Synthesis of multi-functionalized 1-azabicycles through MAOS acid catalyzed formal aza-[3+3] cycloaddition of heterocyclic enaminones with oxazolones

Article abstract of DOI:10.1016/j.tetlet.2013.04.055

This study describes the combination of microwave heating and green acid catalysis by Bi(NO₃)₃·5H₂O and AcOH as a practical one-pot diastereoselective synthetic route to alkaloid-like multi-functionalized 3,4-disubstituted indolizidinones and quinolizidinones from cyclic enaminones and Erlenmeyer-Plo?chl azalactone derivatives, as an alternative methodology to access these synthetically and biologically important classes of structural scaffolds in a simple way. The potential biological activity of some synthesized alkaloid-like derivatives was tested against the human tumor lineage hepatoma (HepG-2), and their inhibitory effect evaluated after 24 and 48 h. The indolizidine-like scaffold appears to be crucial to biological activity in the investigated compounds.

Full text of DOI:10.1016/j.tetlet.2013.04.055

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of multi-functionalized 1-azabicycles through MAOS acid
catalyzed formal aza-[3+3] cycloaddition of heterocyclic enaminones
with oxazolones
Silvio Cunha a,b, , Raimundo Francisco dos Santos Filho a,b, Katharine Hodel Saraiva c,
⇑
Alene Vanessa Azevedo-Santos c, Diego Menezes c
a Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, Salvador, BA 40170-290, Brazil
b Instituto Nacional de Ciência e Tecnologia—INCT em Energia e Ambiente, Universidade Federal da Bahia, Campus de Ondina, Salvador, BA 40170-290, Brazil
c Núcleo de Biotecnologia e Bioprospecção (NBBio), Escola Bahiana de Medicina e Saúde Pública, Salvador, BA 40050-420, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
This study describes the combination of microwave heating and green acid catalysis by Bi(NO3)3Á5H2O
and AcOH as a practical one-pot diastereoselective synthetic route to alkaloid-like multi-functionalized
3,4-disubstituted indolizidinones and quinolizidinones from cyclic enaminones and Erlenmeyer–Plöchl
azalactone derivatives, as an alternative methodology to access these synthetically and biologically
important classes of structural scaffolds in a simple way. The potential biological activity of some synthe-
sized alkaloid-like derivatives was tested against the human tumor lineage hepatoma (HepG-2), and their
inhibitory effect evaluated after 24 and 48 h. The indolizidine-like scaffold appears to be crucial to bio-
logical activity in the investigated compounds.
Received 21 March 2013
Revised 10 April 2013
Accepted 15 April 2013
Available online xxxx
Keywords:
Indolizidinones
Quinolizidinones
Erlenmeyer–Plöchl azalactones
Bi(NO3)3Á5H2O
Ó 2013 Elsevier Ltd. All rights reserved.
Microwave heating
Introduction
same 2-pyridones,13 and Stille and co-workers extended this aza-
Polysubstituted and multi-functionalized 1-azabicyclics such as
indolizidinones and quinolizidinones are alkaloid-like privileged
structural scaffolds which have been studied due to their relevant
biological activities.1–4 In this way, the formal aza-[3+3] cycloaddi-
tion has emerged as a powerful5–7 and sustainable synthetic meth-
od to these heterocycles.8 The subclasses of 3-amido-4-aryl
dihydroindolizide-2-one and dihydroquinolizidine-2-one deriva-
tives, and unsaturated analogues, have attracted increased atten-
tion due to their potential as peptidomimetics and anticancer
compounds.9,10 In this context, we rationalized that such azabicy-
cles should be accessed by a formal aza-[3+3] cycloaddition of cyc-
lic enaminones and Erlenmeyer–Plöchl azalactones because acyclic
enaminones were effective in the synthesis of monocyclic lactams
using such approach. In this way, Eynde and co-workers described
a thermally induced formal aza-[3+3] cycloaddition reaction of
acyclic enaminones with oxazolones,11 and later extended these
reactions to a microwave (MW) solvent-free condition.12 In an
independent work, Chiba and Takahashi reported the synthesis of
Eynde et al.11,12
O
N
R1
1985: chlorobenzene
reflux
or
Ar
R1
Ar
N
N
+
H
O
1997: solvent-free
N
H
Ph
H
H
MW
O
O
O
O
Ph
only cis isomer
Eynde et al., 1985 and 199711,12 1985: EtOH, EtONa
Chiba and Takahashi, 198513
reflux
O
N
R1
or
1997: solvent-free
R1
OEt
MW
N
+
O
or
N
H
H
H
H
Ph
N
1985: Dioxane, Et3N
O
O
reflux
O
O
Ph
O
R1
Stille et al., 199714
R1
OEt
DMF
reflux
O
N
+
N
N
O
H
H
N
Ph
O
O
O
O
O
O
O
Ph
Figure 1. Previously reported formal aza-[3+3] cycloaddition of acyclic enaminones
with azalactones.
⇑
Corresponding author.
E-mail address: silviodc@ufba.br (S. Cunha).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.055
Please cite this article in press as: Cunha, S.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.055

2
S. Cunha et al. / Tetrahedron Letters xxx (2013) xxx–xxx
R
the association of acid catalysis and microwave assisted organic
R = C6H5 (2a), 4-ClC6H4 (2b),
synthesis (MAOS) is pivotal to the formation of the multi-function-
alized 1-azabicycles, switching diastereoselectivity in relation to
previously described monocycles, Figure 1.
4-NO2C6H4 (2c), 3-NO2C6H4 (2d),
2-NO2C6H4 (2e), 4-MeOC6H4 (2f),
4-HOC6H4 (2g), 4-Me2NC6H4 (2h),
3,4-(OCH2O)C6H3 (2i), furan-2-yl (2j)
N
O
O
Ph
2a-j
Results and discussion
Figure 2. Tested azalactones in the formal aza-[3+3].
To synthesize a representative set of alkaloid-like multi-func-
tionalized indolizidinones and quinolizidinones, heterocyclic
enaminones 1a,b16 and ten azalactones 2a–j17 were prepared, Fig-
ure 2 and Scheme 1. Whereas all reagents were solids, the solvent-
free condition12 was not applicable, and thus the model reaction of
1a and 2a was investigated in several conditions to allow the opti-
mization of reaction parameters in search of the most general one.
Toward this end, we first tried the reaction in acetonitrile at room
temperature, but the reagents were recovered without any change,
and this was the same result under reflux condition, Table 1 (en-
tries 1 and 2). Thus, our enrollment with the synthetic application
of bismuth salts in organic synthesis18,19 prompted us to try such
Lewis acids. To our delight, when a small amount of Bi(NO3)3Á5H2O
was added to the reaction mixture, a slow transformation took
place and the planned bicyclic lactam 3a was obtained in excellent
yield (Table 1, entry 3 and Scheme 1).
Due to the long reaction time other solvents were investigated
(entries 4–6), but only complex mixtures were formed. Despite re-
agents were consumed with other tested salts (entries 7 and 8), no
satisfactory yields were observed, and with SnCl2 a non-selective
reaction took place (entry 8), being the sole example where the
cis isomer 3b was the major one. In this way, microwave (MW)
and ultrasound irradiation were tentatively employed in order to
optimize yield and reaction time. The reaction of 1a and 2a under
MW heating without catalyst afforded compound 3a in a short
reaction time but the yield dropped in comparison to conventional
heating (entries 3, 9, and 10; for the stereochemical assignment of
3a, see below). When the reaction was carried out under MW in
the presence of Bi(NO3)3Á5H2O compound 3a was isolated with a
shorter reaction time and with same excellent yield obtained un-
der conventional heating (entries 3 and 11, Table 1).
O
N
O
O
O
N
O
4
3
H
H
+
N
N
O
O
Ph
Ph
O
3a 93%, 96h
3a 93%, 1.5h MW or
3a 93%, 0.5h MW AcOH 10mol%
3b 0%
O
O
O
Cl
4
74%, 48h
72%, 1.5h MW or
71%, 0.5h MW
AcOH 10mol%
N
H
N
O
Ph
2a, Ar = Ph, R2 = Ph
2b, Ar = 4ClPh, R2 = Ph
2c, Ar = 4NO2Ph, R2 = Ph
2k, Ar = Ph, R2 = CH3
O
N
O
NO2
O
O
NO2
Bi(NO3)3 10mol%
CH3CN, reflux
H
N
H
+
N
N
O
O
Ph
5a 0%
Ar
O
Ph
O
2a-d
5b 15%, 19h
N
5a + 5b 40% (1:2.5), 28h in EtOH
AcOH 10mol% and Ultrasound
2
R
O
O
O
O
O
N
O
OCH3
N
H
+
H
N
N
(
)
n
O
O
NH
O
O
O
R1
6a + 6b 94% (2:1)
1a, n = 1, R1 = H
O
O
1b, n = 2, R1 = H
The search for additional environmental benign catalyst
prompted us to try the reaction using acetic acid, which allowed
the isolation of 3a in yield as good as obtained under both conven-
1c, n = 1, R1 = CH2OAc
7
64%, 15min
O
N
Ph
O
N
H
O
O
O
OEt
2l
N
Table 1
Ph
8
48%, 20min
99%, 20min
O
Reaction conditions to the formal aza-[3+3] cycloaddition of enaminone 1a and
azalactones 2a to yield 3a
O
N
Ph
N
H
O
Bi(NO3)3 10mol%
EtOH, MW
Catalyst (10 mol %) Conditiona
Time (h) Yield (%)
O
O
Entry Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CH3CN
CH3CN
CH3CN
Toluene
None
None
rt
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
MW 150 W
MW 300 W
MW 150 W
MW 300 W
MW 150 W
MW 300 W
))) 80 Hz rt
))) 80 Hz rt
48
48
96
48
48
48
24
24
2
1
1.5
1
1.5
0.5
smb
smb
93
9
O
Bi(NO3)3Á5H2O
N
Bi(NO3)3Á5H2O
cmc
cmc
cmc
11
Ph
N
H
Dioxane Bi(NO3)3Á5H2O
O
O
Xylene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
Bi(NO3)3Á5H2O
O
BiI3
SnCl2
None
None
52d
75
75
93
45
93
93
50
45
Scheme 1. Formal aza-[3+3] cycloaddition of cyclic enaminones.
annulation to a chiral enaminone,14 Figure 1.
Bi(NO3)3Á5H2O
SnCl2
Despite the great achievements abovementioned, the synthetic
potential of these formal aza-[3+3] cycloadditions is still limited to
acyclic enaminones with the formation of monocyclic heterocycles,
and the conditions developed are somewhat harsh and not directly
applicable to solid cyclic enaminones. Due to our continued
involvement in the synthetic applications of enaminones,15 we
envisioned a strategy to the one-pot synthesis of densely function-
alized indolizidinones and quinolizidinones through the reaction of
cyclic enaminones with oxazolones, and herein we discovered that
AcOH
AcOH
Bi(NO3)3Á5H2O
38
38
Bi(NO3)3Á5H2O
Best conditions in bold.
a
MW: microwave irradiation, and))): ultrasound.
sm: Starting material.
cm: Complex mixture.
b
c
d
3b Major (3a:3b 1:1.6).
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S. Cunha et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
O
N
O
ered in the reactions with 2d–f. Indeed, azalactone 2k derived from
N-acetylglycine (not shown in Fig. 2) was able to afford a clear reac-
tion. Thus, azalactone 2b afforded indolizidinone 4 with almost the
same good yield under the three heating conditions presented in
Scheme 1 (yield was only 40% under ultrasound; data not shown).
Otherwise, in the reaction of azalactone 2c and enaminone 1a with
conventional heating and Bi(NO3)3Á5H2O catalysis, the cis indolizid-
inone 5b was solely isolated albeit in low yield, which formed as a
complex mixture either under MW or conventional heating in the
absence of Lewis acid, Scheme 1. On the other hand, in the catalysis
by AcOH, indolizidinones 5a and 5b were isolated in better yield as a
mixture of diastereomers (1:2.5, respectively). Interestingly, the cis
isomer was the major one, in contrast to the observed behavior to
indolizidinones 3–4 and to the reaction with azalactone 2k where
diastereomers 6a (trans major) and 6b were formed.
OEt
O
Bi(NO3)3 10mol%
O
N
+
O
N
EtOH, MW
20min
Ph
H
Ph
N
H
H
H
O
O
O
1d
2l
10 38%
Scheme 2. Formal aza-[3+3] cycloaddition of acyclic enaminone.
tional and MW heating with Bi(NO3)3Á5H2O catalysis, within the
shortest observed reaction time (entries 3, 11, and 14). Otherwise,
reactions carried out under ultrasound irradiation presented
unsatisfactory performance in the model reaction because yields
were poor and shown a long reaction time when compared to
MW heating (entries 15 and 16).
The direct application of the best protocols to azalactones 2b–j
depicted in Figure 2 was not at all satisfactory. Furthermore, only
azalactones 2b and 2c afforded clean reactions under the best con-
ditions highlighted in Table 1, once the reaction of enaminone 1a
and 2g–j resulted in complex mixtures, and reagents were recov-
With isolated isomers 3a and 4, and mixtures of pairs of insepa-
rable diastereomers 3a–3b, 5a–5b, and 6a–6b in hand, the designa-
tion of which isomer was formed as the major or sole compound
could be possible. The stereochemical assignment was done taking
into account the relative cis–trans stereochemical distinction
3a 48 hours
3a 24 hours
0.08
*
0.08
*
0.06
0.04
0.02
0.00
0.06
0.04
0.02
0.00
Control DMSO
50 µM
100 µM
Control DMSO
50 µM
100 µM
4 48 hours
0.036
0.034
0.032
0.030
0.028
Control DMSO
50 µM
100 µM
10 24 hours
10 48 hours
0.06
0.04
0.02
0.00
0.040
0.035
0.030
0.025
Control DMSO
50 µM
100 µM
Control DMSO
50 µM
100 µM
Figure 3. In vitro effect on HepG2 proliferation of 3a, 4, 5a+b, and 10 after 24 and 48 h. ⁄P <0.05 statistically different (Dunnett).
Please cite this article in press as: Cunha, S.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.055

4
S. Cunha et al. / Tetrahedron Letters xxx (2013) xxx–xxx
realized by Eynde and co-workers in the thermally induced formal
aza-[3+3] cycloaddition reaction of acyclic enaminones with
oxazolones.11,12 Although these described reactions resulted in the
formation of cis-3,4-dihydro-2-pyridones selectively, they also syn-
thesized another set of monocyclic cis- and trans-3,4-dihydro-2-
pyridones structurally analogous to compounds presented in
Scheme 1. Two reported aspects of the 1H NMR were crucial to the
distinction of relative stereochemistry: the chemical shift of CH
hydrogens at positions 3 and 4 is more deshielded for the cis isomer
(dH3cis 4.8–5.0 and dH4cis 4.2–4.4 ppm; dH3trans 4.4–4.6 and dH4trans
3.9–4.1 ppm), and the vicinal coupling constant is larger for the cis
isomer also (3JH3H4cis 7 and 3JH3H4trans 2 Hz).11,12
tionally, it has an increased effect with respect to dose and
exposure time on the tumor cells of HepG2.
It is noteworthy that the indolizidine-like scaffold appears to be
crucial to biological activity, because when monocyclic derivative
10 was tested in the same conditions of indolizidinones 3a, 4,
and 5a–b, it was less effective than 3a and 4 in 24 h. Curiously,
the effect after 48 h was up modulation instead of the inhibitory ef-
fect, Figure 3.
In conclusion, this study shows that the combination of micro-
wave heating and green acid catalysis by Bi(NO3)3Á5H2O or AcOH
constitutes a practical synthetic route to alkaloid-like multi-func-
tionalized indolizidinones and quinolizidinones from heterocyclic
enaminones and Erlenmeyer–Plöchl azalactone derivatives, as an
alternative methodology to access synthetically and biologically
important classes of structural scaffolds in a simple way.20
Application of the above criteria to the mentioned pair of dia-
stereomers 3a–3b, 5a–5b, and 6a–6b allowed cis–trans discrimina-
tion because they were formed in different amounts distinguished
by the 1H NMR spectra. In this way, for the set of deshielded hydro-
gens H3/H4, signals are in the range of dH3 5.0–5.2/dH4 4.5–4.8 ppm
(3JH3H4 7.5–8.1 Hz), and for the other set of less deshielded H3/H4
the corresponding values are dH3 4.8–5.0/dH4 4.2–4.4 ppm (3JH3H4
3.3–4.2 Hz). Thus, comparison of these data with the reported val-
ues fits the first and second hydrogen sets to cis and trans isomers,
respectively.11,12 In this way, application of these criteria revealed
the preferential trans diastereoselectivity for almost all 3,4-dihydro
azabicyclic compounds 3–8 synthesized, whereas the preference to
only cis isomer 5b in the reaction of 2c was observed which has a
very strong electron withdrawing NO2 group at the phenyl ring.
Furthermore, switching diastereoselectivity to trans by the use of
acid catalysis was differential in the synthesis of these 1-azabycy-
cles, in contrast to previously described cis diastereoselectivity in
the formal aza-[3+3] cycloaddition of acyclic enaminones and
Erlenmeyer–Plöchl azalactones.11,12 Curiously, the vicinal coupling
constant of hydrogen H3 with amidic NH presents a larger value
than the coupling with H4. This was proved in a chemical exchange
experiment with D2O for compound 3a, wherein the double dou-
blet at 4.97 ppm (3J 8.5 and 4.0 Hz) changed to a doublet (3J 3.6 Hz).
With a secure procedure developed to the formal aza-[3+3]
cycloaddition, we planned to increase the scope of alkaloid-like
compounds accessed by varying the nature of the electrophilic
component. In this sense, extension of the bismuth catalysis to
the reaction with biselectrophile 2l afforded azabicycle 7 with a
2-pyridone core embedded in its structure and decorated with
new substitution patterns, Scheme 1. The reaction was also ex-
tended to the six membered enaminone 1b, and quinolizidinone
8 could thus be isolated. The lower yield for this less reactive
enaminone is in accordance to other related azaannulations.15b
Additionally, chiral enaminone 1c afforded indolizidinone 9 quan-
titatively, as indicated through analysis of 1H NMR spectrum of
crude reaction mixture, although it suffered decomposition when
submitted to chromatographic purification. As mentioned before,
the combination of bismuth catalysis and MW irradiation was effi-
cient in the synthesis of densely substituted bicyclic heterocycles
in a trans-selective one-pot reaction, as can be seen in Scheme 1.
To compare the performance of developed methodology with
those previously described to acyclic liquid enaminone by Eynde12
or Chiba and Takahashi,13 enaminone 1d was reacted with Erlen-
meyer–Plöchl azalactone 2l under microwave heating and catalysis
by Bi(NO3)3Á5H2O. The developed methodology was not as effective
as the described methods because yield was low, Scheme 2.
To gain an insight into the potential biological activity of syn-
thesized alkaloid-like compounds, derivatives 3, 4, and 5a–b were
tested against the human tumor lineage hepatoma (HepG-2), being
their inhibitory effect evaluated after 24 and 48 h, in the tested
concentration, Figure 3. Compounds 3a, 4 and the mixture 5a–b
were active after 24 h. However, only compound 3a maintained
its inhibitory effect after 48 h, and shown a significant statistic dif-
ference when compared to DMSO in both the tested times. Addi-
Acknowledgments
The authors gratefully acknowledge the financial support of
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq) and Fundação de Amparo à Pesquisa do Estado da Bahia
(FAPESB). We also thank CNPq for fellowship to R.F.S.F., and a re-
search fellowship to S.C., and Professor Mauricio Victor for discus-
sion and comments.
Supplementary data
Supplementary data (experimental procedures, IR, 1H NMR and
13C NMR spectra for 3–10) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.04.055.
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Please cite this article in press as: Cunha, S.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.055