A facile synthesis of novel ferrocene grafted spiro-indenoquinoxaline pyrrolizidines via one-pot multicomponent [3+2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2012.09.104

A facile one-pot synthesis of novel ferrocene grafted spiro- indenoquinoxaline pyrrolizidines via multicomponent-[3+2]-cycloaddition of azomethine ylides is described. The methodology is very simple and applicable to a wide variety of ferrocene derived di

Full text of DOI:10.1016/j.tetlet.2012.09.104

Tetrahedron Letters 53 (2012) 6676–6681
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Tetrahedron Letters
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A facile synthesis of novel ferrocene grafted spiro-indenoquinoxaline
pyrrolizidines via one-pot multicomponent [3+2] cycloaddition of
azomethine ylides
⇑
A. R. Suresh Babu, D. Gavaskar, R. Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2012
Revised 21 September 2012
Accepted 23 September 2012
Available online 2 October 2012
A facile one-pot synthesis of novel ferrocene grafted spiro-indenoquinoxaline pyrrolizidines via multi-
component-[3+2]-cycloaddition of azomethine ylides is described. The methodology is very simple and
applicable to a wide variety of ferrocene derived dipolarophiles. The structures of cycloadducts were
confirmed by spectroscopic analysis. X-ray analysis of one of the analogs, adds conclusive support to
the proposed structures.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ferrocene
1,2-Phenylenediammine
Azomethine ylide
Cycloaddition
Spiro-indenoquinoxaline
Pyrrolizidines
Synthesis of novel pharmacological agents with minimum num-
ber of steps and less time is a major challenge for chemists.1 In
general; the conventional approach involves the use of multistep
reaction sequences which are typically associated with low yields,
high cost, and tedious isolation and purification of the resulting
products. However, multicomponent reactions (MCRs) offer a valu-
able solution for such a situation2,3 and they constitute a highly
effective one pot procedure that has many advantages including
atom economy and convenience in the construction of new bonds
in a single step, paving way for the synthesis of complex heterocy-
clic compounds.4
Ferrocene derivatives remain at the forefront of attention offer-
ing advantage over other organometallics due to their synthetic
versatility, thermal and photochemical stability, and biological
activity. Hence, there has been a renewed interest in the synthesis
of ferrocene based heterocycles with potential applications.
The intermolecular [3+2]-cycloaddition reactions of azomethine
ylides with olefinic and acetylenic dipolarophiles represent an
important approach for the formation of azaheterocycles such as
pyrrolidines and pyrrolizidines prevalent in a variety of biologi-
cally active compounds.5–7 Indenoquinoxaline derivatives are
important classes of nitrogen containing heterocycles which con-
stitute useful intermediates in the organic synthesis.8 In the recent
years, construction of spiro compounds by intermolecular [3+2]-
cycloaddition reactions of azomethine ylides has been well devel-
oped and the reactions proceed with high regioselectivity.9,10
Hence, with renewed interest in such complex ferrocene appended
heterocycles and in continuation of our research in the area of
1,3-dipolar cycloaddition,11–14 we herein report for the first time,
a mild, expeditious, and a facile four-component, one-pot synthesis
of novel ferrocene grafted monospiro-indenoquinoxaline pyrrolizi-
dines through 1,3-dipolar cycloaddition of azomethine ylide gener-
ated from 1,2-phenylenediamine, ninhydrin, and L-proline with
various unusual ferrocene derived dipolarophiles. Some of the
properties of ferrocene derived dipolarophiles are mentioned in
Table 1.
Initially, the four-component reaction of ninhydrin 2, 1,2-phen-
ylenediammine 3, L-proline 4, and ferrocene derived dipolarophile
1a was investigated (Scheme 1).
The one-pot four-component reaction proceeded well in meth-
anol as a solvent at reflux temperature to give ferrocene grafted
spiro-indenoquinoxaline pyrrolizidine as the only product which
was characterized on the basis of spectroscopic data. Thus, the IR
spectrum of spiro[2.110]indeno[1,2-b]quinoxaline-3-ferrocenoyl-
4-(p-methoxylphenyl)-pyrrolizidine 5a showed absorption at
1660 cmꢀ1 indicating the presence of a carbonyl group. In 1H
NMR spectrum of the product 5a the characteristic multiplets of
pyrrolizidine ring appeared at
d 1.72–2.78. Additionally, the
pyrrolizidine ring proton attached to the p-methoxylphenyl ring
0
appeared as a triplet at d 4.10 (H1 , J = 10.5 Hz). The pyrrolizi-
dine–NCH proton appeared as a doublet of triplet at d 4.53
⇑
Corresponding author. Tel.: +91 44 22202811; fax: +91 44 22300488.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.104

A. R. Suresh Babu et al. / Tetrahedron Letters 53 (2012) 6676–6681
6677
Table 1
Physical properties and chemical yield of the ferrocene derived dipolarophile 1a–c/10a–b/12/14/16 and their [3+2]-cycloaddition product with 1,2-phenylenediammine 2,
ninhydrin 3, and L-proline 4
D
Color
(solid)
Mp (°C)
Y (%)
B[26]
IR KBr
(C@O)
(cmꢀ1
P
R
X
Color
(solid)
Mp (°C)
Methanol/
reflux
T (h) Y (%)
Toluene/
reflux
T (h) Y (%)
IR KBr
(C@O)
(cmꢀ1
c
c
A
B[26]
A
)
)
1a
1b
1c
10a
10b
12
Red
Red
Red
Red
Red
Red–brown
Red
148–149
190–191
142–143
153
144–145
153
149
192
141
152
54
90
62
90
84
92
62
90
53
92
63
92
83
90
57
93
1646
5a
5b
5c
11a
11b
13
OMe
NO2
H
—
—
—
—
—
—
—
—
O
S
—
—
—
Pale Orange
Pale Orange
Pale Orange
Pale Yellow
Pale Orange
Pale brown
Pale Orange
Pale yellow
118–120
145–146
134–136
152–154
138–139
145–146
196–198
116–118
3.6
3.0
4.0
5.4
4.0
4.2
5.5
5.4
78
86
80
82
80
90
83
88
6.5
5.0
6.0
—
—
—
40
48
45
—
—
—
1660
1658
1650
1652
1642
1658
1643
1668
1664
1668
1656
1674
1664
146
152–153
211–213
167–170
14
16
212
168–169
15
17
—
—
—
—
Blue
1712, 1718
1728, 1734
D = dipolarophile; Y (%) = Yield in percentage; A = obtained; B = reported; mp = melting point; P = product; T (h) = time in hour.
R
O
O
Fe
H
NH2
NH2
OH
OH
H
N
H
Fe
MeOH
Reflux
H
COOH
N
H
H
O
O
N
R
N
3
2
1a-c
5a-c
R = OMe, NO2, H
Scheme 1. Synthesis of ferrocene grafted spiro-indenoquinoxaline-pyrrolizidine 5.
0
0
(H7 a, J = 9.9, 6.3 Hz,) whereas the pyrrolizidine proton attached to
and H2 . The formation of the regioisomer 6 was not observed
due to the unfavorable transition states (TS3 and TS4) as depicted
in Figs. 2 and 3.
the ferrocenoyl moiety is more deshielded and exhibited a doublet
0
at d 4.67 (H2 , J = 11.1 Hz). The ferrocenyl protons exhibited triplet
at d 3.25 (J = 1.2 Hz), singlet at d 3.44, doublet at d 3.60 (J = 1.2 Hz),
multiplet at d 3.99–4.01, and triplet at d 4.31 (J = 1.2 Hz). The meth-
oxy group attached to the phenyl ring exhibited a singlet at d 3.68.
The aromatic protons appeared as a multiplet in the region d 6.87–
8.32.
These observations are also consistent and supportive with the
X-ray crystal structure of a series of diverse ferrocene appended
spiro-oxindolo-pyrrolizidines and dispiro-indenoquinoxaline-
pyrrolidines reported recently by us.18 Encouraged by the results
obtained by using the dipolarophile 1a, we extended the one-pot
four-component reaction involving other ferrocene derived dipol-
arophiles (1b–c, 10a–b, 12, 14, and 16)19a–c with ninhydrin 2,
The off resonance decoupled 13C NMR spectra of 5a exhibited
characteristic peaks for the spiro carbon and carbonyl group at-
tached to the ferrocene moiety at 76.55 and 197.81 ppm respec-
tively and the signals for all other carbons are located at
appropriate chemical shifts in agreement with the proposed struc-
ture. The formation of the product was confirmed by mass spectral
and elemental analyses. The mass spectrum of 5a showed a peak at
m/z 493 (M+).
1,2-phenylenediammine 3, and L-proline 4 under optimized condi-
tions in refluxing methanol to afford a series of novel ferrocene
grafted mono-spiro-indenoquinoxaline-pyrrolizidines (5b–c, 11a–
b, 13, 15, and 17) in good yields (78–90%) (Table 1). Their struc-
tures were confirmed through spectral analysis.
In order to improve the yield of the product, the one-pot four-
component reaction was also carried out in toluene for the dipol-
arophiles 1a–c and it was found that even under refluxing
condition, there was no improvement in the isolated yield of the
cycloadducts. This is attributed to the poor solubility of reactant
The formation of the ferrocene grafted spiro-indeno[1,2-b]quin-
oxaline-11,30-pyrrolizidine scaffold probably involves a complex
multistep sequence of events. The multicomponent reaction pro-
ceeds through cyclocondensation of ninhydrin 2 and phenylenedi-
amine 3 to give indenoquinoxline-11-one 7,15 which further
in toluene specially the amino acid, L-proline 4 which is responsi-
condensed with
L
-proline 4 to produce 1,3-dipole, azomethine
ble for the formation of azomethine ylide with indenoquinoxa-
line-11-one 8. Hence, methanol was invariably, chosen as a
solvent for conducting the reaction with other dipolarophiles
10a–b, 12, 14, and 16.
ylide 9 by thermal decarboxylation of 816 (Fig. 1).
The 1,3-dipole 9 subsequently undergoes cycloaddition reaction
with chalcone 1, to give the product 5. In TS 1, R substituted phenyl
ring gets sufficiently away from the indenoquinoxaline structure,
therefore TS1 has lower steric hindrance compared to TS2 in which
the R substituted phenyl ring is close to proline moiety. Conse-
quently, the reaction proceeds via exo-transition state (TS1) (Figs. 2
and 3).
Schemes 2–4 depict the reaction of 1-ferrocenyl-3-furyl-
prop-2-ene-1-one
10a/1-ferrocenyl-3-thienyl-prop-2-ene-1-one
10b/1-ferrocenyl-3-pyridyl-prop-2-ene-1-one 12 and 1,3-diferroce-
nyl-prop-2-ene-1-one 14 with ninhydrin 2, 1,2-phenylenediammine
3, and L-proline 4 under optimized conditions in refluxing methanol
Stereochemical assignments of the cycloadduct 5a were made
on the basis of NOE studies and comparison with previously re-
ported values in similar systems.17 The possibility of the formation
leading to the formation of ferrocene substituted spiro-indenoqui-
noxaline-pyrrolizidines 11a, 11b, 13, and 15 as evidenced by TLC
and spectral analysis. All the newly synthesized cylcoadducts were
obtained in good yields (Table 1).
To further expand the scope of this one-pot four-component
1,3-dipolar cycloaddition reaction, we successfully accomplished
the synthesis of ferrocene grafted dispiro-indenoquinoxaline
of other isomer, via TS2, was ruled out by 1H NOESY studies.
0
For example irradiation of H1 at d = 4.10 (J = 10.5 Hz) caused no
0
0
considerable enhancement of H2 and H7 a at d 4.67 and 4.53
0
0
respectively, supporting the trans-arrangement of H1 with H7 a

6678
A. R. Suresh Babu et al. / Tetrahedron Letters 53 (2012) 6676–6681
O
7
O
O
O
N
OH
OH
NH2
NH2
CH3OH, Reflux
-2H2O
-H2O
H2O
O
N
O
3
2
COOH
4
N
H
O
O
O
O
N
O-
N
OH
H2O
N
OH
HO
-H+
N
O-
-H2O
-O
H
N
N
N
N
N
N
N
N
O
-CO2
N
N
O
N
N
N
N
8
9
Figure 1. Mechanism for the formation of azomethine ylide 9 from ninhydrin 2, 1,2-phenylenediammine 3, and L-proline 4.
OMe
Fe
OMe
OMe
Fe
7aH'
H1'
H2'
H
O
H
H
7'
5' N
3'
O
O
H
N
N
N
H
N
Fe
1a
N
N
5a
OMe
Transition State TS1
N
MeO
MeO
N
Fe
O
H
9
H
Fe
7aH'
H1'
O
H
H
H2'
N
7'
N
5' N
N
3'
Fe
O
N
N
Transition State TS2
5a'
Figure 2. The proposed mechanism for one-pot four-component synthesis of ferrocene grafted spiro-indenoquinoxaline-pyrrolizidine 5.
pyrrolizidine 17 by the reaction of 2-ferrocenylmethylidene-
1,3-indanedione 16,19d ninhydrin 2, 1,2-phenylenediammine 3,
and L-proline 4 under optimized reaction condition (Scheme 5).
The cycloadduct was obtained in good yield and was confirmed
by spectral analysis.
deduced on the basis of 1H NOESY. Irradiation of pyrrolizidine ring
proton attached directly to the ferrocene moiety at d 5.02 did not
cause any enhancement of the signal for the pyrrolizidine–NCH
proton which appeared as a multiplet at d 4.62–4.66 supporting
the mutual trans-arrangement of the pyrrolizidine ring proton
attached to the ferrocene moiety and the pyrrolizidine–NCH
proton.
The IR spectrum of 17 showed peaks at 1728 and 1734 cmꢀ1
due to the indanedione ring carbonyls. In the 1H NMR spectrum
of 17, the pyrrolizidine ring proton attached directly to the
ferrocene moiety appeared as a doublet at d 5.02 (J = 10.2 Hz)
which clearly showed the regiochemistry of the cycloaddition
reaction. If the other regioisomer 18 had formed, then the 1H
NMR spectrum would have shown a singlet for the pyrrolizidine
ring proton attached directly to the ferrocene moiety and this is
not observed. The stereochemistry of the cycloadducts 17 was
The signals in the 13C NMR spectrum of 17 at 74.14 and
75.67 ppm correspond to the two spiro carbons. The indanedione
ring carbonyls resonated at 188.43 and 189.50 ppm, respectively.
Moreover, the presence of a molecular ion peak at m/z 626 (M+)
in the mass spectrum of 17 confirmed the structure of the cycload-
duct. The formation of indenoquinoxaline-11-one and regio- and
stereochemical outcome of the cycloaddition reaction was unam-

A. R. Suresh Babu et al. / Tetrahedron Letters 53 (2012) 6676–6681
6679
MeO
O
Fe
7aH'
H1'
O
H
Fe
H
7'
H2'
OMe
5' N 3'
Fe
O
N
H
H
N
N
H
N
N
N
MeO
6a
1a
Transition State TS3
N
Fe
N
Fe
H
O
Fe
H
9
7aH'
O
H
O
H1'
H2'
7'
OMe
H
OMe
5' N
H
N
3'
N
N
OMe
N
N
Transition State TS4
6a'
Figure 3. The proposed mechanism for the non-formation of regioisomer 6a and 6a0 due to unfavourable transition states TS3 and TS4.
O
O
X
H
H
Fe
H
NH2
NH2
OH
OH
Fe
MeOH
Reflux
COOH
N
H
H
X
N
O
O
N
N
10a-b
3
2
X = O, S
11a-b
Scheme 2. Synthesis of ferrocene grafted spiro-indenoquinoxaline furyl/thienyl pyrrolizidines 11.
N
O
O
Fe
H
NH2
NH2
OH
OH
H
N
H
Fe
MeOH
Reflux
H
COOH
N
H
H
O
O
N
N
N
12
3
2
13
Scheme 3. Synthesis of ferrocene grafted spiro-indenoquinoxaline pyridyl pyrrolizidine 13.
Fe
O
H
NH2
NH2
H
OH
OH
Fe
H
H
H
MeOH
Reflux
Fe
COOH
N
H
O
N
O
Fe
O
N
N
3
2
14
15
Scheme 4. Synthesis of ferrocene grafted spiro-indenoquinoxaline ferrocenyl pyrrolizidine 15.
biguously ascertained by a single crystal X-ray analysis of one of
the pyrrolizidine analogs in the spiro-indanedione-indenoquinoxa-
line series obtained by the reaction of 2-benzylidene-1,3-indanedi-
In conclusion, we have synthesized
a
series of hitherto
unknown novel ferrocene grafted spiro-indenoquinoxaline pyrro-
lizidines via a facile one-pot four-component cycloaddition reac-
tion.21 The compounds synthesized carry a diverse substitution
one with ninhydrin 2, 1,2-phenylenediammine 3, and L
-proline 4.20

6680
A. R. Suresh Babu et al. / Tetrahedron Letters 53 (2012) 6676–6681
Sons: New York, 2002; p 169.; (c) Gothelf, K. V. Cycloaddition Reactions in
O
O
O
Organic Synthesis; Kobaya-shi, S., Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; Chapter 6, p 211.; (e) Shanmugam, P.; Viswambharan, B.;
Madhavan, S. Org. Lett. 2007, 9, 4095.
H
NH2
NH2
OH
OH
COOH
N
H
11. SureshBabu, A. R.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 4487.
12. Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett. 2009, 50, 2818.
13. Suresh Babu, A. R.; Raghunathan, R. Synth. Commun. 2009, 39, 2889.
14. Suresh Babu, A. R.; Raghunathan, R. Synth. Commun. 2010, 40, 2311.
15. (a) Posner, G. H. Chem. Rev. 1986, 86, 23; (b) Azizian, J.; Mohammaddizadeh, M.
R.; Karimi, N.; Kazemizadeh, Z.; Mohammadi, A. A.; Karimi, A. Heteroat. Chem.
2005, 16, 549; (c) Son, J. K.; Park, J. G.; Jahng, Y. D. Heterocycl. Commun. 2003, 9,
621; (d) Azizian, J.; Mohammaddizadeh, M. R.; Zomorodbakhsh, S.;
Mohammadi, A. A.; Karimi, A. R. Arkivoc 2007, 1, 24.
O
Fe
4
3
16
2
MeOH
Reflux
16. (a) Broggini, G.; Zecchi, G. Synthesis 1999, 905; (b) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272; (c) Azizian, J.; Karimi, A. R.; Kazemizadeh,
Z.; Mohammadi, A. A.; Mohammaddizadeh, M. R. Tetrahedron Lett. 2005, 46,
6155; (d) Azizian, J.; Karimi, A. R.; Kazemizadeh, Z.; Mohammadi, A. A.;
Mohammaddizadeh, M. R. Synthesis 2004, 14, 2263; (e) Suresh Babu, A. R.;
Raghunathan, R. Synth. Commun. 2009, 39, 347.
17. (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817; (b) Coulter, T.; Grigg,
R.; Malone, J. F.; Sridharan, V. Tetrahedron Lett. 1991, 32, 5417; (c) Grigg, R.;
Idle, J.; Mc Meekin, M.; Surendrakumar, S.; Vinod, D. J. Chem. Soc., Perkin Trans.
1 1988, 2693.; (d) Grigg, R.; Idle, J.; Mc Meekin, M.; Surendrakumar, S.; Vinod,
D. J. Chem. Soc., Perkin Trans. 1 1988, 2703.
O
Fe
H
O
H
H
O
N
H
N
N
Fe
O
N
N
18. (a) A complete data of our report on the crystal structure of two analogs in
N
ferrocene appended spiro-oxindolopyrrolizidine namely Spiro-[2.30]-50,70-
18
Spiro-[2.30]-
17
dibromooxindole-3-ferrocenoyl-4-furyl-pyrrolizidine
and
oxindole-3-(p-methoxybenzoyl)-4-ferrocenyl-pyrrolizidine can be obtained
from the Cambridge Crystallographic Data Centre with the deposition
Scheme 5. Synthesis of ferrocene grafted dispiro-indenoquinoxaline indane-1,3-
dione pyrrolizidine 17.
number
CCDC
6756597
and
CCDC
29236.
Data
acquisition:
deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk/deposit; (b) Suresh
Babu, A. R.; Raghunathan, R. Synth. Commun. 2008, 38, 1433; (c) Suresh Babu,
A. R.; Raghunathan, R. Synth. Commun. 2009, 39, 347.
19. (a) Vilemin, D.; Martin, B.; Puciova, M.; Toma, S. J. Organomet. Chem. 1994, 484,
27; (b) Ji, S. J.; Shen, Z. L.; Wang, S. Y. Chin. Chem. Lett. 2003, 14, 663; (c)
Mendez, D. I.; Klimova, E.; Klimova, T.; Fernando, L.; Hernandez, S. O.; Marinez,
M. G. J. Organomet. Chem. 2003, 679, 10; (d) Stankovic, E.; Elecko, P.; Toma, S.
Chem. Pap. 1996, 50, 68.
20. Gayathri, D.; Aravindan, P. G.; Velmurugan, D.; Ravikumar, K.; Suresh Babu, A.
R. Acta Cryst. 2005, E61, o3124.
21. General procedure for the synthesis of ferrocene based spiro-indenoquinoxaline
pyrrolizidines: A mixture of ninhydrin 2 (1 mmol) and 1,2-phenylenediamine 3
(1 mmol) was stirred for 10 min in 10 mL of methanol followed by the addition
pattern by choice. This method offers several advantages including
its simplicity with a one-pot four-component approach, mild reac-
tion conditions, easy workup, affording the desired products from
readily and cheaply available starting materials in a single step.
This method is general and is applicable to a variety of unusual
ferrocene derived dipolarophiles to synthesize such complex
highly substituted pyrrolizidines containing ferrocene and spiro-
indenoquinoxaline moiety of biological significance.
of L-proline 4 (1 mmol). To this mixture, a solution of dipolarophile 1a
(1 mmol) in 10 ml of methanol was added. The mixture was then refluxed until
completion of the reaction as evidenced by TLC. The solvent was removed
under reduced pressure and the crude product obtained was purified by
column chromatography using petroleum ether/ethyl acetate (4:1) as eluent.
Alternatively, the reaction could also be carried out in toluene using a Dean-
Acknowledgments
A.R.S. thanks CEFIPRA (le Centre Indo - Français Pour la Recherche
Avancée) for the nomination under postdoctoral programme-2012.
R.R. thanks DST and DST-FIST, New Delhi, for financial support.
Stark
apparatus.
Spiro-[2.110]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(p-
methoxylphenyl)- pyrrolizidine 5a: 1H NMR (300 MHz, CDCl3): d 1.72–1.98 (m,
2H), 2.00–2.22 (m, 2H), 2.43–2.46 (m, 1H), 2.72–2.78 (m, 1H), 3.25 (t, J = 1.2 Hz,
1H), 3.44 (s, 5H), 3.60 (d, 0J = 1.2.Hz 1H), 3.68 (s, 3H, –OMe), 3.99–4.01 (m, 1H),
4.10 (t, J = 10.5 Hz, 1H, H1 ), 4.30–4.31 (t, J = 1.2 Hz, 1H), 4.53 (dt, J = 9.9, 6.3 Hz,
References and notes
0
0
1H, H7 a), 4.67 (d, J = 11.1 Hz, 1H, H2 ), 6.87–6.90 (m, 2H), 7.30–7.42 (m, 2H),
7.56–7.72 (m, 5H), 7.89–7.92 (m, 1H), 7.99–8.02 (m, 1H), 8.30–8.32 (m, 1H);
13C NMR (75 MHz, CDCl3): d 24.76, 27.71, 45.68, 49.76, 52.92, 64.97, 65.97,
66.44, 66.77, 69.15, 69.72, 72.54, 74.16, 76.55, 111.82, 119.62, 126.15, 126.32,
122.63, 127.01, 127.04, 127.14, 127.42, 128.38, 130.58, 134.95, 139.68, 140.39,
141.56, 150.60, 156.58, 163.03, 197.81 ppm; EIMS m/z: 631(M+); CHN analysis
Calcd for C39H33N3O2Fe: C, 74.17; H, 5.27; N, 4.21%. Found: C, 74.36; H, 5.35; N,
4.29%. Spiro-[2.110]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-furyl-pyrrolizidine
11a: 1H NMR (300 MHz, CDCl3): d 1.80–2.20 (m, 4H), 2.48–2.52 (m, 1H),
2.68–2.72 (m, 1H), 3.40 (s, IH), 3.71 (s, 5H), 4.04 (s, 1H), 4.10 (s, 1H), 4.37 (t,
1. Schreiber, S. L. Science 2000, 287, 1964.
2. Terrett, N. K. Combinatorial Chemistry; Oxford University Press: New York,
1998.
3. For reviews, see: (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur.
J. 2000, 6, 3321; (b) Ugi, J.; Heck, S. Comb. Chem. High Throughput Screening
2001, 4, 10; (c) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopala, L. Acc. Chem. Res. 2003, 36, 899.
4. (a) Weber, L. Drug Discovery Today 2002, 7, 143; (b) Domling, A. Curr. Opin.
Chem. Biol. 2002, 6, 306.
5. Shi, F.; Mancuso, R.; Larock, R. C. Tetrahedron Lett. 2009, 50, 4067.
6. Pearson, W. H. Studies in Natural Product Chemistry; Rahman, A. U., Ed.; Elsevier:
Amsterdam, 1998; Vol. 1, p 323.
7. (a) Hartmann, T.; Witte, L. Chemistry, Biology and Chemoecology of
Pyrrolizidine Alkaloids In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon Press: Oxford, UK, 1995; Vol. 9, p 323; (b)
Monlineux, R. J. In Alkaloids: Chemical and Biological Perspective; Pelletier, S. W.,
Ed.; Wiley: New York, 1987. Chapter 1.
0
0
J = 10.8 Hz, 1H, H1 ), 4.40 (s, 1H), 4.62–4.66 (m, 1H, H7 a), 4.90 (d, J = 11.4 Hz,
0
1H, H2 ), 6.37–6.43 (m, 2H), 7.41–8.38 (m, 9H); 13C NMR (75 MHz, CDCl3): d
27.33, 29.68, 30.53, 46.06, 47.91, 63.96, 68.42, 69.47, 71.71, 72.37, 75.08, 78.84,
106.95, 110.65, 122.11, 128.43, 128.82, 129.56, 130.82, 137.34, 141.58, 142.10,
142.79, 143.71, 153.06, 153.77,164.91, 199.59 ppm; EIMS m/z: 591 (M+); CHN
analysis Calcd for C36H29N3O2Fe: C, 73.10; H, 4.94; N, 7.10%. Found: C, 72.93; H,
5.07; N, 7.22. Spiro-[2.110]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-pyridyl-
pyrrolizidine 13: 1H NMR (300 MHz, CDCl3): d 1.80–2.03 (m, 4H), 2.43–2.45
8. (a) Gazit, A.; App, H.; Mc Mahon, G.; Chen, J.; Levitzki, A.; Bohmer, F. D. J. Med.
Chem. 1996, 39, 2170; (b) Sehlstedt, U.; Aich, P.; Bergman, J.; Vallberg, E. I.;
Norden, B.; Graslund, A. J. Mol. Biol. 1998, 278, 3156; (c) Trillo, R. P.; Univ.
Microfilms (Ann. Arbor. Mich.), L.C. card no. Mic. 59–4672, 106, Dissertation
Abstr. 1959, 20, 1597.; (d) Igor, A. S.; Liliya, N. K.; Andrei, I. K.; Tracey, S. H.;
Irina, K.; David, W. P.; Mark, A. J.; Mark, T. Q. Mol. Pharmacol. 2012, 81, 832.
9. (a) Ruck-Braun, K.; Freysoldt, T. H. E.; Wierschem, F. Chem. Soc. Rev. 2005, 34,
507; (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484; (c)
SureshBabu, A. R.; Raghunathan, R.; Madhivanan, R.; Ompraba, G.; Velmurugan,
D.; Raghu, R. Curr. Chem. Biol. 2008, 2, 312; (d) Babu, A. R. S.; Raghunathan, R.;
Kumaresan, K.; Raaman, N. Curr. Chem. Biol. 2009, 3, 432.
(m, 1H), 2.78–2.80 (m, 1H), 3.18 (s, IH), 3.45 (s, 5H), 3.63 (s, 1H), 4.03 (d,
0
J = 2.1 Hz, 1H), 4.13 (t, J = 10.2 Hz, 1H, H10 ), 4.32 (d, J = 1.2 Hz, 1H), 4.52–4.58
0
(m, 1H, H7 a), 4.68 (d, J = 10.8 Hz, 1H, H2 ), 7.32–7.51 (m, 2H), 7.66–7.72 (m,
2H), 7.90–8.04 (m, 4H), 8.28–8.56 (m, 2H); 13C NMR (75 MHz, CDCl3): d 26.93,
29.74, 47.99, 52.08, 60.36, 67.08, 68.97, 69.51, 71.80, 72.66, 74.67, 75.84,
122.17, 124.05, 128.34, 129.13, 129.70, 130.93, 137.46, 141.97, 142.83, 143.43,
146.15, 149.15, 150.09, 150.77, 153.03, 165.16, 200.34 ppm; EIMS m/z: 605
(M+); CHN analysis Calcd for C37H30N4OFe: C, 73.75; H, 5.02; N, 9.29%. Found:
C, 73.88; H, 5.20; N, 9.45%. Spiro-[2.110]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-
4-ferrocenyl pyrrolizidine 15: 1H NMR (300 MHz, CDCl3): d 1.88–2.20 (m, 4H),
2.28–2.68 (m, 2H), 3.29 (s, 1H), 3.54 (s, 2H), 3.57 (s, 1H), 3.66 (s, 5H), 4.08 (t,
0
10. (a) Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105; (b) Harwood, L. M.;
Vickers, R. J. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley &
J =011 Hz, IH, H1 ), 4.21 (s, 2H), 4.25 (s, 2H), 4.27 (s, 5H), 4.52 (d, J = 11.0 Hz, 1H,
0
H7 a), 4.88 (d, J = 11.1 Hz, 1H, H2 ), 7.34–8.26 (m, 8H, ArH); 13C NMR (75 MHz,
CDCl3): d 27.38, 28.68, 31.95, 44.27, 46.03, 64.89, 66.38, 67.67, 67.96, 68.40,

A. R. Suresh Babu et al. / Tetrahedron Letters 53 (2012) 6676–6681
6681
68.92, 69.92, 70.75, 74.44, 78.80, 120.96, 127.44, 127.96, 128.36, 128.73,
4.08 (s, 5H), 4.62–4.66 (m, 1H), 5.02 (d, J = 10.2.Hz, 1H), 7.30–8.27 (m, 8H); 13
C
NMR (75 MHz, CDCl3): d 20.00, 28.65, 47.90, 59.34, 66.36, 67.74, 69.72, 74.25,
75.14, 75.67 123.17, 123.66, 128.61, 129.21, 130.12, 130.51, 131.44, 133.65,
135.73, 138.84, 140.45, 141.16, 141.57, 142.43, 148.39, 155.53, 170.07, 189.50,
188.43 ppm; EIMS m/z: 626 (M+); CHN analysis Calcd for C29H24N2O3Br2Fe: C,
74.79; H, 4.63; N, 6.71%. Found: C, 74.94; H, 4.48; N, 6.55%.
129.75, 136.31, 141.11, 141.77, 143.36, 152.25, 164.06, 200.21 ppm; EIMS m/z:
709 (M+); CHN analysis Calcd for C42H35N3OFe2: C, 71.10; H, 4.97; N, 5.92%;
Found: C, 70.95; H, 5.11; N, 6.08%. Spiro-[2.110]-indeno- [1,2-b]quinoxaline-
spiro-[3.20]indane-10,30-dione-4 ferrocenyl- pyrrolizidine 17: 1H NMR (300 MHz,
CDCl3): d 2.10–2.20 (m, 2H), 2.32–2.42 (m, 2H), 2.58–2.68 (m, 2H), 3.42 (s, 1H),