Regioselective threefold aromatic substitution of benzoic acid derivatives by dearomatization, regioselective functionalization, and rearomatization

Article abstract of DOI:10.1002/anie.201300259

Ipso, meta, and para: Benzoic acid derivatives can be highly regioselectively substituted at the ipso, meta, and para positions. The reaction sequence comprises an alkylative Birch reduction, a 4-alkylation, a palladium-catalyzed γ-arylation, and an oxidative rearomatization (see scheme). All the reactions are robust and experimentally easy to conduct. Copyright

Full text of DOI:10.1002/anie.201300259

Angewandte
Chemie
DOI: 10.1002/anie.201300259
Arene Functionalization
Regioselective Threefold Aromatic Substitution of Benzoic Acid
Derivatives by Dearomatization, Regioselective Functionalization, and
Rearomatization**
Eva Koch and Armido Studer*
Substituted arenes are ubiquitous and important in various
fields of modern science. They occur in natural products, in
drugs, in agrochemicals, as ligands in catalysis, in biology, and
in materials science. Despite the high efficiency of the
classical functionalization methods, such as electrophilic,
nucleophilic, and homolytic aromatic substitution, develop-
ment of novel processes for regioselective functionalization of
arenes is still of importance.[1] Transition-metal-mediated
couplings have become highly valuable and recent research in
ꢀ
this area has focused on the direct C H functionalization of
arenes and heteroarenes.[1,2] In many of these transformations
a heteroatom or a functional group is necessary to direct the
reaction towards a regioselective ortho functionalization.[2]
More recently, reports have appeared on arene functionali-
zation in meta position of a directing group[3] and even a few
reports on the para arylation have been disclosed.[4] An
alternative elegant approach for arene functionalization was
introduced by Linker and co-workers (Scheme 1).[5] Benzoic
acid derivatives were regioselectively ipso-alkylated by alky-
lative Birch reduction and subsequent decarbonylative rear-
omatization to eventually afford the corresponding ipso-
substituted arene.
Scheme 1. Functionalization of benzoic acid derivatives by the Birch
reaction, chemical modification, and rearomatization.
More recently, Clive and Sunasee extended that concept
and developed a reaction sequence which allows for ipso,
para-disubstitution of benzoic acids.[6] Herein we show that
the dearomatization/rearomatization approach can be
applied to the highly regioselective threefold aromatic sub-
stitution of the ipso, meta, and para position in various
benzoic acid derivatives. By this route, highly substituted
arenes are readily available.
We first tested our approach for ipso/meta disubstitution
of benzoic acid derivatives. To this end, we prepared cyclo-
hexadiene carboxylic acid 1a by the established alkylative
Birch reaction using NH3, Li, and iPrI.[7] Functionalization of
the 3-position was achieved by a palladium-catalyzed decar-
boxylative g-arylation recently introduced by us.[8,9] Under
slightly modified conditions, cyclohexadiene 2a was isolated
in 84% yield (Scheme 2). Quantitative oxidative rearomati-
[*] E. Koch, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149, Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
Scheme 2. Preparation of various 1,3-disubstituted arenes.
zation to 3a was achieved with DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, 1.1–1.5 equiv) in toluene at room
temperature.[10] We found that the 3-arylation and oxidation
are most conveniently conducted as a one-pot process by
[**] We thank the Fonds der Chemischen Industrie for support (stipend
to E. K.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300259.
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directly adding DDQ to the reaction mixture and 3a was
isolated in 91% overall yield. Various 1,3-disubstituted arenes
3b–e were successfully prepared in good to excellent yields
from 1a by this method. However, in some cases the DDQ-
mediated oxidation was not a clean reaction and rearomati-
zation was better conducted with the TEMPO+ BF4ꢀ salt[11] in
CH2Cl2. Starting the sequence with substituted benzoic acid
derivatives or with 1-naphthalene carbocylic acid, arenes 3 f–
h were obtained (75–95% overall yield for the arylation and
rearomatization steps).
storable Birch products represents a very robust convenient
route for arene-library synthesis for which the intermediates
of type 2 and 4 do not have to be purified. Yields given in
Scheme 3 and 4 correspond to yields of isolated products over
three steps starting with Birch products of type 1.
To document the scope with respect to the aryl substituent
we investigated the sequence using cyclohexadiene acid 1 f,
Me2SO4 for the 4-alkylation, and various aryl iodides to give
the tetrasubstituted arenes 5a–m (Scheme 3). These multistep
We then studied the diastereoselective 4-alkylation of 1-
substituted cyclohexa-2,5-diene-1-carboxylic acids of type 1.
The reaction was optimized on diene 1 f (R1 = H, R2 = CH3,
R3 = iPr, Table 1).[12] The challenge was to find a method
Table 1: Diastereoselective 4-alkylation of acids 1b,c,f–h.
Entry
R1
R2
R3
R4
Product
Yield [%]
1
2
3
4
5
6
7
8
9
H
H
CH3
H
H
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
H
iPr
iPr
iPr
iPr
iPr
iPr
CH3
iPr
iPr
CH3
CH2CH3
CH3
iPr
Bn
Bn
CH3
CH3
CH3
4a
4b
4c
4d
4e
4 f
4g
4h
4i
95
74
76
55
84
70
90
95
95
H
CH3
Scheme 3. Transformation of 1 f to arenes 5a–m.
-C4H4-
which allows for highly regioselective alkylation at the 4-
position of the 2,5-diene. Moreover, alkylation had to be
highly trans-diastereoselective because palladium-catalyzed
decarboxylative g-arylation does not work well on cis-4-alkyl-
cyclohexa-2,5-diene-1-carboxylic acids.[13] Deprotonation was
best conducted with nBuLi (2.2 equiv) in THF at ꢀ788C in
the presence of tetramethylethylenediamine (TMEDA;
2.2 equiv). Alkylation with soft electrophiles, such as MeI
provided 4a in a low yield, because of competing single-
electron transfer from the lithiated cyclohexadiene to MeI.
However, methylation with Me2SO4 gave 4a as a single
diastereoisomer[14] in 95% yield (Table 1, entry 1). Other hard
electrophiles, such as Et2SO4, iPrBr, and BnCl also provided
good yields in the alkylation of 1 f (4b, 4d, 4e; entries 2, 4,
and 5). Using the robust Birch chemistry other substrates of
type 1 were prepared and subjected to the 4-alkylation to give
4c, 4 f–i (entries 3, 6–9). In all cases, reaction occurred with
complete stereocontrol.
We tested the threefold arene substitution in a reaction
sequence consisting of alkylative Birch reaction, 4-alkylation,
decarboxylative g-arylation, and DDQ-mediated rearomati-
zation on various aromatic carboxylic acids. The Birch
products were purified, but intermediates of type 4 obtained
after the 4-alkylation were not purified and the g-arylation/
dearomatization was performed as a one-pot process accord-
ing to Scheme 2. Hence, the sequence starting with readily
transformations were generally conducted at the 0.3 mmol
scale. A larger scale experiment (2 mmol) for the synthesis of
5c showed a slightly lower but still good yield (65% versus
50%). Aryl iodides bearing electron-donating substituents at
the para position provided higher yields than those containing
electron-withdrawing groups. However, only small electronic
effects were noted for the meta-substituted systems (5g–i).
Pleasingly, the reaction sequence also worked well with more
bulky aryl iodides bearing ortho substituents. Even, ortho,or-
tho’-disubstituted aryl iodides afforded the targeted products
5l and 5m. However, for the bulkiest congener 5m a signifi-
cantly lower yield was obtained. We also varied the R1–R4
substituents using a-naphthyliodide as the aryl component
(Scheme 4). R1 and R2 substituents were readily varied by
choosing the appropriately substituted benzoic acid deriva-
tives for the initial Birch reaction. Variation of R3 and R4 was
achieved by varying the electrophile in the two alkylation
reactions. This sequence allowed differently substituted
arenes 5n–u to be prepared.[15] As shown for 5t, fivefold
substituted arenes are accessible. Steric demands of the R4
substituent influenced reaction outcome and yields decreased
in going from the methyl (see 5k in Scheme 3) to benzyl (5o),
ethyl (5n), isopropyl (5p). Derivatives with R1 ¼ Hwere
isolated in slightly lower yields (5r,s) and also substituted
naphthalenes, such as 5u, are available by this novel route
with complete regiocontrol.
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Scheme 4. Preparation of highly substituted arenes 5n–u.
In conclusion, we reported a novel method for the
preparation of highly substituted arenes[16] starting from
readily available benzoic acid derivatives. The sequence
consists of an alkylative Birch reduction, allylic cyclohexa-
diene alkylation, decarboxylative g-arylation, and rearomati-
zation. All the reactions used in this sequence are robust
transformations which are experimentally easy to conduct.
Experimental Section
General procedure for the stereoselective alkylation of 2,5-cyclo-
hexadiene-1-carboxylic acid derivatives, arylation by a palladium-
catalyzed decarboxylative coupling reaction, and oxidation.
n-Butyllithium (1.6m in n-hexane, 2.2 equiv) and TMEDA
(2.2 equiv) were added slowly at ꢀ788C to a solution of the
corresponding 2,5-cyclohexadiene-1-carboxylic acid in anhydrous
THF (0.3m) resulting in a yellow solution. After stirring for 30 min
the alkylation reagent (1.1–2.0 equiv) was added dropwise. If the
reaction mixture did not turn pale after 10 min, the mixture was
allowed to warm slowly to room temperature until the point of
discoloration. The discoloration temperature was maintained for
10 min before continuing warming to room temperature. The reaction
was stopped by adding aq. HCl (2m, 3 mL) and extracted with CH2Cl2
(3 ꢀ 10 mL). The combined organic layers were dried over MgSO4 and
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(1.1 equiv), Cs2CO3 (1.1 equiv), and [Pd(dba)2] (10 mol%) were
added. The resulting mixture was stirred under argon at 1108C for 17–
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was stirred for 1 h, the solids were removed by filtration, and the
solvent was removed from the filtrate under reduced pressure. The
crude mixture was purified by flash chromatography to afford the
desired arene.
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Received: January 11, 2013
Published online: March 26, 2013
ꢀ
Keywords: aromatic substitution · arylation · C C coupling ·
palladium · synthetic methods
.
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ꢀ
2,5-diene-1-carboxylic acid with p-tolyl I provided only 18% of
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Information).
[14] In the NMR spectrum of the crude product the other isomer was
not identified.
[15] The remaining position ortho to the aryl group cannot be
substituted by this chemistry since decarboxylative g-arylation of
2,6-disubstituted 1-alkylcyclohexa-2,5-diene-1-carboxylic acids
did not work.
[16] Alternative methods for preparation of highly substituted
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