As a first step, we studied the weak-base-promoted
O-substitution of resorcin[4]arene 1 under the so-called
“alternate alkylation” conditions, which are known to
afford the 1,3,5,7-tetrasubstitution in the calix[8]arene
series.10 Therefore, we subjected octol 1 to alkylation with
an excess of benzyl bromide (10 equiv) in the presence of
K2CO3 (4 equiv) as the weak base in acetone at reflux.
Column chromatography of the crude reaction mixture
afforded four tetra-O-benzylated derivatives (Table 1,
entry 1), namely, 2a (8%), 3a (26%), 4a (9%), and 5a
(23%).11 This result is particularly interesting because 40
partially substituted derivatives (excluding the enantio-
mers) could be theoretically obtainable from 1 and, in par-
ticular, 12 possible tetrasubstituted regioisomers.12
Table 1. O-Substitution Products of Resorcin[4]arene (1) in
Acetone at Reflux
electrophile
(equiv)
base
time
(h)
isolated compd
(yield %)a
entry
1
(equiv)
PhCH2Br
(10)
K2CO3
14
4
2a (8), 3a (26),
4a (9), 5a (23)
2b (10), 3b (28),
4b (12),b 5b (32)b
2c (9), 3c (25),
4c (11),b 5c (30)b
2d (7), 3d (21),
4d (9),b 5d (27)b
(4.0)
2
3
4
BrCH2COOEt
(5)
K2CO3
(4.0)
MeI
K2CO3
(4.0)
5
(50)
n-PrI
K2CO3
(4.0)
14
(10)
a The yields refer to procedures optimized by changing reaction times
and equivs of electrophile. b In this instance, compounds 4 and 5 were
obtained as a mixture only resolvable by HPLC.
The Cs 1,2,4,7-tetrasubstitution pattern of 4a was pro-
ven by thepresenceoftwo setsof threeArH resonances ina
1:2:1 ratio (Figure 1c) that excluded the Cs 1,2,3,4- and
1,4,6,7-tetrasubstitution patterns. The remaining Cs
1,2,3,8-tetrasubstitution was excluded on the basis of clear
ROESY correlations between OH and OCH2 resonances,
only compatible with the 1,2,4,7 pattern. An alternative
way to assign this substitution pattern can be based on the
different chemical shift of “isolated” (6.78ꢀ7.10 ppm) or
“H-bonded” (8.02ꢀ9.20 ppm) OH groups.13,14 In fact, 4a
shows only isolated OH groups resonating in the
6.85ꢀ6.91 ppm range and only compatible with the
1,2,4,7-tetrasubstitution pattern.
The unsymmetrical 1,2,4,6-substitution pattern of 5a,
evidenced by eight ArH singlets, was also assigned by
considering the presence of four isolated OH signals
(7.08, 6.98, 6.86, and 6.82 ppm) only compatible with the
1,2,4,6-tetrasubstitution (Figure 1d). A ROESY spectrum
was in full accordance with this conclusion.
This unexpected good regioselectivity with respect to the
statistical distribution induced us to extend the above
conditions to other alkylating agents, such as ethyl bro-
moacetate, methyl iodide, and n-propyl iodide. As shown
in Table 1 (entries 2ꢀ4), in all of these instances, the same
regiochemical outcome was observed, suggesting a wide
applicability for this procedure.11 The only attention to be
paid is in regards to the modulation of reaction time and
equivalents of electrophile according to its reactivity or
volatility (from 4 to 14 h and from 5 to 50 equiv, respec-
tively, Table 1).
Structure assignment for the above O-substituted
resorcin[4]arenes relied essentially on spectral analysis.
The tetrasubstitution was confirmed by ESI(þ) MS spec-
tra, while the assignment of the substitution pattern was
based on a careful analysis of 1H and 13C NMR data aided
by 2D NMR experiments.11 The C4 symmetry of 2a was
straightforwardly proved by the presence in the 1H NMR
spectrum of one signal for the bridging methine groups,
two singlets for the upper and lower ArH protons, and one
resonance for benzylic OCH2 groups (Figure 1a). In a
similar way, the C2v symmetry of 1,2,5,6-tetrasubstituted
3a was demonstrated by one resonance for the ArCHAr
groups and four singlets for the upper and lower ArH
protons (Figure 1b).
(13) This method has been successfully applied in the calixarene
series. See, refs 10a and 10c and the following: (a) Kraft, D.; Arnecke,
€
R.; Bohmer, V.; Vogt, W. Tetrahedron 1993, 49, 6019. (b) Stewart, D. R.;
Krawiec, M.; Kashyap, R. P.; Watson, W. H.; Gutsche, C. D. J. Am.
Chem. Soc. 1995, 117, 586. (c) Cunsolo, F.; Consoli, G. M. L.; Piattelli,
M.; Neri, P. J. Org. Chem. 1998, 63, 6852. (d) Gaeta, C.; Gregoli, L.;
Neri, P. Tetrahedron Lett. 2002, 43, 9521. (e) Martino, M.; Gaeta, C.;
Neri, P. Tetrahedron Lett. 2004, 45, 3387. (f) Li, H.; Zhan, J. J. Incl.
Phenom. Macrocycl. Chem. 2008, 60, 379.
(14) Typical chemical shift values of isolated OH groups in resorci-
narenes are those of 1,3,5,7 2a and 1,2,5,6 3a. For analogous values of
H-bonded OHs, see: Cram, D. J.; Tunstad, L. M.; Knobler, C. B. J. Org.
Chem. 1992, 57, 528.
(15) For the syn-distal O-substitution of calix[4]arenes, see: (a) van
Loon, J.-D.; Arduini, A.; Coppi, L.; Verboom, W.; Pochini, A.; Ungaro,
R.; Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1990, 55, 5639. (b)
Collins, E. M.; McKervey, M. A.; Madigan, E.; Moran, M. B.; Owens,
M.; Ferguson, G.; Harris, S. J. J. Chem. Soc., Perkin Trans. 1 1991, 3137.
(c) Caccamese, S.; Bottino, A.; Cunsolo, F.; Parlato, S.; Neri, P.
Tetrahedron: Asymmetry 2000, 11, 3103. For calix[5]arenes, see: (d)
Notti, A.; Parisi, M. F.; Pappalardo, S. In Calixarenes 2001; Asfari, Z.,
€
Bohmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, The
Netherlands, 2001; Chapter 3, pp 54ꢀ70. For 1,3,5-trisubstitution of
calix[6]arenes, see: (e) Janssen, R. G.; Verboom, W.; Reinhoudt,
D. N.; Casnati, A.; Freriks, M.; Pochini, A.; Ugozzoli, F.; Ungaro,
R.; Nieto, P. M.; Carramolino, M.; Cuevas, F.; Prados, P.; de Mendoza,
J. Synthesis 1993, 380. (f) Neri, P.; Consoli, G. M. L.; Cunsolo, F.;
Piattelli, M. Tetrahedron Lett. 1994, 35, 2795. For 1,2,4,6-tetrasubstitu-
tion of calix[7]arenes, see: (g) Martino, M.; Gregoli, L.; Gaeta, C.; Neri,
P. Org. Lett. 2002, 4, 1531.
(11) See Supporting Information for further details.
(12) These 40 partially substituted regioisomers are represented in
Chart S3 of Supporting Information.
Org. Lett., Vol. 13, No. 18, 2011
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