Synthesis of Highly Substituted Arenes via Cyclohexadiene-Alkene C-H Cross Coupling and Aromatization

Article abstract of DOI:10.1021/acscatal.8b00083

The development of a cross-coupling method for the regioselective β-alkenylation of 2,5-cyclohexadiene carboxylic acid derivatives to form ortho-alkenylarenes through in situ decarboxylation and aromatization is described. The carboxylic acid functionality is used as a traceless directing group for efficient and mild β-alkenylation. The modular sequence comprises a reductive Birch α-alkylation, ionic ?-alkylation followed by a Pd-catalyzed decarboxylative β-alkenylation with subsequent aromatization resulting in an overall three-fold ipso-para-ortho functionalization of readily accessed benzoic acid derivatives. Efficient synthesis of various alkyl-alkenylarenes under mild conditions in moderate to excellent yields is presented.

Full text of DOI:10.1021/acscatal.8b00083

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Letter
Synthesis of Highly Substituted Arenes via Cyclohexadiene–
Alkene C–H Cross Coupling and Aromatization
Anup Bhunia, and Armido Studer
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00083 • Publication Date (Web): 11 Jan 2018
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ACS Catalysis
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Synthesis of Highly Substituted Arenes via Cyclohexadiene–Alkene
C–H Cross Coupling and Aromatization
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Anup Bhunia and Armido Studer*
Institute of Organic Chemistry, University of Münster, Corrensstrasse 40, 48149 Münster, Germany
Supporting Information Placeholder
ABSTRACT: The development of a cross-coupling method for the regioselective β-alkenylation of 2,5-cyclohexadiene carboxylic
acid derivatives to form ortho-alkenylarenes through in situ decarboxylation and aromatization is described. The carboxylic acid
functionality is used as a traceless directing group for efficient and mild β-alkenylation. The modular sequence comprises a reduc-
tive Birch α-alkylation, ionic δ-alkylation followed by a Pd-catalyzed de-
carboxylative β-alkenylation with subsequent aromatization resulting in
an overall threefold ipso-para-ortho functionalization of readily ac-
cessed benzoic acid derivatives. Efficient synthesis of various alkyl-
alkenylarenes under mild conditions in moderate to excellent yields is
presented.
α−
R1
Birch
R2
alkylation
alkylation
H
CO2
δ−
R1
TM-catalyzed
R4
R3
β−
alkenylation/
rearomatization
62 examples
KEYWORDS: palladium catalysis, C−H activation, decarboxylation, aromatic substitution, synthetic methods
Highly substituted arenes are versatile reagents and valua-
ble targets in synthetic chemistry.1 Transition-metal-catalyzed
C–H functionalization of aromatic rings has been intensively
studied to access multi-substituted arenes2 and direct arene
C–H alkenylation to provide styrene derivatives has been in
focus.3 Considering transition-metal catalysis, arene alkenyla-
tion is generally conducted by the Heck reaction,4 where a
stoichiometric amount of an organometallic reagent, organo-
halide or pseudohalide is required. Alternatively, the direct
Pd(ll)-catalyzed Fujiwara-Moritani coupling of arenes with ac-
tivated alkenes offers an atom economical route to styrenes.5
However, by applying a direct arene C–H functionalization
strategy the regioselectivity problem arises.
developed an efficient Rh-catalyzed ortho alkenylation of aro-
matic acids (Scheme 1b).11 However, in all these processes pro-
todecarboxylation is not achieved during C–H functionaliza-
tion. Decarboxylation requires high temperature, a stoichio-
metric amount of Cu(ll) or Ag(l) salt as an oxidant and unde-
sired side products such as ortho,ortho’ bisfunctionalized car-
boxylic acids are formed prior to decarboxylation. Therefore,
the development of an efficient method for regioselective or-
tho alkenylation directed by the acid functionality that is effi-
ciently removed in situ after C−H functionalization under
mild conditions is still highly desirable.
Previous work:
a) Decarboxylative ipso functionalization
R
H
CO2
As a solution, the use of a directing group assisting selective
cleavage of the proximal arene C–H bond allows for highly se-
lective ortho functionalization.6a-d Directing groups leading to
selective meta or para functionalization have also been intro-
duced.6e-h However, installation and detachment of the direct-
ing group require extra steps. In this context, the carboxylic
acid functionality has proved to be an efficient directing
group.7 The acid functionality can be traceless removed by
protodecarboxylation8 or alternatively be used for generation
of aryl metal intermediates resulting in ipso-substitutions. In
2002, Myers disclosed Pd-catalyzed decarboxylative Heck-
type olefination of aromatic acids (Scheme 1a).9a This seminal
work has fostered further studies and Gooβen reported Cu-
catalyzed decarboxylative coupling between aromatic acids
and aryl halides or triflates to form biaryls.9b Daugulis dis-
closed Pd-catalyzed ortho C–H arylation of aromatic acids us-
ing the carboxylic acid functionality as a traceless directing
group.10a Ortho arylation of aromatic acids have also been in-
vestigated by Gooβen,10b Zhang,10c Larrosa,10d Su10e and Miura
TM catalysis
b) Decarboxylative ortho functionalization
CO2H
TM catalysis
R
This work:
c) Modular ipso-para-ortho functionalization
α−
Birch
δ−
R1
alkylation
H
CO2
alkylation
TM-catalyzed
R3
R2
β−
alkenylation/
rearomatization
Scheme 1. Transition-metal catalysed decarboxylative
alkenylation.
Our recent efforts revealed that 2,5-cyclohexadiene carbox-
ylic acids undergo Pd-catalyzed decarboxylative γ-arylation
with aryl iodides.12a-b The same reactivity was found for acyclic
analogs12c and was applied to the total synthesis of resveratrol-
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based natural products, macheriols, and THC.12d-e We envis-
aReactions were carried out with 1a (0.2 mmol), 2a (0.4
mmol), Cs2CO3 (0.22 mmol) in 0.5 mL solvent under argon,
Yield of isolated 3a is given. bYield determined by GC. cReac-
tion performed without Cs2CO3. d2 mol% Pd(TFA)2 used.
1
2
3
4
5
6
7
8
aged that the carboxylate group in 2,5-cyclohexadien-1-car-
boxylic acids can act as a traceless directing group for Pd-cat-
alyzed β-alkenylation with subsequent decarboxylative oxida-
tive aromatization to afford ortho-alkenylarenes (Scheme 1c).
Notably, the starting 2,5-cyclohexadiene carboxylic acids are
easily prepared through alkylative Birch reduction which al-
lows to introduce the ipso R1-substituent into the starting ben-
zoic acid core.13 Moreover, such acids are readily alkylated at
the δ-position to access 1,4-dialkylcyclohexa-2,5-diene-1-car-
boxylic acids,12b addressing the para position (R2-substituent)
of the initial benzoic acid core structure and the decarboxyla-
tive cross coupling eventually installs the third substituent,
thereby also regenerating the parent arene structure. We
show herein that this modular sequence offers an efficient
route to the regioselective threefold ipso-para-ortho substitu-
tion of various aromatic acids.
Solvent change to propionic acid in combination with
TEMPO as an oxidant increased the yield to 90% (Table 1, en-
try 11) and a good result was also obtained in acetic acid (Table
1, entry 12).14 In acidic media, Pd(OAc)2 was again inferior to
Pd(TFA)2 (Table 1, entry 13) and the highest yield was obtained
upon lowering the reaction temperature to 80 °C to afford 3a
in excellent 93% yield (Table 1, entry 14). These conditions
were regarded as optimal since lowering of the catalyst load-
ing, lowering temperature or replacing TEMPO by O2 led to
worse results (Table 1, entries 15-17). Importantly, this process
provides selectively mono-alkenylation product 3a without
formation of any detectable amount of the corresponding bis-
styrenylated arene. Reaction performed at 5 mmol scale af-
forded 3a in 84% yield, documenting the robustness of the
novel sequence.
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We first focused on the ipso-ortho disubstitution of benzoic
acid. The acid 1a was readily prepared by reductive Birch
methylation of benzoic acid with NH3, Li, and iodomethane.13
For ortho alkenylation, 1a was treated with styrene in the pres-
ence of 5 mol% Pd(TFA)2 and Ag2CO3 (4.0 equiv) in a
DMSO/DMF solvent mixture at 110 °C for 12 h and the targeted
3a was formed in 31% yield (Table 1, entry 1). A similar yield
resulted in DMF (Table 1, entry 2), but in DMSO or in toluene
3a was formed only in traces (Table 1, entries 3 and 4). Oxidant
screening in DMF revealed that Cu(OAc)2 and Cu(OTf)2 pro-
vide slightly improved yields but O2 and TEMPO are not suit-
able oxidants in this solvent (Table 1, entries 5-8). An im-
proved result was achieved with AgOAc affording 3a in 55%
yield (Table 1, entry 9). Replacing Pd(TFA)2 by Pd(OAc)2 led
to a significantly reduced yield (Table 1, entry 10).
Table 2. Variation of the alkene component
(5 mol%)
H
CO2
Pd(TFA)2
R
TEMPO (4.0 equiv)
+
R
EtCO
2H, 80 °C
3
2
1a
R
R
R
(70%, R = Me)
(74%, R = Br)
(68%, R = F)
(79%, R = OMe)
(60%, R = Br)
(72%, R = F)
(93%, R = H)
(78%, R = tBu)
(89%, R = Ph)
(68%, R = OAc)
(75%, R = F)
(81%, R = Cl)
(80%, R = Br)
(81%, R = CF
3i
3j
3k
3l
3m
3n
3a
3b
3c
3d
3e
3f
Table 1. Reaction optimization: alkenylation of 1a with
styrene to give 3aa
F5
3g
3h
(67%)
(81%)
3o
)
3
H
3p
CO2
catalyst (5 mol%)
oxidant (4.0 equiv)
Ph
F
O
+
Ph
2a
Catalyst
R
solvent, temperature
12 h
O
3a
1a
En-
(48%)
(49%)
O
3s
3t
3u
3q
3r
(34%, R = H)
(44%, R = Me)
Solvent
T [°C]
Oxidant
Yield (%)
(83%, R = Ph)
O
try
OR
N
1
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
5% DMSO/DMF 110
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Cu(OAc)2
Cu(OTf)2
O2
31
(77%, R = Me)
(75%, R = tBu)
(74%)
2
DMF
110
110
110
110
110
110
110
110
110
110
110
110
80
80
50
30
3v
O
3z
3w
3x
3y
3
DMSO
Toluene
DMF
<5b
<5b
39
CF3
H
(80%, R = CH2
(82%, R = Ph)
)
4
O
H
H
O
P
5
O
OEt
OEt
6
DMF
46
<5b
<5b
55
(87%)[a]
3ab
(82%)
7
DMF
3aa
O
8
DMF
TEMPO
AgOAc
Ag2CO3
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
O2
O
9
DMF
O
10
11
12
13
14
15
16
17
Pd(OAc)2 DMF
23
[a]
3ac
(83%)
Pd(TFA)2
Pd(TFA)2
EtCO2H
MeCO2H
90
80
85
93c
60d
12b
<5b
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), Pd(TFA)2
(0.025 mmol), propanoic acid (1.5 mL), TEMPO (2.0 mmol),
80 °C, 12 h. a1a (0.6 mmol) and 2 (0.5 mmol) used.
Pd(OAc)2 EtCO2H
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
EtCO2H
EtCO2H
EtCO2H
EtCO2H
We next investigated the scope by varying the alkene compo-
nent (Table 2). Styrene derivatives bearing an electron–donat-
ing or withdrawing group at the ortho, meta or para position
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ACS Catalysis
of the aromatic ring are tolerated to afford 3a–3n with com-
To achieve threefold ipso-para-ortho substitution of ben-
zoic acid derivatives, acids 1 were alkylated at the δ-position
to form 1,4-dialkylcyclohexa-2,5-diene-1-carboxylic acid deriv-
atives 4 with moderate to good yields with variable diastere-
oselectivity by double deprotonation of the acid 1 with n-BuLi
and TMEDA in THF at -78°C and C-alkylation upon warming
to room temperature (see SI).12b Importantly, the diastereose-
lectivity of the δ-alkylation is not of importance since both iso-
mers undergo the rearomatizing ortho-alkenylation with sim-
ilar efficiency. Hence, separation of the two diastereoisomers
was not necessary substantially improving practicability of the
overall transformation. Reaction with styrene and methyl
acrylate worked well on 1,4-dimethyl-2,5-cyclohexadiene car-
boxylic acid to provide 5a and 5b in 72% and 62% yield, re-
spectively (Table 4). Similar yields were noted for the 4-ethyl
substituted acid (5c, 5d) and steric effects at the 4-position are
not important since the isopropyl-derivatives 5e and 5f were
isolated in good yields. The modularity of our approach read-
ily allowed varying the R1 and R3-substituents (see 5g−5l). The
tetrasubstituted arenes 5m and 5n were isolated along with
their regioisomers 5m’ and 5n’ with 5:1 selectivity.
1
2
3
4
5
6
7
8
plete E-selectivity in good to excellent yields. Pentafluorovi-
nylbenzene and 2-vinylnaphthalene gave 3o and 3p in reason-
able yields and also 2-vinylbenzofuran could be employed (see
3q). 1,1-Disubstituted styrenes are tolerated (see 3r). Acrolein,
methyl vinyl ketone and phenyl vinyl ketone reacted with 1a
to the alkenylated products 3s–3u in moderate to good yields.
Various acrylates, N,N-dimethyl acrylamide and diethyl vinyl
phosphonate underwent smooth cross coupling to afford 3v–
3aa. Late stage functionalization of more complex acrylates
derived from cholesterol and vitamin E gave 3ab and 3ac.
Non-activated alkenes, such as 1-decene, did not engage in
this sequence.
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We next varied the acid component (for acid preparation, see
SI). Cross coupling and aromatization worked well on 1-ethyl
and 1-isopropyl substituted acids (Table 3, see 3ad–3ag). The
reaction of 1,2-disubstituted acids with styrene and methyl
acrylate afforded 1,2,3-trisubstituded arenes 3ah–3ak in good
yields. In case of 1-methyl-3-fluoro-2,5-cyclohexadiene carbox-
ylic acid, two regioisomers were formed with styrene (3al and
3al’) and also with methyl acrylate (3am and 3am’). The steri-
cally less encumbered 1,3,4-trisubstituted regioisomers were
formed as major compounds in moderate 3:1 regioselectivity.
Selectivity improved to 5:1 upon switching to the 3-methyl-
substituted congener (3an, 3ao) and with the bulkier 3-isopro-
pyl-substituted acid, C−H alkenylation occurred with com-
plete regiocontrol ( 3ap, 3aq). Our method allows preparing
tetrasubstituted arenes 3ar−3au and also a naphthalene car-
boxylic acid was successfully used as a substrate (3av).
Table 4. Preparation of highly substituted arenes
R1
R1 CO2H
(5 mol%)
R4
Pd(TFA)2
TEMPO (4.0 equiv)
R2
+
R4
R2
EtCO
2H, 80 °C
R3
R3
4
2
5
R4
R4
R4
Table 3. Variation of the acids
R1
(72%, R4 = Ph)
(62%, R4 = CO
(72%, R4 = Ph)
(61%, R4 = CO
(76%, R4 = Ph)
(66%, R4 = CO
R1 CO2H
(5 mol%)
5a
5b
5e
5f
5c
5d
R3
Pd(TFA)2
2Me)
2Me)
R4
2Me)
TEMPO (4.0 equiv)
R2
+
R3
R2
EtCO
R4
2H, 80 °C
R4
2
3
1
Ph
R3
R3
R3
(88%, R4 = Ph)
(75%, R4 = CO
4 = Ph)
(78%, R4 = Ph)
(69%, R4 = CO
5g
5h
5k
5i
5j
(76%, R
(64%, R4 = CO
5l
2Me)
2Me)
2Me)
(74%, R3 = Ph)
(71%, R3 = CO
(74%, R3 = Ph)
(69%, R3 = CO
(78%, R3 = Ph)
3ad
3ae
3ah
3ai
3af
R4
(81%, R3 = CO
R4
2Me) 3ag
2Me)
2Me)
+
R3
R3
R3
+
4 = Ph, rr = 5:1)[a]
F
5m + 5m´
5n + 5n´
F
(69%, R
(80%, R4 = CO
(72%, R3 = Ph, rr = 3:1)[a]
(60%, R3 = CO
(55%, R3 = Ph)
(88%, R3 = CO
2Me, rr = 5:1)[b]
3al + 3al´
3aj
2Me, rr = 3:1)[b]
R3
3am + 3am´
3ak
2Me)
Reaction conditions: 4 (0.5 mmol), 2 (1.0 mmol), Pd(TFA)2
(0.025 mmol), EtCO2H (1.5 mL), TEMPO (2.0 mmol), 80 °C, 12
h. aIsolated as a mixture of isomers. bMajor isomer isolated.
R3
R3
+
3 = Ph, rr = 5:1)[a]
(81%, R3 = Ph)[c]
3an + 3an´
3ap
(83%, R
(80%, R3 = CO
(79%, R3 = CO
2Me, rr = 5:1)[b] 3aq
2Me)[c]
To shed light on the mechanism of this decarboxylative
functionalization, additional experiments were conducted
(Scheme 2). Oxidative cross coupling of the methyl ester 6
with styrene to give 7 did not work, revealing that the direct-
ing acid is crucial for the C−H alkenylation (Scheme 2, eq. 1).
The intramolecular kinetic isotope effect in the reaction of 1a-
D with styrene was 2.7:1 indicating that the C−H activation
likely occurs via a concerted metalation deprotonation (CMD)
mechanism (Scheme 2, eq. 2).15 To address the decarboxyla-
tion rearomatization steps, we reacted 4f in the absence of sty-
rene and obtained 8 in 90% yield (Scheme 2, eq. 3). Repeating
the experiment in the absence of the Pd-catalyst afforded only
30% of 8, indicating that the Pd salt is likely involved in the
3ao + 3ao´
R3
R3
CO2Me
(62%, R3 = Ph)
(59%, R3 = CO
(61%, R3 = Ph)
3ar
3at
(33%)
(56%, R3 = CO
3av
3as
2Me) 3au
2Me)
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), Pd(TFA)2
(0.025 mmol), EtCO2H (1.5 mL), TEMPO (2.0 mmol), 80 °C, 12
h. aIsolated as mixture of isomers. bMajor isomer isolated. crr
= 20:1.
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decarboxylation.16 If the reaction of 1a with styrene is con-
In summary, we have developed a method for highly regi-
oselective ortho alkenylation of cyclohexadiene carboxylic ac-
ids. The process uses Pd-catalysis and proceeds via selective
and rare19 alkenyl/alkenyl C−H cross coupling followed by ox-
idative decarboxylation. The starting carboxylic acids are
readily prepared by reductive Birch alkylation. The 4-position
in these cyclohexadiene acids is easily alkylated using classical
ionic chemistry. Ortho alkenylation followed by oxidative de-
carboxylation provide multi-substituted arenes with moder-
ate to excellent yields. This sequential multi-functionalization
allows for efficient preparation of highly substituted arenes
that are difficult to access by other methods.
1
2
3
4
5
6
7
8
ducted with only 2 equivalents of TEMPO, 3a was isolated in
40% showing that C−H alkenylation is slower than the down-
stream decarboxylation aromatization steps. This is also in
line with the fact that we did not identify any double styrenyl-
ated arene as a final product.
Me
CO2
(5 mol%)
Me
CO2
Pd(TFA)2
Ph
TEMPO (4.0 equiv)
+
Ph
(1)
(2)
EtCO
2H, 80 °C
9
12 h
7
2a
6
(not formed)
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(5 mol%)
Pd(TFA)2
TEMPO (4.0 equiv)
H
CO2
Ph
H/D
D
+
Ph
ASSOCIATED CONTENT
EtCO
2H, 80 °C
12 h
= 2.7:1
:
3a 3a-D = 1:2.7
-D
1a
2a
k
H/kD
AUTHOR INFORMATION
Corresponding Author
studer@uni-muenster.de
Notes
(5 mol%)
Pd(TFA)2
TEMPO (2.0 equiv)
H
CO2
(3)
EtCO
2H, 80 °C
12 h
The authors declare no competing financial interest.
4f
8
8
(90%)
(30% without Pd(TFA)2)
Supporting Information
Scheme 2. Mechanistic studies.
The supporting Information is available free of charge on the
ACS Publications website at DOI:
Based on these studies we propose the following mecha-
nism (Scheme 3).17 The cycle starts with the formation of com-
plex A. C−H activation by CMD generates the carbopalla-
dium(ll) intermediate B followed by insertion of styrene to
form C, which undergoes β-hydride elimination to afford D.
Due to the fact that 4 equivalents of TEMPO are required (see
above), we assume that TEMPO abstracts a H-atom from the
weak Pd−H bond in D and the thus generated Pd(I)-complex
gets trapped by the second equivalent of TEMPO to generate
E after ligand exchange with HX. Pd-mediated decarboxyla-
tion and aromatization18 give 3a and HPd(II)X. HPd(II)X fur-
ther reacts via α-elimination to Pd(0) that is oxidized by 2
equivalents of TEMPO to give after ligand exchange PdX2 and
2 TEMPOH.14
Experimental procedures and spectral data for all new com-
pounds (PDF).
ACKNOWLEDGMENT
This work has been supported by the Deutsche Forschungsge-
meinschaft and the Alexander von Humboldt Foundation
(postdoctoral fellowship to A.B.).
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H
CO2
2 TEMPOH
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+ 2 HX
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1a
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Pd
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F
3C
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E
Pd(ll)
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B
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2 TEMPOH
O
Pd(ll)
Ph
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2 TEMPO
+ 2 HX
2a
D
C
Scheme 3. Postulated mechanism.
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