Synthesis of 3-carboxylated indoles through a tandem process involving cyclization of 2-ethynylanilines followed by CO2 fixation in the absence of transition metal catalysts

Article abstract of DOI:10.1021/ol300958c

In this study, a facile synthesis of 3-carboxylated indoles involving a tandem-type cyclization of 2-ethynylanilines and subsequent CO₂ fixation at the 3-position of the indole ring is realized. The reaction proceeds efficiently at 65 °C under

Full text of DOI:10.1021/ol300958c

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2622–2625
Synthesis of 3-Carboxylated Indoles
through a Tandem Process Involving
Cyclization of 2-Ethynylanilines Followed
by CO2 Fixation in the Absence of
Transition Metal Catalysts
Kiyofumi Inamoto,* Narumi Asano, Yuka Nakamura, Misato Yonemoto, and
Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki,
Aoba-ku, Sendai 980-8578, Japan
inamoto@m.tohoku.ac.jp; ykondo@m.tohoku.ac.jp
Received April 13, 2012
ABSTRACT
In this study, a facile synthesis of 3-carboxylated indoles involving a tandem-type cyclization of 2-ethynylanilines and subsequent CO2 fixation at
the 3-position of the indole ring is realized. The reaction proceeds efficiently at 65 °C under 10 atm of CO2, giving rise to variously substituted
3-carboxylated indoles, generally in high yields. An inorganic base, such as K2CO3, is the only reagent required, and the addition of transition
metal catalysts is not necessary. The method provides a novel, simple, and promising strategy for CO2 fixation in the research field of heterocyclic
chemistry.
The fixation of CO2 into certain molecules has recently
attracted considerable attention because CO2 is inexpen-
sive, easy-to-handle, and nontoxic; thus it can be consid-
ered as an ideal, renewable C1 unit in organic synthesis.1
As a carbon nucleophile, highly reactive organometallic
reagents such as organolithiums and Grignard reagents
have been employed with relatively less reactive CO2 for
the synthesis of carboxylic acids and their derivatives;
however, the low functional group compatibility of these
methods limits their practical use in organic synthesis. In
2006, Iwasawa’s group reported a method for the carboxy-
lation of aryl and alkenylboronic esters using CO2 in the
presence of a rhodium catalyst.2b It was later found that
copper-based catalytic systems also participate in a similar
carboxylation of boronic esters.2d,e Moreover, Oshimaand
Yorimitsu,2c and Dong2f independently reported the Ni-
and Pd-catalyzed coupling of organozinc reagents with
CO2. Recently, Pd-catalyzed direct transformation of aryl
bromides to the corresponding aryl carboxylic acids in
the presence of 1 atm of CO2 was realized.2h Although
these catalytic processes2 provide novel, efficient routes to
aryl and alkylcarboxylic acids under much milder condi-
tions, the need for the use of a stoichiometric amount of
(2) For selected recent examples of the CO2 fixation in the presence of
a transition metal catalyst, see: (a) Takimoto, M.; Nakamura, Y.;
Kimura, K.; Mori, M. J. Am. Chem. Soc. 2004, 126, 5956. (b) Ukai, K.;
Aoki, M.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2006, 128, 8706. (c)
Ochiai, H.; Jang, M.; Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett.
2008, 10, 2681. (d) Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org.
Lett. 2008, 10, 2697. (e) Ohishi, T.; Nishimura, M.; Hou, Z. Angew.
Chem., Int. Ed. 2008, 47, 5792. (f) Yeung, C. S.; Dong, V. M. J. Am.
Chem. Soc. 2008, 130, 7826. (g) Takaya, J.; Iwasawa, N. J. Am. Chem.
(1) For selected recent reviews on the use of CO2 in organic synthesis,
see: (a) Louie, J. Curr. Org. Chem. 2005, 9, 605. (b) Sakakura, T.; Choi,
J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365. (c) Darensboug, D. J.
Chem. Rev. 2007, 107, 2388. (d) Correa, A.; Martın, R. Angew. Chem.,
´
Int. Ed. 2009, 48, 6201. (e) Aresta, M.; Dibenedetto, A. Dalton Trans.
2010, 39, 3347. (f) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010, 39, 3347.
(g) Ackermann, L. Angew. Chem., Int. Ed. 2011, 50, 3842. (h) Zhang, Y.;
Riduan, S. N. Angew. Chem., Int. Ed. 2011, 50, 6210w. (i) Boogaerts,
I. I. F.; Nolan, S. P. Chem. Commun. 2011, 47, 3021.
´
Soc. 2008, 130, 15254. (h) Correa, A.; Martın, R. J. Am. Chem. Soc.
2009, 131, 15974. (i) Dang, L.; Lin, Z. Organometallics 2010, 29, 917.
r
10.1021/ol300958c
Published on Web 05/07/2012
2012 American Chemical Society

complexes and bases, have so far been reported to mediate
or catalyze the cyclization process.4 These methods gen-
erally afford 3-unsubstituted indoles; in some cases, how-
ever, subsequent functionalization of the 3-position, in-
cluding carbonylation, allylation, alkenylation, and aryla-
tion, can be performed in a one-pot manner, particularly in
the presence of transition metal catalysts.5
Table 1. Screening of Reaction Parametersa
Herein we report a novel approach for synthesiz-
ing indole 3-carboxylic acids from the corresponding
2-ethynylaniline derivatives. The process involves a tan-
dem-type, cyclizationÀcarboxylation sequence and pro-
ceeds efficiently under 10 atm of CO2 without the addition
of any transition metal catalyst. An inorganic base such as
K2CO3 isthe only reagent required. Themethod represents
the first example of the synthesis of carboxylated hetero-
cyclic compounds involving both cyclization and sub-
sequent CO2 fixation processes and provides a novel,
convenient, and highly practical route to 3-carboxylated
indoles.6
During the course of our studies on CO2 fixation
employing transition metal catalysts,7 it was found that
the reaction of ethynylaniline 1a in the presence of a
catalytic amount of CuI and 10 equiv of K2CO3 under a
CO2 atmosphere at 50 °C afforded 3-carboxylated indole
2a (Table 1, entry 1). Interestingly, the process proceeded
to some extent even in the absence of a copper catalyst
(entry 2). Intrigued by this unexpected metal-free process,
further examination of the reaction parameters was per-
formed. While increasing the pressure of CO2 to 10 atm
had little effect on the reaction efficiency (entries 3À5),
raising the reaction temperature from 50 to 65 °C resulted
in a drastic improvement in the yield; in this case, the
desired product 2a was obtained in 93% yield (entry 6).
Use of a decreased amount of K2CO3 led to a lower yield
(entry 8), and essentially, no product was obtained from
the reaction in the absence of K2CO3 (entry 9). Among a
variety of solvents tested, DMF was found to be the best
(entry 6 vs entries 10À13).8 Moreover, although the use of
K3PO4 or NaOtBu as a base gave lower conversions
(entries 14 and 15), the reactions in the presence of other
yieldb (%)
x (atm) temp (°C) 2a 3a 1a
entry base (equiv)
solvent
1c
2
3
4
5
6
7
8
9
K2CO3 (10) DMF
K2CO3 (10) DMF
1
50
50
50
50
50
65
80
65
65
65
65
65
65
65
65
65
65
29 30 36
1
14
25
24
20
93
92
75
0
0
0
0
0
7
8
0
0
0
85
75
75
75
0
K2CO3 (10) DMF
K2CO3 (10) DMF
K2CO3 (10) DMF
K2CO3 (10) DMF
K2CO3 (10) DMF
3
6
10
10
10
10
10
10
10
10
10
10
10
10
10
0
K2CO3 (6)
none
DMF
DMF
22
>99
>99
10 K2CO3 (10) 1,4-dioxane
11 K2CO3 (10) toluene
12 K2CO3 (10) MeCN
13 K2CO3 (10) Et3N
14 K3PO4 (10) DMF
15 NaOtBu (10) DMF
16 Cs2CO3 (10) DMF
0
0
16 84
0
5
4
7
90
96
26
0
67
40 19 39
87
86
7
8
3
5
17 KH (10)
DMF
a Reaction conditions: 1a (0.25 mmol), a base, and a solvent (3 mL)
under a CO2 atmosphere. b Isolated yield. c With addition of CuI (6 mol %).
organometallic species or prefunctionalized substrates
(aryl halides) remains a disadvantage. The direct carboxy-
lation of CÀH bonds of azoles and electron-deficient
arenes was first achieved by Nolan using a catalytic amount
of a Au(I)ÀNHC complex.3a The process efficiently pro-
ceeds at room temperature in the presence of a stoichio-
metric amount of KOH base under 1.5 bar (∼1.5 atm) of
CO2. Subsequent reports indicated that a copper version of
the catalyst also participates in a similar CÀHcarboxylation
in the presence of CO2 (1 or 1.5 bar).3b,c Recently, the
chelating-group-directed carboxylation of unactivated
aryl CÀH bonds was accomplished in the presence of a
Rh catalyst.3d
(4) For recent reviews, see: (a) Balme, G.; Bouyssi, D.; Lomberget,
T.; Monteiro, N. Synthesis 2003, 2115. (b) Zeni, G.; Larock, R. C. Chem.
Rev. 2004, 104, 2285. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873. (d) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469.
(5) For selected examples, see: (a) Iritani, K.; Matsubara, S.;
Utimoto, K. Tetrahedron Lett. 1988, 29, 1799. (b) Kondo, Y.; Shiga,
F.; Murata, N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994, 50,
11803. (c) Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi,
L. M. Org. Lett. 2002, 4, 1355. (d) Barluenga, J.; Trincado, M.; Rubio,
In contrast, the indole scaffold frequently occurs in a
range of biologically active compounds, including natural
products and designed medicinal agents. Therefore, the
development of more practical and efficient procedures for
synthesizing indoles still remains an area of intensive
research. Among a variety of methods, the ring closing
reactions of 2-ethynylaniline derivatives have become a
versatile and efficient tool for constructing the indole
nucleus. A wide range of reagents, including various metal
ꢀ
E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406. (e) Hiroya,
K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (f) Boyer, A.;
Isono, N.; Lackner, S.; Leutens, M. Tetrahedron 2010, 66, 6468. (g)
Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412. (h)
Huang, J.; Macdonald, S. J. F.; Harrity, J. P. A. Chem. Commun. 2010,
46, 8770. (i) Han, X.; Lu, X. Org. Lett. 2010, 12, 3336.
(6) (a) Base-mediated carboxylation of relatively acidic CÀH bonds
of azoles using CO2 has recently been reported; see: Vechorkin, O.; Hirt,
N.; Hu, X. Org. Lett. 2010, 12, 3567. (b) For transition-metal-free
carboxylation of organozinc reagents using CO2, see: Kobayashi, K.;
Kondo, Y. Org. Lett. 2009, 11, 2035.
(3) (a) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132,
8858. (b) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int.
Ed. 2010, 49, 8670. (c) 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. (d) Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2011, 133, 1251.
(7) Inamoto, K.; Asano, N.; Kobayashi, K.; Yonemoto, M.; Kondo,
Y. Org. Biomol. Chem. 2012, 10, 1514.
(8) DMF is also an efficient solvent in the previously reported our
transition-metal-free carboxylation of organozinc reagents, see ref 6b.
Org. Lett., Vol. 14, No. 10, 2012
2623

Table 2. Substrate Scope of the Processa
Scheme 1. Plausible Reaction Mechanism
affording the corresponding indoles.5 Considering the
possibilitythatsuchtrace amounts of metalsinthe reaction
mixture were catalyzing our process, quantitative elemen-
tal analyses of 1a, K2CO3, and DMF were performed via
inductively coupled plasma-mass spectrometry (ICP-MS).
Fe was found to be the most abundant element in 1a,
although in significantly low concentration (48.92 ppb).
Furthermore, the concentration of other metals such as Pd
and Cu was also found to be extremely low (below 5 ppb).
Although the possible involvement of transition metals
cannot be completely eliminated, such a catalytic process is
unlikely to be operating in this reaction.9
To prove the generality of the method, the process was
examined using variously substituted 2-ethynylanilines
1bÀm (Table 2). Substrates possessing an electron-donat-
ing (ÀOMe) or an electron-withdrawing group (ÀCO2Me,
ÀCN) at the para- or meta-position were suitable for the
process, providing the corresponding indoles 2bÀe, gen-
erally in good to high yields (entries 2À5). Halogen atoms
such as ÀF, ÀCl, and ÀBr on the benzene ring were also
tolerated during the reaction (entries 6À9). In addition,
substrate 1j, which has a terminalÀBu group on the alkyne
(R in Table 2), provided the desired product 2j in moderate
t
yield (entry 10), whereas the introduction of a À Bu group
completely inhibited the process (entry 11). Although
N-mesyl and N-benzylethynylanilines (1l and 1m) were
completely inactive (entries 12 and 13), the reaction of
2-ethynylphenol 1n provided benzofuran 2n efficiently and
in quantitative yield (entry 14).
Although the precise reaction mechanism remains to be
elucidated, it seems reasonable to assume that the process
occurs via the pathway shown in Scheme 1, which involves
a base-promoted deprotonation of 1and subsequent amina-
tive cyclization, followed by CO2 fixation at the 3-position
a Reaction conditions: 1 (0.25 mmol), K2CO3 (2.5 mmol), and DMF
(3 mL) under a CO2 atmosphere. b Isolated yield. c Yield of 3 in
parentheses. d MS 4 A was added. e 48 h of reaction time.
bases such as Cs2CO3 and KH provided a yield similar to
that obtained with K2CO3 (entries 16 and 17).
Transition metals such as Pd and Cu have been known
to catalyze the cyclization of 2-ethynylaniline derivatives,
(9) For detailed results of ICP-MS as well as the effect of the addition
of transition metals, see Supporting Information.
2624
Org. Lett., Vol. 14, No. 10, 2012

of the indole nucleus. On the other hand, it was found that
the reaction of independently prepared indole 3a did not
furnish carboxylated product 2a at all under the optimized
reaction conditions.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (B) (No. 23390002),
a Grant-in-Aid for Challenging Exploratory Research
(No. 23659001), a Grant-in-Aid for Young Scientists (B)
(No. 23790002) from Japan Society for the Promotion of
Science, and a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations
by Organocatalysts” (No. 23390002) from The Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
In summary, a novel method for the synthesis of 3-
carboxylated indoles from the corresponding 2-ethynyla-
niline derivatives through a tandem-type, cyclizationÀ
carboxylation sequence has been developed. K2CO3 is the
only reagent required to mediate the process, and the
reaction proceeds efficiently under 10 atm of CO2 without
the addition of any transition metal catalyst. The yields are
generally high, and good functional group compatibility is
observed, thus providing a facile, efficient, and convenient
route to 3-carboxylated indoles. Further studies to unveil
the precise reaction mechanism of the process, as well as to
apply this approach to the construction of other carboxy-
lated heterocycles, are underway.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic and analytical data for
compounds 1À3. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2625