Zeolite-catalyzed simple synthesis of isochromans via the oxa-Pictet-Spengler reaction

Article abstract of DOI:10.1039/b601314g

The synthesis of isochromans via oxa-Pictet-Spengler reaction using a modified small pore size zeolite E4 as catalyst was investigated. Ersorb-4 (E4) is a clinoptylolite-type zeolite material with high silicon content. The reaction of 2-phenylethanol deri

Full text of DOI:10.1039/b601314g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Zeolite-catalyzed simple synthesis of isochromans via the
oxa-Pictet–Spengler reaction
Adrienn Hegedu¨s and Zolta´n Hell*
Received 26th January 2006, Accepted 9th February 2006
First published as an Advance Article on the web 27th February 2006
DOI: 10.1039/b601314g
The modified small pore size zeolite E4a has been found to be
an efficient catalyst for the synthesis of isochromans via the
oxa-Pictet–Spengler reaction. This method is simple, cheap,
environmentally-friendly and gives the isochromans in high
yield.
of E4 was identical to the spectrum of clinoptylolite. It has a
specific surface of 40 m2 g−1 (determined by the BET method with
nitrogen at the temperature of liquid nitrogen). E4 has a slightly
surface acidic character. The pH of its aqueous suspension is
about 5.5. The high silicon content yields high chemical resistance.
It is stable until 500–600 ◦C. It can adsorb small molecules
such as water, hydrochloric acid, ammonia, methanol, etc. It
is environmentally-friendly, nontoxic, recoverable, reusable and
inexpensive. E4a is the more acidic modification of E4 (the pH of
its aqueous suspension is about 3). The original E4 was modified
by ionic exchange to change the surface acidity of the material.
Recently we reported that E4 showed good activity in
different condensation reactions such as synthesis of oxazo-
line derivatives from b-aminoalcohols and carboxylic acids,8
preparation of 2-arylimidazolines, 2-arylbenzoxazoles,9 and 2-
arylbenzimidazoles.10 E4a has been found to be a good cat-
alyst in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones,11
and 1,5-benzodiazepine derivatives,12 and in the preparation
of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler
reaction.13
The oxa-Pictet–Spengler reaction is the oxygen analogue of the
Pictet–Spengler reaction. While in the Pictet–Spengler reaction a
b-phenylethylamine derivative reacts with a carbonyl compound,
generating an imine (Schiff’s base), which undergoes cyclization
via an intramolecular electrophilic aromatic substitution yielding
an isoquinoline derivative,1 in the oxa-Pictet–Spengler reaction
a 2-phenylethanol derivative reacts with an aldehyde or a ketone
to give an isochroman (3,4-dihydro-1H-benzo[c]pyrane) structure.
This reaction was reported for the first time by Wunsch and Zott
in 1992.2 The authors used ZnCl2 and HCl gas, 2–3 equivalents
p-toluenesulfonic acid or Lewis acids (TiCl4, AlCl3, SnCl4) as
catalyst, dioxane, nitrobenzene or benzene as solvent, and high
reaction temperatures. This method has some disadvantages:
harmful, not recoverable catalysts and long reaction times (24–
66 h).
There are some new methods in the literature for the oxa-Pictet–
Spengler reaction, for example the use of catalytic amounts of p-
toluenesulfonic acid in methanol at 4 ◦C,3 oleic acid in methanol at
21 ◦C, or using dehydrating agents (molecular sieves or anhydrous
Na2SO4) beside the catalyst.4 But these methods also require long
reaction times (48 h for ketones and 24 h for aldehydes; and
one week in the case of oleic acid catalyst). Using HCl gas as
catalyst in dioxane, the reaction time was only one hour.5
The application of solid acids and bases (natural and modified
clay minerals, montmorillonites, zeolites, mixed oxides, layered
double hydroxides) as efficient catalysts in organic synthesis has
been widely studied.6 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 the reaction mixtures and
reused with good results.
Based on the results obtained for the Pictet–Spengler cycliza-
tion, we examined the oxa-Pictet–Spengler reaction under mild
conditions. The reaction of 2-(3,4-dimethoxyphenyl)ethanol and
4-chlorobenzaldehyde in the presence of E4a in toluene resulted
in the formation of 1-(4-chlorophenyl)-6,7-dimethoxyisochroman
with good yield (Fig. 1). The optimal reaction conditions were
determined in this reaction. The best result was obtained using
0.5 g E4a and 2 mmol 2-phenylethanol in toluene as solvent at
110 ◦C. The weaker acidic E4 showed no activity. No reaction
was observed using the strongly acidic KSF/0 montmorillonite
˚
alone or in a mixture with 4 A molecular sieves. This can be
explained by the fact that in the Ersorb catalysts both acidic sites
and pores for binding water are present, thus, deliberated water
can be immediately fixed in the pores of the catalyst.
We examined the reaction of 2-phenylethanol derivatives with
aromatic and aliphatic aldehydes and ketones. The results are
summarized in Tables 1 and 2. The optimal reaction time was
15 h for aldehydes and 35 h for ketones in the reaction of 2-
(3,4-dimethoxyphenyl)ethanol. These were significantly shorter
than the reaction time required using p-toluenesulfonic acid or
ZnCl2/HCl as catalyst.2–4 In the case of 2-phenylethanol the
required reaction time was 40 h for aldehydes and 48 h for ketones,
because of the lack of the activating methoxy groups. Aliphatic
aldehydes and ketones also gave the appropriate isochroman
derivatives. For aliphatic aldehydes the optimal reaction time was
20 h. In these cases the reaction temperature was lower (Table 1,
entries 10 and 11), because of the lower boiling points of the
aldehydes. The workup of the reaction mixture was very easy;
Ersorb-4 (E4) is a clinoptylolite-type zeolite material with high
silicon content (Si : Al ratio 5 : 1).7 The original mineral is mod-
ified by ion exchanges and with other water-phase technologies
followed by a thermal treatment yielding a Ca–K mixed cation-
˚
based adsorbent with 4 A pore size. The composition of E4 can be
described as follows: SiO2 73.0%, Al2O3 11.2%, Fe2O3 1.17%, K2O
5.12%, Na2O 0.38%, CaO 2.20%, MgO 0.44%. The XRD spectrum
Department of Organic Chemical Technology, Budapest University of
Technology and Economics, H-1521, Budapest, Hungary. E-mail: zhell@
mail.bme.hu; Fax: (+36 1) 463 3648; Tel: (+36 1) 463 1414
1220 | Org. Biomol. Chem., 2006, 4, 1220–1222
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Fig. 1
Table 1 Reaction of 2-phenylethanol derivatives with aldehydesa
Entry
R1
R2
R3
R4
Reaction time/h
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
O–CH2–O
O–CH2–O
H
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-CH3O–C6H4
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
15
15
15
15
15
15
15
15
15
20
20
15
15
40
40
40
40
97
95c
95d
92
83
83c
89
85
77
70e
79f
91
86
81
88
90
84
C6H5
4-(CH3)2N–C6H4
3-NO2–C6H4
2-Br–C6H4
CH3–CH2
CH3–CH2–CH2
4-CH3O–C6H4
C6H5
H
H
H
H
C6H5
H
H
H
4-Cl–C6H4
4-CH3O–C6H4
3-NO2–C6H4
a 2 mmol alcohol, 2 mmol aldehyde, 0.5 g E4a, toluene, 110 ◦C. b Preparative yield. c Recycled E4a. d Third use of E4a. e Reaction temperature 50 ◦C.
f Reaction temperature 70 ◦C.
Table 2 Reaction of 2-phenylethanol derivatives with ketonesa
Entry
R1
R2
R3
R4
Reaction time/h
Yieldb (%)
1
2
3
4
5
6
7
8
9
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
H
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
H
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
35
35
35
35
35
35
35
35
48
48
83
80c
87
90
91
77
75
64d
77
82
4-CH3O–C6H4
4-CH3–C6H4
4-Cl–C6H4
3-CH3O–C6H4
2-CH3–C6H4
CH3–CH2
C6H5
10
H
H
4-CH3O–C6H4
a 2 mmol alcohol, 2 mmol ketone, 0.5 g E4a, toluene, 110 ◦C. b Preparative yield. c Recycled E4a. d Reaction temperature 80 ◦C.
the catalyst was filtered out and the solvent was evaporated. The
catalyst could be recycled easily without significant loss of a◦ctivity
after washing it with acetone following by heating at 120 C for
4 h (Table 1, entries 2, 3 and 6; Table 2, entry 2).
compound showed a sharp singlet at 6.2 ppm which corresponds
to the signal of the CH group in the appropriate diphenylmethanol
derivative.14 This compound subjected to further reaction under
the same reaction conditions gave the appropriate isochroman.
Based on these data we propose a new two-step mechanism for the
oxa-Pictet–Spengler reaction catalyzed by zeolite; the first step is
an electrophilic aromatic substitution, and the intermediate thus
formed loses water yielding the isochroman (Scheme 2).
In summary, the results show that the modified zeolite-
type adsorbent E4a is a suitable catalyst for the oxa-Pictet–
Spengler reaction. The method is simple, convenient, cheap and
environmentally-friendly, the catalyst can be recycled without any
loss of activity.†
In the literature there is a three-step mechanism for the oxa-
Pictet–Spengler reaction.3 In the first step, the reaction of the
carbonyl compound and the alcohol results in a hemiacetal in
the presence of acid catalyst, then this hemiacetal loses water
and gives a reactive intermediate, which finally undergoes an
intramolecular electrophilic aromatic substitution yielding the
isochroman derivative (Scheme 1). We examined the mecha-
nism of the reaction of 2-(3,4-dimethoxyphenyl)ethanol and 4-
chlorobenzaldehyde. The reaction was stopped after 8 h and the
reaction mixture was investigated by TLC. Two compounds were
detected; the expected product and another, which was separated
by column chromatography. The 1H NMR spectrum of this
The financial support of the Hungarian Scientific Research
Fund Programs (OTKA Grant No. T 037757) is gratefully
acknowledged.
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Scheme 1
Scheme 2
4 M. Guiso, A. Bianco, C. Marra and C. Cavarischia, Eur. J. Org. Chem.,
2003, 3407.
5 A. Chimirri, G. De Sarro, A. De Sarro, R. Gitto, S. Grasso, S.
Quartarone, M. Zappala, P. Giusti, V. Libri, A. Constanti and A. G.
Chapman, J. Med. Chem., 1997, 40, 1258.
6 See e.g. P. Laszlo, Science, 1987, 235, 1473.
7 G. Klopp, J. Papp, J. Go¨ro¨g and T. Ma´ndy, Hungarian Pat. No. 153556,
see also GB Pat. 1150277, 1967.
8 A. Cwik, Z. Hell, A. Hegedu¨s, Z. Finta and Z. Horva´th, Tetrahedron
Lett., 2002, 43, 3985.
9 A. Hegedu¨s, I. V´ıgh and Z. Hell, Heteroat. Chem., 2004, 15, 428.
10 A. Hegedu¨s, Z. Hell and A. Potor, Synth. Commun., in press.
11 A. Hegedu¨s, Z. Hell and I. V´ıgh, Synth. Commun., 2006, 36,
129.
Notes and references
† Pretreatment of the catalyst: before each experiment, a sample of E4a
was powdered and heated at 120 ◦C for 2 h. A typical protocol for the
reaction: a mixture of 2 mmol of 2-phenylethanol derivative, 2 mmol of
aldehyde/ketone and 0.5 g E4a in toluene (10 mL) was heated at 110 ◦C
for a time indicated in Tables 1 and 2. The solid was filtered off, the
filtrate was evaporated and the residue characterized. All products have
satisfactory physical and spectral data (melting point, 1H NMR). Selected
data of 1-(4-methoxy-phenyl)-6,7-dimethoxyisochroman (Table 1, entry
◦
1
4): mp 97–98 C (ethanol); H NMR (300 MHz, CDCl3): 2.60 and 2.95
(m, 2H, CH2), 3.90 and 4.18 (m, 2H, CH2), 3.72 (s, 9H, CH3O), 5.62 (s,
1H, CH), 6.30–7.20 (m, 6H, Ar).
1 A. Pictet and T. Spengler, Berichte, 1911, 44, 2030.
2 B. Wunsch and M. Zott, Liebigs Ann. Chem., 1992, 39.
3 M. Guiso, C. Marra and C. Cavarischia, Tetrahedron Lett., 2001, 42,
6531.
12 A. Hegedu¨s, Z. Hell and A. Potor, Catal. Lett., 2005, 105, 229.
13 A. Hegedu¨s and Z. Hell, Tetrahedron Lett., 2004, 45, 8553.
14 C. Krug and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124,
1674.
1222 | Org. Biomol. Chem., 2006, 4, 1220–1222
This journal is
The Royal Society of Chemistry 2006
©