Syntheses of aromatic substituted 6′-thiothalidomides

Article abstract of DOI:10.1055/s-0028-1083179

A resurgence of interest in thalidomide has occurred as a consequence of its diverse immunomodulatory and anticancer actions, which has fuelled interest in synthetic analogues with higher potencies or less undesirable side effect profiles. Several novel aromatic substituted 6′-thiothalidomides were synthesized whose synthetic route and strategy were developed on the basis of an analysis of reaction mechanisms. The regioselectivity of mono-thionation of aromatic substituted thalidomides with Lawesson's reagent is described, and the chemoselectivity of hydrogenation between the nitro group and 6′-thiocarbonyl group is discussed. Full characterization of eight substituted 6′-thiothalidomides is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083179

PAPER
3415
Syntheses of Aromatic Substituted 6¢-Thiothalidomides
A
romatic Substituted 6
¢
-
e
Thiothalido
i
midesming Luo,a Qian-sheng Yu,a David Tweedie,a Jeffery Deschamps,b Damon Parrish,b Harold W. Holloway,a
Yazhou Li,a Arnold Brossi,c Nigel H. Greig*a
a
Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National
Institutes of Health, 251 Bayview Blvd., Baltimore, MD 21224, USA
Fax +1(410)5588695; E-mail: Greign@grc.nia.nih.gov
Laboratory for the Structure of Matter, Department of the Navy, Naval Research Laboratory, Washington, DC 20375, USA
School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA
b
c
Received 29 April 2008; revised 25 June 2008
O
O
N
O
1'
NH
7
4
1
Abstract: A resurgence of interest in thalidomide has occurred as a
consequence of its diverse immunomodulatory and anticancer ac-
tions, which has fuelled interest in synthetic analogues with higher
potencies or less undesirable side effect profiles. Several novel aro-
matic substituted 6¢-thiothalidomides were synthesized whose syn-
thetic route and strategy were developed on the basis of an analysis
of reaction mechanisms. The regioselectivity of mono-thionation of
aromatic substituted thalidomides with Lawesson’s reagent is de-
scribed, and the chemoselectivity of hydrogenation between the
nitro group and 6¢-thiocarbonyl group is discussed. Full character-
ization of eight substituted 6¢-thiothalidomides is reported.
2
6
5
2'
6'
3'
O
3
4' 5'
Figure 1 Structure of thalidomide
potently lower TNF-a levels without toxicity.6 This likely
occurs by reducing TNF-a synthesis rate through transla-
tional regulation, and appears to translate from cell culture
studies into animals.11 Accordingly, synthetic investiga-
tion of aromatic substituted thiothalidomides may provide
pharmacologically interesting compounds of potential
clinical value. Herein, we describe the synthesis, isolation
and identification of aromatic substituted 6¢-thiothalido-
mides.
Key words: 6¢-thiothalidomides, TNF-a, thionation, regioselec-
tivity, HMBC
Thalidomide [Figure 1; a-(N-phthalimido)glutarimide; 1]
has led a chequered pharmaceutical life. Withdrawn as a
sedative as a consequence of its teratogenicity during the
late 1950s, it was found to be effective in the management
of erythema nodosum leprosum (ENL) reactions of lepro-
sy in the 1960s, and its immunomodulatory and anticancer
actions have made it a focus of pharmaceutical interest in
recent decades.1–3 The current therapeutic promise of tha-
lidomide has motivated efforts to synthesize new, more
effective analogues with reduced toxicity, and several in-
teresting classes of compounds have subsequently been
developed.4–8 A primary mechanism that likely underlies
the activity of thalidomide in ENL involves a reduction in
the levels of tumor necrosis factor-a (TNF-a),9,10 a pro-
inflammatory cytokine whose initial release is critical in
mediating a protective inflammatory response following
an insult, but whose over-production is detrimental and
associated with clinical disorders such as rheumatoid ar-
thritis, Crohn’s diseases and several neurodegenerative
conditions.11 Amongst recent thalidomide analogues, 4-
amino substituted versions were found to be potent inhib-
itors of TNF-a release,4,5 as assessed in cultured human
peripheral blood mononuclear cells challenged to lipo-
polysaccharide (LPS), a major component of the outer
membrane of gram-negative bacteria that is used as a
pharmacological tool to induce TNF-a synthesis and re-
lease. Thiocarbonyl substituted thalidomides, similarly,
The preparation of starting materials 3–7 is concisely
shown in Scheme 1. The preparation of 3 was reported by
Wyrick;12 compounds 6 and 7 were obtained via a route
described by Zhu and colleagues.6
The syntheses of aromatic substituted thalidomides are
shown in Table 1. Whereas similar pathways for con-
structing the thalidomide skeleton have been report-
ed,4,6,13,14 it was envisioned that the use of 1,3-
dicyclohexylcarbodiimide (DCC) would allow substitut-
ed phthalic acids to be directly applied to the condensation
of thalidomide analogues, instead of substituted phthalic
anhydrides. For example, 4-hydroxyphthalic acid 2 could
be directly converted into its corresponding anhydride 3,
and then reacted with 7 in one-pot to give product 9
(36%). DCC as a dehydrating condensing agent was also
used for the synthesis of some naturally occurring phtha-
lides from Alternaria species.15 Reactants 4 and 7 were re-
fluxed to afford 28% of 9 in addition to 10% of 10. This
suggested that there was an equilibrium between a hy-
droxy and an acetoxy at the 5-position of thalidomide in
acetic acid.
The syntheses of aromatic substituted 6¢-thiothalidomides
are shown in Table 2. The mono-thionation of aromatic
substituted thalidomides principally takes place at the 6¢-
position using Lawesson’s reagent. This is likely as a con-
sequence of this position being the least sterically hin-
dered of the available four amido carbonyl groups (1-, 3-,
2¢- and 6¢-position) of the thalidomide skeleton (Figure 2),
SYNTHESIS 2008, No. 21, pp 3415–3422
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083179; Art ID: M02108SS
© Georg Thieme Verlag Stuttgart · New York

3416
W. Luo et al.
PAPER
O
O
O
O
O
O
BnBr, MeCN
BnO
HO
K2CO3, r.t., 113 h, 93%
3
5
O
OH
OH
HO
O
O
O
O
2
AcO
4
O
O
O
OH
NH
TFA, CH2Cl2
NH
CDI, THF
–
+
BocHN
BocHN
O
CF3CO2HN
O
reflux, 24 h, 47%
r.t., 4 h, 98%
CONH2
6
7
Scheme 1 Preparation of main starting materials
Table 1 Syntheses of Aromatic Substituted Thalidomides
O
O
O
N
O
O
NH
O
NH
O
O
+
–
reflux
CF3CO2H3N
O
+
R2
R2
R1
R1
7
Reactant
Product
Entry
Reactant
Solvent
Product
Time (h)
Yield (%)
R1
OH
H
R2
R1
OH
H
R2
1a
2b
3
H
Et3N/THF
AcOH
AcOH
AcOH
AcOH
AcOH
8
H
96.0
24.0
52.5
42.0
4.5
76
50
10
41
55
75
3
4
5
OH
OAc
OBn
NO2
Cl
9
OH
OAc
OBn
NO2
Cl
H
10
11
12c
14
H
4
H
H
5
H
H
6
H
H
4.5
a Reagents and conditions: (i) 7, 3-hydroxyphthalic anhydride, Et3N, THF, reflux, 24 h; (ii) DCC, DMAP (cat.), reflux, 72 h.
b Alternatively: (i) 2, DCC, THF, r.t., 24 h; (ii) 7, AcOH, reflux, 4.5 h, to give 9, overall yield 36%.
c Reduction of 12 (acetone, 10% Pd/C, H2, 40lbs, r.t., 3 h), gave 5-aminothalidomide 13 (73%).
which allows the approach and attack of Lawesson’s re- domides detailed in Table 2, when a hydroxy or amino
agent at the 6¢-position.
substituted thalidomide was thionated with Lawesson’s
reagent, the yield of the corresponding 6¢-thiothalidomide
was reduced [see entry 2 (16%) and entry 6 (8%)], since
the hydroxy and amino group compete with the carbonyl
group for reaction with Lawesson’s reagent. The position
of such a competitive group on the thalidomide skeleton
is clearly important, and is exemplified by comparing en-
In Figure 2, thalidomide is shown in its lowest energy
conformation. As thionation of the carbonyl group with
Lawesson’s reagent primarily proceeds via a mechanism
involving a cyclic transition state between the dithiophos-
phine ylide and carbonyl group, the 6¢-position is the most
favored. In the case of the aromatic substituted thiothali-
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

PAPER
Aromatic Substituted 6¢-Thiothalidomides
3417
Table 2 Syntheses of Aromatic Substituted 6¢-Thiothalidomides
O
O
O
O
N
O
NH
NH
Lawesson's reagent
S
N
O
O
reflux
R2
R2
R1
R1
Entry
Structure
Reactant
Solvent
Structure
Product
R1
Time (h)
Yield (%)
R1
R2
R2
H
1
2
8
OH
H
H
toluene
pyridine
toluene
pyridine
toluene
toluene
pyridine
toluene
toluene
pyridine
15a
OH
89.0
47.0
76.0
120.5
91.0
103.0
47.0
90.0
91.5
47.0
37
45
16
38
46
13
20
21
8
9
OH
17
H
OH
3
4
10
11
H
H
OAc
OBn
18b
19
H
H
OAc
OBn
5
6
7
12
13
14
H
H
H
NO2
NH2
Cl
20c
21
H
H
H
NO2
NH2
Cl
22
56
a Reaction of 15 (Ac2O, toluene, reflux, 3 h), gave 16 (44%).
b Reaction of 18 [NaHCO3 (sat.), MeOH, r.t., 1 h], gave 17 (73%).
c Reaction of 20 (acetone, 10% Pd/C, H2, 40lbs, r.t., 2 h), gave 21 (95%).
tries 1 and 2 (Table 2), where a hydroxy group lies in the
4- or 5-position, respectively, and provide 37% and 16%
yields of the corresponding 6¢-thiothalidomides. As a con-
sequence of the steric effects, which are greater for the 4-
hydroxy than the 5-hydroxy group of thalidomide, the lat-
ter more readily reacts with Lawesson’s reagent or its
dithiophosphine ylide, and hence generation of the desired
6¢-thiothalidomide is reduced. Moreover, when thionation
of different moieties at the same position takes place, such
as between the 5-hydroxy or 5-amino with the 6¢-carbonyl
group, as detailed in Table 2 (entries 2 and 6), the 5-amino
more effectively decreases the yield of 6¢-thiothalido-
mide. Hence, in order to obtain hydroxy or amino substi-
tuted 6¢-thiothalidomide in reasonable yields, the
corresponding acetoxy or nitro substituted thiothalido-
mides were first synthesized. These were then hydrolyzed
or reduced in 75 and 95% yield, respectively, to the de-
sired compounds. The 95% yield for the latter conversion
indicates that there is a high chemoselectivity of hydroge-
nation between the nitro group and the thiocarbonyl group
of the aromatic substituted 6¢-thiothalidomide when palla-
dium was used as a catalyst. On the other hand, by using
pyridine as the thionation solvent (Table 2; entries 1, 2, 4
and 7), the yields of the corresponding aromatic substitut-
ed 6¢-thiothalidomides were higher than those obtained in
toluene, due to more advantageous formation of the
dithiophosphine ylide (Scheme 2).16
Figure 2 Structure of thalidomide generated from energy-minimi-
zation by computer modeling
S
S
S
S
+
P
MeO
P
P
OMe
MeO
–
S
S
Scheme 2 Lawesson’s reagent and dithiophosphine ylide
pound has previously been characterized by IR, 1H NMR,
31P NMR, MS and elemental analysis.17 Herein, we report
its X-ray crystallographic structure, which appeared as an
interesting twinned structure (Figure 3).18
The structural proofs of compounds 15–22 are based on
1D and 2D NMR spectra, GC-MS and elemental analyses.
The 6¢-thiocarbonyl group is identified as a correlative
peak of 6¢-C/5¢-H in the (1H-detected) heteronuclear mul-
tiple-bond correlation (HMBC) spectrum (Table 3). Fur-
thermore, X-ray crystallographic analyses of 15 and 18
confirmed the structural assignments (Figure 4 and
Figure 5).19,20
Interestingly, trimeric p-methoxyphenylthionophosphine
oxide (23) was isolated from the reaction of aromatic sub-
stituted thalidomides with Lawesson’s reagent. This com-
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

3418
W. Luo et al.
PAPER
Figure 5 Compound 18 and its X-ray crystallographic structure
shifts of the 6¢-thiocarbonyl group (d = 210.9 ppm in
DMSO-d6). This shift thus provides a potentially valuable
means for identifying the 6¢-thiocarbonyl group.
In summary, a synthetic route and strategy to generate ar-
omatic substituted 6¢-thiothalidomides is described. In the
presence of 1,3-dicyclohexylcarbodiimide, substituted
phthalic anhydride and its acid were utilized in the con-
densation of 3-aminoglutarimide to build a thalidomide
skeleton. In the mono-thionation of aromatic substituted
thalidomides with Lawesson’s reagent, there is a 6¢-posi-
tion regioselectivity among the four available amido car-
bonyl groups, and selection of pyridine as solvent, rather
than toluene, provided higher yields. In the event that a
hydroxy or amino substituent group is present on the phe-
nyl of the glutarimide ring of a thalidomide analogue, pro-
tection prior to thionation is necessary. In addition, our
results demonstrate an excellent chemoselectivity of hy-
drogenation between the nitro and the 6¢-thiocarbonyl
group using palladium as catalyst. Finally, within the con-
fines of the current study, it was found that substituent
groups on the phenyl ring do not effect the 13C NMR
chemical shift of the thiocarbonyl group of an aromatic
substituted 6¢-thiothalidomide.
Figure 3 Compound 23 and its X-ray crystallographic structure
Figure 4 Compound 15 and its X-ray crystallographic structure
Taken together, these data suggest that substituent groups
on the phenyl ring have no effect on the 13C chemical
Table 3 Important Properties of Aromatic Substituted 6¢-Thiothalidomides
Com-
pound
Chemical shift (ppm)a
HMBC
Elemental analysisc
C
6¢-C
5¢-H
6¢-C/5¢-H correlation
H
N
15
16
17
18
19
20
21
22
210.9
206.7b
210.9
210.9
210.9
210.9
210.9
210.9
2.43–2.60
2.72–3.07b
2.43–2.62
2.48–2.65
2.44–2.56
2.46–2.59
2.44–2.60
2.43–2.65
+
53.71 (53.79)
54.48 (54.21)
52.09 (52.17)
54.88 (54.21)
63.37 (63.14)
48.88 (48.90)
50.31 (50.81)
50.72 (50.57)
3.55 (3.47)
3.91 (3.64)
3.40 (3.70)
3.73 (3.64)
4.54 (4.24)
2.88 (2.84)
3.58 (4.26)
2.87 (2.94)
9.36 (9.65)
8.31 (8.43)
9.03 (9.36)
8.38 (8.43)
6.57 (7.36)
12.95 (13.16)
13.24 (13.67)
9.01 (9.07)
b
+
+
b
+
+
b
+
+
+
a In DMSO-d6/TMS.
b In CDCl3/TMS.
c Calculated values given in parentheses.
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

PAPER
Aromatic Substituted 6¢-Thiothalidomides
3419
nitrogen. After evaporation of the solvents, the residue was recrys-
tallized from EtOAc to afford 9.
Melting points were determined with a Fisher–Johns apparatus and
1
are uncorrected. H NMR, 13C NMR and 2D NMR were recorded
on a Bruker AC-300 spectrometer. GC-Mass spectra were per-
formed on a Hewlett–Packard 5973 GC-MS with chemical ioniza-
tion. Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA. X-ray crystallographic structural studies were per-
formed at the Laboratory for the Structure of Matter, Naval Re-
search Laboratory, Washington, D.C.
Yield: 0.80 g (36%); grayish powder; mp 315 °C (dec.).
1H NMR (300 MHz, DMSO-d6): d = 1.98–2.10 (m, 1 H, 4¢-CH),
2.46–2.63 (m, 2 H, 5¢-CH), 2.80–2.98 (m, 1 H, 4¢-CH), 5.02–5.16
(m, 1 H, 3¢-CH), 7.16 (d, J = 7.2 Hz, 1 H, 6-CH), 7.19 (s, 1 H, 4-
CH), 7.76 (d, J = 7.2 Hz, 1 H, 7-CH), 11.12 (s, 1 H, NH), 11.20 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 22.44, 31.30, 49.21, 110.32,
121.11, 121.76, 125.96, 134.43, 163.90, 167.28, 167.38, 170.33,
173.12.
4-Acetoxyphthalic Anhydride (4)
A solution of 4-hydroxyphthalic acid (2; 5.39 g, 29.6 mmol) and
Ac2O (26 mL) in toluene (100 mL) was refluxed for 2 h. The prod-
uct was crystallized from the reaction solvents to give 4.
GC-MS (CI/CH4): m/z = 275 [M + H]+, 259, 245, 217, 205, 163.
Yield: 2.64 g (43%); white needle crystals; mp 89–91 °C.
2-(2,6-Dioxo-3-piperidinyl)-5-acetoxy-1H-isoindole-1,3(2H)-di-
one (10)
A mixture of 4-acetoxyphthalic anhydride (4; 1.82 g, 8.83 mmol)
and 7 (2.14 g, 8.84 mmol) in AcOH (67 mL) was refluxed for 52 h
under nitrogen. Thereafter, the solution was concentrated and re-
crystallized from either EtOAc or MeOH to give 10 and 9 (0.79 g,
28%).
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H, CH3CO), 7.61 (d,
J = 8.3 Hz, 1 H, 5-CH), 7.80 (s, 1 H, 3-CH), 8.06 (d, J = 8.3 Hz,
1 H, 6-CH).
13C NMR (75 MHz, CDCl3): d = 21.05, 119.09, 127.14, 128.13,
129.67, 133.16, 156.75, 161.86, 161.89, 168.14.
GC-MS (CI/CH4): m/z = 207 [M + H]+, 193, 179, 165, 120.
Yield: 0.28 g (10%); white crystals; mp 220–221 °C.
4-Benzyloxyphthalic Anhydride (5)
1H NMR (300 MHz, DMSO-d6): d = 1.89–2.01 (m, 1 H, 4¢-CH),
2.20 (s, 3 H, CH3CO2), 2.33–2.56 (m, 2 H, 5¢-CH), 2.68–2.84 (m,
1 H, 4¢-CH), 4.98–5.09 (m, 1 H, 3¢-CH), 7.49 (d, J = 7.3 Hz, 1 H, 6-
CH), 7.65 (s, 1 H, 4-CH), 7.88 (d, J = 7.3 Hz, 1 H, 7-CH), 11.30 (s,
1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 21.25, 22.28, 31.27, 49.49,
118.02, 125.45, 128.50, 128.74, 133.37, 155.75, 166.62, 166.75,
169.19, 170.14, 173.10.
A mixture of 4-hydroxyphthalic anhydride (3; 1.37 g, 8.34 mmol),
benzyl bromide (1.43 g, 8.36 mmol) and K2CO3 (1.23 g, 8.90 mmol)
in MeCN (110 mL) was stirred at r.t. for 113 h. Thereafter, the re-
action mixture was concentrated and purified by column chroma-
tography on silica gel (CH2Cl2–MeOH, 4:1) to afford 5.
Yield: 1.96 g (93%); white crystals; mp 202–204 °C.
1H NMR (300 MHz, DMSO-d6): d = 5.20 (s, 2 H, PhCH2), 7.10–
7.80 (m, 8 H, ArH).
13C NMR (75 MHz, DMSO-d6): d = 70.71, 114.92, 116.97, 123.99,
128.82, 129.09, 129.56, 132.26, 137.45, 138.06, 161.48, 168.40,
170.18.
GC-MS (CI/CH4): m/z = 317 [M + H]+, 289, 274, 84.
2-(2,6-Dioxo-3-piperidinyl)-5-benzyloxy-1H-isoindole-1,3(2H)-
dione (11)
A mixture of 4-benzyloxyphthalic anhydride (5; 704 mg, 2.77
mmol) and 7 (671 mg, 2.77 mmol) in AcOH (46 mL) was refluxed
for 42 h under nitrogen. Thereafter, the solution was concentrated
and purified by column chromatography on silica gel (CH2Cl2–
MeOH, 15:1) to give 11.
GC-MS (CI/CH4): m/z = 255 [M + H]+, 205, 165, 119, 91.
2-(2,6-Dioxo-3-piperidinyl)-4-hydroxy-1H-isoindole-1,3(2H)-
dione (8)
To a stirred suspension of 7 (1.25 g, 5.16 mmol) in THF (100 mL)
at r.t., was added a solution of 3-hydroxyphthalic anhydride (0.85 g,
5.16 mmol) in THF (50 mL) and Et3N (1.06 g). After 10 min, the
resulting solution was refluxed for 24 h under nitrogen. Thereafter,
the reaction mixture was cooled to r.t. and DCC (1.06 g, 5.16 mmol)
and a catalytic amount of DMAP were added. The mixture was re-
fluxed for 72 h under nitrogen then the concentrated crude product
was purified by column chromatography on silica gel (EtOAc–
MeOH, 3:1) to give 8.
Yield: 414 mg (41%); white crystals; mp 213–215 °C.
1H NMR (300 MHz, CDCl3): d = 2.01–2.10 (m, 1 H, 4¢-CH), 2.61–
2.87 (m, 3 H, 5¢-CH, 4¢-CH), 4.84–4.91 (m, 1 H, 3¢-CH), 5.11 (s,
2 H, PhCH2), 7.17–7.77 (m, 8 H, ArH), 8.10 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 24.63, 33.35, 51.26, 72.82, 111.33,
123.08, 125.72, 127.55, 129.45, 130.51, 130.79, 136.27, 137.28,
166.06, 168.90, 169.06, 170.08, 172.94.
GC-MS (CI/CH4): m/z = 365 [M + H]+, 337, 303, 275, 254, 164.
Yield: 1.07 g (76%); white powder; mp 275–276 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.98–2.09 (m, 1 H, 4¢-CH),
2.45–2.62 (m, 2 H, 5¢-CH), 2.80–2.98 (m, 1 H, 4¢-CH), 5.01–5.12
(m, 1 H, 3¢-CH), 7.24 (d, J = 8.1 Hz, 1 H, 5-CH), 7.30 (d, J = 7.2
Hz, 1 H, 7-CH), 7.65 (t, J = 7.7 Hz, 1 H, 6-CH), 11.13 (s, 1 H, NH).
13C NMR (75 MHz, CD3OD): d = 24.06, 32.57, 50.75, 116.33,
116.49, 124.86, 135.04, 137.86, 157.25, 168.78, 169.20, 171.90,
175.04.
2-(2,6-Dioxo-3-piperidinyl)-5-nitro-1H-isoindole-1,3(2H)-di-
one (12)
To a stirred solution of 7 (0.95 g, 3.92 mmol) in AcOH (30 mL) at
r.t. was added 4-nitrophthalic anhydride (0.76 g, 3.94 mmol). The
reaction mixture was refluxed for 4.5 h under nitrogen and then
evaporated to remove AcOH. The residue was recrystallized from
EtOAc to give 12.
GC-MS (CI/CH4): m/z = 275 [M + H]+, 247, 230, 189, 164.
Yield: 0.66 g (55%); purplish crystals; mp 230–231 °C (Lit.21 229–
230 °C).
2-(2,6-Dioxo-3-piperidinyl)-5-hydroxy-1H-isoindole-1,3(2H)-
dione (9)
A solution of 4-hydroxyphthalic acid (2; 1.48 g, 8.13 mmol) and
DCC (1.68 g, 8.13 mmol) in THF (88 mL) was stirred for 24 h at r.t.
under nitrogen. Thereafter, a solution of 7 (1.97 g, 8.14 mmol) in
AcOH (62 mL) was added dropwise to the above reaction system.
The mixture was continuously stirred and refluxed for 4.5 h under
2-(2,6-Dioxo-3-piperidinyl)-5-amino-1H-isoindole-1,3(2H)-di-
one (13)
A mixture of 12 (793 mg, 2.62 mmol) and 10% Pd/C (400 mg) in
acetone (50 mL) was shaken at r.t. for 3 h under H2 (40 lbs). The
mixture was filtered and concentrated to afford 13.
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

3420
W. Luo et al.
PAPER
Yield: 0.53 g (73%); yellow crystals; mp 320–322 °C (Lit.21 319–
321 °C).
trating, the residue was purified by column chromatography on
silica gel (CH2Cl2–EtOH, 17:1) to give 17.
Yield: 56 mg (38%); brown crystals; mp 316–318 °C.
2-(2,6-Dioxo-3-piperidinyl)-5-chloro-1H-isoindole-1,3(2H)-di-
one (14)
To a stirred solution of 7 (2.10 g, 8.67 mmol) in AcOH (66 mL) at
r.t., was added 4-chlorophthalic anhydride (1.58 g, 8.67 mmol). The
reaction mixture was refluxed for 4.5 h under nitrogen and then
evaporated to remove AcOH. The residue was recrystallized from
EtOAc to give 14.
1H NMR (300 MHz, DMSO-d6): d = 1.98–2.15 (m, 1 H, 4¢-CH),
2.43–2.62 (m, 2 H, 5¢-CH), 3.11–3.28 (m, 1 H, 4¢-CH), 5.11–5.28
(m, 1 H, 3¢-CH), 7.12 (d, J = 7.2 Hz, 1 H, 6-CH), 7.17 (s, 1 H, 4-
CH), 7.71 (d, J = 7.2 Hz, 1 H, 7-CH), 11.20 (s, 1 H, NH), 12.65 (s,
1 H, OH).
13C NMR (75 MHz, DMSO-d6): d = 24.10, 41.12, 49.01, 109.48,
110.37, 121.14, 121.70, 126.03, 134.39, 163.94, 167.19, 167.63,
210.89.
Yield: 1.9 g (75%); pinkish powder; mp 312–313 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.01–2.12 (m, 1 H, 4¢-CH),
2.50–2.68 (m, 2 H, 5¢-CH), 2.81–2.99 (m, 1 H, 4¢-CH), 5.11–5.22
(m, 1 H, 3¢-CH), 7.90–8.05 (m, 3 H, ArH), 11.15 (s, 1 H, NH).
GC-MS (CI/CH4): m/z = 291 [M + H]+, 275, 259, 207, 188, 176,
148.
13C NMR (75 MHz, DMSO-d6): d = 22.25, 31.25, 49.55, 123.97,
125.55, 130.13, 133.55, 135.05, 140.11, 166.27, 166.61, 170.02,
173.05.
Anal. Calcd for C13H10N2O4S·0.5H2O: C, 52.17; H, 3.70; N, 9.36.
Found: C, 52.09; H, 3.40; N, 9.03.
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-acetoxy-1H-isoindole-
1,3(2H)-dione (18)
GC-MS (CI/CH4): m/z = 293 [M + H]+, 265, 248, 182, 139.
A mixture of 10 (400 mg, 1.26 mmol) and Lawesson’s reagent (280
mg, 0.69 mmol) in toluene (250 mL) was refluxed for 91 h under ni-
trogen. Thereafter, the solvent was removed and the residue was re-
crystallized from MeOH to afford 18.
2-(2-Oxo-6-thioxo-3-piperidinyl)-4-hydroxy-1H-isoindole-
1,3(2H)-dione (15)
To a stirred solution of 8 (0.28 g, 1.02 mmol) in toluene (155 mL)
at r.t., was added Lawesson’s reagent (0.22g, 0.54 mmol). The reac-
tion mixture was refluxed for 89 h under nitrogen. After concentra-
tion, the residue was purified by column chromatography on silica
gel (CH2Cl2–MeOH, 15:1) to give 15.
Yield: 195 mg (46%); yellow crystals; mp 191–193 °C.
1H NMR (300 MHz, CDCl3): d = 2.09–2.21 (m, 1 H, 4¢-CH), 2.37
(s, 3 H, CH3CO2), 2.71–3.09 (m, 2 H, 5¢-CH), 3.49–3.60 (m, 1 H,
4¢-CH), 4.98–5.10 (m, 1 H, 3¢-CH), 7.48 (d, J = 7.2 Hz, 1 H, 6-CH),
7.65 (s, 1 H, 4-CH), 7.90 (d, J = 7.2 Hz, 1 H, 7-CH), 9.40 (s, 1 H,
NH).
1H NMR (300 MHz, DMSO-d6): d = 2.03–2.15 (m, 1 H, 4¢-CH),
2.36 (s, 3 H, CH3CO2), 2.48–2.65 (m, 2 H, 5¢-CH), 3.18–3.28 (m,
1 H, 4¢-CH), 5.22–5.33 (m, 1 H, 3¢-CH), 7.64 (d, J = 7.2 Hz, 1 H, 6-
CH), 7.79 (s, 1 H, 4-CH), 8.01 (d, J = 7.2 Hz, 1 H, 7-CH), 12.68 (s,
1 H, NH).
13C NMR (75 MHz, CDCl3): d = 21.45, 24.70, 40.76, 49.71, 118.12,
125.67, 128.08, 129.07, 133.87, 155.98, 165.32, 166.51, 166.69,
168.84, 206.67.
13C NMR (75 MHz, DMSO-d6): d = 21.24, 24.20, 49.30, 79.50,
118.06, 125.50, 128.53, 128.70, 133.70, 155.78, 166.49, 166.62,
167.40, 169.18, 210.89.
Yield: 0.11 g (37%); yellow flaky crystals; mp 252–255 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.00–2.10 (m, 1 H, 4¢-CH),
2.43–2.60 (m, 2 H, 5¢-CH), 3.18–3.29 (m, 1 H, 4¢-CH), 5.14–5.24
(m, 1 H, 3¢-CH), 7.28 (d, J = 9.0 Hz, 1 H, 5-CH), 7.35 (d, J = 7.2
Hz, 1 H, 7-CH), 7.66 (t, J = 7.9 Hz, 1 H, 6-CH), 11.14 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 24.02, 41.13, 48.79, 113.45,
114.70, 123.96, 133.45, 136.79, 155.86, 166.02, 167.23, 167.66,
210.92.
GC-MS (CI/CH4): m/z = 291 [M + H]+, 275, 263, 247, 164.
Anal. Calcd for C13H10N2O4S: C, 53.79; H, 3.47; N, 9.65. Found: C,
53.71; H, 3.55; N, 9.36.
2-(2-Oxo-6-thioxo-3-piperidinyl)-4-acetoxy-1H-isoindole-
1,3(2H)-dione (16)
To a stirred suspension of 15 (67.0 mg, 0.231 mmol) in toluene (18
mL) at r.t., was added Ac2O (1 mL). The reaction mixture was re-
fluxed for 3 h under nitrogen. Thereafter, the solvent together with
excess Ac2O were removed. The residue was recrystallized from
EtOAc to afford 16.
GC-MS (CI/CH4): m/z = 333 [M + H]+, 317, 289, 275, 205, 164.
Anal. Calcd for C15H12N2O5S: C, 54.21; H, 3.64; N, 8.43. Found: C,
54.88; H, 3.73; N, 8.38.
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-benzyloxy-1H-isoindole-
1,3(2H)-dione (19)
Yield: 34.0 mg (44%); yellow needle crystals; mp 179–181 °C.
A mixture of 11 (220 mg, 0.60 mmol) and Lawesson’s reagent (136
mg, 0.34 mmol) in toluene (440 mL) was refluxed for 103 h under
nitrogen. Thereafter, the solvent was removed and the residue was
purified by column chromatography on silica gel (CH2Cl2–MeOH,
9:1) to give 19.
1H NMR (300 MHz, CDCl3): d = 2.11–2.21 (m, 1 H, 4¢-CH), 2.44
(s, 3 H, CH3CO2), 2.72–3.07 (m, 2 H, 5¢-CH), 3.49–3.58 (m, 1 H,
4¢-CH), 4.95–5.04 (m, 1 H, 3¢-CH), 7.35–7.82 (m, 3 H, ArH), 9.40
(s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 21.05, 24.65, 40.72, 49.56, 121.87,
123.01, 129.30, 133.57, 136.63, 147.34, 165.16, 165.24, 166.63,
168.86, 206.67.
Yield: 30 mg (13%); gum.
1H NMR (300 MHz, DMSO-d6): d = 2.01–2.11 (m, 1 H, 4¢-CH),
2.44–2.56 (m, 2 H, 5¢-CH), 3.15–3.25 (m, 1 H, 4¢-CH), 5.16–5.28
(m, 1 H, 3¢-CH), 5.34 (s, 2 H, PhCH2), 7.32–7.90 (m, 8 H, ArH),
12.65 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 24.06, 41.12, 49.13, 70.59,
108.89, 121.30, 123.10, 124.98, 128.16, 128.51, 128.91, 134.22,
136.39, 164.06, 166.98, 167.07, 167.56, 210.90.
GC-MS (CI/CH4): m/z = 333 [M + H]+, 291, 275, 259, 164.
Anal. Calcd for C15H12N2O5S: C, 54.21; H, 3.64; N, 8.43. Found: C,
54.48; H, 3.91; N, 8.31.
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-hydroxy-1H-isoindole-
1,3(2H)-dione (17)
To a stirred solution of 9 (0.14 g, 0.51 mmol) in pyridine (21 mL)
at r.t., was added Lawesson’s reagent (0.10 g, 0.25 mmol). The re-
action mixture was refluxed for 120 h under nitrogen. After concen-
GC-MS (CI/CH4): m/z = 381 [M + H]+, 255, 207, 165, 91.
Anal. Calcd for C20H16N2O4S: C, 63.14; H, 4.24; N, 7.36. Found: C,
63.37; H, 4.54; N, 6.57.
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

PAPER
Aromatic Substituted 6¢-Thiothalidomides
3421
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-nitro-1H-isoindole-1,3(2H)-
dione (20)
A mixture of 12 (190 mg, 0.63 mmol) and Lawesson’s reagent (139
mg, 0.34 mmol) in toluene (100 mL) was refluxed for 90 h under ni-
trogen. Thereafter, the solvent was removed and the residue was pu-
rified by column chromatography on silica gel (hexane–EtOAc–
MeOH, 1:1:0.3) to give 20.
13C NMR (75 MHz, DMSO-d6): d = 23.91, 41.06, 49.34, 124.04,
125.59, 130.11, 133.53, 135.08, 140.15, 166.15, 166.49, 167.31,
210.87.
GC-MS (CI/CH4): m/z = 309 [M + H]+, 293, 281, 265.
Anal. Calcd for C13H9ClN2O3S: C, 50.57; H, 2.94; N, 9.07. Found:
C, 50.72; H, 2.87; N, 9.01.
Yield: 42 mg (21%); yellow crystals; mp 231–233 °C.
1H NMR (300 MHz, CDCl3): d = 2.15–2.26 (m, 1 H, 4¢-CH), 2.81–
3.08 (m, 2 H, 5¢-CH), 3.50–3.59 (m, 1 H, 4¢-CH), 5.02–5.10 (m,
1 H, 3¢-CH), 8.09 (d, J = 7.8 Hz, 1 H, 7-CH), 8.65 (d, J = 7.8 Hz,
1 H, 6-CH), 8.70 (s, 1 H, 4-CH), 9.38 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 24.18, 40.31, 49.82, 119.27,
125.13, 129.72, 133.09, 136.01, 152.02, 164.48, 164.83, 165.09,
205.85.
Acknowledgment
This research was supported in part by the Intramural Research Pro-
gram of the National Institute on Aging, National Institutes of
Health. The authors are indebted to the Intramural Research Pro-
gram of the National Institute on Drug Abuse, NIH, for use of NMR
equipment.
GC-MS (CI/CH4): m/z = 320 [M + H]+, 302, 290, 274, 246, 229,
193, 163.
References
(1) Franks, M. E.; Macpherson, G. R.; Figg, W. D. Lancet 2004,
363, 1802.
(2) Bartlett, J. B.; Dredge, K.; Dalglish, A. G. Nat. Rev. Cancer
2004, 4, 314.
(3) Bartlett, J. B.; Tozer, A.; Stirling, D.; Zeldis, J. B. Br. J.
Cancer 2005, 93, 613.
(4) Muller, G. W.; Chen, R.; Huang, S. Y.; Corral, L. G.; Wong,
L. M.; Patterson, R. T.; Chen, Y.; Kaplan, G.; Stirling, D. I.
Bioorg. Med. Chem. Lett. 1999, 9, 1625.
(5) Fujimoto, H.; Noguchi, T.; Kobayashi, H.; Miyachi, H.;
Hashimoto, Y. Chem. Pharm. Bull. 2006, 54, 855.
(6) Zhu, X.; Giordano, T.; Yu, Q. S.; Holloway, H. W.; Perry, T.
A.; Lahiri, D. K.; Brossi, A.; Greig, N. H. J. Med. Chem.
2003, 46, 5222.
(7) Aragon-Ching, J. B.; Li, H.; Gardner, E. R.; Figg, W. D.
Recent Pat. Anti-Cancer Drug Discovery 2007, 2, 167.
(8) Greig, N. H.; Brossi, A.; Holloway, H. W.; Zhu, X.; Yu, Q.
S. WO Patent 2005028436, 2005.
(9) Sampaio, E. P.; Kaplan, G.; Miranda, A.; Nery, J. A.;
Miguel, C. P.; Viana, S. M.; Sarno, E. N. J. Infect. Dis. 1993,
168, 408.
(10) Walker, S. L.; Waters, M. F.; Lockwood, D. N. Lepr. Rev.
2007, 78, 197.
Anal. Calcd for C13H9N3O5S: C, 48.90; H, 2.84; N, 13.16. Found:
C, 48.88; H, 2.88; N, 12.95.
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-amino-1H-isoindole-
1,3(2H)-dione (21)
A mixture of 20 (21.5 mg, 0.07 mmol) and 10% Pd/C (20 mg) in
acetone (10 mL) was shaken at r.t. for 2 h under H2 (40 lbs). The
mixture was filtered and concentrated to afford 21.
Yield: 19 mg (95%); yellow crystals; mp 298 °C (dec.).
Alternatively, a mixture of 13 (58 mg, 0.21 mmol) and Lawesson’s
reagent (47 mg, 0.12 mmol) in toluene (50 mL) was refluxed for 91
h under nitrogen. Thereafter, the solvent was removed and the resi-
due was purified by column chromatography on silica gel (hexane–
EtOAc–MeOH, 1:1:0.3) to give 21 (5 mg, 8%).
1H NMR (300 MHz, DMSO-d6): d = 2.01–2.11 (m, 1 H, 4¢-CH),
2.44–2.60 (m, 2 H, 5¢-CH), 3.15–3.30 (m, 1 H, 4¢-CH), 5.12–5.26
(m, 1 H, 3¢-CH), 7.06 (d, J = 7.5 Hz, 1 H, 6-CH), 7.12 (s, 1 H, 4-
CH), 7.65 (d, J = 7.5 Hz, 1 H, 7-CH), 9.06 (s, 1 H, Ar-NH2), 9.49 (s,
1 H, Ar-NH2), 12.61 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 24.16, 41.14, 48.88, 105.61,
115.65, 119.70, 125.19, 133.84, 157.72, 167.26, 167.63, 167.75,
210.91.
GC-MS (CI/CH4): m/z = 290 [M + H]+, 251, 235, 227, 207, 191,
178, 163.
(11) Tweedie, D.; Sambamurti, K.; Greig, N. H. Curr. Alzheimer
Res. 2007, 4, 378.
(12) Wyrick, S. D.; Smith, F. T.; Kemp, W. E.; Grippo, A. A.
J. Med. Chem. 1987, 30, 1798.
(13) Turk, B. E.; Jiang, H.; Liu, J. O. Proc. Natl. Acad. Sci. USA
1996, 93, 7552.
Anal. Calcd for C13H11N3O3S·H2O: C, 50.81; H, 4.26; N, 13.67.
Found: C, 50.31; H, 3.58; N, 13.24.
(14) Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Org. Lett.
2-(2-Oxo-6-thioxo-3-piperidinyl)-5-chloro-1H-isoindole-
1,3(2H)-dione (22)
To a stirred solution of 14 (1.00 g, 3.42 mmol) in pyridine (26 mL)
at r.t., was added a solution of Lawesson’s reagent (0.76 g, 1.88
mmol) in pyridine (7 mL) under nitrogen. The reaction mixture was
refluxed for 47 h. Thereafter, the solvent was removed and the res-
idue was recrystallized from EtOAc to give 22.
2003, 5, 2865.
(15) Hariprakasha, H. K.; Rao, G. S. R. S. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1998, 37, 851.
(16) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(17) (a) Scheibye, S.; Kristensen, J.; Lawesson, S. Q.
Tetrahedron 1979, 35, 1339. (b) Pedersen, B. S.; Lawesson,
S. Q. Tetrahedron 1979, 35, 2433.
(18) X-ray crystal data for 23: Empirical formula: C21H21O6P3S3;
Colorless; Formula weight: 558.47; Crystal system =
triclinic; Space group P1; Unit cell dimensions: a = 9.644
(4) Å, b = 12.105 (5) Å, c = 20.512 (9) Å; a = 86.147 (9)°,
b = 85.609 (8)°, g = 82.504 (9)°; V = 2363.2 (18) Å3; Z = 4;
T = 103 (1) K; F000 = 1152; R1 = 0.0554, wR2 = 0.1595. The
supplementary crystallographic data for this structure
(CCDC 682848) can be obtained free of charge from the
Cambridge Crystallographic Data Centre via the following
website: www.ccdc.cam.ac.uk/products/csd/request.
Yield: 0.6 g (56%); yellow crystals; mp 215–217 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.01–2.15 (m, 1 H, 4¢-CH),
2.43–2.65 (m, 2 H, 5¢-CH), 3.14–3.30 (m, 1 H, 4¢- CH), 5.23–5.37
(m, 1 H, 3¢-CH), 7.95 (s, 2 H, 6-CH, 7-CH), 8.06 (s, 1 H, 4-CH),
12.89 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 23.91, 41.06, 49.34, 124.04,
125.59, 130.11, 133.53, 135.08, 140.15, 166.15, 166.49, 167.31,
210.87.
GC-MS (CI/CH4): m/z = 309 [M + H]+, 293, 281, 265.
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York

3422
W. Luo et al.
PAPER
Space group P1; Unit cell dimensions: a = 6.8299 (7) Å,
(19) X-ray crystal data for 15: Empirical formula: C13H10N2O4S;
Yellow; Formula weight: 290.29; Crystal system =
b = 7.9952 (9) Å, c = 14.1890 (15) Å; a = 86.247 (5)°,
b = 83.849 (5)°, g = 82.475 (5)°; V = 762.68 (14) Å3; Z = 2;
T = 293 (2) K; F000 = 344; R1 = 0.0982, wR2 = 0.2851. The
supplementary crystallographic data for this structure
(CCDC 682850) can be obtained free of charge from the
Cambridge Crystallographic Data Centre via the following
website: www.ccdc.cam.ac.uk/products/csd/request.
(21) Muller, G. W.; Stirling, D. I.; Chen, R. S. C. US Patent
5,635,517, 1997.
monoclinic; Space group P21/c; Unit cell dimensions:
a = 12.677 (7) Å, b = 13.698 (8) Å, c = 7.520 (4) Å; a = 90°,
b = 105.474 (11)°, g = 90°; V = 1258.6 (12) Å3; Z = 4;
T = 293 (2) K; F000 = 600; R1 = 0.0764, wR2 = 0.2009. The
supplementary crystallographic data for this structure
(CCDC 682849) can be obtained free of charge from the
Cambridge Crystallographic Data Centre via the following
website: www.ccdc.cam.ac.uk/products/csd/request.
(20) X-ray crystal data for 18: Empirical formula: C15H12N2O5S;
Yellow; Formula weight: 332.33; Crystal system = triclinic;
Synthesis 2008, No. 21, 3415–3422 © Thieme Stuttgart · New York