Expeditious construction of spiro-pyrrolidines by an autocatalytic one-pot, five-component, 1,3-dipolar cycloaddition of in situ generated azomethine ylides and olefinic dipolarophiles

Article abstract of DOI:10.1002/ejoc.201100297

Two series of previously unknown spiro-pyrrolidine derivatives were prepared by a five-component reaction that employed ninhydrin, 1,2-phenylenediamine, sarcosine, aldehydes, and malononitrile or cyanoacetic ester in a solvothermal synthesis. This is the first report of an autocatalytic five-component reaction involving a classical Huisgen reaction, in which the dipole - an azomethine ylide - and the dipolarophile were simultaneously generated in situ. The 1,3-dipolar cycloaddition reaction was found to proceed in a highly regio- and diastereoselective manner. The methodology for the preparation of the spiro-pyrrolidines could be an ideal tool for green chemistry and the synthesis of alkaloids. The highly regio- and stereoselective synthesis of new spiro-pyrrolodines by a combination of a five-component tandemKnoevenagel reaction with a [3+2] dipolarcycloaddition is described, for which azomethine ylides and olefinic dipolarophiles are generated in situ. Copyright

Full text of DOI:10.1002/ejoc.201100297

FULL PAPER
DOI: 10.1002/ejoc.201100297
Expeditious Construction of Spiro-Pyrrolidines by an Autocatalytic One-Pot,
Five-Component, 1,3-Dipolar Cycloaddition of in situ Generated Azomethine
Ylides and Olefinic Dipolarophiles
[a]
[a]
[a]
[a]
Ming Li,* Fu-Meng Gong, Li-Rong Wen,* and Zhao-Rui Li
Keywords: Spiro compounds / Nitrogen heterocycles / Cycloaddition / Azomethine ylides / Multicomponent reactions /
Solvothermal synthesis
Two series of previously unknown spiro-pyrrolidine deriva- in which the dipole – an azomethine ylide – and the di-
tives were prepared by a five-component reaction that em-
ployed ninhydrin, 1,2-phenylenediamine, sarcosine, alde-
hydes, and malononitrile or cyanoacetic ester in a solvother-
mal synthesis. This is the first report of an autocatalytic five-
component reaction involving a classical Huisgen reaction,
polarophile were simultaneously generated in situ. The 1,3-
dipolar cycloaddition reaction was found to proceed in a
highly regio- and diastereoselective manner. The methodol-
ogy for the preparation of the spiro-pyrrolidines could be an
ideal tool for green chemistry and the synthesis of alkaloids.
and possess antiviral and local anesthetic activities.[6]
Therefore, the synthesis of these compounds has become an
Introduction
A major challenge of modern drug discovery is the de- important target in recent years.
sign of highly efficient chemical reaction sequences that
The cycloaddition reaction of 1,3-dipoles with olefinic or
provide maximum structural complexity and diversity with acetylenic dipolarophiles, discovered by Huisgen as early
[
7]
[8]
a minimum number of synthetic steps to assemble com- as 1963 and developed by Woodward and Hoffmann and
pounds with interesting properties.[1] One of the ways to Houk et al., has became a general and important strategy
fulfill these goals is the development and use of multicom- for the construction of five-membered heterocycles contain-
ponent reactions (MCRs).[ MCRs are important for gen- ing spiro-pyrrolidines, which are prevalent in a variety of
[9]
2]
[
4f,10]
erating high levels of diversity because they allow more than biologically active compounds.
In recent years, the con-
two building blocks to be combined in a practical, time- struction of spiro-heterocycles by 1,3-dipolar cycloaddition
saving, one-pot operation, giving rise to complex structures reactions of azomethine ylides has been well developed with
[
11]
by simultaneous formation of two or more bonds from sim- high regio- and stereoselectivity.
ple substrates. Because of these advantages, developing new reactions have the same limitation of advance preparation
However, all of these
[
12]
MCRs with environmentally benign methods has been rec- of dipolarophiles and some involving catalysts.
ognized as one of the most important topics of green chem- soned that simultaneous in situ generation of both the azo-
We rea-
[
3]
istry.
Functionalized pyrrolidines are one of the significant would be essential for reaction efficiency and practicality.
central skeletons for numerous alkaloids and pharmacologi-
A retrosynthetic strategy for the construction of the
cally important compounds.[4] Spiro compounds, particular spiro-pyrrolidines is shown in Figure 1.
methine ylide intermediate and the olefinic dipolarophile
spiro-pyrrolidines, have gained significant attention due to
In view of the advantages of MCRs and tandem reac-
their interesting biological activities, such as antimicrobial, tions, and prompted by our previous research on MCRs,[
13]
[5]
antitumor, and antibiotic properties. Some spiro-pyrrol- we herein describe our studies on a more convenient and
idines are potential antileukemic and anticonvulsant agents, powerful extension of the Huisgen synthesis for spiro-het-
erocycles, which proceeds by a five-component tandem re-
action: a Knoevenagel condensation/1,3-dipolar cycload-
dition sequence of ninhydrin (1), 1,2-phenylenediamine (2),
sarcosine (3), active methylene compounds 4, and aldehydes
5 in one-pot without the isolation of dipolarophiles
[
a] State Key Laboratory Base of Eco-Chemical Engineering,
College of Chemistry and Molecular Engineering, Qingdao
University of Science and Technology,
Qingdao 266042, P. R. China
Fax: +86-532-84023927
E-mail: liming928@qust.edu.cn
(Scheme 1). Such a strategy would provide access to a rapid
wenlirong@qust.edu.cn
synthesis of spiro-heterocycles that are otherwise accessible
only through multistep syntheses.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100297.
3482
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3482–3490

Spiro-Pyrrolidines by Five-Component Cycloaddition
Figure 1. Retrosynthetic strategy for spiro-pyrrolidine synthesis. EWG = electron-withdrawing group.
Scheme 1. One-pot, five-component synthesis of spiro-pyrrolidines.
Results and Discussion
Table 1. Optimization of reaction conditions for the five-compo-
nent reaction.
The Knoevenagel condensation is a well-established reac-
tion for the construction of α,β-unsaturated compounds as
excellent dipolarophiles. First, the condensation reaction of
Entry Solvent
Temp. [°C] Time [h]
Yield [%][a]
69[
b]
1
2
3
4
5
6
7
8
9
ethanol
ethanol
ethanol
toluene
1,4-dioxane
acetonitrile
methanol
ethanol
78
78
78
110
101
82
12
12
12
24
19
16
13
2
78[
c]
4a and 5a was examined. As expected, it could not take
[d]
76
36
place at room temperature without any catalyst in ethanol,
even at reflux for 30 min. Sarcosine 3 (0.2 equiv.), one of
our starting materials, was added to the mixture, conse-
quently, the reactants were completely converted at reflux
in only 5 min (monitored by TLC). In regard to this, the
amount of 3 for this five-component reaction of 1, 2, 3, 10
malononitrile 4a, and 4-chlorobenzaldehyde (5a) in ethanol 11
[c]
c]
51[
55[
c]
c]
e]
[
65
65
100
100
120
120
140
160
88[
[e]
ethanol
3
2
4
2
83
79
[e]
ethanol
complex mixture[
e]
e]
e]
H
H
2
H
2
2
O
O
O
[
1
2
complex mixture
was investigated without any other catalyst. The yield of 6a
was improved from 69 to 78% when 3 was added from 1.0
13
2
complex mixture[
[
a] Isolated yield. [b] 1.0 equiv. of 3. [c] 1.2 equiv. of 3. [d] 1.3 equiv.
(Table 1, entry 1) to 1.2 equiv. (Table 1, entry 2), but more
of 3. [e] Reaction conducted in a sealed vessel.
3
did not further improve the yield of 6a (Table 1, entry
3). From these results, it was concluded that, in our MCR,
sarcosine 3 played a dual role because it was not only a key size chemical compounds that are extremely difficult to pro-
substrate in the tandem reaction, but also an effective cata- duce by traditional methods. Solvothermal synthesis is nor-
lyst for the Knoevenagel condensation reaction between 4a mally carried out in a pressure vessel in which common
and 5a. Next, this five-component reaction was performed solvents, such as alcohols, will be stable beyond their boil-
in different solvents. The results showed the solvents also ing points under a high pressure.
clearly affected the yield of 6a (Table 1, entries 4–6). In tolu-
Excitingly, the yield of 6a increased to 88% as expected
ene, acetonitrile, or 1,4-dioxane, the yields of 6a were lower and the reaction time was shortened to 2 h when the reac-
and longer reaction times were required than in ethanol or tion of 1, 2, 3, 4a, and 5a in ethanol was carried out in a
methanol (Table 1, entries 2 and 7). It can thus be con- pressure vessel at 100 °C (Table 1, entry 8). However, pro-
cluded that for this MCR a protic solvent, such as ethanol, longed reaction times or higher temperatures failed to fur-
is superior to an aprotic one.
ther improve the yield (Table 1, entries 9 and 10). It is clear
However, we observed in our experiment that simply stir- that utilization of our modified method could increase the
ring the reaction mixture under the above-described opti- yield and reduce the reaction time simultaneously. It should
mum conditions was not sufficient due to, in part, the low be mentioned that the reaction under hydrothermal condi-
solubility of the starting materials or intermediates in eth- tions at 120, 140, or 160 °C, afforded rather complex mix-
anol. To further improve the yield, the solvothermal method tures (Table 1, entries 11–13). Therefore, the optimum reac-
was exploited for this reaction. Increasing interest in solvo- tion condition are those shown for entry 8 in Table 1.
thermal syntheses derives from advantages in terms of the
According to the optimized conditions, various alde-
increased solubility and high reactivity of compounds, easy hydes 5a–p were used in this reaction to give spiro-pyrrol-
control of solution reactions, less air pollution, and low en- idines 6a–p in high yields of 80–92% (Table 2). It can be
[
14]
ergy consumption. It is the preferred method to synthe- observed that the process tolerates aromatic aldehydes with
Eur. J. Org. Chem. 2011, 3482–3490
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3483

M. Li, F.-M. Gong, L.-R. Wen, Z.-R. Li
FULL PAPER
both electron-donating and -withdrawing substituents, in- aldehyde or butyraldehyde were employed, the reactions
cluding more sterically hindered ortho substituents (Table 2, were usually very slow and resulted in a complicated mix-
entries 6–9), and even heteroaromatic aldehydes such as fu- ture of the products. The identification of spiro-pyrrolidines
1
13
ran-2-carbaldehyde (Table 2, entry 16). In all case, the reac- 6a–p was unequivocally ascertained by their H NMR,
C
tions proceeded smoothly and only single diastereoisomers NMR, IR, HRMS spectra.
of spiro-pyrrolidines were afforded in high yields. Unfortu-
Encouraged by this success, we next used ethyl 2-cyano-
nately, however, when aliphatic aldehydes such as propion- acetate (4b) instead of 4a to investigate the reaction under
Table 2. Five-component synthesis of products 6 by the solvothermal method.[a]
[a] Reaction in ethanol, in a sealed vessel at 100 °C, and the molar ratio of 1/2/3/4a/5 was 1:1:1.2:1:1. [b] Isolated yield.
3
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Spiro-Pyrrolidines by Five-Component Cycloaddition
the same optimized conditions as those described above 7b–m. The identification of spiro-pyrrolidines 7a–m was un-
1
13
(
Table 3). Our experimental results showed that the reaction equivocally ascertained by their H NMR, C NMR, IR,
time of 4b with 1, 2, 3, and 5a was longer and the yield of HRMS spectra.
product 7a was lower: only 61% yield after 20 h was ob-
The above experimental results suggested that this reac-
tained by the traditional method, whereas the yield of 7a tion was highly regioselective. The dipolar cycloaddition of
was promoted to 79% in 7 h by the solvothermal method. an azomethine ylide, generated from 1, 2, and 3, to a di-
Twelve different aromatic aldehydes were employed in this polarophile arylidenemalononitrile (or ethyl 2-cyano-3-aryl-
five-component reaction to give corresponding products acrylate), derived from 4a (or 4b) and aromatic aldehydes
Table 3. Synthesis of compounds 7 by the solvothermal method.[a]
[a] Reaction in ethanol, in a sealed vessel at 100 °C, and the molar ratio of 1/2/3/4b/5 was 1:1:1.2:1:1. [b] Isolated yield.
Eur. J. Org. Chem. 2011, 3482–3490
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Li, F.-M. Gong, L.-R. Wen, Z.-R. Li
FULL PAPER
5, could proceed by two possible paths, A or B, leading to
two corresponding regioisomers 6 (or 7) or 6Ј (or 7Ј), as
shown in Scheme 2. In fact, our reaction proceeded exclu-
sively by path A, in which the electron-rich carbon of the
azomethine ylide added to the β-carbon of the α,β-unsatu-
rated moiety of the arylidenemalononitrile (or ethyl 2-cy-
ano-3-arylacrylate), resulting in a single regioisomer 6 (or
7), while no trace of another regioisomer 6Ј (or 7Ј) was
detected. Furthermore, this reaction was also found to be
diastereoselective. The 1,3-diporal cycloaddition reaction of
the azomethine ylide with an arylidenemalononitrile (or
ethyl 2-cyano-3-arylacrylate) could proceed by two meth-
ods, a or b, as shown in Scheme 2, but only a single exo
adduct 6 (or 7) was obtained due to the thermodynamically
more stable method a, whereas an endo isomer, such as 6Ј
(or 7ЈЈ) resulting from method b was not observed. The
regioselectivity and stereochemistry of this cycloaddition
were unambiguously ascertained by single-crystal X-ray
analysis of the cycloadducts 6b, 6g, and 7j, in which the
[
15]
COOEt group is trans to the Ar group in 7j (Figure 2).
Figure 2. X-ray structures of 6b, 6g, and 7j.
11 subsequently undergoes cycloaddition to 10 as a di-
polarophile to produce, diastereoselectively, the new prod-
ucts 6 or 7 (Scheme 3).
Scheme 2. The regio- and stereoselective outcome of cycloaddition.
A proposed mechanism for this new domino reaction is
outlined in Scheme 3. Based on this mechanism, sarcosine 3
is an effective catalyst for the formation of the Knoevenagel
adducts 10, readily prepared in situ from active methylene
compounds 4 and aldehydes 5 via iminium ion 8 and am-
monium ion 9. At the same time, the condensation reaction
of 1 and 2 leads to indenoquinoxaline-11-one (12), followed
by formation of azomethine ylide 11 by thermal decarbox-
ylation of mixtures of 3 and 12. Next, the formed 1,3-dipole Scheme 3. A reasonable mechanism for the domino reaction.
3
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Spiro-Pyrrolidines by Five-Component Cycloaddition
(
2ЈS,4ЈR)-4Ј-(4-Fluorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
Conclusions
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6b): Primrose yellow
1
We have successfully developed an operationally simple, solid; m.p. 208–209 °C. H NMR ([D
2 H, ArH), 5.48–5.51 (dd, J = 6.5, 7.0 Hz, 1 H, CH), 4.04–4.06
m, 1 H, NCH ), 3.92–3.96 (m, 1 H, NCH ), 2.03 (s, 3 H, NCH
ppm. C NMR ([D ]DMSO): δ = 164.0, 162.0, 158.2, 152.9, 142.8,
6
]DMSO): δ = 7.34–8.30 (m,
1
(
autocatalytic, one-pot, five-component reaction to synthe-
size new spiro-pyrrolidines by employing 1, 2, 3, aldehydes
and malononitrile or cyanoacetic ester. This is the first re-
port of the preparation of title compounds by solvothermal
synthesis in a highly regio- and stereoselective manner.
Sarcosine 3 plays a dual role, serving as a key substrate as
well as an efficient catalyst in this reaction. Moreover, this
method can be considered as an ideal tool for green synthe-
sis because (1) rapid assembly of heterocyclic molecules by
a five-component process minimizes the generation of
waste; (2) both azomethine ylide and olefinic dipolarophiles
are simultaneously generated in situ without the need to
isolate intermediates; (3) the process has high atom econ-
2
2
3
)
1
3
6
1
1
5
7
4
40.9, 140.7, 138.4, 133.2, 132.9, 132.1, 131.6, 131.5, 131.2, 130.9,
30.6, 129.6, 126.8, 123.1, 116.6, 116.4, 113.5, 113.2, 78.4, 55.8,
1.8, 50.1, 35.1 ppm. IR (KBr): ν˜ = 2247, 1635, 1512, 1464, 838,
–1
+
71 cm . HRMS (ESI-TOF): calcd. for C27
19 5
H N F [M + H]
32.1624; found 432.1643.
(
2ЈS,4ЈR)-4Ј-(4-Bromophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6c): Primrose yellow
1
solid; m.p. 203–204 °C. H NMR ([D
2 H, ArH), 5.50–5.54 (dd, J = 6.5, 7.0 Hz, 1 H, CH), 4.08–4.11
m, 1 H, NCH ), 3.93–3.97 (m, 1 H, NCH ), 2.03 (s, 3 H, NCH
ppm. C NMR ([D ]DMSO): δ = 158.3, 153.1, 143.0, 141.1, 140.8,
6
]DMSO): δ = 7.32–8.29 (m,
1
(
2
2
3
)
13
6
omy and is ecologically benign, since only four molecules 138.6, 134.7, 133.5, 133.1, 132.8, 132.4, 131.8, 131.1, 130.8, 129.9,
of water and one molecule of CO are lost; and (4) multiple 127.0, 123.4, 123.3, 113.6, 113.4, 78.6, 55.7, 51.9, 50.4, 35.3 ppm.
2
–
1
IR (KBr): ν˜ = 2249, 1632, 1509, 1492, 830, 774 cm . HRMS (ESI-
TOF): calcd. for C27
bonds and stereocenters are formed in a single reaction.
Therefore, this one-pot, autocatalytic transformation clearly
represents an appealing methodology for the synthesis of
+
19 5
H N Br [M + H] 492.0824; found 492.0844.
(
2ЈS,4ЈR)-4Ј-(3-Fluorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
spiro-pyrrolidines both in academia and pharmaceutical in- oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6d): Brown yellow so-
1
dustries.
lid; m.p. 197–198 °C. H NMR (CDCl ): δ = 7.13–8.28 (m, 12 H,
3
ArH), 5.54–5.57 (dd, J = 7.0, 7.0 Hz, 1 H, CH), 3.99–4.03 (m, 1
H, NCH
2
), 3.97–3.98 (m, 1 H, NCH
3C NMR (CDCl
): δ = 163.9, 162.0, 158.0, 153.1, 143.1, 141.0,
140.5, 138.6, 137.0, 132.3, 131.8, 130.9, 130.6, 130.0, 129.7, 129.5,
2 3
), 2.08 (s, 3 H, NCH ) ppm.
1
3
Experimental Section
1
5
7
4
26.7, 124.7, 122.7, 116.3, 116.1, 115.9, 112.7, 112.5, 78.2, 55.8,
General: All reagents and solvents were obtained from commercial
suppliers and used without further purification. All reagents were
weighed and handled in air at room temperature. Chromatography
refers to open column chromatography on silica gel (100–
1.1, 50.6, 34.8 ppm. IR (KBr): ν˜ = 2246, 1615, 1509, 1453, 873,
–
1
+
65 cm . HRMS (ESI-TOF): calcd. for C27
32.1624; found 432.1612.
19 5
H N F [M + H]
2
00 mesh). Melting points were recorded on a RY-1 microscopic
(2ЈS,4ЈR)-4Ј-(3-Bromophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
1
melting apparatus. H NMR spectra were recorded at 500 MHz
and 13C NMR spectra were recorded at 125 MHz by using a Bruker
Avance 500M spectrometer. Chemical shifts were reported in parts
per million (δ) relative to tetramethylsilane (TMS). IR spectra were
recorded on a Nicolet iS10 FT-IR spectrometer and only major
signals are reported in cm . Mass spectra were recorded on an
Ultima Global spectrometer with an ESI source. X-ray single-crys-
tal diffraction was performed on a Saturn 724+ instrument.
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6e): Primrose yellow
1
solid; m.p. 204–205 °C. H NMR (CDCl
3
): δ = 7.35–8.26 (m, 12
H, ArH), 5.48–5.52 (dd, J = 7.0, 7.0 Hz, 1 H, CH), 3.98–4.02 (m,
1 H, NCH ), 3.95–3.97 (m, 1 H, NCH ), 2.07 (s, 3 H, NCH ) ppm.
3C NMR (CDCl
): δ = 157.9, 153.1, 143.1, 141.0, 140.4, 138.6,
2
2
3
1
3
–1
136.8, 132.3, 132.1, 131.8, 130.9, 130.6, 130.0, 129.7, 129.5, 126.7,
123.1, 122.7, 112.6, 112.5, 78.3, 55.9, 51.1, 50.5, 34.8 ppm. IR
–
1
(KBr): ν˜ = 2247, 1636, 1509, 1465, 864, 757 cm . HRMS (ESI-
+
19 5
TOF): calcd. for C27H N Br [M + H] 492.0824; found 492.0806.
General Procedures for the Synthesis of Compounds 6 and 7 (6a):
1,2-Phenylenediamine 2 (0.108 g, 1 mmol) in EtOH (10 mL) was
(2ЈS,4ЈS)-4Ј-(2-Fluorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
added to ninhydrin 1 (0.178 g, 1 mmol) . The mixture was stirred
for 10 min. sarcosine 3 (0.107 g, 1.2 mmol), malononitrile 4a
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6f): Primrose yellow
1
solid, M.p. 230–231 °C. H NMR (CDCl
3
): δ = 7.21–8.30 (m, 12
(
0.066 g, 1 mmol), and 4-chlorobenzaldehyde 5a (0.140 g, 1 mmol)
H, ArH), 5.99–6.03 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.05–4.09 (m,
1 H, NCH ), 3.99–4.02 (m, 1 H, NCH ), 2.12 (s, 3 H, NCH ) ppm.
3C NMR (CDCl
): δ = 162.5, 160.5, 158.0, 153.0, 143.1, 141.1,
were then added to this solution. Then, the turbid solution was put
in a Teflon-line stainless bomb, which was sealed and then heated
at 100 °C for 2 h. After completion of the reaction, as indicated by
TLC, excess EtOH was distilled off. The crude product obtained
was recrystallized from EtOH to afford the pure product 6a.
2
2
3
1
3
140.5, 138.8, 132.2, 131.7, 130.8, 130.7, 130.1, 129.6, 129.4, 126.7,
124.7, 122.7, 122.0, 121.9, 116.1, 115.9, 112.8, 112.4, 78.4, 55.9,
50.2, 43.3, 34.9 ppm. IR (KBr): ν˜ = 2250, 1633, 1509, 1495, 827,
–
1
+
7
4
60 cm . HRMS (ESI-TOF): calcd. for C27
32.1624; found 432.1615.
19 5
H N F [M + H]
(
2ЈS,4ЈR)-4Ј-(4-Chlorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6a): Primrose yellow
1
solid; m.p. 196–197 °C. H NMR ([D
2 H, ArH), 5.48–5.51 (dd, J = 6.5, 7.0 Hz, 1 H, CH), 4.04–4.07
m, 1 H, NCH ), 3.94–3.98 (m, 1 H, NCH ), 2.04 (s, 3 H, NCH
ppm. C NMR ([D ]DMSO): δ = 159.8, 158.3, 153.1, 143.0, 141.1,
6
]DMSO): δ = 7.60–8.32 (m,
(2ЈS,4ЈS)-4Ј-(2-Chlorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
1
(
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6g): Primrose yellow
1
2
2
3
)
solid; m.p. 243–244 °C. H NMR (CDCl
3
): δ = 7.36–8.28 (m, 12
13
6
H, ArH), 6.39–6.43 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.06–4.10 (m,
1 H, NCH ), 3.82–3.85 (m, 1 H, NCH ), 2.08 (s, 3 H, NCH ) ppm.
3C NMR (CDCl
): δ = 158.0, 153.1, 143.1, 141.0, 140.5, 138.8,
1
1
40.8, 138.6, 134.6, 134.3, 133.5, 133.1, 132.4, 131.5, 131.1, 130.8,
28.9, 127.0, 123.4, 113.6, 113.4, 78.6, 55.8, 51.9, 50.3, 35.3 ppm.
2
2
3
1
3
–1
IR (KBr): ν˜ = 2247, 1637, 1509, 1495, 831, 754 cm . HRMS (ESI-
TOF): calcd. for C27
135.7, 132.8, 132.2, 131.7, 130.8, 130.3, 130.1, 129.6, 129.5, 127.3,
126.8, 122.7, 112.9, 112.3, 78.8, 57.4, 49.9, 45.5, 34.9 ppm. IR
+
19 5
H N Cl [M + H] 448.1329; found 448.1320.
Eur. J. Org. Chem. 2011, 3482–3490
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3487

M. Li, F.-M. Gong, L.-R. Wen, Z.-R. Li
FULL PAPER
–
1
–1
(KBr): ν˜ = 2250, 1634, 1509, 1475, 863, 754 cm . HRMS (ESI-
35.4, 21.5 ppm. IR (KBr): ν˜ = 2251, 1509, 1456, 819, 761 cm .
+
+
TOF): calcd. for C27
H
19
N
5
Cl [M + H] 448.1329; found 448.1337.
HRMS (ESI-TOF): calcd. for C28
28.1894.
H
22
N
5
[M + H] 428.1875; found
4
(
2ЈS,4ЈS)-4Ј-(2-Bromophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6h): Primrose yellow (2ЈS,4ЈR)-4Ј-(3-Methoxyphenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
1
solid; m.p. 245–246 °C. H NMR (CDCl
3
): δ = 7.30–8.28 (m, 12 oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6n): Yellow solid;
1
H, ArH), 6.48–6.52 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.09–4.13 (m,
), 3.82–3.86 (m, 1 H, NCH
C NMR (CDCl ): δ = 158.0, 153.1, 143.0, 141.2, 140.4, 138.7,
34.5, 133.5, 132.2, 131.8, 130.5, 130.4, 130.1, 129.7, 129.4, 128.0,
26.8, 126.5, 122.7, 112.9, 112.2, 78.8, 57.7, 49.9, 47.9, 35.0 ppm.
IR (KBr): ν˜ = 2247, 1509, 1495, 754 cm . HRMS (ESI-TOF):
m.p. 190–191 °C. H NMR (CDCl
5.50–5.54 (dd, J = 7.0, 7.5 Hz, 1 H, CH), 4.01–4.03 (m, 1 H,
NCH ), 3.95–3.99 (m, 1 H, NCH ), 3.87 (s, 3 H, OCH ), 2.08 (s, 3
H, NCH ): δ = 160.0, 158.1, 153.1, 143.0,
3
): δ = 6.97–8.25 (m, 12 H, ArH),
1
H, NCH
2
2 3
), 2.12 (s, 3 H, NCH ) ppm.
1
3
3
2
2
3
1
3
1
1
3 3
) ppm. C NMR (CDCl
141.0, 140.7, 138.6, 135.9, 132.3, 131.7, 130.1, 129.6, 129.5, 126.8,
122.7, 121.1, 114.8, 114.5, 112.9, 112.7, 78.3, 55.9, 55.4, 51.2, 51.0,
–1
+
–1
calcd. for C27
2ЈS,4ЈS)-4Ј-(2,4-Dichlorophenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6i): Primrose yellow
H
19
N
5
Br [M + H] 492.0824; found 492.0812.
34.9 ppm. IR (KBr): ν˜ = 2246, 1635, 1508, 1492, 871, 762 cm .
22 5
H N
O [M + H]+ 444.1824;
HRMS (ESI-TOF): calcd. for C28
found 444.1843.
(
1
solid; m.p. 229–231 °C. H NMR ([D
1 H, ArH), 6.08–6.11 (dd, J = 6.0, 6.0 Hz, 1 H, CH), 4.02–4.06
m, 1 H, NCH ), 3.90–3.94 (m, 1 H, NCH ), 2.03 (s, 3 H, NCH
ppm. C NMR ([D ]DMSO): δ = 158.4, 153.2, 143.1, 141.1, 140.5,
6
]DMSO): δ = 7.69–8.27 (m,
(2ЈS,4ЈR)-4Ј-(3,4-Dimethoxyphenyl)-1Ј-methylspiro[indeno[1,2-b]-
1
quinoxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6o): Brown yel-
1
(
2
2
3
)
low solid; m.p. 200–201 °C. H NMR (CDCl
3
): δ = 6.95–8.20 (m,
13
6
11 H, ArH), 5.49–5.52 (dd, J = 8.0, 8.0 Hz, 1 H, CH), 3.99 (m, 1
H, NCH ), 3.97 (m, 1 H, NCH ), 3.96 (s, 3 H, OCH ), 3.93 (s, 3
H, OCH ), 2.08 (s, 3 H, NCH ) ppm. C NMR (CDCl ): δ =
1
1
3
38.7, 136.0, 135.3, 133.5, 133.2, 132.7, 132.5, 131.4, 130.6, 130.1,
29.9, 128.9, 127.1, 123.4, 113.4, 113.3, 79.1, 57.1, 50.5, 45.7,
5.3 ppm. IR (KBr): ν˜ = 2252, 1634, 1509, 1468, 827, 765 cm . 158.1, 153.1, 149.7, 149.2, 143.0, 141.0, 140.8, 138.6, 132.2, 131.7,
HRMS (ESI-TOF): calcd. for C27
found 482.0946.
2
2
3
1
3
3
3
3
–
1
+
H
18
N
5
Cl
2
[M + H] 482.0939; 130.8, 130.1, 129.6, 129.5, 126.7, 126.5, 122.7, 121.4, 113.0, 111.9,
111.3, 78.2, 56.1, 55.9, 51.5, 51.1, 34.9 ppm. IR (KBr): ν˜ = 2247,
–
1
1
636, 1520, 1464, 858, 761 cm . HRMS (ESI-TOF): calcd. for
(
2ЈS,4ЈR)-1Ј-Methyl-4Ј-(4-nitrophenyl)spiro[indeno[1,2-b]quin-
[M + H]+ 474.1930; found 474.1934.
29 24 5 2
C H N O
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6j): Yellow solid; m.p.
1
93–194 °C. 1H NMR (CDCl
3
): δ = 7.71–8.28 (m, 12 H, ArH),
(2ЈS,4ЈR)-4Ј-(Furan-2-yl)-1Ј-methylspiro[indeno[1,2-b]quinoxaline-
5
.64–5.67 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.06–4.10 (m, 1 H, 11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6p): Primrose yellow solid;
1
3
1
NCH
2
), 4.01–4.03 (m, 1 H, NCH
): δ = 157.8, 153.1, 148.5, 143.2, 141.9, 141.0, 140.2,
38.8, 132.5, 132.0, 131.1, 130.0, 129.8, 129.7, 126.7, 122.9, 112.4,
8.3, 55.9, 51.0, 50.7, 34.9 ppm. IR (KBr): ν˜ = 2250, 1637, 1523,
2
), 2.10 (s, 3 H, NCH
3
) ppm.
C
m.p. 195–196 °C. H NMR (CDCl
3
): δ = 6.48–8.19 (m, 11 H, ArH),
NMR (CDCl
3
5.64–5.67 (dd, J = 7.0, 7.0 Hz, 1 H, CH), 4.01–4.04 (m, 1 H,
1
3
1
7
1
NCH
2
), 3.91–3.95 (m, 1 H, NCH
2
), 2.06 (s, 3 H, NCH
3
) ppm.
C
NMR (CDCl
3
): δ = 158.1, 153.1, 148.7, 143.8, 143.2, 141.0, 140.5,
–1
465, 864, 775 cm . HRMS (ESI-TOF): calcd. for C27
H
19
N
6
O
2
138.7, 132.4, 131.8, 130.9, 130.1, 129.7, 129.6, 126.7, 122.8, 112.6,
[
M + H]+ 459.1569; found 459.1564.
112.5, 110.9, 109.7, 78.0, 54.2, 49.5, 45.4, 34.8 ppm. IR (KBr): ν˜ =
–
1
2
248, 1631, 1507, 1464, 859, 758 cm . HRMS (ESI-TOF): calcd.
(
2ЈS,4ЈR)-1Ј-Methyl-4Ј-phenylspiro[indeno[1,2-b]quinoxaline-11,2Ј-
for C25
18 5
H N
O [M + H]+ 404.1511; found 404.1520.
pyrrolidine]-3Ј,3Ј-dicarbonitrile (6k): Primrose yellow solid; m.p.
1
1
96–197 °C. H NMR ([D
6
]DMSO): δ = 7.46–8.30 (m, 13 H, ArH), Ethyl (2ЈS,3ЈR,4ЈR)-4Ј-(4-Chlorophenyl)-3Ј-cyano-1Ј-methylspiro-
5
.47–5.51 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.06–4.10 (m, 1 H, [indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7a): Yel-
1
3
1
NCH
2
), 3.92–3.96 (m, 1 H, NCH
]DMSO): δ = 158.4, 153.2, 143.0, 141.1, 141.0, 138.6,
35.1, 133.5, 133.1, 132.4, 131.1, 130.8, 127.0, 123.4, 113.8, 113.5,
8.7, 55.8, 52.0, 51.0, 35.4 ppm. IR (KBr): ν˜ = 2248, 1632, 1509,
2
), 2.08 (s, 3 H, NCH
3
) ppm.
C
low solid; m.p. 206–207 °C. H NMR (CDCl
12 H, ArH), 5.53–5.57 (dd, J = 6.0, 6.0 Hz, 1 H, CH), 4.02–4.06
(m, 1 H, NCH ), 3.81–3.85 (m, 1 H, NCH ), 3.56 (q, J = 7.2 Hz,
2 H, OCH CH ), 2.02 (s, 3 H, NCH ), 0.55 (t, J = 7.2 Hz, 3 H,
OCH CH ) ppm. C NMR (CDCl ): δ = 163.8, 158.9, 153.5,
143.4, 142.5, 141.0, 138.4, 136.2, 134.0, 132.1, 131.1, 130.8, 130.4,
3
): δ = 7.27–8.27 (m,
NMR ([D
6
1
7
1
2
2
2
3
3
–1
13
456, 863, 778, 689 cm . HRMS (ESI-TOF): calcd. for C27
H
20
N
5
2
3
3
[
M + H]+ 414.1719; found 414.1728.
1
4
30.2, 129.3, 129.2, 128.7, 126.8, 121.9, 116.5, 77.7, 63.1, 62.7, 58.2,
(
2ЈS,4ЈR)-4Ј-(4-Methoxyphenyl)-1Ј-methylspiro[indeno[1,2-b]quin-
6.7, 34.8, 13.2 ppm. IR (KBr): ν˜ = 2242, 1748, 1616, 1508, 835
oxaline-11,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6l): Primrose yellow
–
1
+
24 4 2
cm . HRMS (ESI-TOF): calcd. for C29H N O Cl [M + H]
1
solid; m.p. 231–232 °C. H NMR ([D
2 H, ArH), 5.42–5.45 (dd, J = 6.5, 7.0 Hz, 1 H, CH), 4.01–4.03
m, 1 H, NCH ), 3.88–3.91 (m, 1 H, NCH ), 3.79 (s, 3 H, OCH ),
.07 (s, 3 H, NCH
) ppm. 13C NMR ([D
6
]DMSO): δ = 7.05–8.31 (m,
495.1588; found 495.1568.
1
(
2
1
1
3
2
2
3
Ethyl
(2ЈS,3ЈR,4ЈR)-3Ј-Cyano-4Ј-(4-fluorophenyl)-1Ј-methylspiro-
3
6
]DMSO): δ = 160.3, 158.2, [indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7b): Yel-
1
52.9, 142.7, 140.8, 138.3, 133.2, 132.8, 132.1, 130.9, 130.6, 129.6,
26.7, 126.3, 123.1, 114.9, 113.6, 113.3, 78.3, 58.3, 55.7, 52.0, 50.3,
low solid; m.p. 190–191 °C. H NMR (CDCl
12 H, ArH), 5.54–5.57 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.01–4.05
), 3.81–3.84 (m, 1 H, NCH ), 3.55 (q, J = 7.0 Hz,
), 2.01 (s, 3 H, NCH ), 0.55 (t, J = 7.0 Hz, 3 H,
): δ = 163.9, 163.6, 161.6,
59.0, 153.6, 143.5, 142.5, 141.0, 138.5, 133.4, 132.1, 131.4, 131.3
3
): δ = 7.08–8.25 (m,
–1
5.1 ppm. IR (KBr): ν˜ = 2247, 1509, 1495, 754 cm . HRMS (ESI- (m, 1 H, NCH
2
2
+
TOF): calcd. for C28
H
22
N
5
O [M + H] 444.1824; found 444.1824.
2 H, OCH
2
CH
3
3
1
3
OCH CH ) ppm. C NMR (CDCl
2
3
3
(
1
2ЈS,4ЈR)-1Ј-Methyl-4Ј-(p-tolyl)spiro[indeno[1,2-b]quinoxaline-
1
1
6
1
1,2Ј-pyrrolidine]-3Ј,3Ј-dicarbonitrile (6m): Primrose yellow solid;
30.7, 130.3, 130.2, 129.2, 126.9, 121.9, 116.5, 115.4, 115.3, 77.8,
1
m.p. 208–209 °C. H NMR ([D
ArH), 5.42–5.46 (dd, J = 6.5, 7.0 Hz, 1 H, CH), 4.03–4.06 (m, 1
H, NCH ), 3.89–3.93 (m, 1 H, NCH ), 2.35 (s, 3 H, CH ), 2.03 (s,
H, NCH ]DMSO): δ = 158.5, 153.2, 143.0,
) ppm. 13C NMR ([D
6
]DMSO): δ = 7.32–8.32 (m, 12 H,
3.2, 62.6, 58.3, 46.6, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2237, 1747,
–
1
24 4 2
617, 1512, 842 cm . HRMS (ESI-TOF): calcd. for C29H N O F
2
2
3
M + H]+ 479.1883; found 479.1889.
[
3
1
1
3
6
41.1, 141.0, 139.4, 138.6, 133.4, 133.1, 132.3, 132.0, 131.1, 130.8,
30.4, 129.8, 129.4, 127.0, 123.4, 113.8, 113.5, 78.6, 55.8, 52.1, 50.8,
Ethyl (2ЈS,3ЈR,4ЈR)-4Ј-(4-Bromophenyl)-3Ј-cyano-1Ј-methylspiro-
[indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7c): Yel-
3488
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3482–3490

Spiro-Pyrrolidines by Five-Component Cycloaddition
1
low solid; m.p. 209–210 °C. H NMR (CDCl
1
3
): δ = 7.26–7.77 (m,
CH), 4.06–4.10 (m, 1 H, NCH
(q, J = 7.0 Hz, 2 H, OCH CH
), 3.55 (q, J = 7.0 Hz, 7.0 Hz, 3 H, OCH CH ) ppm. C NMR (CDCl
), 0.54 (t, J = 7.0 Hz, 3 H, 153.8, 143.1, 142.3, 141.0, 138.8, 135.7, 135.5, 131.8, 130.8, 130.4,
3
): δ = 163.8, 159.0, 153.6, 130.0, 129.5, 129.1, 127.1, 127.0, 122.1, 116.8, 62.9, 62.7, 58.8, 43.9,
2
), 3.72–3.75 (m, 1 H, NCH
), 2.01 (s, 3 H, NCH ), 0.61 (t, J =
): δ = 163.9, 160.0,
2
), 3.61
2 H, ArH), 5.51–5.54 (dd, J = 6.5, 6.0 Hz, 1 H, CH), 4.00–4.05
m, 1 H, NCH ), 3.79–3.83 (m, 1 H, NCH
), 2.01 (s, 3 H, NCH
) ppm. 13C NMR (CDCl
43.5, 142.6, 141.0, 138.5, 136.8, 132.0, 131.6, 131.4, 130.7, 130.3,
30.1, 129.2, 126.9, 122.2, 121.9, 116.4, 110.0, 77.8, 63.1, 62.6, 58.2,
6.8, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2243, 1748, 1634, 1508, 832
cm . HRMS (ESI-TOF): calcd. for C29
2
3
3
1
3
(
2
2
2
3
3
2
H, OCH
CH
2
CH
3
3
OCH
2
3
–
1
1
1
4
34.4, 13.0 ppm. IR (KBr): ν˜ = 2241, 1744, 1618, 1510, 759 cm .
24 4 2
H N O
Cl [M + H]+ 495.1588;
HRMS (ESI-TOF): calcd. for C29
found 495.1594.
–1
Br [M + H]+
H
24
N
4
O
2
Ethyl
(2ЈS,3ЈR,4ЈR)-3Ј-Cyano-1Ј-methyl-4Ј-(4-nitrophenyl)spiro-
539.1083; found 539.1074.
[
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7i): Yel-
1
Ethyl
[
(2ЈS,3ЈR,4ЈR)-3Ј-Cyano-4Ј-(3-fluorophenyl)-1Ј-methylspiro- low solid; m.p. 204–205 °C. H NMR (CDCl
12 H, ArH), 5.65–5.68 (dd, J = 6.0, 6.0 Hz, 1 H, CH), 4.09–4.13
(m, 1 H, NCH ), 3.84–3.87 (m, 1 H, NCH ), 3.56 (q, J = 7.0 Hz,
2 H, OCH CH ), 2.03 (s, 3 H, NCH ), 0.54 (t, J = 7.0 Hz, 3 H,
), 3.56 (q, J = 7.0 Hz, OCH CH ) ppm. C NMR (CDCl ): δ = 163.7, 158.7, 153.6,
), 0.54 (t, J = 7.0 Hz, 3 H, 147.8, 145.6, 143.1, 142.6, 140.9, 138.6, 132.2, 130.9, 130.8, 130.5,
): δ = 163.8, 161.8, 159.0, 130.1, 129.4, 129.3, 126.8, 126.5, 123.6, 122.0, 116.2, 77.7, 63.0,
53.5, 143.4, 142.5, 140.9, 140.3, 138.5, 132.0, 130.7, 130.3, 130.1, 62.9, 58.1, 46.9, 38.4, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2246, 1748,
3
): δ = 7.27–8.27 (m,
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7d): Yel-
1
low solid; m.p. 164–165 °C H NMR (CDCl
2 H, ArH), 5.54–5.57 (dd, J = 6.5, 6.0 Hz, 1 H, CH), 4.03–4.07
m, 1 H, NCH ), 3.83–3.86 (m, 1 H, NCH
), 2.01 (s, 3 H, NCH
) ppm. 13C NMR (CDCl
3
): δ = 7.03–8.18 (m,
2
2
1
2
3
3
1
3
(
2
2
2
3
3
2
H, OCH
CH
2
CH
3
3
OCH
2
3
3
1
1
7
1
–
1
29.9, 129.2, 126.9, 125.2, 121.9, 116.9, 116.7, 116.3, 115.0, 114.9,
7.8, 63.1, 62.7, 58.0, 46.9, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2245,
747, 1616, 1512, 864, 720 cm . HRMS (ESI-TOF): calcd. for
1601, 1519, 855 cm . HRMS (ESI-TOF): calcd. for C29
24 5 4
H N O
[M + H]+ 506.1828; found 506.1839.
–1
Ethyl (2ЈS,3ЈR,4ЈR)-3Ј-Cyano-1Ј-methyl-4Ј-phenylspiro[indeno[1,2-
+
C
29
H
24
N
4
O
2
F [M + H] 479.1883; found 479.1881.
Ethyl (2ЈS,3ЈR,4ЈR)-4Ј-(3-Bromophenyl)-3Ј-cyano-1Ј-methylspiro-
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7e): Yel-
b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7j): Yellow solid;
1
m.p. 179–180 °C. H NMR (CDCl
3
): δ = 7.37–8.17 (m, 13 H, ArH),
[
5.59–5.63 (dd, J = 6.4, 6.4 Hz, 1 H, CH), 4.06–4.10 (m, 1 H,
NCH ), 3.92–3.95 (m, 1 H, NCH ), 3.59 (q, J = 7.0 Hz, 2 H,
), 0.59 (t, J = 7.0 Hz, 3 H,
) ppm. C NMR (CDCl ): δ = 163.9, 159.1, 153.5,
1
low solid; m.p. 184–185 °C H NMR (CDCl
2 H, ArH), 5.51–5.54 (dd, J = 6.0, 6.5 Hz, 1 H, CH), 4.02–4.06
m, 1 H, NCH ), 3.82–3.85 (m, 1 H, NCH ), 3.58 (q, J = 7.0 Hz, OCH
), 2.02 (s, 3 H, NCH
) ppm. 13C NMR (CDCl
43.3, 142.5, 140.9, 140.1,138.5, 133.0, 132.0, 131.1, 130.7, 130.3,
3
): δ = 7.27–8.13 (m,
2
2
1
OCH
2
CH
3
), 2.07 (s, 3 H, NCH
3
1
3
(
2
2
2
CH
3
3
2
H, OCH
CH
2
CH
3
3
), 0.57 (t, J = 7.0 Hz, 3 H, 143.5, 142.4, 140.9, 138.4, 137.5, 132.0, 130.6, 130.2, 130.1, 129.6,
): δ = 163.8, 159.0, 153.5, 129.2, 129.1, 128.4, 128.0, 126.9, 121.8, 116.5, 77.8, 63.3, 62.5, 58.1,
47.2, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2244, 1747, 1617, 1509, 774,
OCH
2
3
3
1
1
6
1
–
1
+
30.1, 130.0, 129.2, 129.1, 128.1, 126.9, 122.4, 121.9, 116.3, 77.7,
704 cm . HRMS (ESI-TOF): calcd. for C29
461.1978; found 461.1984.
25 4 2
H N O [M + H]
3.1, 62.7, 58.1, 46.9, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2245, 1739,
–
1
617, 1509, 795, 703 cm . HRMS (ESI-TOF): calcd. for
Ethyl (2ЈS,3ЈR,4ЈR)-3Ј-Cyano-1Ј-methyl-4Ј-(p-tolyl)spiro[indeno[1,2-
+
C
29
H
24
N
4
O
2
Br [M + H] 539.1083; found 539.1072.
Ethyl (2ЈS,3ЈR,4ЈR)-4Ј-(3-Chlorophenyl)-3Ј-cyano-1Ј-methylspiro-
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7f): Yel-
b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7k): Yellow solid;
1
m.p. 194–195 °C. H NMR (CDCl
3
): δ = 7.22–8.11 (m, 12 H, ArH),
[
5.52–5.55 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 3.99–4.03 (m, 1 H,
NCH ), 3.86–3.89 (m, 1 H, NCH ), 3.55 (q, J = 7.5 Hz, 2 H,
OCH CH ), 2.37 (s, 3 H, ArCH ), 2.02 (s, 3 H, NCH ), 0.54 (t, J
), 3.56 (q, J = 7.0 Hz, = 7.5 Hz, 3 H, OCH CH ) ppm. C NMR (CDCl ): δ = 164.0,
), 0.55 (t, J = 7.0 Hz, 3 H, 159.2, 153.5, 143.6, 142.4, 141.0, 138.4, 137.6, 134.4, 131.9, 130.6,
): δ = 163.8, 159.0, 153.6, 130.2, 129.5, 129.1, 126.9, 121.8, 116.6, 77.8, 63.4, 62.4, 58.2, 47.0,
43.4, 142.5, 141.0, 139.9, 138.5, 134.2, 132.1, 130.8, 130.4, 130.1, 34.7, 21.1, 13.1 ppm. IR (KBr): ν˜ = 2243, 1750, 1616, 1508, 826
1
low solid; m.p. 180–181 °C. H NMR (CDCl
2 H, ArH), 5.50–5.54 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 4.02–4.06
m, 1 H, NCH ), 3.82–3.85 (m, 1 H, NCH
), 2.01 (s, 3 H, NCH
) ppm. 13C NMR (CDCl
3
): δ = 7.26–8.27 (m,
2
2
1
2
3
3
3
1
3
(
2
2
2
3
3
2
H, OCH
CH
2
CH
3
3
OCH
2
3
3
1
1
6
1
–
1
+
29.7, 129.3, 129.2, 128.3, 127.7, 126.9, 121.9, 116.3, 77.8, 63.1,
2.7, 58.1, 46.9, 34.7, 13.1 ppm. IR (KBr): ν˜ = 2244, 1739, 1617,
cm . HRMS (ESI-TOF): calcd. for C30
475.2134; found 475.2137.
27 4 2
H N O [M + H]
–1
509, 796, 708 cm . HRMS (ESI-TOF): calcd. for C29
H
24
N
4
O
2
Cl
Ethyl (2ЈS,3ЈR,4ЈR)-3Ј-Cyano-4Ј-(4-methoxyphenyl)-1Ј-methylspi-
[
M + H]+ 495.1588; found 495.1596.
ro[indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate
(7l):
1
Ethyl
(2ЈS,3ЈR,4ЈS)-3Ј-Cyano-4Ј-(2-fluorophenyl)-1Ј-methylspiro- Yellow solid; m.p. 175–176 °C. H NMR (CDCl
3
): δ = 6.94–8.17
[
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate(7 g): Yel-
(m, 12 H, ArH), 5.51–5.55 (dd, J = 6.5, 6.5 Hz, 1 H, CH), 3.98–
4.02 (m, 1 H, NCH ), 3.84–3.87 (m, 1 H, NCH ), 3.82 (s, 3 H,
OCH ), 3.55 (q, J = 7.0 Hz, 2 H, OCH CH ), 2.02 (s, 3 H, NCH ),
), 3.60 (q, J = 7.0 Hz, 0.54 (t, J = 7.0 Hz, 3 H, OCH CH ) ppm. C NMR (CDCl ): δ =
), 0.59 (t, J = 7.0 Hz, 3 H, 164.1, 159.4, 159.2, 153.6, 143.7, 142.5, 141.0, 138.4, 132.0, 130.8,
): δ = 163.9, 162.6, 160.6, 130.7, 130.3, 130.2, 129.4, 129.2, 126.9, 121.9, 116.7, 113.9, 77.9,
59.6, 153.7, 143.2, 142.4, 141.0, 138.7, 131.9, 130.8, 130.1, 129.7, 63.5, 62.5, 58.3, 55.3, 46.8, 34.7, 13.2 ppm. IR (KBr): ν˜ = 2241,
1
low solid; m.p. 173–174 °C H NMR (CDCl
2 H, ArH), 5.83–5.86 (dd, J = 6.0, 6.0 Hz, 1 H, CH), 4.03–4.08
m, 1 H, NCH ), 3.83–3.87 (m, 1 H, NCH
), 2.01 (s, 3 H, NCH
) ppm. 13C NMR (CDCl
3
): δ = 7.08–8.28 (m,
2
2
1
(
2
3
2
3
3
1
3
2
2
2
3
3
H, OCH
CH
2
CH
3
3
OCH
2
3
3
1
1
6
1
–
1
29.6, 129.2, 126.9, 124.8, 124.7, 124.3, 122.0, 116.6, 115.6, 115.4,
1749, 1614, 1514, 1253, 831 cm . HRMS (ESI-TOF): calcd. for
2.8, 62.6, 57.7, 40.9, 34.5, 13.0 ppm. IR (KBr): ν˜ = 2245, 1744,
30 27 4 3
C H N O
[M + H]+ 491.2083; found 491.2091.
–1
24 4 2
617, 1509, 760 cm . HRMS (ESI-TOF): calcd. for C29H N O F
Ethyl (2ЈS,3ЈR,4ЈR)-3Ј-Cyano-4Ј-(furan-2-yl)-1Ј-methylspiro[indeno-
1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate (7m): Brown
[
M + H]+ 479.1883; found 479.1894.
[
1
Ethyl
[
(2ЈS,3ЈR,4ЈS)-4Ј-(2-Chlorophenyl)-3Ј-cyano-1Ј-methylspiro-
yellow solid; m.p. 188–189 °C. H NMR (CDCl
(m, 11 H, ArH), 5.65–5.68 (dd, J = 7.0, 7.5 Hz, 1 H, CH), 3.99–
4.02 (m, 1 H, NCH ), 3.92–3.96 (m, 1 H, NCH ), 3.63 (q, J =
7.0 Hz, 2 H, OCH CH ), 2.01 (s, 3 H, NCH ), 0.58 (t, J = 7.0 Hz,
3
): δ = 6.42–8.24
indeno[1,2-b]quinoxaline-11,2Ј-pyrrolidine]-3Ј-carboxylate
(7h):
): δ =
1
Primrose yellow solid; m.p. 171–172 °C. H NMR (CDCl
7
3
2
2
.25–8.26 (m, 12 H, ArH), 6.19–6.22 (dd, J = 6.5, 6.5 Hz, 1 H,
2
3
3
Eur. J. Org. Chem. 2011, 3482–3490
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3489

M. Li, F.-M. Gong, L.-R. Wen, Z.-R. Li
FULL PAPER
3
1
1
3
H, OCH
2
CH
3
) ppm. 13C NMR (CDCl
3
): δ = 163.6, 158.9, 153.4,
h) Y. Ban, N. Taga, T. Oishi, Chem. Pharm. Bull. 1976, 24,
736–751.
51.1, 143.1, 142.7, 142.5, 140.9, 138.4, 132.1, 130.8, 130.3, 130.1,
29.2, 129.1, 126.8, 121.9, 116.3, 110.6, 108.7, 62.7, 61.7, 55.2, 42.1,
4.6, 13.2 ppm. IR (KBr): ν˜ = 2242, 1748, 1616, 1508, 775 cm .
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Received: March 3, 2011
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3490
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3482–3490