Synthesis of isoquinoline alkaloid derivatives from eugenol

Article abstract of DOI:10.1007/s10600-012-0222-4

Alkylation under phase-transfer catalysis conditions (18-crown-6/KOH) of eugenol was used for cyclocondensation with nitriles (Ritter reaction), the products of which were isoquinoline derivatives.

Full text of DOI:10.1007/s10600-012-0222-4

Chemistry of Natural Compounds, Vol. 48, No. 2, May, 2012 [Russian original No. 2, March-April, 2012]
SYNTHESIS OF ISOQUINOLINE ALKALOID
DERIVATIVES FROM EUGENOL
*
A. G. Mikhailovskii, O. V. Surikova,
E. S. Limanskii, and M. I. Vakhrin
UDC 547.913+547.94+547.833.3
Alkylation under phase-transfer catalysis conditions (18-crown-6/KOH) of eugenol was used for
cyclocondensation with nitriles (Ritter reaction), the products of which were isoquinoline derivatives.
Keywords: eugenol, phase-transfer catalysis (18-crown-6/KOH), alkylation, nitriles, Ritter reaction, isoquinoline
derivatives, imines and enamines, dioxyline and papaverine analogs.
Eugenol (1, 4-allyl-2-methoxyphenol) is the main constituent of essential oil from Syzygium aromaticum (Eugenia
caryophyllata) (Myrtaceae), Camelia sasanqua (Theaceae), certain basil species (Ocimum) (Lamiaceae), and other plants [1, 2].
Various isoquinoline derivatives, many of which can be viewed as synthetic alkaloid analogs, were prepared earlier
by cyclocondensation of nitriles with dialkylbenzylcarbinols (Ritter reaction) [3]. The capability for this type of
cyclocondensation involving instead of a carbinol 3,4-dimethoxy- and 3,4-methylenedioxyallylbenzenes, which are very similar
to eugenol, was demonstrated in classical seminal studies [4, 5]. The goal of the present study was to use in analogous
syntheses eugenol derivatives and nitriles that were verified by us earlier in reactions with carbinols.
Syntheses with a protected phenol hydroxyl were carried out first. The studies showed that the eugenol hydroxyl can
be alkylated practically quantitatively under phase-transfer catalysis conditions using 18-crown-6/KOH. Alkylation of 1 by
iodomethane or iodoethane formed the corresponding ethers 2 and 3, which were used without further purification in the next
step of the Ritter cyclocondensation. Use of hydrogen cyanide [6], acetonitrile [7], and homoveratryl nitrile instead of
benzylcyanide [8], chloroacetonitrile [9], and 3-cyanocoumarin [10] as the nitrile component formed the corresponding
3,4-dihydroisoquinolines 4–8. By analogy, reaction of allylbenzenes 2 and 3 with cyanoacetic acid amide produced amides 9
and 10 [11]. The fact that the cyclization occurred without protecting the phenol hydroxyl was interesting. The reaction of
eugenol with cyanoacetamide gave enaminoamide 11.
MeO
HO
MeO
R O
a
1
1
2, 3
c
b
c
Me
NH
MeO
R O
Me
5
8
4
H
MeO
R O
H
N
1
1
1
O
R
2
NH
2
9 - 11
4 - 8
4: R = Et, R = H; 5: R = R = Me
1
2
1
2
6: R = Me, R = 3,4-dimethoxybenzyl; 7: R = Me, R = CH Cl
1
2
1
2
2
8: R = Me, R = 3-coumarinyl; 2, 9: R = Me; 3, 10: R = Et; 11: R = H
1
2
1
1
1
a. R I, 18-crown-6/KOH; b. R CN; c. NCCH C(O)NH
2
1
2
2
Perm State Pharmaceutical Academy, 614990, Perm, Ul. Polevaya, 2; e-mail: neorghim@pfa.ru. Translated from
Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2012, pp. 254–256. Original article submitted September 8, 2011.
©
0009-3130/12/4802-0285 2012 Springer Science+Business Media, Inc.
285

The principal structural feature of the prepared isoquinolines 4–11 was the presence in the 3-position of a methyl,
which related them to dioxyline [12], which exhibits spasmolytic activity. Compound 6 was 3-methyl-3,4-dihydropapaverine.
Compound 8 combined simultaneously two natural and biologically active moieties, isoquinoline and coumarin. Isoquinoline
derivatives, e.g., compounds with methoxy- and hydroxyls in the 6,7-positions are related structurally to corypalline and
isosalsoline, respectively [13].
Isoquinoline derivatives 8–11 were identified as the bases; all others, as the hydrochlorides.
IR spectra of all compounds as the bases were recorded from CHCl solutions at concentration 0.01 mol/L. Bases
3
4–7 were prepared by treating solutions of the corresponding hydrochlorides with NH OH with subsequent extraction of the
4
base by Et O, drying, and distillation of the solvent. Spectra of azomethine bases 4–8 contained an absorption band for the
2
–1
imine in the range 1630–640 cm . The spectrum of coumarin derivative 8 had an absorption band for the lactone carbonyl
–1
–1
(1720 cm ). The spectrum of 11 showed a phenol hydroxyl band (3210 cm ). Spectra of amide bases 9–11 exhibited
–1
–1
absorption bands for chelated carbonyl (1610–1620 cm ) and NH (3100–3150 cm ). This was consistent with the
Z-configuration of the base that was stabilized by an intramolecular H-bond.
All PMR spectra contained a doublet for the 3-CH in the range 1.12–1.56 ppm and a multiplet for the 3-H proton in
3
the range 3.20–3.59 ppm (4.26 in the spectrum of the salt of 7). Aset of resonances characteristic of a CH H system (4-CH )
A
B
2
was also observed in the range 2.70–3.07 ppm. Spectra of bases 4–8, which existed in the imine form, differed from those of
enamines 9–11. Spectra of the last ones had singlets for the vinyl proton (~5 ppm) and the ring NH proton (~9.5 ppm). The
position of the NH singlet at weak field in addition to data from IR spectra indicated that an H-chelate ring was present.
EXPERIMENTAL
PMR spectra of 7 and 11 were recorded in DMSO-d ; of all others, in CDCl . PMR spectra were recorded with
6
3
HMDS internal standard on a Bruker DRX 300 instrument (300 MHz). IR spectra were recorded on a Specord-80 spectrometer.
The purity of the products was checked by TLC on Silufol UV-254 plates using Me CO:EtOH:CHCl (1:3:6) with detection
2
3
by Br vapor. All compounds were recrystallized from i-PrOH. Elemental analyses for C, H, N, and Cl agreed with those
2
calculated.
3,4-Dimethoxyallylbenzene (2) and 3-Methoxy-4-ethoxyallylbenzene (3).
A mixture of eugenol (21.6 mL,
0.12 mol), the appropriate alkyl iodide (0.15 mol), and 18-crown-6 (0.5 g, 0.019 mol) in the presence of KOH (20 g, 0.36 mol)
in benzene (150 mL) was stirred vigorously at 40-50°C for 2 h, cooled to 20°C, and filtered. The solid was rinsed with
benzene (2 ꢀ 50 mL). The filtrate was concentrated to a volume of ~70 mL. The resulting solution was used without further
purification.
6-Methoxy-7-ethoxy-3-methyl-3,4-dihydroisoquinoline (4). The benzene solution of 3 was treated with KCN
(6.5 g, 0.1 mol) and glacial acetic acid (15 mL) and dropwise with conc. H SO (30 mL). The mixture was stirred vigorously
2
4
at 50–60°C for 30 min and poured into icewater (30 mL). The benzene layer was separated. The aqueous phase was neutralized
by ammonia solution. The base crystallized upon cooling to 5–7°C. It was filtered off, dried, and dissolved in EtOAc
(250 mL). Purging with dry HCl produced the hydrochloride that was filtered off, dried, and recrystallized. Yield 70%
calculated per KCN. C H NO ·HCl, mp 117–118°C.
13 17
2
PMR spectrum (ꢁ, ppm, J/Hz): 1.34 (3H, t, J = 8, CH CH ); 1.45 (3H, d, J = 8, 3-CH ); 3.07 (1H, m, 3-H); 3.02 (2H,
3
2
3
dd, J = 8, 4-CH H ); 3.72 (3H, s, CH O); 3.83 (2H, q, J = 8, CH CH ); 7.05 (1H, s, H-5); 7.46 (1H, s, H-8); 8.86 (1H, s,
AB
A
B
3
3
2
+
HC=N); 13.52 (1H, s, NH ).
1,3-Dimethyl-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (5) was synthesized analogously using
methyliodide instead of iodoethane. Yield 82%, C H NO ·HCl, mp 220–222°C.
13 17
2
PMR spectrum (ꢁ, ppm, J/Hz): 1.56 (3H, d, J = 8, 3-CH ); 3.27 (1H, m, 3-H); 3.02 (2H, dd, J = 8, 4-CH H ); 3.85
3
AB
A B
+
(3H, s, 1-CH ); 3.92 (3H, s, CH O); 3.97 (3H, s, CH O); 6.80 (1H, s, H-5); 7.15 (1H, s, H-8); 14.26 (1H, s, NH ).
3
3
3
1-(3,4-Dimethoxybenzyl)-3-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (6) was prepared
analogously using iodomethane and 3,4-dimethoxyphenylacetic (homoveratryl) acid nitrile (17.7 g, 0.1 mol). Yield 52%,
C H NO ·HCl, mp 176–178°C.
21 25
4
PMR spectrum (ꢁ, ppm, J/Hz): 1.62 (3H, d, J = 7, 3-CH ); 2.82 (2H, dd, J = 8, 4-CH H ); 3.40 (1H, m, 3-H); 3.80,
3
AB
A B
+
3.85, 3.95, 3.97 (12H, 4 singlets, 4CH O); 4.01 [2H, d, J = 8, CH C H (MeO) ]; 6.74–7.65 (5H, m, Ar); 12.83 (1H, s, NH ).
3
2
6
3
2
286

1-Chloromethyl-3-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (7) was prepared analogously
using iodomethane and chloroacetonitrile (6.3 mL, 0.1 mol). Yield 67%, C H NO Cl·HCl, mp 208–210°C.
13 16
2
PMR spectrum (ꢁ, ppm, J/Hz): 1.40 (3H, d, J = 7, 3-CH ); 3.07 (2H, dd, J = 8, 4-CH H ); 3.83, 3.93 (6H, 2
3
AB
A B
+
singlets, 2CH O); 4.21 (1H, m, 3-H); 5.36 (2H, d, J = 6, CH Cl); 7.18 (1H, s, H-5); 7.50 (1H, s, H-8); 14.05 (1H, s, NH ).
3
2
1-(3-Coumarinyl)-3-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline (8) was prepared analogously using
3-cyanocoumarin (17.1 g, 0.1 mol). The crystalline precipitate forming after neutralization of the solution by ammonia was
filtered off, dried and recrystallized. Yield 57%, C H NO , mp 130–132°C.
21 19
2
PMR spectrum (ꢁ, ppm, J/Hz): 1.20 (3H, d, J = 8, 3-CH ); 3.27 (1H, m, 3-H); 2.76 (2H, dd, J = 8, 4-CH H ); 3.50
3
AB
A B
(1H, s, 3-H); 3.75 (3H, s, CH O); 3.92 (3H, s, CH O); 7.26–7.41 (6H, m, Ar); 8.15 (1H, s, coumarin HC=).
3
3
(3-Methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-idene)acetamide (9) was synthesized analogously to
8 using cyanoacetamide (8.4 g, 0.1 mol). Yield 77%, C H N O , mp 115–117°C.
14 18
2 3
PMR spectrum (ꢁ, ppm, J/Hz): 1.12 (3H, d, J = 8, 3-CH ); 2.70 (2H, dd, J = 8, 4-CH H ); 3.60 (1H, m, 3-H); 3.92
3
AB
A B
(6H, s, 2CH O); 4.87 (2H, s, NH CO); 5.02 (1H, s, HC=); 7.20 (1H, s, 5-H); 7.06 (1H, s, 5-H); 7.20 (1H, s, 8-H); 9.43 (1H, s,
3
2
NH-ring).
(3-Methyl-6-methoxy-7-ethoxy-1,2,3,4-tetrahydroisoquinolin-1-idene)acetamide (10) was prepared by the method
for synthesizing 8 and 9 with the difference that iodoethane was used instead of iodomethane. Yield 73%, C H N O ,
15 20
2 3
mp 50–52°C.
PMR spectrum (ꢁ, ppm, J/Hz): 1.32 (3H, t, J = 7, CH CH ); 1.47 (3H, d, J = 7, 3-CH ); 2.83 (2H, dd, J = 9,
3
2
3
AB
4-CH H ); 3.59 (1H, m, 3-H); 3.90 (3H, s, CH O); 4.03 (2H, q, J = 7, CH CH O); 4.87 (2H, s, NH CO); 4.90 (1H, s, HC=);
A
B
3
3
2
2
6.62 (1H, s, 5-H); 7.08 (1H, s, 8-H); 9.50 (1H, s, NH-ring).
(3-Methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-idene)acetamide (11). A mixture of eugenol
(18 mL, 0.1 mol) and cyanoacetamide (8.4 g, 0.1 mol) in benzene (150 mL) was treated successively with glacial acetic acid
(15 mL) and dropwise with conc. H SO (30 mL). Then the reaction was carried out analogously as for 8–10 with the
2
4
exception that the aqueous phase was neutralized by anhydrous NaHCO , adding it in small portions to avoid foaming. Yield
3
54%, C H N O , mp 218–220°C.
13 16
2 3
PMR spectrum (ꢁ, ppm, J/Hz): 1.16 (3H, d, J = 8, 3-CH ); 2.78 (2H, dd, J = 8, 4-CH H ); 3.30 (1H, m, 3-H); 3.83
3
AB
A B
(3H, s, CH O); 4.86 (1H, s, HC=); 6.18 (2H, s, NH CO); 6.64 (1H, s, 5-H); 6.88 (1H, s, 8-H); 8.81 (1H, s, OH); 9.26 (1H, s,
3
2
NH-ring).
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