Regioselective ipso formylation of p-tert-butylcalix[4]arene

Article abstract of DOI:10.1016/j.tetlet.2005.08.041

A convenient procedure for direct introduction of one formyl group into p-tert-butylcalix[4]arenes through ipso substitution is described.

Full text of DOI:10.1016/j.tetlet.2005.08.041

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7259–7262
Regioselective ipso formylation of p-tert-butylcalix[4]arene
H. M. Chawla,* N. Pant* and Bindu Srivastava
Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi 110016, India
Received 7 May 2005; revised 4 August 2005; accepted 10 August 2005
Dedicated to Professor Sukhdev on his birthday (17th June)
Abstract—A convenient procedure for direct introduction of one formyl group into p-tert-butylcalix[4]arenes through ipso substi-
tution is described.
Ó 2005 Published by Elsevier Ltd.
Calixarenes are phenolic metacyclophanes that can be
tailored to obtain novel molecular receptors for mole-
cular recognition.1 Their diverse applications have been
primarily due to functionalization at the hydroxyl group
(lower rim) and/or at the p-position of the phenolic units
(upper rim) of the calixarene architecture. Formyl calix-
[n]arenes are one of the most important types of sub-
strates for synthesizing substituted calixarenes. Several
studies have been reported in recent years on the intro-
duction of formyl groups into calixarenes2–4 with or
without regioselectivity. Likewise, the synthesis of
mono-, di-, tri- and tetraformylated calix[4]arenes in
low yields reported by Pochini and co-workers,3 has been
modified by our group.4a It has been determined that all
the procedures described thus far, for formylated calixa-
renes (exhaustive or regioselective), involve a three-step
sequence which includes (i) de-tert-butylation, (ii) treat-
ment with alkyl halide to yield calix[4]arene ethers and
(iii) formylation to yield formyl calix[4]arenes.
tert-butylcalix[4]arenes, which may initiate new vistas
in calixarene chemistry.
The required starting materials were obtained by litera-
ture procedures or minor modifications thereof. For
example, monoetherification9 of 1a was performed with
LiOH and an alkyl halide in dry dimethylformamide
(DMF) at room temperature for 48 h to give 2a10 and
3a in 85% and 73% yields, respectively. The diether
calix[4]arenes (4a,11 5a12 and 6a13) were synthesized by
the reported procedures.
ipso Formylation of p-tert-butylcalix[4]arene was carried
out as shown in Scheme 1. For instance, 5a was sub-
jected to ipso-monoformylation using dichloromethyl
methyl ether in the presence of TiCl4 as Lewis acid cat-
alyst at room temperature for 24 h to yield 5b in 68%
1
yield. The H NMR spectrum of 5b14 showed a typical
AB pattern represented by two pairs of doublets be-
tween d 3.31 and 3.42 and d 4.27 and 4.31 for the axial
and equatorial protons, respectively, indicating that 5b
exists in the cone conformation. The aldehydic proton
appeared as a nonexchangeable singlet at d 9.78, while
the OH protons appeared at d 7.92 and d 9.27, disap-
Though ipso substitution involving nitro,5 sulfonate,6
acyl7 and bromo8 groups at the upper rim of calix[n]-
arenes has been reported by us and others, experimental
conditions for the synthesis of formyl calix[4]arenes via
ipso substitution of a p-tert-butyl group have not been
described so far.
1
pearing on exchange with D2O. Comparison of the H
NMR data of 5b with that of starting compound 5a
indicated that the downfield shift of the characteristic
peak of one of the phenolic OH groups from d 7.8 to
d 9.27 is perhaps due to ipso formylation at the p-posi-
tion of the phenolic unit.
We report herein, a method to achieve the direct replace-
ment of one p-tert-butyl group by a formyl group in p-
Analogously, following the same experimental protocol,
2a, 3a and 4a were converted into 2b, 3b and 4b, respec-
tively. Six examples of monoformylated calix[4]arenes
synthesized by the optimized procedure are shown in
Keywords: p-tert-Butylcalix[4]arene; ipso Formylation; Monoformyl
calixarenes.
*
Corresponding authors. Tel.: +91 11 26591517; fax: +91 11
26591502; e-mail: hmchawla@chemistry.iitd.ernet.in
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.041

7260
H. M. Chawla et al. / Tetrahedron Letters 46 (2005) 7259–7262
OR1
OH
OH
R1
OH
iii
i
CHO
OH
2a CH3
3a n-C4H9
iii
4
OH
OR3
OR2
OR1
1a
ii
1b R1 = R2 = R3 = H
2b R2 = CH3; R1 = R3 = H
3b R2 = n- C4H9; R1 = R3 = H
4b R2 = H; R1 = R3 = CH3
5b R2 = H; R1 = R3 = n-C3H7
6b R2 = H; R1 = R3 = n-C4H9
iii
OR2
OR2
OH
OH
R2
4a CH3
5a n-C3H7
6a n-C4H9
Scheme 1. Reagents and conditions: (i) R1X, LiOH, DMF, rt; (ii) R2X, K2CO3, CH3CN, reflux; (iii) Cl2CHOCH3, TiCl4, DCM, rt.
Table 1. The optimized yield of 5-monoformyl-
tris(11,17,23-tert-butyl)-25,27-di-propoxycalix[4]arene
5b could be obtained by using 50 equiv each of TiCl4
and dichloromethyl methyl ether. A larger excess of
the formylating reagent did not lead to multiformylation
(Table 2). Even when 5b was subjected to further ipso
formylation, formation of di-, tri- and tetraformylated
compounds could not be detected in the reaction
mixture.
bridge, and 12 singlets in the 13C NMR for aromatic
carbons revealed that 2b is the distal isomer which was
confirmed by a COSY NMR spectrum. Though the
1H NMR spectral pattern for 3b was not unambiguous,
COSY and 13C NMR data favour the distal disposition
of the formylated and alkylated phenol ring.15
The reaction was found to be dependent upon the tem-
perature. The optimum yield of monoformyl derivative
5b (68%) was obtained when the reaction was performed
at 35 °C. Lowering the reaction temperature from 35 to
0 °C was found to decrease the overall yield of the ipso
formylated product (Table 3). Thus, when the reaction
was performed at low temperature (0 °C), it required
approximately 48 h for completion. At reflux tempera-
ture, the same reaction required 4 h for completion but
with a decreased yield of the target compound. These re-
sults are contrary to those observed in earlier published
methods on formylation of debutylated calixarenes
when larger yields of mono- and diformyl derivatives
were obtained at lower temperatures.3a
The regio and conformational isomerism of the synthe-
sized monoformylated derivatives is being examined,
however, preliminary NMR (1H, 13C and COSY) analy-
sis revealed that the cone conformation of the calixa-
renes is preserved in the reaction. The formyl group is
introduced at the aromatic position, which is not alk-
oxylated at the para position. In the case of monoalkyl-
ated
monoformylated-tris(p-tert-butyl)calix[4]arenes,
the formyl group in principle can be attached to the dis-
tal aromatic ring in front of the alkylated phenol or on
the proximal aromatic ring. The appearance of two sing-
lets, each for the p-tert-butyl group and the methylene
Apparently, it appears that further formylation of
monoformyl tris(tert-butyl)calix[4]arenes does not take
place presumably due to steric crowding of the potential
intermediate involved and the relative stability of differ-
ent formyl calixarene derivatives.
Table 1. Different products of ipso formylation
Entry
Reactant
Reaction time (h)
Product
Yield (%)
1
2
3
4
5
6
1a
2a
3a
4a
5a
6a
18
10
53
15
24
65
1b
2b
3b
4b
5b
6b
65
72
57
63
68
55
We conclude that the selective monoformylated calix[4]-
arenes can be obtained through ipso formylation of p-
tert-butylcalix[4]arene ethers. The reaction is sensitive
to temperature and reagent concentration but seems
to be independent of the ether group at the lower rim.
This convenient access to monoformyl p-tert-butyl-
calix-[n]arenes opens a new perspective on calix[4]arene
chemistry.
Table 2. Effect of reaction conditions on the yields of compound 5b
TiCl4
(equiv)
Cl2CHOCH3
(equiv)
Time
(h)
Product
Yield
(%)
Table 3. Effect of the temperature and reaction time on the formyl-
ation of 5a
25
30
35
40
50
75
50
30
35
40
50
75
12
48
48
48
18
10
5b
5b
5b
5b
5b
5b
37
40
55
57
68
68
Temperature (°C)
Time (h)
Yield (%)
0
25
35
Reflux
48
24
18
4
68
68
55
45

H. M. Chawla et al. / Tetrahedron Letters 46 (2005) 7259–7262
7261
(0.07 mmol) in dichloromethane (35 mL) were added a
solution of 1,1-dichloromethyl methyl ether (3.5 mmol) in
dichloromethane (5 mL) and a solution of titanium
tetrachloride (3.5 mmol) in dichloromethane (5 mL) simul-
taneously and as quickly as possible. The reaction mixture
was stirred at room temperature until the starting material
had been consumed (TLC) and was quenched with ice cold
water (50 mL). The organic layer was separated, washed
twice with water and dried (Na2SO4). The solvent was
evaporated under reduced pressure and the residue was
purified by column chromatography to yield the desired
monoformyl calix[4]arene product. The synthesis and
characterization of new monoformyltris(p-tert-butyl)ca-
lix[4]arenes are discussed below: Compound 1b: Starting
compound 1a, reaction time 18 h, eluent chloroform.
Compound 1b; 65% yield; mp > 250 °C. Found: C, 79.50;
H, 7.75. C41H48O5 requires C, 79.32; H, 7.79; FAB-MS
m/z Calcd: 620.82. Found 620. 1H NMR (300 MHz,
CDCl3): d 1.18, 1.21 (2s, 27H, –C(CH3)3), 3.53 (br s, 4H,
ArCH2Ar), 4.26 (br s, 4H, ArCH2Ar), 7.03, 7.08, 7.10 and
7.61 (4s, 8H, ArH), 9.7 (s, 1H, CHO), 10.33 (s, 4H, D2O
exch. OH). Compound 2b: Starting compound 2a, reac-
tion time 10 h, recrystallization: chloroform/methanol.
Compound 2b: 72% yield; mp 112 °C. Found: C, 79.50; H,
7.92. C42H50O5 requires C, 79.46; H, 7.94; FAB-MS m/z
Acknowledgements
The authors acknowledge the SAIF, Lucknow for FAB-
MS spectra and financial assistance received from the
Department of Science and Technology (Govt. of In-
dia), CSIR and the University Grants Commission, for
a junior research fellowship to B.S.
References and notes
1. (a) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713–1734;
(b) Ludwig, R. Fres. J. Anal. Chem. 2000, 367, 103–128.
2. Komori, T.; Shinkai, S. Chem. Lett. 1992, 901–904.
3. (a) Arduini, A.; Fanni, S.; Manfredi, G.; Pochini, A.;
Ungaro, R.; Sicuri, A. R.; Ugozzoli, F. J. Org. Chem.
1995, 60, 1448–1453; (b) Arduini, A.; Manfredi, G.;
Pochini, A.; Sicuri, A. R.; Ungaro, R. J. Chem. Soc.,
Chem. Commun. 1991, 936–937.
4. (a) Arora, V.; Chawla, H. M.; Santra, A. Tetrahedron
2002, 58, 5591–5597; (b) Sartori, A.; Casnati, A.; Mand-
olini, L.; Sansone, F.; Reinhoudt, D. N.; Ungaro, R.
Tetrahedron 2003, 59, 5539–5544.
5. (a) Kumar, S.; Varadarajan, R.; Chawla, H. M.; Hundal,
G.; Hundal, M. S. Tetrahedron 2004, 60, 1001–1005;
(b) Redon, S.; Li, Y.; Reinaud, O. J. Org. Chem. 2003, 68,
7004–7008.
6. Kumar, S.; Chawla, H. M.; Varadarajan, R. Indian J.
Chem. 2003, 42B, 2863–2865.
1
Calcd: 634.84. Found: 635. H NMR (300 MHz, CDCl3):
d 0.88, and 1.22 (2s, 27H, –C(CH3)3), 3.34 and 3.44 (2d,
4H, J = 13 Hz, ArCH2Ar), 3.89 (s, 3H, –OCH3), 4.18 (d,
4H, J = 13.2 Hz, ArCH2Ar), 6.68, 6.78, 7.00 and 7.18 (4s,
8H, ArH), 9.76 (s, 1H, CHO), 8.44 and 7.58 (2s, 3H, D2O
exch. OH); 13C NMR (CDCl3): d 31.0, 31.2, 31.3, 31.6,
63.5, 125.0, 125.3, 126.2, 127.7, 128.4, 129.0, 130.8, 132.5,
147.4, 150.1, 151.0, 159.5, 191.1. Compound 3b: Starting
compound 3a, reaction time 53 h, eluent for chromato-
graphy (hexane–chloroform 1:1). Compound 3b: 57%
yield; mp 125 °C. Found: C, 79.73; H, 8.37. C45H56O5
requires C, 79.84; H, 8.34; FAB-MS m/z Calcd: 676.92.
7. Kumar, S.; Chawla, H. M.; Varadarajan, R. Tetrahedron
Lett. 2002, 43, 2495–2498.
8. Kumar, S.; Chawla, H. M.; Varadarajan, R. Tetrahedron
Lett. 2002, 43, 7073–7075.
9. The physical constants and spectroscopic data for starting
materials (2a,10 4a,11 5a12 and 6a13 were identical
with those published earlier in Refs. 10–13). General
experimental procedure for the synthesis of 25-mono-
alkoxy-5,11,17,23-tetrakis(tert-butyl)calix[4]arene 2a, 3a: A
suspension of 5,11,17,23-tetra-(tert-butyl)calix[4]arene (1.5
mmol), LiOH (30 mmol) and alkyl halide (10 mmol) in
DMF (10 mL) was stirred at room temperature for 48 h.
The reaction mixture was quenched with 10% HCl
(100 mL) and extracted with chloroform. The organic
phase was separated and washed with water. The CHCl3
layer was dried over Na2SO4 and the solvent distilled to
afford a crude product which could be purified by column
chromatography (hexane–chloroform 1:1). Compound 3a:
Found: C, 81.51; H, 9.11. C48H64O4 requires C, 81.77; H,
1
Found: 677. H NMR (300 MHz, CDCl3): d 0.90 (t, 3H,
J = 7.2 Hz, CH3), 1.07, 1.09 and 1.36 (3s, 27H, –C(CH3)3),
1.26 (sextet, 2H, J = 4.5 Hz, OCH2CH2CH2CH3), 1.79
(quintet, 2H, J = 7.1 Hz, –OCH2CH2CH2CH3), 3.21 and
3.26 (2d, 4H, J = 13.7 Hz, ArCH2 Ar), 3.52 (t, 2H,
J = 7.2 Hz, –OCH2), 3.84 and 3.90 (2d, 4H, ArCH2Ar),
6.74, 6.81, 6.85, 6.89, 6.94, 7.15, 7.24 and 7.19 (8s, 8H,
ArH), 8.17 (s, 1H, CHO), 8.76 and 7.57 (2s, 3H, D2O exch.
OH). 13C NMR (CDCl3): d 14.0, 22.6, 25.9, 29.7, 29.9,
31.2, 31.9, 78.0, 125.0, 125.4, 128.5, 129.3, 130.8, 132.3,
141.2, 146.6, 149.8, 150.8, 151.7, 159.6, 190.8. Compound
4b: Starting compound 4a, reaction time 15 h, eluent
hexane–EtOAc 95:5. Compound 4b: 63% yield; mp
114 °C. Found: C, 79.50; H, 8.01. C43H52O5 requires
C, 79.59; H, 8.08; FAB-MS m/z Calcd: 648.87. Found:
649. 1H NMR (300 MHz, CDCl3): d 1.02 and 1.24 (2s,
27H, –C(CH3)3), 3.24 and 3.27 (2d, 4H, J = 13.3 Hz,
ArCH2Ar), 3.83 (s, 6H, –OCH3), 4.11 (d, 4H, J = 13.1 Hz,
ArCH2Ar), 6.71, 6.77, 7.01 and 7.04 (4s, 8H, ArH), 9.85 (s,
1H, CHO), 7.36 and 8.32 (2s, 2H, D2O exch. OH).
Compound 5b: Starting compound 5a, reaction time 24 h,
solvent for recrystallization: chloroform/methanol.
Compound 5b: 68% yield; mp 109–110 °C. Found: C,
80.10; H, 8.65. C47H60O5 requires C, 80.07; H, 8.58;
FAB-MS m/z Calcd: 704.98. Found: 705. 1H NMR
(300 MHz, CDCl3): d 1.03 and 1.25 (2s, 27H, –C(CH3)3),
1.3 (t, 6H, J = 6.4 Hz, –OCH2CH2CH3), 2.05 (sextet, 4H,
J = 6.69 Hz, –OCH2CH2CH3), 3.31 and 3.42 (2d, 4H,
J = 13.1 Hz, ArCH2Ar), 3.95 (t, 4H, J = 8.9 Hz, –OCH2-
CH2CH3), 4.27 (d, 4H, J = 12.7 Hz, ArCH2Ar), 6.85, 6.94,
7.03 and 7.62 (4s, 8H, ArH), 9.78 (s, 1H, CHO), 7.92 and
9.27 (2s, 2H, D2O exch. OH); 13C NMR (CDCl3): d 10.8,
1
9.15; FAB-MS m/z Calcd: 704.48. Found 705. H NMR
(300 MHz, CDCl3): d 1.18, 1.21 and 1.26 (3s, 36H,
–C(CH3)3), 1.09 (t, 3H, J = 7.3 Hz, CH3), 1.67 (quintet,
2H, J = 7.4 Hz, –OCH2CH2CH2CH3), 2.13 (quintet, 2H,
J = 7.35 Hz, –OCH2CH2CH2CH3), 3.37 and 3.42 (2d, 4H,
J = 14.1 Hz, ArCH2Ar), 4.13 (t, 2H, J = 6.9 Hz, OCH2),
4.25 and 4.34 (2d, 4H, J = 13.7 Hz, ArCH2Ar), 6.98, 7.01,
7.03, 7.07 (4s, 8H, ArH), 9.41 and 9.96 (2s, 3H, D2O exch.
OH).
10. Dijkstra, P. J.; Brunink, J. A.; Bugge, K. E.; Reinhoudt,
D. N.; Harkema, S.; Ungaro, R.; Ugozzoli, F.; Ghidini, E.
J. Am. Chem. Soc. 1989, 111, 7567–7575.
11. Casnati, A.; Arduini, A.; Ghidini, E.; Pochini, A.; Ungaro,
R. Tetrahedron 1991, 47, 2221–2228.
12. Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47,
4325–4342.
13. Talanov, V. S.; Barsch, R. A. J. Chem. Soc., Perkin Trans.
1 1999, 1957–1961.
14. General procedure for the synthesis of monoformyl
calix[4]arenes (1–6)b: To
a solution of calix[4]arene

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H. M. Chawla et al. / Tetrahedron Letters 46 (2005) 7259–7262
23.4, 31.1, 31.6, 34.0, 78.2, 124.9, 125.2, 126.1, 127.6,
1.0 (t, 6H, J = 7.1 Hz, CH3), 1.68 (sextet, 4H, J = 7.14 Hz,
–OCH2CH2CH2CH3), 1.95 (quintet, 4H, J = 6.5 Hz,
–OCH2CH2CH2CH3), 3.24 and 3.35 (2d, 4H, J = 13.1
Hz, ArCH2Ar), 3.91 (t, 4H, J = 7.0 Hz, –OCH2), 4.20 (d,
4H, J = 12.6 Hz, ArCH2Ar), 6.77, 6.89, 6.96 and 7.55 (4s,
8H, ArH), 9.71 (s, 1H, CHO), 9.17 and 7.81 (2s, 2H, D2O
exch. OH).
128.3, 128.9, 130.9, 131.3, 133.3, 141.6, 147.3, 149.8, 150.4,
160.0, 191.1. Compound 6b: Starting compound 6a,
reaction time 65 h, solvent for recrystallization: chloro-
form/methanol. Compound 6b: 55% yield; mp 143 °C.
Found: C, 80.32; H, 8.75. C49H64O5 requires C, 80.29; H,
1
8.75; FAB-MS m/z Calcd: 733.03. Found: 733. H NMR
(300 MHz, CDCl3): d 0.95 and 1.18 (2s, 27H, –C(CH3)3),
15. We thank the referee for helpful advice.