Nitromethane as a surrogate cyanating agent: 7-: N, N-dimethylamino-4-hydroxycoumarin-catalyzed, metal-free synthesis of α-iminonitriles

Article abstract of DOI:10.1039/d0gc03411h

An efficient, metal/alkali-cyanide free approach for the synthesis of α-iminonitriles via kinetically controlled, base-mediated and 1,3-diketone-catalyzed reaction is reported. The preparation of target compounds was realized by condensation of substituted anilines and aldehydes in nitromethane as a surrogate cyanating agent and as a solvent. This strategy was further improved by replacing aldehydes and nitromethane with β-nitrostyrene and ethanol, respectively, rendering the methodology greener. The catalytic role played by 1,3-diketones such as 7-N,N-dimethylamino-4-hydroxycoumarin in this three-component reaction was investigated, and a plausible mechanism was proposed based on control experiments.

Full text of DOI:10.1039/d0gc03411h

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PleaseGdroeennoCt haedmjuissttrmy argins
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DOI: 10.1039/D0GC03411H
ARTICLE
Nitromethane as a Surrogate Cyanating Agent: 7-N,N-
Dimethylamino-4-Hydroxycoumarin-Catalyzed, Metal-Free
Synthesis of α-Iminonitriles
Received 00th January 20xx,
Accepted 00th January 20xx
Iddum Satyanarayana,a Kiran B. Manjappab* and Ding-Yah Yanga,b
*
DOI: 10.1039/x0xx00000x
An efficient, metal/alkali-cyanide free approach for the synthesis of α‐iminonitriles via kinetically controlled, base-mediated
and 1,3-diketone-catalyzed reaction is reported. The preparation of target compounds was realized by condensation of
substituted anilines and aldehydes in nitromethane as a surrogate cyanating agent and as a solvent. This strategy was further
improved by replacing aldehydes and nitromethane with -nitrostyrene and ethanol, respectively, rendering the
methodology greener. The catalytic role played by 1,3-diketones such as 7-N,N-dimethylamino-4-hydroxycoumarin in this
three-component reaction was investigated, and a plausible mechanism was proposed based on control experiments.
alkynes in Schmidt-type amides and the preparation of
nitriles.10 Radosevich et al. have recently reported the versatility
of nitromethane as a surrogate for methylamine.11 For the
Introduction
Nitriles constitute an integral part of numerous natural
products, agrochemicals, secondary metabolites, and active
pharmaceutical ingredients.1-3 They often serve as an essential
cases of nitromethane as a CN source, Yu et al. have reported
the first example of copper-mediated, chelate-driven arene
cyanation with nitromethane back in 2006 (Scheme 1).12a Since
then, only a few related reactions have been documented
(Scheme 1),12b-e and most of them required metals as a catalyst.
While the construction of C-N bonds via metal-free radical
C(sp3)-H functionalization to avoid the high toxicity of transition
metals has been well developed,13 the metal-free cyanation
using nitromethane as a surrogate cyanating source remains to
be a challenging task.
precursor for the construction of N‐heterocycles, carbonyl
compounds and amines. Owing to nitriles’ broad reactivity,
exploring the methodologies for efficient cyanation is a long-
standing interest of organic chemists.4 Undoubtedly, hydrogen
cyanide is one of the simplest yet impractical reagents to be
used for the CN group introduction. Commonly practiced
cyanation involves the extensive use of metal cyanides,5a-d
isocyanide,5e-h tosylcyanide,5i ethyl cyanoacetate,5j TBN (tert-
butyl nitrite)5k,l, and NCTS (N-cyano-N-phenyl-p-toluene
sulfonamide).5m-o Most of these reagents suffer from high
toxicity and thus require stringent precautions while handling.
Despite their adverse effect, usage of such toxic, hazardous and
lethal reagents has become one of the irreplaceable ways in
many synthetic conversions. Therefore, searching for the less
toxic and non-metal cyanide-based reagents to function as a
surrogate source for cyanide remains highly desired.6 Although
numerous efforts to introduce new non-cyanide reagents such
as DMSO7 and urea8 for cyanation in the past, those cyanide
alternatives were sparingly used in the synthesis.
Nitromethane is used as a solvent as well as a source for carbon,
amine and nitrile to construct functional building blocks that
can further be employed in various transformations.9 For
instance, Jiao and co-workers have discovered the ability of
nitromethane to donate its nitrogen to aldehydes, ketones and
a.Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan.
Boulevard, Xitun District, Taichung 40704, Taiwan
b.Graduate Program for Biomedical and Materials Science, Tunghai University, No.
1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan
Scheme 1 The previous reports of using nitromethane as a cyanating agent.
Email: kiran@thu.edu.tw, yang@thu.edu.tw
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Iminonitriles are the cyano-bearing imines that often serve as
precursors for various functional group transformations.14
Additionally, they can also function as cyanating reagents to
introduce the CN group onto arenes.15 Currently, the most
Journal Name
α
‐
Results and Discussion
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DOI: 10.1039/D0GC03411H
Recently, we have reported an efficient methodology for the
preparation of -enaminone 4a via a one-pot, three-component
reaction of arylamine , aldehyde and 4-hydroxycoumarin (3a)
using nitromethane as a solvent (Scheme 3, a).18 During the
extensive substrate scope studies, we have serendipitously
discovered the formation of α‐iminonitrile in the reaction with

1
2
conventional approach to the preparation of α‐iminonitriles still
resorts to the toxic metal/non-metal cyanide reagents,
including KCN,16a NaCN,16b, TMSCN,16c TMSN3,16d isocyanides16e,
and triazole ring-opening16f,g pathway (Scheme 2, a‒e).
Recently, Ye and co-workers17 have reported the efficient
specific substrates. For example, when a mixture of amine
5,
aldehyde and 7-N,N-dimethylamino-4-hydroxycoumarin (3b
6
)
synthesis of pyridine-derived α‐iminonitriles via Ce(OTf)3-
was refluxed in the presence of three equiv. of DABCO as a base
in nitromethane, the α‐iminonitrile 7k was obtained as a major
product (Scheme 3, b). Surprisingly, the expected -enaminone
4b was not observed in this reaction. The spectroscopic and
ORTEP crystal analysis unambiguously confirmed the molecular
structure of 7k (Scheme 3).19
catalyzed condensation of 2-aminopyridines with nitroalkenes
(Scheme 2, f). Although this strategy is metal cyanide-free, it
lacks substrate generality since the arylamines are limited to 2-
aminopyridines only. Thus, the development of a novel strategy
for the preparation of α‐iminonitrile under cyanide-free and
transition metal-free conditions with broad substrate scope is
highly preferable. Herein, a metal/alkali-cyanide free and
multicomponent approach to the preparation of structurally
diverse α‐iminonitriles is reported. The present methodology
features the usage of readily available arylamines and
aldehydes as the substrates; the dual role of nitromethane as a
surrogate cyanating agent and as a solvent. Additionally,
considering the toxicity of nitromethane, an effort has been
made to limit its use as reagent only by substituting it with
environmentally benign solvent ethanol. Furthermore, 1,3-
diketones such as 7-N,N-dimethylamino-4-hydroxycoumarin
are employed as an organocatalyst to replace the commonly
used transition metals in this transformation. Eventually, the
mechanism of this three-component reaction is investigated by
performing control experiments as well as isolating the key
intermediates.
Scheme 3 Synthesis of -enaminone 4a (a) and α‐iminonitrile 7k (b).
Intrigued by the unexpected results and envisaged the
importance of α‐iminonitriles,20 we have launched the
systematic investigation to discern the formation of α‐
iminonitriles in terms of the influence of the base, reaction
conditions, and the role played by 4-hydroxycoumarin in this
MCR. Table 1 summarizes the screening of the optimized
conditions for
-iminonitrile formation. The generation of -
enaminone 4c is ubiquitous in this MCR and could be isolated as
the major product when DMAP, TEA, DIPEA, pyridine or Cs2CO3
were employed as a base (Table 1, entries 1‒7). Nevertheless,
the yield of
tuning the conditions and thereby enhancing the formation of
the desired -iminonitrile 7a. For instance, increasing the
amount of DABCO from two to three equiv. enhanced the
product ratio of -iminonitrile 7a to -enaminone 4c (Table 1,
-enaminone could be minimized through fine-



entries
1
and 8). Further, bringing down the reaction
o
temperature from reflux to 80 C suppressed the formation of

-enaminone 4c from 50 to 43% (Table 1, entries 8 and 9).
Employing excess of base, lowering the reaction temperature
and shortening the reaction time were found to be beneficial to
the formation of
screened, DABCO was proved to be the most commending one
over others for the generation of -iminonitrile 7a
-iminonitrile 7a. Finally, among the bases

.
Scheme 2 Previous and present synthesis of α-iminonitriles.
2 | J. Name., 2012, 00, 1-3
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predominately gave the
methodology worked only for the aryl system.

-enaminones. HVieewnAcreti,cle Otnhlinies
Table 1 Optimization for the formation of -iminonitrile 7a.
DOI: 10.1039/D0GC03411H
Table 2 Screening of 1,3-diketones 3a‒d.
Entry
Base
Equiv. Time
(h)
Temp.
(oC)
Yield (%)
Entry
1,3-Diketone
Equiv.
7k
(Yield %)
52
7a
33
26
5
trace
trace
20
trace
37
41
4c
67
1a
2
3
4
5
6
7
8b
9
DABCO
DMAP
DBU
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
2
2
2
2
4
6
6
2
2
4
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
1
2
3
7-N,N-dimethylamino-4-hydroxycoumarin
0.5
1
(3b)
37
10
68
50
19
35
50
43
51c
7-N,N-dimethylamino-4-hydroxycoumarin
74
76
(3b)
TEA
7-N,N-dimethylamino-4-hydroxycoumarin
2
DIPEA
pyridine
Cs2CO3
DABCO
DABCO
DABCO
(3b)
dimedone (3d)
4-hydroxycoumarin (3a)
7-N,N-diethylamino-4-hydroxycoumarin
(3c)
4
5
6
1
1
1
10
27
68
10
80
38
Note aLess than 1.0 equiv. of the base resulted in poor conversion; bNo significant
increase for 7a if more than 3.0 equiv. of base were added. cExtended reaction time
favored for the formation of -enaminone.
Since the added coumarin 3b did not incorporate into the
molecular structure of the product
-iminonitriles, the role
played by 1,3-diketone in this MCR remained elusive. Several
cyclic 1,3-diketones were evaluated for their competence to
facilitate the reaction, as shown in Table 2. All four 1,3-
diketones employed in the MCR were found to be able to
promote product formation with varying extents. Coumarin 3b
with an electron-donating group on benzene moiety gave better
yield than the unsubstituted 4-hydroxycoumarin 3a and
dimedone 3d (Table 2, entries 3‒5). An increasing amount of
coumarin 3b from 0.5 to 1.0 equivalent enhanced the formation
of
-iminonitrile 7k from 52 to 74% (Table 2, entries 1‒2).
Nevertheless, further increments of 3b failed to influence the
yield significantly. Thus, heating of amine and aldehyde in the
presence of DABCO (3 equiv.) and coumarin 3b (1 equiv.) in
o
nitromethane at 80 C for 2 h was employed as the standard
reaction conditions for subsequent substrate scope studies.
Figure 1 lists the structures and yields of the prepared
iminonitriles 7a wide range of functionalized


-
-
‒w. A
iminonitriles could be prepared in moderate to good yields,
indicating the reaction has a high tolerance to functional
groups. While a lower yield of 41% (7a) was recorded in the case
of unsubstituted aldehyde and aniline, a significant increase in
yield was observed when either an electron-donating or
electron-withdrawing substituent was introduced onto aniline
or aldehyde. For instance, the introduction of an electron-
donating group on the substrates aldehyde and amine rendered
good yields up to 74% (7k). A similar phenomenon was also
observed when an electron-withdrawing group was introduced,
implying the yield of this MCR was critically influenced by the
inductive effect. Moreover, the reaction also worked well for
other heteroaromatic scaffolds such as quinoline (7j), pyridine
Figure 1 Structures and yields of the prepared -iminonitriles 7a‒w.
(7i, 7s, 7t) and thiophene (7v, 7w). When an alkyl amine or
aldehyde was employed as the substrate, the reaction
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DOI: 10.1039/D0GC03411H
To gain insights into the mechanism of this reaction and the role
played by coumarin 3b, a series of control experiments were
designed and performed, as shown in Scheme 4. Condensation
of aldehyde
product
a). The subsequent reaction of
under standard conditions generated
yield (78%). Interestingly, when aniline
heated in nitromethane in the absence of coumarin 3b, a
complex mixture was observed, and no expected -iminonitrile
was detected (Scheme 4, b). This observation suggests that
coumarin 3b is indispensable for -iminonitrile formation. It is
6
8 (
and nitromethane gave the corresponding Henry
-nitrostyrene) under reflux conditions (Scheme 4,
with amine and coumarin 3b
-iminonitrile 7k in good
and aldehyde were
8
5

5
6


worth mentioning that heating of coumarin 3b alone in
nitromethane under standard conditions gave the coumarin-
fused oxazole
attempt to isolate the possible intermediates from the reaction,
p-bromobenzaldehyde (10) was reacted with aniline and
9 as the major product (Scheme 4, c). In an
5
coumarin 3b in nitromethane in the presence of only one
equiv. of DABCO. Luckily, the 2,3-dihydrofuro[3,2-c]coumarin
11 was isolated in 17% yield in addition to the expected
-
iminonitrile 7u (Scheme 4, d). The X-ray crystallography studies
further confirmed the molecular structure of 11 (see the SI). The
isolation of 11 prompted us to believe that the Michael adduct
12 might be one of the intermediates in this reaction since 11
was likely to be formed by intramolecular cyclization of 12
through the removal of HNO2. To further validate this
hypothesis, two putative intermediates 12 and 13 were
Scheme 4 Control experiments.
prepared by the coupling of 4-hydroxycoumarins with
nitrostyrene according to the literature procedure.21 When the
prepared 12 was refluxed with aniline and DABCO (3.0 equiv.)
in toluene for 15 min, the -enaminone 4a was isolated as the
major product in 62% along with a trace amount of
iminonitrile 7a (Scheme 4, e). Preparation of pure 13 proved to
be difficult since it could not be separated from the starting
material coumarin 3b. The inseparable mixture of 13 and 3b was
-
From control experiments, we discovered that the readily
available Henry product can serve as an alternate substrate to
react with amine in toluene, leading to the generation of
iminonitrile 7k without utilizing nitromethane as a solvent. This
finding prompted us to further investigate the reaction
conditions to reduce the use of excessive nitromethane,
rendering the process greener. Table 3 summarizes the
optimization reactions of -nitrostyrene 8 and amine 5 in the
presence of coumarin 3b as a catalyst under various conditions.
During the screening process, a pronounced solvent effect on
8
1
5
-

-
then heated with aniline
80 C for 15 min. To our delight, a complete conversion of 13
5
and DABCO (3.0 equiv.) in toluene at
o
into the corresponding
-iminonitrile 7k was observed, and no
the formation of
polar aromatic solvent like toluene enhanced the formation of
-iminonitrile 7k (Table 3, entry 1; 78%), whereas polar aprotic
-iminonitrile 7k was observed. That is, a non-
trace of the corresponding

-enaminone was detected (Scheme
4, f). Hence, our studies indicate that compounds 12 and 13 are
indeed the intermediates for these three-component reactions,
whereas coumarin 3b serves as a sacrificial agent in generating

solvents such as ACN, dioxane and THF inhibited it (Table 3,
entries 2‒4). To our delight, when the reaction was performed
in a protic solvent such as EtOH, the yield of 7k rose to 82%
along with the recovery of 20% of coumarin 3b (Table 3, entry
5). Besides, the loadings of coumarin 3b and DABCO were also
screened. Our studies indicate that the yield of 7k was
proportional to the loadings of coumarin 3b (Table 3, entries 5‒
7), and a decreasing amount of DABCO loadings resulted in
lower product conversion (Table 3, entries 7‒9). As for the
temperature effect, a limited amount of product formation was
detected even when the reaction was carried out at room
temperature. Nevertheless, prolonged reaction time at that
temperature led to the formation of a complex mixture. The
increase of reaction temperature enhanced the product
formation with maximum yield at 80 oC for 30 min (7k, 82%).
the -iminonitriles.
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believe that the nitrile 20 is also highly susceptible to
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DOI: 10.1039/D0GC03411H
Table 3 Optimization for the formation of
-iminonitrile 7k.
nucleophilic attack by aniline
1 to give the tetrahedral
intermediate 21. Final expulsion of coumarin 3a from 21
furnishes the target -iminonitrile 7a

.
Entry
Solvent
DABCO
(equiv.)
3.0
3.0
3.0
3.0
3.0
3.0
3b
(equiv.)
1.0
1.0
1.0
1.0
1.0
0.5
7k
(Yield %)
78
3b
Recovery (%)
1
2
3
4
5
6
PhMe
ACN
dioxane
THF
EtOH
EtOH
trace
<5
trace
trace
20
10
42
36
82
64
10
7
8
9a
EtOH
EtOH
EtOH
3.0
2.0
1.0
0.3b
1.0
1.0
38
58
26
5
<10
<5
Note: areaction did not reach completion; bdecrease the loading of 3b resulted in
less yield of 7k.
The optimization of the reaction between Henry product
amine in ethanol has certainly brought a greener approach to
the preparation of -iminonitriles 7k. This modified strategy has
8 and
5

not only aided in moderately enhancing the yield (74% to 82%)
but also partially recovering of coumarin 3b. Hence, several
previously synthesized
-iminonitriles (Figure 1, 7a, 41%; 7c,
48%; 7l, 48%) were re-prepared by this modified methodology.
As expected, cleaner conversion along with improved yields
were observed (7a, 45%; 7c, 58%; 7l, 56%). To further expand
the scope of this reaction, some alkylamines and alkyl Henry
products were examined to test their compatibility.
Unfortunately, all attempts failed to yield any corresponding
Scheme 5 Plausible mechanism for the formation of -enaminone 4a and -
iminonitrile 7a.
alkyl-substituted
present methodology.
-iminonitriles, which is a limitation of the
In the course of the formation of -iminonitrile 7a, coumarin 3a
is proposed to function as an organocatalyst, which at first
serves as a nucleophile to trap Henry product 14 at the initial
stage of the reaction. However, at the later stage of the
reaction, coumarin 3a acts as a leaving group by being expelled
from the tetrahedron intermediate 21. Nevertheless, due to the
Based on the crucial information retrieved from the control
experiments along with the isolation of the putative reaction
intermediate, a plausible mechanism for the preparation of
enaminone 4a and -iminonitrile 7a is proposed (Scheme 5).
The initiation of the reaction starts with the formation of Henry
product 14 by the condensation of aldehyde and
nitromethane. The subsequent attack by coumarin 3a onto 14
via Michael addition presumably yield the adduct 12. We
envision that compound 12 might be the key intermediate
-

competitive reactions such as the formation of
4a, 2,3-dihydrofuro[3,2-c]coumarin 22 and coumarin-fused
oxazole , a stoichiometric rather than catalytic amount of
-enaminone
2
9
coumarin 3a is required for this MCR.
To demonstrate the feasibility of a large scale preparation of -
leading to the formation of either
-enaminone 4a or -
iminonitriles by the modified methodology, a gram-scale
reaction for the preparation of -iminonitrile 7k was carried
out, as shown in Scheme 6. Hence, 1.0 g of -nitrostyrene (1
equiv.) was reacted with 0.8 g of amine (1.1 equiv.) and 1.1 g
of coumarin 3b (1 equiv.) in EtOH (20 mL) under standard
reaction conditions. As a result, 1.1 g of -iminonitrile 7k (72%)
iminonitrile 7a, depending upon the reaction conditions. For
instance, under reflux conditions (Path I, thermodynamic
control), the adduct 12 undergoes nitromethane elimination to
furnish the α,β-unsaturated ketone 15. The subsequent


8
5
conjugate addition of aniline
1 to 15 generates the compound

16. Final oxidative dehydrogenation results in the formation of
the β-enaminone 4a. On the other hand, at a lower temperature
(Path II, kinetic control), the adduct 12 proceeds to a base-
mediated isomerization to yield compound 18 through iminium
oxide 17. Compound 18 then undergoes sequential dehydration
or vinylogous elimination22 of water via the oxime 19 to afford
the nitrile 20. Similar to that of α,β-unsaturated ketone 15, we
was obtained, indicating that the reaction yield did not
compromise markedly by a large-scale synthesis. Further, 182
mg (17%) of catalyst 3b was recovered from the reaction.
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6680; (d) X. Zong, Q. Z. Zheng and N. Jiao, Org. Biomol.
View Article Online
Chem., 2014, 12, 1198‒1202.
5
(a) A. V. Ushkov and V. V. GDruOsI:h1i0n.,10J3.9/ADm0G.C0C3h4e1m1H.
Soc., 2011, 133, 10999‒11005; (b) R. K. Arvela and N. E.
Leadbeater, J. Org. Chem., 2003, 68, 9122‒9125; (c) X.
Jia, D. Yang, S. Zhang and J. Cheng, Org. Lett., 2009, 11
,
4716‒4719; (d) B. V. S. Reddy, Z. Begum, Y. J. Reddy and
J. S. Yadav, Tetrahedron Lett., 2010, 51, 3334‒3336; (e)
S. Xu, X. Huang, X. Hong and B. Xu, Org. Lett., 2012, 14
,
Scheme 6. Gram-scale preparation of
-iminonitrile 7k
.
4614‒4617; (f) J. Peng, J. Zhao, Z. Hu, D. Liang, J. Huang
and Q. Zhu, Org. Lett., 2012, 14, 4966‒4969; (g) X. Hong,
H. Wang, G. Qian, Q. Tan and B. Xu, J. Org. Chem., 2014,
79, 3228‒3237; (h) X. Jiang, J. M. Wang, Y. Zhang, Z.
Chen, Y. M. Zhu and S. J. Ji, Tetrahedron, 2015, 71, 4883‒
4887; (i) S. Kamijo, T. Oshikawa and M. Inoue, Org. Lett.,
2011, 13, 5928‒5931; (j) S. Zheng, C. Yu and Z. Shen,
Org. Lett., 2012, 14, 3644‒3647; (k) Z. Shu, Y. Ye, Y.
Deng, Y. Zhang and J. Wang, Angew. Chem., Int. Ed.
2013, 52, 10573‒10576; (l) D. Tsuchiya, Y. Kawagoe, K.
Moriyama and H. Togo, Org. Lett., 2013, 15, 4194‒4197;
(m) T. J. Gong, B. Xiao, W. M. Cheng, W. Su, J. Xu, Z. Liu,
L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 10630‒
10633; (n) M. Chaitanya, D. Yadagiri and P. Anbarasan,
Org. Lett., 2013, 15, 4960‒4963; (o) Y. Yang and S. L.
Buchwald, Angew. Chem., Int. Ed., 2014, 53, 8677‒8681.
For a recent review on non-toxic cyanation agents, see:
M. N. Alexander and T. Opatz, Org. Biomol. Chem., 2019,
17, 11‒23.
X. Ren, J. Chen, F. Chen and J. Cheng, Chem. Commun.,
2011, 47, 6725‒6727.
K. Zheng, B. Liu, S. Chen and F. Chen, Tetrahedron Lett.,
2013, 54, 5250‒5252.
X. Qi, J.-B. Peng and X.-F. Wu, in Solvents as Reagents in
Organic Synthesis: The Applications of Nitromethane as
Reagent and Solvent in Organic Synthesis, ed. Wiley-
VCH Verlag GmbH & Co. KGaA. 2018, 377‒402.
To the best of our knowledge, this synthesis of

-iminonitrile
from arylamine and aldehyde represents the first example
which employs nitromethane as a surrogate cyanating agent
under metal-free conditions. Likewise, for the first time, cyclic
1,3-diketone, that is, 7-N,N-dimethylamino-4-hydroxycoumarin
is utilized to function as an organocatalyst to catalyze organic
reactions.
Conclusions
In summary, we have demonstrated that α‐iminonitriles can be
constructed via 7-N,N-dimethylamino-4-hydroxycoumarin-
catalyzed condensation of anilines and aromatic aldehydes
using nitromethane as a surrogate cyanating agent. The scope
of this cyanide/metal-free reaction was illustrated by the
preparation of 23 α‐iminonitrile analogues with moderate to
good yields along with good functional group tolerance.
Alternately, the target compounds could also be prepared by
6
7
8
9
direct coupling of -nitrostyrenes with anilines in the presence
of a coumarin catalyst in ethanol. Our studies suggested that
product formation is favored under kinetically controlled
conditions and facilitated by 1,3-diketones such as 7-N,N-
dimethylamino-4-hydroxycoumarin. Further, the application of
this quasi-pioneering activation of nitromethane and 1,3-
diketone-catalyzed reaction to the synthesis of other organic
molecules is currently underway.
10 J. Liu, C. Zhang, Z. Zhang, X. Wen, X. Dou, J. Wei, X. Qiu,
S. Song and N. Jiao, Science, 2020, 367, 281‒285.
11 G. Li, Z. Qin and A. T. Radosevich, J. Am. Chem.
Soc. 2020, 142, 16205‒16210.
12 (a) X. Chen, X. S. Hao, C. E. Goodhue and J. Q. Yu, J. Am.
Chem. Soc., 2006, 128, 6790‒6791; (b) K
.
Motokura, K
.
Matsunaga, A. Miyaji, S. Yamaguchi and T. Baba,
Tetrahedron Lett., 2014, 55, 7034‒7038 ; (c) Z.-H. Wang,
X.-M. Ji, M.-L. Hub and R.-Y. Tang, Tetrahedron Lett.,
2015, 56, 5067‒5070; (d) Y. Ogiwara, H. Morishita, M.
Sasaki, H. Imai, and N. Sakai, Chem. Lett. 2017, 46, 1736‒
1739; (e) R. Saikia, S. D. Baruah, R. C. Deka, A. J. Thakur
and U. Bora, Eur. J. Org. Chem., 2019, 36, 6211‒6216.
13 S.-Z. Song, Y.-N. Meng, Q, Li and W. T. Wei, Adv. Synth.
Catal., 2020, 362, 2120‒2134.
Conflicts of interest
There are no conflicts to declare.
Acknowledgment.
We thank the Ministry of Science and Technology of the
Republic of China, Taiwan, for financially supporting this
research under Contract No. MOST 108-2113-M-029-001.
14 Application of α
V. Kumar and A. P. Bhaduri, Synth. Commun., 2006, 36
715‒727; (b) X. You, X. Xie, R. H. Sun, H. Y. R. Chen, S. Li
and Y. H. Liu, Org. Chem. Front., 2014, , 940‒946; (c) R.
‐iminonitriles: (a) A. Roychowdhury, V.
,
1
Surmont, B. De Corte and N. De Kimpe, Tetrahedron
Lett., 2009, 50, 3877‒3880; (d) A. V. Varlamov, D. G.
Grudinin, A. A. Eganov, A. I. Chernyshev and A. N. Levov,
Chem. Heterocycl. Compd., 2005, 41, 872‒876; (e) P.
Sarnpitak and M. Krasavin, Tetrahedron, 2013, 69
2289‒2295.
Notes and references
1
F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk and B. C.
Shook, J. Med. Chem., 2010, 53, 7902‒7917.
,
2
3
F. F. Fleming, Nat. Prod. Rep., 1999, 16, 597‒606.
C. A. Tolman, R. J. McKinney, W. C. Seidel, J. D. Druliner
and W. R. Stevens, Adv. Catal., 1985, 33, 1‒46.
15
α
‐
Iminonitriles as cyanating agents: (a) Z. B. Chen, F. L.
Zhang, Q. Yuan, H. F. Chen, Y. M. Zhu and J. K. Shen, RSC
Adv., 2016, , 64234‒64238; (b) Z. Chen, P. Liang, B. Liu,
6
4
(a) C. Qin and N. Jiao, J. Am. Chem. Soc., 2010, 132,
H. Luo, J. Zheng, X. Wen, T. Liua and M. Ye, Org. Biomol.
Chem., 2018, 16, 8481‒8485; (c) Y. L. Shi, Q. Yuan, Z. B.
15893‒15895; (b) T. Wang and N. Jiao, J. Am. Chem.
Soc., 2013, 135, 11692‒11695; (c) T. Shen, T. Wang, C.
Qin and N. Jiao, Angew. Chem., Int. Ed., 2013, 52, 6677‒
Chen, F. L. Zhang, K. Liu and Y. M. Zhu, Synlett, 2018, 29
,
6 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
359‒363; (d) N. R. Rondla, J. M. Ogilvie, Z. Pan and C. J.
ARTICLE
View Article Online
Douglas, Chem. Commun., 2014, 50, 8974‒8977.
16 (a) J. G. Smith and D. C. Irwin, Synthesis, 1978, 894; (b)
B. S. Jursic, F. Douelle, K. Bowdy and Ed. D. Stevens,
Tetrahedron Lett., 2002, 43, 5361‒5365; (c) P. Fontaine,
DOI: 10.1039/D0GC03411H
A. Chiaroni, G. Masson and J. Zhu, Org. Lett., 2008, 10
,
1509‒1512; (d) F. Chen, X. Huang, Y. Cui and N. Jiao,
Chem. Eur. J., 2013, 19, 11199‒11202; (e) Z. B. Chen, Y.
Zhang, Q. Yuan, F. L. Zhang, Y. M. Zhu and J. K. Shen, J.
Org. Chem., 2016, 81, 1610‒1616; (f) Y. Su, J. L.
Petersen, T. L. Gregg and X. Shi, Org. Lett., 2015, 17
,
1208‒1211; (g) A. H. Kalbandhe, A. C. Kavale and N. N.
Karade, Eur. J. Org. Chem., 2017, 1318‒1322.
17 Z. Chen, P. Liang, J. Zheng, Z. Zhou, X. Wen, T. Liu and M.
Ye, ACS Omega, 2018, 3, 12520‒12529.
18 W. C. Hsieh, K. B. Manjappa and D. Y. Yang, RSC Adv.,
2019, , 34088‒34094.
19 Crystallographic data (excluding structure factors) for
7k and 11 have been deposited with the Cambridge
9
,
9
Crystallographic Data Centre as supplementary
publication number CCDC-2023156, 2023155 and
2023154, respectively.
20 (a) J. J. Garcia, N. M. Brunkan and W. D. Jones, J. Am.
Chem. Soc., 2002, 124, 9547‒9555; (b) Y. Nakao, A.
Yada, S. Ebata and T. Hiyama, J. Am. Chem. Soc., 2007,
129, 2428‒2429; (c) M. Tobisu, Y. Kita, Y. Ano, N.
Chatani, J. Am. Chem. Soc., 2008, 130, 15982‒15989; (d)
D. G. Yu, M. Yu, B. T. Guan, B. J. Li, Y. Zheng, Z. H. Wu
and Z. J. Shi, Org. Lett., 2009, 11, 3374‒3377; (e) Y. Kita,
M. Tobisu, N. Chatani, Org. Lett., 2010, 12, 1864‒1867.
21 D. K. Barange, V. Kavala, C. W. Kuo, P. M. Lei and C. F.
Yao, Tetrahedron, 2011, 67, 2870‒2877.
22 N. M. Moreira, L. S. R. Martelli, K. I. R. de Julio, J. Z.
Schpector, T. Opatz, and A. G. Corrêa, Eur. J. Org. Chem.,
2020, 29, 4563‒4570.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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