Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations

Article abstract of DOI:10.1016/j.tet.2006.10.074

We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.

Full text of DOI:10.1016/j.tet.2006.10.074

Tetrahedron 63 (2007) 337–346
Microwave-assisted solvent-free intramolecular 1,3-dipolar
cycloaddition reactions leading to hexahydrochromeno[4,3-b]-
pyrroles: scope and limitations
*
ꢁꢀ
Jirı Pospısil and Milan Potacek
ꢀꢁ
ꢁꢀ
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotlaꢁrꢀskaꢁ 2, 611 37 Brno, Czech Republic
Received 7 July 2006; revised 11 October 2006; accepted 27 October 2006
Available online 20 November 2006
Abstract—We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cyclo-
additions proceed under these conditions within 15–40 min in 16–84% yields. An influence of the microwave irradiation upon various [3+2]
cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the di-
polarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These obser-
vations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of
activated olefins was also described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Such compounds can be accessible by the cycloaddition
reaction between aldehyde 2 and amine 3. These particular
reagents were previously studied under the classical reaction
conditions6 (various solvents, classical heating, various cat-
alysts) and microwave heating using toluene as a solvent,7
but low reaction yields, selectivity and/or long reaction times
dissuade from the more systematic study of the reaction.
Therefore, understanding of the substitution influence on
the reactivity and reaction selectivity has not been known.
Recently, we have reported a development of a simple, rapid,
one pot and solvent-free synthesis of compounds with gen-
eral pattern 6 (Table 1).8 In that paper, the steric properties
of the nitrogen atom substitution upon the reaction yields
were discussed. We have observed that increasing steric
Short and efficient synthesis of complex organic structures is
a dream of each chemist. Moreover nowadays, ecological as-
pects and atom efficiency processes enter into the consider-
ation when a new compound synthesis is proposed. Aware of
this situation, we have focused our attention on the synthesis
of fused heterocycles by intramolecular 1,3-dipolar cycload-
dition1 under solvent-free conditions.2 We anticipated that
microwave initiation of the reaction is essential in our case
to avoid the degradation of the newly formed heterocycles.3
To demonstrate our approach, a family of compounds con-
taining hexahydrochromeno[4,3-b] pyrrolidine skeleton (1)
was chosen (Scheme 1). Such compounds are known to be
non-competitive antagonists of the muscular nicotin recep-
tor.4 Moreover, similar structure motive is contained in var-
ious natural compounds, such as martinelline5 and sceletium
alkaloid A-4.6
Table 1. The influence of the nitrogen atom substitution on the reaction
yields
R1
CO2Et
O
N
R1
HN
H
µW, 200°C
+
CO2Et
O
R3
EWG
O
4
5
6
O
R2
N
R3
HN
R1
H
R2
Entry Amine R1
Reaction time Product Yielda
+
EWG
[min]
[%]
O
R1
O
1
2
3
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Benzyl
Ethyl
n-Butyl
Isopropyl
1-Adamantyl 60
tert-Butyl 60
15
15
15
30
6a
6b
6c
6d
—
—
83
81
80
79
—
—
Scheme 1.
Keywords: Intramolecular cycloaddition; Azomethine ylides; Solvent-free
synthesis; Microwave-assisted synthesis; 1,3-Dipolar cycloaddition.
* Corresponding author. Tel.: +420 549 496 615; fax: +420 549 492 688;
e-mail: potacek@chemi.muni.cz
a
All yields are for pure, fully characterized, products.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.074

338
J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
demands of the nitrogen atom substituent decreased the
reaction yield. However, in none of the cases, any of the
starting materials, neither aldehyde 4 nor amine 5, were
reisolated after the reaction. In all cases, only the products
of degradation9 were obtained along with desired cycload-
ducts 6. Therefore, the evaluation of all possible reaction in-
termediates and their ability to degradation was investigated.
during the water elimination step, the hydrogen atom in in-
termediate 12 attached to the nitrogen atom might compete
with the hydrogen atom attached to the a-carbon next to the
carbonyl group. Hence, the reaction could proceed via two
different intermediates, 13 and 16, respectively, leading
then to three possible products 14, 15 and 17.
Since an amide hydrogen atom is more acidic (pKaw20
(DMSO))11 than the hydrogen atom situated on an a-carbon
next to the amide group (pKaw26 (DMSO))11 and because
the water elimination step is irreversible under the reaction
conditions,12 only the intermediate 16 formation should be
anticipated (pathway B).
Herein, we would like to discuss our results obtained during
our reaction intermediates stability testing. Additionally, the
influence of other substituents placed on the amine 5 as well
as on aldehyde 4 upon the reaction yield and selectivity will
be discussed.
According to our expectation, compound 17 was observed as
the only product of the reaction and isolated in 85% yield
(GC yield—92%).13 In this stage, we have concluded that
the degradation of dipole intermediate 13 is responsible
for the degradation products observed in the reaction.14
2. Results and discussion
The reaction mechanism of the 1,3-dipolar reactions
between aldehyde 4 and amine 5a has been postulated as
shown in Scheme 2.1e As one can see, all three putative
intermediates 7, 8 and 9 are possible candidates to undergo
decomposition under the microwave irradiation, because
they possess a dipole in the molecule. It is known that micro-
waves interact only with molecules containing a dipole.10
To bring the evidence for our conclusions, we have decided
to use other electron-withdrawing groups to stabilize the
generated dipole intermediate 19 (Table 2). Different elec-
tron-withdrawing groups should have two main impacts on
the dipole 19, stability and reactivity.
O
O
Bn
NH
Stronger electron-withdrawing groups like cyano group
should facilitate the H2O molecule elimination during inter-
mediate 19 generation due to higher acidity of the hydrogen
atom attached to the carbon next to cyano group.15 Thus, the
generation of the 1,3-dipole should be faster.
CO2Et
Bn
HN
H
µW, 200°C
+
CO2Et
5a
O
O
O
4
7
On the contrary, the presence of the cyano group on the di-
pole 19 causes decreasing of the HOMO orbital energy of
the 1,3-dipole.1e,16 Since in all cases the dipoles react with
the same dipolarophile, the reaction of the cyano derivative
of 19 should require higher DGs than similar ester or amide
derivatives. Therefore, the generated 1,3-dipole should be
present in the reaction mixture longer than its ester analogue
and the prolonged interaction of microwaves with it could
cause the 1,3-dipole degradation and would be reflected in
the lower reaction yield.
Bn
N
Bn
N
- H2O
CO2Et
CO2Et
OH
O
O
O
9a
8
Bn
N
CO2Et
CO2Et
Bn
N
9b
Bn
N
O
6
Based on the same logic, the presence of less electron-with-
drawing groups on the dipole 19 should lead to the higher re-
action yields, even though the acidity of the hydrogen atom
next to electron-withdrawing group is lower compared to
ester stabilized 1,3-dipole. The gap between HOMO of the
dipole and LUMO of the dipolarophile should be smaller.
The results obtained in the reaction using various EWG
groups on the dipole intermediate 19 are presented in Table 2.
CO2Et
9c
Scheme 2.
First we focused our attention on the stability of intermedi-
ates 7 and 8. To evaluate if these two intermediates undergo
decomposition under the reaction conditions, amine 10 hav-
ing another acidic hydrogen in the molecule was used in the
reaction with aldehyde 4 and tested under microwave condi-
tions (Scheme 3). We expected that amine 10 would bring
additional acidic hydrogen into the reacting system, and
therefore a competitive reaction to azomethine ylide 13 for-
mation leading to intermediate 16 might be expected.
The reaction of cyano-stabilized dipole 19 gave, as expected,
desired cycloadduct even at prolonged time only in low yield
(Table 2, entry 1).14 On the other hand, the presence of ethyl-
oxy carbonyl group on the dipole 19 furnished desired tricy-
cle in 84% yield (Table 2, entry 2).17 To our great surprise,
when iso-propyloxy and tert-butyloxy carbonyl groups were
used, the drop in the yield of corresponding cycloadducts
was observed (Table 2, entries 3 and 4).
As one can see, the first two steps of the reaction (leading to
intermediates 11 and 12) are the same as in the case of
Scheme 2. In the structures, the ester group has been
substituted by a secondary amide group. Consequently,
We expect that in these cases the reactivity of the dipole is
the same as in the case of ethyloxy carbonyl stabilized

J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
339
O
O
Bn
NH
O
O
Bn
HN
O
H
µW, 200°C
N
H
+
O
O
O
N
H
4
10
11
Bn
N
Bn
N
O
N
H
- H2O
Pathway A
N
H
OH
O
12
13a
- H2O
Pathway B
Bn
N
O
Bn
N
O
N
N
H
O
O
13b
16
1,3-dipolar
cycloaddition
O
Bn
N
Bn
N
O
H
NH
Bn
H
N
NH
N
O
O
H
H
14
O
17
15
O
Scheme 3.
dipole, but that sterically bulkier groups presented on the
dipole caused additional obstacle during the dipole–dipolaro-
phile interaction. Thus, the dipoles interact with the dipo-
larophiles in the microwave field only when treated for a
longer time. The longer time causes degradation of generated
dipole.
Addition of maleic anhydride to the reaction mixture of al-
dehyde 4 and amine 5a resulted in the formation of two prod-
ucts, 6a and 21, in 95% yield. Products of intramolecular
cycloaddition 6a and that of an intermolecular reaction 21
were formed in a 1:4 ratio. The addition of N-tert-butyl-
maleimide resulted in the formation of intra- (6a) and inter-
molecular products (exo-22 and endo-22) in a 1:3.3 ratio and
85% yield. The products of intermolecular reaction, endo-
22 and exo-22, resulting from exo and endo approach of
the dipolarophile to dipole (Fig. 1) are formed in a 1:1.3
ratio.
The same phenomena was observed also in the case of N,N-
dialkylamino carbonyl groups, which were used to stabilize
the generated dipole 19 (Table 2, entries 5–7).
Next, we have focused on trapping the generated azo-
methine ylide before its decomposition. Therefore, maleic
anhydride and N-tert-butylmaleimide, respectively, as ex-
cellent dipolarophiles,18 were added to the reaction mixture
(Scheme 4).
In both cases, intermolecular product(s) are preferred. This
is probably due to the high concentration of components in
the reaction mixture (no molecules of solvent, which can
dilute it, are present). Thus, intermolecular reaction of the
Table 2. The reactivity of the dipole 19 substituted with different EWG groups
EWG
Me
O
Me
N
N
Me
HN
EWG
H
µW, 200°C
+
EWG
18
O
O
O
4
19
20
Entry
Amine
EWG
Time [min]
Product
Yielda [%]
1
2
3
4
5
6
7
18a
18b
18c
18d
18e
18f
CN
30
15
40
40
40
40
60
20a
20b
20c
20d
20e
20f
—
17
84
38
17
45
16
—
CO2Et
CO2Pri
CO2But
CONMe2
CONPri2
CON(Et)Ts
18g
a
All yields are for pure, fully characterized, products.

340
J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
Bn
N
Bn
N
CO2Et
O
O
Bn
O
Ar
CO2Et
CO2Et
Ar
N
Bn
HN
H
H
µW
+
+
H
H
H
H
+
+
X
CO2Et
15 min, 200°C
H
O
O
O
O
X
X
O
O
t
4
5a
X = O or NBu
21, X = O
exo-22, X = NBu
6a
t
t
endo-22, X = NBu
Ar = o-(allyloxy)phenyl
X=O, 95%, intra:inter = 1:4
X=NBut, 85%, intra:inter = 1:3.3 (exo:endo = 1:1.3)
Scheme 4.
H
H
H
Therefore, for our purposes three different dipolarophile
substituents were chosen, the methyl group (aldehydes
23d,e), the methoxycarbonyl group (aldehydes 23a,b) and
the phenyl group (aldehyde 23c).
CO2Et
CO2Et
R
R
O
N
N
O
X
Ar
Ar
H
X
O
exo
O
endo
The reactions of aldehydes containing trans u-substituted
double bond in the ortho position to the formyl group were
carried out at first (Table 3, entries 1,3 and 4). We have ob-
served that aldehydes 23a,c afforded two pairs of products
(Table 3, entries 1 and 3). Products 24a and 25a (from alde-
hyde 23a) were formed in a 3.8:1 ratio. In the case of prod-
ucts 24c and 25c formed from aldehyde 23c, the product
ratio decreased to 2.2:1. During the reaction of aldehyde
23d with amine 5a no traces of the desired product(s) were
observed (Table 3, entry 4). The overall yields decreased
from very good (79%—with methoxycarbonyl group as
the dipolarophile substituent, Table 3, entry 1) through mod-
erate (54%—phenyl group, entry 3) to none (methyl group,
entry 4).
Figure 1.
dipole with the highly reactive dipolarophile (maleic anhy-
dride) is preferred over the intramolecular one.
The overall yield in the case of reaction with maleic
anhydride is 95%. Therefore, we can conclude that most
of the generated azomethine ylide 9 reacts with the dipolaro-
phile present and forms the products 6a and 21. Probably
only a small quantity of generated azomethine ylide 9
under the reaction conditions decomposes. It implies
that azomethine ylide is rather stable if there is a proper
dipolarophile available for rapid transformation to the
product.
Then reactions of aldehydes containing dipolarophiles in cis
configuration (23b,e) and amine 5a were then examined.
The reaction of aldehyde 23b and amine 5a proceeded to
the formation of three products, 24a, 24b and 25a (Table
3, entry 2). Compound 24b was the main product of the
reaction and was formed in 82% yield. The traces of com-
pounds 24a and 25a were detected only (by GC and
1H NMR) in the reaction mixture and were not isolated.
However, these two products are formed also in the case of
reaction of the aldehyde 23a. The possible explanation for
this finding will be discussed later. The reaction of aldehyde
In the case of N-tert-butylmaleimide, the overall yield of the
reaction is only 85%. Thus, probably a little bit larger
quantity of the generated azomethine ylide decomposes
during the reaction. We suppose that in this case an
approach of the dipole to the dipolarophile might be compli-
cated by the presence of the bulky group (tert-butyl) on the
dipolarophile.
2.1. cis/trans Disubstituted intramolecular
dipolarophiles and their reaction selectivity
Table 3. Cycloaddition reaction of cis/trans intramolecular dipolarophiles
The question, whether the change of the substituent in u-
position of a dipolarophile or the change of dipolarophile
configuration is reflected in the substrate reactivity and con-
sequently in the reaction selectivity, became another field
of our interest.
CO2Et
R2
CO2Et
R2
Bn
H
Bn
H
Bn
N
O
N
N
CO2Et
5a
R1
H
R1
H
H
R2
H
+
R1
µW, 200°C
O
O
25
O
24
23
It is known that the properties of dipolarophile substituents16
have a great influence upon dipolarophile reactivity in the
course of 1,3-dipolar cycloaddition. For azomethine ylides,
better reactivity was found in the presence of an EWG group
on the dipolarophile than in the presence of an EDG.19 The
electronic influence of dipolarophile substituents could be
divided into three basic groups: (1) alkyl substituents (in-
creasing HOMO and decreasing LUMO energy of dipolaro-
phile), (2) EWG substituents (decreasing HOMO and
decreasing LUMO energy) and (3) EDG substituents (in-
creasing HOMO and increasing LUMO energy).1,18,19
Entry Aldehyde R1
R2
Time Product(s) Yielda Ratiob
[min]
15
[%]
1
2
3
4
5
23a
23b
23c
23d
23e
CO2Me
H
Phenyl
Methyl
H
H
24a+25a 79
3.8:1
>99:1
2.2:1
—
CO2Me 15
H
H
24bc
82
24c+25c 54
30
60
—
24e
—
62
Methyl 40
>99:1
a
b
c
All yields are for pure, fully characterized, products.
Determined by GC–MS.
Another 4% of 24a and 1% of 25a were detected in the reaction mixture,
however, not isolated.

J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
341
23e with amine 5a proceeded to the formation of only one
stereoisomer 24e in 63% yield.
Therefore, for cis dipolarophiles DGs of TS A is smaller
than DGs of TS B and thus only one diastereomer 24 is
formed under the reaction conditions.
The reaction yields in the cases of cis disubstituted dipolaro-
philes were higher than those in the cases of trans configu-
ration, particularly, when the methyl group was used as
a substituent on the dipolarophile. Product 24e was formed
in 63% yield (Table 3, entry 5) comparatively with no prod-
uct in the reaction of the aldehyde 23d and amine 5a (Table
3, entry 4).
For the formation of both TS, flexibility of the O–CH2–
CH] group is important. Therefore to prove our assumption
of TSs, aldehyde 26 was used as a dipolarophile. We suppose
that exchange of the CH2 group for CO diminishes the flex-
ibility of the substrate and might prevent the TS A and TS B
formation. From an electronic point of view, the additional
EWG group on the dipolarophile should make the 1,3-di-
polar cycloaddition more feasible.16
As one can see, there is a large difference between the
reactions of dipolarophiles with cis and trans configuration.
The dipolarophiles having trans configuration react with
worse selectivity and give two cycloadducts. Dipolarophiles
with cis configuration afford one stereoisomer only. The
second most remarkable difference was observed in the
case of a methyl substituent on the dipolarophile (aldehydes
23d,e).
During the reaction of aldehyde 26 with amine 5a no ex-
pected product 32 was observed in the reaction mixture
(Scheme 5). Only isomerization of compound 26 to trans
isomer 27 was detected as a newly formed product.
CO2Et
CO2Me
H
O
Bn
N
O
O
Bn
H
N
CO2Et
X 5a
H
H
O
We assume that steric requirements might play a role in the
TS of the reaction. On the base of the knowledge of Houk
et al.,20 who showed by quantum calculation methods that
the 1,3-DC proceeds via an early TS as well as on the
Hammond postulate,21 we suggest two TSs leading to the
products 24 and 25, respectively (Fig. 2). TSs exhibiting
a syn conformation of the azomethine ylide are not consi-
dered because no product containing such a configuration
on the pyrrolidine ring was identified.
OMe
µW, 200°C
O
O
26
32
Scheme 5.
2.2. cis/trans Isomerization of activated double bonds
under the microwave irradiation
TS A leading to product 24 is characterized by a steric
repulsion between the substituent R1 and the ester group
on the dipole. Such repulsion does not exist for the substitu-
ent R2 and therefore the reaction of the dipolarophile with
cis configuration (R2sH) via this TS A is energetically
preferred.
Finally another important fact, which appeared during the
experiments, has to be discussed. Traces of stereoisomers
24a and 25a were found in the reaction mixture when alde-
hyde 23b reacted with amine 5a. Because these two products
are the main products of the reaction of aldehyde 23a and
amine 5a, we propose that cis/trans isomerization occurred
in the reaction mixture during the reaction.
In the case of TS B leading to compound 25, there is negli-
gible steric repulsion for the substituent R1 and the thermo-
dynamically more stable pyrrolidine ring is formed. Thus,
TS B should be preferred by the dipolarophiles having trans
geometry (R2¼H). On the other hand, there is a strong en-
tropy factor influence on TS B formation. One can see that
the second formed ring (six-membered ring) has to adopt
for entropy reasons an energetically more demanding con-
formation, in which TS B is formed. For this reason TS B
is disfavoured over TS A.
To prove the assumption, a series of experiments were car-
ried out during which the cis/trans isomerization of com-
pounds 23a,b,d,e, 26, 27, 28, 29, 30 and 31 was examined.
Because the direct observation of cis/trans isomerization
during the reaction is impossible, a different approach was
used. The previously mentioned compounds were irradiated
for 15 min and then they were rapidly cooled to 0 ꢀC. The
cooled reaction mixture was analyzed and the presence
1
of cis and trans isomers was identified by GC and/or H
NMR.
H
H
R3
CO2Et
R2
R3
CO2Et
R1
N
N
During our experiments, an isomerization of olefins
substituted by EDG as well as an isomerization of trans ole-
fin to cis isomer was not observed. However, in the case of
cis olefins substituted by EWG substituents, the situation
was different. The isomerization of cis to trans isomers
was observed if there was at least one carboxylic group on
the irradiated olefin. In the case of compounds 23b and 29,
15% of trans isomer 23a and 10% of trans isomer 30, respec-
tively, were identified after 15 min of irradiation (Scheme 6
and Graph S-2).22 In the case of two carboxylic groups on
the olefin (compounds 26 and 28), the trans isomers 27
and 31, respectively, were formed in the reaction mixture
nearly quantitatively within 15 min (Graph S-3).
H
R2
H
R1
H
O
O
H
TS A
TS B
R3
H
CO2Et
R2
R1
R3
H
CO2Et
R2
N
N
R1
H
H
O
O
24
25
Figure 2.

342
J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
HO
INSTRUMENTS TRIO 1000 spectrometer as a detector.
µW, 200°C, 15 min
µW, 200°C, 15 min
HO
O
CO2Me
10%
HPLC chromatography was carried out on SHIMADZU
LC-20AD with RP-HPLC glass column SGC C-18 (7 mm;
3ꢁ150 nm). SHIMADZU SPD-10 A was used as UV detec-
tor. Flash column chromatography was carried out on Merck
silica 63–100 mm using petroleum ether/ethyl acetate as
a mobile phase (for the precise ratio consult data below).
29
30
CO2Me
O
O
H
H
15%
CO2Me
O
23b
23a
CO2Me
The structure determination was carried out with a help of
2D-COSY, HSQC, HMBS and 2D-NOESY NMR experi-
ments.
µW, 200°C, 15 min
HO2C
HO2C
CO2Me
98%
CO2Me
28
31
Experimental procedures and characterization of amines 5,
10 and 18a–g,23 aldehydes 4 and 23a–e24 and olefins 2825
and 2926 can be found in Supplementary data.
O
H
O
O
O
99%
H
O
µW, 200°C, 15 min
OMe
O
OMe
4.2. General method for the preparation of
hexahydrochromeno[4,3-b]pyrroles
26
27
O
O
Scheme 6.
Mixture of aldehyde 4 or 23 (2.5 mmol) and amine 5, 10 or
18a–f (2.5 mmol) was irradiated under stirring from 15 to
60 min. Temperature of the reaction mixture was maintained
at 200 ꢀC. Reaction mixture was allowed to cool down to rt
and separated by column chromatography (petroleum ether/
ethyl acetate). The structure determination was made with
help of 2D-COSY, HSQC, HMBS and 2D-NOESY experi-
ments and by comparison with known compounds.6b
Therefore, we can assume that the small amount of products
24a and 25b in the reaction mixture of aldehyde 23b and
amine 5a could be explained by the isomerization of a small
amount of aldehyde 23b to aldehyde 23a. In situ formed al-
dehyde 23a then reacts with amine 5a and affords products
24a and 25a.
CN
3. Conclusion
H2
Me
9b N1
2
H3
H
3
9
6
9b
We have developed a simple protocol for intramolecular
1,3-dipolar cycloadditions of azomethine ylides leading to
tricyclic hexahydrochromeno[4,3-b]pyrroles skeletons. The
desired tricyclic molecules were prepared in moderate to
very good yield and selectivity. Moreover, an influence of
various electron-withdrawing groups upon the dipole stabil-
ity and reactivity was established. Additionally, the influence
of the dipolarophile double bond geometry on the reaction
selectivity was observed and rationalized. These observa-
tions led us to propose preferred TSs of the cycloaddition.
H3'
8
7
9a
5a
3a
H3a
H4
O5 4
H4'
4.2.1. (2R*,3aS*,9bR*)-1-Methyl-1,2,3,3a,4,9b-hexa-
hydrochromeno[4,3-b]pyrrole-2-carbonitrile (20a).
Compound 20a was prepared by the reaction of aldehyde 4
(405 mg, 2.5 mmol) with amine 18a (175 mg, 2.5 mmol), ir-
radiated for 30 min. Flash chromatography (4:1) gave 91 mg
(17%) of 20a as a yellow oil. IR (NaCl) n (cmꢂ1) 3061 (w),
2981 (m), 2935 (m), 2875 (w), 2265 (w, CN), 1607 (w), 1484
(w), 1456 (m), 1245 (m), 1184 (s), 1095 (s), 1008 (m), 751
(m). 1H NMR (300 MHz, CDCl3) d 1.84 (ddd, 1H,
Finally, an isomerization of activated double bond under the
microwave irradiation was described.
J3,3 ¼13.5, J3 ,2¼8.9, 3J3 ,3a¼2.3 Hz, H-30), 2.17 (ddd, 1H,
2
2
3
0
0
0
3
3
0
J3,3 ¼13.5, J3,3a¼8.3, J3,2¼4.3 Hz, H-3), 2.46–2.51 (m,
4. Experimental section
4.1. General remarks
2
0
1H, H-3a), 2.60 (s, 3H, NCH3), 3.92 (dd, 1H, J4,4 ¼11.6,
3J4,3a¼2.7 Hz, H-4), 3.52 (d, 1H, J9b,3a¼6.3 Hz, H-9b),
3
2
3
4.17 (dd, 1H, J4 ,4¼11.6, J4 ,3a¼4.3 Hz, H-40), 4.55 (dd,
0
3
0
3
0
1H, J2,3 ¼8.9, J2,3¼4.3 Hz, H-2), 6.94–7.32 (m, 4H,
arom. CH). 13C NMR (75 MHz, CDCl3) d 31.1 (C-3), 34.4
(C-3a), 36.3 (NCH3), 54.7 (C-2), 59.5 (C-9b), 67.8 (C-4),
117.8 (CN), 117.6, 120.3, 122.5, 129.0, 132.3, 155.8
(arom. CH and Cq). EI-MS m/z (%) 214.2 (M+, 1), 198.2
(5), 186.8 (100), 130.9 (26), 115.0 (34), 62.9 (31), 50.9
(38). Calcd for C13H14N2O (214.26): C 72.87, H 6.59, N
13.07; found: C 72.89, H 6.61, N 13.03.
Melting points were measured on a Kofler hot stage VEB
Wagetechnik Rapido 79/2106. IR spectra were recorded on
a FTIR ATI MATTSON spectrophotometer in NaCl cell or
KBr tablets (w—week, m—medium, s—strong signals). Mi-
crowave irradiation was carried out in PROLABO 402 Syn-
thewave oven (power 300 W, frequency 2450 MHz). NMR
spectra were recorded on Avance 300 Varian apparatus
1
with working frequency of 300 MHz for H and 75 MHz
for 13C in CDCl3 with TMS as an internal standard. Chemi-
cal shifts are given in parts per million, coupling constants J
in Hertz. Mass spectra were recorded on a FISONS INSTRU-
MENTS TRIO 1000 spectrometer in positive mode with
EI. Gas chromatography was carried out on SPIRA KI 8 col-
umn (30 m, 5% diphenyldimethylsiloxane) with FISONS
CO2Et
H2
Me
9bN1
2
H3
H
3
9
6
9b
H3'
8
7
9a
5a
3a
H3a
H4
O5 4
H4

J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
343
4.2.2. Ethyl-(2R*,3aS*,9bR*)-1-methyl-1,2,3,3a,4,9b-
hexahydrochromeno[4,3-b]pyrrole-2-carboxylate (20b).
Compound 20b was prepared by the reaction of aldehyde
4 (405 mg, 2.5 mmol) with amine 18b (293 mg, 2.5 mmol),
irradiated for 15 min. Flash chromatography (7:1) gave
549 mg (84%) of 20b as a yellowish oil. IR (NaCl) n
(cmꢂ1) 3022 (m), 2944 (s), 2882 (s), 1722 (s, C]O), 1609
(m), 1580 (m), 1490 (m), 1451 (m), 1230 (w), 1195 (m),
4.2.4. tert-Butyl-(2R*,3aS*,9bR*)-1-methyl-1,2,3,3a,4,9b-
hexahydrochromeno[4,3-b]pyrrole-2-carboxylate (20d).
Compound 20d was prepared by the reaction of aldehyde 4
(405 mg, 2.5 mmol) with amine 18d (363 mg, 2.5 mmol),
irradiated for 40 min. Flash chromatography (19:1) gave
123 mg (17%) of 20d as a slightly yellow oil. IR (NaCl)
n (cmꢂ1) 3071 (w), 2967 (m), 2936 (m), 2871 (m), 2791
(w), 1723 (s, C]O), 1609 (w), 1488 (m), 1452 (w), 1260
1
1
1048 (w), 761 (w). H NMR (300 MHz, CDCl3) d 1.32 (t,
0
(m), 1150 (s), 1052 (m), 755 (m). H NMR (300 MHz,
CDCl3) d 1.52 (s, 9H, C(CH3)3), 1.96 (ddd, 1H, 2J3,3 ¼13.2,
2
3H, 3J¼7.3 Hz, OCH2CH3), 1.99 (ddd, 1H, J3 ,3¼13.5,
0
3
3
2
3
2
J3 ,2¼8.6, J3 ,3a¼4.0 Hz, H-30), 2.19 (ddd, 1H, J3,3
¼
J3 ,2¼8.6, 3J3 ,3a¼4.5 Hz, H-30), 2.17 (ddd, 1H, J3,3 ¼13.2,
0
0
0
0
0
0
3
3
3
13.5, J3,3a¼8.5, J3,2¼3.0 Hz, H-3), 2.52–2.63 (m, 1H,
3J3,3a¼8.8, J3,2¼3.3 Hz, H-3), 2.52 (s, 3H, NCH3), 2.64–
3
3
H-3a), 2.63 (s, 3H, NCH3), 3.87 (dd, 1H, J2,3 ¼8.6,
2.69 (m, 1H, H-3a), 3.64 (dd, 1H, 3J2,3 ¼8.6, J2,3¼3.3 Hz,
0
0
3J2,3¼3.0 Hz, H-2), 3.96 (dd, 1H, J4,4¼11.7, J4,3a
¼
H-2), 3.89 (dd, 1H, J4,4 ¼10.6, J4,3a¼8.3 Hz, H-4), 3.96
0 0
2
3
2
3
0
4.6 Hz, one of H-4), 4.00 (dd, 1H, 2J4,4¼11.7, 3J4,3a¼2.0 Hz,
(dd, 1H, J4 ,4¼10.6, J4 ,3a¼4.6 Hz, H-40), 4.04 (d, 1H,
3J9b,3a¼6.3 Hz, H-9b), 6.90–7.22 (m, 4H, arom. CH). 13C
NMR (75 MHz, CDCl3) d 28.5 (C(CH3)3), 30.8 (C-3), 35.2
(C-3a), 35.9 (NCH3), 59.0 (C-9b), 65.2 (C-2), 68.5 (C-4),
80.3 (C(CH3)3), 117.5, 120.4, 122.7, 128.7, 133.1, 156.0
(arom. CH and Cq), 173.8 (C]O). EI-MS m/z (%) 289.9
(M+, 2), 168.3 (4), 167.0 (34), 150.2 (7), 149.0 (100),
113.3 (8), 83.0 (8), 71.0 (13), 70.0 (11), 57.0 (43), 42.9
(28), 40.9 (33). Calcd for C17H23NO3 (289.37): C 70.56, H
8.01, N 4.84; found: C 70.58, H 7.99, N 4.86.
2
3
3
the other of H-4), 4.11 (d, 1H, J9b,3a¼6.3 Hz, H-9b), 4.18
(dq, 2H, 3J¼7.3, 2J¼2.3 Hz, OCH2CH3), 6.81–7.23 (m, 4H,
arom. CH). 13C NMR (75 MHz, CDCl3) d 14.6 (OCH2CH3),
30.4 (C-3), 35.2 (C-3a), 38.7 (NCH3), 58.3 (C-2), 60.0 (C-
9b), 60.3 (OCH2CH3), 68.3 (C-4), 117.3, 120.3, 122.5,
128.9, 132.4, 156.0 (arom. CH and Cq), 174.5 (C]O). EI-
MS m/z (%) 262.3 (M++H, 39), 203.7 (7), 202.3 (100),
173.2 (15), 159.0 (21), 144.7 (22), 131.0 (58), 115.0 (12),
107.1 (13), 55.9 (13). Calcd for C15H19NO3 (261.32): C
68.94, H 7.33, N 5.36; found: C 68.92, H 7.34, N 5.32.
CONMe2
i
H2
Me
CO2Pr
N1
2
H2
Me
H3
H9b
N1
2
H9b
3
H3
9
6
9b
H3'
3
9
9b
8
7
9a
5a
3a
4
H3'
H3a
H4
8
7
9a
5a
3a
H34a
H
O5 4
O5
6
H4'
H4'
4.2.3. 2-Propyl-(2R*,3aS*,9bR*)-1-methyl-1,2,3,3a,4,9b-
hexahydrochromeno[4,3-b]pyrrole-2-carboxylate (20c).
Compound 20c was prepared by the reaction of aldehyde 4
(405 mg, 2.5 mmol) with amine 18c (328 mg, 2.5 mmol),
irradiated for 40 min. Flash chromatography (5:1) gave
4.2.5. N,N-Dimethyl-(2R*,3aS*,9bR*)-1-methyl-1,2,3,3a,
4,9b-hexahydrochromeno[4,3-b]pyrrole-2-carboxamide
(20e). Compound 20e was prepared by the reaction of alde-
hyde 4 (405 mg, 2.5 mmol) with amine 18e (190 mg,
2.5 mmol), irradiated for 40 min. Flash chromatography
(10:1) gave 293 mg (45%) of 20e as white crystals. Mp
(58–59 ꢀC). IR (KBr) n (cmꢂ1) 3007 (w), 2968 (m), 2930
(m), 2871 (w), 2833 (w), 1737 (s, C]O), 1582 (w), 1480
261 mg (38%) of 20c as a yellow oil. IR (NaCl) n (cmꢂ1
)
3064 (w), 2980 (m), 2935 (m), 2879 (w), 2802 (w), 1732 (s,
C]O), 1608 (w), 1484 (w), 1456 (m), 757 (m), 1198 (s),
1106 (s), 1018 (m), 756 (m). H NMR (300 MHz, CDCl3)
1
1
3
(w), 1441 (m), 1257 (m), 1044 (m), 758 (m). H NMR
0
d 1.30 (dt, 6H, J¼6.6, 4.5 Hz, CH(CH3)2), 1.84 (ddd, 1H,
2
3
2
3
3
J3,3 ¼13.1, J3 ,2¼9.9, J3 ,3a¼2.3 Hz, H-30), 2.17 (ddd,
0
0
2
0
0
(300 MHz, CDCl3) d 1.99 (ddd, 1H, J3,3 ¼13.1, J3 ,2¼
3
2
0
0
0
8.1, J3 ,3a¼4.5 Hz, H-30), 2.19 (ddd, 1H, J3,3 ¼13.1,
3
3
1H, J3,3 ¼13.1, J3,3a¼7.3, J3,2¼4.3 Hz, H-3), 2.40–2.46
0
3J3,3a¼8.7, J3,2¼3.9 Hz, H-3), 2.49 (s, 3H, NCH3), 2.85
3
2
(m, 1H, H-3a), 2.65 (s, 3H, CH3), 3.92 (dd, 1H, J4,4
10.6, J4,3a¼3.3 Hz, H-4), 3.96 (d, 1H, J9b,3a¼6.6 Hz, H-
¼
3
3
(m, 1H, H-3a), 2.95 and 2.99 (two s, 3H+3H, N(CH3)2),
0
2
3
2
3
9b), 4.17 (dd, 1H, J4 ,4¼10.6, J4 ,3a¼4.6 Hz, H-40), 4.55
0
0
3.92 (dd, 1H, J4,4 ¼10.6, J4,3a¼3.2 Hz, H-4), 3.96 (dd,
3
3
2
3
3
0
0
0
1H, J2,3 ¼8.1, J2,3¼3.9 Hz, H-2), 4.25 (dd, 1H, J4 ,4¼
(dd, 1H, J2,3 ¼9.9, J2,3¼4.3 Hz, H-2), 5.07–5.12 (m, 1H,
CH(CH3)3), 6.86–7.41 (m, 4H, arom. CH). 13C NMR
(75 MHz, CDCl3) d 22.1 (CH(CH3)2), 30.8 (C-3), 38.7
(NCH3), 42.3 (C-3a), 64.6 (C-9b), 68.2 (C-2), 68.2
(CH(CH3)2), 71.0 (C-4), 116.6, 120.2, 122.6, 128.9, 132.6,
154.2 (arom. CH and Cq), 173.6 (C]O). EI-MS m/z (%)
275.5 (M+, 7), 274.3 (7), 261.6 (5), 260.2 (35), 233.4 (11),
232.2 (100), 218.1 (11). Calcd for C16H21NO3 (275.34): C
69.79, H 7.69, N 5.09; found: C 69.82, H 7.72, N 5.09.
3
3
10.6, J4 ,3a¼4.6 Hz, H-40), 4.32 (d, 1H, J9b,3a¼6.8 Hz,
H-9b), 6.90–7.27 (m, 4H, arom. CH). 13C NMR (75 MHz,
CDCl3) d 34.2 (C-3), 36.8 (NCH3), 37.5 (C-3a), 38.6
(N(CH3)2), 60.0 (C-9b), 63.2 (C-2), 66.7 (C-4), 115.1,
120.1, 122.2, 129.4, 132.6, 156.8 (arom. CH and Cq),
165.5 (C]O). Calcd for C15H20N2O2 (260.33): C 69.20, H
7.74, N 10.76; found: C 69.19, H 7.73, N 10.76.
0
i
CON(Pr )2
CO2But
H2
Me
H2
N1
Me
2
H3
H9b
N1
2
H9b
H3
3
9
6
9b
3
H3'
9
6
9b
H3'
8
7
9a
5a
3a
4
8
7
9a
5a
3a
H3a
H4
H3a
H4
4
O5
O5
H4'
H4'

344
J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
4.2.6. N,N-Di-(2-propyl)-(2R*,3aS*,9bR*)-1-methyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2-car-
boxamide (20f). Compound 20f was prepared by the
reaction of aldehyde 4 (405 mg, 2.5 mmol) with amine 18f
(431 mg, 2.5 mmol), irradiated for 40 min. Flash chromato-
graphy (9:1) gave 127 mg (16%) of 20f as white crystals. Mp
(91–92 ꢀC). IR (KBr) n (cmꢂ1) 3004 (w), 2967 (m), 2931
(m), 2869 (w), 2834 (w), 1735 (s, C]O), 1583 (w), 1486
C23H25NO5 (395.45): C 69.86, H 6.37, N 3.54; found: C
69.81, H 6.32, N 3.49.
CO2Et
H2
Bn
N1
2
H9b
H3
CO2Me
3
9
9b
8
7
9a
5a
3a
H3a
H4
4
O5
6
H4'
1
(w), 1444 (m), 1256 (m), 1045 (m), 760 (m). H NMR
(300 MHz, CDCl3) d 1.26 (d, 6H, 3J¼6.6 Hz, one of
CH(CH3)2), 1.41 (d, 6H, 3J¼6.6 Hz, the other of
2
3
0
0
CH(CH3)2), 2.02 (ddd, 1H, J3,3 ¼12.9, J3 ,2¼8.3,
3
2
J3 ,3a¼4.6 Hz, H-30), 2.22 (ddd, 1H, J3,3 ¼12.9,
4.2.8. 2-Ethyl-3-methyl-(2R*,3R*,3aR*,9bR*)-1-benzyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2,3-di-
carboxylate (25a). Compound 25a was prepared by the
reaction of aldehyde 23a (586 mg, 2.5 mmol) with amine
5a (483 mg, 2.5 mmol), irradiated for 15 min. Flash chroma-
tography (7:1) gave 170 mg (17%) of 25a as a yellowish oil.
IR (NaCl) n (cmꢂ1) 3067 (m), 3020 (m), 2945 (s), 2876 (s),
1727 (s, C]O), 1608 (m), 1578 (m), 1467 (m), 1445 (m),
1230 (w), 1189 (w), 1049 (w), 762 (w). 1H NMR (300 MHz,
0
0
3J3,3a¼8.6, J3,2¼4.0 Hz, H-3), 2.52 (s, 3H, CH3), 2.78–
3
2.83 (m, 1H, H-3a), 3.76–3.81 (m, 2H, N(CH(CH3)2)2)
3.92 (dd, 1H, 2J4,4 ¼10.7, J4,3a¼3.2 Hz, H-4), 3.96 (dd, 1H,
3
0
3
3
3
2
0
0
J2,3 ¼8.3, J2,3¼4.6 Hz, H-2), 4.17 (dd, 1H, J4 ,4¼10.7,
3
J4 ,3a¼4.5 Hz, H-40), 4.34 (d, 1H, J9b,3a¼6.9 Hz, H-9b),
0
6.91–7.20 (m, 4H, arom. CH). 13C NMR (75 MHz,
CDCl3) d 22.0 (CH(CH3)2), 31.4 (C-3), 35.4 (NCH3), 36.2
(C-3a), 46.1 (CH(CH3)2), 60.0 (C-9b), 61.9 (C-2), 68.6 (C-
4), 117.3, 119.9, 122.4, 128.8, 132.9, 156.0 (arom. CH and
Cq), 165.1 (C]O). EI-MS m/z (%) 317.4 (M++1, 6), 315.5
(4), 314.4 (3), 189.5 (15), 188.2 (100), 130.9 (14), 81.8
(8), 42.8 (13). Calcd for C19H28N2O2 (316.44): C 72.12, H
8.92, N 8.85; found: C 72.15, H 8.90, N 8.84.
3
CDCl3) d 1.19 (t, 3H, J¼7.3 Hz, OCH2CH3), 2.80 (dddd,
3
3
3
3
0
1H, J3a,3¼11.0, J3a,9b¼11.0, J3a,4¼10.5, J3a,4 ¼2.0 Hz,
3
3
H-3a), 3.22 (dd, 1H, J3a,3¼10.9, J3,2¼5.4 Hz, H-3), 3.59
2
(d, 1H, J¼13.2 Hz, one of NCH2Ph), 3.79 (s, 3H, OCH3),
3
3
4.10 (dd, 1H, J4 ,4¼9.9, J4 ,3a¼2.0 Hz, H-40), 4.18 (d,
0
0
3
3
1H, J2,3¼5.4 Hz, H-2), 4.21 (d, 1H, J9b,3a¼11.0 Hz,
H-9b), 4.25 (q, 2H, 3J¼7.3 Hz, OCH2CH3), 4.34 (d,
1H, 2J¼13.2 Hz, the other of NCH2Ph), 4.52 (dd, 1H,
CO2Et
3
3
H2
Bn
0
J4,3a¼10.9, J4,4 ¼9.9 Hz, H-4), 6.90–7.49 (m, 9H, arom.
N1
2
H9b
CH). 13C NMR (75 MHz, CDCl3) d 14.2 (OCH2CH3), 42.5
(C-3), 49.4 (C-3a), 52.7 (OCH3), 53.4 (NCH2Ph), 58.8 (C-
9b), 61.1 (OCH2CH3), 64.8 (C-2), 69.8 (C-4), 116.9, 125.9,
126.3, 128.4, 128.6, 128.9, 130.5, 138.7, 157.7 (arom. CH
and Cq), 172.3 and 173.4 (C]O). EI-MS m/z (%) 396.8
(M++1, 1), 395.1 (M+, 1), 324.2 (12), 323.2 (25), 222.3
(80), 320.5 (16), 260.5 (7), 174.2 (5), 173.1 (20), 172.1
(10), 131.0 (15), 92.1 (5), 90.9 (100), 64.8 (18). Calcd for
C23H25NO5 (395.45): C 69.86, H 6.37, N 3.54; found: C
69.84, H 6.35, N 3.52.
CO2Me
3
9
9b
H3
8
7
9a
5a
3a
H3a
H4
4
O5
6
H4'
4.2.7. 2-Ethyl-3-methyl-(2R*,3S*,3aS*,9bR*)-1-benzyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2,3-di-
carboxylate (24a). Compound 24a was prepared by the
reaction of aldehyde 23a (586 mg, 2.5 mmol) with amine
5a (483 mg, 2.5 mmol), irradiated for 15 min. Flash chroma-
tography (7:1) gave 620 mg (62%) of 24a as a yellowish oil.
IR (NaCl) n (cmꢂ1) 3067 (m), 3020 (m), 2945 (s), 2876 (s),
1725 (s, C]O), 1608 (m), 1580 (m), 1490 (m), 1445 (m),
1230 (w), 1189 (w), 1049 (w), 762 (w). 1H NMR
CO2Et
H2
Bn
N1
2
H3
CO2Me
H9b
3
9
6
9b
8
7
9a
5a
3a
H3a
H4
4
O5
3
H4'
(300 MHz, CDCl3) d 1.31 (t, 3H, J¼7.3 Hz, OCH2CH3),
3
3
3
0
3.39 (dddd, 1H, J3a,3¼9.3, J3a,9b¼8.3, J3a,4 ¼3.6,
3J3a,4¼1.7 Hz, H-3a), 3.43 (dd, 1H, 3J3,3a¼9.3,
3J3,2¼6.6 Hz, H-3), 3.58 (d, 1H, 2J¼13.2 Hz, one of
3
NCH2Ph), 3.72 (s, 3H, OCH3), 3.93 (d, 1H, J2,3¼6.6 Hz,
4.2.9. 2-Ethyl-3-methyl-(2R*,3R*,3aS*,9bR*)-1-benzyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2,3-di-
carboxylate (24b). Compound 24b was prepared by the
reaction of aldehyde 23b (586 mg, 2.5 mmol) with amine
5a (483 mg, 2.5 mmol), irradiated for 15 min. Flash chroma-
tography (8:1) gave 811 mg (82%) of 24b as a yellowish oil.
IR (NaCl) n (cmꢂ1) 3064 (m), 3019 (m), 2940 (s), 2876 (s),
1725 (s, C]O), 1723 (s, C]O), 1605 (m), 1581 (m), 1486
(m), 1447 (m), 1235 (w), 1189 (w), 1049 (w), 754 (w).
1H NMR (300 MHz, CDCl3) d 1.32 (t, 3H, 3J¼7.3 Hz,
3
3
H-2), 3.97 (dd, 1H, J4 ,4¼11.6, J4 ,3a¼3.6 Hz, H-40), 4.11
0
0
3
2
(d, 1H, J9b,3a¼8.3 Hz, H-9b), 4.22 (d, 2H, J¼13.2 Hz,
3
NCH2Ph), 4.27 (q, 2H, J¼7.3 Hz, OCH2CH3), 4.31 (dd,
3
3
0
1H, J4,4 ¼11.6, J4,3a¼1.7 Hz, H-4), 6.90–7.41 (m, 9H,
arom. CH). 13C NMR (75 MHz, CDCl3) d 14.6 (OCH2CH3),
41.4 (C-3a), 47.7 (C-3), 52.1 (NCH2Ph), 52.1 (OCH3), 58.8
(C-9b), 60.6 (OCH2CH3), 63.6 (C-2), 69.8 (C-4), 118.0,
121.5, 127.3, 128.3, 128.7, 130.5, 138.7, 157.7 (m, 9H,
arom. CH and Cq), 171.5 and 172.1 (C]O). EI-MS m/z
(%) 396.8 (M++H ,1), 395.1 (M+, 1), 324.2 (15), 222.3
(95), 320.5 (15), 260.5 (5), 174.2 (2), 173.1 (14), 172.1
(15), 131.0 (13), 92.1 (8), 90.9 (100), 64.8 (18). Calcd for
3
OCH2CH3), 3.40 (m, 1H, H-3a), 3.51 (dd, 1H, J3,3a¼7.2,
3J3,2¼6.9 Hz, H-3), 3.62 (d, 1H, 2J¼13.2 Hz, one of
3
NCH2Ph), 3.75 (s, 3H, OCH3), 3.99 (d, 1H, J2,3¼6.9,

J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
345
3
3
H-2), 4.05 (dd, 1H, J4 ,4¼11.3, J4 ,3a¼3.4 Hz, H-40), 4.15
(NaCl) n (cmꢂ1) 3061 (w), 3028 (w), 2961 (m), 2928 (m),
2855 (m), 1728 (s, C]O), 1606 (m), 1491 (m), 1453 (m),
1261 (m), 1187 (s), 1029 (m), 753 (m), 699 (m). H NMR
0
0
3
2
(d, 1H, J9b,3a¼8.3 Hz, H-9b), 4.23 (d, 2H, J¼13.2 Hz,
3
1
NCH2Ph), 4.27 (q, 2H, J¼7.3 Hz, OCH2CH3), 4.31 (dd,
3
3
3
0
1H, J4,4 ¼11.3, J4,3a¼1.8 Hz, H-4), 6.91–7.42 (m, 9H,
arom. CH). 13C NMR (75 MHz, CDCl3) d 14.5 (OCH2CH3),
41.6 (C-3), 47.6 (C-3a), 51.8 (NCH2Ph), 53.4 (OCH3), 59.5
(C-2), 61.2 (OCH2CH3), 63.8 (C-9b), 70.2 (C-4), 117.3,
126.2, 126.7, 128.5, 128.7, 129.1, 130.7, 138.5, 158.1
(arom. CH and Cq), 171.6 and 172.2 (C]O). EI-MS m/z
(%) 396.8 (M++H, 1), 395.1 (M+, 1), 324.2 (12), 222.3
(95), 320.5 (15), 260.5 (5), 174.2 (6), 173.1 (19), 172.1
(18), 131.0 (13), 92.1 (8), 91.0 (100), 64.8 (18). Calcd for
C23H25NO5 (395.45): C 69.86, H 6.37, N 3.54; found:
C 69.84, H 6.39, N 3.51.
(300 MHz, CDCl3) d 0.98 (t, 3H, J¼7.1 Hz, OCH2CH3),
3
2.59–2.63 (m, 1H, H-3a), 3.35 (dd, 1H, J3,2¼7.6,
3
3J3,3a¼6.6 Hz, H-3), 3.56 (d, 1H, J2,3¼7.6 Hz, H-2), 3.70
(dq, 2H, 3J¼7.0, 2J¼5.9 Hz, OCH2CH3), 3.91 (d, 1H,
2
2J¼13.5 Hz, one of CH2Ph), 4.10 (dd, 1H, J4,4¼11.2,
3J4,3a¼4.0 Hz, one of the H-4), 4.15 (d, 1H, 3J9b,3a¼7.3 Hz,
H-9b), 4.28 (dd, 1H, 2J4,4¼11.1, 3J4,3a¼7.0 Hz, the other of
2
H-4), 4.38 (d, 1H, J¼13.5 Hz, the other of CH2Ph), 6.84–
7.37 (m, 14H, arom. CH). 13C NMR (75 MHz, CDCl3) d
14.1 (OCH2CH3), 43.6 (C-3a), 50.2 (C-3), 58.4 (CH2Ph),
60.8 (OCH2CH3), 61.4 (C-9b), 65.7 (C-4), 74.1 (C-2),
117.2, 119.4, 121.6, 125.4, 125.9, 127.4, 127.5, 128.1, 128.9,
130.2, 132.6, 135.2, 138.1, 148.5 (arom. CH and Cq), 172.9
(C]O). EI-MS m/z (%) 413.5 (M+, 1), 374.1 (3), 300.6 (1),
283.1 (5), 211.7 (20), 210.1 (97), 192.1 (17), 181.5 (13), 92.0
(18), 90.9 (100), 64.8 (31). Calcd for C27H27NO3 (413.51):
C 78.42, H 6.58, N 3.39; found: C 78.44, H 6.56, N 3.38.
CO2Et
H2
Bn
N1
2
H3
H9b
3
9
6
9b
8
7
9a
5a
3a
H3a
H4
4
O5
H4
CO2Et
H2
Bn
4.2.10. Ethyl-(2R*,3R*,3aS*,9bR*)-1-benzyl-3-phenyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2-car-
boxylate (24c). Compound 24c was prepared by the reaction
of aldehyde 23c (596 mg, 2.5 mmol) with amine 5a (483 mg,
2.5 mmol), irradiated for 30 min. Flash chromatography
(19:1) gave 383 mg (37%) of 24c as an orange oil. IR (NaCl)
n (cmꢂ1) 3062 (w), 3028 (w), 2959 (m), 2924 (m), 2853 (m),
1727 (s, C]O), 1605 (m), 1490 (m), 1452 (m), 1261 (m),
1183 (s), 1029 (m), 748 (m), 699 (m). 1H NMR (300 MHz,
N1
2
H3
H9b
3
9
6
9b
10
CH3
8
7
9a
5a
3a
H3a
H4
4
O5
H4'
4.2.12. Ethyl-(2R*,3R*,3aS*,9bR*)-1-benzyl-3-methyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2-car-
boxylate (24e). Compound 24e was prepared by the reaction
of aldehyde 23e (441 mg, 2.5 mmol) with amine 5a
(483 mg, 2.5 mmol), irradiated for 40 min. Flash chromato-
graphy (9:1) gave 544 mg (62%) of 24e as slightly brown
crystals. Mp (70–72 ꢀC). IR (KBr) n (cmꢂ1) 3062 (m),
3029 (m), 2962 (m), 2929 (m), 2856 (m), 1726 (s, C]O),
1602 (w), 1489 (w), 1454 (w), 1218 (m), 1184 (s), 1139
(m), 1027 (m), 756 (m), 700 (m). 1H NMR (300 MHz,
3
CDCl3) d 0.83 (t, 3H, J¼7.4 Hz, OCH2CH3), 3.35–3.39
3
3
(m, 1H, H-3a), 3.71 (dd, 1H, J3,2¼6.3, J3,3a¼7.3 Hz,
H-3), 3.79 (d, 1H, 2J¼13.5 Hz, one of CH2Ph), 3.84 (d, 1H,
2
3
3J2,3¼6.3 Hz, H-2), 3.98 (dd, 1H, J4,4¼11.2, J4,3a
¼
2
3.6 Hz, one of the H-4), 4.06 (dd, 1H, J4,4¼11.2,
3J4,3a¼3.0 Hz, the other of H-4), 4.20 (q, 2H, J¼7.3 Hz,
3
OCH2CH3), 4.34 (d, 1H, 2J¼13.5 Hz, the other of CH2Ph),
3
4.38 (d, 1H, J9b,3a¼8.9 Hz, H-9b), 6.98–7.43 (m, 14H,
arom. CH). 13C NMR (75 MHz, CDCl3) d 14.0 (OCH2CH3),
42.7 (C-3a), 48.4 (C-3), 58.0 (CH2Ph), 59.4 (C-9b), 60.4
(OCH2CH3), 68.3 (C-2), 68.5 (C-4), 117.9, 120.1, 122.3,
125.1, 126.2, 127.6, 128.3, 128.6, 129.1, 130.3, 132.9, 134.8,
139.8, 157.0 (arom. CH and Cq), 172.3 (C]O). EI-MS m/z
(%) 413.7 (M+, 1), 374.4 (2), 300.2 (2), 283.4 (4), 211.5
(19), 210.2 (98), 192.2 (17), 181.1 (12), 92.1 (17), 90.9
(100), 64.9 (30). Calcd for C27H27NO3 (413.51): C 78.42,
H 6.58, N 3.39; found: C 78.45, H 6.57, N 3.41.
3
CDCl3) d 1.04 (d, 3H, J10,3¼6.9 Hz, H-10), 1.25 (t, 3H,
3J¼7.3 Hz, CO2CH2CH3), 2.45–2.51 (m, 1H, H-3a), 2.51–
3
2.64 (m, 1H, H-3), 3.55 (d, 1H, J2,3¼7.3 Hz, H-2), 3.73
(d, 1H, 2J¼13.2 Hz, one of NCH2Ph), 3.91 (dd, 1H, 2J4 ,4
¼
0
3
2
11.2, J4 ,3a¼3.6 Hz, H-40), 4.09 (dd, 1H, J4,4 ¼11.1,
3J4,3a¼3.0 Hz, H-4), 4.18 (q, 2H, 3J¼7.3 Hz, CO2CH2CH3),
4.24 (d, 1H, 3J¼13.2 Hz, the other of NCH2Ph), 4.47 (d, 1H,
3J9b,3a¼8.3 Hz, H-9b), 6.90–7.37 (m, 9H, arom. CH). 13C
NMR (75 MHz, CDCl3) d 14.3 (C-10), 14.7 (CH2CH3),
36.7 (C-3), 45.6 (C-3a), 53.0 (CH2Ph), 59.1 (C-9b), 60.0
(CH2CH3), 66.9 (C-2), 68.4 (C-4), 117.8, 121.3, 126.4,
127.1, 128.3, 128.4, 128.9, 130.5, 139.2, 157.0 (arom. CH
and Cq), 178.3 (C]O). EI-MS m/z (%) 353.1 (M++2, 9),
352.0 (M++1, 17), 351.4 (M+, 4), 279.5 (14), 278.2 (100),
260.1 (5), 187.3 (4), 186.3 (8), 148.9 (13), 130.7 (10), 90.8
(48). Calcd for C22H25NO3 (351.44): C 75.19, H 7.17,
N 3.99; found: C 75.20, H 7.19, N 3.98.
0
0
CO2Et
H2
Bn
N1
2
H3
H9b
3
9
6
9b
8
7
9a
5a
3a
H3a
H4
4
O5
H4
4.2.11. Ethyl-(2R*,3S*,3aR*,9bR*)-1-benzyl-3-phenyl-
1,2,3,3a,4,9b-hexahydrochromeno[4,3-b]pyrrole-2-car-
boxylate (25c). Compound 25c was prepared by the reaction
of aldehyde 23c (596 mg, 2.5 mmol) with amine 5a
(483 mg, 2.5 mmol), irradiated for 30 min. Flash chromato-
graphy (19:1) gave 176 mg (17%) of 25c as an orange oil. IR
Acknowledgements
The research was supported by a grant from the Ministry of
Education (COST OC D29.002).

346
J. Pospꢁısꢀil, M. Potaꢁcꢀek / Tetrahedron 63 (2007) 337–346
9. This very polar fraction, which sticks on the silica gel, pre-
Supplementary data
sented a very complicated mixture of probably decomposed
reaction intermediates, which was not possible to analyze. At
first, we have expected the formation of product of the
Claisen rearrangement, however, this product was not observed
in the reaction mixture.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.10.074.
References and notes
10. (a) Jacob, J.; Chia, L. H. L.; Boey, F. Y. C. J. Mater. Sci. 1995,
30, 5321–5327; (b) Laurent, R.; Laporterie, A.; Dubac, J.;
Berlan, J.; Lefeuvre, R.; Audhuy, M. J. Org. Chem. 1992, 57,
7099–7102; (c) Strauss, C. R.; Trainor, R. W. Aust. J. Chem.
1995, 48, 1665–1671; (d) Barghust, D. R.; Mingos, D. M. P.
J. Chem. Soc., Chem. Commun. 1992, 674–677.
11. Taft, R. W.; Bordwell, F. G. Acc. Chem. Res. 1988, 21, 463–
469.
12. The condensation of the water was observed above the open
reaction vessel in the course of the reaction.
13. This reaction is possible to extend to other aldehydes as well as
N-alkyl 2-alkylaminoacetamides and represents an elegant way
for the preparation of 1,2,3-trialkyl substituted imidazolin-4-
ones. Desired compounds are formed generally in 5 min
(200 ꢀC, mW) in 90–96% yields. Interestingly, the reaction is
possible to carry out under the classical heating with compara-
ble yields, however, the reaction times are longer (30 min).
1. (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809;
(b) Eberbach, W. Science of Synthesis, Houben–Weyl Methods
of Molecular Transformation; Thieme: Stuttgart, 2004; Vol. 27,
pp 441–498; (c) Harwood, L. M.; Vickers, R. J. Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley: New York, NY, 2003; p 169; (d) Najera,
C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150; (e)
Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, NY, 1984; Vol. 1, p 1; (f) Wade, P.
Comprehensive Organic Synthesis; Trost, B. M., Flemming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1111–1168.
2. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074.
3. De la Hoz, A.; Diaz-Ortiz, A.; Langa, F. Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH GmbH &
KGaA: Weinheim, Germany, 2002; pp 295–343.
ꢁꢀ
See: Pospısil, J.; Potacek, M. Heterocycles 2004, 63, 1165–
ꢁꢀ
1173.
4. Rossini, M.; Budriesi, R.; Bixel, M. G.; Bolognesi, M. L.;
Chiarini, A.; Hucho, F.; Krogsgaard-Larsen, P.; Mellor, A.;
Minarini, I. R.; Tumiatti, V.; Usherwood, P. N. R.;
Melchiorre, C. J. Med. Chem. 1999, 42, 5212–5223.
14. Interestingly, no products of the intermolecular reaction
(dimers, trimers,.) were observed in the reaction mixture
(GC–MS).
15. pKa of the hydrogen atom attached to the carbon next to cyano
group isw25; pKa of the equivalent hydrogen atom attached to
the carbon next to ester group isw28. The values are valid in
DMSO (see Ref. 11).
5. (a) Mahmud, H.; Lovely, C. J.; Rasika Dias, H. V. Tetrahedron
2001, 57, 4095–4105; (b) Witherup, K. M.; Ransom, R. M.;
Graham, A. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga,
S. L. J. Am. Chem. Soc. 1995, 117, 6682–6685.
16. Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990.
6. (a) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106,
7175–7178; (b) Kanemasa, S.; Sakamoto, K.; Tsuge, O. Bull.
Chem. Soc. Jpn. 1989, 62, 1960–1968; (c) Martin, S. F.;
Cheavens, T. H. Tetrahedron Lett. 1989, 30, 7017–7020; (d)
Grigg, R.; Savic, V.; Thornton-Pett, M. Tetrahedron 1997, 53,
10633–10642; (e) See Ref. 6c; (f) Gong, Y.-D.; Najdi, S.;
Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63,
3081–3086; (g) Bashiardes, G.; Safir, I.; Mohamed, A. S.;
Barbot, F.; Laduranty, J. Org. Lett. 2003, 5, 4915–4918; (h)
Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron
Lett. 2003, 44, 8417–8420.
17. Stabilities of aldehyde 4, amines 18a–c and cycloadducts
20a–c under the reaction conditions were tested and all the
compounds were reisolated in >85% yield. Typical tempera-
ture profile of the reaction is presented in Graph S-1 and can
be found in Supplementary data.
18. (a) Grigg, R.; Gunaratane, H. Q. N.; Kemp, J. J. Chem. Soc.,
Perkin Trans. 1 1984, 41–46; (b) Grigg, R. Chem. Soc. Rev.
1987, 16, 89–121.
19. Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: Chichester, England, 1976; p 96.
20. Houk, K. N.; Paddon-Row, M.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D.; Metz, J. T.; Li, Y.; Loncharich,
R. J. Science 1986, 231, 1108–1117.
7. (a) See Ref. 6g; (b) Zhang, W.; Lu, Y.; Geib, S. Org. Lett. 2005,
7, 2269–2272.
ꢁꢀ
ꢁꢀ
8. Pospısil, J.; Potacek, M. Eur. J. Org. Chem. 2004, 710–716;
Other microwave-assisted solvent-free reactions of azomethine
ylides: (a) Jayashankaran, J.; Manian, R. D. R. S.; Venkatesan,
R.; Raghunathan, R. Tetrahedron 2005, 61, 5595–5598; (b)
Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R.
Tetrahedron Lett. 2004, 45, 7303–7305; (c) Azizian, J.;
Karimi, A. R.; Dastkhan, R.; Mohammadi, A. A.;
Mohammadizadeh, M. R. J. Chem. Res. 2004, 347–349; (d)
21. Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334–338.
22. The progress of the cis/trans isomerization during the reaction
1
was monitored by H NMR. See Supplementary data Graph
S-2.
23. (a) Tam, W. J. Org. Chem. 2001, 66, 5113–5123; (b) Weaver,
W. E.; Whaley, W. M. J. Am. Chem. Soc. 1947, 69, 515–516
and 1144–1145; (c) Swensen, A. D.; Weaver, W. E. J. Am.
ꢁ
ꢁꢀ
ꢁꢀ
Travnıcek, M.; Potacek, M. ARKIVOC 2001, 156–163; (e)
Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem. Soc.,
Perkin Trans. 1 2001, 452–456; (f) Azizian, J.; Asadi, A.;
Jadidi, K. Synth. Commun. 2001, 31, 2727–2733; (g) Langa,
F.; De la Cruz, P.; De la Hoz, A.; Espildora, E.; Cossio, F. P.;
Lecea, B. J. Org. Chem. 2000, 65, 2499–2507; (h) Fraga-
Dubreuil, J.; Cherouvrier, J. R.; Bazureau, J. P. Green Chem.
2000, 2, 226–229; (i) Lerestif, J. M.; Perrocheau, J.; Tonnard,
F.; Bazureau, J. P.; Hamelin, J. Tetrahedron 1995, 51, 6757–
6774.
ꢁꢀ
Chem. Soc. 1948, 70, 4060–4061; (d) Travnıcek, M.;
ꢁꢀ
Potacek, M. Molecules 1999, 4, 238–244; (e) Saha, U. K.;
Roy, R. J. Chem. Soc., Chem. Commun. 1995, 2571–2573.
24. Shimizu, T.; Hayashi, Y.; Kitora, Y.; Teramura, K. Bull. Chem.
Soc. Jpn. 1982, 55, 2450–2455.
25. Maruoka, K.; Akaruta, M.; Saito, S.; Susumu, O.; Yamamoto,
H. J. Am. Chem. Soc. 1994, 116, 6153–6158.
26. Kende, A. S.; Fludzinski, P. Organic Syntheses; Wiley: New
York, NY, 1990; Collect. Vol. 7, p 221.