Traceless solid-phase synthesis of multiple sulfonamide-containing cyclic sulfides exploiting microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.05.028

In this Letter, a new synthetic method of sulfonamide-containing cyclic sulfides using a microwave-assisted traceless solid-phase approach is described. Using this new method, many highly pure cyclic sulfides were efficiently synthesized based on intramol

Full text of DOI:10.1016/j.tetlet.2009.05.028

Tetrahedron Letters 50 (2009) 4364–4367
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Traceless solid-phase synthesis of multiple sulfonamide-containing cyclic
sulfides exploiting microwave irradiation
b
a
Kunio Saruta a,b, , Tsuyoshi Ogiku , Koichi Fukase
*
a Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka-shi, Osaka 560-0043, Japan
b Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Corporation, 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, a new synthetic method of sulfonamide-containing cyclic sulfides using a microwave-
assisted traceless solid-phase approach is described. Using this new method, many highly pure cyclic sul-
fides were efficiently synthesized based on intramolecular alkylation of the sulfides followed by elimina-
tion of the desired products from the generated sulfonium salts.
Received 3 May 2009
Accepted 14 May 2009
Available online 18 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Traceless
Solid-phase synthesis
Cyclic sulfides
Compounds having sulfonamide-containing cyclic sulfide skele-
tons (A–C, Fig. 1) are known to show a number of intriguing biolog-
ical activities, such as antimalarial effect,1 VLA-4 antagonistic
effect,2 RyR receptors modulatory effect,3 antiobesity effect,4 and
inhibitory effect on matrix metalloproteinase,5 TACE,6 phenyletha-
nolamine N-methyltransferase,7 FKBP12,8 carbonic anhydrase,9
IKK2,10 and type II 17b-hydroxysteroid dehydrogenase.11 There-
fore, it is believed that these skeletons and their analogs are very
attractive templates for chemical libraries to generate novel bioac-
tive compounds in high-throughput screenings (HTS).
To generate a high rate of hits in HTS, diversity of compounds is
extremely important. However, most reported chemical libraries
are designed based on a single scaffold,12 the diversity of which
is relatively low because all compounds in the library have the
same structure as the scaffold. One of the purposes of our work
is to construct highly diverse chemical libraries containing multi-
ple scaffolds using the same synthetic approach. With respect to
cyclic sulfide skeletons, our method can efficiently provide not
only existing scaffolds1–11 (A–C, Fig. 1) but also novel scaffolds
(D–G, Fig. 1) we first report herein, on the selection of appropriate
building blocks.
chemical library development due to the purification required in
each step. Although solid-phase methods can omit purification of
synthetic intermediates, they generate final products with resin-
tethering substituents that are polar. This often compromises the
bioavailability and reduces the structural diversity of the chemical
library. In addition, products obtained by cleavage of the resin in
the final step are often mixtures of the desired compounds with
many kinds of impurities generated by incomplete reactions on
the polymer support in the previous steps. We have developed
new traceless solid-phase synthesis where the intramolecular
alkylation of the amine or sulfide and the following debenzylation
of the resulting ammonium or sulfonium salts by SN2 reaction af-
ford the desired cyclic products. While the last debenzylation step
might accompany SN2 reaction at the intracyclic
a
-carbon atoms of
existing scaffolds
O
S
N
O
S
N
O
S
N
O
R
O
R
O
R
R
R
R
Another purpose of our work is to synthesize drug-like com-
pounds without the tedious purification steps. Compounds A–C
have previously been synthesized using conventional solution-
phase methods1–11, although these methods are somewhat prob-
lematic for development of chemical libraries. Solution-phase
methods are inappropriate for multi-step syntheses involved in
S
A
B
S
C
S
R
novel scaffolds
O
S
N
O
R
O
S
O
O
S
O
R
R
O
R
S
O
N
N
N
R
R
R
R
R
R
F
R
G
S
D
S
E
S
S
* Corresponding author. Tel.: +81 6 6300 2567; fax: +81 6 6300 2564.
E-mail address: saruta.kunio@ma.mt-pharma.co.jp (K. Saruta).
Figure 1. Sulfonamide-containing cyclic sulfides.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.028

K. Saruta et al. / Tetrahedron Letters 50 (2009) 4364–4367
4365
high purity without purification by column chromatography.16,17
The cyclization reaction was also carried out under conventional
heating conditions in a sealed tube at the same temperature
(180 °C) for the same reaction time (1 h) in order to assess the util-
ity of microwave irradiation. Interestingly, microwave heating
gave the much better yield of 12a (88%, Table 1, entry 1) than con-
ventional heating (27%). It implied that the non-thermal effect of
microwave promoted cyclization and/or cleavage.18
O
S
N
O
S
N
O
R
O
R
O
S
N
O
R
traceless
cleavage
µW
Cl
S
S
S
To demonstrate the usefulness of this approach, several sulfon-
amide-containing cyclic sulfides were synthesized. The representa-
tive results are shown in Table 1. Various aryl and alkyl groups
were introduced into R2 giving compounds with high purity and
good total yield (entries 1–5). A compound with a functional group
such as a basic nitrogen could also be obtained (entry 4). Construc-
tion of seven- and eight-membered rings (entries 6 and 7) and con-
densed rings (entries 8–11), both of which are regarded as novel
scaffolds, was also possible by switching the building blocks. This
finding indicates that this synthetic route can expand diversity of
the libraries without any difficulties, making the discovery of
new bioactive compounds in HTS more favorable. It is generally
known that solution-phase construction of medium-sized rings
containing eight- and nine-membered rings is often attended with
undesirable intermolecular reactions and therefore results in low
yields or failure. By contrast, our method afforded the eight- and
nine-membered rings in yields comparable to those of the six-
and seven-membered rings (entries 1 and 6 vs entries 7, 8, and
11). The pseudo high-dilution effect on the solid support probably
favored the intramolecular cyclization over the intermolecular side
reaction.19
Scheme 1.
the sulfonium cation, the resulting alkyl iodides recyclize to regen-
erate the sulfonium salt or remain intact on the solid supports, not
reducing the purity of the products. In addition, most of the pre-
sumably unreacted intermediates are not detached from solid sup-
ports at the end of the reaction. We have previously reported the
synthesis of thiomorpholin-3-ones as cyclic sulfides and two kinds
of cyclic tertiary amines using this strategy.13 In those syntheses,
intermediates possessing
a-chloroacetamide moiety with strong
alkylating activity were cyclized under mild conventional heating
conditions. In the present study, we have established the synthetic
method of sulfonamide-containing cyclic sulfides using a similar
strategy (Scheme 1). Since the alkyl chloride moiety in cyclization
precursors showed much weaker reactivity, microwave irradiation
was used to promote the ring-forming reaction under higher tem-
perature. Interestingly, conventional heating was not as effective
as microwave irradiation as described below. A polymer-supported
base was used as hydrogen chloride scavenger.
The synthesis began with nucleophilic displacement of the ben-
zyl chloride on the Merrifield resin 1 with the sulfanylalcohols 2
(Scheme 2). Next, under the traditional Mitsunobu conditions with
the N-Boc-protected sulfonamides 4, the polymer-supported alco-
hols 3 were converted to the N-alkyl-N-Boc-proctected sulfona-
mides 5, which in turn provided the deprotected sulfonamides 6
by n-BuNH2.14 6 were then alkylated by the mono-TBS-protected
diols 7 under the improved Mitsunobu conditions with N,N,N0,N0-
tetramethylazodicarboxamide (TMAD) and n-Bu3P.15 The resulting
9 was transformed into the alkyl halides 10. Intramolecular cycli-
zation of 10 and debenzylation of the sulfonium salts 11 were car-
ried out under microwave irradiation to provide the product 12 in
In conclusion, a novel traceless solid-phase synthesis of multi-
ple sulfonamide-containing cyclic sulfides based on the Merrifield
resin has been developed. Using this new method, we are currently
constructing novel and diverse chemical libraries for HTS. Informa-
tion of the biological activity of the synthesized multiple sulfon-
amide-containing cyclic sulfides will be reported in due course.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.028.
R1
O
S
N
O
S
N
O
R2
H
O
R2
R1
R1
Cl
OH
R2
S
S
O
R3
R1
n
Boc
a
c
S
b
d
S
Boc
n
+
O
N
HO
OTBS
n
OH
+
+
HS
H
m
n
2a
1
7b
4
3
6
5
O
S
N
O
S
N
O
S
N
R2
O
R2
O
S
N
R2
O
R2
R1
R1
O
O
R1
O
S
N
R2
O
S
S
n
n
R3
S
m
e
m
f
g
n
n
m
R3
R3
R1
m
R3
R3
S
n
S
OTBS
OH
R1
m
Cl
8
9
10
12
I
11
HS
OH
b
HO
HO
a 2 =
HO
OTBS
7
=
HS
OTBS
OTBS
7a
OH
7c
7b
HO
OTBS
2a
2b
7d
Scheme 2. Reagents and conditions: (a) 2 (3 equiv), DBU (4 equiv), DMF, rt, 24 h; (b) 4 (4 equiv), PPh3 (4 equiv), DEAD (4 equiv), THF, rt, 24 h; (c) n-BuNH2, rt, 24 h; (d) 7
(4 equiv), TMAD (4 equiv), n-Bu3P (4 equiv), THF, rt, 24 h; (e) 1 M TBAF/THF, rt, 24 h; (f) Cl3CCCl3 (4 equiv), PPh3 (4 equiv), CH2Cl2, rt, 24 h; (g) CsI (2 equiv), piperidinomethyl
polystyrene (2 equiv), dioxane, water, 180 °C, 1–2 h.

4366
K. Saruta et al. / Tetrahedron Letters 50 (2009) 4364–4367
Table 1
Syntheses of sulfonamide-containing cyclic sulfides 12
Entry
2
7
Time of condition g (h)
Product
Yielda (%) purityb (%)
Me
O
S
N
O
O
O
1
2a
7a
1
88 (98)
12a
S
OMe
O
S
N
2
2a
7a
1
91 (98)
12b
S
O
S
N
CF3
12c
3
4
2a
2a
7a
7a
1
1
89 (96)
62 (94)
S
O
S
N
O
O
NMe2
12d
S
O
S
N
5
6
2a
2a
7a
7b
1
1
70 (98)
68 (97)
12e
S
Me
Me
O
S
N
O
O
12f
S
O
S
N
7
8
2a
2a
7c
1
1
71 (91)
93 (98)
12g
S
Me
O
S
N
O
7d
12h
S
Me
O
S
N
O
9
2b
2b
2b
7a
7b
7d
2
2
2
62 (98)
53 (98)
74 (99)
12i
S
Me
O
S
N
O
10
12j
S
Me
O
S
N
O
11
12k
S
a
Isolated overall yields (seven steps) based on the 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 nm.

K. Saruta et al. / Tetrahedron Letters 50 (2009) 4364–4367
4367
Compound 12a: 4-[(4-Methylphenyl)sulfonyl]-1,4-thiazaperhydroine: 1H NMR
(400 MHz, DMSO-d6): d 2.42 (3H, s), 2.64–2.67 (4H, m), 3.16–3.18 (4H, m), 7.46
(2H, d, J = 8.19 Hz), 7.63 (2H, d, J = 8.19 Hz); 13C NMR (100 MHz, CDCl3): d 21.5,
References and notes
1. Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K.; Nagle, A.;
Adrián, F.; Matzen, J. T.; Anderson, P.; Nam, T.; Gray, N. S.; Chatterjee, A.; Janes,
J.; Yan, S. F.; Trager, R.; Caldwell, J. S.; Schultz, P. G.; Zhou, Y.; Winzeler, E. A.
Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9059–9064.
2. Huryn, D. M.; Konradi, A. W.; Ashwell, S.; Freedman, S. B.; Lombardo, L. J.;
Pleiss, M. A.; Thorsett, E. D.; Yednock, T.; Kennedy, J. D. Curr. Top. Med. Chem.
2004, 4, 1473–1484.
3. Marks, A. R.; Landry, D. W.; Deng, S.; Cheng, Z. Z.; Lehnart, S. E. US Patent
0,194,767, 2006.
4. Kilpatrick, I, C. WO Patent 00,185, 2001.
5. Almstead, N. G.; Bradley, R. S.; Pikul, S.; De, B.; Natchus, M. G.; Taiwo, Y. O.; Gu,
F.; Williams, L. E.; Hynd, B. A.; Janusz, M. J.; Dunaway, C. M.; Mieling, G. E. J.
Med. Chem. 1999, 42, 4547–4562.
6. Zask, A.; Kaplan, J.; Du, X.; MacEwan, G.; Sandanayaka, V.; Eudy, N.; Levin, J.;
Jin, G.; Xu, J.; Cummons, T.; Barone, D.; Ayral-Kaloustian, S.; Skotnicki, J. Bioorg.
Med. Chem. Lett. 2005, 15, 1641–1645.
7. Gee, C. L.; Drinkwater, N.; Tyndall, J. D. A.; Grunewald, G. L.; Wu, Q.; McLeish,
M. J.; Martin, J. L. J. Med. Chem. 2007, 50, 4845–4853.
8. Sun, F.; Li, P.; Ding, Y.; Wang, L.; Bartlam, M.; Shu, C.; Shen, B.; Jiang, H.; Li, S.;
Rao, Z. Biophys. J. 2003, 85, 3194–3201.
27.3, 47.9, 127.5, 129.8, 133.8, 143.8;IR(ATR)
545; HRMS (ESI): calculated for C11H16NO2S2 [M+H]+ 258.0616, found 258.0626.
Compound 12b: 4-[(4-Methoxyphenyl)sulfonyl]-1,4-thiazaperhydroine
1H
mmax:1336, 1160,894, 715, 703, 584,
:
NMR (400 MHz, DMSO-d6): d 2.65–2.67 (4H, m), 3.14–3.17 (4H, m), 3.86 (3H, s),
7.16 (2H, d, J = 8.70 Hz), 7.67 (2H, d, J = 8.70 Hz); 13C NMR (100 MHz, CDCl3): d
27.3, 47.9, 55.6, 114.4, 128.3, 129.5, 163.1; IR (ATR) mmax: 1258, 1156, 1093, 899,
853, 705, 583, 555; HRMS (ESI): calculated for C11H16NO3S2 [M+H]+ 274.0566,
found 274.0578.
Compound 12c: 4-{[(3-(Trifluoromethyl)phenyl]sulfonyl}-1,4-thiazaperhydr-
oine: 1H NMR (400 MHz, DMSO-d6): d 2.67–2.69 (4H, m), 3.26–3.29 (4H, m),
7.93 (1H, t, J = 7.94 Hz), 7.99 (1H, s), 8.09 (1H, d, J = 7.94 Hz), 8.14 (1H, d,
J = 7.94 Hz); 13C NMR (100 MHz, CDCl3): d 27.3, 47.9, 123 (q, J = 271 Hz), 124.3 (q,
J = 3.80 Hz), 129.6 (q, J = 3.60 Hz), 130.1, 130.5, 132.0 (q, J = 33.5 Hz), 138.4; IR
(ATR) mmax: 1165, 1124, 1068, 693, 568; HRMS (ESI): calculated for C11H13NO2F3S2
[M+H]+ 312.0345, found 312.0334.
Compound 12d: 4-{[(5-(Dimethylamino)naphthyl]sulfonyl}-1,4-thiazaper-
hydroine: 1H NMR (400 MHz, DMSO-d6): d 2.59–2.62 (4H, m), 2.84 (6H, s),
3.43–3.45 (4H, m), 7.28 (1H, d, J = 7.68 Hz), 7.60–7.68 (2H, m), 7.12–7.13 (1H, m),
8.20 (1H, d, J = 8.70 Hz), 8.52 (1H, d, J = 8.45 Hz); 13C NMR (100 MHz, CDCl3): d
27.3, 45.4, 47.3, 115.3, 119.4, 123.1, 128.1, 130.1, 130.3, 130.7, 133.5, 151.8; IR
9. Cross, P. E.; Gadsby, B.; Holland, G. F.; McLamore, W. M. J. Med. Chem. 1978, 21,
845–850.
(ATR)m
max:1318, 1080, 913, 568;HRMS(ESI):calculated forC16H21N2O2S2 [M+H]+
337.1038, found 337.1030.
10. Bingham, A. H.; Davenport, R. J.; Fosbeary, R.; Gowers, L.; Knight, R. L.; Lowe, C.;
Owen, D. A.; David, M.; Pitt, W. R. Bioorg. Med. Chem. Lett. 2008, 8, 2273–2278.
11. Wood, J.; Bagi, C. M.; Akuche, C.; Bacchiocchi, A.; Baryza, J.; Blue, M.-L.; Brennan,
C.; Campbell, A.-M.; Choi, S.; Cook, J. H.; Conrad, P.; Dixon, B. R.; Ehrlich, P. P.;
Gane, T.; Gunn, D.; Joe, T.; Johnson, J. S.; Jordan, J.; Kramss, R.; Liu, P.; Levy, J.;
Lowe, D. B.; McAlexander, I.; Natero, R.; Redman, A. M.; Scott, W. J.; Town, C.;
Wang, M.; Wang, Y.; Zhang, Z. Bioorg. Med. Chem. Lett. 2006, 16, 4965–4968.
Compound 12e: 4-(Benzylsulfonyl)-1,4-thiazaperhydroine: 1H NMR (400 MHz,
DMSO-d6): d 2.55–2.57 (4H, m), 3.31–3.32 (4H, m), 4.43 (2H, s), 7.35–7.42(5H, m);
13C NMR (100 MHz, CDCl3): d 27.7, 48.0, 57.6, 128.7, 128.9, 130.4, 130.7; IR (ATR)
m
max: 1149, 899, 699, 528; HRMS (ESI): calculated for C11H16NO2S2 [M+H]+
258.0616, found 258.0623.
Compound 12f: 4-[(4-Methylphenyl)sulfonyl]-1,4-thiazaperhydroepine: 1H NMR
(400 MHz, DMSO-d6): d 1.86–1.92 (2H, m), 2.39 (3H, s), 2.67–2.74 (4H, m), 3.32–
3.41 (4H, m), 7.41 (2H, d, J = 8.19 Hz), 7.69 (2H, d, J = 8.19 Hz); 13C NMR (100 MHz,
ˇ
12. Krchnák, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61–91.
13. Some other examples of solid-phase synthesis accompanied by cyclization on
the solid support revealed that the target heterocycles showed high purity
without further post-cleavage purification, see: (a) Saruta, K.; Ogiku, T. Chem.
Lett. 2007, 36, 1430–1431; (b) Saruta, K.; Ogiku, T. Tetrahedron Lett. 2008, 49,
424–427; (c) Saruta, K.; Ogiku, T. Chem. Lett. 2008, 37, 820–821.
14. N-Boc groups are generally cleaved by TFA or other strong acids, which are
relatively troublesome to handle, and these may cause decrease in yield and
purity and restrict the number of available building blocks, thereby lowering
diversity of the chemical library. To avoid these disadvantages, n-BuNH2 was
adopted as a mild reagent for deprotection. For other examples of cleavage by
amines, see: Leif, G.; Kerstin, G.; Ulf, R. Acta Chem. Scand. B 1987, 41, 18–23.
15. On the N-alkylation of mono-N-alkyl sulfonamides, TMAD with n-Bu3P gave
much better results than traditional DEAD with Ph3P, see: Tsunoda, T.; Otsuka,
J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994, 23, 539–542.
CDCl3): d 21.8, 31.0, 31.9, 35.5, 48.8, 53.8, 126.8, 129.7, 136.8, 143.2; IR (ATR) mmax
:
1329, 1156, 714, 546; HRMS (ESI): calculated for C12H18NO2S2 [M+H]+ 272.0773,
found 272.0787.
Compound 12g: 4-[(4-Methylphenyl)sulfonyl]-1,4-thiazaperhydroocine: 1H
NMR (400 MHz, DMSO-d6): d 1.71–1.77 (2H, m), 1.85–1.91 (2H, m), 2.39 (3H, s),
2.71–2.73 (2H, m), 2.90–2.93 (2H, m), 3.09–3.11 (2H, m), 3.29–3.32 (2H, m), 7.42
(2H, d, J = 7.94 Hz), 7.66 (2H, d, J = 7.94 Hz); 13C NMR (100 MHz, CDCl3): d 21.5,
23.6, 27.0, 31.6, 33.5, 49.6, 51.0, 127.2, 129.7, 134.9, 143.3; IR (ATR) mmax: 1324,
1155, 693, 647, 591, 546; HRMS (ESI): calculated for C13H20NO2S2 [M+H]+
286.0929, found 286.0947.
Compound 12h: 5-[(4-Methylphenyl)sulfonyl]-1H,3H,4H,6H-benzo[f]1,4-thia-
zaperhydroocine: 1H NMR (400 MHz, DMSO-d6): d 2.42 (3H, s), 2.46–2.52 (2H,
m), 3.49–3.52 (2H, m), 4.03 (2H, s), 4.42 (2H, s), 7.21–7.31 (4H, m), 7.44 (2H, d,
J = 8.19 Hz), 7.73 (2H, d, J = 8.19 Hz); 13C NMR (100 MHz, CDCl3): d 21.5, 29.3, 32.9,
50.4, 51.0, 127.1, 127.7, 129.1, 129.9, 130.5, 134.3, 136.0, 136.9, 143.6; IR (ATR)
16. The 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 (9.09 ml, 116 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 (ꢀ5), water (ꢀ5), MeOH (ꢀ5), THF (ꢀ5),
Et2O (ꢀ5), and MeOH (ꢀ5) and dried in vacuo (3: 21.4 g; equivalent to
m
max: 1330, 1156, 718, 651, 543; HRMS (ESI): calculated for C17H20NO2S2 [M+H]+
334.0929, found 334.0922.
Compound 12i: 4-[(4-Methylphenyl)sulfonyl]-2H,3H,5H-benzo[f]1,4-thiazaper-
hydroepine: 1H NMR (400 MHz, DMSO-d6): d 2.37 (3H, s), 2.77–2.79 (2H, m),
3.65–3.52 (2H, m), 4.51 (2H, s), 7.27–7.32 (2H, m), 7.35 (2H, d, J = 7.94 Hz), 7.41–
7.47 (2H, m), 7.60 (2H, d, J = 7.94 Hz); 13C NMR (100 MHz, CDCl3): d 21.5, 33.8,
52.3, 54.0, 127.0, 128.1, 128.2, 129.7, 130.4, 132.9, 136.0, 137.0, 142.1, 143.3; IR
1.81 mmol/g). To
a
mixture of the resin
3 (11.9 g, 21.6 mmol), N-(tert-
(23.4 g, 86.4 mmol), and PPh3
Butoxycarbonyl)-p-toluenesufonamide
4
(22.7 g, 86.4 mmol) in THF (200 ml) was added dropwise 40% toluene
solution of DEAD (40 ml, 86.4 mmol) at 0 °C for 30 min. After stirring for
10 min, the whole was allowed to stir at room temperature for 24 h. The resin
was washed with CH2Cl2 (ꢀ5), THF (ꢀ5), MeOH (ꢀ5), THF (ꢀ5), Et2O (ꢀ5), and
MeOH (ꢀ5) and dried in vacuo (5: 21.4 g; equivalent to 1.17 mmol/g). To the
resin 5 (3.08 g, 3.6 mmol) was added n-BuNH2 (20 ml), and the whole was
allowed to stir at room temperature for 24 h. The resin was washed with
Et3N-DMF (1:4, x5), DMF (ꢀ5), CH2Cl2 (ꢀ5), THF (ꢀ5), Et2O (ꢀ5), and MeOH
(ꢀ5) to give 6. To a mixture of the obtained resin 6, 2-(tert-Buthyldimeth-
ylsilanyloxy)ethanol 7 (2.54 g, 14.4 mmol) and n-Bu3P (3.6 g, 14.4 mmol) in
THF (200 ml) was added N,N,N0,N0-tetramethylazodicarboxamide (2.48 g,
14.4 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 water (ꢀ3), DMF (ꢀ5),
MeOH (ꢀ5), THF (ꢀ5), Et2O (ꢀ5), and MeOH (ꢀ5) to give 8. To the resin 8 was
added 1 M THF solution of TBAF (25 ml), and the whole was allowed to stir at
room temperature for 24 h. The resin was washed with THF (ꢀ5), MeOH (ꢀ5),
THF (ꢀ5), and MeOH (ꢀ5) to give 9. The obtained resin 9 was swollen with a
mixture of PPh3 (3.78 g, 14.4 mmol), hexachloroethane (3.41 g, 14.4 mmol),
and CH2Cl2 (40 ml) and the mixture was stirred for 24 h at room temperature.
The resin was then washed with CH2Cl2 (ꢀ5), MeOH (ꢀ5), THF (ꢀ5), Et2O (ꢀ5),
and MeOH (ꢀ5) to give 10. To the resin 10 were added CsI (312 mg, 1.2 mmol),
piperidinomethyl polystyrene (400 mg, 1,2 mmol, Polymer Laboratories;
3.0 mmol/g), dioxane (12 ml), and water (3 ml). The mixture was then
heated in a microwave at 180 °C for 1 h. The resin was washed with water
(ꢀ3), MeOH-CHCl3 (1:4, x3), and MeOH (ꢀ5) 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 12a as pale
yellow solid (130 mg, 88%).
(ATR) mmax: 1327, 1149, 1090, 1071, 1054, 553, 543; HRMS (ESI): calculated for
C16H18NO2S2 [M+H]+ 320.0773, found 320.0786.
Compound 12j: 5-[(4-Methylphenyl)sulfonyl]-2H,3H,4H,6H-benzo[g]1,5-thia-
zaperhydroocine: 1H NMR (400 MHz, DMSO-d6): d 1.66–1.72 (2H, m), 2.41 (3H,
s), 2.72–2.75 (2H, m), 3.30–3.36 (2H, m), 4.58 (2H, s), 7.32–7.45 (5H, m), 7.59 (1H,
d, J = 7.68 Hz), 7.76 (2H, d, J = 8.45 Hz); 13C NMR (100 MHz, CDCl3): d 21.5, 29.3,
36.5, 47.1, 51.9, 127.1, 129.1, 129.8, 131.5, 135.0, 136.6, 137.2, 141.7, 143.2; IR
(ATR) mmax: 1154, 1092, 749, 715, 653, 606; HRMS (ESI): calculated for
C17H20NO2S2 [M+H]+ 334.0929, found 334.0917.
Compound 12k: 12-[(4-Methylphenyl)sulfonyl]-6H,11H,13H-dibenzo[b,g]1,5-
thiazaperhydroonine: 1H NMR (400 MHz, DMSO-d6): d 2.45 (3H, s), 4.14 (2H, s),
4.21 (2H, s), 4.47 (2H, s), 7.00–7.14 (5H, m), 7.21–7.29 (2H, m), 7.36–7.38 (1H, m),
7.48 (2H, d, J = 8.45 Hz), 7.84 (2H, d, J = 8.45 Hz); 13C NMR (100 MHz, CDCl3): d
21.6, 37.9, 47.4, 49.7, 127.3, 127.7, 128.3, 128.4, 128.6, 129.8, 130.3, 131.3, 131.4,
133.9, 134.8, 136.8, 137.4, 137.7, 141.1, 143.4; IR (ATR) mmax: 1327, 1150, 909,
719, 614, 527; HRMS (ESI): calculated for C22H22NO2S2 [M+H]+ 396.1086, found
396.1074.
17. Initially, the last cyclization–debenzylation step was run by refluxing the
mixed solvent of dioxane and water for 24 h in the presence of only CsI under
conventional heating condition. However, the product (12a) was formed in
only 25% yield, suggesting that more vigorous conditions were required to
facilitate this reaction. We then tried running the reaction in the microwave at
180 °C for 1 h and the yield increased to over 90%. Unfortunately, impurities
probably generated under the acidic condition by hydrolysis of resin-bound
benzyl halides were detected by 1H NMR. To scavenge the acids and improve
purity, piperidinomethyl polystyrene was added. Addition of Triethylamine
also gave a similar result regarding yield and purity.
18. For other examples about the non-thermal effect of microwave, see: (a)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (b) de la Hoz, A.; Diaz-
Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164–178.
All products gave satisfactory 400 MHz 1H NMR, 100 MHz 13C NMR, IR and MS
spectra. The spectral data of 12 are given below.
19. Lee, J.; Griffin, J. H. J. Org. Chem. 1996, 61, 3983.