Novel rearrangement of N-enoyl oxazolidinethiones to N-substituted 1,3-thiazine-2,4-diones promoted by NbCl5

Article abstract of DOI:10.1016/j.tetlet.2005.12.019

NbCl₅ has been employed as promoter of a novel rearrangement to afford chiral N-substituted 1,3-thiazine-2,4-diones with one or two new stereogenic centers from di- and trisubstituted N-enoyl oxazolidinethiones. The trisubstituted E-isomers pro

Full text of DOI:10.1016/j.tetlet.2005.12.019

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1153–1156
Novel rearrangement of N-enoyl oxazolidinethiones to
N-substituted 1,3-thiazine-2,4-diones promoted by NbCl5
a
b
a
b
´
`
Hector Hernandez, Sylvain Bernes, Leticia Quintero, Estibaliz Sansinenea
and Aurelio Ortiza,*
aCentro de investigacio´n, de la Facultad de Ciencias Quı´micas, de la Beneme´rita Universidad Auto´noma de Puebla,
Puebla Pue. 72570, Mexico
bInstituto de Ciencias, de la Beneme´rita Universidad Auto´noma de Puebla, Puebla Pue. 72570, Mexico
Received 12 November 2005; revised 2 December 2005; accepted 5 December 2005
Abstract—NbCl5 has been employed as promoter of a novel rearrangement to afford chiral N-substituted 1,3-thiazine-2,4-diones
with one or two new stereogenic centers from di- and trisubstituted N-enoyl oxazolidinethiones. The trisubstituted E-isomers pro-
vide the anti-diastereomers mainly.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The six membered heterocyclic 1,3-thiazine-2,4-dione
type has been the subject of great interest because of
its different biological activities; for example, 5-ethyl-6-
phenyl-1,3-thiazine-2,4-dione has been demonstrated to
be an anesthetic agent, however also has exhibited unde-
sirable side effects, as thrombophlebitis.1 3-(b-amino-
ethyl)-1,3-thiazine-2,4-dione hydrochloride has been
reported to have antiradiation activity.2 Substituted
1,3-thiazine-2,4-diones and 1,3-thiazine-4-ones were pat-
ented as useful sedatives, hypnotics, intravenous anes-
thetics, or anticonvulsants.2
Compounds (2a–f) were prepared from 1 as previously
described.5 Each of the compounds were added to a
solution of (3.0 equiv) NbCl5 in 100 mL of CH2Cl2 at
ꢀ78 ꢁC, followed by stirring at room temperature to
provide the compounds (3a–f) as shown in Schemes 1
and 2.
S
S
O
a
O
NH
O
N
R1
Much of the research in heterocyclic chemistry is con-
cerned with the development of new methods for ring
syntheses. The synthesis of the 1,3-thiazine-2,4-dione
ring has been performed by different methods, for exam-
ple, condensation of thiourea with a,b-unsaturated carb-
oxylic acids in phosphoric acid3a or sulfuric acid,3b
addition reaction of ethylenethiourea,4a thiourea,4b
ethyl thioglycolate,4b or O-ethyl allylthiocarbamate4c
to b-haloacids. The first chiral 1,3-thiazinedione has
been obtained by addition reaction of an oxazolidine-
thione to N-enoyl oxazolidinethione.4d In this letter we
describe a novel rearrangement carried out with N-enoyl
oxazolidinethiones using NbCl5 as a promoter to pro-
vide chiral N-substituted 1,3-thiazine-2,4-diones.
1
2a R1 = Me
2b R1 = Ph
2c R1 = iPr
b
R1
N
R2
S
O
O
3a R1= Me R2 = H 4a R1 = H R2 = Me
3b R1= Ph R2 = H 4b R1= H R2 = Ph
3c R1 = iPr R2 = H 4c R1 = H R2 = iPr
*
Scheme 1. Reagents and conditions: (a) NaH, R1CHCHCOCl, 0 ꢁC
Corresponding author. Tel.: +52 222 2295500x7518; fax: +52 222
CH2Cl2; (b) NbCl5 (3.0 equiv), CH2Cl2, rt.
2295584; e-mail: jaortizm@siu.buap.mx
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.019

1154
H. Herna´ndez et al. / Tetrahedron Letters 47 (2006) 1153–1156
R1
R1
S
O
R2
O
R2
O
6
S
S1
5
4
O
N
R1
b
2
+
3
O
N
O
N
R2
(4d-4f)
(3d-3f)
2d = R1 = Me, R2 = Me
2e = R1 = Ph, R2 = Me
2f = R1 = R2 = - (CH2)4
3d = 4d R1 = Me, R2 = Me
3e = 4e R1 = Ph, R2 = Me
3f = 4f R1 = R2 = -(CH2)4
Scheme 2. Reagents: (b) NbCl5 3.0 equiv, CH2Cl2, H2O.
This rearrangement was carried out with di-(2a–c) and
trisubstituted N-enoyl oxazolidinethiones (2d–f) to pro-
vide heterocyclic compounds with one (3a–c) or two
(3d–f) new chiral centers (Scheme 2), in a range of 16–
87% yield, all of them as colorless liquids, except for
3f and 4e as white solid compounds. The results of these
reactions are shown in Table 1.
Table 1. Rearrangement of N-enoyl oxazolidinethiones
Products
t (h)a
Yield (%)b
dr (3:4)c
3a/4a
3b/4b
3c/4c
3d/4d
3e/4e
3f/4f
48
12
48
14
16
12
60.0
87.0
18.0
16.0
55.0
82.0
98/2
98/2
98/2
83/17
60/40
96/4
a t = time.
b Purified yield.
c Diastereomeric isomer ratios were determined by 1H and 13C NMR
on the crude products.
Figure 1. Molecular structure of adduct 4e.
which is homologous to b-mercapto, the compound pre-
From the data in Table 1, it was observed that the for-
mation of new chiral centers in compounds 3a–c and 3f
is highly diastereoselective, however in the case of com-
pounds 3d and 3e there is a notable difference in the dia-
stereomeric isomer ratios maybe because the formation
of the second new chiral center is through a diastereo-
selective protonation reaction, giving at room temperature
modest diastereoselectivity. The stereochemical outcome
of the major diastereomers can be rationalized by com-
viously described.5
Absolute configuration for majority compounds (3a–f)
was assigned on the basis of the comparison between
the 1,3-thiazines and the b-mercapto compounds previ-
ously described.5 The formation of 3 can be explained
by the previous formation of the immonium ion I,5c
which is obtained by an intramolecular sulfur transfer
to C(b) in the N-enoyl oxazolidinethione 2 as a plausible
conjecture. The unexpected elimination reaction led to
the formation of the double bond in 3 as shown in
Scheme 3.
3
parison of the JHH values for thiazines (3d–f and 4e)
and the use of a generalized Karplus type relationship6
that allowed to establish the relative configuration of
the two newly created stereogenic centers as anti for
3d–f and syn for 4e (as shown in Table 2). The absolute
configuration at the newly formed stereogenic centers
(C-5, C-6) are R and S, respectively, as established by
X-ray analysis of the minority compound 4e (Fig. 1),7
The rearrangement was explored using the compounds
2a and 2b employing different amounts of promoter to
provide the thiazines (3a,b) or b-mercapto carbonyl
adducts5a (5a,b) as shown in Scheme 4. The results of
these reactions are shown in Table 3.
Table 2. Comparison of the vicinal coupling constants
From the data in Table 3, it was observed that the for-
mation of the thiazines 3a and 3b was carried out
through a competitive reaction to the formation of the
b-mercapto carbonyl adducts (5a and 5b). When 3 equiv
of NbCl5 was used, the thiazine ring was favored while
the use of 1.2 equiv lead to well known b-mercapto com-
Products
3JH-5-H-6 (Hz)
Dihedral angle (ꢁ)
3d-(5S,6R)
3e-(5S,6S)
3f-(5S,6R)
4e-(5R,6S)
7.2
10.2
12.0
4.2
139
155
170
51

H. Herna´ndez et al. / Tetrahedron Letters 47 (2006) 1153–1156
1155
diastereomeric mixture of b-mercapto adducts 5a. For
the formation of the double bond in the thiazines we
currently do not have a rational explanation, since the
rearrangement was further investigated using 2b with
3 equiv of NbCl5 and 1.5 equiv of NEt3 to provide the
thiazine 3b in 60% yield in a reaction time of 6 h. Thi-
azines 3a and 3b were treated with 3 equiv of NaIO4
and a catalytic amount of OsO4 in THF/H2O, to provide
ketones 6a and 6b in 46% and 50% yield, respectively.
To ketone 6b was added NaBH4 in MeOH at 0 ꢁC to
provide a diastereomeric mixture of (4S,5S)-8a and
(4S,5R)-4-isopropyl-5-methyl oxazolidinone10 8b in a
R1
S
O
S
O
N
R1
O
N
O-NbCl4
Cl
2
I
R1
N
S
O
O
ratio 60:40, and the respective mercapto alcohol 7 in
25
44% yield, ½aꢁD ꢀ45 (c 0.5, CHCl3) as shown in Scheme
5.
3
Scheme 3. Possible course of the transformation of 2 to 3.
R1
N
R1
N
S
S
a
O
O
O
O
O
R1
S
O
N
O
+
3a R1 = Me
3b R1 = Ph
6a R1 = Me
6b R1 = Ph
S
O
Promoter
CH Cl
O
N
R1
3a R1= Me 3b R1= Ph
2
2
Ph
S
O
O
O
SH
R1
SH
b
O
NH
O
N
+
HO
Ph
O
O
N
O
R1
2a R1= Me 2b R1= Ph
R2
8a R1 = Me, R2 = H
8b R1 = H, R2 = Me
7
6b
5a R1= Me 5b R1= Ph
Scheme 5. Reagents: (a) NaIO4, OsO4, THF/H2O; (b) NaBH4,
MeOH.
Scheme 4.
Complete assignment11 of the 1H and 13C NMR spectra
of 3a–f and 4e was achieved by 2D proton–proton and
2D carbon–proton correlated experiments.
Table 3. Optimization of the reaction of 2a and 2b
Compound Promoter (equiv) T (ꢁC)/t (h) Yielda 3/5 drb
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
SnCl4 (1.2)
SnCl4 (3.0)
NbCl5 (1.2)
NbCl5 (2.0)
NbCl5 (3.0)
NbCl5 (1.2)
NbCl5 (1.2)
NbCl5 (2.0)
NbCl5 (3.0)
NbCl5 (3.0)
25/12
25/18
25/12
25/12
25/48
25/14
40/2
25/14
40/4
25/12
0/40
0/43
0/45
15/24
60/0
60/0
70/30
69/31
68/32
90/10
98/2
76/24
57/43
80/20
98/2
In conclusion we have found that NbCl5 is an excellent
promoter of a new rearrangement that was carried out
in N-enoyl oxazolidinethiones to give chiral N-substi-
tuted 1,3-thiazine-2,4-diones with one or two new chiral
centers. The E-isomers 2d–f provide the anti-diastereo-
isomers, 3d–f as main products.
40/0
40/50
82/15
87/0
98/2
Acknowledgments
a Purified yield.
b Diastereomeric isomer ratios were determined by 1H and 13C NMR
on the crude products of the major diastereoisomer.
We thank VIEP (project) 37/G/NAT/05. H.H. acknow-
ledges a grant from Promep.
pound.5 We also studied the effect of the temperature: at
40 ꢁC in 2b with 1.2 and 3.0 equiv of NbCl5, it was ob-
served that the reaction was oriented preferably to prod-
uct 3b in a shorter reaction time than at room
temperature. Compound 2a was treated with 1.2 and
3.0 equiv of SnCl4 at rt, and in both cases provided a
References and notes
1. Taborsky, R. G.; Starkey, R. J. J. Med. Chem. 1962, 5,
775–780.
2. Campaigne, E.; Nargund, P. K. J. Med. Chem. 1964, 7,
132–135.

1156
H. Herna´ndez et al. / Tetrahedron Letters 47 (2006) 1153–1156
1
3. (a) Taborsky, R. G. J. Org. Chem. 1958, 23, 1779–1780;
Compound 3c. H NMR (400 MHz, CDCl3) d: 5.10 (1H,
s, H-10), 5.05 (1H, s, H-10), 4.83 (1H, d, J = 11.2 Hz,
H-30), 3.17 (1H, ddd, J = 3.3, 7.2, 10.0 Hz, H-6), 3.04
(1H, dd, J = 3.6, 15.2 Hz, H-5), 2.75 (1H, m, H-40), 1.86
(1H, m, CH-6), 1.73 (3H, s, CH3-20), 1.05 (3H, d,
J = 6.0 Hz, CH3), 1.04 (3H, d, J = 6.4 Hz, CH3), 0.97
(3H, d, J = 6.4 Hz, CH3-40), 0.82 (3H, d, J = 6.4 Hz,
CH3-50). 13C NMR (100 MHz, CDCl3) d: 171.2 (CO),
169.1 (CO), 141.3 (C-20), 116.4 (C-10), 65.2 (C-30),
44.0 (C-6), 39.4 (C-5), 26.6 (C-40), 32.2 (CH-6), 22.0
(CH3-20), 21.3(CH3-50), 19.7 (CH3), 19.6 (CH3-40), 19.5
(b) Van Der Vliet, P. N. W.; Hamersma, J. A. M.;
Speckamp, W. N. Tetrahedron 1985, 41, 2007–2010.
4. (a) Campaigne, E.; Wani, M. C. J. Org. Chem. Soc. 1964,
29, 1715–1719; (b) Sohda, T.; Mizuno, K.; Tawada, H.;
Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Chem. Pharm.
Bull. 1982, 30, 3563–3573; (c) Campaigne, E.; Nargund, P.
K. J. Org. Chem. 1964, 29, 224–226; (d) Ortiz, A.;
`
Quintero, L.; Mendoza, G.; Bernes, S. Tetrahedron Lett.
2003, 44, 5053–5055.
´
5. (a) Ortiz, A.; Quintero, L.; Hernandez, H.; Maldonado, S.;
25
`
Mendoza, G.; Bernes, S. Tetrahedron Lett. 2003, 44, 1129–
(CH3), ½aꢁD ꢀ15.1 (c 0.9, CHCl3).
1
´
1132; (b) Ortiz, A.; Hernandez, H.; Mendoza, G.; Quin-
Compound 3d. H NMR (400 MHz, CDCl3) d: 5.10 (1H,
s, H-10), 5.06 (1H, s, H-10), 4.85 (1H, d, J = 10.8 Hz, H-
30), 3.10 (1H, dq, J = 6.8, 7.2 Hz, H-6), 2.85 (1H, dq,
J = 6.8, 7.2 Hz, H-5), 2.76 (1H, m, H-40), 1.71 (3H, s,
CH3-20), 1.45 (3H, d, J = 6.8 Hz, CH3-6), 1.40 (3H, d,
J = 6.8 Hz, CH3-5), 0.97 (3H, d, J = 6.4 Hz, CH3-50),
0.84 (3H, d, J = 6.8 Hz, CH3-50). 13C NMR (100 MHz,
CDCl3) d: 173.7 (2CO), 140.5 (C-20), 116.0 (C-10), 65.0
(C-30), 45.6 (C-6), 38.1 (C-5), 27.1 (C-40), 21.8 (C-20),
`
tero, L.; Bernes, S. Tetrahedron Lett. 2005, 46, 2243–2246;
(c) Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden,
A. J. Am. Chem. Soc. 2001, 123, 5602–5603.
6. Cerda-Garcıa-Rojas, C. M.; Zepeda, L. G.; Joseph-
´
Nathan, P. Tetrahedron Comput. 1990, 3, 113.
7. Crystal data for 4e: C18H23NO2S, M = 317.43, colorless
plate, 0.60 · 0.20 · 0.08 mm3, space group C2, cell para-
˚
meters a = 22.097 (4), b = 8.6353 (15), c = 20.372 (3) A,
25
b = 109.32 (2)ꢁ, Z = 8, Z0 = 2, Dc = 1.150 g cmꢀ3, 9384
21.4 (C-8), 21.4 (C-50), 19.4 (C-40), 15.4 (C-7). ½aꢁD ꢀ49.9
reflections collected on a Bruker P4 diffractometer at room
(c 1.3, CHCl3).
1
˚
temp., with the Mo-Ka radiation (k = 0.71073 A) in the
Compound 3e. H NMR (300 MHz, CDCl3) d: 7.40 (5H,
range 2h = 3.78–50.00ꢁ, of which 4786 are unique
(Rint = 0.039), 407 variables refined: R1 = 0.0424 [2723
data with I > 2r(I)] and wR2 = 0.1235 [all data].8 Absolute
configuration was determined starting from the known
configuration at C8 and confirmed by the refinement of a
Flack parameter based on 1354 measured Friedel pairs,
v = 0.02(15).9 Complete data have been deposited with the
CCDC, reference 289253. Structure factors and raw files
are available on request to authors.
m, Ph), 5.11 (1H, s, H-10), 5.06 (1H, s, H-10), 4.86 (1H, d,
J = 10.8 Hz, H-30), 4.23 (1H, d, J = 10.2 Hz, H-6), 3.24
(1H, dq, J = 10.2, 6.9 Hz, H-5), 2.75 (1H, m, H-40), 1.73
(3H, s, CH3-20), 1.18 (3H, d, J = 6.9 Hz, CH3-5), 0.98
(3H, d, J = 6.6 Hz, CH3-40), 0.84 (3H, d, J = 6.6 Hz,
CH3-50). 13C NMR (75 MHz, CDCl3) d: 173.0 (CO),
169.0 (CO), 141.1 (C-20), 136.3 (Ci), 129.0 (Cm), 128.7
(Cp), 128.5 (Co), 116.2 (C-10), 66.0 (C-30), 47.1 (C-6),
45.4 (C-5), 26.3 (C-40), 21.6 (CH3-20), 21.1 (CH3-40), 19.4
25
8. Sheldrick, G. M. SHELXL97, University of Go¨ttingen,
Germany, 1997.
(CH3-50), 14.7 (CH3-5). ½aꢁD +7.77 (c 1.6, CHCl3).
1
Compound 4e. H NMR (300 MHz, CDCl3) d: 7.36 (3H,
9. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.
m, Ph),7.23 (2H, m, Ph), 5.14 (1H, s, H-10), 5.11 (1H, s ,
H-10), 4.92 (1H, d, J = 11.1 Hz, H-30), 4.60 (1H, d,
J = 4.2 Hz, H-6), 3.30 (1H, qd, J = 6.9, 4.2 Hz, H-5),
2.82 (1H, m, H-40), 1.76 (3H, s, CH3-20), 1.22 (3H, d,
J = 6.9 Hz, CH3-5), 0.98 (3H, d, J = 6.6 Hz,CH3-50), 0.86
(3H, d, J = 6.6 Hz,CH3-50). 13C NMR (75 MHz, CDCl3)
d: 173.3 (CO), 168.5 (CO), 140.7 (C-20), 135.5 (Ci), 129.0
(Cm), 128.6 (Cp), 127.8 (Co), 116.6 (C-10), 65.7 (C-30),
45.7 (C-6), 44.3 (C-5), 26.8 (C-40), 21.6 (CH3-20), 21.2
´
10. Mendoza, G.; Hernandez, H.; Quintero, L.; Sosa-Riva-
`
deneyra, M.; Bernes, S.; Sansinenea, E.; Ortiz, A. Tetra-
hedron Lett. 2005, 46, 7867–7870.
11. Compound 3a. 1H NMR (400 MHz, CDCl3) d: 5.02 (1H, s,
H-10), 5.00 (1H, s, H-10), 4.77 (1H, d, J = 11.6 Hz, H-30),
3.40 (1H, m, H-6), 2.97 (1H, dd, J = 4.4, 16.4 Hz, H-5),
2.72 (1H, dd, J = 8.8, 14.8 Hz, H-5), 2.70 (1H, m, H-40),
1.65 (3H, s, CH3-20), 1.33 (3H, d, J = 6.0 Hz, CH3-6),
0.90 (3H, d, J = 7.2 Hz, CH3-50), 0.75 (3H, d, J = 7.2 Hz,
CH3-50). 13C NMR (100 MHz, CDCl3) d: 170.2 (CO),
168.3 (CO), 140.6 (C-20), 116.1 (C-10), 65.0 (C-30), 43.0
(C-5), 31.8 (C-6), 26.6 (C-40), 21.7 (CH3-20), 21.2 (CH3-50),
25
(CH3-50), 19.6 (CH3-50), 12.7 (CH3-5). ½aꢁD ꢀ89.6 (c 1.9,
CHCl3). Mp 52 ꢁC.
1
Compound 3f. H NMR (400 MHz, CDCl3) d: 5.06 (1H,
s, H-10), 5.00 (1H, s, H-10), 4.80 (1H, d, J = 10.0 Hz, H-
30), 3.20 (1H, ddd, J = 4.0, 11.6, 12.0 Hz, H-6), 2.70 (1H,
m, H-40), 2.50 (1H, ddd, J = 4.0, 11.6, 12.0, H-5), 2.30
(1H, m, H-7e), 1.97, 1H, m, H-10e), 1.91 (1H, m, H-8e),
1.84 (1H, m, H-9e), 1.71 (3H, s, CH3-20), 1.45–1.28 (4H,
br, H-7ax–H-10ax) 0.96 (3H, d, J = 6.4 Hz, CH3-50), 0.80
(3H, d, J = 6.4 Hz, CH3-50). 13C NMR (100 MHz,
CDCl3) d: 172.5 (CO), 168.1 (CO), 141.4 (C-20), 116.0
(C-10), 65.8 (C-30), 47.7 (C-5), 39.6 (C-6), 31.5 (C-10),
27.1 (C-7), 26.0 (C-40), 25.0 (C-8), 25.0 (C-9), 21.6 (CH3-
25
20.6 (CH3-40), 19.4 (CH3-50). ½aꢁD ꢀ39.5 (c 2.1, CHCl3).
1
Compound 3b. H NMR (300 MHz, CDCl3) d: 7.40 (5H,
m, Ph), 5.12 (1H, s, H-10), 5.07 (1H, s, H-10), 4.86 (1H, d,
J = 10.8 Hz, H-30), 4.60 (1H, dd, J = 5.1, 9.6 Hz, H-6),
3.28 (2H, m, H-5), 2.77 (1H, m, H-40), 1.71 (3H, s, CH3-20),
0.98 (3H, d, J = 6.6 Hz, CH3-50), 0.84 (3H, d, J = 6.6 Hz,
CH3-50). 13C NMR (100 MHz, CDCl3) d: 170.1 (CO),
168.5 (CO), 141.0 (C-20), 136.4 (Ci), 129.2 (Cm), 128.8
(Cp), 127.2 (Co), 116.4 (C-10), 65.4 (C-30), 42.7 (C-5), 40.7
(C-6), 26.5 (C-40), 21.7 (CH3-20), 21.2 (CH3-50), 19.6 (CH3-
25
20), 21.3 (CH3-50), 19.6 (CH3-50). ½aꢁD ꢀ60.1 (c 2.8,
25
50). ½aꢁD ꢀ21.7 (c 1.2, CHCl3).
CHCl3). Mp 32 ꢁC.