Regioselective synthesis of alkylarenes by two-step ipso-substitution of aromatic dicarboxylic acids

Article abstract of DOI:10.1002/ejoc.201200823

A strategy for the regioselective alkylation of arenes was developed, starting from commercially available and inexpensive terephthalic acid or naphthalene-1,4-dicarboxylic acid. The method entails a formal ipso-substitution of the carboxylate groups by a sequence of reductive alkylation under Birch conditions and subsequent acid-mediated rearomatization with loss of carbon monoxide and carbon dioxide. More than 20 different arenes with various side-chains were synthesized. With naphthalene-1,4-dicarboxylic acid as starting material, we were able to control the degree of alkylation by choosing the appropriate electrophile in the Birch reduction. Thus, bisalkylated naphthalenes and naphthoic acids became available chemoselectively. All reactions afforded a single regioisomer exclusively in high yields. Overall, aromatic dicarboxylic acids are suitable substrates for a two-step ipso-substitution that allows the selective synthesis of alkylated benzenes and naphthalenes.

Full text of DOI:10.1002/ejoc.201200823

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FULL PAPER
DOI: 10.1002/ejoc.201200823
Regioselective Synthesis of Alkylarenes by Two-Step ipso-Substitution of
Aromatic Dicarboxylic Acids
Andrea Bramborg[a] and Torsten Linker*[a]
Keywords: Synthetic methods / Alkylation / Birch reduction / Arenes / Regioselectivity
A strategy for the regioselective alkylation of arenes was de-
material, we were able to control the degree of alkylation by
veloped, starting from commercially available and inexpen- choosing the appropriate electrophile in the Birch reduction.
sive terephthalic acid or naphthalene-1,4-dicarboxylic acid.
The method entails a formal ipso-substitution of the carb-
oxylate groups by a sequence of reductive alkylation under
Birch conditions and subsequent acid-mediated rearomatiza-
tion with loss of carbon monoxide and carbon dioxide. More
than 20 different arenes with various side-chains were syn-
thesized. With naphthalene-1,4-dicarboxylic acid as starting
Thus, bisalkylated naphthalenes and naphthoic acids be-
came available chemoselectively. All reactions afforded a
single regioisomer exclusively in high yields. Overall, aro-
matic dicarboxylic acids are suitable substrates for a two-step
ipso-substitution that allows the selective synthesis of alkyl-
ated benzenes and naphthalenes.
oped, respectively, copper- and palladium-catalyzed C–C
coupling protocols proceeding with the evolution of carbon
dioxide.[11] However, in these cases, only arylations and vin-
ylations were possible, and no alkylations were described.
During the course of our investigations on singlet-oxygen
chemistry, we discovered an unexpected aromatization of
1,4-cyclohexadienes 2 derived from o-toluic acid (1) by re-
ductive alkylation under Birch conditions (Scheme 1).[12]
The reaction proceeded under acidic conditions, and was
accompanied by the formation of carbon monoxide. Based
on these results, we developed an efficient two-step ipso-
substitution of different aromatic monocarboxylic acids by
alkyl groups, applying a sequence of alkylative Birch re-
duction and subsequent treatment with the strongly acidic
and hygroscopic chlorosulfonic acid.[13]
Introduction
The efficient functionalization of arenes has always been
an important target in organic chemistry and industrial
processes.[1] In this context, the formation of C–C bonds is
of special interest, and it has given rise to many publica-
tions concerning different synthetic routes. Classical meth-
ods such as Friedel–Crafts alkylation often give insufficient
regioselectivities, and bisalkylations are especially difficult
to realize using such methods.[2] The more selective Friedel–
Crafts acylation[3] requires subsequent reduction of the
carbonyl group.[4] Modern strategies[5] such as Stille,[6]
Heck,[7] Sonogashira,[8] or Suzuki couplings,[9] often start-
ing from aryl halides, proceed under mild conditions and
result in the fomation of a single regioisomer. Yet many
methods require laborious syntheses of starting materials,
or expensive Pd catalysts, or involve the use of toxic metal
organyls. In addition, many procedures are limited to the
formation of C–C bonds to sp2- or sp-centers due to com-
peting β-hydride elimination. One exception is the iron(III)-
catalyzed alkylation of chloroarenes with Grignard rea-
gents, which leads to alkyl-substituted arenes in high
yields.[10] The substitution of the carboxylate group of aro-
matic carboxylic acids offers an interesting alternative to
the already mentioned methodologies, since these acids are
commercially available and often inexpensive industrial
bulk products. Gooßen et al. and Myers et al. have devel-
Scheme 1. Unexpected formation of arenes 4 during the photooxy-
genation of 1,4-cyclohexadienes 2.
[a] Department of Chemistry, University of Potsdam,
Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
Fax: +49-331-977-5056
E-mail: linker@uni-potsdam.de
However, in our initial studies, we only investigated mo-
nocarboxylic acids. Very recently, we became interested in
the ipso-substitution of terephthalic acid (5), and described
Homepage: www.chem.uni-potsdam.de/ochome
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200823.
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A. Bramborg, T. Linker
FULL PAPER
our results in a communication.[14] Birch reduction and sub-
sequent alkylation was realized with this arene for the first
time, with cyclohexadienes 6 being formed in good yields
(Scheme 2). Reaction with chlorosulfonic acid resulted in
rearomatization, and gave easy access to 1,4-dialkylbenz-
enes 7 with excellent regioselectivities. In addition, we found
evidence for an interesting mechanism involving two subse-
quent C–C bond cleavages with the evolution of carbon
monoxide and carbon dioxide, which we called a tandem
decarbonylation–decarboxylation.
Results and Discussion
ipso-Substitution of Terephthalic Acid
Terephthalic acid (5) is a commercially available and in-
expensive starting material. Although the Birch reduction
is an established and often used transformation in organic
chemistry,[15] we succeeded in the reductive alkylation of
this aromatic diacid only very recently.[14] It was important
to have a high dilution in liquid ammonia, due to the low
solubility of the intermediate tetraanions 8. We applied
these conditions to electrophiles bearing different func-
tional groups to examine the scope and limitations, and to
gain mechanistic insight into such Birch reductions
(Table 1). Indeed, 4-bromo-1-butene afforded cyclohexa-
diene 6b in full conversion, and remarkably in a higher yield
than that obtained with allyl bromide (Table 1, entries 1
and 2). This is a further proof of our hypothesis that an
electron transfer from the intermediate tetraanion 8 to allyl
bromide results in lower conversions, and in the reisolation
of terephthalic acid (Scheme 3).
Scheme 2. ipso-Substitution of terephthalic acid (5).
In our recent communication we investigated only the
ipso-substitution of terephthalic acid with a few alkyl hal-
ides.[14] To extend our methodology, we became interested
in the introduction of other functional groups, and also in
the use of another diacid as starting material. In this paper,
we describe our results on the Birch reduction of tere-
phthalic acid in the presence of other electrophiles, and on
the subsequent rearomatization of the cyclohexadienes. We
found some interesting mechanistic features, and we will
discuss the scope and limitations of such ipso-substitutions.
Additionally, we present the first successful Birch reduction
of naphthalene-1,4-dicarboxylic acid (15) with subsequent
Scheme 3. Competing electron transfer (ET) from tetraanion 8 to
allyl bromide.
Additionally, other functional groups like ethers or acet-
alkylation. The rearomatization of the resulting dihydro- als are tolerated during the bisalkylation of terephthalic
naphthalenes proceeded smoothly to give alkylated naphth- acid (5) under Birch conditions (Table 1, entries 3 and 4).
alenes as single regioisomers in high yields. We want to Thus, the electrophiles 3-(2-bromoethoxy)prop-1-ene[16] and
demonstrate in this full paper, that the mechanistically 2-(2-bromoethyl)-1,3-dioxolane reacted smoothly to give
interesting ipso-substitution of aromatic diacids is a conve- the corresponding 1,4-cyclohexadienes (i.e., 6c and 6d) in
nient method for the regioselective synthesis of various bi- good to high yields. All the reactions showed a preference
salkylated arenes.
for the formation of the trans-configured products trans-6.
Table 1. Birch reduction and alkylation of terephthalic acid (5).
Entry
RX (10 equiv.)
Product (yield [%])[a]
trans/cis[b]
1
2
3
4
5
6
7
allyl bromide
4-bromo-1-butene
6a (74)[c]
6b (87)
60:40
65:35
80:20
85:15
–
–
–
3-(2-bromoethoxy)prop-1-ene[d]
2-(2-bromoethyl)-1,3-dioxolane
2-chloroacetonitrile
6c (93)
6d (78)
6e (0)
ethyl 4-bromobutyrate
4-bromobutyronitrile
13f (89)[e]
13g (85)[e]
[a] Yield of purified product. [b] Determined from the NMR spectra of the crude products. [c] Lower yield, due to incomplete conversion
(Ref.[14]). [d] Synthesis over two steps.[16] [e] Formation of monoalkylated 1,3-cyclohexadienes 13f and 13g.
2
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Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
This can be rationalized by steric interactions in the second curred under the strongly acidic reaction conditions. In the
alkylation step, consistent with our previous studies.[14]
attempted reaction of dioxolanyl-substituted diacid 6d,
Although we could introduce ethyl acetate or acetonitrile some aldehyde signals were seen in the NMR spectrum of
substituents during the Birch reduction of toluic or naphth- the crude reaction mixture, due to cleavage of the protecting
oic acid,[13] these reactions failed with terephthalic acid group. Again, no defined product could be isolated after
(5), since no consumption of the starting material was ob- column chromatography.
served (Table 1, entry 5). We explain this behavior by a frag-
To overcome the problem of the strongly acidic condi-
mentation of the monoalkylated intermediate 9e by cleavage tions, we turned our attention to reactions in the presence
of a stabilized carbanion 10. The terephthalate is finally of lead tetraacetate and lithium chloride. This method was
protonated during work-up to reform the starting material developed for aromatizations of cyclohexa-2,5-diene-1-
(Scheme 4).
carboxylic acids with concomitant decarboxylation by a
radical pathway.[18] Since only the reaction of monoacids
has only been described to date, we tested this reagent on
simple diacid 6h with two ethyl substituents. Indeed, 1,4-
diethylbenzene (7h) was isolated in 80% yield (Scheme 6).
Although toxic reagents have to be used, this is the first
example of a C–C double-bond cleavage in the presence of
Pb(OAc)4, and this method might be used for the regiose-
lective synthesis of other arenes. Unfortunately, alkenyl-
substituted cyclohexadienes 6a–c were again unstable under
the reaction conditions, presumably because of lead-medi-
ated additions to the double bonds.[19] On the other hand,
the dioxolane ring was not cleaved by lead tetraacetate,
which allowed the introduction of this functional group and
the regioselective synthesis of 1,4-bisalkyl benzene 7d in
84% yield (Scheme 6).
Scheme 4. Proposed fragmentation of monoalkylated anion 9e.
To overcome this problem of fragmentation, we used
electrophiles with longer alkyl chains between the halide
leaving group and the ester and nitrile functional groups.
Indeed, ethyl 4-bromobutyrate and 4-bromobutyronitrile
gave full conversion of terephthalic acid, and cyclohexa-
dienes were isolated in high yields (Table 1, entries 6 and 7).
Surprisingly, it was not the expected 1,4-bisalkylated 2,5-
cyclohexadienes (i.e., 6) that were formed, but rather
monoalkylated 1,3-dienes 13f and 13g. Although a double-
bond migration during the Birch reduction, as discussed by
other groups,[17] cannot be completely ruled out, the strik-
ing difference between entries 6 and 7 on the one hand and
all other Birch reductions on the other suggests that an-
other explanation is required. Our mechanistic rationale is
based on monoalkylated intermediates 11, with acidic CH
protons α to the ester or nitrile groups (Scheme 5). Thus,
intramolecular proton-transfer to the double bond is pos-
sible, and this would give 1,3-cyclohexadienes 13 after
work-up. This new hypothesis might be interesting for the
discussion of the regioselectivity of the Birch reduction in
general.
Scheme 6. Decarboxylations of cyclohexadienes 6.
For the aromatization of 1,3-cyclohexadienes 13f and
13g, we could use our previously developed procedure with
the less toxic chlorosulfonic acid in dry dichloromethane at
0 °C. Thus, p-substituted benzoic acids 14f and 14g were
isolated in high yields, presumably by a tandem dehy-
dration–decarbonylation sequence (Scheme 7). This demon-
strates that functional groups like esters or nitriles, which
are of interest for further transformations like reductions,
are tolerated under the reaction conditions. Thus, this first
example of an aromatization of a 1,3-cyclohexadiene under
acidic conditions opens a regioselective access to p-substi-
tuted benzoic acids from terephthalic acid.
Scheme 5. Proposed mechanism for the formation of 1,3-cyclo-
hexadienes 13 by intramolecular proton transfer during the Birch
reduction.
In summary, we have been able to extend the scope of
the Birch reduction and subsequent alkylation of tere-
phthalic acid to tolerate other functional groups, like ethers,
For the final ipso-substitution, we first used chlorosulf- acetals, esters, and nitriles. With certain electrophiles, we
onic acid, which was a suitable reagent for the rearomatiza- observed hitherto unknown fragmentations or intramolecu-
tion of simple alkyl-substituted compounds.[14] However, lar proton transfers during the reactions. The formation of
with hitherto unknown cyclohexadienes 6b and 6c with 1,3-cyclohexadienes might be particularly interesting in the
double bonds in the side-chain, only a brown sticky mate- context of the general mechanism of Birch reductions.
rial was obtained, indicating that polymerization had oc- Some functional groups are not stable in the presence of
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The first reactions were conducted with a 50 mm concen-
tration of naphthalene-1,4-dicarboxylic acid (15) in liquid
ammonia and lithium as reducing agent, conditions dif-
ferent from those used with terephthalic acid. Iodomethane
was used as the electrophile, since it allowed an easy in-
terpretation of the NMR spectra of the crude products. The
reaction proceeded to full conversion, and yielded bis- and
monomethylated 1,4-dihydronaphthalene-1,4-dicarboxylic
acids 16a and 17a as a mixture of trans and cis isomers
(Table 2, entry 1). Importantly, no further reduction of the
second, unfunctionalized aromatic ring was observed, due
to its higher electron density. The ratio of 16a/17a was 4:1,
thus bisalkylation predominated. To obtain a higher selec-
tivity for monoalkylation, we protonated with 1–2 equiv.
tert-butyl alcohol before adding iodomethane. This alcohol
has often been used as a proton source in Birch re-
ductions.[15] However, the resulting mixture just contained
10% more monoalkylation product 17a than was seen in
the first experiment (Table 2, entry 2). This observation can
be rationalized with the HSAB (hard/soft acid/base) con-
cept.[20] Protons are hard Lewis acids, and prefer proton-
ation of the strongly Lewis basic amide anions or the carb-
oxylate oxygen instead of the weakly Lewis basic C1 or C4.
Consequently, the resulting enolate is still reactive for bisal-
kylation. Thus, the degree of alkylation could not be influ-
enced by the addition of alcohols, and depends only on the
corresponding alkylation agent (vide infra). However, a sep-
aration of mono- and bisalkylated products 16a and 17a
was possible by column chromatography, and the overall
yield was 91%.
Scheme 7. Proposed mechanism of the rearomatization of 1,3-cy-
clohexadienes 13.
chlorosulfonic acid, but esters and nitriles are tolerated.
Lead tetraacetate was used for the aromatization of diacids
for the first time, which allowed the introduction of more
sensitive acetal groups. Finally, the aromatization of 1,3-
cyclohexadienes proceeded under mild conditions, which al-
lowed the selective synthesis of p-substituted benzoic acids
from terephthalic acid.
ipso-Substitution of Naphthalene-1,4-dicarboxylic Acid
To extend the scope of the ipso-substitution of aromatic
dicarboxylic acids, we chose naphthalene-1,4-dicarboxylic
acid (15) as starting material. This is an inexpensive, com-
mercially available arene, and its Birch reduction was hith-
erto unknown. In principle, both aromatic rings might be
reduced and the degree of alkylation after the addition of
alkyl halides had to be examined. Furthermore, the condi-
tions for the subsequent aromatization had to be carefully
optimized.
To examine the scope of the Birch reduction of naphth-
alene-1,4-dicarboxylic acid (15), we investigated other hal-
ides and the degree of alkylation (Table 2, entries 3–10). We
did not use electrophiles with double bonds, because of the
expected problems during rearomatization. Interestingly,
less sterically demanding reagents like iodomethane or
Table 2. Birch reduction of naphthalene-1,4-dicarboxylic acid (15).
Entry
RX (10 equiv.)
Product (yield [%])[a]
trans/cis[b]
Product (yield [%])[a]
trans/cis[b]
1
2
3
4
5
6
7
8
9
MeI
MeI[c]
16a (73)
16a (62)
16b (71)
16c (54)
16d (5)
60:40
50:50
70:30
90:10
Ͼ 95:5
Ͼ 95:5
–
80:20
–
–
17a (18)
17a (27)
17b (24)
17c (9)
17d (90)
17e (91)
17f (80)
17g (27)
17h (91)
17i (87)
50:50
40:60
40:60
20:80
30:70
10:90
Ͻ 5:95
30:70
Ͻ 5:95
Ͻ 5:95
EtBr
iPrBr[d]
nHexBr
nOctBr
BnBr
16e (5)
16f (Ͻ 5)
16g (63)
16h (5)
1-bromo-4-chlorobutane
ethyl 4-bromobutyrate
4-bromobutyronitrile
10
16i (5)
[a] Yield of isolated product after column chromatography or crystallization. [b] Determined from NMR spectra. [c] Addition of 1 equiv.
tert-butyl alcohol before adding iodomethane. [d] Yields of dihydronaphthalenes 16c and 17c were lower because of the formation of 4-
isopropylnaphthalenecarboxylic acid (22c; 30%).
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Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
products 16. The predominant trans configuration of prod-
ucts 16 is consistent with the results from terephthalic acid
(Table 1 and ref.[14]), and can be rationalized by steric inter-
actions with the alkyl group (Scheme 8). This explains why
more sterically demanding halides give high trans selectivi-
ties (Table 2). On the other hand, protonation, which leads
to monoalkylated 1,4-dihydronaphthalenes 17, should oc-
cur at the oxygen, due to the HSAB concept (vide supra).
Thus, enol 19 is formed in the first step, which can tauto-
merize to acid 20, stabilized by intramolecular coordination
with lithium ions. After work-up, the cis isomer is formed
predominantly (Scheme 8).
All Birch reductions of naphthalene-1,4-dicarboxylic
acid (15) proceeded smoothly to give eight alkylated 1,4-
dihydronaphthalenes 16 and 17 in very good yields
(Table 2). Although the separation of cis and trans isomers
was not possible, their structures were assigned by NMR
spectroscopy and X-ray analysis (see Supporting Infor-
mation). Furthermore, the monoalkylated products (i.e., 16)
Scheme 8. Different reaction pathways of intermediate trianion 18.
bromoethane show a preference for bisalkylation (to give could be isolated in analytically pure form by column
16), whereas bulkier alkyl halides (e.g., bromohexane, chromatography or crystallization (see Experimental Sec-
bromooctane, benzyl bromide) gave monoalkylated dihydro- tion). Another advantage is that mixtures of cis and trans
naphthalenes 17 almost exclusively. This can be rationalized isomers can be used directly for the rearomatizations (vide
by an electronic stabilization of the intermediate trianion infra). Only the Birch reduction with 2-bromopropane as
(i.e., 18) by the adjacent benzene ring (Scheme 8). Further- electrophile showed different behavior, giving 1,4-dihdro-
more, this ring causes steric hindrance. Thus, the alkylations naphthalenes 16c and 17c in remarkably lower yields
proceeded more slowly than with terephthalic acid, al- (Table 2, entry 4). Additionally, the formation of a gas was
lowing competing protonation, which results in monoalkyl- observed already during the acidic work-up, indicating a
ated product 17.
proton-catalyzed rearomatization, as discussed below. In-
Interestingly, monoalkylated 1,4-dihydronaphthalenes 17 deed, 4-isopropyl-1-naphthalenecarboxylic acid (22c) was
are formed mainly as cis isomers, in contrast to bisalkylated isolated in 30% yield as a by-product.
Table 3. Rearomatization of dihydronaphthalenes 16 and 17.
Entry
Dihydronaphthalene
R1
R2
R3
Naphthalene (yield [%])[a]
1[b]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
16b
16a
16b
16c
16d
16e
16g
17a
17b
17c
17d
17e
17f
17g
17h
17i
Et
Me
Et
iPr
nHex
nOct
(CH2)4Cl
Me
Et
iPr
nHex
nOct
Bn
Et
Me
Et
Et
Me
Et
CO2H
nHex
nOct
(CH2)4Cl
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
21b (56)[c]
21a (85)
21b (86)
22c (84)
21d (91)
21e (90)
21g (89)
22a (91)
22b (86)
22c (90)
22d (85)
22e (86)
22f (81)
22g (92)
22h (89)
22h (85)
iPr
nHex
nOct
(CH2)4Cl
H
H
H
H
H
H
H
H
H
(CH2)4Cl
C3H6CO2Et
(CH2)3CN
[a] Yield of analytically pure product, isolated by column chromatography. [b] Addition of chlorosulfonic acid (1 m) to the dihydronaphtha-
lene. All other reactions (entries 2–16) were performed by the inverse addition method. [c] Formation of sulfonation products.
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For the rearomatization of the 1,4-dihydronaphthalene-
1,4-dicarboxylic acids, we used chlorosulfonic acid again,
which worked well for simple alkyl-substituted terephthalic
acid.[14] However, the higher reactivity of naphthalenes than
benzenes in SE(Ar) reactions had to be taken into account.
Furthermore, the solubility of the diacids in dichlorometh-
ane was very low. Therefore, we optimized the conditions
with bisethylated compound 16b, which was easy to analyze
by NMR spectroscopy. Thus, 2 equiv. ClSO3H (1 m) was
added to a suspension of the starting material in dichloro-
methane at 0 °C. Due to the low solubility, the reaction pro-
ceeded slowly, and full consumption of starting material
was only achieved after 30 min. The NMR spectrum of the
crude reaction mixture was complex and indicated the pres-
ence of sulfonation products as well as 1,4-diethylnaphth-
alene (21b), which was finally isolated in only 56% yield
after column chromatography (Table 3, entry 1).
Scheme 9. Proposed mechanisms for the aromatizations to
naphthalenes 21 and 22.
Neither changing the solvent (chloroform) nor varying
the temperature (25, –15, –30 °C) resulted in higher yields.
Obviously, the contact time of the arene product with chlo-
rosulfonic acid was too long, and this resulted in the forma-
tion of sulfonation by-products. Finally, we solved this
problem by adding dihydronaphthalene 16b to a 1 m solu-
tion of chlorosulfonic acid in chloroform at 0 °C. The reac-
tion was quenched after only 2 min by adding the mixture
to a saturated sodium carbonate solution (5 mL). Indeed,
the desired 1,4-diethylnaphthalene (21b) was now isolated
in 86% yield after column chromatography in analytically
pure form (Table 3, entry 3). This inverse addition is a re-
markable improvement compared to our previous studies,
and it might be used in other ipso-substitutions as well.
We used this successful procedure for all other mono-
and bisalkylated 1,4-dihydronaphthalenes 16 and 17
(Table 3). In all, 15 different naphthalenes were isolated in
analytically pure form in high yields as single regioisomers
(see Exp. Section). Bisalkylated starting materials 16 gave
1,4-dialkylnaphthalenes 21 (Table 3, entries 1–3 and 5–7),
whereas monoalkylated 1,4-dihydronaphthalenes 17 yielded
exclusively 4-alkyl-1-naphthalenecarboxylic acids 22
(Table 3, entries 8–16). Only 1,4-bisisopropyl derivative 16c
showed a different reactivity and afforded 4-isopropyl-1-
is faster, which results in product 22c and finally 2-chloro-
propane, which was detected in the NMR spectra.
In summary, we have realized the Birch reduction of 1,4-
naphthalenedicarboxylic acid for the first time. Mono- and
bisalkylated 1,4-dihydronaphthalenes were isolated in high
yields, although the degree of alkylation could not be con-
trolled. The formation of cis and trans isomers in different
ratios is interesting in the context of the mechanism of
Birch reductions. For the rearomatizations, a new experi-
mental protocol with chlorosulfonic acid was developed,
which afforded naphthalenes as single regioisomers in high
yields. The formation of the different products can be ex-
plained by a general mechanism of decarbonylations and
decarboxylations, which should also operate in other ipso-
substitutions. Overall, starting from the inexpensive precur-
sor naphthalene-1,4-dicarboxylic acid, various alkyl-substi-
tuted naphthalenes were synthesized in only two steps as
single regioisomers in high yields.
Conclusions
Aromatic dicarboxylic acids are suitable starting materi-
naphthalenecarboxylic acid (22c) in 84% yield (Table 3, en- als for the regioselective synthesis of alkylarenes. Tere-
try 4). The formation of these various products supports phthalic and naphthalene-1,4-dicarboxylic acids are inex-
our previous mechanistic hypothesis for ipso-substitutions pensive precursors that undergo Birch reduction and subse-
of other aromatic carboxylic acids,[13,14] which is summa- quent alkylation in high yields. We used electrophiles con-
rized in Scheme 9.
taining ester, nitrile, and acetal groups for the first time,
In the first step, protonation of one carboxylic acid thus extending the scope of this method. Interesting frag-
group with the strong chlorosulfonic acid affords, after de- mentations or intramolecular proton transfers during the
hydration and decarbonylation, carbenium ion 23. Now Birch reductions gave mechanistic insight in this reaction.
three different reaction pathways are possible. For monoal- With naphthalene-1,4-dicarboxylic acid as precursor, the
kylated 1,4-dihydronaphthalenes 17 (R2 = H) deproton- different ratios of mono- and bisalkylated products and cis
ation is obvious, leading directly to 4-alkyl-1-naphth- and trans isomers were rationalized by a change in the reac-
alenecarboxylic acids 22. Bisalkylated derivatives 16 (R2 = tion pathway. More than 20 new dihydro derivatives were
alkyl) cannot react by this pathway. Thus, cleavage of the isolated in high yields in analytically pure form.
C–C bond to the carboxylic acid takes place to give 1,4-
For the subsequent rearomatizations, we used inexpen-
bisalkyl naphthalenes 21 in high yields by a decarboxyl- sive chlorosulfonic acid. We developed a new experimental
ation. Finally, for 1,4-diisopropyl-1,4-dihydronaphthalene protocol for 1,4-dihydronaphthalenes, which afforded
(16c) (R2 = iPr), the cleavage of a stabilized carbenium ion higher yields of naphthalenes. Some functional groups were
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 15-08-12 15:31:47
Pages: 13
Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
13C NMR (75 MHz, [D6]DMSO): δ = 29.1, 38.6 (t, C-4 and C-5),
47.9 (s, C-1), 115.5 (t, C-7), 128.9 (d, C-2), 138.6 (d, C-6), 174.9 (s,
not stable under the strongly acidic conditions, but we
could use lead tetraacetate for the aromatization of diacids
for the first time. The formation of mono- and bisalkylated
naphthalenes was important from the point of view of the
mechanism of the reactions in the presence of chlorosul-
fonic acid. Thus, a deprotonation, a tandem decarb-
onylation–decarboxylation sequence or the cleavage of an
isopropyl group can compete. Overall, we have extended the
scope of the ipso-substitution of aromatic carboxylic acids
to tolerate other functional groups, and applied the method
to naphthalene-1,4-dicarboxylic acid for the first time.
Starting from inexpensive precursors, various alkyl-substi-
tuted arenes were synthesized in only two steps as single
regioisomers in high yields.
C-3) ppm. IR (methanol): ν = 2945, 2857, 2628, 1686, 1640, 1414,
˜
1399, 1281, 1252, 1093, 991, 951, 915, 791 cm–1. C16H20O4 (276.33):
calcd. C 69.55, H 7.30; found C 69.19, H 7.183.
1,4-Bis[2-(allyloxy)ethyl]cyclohexa-2,5-diene-1,4-dicarboxylic Acid
(6c): White solid (93%); m.p. 160–162 °C. Rf = 0.43 (dichlorometh-
ane/methanol = 10:1). trans isomer: 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.87 (t, J = 7.2 Hz, 4 H, 4-H), 3.26 (t, J = 7.2 Hz, 4
H, 5-H), 3.80 (dt, J = 5.4, J = 1.5 Hz, 4 H, 6-H), 5.12 (ddd, J =
17.3, J = 10.4, J = 2.0 Hz, 4 H, 8-H), 5.73–5.83 (m, 2 H, 7-H), 5.79
(s, 4 H, 2-H), 12.57 (br. s, 1 H, -COOH) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 38.4 (t, C-4), 46.5 (s, C-1), 66.4 (t, C-5), 71.3 (t,
C-6), 116.6 (t, C-8), 128.5 (d, C-2), 135.6 (d, C-7), 174.7 (s, C-3)
1
ppm. cis isomer: H NMR (300 MHz, [D6]DMSO): δ = 1.89 (t, J
= 7.2 Hz, 4 H, 4-H), 3.28 (t, J = 7.2 Hz, 4 H, 5-H), 3.85 (dt, J =
5.3, J = 1.5 Hz, 4 H, 6 H), 5.15 (ddd, J = 17.3, J = 10.4, J = 2.0 Hz,
4 H, 8-H), 5.80–5.88 (m, 2 H, 7-H), 5.79 (s, 4 H, 2-H), 12.57 (br.
s, 1 H, -COOH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 38.3
(t, C-4), 46.6 (s, C-1), 66.7 (t, C-5), 71.2 (t, C-6), 116.7 (t, C-8),
128.7 (d, C-2), 135.7 (d, C-7), 174.5 (s, C-3) ppm. IR (methanol):
Experimental Section
General Methods: Commercially available chemicals and solvents
were used as purchased or purified by standard methods. TLC was
performed on aluminium sheets coated with silica gel 60 F254
(Merck). Column chromatography was carried out with silica gel
LC60A 40–63 μm (Davisil). NMR spectra were recorded with
Bruker Avance 300 MHz and 500 MHz spectrometers. Deuterated
solvents were used as internal standards. Melting points were mea-
sured with MEL-TEMP II and Electrothermal BI 9100 instru-
ments. IR spectra were recorded with a Nicolet 6700 FT-IR spec-
trometer. Elemental analyses were performed with a Vario EL III
(ELEMENTAR) apparatus. Mass spectra were recorded with ESI-
Q-TOF (Waters) and Thermo DSQII (Axel Semrau GmbH) spec-
trometers.
ν = 2970, 2855, 1690, 1455, 1417, 1397, 1348, 1270, 1106, 1012,
˜
953, 914, 812, 785, 739 cm–1. C18H24O6 (336.38): calcd. C 64.27, H
7.19; found C 64.12, H 7.09.
1,4-Bis[2-(1,3-dioxolan-2-yl)ethyl]cyclohexa-2,5-diene-1,4-di-
carboxylic Acid (6d): White solid (78%); m.p. 249–253 °C. Rf = 0.28
(dichloromethane/methanol
=
10:1). 1H NMR (300 MHz,
[D6]DMSO, cis and trans isomers overlapping): δ = 1.30–1.46 (m,
4 H, 4-H), 1.59–1.72 (m 4 H, 5-H), 3.69–3.87 (m, 8 H, 7-H), 4.71
(t, J = 4.6 Hz, 2 H, 6-H), 5.76 (s, 4 H, 2-H) ppm, -COOH not
detected. trans isomer: 13C NMR (75 MHz, [D6]DMSO): δ = 29.3
(t, C-4), 33.4 (t, C-5), 47.9 (s, C-1), 65.1 (t, C-7), 104.1 (d, C-6),
General Procedure for the Birch Reductions of Terephthalic Acid (5): 129.3 (d, C-2), 175.6 (s, C-3) ppm. cis isomer: 13C NMR (75 MHz,
Lithium (555 mg, 80 mmol) was added in small portions at –78 °C
to a suspension of terephthalic acid (1.66 g, 10.0 mmol) in liquid
ammonia (500 mL) until the blue color persisted. After 5 h at this
temperature, the alkyl halide (100 mmol, 10 equiv.) was added
slowly. The ammonia was evaporated overnight, and the solid resi-
due was dissolved in water (100 mL). After cooling to 0 °C, concen-
trated aqueous HCl was slowly added until pH 1 was reached, and
the resulting precipitate was filtered off and dried in a desiccator.
Products 6 and 13 were purified by recrystallization.
[D6]DMSO): δ = 29.6 (t, C-4), 33.8 (t, C-5), 48.0 (s, C-1), 65.1 (t,
C-7), 104.1 (d, C-6), 129.3 (d, C-2), 175.7 (s, C-3) ppm. IR (meth-
anol): ν = 2950, 2881, 2360, 1686, 1398, 1264, 1140, 1028, 992, 942,
˜
886, 799, 766 cm–1. C18H24O8 (368.38): calcd. C 58.69, H 6.57;
found C 58.40, H 6.415.
1,4-Diethylcyclohexa-2,5-diene-1,4-dicarboxylic Acid (6h):[14] White
solid (93%); m.p. 189–191 °C. Rf = 0.43 (dichloromethane/meth-
anol, 5:1). trans isomer: 1H NMR (300 MHz, [D4]methanol): δ =
0.84 (t, J = 7.5 Hz, 6 H, 5-H), 1.76 (q, J = 7.5 Hz, 4 H, 4-H), 5.92
(s, 4 H, 2-H), 12.46 (br. s, 2 H, -COOH) ppm. 13C NMR (75 MHz,
[D4]methanol): δ = 7.9 (q, C-5), 32.2 (t, C-4), 48.9 (s, C-1), 128.7
1,4-Diallylcyclohexa-2,5-diene-1,4-dicarboxylic Acid (6a):[14] White
solid (1.83 g, 74%); m.p. 176–178 °C. Rf = 0.35 (dichloromethane/
methanol, 10:1). 1H NMR (300 MHz, [D6]DMSO, cis and trans (d, C-2), 176.9 (s, C-3) ppm. cis isomer: 1H NMR (300 MHz,
isomers overlapping): δ = 2.33 (d, J = 7.2 Hz, 4 H, 4-H), 4.95–5.06
(m, 4 H, 6-H), 5.50–5.65 (m, 2 H, 5-H), 5.81 (s, 4 H, 2-H), 11.59 (br.
s, 2 H, -COOH) ppm. trans isomer: 13C NMR (75 MHz, CDCl3): δ
= 44.0 (t, C-4), 48.1 (s, C-1), 118.7 (t, C-6), 128.7 (d, C-2), 133.8 (d,
[D4]methanol): δ = 0.89 (t, J = 7.5 Hz, 6 H, 5-H), 1.77 (q, J =
7.5 Hz, 4 H, 4-H), 5.92 (s, 4 H, 2-H), 12.46 (br. s, 2 H, -COOH)
ppm. 13C NMR (75 MHz, [D4]methanol): δ = 8.4 (q, C-5), 32.3 (t,
C-4), 49.0 (s, C-1), 128.9 (d, C-2), 175.7 (s, C-3 ppm). IR (KBr): ν
˜
C-5), 174.7 (s, C-3) ppm. cis isomer: 13C NMR (75 MHz, CDCl3): δ = 2976, 1684, 1410, 1272, 1118, 1073, 946, 912, 776 cm–1. C12H16O4
= 44.2 (t, C-4), 48.0 (s, C-1), 118.8 (t, C-6), 128.6 (d, C-2), 133.9 (224.26): calcd. C 64.27, H 7.19; found C 64.33, H 7.19.
(d, C-5), 174.6 (s, C-3) ppm. IR (KBr): ν = 3080, 2916, 1691, 1234,
˜
4-(4-Ethoxy-4-oxobutyl)cyclohexa-1,3-diene-1,4-dicarboxylic Acid
915 cm–1. C14H16O4 (248.28): calcd. C 67.73, H 6.50; found C
67.68, H 6.56.
(13f): White solid (89%); m.p. 295–299 °C. Rf = 0.43 (dichloro-
1
methane/methanol = 10:1). H NMR (300 MHz, [D4]methanol): δ
1,4-Di(but-3-enyl)cyclohexa-2,5-diene-1,4-dicarboxylic Acid (6b):
= 1.58 (t, J = 7.0 Hz, 3 H, 14-H), 1.32–1.63 (m, 4 H, 9- and 10-
H), 2.10 (t, J = 6.6 Hz, 2 H, 11-H), 2.33 (dd, J = 20.0, 4.0 Hz, 1
White solid (87%); m.p. 230–233 °C. Rf = 0.32 (dichloromethane/
1
methanol = 10:1). H NMR (300 MHz, [D6]DMSO, cis and trans H, 5-Ha), 2.75 (dd, J = 20.0, 4.0 Hz, 1 H, 5-Hb), 3.92 (q, J = 7.0 Hz,
isomers overlapping): δ = 1.60–1.97 (m, 8 H, 4- and 5-H), 4.87–
2 H, 13-H), 5.77 (d, J = 9.9 Hz, 1 H, 3-H), 6.24 (d, J = 9.9 Hz, 1
5.02 (m, 4 H, 7-H), 5.68–5.87 (m, 2 H, 6-H), 5.82 (s, 4-H, 2-H), H, 2-H), 6.77 (t, J = 4.0 Hz, 1 H, 6-H) ppm, -COOH not detected.
12.63 (br. s, 2 H, -COOH) ppm. trans isomer: 13C NMR (75 MHz,
[D6]DMSO): δ = 28.8, 38.1 (t, C-4 and C-5), 48.0 (s, C-1), 115.4 (t,
C-7), 128.9 (d, C-2), 138.7 (d, C-6), 175.2 (s, C-3) ppm. cis isomer:
13C NMR (75 MHz, [D4]methanol): δ = 14.1 (q, C-14), 20.2 (t, C-
10), 31.4, 34.5 (t, C-9 and C-11), 37.0 (t, C-5), 45.4 (s, C-4), 60.7
(t, C-13), 121.8, 130.0, 136.7 (d, C-2, C-3, C-6), 127.6 (s, C-1),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20823
/KAP1
Date: 15-08-12 15:31:47
Pages: 13
A. Bramborg, T. Linker
FULL PAPER
167.8, 174.0, 177.6 (s, C-7, C-8, C-12) ppm. IR (dichloromethane):
methane): ν = 3170, 2950, 1727, 1677, 1611, 1575, 1427, 1380, 1321,
˜
ν = 2945, 2554, 2371, 2244, 1692, 1653, 1417, 1285, 1121, 1089,
1289, 1257, 1174, 1020, 938, 863 cm–1. C13H16O4 (236.27): calcd. C
66.09, H 6.83; found C 66.11, H 6.629.
˜
939, 772, 731 cm–1. HRMS: calcd. for C14H18O6 [M + H]+ 283.12;
found 283.1211.
4-(3-Cyanopropyl)benzoic Acid (14g):[22] White solid (89%); m.p.
156–158 °C (lit. m.p. 158–160 °C). Rf = 0.26 (dichloromethane/
4-(3-Cyanopropyl)cyclohexa-1,3-diene-1,4-dicarboxylic Acid (13g):
1
White solid (85%); m.p. 335–338 °C. Rf = 0.44 (dichloromethane/
methanol = 30:1). H NMR (300 MHz, CDCl3): δ = 2.04 (quint, J
1
methanol = 10:1). H NMR (300 MHz, CDCl3): δ = 1.53–1.90 (m, = 7.3 Hz, 2 H, 7-H), 2.37 (t, J = 7.0 Hz, 2 H, 8-H), 2.88 (t, J =
4 H, 9- and 10-H), 2.44 (t, J = 6.8 Hz, 2 H, 11-H), 2.53 (dd, J =
19.1, 5.1 Hz, 1 H, 5-Ha), 2.93 (dd, J = 19.1, 5.1 Hz, 1 H, 5-Hb),
5.96 (d, J = 9.9 Hz, 1 H, 3-H), 6.44 (d, J = 9.9 Hz, 1 H, 2-H), 6.95
(t, J = 4.6 Hz, 1 H, 6-H) ppm, -COOH not detected. 13C NMR
(75 MHz, [D4]methanol): δ = 16.8, 20.4, 31.1 (t, C-9–C-11), 36.00
(t, C-5), 44.7 (s, C-4), 119.1 (s, C-12), 121.7, 128.8, 135.8 (d, C-
7.5 Hz, 2 H, 6-H), 7.32, 8.08 (d, J = 8.2 Hz, 2 H, 2-H and 3-H),
9.95 (br. s, 1 H, -COOH) ppm. 13C NMR (75 MHz, CDCl3): δ =
16.6, 26.7, 34.6 (t, C-6–C-8), 119.2 (t, C-9), 127.9 (s, C-4), 128.8,
130.8 (d, C-2 and C-3), 146.3 (s, C-1), 171.7 (s, C-5) ppm. IR
(dichloromethane): ν = 2923, 2547, 2244, 1683, 1609, 1575, 1515,
˜
1425, 1292, 1218, 1182, 1128, 929, 867, 844, 826 cm–1. C11H11NO2
2, C-3, C-6), 127.3 (s, C-1), 167.0, 176.6 (s, C-7, C-8) ppm. IR (189.21): calcd. C 69.83, H 5.86, N 7.40; found C 69.65, H 5.736,
(dichloromethane): ν = 2937, 2544, 2362, 2245, 1689, 1646, 1421,
N 7.233.
˜
1280, 1107, 1091, 939, 763, 724 cm–1. C12H13NO4 (235.24): calcd.
C 61.27, H 5.57, N 5.95; found C 61.10, H 5.45, N 5.83. HRMS:
calcd. for C12H13NO4 [M + Na]+ 258.0742; found 258.0727.
General Procedure for the Birch Reductions of Naphthalene-1,4-di-
carboxylic Acid (15): Lithium (555 mg, 80 mmol) was added in
small portions at –78 °C to a suspension of naphthalene-1,4-dicarb-
oxylic acid (15) (2.16 g, 10.0 mmol) in liquid ammonia (150 mL)
until the blue color persisted. After 2 h at this temperature, the
alkyl halide (100 mmol, 10 equiv.) was added slowly. The reaction
mixture was warmed up to –35 °C before adding 1-bromohexane,
1-bromooctane, and benzyl bromide. The ammonia was evaporated
overnight, and the solid residue was dissolved in water (100 mL).
After cooling to 0 °C, concentrated HCl was slowly added until
pH 1 was reached, and the resulting precipitate was continuously
extracted with chloroform. After removal of the solvent, products
16 and 17 were purified by column chromatography.
General Procedure for the Halodecarboxylation of Cyclohexadiene-
dicarboxylic Acids 6: Cyclohexadiene 6 (2.0 mmol) was suspended
in chloroform (100 mL), and lead tetraacetate (5.0 mmol,
2.5 equiv.) and lithium chloride (5.0 mmol, 2.5 equiv.) were added.
The yellow reaction mixture was heated at reflux for 3 h. The white
suspension was washed with saturated Na2S2O3 solution
(2ϫ20 mL) and water (20 mL), and the organic fraction was dried
with MgSO4. After removal of the solvent, arenes 7 were purified
by column chromatography (dichloromethane).
1,4-Bis[2-(1,3-dioxolan-2-yl)ethyl]benzene (7d): White solid (84%);
1
1,4-Dimethyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (16a):
White solid (73%). Rf = 0.23 (dichloromethane/methanol = 100:1).
trans isomer: 1H NMR (300 MHz, [D4]methanol): δ = 1.60 (s, 6 H,
7-H), 5.93 (s, 2 H, 2-H), 7.28 (dd, J = 5.8, J = 3.6 Hz, 2 H, 3-H),
7.40 (dd, J = 5.8, J = 3.6 Hz, 2 H, 4-H) ppm, -COOH not detected.
13C NMR (75 MHz, [D4]methanol): δ = 28.6 (t, C-7), 48.4 (s, C-
1), 128.3, 128.5, 130.6 (d, C-2–C-4), 137.6 (s, C-5), 178.2 (s, C-6)
m.p. 70–72 °C. Rf = 0.63 (dichloromethane). H NMR (300 MHz,
CDCl3): δ = 1.92–2.02 (m, 4 H, CH2), 2.72 (t, J = 8.2 Hz, 4 H,
CH2), 3.82–4.02 (m, 8 H, CH2), 4.89 (t, J = 4.7 Hz, 2 H, CH), 7.13
(s, 4 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.8 (t, C-
3), 35.6 (t, C-4), 65.0 (t, C-6), 104.0 (d, C-5), 128.5 (d, C-2), 139.2
(s, C-1) ppm. IR (dichloromethane): ν = 3011, 2942, 1736, 1519,
˜
1447, 1409, 1231, 1199, 1133, 1071, 1029, 971, 943, 887, 762 cm–1.
HRMS: calcd. for C16H22O4 [M]+ 278.1518; found 278.1509.
1
ppm. cis isomer: H NMR (300 MHz, [D4]methanol): δ = 1.60 (s,
6 H, 7-H), 5.87 (s, 2 H, 2-H), 7.25 (dd, J = 5.9, J = 3.8 Hz, 2 H,
3-H), 7.36 (dd, J = 5.9, J = 3.8 Hz, 2 H, 4-H) ppm, -COOH not
detected. 13C NMR (75 MHz, [D4]methanol): δ = 28.2 (t, C-7), 48.3
(s, C-1), 128.1, 128.2, 130.2 (d, C-2–C-4), 137.9 (s, C-5), 178.4 (s,
1,4-Diethylbenzene (7h):[21] Colorless liquid (85%); n2D0 = 1.4948 (lit.
n2D0 = 1.4947); Rf = 0.89 (dichloromethane). H NMR (300 MHz,
1
CDCl3): δ = 1.22 (t, J = 7.6 Hz, 6 H, CH3), 2.61 (q, J = 7.6 Hz, 4
H, CH2), 7.11 (s, 4 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 15.6 (q, CH3), 28.4 (t, CH2), 127.8 (d, C-Ar), 141.4 (s, C-Ar)
ppm.
C-6) ppm. IR (methanol): ν = 2977, 2925, 2638, 1702, 1469, 1435,
˜
1383, 1275, 1261, 1201, 1093, 971, 849 cm–1. HRMS: calcd. for
C14H14O4 [M]+ 246.0892; found 246.0885.
General Procedure for the Rearomatization of 1,3-Cyclohexadiene-
dicarboxylic Acids 13: Cyclohexadiene 13 (2.0 mmol) was sus-
pended in dry dichloromethane (10 mL) and cooled to 0 °C. A
solution of chlorosulfonic acid (2.0 to 4.0 mmol, 1 m in dichloro-
methane) was added dropwise with evolution of CO, until TLC
showed full conversion. The solution was poured into ice-cold
water, and the aqueous phase was extracted with dichloromethane
(3ϫ10 mL). The combined organic phases were dried with MgSO4.
After removal of the solvent, arenes 14 were purified by column
chromatography (dichloromethane/methanol).
1-Methyl-1,4-dihydronaphthalene-1,4-dicarboxylic
Acid
(17a):
White solid (18%); m.p. 155–158 °C. Rf = 0.12 (dichloromethane/
methanol = 100:1). trans isomer: 1H NMR (300 MHz, [D4]meth-
anol): δ = 1.59 (s, 3 H, 12-H), 4.45 (d, J = 3.7 Hz, 1 H, 4-H), 6.01
(d, J = 10.0 Hz, 1 H, 2-H), 6.05 (dd, J = 10.0, J = 3.7 Hz, 1 H, 3-
H), 7.19–7.38 (m, 4 H, 5-H–8-H) ppm, -COOH not detected. 13C
NMR (75 MHz, [D4]methanol): δ = 27.5 (t, C-12), 48.6 (d, C-4),
48.8 (s, C-1), 124.5, 128.1, 128.4, 128.7, 129.6 (d, C-2, C-3, C-5–C-
8), 132.2, 138.2 (s, C-9 and C-10), 176.0, 177.0 (s, C-11 and C-12)
1
ppm. cis isomer: H NMR (300 MHz, [D4]methanol): δ = 1.60 (s,
4-(4-Ethoxy-4-oxobutyl)benzoic Acid (14f): White solid (91%); m.p.
65–67 °C. Rf = 0.10 (dichloromethane/methanol = 50:1). 1H NMR
3 H, 13-H), 4.45 (d, J = 3.7 Hz, 1 H, 4-H), 5.98 (d, J = 10.0 Hz, 1
H, 2-H), 6.08 (dd, J = 10.0, J = 3.7 Hz, 1 H, 3-H), 7.19–7.38 (m,
(300 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3 H, CH), 1.96 (quint, 4 H, 5-H–8-H) ppm, -COOH not detected. 13C NMR (75 MHz,
J = 7.5 Hz, 2 H, 7-H), 2.32 (t, J = 7.4 Hz, 2 H, 8-H), 2.70 (t, J = [D4]methanol): δ = 28.2 (t, C-12), 47.5 (d, C-4), 48.6 (s, C-1), 123.6,
7.6 Hz, 2 H, 6-H), 4.11 (q, J = 7.1 Hz, 2 H, 10-H), 7.26, 8.01 (d, J 128.0, 128.5, 128.6, 129.8 (d, C-2, C-3, C-5–C-8), 132.9, 139.0 (s, C-
= 8.3 Hz, 2 H, 2-H and 3-H), 12.43 (br. s, 1 H, -COOH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2 (q, C-11), 26.1, 33.5, 35.1 (t, C-
6–C-8), 60.5 (t, C-10), 127.2 (s, C-4), 128.6, 130.4 (d, C-2 and C-
3), 148.0 (s, C-1), 172.1, 173.5 (s, C-5 and C-9) ppm. IR (dichloro-
9 and C-10), 176.4, 178.5 (s, C-11 and C-12) ppm. IR (methanol): ν
˜
= 3034, 2970, 2934, 2626, 1698, 1489, 1450, 1381, 1286, 1260, 1207,
1085, 968, 856 cm–1. C13H12O4 (232.24): calcd. C 67.23, H 5.21;
found C 67.25, H 5.23.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20823
/KAP1
Date: 15-08-12 15:31:47
Pages: 13
Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
1,4-Diethyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (16b): detected. trans isomer: 13C NMR (75 MHz, [D4]methanol): δ =
White solid (71%); m.p. 243–244 °C. Rf = 0.27 (dichloromethane/
17.8, 19.1 (q, C-14 and C-14Ј), 36.3 (d, C-13), 49.1 (d, C-4), 56.1
(s, C-1), 126.4, 126.7, 127.4, 127.8, 128.3, 129.1 (d, C-2, C-3, C-5–
methanol = 100:1). trans isomer: 1H NMR (300 MHz, [D4]meth-
anol): δ = 0.66 (t, J = 7.3 Hz, 6 H, 8-H), 2.12 (dt, J = 14.7, J = C-8), 133.3, 136.3 (s, C-9 and C-10), 177.0, 177.2 (C-11 and C-12)
7.3 Hz, 2 H, 7-Ha), 2.35 (dt, J = 14.7, J = 7.3 Hz, 2 H, 7-Hb), 5.95
(s, 2 H, 2-H), 7.30 (dd, J = 5.9, J = 3.4 Hz, 2 H, 3-H), 7.45 (dd, J
= 5.9, J = 3.4 Hz, 2 H, 3-H) ppm, -COOH not detected. 13C NMR
(75 MHz, [D4]methanol): δ = 9.4 (q, C-8), 32.6 (t, C-7), 52.9 (s, C-
1), 128.3, 128.6, 131.2 (d, C-2–C-4), 136.5 (s, C-5), 177.8 (s, C-6);
cis isomer: 1H NMR (300 MHz, [D4]methanol): δ = 0.65 (t, J =
ppm. cis isomer: 13C NMR (75 MHz, [D4]methanol): δ = 18.1, 18.6
(q, C-14 and C-14Ј), 38.7 (d, C-13), 46.6 (d, C-4), 54.8 (s, C-1),
125.2, 126.0, 127.3, 127.6, 128.2, 130.2 (d, C-2, C-3, C-5–C-8),
132.7, 136.4 (s, C-9 and C-10), 177.4, 177.7 (C-11 and C-12) ppm.
IR (methanol): ν = 2965, 2874, 2630, 1698, 1495, 1455, 1436, 1388,
˜
1365, 1259, 1217, 1007, 929, 750 cm–1. C15H16O4 (260.29): calcd. C
7.5 Hz, 6 H, 8-H), 2.05 (dt, J = 14.8, J = 7.5 Hz, 1 H, 7-Ha), 2.18 69.22, H 6.20; found C 69.03, H 6.15.
(dt, J = 14.8, J = 7.5 Hz, 1 H, 7-Hb), 5.89 (s, 2 H, 2-H), 7.24 (dd,
trans-1,4-Dihexyl-1,4-dihydronaphthalene-1,4-dicarboxylic
Acid
J = 5.9, J = 3.4 Hz, 2 H, 3-H), 7.40 (dd, J = 5.9, J = 3.4 Hz, 2 H,
3-H) ppm, -COOH not detected. 13C NMR (75 MHz, [D4]meth-
anol): δ = 9.1 (q, C-8), 34.2 (t, C-7), 52.8 (s, C-1), 127.9, 128.2,
130.0 (d, C-2–C-4), 137.1 (s, C-5), 178.1 (s, C-6) ppm. IR (meth-
(16d): White solid (5%); m.p. 218–221 °C. Rf = 0.41 (dichlorometh-
ane/methanol = 100:1). H NMR (300 MHz, CDCl3): δ = 0.83 (t,
1
J = 6.8 Hz, 6 H, 12-H), 1.05–1.28 (m, 16 H, 8–11-H), 2.01 (dt, J =
12.3, J = 4.1 Hz, 2 H, 7-Ha), 2.35 (dt, J = 12.3, J = 4.1 Hz, 2 H,
7-Hb), 5.91 (s, 2 H, 2-H), 7.30 (dd, J = 5.9, J = 3.4 Hz, 2 H, 3-H),
7.41 (dd, J = 5.9, J = 3.4 Hz, 2 H, 4-H), 9.91 (br. s, 2 H, -COOH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (q, C-12), 22.6, 24.7,
29.6, 31.7 (t, C-11–C-8), 38.1 (t, C-7), 51.4 (s, C-1), 127.2, 128.3,
130.2 (d, C-2–C-4), 134.3 (s, C-5), 178.6 (s, C-6) ppm. IR (chloro-
anol): ν = 2971, 2936, 2879, 2619, 1702, 1489, 1450, 1381, 1263,
˜
1207, 1088, 1025, 924, 857 cm–1. C16H18O4 (274.32): calcd. C 70.06,
H 6.61; found C 69.99, H 6.55.
1-Ethyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (17b): White
solid (24%); m.p. 277–278 °C. Rf = 0.18 (dichloromethane/meth-
anol = 100:1). 1H NMR (300 MHz, [D4]methanol, cis and trans
isomers overlapping): δ = 0.55 (t, J = 7.3 Hz, 3 H, 14-H), 2.03 (dt,
J = 14.0, J = 7.3 Hz, 1 H, 13-Ha), 2.32 (dt, J = 14.0, J = 7.3 Hz,
1 H, 13-Hb), 4.46 (d, J = 4.0 Hz,1 H, 4-H), 5.87 (d, J = 10.0 Hz, 1
H, 2-H), 6.20 (dd, J = 10.0, J = 4.0 Hz, 1 H, 3-H), 7.20–7.44 (m,
4 H, 5-H–8-H) ppm, -COOH not detected. trans isomer: 13C NMR
(75 MHz, [D4]methanol): δ = 8.0 (q, C-14), 31.0 (t, C-13), 46.8 (d,
C-4), 51.7 (s, C-1), 124.6, 126.9, 127.4, 127.9, 128.4, 130.7 (d, C-2,
C-3, C-5–C-8), 131.4, 133.9 (s, C-9 and C-10), 175.1, 176.2 (C-11
and C-12) ppm. cis isomer: 13C NMR (75 MHz, [D4]methanol): δ
= 8.5 (q, C-14), 31.6 (t, C-13), 46.1 (d, C-4), 51.2 (s, C-1), 123.8,
127.1, 127.3, 127.6, 128.4, 130.8 (d, C-2, C-3, C-5–C-8), 131.6,
134.4 (s, C-9 and C-10), 175.0, 176.4 (C-11 and C-12) ppm. IR
form): ν = 2955, 2928, 2858, 2629, 1697, 1489, 1466, 1446, 1403,
˜
1272, 935, 780 cm–1. C24H34O4 (386.53): calcd. C 74.58, H 8.87;
found C 74.45, H 8.659.
cis-1-Hexyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (17d):
White solid (90%). Rf = 0.36 (dichloromethane/methanol = 100:1).
1H NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 7.1 Hz, 3 H, 17-H),
0.95–1.34 (m, 8 H, 14-H–16-H), 2.01 (t, J = 13.0 Hz, 1 H, 13-Ha),
2.36 (t, J = 13.0 Hz, 1 H, 13-Hb), 4.48 (d, J = 4.4 Hz, 1 H,4-H),
5.88 (d, J = 9.9 Hz, 1 H, 2-H), 6.15 (dd, J = 9.9, J = 4.4 Hz, 1 H,
3-H), 7.20–7.47 (m, 4 H, 5-H–8-H), 11.0 (br. s, 2 H, -COOH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.3 (q, C-18), 22.9, 24.4, 29.8,
31.9 (t, C-17–C-14), 38.4 (t, C-13), 47.4 (d, C-4), 51.8 (s, C-1),
124.7, 127.6, 128.1, 128.6, 129.2, 131.7 (d, C-2, C-3, C-5–C-8),
131.4, 134.5 (s, C-9 and C-10), 177.7, 178.8 (s, C-11 and C-12) ppm.
(methanol): ν = 3149, 2967, 2936, 2878, 1720, 1684, 1669, 1489,
˜
1445, 1381, 1232, 1183, 1150, 982, 876 cm–1. C14H14O4 (246.26):
calcd. C 68.28, H 5.73; found C 68.29, H 5.766.
IR (methanol): ν = 2927, 2855, 2359, 1694, 1491, 1461, 1398, 1263,
˜
938, 802, 754 cm–1. C18H22O4 (302.37): calcd. C 71.50, H 7.33;
found C 71.23, H 7.16.
1,4-Diisopropyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (16c):
White solid (54%). Rf = 0.35 (dichloromethane/methanol = 100:1).
trans isomer: 1H NMR (300 MHz, [D4]methanol): δ = 0.46 (d, J =
6.7 Hz, 3 H, 8-H), 1.02 (d, J = 6.7 Hz, 3 H, 8-HЈ), 2.72 (septet, J
= 6.7 Hz, 1 H, 7-H), 5.97 (s, 2 H, 2-H), 7.27 (dd, J = 6.0, J =
3.4 Hz, 2 H, 3-H), 7.63 (dd, J = 5.9, J = 3.4 Hz, 2 H, 2-H) ppm,
-COOH not detected. 13C NMR (75 MHz, [D4]methanol): δ = 18.7,
18.9 (q, C-8 and C-8Ј), 36.4 (d, C-7), 53.8 (s, C-1), 125.6, 126.8,
127.3 (d, C-2–C-4), 135.9 (s, C-5), 175.3 (s, C-6) ppm. cis isomer:
1H NMR (300 MHz, [D4]methanol): δ = 0.39 (d, J = 6.7 Hz, 6 H,
8-H), 0.97 (d, J = 6.7 Hz, 6 H, 8-HЈ), 2.55 (septet, J = 6.7 Hz, 2
H, 7-H), 5.97 (s, 2 H, 2-H), 7.24 (dd, J = 6.0, J = 3.4 Hz, 2 H, 3-
H), 7.58 (dd, J = 5.9, J = 3.4 Hz, 2 H, 2-H) ppm, -COOH not
detected. 13C NMR (75 MHz, [D4]methanol): δ = 17.8, 19.1 (q, C-
8 and C-8Ј), 37.9 (d, C-7), 53.6 (s, C-1), 125.4, 126.8, 127.3 (d, C-
trans-1,4-Dioctyl-1,4-dihydronaphthalene-1,4-dicarboxylic
Acid
(16e): White solid (5%); m.p. 169–171 °C. Rf = 0.46 (dichlorometh-
1
ane/methanol = 100:1). H NMR (300 MHz, CDCl3): δ = 0.86 (t,
J = 6.8 Hz, 6 H, 14-H), 1.03–1.33 (m, 24 H, 8-H–13-H), 2.00 (dt,
J = 13.1, J = 3.8 Hz, 2 H, 7-Ha), 2.33 (dt, J = 12.3, J = 4.1 Hz, 2
H, 7-Hb), 5.91 (s, 2 H, 2-H), 7.29 (dd, J = 5.9, J = 3.4 Hz, 2 H, 3-
H), 7.41 (dd, J = 5.9, J = 3.4 Hz, 2 H, 4-H), 10.22 (br. s, 2 H,
-COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2 (q, C-14),
22.7, 24.8, 29.3, 29.5, 30.0, 32.0 (t, C-13–C-8), 38.2 (t, C-7), 51.5
(s, C-1), 127.3, 128.4, 130.2 (d, C-2–C-4), 134.3 (s, C-5), 178.5 (s,
C-6) ppm. IR (chloroform): ν = 2922, 2854, 2630, 1693, 1489, 1466,
˜
1445, 1403, 1270, 936 cm–1. C28H46O4 (446.67): calcd. C 75.98, H
9.56; found C 75.85, H 9.23.
cis-1-Octyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (17e):
White solid (91%). Rf = 0.41 (dichloromethane/methanol = 100:1).
1H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3 H, 20-H),
0.98–1.38 (m, 12 H, 14–18-H), 1.96–2.08 (m, 2 H, 13-H), 4.49 (d,
J = 4.5 Hz, 1 H, 4-H), 5.91 (d, J = 10.0 Hz, 1 H, 2-H), 6.18 (dd, J
= 10.0, J = 4.5 Hz, 1 H, 3-H), 7.20–7.48 (m, 4 H, 5-H–8-H), 10.94
(br. s, 2 H, -COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1
(q, C-20), 22.7, 24.1, 29.2, 29.3, 29.8, 31.8 (t, C-19–C-14), 38.2 (t,
C-13), 46.8 (d, C-4), 51.3 (s, C-1), 124.2, 127.4, 127.8, 128.3, 128.9,
131.4 (d, C-2, C-3, C-5–C-8), 131.0, 134.1 (s, C-9 and C-10), 177.3,
2–C-4), 136.4 (s, C-5), 175.7 (s, C-6) ppm. IR (methanol): ν = 2966,
˜
2875, 2622, 1692, 1489, 1466, 1389, 1261, 1215, 1007, 928 cm–1.
HRMS: calcd. for C24H34O4 [M]+ 386.2457; found 386.2446.
1-Isopropyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (17c):
White solid (9%). Rf = 0.26 (dichloromethane/methanol = 100:1).
1H NMR (300 MHz, [D4]methanol, cis and trans isomers overlap-
ping): δ = 0.49 (d, J = 6.9 Hz, 3 H, 14-H), 1.13 (d, J = 6.9 Hz, 3
H, 14Ј-H), 2.85 (septet, J = 6.9 Hz, 1 H, 13-H), 4.41 (d, J = 3.9 Hz,
1 H, 4-H), 6.05 (d, J = 10.0 Hz, 1 H, 2-H), 6.26 (dd, J = 10.0, J =
3.9 Hz, 1 H, 3-H), 7.18–7.36 (m, 4 H, 5–8 H) ppm, -COOH not 178.6 (s, C-11 and C-12) ppm. IR (methanol): ν = 2951, 2922, 2853,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20823
/KAP1
Date: 15-08-12 15:31:47
Pages: 13
A. Bramborg, T. Linker
FULL PAPER
2620, 1688, 1493, 1466, 1398, 1247, 1214, 940 cm–1. HRMS: calcd.
46.9 (d, C-4), 50.9 (s, C-1), 60.4 (t, C-17), 124.8, 127.0, 127.9, 128.3,
128.8, 130.9 (d, C-2, C-3, C-5–C-8), 131.0, 133.5 (s, C-9 and C-10),
173.4, 177.7, 178.8 (s, C-11, C-12 and C-16) ppm. IR (methanol):
for C20H26O4 [M]+ 330.1831; found 330.1828.
cis-1-Benzyl-1,4-dihydronaphthalene-1,4-dicarboxylic Acid (17f):
White solid (80%); m.p. 156–158 °C. Rf = 0.35 (dichloromethane/
ν = 2941, 1704, 1490, 1446, 1374, 1263, 1197, 1104, 1022, 911,
˜
761 cm–1. C18H20O6 (332.35): calcd. C 65.05, H 6.07; found C
64.99, H 5.98.
1
methanol = 100:1). H NMR (300 MHz, [D4]methanol): δ = 3.31
(d, J = 13.9 Hz, 1 H, 12-Ha), 3.50 (d, J = 13.9 Hz, 1 H, 12-Hb),
4.40 (d, J = 4.1 Hz, 1 H, 4-H), 5.76 (d, J = 10.1 Hz, 1 H, 2-H),
5.84 (dd, J = 10.1, J = 4.1 Hz, 1 H, 3-H), 7.13–7.30 (m, 9 H, 5-H–
8-H and 14–16-H) ppm, -COOH not detected. 13C NMR (75 MHz,
[D4]methanol): δ = 43.9 (t, C-12), 49.6 (d, C-4), 49.8 (s, C-1), 124.8,
127.5, 127.8, 128.6, 128.8, 128.9, 129.8, 130.1, 131.4 (d, C-2, C-3,
C-5–C-8, C-14–C-16), 130.7, 135.1 (s, C-9 and C-10), 177.0, 177.9
cis-1-(3-Cyanopropyl)-1,4-dihydronaphthalene-1,4-dicarboxylic Acid
(17i): White solid (87%); m.p. 268–270 °C. Rf = 0.32 (dichloro-
methane/methanol = 100:1). 1H NMR (300 MHz, CDCl3): δ =
0.98–1.12 (m, 1 H, 14-Ha), 1.32–1.49 (m, 1 H, 14-Hb), 2.11 (t, J =
13.0 Hz, 1 H, 13-Ha), 2.22 (t, J = 7.1 Hz, 2 H, 15-H), 2.36 (t, J =
13.0 Hz, 1 H, 13-Hb), 4.51 (d, J = 4.5 Hz, 1 H, 4-H), 5.87 (d, J =
10.1 Hz, 1 H, 2-H), 6.22 (dd, J = 10.1, J = 4.5 Hz, 1 H, 3-H), 7.23–
7.47 (m, 4 H, 5-H–8-H), 11.09 (br. s, 2 H, -COOH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.0, 20.4 (t, C-14 and C-15), 36.9 (t, C-13),
46.3 (d, C-4), 50.7 (s, C-1), 119.2 (s, C-16), 125.1, 126.9, 128.2,
128.6, 129.1, 130.0 (d, C-2, C-3, C-5–C-8), 130.6, 132.9 (s, C-9 and
(s, C-11 and C-12) ppm. IR (chloroform): ν = 3028, 2963, 2933,
˜
2865, 2601, 1693, 1485, 1454, 1378, 1251, 1013 cm–1. C19H16O4
(308.33): calcd. C 74.01, H 5.23; found C 73.83, H 5.09.
1,4-(4-Chlorbutyl)-1,4-dihydronaphthalene-1,4-dicarboxylic
Acid
(16g): White solid (63%). Rf = 0.36 (dichloromethane/methanol =
100:1). 1H NMR (300 MHz, [D4]methanol, cis and trans isomers
overlapping): δ = 0.84–1.01, 1.20–1.42, 1.60–1.82 (m, 8 H, 8- and
9-H), 2.05 (dt, J = 13.2, J = 4.2 Hz, 2 H, 7-Ha), 2.38 (dt, J = 13.2,
J = 4.2 Hz, 2 H, 7-Hb), 3.40–3.51 (m, 4 H, 10-H), 5.96 (s, 2 H, 2-
H), 7.32 (dd, J = 5.8, J = 3.4 Hz, 2 H, 3-H), 7.42 (dd, J = 5.8, J
= 3.4 Hz, 2 H, 4-H), 9.37 (br. s, 2 H, -COOH) ppm. trans isomer:
13C NMR (75 MHz, [D4]methanol): δ = 22.2 (t, C-8), 32.6, 37.3 (t,
C-7 and C-9), 44.8 (t, C-10), 51.2 (s, C-1), 127.2, 128.7, 130.2 (d,
C-2–C-4), 133.9 (s, C-5), 178.0 (s, C-6) ppm. cis isomer: 13C NMR
(75 MHz, [D4]methanol): δ = 22.1 (t, C-8), 32.8, 38.9 (t, C-7 and
C-9), 44.7 (t, C-10), 50.9 (s, C-1), 127.0, 128.3, 129.7 (d, C-2–C-4),
C-10), 176.9, 177.4 (s, C-11 and C-12) ppm. IR (methanol): ν =
˜
2948, 2250, 1701, 1489, 1147, 1422, 1266, 1203, 1020, 910,
857 cm–1. C16H15NO4 (285.30): calcd. C 67.36, H 5.30, N 4.91;
found C 67.12, H 5.06, N 4.80.
General Procedure for the Rearomatization of 1,4-Dihydronaphth-
alenedicarboxylic Acids 16: Dihydronaphthalene 16 (1.0 mmol) was
added to a solution of chlorosulfonic acid (5 mL, 1 m in chloro-
form) at 0 °C. After 1–2 min, the reaction mixture was poured into
saturated sodium carbonate solution (5 mL). After separation of
the organic layer, the aqueous phase was xtracted with chloroform
(3ϫ5 mL) and the combined organic phases were dried with
MgSO4. After removal of the solvents, arenes 21 were purified by
column chromatography (hexane).
134.5 (s, C-5), 179.9 (s, C-6) ppm. IR (methanol): ν = 3035, 2939,
˜
2869, 2612, 1936, 1697, 1489, 1447, 1371, 1279, 1199, 1022, 928,
872 cm–1. C20H24Cl2O4 (399.31): calcd. C 60.16, H 6.06; found C
59.98, H 5.94.
1,4-Dimethylnaphthalene (21a):[23] Colorless liquid (85%). n2D0
=
1.6135 (lit. n2D0 = 1.6132). Rf = 0.41 (hexane). 1H NMR (300 MHz,
CDCl3): δ = 2.64 (s, 6 H, CH3), 7.18 (s, 2 H, Ar-H), 7.45 (dd, J =
6.5, J = 3.3 Hz, 2 H, Ar-H), 7.97 (dd, J = 6.5, J = 3.3 Hz, 2 H,
Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.3 (q, CH3), 124.6,
125.3, 126.2 (d, C-Ar), 132.2, 138.8 (s, C-Ar) ppm.
1-(4-Chlorbutyl)-1,4-dihydronaphthalene-1,4-dicarboxylic
Acid
(17g): White solid (27%). Rf = 0.31 (dichloromethane/methanol =
100:1). 1H NMR (300 MHz, CDCl3, cis and trans isomers overlap-
ping): δ = 0.72–0.92, 1.10–1.31, 1.59–1.77 (m, 4 H, 14- and 15-H),
1.99 (dt, J = 13.2, J = 4.1 Hz, 1 H, 13-Ha), 2.45 (dt, J = 13.2, J =
4.1 Hz, 1 H, 13-Hb), 3.37–3.48 (m, 2 H, 16-H), 4.50 (d, J = 4.7 Hz,
1 H, 4-H), 5.80 (d, J = 10.0 Hz, 1 H, 2-H), 6.19 (dd, J = 10.0, J =
4.7 Hz, 1 H, 3-H), 7.15–7.40 (m, 4 H, 5-H–8-H), 8.75 (br. s, 2 H, -
COOH) ppm. trans isomer: 13C NMR (75 MHz, [D4]methanol): δ
= 21.4 (t, C-14), 32.6, 36.7 (t, C-13 and C-15), 44.5 (t, C-16), 49.3
(d, C-4), 52.1 (s, C-1), 125.4, 126.3, 127.4, 127.6, 128.1, 130.6 (d,
C-2, C-3, C-5–C-8), 132.6, 134.3 (s, s, C-9 and C-10), 176.2, 176.8
(s, C-11 and C-12) ppm. cis isomer: 13C NMR (75 MHz, [D4]meth-
anol): δ = 21.6 (t, C-14), 32.7, 36.3 (t, C-13 and C-15), 44.8 (t, C-
16), 49.3 (d, C-4), 53.4 (s, C-1), 125.7, 126.7, 127.3, 127.5, 128.6,
130.2 (d, C-2, C-3, C-5–C-8), 132.6, 134.2 (s, C-9 and C-10), 176.5,
1,4-Diethylnaphthalene (21b):[24] Colorless liquid (86%). n2D0
=
1.5951 (lit. n1D3.1 = 1.597). Rf = 0.43 (hexane). 1H NMR (300 MHz,
CDCl3): δ = 1.53 (t, J = 7.5 Hz, 6 H, CH3), 3.24 (q, J = 7.5 Hz, 4
H, CH2), 7.42 (s, 2 H, Ar-H), 7.65 (dd, J = 6.5, J = 3.3 Hz, 2 H,
Ar-H), 8.23 (dd, J = 6.5, J = 3.3 Hz, 2 H, Ar-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.31 (q, CH3), 26.1 (t, CH2), 124.7, 124.9,
125.4 (d, C-Ar), 132.4, 138.5 (s, C-Ar) ppm.
1,4-Dihexylnaphthalene (21d):[13d] Colorless liquid (91%). Rf = 0.56
1
(hexane). H NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 6.5 Hz, 6
H, CH3), 1.35–1.52 (m, 12 H, CH2), 1.79 (quint, J = 7.7 Hz, 4 H,
CH2), 3.08 (t, J = 7.5 Hz, 4 H, CH2), 7.28 (s, 2 H, Ar-H), 7.53 (dd,
J = 6.5, J = 3.3 Hz, 2 H, Ar-H), 8.11 (dd, J = 6.5, J = 3.3 Hz, 2
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3 (q, CH3),
22.9, 29.7, 31.0, 32.0, 33.2 (t, CH2), 124.7, 125.2, 125.7 (d, C-Ar),
132.4, 137.2 (s, C-Ar) ppm.
177.0 (s, C-11 and C-12) ppm. IR (methanol): ν = 3035, 2939, 2869,
˜
2612, 1936, 1697, 1489, 1447, 1371, 1279, 1199, 1022, 928,
872 cm–1. HRMS: calcd. for C16H17ClO4 [M]+ 308.0815; found
308.0809.
1,4-Dioctylnaphthalene (21e): Colorless liquid (90%). Rf = 0.59
1
cis-1-(4-Ethoxy-4-oxobutyl)-1,4-dihydronaphthalene-1,4-dicarb- (hexane). H NMR (300 MHz, CDCl3): δ = 0.97 (t, J = 7.0 Hz, 6
oxylic Acid (17h): White solid (91%); m.p. 249–252 °C. Rf = 0.39
H, CH3), 1.20–1.61 (m, 20 H, CH2), 1.82 (quint, J = 7.5 Hz, 4 H,
CH2), 3.08 (t, J = 7.8 Hz, 4 H, CH3), 7.30 (s, 2 H, Ar-H), 7.55 (dd,
(dichloromethane/methanol = 100:1). 1H NMR (300 MHz, [D4]-
methanol): δ = 1.18 (t, J = 7.1 Hz, 3 H, 18-H), 0.95–1.09 and 1.28– J = 6.5, J = 3.3 Hz, 2 H, Ar-H), 8.14 (dd, J = 6.5, J = 3.3 Hz, 2
1.43 (m, 2 H, 14-H), 1.99 and 2.39 (dt, J = 13.1, J = 4.5 Hz, 2 H,
13-H), 2.20 (t, J = 7.4 Hz, 2 H, 15-H), 4.04 (q, J = 7.1 Hz, 2 H,
17-H), 4.48 (d, J = 4.5 Hz, 1 H, 4-H), 5.88 (d, J = 10.0 Hz, 1 H,
2-H), 6.19 (dd, J = 10.0, J = 4.5 Hz, 1 H, 3-H), 7.19–7.43 (m, 4 H,
5-H–8-H), 11.18 (br. s, 2 H, -COOH) ppm. 13C NMR (75 MHz,
[D4]methanol): δ = 14.1 (q, C-18), 19.6, 30.1, 34.3 (t, C-13–C-15),
H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2 (q, CH3),
22.8, 29.5, 29.7, 30.1, 31.1, 32.1, 33.3 (t, CH2), 124.7, 125.2, 125.7
(d, C-Ar), 132.4, 137.2 (s, C-Ar) ppm. IR (chloroform): ν = 3085,
˜
2941, 2870, 1868, 1599, 1525, 1463, 1399, 1314, 1178, 1028, 987,
835, 801 cm–1. C26H40 (352.60): calcd. C 88.57, H 11.43; found C
88.25, H 11.31.
10
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Pages: 13
Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
1,4-Bis(4-chlorbutyl)naphthalene (21g): Colorless liquid (89%). Rf
= 0.40 (hexane). H NMR (300 MHz, CDCl3): δ = 1.88–1.96 (m,
1432, 1272, 1249, 1201, 1136, 918 cm–1. C17H20O2 (256.34): calcd.
C 79.65, H 7.86; found C 79.23, H 7.37.
1
8 H, 8- and 9-H), 3.10 (t, J = 7.3 Hz, 4 H, 7-H), 3.60 (t, J = 6.2 Hz,
4 H, 10-H), 7.26 (s, 2 H, 2-H), 7.54 (dd, J = 6.5, J = 3.3 Hz, 2 H,
3-H), 8.08 (dd, J = 6.5, J = 3.3 Hz, 2 H, 4-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.1, 32.4, 32.7 (t, C-7–C-9), 45.0 (t, C-10),
124.6, 125.5, 125.8 (d, C-2–C-4), 132.3, 136.5 (s, C-1 and C-5) ppm.
4-Octyl-1-naphthalenecarboxylic Acid (22e): White solid (86%);
m.p. 129–131 °C. Rf = 0.15 (dichloromethane/methanol = 100:1).
1H NMR (300 MHz, CDCl3): δ = 0.75 (t, J = 6.8 Hz, 3 H, CH3),
1.05–1.36 (m, 10 H, CH2), 1.62 (quint, J = 7.6 Hz, 2 H, CH2), 2.98
(t, J = 7.6 Hz, 2 H, CH2), 7.22 (d, J = 7.4 Hz, 1 H, Ar-H), 7.36–
7.51 (m, 2 H, Ar-H), 7.97 (d, J = 8.0 Hz, 1 H, Ar-H), 8.01 (d, J =
7.4 Hz, 1 H, Ar-H), 8.87 (d, J = 8.2 Hz, 1 H, Ar-H) ppm, -COOH
not detected. 13C NMR (75 MHz, CDCl3): δ = 14.0 (q, CH3), 22.7,
29.3, 29.5, 29.8, 30.7, 31.9, 33.6 (t, CH2), 124.3, 124.8, 125.9, 126.7,
127.1, 130.8 (d, C-Ar), 126.6, 132.0, 132.3, 145.4 (s, C-Ar), 170.8
IR (chloroform): ν = 3071, 2938, 2865, 1877, 1595, 1516, 1461,
˜
1392, 1309, 1163, 1031, 980, 839, 814 cm–1. C18H22Cl2 (309.28):
calcd. C 69.90, H 7.17; found C 69.57, H 7.338.
General Procedure for the Rearomatization of 1,4-Dihydronaphth-
alenedicarboxylic Acids 17: Dihydronaphthalene 17 (1.0 mmol) was
added to a solution of chlorosulfonic acid (5 mL, 1 m in chloro-
form) at 0 °C. After 1–2 min, the reaction mixture was poured into
ice-cold water (10 mL). After separation of the organic layer, the
aqueous phase was extracted with chloroform (3ϫ5 mL), and the
combined organic phases were dried with MgSO4. After removal
of the solvents, arenes 22 were purified by column chromatography
(dichloromethane/methanol).
(s, C-11) ppm. IR (methanol): ν = 3013, 2929, 1682, 1463, 1408,
˜
1280, 1249, 1017 cm–1. C19H34O2 (294.48): calcd. C 80.24, H 8.51;
found C 80.16, H 8.296.
4-Benzyl-1-naphthalenecarboxylic Acid (22f): White solid (81%);
1
m.p. 135–138 °C. Rf = 0.85 (dichloromethane/methanol = 5:1). H
NMR (300 MHz, [D4]methanol): δ = 4.47 (s, 2 H, CH2), 7.11–7.29
(m, 5 H, Ar-H), 7.33 (d, J = 7.5 Hz, 1 H, Ar-H), 7.44–7.54 (m, 2
H, Ar-H), 8.07 (d, J = 8.7 Hz, 1 H, Ar-H), 8.12 (d, J = 7.5 Hz, 1
H, Ar-H), 8.93 (d, J = 8.7 Hz, 1 H, Ar-H) ppm, -COOH not de-
4-Methyl-1-naphthalenecarboxylic Acid (22a):[25] Colorless crystals
(91%); m.p. 178–181 °C (lit; m.p. 179–181 °C). Rf = 0.36 (dichloro-
1
methane/methanol = 10:1). H NMR (300 MHz, CDCl3): δ = 2.72 tected. 13C NMR (75 MHz, [D4]methanol): δ = 40.0 (t, CH2),
(s, 3 H, CH3), 7.41 (d, J = 7.4 Hz, 1 H, Ar-H), 7.51–7.65 (m, 2 H, 125.5, 126.8, 126.9, 127.2, 127.7, 129.2, 129.4, 130.6, 130.7 (d, C-
Ar-H), 8.03 (d, J = 8.2 Hz, 1 H, Ar-H), 8.19 (d, J = 7.4 Hz, 1 H,
Ar-H), 9.05 (d, J = 8.2 Hz, 1 H, Ar-H) ppm, -COOH not detected.
13C NMR (75 MHz, CDCl3): δ = 20.1 (q, CH3), 124.5, 125.6, 126.1,
126.5, 127.4, 131.1 (d, C-Ar), 128.2, 131.7, 133.0, 141.0 (s, C-Ar),
171.2 (s, C-11) ppm.
Ar), 127.6, 130.8, 132.7, 133.4, 143.2 (s, C-Ar), 172.0 (s, C-11) ppm.
IR (methanol): ν = 3035, 3011, 2921, 1695, 1468, 1480, 1312, 1265,
˜
1258, 1023, 998 cm–1. HRMS: calcd. for C18H14O2 [M]+ 262.0994;
found 262.0989.
4-(4-Chlorbutyl)-1-naphthalenecarboxylic Acid (22g): White solid
(92%); m.p. 158–161 °C. Rf = 0.56 (dichloromethane/methanol =
10:1). 1H NMR (300 MHz, CDCl3): δ = 1.85–1.96 (m, 4 H, 13-
4-Ethyl-1-naphthalenecarboxylic Acid (22b):[26] Colorless crystals
(86%); m.p. 123–126 °C (lit; m.p. 125–127 °C). Rf = 0.42 (dichloro-
1
methane/methanol = 10:1). H NMR (300 MHz, CDCl3): δ = 1.41 and 14-H), 3.12 (t, J = 7.1 Hz, 2 H, 12-H), 3.57 (t, J = 6.1 Hz, 2
(d, J = 7.5 Hz, 6 H, CH3), 3.85 (q, J = 7.5 Hz, 1 H, CH2), 7.41 (d, H, 15-H), 7.34 (d, J = 7.5 Hz, 1 H, Ar-H), 7.53–7.66 (m, 2 H, Ar-
J = 7.5 Hz, 1 H, Ar-H), 7.55–7.69 (m, 2 H, Ar-H), 8.14 (d, J = H), 8.08 (d, J = 8.4 Hz, 1 H, Ar-H), 8.11 (d, J = 7.5 Hz, 1 H, Ar-
8.6 Hz, 1 H, Ar-H), 8.33 (d, J = 7.5 Hz, 1 H, Ar-H), 9.16 (d, J =
H), 9.00 (d, J = 8.2 Hz, 1 H, Ar-H) ppm, -COOH not detected.
8.3 Hz, 1 H, Ar-H) ppm, -COOH not detected. 13C NMR 13C NMR (75 MHz, CDCl3): δ = 27.8, 32.5, 32.7 (t, C-12–C-14),
(75 MHz, CDCl3): δ = 14.8 (q, CH3), 26.6 (d, CH2), 123.9, 124.2, 44.7 (t, C-15), 124.0, 124.9, 126.2, 126.7, 127.2, 129.8 (d, C-Ar),
126.2, 126.8, 127.5, 131.7 (d, C-Ar), 125.0, 132.1, 132.3, 147.3 (s,
C-Ar), 172.5 (s, C-11) ppm.
4-Isopropyl-1-naphthalenecarboxylic Acid (22c):[27] Colorless crys-
tals (90%); m.p. 150–152 °C (lit; m.p. 153–153.5 °C). Rf = 0.21
(dichloromethane/methanol = 50:1). 1H NMR (300 MHz, CDCl3):
126.3, 131.9, 132.2, 143.6 (s, C-Ar), 167.7 (s, C-11) ppm. IR (chlo-
roform): ν = 3029, 2966, 1723, 1675, 1579, 1458, 1426, 1365, 1346,
˜
1264, 1166, 1089, 1012, 907 cm–1. C15H15ClO2 (262.74): calcd. C
68.57, H 5.75; found C 68.42, H 5.793.
4-(4-Ethoxy-4-oxobutyl)-1-naphthalenecarboxylic Acid (22h): White
δ = 1.45 (d, J = 6.8 Hz, 6 H, CH3), 3.85 (septet, J = 6.8 Hz, 1 H, solid (89%); m.p. 97–101 °C. Rf = 0.18 (dichloromethane/methanol
CH), 7.52 (d, J = 7.8 Hz, 1 H, Ar-H), 8.06–8.21 (m, 2 H, Ar-H), = 50:1). 1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.4 Hz, 3
8.25 (d, J = 9.1 Hz, 1 H, Ar-H), 8.41 (d, J = 7.7 Hz, 1 H, Ar-H),
H, 17-H), 2.05–2.18 (m, 2 H, 13-H), 2.44 (t, J = 7.2 Hz, 2 H, 14-
9.20 (d, J = 8.2 Hz, 1 H, Ar-H), 12.38 (br. s, 1 H, -COOH) ppm. H), 3.20 (t, J = 7.4 Hz, 2 H, 12-H), 4.17 (q, J = 7.4 Hz, 2 H, 16-
13C NMR (75 MHz, CDCl3): δ = 23.5 (q, CH3), 29.3 (d, CH), H), 7.41 (d, J = 7.5 Hz, 1 H, Ar-H), 7.57–7.69 (m, 2 H, Ar-H),
121.0, 123.8, 126.2, 126.9, 127.4, 132.0 (d, C-Ar), 124.0, 132.2,
132.3, 152.0 (s, C-Ar), 173.5 (s, C-11) ppm. IR (dichloromethane):
8.17 (d, J = 8.0 Hz, 1 H, Ar-H), 8.33 (d, J = 7.5 Hz, 1 H, Ar-H),
9.15 (d, J = 8.2 Hz, 1 H, Ar-H), 11.46 (br. s, 1 H, -COOH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.4 (q, C-17), 25.8 (t, C-13),
33.1 (t, C-12), 34.1 (t, C-14), 60.6 (t, C-16), 124.4, 125.3, 126.5,
126.8, 127.8, 131.7 (d, C-Ar), 124.5, 132.2, 132.4, 145.0 (s, C-Ar),
ν = 3060, 2965, 2629, 1678, 1580, 1518, 1462, 1432, 1410, 1385,
˜
1365, 1277, 1251, 1149, 1063, 1042, 1021, 924, 850, 775 cm–1.
C14H14O2 (214.26): calcd. C 78.48, H 6.59; found C 78.18, H 6.65.
173.0, 173.4 (s, C-11 and C-15) ppm. IR (dichloromethane): ν =
˜
4-Hexyl-1-naphthalenecarboxylic Acid (22d): White solid (85%);
m.p. 149–151 °C. Rf = 0.08 (dichloromethane/methanol = 100:1).
1H NMR (300 MHz, CDCl3): δ = 0.77 (t, J = 6.8 Hz, 3 H, CH3),
1.11–1.33 (m, 6 H, CH2), 1.57 (quint, J = 7.5 Hz, 2 H, CH2), 2.98
3025, 2956, 1727, 1687, 1590, 1463, 1426, 1412, 1374, 1339, 1321,
1264, 1248, 1166, 1075, 1025, 908, 870, 790 cm–1. C17H18O4
(286.33): calcd. C 71.31, H 6.34; found C 71.22, H 6.214.
(t, J = 7.5 Hz, 2 H, CH2), 7.34 (d, J = 7.5 Hz, 1 H, Ar-H), 7.50– 4-(3-Cyanopropyl)-1-naphthalenecarboxylic Acid (22i): White solid
7.62 (m, 2 H, Ar-H), 8.04 (d, J = 7.5 Hz, 1 H, Ar-H), 8.07 (d, J =
8.3 Hz, 1 H, Ar-H), 8.92 (d, J = 7.8 Hz, 1 H, Ar-H) ppm, -COOH
not detected. 13C NMR (75 MHz, CDCl3): δ = 14.5 (q, CH3), 22.7,
29.3, 30.9, 31.7, 33.3 (t, CH2), 124.8, 125.5, 126.2, 126.7, 126.8,
127.6, 130.2 (d, C-Ar), 126.6, 131.8, 132.3, 144.7 (s, C-Ar), 169.4
(85%); m.p. 191–194 °C. Rf = 0.15 (dichloromethane/methanol =
50:1). H NMR (300 MHz, CDCl3): δ = 1.86 (quint, J = 7.4 Hz, 2
H, 13-H), 2.21 (t, J = 7.0 Hz, 2 H, 14-H), 3.05 (t, J = 7.6 Hz, 2 H,
12-H), 7.15 (d, J = 7.4 Hz, 1 H, Ar-H), 7.31–7.38 (m, 2 H, Ar-H),
7.83 (d, J = 9.6 Hz, 1 H, Ar-H), 7.89 (d, J = 7.4 Hz, 1 H, Ar-H),
8.73 (d, J = 9.6 Hz, 1 H, Ar-H) ppm, -COOH not detected. 13C
1
(s, C-11) ppm. IR (methanol): ν = 2950, 1672, 1587, 1517, 1461,
˜
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Pages: 13
A. Bramborg, T. Linker
FULL PAPER
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˜
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Received: June 20, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20823
/KAP1
Date: 15-08-12 15:31:47
Pages: 13
Two-Step ipso-Substitution of Aromatic Dicarboxylic Acids
Synthesis of Alkylarenes
A. Bramborg, T. Linker* ................. 1–13
Regioselective Synthesis of Alkylarenes by
Two-Step ipso-Substitution of Aromatic
Dicarboxylic Acids
The transformation from acid to alkyl
groups is the result of a simple two-step se-
quence that allows the regioselective syn-
thesis of substituted benzenes and naphth-
alenes 4 or 5 from inexpensive terephthalic
acid or naphthalene-1,4-dicarboxylic acid
1 in high yields. The formation of inter-
mediates 2 and 3 is interesting in the con-
text of the mechanism of the Birch re-
duction, and the rearomatizations proceed
by different reaction pathways.
Keywords: Synthetic methods / Alkylation /
Birch reduction / Arenes / Regioselectivity
Eur. J. Org. Chem. 0000, 0–0
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