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Investigations on the Amidine System in Amidinobenzisothiazole Derivatives.

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217
Amidinobenzisothiazoles
Investigations on the Amidine System in Amidinobenzisothiazole
Derivatives
Alessia Bacchi, Mauro Carcelli, and Giancarlo Pelizzi*
Dipartimento di Chimica Generale e Inorganica, Chimica Analitica, Chimica Fisica, Universitl di Parma, Viale delle Scienze, 1-43100 Parma, Italy
Paola Vicini
Dipartimento Farmaceutico, Universitl di Parma, Vide delle Scienze, 1-43100 P m a , Italy
Received May 25, 1994; revised form received July 26, 1994
The aminolimino equilibrium is studied in free bases and hydrochloride
salts of amidinobenzisothiazole derivatives by IR and ‘H-NMR spectroscopy. The X-ray crystallographic analysis of two of these compounds
shows that the free base exists as amino form whereas the hydrochloride as
imino form.
Amidine derivatives show a wide spectrum of pharmacological activity’).
Our recent investigations on benzisothiazoles of pharmaceutical interest
were aimed at synthetizing new 3-amidinobenzisothiazoleswhich, as
shown in a preliminary pharmacological study, possess interesting analgesic and antiphlogistic activity2). In a continuation of these studies, and in
view of the observation that there has been considerable interest in the
study of the tautomeric behaviour of N-acyl and N-aryl amidines by many
different experimental and theoretical methods3),we decided to study the
tautomeric phenomenon induced by the amidine group of 3-amidinobenzisothiazoles.
Untersuchungen des Amidin-Systems in AmidinobenzisothiazoI-Derivaten
Das Amin/Imin-Gleichgewicht der Titelverbindungen als freie Basen und
als Hydrochloride wurde durch IR- und ‘H-NMR-Spektroskopie untersucht. Die Rontgenstrukturanalyse von zwei Derivaten zeigt, dab die freien Basen als Amine, die Hydrochloride als Imine vorliegen.
The protonation of the heterocycle N-atom is less probable, as it implies resonance forms in which aromaticity is
lost:
(VIII)
m\N-r
. NH
R
H
(111)
Scheme 1
Our interest was focused on the amino-imino equilibrium
because it is probably involved in the binding process of
bioactive molecules as 3-amidinobenzisothiazoles.
The amino-imino equilibrium concerns the free bases and
the protonated forms. In the hydrochlorides protonation of
the amidino functional group generally occurs on the
imino-N because of delocalization of the positive charge:
*
Scheme 3
In order to establish unequivocally the overall structural
assignment of these compounds, as well as to explore a little further the factors which affect the geometry of the amidine fragment, the following compounds and the respective
hydrochlorides have been studied.
Within this context, the X-ray crystal structure of 2a and
2a * HCI was determined and our earlier IR- and ‘H-NMR
data2)were completed.
This work was supported by grants from Minister0 dell’Universith e
della Ricerca Scientifica e Tecnologica, MURST. Thanks are due to Mr. E.
Barlesi for technical assistance.
Arch. Pharm. (Weinheim) 328.21 7-221(1995)
0 VCH Verlagsgesellschaft mbH, D-6945 1 Weinheim, 1995
0365-6233/95/0303-0217 $5.00
+ .25/0
218
Pelizzi and coworkers
Tab 2: Atomic coordinates (x 10“) and equivalent isotropic displacement
parameters
x lo4) (one third trace of the diagonalized matrix), with
e.s.d.’s in parentheses, for compound 2a
(AZ
1
x/a
2
R
H
CH3
H
CH3
la
lb
2a
2b
Scheme 4
Experimental Part
All compounds were obtained following described procedures’).
Preliminary analysis of the crystals and the subsequent data collection
were performed on a Siemens AED single-crystal diffractometer using Nifiltered Cu Ka radiation (h = 1.54178 A). In both cases automatic peak
search and indexing procedures in conjunction with a cell reduction program yielded a monoclinic cell and the observed systematic absences identified the correct space group as P2,/a. The crystallographic data for both
compounds are given in Tab. 1 together with some details of data collecTab. 1: Experimental data for the crystallographic analyses
Compound
Formula
M
2a. HCI
2a
C14H1 IN3S
253.32
C14H14cw3os
307.80
I6.457(5)
Y/b
2/c
ueq
84.1(9)
570(4)
4053.5 4 )
-3231
3456 (1
-2907
555 ( 3 )
506(12)
2997(1
-861
2269(3)
451 (11)
2463(1
-4124
1053(3)
484 ( 1 3 )
4324(1
-1466
1353(3)
459(13)
4837 ( 2
-84 9
1659( 4 )
564 (16)
4940(2
659(13
2734(5
637 ( 1 8 )
4544 ( 2
1573( 1 3
3508(4
607 ( 1 7 )
4042(2
968(11
3215(4
510 ( 1 5 )
3927 (1
-603(10
2130(3
427(13)
3436(1
-1543(11
1631(3
434(13)
2554 ( 1
-2106(10
1979(3
392(12)
2102 ( 1)
-1132(10)
2712(3)
405(13)
2178(1)
474(11)
3797(4)
480(14)
1766(1)
1371 ( 1 3 )
4501(4)
543 (15)
1272(2)
7 2 7 (12 )
4110 ( 4 )
531 ( 1 6 )
1192 ( 2 )
-828( 12 )
3034(4)
559(16)
1603(1)
-1758( 1 2 )
2339 ( 4 )
504(14)
A
26.090(5)
b, 8,
c, A
4.120( 1)
7.554(2)
11.126(2)
I1.777(3)
2737 (15)
-4915(105)
608(34)
623( 133)
0,
2183( 1 4 )
-5158 ( 9 5 )
1041(31)
439(118)
a,
90.50( I )
101.14(2)
v, A3
1195.9(4)
1436.5(7)
Z
D, , gcm-3
4
1.407
4
1.423
F(000)
1-1 (Cu Ka), cm-1
528
22.59
640
4.10
No. of measured reflections
2707
3063
No. of unique reflections
Criterion for observed refl.
2257
2708
Fo>3a(Fo)
Fo>WFO)
1317.8( 4 )
2429.1(11)
No. of ref. used in refinement 1334
2426
1‘I 1 4 ( 1)
1816(4)
10714 ( 2 )
455 ( 8 )
No. of refined parameters
207
238
1306(1)
1231(3)
12498(2)
405(7)
R
0.0468
0.0809
O
Features common to the two analyses are: space group P2,/a, Cu K a radiation, 9-29 scan technique, 9 range 3-70’ (* h + k + l).
Tab. 3: Atomic coordinates (x lo4) and equivalent isotropic displacement
parameters (A’ x lo4) (one third trace of the diagonalized matrix), with
e.s.d.’s in parentheses, for compound 2 a . HCI
~~
x/a
2 /c
9352.0( 6 )
ueq
460(3)
2608(2)
58(4)
12545(2)
482 ( 8 )
315(2)
2574 ( 3 )
9587(2)
387 ( 8 )
3015(4)
8822 ( 3 )
470 ( 9 )
-1140(2)
2977(5)
9240(3)
527 ( 1 0
-1159 ( 2 )
2496(4)
10378(3)
507 ( 1 0
- 4 4 1( 2 )
2069(4)
11135(3)
441( 9 )
305(2)
2114 ( 4 )
10736 ( 2 )
374 ( 8 )
1133(2)
1712(4)
11324(2)
382(8)
2001(2)
453(4)
13060( 2 )
397(8)
2052(2)
87(4)
14301(2)
410(8)
1349(2)
-4 1 6 ( 4 )
14722 ( 3 )
502(9)
-4 1 8 ( 2 )
tion and structure refinement. The unit-cell dimensions were determined
on the basis of a least-squares analysis of the 9 values of 30 reflections
chosen from different regions of reciprocal space. No loss of intensity of
standard reflections was detected during data collection. Intensity data
were processed with the peak profile analysis procedure and corrected for
Lorentz-, polarization-, and absorption-effects. Both structures were solved
by direct methods and refined by full-matrix least-squares procedures
based on F for 2a and F2 for 2a . HCI. The X-ray analysis showed the
presence of a water molecule of crystallization in 2a . HCI. Thermal
parameters were refined anisotropically for all non-Hi-atoms and isotropically for H-atoms, all of which were located in inner-data difference Fourier maps. The final difference Fourier synthesis showed no peak with elec-
Y/b
Arch. Pharm. (Weinheim) 328,217-221 (1995)
219
Amidinobenzisothiazoles
X-ray Structures
Table 3: Continued.
1402(2)
-649(5)
15892(3)
578 (11)
2152 (2)
-388(5)
16655(3)
596(11)
2846 (2)
66(4)
16239(3)
545(10)
2807(2)
296(4)
15062(2)
458(9)
4372.9(4)
504(3)
-1541.2 (11) 13425.9 (6)
338(2)
2947(4)
13840(2)
557 (8)
446 (27)
2792(56)
14518 (40)
608( 112)
103 (27)
3823(58)
13616(34)
539 (108)
989( 20)
1623(40)
12952(26)
371(75)
2591 (26)
366(56)
11859(40)
633 (109)
2992 (24)
-499(51)
12871(33)
490(91)
The molecular structures of compounds 2a and 2a . HCI
are illustrated in Figs. 1 and 2 along with the numbering
schemes, whereas Tab. 4 reports bond distances and angles
for both compounds, so enabling a detailed comparison
between the two structures. In both 2a and 2a . HCI the
molecule, as a whole, has a non-planar configuration, in
which the two individually planar portions, i.e. the benzisothiazole (atoms of which are coplanar within 0.02 A in 2a
and 0.03 A in 2a HCI) and the phenyl rings are twisted
relative to the amidine moiety by 13.0(1) and 12.7(1)O in
2a, and 16.6(1) and 36.7( 1)” in 2a * HCI.
1
Tab. 4: Selected bond distances (A) and angles
theses for compounds 2a and 2 a . HCI
2a
tron density greater than 0.25 for 2a and 0.59 eA-’ for 2a . HCI. Complex
neutral-atom scattering factors and anomalous dispersion corrections were
taken from ref!). Calculations were carried out on the GOULD POWERNODE 6040 and ENCORE91 computers of the “Centro di Studio per la
Strutturistica Diffrattometrica del CNR (Parma)” using the programs
SIR925’, SHELX76”. SHELXL92”, PARST’”, ORTEP9), and PLUTO”’.
Final atomic coordinates are listed in Tab. 2 for 2a and in Tab. 3 for 2a .
HCI.
Infrared spectra (4000-400 cm-’) (KBr): Nicolet 5PC FT-IR spectrometer.- ‘H-NMR spectra: Bruker AC 100 instrument at 298 K: chemical
shifts in ppm referred to TMS.
Results and Discussion
N ( l ) - S -C(l)
N(l) -C(7)
C(7) N(2) -C(8)
S
C(l) -C(6)
s -C(l)-C(2)
C(2) C(l) -C(6)
C(1) C(2) -C(3)
C(2) C(3) -C(4)
C(3) C(4) -C(5)
C(4) C(5) -C(6)
C(l) C(6) 435)
C(5) C(6) -0
C(l) C(6) -C(7)
“2)
C(7) -C(6)
N(11 C(7) -W)
N(11 C(7) -N(2)
N(2) C(8) -N(3)
N(3) C(8) -C(9)
N(2) C(8) -C(9)
C(8) C(9)- C(14)
C(8) C(9) -C(10)
C(l0) - C(9) -C(14)
S
,
IV131
Fig. 1 ORTEP diagram for compound 2a. Thermal ellipsoids are drawn at
the 50% probability level.
--
--
--
-
Fig. 2 ORTEP diagram of compound 2a . HCI. Thermal ellipsoids are
drawn at the S O 6 probability level.
Arch. Pharm. (Weinheim) 328,217-221 (1995)
(”)
with e.s.d.’s in paren-
2a. HCI
1.679(3)
1.723(4)
1.324(5)
1.380(4)
1.304(5)
1.343(5)
1.401(5)
1.401 (5)
1.372(7)
1.402(7)
1.371 (6)
1.400(6)
1.447(5)
1.495(5)
1.675(3)
1.729(3)
1.304(4)
1.403(3)
1.342(3)
1.299(4)
1.399(4)
1.401(4)
1.372(5)
1.395(5)
1.374(4)
1.396(4)
1.438(4)
1.474(4)
94.4(2)
111.2(3)
122.0(3)
108.9(3)
130.2(3)
120.9(3)
118.3(4)
121.1(5)
120.9(4)
119.0(4)
119.8(4)
129.6(3)
110.7(3)
119.0(3)
114.7(3)
126.3(3)
125.7(4)
116.7(3)
117.5(3)
122.0(3)
119.6(3)
118.4(3)
94.1(1)
110.7(2)
126.2(2)
109.2(2)
130.0(2)
120.8(3)
117.6(3)
122.1(3)
120.6(3)
118.5(3)
120.5(3)
130.2(3)
109.3(2)
121S(2)
116.7(3)
121.9(2)
121.9(3)
121.2(3)
116.8(2)
119.3(2)
120.7(3)
119.9(3)
As is evident from the data quoted in Tab. 4, significant
differences between the two molecular geometries are
found only in the amidine fragment, the agreement being
very good in the rest of the molecule. The N(2)C(8)
C(9)N(3) skeleton is not strictly planar in 2a, where C(8) is
0.014 A out of the plane of the other three atoms, while an
220
Pelizzi and coworkers
almost perfectly planar shape is assumed in 2a . HCI. These
results are well supported by X-ray diffraction studies
reported in ref. 3: the arnidine derivatives exhibit a greater
mean value deviation from planarity with respect to the
amidinium salts derivatives. Also in accordance with lit.
reports are the bond distances involving the N-atoms in 2a,
where as a consequence of conjugation the formal C(8)N(2) double bond is slightly elongated (1.304(5) A) and the
formal C(8)-N(3) single bond is considerably shortened
(1.343(5) A). It is, therefore, quite apparent that compound
2a exists in the tautomeric form I. Unlike 2a, an unexpectedly marked difference between the two C-N bonds occurs
in 2a HCI (C(8)-N(2) 1.342(3), C(8)-N(3) 1.299(4) A)
with the double bond mainly localized between C(8) and
N(3), so indicating that the salt adopts structure V. This
observation contrasts with equal distances so far reported
for this group in amidinium salts derivatives as a direct consequence of the almost identical state of the two N-atoms3).
Presumably, an explanation of our findings can be found in
the different nature of the substituents at the two N-atoms
as well as in differences of their environment (see below).
Bond orders calculations were carried out according to the
Donohue's formula x = Ar/(O.627-2Ar) as given in ref. 11,
where x is the measure of double bond character in the
observed C-N bond length and Ar is the standard single CN bond length (1.474 A) minus the observed C-N bond
length, yielding the following values for our compounds:
C(8)-N(2) x = 0.59 in 2a and 0.47 in 2a . HCI; C(8)-N(3) x
= 0.47 in 2a and 0.61 in 2a . HCI. As expected, in 2a . HCI
the H-atom of HC1 was transferred to the imino N(2) atom.
The effect of the protonation is well reflected in the widening of the angle at N(2) (1 26.2(2)") and in the narrowing of
the adjacent angles N( l)-C(7)-N(2) (121.9(2)") and N(2)C(8)-N(3) (121.9(3)"). In contrast, in 2a the angle at N(2) is
smaller by 4.2" and, concurrently, both the other two angles
increase to about 4". It can be added that in both compounds the angle at C(8) is larger than 120" and this seems
to be a rule in cis-amidine systems, the value for the transamidine derivatives being about 1 1
In each compound
the molecule has an intramolecular H-bond between the
amino N(3) and the adjacent heterocycle N( 1). The geometrical features of these bonds are:
in 2a
N(3)...N( 1) 2.702(5) A;
N(3)-H( 1N3)-N( 1) 125"
in 2a * HCI N(3)-N(l) 2.712(4) A;
N(3)-H( lN3)*-N(1) 131"
Bonding parameters in the benzisothiazole system of the
two compounds compare rather closely (with the only,
small exception of the N(l)-C(7) bond, which is 1.324(5) 8,
in 2a and 1.304(4) 8, in 2a . HCI) and in turn are in very
good agreement with those observed for similar systems in
1,2-benzisothiazole derivative^'^,'^,'^) . Concerning crystal
packing, structure 2a consists of discrete molecular units,
the closest distance of approach involving non-H-atoms
occurs between the N(3) atoms of symmetry-related molecules (N(3)-..N(3) (1/2-x, y-1/2, -z) 3.128(5) A). As regards
2a . HCI, of particular relevance is the role played by the
H-bond in stabilizing the crystal lattice. The H-bonds which
-
are between the organic molecule, the free chlorine ion, and
the water molecule, generate chains where H20 functions as
donor to CI and as acceptor to N(2) (O...Cl (x-1/2, 1/2-y, z)
3.136(3) A, 0-H(2).*.C1 166"; N(2)...0 2.773(4) A, N(2)H(N2)-0 168") and C1 is further hydrogen-bonded to N(3)
(N(3)..C13.132(3) A; N(3)-H(2N3)...Cl 160").
Spectroscopic Characterization
In all the IR-spectra there is a complex pattern between
680 and 800 cm-' due to the out of plane bending of the
ring hydrogens and some bands near 3000 cm-' due to the
stretching of the C-H bonds. In the spectra of the bases
there are only two bands above 3100 cm-I, which can be
attributed to the asymmetric and symmetric -NH2 group
stretching vibrations (Tab. 5). This fact, together with the
Tab. 5: Selected IR data ( c m ~ 'for
) the bases and their hydrochlorides
Amidine I
Compounds
l b
3 2 6 5 ( m s ) , 3 100(m,br)
3 305 (m), 3 1OO(br ,sh)
1633(ms)
163 l ( m )
2a
3440(ms),3287(m)
16 15( s)
2b
3450( s), 3267 (m)
16 12( vs)
l a HCI
3205(m),2818(m,br)
3205(~),2943(s,br)
1678(s)
1680(vs)
3230(m),2956( m,hr)
3 185(w),2856(m,br)
1670(s)
1665(vs)
la
l b . HCI
2a. HCI
2 b . HCI
X-ray diffraction analysis of 2a and lit. findings16.") induce
us to conclude that in the solid state all the bases exist as
amino tautomer I. Amidine I band, which arises from vas,
(N=C-N), appears as a strong band near 1633 in l a and
1615 in 2a. The latter lower value agrees well with the larger electronic delocalization induced by the aromatic ring
in the C-phenyl-substituted amidine18). In the IR-spectra of
the hydrochlorides, near 3200 cm-I, there is a strong, well
resolved band, attributable to the NH stretching mode; at
upper values there is another broad band, probably due to
the solvating water, while the broad band between 3000 and
2700 cm-' can be assigned to the stretching modes of the
=+NH2 group. In comparison with the IR-spectra of the
bases, there is a considerable upper shift (40-60 cm-I) of the
amidine I band, as observed in similar compound^'^). These
features and the results of the X-ray diffraction analysis of
2a . HCI move us to conclude that in the solid state all our
hydrochlorides are stable as V.
In solution the situation is more complex and, in some
way, unexpected (Tab. 6): the 'H-NMR spectra of the bases
show two broad, D 2 0 exchangeable peaks with the same
area above 9 and 5 ppm and this last one is strongly affected by change of solvent (in [D6]DMS0 it is found above 8
ppm2)). This pattern could derive from tautomer I1 or 111,
but not from I which is the stable one in the solid state. On
Arch. Pharm. (Weinheim)328,217-221 (I9951
22 1
Amidinobenzisothiazoles
Tab. 6: 'H-NMR data (6, ppm) for the bases (CDCI,) and their hydrochlorides ([D,]DMSO)
la
9.73 (hr.s.1 H NH); 8.25-7.39 (m.4 H arom.); 5.66 (hr,s,l H NH); 2.26
l b
(s,3 H CH3)
9.77 (br,s,l H NH); 8.01-7.24 (m.3 H arom.); 5.67 (hr,s,l H NH);
2.49 ( ~ , 3H CH3); 2.26 ( ~ , 3H CH3)
2a
10.04 (hr,s,l H NH); 8.47-7.35 (m,9 H arom.); 6.20 (hr.s.1 H NH)
2b
10.07 (hr.s,l H NH); 8.32-7.32 (m,8 H arom.); 6.11 (br,s,l H NH);
2.50 (s.3 H CH,)
l a . HCI
13.57 (br,s,lH NH); 11.42 (br, s, 1 H NH ); 11.14 (br,s,l H NH); 9.507.66 (m, 4 H arom.); 3.10 (s,3 H CH3)
l b . HCI
13.05 (hr,s,l H NH); 11.02 (br,s,l H NH); 10.65 (hr,s,l H NH); 8.937.48 (m,H arom.); 2.65 (s.3 H CH3); 2.47 (s,3 H CH,)
2a. HCI
12.87 (br,s,l H NH); 11.09 ( hr,s,l H NH); 10.89 (br,s,l H NH); 8.927.54 (m.9 H arom.)
2b. HCI
12.90 (br,s,l H NH); 11.17 (br,s,l H NH); 10.86 (br,s,l H NH); 8.527.53 (m, 8 H arom.); 2.50 (s, 3 H CH3)
the contrary, the 'H-NMR spectra of the salts agree well
with IR-data and X-ray diffraction analysis of 2a * HCI, if
we think that the signal of the imino-H is near 13 ppm and
the two amino ones, which are not equivalent after protonation, as C-N(amino) has a double bond character and the
rotation is so hindered, give the two slightly broadened signals near 11 ppm.
6
7
8
9
10
I1
Supplementary material has been deposited with the Cambridge Crystallographic Data Centre.
12
13
References
1
5
J. V. Greenhill, P. Lue in Progress in Medicinal Chemistry, Vol. 30
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14
IS
16
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investigation, amidine, system, derivatives, amidinobenzisothiazole
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