First synthesis of stable 5-alkyl- or 4,5-dialkyl-substituted 1,2-thiazinylium salt

Article abstract of DOI:10.1016/S0040-4039(01)00684-0

5-t-Butyl-1,2-thiazinylium 6c and rigid 5,8-ethano-5,8-dihydrobenzo[d]-1,2-thiazinylium salts 17 without conjugated stabilization with the aromatic ring at the 4- or 5-position of the thiazine ring have been successfully obtained as crystals.

Full text of DOI:10.1016/S0040-4039(01)00684-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4183–4186
First synthesis of stable 5-alkyl- or 4,5-dialkyl-substituted
1,2-thiazinylium salt
Hiroshi Shimizu,a,* Naoyuki Okadab and Mitsuhiro Yoshimatsub
aGifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, Japan
bDepartment of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
Received 12 March 2001; revised 13 April 2001; accepted 27 April 2001
Abstract—5-t-Butyl-1,2-thiazinylium 6c and rigid 5,8-ethano-5,8-dihydrobenzo[d]-1,2-thiazinylium salts 17 without conjugated
stabilization with the aromatic ring at the 4- or 5-position of the thiazine ring have been successfully obtained as crystals. © 2001
Elsevier Science Ltd. All rights reserved.
Recently, much attention has been paid to hetero
Diels–Alder reactions as powerful tools for the con-
struction of heterocyclic compounds.1 We have
reported the unique [2++4]-type polar cycloadditions
across the NꢀS+ bond of tricyclic dibenzo[c,e]-
[1,2]thiazinylium salt with 1,3-butadienes.2 Further-
more, we have also succeeded in the synthesis of mono-
cients of the salts obtained from the MOPAC PM3
calculation. These cycloadducts having a sulfonium ion
structure have also been reported to be easily converted
into other useful 1,2-thiazine derivatives. 4,5-Diphenyl-
1,2-thiazinylium salt is very stable and is one of the few
examples of monocyclic 1,2-thiazinylium salts synthe-
sized up to now,5 and it is considered to be stabilized by
the resonance interactions with the 4- and/or 5-phenyl
group. Our next interest is the synthesis of 5-alkyl- or
4,5-dialkyl-1,2-thiazinylium salts bearing no phenyl
substituent on the 1,2-thiazinylium ring to further
investigate the substituent effect on the stability and
reactivities of 1,2-thiazinylium salts. Here we report the
first synthesis of 5-alkyl- or 4,5-dialkyl-1,2-thiazinylium
salts.
cyclic
4,5-diphenyl-1,2-thiazinylium
salt,
which
provided several 1,2-thiazines having novel biological
activities;3 however, the reactions with 1,3-butadienes
underwent the [2++4]cycloaddition across the CꢀS+
bond of the 1,2-thiazinylium salt, not across the NꢀS+
bond, to give 1,6-(2-buteno)-6H-1,2-thiazinylium salts,
exclusively4 (Scheme 1). The high regioselectivity of the
cycloadditions was explained in terms of LUMO coeffi-
R
R
Ph
Ph
Ph
N
Ph
Ph
R
R
Ph
R
R
Nu
S
S
S
N
N
ClO4
ClO4
Nu
Nu = OMe, OEt, NHPh
NaH
R
Ph
N
Ph
N
Ph
R
R
Ph
R
+
S
S
Scheme 1.
Keywords: 5-alkyl-1,2-thiazinylium salt; monocyclic 1,2-thiazine; [2++4]cycloaddition.
* Corresponding author. Tel.: +00 81 58 237 3931; fax: +00 81 58 237 5979; e-mail: shimizu@gifu-pu.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00684-0

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H. Shimizu et al. / Tetrahedron Letters 42 (2001) 4183–4186
drous trifluoromethanesulfonic acid (Scheme 3). The
The preparation of 5H-1,2-thiazines 5a–c was achieved
as shown in Scheme 2. According to our previous
report, 3,6-dihydro-2H-1,2-thiazine 1-oxides 4a–c were
obtained in good to high yields from the reactions of
N-sulfinamide 2 with 1,3-butadienes, followed by
reduction with Zn. The Pummerer reactions of 4a–c
with trifluoroacetic anhydride gave only low yields of
the desired 5H-1,2-thiazines 5a–c. Therefore, we exam-
ined other methods for the conversion of thiazine 1-
oxides 4 to the 1,2-thiazines 5. We found that
polyphosphoric acid trimethylsilyl ester (PPSE),6 which
has been usually used for dehydration of alcohols, acts
as an effective dehydrating agent. The treatment of
4a–c with PPSE afforded the 1,2-thiazines 5a–c in high
yields.
precipitated white powder was immediately collected by
1
filtration and subjected to H NMR measurement by
which the formation of 4,5-dimethyl-1,2-thiazinylium
trifluoromethanesulfonate (6b) was observed.9 The sig-
nals of both 3- and 6-H of 6b appeared at l 10.03 and
10.77, respectively.
We further investigated the preparation of 5-t-butyl-
1,2-thiazinylium salt bearing no active hydrogen of the
δH4 8.62 (d,J 5Hz)
δH6 11.04 (s)
Me
Me
Me
H
H
H
OEt
ii
i
S+
S
S
First, we examined the synthesis of 5-methyl-1,2-
thiazinylium salt 6a from 5a by our original method
using SO2Cl2/70% HClO4, which was very effective for
the preparation of 4,5-diphenyl-1,2-thiazinylium salt;
however, the desired 6a could not be isolated at room
temperature because of its high moisture sensitivity.
Therefore, we attempted the in situ formation of 1,2-
thiazinylium perchlorate 6a. Treatment of 5a with
SO2Cl2 at −30°C and the successive reaction with
HClO4 afforded 5-methyl-1,2-thiazinylium perchlorate
N
N
N
ClO4
6a
5a
7a (9%)
δH3 10.12 (d, J 5Hz)
δH6 10.77 (s)
Me
Me
Me
H
H
Me
iii
S+
S
N
N
CF3SO3
6b
5b
1
(6a), although it was not a pure salt. The H NMR
δH3 10.03 (s)
spectrum of the perchlorate 6a exhibited the character-
istic protons of the imine H at l 10.12 (d, J 5 Hz) and
the proton a to the sulfur atom at l 11.04 (s).7 In order
to confirm the formation of 6a, the in situ formed 6a at
−30°C was treated with NaOEt to give 6-ethoxy-5-
methyl-1,2-thiazine (7a) in 9% yield8 (Scheme 3).
Scheme 3. Reagents: (i) SO2Cl2/70% HClO4; (ii) NaOEt/
EtOH; (iii) SO2Cl2/CF3SO3H/−30°C.
t-Bu
t-Bu
t-Bu
Nu
ii
i
Next, we examined the preparation of 4,5-dimethyl-1,2-
thiazinylium salt 6b; however, the attempts provided
almost the same result as that of 6a. The product was a
powder, which could not be dissolved in any solvent.
These results suggest that 5-methyl- or 4,5-dimethyl-
1,2-thiazinylium salts are labile to the moisture and
would easily undergo polymerization via the deproto-
nation of the 4- or 5-methyl group of the 1,2-thi-
azinylium salts 6a,b. Since 70% HClO4 contains 30%
water, we further investigated the in situ formation of
6b under dry conditions. An addition of SO2Cl2 to a
CH2Cl2 solution of 5b at −78°C provided a yellow
suspension, which was successively treated with anhy-
S
S+
ClO4
6c (87%)
S
N
N
N
7c (Nu = OMe) (91%)
5c
iii
t-Bu
t-Bu
ClO4
Me
Me
Me
S+
N
S
N
+
ClO4
Me
9c
8c (87%)
Scheme 4. Reagents: (i) SO2Cl2/70% HClO4; (ii) NaOMe/
MeOH; (iii) 2,3-dimethyl-1,3-butadiene/MeCN.
R2
R1
ii
i
O
Cl3CCH2OCON
S
Cl3CCH2OCONH2
S
2
1
N
O
R2
R2
CO2CH2CCl3
R1
R1
iii
a: R1 = H; R2 = Me
b: R1 = R2 = Me
c: R1 = H; R2 = t-Bu
3a (88%)
3b (78%)
3c (75%)
iv
S
S
N
H
N
O
5a(quant.)
5b (91%)
5c (89%)
4a (46%)
4b (92%)
4c (55%)
PPSE = polyphosphoric acid
trimethylsilyl ester
Scheme 2. Reagents: (i) SOCl2/pyridine/ether; (ii) 1,3-butadiene; (iii) Zn/t-BuOH; (iv) PPSE/CH2Cl2.

H. Shimizu et al. / Tetrahedron Letters 42 (2001) 4183–4186
4185
CH2I
CH2I
CH2OH
CH2OH
CH2OTs
CH2OTs
i
ii
iii
10
13 (96%)
12 (45%)
11 (43%)
vi
O
v
iv
S
S
O
N
S
N
N
H
CO2CH2CCl3
15 (79%)
14 (61%)
16 (54%)
Ts: p-toluenesulfonyl
vii
+
S
N CF3SO3
17 (57%)
Scheme 5. Reagents: (i) TsCl/pyridine; (ii) NaI/acetone; (iii) t-BuOK/t-BuOH; (iv) Cl3CCH2OCONH2/SOCl2/pyridine/ether; (v)
Zn/t-BuOH; (vi) PPSE/CH2Cl2; (vii) SO2Cl2/CF3SO3H/0°C.
2. Shimizu, H.; Hatano, T.; Matsuda, T.; Iwamura, T.
Tetrahedron Lett. 1999, 40, 95–96.
5-alkyl group (Scheme 4). The general method using
SO2Cl2/70% HClO4 afforded 1,2-thiazinylium salt 6c as
stable colorless needles.10 The reactions of 6c with
nucleophiles were studied. The reaction with NaOMe
gave 6-methoxy-1,2-thiazine (7c)11 in high yield. We
have been interested in the regiochemistry of [2++4]-
type polar cycloaddition of 1,2-thiazinylium salts with
1,3-dienes, as described above. In line with this interest,
we investigated the cycloaddition of the salt 6c. Treat-
ment with 2,3-dimethyl-1,3-butadiene provided 5-t-
butyl-1,6-(2,3-dimethyl-2-buteno)-6H-1,2-thiazinium
perchlorate (8c), not 9c, showing that the [2++4] polar
cycloaddition reaction of the salt 6c occurred across the
CꢀS+ bond, and not across the NꢀS+ bond, of the
thiazinylium ring. The structure of 8c was determined
by 1H NMR spectral data, showing the methylene
protons b to the sulfur atom at l 2.32 (dd, J 18 and 10
Hz) and 2.50 (dd, J 18 and 6 Hz) and a methine proton
coupled with those methylene protons at l 4.42 (dd, J
10 and 6 Hz).12
3. (a) Lombardino, J. G. Nonsteroidal Anti-inflammatory
Drugs; Wiley: New York, 1985; (b) Garigipati, R. S.;
Cordova, R.; Parvez, M.; Weinreb, S. M. Tetrahedron
1986, 42, 2979–2983; (c) Bonacorso, H. G.; Bittencourt,
S. R. T.; Lourega, R. V.; Flores, A. F. C.; Zanatta, N.;
Martins, M. A. P. Synthesis 2000, 1431–1434.
4. Shimizu, H.; Hatano, T.; Iwamura, T. Tetrahedron Lett.
1999, 40, 1505–1508.
5. Boese, R.; Haas, A.; Heß, T. Chem. Ber. 1992, 125,
581–589.
6. (a) Imamoto, T.; Matsumoto, T.; Yokoyama, M.;
Yamaguchi, K. J. Org. Chem. 1984, 49, 1105–1110; (b)
Yoshimatsu, M.; Yamada, H.; Shimizu, H.; Kataoka, T.
J. Chem. Soc., Chem. Commun. 1994, 2107–2108; (c)
Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu,
H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798–4802; (d)
Yoshimatsu, M.; Fuseya, T. Chem. Pharm. Bull. 1996, 44,
1954–1957.
1
7. Characterization data of 6a: IR w 1090 (ClO4−); H NMR
l 2.85 (3H, s, Me), 8.62 (1H, d, J 5 Hz, 4-H), 10.12 (1H,
d, J 5 Hz, 3-H), 11.04 (1H, s, 6-H); MS m/z 111 (M+−
ClO4−).
Finally, we performed the preparation of 5,8-ethano-
5,8-dihydrobenzo[d]-1,2-thiazinylium salt which is
expected to be resistant to the deprotonation at the
4,5-disubstituted moiety according to the Bredt’s rule.
5,6-Dimethylenebicyclo[2.2.2]oct-2-ene 13 was prepared
using the usual method, as shown in Scheme 5. The
p-toluenesulfonylation and subsequent iodination of
the diol 10 afforded 5,6-bis(iodomethyl)bicyclo[2.2.2]-
oct-2-ene 12 in moderate yields.13 The diiodide 12 was
treated with a large excess of t-BuOK in t-BuOH under
reflux conditions to give 13 in high yield. The general
procedure for the preparation of thiazinylium salts with
the diene 13 provided the desired 1,2-thiazinylium tri-
fluoromethanesulfonate 1714 as a rather stable salt. We
are now investigating the chemistry of this unique
4,5-disubstituted 1,2-thiazinylium salt 17.
1
8. Characterization data of 7a: IR w 1120 (ether); H NMR
l 0.88 (3H, t, J 7 Hz, Me), 2.13 (3H, s, Me), 3.28–3.39
(1H, m, CH2), 3.63–3.70 (1H, m, CH2), 5.08 (1H, s, 6-H),
6.23 (1H, d, J 4 Hz, 4-H), 8.07 (1H, d, J 4 Hz, 3-H); MS
m/z 112 (M+−OEt).
9. Characterization data of 6b: 1H NMR l 2.74 (3H, s, Me),
2.82 (3H, s, Me), 10.03 (1H, s, 3-H), 10.77 (1H, s, 6-H).
10. Characterization data of 6c: colorless prisms, mp 188–
191°C, IR w 1110 (ClO4−), 1H NMR l 1.48 (9H, s,
Me×3), 8.83 (1H, d, J 4 Hz, 4-H), 10.18 (1H, d, J 4 Hz,
3-H), 11.23 (1H, s, 6-H); 13C NMR l 29.52 (q×3), 38.81
(s), 137.13 (d), 165.17 (d), 175.97 (d); MS m/z 154
(M+−ClO4). Anal. calcd for C8H12ClNO4S: C, 37.87; H,
4.77; N, 5.52. Found: C, 37.69; H, 4.72; N, 5.51.
1
11. Characterization data of 7c: IR w 1060 (ether); H NMR
l 1.23 (9H, s, Me×3), 3.27 (3H, s, OMe), 5.07 (1H, s,
6-H), 6.29 (1H, d, J 4 Hz, 4-H), 8.22 (1H, d, J 4 Hz,
3-H), 13C NMR l 29.38 (q×3), 35.96 (s), 52.76 (q), 75.98
(d), 115.63 (d), 145.57 (s), 153.61 (d); high-resolution
mass calcd for C9H15NOS: 185.0874, found m/z
185.0877.
References
1. Boger, D. L.; Weinreb, S. M. In Hetero Diels–Alder
Methodology in Organic Synthesis; Wasserman, H. H.,
Ed.; Academic Press, 1987; p. 1.

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H. Shimizu et al. / Tetrahedron Letters 42 (2001) 4183–4186
12. Characterization data of 8c: white powder, mp 109–
111°C, IR w 1080 (ClO4−); 1H NMR l 1.28 (9H, s,
Me×3), 1.80 (3H, s, Me), 1.87 (3H, s, Me), 2.32 (1H, dd,
J 18 and 10 Hz, 7-H), 2.50 (1H, dd, J 18 and 6 Hz, 7-H),
4.02 (1H, d, J 18 Hz, 10-H), 4.42 (1H, dd, J 10 and 6 Hz,
6-H), 4.59 (1H, d, J 18 Hz, 10-H), 6.44 (1H, d, J 4 Hz,
4-H), 8.47 (1H, d, J 4 Hz, 3-H); 13C NMR l 19.58 (q),
20.91 (q), 28.40 (q×3), 30.72 (t), 35.36 (d), 38.26 (s), 40.00
(t), 117.04 (s), 118.02 (d), 129.40 (s), 163.02 (s), 170.78
(d); MS m/z 236 (M+−ClO4). Anal. calcd for
C14H22ClNO4S1/2H2O: C, 48.76; H, 6.72; N, 4.06.
Found: C, 48.70; H, 6.65; N, 4.05.
13. Bailey, J. W.; Lawson, B. W. J. Am. Chem. Soc. 1957, 79,
1444–1447.
14. Characterization data of 17: brown powder, mp 95–98°C
(dec.), IR w 1160 (SO3); 1H NMR l 1.49–1.60 (2H, m,
CH2), 1.78–1.92 (2H, m, CH2), 4.68–4.70 (1H, m, CH),
4.76–4.79 (1H, m, CH), 6.65–6.71 (2H, m, olefinic H),
10.17 (1H, d, J 1 Hz, 4-H), 10.95 (1H, d, J 1 Hz, 1-H);
13C NMR l 24.27 (d), 24.47 (d), 42.44 (t), 42.71 (t),
134.26 (d), 134.34 (d), 159.25 (s), 159.78 (s), 160.42 (d),
169.74 (d).
.