Diastereoselective synthesis of 3,6-dihydro-2H-1,3,4- thiadiazines

Article abstract of DOI:10.1016/S0957-4166(98)00108-6

Thionation of the benzil hydrazones 3 with Lawesson's reagent afforded the 3,6-dihydxo-2H-1,3,4-thiadiazines 4 by an intramolecular cyclisation. This reaction was shown to be diastereospecific and allowed the formation of the exo compounds 4b-e. When the homochiral SAMP-hydrazone 3f was used, the reaction afforded enantiomerically pure (4R,6R,9S)-4f.

Full text of DOI:10.1016/S0957-4166(98)00108-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1531–1537
Diastereoselective synthesis of 3,6-dihydro-2H-1,3,4-
thiadiazines
Jean-Damien Charrier, Alain Reliquet and Jean Claude Meslin ∗
Laboratoire de Synthèse Organique, UMR CNRS 6513, Faculté des Sciences et des Techniques, 2 rue de la Houssinière,
44072 Nantes Cedex, France
Received 23 February 1998; accepted 12 March 1998
Abstract
Thionation of the benzil hydrazones 3 with Lawesson’s reagent afforded the 3,6-dihydro-2H-1,3,4-thiadiazines4
by an intramolecular cyclisation. This reaction was shown to be diastereospecific and allowed the formation of the
exo compounds 4b–e. When the homochiral SAMP–hydrazone 3f was used, the reaction afforded enantiomerically
pure (4R,6R,9S)-4f. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
1,3,4-Thiadiazines are of great interest since many compounds possessing this structure have use-
ful applications in very different areas such as pharmacology,1 agriculture2 or photography.3 Several
reviews4 report the preparation of this six-membered heterocyclic system and its use in the synthesis of
other heterocycles. In this report, we describe an original method leading to the 3,6-dihydro-2H-1,3,4-
thiadiazines 4 using a diastereospecific reaction.
2. Results and discussion
We have recently shown in our studies on 4-amino-1-thia-4-azabutadienes that the α-
hydrazonothioamides 1 can isomerise into 3,6-dihydro-2H-1,3,4-thiadiazines 2 by simple heating5
(Scheme 1).
The dialkylhydrazones 3 were prepared as previously described6 by condensation of benzil with one
equivalent of a dialkylhydrazine. The compounds 3 thus obtained were treated with Lawesson’s reagent
(LR) to give the dihydrothiadiazines 4 without isolation of any intermediates (Scheme 2).
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00108-6

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Scheme 1.
Scheme 2.
This type of intramolecular cyclisation has already been described by D. N. Reinhoudt7 and J. P.
Pradère8 who obtained 1,3-thiazines from thioamide vinylogues. M. Hojo also prepared thiadiazines by
a similar method.9
The mechanism for the transformation of 3 into 4 involves an intermediate thiocarbonyl compound 5
whose mesomeric form 6 is transformed by [1,5]-proton shift to the intermediate 7. Cyclisation resulting
from nucleophilic addition of the thiolate to the iminium ion in 7 then leads to the dihydrothiadiazine 4
(Scheme 3).
Scheme 3.
When the cyclic hydrazines (N-aminopyrrolidine, N-aminopiperidine, N-aminomorpholine, N-
aminohomopiperidine) were used in this reaction, the resultant compound 4 possessed two stereogenic
1
centres and so two diastereomers were possible. However, only one diastereomer was detected by H
and 13C NMR spectroscopy. Furthermore, chiral HPLC10 showed only two peaks of equal intensity
corresponding to the two expected enantiomers.
The diastereoselectivity of this reaction is easily explained by considering the geometry of the
‘thiolate iminium’ species 8 and 9. In this intermediate, the first chiral centre is already present and
its stereochemistry can be either R (species 8a,b) or S (species 9a,b). Attack of the thiolate can then
occur only on that face of the iminium ion in which steric interactions between the two bulky aromatic
rings are minimised. Addition of a thiolate ion 8 with the R configuration thus takes place on the Re face
of the iminium ion whereas a thiolate ion 9 with the S configuration adds to the Si face (Scheme 4).
By this mechanism the diastereomer RR–SS (4b1,b2) is obtained. At this stage the sole evidence for
the relative stereochemistry of 4 was based on comparison of the 1H NMR spectra of compounds 4a and
4b–e. In 4a the proton in position 6 was coupled (4J=1.8 Hz) to only one of the protons in position 2

J.-D. Charrier et al. / Tetrahedron: Asymmetry 9 (1998) 1531–1537
1533
Scheme 4.
which has been proved to be Hcis by an NOE experiment which showed enhancement of Hcis when H6
was irradiated (Scheme 5).
Scheme 5.
For the compounds 4b–e no coupling constant was observed between H2 and H6. Both protons are
thus in a trans relationship. This observation confirms the stereochemistry expected from the proposed
mechanism.
The synthesis was now investigated using a cyclic hydrazine bearing a chiral centre: SAMP11 ((S)-
1-amino-2-methoxymethylpyrrolidine). The bulky methoxymethyl group will hinder the Si face of the
intermediate ‘thiolate iminium’ 10b so that ring closure of this species will be impossible. The thiadiazine
4f resulting from the ring closure of the species 10a was thus obtained as a pure stereoisomer with
absolute configuration 4R,6R,9S as proved by X-ray structure analysis12 (Scheme 6).
Scheme 6.

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3. Conclusion
Current interest in the 1,3,4-thiadiazines skeleton justifies development of new methods to synthesize
compounds with this basic structure. In the novel approach presented here, we show that our method
has high diastereoselectivity: the dihydrothiadiazines 4b–e are obtained as the sole diastereomers.
The two stereogenic centres created in these compounds have an exo relationship. In the presence of
SAMP–hydrazone, complete asymmetric induction yields the single enantiomer (4R,6R,9S)-4f.
4. Experimental
Melting points are uncorrected (Reichert microscope), optical rotations were obtained using an AA.10
optical activity polarimeter, NMR spectra were recorded using a Bruker AC 200 spectrometer with Me4Si
as internal reference (δ given in ppm, J in hertz), IR spectra (film or KBr pellets) were measured on a
Bruker IFS 85 spectrometer, MS spectra were taken on a Hewlett Packard 5989 spectrometer. Flash
chromatography was performed on Merck kieselgel 60 Art. 7734 or 9385 silica gel. All reactions were
performed under an inert atmosphere (N2) and all the solvents were freshly distilled using standard
procedures.
4.1. Typical procedure for preparation of benzil monohydrazones 3
The N,N-dialkylhydrazine (5×10−3 mol) [or its hydrochloride salt (7.5×10−3 mol) for 3b] was added
to a solution of benzil (5×10−3 mol) and acetic acid (5×10−3 mol) [or sodium acetate (7.5×10−3 mol)
for 3b] in ethanol (8 mL). The solution was stirred for 20 h under N2 at room temperature. The solvent
was removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL) and washed
with brine (20 mL). The organic layer was dried with MgSO4 and the solvent was removed under reduced
pressure. The crude compounds were purified by flash chromatography using dichloromethane as eluent.
The compounds 3a–e were crystallised from ethyl acetate.
4.2. Benzil N,N-dimethylmonohydrazone 3a
Pale yellow crystals: mp 99°C; yield 92%; IR (KBr): 2893, 1619, 1532, 1315, 1293, 1204, 1065,
1
1022, 874, 739, 725, 701, 694, 670 cm−1; H NMR (CDCl3) δ: 2.59 (s, 3H, CH3), 2.88 (s, 3H, CH3),
7.34–7.87 (m, 10H, 2C6H5); 13C NMR δ: 46.9 (CH3), 127.3 (CH), 127.6 (CH), 127.9 (CH), 130.2 (CH),
130.3 (CH), 130.5 (CH), 135.5 (C), 138.4 (C), 139.6 (C), 192.5 (CO); MS m/z: 252 (M+). Anal. calcd for
C16H16N2O: C, 76.17; H, 6.39; N, 11.10. Found: C, 76.44; H, 6.44; N, 11.19.
4.3. Benzil-N-pyrrolidinomonoimine 3b
Pale yellow crystals: mp 114°C; yield 58%; IR (KBr): 3042, 2968, 2870, 1628, 1530, 1288, 1082,
1069, 877, 857, 730, 701, 676 cm−1; 1H NMR (CDCl3) δ: 1.76 (m, 4H, 2CH2), 3.15 (m, 4H, 2NCH2),
7.34–7.91 (m, 10H, 2C6H5); 13C NMR δ: 24.2 (2CH2), 55.1 (2NCH2), 127.2 (CH), 127.3 (CH), 127.7
(CH), 130.3 (CH), 130.4 (CH), 130.5 (CH), 135.8 (C), 137.9 (C), 139.8 (C), 192.4 (CO); MS m/z: 278
(M+).

J.-D. Charrier et al. / Tetrahedron: Asymmetry 9 (1998) 1531–1537
1535
4.4. Benzil-N-piperidinomonoimine 3c
Yellow crystals: mp 71°C; yield 86%; IR (KBr): 3057, 2939, 2819, 1675, 1597, 1470, 1449, 1447,
1
1316, 1229, 1215, 1036, 940, 786, 776, 729, 699, 641 cm−1; H NMR (CDCl3) δ: 1.34–1.40 (m, 6H,
3CH2), 2.73 (m, 4H, 2NCH2), 7.34–7.89 (m, 10H, 2C6H5); 13C NMR δ: 23.5 (CH2), 24.8 (2CH2), 55.9
(2NCH2), 127.4 (CH), 128.3 (CH), 128.7 (CH), 129.0 (CH), 130.4 (CH), 130.8 (CH), 133.0 (C), 135.9
(C), 166.3 (CN), 196.4 (CO); MS m/z: 292 (M+). Anal. calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58.
Found: C, 78.30; H, 6.88; N, 9.40.
4.5. Benzil-N-morpholinomonoimine 3d
Pale yellow crystals: mp 109°C; yield 90%; IR (KBr): 2973, 2893, 2846, 1673, 1596, 1450, 1446,
1329, 1305, 1269, 1262, 1226, 1108, 1073, 969, 946, 907, 861, 776, 734, 707, 698, 693, 652 cm−1; 1H
NMR (CDCl3) δ: 2.80 (m, 4H, 2NCH2), 3.53 (m, 4H, 2OCH2), 7.31–7.92 (m, 10H, 2C6H5); 13C NMR
δ: 55.1 (2NCH2), 65.8 (2OCH2), 127.5 (CH), 128.4 (CH), 128.7 (CH), 128.8 (CH), 131.2 (CH), 133.6
(CH), 132.5 (C), 135.6 (C), 168.0 (CN), 196.3 (CO); MS m/z: 294 (M+). Anal. calcd for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.46; H, 6.14; N, 9.30.
4.6. Benzil-N-homopiperidinomonoimine 3e
Pale yellow crystals: mp 99°C; yield 58%; IR (KBr): 3049, 2937, 2858, 1626, 1550, 1442, 1318, 1312,
1304, 1285, 1077, 1070, 877, 726, 704, 698 cm−1; 1H NMR (CDCl3) δ: 1.52 (m, 8H, 4CH2), 3.30 (m,
4H, 2NCH2), 7.25–7.87 (m, 10H, 2C6H5); 13C NMR δ: 27.5 (2CH2), 27.6 (2CH2), 57.1 (2NCH2), 127.1
(CH), 127.6 (CH), 127.7 (CH), 130.0 (CH), 130.1 (CH), 130.2 (CH), 136.1 (C), 136.5 (C), 140.2 (C),
193.5 (CO); MS m/z: 306 (M+). Anal. calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C, 78.62;
H, 7.28; N, 9.03.
4.7. Benzil-N-((S)-2-methoxymethylpyrrolidino)monoimine 3f
Yellow oil: [α]20 +191 (c 1.00, CHCl3); yield 82%; IR (film): 3056, 3023, 2974, 2925, 2876, 2828,
D
1
1636, 1597, 1579, 1543, 1489, 1444, 1283, 1200, 701 cm−1; H NMR (CDCl3) δ: 1.62–1.95 (m, 4H,
2CH2), 2.69 and 2.81 (2m, 2H, NCH2), 3.32 (s, 3H, CH3), 3.49 (d, J=5.3 Hz, 2H, OCH2), 3.72 (m, 1H,
CH), 7.32–7.87 (m, 10H, 2C6H5); 13C NMR δ: 23.8 (CH2), 26.10 (CH2), 53.9 (NCH2), 59.3 (CH3), 65.6
(CH), 73.9 (OCH2), 127.4 (CH), 127.5 (CH), 127.9 (CH), 130.2 (CH), 130.5 (CH), 130.7 (CH), 135.7
(C), 138.1 (CH), 140.2 (C), 192.9 (CO); MS m/z: 322 (M+). Anal. calcd for C20H22N2O2: C, 74.51; H,
6.88; N, 8.69. Found: C, 74.36; H, 6.78; N, 8.43.
4.8. Typical procedure for preparation of 3,6-dihydro-2H-1,3,4-thiadiazines 4
Lawesson’s reagent (1.5×10−3 mol) was added to a solution of the benzil hydrazone 3 (3×10−3 mol) in
anhydrous benzene (15 mL). The mixture was refluxed under an inert atmosphere (N2) for 15 h. Solvents
were removed under reduced pressure and the residue was chromatographed using dichloromethane:light
petroleum (7:3) as eluent. The compounds 4 were crystallised from diethyl ether.

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4.9. 3-Methyl-5,6-diphenyl-3,6-dihydro-2H-1,3,4-thiadiazine 4a
Pale yellow crystals: mp 96°C; yield 89%; IR (KBr): 3052, 3022, 2940, 2864, 1578, 1556, 1492, 1445,
1402, 1336, 1212, 1006, 766, 721, 694, 671 cm−1; 1H NMR (CDCl3) δ: 3.27 (s, 3H, CH3), 3.99 (d, J=13.0
Hz, 1H, CH), 4.09 (dd, J=13.0 Hz and J=1.8 Hz, 1H, CH), 5.01 (d, J=1.8 Hz, 1H, CH), 7.17–7.63 (m,
10H, 2C6H5); 13C NMR δ: 38.6 (CH), 45.5 (CH2), 46.1 (CH3), 124.8 (CH), 127.3 (CH), 127.4 (CH),
128.2 (CH), 128.3 (CH), 128.6 (CH), 137.0 (C), 138.8 (C), 141.6 (C); MS m/z: 268 (M+). Anal. calcd for
C16H16N2S: C, 71.61; H, 6.01; N, 10.44; S, 11.95. Found: C, 71.65; H, 6.05; N, 10.48; S, 11.80.
4.10. 3,4-Diphenyl-5-thia-1,2-diazabicyclo[4.3.0]non-2-ene 4b
White crystals: mp 135°C; yield 85%; IR (KBr): 3055, 2941, 2872, 1592, 1543, 1489, 1441, 1203,
1128, 1102, 1006, 880, 831, 762, 726, 692 cm−1; 1H NMR (CDCl3) δ: 1.90 (m, 2H, CH2), 2.41 (m, 2H,
CH2), 3.56 and 3.94 (2m, 2H, NCH2), 4.10 (t, J=7.0 Hz, 1H, CH), 5.14 (s, 1H, CH), 7.17–7.64 (m, 10H,
2C6H5); 13C NMR δ: 21.8 (CH2), 30.5 (CH2), 41.6 (CH), 54.3 (CH), 54.4 (CH2), 124.7 (CH), 127.1
(CH), 127.3 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 136.9 (C), 138.7 (C), 141.0 (C); MS m/z: 294
(M+).
4.11. 3,4-Diphenyl-5-thia-1,2-diazabicyclo[4.4.0]dec-2-ene 4c
White crystals: mp 142°C; yield 83%; IR (KBr): 2936, 2823, 1581, 1559, 1491, 1450, 1366, 1119,
1
1103, 1074, 978, 961, 828, 767, 722, 695 cm−1; H NMR (CDCl3) δ: 1.38–1.86 (m, 6H, 3CH2), 3.08
and 3.93 (ddd, J=12.2, 9.1, 6.3 Hz and ddd, J=12.2, 5.0, 3.4 Hz, 2H, NCH2), 3.69 (dd, J=11.2 Hz and
J=2.9 Hz, 1H, CH), 4.97 (s, 1H, CH), 7.18–7.56 (m, 10H, 2C6H5); 13C NMR δ: 24.2 (CH2), 25.9 (CH2),
30.2 (CH2), 40.8 (CH), 53.4 (CH), 56.1 (CH2), 125.4 (CH), 127.3 (CH), 127.6 (CH), 128.0 (CH), 128.2
(CH), 128.7 (CH), 136.7 (C), 138.5 (C), 143.5 (C); MS m/z: 308 (M+). Anal. calcd for C19H20N2S: C,
73.99; H, 6.54; N, 9.08; S, 10.39. Found: C, 73.73; H, 6.55; N, 8.78; S, 10.24.
4.12. 3,4-Diphenyl-8-oxa-5-thia-1,2-diazabicyclo[4.4.0]dec-2-ene 4d
White crystals: mp 177°C; yield 61%; IR (KBr): 3062, 2966, 2852, 1583, 1560, 1493, 1445, 1143,
1114, 1070, 1007, 982, 762, 717, 693 cm−1; 1H NMR (CDCl3) δ: 3.35 and 3.73 (ddd, J=12.4, 10.9, 3.9
Hz and dt, J=12.4, 2.1 Hz, 2H, NCH2), 3.56 (dd, J=10.4, 9.6 Hz, 1H, CH), 3.84–4.05 (m, 4H, 2CH2),
5.06 (s, 1H, CH), 7.20–7.58 (m, 10H, 2C6H5); 13C NMR δ: 40.1 (CH), 53.0 (CH), 54.6 (CH2), 67.7
(CH2), 68.4 (CH2), 125.5 (CH), 127.6 (CH), 128.0 (CH), 128.3 (CH), 128.9 (CH), 138.0 (C), 138.2 (C),
142.6 (C); MS m/z: 310 (M+). Anal. calcd for C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found:
C, 69.53; H, 5.83; N, 8.97; S, 10.15.
4.13. 9,10-Diphenyl-8-thia-1,11-diazabicyclo[5.4.0]undec-10-ene 4e
White crystals: mp 116°C; yield 57%; IR (KBr): 3057, 3020, 2932, 2918, 2848, 1580, 1545, 1492,
1364, 1223, 1123, 956, 914, 762, 722, 692 cm−1; 1H NMR (CDCl3) δ: 1.51–2.20 (m, 8H, 4CH2), 3.86
(d, J=7.8 Hz, 1H, CH), 3.86 and 4.24 (d, J=7.8 Hz and t, J=5.2 Hz, 2H, CH2), 5.17 (s, 1H, CH), 7.12–7.60
(m, 10H, 2C6H5); 13C NMR δ: 26.6 (CH2), 29.3 (CH2), 30.2 (CH2), 31.6 (CH2), 42.6 (CH), 57.6 (CH2
and CH), 124.5 (CH), 126.5 (CH), 127.1 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 132.1 (C), 139.1

J.-D. Charrier et al. / Tetrahedron: Asymmetry 9 (1998) 1531–1537
1537
(C), 143.2 (C); MS m/z: 322 (M+). Anal. calcd for C20H22N2S: C, 74.49; H, 6.88; N, 8.69; S, 9.94. Found:
C, 74.64; H, 6.80; N, 8.80; S, 9.92.
4.14. (4R,6R,9S)-9-Methoxymethyl-3,4-diphenyl-5-thia-1,2-diazabicyclo[4.3.0]non-2-ene 4f
White crystals: mp 116°C; [α]20 −461 (c 1.00, CHCl3); yield 70%; IR (KBr): 3013, 2913, 2895,
D
2824, 1577, 1544, 1494, 1449, 1281, 1194, 1130, 1089, 712, 694 cm−1; 1H NMR (CDCl3) δ: 1.85–2.19
and 2.31–2.52 (2m, 4H, 2CH2), 3.47 (s, 3H, CH3), 3.74–3.81 and 3.95 (m and dd, J=12.7, 6.3 Hz, 3H,
CH and CH2), 4.20 (t, J=7.2 Hz, 1H, CH), 5.12 (s, 1H, CH), 7.11–7.72 (m, 10H, 2C6H5); 13C NMR δ:
25.9 (CH2), 29.0 (CH2), 40.8 (CH), 55.0 (CH), 59.4 (CH3), 64.0 (CH), 74.0 (CH2), 124.5 (CH), 127.0
(CH), 127.1 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 135.8 (C), 138.6 (C), 140.8 (C); MS m/z: 338
(M+). Anal. calcd for C20H22N2OS: C, 70.97; H, 6.55; N, 8.28; S, 9.47. Found: C, 70.78; H, 6.41; N,
8.00; S, 9.18.
Acknowledgements
MESR is acknowledged for financial support (J.-D. C.). The authors are most grateful to Professor D.
W. Young, Dr. S. Drumel and K. Vallé.
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10. Column: ODH; eluent: hexane:isopropanol (95:5); pressure: 0.7 torr.
11. SAMP is commercially available, but can also be prepared in six steps from (S)-proline: D. Enders, P. Fey, H. Kipphardt,
Org. Synth. 1987, 65, 173–182 and references cited therein.
12. Crystals of 4f (1.2×0.53×0.13 mm) grown from CHCl3. C20H22N2OS, M=338.47, orthorhombic; a=8.217 Å, b=12.595
Å, c=17.300 Å, Z=4, space group: P212121, ρcalc=1.255 g cm−3. Mo-Kα radiation λ=0.7107 Å, 6425 reflections were
measured of which 2496 were unique with I>2σ(I). Crystallographic calculations were carried out using the Siemens
SHELXTL-PLUS program. The final Rw2 and R parameters were 0.1379 and 0.054.