A synthetic method to access symmetric and non-symmetric 2-(N,N'-disubstituted)guanidinebenzothiazoles

Article abstract of DOI:10.3390/molecules170910178

Symmetric and non-symmetric 2-(N-H, N-methyl, N-ethylenyl and N-aryl)guanidinebenzothiazoles were synthesized from the reaction of ammonia, methylamine, pyrrolidine and aniline with dimethyl benzo[d]thiazol-2-yl- carbonodithioimidate (5) as intermediate. The products were characterized by ¹H-, ¹³C-NMR spectroscopy and three of them by X-ray diffraction analysis. HN-phenyl protons formed intramolecular hydrogen bonds that assist the stereochemistry of the second substituent, whereas the HN-alkyl protons were involved in intermolecular hydrogen bonding.

Full text of DOI:10.3390/molecules170910178

Molecules 2012, 17, 10178-10191; doi:10.3390/molecules170910178
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Synthetic Method to Access Symmetric and Non-Symmetric
2-(N,N'-disubstituted)guanidinebenzothiazoles
Alejandro Cruz *, Itzia I. Padilla-Martínez and Efrén V. García-Báez
Departamento de Ciencias Básicas de la Unidad Profesional Interdisciplinaria de Biotecnología del IPN,
Av. Acueducto s/n, Barrio la Laguna Ticomán, México, D.F., 07340, Mexico
* Author to whom correspondence should be addressed; E-Mail: alecruz@ipn.mx;
Tel.: +5-557-296-000 (ext. 56324); Fax: +5-557-296-000 (ext. 563054).
Received: 26 June 2012; in revised form: 14 August 2012 / Accepted: 15 August 2012 /
Published: 24 August 2012
Abstract: Symmetric and non-symmetric 2-(N-H, N-methyl, N-ethylenyl and
N-aryl)guanidinebenzothiazoles were synthesized from the reaction of ammonia,
methylamine, pyrrolidine and aniline with dimethyl benzodthiazol-2-yl-carbono-
1
dithioimidate (5) as intermediate. The products were characterized by H-, 13C-NMR
spectroscopy and three of them by X-ray diffraction analysis. HN-phenyl protons formed
intramolecular hydrogen bonds that assist the stereochemistry of the second substituent,
whereas the HN-alkyl protons were involved in intermolecular hydrogen bonding.
Keywords: 2-aminobenzothiazole; dithiomethylcarboimidate; isothiourea; benzothiazole;
guanidine
1. Introduction
The guanidine group has attracted considerable attention since it is found in a wide array of natural
and synthetic biologically active compounds [1–3]. The guanidine groups are categorized as
organosuperbases whose basicity is magnified because of the resonance stabilization of the
corresponding conjugated acids. These molecules are basic enough (pKa of their conjugated acids is
around 12.5) to form intermolecular contacts mediated by H-bonding interactions [4]. Its positive
charge, resulting from protonation in a wide range of pH values, plays an important role in forming
specific intermolecular interactions, comprising key-steps of many biological reactions including
enzyme-mediated processes and interaction of hormones with their receptors [5]. The guanidinium

Molecules 2012, 17
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moiety interacts with functional groups present in enzymes or receptors on the basis of hydrogen
bonds and electrostatic interactions to form intermolecular associations. Thus, they are useful
pharmacophores in medicinal chemistry [6]. Moreover, synthetic guanidines have found wide
applications in the engineering of advanced synthetic molecular recognition devices, sensors, organic
materials and phase-transfer catalysts [7,8]. Recently, it has been demonstrated that by introduction of
chirality in one of the guanidinyl nitrogen atoms [9–11], the resulting chiral guanidines were effective
in catalytic [12–15] and stoichiometric asymmetric synthesis [16,17]. Due to this, continued interest
has been shown in the transformation of amines into the corresponding guanidines, because the
guanidine group, instead of an existing amino group, can significantly increase the potency and/or
selectivity of biologically active compounds [18–20].
Typically, the synthesis of guanidine-containing compounds involves the treatment of an amine
with an electrophilic amidine species. The most commonly used reagents include cyanamide (1) [21],
O-methylisourea hydrogen sulfate (2a) [22], S-methyl isothiouronium salts (2b) [23–25], pyrazole-1-
carboxamidine (2c) [26], N-protected thiourea (3a) [27–29], (S-methyl or -aryl)isothiourea (3b) [30–33]
or pyrazole-1-carboxamidine (3c) derivatives [34,35] (Figure 1). To increase yields, new reagents with
electron-withdrawing substituents have been developed in the recent years [36,37].
Figure 1. Electrophilic amidine species used to generate guanidines from amines,
LG = leaving group.
LG
S
LG
N Prot
_
+
H2N C N
X
NH2
H2N
Prot
N
N Prot
Prot N
H
H
H
1
2
3
3a
LG (1, 2) = OMe, a; SMe, b; Pyrazolyl, c
LG (3) = SMe, b; Pyrazolyl, c
The synthesis of guanidines from thioureas and isothioureas are the most commons strategies used
for the construction of the guanidine functionality. In the case of thioureas, they are activated through
the reaction with DIC, EDCI, Hg2+ (most popular but toxic), 2-chloro-1-methylpyridinium iodide,
2,4-dinitrofluorobenzene, etc. Recently, a bismuth catalyst has been found to afford high yields
(70%–97%) [38]. The attachment of thiourea groups to a solid phase has been used as precursor of
guanidinium groups [39]. Recently, it has been demonstrated that guanylilation of an amine from a
thiourea, involves the attack of the amine on what is generally accepted to be a carbodiimide
intermediate [40–46].
Diphenylcarbodiimide has been used for the synthesis of diphenylguanidinobenzothiazole [47] and
dicyandiamide for the synthesis of 2-guanidinobenzothiazole [48]. However, to the best of our
knowledge, there is no reports about non-symmetrical guanidines derived from 2-aminobenzothiazole.
We have reported [49] a detailed study and characterization of the intermediates involved in
the synthesis of dimethyl benzodthiazol-2-ylcarbonodithioimidate (5), from the reaction of
2-aminobenzothiazole (4) with carbon disulfide in basic media, using DMF as solvent [50]. Two
molecules of HSMe are displaced when 5 reacts with o-XH substituted anilines in refluxing DMF to
get NH-bisbenzazoles 7 [51–53] (Scheme 1). We found that the reaction proceeds through the

Molecules 2012, 17
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intermediacy of isothiourea derivatives 6a–c when o-XH anilines are refluxed 16 h in ethanol. Under
these conditions, isothiourea 6c could be isolated and the reaction was extended to m- and
p-phenylenediamines [54]. In the same work, we reported the synthesis of S-methyl-N-
alkylbenzothiazolyl-isothioureas 8a–d when ammonia, methylamine, pyrrolidine, aniline and
1,4-piperazine were used (Scheme 2).
Scheme 1. NH-bisbenzazoles from dimethyl benzodthiazol-2-ylcarbonodithioimidate (5).
S
S
1) NaOH
2) CS2
N
N
N
H2N
HX
X
S
S
N
N
SCH3
NH2
N
DMF
Reflux
H
H N
N
SCH3
SCH3
N
3) NaOH
4) CH3I
4
a b
5
c
7
X
X = O, S, NH
6
H
Scheme 2. S-methylisothioureas 8, cyanamides 9 and guanidines 10 derived from
2-aminobenzothiazole 4, through dimethyl benzodthiazol-2-ylcarbonodithioimidate 5.
C N
S
N
R = H, a; CH3, b
N
9
R
NH3
S
R1NH2
S
N
R1 = H, a; Me, b; -(CH2)4-, c; Ph d
N
SCH3
SCH3
N
N
SCH3
R1
5
H N
8
R2NH2
S
R1 = H: R2 = H, a; Me, b; -(CH2)4-, c
R2
N
R1 = Ph: R2 = H, d; Me, e; -(CH2)4-, f; Ph, g
R1 = Me: R2 = Me, h; -(CH2)4-, i
R1 = R2 = -(CH2)4-, j
N
NH
H
N
10
R1
In continuation of this work, we were interested in extending the routes of synthesis of guanidine
compounds, in this sense, we generalized this reaction to prepare symmetrical 10g,h,j and
nonsymmetrical 10b–f,i guanidine derivatives obtained from 2-aminobenzothiazole (4, Scheme 2).
Herein we report the preparation and 1H and 13C-NMR structural study of a series of guanidines 10b–j.
The isolation of S-methylisothiourea intermediates 8 is important since their remaining reactive
S-methyl group was subsequently substituted by amines to form the guanidine group.
2. Results and Discussion
When dithiocarboimidate 5 reacts with one molar equivalent of ammonia, alkylamine or aniline in
ethanol, one molar equivalent of thiomethanol was evolved to afford the corresponding
S-methylbenzothiazolyl-isothiourea 8a–d as isolable intermediates (Scheme 2). Ammonia required

Molecules 2012, 17
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72 h and alkylamine 48 h on stirring at room temperature, to be completed, whereas aniline required
24 h in refluxing ethanol.
The reaction of isothiourea intermediates 8a–d with a second equivalent of several amines
(ammonia, methylamine, aniline and pyrrolidine) was then carried out. When the reaction of
isothiourea intermediate 8a was performed with excess ammonia in refluxing ethanol, 2-cyanamido-
benzothiazole 9a crystallized as the only product in a 62% yield. The X-ray diffraction structure of 9a
is shown in Figure 2, along with a summary of representative distances and angles. The N12-C11 bond
length is the shortest N–C bond, its value of 1.155(3) Å is in the characteristic range of a triple bond [55],
confirming the presence of the cyano group. In addition, N10-C11 1.337(3) Å and N3-C2 1.338(3) Å
are in agreement with a single bond whereas the shorter N10-C2 [1.311(3) Å] bond length is more
appropriate for a double bond character. On the other hand, the X-ray diffraction structure of 9a shows
that the mobile hydrogen atom prefers to stay on the benzothiazole nitrogen because of two
intermolecular interactions, N3-H3···N10, stabilize the molecule as a dimer H3···N10 = 2.01 Å,
N3···N10 = 2.866(2) Å, N3-H3···N10 = 174°; symmetry code: –x, −y, 1−z. In this arrangement, the
nitrile group is cis positioned to the sulfur atom, thus the electronic conjugation is extended from the
benzothiazole system to the nitrile group. The torsion angles S1-C2-N10-C11 −1.0°(3) and C11-N10-
C2-N3 178.3°(2) are in agreement with a planar molecule. The nitrile is a polarized functional group
whose interaction with sulfur atom, as Lewis acid, is favored by cis configuration N12···S1 = 3.160(3) Å
and C7-H7···N12 interaction [H7···N12 = 2.677 Å, C7-N12 = 3.343(4) Å, C7-H7···N12 = 138°;
symmetry code: 1−x, 1−y, 1−z].
Figure 2. Molecular structure of 2-cyanamidabenzothiazole 9a (left) and hydrogen
bonding scheme (right). Selected bond lengths (Å) and angles (°): S(1)-C(2) = 1.744(2),
N(3)-C(2) = 1.338(3), N(10)-C(2) = 1.311(3), N(10)-C(11) = 1.337(3), N(12)-C(11) =
1.155(3), C(2)-N(10)-C(11) = 118.90(19), S(1)-C(2)-N(3) = 112.59(16), S(1)-C(2)-N(10) =
126.44(18), N(3)-C(2)-N(10) = 121.0(2), S(1)-C(8)-C(9) = 111.40(16), N(3)-C(9)-C(8) =
111.69(19), N(10)-C(11)-N(12) = 174.3(3), C(8)-S(1)-C(2)-N(3) = 0.40(17), C(8)-S(1)-
C(2)-N(10) = 179.7(2), S1-C2-N10-C11 = −1.0°(3), C(11)-N(10)-C(2)-N(3) = 178.3(2).

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Compound 9a is formed when S-methylisothiourea 8a suffers HSMe group elimination promoted
by the basic media (Scheme 3). The proposed mechanistic pathway involves the participation of
NH4OH to remove one NH hydrogen atom from 8a to in situ form the ammonium intermediate I,
which is stabilized as the tautomer intermediate II. A second molecule of NH4OH promotes the
elimination of the HSMe group to generate the nitrile 9a. The intermediate II was transformed to
8-NMe, (δ = 3.80 NMe, 2.66 SMe) by reaction with one molar equivalent of NaOH and CH3I, which is
readily transformed into 2-cyanamide-N-methylbenzothiazole compound 9b by a second molar
equivalent of NaOH (Scheme 3).
Scheme 3. Thioamidines II and 8-NMe as intermediates in the formation of 2-cyanoimino-
benzothiazoles 9a and 9b.
_
OH
H
+
NH3
H
N
CN
SCH3
S
S
N
N
N
H
-CH3SH
N
H
S
S
-H2O
SCH3
9a
N
N
II
_
N
N
H
H
SCH3
N
N
N
+
H
H
_
C
8a
H
M
3I
SCH3
S
+
CN
S
HO
M
NaOH
N
I
N
N
-CH3SH
N
M
= N
H ,
Na
4
CH3
CH3
9b
8-NMe
Compound 9a was characterized in solution by NMR. The nitrile carbon atom appears as a small
signal at 117.7 ppm, very similar to the observed value of 118.7 ppm in benzonitrile [56]. The mass
spectrometry M+ = 175 m/z (100%) and elemental analysis, are in agreement with the proposed
structure. Under the same conditions already described for 8a, isothioureas 8b and 8c failed to react
with an excess of ammonia to give nonsymmetrical guanidines 10b and 10c respectively, and the
starting materials were recovered, however, the reaction of isothiourea 8d with an excess of ammonia,
affords the nonsymmetrical guanidine 10d as the only product. In this case, the acidic aniline hydrogen
is intramolecularly engaged with the benzothiazole nitrogen atom. This hydrogen bonding interaction
is strong enough to polarize the imine carbon and favors the substitution of the SMe group
by ammonia.
On the basis of this result, the reaction of isothiourea 8a with methylamine and pyrrolidine were
carried out to get nonsymmetrical guanidines 10b and 10c, after refluxing in ethanol for 4 and 2 days,
respectively. The reaction of 8a with aniline failed to give the corresponding guanidine compound
10d, even after 4 days in refluxing ethanol. Under these conditions, aniline is not nucleophilic enough
to add to the carbodiimide intermediate II. The reaction of isothiourea 8b or 8c with one molar
equivalent of methylamine or pyrrolidine in refluxing ethanol for 8 h afforded the corresponding
guanidines 10h,i or guanidines 10i,j, respectively. Symmetric guanidines 10h,j can also be obtained
when dithiocarboimidate 5 is reacted with two molar equivalents of the corresponding amine in
refluxing ethanol for 8 h.

Molecules 2012, 17
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The reaction of isothiourea 8d with one molar equivalent of methylamine, pyrrolidine and aniline
was tested. After 3 days in refluxing ethanol, the corresponding nonsymmetrical guanidines 10e and
10f, were obtained. The reaction with aniline required harsh conditions: refluxing DMF or solventless
1
heating. In the H-NMR spectrum of 10g, only aromatic protons and a broad signal at 12.4 ppm,
13
assigned to the N-H protons, were observed. Moreover, sixteen signals in the C-NMR spectrum are
indicative of the presence of the 2-N,N-diphenyl guanidinebenzothiazole 10g (Tables 1 and 2). The
mass spectrometry data M+ = 344 m/z (19%) is in agreement with the proposed structure.
Table 1. 1H-NMR chemical shifts of compounds 9a–b, 10b–j.
HN
7
8
SCH3
CN
N
S
N
S
S
6
5
N
N
2
N
R
N
R
NR1R2
NR1R2
9
4
9
10a-j
NCH3, SCH3
8-NMe
Comp.
8-NMe a
9a a
H4
H5
H6
H7
NH
NPh
N(CH2CH2)2
8.00
7.75
7.58
7.62
7.63
7.61
7.69
7.66
7.73
7.61
7.60
7.51
7.76
7.27
7.46
7.21
7.21
7.30
7.30
7.32
7.61
7.24
7.31
7.03
7.04
7.14
7.17
7.18
7.46
7.39
7.24
7.42
7.44
7.59
7.63
7.63
7.31
7.55
7.57
7.49
9.8
3.80, 2.66
9b b
3.62
2.75
10b a
10c a
10d b
10e b
10f b
10g a
10h b
10i b
7.7
8.2
3.4, 1.8
3.4, 1.8
7.4–7.3
7.5–7.3
7.3–7.1
7.4–7.3
11.2
11.6
11.9
9.6
2.97
7.24
7.26
7.20
7.10
7.08
7.00
2.92
3.53
8.9
3.0, 1.9
3.4, 1.8
10j b
a DMSO-d6; b CDCl3
。
Table 2. 13C-NMR chemical shift of compounds 9a–b, 10b–j, in DMSO-d6.
Comp.
C2
C4
C5
C6
C7
C8
C9
C11 NCH3, SCH3
Ph
8-NMe a 166.0 114.6 124.1 124.6 128.7 126.2 138.5 175.1
33.6, 15.7
9a a
9b b
174.0 114.0 123.7 124.4 128.2 125.0 139.4 117.7
171.5 112.2 122.9 124.8 127.9 123.3 139.4 116.9
158.4 125.9 122.3 121.4 118.9 130.9 152.5 174.3
155.4 125.9 122.2 121.4 119.0 130.9 152.6 174.4
156.0 125.7 122.7 122.1 119.6 131.3 151.8 173.7
154.6 125.6 122.5 121.2 119.5 131.7 151.9 174.5
154.4 125.6 122.4 121.1 119.6 132.0 151.9 173.8
151.5 125.8 121.5 121.3 119.9 132.0 151.0 173.6
157.2 125.5 122.2 121.0 119.1 131.6 152.2 174.7
159.2 125.4 122.0 121.0 119.1 132.1 152.2 173.6
158.0 125.2 121.2 121.8 119.1 133.4 153.3 171.3
31.3
28.3
10b a
10c a
10d b
10e b
10f b
10g a
10h b
10i b
10j b
136.8, 130.2, 125.7, 127.0
137.0, 130.2, 126.9, 126.0
139.9, 129.5, 125.6, 123.3
137.3, 129.8, 123.6, 123.0
28.6
28.2
31.5
N(CH2CH2): 46.9, 25.5 (10c); 49.3, 25.6 (10f); 49.2, 25.7 (10i); 49.6, 25.6 (10j). a DMSO-d6; b CDCl3
。

Molecules 2012, 17
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Comparison of 13C-NMR chemical shifts of guanidine compounds 10 to those of dimethyl
benzodthiazol-2-ylcarbonodithioimidate 5, shows that C2 and C11 are shifted to low frequencies by
approximately 10 and 2 ppm, respectively (Table 2). This effect is explained by the extended
conjugation of N12 and N13 electron pairs to the benzothiazole ring, increasing the electronic
protection of C2 atom. This effect also shifts C7 and C8 to low frequencies by 6 and 3 ppm,
respectively. In contrast, C2 is shifted by 6.5 ppm to higher frequencies in 2-aminonitrilebenzothiazole 9a.
Nonsymmetrical guanidines 10f and 10i were crystallized from ethanol; their molecular structures
are shown in Figures 3 and 4, respectively. The aniline N-H proton in 10f is intramolecularly bridged
with benzothiazole nitrogen H17···N3 = 2.13 Å, N17···N3 = 2.697(3) Å, N17-H17···N3 = 123°,
forcing the guanidine group to be in the same plane of the benzothiazole ring N17-C11-N10-C2 =
−1.7(3)° and N12-C11-N10-C2 = −179.62(17°). In addition, two phenyl hydrogen atoms make
intermolecular CH··· contacts: H19 with guanidine carbon atom H19···C11 = 2.792 Å, C19···C11 =
3.684(3) Å, C19-H19···C11 = 160.9°; symmetry code: 1−x, −y, 1−z, and H20 with the  electrons of
the benzothiazole aromatic ring H20··· = 3.130 Å, C20··· = 3.898(3) Å, C20-H20··· = 141.2°,
symmetry code: 1−x, −1/2+y, 1/2−z.
Figure 3. Molecular structure of guanidine 10f (left) and intermolecular interactions
(right). Selected bond lengths (Å) and angles (°): S(1)-C(2) = 1.774(2), N(3)-C(2) =
1.310(3), N(10)-C(2) = 1.354(3), N(10)-C(11) = 1.332(3), N(12)-C(11) = 1.343(3),
N(17-C(11) = 1.360 (3), C(2)-N(10)-C(11) = 121.06(17), S(1)-C(2)-N(3) = 114.34(15),
S(1)-C(2)-N(10) = 114.72(14), N(3)-C(2)-N(10) = 130.94(18), S(1)-C(8)-C(9) = 109.07(15),
N(3)-C(9)-C(8) = 115.67(18), N(10)-C(11)-N(12) = 116.97(17), C(8)-S(1)-C(2)-N(3) =
−0.82(16), C(8)-S(1)-C(2)-N(10) = 179.46(15), S1-C2-N10-C11 = −172.69°(15),
C(11)-N(10)-C(2)-N(3) = 7.7(3), N(12)-C(11)-N(10)-C(2) = −179.62(17), N(17)-C(11)-
N(10)-C(2) = −1.7(3), N(10)-C(11)-N(12)-C(13) = −4.0(3), N(10)-C(11)-N(12)-C(16) =
155.66(19), N(17)-C(11)-N(12)-C(13) = 177.99(19), N(17)-C(11)-N(12)-C(16) = −22.4(3).

Molecules 2012, 17
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Figure 4. Molecular structure of guanidine 10i (left) and intermolecular interactions
(right). Selected bond lengths (Å) and angles (°): S(1)-C(2) = 1.779(7), N(3)-C(2) =
1.310(8), N(10)-C(2) = 1.329(9), N(10)-C(11) = 1.332(8), N(12)-C(11) = 1.340(8),
N(17)-C(11) = 1.330(7), C(2)-N(10)-C(11) = 122.0(5), S(1)-C(2)-N(3) = 113.4(5),
S(1)-C(2)-N(10) = 117.3(5), N(3)-C(2)-N(10) = 129.1(6), S(1)-C(8)-C(9) = 109.9(5),
N(3)-C(9)-C(8) = 114.8(5), N(10)-C(11)-N(12) = 123.5(5), C(8)-S(1)-C(2)-N(3) = −1.0(5),
C(8)-S(1)-C(2)-N(10) = −176.8(5), S1-C2-N10-C11 = −149.3°(5), C(11)-N(10)-C(2)-N(3)
= 35.8(10), N(12)-C(11)-N(10)-C(2) = 39.2(9), N(17)-C(11)-N(10)-C(2) = −144.6(6),
N(10)-C(11)-N(12)-C(13) = 13.2(9), N(10)-C(11)-N(12)-C(16) = 177.3(6), N(17)-C(11)-
N(12)-C(13) = −163.0(6), N(17)-C(11)-N(12)-C(16) = 1.0(9).
Moreover, in the case of guanidine 10i, derived from two alkylamines, the conformation is not
fixed by intramolecular hydrogen bonding as in 10f, the methylamine N-H proton is intermolecularly
hydrogen bonded with benzothiazole nitrogen of a second molecule and so on to get an helix-like
polymer H17···N23 = 2.16Å, N17···N23 = 2.973(6), N17-H17···N23 =158°; symmetry code: x, y ,z
and H37···O3 = 2.19 Å, N37···O3 = 2.997(7) Å, N37-H37···O3 =157°; symmetry code: x, 1−y, z, this
forces the plane of the guanidine system approximately 35° out of the benzothiazole mean plane
N17-C11-N10-C2 = −144.6(6)°, N12-C11-N10-C2 = 39.2 (9)° in agreement with the steric demand
of the pyrrolidine moiety.
The proton NMR chemical shift of the NH protons of compounds 10f and 10i are in 11.5 and
8.9 ppm respectively. These results show that aniline N-H hydrogen atom of guanidine 10f is involved
in hydrogen bonding in solution whereas the NH of 10i is not. This result is explained because of, in
the case of compound 10f, the electron pairs of the aniline nitrogen atom are conjugated with the
aromatic ring making the NH more acid and thus able for hydrogen bonding. The same effect is
1
observed in the H-NMR spectra of the series of non-symmetric guanidines based on aniline
derivatives. The NH protons are in 11.2 for 10e, 11.6 for 10f and 12.4 for 10g. This intramolecular
interaction, make the benzothiazole ring and the guanidine system to be in the same plane, increasing
the electronic protection on C2 atom and, shifting the corresponding 13C-NMR signals by
approximately 3 ppm to lower frequencies, in comparison with guanidines without this group, Table 2.

Molecules 2012, 17
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3. Experimental
3.1. General Procedures
Melting points were measured on an Electrothermal IA apparatus and are uncorrected. IR spectra
were recorded in a film on ZnSe using a Perkin-Elmer 16F PC IR spectrophotometer. 1H and 13C-NMR
spectra were recorded on a Varian Mercury 300 MHz (1H, 300.08; 13C, 75.46 MHz). The spectra were
measured with tetramethylsilane as internal reference following standard techniques. Physicochemical
data is listed in Table 3. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited in the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 10f (820770), 10i (820769), and 9a (820768). A summary of collection
and refinement X-ray data are listed in Table 4. For this compound, H atoms were treated as riding
atoms, with C–H distances in the range of 0.93–0.96 Å and N-H distances of 0.82 Å. X-ray diffraction
cell refinement and data collection: BRUKER SMART APEX Diffractometer and SAINT [57],
programs used to solve structures: SHELXS-97 [58], software used to prepare material for publication:
PLATON [59] and WinGX [60]. 2-Aminobenzothiazole 4 was a commercial product. Dimethyl
benzodthiazol-2-ylcarbonodithioimidate 5 was prepared according to a literature procedure [7].
Table 3. Complementary data of the starting materials 4, 5, 9a and guanidines10b–j.
Elemental analysis
Yield
(%)
Physical
M.p.
(°C)

m/z
(%M+)
Found (calculated)
Comp.
appearance
(cm−1)
C
H
N
4
5
SM
82
White solid
126–129
72–73
Yellow powder
509, 1464
254(20)
47.05
3.95
11.13
(47.24) (3.94) (11.02)
54.02 3.03 23.73
(54.85) (2.85) (24.00)
52.14 4.88 27.20
(52.42) (4.85) (27.18)
58.13 5.71 22.40
(58.53) (5.69) (22.76)
57.42 4.57 19.05
(62.68) (4.48) (20.89)
63.14 4.98 19.95
(63.83) (4.96) (19.86)
66.99 5.70 17.72
(67.08) (5.59) (17.39)
68.19 4.72 16.17
(69.76) (4.65) (16.28)
54.80 5.49 24.24
(54.54) (5.45) (25.45)
9a
62
88
92
76
89
90
60
90
92
89
Colorless crystals 198–199 2186, 1600, 1580 175(100)
10b
10c
10d
10e
10f
10g
10h
10i
White powder
White powder
White powder
White powder
158–160 3406, 3260, 1624 206(100)
242–244
148–150
145–147
3395, 3161,
1609, 1547
3436, 3198,
1613, 1568
3418, 3200,
1597, 1560
3395, 3161,
1609, 1547
246(100)
Colorless crystals 184–186
White powder
127–129 3400, 1613, 1580
1602, 1574
344(19)
Brownish liquid
220(100)
Colorless crystals 136–137
Brownish liquid
3210, 3080,
1588, 1524
59.63
(60.0)
6.24
21.71
(6.15) (21.54)
10j
300(100) 63.2512 5.9812 19.12
(64.00) (6.66) (18.66)

Molecules 2012, 17
10187
Table 4. X-ray crystal data of compounds 10g, 10i and 9a.
Compound
10f
10i
9a
Unit cell information
Cell axes Åa
11.3477[13]
9.0463[11]
16.5004[19]
90.0000
101.858[2]
90.0000
Monoclinic
P 2l/c
14.3400[20]
7.8188[12]
24.1730[40]
90.000[0]
101.858[2]
90.000[0]
Orthorhombic
P na2l
5.6230[10]
8.2300[9]
17.2290[10]
90.000[0]
90.000[0]
90.000[0]
Monoclinic
P 2l/c
b
c
Cell angles deg


Crystal system
Space group
Molecular Formula
Density g cm−1
Formula weight
No. Form. Units Z
C18H18N4S
1.29
C13H16N4S
1.28
C8H5N3S
1.46
322.4
520.7
175.2
4
4
4
Reflection data
No. Meas.
No. Uniq.
No. Obs.
15334
22566
4245
3049
3406
1544
1278
2920
2630
Current refinement
No. Reflen.
No. Param.
2920
208
4245
325
1544
110
Delta-rhoeÅ−3max, min 0.242, −0.280 0.922, −0.272 0.274, −0.283
R_all, R_obs
0.054, 0.049
0.125, 0.121
0.102, 0.073
0.189, 0.166
0.054, 0.049
0.127, 0.116
wR2_all, wR2_aobs
3.2. General Procedure to Get Isothiourea Intermediates 8
In a 100 mL flask, dimethyl benzodthiazol-2-ylcarbonodithioimidate 5 (1.0 g, 3.94 mmol) was
dissolved in ethanol (10 mL), three molar equivalents of ammonia, or one molar equivalent of the
respective aliphatic or aromatic amine were added and the mixture was stirred for 72 h, in the case of
ammonia, 48 h in the case of alkylamine or pyrrolidine and 24 h in refluxing in the case of aniline to
get the corresponding isothiourea compounds.
3.3. General Procedure to Obtain Guanidines 10
In a 100 mL flask, isothiourea compound 5 (1.0 g, 3.94 mmol) was dissolved in ethanol (10 mL)
with one molar equivalent of the corresponding amine and refluxed for 16 h to get guanidines
10b–e,g–j or from carboimidate 5 with 2 molar equivalents of the amine in refluxing ethanol for 16 h,
in the case of alkylamines, or refluxing DMF, in the case of aniline, to get the corresponding guanidine
compounds 10h,j. The solvent was eliminated by evaporation; the resulting solid was washed with
cold ethanol, ketone or chloroform, then dissolved in ethanol and after precipitation or crystallization,
filtered and air dried to give a white solid.

Molecules 2012, 17
10188
4. Conclusions
We have demonstrated the preparation of symmetric and non-symmetric guanidines from the
reaction of dimethyl benzodthiazol-2-ylcarbonodithioimidate (5) and primary or secondary amines in
refluxing ethanol, through the displacement of two molecules of HSMe. The reaction proceeds
through isothiourea intermediates which, in strongly basic media, are transformed in
(Z)-2-cyanamidabenzothiazoles. Alkylamines are nucleophilic enough to easily perform both
substitutions leading to guanidines, whereas the second substitution with aniline requires harsh
conditions. Intramolecular hydrogen bonding between the NH of the aniline group and benzothiazole
nitrogen in S-methylisothiourea 8d, leads to a cis-disposition between them and thus controlling the
stereochemistry of the second substitution. The NH of alkylamines is not acidic enough to form
intramolecular hydrogen bonding and intermolecular interactions are found instead. In any case the
preferred rotamer observed in the solid state is trans to the sulfur atom of benzothiazole ring.
Acknowledgments
A. Cruz thanks CONACYT Grant 52351 and Secretaría de Investigación y Posgrado del Instituto
Politécnico Nacional (SIP-IPN), Grant 20070101 for financial support.
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Sample Availability: Samples of the compounds 10f and 10i are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
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