Synthesis of resorcin[4]arene bearing self-folding substituent

Article abstract of DOI:10.1016/j.tetlet.2011.04.085

Thiomethylation of resorcin[4]arene using N,N-diisopropyl-2- aminoethanethiol hydrochloride and formaldehyde [1:4:4 molar ratio] carried out in methanol/acetic acid [1:1 v/v] at 60 °C produced monofunctionalized product 3 in 68% yield. The introduced subs

Full text of DOI:10.1016/j.tetlet.2011.04.085

Tetrahedron Letters 52 (2011) 3367–3370
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of resorcin[4]arene bearing self-folding substituent
Yoshinori Enmi a, Kazuhiro Kobayashi a, Hisatoshi Konishi a, , Minoru Morimoto b
⇑
a Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
b Research Center for Bioscience and Technology, Tottori University, Koyama, Tottori 680-8550, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiomethylation of resorcin[4]arene using N,N-diisopropyl-2-aminoethanethiol hydrochloride and
formaldehyde [1:4:4 molar ratio] carried out in methanol/acetic acid [1:1 v/v] at 60 °C produced
monofunctionalized product 3 in 68% yield. The introduced substituent was intramolecularly self-
included into the cavity. This self-inclusion reduced the reactivity of the aromatic rings and inhibited
further functionalization.
Received 10 March 2011
Revised 19 April 2011
Accepted 21 April 2011
Available online 30 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Resorcin[4]arene
Self-inclusion
Thiomethylation
Monofunctionalization
Resorcin[4]arenes are cavity-shaped molecules. Their ready
availability and the ease with which they can be chemically mod-
ified resulted in these macrocyclic compounds being the focus of
attention for constructing supramolecular architectures.1 The
macrocycles can be easily modified by aromatic electrophilic
substitutions at the 2-position of the resorcinol units. Among these
substitutions, the Mannich reaction is one of the most widely
employed in the synthesis of functionalized resorcin[4]arenes.2
Generally, the reaction of resorcin[4]arenes with secondary amines
and formaldehyde leads to the complete substitution of the resor-
cinol rings to give tetraaminomethylated derivatives.
We have previously reported that the condensation of resor-
cin[4]arenes 1 with N,N0-diethylethylenediamine and an excess of
formaldehyde in a mixed solvent of methanol and acetic acid
[1:1 v/v] leads to the singly bridged resorcinarene dimer 2
(Scheme 1).3 To the best of our knowledge, this reaction is the only
example of the monoaminomethylation of unmodified resor-
cin[4]arenes. Because all attempts to react resorcinarene 1 with
one equivalent or less of diethylamine and formaldehyde failed to
give any individual partially aminomethylated derivatives, it was
concluded that the reactivity of 2 toward further aminomethylation
is much lower than that of 1. In addition, the selective formation of
dimer 2 was dependent on the kind of diamine used. In practice,
when N,N0-dialkylphenylenediamines were used as the bridging
agent, the reaction produced a very complex mixture and the dou-
ble resorcin[4]arene derivatives could not be isolated. Thus, we
hypothesized that the selectivity of the aminomethylation was
due to a specific conformation of 2 in the reaction solvent. Small
alkylammonium ions are favorable guest molecules for resor-
cin[4]arenes in methanol.4 In our case, the amino function of the
bridging moiety was supposed to be protonated in the reaction sol-
vent (acetic acid/methanol); therefore, it was expected that the
bridging aliphatic chain would be intramolecularly included be-
tween two resorcin[4]arene cavities. This encapsulation of posi-
tively charged moiety was thought to account for the decreased
reactivity of resorcin[4]arene toward electrophilic substitution. As
a working hypothesis, we assume that, in the case of aromatic elec-
trophilic substitution, the self-inclusion of a substituent having an
appropriate chain length and terminating with an amino group
inhibits further functionalization of the aromatic ring of resor-
cin[4]arene. Therefore, we decided to perform the Mannich-type
thiomethylation5 of resorcin[4]arene using N,N-dialkyl-2-amino-
ethanethiol in acidic conditions.
The synthesis of monothiomethylated resorcin[4]arene is shown
in Scheme 1. The reaction conditions and yields are summarized in
Table 1. The use of a higher concentration of the reactants gave
improvement in the selectivity, and yield of 3 (entry 6). Thus, reac-
tion of resorcin[4]arene 1 with N,N-diisopropyl-2-aminoethane-
thiol hydrochloride and formaldehyde [1:4:4 molar ratio] was
conducted in methanol/acetic acid [1:1 v/v] at 60 °C for 24 h. Then,
the crude product was purified by slow vapor diffusion of ethyl ace-
tate into its methanol solution at room temperature to produce 3 in
68% yield.6
The 1H NMR spectrum of 3 in DMSO-d6 (Fig. 1a) showed five
singlets for aromatic protons at d 6.09 (1H), 6.19 (2H), 7.24
(1H),7.26 (2H), and 7.28 (1H) ppm; one quartet for methine pro-
tons at the bridge positions at d 4.38 (4H) ppm; two doublets for
methyl protons at the bridge positions at d 1.55 (6H) and 1.60
⇑
Corresponding author. Tel./fax: +81 857 31 5262.
E-mail address: konis@chem.tottori-u.ac.jp (H. Konishi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.085

3368
Y. Enmi et al. / Tetrahedron Letters 52 (2011) 3367–3370
Scheme 1. Synthesis of diazahexamethylene-bridged resorcin[4]arene dimer.
Table 1
respectively. These upfield shifts appear to be due to the ring cur-
rent effect of the aromatic rings, indicating the enhancement of
the interaction between the amino moiety and the resor-
cin[4]arene core in methanol. In addition, these chemical shifts
were independent of the concentration of 3 in the range of
4.6 ꢀ 10ꢁ3 to 2.3 ꢀ 10ꢁ4 mol/l. Hence, we concluded that the
interaction operates intramolecularly and that the substituent
bent toward the cavity, forming a self-inclusion complex. Because
it is well known that positively charged guests have a high affin-
ity toward the cavity of resorcin[4]arenes,7 it was hypothesized
that some signals of the substituent would show an up-field shift
Effect of reaction conditions on the thiomethylation of 1 (Scheme 2)
Entry
1
Thiol
Formaldehyde Solvent
(ml)
Temp (°C) Yield (%)
Time (h)
(mmol) (mmol) (mmol)
1
2
0.5
1
0.5
1
0.5
4
AcOH (10) rt, 2 h
50 °C, 5 h
rt, 2 h
Complex
mixture
35a
AcOH (5)
50 °C, 15 h
100 °C, 3 h
rt, 2 h
3
4
5
6
1
4
8
AcOH (5)
45a
80 °C, 5 h
1.0
1
1.0
1
2.0
4
MeOH (10) rt, 2 h
AcOH (10) 50 °C, 5 h
MeOH (5)
Complex
mixture
43a
(D
d: dCD3ODꢁdCD3OD+Acid) when the nitrogen atom is protonated.
60 °C
However, the addition of a few drops of trifluoroacetic acid to
the NMR sample tube did not result in appreciable chemical shift
changes of the signals of the substituent as shown in Figure 1c
and as listed in Table 2. Interestingly, the signal for the isopropyl
AcOH (5)
24 h
0.5
2.0
2.0
MeOH (1) 60 °C
AcOH (1) 24 h
68b
a
Determined by NMR analysis.
Isolated yields.
b
Table 2
1H chemical shifts of protons of substituent of 3 in DMSO-d6 and CD3OD (without
(6H) ppm, and four broad singlets for OH groups at 8.09 (2H), 8.78
(2H), 9.05 (2H), 9.90 (2H) ppm. This spectral pattern agrees well
CF3COOH and with CF3COOH)
with that of monofunctionalized resorcin[4]arene having
a
Protona
dDMSO-d6
dCD3OD
dCD3OD+Acid
D
db
symmetric structure with a -plane. The chemical shifts of the
r
a
b
c
d
e
3.60
2.46
2.42
2.94
0.92
3.86
2.74
2.35
2.64
0.21
3.86
2.75
2.36
2.70
0.00
0.01
0.01
0.06
protons of the substituent are listed in Table 2. The protons of
the substituent are labeled as shown in Scheme 2. The signals of
the methyl (label e) and methine (label d) protons of the isopropyl
groups appeared at 0.92 ppm (doublet) and 2.94 ppm (septet),
respectively, in DMSO-d6.
0.10/0.31
-0.11/0.10
a
Proton labels are shown in Figure 2.
When the 1H NMR spectrum of 3 was taken in CD3OD (Fig. 1b),
the methyl and methine signals shifted to 0.20 and 2.63 ppm,
b
D
d = dCD3OD+Acidꢁd CD3OD: Chemical shift changes on the addition of trifluoro-
acetic acid. Minus sign indicates an upfield shift.
Figure 1. 400 MHz 1H NMR spectra of 3 in (a) DMSO-d6 (b) CD3OD without CF3COOH, and (c) CD3OD with CF3COOH. For proton labeling, see Scheme 2.

Y. Enmi et al. / Tetrahedron Letters 52 (2011) 3367–3370
3369
Scheme 2. Monothiomethylation of resorcin[4]arene under acidic conditions and proton labels of substituent.
methyl protons (label e) changed from one doublet (0.20 ppm) to
two doublets (0.10 and 0.31 ppm), whereas, the methine signal
(label d) remained as one septet. These spectral changes can be
explained by considering the protonation of the amine function.8
The protonation of the nitrogen atom resulted in the inhibition of
nitrogen inversion, rendering gem-dimethyl of the isopropyl
group diastereotopic (Fig. 2). Hence, the appearance of the two
methyl signals provides direct evidence for the formation of
ammonium ions in the solution.
Figure 3. Reference compound 4 and proton labels of substituent.
The 13C NMR spectrum of 3 (CD3OD) showed fourteen singlets
in the aromatic region, indicating a mono-substituted resor-
cin[4]arene structure with Cs symmetry on the NMR time scale.
The isopropyl methyl carbon appeared at 17.5 ppm as a singlet.
As in the case of the 1H NMR spectrum, two 13C signals of the iso-
propyl methyl groups were observed at 16.6 and 18.0 ppm in the
presence of trifluoroacetic acid, which is consistent with the above
mentioned hypothesis that diastereotopic methyl groups are
formed by protonation of the nitrogen atom.
To understand the reason behind this unexpected effect of the
addition of an acid on the 1H chemical shift changes, the 4,6-di-
tert-butylresorcinol derivative 4 was used as a reference compound
(Fig. 3),9 and its 1H NMR spectra were determined in CD3OD in the
presence and absence of trifluoroacetic acid. When a few drops of
trifluoroacetic acid were added to the NMR sample of 4 in CD3OD,
the signals of the substituent shifted to a lower magnetic field
(the protons of the substituent are labeled as shown in Fig. 2): from
3.98 to 4.04 ppm for Ha, from 3.04 to 3.24 ppm for Hb, from 2.53 to
2.81 ppm for Hc, from 3.10 to 3.70 ppm for Hd, and from 1.00 to
1.31/1.33 ppm for He. The appearance of the isopropyl methyl sig-
nals (He) as a pair of doublets indicates the formation of ammonium
ions. Hence, the lower shift induced by the addition of acid can be
ascribed to the electrostatic effect of the positively charged nitro-
gen atom. On the basis of these findings, we conclude that the ex-
pected upfield shifts of the signals of the substituent of 3 due to
the enhancement of the ring current effect on the addition of an
acid are compensated by the downfield shifts caused by the forma-
tion of ammonium ions, resulting in no chemical shift changes.
The stick model shown in Figure 4 is that of protonated 3 opti-
mized by molecular mechanics calculation (MM3⁄ force field).10 In
this model, the resorcin[4]arene core adopts a symmetrical cone
conformation and one of the isopropyl groups inserts itself into
the cavity. This conformation is compatible with the 1H NMR
Figure 4. Competitive complexation equilibrium between self-inclusion and com-
plexation with tetraethylammonium bromide. Stick model of resorcin[4]arene
bearing protonated substituent is optimized MM3⁄ force field calculation.
spectra in CD3OD. The stability of the self-inclusion was examined
by a 1H NMR competitive complexation experiment of 3 with Et4NBr
in CD3OD in the presence of trifluoroacetic acid (scheme shown
in Fig. 4). When 6 equiv of Et4NBr was added to the NMR sample
in CD3OD with trifluoroacetic acid, the methyl signals (a pair of
doublets) of the isopropyl groups shifted down field by 0.05 ppm.
Assuming that the chemical shifts of the isopropyl methyl
groups in the inclusion complex (3ꢂEt4NBr) are equal to those of
4 observed in CD3OD/CF3COOH, the complexation induced shift
of the methyl signal in the self-inclusion conformer is estimated
to be 1.12 ppm. Thus, the molar fraction of 3ꢂEt4NBr in the equilib-
rium composition is calculated to be 0.045. In this experiment, the
initial concentrations of
3
and Et4NBr are 4.6 ꢀ 10ꢁ3 and
28 ꢀ 10ꢁ3 mol/l, respectively. Therefore, the equilibrium concen-
trations of 3, Et4NBr, and 3ꢂEt4NBr are 4.4 ꢀ 10ꢁ3, 27.8 ꢀ 10ꢁ3
,
and 0.21 ꢀ 10ꢁ3 mol/l, respectively. Then, the association constant
for the formation of 3ꢂEt4NBr is calculated to be 1.7 Mꢁ1. This value
is much smaller than that of the complexation formation between
resorcin[4]arene 1 and Et4NBr, 7.0 ꢀ 10 Mꢁ1, in methanol.11 This is
indicative of the high stability of the self-inclusion complex.
The self-inclusion of the substituent is believed to play a
dominant role in controlling the selectivity of the reaction. The
inclusion of a positively charged moiety into the cavity might
reduce the reactivity of the aromatic rings, inhibiting further
functionalization. We also examined the thiomethylation of
Figure 2. Pair of diastereotopic CH3 protons of isopropyl group of protonated
substituent.

3370
Y. Enmi et al. / Tetrahedron Letters 52 (2011) 3367–3370
5. (a) Konishi, H.; Yamaguchi, H.; Miyashiro, M.; Kobayashi, K.; Morikawa, O.
Tetrahedron Lett. 1996, 37, 8547–8548; (b) Morikawa, O.; Miyashiro, M.;
Yamaguchi, H.; Kobayashi, K.; Konishi, H. J. Supramol. Chem. 1999, 11, 67–72;
(c) Morikawa, O.; Nakanishi, K.; Miyashiro, M.; Kobayashi, K.; Konishi, H.
Synthesis 2000, 233–236.
resorcin[4]arene using N,N-dimethyl-2-aminoethanethiol under
analogous conditions. However, the reaction gave a complex mix-
ture from which no distinct product could be isolated. Bulkiness of
the alkyl groups on the nitrogen atom may play an important role
for the selectivity in the reaction.
In summary, the results in this Letter represent the first exam-
ple of an efficient synthesis of monofunctionalized derivative from
unmodified resorcin[4]arene. Thiomethylation of resorcin[4]arene
using N,N-diisopropyl-2-aminoethnethiol in methanol/acetic acid
produced monofunctionalized resorcin[4]arene. 1H NMR experi-
ments yielded evidence on the conformational properties of the
self-inclusion of the substituent of 3 in solution. It is concluded
that the first substituent inhibits further functionalization in meth-
anol/acetic acid. On the other hand, further functionalization may
be performed in solvents, such as DMSO. Further studies on the
preparation of novel resorcin[4]arene derivatives are currently un-
der way in our laboratory.
6. 14,16,54,56-tetraethyl-34,36,74,76-tetranitro-2,4,6,8-tetraoxa-1,3,5,7-
tetrabenzenacyclooctaphane (3): Resorcin[4]arene 1 (0.25 g, 0.50 mmol) was
dissolved in hot methanol (1.0 ml). Acetic acid (1 0 ml) was added to this
solution with stirring. After cooling the solution to room temperature, N,N-
diisopropyl-2-aminoethanethiol hydrochloride (0.39 g, 2.0 mmol) and 36%
aqueous formaldehyde (0.17 g, 2.0 mmol) were added, and the mixture was
then stirred at 60 °C for 24 h. The solution was concentrated to one half volume
by rotary evaporation, diluted with water, and extracted with ethyl acetate.
The organic phase was evaporated to give crude product, which was then
dissolved in methanol (5 ml). Vapor diffusion of ethyl acetate into this solution
yielded monosubstituted product
3 (0.225 g, 68%) mp 185 °C. Calcd for
C
41H51NO8S (C2H4O2)2ꢂ(H2O)2: C, 61.84; H, 7.27; N, 1.60. Found: C, 61.95; H,
7.54; N, 1.80. MALDI-TOF/MS (DHB): m/z 718.2 (M+1). 400 MHz 1H NMR
(DMSO-d6, 30 °C): d 0.923 (d, 12H, –CH(CH3)2), 1.557 (d, 6H, bridge CH3),
1.596(d, 6H, bridge CH3), 2.420 (t, 2H, –CH2N–), 2.460 (t, 2H, –SCH2–), 2.953
(sep, 2H, –CH(CH3)2), 3.602 (s, 2H, ArCH2S), 4.375 (q, 4H, bridge H), 6.088 (s, 1H,
ArH), 6.193 (s, 2H, ArH), 7.238 (s, 1H, ArH), 7.257 (s, 2H, ArH), 7.284 (s, 1H,
ArH). 400 MHz 1H NMR (CD3OD, 30 °C): d 0.20 (d, 12H, –CH(CH3)2), 1.755 (d,
6H, bridge CH3), 1.770 (d, 6H, bridge CH3), 2.332 (t, 2H, –CH2N–), 2.633 (sep,
2H, –CH(CH3)2), 2.752 (t, 2H, –SCH2–), 3.860 (s, 2H, ArCH2S), 4.560 (q, 2H,
bridge H), 4.638 (q, 2H, bridge H), 6.129 (s, 1H, ArH), 6.175 (s, 2H, ArH), 7.339
(s, 2H, ArH), 7.391 (s, 1H, ArH), 7.428 (s, 1H, ArH), 8.09 (bs, 2H, OH), 8.78 (s, 2H,
OH), 9.05 (s, 2H, OH), 9.90 (s, 2H, OH). 150 MHz 13C NMR (CD3OD, 30 °C): d
17.5, 19.9, 20.0, 27.1, 29.1, 29.4, 30.4, 49.6, 56.0, 104.1, 104.2, 114.1, 122.2,
123.8, 125.0, 126.3, 126.7, 126.9, 127.1, 152.3, 153.1, 153.6, 153.7.
7. (a) Mäkinen, M.; Vainiotalo, P.; Nissinen, M.; Rissanen, K. J. Am. Soc. Mass
Spectrom. 2003, 14, 143–151; (b) Salorinne, K.; Tero, T.-R.; Riikonen, K.;
Nissinen, M. Org. Biomol. Chem. 2009, 7, 4211–4217.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.085.
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