Novel synthesis of cis-nickel(II) 3-alkylimino-3-alkyl(or aryl)thio-1-arylpropenethiolates and their application to the preparation of 5-aryl-3-(arylthio)isothiazoles

Article abstract of DOI:10.1021/jo010631r

Treatment of (E)-3-alkylamino-3-alkylthio-1-(thioaroyl)propenes 2 with Ni(OAc)₂·4H₂O in EtOH at room temperature gave cis-Ni(II)-3-alkylimino-3-alkylthio-1-aryl- propenethiolates 3 in excellent yields. Heating a mixture of 3 and alkyl- or arylthiols in 1,2-dichloroethane gave new ketene S,N-acetals 4 having new alkyl- or arylthio groups depending on the thiols employed. For the first time, 5-aryl-3-(arylthio)isothiazoles were prepared from 2 with an arylthio group according to a known procedure.

Full text of DOI:10.1021/jo010631r

SCHEME 1
Novel Syn th esis of cis-Nick el(II)
3-Alk ylim in o-3-a lk yl(or
a r yl)th io-1-a r ylp r op en eth iola tes a n d Th eir
Ap p lica tion to th e P r ep a r a tion of
5-Ar yl-3-(a r ylth io)isoth ia zoles
Dong J oon Lee, Bo Sung Kim, and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul
National University, Seoul 151-742, Korea
kkim@plaza.snu.ac.kr
Received J une 20, 2001
Abstr a ct: Treatment of (E)-3-alkylamino-3-alkylthio-1-
(thioaroyl)propenes 2 with Ni(OAc)2‚4H2O in EtOH at room
temperature gave cis-Ni(II)-3-alkylimino-3-alkylthio-1-aryl-
propenethiolates 3 in excellent yields. Heating a mixture of
3 and alkyl- or arylthiols in 1,2-dichloroethane gave new
ketene S,N-acetals 4 having new alkyl- or arylthio groups
depending on the thiols employed. For the first time, 5-aryl-
3-(arylthio)isothiazoles were prepared from 2 with an aryl-
thio group according to a known procedure.
other method involves the thermal elimination of sulfur
from 1,4,2-dithiazines, yielding 3-(methylthio)isothiazoles
along with other products.7 Of course, these methods are
incompatible with the synthesis of the title compounds
due to the failure to achieve SN2 nucleophilic displace-
ment in the case of an aryl halide. Therefore, we were
interested in exploring a synthetic method for 5-aryl-3-
(arylthio)isothiazoles.
Among numerous isothiazole derivatives,1 3-alkylthio-
isothiazoles have attracted much attention due to their
biological applications such as fungicides,2 insect repel-
lent,3 and antiviral agents against enterovirus and ECHO
9.4 Introduction of alkylthio groups for the synthesis of
3-(alkylthio)isothiazoles has been basically achieved by
two different methods. The first method, which has been
utilized most widely, involves nucleophilic displacement
of halide ion by alkylthiolates. For instance, 4-cyano-3,5-
(dimethylthio)isothiazole was prepared by treatment of
2-cyanoethylthioamide with a hydroxide base in carbon
disulfide, followed by addition of iodomethane and iodine
in sequence.5 Alternatively, the reaction of the disodium
salt of 4-cyano-3,5-(dimercapto)isothiazole (readily avail-
able from dicyanoethylenedithiolate and sulfur) with
alkyl halides afforded 4-cyano-3,5-(dialkylthio)isothia-
zoles.6 Treatment of 3,5-dichloro-4-cyanoisothiazole with
sodium sulfide in the presence of iodomethane also led
to the foregoing isothiazole derivatives.4,6c However, the
latter reaction was accompanied by ring cleavage. The
During the course of our study exploring the potential
synthetic utility of (E)-thioaroylketene S,N-acetals 2,8
which were prepared by treatment of 2-alkyl-3-alkylthio-
5-arylisothiazolium halides 1 with NaBH4 in EtOH at
room temperature,9 we found that compound 2a (Ar1 )
Ph, R1 ) R2 ) Me) reacted with Ni(OAc)2‚4H2O for 4 h
in EtOH at room temperature to give a dark brown solid
3 (Scheme 1), whose structure was determined on the
basis of spectroscopic and analytical data. The X-ray
single-crystal structure of 3a (Ar1 ) Ph, R1 ) R2 ) Me)
clearly shows that two molecules of 2a make a type of a
cis square planar complex10 by coordinating thione sul-
furs and nitrogen atoms with an Ni(II) ion.
Similarly, the reactions with other thioaroylketene
S,N-acetals 2b-g under the same conditions gave nickel
complexes 3b-g in good to excellent yields (Table 1).
Compounds 3 are stable toward bases such as alkyl-
amines, i.e., i-PrNH2 and (n-Bu)2NH, and aqueous KOH,
whereas decomplexation occurs in HOAc to give 2.
(6) (a) Hatchard, W. R. J . Org. Chem. 1963, 28, 2163-2164. (b)
So¨derba¨ck, E. Acta Chem. Scand. 1963, 17, 362-376. (c) Hatchard,
W. R. J . Org. Chem. 1964, 29, 660-665. (d) Gewald, K. J . Prakt. Chem.
1966, 31, 214-218. (e) Wooldridge, K. R. H. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic Press: New
York, 1972; Vol. 14, pp 1-41. (f) Hoyer, G. A.; von Manfred Kless, M.
Tetrahedron Lett. 1969, 4265-4268. (g) Poite, J . C.; J ulien, J .; Vincent,
E. J .; Roggero, J . Bull. Soc. Chim. Fr. 1972, 6, 2296-2299. (h) Gewald,
K.; Radke, W.; Hain, U. J . Prakt. Chem. 1980, 322, 1021-1031.
(7) Fangha¨nel, E. Z. Chem. 1965, 5, 386.
(8) Kim, B.; Kim, K. J . Org. Chem. 2000, 65, 3690-3699.
(9) Kim, S. H.; Kim, K.; Kim, K.; Kim, J .; Kim, J . H. J . Heterocycl.
Chem. 1993, 30, 929-938.
(10) Selected bond angles (deg) and bond lengths (Å) of 3a : N(1)-
Ni-N(1)#1 92.8(2), N(1)-Ni-S(2)#1 161.9(9), N(1)#1-Ni-S(2)#1 95.15-
(8), N(1)-Ni-S(2) 161.93(9), S(2)#1-Ni-S(2) 82.05(5), Ni-N(1) 1.936-
(3), Ni-N(1)#1 1.936(3), Ni-S(2)#1 2.1602(10), Ni-S(2) 2.1602(10).
(1) (a) Pain, D. L.; Peart, B. J .; Wooldridge, K. R. H. In Compre-
hensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 6, pp 131-175. (b) Chapman, R. F.;
Peart, B. J . In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 3, pp 319-372.
(2) (a) Merck, A.-G. Netherlands Pat. 6, 703, 832, 1967; Chem. Abstr.
1968, 69, 96708. (b) Merck, A.-G. Netherlands Pat. 6, 808, 400, 1968;
Chem. Abstr. 1969, 71, 124429.
(3) Caton, M. P. L.; Slack, R. J . Chem. Soc. C 1968, 1402-1404.
(4) (a) Cutri, C. C. C.; Garozzo, A.; Siracusa, M. A.; Sarva´, M. C.;
Tempera, G.; Geremia, E.; Pinizzotto, M. R.; Guerrera, F. Bioorg. Med.
Chem. 1998, 6, 2271-2280. (b) Cutri, C. C. C.; Garozzo, A.; Siracusa,
M. A.; Sarva´, M. C.; Castro, A.; Geremia, E.; Pinizzotto, M. R.;
Guerrera, F. Bioorg. Med. Chem. 1999, 7, 225-230.
(5) Gewald, K. Chem. Ber. 1968, 101, 383-390.
10.1021/jo010631r CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/21/2002
J . Org. Chem. 2002, 67, 5375-5377
5375

TABLE 1. Syn th esis of Com p lexes 3 by Rea ction
betw een (E)-3-Alk yla m in o-3-a lk ylth io-1-(th ioa r oyl)-
p r op en es 2 a n d Ni(OAc)2‚4H2O in EtOH a t Room
Tem p er a tu r e
SCHEME 2
substrate
Ar1
R1
R2 product time (h) yielda (%)
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Me Me
Me i-Pr
Et Me
Et n-Pr
3a
3b
3c
3d
3e
3f
4
4
3
4
4
4
4
92
91
86
87
92
90
96
3-MeOC6H4 Me Me
4-ClC6H4 Me Me
4-MeOC6H4 Et Me
2g
3g
a
Isolated yields.
TABLE 2. Syn th esis of Keten e S,N-Acetels 4 by
TABLE 3. Syn th esis of 3-(Ar ylth io)isoth ia zoles 6 by
Rea ction of Com p ou n d s 4 w ith I2 in EtOH a t Room
Tem p er a tu r e to Give Isoth ia zoliu m Tr iiod id es 5
F ollow ed by Tr ea tm en t w ith KI a t 120 °C in DMSO
Rea ction betw een Com p lexes 3 a n d R3SH in Reflu xin g
1,2-Dich lor oeth a n e
complex
R1
R3
product
time (h) yielda (%)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3c
3f
Me n-Pr
Me Allyl
Me Ph
Me 4-MeOC6H4
Me 4-MeC6H4
Me 4-BrC6H4
Me 2-MeOC6H4
Me 2-ClC6H4
Me 2-BrC6H4
Me 2-naphthyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
8
8
12
12
10
9
48
10
12
12
10
12
12
12
12
78
66
62
51
69
70
22
50
43
30
64
63
43
60
38
time
(min)
yielda
(%)
time
(h)
yielda
(%)
substrate
compd
compd
4c
4d
4e
4f
4g
4h
4i
4j
4l
4m
4n
4o
30
30
30
30
30
30
30
30
30
30
30
30
5c
5d
5e
5f
5g
5h
5i
5j
5l
5m
5n
5o
80
90
87
75
63
69
85
85
86
79
88
70
4
5
5
5
5
3
4
4
4
4
4
4
6c
6d
6e
6f
6g
6h
6i
6j
6l
6m
6n
6o
76
92
91
86
87
67
84
85
86
79
74
74
Et
Ph
Me Ph
3f
Me 2-BrC6H4
3g
3g
Et
Et
Ph
2-BrC6H4
a
Isolated yields.
a
Isolated yields.
Interestingly, treatment of 3 (Ar1 ) Ph, R1 ) alkyl, R2 )
Me) with alkanethiols as well as arenethiols in 1,2-
dichloroethane at reflux gave new ketene S,N-acetals 4
in which the R2S group of 3 is replaced by either a new
alkylthio group (4a -b) or arylthio group (4c-o) depend-
ing on the thiols employed. Reaction times and product
yields are summarized in Table 2.
The replacement of the R2S group by other alkylthio
groups by this method appears to be a convenient
alternative to the direct reduction of the corresponding
compounds 1, which are synthesized from cinnamic acid
derivatives8 by a multistep sequence. Moreover, this
methodology is useful for preparing thioaroylketene S,N-
acetals bearing an arylthio group, which have been
hitherto inaccessible.
Since compounds 4c-o were in hand, 3-arylthio-
isothiazoles 6 were synthesized according to a known
procedure11 (Scheme 2). Reaction times and yields of
compounds 5 and 6 are summarized in Table 3.
In summary, we have developed a synthetic method
for 3-alkylamino-1-aryl-3-(arylthio)propenethiones 4 uti-
lizing an Ni(II) complex 3. 3-Arylthio-5-phenylisothia-
zoles can be readily prepared starting from 4 using a two-
step procedure.
Me4Si as an internal standard unless otherwise stated. J values
are given in hertz. IR spectra were obtained in KBr or as thin
films on KBr plates. GC-MS spectra were obtained by electron
impact at 70 eV from the National Center for Inter-University
Research Facilities, Seoul National University. Elemental analy-
ses were carried out by the Korea Basic Science Research
Institute. Column chromatography was performed using silica
gel (70-230 mesh, ASTM). Melting points are uncorrected.
Thioaroylketene S,N-acetals 2 were prepared by a documented
procedure.9 Reagent-grade 1,2-dichloroethane was used without
further purification.
Gen er a l P r oced u r e for th e Syn th esis of Ni(II) 3-Alk yl-
a m in o-1-a r yl-3-(a r ylth io)p r op en oth iola tes (3). To a solution
of 3-alkylamino-3-alkylthio-1-arylpropenethiones 2 (0.193-1.49
mmol) in EtOH (5-15 mL) was added Ni(OAc)2‚4H2O (0.097-
0.746 mmol) at room temperature. The mixture was stirred for
3-6 h at room temperature by the time Ni(OAc)2‚4H2O was
completely dissolved, and a dark brown solid was precipitated
out. The solid was filtered, washed with ether, and recrystallized
from a mixture of CH2Cl2 and EtOH. Yields are given in Table
1.
Gen er a l P r oced u r e for th e Syn th esis of 3-Alk yla m in o-
3-a lk yl(or a r yl)th io-1-a r ylp r op en eth ion es (4). To a solution
of 3 (0.097-0.158 mmol) in 1,2-dichloroethane (10-15 mL) was
added a large excess of thiol (0.472-1.21 mmol). The mixture
was heated for 8-12 h at reflux and then cooled to room
temperature. To the cooled mixture was added sodium cyanide
(0.097-0.158 mmol), and the mixture was stirred for an ad-
ditional 20 min. Removal of the solvent in vacuo gave a residue,
which was chromatographed on a silica gel (1.5 × 15 cm) with
a 1:9 mixture of EtOAc and n-hexane as the eluent to give 4.
Yields are given in Table 2.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, in CDCl3 solution containing
Gen er al P r ocedu r e for th e Syn th esis of 5-Ar yl-3-ar ylth io-
2-m eth ylisoth ia zoliu m Tr iiod id es (5). To a stirred solution
of 4 (0.156-0.506 mmol) in EtOH (30 mL) was added dropwise
a solution of iodine (0.6-2.1 mmol) in EtOH (20 mL) until the
(11) McKinnon, D. M.; Robak, E. A. Can. J . Chem. 1968, 46, 1855-
1858.
5376 J . Org. Chem., Vol. 67, No. 15, 2002

spot corresponding to 4 disappeared on TLC (silica gel, 1:4
EtOAc:n-hexane). The yellow triiodide 5 formed was filtered,
washed with ether, and recrystallized from a mixture of CH2-
Cl2 and EtOH. Yields are given in Table 3.
from International Tables for X-ray Crystallography, Vol. IV,
1974.12 Atomic coordinates, bond lengths, angles, and thermal
parameters have been deposited at the Cambridge Crystal-
lographic Data Centre.13
Gen er a l P r ocd u r e for th e Syn th esis of 5-Ar yl-3-(a r yl-
th io)isoth ia zoles (6). To a stirred solution of 5 (0.099-0.152
mmol) in DMSO (20 mL) was added KI (0.199-0.301 mmol).
The mixture was heated for 3-5 h at 120 °C. Removal of the
solvent in vacuo gave a residue, which was chromatographed
on a silica gel (1.5 × 15 cm) with a 1:15 mixture of EtOAc and
n-hexane as the eluent to give 6. Yields are given in Table 3.
X-r a y Str u ctu r e An a lysis of Com p ou n d 3a . A single
crystal of 3a was obtained from a mixture of CH2Cl2 and EtOAc.
The data were collected using graphite-monochromated Mo KR
radiation. The structure was inferred by direct methods and
subsequent Fourier maps. Refinements were carried out by full-
matrix least-squares techniques. Non-hydrogen atoms were
anisotropically refined. Atomic scattering factors were taken
Ackn owledgm en t. Financial support from the Brain
Korea 21 program is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
IR, and elemental analyses of 2b-g, 3a -g, 4a -o, 5c-j, 5l-
o, 6c-j, and 6l-o, X-ray crystallographic data of 3a , and an
ORTEP drawing of an Ni(II) 3-methylimino-3-methylthio-1-
phenylpropenethiolate (3a ). This material is available free of
charge via the Internet at http://pubs.acs.org.
J O010631R
(12) Kynoch Press, Birmingham, England.
(13) CCDC-176866.
J . Org. Chem, Vol. 67, No. 15, 2002 5377