Direct C-H carboxylation with carbon dioxide using 1,2,3-triazol-5-ylidene copper(I) complexes

Article abstract of DOI:10.1021/ol301760n

1,2,3-Triazol-5-ylidene copper(I) complexes (tzNHC-Cu) efficiently catalyzed the direct C-H carboxylation of benzoxazole and benzothiazole derivatives with CO₂ to give the corresponding esters in excellent yields after treatment with alkyl iodi

Full text of DOI:10.1021/ol301760n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct CÀH Carboxylation with Carbon
Dioxide Using 1,2,3-Triazol-5-ylidene
Copper(I) Complexes
Hiroshi Inomata,† Kenichi Ogata,† Shin-ichi Fukuzawa,*,† and Zhaomin Hou‡
Department of Applied Chemistry, Institute of Science Engineering, Chuo University,
1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan, and Organometallic Chemistry
Laboratory and Advanced Catalyst Research Team, RIKEN Advanced Science Institute,
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
orgsynth@kc,chuo-u.ac.jp
Received June 27, 2012
ABSTRACT
1,2,3-Triazol-5-ylidene copper(I) complexes (tzNHC-Cu) efficiently catalyzed the direct CÀH carboxylation of benzoxazole and benzothiazole
derivatives with CO2 to give the corresponding esters in excellent yields after treatment with alkyl iodide. The tzNHC copper(I) complex, i.e.,
[(TPr)CuCl], worked somewhat more effectively than the corresponding imidazol-2-ylidene copper(I) complex [(IPr)CuCl] to give the carboxylation
product in higher yields.
Carbon dioxide (CO2) is of current interest in organic
synthesis as a useful C1 source because it is an abundantly
available, inexpensive, innoxious, and promising renew-
able resource.1 As a result, CO2 fixation has been inten-
sively studied academically and industrially. However,
organometallic reagents should be employed in CÀC
bond-forming reactions with CO2 due to its high thermo-
dynamic stability and low reactivity. Traditionally, the
challenge of CO2 fixation has been addressed through
the use of strongly nucleophilic organometallic com-
pounds, such as Grignard reagents.2
Other preactivated substrates such as organic halides
have served as alternatives to carboxylation.3 A more
desirable synthesis of carboxylic acids would be the direct
carboxylation of CÀH bonds.4 In recent years, Hou
and Nolan’s research groups independently succeeded
in the CÀH carboxylation of aromatic compounds using
N-heterocyclic carbene (NHC) metal complexes as cata-
lysts under mild reaction conditions.4aÀc The NHC metal
complexes provide an effective method for the synthesis
of heteroaryl carboxylic acid derivatives, which are bio-
logically active compounds.5
† Chuo University.
‡ RIKEN Advance Science Institute.
(1) For reviews, see: (a) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010,
39, 3347. (b) Cokoja, M.; Bruckmeier, C.; Rieger, B.; Herrmann, W. A.;
€
Kuhn, F. E. Angew. Chem., Int. Ed. 2011, 50, 8510. (c) Sakakura, T.;
Choi, J. C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (d) Eghbali, N.; Li,
C. J. Green Chem. 2007, 9, 213.
(2) (a) Riss, P. J.; Lu., S.; Telu, S.; Aigbirhio, F. I.; Pike, V. W. Angew.
Chem., Int. Ed. 2012, 51, 1. (b) Ohishi, T.; Zhang, L.; Nishiura, M.; Hou,
Z. Angew. Chem., Int. Ed. 2011, 50, 8114. (c) Dang, L.; Lin, Z.
Organometallics 2010, 29, 917. (d) Correa, A.; Martin, R. Angew. Chem.,
Int. Ed. 2009, 48, 6201. (e) Kobayashi, K.; Kondo, Y. Org. Lett. 2009, 11,
2035. (f) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008,
47, 5792. (g) Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org. Lett.
2008, 10, 2697. (h) Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2008,
130, 7826. (i) Ochiai, H.; Jang, M.; Hirano, K.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2008, 10, 2681. (j) Ukai, K.; Aoki, M.; Takaya, J.; Iwasawa,
N. J. Am. Chem. Soc. 2006, 128, 8706.
(3) (a) Correa, A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974. (b)
Amatore, C.; Jutand, A.; Khalil, F.; Nielsen, M. F. J. Am. Chem. Soc.
1992, 114, 7076. (c) Amatore, C.; Jutand, A. J. Am. Chem. Soc. 1991,
113, 2819.
(4) (a) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int.
Ed. 2010, 49, 8670. (b) Boogaerts, I. I. F.; Fortman, G. C.; Furst,
M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed. 2010, 49,
8674. (c) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132,
8858. (d) Ackermann, L. Angew. Chem., Int. Ed. 2011, 50, 2. (e) Mizuno,
H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2011, 133, 1251.
r
10.1021/ol301760n
XXXX American Chemical Society

We recently have shown that the 1,2,3-triazol-5-ylidene
(this type of carbene is abbreviated as tzNHC to distinguish
it from conventional NHCs)6 copper(I) complex is a more
active catalyst for the copper-catalyzed azide alkyne cy-
cloaddition (CuAAC) reaction than the corresponding
imidazol-2-ylidene NHC copper analogue.7 The tzNHC
copper(I) successfully catalyzed the reaction between a
sterically crowded alkyne and a sterically crowded azide
to give a highly sterically crowded 1,2,3-triazole in a
reasonable yield. The efficiency of the tzNHC copper(I)
complex may be attributed to the stronger donor property
of the 1,2,3-triazol-5-ylidene ligand.8 In order to extend the
tzNHC ligands and their metal complexes to various
synthetic reactions, we have applied the tzNHC-copper(I)
complex to the CÀH carboxylation of heteroaryl com-
pounds with CO2. We report here that the tzNHC-copper
complex catalyzed direct CÀH carboxylation effectively,
not only with benzoxazole but also with benzothiazole
derivatives.
first prepared in this work, and (TPh)CuCl and (TMes)-
CuCl were prepared previously.We first evaluated the
activity of (TPr)CuCl by carrying out a time-dependent
monitoring of the reaction of benzoxazole 1a with CO2.
The yield vs time graphs of (TPr)CuCl and the correspond-
ing imidazol-2-ylidene copper(I) complex, i.e., (IPr)CuCl,
for comparison are shown in Figure 2. A typical reaction
was carried out as follows. To a Schlenk tube were added
1.2 equiv of t-BuOK (with respect to benzoxazole) and
copper complex (5 mol %) in THF. Next, CO2 gas was
introduced into the tube followed by the addition of
benzoxazole. The tube was sealed and heated at 80 °C
under 1 atm of CO2 for the prescribed times. THF was
removed under vacuum, MeI (2 equiv to benzoxazole) in
DMF was added to the tube, and the solution was heated
at 80 °C for 1 h. No decomposition of the catalysts or
precipitation of metallic copper was observed during the
reaction. The product benzoxazole carboxylic acid was
thus transformed to its methyl ester, and yields were
determined by GC using biphenyl as an internal stan-
dard. As seen in the graph, (TPr)CuCl catalyzed the
reaction faster than (IPr)CuCl, and the yield of the
product reached 91% after 3 h. The reaction with
(TPr)CuCl was nearly complete after 5 h to give the
product in 93% yield, while the reaction with (IPr)CuCl
gave the product in 86% yield. The yield was constant
after 8 h for the reactions with both (TPr)CuCl and
(IPr)CuCl, showing that the reaction was terminated
within 8 h, although the CÀH carboxylation catalyzed
by (IPr)CuCl was carried out for 14 h in the original
work by Hou’s research group.4a
1,4-Diaryl-3-methyl-1,2,3-triazol-5-ylidene-copper(I)
complexes, i.e., (tzNHC)CuCl, were prepared by our pre-
vious method.7 The abbreviations used in this paper for
these tzNHC ligands are as follows: TPh, Ar = Ph; TMes,
Ar = mesityl (2,4,6-trimethylphenyl); TPr, Ar = 2,6-
diisopropylphenyl (shown in Figure 1). (TPr)CuCl was
Figure 1. 1,2,3-Triazol-5-ylidene copper and imidazol-2-ylidene
copper complexes.
(5) (a) Stover, J. S.; Shi, J.; Jin, W.; Vogt, P. K.; Boger, D. J. Am.
Chem. Soc. 2009, 131, 3342. (b) Yin, Y.; Lin, L.; Ruiz, C.; Cameron,
M. D.; Pocas, J.; Grant, W.; Schroeter, T.; Chen, W.; Duckett, D.;
Schuerer, S.; Lo Grasso, P.; Feng, Y. Bioorg. Med. Chem. Lett. 2009, 19,
6686. (c) Meroni, G.; Ciana, P.; Maggi, A.; Santaniello, E. Synlett 2009,
2682.
(6) For recent examples of tzNHCs, see: (a) Canseco-Gonzalez, D.;
€
Gniewek, A.; Szulmanowicz, M.; Muller-Bunz, H.; Trzeciak, A. M.;
Albrecht, M. Chem.;Eur. J. 2012, 18, 6605. (b) Yuan, D.; Huynh, H. V.
Organometallics 2012, 31, 405. (c) Keske, E. C.; Zenkina, O. V.; Wang,
R.; Crudden, C. M. Organometallics 2012, 31, 456. (d) Lalrempuia, R.;
€
Muller-Bunz, H.; Albrecht, M. Angew. Chem., Int. Ed. 2011, 50, 9969. (e)
Kilpin, K.; Paul, U. S. D.; Lee, A.-L.; Crowly, J. D. Chem. Commun.
2011, 47, 328. (f) Prades, A.; Peris, E.; Albrecht, M. Organometallics
2011, 30, 1162. (g) Poulain, A.; Canseco-Gonzalez, D.; Hynes-Roche,
€
R.; Muller-Bunz, H.; Schuster, O.; Stoeckli-Evans, H.; Neels, A.;
Albrecht, M. Organometallics 2011, 30, 1021. (h) Saravanakumar, R.;
Ramkumar, V.; Sankararaman, R. Organometallics 2011, 30, 1689. (i)
Keitz, B. K.; Bouffard, J.; Bertrand, G.; Grubbs, R. H. J. Am. Chem.
Soc. 2011, 133, 8498. (j) Guisado-Barrrios, G.; Bouffard, J.; Donnadieu,
B.; Bertrand, G. Angew. Chem. Int. Ed. 2010, 49, 4759.
Figure 2. Time vs yield (%) plot for (TPr)CuCl-catalyzed direct
carboxylation of benzoxazole: (2) (TPr)CuCl; ([) (IPr)CuCl.
(7) (a) Nakamura, T.; Terashima, T.; Ogata, K.; Fukuzawa, S.-i.
Org. Lett. 2011, 13, 620. Related recent papers on tzNHCs: (b)
Nakamura, T.; Ogata, K.; Fukuzawa, S.-i. Chem. Lett. 2010, 39, 920.
(c) Inomata, S.; Hiroki, H.; Terashima, T.; Ogata, K.; Fukuzawa, S.-i.
Tetrahedron 2011, 67, 7263. (d) Terashima, T.; Inomata, S.; Ogata, K.;
Fukuzawa, S.-i. Eur. J. Inorg. Chem. 2012, 1387.
(8) (a) For a review, see: Crowley, J. D.; Lee, A.-L.; Kilpin, K. L.
Aust. J. Chem. 2011, 64, 1118. (b) Mathew, P.; Neels, A.; Albrecht, M. J.
Am. Chem. Soc. 2008, 130, 13534. (c) Guisado-Barrios, G.; Bouffard, J.;
Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 4759.
B
Org. Lett., Vol. XX, No. XX, XXXX

The catalytic activities of the other tzNHC-copper(I)
complexes [(TMes)CuCl, (TPh)CuCl] and the imidazol-2-
ylidene copper(I) complex [(IMes)CuCl] were also exam-
ined under the same conditions. The results are summar-
ized in Table 1 where isolated yields by PTLC were shown.
These complexes catalyzed the reaction slower than
(TPr)CuCl and (IPr)CuCl and required a longer reaction
time (14 h) to obtain reasonable yields, albeit lower than
those achieved with (TPr)CuCl and (IPr)CuCl. From these
experiments, tzNHC-copper(I) complexes showed some-
what higher catalytic activities than their corresponding
NHC-copper(I) complexes; however, both of them gave
almost the same product yields after a long reaction time.
The more sterically hindered and more electron-rich li-
gands made the catalyst more active, whereas (TPh)CuCl
was the least active catalyst. However, (TPh)CuCl can still
be used practically as a catalyst considering the accessi-
bility of its precursor (1,4-diphenyl-1,2,3-triazole) by the
click reaction and gives a moderate but higher yield (75%)
than (IMes)CuCl. It must be noted that 1,2,3-triazolium
salt (carbene precursor) alone hardly catalyzed the reac-
tion (Table 1, entry 6).
observed. For the reaction with 4-methylbenzoxazole,
the product was obtained in low yield (entry 7) as with
(IPr)CuCl (50%),4a perhaps due to steric repulsion be-
tween the substituent at the 4-position and the ligand of the
complex. When the less hindered (TPh)CuCl catalyst was
used instead of (TPr)CuCl, the yield was improved up to
77% (entry 8). For stericallydemanding substrates, the less
hindered (TPh)CuCl may be suitable as a catalyst.
Table 2. Direct Carboxylation with Substituted Benzoxazolesa
entry
R
product, yield (%)b
1
2
3
4
5
6
7
8c
1b, 5-Me
1c, 6-Me
1d, 5-Ph
1e, 5-NO2
1f, 5-Cl
2b, 79
2c, 68
2d, 88
2e, 41
2f, 69
2g, 86
2h, 42
2h, 77
1g, 5-Br
1h, 4-Me
1h, 4-Me
Table 1. Optimization of the Copper-Catalyzed Direct Car-
boxylation of Benzoxazole with CO2
a
a 1bÀh (1.0 mmol), t-BuOK (1.2 mmol), (TPr)CuCl (0.05 mmol);
THF (5 mL), CO2 (1 atm), 80 °C, then evaporation of THF under
vacuum, DMF (5 mL), MeI (2.0 mmol), 80 °C, 1 h. b Isolated yield.
c (TPh)CuCl was used as a catalyst.
Next, the (TPr)CuCl catalyst was applied to the reaction
with other azoles such as benzothiazole and N-methylben-
zimidazole under the same conditions. For the reaction
with benzothiazole, the corresponding methyl ester was
obtained in 75% yield after methylation of the carboxylic
acid, while a trace amount of carboxylation product was
obtained from N-methylbenzimidazole. It is amazing
that (TPr)CuCl afforded the carboxylation product of
benzothiazole in good yield (75%) considering that
(IPr)CuCl only gives a trace amount of the product.9 The
substratescopeof various substituted benzothiazoles3aÀg
was examined, and the results are summarized in Table 3.
Electron-donating substituents at the 6-position gave
yields comparable to that with an electron-neutral sub-
strate (entries 1À3), while electron-withdrawing substitu-
ents gave lower yields of products (entries 4À5). The
reactions with 4-substituted benzothiazoles gave trace
amounts of products, and the use of (TPh)CuCl gave
products in low yields (entries 6À7).
entry
[Cu]
time (h)
yield (%)b
1
2
3
4
5
6
(TPr)CuCl
(IPr)CuCl
8
8
86
84
77
71
75
0
(TMes)CuCl
(IMes)CuCl
(TPh)CuCl
14
14
14
14
TPr HBF4
3
a Benzoxazole (1.0 mmol), t-BuOK (1.2 mmol), [Cu] (0.05 mmol);
THF (5 mL), CO2 (1 atm), 80 °C, then evaporation of THF under
vacuum, DMF (5 mL), MeI (2.0 mmol), 80 °C, 1 h. b Isolated yield.
The carboxylation of various substituted benzoxazoles
1bÀh was examined using the most effective (TPr)CuCl
catalyst under the same conditions. The product car-
boxylic acids were isolated as their methyl esters after
alkylation with MeI as the prescribed method. The results
are summarized in Table 2. The reaction with 5- and
6-methylbenzoxazolesaffordedthe products ingood yields
(entries 1À2). The reaction with 5-phenylbenzoxazole also
gave a high yield (88%) (entry 3). The reaction with
5-nitrobenzoxazole gave a low yield (41%) which was on
the same order as (IPr)CuCl (entry 4). 5-Halogenated
(R = Cl, Br) benzoxazoles tolerated the reaction, with
carboxylation occurring only at the 2-oxazole carbon to
give the corresponding esters in good yields (entries 5À6);
carboxylation at the C-halogen position was hardly
We attempted to isolate the intermediate of the reac-
tion to elucidate the reaction mechanism. Thus, when
benzoxazole was treated with a stoichiometric amount of
(9) Since the (IPr)CuOH complex is reported to be an effective
catalyst for a direct CÀH carboxylation of benzothiazole, we planned
to prepare (TPr)CuOH.4b However, a recent report shows that trans-
metallation of tzNHCsCuCl with CsOH gives tzNHC oxide, not copper
€
hydroxide. Petronilho, A.; Muller-Bunz, H.; Albrecht, M. Chem. Com-
mun. 2012, 48, 6499.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Direct Carboxylation with Substituted Benzothiazolesa
Scheme 1. Plausible Reaction Mechanism
entry
R
product, yield (%)b
1
3a, H
4a, 75
4b, 79
4c, 72
4d, 66
4e, 44
4f, 33
4g, 34
2
3b, 6-Me
3c, 6-MeO
3d, 6-Cl
3e, 6-Br
3f, 4-Me
3g, 4-Cl
3
4
5
6c
7c
a 3aÀg (1.0 mmol), t-BuOK (1.2 mmol), (TPr)CuCl (0.05 mmol);
THF (5 mL), CO2 (1 atm), 80 °C, then evaporation of THF under
vacuum, DMF (5 mL), MeI (2.0 mmol), 80 °C, 1 h. b Isolated yield.
c (TPh)CuCl was used as a catalyst.
change with t-BuOK, during which time the copper alk-
oxide regenerates.
In conclusion, we have prepared 1,2,3-triazol-5-yidene
based copper complexes that catalyzed the direct CÀH
carboxylation of heteroaromatic compounds effectively to
give the corresponding carboxylic acids and esters. The
complexes promoted the reaction somewhat more effec-
tively than the corresponding imidazol-2-ylidene copper
complexes. (TPr)CuCl was the most effective catalyst, but
readily accessible (TPh)CuCl could be used practically as
well.
(TPr)CuCl and t-BuOK, the benzoxazole copper complex
5 was isolated in 49% yield. In the 13C NMR spectrum
(THF-d8), distinctive signals were observed at 171.5 and
196.0 ppm. The former signal is readily assigned to the
carbene carbon of 1,2,3-triazol-5-ylidene, and the latter
signal can be assigned as the oxazole C-Cu since the signal
of C-Cu is observed at a similar position (195.8 ppm) in
the corresponding imidazol-2-ylidene copper complex,
(IPr)(benzoxazole)Cu. It is reasonable to identify the
copper complex as the (TPr)(benzoxazole)Cu complex.
We can assume the reaction mechanism is similar to that
proposed for the (IPr)CuCl-catalyzed reaction.4a,10
Acknowledgment. This study was financially supported
by a Grant-in-Aid, No. 22550044, for Scientific Research
from the Japan Society for the Promotion of Science
(JSPS) and a Chuo University Grant for Special Research.
Inthe first step, (TPr)Cu(OBut) isgenerated by the metal
exchange reaction of (TPr)CuCl with t-BuOK, and then
the copper alkoxide reacts with benzoxazole to afford
(TPr)(benzoxazole)Cu by deprotonation (CÀH activation)
of the benzoxazole CÀH bond (Scheme 1). Insertion of
CO2 into the CuÀC bond yields the copper carboxylate 6,
which leads to the potassium carboxylate by metal ex-
Supporting Information Available. Full experimental
procedures, characterization data, and 1H and 13C NMR
spectra (PDF) for all products; crystallographic data for
(TPr)CuCl in a CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Ariafard, A.; Zarkoob, F.; Batebi, H.; Stranger, R.; Yate, B. F.
Organometallics 2011, 30, 6218.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX