Novel and efficient synthesis of 4,7-dihydro-1H-pyrrolo[2,3-b]pyridine derivatives via one-pot, three-component approach from N-substituted 5-amino-3-cyanopyrroles, various carbonyl and active methylene compounds

Article abstract of DOI:10.1016/j.tet.2013.04.115

An efficient route to novel 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with incorporated tetrahedral fragment in the position-4 via three-component reaction of N-substituted 5-amino-3-cyanopyrroles, various carbonyl and active methylene compounds has been developed. In the same time, by using developed methods here, the 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with fused 4-spiro-frameworks were synthesized starting from isatins and a set of 1,2-dicarbonyl compounds. The reactions were carried out under mild conditions using ethanol, acetic acid or 1,4-dioxane as solvent.

Full text of DOI:10.1016/j.tet.2013.04.115

Tetrahedron xxx (2013) 1e13
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel and efficient synthesis of 4,7-dihydro-1H-pyrrolo[2,3-b]
pyridine derivatives via one-pot, three-component approach from
N-substituted 5-amino-3-cyanopyrroles, various carbonyl and active
methylene compounds
,
,b,
Marcelo Vilches-Herrera a b, Anke Spannenberg b, Peter Langer a
*
,
,c,
Viktor O. Iaroshenko a
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b
€
Leibnitz Institute fur Katalysis; Albert Einstein Str., 18059 Rostock, Germany
c National Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kyiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route to novel 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with incorporated tetrahedral frag-
ment in the position-4 via three-component reaction of N-substituted 5-amino-3-cyanopyrroles, various
carbonyl and active methylene compounds has been developed. In the same time, by using developed
methods here, the 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with fused 4-spiro-frameworks were syn-
thesized starting from isatins and a set of 1,2-dicarbonyl compounds. The reactions were carried out
under mild conditions using ethanol, acetic acid or 1,4-dioxane as solvent.
Received 5 January 2013
Received in revised form 23 April 2013
Accepted 24 April 2013
Available online xxx
Keywords:
Multicomponent reaction
Heterocyclization
Ó 2013 Elsevier Ltd. All rights reserved.
Dihydro-1H-pyrrolo[2,3-b]pyridines
Active methylene compounds
1,2-Dicarbonyl compounds
Spiroxindole derivatives
1. Introduction
compound-libraries for evaluation as lead or hit compounds in drug
discovery.1g
Multicomponent reactions (MCRs) make it possible to synthe-
size target molecules with great efficiency and atom economy.1
Using this approach more than two adducts can be converted di-
rectly into product by one-pot simultaneous or sequential reaction.
In contrast with multistep synthesis they are more efficient because
several bonds are formed in one sequence without isolation of any
intermediates.2 Even when the first MCRs are dated by the middle
of 19th century, a new interest has renewed for such reactions, not
just because of minimization of waste, but also solvents, reagents,
adsorbents, and energy are dramatically decreased. Because of the
significant therapeutic potential associated with heterocyclic
compounds such reactions, coupled with high-throughput bi-
ological screening, are one of the best tools to generate large
1H-Pyrrolo[2,3-b]pyridine heterocyclic system can be consid-
ered as bioisosteres of the indole moiety, which represents im-
portant structure class in drug discovery.3 The 1H-pyrrolo[2,3-b]
pyridine framework is present in several natural products.4 Despite
of that this heterocyclic system has attracted considerable interest
of the scientific community due its physicochemical and pharma-
cological properties.5 For instance variolins, a group of marine
heterocycle substances isolated from the Antarctic sponge Kirkpa-
trickia variolosa, have exhibited a potent cytotoxic activity against
P388 murine leukaemia cell lines, particularly variolin B.6,7 In ad-
dition azaindoles have also found applications in synthesis as
prominent materials for electronic devices due to their lumines-
cence properties,8 and in coordination chemistry.9 In contrary, the
correspondent dihydro-analogues, namely 4,7-dihydro-1H-pyrrolo
[2,3-b]pyridines are rear in the literature. Nevertheless,
some scarce information indicates handful representatives
manly containing 4,7-dihydro-1H-pyrrolo[2,3-b]pyridine scaffold
incorporated into the more complex polycyclic structure.10 The 4-
* Corresponding authors. E-mail addresses: viktor.iaroshenko@uni-rostock.de,
iva108@googlemail.com (V.O. Iaroshenko).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.115
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

2
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
spiro-fused 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines are not known
to date.
out first at room temperature, than the temperature was slowly
increased until the reflux. The progress of the reaction was moni-
tored by TLC. Performing the reaction in 1,4-dioxane the lowest
yield of 30% for compound 4aa was obtained, in contrary using DMF
and ethanol we have reached 42 and 60% yields of the corre-
sponding product 4aa, respectively. Based on our previous work,11
Recently we have demonstrated the one-pot, three-component
synthesis of 7-azaindole derivatives from N-substituted 5-amino-
1H-pyrrole-3-carbonitriles, various aldehydes, and active methy-
lene compounds.11 As intermediates in some cases we have
detected and succeed to isolate many 4,7-dihydro-1H-pyrrolo[2,3-
b]pyridines. To our best knowledge this was the first synthetic
method towards 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines by mul-
ticomponent reaction as well as the first application of 5-
aminopyrroles in multicomponent synthesis. Current work is
a logical continuation of our previous research regarding the syn-
thesis libraries of 4,7-dihydro-1H-pyrrolo[2,3-b]pyridine de-
rivatives; herein we detail a three-component reaction using
different active ketones, 5-aminopyrroles and 1,3-dicarbonyl
compounds to afford the 4-fused 4,7-dihydro-1H-pyrrolo[2,3-b]
pyridines derivatives. The method discussed vide infra also can be
applied to the construction 4-spiro-fused dihydro-1H-pyrrolo[2,3-
b]pyridine libraries.
we thought that the using of ethanol as a solvent of choice and L-
proline as a catalyst would be the best reaction condition for the
current reaction, however, to our great disappointment the yield
remained unchanged. When the reaction was conducted in acetic
acid, surprisingly the yield of 4aa aroused up to 70%. As a next
logical step of our study, we decided to test the systems: acetic acid/
L-proline and acetic acid/ammonium acetate as a reaction medium,
the latest reaction conditions delivered product 4aa in a yield of
81%. These were our solvent/base of choice to afford the required
spiroxindoles derivatives 4 (Scheme 1, Table 1).
The procedure was simple and easy to operate, generally the
reaction was completed after 6e8 h and precipitate, corresponding
to the product, was formed in almost all the cases and was sepa-
rated by simple filtration. As can be seen in Tables 1 and 2, the
method probed into work with a wide variety of isatin substrates 2,
containing electron withdrawing or electron donating groups such
as bromine, chlorine, nitro or trifluoromethoxy. N-Methyl
substituted isatins also showed to be suitable for the reaction (Table
1, entries 2 and 8, and Table 2 entries 2, 6, 7 and 9). In all these cases
good yields in the range from 51 to 86% were obtained (Table 1),
except when 5-amino-1-cyclohexyl-1H-pyrrole-3-carbonitrile 3b
was used, in this case the yield went down to 30% (Table 2, entry 7).
Previously, similar reaction mode has been reported with amino-
pyrazoles,16 nevertheless the usage of 5-amino-3-cyanopyrroles 3
in the reactions of this type has not been documented in the lit-
erature. In the same time different cyclic active methylene com-
pounds like 1b, c were also used; the reaction in all cases delivered
desired spiroxindoles 5 and 6 (Scheme 2). On the other hand, the
2. Results and discussion
During the last decade Iaroshenko’s group11 developed a series
of new cyclocondensation reactions of electron-rich aminohetero-
cycles with 1,3-CCC- and 1,3-CNC-dielectrophiles, these resulted in
the synthesis of many purines, purine-like scaffolds and purine
isosteres. Using our recent experience12 we have concentrated on
developing synthetic methods towards the 4,7-dihydro-1H-pyrrolo
[2,3-b]pyridines frameworks containing tetrahedral carbon nuclei
in the postion-4 of the annulated 1,4-dihydropyridine ring. We
have assumed the novelty of this scaffold and as result its possible
application in the medicine chemistry and drug design as a poten-
tial target for the combinatorial aspect of biology-oriented syn-
thesis (BIOS),13 for the creation of natural-product-derived and
natural-product-inspired compound libraries.
introduction of 4-hydroxycoumarin 1d in this reaction, as active b-
dicarbonyl compound, afforded the spiroxindoles 7. Previous re-
ports have shown that when 4-hydroxycoumarin 1d has been used,
a cleavage of the coumarone ring can be possible.17 As we have
observed in this study, the reaction occurs via rupture of the CeO
bond and consequent ring opening delivering corresponding
products 7 (Scheme 2, Table 2). This reaction took place only in
ethanol under reflux; other reaction conditions experienced
a failure.
To explore the scope of this reaction to form new spiroheter-
ocyclic derivatives, we investigated the use of acenaphtylene-1,2-
dione 2i to afford the N-substituted-2,60-dioxo-10,50,60,70-tetrahy-
dro-2H-spiro[acenaphthylene-1,40-pyrrolo[2,3-b]pyridine]-30-car-
bonitriles 8e10 (Scheme 3). As expected the reaction proceeded
with fair to good yields using ethanol as a solvent and the reactions
were under reflux (Table 3). In this case our standard reaction
conditions, namely the acetic acid/ammonium acetate have shown
less efficiency.
Previous reports have also shown that diverse spirocyclic com-
pounds as well as pharmacologically relevant 3-spiro-fused oxin-
doles can be generated by using 5-aminopyrazoles.14 However, to
the best of our knowledge, the combinatorial synthesis of spirox-
indoles fused with
a
4,7-dihydro-1H-pyrrolo[2,3-b]pyridine
framework has not been reported hitherto. Thus, we envisioned
that these scaffolds could be synthesized by a one-pot reaction of
N-substituted 5-amino-3-cyanopyrroles, commercially available
isatins and adequate 1,3-dicarbonyl compounds, such as Meldrum’s
acid 1a, tetronic acid 1b, 1,3-dimedione 1c and 4-hydroxycoumarin
1d (Fig. 1). To further explore the potential of this synthetic pro-
tocol, we also investigated the reactions with other 1,2-dicarbonyl
compounds 2iel (Figs. 2 and 3).
Finally, we decided to expand the versatility of this methodology
using acyclic 1,2-dicarbonyl compounds 2jel such as methyl 2-oxo-
2-phenylacetate 2j, 3,4-hexadione 2k and ethyl 2-oxopropanoate 2l
(Scheme 4). Unfortunately our optimal reaction condition de-
veloped for the synthesis of 4,7-dihydro-1H-pyrrolo[2,3-b]pyridine
series 4e10 experienced a failure when we set 1,2-dicarbonyl
compounds 2jel under investigation.
Fig. 1. 1,3-Dicarbonyl compounds 1 used for the synthesis of 4,7-dihydro-1H-pyrrolo
[2,3-b]pyridines.
In our initial studies various conditions were evaluated to find
an appropriate medium for the synthesis of spiroxindole de-
rivatives. Initially, we tested the reaction of isatin 2a, 5-amino-1-
tert-butyl-pyrrole-3-carbonitrile 3a and Meldrum’s15 acid 1a in
different solvents, including ethanol, dimethylformamide (DMF),
acetic acid, acetic acid/proline,11 acetic acid/ammonium acetate,
and 1,4-dioxane. All the reactions of this model system were carried
On this stage we had to renovate the search of suitable reaction
conditions. In order to find the optimal reaction medium we tested
different solvents including ethanol, DMF, 1,4-dioxane and acetic
acid. When we reacted methyl 2-oxo-2-phenylacetate 2j with 1a
and 3b, the acetic acid was in this case the best solvent isolated
product 11ba with 42% yield. Nevertheless when we carried out the
reaction in two steps, first the condensation of Meldrum’s acid with
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
3
Isatins 2a-h
R1
H
R2
H
2a
2b
2c
2d
2e
2f
CH3
H
H
Cl
H
OCF3
Br
H
H
F
H
NO2
H
2g
2h
Ph
Fig. 2. 1,2-Dicarbonyl compounds 2 used for the synthesis of 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines.
Table 1
Synthesis of compounds 4
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
9
H
CH3
H
H
H
H
H
Ph
H
H
H
H
Cl
OCF3
Br
F
NO2
H
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
4aa
4ab
4ac
4ad
4ae
4af
4af
4ah
4bf
4cb
81
73
86
52
51
75
70
55
57
58
Fig. 3. 5-Aminopyrroles 3aec used for the synthesis of 4,7-dihydro-1H-pyrrolo[2,3-b]
pyridines.
methyl 2-oxo-2-phenylacetate 2j in the presence of TiCl4, according
to the literature procedure,18 and then cyclization with 3 in ethanol,
the yield raised up to 77% (entry 4, Table 4). As following, with this
reaction conditions in hand we synthesized the series of com-
pounds 11aae11cb. In contrary, for the synthesis of compounds
12b, c the best solvent was 1,4-dioxane; for all reactions good yields
were obtained, however the use of methyl 2-oxo-2-phenylacetate
2j and 3,4-hexadione 2k showed to be more difficult to handle
particularly with dimedone 1c and 4-hydroxycoumarin 1d. Next we
have concentrated on the combination of dimedone 1c and 4-
hydroxycumarin 1d with 1,2-dicarbonyl compounds 2jel and 5-
aminopyrroles 3aec correspondingly. In these two cases the best
reaction medium appeared to be ethanol and 1,4-dioxane under
reflux (Table 4). Here it was not possible to gain excellent yields;
nevertheless we succeed the synthesis of scaffolds 14 and 15 with
fair yields in the range of 34e67%.
F
H
Cyclohexyl
p-OMeebenzyl
10
functionality and shows less reactivity. Contrary, the carbonyl
groups in the 3-thioisatin are equally reactive or susceptible to
suffer nucleophilic attacks with the equal velocity, resulting after
reaction in a complex mixture that was not possible to separate,
even when it was carried out at ꢀ10 ꢁC. We wanted to probe the
scope of the reaction by using a tricarbonyl compound. For that
reason we took ninhydrin instead of isatin, but the reaction was
unsuccessful. Then we tried the reaction in two steps, first the
condensation with tetronic acid 1b19 and then the cyclization with
the 5-aminopyrrole. Unfortunately, the latter step failed. The tri-
We tested also other compounds, on the first glance suitable for
the multicomponent reactions, such as 3-thioisatin, ninhydrin and
2,2,2-trifluoro-1-phenylethanone. In the case of 3-thioisatin, even
when it can be considered as an analogue of isatin, the reactivity of
the carbonyl groups is completely different. The carbonyl group in
the position-3 of the isatin is the reactive entity of the molecule,
because of the carbonyl group in the position-2 belongs to an amide
fluoromethyl group, attached to the b-position of 1,2-dicetones,
activates neighbouring carbonyl group; we thought that such
compounds would be appropriate substrates for this chemistry,
however the reaction did not work neither with 2,2,2-trifluoro-1-
phenylethanone nor with 1,1,1-trifluoropropan-2-one under any
of mentioned before conditions as well as by the protracted reflux
in toluene, benzene, dichloromethane or chloroform with the set of
Scheme 1. Reactions of Meldrum’s acid 1a with isatins 2aeh and 5-amino-3-cyanopyrroles 3. Reaction conditions: (i) AcOH/AcONH4, reflux.
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

4
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
Table 2
Synthesis of compounds 5, 6, 7
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
H
CH3
H
H
H
Ph
CH3
H
CH3
H
H
H
H
H
H
H
H
H
OCF3
Br
F
H
H
H
H
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
Cyclohexyl
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
Cyclohexyl
tert-Bu
5aa
5ab
5ad
5ae
5af
5ah
5bb
6aa
6ab
6ac
6ad
6ag
6ba
7ad
7ag
7ba
57
63
37
64
61
37
30
79
57
65
64
66
41
69
38
59
9
10
11
12
13
14
15
16
Cl
OCF3
NO2
H
OCF3
NO2
H
tert-Bu
Cyclohexyl
Scheme 3. Reactions of active methylene compounds 1a, b and 1d with 5-amino-3-
cyanopyrroles 3 and 2i. Reaction conditions: (i) EtOH, reflux.
Table 3
Synthesis of compounds 8, 9, 10
Entry
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
tert-Bu
Cyclohexyl
tert-Bu
Cyclohexyl
p-MeOebenzyl
tert-Bu
Cyclohexyl
p-MeOebenzyl
8aa
8ba
9ab
9bb
9bd
10ad
10bd
10dd
71
55
82
73
38
65
56
35
4. Experimental part
4.1. General
Scheme 2. Reactions of active methylene compounds 1bed with isatins 2aeh and
5-amino-3-cyanopyrroles 3aec. Reaction conditions: (i) AcOH/AcONH4, reflux; (ii)
EtOH, reflux.
The dry solvents ethanol and 1,4-dioxane were purchased di-
rectly from ACROS as AcroSeal bottles. Acetic acid was purchased
from VWR. For 1H and 13C NMR spectra the deuterated solvents
indicated were used. Mass spectrometric data (MS) were obtained
by electron ionization (EI, 70 eV), chemical ionization (CI, iso-
butane) or electrospray ionization (ESI). For preparative scale
chromatography silica gel 60 (0.063e0.200 mm, 70e230 mesh)
was used. Compounds 3 were obtained by method described pre-
viously; 1,2- and 1,3-dicarbonyl are commercially available
compounds.
acidic catalysts such as PTSA, TiCl4, AlCl3, AlBr3, AgO2CCF3, AgOTrf,
Bi(OTrf)3, Zn(OTrf)2, and many other salts. Simple ketones, such as
1H-inden-2(3H)-one, cyclopropyl(phenyl)methanone as well as
hydroxyketones such as 2-hydroxy-1,2-diphenylethanone did also
not work, even after we tested the reaction in a variety of
conditions.
Finally, the structures of several scaffolds synthesized, namely
compounds 9bb and 11cb were corroborated by the means of 1D
and 2D NMR methods and X-ray analysis (Figs. 1 and 2 in
Supplementary data).20
4.2. Procedure Adgeneral procedure for the synthesis of
3. Conclusion
compounds 4, 5, 6 and 7
In summary we have developed an efficient synthetic route to
access in a one-pot manner new spirocyclic heterocyclic scaffolds
containing 1,4-dihydropyridine framework. Furthermore we illus-
trated the versatility of this multicomponent reaction by using
cyclic and non-cyclic 1,2-dicarbonyl substrates. In total about 50
new compounds, that can be used as substrates for both organic
and medicinal research, were synthesized.
A mixture of the corresponding 1,3-dicarbonyl compound
(1 equiv), the corresponding isatin (1 equiv), 5-amino-1H-pyrrole-
3-carbonitrile (1 equiv) and ammonium acetate (5 equiv) was
refluxed in acetic acid for 4e6 h. For compounds 7 ethanol was used
as a solvent without any base. The precipitate was collected and, if
necessary, purified by column chromatography (eluent: n-heptane/
ethylacetate).
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
5
4.4. Procedure Cdgeneral procedure for the synthesis of
compounds 11, 12, 13 and 14
A mixture of the corresponding carbonyl compound (1 equiv),
the corresponding 1,2-dicarbonyl compounds (1 equiv) and 5-
amino-1H-pyrrole-3-carbonitrile (1 equiv) was added to 10 mL of
ethanol (compounds 13), 1,4-dioxane (compounds 14), or acetic
acid (compounds 12) and heated under reflux for 4e6 h. The pre-
cipitate was collected and, if necessary, purified by column chro-
matography (eluent: n-heptane/ethylacetate).
For the preparation of compounds 11 the method communi-
cated in Ref. 18 has particularly been used.
5. Analytical data
5.1. 10-tert-Butyl-2,60-dioxo-10,50,60,70-tetrahydrospiro[indo-
line-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile (4aa)
The product was isolated as a light yellow solid, yield 81%, mp
291e293 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d 1.56 (9H, s, (CH3)3),
2.66 (1H, d, J¼15.8 Hz, CH2), 2.81 (1H, d, J¼15.8 Hz, CH2), 6.89 (2H,
m, AreH), 7.18 (2H, m, AreH), 7.35 (1H, s, AreH), 10.14 (1H, s, NH),
10.61 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.2 (CH3)3,
40.3 (CH2), 46.2 (Ce), 57.8 (Ce), 86.1 (Ce), 103.5 (Ce), 109.8 (CHe),
114.6 (Ce), 122.0 (CHe), 123.1 (CHe), 123.6 (CHe), 128.8 (CHe),
131.2 (Ce), 131.4 (Ce), 141.5 (Ce), 168.4 (Ce), 177.7 (Ce); MS (GC,
70 eV): m/z (%) 334 (Mþ, 49), 277 (89), 250 (68); HRMS (ESI): calcd
for C19H19N4O2 (Mþ1) 335.1503, found 335.1507; IR (ATR, cmꢀ1):
3172 (w), 2230 (w), 1715 (s), 1672 (s), 1471 (m), 1208 (m), 748 (s),
606 (s).
2
R1
R2
Ph
OCH3
2j
2i
2l
CH3 OCH2CH3
CH3CH2 CH3CH2
5.2. 10-tert-Butyl-1-methyl-2,60-dioxo-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4ab)
Scheme 4. Reactions of active methylene compounds 1aed with 5-amino-3-
cyanopyrroles 3 and 2jel. Reaction conditions: (i) see the notes of Table 4.
The product was isolated as a white solid, yield 73%, mp
326e327 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.59 (9H, s, (CH3)3),
Table 4
Synthesis of compounds 11, 12, 13, 14
2.77 (1H, d, J¼15.7 Hz, CH2), 2.84 (1H, d, J¼15.7 Hz, CH2), 3.19
(3H, s, NCH3), 7.10 (2H, m, AreH), 7.20 (1H, d, J¼7 Hz, AreH),
7.32e7.41 (2H, m, AreH), 10.23 (1H, s, NH); 13C NMR (62.9 MHz,
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
Ph
OCH3
tert-Bu
tert-Bu
tert-Bu
Cyclohexyl
Cyclohexyl
p-MeOebenzyl
p-MeOebenzyl
tert-Bu
11aa
11ab
11ac
11ba
11bb
11ca
11cb
12aa
12ab
12bb
12cb
13ab
13bb
14ab
14bb
14cb
70a
CH3
CH3CH2
Ph
CH3
Ph
OCH2CH3
CH3CH2
OCH3
OCH2CH3
OCH3
73a
DMSO-d6):
d 26.1 (CH3), 29.2 (CH3)3, 39.9 (CH2), 45.8 (Ce), 57.8
70a
(Ce), 86.0 (Ce), 103.5 (Ce), 108.9 (CH), 114.5 (Ce), 122.7 (CHe),
123.0 (CHe), 123.2 (CHe), 128.9 (CHe), 130.8 (Ce), 131.2 (Ce),
142.8 (Ce), 168.4 (Ce), 175.9 (Ce); MS (GC, 70 eV): m/z (%) 348
(Mþ, 44), 291 (100), 250 (36); HRMS (ESI): calcd for C20H21N4O2
(Mþ1) 349.1659, found 349.1664; IR (ATR, cmꢀ1): 3140 (w), 2220
(w), 1704 (s), 1668 (s), 1614 (w), 1469 (m), 1347 (s), 1208 (m),
1008 (w), 742 (s), 626 (w).
77a (42)b
57a
65a
CH3
Ph
OCH2CH3
OCH3
68a
42c
9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
tert-Bu
67c
10
11
12
13
14
15
16
Cyclohexyl
p-MeO-benzyl
tert-Bu
Cyclohexyl
tert-Bu
40c
64c
55d
58d
67c
5.3. 10-tert-Butyl-5-chloro-2,60-dioxo-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4ac)
Cyclohexyl
p-MeO-benzyl
34c
47c
a
Two-step sequential reaction after Ref. 18.
AcOH reflux.
1,4-Dioxane reflux.
b
c
The product was isolated as a white solid, yield 86%, mp
334e335 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.59 (9H, s, (CH3)3),
d
EtOH reflux.
2.68 (1H, d, J¼15.7 Hz, CH2), 3.03 (1H, d, J¼15.7 Hz, CH2), 6.93 (1H,
d, J¼8.3 Hz, AreH), 7.31 (2H, m, AreH), 7.41 (1H, s, AreH), 10.15 (1H,
4.3. Procedure Bdgeneral procedure for the synthesis of
s, NH), 10.75 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.2
compounds 8, 9, 10
(CH3)3, 39.6 (CH2), 46.4 (Ce), 57.9 (Ce), 86.0 (Ce), 102.8 (Ce), 111.2
(CHe), 114.5 (Ce), 123.2 (CHe), 124.0 (CHe), 125.9 (Ce), 128.8
(CHe), 131.4 (Ce), 133.1 (Ce), 140.7 (Ce), 168.3 (Ce), 177.5 (Ce); MS
(GC, 70 eV): m/z (%) 368 (Mþ, 34), 311 (64), 284 (34); HRMS (ESI):
calcd for C19H18N4O325Cl (Mþ1) 369.1113, found 369.1114; IR (ATR,
cmꢀ1): 3280 (w), 2229 (w), 1727 (s), 1698 (s), 1614 (w), 1471 (m),
1199 (m), 821 (s), 615 (w).
A mixture of Meldrum’s acid (1 equiv), the corresponding 1,2-
dicarbonyl compound (1 equiv) and 5-amino-1H-pyrrole-3-
carbonitrile derivative (1 equiv) was refluxed in ethanol 4e6 h.
The precipitate was collected and, if necessary, purified by column
chromatography (eluent: n-heptane/ethylacetate).
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

6
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
5.4. 10-tert-Butyl-2,60-dioxo-5-(trifluoromethoxy)-10,50,60,70-
tetrahydrospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-car-
bonitrile (4ad)
114.5 (Ce), 119.9 (CHe), 123.4 (CHe), 126.3 (CHe), 131.7 (Ce), 132.0
(Ce), 142.4 (Ce), 148.6 (Ce), 168.2 (Ce), 178.3 (Ce); HRMS (ESI):
calcd for C19H18N5O4 (Mþ1) 380.1353, found 380.1357; IR (ATR,
cmꢀ1): 3212 (w), 2227 (w), 1748 (m), 1690 (s), 1326 (s), 1202 (s),
1079 (w).
The product was isolated as white a solid, yield 52%, mp
299e300 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.61 (9H, s, (CH3)3),
2.66 (1H, d, J¼15.9 Hz, CH2), 3.14 (1H, d, J¼15.7 Hz, CH2), 7.01 (1H, d,
5.8. 10-tert-Butyl-2,60-dioxo-1-phenyl-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4ah)
J¼8.3 Hz, AreH), 7.24e7.35 (2H, m, AreH), 7.41 (1H, s, AreH), 10.17
(1H, s, NH),10.78 (1H, s, NH); 19F NMR (DMSO-d6):
d
ꢀ57.19; 13C NMR
(62.9 MHz, DMSO-d6): d 29.2 (CH3)3, 39.4 (CH2), 46.6 (Ce), 57.9 (Ce),
86.1 (Ce), 102.6 (Ce), 110.6 (CHe), 114.0e126.2 (CeF, q,
1JCeF¼255.4 Hz), 114.3 (Ce), 117.9 (CHe), 122.2 (CHe), 123.1 (CHe),
131.5 (Ce),132.6 (Ce),141.2 (Ce),143.5e143.4 (CeF, q, 3JCeF¼1.8 Hz),
168.3 (Ce),177.9 (Ce); MS (GC, 70 eV): m/z (%) 418 (Mþ, 28), 361 (46),
334 (24); HRMS (ESI): calcd for C20H18F3N4O3 (Mþ1) 419.1326,
found 419.1329; IR (ATR, cmꢀ1): 3202 (w), 2225 (w), 1714 (m), 1681
(s), 1482 (m), 1247 (m), 1206 (s), 1166 (s), 614 (w).
The product was isolated as a white solid, yield 55%, mp
310e312 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.62 (9H, s, (CH3)3),
2.97 (1H, d, J¼15.7 Hz, CH2), 3.03 (1H, d, J¼15.7 Hz, CH2), 6.78 (1H,
d, J¼7.7 Hz, AreH), 7.14 (1H, m, AreH), 7.30 (2H, m, AreH), 7.45 (1H,
s, AreH), 7.52 (3H, m, AreH), 7.63 (2H, m, AreH), 10.31 (1H, s, NH);
13C NMR (62.9 MHz, DMSO-d6):
d 29.2 (CH3)3, 40.1 (CH2e), 46.1
(Ce), 57.9 (Ce), 85.9 (Ce), 103.7 (Ce), 109.3 (CHe), 114.9 (Ce), 123.2
(CHe), 123.3 (CHe), 123.6 (CHe), 126.9 (CHe), 128.3 (CHe), 129.0
(CHe), 129.6 (CHe), 130.8 (Ce), 131.2 (Ce), 134.1 (Ce), 142.7 (Ce),
168.3 (Ce), 175.5 (Ce); MS (GC, 70 eV): m/z (%) 410 (Mþ, 45), 353
(100), 325 (64); HRMS (ESI): calcd for C25H23N4O2 (Mþ1) 411.1816,
found 411.1818; IR (ATR, cmꢀ1): 3149 (w), 2220 (w), 1725 (s), 1678
(s), 1605 (m), 1495 (m), 1327 (m), 1204 (m), 752 (s), 693 (m).
5.5. 5-Bromo-10-tert-butyl-2,60-dioxo-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4ae)
The product was isolated as a white solid, yield 51%, mp
309e310 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.59 (9H, s, (CH3)3),
2.72 (1H, d, J¼15.9 Hz, CH2), 2.97 (1H, d, J¼15.9 Hz, CH2), 6.97 (1H, t,
J¼8.1 Hz, AreH), 7.20 (1H, d, J¼7.0 Hz, AreH), 7.41 (1H, s, AreH),
7.46 (1H, dd, J1¼8.1 Hz, J2¼1 Hz, AreH), 10.20 (1H, s, NH), 10.94 (1H,
5.9. 10-Cyclohexyl-5-fluoro-2,60-dioxo-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4bf)
s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.2 (CH3)3, 40.0 (CH2),
47.3 (Ce), 57.9 (Ce), 86.1 (Ce), 102.1 (Ce), 102.8 (Ce), 114.5 (Ce),
122.9 (CHe), 123.2 (CHe), 123.7 (CHe), 131.4 (Ce), 131.8 (CHe),
132.9 (Ce), 141.1 (Ce), 168.2 (Ce), 177.6 (Ce); MS (GC, 70 eV): m/z
(%) 412 (Mþ, 22), 357 (38), 314 (25); HRMS (ESI): calcd for
The product was isolated as a white solid, yield 55%, mp
235e237 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.16e1.28 (1H, m, c-
HexeH), 1.33e1.49 (2H, m, c-HexeH), 1.54e1.73 (3H, m, c-HexeH),
1.77e2.00 (4H, m, c-HexeH), 2.63 (1H, d, J¼15.9 Hz, CH2), 3.08 (1H,
d, J¼15.9 Hz, CH2), 4.08e4.22 (1H, m, c-HexeH), 6.91 (1H, dd,
J1¼8.2 Hz, J2¼4.3 Hz, AreH), 7.14 (2H, m, AreH), 7.44 (1H, s, AreH),
79
C
H
19 18
BrN4O2 (Mþ1) 413.0608, found 430.0612; IR (ATR, cmꢀ1):
3152 (w), 2227 (w), 1727 (s), 1677 (s), 1469 (m), 1321 (m), 1201 (m),
736 (s).
10.60 (1H, s, NH), 10.77 (1H, s, OH); 19F NMR (DMSO-d6):
d
ꢀ121.3;
13C NMR (62.9 MHz, DMSO-d6):
d 24.5 (CH2e), 24.9 (CH2), 24.9
5.6. 10-tert-Butyl-5-fluoro-2,60-dioxo-10,50,60,70-tetrahy-
drospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(4af)
0
(CH2), 32.8 (CH2), 32.9 (CH2), 46.9e47.0 (CeF, d, 4 JCeF¼1.4 Hz), 54.1
30
(CH2), 87.2 (Ce), 99.6 (Ce), 110.6e110.5 (CeF, d,
J
¼8.2 Hz),
CeF
111.9e111.6 (CeF, d, 2JCeF¼24.7 Hz), 114.5 (Ce), 115.3e114.9 (CeF, d,
20
J
¼23.4 Hz), 121.7 (CHe), 131.5 (Ce), 132.9e132.7 (CeF, d,
4
CeF
The product was isolated as a brown solid, yield 75%, mp
3JCeF¼8.2 Hz), 138.08e138.1 (CeF, d, JCeF¼1.4 Hz), 160.1e156.3
(CeF, d, 1JCeF¼237.1 Hz), 168.1 (Ce), 178.1 (Ce); MS (GC, 70 eV): m/z
(%) 378 (Mþ, 100), 295 (44), 268 (45); HRMS (EI): calcd for
277e279 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.59 (9H, s, (CH3)3),
2.64 (1H, d, J¼15.7 Hz, CH2), 3.04 (1H, d, J¼15.7 Hz, CH2), 6.90 (1H,
dd, J1¼8.3 Hz, J2¼4.3 Hz, AreH), 7.11 (2H, m, AreH), 7.40 (1H, s,
AreH), 10.14 (1H, s, NH), 10.62 (1H, s, NH); 19F NMR (DMSO-d6):
C
21H19N4FO2 (Mþ1) 378.1487, found 378.1487; IR (ATR, cmꢀ1):
ꢀ121.1; 13C NMR (62.9 MHz, DMSO-d6):
d 29.2 (CH3)3, 39.7
3220 (w), 2220 (w), 1720 (s), 1705 (s), 1486 (s), 1175 (m), 600 (s).
Anal. Calcd for C21H19FN4O2: C, 66.66; H, 5.06; N, 14.81. Found: C,
66.27; H, 5.07; N, 14.84.
d
40
(CH2e), 46.6e46.7 (CeF, d, JCe30F¼1.8 Hz), 57.9 (Ce), 86.1 (Ce),102.9
(Ce), 110.6e110.7 ( CeF, d, JCeF¼7.8 Hz), 111.7e111.9 (CeF, d,
20
2
J
¼24.7 Hz), 114.5 (Ce), 115.0e115.4 ( CeF, d, JCeF¼23.4 Hz),
CeF
3
123.2 (CHe), 131.4 (Ce), 132.6e132.7 (CeF, d, JCeF¼8.2 Hz),
5.10. 10-(4-Methoxybenzyl)-1-methyl-2,60-dioxo-10,50,60,70-tet-
rahydrospiro[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbon-
itrile (4cb)
4
138.0e138.1 ( CeF, d, JCeF¼1.83 Hz), 156.3e160.1 ( CeF, d,
1JCeF¼237 Hz), 177.8 (Ce), 168.3 (Ce); MS (GC, 70 eV): m/z (%) 352
(Mþ, 44), 295 (67), 268 (40); HRMS (ESI): calcd for C19H18FN4O2
(Mþ1) 353.1408, found 353.1412; IR (ATR, cmꢀ1): 3207 (w), 2220
(w), 1657 (s), 1651 (s), 1486 (m), 1200 (m), 821 (w), 612 (w).
The product was isolated as a white solid, yield 58%, mp
224e226 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 2.69e2.75 (1H, dd,
J¼16.1 Hz, CH2), 2.88e2.94 (1H, dd, J¼15.9 Hz, CH2), 3.18 (3H, s,
NCH3), 3.77 (3H, s, OCH3), 5.14 (2H, s, CH2), 6.98 (2H, d, J¼8.5 Hz,
AreH), 7.10 (2H, m, AreH), 7.24 (3H, m, AreH), 7.37 (2H, m, AreH),
5.7. 10-tert-Butyl-5-nitro-2,60-dioxo-10,50,60,70-tetrahydrospiro
[indoline-3,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile (4ag)
10.96 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 26.1 (CH3), 39.9
The product was isolated as a brown solid, yield 70%, mp
(CH2), 46.1 (Ce), 48.3 (CH2), 55.1 (OCH3e), 87.3 (Ce), 100.8 (CHe),
108.8 (Ce), 114.1 (CHe), 114.2 (Ce), 122.7 (CHe), 123.2 (CHe), 124.8
(CHe), 128.4 (Ce), 128.9 (CHe), 129.0 (CHe), 130.7 (Ce), 131.9 (Ce),
143.0 (Ce), 158.9 (Ce), 168.2 (Ce), 176.1 (Ce); MS (GC, 70 eV): m/z
(%) 412 (Mþ, 10), 121 (100); HRMS (ESI): calcd for C24H20N4O3
(Mþ1) 413.1608, found 413.1600; IR (ATR, cmꢀ1): 3102 (w), 2217
(w), 1688 (s), 1682 (s), 1606 (m), 1515 (m), 1288 (m), 1256 (m), 1173
331e333 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.60 (9H, s, (CH3)3),
2.73 (1H, d, J¼15.7 Hz, CH2), 3.27 (1H, d, J¼15.7 Hz, CH2), 7.13 (1H, d,
J¼8.7 Hz, AreH), 7.43 (1H, s, AreH), 8.18 (1H, d, J¼2.3 Hz, AreH),
8.27 (1H, dd, J1¼8.7 Hz, J2¼2.3 Hz, AreH), 10.25 (1H, s, NH), 11.33
(1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.2 (CH3)3, 38.9
(CH2e), 46.2 (Ce), 58.0 (Ce), 85.8 (Ce), 102.1 (Ce), 110.1 (CHe),
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
7
(m), 1131 (m), 757 (s). Anal. Calcd for C24H20N4O3: C, 69.89; H, 4.89;
N, 13.58. Found: C, 69.59; H, 4.84; N, 13.51.
10.12 (1H, s, NH), 10.70 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
28.8 (CH3)3, 47.8 (Ce), 57.5 (Ce), 66.0 (CH2), 86.2 (Ce), 94.8 (Ce),
d
102.7 (Ce), 111.3 (CHe), 113.4 (Ce), 114.3 (Ce), 124.3 (CHe), 127.2
(CHe), 129.7 (Ce), 131.3 (CHe), 136.7 (Ce), 141.1 (Ce), 158.4 (Ce),
170.2 (Ce), 177.3 (Ce); MS (GC, 70 eV): m/z (%) 452 (Mþ, 33), 394
5.11. 1-tert-Butyl-20,5-dioxo-1,5,7,8-tetrahydrospiro[furo[3,4-
b]pyrrolo[3,2-e]pyridine-4,30-indoline]-3-carbonitrile (5aa)
(100), 352 (38); HRMS (ESI): calcd for
C
21H18N4O3Br(Mþ1)
The product was isolated as a white solid, yield 57%, mp
453.0556, found 453.0555; IR (ATR, cmꢀ1): 3163 (w), 2227 (w), 1711
(s), 1632 (s), 1537 (s), 1516 (s), 1199 (m), 813 (m).
302e304 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.62 (9H, s, (CH3)3),
5.00 (2H, s, CH2), 6.88 (3H, m, AreH), 7.19 (1H, m, AreH), 7.40 (1H, s,
AreH), 10.06 (1H, s, NH), 10.54 (1H, s, NH); 13C NMR (62.9 MHz,
DMSO-d6): d 28.9 (CH3)3, 47.7 (Ce), 57.5 (Ce), 65.9 (CH2), 86.5 (Ce),
5.15. 1-tert-Butyl-50-fluoro-20,5-dioxo-1,5,7,8-tetrahydrospiro
[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indoline]-3-
carbonitrile (5af)
95.5 (Ce), 103.5 (Ce), 109.3 (CHe), 114.3 (Ce), 121.7 (CHe), 124.1
(CHe), 124.4 (CHe), 128.4 (CHe), 129.6 (Ce), 134.6 (Ce), 141.8 (Ce),
158.1 (Ce), 170.2 (Ce), 177.7 (Ce); MS (GC, 70 eV): m/z (%) 372 (Mþ,
36), 316 (100), 274 (64); HRMS (ESI): calcd for C21H19N4O3 (Mþ1)
375.1452, found 375.1451; IR (ATR, cmꢀ1): 3265 (w), 2224 (w), 1710
(s),1638 (s),1536 (s),1512 (s),1469 (m),1332 (s),1199 (m),1056 (m),
759 (s). Anal. Calcd for C21H18N4O3: C, 67.37; H, 4.85; N, 14.88.
Found: C, 67.07; H, 4.85; N, 15.04.
The product was isolated as a white solid, yield 61%, mp
274e276 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d 1.63 (9H, s, (CH3)3),
5.01 (2H, s, CH2), 6.85 (2H, m, AreH), 7.01e7.02 (1H, m, AreH), 7.43
(1H, s, AreH), 10.11 (1H, s, NH), 10.53 (1H, s, NH); 19F NMR (DMSO-
d6):
d
ꢀ122.01; 13C NMR (62.9 MHz, DMSO-d6):
d 34.1 (CH3)3, 53.4
40
(Ce), 53.3e53.4 (CeF, d,
J
¼1.8 Hz), 62.7 (Ce), 71.2 (CH2), 91.5
CeF
3
(Ce), 100.2 (Ce), 108.1 (Ce), 115.3e115.2 (CeF, d, JCeF¼7.8 Hz),
5.12. 1-tert-Butyl-10-methyl-20,5-dioxo-1,5,7,8-
tetrahydrospiro[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indo-
line]-3-carbonitrile (5ab)
117.5e117.1 (CeF, d, 2JCeF¼24.3 Hz), 119.5 (Ce), 120.2e119.8 (CeF, d,
20
30
J
J
¼23.4 Hz), 129.5 (CH), 134.9 (Ce), 141.3e141.1 (CeF, d,
CeF
4
¼7.3 Hz), 143.3e143.2 (CeF, d, JCeF¼1.8 Hz), 161.6e165.4
CeF
(CeF, d, 1JCeF¼237.1 Hz), 175.4 (Ce), 163.6 (Ce), 183.0 (Ce); MS (GC,
70 eV): m/z (%) 390 (Mþ, 36), 334 (100), 292 (51); HRMS (ESI): calcd
for C21H18FN4O3 (Mþ1) 393.1357, found 393.1353; IR (ATR, cmꢀ1):
3169 (w), 2229 (w), 1712 (s), 1630 (s), 1537 (s), 1486 (s), 1198 (m),
1026 (m), 800 (m).
The product was isolated as a white solid, yield 63%, mp
327e329 ꢁC. 1H NMR (250 MHz, DMSO-d6):
d 1.58 (9H, s, (CH3)3),
3.16 (3H, s, CH3), 4.99 (2H, s, CH2), 6.98 (3H, m, AreH), 7.26 (1H, m,
AreH), 7.36 (1H, s, AreH), 10.10 (1H, s, NH); 13C NMR (62.9 MHz,
DMSO-d6):
d 26.1 (CH3e), 28.9 (CH3)3, 47.2 (Ce), 57.5 (Ce), 66.0
(CH2e), 86.2 (Ce), 95.0 (Ce), 103.8 (Ce), 108.2 (CHe), 114.3 (Ce),
122.5 (CHe), 124.0 (CHe), 128.6 (CHe), 129.4 (Ce), 133.9 (Ce), 143.0
(Ce), 158.4 (Ce), 170.2 (Ce), 176.1 (Ce); MS (GC, 70 eV): m/z (%) 388
(Mþ, 68), 360 (37), 304 (67); HRMS (ESI): calcd for C22H21N4O3
(Mþ1) 389.1611, found 389.1608; IR (ATR, cmꢀ1): 3260 (w), 2230
(w),1738 (s),1687 (s),1641 (s),1539 (m),1514 (m),1029 (m), 752 (s).
Anal. Calcd for C21H18N4O3: C, 68.03; H, 5.34; N, 14.42. Found: C,
67.60; H, 5.34; N, 14.23.
5.16. 1-tert-Butyl-20,5-dioxo-10-phenyl-1,5,7,8-tetrahydrospiro
[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indoline]-3-
carbonitrile (5ah)
The product was isolated as a light yellow solid, yield 37%, mp
327e329 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.64 (9H, s, (CH3)3),
5.06 (2H, s, CH2), 6.68 (1H, d, J¼7.7 Hz, AreH), 7.07 (2H, m, AreH),
7.24 (1H, m, AreH), 7.50 (4H, m, AreH), 7.63 (2H, m, AreH), 10.19
(5H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 28.9 (CH3)3, 47.5 (Ce),
5.13. 1-tert-Butyl-20,5-dioxo-50-(trifluoromethoxy)-1,5,7,8-
tetrahydrospiro[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indo-
line]-3-carbonitrile (5ad)
57.6 (Ce), 66.2 (CH2), 86.3 (Ce), 95.5 (Ce), 103.6 (Ce), 108.5 (CHe),
114.7 (Ce), 123.1 (CHe), 124.3 (CHe), 124.7 (CHe), 126.9 (CHe),
128.2 (CHe), 128.7 (CHe), 129.6 (CHe), 129.7 (Ce), 133.5 (Ce), 134.6
(Ce), 142.9 (Ce), 158.2 (Ce), 170.3 (Ce), 175.6 (Ce); MS (GC, 70 eV):
m/z (%) 3450 (Mþ, 85), 422 (96), 366 (100); HRMS (ESI): calcd for
The product was isolated as a white solid, yield 37%, mp
303e305 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.63 (9H, s, (CH3)3),
C
27H22N4O3 (M) 450.1686, found 450.1688; IR (ATR, cmꢀ1): 3273
5.02 (2H, s, CH2), 6.95 (2H, m, AreH), 7.23 (1H, dd, J1¼8 Hz, J2¼1 Hz,
AreH), 7.44 (1H, s, AreH), 10.14 (1H, br s, NH), 10.76 (1H, s, NH); 19
F
(w), 2224 (w), 1747 (m), 1690 (s), 1655 (s), 1533 (m), 1513 (m), 1197
(m), 1030 (s), 765 (m). Anal. Calcd for C27H22N4O3: C, 71.99; H, 4.92;
N, 12.44. Found: C, 71.61; H, 5.06; N, 12.14.
NMR (DMSO-d6):
d
ꢀ57.13; 13C NMR (62.9 MHz, DMSO-d6):
d 28.8
(CH3)3, 48.1 (Ce), 57.5 (Ce), 66.0 (CH2e), 86.2 (Ce), 94.7 (Ce), 102.6
(Ce), 110.1 (CHe), 114.0e126.2 (CeF, q, 1JCeF¼251.7 Hz), 114.1 (Ce),
118.0 (CHe), 121.7 (CHe), 124.3 (CHe), 129.7 (Ce), 135.8 (Ce), 141.1
5.17. 1-Cyclohexyl-10-methyl-20,5-dioxo-1,5,7,8-
tetrahydrospiro[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indo-
line]-3-carbonitrile (5bb)
3
(Ce), 143.4e143.5 (CeF, q, JCeF¼1.8 Hz), 158.5 (Ce), 170.2 (Ce),
177.8 (Ce); MS (GC, 70 eV): m/z (%) 456 (Mþ, 27), 400 (100), 358
(44); HRMS (ESI): calcd for C22H18N4O4F4 (Mþ1) 459.1275, found
459.1272; IR (ATR, cmꢀ1): 3271 (w), 2224 (w), 1714 (s), 1639 (s),
1537 (m), 1515 (m), 1199 (s), 1053 (m), 1024 (m), 803 (m). Anal.
Calcd for C22H17N4O4F4: C, 57.64; H, 3.74; N, 12.22. Found: C, 57.35;
H, 3.67; N, 11.82.
The product was isolated as a light yellow solid, yield 30%, mp
352e355 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.14e1.29 (1H, m, CH),
1.33e1.49 (2H, m, CH),1.56e1.75 (3H, m, CH),1.83e1.93 (4H, m, CH),
3.19 (3H, s, CH3), 3.86e4.22 (1H, m, CH), 5.05 (2H, s, CH2), 7.02 (3H,
m, AreH), 7.30 (1H, m, AreH), 7.45 (1H, s, AreH),10.75 (1H, br s, NH);
5.14. 50-Bromo-1-tert-butyl-20,5-dioxo-1,5,7,8-tetrahydrospiro
[furo[3,4-b]pyrrolo[3,2-e]pyridine-4,30-indoline]-3-
carbonitrile (5ae)
13C NMR (62.9 MHz, DMSO-d6):
d 24.5 (CH2), 25.0 (CH2), 26.0 (CH3),
32.6 (CH2), 47.2 (Ce), 54.8 (CH), 65.4 (CH2), 87.4 (Ce), 95.3 (Ce),101.7
(Ce),108.2 (CHe),114.3 (Ce),122.5 (CHe),122.7 (CHe),124.0 (CHe),
128.6 (CHe), 129.7 (Ce), 133.8 (Ce), 142.9 (Ce), 158.6 (Ce), 170.2
(Ce),176.1 (Ce); MS (GC, 70 eV): m/z (%) 414 (Mþ, 83), 386 (100), 370
(48); HRMS (ESI): calcd for C24H22N4O3 (Mþ1) 414.1686, found
414.1696; IR (ATR, cmꢀ1): 3136 (w), 2229 (w), 1744 (m), 1725 (m),
1681 (s), 1647 (s), 1551 (s), 1334 (m), 1222 (m), 1027 (m), 757 (s).
The product was isolated as a yellow solid, yield 64%, mp
287e289 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.62 (9H, s, (CH3)3),
5.00 (2H, s, CH2), 6.82 (1H, d, J¼8.3 Hz, AreH), 7.10 (1H, d, J¼2.1 Hz,
AreH), 7.38 (1H, dd, J1¼8.1 Hz, J2¼2.1 Hz, AreH), 7.43 (1H, s, AreH),
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

8
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
5.18. 10-tert-Butyl-70,70-dimethyl-2,50-dioxo-10,50,60,70,80,90-hex-
ahydrospiro[indoline-3,40-pyrrolo[2,3-b]quinoline]-30-car-
bonitrile (6aa)
85.9 (Ce), 103.1 (Ce), 105.4 (Ce), 109.3 (CHe), 114.0 (Ce),
114.4e126.2 (CeF, q, JCeF¼254.9 Hz), 116.2 (CHe), 120.3 (CHe),
124.0 (CHe), 128.4 (Ce), 138.6 (Ce), 141.3 (Ce), 142.9e142.8 (CeF, q,
3JCeF¼1.9 Hz), 152.4 (Ce), 179.4 (Ce), 193.1 (Ce); MS (GC, 70 eV): m/
z (%) 496 (Mþ, 15), 454 (27), 398 (100); HRMS (ESI): calcd for
The product was isolated as a orange solid, yield 79%, mp
304e305 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.04 (3H, s, CH3), 1.09
C
26H26F3N4O3 (Mþ1) 499.1951, found 499.1458; IR (ATR, cmꢀ1):
(3H, s, CH3), 1.63 (9H, s, (CH3)3), 1.97e2.20 (2H, m, CH2), 2.72 (2H, d,
J¼16.1 Hz, CH2), 6.80 (3H, m, AreH), 7.10 (1H, m, AreH), 7.32 (1H, s,
AreH), 8.77 (1H, br s, NH), 10.26 (1H, s, NH); 13C NMR (62.9 MHz,
3290 (w), 2224 (w), 1710 (s), 1608 (s), 1526 (s), 1504 (s), 1486 (m),
1262 (s), 1191 (m).
DMSO-d6):
d 26.7 (CH3e), 28.4 (CH3e), 29.2 (CH3)3, 32.0 (Ce), 41.0
5.22. 10-tert-Butyl-70,70-dimethyl-5-nitro-2,50-dioxo-
10,50,60,70,80,90-hexahydrospiro[indoline-3,40-pyrrolo[2,3-b]
quinoline]-30-carbonitrile (6ag)
(CH2e), 49.3 (CH2e), 50.3 (Ce), 57.3 (Ce), 86.1 (Ce),104.1 (Ce),106.1
(Ce),108.7 (CHe),114.5 (Ce),120.9 (CHe),122.7 (CHe),123.8 (CHe),
127.2 (CH), 127.9 (Ce), 137.2 (Ce), 142.0 (Ce), 151.8 (Ce), 179.3 (Ce),
193.1 (Ce); MS (GC, 70 eV): m/z (%) 412 (Mþ,14), 370 (42), 314 (100);
HRMS (ESI): calcd for C25H27N4O2 (Mþ1) 415.2128, found 415.2122;
IR (ATR, cmꢀ1): 3314 (w), 3115 (w), 2219 (w), 1708 (s), 1613 (s), 1524
(s), 1505 (s), 1469 (m), 1329 (m), 1209 (m), 747 (m).
The product was isolated as a yellow solid, yield 66%, mp
273e275 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.04 (3H, s, CH3), 1.07
(3H, s, CH3), 1.63 (9H, s, (CH3)3), 2.09 (2H, dd, J1¼16.2 Hz,
J2¼20.1 Hz, CH2), 2.76 (2H, dd, J1¼26.5 Hz, J2¼17.2 Hz, CH2), 7.00
(1H, d, J¼8.7 Hz, AreH), 7.38 (1H, s, AreH), 7.62 (1H, d, J¼1.9 Hz,
AreH), 8.13 (1H, dd, J1¼8.5 Hz, J2¼2.1 Hz, AreH), 11.10 (1H, s, NH);
5.19. 10-tert-Butyl-1,70,70-trimethyl-2,50-dioxo-10,50,60,70,80,90-
hexahydrospiro[indoline-3,40-pyrrolo[2,3-b]quinoline]-30-car-
bonitrile (6ab)
13C NMR (62.9 MHz, DMSO-d6):
d 27.2 (CH3), 27.8 (CH3), 29.1 (CH3)3,
32.1 (Ce), 40.8 (CH2), 50.0 (CH2), 57.6 (Ce), 85.7 (Ce), 102.4 (Ce),
105.2 (Ce), 108.9 (CHe), 114.4 (Ce), 118.0 (CHe), 124.4 (CHe), 125.1
(CHe), 128.2 (Ce), 137.9 (Ce), 141.8 (Ce), 149.0 (Ce), 152.8 (Ce),
171.9 (Ce), 179.8 (Ce), 193.6 (Ce); HRMS (ESI): calcd for
The product was isolated as a light yellow solid, yield 57%, mp
300e307 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.02 (3H, s, CH3), 1.08
C
25H26N5O4 (Mþ1) 460.1979, found 460.1988; IR (ATR, cmꢀ1): 3324
(3H, s, CH3), 1.61 (9H, s, (CH3)3), 2.02 (2H, dd, J1¼34.5 Hz, J2¼13 Hz,
CH2), 2.72 (2H, dd, J1¼17 Hz, J2¼7.6 Hz, CH2), 3.16 (3H, s, CH3), 6.86
(3H, m, AreH), 7.20 (1H, m, AreH), 7.30 (1H, s, AreH), 8.83 (1H, br s,
(w), 2216 (w), 1722 (s), 1614 (s), 1526 (s), 1512 (s), 1335 (s), 1209 (m),
1189 (m).
NH); 13C NMR (62.9 MHz, DMSO-d6):
d 25.6 (CH3), 26.6 (CH3), 28.5
(CH3), 29.1 (CH3)3, 32.0 (Ce), 40.9 (CH2), 48.9 (Ce), 50.2 (CH2), 57.3
(Ce), 85.8 (Ce), 104.5 (Ce), 105.7 (Ce), 107.5 (CHe), 114.7 (Ce),
121.7 (CHe), 122.4 (CHe), 123.7 (CHe), 127.4 (CHe), 127.9 (Ce),
136.4 (Ce), 143.0 (Ce), 152.1 (Ce), 177.8 (Ce), 193.1 (Ce); HRMS
(ESI): calcd for C26H29N4O2 (Mþ1) 429.2285, found 429.2286; IR
(ATR, cmꢀ1): 3301 (w), 2220 (w), 1693 (s), 1606 (s), 1525 (s), 1504
(s), 1327 (m), 1207 (s), 746 (s).
5.23. 10-Cyclohexyl-70,70-dimethyl-2,50-dioxo-10,50,60,70,80,90-
hexahydrospiro[indoline-3,40-pyrrolo[2,3-b]quinoline]-30-car-
bonitrile (6ba)
The product was isolated as a white solid, yield 41%, mp
274e277 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.03 (3H, s, CH3), 1.07
(3H, s, CH3), 1.20 (1H, m, CH), 1.35e1.74 (5H, m, CH), 1.80e1.95 (4H,
m, CH), 2.01e2.18 (2H, m, CH2), 2.55e2.66 (2H, m, CH2), 4.17e4.22
(1H, m, CH), 6.78 (3H, m, AreH), 7.07 (1H, m, AreH), 7.36 (1H, s,
AreH), 9.67 (1H, s, NH), 10.2 (1H, s, NH); 13C NMR (62.9 MHz,
5.20. 10-tert-Butyl-5-chloro-70,70-dimethyl-2,50-dioxo-
10,50,60,70,80,90-hexahydrospiro[indoline-3,40-pyrrolo[2,3-b]
quinoline]-30-carbonitrile (6ac)
DMSO-d6):
d 24.6 (CH2), 25.1 (CH2), 26.8 (CH3), 28.3 (CH3), 32.1
(Ce), 32.8 (CH2), 40.9 (CH2), 49.5 (Ce), 50.4 (CH2), 53.9 (CHe), 87.5
(Ce), 101.6 (Ce), 106.3 (Ce), 108.7 (CHe), 114.6 (Ce), 121.0 (CHe),
122.4 (CHe), 122.7 (CHe), 127.1 (CHe), 128.1 (Ce), 137.3 (Ce),
142.0 (Ce), 151.7 (Ce), 179.4 (Ce), 192.9 (Ce); MS (GC, 70 eV): m/z
(%) 440 (Mþ, 51), 396 (71), 348 (88); HRMS (ESI): calcd for
The product was isolated as a white solid, yield 65%, mp
312e315 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.03 (3H, s, CH3), 1.06
(3H, s, CH3), 1.61 (9H, s, (CH3)3), 2.07 (2H, dd, J¼1 Hz, CH2), 2.70 (9H,
dd, J¼1 Hz, CH2), 6.76 (2H, m, AreH), 7.14 (1H, dd, J1¼8 Hz, J2¼2 Hz,
AreH), 7.33 (1H, s, AreH), 8.82 (1H, br s, NH), 10.41 (1H, s, NH); 13
C
C
27H28N4O2 (Mþ1) 440.2206, found 440.2201; IR (ATR, cmꢀ1):
NMR (62.9 MHz, DMSO-d6): d 27.1 (CH3e), 28.0 (CH3e), 29.1 (CH3)3,
3276 (w), 2224 (w), 1693 (s), 1616 (s), 1532 (s), 1326 (m), 1217 (m),
744 (s).
32.0 (Ce), 40.9 (CH2e), 49.7 (Ce), 50.2 (CH2e), 57.4 (Ce), 85.9 (Ce),
103.2 (Ce), 105.6 (Ce), 110.1 (CHe), 114.4 (Ce), 122.7 (CHe), 124.1
(CHe), 124.8 (Ce), 127.1 (CHe), 128.0 (Ce), 139.0 (Ce), 141.2 (Ce),
152.3 (Ce), 179.0 (Ce), 193.3 (Ce); MS (GC, 70 eV): m/z (%) 446 (Mþ,
16), 404 (41), 348 (100); HRMS (ESI): calcd for C25H26ClN4O2 (Mþ1)
449.1740, found 449.1746; IR (ATR, cmꢀ1): 3311 (w), 2216 (w), 1711
(s), 1614 (s), 1525 (s), 1506 (s), 1208 (m), 811 (m), 559 (s).
5.24. 10-tert-Butyl-50-(2-hydroxybenzoyl)-2,60-dioxo-5-(tri-
fluoromethoxy)-10,50,60,70-tetrahydrospiro[indoline-3,40-pyr-
rolo[2,3-b]pyridine]-30-carbonitrile (7ad)
The product was isolated as a white solid, yield 69%, mp
5.21. 10-tert-Butyl-70,70-dimethyl-50-methylene-2-oxo-5-(tri-
fluoromethoxy)-10,50,60,70,80,90-hexahydrospiro[indoline-3,40-
pyrrolo[2,3-b]quinoline]-30-carbonitrile (6ad)
234e236 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.61 (9H, s, (CH3)3),
6.04 (1H, s, CH), 6.93 (3H, m, AreH), 7.21 (1H, m, AreH), 7.45 (3H,
m, AreH), 7.89 (1H, m, AreH), 10.43 (1H, s, NH), 10.60 (1H, s, NH),
11.17 (1H, s, OH); 19F NMR (DMSO-d6):
(62.9 MHz, DMSO-d6): d 29.3 (CH3)3, 48.2 (Ce), 56.1 (Ce), 58.2
d
ꢀ57.35; 13C NMR
The product was isolated as a yellow solid, yield 64%, mp
230e232 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.00 (3H, s, CH3), 1.07
(CHe), 86.2 (Ce), 104.7 (Ce), 110.2 (CHe), 113.7 (Ce), 114.0e126.2
(CeF, q, JCeF¼255.4 Hz), 117.5 (CHe), 117.7 (CHe), 119.2 (CHe), 122.0
(Ce), 122.4 (CHe), 123.4 (CHe), 130.4 (Ce), 130.6 (Ce), 131.2 (CHe),
(3H, s, CH3), 1.62 (9H, s, (CH3)3), 2.08 (2H, dd, J1¼17.2 Hz, J2¼22.5 Hz,
CH2), 2.70 (2H, dd, J1¼16.5 Hz, J2¼45.5 Hz CH2), 6.73 (1H, s, AreH),
6.84 (1H, d, J¼8.3 Hz, AreH), 7.10 (1H, d, J¼7.4 Hz, AreH), 7.34 (1H,
s, AreH), 8.91 (1H, br s, NH), 10.47 (1H, s, NH); 19F NMR (DMSO-d6):
3
136.1 (CHe), 142.9 (Ce), 143.0e143.1 (CeF, q, JCeF¼1.9 Hz), 159.8
(Ce), 167.1 (Ce), 177.4 (Ce), 198.0 (Ce); HRMS (ESI): calcd for
d
ꢀ57.27; 13C NMR (62.9 MHz, DMSO-d6):
d
26.4 (CH3), 28.4 (CH3),
C
27H22F3N4O5 (Mþ1) 539.1536, found 539.1535; IR (ATR, cmꢀ1):
29.1 (CH3), 32.0 (Ce), 41.1 (CH2), 49.8 (Ce), 50.2 (CH2), 57.4 (Ce),
3163 (w), 2224 (w), 1714 (s), 1682 (m), 1487 (m), 1253 (m), 615 (m).
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
9
5.25. 10-tert-Butyl-50-(2-hydroxybenzoyl)-5-nitro-2,60-dioxo-
10,50,60,70-tetrahydrospiro[indoline-3,40-pyrrolo[2,3-b]pyri-
dine]-30-carbonitrile (7ag)
(1H, d, J¼7.9 Hz, AreH), 10.91 (1H, br s, NH); 13C NMR (62.9 MHz,
DMSO-d6): d 24.5 (CH2), 24.9 (CH2), 32.8 (CH2), 40.1 (CH2), 51.2 (Ce),
54.1 (CHe), 87.3 (Ce), 101.3 (Ce), 114.5 (Ce), 120.6 (CHe), 121.6
(CHe), 122.4 (CHe), 125.0 (CHe), 128.8 (CHe), 128.9 (CHe), 130.3
(Ce), 130.6 (Ce), 131.3 (Ce), 132.4 (CHe), 140.2 (Ce), 140.7 (Ce),
168.4 (Ce), 203.5 (Ce); MS (GC, 70 eV): m/z (%) 395 (Mþ, 100), 366
(28), 284 (59); HRMS (ESI): calcd for C25H21N3O2 (Mþ1) 395.1628,
found 395.1629; IR (ATR, cmꢀ1): 3280 (w), 2218 (w), 1713 (s), 1683
(s), 1494 (m), 1326 (s), 1178 (m), 784 (s).
The product was isolated as a brown solid, yield 38%, mp 310 ꢁC.
1H NMR (300 MHz, DMSO-d6):
d 1.63 (9H, s, (CH3)3), 6.23 (1H, s,
CH), 6.95 (2H, m, AreH), 7.11 (1H, d, J¼8.7 Hz, AreH), 7.51 (2H, m,
AreH), 7.87 (2H, d, J¼7.7 Hz, AreH), 8.24 (2H, dd, J1¼8.5 Hz,
J2¼1.7 Hz, AreH), 8.35 (1H, m, AreH), 10.50 (1H, br s, OH), 11.15 (1H,
s, NH), 11.22 (1H, br s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.3
(CH3)3, 47.7 (Ce), 56.0 (Ce), 58.3 (CHe), 86.0 (Ce), 104.1 (Ce), 109.7
(CHe), 113.9 (Ce), 117.6 (CHe), 119.2 (CHe), 119.8 (CHe), 122.0 (Ce),
123.8 (CHe), 126.6 (CHe), 130.1 (Ce), 130.8 (Ce), 131.3 (CHe), 136.2
(CHe), 142.0 (Ce), 150.4 (Ce), 159.8 (Ce), 166.9 (Ce), 177.9 (Ce),
197.7 (Ce); HRMS (ESI): calcd for C26H22N5O6 (Mþ1) 500.1564,
found 500.1561; IR (ATR, cmꢀ1): 3155 (w), 2226 (w), 1726 (s), 1682
(s), 1525 (m), 1332 (s), 1194 (m), 1157 (m), 709 (s), 555 (s).
5.29. 10-tert-Butyl-2,50-dioxo-10,50,70,80-tetrahydro-2H-spiro
[acenaphthylene-1,40-furo[3,4-b]pyrrolo[3,2-e]pyridine]-30-
carbonitrile (9ab)
The product was isolated as a yellow solid, yield 82%, mp
259e263 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.65 (9H, s, (CH3)3),
5.08 (2H, br s, CH2), 7.35 (2H, m, AreH), 7.88 (4H, m, AreH), 8.34
(1H, d, J¼7.9 Hz, AreH), 10.17 (1H, br s, NH); 13C NMR (62.9 MHz,
5.26. 10-Cyclohexyl-50-(2-hydroxybenzoyl)-2,60-dioxo-
10,50,60,70-tetrahydrospiro[indoline-3,40-pyrrolo[2,3-b]pyri-
dine]-30-carbonitrile (7ba)
DMSO-d6): d 28.9 (CH3)3, 52.4 (Ce), 57.5 (Ce), 66.2 (CH2), 86.3 (Ce),
96.4 (Ce), 104.6 (Ce), 114.2 (Ce), 121.1 (CHe), 122.1 (CHe), 124.2
(CHe), 124.7 (CHe), 128.6 (CHe), 129.0 (CHe), 129.6 (Ce), 129.6
(Ce), 131.8 (CHe), 132.1 (Ce), 141.5 (Ce), 142.6 (Ce), 158.5 (Ce),
170.5 (Ce), 203.6 (Ce); MS (GC, 70 eV): m/z (%) 365 (Mþ, 24), 309
(100), 280 (16); IR (ATR, cmꢀ1): 3270 (w), 2220 (w), 1713 (s), 1640
(s), 1532 (s), 1513 (s), 1328 (m), 1201 (m), 1048 (m), 784 (s). Anal.
Calcd for C25H19N3O3: C, 73.34; H, 4.68; N, 10.26. Found: C, 73.49; H,
4.87; N, 9.85.
The product was isolated as a yellow solid, yield 59%, mp
297e299 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.25 (1H, m, CH2), 1.44
(2H, m, CH2), 1.57e1.76 (3H, m, CH2), 1.89e1.98 (4H, m, CH2),
4.02e4.29 (1H, m, CH), 6.03 (1H, br s, CH), 6.92 (4H, s, AreH), 7.27
(2H, m, AreH), 7.52 (2H, m, AreH), 7.98 (1H, m, AreH), 10.42 (1H, br
s, OH), 11.00 (1H, br s, NH), 11.29 (1H, br s, NH); 13C NMR (62.9 MHz,
DMSO-d6):
d
24.5 (CH2), 25.0 (CH2), 32.7 (CH2), 48.2 (Ce), 54.4
5.30. 10-Cyclohexyl-2,50-dioxo-10,50,70,80-tetrahydro-2H-spiro
[acenaphthylene-1,40-furo[3,4-b]pyrrolo[3,2-e]pyridine]-30-
carbonitrile (9bb)
(CHe), 56.4 (CHe), 87.5 (Ce), 102.3 (Ce), 109.4 (CHe), 114.0 (Ce),
117.5 (CHe), 119.2 (CHe), 121.4 (CHe), 121.7 (CHe), 122.0 (Ce),
123.3 (CHe), 128.8 (Ce), 128.9 (CHe), 130.6 (Ce), 131.3 (CHe), 136.1
(CHe), 143.6 (Ce), 159.9 (Ce), 167.3 (Ce), 177.6 (Ce), 198.2 (Ce);
HRMS (ESI): calcd for C28H25N4O4 (Mþ1) 481.1870, found 481.1879;
IR (ATR, cmꢀ1): 3137 (w), 2222 (w), 1713 (s), 1682 (s), 1471 (m), 1191
(m), 744 (s). Anal. Calcd for C28H24N4O4: C, 69.99; H, 5.03; N, 11.66.
Found: C, 70.27; H, 5.20; N, 11.41.
The product was isolated as
a
yellow solid, yield 73%,
1.16e1.33 (1H, m,
295e297 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
CH2), 1.45 (2H, q, J¼11.4 Hz, CH2), 1.55e1.81 (3H, m, CH2), 1.91e2.12
(4H, m, CH2), 4.10 (1H, m, CH), 5.12 ( 2H, s, CH2), 7.34 (1H, d,
J¼6.6 Hz, AreH), 7.44 (1H, s, AreH), 7.71 (1H, t, J¼7.5 Hz, AreH),
7.88 (1H, m, AreH), 7.94e8.11 (2H, m, AreH), 8.35 (1H, d, J¼7.9 Hz,
5.27. 10-tert-Butyl-2,60-dioxo-10,50,60,70-tetrahydro-2H-spiro
[acenaphthylene-1,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(8aa)
AreH), 10.82 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 24.5
(CH2), 25.1 (CH2), 32.6 (CH2), 52.3 (Ce), 54.8 (CH), 65.5 (CH2), 87.5
(Ce), 96.7 (Ce), 102.5 (Ce), 114.2 (Ce), 121.0 (CH), 122.0 (CH), 122.9
(CH),124.6 (CH),128.6 (CH),128.9 (CH), 129.6 (Ce), 129.8 (Ce),131.8
(CH),132.0 (Ce),141.4 (Ce), 142.5 (Ce),158.6 (Ce),170.5 (Ce), 203.5
(Ce); MS (GC, 70 eV): m/z (%) 435 (Mþ, 30), 391 (71), 309 (100);
HRMS (EI): calcd for C27H21N3O3 (Mþ1) 435.1577, found 435.1576;
IR (ATR, cmꢀ1): 3136 (w), 2220 (w), 1750 (s), 1682 (s), 1651 (s), 1545
(s), 1330 (s), 1210 (m), 1023 (m), 780 (s).
The product was isolated as a yellow solid, yield 71%, mp 330 ꢁC.
1H NMR (300 MHz, DMSO-d6):
d 1.61 (9H, s, (CH3)3), 2.83 (1H, d,
J¼15.7 Hz, CH2), 3.13 (1H, d, J¼15.7 Hz, CH2), 7.35 (1H, s, AreH), 7.57
(1H, d, J¼7 Hz, AreH), 7.75 (1H, m, AreH), 7.91 (1H, m, AreH), 8.04
(2H, m, AreH), 8.37 (1H, d, J¼7.9 Hz, AreH), 10.28 (1H, s, NH); 13C
NMR (62.9 MHz, DMSO-d6): d 29.2 (CH3)3, 39.9 (CH2), 51.0 (Ce), 57.9
(Ce), 86.1 (Ce), 104.5 (Ce), 114.5 (Ce), 120.6 (CHe), 122.4 (CHe),
123.1 (CHe), 125.0 (CHe), 128.8 (CHe), 128.9 (CHe), 130.3 (Ce),
130.8 (Ce), 131.2 (Ce), 132.5 (CHe), 140.2 (Ce), 140.6 (Ce), 168.6
(Ce), 203.3 (Ce); MS (GC, 70 eV): m/z (%) 369 (Mþ, 75), 313 (50),
284 (100); HRMS (EI): calcd for C23H19N3O2 (Mþ1) 369.1472, found
369.1474; IR (ATR, cmꢀ1): 3153 (w), 2221 (w), 1710 (s),1673 (s), 1341
(s), 1204 (m), 776 (s).
5.31. 10-(4-Methoxybenzyl)-2,50-dioxo-10,50,70,80-tetrahydro-
2H-spiro[acenaphthylene-1,40-furo[3,4-b]pyrrolo[3,2-e]pyri-
dine]-30-carbonitrile (9cb)
The product was isolated as a yellow solid, yield 38%, mp
275e278 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 3.79 (3H, s, OCH3),
5.10 (2H, br s, CH2), 5.17 (2H, s, CH2), 7.01 (2H, d, J¼8.5 Hz, AreH),
7.33 (4H, m, AreH), 7.71 (1H, m, AreH), 7.88 (1H, m, AreH), 8.04
(2H, m, AreH), 8.34 (1H, d, J¼8.1 Hz, AreH), 10.93 (1H, s, NH); 13C
5.28. 10-Cyclohexyl-2,60-dioxo-10,50,60,70-tetrahydro-2H-spiro
[acenaphthylene-1,40-pyrrolo[2,3-b]pyridine]-30-carbonitrile
(8ba)
NMR (62.9 MHz, DMSO-d6):
d 48.5 (CH2), 52.4 (Ce), 55.1 (OCH3),
65.5 (CH2), 87.8 (Ce), 96.8 (Ce), 103.0 (Ce), 113.8 (Ce), 114.2 (CH),
121.0 (CH), 122.1 (CH), 124.7 (CH), 126.0 (CH), 128.1 (CH), 128.6 (Ce),
128.7 (Ce), 129.0 (CH), 129.6 (Ce), 130.5 (Ce), 131.8 (CH), 131.9 (Ce),
141.4 (Ce), 142.4 (Ce), 158.7 (Ce), 159.0 (Ce), 170.5 (Ce), 203.4
(Ce); MS (GC, 70 eV): m/z (%) 473 (Mþ, 14), 429 (21), 121 (100);
HRMS (EI): calcd for C29H19N3O4 (Mþ1) 473.1370, found 473.1364;
IR (ATR, cmꢀ1): 3026 (w), 2220 (w), 1739 (s), 1694 (s), 1650 (s), 1548
(s), 1514 (s), 1325 (m), 1250 (s), 1173 (m), 1026 (m), 782 (s).
The product was isolated as a yellow solid, yield 55%, mp
335e337 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.13e1.31 (1H, m,
CH2), 1.34e1.55 (2H, m, CH2), 1.55e1.76 (3H, m, CH2), 1.83e1.98 (4H,
m, CH2), 2.85 (1H, d, J¼15.9 Hz, CH2), 3.19 (1H, d, J¼15.9 Hz, CH2),
4.21 (1H, m, CH), 7.40 (1H, br s, AreH), 7.62 (1H, d, J¼6.4 Hz, AreH),
7.79 (1H, m, AreH), 7.92 (1H, m, AreH), 8.08 (2H, m, AreH), 8.40
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

10
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
5.32. 10-tert-Butyl-50-(2-hydroxybenzoyl)-2,60-dioxo-10,50,60,70-
tetrahydro-2H-spiro[acenaphthylene-1,40-pyrrolo[2,3-b]pyri-
dine]-30-carbonitrile (10ad)
OCH3), 7.18 (2H, m, AreH), 7.34 (3H, m, AreH), 7.54 (1H, s, AreH),
10.07 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
29.1 (CH3)3,
d
43.5 (CH2), 50.5 (Ce), 52.4 (OCH3e), 57.8 (Ce), 88.0 (Ce), 104.6
(Ce), 115.6 (Ce), 124.0 (CHe), 126.9 (CHe), 127.3 (CHe), 128.3
(CHe), 130.2 (Ce), 140.2 (Ce), 168.0 (Ce), 172.5 (Ce); MS (GC,
70 eV): m/z (%) 351 (Mþ, 18), 292 (27), 236 (100); HRMS (EI):
calcd for C20H21N3O3 (Mþ1) 351.1580, found 351.1577; IR (ATR,
cmꢀ1): 3231 (w), 2222 (w), 1731 (m), 1681 (s), 1674 (s), 1494 (m),
1199 (m), 698 (m).
The product was isolated as a yellow solid, yield 65%, mp
270e272 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.64 (9H, s, (CH3)3),
6.29 (1H, s, CH), 6.91 (2H, d, J¼8.3 Hz, AreH), 7.38 (1H, s, AreH),
7.47 (1H, m, AreH), 7.63 (2H, m, AreH), 7.88 (2H, m, AreH), 8.00
(2H, m, AreH), 8.29 (1H, d, J¼8.1 Hz, AreH), 10.55 (1H, s, NH), 11.01
(1H, s, OH); 13C NMR (62.9 MHz, DMSO-d6):
d 29.3 (CH3)3, 52.4 (Ce),
58.0 (CHe), 58.2 (Ce), 86.6 (Ce), 106.1 (Ce), 113.6 (Ce), 117.6 (CHe),
119.2 (CHe), 120.5 (CHe), 121.7 (CHe), 121.9 (Ce), 123.4 (CHe),
125.3 (CHe), 128.5 (CHe), 128.6 (CHe), 130.1 (Ce), 130.3 (Ce), 131.2
(CHe), 131.4 (CHe), 131.9 (Ce), 136.1 (CHe), 138.1 (Ce), 141.7 (Ce),
159.7 (Ce), 167.6 (Ce), 197.4 (Ce), 201.4 (Ce); MS (GC, 70 eV): m/z
(%) 489 (Mþ, 35), 368 (6), 312 (100); HRMS (EI): calcd for
5.36. Ethyl 1-tert-butyl-3-cyano-4-methyl-6-oxo-4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (11ab)
The product was isolated as a white solid, yield 73%, mp
210e212 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.19 (3H, t, J¼6 Hz,
CH3), 1.57 (9H, s, (CH3)3), 1.62 (3H, s, CH3), 2.62 (1H, d, J¼15.5 Hz,
C
30H23N3O4 (Mþ1) 489.1683, found 489.1678; IR (ATR, cmꢀ1): 3153
CH2), 2.79 (1H, d, J¼15.5 Hz, CH2), 4.11 (2H, q, CH2), 7.46 (1H, s,
(w), 2220 (w), 1673 (s), 1634 (s), 1493 (s), 1343 (m), 1469 (m), 1194
(m), 1160 (m), 782 (s).
AreH), 9.98 (1H, br s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 13.7
(CH3), 22.3 (CH3), 29.1 (CH3)3, 41.0 (Ce), 42.1 (CH2), 57.5 (Ce), 60.7
(CH2), 86.5 (Ce), 105.4 (Ce), 116.5 (Ce), 123.3 (CHe), 129.7 (Ce),
168.7 (Ce), 173.2 (Ce); IR (ATR, cmꢀ1): 3219 (w), 2216 (w), 1722 (s),
1674 (s), 1352 (m), 1209 (m), 1156 (m), 1131 (m), 629 (s).
5.33. 10-Cyclohexyl-50-(2-hydroxybenzoyl)-2,60-dioxo-
10,50,60,70-tetrahydro-2H-spiro[acenaphthylene-1,40-pyrrolo
[2,3-b]pyridine]-30-carbonitrile (10bd)
5.37. 1-tert-Butyl-4-ethyl-6-oxo-4-propionyl-4,5,6,7-
The product was isolated as a yellow solid, yield 56%, mp
tetrahydro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (11ac)
290e292 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.14e1.27 (1H, m,
CH2), 1.34e1.48 (2H, m, CH2), 1.57e1.73 (3H, m, CH2), 1.80e2.01 (4H,
m, CH2), 4.11e4.23 (1H, m, CH), 6.35 (1H, s, CH), 6.91 (2H, m, AreH),
7.40 (1H, s, AreH), 7.48 (1H, m, AreH), 7.66 (2H, m, AreH), 7.89 (2H,
m, AreH), 8.01 (2H, m, AreH), 8.29 (1H, d, J¼7.9 Hz, AreH), 11.02
The product was isolated as a white solid, yield 70%, mp
257e259 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 0.85 (6H, m,
J¼7.6 Hz, J¼7.2 Hz, CH3), 1.53 (9H, s, (CH3)3), 1.97 (1H, m, CH2),
2.24 (1H, m, CH2), 2.42 (1H, d, J¼15.5 Hz, CH2), 2.48 (2H, q, 7.4 Hz),
2.75 (1H, d, J¼15.7 Hz, CH2), 7.52 (1H, s, AreH), 9.86 (4H, s, NH);
(1H, s, NH), 11.13 (1H, s, OH); 13C NMR (62.9 MHz, DMSO-d6):
d 24.5
(CH2), 25.0 (CH2), 32.8 (CH2), 52.7 (Ce), 54.5 (CH), 58.1 (CH), 87.6
(Ce), 103.0 (Ce), 113.7 (Ce), 117.5 (CHe), 119.2 (CHe), 120.4 (CHe),
121.8 (CHe), 121.9 (CHe), 125.3 (CHe), 128.5 (CHe), 128.6 (CHe),
130.1 (Ce), 130.3 (Ce), 131.3 (CHe), 131.4 (CHe), 131.8 (Ce), 136.1
(CHe), 138.0 (Ce), 141.7 (Ce), 159.8 (Ce), 167.4 (Ce), 197.7 (Ce),
201.6 (Ce); MS (GC, 70 eV): m/z (%) 515 (Mþ, 31), 394 (100), 312
(55); IR (ATR, cmꢀ1): 3125 (w), 2220 (w), 1722 (s), 1670 (s), 1634 (s),
1340 (w), 1155 (m), 755 (s).
13C NMR (62.9 MHz, DMSO-d6):
d 8.3 (CH3), 8.4 (CH3), 26.4 (CH2),
29.0 (CH3)3, 29.2 (CH2), 37.8 (CH2), 51.4 (Ce), 57.7 (Ce), 86.5 (Ce),
103.5 (Ce), 117.1 (Ce), 124.1 (CHe), 130.6 (Ce), 169.4 (Ce), 209.3
(Ce); MS (GC, 70 eV): m/z (%) 301 (Mþ, 2), 244 (34), 188 (100);
HRMS (ESI): calcd for
C
17H23N3O2 (Mþ1) 301.1787, found
301.1785; IR (ATR, cmꢀ1): 3149 (w), 2215 (w), 1705 (s), 1668 (s),
1346 (s), 1207 (s).
5.38. Methyl 3-cyano-1-cyclohexyl-6-oxo-4-phenyl-4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (11ba)
5.34. 50-(2-Hydroxybenzoyl)-10-(4-methoxybenzyl)-2,60-di-
oxo-10,50,60,70-tetrahydro-2H-spiro[acenaphthylene-1,40-pyr-
rolo[2,3-b]pyridine]-30-carbonitrile (10dd)
The product was isolated as a white solid, yield 77%, mp
310e312 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.22 (1H, m, CH2), 1.39
The product was isolated as a yellow solid, yield 35%, mp
(2H, m, CH2), 1.52e1.74 (3H, m, CH2), 1.75e1.99 (4H, m, CH2), 2.94
(1H, d, J¼15.8 Hz, CH2), 3.20 (1H, d, J¼15.8 Hz, CH2), 3.70 (3H, s,
OCH3), 3.99e4.23 (1H, m, CH), 7.18 (2H, d, J¼7.3 Hz, AreH), 7.36 (3H,
m, AreH), 7.58 (1H, s, AreH), 10.73, (1H, br s, NH); 13C NMR
248e250 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 3.88 (3H, br s, OCH3),
4.96e5.53 (2H, m, CH2), 6.40 (1H, br s, CH), 6.97 (4H, m, AreH),
7.41e8.1 (10 H, m, AreH), 8.37 (1H, br s, AreH), 11.03 (1H, br s, NH),
11.35 (1H, br s, OH); 13C NMR (62.9 MHz, DMSO-d6):
d
48.5 (CH2),
(62.9 MHz, DMSO-d6): d 24.5 (CH2), 24.9 (CH2), 32.7 (CH2), 44.0
52.9 (Ce), 55.1 (OCH3e), 58.1 (CHe), 87.7 (Ce), 103.4 (Ce), 113.4
(Ce), 114.2 (CHe), 117.5 (CHe), 119.2 (CHe), 120.4 (CHe), 121.8
(CHe), 122.0 (Ce), 124.9 (CHe), 125.3 (CHe), 128.2 (Ce), 128.5
(CHe), 128.6 (CHe), 129.3 (CHe), 130.1 (Ce), 130.8 (Ce), 130.9 (Ce),
131.2 (CHe), 131.4 (CHe), 131.8 (Ce), 136.1 (Ce), 137.9 (Ce), 141.7
(Ce), 159.0 (Ce), 159.6 (Ce), 167.3 (Ce), 197.4 (Ce), 201.6 (Ce); MS
(GC, 70 eV): m/z (%) 253 (100), 226 (16); HRMS (ESI): calcd for
(CH2), 50.9 (Ce), 52.4 (OCH3e), 54.1 (CHe), 89.4 (Ce), 100.8 (Ce),
115.8 (Ce), 122.7 (CHe), 126.6 (CHe), 127.3 (CHe), 128.4 (CHe),
130.5 (Ce), 140.7 (Ce), 167.8 (Ce), 172.6 (Ce); MS (GC, 70 eV): m/z
(%) 377 (Mþ, 15), 318 (100), 236 (41); HRMS (EI): calcd for
C
22H23N3O3 (Mþ1) 377.1733, found 377.1736; IR (ATR, cmꢀ1): 3253
(w), 2940 (w), 2224 (w), 1724 (s), 1692 (s), 1529 (m), 1500 (m), 1290
(w), 1231 (m), 1175 (m), 1065 (m), 759 (s), 702 (s), 607 (s). Anal.
Calcd for C22H23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.81; H,
6.08; N, 11.27.
C
34H24N3O5 (Mþ1) 554.1710, found 554.1718; IR (ATR, cmꢀ1): 3182
(w), 2224 (w), 1712 (s), 1699 (s), 1638 (s), 1515 (m), 1239 (m), 1176
(m), 1153 (m), 748 (m).
5.39. Ethyl 3-cyano-1-cyclohexyl-4-methyl-6-oxo-4,5,6,7-
5.35. Methyl 1-tert-butyl-3-cyano-6-oxo-4-phenyl-4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (11aa)
tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (11bb)
The product was isolated as a white solid, yield 57%, mp
The product was isolated as a yellow solid, yield 70%, mp
263e265 ꢁC. 1H NMR (300 MHz, DMSO-d6):
CH3), 1.17e1.45 (3H, m, CH2), 1.46e1.73 (6H, m, CH2), 1.73e2.03
(4H, m, CH2), 2.60 (1H, d, J¼15.9 Hz, CH2), 2.62 (3H, s, CH3), 2.75
d
1.14 (3H, t, J¼7.1 Hz,
85 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.57 (9H, s, (CH3)3), 3.03
(1H, d, J¼15.5 Hz, CH2), 3.19 (1H, d, J¼15.5 Hz, CH2), 3.70 (3H, s,
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
11
(1H, d, J¼15.9 Hz, CH2), 3.91e4.24 (m, 3 H, CHCH2), 7.45 (1H, s,
AreH), 10.55 (1 H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
13.7
5.43. Ethyl 1-tert-butyl-3-cyano-4-methyl-5-oxo-4,5,7,8-
tetrahydro-1H-furo[3,4-b]pyrrolo[3,2-e]pyridine-4-
d
(CH3), 22.3 (CH3), 24.5 (CH2), 24.8 (CH2), 32.9 (CH2), 41.3 (Ce),
42.4 (CH2), 53.9 (CH), 60.7 (CH2), 87.9 (Ce), 102.2 (Ce), 116.5 (Ce),
121.9 (CH), 129.8 (Ce), 168.6 (Ce), 173.3 (Ce); MS (GC, 70 eV): m/z
(%) 329 (Mþ, 15), 256 (100), 174 (57); HRMS (EI): calcd for
carboxylate (12ab)
The product was isolated as a white solid, yield 67%, mp
248e251 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.17 (3H, t, J¼7.1 Hz,
C
18H23N3O3 (Mþ1) 329.1733, found 329.1735; IR (ATR, cmꢀ1):
CH3), 1.58 (9H, s, (CH3)3), 1.72 (3H, s, CH3), 4.00e4.19 (2H, m, CH2),
3131 (w), 2938 (w), 2217 (w), 1723 (s), 1673 (s), 1544 (s), 1351 (s),
1187 (m), 1098 (m), 1015 (m), 773 (s), 621 (s). Anal. Calcd for
4.90 (2H, s, CH2), 7.45 (1H, s, AreH), 9.78 (1H, br s, NH); 13C NMR
(62.9 MHz, DMSO-d6):
d 13.9 (CH3), 24.1 (CH3), 28.8 (CH3)3, 41.8
C
18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.74; H, 6.98;
(Ce), 57.3 (Ce), 60.8 (CH2), 65.4 (CH2), 86.7 (Ce), 97.7 (Ce), 105.4
(Ce), 115.8 (Ce), 124.2 (CHe), 128.1 (Ce), 156.8 (Ce), 171.1 (Ce),
172.0 (Ce); MS (GC, 70 eV): m/z (%) 269 (Mþ, 25), 213 (100), 184
(67); HRMS (ESI): calcd for C18H21N3O4 (Mþ1) 344.1604, found
344.1603; IR (ATR, cmꢀ1): 3382 (m), 2979 (w), 2221 (m), 1727 (w),
1703 (s), 1643 (s), 1533 (s), 1515 (s), 1205 (s), 999 (s).
N, 12.97.
5.40. Methyl 3-cyano-1-(4-methoxybenzyl)-6-oxo-4-phenyl-
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate
(11ca)
The product was isolated as a yellow solid, yield 65%, mp
5.44. Ethyl 3-cyano-1-cyclohexyl-4-methyl-5-oxo-4,5,7,8-
tetrahydro-1H-furo[3,4-b]pyrrolo[3,2-e]pyridine-4-
carboxylate (12bb)
102e104 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
2.87 (1H, d, J¼15.9 Hz,
CH2), 3.12 (1H, d, J¼15.9 Hz, CH2), 3.66 (3H, s, OCH3), 3.73 (3H, s,
OCH3), 5.09 (2H, s), 6.93 (2H, m, AreH), 7.15 (4H, m, AreH), 7.33
(3H, m, AreH), 7.48 (1H, s, AreH), 10.81 (1H, s, NH); 13C NMR
The product was isolated as a white solid, yield 40%, mp
(62.9 MHz, DMSO-d6):
d
44.0 (CH2), 48.3 (CH2), 51.1 (OCH3), 52.5
298e300 ꢁC.1H NMR (300 MHz, DMSO-d6):
d
1.14 (3H, t, J¼7 Hz, CH3),
(OCH3), 55.1 (Ce), 89.7 (Ce), 101.4 (Ce), 114.2 (Ce),115.5 (Ce),126.0
(CHe), 126.6 (CHe), 127.4 (CHe), 128.3 (Ce), 128.5 (CHe), 128.9
(CHe), 131.1 (Ce), 140.6 (Ce), 158.9 (Ce), 167.7 (Ce), 172.5 (Ce); MS
(GC, 70 eV): m/z (%) 415 (Mþ, 6), 121 (100); HRMS (EI): calcd for
1.17e1.44 (3H, m, CH2), 1.44e1.66 (3H, m, CH2), 1.68 (3H, s, CH3),
1.75e1.94 (4H, m, CH2), 3.87e4.00 (1H, m, CH), 4.06 (2H, q, J¼6.8 Hz,
CH2), 4.88 (2H, dd, J1¼16.4Hz, J2¼18.7Hz, CH2), 7.47 (1H, s, AreH);13
C
NMR (62.9 MHz, DMSO-d6): d 13.9 (CH3), 24.1 (CH3), 24.5 (CH2), 25.0
C
24H21N3O4 (Mþ1) 415.1526, found 415.1525; IR (ATR, cmꢀ1): 3126
(CH2), 32.7 (CH2), 42.0 (Ce), 54.4 (CH), 60.7 (CH2), 64.9 (CH2), 88.0
(Ce), 97.6 (Ce), 103.1 (Ce), 115.9 (Ce), 122.8 (CH), 129.2 (Ce), 157.6
(Ce), 171.3 (Ce), 172.1 (Ce); MS (GC, 70 eV): m/z (%) 295 (32), 213
(100), 184 (30); HRMS (ESI): calcd for C20H24N3O4 (Mþ1) 370.1761,
found 370.1758; IR (ATR, cmꢀ1): 3217 (w), 2221 (w),1748 (s),1691 (s),
1652 (s), 1551 (s), 1452 (m), 1332 (m), 1278 (m), 990 (s), 575 (m).
(w), 2224 (w), 1728 (m), 1513 (s), 1245 (s), 1175 (m), 699 (m). Anal.
Calcd for C24H21N3O4: C, 69.39; H, 5.10; N, 10.11. Found: C, 69.54; H,
5.45; N, 9.85.
5.41. Ethyl 3-cyano-1-(4-methoxybenzyl)-4-methyl-6-oxo-
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate
(11cb)
5.45. Ethyl 3-cyano-1-(4-methoxybenzyl)-4-methyl-5-oxo-
4,5,7,8-tetrahydro-1H-furo[3,4-b]pyrrolo[3,2-e]pyridine-4-
carboxylate (12cb)
The product was isolated as a white solid, yield 68%, mp
139e142 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.14 (3H, t, J¼7.1 Hz,
CH3), 1.59 (3H, s, CH3), 2.58 (1H, d, J¼15.9 Hz, CH2), 2.74 (1H, d,
J¼15.9 Hz, CH2), 3.75 (3H, s, OCH3), 4.06 (2H, m, CH2), 5.07 (2H, dd,
J1¼15.3 Hz, J2¼34.6 Hz, CH2), 6.94 (2H, d, J¼8.7 Hz, AreH), 7.20
(2H, d, J¼8.7 Hz, AreH), 7.41 (1H, s, AreH), 10.66 (1H, s, NH); 13C
The product was isolated as a yellow solid, yield 64%, mp
221e223 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.17 (3H, t, J¼6.9 Hz,
CH3), 1.74 (3H, s, CH3), 3.77 (3H, s, OCH3), 4.11 (2H, q, J¼6.9 Hz, CH2),
4.85 ( 2H, dd, J1¼16.4 Hz, J2¼19.2 Hz, CH2), 5.09 (2H, s, CH2), 6.97 (
2H, d, J¼8.3 Hz, AreH), 7.22 ( 2H, d, J¼8.3 Hz, AreH), 7.49 (1H, s,
NMR (62.9 MHz, DMSO-d6):
d 13.7 (CH3e), 22.1 (CH3e), 41.4 (Ce),
42.2 (CH2e), 48.1 (CH2e), 55.0 (OCH3e), 60.8 (CH2e), 88.0 (Ce),
102.7 (Ce), 114.1 (CHe), 116.2 (Ce), 125.2 (CHe), 128.4 (Ce), 128.9
(CHe), 130.4 (Ce), 158.9 (Ce), 168.6 (Ce), 173.3 (Ce); MS (GC,
70 eV): m/z (%) 367 (Mþ, 5), 121 (100); HRMS (ESI): calcd for
AreH), 10.53 (1H, br s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 13.9
(CH3), 24.0 (CH3), 42.0 (Ce), 48.4 (CH2), 55.1 (OCH3), 60.8 (CH2),
64.8 (CH2), 88.3 (Ce), 98.1 (Ce), 103.8 (Ce), 114.2 (CH), 115.5 (Ce),
126.1 (CH), 128.1 (Ce), 128.7 (CH), 129.1 (Ce), 157.1 (Ce), 159.0 (Ce),
171.1 (Ce), 171.9 (Ce); MS (GC, 70 eV): m/z (%) 407 (Mþ, 2), 334 (25),
121 (100); HRMS (ESI): calcd for C22H22N3O5 (Mþ1) 408.1554,
found 408.1549; IR (ATR, cmꢀ1): 3203 (w), 2223 (w), 1712 (s), 1625
(s), 1541 (s), 1513 (s), 1328 (m), 1254 (m), 1027 (m), 1009 (m), 611
(m). Anal. Calcd for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found:
C, 65.00; H, 5.20; N, 10.46.
C
20H21N3O4 (Mþ1) 367.1526, found 367.1527; IR (ATR, cmꢀ1): 3286
(w), 2222 (w), 1695 (s), 1511 (s), 1460 (m), 1251 (s), 810 (s). Anal.
Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C, 65.57;
H, 5.78; N, 11.55.
5.42. Methyl 1-tert-butyl-3-cyano-5-oxo-4-phenyl-4,5,7,8-
tetrahydro-1H-furo[3,4-b]pyrrolo[3,2-e]pyridine-4-
carboxylate (12aa)
5.46. Ethyl 1-tert-butyl-3-cyano-4,7,7-trimethyl-5-oxo-
4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-4-
carboxylate (13ab)
The product was isolated as a white solid, yield 42%, mp
225e227 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.63 (9H, s, (CH3)3),
4.91 (2H, dd, J¼16.4 Hz, CH2), 7.24 (5H, m, AreH), 7.53 (1H, s, AreH),
10.00 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
28.8 (CH3)3,
The product was isolated as a white solid, yield 55%, mp
d
201e204 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.04 (3H, s, CH3), 1.05
51.3 (Ce), 52.2 (OCH3), 57.4 (Ce), 65.1 (CH2), 88.4 (Ce), 97.5 (Ce),
102.9 (Ce), 115.4 (Ce), 125.0 (CHe), 126.4 (CHe), 127.4 (CHe), 127.9
(CHe), 129.5 (Ce), 142.5 (Ce), 156.0 (Ce), 170.5 (Ce), 171.4 (Ce); MS
(GC, 70 eV): m/z (%) 331 (32), 275 (100), 246 (59); HRMS (ESI): calcd
for C22H22N3O4 (Mþ1) 392.1604, found 392.1605; IR (ATR, cmꢀ1):
3296 (w), 2227 (w), 1754 (s), 1727 (s), 1658 (s), 1531 (s), 1506 (s),
1224 (m), 1197 (s), 1031 (s), 1010 (s), 693 (s).
(3H, s, CH3), 1.13 (3H, t, J¼7.1 Hz, CH3), 1.55 (3H, s, CH3), 1.57 (9H, s,
(CH3)3), 2.12 (2H, dd, J¼15.9 Hz, CH2), 2.60 (2H, dd, J¼17 Hz, CH2),
3.82e4.14 (2H, m, CH2), 7.35 (1H, s, AreH), 8.47 (1H, s, NH); 13C
NMR (62.9 MHz, DMSO-d6): d 13.9 (CH3), 25.9 (CH3), 27.4 (CH3), 27.6
(CH3), 29.1 (CH3)3, 32.0 (Ce), 40.8 (CH2), 42.9 (Ce), 50.6 (CH2), 57.2
(Ce), 59.8 (CH2), 86.1 (Ce), 106.2 (Ce), 109.3 (Ce), 115.6 (Ce), 123.7
(CHe), 126.9 (Ce), 150.3 (Ce), 173.1 (Ce), 194.1 (Ce); IR (ATR,
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

12
M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
cmꢀ1): 3307 (w), 2220 (w), 1731 (s), 1617 (s), 1523 (s), 1504 (s), 1326
(m), 1098 (m).
CH3), 1.60 (3H, s, CH3), 3.78 (3H, s, OCH3), 4.00e4.15 (2H, m, CH2),
5.05 (1H, d, J¼15.3 Hz, CH2), 5.20 (1H, d, J¼15.3 Hz, CH2), 5.27 (1H, s,
CH), 6.96 (4H, m, AreH), 7.24 (2H, m, AreH), 7.47 (1H, s, AreH), 7.52
(1H, m, AreH), 7.89 (1H, dd, J1¼8.0 Hz, J2¼1.42 Hz, AreH); 13C NMR
5.47. Ethyl 3-cyano-1-cyclohexyl-4,7,7-trimethyl-5-oxo-
4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-4-
carboxylate (13bb)
(62.9 MHz, DMSO-d6):
d 13.6 (CH3), 19.4 (CH3), 43.4 (Ce), 48.3
(CH2), 55.1 (OCH3), 58.9 (CH), 60.4 (CH2), 87.5 (Ce), 103.1 (Ce), 114.1
(CHe), 116.1 (Ce),117.5 (CHe), 119.2 (CHe), 122.8 (Ce),125.5 (CHe),
128.3 (Ce), 129.0 (CHe), 130.5 (Ce), 131.3 (CHe), 136.0 (CHe), 158.9
(Ce), 159.8 (Ce), 167.4 (Ce), 172.5 (Ce), 198.7 (Ce); MS (GC, 70 eV):
m/z (%) 487 (Mþ, 1), 325 (6), 121 (100); HRMS (ESI): calcd for
The product was isolated as a yellow solid, yield 58%, mp
246e248 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d 1.02 (6H, br s, CH3),
1.09 (3H, t, J¼7 Hz, CH3), 1.14e1.25 (1H, m, CH2), 1.26e1.51 (3H, m,
CH2), 1.54 (3H, s, CH3), 1.57e1.71 (2H, m, CH2), 1.73e1.92 (4H, m,
CH2), 2.10 (2H, dd, J1¼15.7 Hz, J2¼29.7 Hz, CH2), 2.41 (2H, dd,
J1¼16.2 Hz, J2¼29.8 Hz, CH2), 3.83e4.18 (3H, m, CH), 7.38 (1H, s,
C
27H26N3O6 (Mþ1) 488.1816, found 488.1803; IR (ATR, cmꢀ1): 3030
(w), 2222 (w), 1679 (s), 1635 (m), 1246 (s), 1208 (s), 1153 (s), 1029
(m), 750 (s). Anal. Calcd for C27H25N3O6: C, 66.52; H, 5.17; N, 8.62.
Found: C, 66.56; H, 5.14; N, 8.85.
AreH), 9.35 (1H, br s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 14.0
(CH3), 24.6 (CH2), 25.0 (CH2), 25.9 (CH3), 27.2 (CH3), 27.9 (CH3), 32.2
(CH2), 32.6 (Ce), 40.8 (CH2), 43.2 (Ce), 50.7 (CH2), 53.8 (CH), 59.8
(CH2), 87.6 (Ce), 103.7 (Ce), 109.5 (Ce), 115.7 (Ce), 122.3 (CH), 127.2
(Ce), 150.3 (Ce), 173.2 (Ce), 193.8 (Ce); MS (GC, 70 eV): m/z (%) 409
(Mþ, 9), 336 (100), 254 (77); HRMS (ESI): calcd for C24H31N3O3
(Mþ1) 409.2359, found 409.2364; IR (ATR, cmꢀ1): 3302 (w), 2942
(w), 2224 (m), 1725 (s), 1642 (m), 1628 (m), 1531 (s), 1508 (m), 1423
(m), 1327 (m), 1222 (m), 1102 (m).
Acknowledgements
€
Financial support by the BMBF ‘REMEDIS’dproject ‘Hohere
€
Lebensqualitat durch neuartige Mikroimplantate’ (grant no.
03IS2081A) is gratefully acknowledged. Financial support by the
DAAD (scholarships for M.V.-H.) is acknowledged.
5.48. Ethyl 1-tert-butyl-3-cyano-5-(2-hydroxybenzoyl)-4-
methyl-6-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-
4-carboxylate (14ab)
Supplementary data
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra of all compounds. Supplementary data associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2013.04.115.
The product was isolated as a white solid, yield 67%, mp
258e260 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.10 (3H, t, J¼7 Hz,
CH3), 1.59 (12H, s, CH3), 4.08 (2H, m, CH2), 5.25 (1H, s, CH), 6.99 (2H,
m, AreH), 7.51 (2H, m, AreH), 7.93 (1H, d, J¼7.7 Hz, AreH), 10.26
(1H, br s, NH), 11.38 (1H, br s, OH); 13C NMR (62.9 MHz, DMSO-d6):
References and notes
d
13.6 (CH3), 19.6 (CH3), 29.1 (CH3), 42.9 (Ce), 57.9 (Ce), 58.6 (CHe),
1. (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187e191; (b) Toure, B. B.; Hall, D. G. Chem.
Rev. 2009, 109, 4439e4486; (c) Domling, A. Chem. Rev. 2006, 106, 17e89; (d)
Chebanov, V. A.; Gura, K. A.; Desenko, S. M. Top. Heterocycl. Chem. 2010, 23,
41e84; (e) Kumaravel, K.; Vasuki, G. Curr. Org. Chem. 2009, 13, 1820e1841; (f)
Multicomponent Reactions; Zhu, J.-P., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005; p 1499; (g) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
112, 3083e3135.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115e136.
60.3 (CH2), 86.1 (Ce), 105.6 (Ce), 116.5 (Ce), 117.6 (CHe), 119.2
(CHe), 122.7 (Ce), 123.8 (CHe), 130.0 (Ce), 131.3 (CHe), 136.0
(CHe), 159.9 (Ce), 167.6 (Ce), 172.3 (Ce), 198.8 (Ce); MS (GC,
70 eV): m/z (%) 331 (Mþ, 35), 275 (100), 246 (59); IR (ATR, cmꢀ1):
3218 (w), 2227 (w), 1725 (s), 1674 (s), 1634 (s), 1349 (m), 1219 (m),
1188 (m), 1158 (m), 752 (s), 619 (s). Anal. Calcd for C23H25N3O5: C,
65.24; H, 5.95; N, 9.92. Found: C, 64.99; H, 5.97; N, 9.81.
€
3. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930.
4. Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109,
3080e3098.
5. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc.
Rev. 2007, 36, 1120e1132.
6. Fresneda, P. M.; Molina, P.; Bleda, J. A. Tetrahedron 2001, 57, 2355e2363.
7. Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares, I.; Cuevas, C.; Molina, P.
J. Med. Chem. 2006, 49, 1217e1221.
5.49. Ethyl 3-cyano-1-cyclohexyl-5-(2-hydroxybenzoyl)-4-
methyl-6-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-
4-carboxylate (14bb)
8. Jia, W. L.; Bai, D. R.; McCormick, T.; Liu, Q. D.; Motala, M.; Wang, R. Y.; Seward,
C.; Tao, Y.; Wang, S. Chem.dEur. J. 2004, 10, 994e1006.
The product was isolated as a white solid, yield 34%, mp
252e255 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.09 (3H, t, J¼7.1 Hz),
9. Zhao, S. B.; Wang, S. Chem. Soc. Rev. 2010, 39, 3142e3156.
10. (a) Levacher, V.; Benoit, R.; Duflos, J.; Dupas, G.; Bourguignon, J.; Queguiner, G.
Tetrahedron 1991, 47, 429e440; (b) Plieninger, H.; Schach von Wittenau, M.;
Kiefer, B. Chem. Ber. 1958, 91, 2095e2103; (c) El-Ahl, A.-A. S. Synth. Commun.
2000, 30, 2223e2231; (d) Levacher, V.; Boussad, N.; Dupas, G.; Bourguignon, J.;
1.16e1.47 (3H, m, CH2),1.53e1.71 (6H, m, CH),1.77e1.96 (4H, m, CH),
3.96e4.13 (3H, m, CH), 5.26 (1H, s, CH), 6.96 (2H, m, AreH), 7.53 (2H,
m, AreH), 7.93 (1H, dd, J1¼8.1 Hz, J2¼1.3 Hz, AreH),10.86 (1H, s, OH),
11.39 (1H, s, NH); 13C NMR (62.9 MHz, DMSO-d6):
d 13.6 (CH3), 19.5
ꢀ
Queguiner, G. Tetrahedron 1992, 47, 831e840.
11. Vilches-Herrera, M.; Knepper, I.; de Souza, N.; Villinger, A.; Sosnovskikh, V.;
(CH3), 24.5 (CH2), 24.8 (CH2), 32.7 (CH2), 32.9 (Ce), 43.3 (Ce), 54.2
(CH), 59.0 (CH), 60.3 (CH2), 87.3 (Ce), 102.6 (Ce), 116.5 (Ce), 117.6
(CH), 119.1 (CH), 122.3 (CH), 122.6 (Ce), 130.0 (Ce), 131.4 (CH), 136.1
(CH),160.0 (Ce),167.5 (Ce),172.5 (Ce),199.1 (Ce); HRMS (ESI): calcd
for C25H28N3O5 (Mþ1) 450.2023, found 450.2023; IR (ATR, cmꢀ1):
2931 (w), 2219 (w),1723 (m),1687 (s),1634 (m),1444 (w),1339 (m),
1215 (m), 751 (s). Anal. Calcd for C25H27N3O5: C, 66.80; H, 6.05; N,
9.35. Found: C, 66.78; H, 6.04; N, 9.54.
Iaroshenko, V. O. ACS Comb. Sci. 2012, 14, 434e441.
12. (a) Kotljarov, A.; Irgashev, R. A.; Iaroshenko, V. O.; Sevenard, D. V.; Sosnovskikh,
V. Y. Synthesis 2009, 3233e3242; (b) Kotljarov, A.; Iaroshenko, V. O.; Vo-
lochnyuk, D. M.; Irgashev, R. A.; Sosnovskikh, V. Y. Synthesis 2009, 3869e3879;
(c) Iaroshenko, V. O.; Mkrtchyan, S.; Ghazaryan, G.; Hakobyan, A.; Maalik, A.;
Supe, L.; Villinger, A.; Tolmachev, A.; Ostrovskyi, D.; Sosnovskikh, V. Y.; Gho-
chikyan, T. V.; Langer, P. Synthesis 2011, 469e479; (d) Mkrtchyan, S.; Iar-
oshenko, V. O.; Dudkin, S.; Gevorgyan, A.; Vilches-Herrera, M.; Ghazaryan, G.;
Volochnyuk, D.; Ostrovskyi, D.; Ahmed, Z.; Villinger, A.; Sosnovskikh, V. Y.;
Langer, P. Org. Biomol. Chem. 2010, 8, 5280e5284; (e) Iaroshenko, V. O.;
Mkrtchyan, S.; Gevorgyan, A.; Vilches-Herrera, M.; Sevenard, D. V.; Villinger, A.;
Ghochikyan, T. V.; Saghiyan, A.; Sosnovskikh, V. Y.; Langer, P. Tetrahedron 2012,
2532e2543; (f) Iaroshenko, V. O.; Mkrtchyan, S.; Gevorgyan, A.; Miliutina, M.;
Villinger, A.; Volochnyuk, D.; Sosnovskikh, V. Y.; Langer, P. Org. Biomol. Chem.
2012, 10, 890e894.
5.50. Ethyl 3-cyano-5-(2-hydroxybenzoyl)-1-(4-
methoxybenzyl)-4-methyl-6-oxo-4,5,6,7-tetrahydro-1H-pyr-
rolo[2,3-b]pyridine-4-carboxylate (14cb)
13. Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Angew. Chem., Int. Ed. 2011, 50,
10800e10826.
The product was isolated as a white solid, yield 47%, mp
14. (a) Chen, H.; Shi, D. J. Comb. Chem. 2010, 12, 571e576; (b) Balamurugan, K.;
Perumal, S.; Menendez, J. C. Tetrahedron 2011, 67, 3201e3208; (c) Ryabukhin, S.
199e201 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
1.11 (3H, t, J¼7.1 Hz,
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115

M. Vilches-Herrera et al. / Tetrahedron xxx (2013) 1e13
13
V.; Granat, D. S.; Plaskon, A. S.; Shivanyuk, A. N.; Tolmachev, A. A.; Volovenko,
Y. M. ACS Comb. Sci. 2012, 465e470.
19. Grob-Schmidt, D.; Seemuth, P. D.; Zimmer, H. J. Org. Chem. 1983, 48,
1914e1916.
15. Ma, N.;Jiang, B.;Zhang, G.;Tu, S. J.;Wever, W.;Li, G.Green Chem. 2010,12,1357e1361.
16. Quiroga, J.; Portillo, S.; Perez, A.; Galvez, J.; Abonia, R.; Insuasty, B. Tetrahedron
Lett. 2011, 52, 2664e2666.
17. Bazgir, A.; Ahadi, S.; Ghahremanzadeh, R.; Khayasi, H. R.; Mirzaei, P. Ultrason.
Chem. 2010, 17, 447e452.
18. Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801e2804.
20. Crystallographic data (excluding structure factors) for the structure 9bb and
11cb, reported in this paper have been deposited with the Cambridge Crys-
tallographic Data Centre as supplementary publication nos. 916825 and 916826
and can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.
uk, or via www.ccdc.cam.ac.uk/data_request/cif.
ꢀ
ꢀ
Please cite this article in press as: Vilches-Herrera, M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.115