Utilization of the hydroxyalkylation reaction to prepare bis(benzocrown ethers)

Article abstract of DOI:10.1016/j.tetlet.2012.01.049

The hydroxyalkylation reaction has been used to condense benzocrown ethers with various aldehydes and ketones. The condensation reactions are catalyzed by triflic or sulfuric acid. The products from the reactions are bis(benzocrown ethers) and they are fo

Full text of DOI:10.1016/j.tetlet.2012.01.049

Tetrahedron Letters 53 (2012) 1701–1704
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Utilization of the hydroxyalkylation reaction to prepare bis(benzocrown ethers)
⇑
Matthew E. Zielinski, Adam F. Tracy, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydroxyalkylation reaction has been used to condense benzocrown ethers with various aldehydes
and ketones. The condensation reactions are catalyzed by triflic or sulfuric acid. The products from the
reactions are bis(benzocrown ethers) and they are formed in good yields (42–98%, 13 examples).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 30 November 2011
Revised 10 January 2012
Accepted 12 January 2012
Available online 2 February 2012
Keywords:
Crown compounds
Condensation
Heterocycles
Electrophilic aromatic substitution
Superacid
Since their discovery by Pederson in 1967, crown ethers and re-
lated substances have been useful in a variety of applications.1
Their abilities to complex metal cations have made them useful
as ionophores, phase transfer catalysts, and components in ionse-
lective electrodes.2 Because of the many applications of crown
ethers and functionalized derivatives, there continues to be a need
for new synthetic methods leading to crown ether products. Ben-
zocrown ethers may be considered activated, electron rich arenes.
As such, functionalized benzocrown ethers may be readily
prepared using Friedel–Crafts type chemistry.3 We and others have
recently demonstrated that the hydroxylalkylation condensation is
an outstanding synthetic method leading triarylmethanes,4
functionalized heterocycles,5 and condensation polymers.6 The
hydroxyalkylation reaction typically involves the condensation of
an aldehyde or ketone with activated aromatic compounds, such
as aryl ethers or phenols.7 Less reactive arenes may also form
condensation products if the aldehyde or ketone generates highly
electrophilic intermediates. In the following manuscript, we
describe our studies involving the hydroxyalkylation reaction with
benzocrown ethers leading to the preparation of bis(benzocrown
ether) products.
of the crude mixture by NMR reveals very high regioselectivity in
the reaction with benzo-18-crown-6 (2).
H
N
CF3SO3H
O
2 Benzo-18-C-6
Cl
O
67%
1
NH
Cl
O
O
O
O
O
O
O
O
O
O
O
O
O
3
ð1Þ
Other isatins (4–6) likewise give the condensation products
(10–12) in reactions with benzo-18-crown-6 (2). Ninhydrin (7) re-
acts efficiently with arenes at the 2-position, so condensation with
compound 2 gives product 13 in a good yield. In this case, H2SO4 is
superior to CF3SO3H in promoting the condensation. The quinone 8
also provides a bis(benzocrown ether) product (14), as does the
heterocyclic aldehyde (9). Condensation reactions were also
accomplished with benzo-15-crown-5 (22) and benzo-12-crown-
4 (23, Table 2).
Superacid-promoted hydroxyalkylations have been utilized in
several types of condensations leading to macromolecules.6
Recently, Zolotukhin and co-workers described the hydroxyalkyla-
tion reaction of isatin with a series of dibenzocrown ethers using
methanesulfonic acid and P2O5 as an acid catalyst.8 By the
utilization of dibenzo-18-crown-6 and triflic acid, we have
accomplished similar condensations to prepare crown-containing
Our initial studies involved reacting a series of aldehydes and
ketones with benzo-18-crown-6 in the presence of the Brønsted
superacid, CF3SO3H (Eq. 1 and Table 1). For example, 5-chloroisatin
(1) is reacted with benzo-18-crown-6 (2) in CF3SO3H and the
condensation product 3 is formed in a good yield (Eq. 1). The
reaction is best done with an excess of CF3SO3H (8 equiv). Analysis
⇑
Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4802.
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.049

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M. E. Zielinski et al. / Tetrahedron Letters 53 (2012) 1701–1704
Table 1
Acid-catalyzed reactions of carbonyl compounds (4–9) with benzo-18-crown-6 (2)
Starting material
Product
Yield (%)
55a
Ph
N
Ph
N
O
O
O
Ar
Ar
O
4
10
CH3
CH3
N
N
O
68a
Ar
Ar
O
11
5
H
H
N
N
O
O
97a
O2N
O2N
Ar
O
Ar
12
6
O
O
Ar
Ar
OH
OH
72b
O
O
O
13
7
O
Ar
O
Ar
98a
8
14
Ar
O
Ar
N
N
65a
H
H
15
9
O
O
O
O
O
O
Ar
a
Reaction with 2.0 equiv (2), 8 equiv TfOH, CHCl3, 25 °C.
Reaction with 2.0 equiv (2), 8 equiv H2SO4, CHCl3, 25 °C.
b
macromolecules (Scheme 1). Reaction of isatin 5 leads to the A2B2-
type condensation polymer 24, a hard off-white solid which soft-
ens at about 170 °C.
amide-type carbonyl groups. Analysis of the polymer 24 shows sin-
gle carbonyl absorption at 1684 cmꢀ1. This is consistent with the
formation of a condensation polymer, because entrapped or unre-
acted isatin 5 would exhibit two carbonyl absorptions. Likewise,
polymer 25 shows no absorptions in the carbonyl region of the
infrared spectrum.9 As noted previously by Zolotukhin, the con-
densation reactions with dibenzo-18-crown-6 likely produces the
pair of regioisomeric repeat units (electrophilic attack at the 4,40
positions and at the 4,50 positions of the dibenzo-18-crown-6).
In summary, we have found that hydroxyalkylation reactions
can lead to products having two benzocrown units.10 These con-
versions are effectively promoted by triflic acid and in some cases
sulfuric acid. With a variety of electrophilic systems, good regiose-
A similar condensation was accomplished with 2-pyridinecar-
boxaldehyde (9) to give the macromolecule 25. Poor solubility in
organic solvents prevented GPC analysis of polymers 24 and 25,
however NMR analysis could be accomplished by dissolving the
polymers in CF3CO2D.9 For structure 24, the 1H NMR spectrum is
consistent with the presence of both oxyindole and crown ether
structures. Further analysis was done by infrared spectroscopy,11
comparing the carbonyl absorption bands of compound 5 and the
polymeric product. N-Methylisatin exhibits strong absorption
bands at 1727 and 1604 cmꢀ1, respectively, for the ketone and

M. E. Zielinski et al. / Tetrahedron Letters 53 (2012) 1701–1704
1703
Table 2
Condensations with benzo-15-crown-5 and benzo-12-crown-4
Starting material
Product
Yield
H
N
H
N
16, R = Ar1 95%
19, R = Ar2 92%
O
O
O2N
O2N
R
O
O
R
6
7
O
R
17,
OH
OH
R = Ar1 77%
20
, R = Ar2 65%
R
O
O
R
O
N
N
18, R = Ar1 49%
21, R = Ar2 94%
H
R
H
9
O
O
O
O
O
O
Ar1
Ar2
O
O
O
CH3
N
Acknowledgment
CF3SO3H
O
We gratefully acknowledge the support of the NIH-National
Institute of General Medical Sciences (GM085736-01A1).
Dibenzo-18-C-6
CH2Cl2
O
5
CH3
N
Supplementary data
O
O
O
O
O
Supplementary data (NMR spectra of products) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2012.01.049.
O
O
n
24
References and notes
O
1. (a) Pederson, C. J. J. Am. Chem. Soc. 1967, 89, 2495; (b) Pederson, C. J. J. Am. Chem.
Soc. 1967, 89, 7017.
CF3SO3H
N
2. (a) Crown Ethers and Analogous Compounds; Hiraoka, M., Ed.; Elsevier:
Amsterdam, 1992; (b) Kralj, M.; Tusek-Bozic, L.; Frkanec, L. ChemMedChem
2008, 3, 1478; (c) Rusalov, M. V.; Uzhinov, B. M.; Alfimov, M. V.; Gromov, S. P.
Russ. Chem. Rev. 2010, 79, 1099; (d) Fery-Forgues, S.; Al-Ali, F. J. Photochem.
Photobiol. C Photochem. Rev. 2004, 5, 139.
3. (a) Sharghi, H.; Jokar, M.; Doroodmand, M. M.; Khalifeh, R. Adv. Synth. Catal.
2010, 352, 3031; (b) O’Connor, M. J.; Boblak, K. N.; Spitzer, A. D.; Gucciardo, P.
A.; Baumann, A. M.; Peter, J. W.; Chen, C. Y.; Peter, R.; Mitton, A. A.; Klumpp, D.
A. Tetrahedron Lett. 2010, 51, 4984; (c) Kotha, S.; Brahmachary, E. Indian J.
Chem., Sect. B: Org. Chem. 2001, 40B, 1; (d) Barboiu, M.; Supuran, C. T.; Luca, C.;
Popescu, G.; Barboiu, C. Liebigs Ann. 1996, 6, 959; (e) Akkus, H.; Gul, A. Org. Prep.
Proced. Int. 1995, 27, 668; (f) Warshawsky, A.; Kahana, N. J. Am. Chem. Soc. 1982,
104, 2663.
H
Dibenzo-18-C-6
CH2Cl2
9
H
N
O
O
O
O
O
O
n
25
Scheme 1.
4. (a) Prakash, G. K. S.; Panja, C.; Shakhmin, A.; Shah, E.; Mathew, T.; Olah, G. A. J.
Org. Chem. 2009, 74, 8659; (b) Alvaro, M.; Garcia, H.; Sanjuan, A.; Espla, M. Appl.
Catal., A. 1998, 175, 105; (c) Koltunov, K. Yu.; Walspurger, S.; Sommer, J. Catal.
Lett. 2004, 98, 89.
5. (a) Prakash, G. K. S.; Paknia, F.; Chacko, S.; Mathew, T.; Olah, G. A. Heterocycles
2008, 76, 783; (b) Sheets, M. A.; Li, A.; Bower, E. A.; Weigel, A. R.; Abbott, M. P.;
Gallo, R. M.; Mitton, A. A.; Klumpp, D. A. J. Org. Chem. 2009, 73, 2502; (c)
Klumpp, D. A.; Zhang, Y.; Kindelin, P. J.; Lau, S. Tetrahedron 2006, 62, 5915; (d)
Zhang, Y.; Klumpp, D. A. Tetrahedron Lett. 2002, 43, 6841; (e) Klumpp, D. A.;
Jones, A.; Lau, S.; DeLeon, S.; Garza, M. Synthesis 2000, 1117; (f) Klumpp, D. A.;
Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1998, 63, 4481.
lectivities are observed in these conversions. Bis(benzocrown
ethers) are useful in a variety of applications and this chemistry
provides ready access to these systems. In addition to the bis(ben-
zocrown ether) products, we have found that macromolecules can
be produced by hydroxyalkylation with dibenzo-18-crown-6 as a
substrate.

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M. E. Zielinski et al. / Tetrahedron Letters 53 (2012) 1701–1704
6. Gozman-Gutierrez, M. T.; Nieto, D. R.; Fomine, S.; Morales, S. L.; Zolotukhin, M.
G.; Hernandez, M. C. G.; Kricheldorf, H.; Wilks, E. S. Macromolecules 2011, 44,
194. and references cited therein.
300 MHz): d, 3.4–3.8, 5.44 and 5.46, 6.10–6.12, 6.36–6.43, 7.15–7.20, 7.34–
7.37, 7.93–7.95, 8.05–8.09. IR: 2855, 1506, 1249, 1118, 1052, 944, 751
637 cmꢀ1
.
7. (a) Hofmann, J. E.; Schriesheim, A. In Friedel–Crafts and Related Reaction; Olah,
G. A., Ed.; Wiley: New York, NY, 1964; vol. 2, pp 597–640; (b) March, J.
Advanced Organic Chemistry, 4th ed.; Wiley: New York, NY, 1992. p. 548–549.
8. Zolotukhin, M. G.; Hernandez, M. C. G.; Lopez, A. M.; Fomina, L.; Cedillo, G.;
Nogales, A.; Ezquerra, T.; Rueda, D.; Colquhoun, H. M.; Fromm, K. M.; Ruiz-
Trevino, A.; Ree, M. Macromolecules 2006, 39, 4696.
10. General procedure: The carbonyl substrate (0.1 g) is dissolved in 1–2 mL of
anhydrous CHCl3 and 2.0 equiv of a benzocrown ether is added to the solution.
To this mixture, CF3SO3H (8.0 equiv; H2SO4 may be used in some cases) is
added dropwise with stirring. The reaction is stirred at room temperature for at
least 2 h, after which, the mixture is poured over several grams of ice. The
resulting solution is extracted three times with CHCl3. The organic phase is
subsequently washed three times with water and dried over MgSO4 solution.
Removal of the solvent provides the product.
9. Data for polymeric products. 24: 1H NMR (CF3CO2D, 300 MHz): d = 3.15–3.22,
3.60–3.90, 3.95–4.05, 6.50–6.64, 6.67–6.75, 6.75–6.88, 7.00–7.14, 7.24–7.38.
IR: 2914, 2871, 1719, 1520, 1255, 1123, 750, 639 cmꢀ1. 25: 1H NMR (CF3CO2D,