Base-catalyzed synthesis of amides and imines via C-C and CC bond cleavage

Article abstract of DOI:10.1039/c4ra14234a

A transition metal free base catalyzed approach for C-N bond formation via C-C and CC bond activation has been developed. The N-arylureas reacted smoothly with 1,3-dicarbonyls and α,β-unsaturated ketones to furnish the corresponding amides and imines respectively in moderate to excellent yields.

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ARTICLE TYPE
Base–Catalyzed Synthesis of Amides and Imines via C–C and C=C Bond
Cleavage
Dilip Kumar T. Yadav and Bhalchandra M. Bhanage*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
synthesis.17 Firstly, carbon–carbon bond activation of 1,3ꢀ
A transition metal free base catalyzed approach for C–N
50 diketones with aryl halides to acyl ketones was reported by Lei in
2010.18 Subsequently, various protocols have been developed for
carbon–carbon bond activation of 1,3ꢀdiketones.19 Recently,
H2O2 mediated oxidative reaction of aromatic amine with 1,3ꢀ
diketone was reported for the amide synthesis.20 Nowadays, much
55 attention have been made on the base catalyzed one pot synthesis
of various organic compounds.21 Hence, to perform various
transformations by using inexpensive and easily available base is
a promising research area. Most recently Zhang’s group have
reported the base catalyzed C–C bond cleavage of 1,3ꢀdiketones
60 to furnish the corresponding esters.22 The results inspire us to
investigate whether amides could be synthesized via C–C bond
cleavage of 1,3ꢀdiketones by using base. The Nꢀarylureas are
stable, easy to store, handle and can be easily prepared.
Moreover, it has been extensively employed as a new type of
65 coupling partners in the organic synthesis.23 Hence, Nꢀarylureas
could be used as other alternatives to amines for the preparation
of nitrogen containing compounds. To our knowledge, Nꢀ
arylureas have never been used for the synthesis of amides with
1,3ꢀdiketones. Here, we report a novel, simple, efficient, solvent
70 and transition metal free methodology for the synthesis of amides
from Nꢀarylureas and 1,3ꢀdiketones by using inexpensive and
easily available base (Scheme 1).
bond formation via C–C and C=C bond activation has been
developed. The Nꢀarylureas were reacted smoothly with 1,3ꢀ
dicarbonyls and α,βꢀunsaturated ketones to furnish the
10 corresponding amides and imines respectively in moderate to
excellent yields.
Introduction
Amides are one of the abundant and important units present in
pharmaceuticals, polymers, agrochemicals, natural products and
15 biological systems.1 In addition, they have wide application as
versatile building blocks in the organic synthesis.2 Hence, the
development of efficient and versatile practical methods for the
synthesis of amides has always been an important topic in the
organic chemistry. The main synthetic route for amide bond
20 formation is condensation of amines with activated carboxylic
acid derivatives.3 Other methods for amide synthesis are
transition metal catalyzed amidation of aryl halides with nitrogen
containing reagents,4 the oxidative amidation of aldehydes,5
ketones,6 alcohols,7 amines,8 Schmidt rearrangement,9a Curtius
25 rearrangement,9b
Beckmannn
rearrangement,10
aminocarbonylation of haloarenes and alkynes,11 transition metal
catalyzed cleavage of carbon–carbon bond with a nitrogen
source.12 However, these protocols suffer from one or more
drawbacks such as use of transition metals, unstable starting
30 compounds, toxic solvents, costly reagents. Hence, the
development of simple, efficient and environmentally friendly
protocol for the synthesis of amides would be highly desirable.
Recently, selective carbon–carbon bond cleavage (activation)
by transition metals have attracted great scope in organic and
35 organometallic chemistry.13 To facilitate C–C bond activation
different methods have been developed such as chelation
assistance,14 the relief of ring strain15 and employing functional
fragmentation as the leaving groups includes carboxylic acids,16a,b
nitriles,16c,d and carbonyls.16e The 1,3ꢀdiketones have emerged as
40 an important substrates for C–C bond activation in the organic
75
80
85
*Department of Chemistry, Institute of Chemical Technology, Matunga,
Mumbai-400019. India.
Tel.: +91-22-33612601; fax: +91-22-33611020;
45 E-mail: bm.bhanage@gmail.com, bm.bhanage@ictmumbai.edu.in
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
90 Scheme 1: Various C–C bond cleavage reactions.
[journal], [year], [vol], 00–00 | 1
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arylurea derivative (1b) exhibits the steric effect and provided
corresponding Nꢀ(oꢀtolyl)benzamide (3b) in 68% yield (Table 2,
entry 2). The reaction of Nꢀarylureas bearing electron donating
groups such as (–CH3, –OMe) afforded the corresponding
45 products 3c–3d in excellent yields (Table 2, entries 3–4).
Furthermore Nꢀarylurea derivatives bearing haloꢀsubstituents (–
Cl, –Br) also provided the corresponding products 3e–3f in
Results and discussion
To optimize the reaction conditions Nꢀphenylurea (1a) and 1,3ꢀ
diphenyl propaneꢀ1,3ꢀdione (2a) was chosen as a model substrate
for the baseꢀcatalyzed synthesis of amide. A series of experiments
were carried out to study the effect of various reaction parameters
such as base, temperature and time (Table 1). Initially, we have
screened various bases such as KOH, NaOH, K2CO3, Na2CO3,
LiOH, tꢀBuONa, tꢀBuOK and Cs2CO3 for the synthesis of Nꢀ
phenylbenzamide (3a) (Table 1, entries 1–8). It was observed that
5
Table 2: Substrate study for the synthesis of amidesa
10 among the various bases, KOH gave the best yield of the desired
product 3a and hence was used for further studies (Table 1, entry
1). However, other bases like NaOH, K2CO3, Na2CO3, LiOH, tꢀ
BuONa, tꢀBuOK and Cs2CO3 furnished the 3a in moderate to
good yields (Table 1, entries 2–8). However, the product
15 formation was not observed in the absence of the base (Table 1,
entry 9). Subsequently, we studied the effect of base loading and
it was found that 0.4 mmol of KOH furnished 3a in excellent
yield (Table 1, entry 10). Consequently, we have also examined
the effect of reaction time and temperature for the effective
20 progress of the reaction, and observed that 24 h was the optimum
time required for completion of the reaction (Table 1, entry 11). It
was found that the yield of 3a decreases with decrease in reaction
temperature from 135 °C to 125 °C (Table 1, entry 12).
Furthermore, for the possibility of involvement of trace amount
25 of transition metal in the reagent grade KOH, we have also
examined the reaction by using KOH 99.99% (metal basis) (Alfa
Aesar) and no change in the yield of 3a was observed (Table 1,
entry 13).
50
Entry
Nꢀarylurea
1,3ꢀdiketone
Product
Yield
(%)b 3
1
90
2
3
4
5
2a
2a
2a
2a
68
92
93
74
6
2a
65
82
Table 1: Optimization of the reaction conditionsa
O
O
O
H
N
30
NH2
base
7
8
1a
1a
N
+
H
O
temp., time
2a
1a
3a
Entry
Base (mmol)
Time (h)
Yield (%)b 3a
85
87
1
2
3
KOH
NaOH
K2CO3
24
24
24
76
71
68
9
1a
1a
1a
4
5
Na2CO3
LiOH
24
24
24
24
24
24
24
20
24
24
63
58
68
70
75
0
60
63
10
11
6
tꢀBuONa
tꢀBuOK
Cs2CO3
ꢀ
7
8
9
12
13
1a
1a
35:40
36:43
10
11
12c
13d
KOH (0.4)
KOH (0.4)
KOH (0.4)
KOH (0.4)
92
78
73
92
20:24:31
14
1a
1a
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Base (0.2 mmol),
35 135 °C, 24 h. b GC yield. c 125 °C. d KOH 99.99% (metal basis).
With these optimized reaction conditions in hand, we have
studied the scope of developed protocol for the synthesis of
various kinds of structurally diverse amides from Nꢀarylureas and
1,3ꢀdiketones. Firstly, different Nꢀarylurea derivatives were
40 examined for the synthesis of amides. The orthoꢀsubstituted Nꢀ
30:38
15
a
Reaction conditions: Nꢀarylureas (1 mmol), 1,3ꢀdiketones (1.5 mmol),
KOH (0.4 mmol ), 135 °C, 24 h. b isolated yield.
2
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Table 3: Substrate study for the synthesis of iminesa
(3n) and ethyl 3ꢀ(phenylamino)butꢀ2ꢀenoate (3o) products (Table
2, entry 14). Subsequently, aromatic βꢀ keto ester (2j) was also
studied with 1a and it was found that mixture of amide 3a and
carbamate 3n were obtained (Table 2, entry 15).
25
Imines are important intermediates in the synthesis of nitrogen
heterocycles, fine chemicals, pharmaceuticals and agricultural
chemicals.24,25 In addition, they also act as a electrophiles in
Entry
Nꢀarylurea
α,βꢀunsaturated
ketone
Product
Yield
(%)b 5
1
2
77
62
various
transformations
including
addition
reactions,
condensations, reductions and cyclization.25 Moreover, imines
30 also display wide range of biological activities such as antiꢀ
inflammatory, antiꢀbacterial, antiꢀfungal, antiꢀviral properties.26
Thus, the progress toward newer methods for the synthesis of
imines is also significant interest among the organic synthetic
community. The literature study reveals that α,βꢀunsaturated
35 ketone undergoes thermal decomposition in the presence of
aniline at very high temperature to provide the corresponding
imine derivative.27 So, the scope of developed protocol was
further expanded for the synthesis of imines by using Nꢀarylureas
and α,βꢀ unsaturated ketones. It was observed that the reaction of
40 1a with chalcone (4a) under the optimized reaction conditions
furnished the desired Nꢀbenzylideneaniline (5a) in 77% yield
(Table 3, entry 1). Next, Nꢀarylurea bearing orthoꢀsubstituent
exhibits stericꢀeffect on the reaction yield and gave corresponding
Nꢀbenzylideneꢀ2ꢀmethylaniline (5b) in 62% yield (Table 3, entry
45 2). Furthermore, Nꢀarylureas having electron donating
substituents at paraꢀposition (–CH3, –OMe) were converted into
corresponding imine derivatives 5c–5d in good yields (Table 3,
entries 3–4). Next, it was observed that 1a bearing halogen
substituents (–Cl, –Br) were also well tolerated and gave
50 respective imine products 5e–5f in moderate yields (Table 3,
entries 5–6). Furthermore, we have also examined the substituted
chalcone derivatives with 1a and it was observed that 4a with
electron donating substituents (–CH3, –OMe) provided the
corresponding imines 5g–5h in good yields (Table 3, entries 7–
55 8). Subsequently, the reaction of 1a with disubstituted chalcone
derivatives provided respective imine derivatives 5i–5j in good
yields (Table 3, entries 9–10). Furthermore, the reaction of 1a
with 4a bearing halo substituents also furnished the
corresponding imine derivatives 5k–5n in moderate yields (Table
60 3, entries 11ꢀ14). Next, the reaction of 1a with 4j provided
corresponding Nꢀ(thiophenꢀ2ꢀylmethylene)aniline (5o) in 71%
yield (Table 3, entry 15).
4a
4a
3
78
H
N
NH2
1d O
4
5
4a
4a
80
65
O
6
7
8
9
4a
63
76
79
65
1a
1a
1a
10
81
1a
1a
O
F
5k N
11
12
63
61
4f
F
1a
1a
13
64
O
1a
1a
14
15
68
71
4i
Br
Based on our experimental observation and literature report,28
we propose a plausible reaction mechanism for the synthesis of
65 amide (Scheme 2). Firstly, when Nꢀarylurea is heated with base at
135 °C, it undergoes thermal decomposition to provide aniline
5
a Reaction conditions: Nꢀarylureas (1 mmol), α,βꢀunsaturated ketones (1.5
mmol), KOH (0.4 mmol ), 135 °C, 24 h. b isolated yield.
moderate yields (Table 2, entries 5–6). Next, various 1,3ꢀdiketone
derivatives were also studied for the synthesis of amides. It was
found that 2a bearing electron donating substituents (–CH3, –
and its formation was confirmed by GCꢀMS, H and 13C NMR
1
spectroscopic techniques. However, aniline formation was not
observed in the absence of the base. This confirms that under the
70 thermal condition and in the presence of basic medium, 1a was
converted into corresponding aniline. Next, the aniline derivative
reacts with carbonyl derivative to form the corresponding
intermediate A which finally undergoes C–C bond cleavage to
furnish the desire product 3a and acetophenone as a side product.
75 Furthermore, based on literature report27 and our observation, we
have also found that α,βꢀunsaturated ketone reacts with aniline
formed from Nꢀarylurea under optimized reaction condition to
furnish corresponding imine derivative (Scheme 3).
10 OMe) furnished the desired amides 3g–3i in excellent yields
(Table 2, entries 7–9). Furthermore, the reaction of 1a with 2a
bearing halo substituents also provided the respective amides 3j–
3k in good yields (Table 2, entries 10–11). Next, the
unsymmetrical 1ꢀphenylbutaneꢀ1,3ꢀdione (2g) was also studied
15 with 1a and it was found that mixture of amides 3a and 3l were
obtained (Table 2, entry 12). However, the reaction of 1a with
aliphatic diketone such as acetylactone (2h) provided the mixture
of Nꢀphenylacetamide (3l) and βꢀenaminone (3m) products
(Table 2, entry 13). Furthermore, the reaction of 1a with aliphatic
20 βꢀ keto ester (2i) provided the mixture of amide (3l), carbamate
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combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduce pressure to afford the crude product.
40 The crude product was purified by column chromatography
(basic alumina saturated with Et3N, 100ꢀ200 mesh, PE) to
provide the desired pure product. The identity of product was
confirmed by 1H and 13C NMR spectroscopic analysis.
Acknowledgements
45 The author D. K. T. Yadav is greatly thankful to the UGC
(University Grant Commission), India for providing the
fellowship.
Scheme 2: Proposed mechanism for the synthesis of amide.
Notes and references
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2
3
Scheme 3: Proposed mechanism for the synthesis of imine.
5
Conclusion
In conclusion, we have developed a novel base catalyzed
approach for the synthesis of amides and imines via C–C and
C=C cleavage of 1,3ꢀdiketones and α,βꢀunsaturated ketones with
Nꢀarylureas. Here, we have firstly demonstrated that Nꢀarylureas
10 can be envisioned as a new type of coupling partners for 1,3ꢀ
diketones and α,βꢀunsaturated ketones. The various amides and
imines could be efficiently synthesized by this method in good to
excellent yields. Due to the generality of the process, the
developed protocol will cover a wide application in organic
15 synthesis. Hence, the developed protocol sounds to be highly
efficient, novel methodology for the synthesis of amides as well
as imines and have wide substrate applicability.
4
5
6
7
Experimental Section
A typical experimental procedure for the synthesis of amide
20 from Nꢀarylurea and 1,3ꢀdicarbonyl:
A 20 mL schlenk tube equipped with magnetic stirring bar was
charged with Nꢀarylurea (1 mmol), 1,3ꢀdicarbonyl (1.5 mmol),
KOH (0.4 mmol) and was placed in a preheated oil bath for 24 h
at 135 °C. After cooling down reaction mixture to room
25 temperature, it was extracted with ethyl acetate (3×5 mL) and the
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduce pressure. The crude product was
directly purified by column chromatography (silica gel, 100ꢀ200
mesh, PE–EtOAc) to furnish the corresponding pure product. The
30 identity of product was confirmed by 1H and 13C NMR
spectroscopic analysis.
A typical experimental procedure for the synthesis of imine
from Nꢀarylurea and α,βꢀunsaturated ketone:
A mixture of Nꢀarylurea (1 mmol), α,βꢀunsaturated ketone (1.5
35 mmol), KOH (0.4 mmol) was heated at 135 °C for 24 h in a
sealed 20 mL schlenk tube. After cooling the reaction mixture to
room temperature, it was extracted with ethyl acetate (3×5 mL),
8
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DOI: 10.1039/C4RA14234A
Base–Catalyzed Synthesis of Amides and Imines via C–C and C=C Bond Cleavage
Dilip Kumar T. Yadav and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology,
Matunga, Mumbaiꢀ 400019, India
A simple and efficient protocol has been developed for the synthesis of amides and imines
from 1,3ꢀdicarbonyls and α,βꢀunsaturated ketones respectively with Nꢀarylureas in the
presence of inexpensive and easily available KOH base under solvent free condition.