Mandelonitrile in synthesis of partially hydrogenated isoquinoline derivatives

Article abstract of DOI:10.1134/S107042721008032X

New procedures for preparing tetrahydroisoquinoline derivatives using available chemicals are described. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S107042721008032X

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2010, Vol. 83, No. 8, pp. 1489−1493. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Kharitonova, A.A. Gorbunov, Yu.V. Shklyaev, 2010, published in Zhurnal Prikladnoi Khimii, 2010, Vol. 83, No. 8, pp. 1383−1387.
Mandelonitrile in Synthesis of Partially Hydrogenated
Isoquinoline Derivatives
A. V. Kharitonova, A. A. Gorbunov, and Yu. V. Shklyaev
Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences, Perm, Russia
Received March 10, 2010
Abstract—New procedures for preparing tetrahydroisoquinoline derivatives using available chemicals are
described.
DOI: 10.1134/S107042721008032X
1,2,3,4-Tetrahydroisoquinoline (THIQ) derivatives
widelyoccurinthenatureandexhibithighpharmacological
activity [1–3]. The most widely used route of their
synthesis is the Pictet–Spengler reaction [4]. With the aim
to develop new routes to THIQ derivatives and expand
the range of chemicals suitable for their synthesis, we
performed a three-component reaction of mandelonitrile,
isobutyraldehyde, and activated arenes. We expected
that the reaction of mandelonitrile, isobutyraldehyde,
and veratrole would yield 1-benzoyl-6,7-dimethoxy-
3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 1a owing
to imine–enamine tautomerism in intermediate A and
transformation of the hydroxy group at the double bound
into keto group (Scheme 1).
We found that the reaction performed with freshly
prepared mandelonitrile yielded an equimolar mixture of
[6,7-dimethoxy-3,3-dimethyl-3,4-dihydroisoquinolin-
1(2Н)-ylidene](phenyl)methanol 1 and 1-benzoyl-6,7-
dimethoxy-3,3-dimethyl-3,4-dihydroisoquinoline2.The
physicochemical constants of 2 fully agree with those
reported in [5]. Apparently, product 2 originates from
oxidationoftheintermediate3,3-dialkyl-6,7-dimethoxy-
Scheme 1.
MeO
MeO
MeO
H2SO4
Me
Me
CHO
NC
Ph
OH
+
+
N
MeO
Ph
OH
A
[O]
MeO
MeO
MeO
MeO
MeO
MeO
N
O
NH
OH
NH
O
Ph
Ph
Ph
1a
2
1
1489

1490
KHARITONOVA et al.
1-(α-hydroxybenzyl)-3,4-dihydroisoquinoline А under
the reaction conditions. The existence of 1 in the enol
form follows from the absence of the methine proton
signal in the 1Н NMR spectrum, of the carbonyl carbon
signal in the 13С NMR spectrum, and of the carbonyl
absorption band in the IR spectrum. At the same time,
It should be noted that, according to GC–MS,
4-chloroanisole and 4-fluoroanisole give exclusively
diphenylacetonitrile derivatives (93%) instead of the
expected spirocyclic systems, as shown in [7].
Along with the attack of mandelonitrile by carbenium
ion A' formed by isobutyraldehyde and activated arene,
carbocation can also be formed under the reaction
conditions from mandelonitrile itself. Because of the
presence of the electron-withdrawing nitrile group at the
carbocationic center, cation B will be more reactive than
cation A containing a donor substituent (Scheme 2).
1
the Н NMR spectrum contains a broadened singlet
at 12.43 ppm. A quantum-chemical calculation (АМ1
program, Hyperhem 8.0 package) showed that the
enol form 1 is more stable than the keto form 1a by
approximately 23 kcal (99.21 against 122.95).
With commercially available mandelonitrile (Lan-
caster), the three-component synthesis yields unsym-
metrical diphenylacetonitrile derivatives described
previously in a US patent [6], and 1-benzoyl-3,3-di-
methyl-3,4-dihydroisoquinolines are detected in the
reaction mixture only in trace amounts. Analysis by gas
chromatography–mass spectrometry (GC–MS) shows
that the mixtures contain simultaneously several isomers
of diarylacetonitrile.
Presumably, storage of mandelonitrile is accompani-
ed, owing to contact with atmospheric oxygen, by
formation of impurities that cannot be removed by
distillation and significantly affect the reaction course.
In the three-component synthesis with freshly prepared
mandelonitrile, we avoided the effect of this factor and
obtained the enol form of 1-benzoyl-3,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline 1.
Scheme 2.
MeO
MeO
MeO
MeO
MeO
MeO
HO
CN
+
+
+
NH
+
OH
CN
A
A'
O
Ph
Ph
HO
CN
+
Ph
MeO
MeO
MeO
MeO
Scheme 3.
MeO
H+
CN
C
N
C
N
+
MeO
B
Ph
OH
MeO
MeO
MeO
MeO
HO
CN
H2SO4
+
N
Ph
Ph
O
2
Ph
OMe OH
OMe
MeO
MeO
HO
CN
H2SO4
+
N
O
Ph
3
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MANDELONITRILE IN SYNTHESIS OF HYDROGENATED ISOQUINOLINE DERIVATIVES
1491
Taking into account the previous data on the use of
the linear synthesis scheme with steadily high yields of
the target products, it was appropriate to estimate the
yield of the desired 1-benzoyl-3,3-dimethyl-1,2,3,4-
tetrahydroisoquinolines in the Ritter reaction. We found
that dimethoxy-substituted carbinols enter into the
Ritter reaction with mandelonitrile to form exclusively
on Sorbfil plates in the trichloromethane–acetone
system (9 : 1). The chromatograms were visualized with
a 0.5% solution of chloranil in toluene. Separations by
column chromatography were performed on silica gel
(Lancaster, 0.060– 0.2 mm).
Diphenylacetonitriles were not isolated from the
reaction mixture and were detected only by GC–MS.
1-benzoyl-3,3-dimethyl-3,4-dihydroisoquinolines
2
[6,7-Dimethoxy-3,3-dimethyl-3,4-dihydroiso-
quinolin-1(2Н)-ylidene](phenyl)methanol 1. A mix-
ture of 6.65 g (50 mmol) of mandelonitrile, 3.60 g
(50 mmol) of isobutyraldehyde, and 6.90 g (50 mmol) of
veratrole was added dropwise with stirring and cooling
by a water–ice mixture to 40 ml of concentrated H2SO4.
The resulting mixture was stirred for 15 min, poured onto
150 g of crushed ice, alkalized with aqueous ammonia
to pH 7–8, and extracted with dichloromethane (3 ×
30 ml). The organic layer was washed with 100 ml of
water, filtered, and left to crystallize. The precipitate
was filtered off. Yellow crystals, yield 3.20 g (20%), mp
231–234°С. IR spectrum, ν, cm–1: 1639 (С=С), 3180
and 3 (Scheme 3).
When we performed the synthesis with carbinols
prepared by the Grignard reaction from cyclopentanone
or cyclohexanone and benzylmagnesium chloride, we
isolated by column chromatography the corresponding
1-benzoyl-3,3-tetra(or penta)methylene-3,4-dihydroiso-
quinoline 4 or 6 and 3,3-tetra(or penta)methylene-3,4-
dihydroisoquinoline 5 or 7, unsubstituted at 1-position.
Formation of these compounds can be accounted for by
the fact that under the reaction conditions mandelonitrile
occurs in equilibrium with its synthetic precursors,
benzaldehyde and hydrogen cyanide:
1
(NH), 3292 (ОН). Н NMR spectrum, δ, ppm: 1.37,
1.47 two s (6Н, gem-Ме); 2.98 s (2Н, 4-СН2); 3.62 s
(3Н, 6-ОМе); 3.82 s (3Н, 7-ОМе); 6.57 s (1Н, 5-Нaryl);
7.01 s (1Н, 8-Нaryl); 7.29–7.53 m (6Н, Нphenyl + 1-H);
12.43 br. s (1Н, ОН). Mass spectrum, m/z (Irel, %): 323
[M]+· (34); 308 [M – Me]+ (100); 292 [М – МеО] (73);
280 [M – Me – MeO] (23). The mass spectrum of 1 fully
coincides with that of 2, apparently, because of easy
dehydrogenation due to thermolysis in the vaporizer.
Found, %: C 73.79, H 7.13, N 4.31. C20H23NO3.
Calculated, %: C 73.82, H 7.12, N 4.30.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80
spectrometer from mulls in mineral oil, and the 1Н NMR
spectra, on a Varian Mercury Plus 300 spectrometer
(300 MHz) in DMSO-d6 and СDCl3, internal reference
HMDS. Elemental analysis was performed with
a CHNS-932 device (LECO Corporation). A GC–MS
study was performed with an Agilent GC 6890N MSD
5975B device (electron impact, 70 eV). The reaction
progress and product purity were monitored by TLC
1-Benzoyl-6,7-dimethoxy-3,3-dimethyl-3,4-di-
Scheme 4.
H2SO4
HO
HO
CN
CN
+
+
+
HO
HO
N
N
N
Ph
Ph
O
O
Ph
5
7
4
6
H2SO4
+
N
Ph
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010

1492
KHARITONOVA et al.
spectrum, m/z (Irel, %): 289 [М]+· (70); 260 [М – С2Н5]+
(100). Found, %: C 82.82, H 6.90, N 5.03. C20H19NO.
Calculated, %: С 83.01, H 6.62, N 4.84.
hydroisoquinoline 2. The mother liquor from the syn-
thesis of 1 was evaporated to dryness, and the residue
was crystallized from ethanol. Yellow crystals, yield
3.07 g (19%), mp 133–135°С. IR spectrum, ν, cm–1:
3,3-Tetramethylene-3,4-dihydroisoquinoline
1
1648 (С=N), 1688 (С=О). Н NMR spectrum, δ, ppm:
5. Yield 0.46 g (25%). Light brown oil, Rf 0.45. IR
1.27 s (6Н, gem-Ме); 2.73 s (2Н, 4-СН2); 3.69 s (3Н,
6-ОМе); 3.86 s (3Н, 7-ОМе); 6.65 s (1Н, 5-Нaryl); 6.78 s
(Н, 8-Нaryl); 7.37–8.00 m (5Н, Нphenyl). Mass spectrum,
m/z (Irel, %): 323 [M]+· (34); 308 [M – Me]+ (100); 292
[М – МеО] (73); 280 [M – Me – MeO] (23). Found,
%: С 74.37, H 6.60, N 4.30. C20H21NO3. Calculated, %:
С 74.28, Н 6.55, N 4.33.
1
spectrum, ν, cm–1: 1668 (С=N). Н NMR spectrum, δ,
ppm: 1.21–1.91 m (8Н, СН2cyclopentyl); 2.79 s (2Н, 4-Н);
7.11–7.51 m (3Н, 5,6,7-H); 8.08–8.11 m (1Н, 8-Н); 8.3 s
(1Н, 1-Н). Mass spectrum, m/z (Irel, %): 185 [М]+· (100);
157 [M – C2H4]+ (50); 143 [M – C2H4 – N]+ (55). Found,
%: C 84.53, H 8.41, N 7.70. C13H15N. Calculated, %:
С 84.28, H 8.16, N 7.56.
1-Benzoyl-5,6-dimethoxy-3,3-dimethyl-3,4-
dihydroisoquinoline 3. A mixture of 0.96 g (0.005 mol)
of 1-(2,3-dimethoxyphenyl)-2-methylpropan-1-ol and
0.66 g (0.005 mol) of mandelonitrile was added dropwise
to 5 ml of cooled concentrated H2SO4. The reaction
mixture was stirred for 20 min at 20°С and poured onto
100 g of crushed ice. The aqueous layer was alkalized
with aqueous ammonia to pH 7–8. The oil that separated
in the process was extracted with trichloromethane (2 ×
30 ml). The extract was dried over MgSO4, and the
solvent was distilled off. The products were separated
chromatographically (eluent trichloromethane–acetone,
30 : 1). Yield 1.20 g (37%). Light brown oil, Rf 0.4. IR
spectrum, ν, cm–1: 1636 (С=N), 1678 (C=О). 1Н NMR
spectrum, δ, ppm: 1.33 s (6Н, gem-Ме); 2.87 s (2Н,
4-Н); 3.86, 3.81 two s [6Н, 5,6-(ОМе)2]; 6.70 d (1Н,
7-H, J = 8.4 Hz); 7.03 d (1Н, 8-Н, J = 9 Hz); 7.41–
7.47 m (2Н, 5’,3’-Нphenyl); 7.54–7.59 m (1Н, 4’-Нphenyl);
8.00–8.04 d.d (2Н, 2’,6’-Нphenyl). Mass spectrum, m/z
(Irel, %): 323 [M]+· (11); 308 [M – Me]+ (84); 292
[М – МеО]+ (100). Found, %: C 74.40, H 6.80, N 4.50.
C20H21NO3. Calculated, %: С 74.28, H 6.55, N 4.33.
1-Benzoyl-3,3-pentamethylene-3,4-dihydro-
isoquinoline 6 was prepared similarly to 1 from
1.9 g (0.01 mol) of 1-benzylcyclohexanol and 1.33 g
(0.01 mol) of mandelonitrile. The products were isolated
by chromatographic separation in the hexane–ethyl
acetate system (1 : 1). Yield 0.31 g (10%). Light brown
oil, Rf 0.6. IR spectrum, ν, cm–1: 1654 (С=N), 1688
(С=О). 1Н NMR spectrum, δ, ppm: 1.24–1.74 m (10Н,
СН2cyclohexyl); 2.86 s (2Н, 4-Н); 7.14–7.26 m (3Н, 5,6,7-
H); 7.32–7.47 m (3Н, 3',4',5'-Нphenyl); 7.55–7.61 m (1Н,
8-Н); 8.04–8.07 d.d (2Н, 2’,6’-Нphenyl). Mass spectrum,
m/z (Irel, %): 303 [M]+· (100); 260 [M – C3H7] (100); 198
[M – C6H5CO] (27). Found, %: C 82.91, H 7.15, N 4.77.
C21H21NO. Calculated, %: С 83.13, H 6.98, N 4.62.
3,3-Pentamethylene-3,4-dihydroisoquinoline 7.
Yield 0.45 g (22.5%). Light brown oil, Rf 0.3. IR
1
spectrum, ν, cm–1: 1688 (С=N). Н NMR spectrum,
δ, ppm: 1.42–1.71 m (10Н, СН2cyclohexyl); 2.73 s (2Н,
4-Н); 7.01–7.35 m (4Н, Harom); 8.27 s (1Н, 1-Н). Mass
spectrum, m/z (Irel, %): 199 [M]+· (75); 156 [M – C3H7]
(100).Found, %: C 84.59, H 8.73, N 7.15. C14H17N.
Calculated, %: С 84.37, H 8.60, N 7.03.
Similarly, from 1-(3,4-dimethoxyphenyl)-2-methyl-
propan-1-ol we obtained compound 2, yield 42%. The
constants of 2 are given above.
CONCLUSIONS
(1) The reaction of freshly prepared mandelonitrile,
isobutyraldehyde, and veratrole in concentrated sulfuric
acid yields a mixture of 1-benzoyl-3,3-dimethyl-3,4-
dihydroisoquinoline and enol form of 1-benzoyl-3,3-
dimethyl-1,2,3,4-tetrahydroisoquinoline.
1-Benzoyl-3,3-tetramethylene-3,4-dihydroiso-
quinoline 4 was prepared similarly to 3 from 1.76 g
(0.01 mol) of 1-benzylcyclopentanol and 1.33 g
(0.01 mol) of mandelonitrile. The products were
isolated by chromatographic separation in the hexane–
ethyl acetate system (3 : 1). Yield 0.46 g (16%). Light
brown oil, Rf 0.6. IR spectrum, ν, cm–1: 1628 (С=N),
(2) The reactions of commercially available mandelo-
nitrile, isobutyraldehyde, and activated arenes (veratrole,
1,4-dimethoxybenzene, o- and p-xylenes, p-chloro- and
p-fluoroanisoles) in concentrated sulfuric acid yield
as major products symmetrical and unsymmetrical
diphenylacetonitriles.
1
1670 (C=О). Н NMR spectrum, δ, ppm: 1.72–1.90
m (8Н, СН2cyclopentyl); 2.88 s (2Н, 4-Н); 7.16–7.25 m
(3Н, 5,6,7-H); 7.13–7.46 m (3Н, 3',4',5'-Нphenyl); 7.54–
7.59 m (1Н, 8-Н); 8.02–8.05 d.d (2Н, 2',6'-Нphenyl). Mass
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MANDELONITRILE IN SYNTHESIS OF HYDROGENATED ISOQUINOLINE DERIVATIVES
1493
on Chemistry of Natural Compounds), Tolstikov, G.A.,
Ed., Novosibirsk: Nauka, 2000.
(3) The reaction of mandelonitrile with cyclo-
alkylbenzylcarbinols in concentrated sulfuric acid yields
a mixture of the corresponding 3,3-polymethylene-3,4-
dihydroisoquinoline (major product) and 1-benzoyl-3,3-
polymethylene-3,4-dihydroisoquinoline.
2. Shamma, M. and Moniot, J.L., Isoquinoline Alkaloids
Research, 1972–1977, New York: Plenum, 1978.
3. Schuster, H.F. and Kathawala, F., The Chemistry of Hetero-
cyclic Compounds, Taylor, E.C. and Weissberger, A., Eds.,
New York: Wiley, 1995.
ACKNOWLEDGMENTS
4. Cox, E.D. and Cook, J.M., Chem. Rev., 1995, vol. 95,
The study was financially supported by the Program
of the Presidium of the Russian Academy of Sciences
“New Principles and Methods of Directional Synthesis
of Substances with Preset Properties.”
pp. 1797–1842.
5. Shklyaev, Yu.V., Eltsov, M.A., Rozhkova, Yu.S., et al.,
Heteroatom Chem., 2004, vol. 15, no. 7, pp. 481–486.
6. US Patent 2443246.
7. Shklyaev, Yu.V., Nifontov, Yu.V., Shashkov, A.S., and
Firgang, S.I., Izv. Ross. Akad. Nauk, Ser. Khim., 2002,
no. 12, pp. 2075–2078.
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 8 2010