Novel Petasis boronic acid reactions with indoles: synthesis of indol-3-yl-aryl-acetic acids

Article abstract of DOI:10.1016/j.tetlet.2008.08.029

Indoles can serve as substrates for the Petasis boronic acid-Mannich reaction, providing a practical synthetic route for C-C bond formation in α-(N-substituted indole)carboxylic acids. The scope and limitations of this method have been examined.

Full text of DOI:10.1016/j.tetlet.2008.08.029

Tetrahedron Letters 49 (2008) 6762–6764
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Tetrahedron Letters
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Novel Petasis boronic acid reactions with indoles:
synthesis of indol-3-yl-aryl-acetic acids
*
Dinabandhu Naskar , Subhasish Neogi, Amrita Roy, Ashis Baran Mandal
Syngene International Ltd, Biocon Park, Plot No. 2 and 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Indoles can serve as substrates for the Petasis boronic acid-Mannich reaction, providing a practical
Received 11 June 2008
Revised 29 July 2008
Accepted 7 August 2008
Available online 1 October 2008
synthetic route for C–C bond formation in
limitations of this method have been examined.
a
-(N-substituted indole)carboxylic acids. The scope and
Ó 2008 Published by Elsevier Ltd.
In recent years the Petasis boronic acid-Mannich multicompo-
nent reaction has been of considerable utility for the synthesis of
oxyphenylboronic acid is shown in Scheme 1.3c,8,10 Initial
studies involved reactions with N-methylindole and glyoxylic
acid monohydrate affording the presumed intermediate II
which might be formed via nucleophilic addition of 1 to gly-
oxylic acid in 1,4-dioxane under reflux conditions. The adduct
II then reacted with p-methoxyphenylboronic acid to afford
the desired product 2a.
a-amino acid derivatives in one step using a large variety of com-
mercially available boronic acids and amines as building blocks in
combinatorial chemistry and drug discovery.1–4 The reaction is
most efficient with alkenyl and electron-rich aromatic boronic
acids, secondary amines, and sterically hindered primary amines,
although anilines, unprotected amino acids, and peptides,1a,b boro-
nic acid esters,1e,f hydrazine,5 hydroxylamine and sulfinamide,6
and tertiary aromatic amines7 can also participate. In earlier stud-
ies, it was shown that 1,3,5-trioxygenated benzenes can also par-
ticipate in this reaction for the formation of two carbon-carbon
When R = Me, R1 and R2 = H and R3 = aryl (2a–2d), the
reactions proceeded quite well, affording the corresponding
a-(N-substituted indole)carboxylic acids in yields ranging from
49% to 60% after HPLC purification. When R3 = heterocyclic
(2e–2f), the corresponding products were obtained in 47–51%
yields after purification. It should be noted that when
R3 = aryl containing an electron-withdrawing group (2g–2h),
the reaction afforded 42–48% yields of the desired products
after HPLC purification. It is interesting to note that when
R2 = Me (2i) or Et (2j) these reactions also proceeded affording
41% and 39% yields of the products, respectively, after purifi-
cation. When R = Me, Et, –CH(Me)2, and R1 = 6-Br and 5-Br,
(2k–2n), the reactions proceeded to afford the corresponding
bonds in a-(1,3,5-tri-oxygenated phenyl)carboxylic acids with four
points of diversity,8 whereas in the Petasis reaction, a carbon–car-
bon and a carbon–nitrogen bond are formed.1a,b To our knowledge,
N-substituted indoles have not been studied previously as sub-
strates for this reaction.1–8 In this letter, we report a mild, practical,
and novel method for the synthesis of two C–C bonds in
a-(N-
substituted indole)carboxylic acids using the Petasis-boronic
acid-Mannich reaction.
Commercially available substrates 1 were subjected to stan-
dard Petasis boronic acid-Mannich reaction conditions, i.e.,
1 equiv each of 1, glyoxylic acid monohydrate and an organobo-
ronic acid with stirring under reflux conditions in dioxane for
12 h (Table 1).9
a-(N-substituted indole)carboxylic acids ranging from 60% to
70% yields after purification. However, when R, R1 R2 = H,
,
(2o) and R, R1 = H, R2 = Me (2p) the corresponding products
were obtained in poor yields ranging from 26% to 30% after
purification.
The proposed mechanism for the reaction of N-methyl-
indole with glyoxylic acid in the presence of p-meth-
In summary, N-substituted indole can replace the amine com-
ponent in the Petasis boronic acid-Mannich reaction, yielding
products in which two carbon–carbon bonds have been formed
during the multicomponent condensation. The resulting
a-(N-
substituted indole)carboxylic acids 2 contain four points of diver-
sity. To the best of our knowledge these compounds have not
been synthesized previously.
* Corresponding author. Tel.: +91 80 2808 3130; fax: +91 80 2808 3150.
E-mail addresses: dinabandhu.naskar@syngeneintl.com, dbn70@yahoo.com (D.
Naskar).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.08.029

D. Naskar et al. / Tetrahedron Letters 49 (2008) 6762–6764
6763
Table 1
Petasis boronic acid-Mannich reactions of indoles
HO2C R3
R2
R3B(OH)2
O
R1
R1
N
R
N
R
2
1
R2
CO2H
R = H, Me, Et, -CH(CH3)2
R1 = H, 6-Br, 5-Br
Dioxane/
reflux
R2 = H, Me, Et.
R3 = aryl, heterocyclic
Product
R
R1
H
R2
H
R3
Yielda (%)
60
Mp (°C)
2a
Me
118–119
OMe
OMe
OMe
2b
Me
H
H
50
Liquid
2c
Me
Me
H
H
H
H
49
51
132–133
121–122
SMe
2d
2e
Me
H
H
47
Liquid
S
2f
Me
Me
Me
Me
H
H
H
H
H
45
48
42
41
Liquid
S
2g
2h
2i
H
93–94
Liquid
Br
H
F
Me
164–165
OMe
O
2j
Me
Me
Et
H
Et
H
H
39
70
68
Liquid
72–73
71–72
O
2k
2l
6-Br
6-Br
OMe
OMe
2m
2n
6-Br
5-Br
H
H
60
62
153–154
176–177
OMe
OMe
Me
2o
H
H
H
H
H
30
26
168–169
141–142
OMe
OMe
2p
Me
a
All yields refer to pure, isolated products. All compounds have been characterized by LC–MS, 1H NMR, and 13C NMR.

6764
D. Naskar et al. / Tetrahedron Letters 49 (2008) 6762–6764
HO2C
H
HO2C
OH
OH
OH
OH
R1
B
N
N
N
R
R = Me
1
R
R
I
II
O
H
CO2H. H2O
OH
OH
OH
OH
O
B
R
B OH
O
O
R
B OH
O
R
O
O
OH2
N
R
N
R
N
V
IV
III
R
R
R
OH
OH
OH
B
O
H
H
O
O
2a
N
N
VI
R
R
Scheme 1. Proposed mechanism for the reaction of N-methylindole with glyoxylic acid in the presence of p-methoxyphenylboronic acid.
5. (a) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett. 2002, 43, 6845;
Acknowledgement
(b) Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003,
44, 603; (c) Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski, R.; Chen, J. J.
Tetrahedron Lett. 2003, 44, 5121; (d) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock,
D. E. Tetrahedron Lett. 2003, 44, 6297.
The authors gratefully acknowledge Dr. Goutam Das, COO,
Syngene International Ltd for his invaluable support.
6. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44, 8865.
7. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44, 5819.
8. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44, 8861.
9. General procedure for the Petasis boronic acid-Mannich reactions of N-
References and notes
methylindole 2a: To
a stirred mixture of glyoxylic acid monohydrate
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(0.131 g, 1 mmol) followed by 4-methoxyphenylboronic acid (0.152 g,
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lm particle
size), mobile phase 0.1% aqueous TFA/CH3CN linear gradient over 55 min,
60 mL/min] to give 0.171 g (60%) of 2a as a reddish solid. mp: 118–119 °C;
Rf = 0.26 (50% EtOAc–hexane); analytical HPLC: YMC-ODS-AQ (4.6 Â 250 mm,
5 lm particle size), mobile phase 0.1% trifluoroacetic acid/CH3CN linear
gradient over 25 min, 0.8 mL/min, one peak detected by ELS and UV at
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2H), 7.38 (d, J = 8.7, 2H), 7.46 (d, J = 8.0, 1H); 13C NMR (CDCl3, 100 MHz): d
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