Concise synthesis of semicarbazides and formylhydrazines via direct addition reaction between aromatic azoarenes and N-substituted formamides

Article abstract of DOI:10.1039/c4ra17015f

The addition reactions between aromatic azoarenes and N-substituted formamides are described. This direct and practical method provides a novel approach for the synthesis of formylhydrazines and semicarbazides in the presence of NaI/DTBP and imidazole/DCP catalytic systems, respectively. It can be seen that C-H or C-N from N-substituted formamides could be cleaved selectively under such transition-metal-free conditions. This is the first successful example of direct addition of N-substituted formamides to a NN bond.

Full text of DOI:10.1039/c4ra17015f

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Concise synthesis of semicarbazides and
formylhydrazines via direct addition reaction
Cite this: RSC Adv., 2015, 5, 19301
between aromatic azoarenes and N-substituted
formamides†
Received 25th December 2014
Accepted 2nd February 2015
a
Defu Liu, Jincheng Mao, ab Guangwei Rong,a Hong Yan,a Yang Zhenga and Jie Chena
*
DOI: 10.1039/c4ra17015f
www.rsc.org/advances
The addition reactions between aromatic azoarenes and N- alkenylmagnesium generated in situ from FeCl2 and EtMgBr
substituted formamides are described. This direct and practical produced an (E)-b-unsaturated aldehyde through the cleavage of
method provides
a novel approach for the synthesis of for- C–N close to carbonyl group of DMF [Scheme 1, eqn (2)].
mylhydrazines and semicarbazides in the presence of NaI/DTBP and Therefore, the direct addition of DMF to carbon–carbon double
imidazole/DCP catalytic systems, respectively. It can be seen that C–H and triple bonds could provide an effective approach to prepare
or C–N from N-substituted formamides could be cleaved selectively a series of unsaturated carbonyl compounds. Herein, we report
under such transition-metal-free conditions. This is the first successful the rst transition-metal-free addition of formamides to a
example of direct addition of N-substituted formamides to a N]N nitrogen–nitrogen double bond via selective cleavage of a C–H
bond.
or C–N bond of a formamide.
As we know, azo compounds, that function as organic dyes,
pigments, food additives, indicators and radical reaction
initiators, are widely used in industry.7 In recent years, studies
on the chemistry of azodicarboxylates have received signicant
attention in organic synthesis.8 Dialkyl azodicarboxylates are
excellent electrophiles, which have been successfully used for
C–N bond formation reactions via the addition of C–H bond to
the N]N double bond of dialkyl azodicarboxylates.9 However,
compared to dialkyl azodicarboxylates, the N]N double bond
in aromatic azoarenes has less reactivity. To the best of our
knowledge, only a very few of precedents have been reported
for C–H addition to the N]N double bond of aromatic
In the past several years, N,N-dimethylformamide (DMF) was
not only used as a polar solvent for various catalytic reactions,
but also employed as a multipurpose precursor for various units
in various reactions.1 Among these, formylation and amino-
carbonylation are the most important contributions from
DMF.2 In this way, many groups focused on such trans-
formations through direct substitution with a carbon–halogen
or C–H bond.3 However, the intermolecular addition of form-
amides has attracted little attention. In 2009, Nakao and
Hiyama rst reported that the intermolecular hydro-
carbamoylation reactions of alkynes and 1,3-dienes could be
catalyzed by nickel and a Lewis acid to synthesize unsaturated
amides.4 In 2010, Tsuji and co-workers demonstrated that
formamides could be successfully added to internal or terminal
alkynes to afford the same products.5 It can be seen that this
transformation undergoes the cleavage of C–H close to carbonyl
group of the formamides [Scheme 1, eqn (1)]. Differently,
Nakamura and co-workers6 found that the addition of DMF with
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China. E-mail: jcmao@suda.edu.cn
bState Key Laboratory of Oil and Gas Reservoir Geology and Exploitation, Southwest
Petroleum University, Chengdu 610500, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures,
1H, 13C, HRMS spectral data and analytical data for the products. CCDC 1040947.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra17015f
Scheme 1 Intermolecular addition of formamides to unsaturated
bonds (C]C, C^C and N]N).
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azoarenes.10 For example, Kisch group disclosed one example PhCOCl, the desired product 3a was only obtained in 38%
of semiconductor-catalyzed photoaddition of olens and enol yield, and increased the amount of PhCOCl to 40 mmol%,
ethers to 1,2-diazenes.10b However, in this paper, we will resulted in 65% yield of 3a (Table 1, entry 11). However,
differently show an simple protocol for the preparation of the changing the amount of NaI could not improve the product of
desired formylhydrazines and semicarbazides through the 3a (Table 1, entry 12). In traditional reports for the N-for-
direct addition of formamides to aromatic azoarenes in the mylation of primary amines in DMF, imidazoles were oen
presence of NaI/di-tert-butyl peroxide (DTBP) and imidazole/ utilized.11 Then, imidazole was added to the reaction when
dicumyl peroxide (DCP) catalytic systems, respectively.
DCP was used as oxidant, and the product 4a was obtained in
At the beginning of our investigation, readily available 68% yield (Table 1, entry 13). However, the substituted imid-
azobenzene (1a) and DMF (2a) were selected as the model azoles, some other heterocycles or changing the amount of
substrates to optimize the reaction conditions, and the related PhCOCl were not favorable for the reaction (Table 1, entries
results are listed in Table 1. It was found that the combination 14–19).
of azobenzene (1a, 0.5 mmol) with DTBP (2.0 mmol) in DMF at
With the optimized conditions of the aminocarbonylation of
120 ꢀC for 24 h could generate the product 3a in 25% yield azobenzene in hand (Table 1, entry 11), we began to examine the
(Table 1, entry 1). When PhCOCl (0.2 equiv.) was added to the scope and the limitation of this method (Table 2). As can be
reaction, we not only obtained 3a in 31% yield, but also got the seen from Table 2, the reaction of different azoarenes with
N-formylated product 4a in 17% yield (Table 1, entry 2). To our various formamides could generate the desired products in
delight, when the oxidant was replaced by DCP, the desired 4a moderate to good yields. The para-substituted symmetrical
was obtained in 60% yield, while 3a was not acquired (Table 1, azobenzenes with electron-withdrawing groups, such as F, Cl,
entry 3). However, low yields were obtained when t-butyl Br, CF3O and CO2Et could react with DMF to afford the corre-
hydroperoxide (TBHP) and p-benzoquinone (BQ) were used as sponding products 3b, 3c, 3d, 3e and 3i in 35–63% yields.
oxidants (Table 1, entries 4–5). When the iodides were added Besides, when the para-substituted unsymmetrical azobenzene
to the catalyst system, the product was obviously improved to 2-(4-bromophenyl)-1-(4-iodophenyl)-N,N-dimethylhydrazine-
around 50%. Besides, the product 4a was obtained in trace carboxamide was used to react with DMF, 3f was obtained in
(Table 1, entries 6–9). Through the above examination of the 43% yield. Substitutions on the meta-positions were also well
data, we can conclude that when DTBP was used as oxidant, 3a tolerated. 3,3-Dichloroazobenzene and 3,3-dibromoazobenzene
was obtained as the predominant product and when DCP was coupled with DMF smoothly to afford the product 3g and 3h in
used as oxidant, 4a was acquired as the main product. Without 63% and 64% yields, respectively. Similarly, as for
Table 1 Optimization of reaction conditions for the reaction of azobenzene with DMFa
Entry
Oxidant
Additive (equiv.)
Yieldb of 3a (%)
Yieldb of 4a (%)
1c
2
3
4
5
6
7
8
9
DTBP
DTBP
DCP
TBHP
BQ
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
—
—
—
—
—
I2 (0.2)
NaI (02)
KI (0.2)
25
31
Trace
10
Trace
47
57
51
51
38
65
42
10
<10
<10
<10
<10
15
NR
17
60
14
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
68
55
43
15
18
30
44
TBAI (0.2)
NaI (0.2)
NaI (0.2)
10c
11d
12e
13
14
15
16
17
18d
19e
NaI (0.2)
Imidazole (1.0)
2-Methylimidazole (1.0)
4-Methylimidazole (1.0)
Dipyridyl (1.0)
Piperazine (1.0)
Imidazole (1.0)
Imidazole (1.0)
14
a
b
Reaction conditions: azobenzene (0.5 mmol), oxidant (2 mmol, 4 equiv.), PhCOCl (20 mol%), DMF (2 mL), 120 ꢀC, 24 h, air. Yield of isolated
product. c No PhCOCl. d PhCOCl (40 mol%). e PhCOCl (10 mol%).
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Table 2 Preparation of semicarbazides through the addition reaction Table 3 Preparation of formylhydrazines through the addition reac-
between aromatic azoarenes and N-substituted formamidesa,b
tion between aromatic azoarenes and N-substituted formamidesa
Entry
Product 4
Yieldb of 4 (%)
1
68
2
3
4
5
40
53
67
30
6
41
a
Reaction conditions: azobenzene (0.5 mmol), NaI (20 mol%), DTBP
(2 mmol, 4 equiv.), PhCOCl (40 mol%), DMF (2 mL), 120 ꢀC, 24 h, air.
b
c
d
Yield of isolated product. DCP as oxidant. Ratio of regioisomers
(Based on 1HNMR).
7c
NR
unsymmetrical azobenzenes, reaction with formamides affor-
ded the corresponding product 3j, 3k and 3l with good yields. It
is noteworthy that halo-substituted azobenzene compounds
could also be tolerated well, which could be used for the further
transformations. The reactions of other formamide derivatives
with 1a also gave the corresponding products (3m–3p) in
moderate to excellent yields. Besides, the addition of N-benzy-
a
Reaction conditions: azobenzene (0.5 mmol), imidazole (0.5 mmol,
1 equiv.), DCP (2 mmol, 4 equiv.), PhCOCl (20 mol%), DMF (2 mL),
120 ꢀC, 24 h. b Yield of isolated product. c N,N-Dimethylacetamide as 2a.
lideneaniline with DMF afforded the corresponding products diazene with DMF provided 4b in 40% yield (Table 3, entry 2),
with reduced yields (3q). while the (E)-1,2-bis(4-chlorophenyl)diazene and (E)-1,2-bis(4-
Moreover, we examined the formylation of various azo- bromophenyl)diazene gave the corresponding product 4c, 4d
benzenes as shown in Table 3. It was found that the reactions in 53% and 67% yields, respectively (Table 3, entries 3–4). It is
were carried out with moderate to good yields as for both probably due to the different electronic absorption of halogen.
electron-donating and electron-withdrawing groups on the However, (E)-1,2-bis(4-(triuoromethoxy) phenyl)diazene only
aromatic rings from azobenzenes. As shown in entry 1, Table 1, gave 30% yield. Besides, the azobenzenes containing electron-
the addition of azobenzene with DMF afforded 4a in 68% yield donating groups, such as Me, gave the formylated products in
and the X-ray crystallization could prove the structure (Table 3, 41% yields. To our disappointment, N,N-dimethylacetamide did
entry 1). As expected, formylation of (E)-1,2-bis(4-uorophenyl) not work (Table 3, entry 7).
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In summary, we have shown that the direct C–H addition of
formamides to the N]N double bond of aromatic azo
compounds under transition-metal-free catalytic conditions. It
is interesting to nd that such selective cleavage of the N-
substituted formamides will afford the N-formylated products
and hydroacylated products, which will be the direct and
practical method to prepare formylhydrazines and semi-
carbazides in the presence of NaI/DTBP and imidazole/DCP
catalytic systems, respectively. To date and to the best of our
knowledge, this is the rst report of direct hydroacylation and
formylation of formamides to aromatic azo compounds. The
further application of our method in biologically active mole-
cules is underway in our laboratory.
Scheme 2 The control experiments to prove the mechanism.
To probe the mechanism of this transformation, some
additional experiments in the presence of radical scavengers
have been performed. As shown in Scheme 2, BQ and 4-
acetamido-TEMPO (4 equiv.) could completely inhibit the
hydroacylation of formamides to azobenzenes in the presence
of NaI/DTBP, which suggested that the transformation may
proceed via a radical process. However, the formylation of
azobenzene could not be inhabited using the catalytic system
of imidazole/DCP when the radical scavengers 4-acetamido-
TEMPO (4 equiv.) was added, and the desired product was
obtained in 50% yield.
Acknowledgements
We are grateful to the grants from the Scientic Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry, the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, and the Key
Laboratory of Organic Synthesis of Jiangsu Province.
Based on the above reaction results, we have proposed the
possible mechanism of the reaction as shown in Scheme 3.
For the reaction between azobenzene and DMF in the pres-
ence of NaI/DTBP/PhCOCl, homolytic cleavage of DTBP will
generate an alkoxyl radical. Then, this radical species will
abstract a hydrogen atom from DMF, thus leading to the
desired free-radical of amide,3 which undergoes the addition
to 1a to generate an adduct free-radical.8d,12 Finally, this free-
radical abstracts a hydrogen atom from DMF (generated
during the reaction) to afford the desired 3a. The role of NaI
and PhCOCl is still not very clear and need to be investigated.
In view of preparing formylhydrazines through the addition
reaction between aromatic azoarenes and DMF, we assumed
that DMF in the presence of PhCOCl, will generate the Vils-
meier reagents, which are usually prepared from N,N-disub-
stituted formamides and acid chlorides, and then the
Vilsmeier reagents13 reacted with azobenzene to give the
hydroacylated product (3) and formylated product (4), and the
mechanism is still under investigation.
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Scheme 3 Plausible mechanism.
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