Retropinacol rearrangement in the synthesis of 3,3,4-trimethyl-3,4-dihydroisoquinoline derivatives

Article abstract of DOI:10.1134/S107042800912015X

Three-component condensation of veratrole with pivalaldehyde and nitriles (ethyl cyanoacetate, cyanoacetamide, and benzonitrile) in concentrated sulfuric acid leads to the formation of 1-substituted 6,7-dimethoxy-3,3,4-trimethyl-3,4-dihydroisoquinolines.

Full text of DOI:10.1134/S107042800912015X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1843–1846. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Yu.V. Shklyaev, M.Yu. Gilev, O.A. Maiorova, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 12,
pp. 1845–1847.
Retropinacol Rearrangement in the Synthesis
of 3,3,4-Trimethyl-3,4-dihydroisoquinoline Derivatives
Yu. V. Shklyaev, M. Yu. Gilev, and O. A. Maiorova
Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences,
ul. Akademika Koroleva 3, Perm, 614013 Russia
e-mail: yushka@newmail.ru
Received October 3, 2008
Abstract—Three-component condensation of veratrole with pivalaldehyde and nitriles (ethyl cyanoacetate,
cyanoacetamide, and benzonitrile) in concentrated sulfuric acid leads to the formation of 1-substituted 6,7-di-
methoxy-3,3,4-trimethyl-3,4-dihydroisoquinolines.
DOI: 10.1134/S107042800912015X
We previously reported [1–3] that isobutyralde-
hyde, 2-ethylhexanal, and cyclohexanecarbaldehyde
react with activated arenes and nitriles in concentrated
sulfuric acid to give 3,3-dialkyl-3,4-dihydroisoquino-
line derivatives. It is also known that 3,3,4,4-tetra-
methyl-3,4-dihydroisoquinoline derivatives exhibiting
a broad spectrum of biological activity [4] can be syn-
thesized via retropinacol rearrangement of 3,3-di-
methyl-2-phenylbutan-2-ol [5].
In fact, the reaction of equimolar amounts of vera-
trole, pivalaldehyde, and ethyl cyanoacetate in concen-
trated sulfuric acid gave ethyl 6,7-dimethoxy-3,3,4-tri-
methyl-1,2,3,4-tetrahydroisoquinolin-1-ylideneacetate
(II) (Scheme 2). Compound II was also synthesized by
reaction of ethyl cyanoacetate with 2-(3,4-dimethoxy-
phenyl)-3-methylbutan-2-ol (III) which can readily be
prepared from 3,4-dimethoxyacetophenone and isopro-
pylmagnesium bromide in tetrahydrofuran. The yield
of compound II in the first case (method a, 21%) was
thrice as small as in the second (method b, 65%).
Presumably, the three-component condensation
(method a) is accompanied by Danilov rearrangement
[6] of initial pivalaldehyde (Scheme 3), which is re-
sponsible for the poor yield of II.
We expected analogous retropinacol rearrangement
to occur in the three-component reaction of an activat-
ed arene with nitriles and pivalaldehyde. In this case,
the first step is formation of the corresponding carbinol
I according to Baeyer [1]. Dehydration of I in sulfuric
acid yields carbocation A which should undergo retro-
pinacol rearrangement with formation of carbocation B
as key intermediate in the synthesis of 3,4-dihydroiso-
quinolines according to Ritter [1] (Scheme 1).
Analogous rearrangement was also observed in the
reaction with isobutyraldehyde, but its rate was con-
siderably lower than that for pivalaldehyde. This fol-
Scheme 1.
OH
Me
Me
Me
Me
MeO
MeO
MeO
MeO
MeO
MeO
H+
H+
+
Me3CCHO
–H2O
Me
Me
I
A
Me
MeO
MeO
Me
Me
B
1843

SHKLYAEV et al.
1844
Scheme 2.
Me
Me
Me
MeO
MeO
MeO
MeO
+
Me3CCHO + NCCH2COOEt
a
NH
COOEt
II
Me OH
MeO
MeO
Me
+
NCCH2COOEt
II
b
Me
III
lowed from the formation of 1:2 adduct from isobutyr-
aldehyde and nitrile in sulfuric acid [7] (Scheme 4).
The same adduct is always formed in three-component
condensation of arenes with isobutyraldehyde and
nitriles [1], but almost no such product is obtained in
three-component condensations with pivalaldehyde (it
can be detected only by GC–MS).
results in fast formation of isopropyl methyl ketone
(Scheme 3) which does not react further. The conden-
sation of veratrole with pivalaldehyde and ethyl cyano-
acetate at a ratio of 1:2:1 gave 44% of isoquinoline II,
whereas the use of 1-(3,4-dimethoxyphenyl)-2,2-di-
methylpropan-1-ol (I) [prepared by reduction of
1-(3,4-dimethoxyphenyl)-2,2-dimethylpropan-1-one
with sodium tetrahydridoborate in alcohol] as starting
compound ensured a yield of II comparable with that
obtained according to method b (63%, Scheme 6).
Likewise, three-component condensations of vera-
trole with pivalaldehyde and cyanoacetamide or benzo-
nitrile in sulfuric acid gave compounds VI and VII in
24 and 14% yield, respectively (Scheme 7).
Scheme 3.
Me
Me
O
H2SO4, 0–5°C
Me3CCHO
Me
Scheme 4.
Me
Me
O
O
H2SO4
EXPERIMENTAL
Me2CHCHO
+ 2RCN
R
N
H
N
H
R
The IR spectra were recorded on a UR-20 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Varian Mercury
PLUS 300 spectrometer at 300 MHz using CDCl3 as
solvent and tetramethylsilane as internal reference. The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates using
chloroform–acetone (9:1) as eluent; spots were detect-
ed by treatment with a 0.5% solution of 2,3,5,6-tetra-
chloro-1,4-bezoquinone in toluene. The elemental
compositions were determined on a LECO CHNS-932
In addition, the reaction of veratrole with pivalal-
dehyde was accompanied by formation of no more
than 5% of 9,10-di-tert-butyl-2,3,6,7-tetramethoxyan-
1
thracene (IV) (according to the H NMR data;
Scheme 5), whereas analogous anthracene derivative is
obtained from isobutyraldehyde in almost quantitative
yield [8]. Compound V was not isolated from the reac-
tion mixture and was identified only on the basis of the
GC–MS data. Obviously, the Danilov rearrangement
Scheme 5.
Bu-t
Me
MeO
MeO
MeO
MeO
OMe
OMe
MeO
MeO
Me
H+
+
Me3CCHO
+
Me
Bu-t
IV
V (~30%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RETROPINACOL REARRANGEMENT IN THE SYNTHESIS OF 3,3,4-TRIMETHYL-...
1845
Scheme 6.
Me
OH
Me
Me
Me
Me
MeO
MeO
MeO
MeO
H2SO4
+
NCCH2COOEt
NH
Me
COOEt
I
II
Scheme 7.
Me
Me
Ph
Me
Me
Me
Me
MeO
MeO
MeO
MeO
MeO
MeO
NCCH2CONH2
PhCN
+
Me3CCHO
NH
N
CONH2
VI
VII
analyzer. Gas chromatographic–mass spectrometric
identification of some compounds was performed on
an Agilent GC 6890N MSD 5975B instrument (elec-
tron impact, 70 eV).
OCH2, J = 7.1 Hz), 5.01 s (1H, 1-CH), 6.65 s (1H,
5-H), 7.01 s (1H, 8-H), 8.83, br.s (1H, NH). Found, %:
C 67.54; H 7.80; N 4.47. C18H25NO4. Calculated, %:
C 67.69; H 7.89; N 4.39.
Ethyl (6,7-dimethoxy-3,3,4-trimethyl-1,2,3,4-
tetrahydroisoquinolin-1-ylidene)acetate (II).
a. A mixture of 1.38 g (0.01 mol) of veratrole, 0.86 g
(0.01 mol) of pivalaldehyde, and 1.13 g (0.01 mol) of
ethyl cyanoacetate was added dropwise under vigorous
stirring to 3 ml of 94% sulfuric acid, maintaining the
temperature at 5–10°C. The mixture was stirred for 1 h
without external cooling, poured into 200 ml of water,
and neutralized by adding dry sodium carbonate to
pH 8–9. A part of water, 50 ml, was removed by steam
distillation, and the residue was cooled and extracted
with 50 ml of benzene. The extract was washed with
water (2×50 ml), dried, and evaporated on a rotary
evaporator, and the residue was recrystallized from
hexane. Yield 0.67 g (21%), mp 120–121°C. The reac-
tion with 2 equiv of pivalaldehyde, other conditions
being equal, gave 1.4 g (44%) of compound II.
b. A mixture of 2.24 g (0.01 mol) of 2-(3,4-di-
methoxyphenyl)-3-methylbutan-2-ol (prepared from
3,4-dimethoxyacetophenone and isopropylmagnesium
bromide in THF) and 1.13 g (0.01 mol) of ethyl cyano-
acetate was added dropwise under vigorous stirring to
3 ml of 94% sulfuric acid, maintaining the temperature
at 5–10°C. The mixture was then treated as described
above in a to isolate 2.1 g (65%) of compound II.
1H NMR spectrum, δ, ppm: 1.20 s (3H, 3-Meeq), 1.27 s
(3H, 3-Meax), 1.16 d (3H, 4-Me, J = 8 Hz), 1.30 t (3H,
CH2CH3, J = 7.1 Hz), 2.64 q (1H, 4-H, J = 10 Hz),
3.87 s (3H, 6-OMe), 3.91 s (1H, 7-OMe), 4.15 q (2H,
c. Compound II was also obtained as described
above in b from 1-(3,4-dimethoxyphenyl)-2,2-dimeth-
ylpropan-1-ol (I) prepared by reduction of 2.22 g
(0.01 mol) of 1-(3,4-dimethoxyphenyl)-2,2-dimethyl-
propan-1-one with NaBH4 in alcohol and used without
additional purification. Yield 2.01 g (63%).
(6,7-Dimethoxy-3,3,4-trimethyl-1,2,3,4-tetra-
hydroisoquinolin-1-ylidene)acetamide (VI) was syn-
thesized as described above in a from 1.38 g (0.01 mol)
of veratrole, 0.86 g (0.01 mol) of pivalaldehyde,
and 0.84 g (0.01 mol) of cyanoacetamide. Yield 0.7 g
1
(24%), oily substance. H NMR spectrum, δ, ppm:
1.16 s (6H, 3-Me), 1.19 d (3H, 4-Me, J = 8 Hz), 2.59 q
(1H, 4-H, J = 10 Hz), 3.89 s (3H, 6-OMe), 3.90 s (3H,
7-OMe), 4.82 br.s (2H, NH2), 4.88 s (1H, 1-CH),
6.64 s (1H, 5-H), 7.04 s (1H, 8-H), 9.44 br.s (1H, NH).
Found, %: C 66.07; H 7.80; N 9.53. C16H22N2O3. Cal-
culated, %: C 66.19; H 7.64; N 9.65.
6,7-Dimethoxy-3,3,4-trimethyl-1-phenyl-3,4-di-
hydroisoquinoline (VII) was synthesized as described
above in a from 1.38 g (0.01 mol) of veratrole, 0.86 g
(0.01 mol) of pivalaldehyde, and 1.03 g (0.01 mol) of
benzonitrile. Yield 0.43 g (14%), mp 117–119°C
1
(aqueous alcohol, 1:1). H NMR spectrum, δ, ppm:
1.18 s (3H, 3-CH3), 1.28 s (3H, 3-CH3), 1.20 d (3H,
4-H, J = 8 Hz), 2.69 q (1H, 4-H, J = 10 Hz), 3.68 s
(3H, 6-OCH3), 3.94 s (3H, 7-OCH3), 6.69, s (1H, 5-H),
6.76 s (1H, 8-H), 7.39–7.41 m (3H, p-H, m-H), 7.54–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

SHKLYAEV et al.
1846
2. Shklyaev, Yu.V., Gilev, M.A., Maiorova, O.A., and
7.57 m (2H, o-H). Found, %: C 77.49; H 7.60; N 4.61.
C20H23NO2. Calculated, %: C 77.64; H 7.49; N 4.53.
Tolstikov, A.G., Butlerov. Soobshch., 2005, vol. 7, p. 40.
3. Glushkov, V.A., Rozhkova, Yu.S., Vakhrin, M.I., and
Shklyaev, Yu.V., Khim. Geterotsikl. Soedin., 2005, no. 8,
p. 1198.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 07-03-00001), by the joint program of the Ural and
Siberian Divisions of the Russian Academy of
Sciences “Target-Oriented Synthesis and Optimization
of Properties of Biologically Active Compounds,” and
by the program of the Presidium of the Russian
Academy of Sciences “Development of New Methods
for the Preparation of Chemical Compounds and
Design of New Materials.”
4. Ogawa, M., Takaoka, Y., and Ohhata, A., US Patent
no. 6 956 033, 2005; http://www.patentstorm.us/
patents/6956033.html.
5. Shklyaev, Yu.V. and Gilev, M.A., Russian Patent
no. 2326114, 2008; Byull. Izobret., 2008, no. 16.
6. Vatsuro, K.V. and Mishchenko, G.L., Imennye reaktsii v
organicheskoi khimii (Name Reactions in Organic Chem-
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7. Zil’berman, E.N., Reaktsii nitrilov (Reactions of Nitriles),
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