Selective synthesis of 1,4-dialkylbenzenes from terephthalic acid

Article abstract of DOI:10.1002/adsc.201000322

Terephthalic acid reacts with alkyl halides under Birch conditions to substituted 1,4-cyclohexadienes in high yields and good stereoselectivities. Electrophiles containing ester or nitrile groups undergo a surprising fragmentation under the reaction conditions. Subsequent treatment with chlorosulfonic acid proceeds by an interesting tandem decarbonylationldecarboxylation, affording 1,4-dialkylbenzenes in excellent regioselectivity. Thus our new method is superior to classical Friedel-Crafts alkylations.

Full text of DOI:10.1002/adsc.201000322

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DOI: 10.1002/adsc.201000322
Selective Synthesis of 1,4-Dialkylbenzenes from Terephthalic
Acid
Andrea Bramborga and Torsten Linkera,*
a
Department of Chemistry, University of Potsdam, Karl-Liebknecht Str. 24–25, 14476 Potsdam/Golm, Germany
Fax : (+49)-331-977-5056; phone: (+49)-331-977-5212; e-mail: linker@uni-potsdam.de
Received: April 26, 2010; Revised: August 11, 2010; Published online: September 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000322.
Abstract: Terephthalic acid reacts with alkyl halides
under Birch conditions to substituted 1,4-cyclohexa-
dienes in high yields and good stereoselectivities.
Electrophiles containing ester or nitrile groups un-
dergo a surprising fragmentation under the reaction
conditions. Subsequent treatment with chlorosulfon-
ic acid proceeds by an interesting tandem decarbon-
ylation/decarboxylation, affording 1,4-dialkylben-
zenes in excellent regioselectivity. Thus our new
method is superior to classical Friedel–Crafts alky-
lations.
thalenes and functionalized derivatives.[8] However,
the transformations required a proton para to the
newly introduced alkyl chain as leaving group. Herein
we describe a new approach for arene alkylations
starting from inexpensive terephthalic acid. The reac-
À
tions proceed under double C C bond cleavage by an
interesting tandem decarbonylation–decarboxylation,
and open a selective entry to 1,4-dialkylbenzenes
from easily available precursors.
The Birch reduction of arenes is a powerful method
for the synthesis of 1,4-cyclohexadienes on a large
scale.[9] Especially benzoic acids react with high regio-
selectivity and allow subsequent alkylations in a one-
pot procedure.[10] However, to the best of our knowl-
edge, this reductive alkylation was never applied to
terephthalic acid (1), although it is a very cheap start-
ing material. Therefore, we investigated the Birch re-
duction in the presence of various alkyl halides 3 and
Keywords: alkylations; arenes; Birch reductions; re-
action mechanisms; synthetic methods
Alkylarenes represent important industrial products optimized the conditions with bromoethane (3a) as
and are used as intermediates in organic synthesis.[1] model compound (Table 1).
However, the direct Friedel–Crafts bis-alkylation of
First experiments were conducted with lithium as
benzene is difficult to control and affords regioiso- metal and a 0.05M solution of terephthalic acid (1) in
meric mixtures.[2] The more selective Friedel–Crafts liquid ammonia (entry 1), suitable conditions in our
acylation with subsequent reduction of the ketone previous studies on toluic acids.[11] Indeed, the 1,4-di-
group requires many steps.[3] Modern methodologies ethyl-2,5-cyclohexadiene 4a was isolated in 73% yield,
start from aryl halides which are coupled with organo- due to a moderate conversion of only 80%. There-
boron, -magnesium, -zinc or -indium compounds in fore, we replaced lithium by sodium and potassium,
the presence of various catalysts.[4] However, the syn- metals as often applied in Birch reductions,[9] but the
thesis of the precursors is often tedious, and many re- conversions were even lower (entries 2 and 3). This
actions are limited to sp2 and sp centers due to com- can be rationalized by the bad solubility of the inter-
peting b-hydride eliminations.
mediately formed tetraanion 2 in liquid ammonia, re-
Aromatic carboxylic acids offer an interesting alter- sulting in its slow alkylation and reoxidation to ter-
native, since they are commercially available, inex- ephthalic acid during work-up. Co-solvents like etha-
pensive industrial raw materials.[5] Gooßen et al. de- nol or tetrahydrofuran did not increase the solubility,
scribed coupling reactions and proto-decarboxylations but simple dilution (0.01M) with more ammonia led
of such compounds in the presence of copper or silver to a homogenous solution, full conversion and afford-
catalysts.[6] Our group has developed a simple two- ed the 1,4-bis-ethyl-2,5-cyclohexadiene 4a in 93%
step ipso substitution of benzoic acids by alkyl halides yield (entry 4). We applied this optimized procedure
via Birch reduction and subsequent decarbonylation.[7] to various alkyl halides 3, and the products 4b–d were
Very recently, we applied this methodology to naph- isolated on a 10-mmol scale in high yields in analyti-
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2195

Andrea Bramborg and Torsten Linker
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Table 1. Birch reduction of terephthalic acid (1) to the substituted 2,5-cyclohexadienes 4.
Entry
M
Concentration [mM]
Conversion [%][a]
trans:cis Ratio[a]
4 (Yield [%])[b]
À
R X (3)
1
2
3
4
5
6
7
8
Li
Na
K
EtBr (3a)
EtBr (3a)
EtBr (3a)
EtBr (3a)
50
50
50
10
10
10
10
10
10
10
10
10
10
80
35
15
>97
>97
>97
>97
>97
80
60:40
25:75
20:80
80:20
40:60
>95:5
>95:5
90:10
>95:5
60:40
–
4a (73)
4a (29)
4a (12)
4a (93)
4b (83)
4c (89)
4d (84)
4e (85)
4f (73)
4g (74)
–
Li
Li
Li
Li
Li
Li
Li
Li
Li
Li
MeI (3b)
n-HexBr (3c)
n-OctBr (3d)
i-PrBr (3e)
BnBr (3f)
AllylBr (3g)
EtO2CCH2Br (3h)
CNCH2Br (3i)
9
10
11
12
13
85
<5
<5
>97
–
–
Cl
N
85:15
4j (96)
[a]
Determined by NMR spectra of the crude products.
Yield of analytically pure product, isolated by crystallization or column chromatography.
[b]
cally pure form (entries 5–8, Experimental Section,
Supporting Information).
The cis and trans isomers 4 showed different char-
acteristic NMR signals and could be directly used as
Interestingly, all reactions afforded exclusively the mixtures for the synthesis of 1,4-dialkylbenzenes (see
bis-alkylated products 4, mono-alkylation was not ob- below). On the other hand, their separation was possi-
served. Furthermore, trans isomers were formed with ble by crystallization, and the configuration was un-
high selectivity with sterically demanding electro- equivocally proven by an X-ray structure of the trans-
philes 3c–f (entries 6–9). This can be explained by the 1,4-diethyl-2,5-cyclohexadiene 4a (Supporting Infor-
mono-alkylated intermediate 5, which is attacked mation).
preferentially anti to the substituent R (pathway A,
Subsequently, we investigated other functionalized
Figure 1). On the other hand, for smaller electrophiles alkyl halides under Birch conditions (Table 1). Benzyl
3a and 3b these interactions are less distinctive and (3f) and allyl bromides (3g) afforded somewhat lower
the cis isomers are formed as well (pathway B). Fur- conversions and yields (entries 9 and 10), which can
ther mechanistic evidence was found with sodium and be rationalized by the oxidation of the tetraanion 2
potassium as counterions. Now the carboxylate group by electron transfer to the reactive halide. Surprising-
becomes sterically more demanding and the cis-selec- ly, only terephthalic acid (1) was isolated after the re-
tivity increases (entries 2 and 3). For the same reason, action with bromoethyl acetate (3h) and bromoaceto-
more of cis-4a was formed in our first experiment nitrile (3i) (entries 11 and 12), although such electro-
(entry 1), since the higher concentration leads to philes gave good yields with toluic and naphthoic
more counterions at the carboxylate group. Although acids.[8] Our mechanistic explanation is based on the
we describe herein the first reductive alkylation of mono-alkylated intermediate 5h (or 5i, respectively),
terephthalic acid (1), the stereoselectivities are com- which can undergo a fragmentation, due to the forma-
parable to those of Birch reductions of anthracenes.[12] tion of a stabilized ester enolate 6 (Scheme 1).
Finally, we succeeded in the synthesis of cyclohexa-
diene 4j with a halogen atom in the side chain in ex-
cellent yield (Table 1, entry 13), which is an interest-
ing substrate for further transformations. Nucleophilic
substitutions or radical reactions should allow the in-
troduction of other functional groups. Overall, we
have demonstrated the reductive alkylation of tereph-
Figure 1. Preferred reactions of carboxylate 5.
thalic acid (1) with various electrophiles 3 for the first
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Adv. Synth. Catal. 2010, 352, 2195 – 2199

Selective Synthesis of 1,4-Dialkylbenzenes from Terephthalic Acid
ides are tolerated under the reaction conditions
(entry 8), which afforded arene 7j in high yield and
should allow further transformations. Thus, we have
realized the regioselective synthesis of various 1,4-dia-
lkylbenzenes from easily available terephthalic acid
(1) in only two steps.
Scheme 1. Fragmentation of mono-alkylated intermediate
5h.
The formation of the arenes 7 is interesting from
À
the mechanistic point of view, since two C C bonds
have to be cleaved during the aromatization. In the
time, which offered easy access to the hitherto un- first step, protonation of the carboxylic acid with the
known 1,4-bis-alkylated 2,5-cyclohexadienes 4 in high stronger Brønsted acid affords intermediate 8, which
yields and stereoselectivities.
undergoes dehydration and decarbonylation to the
To obtain the desired 1,4-dialkylbenzenes, two acid stabilized carbenium ion 9 (Scheme 2). Thus, chloro-
groups had to be cleaved in the next step. Free radical sulfonic acid has two advantages, the strong acidity
or oxidative decarboxylations have been applied for and hygroscopicity, making it a superior reagent for
simple cyclohexadiene-monocarboxylic acids.[13] How- the transformation of cyclohexadienes 4, in accord-
ever, a proton is required in the 4-position, and lead ance to our previous studies.[7,8]
tetraacetate is problematic due to its high toxicity.
Thus, we investigated the reactions of 2,5-cyclohexa-
dienes 4 in the presence of chlorosulfonic acid
(Table 2), a reagent that we developed for the aroma-
tization of monocarboxylic acids.[7,8]
Indeed, full conversion was observed even at 08C,
and we isolated the 1,4-dialkylbenzenes 7 in moderate
to high yields in analytically pure form (Table 2, Sup-
porting Information). Only the bisallyl derivative 4g
polymerized under the acidic reaction conditions
(entry 7) and some amount of p-xylene (7b) was lost
during work-up, due to its volatility (entry 2). Best re-
sults were obtained for arenes 7c and 7d with long
alkyl chains (entries 3 and 4), which are attractive
precursors for the synthesis of organic materials with
interesting properties.[14] Furthermore, even halogen-
Scheme 2. Proposed mechanism for the formation of arenes
7.
Table 2. Synthesis of 1,4-dialkylbenzenes 7.
Since direct deprotonation of carbenium ion 9 is
not possible due to the quaternary carbon atom, the
À
only pathway to arenes 7 is an additional C C bond
cleavage under decarboxylation (Scheme 2). The for-
mation of CO and CO2 was unequivocally proven by
chemical trapping and IR spectroscopy (Supporting
Information).
Further evidence for such a mechanism was found
with cyclohexadiene 4e (R=i-Pr). Now the fragmen-
tation of the alkyl group is faster, since a stabilized
secondary isopropyl cation is formed, which affords 2-
chloropropane as side-product under the reaction
conditions (Supporting Information). Thus, 4-isopro-
pylbenzoic acid (10) was isolated in 84% yield
(Table 2, entry 5). Overall, the reaction proceeds by
an interesting tandem decarbonylation–decarboxyla-
tion, which was hitherto unknown and offers easy
Entry Cyclohexadiene
R
Conv.
[%][a]
Arene 7
4
[%][b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4j
Et
Me
n-Hex
n-Oct
i-Pr
Bn
Allyl
Cl
>97
>97
>97
>97
>97
>97
>97
7a (85)
7b (64)
7c (91)
7d (95)
10 (84)[c]
7f (78)
–
(CH2)4 >97
7j (92)
À
[a]
[b]
access to arenes 7 by a double C C bond cleavage.
Determined by TLC.
Yield of analytically pure product, isolated by column
chromatography.
In conclusion, we have developed a convenient and
selective synthesis of 1,4-dialkylbenzenes. The hither-
to unknown Birch reduction of terephthalic acid af-
[c]
Formation of 4-isopropylbenzoic acid (10).
Adv. Synth. Catal. 2010, 352, 2195 – 2199
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2197

Andrea Bramborg and Torsten Linker
COMMUNICATIONS
Arene Chemistry, (Ed.: D. Astruc), Wiley-VCH, Wein-
heim, 2002.
forded bisalkylated products in high yields and stereo-
selectivities. A surprising fragmentation was observed
with electrophiles containing ester or nitrile groups.
The rearomatization proceeded smoothly with chloro-
sulfonic acid by an interesting tandem dehydration–
decarbonylation–decarboxylation. Finally, 1,4-dialkyl-
benzenes were isolated in high yields and exclusive
regioselectivity, which is superior to classical Friedel–
Crafts alkylations. Future studies will focus on the
synthesis of functionalized arenes and applications in
natural product chemistry.
[2] Books: a) Friedel–Crafts and Related Reactions, Vol. II,
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del–Crafts Alkylations, (Eds.: M. Bandini, A. Umani-
Ronchi), Wiley-VCH, Weinheim, 2009.
[3] J. Jovanovic, F. Boberg, G. R. Schultze, Justus Liebigs
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[4] Books: a) Metal-Catalyzed Cross-Coupling Reactions,
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kermann), Wiley-VCH, Weinheim, 2009; c) boron: N.
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Experimental Section
General Procedure for the Birch Reductions
Lithium (0.555 g, 80 mmol) was added in small portions at
À788C to a suspension of terephthalic acid (1) (1.66 g,
10.0 mmol) in liquid ammonia (500 mL) until the blue color
persisted. After five hours at this temperature, the alkyl
halide 3 (100 mmol) was added slowly. The reaction mixture
À
was allowed to warm up to 358C before adding 1-bromooc-
[5] Industrial Organic Chemistry, (Eds.: K. Weissermel, H.-
tane (3d) and benzyl bromide (3f). Ammonia was evaporat-
ed over night, and the solid residue was dissolved in water
(100 mL). After cooling to 08C, concentrated HCl was
added to reach pH 1, and the resulting precipitate was fil-
tered off and dried in a desiccator. The products were puri-
fied by recrystallization (4a, 4b, 4e, 4g from water; 4c, 4d,
4f, 4j from water/ethanol 1/1) and gave correct analytical
data, including elemental analysis (Supporting Information).
J. Arpe), Wiley-VCH, Weinheim, 2003.
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General Procedure for the Synthesis of 1,4-
Dialkylbenzenes 7
The cyclohexadienes 4 (2.0 mmol) were suspended in dry di-
chloromethane (10 mL) and cooled to 08C. A solution of
chlorosulfonic acid (2.0 to 4.0 mmol, 1M in dichlorome-
thane) was added dropwise under evolution of CO and CO2
until TLC showed full conversion. The solution was neutral-
ized with saturated sodium carbonate (20 mL) and the aque-
ous phase was extracted with dichloromethane (4ꢁ10 mL).
The combined organic phases were dried over magnesium
sulfate. After removal of the solvent, the arenes 7 were puri-
fied by column chromatography on silica gel (dichlorome-
thane) and gave correct analytical data, including elemental
analysis (Supporting Information).
[10] a) H. van Bekkum, C. B. van den Bosch, G. van Min-
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Acknowledgements
This work was generously supported by the University of
Potsdam.
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