Simple and efficient methodology to prepare guanidines from 1,3-disubstituted thioureas

Article abstract of DOI:10.1016/j.tetlet.2016.02.107

Guanidinium salts were efficiently prepared by desulfurization reactions of 1,3-disubstituted thioureas using KICl₂ in the presence of amines. The reactions were successfully carried out at room temperature, in short reaction time, affording cy

Full text of DOI:10.1016/j.tetlet.2016.02.107

Tetrahedron Letters 57 (2016) 1585–1588
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and efficient methodology to prepare guanidines
from 1,3-disubstituted thioureas
⇑
Márcio V. Costa, Lúcia Cruz de Sequeira Aguiar , Luiz Fernando B. Malta, Gil M. Viana, Bruno B. S. Costa
Instituto de Química, Universidade Federal do Rio de Janeiro, CT Bloco A Lab. 617/641, Rio de Janeiro 21941-909, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Guanidinium salts were efficiently prepared by desulfurization reactions of 1,3-disubstituted thioureas
using KICl2 in the presence of amines. The reactions were successfully carried out at room temperature,
in short reaction time, affording cyclic/acyclic guanidines (hydrochloride salts) in high chemical yields.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 8 January 2016
Revised 24 February 2016
Accepted 26 February 2016
Available online 27 February 2016
Keywords:
Guanidines
Potassium dichloroiodate
Thioureas
Guanylating agent
Carbodiimides
Guanidines are versatile organic compounds widely described
by their applications1 as strong organobases, organocatalysts,
ancillary ligands, anion hosts, fluorescent molecular probes, ionic
liquids, and molecular transporters. It has been reported that
involving the reaction of a-chloroaldoxime O-methanesulfonates
with alkyl amines.6 Akamanchi and Dangate disclosed a one-pot
oxidative condensation procedure using o-iodoxybenzoic acid
and trimethylamine or ammonia as base, for the synthesis of
guanidines from the reaction between both 1,3-disubstituted
thioureas and amines/ammonia.7 Apart from that, in a recent work,
Looper and co-workers revealed the synthesis of bicyclic guanidi-
nes highly substituted, via a cascade silver (I)-catalyzed hydroam-
ination/Michael addition sequence.8
guanidine-containing molecules display
a range of biological
activities, such as anticancer,2a antibiotic,2b antiparasitic,2c
antiprotozoal,2d antifungal,2e antiviral,2f–i anti-inflammatory,2j
and others.2k Moreover, compounds with guanidine functionality
may exhibit activities as Ca+2 channel blockers,2l apoptosis-
inducing action2m and their salts have shown prominent ability
in binding oxoanions,1h,i being applied in biological studies of
molecular recognition.3
The use of thioureas as starting material, to afford guanidines,
constitutes a simple and good strategy. The advantage comes from
the facile preparation of thioureas, usually obtained by the reaction
of amines (aliphatic/aryl) and corresponding isothiocyanates.9
Guanidines are synthesized from thioureas via desulfurization
reactions, mediated by reagents such as mercuric (II) chloride,10a
Due to the importance of cyclic/acyclic guanidines, several
synthetic methods have been developed and described in the
literature. Typical methods involve the reaction between primary
and secondary amines (or ammonia) and a guanylating agent,
such as: N,N0,N00-tri-Boc-guanidine, benzotriazole-1-carboxami-
dines, chloroformamidines, cyanamides, carbodiimides, triflyl-
N-iodosuccinimide,10b
bismuth
nitrate
pentahydrate,10c
Mukaiyama’s reagent,10d,e iodine,10f and others.1b,4a,d In order to
overcome drawbacks presented by classical methods such as
longer reaction times, lower reaction yields and toxic or expensive
reagents usage, more benign11 and catalytic12 approaches to prepare
guanidines have been developed.
guanidines,pyrazole-1-carboximidamides,
dichloroisocyanides,
S-alkylisothiouronium salts, and isothioureas/thioureas.1b,4
Recently, bicyclic guanidines were prepared by Walker and
Madalengoitia by reactions between aza-norbornenes and
carbodiimides (in situ generated), through a 1,3-diaza-Claisen
rearrangement.5 Yamamoto et al. reported a one-pot synthesis of
N,N0,N00-trisubstituted guanidines via a Tiemann rearrangement
Herein, we report an efficient and straightforward method to
obtain guanidinium salts 1 from 1,3-disubstituted thioureas 2
using potassium dichloroiodate (KICl2) as desulfurization agent,
in the presence of an amine (Route A: Guanylation of thioureas—
Scheme 1).
13a
KICl2
is a mild oxidizing agent, convenient for iodochlorina-
⇑
tion of multiple bonds13b and as an iodinating agent for
Corresponding author. Tel.: +55 021 3938 7140.
E-mail address: luciasequeira@yahoo.com.br (L.C. de Sequeira Aguiar).
http://dx.doi.org/10.1016/j.tetlet.2016.02.107
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

1586
M. V. Costa et al. / Tetrahedron Letters 57 (2016) 1585–1588
Guanylation of thioureas
n
S
NH
.
H
N
N
S
NR3 HCl
KICl2 / Amine
R
KICl2 aq (pH=3)
R1
R2
N
H
N
H
R1
R2
n
HCl
N
H
N
H
NR
N
H
N
H
Z
Route A
CH3CN; rt (30min)
Z
2
1
2e-l
1e-l (tautomeric mixture)
68 - >97%
e: Z = NO2; n = 1; R = Bn
f: Z = NO2; n = 1; R = Ph
g: Z = H; n = 1; R = Bn
h: Z = H; n = 1; R = Ph
i: Z = NO2; n = 2; R = Ph
KICl2
Route B
j: Z = NO2; n = 2; R = Bn
k:Z = H; n = 2; R = Ph
l: Z = H; n = 2; R = Bn
Oxidation of thioureas
Tetrahedron Letters 54 (2013) 936-940
O
R1
R2
N
N
H
H
3
NH
NH
NH
N
N
N
Scheme 1. Guanylation (Route A) and oxidation/iodination (Route B)14 of thioureas
N
N
N
Ph
with the use of KICl2.
Bn
Bn
O2N
O2N
1e (>97%)
1f (>97%)
1g (93%)
(heterocyclic) aromatic compounds.13a,c,14 Aqueous solution of
KICl2 can be easily prepared in the laboratory, as described by
Larsen et al.,13a and it is stable at room temperature without any
appreciable concentration loss for a considerably long period
(long shelf life >3 years).
NH
N
N
NH
N
N
NH
Bn
N
N
Ph
Ph
O2N
O2N
1h (>97%)
1i (86%)
1j (68%)
Recently, our group disclosed an efficient reaction protocol for
the synthesis of substituted ureas via treatment of thioureas with
aqueous potassium dichloroiodate (KICl2).14 By tuning the reaction
condition, thioureas bearing activated N-aryl substituents may
undergo selective oxidation or sequential oxidation/iodination,
N
NH
N
NH
Cyclic guanidines
N
N
forming iodoaryl substituted ureas in the latter case (Route B14
:
Ph
1k (>97%)
Bn
Oxidation of thioureas—Scheme 1).
1l (>97%)
Initially, we investigated the preparation of acyclic guanidines
1a–d (Scheme 2).15 Thioureas 2a–d were synthesized from the
reaction of benzyl (BITC) or phenylisothiocyanate (PITC) and corre-
sponding amines, according to the literature.9
Scheme 3. Synthesis of cyclic guanidines 1e–l from diamines-derived thioureas.
Guanylation reactions were carried out treating the thiourea/
CH3CN solutions with excess of KICl2 (10 equiv; pH = 3), in the
presence of butyl or cyclohexylamine. The reaction mixtures were
kept at room temperature for about 30 minutes, treated with satu-
rated aqueous NaHSO3 solution, affording after isolation guani-
dinium salts in moderate to high yields (1a: >97%; 1b: 67%; 1c:
87%, 1d: 90%)—Scheme 2.
Attempts to use arylamines (lower nucleophilicity), ammonium
hydroxide or ammonium acetate were carried out, however guany-
lation was not effective and the products were obtained in very
low yields. The guanidines 1a–d were characterized by IR, NMR
and HRMS. The absence of signals around 179–183 ppm (C@S)
and the observation of signals at 155–160 ppm (C@NR) in 13C
NMR, besides the occurrence of broad absorption bands in IR spec-
tra indicate the formation of guanidine moiety. It may be worth
mentioning that acyclic guanidines, even on salt forms, have low
stability and high tendency to hydrolyze towards their correspond-
ing ureas, whose signals can be observed in some NMR spectra.
We have also investigated the preparation of cyclic guanidines
employing the same desulfurization methodology (KICl2; pH = 3),
with no addition of an external amine (Scheme 3).15 In these cases,
diamines-derived thioureas 2e–l were synthesized from aryldiami-
nes, obtained by a methodology recently developed in our labora-
tory (copper oxide-catalyzed CAN cross-coupling reaction).16
Regardless of the formed ring size, cyclic guanidines 1e–l were
also obtained in good to high chemical yields (68–>97%), with no
need of purification. They could be distinguished (NMR) from their
corresponding thioureas through their aliphatic methylene signals
(NCH2(CH2)nCH2N). In 1H NMR spectra, it was observed a different
pattern for the signals of guanidines and thioureas, with all guani-
dines-methylene signals occurring in higher chemical shifts than
the same signals in corresponding thioureas.17
Although no mechanistic studies have been performed, the for-
mation of a carbodiimide intermediate promoted by KICl2 could be
implied to justify the guanidine moieties obtained (Scheme 4).18
Motivated by the search for new cores of polyamine-containing
molecules of medicinal interest, we investigated the applicability
of our new protocol to prepare 7-chloro-4-aminoquinoline-derived
guanidines. The quinoline scaffold is present in several pharmaco-
logically active synthetic/natural compounds.19 Structure–activity
relationship studies on antimalarial compounds suggest that 7-
chloro-4-aminoquinoline skeleton is obligatory for the activity.19a
It is also interesting to note that simple structure modifications
have led to potent activity-bearing compounds against
chloroquine-resistant strains (CQ-R) and some of these molecules
are in clinical trials.19a With these facts in mind, we synthesized
n
NH
S
N
H
N
R3
.
HCl
NR
KICl2 aq (pH =3)
KICl2
S
N
R
N
H
N
H
.
HCl
R2
CH3CN; rt (30 min)
R1
R2
n
R1
Z
N
H
N
H
N
H
N
H
1e-l
Z
2e-l
R3NH2
carbodiimide intermediate
2a-d
1a-d (tautomeric mixture)
(R3 = Bu or Cy)
H
N
a: R1 = R2 = Bn
a: R1 = R2 = Bn; R3 = Bu
b: R1 = R2 = Ph; R3 = Bu
c: R1 = Bn; R2 = R3 = Cy
d: R1 = Ph; R2 = Bn; R3 = Bu
N
C N R
n
67 - >97%
b: R1 = R2 = Ph
c: R1 = Bn; R2 = Cy
d: R1 = Ph; R2 = Bn
Z
Scheme 2. Preparation of acyclic guanidinium salts 1a–d.
Scheme 4. Proposed carbodiimide intermediate for synthesis of cyclic guanidines.

M. V. Costa et al. / Tetrahedron Letters 57 (2016) 1585–1588
1587
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H
N
H
N
NH2
n
HN
N
HN
N
S
PITC or BITC
CH2Cl2; rt
2m: n = 0 (93%)
2n: n = 1 (89%)
Cl
Cl
3
KICl2 aq.
CH3CN
rt; 30 min
NH
N
N
.
n
N
N
N
n
N
H
.
HCl
HCl
1m: n = 0 (98%)
1n: n = 1 (95%)
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N
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Scheme 5. Synthesis of guanidines derived from 7-chloro-4-aminoquinoline.
the key intermediates 2m–n (Scheme 5) from the reaction of
phenylisothiocyanate or benzylisothiocyanate with 4-(2-
aminoethyl)amino-7-chloro-quinoline (3), prepared according to
the literature.19g
The target cyclic guanidines 1m–n were obtained in high yields
(95–98%), using the same reaction conditions reported in Schemes
2 and 3 (KICl2; rt; 30 min).15 They were characterized by spectro-
scopic methods and their spectra compared to corresponding
(thiourea) urea spectra, in order to certify the absence of this com-
pound in the guanidine–tautomeric mixture. The guanidines syn-
thesized are currently being screened for pharmacological activity.
In summary, KICl2 was found for the first time to be useful for
the construction of cyclic and acyclic guanidinium salts from 1,3-
disubstituted thioureas. This simple protocol presents advantages
such as short reaction time, high yields of products and mild reac-
tion conditions, which makes it very useful and an attractive pro-
cess for the synthesis of highly targeted compounds. In addition,
the use of aqueous KICl2 for the desulfurization of thioureas offers
advantages in terms of safety and ease of use in comparison to
other methods that often employ toxic and hazardous materials
or expensive reagents usage.
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Acknowledgements
15. General procedure for synthesis of guanidines 1a–n: To a solution of thiourea 2a–
n (0.5 mmol) in 5 mL of acetonitrile was added 1.3 mL (10 equiv) of an aqueous
solution of potassium dichloroiodate (ꢀ2 M; pH = 3) and 0.5 mmol of butyl or
cyclohexylamine (acyclic guanidines) or no external amine addition (cyclic
guanidines). The mixture was stirred at room temperature for 30 min. Then,
the reaction was quenched with saturated aqueous NaHSO3 (15 mL). The
aqueous mixture was extracted with ethyl acetate (4 ꢁ 10 mL), dried over
anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give
the desired product. N,N0-dibenzyl-N00-butylguanidine hydrochloride (1a). Pale
yellow solid; IR (KBr): 3478, 3353, 3027, 2874, 1626, 1572, 1246, 750,
The authors would like to thank CNPq, CAPES and FAPERJ for
their financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
107.
696 cmꢂ1 1H NMR (200 MHz, CDCl3): d = 7.35–7.17 (m, 10H), 5.21 (br t, 2H),
;
4.31 (d, J = 5.8 Hz, 4H), 2.93 (t, J = 7.7 Hz, 2H), 1.80–1.60 (m, 2H), 1.47–1.26 (m,
2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): d = 159.0; 139.1; 128.8;
127.4; 127.3; 44.5; 40.1; 29.3; 19.9; 13.6; HRMS-ESI: m/z [M+H]+ calculated for
References and notes
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