An expedient ultrasonic assisted one-pot four component synthesis of novel ferrocene grafted pyrrolidine heterocycles via [3 + 2]-cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.jorganchem.2013.08.014

An expedient one-pot four component ultrasonic assisted synthesis of novel ferrocene grafted spiro-pyrrolidine heterocycles via [3 + 2]-cycloaddition of azomethine ylides is described. The protocol provides a mild reaction conditions, high yield of product in short reaction time, high regioselectivity, operational simplicity and applicable to a wide variety of ferrocene derived dipolarophiles for the efficient synthesis of ferrocene appended heterocycles. The structures of cycloadducts were confirmed by spectroscopic analysis. X-ray analysis of the products adds conclusive support to the proposed structure.

Full text of DOI:10.1016/j.jorganchem.2013.08.014

Accepted Manuscript
An expedient ultrasonic assisted one-pot four component synthesis of novel ferrocene
grafted pyrrolidine heterocycles via [3+2]-cycloaddition of azomethine ylides
A.R. Suresh Babu, D. Gavaskar, R. Raghunathan
PII:
S0022-328X(13)00636-0
10.1016/j.jorganchem.2013.08.014
JOM 18214
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 5 July 2013
Revised Date: 31 July 2013
Accepted Date: 4 August 2013
Please cite this article as: A.R. Suresh Babu, D. Gavaskar, R. Raghunathan, An expedient ultrasonic
assisted one-pot four component synthesis of novel ferrocene grafted pyrrolidine heterocycles via
[3+2]-cycloaddition of azomethine ylides, Journal of Organometallic Chemistry (2013), doi: 10.1016/
j.jorganchem.2013.08.014.
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ACCEPTED MANUSCRIPT
An expedient ultrasonic assisted one-pot four component synthesis of novel
ferrocene grafted pyrrolidine heterocycles via [3+2]-cycloaddition of
azomethine ylides
a
a
a
A.R.Suresh Babu, D. Gavaskar, R. Raghunathan *
Graphical Abstract
O
O
H R'
N
H
H
R
R
OH
OH
NH2
NH2
Ultrasound
MeOH
H
H
CH3
NH-CH2-COOH
O
H
R'
Reflux
N
O
Y
N
R / R' =
Fe
R''
X = S, R'' =
X = O, S, R'' = H
X
S
Y = H, Cl, Br, Me

ACCEPTED MANUSCRIPT
An expedient ultrasonic assisted one-pot four component
synthesis of novel ferrocene grafted pyrrolidine heterocycles
via [3+2]-cycloaddition of azomethine ylides
a
a
a
A.R. Suresh Babu, D.Gavaskar and R. Raghunathan *
a
*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600 025, INDIA.
Abstract- An expedient one-pot four component ultrasonic assisted synthesis of novel ferrocene
grafted spiro-pyrrolidine heterocyles via [3+2]-cycloaddition of azomethine ylides is described.
The protocol provides a mild reaction conditions, high yield of product in short reaction time,
high regioselectivity, operational simplicity and applicable to a wide variety of ferrocene derived
dipolarophiles for the efficient synthesis of ferrrocene appended heterocycles. The structures of
cycloadducts were confirmed by spectroscopic analysis. X-ray analysis of the products adds
conclusive support to the proposed structure.
Keywords- Ultrasound irradiation, Multicomponent reaction (MCR), Ferrocene, Azomethine
ylide, Cycloaddition, Spiro-heterocycle, Pyrrolidine.
1
. Introduction
Ferrocene and its derivatives have captured worldwide attentions on account of their fascinating
sandwich structure and properties and its noteworthy advantage over other organometallics. They
have shown a broad variety of applications as complex material, pharmacology, organic
synthesis, etc. Incorporation of a ferrocene fragment into a molecule of an organic compound
imparts the chemical and physicochemical properties that are absent or little manifested in the
Corresponding author:Telephone: 9144 22202811. Fax: +91 4422300488.
E – mail: ragharaghunathan@yahoo.com

ACCEPTED MANUSCRIPT
parent substance making them suitable for wide application [1-6]. Specifically, ferrocene based
heterocyles possess enhanced anti-bacterial, anti-fungal, anti-malarial and anti-cancer activity,
among many others [7-11]. Hence, there has been renewed interest in the synthesis of ferrocene
based heterocycles.
Multi-component reactions (MCRs) constitutes a highly effective one pot procedure with
advantages for the synthesis of complex heterocyclic compounds in a much simpler way than the
conventional time consuming multi-step reaction sequences [12-15]. Ultrasound irradiation has
emerged as a very significant non-traditional technique in organic synthesis and has a profound
impact on the way chemists approach organic and parallel synthesis addressing the growing
environmental concerns. The salient features and benefits of this technique includes reduced
reaction times and enhanced reaction rates, reduced energy and solvent consumption,
suppression of side products, enhanced selectivity, improved yields, relative to traditional
thermal heating [16-20].
The intermolecular [3+2]-cycloaddition reactions of azomethine ylides with olefinic and
acetylenic dipolarophiles represent a highly selective approach for the formation of aza- and
spiro heterocycles prevalent in a variety of biologically active compounds [21-23].
Indenoquinoxaline derivatives are important classes of nitrogen containing heterocycles with
significant biological activity [24,25]. Only a few reports are available on the use of ultrasonic
irradiation in 1,3-dipolar cycloaddition reactions [26-31]. More specifically, scanty reports are
available for the synthesis of spiro-heterocycles. It is noteworthy that all of them were
synthesized only via a three-component reaction [32-34].

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2
. Results and discussion
In continuation of our research in the area of cycloaddition reactions and with renewed interest in
such complex ferrocene appended heterocycles [35-38], we herein report for the first time, a
mild, rapid and a facile four-component, ultrasonic assisted one-pot synthesis of novel ferrocene
grafted monospiro-indenoquinoxaline pyrrolidine heterocyles through 1,3-dipolar cycloaddition
of azomethine ylide generated from 1,2-phenylenediamine, ninhydrin and sarcosine with
various unusual ferrocene derived dipolarophiles.
The one-pot four-component ultrasonic irradiated reaction involving ninhydrin 2, 1,2-
phenylenediamine 3, sarcosine 4 and ferrocene derived dipolarophile 1a proceeded at reflux
temperature in methanol, to give ferrocene grafted spiro-indenoquinoxaline pyrrolidine as the
only product which was characterized on the basis of spectroscopic data. Mechanistically, this is
presumably a complex multistep sequence of events that involves, initial ultrasonic assisted
heterocyclization of phenylenediamine 3 with ninhydrin 2 giving indenoquinoxline-11-one 7
[
39] which further condensed with sarcosine 4 to produce 1,3-dipole, azomethine ylide 9 via
thermal decarboxylation of 8 [40] (Figure 1). The azomethine ylide 9 further undergoes
cycloaddition reaction across the isolated double bond of the ferrocene derived dipolarophile 1a
to afford the desired product 5a (Scheme 1). Thus, the IR spectrum of 1-N-Methyl-spiro-[2.11’]-
indeno-[1,2-b]-quinoxaline-3-ferrocenoyl-4-phenyl-pyrrolidine 5a showed absorption at 1660
-1
1
cm indicating the presence of a carbonyl group. The H NMR spectrum of the product 5a
exhibited peaks at δ 1.92 (s, 3H), 3.11 ( t, J = 1.2 Hz, 1H), 3.51 ( s, 5H), 3.65 ( t, J = 8.1 Hz, 1H),
3
4
.79 – 3.81 ( m, 1H), 4.04 ( t, J = 9.6 Hz, IH), 4.13 – 4.15 ( m, 1H), 4.40 ( d, J = 9.6 Hz, 1H),
.47 – 4.49 (m, 1H), 4.69 – 4.78 ( m, 1H), 7.34 – 7.51 ( m, 5H), 7.81 – 7.89 ( m, 4H), 7.93 (d, J
=
7.5 Hz, 1H), 8.14 - 8.16 (m, 1H), 8.37 – 8.39 ( m, 1H). The –NCH proton exhibited a singlet
3
at δ 1.92. The –NCH protons of the pyrrolidine ring appeared as triplets at δ 3.65 and δ 4.04.
2

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The pyrrolidine ring proton attached to the aryl moiety exhibited a multiplet in the region δ 4.69
–
4
4.78. The pyrrolidine ring proton attached to the ferrocenoyl moiety exhibited a doublet at δ
.40. The ferrocenyl protons exhibited a triplet and a singlet at δ 3.11 and δ 3.51 and multiplets
in the region δ 3.79 – 3.81, δ 4.13 – 4.15, δ 4.47 – 4.49. The aromatic ring protons appeared as a
doublet at δ 7.93 and multiplets in the region δ 7.34 – 7.51, δ 7.81 – 7.89, δ 8.14 - 8.16, δ 8.37 –
1
3
8
4
7
2
.39. The off-resonance proton decoupled C spectrum of 5a exhibited peaks at δ 34.55 and
4.87 ppm due to the pyrrolidine –NCH and –NCH carbons. The spiro carbon resonated at δ
3
2
9.06 ppm. The carbonyl group attached to the ferrocene and the pyrrolidine ring resonated at δ
00.55 ppm and the signals of all other carbons are located at appropiate chemical shifts in
agreement with the proposed structure. The formation of the product was confirmed by mass
spectral and elemental analysis. The high resolution mass spectrum of 5a showed a molecular
+
ion peak at 575.4924 (M ). The structure of the product was ambiguously determined by single
crystal X-ray analysis of 5a (Figure 2) [41] and 5c (Figure 3) [42]
In order to optimize and compare the reaction condition and improve the chemical yield of the
product, the one pot four-component reaction was carried out in refluxing toluene for the various
dipolarophiles (1a, 1b and 14b). The results showed that even under refluxing condition for
prolonged time in toluene, (7.0 – 7.3 h), there was not much significant increase in the isolated
yield of product (42- 48%). However, in refluxing methanol, better chemical yield of the product
was obtained (reaction time: 4.5 - 4.7 h.; isolated chemical yield: 70 -74%) due to the better
solubility of all the reactants favoring the easy formation of azomethine ylide 9. But the reaction
rate and isolated yield of the product was excellent when the reaction mixture was sonicated in
refluxing methanol (reaction time: 1.1 – 1.5 h.; isolated chemical yield: 86 - 90%) rather than the
traditional thermal heating which can be attributed to the enhanced mass transfer in shorter time

ACCEPTED MANUSCRIPT
duration due to cavitation on ultrasonicating the reaction mixture [19,20]. Hence, ultrasonic
irradiation of the reaction mixture in refluxing methanol was chosen as the optimum condition
for invariably conducting the one-pot multicomponent reaction with various other dipolarophiles
(1c, 10a-b, 12, 14a, 14c and 16) (Table 1).
Schemes 2 & 3 depicts the ultrasonic promoted reaction of 1-ferrocenyl-3-furyl-prop-2-ene-1-
one 10a/1-ferrocenyl-3-thienyl-prop-2-ene-1-one 10b and 1-ferrocenyl-3-(2’, 2’’-bithienyl)-
prop-2-ene-1-one 12 with ninhydrin 2, 1,2 phenylenediamine 3 and sarcosine 4 in refluxing
methanol leading to the formation of ferrocene appended spiro-indenoquinoxaline pyrrolidines
1
1a, 11b and 13 as evidenced by TLC, spectral analysis. All the newly synthesised cycloadducts
were obtained in good yields (Table 1). The IR spectrum of 1-N-methyl-spiro-[2.11’]-indeno-
-1
[
1,2-b]-quinoxaline-3-ferrocenoyl-4-thienyl-pyrrolidine 11b showed absorption at 1660 cm
1
indicating the presence of a carbonyl group. The H NMR spectrum of the product 11b
demonstrated a singlet peak for –NCH at δ 1.92. The –NCH protons of the pyrrolidine ring
3
2
appeared as triplets at δ 3.68 and δ 4.05. The pyrrolidine ring proton attached to the thienyl
moiety exhibited a doublet of doublet at δ 5.06 whereas the pyrrolidine ring proton attached to
the ferrocenoyl moiety exhibited a doublet at δ 4.38. The ferrocenyl protons exhibited triplets at
δ 3.09 and δ 3.83, a singlet at δ 3.64, doublets at δ 4.17 and δ 4.51. The aromatic ring protons
exhibited a triplet and doublet at δ 7.01 and δ 7.92 and multiplets in the region δ 7.31 – 7.34, δ
7
.36 – 7.38, δ 7.40 – 7.42, δ 7.46 – 7.48, δ 7.80 – 7.83, δ 8.14 - 8.18 and δ 8.36 – 8.38. The off-
1
3
resonance proton decoupled C spectrum of 11b exhibited peaks at δ 34.43 and 39.99 ppm due
to the pyrrolidine –NCH and –NCH carbons. The spiro carbon and carbonyl group resonated at
3
2
δ 79.03 and δ 200.52 ppm and the signals of all other carbons are located at appropiate chemical
shifts in agreement with the proposed structure. The formation of the product was confirmed by

ACCEPTED MANUSCRIPT
mass spectral and elemental analysis. The high resolution mass spectrum of 11b showed a
+
molecular ion peak at 581.1526 (M ). The structure of the product was further unambiguously
determined by single crystal X-ray analysis of 11a (Figure 4) [43] Similar results were obtained
for the product 11a and 13 (vide experimental).
To further expand and to generalize the highly regioselective nature of the reaction as observed
with the dipolarophiles 1a-c , 10 a-b and 12, the scope of this one pot four-component 1,3-
dipolar cycloaddition reaction was further expanded and carried out with the dipolarophiles 1-
phenyl-3-ferrocenyl-3-prop-2-ene-1-one derivatives 14 a-c. Ultrasonic irradiation of these
dipolarophiles 14 a-c with ninhydrin 2, 1,2 phenylenediamine 3 and sarcosine 4 in refluxing
methanol finally afforded the desired ferrocene grafted spiro-indenoquinoxaline pyrrolidines
1
5a-c in good yield (84 – 87%) as depicted in the Scheme 4 (Table 1). A detailed spectroscopic
characterization of the products confirmed their formation. Thus, the IR spectrum of 1-N-methyl-
spiro-[2.11’]-indeno-[1,2-b]-quinoxaline-3-benzoyl-4-ferrocenyl-pyrrolidine 15a showed
-1
1
absorption at 1672 cm indicating the presence of a carbonyl group. In the H NMR spectrum of
the product 15a , –NCH proton exhibited a singlet at δ 1.95. The –NCH protons of the
3
2
pyrrolidine ring appeared as triplets at δ 3.69 and δ 3.92. The pyrrolidine ring proton attached to
the benzoyl moiety exhibited a triplet at δ 4.40 whereas the pyrrolidine ring proton attached to
the ferrocenyl moiety exhibited a doublet at δ 4.87. The ferrocenyl protons exhibited doublets at
δ 4.13 and δ 4.22 and a singlet at δ 4.30. The aromatic ring protons exhibited doublets at δ 6.87,
δ 8.05 and δ 8.25 and multiplets in the region δ 7.05 – 7.09, δ 7.30 – 7.32, δ 7.50 – 7.52, δ 7.72 –
1
3
7
3
9
.76. The off-resonance proton decoupled C spectrum of 15a exhibited peaks at δ 35.11 and
8.13 ppm due to the pyrrolidine –NCH and –NCH carbons. The spiro carbon resonated at δ
3
2
0.24 ppm. The carbonyl group attached to the ferrocene and the pyrrolidine ring resonated at δ

ACCEPTED MANUSCRIPT
1
98.58 ppm and the signals of all other carbons are located at appropiate chemical shifts in
agreement with the proposed structure. The formation of the product was confirmed by mass
spectral and elemental analysis. The high resolution mass spectrum of 15a showed a molecular
+
ion peak at 575.4718 (M ). The structure of the product 15a was ambiguously determined by
single crystal X-ray analysis of 15a (Figure 5) [44]. Similar results were obtained for the product
1
5b and 15c (vide experimental).
In our final experiment, sonicating a mixture of ninhydrin 2, 1,2-phenylenediamine 3 and
sarcosine 4 and unusual 1-ferrocenyl-3-ferrocenyl-3-prop-2-ene-1-one as dipolarophile 16 in
refluxing methanol afforded the cycloadduct 17 which has two ferrocene moieties on the
pyrrolidine platform (Scheme 5). The IR spectrum of 1-N-Methyl-spiro-[2.11’]-indeno-[1,2-b]-
-1
quinoxaline-3-ferrocenoyl-4-ferrocenyl-pyrrolidine 17 showed absorption at 1660 cm
1
indicating the presence of a carbonyl group. The H NMR spectrum of the product 17 exhibited
peaks at δ 1.94 (s, 3H), 3.08 (t, J = 9.0, 1H), 3.70 (t, J = 9.0 Hz, 1H), 3.72 ( d, J = 2.4 Hz, 6H),
4
.04 (s, 2H), 4.11 (s, 2H), 4.22 (t, J = 9.0 Hz, 1H), 4.31 (d, J = 2.7 Hz, 6H), 4.41 (s, 2H), 4.65
dd, J = 9.1 Hz, 6.3 Hz,1H), 7.24 – 7.27 (m, 3H), 7.74 – 7.84 (m, 2H), 7.86 – 7.94 (m, 1H), 8.12
8.16 (m, 1H), 8.28 – 8.36 (m, 1H). The –NCH proton exhibited a singlet at δ 1.94. The –NCH
(
–
3
2
protons of the pyrrolidine ring appeared as triplets at δ 3.08 and δ 3.70. The pyrrolidine ring
proton attached to the ferrocenoyl moiety exhibited a triplet at δ 4.22 whereas the pyrrolidine
ring proton attached to the ferrocenyl moiety exhibited a doublet of doublet at δ 4.65. The
ferrocenyl protons exhibited doublets at δ 3.72 and δ 4.31 and singlets at δ 4.04, δ 4.11 and δ
4
7
.41. The aromatic ring protons exhibited multiplets in the region δ 7.24 – 7.27, δ 7.74 – 7.84, δ
.86 – 7.94, δ 8.12 – 8.16 and δ 8.28 – 8.36. The formation of the product was confirmed by
mass spectral and elemental analysis. The high resolution mass spectrum of 17 showed a

ACCEPTED MANUSCRIPT
+
molecular ion peak at 683.0554 (M ). The structure of the product was ambiguously determined
by single crystal X-ray analysis of 17 (Figure 6) [45].
3
. Conclusion
In conclusion, we have synthesized a series of hitherto unknown novel ferrocene grafted spiro-
indenoquinoxaline pyrrolidines via a facile one-pot four component ultrasonic assisted [3+2]-
cycloaddition reaction of azomethine ylides to various unusual ferrrocene derived dipolarophiles.
The compounds synthesized carry diverse substitution pattern by choice. This method offers
several advantages including its operational simplicity, selectivity with enhanced reaction rate in
a one-pot four component approach, mild reaction 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 ferrrocene derived dipolarophiles to synthesise
such complex highly substituted pyrrolidines containing ferrocene and spiro-indenoquinoxaline
moiety of biological significance.
4
4
. Experimental
.1 General considerations
All melting points were uncorrected. IR spectra were recorded on a SHIMADZU 8300 series FT-
1
IR instrument. H NMR spectra were recorded in CDCl using TMS as an internal standard on a
3
1
3
BRUKER 300 spectrometer at 300 MHz. C NMR was recorded on a BRUKER 300
spectrometer at 75 MHz. High resolution mass spectra were recorded on a JEOL-GC-MATE II
mass spectrometer (70 Energy eV, Quadrapole double focusing mass analyzer with
photomultiplier tube detector). Experiment under ultrasound irradiation was carried out in a
EQUITRON ultrasonic bath/cleaner model having maximum power output of 170W and 43 KHz
operating frequency. Elemental analysis was carried out on Perkin–Elmer 2400 B instrument.

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Column chromatography was performed on silica gel (ACME, 100–200 mesh). Routine
monitoring of the reactions was made using thin layer chromatography developed on glass plates
coated with silica gel-G (ACME) of 0.25 mm thickness and visualized with iodine. For dry
experiments, glassware’s used were thoroughly dried in a hot air-oven, cooled and assembled
under a stream of nitrogen. Solvents were reagent grade and were purified according to standard
procedures. The starting materials ferrocene, 1,2-phenylenediammine, ninhydrin and sarcosine
were purchased commercially and used as such. Ferrocene based dipolarophiles were
synthesized as per the literature procedures [46,47].
4
.1.1 General procedure for the synthesis of ferrocene based spiro-indenoquinoxaline
pyrrolidine heterocycles: (a) By Ultrasonic irradiation: A mixture of ninhydrin 2 (1 mmol)
and 1,2-phenylenediamine 3 (1 mmol) was sonicated with stirring for 5 min in 10 mL of
methanol followed by the addition of sarcosine 4 (1 mmol). To this mixture, a solution of
dipolarophile 1a (1 mmol) in 10 mL of methanol were added. The mixture was then sonicated
under refluxing condition until completion of the reaction as evidenced by TLC in petroleum
ether-ethyl acetate mixture (4.5: 0.5) and visualization was accomplished in an iodine chamber.
After the completion of the reaction, the solvent was removed under reduced pressure and the
crude product purified by column chromatography using petroleum ether/ethyl acetate (4.5: 0.5)
as eluent and further recrystallised in methanol. (b) By Conventional Method: A mixture of
ninhydrin 2 (1 mmol) and 1,2-phenylenediamine 3 (1 mmol) was sonicated with stirring for 15
min in 10 mL of methanol followed by the addition of sarcosine 4 (1 mmol). To this mixture, a
solution of dipolarophile 1a (1 mmol) in 10 mL of methanol were added. The mixture was then
refluxed until completion of the reaction as evidenced by TLC in petroleum ether-ethyl acetate
mixture (4.5: 0.5) and visualization was accomplished in an iodine chamber. After the

ACCEPTED MANUSCRIPT
completion of the reaction, the solvent was removed under reduced pressure and the crude
product purified by column chromatography using petroleum ether/ethyl acetate (4.5: 0.5) as
eluent and further recrystallised in methanol. Alternatively, the reaction can also be carried out in
toluene using a Dean Stark apparatus.
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-phenyl-pyrrolidine 5a :
Eluent: petroleum ether/ethylacetate (4.5 : 0.5), R value: 0.5; pale reddish-orange solid; IR
f
-1 1
(
KBr): 1666 cm ; HNMR (300 MHz, CDCl ): δ 1.92 (s, 3H), 3.11 ( t, J = 1.2 Hz, 1H), 3.51 (
3
s, 5H), 3.65 ( t, J = 8.1 Hz, 1H), 3.79-3.81 ( m, 1H), 4.04 ( t, J = 9.6 Hz, IH), 4.13-4.15 ( m, 1H),
.40 ( d, J = 9.6 Hz, 1H), 4.47-4.49 (m, 1H), 4.69-4.78 ( m, 1H), 7.34-7.51 ( m, 5H), 7.81-7.89 (
4
1
3
m, 5H), 7.93 (d, J = 7.5 Hz, 1H), 8.14-8.16 (m, 1H), 8.37-8.39 ( m, 1H) ; C NMR (75 MHz,
CDCl ): δ 34.55, 44.87, 61.90, 65.14, 68.39, 68.46, 69.20, 71.90, 72.33, 74.52, 79.06, 121.45,
3
1
27.23, 127.72, 128.78, 128.92, 129.28, 129.39, 129.74, 130.03, 131.76, 137.19, 141.66, 142.53,
1
42.64, 145.89, 153.99, 164.89, 200.55 ppm ; HRMS calculated for C H ON Fe m/z:
3
6
29
3
+
5
75.4921; found 575.4924 (M ); CHN analysis calculated for C H ON Fe : C, 75.13; H, 5.07;
36 29 3
N, 7.29; Found: C, 75.25; H, 5.18; N, 7.16%.
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(p-chlorophenyl)-
pyrrolidine 5b : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-
f
-1 1
orange solid; IR (KBr): 1668 cm ; HNMR (300 MHz, CDCl ): δ 1.90 (s, 3H), 3.16 ( s, 1H),
3
3
.55 ( s, 5H), 3.62 ( t, J = 9.3 Hz, 1H), 3.82 ( d, J = 1.2 Hz, 1H), 3.97 ( t, J = 9.3 Hz, IH), 4.16 (
s, 1H), 4.33 ( d, J = 9.3 Hz, 1H), 4.48 (d, J = 1.2 Hz, 1H), 4.72 ( dd, J = 9.3 Hz, 7.5 Hz, 1H),
13
7
.32-7.84 ( m, 4H), 7.93 (d, J = 7.5 Hz, IH), 8.16-8.19 (m, 1H), 8.34-8.38 ( m, 1H) ; C NMR
(
75 MHz, CDCl ): δ 34.47, 44.09, 61.86, 64.95, 68.30, 68.54, 68.90, 71.99, 72.44, 74.47, 78.91,
3
1
21.49, 127.60, 128.86, 129.00, 129.32, 129.46, 129.81, 129.94, 130.11, 131.77, 132.87, 137.22,

ACCEPTED MANUSCRIPT
1
41.31, 141.61, 142.56, 145.69, 164.89, 175.83, 200.54 ppm ; HRMS calculated for
+
C H OClN Fe m/z: 609.9372; Found 609. 9374 (M ); CHN analysis calculated for
36
28
3
C H OClN Fe : C, 70.89; H, 4.62; N, 6.88; Found: C, 70.77; H, 4.72; N, 6.79%.
36
28
3
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(p-methylphenyl)-
pyrrolidine 5c : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-
f
-1
1
orange solid; IR (KBr) cm : ν(C=O) 1659 ; HNMR (300 MHz, CDCl ): δ 1.91 (s, 3H), 2.31 ( s,
3
3
H), 3.12 ( d, J = 1.3 Hz, 1H), 3.53 ( s, 5H), 3.62 ( t, J = 8.1 Hz, 1H), 3.80 ( dd, J = 2.5 Hz, 1.5
Hz, 1H), 4.00 ( t, J = 9.4 Hz, IH), 4.14 ( dd, J = 1.5, 0.9 Hz, 1H), 4.40 ( d, J = 9.3 Hz, 1H), 4.47
t, J = 1.2 Hz, 1H), 4.68 ( dd, J = 9.3 Hz, 7.5 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.34-7.42 ( m,
H), 7.52 ( d, J = 7.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.81-7.84 ( m, 2H), 7.93 (d, J = 7.2 Hz,
(
2
1
3
IH), 8.16 (t, J = 9.5 Hz, 1H), 8.38 ( d, J = 9.9 Hz, 1H) ; C NMR (75 MHz, CDCl ): δ 21.11,
3
3
1
1
5
5
1
4.57, 44.46, 61.98, 65.02, 68.46, 69.23, 71.87, 72.30, 74.56, 79.13, 121.43, 122.55, 124.80,
27.73, 128.56, 128.89, 129.25, 129.40, 129.68, 130.02, 130.29, 131.62, 131.74, 132.46, 132.52,
36.73, 137.16, 139.45, 141.66, 164.90, 200.67 ppm ; HRMS calculated for C H ON Fe m/z:
3
7
31
3
+
89.5189; Found: 589.5188 (M ); CHN analysis calculated for C H ON Fe : C, 75.38; H,
3
7
31
3
.30; N, 7.12; Found: C, 75.58; H, 5.45; N, 7.25%.
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(furyl)-pyrrolidine 11a :
Eluent: petroleum ether/ethylacetate (4.7 : 0.3), R value: 0.5; pale reddish-orange solid; IR
f
-1
1
(
KBr) cm : ν(C=O) 1668 ; HNMR (300 MHz, CDCl ): δ 1.96 (s, 3H), 3.70 ( t, J = 8.25 Hz,
3
1
H), 3.92 (t, J = 8.85 Hz, 1H), 4.13 (s, 2H), 4.28 (s, 2H), 4.30 (s, 5H), 4.42 (dd, J = 9.0 Hz, 7.6
Hz, IH), 4.86 (d, J = 9.3 Hz, 1H), 6.73 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.5 Hz, 2H), 7.07 (t, J =
.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.72-7.77
7
1
3
(
m, 3H), 8.05-8.08 (m, 1H), 8.25-8.28 (m, 1H) ; C NMR (75 MHz, CDCl ): δ 35.01, 38.06,
3

ACCEPTED MANUSCRIPT
6
1
1
0.53, 63.21, 66.54, 67.47, 67.55, 68.04, 68.62, 75.06, 90.15, 121.38, 127.38, 127.43, 127.65,
28.97, 129.07, 129.29, 129.73, 131.51, 132.38, 137.02, 137.21, 141.65, 142.43, 145.87, 153.78,
63.50, 198.51 ppm ; HRMS calculated for C H O N Fe m/z: 565.4533; Found: 565.4531
3
4
27
2
3
+
(
M ); CHN analysis calculated for C H O N Fe : C, 72.22; H, 4.81; N, 7.43; Found: C, 72.01;
34 27 2 3
H, 5.03; N, 7.61%.
1
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(thienyl)-pyrrolidine
1b : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-orange solid; IR
f
-1
1
(
KBr) cm : ν(C=O) 1660; HNMR (300 MHz, CDCl ): δ 1.91 (s, 3H), 3.09 ( t, J = 1.2.Hz, 1H),
3
3
.64 ( s, 5H), 3.68 ( t, J = 9.0 Hz, 1H), 3.83 ( d, J = 2.4 Hz, 1H), 4.05 ( t, J = 9.0 Hz, IH), 4.17 (
d, J = 1.2 Hz, 1H), 4.38 ( d, J = 9.0 Hz, 1H), 4.51 (t, J = 1.2 Hz, 1H), 5.06 ( dd, J = 9.6 Hz, 7.5
Hz, 1H), 7.01 (t, J = 3.3 Hz, 1H), 7.31–7.34 ( m, 2H), 7.36-7.38 (m, 1H), 7.40-7.42 (m, 1H), 7.46
-7.48 (m, 1H), 7.80-7.83 ( m, 2H), 7.92 (d, J = 7.2 Hz, IH), 8.14-8.18 (m, 1H), 8.36-8.38 ( m,
1
3
1
7
1
H) ; C NMR (75 MHz, CDCl ): δ 34.43, 39.99, 62.38, 65.57, 68.40, 68.65, 69.45, 72.07,
3
6.75, 79.03, 121.51, 121.51, 124.42, 125.69, 127.01, 127.64, 129.02, 129.29, 129.54, 129.85,
30.18, 131.84, 132.50, 136.63, 137.21, 139.32, 140.48, 164.78, 200.52 ppm ; HRMS calculated
+
for C H ON SFe m/z: 581.1520; Found: 581.1526 (M ); CHN analysis calculated for
3
4
27
3
C H ON SFe : C, 70.26; H, 4.68; N, 7.23; Found: C, 70.40; H, 4.77; N, 7.34%.
34
27
3
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-(2’’,2’’’-bithienyl)-
pyrrolidine 13 : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-
f
-1
1
orange solid; IR (KBr) cm : ν(C=O) 1666 ; HNMR (300 MHz, CDCl ): δ 1.94 (s, 3H), 3.12 (
3
t, J = 1.2.Hz, 1H), 3.70 ( t, J = 11.1 Hz, 1H), 3.73 ( s, 5H), 3.84 ( d, J = 1.2 Hz, 1H), 4.04 ( t, J =
9
.0 Hz, IH), 4.18 ( d, J = 1.2 Hz, 1H), 4.39 ( d, J = 9.0 Hz, 1H), 4.52 (t, J = 1.2 Hz, 1H), 5.02 (
dd, J = 9.6 Hz, 6.9 Hz, 1H), 6.99 (t, J = 4.35 Hz, 1H), 7.06 (d, J = 3.9 Hz, 1H), 7.32-7.42 (d, J =

ACCEPTED MANUSCRIPT
7
.2 Hz, 1H), 7.81-7.84 (m, 2H), 7.92 (d, J = 7.2 Hz, 1H), 8.15-8.18 (m, 1H), 8.38-8.41 (m, 1H) ;
1
3
C NMR (75 MHz, CDCl ): δ 34.44, 40.18, 62.01, 65.26, 68.28, 68.66, 71.95, 72.41, 74.35,
3
7
1
9.05, 121.44, 123.36, 123.48, 124.10, 126.30, 127.56, 127.72, 128.96, 129.25, 129.46, 129.76,
30.08, 131.72, 136.31, 137.28, 141.68, 142.55, 145.16, 145.65, 164.48, 200.46 ppm ; HRMS
+
calculated for C H ON S Fe m/z: 663.6461; Found: 663.6468 (M ); CHN analysis calculated
3
8
29
3 2
for C H ON S Fe : C, 68.77; H, 4.40; N, 6.33; Found: C, 68.89; H, 4.29; N, 6.42%.
3
8
29
3 2
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-benzoyl-4-ferrocenyl-pyrrolidine 15a :
Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-orange solid; IR
f
-1
1
(
KBr) cm : ν(C=O) 1672 ; HNMR (300 MHz, CDCl ): δ 1.95 (s, 3H), 3.69 (t, J = 8.25, 1H),
3
3
.92 (t, J = 8.5 Hz, 1H), 4.13 (d, J = 1.2. Hz, 2H), 4.22 (d, J = 1.2 Hz, 2H), 4.30 (s, 5H), 4.40 (t,
J = 8.5 Hz, 1H), 4.87 (d, J = 9.0 Hz, 1H), 6.73 (t, J = 7.5 Hz, 2H), 6.87 (d, J = 10.0 Hz, 2H),
.05-7.09 ( m, 1H), 7.30-7.32 (m, 1H), 7.50-7.52 (m, 1H), 7.72-7.76 (m, 3H), 8.05 (d, J = 9.6
7
13
Hz, 1H), 8.25 ( d, J = 9.6 Hz, 1H); C NMR (75 MHz, CDCl ): δ 35.11, 38.13, 63.29, 66.62,
3
6
1
7.63, 68.70, 74.56, 90.24, 127.46, 127.51, 127.73, 129.05, 129.16, 129.36, 129.81, 129.84,
+
32.46, 153.87, 163.59, 198.58 ppm ; HRMS calculated for C H ON Fe m/z: 575.4721 (M );
3
6
29
3
Found: 575.4718 ; CHN analysis calculated for C H ON Fe : C, 75.13; H, 5.07; N, 7.30;
36
29
3
Found: C, 75.29; H, 5.21; N, 7.41%.
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-(p-chlorobenzoyl)-4-ferrocenyl-
pyrrolidine 15b : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-
1
f
-1
1
orange solid; IR (KBr) cm : ν(C=O) 1680 ; HNMR (300 MHz, CDCl ): δ 1.96 (s, 3H), 3.69 (t,
3
J = 8.4, 1H), 3.92 (t, J = 8.7 Hz, 1H), 4.13 (d, J = 1.2. Hz, 2H), 4.24 (d, J = 1.2 Hz, 1H), 4.28 (s,
5
H), 4.42 (t, J = 8.7 Hz, 1H), 4.77 (d, J = 9.3 Hz, 1H), 6.73 (t, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4
Hz, 2H), 7.31-7.52 (m, 3H), 7.73-7.81 (m, 3H), 8.10 (d, J = 9.6 Hz, 1H), 8.25 ( d, J = 9.6 Hz,

ACCEPTED MANUSCRIPT
1
3
1
6
1
H); C NMR (75 MHz, CDCl ): δ 34.96, 38.25, 60.45, 63.15, 66.46, 67.53, 67.61, 68.04,
3
8.62, 75.05, 89.86, 121.55, 127.45, 128.00, 128.76, 129.13, 129.19, 129.45, 129.68, 129.92,
31.55, 135.47, 137.03, 138.86, 141.61, 142.50, 145.65, 153.67, 163.32, 197.21 ppm ; HRMS
+
calculated for C H OClN Fe m/z: 609.9372; Found: 609.9371 (M ); CHN analysis calculated
3
6
28
3
for C H OClN Fe : C, 70.89 ; H, 4.62; N, 6.88; Found: C, 71.02; H, 4.71; N, 6.78%.
3
6
28
3
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-(p-bromobenzoyl)-4-ferrocenyl-
pyrrolidine 15c : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-
f
-1
1
orange solid; IR (KBr) cm : ν(C=O) 1680 ; HNMR (300 MHz, CDCl ): δ 1.96 (s, 3H), 3.70 (t,
3
J = 8.1, 1H), 3.91 (t, J = 9.0 Hz, 1H), 4.13 (d, J = 1.2. Hz, 2H), 4.24 (d, J = 1.2 Hz, 1H), 4.28 (s,
5
H), 4.41 (t, J = 8.1 Hz, 1H), 4.76 (d, J = 9.3 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.4
Hz, 2H), 7.34-7.37 (m, 1H), 7.45-7.49 (m, 2H), 7.75-7.82 (m, 3H), 8.10 (d, J = 9.6 Hz, 1H), 8.26
13
(
d, J = 9.6 Hz, 1H); C NMR (75 MHz, CDCl ): δ 34.98, 38.30, 60.42, 63.20, 66.40, 67.56,
3
6
1
7.58, 68.10, 68.70, 75.12, 89.90, 121.50, 127.52, 127.98, 128.78, 129.07, 129.11, 129.40,
29.60, 129.97, 131.50, 135.28, 137.20, 138.76, 141.66, 142.48, 145.70, 153.72, 163.51, 197.56
+
ppm ; HRMS calculated for C H OBrN Fe m/z: 655.3961; Found: 655.3966 (M ); CHN
3
6
29
3
analysis calculated for C H OBrN Fe : C, 65.47; H, 4.45; N, 6.41; Found: C, 65.51; H, 4.53;
3
6
29
3
N, 6.49%.
1
1
-N-Methyl-spiro-[2.11’]-indeno[1,2-b]quinoxaline-3-ferrocenoyl-4-ferrocenyl-pyrrolidine
7 : Eluent: petroleum ether/ethylacetate (4.8 : 0.2), R value: 0.5; pale reddish-orange solid; IR
f
-1
1
(
KBr) cm : ν(C=O) 1660 ; HNMR (300 MHz, CDCl ): δ 1.94 (s, 3H), 3.08 (t, J = 9.0, 1H),
3
3
1
7
.70 (t, J = 9.0 Hz, 1H), 3.72 ( d, J = 2.4 Hz, 6H), 4.04 (s, 2H), 4.11 (s, 2H), 4.22 (t, J = 9.0 Hz,
H), 4.31 (d, J = 2.7 Hz, 6H), 4.41 (s, 2H), 4.65 (dd, J = 9.1 Hz, 6.3 Hz,1H), 7.24-7.27 (m, 3H),
.74-7.84 (m, 2H), 7.86 -7.94 (m, 1H), 8.12-8.16 (m, 1H), 8.28-8.36 (m, 1H); HRMS calculated

ACCEPTED MANUSCRIPT
+
for C H ON Fe m/z: 683.0547; Found: 683.0554 (M ); CHN analysis calculated for
4
0
33
3
2
C H ON Fe : C, 70.33; H, 4.86; N, 6.15; Found: C, 70.47; H, 4.75; N, 6.27%.
40
33
3
2
Acknowledgements
One of the authors D.G thanks CSIR-UGC for award of junior research fellowship. R.R thanks
DST for financial assistance and UGC for BSR Faculty Fellowship.
References
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Liliya
,
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Andrei,
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H.
http://molpharm.aspetjournals.org/content/early/2012/03/20/mol.111.077446.abstract - aff-2Tracey,
W. P. David , A. J. Mark, T. Q. Mark.
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(thienyl)-pyrrolidine can be obtained from the Cambridge Crystallographic Data Centre with
the deposition number CCDC 927300. Data acquisition: deposit@ccdc.cam.ac.uk,

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http://www.ccdc.cam.ac.uk/deposit
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ferrocenyl-pyrrolidine can be obtained from the Cambridge Crystallographic Data Centre
with the deposition number CCDC 927301. Data acquisition: deposit@ccdc.cam.ac.uk,
http://www.ccdc.cam.ac.uk/deposit
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ACCEPTED MANUSCRIPT
R
O
O
O
Fe
H
NH2
OH
Ultrasound
MeOH
H
N
H
CH3
Fe
H
H
H
OH
NH-CH -COOH
2
NH2
Reflux
O
N
R
N
1
a-c
2
3
R = H, Cl, Me
5a-c
Scheme 1 Synthesis of ferrocene grafted spiro-indenoquinoxaline-pyrrolidines 5a-c
O
O
X
H
H
Fe
H
NH2
OH
OH
Ultrasound
MeOH
H
H
Fe
CH3
H
X
NH-CH -COOH
NH2
2
N
Reflux
O
O
N
N
1
0a-b
2
3
X = O, S
1
1a-b
Scheme 2 Synthesis of ferrocene grafted spiro-indenoquinoxaline pyrrolidines 11a-b
S
O
O
S
H
H
Fe
OH
OH
NH2
Ultrasound
MeOH
H
Fe
CH3
H
H
H
NH2
NH-CH -COOH
N
2
O
S
Reflux
O
N
N
S
1
2
2
3
13
Scheme 3 Synthesis of ferrocene grafted spiro-indenoquinoxaline pyrrolidine 13

ACCEPTED MANUSCRIPT
R
Fe
H
O
H
H
H
Ultrasound
MeOH
NH2
OH
H
CH3
N
Fe H
R
NH-CH -COOH
O
2
Reflux
N
OH
O
NH2
O
N
R = H, Cl, Br
4 a-c
1
2
3
15 a-c
Scheme 4 Synthesis of ferrocene grafted spiro-indenoquinoxaline pyrrolidine 15a-c
Fe
O
H
H
Fe
O
OH
OH
NH2
H
H
Ultrasound
MeOH
CH3
H
Fe H
NH-CH -COOH
N
O
NH2
2
Reflux
Fe
N
O
N
1
7
1
6
2
3
Scheme 5 Synthesis of diferrocene grafted spiro-indenoquinoxaline pyrrolidine 17

ACCEPTED MANUSCRIPT
O
O
O
O
OH
OH
NH2
NH2
N
H O
2
O
H O
2
N
O
2
3
7
O
CH3
N
N
O
-CO2
NH-CH -COOH
2
N
N
4
N
N
9
8
Figure 1 Mechanism for the formation of azomethine ylide 9 from ninhydrin 2, 1,2-
phenylenediammine 3 and sarcosine 4
Figure 2. ORTEP diagram of cycloadduct 5a

ACCEPTED MANUSCRIPT
Figure 3. ORTEP diagram of cycloadduct 5c
Figure 4. ORTEP diagram of cycloadduct 11a

ACCEPTED MANUSCRIPT
Figure 5. ORTEP diagram of cycloadduct 15a
Figure 6. ORTEP diagram of cycloadduct 17

ACCEPTED MANUSCRIPT
Table 1. [3+2]-cycloadition reaction of ferrocene derived dipolarophiles 1a-c / 10a-b / 12 /
1
4 a-c / 16 with 1,2-phenylenediammine 2, ninhydrin 2 and sarcosine 4
Conventional Method
Toluene/reflux Methanol/reflux Methanol/reflux
T(h) Y(%) T(h) Y(%)
T(h) Y(%) Melting Point ( C)
Ultrasonic Irradiation
X
Product R
o
5
a
-
-
H
244-246
201-203
7
.0
46
-
4.7
-
74
-
1.4
1.3
86
90
83
85
5
b
Cl
Me
-
5
c
-
7.3
42
-
4
.8
70
-
220-223
218-220
224-226
1.3
1.2
1
1
1a
1b
-
-
O
-
-
-
-
-
S
-
-
-
-
1
1
.4
.1
83
82
84
86
87
84
1
3
-
-
-
-
-
-
2
28-230
1
5a
-
H
-
1
.5
184-186
181-183
208-210
193-195
1
1
5b
5c
Cl
Br
-
-
-
-
7.1
72
48
-
4.5
1
.4
-
-
-
-
1.5
1.5
-
-
1
7
-
T(h) = Time in hour; Y (%) = Yield in percentage

ACCEPTED MANUSCRIPT
Highlights
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Rapid access to ferrocene based heterocycles through ultrasonication
Single step multicomponent reaction