Isochromans from 2-(3′,4′-dihydroxy)phenylethanol

Article abstract of DOI:10.1016/S0040-4039(01)01307-7

A facile method to obtain an isochromanic structure was achieved by the oxa-Pictet-Spengler reaction using 2-(3′,4′-dihydroxy)phenylethanol as starting material. The reaction was performed in very mild conditions on a series of carbonylic compounds. Yields were always satisfactory.

Full text of DOI:10.1016/S0040-4039(01)01307-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6531–6534
Isochromans from 2-(3%,4%-dihydroxy)phenylethanol
Marcella Guiso,* Carolina Marra and Claudia Cavarischia
Dipartimento di Chimica Universita` ‘La Sapienza’, Piazzale Aldo Moro 5, 00185 Rome, Italy
Received 4 June 2001; revised 13 July 2001; accepted 19 July 2001
Abstract—A facile method to obtain an isochromanic structure was achieved by the oxa-Pictet–Spengler reaction using
2-(3%,4%-dihydroxy)phenylethanol as starting material. The reaction was performed in very mild conditions on a series of carbonylic
compounds. Yields were always satisfactory. © 2001 Elsevier Science Ltd. All rights reserved.
The oxa-Pictet–Spengler reaction is a variation of the
Pictet–Spengler reaction. While in the Pictet–Spengler
reaction a compound with a phenethylamine structure
reacts with an aldehyde or a ketone to give a Schiff
base and subsequently the Friedel–Crafts cyclization of
the iminium salt gives an isoquinoline derivative,1 in the
oxa-Pictet–Spengler reaction, a compound such as a
2-phenylethanol reacts with an aldehyde or a ketone to
give a 3,4-dihydro-1H-benzo[c]pyranic (isochromanic)
structure. This reaction was described in 19922 and was
accomplished under difficult operative conditions. The
authors used ZnCl2¯HCl gas, or p-toluenesulfonic acid,
etc. as Friedel–Crafts catalyst, and high reaction tem-
peratures. It has been reported3 that activated sub-
strates needed moderately milder conditions.
in the Oleaceae family, both as a free compound and
glycosilate or esterified as in oleuropein.4
Isochromanic structures seem to be very rare in nature,
and until now only a few examples have been
described,5–7 among which is compound 2.5
By our method we carried out a series of reactions
using 16 different carbonyl compounds (compounds
3–18 in Table 1 and Scheme 1) both aldehydes and
ketones, obtaining the corresponding isochromans
(compounds 2, 19–33 in Table 1 and Scheme 1). This
series of reactions was carried out at low temperature;
generally at 4°C, using p-toluenesulfonic acid as a
catalyst. From a synthetic point of view, our procedure
constitutes a significant improvement of the oxa-Pictet–
Spengler reaction, it does not give side-products and it
may be useful to synthesise, with satisfactory yields, a
set of hydroxysubstituted isochromans. The yields of
the reactions are summarised in Table 1.
We performed the oxa-Pictet–Spengler reaction in very
mild operative conditions and in this paper we report
that an activated substrate such 2-(3%,4%-dihy-
droxy)phenylethanol 1 undergoes the oxa-Pictet–Spen-
gler reaction even using a very mild acid catalyst, such
as a fatty acid. Compound 1, whose trivial name is
hydroxytyrosol, is characterised by an ortho-diphenolic
structure, which is responsible for its very high reactiv-
ity in redox and non redox reactions. In addition,
hydroxytyrosol is a widespread natural product, mainly
Hydroxytyrosol 1 reacts with carbonylic compounds,
giving at first an hemiacetalic linkage between its pri-
mary alcoholic function and the carbonylic function of
the aldehyde or ketone, as reported in Scheme 2. Then
the hemiacetalic intermediate loses a water molecule
HO
OH
HO
O
O
+
HO
R1
R2
HO
R1 R2
3-18
2, 19-33
1
Scheme 1.
Keywords: isochromans; oxa-Pictet–Spengler reaction; hydroxytyrosol.
* Corresponding author. Fax: +3906490631; e-mail: marcella.guiso@uniroma1.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01307-7

Table 1.
Reagents
Yield
(%)
Obtained producta
NMRb data (solvent): chemical shift in ppm from TMS, J in Hz
1 Acetone, 3
63
2
R1=CH3 R2=CH3
1H NMR (CD3OD): 6.58 (1H, s, H-5);6.50 (1H, s, H-8); 3.80 (2H, t, J=5.5 2H-3); 2.65 (2H, t, J=5.5, 2H-4); 1.45 (6H, s,
2CH3)
1 Methylpropyl ketone, 4
48 19 R1=CH3 R2=n-propyl 1H NMR (CDCl3): 6.54 (2H, H-5, H-8); 3.87 (2H, m, 2H-3); 2.53 and 2.73 (2H, m, 2H-4); 1.41 (3H, s, CH3 in C-1); R2
moiety: 1.71 (2H, m, CH2); 1.05 and 1.38 (2H, m, CH2 at C-1). 0.81 (3H, t, J=7.2, CH3); 13C NMR: 142.2 C-6; 141.8 C-7;
134.6 C-8a; 126.0 C-4a; 114.9 C-5;112.2; C-8; 76.8 C-1; 59.7 C-3; 28.9 C-4; 16.8 CH3 at C-1; R2 moiety at C-1. 45.2; 27.8;
14.32
1 Isopropylmethyl ketone, 5 35 20 R1=CH3 R2=iso-propyl 1H NMR (CDCl3): 6.64 (1H, s, H-5); 6.59 (1H, s, H-8); 3.93 (2H, t, J=6 2H-3); 2.71 (2H, t, J=6.0 2H-4); 1.64 (3H, s, R1);
R2 moiety: 1.40–1.60 (7H)
1 Vanillin, 6
76 21 R1=H
R2=4-OH,
1H NMR (CD3OD): 6.47 (1H, s, H-5); 6.06 (1H, s, H-8); 5.41 (1H, s, H-1); 4.00 and 3.72 (2H, m, 2H-3); 2.84 and 2.52 (2H,
3-OCH3-phenyl m, 2H-4); R2 moiety: 6.6–6.8 (3H); 3.68 (3H, s, OCH3). 13C NMR: 145.3 C-6; 144.5 C-7; 135.3 C-8a; 126.1 C-4a; 115.9 C-5;
114.6 C-8; 80.9 C-1; 65.1 C-3; 29.1 C-4; R2 moiety: 148.9; 147.5; 129.9; 123.1; 113.3; 115.6;.56.3
1 p-OH benzaldehyde, 7
87 22 R1=H
R2=p-OH
phenyl
1H NMR (CD3OD): 6.55 (1H, s, H-5); 6.11 (1H, s, H-8); 5.50 (1H, s, H-1); 4.05 and 3.80 (2H, m, 2H-3); 2.91 and 2.59 (2H,
m, 2H-4); R2 moiety: 7.08 (2H, d*) and 6.74 (2H, d*). 13C NMR: 145.2 C-6; 144.5 C-7; 134.8 C-8a; 126.1 C-4a; 115.8 C-5;
114.6 C-8; 80.5 C-1; 64.9 C-3; 29.1 C-4; R2 moiety: 158.4; 131.4; 129.9; 115.9
1 Cyclohexan-carbaldehyde, 8 82 23 R1=H
R2=cyclohexyl 1H NMR (CDCl3): 6.57 (2H, s, H-5 and H-8); 4.50 (1H, s, H-1); 4.11 and 3.63 (2H, m, 2H-3); 2.40 and 2.83 (2H, m, 2H-4);
1.0–1.9 (R2 moiety). 13C NMR: 142.0 C-6; 141.8 C-7; 129.8 C-8a; 127.4 C-4a; 115.1 C-5; 111.7 C-8; 79.9 C-1; 64.1 C-3; 30.2
C-4; R2 moiety: 43.6; 28.7; 26.9; 26.5; 26.4; 25.5
R2=o-OH
phenyl
/
1 o-OH benzaldehyde, 9
1 m-OH benzaldehyde, 10
42 24 R1=H
80 25 R1=H
1H NMR (CDCl3): 6.65 (1H, s, H-5); 6.27 (1H, s, H-8); 5.71 (1H, s, H-1) 4.22 and 3.92 (2H, m, 2H-3); 3.00 and 2.73 (2H,
m, 2H-4); R2 moiety: 6.7–7.1 (4H)
R2=m-OH
phenyl
1H NMR (CD3OD): 6.73 (1H, s, H-5); 6.15 (1H, s, H-8), 5.49 (1H, s, H-1); 3.81 and 4.06 (2H, m, 2H-3); 2.60 and 2.91 (2H,
m, 2H-4); R2 moiety: 7.14 (1H, t, J=7.5, H-5%); 6.77 (1H, d, J=7.5, H-6%); 6.71 (1H, m, H-4%); 6.70 (1H, s*, H-2); 13C NMR
145. (C-6); 145.3 (C-7); 129.5 (C-8a); 126.1 (C-4a); 115.9 (C-5); 114.5 (C-8); 80.7 (C-1); 65.0 (C-3); 29.1 (C-4); R2 moiety:
158.4; 144.5; 116.8; 115.9; 130.2; 121.3
1 m-NO2 benzaldehyde, 11
95 26 R1=H
R2=m-NO2
phenyl
1H NMR (CDCl3): 6.62 (1H, s, H-5); 6.13 (1H, s, H-8); 5.68 (1H, s, H-1); 4.11 and 3.87 (2H, m, 2H-3), 2.99 and 2.65 (2H,
m, 2H-4); R2 moiety: 8.12 (2H, m, H-2%,4%); 7.62 (1H, d*, H-6%); 7.48 (1H, t, J=7.8, H-5%); 13C NMR: 143.0 (C-6); 142.1
(C-7); 127.8 (C-8a); 126.2 (C-4a); 115.2 (C-5); 113.1 (C-8); 78.2 (C-1); 64.1 (C-3); 27.8 (C-4); R2 moiety: 148.2; 144.2; 134.9;
129.4; 123.6; 123.1
2
(
1 o-NO2 benzaldehyde, 12
58 27 R1=H
R2=o-NO2
phenyl
R2=p-OCH3
phenyl
1H NMR (CDCl3): 6.63 (1H, s, H-5); 6.27 (1H, s, H-8); 6.17 (1H, s, H-1); 4.07 and 3.84 (2H, m, 2H-3); 2.95 and 2.2 (2H, m,
2H-4); R2 moiety: 7.81 (1H, dd, J=8.2, 1.8, H-3%); 7.38-7.55 (3H, H-4%, H-5%, H-6%)
6
1 p-OCH3 benzaldehyde, 13 80 28 R1=H
1H NMR (CDCl3): 6.63 (1H, s, H-5); 6.20 (1H, s, H-8); 5.54 (1H, s, H-1); 3.84 and 4.11 (2H, m, 2H-3); 2.62 and 2.98 (2H,
m, 2H-4); R2 moiety: 7.19 (2H, d, J=8.4, H-2%, H-6%); 6.84 (2H, d, J=8.4, H-3%, H-5%); 3.78 (OCH3); 13C NMR: 142.7 (C-6);
141.7 (C-7); 130.4 (C-8a); 127.0 (C-4a); 115.2 (C-5); 113.8 (C-8); 79.0 (C-1); 64.1 (C-3); 28.4 (C-4); R2 moiety: 159.7; 134.7;
130.2; 114.0; 55.5
4
1 p-Cl benzaldehyde, 14
90 29 R1=H
R2=p-Cl
phenyl
1H NMR (CDCl3): 6.55 (1H, s, H-5); 6.09 (1H, s, H-8); 5.53 (1H, s, H-1); 3.82 and 4.07 (2H, m, 2H-3); 2.59 and 2.92 (2H,
m, 2H-4); R2 moiety: 7.25 (2H, d, J=8.4, C-3% and C-5%), 7.16(2H, d, J=8.4, C-2% and C-6%).13C NMR: 142.9 (C-6); 141.9
(C-7); 128.7 (C-8a); 126.1 (C-4a); 114.9 (C-5); 113.2 (C-8); 78.5 (C-1); 63.9 (C-3); 27.9 (C-4); R2 moiety 133.9; 130.2; 128.5
1H NMR (CDCl3): 6.57 (1H, s, H-5); 6.56 (1H, s, H-8); 4.61 (1H, dd, J=7.1, 3.0, H-1); 4.07 and 3.70 (2H, m, 2H-3); 2.82
and 2.52 (2H, m, 2H-4) R2 moiety: 1.76 (2H, m, 2H C-1%); 1.38 (4H, 2H C-2% and 2H C-3%); 0.90 (3H, t, J=6.9, CH3)
1H NMR (CDCl3): 6.61 (1H, s, H-5); 6.18 (1H, s, H-8); 5.57 (1H, s, H-1); 4.10 and 3.85 (2H, m, 2H-3); 2.98 and 2.63 (2H,
m, 2H-4); R2 moiety 7.28 (5H)
1 Pentanal, 15
1 Benzaldehyde, 16
1 Butanal, 17
50 30 R1=H
60 31 R1=H
64 32 R1=H
R2=n-butyl
R2=phenyl
R2=n-propyl 1H NMR (CDCl3): 6.58 (1H, s, H-5); 6.57 (1H, s, H-8); 4.65 (1H, t, J=5.5, H-1); 4.09 and 3.75 (2H, m, 2H-3), 2.82 and 2.55
(2H, m, 2H-4); R2 moiety: 1.75 (2H, m, 2H-1%); 1.48 ( 2H, m, 2H-2%); 0.93 (3H, t, J=7.2, CH3)
R2=2-(E)-2-
1 (E)-2-methyl-2-butenal, 18 57 33 R1=H
1H NMR (CDCl3): 4.94 (1H, s, H-1); 4.18 and 3.75 (2H, m, 2H-3); 2.90 and 2.45 (2H, m, 2H-4); 6.59 (1H, s, H-5); 6.47 (1H,
butenyl
s, H-8); R2 moiety: 1.43 (3H, s, CH3); 1.65 (3H, d, J=6.3, CH3); 5.61 (1H, m, H-10)
a Safisfactory microanalyses obtained: C 0.35, H 0.16).
b Varian, Mercury 300.
* Unshaped signal.

M. Guiso et al. / Tetrahedron Letters 42 (2001) 6531–6534
6533
Scheme 2.
We selected aldehydes and ketones for these experi-
ments that were present in olive oil together with
hydroxytyrosol 1 and oleic acid9 and also successively
investigated the presence of isochromans in this food-
stuff. The obtained compounds in this second set of
reactions and their yields are reported in Table 2.
and gives an isochroman, closing a six-membered ring
at the position, on the phenyl moiety, which results in
activation by the para hydroxyl group.
The reaction time necessary to obtain the isochroman
with satisfactory yields is different for aldehydes and
ketones, indeed 1 reacts faster with aldehydes (generally
1 day at 4°C) than with ketones (2 days at 4°C). In our
experiments, we observed that the more hindered
ketones give, in the usual operative conditions, the
isochroman with lower yields (see Table 1), as shown
by the different reaction yields of isopropyl-methyl-
ketone 5 and acetone 3. This effect increases when the
steric crowding increases; and very hindered ketones,
such as benzophenone or acetophenone, do not react at
all with 1. It is also possible to point out a different
reactivity between aromatic and aliphatic aldehydes. In
fact, the aromatic aldehydes generally give the corre-
sponding isochroman with higher yields than aliphatic
ones, probably because in the aromatic aldehydes the
positive charge present on the reaction intermediate (see
Scheme 2) may give a resonance on the aromatic ring,
so increasing the stability of the intermediate cation,8 or
because these aldehydes can not undergo enolisation.
We have selected the carbonylic compounds reported in
Table 1 to also investigate the effects of substituents on
aromatic ring, but as shown by data of Table 1, we
have noted only steric effects. In fact, the aromatic
aldehydes with a substituent in the ortho position give
lower yields than those with substituents in the para or
meta positions.
As some isochromans were isolated from natural
matrices5–7 and we demonstrated the possibility that 1
can react with carbonylic compounds in very mild
conditions (low temperature, mild acid catalysis) by an
oxa-Pictet–Spengler reaction, the doubt is if all the
isochromans that were isolated until now are true natu-
ral compounds or artefacts arising from the isolation
procedure.
We are convinced that some of these may be natural
products, while others could arise from a spontaneous
acid-catalysed reaction. An example could be the
isochroman 2 isolated from the leaves of Tectaria
subtriphylla5 by an acetone extraction.
So it is necessary to look for these products in the
natural matrices, having in mind the possibility of an
oxa-Pictet–Spengler reaction.
Experimental procedures
First series (p-toluenesulfonic acid): 20 mg of 1 was
dissolved in methyl alcohol (1 ml) together with the
selected carbonylic compound (3–18) in a 1:1 molar
ratio. A catalytic amount of p-toluenesulfonic acid was
added. The mixture was left to react at 4°C for the
required period of time (about 24 h for aldehydes and
48 h for ketones). After a chromatographic control on
a silica gel plate, the volume of the reaction mixture is
As previously reported, p-toluenesulfonic acid was used
as a catalyst in the first series of reactions. Afterwards
we tried to verify if the reaction could also be per-
formed by using a weaker acid, such as a fatty acid. We
selected oleic acid because it is present in the same
natural matrix as the hydroxytyrosol 1, olives and olive
oil.
Table 2.
Reagents
Yield (%)
Obtained producta
It has been noted that 1 reacts in the presence of oleic
acid with carbonylic compounds, but in this case it is
necessary to have a longer reaction time (1 week), and
an increase in the temperature (room temperature,
about 21°C), nevertheless lower yields are observed
than when using p-toluenesulfonic acid as a catalyst.
1 Acetone, 3
1 Benzaldehyde, 16
1 Pentanal, 15
40
30
35
20
2
31
30
20
1 Methyl isopropylketone, 5
a Satisfactory microanalyses obtained: C 0.35, H 0.16.

6534
M. Guiso et al. / Tetrahedron Letters 42 (2001) 6531–6534
cut in half under reduced pressure at low temperature,
diluting with ethyl acetate (25 ml). The organic layer is
washed with a saturated solution of NaCl until neutral-
ity, dried with anhydrous Na2SO4, concentrated and
the residue purified by chromatography on silica gel, by
eluting usually with 9:1 CHCl3/MeOH.
References
1. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030–2036.
2. Wunsch, B.; Zott, M. Liebigs Ann. Chem. 1992, 39–
45.
3. Wunsch, B.; Zott, M.; Hofner, G. Arch. Pharm. 1992, 325,
733–739.
Second series (oleic acid): 20 mg of 1 is dissolved in
methyl alcohol (1 ml) together with the selected car-
bonylic compound (3, 5, 14, 15) in a 1:1 molar ratio. A
catalytic amount of oleic acid was successively added.
The mixture was left to react at 21°C for a week. After
chromatographic control on silica gel plate, the oleic
acid was extracted with hexane, methanol was evapo-
rated under reduced pressure and the residue was
purified as above.
4. Panizzi, L.; Scarpati, M. L.; Oriente, G. Gazz. Chim. Ital.
1960, 90, 1449–1485.
5. Hsu, F. L.; Chen, J. Y. Phytochemistry 1993, 34 (6),
1625–1627.
6. Ralph, J.; Peng, J.; Lu, F. Tetrahedron Lett. 1998, 39 (28),
4963–4964.
7. Ralph, J.; Peng, J.; Lu, F. Phytochemistry 1999, 50 (4),
659–666.
8. Schmitz, E.; Eichhorn, I. In The Chemistry of the Ether
Linkage: Acetals and Hemiacetals; Patai, S., Ed.; Inter-
science publishers John Wiley & Son, 1967; pp. 309–351.
9. Balestrieri F.; Bottari E.; Festa M.R.; Marini D.; Metodi
Acknowledgements
di analisi di prodotti alimentari OLI
e
GRASSI;
Financial support from MURST.
SO.GRA.ME s.p.a. Cercola (NA), 1988, pp. 26–27.