The synthesis of cyanoformamides via a CsF-promoted decyanation/oxidation cascade of 2-dialkylamino-malononitriles

Article abstract of DOI:10.1039/C9OB00510B

A mild and efficient method for the synthesis of cyanoformamides from N,N-disubstituted aminomalononitriles with CsF as the promoter has been developed. This method features a wide substrate scope and high reaction efficiency, and will facilitate corresponding cyanoformamide-based biological studies and synthetic methodology development.

Full text of DOI:10.1039/C9OB00510B

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The Synthesis of Cyanoformamides via a CsF-Promoted
Decyanation/Oxidation
Cascade
of
2-Dialkylamino-
Malononitriles†
Received 00th January 20xx,
Accepted 00th January 20xx
Lin-Sheng Lei,a Cao-Gen Xue,a Xue-Tao Xu,b Da-Ping Jin,a Shao-Hua Wang,*ab Wen Bao,a Huan
Liang,a Kun Zhang,b and Abdullah M. Asiric
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild and efficient method for the synthesis of cyanoformamides
has been developed from N,N-disubstituted aminomalononitriles
with CsF as the promoter. This method features a wide substrate
scope and high reaction efficiency, and will facilitate
corresponding cyanoformamide-based biological studies and
synthetic methodology development.
Cyanoformamides (carbamoyl cyanides), as a kind of versatile
synthetic building blocks,1 have been widely applied in the synthesis
Fig. 1 Selected bioactive molecules with a cyanoformamide
moiety
of
a
variety of synthetically useful intermediates, such as
substituted
lactams,3 acrylonitriles,4
tetrazoles,2
symmetric/asymmetric substituted ureas,5 unsymmetrical ketones,6
and other heterocyclic compounds.7 In addition, such type of
structural unit exists in natural products.8-11 Selected examples
include 1) ceratinamine (Figure 1), which has been isolated in 1996
by Fusetani and co-workers from the marine sponge
Pseudoceratina purpurea, and synthesized by Ganem and
Schoenfeld;8 2) 7-hydroxyceratinamine and N-methylceratinamine
(Figure 1), another two structurally related cyanoformamides with
ceratinamine, that were isolated by Schmitz and Scheuer,
respectively;9-10 3) N,N-dimethylcyanoformamide (Figure 1), which
is a degradation product of pesticides and can be extracted from
vegetables and fruits such as tomatoes, oranges and apples.11
Corresponding bioactivity screening has revealed that ceratinamine
exhibits good cytotoxic and effective antifouling activities.7a
series of synthetic methodologies (Scheme 1).1b,5a,12-23 Generally,
primary and secondary amines are normally used for the
preparation of cyanoformamides by a reaction with carbonyl
cyanide or triphosgene followed by substitution with cyanide ion.12
Later on, some other reagents like isonitroso Meldrum’s acid,13
cyanogen,1b tetracyanoethylene,14 tetraalkyl-cyanoformamidinium
salt,15 4-chloro-5H-1,2,3-dithiazol-5-one,5a or dichlorosulfenyl
chlorides16 have been applied to the synthesis of similar types of
synthetic intermediates. In recent years, because of the special
chemical properties of cyanoformamides, some other more direct
synthetic strategies have been developed by researchers. For
example, Muñoz and co-workers have developed a method using
primary
amine,
tetramethylphenylguanidine
and
cyanophosphonate under an atmosphere of carbon dioxide.20
Zhang and Dong reported a one-pot synthesis of cyanoformamides
from 1-acyl-1-carbamoyl oximes in the presence of POCl3.21 In the
same year, Hai and Wu described a synthesis of cyanoformamides
through PhI(OAc)2-promoted oxidation of 2-oxoaldehydes.22 In 2017,
Schwartz’s group developed a method from carbamoyl imidazoles
under solvent-free conditions.23 Despite the methodologies
mentioned above, most of them still suffer drawbacks such as harsh
reaction conditions, multi-step manipulations, requiring expensive
and toxic reagents, or unsatisfactory substrate generality. Therefore,
it is necessary to further explore this topic in the pursuit of
alternate efficient methods and potential synthetic utility of
cyanoformamides.
Because of their special utilities in organic synthesis as well as the
biological activities of related natural products, cyanoformamides
have attracted the attention of synthetic chemists, leading to a
a. School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: wangshh@lzu.edu.cn
b. School of Chemical and Environmental Engineering, Wuyi University,
Jiangmen 529020, P. R. China
c. Chemistry Department, King Abdulaziz University,
Jeddah 21589, Saudi Arabia
† Patent pending, Chinese patent application (No. 201910152168.7).
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reaction conditionsa
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DOI: 10.1039/C9OB00510B
Catalyst
(eqiv)
Temp.
(ºC)
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
Time
(h)
12
12
12
12
12
12
12
12
12
12
12
12
Yieldb
(%)
52
59
86
86
86
37
71
Entry
Solvent
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
DMSO
DMF
THF
DCE
DCM
MeOH
CsF (0.5)
CsF (1)
CsF (2)
CsF (5)
CsF (10)
CsF (2)
CsF (2)
CsF (2)
CsF (2)
CsF (2)
CsF (2)
CsF (2)
40
62
40
Scheme 1. Selected methodologies for the synthesis of
cyanoformamides
10
11
12
44
n.d.c
In our previous work, we have developed a copper-catalyzed
method for the synthesis of N,N-disubstituted aminomalonitriles
using formamide and TMSCN (Scheme 2, eq 1).24 Inspired by the
structural features of N,N-disubstituted aminomalononitrile, we
have successfully developed two efficient strategies for the
synthesis of multi-substituted pyrroles and pyrazoles.25 In
connection with our interests in the development of N,N-
disubstituted aminomalononitrile related synthetic methodologies
and the report of an oxidative amidation reaction by Hayashi
(Scheme 2, eq 2),26 we envisaged that the cyanocarboxamide
compounds could be obtained directly from N,N-disubstituted
aminomalononitriles by a decyanation/oxidation cascade (Scheme
2, eq 3). As such, we herein present an efficient method for the
n.d.c
60
13
EtOH
CsF (2)
12
14
15
16
17
18
19
20
21
22
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Cs2CO3 (2)
CsOAc (2)
NaOH (2)
Et3N (2)
DBU (2)
Na2CO3 (2)
CsF (2)
CsF (2)
CsF(2)
CsF (2)
12
12
12
12
12
12
12
12
6
27
n.d.c
48
65
44
65
84
33
83
60
25
reflux
60
60
23
24
a
Reaction conditions: 1a (0.34 mmol, 50 mg), solvent (2.0 mL,
anhydrous), promoter under dry air atmosphere. Isolated yield.
b
c
n.d. = not detected.
synthesis
of
cyanoformamides
from
N,N-disubstituted
aminomalononitriles through the simple treatment with CsF.
2a, however, no better yield was obtained compared with the
reaction in CH3CN. Subsequently, some other bases were applied to
this transformation (Table 1, entries 14 to 19). All of them yielded
inferior results, and no product was observed with the use of NaOH
(Table 1, entry 16). Moreover, performing the reaction at different
temperatures and durations did not result in better outcomes.
Therefore, the use of CsF as the promoter in CH3CN for 12 h was
selected as the final reaction conditions for further investigation.
With the optimal reaction conditions in hand (Table 1, entry 3),
the substrate scope of this reaction was then investigated. As
shown in Table 2,
a
variety of N,N-disubstituted
aminomalononitriles can be applied to this transformation affording
the expected cyanoformamides in moderate to good yields. When
both of the substituents on the nitrogen atom of substrate 1 were
alkyl groups, all substrates gave the desired products in good yields,
except for product 2c with a moderate yield of 55%, indicating no
clear steric effect. In the case of cyclohexanamine or morpholine
substituted aminomalonitriles, all substrates afforded the expected
products in good yields regardless of the presence of methyl
group(s) on the ring (products 2f to 2j). Moreover, varying the
combination of R1 and R2 to a substituted phenyl and an alkyl group
was also successful (products 2k to 2t). Different from the results
Scheme 2. The design of the reaction
Following the original design, we first attempted the viability of
this transformation using compound 1a as the model substrate
(Table 1). The initial test with CsF as the promoter resulted in the
expected product 1a in 52% yield in CH3CN at 60 ºC (Table 1, entry
1). Further variation in the amount of CsF confirmed that 2
equivalents is optimal (Table 1, entry 3). Next, the reaction was
carried out in different solvents (Table 1, entries 6 to 13). Most the
solvents except MeOH and EtOH could afford the product
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Table 2. Substrate scope investigationa
practicability of this methodology, a gram scale reaction was carried
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DOI: 10.1039/C9OB00510B
out with substrate 1b, and the product 2b was obtained in 73%
yield.
Scheme 3. Control experiments
In order to gain some insight into the mechanism of this
transformation, some control experiments were performed
(Scheme 3). When the reaction of 1a was carried out under an
argon atmosphere, product 2a was obtained in a much lower yield
of 14%. In contrast, the same product with 85% yield was produced
under oxygen atmosphere. These results indicate the importance of
oxygen for this transformation. Furthermore, only 20% yield of 2a
was isolated by adding 1 equivalent of TEMPO in the reaction
mixture, which supports a possible radical reaction process. The
presence of water showed a negative impact for the reaction of 1a,
which afforded 2a in a yield of 35%. Based on the experimental
results mentioned above, this reaction might go through a process
similar to the one reported by Hayashi.26
aReaction conditions: 1 (50 mg, 1equiv), CsF (2 equiv), in CH3CN
(2.0 mL, anhydrous) under dry air atmosphere at 60 oC for 12 h;
isolated yields.b1 g of 1b was used.
In conclusion, we have successfully developed a CsF-promoted
decyanation of N,N-disubstituted aminomalononitrile, which
provides an alternative method for the synthesis of
cyanoformamide. This method features a wide substrate scope and
high reaction efficiency, and will facilitate corresponding
above, clear steric and electronic effects were observed when there
was a substituent on the phenyl ring. For example, the yield of the
substrates with a substituent para to the nitrogen atom was always
higher than those with a substituent ortho to the nitrogen atom
(products 2l vs 2m, 2n and 2o vs 2q and 2r). Additionally, the
presence of electron withdrawing groups on the phenyl ring gave
lower yields than the substrates with an electron donating group at
the same position (products 2l, 2m, 2p vs 2n, 2o, 2q, 2r). When R1
group was phenyl, increasing the size of R2 group would slightly
reduce the yield of the corresponding product (products 2s to 2u).
It should be noted that the presence of a halogen substituent as
well as the benzyl group in the products provides additional
reaction site for further derivatization. Furthermore, the substrates
with a 2,3-hydroindole (1v) or tetrahydroisoquinoline (1w) moiety
were also amenable to this transformation to give corresponding
product 2v (40% yield) and 2w (92% yield). When R1 was methyl,
the substrates with different benzyl groups (R2) were also subjected
to this reaction leading to the expected cyanoformamides in good
yields. Similar to the results above, the presence of an electron
donating group on the phenyl ring gave better yields than those
with an electron withdrawing one. In order to demonstrate the
cyanoformamide-based
biological
studies
and
synthetic
methodology development. Currently, application of this method is
ongoing in the same lab.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the NSFC (21272073, 21472077
and 21772071), the Department of Education of Guangdong
Province (Nos. 2017KTSCX185, 2017KSYS010, 2016KCXTD005),
and the Fundamental Research Funds for the Central
Universities (lzujbky-2018-134).
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Notes and references
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DOI: 10.1039/C9OB00510B
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Graphic Abstract
The Synthesis of Cyanoformamides via a CsF-Promoted Decyanation/Oxidation
Cascade of N,N-Disubstituted Aminomalononitriles
R1
CN
CN
R1
CN
O
CsF, CH3CN
60 °C
28 examples
up to 92% yield
N
N
R2
R2
1
2
R1/ R2 = Alkyl, Aryl, heteroaryl