Aniline exchange of 2-aryl-4,5-diphenyl-substituted isothiazolium salts

Article abstract of DOI:10.1515/znb-2008-0413

4,5-Diphenyl-substituted N-(R¹-aryl)-isothiazolium salts 4 react with anilines 2 (R²) to form 4,5-disubstituted N-(R ₂-aryl)-isothiazolium salts 4. The influence of donor and acceptor substituents in the W-aryl ring of 4 and in the anilines 2 on the course of the exchange was studied. The structure of the salts 4 was confirmed by a crystal structure determination of 4i.

Full text of DOI:10.1515/znb-2008-0413

Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts
Janine Wolfa, Joachim Sielerb, and Ba¨rbel Schulzea
a Institute of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103, Leipzig,
Germany
b Institute of Inorganic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig,
Germany
Reprint requests to Prof. Dr. B. Schulze. Fax: 0341/9736599.
E-mail: bschulze@chemie.uni-leipzig.de
Z. Naturforsch. 2008, 63b, 473 – 477; received February 19, 2008
Dedicated to Professor Dr. Klaus Hafner on the occasion of his 80th birthday
4,5-Diphenyl-substituted N-(R1-aryl)-isothiazolium salts 4 react with anilines 2 (R2) to form 4,5-
disubstituted N-(R2-aryl)-isothiazolium salts 4. The influence of donor and acceptor substituents in
the N-aryl ring of 4 and in the anilines 2 on the course of the exchange was studied. The structure of
the salts 4 was confirmed by a crystal structure determination of 4i.
Key words: 4,5-Diphenyl-isothiazolium Salts, Aniline Exchange
Introduction
The reactivity of isothiazolium salts toward nucleo-
philes is higher than that of isothiazoles. As a conse-
quence, the tendency of nucleophilic ring cleavage by
quaternization of isothiazoles increases [1].
Isothiazolium salts are characterized by a high syn-
thetic potential [1]. Therefore, they react with N-nucl- anilines 2.
Scheme 1. Reaction of 4,5-dialkyl-isothiazolium salts 1 with
eophiles like ammonia, primary amines, hydrazines
rearranged 3,4-disubstituted salts 3 (R1) (Scheme 1)
[1, 12].
and hydroxylamines by ring transformation and with
retention of the ring size to isothiazoles, pyrazoles and
oxazoles [2, 3]. The synthesis of 3-aminopyrroles by
ring transformation of substiuted 5-aminoisothiazol-
ium salts has been investigated [4]. N-Aryl-isothia-
zolium salts with an active methyl or methylene group
in 5-position of the isothiazole ring rearrange in a
base-induced reaction with secondary amines such as
DCHA by deprotonation and oxidative dimerization
Here, we report on our studies of the reaction of 5-
phenyl-isothiazolium salts 4 (R1) with substituted ani-
lines 2 (R2).
Results and Discussion
The isothiazolium salts 4 were conveniently syn-
to thieno-annulated N-aryl-6aλ4-thia-1,6-diazapental- thesized by intramolecular cyclocondensation of β-
enes [5 – 9], spirocyclic isothiazolium salts [10, 11] thiocyanatovinyl aldehydes and anilines 2 in the pres-
and thianthrene derivatives [10]. In contrast, weaker ence of perchloric and glacial acetic acid [8]. The sub-
bases, such as substituted anilines, compete due to their stituents of the 2-aryl ring (R1/R2) were graded accord-
basicity and nucleophilicity in the reaction with N- ing to the pKa value of the corresponding anilinium
aryl-4,5-dialkyl-isothiazolium salts. Thus, ring trans- ions.
formation occurs by nucleophilic attack of aniline at
We have investigated the reaction of these 4,5-di-
the 5-position inducing virtually a migration of the phenyl-isothiazolium salts 4 (R1) with various sub-
sulfur atom to the 3-position of the ring and elimina- stituted anilines 2 (R2) in the presence of methanol
tion of aniline. The reaction of 5-methyl- or methyl- (50 ◦C, 22 h). After purification and isolation the new
en-substituted salts 1 with anilines 2 (R1) thus gives isothiazolium salts 4 (R2) were received. Interestingly,
c
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474
J. Wolf et al. · Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts
2/4/5
R1/R2
2-NO2
4-NO2
4-SO2CH3
3-NO2
4-CO2CH3
3-OCH3
2-OCH3
H
a
b
c
d
e
f
g
h
i
4-OCH3
Scheme 2. Reaction of 4,5-diphenyl-isothiazolium salts 4 with anilines 2.
all 5-phenyl-isothiazolium salts 4 (R1) react exclu-
sively by aniline exchange to give salts 4 with R2 in
the N-aryl ring and in no case by ring transformation
and exchange of aniline to 3,4-diphenylisothiazolium
salts 5 (Scheme 2), observed previously for 5-methyl-
or methylen-substituted salts (see Scheme 1) [12].
Further, we studied the influence of substituents
in the N-aryl ring of salts 4. In previous stud-
ies, Noack [13] found that the reaction of acceptor-
substituted salts 1 (R = CH3, R1 = 4-Cl, 4-Br) with
donor-substituted anilines 2 (R2 = 4-CH3, 4-OCH3) al-
ways yields salts 3 bearing an electron-donating sub-
stituent R2 after ring transformation and exchange of
the aniline moiety. Similar results could also be ex-
pected for the aniline exchange of 4,5-diphenyl-iso-
thiazolium salts 4.
Table 1. Aniline exchange of salts 4a, b, d.
Educt 4 Aniline 2
Product 4 (R2) Yield (%)
a [14] (R1 = 2-NO2) g (R2 = 2-OCH3) 4g
b [15] (R1 = 4-NO2) i (R2 = 4-OCH3) 4i [17]
d [16] (R1 = 3-NO2) f (R2 = 3-OCH3) 4f
73
58
55
Table 2. Aniline exchange of salts 4a – e.
Educt 4
Aniline 2
Product 4
Yield [%]
h (R2 = H) h [17] (R2 = H) 89
a [14] (R1 = 2-NO2)
b [15] (R1 = 4-NO2) h (R2 = H) h [17] (R2 = H) 91
c (R1 = 4-SO2CH3)
d [16] (R1 = 3-NO2) h (R2 = H) h [17] (R2 = H) 91
e (R1 = 4-CO2CH3) h (R2 = H) h [17] (R2 = H) 93
h (R2 = H) h [17] (R2 = H) 62
The mechanism of aniline exchange could be ex-
plained by the nucleophilic attack of the aniline 2 (R2)
Therefore, the acceptor-substituted salts 4a [14], at the C-3 carbon atom of the isothiazolium ring to
b [15] and 4d [16] (R1) were reacted with donor- form the intermediate 6, followed by S–N ring cleav-
substituted anilines 2f, g, i in alcohol (Table 1). Not age resulting in the acyclic species 7. After elimi-
surprisingly, the salts 4a, b, c (R1) were converted
nation of aniline 2 (R1) and nucleophilic N→S cy-
by exchange of aniline to isothiazolium salts 4f, g clization the aniline exchanged salt 4 (R2) is obtained
and 4i [17] (R2) in good yields (55 – 73 %). Compared (Scheme 3) [3]. In another possible pathway of this
to the conventional synthesis of the donor-substituted transformation, the aniline 2 (R2) undergoes nucle-
salts 4f, g and 4i [17] (31– 42 %) by intramolecu- ophilic attack at the sulfur atom of salt 4 (R1) to form
lar cyclocondensation of β-thiocyanatovinyl aldehy- 7 by ring cleavage. After cyclization to give the inter-
des with anilines 2, the transformation of acceptor- mediate 6 and elimination of aniline 2 (R1) from the
substituted salts 4 by aniline exchange is a good alter- C-3 position of the isothiazole the salt 4 (R2) is ob-
native method to receive salts 4f, g and 4i in improved tained [2].
yields.
Further, we studied the reaction of acceptor-
It should be noted that in all transformations re- substituted salts 4a [14], b [15], c, d [16], e with the
ported here, in salt 4, e. g. 4a [14] (R1 = 2-NO2), the unsubstituted aniline 2h (R2 = H). The results are pre-
aniline group present in the precursor was displaced by sented in Table 2. In all of these cases, the transforma-
a more strongly basic aniline 2, e. g. 2g (R2 = 2-OCH3), tion by aniline exchange gave the unsubstituted salt 4h
to form the salt 4g (R2).
[17] in good to high yields (62 – 93 %).
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J. Wolf et al. · Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts
475
R2
_
NH
R2
R1
R1
H N 2
2
N+
N
- HClO4
_
S
S
6
ClO4
4
R2
R2
N_
HClO4
N+
R1
S
_
ClO4
-
H N2
S
2
7
NH
4
Scheme 3. Proposed mechanism of ani-
line exchange of 4,5-diphenyl-isothiazolium
salts 4.
R1
Fig. 1. Molecular structure of the 2-(4-
methoxyphenyl)-4,5-diphenylisothiazolium
cation of 4i in the crystal.
We also investigated the conversion of isothiazolium the crystallographic data are given in the Experimental
salt 4h [17] (R1 = H) with substituted anilines 2a – e Section.
(R2). As expected, in no cases an aniline-exchanged
In summary, the reaction of 4,5-diphenyl-isothiazol-
salts 4a – e (R2) could be obtained, and the starting salt
4h (R1 = H) was recovered.
ium salts 4 (R1) with various substituted anilines 2 (R2)
gives the salts 4 with R2 by exchange and elimination
All synthesized isothiazolium salts were charac- of aniline 2 (R1). We have developed an useful method
1
terized after the ring transformation by H, 13C and for the synthesis of donor-substituted salts 4f, g and
IR spectroscopy as well as mass spectrometry (see 4i [17]. The aniline exchange proposed for the 3,4-
Experimetal Section). The structure of the aniline- diphenyl salts 5, was confirmed by an X-ray structure
exchanged isothiazolium salt 4i (R2 = 4-OCH3) was determination of 4i. This rules out any ring transforma-
confirmed by a crystal structure determination. The tion which was encountered with 4,5-dialkyl-isothia-
structure of the cation of 4i is presented in Fig. 1, and zolium salts 1.
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476
J. Wolf et al. · Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts
Experimental Section
General
(s, 3H, OCH3), 7.24 – 7.62 (m, 14H, arom. H), 9.97 (s,
1H, 3-H). – 13C NMR ([D6]DMSO): δ = 56.0 (OCH3),
109.0, 115.0, 117.4, 125.9 (C-4), 128.9, 129.1, 129.4, 129.5,
M. p.: Boetius micro melting point apparatus; corrected.
IR spectra: Genesis FTIR Unicam Analytical System (ATI
Mattson); KBr pellets. 1H and 13C NMR spectra: Varian
Gemini-300 and Bruker Avance DRX-400; δ in ppm rel. to
Si(CH3)4 as internal standard. MS: Quadrupole-MS VG 12-
250; 70 eV. Elemental analyses: Heraeus CHNO Rapid Ana-
lyzer.
129.6, 131.5, 132.2, 135.2, 137.5, 157.4 (C-OCH3), 160.4
(C-3), 165.4 (C-5). – ESI-MS: m/z = 344.1 [M–ClO4]+. –
C22H18ClNO5S (443.91): calcd. C 59.63, H 4.09, N 3.16,
S 7.22; found C 59.67, H 4.28, N 3.26, S 7.31.
2-(2-Methoxyphenyl)-4,5-diphenylisothiazolium perchlorate
(4g)
General procedure for the preparation of salts 4
◦
Yield: 32 %, m. p. 164 – 168 C. – IR (KBr): ν = 1093 s
(ClO4) cm−1. – 1H NMR ([D6]DMSO): δ = 4.03 (s, 3H,
OCH3), 7.28 – 7.31 (t, 1H, arom. H), 7.48 – 7.58 (m, 10H,
arom. H), 7.64 (d, J = 6.8 Hz, 1H, arom. H), 7.69 – 7.73
(t, 1H, arom. H), 7.99 (d, J = 7.6 Hz, 1H, arom. H),
9.90 (s, 1H, 3-H). – 13C NMR ([D6]DMSO): δ = 56.8
(OCH3), 113.7, 121.4, 125.2 (C-4), 125.8, 126.4, 128.7,
129.1, 129.4, 129.5, 129.6, 132.1, 133.0, 134.1, 151.8 (C-
OCH3), 159.0 (C-3), 166.4 (C-5). – ESI-MS: m/z = 344.1
[M–ClO4]+. – C22H18ClNO5S (443.91): calcd. C 59.63,
H 4.09, N 3.16, S 7.22; found C 59.88, H 3.95, N 3.17,
S 6.99.
The new salts 4c, e, f, g were prepared according to a lit-
erature procedure [8]. Compounds 4a [14], 4b [15], 4d [16],
4h [17] and 4i [17] have been described elsewhere.
2-(4-Methylsulfonylphenyl)-4,5-diphenylisothiazolium
perchlorate (4c)
◦
Yield: 59 %, m. p. 219 – 223 C. – IR (KBr): ν = 1089 s
(ClO4), 1152 s (SO2CH3), 1299 s (SO2CH3) cm−1. –
1H NMR ([D6]DMSO): δ = 3.36 (s, 3H, SO2CH3), 7.44 –
7.64 (m, 10H, arom. H), 8.26 – 8.33 (m, 4H, arom. H), 10.08
(s, 1H, 3-H). – 13C NMR ([D6]DMSO): δ = 43.2 (SO2CH3),
124.5, 125.8 (C-4), 128.7, 128.8, 129.2, 129.4, 129.4,
129.6, 129.7, 132.3, 135.5, 140.1 (C-SO2CH3), 143.1, 158.0
(C-3), 166.7 (C-5). – ESI-MS: m/z = 392.1 [M–ClO4]+. –
C22H18ClNO6S2 (491.97): calcd. C 53.71, H 3.69, N 2.85,
S 13.04; found C 53.66, H 3.63, N 2.99, S 13.25.
Crystal structure determination of 4i
C22H18ClNO5S, Mr = 443.88, T = 213(2) K. Suitable sin-
gle crystals were obtained from ethanol. Crystal size: 0.20×
0.20 × 0.10 mm3; monoclinic crystal system, space group
2-(4-Methoxycarbonylphenyl)-4,5-diphenylisothiazolium
perchlorate (4e)
˚
P21/c, a◦= 11.567(2), b = 21.210(4), c = 16.877(3) A, β =
91.51(2) , V = 4139.1(13) A , Z = 8, ρcalcd = 1.425 g cm−3
,
3
˚
µ(MoKα ) = 0.32 mm−1. The intensities were measured on a
◦
Yield: 49 %, m. p. 199 – 203 C. – IR (KBr): ν = 1087 s
(ClO4), 1286 s (CO2CH3), 1720 s (C=O) cm−1. – 1H NMR
([D6]DMSO): δ = 3.93 (s, 3H, CO2CH3), 7.46 – 7.66 (m,
10H, arom. H), 8.19, 8.31 (2 d, J = 8.7 Hz, 4H, arom. H),
10.10 (s, 1H, 3-H). – 13C NMR ([D6]DMSO): δ = 52.7
(CO2CH3), 123.3, 125.8 (C-4), 128.8, 129.1, 129.4, 129.6,
129.6, 131.3, 132.0, 132.3 (C-CO2CH3), 135.5, 139.9, 157.7
(C-3), 165.0 (CO2CH3), 166.3 (C-5). – ESI-MS: m/z = 372.1
[M–ClO4]+. – C23H18ClNO6S (471.92): calcd. C 58.54,
H 3.84, N 2.97, S 6.79; found C 58.04, H 3.77, N 2.95,
S 6.99.
Stoe IPDS1 diffractometer with graphite-monochromatized
˚
MoKα radiation (λ = 0.71073 A). θ range for data col-
lection: 2.27 – 27.94◦, index ranges −15 ≤ h ≤ 15, −27 ≤
k ≤ 26, −22 ≤ l ≤ 22. Reflections collected: 32992, in-
dependent reflections: 9824 [R(int) = 0.090], transmission
(max./min): 0.997/0.939. The structure was solved with Di-
rect Methods and refined with full-matrix least-squares on
F2 (SHELXS/L-97 [18]). Data/parameters = 9824/541. Fi-
nal R1/wR2 [I ≥ 2σ(I)]: 0.074/0.187, Final R1/wR2 (all
data): 0.163/0.2−113; largest peak/hole in final difference map:
˚
0.62/−0.53 e A
.
2-(3-Methoxyphenyl)-4,5-diphenylisothiazolium perchlorate
(4f)
CCDC 678529 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data request/cif.
Yield: 31 %, m. p. 139 – 144 ◦C. – IR (KBr): ν =
1083 s (ClO4) cm−1. – 1H NMR ([D6]DMSO): δ = 3.86
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J. Wolf et al. · Aniline Exchange of 2-Aryl-4,5-diphenyl-substituted Isothiazolium Salts
477
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