The oxa-Pictet-Spengler reaction: A highlight on the different efficiency between isochroman and phthalan or homoisochroman derivative syntheses

Article abstract of DOI:10.1002/ejoc.200700692

Recently we reported that 6-hydroxy- and 6,7-dihydroxy-isochromans can be obtained under very mild conditions and with very good yield by a one-pot synthesis based on a modified oxa-Pictet-Spengler reaction. In this paper, we demonstrate that the above reaction is also useful for the synthesis of hydroxyphthalans, and we discuss the effects of the substituents on the alcoholic aromatic ring on the course of the reaction, as well as those on the aldehydic structure. We also report a synthesis of hydroxyhomoisochromans performed by the same method. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700692

FULL PAPER
DOI: 10.1002/ejoc.200700692
The Oxa-Pictet–Spengler Reaction: A Highlight on the Different Efficiency
between Isochroman and Phthalan or Homoisochroman Derivative Syntheses
Marcella Guiso,[a] Abduelhakem Betrow,[a] and Carolina Marra*[a]
Keywords: Fused-ring systems / Oxygen heterocycles / Synthetic methods
Recently we reported that 6-hydroxy- and 6,7-dihydroxy-
isochromans can be obtained under very mild conditions and
with very good yield by a one-pot synthesis based on a modi-
stituents on the alcoholic aromatic ring on the course of the
reaction, as well as those on the aldehydic structure. We also
report a synthesis of hydroxyhomoisochromans performed by
fied oxa-Pictet–Spengler reaction. In this paper, we demon- the same method.
strate that the above reaction is also useful for the synthesis
of hydroxyphthalans, and we discuss the effects of the sub-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
aldehydes and a yield of about 70% was obtained with ali-
phatic aldehydes; (4) steric hindrance in the heterocyclic
ring closure is of importance: ortho-substituted aromatic al-
dehydes or aliphatic ketones afforded the corresponding
isochromans in about 60% yield, whereas aromatic ketones
were unreactive; (5) the yield was improved when a dehy-
drating agent was added to the reaction mixture; (6) the
reaction temperatures ranged from 4 to 25 °C according to
the reagents used; (7) it is possibility to perform this reac-
tion with a very mild acid catalyst, such as oleic acid, and
also by using extra virgin olive oil as the solvent, which is
a very different medium than methanol (the solvent usually
employed).
Introduction
In previous papers,[1,2] we reported the high-yield synthe-
sis, performed under very mild conditions, of a series of 1-
substituted hydroxyisochromans from suitable hydroxy-
phenylethyl alcohols and carbonyl compounds. This one-
pot synthesis is based on a modified oxa-Pictet–Spengler
reaction,[3–5] in which the aromatic carbon atom involved
in the heterocyclic ring closure is strongly activated by a
para-hydroxy or a para-methoxy functionality and thus acts
as a nucleophile. Here we report the synthesis of 1-substi-
tuted hydroxyphthalans and 1-substituted hydroxyhomo-
isochromans performed by the same reaction in order to
verify if this synthetic pathway could still be successfully
applied to obtain different heterocyclic ring structures.
In the cited papers,[1,2] we rationalized the course of our
modified oxa-Pictet–Spengler reaction, which afforded hy-
droxyisochromans, according to Scheme 1 and we pointed
out the following reaction features: (1) the presence an acti-
vating group, such as a hydroxy group, in the para position
to the carbon atom involved in the heterocyclic ring closure
is compulsory on the alcoholic reagent aromatic ring; (2)
there was no difference in yield by using 3-hydroxy- over
In addition we proved that hydroxyisochromans could
spontaneously form in extra virgin olive oil by the isolation,
from this matrix,[4] of small amounts of 1-phenyl-6,7-dihy-
droxyisochroman and 1-(4-hydroxy-3-methoxy-phenyl)-6,7-
dihydroxyisochroman.
Results and Discussion
The phthalan (1,3-dihydroisobenzofuran) structure is im-
3,4-dihydroxyphenylethyl alcohol; (3) a yield of Ն90% was portant (Figure 1), not only because it is present in some
obtained when the reaction was performed with aromatic natural compounds[5] but also because it is a good synthon
Scheme 1. Synthesis of isochromans.
for obtaining complex molecules.[6–18] In recent years, these
compounds were studied for their antihistamine,[21] anti-
[a] Dipartimento di Chimica Università “Sapienza” di Roma
Piazzale Aldo Moro 5, 00185 Roma Italy
depressant,[22–24] and other biological or pharmacological
Fax: +39-0649631
E-mail: carolina.marra@uniroma1.it
activities.[19,20] Moreover, some phthalan derivatives are uti-
Eur. J. Org. Chem. 2008, 1967–1976
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1967

M. Guiso, A. Betrow, C. Marra
FULL PAPER
lized in the agricultural industry as herbicides[25] and fungi- ucts arising from electrophilic aromatic substitution on the
cides;[26–28] other uses include colorants[29] and perfumes.[30] strongly activated alcoholic ring, mainly if aliphatic or para-
Many methods to synthesize phthalans have been re- donor substituted aromatic aldehydes were used. The for-
viewed.[31,32] Most of these are based on a nucleophilic sub- mation of these last by-products was generally prevented by
stitution reaction, which results in intramolecular cycliza- using chloroacetic acid as the catalyst instead of p-tolu-
tion. Starting compounds are, for example, o-phthalyl enesulfonic acid. Obtained phthalans and relative yield are
alcohol[33–37] or o-phthalyl halides.[38–43]
listed in Table 1.
The data shown in Table 1 show that: (1) Phthalan deriv-
atives were always obtained with a lower yield than those
of the isochromans prepared from the same aldehyde,
mainly when an aliphatic aldehyde was used. (2) Best yields
were achieved by using 3-hydroxybenzylalcohol (1). When
we tried to react 2 with an aliphatic aldehyde only the di-
arylation product arising from the electrophilic aromatic
substitution at C-4 was obtained. No phthalan derivative
was detected (Scheme 3).
Figure 1. 1,3-Dihydroisobenzofuran.
We synthesized hydroxyphthalans under the same condi-
tions used for the synthesis of isochromans (see Experimen-
tal Section), but in some cases the temperature was in-
creased to 38 °C. We used 3-hydroxybenzyl alcohol (1), 3,5-
dihydroxybenzyl alcohol (2), and 3,5-dimethoxybenzyl
alcohol (3) and a group of aromatic, as well as aliphatic,
aldehydes chosen from those successfully used for the syn-
thesis of isochromans. The use of 3,4-dihydroxybenzyl
alcohol, which has the same substitution pattern of hy-
droxytyrosol used in the synthesis of isochromans, was ob-
viously impossible owing to the quick formation of its
stable benzylic carbocation, which subsequently afforded an
Scheme 3. Reaction involving the use of aliphatic aldehydes.
In addition, the reaction times were strongly dependent
ether derivative. The use of an aprotic solvent instead of on the structures of both reagents. When we used alcohol
methanol did not increase the yield of phthalan, but low- 1, the reaction with any aldehyde went on for about a week
ered it instead. A possible reaction pathway is shown in at 37 °C; therefore, these reactions were performed under
Scheme 2.
an atmosphere of argon to avoid aldehyde oxidation. When
Phthalans obtained from the above benzyl alcohols were we used alcohol 2, reaction times and temperatures were
always accompanied by aldehyde acetals (methyl and mixed dependent on the aldehyde structure. The reaction per-
acetals that we omitted in this paper for brevity) and those formed with electron-withdrawing-substituted aromatic al-
prepared from 2 and 3 were also accompanied by side prod- dehydes required (with para-toluenesulfonic acid as a cata-
Scheme 2. Synthesis of phthalans.
1968
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1967–1976

Isochroman and Phthalan or Homoisochroman Derivative Syntheses
Table 1. Oxa-Pictet–Spengler synthesis of phthalans.
R1
R2
R3
R4
R5
Yield [%]
T [°C]
t [h]
Product
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OCH3
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
OCH3
60
56
62
55
50
55
61
61
55
25
61
57
61
50
38
38
38
38
38
38
38
38
38
38
38
38
38
4
48
48
48
48
48
48
48
48
48
48
48
48
48
2
7
8
OCH3
OCH3
OCH2O
OH
NO2
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
OCH3
H
NO2
OCH3
H
H
OCH3
OCH3
R6 = CH3(CH2)3
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OCH3
OCH3
OCH3
H
H
H
H
H
H
OCH3
OCH3
H
H
H
H
H
NO2
Cl
H
H
OH
OCH3
H
OCH3
OH
OCH2O
N(CH3)2
NO2
OCH2O
H
H
H
NO2
H
H
15/29[a]
27/48[a]
33/57[a]
33/58[a]
17/33[a]
25/45[a]
32
45
43
47
4/38[a]
4/38[a]
4/38[a]
4/38[a]
4/38[a]
4/38[a]
4
38
38
38
2/48[a]
2/48[a]
2/48[a]
2/48[a]
2/48[a]
2/48[a]
2
48
48
48
H
OCH3
OCH3
OCH3
H
H
OCH3
OCH3
[a] Data obtained by using chloroacetic acid as the catalyst.
lyst), at least 2 d and 37 °C, whereas those performed with six-membered ring could undergo closure avoided the pos-
electron-donating-substituted aromatic aldehydes required sibility of side reactions, as demonstrated by the formation
only a few minutes to a few hours at 4 °C. In this case, to of isochroman 33 (90% yield) by treating 2-(3,5-dimeth-
avoid the simultaneous electrophilic aromatic substitution oxyphenyl)ethanol with piperonal. In this reaction, in fact,
reaction, a milder catalyst, such as chloroacetic acid, was no byproduct was detected. On the contrary, when aliphatic
used. The reaction time obviously increased.
aldehydes are involved, the difficult closure of the phthalan
As previously reported, the hypothetical reaction path- ring shifts the equilibrium to the formation of the less-hin-
way for the synthesis of hydroxyisochromans could proceed dered acetals and of the arylation products. The formation
by preliminary carbocation formation at the C-1 aldehydic of only 31 and 32 could support this hypothesis. The aro-
carbon atom; in addition, the attack could happen at the matic aldehydes may provide some minor steric hindrance
protonated hemiacetalic or acetalic structure (Scheme 1). in the closure of the phthalan ring. Among these, the ones
This synthetic way is also in accordance with the Baldwin having electron-donating substituents contemporaneously
rules,[44,45] which favor 6-endo-trig and the 6-exo-tet ring form also the arylation products, probably by the great sta-
closure. The synthesis of the phthalans could follow the bility of the intermediate carbocation. On the contrary,
same pathway, but in this case, the 5-endo-trig path is not those with electron-withdrawing substituents give only the
favored. In addition, the steric hindrance shown by the sub- oxa-Pictet–Spengler reaction.
stituents at the aldehydic C-1 atom during the closure of
The synthesis of hydroxyhomoisochromans, performed
the unsaturated five-membered ring could hamper the com- under the same conditions, gave poor yield (see Table 2). In
pound from adopting the correct orientation. Therefore, in this case, the seven-membered ring closure is hampered by
the synthesis of isochromans, the great ease with which the the relatively low probability of achieving the required mo-
Eur. J. Org. Chem. 2008, 1967–1976
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1969

M. Guiso, A. Betrow, C. Marra
FULL PAPER
versed. Purification of the products was achieved by solid-liquid
column chromatography on Merck 0.063–0.20 nm silica gel treated
with diluted HCl, then washed with hot water to eliminate Cl– ions,
dried and activated at 120 °C for 24 hrs. Silica gel was treated with
10% of water before using. The eluting solutions were determined
on a case by case basis. TLC was performed on Silica gel 60 F254
Merck plates and visualized by spraying with 2  H2SO4 and heat-
ing. Microanalyses were performed with a CE Instrument. MS
analyses were performed with a triple quadrupole PE-SCIEX API
365 (Perkin–Elmer Sciex Instruments Foster City, CA USA),
equipped with Turboin Spray interface in negative-ion mode. Melt-
ing points were determined with a Mettler FP 80 apparatus. All
reagents were purchased from Fluka, and all solvents were pur-
chased from Carlo Erba. IR spectra were obtained with a infrared
spectrophotometer IR-470, Shimadzu by using 1% concentration;
CHCl3 was used as the solvent, and it was passed through a Al2O3
column before use.
lecular orientation. It should be noted that the yield ob-
tained by using 3-(3,4-dihydroxyphenyl)-1-propanol (5) is
generally higher than that obtained with 3-(3-hy-
droxyphenyl)-1-propanol (6).
Table 2. Oxa-Pictet–Spengler synthesis of homoisochromans.[a]
R1
R2
R3
R4
R5
Yield [%] Product
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
OCH3
Cl
NO2
OCH2O
OH
OCH3
H
H
H
H
H
45
44
41
43
45
42
40
45
45
35
21
20
25
21
21
22
22
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
m-Hydroxybenzyl Alcohol (1): m-OH benzaldehyde (100 mg, ca.
0.82 mmol) was suspended in water (3 mL) and then an excess
amount of NaBH4 (63 mg, ca. 1.7 mmol) was added over the
course of 30 min at room temperature. The excess amount of
NaBH4 was destroyed by slowly adding HCl (6 ) to the chilled
solution until it reached pH = 5. The water solution was extracted
with EtOAc, 3ϫ20 mL), and the combined organic layer was
washed with a brine solution until neutrality. The residue obtained
after evaporation in vacuo of the volatile material (110 mg) con-
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
NO2
OCH3 OCH3
H
H
H
H
H
H
H
H
COOCH3
H
OCH3
Cl
NO2
H
1
tained pure 1 as checked by its H NMR spectrum in CDCl3.
General Synthesis of 1,3-Dihydroisobenzofuran-5-ol, 1,3-Dihydroiso-
benzofuran-5,7-diol, 1,3-Dihydro-5,7-dimethoxyisobenzofuran, 6,8-
Dimethoxyisochroman,
Benzo-2-oxacycloheptene-7,8-diol,
and
OCH2O
N(CH3)2
Benzo-2-oxacycloheptene-7-ol Derivatives: Alcohol 1, 2, 3, 4, 5,or 6
(30 mg, respectively, 0.24 mmol, 0.21 mmol, 0.16 mmol, 0.17 mmol,
0.19 mmol, 0.18 mmol), was dissolved in anhydrous methanol
(1 mL) and an equimolar quantity of aldehyde was added together
with catalytic amounts of p-toluenesulfonic acid and anhydrous
Na2SO4 (100 mg) or molecular sieves. Reaction times and tempera-
tures were different according to the utilized aldehydes (Tables 1
and 2). Reactions requiring longer periods were performed under
an atmosphere of Ar. After chromatographic control on a silica-
gel plate, the volume of the reaction mixture was cut in half under
reduced pressure at low temperature and then diluted with EtOAc,
25 mL). The organic layer was washed with a brine solution until
neutrality, and the residue obtained after evaporation in vacuo of
the volatile material was purified on a silica-gel (ratio 1:100) col-
umn by eluting with different solvents mixture. The reactions were
also carried out by using a greater concentration (1 g of 1, 2, 3, 4,
5, or 6 dissolved in 9 mL of anhydrous MeOH), and the obtained
products and yields were unchanged.
H
[a] The reactions were carried out at 37 °C for one week.
Conclusions
The above-reported results show that our modification
of the oxa-Pictet–Spengler reaction may be useful to syn-
thesize hydroxyphthalans and hydroxyhomoisochromans
even if the yields are less satisfactory than those for hy-
droxyisochromans. It is noteworthy, in this case, that the
closure of a five-membered ring appears more difficult than
that of γ-lactone rings,[46] but the double bond presence in
the intermediate and the steric hindrance of the aldehydic
residue may hamper the closure. The low yields found in
the synthesis of hydroxyhomoisochromans are in agreement
with the difficulties involved in achieving the required mo-
lecular orientation. Therefore, this synthetic way is less
interesting with the use of the described experimental con-
ditions and could hamper the spontaneous formation of
both kinds of compounds, contrary to what was found for
hydroxyisochromans.
1-Phenyl-1,3-dihydroisobenzofuran-5-ol (7): The reaction was car-
ried out as reported in the general procedure. The residue was puri-
fied on silica gel (CHCl3/EtOAc, 8:2) to afford pure 7 (31 mg,
1
0.15 mmol, 60%). H NMR (300 MHz, CDCl3): δ = 7.26–7.36 (5
H, ArH), 6.84 (d, J = 8.1 Hz, 1 H, 7-H), 6.68 (br. s, 1 H, 4-H),
6.66 (dd, J6,7 = 8.1 Hz, J6,4 = 2.1 Hz, 1 H, 6-H), 6.09 (br. s, 1 H,
1-H), 5.24 (dd, J3b,3a = 12.0 Hz, J3b,1 = 2.4 Hz, 1 H, 3b-H), 5.11
(d, J3a,3b = 12.0 Hz, 1 H, 3a-H) ppm. 13C NMR (75 MHZ, CDCl3):
δ = 155.6 (C-5), 142.0 (C-3a),; 140.7 (C-1Ј), 133.8 (C-7a), 128.4 (C-
2Ј and C-6Ј), 128.0 (C-4Ј), 126.9 (C-3Ј and C-5Ј), 123.1 (C-7), 114.9
Experimental Section
General Remarks: 1H and 13C NMR spectra were measured with a
Varian Mercury 300 MHz spectrometer, chemical shifts are ex-
pressed in ppm relative to TMS and J values are quoted in Hz.
NMR spectroscopic data marked with an asterisk (*) may be re-
(C-6), 107.6 (C-4), 85.9 (C-1), 72.9 (C-3) ppm. IR (CHCl ): ν =
˜
3
3600, 3320, 2980, 1610, 1460, 1370, 1250, 1120, 1020 cm–1. MS:
m/z = 213.2 [M – H]–. C14H12O2 (212.25): calcd. C 79.23, H 5.70;
found C 79.04, H 5.75.
1970
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Eur. J. Org. Chem. 2008, 1967–1976

Isochroman and Phthalan or Homoisochroman Derivative Syntheses
1-(4Ј-Chlorophenyl)-1,3-dihydroisobenzofuran-5-ol (8): The reaction
was carried out as reported in the general procedure. The residue
CDCl3): δ = 6.68–6.94 (6 H, ArH), 6.05 (br. s, 1 H, 1-H), 5.25 (dd,
J3b,3a = 12.4 Hz, J3b,1 = 2.2 Hz, 1 H, 3b-H), 5.13 (d, J3a,3b
12.4 Hz, 1 H, 3a-H), 3.84 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz,
=
was purified on silica gel (CHCl3/EtOAc, 9:1) to afford pure 8
1
(33 mg, 0.13 mmol, 56%). H NMR (300 MHZ, CDCl3): δ = 7.30 CDCl3): δ = 158.3 (C-5), 156.2 (C-4Ј), 149.3 (C-3Ј), 141.2 (C-3a),
(d, J3Ј,5Ј = 8.4 Hz, 2 H, 3Ј-H, 5Ј-H), 7.23 (d, J2Ј,6Ј = 8.4 Hz, 2 H,
2Ј-H, 6Ј-H), 6.82 (d, J7,6 = 8.2 Hz, 1 H, 7-H), 6.71 (br. s, 1 H, H-
135.3 (C-1Ј), 131.3 (C-7a), 128.4 (C-7), 119.3 (C-6Ј), 115.3* (C-6),
111.2 (C-2Ј), 108.7 (C-5Ј), 107.3 (C-4), 85.5 (C-1), 72.5 (C-3), 55.4
4), 6.67 (br. d, J6,7 = 8.2 Hz, 1 H, 6-H), 6.05 (br. s, 1 H, 1-H), 5.23 (OCH ) ppm. IR (CHCl ): ν = 3300, 2950, 1670, 1530, 1470, 1350,
˜
3
3
(dd, J3b,3a = 12.3 Hz, J3b,1 = 2.1 Hz, 1 H, 3b-H), 5.12 (d, J3a,3b
=
1130 cm–1. MS: m/z = 257.3 [M – H]–. C15H14O4 (258.27): calcd. C
12.3 Hz, 1 H, 3a-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.7
(C-5), 141.1* (C-3a), 140.9* (C1Ј), 134.0 (C-4Ј), 133.8* (C-7a),
128.7 and 128.3 (C-2Ј, C-3Ј, C-5Ј, C-6Ј), 123.1 (C-7), 115.0 (C-6),
69.76, H 5.46; found C 69.38, H 5.55.
1-(4Ј-Nitrophenyl)-1,3-dihydroisobenzofuran-5-ol (13): The reaction
was carried out as reported in the general procedure. The obtained
oil product was purified on silica gel (CHCl3/EtOH, 95:5) to afford
13 (38 mg, 0.15 mmol, 61%). 1H NMR (300 MHz, CD3COCD3):
δ = 8.22 (d, J = 8.7 Hz, 2 H, 3Ј-H, 5Ј-H), 7.67 (d, J = 8.7 Hz, 2 H,
107.8 (C-4), 85.2 (C-1), 73.0 (C-3). IR (CHCl ): ν = 3600, 3300,
˜
3
2850, 1660, 1600, 1500, 1460, 1360, 1290, 1190, 1080, 1020 cm–1.
MS: m/z = 245.7 [M – H]–. C14H11ClO2 (246.69): calcd. C 68.16,
H 4.49, Cl 14.37; found C 67.84, H 4.57, Cl 14.20.
2Ј-H, 6Ј-H), 6.94 (d, J6,7 = 8.4 Hz, 1 H, 7-H), 6.82 (d, J6Ј,4Ј
=
1-(4Ј-Methoxyphenyl)-1,3-dihydroisobenzofuran-5-ol (9): The reac-
tion was carried out as reported in the general procedure. The resi-
due was purified on silica gel (CHCl3/EtOAc, 8:2) to afford pure 9
(36 mg, 0.15 mmol, 62%). H NMR (300 MHz, CDCl3): δ = 7.25
(d, J2Ј,6Ј = 8.8 Hz, 2 H, 2Ј-H and 6Ј-H), 6.87 (d, J3Ј,5Ј = 8.8 Hz, 2
H, 3Ј-H and 5Ј-H), 6.85 (d, J6,7 = 7.8 Hz, 1 H, 7-H), 6.70 (d, J6,7
2.4 Hz, 1 H, 4-H), 6.73 (dd, J6,7 = 8.4 Hz, J6,4 = 2.4 Hz, 1 H, 6-
H), 6.21 (s*, 1 H, 1-H), 5.29 (dd, J3b,3a = 12.6 Hz, J3b,1 = 2.7 Hz,
1 H, 3b-H), 5.11 (d, J3a,3b = 12.3 Hz, 1 H, 3a-H) ppm. 13C NMR
(75 MHz, CD3COCD3): δ = 158.4 (C-5), 151.7 (C-4Ј), 141.4 (C-
3a), 132.8 (C-7a), 127.9 (C-7Ј and C-6Ј) 124.2 (C-3Ј), 123.4 (C-7),
115.7 (C-6), 124.2 (C-3Ј and C-5Ј), 85.0 (C-1), 73.9 (C-3) ppm. IR
1
= 7.8 Hz, 1 H, 6-H), 6.73 (s, 1 H, 4-H), 6.08 (br. s, 1 H, 1-H), 5.24 (CDCl ): ν = 3600, 3300, 2850, 1660, 1600, 1500, 1460, 1360, 1290,
˜
3
(dd, J3a,3b = 12.2 Hz, J3b,1 = 2.2 Hz, 1 H, 3b-H), 5.12 (d, J3a,3b
=
1190, 1080, 1020 cm–1. MS: m/z = 256.23 [M – H]–. C14H11NO4
12.2 Hz, 1 H, 3a-H), 3.79 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, (257.25): calcd. C 65.37, H 4.31, N 5.44; found C 64.80, H 3.93, N
CDCl3): δ = 157.0 (C-4Ј), 155.9 (C-5), 141.2 (C-3a), 134.5 (C-1Ј), 5.13.
131.2 (C-7a), 128.6 (C-7), 123.3 (C-2Ј and C-6Ј), 115.0* (C-6),
1-(3Ј-Nitrophenyl)-1,3-dihydroisobenzofuran-5-ol (14): The reaction
114.1* (C-4), 107.8 (C-3Ј and C-5Ј), 85.7 (C-1), 72.7 (C-3), 55.4
was carried out as reported in the general procedure. The obtained
(methoxy carbon) ppm. IR (CHCl ): ν = 3320, 2960, 1650, 1520,
˜
3
oil product was purified on silica gel (CHCl3/EtOH, 95:5) to afford
14 (38 mg, 0.15 mmol, 61%). 1H NMR (300 MHz, CD3COCD3):
δ = 8.21 (t, J = 1.8 Hz, 1 H, 2Ј-H), 8.15 (dm, 1 H, 4Ј-H), 7.83 (d*,
1 H, 6Ј-H), 7.65 (t, J = 8.1 Hz, 1 H, 5Ј-H), 6.94 (d, J = 8.1 Hz, 1
H, 7-H), 6.82 (s*, 1 H, 4-H), 6.73 (dd, J = 8.4 Hz, J = 2.4 Hz, 1
1480, 1280, 1130 cm–1. MS: m/z = 241.2 [M – H]–. C15H14O3
(242.27): calcd. C 74.36, H 5.82; found C 74.28, H 5.90.
1-(3Ј,4Ј-Dimethoxyphenyl)-1,3-dihydroisobenzofuran-5-ol (10): The
reaction was carried out as reported in the general procedure. The
residue was purified on silica gel (CHCl3/EtOAc, 8:2) to afford pure
H, 6-H), 6.22 (s*, 1 H, 1-H), 5.29 (dd, J3a,3b = 12.6 Hz, J3b,1
=
10 (36 mg, 0.13 mmol, 55%). 1H NMR (300 MHz, CDCl3): δ = 2.7 Hz, 1 H, 3b-H), 5.11 (d, J3a,3b = 12.6 Hz, 1 H, 3a-H) ppm. 13C
6.7–6.9 (6 H, ArH), 6.09 (s*, 1 H, 1-H), 5.25 (d*, J3a,3b = 12.3 Hz,
1 H, 3a-H), 5.12 (d, J3a,3b = 12.3 Hz, 1 H, 3b-H), 3.85 (s, 3 H,
NMR (75 MHz, CD3COCD3): δ = 157.9 (C-5), 148.7 (C-3Ј), 146.1
(C-1Ј), 141.0 (C-3a), 132.3 (C-2Ј), 132.9 (C-7a) 129.9 (C-4Ј), 123.0
OCH3), 3.90 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ (C-7), 122.5 (C-6Ј), 121.0 (C-5Ј), 115.1 (C-6), 107.9 (C-4), 84.4 (C-
= 155.4 (C-5), 149.1 (C3Ј and C-4Ј), 141.2 (C-3a), 134.6 (C-1Ј), 1), 73.1 (C-3) ppm. IR (CDCl ): ν = 3600, 3300, 2850, 1660, 1600,
˜
3
134.3 (C-7a), 123.2 (C-7), 119.5 (C-6Ј), 114.8 (C-6), 110.9 (C-2Ј), 1500, 1460, 1360, 1290, 1190, 1080, 1020 cm–1. MS: m/z = 256.3
110.2 (C-5Ј), 107.7 (C-4), 85.8 (C-1), 72.7 (C-3), 56.0 and 55.9 [M – H]–. C14H11NO4 (257.25): calcd. C 65.37, H 4.31, N 5.44;
(methoxy carbons). IR (CHCl ): ν = 3300, 2950, 1660, 1520, 1460, found C 64.90, H 3.97, N 5.10.
˜
3
1280, 1130 cm–1. MS: m/z = 271.3 [M – H]–. C16H16O4 (272.30):
calcd. C 70.58, H 5.92; found C 70.22, H 6.07.
1-(3Ј,4Ј,5Ј-Trimethoxyphenyl)-1,3-dihydroisobenzofuran-5-ol (15):
The reaction was carried out as reported in the general procedure.
1-(3Ј,4Ј-Methylenedioxyphenyl)-1,3-dihydroisobenzofuran-5-ol (11): The obtained oil product was purified on silica gel (CHCl3/EtOAc,
The reaction was carried out as reported in the general procedure.
8:2) to afford 15 (36 mg, 0.13 mmol, 55%). 1H NMR (300 MHz,
CDCl3): δ = 6.89 (d, J6,7 = 8.1 Hz, 1 H, 7-H), 6.72 (s*, 1 H, 4-H),
The residue was purified on silica gel (CHCl3/EtOAc, 8:2) to afford
1
pure 11 (31 mg, 0.12 mmol, 50%). H NMR (300 MHz, CDCl3): δ 6.70 (dd, J7,6 = 8.1 Hz, J6,4 = 2.1 Hz, 1 H, 6-H), 6.54 (s, 2 H, 2Ј-
= 6.85 (d, J6Ј,5Ј = 7.8 Hz, 1 H, 6Ј-H), 6.83 (d, J7,6 = 8.4 Hz, 1 H,
H and 6Ј-H), 6.03 (s*, 1 H, 1-H), 5.24 (dd, J3b,3a = 12.0 Hz, J3b,1
7-H), 6.78 (d, J5Ј,6Ј = 7.8 Hz, 1 H, 5Ј-H), 6.71 (br. s, 2 H, 4-H, 2Ј- = 2.4, 1 H, 3b-H), 5.12 (d, J3a,3b = 12.0 Hz, 1 H, 3a-H), 3.81and
H), 6.69 (d, J6,7 = 8.4 Hz, 1 H, 6-H), 6.02 (br. s, 1 H, 1-H), 5.93
(s, 2 H, OCH2O), 5.22 (dd, J3b,3a = 12.6 Hz, J3b,1 = 1.8 Hz, 1 H,
3b-H), 5.09 (d, J3a,3b = 12.6, 1 H, 3a-H) ppm. 13C NMR (75 MHz,
3.82 (s, 9 H, 3 OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.8
(C-5), 153.2 (C-3Ј and C-5Ј), 140.9 (C-3a and C-4Ј), 137.7 (C-1Ј),
133.3 (C-7a), 123.0 (C-7), 114.9 (C-6), 107.7 (C-4), 104.0 (C-2Јand
CDCl3): δ = 162.8 (C-5), 155.4 (C-3Ј), 147.4 (C-4Ј), 141.5 (C-3a), C-6Ј), 86.0 (C-1), 72.8 (C-3), 60.8 (OCH3), 56.1 (2 OCH3) ppm. IR
140.9 (C-7a), 136.1 (C-1Ј), 123.1 (C-7), 120.6 (C-6Ј), 114.8 (C-6), (CDCl ): ν = 3300, 2950, 1660, 1520, 1460, 1280, 1130 cm–1. MS:
˜
3
107.9* (C-2Ј), 107.5* (C-5Ј), 107.4* (C-4), 100.9 (dioxymethylene
m/z = 301.3 [M – H]–. C17H18O5 (302.33): calcd. C 67.54, H 6.00;
carbon), 85.7 (C-1), 72.6 (C-3) ppm. IR (CHCl ): ν = 3300, 2950,
found C 67.15, H 5.89.
˜
3
1660, 1520, 1480, 1360, 1130 cm–1. MS: m/z = 255.3 [M – H]–.
1-Butyl-1,3-dihydroisobenzofuran-5-ol (16): The reaction was car-
ried out as reported in the general procedure. The residue was puri-
fied on silica gel (CHCl3/EtOAc, 8:2) to afford pure 16 (12 mg,
C15H12O4 (256.26): calcd. C 70.31, H 4.72; found C 70.03, H 4.81.
1-(4Ј-Hydroxy-3Ј-methoxyphenyl)-1,3-dihydroisobenzofuran-5-ol
(12): The reaction was carried out as reported in the general pro-
cedure. The residue was purified on silica gel (CHCl3/EtOAc, 9:1)
1
0.06 mmol, 25%). H NMR (300 MHz, CDCl3): δ = 6.76 (d, J =
8.4 Hz, 1 H, 7-H), 6.72 (d, J = 8.4 Hz, 1 H, 6-H), 6.70 (s, 1 H, 4-
H), 5.35 (t, J = 7.2 Hz, 1 H, 1-H), 4.43 (d, J3a,3b = 12.6 Hz, 1
1
to afford pure 12 (34 mg, 0.13 mmol, 55%). H NMR (300 MHz,
Eur. J. Org. Chem. 2008, 1967–1976
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1971

M. Guiso, A. Betrow, C. Marra
FULL PAPER
H, 3a-H), 4.09 (d, J3a,3b = 12.6 Hz, 1 H, 3b-H), 2.82–1.83 (9 H,
CH2CH2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.0
(C-5), 141.8 (C-3a), 132.9 (C-7a), 123.1 (C-7), 114.6 (C-6), 107.6
119.9 (C-7a), 102.6 (C-4), 99.6 (C-6), 86.4 (C-1), 74.1 (C-3) ppm.
IR (CHCl ): ν = 3600, 3300, 2970, 1610, 1470, 1370, 1250, 1130,
˜
3
1020 cm–1. MS: m/z = 227.2 [M – H]–. C14H12O3 (228.25): calcd. C
(C-4), 84.9 (C-1), 72.5 (C-3), 35.8 (C-1Ј), 27.4 (C-2Ј), 22.9 (C-3Ј9, 73.67, H 5.30; found C 73.59, H 5.37.
14.2 (C-4Ј) ppm. IR (CHCl ): ν = 3600, 3300, 2920, 1680, 1660,
˜
3
1-(4Ј-Hydroxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol 21: The re-
action was carried out as reported in the general procedure. The
obtained oil product was purified on silica gel (Et2O/hexane, 8:2)
to afford pure 21 (8 mg, 0.03 mmol, 15%). The reaction was also
carried out by using chloroacetic acid to afford pure 21 (17 mg,
1560, 1460, 1390, 1270, 1130, 1090 cm–1. MS: m/z = 191.2
[M – H]–. C12H16O2 (192.26): calcd. C 74.97, H 8.39; found C
74.77, H 8.45.
1-(4Ј-Nitrophenyl)-1,3-dihydroisobenzofuran-5,7-diol (17): The reac-
tion was carried out as reported in the general procedure. The resi-
due was purified on silica gel (Et2O/hexane, 8:2) to afford pure 17
1
0.07 mmol, 29%). H NMR (300 MHz, CD3OD): δ = 7.05 (d, J =
8.4 Hz, 2 H, 2Ј-H, 6Ј-H), 6.69 (d, J = 8.4 Hz, 2 H, 3Ј-H, 5Ј-H),
(35 mg, 0.13 mmol, 61%). 1H NMR (300 MHz, CD3OD): δ = 8.12 6.21 (d*, J = 1.5 Hz, 1 H, 4-H), 6.14 (d*, J = 1.8 Hz, 1 H, 6-H),
(d, J3Ј,5Ј = 8.7 Hz, 2 H, 3Ј-H and 5Ј-H), 7.54 (d, J2Ј,6Ј = 8.7 Hz, 2
H, 2Ј-H and 6Ј-H), 6.23 (m, 1 H, 4-H), 6.16 (d, J1,3b = 2.4 Hz, 1
6.01 (d*, J = 2.1 Hz, 1 H, 1-H), 5.08 (dd, J3b,3a = 12.0 Hz, J3b,1
2.7 Hz, 1 H, 3b-H), 4.92 (d, J3a,3b = 12.0 Hz, 1 H, 3a-H) ppm. IR
(CDCl ): ν = 3300, 2950, 1690, 1520, 1450, 1390, 1270, 1250, 1090,
=
H, 1-H), 6.14 (m, 1 H, 6-H), 5.21 (dd, J3b,3a = 12.3 Hz, J3b,1
=
˜
3
2.4 Hz, 1 H, 3b-H), 5.03 (d, J3a,3b = 12.3 Hz, 1 H, 3a-H) ppm. 13C 1020 cm–1. MS: m/z = 242.1 [M – H]–. C14H12O4 (243.1): calcd. C
NMR (75 MHz, CD3OD): δ = 160.9 (C-5), 154.3 (C-7), 151.5 (C- 68.48, H 4.95; found C 68.25, H 4.97.
4Ј), 148.7 (C-1Ј), 143.2 (C-3a), 129.2 (C-3Ј and C-5Ј), 124.2 (C-2Ј
1-(4Ј-Methoxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol (22): The
and C-6Ј), 119.4 (C-7a), 102.7 (C-4), 99.9 (C-6), 85.2 (C-1), 74.8
reaction was carried out as reported in the general procedure. The
(C-3) ppm. IR (CHCl ): ν = 3600, 3050, 2900, 1660, 1530, 1470,
˜
3
obtained oil product was purified on silica gel (CHCl3/EtOH, 96:4)
to afford pure 22 (15 mg, 0.06 mmol, 27%). The reaction was also
carried out by using chloroacetic acid to afford pure 22 (30 mg,
1360, 1250, 1130 cm–1. MS: m/z = 272.2 [M – H]–. C14H11NO5
(273.24): calcd. C 61.54, H 4.06, N 5.13; found C 61.41, H 4.15, N
5.01.
1
0.10 mmol, 48%). H NMR (300 MHz, CD3COCD3): δ = 7.20 (d,
1-(4Ј-Chlorophenyl)-1,3-dihydroisobenzofuran-5,7-diol (18): The re-
action was carried out as reported in the general procedure. The
residue was purified on silica gel (Et2O) to afford pure 18 (26 mg,
0.10 mmol, 50%). 1H NMR (300 MHz, CD3OD): δ = 7.25 (s, 4 H,
J = 8.7 Hz, 2 H, 2Ј-H, 6Ј-H), 6.82 (d, J = 8.7 Hz, 2 H, 3Ј-H, 5Ј-
H), 6.30 (m, 1 H, 4-H), 6.25 (d*, J = 1.8 Hz, 1 H, 6-H), 6.05 (d*,
J = 1.8 Hz, 1 H, 1-H), 5.09 (dd, J3a,3b = 12.3 Hz, J3b,1 = 2.1 Hz, 1
H, 3a-H), 4.91 (d, J3b,3a = 12.3 Hz, 1 H, 3b-H), 3.75 (s, 3 H, OCH3)
2Ј-H, 3Ј-H, 5Ј-H, 6Ј-H), 6.21 (s, 1 H, 4-H), 6.14 (s, 1 H, 6-H), 6.05 ppm. IR (CDCl ): ν = 3429, 2963, 1610, 1511, 1463, 1303, 1247,
˜
3
(d, J1,3b = 1.8 Hz, 1 H, 1-H), 5.13 (dd, J3b,3a = 12.3 Hz, J3b,1
=
1173, 1107, 1030, 802, 757, 553 cm–1. MS: m/z = 257.1 [M – H]–.
1.8 Hz, 1 H, 3b-H), 4.97 (d, J3a,3b = 12.3 Hz, 1 H, 3a-H) ppm. 13C C15H14O4 (258.28): calcd. C 69.76, H 5.46; found C 69.52, H 5.58.
NMR (75 MHz, CDCl3): δ = 158.6 (C-5), 152.2 (C-7), 141.3 (C-
1-(3Ј,5Ј-Dimethoxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol (23):
3a), 140.6 (C-1Ј), 132.3 (C-6Ј), 128.0 (C-2Ј and C-6Ј), 127.2 (C-3Ј
The reaction was carried out as reported in the general procedure.
and C-5Ј), 117.9 (C-7a), 100.8 (C-6), 83.6 (C-1), 72.4 (C-3) ppm.
The obtained oil product was purified on silica gel (CHCl3/EtOH,
IR (CHCl ): ν = 3600, 3300, 2950, 1700, 1610, 1500, 1420, 1380,
˜
3
96:4) to afford pure 23 (21 mg, 0.07 mmol, 33%). The reaction was
also carried out by using chloroacetic acid to afford pure 23 (40 mg,
0.10 mmol, 48%). H NMR (300 MHz, CDCl3): δ = 6.46 (d, J =
1270, 1080, 1020 cm–1. MS: m/z = 261.7 [M – H]–. C14H11ClO3
(262.69): calcd. C 64.01, H 4.22, Cl 13.50; found C 63.84, H 4.33,
Cl 13.42.
1
2.4 Hz, 2 H, 6Ј-H, 2Ј-H), 6.35 (t, J = 2.4 Hz, 1 H, 4Ј-H), 6.22 (m,
1-(3Ј-Nitrophenyl)-1,3-dihydroisobenzofuran-5,7-diol (19): The reac-
tion was carried out as reported in the general procedure. The ob-
tained oil product was purified on silica gel (Et2O/hexane, 8:2) to
afford pure 19 (25 mg, 0.09 mmol, 45 %). 1H NMR (300 MHz,
CD3OD): δ = 8.17 (t, J = 2.1 Hz, 1 H, 2Ј-H), 8.08 (d*, J = 8.1 Hz,
1 H, 4Ј-H), 7.73 (d*, J = 8.1 Hz, 1 H, 2Ј-H), 7.50 (t, J = 8.1 Hz, 1
1 H, 4-H), 6.16 (d*, J5,4 = 1.8 Hz, 1 H, 6-H), 6.02 (d*, J1,3b =
1.8 Hz, 1 H, 1-H), 5.11 (dd, J3a,3b = 12.0 Hz, J3b,1 = 2.7 Hz, 1 H,
3a-H), 4.96 (d, J3a,1 = 12.0 Hz, 1 H, 3b-H), 3.71 (s, 6 H, 2 OCH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 160.2 (C-3Ј and C-5Ј), 158.5
(C-5), 152.2 (C-7), 141.5 (C-3a), 144.0 (C-1Ј), 118.0 (C-7a), 104.5
(C-2Ј and C-6Ј), 100.9 (C-4), 98.7 (C-4Ј), 97.9 (C-6), 84.3 (C-1),
H, 5Ј-H), 6.24 (d*, J = 0.9 Hz, 1 H, 4-H), 6.18 (d*, J1,3b = 1.5 Hz, 72.2 (C-3), 53.8 (2 CH O) ppm. IR (CDCl ): ν = 3600, 3300, 2950,
˜
3
3
1 H, 1-H), 6.15 (d*, 1 H, 6-H), 5.20 (dd, J3a,3b = 12.6 Hz, J3b,1
=
1700, 1610, 1470, 1370, 1260 1150, 1070, 940 cm–1. MS: m/z = 287.8
2.7 Hz, 1 H, 3b-H), 5.04 (d, J3a,3b = 12.6 Hz, 1 H, 3a-H) ppm. 13C [M – H]–. C16H16O5 (288.30): calcd. C 66.66, H 5.59; found C
NMR (75 MHz, CD3OD): δ = 160.6 (C-5), 153.4 (C-7), 149.3 (C- 66.02, H 5.11.
3Ј), 146.2 (C-1Ј), 143.1 (C-3a), 134.4 (C-6Ј), 130.1 (C-5Ј), 122.8 (C-
1-(3Ј,4Ј,5Ј-Trimethoxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol
2Ј), 123.2 (C-4Ј), 119.2 (C-7a), 102.6 (C-4), 99.8 (C-6), 85.0 (C-1),
(24): The reaction was carried out as reported in the general pro-
74.6 (C-3) ppm. IR (CDCl ): ν = 3600, 3050, 2900, 1660, 1530,
˜
3
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOH, 94:6) to afford pure 24 (22 mg, 0.07 mmol, 33%). The reac-
tion was also carried out by using chloroacetic acid to afford pure
24 (39 mg, 0.1 mmol, 58%). 1H NMR (300 MHz, CDCl3): δ = 6.57
(s, 2 H, 2Ј-H, 6Ј-H), 6.28 (s*, 1 H, 4-H), 6.12 (s*, 1 H, 6-H), 6.05
(s*, 1 H, 1-H), 5.57 (br. s, 2 H, 2 OH), 5.17 (d, J3a,3b = 12.3 Hz, 1
H, 3a-H), 5.02 (d, J3b,3a = 12.3 Hz, 1 H, 3b-H), 3.75 (s, 6 H, 2
CH3O), 3.80 (s, 3 H, CH3O) ppm. 13C NMR (75 MHz, CDCl3): δ
= 157.8 (C-5), 142.1 (C-4Ј), 153.3 (C-3Ј and C-5Ј), 151.4 (C-7),
142.7 (C-3a), 136.4 (C-1Ј), 118.9 (C-7a), 104.4 (C-2Ј and C-6Ј),
1470, 1360, 1250, 1130 cm–1. MS: m/z = 272.1 [M – H]–.
C14H11NO5 (273.24): calcd. C 61.54, H 4.06, N 5.13; found C
61.18, H 3.95, N 4.97.
1-Phenyl-1,3-dihydroisobenzofuran-5,7-diol (20): The reaction was
carried out as reported in the general procedure. The residue was
purified on silica gel (CHCl3/MeOH, 95:5) to afford pure 20
1
(25 mg, 0.11 mmol, 50 %). H NMR (300 MHz, CD3OD): δ =
7.26–7.19 (5 H, ArH), 6.23 (m, 1 H, 4-H), 6.14 (m, 1 H, 6-H), 6.08
(m, 1 H, 1-H), 5.13 (dd, J3a,3b = 12.0 Hz, J3a,1 = 2.4 Hz, 1 H, 3a-
H), 4.97 (d, J3b,3a = 12.0 Hz, 1 H, 3b-H) ppm. 13C NMR (75 MHz, 102.3 (C-4), 100.3 (C-6), 84.7 (C-1), 73.3 (C-3), 60.8 (CH3O), 56.1
CD3OD): δ = 160.2 (C-5), 154.0 (C-7), 143.4* (C-1Ј), 143.1* (C- (2 CH O) ppm. IR (CDCl ): ν = 3600, 3300, 2950, 1700, 1610,
˜
3
3
3a), 128.9 (C-2Ј and C-6Ј), 128.5 (C-4Ј), 128.3 (C-3Ј and C-5Ј),
1470, 1370, 1260 1150, 1070, 940 cm–1. MS: m/z = 317.2
1972
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1967–1976

Isochroman and Phthalan or Homoisochroman Derivative Syntheses
[M – H]–. C17H18O6 (318.33): calcd. C 64.14, H 5.70; found C 5,7-Dimethoxy-1-(3Ј,4Ј-methylenedioxyphenyl)-1,3-dihydroisobenzo-
64.02, H 5.18.
furan (29): The reaction was carried out as reported in the general
procedure. The obtained solid product was purified on silica gel
(hexane/Et2O, 6:4) to afford pure 29 (20 mg, 0.07 mmol, 43%). H
NMR (300 MHz, CDCl3): δ = 6.70–6.85 (m, 3 H, 2Ј-H, 5Ј-H, 6Ј-
H), 6.40 (s*, 1 H, 4-H), 6.34 (d*, J = 2.1 Hz, 1 H, 6-H), 6.12 (m,
1 H, 1-H), 5.92 (s, 2 H, OCH2O), 5.25 (dd, J3b,3a = 12.0 Hz, J3b,1
= 2.4 Hz, 1 H, 3b-H), 5.08 (d, J3a,3b = 12.0 Hz. 1 H, 3a-H), 3.82
1-(4Ј-Hydroxy-3Ј-methoxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol
(25): The reaction was carried out as reported in the general pro-
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOH, 85:15) to afford pure 25 (10 mg, 0.03 mmol, 17%). The reac-
tion was also carried out by using chloroacetic acid to afford pure
25 (18 mg, 0.07 mmol, 33%). 1H NMR (300 MHz, CDCl3): δ =
6.81 (s, 1 H, 6Ј-H), 6.70 (s, 2 H, 2Ј-H, 5Ј-H), 6.22 (m, 1 H, 4-H),
6.14 (d*, J = 2.1 Hz, 1 H, 6-H), 6.02 (d*, J = 1.8 Hz, 1 H,1-H),
5.06 (dd*, J3a,3b = 12.3 Hz, J3b,1 = 2.7 Hz, 1 H, 3b-H), 4.93 (d,
J3a,3b = 12.3 Hz, 1 H, 3a-H), 3.77 (s, 3 H, OCH3) ppm. IR (CDCl3):
1
(s, 1 H, OCH ), 3.66 (s, 1 H, OCH ) ppm. IR (CDCl ): ν = 3550,
˜
3
3
3
3300, 2950, 2050, 1855, 1625, 1505, 1450, 1380, 1260, 1240, 1155,
1135, 1110, 1080, 1030 cm–1. MS: m/z = 299.2 [M – H]–. C17H16O5
(300.31): calcd: C 67.99, H 5.37; found C 67.67, H 5.44.
ν = 3550, 3350, 2950, 1660, 1500, 1465, 1360, 1300, 1160 cm–1. MS:
5,7-Dimethoxy-1-(3Ј,5Ј-dimethoxyphenyl)-1,3-dihydroisobenzofuran
(30): The reaction was carried out as reported in the general pro-
cedure. The obtained solid product was purified on silica gel (hex-
ane/Et2O, 6:4) to afford 30 (23 mg, 0.08 mmol, 47%). 1H NMR
(300 MHz, CDCl3): δ = 6.50 (d, J = 2.3 Hz, 2 H, 6Ј-H and 2Ј-H),
6.39 (s, 1 H, 4-H), 6.33 (d*, J = 1.8 Hz,1 H, 6-H), 6.34 (d*, J =
˜
m/z = 259.2 [M – H]–. C14H12O5 (260.24): calcd. C 64.61, H 4.65;
found C 64.58, H 4.52.
1-(3Ј,4Ј-Methylenedioxyphenyl)-1,3-dihydroisobenzofuran-5,7-diol
(26): The reaction was carried out as reported in the general pro-
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOAc, 8:2) to afford a pure 26 (12 mg, 0.05 mmol, 25%). The
reaction was also carried out by using chloroacetic acid to afford
2.4 Hz, 1 H, 4Ј-H), 6.50 (d, J = 2.4 Hz, 2 H, 2Ј-H and 6Ј-H), 6.14
3b,1
(d*, 1 H, 1-H), 5.27 (dd, J3a,3b = 12.4 Hz,
J = 2.7 Hz, 1 H, 3a-
H), 5.09 (d, 3a,1J = 12.4 Hz,1 H, 3b-H), 3.82 (s, 3 H, OCH3), 3.76
(s, 6 H, 2 OCH ), 3.72 (s, 3 H, OCH ) ppm. IR (CDCl ): ν = 3600,
1
pure 26 (26 mg, 0.09 mmol, 45%). H NMR (300 MHz, CDCl3): δ
˜
3
3
3
= 6.90 (dd, J6Ј,5Ј = 7.8 Hz, J6Ј,2Ј = 1.5 Hz, 1 H, 6Ј-H), 6.80 (d, J5Ј,6Ј
= 7.8 Hz, 1 H, 5Ј-H), 6.78 (s*, 1 H, 2Ј-H), 6.34 (s*, 1 H, 4-H), 6.20
(br. s*, 1 H, 6-H), 6.03 (s*, 1 H, 1-H), 5.96 (s, 2 H, OCH2O), 5.19
3300, 2950, 1700, 1610, 1470, 1370, 1250, 1220, 1150, 1060, 1070,
940 cm–1. MS: m/z = 315.2 [M – H]–. C18H20O5 (316.36): calcd. C
68.34, H 6.37; found C 68.03, H 6.42.
(dd*, J3b,3a = 12.3 Hz, J3b,1 = 2.4 Hz, 1 H, 3b-H), 5.05 (d, J3a,3b
=
1,1-Bis[1-(2Ј,6Ј-dihydroxy-4Ј-hydroxymethylphenyl)]ethane (31): The
reaction was carried out as reported in the general procedure at
4 °C for 2 h. The residue was purified on silica gel (Et2O) to afford
12.3 Hz, 1 H, 3a-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.5
(C-5), 152.2 (C-7), 147.0 (C-4Ј), 146.7 (C-3Ј), 141.5 (C-3a), 135.7
(C-1Ј), 120.1 (C-6Ј), 118.1 (C-7a), 106.7 (C-2Ј and C-5Ј), 100.9 (C-
4), 100.3 (OCH2O) 97.9 (C-6), 84.3 (C-1), 72.0 (C-3) ppm. IR
1
pure 31 (12 mg, 0.04 mmol, 33%). H NMR (300 MHz, CD3OD):
δ = 6.39 (s, 4 H, 3Ј-H and 5Ј-H), 4.58 (t, J = 8.1 Hz, 1 H, 1-H),
4.41 (s, 4 H, 2 CH2OH), 2.30 (m, 2 H, 2-H), 0.86 (t, J = 7.2 Hz, 3
H, 3-H) ppm. 13C NMR (75 MHz, CD3OD): δ = 156.5 (C-2Ј and
C-6Ј), 142.4 (C-4Ј), 116.6 (C-1Ј), 107.8 (C-3Ј and C-5Ј), 64.8 (hy-
droxymethyl carbon), 57.4 (C-1), 25.0 (C-2), 14.0 (C-3) ppm. MS:
m/z = 319.3 [M – H]–. C17H20O6 (320.35): calcd. C 63.74, H 6.29;
found C 63.66, H 6.33.
(CDCl ): ν = 3550, 3300, 2900, 2050, 1860, 1625, 1510, 1450, 1380,
˜
3
1260, 1240, 1160, 1130, 1110, 1080, 1040, 940, 880 cm–1. MS: m/z
= 271.2 [M – H]–. C15H12O5 (272.26): calcd. C 66.17, H 4.44; found
C 65.58, H 4.02.
1-(4Ј-N,N-Dimethylaminophenyl)-1,3-dihydroisobenzofuran-5,7-diol
(27): The reaction was carried out as reported in the general pro-
cedure. The obtained oil product was purified on silica gel (CHCl3/
MeOH, 95:05) to afford pure 27 (12 mg, 0.07 mmol, 32%). 1H
NMR (300 MHz, CD3OD): δ = 7.07 (d, J = 8.7 Hz, 2 H, 2ЈH,
6ЈH), 6.71 (d, J = 8.7 Hz, 2 H, 3Ј-H and 5Ј-H), 6.22 (m, 1 H, 4-
H), 6.14 (d*, J = 2.1 Hz, 1 H,6-H), 6.02 (d*, J = 1.8 Hz, 1 H, 1-
H), 5.07 (dd, J3b,3a = 12.0 Hz, J3b,1 = 2.7 Hz, 1 H, 3b-H), 4.92 (d,
J = 12.0 Hz, 1 H, 3a-H), 3.29 (s, 6 H, 2 CH3) ppm. 13C NMR
(75 MHz, CD3OD): δ = 160.0 (C-5), 153.8 (C-7), 151.9 (C-4Ј),
143.2 (C-3a), 131.5 (C-1Ј), 129.2 (C-2Ј and C-6Ј), 113.7 (C-3Ј and
C-5Ј), 120.0 (C-7a), 102.6 (C-4), 99.6 (C-6), 86.3 (C-1), 73.6 (C-3),
1,1-Bis[1-(2Ј,6Ј-dihydroxy-4Ј-hydroxymethylphenyl)]butane (32):
The reaction was carried out as reported in the general procedure
at 38 °C for 48 h by using chloroacetic acid as the catalyst. The
residue was purified on silica gel (Et2O/hexane, 8:2) to afford pure
32 (9 mg, 0.03 mmol, 25%). 1H NMR (300 MHz, CD3OD): δ =
6.39 (s, 4 H, 3Ј-H and 5Ј-H), 4.68 (t, J = 7.8 Hz, 1 H, 1-H), 4.41
(s, 4 H, 2 CH2OH), 2.27 (m, 2 H, 2-H), 1.26 (m, 4 H, 3-H and 4-
H), 0.85 (t, J = 7.2 Hz, 3 H, 3 5-H) ppm. 13C NMR (75 MHz,
CD3OD): δ = 156.4 (C-3 and C-7), 142.4 (C-5), 116.8 (C-2), 107.9
(C-4 and C-6), 64.8 (hydroxymethyl carbon), 33.1 (C-1), 32.4 (C-
1Ј), 31.6 (C-3), 23.6 (C-4), 14.4 (C-5) ppm. MS: m/z = 347.4 [M –
H]–. C19H24O6 (348.40): calcd. C 65.50, H 6.94; found C 65.38, H
7.02.
41.4 (CH ) ppm. IR (CDCl ): ν = 3443), 2920, 2852, 1651, 1557,
˜
3
3
1456, 1353, 1105, 978, 812 cm–1. MS: m/z = 270.2 [M – H]–.
C16H17NO3 (271.32): calcd. C 70.83, H 6.32, N 5.16; found C
70.75, H 6.43.
1-(3Ј,4Ј-Methylenedioxyphenyl)-6,8-dimethoxyisochroman (33): The
5,7-Dimethoxy-1-(4Ј-nitrophenyl)-1,3-dihydroisobenzofuran (28): reaction was carried out as reported in the general procedure at
The reaction was carried out as reported in the general procedure.
The obtained solid product was purified on silica gel (hexane/Et2O,
6:4) to afford 28 (22 mg, 0.072 mmol, 45%). H NMR (300 MHz,
4 °C for 24 h. The residue was purified on silica gel (CHCl3/hexane,
8:2) to afford pure 33 (44 mg, 0.14 mmol, 89 %). 1H NMR
(300 MHz, CDCl3): δ = 2.6–3.1 (m, 2 H, 4-H), 3.59 (s, 3 H, OCH3),
1
CDCl3): δ = 8.17 (d, J = 7.7 Hz, 2 H, 3Ј-H and 5Ј-H), 7.51 (d, J = 3.82 (s, 3 H, OCH3), 3.9–3.7 (m, 2 H, 3-H), 5.79 (s, 1 H, 1-H), 5.92
7.7 Hz, 2 H, 2Ј-H and 6Ј-H), 6.42 (m, 1 H, 4-H), 6.32 (s, 1 H, 6- (s, 2 H, OCH2O), 6.27 (d*, J = 2.2 Hz, 1 H, 7-H), 6.33 (d*, J =
H), 6.25 (m, 1 H, 1-H), 5.35 (dd, J3b,3a = 12.3 Hz, J3b,1 = 2.4 Hz, 2.2 Hz, 1 H, 5-H), 6.63 (dd, J = 7.8 Hz, J = 2.0 Hz, 1 H, 6Ј-H),
1 H, 3b-H), 5.05 (d, J3a,3b = 12.3 Hz, 1 H, 3a-H), 3.81 (s, 3 H, 6.71 (d, J = 2.0 Hz, 1 H, 2Ј-H), 6.72 (d, J = 7.8 Hz, 1 H, 5Ј-H)
OCH ), 3.66 (s, 3 H, OCH ) ppm. IR (CDCl ): ν = 3620, 3050, ppm. 13C NMR (75 MHz, CDCl3): δ = 28.8 (C-4), 55.2 (2 OCH3),
˜
3
3
3
2900, 1660, 1525, 1470, 1355, 1250, 1220, 1130, 1060 cm–1. MS:
m/z = 300.2 [M – H]–. C16H15NO5 (301.30): calcd. C 63.78, H 5.02,
N 4.65; found C 63.62, H 5.15, N 4.39.
59.3 (C-3), 73.4 (C-1) 96.6 (C-7), 100.8 (OCH2O), 104.2 (C-5),
107.5 (C-2Ј), 108.9 (C-5Ј), 117.5 (C-8a), 121.9 (C-6Ј), 136.1 (C-1Ј),
136.4 (C-4a), 146.7 (C-3Ј), 147.3 (C-4Ј), 157.1 (C-6), 159.5 (C-8)
Eur. J. Org. Chem. 2008, 1967–1976
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1973

M. Guiso, A. Betrow, C. Marra
FULL PAPER
ppm. IR (CDCl ): ν = 3300, 2935, 1650, 1480, 1340, 1148 cm–1.
3.04 (m, 1 H, 5b-H), 3.92 (m, 1 H, 3a-H), 4.25 (m, 1 H, 3b-H),
˜
3
MS: m/z = 313.3 [M – H]–. C18H18O5 (314.34): calcd. C 68.72, H 5.14 (br. s, 2 H, 2 OH), 5.57 (s, 1 H, 1-H), 5.96 (s*, 2 H, CH2),
5.77; found C 68.32, H 5.42.
6.16 (s, 1 H, 9-H), 6.71 (s, 1 H, 6-H), 6.77 (d*, J = 8.4 Hz, 1 H, 6Ј-
H), 6.80 (d*, J = 8.4 Hz, 1 H, 5Ј-H-5Ј), 6.85 (1 H, 2Ј-H) ppm. IR
1-Phenylbenzo-2-oxacycloheptene-7,8-diol (34): The reaction was
carried out as reported in the general procedure. The obtained oil
product was purified on silica gel (CHCl3/EtOH, 93:7) to afford
(CDCl ): ν = 3600, 3350, 3000, 2900, 1720, 1620, 1500, 1450, 1380,
˜
3
1 2 4 0 , 1 1 4 0 , 1 0 9 0 , 1 0 4 0 c m – 1 . M S : m / z = 2 9 9 . 2
[M – H]–. C17H16O5 (300.31): calcd. C 67.99, H 5.37; found C
67.68, H 5.44.
1
pure 34 (16 mg, 0.06 mmol, 35%). H NMR (300 MHz, CDCl3): δ
= 1.88 (m, 2 H, 4-H), 2.88 (m, 1 H, 5a-H), 3.10 (m, 1 H, 5b-H),
3.96 (m,1 H, 3a-H), 4.30 (m, 1 H, 3b-H), 5.08 (br. s, 1 H, OH),
5.27 (br. s, 1 H, OH), 5.67 (s, 1 H, 1-H), 6.08 (s, 1 H, 9-H), 6.74 (s,
1 H, 6-H), 7.25 (m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 30.2 (C-5), 34.2 (C-4), 55.3 (OCH3), 73.2 (C-3), 83.2 (C-1), 127.4
(C-3 and C-5Ј), 116.0 (C-9), 117.0 (C-6), 128.4 (C-2ЈЈ and C-6Ј),
141.1 (C-1Ј), 135.5 (C-5a), 135.5 (C-9a), 140.6 (C-7), 142.6 (C-8),
1-(4Ј-Hydroxy-3Ј-methoxyphenyl)benzo-2-oxacycloheptene-7,8-diol
(39): The reaction was carried out as reported in the general pro-
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOH, 93:7) to afford pure 39 (17 mg, 0.06 mmol, 32%). 1H NMR
(300 MHz, CD3OD): δ = 1.80 (m, 2 H, 4-H), 2.80 (m, 1 H, 5a-H),
3.07 (m, 1 H, 5b-H), 3.94 (m, 1 H, 3a-H), 4.18 (m, 1 H, 3b-H),
3.88 (s, 3 H, OCH3), 5.60 (s, 1 H, 1-H), 6.08 (s, 1 H, 9-H), 6.62 (s,
1 H, 6-H), 6.70 (dd, J = 8.1 Hz, J = 2.1 Hz, 1 H, 6Ј-H), 6.78 (d, J
= 8.1 Hz, 1 H, 5Ј-H), 6.89 (d, J = 2.1 Hz, 1 H, 2Ј-H) ppm. 13C
NMR (75 MHz, CD3OD): δ = 31.6 (C-5), 35.0 (C-4), 56.3 (CH3O),
73.9 (C-3), 84.6 (C-1), 117.8 (C-2Ј), 115.6 (C-9), 117.0 (C-6), 118.0
(C-5Ј), 121.0 (C-6Ј), 134.0 (C-1Ј), 134.9 (C-5a), 135.4 (C-9a), 143.1
127.5 (C-4Ј) ppm. IR (CDCl ): ν = 3629, 1718, 1613, 1500, 1448,
˜
3
1232, 1097, 1028 cm–1. MS: m/z = 255.2 [M – H]–. C16H16O3
(256.30): calcd. C 74.98, H 6.29; found C 74.65, H 6.34.
1-(4Ј-Methoxyphenyl)benzo-2-oxacycloheptene-7,8-diol (35): The re-
action was carried out as reported in the general procedure The
obtained oil product was purified on silica gel (CHCl3/EtOH, 93:7)
1
(C-6Ј), 144.7 (C-8), 146.6 (C-4Ј), 148.6 (C-3Ј) ppm. IR (CDCl ): ν
˜
3
to afford pure 35 (17 mg, 0.06 mmol, 34%). H NMR (300 MHz,
= 3430, 2950, 1690, 1650, 1520, 1450, 1390, 1275, 1247, 1090, 1060,
1020, 784 cm–1. MS: m/z = 301.3 [M – H]–. C17H18O5 (302.38):
calcd. C 67.54, H 6.00; found C 67.49, H 6.12.
CDCl3): δ = 1.85 (m, 2 H, 4-H), 2.86 (m, 1 H, 5a-H), 3.05 (m, 1
H, 5b-H), 3.82 (s, 3 H, OCH3), 3.93 (m, 1 H, 3a-H), 4.26 (m, 1 H,
3b-H), 5.08 (br. s, 1 H, OH), 5.27 (br. s, 1 H, OH), 5.60 (s, 1 H, 1-
H), 6.11 (s, 1 H, 9-H), 6.71 (s, 1 H, 6-H), 6.90 (d, J = 9.0 Hz, 2 H,
1-(3Ј,4Ј-Dimethoxyphenyl)benzo-2-oxacycloheptene-7,8-diol (40):
The reaction was carried out as reported in the general procedure.
The obtained oil product was purified on silica gel (CHCl3/MeOH,
93:7) to afford pure 40 (17 mg, 0.05 mmol, 30 %). 1H NMR
(300 MHz, CDCl3): δ = 1.84 (m, 2 H, 4-H), 2.86 (m, 1 H, 5a-H),
3.08 (m, 1 H, 5b-H), 3.85 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
3.92 (m, 1 H, 3a-H), 4.29 (m, 1 H, 3b-H), 5.28 (br. s, 1 H, OH),
5.35 (br. s,1 H, OH), 5.61 (s, 1 H, 1-H), 6.12 (s*, 1 H, 9-H), 6.74
(s, 1 H, 6-H), 6.78–6.88 (2 H, 5Ј-H and 6Ј-H), 6.91 (s*, 1 H, 2Ј-H)
3Ј-H and 5Ј-H), 7.23 (d, J = 9.0 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 30.1 (C-5), 34.2 (C-4), 55.4 (OCH3),
72.9 (C-3), 82.8 (C-1), 113.6 (C-3Ј and C-5Ј), 115.8 (C-9), 116.8 (C-
6), 128.3 (C-2Ј and C-6Ј), 133.0 (C-1Ј), 135.0 (C-5a), 135.3 (C-9a),
140.4 (C-7), 142.4 (C-8), 158.7 (C-4Ј) ppm. IR (CDCl ): ν = 3300,
˜
3
2950, 1680, 1660, 1520, 1460, 1390, 1290, 1240, 1140, 1080 cm–1.
MS: m/z = 285.10 [M – H]–. C17H18O4 (286.33): calcd. C 71.31, H
6.34; found C 71.04, H 6.42.
ppm. IR (CDCl ): ν = 3440, 2935, 2840, 1600, 1515, 1455, 1423,
˜
3
1-(4Ј-Chlorophenyl)benzo-2-oxacycloheptene-7,8-diol (36): The reac-
tion was carried out as reported in the general procedure. The ob-
tained oil product was purified on silica gel (CHCl3/MeOH, 93:7)
to afford pure 36 (16 mg, 0.05 mmol 31%) as a white solid. 1H
NMR (300 MHz, CDCl3): δ = 1.85 (m, 2 H, 4-H), 2.84 (m, 1 H,
5a-H), 3.09 (m, 1 H, 5b-H), 3.94 (m, 1 H, 3a-H), 4.27 (m, 1 H, 3b-
H), 5.08 (br. s, 2 H, 2 OH), 5.62 (s, 1 H, 1-H), 6.03 (s, 1 H, 9-H),
6.72 (s, 1 H, 6-H), 7.27 (d, J = 8.4 Hz, 2 H, 2Ј-H and 6Ј-H), 7.4
1345, 1295, 1204, 1150, 1065, 1027, 840, 752 cm–1. MS: m/z = 315.3
[M – H]–. C18H20O5 (316.36): calcd. C 68.34, H 6.37; found C
68.12, H 6.41.
1-(3Ј,5Ј-Dimethoxyphenyl)benzo-2-oxacycloheptene-7,8-diol (41):
The reaction was carried out as reported in the general procedure.
The obtained oil product was purified on silica gel (CHCl3/EtOAc,
8:2) to afford pure 41 (20 mg, 0.06 mmol, 35 %). 1H NMR
(300 MHz, CDCl3): δ = 1.85 (m, 2 H, 4-H), 2.86 (m, 1 H, 5a-H),
3.11 (m, 1 H, 5b-H), 3.78 (s, 6 H, 2 OCH3), 3.95 (m, 1 H, 3a-H),
4.31 (m, 1 H, 3b-H), 4.86 (br. s, 1 H, OH), 5.13 (br. s, 1 H, OH),
5.58 (s, 1 H, 1-H), 6.15 (s, 1 H, 9-H), 6.41 (d, J = 2.1 Hz, 1 H, 4Ј-
H), 6.52 (d, J = 2.1 Hz, 2 H, 2Ј-H and 6Ј-H), 6.74 (s, 1 H, 6-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 30.2 (C-5), 34.3 (C-4), 55.0
(2 CH3O), 73.7 (C-3), 82.0 (C-1), 99.6 (C-4Ј), 105.0 (C-2Ј and C-
6Ј), 115.6 (C-9), 116.8 (C-9), 135.4 (C-5a), 135.3 (C-9a), 140.3 (C-
7), 142.4 (C-8), 143.2 (C-1Ј), 160.5 (C-3Ј and C-5Ј) ppm. IR
(d, J = 8.4 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. IR (CDCl ): ν = 3383,
˜
3
2938, 2847, 1607, 1515, 1490, 1455, 1344, 1294, 1214, 1089, 1014,
938, 886, 757 cm–1. MS: m/z = 289.5 [M – H]–. C16H15ClO3
(290.75): calcd. C 66.10, H 5.20; found C 65.99, H 5.38.
1-(4Ј-Nitrophenyl)benzo-2-oxacycloheptene-7,8-diol (37): The reac-
tion was carried out as reported in the general procedure. The ob-
tained oil product was purified on silica gel (CHCl3/EtOH, 95:5)
1
to afford pure 37 (18 mg, 0.06 mmol, 33%). H NMR (300 MHz,
CDCl3): δ = 1.86 (m, 2 H, 4-H), 2.85 (m, 1 H, 5a-H), 3.12 (m, 1
H, 5b-H), 3.96 (m, 1 H, 3a-H), 4.32 (m, 1 H, 3b-H), 5.20 (br. s, 2
H, 2 OH) 5.74 (s, 1 H, 1-H), 5.93 (s, 1 H, 9-H), 6.74 (s, 1 H, 6-H),
7.53 (d, J = 8.7 Hz, 2 H, 2Ј-H and 6Ј-H), 8.20 (d, J = 8.7 Hz, 2 H,
(CDCl ): ν = 3447), 2938, 2847, 1598, 1515, 1456, 1428, 1347, 1295,
˜
3
1204, 1154, 1065, 1027, 839, 752 cm–1. MS: m/z = 315.3 [M – H]–.
C18H20O5 (316.36): calcd. C 68.34, H 6.37; found C 68.12, H 6.10.
3Ј-H and 5Ј-H) ppm. IR (CDCl ): ν = 3441, 2944, 2360, 1607,
˜
3
1-(3Ј,4Ј,5Ј-Trimethoxyphenyl)benzo-2-oxacycloheptene-7,8-diol (42):
The reaction was carried out as reported in the general procedure.
The obtained oil product was purified on silica gel (CHCl3/EtOAc,
8:2) to afford pure 42 (22 mg, 0.06 mmol, 35 %). 1H NMR
1517, 1456, 1346, 1295, 1205, 1085, 1044, 891, 742 cm–1. MS: m/z
= 300.2 [M – H]–. C16H15NO5 (301.30): calcd. C 63.78, H 5.02, N
4.65; found C 63.53, H 5.13.
1-(3Ј,4Ј-Methylenedioxyphenyl)benzo-2-oxacycloheptene-7,8-diol (300 MHz, CDCl3): δ = 1.85 (m, 2 H, 4-H), 2.84 (m, 1 H, 5a-H),
(38): The reaction was carried out as reported in the general pro-
3.12 (m, 1 H, 5b-H), 3.78 (s, 6 H, 2 OCH3), 3.81 (s, 3 H, OCH3),
3.95 (m, 1 H, 3a-H), 4.32 (m, 1 H, 3b-H), 5.44 (br. s, 1 H, OH),
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOH, 95:5) to afford pure 38 (19 mg, 0.06 mmol, 35%). 1H NMR 5.57 (s, 1 H, 1-H), 6.13 (s, 1 H, 9-H), 6.60 (s, 2 H, 2Ј-H and 6Ј-H),
(300 MHz, CDCl3): δ = 1.83 (m, 2 H, 4-H), 2.87 (m, 1 H, 5a-H), 6.74 (s, 1 H, 6-H) ppm. IR (CDCl ): ν = 3445, 2930, 2845, 1598,
˜
3
1974
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1967–1976

Isochroman and Phthalan or Homoisochroman Derivative Syntheses
1515, 1454, 1428, 1340, 1295, 1204, 1154, 1065, 1027, 839, (285.30): calcd. C 67.36, H 5.30, N 4.91; found C 64.20, H 5.03, N
752 cm–1. MS: m/z = 345.2 [M – H]–. C19H22O6 (346.38): calcd. C
4.70.
65.88, H 6.40; found C 64.98, H 6.02.
1-(3Ј-Nitrophenyl)benzo-2-oxacycloheptene-7-ol (48): The reaction
was carried out as reported in the general procedure. The obtained
oil product was purified on silica gel (Et2O/hexane, 75:25) to afford
1-(4Ј-Methoxycarbonylphenyl)benzo-2-oxacycloheptene-7,8-diol
(43): The reaction was carried out as reported in the general pro-
cedure. The obtained oil product was purified on silica gel (CHCl3/
EtOH, 95:5) to afford pure 43 (16 mg, 0.05 mmol, 30%). 1H NMR
(300 MHz, CD3OD): δ = 1.81 (m, 2 H, 4-H), 2.79 (m, 1 H, 5a-H),
3.12 (m, 1 H, 5b-H), 3.94 (m, 1 H, 3a-H), 3.90 (s, 3 H, OCH3),
4.22 (m, 1 H, 3b-H), 5.74 (s, 1 H, 1-H), 5.90 (s, 1 H, 9-H), 6.63 (s,
1 H, 6-H), 7.42 (d, J = 8.4 Hz, 2 H, 6Ј-H and 2Ј-H), 8.00 (d, J =
1
pure 48 (12 mg, 0.04 mmol, 21%). H NMR (300 MHz, CDCl3): δ
= 1.91 (m, 2 H, 4-H), 2.94 (m, 1 H, 5a-H), 3.17 (m,1 H, 5b-H),
3.97 (m, 1 H, 3a-H), 4.32 (m, 1 H, 3b-H), 4.79 (br. s, 1 H, OH),
5.80 (s, 1 H, 1-H), 6.34 (d, J = 8.4 Hz, 1 H, 9-H), 6.46 (dd, J =
8.4 Hz, J = 2.4 Hz, 1 H, 8-H), 6.73 (d, J = 2.4 Hz, 1 H, 6-H), 7.56
(t, J = 8.1 Hz, 1 H, 5Ј-H), 7.70 (d*, J = 8.1 Hz, 1 H, 6Ј-H), 8.19
(dm, J = 8.1 Hz, 1 H, 4Ј-H), 8.25 (1 H, 2Ј-H) ppm. IR (CDCl ): ν
˜
8.4 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. IR (CDCl ): ν = 3600, 3400,
˜
3
3
= 3444, 3100, 1609, 1525, 1457, 1347, 1297, 1095, 1014, 852 cm–1.
MS: m/z = 284.2 [M – H]–. C16H15NO4 (285.30): calcd. C 67.36, H
5.30, N 4.91; found C 67.18, H 5.12.
2950, 1720, 1620, 1510, 1450, 1280, 1130, 1090 cm–1. MS: m/z =
299.2 [M – H]–. C17H16O5 (300.31): calcd. C 67.99, H 5.35; found
C 67.77, H 5.44.
1-(3Ј,4Ј-Methylenedioxyphenyl)benzo-2-oxacycloheptene-7-ol (49):
The reaction was carried out as reported in the general procedure.
The obtained oil product was purified on silica gel (CHCl3/MeOH,
95:5) to afford pure 49 (12 mg, 0.04 mmol, 22 %). 1H NMR
(300 MHz, CDCl3): δ = 1.87 (m, 2 H, 4-H), 2.94 (m, 1 H, 3a-H),
3.12 (m, 1 H, 3b-H), 3.94 (m, 1 H, 5a-H), 4.26 (m, 1 H, 5b-H),
4.69 (br. s, 1 H, OH), 5.62 (s, 1 H, 1-H), 5.96 (d, J = 4.2 Hz, 2 H,
OCH2O), 6.48 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 H, 8-H), 6.53 (d, J =
8.4 Hz, 1 H, 9-H), 6.68 (d, J = 2.4 Hz, 1 H, 6-H), 6.77 (d, J =
8.1 Hz, 1 H, 6Ј-H), 6.81 (d, J = 8.1 Hz, 1 H, 5Ј-H), 6.86 (d, J =
1-Phenylbenzo-2-oxacycloheptene-7-ol (44): The reaction was car-
ried out as reported in the general procedure. The obtained oil
product was purified on silica gel (CHCl3/EtOAc, 8:2) to afford
1
pure 44 (10 mg, 0.04 mmol, 21%). H NMR (300 MHz, CDCl3): δ
= 1.89 (m, 2 H, 4-H), 2.94 (m, 1 H, 5a-H), 3.16 (m, 1 H, 5b-H),
3.97 (m, 1 H, 3a-H), 4.29 (m, 1 H, 3b-H), 5.70 (s, 1 H, 1-H), 6.45
(s*, 2 H, 8-H and 9-H), 6.70 (s*, 1 H, 6-H): 7.30–7.40 (m, 5 H,
ArH) ppm. IR (CDCl ): ν = 3631, 2980, 1684, 1604, 1497, 1448,
˜
3
1248, 1097, 1028, 803 cm–1. MS: m/z = 239.2 [M – H]–. C16H16O2
(240.30): calcd. C 79.97, H 6.71; found C 79.78, H 6.74.
1.5 Hz, 1 H, 2Ј-H) ppm. IR (CDCl ): ν = 3300, 2947, 1653, 1604,
˜
3
1520, 1480, 1352, 1130 cm–1. MS: m/z = 283.2 [M – H]–. C17H16O4
1-(4Ј-Methoxyphenyl)benzo-2-oxacycloheptene-7-ol (45): The reac-
tion was carried out as reported in the general procedure. The ob-
tained oil product was purified on silica gel (CHCl3/MeOH, 95:5)
(284.31): calcd. C 71.82, H 5.67; found C 71.60, H 5.77.
1
1-(4Ј-N,N-Dimethylaminophenyl)benzo-2-oxacycloheptene-7-ol (50):
The reaction was carried out as reported in the general procedure.
The obtained oil product was purified on silica gel (CHCl3/MeOH,
95:5) to afford pure 50 (12 mg, 0.04 mmol, 22 %). 1H NMR
(300 MHz, CDCl3): δ = 1.86 (m, 2 H, 4-H), 2.94 (m, 1 H, 5a-H),
2.96 (s, 6 H, 2 CH3), 3.10 (m, 1 H, 5b-H), 3.93 (m, 1 H, 3a-H),
4.25 (m, 1 H, 3b-H), 4.79 (br. s, 1 H, OH), 5.63 (s, 1 H, 1-H), 6.45
(dd, J = 8.4 Hz, J = 2.4 Hz, 1 H, 8-H), 6.56 (d, J = 8.4 Hz, 1 H,
9-H), 6.68 (d, J = 2.4 Hz, 1 H, 6-H), 6.76 (d, J = 8.4 Hz, 2 H, 3Ј-
H and 5Ј-H), 7.19 (d, J = 8.4 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. IR
to afford pure 45 (11 mg, 0.04 mmol, 20%). H NMR (300 MHz,
CDCl3): δ = 1.87 (m, 2 H, 4-H), 2.94 (m, 1 H, 5a-H), 3.11 (m, 1
H, 5b-H), 3.90 (s, 3 H, OCH3), 3.95 (m, 1 H, 3a-H), 4.26 (m, 1 H,
3b-H), 4.70 (br. s, 1 H, OH), 5.66 (s, 1 H, 1-H), 6.45 (dd, J =
8.4 Hz, J = 2.4 Hz, 1 H, 8-H), 6.49 (d, J = 8.4 Hz, 1 H, 9-H), 6.69
(d, J = 2.4 Hz, 1 H, 6-H), 6.92 (d, J = 9.0 Hz, 2 H, 3Ј-H and 5Ј-
H) 7.26 (d, J = 9.0 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. IR (CDCl ): ν
˜
3
= 3620, 2835, 1636, 1604, 1448, 1247, 1040, 784 cm–1. MS: m/z =
269.3 [M – H]–. C17H18O3 (270.33): calcd. C 75.53, H 6.71; found
C 75.41, H 6.65.
(CDCl ): ν = 3420, 2920, 2349, 2260, 1604, 1448, 1353, 1097,
˜
3
1028 cm–1. MS: m/z = 282.3 [M – H]–. C18H21NO2 (283.37): calcd.
1-(4Ј-Chlorophenyl)benzo-2-oxacycloheptene-7-ol (46): The reaction
was carried out as reported in the general procedure. The obtained
oil product was purified on silica gel (Et2O/hexane, 8:2) to afford
C 76.30, H 7.47, N 4.94; found C 76.15, H 7.15, N 4.66.
1
pure 46 (14 mg, 0.05 mmol, 25%). H NMR (300 MHz, CDCl3): δ
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77, 405–411.
= 1.88 (m, 2 H, 4-H), 2.93 (m, 1 H, 5a-H), 3.14 (m, 1 H, 5b-H),
3.95 (m, 1 H, 3a-H), 4.28 (m, 1 H, 3b-H), 5.67 (s, 1 H, 1-H), 6.41
(d, J = 8.4 Hz, 1 H, 9-H), 6.46 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 H,
8-H), 6.70 (d, J = 2.4 Hz, 1 H, 6-H), 7.28 (d, J = 8.7 Hz, 2 H, 2Ј-
H and 6Ј-H), 7.35 (d, J = 8.7 Hz, 2 H, 3Ј-H and 6Ј-H) ppm. IR
(CDCl ): ν = 3600, 1684, 1636, 1604, 1567, 1447, 1246, 1090, 1028,
˜
3
803 cm–1. MS: m/z = 273.7 [M – H]–. C16H15ClO2 (274.75): calcd.
C 69.95, H 5.50; found C 69.72, H 5.40.
1-(4Ј-Nitrophenyl)benzo-2-oxacycloheptene-7-ol (47): The reaction
was carried out as reported in the general procedure. The obtained
oil product was purified on silica gel (Et2O/hexane, 75:25) to afford
[7] A. A. Qureshi, R. W. Rickards, A. Kamal, Tetrahedron 1967,
23, 3801–3808.
[8] B. A. Keay, R. Rodrigo, J. Am. Chem. Soc. 1982, 104, 4725–
4727.
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2712–2720.
1
pure 47 (12 mg, 0.04 mmol, 21%). H NMR (300 MHz, CDCl3): δ
= 1.90 (m, 2 H, 4-H), 2.92 (m, 1 H, 5a-H), 3.17 (m, 1 H, 5b-H),
3.97 (m, 1 H, 3a-H), 4.32 (m, 1 H, 3b-H), 4.79 (br. s, 1 H, OH),
5.79 (s, 1 H, 1-H), 6.31 (d, J = 8.4 Hz, 1 H, 9-H), 6.46 (dd, J =
8.4 Hz, J = 2.4 Hz, 1 H, 8-H), 6.73 (d, J = 2.4 Hz, 1 H, 6-H), 7.55
(d, J = 8.7 Hz, 2 H, 2Ј-H and 6Ј-H), 8.25 (d, J = 8.7 Hz, 2 H, 3Ј-
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6210.
H and 5Ј-H) ppm. IR (CDCl ): ν = 3630, 2944, 2360, 1604, 1520,
˜
3
1347, 1248, 1097, 852 cm–1. MS: m/z = 284.2 [M – H]–. C16H15NO4
Eur. J. Org. Chem. 2008, 1967–1976
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1975

M. Guiso, A. Betrow, C. Marra
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1967–1976