Microwave-assisted synthesis of novel ferrocenyl pyrrolizidines

Article abstract of DOI:10.3184/174751912X13418562888522

Microwave-assisted synthesis of ferrocenyl pyrrolizidines containing cyano groups has been accomplished in moderate yields via a facile [3+2]-cycloaddition reaction of several azomethine ylides, derived from aromatic aldehydes and proline, with 1, 1-dicyano-2-ferrocenylethene as the dipolarophile. This method offers several advantages such as short reaction time and simple procedure.

Full text of DOI:10.3184/174751912X13418562888522

536 RESEARCH PAPER
SEPTEMBER, 536–538
JOURNAL OF CHEMICAL RESEARCH 2012
Microwave-assisted synthesis of novel ferrocenyl pyrrolizidines
Zhang Yu-Mei*, Liu Peng, Zhang Hong-Li, Feng Guo-Liang and Geng Li-Jun
College of Sciences, Hebei University of Science &Technology, Shijiazhuang, 050018, P. R. China
Microwave-assisted synthesis of ferrocenyl pyrrolizidines containing cyano groups has been accomplished in mod-
erate yields via a facile [3+2]-cycloaddition reaction of several azomethine ylides, derived from aromatic aldehydes
and proline, with 1, 1-dicyano-2-ferrocenylethene as the dipolarophile. This method offers several advantages such
as short reaction time and simple procedure.
Keywords: ferrocene, pyrrolizidines, cycloaddition, azomethine ylides, microwave irradiation
Ferrocene derivatives containing heterocyclic systems have
attracted much attention in recent years for their applications
in various areas of organic materials, such as electrochemis-
try,1–3 asymmetric catalysis4,5 and biologically active compounds.6,7
Many ferrocene-based heterocycles exhibit anti-bacterial and
anti-fungal properties.8,9 The chemistry of pyrrolidine and its
derivatives is of great interest due to their occurrence in a vari-
ety of natural products endowed with numerous biological
activities.10 Consequently integration of a ferrocene moiety
with pyrrolidine derivatives may increase their biological
activities or create new medicinal properties.11–13
Here we report the synthesis of new ferrocenyl pyrroli-
zidines through [3+2] cycloaddition of azomethine ylides
under microwave irradiation which has been widely used in
organic synthesis because it can accelerate organic reactions.
In addition, some attempts have been made to carry out
the reactions without a solvent or in the presence of a small
amount of a solvent under microwave irradiation.14–16 Further
investigation of the transformation of the cyano groups to other
functionalities is under investigation in our research group.
out under different conditions and the results are shown in
Table 1.
Conventional toluene reflux afforded the compounds (5) in
moderate yields but required longer reaction times (method
A). Compared with method A, method B significantly reduces
the reaction time, which is conducted in toluene under micro-
wave irradiation conditions. In our final series of experiments,
we examined the equivalent solvent-free reaction, simply by
mixing the three components under microwave irradiation
conditions (method C). We found it took much less time than
method B clearly indicating the advantage of this application
of microwave irradiation.
The structures of the ferrocenyl pyrrolidines (5) were con-
firmed using IR, 1H NMR and elemental analysis. The spectro-
scopic data of the prepared compounds are fully consistent
with the expected structures. The IR spectrum of the ferrocenyl
pyrrolizidine (5a) shows a peak at about 2250 cm−1 due to the
Table 1 Synthesis of (5) using different reaction conditions
Entry
R
Method A
Method B
Method C
Results and discussion
Time Yield
Time
Yield
/%a
Time
Yield
/%a
/h
/%a
/min
/min
The preparation of the novel ferrocenyl pyrrolizidines has
been carried out in two steps from commercially available
ferrocenecarboxaldehyde (1). First, by reaction with an equiv-
alent amount of malononitrile (2), under basic conditions
as shown in Scheme 1, the ferrocene derivative 3 was prepared
by Knoevenagel condensation.17 In the second stage of the
synthesis, the reaction of 1, 1-dicyano-2-ferrocenylethene (3)
as the dipolarophile with various azomethine ylides generated
from aromatic aldehydes (4) and proline afforded a series of
novel ferrocenyl pyrrolizidines (5). The reactions were carried
1
2
3
4
5
H
16
16
15
52
56
48
53
50
18
15
15
15
15
49
54
48
54
51
10
10
10
10
10
50
53
46
55
52
Me
i-Pro
2,3-DiMe 15
OMe
16
Method A: Conventional toluene/reflux; Method B: toluene
with microwave irradiation; Method C: neat with microwave
irradiation.
a Isolated yield.
Scheme 1 Preparation of ferrocenyl pyrrolizidines (5).
* Correspondent. E-mail: zhangym.jy@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2012 537
cyano group. In the 1H NMR spectra of the product, the hydro-
gen atoms of the unsubstituted cyclopentadienyl moiety appear
as a sharp singlet at about δ 3.71. The protons of the ferrocene
substituted cyclopentadienyl moiety appear as multiplets at
about δ 3.91–4.01 and δ 4.06–4.46. The pyrrolizidine ring
protons occur as multiplets in the region δ 2.06–2.90. The H
proton of the pyrrolizidine ring attached to the ferrocene core
appears as a doublet at δ 3.92 (J = 11.0 Hz) which clearly
proves the regiospecificity in formation of the cycloadduct
(5a) and signals at 6.97–7.73 ppm arise from the phenyl pro-
tons. Similar results were obtained with ferrocene derivatives
(3) affording the cycloadducts 5b–e. The structure of 5d
was finally confirmed by X-ray diffraction studies (Fig. 1),
which further proved the structure and regiospecificity of the
cycloadduct.
for the given time at 120 °C. This reaction was controlled with the
temperature of microwave oven at 120 °C and a power of 450W. After
the completion of the reaction (the reaction was followed by TLC), the
mixture was allowed to cool to room temperature. The crude product
was chromatographed on silica gel (200–300 mesh) using a mixture of
petroleum ether and ethyl acetate (10/1) as eluent to afford the pure
ferrocenyl pyrrolizidines (5a–e).
Method C: Solvent-free [3+2]-cycloaddition reaction under micro-
wave-irradiation: A mixture of a chosen aromatic aldehyde (1a–,
2 mmol) L-proline (2 mmol) and 1,1-dicyano-2-ferrocenylethene (3)
(2 mmol) was irradiated for the given time at 120 °C. This reaction
was controlled with the temperature of the microwave oven at 120 °C
for the given time and the power at 450W. After the completion of the
reaction (the reaction was followed by TLC), the mixture was allowed
to cool to room temperature. The crude product was chromatographed
on silica gel (200–300 mesh) using a mixture of petroleum ether
and ethyl acetate (10/1)as eluent to afford the pure ferrocenyl
pyrrolizidines (5a–e).
In conclusion, we have synthesised a series of hitherto
unknown ferrocenyl pyrrolidines (5) through the [3+2]-cyclo-
addition of azomethine ylides with unusual ferrocene dipola-
rophiles. We obtained the title compounds (5) using three
methods, but found that under microwave irradiation conditions
the reaction times are greatly reduced.
1
(5a): Yellow crystals; m.p. 178–181 °C. HNMR (CDCl3) δ 1.93
(1H, m, CH2CH2–), 2.04–2.21 (3H, m, CH2CH2–), 2.62–2.76 (1H,
m, NCH2–), 2.88–2.91 (1H, m, NCH2–), 3.72 (5H, s, Fc-unsubst.
Ring), 3.92 (2H, d, J = 11.0 Hz, FcCH–), 4.02 (2H, d, J = 10.5 Hz,
NCH–), 4.03–4.48 (5H, m, FeC5H4, C(CN)2CH–), 7.23–7.50 (5H,
Ph-H). IR (KBr) ν/cm−1: 2248, 1103, 999.8, 749, 501, 483. Anal.
Calcd for C25H23 N3Fe: C, 71.27; H, 5.50; N, 9.97. Found: C, 71.36; H,
5.15; N, 9.87%.
Experimental
All reactions were monitored by TLC. Melting points (uncorrected)
were measured with a XT4 melting point apparatus. 1H NMR spectra
were recorded on a Varian VXR 500 (500 MHz) spectrometer, using
CDCl3 as solvent and TMS as the internal standard. IR spectra were
determined on a Nicolet 6700 spectrophotometer using KBr pellets.
Elementary analyses were performed using a Heraeus CHN-O-RAPID
analyser. Microwave reactions were carried out in a Xianghu XH-
100B microwave oven. TLC analysis was performed on 0.25mm silica
gel GF254 plates. All chemicals were purchased and used without
further purification.
The title compound was prepared according to Scheme 1 and
1,1-dicyano-2-ferrocenylethene (3) m.p. 99–101 °C. IR (KBr, cm−1):
2190 (CN); 1629 (C=C); 1101, 992, 814 was prepared by literature
methods.17
1
(5b): Yellow crystals; m.p. 183–185 °C. HNMR (CDCl3) δ 1.95
(1H, m, CH2CH2–), 2.06–2.23 (3H, m, CH2CH2–), 2.35 (3H, s,
CH3–), 2.61–2.74 (1H, m, NCH2–), 2.86–2.90 (1H, m, NCH2–), 3.71
(5H, s, Fc-unsubst. Ring), 3.94 (2H, d, J = 10.5 Hz, FcCH–), 4.01 (2H,
d, J = 10.5Hz, NCH–), 4.06–4.46 (5H, m, FeC5H4, C(CN)2CH–),
7.22 (2H, d, J = 7.5 Hz, Ph-H), 7.36 (2H, d, J = 8.0 Hz, Ph-H). IR
(KBr) ν/cm−1: 2250, 1105, 1000.8, 748, 500, 481. Anal. Calcd for
C26H25 N3Fe: C, 71.73; H, 5.79; N, 9.65. Found: C, 72.15; H, 6.06; N,
9.23%.
1
(5c): Yellow crystals; m.p. 184–187 °C. HNMR (CDCl3) δ 1.25
(6H, d, J = 7.0 Hz, CH(CH3)2-), 1.92–2.10 (3H, m, CH2CH2–),
2.30–2.34 (1H, m, CH2CH2–), 2.58–2.63 (1H, m, C(CN)2CH–),
2.89–3.01 (2H, m, NCH2), 3.53 (1H, d, Ph-CH–), 3.97–4.00 (1H, q,
CH(CH3)2-), 4.01 (5H, s, Fc-unsubst. Ring), 4.21–4.44 (5H, m,
FeC5H4, FcCH–), 7.25 (2H, d, J = 5.0 Hz, Ph-H),7.53 (2H, d, J =
8.0 Hz, Ph-H). IR (KBr) ν/cm−1: 2246, 1105, 999.9, 769, 713, 504,
487. Anal. Calcd for C28H29 N3Fe: C, 72.57; H, 6.31; N, 9.07. Found:
C, 72.50; H, 6.56; N, 9.03%.
Synthesis of ferrocenylpyrrolidines (5)
Method A: Under thermal-heating conditions: A mixture of a chosen
aromatic aldehyde (4a–e) (2 mmol) L- proline (2 mmol) and 1,1-dicy-
ano-2-ferrocenylethene (3) (2 mmol) in toluene (15 mL) was mixed in
a round-bottomed flask. The reaction mixture was heated in an oil
bath at reflux for the desired time. After cooling to room temperature,
the reaction mixture was isolated by separation on a silica gel column
with ethyl acetate-petroleum ether (1/10) as the eluent to afford pure
ferrocenyl pyrrolizidines (5a–e).
1
(5d): Yellow crystals; m.p. 165–167 °C. HNMR (CDCl3) δ 1.93–
1.97 (1H, m, CH2CH2–), 2.11–2.25 (3H, m, CH2CH2–), 2.68 (1H,
m, NCH2–), 2.25 (1H, m, NCH2), 3.81 (3H, s, OCH3), 3.74 (5H, s,
Fc-unsubst. Ring), 3.94 (2H, d, J = 11.0 Hz, FcCH–), 3.94 (2H, d, J =
10.5 Hz, NCH–),4.04 (1H, s, FeC5H4), 4.15 (1H, s, FeC5H4), 4.23
(1H, s, FeC5H4), 4.29 (1H, m, NCH–), 4.46 (1H, s, FeC5H4), 6.94
(2H, d, J = 6.8 Hz, Ph-H), 7.37. (2H, d, J = 8.5 Hz, Ph-H). IR (KBr)
ν/cm−1: 2249, 1103, 1000.6, 752, 710, 500, 486. Anal. Calcd for C26H25
N3OFe: C, 69.19; H, 5.58; N, 9.31. Found: C, 70.06; H, 5.85; N,
9.36%.
Method B: Using microwave-irradiation: A mixture of a chosen
aromatic aldehyde (4a–e, 2 mmol) L- proline (2 mmol) and 1,1-dicy-
ano-2-ferrocenylethene (3) (2 mmol) in toluene (2 mL) was irradiated
1
(5e): Yellow crystals; m.p. 178–181 °C. HNMR (CDCl3) δ 1.92–
1.95 (1H, m, CH2CH2–), 2.11–2.23 (3H, m, CH2CH2–), 2.25 (3H, s,
CH3), 2.32 (3H, s, CH3), 2.70–2.75 (1H, m, NCH2–), 2.86–2.91 (1H,
m, NCH2–), 3.68 (5H, s, Fc-unsubst. Ring), 3.91 (2H, d, J = 11.0 Hz,
FcCH–), 4.02 (2H, d, J = 10.5 Hz, NCH–), 4.08–4.45 (5H, m, FeC5H4,
C(CN)2CH–), 7.16–7.25 (3H, m, Ph-H). IR (KBr) ν/cm−1: 2246, 1105,
999.9, 769, 713, 504, 487. Anal. Calcd for C27H27 N3Fe: C, 72.17; H,
6.06; N, 9.35. Found: C, 72.50; H, 5.89; N, 9.73%.
X-ray crystal-structure analysis of 5d
Crystals suitable for X-ray structure determination were obtained
from the filtration by slow evaporation of the solvent. C26H25FeN3O,
Mr=451.34, Monoclinic, P2(1)/n, a=10.4228(13)Å, b=11.4180(14)
Å, c = 18.339(2) Å, V = 2127.3(5) Å3, Dx = 1.409 g cm−3, Z = 4, T =
113(2)K. Slow evaporation of the compound (5d) in petroleum ether
and ethyl acetate yielded single crystals suitable for X-ray analysis.
An orange block crystal with approximate dimensions of 0.26 × 0.22
× 0.20 mm was mounted on a Bruker Smart 1000 CCD diffractometer
equipped with a graphite monochromator data collection. The
determination of the unit cell parameters and data collections were
performed at 113(2) K, using graphite monochromated MoKα (λ =
0.71073 A) radiation. A total of 21430 reflections with 5011 unique
ones with Rint = 0.0544 reflections were measured in the range of
Fig. 1 ORTEP drawing of the structure (3b), thermal ellipsoids
are drawn at 30% probability level.

538 JOURNAL OF CHEMICAL RESEARCH 2012
2.07≤θ≤27.82 º with an oscillation method. All data were corrected
using the SADABS method. The structure was solved by direct meth-
ods using the SHELXL-97 program and refined by full-matrix least-
squares on F2. All non–hydrogen atoms were refined anisotropically,
and hydrogen atoms were added according to theoretical modes. The
final cycle of refinement gave R = 0.0336, wR = 0.0845 (the weight-
ing scheme was w =1/[s2(F02)+(0.0362P)2] where P = (F02+2Fc2)/3).
The final refinement was performed by full matrix least-squares meth-
ods with anisotropic thermal parameters for non-hydrogen atoms on
F2. Molecular graphics were drawn with the program package XP. Full
crystallographic details have been deposited with the Cambridge
Crystallographic Data Center and allocated the deposition number
CCDC-885652. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/data\ request/cif, by e-mailing data\ request@ccdc.
cam.ac.uk, or by contacting the Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
References
1
2
3
4
5
6
M. Muraoka, S.L. Gillett and T.W. Bell, Angew. Chem. Int. Ed., 2002, 41,
3653.
R. Pike, L.C. Ryder, B.R. Horrocks, W. Clegg, B.A. Connolly and
A. Houlton, Chem. Eur. J., 2005, 11, 344.
M. Sailer, Rominger and T.J.J. Müller, J. Organomet. Chem., 2006, 691,
299.
T.J. Zhu, Q.S. Wu, P. Chen andY.P. Ding, J. Organomet. Chem., 2009, 694,
21.
L. Diab, M. Gouygou, E. Manoury, P. Kalck and M. Urrutigoïty,Tetrahedron
Lett., 2008, 49, 5186.
C-S.Juan M., O-S Emilia, G-F Luis and V-B. Antonio, Org. Biomol. Chem.,
2008, 22, 4230.
7
8
9
H.Y. Suni II, J. Electrochem. Soc., 2008, 155, 350.
J.X. Fang, Z. Jin, T. Liu and W. Liu, J. Organomet. Chem., 2003, 674, 1.
Z. Jin, A.H. Huo, T. Liu, Y. Hu, J.B. Liu and Fang, J.X.J. Organomet,
Chem., 2005, 690, 1226.
10 J.W. Daly, T.W. Spande, N. Whittaker, R.J. Highet, D. Feigl, N. Noshimori,
T. Tokuyama and C.W. Meyers, J. Nat. Prod., 1986, 46, 265.
11 R. Prasanna, S. Purushothaman, M. Suresh, and R. Raghunathan,
Tetrahedron Lett., 2011, 52, 792.
12 S. Kathiravan, R. Raghunathan, G. Suresh and G.V. Siva. Med. Chem. Res.,
published online: 11 November 2011.
13 S. Kathiravan and R. Raghunathan. Tetrahedron Lett., 2009, 50, 6116.
14 C.O. Kappe, Angew. Chem. Int. Ed., 2004, 43, 6250.
15 M. Akhter, S. Habibullah, S.M. Hasan, M.M. Alam, N. Akhter and
M. Shaquiquzzaman, Med. Chem. Res., 2011, 20, 1147.
16 Procopio, A. De Nino, M. Nardi, M. Oliverio, R. Paonessa and R. Pasceri.
Synlett, 2010, 12, 1849.
This work was financially supported by Hebei Province
Science and Technology Support Plan Project (11207184D)
and a fund of Hebei University of Science and Technology
(No. XL201137).
Received 2 May 2012; accepted 27 June 2012
Paper 1201288 doi: 10.3184/174751912X13418562888522
Published online: 28 August 2012
17 M. Asiri, Molbank, 2005, M403.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.