Synthesis of 7- (or 6-)hydroxy derivatives of 3,3-dimethyl-3,4- dihydroisoquinoline

Article abstract of DOI:10.1007/s10593-009-0268-9

When treated with cyanoacetic ester in conc. H₂SO₄ 1-(4-hydroxy-3-methoxyphenyl)- and 1-(3-hydroxy-4-methoxyphenyl)-2-methylpropan- 1-ol form ethyl 7-hydroxy-6-methoxy-3,3-dimethyl(or 6-hydroxy-7-methoxy- 3,3-dimethyl)-1,2,3,4-tetrahydroisoquinolylidene-1-acetate.

Full text of DOI:10.1007/s10593-009-0268-9

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
SYNTHESIS OF 7- (OR 6-)HYDROXY
DERIVATIVES OF 3,3-DIMETHYL-
3,4-DIHYDROISOQUINOLINE
Yu. V. Shklyaev1*, T. S Vshivkova1, and A. G. Tolstikov1
When treated with cyanoacetic ester in conc. H2SO4 1-(4-hydroxy-3-methoxyphenyl)- and 1-(3-hydroxy-
4-methoxyphenyl)-2-methylpropan-1-ol form ethyl 7-hydroxy-6-methoxy-3,3-dimethyl(or 6-hydroxy-
7-methoxy- 3,3-dimethyl)-1,2,3,4-tetrahydroisoquinolylidene-1-acetate.
Keywords: vanillin, 3,3-dimethyldehydrosalsoline, 3,3-dimethyldehydroisosalsoline, isovanillin.
6(or 7-)-Hydroxy-7-(or-6-)methoxy derivatives of isoquinolines hydrogenated in the heterocyclic
fragment are quite widely distributed in nature. These include e.g. salsoline, isosalsoline, N-methylisosalsoline,
lophocerine, corypaline, O-methylanhalonidine, pseudolaudanine, and many others [1-8]. At the same time,
3,3-dimethyl analogs of these compounds have hardly been studied. It can be recalled that 3,3-dimethyl-
3,4-dihydroisoquinoline N-oxide [9] is a powerful agent used in septic and traumatic shock and in a recent US
patent [10] relating to preparation of 1-substituted 3,3,4,4-tetramethyl-3,4-dihydroisoquinolines. It is clear that
reduction of 3,4-dihydroisoquinolines to 1,2,3,4-tetrahydro derivatives is a routine problem.
The simplest method for preparing 3,3-dialkyl-3,4-dihydroisoquinolines is the reaction of
dimethylbenzylcarbinol with nitriles [11] or a three-component reaction of an activated arene, isobutyraldehyde,
and nitriles in conc. H2SO4 [12]. It is known that free phenols are readily sulfonated in conc. H2SO4 hence the
simplest method for synthesis of 7-hydroxy-6-methoxy-1,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolines is the
reaction of carbinol 2 (prepared from the 4-benzyloxy-3-methoxybenzaldehyde (1) substituted at the phenol
oxygen atom using isopropyl magnesium bromide) and cyanoacetic ester with subsequent hydrolysis of the ethyl
7-benzyloxy-6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1-acetate
(3)
to
7-benzyloxy-
6-methoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline (4) and removal of the benzyl protection by hydrogenation
with simultaneous reduction to the tetrahydro derivative.
It was found that, the cyclization reaction conditions to compound 3 were accompanied by removal of
the benzyl group and immediate formation of the 7-hydroxy derivative 5 which was readily transformed to the
3,3-dimethyldehydroisosalsoline 6. A small amount of compound 3 was also separated in which the benzyl
group was retained.
_______
* To whom correspondence should be addressed, e-mail: cheminst@mpm.ru, yushka@newmail.ru.
1Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences, Perm 614013, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 421-425, March, 2009. Original
article submitted November 27, 2007.
0009-3122/09/4503-0341©2009 Springer Science+Business Media, Inc.
341

OH
MeO
BzO
CHO
MeO
BzO
Me
i-PrMgBr
+
Me
1
2
Me
Me
MeO
MeO
BzO
Me
Me
MeO
HO
Me
Me
NH
NH
N
BzO
Me
Me
3,3-dimethylisosalsoline
CO2Et
3
4
Me
Me
Me
Me
MeO
MeO
N
NH
HO
HO
Me
6
5
CO2Et
Separation of compound 5 from the reaction product led us to study the possibility of its synthesis from
carbinol 7 prepared directly from vanillin and this gave an almost 2.5 times increase in the yield of the target
compound 5.
OH
Me
MeO
HO
5
+
NC
CO2Et
Me
7
A similar reaction with carbinol 8 prepared from isovanillin gave compound 9 in 24% yield. This is due
to the difficulty of crystallizing ester 9 since chromato gas chromatographic data on the neutralized reaction
product shows the yields of compounds 5 and 9 from the corresponding carbinols to be around 70%. Ester 9 is
readily converted to 3,3-dimethyldehydrosalsoline 10 via hydrolysis with 10% sulfuric acid.
OH
Me
Me
Me
Me
HO
HO
Me
HO
NC
+
COOEt
NH
N
Me
MeO
MeO
MeO
Me
8
10
COOEt
9
Hence we have discovered routes to preparation of 7(or 6)-hydroxy-3,4-dihydroisoquinolines which
open up broad possibilities for synthesizing analogs of known alkaloids modified at the ring 3 position.
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument using vaseline oil. 1H NMR spectra were registered on
a MercuryPlus-300 spectrometer (300 MHz) using DMSO-d6 and HMDS internal standard. Mass spectra were
342

obtained on an Agilent GC 6890N MSD 5975B spectrometer (EI, 70 eV). Elemental analysis was performed on
a CHNS-932 LECO Corporation analyzer. Monitoring of the reaction course and purity of the compounds
obtained was carried out by TLC on Silufol plates in the system chloroform–acetone (9:1) and revealed using a
5% solution of chloranil in toluene.
Carbinols 2, 7 and 8 were prepared via organomagnesium synthesis from isopropylmagnesium bromide
and benzylvanillin, vanillin, and isovanillin respectively as a mixture with the corresponding styrene (~ 3:2 by
LC) and were used without additional purification [13].
Synthesis of Compounds 3, 5, 6, 9, and 10 (General Method). A mixture of 1-(4-hydroxy-3-methoxy-
phenyl)-2-methylpropanol (7) (for preparing compounds 5 and 6) or 1-(3-hydroxy-4-methoxyphenyl)-2-methyl-
propanol (8) (for compounds 9 and 10) (1.95 g, 0.01 mol) and cyanoacetic ester (1.13 g, 0.01 mol) was added
dropwise with vigorous stirring to 98% H2SO4 (8 ml) cooled to 5-10ºC. The product was stirred for 30 min at
room temperature. The reaction mixture was poured into water and neutralized using sodium carbonate to pH
7-8, extracted with chloroform (3×50 ml), and the combined organic layer was washed with water and dried
over magnesium sulphate. Chloroform was distilled off and the residue was crystallized from the appropriate
solvent. Compound 3 was separated by fractional crystallization of the mixture of esters 3 and 5 from methanol.
The yield of compound 5 by this method was 22%.
Compounds 6 and 10 were prepared by refluxing compounds 5 and 9 in 10% H2SO4 for 3 h, cooling to
room temperature, and subsequent separation as reported above.
Ethyl 7-benzyloxy-6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1-acetate (3). Mp
1
207-209ºC (methanol); yield 8%. IR spectrum, ν, cm-1: 3360 (NH), 1630 (sh, C=O); 1620 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 1.09 (3H, t, J = 7.2, OCH2CH3); 1.17 (6H, s, 3,3-(CH3)2); 2.70 (2H, s, H-4); 3.87 (3H,
s, 6-OCH3); 3.92 (2H, q, J = 7.2, OCH2CH3); 4.24 (2H, s, OCH2C6H5); 4.54 (1H, s, CH=CH–); 6.80 (1H, s,
H-5); 8.40 (1H, s, H-8). Mass spectrum, m/z (Irel, %): 381 [M]+ (60), 352 (10), 336 (13), 290 (35), 262 (20), 230
(14), 178 (19), 165 (20).
Ethyl 7-Hydroxy-6-methoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1-acetate (5). Mp
148-151ºC (ethanol); yield 56% (carbinol 7). IR spectrum, ν, cm-1: 3460, 3270, 1640, 1602, 1574, 1512.
1H NMR spectrum, δ, ppm (J, Hz): 1.25 (6H, s, 3,3-(CH3)2); 1.30 (3H, m, OCH2CH3); 2.72 (2H, s, H-4); 3.91
(3H, s, 6-OCH3); 4.12 (2H, q, J = 7.2, OCH2CH3); 5.00 (1H, s, –CH=C–); 5.50 (1H, br. s, 7-OH); 6.58 (1H, s,
H-5); 7.21 (1H, s, H-8); 8.90 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 291 [M]+ (52), 276 [M-CH3]+ (20),
246 [M-OC2H5]+ (20), 230 [M-OOC2H5]+ (100), 219 (23), 204 (27). Found, %: C 66.18; H 7.21; N 4.85.
C16H21NO4. Calculated, %: C 65.96; H 7.27; N 4.81.
7-Hydroxy-6-methoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline (6). Mp 194-204ºC (a mixture of
ethyl acetate and hexane); yield 53% (29% based on the starting carbinol 7). IR spectrum, ν, cm-1: 1632, 1612,
1
1560, 1512. H NMR spectrum, δ, ppm: 1.19 (6H, s, 3,3-(CH3)2); 2.29 (3H, s, 1-CH3); 2.60 (2H, s, H-4); 3.91
(3H, s, 6-OCH3); 6.61 (1H, s, H-5); 7.07 (1H, s, H-8). Mass spectrum, m/z (Irel, %): 219 [M]+ (91), 204
[M-CH3]+ (100), 189 (20), 177 (41), 162 (14). Found, %: C 71.29; H 7.76; N 6.44. C13H17NO2. Calculated, %:
C 71.21; H 7.81; N 6.39.
Ethyl 6-Hydroxy-7-methoxy-3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1-acetate (9). Mp
1
135-137ºC (ethanol); yield 24%. IR spectrum, ν, cm-1: 3280, 3000, 1636, 1592, 1516. H NMR spectrum, δ,
ppm (J, Hz): 1.25 (6H, s, 3,3-(CH3)2); 1.28 (3H, m, OCH2CH3); 2.71 (2H, s, H-4); 3.90 (3H, s, 7-OCH3); 4.15
(2H, q, J = 7.2, OCH2CH3); 4.99 (1H, s, –CH=C–); 5.86 (1H, s, 6-OH); 6.68 (1H, s, H-5); 7.11 (1H, s, H-8);
8.93 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 291 [M]+ (31), 276 [M-CH3]+ (20), 246 [M-OC2H5]+ (17), 230
[M-OOC2H5]+ (100), 219 (15), 204 (40). Found, %: C 65.83; H 7.33; N 4.86. C16H21NO4. Calculated, %:
C 65.96; H 7.27; N 4.81.
6-Hydroxy-7-methoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline (10). Mp 195-196ºC (mixture of
ethyl acetate and hexane); yield 20% (based on starting carbinol 8). IR spectrum, ν, cm-1: 3200, 1615, 1585,
1
1512. H NMR spectrum, δ, ppm: 1.30 (6H, s, 3,3-(CH3)2); 2.45 (3H, s, 1-CH3); 2.67 (2H, s, H-4); 3.79 (3H, s,
343

7-OCH3); 5.50 (1H, br. s, 6-OH); 6.44 (1H, s, H-5); 6.85 (1H, s, H-8). Mass spectrum, m/z (Irel, %): 219 [M]+
(100), 204 [M-CH3]+ (85), 189 (34), 177 (53), 162 (15). Found, %: C 71.34; H 7.75; N 6.43. C13H17NO2.
Calculated, %: C 71.21; H 7.81; N 6.39.
This work was carried out with financial support from a Russian Federation President grant for leading
science schools No. NSh-5812.2006.3, the RFFI grants 07-03-00001 and 07-03-96012, and also the Ural and
Siberian Branches of the Russian Academy of Sciences collaborative program for "Synthetic route and
optimization of properties of biologically active compounds"
REFERENCES
1.
2.
A. P. Orekhov, Chemistry of Alkaloids [in Russian], Moscow (1955), p. 859.
W. J. Gensler, in: R. Elderfield (editor), Heterocyclic Compounds [Russian translation], vol. 4, Inostr.
Lit., Moscow (1955), p. 264.
3.
W. M. Whaley and T. R. Govindachari in: Organic Reactions [Russian translation], vol 6, Inostr. Lit.,
Moscow (1953), p. 98.
4.
5.
W. J. Gensler in: Organic Reactions [Russian translation], vol. 6, Inostr. Lit, Moscow (1953), p. 218.
P. A. Klare in: D. Barton and W. D. Ollis (editors), Comprehensive Organic Chemistry, [Russian
translation], vol. 8, Khimiya, Moscow (1985), p. 255.
6.
7.
M. Shamma, The Isoquinoline Alkaloids, Academic Press, New York (1972).
M. Shamma and J. L. Moniot, Isoquinoline Alkaloids Research 1972-1977, Plenum Press, New York,
London (1978), 426 p.
8.
A. A. Semenov, Outline of the Chemistry of Natural Compounds [in Russian], Nauka, Novosibirsk
(2000), 664 p.
9.
T. J. N. Watson, J. Org. Chem., 63, 406 (1998).
10.
Mikio
Ogawa,
Yoshikazu
Takaoka,
and
Akira
Ohhata,
US
Pat.
6956033;
www.freepatentsonline.com/6956033.html
11.
V. S. Shklyaev, B. B. Aleksandrov, G. I. Legotkina, M. S. Gavrilov, M. I. Vakhrin, and
A. G. Mikhailovskii, Khim. Geterotsikl. Soedin., 1560 (1983). [Chem. Heterocycl. Comp., 19, 1242
(1983)].
12.
13.
Yu. V. Shklyaev and Yu. V. Nifontov, Izv. Akad. Nauk, Ser. Khim., 780 (2002).
Yu. S. Rozhkova, Dissertation Cand. Chem. Sci., Perm (2006).
344