A one-pot, three-component regiospecific synthesis of dispiropyrrolidines containing a thiophenone ring via 1,3-dipolar cycloaddition reactions of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2013.03.023

The synthesis of new dispiropyrrolidines containing a thiophenone ring has been achieved by a one-pot, three-component 1,3-dipolar cycloaddition reaction. Unsaturated thiophenone dipolarophiles were reacted with azomethine ylides, generated in situ from sarcosine and cycloketone derivatives (isatin, ninhydrin, acenaphthoquinone), to produce the corresponding cycloadducts in good yields (70-90%). The cycloaddition reaction was found to be highly regio- and diastereoselective.

Full text of DOI:10.1016/j.tetlet.2013.03.023

Tetrahedron Letters 54 (2013) 2520–2524
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A one-pot, three-component regiospecific synthesis of dispiropyrrolidines
containing a thiophenone ring via 1,3-dipolar cycloaddition reactions of
azomethine ylides
Firouz Matloubi Moghaddam a, , Mohammad Reza Khodabakhshi a, Zahra Ghahremannejad a,
⇑
Behzad Koushki Foroushani a, Seik Weng Ng b
a Laboratory of Organic Synthesis and Natural Products, Department of Chemistry, Sharif University of Technology, Azadi Street, PO Box 11155-9516, Tehran, Iran
b Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new dispiropyrrolidines containing a thiophenone ring has been achieved by a one-pot,
three-component 1,3-dipolar cycloaddition reaction. Unsaturated thiophenone dipolarophiles were
reacted with azomethine ylides, generated in situ from sarcosine and cycloketone derivatives (isatin, nin-
hydrin, acenaphthoquinone), to produce the corresponding cycloadducts in good yields (70–90%). The
cycloaddition reaction was found to be highly regio- and diastereoselective.
Received 15 December 2012
Revised 18 February 2013
Accepted 6 March 2013
Available online 21 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylide
Three-component reaction
1,3-Dipolar cycloaddition
Dispiropyrrolidine
Spiro oxindole
Multicomponent reactions are very appealing since they can be
utilized to prepare combinatorial structures with privileged prop-
erties.1 These types of reactions have advantages over conventional
linear syntheses, including reduced number of synthetic steps,
shorter reaction times, high degrees of atom economy and environ-
mental friendliness, which allow the preparation of diverse struc-
tures in a rapid and cost-effective manner.2
One the other hand, the 1,3-dipolar azomethine ylide cycloaddi-
tion reaction is a simple and very powerful tool for the construction
of pyrrolidine and spiropyrrolidine heterocycles.3 Spiropyrrolidine
compounds exhibit widespread biological activities such as anti-
convulsant,4 potential antileukaemic,5 local anaesthetic6 and anti-
viral.7 In addition, spiropyrrolidine oxindole skeletons also
demonstrate wide biological applications as antibacterial8 and anti-
viral9 agents as well as having local anaesthetic10 properties, and
they are found in the structures of natural alkaloids such as horsfil-
line, elacomine, MDM2-p53 and spirotryptostatine (Fig. 1). There-
fore, the synthesis of newly substituted spiropyrrolidine oxindole
derivatives11 has attracted the attention of synthetic organic
chemists.
thiophenone-based natural products, which exhibits antibiotic
activity against many species of pathogens including gram-positive
and gram-negative bacteria,12 mycobacterium tuberculosis13 and
the malaria parasite, Plasmodium falciparum.14 Thiolactomycin
NH
NMe
MeO
O
O
N
H
N
H
HO
elacomine
horsfiline
N
Me2N
O
O
H
O
H
N
NH
Cl
Cl
O
O
The thiophenone functionality is found in many compounds.
Thiolactomycin is one of the most important biologically active
N
H
N
H
MeO
spirotryptostatine A
MDM2-p53
⇑
Corresponding author. Tel.: +98 21 66165309; fax: +98 21 66012983.
E-mail address: matloubi@sharif.edu (F.M. Moghaddam).
Figure 1. Biologically important molecules containing a spiropyrrolidinyl oxindole
skeleton.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.023

F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2520–2524
2521
O
O
R1
R1
O
O
NH
R1
O
O
O
N
H
O
NMe
O
O
O
3a
O
3b
NMe
N
S
N
S
O
CH3NHCH2CO2H
CH3NHCH2CO2H
O
N
S
CO2Me
MeO2C
MeO2C
4a-d
2
5a-d
1a-d
O
O
CH3NHCH2CO2H
3c
R1
O
O
NMe
N
S
O
MeO2C
6a-d
Scheme 1. Synthesis of dispiropyrrolidine-containing thiophenone ring derivatives 4–6.
also exhibits inhibitory activity against fatty acid synthase FAS I
and FAS II systems.15
Table 2
Structures of synthesized compounds 5a–d
R1
R1
CH3NHCH2CO2H
2
O
S
MeO2C
5a-d
Table 1
O
O
O
N
CH3OH
Structures of synthesized compounds 4a–d
O
O
3 h , reflux
R1
R1
N
S
CH3NHCH2CO2H
N
NH
CO2Me
O
O
2
O
1a-d
O
O
O
CH3OH
O
O
3b
N
3 h , reflux
Entry
R1
Producta
Yieldb (%)
N
S
N
S
CO2Me
N
O
O
MeO2C
4a-d
H
1a-d
3a
O
Entry
R1
Producta
Yieldb (%)
O
O
NMe
1
2
3
4
H
86
91
82
87
NH
N
N
N
N
S
O
O
NMe
O
MeO2C
5a
1
H
82
N
N
S
O
Me
MeO2C
4a
O
O
O
NMe
Me
NH
Me
Br
Ph
O
S
MeO2C
4b
O
S
NMe
2
3
4
Me
87
77
80
O
MeO2C
5b
O
Br
Br
O
O
NH
O
NMe
O
S
MeO2C
4c
O
NMe
Br
S
N
N
O
MeO2C
5c
O
Ph
Ph
NH
O
O
O
O
O
NMe
NMe
Ph
S
S
O
O
MeO2C
4d
MeO2C
5d
a
a
The products were characterized by IR, NMR, MS and elemental analysis.
Isolated yield after recrystallization.
The products were characterized by IR, NMR, MS and elemental analysis.
Isolated yield after recrystallization.
b
b

2522
F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2520–2524
Table 3
To the best of our knowledge, this is the first report in which
Structures of synthesized compounds 6a–d
unsaturated thiophenones are employed as dipolarophiles in
cycloaddition reactions of azomethine ylides for the synthesis of
dispiropyrrolidines.
R1
R1
CH3NHCH 2CO2H
In continuation of our research devoted to the development of
cycloaddition reactions16 and the synthesis of heterocyclic sys-
tems,17 we herein report an efficient, highly atom-economic and
regioselective preparation of novel dispiropyrrolidine moieties con-
taining a thiophenone ring. The derivatives 4–6 were synthesized
via a one-pot, three-component reaction of methyl 2-[(Z)-4-aryl-5-
morpholino-3-oxo-2,3-dihydrothiophen-2-ylidene]acetate deriva-
tives 1, sarcosine 2 and various active cycloketones 3 (Scheme 1).
In the first step, we prepared starting materials 1a–d via the
reactions of thioacetomorpholides with dimethyl acetylenedicar-
boxylate (DMAD) in the presence of K2CO3 in toluene as the sol-
vent, according to the method developed in our laboratory.18
Next, we examined the three-component reaction of 1a and sar-
cosine (2) and isatin (3a) in various solvents including methanol,
toluene, tetrahydrofuran and acetonitrile under reflux conditions.
The best results were obtained by refluxing the mixture in metha-
nol to afford the dispiropyrrolidine oxindole 4a.
To investigate the scope of this procedure, we reacted
compounds 1a–d with sarcosine (2) and isatin (3a) to give the
derivatives 4a–d in good yields (Table 1).
To extend the applicability of the reaction to other cycloke-
tones, sarcosine (2) and ninhydrin (3b) were reacted with
substrates 1a–d under the same reaction to afford the derivatives
5a–d in good yields (Table 2).
Moreover, the reactions of 1a–d with acenaphthoquinone 3c
were accomplished to afford the derivatives 6a–d (Table 3).
The structures and regiochemistry of products 4–6 were charac-
terized by IR, 1H NMR and 13C NMR spectroscopy and by elemental
analysis.19 For example, the IR spectrum of cycloadduct 4a showed
characteristic absorptions at 3220, 1732, 1685, 1628 and 1544 cmꢀ1
corresponding to the NH amide, ester, oxindole ring carbonyl, thio-
phenone carbonyl and alicyclic double bond, respectively. In the 1H
NMR spectrum of 4a two singlets appeared at d 2.25 and 3.70 for
the –NCH3 and –OCH3 methyls, respectively. The methylene pro-
2
O
O
O
NMe
CH3OH
3 h , reflux
O
O
N
S
N
S
CO2Me
O
O
MeO 2C
1a-d
6a-d
3c
Producta
Entry
R1
Yieldb (%)
O
O
NMe
1
H
75
72
70
74
N
O
S
MeO2C
6a
Me
O
O
NMe
2
3
4
Me
N
O
S
MeO2C
6b
Br
O
O
NMe
Br
N
O
S
MeO2C
6c
Ph
O
O
NMe
tons of the –NCH2 of the pyrrolidine ring and the –CH proton
a
Ph
to the ester functional group occurred as three doublets of doublets
at d 3.83, 4.58 and 5.10, respectively, confirming the structure of
regioisomer 4a. In contrast, if the other possible regioisomer 40a
N
O
S
MeO2C
6d
had formed, the proton at the position
a to the ester would have
a
appeared as a singlet in the 1H NMR spectrum. In the 13C NMR
The products were characterized by IR, NMR, MS and elemental analysis.
Isolated yield after recrystallization.
b
spectrum of 4a, the two spiro quaternary carbons resonated at d
Figure 2. ORTEP diagrams of compounds 4c and 5a.

F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2520–2524
2523
H
N
O
O
NH
N
OH
O
S
N
O
H
O
N
O
Me
MeOH
-H2O
NMe
O
O
CO2Me
N
S
CO2Me
+
N
-CO2
O
O
O
N
pa
th
A
path B
H
O
N
NH
H
O
S
O
S
O
O
NH
NMe
NMe
N
N
O
O
MeO2C
MeO2C
4
Scheme 2. A plausible mechanism for the formation of compounds.
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74.6 and 81.3. Furthermore, there were three carbonyl carbons at d
171.4, 173.8 and 190.9 corresponding to the oxindole, ester and
thiophenone. Finally, the regio- and stereochemical outcome of
the cycloaddition reactions was unambiguously ascertained by sin-
gle crystal X-ray analysis of cycloadducts 4c and 5a (Fig. 2).20
A proposed reaction mechanism for the formation of the dispi-
ropyrrolidine oxindole containing thiophenone ring system using
4a as an example, is shown in Scheme 2. The mechanism involves
the formation of an azomethine ylide, formed via decarboxylative
condensation of isatin and sarcosin, which then undergoes 1,3-
dipolar cycloaddition with substrate 1 to produce the cycloadduct
4 via path A (Scheme 2).
In conclusion, we have described an efficient synthesis of dispi-
ropyrrolidine-containing thiophenone ring derivatives through a
one-pot, three-component reaction of azomethine ylides with
unsaturated thiophenone derivatives. This reaction has several
advantages, such as operational simplicity, high atom efficiency,
good yields, short reaction times and a catalyst-free procedure.
The reaction itself proceeds in a highly regio- and stereocontrolled
fashion.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.023.
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References and notes
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2000, 3815–4195.
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5417; (b) Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett.
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Tetrahedron Lett. 2000, 41, 6217; (d) Grigg, R.; Aly, M. F.; Sridharan, V.;
Thianpatangul, S. J. Chem. Soc., Chem. Commun. 1984, 182; (e) Nair, V.; Sheela, K.
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2005, 105, 2765–2809; (g) Bakthadoss, M.; Sivakumar, N.; Sharada, D. S.
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2005, 20, 245–250.
19. General procedure for the synthesis of dispiropyrrolidine-containing thiophenones
4–6: A mixture of (E)-3-benzylidene-indolin-2-one 1a–d (1 mmol), sarcosine 2
(98 mg, 1.2 mmol) and cycloketones (isatin, ninhydrin or acenaphtoquinone) 3
(1.2 mmol) was refluxed for 3 h in MeOH (7 ml). After completion of the
reaction as monitored by TLC, the solvent was removed under vacuum and the
residue was subjected to flash chromatography using petroleum ether/EtOAc
(1:2) as eluent. The product was crystallized from EtOH to afford the pure
product. Ethyl (3Sꢁ,300Rꢁ,40Sꢁ)-10-methyl-500-morpholin-4-yl-2,300-dioxo-1,2-
dihydro-300H-dispiro[indole-3,20-pyrrolidine-30,200-thiophene]-40-carboxylate
(4a). Yield: 82%, white powder, mp 220–222 °C; 1H NMR (500 MHz, CDCl3):
d = 2.25 (3H, s), 3.20–3.30 (4H, m), 3.45–3.55 (4H, m), 3.60–3.62 (1H, m), 3.70
4. (a) Jiang, H.; Zhao, J.; Han, X.; Zhu, S. Tetrahedron 2006, 62, 11008; (b) Coutouli-
Argyropoulou, E.; Lianis, P.; Mitakou, M.; Giannoulis, A.; Nowak, J. Tetrahedron

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F. M. Moghaddam et al. / Tetrahedron Letters 54 (2013) 2520–2524
(3H, s), 3.83 (1H, dd, J = 6.9, 8.8 Hz), 4.58 (1H, dd, J = 8.7, 10.9 Hz), 5.10 (1H, dd,
190.9; IR (KBr): 3220, 1732, 1685, 1628, 1544 cmꢀ1
27H27N3O5S: C, 64.14; H, 5.38; N, 8.31. Found: C, 64.05; H, 5.30; N, 8.44.
20. Crystallographic data for 4c and 5a have been deposited at the Cambridge
Crystallographic Data Centre, with the deposition numbers CCDC 911697 4c
and 911696 5a, respectively.
; Anal. Calcd for
J = 6.7, 11.1 Hz), 6.71 (2H, d, J = 7.6 Hz, Ar-H), 6.90–6.97 (2H, m, Ar-H), 7.12–
C
7.25 (3H, m, Ar-H), 7.68 (1H, d, J = 6.5 Hz, Ar-H), 8.71 (1H, s, NH); 13C NMR
(125 MHz, CDCl3): d = 35.4, 50.2, 51.5, 52.7, 53.7, 66.6, 74.6, 81.3, 109.6, 120.3,
125.9, 127.2, 128.9, 129.1, 130.4, 131.5, 132.0, 136.5, 137.4, 142.5, 171.4, 173.8,