A convenient synthesis of dihydro- and tetrahydro-1,3-thiazine derivatives from β-aryl-β-amino acids

Article abstract of DOI:10.1016/j.tetlet.2003.12.027

A facile synthesis of 2-alkyl-4-aryl-5,6-dihydro-4H-1,3-thiazines and cis-2-alkyl-4-aryl-3,4,5,6-tetrahydro-2H-1,3-thiazines with potential therapeutic interest was achieved starting from readily accessible β-aryl-β-amino acids.

Full text of DOI:10.1016/j.tetlet.2003.12.027

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1503–1505
A convenient synthesis of dihydro- and tetrahydro-1,3-thiazine
derivatives from b-aryl-b-amino acids
Nicolas Leflemme, Patrick Dallemagne* and Sylvain Rault
Centre d’Etudes et de Recherche sur le Mꢀedicament de Normandie, UFR des Sciences Pharmaceutiques,
1 rue Vaubꢀenard 14032 CAEN cedex, France
Received 5 November 2003;revised 1 December 2003;accepted 5 December 2003
Abstract—A facile synthesis of 2-alkyl-4-aryl-5,6-dihydro-4H-1,3-thiazines and cis-2-alkyl-4-aryl-3,4,5,6-tetrahydro-2H-1,3-thia-
zines with potential therapeutic interest was achieved starting from readily accessible b-aryl-b-amino acids.
Ó 2003 Elsevier Ltd. All rights reserved.
The literature for heterocyclic pharmaceutical agents
includes sulfur-containing compounds that have been
reported as antimalarial agents,1 HIV-1 inhibitors,2 and
antimicrobial agents.3 Among these derivatives, several
5,6-dihydro-4H-1,3-thiazines were recently reported as
cholecystokinin antagonists4 or antimycobacterial
agents.5
The Mitsunobu procedure8;9 was used to perform the
internal cyclization of hydroxy substituted thioamides
6a–c using 1.5 equiv of PPh3/DEAD in toluene. After
48 h at room temperature the reaction was complete,
however the expected products 7a–c were isolated only
with difficulty by silica gel column chromatography.
Alternatively a method involving activation of hydroxyl
group with mesyl chloride in the presence of Et3N10 led
to the isolation of compounds 7a–c after 12 h and with
an easier purification step.
With the aim to enlarge this chemical family with
potential therapeutic interest, we wish to describe herein
a facile synthesis of 2-alkyl-4-aryl-5,6-dihydro-4H-1,3-
thiazines and cis-2-alkyl-4-aryl-3,4,5,6-tetrahydro-2H-
1,3-thiazines starting from readily accessible b-aryl-b-
amino acids.
The selective reduction of the C@N double bond has
been shown to occur with excellent diastereoselectivity
to generate stereospecifically trans- or cis-2,6-disubsti-
tuted piperidines11 and tetrasubstituted piperazines.12 In
our case we observed that the use of the acid-catalyzed
NaBH3CN reduction,13 at )20 °C in MeOH, afforded
cis-tetrahydrothiazines 8a–c with high diastereo-selec-
tivity (only one product was detected by 1H NMR
spectroscopy). By extrapolation, the product was
assigned as the cis isomer because the rear approach of
the hydride ion towards the imino p bond was preferred
due to the stabilization of the low-lying vacant orbital of
the imine through electron delocalization from the sul-
fur lone-pair electrons into this latter.11 This hypothesis
was confirmed by the coupling constants measured from
In a first step, b-aryl-b-amino acids 2a–c were readily
prepared by applying the Rodionow–Johnson proce-
dure6 using the appropriate arylcarboxaldehyde 1a–c.
The former were then treated with 2 equiv of LiAlH4 in
refluxing THF to afford the alcohols 3a–c. The third step
consisted of acylation of the amine using acetic anhy-
dride in pyridine, which at the same time led to pro-
tection of the hydroxyl function. LawessonÕs reagent7
was used to convert the amide to the corresponding
thioamide in excellent yields and the ester group was
cleaved under aqueous alkaline conditions to afford
derivatives 6a–c.
1
the H NMR spectra (Scheme 1).
In summary, this procedure can be easily generalized
because of the easy access to a large variety of b-aryl-b-
amino acid starting materials.14
Keywords: 5,6-Dihydro-4H-1,3-thiazines;3,4,5,6-Tetrahydro-2 H-1,3-
thiazines; b-Aryl-b-amino acids.
The biological evaluation of these new compounds is
now under investigation.
* Corresponding author. Tel.: 33-2-31565910;fax: 33-2-31931188;
e-mail: dallemagne@pharmacie.unicaen.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.027

1504
N. Leflemme et al. / Tetrahedron Letters 45 (2004) 1503–1505
NH2
NH2
O
O
b
a
c
Ar
H
Ar
OH
Ar
OH
3a-c : 58-70%
1a-c
2a-c : 52-64%
O
S
HN
CH3
O
HN
CH3
O
d
e
O
CH3
Ar
O
CH3
Ar
5a-c : 91-94%
4a-c : 89-92%
CH3
CH3
S
HN
S
N
S
HN
CH3
OH
g
f
Ar
Ar
Cl
Ar
8a-c : 80-87%
7a-c : 76-80%
6a-c : 88-97%
S
Ar =
a
b
c
Scheme 1. Reagents and conditions: (a) Ammonium acetate (2 equiv), malonic acid (1 equiv), EtOH, reflux, 6 h;(b) LiAlH (2 equiv), THF, reflux,
4
12 h;(c) Acetic anhydride (5 equiv), pyridine, rt, 12 h;(d) Lawesson Õs reagent (0.55 equiv), THF, 40 °C, 2 h;(e) NaOH 4 N, THF/H 2O (1:1), rt, 2 h;(f)
Method A: PPh3 (1.5 equiv), DEAD (1.5 equiv), toluene, rt, 48 h;Method B: MsCl (1.05 equiv), Et 3N (2.1 equiv), CH2Cl2, rt, 12 h;(g) PPTS (2 equiv),
NaBH3CN (2 equiv), MeOH, )20 °C to rt, 4 h.
8. (a) Mitsunobu, O.;Yamada, M.;Mukaiyama, T.
Bull.
Acknowledgements
Chem. Soc. Jpn. 1967, 40, 935;(b) Mitsunobu, O.
Synthesis 1981, 1;(c) Castro, B. R. Org. React. 1983, 29, 1;
(d) Hughes, D. L. Org. React. 1992, 42, 335.
9. Leflemme, N.;Marchand, P.;Gulea, M.;Masson, S.
Synthesis 2000, 1143.
We appreciate the financial support provided by the
ꢁ
doctorate grant to N.L. (1999–2002) and the ÔGroupe de
ÔMinistere de la Recherche et de la TechnologieÕ for a
Recherche ServierÕ.
10. Abrunhosa, I.;Gulea, M.;Levillain, J.;Masson, S.
Tetrahedron: Asymmetry 2001, 12, 2851.
11. (a) Matsumura, Y.;Maruoka, K.;Yamamoto, H. Tetra-
hedron Lett. 1982, 23, 1929;(b) Maruoka, K.;Miyazaki,
T.;Ando, M.;Matsumura, Y.;Sakane, S.;Hattori, K.;
Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831.
12. Nantz, M. H.;Lee, D. A.;Bender, D. M.;Roohi, A. H.
J. Org. Chem. 1992, 57, 6653.
References and notes
1. Vennerstrom, I.;Makler, M. T.;Angerhofer, C. K.;
Williams, J. A. Antimicrob. Agents Chemother. 1995, 39,
2671.
2. Kunze, B.;Jansen, R.;Pridzun, L.;Jurkiewicz, E.;
Hunsmann, G.;Hofle, G.;Reichenbach, H. J. Antibiot.
1993, 46, 1752.
3. Erol, D. D.;Aytermir, M. D.;Yulug, N. Eur. J. Med.
Chem. 1996, 31, 731.
4. Bourzat, J. D.;Cotrel, C.;Guyon, C.;Pitchen, Ph. US
Patent 4994569, 1991.
5. Koketsu, M.;Tanaka, K.;Takenaka, Y.;Kwong, C. D.;
Ishihara, H. Eur. J. Pharm. Sci. 2002, 15, 307.
6. (a) Rodionow, V. M.;Postovskaja, E. A. J. Am. Chem.
Soc. 1929, 51, 841;(b) Johnson, T. R.;Livak, J. E. J. Am.
Chem. Soc. 1936, 58, 299;(c) Tan, C. Y. K.;Weaver, D. F.
Tetrahedron 2002, 58, 7449.
7. (a) Thomsen, I.;Clausen, K.;Scheibye, S.;Lawesson,
S.-O. Org. Synth. 1984, 62, 158;(b) Cherkasov, R. A.;
Kutyrev, G. A.;Pudovik, A. N. Tetrahedron 1985, 41,
2567.
13. Borch, R. F.;Bernstein, M. D.;Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
1
14. All new compounds reported were characterised (IR, H
and 13C NMR, HRMS and/or elemental analyses). Typ-
ical experimental procedure: To a solution of 3a
(3.30 mmol) in dry pyridine (5 mL) was added dropwise
acetic anhydride (16.50 mmol) and the reaction mixture
was stirred for 12 h at rt. The solvents were evaporated
under reduced pressure and the residue was poured into
10% aqueous solution of K2CO3. The resulting mixture
was extracted with CH2Cl2, dried over calcium chloride
and evaporated to dryness. The residue was purified by
silica gel chromatography using diethyl ether as eluent to
give 3-acetylamino-3-phenylpropyl acetate 4a (91%) as
white crystals. Mp: 90 °C. IR (KBr) 3311, 3060, 3029,
2972, 2923, 2839, 1732, 1650, 1547, 1426, 1370, 1242, 756,
703 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d 7.36–7.26 (m,
3
5H, Harom), 5.97 (d, J ¼ 7:9 Hz, 1H, NH), 5.12 (m, 1H,

N. Leflemme et al. / Tetrahedron Letters 45 (2004) 1503–1505
1505
CH), 4.05 (m, 2H, CH2O), 2.14 (m, 2H, CH2), 2.01 (s, 3H,
CH3CO2), 1.98 (s, 3H, CH3CONH). 13C NMR (100 MHz,
CDCl3) d 170.9, 169.3, 141.2, 128.7, 127.6, 126.4, 61.3,
50.6, 34.7, 23.3, 20.9. Anal. Calcd for C13H17NO3: C,
66.36;H, 7.28;N, 5.95. Found: C, 66.42;H, 7.44;N, 5.81.
To a solution of 4a (2.10 mmol) in dry THF (10 mL) was
added LawessonÕs reagent (1.155 mmol) in one portion.
After stirring for 2 h at 40 °C, the reaction mixture was
quenched with water and extracted twice with diethyl
ether. The combined organic layers were dried over
MgSO4 and evaporated to dryness. The residue was
purified by chromatography on silica gel eluting with
Et2O/petroleum ether (8:2) to give the pure 3-thioacetyl-
amino-3-phenylpropyl acetate 5a (94%) as a colourless oil.
IR (KBr) 3302, 3240, 3030, 2953, 1738, 1720, 1534, 1456,
solution of 6a (2.20 mmol) in dry toluene (5 mL), cooled
in an ice bath, were added successively PPh3 (3.30 mmol)
and DEAD (3.30 mmol). The reaction mixture was stirred
for 48 h at rt and a white precipitate of diethyl hydrazine-
N,N0-dicarboxylate was formed. The precipitate was
filtered off and the solvent was removed in vacuo. The
crude mixture was chromatographed on silica gel using
Et2O/petroleum ether (1:1) to afford the pure compound
1
7a (76%) as a colourless oil. H NMR (400 MHz, CDCl3)
d 7.34–7.23 (m, 5H, Harom), 4.58 (d, 3J ¼ 6:8 Hz, 1H, CH),
3.06 (ddd, 2J ¼ 12:2 Hz, 3J ¼ 4:0, 10.0 Hz, 1H, CHHS),
2.85 (ddd, 2J ¼ 12:2 Hz, 3J ¼ 3:9, 6.6 Hz, 1H, CHHS),
4
2.22 (d, J ¼ 1:2 Hz, 3H, CH3), 2.10 (m, 1H, CHH), 1.69
(m, 1H, CHH). 13C (100 MHz, CDCl3) d 157.8, 143.7,
128.2, 126.6, 126.5, 59.4, 28.1, 26.7, 24.6. Anal. Calcd for
C11H13NS: C, 69.06;H, 6.85;N, 7.32. Found: C, 68.81;H,
6.80;N, 7.42. Method B: To a stirred solution of 6a
(2.20 mmol) in dry dichloromethane, cooled in an ice bath,
were added successively Et3N (4.62 mmol) and mesyl
chloride (2.31 mmol). The reaction mixture was stirred for
12 h at rt. After addition of water, the solution was
extracted twice with dichloromethane. The combined
organic layers were dried over calcium chloride and
evaporated to dryness. The residue was purified by silica
gel chromatography to afford 7a (79%). To a solution of
7a (1.30 mmol) in dry methanol (5 mL), cooled at )20 °C,
were added successively PPTS (2.60 mmol) and sodium
cyanoborohydride (2.60 mmol). The reaction mixture was
slowly allowed to warm to rt over 4 h and then quenched
with a saturated aqueous NaHCO3 solution. The solution
was extracted twice with CHCl3, the combined organic
layers were dried over calcium chloride and evaporated to
dryness. The residue was purified by silica gel chromato-
graphy using Et2O to afford the pure 2-methyl-4-phenyl-
tetrahydro-2H-1,3-thiazine 8a (82%) as white crystals. Mp:
59 °C. IR (KBr) 3288, 3056, 3025, 2966, 2926, 2888, 1469,
1384, 1368, 1242, 1172, 1039, 699 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 7.78 (d; 3J ¼ 6:2 Hz, 1H, NH),
7.38–7.30 (m, 5H, Harom), 5.76 (m, 1H, CH), 4.08 (m, 2H,
CH2O), 2.54 (s, 3H, CH3C@S), 2.37 (m, 1H, CHH), 2.23
(m, 1H, CHH), 2.01 (s, 3H, CH3C@O). 13C NMR
(100 MHz, CDCl3) d 200.3, 171.1, 139.2, 128.9, 128.1,
126.8, 61.2, 56.7, 34.4, 33.4, 20.9. Anal. Calcd for
C13H17NO2S: C, 62.12;H, 6.82;N, 5.57. Found: C,
61.89;H, 6.68;N, 5.73. To a stirred solution of
5a
(1.90 mmol) in THF (5 mL) was added an aqueous NaOH
(4 M) solution (5 mL). After stirring for 2 h at rt, the
solution was neutralized with an aqueous HCl (4 M)
solution and extracted twice with diethyl ether. The
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The residue was purified by
chromatography on silica gel eluting with Et2O to give
the pure N-(3-hydroxy-1-phenylpropyl)thioacetamide 6a
(97%) as white crystals. Mp: 126 °C. IR (KBr) 3280, 3225,
3048, 2955, 2929, 2881, 1659, 1549, 1452, 1391, 1364, 1246,
1
1020, 724, 693 cmꢀ1. H NMR (400 MHz, CDCl3) d 8.12
3
(d, J ¼ 6:4 Hz, 1H, NH), 7.39–7.30 (m, 5H, Harom), 5.87
(m, 1H, CH), 3.68 (m, 2H, CH2OH), 2.89 (br s, 1H, OH),
2.58 (s, 3H, CH3C@S), 2.21 (m, 1H, CHH), 2.04 (m, 1H,
CHH). 13C NMR (100 MHz, CDCl3) d 200.4, 139.3, 128.7,
127.8, 126.8, 58.5, 57.0, 36.9, 34.0. Anal. Calcd for
C11H15NOS: C, 63.12;H, 7.22;N, 6.69. Found: C, 63.25;
H, 7.29;N, 6.80. Synthesis of 2-methyl-4-phenyl-5,6-
dihydro-4H-1,3-thiazine 7a, Method A: To a stirred
1424, 1364, 1249, 1131, 812, 736, 702 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) d 7.37–7.26 (m, 5H, Harom:), 4.34 (q,
3J ¼ 6:5 Hz, 1H, CHCH3), 3.77 (dd, 3J ¼ 2:2, 11.7 Hz,
1H, CHPh), 3.19 (m, 1H, CHHS), 2.93 (m, 1H, CHHS),
2.03 (m, 1H, CHH), 1.67 (m, 1H, CHH), 1.45 (d,
3J ¼ 6; 5 Hz, 3H, CH3). Anal. Calcd for C11H15NS: C,
68.35;H, 7.82;N, 7.25. Found: C, 68.44;H, 8.01;N, 7.21.