One-pot synthesis of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2- naphthenoate

Full text of DOI:10.1134/S1070363210040328

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 870–871. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.G. Tribulovich, A.V. Garabadzhiu, I. Kalvins, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4, pp. 700–701.
LETTERS
TO THE EDITOR
One-Pot Synthesis of Methyl 6-[3-(1-Adamantyl)-4-
methoxyphenyl]-2-naphthenoate
V. G. Tribulovicha, A. V. Garabadzhiub, and I. Kalvinsc
a Research Institute of Influenza, North-West Branch, Russian Academy of Medical Sciences,
ul. Professora Popova 15/17, St. Petersburg, 196376 Russia
e-mail: tribulovich@rambler.ru
b St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
c Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
Received November 24, 2009
DOI: 10.1134/S1070363210040328
The key stage at the constructing backbone of 6-[3-
(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid
(Adapalene) molecule is the formation of a C–C bond
between 3-(1-adamantyl)-4-methoxyphenyl and 2-
carbomethoxy-6-naphthyl fragments. Among the most
effective modern methods of C–C bond formation is
known the process of catalytic coupling according to
the method of Suzuki–Miyaura [1].
The main advantage of direct catalytic heterofunc-
tionalization of aryl halides is its easy technological
application. Conditions of this reaction differ only
slightly from that of Suzuki–Miyaura cross-coupling
reaction (the latter requires a stronger base), therefore
it is possible to carry out these two processes without
separation of the intermediate arylboric acid pinacol
ester, that is, to arrange it as a one-pot synthesis [3, 4].
To use this method, one of the coupled fragments
should bear a boron-containing functional group. For
introducing such a group the most widely used method
is the transmetallation of preliminarily prepared Grignard
reagents or lithium derivatives at the action of a boron
compounds with halogen or alkoxy residue as a
leaving group.
The main factors hampering wide technological
application of the direct catalytic heterofunctionaliza-
tion is the high cost of boron-containing nucleophilic
reagents and a difficult selection an appropriate
catalytic system providing acceptable yield of the
product. According to our new data, the most effective
ligand for the one-pot synthesis of methyl 6-[3-(1-
adamantyl)-4-methoxyphenyl]-2-naphthenoate is 2-(di-
cyclohexylphosphino)-2',6'-dimethoxybiphenyl (Sphos).
We found experimentally that pinacolborane is the
optimal reagent for the heterofunctionalization.
An alternative method of introducing this func-
tional group is catalytic coupling of boron-containing
nucleophilic agent with electrophilic aryl substrate,
which unlike the transmetallation reaction can be
performed in one stage [2].
CH3
O
O
H3C
O
BH
OCH3
H3C
O
OCH3
Br
CH3
Br
Na2CO3
SPhos, N(C2H5)3
Pd(OAc)2
O
O
CH3
CH3
870

871
ONE-POT SYNTHESIS OF METHYL 6-[3-(1-ADAMANTYL)-...
1H NMR spectrum (DMSO-d6), δ, ppm: 1.79 s
(6Н), 2.10 s (3Н), 2.16 s (6Н), 3.90 s (3H), 3.94 s
(3H), 6.99 d (1H, J = 8 Hz), 7.51 s (1H), 7.52 d (1H,
J = 8 Hz), 7.78 d (1H, J = 9 Hz), 7.94 d (1H, J = 9 Hz),
7.98–8.02 m (3H), 8.55 s (1H).
Мethyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-
naphthenoate. A 3-liter two-neck round-bottom flask
was charged with 800 ml of dioxane, 100 g (0.31 mol)
of 2-(1-adamantyl)-4-bromoanisole, 94 g (130 ml,
0.93 mol) of triethylamine, 3.5 g (0.0155 mol, 5 mol %)
of palladium acetate, and 12.7 g (0.031 mol, 10 mol %)
of 2-dicyclohexylphosphyno-2',6'-dimethoxybiphenyl
(Sphos). The resulting solution was stirred for 30 min
under argon, and 51 g (58 ml, 0.4 mol) of pinacol
boronate solution in 300 ml of dioxane was added in
one portion. The reaction mixture was refluxed at
stirring under slow flow of dry argon for 12 h. Then
the reaction mixture was cooled to room temperature,
61 g (0.23 mol) of methyl 6-bromo-2-naphthenoate was
dissolved in it and a solution of 127 g (1.2 mol) of
sodium carbonate in 600 ml water was added. The
reaction was carried out under argon at vigorous
mechanical stirring at 80°С for 4 h.
Use of dipalladium tris-(dibenzylideneacetone)
[Pd2(dba)3] instead of palladium acetate is shown to
change insignificantly the pinacol 3-(1-adamantyl)-4-
methoxyphenylboronate yield. 2,2'-Bis-(diphenylphos-
phino)diphenyl ether (DPEphos) as a ligand reduces
the methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-
naphthenoate yield to 59%. Use of 1,1'-bis(diphenyl-
phosphino)ferrocene or triphenylphosphine as the
ligands decrease the product yield to 28% and 9%
respectively. Application of bis-pinacolatodiboron as
functionalizing agent led to a considerable decrease in
the product yield.
The GLC analysis was performed on a Varian 3700
instrument with flame-ionization detector. The 1H
NMR spectra were recorded on a Bruker AMX-500
spectrometer from solutions in DMSO-d6 using TMS
as internal reference.
After the reaction completing, the mixture was
cooled to ambient temperature and filtered without
separating layers. The main part of the reaction
product precipitated. To get the remaining part of the
product, the organic layer was evaporated to 1/4
volume and cooled. The precipitates formed were
filtered off and combined. The crude product was
dissolved in 500 ml of N,N-dimethylacetamide, hot
solution was filtered, evaporated to a volume of
300 ml, and then left for 16 h at room temperature for
crystallization. The crystals formed were filtered off
and dried at 150–180°С for 2 h. 87 g of methyl 6-[3-
(1-adamantyl)-4-methoxyphenyl]-2-naphthenoate was
obtained [yield 66% based on 2-(1-adamantyl)-4-
bromoanisole], mp 222–225°С. Purity of the product
obtained was higher than 99%.
REFERENCES
1. Miyaura, N. and Suzuki, A., Chem. Rev., 1995, vol. 95,
no. 7, p. 2457.
2. Ishiyama, T. and Murata, M., J. Org. Chem., 1995, vol. 60,
no. 23, p. 7508.
3. Zhu, L. and Duquette, J., J. Org. Chem., 2003, vol. 68,
no. 9, p. 3729.
4. Broutin, P.-E. and Cerna, I., Org. Lett., 2004, vol. 6,
no. 24, p. 4419.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010