Carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions in water for the synthesis of 3-substituted indoles

Article abstract of DOI:10.1021/ol062031q

(Chemical Equation Presented) The carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and indoles in water have been developed. The aza-Friedel-Crafts products could be easily transformed to various 3-subst

Full text of DOI:10.1021/ol062031q

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4939-4942
Carboxylic Acid Catalyzed
Three-Component Aza-Friedel−Crafts
Reactions in Water for the Synthesis of
3-Substituted Indoles
Seiji Shirakawa and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
The HFRE DiVision, ERATO, Japan Science and Technology Agency (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received August 17, 2006
ABSTRACT
The carboxylic acid catalyzed three-component aza-Friedel
developed. The aza-Friedel Crafts products could be easily transformed to various 3-substituted indoles including biologically active compounds.
This system offers a novel efficient method for the synthesis of 3-substituted indoles.
−Crafts reactions of aldehydes, primary amines, and indoles in water have been
−
3-Substituted indoles of type 1 have attracted much attention
due to the broad scope of their biological activitiy (Figure
1).1 Recent examples of type 1 indoles in medicinal chemistry
natural products incorporating this structural key element are
known.4 As a result of their biological and synthetic
importance, a variety of methods have been reported for the
preparation of 3-substituted indoles.5 Although these methods
constitute a valuable addition to the chemical literature, a
(1) (a) Sundberg, R. J. In Indoles; Academic Press: San Diego, 1996.
(b) Sundberg, R. J. In The Chemistry of Indoles; Academic Press: New
York, 1970.
(2) (a) Le´ze´, M.-P.; Le Borgne, M.; Marchand, P.; Loquet, D.; Kogler,
M.; Le Baut, G.; Palusczak, A.; Hartmann, R. W. J. Enzyme Inhib. Med.
Chem. 2004, 19, 549. (b) Le Borgne, M.; Marchand, P.; Delevoye-Seiller,
B.; Robert, J.-M.; Le Baut, G.; Hartmann, R. W.; Palzer, M. Bioorg. Med.
Chem. Lett. 1999, 9, 333.
(3) (a) Deng, J.; Sanchez, T.; Neamati, N.; Briggs, J. M. J. Med. Chem.
2006, 49, 1684. (b) Contractor, R.; Samudio, I. J.; Estrov, Z.; Harris, D.;
McCubrey, J. A.; Safe, S. H.; Andreeff, M.; Konopleva, M. Cancer Res.
2005, 65, 2890.
Figure 1. Biologically active 3-substituted indoles.
include 2, which was reported to act as a nonsteroidal
aromatase inhibitor against breast cancer,2 and 3, which
worked as a HIV-1 integrase inhibitor.3 Furthermore, many
(4) (a) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442. (b) Somei, M.;
Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (c) Lounasmaa, M.; Tolvanen,
A. Nat. Prod. Rep. 2000, 17, 175.
10.1021/ol062031q CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/23/2006

truly efficient, diverse synthetic scheme6 for type 1 indoles
is still required to construct further indole libraries for
medicinal chemistry.
Our strategy for the synthesis of type 1 indoles involves
a three-component aza-Friedel-Crafts (AFC) reaction7 in
water8 (Scheme 1). The AFC product 4 contains a reactive
velopment of selective three-component AFC reactions with
aromatic aldehydes, primary amines, and indoles.
Recently our group has developed several acid-catalyzed
C-C bond-forming reactions in water.12,13 On the basis of
these findings, we first searched for an efficient catalyst in
the model three-component AFC reaction of 2-naphthalde-
hyde (2-NpCHO), o-anisidine (H2N-OMP), and 1-methylin-
dole (1-MeInd) in water (Table 1). Although AcOH and TFA
Scheme 1. Synthetic Scheme of 3-Substituted Indoles Using
AFC Reactions
Table 1. Effect of Catalysts
C-N bond, which could be easily transformed to various
functional groups. However, three-component AFC reactions
of aromatic aldehydes, primary amines, and indoles are to
the best of our knowledge unknown, because the initial
product 4 is highly reactive and further addition of indoles
gives undesired adduct 5 (Scheme 2).9,10 In addition, aromatic
entry
catalyst
none
AcOH
TFA
Sc(DS)3
DBSA
C9H19COOH
C5H11COOH
C7H15COOH
C8H17COOH
4a/5aa
yield of 4a (%)a
1
2
3
4
5
6
7
8
>20:1
>20:1
>20:1
3.3:1
5
5
6
46
65
80 (3b, 4c)
6
43
63
78
45
28
91
5.2:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Scheme 2. Side Pathways of AFC Reactions
9
10
11
12
13
C
C
C
10H21COOH
11H23COOH
13H27COOH
C9H19COOHd
a Determined by 1H NMR analysis. b Reaction in CH2Cl2. c Reaction in
THF. d 10 mol % of catalyst was used.
did not show any catalytic ability for the system (entries 2
and 3), scandium tris(dodesyl sulfate) (Sc(DS)3) and do-
decylbenzenesulfonic acid (DBSA), which are known as
effective catalysts for three-component Mannich reactions
in water,13 promoted the reaction effectively; however, a
certain amount of undesired adduct 5a was formed (entries
4 and 5). After screening other catalysts, it was revealed that
decanoic acid (C9H19COOH) efficiently promoted the reac-
tion without formation of 5a (entry 6). Interestingly, this
efficient catalysis occurred sluggishly in organic solvents
such as CH2Cl2 and THF (entry 6, in parentheses). Further-
more, the length of the alkyl chains of the carboxylic acids
was found to be crucial for this reaction. Decanoic acid
(C9H19COOH) gave the best result, and it was noted that
use of carboxylic acids with shorter or longer alkyl chains
resulted in lower yields (entries 7-12). Finally, it was
discovered that increasing the catalyst loading could further
improve the yield of the desired product (entry 13).14
aldehydes are themselves known to react with indoles directly
to afford the undesired bisindolyl products 5.11 In an effort
to address these shortcomings, we initially undertook de-
(5) (a) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett
2005, 1199. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem.,
Int. Ed. 2004, 43, 550. (c) Comins, D. L.; Stroud, E. D. Tetrahedron Lett.
1986, 27, 1869.
(6) (a) Schreiber, S. L. Chem. Eng. News 2003, 81, 51. (b) Spring, D.
R. Org. Biomol. Chem. 2003, 1, 3867.
(7) For recent examples of AFC reactions of R-iminoesters, see: (a) Zhao,
J.-L.; Liu, L.; Zhang, H.-B.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synlett 2006,
96. (b) Jiang, B.; Huang, Z.-G. Synthesis 2005, 2198. (c) Johannsen, M.
Chem. Commun. 1999, 2233.
(8) For Friedel-Crafts-type reactions in water, see: (a) Zhuang, W.;
Jørgensen, K. A. Chem. Commun. 2002, 1336. (b) Manabe, K.; Aoyama,
N.; Kobayashi, S. AdV. Synth. Catal. 2001, 343, 174.
(9) (a) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett.
2005, 46, 1751. (b) Mi, X.; Luo, S.; He, J.; Cheng, J.-P. Tetrahedron Lett.
2004, 45, 4567. (c) Xie. W.; Bloomfield, K. M.; Jin, Y.; Dolney, N. Y.;
Wang, P. G. Synlett 1999, 498.
(10) A few examples of selective AFC reactions of indoles to aryl imines
were reported; see: (a) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-X.;
Zhou, Q.-L. Org. Lett. 2006, 8, 1621. (b) Esquivias, J.; Go´mez Arraya´s,
R.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 629. (c) Wang, Y.-
Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128,
8156.
(11) For recent examples, see: (a) Deb, M. L.; Bhuyan, P. J. Tetrahedron
Lett. 2006, 47, 1441. (b) Yadav, J. S.; Reddy, B. V. S.; Sunitha, S. AdV.
Synth. Catal. 2003, 345, 349.
(12) (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (b)
Hamada, T.; Manabe, K.; Kobayashi, S. Chem. Eur. J. 2006, 12, 1205. (c)
Azoulay, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2005, 7, 4593.
(13) (a) Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001, 57,
2537. (b) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 7202.
4940
Org. Lett., Vol. 8, No. 21, 2006

Armed with this information, we then investigated the
substrate generality of decanoic acid catalyzed AFC reactions
(Table 2). To increase the synthetic utility of the procedure,
workup and recrystallization, the desired product 4a was
isolated in 83% yield. It is noteworthy that the present
method is very simple and that the pure AFC product can
be obtained without tedious column chromatography.
Further examples of the synthetic utility of the present
method are demonstrated by the transformation of the AFC
product to various 3-substituted indole derivatives (Scheme
4). As a result of the high reactivity of the C-N bond, AFC
Table 2. Synthesis of Aromatase Inhibitor Type Compounds 7
via Three-Component Aza-Friedel-Crafts Reactions in Water
Scheme 4. Transformations of Aza-Friedel-Crafts Product
4aa
entry
R1
indole
yield (%)a
1
2
3
4
5
6
7
8b
9
2-naphthyl
Ph
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
82 (7a)
90 (7b)
89 (7c)
85 (7d)
73 (7e)
57 (7f)
53 (7g)
63 (7h)
82 (7i)
64 (7j)
70 (2)
4-MeO-C6H4
4-Cl-C6H4
3-thienyl
(CH3)2CHCH2
c-C6H11
Ph
Ph
Ph
4-F-C6H4
10c
11d
a Isolated yield. b Reaction conditions in the second step ) Tol, rt, 12
h. c Reaction conditions in the second step ) Tol, 70 °C, 1 h. d Reaction
conditions in the first step ) H2O, 50 °C, 48 h.
a Reagents and Conditions: (a) 5-MeO-indole (1.2 equiv), DBSA
(10 mol %), H2O, rt, 24 h; (b) N,N-dimethyl-m-anisidine (1.2 equiv),
Sc(OTf)3 (10 mol %), toluene, 70 °C, 24 h; (c) PhSH (3 equiv),
Sc(OTf)3 (10 mol %), toluene, 70 °C, 24 h; (d) Sn(CH2CHdCH2)4
(1.2 equiv), Sc(OTf)3 (10 mol %), toluene, 70 °C, 24 h; (e)
Me3SiO(Ph)CdCH2 (2 equiv), Sc(OTf)3 (10 mol %), toluene, 70
°C, 24 h; (f) Sc(OTf)3 (10 mol %), toluene, 70 °C, 24 h.
AFC products were directly transformed to imidazole-
substituted compounds 7. Thus, after the AFC reactions the
crude products were treated with CDI in the presence of
Sc(OTf)3 as a catalyst. As shown in Table 2, the reactions
of aldehydes bearing aromatic, heteroaromatic, and alkyl
groups gave the corresponding products in moderate to high
yields in two steps. Moreover, a range of indole deriva-
tives could be employed in the reaction system. It should be
noted that nonsteroidal aromatase inhibitor 2 itself (entry 11)
and its derivatives were prepared efficiently using these
reactions.
product 4a was readily converted to various nucleophiles in
the presence of DBSA or Sc(OTf)3 as a catalyst. Friedel-
Crafts type substitution reactions occurred cleanly by treat-
ment with electron-rich heteroaromatic or aromatic com-
pounds to afford the unsymmetrical triaryl methanes 8
and 9, respectively.15 Substitution using thiol, allyltin, and
silyl enol ether nucleophiles also proceeded smoothly and
gave the valuable compounds 10, 11, and 12 in good
yields. Furthermore, when 4a was treated with Sc(OTf)3
without addition of any nucleophile in toluene, triaryl
methane 13 was obtained via cleavage of the C-N bond of
4a followed by Friedel-Crafts-type addition of the cleaved
o-anisidine.
The present AFC reaction was conducted on a 10 mmol
scale (Scheme 3). Accordingly, 2-naphthaldehyde was treated
In summary, we have developed a novel protocol for three-
component AFC reactions of aldehydes, primary amines, and
indoles in water catalyzed by carboxylic acids. The AFC
reactions have been known to be difficult to control, but the
present reaction system enabled the desired products to be
obtained in high yields. It is noted that the reaction proceeded
Scheme 3. Larger Scale Synthesis
(14) The reaction under neat conditions caused a slight decrease of the
selectivity of 4a/5a.
(15) Friedel-Crafts-type substitution reactions via cleavage of a C-N
bond were also reported in ref 10b.
with o-anisidine and 1-methylindole successively in water
in the presence of 10 mol % of decanoic acid. After simple
Org. Lett., Vol. 8, No. 21, 2006
4941

under nonmetallic conditions in water and that various
3-substituted indoles including biologically active compounds
were prepared by utilizing the reactive C-N bond. This
simple system offers a novel efficient method for the syn-
thesis of various 3-substituted indoles.
of the Promotion of Science (JSPS). S.S. thanks the JSPS
for a postdoctoral research fellowship.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
OL062031Q
4942
Org. Lett., Vol. 8, No. 21, 2006