Selective methylation of phloroglucinol in the presence of a glycoluril clip

Article abstract of DOI:10.1016/j.tetlet.2013.05.042

Methylation of phloroglucinol was performed using dimethyl sulfate as the methylating agent in the presence and absence of a glycoluril clip. The results showed that the yield of the di-methylated product decreased significantly in the presence of a glycoluril clip (host), due to the formation of a host-guest complex between the clip and phloroglucinol. Also, the reaction was conducted with different quantities (mol %) of the host.

Full text of DOI:10.1016/j.tetlet.2013.05.042

Tetrahedron Letters 54 (2013) 3855–3857
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Tetrahedron Letters
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Selective methylation of phloroglucinol in the presence
of a glycoluril clip
⇑
Esmail Rezaei-Seresht , Behrooz Maleki, Zeinab Amiri-Moghaddam, Sara Taghizadeh
Department of Chemistry, School of Sciences, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Methylation of phloroglucinol was performed using dimethyl sulfate as the methylating agent in the
presence and absence of a glycoluril clip. The results showed that the yield of the di-methylated product
decreased significantly in the presence of a glycoluril clip (host), due to the formation of a host–guest
complex between the clip and phloroglucinol. Also, the reaction was conducted with different quantities
(mol %) of the host.
Received 25 March 2013
Revised 28 April 2013
Accepted 10 May 2013
Available online 18 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycoluril clip
Methylation
Phloroglucinol
Selectivity
Reaction control through complexation of a substrate by a
supramolecular host is a relatively new concept. Complexation
influences the chemical reactivity, including chemo-, regio-, and
stereoselectivity of the complexed substrate.1 Several host systems
have been introduced and developed for enhancing the reactivity
and/or selectivity in various chemical transformations in supramo-
lecular systems. For example, molecular clips derived from propan-
ediurea promoted regioselectivity in the SO2Cl2-mediated
electrophilic aromatic chlorination of o-cresol.2 Breslow and
Campbell reported the selective aromatic substitution of anisole
bound in the cavity of cyclodextrin.3 The host cyclodextrin has also
been used for increasing positional selectivity in the bromination
of acetanilide with pyridinium dichlorobromate, so that only the
gen bond, p–p stacking interactions, and a so-called ‘cavity
effect’.9–11 For example, a value of Ka = 200 MÀ1 has been reported
for the complex of a glycoluril host with resorcinol in CDCl3.10
The binding properties of the glycoluril hosts encouraged us to
investigate their possible roles in the selectivity of reactions with a
guest, for example, resorcinols. Phloroglucinol (1) was a good sub-
strate for this study; this compound has the resorcinol skeleton
and therefore, behaves as a good guest toward glycoluril hosts.
Glycoluril 2, which is readily prepared in two steps from benzil,12
OH
Chemical
para-isomer was produced in the presence of a
-cyclodextrin.4 Oxi-
reactions
dation of benzene to phenol using N2O as the oxidant in the pres-
ence of a zeolite host has been reported with selectivity close to
100%.5 Calix[n]arenes, which possess cavities of various sizes, have
been utilized to increase the selectivity in organic reactions. For
example, Ramamurthy et al. investigated the selectivity in the pho-
tochemistry of benzoin alkyl ethers using calix[6]arene and ca-
lix[8]arene systems as supramolecular hosts.6
A series of host molecules derived from the concave molecule,
glycoluril, have been developed by Nolte’s group.7,8 These hosts
possess a well-defined and rigid U-shaped cavity, which is formed
by the glycoluril framework and two aromatic side walls. With
their preorganized cleft, they are good hosts for a 1,3-dihydroxy-
benzene guest molecule in a chloroform solution through hydro-
OH
O
H
O
H
O
O
O
H
O
H
N
N
N
N
O
O
N
N
N
N
⇑
Corresponding author. Tel.: +98 571 400 3267; fax: +98 571 441 1161.
E-mail address: rezaei_seresht@yahoo.com (E. Rezaei-Seresht).
Figure 1. Schematic presentation of the formed complex between the guest
phloroglucinol (1) and the glycoluril host 2 (dashed lines indicate hydrogen bonds).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.042

3856
E. Rezaei-Seresht et al. / Tetrahedron Letters 54 (2013) 3855–3857
Table 2
Isolated yields of the products of reactions 1 and 2
Reaction
Isolated yield (%)
Compound 3 Compound 4
3:4 Ratio
Selectivitya (%)
1
2
36
41
16
5
2.1:1
8.4:1
69
89
a
Selectivity is defined as mono-methylated product/(mono-methylated prod-
uct + dimethylated product) Â 100.
Table 3
Effect of the host/guest molar ratio on the isolated yields and selectivity
Host/guest molar
ratio
Isolated yield (%)
Compound Compound
3:4
Ratio
Selectivitya
(%)
3
4
1:1
41
39
38
37
5
8.4:1
3.7:1
3.2:1
3.0:1
89
79
76
75
Figure 2. Computer-optimized complex of guest 1 and host 2 (hydrogen atoms in
the host have been omitted for clarity, dashed lines indicate hydrogen bonds).
0.75:1
0.5:1
0.25:1
11
12
12
a
Selectivity is defined as mono-methylated product/(mono-methylated prod-
Table 1
uct + dimethylated product) Â 100.
Calculated interaction energy between host 2 and guest 1, and the distances between
atoms in the formed complex at the B3LYP/6-311G level
Host
Interaction energya (kJ/mol)
Distancesb (Å)
1.84023 1.84770
TLC of reaction 2 showed spots belonging to unreacted guest 1,
5-methoxyresorcinol (3) [and 3,5-dimethoxyphenol (4)], and host
2 (Scheme 1). Moreover, no tri-methylated product was observed
under either reaction conditions. The products of the reactions
were purified by column chromatography, and their isolated yields
obtained (Table 2).
2
À87.69196923
a
The interaction energy was calculated by subtracting the energies of the host
and guest from the minimum complex energy.
Distances (lengths) of the two formed hydrogen bonds between the host and
guest molecules (see Fig. 2).
b
In the next step, the effect of the host/guest molar ratio on the
selectivity of reaction 2 was investigated. Thus, reaction 2 was run
in various host/guest molar ratios of less than 1:1 and the results
showed a decrease in the selectivity due to fewer host–guest inter-
actions (Table 3).
To find other features of our reaction, we examined the recy-
cling and reusability of the host 2. Therefore, once reaction 2 was
completed, the mixture was worked-up in such a manner that it
yielded the purified host 2 with nearly complete recovery.15
In conclusion, we have shown that host 2 promotes the selectiv-
ity of phloroglucinol O-methylation through the formation of a
host–guest complex. The mono- and di-methylated derivatives
were obtained as the major and minor products respectively.
Moreover, the host was readily recycled and reused.
was selected as the host for this work. First, we assumed that due
to the formation of a host–guest complex between host 2 and guest
1, the guest molecule entered into the cavity of the host and two of
its hydroxyl groups were engaged in hydrogen bonding with the
carbonyl groups of the host (Fig. 1). Accordingly, the third hydroxyl
group of the guest remains free (compared to the other hydroxyl
groups), and it can be manipulated selectively.
The formation of a host–guest complex between host 2 and
guest 1 was also examined computationally. As shown in Figure 2,
guest 1 in the optimized structure of the host–guest complex is
bound into the cavity of the host, and only one of its hydroxyl
groups is free. Moreover, the calculations gave
a value of
À87.69196923 kJ/mol for the interaction energy of the computer-
optimized complex shown in Figure 2 (Table 1).
References and notes
To demonstrate this experimentally, two methylation reactions
were run under commonly-used O-methylation reaction condi-
tions as follows: reaction of guest 1 with dimethyl sulfate in the
presence of sodium carbonate in acetonitrile at 35 °C for 72 h
(reaction 1),13 and reaction of guest 1 with dimethyl sulfate in
the presence of sodium carbonate and host 2 in acetonitrile–
dichloromethane (reaction 2).14 The two reaction mixtures were
analyzed by TLC and for reaction 1 (control reaction) three spots
including the unreacted guest 1, the mono-methylated product 3
(5-methoxyresorcinol), and di-methylated product 4 (3,5-dime-
thoxyphenol) were observed on the TLC plate. In contrast, the
1. Yang, C.; Ke, C.; Liu, Y.; Inoue, Y. Reaction Control by Molecular Recognition – A
Survey from the Photochemical Perspective. In Molecular Encapsulation; John
Wiley & Sons Ltd, 2010; pp 1–42.
2. Bugnet, E. A.; Nixon, T. D.; Kilner, C. A.; Greatrex, R.; Kee, T. P. Tetrahedron Lett.
2003, 44, 5491.
3. Breslow, R.; Campbell, P. J. Am. Chem. Soc. 1969, 91, 3085.
4. Dumanski, P. G.; Easton, C. J.; Lincoln, S. F.; Simpson, J. S. Aust. J. Chem. 2003, 56,
1107.
5. Suzuki, E.; Nakashiro, K.; Ono, Y. Chem. Lett. 1988, 17, 953.
6. Kaliappan, R.; Kaanumalle, L. S.; Ramamurthy, V. Chem. Commun. 2005, 4056.
7. Rowan, A. E.; Elemans, J. A. A. W.; Nolte, R. J. M. Acc. Chem. Res. 1999, 32, 995.
8. Elemans, J. A. A. W.; Rowan, A. E.; Nolte, R. J. M. Ind. Eng. Chem. Res. 2000, 39,
3419.
OH
OMe
OMe
O
Na2CO3, 35 oC, 72 h
MeO
S
OMe
+
+
In the absence or presence of host 2
HO
OH
O
HO
OH HO
OMe
1
4
3
Scheme 1. Methylation of guest 1 in the absence or presence of host 2.

E. Rezaei-Seresht et al. / Tetrahedron Letters 54 (2013) 3855–3857
3857
9. Sijbesma, R. P.; Kentgens, A. P. M.; Nolte, R. J. M. J. Org. Chem. 1991, 56, 3199.
10. Sijbesma, R. P.; Kentgens, A. P. M.; Lutz, E. T. G.; van der Maas, J. H.; Nolte, R. J.
M. J. Am. Chem. Soc. 1993, 115, 8999.
11. Reek, J. N. H.; Priem, A. H.; Engelkamp, H.; Rowan, A. E.; Elemans, J. A. A. W.;
Nolte, R. J. M. J. Am. Chem. Soc. 1997, 119, 9956.
(0.42 g) was purified by column chromatography (silica; CH2Cl2/MeOH, 30:1 v/
v) to yield 3 (114 mg, 36%) and 4 (52 mg, 16%).
14. A mixture of phloroglucinol (0.32 g, 2.5 mmol) and Na2CO3 (1.98 g) in MeCN
(30 mL) was added to a solution of host 2 (1.25 g, 2.5 mmol) in CH2Cl2 (20 mL),
and the resulting mixture was stirred at rt for 45 min. Then, Me2SO4 (0.12 mL,
2.8 mmol) was added and the mixture was heated at 35 °C for 72 h. The
mixture was filtered and the brown mother liquor was evaporated to dryness
in vacuo. The residue (0.45 g) was purified by column chromatography (silica;
CH2Cl2/MeOH, 30:1 v/v) to yield 3 (132 mg, 41%) and 4 (16 mg, 5%).
15. After completion of reaction 2, the mixture was filtered, and the mother liquor
was evaporated to dryness. The resulting brown residue was heated in
refluxing MeOH (40 mL) for 20 min. Then, the mixture was filtered and the
precipitate was washed with boiling H2O (40 mL). The precipitate was
dissolved in CH2Cl2, filtered, and the solution was finally concentrated to
yield the purified host 2 with nearly 100% recovery. The recovered host 2 was
recycled, and reused without difficulty.
12. Step 1, Synthesis of 3a,6a-diphenylglycoluril. This compound was synthesized
according to a literature procedure.16 Step 2, Synthesis of host 2. This compound
was prepared using
a
procedure described previously,17 with slight
modification as follows: 3a,6a-diphenylglycoluril (1.65 g, 5.6 mmol) and
freshly ground KOH (3.14 g, 56.0 mmol) in DMSO (40 mL) were heated at
120 °C with vigorous stirring for 20 min. 1,2-Bis(bromomethyl)benzene
(3.17 g, 12.0 mmol) was added in one portion and stirring was continued at
this temperature for 2 h. On cooling, the mixture was added to H2O (400 mL)
and stirred for 30 min. The resulting precipitate was collected by filtration,
washed with H2O (3 Â 100 mL) and Et2O (3 Â 50 mL), and then dried under
vacuum to yield 1.71 g (61%) of host 2.
13. A mixture of phloroglucinol (0.32 g, 2.5 mmol) and Na2CO3 (1.98 g) in MeCN
(30 mL) was stirred at rt for 45 min. Then, Me2SO4 (0.12 mL, 2.8 mmol) was
added and the mixture was heated at 35 °C for 72 h. The mixture was filtered
and the brown mother liquor was evaporated to dryness in vacuo. The residue
16. Jansen, K.; Wego, A.; Buschmann, H.-J.; Schollmeyer, E.; Döpp, D. Des.
Monomers Polym. 2003, 6, 43.
17. Creaven, B. S.; Gallagher, J. F.; McDonagh, J. P.; McGinley, J.; Murray, B. A.;
Whelan, G. S. Tetrahedron 2004, 60, 137.