Synthesis of densely functionalized 3a,4-dihydro-1 H-pyrrolo[1,2- b]pyrazoles via base mediated domino reaction of vinyl malononitriles with 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1021/ol401336s

A domino reaction of vinyl malononitriles (VMs) with 1,2-diaza-1,3-dienes (DDs) produce unprecedented 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazole systems in a chemo-, regio-, and stereoselective fashion. This base promoted (DIPEA) one-pot transformation involving multiple steps constructs one new C-C bond, two C-N bonds, and two new fused heterocyclic rings with total atom economy.

Full text of DOI:10.1021/ol401336s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Densely Functionalized
3a,4-Dihydro‑1H‑Pyrrolo[1,2‑b]Pyrazoles
via Base Mediated Domino Reaction of
Vinyl Malononitriles with 1,2-Diaza-1,3-dienes
Orazio A. Attanasi,† Gianfranco Favi,*,† Athina Geronikaki,‡ Fabio Mantellini,†
Giada Moscatelli,† and Aliki Paparisva‡
Department of Biomolecular Sciences, Section of Organic Chemistry and Organic
Natural Compounds, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino
(PU), Italy, and School of Pharmacy, Department of Pharmaceutical Chemistry,
Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
gianfranco.favi@uniurb.it
Received March 25, 2013; Revised Manuscript Received May 13, 2013
ABSTRACT
A domino reaction of vinyl malononitriles (VMs) with 1,2-diaza-1,3-dienes (DDs) produce unprecedented 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazole
systems in a chemo-, regio-, and stereoselective fashion. This base promoted (DIPEA) one-pot transformation involving multiple steps constructs
one new CꢀC bond, two CꢀN bonds, and two new fused heterocyclic rings with total atom economy.
In pharmaceutical and biomedical research, densely
functionalized and diversified heterocyclic molecules can
be extremely useful for obtaining biological leads and
exploring molecular recognition events. Therefore, the
availability of efficient and practical synthetic procedures
to generate heterocycle modules for the preparation of
natural and biomimetic compounds remains a great chal-
lenge. One of the ways to fulfill this goal is the development
of domino reactions1 which allow the sequential transfor-
mations of two or more reactions in the same reaction
vessel, thereby minimizing the number of laboratory op-
erations, the generation of waste chemicals, time, and cost.
Heteroaromatic molecules containing N-fused bicyclic
fragments (and their partially or completely reduced
analogues) are important components in a large number
of pharmaceutical, agrochemical, and natural products.2,3
Antibacterial and antifungal activities have been ascribed
to many of these N-fused heterocycles. Additionally,
some of them have been identified as potential anxiolytic,
antineoplastic, antiplasmodial, and anticancer agents.4
(2) For review, see: Michael, J. P. Nat. Prod. Rep. 1999, 16, 675–696.
(3) For a review, see: (a) Liu, T.; Fu, H. Synthesis 2012, 44, 2805–
2824. For select examples, see: (b) Zhang, H.; Jin, Y.; Liu, H.; Jiang, Y.;
Fu, H. Eur. J. Org. Chem. 2012, 6798–6803 and references cited therein.
(c) Li, M.; Shao, P.; Wang, S.-W.; Kong, W.; Wen, L.-R. J. Org. Chem.
2012, 77, 8956–8967. (d) Tyagi, V.; Khan, S.; Bajpai, V.; Gauniyal,
H. M.; Kumar, B.; Chauhan, P. M. S. J. Org. Chem. 2012, 77, 1414–
1421. (e) Chernyak, D.; Gevorgyan, V. Org. Lett. 2010, 12, 5558–5560.
(f) Chen, W.; Hu, M.; Wu, J.; Zou, H.; Yu, Y. Org. Lett. 2010, 12, 3863–
3865. (g) Tomilov, Y. V.; Novikov, R. A.; Nefedov, O. M. Tetrahedron
2010, 66, 9151–9158. (h) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V.
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(4) (a) Katritzky, A. R.; Tymoshenko, D. O.; Monteux, D.; Vvedensky,
V.; Nikonov, G.; Cooper, C. B.; Deshpande, M. J. Org. Chem. 2000, 65,
8059–8062. (b) Maryanoff, B. E.; McComsey, D. F.; Ho, W.; Shank, R. P.;
Dubinsky, B. Bioorg. Med. Chem. Lett. 1996, 6, 333–338. (c) Reitz, A. B.;
Gauthier, D. A.; Ho, W.; Maryanoff, B. E. Tetrahedron 2000, 56, 8809–
8812. (d) Rida, S. M.; Soliman, F. S. G.; Badawey, E.; Kappe, T. J.
Heterocycl. Chem. 1988, 25, 1725–1728. (e) Rida, S. M.; Soliman, F. S. G.;
Badawey, E.; El-Ghazzawi, E.; Kader, O.; Kappe, T. J. Heterocycl. Chem.
1988, 25, 1087–1093. (f) Badawey, E.; Kappe, T. Eur. J. Med. Chem. 1995,
30, 327–332. (g) El-Hawash, S. A. M.; Badawey, E.; Kappe, T. Pharmazie
1999, 54, 341–346.
† University of Urbino “Carlo Bo”.
‡ Aristotle University of Thessaloniki.
(1) For recent reviews, see: (a) Pellissier, H. Chem. Rev. 2013, 113,
442–524. (b) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012,
45, 1278–1293. (c) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570–1581. (d) Nicolau, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (e) Tietze,
L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006. (f) Tietze, L. F. Chem. Rev. 1996, 96,
115–136.
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r
10.1021/ol401336s
XXXX American Chemical Society

However, to the best of our knowledge fused 3a,4-dihydro-
1H-pyrrolo[1,2-b]pyrazole (with one nitrogen atom shared
by two rings) has not been reported in the literature.
Accordingly, development of new methodologies to rapidly
assembly strucurally diverse N-fused bicyclic molecules,
such as N-fused pyrrolo-pyrazole scaffolds, are of high
demand.
Scheme 1. Various Pathways for Base-Mediated Annulations
of VMs with Different Michael Acceptors: Construction of
Carbocycles
The vinylogous version of the Michael addition reaction
has emerged as immensely useful, strategic maneuvers in
the art of contemporary organic synthesis.5 Altough viny-
logous addition of vinyl malononitriles (VMs) to suitable
conjugated acceptors including activated R,β-unsaturated
aldehydes6 and ketones,7 alkylidene/isatylidene malono-
nitriles,8,9 nitroalkenes,10 and azodicarboxylates11 was ex-
plored, the reported examples in this area are confined to
synthetize carbocycles (Scheme 1). Recently, Perumal et al.
reported a novel method for the synthesis of functionalized
spirocyclic oxindoles by a one-pot tandem reaction of VMs
with isatylidene malononitriles.8b Vinylogous Michael ad-
dition of VMs with nitroolefins was also realized in the
one-pot synthesis of polysubstituted benzene derivatives.9b
Our ongoing studies on 1,2-diaza-1,3-dienes (DDs)11
1
indicated these as potentially attractive substrates for the
vinylogous Michael reaction.
Scheme 2. Strategy for Synthesis of Pyrrolo-Pyrazole
Compounds from Ketones
We found, in fact, that VMs 2 (obtained from ketones
via a Knovenagel reaction) can react with DDs 1 (obtained
from ketones via a dehydrohalogenation reaction of
R-halogenated hydrazones) in the presence of a base. So
highly functionalized pyrrolo-pyrazole systems 4 can be
obtained by means of a one-pot domino transformation
via hydrazonic adduct intermediate 3 (Scheme 2). Thus,
a novel method for the synthesis of densely funcionalized
(5) For reviews, see: (a) Zanardi, F.; Rassu, G.; Battistini, L.; Curti,
C.; Sartori, A.; Casiraghi, G. In Targets in Heterocyclic Systems;
fused pyrrolo-pyrazole compounds using ketones as the
starting materials is described for the first time.
ꢀ
Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Societa
Chimica Italiana: Rome, 2012; Vol. 16, p 56. (b) Casiraghi, G.;
Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111,
3076–3154.
We began our investigation by studying the vinylogous
Michael addition reaction between the VM 1a and DD 2a
in the presence of a catalytic amount of DIPEA (20 mol %)
inCH3CNatrt(Table1). After5 min, thedisappearanceof
the red color of the starting azoene was observed. The TLC
of the crude mixtures revealed the presence of a single
product spot easily identified as the vinylogous hydrazonic
Michael adduct 3a (89%). Subsequently, we found that the
vinylogous hydrazonic Michael adduct (3a) could undergo
sequential cyclization reactions to give new 3a,4-dihydro-
1H-pyrrolo[1,2-b]pyrazole 4a (Table 1).
Then, we investigated the best conditions for the hetero-
cyclization processes of vinylogous hydrazonic Michael
adduct 3a selected as a model reaction. Various solvents
and DIPEA loading have been tried (Table 1, entries 1ꢀ9),
and the best result (67% yield) was obtained with 100 mol %
DIPEA in CH3CN (Table 1, entry 9). No reaction occurred
without the addition of DIPEA in refluxing CH3OH over-
night (Table 1, entry 5).
(6) (a) Lu, J.; Liu, F.; Zhou, W.-J.; Loh, T.-P. Tetrahedron Lett. 2008,
5389–5392. (b) Bell, M.; Frisch, K.; Jørgensen, A. J. Org. Chem. 2006,
71, 5407–5410. (c) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen, Y.-C.;
Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563–1565.
(7) (a) Kang, T.-R.; Xie, J.-W.; Du, W.; Feng, X.; Chen, Y.-C. Org.
Biomol. Chem. 2008, 6, 2673–2675. (b) Xie, J.-W.; Chen, W.; Li, R.;
Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G.
Angew. Chem., Int. Ed. 2007, 46, 389–392.
(8) (a) Wang, X.-S.; Wu, J.-R.; Zhou, J.; Tu, S.-J. J. Comb. Chem.
2009, 11, 1011–1022. (b) Babu, T. H.; Joseph, A. A; Muralidharan, D.;
Perumal, P. T. Tetrahedron Lett. 2010, 51, 994–996.
(9) (a) Guo, Z.-W.; Li, X.-S.; Zhu, W.-D.; Xie, J.-W. Eur. J. Org.
Chem. 2012, 6924–6932. (b) Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J.
Org. Chem. 2007, 72, 5433–5445. (c) Poulsen, T. B.; Bell, M.; Jørgensen,
A. Org. Biomol. Chem. 2006, 4, 63–70. (d) Xue, D.; Chen, Y.-C.; Wang,
Q.-W.; Cun, L.-F.; Zhu, J.; Deng, J.-G. Org. Lett. 2005, 7, 5293–5296.
(10) Poulsen, T. B.; Alemparte, C.; Jørgensen, A. J. Am. Chem. Soc.
2005, 127, 11614–11615.
(11) For a review on the chemistry of DDs, see: (a) Attanasi, O. A.;
De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.;
Santeusanio, S. Eur. J. Org. Chem. 2009, 3109–3127. For some recent
examples, see: (b) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.;
€
Jorres, M.; Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924–6927. (c)
Attanasi, O. A.; Bartoccini, S.; Favi, G.; Giorgi, G.; Perrulli, F.;
Santeusanio, S. J. Org. Chem. 2012, 77, 1161–1167. (d) Attanasi,
O. A.; De Crescentini, L.; Favi, G.; Mantellini, F.; Nicolini, S. J. Org.
Chem. 2011, 76, 8320–8328. (e) Attanasi, O. A.; Favi, G.; Mantellini, F.;
Moscatelli, G.; Santeusanio, S. J. Org. Chem. 2011, 76, 2860–2866. (f)
Hatcher, J. M.; Coltart, D. M. J. Am. Chem. Soc. 2010, 132, 4546–4547.
With these results in hand, we moved toward the
principal aim of our investigations, the development of
a one-pot domino sequence, leading to bicyclic products
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Reaction of DD 1a with VM 2a: Optimization of the
Reaction Conditions for the Heterocyclization Process (3af4a)a
Table 2. One-Pot Synthesis of Pyrrolo-Pyrazole Systems 4aꢀh:
Reaction Scope of VM 2a with Respect to DDs 1aꢀha
products 4
yield (%)b
DDs 1
entry
1 (R1, R2)
4
1
2
3
4
5
6
7
8
1a (Me, Et)
4a
4b
4c
4d
4e
4f
64
63
67
55
46
71
65
69
DIPEA
(mol %)
t
4a
1b (Me, Me)
1c (Me, t-Bu)
1d (Me, Bn)
1e (Me, Allyl)
1f (Et, Me)
entry
solvent
(°C)
yield (%)b
1
2
3
4
5
6
7
8
9
20
CH2Cl2
CH2Cl2
THF
rt
trace
8
100
20
rt
rt
trace
10
1g (n-Pr, Et)
1h (n-Bu, Me)
4g
4h
100
ꢀ
THF
rt
CH3OH
CH3OH
CH3OH
CH3CN
CH3CN
reflux
rt
ꢀ
20
51
a Reagents and conditions: 1aꢀh (0.5 mmol), 2a (0.6 mmol), DIPEA
(0.6 mmol), CH3CN (3 mL), rt, overnight. b Yield of pure isolated
products.
100
20
rt
56
rt
trace
67
100
rt
a All reactions were performed at a 0.5 mmol scale of 3a. b Yields of
isolated product 4a.
Table 3. One-Pot Synthesis of Pyrrolo-Pyrazole Systems 4iꢀt:
Reaction Scope with Respect to VMs 2bꢀfa
from easily accessible starting materials. Gratifyinly, a one-
pot cascade via DIPEA-assisted double aza-annulations in
CH3CN at rt was found to take place easily, with a good
yield (64%) of the bicyclic product 4a (Table 2, entry 1).
Having established the optimal conditions, the scope
of the one-pot reaction was probed using a range of
doubly EWG activated DDs (1aꢀh)12 reacting with 2-(1-
phenylethylidene)malononitrile 2a13 (Table 2, entries 1ꢀ8).
The increase of the alkyl chain length (R1 = Me, Et,
n-Pr, n-Bu) as well as the nature of the ester group (CO2R2;
R2 = Me, Et, t-Bu, Bn, Allyl) revealed minimal influence
on the reaction yield. In all cases, the reaction proceeded
at rt under very mild reaction conditions, and the desired
functionalized pyrrolo-pyrazole compounds (4aꢀh) were
consistently obtained in moderate to good yields.
The generality of this one-pot reaction shown in Table 2
prompted us to investigate the reaction for a series of
alkylidene malononitriles (2bꢀg) with DDs (1aꢀh). The
results are reported in Table 3. The reaction’s scope proved
to be quite broad with respect to acyclic or cyclic and alkyl
and aryl-substituted VMs 2bꢀf.13 The presence of either
electron-withdrawing or -donating groups on the aro-
matic ring of 2 (2b and 2c) afforded comparable results
(Table 3, entries 1ꢀ5). Both (1-methyl-2-phenylethylidene)-
malononitrile 2d and (1-phenylpropylidene)malononitrile
products 4
yieldb
DDs 1
VMs 2
entry
1 (R1, R2)
2 (R3, R4)
4
(%)
1
1b (Me, Me)
1c (Me, t-Bu)
1a (Me, Et)
1d (Me, Bn)
1a (Me, Et)
1a (Me, Et)
1c (Me, t-Bu)
1c (Me, t-Bu)
1h (n-Bu, Me)
1a (Me, Et)
1f (Et, Me)
2b (H, p-OMe-C6H4)
2b (H, p-OMe-C6H4)
2b (H, p-OMe-C6H4)
2c (H, p-Br-C6H4)
2c (H, p-Br-C6H4)
2d (H, Bn)
4i
50
42
39
49
63
51
50
71
49
52
52c
46c
2
4j
3
4k
4l
4
5
4m
4n
4o
4p
4q
4r
4s
4t
6
7
2d (H, Bn)
8
2e (Me, Ph)
9
2e (Me, Ph)
10
11
12
2e (Me, Ph)
2f (-(CH2)4-)
1a (Me, Et)
2f (-(CH2)4-)
a Reagents and conditions: 1aꢀd,f,h (0.5 mmol), 2bꢀf (0.6 mmol),
DIPEA (0.6 mmol), CH3CN (3 mL), rt, overnight. b Yield of pure
isolated products. c CH2Cl2 was used as the solvent.
(12) DDs 1aꢀh were synthesized from the corresponding chlorohy-
drazones by treatment with a base (see Supporting Information).
(13) VMs 2aꢀf were synthesized via a Knoevenagel reaction from
ketones and malononitriles (see Supporting Information).
Org. Lett., Vol. XX, No. XX, XXXX
C

(regioselective γ Michael addition or VMcR) through
the effect of a base. In the second step, the acidic proton
adjacent to the ester group of hydrazonic Michael adduct 3
is abstracted by DIPEA to produce the azaallylic anion
intermediate I-2. Similar intermediates have been described
by De Kimpe et al. in their excellent review.15 Then, I-2
undergoes intramolecular (5-exo-trig) aza-Michael cycliza-
tion (AMcCR) to give the bicyclic intermediate I-3. Next, a
subsequent (5-exo-dig) cyclization by the carbamic N-atom
on a nitrile function (ACR) leads to the bicyclic imine inter-
mediate I-4. Finally, the resulting I-4 immediately tauto-
merizes to form the more stable amino pyrrolo-pyrazole 4.
In conclusion, we have developed a novel, metal-
free, and atom-economical method for the synthesis of
fully decorated pyrrolo-pyrazole systems by the one-pot,
domino transformation of DDs with VMs under mild
conditions for the first time. The overall transformation
may involve the following steps: vinylogous Michael addi-
tion (VMcR)/aza-Michael cyclization (AMcCR)/aza-
cyclization (ACR)/imine-enamine tautomerization.16
Notably, the reactions are very highly chemo-, regio-,
and stereoselective, simultaneously producing molecular
complexity (two CꢀN bonds, one CꢀC bond, and two
rings) from readily available substrates.
Scheme 3. Plausible Mechanism
Moreover, the presence of different functional groups
around the pyrrole-pyrazole core could furnish interesting
points of postfunctionalization to give a wide range of
useful intermediates that are difficult to obtain via other
procedures.
Further investigations are underway in our laboratory
to determine the applicability and usefulness of this reac-
tion. We hope this approach may be of value to others
seeking novel synthetic fragments with unique properties
for medicinal chemistry.
2e also exhibited good reactivity and the relative pyrrolo-
pyrazole derivatives 4nꢀr were obtained in total regio- and
stereoselective fashion (Table 3, entries 6ꢀ10). Interestingly,
cyclohexanone malononitrile 2f was successfully employed
in the one-pot sequence, thus generating intriguing new
N-bridged tricyclic heterocycles 4s and 4t (Table 3, entries
11 and 12).
All of the products 4aꢀt are new compounds, with the
Acknowledgment. This work was supported by finan-
ꢀ
structures deduced from their IR, mass, 1H NMR, and 13
NMR spectral data.14
C
cial assistance from the Ministero dell’Universita,
dell’Istruzione e della Ricerca (MIUR)ꢀRoma, and the
A plausible mechanism for the formation of these novel
pyrrolo-pyrazoles 4 is pictured in Scheme 3. The first step
involves a facile deprotonation of vinyl malononitrile 2
to furnish vinylogous carbanion I-1 which attacks DD 1
ꢀ
Universita degli Studi di Urbino “Carlo Bo”. We also
cordially thank Dr. Marcelina Arshakyan (University of
Urbino) for her experimental assistance.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(14) The structure of the obtained products 4 was assigned on the
basis of the spectroscopic data of 4a. In particular, the 1H and 13C NMR
spectra of 4a in either CDCl3 or DMSO-d6 exhibit some peculiarities: (i)
one singlet at 5.87 ppm and two broad singlets at 5.03 and 6.06 ppm (all
exchangeable with D2O) attributed to the protons of the diagnostic
primary amino (NH2) and ureido (CONH2) groups, respectively; (ii) two
double doublets at 2.96 and 3.41 ppm ascribable to a CH2 pattern in a
strained pyrrole system where both geminal (2J = 16.2 Hz) and
homoallylic coupling (5J = 1.4 and 2.4 Hz) were observed; (iii) the
presence of two distinctive C-sp3 signals at 41.2 ppm and 63.3 ppm
attributed to methylene (CH2) and quaternary (C) carbons, respectively;
(iv) the presence of four C-sp2 signals (155.8, 153.9, 107.5, and 76.2 ppm)
assignable to the CC double bond of the bicyclic structure. In additiþon
the mass spectrum of 4a displayed a molecular ion peak at m/z = 353 [M ].
(15) For a review on 1-azaallylic anions in heterocyclic chemistry, see:
Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004, 104,
2353–2399.
(16) Although the final yields of these reactions are apparently not
very high, they can be considered good or excellent taking into account
the multiple steps of the whole process.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX