A solid-phase synthetic method for 3,4-dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide derivatives

Article abstract of DOI:10.1016/j.tet.2008.07.031

Utilizing polymer-bound anthranilic acid derivatives, we were able to obtain 3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide derivatives through N-methanesulfonylation by use of sulfonyl chloride, sulfonic acid, or sodium sulfonate, N-alkylation under Mitsunobu condition, and the cyclative cleavage in 8-52% five-step overall isolated yields and 91-99% purities from Wang resin. The reactions on solid phase were monitored by on-bead ATR-FTIR spectroscopic method and checked by help of solution-phase model experiments.

Full text of DOI:10.1016/j.tet.2008.07.031

Tetrahedron 64 (2008) 9060–9072
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A solid-phase synthetic method for 3,4-dihydro-1H-2,1-benzothiazin-4-one
2,2-dioxide derivatives
,
a
,
,
Moon-Kook Jeon a , Myung-Su Kim b, Jeong-Jin Kwon a b, Young-Dae Gong a, Duck-Hyung Lee b
*
a Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea
b Department of Chemistry, Sogang University, Seoul 151-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Utilizing polymer-bound anthranilic acid derivatives, we were able to obtain 3,4-dihydro-1H-2,1-ben-
zothiazine-4-one 2,2-dioxide derivatives through N-methanesulfonylation by use of sulfonyl chloride,
sulfonic acid, or sodium sulfonate, N-alkylation under Mitsunobu condition, and the cyclative cleavage in
8–52% five-step overall isolated yields and 91–99% purities from Wang resin. The reactions on solid phase
were monitored by on-bead ATR-FTIR spectroscopic method and checked by help of solution-phase
model experiments.
Received 26 March 2008
Received in revised form 9 July 2008
Accepted 10 July 2008
Available online 15 July 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Combinatorial chemistry
Solid-phase synthesis
Benzothiazine
Cyclative cleavage
1. Introduction
skeletal diversity generation in diversity-oriented synthesis
(DOS),6d combinatorial scaffold approach,6c or multiple core
Sulfonamides are prevalent structural features of many phar-
maceutical agents.1 The corresponding cyclic sulfonamides have
therefore been pursued as potential pharmaceutical scaffolds in
their own right. Among the variety of cyclic sulfonamides, 3,4-
dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide derivatives 12
have been far less explored compared to the analogous, positionally
isomeric 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide de-
rivatives, among which Meloxicam (2a) and Piroxicam (2b)3 are
commercially successful NSAIDs (nonsteroidal anti-inflammatory
drugs) (Fig. 1). Although some 1H-2,1-benzothiazine 2,2-dioxide
derivatives were recently reported to have biological activities such
as IL-8 receptor antagonistic,4a 5-HT receptor antagonistic,4b factor
Xa inhibitory,4c and reverse transcriptase (RT) inhibitory activi-
ties4d (Fig. 1), the reports have been rare on the biological relevance
of the corresponding 4-oxo derivatives 1 as core structure.
Solid-phase synthesis of combinatorial libraries has emerged as
a powerful tool for efficient drug discovery process.5 In particular,
derivation of various core structures with the same or different
substituents from a versatile intermediate resin has been an in-
teresting strategy for the construction of small molecule libraries
on solid phase, in that varying scaffold as well as substituents might
further increase the diversity of the libraries compared to
depending on a single scaffold.6 The strategy has been called
structure library approach,6b with subtle differences among them
in their capacities. From the point of view, we have recently been
exploring the potential of resin-bound anthranilic acid derivatives
3 and 4 as versatile intermediates for combinatorial generation of
drug-like heterocyclic compound libraries7 (Fig. 1). Previously, we
reported the preparation of the intermediate resins 3 and 4 and the
solid-phase synthesis of 2-cyanoquinazolin-4(3H)-ones 5 and 50,
2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones 6,7b and 4-hydroxy-
quinolin-2(1H)-ones 77a from the resins. In connection with our
target-based drug discovery project for antidiabetic agents, we
needed to establish the efficient synthetic methods for various
cyclic sulfonamide derivatives for the generation of promising hit
series. Herein we would like to present the solid-phase synthetic
method for 3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide
derivatives 1 from resin-bound anthranilic acid derivatives 3 to-
gether with the solution-phase model study and the monitoring
of the solid-phase reactions by on-bead ATR (attenuated total
reflection)-FTIR spectroscopy.
The 3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide skeleton
was synthesized in solution phase by (i) the PPA- or AlCl3-mediated
cyclization of N-arylsulfamoylacetic acids/chlorides prepared from
anilines and chlorosulfonylacetate/chlorosulfonylacetyl chloride,8a–c
and (ii) the base-mediated cyclization of N-sulfonyl anthranilates
prepared from the coupling of anthranilates and sulfonyl chlor-
ides8d–g or from the copper(II)-catalyzed reaction of diphenylio-
donium-2-carboxylate and methanesulfonanilide.8h Further
derivatization of the skeleton was reported by the treatment with
* Corresponding author. Tel.: þ82 42 860 7694; fax: þ82 42 860 7698.
E-mail address: moteta@krict.re.kr (M.-K. Jeon).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.031

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9061
O
4
OH
5
8
R3
O
R3
O
6
7
3
2
R1
R1
1
S
O
S
N
N
O
R2
1
R2
OH
O
N
OH
O
S
N
H
N
H
N
N
N
S
S
O
2a: Meloxicam
O
O
2b: Piroxicam
O
O
O
S
O
O
S
N
O
O
S
N
H
N
H
N
NH
O
Br
(Ref. 4a)
HN
F
(Ref. 4b)
O
N
N
N
O
OH
O
S
O
H2N
N
N
N
O
N
NH
NH2
NH
O
O
S
N
(Ref. 4d)
(Ref. 4c)
O
O
R
O
NH2
N
OMe
NH2
R1
4
3
R2
O
O
OH
O
N
H
R
R3
O
Ph
N
R
N
N
N
R1
R3
O
R1
R1
O
N
N
CN
N
CN
R2
7
6
5
5'
Figure 1.
isocyanates,8f the reaction with benzoyl chlorides followed by
rearrangement,8i and the condensation with benzaldehydes8c to
give the corresponding 3-carboxamido, 3-benzoyl, and 3-benzyli-
dene derivatives. On the other hand, there has been no report
regarding the solid-phase methods for the efficient synthesis of
3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide derivatives 1
to the best of our knowledge. As an approach to solid-phase syn-
thesis of the derivatives 1, we envisioned that the resin-bound
anthranilic acid derivatives 3 could be adapted to the second so-
lution-phase skeletal construction protocol mentioned above, the
base-mediated cyclization of N-sulfonyl anthranilates.9 It would
facilitate the purification of intermediates for the introduction of
substituents around the skeleton (Scheme 1).
preparation of the resins 12 by N-alkylation and the subsequent
N-sulfonylation of the intermediates 3 (Scheme 1, path A) and (ii) the
N-sulfonylation of the resins 3 followed by the N-alkylation for the
intermediates 12 (Scheme 1, path B). The resin-bound anthranilic
acid derivatives 3 common to the two pathways were prepared
from coupling of Wang resin 8 with 2-nitrobenzoic acid (2 equiv) in
the presence of DIC (3 equiv) and DMAP (3 equiv) in CH2Cl2/DMF
(4:1) at rt and subsequent reduction of the resultant resins 9 with
SnCl2$2H2O (10 equiv) in DMF at 80 ꢀC (Scheme 1 and Table 1)
according to our previously reported procedure.7a,b
Treatment of the resin 3a (R1¼H) with benzaldehyde (3 equiv)
under typical reductive alkylation conditions [in the presence of
NaBH(OAc)3 (3 equiv) in DCE] at rt gave the N-benzylated anthra-
nilate resin 10 (R1¼H, R2¼Bn).7a The N-methanesulfonylation of the
resin 10 was tried using 1-propanesulfonyl chloride (3 equiv) and
some base (3 equiv)/solvent systems such as Py/DCM, TEA/DCM,
DIEA/DCM, Py/DMF, t-BuOLi/THF, t-BuOK/THF, and LHMDS/THF at
rt or elevated temperatures. However, t-BuOLi/THF, t-BuOK/THF,
2. Results and discussion
Two pathways for the preparation of the N-alkyl-N-sulfonyl
intermediates 12 were examined from the intermediates 3: (i) the

9062
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
O
O
O
O
.
SnCl2 2H2O
2-nitrobenzoic acid
NO2
NH2
OH
DMF, 80 °C
DIC, DMAP
DCM/DMF, rt
8
R1
R1
9
3
O O
S
(R3 = Et)
base/solvent
rt or heat
O
O
R3
Cl
H
N
benzaldehyde
R2
NaBH(OAc)3
DCE, rt
R1
path A
10 (R1 = H, R2 = Bn)
R3
R3
O O
R3
S
O
O
O
O
O
O
S
O
Cl
path B
S
Et3N
R3
O
R2OH
DIAD, PPh3
THF, rt
O
O
DCM, rt
NH
N
NaH
R1
R2
O O
S
DMF, rt
S
O
R3
N
R1
OH
R2
or
R1
11
12
POCl3, Et3N
DCM, rt
1
O O
R3
S
ONa
POCl3, Et3N
DCM, rt
or
Scheme 1.
Table 1
N-(1-propanesulfonyl)anthranilate 13 in 80% yield and no bis-sul-
fonylated product. However, using pyridine (Table 1, entry 1) as
a base did not bring any change on the IR spectrum of the resin 3a.
Solvents such as toluene (Table 1, entry 4) and DMF (Table 1, entry
6) gave the same results as that for DCM in the presence of Et3N
at rt, but the use of THF (Table 1, entry 5) solvent under the same
conditions resulted in no reaction. On the other hand, considering
the limited commercial availability of methanesulfonyl chloride
derivatives, the corresponding sulfonic acid and sodium sulfonate12
were examined as sources of methanesulfonyl group. The reactions
of the resin 3a under the conditions such as 1-propanesulfonic acid
(3 equiv)/POCl3 (3 equiv)/Et3N (6 equiv) (Table 1, entry 7) or sodium
1-propanesulfonate (3 equiv)/POCl3 (3 equiv)/Et3N (3 equiv) (Table
1, entry 8)13 commonly in DCM at rt gave the same results as that
for 1-propanesufonyl chloride. Additionally, the corresponding PFP
(pentafluorophenyl) sulfonate ester (3 equiv) was also examined in
the presence of DBU (3 equiv) in THF (Table 1, entry 9) or in the
presence of Bu4NCl (3 equiv) and Et3N (3 equiv) in CHCl3 (Table 1,
entry 10), commonly at reflux.14 But the reactions were incomplete.
The subsequent reaction of the resin 11b (R1¼H, R3¼Et) with
benzyl alcohol (3 equiv) furnished the corresponding N-benzyl
derivative resin 12d (R1¼H, R2¼Bn, R3¼Et) under the Mitsunobu
condition (3 equiv DIAD and 3 equiv PPh3) in THF at rt in 12 h.
The N-alkylation step was reproduced for the solution-phase re-
action of methyl N-(1-propanesulfonyl)anthranilate 13 under the
same conditions to afford methyl N-benzyl-N-(1-propane-
sulfonyl)anthranilate 14 in 99% yield. Based on the above results,
we applied the sulfonylation and Mitsunobu conditions to the
resins 3 for the preparation of the variously substituted in-
termediates 12 as depicted in Scheme 1. The solid-phase reactions
to the resins 12 were monitored by ATR-FTIR spectroscopy as ex-
emplified in Figure 2. The resin 11b (R1¼H, R3¼Et) showed a broad
band in the range of w3000–3500 cmꢁ1 instead of two amino
bands at 3493 and 3373 cmꢁ1 for 3a (R1¼H) and the intermediate
12d (R1¼H, R2¼Bn, R3¼Et) exhibited a characteristic band of
Conditions for N-methanesulfonylation of the resin 3a (R1¼H)
Entry
1
Conditions
Conversiona
No
1-Propanesulfonyl chloride (3 equiv), Py (3 equiv),
DCM, rt, 6 h
1-Propanesulfonyl chloride (3 equiv), Et3N (3 equiv),
DCM, rt, 6 h
1-Propanesulfonyl chloride (3 equiv), DIEA
(3 equiv), DCM, rt, 6 h
1-Propanesulfonyl chloride (3 equiv), Et3N (3 equiv),
toluene, rt, 6 h
1-Propanesulfonyl chloride (3 equiv), Et3N (3 equiv),
THF, rt, 6 h
1-Propanesulfonyl chloride (3 equiv), Et3N (3 equiv),
DMF, rt, 6 h
1-Propanesulfonic acid (3 equiv), POCl3 (3 equiv),
Et3N (6 equiv), DCM, rt, 6 h
Sodium 1-propanesulfonate (3 equiv), POCl3
(3 equiv), Et3N (3 equiv), DCM, rt, 6 h
PFPb 1-propanesulfonate (3 equiv), DBU (3 equiv),
THF, 60 ꢀC, 24 h
2
3
4
5
6
7
8
9
10
Complete
Complete
Complete
No
Complete
Complete
Complete
Incomplete
Incomplete
PFP 1-propanesulfonate (3 equiv), Bu4NCl (3 equiv),
Et3N (3 equiv), CHCl3, 60 ꢀC, 24 h
a
Judged on the basis of on-bead ATR-FTIR spectrum.
PFP¼pentafluorophenyl.
b
and LHMDS/THF conditions caused only some cleavage of the resin
10, and the other conditions did not bring any significant change on
the ATR-FTIR10 spectrum of the resin 10.11
Next, we proceeded to the study of solid-phase reactions for the
path
B using excess reagents for methanesulfonylation and
subsequent Mitsunobu reaction starting from the resin 3a (R1¼H).
The sulfonylation conditions using 1-propanesulfonyl chloride
(3 equiv) were examined in the presence of pyridine (3 equiv), Et3N
(3 equiv), or DIEA (3 equiv), commonly in DCM at rt. The use of Et3N
(Table 1, entry 2) or DIEA (Table 1, entry 3) resulted in complete
reactions in 6 h and gave N-(1-propanesulfonyl)anthranilate
resin 11b (R1¼H, R3¼Et), judged on the basis of ATR-FTIR spectrum
(vide infra). The result was further checked by the solution-phase
model reaction of methyl anthranilate with 1-propanesulfonyl
chloride in the presence of Et3N in DCM at rt in 6 h to give methyl
hydrogen bonding-free ester carbonyl group at 1722 cmꢁ1
.
For the final cyclative cleavage15 step, several bases (3 equiv)
were screened for the resin 12f (R1¼H, R2¼Bn, R3¼Ph) (Table 2).
Among the examined conditions, NaH (3 equiv) in DMF at rt gave

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9063
Table 2
Conditions for cyclative cleavage of the resin 12f (R1¼H, R2¼Bn, R3¼Ph)
Entry
Conditions
25 wt % of NaOMe in MeOH (3 equiv), THF, 50 ꢀC, 21 h
Yielda
1
2
3
4
5
6
7
8
12
13
10
11
16
5
12
17
13
21
13
9
25 wt % of NaOMe in MeOH (3 equiv), DMF, 50 ꢀC, 21 h
25 wt % of NaOMe in MeOH (3 equiv), DMSO, 50 ꢀC, 21 h
1 M t-BuOK in THF (3 equiv), THF, 50 ꢀC, 21 h
1 M t-BuOK in THF (3 equiv), DMF, 50 ꢀC, 21 h
1 M t-BuOK in THF (3 equiv), DMSO, 50 ꢀC, 21 h
1 M t-BuOLi in THF (3 equiv), THF, 50 ꢀC, 21 h
1 M t-BuOLi in THF (3 equiv), DMF, 50 ꢀC, 21 h
9
1 M t-BuOLi in THF (3 equiv), DMSO, 50 ꢀC, 21 h
60% dispersion of NaH in mineral oil (3 equiv), DMF, rt, 20 h
60% dispersion of NaH in mineral oil (3 equiv), DMSO, rt, 20 h
1 M LHMDS in hexane (3 equiv), THF, ꢁ20 ꢀC to rt, 8 h
0.5 M KHMDS in toluene (3 equiv), THF, ꢁ20 ꢀC to rt, 8 h
1.4 M s-BuLi in cyclohexane (3 equiv), THF, ꢁ20 ꢀC to rt, 8 h
1.6 M n-BuLi in hexane (3 equiv), THF, ꢁ20 ꢀC to rt, 8 h
10
11
12
13
14
15
6
13
4
a
Five-step overall isolated yield from Wang resin (loading capacity 0.92 mmol/g).
condition (3 equiv NaH, DMF, rt) afforded the corresponding 3,4-
dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide derivatives 1 in
sufficient quantities for primary screening (4–22 mg) from the
various derivative resins 12 (200–300 mg). The yields and purities
of the purified products 1 are summarized in Table 3. The de-
rivatives 1a and 1b possessing hydrogen as R3 substituent were
obtained in relatively high yields (Table 3, entries 1 and 2) com-
pared to those with alkyl and aryl substituents as the correspond-
ing group (Table 3, entries 3, 4, 7, and 8). As shown by the examples
of the entries 8–13 in Table 3, the yields of the cleaved products
were dependent on the substituent on the phenyl moiety of R3
group. The compounds 1y and 1z (Table 3, entries 27 and 28) were
produced in lower yields, probably due to an unfavorable effect of
the substituent at 8 position on the cyclization of 12y and 12z, than
those having R1 group at the other positions (Table 3, entries 8, 17,
Figure 2.
better result albeit not in high yield (Table 2, entry 10) and similarly
the solution-phase model reaction of N-benzyl-N-(1-propane-
sulfonyl)anthranilate 14 under the cyclization conditions gave
a moderate yield of the compound 1d (44%) with the formation of
some unknown side products. Although not optimal, the cleavage
Table 3
Yields and purities of the compounds 1
Entryc
Compound
R1
R2
R3
Yielda (%)
Purityb (%)
1
2
3
4
1a
1b
1c
1d
1d
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Benzyl
Et
Benzyl
Benzyl
Benzyl
Et
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
H
H
Et
Et
Et
Et
Ph
Ph
40
52
11
18
15
19
16
21
15
17
8
93
99
94
99
99
97
98
97
98
99
99
99
96
92
98
d
5d
6e
7
8
9
1gf
1h
1i
2-Nitrophenyl
4-Fluorophenyl
4-Chlorophenyl
4-(Trifluoromethyl)phenyl
10e
11e
12e
13e
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1j
1k
1l
1m
1n
1o
1p
1q
1r
16
9
Benzyl
4-Nitrophenyl
4-Methoxybenzyl
4-Fluorobenzyl
4-Nitrobenzyl
Benzyl
2-Methylbenzyl
3-Fluorobenzyl
Isobutyl
Benzyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
17
20
d
14
11
14
13
24
19
10
17
15
25
9
6-MeO
6-MeO
6-MeO
6-MeO
6-Me
6-Cl
6-Cl
6-Cl
7-F
7-Cl
8-MeO
8-Me
97
96
99
99
99
98
94
95
94
99
92
91
1s
1t
Benzyl
1u
1v
1w
1x
1y
1z
Pyridyl-4-methyl
Thienyl-3-methyl
Benzyl
Benzyl
Benzyl
Benzyl
9
a
Five-step overall isolated yield from Wang resin (loading capacity 0.92 mmol/g).
Determined on the basis of LC–UV(200–400 nm)–MS spectrum of isolated product.
The corresponding sulfonyl chloride under the conditions (Et3N, DCM, rt: Table 1, entry 2) was used for N-sulfonylation of the resin 3 if not noted otherwise.
From 1-propanesulfonic acid/POCl3/Et3N/DCM/rt (Table 1, entry 7).
From the corresponding sodium sulfonate/POCl3/Et3N/DCM/rt (Table 1, entry 8).
The compound was present as enol form in CDCl3. The other compounds exist exclusively as keto forms in the same solvent.
b
c
d
e
f

9064
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
21, 22, 25, and 26). Roughly, the R2 substituent seemed not to have
a critical influence on the success in the final cleavage step. Ex-
ceptionally, the resin 12n (R1¼H, R2¼4-O2N-Bn, R3¼Ph) gave
a complex mixture, probably due to the sensitivity of the 4-nitro-
benzylic protons to the base, from which the desired product could
not be isolated (Table 3, entry 16).
4. Experimental
4.1. General
The Wang resin (loading capacity 0.92 mmol/g, 100–200 mesh)
was obtained from NovaBiochem. Most of reagents used were
purchased from Sigma–Aldrich. The reagents such as PFP 1-pro-
panesulfonate14 and sodium sulfonates16 were prepared by the
literature methods. Solvents were purchased from J.T. Baker and
were HPLC grade. Reactions, filtration, and washing were carried
out on a MiniBlock (Bohdan). Solvent evaporation was performed
on a GeneVac Atlas HT-4 centrifugal evaporator. Crude products
were purified by parallel chromatography using Quad3Ô. ATR-FTIR
spectra were recorded on TravelIRÔ (SensIR Technology) spectro-
photometer. 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance 500 spectrophotometer. LC–UV–MS analyses were
performed on a Waters ZQ mass spectrometer equipped with PDA
The compounds 1 are unknown except 1b,8d and all final
products 1a–m and 1o–z were obtained as solids and characterized
on the basis of 1H NMR, 13C NMR, and LC–UV–MS spectral data. The
keto–enol isomeric behavior of the 3,4-dihydro-1H-2,1-benzo-
thiazine-4-one 2,2-dioxide derivatives 1 seemed to be governed by
R3 group as implicated in the previous literature.8a The derivatives
1a–d with H or Et group at 3-position and the compounds 1e,f, 1h–
m, and 1o–z having Ar group as R3 exist exclusively as keto forms in
CDCl3 solution when judged on the basis of their 1H NMR (3-po-
sition methylene or methine protons at 3.92–5.36 ppm) and 13C
NMR (C-3 and C-4 signals each at 61.8–76.3 and 184.1–188.7 ppm)
spectra. Uniquely, the product 1g with 2-nitrophenyl group as Ar
group at 3-position was observed to be present in the enol form in
CDCl3, which was supported by the fact that its 1H NMR spectrum
showed an hydroxyl proton peak at 8.83 ppm instead of a methine
proton peak and there wasn’t a keto carbonyl carbon peak on the
13C NMR spectrum. Besides, the 3-carboxamido8f and 3-benzoyl8i
derivatives were reported to exist in the enol forms. On the other
hand, the related compounds 7 in Figure 1 existed predominantly
as enol forms regardless of the substituents at 3-position as
described in our previous report.7a The difference between 3,4-
dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxides 1 and 4-hydroxy-
quinolin-2(1H)-ones 7 might be explained in terms of the planarity
of sulfonyl or carbonyl group at 2-position with C3–C4 double bond
in the enol form. In the case of the derivatives 1, the sulfonyl group
seems not to have a significant influence on the stabilization of enol
form because of its tetrahedral geometry.
(200–400 nm) detection using XTerraMS column (C18
, 5 M,
4.6ꢂ100 mm) from Waters. Typical gradient was 5–95% CH3CN/
H2O containing 0.1% trifluoroacetic acid.
4.2. Preparation of 2-nitrobenzoate resins 97a,b
4.2.1. Preparation of 2-nitrobenzoate resin 9a (R1¼H)
To a mixture of Wang resin 8 (0.92 mmol/g, 5.00 g, 4.6 mmol)
and 2-nitrobenzoic acid (1.54 g, 9.21 mmol) in CH2Cl2/DMF (4:1,
60 ml) at rt were added DIC (1.74 g, 13.8 mmol) and DMAP (1.69 g,
13.8 mmol). The mixture was stirred at rt for 9 h. The resin was
filtered, washed several times with CH2Cl2, DMF, and MeOH, and
dried in a vacuum oven to give 9a (5.67 g). On-bead ATR-FTIR 3026,
2922, 1731 (C]O), 1602, 1584, 1533 (NO2), 1513, 1493, 1452, 1349
(NO2), 1287, 1247, 1175, 1122, 1070, 1029, 1016, 856, 824, 756,
697 cmꢁ1
.
The progress of the cleavage step was checked by ATR-FTIR
spectroscopy as exemplified in Figure 2, where the resins showed
the similar fingerprints with the Wang resin 8 after the cleavage
reactions. We performed an experiment to test the reusability of
the resins generated in the cyclative cleavage step. The resin
obtained after the cleavage of 12f (R1¼H, R2¼Bn, R3¼Ph) was first
treated with excess NaOMe/MeOH in THF at rt to detach the pos-
sible residual anthranilate on the resin because it showed the
similar but unidentical IR spectrum with Wang resin. But the op-
eration didn’t make any significant change on the IR spectrum of
the resin. Also, the pretreated resin was subjected to the coupling
condition with 2-nitrobenzoic acid followed by methanolysis by
the use of NaOMe/MeOH in THF at rt, and the cleaved methyl
2-nitrobenzoate was quantified after purification by column chro-
matography. The yield was about 10-fold lower than expected for
freshly used Wang resin. So, the recovered resin was not suitable for
being reused in another cycle of the solid-phase reactions.
4.2.2. Preparation of 5-methoxy-2-nitrobenzoate resin 9b
(R1¼5-MeO)
The resin 9b (5.62 g) was prepared from Wang resin
8
(0.92 mmol/g, 5.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3026, 2921, 1737 (C]O), 1678, 1584, 1513
(NO2), 1492, 1452, 1338 (NO2), 1293, 1228, 1175, 1128, 1063, 1027,
823, 755, 697 cmꢁ1
.
4.2.3. Preparation of 5-methyl-2-nitrobenzoate resin 9c (R1¼5-Me)
The resin 9c (5.72 g) was prepared from Wang resin
8
(0.92 mmol/g, 5.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3025, 2920, 1733 (C]O), 1601, 1591, 1527
(NO2), 1513, 1493, 1452, 1346 (NO2), 1288, 1254, 1200, 1175, 1156,
1129, 1068, 1028, 1016, 946, 907, 824, 749, 696 cmꢁ1
.
4.2.4. Preparation of 5-chloro-2-nitrobenzoate resin 9d (R1¼5-Cl)
The resin 9d (5.82 g) was prepared from Wang resin
8
(0.92 mmol/g, 5.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3026, 2922, 1737 (C]O), 1602, 1573, 1534
(NO2), 1513, 1493, 1452, 1344 (NO2), 1266, 1244, 1176, 1132, 1068,
3. Conclusion
In brief, we were able to establish the solid-phase synthetic
method for 3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide
derivatives 1 utilizing polymer-bound anthranilic acid derivatives
3. The reactions on solid phase were checked by on-bead ATR-FTIR
spectroscopic method and solution-phase model experiments. The
method will enable us to efficiently exploit the molecular diversity
around 3,4-dihydro-1H-2,1-benzothiazine-4-one 2,2-dioxide skel-
eton. Now we are performing the corresponding library generation
using structurally more diverse sulfonylation agents and alcohols.
On the other hand, investigation is in progress into efficient
methods for other heterocyclic compounds utilizing the resin-
bound anthranilic acid derivatives 3 and 4.
1028, 826, 755, 736, 697 cmꢁ1
.
4.2.5. Preparation of 4-fluoro-2-nitrobenzoate resin 9e (R1¼4-F)
The resin 9e (2.29 g) was prepared from Wang resin
8
(0.92 mmol/g, 2.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3026, 2920, 1732 (C]O), 1612, 1586,
1544(NO2), 1513, 1493, 1452, 1367 (NO2), 1264, 1223, 1176, 1110,
1060, 1028, 1017, 943, 907, 875, 820, 808, 755, 697 cmꢁ1
.
4.2.6. Preparation of 4-chloro-2-nitrobenzoate resin 9f (R1¼4-Cl)
The resin 9f (5.81 g) was prepared from Wang resin
8
(0.92 mmol/g, 5.00 g) following the same procedure as described

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9065
for 9a. On-bead ATR-FTIR 3025, 2921, 1738 (C]O), 1601, 1574, 1543
4.3.7. Preparation of 3-methoxyanthranilate resin 3g (R1¼3-MeO)
(NO2), 1512, 1492, 1452, 1349 (NO2), 1276, 1243, 1175, 1155, 1128,
The resin 3g (5.30 g) was prepared from the resin 9g (5.47 g)
following the same procedure as described for 3a. On-bead
ATR-FTIR 3497 (NH2), 3375 (NH2), 3025, 2921, 1687 (C]O),
1613,1602,1586,1548,1511,1492,1477,1452,1376,1299,1272,1237,
1101, 1063, 1028, 1016, 879, 824, 756, 697 cmꢁ1
.
4.2.7. Preparation of 3-methoxy-2-nitrobenzoate resin 9g
(R1¼3-MeO)
1224, 1174, 1160, 1081, 1053, 1029, 1017, 906, 821, 745, 697 cmꢁ1
.
The resin 9g (5.55 g) was prepared from Wang resin
8
(0.92 mmol/g, 5.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3025, 2919, 1728 (C]O), 1602, 1583,
1546 (NO2), 1512, 1492, 1476, 1452, 1372 (NO2), 1290, 1245, 1225,
1192, 1176, 1159, 1120, 1056, 1030, 1014, 960, 907, 852, 822, 753,
4.3.8. Preparation of 3-methylanthranilate resin 3h (R1¼3-Me)
The resin 3h (4.57 g) was prepared from the resin 9h (5.00 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3493 (NH2), 3369 (NH2), 3025, 2921, 1688 (C]O), 1612, 1601,
1585,1569,1511,1493,1452,1377,1298,1278,1240,1173,1156,1082,
697 cmꢁ1
.
1028, 1016, 906, 821, 750, 696 cmꢁ1
.
4.2.8. Preparation of 3-methyl-2-nitrobenzoate resin 9h (R1¼3-Me)
The resin 9h (5.72 g) was prepared from Wang resin
8
4.4. Preparation of N-(methanesulfonyl)anthranilate resins 11
(0.92 mmol/g, 5.00 g) following the same procedure as described
for 9a. On-bead ATR-FTIR 3025, 2920, 1729 (C]O), 1602, 1584, 1540
(NO2), 1513, 1492, 1452, 1370 (NO2), 1280, 1245, 1225, 1176, 1157,
4.4.1. Preparation of N-(methanesulfonyl)anthranilate resin 11a
(R1¼H, R3¼H)
1114, 1072, 1027, 1016, 960, 907, 851, 821, 757, 696 cmꢁ1
.
To a mixture of the anthranilate resin 3a (1.00 g, theoretically
0.85 mmol) and Et3N (258 mg, 2.55 mmol) in CH2Cl2 (15 ml) at rt
was added methanesulfonyl chloride (292 mg, 2.55 mmol). The
mixture was stirred at rt for 12 h. The resin was filtered, washed
several times with CH2Cl2, DMF, and MeOH, and dried in a vacuum
oven to give 11a (1.03 g). On-bead ATR-FTIR 3025, 2922, 1686
(C]O), 1602, 1584, 1512, 1492, 1452, 1372, 1344, 1248, 1154, 1079,
4.3. Preparation of anthranilate resins 37a,b
4.3.1. Preparation of anthranilate resin 3a (R1¼H)
A mixture of the resin 9a (5.00 g, theoretically 4.1 mmol) and
SnCl2$2H2O (9.16 g, 40.6 mmol) in DMF (60 ml) was stirred at 80 ꢀC
for 16 h and the resin was filtered, washed several times with DMF
and MeOH, and dried in a vacuum oven to give 3a (4.77 g). On-bead
ATR-FTIR 3490 (NH2), 3373 (NH2), 3026, 2922, 1689 (C]O), 1614,
1602,1586,1560,1512,1492,1452,1375,1291,1240,1173,1161,1096,
1028, 1016, 964, 909, 823, 754, 697 cmꢁ1
.
4.4.2. Preparation of N-(1-propanesulfonyl)anthranilate resin 11b
(R1¼H, R3¼Et) using 1-propanesulfonyl chloride
The resin 11b (2.07 g) was prepared from the resin 3a (2.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2922, 1687 (C]O), 1602, 1584, 1512, 1492, 1452, 1375,
1337, 1310, 1243, 1174, 1149, 1079, 1028, 1016, 908, 823, 753,
1028, 1016, 822, 751, 737, 697 cmꢁ1
.
4.3.2. Preparation of 5-methoxyanthranilate resin 3b (R1¼5-MeO)
The resin 3b (5.25 g) was prepared from the resin 9b (5.44 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3482 (NH2), 3374 (NH2), 3026, 2922, 1691 (C]O), 1600, 1585,
1564, 1511, 1493, 1452, 1376, 1284, 1215, 1173, 1069, 1029, 1016, 821,
696 cmꢁ1
.
4.4.3. Preparation of N-(1-propanesulfonyl)anthranilate resin 11b
(R1¼H, R3¼Et) using 1-propanesulfonic acid
756, 696 cmꢁ1
.
To a mixture of the anthranilate resin 3a (500 mg, theoretically
0.43 mmol) and Et3N (258 mg, 2.55 mmol) in CH2Cl2 (25 ml) at rt
were added 1-propanesulfonic acid (159 mg, 1.28 mmol) and POCl3
(195 mg, 1.28 mmol). The mixture was stirred at rt for 12 h. The
resin was filtered, washed several times with CH2Cl2, DMF, and
MeOH, and dried in a vacuum oven to give 11b (513 mg).
4.3.3. Preparation of 5-methylanthranilate resin 3c (R1¼5-Me)
The resin 3c (4.80 g) was prepared from the resin 9c (5.00 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3489 (NH2), 3369 (NH2), 3025, 2919, 1688 (C]O), 1600, 1589,
1562,1512,1493,1452,1421,1375,1308,1289,1245,1199,1174,1162,
1087, 1028, 1004, 905, 817, 791, 756, 696 cmꢁ1
.
4.4.4. Preparation of N-(1-propanesulfonyl)anthranilate resin 11b
(R1¼H, R3¼Et) using sodium 1-propanesulfonate
4.3.4. Preparation of 5-chloroanthranilate resin 3d (R1¼5-Cl)
The resin 3d (5.34 g) was prepared from the resin 9d (5.78 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3489 (NH2), 3374 (NH2), 3026, 2921, 1693 (C]O), 1613, 1601,
1556,1512,1492,1452,1376,1288,1223,1174,1121,1079,1028,1016,
To a mixture of the anthranilate resin 3a (500 mg, theoretically
0.43 mmol) and Et3N (130 mg, 1.28 mmol) in CH2Cl2 (25 ml) at rt
were added sodium 1-propanesulfonate (209 mg, 1.28 mmol) and
POCl3 (195 mg, 1.28 mmol). The mixture was stirred at rt for 12 h.
The resin was filtered, washed several times with CH2Cl2, DMF, and
MeOH, and dried in a vacuum oven to give 11b (506 mg).
819, 757, 737, 697 cmꢁ1
.
4.3.5. Preparation of 4-fluoroanthranilate resin 3e (R1¼4-F)
The resin 3e (1.87 g) was prepared from the resin 9e (2.00 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3489 (NH2), 3361 (NH2), 3025, 2920, 1689 (C]O), 1623, 1614,
1601, 1585, 1511, 1493, 1452, 1423, 1376, 1304, 1243, 1175, 1156, 1124,
4.4.5. Preparation of N-(phenylmethanesulfonyl)anthranilate resin
11c (R1¼H, R3¼Ph)
The resin 11c (2.13 g) was prepared from the resin 3a (2.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2922, 1688 (C]O), 1602, 1584, 1512, 1492, 1452, 1376,
1346, 1303, 1243, 1173, 1154, 1079, 1028, 1016, 927, 909, 823, 754,
1083, 1028, 1016, 984, 965, 907, 823, 757, 737, 696 cmꢁ1
.
737, 696 cmꢁ1
.
4.3.6. Preparation of 4-chloroanthranilate resin 3f (R1¼4-Cl)
The resin 3f (5.38 g) was prepared from the resin 9f (5.78 g)
following the same procedure as described for 3a. On-bead ATR-
FTIR 3486 (NH2), 3371 (NH2), 3025, 2920, 1689 (C]O), 1612, 1601,
1584, 1552, 1511, 1493, 1452, 1426, 1377, 1297, 1236, 1174, 1152, 1091,
4.4.6. Preparation of N-[(2-nitrophenyl)methanesulfonyl]-
anthranilate resin 11d (R1¼H, R3¼2-O2N-phenyl)
The resin 11d (533 mg) was prepared from the resin 3a (500 mg)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3025, 2920, 1686 (C]O), 1602, 1584, 1530 (NO2), 1492, 1512,
1028, 1016, 906, 821, 757, 736, 697 cmꢁ1
.

9066
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
1492, 1452, 1347 (NO2), 1309, 1245, 1172, 1147, 1081, 1028, 1017, 933,
860, 822, 753, 737, 696 cmꢁ1
1318, 1248, 1225, 1174, 1152, 1127, 1079, 1028, 1016, 1000, 906, 822,
755, 696 cmꢁ1
.
.
4.4.15. Preparation of 4-chloro-N-(phenylmethanesulfonyl)-
anthranilate resin 11m (R1¼4-Cl, R3¼Ph)
4.4.7. Preparation of N-[(4-fluorophenyl)methanesulfonyl]-
anthranilate resin 11e (R1¼H, R3¼4-F-phenyl)
The resin 11m (3.10 g) was prepared from the resin 3f (3.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2920, 1687 (C]O), 1600, 1584, 1572, 1512, 1492, 1452,
1398, 1378, 1346, 1308, 1239, 1174, 1155, 1105, 1075, 1029, 1016, 944,
The resin 11e (503 mg) was prepared from the resin 3a (500 mg)
following the same procedure as described for 11b using sodium 1-
propanesulfonate. On-bead ATR-FTIR 3026, 2921, 1687 (C]O),
1602, 1585,1511, 1493, 1452,1375,1264,1241,1174,1080,1028,1016,
918, 877, 823, 757, 696 cmꢁ1
.
908, 822, 754, 736, 697 cmꢁ1
.
4.4.16. Preparation of 3-methoxy-N-(phenylmethanesulfonyl)-
anthranilate resin 11n (R1¼3-MeO, R3¼Ph)
4.4.8. Preparation of N-[(4-chlorophenyl)methanesulfonyl]-
anthranilate resin 11f (R1¼H, R3¼4-Cl-phenyl)
The resin 11n (1.03 g) was prepared from the resin 3g (1.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3025, 2919, 1722, 1691 (C]O), 1602, 1584, 1512, 1492, 1452,
1376, 1339, 1301, 1244, 1174, 1154, 1112, 1057, 1028, 1017, 906, 965,
The resin 11f (507 mg) was prepared from the resin 3a (500 mg)
following the same procedure as described for 11b using sodium 1-
propanesulfonate. On-bead ATR-FTIR 3026, 2921, 1688 (C]O),
1602,1584,1511,1493,1452,1374,1263,1242,1174,1154,1080,1028,
822, 753, 696 cmꢁ1
.
1016, 907, 822, 753, 736, 696 cmꢁ1
.
4.4.17. Preparation of 3-methyl-N-(phenylmethanesulfonyl)-
anthranilate resin 11o (R1¼3-Me, R3¼Ph)
4.4.9. Preparation of N-{[(4-trifluoromethyl)phenyl]methane-
sulfonyl}anthranilate resin 11g (R1¼H, R3¼4-F3C-phenyl)
The resin 11o (1.02 g) was prepared from the resin 3h (1.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2922, 1722, 1688 (C]O), 1602, 1584, 1511, 1492, 1452,
1377, 1301, 1265, 1241, 1174, 1154, 1112, 1070, 1028, 1016, 964, 906,
The resin 11g (543 mg) was prepared from the resin 3a (500 mg)
following the same procedure as described for 11b using sodium 1-
propanesulfonate. On-bead ATR-FTIR 3026, 2921, 1686 (C¼O), 1602,
1584, 1512,1492,1452,1421,1378,1324,1247,1156, 1129,1106,1080,
822, 755, 736, 696 cmꢁ1
.
1067, 1019, 928, 824, 755, 736, 697 cmꢁ1
.
4.5. Preparation of N-alkyl-N-(methanesulfonyl)anthranilate
resins 12
4.4.10. Preparation of N-[(4-nitrophenyl)methanesulfonyl]-
anthranilate resin 11h (R1¼H, R3¼4-O2N-phenyl)
The resin 11h (544 mg) was prepared from the resin 3a
(500 mg) following the same procedure as described for 11b using
sodium 1-propanesulfonate. On-bead ATR-FTIR 3025, 2921, 1684
(C]O), 1602, 1585, 1523 (NO2), 1512, 1492, 1452, 1379, 1347 (NO2),
1305, 1246, 1174, 1156, 1108, 1080, 1028, 1016, 930, 856, 823, 755,
4.5.1. Preparation of N-ethyl-N-(methanesulfonyl)anthranilate
resin 12a (R1¼H, R2¼Et, R3¼H)
To
a
mixture of diisopropyl azodicarboxylate (145 mg,
0.717 mmol) and triphenylphosphine (188 mg, 0.717 mmol) in THF
(3 ml) at rt were added the resin 11a (300 mg, theoretically
0.24 mmol) and ethyl alcohol (33 mg, 0.72 mmol). The mixture was
stirred at rt for 12 h. The resin was filtered, washed several times
with CH2Cl2, DMF, and MeOH, and dried in a vacuum oven to give
12a (298 mg). On-bead ATR-FTIR 3026, 2923, 1722 (C]O), 1601,
1584,1512,1492,1452,1373,1340,1289,1241,1170,1145,1097,1064,
736, 696 cmꢁ1
.
4.4.11. Preparation of 5-methoxy-N-(phenylmethanesulfonyl)-
anthranilate resin 11i (R1¼5-MeO, R3¼Ph)
The resin 11i (2.09 g) was prepared from the resin 3b (2.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2920, 1689 (C]O), 1602, 1585, 1512, 1493, 1452, 1376,
1028, 1016, 963, 908, 824, 757, 697 cmꢁ1
.
1346,1284,1219,1174,1155,1071,1029,1016, 907, 822, 756, 696 cmꢁ1
.
4.5.2. Preparation of N-benzyl-N-(methanesulfonyl)anthranilate
resin 12b (R1¼H, R2¼benzyl, R3¼H)
4.4.12. Preparation of 5-methyl-N-(phenylmethanesulfonyl)-
anthranilate resin 11j (R1¼5-Me, R3¼Ph)
The resin 12b (318 mg) was prepared from the resin 11a
(300 mg) following the same procedure as described for 12a. On-
bead ATR-FTIR 3026, 2922, 1722 (C]O), 1601, 1584, 1512, 1493,
1452, 1372, 1339, 1289, 1243, 1174, 1151, 1078, 1028, 1016, 958, 909,
The resin 11j (1.10 g) was prepared from the resin 3c (1.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3025, 2922, 1686 (C]O), 1601, 1585, 1512, 1493, 1452, 1400,
1377, 1344, 1307, 1246, 1204, 1174, 1160, 1113, 1077, 1028, 1017, 946,
823, 755, 697 cmꢁ1
.
907, 875, 822, 791, 757, 736, 696 cmꢁ1
.
4.5.3. Preparation of N-ethyl-N-(1-propanesulfonyl)anthranilate
resin 12c (R1¼H, R2¼Et, R3¼Et)
4.4.13. Preparation of 5-chloro-N-(phenylmethanesulfonyl)-
anthranilate resin 11k (R1¼5-Cl, R3¼Ph)
The resin 12c (302 mg) was prepared from the resin 11b
(300 mg) following the same procedure as described for 12a. On-
bead ATR-FTIR 3026, 2921, 1722 (C]O), 1601, 1585, 1512, 1492,
1452, 1374, 1335, 1290, 1241, 1174, 1141, 1098, 1064, 1028, 1016, 908,
The resin 11k (2.07 g) was prepared from the resin 3d (2.00 g)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2922, 1693 (C]O), 1602, 1584, 1512, 1492, 1452, 1397,
1378, 1346, 1303, 1234, 1174, 1156, 1112, 1076, 1028, 1016, 906, 822,
823, 755, 697 cmꢁ1
.
756, 696 cmꢁ1
.
4.5.4. Preparation of N-benzyl-N-(1-propanesulfonyl)anthranilate
resin 12d (R1¼H, R2¼benzyl, R3¼Et) from the resin 11b prepared
using 1-propanesulfonyl chloride
4.4.14. Preparation of 4-fluoro-N-(phenylmethanesulfonyl)-
anthranilate resin 11l (R1¼4-F, R3¼Ph)
The resin 12d (316 mg)was prepared fromtheresin11b (300 mg)
following the same procedure as described for 12a. On-bead ATR-
FTIR3026, 2922,1722(C]O),1601,1585,1512,1493,1452,1373,1331,
The resin 11l (534 mg) was prepared from the resin 3e (500 mg)
following the same procedure as described for 11a. On-bead ATR-
FTIR 3026, 2921, 1687 (C]O), 1601, 1511, 1493, 1452, 1376, 1349,
1290, 1242, 1175, 1147, 1078, 1028, 1016, 909, 823, 754, 697 cmꢁ1
.

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9067
4.5.5. Preparation of N-benzyl-N-(1-propanesulfonyl)anthranilate
resin 12d (R1¼H, R2¼benzyl, R3¼Et) from the resin 11b prepared
using 1-propanesulfonic acid
The resin 12d (306 mg) was prepared from the resin 11b
(300 mg) following the same procedure as described for 12a.
1512, 1493, 1452, 1346 (NO2), 1243, 1174, 1154, 1076, 1028, 1016, 907,
863, 822, 755, 696 cmꢁ1
.
4.5.14. Preparation of N-(4-methoxybenzyl)-N-(phenylmethane-
sulfonyl)anthranilate resin 12l (R1¼H, R2¼4-MeO-benzyl, R3¼Ph)
The resin 12l (316 mg) was prepared from the resin 11c
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2922, 1720 (C]O), 1602, 1585, 1512, 1493,
1452, 1375, 1345,1286,1245, 1175, 1152, 1133,1112,1076,1029, 1016,
4.5.6. Preparation of N-benzyl-N-(1-propanesulfonyl)anthranilate
resin 12d (R1¼H, R2¼benzyl, R3¼Et) from the resin 11b prepared
using sodium 1-propanesulfonate
The resin 12d (303 mg) was prepared from the resin 11b
(300 mg) following the same procedure as described for 12a.
907, 872, 823, 754, 696 cmꢁ1
.
4.5.15. Preparation of N-(4-fluorobenzyl)-N-(phenylmethane-
sulfonyl)anthranilate resin 12m (R1¼H, R2¼4-F-benzyl, R3¼Ph)
The resin 12m (304 mg) was prepared from the resin 11c
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3025, 2922, 1721 (C]O), 1602, 1584, 1510, 1492,
1452,1375,1346,1289,1241, 1223,1174,1153, 1133,1075,1029,1016,
4.5.7. Preparation of N-ethyl-N-(phenylmethanesulfonyl)-
anthranilate resin 12e (R1¼H, R2¼Et, R3¼Ph)
The resin 12e (304 mg) was prepared from the resin 11c (300 mg)
following the same procedure as described for 12a. On-bead ATR-
FTIR 3026, 2921,1722 (C]O),1601,1585,1512,1492,1452,1373,1345,
907, 824, 756, 696 cmꢁ1
.
1289, 1240, 1173, 1097, 1064, 1029, 1016, 908, 823, 755, 696 cmꢁ1
.
4.5.16. Preparation of N-(4-nitrobenzyl)-N-(phenylmethane-
sulfonyl)anthranilate resin 12n (R1¼H, R2¼4-O2N-benzyl, R3¼Ph)
The resin 12n (306 mg) was prepared from the resin 11c
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2922, 1722 (C]O), 1602, 1585, 1513
(overlapped, NO2), 1493, 1452, 1345 (overlapped, NO2), 1288, 1243,
4.5.8. Preparation of N-benzyl-N-(phenylmethanesulfonyl)-
anthranilate resin 12f (R1¼H, R2¼benzyl, R3¼Ph)
The resin 12f (309 mg) was prepared from the resin 11c
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2921, 1722 (C]O), 1601, 1584, 1512, 1493,
1452, 1373, 1346, 1288, 1242, 1174, 1152, 1133, 1077, 1028, 1016, 907,
1174, 1153, 1134, 1072, 1029, 1016, 907, 857, 824, 754, 696 cmꢁ1
.
823, 754, 696 cmꢁ1
.
4.5.17. Preparation of N-benzyl-5-methoxy-N-(phenylmethane-
sulfonyl)anthranilate resin 12o (R1¼5-MeO, R2¼benzyl, R3¼Ph)
The resin 12o (315 mg) was prepared from the resin 11i
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2923, 1724 (C]O), 1602, 1584, 1512, 1493,
1452, 1421, 1374, 1345, 1284, 1217, 1174, 1152, 1108, 1070, 1029, 1016,
4.5.9. Preparation of N-benzyl-N-[(2-nitrophenyl)methane-
sulfonyl]anthranilate resin 12g (R1¼H, R2¼benzyl,
R3¼2-O2N-phenyl)
The resin 12g (508 mg) was prepared from the resin 11d
(500 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2922, 1720 (C]O), 1602, 1583, 1530 (NO2),
1512, 1492, 1452, 1348 (NO2), 1290, 1243, 1173, 1153, 1078, 1028,
907, 821, 756, 696 cmꢁ1
.
1017, 963, 907, 863, 822, 754, 734, 696 cmꢁ1
.
4.5.18. Preparation of 5-methoxy-N-(2-methylbenzyl)-N-
(phenylmethanesulfonyl)anthranilate resin 12p (R1¼5-MeO,
R2¼2-Me-benzyl, R3¼Ph)
4.5.10. Preparation of N-benzyl-N-[(4-fluorophenyl)methane-
sulfonyl]anthranilate resin 12h (R1¼H, R2¼benzyl, R3¼4-F-phenyl)
The resin 12h (457 mg)wasprepared fromthe resin 11e (450 mg)
following the same procedure as described for 12a. On-bead ATR-
FTIR 3026, 2919,1720 (C]O),1602,1585,1511,1493,1452,1374,1290,
The resin 12p (317 mg) was prepared from the resin 11i
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2921, 1724 (C]O), 1602, 1584, 1511, 1493,
1452, 1421, 1374, 1343, 1285, 1218, 1174, 1153, 1108, 1068, 1029, 1016,
1240, 1226, 1174, 1095, 1074, 1028, 1016, 907, 821, 752, 696 cmꢁ1
.
907, 822, 756, 697 cmꢁ1
.
4.5.19. Preparation of N-(3-fluorobenzyl)-5-methoxy-N-(phenyl-
methanesulfonyl)anthranilate resin 12q (R1¼5-MeO,
4.5.11. Preparation of N-benzyl-N-[(4-chlorophenyl)methane-
sulfonyl]anthranilate resin 12i (R1¼H, R2¼benzyl,
R3¼4-Cl-phenyl)
R2¼3-F-benzyl, R3¼Ph)
The resin 12q (314 mg) was prepared from the resin 11i
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2921, 1724 (C]O), 1602, 1584, 1512, 1493,
1452, 1422, 1373, 1285, 1219, 1174, 1152, 1108, 1068, 1029, 1016, 907,
The resin 12i (456 mg) was prepared from the resin 11f (450 mg)
following the same procedure as described for 12a. On-bead ATR-
FTIR 3025, 2919, 1720 (C]O), 1601, 1584, 1511, 1493, 1452, 1373,
1241, 1225, 1174, 1093, 1028, 1016, 907, 822, 751, 696 cmꢁ1
.
875, 821, 756, 697 cmꢁ1
.
4.5.12. Preparation of N-benzyl-N-{[(4-trifluoromethyl)-
phenyl]methanesulfonyl}anthranilate resin 12j
4.5.20. Preparation of N-iso-butyl-5-methoxy-N-(phenyl-
methanesulfonyl)anthranilate resin 12r (R1¼5-MeO, R2¼iso-butyl,
R3¼Ph)
(R1¼H, R2¼benzyl, R3¼4-F3C-phenyl)
The resin 12j (442 mg) was prepared from the resin 11g
(450 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2921, 1721 (C]O), 1637, 1601, 1512, 1493,
1452, 1421, 1347, 1324, 1245, 1173, 1155, 1125, 1067, 1028, 1019, 907,
The resin 12r (312 mg) was prepared from the resin 11i
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2923, 1722 (C]O), 1601, 1584, 1511, 1493,
1452, 1421, 1373, 1346, 1285, 1217, 1174, 1152, 1108, 1062, 1030, 1016,
823, 755, 696 cmꢁ1
.
962, 905, 822, 756, 697 cmꢁ1
.
4.5.13. Preparation of N-benzyl-N-[(4-nitrophenyl)methane-
sulfonyl]anthranilate resin 12k (R1¼H, R2¼benzyl,
4.5.21. Preparation of N-benzyl-4-methyl-N-(phenylmethane-
sulfonyl)anthranilate resin 12s (R1¼4-Me, R2¼benzyl, R3¼Ph)
The resin 12s (1.07 g) was prepared from the resin 11j (1.00 g)
following the same procedure as described for 12a. On-bead ATR-
FTIR 3026, 2921, 1720 (C]O), 1601, 1584, 1512, 1493, 1452, 1344,
R3¼4-O2N-phenyl)
The resin 12k (447 mg) was prepared from the resin 11h
(450 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2920, 1721 (C]O), 1638, 1602, 1524 (NO2),

9068
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
1294, 1263, 1245, 1201, 1174, 1150, 1112, 1075, 1028, 1017, 908, 875,
823, 757, 736, 696 cmꢁ1
mineral oil (11 mg, 0.47 mmol) and the mixture was stirred at rt for
20 h. The resin was filtered and washed with MeOH (1 mlꢂ3). The
filtrate was evaporated in vacuo, acidified to pH 3–4 with 3 N
hydrochloric acid, and extracted with methylene chloride (1 mlꢂ3).
The organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by a silica gel column chromatography
(8:1 mixture of n-hexane and ethyl acetate) to give 1a (14 mg, 40%;
93% purity on the basis of LC–UV–MS spectrum). 1H NMR
.
4.5.22. Preparation of N-benzyl-5-chloro-N-(phenylmethane-
sulfonyl)anthranilate resin 12t (R1¼5-Cl, R2¼benzyl, R3¼Ph)
The resin 12t (311 mg) was prepared from the resin 11k (300 mg)
following the same procedure as described for 12a. On-bead ATR-
FTIR 3026, 2921,1726 (C]O),1602,1584,1512,1493,1452,1347,1285,
1224, 1174, 1153, 1108, 1075, 1028, 1016, 908, 821, 755, 696 cmꢁ1
.
(500 MHz, CDCl3)
d
1.41 (t, J¼7.1 Hz, 3H), 4.07 (q, J¼7.1 Hz, 2H), 4.29
(s, 2H), 7.20–7.27 (m, 2H), 7.66 (t, J¼8.3 and 1.7 Hz, 1H), 8.14 (dd,
4.5.23. Preparation of 5-chloro-N-(phenylmethanesulfonyl)-
N-(pyridyl-4-methyl)anthranilate resin 12u (R1¼5-Cl,
J¼8.3 and 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 14.4, 41.5, 62.1,
118.1, 123.6, 123.8, 129.7, 136.5, 143.2, 184.2; MS (ESI) m/z 226
R2¼pyridyl-4-methyl, R3¼Ph)
([MþH]þ).
The resin 12u (307 mg) was prepared from the resin 11k
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2923, 1726 (C]O), 1601, 1585, 1512, 1493,
1452, 1373, 1349, 1286, 1224, 1174, 1154, 1108, 1070, 1029, 1016, 907,
4.6.2. Preparation of 1-benzyl-3,4-dihydro-1H-2,1-benzothiazin-
4-one 2,2-dioxide 1b (R1¼H, R2¼benzyl, R3¼H)
The compound 1b (22 mg, 52%; 99% purity on the basis of
LC–UV–MS spectrum) was prepared from the resin 12b (200 mg)
following the same procedure as described for 1a. 1H NMR
876, 822, 757, 697 cmꢁ1
.
4.5.24. Preparation of 5-chloro-N-(phenylmethanesulfonyl)-
N-(thienyl-3-methyl)anthranilate resin 12v (R1¼5-Cl,
(500 MHz, CDCl3)
d
4.24 (s, 2H), 5.16 (s, 2H), 7.14 (d, J¼8.3 Hz, 1H),
7.22 (t, J¼8.3, 1H), 7.30–7.36 (m, 5H), 7.55 (dt, J¼8.3 and 1.7 Hz, 1H),
R2¼thienyl-3-methyl, R3¼Ph)
8.11 (dd, J¼8.3 and 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 51.3,
The resin 12v (306 mg) was prepared from the resin 11k
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2922, 1727 (C]O), 1602, 1585, 1512, 1493,
1452, 1373, 1349, 1285, 1232, 1175, 1153, 1108, 1075, 1029, 1017, 879,
61.8, 119.8, 123.9, 124.3, 127.0, 128.2, 129.1, 129.4, 135.3, 136.4, 143.6,
184.1; MS (ESI) m/z 288 ([MþH]þ).
823, 756, 696 cmꢁ1
.
4.6.3. Preparation of 1,3-diethyl-3,4-dihydro-1H-2,1-benzothiazin-
4-one 2,2-dioxide 1c (R1¼H, R2¼Et, R3¼Et)
The compound 1c (4 mg, 11%; 94% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12c (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
4.5.25. Preparation of N-benzyl-4-fluoro-N-(phenylmethane-
sulfonyl)anthranilate resin 12w (R1¼4-F, R2¼benzyl, R3¼Ph)
The resin 12w (302 mg) was prepared from the resin 11l
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2921, 1723 (C]O), 1602, 1585, 1512, 1493,
1452, 1349, 1285, 1243, 1174, 1153, 1108, 1080, 1028, 1016, 908, 824,
d
1.17 (m, 3H), 1.43 (t, J¼7.2 Hz, 3H), 1.97–2.03 (m, 1H), 2.16–2.22 (m,
1H), 3.92 (m, 1H), 4.07 (q, J¼7.2 Hz, 2H), 7.15 (d, J¼8.4 Hz, 1H), 7.19
(t, J¼8.4 Hz, 1H), 7.63 (dt, J¼8.4 and 1.7 Hz, 1H), 8.14 (dd, J¼8.4 and
1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 11.4, 14.5, 19.9, 40.4, 72.0,
757, 737, 696 cmꢁ1
.
116.7, 123.0, 123.2, 130.0, 136.0, 142.6, 187.2; MS (ESI) m/z 254
([MþH]þ).
4.5.26. Preparation of N-benzyl-4-chloro-N-(phenylmethane-
sulfonyl)anthranilate resin 12x (R1¼4-Cl, R2¼benzyl, R3¼Ph)
The resin 12x (304 mg) was prepared from the resin 11m
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3025, 2922, 1723 (C]O), 1601, 1587, 1512, 1493,
1452, 1348, 1264, 1239, 1175, 1152, 1133, 1100, 1075, 1028, 1016, 908,
4.6.4. Preparation of 1-benzyl-3-ethyl-3,4-dihydro-1H-2,1-benzo-
thiazin-4-one 2,2-dioxide 1d (R1¼H, R2¼benzyl, R3¼Et) from the
resin 12d prepared using 1-propanesulfonyl chloride
The compound 1d (8 mg, 18%; 99% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12d (200 mg)
following the same procedure as described for 1a. 1H NMR
877, 824, 757, 736, 696 cmꢁ1
.
4.5.27. Preparation of N-benzyl-4-chloro-N-(phenylmethane-
sulfonyl)anthranilate resin 12y (R1¼3-MeO, R2¼benzyl, R3¼Ph)
The resin 12y (308 mg) was prepared from the resin 11n
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3026, 2922, 1724 (C]O), 1602, 1584, 1512, 1492,
1452, 1374, 1345, 1264, 1243, 1174, 1154, 1111, 1056, 1028, 907, 823,
(500 MHz, CDCl3)
d
1.19 (t, J¼7.5 Hz, 3H), 2.04–2.11 (m, 1H), 2.20–
2.28 (m, 1H), 3.97 (dd, J¼8.1 and 5.5 Hz, 1H), 5.08 (d, J¼17.0 Hz,
1H), 5.26 (d, J¼17.0 Hz, 1H), 7.03 (d, J¼8.3 Hz, 1H), 7.18 (t,
J¼8.3 Hz, 1H), 7.31 (t, J¼7.1 Hz, 1H), 7.35–7.42 (m, 4H), 7.49 (dt,
J¼8.3 and 1.7 Hz, 1H), 8.12 (dd, J¼8.3 and 1.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
d 11.6, 19.7, 50.5, 72.2, 118.1, 122.4, 123.6, 126.6,
753, 736, 696 cmꢁ1
.
127.9, 129.1, 129.7, 135.9, 136.0, 143.2, 187.0; MS (ESI) m/z 316
([MþH]þ).
4.5.28. Preparation of N-benzyl-4-chloro-N-(phenylmethane-
sulfonyl)anthranilate resin 12z (R1¼3-Me, R2¼benzyl, R3¼Ph)
The resin 12z (301 mg) was prepared from the resin 11o
(300 mg) following the same procedure as described for 12a.
On-bead ATR-FTIR 3025, 2922, 1725 (C]O), 1687, 1602, 1584, 1511,
1492, 1452, 1375, 1301, 1264, 1241, 1174, 1145, 1110, 1075, 1028, 1016,
4.6.5. Preparation of 1-benzyl-3-ethyl-3,4-dihydro-1H-2,1-benzo-
thiazin-4-one 2,2-dioxide 1d (R1¼H, R2¼benzyl, R3¼Et) from the
resin 12d prepared using 1-propanesulfonic acid
The compound 1d (7 mg, 15%; 99% purity on the basis of LC–MS
spectrum) was prepared from the resin 12d (200 mg) following the
same procedure as described for 1a.
906, 822, 756, 736, 696 cmꢁ1
.
4.6. Preparation of 3,4-dihydro-1H-2,1-benzothiazin-4-one
2,2-dioxides 1a–m and 1o–z
4.6.6. Preparation of 1-benzyl-3-ethyl-3,4-dihydro-1H-2,1-benzo-
thiazin-4-one 2,2-dioxide 1d (R1¼H, R2¼benzyl, R2¼Et) from the
resin 12d prepared using sodium 1-propanesulfonate
The compound 1d (9 mg, 19%; 97% purity on the basis of LC–MS
spectrum) was prepared from the resin 12d (200 mg) following the
same procedure as described for 1a.
4.6.1. Preparation of 1-ethyl-3,4-dihydro-1H-2,1-benzothiazin-
4-one 2,2-dioxide 1a (R1¼H, R2¼Et, R3¼H)
To
a suspension of the resin 12a (200 mg, theoretically
0.16 mmol) in DMF (2 ml) at rt was added 60% dispersion of NaH in

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9069
4.6.7. Preparation of 1-ethyl-3-phenyl-3,4-dihydro-1H-2,1-
4.6.12. Preparation of 1-benzyl-3-[4-(trifluoromethyl)phenyl]-3,4-
benzothiazin-4-one 2,2-dioxide 1e (R1¼H, R2¼Et, R3¼Ph)
dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1j (R1¼H,
The compound 1e (7 mg, 16%; 98% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12e (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
R2¼benzyl, R3¼4-F3C-phenyl)
The compound 1j (14 mg, 16%; 99% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12j (300 mg) fol-
lowing the same procedure as described for 1a. 1H NMR (500 MHz,
d
1.28 (t, J¼7.1 Hz, 3H), 3.90–4.02 (m, 2H), 5.24 (s, 1H), 7.22 (d,
J¼8.3 Hz, 1H), 7.25–7.27 (m, 1H), 7.28–7.30 (m, 2H), 7.37–7.44 (m,
3H), 7.69 (dt, J¼8.3 and 1.7 Hz, 1H), 8.24 (dd, J¼7.9 and 1.7 Hz, 1H);
CDCl3)
d
5.10 (s, 2H), 5.14 (s, 1H), 7.21 (dd, J¼8.4 and 0.6 Hz, 1H),
7.27–7.31 (m, 3H), 7.31–7.36 (m, 3H), 7.43 (d, J¼8.3 Hz, 2H), 7.62 (dt,
13C NMR (125 MHz, CDCl3)
d 14.5, 41.6, 76.2, 117.6, 123.7, 123.72,
J¼7.9 and 1.6 Hz, 1H), 7.67 (d, J¼8.2 Hz, 2H), 8.20 (dd, J¼7.9 and
127.6, 128.9, 129.7, 130.1, 130.2, 136.4, 143.0, 186.6; MS (ESI) m/z 302
1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 51.9, 75.9, 119.6, 123.7 (q,
([MþH]þ).
J¼271.1 Hz), 124.0, 124.6, 125.9 (q, J¼3.8 Hz), 127.2, 128.4, 129.1
130.0, 130.1, 131.2, 131.9 (q, J¼32.6 Hz), 135.3,136.6, 143.3, 185.7; MS
(ESI) m/z 454 ([MþHþNa]þ).
4.6.8. Preparation of 1-benzyl-3-phenyl-3,4-dihydro-1H-2,1-
benzothiazin-4-one 2,2-dioxide 1f (R1¼H, R2¼benzyl, R3¼Ph)
The compound 1f (11 mg, 21%; 97% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12f (200 mg) fol-
lowing the same procedure as described for 1a. 1H NMR (500 MHz,
4.6.13. Preparation of 1-benzyl-3-(4-nitrophenyl)-3,4-dihydro-1H-
2,1-benzothiazin-4-one 2,2-dioxide 1k (R1¼H, R2¼benzyl,
R3¼4-O2N-phenyl)
The compound 1k (8 mg, 9%; 96% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12k (300 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
CDCl3)
d
5.00 (d, J¼16.8 Hz, 1H), 5.07 (d, J¼16.8 Hz, 1H), 5.18 (s, 1H),
7.14 (d, J¼8.2 Hz, 1H), 7.27–7.34 (m, 8H), 7.38–7.44 (m, 3H), 7.57 (dt,
J¼8.2 and 1.7 Hz, 1H), 8.21 (dd, J¼8.0 and 1.7 Hz, 1H); 13C NMR
d
5.11 (s, 1H), 5.14 (s, 2H), 7.24 (m, 1H), 7.29–7.36 (m, 6H), 7.48–7.51
(m, 2H), 7.65 (dt, J¼7.9 and 1.6 Hz, 1H), 8.20 (dd, J¼7.9 and 1.6 Hz,
1H), 8.25–8.27 (m, 2H); 13C NMR (125 MHz, CDCl3)
52.4, 75.8,
(125 MHz, CDCl3) d 51.8, 76.2, 119.2, 124.0, 124.3, 126.9, 127.4, 128.1,
129.0, 129.1, 129.8, 129.9, 130.3, 135.8, 136.3, 143.6, 186.5; MS (ESI)
d
m/z 364 ([MþH]þ).
120.0, 123.9, 124.0, 124.9, 127.3, 128.5, 129.2, 130.0, 132.0, 133.8,
135.1, 136.7, 143.3, 148.7, 185.3; MS (ESI) m/z 409 ([MþH]þ).
4.6.9. Preparation of 1-benzyl-4-hydroxy-3-(2-nitrophenyl)-1H-
2,1-benzothiazine 2,2-dioxide 1g (R1¼H, R2¼benzyl, R3¼2-O2N-
phenyl)
The compound 1g (13 mg, 15%; 98% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12g (300 mg) fol-
lowing the same procedure as described for 1a. 1H NMR (500 MHz,
4.6.14. Preparation of 1-(4-methoxybenzyl)-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1l (R1¼H, R2¼4-MeO-
benzyl, R3¼Ph)
The compound 1l (9 mg, 17%; 92% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12l (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
CDCl3)
d
5.26 (s, 2H), 7.12 (dt, J¼7.7 and 1.1 Hz, 1H), 7.18–7.30 (m,
5H), 7.31–7.35 (m, 4H), 7.40–7.43 (m, 1H), 7.58 (dd, J¼7.8 and 1.4 Hz,
d
3.78 (s, 3H), 4.94 (d, J¼16.4 Hz, 1H), 5.03 (d, J¼16.4 Hz, 1H), 5.09
1H), 8.01–8.04 (m, 1H), 8.83 (s, 1H, OH); 13C NMR (125 MHz, CDCl3)
(s, 1H), 6.83 (d, J¼8.7 Hz, 2H), 7.18 (d, J¼8.7 Hz, 2H), 7.21 (d,
J¼8.3 Hz, 1H), 7.24–7.28 (m, 3H), 7.37–7.45 (m, 3H), 7.59 (dt, J¼8.3
and 1.7 Hz, 1H), 8.20 (dd, J¼7.9 and 1.7 Hz, 1H); 13C NMR (125 MHz,
d
49.4, 110.2, 111.4, 116.5, 119.6, 119.7, 122.2, 122.5, 122.6, 123.5,
124.8, 127.2,127.6, 128.6,130.0,135.1, 135.6, 136.1, 138.5; MS (ESI) m/
z 432 ([MþHþNa]þ).
CDCl3) d 51.5, 55.3, 76.3, 114.3, 119.6, 124.3, 124.4, 127.4, 127.5, 128.6,
129.0,129.7, 129.8,130.4,136.2,143.6,159.4,186.6; MS (ESI) m/z 394
([MþH]þ).
4.6.10. Preparation of 1-benzyl-3-(4-fluorophenyl)-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1h (R1¼H, R2¼benzyl,
R3¼4-F-phenyl)
4.6.15. Preparation of 1-(4-fluorobenzyl)-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1m (R1¼H,
The compound 1h (14 mg, 17%; 99% purity on the basis of
LC–UV–MS spectrum) was prepared from the resin 12h (300 mg)
following the same procedure as described for 1a. 1H NMR
R2¼4-F-benzyl, R3¼Ph)
The compound 1m (11 mg, 20%; 98% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12m (200 mg)
following the same procedure as described for 1a. 1H NMR
(500 MHz, CDCl3)
d
5.05 (d, J¼16.7 Hz, 1H), 5.10 (d, J¼16.7 Hz,
1H), 5.11 (s, 1H), 7.08–7.12 (m, 2H), 7.17 (dd, J¼8.3 and 0.6 Hz,
1H), 7.27–7.30 (m, 5H), 7.31–7.36 (m, 3H), 7.59 (dt, J¼7.9 and
1.7 Hz, 1H), 8.20 (dd, J¼7.9 and 1.6 Hz, 1H); 13C NMR (125 MHz,
(500 MHz, CDCl3)
d
4.99 (s, 2H), 5.21 (s, 1H), 7.01 (t, J¼8.6 Hz, 2H),
7.10 (d, J¼8.3 Hz, 1H), 7.22–7.29 (m, 5H), 7.38–7.41 (m, 2H), 7.43–
7.46 (m, 1H), 7.58 (dt, J¼8.3 and 1.6 Hz, 1H), 8.22 (dd, J¼7.9 and
CDCl3)
d
51.8, 75.6, 116.2 (d, J¼22.1 Hz), 119.4, 122.9, 123.9, 124.4,
1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 50.8, 76.1, 116.0 (d,
127.0, 128.2, 129.1, 129.9, 132.5 (d, J¼8.5 Hz), 135.5, 136.4, 143.5,
163.6 (d, J¼249.0 Hz), 186.2 (F coupling); MS (ESI) m/z 382
([MþH]þ).
J¼21.4 Hz),118.8,123.9,124.3, 127.4, 128.7 (d, J¼8.4 Hz),129.1, 129.8,
129.9, 130.2, 131.6 (d, J¼3.1 Hz), 136.4, 143.4, 162.4 (d, J¼245.5 Hz),
186.3; MS (ESI) m/z 382 ([MþH]þ).
4.6.11. Preparation of 1-benzyl-3-(4-chlorophenyl)-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1i (R1¼H, R2¼benzyl,
R3¼4-Cl-phenyl)
4.6.16. Preparation of 1-benzyl-6-methoxy-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1o (R1¼6-MeO,
R2¼benzyl, R3¼Ph)
The compound 1i (7 mg, 8%; 99% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12i (300 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
The compound 1o (7 mg, 14%; 97% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12o (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
d
5.05 (d, J¼16.7 Hz, 1H), 5.09 (s, 1H), 5.10 (d, J¼16.7 Hz, 1H), 7.17
(dd, J¼8.3 and 0.6 Hz, 1H), 7.21–7.24 (m, 2H), 7.27–7.30 (m, 3H),
7.31–7.34 (m, 3H), 7.36–7.39 (m, 2H), 7.59 (dt, J¼7.9 and 1.8 Hz,
1H), 8.20 (dd, J¼7.9 and 1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
3.86 (s, 3H), 4.90 (d, J¼16.5 Hz,1H), 5.01 (s, 1H), 5.04 (d, J¼16.5 Hz,
1H), 7.11 (d, J¼9.0 Hz, 1H), 7.17 (dd, J¼9.0 and 3.1 Hz, 1H), 7.24–7.29
(m, 4H), 7.30–7.35 (m, 3H), 7.37–7.45 (m, 3H), 7.64 (d, J¼3.1 Hz, 1H);
d
51.8, 75.6, 119.4, 123.9, 124.5, 125.6, 127.1, 128.2, 129.1, 129.3,
13C NMR (125 MHz, CDCl3)
d 53.1, 55.8, 75.9, 111.4, 121.8, 124.5,
129.9, 131.8, 135.5, 136.1, 136.4, 143.4, 186.0; MS (ESI) m/z 398
([MþH]þ).
125.3, 127.3, 127.6, 128.2, 128.4, 129.0, 129.7, 130.4, 135.7, 137.4,
156.5, 186.8; MS (ESI) m/z 394 ([MþH]þ).

9070
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
4.6.17. Preparation of 6-methoxy-1-(2-methylbenzyl)-3-phenyl-
3,4-dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1p (R1¼6-MeO,
R2¼2-Me-benzyl, R3¼Ph)
4.6.22. Preparation of 6-chloro-3-phenyl-1-(pyridin-4-ylmethyl)-
3,4-dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1u (R1¼6-Cl,
R2¼pyridyl-4-methyl, R3¼Ph)
The compound 1p (6 mg, 11%; 96% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12p (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
The compound 1u (5 mg, 10%; 94% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12u (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
d
2.28 (s, 3H), 3.86 (s, 3H), 4.91 (s, 2H), 5.26 (s,1H), 6.85 (d, J¼9.0 Hz,
d
4.94 (d, J¼18.0 Hz,1H), 4.98 (d, J¼18.0 Hz,1H), 5.36 (s,1H), 6.86 (d,
1H), 7.10 (dd, J¼9.0 and 3.1 Hz, 1H), 7.18–7.21 (m, 3H), 7.31–7.35 (m,
J¼8.8 Hz, 1H), 7.21 (d, J¼5.9 Hz, 2H), 7.28 (d, J¼7.3 Hz, 2H), 7.40–
7.44 (m, 2H), 7.47 (d, J¼7.3 Hz, 1H), 7.51 (dd, J¼8.8 and 2.6 Hz, 1H),
8.21 (d, J¼2.6 Hz, 1H), 8.58 (d, J¼5.9 Hz, 2H); 13C NMR (125 MHz,
3H), 7.40–7.45 (m, 3H), 7.68 (d, J¼3.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3)
d 19.1, 51.1, 55.8, 75.7, 111.4, 121.2, 124.5, 124.7, 126.4, 126.7,
127.7, 127.9, 129.1, 129.8, 130.2, 130.6, 133.9, 134.6, 137.8, 156.3,
CDCl3) d 50.4, 75.8, 119.5, 121.2, 124.6, 127.0, 129.3, 129.6, 130.0,
186.9; MS (ESI) m/z 408 ([MþH]þ).
130.2, 130.5, 136.2, 141.5, 144.9, 150.6, 185.0; MS (ESI) m/z 399
([MþH]þ).
4.6.18. Preparation of 1-(3-fluorobenzyl)-6-methoxy-3-phenyl-3,4-
dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1q (R1¼6-MeO,
R2¼3-F-benzyl, R3¼Ph)
4.6.23. Preparation of 6-chloro-3-phenyl-1-(thiophen-3-ylmethyl)-
3,4-dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1v (R1¼6-Cl,
R2¼thienyl-3-methyl, R3¼Ph)
The compound 1q (7 mg, 14%; 99% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12q (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
The compound 1v (9 mg, 17%; 95% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12v (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
d
3.86 (s, 3H), 4.89 (d, J¼16.8 Hz, 1H), 4.97 (d, J¼16.8 Hz, 1H), 5.15 (s,
1H), 6.95–7.01 (m, 2H), 7.02 (d, J¼9.0 Hz, 1H), 7.08 (d, J¼7.8 Hz, 1H),
7.16 (dd, J¼9.0 and 3.1 Hz, 1H), 7.27–7.33 (m, 3H), 7.38–7.45 (m, 3H),
d
4.97 (d, J¼16.6 Hz, 1H), 5.01 (s, 1H), 5.08 (d, J¼16.6 Hz, 1H), 6.91
(dd, J¼5.0 and 1.3 Hz, 1H), 7.20–7.25 (m, 4H), 7.31 (dd, J¼5.0 and
3.0 Hz, 1H), 7.38–7.46 (m, 3H), 7.57 (dd, J¼8.8 and 2.6 Hz, 1H), 8.15
7.67 (d, J¼3.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 51.9, 55.9, 75.9,
111.6, 114.1 (d, J¼22.4 Hz), 115.2 (d, J¼20.9 Hz), 121.0, 122.6 (d,
J¼2.9 Hz), 124.5, 125.0, 127.7, 129.1, 129.9, 130.3, 130.7 (d, J¼8.1 Hz),
137.2, 138.6 (d, J¼7.3 Hz), 156.5, 163.1 (d, J¼246.5 Hz), 186.6; MS
(ESI) m/z 412 ([MþH]þ).
(d, J¼2.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 47.8, 76.0, 121.2,
123.6, 125.3, 126.6, 126.7, 127.3, 129.1, 129.3, 129.9, 130.4, 130.6,
136.0, 136.1, 141.9, 185.5; MS (ESI) m/z 404 ([MþH]þ).
4.6.24. Preparation of 1-benzyl-7-fluoro-3-phenyl-3,4-dihydro-1H-
2,1-benzothiazin-4-one 2,2-dioxide 1w (R1¼7-F, R2¼benzyl, R3¼Ph)
The compound 1w (10 mg, 15%; 94% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12w (250 mg)
following the same procedure as described for 1a. 1H NMR
4.6.19. Preparation of 1-iso-butyl-6-methoxy-3-phenyl-3,4-
dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide 1r (R1¼6-MeO,
R2¼iso-butyl, R3¼Ph)
The compound 1r (7 mg, 13%; 99% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12r (200 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
4.99 (d, J¼16.9 Hz, 1H), 5.04 (d, J¼16.9 Hz,
1H), 5.23 (s. 1H), 6.81 (dd, J¼10.2 and 2.4 Hz, 1H), 6.95 (dt, J¼7.6
and 2.4 Hz, 1H), 7.26–7.30 (m, 4H), 7.31–7.36 (m, 3H), 7.39–7.46
(m, 3H), 8.25 (dd, J¼8.9 and 6.4 Hz, 1H); 13C NMR (125 MHz,
d
0.90 (d, J¼6.7 Hz, 3H),1.00 (d, J¼6.7 Hz, 3H), 2.08 (m,1H), 3.58 (dd,
J¼14.2 and 6.7 Hz, 1H), 3.61 (dd, J¼14.2 and 6.7 Hz, 1H), 3.88 (s, 3H),
5.23 (s, 1H), 7.15 (d, J¼9.0 Hz, 1H), 7.23–7.26 (m, 1H), 7.30–7.32 (m,
2H), 7.38–7.43 (m, 3H), 7.68 (d, J¼3.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3)
d
51.2, 76.0, 106.1 (d, J¼26.6 Hz), 111.9 (d, J¼21.9 Hz), 120.4,
126.8, 127.1, 128.2, 129.1, 129.2, 129.9, 130.3, 132.7 (d, J¼10.9 Hz),
135.2, 145.8 (d, J¼11.6 Hz), 167.3 (d, J¼257.5 Hz), 184.9; MS (ESI)
m/z 382 ([MþH]þ).
CDCl3)
d 19.9, 20.2, 28.2, 54.6, 55.8, 75.7, 111.5, 120.2, 124.5, 124.7,
127.7, 128.9, 129.7, 130.5, 137.7, 156.0, 187.0; MS (ESI) m/z 360
([MþH]þ).
4.6.25. Preparation of 1-benzyl-7-chloro-3-phenyl-3,4-dihydro-1H-
2,1-benzothiazin-4-one 2,2-dioxide 1x (R1¼7-Cl, R2¼benzyl, R3¼Ph)
The compound 1x (17 mg, 25%; 99% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12x (250 mg) fol-
lowing the same procedure as described for 1a. 1H NMR (500 MHz,
4.6.20. Preparation of 1-benzyl-6-methyl-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1s (R1¼6-Me,
R2¼benzyl, R3¼Ph)
The compound 1s (18 mg, 24%; 99% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12s (300 mg)
following the same procedure as described for 1a. 1H NMR
CDCl3)
d
4.98 (d, J¼16.8 Hz, 1H), 5.04 (d, J¼16.8 Hz, 1H), 5.19 (s, 1H),
7.14 (d, J¼1.9 Hz, 1H), 7.23 (dd, J¼8.6 and 1.9 Hz, 1H), 7.26–7.28 (m,
(500 MHz, CDCl3)
d
2.37 (s, 3H), 4.95 (d, J¼16.7 Hz, 1H), 5.04 (s,
4H), 7.31–7.36 (m,3H), 7.39–7.47 (m, 3H), 8.15 (d, J¼8.6 Hz, 1H); 13
C
J¼16.7 Hz, 1H), 5.12 (s, 1H), 7.04 (d, J¼8.4 Hz, 1H), 7.26–7.29 (m,
NMR (125 MHz, CDCl3) d 51.4, 76.1, 119.1, 122.3, 124.7, 127.0, 127.1,
4H), 7.30–7.34 (m, 3H), 8.00 (d, J¼1.7 Hz, 1H); 13C NMR (125 MHz,
128.3, 129.1, 129.2, 129.9, 130.3, 131.1, 135.1, 142.7, 144.4, 185.4; MS
CDCl3)
d
20.5, 51.9, 76.1, 119.4, 123.9, 127.1, 127.7, 128.0, 128.9,
(ESI) m/z 398 ([MþH]þ).
129.0, 129.6, 129.7, 130.3, 134.3, 135.9, 137.2, 141.3, 186.8; MS (ESI)
m/z 378 ([MþH]þ).
4.6.26. Preparation of 1-benzyl-8-methoxy-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1y (R1¼8-MeO,
R2¼benzyl, R3¼Ph)
4.6.21. Preparation of 1-benzyl-6-chloro-3-phenyl-3,4-dihydro-1H-
2,1-benzothiazin-4-one 2,2-dioxide 1t (R1¼6-Cl, R2¼benzyl, R3¼Ph)
The compound 1t (10 mg, 19%; 98% purity on the basis of LC–
UV–MS spectrum) was prepared from the resin 12t (200 mg) fol-
lowing the same procedure as described for 1a. 1H NMR (500 MHz,
The compound 1y (7 mg, 9%; 92% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12y (300 mg) follow-
ing the same procedure as described for 1a. 1H NMR (500 MHz,
CDCl3)
d
4.04 (s, 1H), 4.13 (s, 1H), 5.12 (d, J¼15.2 Hz, 1H), 5.17 (d,
CDCl3)
d
4.97 (d, J¼16.8 Hz, 1H), 5.05 (d, J¼16.8 Hz, 1H), 5.16 (s, 1H),
J¼15.2 Hz, 1H), 7.10 (dd, J¼7.5 and 1.6 Hz, 1H), 7.14 (dd, J¼7.8 and
1.4 Hz, 1H), 7.29–7.34 (m, 4H), 7.35–7.38 (m,3H), 7.41 (t, J¼8.1 Hz,
1H), 7.73 (dd, J¼7.8 and 1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
7.08 (d, J¼8.8 Hz, 1H), 7.25–7.28 (m, 4H), 7.31–7.34 (m, 3H), 7.39–
7.45 (m, 3H), 7.51 (dd, J¼8.8 and 2.6 Hz, 1H), 8.16 (d, J¼2.6 Hz, 1H);
13C NMR (125 MHz, CDCl3)
d
51.8, 76.0, 120.8, 125.1, 126.9, 127.0,
d 54.2, 56.6, 76.7, 118.5, 121.1, 126.8, 127.4, 128.7, 128.9, 129.0, 129.1,
128.3, 129.1, 129.3, 130.0, 130.2, 130.3, 135.3, 136.0, 142.0, 185.5; MS
129.3, 129.7, 131.2, 132.0, 134.4, 153.3, 187.9; MS (ESI) m/z 394
(ESI) m/z 398 ([MþH]þ).
([MþH]þ).

M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
9071
4.6.27. Preparation of 1-benzyl-8-methyl-3-phenyl-3,4-dihydro-
1H-2,1-benzothiazin-4-one 2,2-dioxide 1z (R1¼8-Me, R2¼benzyl,
R3¼Ph)
122.4, 123.6, 126.6, 127.9, 129.1, 129.7, 135.9, 136.0, 143.2, 187.0; MS
(ESI) m/z 316 ([MþH]þ). In addition to the desired product, two
unknown side products were isolated by subsequent elution
(65 mg eluted by an 8:1 mixture of n-hexane and ethyl acetate, and
33 mg eluted by a 9:1 mixture of CH2Cl2 and methanol).
The compound 1z (7 mg, 9%; 91% purity on the basis of LC–UV–
MS spectrum) was prepared from the resin 12z (300 mg) following
the same procedure as described for 1a. 1H NMR (500 MHz, CDCl3)
d
2.59 (s, 3H), 4.07 (s, 1H), 4.65 (d, J¼15.0 Hz,1H), 5.20 (d, J¼15.0 Hz,
4.8. Experiment on the reusability of the post-cleavage resin
1H), 7.05–7.08 (m, 4H), 7.31–7.38 (m, 6H), 7.40 (t, J¼7.7 Hz, 1H), 7.67
(dd, J¼7.6 and 0.8 Hz, 1H), 7.96 (dd, J¼7.9 and 1.2 Hz, 1H); 13C NMR
The resin (255 mg), recovered from a reaction repeated as de-
scribed in Section 4.6.8, in THF (2 ml) at rt was treated with 25 wt %
(125 MHz, CDCl3)
d 18.1, 55.6, 76.2, 127.2, 127.4, 127.5, 128.7, 129.1,
129.3, 129.4, 130.0, 131.3, 133.2, 134.7, 138.6, 141.7, 188.7; MS (ESI)
of NaOMe in MeOH (760 ml, 3.52 mmol) and the mixture was stirred
m/z 378 ([MþH]þ).
at rt for 12 h. The resin was filtered, washed several times with
MeOH, H2O, and MeOH, and dried in a vacuum oven. To a mixture of
the pretreated resin and 2-nitrobenzoic acid (79 mg, 0.47 mmol) in
CH2Cl2/DMF (4:1, 3 ml) at rt were added DIC (89 mg, 0.71 mmol)
and DMAP (86 mg, 0.71 mmol). The mixture was stirred at rt for
20 h and the resin was filtered, washed several times with CH2Cl2,
DMF, and MeOH, and dried in a vacuum oven. To a suspension of
the resultant resin in THF (2 ml) at rt was added 25 wt % of NaOMe
4.7. Solution-phase model study
4.7.1. Preparation of methyl N-(1-propanesulfonyl)anthranilate 13
A mixture of methyl anthranilate (500 mg, 3.31 mmol) and Et3N
(1.00 g, 9.92 mmol) in CH2Cl2 (20 ml) at rt was added 1-propane-
sulfonyl chloride (1.41 g, 9.92 mmol). The mixture was stirred at rt
for 6 h. The mixture was washed with water, and the organic layer
was dried over MgSO4 and concentrated in vacuo. The residue was
purified by a silica gel column chromatography (8:1 mixture of
n-hexane and ethyl acetate) to give methyl N-(1-propane-
sulfonyl)anthranilate (686 mg, 81%; 99 % purity on the basis of
in MeOH (223 ml, 1.03 mmol) and the mixture was stirred at rt for
12 h. The resin was filtered and washed with MeOH (1 mlꢂ3). The
filtrate was evaporated in vacuo, neutralized with 3 N aqueous
hydrochloric acid, and extracted with methylene chloride (1 mlꢂ3).
The organic layers were dried over MgSO4 and concentrated in
vacuo to give a residue, from which methyl 2-nitrobenzoate (4 mg)
was isolated by silica gel column chromatography (5:1 mixture of
n-hexane and ethyl acetate).
LC–UV–MS spectrum). 1H NMR (500 MHz, CDCl3)
d
1.01 (t, J¼7.5 Hz,
3H), 1.81–1.87 (m, 2H), 3.13 (t, J¼7.9 Hz, 2H), 3.94 (s, 3H), 7.10 (t,
J¼7.4 Hz, 1H), 7.54 (t, J¼8.7 Hz, 1H), 7.76 (d, J¼8.5 Hz, 1H), 8.05 (dd,
J¼8.1 and 1.6 Hz, 1H), 10.4 (s, 1H, NH); 13C NMR (125 MHz, CDCl3)
d
12.8,17.2, 52.5, 53.9,115.1,117.8,122.5,131.5,134.9,141.1,168.4; MS
Acknowledgements
(ESI) m/z 258 ([MþH]þ).
We are grateful to the Center for Biological Modulators and
Seoul Research and Business Development Program (grant number
10574) for financial support of this research.
4.7.2. Preparation of methyl N-benzyl-N-(1-propanesulfonyl)-
anthranilate 14
To
a mixture of diisopropyl azodicarboxylate (707 mg,
3.50 mmol) and triphenylphosphine (917 mg, 3.50 mmol) in THF
(15 ml) were added methyl N-(1-propanesulfonyl)anthranilate
(300 mg, 1.17 mmol) and benzyl alcohol (378 mg, 3.50 mmol). The
mixture was stirred at rt for 2 h. The mixture was evaporated in
vacuo and the residue was purified by a silica gel column chro-
matography (8:1 mixture of n-hexane and ethyl acetate) to give
methyl N-benzyl-N-(1-propanesulfonyl)anthranilate (404 mg, 99
%; 99% purity on the basis of LC–UV–MS spectrum). 1H NMR
References and notes
1. (a) Muegge, I. Med. Res. Rev. 2003, 23, 302–321; (b) Supuran, C. T.; Casini, A.;
Scozzafava, A. Med. Res. Rev. 2003, 23, 535–558.
2. For a general reference for 1,2-thiazines, see: Garigipati, R. S.; Weinreb, S. M.
1,2-Thiazines and their Benzo Derivatives. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996; Vol. 6, pp 349–382.
3. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-C.; Meng, Z.; Potocki,
I.; Hoermann, M. A.; Snow, R. J.; Tschantz, M. A.; Kelly, T. A.; McNeil, D. W.;
Coutts, S. J.; Churchill, L.; Graham, A. G.; David, E.; Grob, P. M.; Engel, W.; Meier,
H.; Trummlitz, G. J. Med. Chem. 1997, 40, 980–989 and the references cited
therein.
4. (a) Nie, H.; Widdowson, K.L. WO 9834929, 1998; Chem. Abstr. 1998, 129,
1756451; (b) Fairhurst, J.; Gallagher, P. WO 2001087881, 2001; Chem. Abstr.
2001, 136, 6015; (c) Li, W.; Marlowe, C. K.; Scarborough, R. M. WO 2001072725,
2001; Chem. Abstr. 2001, 135, 288798; (d) Yoakim, C.; O’Meara, J.; Simoneau, B.;
Ogilvie, W. W.; Deziel, R. WO 2004026875, 2004; Chem. Abstr. 2004, 140,
303707.
(500 MHz, CDCl3)
d
1.01 (t, J¼7.5 Hz, 3H), 1.84–1.89 (m, 2H), 3.03 (t,
J¼7.0 Hz, 2H), 3.92 (s, 3H), 4.64 (br s, 1H), 4.96 (br s, 1H), 7.06 (dd,
J¼7.3 and 1.6 Hz, 1H), 7.23–7.30 (m, 4H), 7.32–7.39 (m, 3H), 7.88
(dd, J¼7.5 and 1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 13.1, 17.2,
52.4, 55.2, 55.7, 127.9, 128.3, 128.4, 128.6, 129.5, 131.0, 131.4, 132.3,
133.3, 136.5, 138.2, 166.5; MS (ESI) m/z 348 ([MþH]þ).
4.7.3. Preparation of 1-benzyl-3-ethyl-3,4-dihydro-1H-2,1-
benzothiazin-4-one 2,2-dioxide 1d
5. Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales, G. A.; Salvino, J. M.;
Zhang, W. J. Comb. Chem. 2007, 9, 855–902.
6. (a) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144–154;
(b) Tempest, P. A.; Armstrong, R. W. J. Am. Chem. Soc. 1997, 119, 7607–7608; (c)
Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124,
1594–1596; (d) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–
58; (e) Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63, 723–727.
7. (a) Jeon, M.-K.; La, H. J.; Ha, D.-C.; Gong, Y.-D. Synlett 2007, 1431–1435; (b) Jeon,
M.-K.; Kim, D.-S.; La, H. J.; Ha, D.-C.; Gong, Y.-D. Tetrahedron Lett. 2005, 46,
7477–7481; (c) Jeon, M.-K.; Kim, D.-S.; La, H. J.; Gong, Y.-D. Tetrahedron Lett.
2005, 46, 4979–4983.
8. (a) Loev, B.; Kormendy, M. F.; Snader, K. M. J. Org. Chem. 1966, 31, 3531–3534; (b)
Musser, J. H.; Kreft, A. F.; Bender, R. H. W.; Kubrak, D. M.; Carlson, R. P.; Chang, J.;
Hand, J. M. J. Med. Chem. 1989, 32, 1176–1183; (c) Hicks, J. L.; Roark, W. H. WO
2004014388, 2004; Chem. Abstr. 2004, 140, 181456; (d) Lombardino, J. G.;
Treadway, N. W., Jr. Org. Prep. Proced. Int. 1971, 3, 33–36; (e) Nakanishi, M.;
Kobayashi, R. JP 46022152,1971; Chem. Abstr.1971, 75, 76820;(f) Lombardino, J. G.
J. Heterocycl. Chem. 1972, 9, 315–317; (g) Hwang, K.-J.; Lee, T.-S. Korean J. Med.
Chem.1999, 9, 75–78; (h) Scherrer, R. A.; Beatty, H. R. J. Org. Chem.1980, 45, 2127–
2131; (i) Coppo, F. T.; Fawzi, M. M. J. Heterocycl. Chem. 1998, 35, 983–987.
9. Besides the preparation of 3,4-dihydro-1H-2,1-benzothiazin-4-one 2,2-dioxide
skeleton, the N-sulfonylanthranilates have been utilized as intermediates
To
a
methyl N-benzyl-N-(1-propanesulfonyl)anthranilate
(300 mg, 0.86 mmol) in DMF (25 ml) at rt was added 60% disper-
sion of NaH in mineral oil (44 mg, 1.3 mmol) and the mixture was
stirred at rt for 2 h. The mixture was evaporated in vacuo, acidified
to pH 3–4 with 3 N hydrochloric acid, and extracted with methy-
lene chloride. The organic layer was dried over MgSO4 and con-
centrated in vacuo. The residue was purified by a silica gel column
chromatography (8:1 mixture of n-hexane and ethyl acetate) to
give 1d (121 mg, 44%; 99% purity on the basis of LC–UV–MS spec-
trum). 1H NMR (500 MHz, CDCl3)
d
1.18 (t, J¼7.5 Hz, 3H), 2.04–2.12
(m, 1H), 2.20–2.28 (m, 1H), 3.97 (dd, J¼8.1 and 5.5 Hz, 1H), 5.08 (d,
J¼17.0 Hz, 1H), 5.26 (d, J¼17.0 Hz, 1H), 7.03 (dd, J¼8.3 and 0.6 Hz,
1H), 7.18 (dt, J¼8.1 and 0.9 Hz, 1H), 7.31 (t, J¼7.1 Hz, 1H), 7.36–7.41
(m, 4H), 7.49 (dt, J¼8.9 and 1.7 Hz, 1H), 8.12 (dd, J¼8.0 and 1.7 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 11.6, 19.7, 29.7, 50.5, 72.2, 118.1,

9072
M.-K. Jeon et al. / Tetrahedron 64 (2008) 9060–9072
in solution phase for the synthesis of various N-containing heterocyclic
Hibert, M. J. Comb. Chem. 2007, 9, 487–500; (n) Mishra, J. K.; Panda, G. J. Comb.
Chem. 2007, 9, 321–338.
10. Yan, B. Acc. Chem. Res. 1998, 31, 621–630.
ring systems such as 1-benzazocin-6-one,9a dibenz[b,e]azepin-11-one,9b
benzo[b]acridin-12-one,9c pyrrolo[3,2-c]quinoline,9d–g 5-spirocyclopropane
isoxazolidine,9h,i quinoline,9j indole,9k 1-benzoazepin-5-one,9l,m and benzo[e]-
1,4-diazepine9n through further transformations. However, there has been no
report regarding utilization of N-sulfonyl anthranilate resin for the synthesis of
heterocyclic systems on solid phase to the best of our knowledge: (a) Proctor,
G. R.; Ross, W. I. J. Chem. Soc., Perkin Trans. 1 1972, 885–889; (b) Dunn, J. P.;
Muchowski, J. M.; Nelson, P. H. J. Med. Chem. 1981, 24, 1097–1099; (c) Mongrain,
C.; Brassard, P. Heterocycles 1993, 36, 2108–2127; (d) Lovely, C. J.; Mahmud, H.
Tetrahedron Lett. 1999, 40, 2079–2082; (e) Hara, O.; Sugimoto, K.; Makino, K.;
Hamada, Y. Synlett 2004, 1625–1627; (f) Takeda, Y.; Nakabayashi, T.; Shirai, A.;
Fukumoto, D.; Kiguchi, T.; Naito, T. Tetrahedron Lett. 2004, 45, 3481–3484; (g)
Hara, O.; Sugimoto, K.; Hamada, Y. Tetrahedron 2004, 60, 9381–9390; (h) Cor-
dero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Salaun, J.; Brandi, A. J. Am. Chem.
Soc. 2000, 122, 8075–8076; (i) Cordero, F. M.; Pisaneschi, F.; Salvati, M.; Pa-
schetta, V.; Ollivier, J.; Salaun, J.; Brandi, A. J. Org. Chem. 2003, 68, 3271–3280;
(j) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron 2004,
60, 3017–3035; (k) Arisawa, M.; Terada, Y.; Takahashi, K.; Nakagawa, M.;
Nishida, A. J. Org. Chem. 2006, 71, 4255–4261; (l) Seto, M.; Aramaki, Y.; Okawa,
T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.-i.; Iizawa, Y.; Baba, M.;
Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 577–590; (m) Boeglin, D.; Bonnet, D.;
11. There has been no report regarding the N-sulfonylation of N-alkylanthranilates
even in solution phase to the best of our knowledge, presumably due to the low
reactivity of the nitrogen nucleophilic center of the N-alkylanthranilates. Our
preliminary results were also not promising, so the further search was not tried
for the suitable conditions.
12. For representative preparative methods for sulfonic acids and sulfonates,
see: (a) Smith, K.; Hou, D. J. Org. Chem. 1996, 61, 1530–1532; (b) Higashiura,
K.; Ienaga, K. J. Org. Chem. 1992, 57, 764–766 and the references cited
therein.
13. As a related example for direct synthesis of sulfonamides from sulfonic acids
and their salts using triphenylphosphine ditriflate, see: Caddick, S.; Wilden,
J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024–1025.
14. For the utilities of the PFP sulfonate esters for the preparation of diverse sul-
fonamides, see: Wilden, J. D.; Judd, D. B.; Caddick, S. Tetrahedron Lett. 2005, 46,
7637–7640 and the references cited therein.
15. For a recent review on cyclative cleavage strategy, see: Pernerstorfer, J. In
Combinatorial Chemistry; Bannwarth, W., Hinzen, B., Eds.; Wiley-VCH: Wein-
heim, 2006; pp 111–142.
16. Hadri, A. E.; Leclerc, G. J. Heterocycl. Chem. 1993, 30, 631–635.