114.1, 56.0; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H12ClNNaO3 312.0403;
found 312.0405.
4-Methoxy-N-(4-methylbenzoyl)benzamide (4ba)4a: According to general procedure, 1c (135
mg, 0.5 mmol), 2ah (126 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4ba
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The Journal of Organic Chemistry
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(104 mg, 77%) as a white solid. H NMR (DMSOꢀd6, 500 MHz): δ 11.08 (s, 1H), 7.91 (d, J =
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8.8 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 3.85 (s,
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3H), 2.39 (s, 3H); C NMR (DMSOꢀd6, 125 MHz): δ 168.6, 167.8, 163.7, 143.3, 131.6, 131.8,
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129.6, 129.6, 126.2, 114.2, 56.0, 21.7; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd. for
C16H15NNaO3 292.0950; found 292.0953.
N-(Cyclopropanecarbonyl)-4-methoxybenzamide (4bb): According to general procedure, 1c
(135 mg, 0.5 mmol), 2ap (96 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4bb
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(94 mg, 86%) as a white solid. mp 148–150 ºC; H NMR (DMSOꢀd6, 500 MHz): δ 10.99 (s,
1H), 7.92 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 2.80–2.25 (m, 1H, merged
with DMSO), 0.93–0.88 (m, 4H); 13C NMR (DMSOꢀd6, 125 MHz): δ 175.4, 165.9, 163.2, 131.0,
125.9, 114.1, 55.9, 14.9, 9.7; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C12H13NNaO3
242.0793; found 242.0798.
N-Benzoyl-4-nitrobenzamide (4bc)7c: According to general procedure, 1d (128 mg, 0.5 mmol),
2aa (118 mg, 0.6 mmol) and VOSO4·xH2O (16 mg, 0.1 mmol) afforded 4bc (60 mg, 44%) as a
white solid using silica gel (100ꢀ200 mesh) and hexane:ethylacetate (9:1) as the eluent. 1H NMR
(DMSOꢀd6, 500 MHz): δ 11.65 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.9 Hz, 2H), 7.97–
7.91 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H); 13C NMR (DMSOꢀd6, 125 MHz):
δ 167.8, 167.5, 149.9, 140.3, 133.7, 133.4, 130.3, 129.2, 128.9, 123.8; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C14H10N2NaO4 293.0538; found 293.0539.
N-Acetylbenzamide (4bd)4c: According to general procedure, 1g (86 mg, 1 mmol), 2ar (271 mg,
1.2 mmol) and VOSO4·xH2O (32 mg, 0.2 mmol) afforded 4bd (121 mg, 74%) as a white solid.
1H NMR (DMSOꢀd6, 500 MHz): δ 11.01 (s, 1H), 7.93–7.89 (m, 2H), 7.65–7.59 (m, 1H), 7.54–
7.49 (m, 2H), 2.35 (s, 3H); 13C NMR (DMSOꢀd6, 125 MHz): δ 172.6, 167.0, 133.6, 133.1,
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