Ultrasound-Assisted Synthesis of N -Acylcyanamides and N -Acyl-Substituted Imidazolones from Carboxylic Acids by Using Trichloroisocyanuric Acid/Triphenylphosphine

Article abstract of DOI:10.1055/s-0039-1691583

A convenient ultrasound-assisted one-pot synthesis of N -acylcyanamides starting from readily available carboxylic acids and sodium cyanamide has been developed. Upon activation in the presence of trichloroisocyanuric acid (TCCA) and triphenylphosphine, a range of carboxylic acids was converted into N -acylcyanamides in good to excellent yields within 10 minutes at room temperature without base. Remarkably, N -acyl-substituted imidazolones were readily accessible through guanylation-cyclization of the in situ generated N -acylcyanamides.

Full text of DOI:10.1055/s-0039-1691583

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, 703–707
letter
703
en
W. Phakhodee et al.
Letter
Synlett
Ultrasound-Assisted Synthesis of N-Acylcyanamides and N-Acyl-
Substituted Imidazolones from Carboxylic Acids by Using Tri-
chloroisocyanuric Acid/Triphenylphosphine
Wong Phakhodeea,b
Dolnapa Yamanoa
Mookda Pattarawarapan*a,b
R'
1. TCCA, PPh3
2. NaNHCN (aq)
O
O
HN
TCCA, PPh3
O
O
CN
NaNHCN (aq)
r.t., 10 min
N
R
OH
R
N
R
N
3.
R'
H
H
a Department of Chemistry and Center of Excellence for Innovation in
Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai
50200, Thailand
H2N
CO2Me
(9 examples,
up to 78% over 3 steps)
R = aryl. alkyl, heteroaryl
(20 examples, 54–98%)
Mookdap55@gmail.com
b Research Center on Chemistry for Development of Health Promoting
Products from Northern Resources, Faculty of Science, Chiang Mai
University, Chiang Mai 50200, Thailand
Received: 11.12.2019
Accepted after revision: 07.01.2020
Published online: 24.01.2020
ygenation of acylisocyanates12 or desulfurization of acyliso-
thiocyanates,13 as well as palladium-catalyzed aminocarbo-
nylation of aryl halides.14 Nevertheless, issues associated
with the methods, including the use of toxic or expensive
reagents or catalysts, limited substrate scope, harsh reac-
tion conditions, and long reaction times, remain to be ad-
dressed.
In recent years, sonochemical methodology has been
applied as a powerful technique for facilitating various
chemical reactions.15 The resulting cavitation effect caused
by ultrasonication can lead to an enhancement in solubility,
diffusivity, penetration, and mass transportation of species
in the reactions.16 Compared to conventional stirring, ultra-
sonication not only shortens reaction times and minimizes
the formation of side products, but also provides a greener
process, lowering the cost of production with less energy
consumption.
Trichloroisocyanuric acid (TCCA) is a versatile N-halo re-
agent that has been applied for chlorination and oxidation
reactions.17 Because of its low cost, ring basicity, and high
chlorine content, it is considered to be an atom-economic
reagent that enables reactions to be carried out in the ab-
sence of added base. As illustrated in Scheme 1, the applica-
tions of TCCA in combination with triphenylphosphine
(PPh3) as a carboxylic acid activator have recently been
demonstrated in the synthesis of various derivatives.18–21
Nonetheless, to the best of our knowledge, the reagent sys-
tem has never been used in the synthesis of N-acylcyana-
mides or under ultrasonication.
DOI: 10.1055/s-0039-1691583; Art ID: st-2019-d0667-l
Abstract A convenient ultrasound-assisted one-pot synthesis of N-
acylcyanamides starting from readily available carboxylic acids and so-
dium cyanamide has been developed. Upon activation in the presence
of trichloroisocyanuric acid (TCCA) and triphenylphosphine, a range of
carboxylic acids was converted into N-acylcyanamides in good to excel-
lent yields within 10 minutes at room temperature without base. Re-
markably, N-acyl-substituted imidazolones were readily accessible
through guanylation-cyclization of the in situ generated N-acylcyana-
mides.
Key words acylation, cyclization, ultrasound, trichloroisocyanuric ac-
id, N-cyanocarboxamides, imidazolones
N-Acylcyanamides or N-cyanocarboxamides are versa-
tile building blocks in organic synthesis. The two-nitrogen
and one-carbon skeleton of the cyanamide moiety enable
them to undergo numerous transformations towards a vari-
ety of interesting N-heterocycles such as quinazolinones,1
benzimidazoles,2 aminooxadiazoles,3 N2-acyl-2-aminoimid-
azoles,4 benzothiazinones and benzothiazoles.5 Their use in
radical cascade reactions also provides access to diverse
compounds including luotonin A,6 dihydroisoquinoli-
nones,6d guanidines,7 as well as N-acylguanidines.8 More-
over, the acylcyanamide unit has been incorporated into
several bioactive molecules as a carboxylic acid bioisostere
to enhance the membrane permeability of potential drug
candidates.9
Because of these features, several methods have been
reported for the synthesis of N-acylcyanamides. The classi-
cal approach is through the reaction between acid chlorides
with sodium cyanamide.10 Other methods involve a direct
coupling of carboxylic acids with cyanamide by using 1,1′-
carbonyldiimidazole (CDI) as the dehydrating agent,11 deox-
Thus, in continuation of our research on the use of
triphenylphosphine (PPh3) with electrophilic additives, we
decided to explore an ultrasound-assisted reaction using
the combination of TCCA and PPh3. Herein, we wish to re-
port a convenient one-pot method for the direct conversion
of carboxylic acids to N-acylcyanamides promoted by
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 703–707
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

704
W. Phakhodee et al.
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa
Previous works
O
O
NHR'R''
or R'OH
TCCA, PPh3
O
O
+
+
+
R
NR'R''(OR') (Ref. 18)
R
OH
CN
CH2Cl2, Et3N
1–2 h
TCCA, PPh3
solvent, )))
OH
N
(1 eq)
(1–2 eq)
NaNHCN
+
H
O
O
TCCA, PPh3
2a
1a
BtH
R
Bt (Ref. 19)
N3 (Ref. 20)
R
OH
CH2Cl2, 4–5 h
(1 eq)
(1 eq)
Entry TCCA
(equiv)
PPh3
NaNHCN
Solvent
CH3CN
Yield
(%)
O
O
(equiv)
(equiv)
TCCA, PPh3
NaN3
R
R
OH
CH2Cl2, 0.5–2 h
(1 eq)
(3–6 eq)
1
2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.4
0.4
0.4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
65
O
O
1,4-dioxane
THF
trace
TCCA, PPh3
KSCN
(2 eq)
+
(Ref. 21)
NCS
R
R
OH
toluene, 40 min
3
n.d.
n.d.
n.d.
84b
81b
72b
90c
(1 eq)
4
DMF
This work
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
O
O
TCCA, PPh3
CN
NaNCN (aq)
(1.2 eq)
+
6
R
N
R
OH
CH2Cl2
))), 10 min
H
(1 eq)
7
Scheme 1 Applications of the TCCA/PPh3 system as a carboxylic acid
8
activator
9
10
62c,d
TCCA/PPh3. The application of the developed protocol to-
ward multicomponent synthesis of N-acyl-substituted im-
idazolone derivatives has also been demonstrated.
a Reaction conditions: benzoic acid (0.42 mmol), solvent (1 mL), sonication
for 10 min; n.d. = not detected.
b H2O (2–3 drops) was added to the mixture.
c NaNHCN was dissolved in H2O (0.5 mL) before adding.
d The reaction was stirred for 90 min.
Initially, we examined the sonochemical reaction by us-
ing benzoic acid (1a) as a model substrate. Since sodium cy-
anamide (NaNHCN) is highly hydrophilic and much less sol-
uble in organic solvents, the effect of the reaction medium
was examined first. Typically, the reaction was carried out
by mixing 1.0 equivalent of benzoic acid with TCCA/PPh3 in
0.5:1.5 molar ratio. After brief sonication at room tempera-
ture until the starting acid was no longer observed on TLC,
NaNHCN (2.0 equiv) was added to the reaction mixture, fol-
lowed by sonication for a further 10 minutes.
According to Table 1, use of acetonitrile as the solvent
led to N-cyanobenzamide (2a) in 65% yield (entry 1),
whereas other polar solvents failed to give the product be-
cause TCCA reacts violently in these media (entries 2–4). In
less polar solvent such as dichloromethane, no conversion
was observed unless a few drops of water were added to as-
sist the solubility of NaNHCN (entries 5 and 6). Further re-
ducing the amount of the cyanamide salt or that of TCCA
and PPh3 slightly lowered the product yield (entries 7 and
8). Nevertheless, to our satisfaction, an increase in the con-
version was observed when NaNHCN was pre-dissolved in
water before adding it to the reaction mixture (entry 9).
Notably, the rate-enhancement effect of ultrasound could
be clearly observed as the reaction performed under stir-
ring provided a lower product yield with extended reaction
time (entry 10).
corresponding N-acylcyanamides 2b–g. Only p-nitrobenzo-
ic acid gave product 2h in moderate yield presumably be-
cause it decomposes easily.14c,23 Notably, m-nitrobenzoic
acid and m-chlorobenzoic acid were effectively converted
into 2i and 2j, respectively, in high yields.
O
O
TCCA, PPh3
CH2Cl2, )))
CN
NaNHCN (aq)
+
R
N
R
OH
H
1
2
O
O
O
CN
CN
CN
N
H
N
N
H
H
Z
X
Z
2k (Z = NO2), 60%
2l (Z = F), 71%
2m (Z = Me), 84%
2n (Z = OMe), 82%
2a (X = H), 90%
2i (Z = NO2), 88%
2j (Z = Cl), 79%
2b (X = OMe), 94%
2c (X = Me), 98%
2d (X = tBu), 92%
2e (X = Ph), 80%
2f (X = Br), 75%
2g (X = Cl), 72%
2h (X = NO2), 54%
O
H
N
CN
CN
N
H
O
2p, 82%
2o, 85%
O
O
O
O
CN
NC
CN
N
H
N
N
H
H
X
HN CN
N
Cl
2r (X = NH), 89%
2s (X = S), 88%
2q, 71%
2t, 82%
Having the optimal reaction conditions in hand (Table 1,
entry 9), we next explored the scope and limitations of the
protocol using various carboxylic acids.22 As shown in
Scheme 2, aromatic substrates having a para substituent
(1b–g) generally provided good to excellent yields of the
Scheme 2 Synthesis of N-acylcyanamides 2
The presence of a substituent at the ortho position
slightly lowered the yields of 2k–n, which is possibly due to
adverse steric effects. It should be noted that a consequence
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 703–707

705
W. Phakhodee et al.
Letter
Synlett
of the mild reaction conditions was that no SNAr side prod-
uct was observed when using o-fluorobenzoic acid as the
substrate. The reaction conditions were also applicable to
carboxylic acids not conjugated with aromatic systems, as
2o and 2p were obtained in good yields without further op-
timization of the reaction conditions. Notably, cinnamic
acid exclusively gave 1,2-addition product 2p without de-
tectable formation of any Michael addition product or dou-
ble bond isomerization. Remarkably, heterocyclic acids
were also viable substrates, undergoing dehydrative amida-
tion to provide 2q–s in good yields. Finally, a diacid sub-
strate underwent double amidation producing N,N-dicy-
anoisophthalamide 2t in 82% yield.
reaction between benzoic acid and NaNHCN in an NMR
tube by using CDCl3 as the solvent. At first, the mixture ex-
hibited a signal at p = –5.32 ppm which is due to PPh3. This
signal completely disappeared after the addition of TCCA,
giving rise to a new major peak at p = 64.62 ppm corre-
sponding to triphenylphosphonium chloride.19,26 Other
lower intensity signals were also observed at p = 59.62,
23.94, and 23.66 ppm that could be attributed to other oxy-
phosphonium species27 (see Figure S1 in the Supporting In-
formation). These signals disappeared upon treatment with
benzoic acid, when a single peak at p = 29.23 ppm corre-
sponding to triphenylphosphine oxide appeared. These data
suggest that most of the acyloxyphosphonium ion was con-
verted rapidly to benzoyl chloride before the addition of the
cyanamide salt.
Taking the above results into consideration, a mecha-
nism of the reaction can be proposed as depicted in Scheme
4. An initial attack at the chloride atoms in TCCA by PPh3
leads to the formation of phosphonium chloride I with a re-
lease of cyanuric acid. This intermediate could further react
with cyanuric acid to form other phosphonium intermedi-
ates such as II. Phosphorylation of the carboxylic acid fol-
lowed by chlorination of III provides an acyl chloride as the
key reactive species. Final nucleophilic acyl substitution
with the cyanamide salt then affords N-acylcyanamide 2.
Imidazolones are important core structures found in a
number of bioactive compounds and pharmaceuticals dis-
playing potent inhibitory activities.24 To demonstrate the
synthetic utility of the developed protocol further, a one-
pot multicomponent reaction of carboxylic acid, sodium
cyanamide, and L-amino acid methyl esters to furnish N-
acyl-substituted imidazolones was attempted.25 The forma-
tion of the desired products could be envisaged through the
addition of an in situ generated N-acylcyanamide with an
-amino acid methyl ester, followed by intramolecular cy-
clization of the intermediate guanidine. As shown in
Scheme 3, the three-component reaction proceeded well
with a range of -amino esters giving the desired products
3 in satisfactory yields over three steps. The presence of
electron-withdrawing substituents slightly lowered the
yields of 3fc and 3la.
Cl
Ph3P
O
O
N
O
Cl
Cl
O
Ph3P
N
N
N
N
Cl
Cl
N
O
N
+
Ph3P Cl
To understand the reaction mechanism better, a 31P{1H}
NMR study was carried out by a real-time monitoring of the
Ph3P
PPh3
O
N
O
O
N
O
Cl
I
II
O
O
O
R'
R'
O
NaNHCN
R
OH
O
O
HN
O
PPh3
Cl
R
NHCN
R
Cl
H2N
CO2Me
– Ph3PO
TCCA, PPh3
R
O
CN
O
R
N
N
R
OH then NaNHCN (aq)
CH2Cl2, )))
R
N
Et3N, DMF
130 °C
III
H
OH
2
H
N
N
2
3
1
HO
N
OH
O
HN
O
HN
O
Scheme 4 Proposed mechanism for the synthesis of N-acylcyanamide 2
O
O
HN
N
H
N
N
N
O
H
N
N
H
In summary, we have developed an ultrasound-assisted
synthesis of N-acylcyanamides from readily available and
inexpensive carboxylic acids. The protocol overcomes the
previous limitations of the syntheses of N-acylcyanamides
by using the low-cost and atom-economic TCCA as reagent
with short reaction times and under mild conditions. The
method not only accommodates various substituents but
also enables rapid access to substituted imidazolone deriva-
tives through a three-component coupling reaction that is
potentially useful for organic and medicinal chemists to de-
velop new synthetic routes toward challenging targets
where other available methods are limited or less effective.
3ab, 70%
3aa, 63%
3ac, 74%
Ph
O
O
HN
O
N
O
HN
O
O
N
N
N
H
H
N
N
H
N
MeO
3bc, 78%
3ae, 77%
3ad, 76%
O
HN
F
O
HN
O
HN
O
O
O
N
N
N
N
H
N
H
N
H
Br
3la, 56%
3ca, 71%
3fc, 68%
Scheme 3 Three-component synthesis of N-acyl-substituted imidazo-
lones 3
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 703–707

706
W. Phakhodee et al.
Letter
Synlett
Funding Information
(11) Krishnaiah, M.; Rodrigues de Almeida, N.; Udumula, V.; Song, Z.;
Chhonker, Y. S.; Abdelmoaty, M. M.; Aragao do Nascimento, V.;
Murry, D. J.; Conda-Sheridan, M. Eur. J. Med. Chem. 2018, 143,
936.
(12) Wong, F. F.; Chen, C.-Y.; Yeh, M.-Y. Synlett 2006, 559.
(13) Chen, C.-Y.; Wong, F. F.; Huang, J.-J.; Lin, S.-K.; Yeh, M.-Y. Tetra-
hedron Lett. 2008, 49, 6505.
(14) (a) Aakerbladh, L.; Odell, L. R. J. Org. Chem. 2016, 81, 2966.
(b) Aakerbladh, L.; Schembri, L. S.; Larhed, M.; Odell, L. R. J. Org.
Chem. 2017, 82, 12520. (c) Mane, R. S.; Nordeman, P.; Odell, L.
R.; Larhed, M. Tetrahedron Lett. 2013, 54, 6912. (d) Wu, X.-F.;
Oschatz, S.; Sharif, M.; Beller, M.; Langer, P. Tetrahedron 2014,
70, 23. (e) Nordeman, P.; Chow, S. Y.; Odell, A. F.; Antoni, G.;
Odell, L. R. Org. Biomol. Chem. 2017, 15, 4875.
This research work was partially supported by Chiang Mai University.
Financial support from The Thailand Research Fund through the Royal
Golden Jubilee Ph.D. Program to D.Y. (Grant No. PHD/0023/2559) and
the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Of-
fice of the Higher Education Commission, Ministry of Education, Thai-
land are also gratefully acknowledged.
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Acknowledgment
We express special appreciation to the Chulabhorn Research Institute
(CRI), Thailand for the ESI-MS analysis.
(15) (a) Banerjee, B. Ultrason. Sonochem. 2017, 35, 1. (b) Kaur, N.
Mini-Rev. Org. Chem. 2019, 16, 481. (c) Mandal, B. ChemistrySe-
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Supporting Information
(16) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443.
Supporting information for this article is available online at
(17) (a) Kolvari, E.; Ghorbani-Choghamarani, A.; Salehi, P.; Shirini, F.;
Zolfigol, M. A. J. Iran. Chem. Soc. 2007, 4, 126. (b) Gaspa, S.;
Carraro, M.; Pisano, L.; Porcheddu, A.; De Luca, L. Eur. J. Org.
Chem. 2019, 3544.
(18) Rodrigues, R. d. C.; Barros, I. M. A.; Lima, E. L. S. Tetrahedron Lett.
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https://doi.org/10.1055/s-0039-1691583.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, 703–707

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W. Phakhodee et al.
Letter
Synlett
(25) Synthesis of N-Acyl-Substituted Imidazolones 3; General
Procedure
chromatography by using 30–50% EtOAc/hexanes as the eluent.
N-(1-Oxo-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-
yl)benzamide (3ae)
Colorless oil; yield: 0.1198g (77%); Rf 0.40(40% EtOAc/hexane).
1H NMR (500 MHz, CDCl3):  = 10.76 (s, 1 H), 8.27 (d, J = 7.5 Hz,
2 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 4.14 (t,
J = 9.0 Hz, 1 H), 3.95 (q, J = 9.0 Hz, 1 H), 3.47 (t, J = 9.0 Hz, 1 H),
2.34–2.11 (m, 3 H), 1.78 (quin, J = 9.0 Hz, 1 H). 13C NMR (125
MHz, CDCl3):  = 177.8, 173.9, 162.0, 136.4, 132.5, 129.9, 128.1,
62.3, 46.6, 27.1, 27.0. TOF-HRMS: m/z [M + H]+ calcd for
Following the above described procedure for the synthesis of
compound 2 using the requisite carboxylic acid (0.64 mmol),
after complete formation of 2 as detected by TLC, the crude
reaction was concentrated under reduced pressure before
adding DMF (1 mL). The mixture was then transferred into a 10
mL pressure tube, followed by addition of the amino acid
methyl ester hydrochloride (0.768 mmol) and NEt3 (0.27 mL,
1.92 mmol). The pressure tube was then placed in a preset oil
bath at 130 °C and the reaction mixture was stirred for 30–40
min. The mixture was then quenched with H2O and extracted
with EtOAc (3 × 10 mL). The combined organic layers were dried
with anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by column
C
13H14N3O2: 244.1086; found: 244.1081.
(26) Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.;
Poulton, A. M. J. Org. Chem. 2011, 76, 6749.
(27) Sugimoto, O.; Tanji, K.-i. Heterocycles 2005, 65, 181.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 703–707