DISTAL Dibromoresorcin[4]arenes Through Selective Deactivation: A Practical Optimization

Article abstract of DOI:10.1002/ejoc.202001031

A simple and straightforward regioselective synthesis of distal disubstituted resorcin[4]arenes was developed, avoiding competing substitution patterns at an early stage via regioselective deactivation. Product limiting reaction steps were optimized by st

Full text of DOI:10.1002/ejoc.202001031

Communication
doi.org/10.1002/ejoc.202001031
EurJOC
European Journal of Organic Chemistry
Resorcinarenes
DISTAL Dibromoresorcin[4]arenes Through Selective
Deactivation: A Practical Optimization
Dominic Danielsiek[a] and Gerald Dyker*[a]
Abstract: A simple and straightforward regioselective synthesis dures throughout the synthesis without requiring column chro-
of distal disubstituted resorcin[4]arenes was developed, avoid- matography. The cyclizing acetalization of distal disubstituted
ing competing substitution patterns at an early stage via regio- resorcinarene octols proved to be a high yield process without
selective deactivation. Product limiting reaction steps were op- oligomer formation, although less sterically controlled com-
timized by starting material recovery and by an improved pro- pared to the usual tetrabromo case.
tocol for ester cleavage while providing simple workup proce-
Introduction
arenes, the acetalized dibromoresorcinarene 3 generally is not
Resorcin[4]arenes, the tetrameric cyclic condensation products
thoroughly purified, but used as a crude product, subsequently
of resorcinol with an aldehyde, represent a versatile class of
leading to unsatisfactory yields.[7]
precursors en route to supramolecular hosts such as cavitands,
carcerands, and hemicarcerands. Their applications spread from
encapsulation of highly reactive compounds[1] and molecular
recognition[2] to the experimental utilization in catalysis[3] and
as stationary phases in chromatography.[4] While carcerands are
composed of two four-fold interconnected resorcin[4]arene
units, giving them an isolated inner shell, hemicarcerands offer
portals for guest-exchange reactions, often implemented by the
lack of at least one interhemispheric linker. Beyond mono-
or trifunctionalization recently reported,[5] distal (or A,C-) di-
functionalized resorcinarenes offer an interesting substitution
pattern to provide a basis for hemicarcerand and cavitand syn-
thesis.[6] Thus, a selective, high-yield access to these precursors
is desirable.
Hitherto two approaches towards difunctionalized resorcin-
arenes are commonly used (Figure 1): Route A is performing a
substoichiometric bromination of the resorcinarene backbone
1 (with regard to the four vacant aromatic upper rim positions),
giving a vast statistical mixture of all possible upper-rim sub-
stitution patterns, including the desired A–C dibrominated re-
sorcinarene 2, followed by acetalization of the mixture. Due to
the similar physical properties of the oligobrominated resorcin-
[a] D. Danielsiek, Prof. Dr. G. Dyker
Faculty of Chemistry and Biochemistry, Ruhr-University Bochum,
Universitätsstraße 150, 44801 Bochum, Germany
E-mail: Gerald.Dyker@rub.de
Figure 1. Previous approaches towards distal disubstituted resorcinarenes.
https://www.ruhr-uni-bochum.de/oc2/dyker/
Supporting information and ORCID(s) from the author(s) for this article are
The other more prominent method (route B) allows for
higher yields, however with a likewise low atom economy[8]
since the resorcinarene backbone 1 is fourfold brominated (4)
and acetalized (5), followed by debromination via lithiation and
hydrolysis. Although target product yields of the latter reaction
have been successfully pushed above the statistical expectancy
available on the WWW under https://doi.org/10.1002/ejoc.202001031.
© 2020 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. · This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial-NoDerivs License, which
permits use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or adapta-
tions are made.
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Figure 2. Distal dibromination via regioselective deactivation. A: MeCN, TEA, p-toluoyl chloride, RT, 16 h. B: THF, NBS, RT, 16 h. C: MeOH, NaOMe, RT, 5 h.
D: DMF, K2CO3, BrCH2Cl, 60 °C, 48 h, E: a) MeOH, NaOH, RT,16 h. b) MeOH, NaOMe, RT, 16 h.
up to 65 %,[9] this reaction pathway is still afflicted with the electrophilic aromatic substitution reactions, determining the
inefficiency of the wasteful late-stage derivatization and a substitution pattern for upcoming reactions. Hence the above-
time-consuming workup procedure. An overall yield between mentioned isolation problems of other routes can be avoided. A
36–55 % over four steps can be calculated.[10]
recently published one-step synthesis of distal difunctionalized
resorcinarene tetraethers exhibits a similar selectivity, starting
from a mixture of resorcinol and 1,3-dimethoxybenzene.[15]
Though satisfying yields are achieved, ester cleavage is pre-
ferred for the benefit of milder reaction conditions and rea-
gents.
While route A depends on a statistical yield distribution in
the product-determining step and is, therefore, neither selective
to the number of introduced substituents nor to the predomi-
nant isomer with respect to the desired twofold functionaliza-
tion, route B presents a procedure with a directing factor. After
the first lithiation at one of the four equivalent positions, the
second lithium–halogen exchange is electrostatically repelled
from the statistically more probable adjacent positions to the
opposing one. Nevertheless, under- and over-lithiation are not
prevented by other means than stoichiometry.
Results and Discussion
Resorcinarene backbones with phenethyl (1a) and pentyl (1b)
To overcome the statistical mismatch of both routes, we de- residues were synthesized according to modified procedures by
veloped a highly regioselective approach (Figure 2), utilizing Cram et al.[16] with yields of 78 % (1a) and 99 % (1b) respec-
a deactivation for electrophilic aromatic substitution. With the tively. To ensure early-stage product determination, p-toluoyl
introduction of four ester functionalities at the resorcinarene chloride was used as an acylating agent in the presence of tri-
scaffold, Shivanyuk et al. presented a method to predefine a ethylamine as a base under vigorous stirring. Since the regio-
distal substitution pattern at an early stage.[11,12] The resulting selectivity is reported to strongly depend on reagents, stoichio-
C2V-symmetrical tetraesters have found application in the syn- metry, solvents, and the precise conditions applied, a strict pro-
thesis of chiral, resorcinarene based ligands for asymmetric ca- tocol was followed.[12]
talysis[13] and the development of photo-switchable molecular
After the introduction of the four p-toluic acid esters, the
two aromatic positions ortho to the free phenols remained to
capsules.[14] It is to be noted, however, that the selectivity of
the fourfold esterification derives from the formation of a com-
plex of 1 with triethylamine, used as a base in this reaction,
locking the resorcinarene in a C2V-symmetric boat configuration
and the peculiar insolubility of the distal tetraester in aceto-
nitrile, being the only isomer to precipitate from the reaction
mixture with yields just below 40 %. A combination of C2V sym-
metry and π–π-interaction favors this selective precipitation
since this solubility effect fails to appear with aliphatic acid moi-
eties like BOC and acetate.
be active for electrophilic substitution. Thus, using NBS we
achieved the twofold bromination in yields of > 99 % [R =
(CH2)2C6H5, 7a] and 95 % (R = C5H11, 7b), well above the 90 %
for the fourfold bromination in the classical route to target com-
pound 3.[10] We found a mild 1.5-fold excess of NBS per vacant
aromatic upper-rim position is sufficient for the reaction,
thereby minimizing the amount of unconverted reagent, which
was easily removed by washing the solid raw product. The re-
sulting crude product was sufficiently pure, since no by-prod-
1
The easy access to 6 provides an ideal basis for the directed ucts e.g. of a substoichiometric bromination were found by H
synthesis of the distal disubstituted target compound 3, as the NMR spectroscopy, where the missing aromatic upper rim sig-
two opposing ester-functionalized phenyls are deactivated for nals, ortho to OH served as diagnostic signals (6a: 6.11 ppm,
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6b: 6.55 ppm), along with the two remaining ones, ortho to the (6a) and 70 % (6b) as “based on recovered starting material”,
esters (7a: 6.90 ppm, 7b: 6.92 ppm).
respectively, by considering the recovered starting material un-
reacted. The final products' overall yields are thus corrected to
57 % (3a) and 48 % (3b), as Table 1 displays. Further methods
to increase conversion like pressure tube reactions,[17] or further
increase of the reaction time[10] were not considered, in favor
of a reliable and upscalable protocol.
Next, the cleavage of the previously introduced ester groups
was targeted, which turned out to be problematic under typical
alkaline conditions as mentioned by Shivanyuk et al.[12] While
1
the successful saponification was proven by H NMR spectro-
scopy, using sodium hydroxide in methanol, the separation of
the resulting resorcinarene octols 2 from the p-toluic acid was
difficult, both, under basic and under neutral or acidic condi-
tions, and led to significant loss of product during workup. We
solved this problem by cleaving off the p-toluic moieties via
transesterification with sodium methoxide since washing easily
separates the methyl p-toluate from the resorcinarene octols 2.
Trace amounts of remaining methyl p-toluate were removed by
drying at 125 °C under vacuum in a Kugelrohr oven but also
showed to be tolerated in the final synthesis step. The cyclizing
tetraacetalization was performed with bromochloromethane
and potassium carbonate as a base. Due to the acetalizing rea-
Table 1. Yields in %.
1
6
7
2
3
3 Total[a]
a (Phenetyl)
b (Pentyl)
78
99
39 (84)[b]
26 (70)[b]
99.5
95
93
86
94
84
26 (57)[b]
18 (48)[b]
[a] Total yield over 5 steps. [b] Corrected yields based on recovered starting
material.
Conclusion
gents low boiling point (68 °C), the reaction was given two days Distal difunctionalized and tetraacetalized resorcinarenes 3a
at 60 °C to avoid reagent loss via volatilization. With up to 94 % and 3b were successfully synthesized using a regioselective ap-
[R = (CH2)2C6H5, 3a] and 84 % (R = C5H11, 3b), these yields proach, deactivating two of four available sites for electrophilic
showed to be well within the range of the reported tetraacetali- aromatic substitution, with the introduction of the four ester
zation reactions, performed at tetrabromo resorcinarenes.[10,17]
As in the previous steps only simple and conserving workup
methods were required, such as filtration, trituration, and dry-
ing, to give the spectroscopically clean difunctionalized resor-
cinarene cavitands in overall yields of 26 % [R = (CH2)2C6H5, 3a]
and 18 % (R = C5H11, 3b) over five steps. We wish to emphasize,
that this tetraacetylization performs to such high yields without
the formation of interbowl oligomerization or substoichiometric
acetalization products since this selectivity has not yet been
reported on distal disubstituted resorcinarenes and was com-
monly assumed to require three or more sterically demanding
upper rim substituents. Only a few examples show the fourfold
cyclizing acetalization at unsubstituted resorcinarenes with
yields higher than 50 %.[18] Most of them require large solubiliz-
ing groups (R) to maintain enough steric hindrance, keeping
sites for intermolecular reaction apart.
groups as the product determining step. Special attention was
turned towards the development of straightforward and upscal-
able syntheses and workups. Thus, time consuming and batch
limiting protocols like column chromatography and pressure
tube techniques were avoided. By successfully recovering the
starting material from the by-products, yields of this step were
increased from 26–39 % to 70–84 %. An alternative method for
ester cleavage via transesterification under alkaline conditions
was developed, enabling an efficient workup, where hitherto
reported protocols suffer a significant loss of product. Further-
more, cyclizing tetraacetalization of distal disubstituted resor-
cinarenes was investigated and proven to be a highly selective
process with yields well above 80 %.
Our methods have shown to significantly improve overall
yields of a five-step synthesis in the range of 50 %, providing
high-yield and high-selectivity access to two versatile precur-
sors for cavitand and hemicarcerand syntheses.
The protocol was crucially optimized by starting material re-
covery in the second stage of the synthesis. Besides the readily
isolated distal tetraesters 6 an indistinctive fraction of by-prod-
ucts remained in the workups mother liquor. In order to under-
stand the principles behind the product and by-product forma-
tion, several attempts to separate these by-products by column
chromatography, crystallization, or solvent-antisolvent precipi-
tation were undertaken but remained unsuccessful. However,
the overall result was improved by developing a procedure for
the recovery of 1 from the by-products mixture: Phenethyl re-
sorcinarene (1a) was readily recovered by saponification of the
by-products with sodium hydroxide in methanol. For the recov-
ery of pentyl resorcinarene (1b) a transesterification with so-
dium methoxide was superior. As a notable convenience, the
recycled starting materials required a mere filtration, washing,
and drying as workup and were immediately used for the next
batch. Based on the calculated amount of by-product, up to
85–88 % of 1 were recovered. Hence the initial yields of the
Experimental Section
General
Dry THF was distilled from sodium-benzophenone prior to use. Eth-
anol, methanol, toluene, ethyl acetate, and n-hexane were pur-
chased in technical grade purity and distilled prior to use. All other
solvents were purchased in p.a. grade. 1H and 13C NMR spectra were
recorded on Bruker DPX-200 (200 MHz), DPX-250 (250 MHz), and
AVIII-300 (300 MHz) instruments and raw processed by Bruker
TopSpin. Further analyses and fine processing were done using
MestReNova version 14.0.1. Solvents for NMR spectroscopy were
used in a 99.8 % deuteration grade and the residual undeuterated
solvent was used as internal reference for calibration. All products
were spectroscopically pure after the procedures given. Unpub-
lished products (2a, 2b, 3a, 7a, 7b) were further purified for com-
plete characterization via flash chromatography using silica as sta-
tionary phase and toluene, ethyl acetate, or ethanol as mobile
tetraesters 6a (39 %) and 6b (26 %) were corrected to 84 % phase.
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1
Experimental Details
154 °C (decomp.). H NMR (300 MHz, CDCl3): δ = 1.60 ppm (s, 4 H,
H2O), 2.15–2.35 (m, 8 H, CH2CH2), 2.46 (s, 12 H, Tol-CH3), 2.53–2.70
(m, 8 H, CH2CH2), 4.47 (t, J = 7.34 Hz, 4 H, CH), 5.62–5.76 (m, 4 H,
OH), 6.78–6.84 (m, 2 H, ArH ortho to OCOTol), 6.97–7.10 (m, 20 H,
C6H5), 7.15 (s, 4 H, ArH lower rim), 7.18 (d, J = 8.1 Hz, 8 H, TolH),
8.03 (d, J = 8.1 Hz, 8 H, TolH). 13C NMR (75.0 MHz, [D6]DMSO): δ =
21.3 ppm (s, Tol-CH3), 34.2 (s, CH2CH2), 35.7 (s, CH), 109.7 (s, ArC-Br),
116.2 (ws observed in HSQC, ArC lower rim), 122.6 (s, ArC ortho and
para to OH), 125.7 (s, ArCH ortho to OCOTol), 126.5 (s, TolC-CO),
128.2 (s, ArCH phenylethyl), 129.4 (s, TolCH ortho to CH3), 130.4 (s,
TolCH meta to CH3), 134.9 (s, ArC ortho and para to both OCOTol),
141.7 (s, ArC-CH2), 144.6 (s, TolC-CH3), 145.7 (s, ArC-OCOTol), 149.1
(s, ArC-OH), 164.2 (s, carbonyl C). MS (MALDI-TOF): m/z (%) = 1573
(22) [M+ + K], 1558 (14) [M+ + Na], 1544 (10) [M+ + K – C2H2], 1528
(63) [M+ + Na – C2H2], 1485 (73) [M+ + K – Tol], 1468 (45) [M+ + Na
2,8,14,20-Tetra-(2-phenylethyl)resorc[4]arene (1a): To a solution
of resorcinol (42.0 g, 381 mmol) in ethanol (300 mL) at 0 °C, concen-
trated HCl (84.0 mL) was added, followed by dropwise addition of
3-phenylpropionaldehyde (50.7 mL, 381 mmol) within 30 minutes.
The mixture was stirred for 24 h at room temperature and 48 h at
reflux before being poured onto ice water. The resulting precipitate
was collected by filtration and washed with a 1:1 mixture of ethanol
and water. Crystallization from methanol yielded 67.4 g (78 %) of
1a as a colorless powder after vacuum drying at room temperature.
Mp: 265 °C (decomp.). 1H NMR (300 MHz, [D6]DMSO): δ = 2.45–
2.53 ppm (m, 18 H, CH2CH2, DMSO), 4.30 (s, 4 H, CH), 6.23 (s, 4 H,
ArH ortho to OH), 7.10–7.27 (m, 20 H, C6H5), 7.46 (s, 4 H, ArH meta
to OH), 9.10 (s, 8 H, OH). 13C NMR (75.0 MHz, [D6]DMSO): δ =
33.3 ppm (s, CH), 34.4 (s, Ar-CH2), 36.0 (s, CH-CH2), 102.5 (s, ArCH
ortho to both OH), 123.5 (s, ArC-CH), 125.0 (s, ArCH meta to both
OH), 125.6 (s, ArCH para to CH2), 128.2, 128.5 (both s, ArC ortho and
meta to CH2), 142.3 (s, ArC-CH2), 151.7 (s, ArC-OH).[16]
– Tol]. IR: ν = 3516 cm–1 (w), 3023 (w), 2938 (w), 2859 (w), 1728 (s),
˜
1609 (m), 1485 (m), 1452 (m), 1177 (s), 1242 (s), 1152 (s), 1076 (s),
1016 (s), 905 (m), 837 (m) 793 (m), 744 (s), 696 (s), 637 (m) EA:
Calculated: [M + 2H2O] C 70.32 %, H 5.26 %; found: C 70.51 %,
H 5.21 %.
4,6,16,18-Tetrahydroxy-2,8,14,20-tetra-(2-phenylethyl)resorc-
[4]arene-10,12,22,24-tetra-p-toluate (6a): To a vigorously stirred
suspension of 1a (40.0 g, 44.2 mmol) in acetonitrile (400 mL), tri-
ethylamine (24.5 mL, 177 mmol) was added rapidly. The mixture
was cooled down to 0 °C, stirred for 15 minutes and p-toluoyl chlor-
ide (23.4 mL, 177 mmol) was added in one portion. After stirring at
room temperature overnight, the resulting precipitate was filtered
off and the filtrate was preserved for starting material recovery. The
filter cake was washed with acetonitrile and water successively and
dried in vacuo to yield 23.9 g (39 %) of 6a as a colorless powder.
Mp: 220 °C (decomp.). 1H NMR (300 MHz, [D6]DMSO): δ = 2.25–
2.60 ppm (m, 47 H, Tol-CH3, CH2CH2, DMSO), 4.56 (s, 4 H, CH), 6.11
(s, 2 H, ArH ortho to OH), 6.96–7.18 (m, 22 H, C6H5, ArH ortho to
OCOTol), 7.38 (d, J = 8.1 Hz, 8 H, TolH), 7.48 (s, 2 H, ArH meta to
OCOTol), 7.69 (s, 2 H, ArH meta to OH), 8.02 (d, J = 8.1 Hz, 8 H, TolH),
8.75 (s, 4 H, OH). 13C NMR (75.0 MHz, [D6]DMSO): δ = 21.3 ppm (s,
Tol-CH3, CH2CH2), 34.2 (s, CH), 101.9 (ws, ArCH ortho to both OH),
116.2 (ws, ArCH ortho to both OCOTol), 119.8 (s, ArC-CH ortho and
para to OH), 125.6 (s, ArCH meta to both OH), 126.9 (s, TolC-COO),
128.2, 128.3 (both s, ArCH phenylethyl, ArCH meta to both OCOTol),
129.4 (s, TolCH ortho to CH3), 129.9 (s, TolCH meta to CH3), 135.5 (s,
ArC-CH ortho and para to OCOTol), 142.0 (s, ArC-CH2 phenylethyl),
143.9 (s, TolC-CH3), 145.0 (s, ArC-OCOTol), 153.7 (s, ArC-OH), 164.2
(s, carbonyl C).[12]
5,17-Dibromo-2,8,14,20-tetra-(2-phenylethyl)resorc[4]-
arene (2a): Under an argon atmosphere, sodium (0.53 g,
22.9 mmol) was placed in a thoroughly dried round-bottomed flask
and methanol (10.0 mL) was added dropwise under ice bath cool-
ing. A solution of 7a (2.20 g, 1.43 mmol) in methanol (25.0 mL) was
slowly added and the mixture was stirred for 5 h at room tempera-
ture before being poured onto 1
M HCl (23.0 mL). The precipitate
was collected by filtration, washed with water and hexane and dried
in vacuo at 125 °C to yield 1.42 g (93 %) of 2a as a red powder. Mp:
1
156 °C (decomp.). H NMR (300 MHz, [D6]DMSO): δ = 2.30 ppm (s,
3H, Toluene), 2.46–2.60 ppm (m, 34 H, CH2CH2, DMSO), 4.25 (s, 4 H,
CH), 6.37 (s, 2 H, ArH ortho to OH), 7.11–7.27 (m, 25 H, C6H5, Tolu-
ene), 7.41–7.57 (m, 4 H, ArH meta to OH), 8.63 (bs, 4 H, OH ortho to
Br), 10.23–10.67 (m, 4 H, OH ortho to H). 13C NMR (75.0 MHz,
[D6]DMSO): δ = 33.9 ppm (s, CH), 34.7 (s, CH2), 102.2 (ws observed
in HSQC, ArCH ortho to OH), 125.0 (s, ArC-CH), 126.2 (s, ArC-CH2),
128.7, (s, ArCH ortho and meta to CH2), 129.0 (s, ArCH para to CH2),
129.6, 129.8 (both s, ArCH lower rim), 142.5 (s, ArC-Br), 148.9, 151.2
(both s, ArC-OH). MS (MALDI-TOF): m/z (%) = 1101 (15) [M+ + K],
1085(23) [M+ + Na], 1075 (15) [M+ + K – C2H2], 1056 (26) [M+ + Na
– C2H2], 1040 (75) [M+ + Na – C2H2 – OH], 995 (100) [M+ + K –
(PhCH CH )]. IR:ν = 3360 cm–1 (m), 3024 (w), 2932 (w), 2860 (w),
˜
2
2
1740 (m), 1719 (m), 1603 (m), 1495 (s), 1473 (s), 1452 (s), 1437 (s),
1350 (m), 1258 (s), 1165 (s), 1088 (s), 905 (w), 839 (m), 746 (s), 696
(s).EA:Calculated:[M+Toluene]C69.67 %,H5.41 %;found:C69.80 %,
H 5.32 %.
Recovery of the Starting Material 1a: The solvent of the previous
filtration was removed under reduced pressure to give the by-prod-
ucts (37.0 g, 26.9 mmol for average M = 1378 g/mol) as a red solid.
Sodium hydroxide (17.1 g, 430 mmol) was dissolved in methanol
(150 mL) and a solution of the by-products in methanol (200 mL)
was added slowly. The mixture was stirred at room temperature
5,17-Dibromo-4(24),6(10),12(16),18(22)-tetramethylenedioxy-
2,8,14,20-tetra-(2-phenylethyl)resorc[4]arene (3a): To a suspen-
sion of 2a (7.67 g, 7.22 mmol) in DMF (200 mL), potassium carb-
onate (13.0 g, 93.8 mmol) was added and the mixture was heated
to 60 °C. After the addition of bromochloromethane (7.25 mL,
108 mmol), the mixture was stirred for 48 h at 60 °C with another
addition of bromochloromethane (7.25 mL, 108 mmol) after 24 h.
The crude product was precipitated by pouring the reaction mix-
overnight and poured onto 1
M HCl (430 mL). The precipitate was
recovered by filtration and washed thoroughly with water and hex-
ane to give 21.4 g (88 %) of 1a as an off-white powder.
5,17-Dibromo-4,6,16,18-tetrahydroxy-2,8,14,20-tetra-(2-phen-
ylethyl)resorc[4]arene-10,12,22,24-tetra-p-toluate (7a): A solu-
tion of 6a (5.73 g, 4.16 mmol) in dry THF (90.0 mL) was cooled
down to 0 °C under exclusion of light and an argon atmosphere.
NBS (2.22 g, 12.5 mmol) was added, prior to stirring for 2 h at 0 °C
ture onto 1
M HCl (95.0 mL), followed by filtration. The filtrate was
triturated and thoroughly washed with water before vacuum drying
at 120 °C to yield 7.50 g (94 %) of 3a as a spectroscopically pure
1
and overnight at room temperature. Methanol (50.0 mL) and so- off-white powder. Mp: 286 °C (decomp.). H NMR (300 MHz, CDCl3):
dium sulfite (0.53 g) were added and the mixture was stirred for δ = 2.37 ppm (s, 6 H, Toluene), 2.45–2.57 (m, 8 H, CH2CH2), 2.63–
another 20 min before removing THF under reduced pressure. Wa- 2.74 (m, 8 H, CH2CH2), 4.46 (d, J = 7.2 Hz, 4 H, OCH2O), 4.90 (t, J =
ter was added and the precipitate was collected by filtration,
washed with water and dried in vacuo at 70 °C to yield 6.36 g
(99.5 %) of 7a as a spectroscopically pure off-white powder. Mp:
7.9 Hz, 4 H, CH), 5.89 (d, J = 7.2 Hz, 4 H, OCH2O), 6.60 (s, 2 H, ArH,
ortho to O), 7.04–7.29 (m, 37 H, C6H5, ArH meta to O, Toluene,
CHCl3). 13C NMR (75.0 MHz, CDCl3): δ = 32.4 ppm (s, CH-CH2), 34.4
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(s, CH2-Ar), 37.1 (s, CH), 99.2 (s, OCH2O), 117.7 (s, ArCH ortho to 5,17-Dibromo-4,6,16,18-tetrahydroxy-2,8,14,20-tetrapentylre-
OCH2O), 120.9, 122.1 (both s, ArC lower rim), 126.3 (s, ArCH para to sorc[4]arene-10,12,22,24-tetra-p-toluate (7b): A solution of 6b
CH2), 128.5, 128.8 (both s, ArCH ortho and meta to CH2), 133.6 (s, (4.00 g, 3.22 mmol) in dry THF (60.0 mL) was cooled down to 0 °C
ArC-Br), 138.3 (s, ArC-CH meta to upper rim H), 139.3 (s, ArC-CH
meta to Br), 141.5 (s, ArC-CH2), 151.2 (s, ArC-OCH2O ortho to Br),
155.2 (s, ArC-OCH2O ortho to upper rim H). MS (MALDI-TOF): To
under exclusion of light and an argon atmosphere. NBS (1.72 g,
9.67 mmol) was added, prior to stirring for 2 h at 0 °C and overnight
at room temperature. Methanol (30.0 mL) and sodium sulfite
enhance ionization, the substrate was doped with N-methylpyridin- (0.20 g) were added and the mixture was stirred for another 20 min
ium iodide. m/z (%) = 1200 (14) [M+ + N-Methylpyridinium], 1124
before removing THF under reduced pressure. Water was added
(21) [M+ + N-Methylpyridinium – Ph], 1110 (80) [M+], 1060 (63) [M+ and the precipitate was collected by filtration, washed with water
– C4H4], 1033 (23) [M+ – Br]. IR: ν = 3024 cm–1 (w), 2934 (w), 2868
and dried in vacuo to yield 4.28 g (95 %) of 7b as a spectroscopi-
˜
(w), 1736 (w), 1667 (w), 1603 (w), 1491 (m), 1452 (m), 1294 (m),
cally pure off-white powder. Mp: 152 °C (decomp.). 1H NMR
1229 (w), 1190 (w), 1092 (s), 1022 (m), 988 (m), 956 (s), 750 (m), 698 (200 MHz, CDCl3): δ = 0.59–0.78 ppm (m, 12 H, CH2CH3), 1.03–1.36
(s), 654 (m), 584 (m), 482 (m). EA: Calculated: [M + 2 Toluene] (m, 24 H, (CH2)3CH3), 1.71–2.08 (m, 8 H, CH-CH2), 2.43 (s, 12 H, Tol-
C 72.33 %, H 5.45 %; found: C 72.43 %, H 5.24 %.
CH3), 4.29 (t, J = 6.9 Hz, 4 H, CH), 5.76 (s, 4H, OH), 6.55 (s, 2 H, ArH
ortho to OCOTol), 7.06 (s, 2 H, ArH lower rim), 7.18 (s, 2 H, ArH lower
rim), 7.28 (d, J = 7.9 Hz, 8 H, TolH), 8.10 (d, J = 7.9 Hz, 8 H, TolH).
13C NMR (75 MHz, [D6]DMSO): δ = 13.8 ppm (s, CH3), 21.3 (s, TolCH3),
22.1, 27.3, 31.3, 34.4 (all s, CH2), 36.3 (CH-CH2), 102.3 (s, ArC-Br),
116.8, 118.0 (both s, ArC lower rim), 123.6 (s, ArC ortho and para to
OH), 124.8 (s, ArCH ortho to OCOTol), 126.4 (s, TolC-CO), 129.3 (s,
TolCH ortho to CH3), 129.8 (s, TolCH meta to CH3), 133.8 (s, ArC ortho
and para to both OCOTol), 144.0 (s, TolC-CH3), 146.0 (s, ArC-OCOTol),
149.7 (s, ArC-OH), 164.0 (s, carbonyl C). MS (FAB): m/z (%) = 1422
2,8,14,20-Tetrapentylresorc[4]arene (1b): To a solution of resor-
cinol (39.6 g, 360 mmol) in a 1:1 mixture of ethanol and water
(300 mL) at 0 °C, concentrated HCl (75.0 mL) was added, followed
by dropwise addition of hexanal (44.5 mL, 360 mmol), diluted with
ethanol (100 mL) within 2 h. The mixture was stirred for 3 d at 60 °C
before water was added. The resulting precipitate was collected by
filtration and washed with water to yield 1b (68.2 g, 99 %) after
vacuum drying as an off-white powder. Mp: 276 °C. 1H NMR
(200 MHz, [D6]DMSO): δ = 0.83 ppm (t, J = 6.1 Hz, 12 H, CH2CH3),
1.18–1.36 (m, 24 H, (CH2)3CH3), 1.84–2.13 (m, 8 H, CH-CH2), 4.21 (t,
J = 6.8 Hz, 4 H, CH), 6.14 (s, 4 H, ArH ortho to OH), 7.15 (s, 4 H, ArH
meta to OH), 8.87 (s, 8 H, OH). 13C NMR (75.0 MHz, [D6]DMSO): δ =
14.0 ppm (s, CH3), 22.3 (s, CH2-CH3), 27.5, 31.5 (both s, CH2), 33.1 (s,
CH-CH2), 34.0 (CH-CH2), 102.4 (s, ArCH ortho to OH), 123.1 (s, ArC),
125.0 (s, ArC), 151.7 (s, ArCOH).[16]
(100) [M+ + Na], 1399 (40) [M+], 1325 (73) [M+ – C5H11]. IR: ν =
˜
3510 cm–1 (w), 2953 (m), 2928 (m), 2859 (m), 1734 (s), 1611 (s), 1479
(s), 1429 (m), 1242 (s), 1177 (s), 1119 (s), 1072 (s), 1017 (s), 897 (w),
835 (m), 745 (s), 687 (m), 637 (w), 613 (w), 474 (w). EA: Calculated:
[M + EtOH] C 65.17 %, H 5.94 %; found: C 65.44 %, H 5.80 %.
5,17-Dibromo-2,8,14,20-tetrapentylresorc[4]arene (2b): Under
an argon atmosphere, sodium (0.49 g, 21.4 mmol) was placed in a
thoroughly dried round-bottomed flask and methanol (10.0 mL)
was added dropwise under ice bath cooling. A solution of 7b
(0.20 g, 0.14 mmol) in methanol (10.0 mL) was slowly added and
the mixture was stirred for 5 h at room temperature before being
4,6,16,18-Tetrahydroxy-2,8,14,20-tetrapentylresorc[4]arene-
10,12,22,24-tetra-p-toluate (6b): To a vigorously stirred suspen-
sion of 1b (15.4 g, 20.0 mmol) in acetonitrile (200 mL), triethylamine
(11.1 mL, 80.0 mmol) was added rapidly. The mixture was cooled
down to 0 °C, stirred for 15 minutes and p-toluoyl chloride (10.6 mL,
80.0 mmol) was added in one portion. After stirring at room tem-
perature overnight, the resulting precipitate was filtered off and the
filtrate was preserved for starting material recovery. The filter cake
was washed with acetonitrile and water successively and dried in
vacuo to yield 6.50 g (26 %) of 6b as a colorless powder. Mp: 155 °C.
1H NMR (300 MHz, CDCl3): δ = 0.66–0.78 ppm (m, 12 H, CH2CH3),
1.12–1.31 (m, 24 H, (CH2)3CH3), 1.69–2.05 (m, 8 H, CH-CH2), 2.41 (s,
12 H, Tol-CH3), 4.39 (t, J = 6.4 Hz, 4 H, CH), 6.55 (s, 2 H, ArH ortho
to OH), 6.82 (s, 2 H, ArH ortho to OCOTol), 7.07 (s, 2 H, ArH meta to
OCOTol), 7.19–7.28 (m, 10 H, TolH, ArH meta to OH), 8.08 (d, J =
8.2 Hz, 8 H, TolH). 13C NMR (75.0 MHz, [D6]DMSO): δ = 14.1 ppm (s,
CH3), 21.9 (s, TolCH3), 22.7, 27.7, 32.0, 35.8 (all s, CH2), 36.1 (CH-CH2),
103.4 (s, ArCH ortho to both OH), 116.0 (s, ArCH ortho to both OCO-
Tol), 118.5 (s, ArC-CH ortho and para to OH), 125.8 (s, ArCH meta to
both OH), 126.6 (s, TolC-COO), 127.4 (s, ArCH meta to both OCOTol),
129.5 (s, TolCH ortho to CH3), 130.4 (s, TolCH meta to CH3), 136.9
(s, ArC-CH ortho and para to OCOTol), 144.7 (s, TolC-CH3), 146.0
(s, ArC-OCOTol), 154.0 (s, ArC-OH), 165.9 (s, carbonyl C).[12]
poured onto 1
M HCl (23.0 mL). The precipitate was collected by
filtration, washed with water and dried in vacuo at 50 °C to yield
0.11 g (86 %) of 2b as a red powder. Mp: 250 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 0.84 ppm (t, J = 6.9 Hz, 12 H, CH3), 1.17 (t, J =
7.11 Hz, EtOAc, overlaid), 1.20–1.38 (m, 24 H, (CH2)3CH3), 1.99 (s, 3
H, EtOAc), 2.16–2.28 (m, 8 H, CH-CH2), 4.03 (q, J = 7.11 Hz, 2H,
EtOAc), 4.15 (t, J = 7.4 Hz, 4 H, CH), 6.32 (s, 2 H, ArH ortho to OH),
7.35–7.44 (m, 4 H, ArH meta to OH), 8.64 (s, 4 H, OH ortho to Br),
10.45 (s, 4 H, OH ortho to H). 13C NMR (62 MHz, [D6]DMSO): δ =
13.9 ppm (s, CH3), 22.3 (s, CH2-CH3), 27.5, 31.3 (both s, CH2), 32.7 (s,
CH-CH2), 34.0 (CH-CH2), 99.8 (s, ArCH ortho to OH), 101.5 (s, ArC-Br),
122.4 (s, ArC), 123.6 (s, ArC), 124.5 (s, ArC), 125.4 (s, ArC), 149.3 (s,
ArCOH), 150.3 (s, ArCOH). MS (FAB): m/z (%) = 949 (41) [M+ + Na],
926 (25) [M+], 855 (100) [M+ – C5H11], 755 (20) [M+ – C5H11 – Br]. IR:
ν = 3377 cm–1 (m), 2953 (m), 2926 (s), 2859 (m), 1614 (m), 1504 (w),
˜
1468 (s), 1439(m), 1377 (w), 1344 (w), 1283 (m), 1186 (s), 1146 (s),
1107 (m), 1082 (s), 899 (w), 837 (m), 638 (w), 563 (w). EA: Calculated:
[M + EtOAc] C 61.54 %, H 6.95 %; found: C 61.61 %, H 6.63 %.
Recovery of the Starting Material 1b: The solvent of the previous
5,17-Dibromo-4(24),6(10),12(16),18(22)-tetramethylenedioxy-
filtration was removed under reduced pressure to give the by-prod- 2,8,14,20-pentylresorc[4]arene (3b): To a suspension of 2b
ucts (21.0 g, 16.9 mmol for average M = 1241 g/mol) as a red solid.
Under an argon atmosphere, sodium (6.22 g, 270 mmol) was placed
in a thoroughly dried round-bottomed flask and methanol (150 mL)
was added dropwise under ice-bath cooling. A solution of the by-
products in methanol (150 mL) was slowly added and the mixture
was stirred at room temperature overnight before being poured
(0.67 g, 0.72 mmol) in DMF (125 mL), potassium carbonate (1.29 g,
9.35 mmol) was added and the mixture was heated to 60 °C. After
the addition of bromochloromethane (0.73 mL, 10.8 mmol), the
mixture was stirred for 48 h at 60 °C with another addition of
bromochloromethane (0.73 mL, 10.8 mmol) after 24 h. The mixture
was filtered and the filtrate was extracted with DCM and water.
onto 1
M
HCl (270 mL). The precipitate was collected by filtration,
Organic phases were combined, washed with 1 M HCl and brine,
washed with hot water, and vacuum dried to give spectroscopically
and dried with magnesium sulfate. The solvent was removed and
pure 1b (11.0 g, 85 %) as an off-white powder.
the resulting solid was vacuum dried to give 3b as an off-white
Eur. J. Org. Chem. 2020, 6570–6575
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6574
© 2020 The Authors. European Journal of Organic Chemistry
published by Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001031
EurJOC
European Journal of Organic Chemistry
powder (0.60 g, 85 %). Mp: 220 °C (decomp.). 1H NMR (300 MHz,
CDCl3): δ = 0.82–1.00 ppm (m, 12 H, CH3), 1.24–1.49 (m, 24 H,
(CH2)3CH3), 2.07–2.38 (m, 8 H, CH-CH2), 4.41 (d, J = 7.1 Hz, 4 H,
OCH2O), 4.79 (t, J = 7.3 Hz, 4 H, CH), 5.86 (d, J = 7.0 Hz, 4 H, OCH2O),
[6] a) H. El Moll, D. Sémeril, D. Matt, L. Toupet, Eur. J. Org. Chem. 2010, 1158;
b) H. El Moll, D. Sémeril, D. Matt, L. Toupet, Adv. Synth. Catal. 2010, 352,
901; c) N. Natarajan, M. Pierrevelcin, D. Sémeril, C. Bauder, D. Matt, R.
Ramesh, Catal. Commun. 2019, 118, 70.
[7] a) D. J. Cram, M. E. Tanner, C. B. Knobler, J. Am. Chem. Soc. 1991, 113,
7717; b) R. G. Chapman, J. C. Sherman, J. Am. Chem. Soc. 1998, 120,
9818.
6.53 (s, 2 H, ArH, ortho to O), 6.88–7.18 (m, 4 H, ArH meta to O). 13
C
NMR (75 MHz, CDCl3): δ = 14.2 ppm (s, CH3), 22.8 (s, CH2-CH3), 27.6,
30.0 (both s, CH2), 32.1 (s, CH-CH2), 37.2(CH-CH2), 99.1 (s, OCH2O),
113.3 (s, ArC-Br),116.9 (s, ArCH ortho to OCH2O), 119.0, 121.0 (both
s, ArC lower rim), 126.3 (s, ArCH para to CH2), 128.5, 128.8 (both s,
ArCH ortho and meta to CH2), 138.5 (s, ArC-CH meta to upper rim
H), 139.5 (s, ArC-CH meta to Br), 152.2 (s, ArC-OCH2O ortho to Br),
155.0 (s, ArC-OCH2O ortho to upper rim H).[19]
[8] B. M. Trost, Science 1991, 254, 1471.
[9]
a) E. S. Barrett, J. L. Irwin, P. Turner, M. S. Sherburn, J. Org. Chem. 2001,
66, 8227; b) A. Aniol, B. Mallick, M. Winter, M. Feigel, J. Mol. Struct. 2017,
1144, 451.
[10]
[11]
X. Liu, R. Warmuth, Nat. Protoc. 2007, 2, 1288.
O. Lukin, A. Shivanyuk, V. V. Pirozhenko, I. F. Tsymbal, V. I. Kalchenko, J.
Org. Chem. 1998, 63, 9510.
[12]
[13]
[14]
[15]
A. Shivanyuk, E. F. Paulus, V. Böhmer, W. Vogt, J. Org. Chem. 1998, 63,
6448.
a) G. Arnott, H. Heaney, R. Hunter, P. Page, Eur. J. Org. Chem. 2004, 5126;
b) G. Arnott, R. Hunter, H. Su, Tetrahedron 2006, 62, 977.
S. Bringmann, R. Brodbeck, R. Hartmann, C. Schäfer, J. Mattay, Org.
Biomol. Chem. 2011, 9, 7491.
J. N. Smith, T. K. Brind, S. B. Petrie, M. S. Grant, N. T. Lucas, J. Org. Chem.
2020, 85, 4574.
L. M. Tunstad, J. A. Tucker, D. J. Cram, et al., J. Org. Chem. 1989, 54, 1305.
E. Román, C. Peinador, S. Mendoza, A. E. Kaifer, J. Org. Chem. 1999, 64,
2577.
a) F. Tancini, T. Gottschalk, W. B. Schweizer, F. Diederich, E. Dalcanale,
Chem. Eur. J. 2010, 16, 7813; b) R. M. Yebeutchou, E. Dalcanale, J. Am.
Chem. Soc. 2009, 131, 2452; c) L. Pirondini, D. Bonifazi, E. Menozzi, E.
Dalcanale, Eur. J. Org. Chem. 2001, 2311.
T. M. Altamore, E. S. Barrett, P. J. Duggan, M. S. Sherburn, M. L. Szydzik,
Org. Lett. 2002, 4, 3489.
Acknowledgments
Open access funding enabled and organized by Projekt DEAL.
Keywords: Selective difunctionalization · Regioselective
deactivation · Macrocycles · Molecular bowls ·
Resorcinarenes · Supramolecular chemistry
[16]
[17]
[1] D. J. Cram, M. E. Tanner, R. Thomas, Angew. Chem. Int. Ed. Engl. 1991, 30,
1024; Angew. Chem. 1991, 103, 1048.
[2] H.-J. Choi, Y. S. Park, J. Song, S. J. Youn, H.-S. Kim, S.-H. Kim, K. Koh, K.
Paek, J. Org. Chem. 2005, 70, 5974.
[3] a) T. M. Bräuer, Q. Zhang, K. Tiefenbacher, Angew. Chem. Int. Ed. 2016,
55, 7698; Angew. Chem. 2016, 128, 7829; b) T. Chavagnan, D. Sémeril, D.
Matt, L. Toupet, Eur. J. Org. Chem. 2017, 2017, 313.
[4] N. Li, R. G. Harrison, J. D. Lamb, J. Inclusion Phenom. Macrocyclic Chem.
2014, 78, 39.
[18]
[19]
[5] D. Loose, A. Aniol, M. Feigel, S. Röhling, G. Dyker, Eur. J. Org. Chem. 2020,
2020, 35.
Received: July 28, 2020
Eur. J. Org. Chem. 2020, 6570–6575
www.eurjoc.org
6575
© 2020 The Authors. European Journal of Organic Chemistry
published by Wiley-VCH GmbH