Synthesis of 1-(3,4-dimethoxyphenylmethyl)-3-phenyl-6,7,8-trimethoxy-3,4- dihydroisoquinoline

Article abstract of DOI:10.1002/jhet.5570420115

In an attempt to ascertain the scope of using ethyl polyphosphate in the Bischler-Napieralsky annelation reaction, a title compound was synthesized and reduced to the respective 1-(3,4-dimethoxyphenyl-methyl)-3-phenyl-6,7,8- trimethoxy-12,3,4-tetrahydrois

Full text of DOI:10.1002/jhet.5570420115

Jan-Feb 2005
109
Synthesis of 1-(3,4-Dimethoxyphenylmethyl)-3-phenyl-6,7,8-
trimethoxy-3,4-dihydroisoquinoline
Adriana F. Ibañez*
Departamento de Química Organica, Facultad de Farmacia y Bioquímica
Universidad de Buenos Aires, Junín 956
(1113) Buenos Aires Argentina
Received February 2, 2004
In an attempt to ascertain the scope of using ethyl polyphosphate in the Bischler-Napieralsky annela-
tion reaction, a title compound was synthesized and reduced to the respective 1-(3,4-dimethoxyphenyl-
methyl)-3-phenyl-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline.
J. Heterocyclic Chem., 42, 109 (2005).
+
Synthesis of 3,4-dihydroisoquinolines substituted at C-3
with a phenyl group is difficult to carry-out by a simple
Fragment ion m/e: 446 [M-H] appears with relative inten-
sity of 1.9 %. The particularly important fragment ion m/e
Bischler-Napieralski reaction using either P O or POCl .
327 likely involves the loss of a CH and H radicals as well
2
5
3
3
It is clear that due to the presence of an electron withdraw-
ing phenyl group the 3-arylisoquinolines are obtained in
low yield. The simplest cases of the Bischler-Napieralski
reaction are well documented and reviewed [1,5].
Nowadays, some of the more complex 3,4-dihydroiso-
quinolines are synthesized by other methods. Using those
methods the title compound has not been reported.
Furthermore, compounds that posses a substitution pattern
like that of the title compound, with 6,7,8-trimethoxy
groups, are present in natural products, and indeed repre-
sent an interesting synthetic target [3-5].
as neutral benzenenitrile.
As follows comparing 3,4-dihydroisoquinoline (1) with
previously reported 1,2,3,4-tetrahydroisoquinolines, a sig-
nificative difference due to presence of C=N bond is
observed [9-11, 13].
Analysis of carbon-13 nuclear magnetic resonance spec-
tra (cmr) of 3,4-dihydroisoquinoline compound (2) com-
pletely agree with those previously reported for 1,2,3,4-
tetrahydrobenzylisoquinolines [9,13]. The signal corre-
sponding to C-1 appears at δ: 54.9 ppm, C-3 signal appears
at δ: 57.1 ppm and C-4 appears at δ: 39.6 ppm and C–9,
which is the CH signal, appears at δ: 42.6 ppm.
A mild agent such as ethyl polyphosphate was previ-
ously reported as a good reagent for the synthesis of 3-
phenyl-isoquinoline compounds [6-13]. The present doc-
ument describes the preparation of 3,4-dihydroisoquino-
line compounds and their reduction behavior [14]. Thus,
Scheme 1, shows the synthesis of 1-(3,4-dimethoxy-
phenylmethyl)-3-phenyl-6,7,8-trimethoxy-3,4-dihydroiso-
quinoline (1) and the reduction to 1-(3,4-dimethoxy-
phenylmethyl)-3-phenyl-6,7,8-trimethoxy-1,2,3,4-tetrahy-
droisoquinoline (2).
The synthetic route was developed through the transfor-
mation of the 1-phenyl-2-(3,4,5-trimethoxyphenyl)ethyl-
amine (3) to N-(3,4-dimethoxy phenylacetyl)-1-phenyl-
3,4,5-trimethoxyphenylethylamine (4), which was then
treated with a chloroform solution of ethyl polyphosphate
to give 1-(3,4-dimethoxyphenylmethyl)-3-phenyl-6,7,8-
trimethoxy-3,4-dihydroisoquinoline in good yield. Again
showing the excellent performance of the ethyl polyphos-
phate (2.68 g/ml) in the cyclodehydratation of amides that
undergo the Bischler-Napieralski reaction [6,11].
2
Proton nuclear magnetic resonance (pmr) spectra is
observed as a complex coupling group of signals (ABX
system) coincident with the intense signals corresponding
to the five CH O groups.
3
In order to assign the structure of (1), Table 1 was con-
structed.
This table contains spectral information corresponding
to several (a total of 22) dimethoxy-3,4-dihydroisoquino-
lines [15]. The dimethoxy-3,4-dihydroisoquinolines mod-
els were constructed by changing the substitution pattern
as depicted in the structure included with Table 1. From
the theoretical values obtained with ACD-lab® it is simple
to conclude that the experimental proton magnetic reso-
nance signals obtained for (1), are correctly assigned. Data
presented are in close agreement with all the 3-phenyl-
The electron impact mass spectra of 1-(3,4-dimethoxy-
phenylmethyl)-3-phenyl-6,7,8-trimethoxy-3,4-dihydroiso-
+.
quinoline do not present a clear molecular ion peak (M ,
m/e: 447). The low intensity of the molecular ion peak, less
than 5 %, is in agreement with the fragmentation observed
in the electron impact mass spectra of 3,4-dihydro-
isoquinolines and 1,2,3,4-tetrahydroisoquinolines [3,12].

110
A. F. Ibañez
Vol. 42
Table 1
Carbon Number, OCH Positions, δ (H) ppm
3
Comp
N°
OCH
Positions
C-3
C-4
C-4
C-5
C-6
C-7
C-8
C-9
C-11 C-12 C-13 C-14
C-15
(H15)
3
(H4a) (H4b) (H5) (H6)
(H7) (H8) (H9) (H10) (H11) (H12) (H14)
6
7
8
9
8, 13
8, 12
8, 11
7, 13
7, 12
7, 11
6, 13
6, 12
6, 11
5, 13
5, 12
5, 11
11, 12
12, 13
12, 14
12, 15
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.9
3.9
3.9
3.9
4.7
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
2.9
3.0
2.9
2.9
2.8
2.6
2.6
2.6
2.7
2.7
2.7
2.6
2.6
2.6
2.7
2.7
2.7
2.7
2.7
2.7
2.7
2.7
2.6
2.7
2.7
2.7
2.7
2.8
6.8
6.8
6.8
6.8
6.8
6.8
6.7
6.7
6.7
7.1
7.1
7.1
7.1
7.1
7.1
7.2
7.2
7.2
3.9
4.0
4.1
3.9
4.0
4.0
3.9
4.0
4.0
3.9
4.0
4.0
4.1
4.0
4.0
4.2
3.9
3.9
4.0
4.0
3.9
3.9
4.2
6.8
6.5
6.9
6.9
7.1
6.9
6.9
7.1
6.9
6.9
7.1
6.9
6.9
7.1
6.9
7.0
6.9
6.8
6.8
6.8
6.9
6.8
6.8
6.8
6.8
6.8
6.8
6.8
6.8
6.6
6.6
6.2
6.8
7.1
6.8
6.9
7.4
7.4
7.3
8.2
8.2
8.2
7.4
7.4
7.4
7.7
7.7
7.7
7.7
7.7
7.0
6.9
6.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1
6.8
7.1
6.8
6.9
6.8
6.8
6.8
7.3
7.3
7.3
7.1
7.1
7.1
7.1
7.1
6.8
6.5
6.8
7.1
6.8
6.9
6.8
6.8
6.8
7.0
7.0
7.0
7.0
7.0
6.8
6.5
6.8
7.1
6.8
6.8
7.0
7.0
7.0
7.0
7.0
6.6
6.8
6.8
6.2
6.2
7.1
7.2
7.2
7.2
7.2
7.2
7.2
6.5
7.2
7.2
7.2
7.2
7.2
7.2
6.5
7.2
7.2
7.2
7.2
7.2
7.2
6.8
7.3
7.3
7.2
7.2
7.3
7.3
6.8
7.3
7.3
7.2
7.2
7.3
7.3
6.8
6, 7
7, 8
5, 8
5, 7
5, 6
6.9
7.0
6.4
6.8
6.7
7.0
7.9
6.4
Scheme 1
1,2,3,4-tetrahydroisoquinolines published and with those
of the new compound (2).
EXPERIMENTAL
The pmr spectra were recorded on a Varian 80A or on a Bruker
WOSYFT spectrometer in CDCl using TMS as internal refer-
3
ence. IR spectra were recorded on a Jasco A-200 as Nujol mulls.
Melting points (uncorrected) were obtained on a Thomas Hoover
apparatus. The EI mass spectra were recorded in a Shimadzu
CGQP 1000 mass spectrometer operating at ionizing electron
energy of 70 eV or 20 eV, in all cases by direct injection of the
samples as chloroform solution [12].
2-(3,4,5-Trimethoxyphenyl)-1-phenyl-ethylamine (3).
2-(3,4,5-Trimethoxyphenyl)-1-phenyl-ethanone oxime
(3.00 g, 10 mmoles), was dissolved in 60 ml of ethanol and 60
ml of 2 N NaOH. The solution was heated at 60 °C while stir-
ring and 4.5 g of raney nickel alloy was added. Once the addi-
tion was completed heat was removed and the solution stirred
for another 60 minutes. The mixture was then filtered through
0.5 cm high bed celite and the filtrate extracted with diethyl
ether. The solution containing the amine was dried with
Na SO and evaporated to give an oil, yield 93%, pmr: δ 1.75
2
4
(2 H, s, NH ); 2,75 (2 H, s, CH ); 3.70 (6 H, s, OCH ); 3.75 (3
2
2
3
H, s, OCH ); 4.10 (1 H, m, CH); 6.25 (2 H, m, Ar); 7.25 (5 H,
3
m, Ar), ppm., ir, ν : 3390 (N-H); 1580 (HC=C); 700 (Ar-H)
-1
and 670 (Ar-H) cm , [16].
N-(3,4-Dimethoxyphenylacetyl)2-(3,4,5-trimethoxyphenyl)-1-
phenylethylamine (4).

Jan-Feb 2005
1-(3,4-Dimethoxyphenylmethyl)-3-phenyl-6,7,8-trimethoxy-3,4-dihydroisoquinoline
111
A solution of homoveratroyl chloride (3,4-dimethoxypheny-
s, OCH ); 3.80 (3 H, s, OCH ); 3.87 (3 H, s, OCH ); 3.90 (6 H,
3 3 3
lacetyl chloride) (2.10 g, 12 mmoles), in 5 ml of CHCl was
m, OCH ); 4.25 (2 H, m, CH ); 4.60 (1 H, m, CH); 6,35 (1 H, s,
3
3 2
added to a solution of the amine (3) (2.70 g, 10 mmoles) and 1.2
Ar); 6,40 (1 H, s, Ar); 6,75 (2 H, s, Ar); 7.30 (5 H, m, Ar) ppm,
cmr: δ 39.6 C-4, 42.6 C-9, 54.9 C-1, 55.5 C-O, 55.8 C-O, 57.1
C-3, 60.4 C-O, 60.4C-O, 111.1 C-5, and 107.4 , 113.4, 121.8,
123.6, 126.4, 127.0, 128.2, 132.0, 132.7, 144.5, 148.5, 151.0,
151.8 ppm, as described in the text.
ml of Et N in 20 ml ClCH . The resulting mixture was stirred for
3
3
60 minutes, after which the solvent was evaporated and the
resulting residue was diluted in 50 ml of water and the residue
was collected by filtration to give compound (4), yield 62 %, mp,
152-154° (ethanol / H O) as white plate crystals, pmr: δ 2.90
Anal. Calcd. for: C H NO (449): C, 72.14; H, 6.95; N, 3.12.
2
27 31
5
(2H, m, CH ); 3.45 (3H, s, OCH ); 3.63 (6H, s, OCH ) 3.75 (6H,
Found: C, 72.16 %, H, 6.90 %, N, 3.10 %.
2
3
3
s, OCH ); 3.85 (3H, s, OCH ); 5.25 (1H, br. q., CH); 5.70 (1H,
3
3
Acknowledgement.
br.d., NH); 6,05 (2H, s, Ar); 6,65 (3H, m, Ar); 7.20 (5H, m, Ar),
-1
ir : ν 3330 (N-H); 1660 (C=O) cm .
We thank to Graciela. Y. Moltrasio Iglesias, CONICET and
Buenos Aires University SECYT Grants and facilities.
Anal. Calcd. for: C H NO (465): C, 69.66; H, 6.71; N, 3.01.
27 31
6
Found: C, 66.68, H, 6.67, N, 3.00.
1-(3,4-Dimethoxyphenylmethyl)-3-phenyl-6,7,8-trimethoxy-3,4-
dihydroisoquinoline (1).
REFERENCES AND NOTES
N-(3,4-Dimethoxyphenylacetyl)2-(3,4,5-trimethoxyphenyl)-1-
phenylethylamide (1.0 mmol) and ethyl polyphosphate (EPP), 2
ml (cc 2.68 g/ml as chloroform solution) were heated for 8 hs at
80 °C in an oil bath. The solvent was evaporated, the residue
[1] A. Bischler and B. Napieralski, Ber, 26,1903 (1893).
[2] W. Whaley, and T. Govindachari, Organic Reaction, Vol. IV,
pp. 74, Roger Adams Eds. John Wiley & Sons, Inc. N. Y. (1951).
[3] J. Comin, M. Vernengo, and V. Deulofeu, The alkaloids, Vol.
X, pp 401, (1968) Academic Press inc. N.Y.
poured in 20 ml of water and extracted with CH Cl (2 x 5 ml), the
2
2
alkaline material was extracted with HCl (3 x 5 ml) and the aque-
ous solution was alkalinized to pH 11. The solution was extracted
with CH Cl (2 x 5 ml) and the 3,4-dihydroisoquinoline purified
[4] A. Brossi, and S. Teitel, Helvetica Chim. Acta., 49 (207),
1757, (1960).
[5] S. Kubota, T. Masui, E. Fujita, and M. Kupchan, J. Org.
Chem., 31, 516 (1966).
2
2
by tlc, Silica gel GF254 plates, chloroform:methanol:ammonia
[6] J. M. Aguirre, E. N. Alesso, C. Somoza, D. G. Tombari, G.
Y. Moltrasio and J. D. Bonafede, Ann. Asoc. Quim. Arg., 73, 391 (1985).
[7] J. M. Aguirre, E. N. Alesso, C. Somoza, D. G. Tombari, A. F.
Ibañez, G. Y. Moltrasio and J. D. Bonafede, Ann. Asoc. Quim. Arg., 75,
393 (1987).
[8] E. N. Alesso, D. G. Tombari, A. F. Ibañez, G. Y. Moltrasio
Iglesias, and J. M. Aguirre, Chem. Pharm. Bull, 36 (8), 2802 (1988).
[9] A. F. Ibañez, G. B. Yaculiano, G. Y. Moltrasio Iglesias, J.
Heterocyclic Chem., 26, 907 (1989).
(20%) as proportion 95:5:I, [9,13] to yield 87 % of an amber oil,
compound (1) described by pmr: δ 2.75 (2H, m, CH ); 3.75 (3H,
2
s, OCH ); 3.80 (3H, s, OCH ); 3.87(3H, s, OCH ); 3.90 (6H, m,
3
3
3
OCH ); 4.25 (2H, m, CH ); 4.70 (1H, m, CH); 6,40 (1H, d, Ar);
3
2
6,80 (3H, m, Ar); 7.30 (5H, m, Ar) ppm; MS (m/e): 446 (1.9 %),
329 (24.5 %), 328 (23.7 %), 327 (100 %), 149 (30 %).
Anal. Calcd. for: C H NO (447): C, 72.46; H, 6.53; N, 3.13.
27 29
5
Found: C,72.48, H, 6.48, N, 3.13.
1-(3,4-Dimethoxyphenylmethyl)-3-phenyl-6,7,8-trimethoxy-
1,2,3,4-tetrahydro isoquinoline (2).
[10] J. M. Aguirre, E. N. Alesso, A. F. Ibañez, D. G. Tombari, and
G. Y. Moltrasio Iglesias, J. Heterocyclic Chem., 26, 25 (1989).
[11] J. M. Aguirre, E. N. Alesso, A. F. Ibañez, and G. Y.
Moltrasio Iglesias, Trends in Heterocyclic Chem., 3, 95 (1993).
[12] A. F. Ibañez, and G. Y. Moltrasio Iglesias, Org. Mass
Spectrometry, 26, 136 (1991).
[13] J. M. Delfino, A. F. Ibañez, and G. Y. Moltrasio Iglesias, J.
Heterocyclic Chem., 33, 265 (1996).
[14] G. J. Kapadia, and M. B. E. Fayez, J. Pharm. Chem. Sci. 59,
1699 (1970).
1-(3,4-Dimethoxyphenylmethyl)-3-phenyl-6,7,8-trimethoxy-
3,4-dihydroisoquinoline, (1) was reduced with sodium borohy-
dride in methanol. Thus, 1.2 mmol of compound 1 was dissolved
in 10 ml of methanol while stirring and then 200 mg of NaBH
4
was added. After stirring for 10 minutes the solvent was evapo-
rated and the residue treated with water and extracted with ethyl
ether (2 x 20 ml). The combined extracts were dried with sodium
sulafet and concentrated in vacuo to give 2 quantitatively as oil
[6]. Compound 2 was purified by tlc, Silicagel GF254, chloro-
form:methanol:ammonia (20%): as proportion 95:5:I, nmr: 1.85
[15] Acdlab® 133 Richmond St. West Suite 605 Toronto, ON.
M5H 2L3 Canada.
[16] B. Reitchert and W. Hoffmann, Arch. Pharm. 247, 217, 21
(1936).
(1 H, s, NH); 2.50 (2 H, m, CH ); 2.75 (1 H, dd, CH); 3.75 (3 H,
2