Study of N-benzoyl-activation in the HgCl2-promoted guanylation reaction of thioureas. Synthesis and structural analysis of N-benzoyl-guanidines

Article abstract of DOI:10.1016/S0040-4020(00)01168-6

In this work, it is demonstrated that the benzoyl group is an activating group for thioureas in the HgCl₂-guanylation reaction. Thus N-benzoyl-thioureas containing electronically neutral and even electron-withdrawing or electron-releasing subst

Full text of DOI:10.1016/S0040-4020(00)01168-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1671±1675
Study of N-benzoyl-activation in the HgCl -promoted guanylation
2
reaction of thioureas. Synthesis and structural analysis of
N-benzoyl-guanidines
a,p
Silvio Cunha, Ma Âõ sa B. Costa, Hamilton B. Napolitano, Carlito Lariucci and Ivo Vencato
a
b
b
b
a
Laborat o rio de Bioatividade MolecularÐInstituto de Qu Âõ mica, Universidade Federal de Goi a s, CP 131,
Campus II, Goi aà nia-GO 74001-970, Brazil
b
Laborat o rio de Cristalogra®a e MateriaisÐInstituto de F Âõ sica, Universidade Federal de Goi a s, CP 131,
Campus II, Goi aà nia-GO 74001-970, Brazil
Received 23 October 2000; accepted 11 December 2000
AbstractÐIn this work, it is demonstrated that the benzoyl group is an activating group for thioureas in the HgCl -guanylation reaction.
2
Thus N-benzoyl-thioureas containing electronically neutral and even electron-withdrawing or electron-releasing substituents are converted
into guanidines with reasonable yields. In addition, NMR and X-ray structural analyses were performed to understand the intra- and
intermolecular features of the synthesized guanidines. q 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
Herein, we described our study of the N-benzoyl-group as
an alternative activation group for thiourea in the guanyla-
Recently, we initiated a research program aimed at the
synthesis of anticonvulsant agents. In this context, we
became interested in the preparation of guanidine deriva-
tives since these substances proved to be potential anti-
tion reaction promoted by HgCl . To the best of our knowl-
2
edge, only one example of N-benzoyl-thiourea conversion
into guanidine has been described in the literature but that
case was limited to electronically and sterically neutral
1
13
convulsant compounds. The guanidinium group is also
present in many natural and synthetic biologically active
substituents.
2
±4
compounds. Due to its large spectrum of activity such
as antibacterial, antidiabetic, antihistaminic, anti-in¯ammatory
2. Results and discussion
4
and cardiovascular activity, the guanidine unit has been
0
converted into guanidines by the HgCl method,
intensively studied as a synthetic goal and a diversity of
new methods has been developed. Advances have been
phase synthesis
While N,N -bis-Boc-thioureas and N-Boc-thiourea are easily
the
1
2,13,16,17
2
5
±9
described both in solid and solution
10±18
use of this starting material can be a drawback if guanidines
containing different N-substituents need to be synthesized,
because deprotection/protection steps are necessary. With
N-benzoyl activation this limitation can be overcome, in
principle, by reacting benzoyl isothiocyanate with an appro-
priate amine followed by the reaction of the resulting N-
benzoyl-thiourea with another different amine. Thus, the
required thioureas 3a±e were prepared in 70±99% yield
by the reaction of primary aromatic and aliphatic amines
of guanidine and, in the latter case, thioureas are the most
versatile starting material because they can be obtained in
high yield from easily available precursors. However, to
ef®ciently convert thiourea into guanidine by the HgCl2
protocol the thiourea should be activated by a strong elec-
tron-withdrawing group, and the most general approach to
0
achieve this is by the use of N,N -bis-Boc-protected thio-
ureas (Scheme 1).
1
2,13,16,17
Scheme 1.
Keywords: guanidines; thioureas; guanylation reaction; X-ray analysis.
Corresponding author. Tel.: 155-62-521-1008; e-mail: silvio@quimica.ufg.br
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01168-6

1
672
S. Cunha et al. / Tetrahedron 57 (2001) 1671±1675
Table 1. Isolated guanidine yields from N-benzoyl-thioureas
with benzoyl isothiocyanate following the literature proce-
and were submitted to guanylation. Results are
summarized in Table 1. The structure of the guanidine 4a
was unambiguously con®rmed by X-ray analysis, as shown
in Fig. 1.
amine 2c. In this case, guanidine 4c was obtained in almost
the same yield as when the electronically neutral amine
2a was reacted with thiourea 3c (2c13a!4c, 60%;
2a13c!4c, 64%). These results suggest that substituent
introduction sequence is not a limiting factor in the guanyla-
1
9,20
dure,
tion reaction promoted by HgCl when N-benzoyl-activated
2
The electronic nature of the N-substituent in the N-benzoyl-
thioureas 3 could vary from electronically neutral, as in 3a,
to electron releasing or electron withdrawing, as in 3b and
thioureas are used.
1
In the H NMR spectra of N-benzoyl-guanidines 4a, 4b and
3c, respectively. Thus, it is apparent that the electronic
nature of R in the thiourea does not affect the pathway
nor the yield of the guanylation reaction and, potentially,
a broad spectrum of guanidines can be obtained. Addition-
ally, to study the effect of the amine in the guanylation
reaction we reacted thiourea 3a with the less nucleophile
4d a broad signal around 10±12 ppm was detectable related
to one N±H proton, suggesting the participation of one
intramolecular hydrogen bond. However, in the spectra of
N-benzoyl-guanidine 4c and 4e, two sharp low ®eld chemi-
1
cal shift signals were present (,13 and ,10.5 ppm, D O
2
exchangeable) characteristic of strong internal hydrogen
bonds. To accommodate this observation the typical
2
1
CvN cis±trans con®gurational interconversion should be
frozen by these internal hydrogen bonds, making the Z-4c
0
con®guration favored over the E-4c (or E-4c ) con®guration
(
Scheme 2).
A common fragmentation pattern emerged from the mass
spectra of 4a±e. In addition to the expected phenyl and
benzoyl ion formation, we observed a peak corresponding
amine ion formation by the loss of neutral carbodiimide
from the guanidines (Scheme 3). In this fragmentation path-
way, aromatic amine ion formation was preferable to an
aliphatic one (only in 4a, with two cyclohexyl groups in
the molecule, was the aliphatic amine ion detectable, albeit
in low relative abundance).
To unambiguously assign the structure of the obtained
guanidines and to gain insight into intra- and intermolecular
Figure 1. X-ray crystallographic structure of molecule 1 of compound 4a.
Displacement ellipsoids are shown at the 30% probability level.

S. Cunha et al. / Tetrahedron 57 (2001) 1671±1675
1673
Scheme 2.
Scheme 3.
interactions, the crystal structure of 4a was determined. The
asymmetric unit has two independent molecules (4a and
3. Experimental
0
atoms. However, the molecules show signi®cant differences
4a ), and Fig. 1 shows the unprimed molecule with labeled
Melting points were determined on a Karl Kolb apparatus
and are uncorrected. Infrared spectra were recorded as KBr
discs on an FT-IR BOMEM MB100 instrument. NMR spec-
only in the torsion angles C2±N3±C4±N5 of 220.8(4) and
2
1
1
0.2(4), C2±N3±C4±N6 of 162.7(2) and 2179.9(2)8
tra were obtained for H at 300 or 400 MHz and for C at 75
or 100 MHz using a Varian Gemini 300, a Bruker AC300P
and a Bruker ARX400 spectrometers at Instituto de
Qu Âõ mica/UNICAMP and at Instituto de Qu Âõ mica/UFSCar.
Chemical shifts are reported in ppm units down®eld from
reference (internal TMS). MS spectra were measured on a
SHIMATSU CG-MS QP-5050 spectrometer at 70 eV.
Elemental analyses were performed on a 2400 CHN
Perkin±Elmer instrument at Instituto de Qu Âõ mica/UNICAMP.
The single crystal X-ray data collection was carried out on a
Nonius CAD-4 diffractometer at Departamento de Qu Âõ mica/
UFSC.
for the unprimed and primed molecules, respectively. The
cyclohexane rings have chair conformation, with some
distortions as can be seen from the Cremer and Pople
2
2
Ê
parameters. C13!C14!¼C18 [Qˆ0.554(3) A, uˆ2.6(3)8,
Ê
fˆ175(9)8; Qˆ0.558(3) A, uˆ3.7(3)8, fˆ14(6)8] and
Ê
C19!C20!¼C24 [Qˆ0.563(3) A, uˆ2.2(3)8, fˆ
Ê
1
10(11)8; Qˆ0.561(3) A, uˆ2.6(3)8, fˆ246(8)8] for the
unprimed and primed molecules, respectively.
As noted in Fig. 1 of 4a, strong hydrogen bonding
occurs between the carbonyl oxygen and the NH group
(
intramolecular
hydrogen
bonds:
N5±HN5¼O1
Ê
0
a pseudo six-membered ring. Also, intermolecular hydrogen
0
0
Ê
[2.627(3) A] and N5 ±HN5 ¼O1 [2.595(3) A]) providing
3.1. General synthetic procedure
0
.51z, 2.932(3) A] and N6 ±HN6 ¼O1 [12x, 22y, 2z,
bonds are observed between N6±HN6¼O1 [x, 1.52y,
0
To a solution of 1 mmol of thiourea in 5 mL of DMF
was added 1 mmol of amine and 2 mmol of Et N and
Ê
0
.092(3) A]. The O1 atom is 0.350(4) A from the least-
0
3
Ê
Ê
3
square plane through the atoms C2 N3 C4 N5 and the O1
then 1 mmol of HgCl was added to the solution with
2
0
atom is 0.042(4) A from the corresponding primed plane.
vigorous magnetic stirring and ice-bath cooling. The
suspension became black after a few minutes and was left
to react for 20 h at room temperature. After this time,
10 mL of ethyl acetate was added and the suspension was
®ltered through a pad of Celite and the pad washed with
Ê
Therefore, the intramolecular hydrogen bonds involving O1
and O1 contribute to the planarity of the conjugated moiety
0
of 4a and 4a .
0
1
0 mL of CH Cl . The ®ltrate was concentrated and
2 2
In summary, we have demonstrated that N-benzoyl-thioureas
are easily converted to guanidines by the HgCl method,
the residue (,5 mL) was dissolved in 15 mL of CH Cl ,
2
2
2
extracted with water (3£15 mL) and dried over
being a versatile starting material to densely substituted
guanidines containing electronically neutral as well as elec-
tron withdrawing and electron releasing groups. In addition,
NMR and X-ray studies have indicated that the guanidines
synthesized here are able to form inter- and intramolecular
hydrogen bonds, and that these features are found in elec-
tronically analogous compounds with anticonvulsant activ-
anhydrous MgSO . After ®ltration the solvent was eva-
4
porated and the crude residue was treated as indicated in
each case.
3.1.1. N1-di(cyclohexylamino)methylenebenzamide (4a).
Recrystallization from ethyl ether/petroleum ether, mp
2
151±1538C. nmax 3289, 1605, 1572 cm . d H (CDCl )
1
1
3
2
5,26
ity. The pharmacological evaluation of guanidines 4a±e
are under investigation and will be described elsewhere.
1.19±1.48 (8H, m); 1.52±1.70 (4H, m); 1.78±1.80
(4H, m); 1.95±2.15 (4H, m); 3.50 (1H, sl); 4.20 (1H, m);

1
674
S. Cunha et al. / Tetrahedron 57 (2001) 1671±1675
7
d
.37±7.48 (3H, m); 8.21 (2H, d, Jˆ7.2 Hz); 10.35 (1H, sl).
132.5 (CH); 139.7 (C ); 140.3 (CH); 147.2 (CH); 154.1 (C );
0 0
1
3
1
C (CDCl ) 24.6 (CH ); 25.5 (CH ); 33.1 (CH ); 49.9
2
158.0 (C ); 177.9 (C ). MS m/z (%): 297 (13) [M 11], 296
0 0
3
2
2
1
(
CH ), 127.7 (CH); 128.9 (CH); 130.7 (CH); 139.2 (C );
2
(64) [M ], 239 (62), 212 (27), 120 (31), 105 (100), 77 (66).
Anal. Calcd for C H N O: C, 68.92%; H, 6.76%; N,
18.92%. Found: C, 68.17%; H, 6.96%; N, 18.60%.
0
1
1
58.3 (C ); 176.9 (C ). MS m/z (%): 328 (12) [M 11],
0 0
17 20
4
1
27 (47) [M ], 245 (26), 164 (46), 105 (100), 77 (57).
3
Anal. Calcd for C H N O: C, 73.39%; H, 8.87%; N,
2
0
29
3
1
2.84%. Found: C, 73.57%; H, 9.01%; N, 13.11%.
3.1.6. Crystal structure of 4a. C20 N O, M
3
H
29
w
ˆ327.46,
monoclinic, space group P2 /c, Zˆ8, aˆ12.120(2), bˆ
1
3
Ê
Ê
21
3.1.2. 1-cyclohexylamino(phenylcarbonylimino)methyl-
15.812(3), cˆ19.692(4) A, bˆ92.12(3)8, Vˆ3771.2(12) A ,
23
Ê
amino-4-methoxybenzene (4b). Recrystallization from
ethyl ether/petroleum ether, mp 129±1318C. n 3356,
d
c
ˆ1.154 mg m , l (Mo Ka)ˆ0.71073 A, mˆ0.072 mm ,
7603 measured re¯ections, 7379 unique (Rintˆ0.046) of
which 3906 were considered as observed with I$2s(I).
The single crystals were obtained by diffusion of petroleum
max
2
594, 1570 cm . d H (CDCl ) 1.10±1.26 (3H, m);
1
1
1
3
1.30±1.51 (2H, m); 1.61±1.73 (3H, m); 2.02±2.05 (2H,
m); 3.84 (3H, s); 4.14 (1H, l); 4.64 (1H, sl); 6.95 (2H, d,
ether into a solution of synthesized guanidine 4a in CH Cl
2 2
Jˆ4.8 Hz); 7.19 (2H, d, Jˆ9.0 Hz); 7.40±7.57 (3H, m);
at room temperature. The structure was solved with direct
methods using shelxs97 and it was re®ned anisotropically
with full-matrix least-squares on F using shelxl97. The
hydrogen atoms were placed at the calculated positions
except those involved in H bonds, found on difference
1
3
23
8
2
.26 (2H, d, Jˆ6.6 Hz); 11.86 (1H, sl). d C (CDCl )
3
2
24
4.6 (CH ); 25.4 (CH ); 33.0 (CH ); 50,0 (CH); 55.4
2
2
2
(
CH ); 115.2 (CH); 127.5 (CH); 127.9 (CH); 128.6 (C );
2 0
1
29.1 (2£CH); 131.1 (CH); 138.9 (C ); 158.6 (C ); 177.6
0
0
1
C ). MS m/z (%): 353 (5) [M 12], 352 (29) [M 11], 351
1
(
maps and re®ned. Final indices: R
(F )ˆ0.139 for 446 re®ned parameters.
(F
1
0
)ˆ0.048, wR
2
0
1
64) [M ], 269 (41), 123 (47), 105 (100), 77 (35). Anal.
2
(
Calcd for C H N O : C, 71.79%; H, 7.12%; N, 11.97%.
Found: C, 71.68%; H, 7.28%; N, 12.12%.
2
1
25
3
2
The crystallographic data were deposited at the Cambridge
Crystallographic Data Center under the number 150974.
Copies of the data can be obtained free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: 144-1223-336033 or e-mail: deposit@ccdc.camac.uk).
3.1.3. 2-cyclohexylamino(phenylcarbonylimino)methyl-
aminopyridine (4c). Recrystallization from benzene/petro-
2
1622, 1592, 1564 cm . d
1
leum ether, mp 107±1098C. n
H (CDCl ) 1.33±1.56 (4H, m); 1.65 (2H, m); 1.76±1.82
max
1
3
(
2H, m); 2.11 (2H, m); 4.31 (1H, m); 6.90 (1H, d,
Jˆ8.2 Hz); 6.97 (1H, dd, Jˆ7.3, 5.2 Hz); 7.37±7.50 (3H,
Acknowledgements
m); 7.66 (1H, dt, Jˆ7.5, 1.8 Hz); 8.26 (3H, m); 10.42 (1H,
1
s); 13.35 (1H, s). d C (CDCl ) 24.5 (CH ); 25.7 (CH );
3
3
2
2
The authors thank the Brazilian Agencies for fellowships to
MBC (PIBIC-UFG/CNPq), IV (CNPq) and HBN (CAPES),
and ®nancial support from FUNAPE-UFG, PADCT-III/
QEQ (No. 620166/97-5). The authors also thank Instituto
de Qu Âõ micaÐUNICAMP (NMR and elemental analyses),
Instituto de Qu Âõ micaÐUFSCar (NMR) for measurements,
and Departamento de Qu Âõ micaÐUFSC for the X-ray single
crystal data collection.
3
2.8 (CH ); 49.8 (CH); 113.7 (CH); 117.8 (CH); 127.8
2
(
1
(
CH); 129.0 (CH); 131.1 (CH); 138.5 (CH); 138.6 (C0);
46.0 (CH); 153.2 (C ); 156.4 (C ); 176.9 (C ). MS m/z
%): 324 (23) [M 12], 323 (100) [M 11], 322 (96)
0
0
0
1
1
1
[M ], 239 (42), 212 (28), 120 (40), 105 (96), 77 (57).
Anal. Calcd for C H N O: C, 70.81%; H, 6.83%; N,
1
9
22
4
1
7.39%. Found: C, 70.89%; H, 6.73%; N, 17.63%.
3.1.4. 4-methoxy-1-[4-methoxyanilino(phenylcarbonyl-
imino)methylamino]benzene (4d). Puri®ed by silica gel
column chromatography (hexane/ethyl acetate 50%) fol-
lowed by recrystallization from CH Cl /petroleum ether,
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2
2
1
1
mp 126±1288C. nmax 3373, 1606, 1568, 1506 cm . d H
(
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