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N
N
R1
N
R1
R
CHO
condensation
N
N
N
H2O
R
I
+
R
-H2O
NC
I
I
CO2Et
OHCHN
CO2Et
CN
CO2Et
R1
CO2Et
NCHO
CO2Et
NCHO
N
R1
N
N
CuI
N
R
Cu
Cu
I
R
N
I
I
I
N
R1
N
CO2Et
R1
N
CO2Et
N
N
H
R
CHO
R
Figure 2. Plausible mechanism for the formation of pyrrolo-fused pyrazoles.
Mechanistically, first the condensation reaction between the
aldehyde and ethylisocyanoacetate takes place followed by addi-
tion of water to the isonitrile moiety. Subsequent Cu-mediated
C–N cross coupling and deformylation afforded the pyrrolo-fused
pyrazole (Fig. 2). We presume that here too the Cu-catalyzed cou-
pling reaction was successful because it was intramolecular in
nature.
In summary, we have demonstrated the synthesis of a variety of
pyrrolo-fused pyrazoles from halogenated pyrazolecarbaldehydes
via a Cu-mediated cascade process in one-step. The strategy is ver-
satile as all types of halogenated pyrazoles irrespective of substitu-
tions and type of halogen gave products in comparable yields.
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˙
ˇ
G.; Šackus, A.; Holzer, W. Eur. J. Org. Chem. 2011, 5123–5133; (e) Guillou, S.;
ˇ
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Acknowledgments
Two of the authors (M.N. and H.B.) acknowledge the financial
support in the form of fellowship from CSIR, New Delhi. Authors
gratefully acknowledge the SAIF Division for providing the spectro-
scopic and analytical data.
6. Cai, Q.; Li, Z.; Wei, J.; Ha, C.; Pei, D.; Ding, K. Chem. Commun. 2009, 7581–7583.
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Supplementary data
9. General procedure as exemplified for the synthesis of ethyl 2,3-diphenyl-2,4-
dihydropyrrolo[3,2-c]pyrazole-5-carboxylate (Table 2, entry 1): To a solution of 4-
iodo-1,5-diphenyl-1H-3-pyrazolecarbaldehyde (250 mg, 0.67 mmol) and
ethylisocyanoacetate (0.073 mL, 0.67 mmol) in DMF (4 mL), Cs2CO3 (434 mg,
1.34 mmol) and CuI (25 mg, 0.0134 mmol) were added and the reaction mixture
was heated at 90 °C for 12 h under nitrogen atmosphere. Thereafter, water
(50 mL) and EtOAc (25 mL) was added and the reaction mass was passed
through a Celite bed and the layers were separated. The aqueous layer was
further extracted with EtOAc (2 Â 20 mL) and the collected organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography of the crude product over silica gel furnished
the pure ethyl 2,3-diphenyl-2,4-dihydropyrrolo[3,2-c]pyrazole-5-carboxylate as
Supplementary data (synthetic procedures, spectroscopic data
of remaining compounds and copies of 1H and 13C NMR of all com-
pounds) associated with this article can be found, in the online ver-
References and notes
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Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon: London, 2008; Vol. 4, p 1; (b)
Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Pyrazoles as Drugs Facts and
Fantasies In Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry: Roma, 2002; Vol. 6, pp 52–98; (c) Marinozzi, M.;
Carotti, A.; Sansone, E.; Macchiarulo, A.; Rosatelli, E.; Sardella, R.; Natalini, B.;
Rizzo, G.; Adorini, L.; Passeri, D.; De Franco, F.; Pruzanski, M.; Pellicciari, R.
Bioorg. Med. Chem. 2012, 20, 3429–3445; (d) Dow, R. L.; Carpino, P. A.; Gautreau,
D.; Hadcock, J. R.; Iredale, P. A.; Kelly-Sullivan, D.; Lizano, J. S.; O’ Connor, R. E.;
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a
white solid (EtOAc:hexanes, 1:9; yield: 166 mg, 75 %). Mp 192–194 °C;
Rf = 0.61 (EtOAc:hexanes, 30:70, v/v); m ;
max (KBr) 1699 (CO2Et), 3067 (NH) cmÀ1
1H NMR (CDCl3, 300 MHz) d = 1.42 (t, 3H, J = 7.1 Hz, CH3), 4.42 (q, 2H, J = 7.1 Hz,
CH2), 7.02 (d, 1H, J = 0.9 Hz, ArH), 7.28–7.31 (m, 2H, ArH), 7.34–7.45 (m, 8H,
ArH), 8.27 (s, 1H, NH); 13C NMR (CDCl3, 50 MHz) d = 14.5, 61.4, 100.1, 122.8,
125.9, 127.9, 128.0, 128.5, 128.6, 129.0, 129.1, 129.8, 134.4, 141.1, 149.0, 162.3;
mass (ES+) m/z = 332.2; ESI-HRMS Calcd for C20H18N3O2[MH]+: 332.1399. Found
332.1399.