One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet-Spengler reaction using zeolite catalysts

Article abstract of DOI:10.1016/j.tetlet.2004.09.097

A new, one-step variation of the Pictet-Spengler reaction has been elaborated using a small pore size zeolite as the catalyst. A new, environmentally friendly variation of the Pictet-Spengler reaction has been elaborated using a small pore size zeolite. The easily separable and recyclable catalyst provided high conversions and a shorter reaction time than the classical acetic acid or trifluoroacetic acid.

Full text of DOI:10.1016/j.tetlet.2004.09.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8553–8555
One-step preparation of 1-substituted tetrahydroisoquinolines
via the Pictet–Spengler reaction using zeolite catalysts
Adrienn Heged u¨ s and Zolt a´ n Hell*
Department of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
Received 15 July 2004; revised 6 September 2004; accepted 13 September 2004
Available online 30 September 2004
Abstract—A new, environmentally friendly variation of the Pictet–Spengler reaction has been elaborated using a small pore size
zeolite. The easily separable and recyclable catalyst provided high conversions and a shorter reaction time than the classical acetic
acid or trifluoroacetic acid.
Ó 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
The application of solid acids and bases (natural and
modified clay minerals, montmorillonites, zeolites,
mixed oxides, layered double hydroxides) as efficient
Numerous naturally occurring alkaloids, that is, tetra-
hydro-b-carbolines (indole alkaloids) or tetrahydroiso-
quinoline derivatives mediate pharmacologically useful
physiological effects. Therefore, the synthesis of these
natural products as well as their analogues is interesting
for both organic synthesis and medicinal chemistry. One
of the most powerful methods for the construction of
these heterocyclic compounds is the Pictet–Spengler
9
catalysts in organic synthesis has been widely studied.
They are important from the environmental point of
view, because they produce less waste, but have excellent
activity and selectivity even on industrial scales, and in
most cases these substances can be recovered from reac-
tion mixtures and reused with good results.
1
cyclisation. The reaction consists of the condensation
Ersorb-4 (E4) is a weakly acidic zeolite-type adsorbent
˚
with a 4A pore size. It can adsorb small molecules such
of a b-phenylethylamine derivative with a carbonyl com-
pound, generating an imine (SchiffÕs base), which under-
goes cyclisation via an intramolecular electrophilic
aromatic substitution yielding the isoquinoline
derivative.
as water, hydrochloric acid, ammonia, methanol, etc.
It has several advantages—it is environmentally
friendly, nontoxic, recoverable, reusable and inexpen-
sive. Recently we reported that E4 showed good activity
in different condensation reactions such as acylation of
1
0
The Pictet–Spengler reaction was traditionally carried
2
amino acids with aromatic acid chlorides, cyclisation
of b-aminoalcohols with carboxylic acids to oxazoline
derivatives, synthesis of 2-arylimidazoline derivatives
–4
out in a protic solvent with acid catalysts,
usually
using acetic acid or trifluoroacetic acid. The reaction
1
1
5
–8
12
have been widely investigated;
published about the effect of an aprotic media, the ste-
reochemistry and the use of solid supported reagents,
thus papers has been
5
and 2-arylbenzoxazole derivatives and tetrahydropyr-
13
anylation of alcohols and phenols.
6
,7
8
but the main principles of the reaction remain the same.
It is a two-step method; first the SchiffÕs base is prepared
and the water is distilled out from the reaction mixture,
then the catalyst is added and the cyclisation is effected.
The method has some disadvantages: long reaction
times (48h for ketones and 24h for aldehydes) and the
catalysts are harmful to the environment.
2
. Results and discussion
Based on the results obtained for these condensation
reactions, we examined the Pictet–Spengler cyclisation
under mild conditions. E4 having only a slightly acidic
14
character, we used its more acidic modification (E4a)
in our reactions. The original E4 was modified by ionic
exchange to change the surface acidity of the material.
The reaction of b-phenylethylamine and acetophenone
in the presence of E4a in ethanol resulted in the
Keywords: Pictet–Spengler reaction; Zeolites; Green chemistry.
*
Corresponding author. Tel.: +36 1 463 1414; fax: +36 1 463 3648;
e-mail: zhell@mail.bme.hu
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.097

8554
A. Heged u¨ s, Z. Hell / Tetrahedron Letters 45 (2004) 8553–8555
R1
R1
NH2
O
E4a
+
NH
R4
ethanol
R2
R
3
R4
R
2
R3
Figure 1.
formation of 1-phenyl-1-methyl-1,2,3,4-tetrahydroiso-
quinoline in one step and good yield (Fig. 1). We exam-
ined the reaction of b-phenylethylamine derivatives with
aromatic and aliphatic ketones and aldehydes. The
results are summarised in Tables 1 and 2. In all cases,
the starting carbonyl compound and the amine disap-
peared from the reaction mixtures and only the inter-
mediate SchiffÕs base and the product were observed.
13; Table 2, entry 10). Using the more acidic KP10
montmorillonite catalyst instead of E4a in the reaction,
no product was obtained. Although KP10 is more acidic
than E4a, it is unable to bind the water formed during
the SchiffÕs base formation. The workup of the reaction
was very easy; the catalyst was filtered out and the sol-
vent was evaporated. The catalyst could be easily recy-
cled without significant loss of activity (Table 1,
entries 4 and 5; Table 2, entry 3).
On increasing the reaction time, the yield increased
(
Table 1, entries 1, 2 and 3; Table 2, entries 1 and 2),
but the longest reaction time was significantly shorter
than the reaction time required using acetic acid or tri-
Thus a new, one-step variation of the Pictet–Spengler
reaction has been developed.
1
,2
fluoroacetic acid as catalyst. Aliphatic ketones and
aldehydes also gave the appropriate tetrahydroisoquino-
line derivatives, but with poorer yields (Table 1, entry
3. Experimental
Pretreatment of the catalyst: before each experiment the
sample of E4a was powdered and heated at 120°C for
2
h.
Table 1. Reaction of b-phenylethylamine derivatives with ketones
1
R
2
R
3
R
4
R
a
Entry
Reaction Yield
(%)
A typical protocol for the reaction: a mixture of 5mmol
of the b-phenylethylamine derivative, 5mmol of the
aldehyde/ketone and 0.8g E4a in ethanol was heated
at 80°C for 20/40h. The solid was filtered off, the filtrate
was evaporated and the residue characterised.
time (h)
1
2
3
4
5
6
7
8
9
H
H
C
C
C
C
C
C
6
6
6
6
6
6
H
H
H
H
H
H
5
5
5
5
5
5
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
10
20
40
40
40
40
40
40
40
40
40
40
40
40
50
75
87
H
H
H
H
b
H
H
83
c
H
H
86
d
Characterisation of the new compounds:
H
H
—
H
H
4-Cl-C
4-Br-C
6
H
4
85
84
89
91
87
81
77
65
OCH
H
3
OCH
H
3
6
H
4
6,7-Dimethoxy-1-methyl-1-(4-bromophenyl)-1,2,3,4-
tetrahydroisoquinoline (Table 1, entry 8): H NMR
1
4-CH
4-CH
3-CH
3
3
3
O-C
-C
O-C
6
H
4
4
1
1
1
1
1
0
1
2
3
4
OCH
OCH
H
3
OCH
OCH
H
3
6
H
4
(CDCl , ppm) d 2.0 (s, 1H, NH), 2.8–3.1 (m, 4H,
3
À1
3
3
6
H
CH ), 6.9–7.9 (m, 6H, Ar), IR (KBr): NH: 3445cm .
Anal. Found: C, 59.51; H, 5.60; N, 3.81%. Calcd for
2
2-Cl-C
2-CH -C
CH -CH
6 4
H
OCH
OCH
3
OCH
OCH
3
3
6
H
4
(C H O NBr): C, 59.68; H, 5.56; N, 3.87%.
18 20 2
3
3
3
2
a 1
b
H NMR yield.
1
-Methyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydro-iso-
1
Recycled E4a.
quinoline (Table 1, entry 9): H NMR (CDCl , ppm) d
3
c
Third use of E4a.
KP10 montmorillonite catalyst instead of E4a.
2
8
8
8
.0 (s, 1H, NH), 2.8–3.3 (m, 4H, CH ), 6.9–7.6 (m,
d
2
À1
H, Ar), IR (KBr): NH: 3440cm . Anal. Found: C,
0.71; H, 7.50; N, 5.58%. Calcd for (C H ON): C,
0.60; H, 7.56; N, 5.53%.
1
7
19
Table 2. Reaction of b-phenylethylamine derivatives with aldehydes
1
R
2
R
3
R
4
R
a
Entry
Reaction Yield
time (h)
6,7-Dimethoxy-1-methyl-1-(4-methylphenyl)-1,2,3,4-
tetrahydroisoquinoline (Table 1, entry 10): H NMR
(%)
1
1
2
3
4
5
6
7
8
9
H
H
C
C
C
6
6
6
H
H
H
5
5
5
H
H
H
H
H
H
H
H
H
H
12
20
20
20
20
20
20
20
20
20
82
100
97
94
98
95
93
89
81
70
(
CDCl , ppm) d 2.2 (s, 1H, NH), 2.6 (s, 3H, CH ), 2.9–
3
3
H
H
b
3.3 (m, 4H, CH ), 7.0–8.1 (m, 6H, Ar), IR (KBr): NH:
2
H
H
À1
3450cm . Anal. Found: C, 76.79; H, 7.70; N, 4.81%.
Calcd for (C H O N): C, 76.74; H, 7.79; N, 4.71%.
H
H
4-CH
4-N(CH
4-Cl-C
3-NO -C
2-Br-C
2-OH-C
CH -CH
3 6 4
O-C H
H
H
3
)
3
-C
6
H
4
19 23
2
OCH
H
3
OCH
H
3
6 4
H
2
6
H
4
6,7-Dimethoxy-1-methyl-1-(3-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (Table 1, entry 11): H NMR
1
OCH
OCH
OCH
3
3
3
OCH
OCH
OCH
3
3
3
6
H
4
6
H
4
(CDCl , ppm) d 2.1 (s, 1H, NH), 2.9–3.3 (m, 4H,
3
À1
10
3
2
CH ), 7.0–7.8 (m, 6H, Ar), IR (KBr): NH: 3440cm
.
2
a 1
b
H NMR yield.
Anal. Found: C, 72.89; H, 7.42; N, 4.40%. Calcd for
(C H O N): C, 72.82; H, 7.39; N, 4.47%.
Recycled E4a.
1
9
23
3

A. Heged u¨ s, Z. Hell / Tetrahedron Letters 45 (2004) 8553–8555
8555
6,7-Dimethoxy-1-methyl-1-(2-methylphenyl)-1,2,3,4-
tetrahydroisoquinoline (Table 1, entry 13): H NMR
3. von Strandtmann, M.; Puchalski, C.; Shavel, J., Jr.
J. Med. Chem. 1964, 7, 141.
1
4
. Brown, R. T.; Chapple, C. J. Chem. Soc., Chem. Commun.
976, 886.
(
CDCl , ppm) d 2.3 (s, 1H, NH), 2.6 (s, 3H, CH ),
3
3
1
3
NH: 3445cm . Anal. Found: C, 76.52; H, 7.71; N,
.0–3.4 (m, 4H, CH ), 6.8–7.9 (m, 6H, Ar), IR (KBr):
2
À1
5. Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.;
Wu, G. S.; Yamanaka, E.; Hutchins, L.; DiPierro, M.;
Cook, J. M. J. Org. Chem. 1979, 44, 535–545.
4
4
.79%. Calcd for (C H O N): C, 76.74; H, 7.79; N,
19 23 2
.79%.
6
. Waldmann, H.; Schmidt, G. Tetrahedron 1994, 50, 11865–
1884.
. Singh, K.; Deb, D. K.; Venugopalan, P. Tetrahedron 2001,
7, 7939–7949.
1
7
5
Acknowledgements
8
9
. Yang, L.; Guo, L. Tetrahedron Lett. 1996, 37, 5041–5044.
. See e.g. Laszlo, P. Science 1987, 235, 1473.
This work was supported by the Hungarian Research
Fund Programs (OTKA Grant No. T 037757).
1
1
1
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0. Hell, Z.; Cwik, A.; Finta, Z.; Horv a´ th, Z. J. Mol. Catal. A:
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1. Cwik, A.; Hell, Z.; Heged u¨ s, A.; Finta, Z.; Horv a´ th, Z.
Tetrahedron Lett. 2002, 43, 3985–3987.
2. Heged u¨ s, A.; V ´ı gh, I.; Hell, Z. Heteroatom Chem., in
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14. Klopp, G. Ph.D. Theses, Budapest, 1975.
References and notes
1
2
. Pictet, A.; Spengler, T. Berichte 1911, 44, 2030–2036.
. Stuart, K.; Woo-Ming, R. Heterocycles 1975, 3, 223.