Ultrasound-assisted synthesis of substituted guanidines from thioureas

Article abstract of DOI:10.1016/j.tetlet.2016.02.050

Ultrasound-assisted synthesis of guanidine derivatives was developed using 2,4,6-trichloro-1,3,5-triazine as an inexpensive dehydrosulfurization reagent. Both 1,3-alkylaryl- and 1,3-diaryl-thioureas were rapidly converted into carbodiimides before subsequent reaction with aromatic or aliphatic amines. The method allows rapid access to highly substituted guanidines in good to excellent yields under mild conditions and with minimal use of solvent.

Full text of DOI:10.1016/j.tetlet.2016.02.050

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Ultrasound-assisted synthesis of substituted guanidines from thioureas
Mookda Pattarawarapan, Subin Jaita, Sirilak Wangngae, Wong Phakhodee
PII:
S0040-4039(16)30159-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.050
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Tetrahedron Letters
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11 February 2016
12 February 2016
Please cite this article as: Pattarawarapan, M., Jaita, S., Wangngae, S., Phakhodee, W., Ultrasound-assisted synthesis
of substituted guanidines from thioureas, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.02.050
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Ultrasound-assisted synthesis of substituted guanidines from thioureas
Mookda Pattarawarapan,* Subin Jaita, Sirilak Wangngae, and Wong Phakhodee
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Chiang Mai University, Chiang Mai 50200, Thailand
To whom correspondence should be addressed.
Department of Chemistry,
Faculty of Science,
Chiang Mai University,
Chiang Mai
50200
Thailand
Tel. +66 5394 3341
Fax. +66 5389 2277
e-mail: mookdap55@gmail.com

Ultrasound-assisted synthesis of substituted guanidines from thioureas
Mookda Pattarawarapan,* Subin Jaita, Sirilak Wangngae, and Wong Phakhodee
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Chiang Mai University, Chiang Mai 50200, Thailand
Abstract
Ultrasound-assisted synthesis of guanidine derivatives was developed using 2,4,6-trichloro-1,3,5-
triazine as an inexpensive dehydrosulfurization reagent. Both 1,3-alkylaryl- and 1,3-diaryl-
thioureas were rapidly converted into carbodiimides before subsequent reaction with aromatic
and aliphatic amines. The method allows rapid access to highly substituted guanidines in good to
excellent yields under mild conditions and with minimal use of solvent.
Keywords guanidine; thiourea; cyanuric chloride, triphenylphosphine; ultrasound
Introduction
Guanidine is an important structural unit often found in many biologically and pharmaceutically
related molecules.1 Owing to its basicity and ability to form strong hydrogen-bond interactions
under physiological conditions, many natural and synthetic guanidine-containing compounds
have increasingly been shown to exhibit a range of biological activities including antibacterial,
antifungal, antiviral, anti-inflammatory, and antitumor.2 Moreover, various substituted
guanidines have been used as key building blocks in the fields of supramolecular chemistry,
synthetic receptors, recognition devices, sensors, as well as catalysis.3
Considering the growing demand for guanidine derivatives, a number of new methods have been
developed for convenient access to this class of compounds.4 Among the available methods,
synthesis from the reaction of an amine with a substituted thiourea proceeding through an in-situ
generated carbodiimide intermediate has been very attractive since the starting materials are
relatively inexpensive and readily available. Various dehydrosulfurization reagents have been
reported such as mercury(II) chloride,5 copper(II) sulfate-silica gel,6 copper(II) chloride,7 2,4,6-

trichloro-1,3,5-triazine (TCT),8 ethyl-3-aminopropyl carbodiimide hydrochloride (EDCI),9,5d and
the Mukaiyama reagent.10 Nevertheless, these protocols suffer from limitations including the use
of toxic metals, expensive reagents, low yields, harsh conditions, and long reaction times.
In the recent years, sonochemical methods have proven to be a powerful technique for
facilitating various chemical reactions.11 Application of ultrasonic energy to the reaction media
can lead to the formation and collapse of small bubbles of gaseous substances.12 This cavitation
effect is responsible for an enhancement in solubility, diffusivity, penetration, and mass
transportation of species in certain reactions. As a consequence, the use of ultrasound in organic
synthesis often shortens reaction times and minimizes the formation of undesired side products
which enhances product yield and selectivity. Additionally, the method is applicable to solvent-
free or low-solvent conditions leading to greener process, lowering the cost of production with
less energy consumption as compared to conventional heating.13
2,4,6-Trichloro-1,3,5-triazine (TCT) is one of the most versatile reagents in organic synthesis
due to its low cost, ready availability, and high reactivity.14 Since all three chlorine atoms on the
triazine ring are susceptible to nucleophilic displacement, TCT can be used as a scaffold for the
synthesis of structurally diverse compounds36 or it can be applied as a dehydrating agent in
various functional group transformations.15 So far, a number of methods have been developed
using TCT as a coupling reagent in the synthesis of carboxylic acid derivatives. To the best of
our knowledge, there is only one study reporting the use of TCT as an activating agent for the
guanylation of amines.8 In this method, TCT was applied in the presence of N-methylmorpholine
in THF at reflux for the dehydrosulfurization of di-Boc-thiourea. However, the reaction with
other substituted thiourea containing substrates was not evaluated.
In a continuation of our on-going research in developing simple and economic reactions
mediated by TCT, we were interested in replacing the traditional promoters used for the
dehydrosulfurization of thiourea derivatives with inexpensive and easy to handle TCT. Special
attention was paid to the use of ultrasound in promoting the reaction with a limited amount of
organic solvent. Thus, in this study, the ultrasound-assisted guanylation of aliphatic and aromatic
amines with substituted thioureas under low solvent conditions was investigated using TCT in
the presence of catalytic triphenylphosphine (PPh3) as the activator.

Results and discussion
To develop the optimal reaction conditions using a minimal amount of solvent, we first
investigated the guanylation reaction using 1-cyclohexyl-3-(4-nitrophenyl)thiourea and
cyclohexylamine as model substrates. In our preliminary study, the sonochemical reaction was
performed using equimolar amounts of TCT and thiourea in the presence of five equivalents of
triethylamine in dichloromethane. The base was used in excess to facilitate the
dehydrosulfurization reaction, while solvent quantity was kept at a minimum (below 250 L
which corresponded to the amount commonly applied under the solvent-drop grinding technique
(< 1.5 L/mg of solid).16 After sonication of the mixture at room temperature for 10 min, the
respective carbodiimide could be detected by TLC. Without isolation of this intermediate,
cyclohexylamine (1.1 equiv) was then added, followed by sonication for a further 10 min.
Unfortunately, the reaction gave a complex mixture containing alkyamino-substituted triazines
as major products whereas the desired guanidine was isolated in low yield (Table 1, entry 1).
Table 1. Optimization of the reaction conditionsa
Entry
PPh3 (equiv)
-
Base
Et3N
Et3N
Cs2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Method
))), rt
))), rt
))), rt
))), rt
Yield (%)
1
2
3
4
5
6
7
8
30
87
53
59
85
45
48
86b
0.1
0.1
0.1
0.1
0.1
0.1
0.1
))), rt
stirring
grinding
))), rt
aReaction conditions: 1-cyclohexyl-3-(4-nitrophenyl)thiourea (0.0757 g, 0.271 mmol), TCT (0.0500 g, 0.271 mmol), PPh3, base
b
(1.355 mmol), dichloromethane (<250 L), 10 min, then cyclohexylamine (0.0296 g, 0.298 mmol), 10 min. TCT (0.0200 g,
0.108 mmol) was used.
Based on our previous experience, we have discovered that reactions mediated by TCT could be
promoted using catalytic amounts of triphenylphosphine.17 This prompted us to further optimize
the reaction conditions using PPh3 as an additive, while other inorganic bases were also screened

as a proton scavenger. According to Table 1, adding PPh3 to the reaction significantly improved
the product yield (entry 2) presumably due to the formation of the activated
triazinylphosphonium chloride which rapidly reacted with thiourea. Upon changing the organic
base to inorganic carbonate bases such as cesium carbonate and potassium carbonate, the yield of
the corresponding guanidine decreased dramatically and several unidentified side-products were
observed (entries 3 and 4). Nevertheless, high conversion was observed when sodium carbonate
was applied as a base (entry 5). Although it is unclear why such a weak base with low solubility
enabled clean conversion of the starting thiourea into the carbodiimide intermediate, it is possible
that other side-reactions or decomposition of intermediates could be pronounced with more
soluble carbonate bases (Cs2CO3 and K2CO3).
The effect of cavitation derived from the applied ultrasound energy was also proven to be
responsible for the yield enhancement under sonochemical conditions as the same reaction
carried out under stirring or grinding gave significantly lower yields (entries 6-7). Since less than
a stoichiometric amount of TCT has been applied in a number of functional group
transformations, the guanylation reaction was further performed using a 1:0.4 molar ratio of the
thiourea and TCT. To our delight, decreasing the amount of TCT did not lead to a decrease in
product yield (entry 8). Considering the benefit of using inexpensive and easy to handle sodium
carbonate, we decided to use these conditions in our further investigation.
With the optimized reaction conditions in hand (Table 1, entry 8), the scope and limitation of the
method were examined. A series of 1,3-disubstituted thioureas were treated with TCT/PPh3 in
the presence of Na2CO3 before being subjected to reaction with various amine nucleophiles
under ultrasonic conditions. It was observed that the presence of an electron-withdrawing group
on the aromatic ring of thioureas led to more favorable addition of the amines due to the
formation of more electron deficient carbodiimide intermediates. The guanidine products were
also obtained in high yields when alkylamines were used. As shown in Table 2, the reaction of 1-
cyclohexyl-3-(4-nitrophenyl)thiourea with primary alkylamine, benzylamine, and secondary
amines proceeded well to afford the corresponding guanidine derivatives in good yields within
10 min (entries 1-3). Guanylation with aromatic amines and heterocyclic amines gave slightly
lower yields (entries 4-6). Other thiourea derivatives containing electron-withdrawing groups
also reacted smoothly with the applied amines (entries 7-11). Interestingly, the reaction using

sterically hindered diisopropylamine proceeded quickly suggesting that the use of ultrasound
energy could help overcome steric effects in the reaction (entry 10).
The reaction times after amine addition to the in-situ generated carbodiimide were found to vary
depending on the reactivity of the carbodiimide. Although 1,3-diphenylthiourea underwent rapid
dehydrosulfurization to give the respective carbodiimide, subsequent reaction with amines
required longer times since the carbodiimide intermediate is less activated (entries 12-13). N,N’-
Alkylarylcarbodiimides were generally less reactive than N,N’-diarylcarbodiimides. Thus, 1-
cyclohexyl-3-phenylthiourea underwent guanylation with cyclohexylamine with extended times
(entries 14-15). It should be noted that the presence of an electron-donating substituent in the
thiourea fragment gives rise to a less electrophilic carbodiimide which significantly decelerates
the guanylation reaction. In accordance with the reported literature,21 the reaction using 1-
cyclohexyl-3-(p-tolyl)thiourea as a substrate was sluggish, however, the respective product was
obtained in an acceptable yield.

Table 2 One-pot synthesis of N,N',N''-substituted guanidinesa
Entry
Thiourea
Amine
Time (min)
Yield (%)Ref
1
10
10
8618
2
3
4
5
6
92
10
10
10
10
87
80
75
83
7
8
9
10
10
10
8719
88
84

10
11
12
10
20
20
92
8018
7820
13
20
7521
14
15
30
25
7518
7822
16
45
6318
aReaction conditions: thiourea (0.271 mmol), TCT (0.0200 g, 0.108 mmol), PPh3 (0.007 g, 0.027 mmol), Na2CO3 (0.0861 g,
0.813 mmol) dichloromethane (250 L), sonication, 10-15 min, then amine (0.298 mmol).
A possible mechanism for this reaction is depicted in Scheme 1. In the first step (n =1), TCT was
activated through the formation of the corresponding triazinylphosphonium salt.17 Displacement
of the phosphonium ion with thiourea then produced intermediate I with concomitant release of
PPh3. Subsequent dehydrosulfurization of I gave carbodiimide along with chloro-substituted
triazine thiol derivative for further reaction with thiourea in the next catalytic cycle until the

triazine-trithiol by-product was formed (n = 3). Finally, nucleophilic attack of an amine on the
electrophilic center of the carbodiimide led to the formation of the guanidine product.
Scheme 1 Proposed mechanism for guanylation mediated by the TCT-PPh3 system.
Conclusion
In summary, a convenient one-pot sonochemical synthesis of highly substituted guanidines has
been developed. Ultrasonic irradiation was found to complement the applied guanylation
conditions where solid reactants and reagents were mixed in a low volume of solvent. Using the
TCT/PPh3/Na2CO3 combination, the guanylation of aliphatic and aromatic amines with 1,3-
disubstituted aryl and alkyl thioureas proceeded rapidly under mild conditions. This facile,
efficient, and economical method represents an excellent alternative to known procedures with
simplicity in reagent handling and experimental setup and avoids an excess of organic solvent.
Acknowledgements
Financial support from the Thailand Research Fund through the Royal Golden Jubilee Ph.D.
Program to S.W. (Grant No. PHD/0206/2556) as well as the Center of Excellence for Innovation
in Chemistry (PERCH-CIC), Chiang Mai University are gratefully acknowledged.

Supplementary data
1H and 13C NMR for representative products are available. Supplementary data related to this
article can be found at http://xxx.
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Graphical Abstract
Leave this area blank for abstract info.
Ultrasound-assisted synthesis of substituted guanidines
from thioureas
Mookda Pattarawarapan,* Subin Jaita, Sirilak Wangngae, and Wong Phakhodee