Incl34h2o-catalyzed trioxane as a new methylating agent for multi-methylated aromatics affording hexamethyl benzene

Article abstract of DOI:10.2174/157017810790533959

In the presence of a catalytic amount of InCl₃-4H₂O, trioxane was first used as the methylating agent for multi- methylated aromatic compounds such as pentamethylbenzene, 1,2,4,5-tetramethylbenzene and 1,3,5-trimethylbenzene to afford hexamethylbenzene in fair to high yields.

Full text of DOI:10.2174/157017810790533959

Letters in Organic Chemistry, 2010, 7, 61-63
61
InCl3·4H2O-Catalyzed Trioxane as a New Methylating Agent for
multi-Methylated Aromatics Affording Hexamethyl Benzene
Song-Jie Chen and Ruimao Hua*
Department of Chemistry, Tsinghua University, Innovative Catalysis Program, Key Laboratory of Organic
Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
Received July 17, 2009: Revised November 11, 2009: Accepted November 16, 2009
Abstract: In the presence of a catalytic amount of InCl3·4H2O, trioxane was first used as the methylating agent for multi-
methylated aromatic compounds such as pentamethylbenzene, 1,2,4,5-tetramethylbenzene and 1,3,5-trimethylbenzene to
afford hexamethylbenzene in fair to high yields.
Keywords: Hexamethylbenzene, indium chloride, methylating agent, trioxane.
INTRODUCTION
was obtained in 92% GC yield, accompanied with the
formation of a small amount of di(pentamethylphenyl)
methane and 2,3,4,5,6-pentamethylbenzyl alcohol (entry 1).
When CHCl3 and 1,2-dichloroethane (DCE) were used as
solvents to replace CH2Cl2, the yield of HMB, after heating
for 8 h was 83% and 84%, respectively (entries 2-3).
However, the use of cyclohexane, DMF and CH3CN as
solvents led to either very low yield of HMB or no reaction
occurrence (entries 4-6). Repeating the reaction in CHCl3
and DCE and increasing the reaction temperature to 110 oC
for 8 h resulted in the formation of HMB in excellent yields,
and in the later case, HMB could be isolated in 83% yield by
column chromatography (silica gel, eluted by petroleum
ether) (entries 7-8). The use of DMF and CH3CN as solvents
resulting in no reaction might be due to the possible reaction
occurring between InCl3·4H2O and the coordinative solvents
to lose the catalytic activity.
Hexamethyl benzene (HMB) is a simple and important
compound used as a high boiling-point solvent in organic
reactions and as an intermediate in the fragrance industry.
The synthesis, reactivity and application of HMB-
coordinated transition metal complexes have been well-
studied [1-3]. In addition, the functionalization of HMB [4,
5] or the coordinated HMB [6] via activation of C-H bond of
methyl group(s) has also become a topic of interest in recent
years. Some of the most common methods for the synthesis
of HMB are the methylation of pentamethylbenzene (PMB)
with MeCl in the presence of AlCl3, the reaction of 1,2,3,4,5-
pentamethylbenzene with MeMgBr, and the reaction of
1,2,3,4,5,6-hexabromobenzene with MeMgI. However, these
known procedures use methyl halides, which are both toxic
and not environmentally-benign, as methylating agents.
Therefore, the development of new methylation procedures
for the synthesis of HMB remains a topic of interest.
In addition, under the reaction conditions of entry 8 of
Scheme 1, the catalytic activity of other acids was also
examined. Although PMB conversion reached up to 90%,
the selectivity for the formation of HMB was low. For
example, when BiCl3 was employed as catalyst, the
conversion of PMB was up to 97%, but only trace amount of
HMB was formed, the major product was bis-(2,3,4,5,6-
pentamethyl-phenyl)methane, which was confirmed by GC-
MS [10]. In the case of H3PMo12O40·nH2O (14 mg) used,
HMB was obtained in 31% yield with 95% conversion of
PMB.
Recently, InCl3·4H2O has been applied as a catalyst in
various organic transformations [7-9]. Our previous work
has disclosed that InCl3·4H2O is an efficient catalyst for the
reaction of an excess amount of electron-rich aromatic
compounds with trioxane to afford diarylated methanes in
good yields [10]. In our continuing studies in the application
of InCl3·4H2O as a catalyst in organic transformations, we
found that InCl3·4H2O could catalyze trioxane as a new
methylating agent in the methylation of multi-methylated
aromatic compounds. In this letter, we report our new
preliminary findings.
In order to evaluate the scope of the present methylation
procedure, the reactions of other methylated benzenes with
trioxane in the presence of InCl3·4H2O were also studied. As
As summarized in Scheme 1, when a mixture of
pentamethylbenzene (PMB), 2.0 equiv. of trioxane and
InCl3·4H2O (5 mol% relative to PMB) in CH2Cl2 in a sealed
shown in Scheme 2, heating
a mixture of 1,2,4,5-
o
tube was heated with stirring at 80 C for 10h, the GC and
tetramethylbenzene (TMB) with 2.0 equiv. of trioxane at 80
oC for 8 h resulted in the complete conversion of TMB,
however, only a trace amount of HMB was found in the
reaction mixture. Increase of the reaction temperature (110
oC) could improve the formation of HMB, and in this case,
the GC yield of HMB was 18%, and the formation of PMB
in 4% GC yield was also observed.
GC-MS analyses of the reaction mixture disclosed that PMB
was consumed completely, and hexamethylbenzene (HMB)
*Address correspondence to this author at the Department of Chemistry,
Tsinghua University, Innovative Catalysis Program, Key Laboratory of
Organic Optoelectronics
& Molecular Engineering of Ministry of
Education, Beijing 100084, China; Fax: +86-10-62771149;
E-mail: ruimao@mail.tsinghua.edu.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

62
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Chen and Hua
O
.
InCl3 4H2O (5 mol%)
+
O
O
solvent
1 : 2
PMB
HMB
conversion
GC yield
entry
1
solvent
temp. (oC) / h
of PMB (%)a
of HMB (%)b
CH2Cl2
CHCl3
80 / 10
80 / 8
> 99
> 99
92
83
2
3
4
5
6
DCE
80 / 8
80 / 8
80 / 8
80 / 8
> 99
42
84
cyclohexane
DMF
< 5
nr
CH3CN
CHCl3
nr
110 / 8
110 / 8
> 99
> 99
93
7
8
DCE
(83)
a Conversion of PMB was determined by GC.
b Number in the parenthesis is isolated yield.
Scheme 1.
O
.
InCl3 4H2O (5 mol%)
HMB
trace
+
+
n
O
O
DCE
80 oC for 8 h:
110 oC for 8 h:
TMB
1 : 2
18% (GC)
conversion: >99%
Scheme 2.
O
.
InCl3 4H2O (5 mol%)
n
+
HMB
+
O
O
DCE
conversion of
mesitylene (%)a
temp. (oC) / h
mesitylene : trioxane
GC yield of
HMB (%)
1 : 2
1 : 5
80 / 8
> 99
> 99
trace
18
110 / 10
a Conversion of mesitylene was determined by GC.
Scheme 3.
In the case of 1,3,5-trimethylbenzene (mesitylene)
employed, mesitylene was consumed completely with 2.0
The reason for the formation of HMB in low yield was
considered to be the easy methylidenated polymerization of
TMB and mesitylene, which became the predominant
reaction under the reaction conditions. In addition, on the
basis of the observed results, it is apparent that the low
o
equiv. of trioxane at 80 C for 8 h, or with 5.0 equiv. of
o
trioxane at 110 C for 10h. A low yield (18% GC) of HMB
was obtained in the later case (Scheme 3).

InCl3·4H2O-Catalyzed Trioxane as a New Methylating Agent
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
63
O
OH
+
.
InCl3 4H2O (5 mol%)
HMB
O
O
DCE, 80 oC, 8 h
1 : 2
conversion: 100%
Scheme 4.
o
[3]
[4]
Mry, D.; Aranzaes, J. R.; Astruc, D. Use of an electron-reservoir
complex together with air to generate N-heterocyclic carbenes. J.
Am. Chem. Soc. 2006, 128, 5602.
Fukuzumi, S.; Yuasa, J. Y.; Satoh, N.; Suenobu, T. Scandium ion-
promoted photoinduced electron transfer from electron donors to
acridine and pyrene: essential role of scandium ion in
photocatalytic oxygenation of hexamethylbenzene. J. Am. Chem.
Soc. 2004, 126, 7585.
Kralj, P.; Zupan, M.; Stavber, S. Remarkable effect of water on
functionalization of the phenyl ring in methyl-substituted benzene
derivatives with F-TEDA-BF. J. Org. Chem. 2006, 71, 3880.
Nlate, S.; Nieto, Y.; Blais, J.-C.; Ruiz, J.; Astruc, D. {FeCp}+-
Induced hexafunctionalization of hexamethylbenzene with
dendrons for the direct synthesis of redox-active iron-centered
metallodendrimers. Chem. Eur. J. 2002, 8, 171.
Frost, C. G.; Hartley, J. P. New applications of indium catalysts in
organic synthesis. Mini-Rev. Org. Chem. 2004, 1, 1.
Kumar, S.; Kaur, P.; Kumar, V. Indium reagents in heterocyclic
chemistry. Curr. Org. Chem. 2005, 9, 1205.
Nakamura, M. Indium-catalyzed addition of carbon units to
acetylenes: development of a new C-C bond formation toward
exploitation of chemical resources. Pure Appl. Chem. 2006, 78,
425.
reaction temperature (80 vs 110 C) favors the formation of
polymers.
Although the exact mechanism of this new methylation
reaction is not yet clear, on the basis of our previous report
in which the formation of benzyl alcohol derivatives was the
key step for the formation of diarylated methanes [10, 11]
and the observation of trace amount of 2,3,4,5,6-
pentamethylbenzyl alcohol in the reaction mixture (vide
supra), we proposed that the formation of 2,3,4,5,6-
pentamethylbenzyl alcohol is the key step in the present
methylation reaction. Therefore, the reaction of 2,3,4,5,6-
pentamethylbenzyl alcohol with trioxane was also examined
as shown in Scheme 4. As expected, 2,3,4,5,6-
pentamethylbenzyl alcohol was completely converted into
HMB in DCE at 80 oC for 8h.
[5]
[6]
[7]
[8]
[9]
In summary, we have demonstrated that trioxane can be
used as a methylating agent for the methylation of tri-, tetra-
and pentamethylbenzene to hexamethylbenzene in fair to
high yield in the presence of a catalytic amount of
InCl3·4H2O [12]. Although the new methylation procedure
has its limitations, it is the first example on the use of
trioxane as methylating agent, which is more
environmentally-friendly compared to traditional ones.
Further investigations are underway in our laboratory to
develop the methylation procedure using trioxane as
methylating agent.
[10]
[11]
Sun, H.-B.; Hua, R.; Yin, Y. An efficient synthesis of
diarylmethanes via InCl3.4H2O-catalyzed dehydration of electron-
rich arenes with trioxane. Tetrahedron Lett. 2006, 47, 2291.
Sun, H.-B.; Li, B.; Chen, S.; Li, J.; Hua, R. An efficient synthesis
of unsymmetrical diarylmethanes from the dehydration of arenes
with benzyl alcohols using InCl3.4H2O/acetylacetone catalyst
system. Tetrahedron 2007, 63, 10185.
[12]
1H and 13C NMR spectra were recorded on JOEL JNM-ECA300
1
spectrometers at 300 MHz and 75 MHz, respectively. H chemical
shifts (ꢁ) were referenced to TMS, and 13C NMR chemical shifts
(ꢁ) were referenced to internal solvent resonance. GC analyses of
organic compounds were performed on an Agilent Technologies
1790 GC (with a SGE-OV1701 25m capillary column) instrument.
GC-MS was obtained on a Shimadzu GCMS-QP2010S.
ACKNOWLEDGEMENTS
A typical procedure for the methylation of PMB with trioxane
to afford HMB (Scheme 1, entry 8): A mixture of PMB (74.1mg,
0.5 mmol), trioxane (90.1, 1.0 mmol) and InCl3·4H2O (7.7 mg,
0.025 mmol) in ClCH2CH2Cl (0.5 mL) in a screw-capped thick-
walled Pyrex tube was heated at 110 oC (oil bath temperature) with
stirring for 8 h. After cooling, the reaction was diluted with toluene
to 2.0 mL and n-C18H38 (46.2 mg, as internal standard) was added.
The resulting mixture was then analyzed by GC and GC-MS.
Volatiles were removed in vacuum and the residue was purified by
column chromatography (silica gel, eluted with petroleum ether).
HMB (67.3 mg, 0.42 mmol, 83 %) was obtained as white solid. GC
analysis of the reaction mixture revealed that HMB was formed in
This project (20573061) was supported by the National
Natural Science Foundation of China and the Specialized
Research Fund for the Doctoral Program of Higher
Education (20060003079). The authors greatly thank Miss
Maria Victoria Abrenica, from Wellesley College, for her
kind English proofreading.
REFERENCES AND NOTES
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99% yield. HMB: 1H NMR (300 MHz, CDCl3) ꢁ 2.20 (s); 13C
NMR (75 MHz, CDCl3) ꢁ132.2, 16.9; GCMS m/z (% relative
intensity): 162 (M+, 47), 147 (100), 119 (9), 105 (9). 91 (13).
[2]
Shin, R. Y. C.; Goh, L. Y. Pentamethylcyclopentadienyl
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