Synthesis of 2,5-asymmetrically substituted 3,4-diaminothieno[2,3- b ]thiophenes by domino reaction

Article abstract of DOI:10.1021/co400069v

A convenient one pot synthesis of 2,5-asymmetrically substituted thieno[2,3-b]thiophenes is developed. The method is based on consecutive domino reactions (S_N2 reaction → Thorpe-Ziegler reaction) using malononitrile and carbon disulfide as starting materials with the generation of potassium 2,2-dicyanoethene-1,1-bis(thiolate) in a solution. The high yield of the target thienothiophenes was achieved using the Ziegler dilution effect.

Full text of DOI:10.1021/co400069v

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Article
Synthesis of 2,5-asymmetrically substituted 3,4-
diaminothieno[2,3-b]thiophenes by domino reaction.
Andrey Alexandrovich Zubarev, Natalia Andreevna Larionova, Lyudmila A
Rodinovskaya, Valery Yu. Mortikov, and Anatoliy Mikhailovich Shestopalov
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400069v • Publication Date (Web): 12 Sep 2013
Downloaded from http://pubs.acs.org on September 16, 2013
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Synthesis of 2,5ꢀasymmetrically substituted 3,4ꢀ
diaminothieno[2,3ꢀb]thiophenes by domino
reaction.
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Andrey A. Zubarev, Natalia A. Larionova, Lyudmila A. Rodinovskaya, Valery Yu. Mortikov and
Anatoliy M. Shestopalov*.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991
Moscow, Russian Federation.
KEYWORDS: thieno[2,3ꢀb]thiophenes, domino reaction, combinatorial synthesis, one pot
synthesis, Ziegler dilution effect.
ABSTRACT: A convenient one pot synthesis of 2,5ꢀasymmetrically substituted thieno[2,3ꢀ
b]thiophenes is developed. The method is based on consecutive domino reactions (SN2 reaction
→ ThorpeꢀZiegler reaction) using malononitrile and carbon disulfide as starting materials with
the generation of potassium 2,2ꢀdicyanoetheneꢀ1,1ꢀbis(thiolate) in a solution. The high yield of
the target thienothiophenes was achieved using the Ziegler dilution effect.
INTRODUCTION
Since the first report by Rudolf Gompper,1 the chemistry of 3,4ꢀdiaminothieno[2,3ꢀ
b]thiophenes has been intensively developed.1-15 This is due to the simplicity of the synthesis of
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these compounds via double alkylation of potassium 2,2ꢀdicyanoetheneꢀ1,1ꢀbis(thiolate). As a
rule, derivatives of bromoacetophenone, bromoacetic acid esters, chloroacetonitrile are used as
alkylating agents. The subsequent double ThorpeꢀZiegler heterocyclization results in the target
compounds.
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On the other hand, these compounds contain several reactive groups thus allowing the
synthesis of hetarylꢀsubstituted thienothiophenes and polyꢀfused heterocyclic systems.
Futhermore, diaminothienothiophenes and their derivatives show biological activity, i.e.
antiallergenic.3 The compounds are also effective “in vitro” against E. coli, S. aureus and
Aspergillus flavus, Fusarium axysporium.8 The basic steps of thienothiophenes chemistry
development and their practical use were described in a review.16 However, the diversity of
these compounds is not large enough, and consequently their biological activity is
insufficiently investigated.
First of all it is due to a limited set of methyleneꢀactive alkylating agents. Moreover, in most
cases thieno[2,3ꢀb]thiophenes are obtained by bisꢀalkylation of 2,2ꢀdicyanoetheneꢀ1,1ꢀ
bis(thiolate) yielding only 2,5ꢀsymmetrically substituted thienothiophenes. Only a few
thienothiophenes, containing different substituents in positions 2ꢀ and 5ꢀ have been
described.3,8,12 Generally, the synthesis of these compounds is multiꢀstep, requires isolation of
intermediates and total yields do not exceed 50 %. To increase yields of target compounds at
large scale, high dilution and long reagent addition times must be used. This method described
for synthesis of macrocycles17-19 to increase yields of products of intraꢀmolecular reactions. We
found that the method increased the regioꢀselectivity of the interꢀmolecular alkylation of 2,2ꢀ
dicyanoetheneꢀ1,1ꢀbis(thiolate).
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RESULTS AND DISCUSSION
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The basic problem in synthesis of asymmetrically substituted thienothiophenes, using various
alkylating agents, is the bisꢀalkylation reaction, lowering yields of target products and
affording a mixture of 2,5ꢀ substituted thieno[2,3ꢀb]thiophenes which are difficult to separate.
The present work is aimed at developing an effective method of synthesis 2,5ꢀ
asymmetrically substituted 3,4ꢀdiaminothieno[2,3ꢀb]thiophenes without isolation of
intermediates. Originally, we tried to use standard methods1 for synthesis of asymmetrically
substituted thienothiophenes. As starting compounds, malononitrile, carbon disulphide and
bromacetophenone were used. To the diluted aqueous ethanolic solution of potassium 2,2ꢀ
dicyanoetheneꢀ1,1ꢀbis(thiolate), obtained by the described technique,20 a solution of an
equimolar amount of bromacetophenone in a minimal quantity of ethanol was added within 30
minutes. Then an equimolar amount of КОН was added and the reaction mixture was heated to
boiling, diluted with water and acidified by an equimolar amount of HBr. During the reaction
both monoꢀ and bisꢀalkylation of the diꢀpotassium salt occurs. However, in the first case a
soluble monoꢀpotassium salt of 5ꢀmercaptothiophene is formed, while the product of bisꢀ
alkylation is transformed in insoluble symmetric thienothiophene. Yields of the byꢀproduct
(symmetric thienothiophene) is 30ꢀ35 %, however it can be filtered off, and the mother solution
is used for reaction with another alkylating reagent. The subsequent cyclization results in target
asymmetrical thienothiophenes, however their yields are only moderate (about 50 %). Attempts
of using the monoꢀpotassium salt, instead of the diꢀpotassium one, did not improve the
situation because the yields of symmetric thienothiophenes were 45ꢀ50 %.
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To increase a regioselectivity of the first alkylation of diꢀpotassium salt 2 we resorted to the
dilution effect. It has been found, that use of the diluted solutions of diꢀpotassium salt 2 and the
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αꢀhalogenmethylcarbonyl compounds 3 and increasing the time of addition of the solution 3 up
to 5ꢀ6 h for the first alkylation step reduced the formation of the byꢀproduct to less than 10 %.
The yields of the targeted asymmetrical thienothiophenes increased to 60ꢀ85% (Scheme 1,
Table 1).
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Figure 1. Diversity of αꢀhalogenmethylcarbonyl compounds 3 and 6.
Thus, we have developed a convenient, highly selective method of synthesis of 2,5ꢀ
asymmetrically substituted 3,4ꢀdiaminothieno[2,3ꢀb]thiophenes 8{1ꢀ4, 1ꢀ20} using simple,
readily available starting compounds without the isolation of any intermediates. As the primary
alkylating agents 3, bromoacetophenones 3{1ꢀ3, 5} and Nꢀsubstituted chloroacetamide 3{4}
were used. αꢀHalogenmethylcarbonyl compounds 6{1ꢀ20} with different substituents from
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compounds 3 were used as the second alkylating agents. The synthetic method developed is
even more convenient since the solution obtained after filtration was used in a combinatorial
synthesis of asymmetrical thienothiophenes.
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Scheme 1. Synthesis of 2,5ꢀasymmetrically substituted thieno[2,3ꢀb]thiophenes 8.
Table 1. Thieno[2,3ꢀb]thiophenes 8.
Entry Product
R1
Ph
Ph
R2
Yield, %
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1
2
8{1, 6}
8{1, 7}
4ꢀFꢀC6H4ꢀ
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77
84
73
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3
4
5
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7
8{1, 8}
8{2, 6}
8{2, 9}
8{2, 8}
8{2, 7}
Ph
Me
4ꢀMeC6H4ꢀ
4ꢀMeC6H4ꢀ
4ꢀMeC6H4ꢀ
4ꢀMeC6H4ꢀ
4ꢀFꢀC6H4ꢀ
3,4ꢀ(MeO)2C6H3ꢀ
Me
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59
53
8
9
10
8{2, 10}
8{2, 11}
8{3, 7}
4ꢀMeC6H4ꢀ
4ꢀMeC6H4ꢀ
4ꢀBrC6H4ꢀ
3,4ꢀMe2ꢀC6H3NHꢀ
2,5ꢀ(MeO)2C6H3NHꢀ
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11
12
8{3, 1}
8{3, 2}
4ꢀBrC6H4ꢀ
4ꢀBrC6H4ꢀ
Ph
4ꢀMeC6H4ꢀ
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Me
Me
Me
Me
Me
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63
80
73
74
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8{4, 12}
8{4, 11}
8{4, 13}
8{4, 14}
8{4, 15}
(CH2)2CHNHꢀ
O
H
N
Cl
Cl
Cl
Cl
Cl
Me
O
2,5ꢀ(MeO)2C6H3NHꢀ
4ꢀ(MeCO)C6H4NHꢀ
3ꢀClꢀC6H4NHꢀ
4ꢀFꢀC6H4NHꢀ
Ph
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H
N
Me
O
H
N
Me
O
H
N
Me
O
H
N
Me
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8{5, 1}
8{5, 7}
3,4,5ꢀ(MeO)3C6H2ꢀ
3,4,5ꢀ(MeO)3C6H2ꢀ
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8{5, 3}
8{5, 16}
8{5, 9}
8{5, 17}
3,4,5ꢀ(MeO)3C6H2ꢀ
3,4,5ꢀ(MeO)3C6H2ꢀ
3,4,5ꢀ(MeO)3C6H2ꢀ
3,4,5ꢀ(MeO)3C6H2ꢀ
4ꢀBrC6H4ꢀ
4ꢀ(MeO)C6H4ꢀ
3,4ꢀ(MeO)2C6H3ꢀ
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8{5, 18}
3,4,5ꢀ(MeO)3C6H2ꢀ
68
77
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26
8{5, 19}
8{5, 20}
3,4,5ꢀ(MeO)3C6H2ꢀ
3,4,5ꢀ(MeO)3C6H2ꢀ
2,4ꢀF2ꢀC6H3NHꢀ
(CH2)2CHNHꢀ
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8{5, 12}
3,4,5ꢀ(MeO)3C6H2ꢀ
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It is known, that (3ꢀaminothiophenꢀ2ꢀyl)(3,4,5ꢀtrimethoxyphenyl)methanone derivatives, as
heterocyclic analogues of phenstatin, show anticancer activity.21-28 However, at present,
analogous containing heterocycle fused to thiophene ring are not known.
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Scheme 2. (3,4,5ꢀTrimethoxyphenyl)methanones 8{5, 1ꢀ20}.
Using the method developed, we synthesized (3,4ꢀdiaminoꢀ5ꢀsubstitutedꢀthieno[2,3ꢀ
b]thiophenꢀ2ꢀyl)(3,4,5ꢀtrimethoxyphenyl)methanones 8{5, 1ꢀ20} (Table 1), containing various
substituents at 5 position in high yields (Scheme 2). Also, in the present work a method of
synthesizing thienothiophenic analogous of phenstatin is reported for the first time.
CONCLUSION
The convenient one pot method of synthesis of 2,5ꢀasymmetrically substituted thieno[2,3ꢀ
b]thiophenes is developed using two consecutive domino reactions (SN2 reaction → Thorpeꢀ
Ziegler reaction). The potassium 2,2ꢀdicyanoetheneꢀ1,1ꢀbis(thiolate), generated in a solution
from malononitrile and carbon disulfide is used as a starting reagent. High selectivity of
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synthesis of the target thienothiophenes was possible to achieve using the RuggliꢀZiegler
dilution effect.
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The combinatorial method developed allowed for easy preparation of a wide set of
asymmetrically substituted thienothiophenes and has been used for the synthesis of
thienothiophenic analogues of phenstatin.
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EXPERIMENTAL PROCEDURES
The 1H NMR spectra were recorded on a “Bruker AM300” (300.13 MHz) using DMSO d6 as
the solvent, a chemical shifts were reported in ppm (δ) and coupling constants (J) values were
13
given in Hertz (Hz). The C NMR spectra were recorded on a “Bruker AM300” (75.47 MHz)
and “Bruker AV 600” (151 MHz) using DMSO d6 as the solvent. The IR spectra recorded on a
“Bruker Alpha” in KBr pellets. Melting points measured on Kofler bench.
Synthesis of thienothiophenes 8. General Procedure.
To solution of 1.4 g (25 mmol) KOH in 50 mL EtOH at 10 0C the malononitrile (1)1.65 g (25
mmol) was added and stirred until dissolution. To the obtained solution CS2 1.5 mL (25 mmol)
and then solution KOH 1.4 g (25 mmol) in 50 mL EtOH were added and stirred for 20 min. To
the reaction mixture 20 mL of H2O was added to dissolve the precipitate. To the resulting
solution (total volume 120 mL) 25 mmol of appropriate alkylating agent 3{1ꢀ5} in 70 ml of
EtOH was added dropꢀwise over 5 h, then solution KOH 1.4 g (25mmol) in 10 mL of H2O was
added and heated up to reflux. To the cooled solution 35 mL of H2O and 2.8 mL (25 mmol) of
concentrated HBr were added and stirred for 30 min before the precipitate was filtered off. The
obtained solution was divided into 5 equal portions and to each portion an appropriate
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alkylhalogenide 6{1ꢀ20} (4.7 mmol) was added and stirred for 10 min. To the solution 1.25 mL
of 20% KOH in water was added and heated to reflux, then cooled down and the precipitate
was filtered off. The thienothiophenes 8 were obtained as pure products, without additional
purification, in 50ꢀ85% yields. (Table 1).
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ASSOCIATED CONTENT
Supporting Information
Further details on the experimental procedures and spectra are given.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Fax: +7(499)135ꢀ5328. Eꢀmail: amsh@ioc.ac.ru
REFERENCES
(1) Gompper, R.; Kutter, E.; Töpfl, W. Neue thiophene und thieno[2,3ꢀb]thiophene.
Justus Liebigs Ann. Chem. 1962, 659, 90 – 101.
(2) Gompper, R. Novel reactions of ambident sulphur compounds. Phosphorus,
Sulfur, Relat. Elem. 1985, 23, 223 – 252.
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(3) Briel, D. New ring systems starting from thiopheneꢀ2ꢀthiolates ꢀ Synthesis and
5
6
7
biological activity. Pharmazie. 1990, 45, 895 – 899.
8
9
(4) Wobig, D. Reaktionen von Dinatriumꢀdicyandithioacetat und Natriumꢀ
dicyanthioacetamiden mit γꢀBromcrotonsaeureꢀDerivaten. Liebigs Ann. Chem.
1990, 1, 115 – 117.
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12
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14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
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35
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56
57
58
59
60
(5) ElꢀShafei, A. K.; AbdelꢀGhany, H. A.; Sultan, A. A.; ElꢀSaghier, A. M. M.
Synthesis of thieno(2,3ꢀb)thiophenes and related structures. Phosphorus, Sulfur,
Silicon, Relat. Elem. 1992, 73, 15 – 26.
(6) ElꢀShafei, A. K.; ElꢀSaghier, A. M. M.; Sultan, A.; Soliman, A. M. Synthesis of
polyfused heterocyclic systems derived from functionally substituted thieno[2,3ꢀ
b]thiophene moiety. Phosphorus, Sulfur, Silicon, Relat. Elem. 1992, 72, 73 – 80.
(7) Artyomov, V. A.; Rodinovskaya, L. A.; Shestopalov, A. M.; Litvinov, V. P. Nꢀ
Cyanochloroacetamidine ꢀ a Convenient Reagent for the Regioselective Synthesis
of Fused Diaminopyrimidines. Tetrahedron. 1996, 52, 1011 – 1026.
(8) Khalil, Z. H.; Yanni, A. S.; Gaber, A. M.; AbdelꢀMohsen, Sh. A. Synthesis and
Reactions of Some New 5ꢀCarbonyl(4ꢀaminoꢀ3ꢀcyanoꢀ2ꢀsubstituted thiopheneꢀ5ꢀ
yl)ꢀ8ꢀhydroxyquinoline as Possible Antimicrobial Agents. Phosphorus, Sulfur,
Silicon, Relat. Elem. 2000, 162, 65 – 80.
(9) Khodairy, A.; AbdelꢀGhany, H. Synthesis of Polyfused Thieno(2,3ꢀb)thiophenes.
Phosphorus, Sulfur Silicon, Relat. Elem. 2000, 162, 259 – 274.
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(10) Comel, A.; Kirsch, G. Efficient One Pot Preparation of Variously Substituted
5
6
7
Thieno[2,3ꢀb]thiophene. J. Heterocycl. Chem. 2001, 38, 1167 – 1172.
8
9
(11) Fedorov, A. E.; Shestopalov, A. M.; Belyakov, P. A. Reactions of (S)ꢀNꢀ
trifluoroacetylꢀ5ꢀbromoꢀ4ꢀoxonorvaline methyl ester with vicinal mercaptonitriles.
Synthesis of δꢀhetarylꢀsubstituted αꢀamino acids. Russ. Chem. Bull. 2003, 52, 2063
– 2069.
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60
(12) Sommen, G.; Comel, A.; Kirsch, G. A Convenient Synthesis of 2,3,4,5ꢀ
Functionalized Thieno[2,3ꢀb]thiophenes. Synthesis. 2003, 5, 735 – 741.
(13) Blanco, G.; Quintela, J. M.; Peinador, C. Synthesis of new heteroaromatic
nitrogen ligands: pyrimido[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2ꢀd]pyrimidines and
1,2,3ꢀtriazine[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2ꢀd]ꢀ1,2,3ꢀtriazines.
J.
Heterocycl. Chem. 2006, 43, 1051 – 1056.
(14) ElꢀSaghier, A. M. M.; Makhlouf, M. A.; Farhat, M. F. 1,4ꢀDiazepines Bearing
Thieno[2,3ꢀb]thiophene and Cyclohexene Carboxylate Moieties. Phosphorus,
Sulfur, Silicon, Relat. Elem. 2006, 181, 1569 – 1582.
(15) Liu, M.ꢀG.; Hu, Y.ꢀG.; Ding, M.ꢀW. New iminophosphoraneꢀmediated synthesis
of thieno[3',2':4,5]thieno[3,2ꢀd]pyrimidinꢀ4(3H)ꢀones and 5Hꢀ2,3ꢀdithiaꢀ5,7ꢀdiazaꢀ
cyclopenta[c,d]indenes. Tetrahedron. 2008, 64, 9052 – 9059.
(16) Litvinov, V. P. The Chemistry of Thienothiophenes. Edit. Katritcky A. Adv. Het.
Chem. 2006, 90, 125 – 203.
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ACS Combinatorial Science
Page 12 of 15
1
2
3
4
5
6
7
8
9
(17) Ziegler, K.; Eberle, H.; Ohlinger, H. Über vielgliedrige Ringsysteme. I. Die
präparativ ergiebige Synthese der Polymethylenketone mit mehr als 6
Ringgliedern. Justus Liebigs Ann. Chem. 1933, 504, 94 – 130.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) Höcker, H. Cyclic and Macrocyclic Organic Compounds – a Personal Review in
Honor of Professor Leopold Ruzichka. Cycl. Macrocycl. Org. Compounds, Kem.
Ind. 2009, 58, (2), 73–80.
(19) Tietze, L. F.; Eicher, T.; Diederichsen, U.; Speicher, A. Reactions and Syntheses
in the Organic Chemistry Laboratory. Wiley VCH Verlag, 2008, 582.
(20) Shestopalov, A. M.; Rodinovskaya, L. A.; Shestopalov, A. A. Combinatorial
Synthesis of Substituted Thieno[3,2ꢀb]pyridines and Other Annulated
Heterocycles via New SN2 → ThorpeꢀZiegler → ThorpeꢀGuareschi Domino
Reactions. J. Comb. Chem., 2010, 12, 9 – 12.
(21) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; CruzꢀLopez, O.; Tolomeo, M.;
Grimaudo, S.; Cristina, A. D.; Pipitone, M. R.; Balzarini, J.; Brancale, A.; Hamel,
E. Substituted 2ꢀ(3',4',5'ꢀtrimethoxybenzoyl)ꢀbenzo[b] thiophene derivatives as
potent tubulin polymerization inhibitors. Bioorg. Med. Chem. 2010, 18, 5114 –
5122.
(22) Romagnoli, R.; Baraldi, P. G.; Cara, C. L.; Hamel, E.; Basso, G.; Bortolozzi, R.;
Viola, G. Synthesis and biological evaluation of 2ꢀ(3',4',5'ꢀ trimethoxybenzoyl)ꢀ3ꢀ
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Page 13 of 15
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2
3
4
aryl/arylaminobenzo[b]thiophene derivatives as a novel class of antiproliferative
5
6
7
agents. Eur. J. Med. Chem. 2010, 45, 5781 – 5791.
8
9
(23) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Casolari, A.; Hamel,
E.; Fabbri, E.; Gambari, R. Synthesis and evaluation of haloacetyl, αꢀ
bromoacryloyl and nitrooxyacetyl benzo[b]furan and benzo[b]thiophene
derivatives as potent antiproliferative agents against leukemia l1210 and K562
cells. Lett. Drug Design Discovery. 2010, 7, 476 – 486.
10
11
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15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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43
44
45
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47
48
49
50
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53
54
55
56
57
58
59
60
(24) Romagnoli, R.; Baraldi, P. G.; Sarkar, T.; Carrion, M. D.; Cara, C. L.; Cruzꢀ
Lopez, O.; Preti, D.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Cristina, A. D.
Synthesis and Biological Evaluation of 1ꢀMethylꢀ2ꢀ(3',4',5'ꢀtrimethoxybenzoyl)ꢀ3ꢀ
aminoindoles as a New Class of Antimitotic Agents and Tubulin Inhibitors. J.
Med. Chem. 2008, 51, 1464 – 1468.
(25) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; CruzꢀLopez, O.; Lopez, C. C.;
Sarkar, T.; Tolomeo, M.; Grimaudo, S. D.; Cristina, A.; Pipitone, M. R.; Balzarini,
J.; Hamel, E.; Gambari, R.; Ilaria, L.; Saletti, R.; Brancale, A. Synthesis and
biological evaluation of 2ꢀ(3',4',5'ꢀtrimethoxybenzoyl)ꢀ3ꢀN,Nꢀdimethylamino
benzo[b]furan derivatives as inhibitors of tubulin polymerization. Bioorg. Med.
Chem. 2008, 16, 8419 – 8426.
(26) Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cara, C. L.; Preti, D.; Fruttarolo,
F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Cristina, A. D.
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5
6
7
8
9
Synthesis and Biological Evaluation of 2ꢀ and 3ꢀAminobenzo[b]thiophene
Derivatives as Antimitotic Agents and Inhibitors of Tubulin Polymerization. J.
Med. Chem. 2007, 50, 2273 – 2277.
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
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43
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45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(27) Romagnoli, R.; Baraldi, P. G.; Remusat, V.; Carrion, M. D.; Cara, C. L.; Preti,
D.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.
Synthesis and Biological Evaluation of 2ꢀ(3',4',5'ꢀTrimethoxybenzoyl)ꢀ3ꢀAmino 5ꢀ
Aryl Thiophenes as a New Class of Tubulin Inhibitors. J. Med. Chem. 2006, 49,
6425 – 6428.
(28) Romagnoli, R.; Baraldi, P. G.; Jung, M. K.; Iaconinoto, M. A.; Carrion, M. D.;
Remusat, V.; Preti, D.; Tabrizi, M. A.; Francesca, F.; Clercq, E. D.; Balzarini, J.;
Hamel, E. Synthesis and preliminary biological evaluation of new antiꢀtubulin
agents containing different benzoheterocycles. Bioorg. Med. Chem. Lett. 2005, 15,
4048 – 4052.
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For Table of Contents Use Only
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Synthesis of 2,5ꢀasymmetrically substituted 3,4ꢀdiaminothieno[2,3ꢀb]thiophenes by domino
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reaction.
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Andrey A. Zubarev, Natalia A. Larionova, Lyudmila A. Rodinovskaya, Valery Yu. Mortikov and
Anatoliy M. Shestopalov*.
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