Cycloaddition of N-(2,2,2-trichloroethylidene)-substituted carboxamides and carbamates to 1,2,4-thiadiazol-5(2H)-imines

Article abstract of DOI:10.1002/hc.10182

1,2,4-Thiadiazol-5(2H)-imines 4 react with N-(2,2,2-trichloroethylidene)-substituted amides 5 to form [3 + 2]-cycloaddition products 6 featured by an extra coordination of the ring sulfur atom to the terminal nitrogen atom of the side 1,3-diazapropenylide

Full text of DOI:10.1002/hc.10182

Heteroatom Chemistry
Volume 14, Number 5, 2003
Cycloaddition of
N-(2,2,2-Trichloroethylidene)-Substituted
Carboxamides and Carbamates to
1,2,4-Thiadiazol-5(2H)-imines
Vladimir S. Zyabrev,1 Mikhail A. Rensky,1 Eduard B. Rusanov,2
and Boris S. Drach1
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1 Murmanskaya St., 02094 Kiev, Ukraine
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanskaya St.,
02094 Kiev, Ukraine
Received 29 November 2001; accepted 4 April 2003
from imidoyl chlorides 1, through their derivatives
ABSTRACT: 1,2,4-Thiadiazol-5(2H)-imines 4 react
2 and 3 (Scheme 1). Nucleophilic agents 4 have al-
with N-(2,2,2-trichloroethylidene)-substituted amides
ready found application in fine organic synthesis.
5 to form [3 + 2]-cycloaddition products 6 featured
The most interesting of their properties is the abil-
by an extra coordination of the ring sulfur atom
ity to take part in [3 + 2]-cycloaddition reactions
to the terminal nitrogen atom of the side 1,3-
as 1,3-dipoles [2–6]. In particular, much has been
diazapropenylidene group, as established by X-ray
studied about their interaction with isocyanates,
diffraction investigation. This coordination evidently
isothiocyanates, and carbodiimides [2]. Here we re-
plays an important role in the alkylation of compounds
port the cycloaddition, to agents 4, of N-(2,2,2-
6 into 8 at the oxygen atom under mild conditions. The
trichloroethylidene)-substituted carboxamides and
S N bond “switch-over” restoring the original 1,2,4-
carbamates 5, in which the electrophilicity of the
ꢀ
C
thiadiazole ring occurs therewith. 2003 Wiley Period-
C N bonds is especially pronounced [7].
icals, Inc. Heteroatom Chem 14:474–480, 2003; Published
online in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/hc.10182
RESULTS AND DISCUSSION
By using the standard method, we synthesized a se-
ries of substituted 1,2,4-thiadiazol-5(2H)-imine hy-
drobromides 3 and the corresponding free bases 4,
which react under mild conditions with N-acyl- or
INTRODUCTION
Substituted 1,2,4-thiadiazol-5(2H)-imines 4 became
accessible in the 1970s when Barnikow [1] and,
at a later date, Goerdeler [2] had proposed a sim-
ple method for preparation of these compounds
N-alkoxycarbonylimines 5, as shown in Scheme 1.
It is more convenient to prepare the cycloaddition
products 6 by treatment of a mixture of the appro-
priate salt 3 and N-substituted amide 7 with triethy-
lamine. The structure of compound 6 incorporating
the 1,2,4-thiadiazolidine ring was confirmed by IR
and NMR (1H, 13C) spectra (Table 1) and by X-ray
crystallographic data for 6h (Fig. 1, Table 2).
Correspondence to: Vladimir S. Zyabrev; e-mail: users@bpci.
kiev.ua.
c
ꢀ
2003 Wiley Periodicals, Inc.
474

Cycloaddition of N-(2,2,2-Trichloroethylidene)-Substituted Carboxamides and Carbamates 475
SCHEME 1
˚
The sulfur atom in compound 6h, as established,
is additionally coordinated by the terminal nitrogen
atom of the side 1,3-diazapropenylidene group. The
tances N(2) C(8) (1.365 A) and N(3) C(15) (1.351
˚
A) are substantially shortened in comparison with
˚
the value of 1.45 A characteristic of a single bond
˚
˚
distances S· · ·N(1) (1.960 A) and S· · ·N(4) (1.916 A),
N(sp2) C(sp2) [10]. It should be noted also the short-
˚
though noticeably elongated as compared to S N
bonds in bivalent sulfur compounds (1.707 A) [8],
ening of the bond N(4) C(25) (1.358 A) evidently
˚
caused by the n–ꢀ interaction of the N(4) atom with
the C O group. Thus the structure of 6h can be rep-
resented as a superimposition of three forms, mono-
cyclic neutral A, monocyclic bipolar B, and bicyclic
C (Scheme 2). A significant contribution of the bipo-
lar forms of type B to the ground state of compounds
6e,g is evident from their IR spectra (Table 1). The
are nevertheless significantly shorter than the sum
˚
of the van der Waals radii (3.35 A) [9]. The bond
system SN(1)C(8)N(2)C(15)N(3)N(4) is planar, and
the maximum deviation of the atoms from the least-
˚
squares plane does not exceed 0.061 A. The triad
N(3)C(23)N(4) forms with this plane a dihedral an-
◦
˚
νC of these compounds is shifted 30–50 cm−1 to
lower frequencies relative to the νC O of disubstituted
gle of 15.1 . The bonds N(1) C(8) (1.303 A) and
O
˚
N(2) C(15) (1.312 A) are longer than the standard
C N double bond (1.27 A). At the same time the dis-
˚
carboxamides.

476 Zyabrev et al.

Cycloaddition of N-(2,2,2-Trichloroethylidene)-Substituted Carboxamides and Carbamates 477
TABLE 2 Selected Geometrical Parameters of 6h
Angle ( ◦)
˚
Bond Length (A)
S N(1)
S N(4)
S C(15)
1.960(2) N(1) S N(4)
1.916(2) N(1) S C(15)
1.733(3) N(4) S C(15)
1.419(3) S N(1) C(1)
1.303(3) S N(1) C(8)
1.365(3) C(1) N(1) C(8)
1.312(3) C(8) N(2) C(15)
1.351(3) C(15) N(3) C(16) 122.6(2)
1.439(3) C(15) N(3) C(23) 116.6(2)
1.466(3) C(16) N(3) C(23) 120.8(2)
1.421(3) S N(4) C(23)
1.358(3) S N(4) C(25)
1.202(3) C(23) N(4) C(25) 108.2(2)
O(3) C(25) N(4) 126.9(3)
166.12(9)
81.14(11)
85.36(11)
115.6(2)
110.9(2)
132.9(2)
111.7(2)
N(1) C(1)
N(1) C(8)
N(2) C(8)
N(2) C(15)
N(3) C(15)
N(3) C(16)
N(3) C(23)
N(4) C(23)
N(4) C(25)
O(3) C(25)
113.0(2)
121.0(2)
S C(15) N(2)
S C(15) N(3)
N(2) C(15) N(3)
120.8(2)
116.6(2)
122.6(2)
The marked structural bipolarity is likely to play
a large role in the alkylation of compounds 6 into 8.
The alkylation proceeds at the oxygen atom under
mild conditions and in most cases rather selectively
as can be seen from the comparison of IR spectra
of the related compounds 6 and 8 (Table 1). Fur-
FIGURE 1 Molecular structure of compound 6h.
It is of interest to compare the structures 6h (A–
C) with similar structures 9 (A–C) [2] and 10 (A, Aꢁ, C)
[11]. It may be considered that the charge delocaliza-
tion over the S N bond in 6h is more significant than
in 9 despite the higher “bipolarity” of 6h (B) com-
pared to 9 (B). The equalization of the bond lengths
in the triad N· · ·S· · ·N of compound 6h approaches
the ideal state found in 10, which is an example of
the classical “bond–no-bond” resonance system.
thermore, the signals at 164 and 172 ppm in the 13
C
NMR spectrum of 8a (see footnote d in Table 1) cor-
respond to those of atoms C(3) and C(5) in 1,2,4-
thiadiazolium cation with a disubstituted amine
group in the 5-position [12]. These findings indicate
that in the process of the alkylation the “switch-over”
of the S N bond and the reestablishment of the hete-
rocycle initially present in reagents 3 and 4 do occur.
SCHEME 2

478 Zyabrev et al.
temperature for 2 h, diluted with water (30 ml),
stirred for 0.5 h, and filtered to separate the product.
Compound 2a: 73% yield, mp 135◦C (MeOH) (lit.
140◦C) [3]. 1H NMR (300 MHz, DMSO-d6, a mixture
of tautomers and stereoisomers) δ = 2.78, 3.11 (d,
3.5:1, CH3); 6.68–7.66 (m, 2C6H5); 8.56, 8.86, 9.59,
9.85, 10.36, 11.82 (s and br s, 2NH). Found: N, 15.54;
S, 11.74%. Calcd for C15H15N3S: N, 15.60; S, 11.90%.
Compound 2b: 92% yield, mp 159◦C (AcOEt) (lit.
SCHEME 3
1
184◦C) [14]. H NMR (300 MHz, CDCl3) δ = 1.30–
It should be noted that analogs of compounds
2.09 (m, 5 CH2), 4.33 (m, CH2CHCH2), 6.66–7.38 (m,
2C6H5), 7.93 (s, NH), 12.08 (d, NH). Found: C, 71.06;
H, 6.90; N, 12.27; S, 9.36%. Calcd for C20H23N3S: C,
71.18; H, 6.87; N, 12.45; S, 9.50%.
3a–e, bearing no substituent at the exocyclic nitro-
gen atom, interact with reagents 7 in the presence
of triethylamine in a different way, without ring-
opening. An example of such a reaction involving salt
3f and 15 N-labeled amide 7f is shown in Scheme 3.
The structure of product 11 was easily deduced from
the 1H NMR spectrum (Table 1).
Compound 2c: 87% yield, mp 133–134◦C (MeCN)
1
(lit. 95◦C) [5]. H NMR (300 MHz, DMSO-d6/CCl4)
δ = 4.63 (d, CH2), 6.92–7.48 (m, 3C6H5), 8.90 (br s,
NH), 10.20 (s, NH) [15]. Found: C, 73.10; H, 5.58;
N, 12.08; S, 9.14%. Calcd for C21H19N3S: C, 73.01; H,
5.54; N, 12.16; S, 9.28%.
CONCLUSION
Compound 2d: 80% yield, mp 126◦C (MeCN). 1H
NMR (300 MHz, CDCl3) δ = 3.79 (s, CH3), 6.74–7.74
(m, 2C6H5, C6H4), 8.16 (s, NH), 14.15 (s, NH). Found:
N, 11.74; S, 8.82%. Calcd for C21H19N3OS: N, 11.63;
S, 8.87%.
The investigation into the structure and proper-
ties of the cycloaddition products of N-acylated
imino derivatives of chloral and substituted 1,2,4-
thiadiazol-5(2H)-imines has widened the knowledge
of heterocycles with a hypervalent sulfur atom, the
chemistry of which is being studied intensively in re-
cent years [13].
Compound 2e: 97% yield, mp 133–134◦C
1
(MeCN). H NMR (300 MHz, DMSO-d6/CCl4, a mix-
ture of tautomers and stereoisomers) δ = 2.21, 2.35
(s, 1:6, CH3C); 3.72, 3.80 (s, 6:1 CH3O); 6.59–7.63
(m, C6H5, 2C6H4); 9.82, 10.01, 10.15, 10.28, 10.44,
14.20 (s, 2NH). Found: N, 11.25; S, 8.56%. Calcd for
C22H21N3OS: N, 11.19; S, 8.54%.
EXPERIMENTAL
General
All the reagents and solvents were commercial prod-
ucts and were used as received unless otherwise indi-
cated. Melting points were determined on a capillary
tube apparatus and were corrected. 1H NMR spectra
were recorded on a Varian Mercury 400 (400 MHz),
a Varian VXR 300 (300 MHz), a Bruker AC 300 (300
MHz), or a Varian Gemini 200 (200 MHz) spectrome-
ter. 13C NMR spectra were obtained on a Varian VXR
300 (75 MHz) spectrometer. TMS was used as the
internal standard.
Synthesis of 1,2,4-Thiadiazol-5(2H)-imine
Hydrobromides 3a–f
To a stirred solution (2a,d) or a suspension (2b,c,e)
of the appropriate 2 (50 mmol) in CHCl3 (50 ml),
pyridine (50 mmol) was added in one portion fol-
lowed by a solution of bromine (50 mmol) in CHCl3
(25 ml) added dropwise in 40 min. The mixture was
stirred for 1 h and precipitated 3a–e was filtered
off and washed with MeOH. The filtrate was con-
centrated in vacuum and the residue was washed
with MeOH to give an additional amount of the
product.
Synthesis of N-Imidoylthioureas 2a–e
To a stirred solution or a suspension of the appro-
priate imidoyl chloride 1 (50 mmol) in anhydrous
MeCN (20 ml), preliminarily dried NaSCN (50 mmol)
dissolved in MeCN (30 ml) was added in 0.5 h at 15–
20◦C. The mixture was stirred for a further 0.5 h and
then a 35% aqueous solution of methylamine (10 ml)
or a solution of cyclohexylamine or of the appropri-
ate aniline (50 mmol) in MeCN (10 ml) was added
dropwise in 0.5 h at 10–12◦C. After the addition was
complete, the reaction mixture was stirred at room
Compound 3a: 95% yield, mp 229◦C dec. Found:
Br, 23.15; N, 12.13; S, 9.25%. Calcd for C15H13N3S·
HBr: Br, 22.94; N, 12.07; S, 9.21%.
Compound 3b: 92% yield, mp 235◦C dec. Found:
Br, 19.26; N, 10.16; S, 7.73%. Calcd for C20H21N3S·
HBr: Br, 19.19; N, 10.09; S, 7.70%.
Compound 3c: 92% yield, mp 172◦C (ClCH2CH2-
Cl). Found: Br, 18.31; N, 9.97; S, 7.54%. Calcd for
C21H17N3S·HBr: Br, 18.23; N, 9.90; S, 7.56%.

Cycloaddition of N-(2,2,2-Trichloroethylidene)-Substituted Carboxamides and Carbamates 479
Compound 3d: 95% yield, mp 218◦C dec. (ClCH2-
diffractometer operating in the ω–2ꢀ scan mode (the
ratio of the scanning rates ω/2ꢀ = 1.2). Intensity
data were collected within the range 1 < ꢀ < 24◦
using graphite monochromated Mo Kꢁ radiation
CH2Cl). Found: Br, 18.03; N, 9.63; S, 7.24%. Calcd for
C21H17N3OS·HBr: Br, 18.15; N, 9.54; S, 7.28%.
Compound 3e: 88% yield, mp 216–218◦C
(AcOH). Found: Br, 17.37; N, 9.33; S, 6.98%. Calcd
for C22H19N3OS·HBr: Br, 17.58; N, 9.25; S, 7.06%.
N-Imidoylthiourea of the formula 4-MeC6H4-
N C(Ph)NHC(S)NH2 [12] was brominated as de-
scribed above to give compound 3f in 92% yield; mp
227–228◦C dec. (EtOH). Found: Br, 22.78; N, 12.13; S,
9.12%. Calcd for C15H13N3S·HBr: Br, 22.94; N, 12.07;
S, 9.21%.
˚
(ꢂ = 0.71069 A). Intensities of 4458 reflections (4261
unique reflections, R = 0.014) were measured.
int
Data were corrected for Lorentz and polarization
effects but not for absorption. The structure was
solved by direct method [19] and refined by full-
matrix least-squares technique in the anisotropic
approximation [20]. In the refinement, 3091 re-
flections with I > 2ꢃ (I) were used. All hydrogen
atoms were located in the difference Fourier maps
and included in the final refinement with fixed
positional and thermal parameters. Convergence
Preparation of Free Base 4e
was obtained at R (F) = 0.035, Rw(F2) = 0.090, and
To a suspension of salt 3e (20 mmol) in EtOH (40 ml),
triethylamine (22 mmol) was added. The mixture
was stirred for 4 h and the product was filtered off;
96% yield, mp 136◦C (EtOH). Found: C, 70.68; H,
5.16; N, 11.33; S, 8.51%. Calcd for C22H19N3OS: C,
70.75; H, 5.13; N, 11.25; S, 8.59%.
1
GOF = 1.037 (334 refined parameters; obs/variable
9.3; the largest and minimal peaks in the final
3
˚
difference map, 0.25 and −0.24 e/A ). The weighting
scheme ω = 1/[ꢃ2(Fo2) + (0.047P)2 + 0.585P] with
P = (Fo2 + 2Fc2)/3 was used.
Full details of the crystal structure determina-
tion have been deposited at the Cambridge Crystal-
lographic Data Centre under number CCDC 172355.
General Procedure for the Synthesis
of 1,2,4-Thiadiazolidines 6a–h
To a stirred mixture of the appropriate reagents 3a–
e (5 mmol) and 7a [16], 7b,c [17], or 7d,e [18]
(5 mmol) in anhydrous CH2Cl2 (10 ml), a solution of
triethylamine (10 mmol) in CH2Cl2 (5 ml) was added
dropwise in 20 min. The mixture was stirred for a
further 4 h and diluted with water (15 ml). The or-
ganic layer was separated, concentrated in vacuum,
and the residue was treated with EtOH (10 ml) to
give crystalline 6a–h. In the case of 6h a portion of
the precipitated product was filtered off before the
addition of water. The title compounds are charac-
terized in Table 1.
Preparation of 1,2,4-Thiadiazolium Salts 8a–c
A mixture of 6b, 6c, or 6d (3 mmol), the appropri-
ate trialkyloxonium tetrafluoroborate (3 mmol) and
anhydrous CH2Cl2 (10 ml) was stirred at room tem-
perature for 48 h, after which time the solvents were
removed under a reduced pressure and the residue
was triturated with AcOEt (5 ml) to give a solid which
was filtered off and redissolved in MeOH (10 ml) at
40–50◦C. A 3 M solution of NaClO4 in MeOH (3 ml)
was added to the resulting solution and, after stand-
ing for 48 h at room temperature, the precipitated
product was filtered off. Compounds 8a–c are char-
acterized in Table 1.
Alternative Method for Preparation
of Compound 6h
Synthesis of Compound 11
To a suspension of 4e (5 mmol) in anhydrous diox-
ane (15 ml), compound 5d [17] (5 mmol) was added.
The mixture was stirred for 6 h and the precipitated
product (77% yield) was separated by filtration.
To a stirred mixture of reactants 3f (5 mmol) and
7f [21] (5 mmol) in anhydrous CH2Cl2 (10 ml), a so-
lution of triethylamine (10 mmol) in CH2Cl2 (5 ml)
was added dropwise in 20 min. The reaction mixture
was stirred for a further 4 h and then the precipitated
product was separated and washed with EtOH. Com-
pound 11 is characterized in Table 1.
X-Ray Crystallography of Compound 6h
A single crystal of 6h (0.18 × 0.26 × 0.61 mm) was
grown from an acetonitrile solution. Crystal data:
¯
C26H23Cl3N4O3S, M = 577.89, triclinic, P1 (N2), a =
˚
REFERENCES
9.594(7), b= 10.915(3), c= 13.221(5) A, α = 95.86(3),
◦
3
˚
β = 93.19(6), γ = 104.27(6) , V = 1330.1(12) A , Z = 2,
Dcalc = 1.44 g · cm−3, µ = 4.59 cm−1. Measurements
were performed at 18◦C on an Enraf-Nonius CAD 4
[1] Barnikow, G.; Ebeling, H. Z Chem 1972, 12, 130.
[2] Goerdeler, J.; Lo¨bach, W. Chem Ber 1979, 112, 517–
531.

480 Zyabrev et al.
[3] Goerdeler, J.; Haag, J.; Lo¨bach, W. Chem Ber 1979,
112, 1288–1296.
[4] L’abbe, G.; Vermeulen, G.; Toppet, S.; King, G. S. D.;
Aerts, J.; Sengier, L. J Heterocycl Chem 1981, 18,
1309–1317.
[5] Goerdeler, J.; Eggers, W. Chem Ber 1986, 119, 3737–
3748.
[6] L’abbe, G.; Albrecht, E.; Toppet, S. J Heterocycl Chem
1992, 29, 1317–1319.
[7] For preliminary communication see Zyabrev, V. S.;
Rensky, M. A.; Drach, B. S. Zh Org Khim 2001, 37,
628–629.
[8] Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer,
L.; Orpen, A. G.; Taylor, R. J Chem Soc, Perkin Trans
II 1987, S1–S19.
[9] Pauling, L. The Nature of the Chemical Bond;
Cornell University Press: New York, 1960;
p. 260.
[10] Burke-Laing, M.; Laing, M. Acta Crystallogr B 1976,
32, 3216–3224.
[12] Zyabrev, V. S.; Kharchenko, A. V.; Pirozhenko, V. V.;
Drach, B. S. Zh Org Khim 1988, 24, 1754–1762.
[13] Minkin, V. I.; Minyaev, R. M. Chem Rev 2001, 101,
1247–1265.
[14] Goerdeler, J.; Weber, D. Chem Ber 1968, 101, 3475–
3490.
[15] Compound 2c exists in the tautomeric form
PhNHC(S)N C(Ph)NHCH2Ph.
[16] Vrabel, V.; Pavelcik, F.; Kello, E.; Miertus, S.; Konecny,
V.; Lokaj, J. Collect Czech Chem Commun 1985, 50,
1619–1628.
[17] Kasper, F.; Boettger, H. Z Chem 1987, 27, 70–71.
[18] Ulrich, U.; Tucker, B.; Sayigh, A. A. R. J Org Chem
1968, 33, 2887–2889.
[19] Sheldrick, G. M. SHELXS-86. Program for the So-
lution of Crystal Structures; University of Go¨ttingen:
Go¨ttingen, Germany, 1986.
[20] Sheldrick, G. M. SHELXS-93. Program for the Refine-
ment of Crystal Structures; University of Go¨ttingen:
Go¨ttingen, Germany, 1993.
[11] Iwasaki, F.; Akiba, K. Bull Chem Soc Jpn 1984, 57,
2581–2583.
[21] Compound 7f was prepared analogously to 7c
(see Ref. [17]).