Access to substituted thiapyrrolizidinones and fused pyridones using the domino N-acyliminium-thionium equilibrium/1,3-dipolar cycloaddition/desulfurization cyclization cascade

Article abstract of DOI:10.1016/j.tet.2006.04.032

Substituted thiapyrrolizidinones and fused pyridones, and quinolizinones were reported efficaciously from suitable thioamides in yields ranging from 30% to 65%. The reaction proceeded in a one-pot procedure as cascade process by the intramolecular 1,3-dip

Full text of DOI:10.1016/j.tet.2006.04.032

Tetrahedron 62 (2006) 6398–6404
Access to substituted thiapyrrolizidinones and fused pyridones
using the domino N-acyliminium-thionium equilibrium/1,3-
dipolar cycloaddition/desulfurization cyclization cascade
a
b
a,*
Abdulkareem Hamid, Hassan Oulyadi and Adam Da ¨ı ch
a
Laboratoire de Chimie, URCOM, EA 3221, UFR des Sciences & Techniques de l’Universite´ du Havre,
B.P: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
b
IRCOF-UMR 6014 CNRS, Place Emile Blondel, Universite´ de Rouen, F-76131 Mt-St-Aignan Cedex, France
Received 10 March 2006; revised 5 April 2006; accepted 6 April 2006
Available online 6 May 2006
Abstract—Substituted thiapyrrolizidinones and fused pyridones, and quinolizinones were reported efficaciously from suitable thioamides in
yields ranging from 30% to 65%. The reaction proceeded in a one-pot procedure as cascade process by the intramolecular 1,3-dipolar cyclo-
addition of thioisom u¨ nchnones followed by desulfurization of the adducts. During these investigations, the mechanistic aspects of the process
were also discussed.
Ó 2006 Published by Elsevier Ltd.
1
. Introduction
These mesoionic ring systems, which are easily prepared by
the reaction of N-monosubstituted thioamides with a-halo-
acyl halides in the presence of 2 equiv of triethylamine are
stabilized by the conjugation effect as shown in Scheme 1
(thionium ion4N-acylimiunim cation4mesoionic specie).
In addition, some extra stabilization could arise from the
conjugation with an exocyclic electron rich aromatic or
Thioisom u¨ nchnones conventionally named 1,3-thiazolium-
-olates (1) and belonging to a five-membered mesoionic
systems are receiving less attention compared to their oxy-
gen homologues as isom u¨ nchnones (1,3-oxazolium-4-olates
2)), (Scheme 1). Since the pioneering work by Potts and
co-workers given on their syntheses and reactivity, it has
been demonstrated now that these species constitute power-
ful intermediates in the synthesis of complex nitrogen-
containing heterocycles. In particular, they offer rapid
access to different heterocyclic compounds containing a
pyridone nucleus useful in natural products syntheses as
well as b-lactams, polyhydrothiophenes in chiral form or
not, thiiranes, thiophenes, etc.
R1
4
1
(
2
2
heteroaromatic system when R is an aryl or heteroaryl
group. As a consequence, these mesomeric betaines exhibit
an interesting synthetic potential, which could be attributed
in addition to (a) the interesting physical properties they pos-
3
6
sess, and importantly (b) the propensity of its thio-carbonyl
ylide dipole to undergo 1,3-dipolar cycloaddition with a
range of double and triple-bond dipolarophiles.
4
4
,5
R1
N
R1
N
Due to the high number of natural and unnatural biological
active molecules containing the thiapyrrolizinone and qui-
7
O
O
O
N
Base
R3
R2
R2
R2
8
nolizinone subunits, the use of that approach is still of con-
tinuous interest in organic synthetic chemistry. Among the
most known naturally occurring alkaloids, oxogambirtan-
S
R3
S
S
R3
1
: Thioisomünchnones
R1
N
1
R1
N
9
10
R
nine (3) and sempervilam (4) belonging to the yohimboid
alkaloids, constitute one of the major subgroups of the indole
class. If these structures have not yet shown any biological
properties, mitragynaline (5a, R¼OMe) as an indole alka-
O
O
O
N
Base
R2
R2
R2
R3
R3
O
R3
O
O
2
: Isomünchnones
1
1
loid, was isolated from the Malaysian Mitragyna speciosa
korth plant. This is used in the Malay Peninsula as a stimulant
Scheme 1. Mesoionic five-membered heterocyclic mesomeric betaines.
1
2
like coca or as substitute from opium. Moreover other
tricyclic benzo- and thieno[a]quinazolines developed by
investigators at Hoffman La-Roche, Ltd have been shown to
be excellent alternatives to molecules with benzodiazepines
Keywords: Thioisom u¨ nchnone; 1,3-Dipolar cycloaddition; Thioamide;
Heterocycle; Domino process; Lawesson’s; Thionation; One-pot procedure.
Corresponding author. Tel.: +33 2 32 74 44 03; fax: +33 2 32 74 43 91;
e-mail: adam.daich@univ-lehavre.fr
*
1
3
scaffolds for the treatment of anxiety and sleep disorders.
0
040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.04.032

A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
6399
On the other hand, pyrrolo[2,1-b]thiazoles are rare scaf-
folds since only few reports are done in the literature. In
this sense, whatever, two related structures were reported
by the Padwa group using that strategy while others de-
scribed some thia-analogues of the glycosidase inhibitors
structure containing thiapyrrolizin-one ring 11 in 49% yield
(Scheme 3).
4
,14
O
O NEt3
O
N
H
Br
N
S
N
S
Br
NEt3
Toluene
Hβ
Hβ
1
polyhydroxylated pyrrolizidinones (6, R ¼H and CO Me;
S
, Br
2
2
15,16
R ¼CO R and CONH ).
The strategy used in these
cases was based on the cyclodehydration of thiazolidines
bearing an hydroxymethyl branched group and an unex-
pected ring contraction of 7,5-fused bicyclic thiazolidine-
lactams, respectively.
2
2
7
A
Dipolarophile B
, 9 and 10
8
O
O
O
O
1
5
1
6
N
8
N
N
O
S
S
S
O
O
O
O
O
N
O
2
. Results and discussion
N
N
O
O
9
O
O
O
O
O
As part of a long-term project dealing with our search for
a simple synthetic route to heterocyclic homologues of the
above structures (Scheme 2), which could be applicable to
the synthesis of different condensed five and six-membered
azacycles, we explore in this paper the intramolecular 1,3-
dipolar cycloaddition of new thioisom u¨ nchnones with
systematically three different dipolarophiles. This process
proceeds in a one-pot procedure and result in the formation
of new substituted 1,3-thiazolidinones and fused pyridones,
heterocyclic scaffolds with promising biological activity.
11
12
13
N
O 10
49%
45%
41%
Scheme 3. Scheme leading to new structures containing thiapyrrolizinone
nucleus as 11, 12, and 13 from betaine B.
Having the best conditions in hand, we examined next the
reaction of the same substrate as above with 2-bromoacetyl
bromide and other dipolarophiles in the presence of triethyl-
amine (Scheme 3). In this context, the commercially avail-
able N-phenylmaleimide (10) and N-benzylmaleimide (11)
were found to be employable efficaciously without the
change of the course of the cascade process as well as the
reaction yields. Indeed, the reaction products, identified as
thiapyrrolizinones 12 and 13, were isolated in 45% and
O
O
N
N
N
H
N
H
MeO C
2
3: Oxogambirtannine
4: Sempervilam
41% yields, respectively, comparables to that obtained for
the thiapyrrolizinone derivative 11.
R2
R
OH
R1
O
N
H
N
HO
As shown in Scheme 4, the suggested reaction mechanism
illustrates three pathways that appear possible. Initially
formed thionium cation A, in equilibrium with correspond-
ing N-acyliminium one C, would lead with triethylamine
to either the thiapyrrolizinone 14 or the carbanion G via
mesoionic five-membered heterocyclic mesomeric betaines
B and D, in equilibrium. No traces of product 14 were found
in the reaction mixture examined by TLC before addition of
a second equivalent of triethylamine, a dipolarophile as well
as at the end of the reaction process before any purification.
Also, no trace of pyridone component 15 as well as corre-
sponding thia-bridged products F, which would be formed
by the intramolecular 1,3-dipolar cycloaddition of 3-thiazo-
lium-4-olate salt (B or D, see Scheme 4), was observed.
Therefore, these thioisom u¨ nchnones species afforded the
thiapyrrolizinones 11, 12, and 13 upon abstraction of the hy-
drogen atom at b-position of nitrogen and/or sulfur atom(s)
in the intermediate (A4C) or (B4D) followed in an ulti-
mate stage by addition of a dipolarophile and protonation
of the resulting carbanion. Interestingly, the process seems
to be general and the key step seems to be the hydrogen
abstraction.
N
S
H
HO
OHC
O
MeO
6
: Thiapyrrolizidines
1
R =H, CO2Me
5
a: Mitragynaline (R=OMe)
b: Corynantheidaline (R=H)
2
5
R =CO2R, CONH2
Scheme 2. Representative structures containing thiapyrrolizinone and quino-
lizinone subunits.
Because of the use of thioisom u¨ nchnone of type B as a di-
pole, in cycloaddition reactions remains unreported, we first
investigated the behavior of this thioisom u¨ nchnone, derived
from pyrrolidine-2-thione (7), in the intramolecular 1,3-
dipolar cycloaddition conditions as shown in Scheme 3.
For this purpose, the requisite pyrrolidine-2-thione (7) was
obtained in one step in quantitative yield by thionation of
pyrrolidine-2-one with 1 equiv of Lawesson’s reagent in dry
toluene at reflux for 3 h and the dipolarophile chosen as the
reaction partner for optimizing conditions was the methyl
acetylenedicarboxylate (8). So, after intensive screening of
reaction conditions, the use of 1.1 equiv of 2-bromoacetyl
bromide, 2.0 equiv of dry triethylamine as a base, 1.5 equiv
of suitable dipolarophile, and anhydrous toluene as solvent
was found to be the most effective combination for obtaining
representative results. Under these conditions, pyrrolidine-
1
7
1
8
1
The H NMR spectra of thiapyrrolizinones 11, 12, and 13 are
characterized by having the olefinic proton of the dihydro-
pyrrole nucleus in the aromatic region (from d¼6.98 up to
7.35 ppm). This was coupled with methylene protons at
b-position of the dihydropyrrole ring and in the case of
2
-thione (7) with 2-bromoacetyl bromide and triethylamine
led to thionium salt A then mesoionic five-membered B,
which after reaction with dipolarophile 9, led to the

6400
A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
O
O
Br
O
O
NEt
X
3
O
NH
S
Br
3
N
N
N
N
NEt
Toluene
Hβ
+ HNEt3
, Br
S
S
, Br
S
14
, Br
7
A
C
ewg 15 ewg
NEt3
-
Sx
N
O
O
O
O
O
N
S
N
NEt3
N
N
Dipolarophile
X
Hβ
(8,9,10)
ewg
ewg
S
S
S
S
ewg F ewg
G
B
D
E
Dipolarophile (8,9,10)
O
protonation/
N
S
isomerisation
ewg
ewg
11, 12, 13
or
H
protonation
single or
double bond
ewg: CO Me, Imide
2
Scheme 4. Mechanistic considerations leading to the formation of substituted thiapyrrolizinone scaffolds 11, 12, and 13.
product 11, they appear as a triplet at d¼6.98 ppm with cou-
pling constant of J¼5.48 Hz. This proton became singlet
when the methylene protons outlined above were irradiated.
purification methyl 4-oxo-4,6-dihydropyrido[2,1-a]iso-
indole-1,2-dicarboxylate (19) as a brown solid in 40% yield
(Scheme 6).
1
Also, the H NMR spectra of 11 showed the presence of three
methylene groups CH demonstrating the carbon–carbon
2
O
Br
O
double-bond migration. As a consequence, the resulting thia-
pyrrolizinone system bearing an exocyclic double-bond in
the conjugation with either the sulfur atom or the carbonyl
function constitutes the thermodynamic isomer.
NH
S
Br
NEt3
Toluene
N
S
, Br
18
J
NEt3
Consistent with the above remark, isoindoline-1-thione (16)
Scheme 5), obtained from oxindole by known procedure
was subjected to our standard protocol outlined above.
Surprisingly, whatever change operated in the experimental
procedure only product namely, thiazolo[3,2-a]indol-3-one
O
8
O
1
9
N
N
S
(
Toluene
reflux
K
O
O
O
O
9
10 Toluene
Toluene
reflux
reflux
(
17), was obtained as the sole reaction product in yields
1
9 40%
2
0
near 65%. Also, when the reaction was repeated using
more than 2 equiv of triethylamine (up to 4 equiv), the reac-
tion profile remains unchanged. The change of dipolarophile
in combination of an excess of triethylamine had also little
effect on the course of the reaction as well as on the yield
of the cyclized product 17. From these considerations, the
benzylic proton abstraction leading to the more stable fused
indole 17 appears to be largely responsible for the differ-
ences observed in the formation of heterocyclic systems
O
O
N
S
N
S
O
O
O
N
O
N
2
0 39%
21 42%
2
1
?
Hz (cis)
S H
O
1
1, 12, 13, and 17, respectively.
0
Hz (trans)
7.04 Hz
S
H
O
3
H
O
R
2
4
N
1
6
5
H
N
(cis)
N
O
O
Br
O
H
Br
NEt3
N
H
7
.04 Hz
(cis)
O
O
O
R
NH
S
NEt3
Toluene
N
S
I
N
S
65%
endo form
exo form
,
Br
Scheme 6. One-pot procedure leading to dihydropyrido[2,1-a]isoindole 19
and thiadiazacyclopenta[c]fluorenetriones 20 and 21.
16
17
Scheme 5. One-pot protocol leading to thiazolo[3,2-a]indol-3-one (17).
As highlight in Scheme 6, the formation of that product
seems to proceed by a cascade process. This implies the for-
mation of thionium ion J, its transformation with NEt into
corresponding thioisom u¨ nchnone salt K followed by the
intramolecular 1,3-dipolar cycloaddition with 8 and desul-
furization of the adduct in an ultimate step. This mechanistic
paradigm was extended efficaciously to other dipolarophiles
as 9 and 10, but surprisingly the process stopped at the
We next directed our attention to explore the behavior of 2,3-
2
2
dihydroisoindole-1-thione (18) under the precedent well
established protocol. The choice of this thioamide is due to
the absence of a proton at a-position of the thio-carbonyl
function. Thus, treatment of 18 in the presence of 1 equiv of
methyl acetylenedicarboxylate (9) according to conditions
outlined above, gave exclusively after chromatography
3

A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
6401
O
bridgehead sulfur components 20 and 21. Indeed, reaction of
8 with 9 and 10 furnished thiadiazacyclopenta[c]fluorene-
triones 20 and 21 in 39% and 42% yields, respectively.
From these results, the reaction appears tolerant with respect
to the nature of dipolarophile and, importantly, it proceeds
without any significant changes in the reaction yields.
Br
Br
NEt3
Toluene
O
1
NH
N
S
N
H
N
H
S
, Br
2
2
L
NEt3
O
O
The structure of these products was assigned on the basis on
N
S
N
S
1
13
their IR, NMR ( H and C experiments including NOE dif-
ference and DEPT program, respectively) as well as elemen-
tal analyses. For instance, the H NMR spectra of 19 showed
N
H
N
H
1
N
M
a non-conventional doublet of doublet with J¼17.12 Hz cen-
Dipolarophile (8,9,10)
O
tered at d¼3.71 ppm, one singlet at d¼6.02 ppm characteris-
N
O
2
3
tics of non-equivalent methylene protons (CH –N) and
2
N
- Sx
N
1
a pyridone proton, respectively. On the other hand, the H
S
H
N
H
O
NMR spectra of fluorenetrione derivative 20 showed besides
nine aromatic protons four aliphatic proton blocks. They
consist of two doublets at d¼3.16 ppm and d¼3.42 ppm
with coupling constant of about J¼7.04 Hz (cis coupling
between H and H , see Scheme 6), a doublet of doublet
O
ewg
O O
ewg
O
23
-
Sx
-
Sx
24 30%
O
4
5
N
N
N
for methylene protons (CH –N as an AB system, which
2
N
H
N
H
appeared at d¼3.62 and 3.80 ppm with coupling constant
O
O
J¼16.43 Hz), and one singlet at d¼5.68 ppm attributed to
O
N
O
2
4
H . Interestingly, product 21 exhibits same profile with,
3
in addition, an AB system at down field centered at
d¼4.77 ppm with J¼14.09 Hz. These data are consistent
2
5
55%
26 52%
2
b,25
with the data described earlier by Potts et al. for the
mesoionic N-phenylmaleimide adduct in the endo configura-
Scheme 7. Tandem process giving N-substituted indoloquinolizinone
products 24, 25, and 26.
tion. In these cases, the coupling constant between the 3 and
4
protons in the endo form was of about 1 up to 1.5 Hz indi-
cating a trans coupling, and between the protons 4 and 5 it
was of J¼7 Hz consistent with a cis coupling. Our observa-
tions were in accordance with these values, indicating the
formation of the thiadiazacyclopenta[c]fluorinetriones 20
and 21 in only the endo configuration.
(ewg¼CO Me) was effective without additional heating.
2
In this case, all the tentative made for isolation of the inter-
mediate 23 failed.
With N-phenylmaleimide (9) and N-benzylmaleimide (10)
2
7
as dipolarophiles, the betaine M under reflux in toluene
gave an extremely colorless solution, which after a classical
work up, indicated the presence of only one product identi-
fied as indolopyrroloquinolizinones 25 and 26 (Scheme 7).
These results demonstrate the effectiveness of the betaine
formation/intramolecular 1,3-dipolar cycloaddition/de-
sulfurization tandem process and the products were isolated
in appreciable yields of 55% and 52%, respectively, more
better than the ones indicated for related structures as above.
This could be explained by the fact that 1,3-thiazolium-4-
olates salts in b-carboline series were more stable in thermal
conditions than betaines formed above in pyrrolidinone, iso-
indolinone, and indolinone heterocycles.
For the generalization and additional demonstration of
our tandem protocol, another class of thioisom u¨ nchnones
fused to six-membered azacyclic system was investigated
(
Scheme 7). In the first step, the requisite 2,3,4,9-tetra-
hydro-b-carboline-1-thione (22) was prepared by two path-
ways from tryptamine. In fact, the reaction of tryptamine
with phosgene in dry toluene gave 2,3,4,9-tetrahydro-b-
carboline-1-one in 78% yield. The thioamide 22 was
obtained in an ultimate step by thionation of the amide with
2
6
Lawesson’s reagent in toluene in 82% yield. This product
was also obtained directly in one step, with however very
modest yield of 29%, when tryptamine was treated with
the NEt /ClCO Et combination in the presence of CS
3
2
2
used as reactant and solvent.
Again, the structure of these products was secured by the
NMR study. Thus, the H NMR spectra of 24, 25, and 26
1
As showed in Scheme 7, the reaction of the above 2,3,4,9-
tetrahydro-b-carboline-1-thione (22) with 2-bromoacetyl
bromide (1.1 equiv) and triethylamine (1 equiv) in toluene
gave the corresponding thionium cation L. By its heating
with additional 1 equiv of triethylamine the mesoionic salt
M was generated and this underwent an external 1,3-dipolar
cycloaddition and desulfurization with methyl acetylene-
dicarboxylate (8) to give after chromatography purification
methyl 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-
showed two triplets characteristics of –N–CH –CH – func-
2
2
tionality from d¼3.11 to 3.19 ppm and from d¼4.47 to
4.89 ppm, respectively, with coupling constants of about
J¼7.03–7.04 Hz. Especially diagnosis was made by the
presence of a singlet proton at d¼6.91, 7.02, and 6.92 ppm
for structures 24, 25, and 26, respectively, characteristic of
the formation of the pyridone nucleus. These values were
in accordance with those reported for compounds containing
the pyridone ring bearing an hydrogen atom at the a-position
8
a,28
1,2-dicarboxylate (24) as red-orange solid in 30% yield.
Here, the tandem route evoked above was evidenced since
the desulfurization of the key adduct intermediate 23
of the thiolactam function.
In the concomitant fashion,
1
3
the C NMR spectra of these products also showed
two methine carbons, which inverted in the DEPT-135

6402
A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
experiments. In the case of product 26, an additional methine
carbon corresponding to the benzyl group also appeared at
bromide at room temperature under an atmosphere of nitro-
gen. The reaction mixture was stirred at room temperature
for 30 min and then heated at 100 C for 3 h. After cooling,
1
3
ꢀ
d¼6.92 ppm in the C NMR spectra but inverted in the
1
3
C NMR, recorded using DEPT-135 technique. These
values, as well as elemental analyses are in accordance
with the proposed structures.
1.39 mL (9.89 mmol) of triethylamine was added to the
solution at room temperature followed 10 min after by drop-
wise addition of a solution of 7.39 mmol of the expected
dipolarophile dissolved in 10 mL of dry toluene. The mix-
ture was heated at reflux for an additional 12 h, cooled to
room temperature, concentrated under reduced pressure,
and chromatographed on a silica gel column using a cyclo-
hexane/AcOEt (4/1) as eluting mixture to give solids in
yields ranging from 30% to 65%.
3. Conclusion
In summary, we have demonstrated the utility of 1,3-thiazo-
lium-4-olates salts, derived from pyrrolidine-2-thione (7)
and isoindoline-1-thione (16), to create with dipolarophiles
a set of diverse and new thiapyrrolizidinones. The reaction
seems to proceed with a hydrogen abstraction as well as
addition of the dipolarophile. This consequently induces
the interruption of the 1,3-dipolar cycloaddition process in
the intramolecular fashion.
4.2.1. Dimethyl (Z)-2-(3-oxo-(5,6-dihydropyrrolo[2,1-
b]thiazol-2(3H)-ylidene)succinate (11). This product was
isolated as a yellow solid in 49% yield and melted at 147–
49 C; IR (KBr) ꢀn max ¼2977 ðCHÞ, 1738 (C]O) cm
ꢀ
ꢁ1
1
;
1
H NMR (CDCl , 300 MHz) d 2.53 (dt, 2H, J¼7.82 and
3
5
.48 Hz, CH –N), 3.71 (s, 2H, CH ), 3.73 (s, 3H, CH ),
2 2 3
Further, with thioisom u¨ nchnones in benzene and indole
series not possessing a hydrogen atom at b-position of the
sulfur atom, the tandem betaine formation/intramolecular
3
6
7
.74 (s, 3H, CH ), 3.91 (dt, 2H, J¼7.04 Hz, CH –CH]),
3
2
1
3
.98 (t, 1H, J¼5.48 Hz, CH]);
C NMR (CDCl ,
3
5 MHz) d 26.6 (CH ), 31.2 (CH ), 48.2 (CH ), 52.1
2
2
2
1
,3-dipolar cycloaddition/desulfurization process was effec-
tive and led to fused pyridones and quinolizinones products
9 and 24–26. Elsewhere, in the case of 2,3-dihydroiso-
q
q
(CH ), 52.3 (CH ), 131.3 (C ), 138.9 (CH]), 152.4 (C ),
3 3
q
1
Anal. Calcd for C H NO S (283.31): C, 50.88%; H,
55.2 (C ), 168.0 (C]O), 168.3 (C]O), 173.0 (C]O);
1
1
2
13
5
indole-1-thione (18) as a betaine precursor, thiadiazacyclo-
penta[c]fluorenetrione derivatives 20 and 21 exclusively in
endo configuration were formed in an interruption of the tan-
dem process as outlined above. Finally, the yields associated
with obtaining these products were generally ranged from
4
.63%; N, 4.94%. Found: C, 50.65%; H, 4.44%; N, 4.81%.
4
2
.2.2. 3-(3-Oxo-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-
-yl)-1-phenylpyrrolidine-2,5-dione (12). This product
was isolated as an orange solid in 45% yield and melted
ꢀ
717 (C]O) cm ; H NMR (CDCl , 300 MHz) d 2.19–
30% to 65%. The latter were higher in betaines derived
from b-carboline.
at 152–154 C; IR (KBr) ꢀn ¼3000 ðCHÞ, 2985 (CH),
max
ꢁ1 1
1
2
1
3
.51 (m, 2H, CH ), 2.55–2.80 (m, 1H, CH), 3.12–3.27 (m,
2
H, CH), 3.45–3.63 (m, 2H, 2CH), 3.75–3.78 (m, 1H,
Finally, these processes might find applications as valuable
strategies in syntheses of potentially active and bioactive
compounds. Studies along this line are currently underway
in our laboratory, and the results will be published soon.
CH), 4.36 (d, 1H, J¼2.35 Hz, CH–S), 7.21–7.24 (m, 3H,
1
3
CH +CH]), 7.25–7.46 (m, 3H, CH );
(
4
C NMR
CDCl , 75 MHz) d 22.6 (CH ), 29.1 (CH ), 42.7 (CH ),
aro
aro
3
2
2
2
q
7.7 (CH), 55.4 (CH), 58.4 (CH), 86.1 (C ), 126.5
q
4. Experimental
(2ꢂCH), 129.2 (CH), 129.4 (2ꢂCH), 131.6 (C ), 170.4
C]O), 173.1 (C]O), 173.7 (C]O); Anal. Calcd for
C H N O S (314.07): C, 61.13%; H, 4.49%; N, 8.91%.
(
4
.1. General
1
6 12 2 3
Found: C, 61.00%; H, 4.31%; N, 8.69%.
All melting points were measured on a Boetius micro hot-
stage and are uncorrected. The infrared spectra of solids
4.2.3. 1-Benzyl-3-(3-oxo-2,3,5,6-tetrahydropyrrolo[2,1-
b]thiazol-2-yl)-1-pyrrolidine-2,5-dione (13). This product
(
a Perkin–Elmer FTIR paragon 1000 spectrometer. The H
potassium bromide) and liquids (neat) were recorded on
1
was isolated as a yellow solid in 41% yield and melted
ꢀ
1
3
and C NMR spectra were recorded on a Bruker 300
300 MHz) instrument in deuteriochloroform unless other
at 158–160 C; IR (KBr) ꢀn ¼3011 ðCHÞ, 2982 (CH),
max
ꢁ
1 1
(
1709 (C]O) cm ; H NMR (CDCl , 300 MHz) d 2.15–
3
indicated solvent and chemical shifts (d) are expressed in
parts per million relative to TMS as internal standard.
Ascending thin layer chromatography was performed on
precoated plates of silica gel 60 F254 (Merck) and the spots
were visualized using an ultraviolet lamp or an iodine vapor.
Mass spectral measurements were recorded on a AEI MS
2.45 (m, 2H, CH ), 2.55–2.72 (m, 1H, CH), 3.08–3.23 (m,
2
1H, CH), 3.31 (d, 1H, J¼7.04 Hz, CH), 3.40–3.57 (m, 1H,
CH), 3.67 (dd, 1H, J¼6.34 and 1.57 Hz, CH), 4.23 (d, 1H,
J¼7.04 Hz, CH–S), 4.64 (d, 2H, J¼2.35 Hz, CH –N),
2
1
3
7.25–7.35 (m, 6H, CH +CH]); C NMR (CDCl ,
aro
3
75 MHz) d 26.5 (CH ), 28.9 (CH ), 42.6 (CH ), 43.1
2
2
2
q
9
02 S spectrophotometer. The elemental analyses were car-
(CH ), 47.7 (CH), 55.5 (CH), 57.9 (CH), 85.6 (C ), 128.1
2
q
ried out by the microanalysis laboratory of INSA, F-76130
Mont-Saint-Aignan, France.
(CH), 128.7 (2ꢂCH), 129.0 (2ꢂCH), 135.1 (C ), 173.7
(C]O), 174.2 (C]O), 178.4 (C]O); Anal. Calcd for
C H N O S (328.09): C, 62.18%; H, 4.91%; N, 8.53%.
Found: C, 62.01%; H, 4.76%; N, 8.42%.
1
7 14 2 3
4
.2. General procedure for the reaction of thioiso-
m u¨ nchnones with dipolarophiles
4.2.4. Thiazolo[3,2-a]indol-3-one (17). This product was
isolated as a yellow solid in 65% yield and melted at 136–
138 C (lit. 141–143 C); IR (KBr) ꢀn max ¼3009 ðCHÞ,
To a solution of thioamide (4.94 mmol) in 30 mL of dry
toluene was added 0.47 mL (5.39 mmol) of 2-bromoacetyl
ꢀ
20
ꢀ

A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
6403
ꢁ
1
1
ꢀ
1784 (C]O), 1760 (C]O) cm
2
3
7
1
7
965 (CH), 1718 (C]O) cm
;
H NMR (CDCl3,
00 MHz) d 4.20 (s, 2H, CH ), 6.85 (s, 1H, CH), 7.15–
164–166 C; IR (KBr) ꢀn ¼3006 ðCHÞ, 2965 (CH),
max
ꢁ
1
1
;
H NMR (CDCl ,
3
2
.31 (m, 2H, CHaro), 7.36–7.44 (m, 1H, CHaro), 8.09 (dd,
H, J¼6.26 and 3.91 Hz, CHaro); C NMR (CDCl3,
300 MHz) d 3.11 (t, 2H, J¼7.04 Hz, CH ), 3.86 (s, 3H,
2
1
3
CH ), 3.91 (s, 3H, CH ), 4.47 (t, 2H, J¼7.04 Hz, CH ),
3
3
2
5 MHz) d 38.4 (CH ), 100.4 (CH), 113.0 (CH), 119.6
2
6.91 (s, 1H, CH), 7.17 (t, 1H, J¼7.04 Hz, CH ), 7.29 (t,
aro
q
(
CH), 122.9 (CH), 122.9 (CH), 124.8 (CH), 132.0 (C ),
1H, J¼7.05 Hz, CH ), 7.43 (d, 1H, J¼7.82 Hz, CH ),
aro
aro
13
q
q
135.7 (C ), 136.8 (C ), 166.6 (C]O); Anal. Calcd for
C H NOS (189.02): C, 63.47%; H, 3.73%; N, 7.40%.
Found: C, 63.21%; H, 3.65%; N, 7.12%.
7.61 (d, 1H, J¼7.83 Hz, CH ), 9.94 (s, 1H, NH);
C
aro
NMR (CDCl , 75 MHz) d 19.3 (CH ), 41.5 (CH ), 53.2
3 2 2
1
0
7
q
q
(CH ), 53.5 (CH ), 106.0 (C ), 112.3 (CH), 118.8 (C ),
3 3
q
1
19.1 (CH), 119.7 (CH), 120.9 (CH), 124.5 (C ), 125.8
q
q
q
q
4
1
.2.5. Methyl 4-oxo-4,6-dihydropyrido[2,1-a]isoindole-
,2-dicarboxylate (19). This product was isolated as
a brown solid in 40% yield and melted at 104–106 C; IR
(CH), 128.5 (C ), 137.8 (C ), 138.9 (C ), 140.9 (C ), 161.5
(C]O), 165.9 (C]O), 169.7 (C]O); Anal. Calcd for
C H N O (352.11): C, 64.77%; H, 4.58%; N, 7.95%.
ꢀ
1
9 16 2 5
(
(
KBr) ꢀn max ¼3004 ðCHÞ, 2942 (CH), 1767 (C]O), 1732
Found: C, 64.45%; H, 4.33%; N, 7.76%.
ꢁ
1 1
C]O), 1700 (C]O) cm ; H NMR (CDCl , 300 MHz)
3
d 3.71 (dd, 2H, J¼17.12 Hz, CH ), 3.79 (s, 3H, CH ), 5.57
4.2.9. 7,8-Dihydro-2-phenylindolo[2,3-a]pyrrolo[3,4-
a]quinolizine-1,3,5(13H)-trione (25). This product was
isolated as a red-orange solid in 55% yield and melted at
2
3
(
s, 3H, CH ), 6.02 (s, 1H, CH), 7.03–7.19 (m, 2H,
3
2
CHaro), 7.39 (d, 1H, J¼7.05 Hz, CHaro), 7.50 (d, 1H,
aro 3
1
3
ꢀ
J¼6.26 Hz, CH ); C NMR (CDCl , 75 MHz) d 38.1
234–236 C; IR (KBr) ꢀn max ¼3010 ðCHÞ, 2954 (CH),
ꢁ
1
1
(
CH ), 52.9 (CH ), 53.0 (CH ), 113.0 (CH), 121.3 (CH),
2
1756 (C]O), 1742 (C]O) cm ; H NMR (DMSO-d ,
6
3
3
q
1
22.1 (CH), 126.6 (CH), 126.9 (CH), 146.2 (C ), 146.9
300 MHz) d 3.24 (t, 2H, J¼7.03 Hz, CH ), 4.59 (t, 2H,
2
q
q
q
q
(
1
(
C ), 150.6 (C ), 153.1 (C ), 154.5 (C ), 161.6 (C]O),
62.1 (C]O), 163.6 (C]O); Anal. Calcd for C H NO
299.08): C, 64.21%; H, 4.38%; N, 4.68%. Found: C,
J¼7.03 Hz, CH ), 7.02 (s, 1H, CH), 7.12–7.30 (m, 2H,
2
1
3
CH ), 7.32–7.69 (m, 7H, CH ), 12.04 (s, 1H, NH);
aro
C
1
6
13
5
aro
NMR (DMSO-d , 75 MHz) d 18.7 (CH ), 20.8 (CH ),
6 2 2
q
6
4.04%; H, 4.15%; N, 4.43%.
111.4 (CH), 113.2 (CH), 119.0 (C ), 119.4 (CH), 120.6
(CH), 123.9 (C ), 124.3 (C ), 124.7 (CH), 126.2 (C ),
q
q
q
q
4.2.6. 3a,7,11b,11c-Tetrahydro-2-phenyl-4,11b-thia-2,6-
diazacyclopenta[c]fluorene-1,3,5(4H)-trione (20). This
127.6 (2ꢂCH), 128.6 (CH), 128.9 (2ꢂCH), 131.5 (C ),
q
q
q
138.0 (C ), 139.8 (C ), 140.3 (C ), 161.8 (C]O), 164.6
(C]O), 167.0 (C]O); Anal. Calcd for C H N O
3 15 3 3
product was isolated as a brown solid in 39% yield and
melted at 218–220 C; IR (KBr) ꢀn max ¼3019 ðCHÞ, 2936
2
ꢀ
CH), 1718 (C]O) cm ; H NMR (CDCl , 300 MHz)
(381.39): C, 72.43%; H, 3.96%; N, 11.02%. Found: C,
72.21%; H, 3.77%; N, 10.86%.
ꢁ
1
1
(
3
d 3.16 (d, 1H, J¼7.04 Hz, CH), 3.42 (d, 1H, J¼7.04 Hz,
CH), 3.62 (d, 1H, J¼16.43 Hz, CH –N), 3.80 (d, 1H,
4.2.10. 2-Benzyl-7,8-dihydroindolo[2,3-a]pyrrolo[3,4-
a]quinolizine-1,3,5(13H)-trione (26). This product was
isolated as a red-orange solid in 52% yield and melted
2
J¼16.43 Hz, CH –N), 5.68 (s, 1H, CH), 7.22–7.36 (m, 4H,
2
1
3
H
), 7.38–7.55 (m, 5H, H );
aro
C NMR (CDCl ,
3
aro
ꢀ
7
8
5 MHz) d 39.5 (CH ), 51.3 (CH), 55.0 (CH), 59.9 (CH),
2
0.4 (C ), 120.4 (CH), 121.1 (CH), 125.6 (2CH), 128.5
at 230–232 C; IR (KBr) ꢀn max ¼3017 ðCHÞ, 2948 (CH),
q
ꢁ1
1
1757 (C]O), 1749 (C]O) cm
;
H NMR (CDCl ,
3
(
CH), 128.7 (CH), 129.1 (CH), 129.4 (2ꢂCH), 131.4 (CH),
300 MHz) d 3.19 (t, 2H, J¼7.04 Hz, CH ), 4.52 (t, 2H,
2
q
q
1
(
43.6 (C ), 145.5 (C ), 168.1 (C]O), 171.4 (C]O), 173.4
C]O); Anal. Calcd for C H N O S (362.07): C,
J¼7.04 Hz, CH ), 4.89 (s, 2H, CH –N), 6.92 (s, 1H, CH),
2
2
1
3
7.14–7.59 (m, 9H, CH), 12.10 (s, 1H, NH); C NMR
(CDCl , 75 MHz) d 19.0 (CH ), 41.4 (CH ), 41.8 (CH ),
2
0 14 2 3
6
3
6.28%; H, 3.89%; N, 7.73%. Found: C, 66.02%; H,
.64%; N, 7.55%.
3
2
2
2
q
112.3 (CH), 118.7 (C ), 119.6 (CH), 120.4 (CH), 123.6
(C ), 123.8 (C ), 123.9 (C ), 124.5 (C ), 126.2 (CH), 127.6
q
q
q
q
4.2.7. 2-Benzyl-3a,7,11b,11c-tetrahydro-4,11b-thia-2,6-
diazacyclopenta[c]fluorene-1,3,5(4H)-trione (21). This
(CH), 128.1 (2ꢂCH), 128.3 (2ꢂCH), 128.5 (CH), 135.1
q
q
q
(C ), 138.1 (C ), 139.7 (C ), 162.0 (C]O), 164.8 (C]O),
167.3 (C]O); Anal. Calcd for C H N O (395.13): C,
product was isolated as a brown solid in 42% yield and
ꢀ
2
4 17 3 3
melted at 208–210 C; IR (KBr) ꢀn ¼3003 ðCHÞ, 2976
max
72.90%; H, 4.33%; N, 10.63%. Found: C, 72.78%; H,
4.14%; N, 10.46%.
ꢁ
1
1
(
CH), 1710 (C]O) cm ; H NMR (CDCl , 300 MHz)
3
d 2.98 (d, 1H, J¼7.04 Hz, CH), 3.26 (d, 1H, J¼7.04 Hz,
CH), 3.46 (s, 2H, CH –N), 4.66 (d, 1H, J¼14.09 Hz, CH –
2
2
Acknowledgements
N), 4.77 (d, 1H, J¼14.09 Hz, CH –N), 5.57 (s, 1H, CH),
2
1
3
7
d 39.3 (CH ), 43.3 (CH ), 51.3 (CH), 55.0 (CH), 59.4
.15–7.44 (m, 9H, H ); C NMR (CDCl , 75 MHz)
aro 3
The authors are grateful to the Libyan Government for a
Graduate Fellowship (2002–2005) attributed to A.H. We
are also grateful for many fruitful discussions throughout
the course of this work with Prof. B. Decroix.
2
2
q
(
1
1
CH), 80.4 (C ), 120.2 (CH), 120.9 (CH), 128.2 (CH),
28.3 (CH), 128.7 (CH), 128.9 (2ꢂCH), 130.4 (2ꢂCH),
q
q
q
35.4 (C ), 143.5 (C ), 145.9 (C ), 167.1 (C]O), 171.9
(
(
6
C]O), 173.9 (C]O); Anal. Calcd for C H N O S
21 16 2 3
376.09): C, 67.00%; H, 4.28%; N, 7.44%. Found: C,
6.87%; H, 4.03%; N, 7.21%.
References and notes
1
. For reviews, see: (a) Potts, K. T. 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York,
NY, 1984; Vol. 2, Chapter 8; (b) Padwa, A. 1,3-Dipolar
Cycloaddition Chemistry; Wiley-Interscience: New York, NY,
4.2.8. Methyl 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]-
quinolizine-1,2-dicarboxylate (24). This product was iso-
lated as a red-orange solids in 30% yield and melted at

6404
A. Hamid et al. / Tetrahedron 62 (2006) 6398–6404
1
984; Vols. 1 and 2; (c) Gingrich, H. L.; Baum, J. S. The
Schneider, F.; Widmer, U. Helv. Chim. Acta 1990, 73, 763; (c)
Scherschlicht, R. R.; Widmer, U. Eur. Pat. EP496274; Chem.
Abstr. 1992, 117, 191707c; (d) Spurr, P. R. Tetrahedron Lett.
1995, 36, 2745.
Chemistry of Heterocyclic Compounds, Oxazoles; Turchi,
I. J., Ed.; Wiley: New York, NY, 1986; Vol. 45, p 731; (d)
Schoffstall, A. M.; Padwa, A. Advances in Cycloaddition;
Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, p 1.
. (a) Potts, K. T.; Houghton, E.; Singh, U. P. J. Org. Chem. 1974,
14. Heidelbaugh, T. M.; Liu, B.; Padwa, A. Tetrahedron Lett. 1998,
39, 4757.
2
3
3
9, 3627; (b) Potts, K. T.; Baum, J.; Houghton, E. J. Org. Chem.
15. Darek, D.; Wadouachi, A.; Uzan, R.; Beaupere, D.;
Nowogrocki, G.; Laplace, G. Tetrahedron Lett. 1996, 37, 49.
16. Agoston, K.; Geyer, A. Tetrahedron Lett. 2004, 45, 1895.
17. Padwa, A.; Kinder, F. R.; Nadler, W. R.; Zhi, L. Heterocycles
1993, 35, 367.
1974, 39, 3631; (c) Potts, K. T.; Baum, J.; Datta, S. K.;
Houghton, E. J. Org. Chem. 1976, 41, 813; (d) Potts, K. T.;
Baum, J.; Houghton, E. J. Org. Chem. 1976, 41, 818; (e)
Potts, K. T.; Chen, S. J.; Kane, J.; Marshall, J. L. J. Org.
Chem. 1977, 42, 1633.
. (a) Potts, K. T. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, NY, 1983; Vol. 2, pp
18. Padwa, A.; Coats, S. J.; Hadjiarapoglou, L. Heterocycles 1994,
39, 219 and Refs. 4a–c cited herein.
19. Wenkert, E.; Hanna, J. M., Jr.; Leftin, M. H.; Michelotti, E. L.;
Potts, K. T.; Usifer, D. J. Org. Chem. 1985, 50, 1125.
20. This product was reported earlier by Friedel & Crafts cycliza-
tion of 1H-indol-3-ylsulfanylacetic acid and 1H-indol-2-yl-
sulfanylacetic acid with polyphosphoric acid in 31% yield and
polyphosphate ester in 65% yield, respectively. For this end,
see: Hamel, P.; Girard, M. J. Heterocycl. Chem. 1996, 33, 1695.
21. The methylene protons of thiazo[3,2-a]indol-3-one (17) are
probably less acid than same ones in related polyhydro-
pyrrolo[2,1-b]thiazoles. In the latter cases, it was reported
that the acylation at the methylene carbon needed strong base
as BuLi. For more details, see: Burgemeister, T.; Dannhard,
G.; Graf, E.; Obergrusberger, R. Arch. Pharm. 1987, 320, 799.
22. Nishio, T.; Okuda, N. J. Org. Chem. 1992, 57, 4000.
23. The magnetically non-equivalences observed in product 19 for
methylene protons is not due to the diastereotopic effect but
probably due to the geometrical constraints.
1
–82; (b) Potts, K. T.; Dery, M. O.; Juzukonis, W. A. J. Org.
Chem. 1989, 54, 1077 and references cited therein; (c) See par-
ticularly Ref. 92 up to 99 in the following review: Jagodzi n´ ski,
T. S. Chem. Rev. 2003, 103, 197.
. (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994,
123; (b) Padwa, A.; Beall, L. S.; Heidelbaugh, T. M.; Liu, B.;
4
5
Sheehan, S. M. J. Org. Chem. 2000, 65, 2684; (c) Padwa, A.;
Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925.
. For representative classes of products, see: (a) Avalos, M.;
Babiano, R.; Cabanillas, A.; Cintas, P.; Higes, F. J.; Jim e´ nez,
J. L.; Palacios, J. C. J. Org. Chem. 1996, 61, 3738; (b) Avalos,
M.; Babiano, R.; Cintas, P.; Clemente, F. R.; Gordillo, R.;
Jim e´ nez, J. L.; Palacios, J. C. J. Org. Chem. 2003, 68, 6338;
(
c) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.;
Jim e´ nez, J. L.; Palacios, J. C. Acc. Chem. Res. 2005, 38, 460.
. Some betaines are highly colored compounds. For this purpose,
see: (a) Potts, K. T.; Rochanapruk, T.; Coats, S. J.;
Hadjiarapoglou, L.; Padwa, A. J. Org. Chem. 1993, 58, 5040;
6
24. No coupling phenomenon was observed between protons H3
4
and H in these cases.
(
1
b) Padwa, A.; Coats, S. J.; Semones, M. A. Tetrahedron Lett.
993, 34, 5405.
25. For similar stereochemical considerations in isom u¨ nchnones
field, see: (a) Padwa, A.; Prein, M. J. Org. Chem. 1997, 62,
6842; (b) Potts, K. T.; Dery, M. O. J. Org. Chem. 1990, 55,
2884; For interesting review reports in this area, see: (c)
Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223; (d)
Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477 and
references cited therein.
26. For the synthesis of the triheterocyclic thiolactam 22, see: (a)
Benovskyf, P.; Stille, J. R. Tetrahedron Lett. 1997, 38, 8475;
(b) Gittos, M. W.; Robinson, M. R.; Verge, J. P.; Davies,
R. V.; Iddon, B.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1976, 33.
7
. (a) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; Grierson, D. S.
J. Org. Chem. 1992, 57, 5661; (b) Marek, D.; Wadouachi, A.;
Beaupere, D. Tetrahedron: Asymmetry 1997, 8, 3223; (c)
Marek, D.; Wadouachi, A.; Beaupere, D. Synthesis 1999,
839; (d) Berges, A. D.; Fan, J.; Devinck, S.; Liu, N.; Dalley,
N. K. Tetrahedron 1999, 55, 6759; (e) Berges, A. D.; Zang,
N.; Hong, L. Tetrahedron 1999, 55, 14251.
˚
. (a) Pemberton, N.; Aberg, V.; Almstedt, H.; Westermark, A.;
Almqvist, F. J. Org. Chem. 2004, 69, 7830; (b) Mitscher,
L. A. Chem. Rev. 2003, 105, 559.
8
9
. Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.;
Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161.
0. Kogure, N.; Nishiya, C.; Kitajima, M.; Takayama, H.
27. The betaines in b-carboline series, which could be isolated in
certain cases, were more stable in thermal conditions than
betaines formed above in pyrrolidinone, isoindolinone, and
indolinone rings.
28. For structures containing pyridone ring, see: (a) Mmutlane,
E. M.; Harris, J. M.; Padwa, A. J. Org. Chem. 2005, 70,
8055; (b) See also Ref. 25b as above; (c) Padwa, A.;
Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64, 8648;
(d) Wang, S.; Cao, L.; Shi, H.; Dong, Y.; Sun, J.; Hu, Y.
Chem. Pharm. Bull. 2005, 53, 67.
1
1
1
1
Tetrahedron Lett. 2005, 46, 5857.
1. Houghton, P. J.; Latiff, A.; Said, I. M. Phytochemistry 1991, 30,
347.
2. Jansen, K. L. R.; Prast, C. J. J. Ethnopharmacol. 1988, 23, 115
and references cited therein.
3. (a) Fischer, U.; Schneider, F.; Widmer, U. Eur. Pat. EP183994;
Chem. Abstr. 1986, 107, 134200b; (b) Fischer, U.; Mobler, H.;