Copper-catalyzed formal c-h carboxylation of aromatic compounds with carbon dioxide through arylaluminum intermediates

Article abstract of DOI:10.1002/asia.201403247

The C-H bond carboxylation of various aromatic compounds with CO₂ was achieved by the deprotonative alumination with a mixed alkyl amido lithium aluminate compound iBu₃Al(TMP)Li followed by the NHC-copper-catalyzed carboxylation of the resulting arylaluminum species, which afforded the corresponding carboxylation products in high yield and high selectivity. In addition to benzene derivatives, heteroarenes such as benzofuran, benzothiophene, and indole derivatives are also suitable substrates. Functional groups such as Cl, Br, I, vinyl, amide, and CN could survive the reaction conditions. Some key reaction intermediates such as the copper aryl and isobutyl complexes and their carboxylation products were isolated and structurally characterized by X-ray crystallographic analyses, thus offering important information on the reaction mechanism.

Full text of DOI:10.1002/asia.201403247

DOI: 10.1002/asia.201403247
Full Paper
Carboxylation
Copper-Catalyzed Formal CÀH Carboxylation of Aromatic
Compounds with Carbon Dioxide through Arylaluminum
Intermediates
Atsushi Ueno,[a] Masanori Takimoto,[a, b] Wylie W. N. O,[a] Masayoshi Nishiura,[a, b]
Takao Ikariya,[c] and Zhaomin Hou*[a, b]
Abstract: The CÀH bond carboxylation of various aromatic
compounds with CO2 was achieved by the deprotonative
alumination with a mixed alkyl amido lithium aluminate
compound iBu3Al(TMP)Li followed by the NHC-copper-cata-
lyzed carboxylation of the resulting arylaluminum species,
which afforded the corresponding carboxylation products in
high yield and high selectivity. In addition to benzene deriv-
atives, heteroarenes such as benzofuran, benzothiophene,
and indole derivatives are also suitable substrates. Function-
al groups such as Cl, Br, I, vinyl, amide, and CN could survive
the reaction conditions. Some key reaction intermediates
such as the copper aryl and isobutyl complexes and their
carboxylation products were isolated and structurally charac-
terized by X-ray crystallographic analyses, thus offering im-
portant information on the reaction mechanism.
Introduction
metal catalysts and show better functional group tolerance,
while alone they do not react with CO2 under the same condi-
tions. Similar carboxylation reactions of organic halides in the
presence of transition-metal catalysts have also been report-
ed.[10]
The use of carbon dioxide (CO2) as a C1 feedstock for the syn-
thesis of valued chemicals has attracted much attention re-
cently because CO2 is an abundant, inexpensive and inherently
renewable carbon source.[1] An efficient and straightforward
use of CO2 in organic synthesis is as a precursor of a carboxyl
unit by reaction with nucleophiles. It is well known that strong
nucleophilic organometallic reagents such as organolithium
and Grignard reagents can react with CO2 to afford carboxylic
acids after hydrolysis.[2] However, such highly reactive organo-
metallic reagents are usually not compatible with polar func-
tional groups (e.g., halides,[3] carbonyl,[4] and cyano groups[5]),
and could be used only for the synthesis of relatively simple
carboxylic acids. Weaker nucleophiles such as organo boron,[6]
silane,[7] zinc,[8] and aluminum compounds,[9] are known to un-
dergo carboxylation with CO2 in the presence of transition-
In principle, the direct carboxylation of CÀH bonds with CO2
is the most efficient way for the synthesis of carboxylic acids;
however, it is more challenging. The carboxylation of some
acidic aromatic CÀH bonds with CO2 was previously achieved
by using NHC-gold and -copper catalysts in the presence of
stoichiometric amounts of bases.[11a–e] Rhodium complexes
were reported to catalyze the CÀH carboxylation of arenes
having a directing group in the presence of two equivalents of
an alkyl aluminum compound.[11f] The carboxylation of an al-
kenyl CÀH bond in 2-hydroxystyrenes was achieved very re-
cently by using Pd catalysts in the presence of an excess
amount of a base, which afforded the corresponding lactone
derivatives.[11g] Despite these recent advances, studies on the
carboxylation of CÀH bonds with CO2 remain limited, and the
search for new protocols for selective CÀH bond carboxylation
with a broader substrate scope is of great interest and impor-
tance.
[a] Dr. A. Ueno, Dr. M. Takimoto, Dr. W. W. N. O, Dr. M. Nishiura, Prof. Z. Hou
Advanced Catalysis Research Group
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
Fax: (+81)48-462-4665
It is known that some aromatic compounds such as anisoles
could be deprotonatively metallated by an alkyl lithium com-
pound such as BuLi. The resulting aryl lithium species could
react with CO2, yielding the corresponding carboxylation prod-
uct.[12] However, such lithiation approach is not compatible
with functional groups. For example, in the case of bromo-sub-
stituted anisoles, the reaction takes place at the CÀBr bond
rather than at the CÀH bond.[12] Recently, Uchiyama and cow-
orkers reported that the mixed alkyl amido lithium aluminate
compound iBu3Al(TMP)Li (TMP=2,2,6,6-tetramethylpiperidide)
E-mail: houz@riken.jp
[b] Dr. M. Takimoto, Dr. M. Nishiura, Prof. Z. Hou
Organometallic Chemistry Laboratory
RIKEN, 2–1 Hirosawa, Wako, Saitama 351-0198 (Japan)
[c] Prof. T. Ikariya
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
O-okayamam Meguro-ku, Tokyo 152-8552 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403247.
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could selectively abstract an ortho-hydrogen atom of some
functionalized aromatic compounds, affording the correspond-
ing arylaluminum species.[13] In our recent studies on the use
of CO2 as a building block for organic synthesis, we found that
NHC-copper complexes could serve as excellent catalysts for
the carboxylation of various alkenylaluminum species with
CO2.[9a] Inspired by these results, we envisioned that the aryla-
luminum species generated by the deprotonative ortho-alumi-
nation of aromatic compounds might be carboxylated with
CO2 in the presence of an NHC-copper catalyst. In this article,
we report our studies on the combination of the deprotona-
tive ortho-alumination of aromatic compounds by
iBu3Al(TMP)Li with the Cu-catalyzed carboxylation of the result-
ing arylaluminum species with CO2, which proved to be
a useful protocol for the selective CÀH carboxylation of various
aromatic compounds with CO2. Functional groups such as Cl,
Br, I, CN, and amide could survive the reaction conditions. The
isolation and reactivity study of some reaction intermediates
were also achieved, thus offering evidence for mechanistic de-
tails.
Table 1. Catalyst screening and optimization of reaction conditions.[a]
Entry
Cat.
T [8C]
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
–
CuCl
(IPr)CuCl
(IPr)CuCl
(IPr)CuCl
–
(IPr)CuOtBu
(IPr)MeCuCl
(SIPr)CuCl
(ICy)CuCl
(IMes)CuCl
(IPr)ClCuCl
IPr·HCl/CuCl
1,10-phenanthroline
/CuCl
r.t.
r.t.
r.t.
60
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–
–
–
–
–
26
43
15
92
–
92
89
85
85
43
38
92
58
KOtBu
KOtBu
–
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu[c]
KOtBu
9
10
11
12
13
14
15
2,2’-tBu-bipyridine/CuCl
r.t.
KOtBu
–
[a] The reactions were carried out using iBu3AlTMPLi (2.0 equiv), substrate
(0.5 mmol), (IPr)CuCl (5 mol%), KOtBu (5 mol%), and CO2 (1 atm) in THF,
unless otherwise noted. [b] Isolated yield. [c] 10 mol% of KOtBu was
used.
Results and Discussion
At first, we examined the carboxylation of the arylaluminum
species 2a generated in situ by the deprotonative ortho-alumi-
nation
of
N,N-diisopropylbenzamide
(1a)
with
(iBu3Al(TMP)Li).[13] The arylaluminum species 2a alone did not
react with CO2 (1 atm) at room temperature,[14] giving almost
quantitatively the starting aromatic compound 1a after hydrol-
ysis (Table 1, entry 1). In the presence of a catalytic amount of
CuCl, the corresponding carboxylic acid 3a was obtained in
26% yield (Table 1, entry 2). When 5 mol% of (IPr)CuCl (IPr=
1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene) was used as
a catalyst, the yield of 3a increased to 43% (Table 1, entry 3).
The reaction at a higher temperature (608C) did not improve
the yield (15%) (Table 1, entry 4). When 5 mol% of KOtBu was
added to the reaction system, the yield of 3a was improved to
92% (Table 1, entry 5). KOtBu alone did not promote the car-
boxylation reaction (Table 1, entry 6). The use of the copper
alkoxide complex (IPr)CuOtBu, which was synthesized by the
reaction of (IPr)CuCl with KOtBu, gave a similar result (Table 1,
entry 7). The copper complexes bearing analogous NHC li-
gands such as IPrMe, SIPr, and ICy (Figure 1) also exhibited
a high activity, comparable with that of (IPr)CuCl (Table 1, en-
tries 8–10). However, the sterically less demanding IMes and
the electron-withdrawing IPrCl ligands (Figure 1) were less ef-
fective under the same conditions (Table 1, entries 11 and 12).
Notably, the combination of CuCl, IPr·HCl, and KOtBu was as ef-
fective as the isolated complex (IPr)CuOtBu (Table 1, entry 13).
1,10-Phenanthroline was less effective, and bipyridine did not
work for this reaction (Table 1, entries 14 and 15).
Figure 1. NHC ligands for the copper catalysts in Table 1.
3). In the case of p-chloro-, p-bromo-, and p-iodo-substituted
N,N-diisopropylbenzamides (1d, 1e, and 1 f), the reaction took
place selectively at the ortho-CÀH bond, affording the corre-
sponding CÀH carboxylation products in high yields (Table 2,
entries 5–7). No reaction at the CÀCl, CÀBr, or CÀI bond was
observed, demonstrating the advantage of the present
method over the lithiation approach using an alkyl lithium re-
agent. In the case of 3-chloro-N,N-diisopropylbenzamide 1g,
the carboxylation product 3g’ was obtained in a moderate
yield (56%, Table 2, entry 8), probably because of the forma-
tion of a benzyne species (which is inactive for carboxylation)
in the deprotonation step.[13b]
We then examined the carboxylation of various substituted
benzene derivatives by using the combination of (IPr)CuCl and
KOtBu as a catalyst. The results are summarized in Table 2. Sim-
ilar to N,N-diisopropylbenzamide (1a), the p-tBu- and p-Ph-sub-
stituted analogues 1b and 1c also underwent the deprotona-
tive ortho-CÀH carboxylation efficiently (Table 2, entries 2 and
The deprotonative ortho-carboxylation of benzonitrile (4)
could also be achieved selectively by this protocol, affording 2-
cyanobenzoic acid (5) in 84% yield (Table 2, entry 9). No reac-
tion was observed at the CN group. Anisole derivatives are
also applicable for this reaction. It is noteworthy that the car-
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an ortho position of the MeO group was obtained in 50%
yield, together with some unidentified byproducts (Table 2,
entry 15).[15] The reaction of 4-allylanisole (6 f) afforded selec-
tively the expected carboxylation product 7 f’, demonstrating
that a C=C bond is compatible with the present reaction con-
ditions (Table 2, entry 16).
Table 2. Deprotonative ortho-carboxylation of aromatic compounds bear-
ing a directing group.[a]
Table 3 summarizes some representative results of the de-
protonative carboxylation of heteroaromatic compounds. Ben-
zofuran (8a), benzothiophene (8b), and N-Boc-indole (8c,
Boc=tert-butoxycarbonyl) could be transformed selectively to
the corresponding 2-CÀH carboxylation products in high yields
(Table 3, entries 1–3).[16] The selective carboxylation at the 2-po-
sition of 8c in the present reaction stands in contrast with the
reactions of indole derivatives promoted by aluminum Lewis
acids[9b] and LiOtBu.[17] In the case of 6-methoxybenzofuran
(8d) and N-Boc-5-methoxy-indole (8e), the reaction took place
selectively at the heterocyclic ring rather than at the MeO-sub-
stituted benzene unit, affording the corresponding 2-carboxy-
lated products 9d’ and 9e’, respectively (Table 3, entries 4 and
5). Similarly, the reaction of 5-bromobenzofuran (8 f) and N-
Boc-5-bromo-indole (8g) gave selectively the 2-CÀH carboxyla-
tion products, while the CÀBr bond remained unchanged
(Table 3, entries 6 and 7).
Entry
Substrate
Product
Yield [%][b]
1
92
1a (X=H)
1b (X=tBu)
3a (X=H)
3b (X=tBu)
2
3
88
71
1c (X=Ph)
3c’ (X=Ph)[c]
3d’ (X=Cl)[c]
3d’ (X=Cl)[c]
3e’ (X=Br)[c]
3 f’ (X=I)[c]
4
1d (X=Cl)
1d (X=Cl)
1e (X=Br)
1 f (X=I)
54
84
74
95
5[d]
6
7
To gain information about the reaction mechanism, we ex-
amined the stoichiometric reaction of (IPr)CuOtBu with the ary-
laluminum species 10 prepared by the reaction of anisole with
iBu3Al(TMP)Li in THF at room temperature (Scheme 1). By frac-
8
9
56
84
1g
4
3g’[c]
5
10
11
90
64
Scheme 1. Stoichiometric reaction of 10 and (IPr)CuOtBu.
6a (X=H)
6b (X=Cl)
7a
tional recrystallization of the reaction products, an iso-butyl
copper complex (IPr)CuiBu (11) and an anisylcopper complex
(IPr)Cu(C6H4-OMe-2) (12) were isolated as colorless crystals in
65% and 8% yields, respectively. X-ray crystallographic studies
revealed that 11 and 12 adopt a similar monomeric structure,
in which the central CuI atom is bonded to one NHC ligand
and one carbyl (iBu, 2-MeO-C6H4) unit (Figure 2). The isolation
7b’ (X=Cl)[c]
7b’ (X=Cl)[c]
7c’ (X=Br)[c]
12[d]
13
14
15
6b (X=Cl)
6c (X=Br)
6d (X=I)
6e (X=SMe)
6 f (X=CH=CHCH3)
86
72
92
50
72
7d’ (X=I)[c]
7e (X=SMe)
7 f’ (X=CH=CHCH3)[c]
16
[a] The reactions were carried out using iBu3Al(TMP)Li (2.0 equiv), sub-
strate (0.5 mmol), (IPr)CuCl (5 mol%), KOtBu (5 mol%), and CO2 (1 atm) in
THF, unless otherwise noted. [b] Isolated yield. [c] The carboxylation prod-
uct was isolated as
a methyl ester derivative after treatment with
TMSCHN2, because it is difficult to isolate the carboxylic acid in a pure
state. [d] (IPrMe)CuCl was used as a catalyst.
boxylation took place selectively at the ortho-CÀH bond, while
the CÀX (X=Cl, Br, I) bonds remained unchanged in the case
of p-halogenated anisole derivatives (Table 2, entries 11–14), in
contrast with what was observed previously in the lithiation
with an alkyl lithium reagent.[12] In the case of 4-methylthioani-
sole (6e), the desired product (7e) formed by carboxylation at
Figure 2. X-ray structures of 11 (left) and 12 (right); thermal ellipsoids are
set at 30% probability. Selected bond lengths [ꢁ] and angles [8] of 11: C(5)–
Cu(1) 1.896(3), C(1)–Cu(1) 1.926(3) and C(1)-Cu(1)-C(8) 177.85(14); 12: C(8)–
Cu(1) 1.9003(17), Cu(1)–C(1) 1.9155(18), and C(1)-Cu(1)-C(8) 171.72(7).
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tion of aromatic compounds with CO2 is shown in
Scheme 3.[18] The deprotonation of an aromatic com-
pound by the aluminate reagent iBu3Al(TMP)Li would
generate the arylaluminum species A,[13] which could
then undergo transmetallation with (IPr)CuOtBu to
give the copper aryl species B with release of Al(Ot-
Bu)(iBu)3Li. The insertion of CO2 into the ArÀCu bond
in B would afford the copper carboxylate complex C.
The transmetallation reaction between C and another
molecule of the arylaluminum species A would then
give the aluminum carboxylate species D and regen-
erate the arylcopper species B. The hydrolysis of D
would yield the carboxylic acid ArCOOH, which on
treatment with TMSCHN2 would then give the ester
derivative ArCOOMe.
Table 3. Deprotonative carboxylation of heteroaromatic compounds.[a]
Entry
1
Substrate
Product
Yield [%][b]
90
8a
8b
9a
9b
2
3
4
94
86
85
8c
8d
8e
9c’[c]
9d’[c]
Conclusions
We have demonstrated that the combination of the
deprotonative ortho CÀH bond alumination of vari-
ous aromatic compounds by an aluminate base
(iBu3Al(TMP)Li) and the subsequent carboxylation of
the resulting arylaluminum species with CO2 in the
presence of a catalytic amount of NHC-copper com-
plex and KOtBu can serve as a useful protocol for the
synthesis of the corresponding carboxylic acids or
their ester derivatives. This protocol features high re-
gioselectivity, high yield, a relatively broad substrate
scope, and certain functional group tolerance. Some
key reaction intermediates have been isolated and
structurally characterized, thus providing important
information on the reaction mechanism.
5
6
7
82
73
72
9e’[c]
9 f’[c]
8 f
8g
9g’[c]
[a] The reactions were carried out using iBu3Al(TMP)Li (2.0 equiv), substrate
(0.5 mmol), (IPr)CuCl (5 mol%), KOtBu (5 mol%), and CO2 (1 atm) in THF unless other-
wise noted. [b] Isolated yield. [c] The carboxylation product was isolated as a methyl
ester derivative after treatment with TMSCHN2, because it is difficult to isolate the car-
boxylic acid in a pure state.
Experimental Section
General Information: Unless otherwise noted, all manip-
of both 11 and 12 in the above reaction suggests that both
ulations were performed under a dry nitrogen or argon atmos-
phere using Schlenk-line techniques or under a nitrogen atmos-
phere in an Mbraun glovebox. Argon and nitrogen were purified
the alkyl (iso-butyl) group and the aryl group in the mixed
aryl/alkyl aluminate species could be transferred to the copper
atom.
When 11 and 12 were exposed to CO2 in C6H6 at room tem-
perature, the insertion of CO2 into the CuÀalkyl and Àaryl
bonds took place smoothly to give the corresponding copper
carboxylate complexes 13 and 14, respectively (Scheme 2).
Complexes 13 and 14 were also structurally characterized by
X-ray diffraction studies (Figure 3).
On the basis of the results described above, a possible reac-
tion pathway for the present deprotonative ortho-carboxyla-
Figure 3. X-ray structures of 13 (left) and 14 (right); thermal ellipsoids are
set at 30% probability. Only one molecule of the two independent mole-
cules (13) and four molecules (14) in the unit cell is shown. Selected bond
lengths [ꢁ] and angles [8] of 13: C(6)–Cu(1) 1.853(4), O(1)–Cu(1) 1.848(3),
O(1)–C(1) 1.276(5), C(1)–O(2) 1.242(7); C(6)-Cu(1)-O(1) 177.59(15), O(1)-C(1)-
O(2) 118.4(15); 14: C(9)–Cu(1) 1.866(5), Cu(1)–O(1) 1.864(4), O(1)–C(1)
1.282(6), C(1)–O(2) 1.207(6); C(1)-Cu(1)-C(8) 171.7(2), O(1)-C(1)-O(2) 125.2.
Scheme 2. Reactions of 11 and 12 with CO2.
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CH(CH3)2), 1.44–1.46 (m, 6H; CH(CH3)2), 3.43–3.57 (m, 2H; CH(CH3)2),
4
7.21 (d, 3JHH =7.8 Hz, 1H; aryl-H), 7.46 (dd, 3JHH =7.8 Hz, JHH
=
3
4
1.4 Hz, 1H; aryl-H), 7.60 (dd, JHH =7.8 Hz, JHH =1.4 Hz, 1H; aryl-H),
7.89 ppm (dd, 3JHH =7.8 Hz, 4JHH =1.4 Hz, 1H; aryl-H); 13C{1H} NMR
(101 MHz, [D6]DMSO, 258C): d=19.3, 19.6, 20.0, 20.6, 44.4, 50.5,
125.8, 127.7, 127.9, 130.0, 132.3, 140.4, 167.0, 168.8 ppm; HRMS
(EI): calcd for C14H19NO3: 249.1365 (M+), found 249.1358.
Synthesis of [(IPr)CuCH2CH(CH3)2] (11) and [(IPr)Cu(C6H4-OMe-2)]
(12): To a solution of iBu3Al(C6H4-OMe-2)Li (10), which was pre-
pared from 6a (108 mg, 1.0 mmol) and iBu3Al(TMP)Li (2.0 mmol)
according to the above-mentioned procedure, in THF (3.0 mL) was
added a solution of [(IPr)Cu(OtBu)] (526 mg, 1.0 mmol) in THF
(5 mL) at room temperature. After stirring for 24 h, the solvent was
removed under reduced pressure and the residue was dissolved in
hexane (4 mL). The solution was kept at À308C for 24 h, affording
(IPr)CuiBu (11) as colorless crystals (335 mg, 0.65 mmol, 65% yield).
The filtrate was concentrated to a half volume in vacuo and was
kept at À308C for 24 h, affording [(IPr)Cu(C6H4-OMe-2)] (12) as col-
Scheme 3. A possible reaction pathway for the deprotonative alumination
and carboxylation
by being passed through a Dryclean column (4 ꢁ molecular sieves,
Nikka Seiko Co.) and a Gasclean GC-RX column (Nikka Seiko Co.).
Flash column chromatography was performed on silica gel 60 N,
40–50 mm (Kanto Chemical Co.). The NMR spectra were recorded
on a JEOL AL-400, JEOL ECS-400 or Bruker DMX-500 spectrometer.
The NMR chemical shifts were referenced to SiMe4 by using residu-
al protio impurities in the deuterated solvent. Abbreviations for
1H NMR are as follows: s=singlet, d=doublet, t=triplet, q=quar-
tet, sept=septet or m=multiplet. Mass spectra (MS) were ob-
tained on a JEOL JMS-700V (EI) or a Waters Synapt G2 (ESI+) mass
spectrometer. Carbon dioxide and other commercially available re-
agents were used without further purification unless otherwise
stated. THF and hexane were dried by an Mbraun SPS-800 solvent
purification system and stored over fresh Na chips in the glovebox.
IPr·HCl,[19a] (IPr)CuCl,[6b] (IPr)Cu(OtBu),[6b] (IPrMe)CuCl,[19b] (IPrCl)CuCl,[7c]
(IMes)CuCl,[19c] (ICy)CuCl, and (SIPr)CuCl[19d] were prepared accord-
ing to literature procedures.
1
orless crystals (45 mg, 0.08 mmol, 8% yield). 11: H NMR (400 MHz,
C6D6, 258C, TMS): d=0.62 (d, 3JHH =5.5 Hz, 2H; CuCH2), 1.03 (d,
3JHH =6.4 Hz, 6H; CuCH2CH(CH3)2), 1.10 (d, J=6.9 Hz, 12H;
3
CCH(CH3)2), 1.47 (d, J=6.9 Hz, 12H; CCH(CH3)2), 2.34 (sept, JHH
=
5.5 Hz, 1H; CuCH2CH(CH3)2), 2.67 (sept, J=6.9 Hz, 4H; CCH(CH3)2),
3
6.27 (s, 2H; NCH), 7.09 (d, JHH =7.8 Hz, 4H; NCCCH), 7.22 ppm (t,
3JHH =7.8 Hz, 2H; NCCCHCH); 13C NMR (101 MHz, C6D6, 258C, TMS):
d=23.9, 25.0, 25.4, 29.0, 30.6, 30.8, 121.8, 124.1, 130.3, 135.6, 145.9,
186.2 ppm; elemental analysis calcd (%) for C31H45CuN2: C 73.11, H
1
8.91, N 5.50; found: C 73.03, H 8.94, N 5.31. 12: H NMR (400 MHz,
[D8]THF, 258C): d=1.24 (d, 3JHH =7.3 Hz, 12H; CH(CH3)2), 1.34 (d,
3JHH =6.9 Hz, 12H; CH(CH3)2), 2.73 (sept, 3JHH =6.9 Hz, 4H;
CH(CH3)2), 3.14 (s, 3H; OCH3), 6.25–6.29 (m, 2H; NCH), 6.56 (dt,
4
3
4
3JHH =7.3 Hz, JHH =1.8 Hz, 1H; aryl-H), 6.80 (dd, JHH =7.3 Hz, JHH
=
1.8 Hz, 1H; aryl-H), 7.34–7.51 ppm (m, 8H; aryl-H); 13C NMR
(101 MHz, [D8]THF, 258C): d=24.1, 29.7, 54.8, 112.6, 119.5, 124.0,
124.7, 130.7, 136.5, 141.2, 146.7, 147.9, 152.4, 168.2, 185.7 ppm; ele-
mental analysis calcd (%) for C34H43CuN2O: C 73.02, H 7.75, N 5.01;
found: C 73.30, H 7.50, N 4.95.
Typical procedures for the carboxylation of arylaluminum spe-
cies generated from deprotonative alumination of benzene de-
rivatives (Table 2, entry 1; synthesis of 3a): To a solution of
2,2,6,6-tetramethylpiperidine (0.17 mL, 1.0 mmol) in THF (3.0 mL)
Synthesis of [(IPr)Cu{OOCCH2CH(CH3)2}] (13): A solution of 11
(510 mg, 1.0 mmol) in benzene (4.0 mL) was treated with CO2 (1.0
atm, balloon) with stirring for 1 h. The solvent was removed under
reduced pressure. The residual white solid was washed with
hexane, dried under reduced pressure, and recrystallized from THF/
hexane (ratio ca. 1:3, total volume 4.0 mL) to give [(IPr)-
Cu{OOCCH2CH(CH3)2}] (13) (470 mg, 0.85 mmol, 85% yield) as col-
orless crystals. 1H NMR (400 MHz, C6D6, 258C, TMS): d=1.24 (d,
placed in
a 30 mL round-bottomed flask was added nBuLi
(0.38 mL, 2.64m in hexane, 1.0 mmol) at À788C, and the resulting
mixture was stirred at 08C for 30 min. The mixture was cooled to
À788C, and iBu3Al (2.0 mL 0.5m in hexane, 1.0 mmol) was added.
The reaction mixture was stirred for 30 min at 08C, affording
a yellow solution of the aluminum ate species (iBu3Al(TMP)Li).[13]
A
solution of N,N-diisopropylbenzamide (1a, 102.7 mg, 0.5 mmol) in
THF (2.0 mL) was added to the prepared solution of iBu3Al(TMP)Li
at À788C and the resulting mixture was stirred at room tempera-
ture for 3 h. Then, to this solution were added KOtBu (2.8 mg,
0.025 mmol) and (IPr)CuCl (12.2 mg, 0.025 mmol, 5 mol%) in THF
(2.0 mL) at À788C. The flask was evacuated and gaseous CO2
stored in a balloon was quickly introduced. The same operation
was repeated for several times. After the mixture was stirred at
room temperature for 20 h, it was hydrolyzed with 10% aqueous
HCl at 08C. Organic compounds were extracted by ethyl acetate
(10 mL, 3 times). The combined organic layers were washed with
water and brine, and dried over anhydrous Na2SO4 and concentrat-
ed in vacuo. The residue was purified by silica gel column chroma-
tography (AcOEt/hexane=1:4 to AcOEt only) to afford the benzoic
acid (3a) in 92% (114.7 mg, 0.46 mmol) yield as a white powder.
iBuCOOH (15) was also isolated in 33% yield (99.6 mg, 0.98 mmol)
(the yield was calculated based on the assumption that all three
iBu groups in the original aluminum ate species were carboxylat-
3
3JHH =7.3 Hz, 12H; CH(CH3)2), 1.34 (d, JHH =6.9 Hz, 12H; CH(CH3)2),
2.73 (sept, 3JHH =6.9 Hz, 4H; CH(CH3)2), 3.14 (s, 3H; OCH3), 6.25–
3
4
6.29 (m, 2H; NCH), 6.56 (dt, JHH =7.3 Hz, JHH =1.8 Hz, 1H; aryl-H),
3
4
6.80 (dd, JHH =7.3 Hz, JHH =1.8 Hz, 1H; aryl-H), 7.34–7.51 ppm (m,
8H; aryl-H); 13C NMR (101 MHz, C6D6, 258C, TMS): d=14.3, 23.0,
23.9, 25.0, 29.1, 32.0, 122.7, 124.3, 130.7, 135.0, 145.8, 177.5,
182.4 ppm; elemental analysis calcd (%) for C32H45CuN2O2: C 69.47,
H 8.20, N 5.06; found: C 69.58, H 8.30, N 5.11.
Synthesis of [(IPr)Cu(OOCC6H4-OMe-2)] (14): A solution of 12
(56 mg, 0.1 mmol) in benzene (4.0 mL) was treated with CO2 (1
atm, balloon) with stirring for 1 h. The solvent was removed under
reduced pressure. The residual white solid was washed with
hexane, dried under reduced pressure, and recrystallized from THF/
hexane (ratio ca. 1:3, total volume 4.0 mL) to give [(IPr)-
Cu(OOCC6H4-OMe-2)] (14) (48 mg, 0.08 mmol, 80% yield) as color-
less crystals. 1H NMR (500 MHz, CD2Cl2, 258C, TMS): d=1.23–1.24
(m, 12H; CH(CH3)2), 1.32–1.33 (m, 12H; CH(CH3)2), 2.57–2.65 (m,
4H; CH(CH3)2), 3.65 (s, 3H; OCH3), 6.72–6.76 (m, 2H; aryl-H), 7.13–
1
ed). 3a: H NMR (400 MHz, [D6]DMSO, 258C): d=1.05–1.06 (m, 6H;
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7.16 (m, 1H; aryl-H), 7.18 (s, 2H; NCH), 7.22–7.24 (m, 1H; aryl-H),
7.36 (d, 3JHH =7.6 Hz, 4H; aryl-H), 7.55 ppm (t, 3JHH =7.6 Hz, 2H;
aryl-H); 13C NMR (126 MHz, CD2Cl2, 258C, TMS): d=23.7, 24.3, 24.5,
28.7, 55.6, 111.6, 119.7, 123.4, 124.1, 129.1, 129.3, 130.3, 130.4,
134.7, 145.8, 156.5, 172.3, 180.5 ppm; elemental analysis calcd (%)
for C35H43CuN2O3: C 69.68, H 7.18, N 4.64; found: C 69.48, H 7.29, N
4.91.
Keywords: aromatic compounds · carbon dioxide · carbene
ligands · carboxylation · copper
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were modelled over three positions at 69%, 21% and 10% occu-
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tions at 85% and 15% occupancies, respectively. Disorder treat-
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disordered over two positions at 54% and 46% occupancies, re-
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propyl substituent of the iPr ligand were modelled over two posi-
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elled over two positions at 83% and 17% occupancies, respective-
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placed at geometrically calculated positions and refined using
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This work was supported by Grant-in-Aid for Scientific Re-
search (S) (No. 26220802) (to Z.H) and (C) (No. 26460029) (to
M.T.) from the JSPS.
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Received: November 5, 2014
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FULL PAPER
Carboxylation
Atsushi Ueno, Masanori Takimoto,
Wylie W. N. O, Masayoshi Nishiura,
Takao Ikariya, Zhaomin Hou*
&& – &&
Deprotonative carboxylation of various
functionalized aromatic compounds has
been achieved by the combination of
the ortho alumination by iBu3Al(TMP)Li
and the subsequent N-heterocyclic car-
bene-copper-catalyzed carboxylation of
the resulting arylaluminum species with
CO2, affording the corresponding car-
boxylation products in high yields and
high selectivity.
Copper-Catalyzed Formal CÀH
Carboxylation of Aromatic
Compounds with Carbon Dioxide
through Arylaluminum Intermediates
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