Multicomponent synthesis of 3-indolepropionic acids

Article abstract of DOI:10.1021/ol0627698

(Chemical Equation Presented) A three-component one-pot procedure (3-MC) was developed to assemble 3-indolepropionic acids from commercially available materials. This new methodology affords the title compounds in high yields and without the use of chroma

Full text of DOI:10.1021/ol0627698

ORGANIC
LETTERS
2007
Vol. 9, No. 2
303-305
Multicomponent Synthesis of
3-Indolepropionic Acids
Mauro F. A. Adamo* and Vivekananda R. Konda
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical
and Medicinal Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s
Green, Dublin 2, Dublin, Ireland
madamo@rcsi.ie
Received November 14, 2006
ABSTRACT
A three-component one-pot procedure (3-MC) was developed to assemble 3-indolepropionic acids from commercially available materials. This
new methodology affords the title compounds in high yields and without the use of chromatography.
Indole 3-propionic acids (IPAs) 1 (Figure 1) are potent
neuroprotective agents.1 IPA completely protects primary
neurons and neuroblastoma cells against oxidative damage
and death caused by exposure to amyloid â-protein, by
inhibition of superoxide dismutase, or by treatment with
hydrogen peroxide. In kinetic competition experiments with
free radical-trapping agents, the capacity of IPA to scavenge
hydroxyl radicals exceeded that of melatonin, an indoleamine
considered to be the most potent naturally occurring scav-
enger of free radicals.1 Additionally, acids 1 are struc-
turally related to the NSAID indomethacin and several
multistep syntheses have been described in studies aimed at
providing the indole acetic acid with preferential COX-2
selectivity.2
(1) Yau-Jan, C.; Burkhard, P.; Rawhi, A. O.; Chain, D. G.; Blas, F.;
Jorge, G.; Pappolla, M. A. J. Biol. Chem. 1999, 274, 21937.
(2) Maguire, A. R.; Plunkett, S. J.; Papot, S.; Clynes, M.; O’Connor,
R.; Touhey, S. Bioorg. Med. Chem. 2001, 9, 745.
Figure 1. Target compounds: 3-indolepropionic acids 1 and
3-substituted indoles 2.
10.1021/ol0627698 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/15/2006

Recently, 3-substituted indoles 2 have been found to
possess several biological activities.3,4 For instance, com-
pounds of structure 2 were found to act as aromatase
inhibitors and have been used to treat breast cancer.3 Other
members of this class have been patented as HIV-1 integrase
inhibitors.4 Additionally, the diaryl methine motif in 1 and
2 is present in a number of drugs and natural products.5 As
a part of our ongoing efforts in developing multicomponent
one-pot procedures using commercially available materials,6-9
we envisaged a novel modular synthesis leading to indole
3-propionic acids 1 and 3-substituted indoles 2 (Figure 1).
A retrosynthetic analysis of targets 1 and 2 showed that 3,5-
dimethyl-4-nitroisoxazole 4 could serve as a starting material
for a sequence of anionic driven reactions (Scheme 1).
Scheme 2. Synthesis of Compounds 2a and 1a
enough to produce 2a in good yield, and that 2a was obtained
in similar yield by reacting together 4, 5, and 6 in a one-pot
process (Scheme 3). The procedure involved premixing
Scheme 1. Retrosynthetic Analysis of Targets 1 and 2
Scheme 3. One-Pot Synthesis of 3-Heteroarylpropionic Acids
1a-l and 4-Nitroisoxazol-5-ethanyl Compounds 2a-l
We have recently reported a one-pot procedure by which
the commercially available isoxazole 4 reacted with an
aromatic aldehyde 5 and acetylacetone in a tandem Knoev-
enagel-Michael reaction.6,8,9 The resulting Michael adducts
were then converted to spiroisoxazolines6 or heteroarylpro-
pionic acids.9 We reasoned that compounds 2 could be
prepared through a Michael reaction of a lithiated indole and
3-methyl-4-nitro-5-styrylisoxazole 3. This disconnection
looked particularly attractive given the large number of
substituted indoles available on the market. Finally, we
planned to prepare 3-indolepropionic acids 1 by hydrolysis
of the 3-methyl-4-nitroisoxazol-5-yl group present in 2.9
We first carried out a stepwise synthesis of compounds
2a and 1a using simple lithiated indole 6 as the nucleophile,
to determine an optimal set of reaction conditions (Scheme
2). We were delighted to observe that 1.1 equiv of 6 was
isoxazole 4 with an aromatic aldehyde 5a-f in the presence
of 0.1 equiv of piperidine and subsequent reaction of the
styrylisoxazoles so obtained with a solution containing 1.1
equiv of lithiated indole 6. We then studied the conversion
of 2a to acid 1a. When compound 2a was reacted with 5
equiv of NaOH in water/methanol compound 1a was
obtained in 79% yield. We briefly investigated the conversion
of 2a to 1a reaction in different solvents including water/
methanol, water/ethanol, water/dioxane, and water/THF.
Interestingly, we identified a mixture of THF/water as an
optimal solvent system, which provided an opportunity to
extend the one-pot procedure established for the preparation
of 2a to access 1a. This procedure, which was optimized by
adjustment of reaction times, temperature, and concentration
of reactants involved reacting isoxazole 4 with an aromatic
aldehyde 5a-f in the presence of 0.1 equiv of piperidine
and subsequent sequential addition of a solution of 1.1 equiv
of lithiated indole 6 followed by a solution of NaOH in water.
We were delighted to observe that compound 1a was
obtained in isolated yield comparable to the stepwise
preparation. Compounds 1a and 2a were obtained pure
without the intervention of chromatography. Compound 2a
was purified by crystallization, while compound 1a was
obtained pure by means of base/acid extraction.
(3) (a) Leze, 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.; Hrtmann, R. W.; Paltzer, M. Bioorg. Med.
Chem. Lett. 1999, 9, 333.
(4) Deng, J.; Sanchez, T.; Neamati, N.; Briggs, J. M. J. Med. Chem.
2006, 49, 1684.
(5) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org.
Lett. 2005, 7, 3821.
(6) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P. J. Org.
Chem. 2005, 70, 8395.
(7) Adamo, M. F. A.; Baldwin, J. E.; Adlington, R. M. J. Org. Chem.
2005, 70, 3307.
(8) Adamo, M. F. A.; S. Chimichi, S.; De Sio, F.; Donati, D.; Sarti-
Fantoni, P. Tetrahedron Lett. 2002, 43, 4157.
(9) Adamo, M. F. A.; Donati, D.; Duffy, E. F. Org. Lett. 2006, 8, 5157.
304
Org. Lett., Vol. 9, No. 2, 2007

Having determined an appropriate set of reaction condi-
tions, we carried out the synthesis of compounds 1a-l in a
one-pot fashion (Scheme 3, Table 1).
Table 2. One-Pot Synthesis of Compounds 2a-l
entry compd
R1
R2
R3
X
yield,a %
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
H
H
H
H
H
Cl
CH3
OCH3
H
C
C
C
C
C
C
C
C
C
N
C
79
74
74
81
80
77
76
73
79
70
78
p-H3C-Ph
p-CH3O-Ph
p-NO2-Ph
p-Cl-Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
Table 1. One-Pot Synthesis of Compounds 1a-l
entry compd
R1
R2
R3
X
yield,a %
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
H
H
H
H
H
Cl
CH3
OCH3
H
C
C
C
C
C
C
C
C
C
N
C
79
74
74
70
73
77
74
73
75
78
72
p-H3C-Ph
p-CH3O-Ph
p-NO2-Ph
p-Cl-Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
OCH3 CH3
H
H
10
11
2k
2l
H
H
2-furyl
a Isolated yields after crystallization.
OCH3 CH3
H
H
10
11
1k
1l
H
H
2-furyl
chromatography. The synthesis of compounds 1 and 2 will
be of interest for those involved in two key areas of medicinal
chemistry such as Alzheimer’s disease and breast cancer
chemotherapy. Finally, both families of compounds are
highly functionalized and could serve as valuable intermedi-
ates for the generation of diverse classes of compounds.
a Isolated yields after acid/base extraction.
The results obtained (Table 1 and 2) showed that a great
deal of diversity could be introduced without varying the
reaction plan. Both electron-withdrawing and electron-
donating groups could be included as R1 or R2.
As the acid products were isolated by a simple extraction
method, the need for chromatography was obviated. Poly-
heterocyclic compounds 2a-l were obtained in high yield
by omitting the hydrolysis step (aqueous base, ∆) (Scheme
3, Table 2). The ease of purification complements the one-
pot procedures making these methodologies facile, practical,
and rapid to execute.
In conclusion we reported two 3-MC one-pot procedures
to prepare two families of products with potential medicinal
properties using inexpensive and commercially available
materials. These syntheses are modular and benefit from a
simple method of purification, which does not require
Acknowledgment. The authors acknowledge the Royal
Society of Chemistry for a grant to M.F.A.A., and the RCSI
Research Committee and PTRLI cycle III for a grant to
V.R.K.
Supporting Information Available: General experimen-
tal details, general one-pot procedure for the preparation of
compounds 1a-l (Table 1) and 2a-l (Table 2), spectroscopic
data of compounds 1a-l and 2a-l, and 1H NMR spectra of
compounds 1a-l and 2a-l. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0627698
Org. Lett., Vol. 9, No. 2, 2007
305