Intramolecular nonbonded S···O interaction recognized in (acylimino)thiadiazoline derivatives as angiotensin II receptor antagonists and related compounds

Article abstract of DOI:10.1021/ja973109o

The intramolecular nonbonded 1,5-type S···O interactions are recognized in the crystalline structures of the (acylimino)thiadiazoline derivatives (1-3) as angiotensin II receptor antagonists. The relative stability of the nonbonded 1,5-type S···O interaction was investigated using the X-ray crystallographic analyses anti the ab initio MO calculations (HF/3-21G*, 6-31G*, and 6-311 +G**) of the simplified model compounds (6, 7, and 9). The concept of mimic-fused bicyclic heterocycles consisting of fairly stable nonbonded S···O interaction seems to be an efficient approach toward the design and development of various drugs.

Full text of DOI:10.1021/ja973109o

3104
J. Am. Chem. Soc. 1998, 120, 3104-3110
Intramolecular Nonbonded S‚‚‚O Interaction Recognized in
(Acylimino)thiadiazoline Derivatives as Angiotensin II Receptor
Antagonists and Related Compounds
Yoshimitsu Nagao,* Terukage Hirata,† Satoru Goto, Shigeki Sano, Akikazu Kakehi,‡
Kinji Iizuka,§ and Motoo Shiro|
Contribution from the Faculty of Pharmaceutical Sciences, The UniVersity of Tokushima,
Sho-machi, Tokushima 770, Japan, Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd.,
1624 Shimokotachi, Koda-cho, Takata-gun, Hiroshima 739-11, Japan, Faculty of Engineering,
The Shinshu UniVersity, 500 Wakazato, Nagano 380, Japan, Kissei Pharmaceutical Co., Ltd.,
4365-1 Kashiwabara, Hotaka, Minamiazumi-gun, Nagano 399-83, Japan, and Rigaku Corporation,
3-9-12 Matubara-cho, Akishima, Tokyo 196, Japan
ReceiVed September 3, 1997
Abstract: The intramolecular nonbonded 1,5-type S‚‚‚O interactions are recognized in the crystalline structures
of the (acylimino)thiadiazoline derivatives (1-3) as angiotensin II receptor antagonists. The relative stability
of the nonbonded 1,5-type S‚‚‚O interaction was investigated using the X-ray crystallographic analyses and
the ab initio MO calculations (HF/3-21G*, 6-31G*, and 6-311+G**) of the simplified model compounds (6,
7, and 9). The concept of mimic-fused bicyclic heterocycles consisting of fairly stable nonbonded S‚‚‚O
interaction seems to be an efficient approach toward the design and development of various drugs.
Introduction
Intramolecular nonbonded interaction between sulfur and
oxygen (or nitrogen) atoms has been observed in a large number
of organosulfur compounds controlling the conformation of
small and large molecules.1 In these molecules, the nonbonded
S‚‚‚O or S‚‚‚N atoms’ distances are significantly shorter than
the sum of the corresponding van der Waals radii (3.32 or 3.35
Å) in the crystalline structure.2 These kinds of interactions also
can be classified into several categories such as 1-3, 1-4, 1-5,
and 1-6 types with the size of the quasi-ring involving S‚‚‚X
(X ) O, N, S, halogens, and other heteroatoms) moieties as
shown in Figure 1.1
In the course of the development of new angiotensin II (AII)
receptor antagonists,3 we recognized a nonbonded 1,5-type S‚‚‚O
close contact in the crystalline structures of three representative
(acylimino)thiadiazoline derivatives (1-3)4 which have potent
AII receptor antagonistic activities. On the basis of their X-ray
crystallographic analyses, the nonbonded atom distances be-
tween the sulfur atom of the thiadiazoline moiety and the oxygen
Figure 1. Equivalent mode to the heterocycles on the basis of S‚‚‚X
nonbonded interaction.
† Wakunaga Pharmaceutical Co., Ltd.
‡ The Shinshu University.
atom of the acyl moiety in the molecules of 1-3 were found to
be 2.610(4), 2.588(3), and 2.542(7) Å, respectively (see dotted
lines in Figure 2).
Recently, Goldstein and his colleagues have studied exten-
sively the intramolecular nonbonded 1,4-type S‚‚‚O interaction
in the thiazole nucleoside analogues (vide infra) which play an
important role on the mechanism of several biological effects
§ Kissei Pharmaceutical Co., Ltd.
| Rigaku Corporation.
(1) (a) Kucsman, A.; Kapovits, I. Organic Sulfur Chemistry: Theoretical
and Experimental AdVances, Bernardi, F., Csizmadia, I. G., Mangini, A.,
Eds.; Elsevier Scientific Publishing Co.: Amsterdam, 1985; p 191-245.
(b) Ohkata, K.; Ohsugi, M.; Yamamoto, K.; Ohsawa, M.; Akiba, K. J. Am.
Chem. Soc. 1996, 118, 6355-6369.
(2) (a) L’abbe, G.; Meervelt, L. V.; Emmers, S.; Dehaen, W.; Toppet,
S. J. Heterocycl. Chem. 1992, 29, 1765-1768. (b) Cohen-Addad, C.;
Lehmann, M. S.; Becker, P.; Pa´rka´nyi, L.; Ka´lma´n, A. J. Chem. Soc., Perkin
Trans. 2 1984, 191-196. (c) Cohen-Addad, C.; Savariault, J.-M.; Lehmann,
M. S. Acta Crystallogr. 1981, B37, 1703-1706. (d) Ka´lma´n, A.; Pa´rka´nyi,
L. Acta Crystallogr. 1980, B36, 2372-2378.
(3) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.;
Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. J. Med. Chem.
1996, 39, 625-656.
(4) (a) Hirata, T.; Nomiyama, J.; Sakae, N.; Nishimura, K.; Yokomoto,
M.; Inoue, S.; Tamura, K.; Okuhira, M.; Amano, H.; Nagao, Y. Bioorg.
Med. Chem. Lett. 1996, 6, 1469-1474. (b) Hirata, T.; Goto, S.; Tamura,
K.; Okuhira, M.; Nagao, Y. Bioorg. Med. Chem. Lett. 1997, 7, 385-388.
(c) Tamura, K.; Okuhira, M.; Amano, H.; Inokuma, K.; Hirata, T.;
Mikoshiba, I.; Hashimoto, K. J. CardioVasc. Pharmacol. 1997, 30, 607-
615.
S0002-7863(97)03109-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/20/1998

S‚‚‚O Interaction in (Acylimino)thiadiazolines
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3105
types S‚‚‚X interactions as shown in Figure 1 seems to be
functionalized as the corresponding 4-, 5-, and 6-membered
heterocycles consisting of both S and X atoms in the molecular
recognition. To see how the (acylimino)thiadiazoline moiety
of 1-3 can be available as a mimic-fused [3.3.0] heterocycle
(Figure 1), we investigated the intramolecular nonbonded 1,5-
type S‚‚‚O interactions of some simplified model compounds
by exploiting their X-ray crystallographic analyses and ab initio
molecular orbital (MO) calculations.
Chemistry
We have reported the syntheses and biological properties of
the three representative (acylimino)thiadiazoline derivatives (1-
3).4 The synthesis of oxadiazoline derivative (4) was carried
out by the modified method in accordance with the preparation
of 3.7
The model compounds 5-ethyl-3-methyl-2-[(trifluoroacetyl)-
imino]-1,3,4-thia(or oxa)diazoline (thia analogue, 7, or oxa
analogue, 9) and 5-propyl-2-(trifluoroacetamido)-1,3,4-thiadia-
zole (6) were selected because of their good-quality crystals
suited for X-ray crystallographic analysis and ease of MO
calculation. Trifluoroacetamide derivatives (5, 6, and 8) were
prepared by trifluoroacetylation of the corresponding 2-amino-
1,3,4-thia(or oxa)diazole derivatives with trifluoroacetic anhy-
dride. Regioselective methylation of 5-ethyl-2-(trifluoroaceta-
mido)-1,3,4-thia(or oxa)diazole (5 or 8) with methyl iodide
proceeded smoothly to afford the (trifluoroacetyl)imino deriva-
tive (7 or 9) (Scheme 1).8
Figure 2. AII receptor antagonists (1-3) having an (acylimino)-
thiadiazoline moiety.
Figure 3. The binding affinities of (acylimino)thiadiazoline derivative
(3) and (acylimino)oxadiazoline derivative (4).
Results and Discussion
1. Crystallographic Studies. Biologically active com-
pounds (1-3) and model compounds (6, 7, and 9) were
recrystallized from suitable solvents to obtain the corresponding
crystals available for X-ray crystallographic analysis. The X-ray
crystallographic data for 1, 3, 6, 7, and 9, except for compound
(2) reported earlier,8 are summarized in Table 1.
The computer-generated drawings of the crystal structures
of three (acylimino)thiadiazoline derivatives (1-3) are shown
in Figure 4. In the represented structures, the part involving
both the thiadiazoline ring and the acyl moiety adopts a plane
conformation (see torsion angles) due to the S‚‚‚O close contact
(1,5-type intramolecular interaction) in each compound. This
planarity was further investigated using the simple model
compounds (7 and 9) as follows.
such as antitumor activity and inhibition against inosine
monophosphate dehydrogenase.5
Similarly, it can be speculated that the intramolecular
nonbonded 1,5-type S‚‚‚O interactions observed in the (acylimi-
no)thiadiazoline derivatives (1-3) may influence not only the
flat conformation of the (acylimino)thiadiazoline moiety of these
compounds but also their antagonistic activities. In fact, the
binding affinity of the oxadiazoline derivative (4: oxa analogue
of 36) to the AII receptor (AT1) was lower than that of the
thiadiazoline derivative (3) as shown in Figure 3.7 The results
caused us to consider a hypothesis that this fairly stable S‚‚‚O
close contact might be one of important factors in causing the
potent AII receptor antagonism of these thiadiazoline derivatives.
The computer-generated drawings of the crystal structures
of (trifluoroacetyl)imino derivatives (7 and 9) are shown in
Figure 5. Selected atom distances, bond angles, and torsion
angles of 7 and 9 are listed in Table 2. Significant close contact
(2.670(4) Å) between sulfur (S1) and oxygen (O1) atoms and
planarity of the S1-C2-N3-C6-O1 moiety (see torsion
angles) were recognized in the molecule of thiadiazoline
derivative (7) like those of the (acylimino)thiadiazoline deriva-
tives (1-3). Surprisingly, similar close contact (2.740(4) Å)
between two oxygen atoms, O1 and O2, and planarity of the
O1-C2-N3-C6-O2 moiety were also recognized in the
oxadiazoline (9) as shown in Figure 5 and Table 2.
It is remarkable that the bond lengths of C2-N3 and N3-
C6 are the same and the bond angles of S1-C2-N3 and N3-
C6-O1 are almost the same in the case of 7 as shown in Table
2. This clearly indicates that the conjugate (quasi) ring system
(S1-C2-N3-C6-O1) due to the fairly stable nonbonded 1,5-
It is apparent that there are several heterocyclic drugs having
potential for intramolecular nonbonded 1,4-, 1,5-, and 1,6-type
S‚‚‚O interactions (vide infra). With this in mind, coupled with
our recent studies on the AII receptor antagonists, we envisage
such kinds of intramolecular nonbonded S‚‚‚X interaction (X
) O, N, S, halogens, and other heteroatoms) providing a
promising gateway for the design and development of new
heterocyclic drugs. Specifically, the mimic heterocyclic moiety
involving these intramolecular nonbonded 1,4-, 1,5-, and 1,6-
(5) (a) Franchetti, P.; Cappellacci, L.; Grifantini, M.; Barzi, A.; Nocentini,
G.; Yang, H.; O’Connor, A.; Jayaram, H. N.; Carrell, C.; Goldstein, B. M.
J. Med. Chem. 1995, 38, 3829-3837. (b) Goldstein, B. M.; Li, H.; Hallows,
W. H.; Langes, D. A.; Franchetti, P.; Cappellacci, L.; Grifantini, M. J. Med.
Chem. 1994, 37, 1684-1688. (c) Li, H.; Hallows, W. H.; Punzi, J. S.;
Marquez, V. E.; Carrell, H. L.; Pankiewicz, K. W.; Watanabe, K. A.;
Goldstein, B. M. Biochemistry 1994, 33, 23-32. (d) Goldstein, B. M.;
Takusagawa, F.; Berman, H. M.; Srivastava, P. C.; Robins, R. K. J. Am.
Chem. Soc. 1983, 105, 7416-7422.
(6) Compound 3 shows the strongest angiotensin II antagonistic activity
in vitro and in vivo among a series of (acylimino)thiadiazoline derivatives.
This compound referred to KRH-594 is now under clinical trial as a
antihypertensive agent in Japan.
(7) Synthesis and detailed biological activity of (acylimino)oxadiazoline
derivative 4 will be reported elsewhere.
(8) Hirata, T.; Shiro, M.; Nagao. Y. Heterocycles 1997, 44, 133-138.

3106 J. Am. Chem. Soc., Vol. 120, No. 13, 1998
Nagao et al.
Scheme 1
Table 1. Summary of X-ray Crystallographic Analyses of Compounds 1, 3, 6, 7, and 9
1
3
6
7
9
formula
C20H19N7OS
405.48
colorless prism
monoclinic
P21/n
C25H21K2N7O3S
577.74
colorless needle
triclinic
C7H8F3N3OS
239.21
colorless prism
triclinic
C7H8F3N3OS
239.21
colorless prism
triclinic
C7H8F3N3O2
223.15
colorless prism
monoclinic
P21/c
formula weight
crystal description
crystal system
space group
lattice constants
a, Å
Ph1
Ph1
Ph1
10.691(5)
11.060(3)
17.399(6)
11.724(3)
16.794(4)
7.372(3)
102.52(3)
106.53(3)
105.86(2)
1268.5(8)
2
10.188(4)
10.884(4)
4.898(1)
91.50(3)
99.60(3)
69.50(3)
501.3(3)
2
5.002(3)
12.049(7)
9.592(7)
111.75(5)
106.47(6)
82.72(6)
514.7(6)
2
6.988(2)
13.996(1)
10.200(1)
b, Å
c, Å
R, deg
â, deg
104.64(3)
94.13(2)
γ, deg
volume, Å3
Z
1990(1)
4
1.353
0.041, 0.059
1.22
0.0325
994.9(3)
4
1.490
0.064, 0.098
1.45
0.0645
density (calcd), g/cm3
residual R, RW
GOF
1.512
0.066, 0.072
1.71
1.585
0.062, 0.091
1.65
1.543
0.044, 0.068
1.33
pa
0.0150
0.0500
0.0455
a See the Experimental Section.
Figure 4. Computer-generated drawings of the compounds (1, 2, and 3) derived from the X-ray coordinates. Dotted lines show the S‚‚‚O close
contacts.
type S‚‚‚O interaction (vide infra) is formed. Here, we
particularly emphasize that the part involving both the thiadia-
zoline ring and the acylimino moiety has not only the plane
conformation but also the novel character which we call the
“mimic-fused bicyclic heterocycle”. Considering that the
antagonistic activity of the thiadiazoline derivative (3) is stronger
than that of the oxadiazoline derivative (4), the formation of
this stable or unstable mimic-fused heterocycle system may be
a considerable factor in causing the activity of 3 or 4.
The flexibility of the (acylimino)thiadiazoline moiety is
restricted due to the double bond of the imine part. Hence, to
further examine this remarkable intramolecular, nonbonded 1,5-

S‚‚‚O Interaction in (Acylimino)thiadiazolines
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3107
Figure 5. Computer-generated drawings of the compounds (7 and 9) derived from the X-ray coordinates. Dotted lines show the S‚‚‚O or O‚‚‚O
close contact.
Table 2. Selected Atom Distances, Bond Angles, and Torsion
Angles of Model Compounds 7 and 9
compounds (7 and 9). The energy gap between 7-CT and
7-CC11 or 7-CT and 7-TT11 in the thiadiazoline derivative (7)
was much larger than that between 9-CT and 9-CC11 or 9-CT
and 9-TT11 in the oxadiazoline derivative (9). It is characteristic
that the energy gap between 7-CT and 7-TT in 7 is quite large
(∆Ε* ) +9.06 kcal/mol) in comparison with that (∆Ε* )
+1.05 kcal/mol) between 9-CT and 9-TT in oxadiazoline
derivative 9. This can be accounted for by the consideration
that the intramolecular nonbonded 1,5-type S‚‚‚O interaction
most likely stabilizes the 7-CT conformer in molecule 7. Thus,
7-CT is regarded as a stable mimic-fused bicyclic heterocycle
rather than a monocyclic one. The computational studies of 7
and 9 led us to encourage the construction of such a system in
this series of derivatives. This consideration is consistent with
the results of X-ray analyses as described above. The existence
of the stable mimic-fused bicyclic heterocycle may be regarded
as one of important reasons why the (acylimino)thiadiazoline
(3) exhibited the higher AII receptor antagonism in comparison
with its oxa analogue (4).
thiadiazoline derivative 7
oxadiazoline derivative 9
Atom Distances (Å)
2.670(4) O1-O2
3.32a
S1-O1
2.740(4)
3.04a
C2-N3
N3-C6
C6-O1
1.327(5) C2-N3
1.328(6) N3-C6
1.225(5) C6-O2
1.294(4)
1.329(4)
1.207(4)
Bond Angles (deg)
S1-C2-N3
C2-N3-C6
N3-C6-O1
C1-S1-C2
129.6(3)
O1-C2-N3
C2-N3-C6
N3-C6-O2
C1-O1-C2
128.3(3)
115.4(4)
129.4(4)
88.3(2)
120.5(2)
131.6(3)
105.1(3)
Torsion Angles (deg)
S1-C2-N3-C6
O1-C6-N3-C2
-1.4(6)
O1-C2-N3-C6
O2-C6-N3-C2
0.1(5)
-7.5(6)
7.2(8)
a Sum of the corresponding van der Waals radii (S and O or O and
O).
type S‚‚‚O interaction between sulfur of the heterocycles and
oxygen of the acyl part, the X-ray crystallographic analysis of
the (acylamino)thiadiazole derivative (6) was investigated as
another simple model compound bearing some steric flexibility.
The computer-generated drawing of the crystal structure of 6
is shown in Figure 6. The S‚‚‚O close contact (2.646(4) Å)
between thiadiazole S1 and O1 of the trifluoroacetamide moiety,
indicating the intramolecular nonbonded 1,5-type S‚‚‚O interac-
tion, was also recognized in the crystal structure of the
(acylamino)thiadiazole derivative (6) as we anticipated. It can
be understandable that the nonbonded S‚‚‚O interaction controls
the conformation of the low molecular weight compound.
2. Computational Studies. The ab initio geometry opti-
mization at the HF/3-21G* level9 was first performed on the
(trifluoroacetyl)imino derivatives (7 and 9) to examine the
relative energy of their three conformers as shown in Scheme
2 using the Gaussian 9210 programs. The geometrical param-
eters were obtained from the structural data of their X-ray
analyses. The results are summarized in Scheme 2 on the basis
of the energy (0 kcal/mol) of 7-CT11 and 9-CT11 at ø ) 180°
(torsion angle of the CdN-C-CF3 moiety).
To characterize further the energy level of this interesting
interaction, another model compound (6) was precisely calcu-
lated. Compound 6 was submitted to the ab initio geometry
optimizations at the HF/3-21G*, 6-31G*,12 and 6-311+G**
levels.13 The results are shown in Figure 7 and Table 3.
In conformers A (torsion angle: 0°) and B (torsion angle:
180°), the difference of the relative energy should be remarkable
at any calculation levels, namely, the torsion angle 180°
conformer is fairly stable in a range of -8.16 to -8.74 kcal/
mol in comparison with the conformer with 0° torsion angle.
The X-ray crystallographic structure of 6 reflects the results of
this calculation, indicating that the intramolecular nonbonded
1,5-type S‚‚‚O interaction can regulate the conformation of the
free rotatory molecule 6. Thus, we realized that the formation
of the stable intramolecular nonbonded 1,5-type S‚‚‚O inter-
action is possible even in a molecule 6 more flexible than 7.
There have been a few reports on the intramolecular,
nonbonded S‚‚‚O interaction exploiting modern computational
methods.14 Csizmadia and his colleagues carried out a quantum
chemical study of the intramolecular 1,5-type S‚‚‚O interaction
by the ab initio SCF-MO method in which they clarified the
relative energy levels of the interaction.15 Employing the ab
initio MO and semiempirical (MNDO) computation, Goldstein
and his colleagues have disclosed the nature and magnitude of
the 1,4-type S‚‚‚O interaction between the thiazole sulfur and
The ab initio computation defined that the conformers (7-
CT and 9-CT)11 observed in their X-ray crystallographic
analysis are most stable among the three conformers of the
(9) Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980,
102, 939-947.
(10) The ab initio calculations were performed using Gaussian 92
programs: Frisch, M. J.; Trucks, G. W.; Head-Gordon, M.; Gill, P. M. W.;
Wong, M. W.; Foresman, J. B.; Johnson, B. G.; Schlegel, H. B.; Robb, M.
A.; Replogle, E. S.; Gomperts, R.; Andres, J. L.; Raghavachari, K.; Binkly,
J. S.; Gonzales, C.; Martin, R. L.; Fox, D. J.; Defrees, D. J.; Baker, J.;
Steward, J. J. P.; Pople, J. A., Gaussian 92; GAUSSIAN, Inc.: Pittsburgh,
1993.
(12) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213-
222.
(13) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys.
1980, 72, 650-654.
(14) (a) Becker, P.; Cohen-Addad, C.; Delly, B.; Hirshfeld, F. L.;
Lehmann, M. S. A Theoretical Study of Short S-O “Non-bonded”
Interaction. In Applied Quantum Chemistry; Smith, V. H., Jr., Schaefer, H.
F., III, Morokuma, K., Eds.; D. Reidel: Boston, 1986; pp 361-373. (b)
Barbieri, G.; Benassi, R.; Taddei, F. J. Mol. Struct. 1989, 184, 269-276.
(15) AÄ ngya´n, J. G.; Poirier, R. A.; Kucsman, AÄ .; Csizmadia, I. G. J.
Am. Chem. Soc. 1987, 109, 2237-2245.
(11) CC, CT, and TT conformers of 7 and 9 mean the cis(heteroring
CdN-)-s-cis(CF3CO-Nd), cis(heteroring CdN-)-s-trans(CF3CO-Nd),
and trans(heteroring CdN-)-s-trans(CF3CO-Nd) arrangements, respec-
tively.

3108 J. Am. Chem. Soc., Vol. 120, No. 13, 1998
Nagao et al.
Figure 6. Computer-generated drawing of the model compound (6) derived from the X-ray coordinates. Dotted line shows the S‚‚‚O close contact.
Scheme 2
Table 3. Ab Initio Calculations of Model Compound 6 at the
Various Calculation Levels
relative energy (kcal/mol)a
ø (deg)
HF/3-21G*
HF/6-31G*
HF/6-311+G**
0
90
180
0.00
0.01
-8.74
0.00
-2.25
-8.16
0.00
-2.75
-8.17
a Each relative energy is the calculation value based on the
corresponding 0° torsion angle conformer (0 kcal/mol).
in the (acylimino)thiadiazoline and (acylamino)thiadiazole
concerned with biological activity.
Conclusion
Figure 7. Ab initio calculation of the model compound (6) at the HF/
3-21G* level.
In conclusion, clear evidence for the intramolecular, non-
bonded 1,5-type S‚‚‚O interactions in the (acylimino)thia-
diazolines (1, 2, 3, and 7) and the (acylamino)thiadiazole (6)
was obtained from their X-ray crystallographic analyses. A
possibility of the similar nonbonded 1,5-type O‚‚‚O interaction
in the (acylimino)oxadiazoline (9) was also suggested on the
basis of its X-ray crystallographic analysis. The satisfactory
relative stability of the conformer having this 1,5-type S‚‚‚O
interaction among possible ones of the simple compounds (6
the furanose oxygen in a thiazole nucleoside, tiazofurin (10).16
To our knowledge, our result described above is the first
example to determine the relative energy of the stable conformer
due to the nonbonded, intramolecular 1,5-type S‚‚‚O interaction
(16) Burling, F. T.; Goldstein, B. M. J. Am. Chem. Soc. 1992, 114, 2313-
2320.

S‚‚‚O Interaction in (Acylimino)thiadiazolines
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3109
169-171 °C (hexane-AcOEt); 1H NMR (CDCl3) 1.06 (t, J ) 7.3 Hz,
3 H), 1.79-1.91 (m, 2 H), 3.01 (t, J ) 7.6 Hz, 2 H); IR (CHCl3) 1651
cm-1 (CdO); EI-MS m/z 239 M+. Anal. Calcd for C7H8F3N3OS: C,
35.15; H, 3.37; N, 17.57. Found: C, 35.35; H, 3.40; N, 17.55.
5-Ethyl-3-methyl-2-[(trifluoroacetyl)imino]-1,3,4-thiadiazoline (7).
To a suspension of 5 (1.33 g, 5.91 mmol) and Na2CO3 (332 mg, 3.16
mmol) in DMF (15 mL) was added methyl iodide (0.50 mL, 8.03
mmol), and then the mixture was stirred for 31 h at room temperature.
The reaction mixture was poured into water and extracted with AcOEt.
The organic layer was washed with water and dried over anhydrous
MgSO4. After evaporation of the solvent in vacuo, the residue was
purified by column chromatography (hexane-AcOEt, 5:1) to give 7
(1.20 g, 85%) as colorless prisms: mp 53-54 °C (CH2Cl2-hexane);
1H NMR (CDCl3) 1.39 (t, J ) 7.5 Hz, 3 H), 2.95 (q, J ) 7.5 Hz, 2 H),
4.02 (s, 3H); IR (CHCl3) 1642 cm-1 (CdO); EI-MS m/z 239 M+. Anal.
Calcd for C7H8F3N3OS: C, 35.15; H, 3.37; N, 17.57. Found: C, 35.08;
H, 3.40; N, 17.62.
5-Ethyl-2-(trifluoroacetamido)-1,3,4-oxadiazole (8). To a suspen-
sion of 2-amino-5-ethyl-1,3,4-oxadiazole (2.0 g, 17.7 mmol) in THF
(30 mL) was added trifluoroacetic anhydride (2.8 mL, 19.9 mmol) at
0 °C followed by stirring for 30 min. The reaction mixture was poured
into aqueous NaHCO3 solution (containing 1.80 g of NaHCO3) and
extracted with AcOEt. The organic layer was washed with water and
dried over anhydrous MgSO4. Evaporation of the solvent in vacuo
afforded 8 (2.89 g, 78%) as colorless solids: mp 105-106 °C (hexane-
AcOEt); 1H NMR (CDCl3) 1.40 (t, J ) 7.5 Hz, 3 H), 2.87 (q, J ) 7.5
Hz, 2 H); IR (CHCl3) 1667, 1596 cm-1 (CdO, CdN); EI-MS m/z 209
M+. Anal. Calcd for C6H6F3N3O2: C, 34.46; H, 2.89; N, 20.09.
Found: C, 34.75; H, 2.92; N, 20.25.
5-Ethyl-3-methyl-2-[(trifluoroacetyl)imino]-1,3,4-oxadiazoline (9).
To a suspension of 8 (367 mg, 1.75 mmol) and diisopropylethylamine
(0.36 mL, 2.07 mmol) in DMF (5 mL) was added methyl iodide (0.15
mL, 2.41 mmol) followed by stirring for 23 h at room temperature.
The reaction mixture was poured into water and extracted with AcOEt.
The organic layer was washed with water and dried over anhydrous
MgSO4. After evaporation of the solvent in vacuo, the residue was
purified by column chromatography (hexane-AcOEt, 5:1 to 3:1) to
give 9 (310 mg, 79%) as colorless prisms: mp 33-35 °C (CH2Cl2-
hexane); 1H NMR (CDCl3) 1.37 (t, J ) 7.5 Hz, 3 H), 2.81 (q, J ) 7.5
Hz, 2 H), 3.65 (s, 3H); IR (CHCl3) 1681, 1641, 1600 cm-1 (CdO,
CdN); EI-MS m/z 223 M+. Anal. Calcd for C7H8F3N3O2: C, 37.68;
H, 3.61; N, 18.83. Found: C, 37.61; H, 3.63; N, 18.94.
Figure 8. Possible explanation of the nonbonded 1,5-type S‚‚‚O
interaction due to no f σ* orbital overlap effect.
and 7) was demonstrated by exploiting the ab initio MO
calculations at the HF/3-21G*, 6-31G*, and 6-311+G** levels.
The relative stability of the conformer having a similar non-
bonded 1,5-type O‚‚‚O interaction in molecule 9 proved to be
unremarkable in comparison with that of the other two corre-
sponding conformers. Although no quantitative data has yet
emerged, the stability of a particular 1,5-type S (with electron-
withdrawing groups)‚‚‚O (with electron-donating groups) and
O‚‚‚O interactions may be due to no (CdO) f σ* (C-S and
C-O) as shown in Figure 8.
Thus, the positive introduction of the mimic-fused bicyclic
heterocycle system consisting of the intramolecular nonbonded
S‚‚‚O interaction into the designed bioactive compounds proves
encouraging for the development of new drugs such as our AII
receptor antagonists (1-3) and other sulfur-containing hetero-
cyclic agents (105, 11,17 12,18 etc.17a) as shown in Figure 9.
Studies on the extension of this concept to an intermolecular
S‚‚‚O interaction are in progress. The intermolecular nonbonded
S‚‚‚O (e.g., oxygen of peptide bond: -CONH-) interactions
between the sulfur-containing bioactive compounds and the
receptors (or enzymes) are anticipated to be a new pharma-
cophore bonding.
Experimental Section
All melting points were determined on a Yanagimoto micro apparatus
and are uncorrected. The infrared (IR) spectra were recorded on a
JASCO J-0085 or a Perkin-Elmer 1720 infrared fourier transform
spectrometer. The proton nuclear magnetic resonance (1H NMR, 200
MHz) spectra were recorded on a JEOL-FX-200. Chemical shifts are
given in δ values (ppm) using tetramethylsilane as an internal standard.
Electron impact (EI) mass spectra (MS) were obtained on a JEOL-
SX-102A instrument. Elementary combustion analyses were within
(0.4% of theoretical values. Column chromatography was performed
using Merck silica gel 60 N (70-230 mesh). 2-Amino-5-ethyl-1,3,4-
thiadiazole was purchased from Aldrich Chemical Co., Ltd. 2-Amino-
5-propyl-1,3,4-thiadiazole and 2-amino-5-ethyl-1,3,4-oxadiazole were
prepared by the procedure described in the literature.19 Ethyl acetate,
tetrahydrofuran, and N,N-dimethylformamide are abbreviated as AcOEt,
THF, and DMF, respectively.
5-Ethyl-2-(trifluoroacetamido)-1,3,4-thiadiazole (5). To a suspen-
sion of 2-amino-5-ethyl-1,3,4-thiadiazole (2.0 g, 15.5 mmol) in toluene
(50 mL) and diisopropylethylamine (2.8 mL, 16.1 mmol) was added
trifluoroacetic anhydride (2.4 mL, 17.0 mmol) at 0 °C, and then the
mixture was stirred for 1 h at room temperature. The reaction mixture
was poured into water, and extracted with AcOEt. The organic layer
was washed with water and dried over anhydrous MgSO4. Evaporation
of the solvent in vacuo afforded 5 (2.95 g, 85%) as colorless solids:
mp 124-126 °C (EtOH); 1H NMR (CDCl3) 1.34 (t, J ) 7.6 Hz, 3 H),
3.07 (q, J ) 7.6 Hz, 2 H); IR (KBr) 1642 cm-1 (CdO); EI-MS m/z
225 M+. Anal. Calcd for C6H6F3N3OS: C, 32.00; H, 2.69; N, 18.66.
Found: C, 32.27; H, 2.74; N, 18.86.
X-ray Studies. Crystallographic data for 1, 3, 6, 7, and 9 are
summarized in Table 1. Rigaku AFC7R diffractometer employing Ni-
filtered Cu KR radiation was used. Three standard reflections monitored
every 150 reflections showed no significant changes during data
collection. An empirical absorption correction based on azimuthal scans
of several reflections was applied for 6 and 9, but not for the others.
Structures were solved by directed methods20 and refined by full-matrix
2
least-squares technique to minimize Σ (w|∆F| ). The weighting scheme
was based on counting statistics and included a factor, p, to down-
weight the intense reflections: w ) [σ2(Fo) + p2|Fo|)2]-1
. All
calculations were performed using teXsan21 crystallographic software
package. Full details of the crystallographic data are deposited in the
Supporting Information.
Computational Studies. All calculations were carried out using
the CONVEX-3440 of Computer Center in University of Tokushima.
The ab initio calculations were performed using the Gaussian 92 system
of programs at the RHF level of the theory using 3-21G*, 6-31G*,
and 6-311+G**.
The geometry of (acylimino)thiadiazoline (7) and (acylimino)-
oxadiazoline (9) was optimized at the ab initio HF/3-21G* level. The
global energy minimum for each compound was normalized to 0 kcal/
mol. As the result of the computation, each CT (cis-s-trans)11
5-Propyl-2-(trifluoroacetamido)-1,3,4-thiadiazole (6). Compound
6 was prepared by the similar method described above (83%): mp
(17) (a) Abtstracts of the 5th Annual Meeting of Division of Medicinal
Chemistry in Japan (Toyama), 1996. (b) Tanaka, R.; Oyama, Y.; Imajo,
S.; Matsuki, S.; Ishiguro, M. Bioorg. Med. Chem. 1997, 5, 1389-1399.
(18) Nagao, Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.;
Shimada, O.; Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243-4249.
(19) Katritzky, A. R.; and Rees, C. W. ComprehensiVe Heterocyclic
Chemistry; Pergamon Press Inc.: New York, 1984; Vol 6.
(20) (a) MITHRIL84: Gilmore, C. J. J. Appl. Crystallogr. 1984, 17, 42-
46. (b) SHELXS86: Sheldrick, G. M., Program for the Solution of Crystal
Structures, University of Gottingen, Germany, 1985. (c) SIR92: Altomare,
A.; Burla, M. C.; Camalli, M.; Cascarano, M.; Giacovazzo, C.; Guagliardi,
A.; Polidori, G. J. Appl. Crystallogr. 1994, 27, 435.
(21) teXsan: Crystal Structure Analysis Package, Molecular Structure
Corporation, 1996.

3110 J. Am. Chem. Soc., Vol. 120, No. 13, 1998
Nagao et al.
Figure 9. Examples of the S‚‚‚O close contact recognized in the heterocyclic agents (10-12).
conformer referred to that of the crystallographic structure (X-ray
analysis) indicated the minimum energy. The relative energies of CC
(cis-s-cis)11 and TT (trans-s-trans)11 conformers were computed, and
the optimized torsion angles ø (CdN-C-CF3) of the CC and TT
conformers were determined. The results are shown in Scheme 2.
The geometry of the model (acylamino)thiadiazole (6) was optimized
at the ab initio HF/3-21G*, 6-31G*, and 6-311+G** levels. In the
case of the HF/3-21G* calculation, several energy values as a function
of torsion angles ø (NdC-N-CO) are calculated in the range 0-180°
(ø). The selected torsion angle ø is defined by the S1-C2-N3-C6
atom arrangements for the (acylamino)thiadiazole (6). The ø ) 0°
conformer refers to the conformation in which the carbonyl oxygen is
antiperiplanar relation to the sulfur of the thiadiazole ring, and the
energy of this conformer was normalized to 0 kcal/mol. The ø value
was incremented in 10° steps and fixed. The geometry at ø ) 180° of
the (acylamino)thiadiazole derivative 6 was based on the X-ray
crystallographic analysis. The results are summarized in Figure 7. In
the case of the HF/6-31G* or 6-311+G** calculation, each relative
energy was calculated for the corresponding conformer at 0°, 90°, and
180° (ø values). The data are indicated in Table 3.
Acknowledgment. This work was partly supported by Grant-
in-Aid for Scientific Research on Priority Areas (No. 09231235
and 09273244) from the Ministry of Education, Science, Sports,
and Culture, Japan.
Supporting Information Available: Detailed crystallo-
graphic and structural data (bond lengths, bond angles, and
torsion angles) for 1, 3, 6, 7, and 9 (106 pages). See any current
masthead page for ordering and Web access instructions.
JA973109O