One-pot synthesis of spiro pyrroloimidazoles and 2-arylimidazoles from 1,2-diaza-1,3-butadienes and arylamidines

Article abstract of DOI:10.1055/s-2007-984508

1,2-Diaza-1,3-butadienes react as Michael acceptors with nitrogen 1,3-dinucleophiles, such as arylamidines, in a one-pot heterocyclization reaction. Depending on the nature of the acyl residue at the terminal carbon of the heterodiene system, spiro pyrrol

Full text of DOI:10.1055/s-2007-984508

LETTER
1691
One-Pot Synthesis of Spiro Pyrroloimidazoles and 2-Arylimidazoles from
1
,2-Diaza-1,3-butadienes and Arylamidines
a
b
a
a
a
a
One-Pot Synthesis
r
of Spiro
a
Pyrroloim
z
idazoles an
i
2-Ary
o
limidazoles A. Attanasi, Gianluca Giorgi, Gianfranco Favi, Paolino Filippone, Samuele Lillini, Francesca R. Perrulli,
a
Stefania Santeusanio*
a
Istituto di Chimica Organica della Facoltà di Scienze e Tecnologie, Università degli Studi di Urbino ‘Carlo Bo’,
Via Sasso 75, 61029 Urbino, Italy
E-mail: santeusanio@uniurb.it
b
Dipartimento di Chimica, Università degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
Received 19 February 2007
H
O
Abstract: 1,2-Diaza-1,3-butadienes react as Michael acceptors
with nitrogen 1,3-dinucleophiles, such as arylamidines, in a one-pot
heterocyclization reaction. Depending on the nature of the acyl
residue at the terminal carbon of the heterodiene system, spiro
pyrroloimidazole derivatives or 2-arylimidazoles can be obtained.
N
N
OR1
R2
+
N
H2N
Ar
O
1
a–i
2a,b
2
a Ar = Ph
Key words: 1,2-diaza-1,3-butadienes, arylamidines, nucleophilic
2b Ar = p-MeOC6H4
additions, cyclizations, spiro compounds
i) DIPEA, THF, r.t.
ii) ∆
1
The electronic features of 1,2-diaza-1,3-butadienes de-
equimolar ratio molar ratio 1:2
1:2
2:1
termine their great affinity to undergo regioselective nu-
cleophilic attack at the terminal carbon of the azo–ene
system (C4) by a variety of carbon- and heteronucleo-
philes affording 1,4-conjugate adducts. These acyclic
intermediates bearing suitable nucleophilic and electro-
philic functions can provide internal cyclization reactions
that represents valuable methods for the construction of
1a–e
1f–i
R1 = Bu
t
R1 = Me, Bu, Bn
t
2
a
R2 = NH2, NHPh
R2 = OMe, OEt, OBn
N(Me)2
N(Et)2
2
b–g
1
heterocyclic rings.
R O
O
OR1
O
Indeed, considering 1,2-diaza-1,3-butadienes 1a–i as
Michael acceptors and arylamidines 2a,b as 1,3-dinucleo-
phile reagents, we explored their reactions to set up a
strategy for the synthesis of compounds containing the
O
HN
NH
NH
N
R2
O
NH
N
HN
Ar
3
4
N
imidazole core since it occurs in a variety of alkaloids
Ar
O
R2
5
and bioactive natural products as well as in pharmaceuti-
6
cal agents.
4a–e
3a–i
Initially, we investigated the reaction between 1,2-diaza- Scheme 1
,3-butadiene derivative 1a, bearing an ester function at
1
C4, and benzamidine (2a) in equimolar ratio in THF at
room temperature. Despite the complete disappearance of
after the disappearance of the starting materials, under
reflux (Scheme 1).
1
a, analysis of the crude mixture revealed unreacted benz-
amidine with a series of intermediates evolving during the
1
7
time. The H NMR spectrum of the main product formed This one-pot procedure was able to afford directly the
8
allowed us to locate the presence in the compound of two unknown spiro pyrroloimidazole derivatives 3a–i (52–
units of 1,2-diaza-1,3-butadiene and one benzamidine 78%, Scheme 1). A plausible mechanism of this spiro-
fragment. This result suggested us that the amidine deriv- annulation reaction is presented in Scheme 2.
ative worked as a nucleophile as well as a base. Therefore,
we planned to carry out the reaction between 1a–e and
9
Similarly to our previous results, the reaction proceeds
via nucleophilic attack of arylamidine derivative 2 at C4
of the conjugated azoalkene system 1 to give hydrazone
intermediate A by Michael-type addition. Subsequent ring
closure at the ester function at C4 gives rise to 2-arylimi-
dazolinone intermediate B. The base-promoted carbanion
formation leads to nucleophilic 1,4-addition to another
azoalkene molecule 1 affording compound C. Under basic
conditions, the two hydrazone side chains of C co-operate
2
a,b in a molar ratio of 2:1, respectively, using DIPEA (2
equiv) as base in THF at room temperature initially, then
SYNLETT 2007, No. 11, pp 1691–1694
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984508; Art ID: D04907ST
©
Georg Thieme Verlag Stuttgart · New York

1
692
O. A. Attanasi et al.
LETTER
O
O
H
N
H
N
OR1
OR1
N
R2
H N
N
R2
N
O
H
O
1
2
NH
A
Ar
H2N
Ar
2
2
–
R H
OR1
O
OR1
HN
NH
H
N
H
O
HN
O
N
O
N
N
HN
Figure 1 Drawing of the crystal structure of 3b·H O
2
Ar
B'
Ar
B
1
O
1
R O
O
OR1
NH
1
R O
O
NH
HN
NH
N
O
O
N
H
H
N
HN
Ar
HN
Ar
N
N
N
O
O
R1
O
R2
R2
O
3
C
R2 = O-substituted
Scheme 2
Figure 2 View of the asymmetric unit of 4c
in the pyrrole ring closure producing spiro pyrroloimida-
zole derivative 3. The hypothesized mechanism is sup-
ported by the occasional isolation of intermediate B in
and mild reaction conditions, difficult to obtain by other
14
procedures. Additionally, since 2-arylimidazoles repre-
15
sent an important class of structures with antifungal,
1
0
hydrazino tautomeric form B¢ as a byproduct in the reac-
tion between 1a and 2a. An X-ray diffraction study of one
of the two diastereomers of 3b confirmed the spiro heter-
obicyclic structure (Figure 1) and allowed the stereo-
chemical assignment of the two stereogenic carbons to be
16
NPY5 receptor antagonism and macromolecular ligand
17
properties, the present study provides a new, simple one-
pot entry to these compounds without any competitive
arylpyrimidine formation.1
4a
Further investigations are currently in progress in order to
improve and extend this strategy.
1
1
established.
Since the ester function at C4 of 1a–e played a key role in
the formation of 3a–i, we proposed that its replacement
with an amide residue would influence the outcome of the
Acknowledgment
reaction. In fact, the reaction between 1f–i and 2a,b car- This work was supported by financial assistance from the M.I.U.R.-
ried out in equimolar ratio and under same reaction condi- Roma (PRIN 2005), and the Università degli Studi di Urbino ‘Carlo
1
2
13
Bo’.
tions, afforded new 2-arylimidazole derivatives 4a–e
52–78%, Scheme 1, Table 1). According to our previous
(
2
b,e
findings, after preliminary conjugate addition, an in-
tramolecular ring closure at the hydrazone function occurs
producing a non-isolable 2-arylimidazoline intermediate
because of its ready aromatization by loss of a hydrazine
residue (Figure 2). The X-ray diffraction study of 4c con-
firmed unequivocally the imidazole structure (Figure 2).11
References and Notes
(
1) (a) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986,
1
1
3
8, 299. (b) Attanasi, O. A.; Filippone, P. Synlett 1997,
128. (c) Boeckman, R. K.; Reed, J.; Ge, P. Org. Lett. 2001,
, 3651. (d) Avalos, M.; Babiano, R.; Cintas, P.; Clemente,
F. R.; Gordillo, R.; Jiménez, J. L.; Palacios, J. C. J. Org.
Chem. 2002, 67, 2241. (e) Palacios, F.; Aparicio, D.; de los
Santos, J. M. Tetrahedron 1999, 55, 13767.
In summary, herein we have reported the one-pot synthe-
sis of novel spiro pyrroloimidazole derivatives under fast
Synlett 2007, No. 11, 1691–1694 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Spiro Pyrroloimidazoles and 2-Arylimidazoles
1693
Table 1 Results of the Synthesis of Spiro Pyrroloimidazoles 3a–i and 2-Arylimidazoles 4a–e
Entry 1,2-Diaza-1,3-butadiene 1
Arylamidine 2
Spiro pyrroloimidazoles 3
2-Arylimidazoles 4
R1
R2
2
Ar
3
Yield (%) C5 (R/S), Yield (%) C5 (R/S), 4
a
a
Yield (%)b
1
C6 (S/R)
C6 (R/S)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1b
1c
1d
1e
1a
1b
1d
1e
1f
t-Bu
Me
OMe
OMe
OEt
2a
2a
2a
2a
2a
2b
2b
2b
2b
2a
2a
2a
2a
2b
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
30
30
36
26
t-Bu
Bn
27
27
OMe
OBn
OMe
OMe
OMe
OBn
NH2
30
22
t-Bu
t-Bu
Me
26
26
4-MeOC H
38
31
6
4
4
4
4
4-MeOC H
3g
3h
3i
31
22
6
Bn
4-MeOC H
32
20
6
t-Bu
t-Bu
t-Bu
t-Bu
Me
4-MeOC H
48
30
6
1
1
1
1
1
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
76
52
71
57
78
1g
1h
1i
NMe2
NEt2
NHPh
NEt2
1g
t-Bu
4-MeOC H
6
4
a
Yield of pure isolated diastereomer.
Yield of pure isolated product.
b
(
2) (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Santeusanio, S. ARKIVOC 2002, (xi), 274;
and the references cited therein. (b) Attanasi, O. A.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org.
Chem. 2002, 2323. (c) Attanasi, O. A.; De Crescentini, L.;
Favi, G.; Filippone, P.; Mantellini, F.; Santeusanio, S.
Synlett 2004, 549. (d) Attanasi, O. A.; Carvoli, G.;
Filippone, P.; Perrulli, F. R.; Santeusanio, S.; Serri, A. M.
Synlett 2004, 1643. (e) Attanasi, O. A.; De Crescentini, L.;
Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.;
Koibe, H. J. Med. Chem. 1996, 39, 323. (c) Carini, D.;
Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.;
Pierce, M. E.; Price, W. A.; Santella, J. B.; Wells, G. J.;
Wexler, R. R. J. Med. Chem. 1991, 34, 2525.
(7) Procedure for the Preparation of Spiro Pyrroloimidazole
Derivatives 3a–i
1,2-Diaza-1,3-butadiene 1a–e (2 mmol), prepared and used
1
b
as a EE/EZ-isomer mixture, and DIPEA (2 mmol) were
dissolved in THF (8 mL) under magnetic stirring. Then solid
arylamidine 2a,b (1 mmol) was added and the reaction
mixture was allowed to stand at r.t. until complete
disappearance of 1a–e (0.25–1 h, monitored by silica gel
TLC). The reaction mixture was then refluxed for the
appropriate time (4–6 h). The solvent was removed under
reduced pressure and the diastereomers of 3a–i were
obtained by silica gel chromatographic separation (eluent:
CH Cl –EtOAc mixtures).
Santeusanio, S. Synlett 2005, 1474. (f) Attanasi, O. A.;
Baccolini, G.; Boga, C.; De Crescentini, L.; Filippone, P.;
Mantellini, F. J. Org. Chem. 2005, 70, 4033. (g) Attanasi,
O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Lillini, S.;
Mantellini, F.; Perrulli, F. R. Synlett 2006, 2731.
(
(
(
(
3) Grimmet, M. R. Imidazoles In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: London, 1996.
2
2
(8) Data for Methyl 7-[(Methoxycarbonyl)amino]-6-[2-
(methoxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-2-
phenyl-1,3,7-triazaspiro[4.4]nona-1,8-diene-9-
carboxylate (3b)
4) (a) Du, H.; He, Y.; Rasapalli, S.; Lovely, C. J. Synlett 2006,
965. (b) Jin, Z. Nat. Prod. Rep. 2005, 22, 196.
(
c) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
5) (a) De Luca, L. Curr. Med. Chem. 2006, 13, 1. (b) Gross,
H.; Kehraus, S.; Koenig, G. M.; Woerheide, G.; Wright, A.
D. J. Nat. Prod. 2002, 65, 1190.
6) (a) Khanna, I.; Weir, R. M.; Xiang, Y. Y.; Xu, X. D.;
Koszyk, F. J.; Collins, P. W.; Kobolt, C. M.; Veenhuinzen,
A. W.; Perkin, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang,
Y. Y.; Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1634. (b) Yanagisawa, H.; Amemiya, Y.;
5R/S,6R/S-Isomer
White powder from EtOAc–n-pentane, mp 161–163 °C
(dec.). IR (Nujol): 3465, 3303, 3244, 3192, 1735, 1721,
–
1 1
1707, 1673, 1648, 1608, 1543, 1515 cm . H NMR (400
MHz, DMSO-d ): d = 1.06 (s, 3 H, CH ), 2.10 (s, 3 H, CH ),
6
3
3
3.46 (s, 3 H, OCH ), 3.60 (s, 3 H, OCH ), 3.69 (s, 3 H,
3
3
OCH ), 6.13 (s, 1 H, NH), 7.53 (t, J = 7.6 Hz, 2 H, Ar), 7.60
3
(t, J = 7.6 Hz, 1 H, Ar), 7.98 (d, J = 7.6 Hz, 2 H, Ar), 8.27 (s,
1
3
Kanasaki, T.; Shimoji, Y.; Fujimoto, K.; Kitahara, Y.; Sada,
T.; Mizuno, M.; Ikeda, M.; Miyamoto, S.; Furukawa, Y.;
1 H, NH), 8.81 (s, 1 H, NH), 11.88 (s, 1 H, NH). C NMR
(100 MHz DMSO-d ): d = 11.58, 16.47, 50.31, 52.34, 81.45,
6
88.87, 96.90, 126.86, 128.37, 128.78, 131.82, 156.29,
Synlett 2007, No. 11, 1691–1694 © Thieme Stuttgart · New York

1
694
O. A. Attanasi et al.
LETTER
(12) Procedure for the Preparation 2-Arylimidazole
1
56.95, 158.41, 163.86, 184.58. MS: m/z (%) = 460 [M+]
(
4), 370 (100), 296 (22), 236 (42). Anal. Calcd for
Derivatives 4a–e
C H N O : C, 52.17; H, 5.25; N, 18.25. Found: C, 52.20;
To a solution of 1,2-diaza-1,3-butadiene 1f–i (1 mmol) and
DIEA (1.2 mmol) in THF (6 mL) solid arylamidine 2a,b (1
mmol) was added under magnetic stirring at r.t. After the
disappearance of 1f–i (0.25–0.5 h) the reaction mixture was
refluxed (4–6 h). Compound 4a was obtained by direct
crystallization from the reaction medium and was filtered off
with satisfactory purity whereas compounds 4b–e were
obtained after chromatographic purification (elution:
CH Cl –EtOAc mixtures).
20
24
6
7
H, 5.22; N, 18.27.
R/S,6S/R-Isomer
Colorless crystals from THF–n-pentane, mp 152–154 °C
5
(
1
dec.). IR (Nujol): 3484, 3435, 3339, 3306, 1744, 1723,
687, 1620, 1602, 1578, 1511 cm . H NMR (400 MHz,
–
1 1
DMSO-d ): d = 1.15 (s, 3 H, CH ), 2.11 (s, 3 H, CH ), 3.42
6
3
3
(
s, 3 H, OCH ), 3.60 (s, 3 H, OCH ), 3.68 (s, 3 H, OCH ),
3 3 3
5.90 (s, 1 H, NH), 7.56 (t, J = 7.6 Hz, 2 H, Ar), 7.62 (t,
2
2
J = 7.6 Hz, 1 H, Ar), 7.90 (s, 1 H, NH), 8.04 (d, J = 7.6 Hz,
(13) Data for N,N-Diethyl-5-methyl-2-phenyl-1H-imidazole-
1
3
2
H, Ar), 8.64 (s, 1 H, NH), 11.65 (s, 1 H, NH). C NMR
4-carboxamide (4c)
(
8
100 MHz DMSO-d ): d = 11.86, 17.06, 50.31, 52.31, 52.46,
Colorless crystals from Et O, mp 187–190 °C. IR (Nujol):
3114, 1595,1566, 1538, 1494 cm . H NMR (400 MHz,
6
2
–
1 1
0.22, 85.91, 96.72, 127.37, 128.35, 128.75, 132.18, 156.46,
1
56.54, 161.88, 163.64, 164.18, 183.08. MS: m/z (%) = 460
DMSO-d ): d = 1.14 (br s, 3 H, CH ), 1.23 (br s, 3 H, CH ),
6
3
3
+
[
M ] (1), 370 (100), 296 (21), 236 (18). Anal. Calcd for
2.40 (s, 3 H, CH ), 3.37 (br s, 2 H, NCH ), 3.77 (br s, 2 H,
3
2
C H N O : C, 52.17; H, 5.25; N, 18.25. Found: C, 52.16;
H, 5.23; N, 18.26.
NCH ), 7.34 (t, J = 7.6 Hz, 1 H, Ar), 7.45 (t, J = 7.6 Hz, 2 H,
2
Ar), 7.90 (d, J = 7.6 Hz, 2 H, Ar), 12.59 (s, 1 H, NH). C
20
24
6
7
1
3
(
9) (a) Attanasi, O. A.; Filippone, P.; De Crescentini, L.; Foresti,
NMR (100 MHz DMSO-d ): d = 10.84, 12.97, 14.68, 39.66,
6
E.; Galarini, R.; Santeusanio, S.; Serra-Zanetti, F. Synthesis
42.45, 124.59, 128.01, 128.70, 130.33, 132.54, 132.76,
+
1995, 1397. (b) Attanasi, O. A.; Filippone, P.; Foresti, E.;
142.21, 164.12. MS: m/z (%) = 257 [M ] (27), 185 (100),
Guidi, B.; Santeusanio, S. Tetrahedron 1999, 55, 13423.
158 (99). Anal. Calcd for C H N O: C, 70.01; H, 7.44; N,
16.33. Found: C, 69.99; H, 7.47; N, 16.35.
(14) (a) Brackeen, M. F.; Stafford, J. A.; Feldman, P. L.;
Karanewsky, D. S. Tetrahedron Lett. 1994, 1635.
1
5
19
3
1
(
10) Data of B': H NMR (400 MHz, DMSO-d ): d = 1.39 (s, 9 H,
6
Ot-Bu), 1.94 (s, 3 H, CH ), 6.86 (s, 1 H, NH), 7.54 (t, J = 7.6
3
Hz, 2 H, Ar), 7.61 (t, J = 7.6 Hz, 1 H, Ar), 7.95 (d, J = 7.6
1
3
Hz, 2 H, Ar), 9.64 (s, 1 H, NH), 11.41 (s, 1 H, NH). C NMR
(b) Zhang, P. F.; Chen, Z. C. Synthesis 2001, 2075.
(c) Yoburn, J. C.; Baskaran, S. Org. Lett. 2005, 7, 3801.
(15) Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.;
Vericat, M. L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-
Rafanell, J.; Forn, J. J. Med. Chem. 1998, 41, 1855.
(16) Elliott, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M.
L.; Hammond, M.; Hank, R. F.; Maurer, T. S.; Baker, D. L.;
DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C. M.;
Cassella, J. V. Bioorg. Med. Chem. Lett. 2003, 13, 3593.
(17) Street, J. P. Tetrahedron Lett. 1991, 32, 3333.
(
100 MHz DMSO-d ): d = 11.99, 27.97, 79.19, 93.64,
6
1
1
2
27.09, 128.38, 128.76, 132.26, 151.66, 152.66, 160.86,
+
81.69. MS: m/z (%) = 317 [M + 1] (0.5), 260 (3), 216 (12),
02 (57), 104 (100).
(
11) Crystallographic data (excluding structure factors) for
compound 3b and 4c have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 637246 and 637245. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44
(
1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
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