A traceless solid phase synthesis of thiomorpholin-3-ones

Article abstract of DOI:10.1016/j.tetlet.2007.11.117

A novel synthesis of thiomorpholin-3-ones using a traceless solid phase approach is described, in which many kinds of thiomorpholin-3-ones were efficiently obtained in high purity based on an intramolecular alkylation of sulfides followed by an elimination of desired thiomorpholin-3-ones from the generated sulfonium salts.

Full text of DOI:10.1016/j.tetlet.2007.11.117

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 424–427
A traceless solid phase synthesis of thiomorpholin-3-ones
Kunio Saruta *, Tsuyoshi Ogiku
Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Corporation, 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Received 10 November 2007; accepted 22 November 2007
Abstract
A novel synthesis of thiomorpholin-3-ones using a traceless solid phase approach is described, in which many kinds of thiomorpholin-
3-ones were efficiently obtained in high purity based on an intramolecular alkylation of sulfides followed by an elimination of desired
thiomorpholin-3-ones from the generated sulfonium salts.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Traceless; Solid phase synthesis; Thiomorpholine-3-one
Compounds having a thiomorpholin-3-one (Fig. 1)
skeleton have been known to show intriguing biological
activities, for example, enhancement of brain noradrena-
line and dopamine turnover,1 hypnotic activity,2 antago-
nism on 5-HT1b receptor3 and EP4 receptor.4 Therefore,
this skeleton is very attractive as a template for chemical
libraries to generate newly-bioactive compounds on high-
throughput screenings.
Compounds 1 have been synthesized using conventional
solution phase methods2,5–7 and solid phase methods,8–10
although both methods are problematic for synthesizing
chemical libraries. Solution phase methods are not applica-
ble or inappropriate for the multi-step syntheses of the
libraries due to purification required in each step. Solid
phase methods can omit the purification of synthetic inter-
mediates but generate the final products with resin-tether-
ing substituents, which are polar and often compromise
bioavailability and reduce structural diversity of the chem-
ical libraries. In addition, products obtained by the cleav-
age of the resin in the final step are often mixtures of
desired compounds with many kinds of impurities gener-
ated by incomplete reactions on the polymer support in
the previous steps. In relation to our research to find new
drugs from the chemical library, we now report an efficient
traceless solid phase synthesis of thiomorpholin-3-ones. In
our strategy depicted in Scheme 1, and to shorten time for
the library construction, we expected that the debenzyl-
ation of sulfonium salts by the SN2 reaction could give
the products in high purity without purification because
by-products generated from incomplete and/or undesired
reactions remain on solid supports.11 While the last
debenzylation step might accompany the SN2 reaction at
the a-position of the carbony group or b-elimination of
the acyclic sulfides, the by-products generated from such
undesirable reactions remain bound to the solid supports
and never reduce the purity of the products. In addition,
R3
N
R2
R1
O
R4
S
Fig. 1. Thiomorpholin-3-one.
R1
R2
S
R1
R2
nucleophile
S
*
Corresponding author. Tel.: +81 6 6300 2562; fax: +81 6 6300 2564.
Scheme 1.
E-mail address: saruta@tanabe.co.jp (K. Saruta).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.117

K. Saruta, T. Ogiku / Tetrahedron Letters 49 (2008) 424–427
425
most of the assumed unreacted intermediates are not
detached from solid supports at the end of the reaction
scheme.12
chloroacetic acids 7. The intramolecular cyclization of 7
and the debenzylation of the sulfonium salts 9 were carried
out in the presence of CsI, providing product 10 in high
purity without purification by column chromatography.
To demonstrate the usefulness of this approach, several
thiomorpholin-3-one derivatives were synthesized.14 The
representative results are shown in Table 1. The alkyl and
aryl groups can be introduced in R1–R4 with high purities
and moderate total yields (entries 1–6), while compounds
with functional groups such as ester and basic nitrogen
could be obtained (entries 4 and 5). Construction of a
7-membered and an 8-membered ring (entries 7 and 8)
The synthesis began with the nucleophilic displacement
of benzyl chloride on Merrifield resin 1 with the sulfanyl-
ethanols 2 (Scheme 2). Next, under the Mitsunobu condi-
tions with N-monosubstituted 2-nitrobenzenesulfonamides
4,13 the polymer-supported alcohols 3 were converted
to the N,N-disubstituted 2-nitrobenzenesulfonamides 5,
which provided the secondary amines 6 by the deprotection
of the 2-nitrobenzenesulfonyl (Ns) group. Then 6 were
transformed into the key intermediates 8 by acylation with
R1 R2
Cl
R1 R2
b
a
S
OH
Ns
R3
n
+
HS
OH
N
H
+
n
2
4
1
3
R1 R2
R1 R2
O
R3
c
R3
d
e
or
S
N
Ns
Cl
S
N
H
n
n
HO
+
R4
7
5
6
R2
R3
N
R1 R2
O
R2
R3
N
n
R1
R3
Cl
f
R4
S
N
S
n
O
O
R4
n
R4
R1
S
I
10
8
9
Scheme 2. (a) Compound 2 (3 equiv), DBU (4 equiv), DMF, rt, 24 h; (b) 4 (2 equiv), PPh3 (2 equiv), DEAD (2 equiv), THF, rt, 16 h; (c) HOCH2CH2SH
(10 equiv), DBU (10 equiv), DMF, rt, 1 h; (d) DIC (12 equiv), 7 (12 equiv), DMF, rt, 20 h; (e) PyBrop (12 equiv), 7 (12 equiv), i-Pr2NEt (24 equiv), rt,
20 h; (f) CsI (1 equiv), dioxane, water, 95 °C, 1–2 h.
Table 1
Syntheses of thiomorpholin-3-one derivatives 10
Entry
10
R1
R2
R3
R4
n
Yielda (%) (Purityb (%)) of 10
1
2
3
4
5
6
7
8
a
10a
10b
10c
10d
10e
10f
10g
10h
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
(4-Br)PhCH2CH2–
(4-Br)PhCH2CH2–
(4-Br)Ph–
(4-Me2N)PhCH2–
(4-MeOCO)PhCH2–
(4-Br)PhCH2CH2–
(4-Br)PhCH2CH2–
(4-Br)PhCH2CH2–
H
H
H
H
H
Me
H
H
0
0
0
0
0
0
1
2
65 (99)
58 (100)
72 (100)
50 (97)
47 (100)
49 (96)
74 (99)
53 (95)
Isolated overall yields (six steps) based on Merrifield resin 1.
b
Reverse-phase HPLC was carried out using CH3CN/20 mM phosphate buffer (pH 6.5). Flow rate: 1 mL/min. Column: ODS. HPLC purities were
determined by summation of integrated HPLC peak areas at 210 or 220 nm.

426
K. Saruta, T. Ogiku / Tetrahedron Letters 49 (2008) 424–427
reactions was confirmed with the elemental analysis of the N,N-
disubstituted 2-nitrobenzenesulfonamides 5 (data not shown).
13. Fukuyama, T.; Jow, C.-K.; Cheng, M. Tetrahedron Lett. 1995, 36,
6373–6374.
was also possible, and this result would expand diversity of
the libraries based on this synthetic route. It is generally
known that solution phase constructions of medium-sized
rings containing 8-membered rings are often attended with
undesirable intermolecular reactions and therefore result in
low yields or failure. By contrast, our method could give
the 8-membered ring in comparable yield to those of
6- and 7-membered rings. We assume that the pseudo
high-dilution condition on the solid supports favored the
intramolecular cyclization over the intermolecular side
reaction.15
In conclusion, a novel traceless solid phase synthesis of
thiomorpholin-3-one derivatives based on the Merrifield
resin has been developed. Using this approach, we are cur-
rently constructing novel and diverse chemical libraries for
high-throughput screening. The information of biological
activities will be reported in due course.
14. Typical experimental procedure is as follows: To Merrifield resin 1
(20.0 g, 38.8 mmol, Polymer Laboratories; 1.94 mmol/g) in DMF
(200 ml) were added DBU (23.2 ml, 155 mmol) and sulfanylethanol 2
(8.17 ml, 117 mmol) at 0 °C. After stirring for 10 min, the whole was
allowed to stir at room temperature for 24 h. The resin was washed
with DMF (Â5), water (Â5), MeOH (Â5), THF (Â5) and Et2O (Â5),
and was dried in vacuo (3: 22.3 g; 100%; equivalent to 1.74 mmol/g).
To a mixture of resin 3 (3.45 g, 6 mmol), N-[2-(4-bromophenyl)ethyl]-
2-nitrobenzenesulfonamide 4 (925 mg, 2.4 mmol) and PPh3 (3.15 g,
12 mmol) in THF (100 ml) was added a 40% toluene solution of
DEAD (5.56 ml, 12 mmol) at 0 °C. After stirring for 2 min, the whole
was allowed to stir at room temperature for 16 h. The resin was
washed with CH2Cl2 (Â5), THF (Â5), MeOH (Â5), THF (Â5), and
Et2O (Â5) to give 5. To resin 5 (3.45 g, 6 mmol) in DMF (10 ml) were
added DBU (1.79 ml, 12 mmol) and sulfanylethanol (842 ll,
12 mmol) at 0 °C. After stirring for 2 min, the whole was allowed to
stir at room temperature for 1 h. The resin was washed with Et3N–
water (1:9, Â3), DMF (Â3), water (Â5), MeOH (Â5), THF (Â5), and
Et2O (Â5) to give 6. The obtained resin 6 was swollen with a mixture
of chloroacetic acid (1.36 g; 14.4 mmol), diisopropylcarbodiimide
(2.23 ml, 14.4 mmol), DMF (12 ml) and the mixture was agitated for
20 h at room temperature. The resin was then washed with DMF
(Â5), Et3N–water (1:9, Â5), THF (Â5), and MeOH (Â5) to give 8.
Resin 8 was swollen with a mixture of CsI (624 mg, 2.4 mmol),
dioxane (8 ml) and water (2 ml) and stirred at 95 °C for 1 h. The resin
was washed with MeOH–CHCl3 (1:4, Â3) and MeOH (Â5) and the
filtrate was evaporated. The residue was partitioned between AcOEt
and saturated aqueous NaHCO3. The organic layer was washed with
10% aqueous Na2S2O3 and brine and dried with Na2SO4. The solvent
was evaporated to provide product 10 as a pale yellow solid (235 mg,
65%).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.117.
References and notes
1. Itoh, Y.; Yamazaki, A.; Ukai, Y.; Yoshikuni, Y.; Kimura, K.
Pharmacol. Toxicol. 1996, 78, 421–428.
All products gave satisfactory 400 MHz 1H NMR, 100 MHz 13C
NMR, IR and MS spectra. The spectral data of 10 are given below:
Compound 10a: 4-[2-(4-bromophenyl)ethyl]-1,4-thiazaperhydroin-3-
one: 1H NMR (400 MHz, DMSO-d6): d 2.80–2.74 (4H, m), 3.20 (2H,
s), 3.54–3.50 (4H, m), 7.21 (2H, d, J = 8.45 Hz), 7.48 (2H, d,
J = 8.45 Hz); 13C NMR (100 MHz, CDCl3): d 26.3, 30.3, 3.33, 50.1,
50.2, 120.4,130.6, 131.6, 137.8, 166.3; IR (KBr) mmax: 2933, 1652, 1484,
1425, 1362, 809, 515; MS: m/z 300/302 [M+H]+. Compound 10b: 4-[2-
(4-bromophenyl)ethyl]-5,6-dimethyl-1,4-thiazaperhydroin-3-one: 1H
NMR (400 MHz, DMSO-d6): d 1.08 (0.8H, d, J = 6.40 Hz), 1.20
(0.8H, d, J = 6.40 Hz), 1.27 (2.2H, d, J = 6.40 Hz), 1.33 (2.2H, d,
J = 6.40 Hz), 2.91–2.71 (2H, m), 3.18–3.03 (2H, m), 3.32 (2H, s),
3.60–3.53 (1H, m), 3.85–3.75 (1H, m), 7.25–7.20 (2H, m), 7.52–7.47
(2H, m); 13C NMR (100 MHz, CDCl3): d 13.6, 17.3, 20.5, 20.8, 26.5,
30.2, 33.3, 33.4, 38.2, 39.1, 49.3, 49.9, 60.3, 61.4, 120.3, 130.6, 131.6,
131.7, 137.7, 138.0, 165.1, 165.2; IR (KBr) mmax: 2975, 2930, 1628,
1488, 1428, 1404, 1072, 1012, 807, 510; MS: m/z 328/330 [M+H]+.
Compound 10c: 4-(4-bromophenyl)-1,4-thiazaperhydroin-3-one: 1H
NMR (400 MHz, DMSO-d6): d 3.03 (2H, t, J = 5.63 Hz), 3.42 (2H, s),
3.96 (2H, t, J = 5.63 Hz), 7.29–3.26 (2H, m), 7.60–7.56 (2H, m); 13C
NMR (100 MHz, CDCl3): d 26.7, 30.6, 52.1, 120.6, 127.8, 132.4,
141.6, 166.8; IR (KBr) mmax: 3056, 2930, 1656, 1489, 1396, 1011, 825,
551; MS: m/z 272/274 [M+H]+. Compound 10d: 4-{[4-(dimethyl-
2. Lehr, H.; Karlan, S.; Goldberg, M. W. J. Med. Chem. 1969, 6,
136–141.
3. Brodney, M. A.; Helal, C. J.; Bronk, B. S.; Liras, S. WO Patent
107,808, 2005.
4. Billot, X.; Colucci, J.; Han, Y.; Wilson, M.-C. U.S. Patent 0,227,969,
2005.
5. Franceschini, N.; Nascimento, S. D.; Sonnet, P.; Guillaume, D.
Tetrahedron: Asymmetry 2003, 14, 3401–3405.
6. Sohda, T.; Mizuno, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.;
Kawamatsu, Y. Chem. Pharm. Bull. 1982, 30, 3563–3573.
7. Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H. Chem. Pharm.
Bull. 1965, 13, 295–299.
8. Nefzi, A.; Dooley, C.; Ostresh, J. M.; Houghten, R. A. Bioorg. Med.
Chem. Lett. 1998, 8, 2273–2278.
9. Mortezaei, R.; Ida, S.; Campbell, D. A. Mol. Divers. 1999, 4,
143–148.
10. Nefzi, A.; Giulianotti, M.; Houghten, R. A. Tetrahedron Lett. 1998,
39, 3671–3674.
11. Some other examples of the solid phase syntheses accompanying the
cyclization on the solid supports revealed that the objective hetero-
cycles showed high purities without any further post-cleavage
purification, see: (a) Matthews, J.; Rivero, R. A. J. Org. Chem.
1997, 62, 6090–6092; (b) Tietze, L. F.; Steinmetz, A. Synlett 1996,
667–668; (c) Saruta, K.; Ogiku, T. Chem. Lett. 2007, 36,
1430–1431.
12. If the polymer-supported alcohols 3 did not react with N-monosub-
stituted 2-nitrobenzenesulfonamides 4 completely, the esters com-
posed of residual 3 and chloroacetic acids 7 might be provided in the
amide formation steps (step d or e on Scheme 2), which might lead to
the formation of the lactones as impurities at the cleavage steps.
Fortunately, such by-products have not been identified so far and the
desired products were provided with high purities, because the
Mitsunobu reactions proceeded perfectly. The proceeding of these
amino)phenyl]methyl}-1,4-thiazaperhydroin-3-one:
1H
NMR
(400 MHz, DMSO-d6): d 2.75 (2H, t, J = 5.89 Hz), 2.86 (6H, s),
3.29 (2H, s), 3.48 (2H, t, J = 5.89 Hz), 4.42 (2H, s), 6.69–6.67 (2H, m),
7.10–7.08 (2H, m); 13C NMR (100 MHz, CDCl3): d 26.4, 30.4, 40.6,
48.0, 50.0, 112.6, 124.4, 129.3, 150.1, 166.4; IR (KBr) mmax: 2932, 2812,
1648, 1533, 1442, 1365, 1189, 807, 586; MS: m/z 251 [M+H]+.
Compound
10e:
methyl
4-[(3-oxo-1,4-thiazaperhydroin-4-yl)
methyl]benzoate: 1H NMR (400 MHz, DMSO-d6): d 2.84 (2H, t,
J = 5.63 Hz), 3.36 (2H, s), 3.57 (2H, t, J = 5.63 Hz), 3.85 (3H, s), 4.64
(2H, s), 7.40 (2H, d, J = 8.19 Hz), 7.94 (2H, d, J = 8.19 Hz); 13C

K. Saruta, T. Ogiku / Tetrahedron Letters 49 (2008) 424–427
427
NMR (100 MHz, CDCl3): d 26.4, 30.5, 49.0, 50.6, 52.1, 127.8, 129.7,
130.1, 142.0, 166.6, 166.7; IR (KBr) mmax: 2988, 2948, 1726, 1649,
1436, 1416, 1282, 1112, 744; MS: m/z 266 [M+H]+.
(4H, m), 7.21 (2H, d, J = 8.45 Hz), 7.47 (2H, d, J = 8.45 Hz); 13C
NMR (100 MHz, CDCl3): d 29.1, 32.9, 33.8, 34.9, 50.1, 50.5, 120.2,
130.6, 131.6, 137.9, 172.6; IR (KBr) mmax: 2931, 1642, 1486, 1448,
1422, 1133, 1011, 803, 512; MS: m/z 314/316 [M+H]+.
Compound
10f:
4-[2-(4-bromophenyl)ethyl]-2-methyl-1,4-thia-
zaperhydroin-3-one: 1H NMR (400 MHz, DMSO-d6): d 1.21 (3H, t,
J = 6.91 Hz), 2.79–2.70 (3H, m), 2.90–2.87 (1H, m), 3.68–3.47(5H,
m), 7.21 (2H, d, J = 8.19 Hz), 7.48 (2H, d, J = 8.19 Hz); 13C NMR
(100 MHz, CDCl3): d 16.2, 26.4, 33.7, 36.1, 49.5, 50.3, 120.3, 130.6,
131.6, 137.9, 170.3; IR (KBr) mmax: 2977, 2933, 1655, 1488, 1451, 1425,
1072, 1011, 811, 508; MS: m/z 314/316 [M+H]+.
Compound 10g: 4-[2-(4-bromophenyl)ethyl]-1,4-thiazaperhydroepin-
3-one: 1H NMR (400 MHz, DMSO-d6): d 1.80–1.75 (2H, m), 2.73
(2H, t, J = 7.94 Hz), 2.80 (2H, t, J = 5.63 Hz), 3.32 (2H, s), 3.46–3.44
Compound 10h: 4-[2-(4-bromophenyl)ethyl]-1,4-thiazaperhydroocin-
3-one: 1H NMR (400 MHz, DMSO-d6): d 1.68–1.62 (2H, m), 1.87–
1.81 (2H, m), 2.64 (2H, t, J = 5.12 Hz), 2.77 (2H, t, J = 7.94 Hz), 3.35
(2H, s), 3.47–3.39 (4H, m), 7.21 (2H, d, J = 8.45 Hz), 7.48 (2H, d,
J = 8.45 Hz); 13C NMR (100 MHz, CDCl3): d 28.9, 29.2, 29.8, 32.8,
33.3, 46.9, 47.2, 120.2, 130.6, 131.6, 138.1, 171.1; IR (KBr) mmax: 2937,
1600, 1485, 1469, 1430, 1234, 1129, 1070, 1010, 806, 516; MS: m/z
328/330 [M+H]+.
15. Lee, J.; Griffin, J. H. J. Org. Chem. 1996, 61, 3983–3986.