C-H carboxylation of heteroarenes with ambient CO2

Article abstract of DOI:10.1039/c6gc00200e

The C-H carboxylation of heteroarenes was achieved under transition metal-free reaction conditions with naturally abundant CO₂ as the C1 source at relatively low temperature. The C-H carboxylation was mediated by KOt-Bu at atmospheric pressure

Full text of DOI:10.1039/c6gc00200e

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DOI: 10.1039/C6GC00200E
ARTICLE TYPE
CH Carboxylation of heteroarenes with ambient CO2†
Sabine Fenner, and Lutz Ackermann*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
The CH carboxylation of heteroarenes was achieved under
establish a more economical and user-friendly method, the
transition metal-free reaction conditions with naturally
reaction was conducted with simple CuCl as the catalyst under
ligand-free reaction conditions, which provided product 3a in a
comparable yield (entry 2). Interestingly, when conducting a test
reaction in the absence of a transition metal catalyst solely with
the base KOt-Bu in DMF at 100 °C, the desired product 3a
was isolated in 80% yield (entry 3). An elevated reaction
temperature of 125 °C failed to afford an improvement (entry 4),
whilst a reaction conducted at 80 °C proceeded efficiently
abundant CO as the C1 source at relatively low temperature.
2
5
0
The CH carboxylation was mediated by KOt-Bu at
atmospheric pressure of CO , and thereby provided atom-
2
3
3
34
1
0
and step-economical access to various heteroaromatic
carboxylic acid derivatives.
5
5
Introduction
(
entries 4 and 5), clearly highlighting the beneficial features of
Strategies for the fixation of carbon dioxide (CO
2
) as an easily
KOt-Bu as compared to Cs CO that required 125 °C (vide
infra). Polar solvents other than DMF, such as NMP, 1,4-
dioxane, THF or DMSO, provided less satisfactory results
2
3
2
5
accessible, inexpensive, naturally abundant, and renewable C1
1
, 2
1
2
2
3
3
5
0
5
0
5
source towards valuable commodity chemicals have attracted
3
major topical interest. While significant progress has been 60 (entries 710), as did apolar toluene (entry 11). However, the
4
-
witnessed in the chemical use of CO during the recent decade,
encouraging result obtained with NMP as the solvent (entry 7)
2
1
4
the vast majority of these procedures require pre-functionalized
indicates the potential of our strategy for the use of greener
1
35
substrates, such as aryl halides or aryl boronic acids. The
synthesis of the prerequisite pre-oxidized arenes calls for a
solvents, such as 1-butylpyrrolidinone or Cyrene. On the
contrary, the CH functionalization performed in DMA furnished
number of reaction steps, which contradicts the principles of 65 carboxylic acid ester 3a with a high efficacy (entry 12).
1
5
green chemistry. In contrast, the direct functionalization of
Interestingly, bases other than KOt-Bu, including Cs
2 3
CO or
otherwise inert CH bonds represents a considerably more atom-
and step-economical strategy, with important advances in direct
Rb CO , proved to be considerably less effective under otherwise
identical reaction conditions (entries 13, and 14), illustrating the
unique power of KOt-Bu as the base, particularly at a reaction
2
3
1
6
1
7, 18
19-21
22, 23
carboxylations
accomplished by Iwasawa,
Nolan,
2
4
25
11
26, 27
28
Hou, Hu, Leitner, and Beller,
our program on catalytic CH activation,
attracted by devising reaction conditions for sustainable CH
among others. Within 70 temperature of 80 °C (entry 15 versus 5).
2
9, 30
we became
a
2
Table 1 Optimization of CH carboxylation with CO .
3
1
carboxylation with ambient CO under mild conditions. As a
2
result of our efforts, we have developed a highly effective
protocol for step-economical CH carboxylations of heteroarenes
with ambient CO under transition metal-free reaction conditions,
2
3
1
on which we now wish to report herein. In contrast to
22-24
previously reported methods,
our CH carboxylation protocol
Entry Base
Solvent
KOt-Bu DMF
KOt-Bu DMF
T
1
[°C]
T
2
[°C]
3a [%]
is operative in the absence of transition metals at relatively low
temperatures of only 80-100 °C.
b
1
80
65
65
65
65
65
40
65
65
65
65
65
65
82
c
2
100
100
125
80
76
3
KOt-Bu DMF
KOt-Bu DMF
KOt-Bu DMF
KOt-Bu DMF
KOt-Bu NMP
KOt-Bu 1,4-dioxane
KOt-Bu THF
KOt-Bu DMSO
KOt-Bu PhMe
KOt-Bu DMA
80
80
71
(10)
69
-
Results and Discussion
4
At the outset of our studies, we chose reaction conditions similar
to the ones previously described for the carboxylations of
5
4
0
6
40
3
2
organoboronic esters with CO
2
(Table 1). Thus, when reacting
7
100
100
65
benzo[d]oxazole (1a) in the presence of 10 mol % of the well-
defined N-heterocyclic carbene copper(I) complex [Cu(IPr)Cl] in
8
9
(4)
52
(11)
77
DMF at 80 °C under an atmosphere of CO , 82% isolated yield of
10
11
12
100
100
100
2
4
5
methylbenzo[d]oxazole-2-carboxylate (3a) were obtained upon
treatment with methyl iodide (2a) (Table 1, entry 1). In order to
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Green Chem., [year], [vol], 00–00 | 1

Green Chemistry
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1
1
1
3
4
5
Cs
Rb
Cs
2
CO
CO
CO
3
DMF
DMF
DMF
100
100
80
65
65
65
69
8
50 conditions, which should prove instrumental for further late-stage
diversification by inter alia cross-coupling technology.View Article Online
2
3
2
3
23
DOI: 10.1039/C6GC00200E
a
Reaction conditions: 1a (1.0 mmol), base (1.2 mmol), solvent
(
5.0 mL), CO
2
(1 atm), T
1
, 18 h; 2a (3.0 mmol), T
2
, 2 h; yields of
55
b
isolated products; GC-conversion in parentheses. With [Cu(IPr)Cl]
c
(10 mol %). With CuCl (10 mol %).
With the optimized reaction conditions in hand, the scope of the
6
6
7
7
8
8
9
0
5
0
5
0
5
0
3
6
C–H carboxylation was explored next (Scheme 1). A series of
representative heteroarenes 1 was successfully converted into the
desired carboxylic acid esters 3 under transition metal-free
5
0
5
0
5
0
5
0
5
2
reaction conditions with atmospheric CO .
[
a]
Scheme 2 C–H carboxylation of oxazoles 4. GC-conversion.
1
1
2
2
3
3
4
4
Finally, we were pleased to observe that 1,3,4-oxadiazoles 6
proved to be viable substrates for the CH carboxylation under
ambient CO2 atmosphere as well, providing the desired
carboxylic acid esters 7a–c with high levels of selectivity control
(
Scheme 3).
[
a]
Scheme 1. C–H carboxylation with ambient CO2.
2 3
Cs CO as
the base.
Various alkyl carboxylates 3 were obtained upon subsequent
esterification with different alkyl iodides 2 under rather mild
reaction conditions. Methyl- as well as chloro-substituted
benzo[d]oxazoles 1b and 1c were site-selectively functionalized,
affording the 2-substituted carboxylic acid esters 3b–d in high
yields after treatment with the corresponding alkyl iodide 2.
Notably, the use of Cs CO as the base under otherwise identical
Scheme 3 C–H carboxylation of oxadiazoles 6.
25,38
Based on literature precedents,
we propose the reaction to
proceed by initial reversible C–H cleavage (Scheme 4), along
with subsequent C–C formation by the action of ambient CO .
2
2
3
reaction conditions resulted in an inferior yield of only 48% for
product 3b. Likewise, it is noteworthy that chloro-substituted
azole 1c provided the corresponding product 3d in an excellent
yield of 91%, whereas Cs
ester 3d. As showcased in
2
CO
3
delivered only 55% of the desired
representative set of C–H
a
functionalizations, our sustainable approach was not restricted to
the use of methyl iodide as the electrophiles, but also allowed
esterification with a variety of alkyl iodides 2. Moreover, our
protocol set the stage for the C–H carboxylation of benzothiazole
in a step-economical fashion. Indeed, the corresponding methyl
ester 3f and hexyl ester 3g were isolated in 66% and 62% yield,
respectively.
9
5
Scheme 4 Proposed mechanism for the C–H carboxylation.
Conclusions
Furthermore, oxazoles 4 served as viable substrates for the C–H
carboxylation, delivering the corresponding carboxylic acid
derivatives 5a–d in a step- and atom-economical manner
2
In summary, we have reported on the use of CO as an easily
1
00 accessible, inexpensive, and renewable C1 source for green C–H
carboxylations under transition metal-free reaction conditions.
Hence, KOt-Bu enabled efficient C–H functionalizations on
3
7
(
Scheme 2). Intriguingly, valuable chlorine substituents on the
heteroarenes were well tolerated under the optimized reaction
3
9
heteroarenes with ample substrate scope under mild reaction
2
| Green Chem., [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 4
Green Chemistry
1
1
1
3.
4.
5.
X. Wang, Y. Liu and R. Martin, J. Am. Chem. Soc., 2015, 137,
6476-6479.
A. Correa and R. Martin, J. Am. Chem. SoVci.e,w2A0rt0ic9le, O1n3li1n,e
conditions, namley at rather low reaction temperature and
ambient pressure of CO2.
6
7
7
5
0
5
1
5974-15975.
DOI: 10.1039/C6GC00200E
L. Ackermann, A. R. Kapdi, H. K. Potukuchi and S. I.
Kozhushkov, in Handbook of Green Chemistry, ed. C.-J. Li,
Wiley-VCH, Weinheim, 2012, pp. 259-305.
Representative reviews on C–H activation: a) J. G. Kim, K.
Shin and S. Chang, Top. Organomet. Chem., 2016, 55, 29-51;
b) M. Moselage, J. Li and L. Ackermann, ACS Catal., 2016, 6,
Acknowledgements
Support by the CaSuS (Catalysis for Sustainable Synthesis) PhD
program is gratefully acknowledged.
1
6.
5
4
98-525; c) O. Daugulis, J. Roane and L. D. Tran, Acc. Chem.
Res., 2015, 48, 1053-1064; d) Y. Segawa, T. Maekawa and K.
Itami, Angew. Chem. Int. Ed., 2015, 54, 66-81; e) N. Kuhl, N.
Schroeder and F. Glorius, Adv. Synth. Catal. 2014, 356, 1443-
Notes and References
1
460; f) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem.
Institut fuer Organische und Biomolekulare Chemie,
Georg-August-Universitaet, Tammannstrasse 2, 37077 Goettingen,
Germany. E-mail: Lutz.Ackermann@chemie.uni-goettingen.de;
Fax: +49 551 396777
Int. Ed., 2014, 53, 74-100; g) J. Wencel-Delord and F. Glorius,
Nature Chem., 2013, 5, 369-375; h) S. R. Neufeldt and M. S.
Sanford, Acc. Chem. Res., 2012, 45, 936-946; i) T. Satoh and
M. Miura, Chem. Eur. J., 2010, 16, 11212-11222; j) L.
Ackermann, R. Vicente and A. Kapdi, Angew. Chem. Int. Ed.,
80
1
1
2
2
0
5
0
5
†
Electronic Supplementary Information (ESI) available: Experimental
1 13
2
009, 48, 9792-9826; k) R. G. Bergman, Nature, 2007, 446,
procedures, characterization data, and H and C NMR spectra for
products. See DOI: 10.1039/b000000x/
8
9
9
5
0
5
391-393, and references cited therein.
A. Uhe, M. Hoelscher and W. Leitner, Chem. Eur. J., 2012,
1
1
7.
8.
1
8, 170-177.
‡
2
Representative procedure for the C–H carboxylation using CO :
S. D. Stoychev, C. M. Conifer, A. Uhe, M. Hoelscher and W.
Leitner, Dalton Trans., 2014, 43, 11180-11189.
H. Mizuno, J. Takaya and N. Iwasawa, J. Am. Chem. Soc.,
Synthesis of methylbenzo[d]oxazole-2-carboxylate (3a): A mixture
of 1a (118 mg, 0.99 mmol), KOt-Bu (135 mg, 1.20 mmol) and DMF
19.
(5.0 mL) was degassed in a Schlenk-tube. The Schlenk-tube was then
2
011, 133, 1251-1253.
flushed with CO via a balloon and CO was bubbled through the
2
2
2
2
2
2
0.
1.
2.
3.
T. Suga, H. Mizuno, J. Takaya and N. Iwasawa, Chem.
Commun., 2014, 50, 14360-14363.
K. Sasano, J. Takaya and N. Iwasawa, J. Am. Chem. Soc.,
2013, 135, 10954-10957.
I. I. F. Boogaerts, G. C. Fortman, M. R. L. Furst, C. S. J. Cazin
and S. P. Nolan, Angew. Chem. Int. Ed., 2010, 49, 8674-8677.
I. I. F. Boogaerts and S. P. Nolan, J. Am. Chem. Soc., 2010,
reaction mixture for 10–20 minutes. After removal of the balloon, the
reaction was heated to 100 °C for 18 h. After cooling to 65 °C, 2a
(
3.00 equiv) was added and the reaction mixture was stirred at 65 °C
for 2 h. At ambient temperature, the reaction mixture was diluted with
O (25 mL) and Et O (25 mL). The aqueous layer was extracted with
O (3 x 25 mL) and the combined organic layers were dried over
SO . Purification by column chromatography (n-pentane/Et O =
0/1  10/1  7/1  5/1) yielded 3a (141 mg, 80%) as a colorless
solid.
H
Et
Na
2
2
2
2
4
2
1
32, 8858-8859.
2
1
1
1
1
1
1
1
1
00 24.
L. Zhang, J. Cheng, T. Ohishi and Z. Hou, Angew. Chem. Int.
Ed., 2010, 49, 8670-8673.
O. Vechorkin, N. Hirt and X. Hu, Org. Lett., 2010, 12, 3567-
3
3
4
4
5
5
6
0
5
0
5
0
5
0
2
2
2
5.
6.
7.
3
569.
Y. Li, T. Yan, K. Junge and M. Beller, Angew. Chem. Int. Ed.,
2014, 53, 10476-10480.
Y. Li, I. Sorribes, T. Yan, K. Junge and M. Beller, Angew.
Chem. Int. Ed., 2013, 52, 12156-12160.
L. Ackermann, Angew. Chem. Int. Ed., 2011, 50, 3842-3844.
L. Ackermann, Synlett, 2007, 507-526.
L. Ackermann, Acc. Chem. Res., 2014, 47, 281-295.
S. Fenner, PhD thesis, Georg-August-University, 2012.
L. Zhang, J. Cheng, T. Ohishi and Z. Hou, Angew. Chem. Int.
Ed., 2010, 49, 8670-8673.
1
.
Q. Liu, L. Wu, R. Jackstell and M. Beller, Nature Commun.,
015, 6, 5933.
T. E. Mueller and W. Leitner, Beilstein J. Org. Chem., 2015,
1, 675-677.
05
2
2.
1
2
2
8.
9.
3
.
For selected recent reviews, see: a) L. Zhang and Z. Hou,
Chem. Sci., 2013, 4, 3395-3403; b) Y. Tsuji and T. Fujiharaa,
Chem. Commun., 2012, 48, 9956-9964; c) M. Cokoja, C.
Bruckmeier, B. Rieger, W. A. Herrmann and F. E. Kühn,
Angew. Chem. Int. Ed., 2011, 50, 8510-8537; d) M. Beller and
U. T. Bornscheuer, Angew. Chem. Int. Ed., 2014, 53, 4527-
10 30.
3
3
1.
2.
3
3.
KOt-Bu was purchased from SIGMA-ALDRICH, where it
was sublimed and analyzed by ICP-MS, which revealed only
trace amounts of transition metals (inter alia <0.5 ppm Fe;
4
2
528; e) K. Huang, C.-L. Sun and Z.-J. Shi, Chem. Soc. Rev.,
011, 40, 2435-2452; f) T. Sakakura, J.-C. Choi and H.
15
20
25
30
Yasuda, Chem. Rev., 2007, 107, 2365-2387, and references
cited therein.
<0.1 ppm Cu, Pd, Ni).
3
4.
(a) For representative
pKa
values,
see
4
5
.
.
I. I. F. Boogaerts and S. P. Nolan, Chem. Commun., 2011, 47,
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm. (b)
For calculated pKa values, see: K. Shen, Y. Fu, J.-N. Li, L.
Liu and Q.-X. Guo, Tetrahedron, 2007, 63, 1568–1576, and
references cited therein. (c) For DFT studies on carboxylations
of heteroarenes by copper(I) complexes, see: A. Ariafard, F.
Zarkoob, H. Batebi, R. Stranger and B. F. Yates,
Organometallics, 2011, 30, 6218–6224.
J. Sherwood, M. D. bruyn, A. Constantinou, L. Moity, C. R.
McElroy, T. J. Farmer, T. Duncan, W. Raverty, A. J. Hunta
and J. H. Clark, Chem. Commun., 2014, 50, 9650-9652.
All direct carboxylation reactions were performed in new
glassware using novel stirring bars.
For detailed information see the Electronic Supporting
Information (ESI).
A. Banerjee, G. R. Dick, T. Yoshino and M. W. Kanan,
Nature, 2016, 531, 215-219.
J. Wencel-Delord, T. Droege, F. Liu and F. Glorius, Chem.
Soc. Rev., 2011, 40, 4740-4761.
3
021-3024.
L. Yang and H. Wang, ChemSusChem, 2014, 7, 962-998.
R. Martin and A. W. Kleij, ChemSusChem 2011, 4, 1259-1263
T. Sakakura, J.-C. Choi and H. Yasuda, Chem. Rev., 2007,
6.
7
8
.
.
1
07, 2365-2387.
P. Braunstein, D. Matt and D. Nobel, Chem. Rev., 1988, 88,
47-764.
7
3
5.
9.
A. Boddien, F. Gaertner, C. Federsel, P. Sponholz, D.
Mellmann, R. Jackstell, H. Junge and M. Beller, Angew.
Chem. Int. Ed., 2011, 50, 6411-6414.
3
3
3
6.
7.
8.
1
0.
11.
2.
K. Beydoun, G. Ghattas, K. Thenert, J. Klankermayer and W.
Leitner, Angew. Chem. Int. Ed., 2014, 53, 11010-11014.
K. Beydoun, T. vom Stein, J. Klankermayer and W. Leitner,
Angew. Chem. Int. Ed., 2013, 52, 9554-9557.
1
X. Wang, M. Nakajima and R. Martin, J. Am. Chem. Soc.,
2
015, 137, 8924-8927.
35 39.
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