A dynamic multicomponent approach for one-pot synthesis of 3-thioisoindolinones

Article abstract of DOI:10.1002/ijch.201200101

A dynamic multicomponent reaction concept has been successfully applied to the syntheses of 3-thioisoindolinones and tricyclic γ-lactams. The reactions were efficiently designed and operated in the absence of any catalyst under mild reaction conditions, r

Full text of DOI:10.1002/ijch.201200101

Full Paper
DOI: 10.1002/ijch.201200101
A Dynamic Multicomponent Approach for One-Pot
Synthesis of 3-Thioisoindolinones
Morakot Sakulsombat,[a] Marcus Angelin,[a] Rꢀmi Caraballo,[a] and Olof Ramstrçm*[a]
Abstract: A dynamic multicomponent reaction concept has
been successfully applied to the syntheses of 3-thioisoindoli-
nones and tricyclic g-lactams. The reactions were efficiently
designed and operated in the absence of any catalyst under
mild reaction conditions, resulting in the convenient varia-
tion of substituents on the N- and S-positions of the target
products.
Keywords: cyclization · dynamic chemistry · heterocycles · isoindolinone · multicomponent reactions
1 Introduction
are thus commonly used in heterocyclic syntheses for the
Isoindolinone (1, Figure 1) constitutes a common core
structure in heterocyclic synthesis, found in many natural
products and biologically active compounds.[1–8] Substitu-
ents on the isoindolinone structure, especially at the 2-
(N-atom) and 3-positions, have been reported in many
studies as essential for the isoindolinone binding activi-
ties, such as in non-steroidal anti-inflammatory drugs,[4,8]
anxiolytic drugs,[6] non-nucleoside HIV reverse transcrip-
tase inhibitors,[5,7] HIV-1 integrase inhibitors,[3] and DNA
gyrase inhibitors.[2] Therefore, in order to meet the syn-
thetic requirements, isoindolinone synthetic routes have
been developed from traditional multistep reactions to
modern multicomponent reactions in single processes,
using a variety of substrate components and cata-
lysts.[2,3,9–14]
preparation of many natural products and bioactive sub-
stances.[18,20,23,25] From economic and practical points of
view, the development of synthetically viable routes to
these compounds is highly attractive, especially in high
throughput and medicinal areas for circumventing tedious
work in the generation of large collections of compounds
by changing substituents on the target core structures.
This synthetic concept is of broad interest – from the
pharmaceutical industry to academic laboratories – for
the development of more facile, concise and efficient
preparations of known target compounds, as well as for
exploiting new and more sophisticated reactions for new
compounds and catalysts.
Recently, we reported a tandem reaction concept for
the stereoselective synthesis of 3-substituted isoindoli-
none derivatives.[26–28] The reversible nitroaldol reactions
between 2-cyanobenzaldehyde and different nitroalkanes
generated nitroaldol adducts, which subsequently under-
went cyclization and irreversible rearrangement, resulting
in diastereomerically enriched 3-subsituted isoindolinone
products. In the present study, the synthesis of isoindoli-
none derivatives has been further addressed, with the ob-
jective of developing a versatile synthetic pathway, with
a higher degree of substitution on the core motif.
For over two centuries, multicomponent reactions have
been established as efficient synthetic methodologies for
the synthesis of complex molecules.[15–25] Three or more
components undergo multistep tandem/cascade reactions
in one-pot processes to form the desired products without
isolation of any intermediates. Multicomponent reactions
In this context, 3-thioisoindolinones 2 have been identi-
fied as particularly versatile intermediates for the synthe-
sis of bioactive isoindolinones, such as isoindolines,[29]
[a] M. Sakulsombat, M. Angelin, R. Caraballo, O. Ramstrçm
KTH – Royal Institute of Technology
Department of Chemistry
Teknikringen 30, S-10044 Stockholm (Sweden)
e-mail: ramstrom@kth.se
Figure 1. Examples of isoindolinone and 3-thioisoindolinone struc-
tures.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ijch.201200101.
Isr. J. Chem. 2013, 53, 127 – 132
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O. Ramstrçm et al.
phthalimides,[30] and polycyclic dihydroisoindolizidi-
nones.[12,31] Recently, their potential inhibitory activities
toward non-nucleoside HIV reverse transcriptase (3),[5,7]
DNA gyrase (4),[2] and HIV-1 integrase (5)[3] have been
reported, showing the importance of thiol substituents.
Even though the syntheses of 3-thioisoindolinones have
been reported in stepwise reactions using acid catalysts
and high reaction temperatures, only low conversions to
the desired products were obtained.[2,3,9,13] Therefore, the
objective of the present study has been to develop an effi-
cient synthetic strategy to N- and S-substituted 3-thioi-
soindolinones 2 in a one-pot process.
stable amide product 2. In principle, the reaction between
aldehyde 6 and thiol 8 can also easily lead to an alterna-
tive 3-thiophthalide product 13 (Scheme 2b),[32] but this
route was not observed under these conditions. These
pathways, based on the two reversible reactions that form
either thioaminal 11 or hemithioacetal 12, and the subse-
quent cyclization, correspond to a Curtin-Hammett-type
situation, where intramolecular amidation of intermediate
11 occurs faster than lactonization of intermediate 12,
providing the more favored amide product 2.
The resulting multicomponent isoindolinone reaction
proved straightforward and efficient. Mixtures of aromat-
ic compound 6, amine 7, and thiol 8 in organic solvent
were stirred overnight in the presence of drying agent
and under ambient atmosphere and temperature. The re-
sulting reaction mixture was filtered and washed with sa-
turated ammonium chloride solution, and the desired
products were obtained in very high conversion and high
purity. The reaction times could also be shortened using
higher temperatures, without concomitant byproduct for-
mation.
A series of 3-substituted isoindolinones were subse-
quently produced, in order to demonstrate the versatility
of the strategy. Thus, two methyl 2-formylbenzoates 6a
and 6b were selected and allowed to react with combina-
tions of different amines and thiols as shown in Table 1.
A variety of aliphatic (7a), aromatic (7b, 7c) and chiral ar-
omatic (7d) amines were chosen to modify the substituent
on the N-center. Various thiols were also selected to in-
troduce different S-substituents, namely alkyl (8d),
phenyl (8c), benzyl (8e), and two esters of different
lengths (8a, 8b). For products from compound 6a, isoin-
dolinone 15 was obtained from n-butylamine 7a and thiol
2 Results and Discussion
Our strategy, which incorporates four substituents (R2,
R3, R4, and R5) on the isoindolinone core structure, was
designed as a one-pot catalyst-free reaction as shown in
Scheme 1. The substituents on the N- and the S-centers
(R2 and R3, respectively) of isoindolinone 2 could be
easily modified using a series of primary amines 7 and
thiols 8, while the substituents on the aromatic ring could
be varied using different methyl 2-formylbenzoates 6.
Scheme 1. Multicomponent approach to 3-thioisoindolinone deriv-
atives 2.
This method is based on two consecutive dynamic pro-
cesses, followed by kinetic cyclization of the resulting in-
termediate (Scheme 2a). Thus, the reaction of a parent
benzaldehyde with a primary amine and a thiol led to the
formation of thioaminal intermediate 11, and spontane-
ous cyclization subsequently yielded the product isoindo-
linone 2. This strategy proved highly efficient, and the re-
actions between methyl 2-formylbenzoate 6, primary
amine 7 and thiol 8 in organic solvents in the presence of
drying agent conveniently provided the desired product 2
in high yields. Following the formation of imine 10, addi-
tion of thiol 8 led to the thioaminal intermediate 11,
which underwent intramolecular amidation to generate
product 2.
Considering the reaction mechanism, the reversible
imine formation is a key step in the 3-thioisoindolinone
synthesis, a process where water is released. However,
the addition of MgSO4 as drying agent proved to be an
efficient way to displace the equilibrium toward imine
formation. Subsequently, reversible nucleophilic addition
of thiol 8 to the imine provided intermediate 11, identi-
fied by NMR, which was irreversibly transformed to
Scheme 2. Proposed reaction mechanisms for the formation of a)
3-thioisoindolinone 2 and b) 3-thiophthalide 13.[31]
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One-Pot Multicomponent Synthesis of 3-Thioisoindolinones
Table 1. Multicomponent reactions for synthesis of 3-thioisoindolinones 15–26.
Entry
Starting material
Aromatic
Product
% Yield[a]
Amine
Thiol
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
7a
7b
7b
7c
7d
7d
8a
8b
8c
8d
8a
8c
15[b]
16[b]
17[b]
18[b]
19[c]
20[c]
21[d]
22[b]
23[b]
24[b]
25[c]
26[d]
91
92
91
94
75
71
93
92
93
92
68
91
14; ClH3N(CH2)2SH
7a
7b
7c
8e
8a
8e
8a
9
10
11
12
7d
14; ClH3N(CH2)2SH
[a] % yield of isolated product. Reaction conditions: [b] R. T., CH2Cl2, 12 h. [c] Reflux, toluene, 24 h, 1:1 diastereomeric ratio. [d] R. T.,
CH2Cl2, triethylamine (2 eq.), 12 h.
8a in dichloromethane at room temperature (Table 1,
entry 1). With the more sterically hindered amines 7b and
7c, products 16–18 were still obtained at room tempera-
ture from thiol 8b, thiophenol 8c and n-butanethiol 8d,
respectively (Table 1, entries 2–4). Chiral amine 7d, (S)-1-
phenylethylamine, was used in order to probe the influ-
Scheme 3. Tricyclic g-lactam formation.
ence of the stereochemistry at the 3-position of the isoin-
dolinone. When the reactions with this amine were car-
ried out at room temperature, the corresponding products
were produced at low conversion. However, when the re-
actions were performed in refluxing toluene, high product
yields were obtained. This indicates that the steric conges-
tion of the chiral moiety on amine 7d affects product for-
mation. No chiral induction at the 3-position was record-
ed in this case, and the reactions with methyl thioglyco-
late 8a and thiophenol 8c (Table 1, entries 5 and 6) gave
the corresponding products 19 and 20 in a 1:1 diastereo-
meric ratio.
Tricyclic g-lactams, potential non-nucleosidic HIV re-
verse transcriptase inhibitors, have been reported.[4,5] In
our current work, the preparation of tricyclic g-lactams
was demonstrated using cysteamine hydrochloride salt 14
(Table 1, entries 7 and 12). Two equivalents of triethyla-
mine base were added to these reactions to deprotonate
the ammonium salt. The reactions between compounds
6a and 6b with cysteamine in dichloromethane at room
temperature efficiently provided the tricyclic isoindoli-
nones 21 and 26, respectively (Scheme 3).
3-Thioisoindolinones 22–25 were obtained from methyl
2-formyl-3,5-dimethoxybenzoate 6b (Table 1, entries 8–
11). The reaction with n-butylamine 7a and benzylthiol 8e
at room temperature produced the corresponding product
22. The reactions of compound 6b with the more sterical-
ly congested amines 7b and 7c still provided products 23
and 24 from thiols 8a and 8e, respectively, at room tem-
perature. This indicated that the 3-methoxy group of
compound 6b does not affect the product formation. The
reaction between compound 6b, chiral amine 7d, and
thioester 8a, in refluxing toluene, yielded the product 25
in a 1:1 diastereomeric ratio (Table 1, entry 11).
3 Conclusions
In this study, a multicomponent reaction concept has
been successfully developed for the syntheses of 3-thioi-
soindolinones and tricyclic g-lactams. The substituents at
the N- and the S-positions of the isoindolinone structure,
important moieties for binding activities in inhibition
studies, were easily modified using different amines and
thiols as starting materials. The multicomponent reactions
were simply carried out in the presence of drying agent in
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O. Ramstrçm et al.
organic solvent, where the reaction temperature and reac-
tion time primarily depended on the steric constriction of
the amine substituents. This synthetic strategy is applica-
ble to the efficient preparation of different 3-thioisoindo-
linones and tricyclic isoindolinones under mild reaction
conditions, resulting in high yields of the target products.
(s, 1H, CH), 7.29 (t, J=7.2 Hz, 1H, CH), 7.47 (t, J=
8.1 Hz, 2H, 2ꢁCH), 7.54–7.61 (m, 3H, 3ꢁCH), 7.66–7.72
(m, 2H, 2ꢁCH), 7.93 (d, J=7.8 Hz, 1H, CH); 13C NMR
(125 MHz, CDCl3, 258) d 21.9, 34.1, 51.9, 64.9, 123.8,
124.2, 124.2, 126.2, 129.2, 129.6, 132.0, 133.0, 136.4, 142.7,
166.6, 171.8. MS (ESI): (m/z) calcd.: 350.08 [M+Na]+,
found: 350.08. HRMS (ESI): (m/z) calcd. for
C18H17NO3SNa: 350.0821 [M+Na]+, found: 350.0819.
2-Phenyl-3-(phenylthio)isoindolin-1-one (17): White
solid, mp 149.6–150.58, 130 mg, 91% yield. 1H NMR
(500 MHz, CDCl3, 258) d 6.34 (s, 1H, CH), 6.89 (d, J=
7.4 Hz, 2H, 2ꢁCH), 7.0 (t, J=7.5 Hz, 2H, 2ꢁCH), 7.2 (t,
J=7.4 Hz, 1H, CH), 7.28 (t, J=7.3 Hz, 1H, CH), 7.40 (t,
J=7.3 Hz, 1H, CH), 7.48 (t, J=7.9 Hz, 2H, 2ꢁCH), 7.60–
7.68 (m, 4H, 4ꢁCH), 7.7 (d, J=7.9 Hz, 1H, CH); 13C
NMR (125 MHz, CDCl3, 258) d 67.0, 123.5, 123.8, 123.9,
125.7, 127.7, 128.6, 129.1, 129.4, 131.9, 132.4, 136.1, 136.8,
142.5, 166.5. MS (ESI): (m/z) calcd.: 340.07 [M+Na]+,
found: 340.07. HRMS (ESI): (m/z) calcd. for
C20H15NOSNa: 340.0766 [M+Na]+, found: 340.0762.
2-Benzyl-3-(butylthio)isoindolin-1-one (18): White
solid, mp 68–69.58, 141 mg, 94% yield. 1H NMR
(500 MHz, CDCl3, 258) d 0.45 (t, J=7.1 Hz, 3H, CH3),
0.84–1.01 (m, 4H, 2ꢁCH2), 1.43–1.52 (m, 1H, CH2), 1.58–
1.68 (m, 1H, CH2), 4.08 (d, J=14.6 Hz, 1H, CH2), 4.98 (s,
1H, CH), 5.07 (d, J=14.8 Hz, 1H, CH2), 6.92–6.98 (m,
1H, CH), 6.98–7.08 (m, 4H, 4ꢁCH), 7.15–7.22 (m, 1H,
CH), 7.23–7.30 (m, 2H, CH2), 7.5 (d, J=7.87 Hz, 1H,
CH); 13C NMR (125 MHz, CDCl3, 258) d 13.8, 22.3, 25.9,
31.2, 43.1, 63.0, 123.8, 123.9, 128.0, 128.9, 129.0, 129.1,
132.3, 132.4, 137.2, 144.0, 167.7. MS (ESI): (m/z) calcd.:
334.12 [M+Na]+, found: 334.12. HRMS (ESI): (m/z)
calcd. for C19H21NOSNa: 334.1236 [M+Na]+, found:
334.1237.
4 Experimental Section
General
Reagents were purchased from commercial sources and
1
used as received. H and 13C NMR data were recorded at
500 (125) MHz. Chemical shifts are reported as d values
(ppm) with CDCl3 (1H NMR d 7.26, 13C-NMR d 77.2) as
internal standard. J values are given in Hertz (Hz). Mass
spectrometry measurements were performed on an LCQ
Advance Max (Finnigan) instrument. High resolution
mass spectrometry measurements were performed on
a ThermoElectron LTQ-Orbitrap high-resolution mass
spectrometer. Thin-layer chromatography (TLC) was per-
formed on precoated silica plates (0.20 mm), visualized
with UV detection. Flash column chromatography was
performed on silica gel 60, 0.040–0.063 mm.
General Procedure for Synthesis of 3-Thioisoindolinones 15–18
and 22–24
A
solution of methyl 2-formylbenzoate (6a or 6b,
0.45 mmol), amine (0.54 mmol) and thiol (0.54 mmol) in
dichloromethane (5 mL) was stirred in the presence of
magnesium sulfate (250 mg) for 12 h. The reaction mix-
ture was filtered and washed with ammonium chloride so-
lution (three times), followed by saturated sodium chlo-
ride solution. The organic layer was dried over magnesi-
um sulfate, and the resulting solution was evaporated
under vacuum. The crude reaction was purified, if neces-
sary, by short column chromatography using a mixture of
ethyl acetate and hexane as eluent (1:4, v/v).
Methyl 2-(2-butyl-3-oxoisoindolin-1-ylthio)acetate (15):
Colorless oil, 120 mg, 91% yield. 1H NMR (500 MHz,
CDCl3, 258) d 0.94 (t, J=7.4 Hz, 3H, CH3), 1.31–1.41 (m,
2H, CH2), 1.52–1.65 (m, 2H, CH2), 2.63 (dd, J=15.2,
4.3 Hz, 2H, CH2), 3.29–3.37 (m, 1H, CH2), 3.50 (s, 3H,
CH3), 3.91–3.99 (m, 1H, CH2), 5.56 (s, 1H, CH), 7.46–7.52
(m, 1H, CH), 7.56–7.62 (m, 2H, 2ꢁCH), 7.83 (d, J=
7.5 Hz, 1H, CH); 13C NMR (125 MHz, CDCl3, 258) d
14.1, 20.4, 28.8, 30.5, 39.2, 52.9, 63.5, 123.8, 124.0, 129.6,
132.3, 132.8, 142.3, 167.6, 170.1. MS (ESI): (m/z) calcd.:
316.09 [M+Na]+, found: 316.03. HRMS (ESI): (m/z)
calcd. for C15H19NO3SNa: 316.0977 [M+Na]+, found:
316.0980.
3-(Benzylthio)-2-butyl-4,6-dimethoxyisoindolin-1-one
(22): Yellow solid, mp 74.6–76.08, 155 mg, 92% yield. H
1
NMR (500 MHz, CDCl3, 258) d 0.89 (t, J=7.4 Hz, 3H,
CH3), 1.23–1.34 (m, 2H, CH2), 1.38–1.53 (m, 2H, CH2),
3.17 (d, J=13.9 Hz, 1H, CH2), 3.25 (d, J=13.6 Hz, 1H,
CH2), 3.22–3.29 (m, 1H, CH), 3.80 (s, 3H, CH3), 3.79–3.87
(m, 1H, CH), 3.85 (s, 3H, CH3), 5.40 (s, 1H, CH), 6.45 (d,
J=2.0 Hz, 1H, CH), 6.93 (d, J=2.0 Hz, 1H, CH), 6.96–
7.01 (m, 2H, 2ꢁCH), 7.10–7.18 (m, 3H, 3ꢁCH); 13C
NMR (125 MHz, CDCl3, 258) d 14.1, 20.4, 30.5, 32.0, 39.0,
55.9, 56.2, 61.7, 98.2, 103.0, 123.5, 127.0, 127.2, 128.5,
129.0, 134.9, 138.0, 155.5, 162.8, 167.5. MS (ESI): (m/z)
calcd.: 394.14 [M+Na]+, found 394.00. HRMS (ESI): (m/
z) calcd. for C21H25NO3SNa: 394.1447 [M+Na]+, found:
394.1443.
Methyl
2-(5,7-dimethoxy-3-oxo-2-phenylisoindolin-1-
ylthio)acetate (23): Colorless liquid, 155 mg, 93% yield.
1H NMR (500 MHz, CDCl3, 258) d 2.81 (d, J=15.1 Hz,
1H, CH2), 2.89 (d, J=15.0 Hz, 1H, CH2), 3.46 (s, 3H,
CH3), 3.89 (s, 3H, CH3), 3.98 (s, 3H, CH3), 6.16 (s, 1H,
CH), 6.66 (d, J=2.2 Hz, 1H, CH), 7.01 (d, J=2.1 Hz, 1H,
CH), 7.27 (t, J=7.0 Hz, 1H, CH), 7.46 (t, J=8.1 Hz, 2H,
Methyl
3-(3-oxo-2-phenylisoindolin-1-ylthio)propa-
noate (16): White solid, mp 125.3–126.08, 135 mg, 92%
1
yield. H NMR (500 MHz, CDCl3, 258) d 2.11–2.22 (m,
3H, CH2), 2.22–2.31 (m, 1H, CH2), 3.59 (s, 3H, CH3), 6.15
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One-Pot Multicomponent Synthesis of 3-Thioisoindolinones
2ꢁCH), 7.60 (d, J=8.0 Hz, 2H, 2ꢁCH); 13C NMR
(125 MHz, CDCl3, 258) d 29.7, 52.5, 56.0, 56.1, 62.6, 98.3,
103.7, 121.8, 123.9, 126.2, 129.2, 134.6, 136.4, 155.5, 163.1,
166.3, 169.9. MS (ESI): (m/z) calcd.: 396.08 [M+Na]+,
found 396.07. HRMS (ESI): (m/z) calcd. for
C19H19NO5SNa: 396.0876 [M+Na]+, found: 396.0869.
2-Benzyl-3-(benzylthio)-4,6-dimethoxyisoindolin-1-one
(24): Colorless liquid, 168 mg, 92% yield. 1H NMR
(500 MHz, CDCl3, 258) d 3.29 (d, J=13.6 Hz, 1H, CH2),
3.36 (d, J=13.6 Hz, 1H, CH2), 3.85 (s, 3H, CH3), 3.97 (s,
3H, CH3), 4.38 (d, J=14.7 Hz, 1H, CH2), 5.31 (d, J=
14.9 Hz, 1H, CH2), 5.33 (s, 1H, CH), 6.54 (d, J=2.0 Hz,
1H, CH), 7.05–7.12 (m, 3H, 3ꢁCH), 7.22–7.30 (m, 3H, 3ꢁ
CH), 7.31–7.41 (m, 5H, 5ꢁCH); 13C NMR (125 MHz,
CDCl3, 258) d 31.5, 43.0, 55.8, 56.2, 61.4, 98.4, 103.2,
123.4, 127.0, 127.9, 128.3, 128.5, 128.9, 129.0, 134.6, 137.2,
138.0, 155.6, 162.9, 167.4. MS (ESI): (m/z) calcd.: 428.12
[M+Na]+, found 428.13. HRMS (ESI): (m/z) calcd. for
C24H23NO3SNa: 428.1290 [M+Na]+, found: 428.1283.
123.6, 123.7, 128.1, 128.4, 128.9, 129.2, 132.0, 132.3, 139.6,
142.9, 168.0, 169.8. MS (ESI): (m/z) calcd.: 364.09 [M+
Na]+, found 364.13. HRMS (ESI): (m/z) calcd. for
C19H19NO3SNa: 364.0977 [M+Na]+, found: 364.0972.
2-((S)-1-phenylethyl)-3-(phenylthio)isoindolin-1-one
(20)[30]: 110 mg, 71% yield.
Diastereomer 1: Yellow solid, mp 149.3–150.38, 54 mg,
1
35% yield. H NMR (500 MHz, CDCl3, 258) d 2.03 (d,
J=7.2 Hz, 3H, CH3), 5.29 (q, J=7.0, 7.6 Hz, 1H, CH),
5.62 (s, 1H, CH), 7.00 (d, J=7.6 Hz, 2H, 2ꢁCH), 7.06 (t,
J=7.6 Hz, 2H, 2ꢁCH), 7.16 (t, J=7.3 Hz, 1H, CH), 7.22–
7.27 (m, 1H, CH), 7.31 (t, J=7.4 Hz, 2H, 2ꢁCH), 7.35 (t,
J=7.3 Hz, 1H, CH), 7.45–7.55 (m, 4H, 4ꢁCH), 7.61 (d,
J=7.8 Hz, 1H, CH); 13C NMR (125 MHz, CDCl3, 258) d
19.6, 54.0, 67.8, 123.3, 123.6, 127.6, 127.7, 128.8, 128.9,
129.0, 131.7, 132.8, 135.0, 142.4, 143.0, 168.5. MS (ESI):
(m/z) calcd.: 368.11 [M+Na]+, found: 368.00.
1
Diastereomer 2: Colorless liquid, 56 mg, 36% yield. H
NMR (500 MHz, CDCl3, 258) d 2.03 (d, J=7.2 Hz, 3H,
CH3), 5.44 (s, 1H, CH), 5.72 (q, J=7.6, 7.1 Hz, 1H, CH),
7.00–7.07 (m, 4H, 4ꢁCH), 7.13 (t, J=7.2 Hz, 1H, CH),
7.28–7.38 (m, 5H, 5ꢁCH), 7.41 (t, J=7.2 Hz, 1H, CH),
7.46 (d, J=7.1 Hz, 2H, 2ꢁCH), 7.64 (d, J=7.5 Hz, 1H,
CH); 13C NMR (125 MHz, CDCl3, 258) d 18.4, 52.2, 66.0,
123.5, 123.5, 128.0, 128.4, 128.5, 128.7, 128.8, 128.8, 130.3,
131.7, 131.8, 134.1, 140.1, 143.8, 168.2. MS (ESI): (m/z):
calcd.: 368.11 [M+Na]+, found: 368.07.
General Procedure for Synthesis of 3-Thioisoindolinones 19, 20
and 25
A
solution of methyl 2-formylbenzoate (6a or 6b,
0.45 mmol), (S)-1-phenylethylamine 7d (0.54 mmol) and
thiol (0.54 mmol) was stirred in refluxing toluene (10 mL)
in the presence of magnesium sulfate (250 mg) for 24 h.
The reaction mixture was filtered and washed with am-
monium chloride solution (three times), followed by satu-
rated sodium chloride solution. The organic layer was
dried over magnesium sulfate, and the resulting solution
was evaporated under vacuum. The crude reaction was
purified by column chromatography using a mixture of
ethyl acetate and hexane as eluent (1:4, v/v).
Methyl 2-(5,7-dimethoxy-3-oxo-2-((S)-1-phenylethyl)i-
soindolin-1-ylthio)acetate (25): 124 mg, 68% yield.
Diastereomer 1: Colorless liquid, 61 mg, 33.5% yield.
1H NMR (500 MHz, CDCl3, 258) d 1.98 (d, J=7.3 Hz,
3H, CH3), 2.62 (d, J=15.6 Hz, 1H, CH2), 2.73 (d, J=
15.3 Hz, 1H, CH2), 3.48 (s, 3H, CH3), 3.85 (s, 3H, CH3),
3.86 (s, 3H, CH3), 5.24 (q, J=7.4, 7.4 Hz, 1H, CH), 5.46
(s, 1H, CH), 6.56 (d, J=1.9 Hz, 1H, CH), 6.91 (d, J=
2.1 Hz, 1H, CH), 7.22 (t, J=7.5 Hz, 1H, CH), 7.29 (t, J=
7.8 Hz, 2H, 2ꢁCH), 7.52 (d, J=7.3 Hz, 2H, 2ꢁCH); 13C
NMR (125 MHz, CDCl3, 258) d 18.8, 29.1, 52.5, 53.2, 55.9,
56.0, 62.7, 97.9, 103.1, 122.4, 127.55, 127.59, 128.6, 135.4,
142.1, 155.4, 162.8, 168.0, 170.2. MS (ESI): (m/z) calcd.:
424.11 [M+Na]+, found: 424.00. HRMS (ESI): (m/z)
calcd. for C21H23NO5SNa: 424.1189 [M+Na]+, found:
424.1183.
Diastereomer 2: Colorless liquid, 63 mg, 34.5% yield.
1H NMR (500 MHz, CDCl3, 258) d 1.92 (d, J=7.2 Hz,
3H, CH3), 2.74 (d, J=15.0 Hz, 1H, CH2), 2.81 (d, J=
15.0 Hz, 1H, CH2), 3.48 (s, 3H, CH3), 3.82 (s, 3H, CH3),
3.85 (s, 3H, CH3), 5.15 (s, 1H, CH), 5.59 (q, J=7.2,
7.1 Hz, 1H, CH), 6.54 (d, J=2.0 Hz, 1H, CH), 6.93 (d, J=
2.0 Hz, 1H, CH), 7.28 (t, J=7.1 Hz, 1H, CH), 7.35 (t, J=
7.4 Hz, 2H, 2ꢁCH), 7.46 (d, J=7.6 Hz, 2H, 2ꢁCH); 13C
NMR (125 MHz, CDCl3, 258) d 17.7, 29.3, 52.3, 52.5, 55.9,
56.0, 61.2, 98.1, 103.1, 122.6, 128.0, 128.5, 128.8, 134.6,
139.6, 155.2, 162.8, 167.7, 170.0. MS (ESI): (m/z) calcd.:
424.11 [M+Na]+, found: 423.93. HRMS (ESI): (m/z)
Methyl 2-(3-oxo-2-((S)-1-phenylethyl)isoindolin-1-ylth-
io)acetate (19): 115 mg, 75% yield.
Diastereomer 1: Yellow solid, mp 71.2–72.88, 56 mg,
1
36% yield. H NMR (500 MHz, CDCl3, 258) d 1.93 (d,
J=7.2 Hz, 3H, CH3), 2.39–2.50 (m, 2H, CH2), 3.42 (s, 3H,
CH3), 5.37 (q, J=7.8, 6.2 Hz, 1H, CH), 5.55 (s, 1H, CH),
7.23 (t, J=6.6 Hz, 1H, CH), 7.30 (t, J=7.2 Hz, 2H, 2ꢁ
CH), 7.47 (t, J=7.2 Hz, 1H, CH), 7.50–7.60 (m, 4H, 4ꢁ
CH), 7.82 (d, J=7.0 Hz, 1H, CH); 13C NMR (125 MHz,
CDCl3, 258) d 18.5, 28.4, 52.5, 52.5, 63.9, 123.6, 123.8,
127.6, 128.6, 129.4, 132.3, 132.7, 141.9, 142.4, 169.4, 169.8.
MS (ESI): (m/z) calcd.: 364.09 [M+Na]+, found 364.07.
HRMS (ESI): (m/z) calcd. for C19H19NO3SNa: 364.0977
[M+Na]+, found: 364.0974.
1
Diastereomer 2: Colorless liquid, 59 mg, 39% yield. H
NMR (500 MHz, CDCl3, 258) d 1.92 (d, J=7.4 Hz, 3H,
CH3), 2.63 (d, J=15.2 Hz, 1H, CH2), 2.76 (d, J=15.6 Hz,
1H, CH2), 3.46 (s, 3H, CH3), 5.21 (s, 1H, CH), 5.68 (q, J=
7.0, 7.8 Hz, 1H, CH), 7.29 (t, J=7.8 Hz, 1H, CH), 7.36 (t,
J=7.2 Hz, 2H, 2ꢁCH), 7.42–7.50 (m, 4H, 4ꢁCH), 7.54 (t,
J=7.4 Hz, 1H, CH), 7.83 (d, J=7.4 Hz, 1H, CH); 13C
NMR (125 MHz, CDCl3, 258) d 17.6, 28.9, 51.9, 52.6, 62.8,
Isr. J. Chem. 2013, 53, 127 – 132
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www.ijc.wiley-vch.de
131

Full Paper
O. Ramstrçm et al.
calcd. for C21H23NO5SNa: 424.1189 [M+Na]+, found:
[3] M. Fardis, H. Jin, S. Jabri, R. Z. Cai, M. Mish, M. Tsiang,
C. U. Kim, Bioorg. Med. Chem. Lett. 2006, 16, 4031.
[4] I. Takahashi, E. Hirano, T, Kawakami, H. Kitajima, Het-
erocycles 1996, 43, 2343.
424.1180.
[5] E. De Clercq, J. Med. Chem. 1995, 38, 2491.
[6] M. Suzuki, M. Uchiumi, M. Murasaki, Psychopharmacology
1995, 121, 442.
General Procedure for Synthesis of 3-Thioisoindolinones 21 and
26
[7] A. Mertens, H. Zilch, B. Konig, W. Schafer, T. Poll, W.
Kampe, H. Seidel, U. Leser, H. Leinert, J. Med. Chem.
1993, 36, 2526.
[8] G. Nannini, P. N. Giraldi, G. Molgora, G. Biasoli, F. Spinelli,
W. Logemann, E. Dradi, G. Zanni, A. Buttinoni, R. Tom-
masini, Arzneim. Forsch. 1973, 23, 1090.
[9] U. Ghosh, R. Bhattacharyya, A. Keche, Tetrahedron 2010,
66, 2148.
[10] X. Huang, J. Xu, J. Org. Chem. 2009, 74, 8859.
[11] R. Medimagh, S. Marque, D. Prim, J. Marrot, S. Chatti, Org.
Lett. 2009, 11, 1817.
A
solution of methyl 2-formylbenzoate (6a or 6b,
0.45 mmol), cysteamine hydrochloride 14 (61 mg,
0.54 mmol) and triethylamine (126 mL, 0.9 mmol) in di-
chloromethane (10 mL) was stirred in the presence of
magnesium sulfate (250 mg) for 12 h. The reaction mix-
ture was filtered and washed with ammonium chloride so-
lution (three times), followed by saturated sodium chlo-
ride solution. The organic layer was dried over magnesi-
um sulfate, and the resulting solution was evaporated
under vacuum. The crude reaction was purified by
column chromatography using a mixture of ethyl acetate
and hexane as eluent (1:4, v/v).
[12] H. Yoda, K.-i. Inoue, Y. Ujihara, N. Mase, K. Takabe, Tetra-
hedron Lett. 2003, 44, 9057.
[13] H. Yoda, N. Kohata, K. Takabe, Synth. Commun. 2003, 33,
1087.
2,3-Dihydrothiazolo[2,3-a]isoindol-5(9bH)-one
(21)[33,34]: White solid, mp 103.4–104.58, 80 mg, 93% yield.
1H NMR (500 MHz, CDCl3, 258) d 3.34–3.45 (m, 3H,
CH2), 4.42–4.50 (m, 1H, CH2), 5.87 (s, 1H, CH), 7.50 (t,
J=8.3 Hz, 2H, 2ꢁCH), 7.58 (t, J=7.4 Hz, 1H, CH), 7.80
(d, J=7.4 Hz, 1H, CH); 13C NMR (125 MHz, CDCl3, 258)
d 36.9, 44.9, 66.4, 123.6, 124.8, 129.6, 131.6, 133.0, 145.5,
171.3. MS (ESI): (m/z) calcd.: 192.05 [M+H]+, found:
192.13.
[14] S. M. Allin, C. J. Northfield, M. I. Page, A. M. Z. Slawin,
Tetrahedron Lett. 1998, 39, 4905.
[15] C. Kalinski, M. Umkehrer, L. Weber, J. Kolb, C. Burdack,
G. Ross, Mol. Diversity 2010, 14, 513.
[16] A. Dçmling, Chem. Rev. 2006, 106, 17.
[17] M. A. Mironov, QSAR Comb. Sci. 2006, 25, 423.
[18] Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymꢀ),
Wiley-VCH, Weinheim, 2005.
[19] D. J. Ramꢃn, M. Yus, Angew. Chem., Int. Ed. 2005, 44,
1602.
[20] R. V. A. Orru, M. de Greef, Synthesis 2003, 1471.
[21] H. Bienaymꢀ, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur.
J. 2000, 6, 3321.
7,9-Dimethoxy-2,3-dihydrothiazolo[2,3-a]isoindol-
5(9bH)-one (26): White solid, mp 143.0–144.58, 103 mg,
1
91% yield. H NMR (500 MHz, CDCl3, 258) d 3.30–3.40
(m, 3H, CH2), 3.85 (s, 3H, CH3), 3.88 (s, 3H, CH3), 4.36–
4.42 (m, 1H, CH2), 5.78 (s, 1H, CH), 6.60 (d, J=1.7 Hz,
1H, CH), 6.87 (d, J=1.7 Hz, 1H, CH); 13C NMR
(125 MHz, CDCl3, 258) d 36.5, 44.5, 56.1, 56.3, 64.2, 98.8,
103.7, 126.6, 134.0, 155.8, 163.2. MS (ESI): (m/z) calcd.:
252.06 [M+H]+, found: 252.07. HRMS (ESI): (m/z)
calcd. for C12H13NO3SNa: 274.0508 [M+Na]+, found:
274.0508.
[22] A. Dçmling, I. I. Ugi, Angew. Chem., Int. Ed. 2000, 39,
3168.
[23] B. B. Tourꢀ, D. G. Hall, Chem. Rev. 2009, 109, 4439.
[24] B. Ganem, Acc. Chem. Res. 2009, 42, 463.
[25] J. D. Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15, 1300.
[26] M. Angelin, M. Rahm, A. Fischer, T. Brinck, O. Ramstrçm,
J. Org. Chem. 2010, 75, 5882.
[27] M. Angelin, A. Fischer, O. Ramstrçm, J. Org. Chem. 2008,
73, 3593.
[28] M. Angelin, P. Vongvilai, A. Fischer, O. Ramstrçm, Chem.
Commun. 2008, 768.
Acknowledgements
[29] A. Couture, E. Deniau, D. Ionescu, P. Grandclaudon, Tetra-
hedron Lett. 1998, 39, 2319.
[30] F. A. Luzzio, D. P. Zacherl, W. D. Figg, Tetrahedron Lett.
1999, 40, 2087.
[31] F. A. Luzzio, D. P. Zacherl, Tetrahedron Lett. 1998, 39, 2285.
[32] M. Sakulsombat, M. Angelin, O. Ramstrçm, Tetrahedron
Lett. 2010, 51, 75.
This work was supported by the Swedish Research Coun-
cil, the Royal Institute of Technology, and the European
Commission (contract no. MRTN-CT-2006-035614).
[33] R. G. Hiskey, S. J. Dominianni, J. Org. Chem. 1965, 30,
1506.
[34] G. L. Oliver, J. R. Dann, J. W. Gates Jr., J. Am. Chem. Soc.
1958, 80, 702.
References
[1] S. Ito, Y. Hirata, Y. Nagatomi, A. Satoh, G. Suzuki, T.
Kimura, A. Satow, S. Maehara, H. Hikichi, M. Hata, H.
Ohta, H. Kawamoto, Bioorg. Med. Chem. Lett. 2009, 19,
5310.
[2] T. Lꢂbbers, P. Angehrn, H. Gmꢂnder, S. Herzig, Bioorg.
Med. Chem. Lett. 2007, 17, 4708.
Received: December 28, 2012
Accepted: January 9, 2013
Published online: February 18, 2013
132
www.ijc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Isr. J. Chem. 2013, 53, 127 – 132