Flexible protocol for the chemo- and regioselective building of pyrroles and pyrazoles by reactions of Danishefsky's dienes with 1,2-diaza-1,3-butadienes

Article abstract of DOI:10.1021/ol800557h

The versatility of the Mukaiyama-Michael-type addition/heterocyclization of Danishefsky's diene with 1,2-diaza-1,3-butadienes was applied to the synthesis of both 4H-1-aminopyrroles and 4.5H-pyrazoles. Thus, the same reagents furnished different types of highly functionalized azaheterocycles essentially depending on their structure: as a matter of fact, R¹ = COOR or CONR2 differently affects the acidity of the proton at the adjacent carbon. An unexpected formation of 5H-1-aminopyrroles from the reactions carried out in water was also observed.

Full text of DOI:10.1021/ol800557h

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1983-1986
Flexible Protocol for the Chemo- and
Regioselective Building of Pyrroles and
Pyrazoles by Reactions of Danishefsky’s
Dienes with 1,2-Diaza-1,3-butadienes
Orazio A. Attanasi,† Gianfranco Favi,†,* Paolino Filippone,† Gianluca Giorgi,‡
Fabio Mantellini,† Giada Moscatelli,† and Domenico Spinelli§
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”, Via I
Maggetti 24, 61029 Urbino, Italy, Centro Interdipartimentale di Analisi e
Determinazioni Strutturali, UniVersita` degli Studi di Siena, Via Aldo Moro,
53100 Siena, Italy, and Dipartimento di Chimica Organica “A. Mangini”, UniVersita`
degli Studi di Bologna, Via San Giacomo 11, 40126 Bologna, Italy
gianfranco.faVi@uniurb.it
Received March 11, 2008
ABSTRACT
The versatility of the Mukaiyama-Michael-type addition/heterocyclization of Danishefsky’s diene with 1,2-diaza-1,3-butadienes was applied to
the synthesis of both 4H-1-aminopyrroles and 4,5H-pyrazoles. Thus, the same reagents furnished different types of highly functionalized
azaheterocycles essentially depending on their structure: as a matter of fact, R1 ) COOR or CONR2 differently affects the acidity of the proton
at the adjacent carbon. An unexpected formation of 5H-1-aminopyrroles from the reactions carried out in water was also observed.
Nitrogen-containing heterocycles are the core structure in a large
number of natural products as well as in many pharmacologi-
cally active compounds.1 Due to the role of azaheterocycles in
bio-organic chemistry, the search for new efficient methods for
their synthesis represents an active field of interest.2,3
The use of an electron-rich diene, in normal and hetero
Diels-Alder cycloadditions,4,5 introduced by Danishefsky
et al., offers a powerful tool in organic chemistry. Danishef-
sky’s diene readily reacts with imines,6 aldehydes,7 alkenes/
alkynes,8 and even some electron-deficient aromatic rings9
to afford the relevant hetero- and carbocyclic rings. Dan-
ishefsky’s diene cycloadditions can be catalyzed by various
Lewis acids, and asymmetric versions have also been
developed.6–10 Over the years, structural modifications of
(1) (a) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton,
C. J., Pergamon Press: New York, 1991; Vol. 8. (b) Southon, I. W.;
Buckingham, J. In Dictionary of Alkaloids; Saxton, J. E., Ed.; Chapman
and Hall: London, 1989. (c) Negwer, M. In Organic-Chemical Drugs and
their Synonyms: (An International SurVey), 7th ed.; Akademie Verlag
GmbH: Berlin, 1994. (d) O’Hagan, D. Nat. Prod. Rep 2000, 17, 435–446.
* To whom correspondence should be addressed. Fax: +390722303441.
† Universita` degli Studi di Urbino.
‡ Universita` degli Studi di Siena.
§ Universita` degli Studi di Bologna.
10.1021/ol800557h CCC: $40.75
Published on Web 04/22/2008
2008 American Chemical Society

Danishefsky’s electron-rich diene improved their reactivity
and selectivity, as well as their acid and heat sensitivity.11
On the other hand, 1,2-diaza-1,3-butadienes12 are highly
versatile reagents that proved to be useful intermediates in
the syntheses of several five- and six-membered azahetero-
cycles.13 The high reactivity of these compounds, related to
the electrophilicity of the terminal carbon atom (C-4) of the
heterodiene system, has been shown to allow the 1,4-addition
(Michael-type) of a variety of carbon and heteronucleo-
philes.14,15 In such a framework, some of our recent efforts
have been addressed in the development of new reactions
able to give carbon-carbon bond formation via the Mu-
kaiyama version of the Michael reaction of silyl enol ethers.16
Thus, we have reported a facile approach to pyrrole and
indole ring skeletons, by Lewis acid (ZnCl2)-catalyzed
Mukaiyama-Michael addition/heterocyclization of enolsilyl
derivatives on 1,2-diaza-1,3-butadienes,15 in which the Lewis
acid catalysis represents an alternative to the alkali enolate
method.
With the aim of extending this approach to reactions of
other (silyloxy)alkene nucleophiles, we investigated the
addition of 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Dan-
ishefsky’s diene, 2a), 1-methoxy-2-methyl-3-trimethylsilyl-
oxy-1,3-pentadiene (2b), and 1-dimethylamino-3-tert-bu-
tyldimethylsilyloxy-1,3-butadiene (Rawal’s diene, 2c) on
some 1,2-diaza-1,3-butadienes (1a-i).
First, we examined the 1,4-addition of 2a on 1,2-diaza-
1,3-butadienes 1a,f in the presence of a catalytic amount of
ZnCl2 in CH2Cl2 at room temperature.15a After the disap-
pearance of the starting 1,2-diaza-1,3-butadienes, the check-
ing of the crude mixtures by TLC revealed the presence of
two products as major components, easily separated by flash
chromatography and identified as the silylated (3a,b) and
the desilylated (4a,e) hydrazonic 1,4-adducts, respectively.
However, the above crude reaction mixtures by treatment
with tetrabutylamonium fluoride (TBAF) directly gave 4a,e
(Scheme 1). All attempts to isolate Diels-Alder products
failed suggesting that this reaction involves a Mukaiyama-
Michael reaction and not a Diels-Alder-type process.17,18
(2) (a) For recent reviews, see Henry, G. D. Tetrahedron 2004, 60, 6043–
6061. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646. (c) Abass, M.
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A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds; Pergamon:
Oxford, 1996; Vol. 5; pp 167-243. (b) Larock, R. C. ComprehensiVe
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15–23. (c) Danishefsky, S. Org. Chem. 1989, 2, 273–297. (d) Herczzegh,
P.; Kovacs, I.; Erdosi, G.; Varga, T.; Agocs, A.; Szilagyi, L.; Sztaricskai,
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Scheme 1. ZnCl2-Catalyzed Mukaiyama-Michael-Type
Addition of Danishefsky’s Diene 2a on 1,2-Diaza-1,3-butadienes
1a,f
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H.; Kurosaki, R.; Inoue, T.; Ikariya, T. Chem. Commun. 1996, 2559–2560.
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Encouraged by these preliminary results, we enlarged the
scope of the previous reaction to a series of 1,2-diaza-1,3-
butadienes 1a-i first testing the reactivity with the Dan-
ishefsky’s diene 2a. Thus, the Mukaiyama-Michael deriva-
tives 4a-h were obtained in good to excellent yields
(Scheme 2).
Interestingly, the 1,4-adducts 4a-d, bearing the ester
group (R1 ) OR) in the R-position to the CdN moiety, with
TFA in THF furnished the relevant 4H-1-aminopyrroles
5a-d in excellent yields via intramolecular ring closure
(Scheme 2).15 It is noteworthy that the more reactive tosyl
1984
Org. Lett., Vol. 10, No. 10, 2008

1,2-diaza-1,3-butadiene 1e (R3 ) Ts) directly furnished the
4H-1-aminopyrrole 5e in 61% yield without ZnCl2 and/or
TBAF catalysis (Scheme 2).
clizations depend on a balance of the acidity of the proton
in the R-position to the amide/ester (COR1) moiety of the
hydrazonic 1,4-adduct 4 and could occur via the common
intermediate B.
Scheme 2. ZnCl2-Catalyzed Mukaiyama-Michael-Type
Addition of 3-Siloxy-1,3-dienes 2a-c on
1,2-Diaza-1,3-butadienes 1a-i. Synthesis of 1-Aminopyrroles
5a-h and pyrazoles 6a-f
Scheme 3
.
Mechanisms for the Formation of 1-Aminopyrrole 5
and Pyrazole 6
In contrast, the 1,4-adducts 4e-h, containing the amide
group (R1 ) NR2) instead of the ester group (R1 ) OR), did
not give the relevant 4H-1-aminopyrroles staying unchanged
by treatment with TFA. This occurrence could be related to
the expected lower acidity of the protons in the R-position
to the CdN moiety of the hydrazonic adduct intermediates
when the amide group replaces the ester one. Surprisingly,
the treatment of the 1,4-adducts 4e-h in THF with wet
Amberlyst 15(H) gave the unexpected 4,5H-pyrazoles 6a-d
(Scheme 2) deriving from an “apparent” rearrangement of
the azoalkene skeleton. A similar heterocyclization process
has never been observed in our 30-year experience in the
field of 1,2-diaza-1,3-butadienes. An X-ray diffraction study
of 6a unequivocally confirmed its structure.
The formation of 6 can be ascribed to a nucleophilic attack
of a water molecule at the hydrazonic function of 4 followed
by intramolecular cyclization (promoted from wet Amberlyst
15(H)) of the nitrogen on the carbonyl group to give a cyclic
aminohemiacetal intermediate (B).
By ring opening, B collapses into the R,ꢀ-unsaturated
hydrazone (C), furnishing an internal transfer of the hydra-
zone moiety. In turn, C aromatizes into the pyrazole 6 via
an intramolecular Michael addition with loss of methanol
molecule (path b, Scheme 3). However, the same 1,4-adduct
4 could furnish the 1-aminopyrrole 5 by intramolecular
nucleophilic attack of the hydrazonic nitrogen (via protot-
ropism CH/NH) at the carbonyl group producing the
intermediate A followed by loss of water molecule (path a,
Scheme 3). The alternative mechanisms of the heterocy-
On the basis of these preliminary results, the scope of the
reaction was extensively explored by using 1-methoxy-2-
methyl-3-trimethylsilyloxy-1,3-pentadiene 2b11a and 1-dim-
ethylamino-3-tert-butyldimethylsilyloxy-1,3-butadiene 2c
(Rawal’s diene).11b–d Both of these 3-siloxy-1,3-dienes
proved effective reagents for the Mukaiyama-Michael
addition on 1,2-diaza-1,3-butadienes (Scheme 2). In fact, the
Danishefsky’s type diene 2b (X ) OMe, R4 ) Me) reacted
with 1,2-diaza-1,3-butadienes 1a-c,g,i to give the 1,4-adduct
intermediates 4i-m, which, in turn, gave rise to different
heterocyclization processes leading to 1-aminopyrroles 5f-h
or pyrazoles 6e,f in excellent yields. Rawal’s diene 2c (X )
NMe2, R4 ) H), known to be substantially more reactive
than Danishefsky’s 2a (X ) OMe, R4 ) H),11b afforded the
1,4-adducts 4n-p without Lewis acid (ZnCl2) catalysis.
Unfortunately, under the same heterocyclization reaction
conditions, 1-aminopyrroles (5) and pyrazoles (6) were not
observed, but only degradation products together with some
unreacted starting materials were recovered. This particular
behavior could be related to the electronic effect of the
dimethylamino group in 2. The NMe2 group increases the
nucleophilicity of 2c, and then facilitates the formation of
4n-p, but at the same time lowers the electrophilic character
of the carbonylic carbon preventing both the heterocycliza-
tion processes.
It can be noted that the carbons of the reagents participate
in a different way in the heterocyclization processes. In the
transformations of 1a-i and 2a,b into 5a-h, two carbons
of the pyrrole ring of 5a-h derive from C-3 and C-4 of the
Org. Lett., Vol. 10, No. 10, 2008
1985

Danishefsky’s dienes 2a,b, while the remaining carbons and
nitrogens come from the 1,2-diaza-1,3-butadienes 1a-i. On
the other hand, in the transformation of 1a-i and 2a,b into
6a-f, three carbons of the pyrazole ring derive from C-1,
C-2, and C-3 of the Danishefsky’s dienes 2a,b, while the
remaining two nitrogens come from the 1,2-diaza-1,3-
butadienes 1a-i.
Very interestingly, a different and unexpected behavior
was observed when Danisheftsky’s diene 2a reacted with
1,2-diaza-1,3-butadienes 1a,f in water and in the absence of
Lewis acids. In fact, 5H-1-aminopyrroles 7a,b, different from
4H-1-aminopyrroles 5a-h obtained via the Mukaiyama-
Michael-type addition/heterocyclization, were formed in good
yields (Scheme 4). These results agree with the fact that the
Danisheftsky’s diene 2a is a synthetic equivalent of 3-ox-
obutanal, likely because the hydrolytic process 2a participates
in the Michael addition as a masked 3-oxobutanal (D). Then,
the following intramolecular nucleophilic attack of hydra-
zonic nitrogen at the highly reactive aldehydic carbonyl group
produces 5H-aminopyrroles 7a,b. These results are supported
by spectroscopic evidence and are in agreement with some
of our previous findings.19
clization sequence has given further examples of its synthetic
utility and versatility, as a function of the experimental
conditions used. In fact, we found that conditions able to
furnish both 4H-1-aminopyrroles (5) and 4,5H-pyrazoles (6).
Moreover, the unexpected formation of 5H-1-aminopyrroles
(7) from 1,2-diaza-1,3-butadienes and Danishefsky’s diene
in water without Lewis acids catalysis further explains their
reactivity. All azaheterocycles synthesized are highly func-
tionalized and, therefore, can be further modified. The
advantage of use the 1,2-diaza-1,3-butadienes as a building
blocks in the modeling of azaheterocycles is the accessibility
of the starting materials and the simplicity of the experi-
mental procedures.
Acknowledgment. This work was supported through the
financialassistanceoftheMinisterodell’Istruzione,dell’Uni-
versita` e della Ricerca (MIUR) Roma, and Universita` degli
Studi di Urbino “Carlo Bo” e di Bologna.
Supporting Information Available: Experimental pro-
cedures, table of products, and full characterization for all
compounds. X-ray crystallographic data (CIF) and ORTEP
drawing of compound 6a. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800557H
Scheme 4. Water-Mediated Addition/Heterocyclization
Reactions of Danishefsky’s Diene 2a on
1,2-Diaza-1,3-butadienes 1a,f. Synthesis of 5H-Aminopyrroles
7a,b
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the pyrrole ring of 7a,b derive from C-1 and C-2 of the
Danishefsky’s diene 2a, while the remaining carbons and
nitrogens come from the 1,2-diaza-1,3-butadienes 1a,f.
For example, different carbons of diene 2a participate in
the formation of 4H-1-aminopyrroles 5a-h or that of 5H-
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