Formal aza-[3+3] versus aza-[3+2] cycloadditions of heterocyclic enaminones with maleic anhydride and maleimides: Skeletally diverse synthesis of pyrrolizidinones, indolizidinones, and pyrroloazepinones

Article abstract of DOI:10.1016/j.tet.2013.10.071

The domino aza-annulation of cyclic enaminones with maleic anhydride and maleimides was investigated, and selectively one-step skeletally diverse synthesis of each alkaloid-like pyrrolizidinone, indolizidinone, and pyrrolo[1,2-a]azepinone was developed, switching between aza-[3+3] and aza-[3+2] modes of formal cycloaddition reactions. For the synthesis of pyrroloazepinones, seven-membered enaminone and maleic anhydride or maleimides are efficient, via the [3+2] mode. To access indolizidinones, five or six-membered enaminones are the choice, and both [3+2] and [3+3] modes were viable exclusively with maleic anhydride. Pyrrolizidinone can be selectively synthesized in good yield through the [3+2] mode, only with five-membered enaminone and N-(4-NO₂Ph)maleimide, under catalysis by PTSA.

Full text of DOI:10.1016/j.tet.2013.10.071

Tetrahedron 70 (2014) 3284e3290
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Formal aza-[3þ3] versus aza-[3þ2] cycloadditions of heterocyclic
enaminones with maleic anhydride and maleimides: skeletally
diverse synthesis of pyrrolizidinones, indolizidinones, and
pyrroloazepinones
,
b
,
a
,
y
a
Silvio Cunha a , Airam Oliveira Santos , Jose Tiago Menezes Correia ,
*
ꢀ
c
ꢀ
Jose Ricardo Sabino
a Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, Salvador, BA 40170-290, Brazil
b
^
Instituto Nacional de Ciencia e Tecnologia-INCT em Energia e Ambiente, Universidade Federal da Bahia, Campus de Ondina, Salvador, BA 40170-290,
Brazil
c
ꢀ
^
Instituto de Física, Universidade Federal de Goias, CP 131, 74001-970 GoianiadGO, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The domino aza-annulation of cyclic enaminones with maleic anhydride and maleimides was in-
vestigated, and selectively one-step skeletally diverse synthesis of each alkaloid-like pyrrolizidinone,
indolizidinone, and pyrrolo[1,2-a]azepinone was developed, switching between aza-[3þ3] and aza-[3þ2]
modes of formal cycloaddition reactions. For the synthesis of pyrroloazepinones, seven-membered en-
aminone and maleic anhydride or maleimides are efficient, via the [3þ2] mode. To access in-
dolizidinones, five or six-membered enaminones are the choice, and both [3þ2] and [3þ3] modes were
viable exclusively with maleic anhydride. Pyrrolizidinone can be selectively synthesized in good yield
through the [3þ2] mode, only with five-membered enaminone and N-(4-NO2Ph)maleimide, under ca-
talysis by PTSA.
Received 3 September 2013
Received in revised form 11 October 2013
Accepted 23 October 2013
Available online 29 October 2013
Keywords:
Enaminone
Heterocycle
Azaanulation
1-Azabicycles
Alkaloid-like
Ó 2013 Elsevier Ltd. All rights reserved.
1969, Agbalyan and Nersesyan
O
1970, Robson and Marcus
3
2
O
1981, Dobeneck
1997, D'Angelo
R
NHR
1. Introduction
3
R
1998, Caballero
2
O
R
O
R
2001, Ila and Junjappa
N
R
1981, Dobeneck
O
Fused bicyclic heterocycles with a bridgehead nitrogen atom are
present in various natural and unnatural bioactive compounds.
Among these heterocycles, 1-azabicyclo[3.3.0]octanes,1 1-
azabicyclo[4.3.0]nonanes,2 and 1-azabicyclo[5.3.0]decanes3 have
been synthesized by diverse approaches because they occur in
pyrrolizidines, indolizidines, and pyrroloazepines, which are three
important classes of structural scaffolds present in alkaloids and
alkaloid analogues with application in medicinal chemistry.4
Maleic anhydride and maleimides are easily available and ver-
satile electrophiles whose use in the synthesis of N-heterocycles,
including 1-azabicycles, is well described.5,6 A particular synthetic
approach involves their direct reaction with an enaminone.7e18
However, a close analysis of the reactions depicted in Fig. 1 reveals
a complex chameleonic behavior of enaminones in the aza-
OH
O
1
1982, Blaton Jr
1998, Caballero
N
R
3
1
3
8
O
2
R
O
O
N
4
NH2
1
Ph
O
R
OH
2
O
R
MeS
N
O
5
9
O
1
MeS
O
R
O
O
N
R
X
1988, Ila and Junjappa
1
1-2
O
H
1988, Ila and Junjappa
3
10
1
R
R
N
6
O
OEt
2
R
O
O
N
7
O
11
O
1970, Robson and
Marcus
2
H
R
EtO
O
O
O
N
OEt
O
N
1971, Blaton Jr
1998, Caballero
2002, Cunha
1
R
OH
1997, Furukawa
N
* Corresponding author. Tel.: þ55 71 3283 6814; fax: þ55 71 3283 6444; e-mail
O
O
N
1, X = O
2, X = NR
2
addresses: silviodc@ufba.br, silvioddc@gmail.com (S. Cunha).
O
R
y
1982, Nagasaka
1982, Nagasaka
~
^
Present address. Instituto Federal de Educac¸ ao, Ciencia e Tecnologia Baiano,
Campus Senhor do Bonfim, Senhor do Bonfim, BA, Caixa Postal 55, 489700-000,
Brazil.
Maleimides
Maleic anhnydride
Fig. 1. Reaction of enaminones with maleic anhydride and maleimides.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.071

S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
3285
Table 1
annulations with the studied electrophiles, whereby small variation
of the nature of substituents of both enaminone and mentioned
electrophiles, may result in significant variation of the double bond
position, and in nature of the obtained heterocycle. The 2-
pyrrolidone nucleus present in compounds 3e5 and 8,9, gener-
ated through formal aza-[3þ2] cycloaddition, predominated in most
of these reactions. The Michael adduct 10 and 11 were observed only
in reactions with maleimides, and 3,4-trans-disubstituted succini-
mide 6 was formed only with maleic anhydride, Fig. 1.
The formation of product 7 is remarkable; while acyclic enam-
inones are prone to react with maleic anhydride through formal
[3þ2] cycloaddition, the five-membered enaminone provides the
indolizidinone 7, which corresponds to a formal aza-[3þ3] cyclo-
addition. This is the unique example, and somewhat not expected,
of such reaction patterns.15
Reaction conditions to the formal aza-cycloaddition of enaminone 12a and maleic
anhydride 1
Entrya
Solvent
Catalyst
(mol %)
Yield (%)
13
14
1
2
3
4
Benzene
CH2Cl2
CHCl3
CH3CN
CH3CN
CH3CN
CH3CN
d
78
85
15
85
81
61
50
d
d
10
d
16
19
36
d
d
d
5b
6c
7
d
BiI3 (10)
BiI3 (100)
a
Reaction carried out 0.1 M in each reagent at rt.
Reaction at reflux.
Reaction carried out 0.6 M using 100 mmol of each reagent at rt.
b
c
Despite the scenario depicted in Fig. 1 represents a significant
contribution in the development of concise synthesis of N-based
heterocycles,19 the synthetic potential of the formal aza-cycload-
dition reactions of heterocyclic enaminones with maleic anhydride/
maleimides in the synthesis of densely substituted 1-azabicycles is
still under-exploited. Inspired by these facts, we decided to develop
a simple and divergent approach adequate to the purpose of syn-
thesize such heterocycles in a quick way, with emphasis on skeletal
diversity.20 This strategy is in connection with our effort devoted to
the development of simple one-pot and/or multicomponent syn-
thetic methodologies, which permit direct access of compounds to
biological evaluation.21 One of such approach employs enami-
nones22 as building blocks for the synthesis of N-heterocycles
through formal aza-cycloaddition reactions.17,23 In this way, we
disclosure herein our ongoing study concerning the formal aza-
[3þ2] and formal aza-[3þ3] cycloaddition reactions of cyclic
enaminones,24 including a chiral one, with maleic anhydride and N-
aryl-maleimides, wherein pyrrolizidinone, indolizidinone, and
pyrroloazepinone heterocycles could be selectively obtained.
Formation of the six-membered ring instead of five one, i.e.,
indolizidinone 13 versus pyrrolizidinone 14 (corresponding to for-
mal aza[3þ3] instead of aza[3þ2] cycloaddition) with the five-
membered enaminone 12a is not well understood, because in all
described reactions of acyclic enaminones with maleic anhydride
the 2-pyrrolidone nucleus is formed.7e13
We rationalized that a solvent effect should be operating in the
competition between the formal aza-[3þ3] versus aza-[3þ2] cy-
cloadditions, because the reactions shown in Fig. 1 with acyclic
enaminones were performed in polar solvents, while Nagasaka
employed benzene. In this way, we reevaluated the reaction of 12a
with 1 in polar solvents. After some experimentation, we discov-
ered that in CH2Cl2 and CH3CN the same indolizidinone 13 was
obtained in yields slightly better than in benzene as solvent (Table
1, entries 2 and 4). Curiously, using CHCl3 as solvent, indolizidinone
13 was obtained together with the isomeric pyrrolizidinone 14
(entry 3), as well as when the reaction was carried out in CH3CN at
reflux (entry 5). Despite 14 being formed in low yield, this aza-
[3þ2] product was not previously observed in the aza-annulation
described by Nagasaka.15
2. Results and discussion
Our synthetic enrollment with bismuth salts as Lewis acids in
organic synthesis21 prompted us to use bismuth iodine in CH3CN,
which increased the amount of isolated aza[3þ2] product 14 (en-
tries 6 and 7), being this the best condition to the one-pot synthesis
of the pyrrolizidinone 14. However, the formal aza[3þ3] product 13
was always formed as the major or exclusive compound in all
conditions herein studied with five-membered enaminone 12a and
maleic anhydride. This was also the result in the reaction of chiral
cyclic enaminone 12b, which allowed isolation of inseparable
mixture of epimeric indolizididinones 15a,b in good yield,
Scheme 1.
The structure of pyrrolizidinone 14 was elucidated based on the
spectral analysis. Moreover, during the synthetic methodology
development, a single crystal of 14 was obtained and its solid state
structure was unambiguously assigned to gain insight into con-
formational bias and intramolecular and intermolecular in-
teractions, Fig. 2.
To gain insight into the synthetic and mechanistic implications
in the reactions of maleic anhydride and maleimides with hetero-
cyclic enaminones en route to azabicycles, five, six, and seven-
membered enaminone derivatives 12aed were prepared, in-
cluding a chiral one.25 In an initial trial, enaminone 12a was reacted
with maleic anhydride 1 in the condition described by Nagasaka
and co-workers for the ethyl ester analogous of 12a.15 In this con-
dition, we obtained indolizidinone 13 in good yield, in a mmol
scale, Scheme 1 and Table 1 (entry 1).
O
MeO
N
O
OMe
O
OH
+
Conditions:
see Table 1
N
OH
13
14
O
O
12a R1 = Me
O
Me
R
2 = H, n = 1
O
O
12b: R1 = Me
R2 = CH2OAc
n = 1
O
OR1
+
Distinction between indolizidinone 13 and isomeric pyrrolizi-
dinone 14 could be easily done through analyses of their 1H NMR
data of the moiety corresponding to the atoms from maleic anhy-
dride, Fig. 3. Thus, the endocyclic conformationally restricted
COCH2CHCO2H spin system of 13 appears as an AMX system, while
the equivalent moiety COCHCH2CO2H of 14 is an ABX one. Besides,
the multiplicities of CH2 in 13 are two double doublet (2.61 and
2.87 ppm), and the methynic hydrogen is a large double doublet
(3.78 ppm). In the pyrrolizidinone 14, the free rotation of exocyclic
OH
( )n
R2
O
O
O
NH
12a-d
N
O
1
CH2Cl2
rt, 24h
AcO
O
12d: R1 = Et
15a,b 73% (1:1)
12c: R1 = Me
CH3CN
rt, 1h
R
2 = H
R
2 = H, n = 2
O
n = 3
O
OMe
CH3CN
rt, 1h
OEt
N
OH
O
N
O
methylene results in almost the same 3J value to the coupling
OH
17 99%
a
16 88%
O
O
constant of the two hydrogen of CH2 with vicinal CH, and then each
Scheme 1. Reactions of cyclic enaminones with maleic anhydride.
hydrogen CH2 of 14 appears as double doublets (3.00 and

3286
S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
membered ring, while they are located at the five-membered ring
of the aza[3þ2] product 16. Moreover, the results of present study
indicated that the formal aza-[3þ3] cycloaddition of maleic anhy-
dride, in useful yields, is exclusive to five-membered heterocyclic
enaminones, while the one-pot synthesis of 1-azabicyclo[4.3.0]
nonane and 1-azabicyclo[5.3.0]decane was accessed by the formal
aza-[3þ2] cycloaddition. However, this approach is not practical to
the synthesis of 1-azabicyclo[3.3.0]octane. To overcome this limi-
tation, we turned our attention to maleimides as alternative bise-
lectrophile, because there is one example of one-step formal aza-
[3þ2] cycloaddition with enaminone in good yield.13
Initially, the search for selective formation of aza-[3þ2] product
with heterocyclic enaminone 12a prompted us to try the reaction
using maleimide 2a in polar and apolar solvents, Scheme 2. How-
ever, only Michael adduct 18 was formed in excellent yield, Table 2
(entries 1e4). Contrary to the clean reaction with 12a, reaction of 2a
with enaminone 12c formed a complex mixture, and after purifi-
cation Michael adduct 19 was isolated in low yield. To our delight,
enaminone 12d afforded aza-[3þ2] products 20 and 21 in quanti-
tative yields from 2a and N-(4-NO2Ph)maleimide 2b, respectively,
in both polar/apolar investigated solvents, Scheme 2. Stimulated by
this results, the best conditions achieved for 12d was extended to
enaminone 12a and maleimide 2b, but here again only Michael
adduct 22 was formed, Table 2 (entries 5e7).
Fig. 2. Ortep27 representation of pyrrolizidinone 14. Displacement ellipsoids are drawn
at the 30% probability level and H atoms are shown as spheres of arbitrary radius.
H
N
H
N
O
O
20 99% O
18
OEt
19 30%
O
O
OMe
OMe
N
NH2
25 67%
O
O
O
O
N
N
Ph
H
O
H
12d R1 = Et
n = 2
N
12a R1 = Me n = 1
12c R1 = Me
n = 2
2a R2 = H
2a R2 = H
O
2a R2 = H
CH3CN rt, 1h
conditions/yields
in Table 2
CH3CN 24h, rt
(12h, reflux) or
PhCH3 24h, rt
(6h, reflux)
OMe
12a
O
OR1
N
H
+
2c R2 = Ph
O
O
N
( )n
CH3CN
+
O
NH
12a,c,d
R2
2a-c
O
PTSA
12d, 2b R2 = 4NO2Ph
CH3CN 15h, reflux or
PhCH3 24h, reflux
OMe
10mol%
reflux,14h
12a, 2b R2 = 4NO2Ph
conditions/yields in
Table 2
Ph
N
N
NO2
NO2
O
O
H
O
OEt
24 8%
NO2
O
O
OMe
N
N
N
+
O
H
O
O
N
N
H
21 99%
OMe
O
23
O
O
N
22
H
Fig. 3. Partial 1H NMR spectra of 13 (top) and 14 (bottom) shown the spin systems
COCH2CHCO2H and COCHCH2CO2H, respectively.
Scheme 2. Reactions of cyclic enaminones with maleimides.
3.12 ppm), and the methynic hydrogen is an apparent triplet
(3.58 ppm), Fig. 3.26
Table 2
Reaction conditions to the reaction of enaminone 12a and maleimides 2a,b
To understand the scope of the aza-annulation, reactions of 1
with six and seven-membered enaminones 12c,d were in-
vestigated. CH3CN was selected as solvent due to the good solubility
of the reagents, and because afforded clean reaction with enami-
none 12a at room temperature. In this condition, only formal aza-
[3þ2] cycloaddition products indolizidinone 16 and pyrroloazepi-
none 17 were generated in excellent yield from 12c and 12d, re-
spectively, Scheme 1. These facts are in contrast with the behavior
of five-membered enaminones 12a,b in the reaction with maleic
anhydride, which form exclusively indolizidinones 13 and 15a,b by
aza-[3þ3] cycloaddition.28
Entry Maleimide Conditions Time Yield (%)
(h)
72
18
22
23
1
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
CH3CN rt
96
94
78
99
2
CH3CN reflux
12
3
PhH reflux
48
4
PhCH3 reflux
24
5
6
7
CH3CN reflux
PhH reflux
PhCH3 reflux
12.5
28
21
95
72
81
8
9
10
11
12
CH3CN rt TFA 100 mol %
CH3CN rt PTSA 20 mol %
CHCl3 reflux TFA 100 mol %
PhCH3 60 ꢀC TFA 100 mol %
CH3CN reflux PTSA 20 mol %
240
216
70
66
14
Complex mixture
28
38
70
It should be pointed out that obtained indolizidinones 13 and 16
are complementary in terms of ring substitution, because in the aza
[3þ3] product 13 the functionalizations are at the new formed six-
8
72

S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
3287
r
r
Evaluating all results herein obtained in the reactions of five-
membered enaminone 12a with anhydride 1 (Table 1, entries
1e5) and maleimides 2a,b (Table 2, entries 5e7) revealed that
formal aza-[3þ3] cycloaddition and Michael reaction are the pre-
dominate reactions under thermal conditions, and acid catalysis
seems to be necessary for the formal aza-[3þ2] cycloaddition can
compete with these reactions (Table 1, entries 6 and 7). With this
work hypothesis in mind, we decided to try the reaction of 12a with
2b under acid conditions. Thus, after some initial experimentation,
the use of acid conditions showed to be adequate, because in al-
most all reactions pyrrolizidinone 23 could be finally isolated (Table
2, entries 8e12). When the solvent was acetonitrile at room tem-
perature, a very slow reaction took place using TFA 100 mol % or
PTSA 20 mol % (entries 8 and 9). In addition, yield increased and
reaction time decreased in the reaction carried out in CHCl3 or
toluene under reflux in the presence of 100 mol % TFA (entries 10
and 11). However, the reaction time was still long with excess acid.
Formation of aza-[3þ2] product 23 could be satisfactorily ac-
complished in good yield as major compound, and in reasonable
reaction time, using catalytic amount of PTSA in CH3CN, Table 2
(entry 12). We extended this best condition to N-phenyl-
maleimide 2c, and Michael adduct 25 was the major product in-
stead of aza-[3þ2] compound 24, Scheme 2.29 These results
indicate that the combination of the strong electron withdrawing
nitro group at N-aryl ring of maleimide, and PTSA catalysis appears
to be crucial to the successful formation of pyrrolizidinone nucleus
through formal aza-[3þ2] cycloaddition reaction of heterocyclic
five-membered enaminone and N-arylmaleimide.
N
CO2CH3
H
O
O
O
H
iv
v
side view
LUMO
O
X
O
X
O
Contrary to the general trend, reaction of 12a with maleimide 2b
furnished a complex mixture when TFA 100 mol % in CH3CN was
used (Table 2, entry 8), but a small amount of indolizidinone 26
could be isolated, Scheme 3. Interestingly, this is the unique ex-
ample to date of one-pot indolizidinone formation from reaction of
maleimide with 12a where double bond migration was observed.
O
O
LUMO
X
N
H
N
O
OR
side view
OR
O
H
O
vi
secondary interaction:
antibonding contribution
symmetry-allowed
O
HOMO
N
OR
H
O
n(
)
n(
)
HOMO
X
O
top view
symmetry-forbidden
N
H
N
O
X
H
OR
OR
O
O
NO2
O
MeO
O
NO2
r
[3+3] exo approximation
[3+3] endo approximation
O
CH3CN
OMe
TFA 100mol%
N
H
Scheme 4. Mechanistic proposals to [3þ3] and [3þ2] aza-annulations (X¼O/NAr):
+
O
reflux 48h
N
(top) stepwise pathways; (bottom) approximation rationalization.
O
12a
N
NH
2b
O
26 9%
O
mode with 1.31 The presence of more flexible six and seven-
membered rings in 12c,d, as compared to 12a, can be responsible
for a sterically hindered environment of transition state alike ib,
avoiding such approximation for these cyclic enaminones, and thus
driving the initial attack of the nitrogen to the carbonyl carbon of 1,
according to aza-[3þ2] pathway in Scheme 4.
Scheme 3. Aza-[3þ3] reactions of cyclic enaminone with maleimide.
Mechanistic considerations were formulated to the formation of
pyrrolizidinones, pyrroloazepinones, and indolizidinones herein
synthesized, and two postulated reaction pathways are exemplified
in Scheme 4 to the reaction of five-membered enaminone and
maleic anhydride.30 The formal aza-[3þ2] cycloaddition can be
rationalized as an ionic stepwise process whereby the key step is
initiated by attachment of the nitrogen of the enaminone to the
carbonyl carbon of 1 via a hard-hard interaction, probably by
a charge controlled reaction. Adduct ia is thus formed, which in
sequence forms maleamic acid derivative iia, Scheme 4. This late
suffers a 5-exo-trig cyclization via a Michael reaction forming
enolate iiia, which gives 14 after proton shift. Meanwhile, the for-
mal aza-[3þ3] cycloaddition pathway to indolizidinone formation
Frontier orbital analysis can also explain the different behavior
of the five-membered enaminones 12a,b and the six- and seven-
membered-ring enaminones 12c,d on reaction with maleic anhy-
dride (Scheme 4, right column). The [3þ3] approach of the reagents
can take place via an endo iv or exo v mode. The signs of the co-
efficients in the HOMO of enaminones32 12aed are favorable to
bonding interaction at carbon 2 and 4 of maleic anhydride with N1
and C3 of 12aed. However, in the [3þ3] endo approach iv, a sec-
ondary antibonding interaction occurs, leading to a transition state,
which should be more energetic than exo approach v. The favored
exo mode v is very sensitive to the bulk and planarity of the re-
agents. Thus, replacement of the more planar five-membered
enaminones 12a,b by the more flexible six and seven-membered
rings of 12c,d results in a more hindered environment, that is,
unfavorable to exo [3þ3] approximation, and thus the [3þ2] re-
action pathway is followed. Similar endo/exo mode to the [3þ2]
reaction is not favored due symmetry-forbidden orbital interaction
depicted in exo vi (Scheme 4, left column).
may be rationalized assuming
a concerted aza-ene reaction
through transition state ib, corresponding to softesoft interaction
under orbital controlled reaction, probably via a compact approx-
imation,31 which gives intermediate iib. In sequence, intra-
molecular N-acylation of iib occurs by the nitrogen attack to the
nearest carbonyl group, forming enolate iiib. Here again, isomeri-
zation to the enamide affords bicycle 13.
The compact transition state for the [3þ3] aza-annulation
When maleimides (where X¼NH or NAr) are used instead of
should explain why enaminones 12c,d did not react by this reaction
maleic anhydride, the soft-soft interactions are boosted. Therefore,

3288
S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
both the five- and six-membered enaminones 12a and 12c, re-
spectively, give iib products (compounds 18 and 19). However, the
seven-membered cyclic enaminone 12d gives predominantly the
[3þ2] product 20. The [3þ2] way is also favored when the Ar group
presents strong electron-withdrawing substituents, since in this
case hardehard interactions are increased. The addition of acid also
favors the hardehard interactions, because the carbonyl pro-
tonation of the maleimide 2b makes it a harder electrophile.33
(qt, J 7.2 Hz, 2H), 2.61 (dd, J 17.1 and J 8.4 Hz, 1H), 2.87 (dd, J 17.1 and
2.1 Hz, 1H), 3.00e3.22 (m, 2H), 3.55e3.72 (m, 2H), 3.66 (s, 3H), 3.78
(dd, J 8.4 and 2.1 Hz,1H), 9.60e9.90 (sl,1H). 13C NMR (CDCl3)
d 20.91
(CH2), 32.10 (CH2), 33.08 (CH2), 38.19 (CH2), 46.19 (CH3), 51.68 (CH),
98.03 (C), 155.55 (C), 167.19 (C), 167.40 (C), 176.45 (C). IR (cmꢁ1):
1739, 1685, 1635, 1380. Anal. Calcd for C11H13NO5: C, 55.23%; H,
5.48%; N, 5.86%. Found: 55.80%; H, 5.27%; N, 5.80%.
4.2.2. Pyrrolizidinone 14 and indolizidinone 13. Acetonitrile,
1 mmol of BiI3,1 h, 36% and 50% yield, respectively. Purified by silica
gel column chromatography eluent hexane/ethyl acetate/methanol
1:1:0.2 (v/v). Compound 14: yellow solid, 36% yields, mp
3. Conclusion
This study shown the successful one-step skeletally diverse
synthesis of alkaloid-like pyrrolizidinones, indolizidinones, and
pyrroloazepinones based on simple domino reactions of hetero-
cyclic enaminones34 with maleic anhydride or N-aryl-maleimides.
To access selectively such heterocycles, the reaction course can
be convenient controlled, switching between aza-[3þ3] and aza-
[3þ2] modes of formal cycloaddition, being modulated by the na-
ture of enaminone, electrophile employed, and acid catalysis. Thus,
for the synthesis of pyrroloazepinones (17, 20, 21), the seven-
membered enaminone and maleic anhydride or maleimides were
efficient, via the [3þ2] mode of cyclization. To access indolizidi-
nones (13, 15, 16) in good yield, five or six-membered enaminones
are the choice, and both [3þ2] and [3þ3] modes were viable ex-
clusively with maleic anhydride. At last but not least, pyrrolizidi-
none 23 could be selectively synthesized in good yield through the
[3þ2] mode only with five-membered enaminone and N-(4-
NO2Ph)maleimide under catalysis by PTSA. In this way, the present
contribution sheds new light on the chameleonic behavior of het-
erocyclic enaminones in the aza-annulations with anhydride
maleic and N-arylmaleimides, as well as increases the synthetic
possibilities of the formal aza-cycloaddition reactions of such
enaminones.34
156.0e157.8 ꢀC. 1H NMR (CDCl3)
d 2.38 (qt, J 7.0 Hz, 2H), 2.91 (dd, J
7.0 and J 3.0 Hz, 1H), 2.95 (dd, J 7.0 and 3.0 Hz, 1H), 3.01 (dd, J 17.1
and 5 Hz, 1H), 3.12 (dd, J 17.1 and 5.2 Hz, 1H), 3.58 (t, J 7.0 Hz, 2H),
3.71 (s, 3H), 3.72e3.76 (m, 1H). 13C NMR (CDCl3)
d 25.76 (CH2),
26.20 (CH2), 33.19 (CH2), 41.42 (CH2), 48.17 (CH3), 51.00 (CH), 101.12
(C), 162.67 (C), 164.05 (C), 175.16 (C), 175.77 (C). IR (cmꢁ1): 1739,
1703, 1668, 1436, 1375. Anal. Calcd for C11H13NO5: C, 55.23%; H,
5.48%; N, 5.86%. Found: 54.99%; H, 5.15%; N, 5.62%.
4.2.3. Indolizidinones 15a,b. Dichloromethane, 24 h, 73% yield,
brown oil (two diastereomers). Purified by silica gel column chro-
matography eluent chloroform/ethanol 7:3 (v/v). Compound 15a:
1H NMR (CDCl3)
d 1.85e2,20 (2H), 1.96 (s, 3H), 2.65 (dd, J 16.8 and
7.8 Hz,1H), 2.93 (dd, J 16.8 and 2.7 Hz,1H), 3.29 (dd, J 9.6 and 2.7 Hz,
1H) 3.70e3.90 (1H), 3.77 (s, 3H), 4.02 (dd, J 11.1 and 3.6 Hz, 1H),
4.31e4.38 (1H), 4.44 (d, J 4.5 Hz, 1H), 4.54e4.62 (m, 1H). 13C NMR
(CDCl3)
d 20.55 (CH3), 24.10 (CH2), 31.07 (CH2), 33.04 (CH2), 38.09
(CH2), 51.68 (CH), 56.63 (CH3), 63.10 (CH2), 97.83 (C), 155.44 (C),
166.85 (C), 167.27 (C), 170.65 (C), 175.80 (C). Compound 15b: 1H
NMR (CDCl3)
d 1.85e2.20 (2H), 2.04 (s, 3H), 2.73 (dd, J 16.8 and
8.4 Hz, 1H), 2.98 (dd, J 16.8 and 3.0 Hz, 1H), 3.38 (dd, J 17.4 and
3.0 Hz, 1H) 3.70e3.90 (1H), 3.77 (s, 3H), 4.10 (dd, J 11.4 and 3.0 Hz,
4. Experimental section
4.1. General
1H), 4.31e4.38 (1H), 4.48 (d, J 4.2 Hz, 1H), 4.54e4.62 (m, 1H). 13
C
NMR (CDCl3)
d 20.76 (CH3), 24.76 (CH2), 31.07 (CH2), 33.77 (CH2),
38.38 (CH2), 51.78 (CH), 56.75 (CH3), 64.27 (CH2), 98.62 (C), 155.78
(C), 166.93 (C), 167.40 (C), 170.89 (C), 176.10 (C).
Melting points were determined on a Microquímica MQAPF 301
hot plate apparatus and are uncorrected. Infrared spectra of solid
samples were recorded as KBr discs, and oleo samples as films, on
an FT-IR BOMEM MB100 instrument. NMR spectra were obtained
for 1H at 250 MHz, 300 MHz or 500 MHz, and for 13C at 62.5 MHz,
75 MHz or 125 MHz using Varian Gemini or INOVA and Brucker
Avance spectrometers. Chemical shifts are reported in parts per
million units downfield from reference (internal TMS or residual
undeuterated solvent). Elemental analyses were performed on
a Flash 2000 Thermo Scientific instrument at Instituto de Química/
UFG. The high resolution mass spectra were recorded using a Q-TOF
equipment (Waters, UK) at Instituto de Química/Unicamp. Mal-
eimides 2b,c35 and enaminones 12aed25 were prepared according
to known procedures.
4.2.4. Indolizidinone 16. Acetonitrile, 1 h. Purified by silica gel col-
umn chromatography eluent hexane/ethyl acetate 1:1 (v/v), yellow
oil, 88% yields. 1H NMR (CDCl3)
d
1.65e1.88 (m, 4H), 2.84e3.15 (m,
2H), 3.39e3.50 (m, 2H), 3.52e3.63 (m, 2H), 3.71 (s, 3H), 9.40e9.80
(sl, 1H). 13C NMR (CDCl3)
19.22 (CH2), 21.55 (CH2), 24.65 (CH2),
d
33.46 (CH2), 40.13 (CH2), 42.34 (CH3), 50.65 (CH), 103.93 (C), 156.15
(C), 164.26 (C), 175.39 (C), 178.71 (C). Anal. Calcd for C12H15NO5: C,
56.91%; H, 5.97%; N, 5.53%. Found: C, 57.23%; H, 6.11%; N, 5.65%.
4.2.5. Pyrrolo[1,2-a]azepinones 17. Acetonitrile,1 h. Purified by silica
gel column chromatography hexane/ethyl acetate 1:1 (v/v), white
solid, 99% yield, mp 153.2e154.7 ꢀC.∙1H NMR (CDCl3)
d 1.28 (t, J
7.0 Hz, 3H), 1.50e1.85 (m, 6H), 2.29e2.42 (m, H), 2.70e2.88 (m, 1H),
2.99 (dd, J 17.1 and 4.9 Hz,1H), 3.19 (dd, J 17.1 and 4.9 Hz,1H), 3.46 (dt,
J 4.9 and 1.2 Hz,1H), 3.49e3.60 (m,1H), 3.82e3.92 (m,1H), 4.09e4.27
4.2. General synthetic procedure for the indolizidinones 13,
15e16, pyrrolizidinone 14, and pyrrolo[1,2-a]azepinone 17
(m, 2H), 10.02 (sl, 1H). 13C NMR (CDCl3)
d 13.91 (CH3), 25.69 (CH2),
26.21 (CH2), 28.17 (CH2), 30.11 (CH2), 33.51 (CH2), 40.63 (CH2), 42.75
(CH), 59.45 (CH2), 103.95 (C), 160.76 (C), 163.71 (C), 175.18 (C), 177.27
(C). IR (cmꢁ1): 3453, 1706, 1691, 1684. Anal. Calcd for C14H19NO5: C,
59.78%; H, 6.81%; N, 4.98%. Found: C, 59.71%; H, 6.65%; N, 5.22%.
A solution of heterocyclic enaminone 12aed (1.0 mmol) and
anhydride maleic 1 (1.0 mmol) in the solvent (5.0 mL) and time
indicated in each case, was magnetic stirring at room temperature.
After this, the reaction mixture was concentrated under reduced
pressure and the residue was purified by column chromatography
on silica gel.
4.3. General synthetic procedure for the pyrrolizidinones 23,
24, pyrrolo[1,2-a]azepinones 20, 21, succinimides 18, 19, 22,
and 25
4.2.1. Indolizidinone 13. Dichloromethane, 0.5 h. Purified by silica
gel column chromatography eluent hexane/ethyl acetate 4:1 (v/v),
A solution of heterocyclic enaminone 12a,b,d (1.0 mmol) and
maleimide 2aec (1.0 mmol) in the solvent (5.0 mL), temperature
brown solid, 85% yield, mp 140.7e142.0 ꢀC. 1H NMR (CDCl3)
d 1.92

S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
3289
and time indicated in each case, was magnetic stirring. After this,
the reaction mixture was concentrated under reduced pressure and
the residue was purified by column chromatography on silica gel
when necessary.
(C), 162.93 (C), 163.43 (C), 169.40 (C), 174.62 (C). IR (cmꢁ1): 3215,
3083, 1683, 1562, 1319, 1089, 854, 752, 607. HRMS (ESI) calcd for
C
17H18N3O6: 360.1196 [MþH]þ; Found: 360.1133 [MþH]þ.
4.3.7. Pyrrolizidinone 24 and Michael adduct 25. Acetonitrile, reflux
14 h. Purified by silica gel column chromatography eluent hexane/
ethyl acetate 3:2 to 1:4 gradient (v/v). 24: white solid, 8% yield. 1H
4.3.1. Michael adduct 18. Toluene, reflux 24 h. The reaction mixture
was concentrated and purification was not necessary, brown oil,
99% yield. 1H NMR (CDCl3)
d
1.89 (m, 2H), 2.32 (dd, J 17.7 and 5.4 Hz,
1H), 2.64 (t, J 7.5 Hz, 2H), 2.81 (dd, J 17.7 and 9.3 Hz, 1H), 8.22 (sl,
1H), 10.91 (sl, 1H). 13C NMR (DMSO-d6)
21.25 (CH2), 31.59 (CH2),
NMR (DMSO-d6) d 2.25e2.36 (m, 2H), 2.81e2.91 (m, 3H), 3.01 (dd, J
5.4 and J 15.9 Hz,1H), 3.45e3.52 (m, 2H), 3.58 (s, 3H), 3.74e3.80 (m,
1H), 7.00 (t, J 7.3 Hz, 1H), 7.27 (t, J 7.8 Hz, 2H), 7.52 (d, J 7.7 Hz, 2H),
d
37.23 (CH2), 41.98 (CH2), 47.70 (CH3), 50.06 (CH), 84.90 (C), 165.79
(C), 167.98 (C), 178.48 (C), 181.64 (C). Anal. Calcd for C11H14N2O4: C,
55.46%; H, 5.92%; N, 11.76%. Found: C, 55.78%; H, 6.32%; N, 11.28%.
9.90 (s,1H). 13C NMR (CDCl3)
d 26.13 (CH2), 26.37 (CH2), 36.79 (CH2),
41.69 (CH2), 49.24 (CH3), 51.25 (CH), 101.40 (C), 120.10 (CH), 124.32
(C), 129.12 (CH), 138.13 (C), 162.82 (C), 164.57 (C), 168.35 (C), 175.91
(C). IR (cmꢁ1): 3464, 3448, 3317, 1693, 1678, 1600, 1539, 1377, 1242,
1084, 760, 698. HRMS (ESI) calcd for C17H19N2O4: 315.1345[MþH]þ;
Found: 315.1368 [MþH]þ.
4.3.2. Michael adduct 19. Acetonitrile, room temperature 8 h. Pu-
rified by silica gel column chromatography hexane/ethyl acetate
1:1 (v/v), brown oil, 30% yield. 1H NMR (CDCl3)
d
1.62e1.83 (m, 6H),
Compound 25: Pale yellow solid, 67% yield. 1H NMR (CDCl3)
2.58 (dd, J 18.3 and 5.6 Hz, 1H), 2.87 (dd, J 18.3 and 8.8 Hz, 1H), 8.83
d
1.99e2.17 (m, 2H), 2.63e2.94 (m, 3H), 3.07 (dd, J 9.7 and 18.1 Hz,
1H), 3.58e3.63 (m, 3H), 3.67 (s, 3H), 7.28 (d, J 7.8 Hz, 2H), 7.35e7.51
(m, 3H), 8.43 (s, 1H). 13C NMR (CDCl3)
21.89 (CH2), 31.79 (CH2),
(sl, 1H), 9.82 (sl, 1H), the rest overlapping signals. 13C NMR (CDCl3)
d
19.73 (CH2), 21.67 (CH2), 26.24 (CH2), 37.50 (CH2), 39.87 (CH2),
d
41.43 (CH), 50.21 (CH3), 86.23 (C), 134.93 (C), 161.83 (C), 169.04 (C),
177.55 (C), 181.22 (C).
36.75 (CH2), 41.06 (CH2), 47.87 (CH3), 50.92 (CH), 85.92 (C), 126.78
(CH), 128.60 (C), 129.36 (CH), 132.84(C), 168.95 (C), 176.38 (C),
179.22 (C). IR (cmꢁ1): 3464, 3367, 2947, 2850, 1709, 1659, 1593,
1385, 1184, 1057, 1033, 779, 683, 613, 536. HRMS (ESI) calcd for
4.3.3. Pyrrolo[1,2-a]azepinones 20. Toluene, reflux 6 h. The reaction
mixture was concentrated and purification was not necessary,
C
17H19N2O4: 315.1345[MþH]þ; Found: 315.1379 [MþH]þ.
yellow solid, 99% yield, mp 149e151 ꢀC. 1H NMR (CDCl3)
d 1.28 (t, J
7.2 Hz, 3H), 1.62e1.82 (m, 6H), 2.80e3.06 (m, 1H), 2.88 (dd, J 15.3
and 6.3 Hz, 1H), 2.94 (dd, J 15.3 and 4.2 Hz, 1H), 3.12e3.25 (m, 1H),
3.56e3.68 (m, 1H), 3.76e3.88 (m, 1H), 4.12e4.25 (m, 2H), 5.37 (sl,
4.3.8. Indolizidinone 26. Pale yellow solid, 9% yield. 1H NMR
(DMSO-d6) 2.13e2.31 (m, 2H), 2.71e2.82 (m, 2H), 2.98 (d, J
d
17.0 Hz,1H), 3.23e3.28 (m, 1H), 3.43e3.47 (m, 1H), 3.53 (s, 3H), 3.92
(d, J 17.0 Hz, 1H), 7.74 (d, J 9.5 Hz, 2H), 8.17 (d, J 9.5 Hz, 2H), 10.73 (s,
1H), 6.02 (sl, 1H). 13C NMR (CDCl3)
d 14.39 (CH3), 26.19 (CH2), 26.60
(CH2), 28.62 (CH2), 30.46 (CH2), 35.44 (CH2), 40.92 (CH2), 43.65
(CH), 59.74 (CH2), 104.46 (C), 160.62 (C), 164.16 (C), 172.06 (C),
177.98 (C). Anal. Calcd for C14H20N2O4: C, 59.99%; H, 7.19%; N, 9.99%.
Found: C, 60.41; H, 8.31%; N, 9.61%.
1H). 13C NMR (DMSO-d6)
d 25.9 (CH2), 26.2 (CH2), 35.3 (CH2), 50.8
(CH), 59.9 (CH3),101.7 (C),119.1 (C),125.4 (C),142.4 (CH),145.6 (CH),
163.5 (C), 164.5 (C), 169.7 (C), 174.6(C).
4.3.4. Pyrrolo[1,2-a]azepinones 21. Acetonitrile, reflux 15 h. The
reaction mixture was concentrated and purification was not nec-
essary, yellow solid, 99% yield, mp 212.8e214 ꢀC. 1H NMR (DMSO-
4.4. X-ray analysis
A single-crystal of 14 suitable for data collection was mounted
d6)
d
1.10e1.20 (m, 3H), 1.60e1.80 (m, 6H), 2.07 (t, J 0.6 Hz, 1H), 2.93
on a Bruker Kappa Apex II Duo diffractometer,36 using Mo K
a
ra-
S micro source device, monochromatized using
multi-layer mirror optics. Data collection has been carried out at
(dd, J 15.9 and 5.1 Hz, 1H), 3.06 (dd, J 15.9 and 5.1 Hz, 1H), 3.54 (t, J
4.5 Hz, 2H), 4.05 (m, 2H), 7.82 (d, J 9 Hz, 2H), 8.30 (d, J 9 Hz, 2H),10.6
diation from an Im
(s, 1H). 13C NMR (DMSO-d6)
d
10.13 (CH3), 21.22 (CH2), 22.17 (CH2),
room temperature by u/4 scans. Cell refinement and data reduction
24.17 (CH2), 25.61 (CH2), 32.34 (CH2), 34.66 (CH2), 38.72 (CH), 55.02
(CH2), 99.55 (C), 114.55 (C), 120.95 (C), 138.02 (CH), 141.16 (CH),
156.57 (C), 159.48 (C), 165.32 (C), 172.79 (C), 180.40 (C). Anal. Calcd
for C20H23N3O6: C, 59.84%; H, 5.78%; N, 10.47%. Found: C, 60.04%; H,
6.02%; N, 10.10%.
was performed with Saint,36 and the structure solution was ob-
tained by Direct Methods using ShelxS97.37 Non hydrogen atoms
were refined with anisotropic displacement parameters and all
hydrogen atoms were refined isotropic with riding constraints to
their parent atoms using ShelxL97.37 C22H21N1O3, T¼293(2) K,
ꢁ
l
¼0.71073 A,
m
¼0.11 mmꢁ1, crystal size 0.27ꢂ0.17ꢂ0.09 mm,
ꢁ
ꢁ
ꢁ
4.3.5. Michael adduct 22. Acetonitrile, reflux 12.5 h. Recrystallized
in ethanol, white solid, 95% yield, mp 171.3e173.5 ꢀC. 1H NMR
monoclinic, P21/n, a¼7.6761(4) A, b¼10.0072(5) A, c¼14.5525(8) A,
3 3
ꢁ
ꢀ
b
¼90.180(3) , volume 1117.86(10) A , Z¼4, Dc¼1.421 Mg/m ,
q
(DMSO-d6)
d
1.90 (m, 2H), 2.55 (dd, J 8.1 and 2.7 Hz, 1H), 2.74 (t, J
range of data collection 2.47e25.73ꢀ, ꢁ9ꢃhꢃ9, ꢁ11ꢃkꢃ12,
ꢁ17ꢃlꢃ17, reflections collected 13,077, independent 2137, R(int)¼
0.028, refinement using Full-matrix least-squares on F2, 1469 data
points, 293 parameters, 566 restraints (whole molecule disorder
8.1 Hz, 2H), 3.15 (dd, J 18 and 9.6 Hz, 1H), 3.30 (s, 3H), 3.47e3.53
(overlapping signals, 2H), 3.78e3.84 (sl, 1H), 7.60 (d, J 8.2 Hz, 2H),
8.28 (sl, 1H), 8.40 (d, J 8.2 Hz, 2H). IR (cmꢁ1): 3360,1709, 1662, 1346.
Anal. Calcd for C17H17N3O6: C, 56.82%; H, 4.77%; N, 11.69%. Found: C,
56.88%; H, 4.77%; N, 11.72%.
0.54/046), GooF 1.101, R1¼0.081, wR2¼0.228 [I>2
s(I)], extinction
coef. 0.004(2), the largest diff. peak and hole are 0.234 and
ꢁꢁ3
ꢁ0.365 e A . The compound crystallizes in a general position of
4.3.6. Pyrrolizidinone 23. Acetonitrile and 20 mol % of PSTA, reflux
72 h. Reaction mixture was cooled to 0 ꢀC and the formed solid was
washed with cold acetonitrile, yellow solid, 74% yield, mp
the unit cell, with static disorder on the whole molecule featured by
the racemic counterparts, which occupations were refined to
0.542(5) and 0.458(5). In the crystal packing the molecules form
intermolecular hydrogen bonds of type O5eH5/O1, ꢀwith donor
204.7e207.8 ꢀC. 1H NMR (DMSO-d6)
d 2.22e2.37 (m, 2H), 2.85e2.89
ꢁ
(m, 2H), 2.94 (dd, J 5.1 and 16.1 Hz, 1H), 3.08 (dd, J 5.4 and 16.1 Hz,
1H), 3.47e3.52 (m, 2H), 3.57 (m, 1H), 3.77e3.85 (m, 1H), 7.78 (d, J
9.2 Hz, 2H), 8.20 (d, J 9.2 Hz, 2H), 10.57 (s, 1H). 13C NMR (DMSO-d6)
acceptor distance of 2.545(11) A, DHA angle of 158.2 , the other
ꢁ
disorder component presents this H-bond geometry 2.553(14) A
DHA angle 163.1ꢀ. This connects molecules related by the screw axis
and builds an infinity linear chain though [010]. These chains are
loosely stacked parallel to the (100) crystal plane.
d
25.58 (CH2), 25.78 (CH2), 35.68 (CH2), 41.08 (CH2), 47.80 (CH3),
50.53 (CH), 100.06 (C), 118.62 (CH), 124.96 (CH), 142.03 (C), 145.15

3290
S. Cunha et al. / Tetrahedron 70 (2014) 3284e3290
20. Schreiber, S. L. Science 2000, 287, 1964e1969; Galloway, W. R. J. D.; Bender, A.;
CCDC 958810 contains the supplementary crystallographic data
Welch, M.; Spring, D. R. Chem. Commun. 2009, 2446e2462; Anagnostaki, E. E.;
Zografos, A. L. Chem. Soc. Rev. 2012, 41, 5613e5625; Connor, C. J. O.; Beckmann,
H. S. G.; Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444e4456; Lachance, H.; Wetzel,
S.; Kumar, K.; Waldmann, H. J. Med. Chem. 2012, 55, 5989e6001.
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.
21. Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lauriucci, C.; Vecanto, I. Tetrahedron
2001, 57, 1671e1675; Cunha, S.; Lima, B. R.; Souza, A. R. Tetrahedron Lett. 2002,
43, 49e52; Cunha, S.; Rodrigues, M. T., Jr.; Silva, C. C.; Napolitano, H. B.; Vencato,
I.; Lariucci, C. Tetrahedron 2005, 61, 10536e10540; Cunha, S.; Rodrigues, M. T., Jr.
Tetrahedron Lett. 2006, 47, 6955e6956; Cunha, S.; Macedo, F. C., Jr.; Costa, G. A.
N.; Neves, D. C.; Souza Neta, L. C.; Vecanto, I.; Sabino, J. R.; Lauriucci, C. J. Braz.
Chem. Soc. 2009, 20, 327e634 For reviews see: Organobismuth Chemistry; Su-
zuki, H., Matano, Y., Eds.; Elsevier: Amsterdam, 2001; Leonard, N. M.; Wieland,
L. C.; Mohan, R. S. Tetrahedron 2002, 58, 8373e8397; Bothwell, J. M.; Krabbe, S.
W.; Mohan, R. S. Chem. Soc. Rev. 2011, 40, 4649e4707; Bismuth-mediated Organic
Reactions; Ollevier, T., Ed.; Springer: Berlin, 2012.
Acknowledgements
The authors gratefully acknowledge the financial support of
Conselho Nacional de Desenvolvimento Científico
e
Tec-
ꢀ
~
nologicodCNPq, Coordenac¸ ao de Aperfeic¸ oamento de Pessoal de
~
ꢂ
Nível SuperiordCAPES, and Fundac¸ ao de Amparo a Pesquisa do
Estado da BahiadFAPESB. We also thank FAPESB for student fel-
lowship J.T.M.C. (PIBIC), CNPq for fellowship to A.O.S. and research
fellowship to S.C., and Professor Mauricio Victor for discussion and
comments.
22. For reviews see: Lue, P.; Greenhill, J. V. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic: New York, NY, 1997; Vol. 67, pp 207e343;
€
Kucklander, V. In The Chemistry of Enamines; Rappoport, Z., Ed.; John Wiley &
Sons: New York, NY, 1994; Part 1, pp 525e639; Elliott, M. C.; Wood, J. L.;
Wordingham, S. V.; Ferraz, H. M.; Gonc¸ alo, E. R. S. Quim. Nova 2007, 30,
957e964; Trends Heterocycl. Chem. 2005, 10, 73e95; Cheng, Y.; Huang, Z. T.;
Wang, M.-X. Curr. Org. Chem. 2004, 8, 325e351; Ferraz, H. M. C.; Pereira, F. L. C.
Quim. Nova 2004, 27, 89e95; Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heter-
ocycl. Chem. 2004, 41, 461e491; Kascheres, C. J. Braz. Chem. Soc. 2003, 14,
945e969; Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463e8480.
23. Cunha, S.; Santos Filho, R. F.; Saraiva, K. H.; Azevedo-Santos, A. V.; Menezes, D.
Tetrahedron Lett. 2013, 54, 3366e3370; Cunha, S.; Gomes, A. T. Tetrahedron Lett.
2012, 53, 6710e6713; Cunha, S.; Damasceno, F.; Ferrari, J. Tetrahedron Lett.
2007, 48, 5795e5798; Cunha, S.; Bastos, R. M.; Silva, P. O.; Costa, G. A. N.;
Vencato, I.; Lariucci, C.; Napolitano, H. B.; Oliveira, C. M. A.; Kato, L.; Silva, C. C.;
Menezes, D.; Vannier-Santos, M. A. Monatsh. Chem. 2007, 138, 111e119; Cunha,
S.; Silva, V. C.; Napolitano, H. B.; Lariucci, C.; Vencato, I. J. Braz. Chem. Soc. 2003,
14, 107e112; Cunha, S.; Kascheres, A. J. Braz. Chem. Soc. 2001, 12, 481e484.
24. Buchanan, G. S.; Feltenberger, J. B.; Hsung, R. P. Curr. Org. Synth. 2010, 7,
363e401 and reference therein. Recent application; Gerasyuto, A. I.; Ma, Z.-X.;
Buchanan, G. S.; Hsung, R. P. Beilstein J. Org. Chem. 2013, 9, 1170e1178.
Supplementary data
IR, 1H NMR, and 13C NMR spectra for 13e25. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.10.071.
References and notes
1. Michael, J. P. Nat. Prod. Rep. 2007, 24, 191e222; Liddell, J. R. Nat. Prod. Rep. 2002,
19, 773e781; Despinoy, X. L. M.; McNab, H. Tetrahedron 2000, 56, 6359e6383.
2. Maison, W.; Prenzel, A. H. G. P. Synthesis 2005, 1031e1048; Pyne, S. G.; Davis, A.
S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004,
2670e2680.
3. Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat. Prod. Rep. 2010, 27, 1908e1937;
ꢀ ꢀ
25. Celerier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org. Chem. 1979, 44, 3089;
ꢀ
Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009, 2421e2435.
Elliott, M. C.; Wordingham, S. V. Synthesis 2006, 1162e1170 and references
therein.
26. For similar distinction of isomeric aza-[3þ3] and aza-[3þ2] products, see:
Rudenko, R. V.; Komykhov, S. A.; Desenko, S. M.; Sen’ko, Y. V.; Shishkin, O. V.;
Konovalova, I. S.; Shishkina, S. V.; Chebanov, V. A. Synthesis 2011, 3161e3167.
27. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837e838.
4. Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241e1251; Hanessian, S.;
McNaughton-Smith, G.; Lobart, H.-G.; Lubell, W. D. Tetrahedron 1997, 38,
12789e12854.
5. For maleic anhydride: Biggs-Houck, J. E.; Davis, R. L.; Wei, J.; Mercado, B. Q.;
Olmstead, M. M.; Tantillo, D. J.; Shaw, J. T. J. Org. Chem. 2012, 77, 160e172;
ꢀ
Gozalez-Lopes, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164e189; Cui, J.; Chai, D. I.;
28. For example of distinct behavior of five and six-membered enaminones in
formal azaannulation, see: Ghosh, S. K.; Buchanan, G. S.; Long, Q. A.; Wei, Y.; Al-
Rashid, Z. F.; Sklenicka, H. M.; Hsung, R. P. Tetrahedron 2008, 65, 883e893.
29. For a recent study on the influence of the N-substituent in the the electronic
effect of imides, see: Lee, H. L.; Yu, J. S.; Lee, C. K. Magn. Reson. Chem. 2009, 47,
711e715.
30. Preliminary study suggests that isolated Michael adducts are not intermediate
in the aza[3þ2]/[3þ3] annulations because when they were submitted to the
best condition for cyclization a very slow reaction took place, or complex re-
action mixtures had formed in some cases. Further mechanistic studies are
under investigation in our laboratory and will be described opportunely.
31. For a study favorable to the compact boat-like transition state in similar re-
action with enamines end Michael acceptors, see: Sevin, A.; Tortajada, J.; Pfau,
M. J. Org. Chem. 1986, 51, 2671e2675.
Miller, C.; Hao, J.; Thomas, C.; Wang, J. Q.; Scheidt, K. A.; Kozmin, S. A. J. Org.
Chem. 2012, 77, 7435e7470; Ulanovskaya, O. A.; Cui, J.; Kron, S. J.; Kozmin, S. A.
Chem. Biol. 2011, 18, 222e230.
6. For maleimides: Cubbage, K. L.; Corrie, T.; Evans, N.; Haddow, M. F.; Booker-
Milburn, K. I. Chem.dEur. J. 2012, 18, 11180e11183; Lainchbury, M.; Taylor, P. M.;
Dohle, W.; Hirst, P.; Booker-Milburn, K. I. J. Org. Chem. 2008, 73, 6497e6505.
7. Agbalyan, S. G.; Nersesyan, L. A. Arm. Khim. Zh. 1969, 22, 40e44.
8. Robson, J. H.; Marcus, E. Chem. Ind. 1971, 1022e1023.
9. von Dobeneck, H.; Bruner, E.; Bunker, H.; Metzner, G.; Schmidt, R.; Weil, E.;
Sonnenbichler, J. Liebigs Ann. Chem. 1981, 410e424.
ꢀ
10. Cave, C.; Gassama, A.; Mahuteau, J.; d’Angelo, J.; Riche, C. Tetrahedron Lett. 1997,
ꢀ
€
38, 4773e4776; d’Angelo, J.; Cave, C.; Desmaele, D.; Gassama, A.; Thominiaux,
C.; Riche, C. Heterocycles 1998, 47, 725e746.
11. Caballero, E.; Madrigal, B.; Medarde, M.; Puebla, P.; Honores, Z.; Martín, E.;
Feliciano, A. S. ACHdModels Chem. 1998, 135, 457e473.
12. Barum, O.; Chakrabarti, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2001, 66,
4457e4461.
32. Palmieri, G.; Cimarelli, C. ARKIVOC 2006, vi, 104e126.
33. Shimo, T.; Itoh, T.; Araki, Y.; Iwanaga, T.; Shinmyozu, T.; Somekawa, K. Het-
erocycles 2011, 83, 47e55.
ꢃ ꢀ
ꢃ
ꢃ ꢀ
ꢀ
34. Bondzic, B. P.; Dzambaski, Z.; Bondzici, A. M.; Markovic, R. Tetrahedron 2012, 68,
9556e9565; Jiang, X.-P.; Cheng, Y.; Shi, G.-F.; Kang, Z.-M. J. Org. Chem. 2007, 72,
2212e2215; Jiang, X.-P.; Cheng, Y.; Shi, G.-F.; Kang, Z.-M. J. Org. Chem. 2007, 72,
6634; Shi, G.-F.; Li, J.-Q.; Jiang, X.-P.; Cheng, Y. Tetrahedron 2008, 64,
5005e5012; Qamar, M.; Hemming, K. Tetrahedron Lett. 2008, 49, 6316e6319;
Kondakal, V.; Qamar, M.; Hemming, K. Tetrahedron Lett. 2012, 53, 4100e4103.
35. Ramos, J. G.; Barralesrienda, J. M.; Chaves, M. S. Anales de Quimica 1977,
139e145.
13. Gupta, A. K.; Ila, H.; Junjappa, H. Synthesis 1988, 284e286.
14. Furukawa, I.; Ade, T.; Fujisawa, H.; Ohta, T. Tetrahedron 1997, 53, 17643e17652.
15. Nagasaka, T.; Inoue, H.; Ichimura, M.; Hamaguchi, F. Synthesis 1982, 848e850;
Nagasaka, T.; Inoue, H.; Hamaguchi, F. Heterocycles 1983, 20, 1099e1107.
16. Blanton, C. D., Jr.; Whidby, J. F.; Briggs, F. H. J. Org. Chem. 1971, 36, 3929e3932.
17. Cunha, S.; Rodovalho, W.; Azevedo, N. R.; Mendonc¸ a, M. O.; Lariucci, C.; Ven-
cato, I. J. Braz. Chem. Soc. 2002, 13, 629e634.
18. Shah, K. R.; Blanton, C. D., Jr. J. Org. Chem. 1982, 47, 502e508.
19. Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F. Chem.
Rev. 2009, 109, 2703e2802.
36. Bruker. APEX, SAINT and SADABS; Bruker AXS: Madison, Wisconsin, USA, 2005.
37. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.