Novel 1,3-dipolar cycloaddition reactions of calix[4]bis(spirodienones): synthesis of isoxazolidine derived macrocycles

Article abstract of DOI:10.1016/j.tetlet.2008.01.082

Calix[4]bis(spirodienones) can perform as either 4π or 2π components in cycloaddition reactions with various carbo- and hetero-dienophiles and with 1,2-benzoquinones leading to the formation of highly functionalized macrocycles. In this Letter we report,

Full text of DOI:10.1016/j.tetlet.2008.01.082

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Tetrahedron Letters 49 (2008) 1750–1752
Novel 1,3-dipolar cycloaddition reactions of calix[4]bis(spirodienones):
synthesis of isoxazolidine derived macrocycles
V. B. Ganga a, E. Suresh b, R. Luxmi Varma a,*
a Organic Chemistry Section, Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (CSIR),
Trivandrum 695 019, India
b Analytical Science Discipline, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India
Received 21 September 2007; revised 4 January 2008; accepted 17 January 2008
Available online 20 January 2008
Abstract
Calix[4]bis(spirodienones) can perform as either 4p or 2p components in cycloaddition reactions with various carbo- and hetero-
dienophiles and with 1,2-benzoquinones leading to the formation of highly functionalized macrocycles. In this Letter we report, highly
regio- and stereoselective 1,3-dipolar cycloaddition reactions of a bis(spirodienone) derivative of calix[4]arene with nitrones that provide
easy access to isoxazolidine derived macrocycles in excellent yields. These isoxazolidine derivatives can be considered as direct precursors
of 1,3-amino alcohols.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Calix[4]bis(spirodienone); C,N-Diarylnitrone; 1,3-Dipolar cycloaddition; Isoxazolidine
The calixarenes comprise an extensively studied class of
macrocyclic and polyphenolic compounds that are strongly
associated with host–guest chemistry.1–5 The derivatization
of calixarenes for the design of selective receptors for
anions, cations and neutral molecules6,7 has been largely
done through the modification of the upper or lower rims.
Lately an interesting molecular skeleton based on calix-
arenes, namely bis(spirodienones), was synthesized through
the oxidative cyclization of the adjacent phenolic hydroxyls
by Biali and Litwak (Scheme 1).8 These spirodienones have
been utilized further by the same group for the modifica-
tions of the calixarene skeleton that are otherwise difficult
But
But
But
But
But
But
O
O
OH
OH
HO
O
O
O
R4NBr3
base
+
O
HO
O
O
But
But
But
But
But
But
2a (RS)
2c (RS)
1
2b (RR/SS)
Scheme 1. Oxidation of calix[4]arene.
*
Corresponding author. Tel.: +91 4712515275; fax: +91 4712491712.
E-mail address: lux_varma@rediffmail.com (R. Luxmi Varma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.082

V. B. Ganga et al. / Tetrahedron Letters 49 (2008) 1750–1752
1751
to achieve.9–15 These are interesting molecular skeletons
bestowed with two very reactive 2,4-cyclohexadienone sys-
tems giving leverage for further modification for the design
of new macrostructures. Systematic studies from our group
have shown their versatility as either 4p or 2p components
in various Diels–Alder16,17 and hetero Diels–Alder reac-
tions.18 We have also reported an addition reaction of
the double bond shown in red with dichlorocarbene.18
The reactivity of this double bond as the dienophile in
cycloaddition with 1,2-benzoquinones and with dichloro-
carbene has prompted us to investigate its reactivity
towards 1,3-dipoles. Among various dipoles, nitrones are
particularly attractive as they undergo facile [3+2] cyclo-
addition with alkenes to afford isoxazolidines which are
direct precursors of 1,3-amino alcohols by reductive cleav-
age at the N–O bond.19–22 From the standpoint of further
functionalization of the calix[4]arene skeleton through
cycloaddition, we undertook an investigation of the 1,3-
dipolar cycloaddition reactions of the bis(spirodienone)
with C,N-diarylnitrones and the results of our findings
are presented in this Letter.
To the best of our knowledge, this is the first report on the
1,3-dipolar cycloaddition to the dienone moiety of a
calix[4]bis(spirodienone). However, it should be mentioned
that the 1,3-dipolar cycloaddition reactions of the azide sub-
stituents of calix[4]bis(azido)spirodienones with dimethyl
acetylenedicarboxylate have been reported earlier by
Simaan et al., which led to the formation of 1,2,3-triazole
substituted products.14
We started our investigation by reacting the most stable
isomer of calix[4]bis(spirodienone) 2a with C-(4-methoxy-
phenyl)-N-phenylnitrone 3a. Treatment of a solution of
2a with 2 equiv of 3a in dry toluene under reflux for 92 h
yielded cycloadduct 4a in good yield (Scheme 2).23 Nitro-
nes were prepared by the literature procedures.24
Fig. 1. ORTEP diagram of 4a (hydrogen atoms omitted for clarity).
Ha, appeared as a singlet at d 6.11. The doublet at d 4.49
(J = 4.8 Hz) was assigned to the benzylic proton, Hc. The
bridgehead proton, Hb, appeared as a doublet at d 3.51
(J = 4.5 Hz). The sharp singlet at d 3.77 corresponded with
the methoxy protons of the nitrone. In the 13C NMR spec-
trum, the carbonyl and spiro carbons appeared at d 190.6
and 88.1, respectively. From the spectral data, it was con-
firmed that the addition occurred at the double bond (red
in color) adjacent to the tert-butyl group as in the case of
1,2-benzoquinones.17 The structure and regiochemistry of
cycloadduct 4a was further established by single crystal
X-ray data (Fig. 1).25
To demonstrate the generality, the reaction was
extended to other C,N-diphenylnitrones (Table 1). In all
the reactions, the 5-isoxazolidines 4a–g were obtained as
single stereo- and regioisomers in very good to excellent
yields. With C-(4-chlorophenyl)-N-phenylnitrone, the reac-
tion was faster compared to the other nitrones and gave a
Product 4a was characterized by conventional spectro-
scopic methods. In the IR spectrum, the carbonyl stretch
appeared at 1659 cmꢀ1. The highly symmetrical nature of
1
Table 1
the product was ascertained from the H NMR spectrum.
In the 1H NMR spectrum, the splitting patterns of the
The reactions of calix[4]bis(spirodienone) 2a with various nitrones
methylene groups were similar to those of 2a. The proton,
But
R
N
O
H
But
O
MeO
O
H
toluene, Ar
110 ˚C, t h
+
O
+
C N
2a
But
O
But
Hc
Hb
O
R
-
N
O
O
But
But
H
But
Ha
N
But
4a-4g
O
R
O
3a-3g
O
H
+
i
O
C N
O
O
+
Ha
But
O
O
Entry
R
Time (h)
Yield (%)
-
O
O
Hb
Hc
1
2
3
4
5
6
7
4-Methoxyphenyl, 3a
4-Tolyl, 3b
92
48
72
44
80
72
85
4a, 73
4b, 75
4c, 90
4d, 99
4e, 98
4f, 84
4g, 86
But
4a (73%)
But
MeO
N
But
3a
Phenyl, 3c
2a
4-Chlorophenyl, 3d
4-Fluorophenyl, 3e
4-Trifluorotolyl, 3f
4-Nitrophenyl, 3g
i) toluene, 110 ˚C, Ar, 92 h
MeO
Scheme 2. 1,3-Dipolar cycloaddition of 2a with C-(4-methoxyphenyl)-N-
phenylnitrone.

1752
V. B. Ganga et al. / Tetrahedron Letters 49 (2008) 1750–1752
7. Mandolini, L.; Ungaro, R. In Calixarenes in Action; Imperial College:
London, 2000.
8. Litwak, A. M.; Biali, S. E. J. Org. Chem. 1992, 57, 1943.
9. Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J. Chem. Soc., Chem.
Commun. 1993, 11.
quantitative yield of cycloadduct 4d. The reactivity was
found to be different for different nitrones. Substituents
at the para position of the C-phenyl group were found to
have no significant influence on the reactivity.
[3+2] Dipolar cycloaddition reactions of nitrones to
alkenes result in 4- or 5-substituted isoxazolidines, the reg-
iochemistry being governed by the electronic nature of the
alkenes. Electron rich or neutral alkenes give rise predom-
inantly to 5-substituted isoxazolidines, whereas a reversal
of regioselectivity is observed in the case of alkenes subs-
tituted with one or more powerful electron withdrawing
groups such as cyano. This has been attributed to the lower
orbital energies of alkenes with electron withdrawing
groups favouring interaction between the HOMO of the
dipole with the LUMO of the alkene which results in the
formation of 4-substituted isoxazolidines. The calix[4]-
bis(spirodienone) can be considered as a neutral alkene
and, as expected a 5-substituted isoxazolidine is formed
exclusively as confirmed by the X-ray crystal structure. It
was also observed that the substituents at the C-phenyl
have no significant effect on the reactivity but the rate of
reaction was considerably influenced by these substituents.
In summary, we have introduced an isoxazolidine moiety
to calix[4]bis(spirodienones) via 1,3-dipolar cycloaddition
of nitrones. The bisadducts were obtained regiospecifically.
Studies to transform the isoxazolidines to the highly func-
tionalized macrocycles are underway and a detailed study
of the reactivity of bis(spirodienones) with C-aryl, N-alkyl-
nitrones and other 1,3-dipoles is in progress.
10. Litwak, A. M.; Grynszpan, F.; Aleksiuk, O.; Cohen, S.; Biali, S. E.
J. Org. Chem. 1993, 58, 393.
11. Aleksuik, O.; Grynszpan, F.; Biali, S. E. J. Org. Chem. 1993, 58, 1994.
12. Grynszpan, F.; Biali, S. E. J. Chem. Soc., Chem. Commun. 1994,
2545.
13. Grynszpan, F.; Aleksiuk, F.; Biali, S. E. J. Org. Chem. 1994, 59,
2070.
14. Simaan, S.; Agbaria, K.; Biali, S. E. J. Org. Chem. 2002, 67, 6136.
15. Biali, S. E. Synlett 2003, 1, 1.
16. Varma, L. R.; Ganga, V. B.; Suresh, E. Tetrahedron Lett. 2005, 46,
3061.
17. Varma, L. R.; Ganga, V. B.; Suresh, E.; Suresh, C. H. Tetrahedron
Lett. 2006, 47, 917.
18. Ganga, V. B.; Sreeja, T.; Suresh, E.; Varma, L. R. Tetrahedron 2007,
63, 4134.
19. Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 2, p 83.
20. Gallos, J. K.; Demeroudi, S. C.; Stathopoulou, C. C.; Dellios, C. C.
Tetrahedron Lett. 2001, 42, 7497.
21. Gallos, J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron Lett. 2001,
42, 5769.
22. Sims, J.; Houk, K. N. J. Am. Chem. Soc. 1973, 95, 5798.
23. Typical experimental procedure: To
a solution of 2a (50 mg,
0.08 mmol) in dry toluene (4 ml) was added 3a (37 mg, 0.16 mmol).
The reaction mixture was heated at 110 °C under an inert atmosphere
for 92 h. The solvent was removed in vacuo and the crude product
was purified by silica gel column chromatography (eluent, 90:10
hexanes/EtOAc) to afford product 4a in 73% yield as a white
crystalline solid. The compound was crystallized from dichloro-
methane/acetonitrile mixture (3:1). Mp >300 °C. IR (KBr) mmax: 2958,
1659, 1595, 1484, 1361, 1320, 1285, 1250, 1167, 876, 749 cmꢀ1 1H
.
t
t
NMR (CDCl3, 300 MHz) 0.92 (s, 18H, Bu), 1.35 (s, 18H, Bu), 1.96
(d, J = 15.3 Hz, 2H, –CH2–), 2.98 (d, J = 15.3 Hz, 2H, –CH2–), 3.44
(d, J = 15.0 Hz, 2H, –CH2–), 3.51 (d, J = 4.5 Hz, 2H, bridgehead H),
3.77 (s, 6H, –OCH3), 4.05 (d, J = 15.3 Hz, 2H, –CH2–), 4.49 (d,
J = 4.8 Hz, 2H, benzylic H), 6.11 (s, 2H, alkenyl H), 6.79 (m, 12 H, Ar
H), 7.09 (s, 2H, ArH of calixarene), 7.20 (m, 4H, ArH), 7.35 (d,
J = 8.7 Hz, 4H). 13C NMR (CDCl3, 75 MHz) 190.6, 159.0, 152.7,
150.9, 144.2, 143.8, 140.5, 134.3, 128.6, 128.5, 126.9, 125.2, 120.7,
120.1, 114.2, 112.6, 90.0, 88.1, 71.6, 60.6, 55.2, 36.4, 34.6, 34.3, 33.þ2,
Acknowledgements
V.B.G. thanks the CSIR, Government of India, New
Delhi for Research Fellowships. Thanks are also due to
Ms. Saumini Mathew and Ms. S. Viji for NMR and mass
spectral data.
References and notes
32.3, 31.9, 27.8, 26.9. MS (FAB): m/z calcd for C72H78N2O8
:
1098.57. Found: 1098.10. Anal. Calcd for C72H78N2O8: C, 78.66; H,
7.15; N, 2.55. Found: C, 76.16; H, 6.84; N, 3.45.26
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93.
¨
Synth. 1973, Coll. Vol. 5, 1124.
25. The crystal structure has been deposited at the Cambridge Crystallo-
graphic Data Centre and allocated the deposition number CCDC
657150.
26. We could not obtain satisfactory microanalytical data for 4a. This
seems to be a feature of several calixarene systems. See: Bo¨hmer, V.;
Jung, K.; Scho¨n, M.; Wolff, A. J. Org. Chem. 1992, 57, 790.
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