Cycloaddition reactions of azomethine ylides with a 9-fluorenone-malononitrile Kn?evenagel adduct

Article abstract of DOI:10.1016/j.tetlet.2008.07.127

Numerous derivatives of spiropyrrolidines and spiropyrrolizines containing cyano groups were successfully synthesized via condensation of sarcosine and proline Schiff bases of several aromatic aldehydes with the Kn?evenagel adduct of 9-fluorenone-malononitrile prepared through a modified procedure. Assignment of the molecular structure was carried out by single crystal X-ray diffraction, as well as by HMBC and ROSEY spectroscopy.

Full text of DOI:10.1016/j.tetlet.2008.07.127

Tetrahedron Letters 49 (2008) 5899–5901
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cycloaddition reactions of azomethine ylides with a 9-fluorenone-malononitrile
Knöevenagel adduct
*
Mehdi Ghandi , Seyed Jamal Tabatabaei Rezaei, Ahmad Yari, Abuzar Taheri
School of Chemistry, University College of Science, University of Tehran, Tehran, PO Box 14155 6455, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Numerous derivatives of spiropyrrolidines and spiropyrrolizines containing cyano groups were success-
fully synthesized via condensation of sarcosine and proline Schiff bases of several aromatic aldehydes
with the Knöevenagel adduct of 9-fluorenone-malononitrile prepared through a modified procedure.
Assignment of the molecular structure was carried out by single crystal X-ray diffraction, as well as by
HMBC and ROSEY spectroscopy.
Received 21 May 2008
Revised 17 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Sarcosine
Proline
Azomethine ylide
Cycloaddition
Cycloadditions are an important group of reactions in organic
synthesis.1 The azomethine ylide represents one of the most reac-
tive and versatile classes of 1,3-dipoles and is trapped readily by a
range of dipolarophiles, either inter or intramolecularly, forming
substituted pyrrolidines.2 The three atom C-N-C unit containing
H3C N
Ar
H3C N
or
R
N
H3C
Ar
Ar
R
S-shaped ylide
W-shaped ylide
four
p-electrons affords a zwitterionic system with the nitrogen
and one of the carbon atoms carrying positive and negative
charges, respectively. As such, this species in combination with
two p-electrons of an alkene or alkyne constitutes a six - electron
N
R
CH3
N
NHCH2CO2H
Ar-CHO
Ar
Ar
system capable of undergoing a [
p4s + p2s] reaction according to
R
Woodward-Hoffmann rules.3
2', 5'-trans-disubstituted
S-shaped ylide
The Knöevenagel condensation is a well-established method for
the synthesis of ,b-unsaturated compounds. It is utilized in vari-
CO2H
N
a
H
N
R
N
ous synthetic transformations and thus we have used this proce-
dure for the synthesis of a 9-fluorenone-malononitrile adduct.4
The simplest approach to an azomethine ylide is the reaction of
a secondary amine such as sarcosine or proline with an aldehyde
(Scheme 1).5 Reaction of the resulting ylide with an alkene either
present in solution or as a functional group present within the
aldehyde structure, via inter- or intramolecular cycloaddition
results in the formation of the corresponding pyrrolidine and
pyrrolizine heterocycles (Scheme 1).6 Spiropyrrolidines and spiro-
pyrrolizines have gained much attention due to their interesting
biological activities.7
X
R
Ar
Ar
2', 5'-cis-disubstituted
W-shaped ylide
Scheme 1. Formation of
disubstituted product from proline.
a single product from sarcosine and a
20,50-trans-
them via reaction of an azomethine ylide with the Knöevenagel ad-
duct of 9-fluorenone-malononitrile. This reaction was expected to
yield a pyrrolidine or a pyrrolizine derivative with the negative
carbon of the azomethine ylide attached to the 9-fluorene carbon
since reaction of an azomethine ylide with double bonds contain-
ing electron-withdrawing groups has been reported to follow the
Michael type addition.8 Subsequent transformation of the cyano
substituent to other functional groups and formation of the
corresponding aldehydes, ketones, esters, and amino acids with
potential biological activities could be carried out easily. Herein,
Our recent interest in pyrrolidine and pyrrolizine derivatives
containing substituents at C30 on the ring prompted us to prepare
* Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.127

5900
M. Ghandi et al. / Tetrahedron Letters 49 (2008) 5899–5901
NC CN
NC CN
CHO
CHO
NH
CH NHCH COOH
+
+
+
3
2
+
COOH
R
R
2
2
1
1
R
R
R
CH3
N
R
N
CH3
N
NC
NC
2'
NC
NC
3'
NC
NC
N
NC
NC
4' 5'
4
6
5
3
R: (a) 4-Me; (b) 4-OMe; (c) 4-Cl; (d) 4-Br; (e) 4-H; (f) 3,4-OMe; (g) 3,4,5-OMe; (h) 4-NO2
Time (h)
Yield (%)
76
5
a
3
a
Time (h)
Yield (%)
7
7
8
6
5
7
6
8
5
8
6
5
4
6
78
70
68
74
77
73
73
b
c
d
e
b
c
d
e
68
74
73
71
73
trace
f
f
g
g
77
44
h
h
10
10
Scheme 2. Synthesis of spiropyrrolidines and spiropyrrolidines.
we are pleased to report the synthesis of a number of pyrrolidine
and pyrrolizine derivatives via condensation of the Knöevenagel
adduct of 9-fluorenone-malononitrile 1 with sarcosine and proline
Schiff bases of several aromatic aldehydes.
The Knöevenagel adduct was prepared via modification9 of the
previously reported procedure.10 Utilization of our modified meth-
od reduced the reaction time with a concomitant increase in the
reaction yield (vide antara). This adduct was subsequently treated
with the Schiff bases obtained from condensation of either sarco-
sine or proline with a number of aromatic aldehydes 2a–h in
refluxing toluene for the appropriate amount of time (Scheme
2).11 The solid products were filtered and recrystallized from meth-
anol resulting in spiropyrrolidines 3a–h and spiropyrrolizines 5a–
h. Identification of the products was carried out by spectroscopic
methods.12 The results are presented in Scheme 2.
The 1H NMR spectrum of 3a exhibited a singlet at d 2.42 for the
4-CH3 protons and another singlet at d 2.55 for the N–CH3 protons.
The N–CH2 protons of the pyrrolidine ring appeared as two dou-
blets at d 3.26 and d 3.73. The benzylic proton resonated as a sin-
glet at d 4.36. The 13C NMR showed a signal at d 66.31 due to the
spiro carbon. The structure of compound 3a was further confirmed
by mass spectrometry which exhibited a molecular ion peak at m/z
375.
Figure 1. ORTEP diagram of compound 3a.
3a was confirmed unequivocally. Therefore, the observation of a
long range coupling in the HMBC spectrum, seems to be a reliable
tool for determination of molecular structure whenever obtaining
the single crystal X-ray structure is not possible.
The configuration of the stereocenter in 5a was assigned using
ROSEY spectroscopy. Protons H20 and H50 (see Scheme 2) showed
no correlation in the ROSEY spectrum (Fig. 3), which implied a
trans arrangement between C-20 and C-50.
In addition to regioselectivity issues (vide supra), the dipolar
cycloaddition reaction can lead to mixtures of stereoisomers. From
the two possible W- and S-shaped ylide geometries obtained from
proline (Scheme 1), the 20,50-cis-disubstituted and the 20,50-trans-
disubstituted products respectively, are anticipated to be formed
via a suprafacial reaction.2 Inspection of the other reported exam-
ples2 and product 5a (Scheme 2), perhaps show some general pref-
erence for cycloaddition through an S-shaped ylide.2
The 1H NMR spectrum of 5a showed a singlet at d 2.13 for the 4-
CH3 protons. The N–CH proton of the pyrrolizine ring (H50) ap-
peared as a triplet at d 4.85 and the benzylic proton (H20) resonated
as a singlet at d 5.12.
As shown in Scheme 2, two possible Michael-type and anti-Mi-
chael type additions can be envisaged for the addition of azome-
thine ylides to 2a–h leading either to 3a–h and 5a–h or 4a–h
and 6a–h, respectively. Confirmation of the product structure
was obtained by single crystal X-ray diffraction of 3a (Fig. 1).13
The reaction proceeded exclusively via Michael-type addition of
the azomethine ylide to the dipolarophile.
Based on the HMBC spectrum of 3a (Fig. 2) and the observation
of the 1,3-coupling of the CN groups (appearing at d 113.2 and d
114) with the benzylic CH (resonating at d 4.36), the structure of
In summary, pyrrolidine and pyrrolizine derivatives containing
two cyano groups at positions 30 and 30, respectively, were success-
fully prepared and identified. Transformation of the cyano groups

M. Ghandi et al. / Tetrahedron Letters 49 (2008) 5899–5901
5901
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.127.
References and notes
1. Kurt, V.; Anker Gothelf, J. Chem. Rev. 1998, 98, 863–909.
2. Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809.
3. (a) Oppolzer, W. Combining C–C Bonds. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, UK, 1991; Vol.
5, (Chapter 4.1); (b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
4. March, J. Advanced Organic Chemistry, Reactions, Mechanisms and Structure, 3rd
ed.; John Wiley & Sons, 1985.
5. (a) George, B.; Imad, S.; Achmet, S. M.; Francis, B.; Joelle, L. Org. Lett. 2003, 5,
4915–4918; (b) Yu, G. G.; Yibo, X. A.; Chris, K.; Darold, M.; Hing, L. S.
Tetrahedron Lett. 2002, 43, 955–957; (c) Mahalingam, P.; Raghavachary, R.
Tetrahedron Lett. 2005, 46, 7197–7200.
6. Ekamabaram, R.; Murugavel, K.; Raghavachary, R. Tetrahedron Lett. 2007, 48,
1835–1839.
7. (a) Waldmann, H. Synlett 1995, 133; (b) Fujimori, S. Jap. Pat. Appl. 88, 2912.; (c)
Fujimori, S. Chem. Abstr. 1990, 112, 98409.
8. (a) Ponnusamy, S.; Baby, V.; Suchithra, M. Org. Lett. 2007, 9, 4095–4098; (b)
Nela, M.; Andrew, N. B.; Stephan, C.; Roberat, W. Tetrahedron Lett. 2006, 47,
5139–5142.
Figure 2. HMBC spectrum of compound 3a.
9. Modified procedure for the preparation of the 9-fluorenone-malononitrile adduct:
To a solution of 9-fluorenone (1 mmol) in absolute ethanol (5 mL) containing 3
drops of piperidine, malononitrile (1.1 mmol) was added and the reaction
mixture was stirred at room temperature for 30 min. The resulting orange
precipitate was then filtered and recrystallized from ethanol to afford the
product (yield 87%, mp: 230–232 °C).
10. Abdel-Rahman, A. H.; Keshk, E. M.; Hannab, M. A.; El-Bady, Sh. M. Bioorg. Med.
Chem. 2004, 12, 2483–2488.
11. Representative procedure for the preparation of fluorene spiro[9.40]-1-N-methyl
(20–arylidene)-30,30–dicyano-pyrrolidine:
A mixture of sarcosine (178 mg,
2.0 mmol), aldehyde (2.0 mmol), and 1 (456 mg, 2.0 mmol) in dry toluene
(20 mL) containing molecular sieves (1000 mg, 3 Å) was refluxed with stirring
for the appropriate time (see Scheme 2). The progress of the reaction was
followed by TLC. After completion, the solvent was removed under reduced
pressure and the resulting solid was recrystallized from methanol to afford a
white crystalline product.
12. Fluorene
spiro[9.40]-1-N-methyl(20–p-methylphenyl)-30,30–dicyano-pyrrolidine
(3a): White crystals, mp: 217–219 °C; 1H NMR (500 MHz, CDCl3) d 2.42 (s,
3H), 2.55 (s, 3H), 3.26 (d, J = 10.1 Hz, 1H), 3.73 (d, J = 10.1 Hz, 1H), 4.36 (s, 1H),
7.30–8.08 (m, 12H); 13C NMR (125 MHz, CDCl3) d 21.77, 40.04, 53.82, 60.71,
66.31, 79.92, 113.37, 114.02, 120.53, 120.97, 126.10, 126.75, 128.25, 128.50,
128.92, 129.99, 130.20, 130.24, 130.57, 140.41, 140.48, 141.30, 144.67, 146.10;
IR(KBr): 2245 cmꢀ1; mass m/z: 375 (M+); Anal. Calcd for C26H21N3: C, 83.2; H,
5.6; N, 11.2. Found: C, 83.12; H, 5.73; N, 11.35. Fluorene spiro [9.40]-1-N-
methyl(20–p-methylphenyl)-30,30–dicyano-pyrrolizine (5a): White crystals, mp:
234–237 °C; 1H NMR (500 MHz, CDCl3) d 1.51 (m, 1H), 1.63 (m, 1H), 2.13 (s,
3H), 2.18 (m, 2H), 2.88 (m, 1H), 3.26 (m, 1H), 4.85 (t, J = 6.3 Hz, 1H), 5.12 (s,
1H),7.05–8.04 (m, 12H); 13C NMR (125 MHz, CDCl3) d 21.34, 27.93, 30.06,
49.63, 52.69, 54.01, 67.75, 71.11, 112.92, 114.24, 120.69, 120.89, 121.48,
125.94, 127.37, 127.99, 128.10, 128.71, 129.95, 130.02, 130.48, 137.58, 139.04,
140.92, 141.56, 142.49; mass m/z: 401 (M+); Anal. Calcd for C28H23N3: C, 83.79;
H, 5.73; N,10.47. Found: C, 83.91; H, 5.84; N, 10.67.
Figure 3. ROSEY spectrum of compound 5a.
to other functionalities is currently under investigation in our re-
search group and is expected to furnish other new pyrrolidine
and pyrrolizine derivatives.
13. Crystallographic data for 3a have been deposited at the Cambridge
Crystallographic Data Centre with the deposition number CCDC 693980.
Copies of these data can be obtained free of charge via www.ccdc.ca-m.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336 033; or e-mail:
deposit@ccdc.cam.ac.uk).
Acknowledgement
The authors thank the University of Tehran for financial support
of this research.