Versatile base-catalyzed route to polycyclic heteroaromatic compounds by intramolecular Aza-Michael addition

Article abstract of DOI:10.1002/ejoc.200601139

A catalytic new synthetic approach to 3,4-dihydropyrazino[1,2-α] indol-1(2H)-ones by intramolecular 1,4-addition of readily available α,β-unsaturated esters, is described. Here, the use of a range of organic as well as inorganic bases (5-10 mol-%) allowed

Full text of DOI:10.1002/ejoc.200601139

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200601139
Versatile Base-Catalyzed Route to Polycyclic Heteroaromatic Compounds by
Intramolecular Aza-Michael Addition
Marco Bandini,*[a] Astrid Eichholzer,[a] Magda Monari,[a] Fabio Piccinelli,[a] and
Achille Umani-Ronchi*[a]
Keywords: Catalysis / Indole / Michael addition / Natural compounds / Pyrrole
A catalytic new synthetic approach to 3,4-dihydropyraz-
ino[1,2-a]indol-1(2H)-ones by intramolecular 1,4-addition of
readily available α,β-unsaturated esters, is described. Here,
the use of a range of organic as well as inorganic bases (5–
10 mol-%) allowed a fast (30 min) and regioselective ring-
closing reaction to be performed in high yields under simple
operational conditions. Moreover, the protocol was effec-
tively employed, as the key step, in the synthesis of the di-
bromopyrrolo alkaloid derivative N-Bn-longamide b.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Development of new catalytic and eco-sustainable syn-
thetic routes to the formation of functionalized physiologi-
cally active polycyclic scaffolds is a longstanding goal for
numerous research teams. Feasibility on several scales and
generality in scope are among the most important aspects
addressed during the design of synthetic strategies. Pyrroles
and their benzo-fused analogous indoles are present in a
large number of biologically active compounds[1] and over
the past decades catalytic intramolecular as well as intermo-
lecular protocols have featured prominently the direct and
selective functionalization of these aza-aromatic systems.[2]
In this scenario, emerging classes of molecular fragments
in medicinal chemistry are 3,4-dihydropyrazino[1,2-a]indol-
1(2H)-ones (1) and 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-
ones (2, Figure 1).[3,4] Here, despite the growing interest for
these compounds, no examples of direct catalytic and re-
gioselective strategies for their preparation have been re-
ported to date.[5]
Figure 1. Intramolecular Michael addition as a key step in the syn-
thesis of polycyclic indole- and pyrrole-based compounds.
from the ready availability of precursors 3a and 4[8] that
furnished 5a in 76% yield (40 min) without the need for
chromatographic purification (Scheme 1).
Taking advantage of our recent reports on catalytic intra-
molecular regioselective C3-alkylations of indoles through
indolyl enones (Michael reaction)[6] and allyl indolyl car-
bonates (allylic alkylation),[7] we envisaged an intramolecu-
lar N1-alkylation variant for the construction of the title
molecular motifs 1 and 2.
Scheme 1. Synthesis of pyrazino-indol-1-one precursor 5a.
After several efforts, we individuated, in the indole-2-car-
boxamide 5a, a potentially useful acyclic precursor for pyr-
azino-indolones 1. The reliability of the pathway arises
Suitable crystals of 5a for single-crystal X-ray diffraction
(Supporting Information) were obtained by slow diffusion
of hexane into a solution of 5a in CH2Cl2 (room temp., 3 d)
and the molecular packing revealed the existence of tight
dimeric adducts stabilized by complementary strong inter-
molecular hydrogen-bonding interactions between the N1-
H atom and the carbonyl (amide) moiety of the coupled
molecule.[9] Then, the strong acidity of the indole N1-H
atom in 5a,[10] probably ascribable to the presence of the
electron-withdrawing group (EWG) at the C2 position, sug-
[a] Dipartimento di Chimica “G. Ciamician”, Università di Bolo-
gna,
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: marco.bandini@unibo.it
achille.umanironchi@unibo.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 2917–2920
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Bandini, A. Eichholzer, M. Monari, F. Piccinelli, A. Umani-Ronchi
Proofs for the molecular structure of the cyclized product
SHORT COMMUNICATION
gested that mild basic conditions could promote the ring-
closing step through deprotonation of the indolyl ring. At came from the X-ray diffraction analysis of single crystals
the same time, the EWG would guarantee a high regioselec- (AcOEt, slow diffusion, room temp., 5 d) of 6a that unam-
tivity toward N1-annulation (kinetic control) by decreasing biguously showed the operating regiospecific, kinetic N-al-
the nucleophilicity of the competitor C3 site (thermo- kylation pathway (Figure 2).
dynamic control).[1a,7a] Efforts in this direction have been
already reported by Banwell and co-workers who proposed
an intramolecular 1,4-addition/alkylation of pyrroles pro-
moted by 3 equiv. of NaOMe to obtain the cyclized com-
pound in 45% isolated yield.[11]
Since that paper had appeared, several studies appeared
in the literature focusing on the N-ring-closing reaction for
the synthesis of polycyclic heteroaromatic compounds;
however, no catalytic versions with general scope of sub-
strates were reported to date.
At the outset of optimization of the reaction conditions,
we considered the intramolecular conjugated addition of 5a
in the presence of catalytic amounts of DABCO (10 mol-
Figure 2. X-ray structure of (Ϯ)-6a (only one enantiomer is shown).
%) that furnished the N-cyclized compound 6a regioselec-
tively.[12] The data collected in Table 1 (Entries 1–3) high-
With the optimized reaction parameters in hand, we en-
visioned the generality of the protocol by subjecting a range
light the expected influence of the reaction medium on the
final outcome.[1a] In particular, by changing the solvent
of variously functionalized indolyl precursors to cyclization
from weakly (CH2Cl2) to strongly coordinating ones
(K2CO3, 10 mol-%, room temp.), and the final outcome is
(CH3CN, DMSO) the reaction rate increased due to the
summarized in Scheme 2. High tolerance toward both elec-
formation of solvent-separated ion pairs. Among them, the
tron-withdrawing and electron-donating groups at the C5
highest reaction rates were reached in DMSO that guaran-
position (X = Cl, Me, MeO) is highlighted by the high
teed 71% conversion into 6a within 4 h. Remarkably, (–)-
yields obtained in the cyclization of 5b–d (see Supporting
sparteine proved to be efficient in the ring-closing reaction
Information) to 6b–d (69–82%). Also enantiomerically pure
of 5a (30 min, 92% yield, Entry 4) with the possibility to
precursor 5e containing a (S)-phenylethylamine unit was cy-
increase the operational simplicity of the protocol by run-
clized successfully under optimal conditions (conv. 93%);
ning the title Michael addition in open-air vials and with
however, 6e was isolated with only moderate diastereoselec-
tivity (dr = 65:35).
reagent-grade DMSO (Entry 5). However, the absence of
stereoinduction in 6a prompted us to test less expensive cat-
alysts, and a brief survey of additives led us to K2CO3 as
the optimal catalytic species (10 mol-%, 30 min, conv.
Ͼ 98%, Entry 6).[13]
Table 1. Optimization of the reaction conditions for the base-cata-
lyzed intramolecular Michael reaction of 5a.[a]
Entry Base
Solvent
T [h] Conv. to 6a [%][b]
1
2
3
4
5
6
7
8
DABCO
DABCO
DABCO
CH2Cl2
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
24
4
4
0.5
3
0.5
1
Ͻ 20
53
71
98 (92)
95
Ͼ 98
Ͼ 98
5
Scheme 2. Catalytic synthesis of functionalized dihydropyraz-
ino[1,2-a]indol-1(2H)-ones.
(–)-sparteine
(–)-sparteine[c]
K2CO3
Then, in the light of recent findings that underline the
beneficial role of aryl groups in the C3 position of the in-
dole core (antibacterial activity), we synthesized the corre-
sponding acyclic precursors 5f,g by Suzuki cross-coupling
reaction {[Pd(PPh3)4]/ArB(OH)2/Na2CO3} in good overall
yield (see Supporting Information). Gratifyingly, the N-cyc-
lization does not seem to be significantly affected by the
presence of the aryl substituents at the C3 position, furnish-
[d]
K2CO3
–
24
[a] All reactions were carried out at room temp. under anhydrous
conditions in the presence of 10 mol-% of catalyst, unless otherwise
specified. [b] Determined by HPLC. Isolated yields are given in
parentheses. In all cases the N/C-alkylation ratio was found to be
Ͼ50:1. [c] Commercial-grade DMSO was used. [d] 5 mol-% of
K2CO3 was employed.
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Polycyclic Heteroaromatic Compounds by Intramolecular Aza-Michael Addition
SHORT COMMUNICATION
Scheme 3. Synthesis of 3-aryl-dihydropyrazino-indolinones 6f,g by K2CO3-catalyzed ring-closing reaction.
ing the desired polycyclic compounds (6f,g) in high isolated with the possibility to extend the method to important pyr-
yields (80–90%, Scheme 3).
role-based secondary metabolites such as longamide b.
In the perspective of exploiting the present catalytic sys- Studies addressed toward the development of stereocon-
tem for the synthesis of important naturally occurring sec- trolled versions of this intramolecular Michael addition are
ondary metabolites bearing a 4,5-dibromopyrrolyl core,[14] under way.
pyrrole-2-carboxamide 7 was readily prepared starting from
commercially available pyrrole-2-carboxylic acid (yield
Experimental Section
53%) and subsequently smoothly cyclized in the presence
of K2CO3 (10 mol-%, DMSO, room temp., 20 min) to pro-
vide 8 in 74% isolated yield (Scheme 4) The regioselective
bromination of the pyrrole ring led to substituted 3,4-dihy-
dropyrrolo[1,2-a]pyrazin-1(2H)-one 9 (47%), a molecular
skeleton embedded in numerous pyrrole alkaloids of Agela-
sida sponges, that was finally hydrolyzed to the derivative
N-Bn-longamide b (10)[4a] in 61% yield.
Typical Procedure for the Synthesis of Indolcarboxamides 5: In a
three-necked round-bottomed flask, equipped with a dropping fun-
nel, the ester 4 (2.6 mmol) was dissolved in anhydrous CH2Cl2
(20 mL). The mixture was cooled to 0 °C when TEA (3.9 mmol)
was added followed by a solution of the corresponding chloride 3
(2.0 mmol), dissolved in CH2Cl2 (5 mL). The reaction mixture was
kept at 0 °C for 1 h, then the reaction was quenched with H2O
(8 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ5 mL)
and the combined organic layers were dried with Na2SO4. The sol-
vent was evaporated under reduced pressure and the crude product
was purified by washing with an appropriate solvent.
Typical K2CO3-Catalyzed Cyclization for the Synthesis of Pyrazino
Compounds 6: In a flame-dried two-necked flask, the indolyl pre-
cursor 5 (0.05 mmol) was dissolved in anhydrous DMSO (1 mL)
and 10 mol-% of K2CO3 was added. After stirring at room temp.
for the specified time (complete consumption of 5 was judged by
TLC and HPLC), the reaction mixture was diluted with AcOEt
(3 mL) and washed with H2O (3ϫ5 mL). After evaporation of the
volatiles, the crude product was purified by flash chromatography.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, analytical and spectral char-
acterization data for all the compounds.
Scheme 4. Racemic synthesis of N-Bn-longamide b. Reagents and
conditions: i) K2CO3 (10 mol-%), DMSO, room temp., 20 min;
ii) NBS, CH2Cl2, room temp.; iii) KOH, MeOH/H2O, reflux, 16 h.
CCDC-623047 (for 5a) and -623048 (for 6a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Conclusion
We described a practical and effective catalytic strategy
for the preparation of unprecedented polycyclic indole/pyr-
role compounds by intramolecular 1,4-addition. The com-
plete regioselectivity observed was guaranteed by the use
of catalytic amounts of K2CO3 that furnished N-alkylated
compounds in a short reaction time. With an unprece-
dented scope for both indole and pyrrole rings, this proto-
col allowed a range of variously functionalized dihydropyr-
Acknowledgments
This work was supported by M.I.U.R (Rome), National project
“Sintesi e stereocontrollo di molecole organiche per lo sviluppo
di metodologie innovative di interesse applicativo”, FIRB Project
(Progettazione, preparazione e valutazione biologica e farmacolog-
ica di nuove molecole organiche quali potenziali farmaci innova-
azinindolones to be readily prepared under mild conditions tivi), Consorzio C.I.N.M.P.I.S. and from University of Bologna.
Eur. J. Org. Chem. 2007, 2917–2920
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M. Bandini, A. Eichholzer, M. Monari, F. Piccinelli, A. Umani-Ronchi
SHORT COMMUNICATION
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Received: December 31, 2006
Published Online: February 23, 2007
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Eur. J. Org. Chem. 2007, 2917–2920