Regioselective synthesis of 2,6-dimethyltetralin: Key precursor to 2,6-dimethylnaphthalene

Article abstract of DOI:10.1021/op050072g

A novel regioselective synthesis for 2,6-dimethyltetralin (2,6-DMT), a key precursor to 2,6-dimethylnaphthalene (2,6-DMN), is described. The synthesis comprises the following three steps; the Heck reaction between commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol, the catalytic reduction of the coupling products, and the acid-catalyzed cyclization of the alcohol intermediate. The process has an advantage over the established processes in that 2,6-DMT is obtained as the only isomer, and the isomerization and/or the complicated separation and purification steps are not required to produce pure 2,6-DMT. 2,6-DMN could be also obtained as a major product depending on the cyclization conditions.

Full text of DOI:10.1021/op050072g

Organic Process Research & Development 2005, 9, 814−817
Communications to the Editor
Regioselective Synthesis of 2,6-Dimethyltetralin:
2,6-Dimethylnaphthalene
Key Precursor to
Byung Hyun Kim, Jong Gil Lee, Woon Ki Kim, and Young Gyu Kim*
School of Chemical and Biological Engineering, Seoul National UniVersity, Seoul 151-744, Republic of Korea
Abstract:
addition of p-xylene to butene or butadiene to generate a
mixture of adducts and then cyclodehydrogenation to furnish
2,6-DMN.6 Kobe Steel and Mobil Technology Company
have investigated the process in which naphthalene or meth-
ylnaphthalene is used as a starting material to produce 2,6-
DMN.7,8 However, most of the above processes yield a mix-
ture of DMN isomers and have to go through an extra separa-
tion and/or purification step to produce pure 2,6-DMN. Some
of them are suffering from low yield of the desired product.
There are 10 possible isomers of DMN, and it is difficult
to obtain pure 2,6-DMN free from other DMN isomers using
conventional separation methods such as distillation or
solvent extraction. In particular, it is troublesome to cleanly
separate 2,6-DMN from 2,7-DMN because they are very
similar in some physical properties.9 Therefore, it is worth-
while to develop a synthetic method for 2,6-DMN free from
other isomers. We have recently developed a regioselective
synthetic process for 2,6-dimethyltetralin (2,6-DMT) whose
conversion to 2,6-DMN by catalytic oxidation is well
established10 and report the results as follows.11
A novel regioselective synthesis for 2,6-dimethyltetralin (2,6-
DMT), a key precursor to 2,6-dimethylnaphthalene (2,6-DMN),
is described. The synthesis comprises the following three steps;
the Heck reaction between commercially available 4-bromo-
toluene and 3-methyl-3-buten-1-ol, the catalytic reduction of
the coupling products, and the acid-catalyzed cyclization of the
alcohol intermediate. The process has an advantage over the
established processes in that 2,6-DMT is obtained as the only
isomer, and the isomerization and/or the complicated separation
and purification steps are not required to produce pure 2,6-
DMT. 2,6-DMN could be also obtained as a major product
depending on the cyclization conditions.
Introduction
2,6-Dimethylnaphthalene (2,6-DMN) is an important raw
material in industry for the synthesis of poly(ethylene
naphthalate) (PEN) and liquid crystalline polymers.1 PEN
is a high performance polyester superior to poly(ethylene
terephthalate) (PET) in many properties such as mechanical,
thermal, and electrical properties. Therefore, it has received
continual attention since the late 1950s because of its high
growth potential in a variety of applications including
packaging. However, PEN has been slow in expanding its
market share because of short monomer supply that is related
to the price and availability of 2,6-DMN.
The mass production of 2,6-DMN by separation from
naphtha oil did not look feasible,2 and various synthetic
methods aimed at its economical production have been
proposed.1,3 BP Amoco has commercialized a four-step
process for 2,6-DMN that involves the isomerization of 1,5-
DMN derived from 5-(o-tolyl)pent-2-ene into 2,6-DMN and
the separation between them.4 Mitsubishi Gas Chemical has
also explored several potential routes to 2,6-DMN.5 Optatech
has studied a well designed process using base-catalyzed
Results and Discussion
Our retrosynthetic analysis for the regioselective synthesis
of 2,6-DMT is shown in Scheme 1. The Heck reaction
between commercially available compounds, 4-halotoluene
(4) and 3-methyl-3-buten-1-ol (5), would provide the key
precursor 3 with an excellent regioselectivity after catalytic
reduction of the coupling product. The regioselectivity in
the Heck reaction of aryl halides with 1,1-disubstituted
alkenes is known to be nearly exclusive to yield the
substitution products at the terminal carbon of the alkenes
(4) (a) Lillwitz, L. D.; Karachewski, A. M. U.S. Patent 5,198,594, 1993. (b)
Sikkenga, D. L.; Zaenger, I. C.; Williams, G. S. U.S. Patent 5,030,781,
1991. (c) Choo, D. H.; Kim, H. J.; Kong, B. H.; Choi, I. S.; Ko, Y. C.; Lee,
H. C.; Kim, J. C.; Lee, J. S. J. Catal. 2002, 207, 183.
(5) (a) Abe, T.; Uchiyama, S.; Ojima, T.; Kida, K. U.S. Patent 5,008,479, 1991.
(b) Abe, T.; Ebata, S.; Machida, H.; Kida, K. U.S. Patent 5,023,390, 1991.
(6) Vahteristo, K.; Halme, E.; Koskimies, S.; Csicsery, S. M.; Laatikainen, M.;
Niemi, V. U.S. Patent 5,952,534, 1999.
(7) Sumitani, K.; Shimada, K. Japan Patent JP 4,013,637, 1992.
(8) Motoyuki, M.; Yamamoto, K.; McWilliams, J. P.; Bundens, R. G. U.S.
Patent 5,744,670, 1998.
(9) Kim, Y. D.; Lee, J. K.; Cho, Y. S. Korean J. Chem. Eng. 2001, 18, 971.
(10) Amelse, J. A. U.S. Patent 5,189,234, 1993.
* Corresponding author. Telephone: +82-2-880-8347. Fax: +82-2-885-6989.
E-mail: ygkim@snu.ac.kr.
(1) For a review, see: Lillwitz, L. D. Appl. Catal. A 2001, 221, 337.
(2) (a) Iwai, Y.; Higuchi, M.; Nishioka, H.; Takahashi, Y.; Arai, Y. Ind. Eng.
Chem. Res. 2003, 42, 5261 and references therein. (b) Kim, S. J.; Kim, S.
C.; Kawasaki, J. Sep. Sci. Technol. 2003, 38, 179.
(3) (a) Chen, T.; Kang, N. Y.; Lee, C. W.; Kim, H. Y.; Hong, S. B.; Roh, H.
D.; Park, Y.-K. Catal. Today 2004, 93, 371. (b) Millini, R.; Frigerio, F.;
Bellussi, G.; Pazzuconi, G.; Perego, C.; Pollesel, P.; Romano, U. J. Catal.
2003, 217, 298. (c) Pu, S.-B.; Inui, T. Appl. Catal. A 1996, 146, 305.
(11) (a) Presented at the 229th American Chemical Society National Meeting,
ORGN No. 881, San Diego, CA, March 13-17, 2005. (b) Kim, Y. G.;
Kim, W. K.; Kim, B. H.; Lee, J. G. International application No. PCT/
KR2005/000507, 2005.
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10.1021/op050072g CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/13/2005

Scheme 1. Retrosynthetic analysis for the regioselective
synthesis of 2,6-DMT and 2,6-DMN
Table 1. Intramolecular Friedel-Crafts alkylations of 3 with
acida
yieldb (%)
entry
acid (equiv)
2
1
1
2
3
4
5
6
7
SnCl4 (2)
BF3‚OEt2 (2)
FeCl3 (2)
22
6
70
76
60
40
34
8
10
TiCl4 (2)
H2SO4 (2)
H3PO4 (2)
CSAc (1.5)
1
a In a pressure tube, 200 °C, 2 h in chlorobenzene (PhCl). b Isolated as a
Scheme 2. Regioselective synthesis of 2,6-DMT
mixture and the ratio determined by GC. c 10-Camphorsulfonic acid.
Table 2. Intramolecular Friedel-Crafts alkylations of 3 with
solid acida
yieldb (%)
entry
solid acid
2
1
1
2
3
4
5
Amberlyst 15
Amberlite IR 120
Nafion NE 450
Nafion 1035
85
74
44
65
71
2
2
33
10
6
Zeolite H-Y
a In a pressure tube, 200 °C, 2 h in PhCl. b Isolated as a mixture and the ratio
determined by GC.
as the only isomeric products.12,13 Cyclization of para-aryl
substituted alcohol 3 under the conditions of a Friedel-Crafts
alkylation reaction should produce the desired isomer 2.
In reality, the Pd-catalyzed coupling reaction of 4-bro-
motoluene (4a) and 5 resulted in the expected para-sub-
stituted product as an isomeric mixture of alkenes 6 together
with aldehyde 7 in a combined yield of 90% (Scheme 2).
Formation of the olefinic mixture 6 can be explained by the
â-hydrogen elimination of the different hydrogens at C-2,
C-4, or C-5 with the initial Pd adduct at C-3. Aldehyde 7 is
most likely obtained from the corresponding enol isomer
derived from the in situ Pd-catalyzed isomerization of the
double bond at C-2 and C-3.13 The ratio of 6 to 7 was about
3:2. The same Heck reaction with 4-iodotoluene (4b) gave
a low yield (25%) of the desired coupling products, and the
major byproduct was a homocoupling product, 4,4′-dimeth-
ylbiphenyl. Although the olefinic mixture 6 and aldehyde 7
were separable by conventional methods, they were reduced
together to the desired key intermediate 3 under the Pt-
catalyzed hydrogenation conditions. The higher yield in the
hydrogenation was obtained at higher hydrogen gas pressure.
Separate reduction reactions of 6 and 7 with different
reducing agents were also possible to give 3. The Pd-
catalyzed hydrogenation of 6 under atmospheric pressure of
hydrogen gas at room temperature gave 3 in 90% yield and
the sodium borohydride (NaBH4) reduction of 7 in methanol
at 0 °C produced 3 in 75% yield.
(Table 1). We were concerned here about the stability and
reactivity of the primary alcohol in the presence of acid. If
the lifetime of the cationic primary carbon is long enough,
a rearrangement problem would complicate the reaction re-
sults.14 There also might be further difficulty by migration
of the methyl group on 2,6-DMT. We were pleased to find
that some of the acids were effective to provide 2,6-DMT
as the only isomeric product. No other isomers were notice-
able. With aluminum chloride (AlCl3) or p-toluenesulfonic
acid (p-TsOH), however, no product was detected (not
shown). Interestingly, a small amount of 2,6-DMN was pro-
duced with iron(III) chloride (FeCl3) and titanium(IV) chlor-
ide (TiCl4) (entries 3 and 4), probably because of the in situ
air oxidation of 2,6-DMT. Commonly used acids in the
Friedel-Crafts alkylation reaction of alcohols such as sulfuric
acid (H2SO4) and phosphoric acid (H3PO4) were not as effec-
tive as the Lewis acids, FeCl3 and TiCl4 (entries 5 and 6).15
We have also screened some solid acids because they can
be easily separated from the reaction mixture and reused to
make them be catalytic in amount (Table 2). The use of solid
acids also would minimize the tendency of the methyl group
migration.16 It is shown that Amberlyst 15, a sulfonic acid
resin, is the most effective in the cyclization reaction and
provides a good yield of 2,6-DMT with a minute amount of
2,6-DMN (entry 1). No rearranged or isomerized adduct was
observed. All of the solid acids used in Table 2 including
Nafion (perfluorinated sulfonic acid resin)17 and acid zeolite
(aluminosilicate)18 produce a mixture of 2,6-DMT and 2,6-
We then investigated the cyclization reaction of 3 under
the Friedel-Crafts alkylation conditions with various acids
(12) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: Chichester,
(14) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973; p 68.
(15) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973; p 47.
(16) (a) Olah, G. A.; Kaspi, J.; Bukala, J. J. Org. Chem. 1977, 42, 4187. (b)
Sohn, J. R. J. Ind. Eng. Chem. 2004, 10, 1.
2004; pp 105-176.
(13) Larock, R. C.; Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989, 30,
6629.
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Table 3. Effect of solvent on the intramolecular
Friedel-Crafts alkylations of 3a
tan-1-ol gave only the dehydrated products (not shown in
Table 4).
yieldb (%)
Finally, we attempted to change the heating method to a
microwave reactor. Automated and focused microwave flash
heating has been recently proven to enhance the preparative
efficiency and to dramatically reduce the reaction time for
various types of organic transformations.19 In the present
study, the microwave assisted alkylation was also successful
to give the expected cyclization product efficiently. Even at
a lower temperature of 150 °C, most of the starting material
was converted to 2,6-DMT in 85% yield only in 10 min and
only a trace of 2,6-DMN was observed.
entry
solvent
PhCl
PhBr
toluene
2
1
1
2
3
4
5
85
79
73
84
73
2
2
1
2
3
Cl2CHCH2Cl
1,4-dioxane
a In a pressure tube, 200 °C, 2 h, Amberlyst 15. b Isolated as a mixture and
the ratio determined by GC.
Table 4. Application of the intramolecular Friedel-Crafts
alkylations to alcoholsa
Conclusion
In summary, we have developed a novel and highly
regioselective synthetic route for 2,6-DMT starting from
commercially available 4a and 5. The Pd-catalyzed coupling
reaction of 4a and 5 produced a mixture of olefins 6 together
with aldehyde 7 that were both para-aryl and terminally
substituted products. The mixture of both 6 and 7 was then
catalytically reduced without separation to the key precursor
3. Finally, para-aryl substituted alcohol 3 was cyclized with
acid to give the desired product, 2,6-DMT, without any other
regioisomers. Some Lewis acids and solid acids were very
effective in the intramolecular Friedel-Crafts alkylation of
the primary alcohol substrate without rearrangement or
migration. At higher temperature, considerable amount of
2,6-DMN was obtained as a major product. Although the
yields in the present study were not optimized, the highly
regioselective method for 2,6-DMT shown here should be
useful for developing an economical and practical process
for 2,6-DMN.
a In a pressure tube, 200 °C, PhCl, Amberlyst 15.
DMN in reasonable yields. It is also worth noting that
production of 2,6-DMN is considerable with the Nafion
resins (entries 3 and 4).
With the results from the solid acids in hand, the effect
of the reaction solvent was examined with Amberlyst 15 as
acid and the results are described in Table 3. Although all
the solvents shown in Table 3 look quite effective to give
2,6-DMT, chlorobenzene (PhCl) and 1,1,2-trichloroethane
(Cl2CHCH2Cl) give better yields than the rest (entries 1 and
4). With every case in Table 3, a very small quantity of 2,6-
DMN is always present in the product.
Next, we tried to find milder reaction conditions with
Amberlyst 15 in PhCl. At a lower temperature of 150 °C,
however, the reaction rate became very slow and the reaction
was not complete in 2 h. Only 2,6-DMT was obtained in
33% yield, and no 2,6-DMN was noticed. At higher temper-
ature of 250 °C, on the other hand, the composition of the
products dramatically changed and 2,6-DMN became a major
product. The yield of 2 was 5%, and that of 1 was 78%.
This result indicates a possible pathway for direct conversion
of compound 3 to 2,6-DMN, but the solid acid was damaged
during the reaction because of high temperature.
Experimental Section
Materials were obtained from commercial suppliers and
used without further purification. Reactions were monitored
by TLC. Commercially available TLC plates (silica gel 60
F254) were visualized under UV light (254 or 365 nm) follow-
ed by molybdophosphoric acid staining. Column chromato-
graphy was performed on silica gel 60 (70-230 mesh,
Merck). The microwave-assisted reaction was performed with
1
a microwave reactor (Discover LabMate, CEM). H NMR
and 13C NMR spectra were measured in CDCl3 at 300 and
75 MHz (JEOL JNM-LA 300), respectively, unless stated
otherwise. High-resolution mass spectra were obtained with
a JEOL JMS-AX505WA gas chromatography-mass spec-
trometer.
The intramolecular Friedel-Crafts alkylation conditions
in the present study were applied to some compounds with
different functional groups (Table 4). The compounds with
an electron-donating group such as a methoxy group were
readily reacted to generate the expected cyclized products.
However, an electron-withdrawing group retarded the reac-
tion rate (entry 2), and the reaction with 4-(4-nitrophenyl)bu-
Olefinic Mixture 6 and 3-Methyl-4-(p-tolyl)butyralde-
hyde (7). To a solution of 4-bromotoluene (4a) (2.5 g, 14.6
mmol) in acetonitrile (100 mL) were added palladium(II)
acetate (164 mg, 0.73 mmol), tri(o-tolyl)phosphine (445 mg,
1.46 mmol), triethylamine (6.1 mL, 43.8 mmol), and 3-meth-
yl-3-buten-1-ol (5) (4.5 mL, 43.8 mmol). The mixture was
heated under reflux for 24 h. After the resulting mixture was
(17) Yamato, T.; Hideshima, C.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem.
1991, 56, 2089.
(18) Espeel, P. H.; Janssens, B.; Jacobs, P. A. J. Org. Chem. 1993, 58, 7688.
(19) For reviews: (a) Loupy, A., Ed. MicrowaVes in Organic Synthesis; Wiley-
VCH: Weinheim, 2002. (b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225.
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cooled to room temperature, the solvent was evaporated
under reduced pressure. Distilled water (100 mL) was added
to the residue, and the aqueous layer was extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were
dried over magnesium sulfate, filtered, and concentrated un-
der reduced pressure. The crude product was chromatograph-
ed on a silica gel column with hexane/ethyl acetate (from
16:1 to 4:1 v/v) to give the olefinic mixture 6 (1.42 g, 55%)
and aldehyde 7 (0.90 g, 35%). The major isomer of 6 was
(E)-3-methyl-4-(p-tolyl)-3-buten-1-ol ((E)-6a); 1H NMR (500
MHz) δ 1.89 (s, 3H), 2.34 (s, 3H), 2.43 (t, 2H, J ) 6.3 Hz),
3.79 (t, 2H, J ) 6.3 Hz), 6.33 (s, 1H), 7.05-7.16 (m, 4H);
13C NMR δ 17.6, 21.1, 43.7, 60.4, 127.6, 128.7, 128.8, 134.2,
134.9, 135.8; HRMS (EI) calcd for C12H16O 176.1201, found
129.0, 135.2, 137.9; HRMS (EI) calcd for C12H18O 178.1358,
found 178.1356.
2,6-Dimethyltetralin (2). To a solution of 3-methyl-4-
(p-tolyl)-1-butanol (3) (50 mg, 0.28 mmol) in chlorobenezene
(2.8 mL) in a pressure tube was added Amberlyst 15 (50mg,
100 wt %), and the reaction mixture was heated at 200 °C
for 2 h. The reaction mixture was then filtered and
concentrated, and the resulting residue was chromatographed
on a silica gel column with hexane as an eluent to afford 39
mg (87%) of mixture of 1 and 2 (1:2 ) 2:85). Data of 2:
1H NMR δ 1.05 (d, 3H, J ) 6.4 Hz), 1.30-1.43 (m, 1H),
1.76-1.92 (m, 2H), 2.21-2.40 (m, 1H), 2.28 (s, 3H), 2.72-
2.83 (m, 3H), 6.87-6.98 (m, 3H); 13C NMR δ 20.9, 22.0,
29.2, 29.4, 31.6, 37.7, 126.2, 128.9, 129.4, 133.8, 134.8,
136.4; HRMS (EI) calcd for C12H16 160.1252, found
160.1258.
Pretreatment of Amberlyst 15: Amberlyst 15 is an
acidic resin (4.7 meq of H+/g), and it was washed sequen-
tially with methanol, an aqueous solution of 2 N HCl, and
distilled water before use. Afterward, the resin was rinsed
using acetone and dried at room temperature to enhance the
catalyst activity.
1
176.1199. Data of 7: H NMR δ 0.98 (d, 3H, J ) 6.6 Hz),
2.32 (s, 3H), 2.18-2.47 (m, 3H), 2.54 (d, 2H, J ) 6.8 Hz),
7.01-7.13 (m, 4H), 9.68-9.71 (m, 1H); 13C NMR δ 19.8,
20.8, 30.1, 42.6, 50.0, 128.9, 128.9, 135.4, 136.7, 202.4;
HRMS (CI) calcd for C12H15O [M - H]+ 175.1123, found
175.1126.
3-Methyl-4-(p-tolyl)-1-butanol (3). To a solution of the
olefinic mixture 6 (1.42 g, 8.07 mmol) and aldehyde 7 (0.90
g, 5.11 mmol) in ethyl acetate (50 mL) in an autoclave was
added 5% Pt/C (5.14 g, 1.32 mmol) at room temperature.
The mixture was stirred under 10 atm of hydrogen gas for 24 h
at room temperature. The resulting mixture was filtered
through Celite. The clear solution was concentrated, and the
residue was chromatographed on a silica gel column with
4:1 hexane/ethyl acetate to give 3 (1.88 g, 80%) as a colorless
Acknowledgment
Authors gratefully acknowledge the financial support by
the Agency for Defence Development of Korea and by the
BK 21 Project funded by the Ministry of Education and
Human Resources Development of Korea. We also thank
Professor Young Keun Chung at the Department of Chem-
istry, Seoul National University for the microwave reactor.
1
oil. H NMR: δ 0.89 (d, 3H, J ) 6.8 Hz), 1.12 (br, 1H),
1.37-1.46 (m, 1H), 1.60-1.71 (m, 1H), 1.82-1.96 (m, 1H),
2.32 (s, 3H), 2.41 (dd, 1H, J ) 13.4 and 7.7 Hz), 2.59 (dd,
1H, J ) 13.4 and 6.4 Hz), 3.60-3.77 (m, 2H), 7.01-7.11
(m, 4H); 13C NMR δ 19.5, 21.0, 31.7, 39.4, 43.3, 61.1, 128.8,
Received for review Received for review May 12, 2005.
OP050072G
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