Sequential protocol for C(sp3)-H carboxylation with CO 2: Transition-metal-catalyzed benzylic C-H silylation and fluoride-mediated carboxylation

Article abstract of DOI:10.1021/ol301431d

One of the most challenging transformations in current organic chemistry is the catalytic carboxylation of a C(sp³)-H bond using CO₂ gas, an inexpensive and ubiquitous C1 source. A sequential protocol for C(sp³)-H carboxylation by employing a nitrogen-directed, metal-assisted, C-H activation/catalytic silylation reaction in conjunction with fluoride-mediated carboxylation with CO₂ was established. The carboxylation proceeded only at the benzylic C(sp³)-Si bond, not at the aromatic C(sp²)-Si, which is advantageous for further manipulations of the products.

Full text of DOI:10.1021/ol301431d

ORGANIC
LETTERS
Sequential Protocol for C(sp3)ꢀH
Carboxylation with CO2: Transition-
Metal-Catalyzed Benzylic CꢀH Silylation
and Fluoride-Mediated Carboxylation
2012
Vol. 14, No. 13
3462–3465
Tsuyoshi Mita,* Kenichi Michigami, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
tmita@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
Received May 23, 2012
ABSTRACT
One of the most challenging transformations in current organic chemistry is the catalytic carboxylation of a C(sp3)ꢀH bond using CO2 gas, an
inexpensive and ubiquitous C1 source. A sequential protocol for C(sp3)ꢀH carboxylation by employing a nitrogen-directed, metal-assisted, CꢀH
activation/catalytic silylation reaction in conjunction with fluoride-mediated carboxylation with CO2 was established. The carboxylation
proceeded only at the benzylic C(sp3)ꢀSi bond, not at the aromatic C(sp2)ꢀSi, which is advantageous for further manipulations of the products.
Carbon dioxide (CO2) is a very attractive C1 feedstock
that should be used more diversely for organic synthesis in
view of the diminishing supplies of conventional petroleum
products starting to become problematic within several
decades. Therefore, considerable efforts have recently been
made for the development of effective CO2 incorporation
reactions.1 Among these technologies, catalytic carboxyla-
tions with CO2 via aromatic C(sp2)ꢀH bond activation
have recently been achieved. Nolan2 and Hou3 indepen-
dently reported pKa-dependent carboxylations of electron-
deficient aromatic compounds catalyzed by Au(I) or Cu(I)
complexes, while Iwasawa reported a chelation-assisted car-
boxylation of 2-aryl pyridine and 1-aryl pyrazole derivatives
catalyzed by Rh(I) complexes.4,5 Although those protocols
are obviously landmarks in catalytic CO2 incorporation
into CꢀH bonds, there is still room for the development
of catalytic carboxylation of a C(sp3)ꢀH bond with CO2,
which should provide a new entry to CO2 incorporation
chemistry.
We recently reported that N-Boc-R-amido benzyl stan-
nanes, which can be prepared from imines or imine
equivalents,6 can be easily carboxylated in the presence of
CsF and CO2 gas to afford the corresponding arylglycine
(5) Without using transition metal catalysts, see: Vechorkin, O.; Hirt,
N.; Hu, X. Org. Lett. 2010, 12, 3567.
(6) (a) Mita, T.; Higuchi, Y.; Sato, Y. Org. Lett. 2011, 13, 2354.
(b) Mita, T.; Higuchi, Y.; Sato, Y. Synthesis 2012, 44, 194.
(7) Mita, T.; Chen, J.; Sugawara, M.; Sato, Y. Angew. Chem., Int. Ed.
2011, 50, 1393.
(8) Mita, T.; Sugawara, M.; Hasegawa, H.; Sato, Y. J. Org. Chem.
2012, 77, 2159.
(9) For benzylic CꢀH silylation, see: Kakiuchi, F.; Tsuchiya, K.;
Matsumoto, M.; Mizushima, E.; Chatani, N. J. Am. Chem. Soc. 2004,
126, 12792 and references cited therein.
(1) For recent reviews on CO2 incorporation reactions, see: (a) Sakakura,
T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (b) Mori, M. Eur. J.
Org. Chem. 2007, 4981. (c) Correa, A.; Martın, R. Angew. Chem., Int.
Ed. 2009, 48, 6201. (d) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010,39, 3347.
(e) Boogaerts, I. I. F.; Nolan, S. P. Chem. Commun. 2011, 47, 3021. (f)
Ackermann, L. Angew. Chem., Int. Ed. 2011, 50, 3842. (g) Cokoja, M.;
€
Bruckmeier, C.; Rieger, B.; Herrmann, W. A.; Kuhn, F. E. Angew. Chem.,
Int. Ed. 2011, 50, 8510.
(2) (a) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132,
8858. (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.
(3) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int. Ed.
2010, 49, 8670.
(10) For benzylic CꢀH borylation, see: (a) Shimada, S.; Batsanov,
A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem., Int. Ed. 2001, 40,
2168. (b) Ishiyama, T.; Ishida, K.; Takagi, J.; Miyaura, N. Chem. Lett.
2001, 1082. (c) Boebel, T. A.; Hartwig, J. F. Organometallics 2008, 27,
6013. For a review on CꢀH borylation, see also: (d) Mkhalid, I. A. I.;
Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev.
2010, 110, 890.
(4) Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2011,
133, 1251.
r
10.1021/ol301431d
Published on Web 06/19/2012
2012 American Chemical Society

derivatives (Scheme 1, eq 1).7,8 If a similar benzylic metalloid
species 2 (M = Sn, Si, or B) could be prepared by a CꢀH
metalation reaction, catalyzed by a transition metal
complex,9,10 the corresponding acid 3 could also become
available following activation of metalloid species 2 with a
fluoride anion under a CO2 atmosphere (eq 2). Ideally, these
two steps could be carried out in one pot11 without isolation
of the benzylic metalloid intermediates 2, which is deemed to
be a formal C(sp3)ꢀH carboxylation with CO2.
Table 1. Carboxylations of Benzylic Metalloids
temp
time
(h)
3a
(%)a
entry
M
(°C)
1
2
3
SnBu3
SiEt3
(2aa)
(2ab)
(2ac)
140
100
140
6
20
86
21
1
B(pin)
0.5
Scheme 1. Synthetic Strategies for R-Aryl Acetic Acids Using
CO2 Gas
a Yields were determined by 1H NMR analysis using 1,1,2,2-tetra-
chloroethane as an internal standard.
of CO2, the synthesis of benzylic silanes was envisioned via
a benzylic C(sp3)ꢀH activation protocol;Kakiuchi and co-
workers have already reported Ru3(CO)12-catalyzed
benzylic C(sp3)ꢀH silylation in the presence of Et3SiH
and norbornene as a hydrogen trapping agent.9 However,
Ir(I)-catalyzed intermolecular CꢀH silylation reactions13
are less developed even though iridium catalysts are well-
known to promote thermal CꢀH borylation reactions.10d
Therefore, we first employed an Ir(I) catalyst to unveil its
reactivity toward C(sp3)ꢀH silylation; 8-methylquinoline 1b
was used as a substrate with a combination of [Ir(cod)Cl]2
and Et3SiH (Scheme 2, method A1). As a result, the C(sp3)ꢀ
H silylation reaction proceeded smoothly and catalytically
even in the absence of norbornene,14 affording 2b in 98%
yield.15 The reaction should not be conducted in a closed
system (e.g., sealed tube) in order to release generated
hydrogen gas. We also investigated Ru3(CO)12-catalyzed
C(sp3)ꢀH silylation according to Kakiuchi’s protocol9 with
some modifications (reactions conducted in a sealed tube),
and 2b was also obtained in 93% yield in the presence of
norbornene (the reported yield: 78%) (method B1). The
chelation mode between 1b and Ir or Ru is expected to be a
stable five-membered one. Subsequently, substrate 1c posses-
sing pyridine as a directing group was selected for C(sp3)ꢀ
H silylation. Both Ir(I) and Ru(0) catalysts were active.
However, product distribution largely depended on the
catalyst employed. The Ir(I) catalyst induced aromatic
C(sp2)ꢀH silylation selectively even when an excess amount
First, simple benzyl stannane, silane, and boron com-
pounds 2aa to 2ac were synthesized to evaluate their
reactivities toward carboxylations with CO2 using 3 equiv
of CsF under 1 atm of CO2 (balloon) (Table 1). Benzyl
stannane 2aa was completely consumed at 140 °C, but after
methyl esterification, only 20% of methyl R-phenyl acetate
(3a) was obtained, probably due to the generation of a large
amount of toluene by the undesired protodestannylation.
To our delight, benzyl silane 2ab was a suitable substrate,
affording 3a in 86% yield within 1 h at 100 °C.12 In contrast,
the reaction became sluggish when using benzyl pinacolbor-
on 2ac at 140 °C, giving 3a only in 21% yield.
Since we found that benzyl silane was a suitable sub-
strate for promoting the carboxylation at ambient pressure
(11) For one-pot procedures for CꢀH borylation and subsequent func-
tionalizations, see: (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.,
Jr.; Smith, M. R., III. Science 2002, 295, 305. (b) Maleczka, R. E., Jr.; Shi,
F.; Holmes, D.; Smith, M. R., III. J. Am. Chem. Soc. 2003, 125, 7792. (c)
Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun.
2003, 2924. (d) Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr.; Smith,
M. R., III. Org. Lett. 2006, 8, 1407. (e) Shi, F.; Smith, M. R., III.; Maleczka,
R. E., Jr. J. Org. Lett. 2006, 8, 1411. (f) Murphy, J. M.; Liao, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 15434. (g) Murphy, J. M.; Tzschucke,
C. C.; Hartwig, J. F. Org. Lett. 2007, 9, 757. (h) Tzschucke, C. C.; Murphy,
J. M.; Hartwig, J. F. Org. Lett. 2007, 9, 761. (i) Kikuchi, T.; Nobuta, Y.;
Umeda, J.; Yamamoto, Y.; Ishiyama, T.; Miyaura, N. Tetrahedron 2008,
64, 4967. (j) Boebel, T. A.; Hartwig, J. F. Tetrahedron 2008, 64, 6824. (k)
Harrisson, P.; Morris, J.; Steel, P. G.; Marder, T. B. Synlett 2009, 147. (l)
Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P. G. Org. Lett. 2009, 11,
3586. (m) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed.
2008, 47, 3004. (n) Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 11389. (o) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2012, 51, 536. (p)Liu, T.;Shao, X.;Wu, Y.;Shen, Q.Angew.
Chem., Int. Ed. 2012, 51, 540.
(13) For iridium-catalyzed CꢀH silylations using hydrosilanes
and disilanes, see: (a) Gustavson, W. A.; Epstein, P. S.; Curtis, M. D.
Organometallics 1982, 1, 884. (b) Ishiyama, T.; Sato, K.; Nishio, Y.;
Miyaura, N. Angew. Chem., Int. Ed. 2003, 42, 5346. (c) Ishiyama, T.;
Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chem. Commun. 2005, 5065.
(d) Saiki, T.; Nishio, Y.; Ishiyama, T.; Miyaura, N. Organometallics
2006, 25, 6068. (e) Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47,
7508. (f) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
17092. (g) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70.
(14) The reaction seemed to proceed via the σ-CAM (σ-complex-
assisted metathesis) process. See: Hartwig, J. F.; Cook, K. S.; Hapke,
M.; Incarvito, C. D.; Fan, Y.; Webster, C. E.; Hall, M. B. J. Am. Chem.
Soc. 2005, 127, 2538. For a review on a σ-CAM, see: Perutz, R. N.; Sabo-
Etienne, S. Angew. Chem., Int. Ed. 2007, 46, 2578.
(12) Carboxylations of C(sp3)ꢀSi bonds by a fluoride anion were
only achieved using specific substrates such as 1-cyano-1-trimethylsi-
lylcyclopropane and (perfluoroalkyl)trimethylsilanes. See: (a) Ohno,
M.; Tanaka, H.; Komatsu, M.; Ohshiro, Y. Synlett 1991, 919. (b) Singh,
R. P.; Shreeve, J. M. Chem. Commun. 2002, 1818. (c) Babadzhanova,
L. A.; Kirij, N. V.; Yagupolskii, Y. L. J. Fluorine Chem. 2004, 125, 1095.
(d) Petko, K. I.; Kot, S. Y.; Yagupolskii, L. M. J. Fluorine Chem. 2008,
129, 301. For fluoride-mediated carboxylations of C(sp2)ꢀSi bonds, see:
(e) Effenberger, F.; Spiegler, W. Chem. Ber. 1985, 118, 3900.
(15) The sp2 carbon of quinoline and quinoxaline was also silylated
(not sp3-selective) when [Ir(cod)OMe]2 with 4,40-di-tert-butyl-2,20-
bipyridine (dtbpy) was used as a catalyst. See ref 13e.
Org. Lett., Vol. 14, No. 13, 2012
3463

of Et3SiH was used (method A2: 7 equiv of Et3SiH
used), while the Ru(0) catalyst induced both C(sp2)ꢀH
and C(sp3)ꢀH silylations (method B2: 7 equiv of
Et3SiH and norbornene used). We considered that this
regioselective silylation was due to the different modes
of metal coordination. Ir prefers a stable five-mem-
bered mode of coordination, while Ru forms not only a
five-membered but also a six-membered metallacycle.
In addition, a seven-membered metallacycle contain-
ing two ruthenium atoms16 derived from trinuclear
Ru3(CO)12 might also be expected as a possible inter-
mediate.
alsoa goodsubstrate for carboxylation;under the fluoride-
mediated conditions, the aromatic C(sp2)ꢀSi bond was
intact and 3c was obtained in 82% yield along with 2ca in
11% yield.
By concatenating Ir(I) or Ru(0)-catalyzed C(sp3)ꢀH
silylation and fluoride-mediated carboxylation,17 we have
established a sequential protocol11 for a formal C(sp3)ꢀH
carboxylation with CO2 (Figure 1). Since CꢀH silylation
did not proceed at all in DMF, the best solvent for the
following carboxylation, solvent exchange was necessary
after the silylation. By installation of a simple solvent
exchange via evaporation of toluene and other volatile
materials (Et3SiH and norbornene if used) followed by the
introduction of DMF, sequential reactions for various
substrates possessing a nitrogen atom at an appropriate
position proceeded smoothly. Aiming at the five-
membered chelation system, [Ir(cod)Cl]2 was employed
for 8-methylquinoline derivatives to afford the corre-
sponding carboxylic acid derivatives 3b, 3d, and 3e in high
yields without affecting other methyl groups at nonchelat-
ing positions. Although 1 was consumed completely in the
silylation step, 1 was regenerated by the undesired proto-
desilylation under the fluoride-mediated conditions, which
can be reused as a substrate for this sequential process.
5-Methylquinoxaline (1f) was also applicable for the se-
quential carboxylation, affording 3f in moderate yield.
Next, various substrates having a pyridine directing group
were examined in the presence of Ru3(CO)12 and norbor-
nene. When 1c was used, monocarboxylate 3c attached to
the TES group on the aromatic ring was obtained in 81%
yield. Again, the aromatic C(sp2)ꢀSi bond was intact
during the fluoride-mediated carboxylation. In addi-
tion, double carboxylations at two benzylic positions
were achieved for 1g, and a primary C(sp3)ꢀH bond was
selectively silylated for 1h. The reaction of methyl
naphthalene 1i proceeded only at the benzylic position
to afford the product in 90% yield. Furthermore, a
pyrimidine as well as a quinoline directing group was
also effective in this sequential protocol, giving the
corresponding methyl esters in moderate yields. Benzox-
azole 1l was also compatible for Ru-catalyzed reaction
(72%) but not for Ir-catalyzed reaction (8%) even
though a favorable five-membered chelation would be
expected for both catalysts.
Scheme 2. Catalytic Benzylic C(sp3)ꢀH Silylations
Given the establishment of high-yielding C(sp3)ꢀH
silylation at a benzylic position, prepared benzyl silanes
2b and 2cb were subjected to fluoride-mediated carboxyla-
tion (Scheme 3: 3 equiv of CsF under 1 atm of CO2).12
Since the desired amino carboxylic acids are water-soluble,
the reaction mixture was directly treated with MeI and
Cs2CO3, affording methyl ester 3b in 91% yield together
with the protodesilylation product 1b in 9% yield. Nota-
bly, 1 atm of CO2 was sufficient for selective carboxylation
in contrast to our previous reports.7,8 Substrate 2cb was
Considering the utility of the remaining silyl group of 3c,
we demonstrated further manipulation of 3c, in which the
C(sp2)ꢀSi moiety could be iodinated quantitatively in the
presence of ICl. The Pd(0)-catalyzed coupling reaction of
4c (e.g., SuzukiꢀMiyaura cross-coupling with phenyl
boronic acid) resulted in CꢀC bond formation without
affecting the acidic methylene carbonyl moiety, affording
5c in 83% yield (Scheme 4).
(17) The reaction of 1b and 1c by using 1.2 equiv of sec-BuLi or LDA
(lateral lithiation) in THF at ꢀ78 °C under CO2 (1 atm) did not give any
carboxylated products; either a sec-butyl group was introduced on the
2-position or no reaction occurred. These observations suggested that
this one-pot process has synthetic utility as well, even though an excess
amount of Et3SiH should be employed. For a review on laterallithiation,
see: Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(16) For chelation-assisted multinuclear intermediates through CꢀH
activations, see: (a) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi,
F.; Murai, S. J. Am. Chem. Soc. 1998, 120, 11522. (b) Kwak, J.; Kim, M.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
3464
Org. Lett., Vol. 14, No. 13, 2012

Figure 1. Reaction conditions: method A: a substrate (0.4 mmol), [Ir(cod)Cl]2 (5mol%),Et3SiH (A1: 5 equiv, A2: 7 equiv), toluene (2.0 M), reflux,
20 h, then CsF (3 equiv), DMF (0.1 M), 100 °C, 2 h, then MeI (2 equiv), Cs2CO3 (2 equiv), rt, 30 min; method B: a substrate (0.3 mmol), Ru3(CO)12
(6 mol %), Et3SiH (B1: 5 equiv, B2: 7 equiv), norbornene (B1: 5 equiv, B2: 7 equiv), toluene (2.0 M), 150 °C (closed), 20 h, then CsF (3 equiv),
DMF(0.1M),100°C, 2 h, then MeI (2 equiv), Cs2CO3 (2 equiv), rt, 30 min. Isolated yields are shown unless otherwise noted. a1.0 equiv of Cs2CO3
was used. b3.0 equiv of Cs2CO3 and 5.0 equiv of MeI were used. cYields were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an
internal standard.
reaction consists of a nitrogen-directed silylation cata-
lyzed by either an Ir(I) or Ru(0) complex and a fluoride-
Scheme 3. Carboxylations of Benzyl Silanes
mediated carboxylation, which could be operated in a
single flask just by changing the reaction solvent. In this
sequential reaction, the C(sp3)ꢀSi bond was selectively
activated by a fluoride anion to promote the following
carboxylation with CO2, affording the desired car-
boxylic acid derivatives in moderate to high yields.
Further substrate scope studies including different di-
recting groups on the aromatic ring as well as the
development of a direct catalytic carboxylation of C-
(sp3)ꢀH are now actively ongoing.
Acknowledgment. This work was financially supported
by Grants-in-Aid for Young Scientists (B) (No. 24750081)
and for Scientific Research (B) (No. 23390001) from the
Japan Society for the Promotion of Science (JSPS), by a
Grant-in-Aid for Scientific Research on Innovative Areas
“Molecular Activation Directed toward Straightforward
Synthesis (No. 23105501)” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and
by the Uehara Memorial Foundation.
Scheme 4. Functionalization of Aromatic CꢀSi Bond
Supporting Information Available. Details of experi-
mental procedures and physical properties of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have developed a novel sequential
protocol for C(sp3)ꢀH carboxylation with CO2 gas. This
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3465