Synthesis under moderate pressure of 3-imidazo[1,2-a]pyridinylidene pyrrol-2-ones

Article abstract of DOI:10.1016/j.tetlet.2016.04.093

Conversion of 3-imidazo[1,2-a]pyridinylidene furan-2-ones into their pyrrol-2-one analogues was achieved efficiently with high yields, using a solution of ammonium hydroxide under moderate pressure conditions. A NMR study showed that the compounds are mainly isolated as E isomers.

Full text of DOI:10.1016/j.tetlet.2016.04.093

Accepted Manuscript
Synthesis under moderate pressure of 3-imidazo[1,2-a]pyridinylidene pyrrol-2-
ones
Nicolas Masurier, Aurélien Lebrun, Damien Canitrot, Jean-Michel Chezal,
Emmanuel Moreau
PII:
S0040-4039(16)30467-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.093
TETL 47593
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 March 2016
20 April 2016
25 April 2016
Please cite this article as: Masurier, N., Lebrun, A., Canitrot, D., Chezal, J-M., Moreau, E., Synthesis under moderate
pressure of 3-imidazo[1,2-a]pyridinylidene pyrrol-2-ones, Tetrahedron Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2016.04.093
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis under moderate pressure of 3-
Leave this area blank for abstract info.
imidazo[1,2-a]pyridinylidene pyrrol-2-ones
Nicolas Masurier, Aurélien Lebrun, Damien Canitrot, Jean-Michel Chezal and Emmanuel Moreau,

1
Tetrahedron Letters
Synthesis under moderate pressure of 3-imidazo[1,2-a]pyridinylidene pyrrol-2-ones.
a,†
b
a
a
a,
Nicolas Masurier , Aurélien Lebrun , Damien Canitrot , Jean-Michel Chezal and Emmanuel Moreau 
a
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France. Inserm, U 990, F-
6
3000 Clermont-Ferrand, France. Centre Jean Perrin, F-63011 Clermont-Ferrand, France.
b
Institut des Biomolécules Max Mousseron (UMR5247 CNRS, UM, ENSCM), Laboratoire de Mesures Physiques, Place Eugène Bataillon, F-34095, Montpellier,
France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Conversion of 3-imidazo[1,2-a]pyridinylidene furan-2-ones into their pyrrol-2-one analogues
was achieved efficiently with high yields, using a solution of ammonium hydroxide under
moderate pressure conditions. A NMR study showed that the compounds are mainly isolated as
E isomers.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Perkin condensation
Imidazo[1,2-a]pyridine
Lactam
Pyrrolinone
Pressure
—
——

Corresponding author. Tel.: +33 4 73 15 08 06; e-mail: emmanuel.moreau@u-clermont1.fr
†
Present address : Institut des Biomolécules Max Mousseron (UMR5247 CNRS, UM, ENSCM), Faculté de Pharmacie 15, Avenue Charles
Flahault, F-34093 Montpellier, France.

2
Tetrahedron
Pyrrol-2-one derivatives are five-membered heterocyclic
studied using 3-formyl-IP
4
to access 3-imidazo
lactams, which exist under three tautomeric forms. 5H-pyrrol-2-
one (also known as 3-pyrrolin-2-one) and 3H-pyrrol-2-one (or 4-1
pyrrolin-2-one) are tautomers of 2-hydroxypyrrole (Figure 1).
According to the substituents introduced on the ring, one form
[1,2-a]pyridinylidene pyrrol-2-one derivatives (Scheme 1).
2
can be predominant or exclusive. Mainly due to the large
number of biological active natural product containing 3-
pyrrolin-2-one moieties (bilirubin, biliverdin, oteromycin,
1
microcolin B, etc) , this isomer has been extensively studied,
compared to the 4-pyrrolin-2-ones. However, compounds
incorporating such heterocycle in their structure have already
exhibited interesting chemical, physical and biological
3
properties. They can be considered as versatile synthetic blocks
and were used as intermediates in the synthesis of (i) highly
3b,c
substituted pyrroles, (ii) new dyes 3fwith fluorescent
3d,e
properties or (iii) organic semiconductors. The 4-pyrrolin-2-
one ring represents also an interesting pharmacophore, which is
known to possess vgarious biological activities: reducing
Scheme 1. Retrosynthetic pathways to access 3-imidazo[1,2-a]pyri-
dinylidene pyrrol-2-one derivatives 1.
3
3a,h,i
cholesterol
uptake,
anti-inflammatory,
antibiotic
3a,j-l
properties,
etc. This heterocycle is found for example in
The direct condensation between 5-phenyl-1H-pyrrol-2(3H)-
violacein, an alkaloid pigment produced by several marine
12
one 5 (R= Ph) and 3-formyl-IP 4 was studied using standard
4
bacteria. In this case, it acts as a chemically mediated resistance
Perkin conditions (i.e. one equivalent of sodium acetate in acetic
5
against predators of the aggressed bacteria. This alkaloid induces
3g,3l,9
anhydride at reflux, Scheme 1, way A).
However, even after
an eukaryotic cell death program and exhibits promising
prolonged heating, only starting materials were recovered.
6
anticancer activities.
Then, we turned out our attention to the second route (Scheme
1, way B), which consists to the conversion of furan-2-one
derivatives 2 (also named butenolides) into their corresponding
pyrrol-2-ones 1 upon treatment with an ammonia solution. These
furan-2-one precursors 2 could be obtained by condensation
between the 3-formyl-IP 4 and γ-ketobutanoic acids 3. Whereas
the reactivity of substituted benzaldehydes with 3-benzoyl-
3
e,3h-k
propionic acids is well documented,
been reported in azaheterocyclic series.
only one example has
13
Firstly, furan-2-one derivative 2a was obtained with a
moderate yield (45%) from 3-formyl-IP 4 and 4-oxo-4-
phenylbutanoic acid 3a after heating at 90°C in a mixture of
acetic anhydride and sodium acetate for 2h30 (Scheme 2). Then,
the conversion of the furan-2-one 2a into its lactam analogue 1a
was then performed. Compound 2a was heated at reflux in a
mixture of ammonium hydroxide/ethanol (1/10, v/v) under
atmospheric pressure as previously reported by A.Y. Egorova in
9
benzenic series. However, no lactam derivative was detected,
even if ammonium solution was frequently added during the
heating, in order to compensate the loss of ammonia. Compound
Figure 1. 2-Hydroxypyrrole, its tautomers and representative
examples of 4-pyrrolin-2-ones
2a was totally recovered at the end, whereas its benzenic
analogue 2a* (prepared with benzaldehyde instead of 3-formyl-
IP, see scheme 2) was totally converted into its corresponding
pyrrol-2-one derivative 1a* using the same experimental
conditions. We assume that the non conversion of 2a into 1a may
be due to the poor reactivity of 3-alkyl-substituted IP derivatives
as already reported by several groups. It seems that the presence
of the IP nucleus decreased the reactivity of the lactone and that
harsher conditions for its conversion are needed.
In an ongoing program concerning the development of new
original antitumour derivatives bearing an imidazo[1,2-
a]pyridine (IP) moiety, we explored the synthesis of 4-pyrrolin-
7
2
-ones connected to the IP nucleus (3-imidazo[1,2-
a]pyridinylidene pyrrol-2-ones). To our knowledge, the literature
reports very few studies involving the condensation of 4-pyrolin-
14
2
-ones in azaheterocyclic series and any with IP nucleus.
However this heterocycle is particularly attractive to design
8
pharmacological active compounds. Indeed, the IP core has
emerged as a privileged structure that has found many
8
a,b
8c-e
8f,g
applications in the CNS, and in anticancer, antiviral, anti-
8h,i
infectives, therapeutic areas.
In benzenic series, two principal methods were reported to
access such structures: the direct Perkin condensation of a
3g,3l,9
substituted 4-pyrrolin-2-one with an aldehyde derivative
and
the conversion of furan-2-ones into their pyrrol-2-one
3e,10,11
analogues.
In this manuscript, these two methods were

3
6
Figure 2 Structural assignment of compound 1a (DMSO d )
In the case of compound 1a, NOESY correlations between the
H-2 of the IP ring (8.64 ppm) and the pyrrol-2-one hydrogen
(6.98 ppm) proved the E configuration of 1a (Figure 2, green
arrow). In the same way, the NOESY correlations between H-5
of the IP ring (8.91 ppm) and the methylenic proton (7.52 ppm)
confirmed the stereochemistry (Figure 2, blue arrow). In the
1
3
analysis of the proton coupled C NMR spectrum, also
highlighted a coupling constant of 7.4 Hz between the methylenic
hydrogen and the carbonyl of compound 1a. This value is
consistent with the E configuration as previously observed by K.
17
Lackey et al. in benzylidene-1H-indol-2-one series. Similar
analysis was performed for compound 2a (data not shown).
In order to study the influence of the benzene substituents on
the antitumor activity in IP series, we suggested to develop others
derivatives 1 using this new methodology. Furthermore, only few
Scheme 2. Synthetic pathway to 3-imidazo[1,2-a]pyridinylidene
pyrrol-2-one derivatives 1a (for conditions, see Table 1).
3
-benzoylpropionic acids are commercially available. The
synthesis of further benzoyl derivatives was carried out, using a
Friedel-Crafts reaction, between 4-substituted benzenes 6b-d
Table 1. Pyrrol-2-ones 1a and 1a* produced via Scheme 2
a
b
d
(scheme 3, R = OMe, F, NHAc) and succinic anhydride in
1
Product
Conditions
% conversion
ratio
E/Z
t
R
E/Z
18
c
dichloroethane. The reaction was carried out with methoxy-
(6b) and fluorobenzene (6c) and offered the corresponding
benzoyl-propionic acids 3b and 3c, with 62% and 76% yields
respectively. Surprisingly, the reaction with 4-iodobenzene was
not successful, probably due to its poor solubility in the reaction
media (starting material was recovered). To prepare the iodo-
derivative, we developed a Friedel-Craft reaction with acetanilide
(compound 6d), which afforded 4-acetamidobenzoylpropionic
acid 7 with 67% isolated yield. The latter was converted into the
corresponding amine derivative, followed by a diazotation
reaction and treatment with an excess of potassium iodide. The 4-
iodobenzoylpropionic acid 3d was then obtained in 40% overall
yield. In the case of trimethoxybenzoylpropionic acid 3e, the
e
1
1
1
a*
a
a
A
A
B
100
0
100
100/0
-
98/2
nd
-
1.21/1.29
a
Conditions A: NH
atmospheric pressure, 24h. Conditions B: NH
NH OAc (1.1 equiv.), 90°C, 3 bars, 4h30.
Determined by HPLC at λ =214 nm
4
OH 28%/EtOH 1/10 v/v, NH
4
OAc (1.1 equiv.), reflux at
OH 28%/EtOH 1/10 v/v,
4
4
b
c
Determined by 1H NMR (integration of the H-2 signal of the IP cycle) and
1
6
by HPLC
d
Retention Time for diastereoisomers E/Z (min)
e
not determinate.
Then, we focused our efforts on the conversion of furan-2-one
derivative 2a into its pyrrol-2-one analogue 1a using a reactor
capable of withstanding high pressures and equipped with an
internal stirring system (see supporting information S27). Briefly,
the compound 2a was poured into an ammonium hydroxide
solution. After closing the reactor, it is heated to 90 ° C resulting
in an increase of the pressure up to 3 bars during 4h30, led to the
total conversion of the furan-2-one derivative leading to
19
procedure described by Hagget and Archer was used. With
these different benzoylpropionic acids in our hands, their
condensation with 3-formyl-IP 4 was then carried out. Furan-2-
ones 2b-e were obtained with moderate yields (26 to 45%, table
1
7
), except for the 4-methoxy derivative 2b which was isolated in
5% yield (Table 2).
15
compound 1a in 90% yield after purification.
Under moderate pressure atmosphere and in a mixture of
ammonia/ethanol, the desired 4-pyrrol-2-one 1b-e were afforded
1
The analysis of compounds 1a and 2a by LC-MS and H-
NMR showed the presence of a mixture of E/Z diastereoisomers
with a clear excess of the E form (>90%). These results are
significantly different than those obtained in benzene series, for
with good to excellent yields (60 to 93% isolated yields, Table
1
2
). The analysis of compounds 1 and 2 by LC-MS and H-NMR
showed the presence of a mixture of E/Z diastereoisomers with a
clear excess of the E form (>90%), except for 2b which was
isolated as a mixture of E/Z in a 74/26 ratio (Tables 1 and 2). It
3e,3h-k
which only E-isomer has been observed.
The
stereochemistry of compounds was investigated by NMR
analysis (Figure 2).

4
Tetrahedron
was noted that the mixture of isomers 2b was successfully
derivatives into their pyrrol-2-one analogues. These reaction
converted into 1b with a ratio E/Z (97/3).
conditions applied on several 3-imidazo[1,2-a]pyridinylidene
furan-2-one derivatives led to the corresponding pyrrol-2-ones,
with high conversion yields. Stereochemistry of all synthesized
compounds was determined by NOESY correlations. We also
observed that stereochemistry of isomer E can be determined by
measuring the coupling constant between the methylenic
hydrogen and the carbonyl of the pyrrol-2-one ring.
References and notes
1
2
3
.
.
.
Pelkey, E.T.; Pelkey, S.J.; Greger, J.G.
Heterocyclic Chemistry, Scriven, E. and Ramsden, C., Eds.;
Elsevier Science: New York, 2015, 115, 151-285.
Schoffield, K. In Hetero-Aromatic Nitrogen Compounds
Pyrroles and Pyridine, 1st ed.; Springer Science+Business Media
School New-York Ed. 1967
In Advances in
–
(a) Ali, Y.; Sharwar Alan, M.; Ali, Y. ; Alama, S.M. ; Hamida, H.
; Hussain, A. Orient. J. Chem. 2014, 30, 1-16; (b) Metten, B.;
Kostermans, M.; Van Baelen, G.; Smet, M.; Dehaen, W.
Tetrahedron 2006, 62, 6018-6028; (c) Abd El-Nabi, H. A.
Tetrahedron 2000, 56, 3013-3020; (d) Aysha, T.; Lunak Jr, S.;
Lycka, A.; Vynuchal, J.; Elias, Z.; Ruzicka, A.; Padelkova Z.;
Hrdina, R. Dyes Pigments 2013, 98, 530-539; (e) Bourotte, M.;
Schmitt, M.; Follenius-Wund, A.; Pigault, C.; Haiech, J.;
Bourguignon, J.-J. Tetrahedron Lett. 2004, 45, 6343-6348; (f) Cai,
Z.; Guo, Y.; Yang, S.; Peng, Q.; Luo, H.; Liu, Z.; Zhang, G.; Liu,
Y.; Zhang, D. Chem. Mater. 2013, 25, 471-478; (g) Cosner, C. C.;
Markiewicz, J. T.; Bourbon, P.; Mariani, C. J.; Wiest, O.; Rujoi,
M.; Rosenbaum, A. I.; Huang, A. Y.; Maxfield, F. R.; Helquist, P.
J. Med. Chem. 2009, 52, 6494-6498; (h) Alam, M. M.; Husain, A.;
Hasan, S. M.; Suruchi; Anwer, T. Eur. J. Med. Chem. 2009, 44,
Scheme 3 Synthesis of 3-benzoylpropionic acids 3
2
636-2642; (i) Husain, A.; Alam Mumtaz, M.; Siddiqui, N. J.
Serb. Chem. Soc. 2009, 74, 103-115; (j) Husain, A.; Khan, M. S.
Y.; Hasan, S. M.; Alam, M. M. Eur. J. Med. Chem. 2005, 40,
1
394-1404; (k) Husain, A.; Alam, M. M.; Shaharyar, M.; Lal, S. J.
Enz. Inhib. Med. Chem. 2010, 25, 54-61; (l) Fina, L.; Igor, D. G.;
Blanka, B. Arch. Pharm. 1990, 323, 901-904.
4
.
(a) Hakvag, S.; Fjaervik, E.; Klinkenberg, G.; Borgos, S. E.;
Josefsen, K.; Ellingsen, T.; Zotchev, S. Mar. Drugs 2009, 7, 576-
5
88; (b) Pantanella, F.; Berlutti, F.; Passariello, C.; Sarli, S.;
Morea, C.; Schippa, S. J. Applied Microbiol. 2007, 102, 992-999;
c) Yada, S.; Wang, Y.; Zou, Y.; Nagasaki, K.; Hosokawa, K.;
Osaka, I.; Arakawa, R.; Enomoto, K. Mar. Biotech. 2008, 10, 128-
32.
(
1
5
6
.
.
(a) Matz, C.; Webb, J. S.; Schupp, P. J.; Phang, S. Y.; Penesyan,
A.; Egan, S.; Steinberg, P.; Kjelleberg, S. PLoS ONE 2008, 3,
e2744; (b) Matz, C.; Deines, P.; Boenigk, J.; Arndt, H.; Eberl, L.;
Kjelleberg, S.; Jurgens, K. Appl. Environ. Microbiol. 2004, 70,
1
593-1599.
(a) Durán, N.; Justo, G. Z.; Ferreira, C. V.; Melo, P. S.; Cordi, L.;
Martins, D. Biotechnol Appl Biochem. 2007, 48, (Pt 3), 127-133;
Scheme 4 Synthesis of the IP-pyrrol-2-one derivatives 1
(b) Ferreira, C. V.; Bos, C. L.; Versteeg, H. H.; Justo, G. Z.;
Table 2. Substituted IP-furanones 2 and IP- pyrrol-2-ones 1 obtained
Duran, N.; Peppelenbosch, M. P. Blood 2004, 104, 1459-1464; (c)
Kodach, L. L.; Bos, C. L.; Duran, N.; Peppelenbosch, M. P.;
Ferreira, C. V.; Hardwick, J. C. H. Carcinogenesis 2006, 27, 508-
516.
(a) Chezal, J. M.; Papon, J.; Labarre, P.; Lartigue, C.; Galmier, M.
J.; Decombat, C.; Chavignon, O.; Maublant, J.; Teulade, J. C.;
Madelmont, J. C.; Moins, N. J. Med. Chem. 2008, 51, 3133-3144;
via Scheme 4.
Compound
c
R
1
R
2
R
3
Yield
Ratio
E/Z
R
t E/Z
a
b
(
%)
45
75
36
40
26
90
80
67
93
60
7
.
2
2
a
b
H
OMe
F
H
H
H
H
OMe
H
H
H
H
OMe
H
H
H
H
OMe
H
H
H
H
OMe
89/11
74/26
98/2
92/8
96/4
98/2
97/3
98/2
92/8
93/7
1.40/1.44
1.39/1.23
1.32/1.29
1.59/1.39
1.42/1.39
1.21/1.29
1.22/1.29
1.11/1.18
1.40/1.48
1.23/1.26
2
c
(b) Andaloussi, M.; Moreau, E.; Masurier, N.; Lacroix, J.;
2
d
I
Gaudreault, R. C.; Chezal, J.-M.; El Laghdach, A.; Canitrot, D.;
Debiton, E.; Teulade, J.-C.; Chavignon, O. Eur. J. Med. Chem.
2008, 43, 2505-2517; (c) Masurier, N.; Debiton, E.; Jacquemet,
A.; Bussiere, A.; Chezal, J. M.; Ollivier, A.; Tetegan, D.;
Andaloussi, M.; Galmier, M. J.; Lacroix, J.; Canitrot, D.; Teulade,
J. C.; Gaudreault, R. C.; Chavignon, O.; Moreau, E. Eur. J. Med.
Chem. 2012, 52, 137-150.
For recent examples, see: (a) Chen, C.-J.; Bando, K.; Ashino, H.;
Taguchi, K.; Shiraishi, H.; Fujimoto, O.; Kitamura, C.;
Matsushima, S.; Fujinaga, M.; Zhang, M.-R.; Kasahara, H.;
Minamizawa, T.; Jiang, C.; Ono, M.; Higuchi, M.; Suhara, T.;
Yamada, K.; Ji, B. Bioorg. Med. Chem. 2014, 22, 4189-4197; (b)
Callaghan, P. D.; Wimberley, C. A.; Rahardjo, G. L.; Berghofer,
P. J.; Pham, T. Q.; Jackson, T.; Zahra, D.; Bourdier, T.; Wyatt, N.;
Greguric, I.; Howell, N. R.; Siegele, R.; Pastuovic, Z.; Mattner, F.;
2
1
e
a
OMe
H
OMe
F
1
b
1
c
1
d
I
1
e
OMe
a
Isolated yield
8.
b
1
13
Determined by H NMR (integration of the H-2 signal of the IP cycle),
C
1
6
coupling NMR and HPLC
c
Retention Time for diastereoisomers E/Z (min)
In conclusion, we demonstrated that the use of a solution of
ammonium hydroxide under a pressure of 3 bars is a convenient
method to convertstereoselectively weakly reactive furan-2-one

5
Loc'h, C.; Gregoire, M. C.; Katsifis, A. Eur J Nucl Med Mol
Imaging 2015, 42, 138-151; (c) Gallud, A.; Vaillant, O.; Maillard,
L. T.; Arama, D. P.; Dubois, J.; Maynadier, M.; Lisowski, V.;
Garcia, M.; Martinez, J.; Masurier, N. Eur. J. Med. Chem. 2014,
19. Haggett, E.; Archer, S. J. Am. Chem. Soc. 1949, 71, 2255-2256.
7
5, 382-390; (d) Arama, D. P.; Soualmia, F.; Lisowski, V.;
Longevial, J. F.; Bosc, E.; Maillard, L. T.; Martinez, J.; Masurier,
N.; El Amri, C. Eur. J. Med. Chem. 2015, 93, 202-213; (e)
Hirayama, T.; Okaniwa, M.; Banno, H.; Kakei, H.; Ohashi, A.;
Iwai, K.; Ohori, M.; Mori, K.; Gotou, M.; Kawamoto, T.; Yokota,
A.; Ishikawa, T. J. Med. Chem. 2015, 58, 8036-8053; (f) Feng, S.;
Hong, D.; Wang, B.; Zheng, X.; Miao, K.; Wang, L.; Yun, H.;
Gao, L.; Zhao, S.; Shen, H. C. ACS Med. Chem. Lett. 2015, 6,
3
59-362; (g) Chezal, J.-M.; Paeshuyse, J.; Gaumet, V.; Canitrot,
D.; Maisonial, A. l.; Lartigue, C.; Gueiffier, A.; Moreau, E.;
Teulade, J.-C.; Chavignon, O.; Neyts, J. Eur. J. Med. Chem. 2010,
4
5, 2044-2047 ; (h) Pethe K.; Bifani P.; Jang J.; Kang S.; Park S.;
Ahn S.; Jiricek J.; Jung J.; Jeon H. K.; Cechetto J.; Christophe T.;
Lee H.; Kempf M.; Jackson M.; Lenaerts AJ.; Pham H.; Jones V.;
Seo MJ.; Kim Y. M.; Seo M.; Seo J. J.; Park D.; Ko Y.; Choi I.;
Kim R.; Kim S. Y.; Lim S.; Yim S. A.; Nam J.; Kang H.; Kwon
H.; Oh C. T.; Cho Y.; Jang Y.; Kim J.; Chua A.; Tan B. H.;
Nanjundappa M. B.; Rao S. P.; Barnes W. S.; Wintjens R.; Walker
J. R.; Alonso S.; Lee S.; Kim J.; Oh S.; Oh T.; Nehrbass U.; Han
S. J.; No Z.; Lee J.; Brodin P.; Cho S. N.; Nam K.; Kim J. Nat.
Med. 2013, 19, 1157-1160; (i) Jose, G.; Suresha Kumara, T. H.;
Nagendrappa, G.; Sowmya, H. B. V.; Sriram, D.; Yogeeswari, P.;
Sridevi, J. P.; Guru Row, T. N.; Hosamani, A. A.; Sujan
Ganapathy, P. S.; Chandrika, N.; Narendra, L. V. Eur. J. Med.
Chem. 2015, 89, 616-627.
9
1
.
Egorova, A. Y. Russ. Chem. Bull. Int. Ed. 2002, 51, 183-184.
0. (a) Yegorova, A.; Kamneva, I.; Shtykova, L. Russ. Chem. Bull.
Int. Ed. 2006, 55, 718-721; (b) Egorova, A. Y.; Nesterova, V. V.
Chem. Heterocycl. Compd. 2004, 40, 1002-1006.
1
1
1. (a) Rao, Y. S. Chem. Rev. 1976, 76, 625-694; (b) Schueler, F. W.;
Hanna, C. J. Am. Chem. Soc. 1951, 73, 3528-3530.
2. (a) Almirante, L.; Mugnaini, A.; De Toma, N.; Gamba, A.;
Murmann, W.; Hidalgo, J. J. Med. Chem. 1970, 13, 1048-1051;
(
b) Masurier, N.; Moreau, E.; Lartigue, C.; Gaumet, V.; Chezal, J.-
M.; Heitz, A.; Teulade, J.-C.; Chavignon, O. J. Org. Chem. 2008,
3, 5989-5992.
7
1
1
3. Hashem, A. I.; Youssef, A. S. A.; Kandeel, K. A.; Abou-Elmagd,
W. S. I. Eur. J. Med. Chem. 2007, 42, 934-939.
4. (a) Li, Z.; Sharma, U. K.; Liu, Z.; Sharma, N.; Harvey, J. N.; Van
der Eycken, E. V. Eur. J. Org. Chem. 2015, 2015, 3957-3962; (b)
Gudmundsson, K. S.; Johns, B. A. Org. Lett. 2003, 5, 1369-1372.
5. Typical Procedure: A reactor capable of withstanding high
pressures and equipped with an internal stirring system (see
supporting information S27) was charged with a solution of 0.69
mmol of furan-2-one (2a) in 150 mL of EtOH. Were then added
1
6
1
0 mg of freshly fused ammonium acetate (0.78 mmol, 1.1 eq) and
5 mL of ammonium hydroxide (25% in water). After closing the
reactor, it is heated to 90 ° C resulting in an increase of the
pressure up to 3 bars during 4h30. After cooling to room
temperature, the reactional medium was concentrated under
reduce pressure. 20 mL of water were added to the residue and the
suspension was filtered and finally washed with water (10 mL) to
offer
3-(imidazo[1,2-a]pyridin-3-ylmethylene)-5-phenyl)-1,3-
dihydro-2H-pyrrol-2-one as a mixture of E/Z diastereoisomers in a
1
9
8/2 ratio (1a). Red solid; mp >300°C (dec.); H NMR (600 MHz,
DMSO d ) of the main diastereoisomer E: δ = 6.96 (s, 1H), 7.11
dd, 1H, J = 6.8, 7.4 Hz), 7.40 (t, 1H, J = 7.4 Hz), 7.43-7.48 (m,
6
(
3
H), 7.50 (s, 1H), 7.72 (d, 1H, J = 8.9 Hz), 7.92 (d, 2H, J = 7.5
13
Hz), 8.60 (s, 1H), 8.89 (d, 1H, J = 6.8 Hz), 10.47 (s, 1H);
C
6
NMR (150 MHz, DMSO d ): δ = 92.3, 112.9, 113.8, 117.4, 122.7,
1
1
25.3, 125.4, 126.9, 127.0, 128.7, 129.2, 129.7, 137.9, 143.8,
46.7, 170.5; HPLC, tr = 1.21 min. MS (ESI+): m/z 288.1
14 3
[M+H]+; HRMS calcd for C18H N O 288.1137, found 288.1135.
1
6. Samples were analyzed by HPLC using an analytical Chromolith
Speed Rod RP-C18 185 Pm column (50x4.6 mm, 5 mm), a flow
rate of 3.0 mL/min and gradients of 100/0 to 0/100 eluents A/B
over
3
min, in which eluents A=H
2
O/0.1% TFA and
B=CH
3
CN/0.1% TFA. Detection was at 214 nm using a
Photodiode Array detector.
1
1
7. Lackey, K.; Cory, M.; Davis, R.; Frye, S. V.; Harris, P. A.;
Hunter, R. N.; Jung, D. K.; McDonald, O. B.; McNutt, R. W.;
Peel, M. R.; Rutkowske, R. D.; Veal, J. M.; Wood, E. R. Bioorg.
Med. Chem. Lett., 2000, 10, 223-226.
8. Srinivas, C.; Haricharan Raju, C. M.; Acharyulu, P. V. R. Org.
Process Res. Dev. 2004, 8, 291-292.

6
Tetrahedron
Highlights
1
) Conversion of 3-imidazopyridinylidene furan-2-
ones into their pyrrol-2-one analogues
) A reactor equipped with an internal stirring
system was used to manage the pressure
) A NMR study showed that the compounds are
mainly isolated as E isomers
2
3