Highly efficient two-step selective synthesis of 2,6-dimethylnaphthalene

Article abstract of DOI:10.1016/j.tetlet.2006.08.102

2,6-Dimethylnaphthalene (2,6-DMN), a key raw material for poly(ethylene naphthalate) (PEN), was selectively synthesized via a two-step process in an overall 66% yield from commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol. The ligand-free Heck reaction of the starting materials produced γ-(p-tolyl)-substituted aldehyde that was cyclized with an acid to give 2,6-DMN after in situ oxidation. No other isomers of 2,6-DMN were found.

Full text of DOI:10.1016/j.tetlet.2006.08.102

Tetrahedron Letters 47 (2006) 7727–7730
Highly efficient two-step selective synthesis of
2,6-dimethylnaphthalene
Byung Hyun Kim, Jong Gil Lee, Taeeun Yim, Hyo-Jin Kim, Hyun Yeong Lee and
Young Gyu Kim*
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Received 21 July 2006; accepted 25 August 2006
Available online 15 September 2006
Abstract—2,6-Dimethylnaphthalene (2,6-DMN), a key raw material for poly(ethylene naphthalate) (PEN), was selectively synthe-
sized via a two-step process in an overall 66% yield from commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol. The
ligand-free Heck reaction of the starting materials produced c-(p-tolyl)-substituted aldehyde that was cyclized with an acid to give
2,6-DMN after in situ oxidation. No other isomers of 2,6-DMN were found.
ꢀ 2006 Elsevier Ltd. All rights reserved.
2,6-Dimethylnaphthalene (2,6-DMN) is an important
raw material for the synthesis of a high performance
polyester, poly(ethylene naphthalate) (PEN).1 PEN has
many superior properties such as gas barrier, mechani-
cal, thermal, and electrical properties compared with
those of poly(ethylene terephthalate) (PET). Thus, it
has a high market potential in a variety of applications
including films, fibers, and packaging. However, PEN
has been slow in expanding its market share because
of a short supply of the monomer, 2,6-naphthalene-
dicarboxylic acid (2,6-NDA), which is closely related
to the price and availability of 2,6-DMN. 2,6-NDA is
prepared from the catalytic oxidation of 2,6-DMN.
product. Thus, it is worthwhile to develop an efficient
synthetic method for 2,6-DMN without any other
isomers.6
We have recently reported the three-step selective syn-
thesis of 2,6-dimethyltetralin (2,6-DMT, 2) that is a pre-
cursor to 2,6-DMN (1) (Scheme 1).7 The process has an
advantage over the established processes in that 2,6-
DMT is obtained as the only isomer but it requires an
extra oxidation step8 to give 2,6-DMN. In continuation
of our investigation on 2,6-DMN, we have developed a
highly efficient two-step and selective process for 2,6-
DMN, where 2,6-DMN is obtained as the only isomer
There have been several synthetic processes designed for
the mass production of 2,6-DMN. BP Amoco has
already commercialized the 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.1,2 Mitsubishi Gas Chemi-
cal,3 Optatech,4 Kobe Steel, and Mobil Technology
Company5 have also reported some useful routes to
2,6-DMN. However, many of them yield a mixture 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 suffer from the low yields of the desired
OH
Pd(OAc)2
P(o-tol)3
OH
O
+
Br
TEA, CH3CN
90%
6a and isomers
+
4
5
H
7
Pt/C, H2 (10 atm)
EtOAc, 80%
OH
H+
Keywords: 2,6-Dimethylnaphthalene; Heck reaction; Aromatic elec-
trophilic cyclodehydration; In situ oxidation.
85%
1, 2,6-DMN
2, 2,6-DMT
3
*
Corresponding author. Tel.: +82 2 880 8347; fax: +82 2 885 6989;
e-mail: ygkim@snu.ac.kr
Scheme 1. The three-step selective synthesis of 2,6-DMT (2).7
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.102

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B. H. Kim et al. / Tetrahedron Letters 47 (2006) 7727–7730
Table 1. Effect of the base on the Heck reaction
and the isomerization and/or the separation steps are
not required. We wish to report the results as follows.9
Entry
Base
Yield (%)
7
6
In Scheme 1, the Heck reaction of 4 and 5 produced
aldehyde 7 as a minor product together with a mixture
of olefinic isomers 6. Both 6 and 7 were reduced without
separation to give alcohol 3.7 We have envisioned here
that an aromatic electrophilic cyclodehydration reac-
tion10 of 7 followed by oxidation8 would produce 2,6-
DMN more efficiently without the reduction step. An
additional advantage of the formation of dihydronaph-
thalene 8 would be a more facile oxidation of 8 into 1
(Scheme 2) because of its more oxidized structure com-
pared to that of tetralin 2. The aldehyde product 7 could
be formed as a major or the only product by the known
in situ isomerization of olefinic alcohols into alde-
hydes.11 Our retrosynthetic scheme for the more efficient
process of 1 via the aldehyde intermediate 7 is shown in
Scheme 2.
1
2
3
4
5
NaHCO3
K3PO4
NaOAc
K2CO3
67
—
60
9
5
10
10
5
Na2CO3
80
Trace
change from NMP to N,N-dimethylacetamide (DMA)
resulted in a large increase in the yield of both products
(45% of 7 and 32% of 6, not shown). Aldehyde 7 is most
likely obtained from the corresponding enol tautomer
derived from the Pd-catalyzed isomerization of the dou-
ble bond that is facilitated by the heterogeneous inor-
ganic base.11b Formation of the olefinic mixture 6 can
also be explained by the b-hydrogen elimination of the
different hydrogens at C-2, C-4 or C-5 with the initial
Pd adduct at C-3.
In the present study, a ligand-free Heck reaction was
carried out for both operational and economical advan-
tage, which would reduce both the separation process of
the phosphorus ligand and the amount of the palladium
catalyst (Scheme 3).12 It has been shown that nature of
the base is often an important factor to determine the
fate of the ligand-free Heck coupling reactions. The
screening results of some bases are shown in Table 1.
The use of bromide 4 required a higher reaction temper-
ature of 130–140 ꢁC.
We then tried to cyclize aldehyde 7 to yield 2,6-dimethyl-
1,2-dihydronaphthalene (8) under the cyclodehydration
conditions with an acid (Scheme 4). We were concerned
here about the stability of 8. It has been reported
that 1,2-dihydronaphthalene is thermolyzed to produce
tetralin (15%), naphthalene (19%), and some C20
compounds (19%) with the starting material, 1,2-dihy-
dronaphthalene (45%), recovered.13
Several Lewis and Brønsted acids were examined for the
electrophilic cyclodehydration reactions (Table 2). We
were pleased to find that the target product 1 was
obtained directly together with some 2,6-DMT (2).
The expected dihydronaphthalene intermediate product
8 was not detected with most of the acids used at 200 ꢁC,
while the use of 10-camphorsulfonic acid (CSA) resulted
in 8 as a major product (entry 8). It is to be noted that
the in situ aromatization of 8 is facile in the present
study because the aromatic cyclodehydration reactions
generally need a hydroxyl group or a double bond at
the a- or b-position to the carbonyl group in the starting
material to generate a fully aromatic ring.10 It is pre-
sumed that the disproportionation reaction of dihydro-
naphthalene 8 facilitated the in situ oxidation reaction
of 8 to give the fully aromatic product 1, while its re-
duced product, tetralin 2, is obtained as a byproduct
(entries 1–3). FeCl3 and TiCl4 were most effective to give
the fully aromatized product 1 predominantly with a
The combination of Pd(OAc)2 and Na2CO3 in N-
methyl-2-pyrrolidinone (NMP) as solvent constituted a
highly active catalyst system for the present ligand-free
Heck reaction and gave almost exclusively aldehyde 7
in good yield (Table 1, entry 5). Interestingly enough,
only alcohols 6 were obtained in low yield with K3PO4
as a base and NMP as a solvent here (entry 2) in con-
trast to the high yield of the ligand-free Heck reactions
as reported in the literature.12c However, the solvent
'oxidation'
8
7
1, 2,6-DMN
'aromatic electrophilic
cyclodehydration'
OH
O
'Heck reaction'
'isomerization'
+
Br
O
4
5
acid
Scheme 2. Retrosynthetic analysis for 2,6-DMN via aldehyde 7.
solvent
200 oC
8
7
in situ
reaction
OH
O
OH
Pd(OAc)2, base
NMP, heat
+
Br
+
2
+
3
4
1
2
4
5
5
7
6c + isomers
Scheme 4. Synthesis of 2,6-DMN by electrophilic cyclodehydration of
7.
Scheme 3. The ligand-free Heck reactions of alcohol 5 for aldehyde 7.

B. H. Kim et al. / Tetrahedron Letters 47 (2006) 7727–7730
7729
Table 2. Electrophilic cyclodehydration reactions with Lewis and
Table 4. Effect of the solvent on the electrophilic cyclodehydrationa
Brønsted acidsa
Entry
Solvent
Yield (%)b
Entry
Acid/equiv
Yield (%)b
2
1
8
2
1
1
2
3
4c
5
1,4-Dioxane
Toluene
Cl2CHCH2Cl
Cl2CHCH2Cl
PhBr
2
4
3
46
4
70
66
80
34
81
80
1
2
3
4
5
6
7c
8
AlCl3/2
—
4
12
8
17
Trace
2
1
—
—
23
59
16
79
75
61
38
26
SnCl4/2
BF3ÆOEt2/2
FeCl3/2
TiCl4/2
H2SO4/2
H3PO4/2
CSA/1.5
—
—
—
—
—
50
6
PhCl
Trace
a In a pressure tube at 200 ꢁC for 2 h.
b Isolated as a mixture and the ratio was determined by GC/MSD.
c Microwave flash heating (120–140 ꢁC, 20 min). 8 (4%) was also
obtained.
a In a pressure tube, 200 ꢁC, 2 h with 1,1,2-trichloroethane.
b Isolated as a mixture and the ratio was determined by GC/MSD.
c 40% of the starting material was recovered.
ough to be removed easily under low vacuum and thus
could be recycled. When the heating method was chan-
ged from conventional heating to microwave flash heat-
ing14 (120–140 ꢁC, 20 min) under the similar conditions
to those of entry 3 in Table 4, the reaction also gave 2
as a major product together with a small amount of 8
(entry 4).
minute amount of 2 (entries 4 and 5). In all cases, any
rearranged or isomerized products such as 2,7-DMN
were not observed.
We have also screened several solid acids because they
can be easily separated from the reaction mixture and
reused to make the process economically favorable (Ta-
ble 3). It is apparent that Amberlystꢂ 15 and Amberliteꢂ
IR 120 that are sulfonic acid resins were very effective in
the cyclodehydration reactions and provided a good
yield of 1 with a tiny amount of 2 at a higher reaction
temperature (entries 1 and 3). At a lower temperature
of 100 ꢁC with Amberlystꢂ 15, 8 was obtained as a
major product in 42% yield, whereas 1 was produced
in only 5% with 50% of the starting material recovered
(not shown). Here, 2 was not detected at all. Production
of 8 at a lower reaction temperature is also significant in
entry 2. All of the solid acids used in Table 3 including
the Nafionꢂ resins and zeolite H-Y produced a mixture
of 1 and 2 or/and 8 in reasonable yields. In the case of
zeolite H-Y, however, a large amount of the expected
dihydronaphthalene product 8 was obtained (entry 6).
In summary, we have developed an efficient and selective
two-step process for 2,6-DMN starting from commer-
cially available 4-bromotoluene (4) and 3-methyl-3-
buten-1-ol (5). The two-step process comprises the li-
gand-free Heck coupling reaction of the starting materi-
als to give aryl substituted aldehyde 7 that underwent
the acid-catalyzed cyclodehydration reaction to give di-
rectly the target compound 1 after in situ oxidation of
the initially expected intermediate 8. Because no other
isomers of 2,6-DMN were produced during the process,
neither the isomerization step nor the separation step
was necessary. The active catalytic system of Pd(OAc)2
developed here without using a phosphine ligand should
enhance the economy of the present process as well. The
overall yield was 66% based on the starting material, 4-
bromotoluene. Although the yield was not optimized in
the present study, the high efficiency and selectivity of
this process should be valuable for developing a novel
and competitive industrial process for 2,6-DMN. In
addition, the synthetic pathway developed for 2,6-
DMN could be easily extended to an efficient and selec-
tive synthesis of other isomers of DMN and other
substituted polyaromatic compounds, which are now
underway in our laboratory.
Next, we have examined the effect of various solvents
with Amberlystꢂ 15 and the results are shown in
Table 4. Among the solvents, chlorobenzene, bromo-
benzene and 1,1,2-trichloroethane were quite effective
to give the target compound 1 in high yield. 1,1,2-Tri-
chloroethane appeared the best choice as the reaction
solvent because its boiling point (110–115 ꢁC) is low en-
Representative procedure. 3-Methyl-4-(p-tolyl)butanal
(7): To a solution of 4-bromotoluene (4, 3.42 g,
20.0 mmol) in NMP (5 mL) in a pressure tube was added
Pd(OAc)2 (4.49 mg, 0.02 mmol), Na2CO3 (4.24 g,
40.0 mmol) and 3-methyl-3-buten-1-ol (5, 3.44 g,
40.0 mmol). The resulting mixture was heated at 130–
140 ꢁC for 24 h. After the reaction mixture was cooled
to room temperature, water (100 mL) was added to the
residue and then the aqueous layer was extracted with
diethyl ether (2 · 100 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude residue was chromato-
graphed on a silica gel column using a mixture of hexane
and EtOAc (from 16:1 to 4:1) to give 2.83 g of 7 (80%) as
Table 3. Aromatic electrophilic cyclodehydration with solid acidsa
Entry
Solid acid
Yield (%)b
8
2
1
1
Amberlystꢂ 15
Amberlystꢂ 15
Amberliteꢂ IR 120
Nafionꢂ NE 450
Nafionꢂ 1035
—
27
—
—
6
3
—
Trace
6
4
4
80
50
83
69
53
18
2c
3
4
5
6
Zeolite H-Y
56
a In a pressure tube at 200 ꢁC for 2 h.
b Isolated as a mixture and the ratio was determined by GC/MSD.
c The reaction was conducted under the reflux conditions.

7730
B. H. Kim et al. / Tetrahedron Letters 47 (2006) 7727–7730
a pale yellow oil. Rf = 0.4 (hexane:EtOAc = 4:1); 1H
NMR: d 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), 7.04 (d, 2H,
J = 7.8 Hz), 7.10 (d, 2H, J = 7.8 Hz), 9.70 (t, 1H,
J = 2.3 Hz); 13C NMR: d 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 [MÀH]+ 175.1123, found 175.1126; Anal.
Calcd for C12H16O: C, 81.77; H, 9.15; O, 9.08. Found:
C, 81.70; H, 9.01; O, 9.29.
4. Vahteristo, K.; Halme, E.; Koskimies, S.; Csicsery, S. M.;
Laatikainen, M.; Niemi, V. U.S. Patent 5,952,534, 1999.
5. (a) Sumitani, K.; Shimada, K. Japan Patent JP 4,013,637,
1992; (b) Motoyuki, M.; Yamamoto, K.; McWilliams,
J. P.; Bundens, R. G. U.S. Patent 5,744,670, 1998.
6. For recent efforts for the production of 2,6-DMN, see: (a)
Millini, R.; Frigerio, F.; Bellussi, G.; Pazzuconi, G.;
Perego, C.; Pollesel, P.; Romano, U. J. Catal. 2003, 217,
298; (b) Iwai, Y.; Higuchi, M.; Nishioka, H.; Takahashi,
Y.; Arai, Y. Ind. Eng. Chem. Res. 2003, 42, 5261; (c) Chen,
T.; Kang, N. Y.; Lee, C. W.; Kim, H. Y.; Hong, S. B.;
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Tsutsui, T.; Ijichi, K.; Inomata, T.; Setiadi; Kojima, T.;
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Korean Application No. 10-2005-0115139, 2005.
2,6-Dimethylnaphthalene (1): To a solution of 3-methyl-
4-(p-tolyl)butanal (7) (2.83 g, 16.1 mmol) in 1,1,2-tri-
chloroethane (5 mL) in a pressure tube was added
Amberliteꢂ IR 120 (2,83 g, 100 wt %). The reaction mix-
ture was heated at 200 ꢁC for 2 h. The resulting mixture
was then filtered and the filtrate was concentrated. The
crude residue was chromatographed on a silica gel col-
umn with hexane to give 2.10 g of 1 (83%) as a white
solid. All the analytical and the spectroscopic data of
1 were identical with those of commercially available
2,6-DMN.
10. Bradsher, C. K. Chem. Rev. 1987, 87, 1277.
Acknowledgements
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R.C.; Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett.
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This work was financially supported by KOSEF
through the Research Center for Energy Conversion
and Storage and by the Division of Advanced Batteries
in NGE Program (Project No. 10016439) and by the
Agency for Defense Development of Korea. We also
thank Professor Young Keun Chung at the Department
of Chemistry, Seoul National University for the micro-
wave reactor.
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