Novel Petasis boronic acid reactions with 1,3,5-tri-oxygenated benzenes

Article abstract of DOI:10.1016/j.tetlet.2003.09.178

1,3,5-tri-Oxygenated benzenes can serve as substrates for the Petasis boronic acid reaction, providing a practical synthetic route for the two C-C bond formation of α-(1,3,5-tri-oxygenated phenyl)carboxylic acids. The scope and limitations of this method have been examined.

Full text of DOI:10.1016/j.tetlet.2003.09.178

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8861–8863
Novel Petasis boronic acid reactions with 1,3,5-tri-oxygenated
benzenes
Dinabandhu Naskar,a,* Amrita Roya and William L. Seibelb
aChembiotek Research International, Block BN, Sector-V, Plot 7, Salt Lake Electronic Complex, Kolkata 700 091, India
bCombinatorial Chemistry Section, Procter & Gamble Pharmaceuticals, Health Care Research Center,
8700 Mason Montgomery Road, Mason, OH 45040, USA
Accepted 19 September 2003
Abstract—1,3,5-tri-Oxygenated benzenes can serve as substrates for the Petasis boronic acid reaction, providing a practical
synthetic route for the two CꢀC bond formation of a-(1,3,5-tri-oxygenated phenyl)carboxylic acids. The scope and limitations of
this method have been examined.
© 2003 Elsevier Ltd. All rights reserved.
In recent years the Petasis boronic acid–Mannich multi-
component reaction has been of considerable interest,
since in one-step, commercially available boronic acids
and amines can be used as building blocks in combina-
torial chemistry to make many diverse a-amino acids
for drug discovery.1–4 The reaction is most efficient with
alkenyl and electron-rich aromatic boronic acids, sec-
ondary amines, and sterically hindered primary amines,
although anilines, unprotected amino acids, and pep-
tides,1a,b boronic acid esters,1e,f hydrazine5 can also
participate. In earlier studies, it was shown that tertiary
aromatic amines can also participate in this reaction for
the two carbonꢀcarbon bond formation of a-(4-N,N-
dialkylamino-2-alkyloxyphenyl)carboxylic acids with
four points of diversity6 where as in the Petasis reac-
tion, a carbonꢀcarbon and a carbonꢀnitrogen bond are
formed.1a,b To our knowledge 1,3,5-tri-oxygenated benz-
enes have not previously been studied as substrates for
this reaction.1–6 In this letter, we report a mild, practi-
cal, and novel method for the synthesis of a-(1,3,5-tri-
oxygenated phenyl)carboxylic acids using chemistry
analogous to the Petasis boronic acid–Mannich reac-
tion, but not incorporating an amine component.
The proposed mechanism of 1,3,5-tri-oxygenated benz-
ene with glyoxylic acid in presence of p-meth-
oxyphenylboronic acid is shown in Scheme 1.3c,8 Initial
studies involved reactions with 1,3,5-tri-methoxy benz-
ene and glyoxylic acid monohydrate affording the pre-
sumed intermediate II which might be formed via
nucleophilic aryl addition to the glyoxylic acid in
p-dioxane under reflux condition. The solvent was
removed and washed with DCM and dried under
reduced pressure to afford the adduct II which was
characterized by LCMS, 1H, 13C NMR and HRMS.9
Treatment of this adduct (II) with p-methoxy phenyl-
boronic acid afforded the expected product 2a.
When R1, R2, R3=Me and R4=aryl (2a–e), the reac-
tions proceeded quite well, affording the corresponding
a-(1,3,5-tri-methoxy phenyl)carboxylic acids ranging
from 50 to 60% yield after HPLC purification. The
reaction was relatively insensitive to R4 substitution,
electron withdrawing, donating and heterocyclic sys-
tems all gave comparable yields. When R4=hetero-
cyclic (2f), and aryl containing electron withdrawing
group (2g, 2h), the corresponding product was obtained
in 49–54% yields after purification. When R4=phenyl,
naphthyl, these reactions also proceeded well affording
59–62% yield of the product. In the case studied, yields
varied considerably with different R1, R2 and R3 of the
1,3,5-tri-oxygenated benzene. When R1=H, R2 and
R3=Me (2k–l), the corresponding product was
obtained in 48-49% yield. Similarly, when R1, R2=H
(2m), the corresponding product was obtained in 40%
yield after purification. However, when R1, R2, R3=H,
(2n), the corresponding product was obtained in
Commercially available substrates 1 were mixed with
one equivalent each of glyoxylic acid monohydrate and
an organoboronic acid, stirred under reflux condition in
dioxane for 12 h. As shown in Table 1, the reaction
produces diphenyl acetic acids generally in 40–62%
yields.7
* Corresponding author. E-mail: naskar.d@pg.com, dinabandhu@
chembiotek.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.178

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D. Naskar et al. / Tetrahedron Letters 44 (2003) 8861–8863
Table 1. Boronic acid–glyoxylic acid reactions of 1,3,5-tri-oxygenated benzene
Scheme 1. Hypothetical mechanism of the reaction of 1,3,5-tri-methoxy benzene with glyoxylic acid in presence of
p-methoxyphenylboronic acid.

D. Naskar et al. / Tetrahedron Letters 44 (2003) 8861–8863
8863
reduced (10%) yield (LCMS) after heating for 1 h,
further heating did not improve the yield of the
product.
3168; (b) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem. Eur. J. 2000, 6, 3321.
5. (a) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetra-
hedron Lett. 2002, 43, 6845; (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.; West, L.;
Portlock, D. E. Tetrahedron Lett. 2003, 44, 6297.
In summary, 1,3,5-tri-oxygenated benzene adds to gly-
oxylic acid and boronic acids in a process similar to
boronic acid–Mannich reaction, yielding products in
which two carbonꢀcarbon bonds are formed in the
multicomponent condensation. To the best of our
knowledge these compounds have not been synthesized
earlier.
6. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E.
Tetrahedron Lett. 2003, 44, 5819.
7. General procedure for boronic acid–glyoxylic acid reactions
of 1,3,5-tri-oxygenated benzene 2a: To a stirred mixture of
glyoxylic acid monohydrate (0.184 mg, 2 mmol) in p-diox-
ane (6 mL) was added 1,3,5-trimethoxybenzene (0.336 mg,
2 mmol) followed by 4-methoxyphenylboronic acid (0.304
mg, 2 mmol). The resulting mixture was refluxed for 12 h
and after this time, the dioxane was removed under
reduced pressure. The residue was purified by preparative
HPLC [Polaris C18 column (250×500 mm, 10 micron
particle size), mobile phase 0.1% aqueous TFA/CH3CN
linear gradient over 55 min, 60 mL/min] to give 0.316 mg
(50%) of 2a as a white solid. Mp: 178–179°C; Rf=0.45
(50% EtOAc:hexane); analytical HPLC: Polaris C18
column (4.6×250 mm, 3 micron particle size), mobile phase
0.1% aqueous phosphoric acid/CH3CN linear gradient
over 30 min, 1 mL/min, one peak detected by ELS and
UV at 215 nm, tR=5.02 min; 1H NMR (CDCl3, 300
MHz): l 3.78 (s, 3H), 3.82 (s, 6H), 3.83 (s, 3H), 5.36 (s,
1H), 6.18 (s, 2H), 6.84 (d, 2H), 7.29 (d, 2H); 13C NMR
(CDCl3, 75 MHz): l 45.39, 55.55, 55.74, 56.14, 92.02,
109.99, 113.79, 130.67, 131.02, 158.54, 158.69, 160.95,
180.11; LCMS (ELSD): 332 (M+H+); HRMS: 333.135017
[calcd for C18H20O6 333.133814 (M+H)+].
References
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9. 1H NMR (CD3OD, 300 MHz): l 3.83 (s, 6H), 3.84 (s, 3H),
5.53 (s, 1H), 6.25 (s, 2H); 13C NMR (CD3OD, 75 MHz): l
55.83, 56.23, 64.63, 91.90, 94.70, 110.09, 160.66, 163.33,
177.92; LCMS (ELSD): 241 (M−H+); HRMS: 243.085709
[calcd for C11H15O6 243.086863 (M+H)+].
4. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,