One-pot synthesis of 6-hydroxyisochromans: The example of demethyl-oxa-coclaurine

Article abstract of DOI:10.1002/ejoc.200300182

Using a modified oxa-Pictet Spengler reaction that we recently described, we synthesized 6-hydroxy-isochromans and their 7-hydroxy derivatives. The successful one step synthesis did not require protecting groups and provided high yields. The obtainment of 1-(4′ -hydroxybenzyl)-6,7-dihydroxyisochroman (1) indicates that this protocol can be used to synthesize oxygenated analogues of benzyl-tetrahydroisoquinoline alkaloids, such as demethyl-coclaurine (2). This methodology could provide a general procedure for the synthesis of hydroxyisochromans. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300182

FULL PAPER
One-Pot Synthesis of 6-Hydroxyisochromans: The Example of
Demethyl-oxa-coclaurine
Marcella Guiso,[a] Armandodoriano Bianco,[a] Carolina Marra,*[a] and
Claudia Cavarischia[a]
Keywords: Natural products / Synthesis design / Isochroman
Using a modified oxa-Pictet Spengler reaction that we re-
cently described, we synthesized 6-hydroxy-isochromans
and their 7-hydroxy derivatives. The successful one step syn-
to synthesize oxygenated analogues of benzyl-tetrahydroiso-
quinoline alkaloids, such as demethyl-coclaurine (2). This
methodology could provide a general procedure for the syn-
thesis did not require protecting groups and provided high thesis of hydroxyisochromans.
yields. The obtainment of 1-(4Ј-hydroxybenzyl)-6,7-dihy-
droxyisochroman (1) indicates that this protocol can be used
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The benzyl-tetrahydro-isoquinoline moiety is present in
the metabolic pattern of many plants and can undergo
modifications to produce a wide range of substances.[1]
Many of these substances are important drugs, including
benzyl-tetrahydro-isoquinoline alkaloids, which are biosyn-
thesized by an enzymatic PictetϪSpengler reaction.[2] In its
simplest form, this reaction consists of the condensation of
a β-phenyl-ethylamine with a carbonyl compound, generat-
ing an iminium salt which undergoes cyclization by means
of an intramolecular electrophilic aromatic substitution.
The oxygenated version of this reaction was reported for
the first time by Wunsch and Zott in 1992 and denominated
‘‘the oxa-PictetϪSpengler reaction.’’[3] In previous work we
proposed modifications to this reaction,[4] the results led us
to hypothesize that this modified version could be gen-
eralized to obtain oxygenated analogues of benzyl-tetra-
hydroisoquinoline alkaloids (i.e. 1-benzyl-isochromans). To
test this hypothesis, we used the modified oxa-
PictetϪSpengler reaction to synthesize 1-(4Ј-hydroxy-
benzyl)-6,7-dihydroxyisochroman (1), the oxygenated ana-
logue of the benzyl-tetrahydroisoquinoline alkaloid de-
methylcoclaurine (2, Figure 1).
Figure 1. Demethyl-oxa-coclaurine (1) and demethylcoclaurine (2)
(3), and (p-hydroxyphenyl)ethanal (4) were identified as the
starting compounds, as shown in Scheme 1. Aldehyde 4 is
a non-commercial product which was prepared by the oxi-
dation of tyrosol (5) with PDC.
The one-pot racemic synthesis of the target compound 1
was performed by a modified version of the protocol we
recently described.[4] This modified procedure allows for the
direct reaction between the two starting compounds, 3 and
4, without requiring protecting groups. We proposed a three
step mechanism[4] for the oxa-PictetϪSpengler reaction, as
depicted in Scheme 1. The first step, the acid-catalyzed for-
mation of the hemiacetal is followed by water loss, which
provides the reactive intermediate that finally undergoes in-
tramolecular electrophilic aromatic substitution, in the acti-
vated position para to the hydroxyl group. Under the mild
experimental conditions adopted, we obtained a high re-
gioselectivity for the aromatic electrophilic substitution, in
the activated less hindered aromatic position. In our pre-
vious work[4] we found that aromatic aldehydes gave higher
yields than aliphatic aldehydes, leading us to hypothesize
that the water elimination step was fundamental. This step
occurs more easily with a homobenzylic hemiacetal. To de-
termine whether or not the water elimination step plays a
key role in the proposed mechanism, we carried out reac-
tions with and without dehydrating agents.
Results and Discussion
On the basis of a simple retrosynthetic analysis for the
synthesis of the demethyl-oxa-coclaurine (1) [i.e., 1-(4Ј-
hydroxybenzyl)-6,7-dihydroxyisochroman], hydroxytyrosol
[a]
`
Dipartimento di Chimica Universita ‘‘La Sapienza’’,
Istituto di Chimica Biomolecolare del CNR
Piazzale Aldo Moro 5, 00185 Roma, Italy
Fax: (internat.) ϩ 39-06/490631
E-mail: carolina.marra@uniroma1.it
Eur. J. Org. Chem. 2003, 3407Ϫ3411
DOI: 10.1002/ejoc.200300182
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3407

M. Guiso, A. Bianco, C. Marra, C. Cavarischia
FULL PAPER
Scheme 1. Proposed mechanism of oxa-PictetϪSpengler reaction
Specifically, we synthesized a series of 6,7-dihydroxy- Table 1. The protocols using dehydrating agents gave higher
isochromans, some of which have been described pre- yields compared to those without for all of the isochromans
viously,[4] with addition of one of two dehydrating agents obtained (14Ϫ21). The highest yields were obtained when
to the reaction mixture: molecular sieves (protocol A) or using molecular sieves as the dehydrating agent (protocol
anhydrous sodium sulfate (Na2SO4) (protocol B). The reac- A). The reactions involving aliphatic carbonyl compounds
tion yields were compared with those previous described generally gave higher increases in yield compared to those
by us without a dehydrating agent (protocol C). Hydroxy- obtained for aromatic carbonyl compounds.
tyrosol (3) and a series of selected carbonyl compounds
Finally, to determine whether or not the hydroxyl group
(6Ϫ13) with aliphatic as well as aromatic structures were at C-7 plays a role in the formation of the isochroman skel-
used. The carbonyl compounds used in our previous work eton, we performed reactions using 2-(3Ј-hydroxyphenyl)e-
and reused here (6Ϫ10) were those that had given the lowest thanol (25) with pentanal (7) and three aromatic aldehydes:
yields of the corresponding isochromans (compounds piperonal (22), p-chlorobenzaldehyde (23), and p-meth-
14Ϫ18). The new isochromans (compounds 19Ϫ21) were oxycarbonylbenzaldehyde (24).
prepared using all three protocols.
Table 2 shows the yields of the corresponding 6-hydroxy-
The results of the modified oxa-PictetϪSpengler reaction isochroman derivatives (26Ϫ29) obtained. As expected, aro-
with and without the dehydrating agents are reported in matic aldehydes afforded the highest yields.
Table 1. Comparison of yields obtained from hydroxytyrosol (3) using protocols A, B, and C
Reagents: 3 and
Yield (%)
protocol A
Yield (%)
protocol B
Yield (%)
protocol C
Obtained product
Acetone (6)
95
80
98
98
95
90
95
95
80
60
90
90
80
73
80
90
63
50
80
80
60
62
72
75
14
15
16
17
18
19
20
21
R1 ϭ CH3
R2 ϭ CH3
Pentanal (7)
R1 ϭ H
R1 ϭ H
R1 ϭ H
R1 ϭ H
R1 ϭ H
R1 ϭ H
R1 ϭ H
R2 ϭ n-butyl
m-OH-benzaldehyde (8)
p-OCH3-benzaldehyde (9)
Benzaldehyde (10)
Isovaleraldehyde (11)
Propanal (12)
R2 ϭ m-OH-phenyl
R2 ϭ p-OCH3-phenyl
R2 ϭ phenyl
R2 ϭ isobutyl
R2 ϭ ethyl
Nonanal (13)
R2 ϭ n-octyl
3408
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Eur. J. Org. Chem. 2003, 3407Ϫ3411

One-Pot Synthesis of 6-Hydroxyisochromans
FULL PAPER
Table 2. Yields obtained from 2-(3Ј-hydroxy-phenyl)-ethanol (25) using protocol A
Reagents: 25 and
Yield (%)
Obtained product
Pentanal (7)
80
98
95
90
26
27
28
29
R ϭ n-butyl
R ϭ 3Ј,4Ј-(methylenedioxy)phenyl
R ϭ p-Cl-phenyl
Piperonal (22)
p-chlorobenz-aldehyde (23)
p-methoxycarbonyl-benzaldehyde (24)
R ϭ p-COOCH3-phenyl
and evaporation of the solvent yielded crude 4, which was used in
the following reaction without purification, to obtain 1. H NMR
The above results indicate that the hydroxyl in the para
position to the reaction site controls the regioselectivity of
the reaction.
1
spectroscopic data of compound 4, partially reported in the litera-
1
ture (reference 6), are listed. H NMR (CD3COCD3): 9.64 (t, J ϭ
To confirm the role of the C-6 hydroxyl group in the
mechanism outlined in Scheme 1, we used 2-(4Ј-hydroxy-
phenyl)ethanol (5) instead of 2-(3Ј-hydroxyphenyl)ethanol
(25), adopting the same experimental conditions described
for the oxa-PictetϪSpengler reaction. The recovery of 2-(4Ј-
hydroxyphenyl)ethanol unchanged suggests that the mecha-
nism outlined in Scheme 1 is the only effective process un-
der the conditions described in the reported protocols.
Given the yields obtained and the very simple experimen-
tal procedure, we propose that the modified oxa-
PictetϪSpengler reaction can be used as a general pro-
cedure for synthesizing 6-hydroxyisochromans and oxygen-
ated analogues of the benzyl-tetrahydroisoquinoline alka-
loids. An objective of future studies could be to determine
how substitution of the nitrogen atom with an oxygen atom
would modify the biological activity.
2.2 Hz, 1 H, 1-H); 7.05 (d, J ϭ 8.1 Hz, 2 H, 2Ј-H and 6Ј-H); 6.82
(d, J ϭ 8.1 Hz, 2 H, 3Ј-,5Ј-H); 3.62 (d, J ϭ 2.2 Hz, 2 H, 2-H) ppm.
Isochroman Synthesis. General Procedure: We used three protocols
to synthesize these compounds: A) with molecular sieves as dehy-
drating agent; B) with anhydrous Na2SO4 as dehydrating agent,
and C) without dehydrating agent. Compounds 14Ϫ21 were pre-
pared according to protocols A, B, and C; and compounds 26Ϫ29
according to protocol A.
A: Phenolic compound 3 or 25 (reaction scale about 20 mg) was
dissolved in anhydrous methyl alcohol,and molecular sieves (about
100 mg) previously dried for one night at 150 °C were added. Car-
bonyl compound (4, 6Ϫ13, 22Ϫ24, 10% molar excess) and a cata-
lytic amount of p-toluenesulfonic acid were added. The mixture
was left to react at 4 °C for 24 h (aldehydes) or for 48 h (acetone).
The molecular sieves were filtered off, the solution was concen-
trated at room temperature in vacuo, diluted with ethyl acetate, and
washed with brine until the pH was neutral. The organic layer was
dried with anhydrous Na2SO4, filtered, evaporated, and the residue
purified by chromatography on a silica gel column eluting with
CHCl3/MeOH (9:1).
Experimental Section
NMR spectra: Varian Mercury 300; NMR spectroscopic data
marked with an asterisk (*) may be reversed. Micro-analyses: CE
Instruments. Chromatography: Merck Silica gel 60, washed with 1
 HCl then with water until the chlorine test was negative, activated
for 48 h at 120 °C, then equilibrated with 10% of water. TLC 5 ϫ
20 Silica gel 60 F254 Merck.
B: The solution was prepared as described in protocol A in the
presence of anhydrous Na2SO4 (100 mg). After the reaction times
reported above, the Na2SO4 was filtered off, the reaction was
worked up, and the residue purified as described above.
C: The reaction was carried out in methyl alcohol without a dehy-
drating agent, as described in Reference 4.
IR spectra were performed by infrared spectrophotometer IR-470,
Shimadzu using 1% concentration.
1-(p-Hydroxybenzyl)-6,7-dihydroxyisochroman (1, racemic demeth-
yloxacoclaurine): Yields: protocol A, 80% (28 mg); protocol B, 75%
(26 mg); protocol C, 60% (21 mg). 1H NMR (CDCl3): 6.56 (s, 1 H,
5-H); 6.22 (s, 1 H, 8-H); 5.55 (s, 1 H, 1-H); 4.14 (m, 1 H, 3-H1);
3.86 (m, 1 H, 3-H2); 3.01 (m, 1 H, 4-H1); 2.65 (m, 1 H, 4-H2); p-
OH phenyl moiety: 7.16 (d, J ϭ 8.4 Hz, 2 H, 2Ј-,6Ј-H); 6.79 (d,
J ϭ 8.4 Hz, 2 H, 3Ј-,5Ј-H) ppm. 13C NMR (C3D6O): 156.2 (C-4Ј);
144.2 (C-7*); 144.0 (C-6*); 131.3 (C-2Ј and C-6Ј); 130.8 (C-1Ј*);
130.0 (C-8a*); 125.9 (C-4a); 115.7 (C-5); 115.4 (C-3Ј and C-5Ј);
112.6 (C-8); 77.3 (C-1); 63.3 (C-3); 42.2 (Cα); 29.1 (C-4) ppm. IR
(CHCl3): ν˜ ϭ 3300, 2950, 1690, 1650, 1520, 1450, 1390, 1270, 1250,
1090, 1020 cmϪ1. Elemental analysis: C16H16O4 (272.29) calcd C
70.58, H 5.92; found C 70.45, H 6.01. [M Ϫ H]Ϫ ϭ 271.0; product
ions: 241.0.
MS and MS\MS analyses were performed on a triple quadrupole
PE-SCIEX API 365 (PerkinϪElmer Sciex Instruments Foster City,
CA USA), equipped with Turboion Spray interface in negative ion
mode. Melting point apparatus: Mettler FP 80. Reagents: Fluka.
Solvents: CarloϪErba.
Hydroxytyrosol (3) was prepared from 3,4-dihydroxyphenyl acetic
acid, according to a previously described protocol.[5]
Oxidation of Tyrosol (5) to Give Compound 4: PDC (2.05 equiv.)
was added in one portion to a solution of tyrosol 5 (100 mg) in
CH2Cl2/EtOAc ϭ 1:0.5 at room temperature, the mixture was al-
lowed to stir for about 5 hours. The mixture was filtered through a
short path of Celite and washed with the reaction solvent (CH2Cl2/
EtOAc ϭ 1:0.5; 70 mL). The pale yellow solution obtained was 1,1-Dimethyl-6,7-dihydroxyisochroman (14): See ref.[4] Yields: pro-
washed with brine and dried with anhydrous Na2SO4. Filtration tocol A, 95% (24 mg); protocol B, 80% (20 mg); protocol C, 63%
Eur. J. Org. Chem. 2003, 3407Ϫ3411
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M. Guiso, A. Bianco, C. Marra, C. Cavarischia
FULL PAPER
(16 mg). m.p. 130Ϫ132 °C. 1H NMR (CDCl3): 6.59 (s, 1 H, 5*-H); 1-Isobutyl-6,7-dihydroxyisochroman (19): Yields: protocol A, 90%
6.56 (s, 1 H, 8*-H); 3.94 (t, J ϭ 5.5 Hz, 2 H, 3-H); 2.70 (t, J ϭ (26 mg); protocol B, 73% (21 mg); protocol C, 62% (18 mg). 1H
5.5 Hz, 2 H, 4-H); 1.49 (s, 6 H, 2 ϫ CH3) ppm. 13C NMR (CDCl3):
NMR (CDCl3): 6.57(s, 1 H, 5*-H); 6.54 (s, 1 H, 8*-H); 4.67 (d*,
142.2 (C-7*); 142.0 (C-6*); 134.9 (C-8a); 124.9 (C-4a); 114.8 (C-5); J ϭ 8.7 Hz, 1 H, 1-H); 4.07 (m, 1 H, 3-H1), 3.75 (m, 1 H, 3-H2);
112.0 (C-8); 74.7 (C-1); 59.8 (C-3); 29.9 (C-1Ј); 28.9 (C-4) ppm. IR 2.78 (m, 1 H, 4-H1); 2.58 (m, 1 H, 4-H2); isobutyl moiety: 1.93 (m,
(CHCl3): ν˜ ϭ 3600, 3300, 2970, 1690, 1660, 1610, 1520, 1450, 1370,
1 H, 2Ј-H); 1.74 (m, 1 H, 1Ј-H1); 1.47 (m, 1 H, 1Ј-H2); 0.98 (d, J ϭ
1290, 1130, 1090 cmϪ1. Elemental analysis: C11H14O3 (194.22) 6.8 Hz, 3 H), 0.93 (d, J ϭ 6.8 Hz, 3 H) methyl groups ppm. 13C
calcd C 68.02, H 7.27; found C 67.86, H 7.33. [M Ϫ H]Ϫ ϭ 193.2; NMR (CDCl3): 142.1 (C-6* and C-7*); 131.4 (C-8a*); 126.0 (C-
product ions: 123.0 and 163.2.
4a*); 115.2 (C-5); 111.7 (C-8); 73.8 (C-1); 62.7 (C-3); 45.3 (C-1Ј);
28.3 (C-4); 24.5 (C-2Ј); 23.9 (C-3Ј); 21.5 (C-4Ј) ppm. IR (CHCl3):
ν˜ ϭ 3580, 3300, 2950, 1650, 1610, 1520, 1460, 1380, 1290, 1160,
1090 cmϪ1. Elemental analysis: C13H18O3 (222.27) calcd C 70.24,
H 8.16; found C 70.03, H 8.32. [M Ϫ H]Ϫ ϭ 221.0; product ions:
176.2 and 205.2.
1-(1Ј-Butyl)-6,7-dihydroxyisochroman (15): See ref.[4] Yields: proto-
col A, 80% (23 mg); protocol B, 60% (17 mg); protocol C, 50%
1
(14 mg). H NMR (CDCl3): 6.57 (s, 1 H, 5*-H); 6.56 (s, 1 H, 8*-
H); 4.61 (dd, 1 H, J1 ϭ 7.1, J2 ϭ 3.0, H2, 1-H); 4.07 (m, 1 H, 3-
H1); 3.70 (m, 1 H, 3-H2); 2.82 (m, 1 H, 4-H1); 2.52 (m, 1 H, 4-H2);
n-butyl moiety: 1.76 (m, 2 H, 1Ј-H); 1.38 (4 H, 2Ј-H and 3Ј-H);
0.90 (t, J ϭ 6.9 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3) 142.0 (C-
7*); 141.9 (C-6*); 130.7 (C-8a); 126.1 (C-4a); 115.1 (C-5); 111.5 (C-
8); 75.7 (C-1); 63.2 (C-3); 35.7 (C-1Ј); 28.5 (C-4); 27.4 (C-2Ј); 22.9
(C-3Ј); 14.1 C-4Ј ppm. IR (CHCl3): ν˜ ϭ 3600, 3300, 2940, 1720,
1650, 1610, 1520, 1460, 1380, 1290, 1160, 1090 cmϪ1. Elemental
analysis: C13H18O3 (222.27) calcd C 70.24, H 8.16; found C 70.00,
H 8.35; [M Ϫ H]Ϫ ϭ 221.0; product ions: 162.2 and 191.2.
1-Ethyl-6,7-dihydroxyisochroman (20): Yields: protocol A, 95%
(24 mg); protocol B, 80% (20 mg); protocol C, 72% (18 mg). 1H
NMR (CDCl3): 6.56 (s, 1 H, 5-H); 6.54 (s, 1 H, 8-H); 4.57 (d, 1 H,
1-H); 4.08 (m, 1 H, 3-H1) 3.72 (m, 1 H, 3-H2), 2.81 (m, 1 H, 4-H1);
2.53 (m, 1 H, 4-H2); ethyl moiety: 1.72 and 1.84 (m, 2 H, 1Ј-H);
0.93 (t, 3 H, CH3) ppm. 13C NMR (CDCl3) 142.1 (C-6*) and (C-
7*); 130.3 (C-8a); 126.4 (C-4a); 115.0 (C-5); 111.5 (C-8); 77.0 (C-
1); 63.5 (C-3); 28.6 (C-1Ј); 28.4 (C-4); 9.6 (C-2Ј) ppm. IR (CHCl3):
ν˜ ϭ 3600, 3300, 2950, 1720, 1610, 1520, 1460, 1340, 1290, 1160,
1090 cmϪ1. Elemental analysis: C11H14O3 (194.22) calcd C 68.02,
H 7.27; found C 67.88, H 7.40. [M Ϫ H]Ϫ ϭ 193.2; product ions:
148.0 and 163.2.
1-(m-Hydroxyphenyl)-6,7-dihydroxyisochroman (16): See ref.[4]
Yields: protocol A, 98% (33 mg); protocol B, 90% (30 mg); protocol
C, 80% (27 mg). m.p. 153Ϫ154 °C. H NMR (CD3OD): 6.73 (s, 1
1
H, 5-H); 6.15 (s, 1 H, 8-H); 5.49 (s, 1 H, 1-H); 4.06 (m, 1 H, 3-H1);
3.81 (m, 1 H, 3-H2); 2.91 (m, 1 H, 4-H1); 2.60 (m, 1 H, 4-H2); m-
hydroxyphenyl moiety: 7.14 (t, J ϭ 7.5 Hz, 1 H, 5Ј-H); 6.77 (d, J ϭ
7.5 Hz, 1 H, 6Ј-H); 6.71 (m, 1 H, 4Ј-H); 6.70 (s*, 1 H, 2Ј-H) ppm.
13C NMR (CDCl3) 158.4 (C-3Ј); 145.4 (C-7*); 145.3 (C-6*); 144.6
(C-1Ј); 130.2 (C-5Ј); 129.5 (C-8a); 126.1 (C-4a); 121.3 (C-6Ј); 119.9
(C-2Ј); 116.8 (C-4Ј); 115.9 (C-5); 114.0 (C-8); 80.7 (C-1); 65.0 (C-
3); 29.1 (C-4) ppm. IR (CHCl3): ν˜ ϭ 3300, 2950, 1680, 1660, 1520,
1460, 1390, 1270, 1120, 1090 cmϪ1. Elemental analysis: C15H14O4
(258.26) calcd C 69.76, H 5.46; found C 69.56, H 5.58. [M Ϫ H]Ϫ ϭ
257.0; product ions: 209.0; 227.0 and 212.1.
1-(1Ј-Octyl)-6,7-dihydroxyisochroman (21): Yields: protocol A, 95%
(34 mg); protocol B, 90% (32 mg); protocol C, 75% (27 mg). 1H
NMR (CDCl3): 6.57 (s, 1 H, 5*-H); 6.56 (s, 1 H, 8*-H); 4.64 (m, 1
H, 1-H); 4.09 (m, 1 H, 3-H1); 3.76 (m, 1 H, 3-H2); 2.82 (m, 1 H,
4-H1); 2.55 (m, 1 H, 4-H2); octyl group: 1.77 (m, 2 H, 1Ј-H); 1.42
(m, 2 H, 2Ј-H); 1.26 (m, 10 H, 3Ј-,4Ј-,5Ј-,6Ј-,7Ј-H); 0.87 (t, 3 H,
CH3) ppm. 13C NMR (CDCl3): δ ϭ 142.2 (C-7*); 142.1 (C-6*);
130.8 (C-8a); 126.1 (C-4a); 115.1 (C-5); 111.6 (C-8); 75.7 (C-1); 63.1
(C-3); 35.9 (C-1Ј); 31.9 (C-7Ј); 29.7 (C-6Ј); 29.6 (C-5Ј); 29.3 (C-4Ј);
28.4 (C-4); 25.2 (C-3Ј); 22.7 (C-2Ј); 14.1 (C-8Ј) ppm. IR (CHCl3):
ν˜ ϭ 3600, 3300, 2920, 1680, 1660, 1520, 1460, 1390, 1290, 1140,
1080 cmϪ1. Elemental analysis: C17H26O3 (278.38) calcd C 73.35,
H 9.41; found C 73.14, H 9.56. [M Ϫ H]Ϫ ϭ 277.0; product ions:
248.0.
1-(p-Methoxyphenyl)-6,7-dihydroxyisochroman (17): See ref.[4]
Yields: protocol A, 98% (35 mg); protocol B, 90% (32 mg); protocol
C, 80% (28 mg). m.p. 173Ϫ174 °C. 1H NMR (CDCl3): 6.63 (s, 1
H, 5-H); 6.20 (s, 1 H, 8-H); 5.54 (s, 1 H, 1-H); 4.11 (m, 1 H, 3-H1);
3.84 (m, 1 H, 3-H2); 2.98 (m, 1 H, 4-H1); 2.62 (m, 1 H, 4-H2); p-
methoxyphenyl moiety: 7.19 (2 H, 2Ј-,6Ј-H); 6.84 (2 H, 3Ј-,5Ј-H);
3.78 (OCH3) ppm. 13C NMR (CDCl3): δ ϭ 159.7 (C-4Ј); 142.7 (C-
7*); 141.7 (C-6*); 134.8 (C-1Ј); 130.4 (C-8a); 130.2 (C-2Ј and C-
6Ј); 127.0 (C-4a); 115.2 (C-5); 114.0 (C-3Ј and C-5Ј); 113.8 (C-8);
79.0 (C-1); 64.1 (C-3); 55.5 (OCH3); 28.4 (C-4) ppm. IR (CHCl3):
ν˜ ϭ 3300, 2950, 1680, 1660, 1520, 1460, 1390, 1290, 1240, 1140,
1080 cmϪ1. Elemental analysis: C16H16O4 (272.29) calcd C 70.58,
H 5.92; found C 70.39, H 6.11. [M Ϫ H]Ϫ ϭ 271.0; product ions:
241.0 and 226.1.
2-(3Ј-Hydroxyphenyl)ethanol (25): 2-(3Ј-Hydroxyphenyl)acetic acid
(0.5 g) was dissolved in anhydrous methanol (50 mL) and two
drops of concentrated H2SO4 were added. After 2 h, the reaction
was concentrated in vacuo, diluted with ethyl acetate, washed with
brine until the pH was neutral, dried with anhydrous sodium sul-
fate, and the solvent evaporated under reduced pressure. The
methyl ester (0.45 g; 82%) was obtained and immediately treated
with an aqueous solution of excess NaBH4. After 2 h, the solution
was acidified with 2  HCl, extracted with ethyl acetate, and
worked up as reported above. The residue obtained was purified by
silica gel column chromatography, eluting with CHCl3/MeOH
(9:1), gave pure 25 (0.37 g; 98%). 1H NMR (CD3OD): 7.15 (t, 1 H,
5Ј-H); 6.50Ϫ6.90 (3 H, 2Ј-,4Ј-,6Ј-H); 3.72 (t, 2 H, 1-H); 2.75 (t, 2
H, 2-H).
1-Phenyl-6,7-dihydroxyisochroman (18): See ref.[4] Yields: protocol
A, 95% (30 mg); protocol B, 80% (25 mg); protocol C, 60% (19 mg).
1H NMR (CDCl3): 6.61 (s, 1 H, 5-H); 6.18 (s, 1 H, 8-H); 5.57 (s,
1 H, 1-H); 4.10 (m, 1 H, 3-H1) 3.85 (m, 1 H, 3-H2); 2.98 (m, 1 H,
4-H1); 2.63 (m, 1 H, 4-H2); phenyl moiety: 7.28 (5 H) ppm. 13C
NMR (CDCl3): δ ϭ 142.7 (C-7*); 141.8 (C-6*); 141.7 (C-1Ј); 128.9 1-(1Ј-Butyl)-6-hydroxyisochroman (26): The reaction was only car-
(C-8a); 128.7 (C-6Ј and C-2Ј); 128.3 (C-5Ј and C-3Ј); 128.1 (C-4Ј); ried out according to protocol A. Yield: 80% (24 mg). 1H NMR
115.9 (C-4a); 114.8 (C-5); 113.4 (C-8); 79.3 (C-1); 63.8 (C-3); 28.1 (CDCl3): 6.94 (d, J ϭ 8.1 Hz, 1 H, 8-H); 6.66 (dd, 1 H, J1 ϭ 8.1,
(C-4) ppm. IR (CCl4): ν˜ ϭ 3800, 3500, 3100, 1700, 1560, 1420,
J2 ϭ 2.7 Hz, 7-H); 6.57 (d, J ϭ 2.7 Hz, 1 H, 5-H); 4.70 (dd, 1 H,
1330, 1250, 1160, 1100 cmϪ1. Elemental analysis: C15H14O3 J1 ϭ 8.0, J2 ϭ 3.0 Hz, 1-H); 4.12 (m, 1 H, 3-H1); 3.76 (m, 1 H, 3-
(242.26) Calcd C 74.36, H 5.82; found C 74.13, H 5.93. [M Ϫ H2); 2.94 (m, 1 H, 4-H1); 2.64 (m, 1 H, 4-H2); n-butyl moiety: 1.80
H]Ϫ ϭ 241.2; product ions: 193.2 and 211.2.
(m, 2 H, 1Ј-H); 1.45 (4 H, 2Ј-,3Ј-H); 0.93 (t, 3 H, 4Ј-H). 13C NMR
3410
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3407Ϫ3411

One-Pot Synthesis of 6-Hydroxyisochromans
FULL PAPER
(CDCl3): 153.6 (C-6); 135.4 (C-4a*); 130.8 (C-8a*); 126.0 (C-8); 1-(p-Methoxycarbonylphenyl)-6-hydroxyisochroman (29): The reac-
114.9, 113.4 (C-5 and C-7); 75.8 (C-1); 63.0 (C-3); 35.8 (C-1Ј); 29.4 tion was only carried out according to protocol A. Yield: 90%
(C-4); 27.5 (C-2Ј); 22.9 (C-3Ј); 14.2 (C-4Ј) ppm. IR (CHCl3): ν˜ ϭ (37 mg). m.p. 147Ϫ148 °C. 1H NMR (CDCl3): 8.20 (2 H, 3Ј-,5Ј-
3300, 2920, 1680, 1660, 1560, 1460, 1390, 1270, 1130, 1090 cmϪ1
.
H); 7.32 (2 H, 2Ј-,6Ј-H); 6.64Ϫ6.56 (3 H, 5-,7-,8-H); 5.73 (s, 1 H,
1-H); 4.18 (m, 1 H, 3-H1); 3.99 (m, 1 H, 3-H2); 3.97 (s, 3 H, OCH3);
3.10 (m, 1 H, 4-H1); 2.78 (m, 1 H, 4-H2) ppm. 13C NMR (CDCl3)
ppm: 167.0 (CϭO), 154.4 (C-6); 147.2 (C-1Ј); 135.1 (C-4a); 129.7
(C-3Ј and C-5Ј); 128.7 (C-2Ј* and C-6Ј*); 128.7 (C-8a*); 128.4 (C-
4Ј); 127.8 (C-8); 114.9 (C-5); 113.5 (C-7); 78.9 (C-1); 63.8 (C-3);
52.2 (OCH3), 28.9 (C-4) ppm. IR (CHCl3): ν˜ ϭ 3600, 3400, 2950,
1720, 1620, 1510, 1450, 1280, 1130, 1090 cmϪ1. Elemental analysis:
C17H16O4 (284.30) calcd C 71.82, H 5.67; found C 71.77, H 5.71.
[M Ϫ H]Ϫ ϭ 283.1; product ions: 193.0 and 89.0.
Elemental analysis: C13H18O2 (206.27) calcd C 75.69, H 8.80; found
C 75.57, H 8.94. [M Ϫ H]Ϫ ϭ 205.2; product ions: 175.0.
1-[3Ј,4Ј-(Methylenedioxy)phenyl]-6-hydroxyisochroman (27): The re-
action was only carried out according to protocol A. Yield: 98%
1
(38 mg). H NMR (CDCl3) ppm: 6.83Ϫ6.73 and 6.65Ϫ6.51 (6 H,
8-,7-,5-,5Ј-,2Ј-,6Ј-H); 5.92 (2 H, dioxy-methylene group); 5.62 (br.
s, 1 H, 1-H); 4.16 (m, 1 H, 3-H1); 3.89 (m, 1 H, 3-H2); 3.05 (m, 1
H, 4-H1); 2.71 (m, 1 H, 4-H2) ppm. 13C NMR (CDCl3): 154.3 (C-
6); 147.6 and 147.3 (C-3Ј and C-4Ј); 136.1 and 135.1 (C-4a* and C-
1Ј*); 129.0 (C-8a*); 128.0 (C-8); 122.5 (C-6Ј); 114.7 (C-5); 113.4 (C-
7); 109.0 (C-5Ј); 107.7 (C-2Ј); 100.9 (acetalic carbon); 79.2 (C-1);
63.5 (C-3); 28.9 (C-4) ppm. IR (CHCl3): ν˜ ϭ 3600, 3350, 3000,
2900, 1720, 1620, 1500, 1450, 1380, 1300, 1240, 1140, 1090, 1040
cmϪ1. Elemental analysis: C16H14O4 (270.27) calcd C 71.10, H 5.22;
found C 70.98, H 5.36. [M Ϫ H]Ϫ ϭ 269.2; product ions: 239.0.
Acknowledgments
Financial support was provided by Ministero dellЈIstruzione
`
dellЈUniversita e della Ricerca (MIUR) and Consiglio Nazionale
delle Ricerche (CNR).
1-(p-Chlorophenyl)-6-hydroxyisochroman (28): The reaction was
1
only carried out using protocol A. Yield: 95% (36 mg). H NMR
[1]
(CDCl3): 7.40Ϫ7.25 (4 H, 2Ј-,3Ј-,5Ј-,6Ј-H); 6.70Ϫ6.50 (3 H, 5-,7-,
-8-H); 5.70 (s, 1 H, 1-H); 4.18 (m, 1 H, 3-H1); 3.90 (m, 1 H, 3-H2);
3.10 (m, 1 H, 4-H1); 2.75 (m, 1 H, 4-H2) ppm. 13C NMR (CDCl3):
154.4 (C-6); 140.7 (C-1Ј); 135.3 (C-4a); 133.8 (C-4Ј); 130.0, (C-2Ј
and C-6Ј); 129.0 (C-8a); 128.5 (C-3Ј and C-5Ј); 128.0 (C-8); 114.8
(C-5); 113.4 (C-7); 78.7 (C-1); 63.7 (C-3); 28.9 (C-4) ppm. IR
(CHCl3): ν˜ ϭ 3600, 3300, 2950, 1660, 1620, 1500, 1450, 1300, 1240,
1140, 1090 cmϪ1. Elemental analysis: C15H13ClO2 (260.70) calcd C
69.10, H 5.03, Cl 13.60; found C 68.98, H 5.24, Cl 13.42. [M Ϫ
H]Ϫ ϭ 259.0; product ions: 229.0.
P. M. Dewick, Medicinal Natural Products, 1998, Wiley, Chich-
ester.
[2]
A. Pictet, T. Spengler, Ber. 1911, 44, 2030Ϫ2036.
[3]
B. Wunsch, M. Zott, Liebigs Ann. Chem. 1992, 39Ϫ45.
[4]
M. Guiso, C. Marra, C. Cavarischia, Tetrahedron Lett. 2001,
42, 6531Ϫ6534.
[5]
A. Bianco, G. Righi, P. Passacantilli, Synth. Commun. 1988,
18(5), 1765Ϫ1771.
S. L. Hazen, F. F. Hsu, J. W. Heinecke, J. Biol. Chem. 1996,
271, 1861Ϫ1867.
[6]
Received March 17, 2003
Eur. J. Org. Chem. 2003, 3407Ϫ3411
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3411