Improved solvent-free synthesis and structure elucidation of (E)- and (Z)-4-(arylmethylene)-3-isochromanones

Article abstract of DOI:10.1002/1099-0690(200209)2002:17<2996::AID-EJOC2996>3.0.CO;2-G

A series of new 4-(arylmethylene)-3-isochromanones 1-17 has been prepared by base-catalyzed Knoevenagel condensations. Stereochemical and conformational analyses were performed by ¹H and ¹³C NMR methods, and X-ray crystallography was used to complement the configurational assignment for a representative product. The reaction generally yields the (E) isomer, but the isomeric composition of the products was influenced by the aromatic aldehyde and usually governed by the stability of the products. Several aldehydes exclusively afforded the (Z) isomer, due to intramolecular steric/electronic interactions reflected in the increased stability of the product. The condensation performed with ortho-hydroxyarenecarbaldehydes furnished the unexpected 3-arylcoumarins or 3-arylbenzocoumarins. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:17<2996::AID-EJOC2996>3.0.CO;2-G

FULL PAPER
Improved Solvent-Free Synthesis and Structure Elucidation of (E)- and
Z)-4-(Arylmethylene)-3-isochromanones
(
[a]
[b]
[c]
ˆ
[a]
[d]
Tam a´ s L o´ r a´ nd,* P e´ ter Forg o´ , Andr a´ s Földesi, Erzs e´ bet Osz, and L a´ szl o´ Pr o´ kai
Keywords: Heterocycles / Lactones / Molecular modeling / NMR spectroscopy / X-ray diffraction
A series of new 4-(arylmethylene)-3-isochromanones 1−17
has been prepared by base-catalyzed Knoevenagel con-
densations. Stereochemical and conformational analyses
were performed by H and C NMR methods, and X-ray
crystallography was used to complement the configurational
ally governed by the stability of the products. Several alde-
hydes exclusively afforded the (Z) isomer, due to intramolec-
ular steric/electronic interactions reflected in the increased
stability of the product. The condensation performed with or-
tho-hydroxyarenecarbaldehydes furnished the unexpected
1
13
assignment for a representative product. The reaction gener- 3-arylcoumarins or 3-arylbenzocoumarins.
ally yields the (E) isomer, but the isomeric composition of the
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
products was influenced by the aromatic aldehyde and usu-
2002)
Introduction
investigated for antifungal effects.[5,9] We have also screened
some homoisoflavones, such as (E)-2-(arylmethylene)-1-
tetralones, (E)-3-(arylmethylene)-4-chromanones and (E)-3-
1-Isochromanone derivatives (isocoumarins) are known
[
10,11]
(arylmethylene)-1-thiochroman-4-ones,
against human
to possess a variety of important biological activities. Oos-
pathogenic yeasts (Cryptococcus neoformans, Candida al-
bicans, Candida parapsilosis, Candida tropicalis, Trichospo-
ron cutaneum and Torulopsis glabrata). In in vitro tests,
some of these showed activities (MIC values) as high as
ponol, a fungal metabolite, displayed antifungal effects
against phytopathogenic fungi[1,2] (Scheme 1). Fusarubine,[3]
an antibiotic of isochromane isolated from Nectria hemato-
cocca strains of Fusarium solani, exhibited antibacterial,
[
12]
antifungal, insecticide and phytotoxic effects.[
4,5]
1.5Ϫ6 µg/mL.
As an extension of these studies, we set
3-Isochro-
out to study the isomeric 4-(arylmethylene)-3-isochrom-
anones in order to gain a better understanding of the struc-
ture-activity relationships.
manone also plays an important role in the utilization of
all fluorene carbon atoms in fluorene metabolism by
Arthrobacter sp. strain F101.[ Some α,β-unsaturated ke-
6]
[
7]
tones are also known to possess antimicrobial effects. 3-
Arylmethylene)-4-chromanones (homoisoflavones) have
(
[8]
been isolated from plants (Liliaceae family), and both nat-
urally occurring and synthetic homoisoflavones have been
[
[
[
[
a]
b]
c]
Department of Biochemistry and Medical Chemistry, Faculty
of Medicine, University of P e´ cs,
7
601 P e´ cs, Hungary
Fax: (internat.) ϩ 36-72/536-225
E-mail: tamas.lorand@aok.pte.hu
Department of Organic Chemistry, Faculty of Science,
University of Szeged,
D o´ m t e´ r 8, 6720 Szeged, Hungary
Fax: (internat.) ϩ 36-62/544-200
E-mail: pforgo@chem.u-szeged.hu
Department of Analytical Chemistry, Faculty of Science,
University of P e´ cs,
Scheme 1. Biologically important isochromane derivatives
7
601 P e´ cs, Hungary
Fax: (internat.) ϩ 36-72/501-518
4-Subsutituted isochromanones have been prepared as
E-mail: foldesiandras@hotmail.com
d]
Center for Drug Discovery, College of Pharmacy, University fusarubine-type models by pH-controlled Knoevenagel
of Florida,
condensations of 3-isochromanone and selected aldehydes
Gainesville, FL 32610-0497, USA
[
13]
such as benzaldehyde and 4-hydroxybenzaldehyde. These
Fax: (internat.) ϩ 1-352/392-8589
E-mail: lprokai@grove.ufl.edu
reactions resulted in mixtures of the appropriate (E) and
2996
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0917Ϫ2996 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2996Ϫ3003

(E)- and (Z)-4-(Arylmethylene)-3-isochromanones
FULL PAPER
(Z) isomers with yields of 8Ϫ30%, but the majority of the Table 1. Isomeric composition of 1Ϫ17
starting 3-isochromanone hydrolysed under the basic condi-
tions to give the corresponding hydroxycarboxylic acids. Compound
Ar
Isomeric composition
Prolonged reaction times only give improved yields
(
46Ϫ60%) with long-chain aliphatic aldehydes,[14] and so
1
Ph
60% (E), 40% (Z)
100% (E)
100% (E)
66% (E), 33% Z)
100% (Z)
100% (Z)
100% (E)
70% (E), 30% (Z)
100% (E)
100% (E)
33% (E), 66% (Z)
coumarin
66% (E), 33% (Z)
20% (E), 80% (Z)
100% (E)
coumarin
100% (E)
2
3
4
5
6
7
8
9
2 6 4
4Ј-HO CC H
3Ј-pyridyl
1Ј-methyl-2Ј-pyrrolyl
2Ј-pyrrolyl
2Ј,6Ј-Cl
2Ј-CH OC
2Ј-ClC
2Ј,3Ј-(CH
2Ј,4Ј-(CH
2Ј-O
2Ј-hydroxy-1Ј-naphthyl
2Ј-furyl
3Ј-indolyl
this synthetic procedure does not allow for efficient or high-
throughput preparation of combinatorial libraries involving
reagents with multiple points of diversification (i.e., substi-
tuted isochromanones and substituted aromatic aldehydes).
In addition, it cannot easily be scaled up for the preparation
of gram quantities of 4-(arylmethylene)-3-isochomanones.
2
C
6
H
3
3
6
H
4
6
H
4
3
O)
O)
2
C
C
6
H
H
3
We now report a new, one-step method for the preparation 10
3
2
6
3
11
12
13
14
2
NC
6
H
4
of this class of compounds that satisfies the above require-
ments, along with the structural verification of the products.
The selection of the aromatic aldehydes in our study was
guided by previous knowledge of the structure-(antimicro- 15
2Ј-BrC H
2Ј-HOC
3Ј-HOC
6
4
bial) activity relationships.[
10,11]
The Knoevenagel con- 16
6
H
4
17
6
H
4
densation involving 3-isochromanones generally yields an
excess of the (E) isomer of the product. On the other hand,
the choice of aromatic aldehyde may under specific circum-
stances bring about the predominant formation of (Z) iso-
mers. With aliphatic aldehydes as reactants, the steric strain
of the product formed was a governing factor.[ Our ex-
perimental efforts were therefore supported by theoretical
studies to address the selectivity observed in the reaction.
their preparation and indicated that they were formed in
thermodynamically controlled reactions.
14]
The generally accepted method used to determine which
1
isomer is present is based solely on the H chemical shift
[
13,14]
of the methine proton (Scheme 3).
observed chemical shift ranges for this proton [δ ϭ
.14Ϫ7.55 ppm for the (E) series versus δ ϭ 7.74Ϫ7.11 ppm
The overlap in the
8
Results and Discussion
for the (Z) series], however, indicates that this way to assign
the configuration is in fact unreliable when one single iso-
mer is formed. In the NOESY or ROESY spectra of the
compounds studied here, the presence of a cross-peak be-
tween α-H and 5-H clearly attests to the steric proximity
of these protons [i.e., the (Z) configuration in the case of
compounds 1Z, 4ZϪ6Z, 8Z, 13Z and 14Z], but spectral
crowding can prevent the use of these techniques (such as
for derivative 11Z, in which α-H and 5-H are isochronous).
In the same way, the (E) configuration is indicated by strong
NOE correlations between aromatic protons 5-H and 6Ј-H
If the Knoevenagel condensation is conducted in alco-
hols, the opening of the lactone ring of the isochromanone
consumes a large portion of the starting material. A
method in which the title compounds were synthesized un-
der solvent-free conditions was therefore developed. Typic-
ally, a few drops of piperidine would be added as a catalyst
to a mixture of 3-isochromanone and an appropriate aro-
matic aldehyde, and the molten reaction mixture would
then be stirred at 140 °C for 1 h. After the reaction mixture
had cooled to room temperature, compounds 1Ϫ17
(for 1E, 2E, 7EϪ11E, 15E and 17E), 5-H and 2Ј-H (for
(Scheme 2 and Table 1) were obtained in better yields
1EϪ3E, 14E and 17E), 5-H and 4Ј-H (for 3E) or 5-H and
(50Ϫ97%) than reported in the literature by traditional
3Ј-H (for 4E and 13E).
methods. The degree of conversion was found to be 100%
under the conditions applied.
Scheme 2. Preparation of 4-(arylmethylene)-3-isochromanones
1؊17
Scheme 3. Numbering of heavy atoms for NMR assignment of 14E
In order to examine the possibility of (E)/(Z) isomeriz-
On the other hand, little is known about the usefulness
ation of the products during the Knoevenagel condensa- of 13C NMR spectroscopy for the assignment of the config-
tion, pure isomers were heated under Ar at 140 °C in the urations of these ene-lactones, in spite of the apparent dif-
presence of piperidine for 1 h. Neither the (E) nor the (Z) ferences in the carbon spectra of the two stereoisomers. It
isomers changed. This finding ruled out the isomerization is worth mentioning here that, for the compounds in this
of the product 4-(arylmethylene)-3-isochromanones during study, the use of [D ]DMSO as NMR solvent results in
6
Eur. J. Org. Chem. 2002, 2996Ϫ3003
2997

ˆ
T. L o´ r a´ nd, P. Forg o´ , A. Földesi, E. Osz, L. Pr o´ kai
FULL PAPER
1
better H chemical shift separation than with CDCl , as
3
exemplified for compound 9E, facilitating the assignment
of the carbon signals. One characteristic difference is the
chemical shift order: δ(C-7) Ͼ δ(C-6) Ͼ δ(C-5) Ͼ δ(C-8)
for the (E) series versus δ(C-6) Ͼ δ(C-7) Ͼ δ(C-8) Ͼ δ(C-
5) for the (Z) series. Similarly, δ(C-8a) Ͼ δ(C-4a) holds for
compounds with the (E) configuration, whereas δ(C-4a) Ͼ
δ(C-8a) applies for the (Z) family. The C-3 signal is more
shielded in the (Z) series (∆δ ഠ 3Ϫ4 ppm), most probably
due to steric crowding. Another straightforward way to cor-
roborate the configuration across the double bond is by in-
1
3
spection of the well-resolved C signal of C-3, which has a
double triplet multiplicity in the proton-coupled experi-
3
ment. The magnitude of the J
coupling constants
α-H,C-3
unequivocally proves the configuration of the double bond
ca. 13 Hz for (Z) isomers, and ca. 7 Hz for (E)]. The UV
[
spectra of the different isomers generally show two absorp-
tion maxima. For compounds 1, 4, 8 and 11, the molar
absorption of higher wavelength maxima is greater for the
Figure 1. X-ray crystallography ORTEP diagram (30% thermal el-
lipsoids) showing the two rotamers in the unit cell of 13E
(
E) isomers. Other than this, there are no characteristic dif-
Table 2. Heats of formation [kcal/mol] of the condensation prod-
ucts 1؊17; parentheses indicate that the isochromanones are not
obtained
ferences between the spectral properties of the (E) and (Z)
isomers. Probably, no extended conjugation exists between
the isochromanone ring and the aryl group; this would ex-
plain the similarities in the UV spectra of the isomers. How-
ever, the tendency described above is not valid for the furyl
derivatives 13E and 13Z, in which the (Z) isomer has a
greater molar absorption at the higher wavelength maxima.
Certainly, in this compound, perfect conjugation can be at-
tained between the isochromanone and the furan ring, and
possibly the most stable conformation is when the furyl ring
is in the plane of the isochromanone ring. It is possible for
this compound to adopt a conformation in which the six
atoms are in plane. In the cases of the five-membered aryl
derivatives (4, 5 and 13) there is generally greater ab-
Compound
(E) isomer(s)
(Z) isomer(s)
1
2
3
4
Ϫ12.9
Ϫ102.0
Ϫ5.5
Ϫ10.8 (E1)
Ϫ11.8 (E2)
Ϫ11.1 (E1)
Ϫ11.0 (E2)
Ϫ25.4
Ϫ49.2
Ϫ18.2
Ϫ82.3
Ϫ87.5
Ϫ12.0
Ϫ101.5
Ϫ5.2
Ϫ10.4 (Z1)
Ϫ10.5 (Z2)
Ϫ9.8 (Z1)
Ϫ16.6 (Z2)
Ϫ26.7
Ϫ48.7
Ϫ17.8
Ϫ83.2
Ϫ86.9
5
6
7
8
9
sorbance at higher wavelength maxima than in the phenyl 10
1
1
1
1
2
3
Ϫ16.9
Ϫ18.4
derivatives. This may relate to a greater degree of conjuga-
tion due to a more planar conformation for these five-mem-
bered compounds, which suffer less steric repulsion than
the phenyl analogs.
Another possible isomer type for several compounds syn-
thesized in this study was found on confirmation of our
spectroscopy-based structure assignment by X-ray crystal-
lography. The unit cell of single crystals grown from 13E
contained an isomer pair obtainable by rotation of the het-
eroaromatic ring (rotamers), as shown in Figure 1. The rot-
amers are designated as 13E1 and 13E2, respectively, de-
pending on whether the oxygen atom of the furyl ring is on
the opposite side to, or on the same side as, the CO group.
[
a]
(Ϫ37.4)
Ϫ38.3 (E1)
Ϫ39.2 (E2)
4.8 (E1)
5.9 (E2)
Ϫ3.7
(Ϫ37.8)
Ϫ38.1 (Z1)
Ϫ38.1 (Z2)
5.9 (Z1)
1.8 (Z2)
Ϫ3.6
14
1
1
1
5
6
7
[
b]
(Ϫ56.4)
Ϫ57.9
(Ϫ56.0)
Ϫ57.0
[
a]
ϭ (1Ϫ42.0 kcal/mol. [b] Coumarin: ∆H
ϭ
f f
Benzocoumarin: ∆H
1Ϫ58.7 kcal/mol.
(
The synthetic procedure was in most cases expected to
A similar convention is used for compounds 4, 5 and 14. provide the (E) isomer with exclusive stereoselectivity, be-
We therefore included these possible rotamers of the com- cause aldol condensations are known usually to afford (E)
pounds in the attempted theoretical interpretation of the isomers, except when a high degree of steric overcrowding
stereoselectivity observed for their formation. This could be renders the (E) isomers less stable than the (Z) isomers.[15,16]
predicted fairly accurately by considering the calculated For example, the condensation of the 2,2-diphenylchrom-
stability (indicated by the heats of formation, ∆H °) of the anone with benzaldehyde furnishes the (Z) isomer.[
17]
f
isomeric reaction products. Table 2 summarizes the ∆Hf° The generally used method to prepare (Z) isomers of the
values for the isomers and, if they exist, rotamers calculated exocyclic α,β-unsaturated cyclic ketones is the photochem-
[
15,16]
by a semiempirical quantum-chemical method (PM3) for ical isomerization of the (E) isomers.
Nevertheless, the
compounds 1Ϫ17.
piperidine-catalyzed condensation of 3-isochromanone with
2998
Eur. J. Org. Chem. 2002, 2996Ϫ3003

(E)- and (Z)-4-(Arylmethylene)-3-isochromanones
FULL PAPER
benzaldehyde, 2-nitrobenzaldehyde, 2-chlorobenzaldehyde,
2
3
-furaldehyde, N-methylpyrrole-2-carbaldehyde and indole-
-carbaldehyde furnished mixtures of the (E) and (Z) iso-
mers, whereas 2,6-dichlorobenzaldehyde and pyrrole-2-car-
baldehyde gave exclusively the (Z) isomers. The mixtures of
isomers were separated by column chromatography, except
for the 14E and 14Z isomeric pair, which readily intercon-
vert.
In the case of 5Z (obtained from pyrrole-2-carbal-
dehyde), the hydrogen-bonded chelate ring stabilizes the (Z)
configuration, according to the IR and NMR spectroscopic
[
18]
data.
This stabilization is also reflected by the decrease
in the PM3-calculated heat of formation (i.e., higher
stability than the other isomeric forms) for the appropriate
rotamer, as given in Table 2. The significance of hydrogen Scheme 4. Structures of coumarins (12, 16) and the possible pre-
cursor isochromanones (A, B)
bonding is apparent, since the same conformation does not
show such a distinct increase in the stability of the corres-
ponding isomer when N-methylpyrrole-2-carbaldehyde is and benzocoumarin from these reactants can be explained
involved as a reactant during condensation (compounds 4E/ by the significant decrease in the ∆H ° relative to the corres-
f
Z), the reaction indeed furnishing a mixture rich in the 4E ponding (arylmethylene)-3-isochromanones, as shown in
isomer, which is the preferred isomer by the underlying Table 2.
mechanism. The observed selectivity (or lack thereof) can
be explained by considering heats of formation for most of
the compounds studied, except for 2,6-dichlorobenzal-
dehyde, which requires further scrutiny.
Conclusion
Knoevenagel condensations of 3-isochromanone with 2-
hydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde did thylene)-3-isochromanones with improved yields in a solv-
In conclusion, we have synthesized a series of 4-(arylme-
1
not yield (arylmethylene)-3-isochromanones. In the
H
ent-free, one-step reaction. These reactions probably pro-
NMR spectra of the products the methylene signal appears ceed as tandem Knoevenagel condensations followed by de-
as a doublet and is coupled to a triplet that disappears upon hydration steps. In several instances these condensations
addition of D O, indicating the presence of an opened lac- unexpectedly furnished the (Z) isomers as sole products,
2
tone ring of the 3-isochromanone moiety, whereas atmo- and the selectivity (or the lack thereof) could be explained
spheric pressure chemical ionization (APCI) mass spectra by considering the relative stability of the isomeric forms.
1
3
showed the expected molecular ions. These observations
C NMR spectroscopic data have been collected for these
could be resolved by invoking a putative internal attack of compounds, and it has been established that the 13C chem-
the ortho-hydroxy group on the carbonyl center, well situ- ical shift of C-3, the chemical shift order of C-6, C-7, C-8
3
ated for such an attack in the intermediate (Z) isomer (A and C-5, and also the Jα-H,C-3 coupling constant can be
and B), which results in the formation of benzocoumarin used to differentiate between the (E) and (Z) isomers, which
derivative 12 or coumarin 16 (Scheme 4) in a way similar to might be especially important when only one stereoisomer
that found in the reaction between a (triphenylphosphoran- is formed in the reaction. The condensation performed with
ylidene)benzofuran-2(3H)-one derivative and salicylal- ortho-hydroxyarenecarbaldehydes furnished the unexpected
[
18]
1
13
dehydes.
consistent with the presence of these skeletons
cially when compared to the product formed from 3-hydro- eral biological effects, such as regulation of plant growth
The observed H and C NMR spectra are 3-arylcoumarins or 3-arylbenzocoumarins. Members of the
[19Ϫ21]
(espe- latter class of compounds have been reported to have sev-
[
23]
xybenzaldehyde). In particular, the ca. 4Ϫ7 ppm shielding and antagonistic action on sex hormones.
The prepara-
of the carbonyl signals in the C data showed increased tion of the 3-arylcoumarins and 3-arylbenzocoumarins usu-
1
3
3
3
conjugation, and the measured (ca. 10 Hz) J
and J
ally employs phenylacetic acid and salicylaldehyde as react-
4
-H,C-2
1-
[
23,24]
coupling values for 16 and 12, respectively, were cle- ants or starts from acrylonitrile derivatives.
However,
arly in good agreement with the presence of the C-3 (for our methods could be considered to be a simple procedure
6) or C-2 (for 12) phenyl-substituted endocyclic double for the one-pot synthesis of several functionalized 3-aryl-
H,C-3
1
[
22]
bond. In order to rule out the possible nucleophilic effect coumarins (e.g., 2Ј-hydroxymethyl derivatives) or 3-arylben-
of the basic catalyst, used in excess because of the acidic zocoumarins.
character of the reagent, the reaction between 3-isochrom-
anone and salicylaldehyde was reexamined with smaller
amounts of catalyst. In a separate experiment, acidification
of the reaction mixture was also performed at the end of
Experimental Section
the reaction. In both cases, the products were identical to General Remarks: The reagents used were purchased from Aldrich
16 in every respect. Again, the formation of the coumarin Chemical Co. and Fluka and were not further purified. Column
Eur. J. Org. Chem. 2002, 2996Ϫ3003 2999

ˆ
T. L o´ r a´ nd, P. Forg o´ , A. Földesi, E. Osz, L. Pr o´ kai
FULL PAPER
chromatography was performed on Merck silica gel (60, particle
size 0.040Ϫ0.063 mm). Thin layer chromatography (TLC) was per-
formed on Merck silica gel plates (60 F254), the eluents are men-
tioned in the description of the new compounds. NMR spectra
anol gave 2E as white crystals (1.10 g, 57% yield). M.p. 201 °C
(decomposition). UV (ethanol): λmax (log ε) ϭ 235 nm (4.88), 327
1
(4.80). H NMR ([D
6
]DMSO): δ ϭ 5.56 (s, 1-H
2
), 7.4Ϫ7.3 (m, 6-
H, 5-H), 7.48 (dt, 7-H), 7.56 (d, 8-H), 7.71 (d, 2Ј-H, 6Ј-H), 7.87 (s,
1
13
13
6
were recorded with Varian Unityϩ 300 (300/75 MHz for H/ C) H-α), 8.02 (d, 3Ј-H, 5-HЈ) ppm. C NMR ([D ]DMSO): δ ϭ 68.9
UNITY
1
13
and Varian
INOVA 400 WB (400/100 MHz for H/ C) spec-
(C-1), 125.9 (C-8), 126.96 (C-5), 127.0 (C-4), 128.0 (C-6), 128.9 (C-
trometers. Chemical shift (δ) data are given in ppm with reference
to TMS ( H NMR), or measured relative to the central peak of
7), 129.4 (C-2Ј, C-6Ј), 129.56 (C-4a), 129.6 (C-3Ј, C-5Ј), 131.2 (C-
1
3
4Ј), 133.4 (C-8a), 136.5 (C-α),138.8 (C-1Ј), 166.8 (dt, Jα-H,C-3
ϭ
the solvents at δ ϭ 76.9 ppm (CDCl
3
) or δ ϭ 39.6 ppm [D
6
]DMSO 7.5, 3
J1-H,C-3 ϭ 5.2 Hz, C-3), 167.5 (COOH) ppm. C17
12 4
H O
13
in C NMR experiments. Signal assignments for each compound
were achieved by double resonance, 1D difference NOE, and 2D
(280.28) calcd. C 72.85, H 4.32; found C 72.76, H 4.51.
1
1
1
13
(E)-4-(Pyridin-3Ј-ylmethylene)-3-isochromanone (3E): This com-
pound was obtained from 3-isochromanone (1.00 g, 6.75 mmol)
and pyridine-3-carbaldehyde (0.72 g, 6.75 mmol). Recrystallization
from methanol gave 3E as faint yellow crystals (1.00 g, 62% yield).
NMR experiments ( H- H COSY, H- C HETCOR, COLOC,
NOESY, ROESY) using standard software. Carbon multiplicities
and overlapping quaternary signals were identified by APT experi-
ments. Assignments were corroborated by spectral simulation (g
NMR, Cherwell Scientific Publishing) and by comparison with lit-
M.p. 131 °C (decomposition). UV (ethanol): λmax (log ε) ϭ 228 nm
1
[
18Ϫ22,25Ϫ27]
sh (4.31) 317 (4.18). H NMR ([D
6
]DMSO): δ ϭ 5.56 (s, 1-H
2
),
erature data.
UV/Vis spectra were recorded with a
7.30 (m, 5-H), 7.33 (m, 6-H), 7.48 (m, 7-H), 7.51 (m, 5Ј-H), 7.58
Beckman DU 65 spectrophotometer in ethanol. Atmospheric pres-
sure chemical ionization (APCI) mass spectra were recorded with
an ion-trap instrument (LCQ, ThermoFinnigan, San Jose, CA).
Melting points were determined with a Boetius hot plate apparatus
and are uncorrected. Molecular modeling was performed with
Chem3D Ultra (version 5.0, CambridgeSoft, Cambridge, MA) in-
(
d, 8-H), 7.84 (s, α-H), 8.00 (dt, 4Ј-H), 8.64 (dd, 6Ј-H), 8.76 (m, 2Ј-
1
3
H) ppm. C NMR ([D
25.9 (C-8), 126.6 (C-5), 127.3 (C-4), 128.1 (C-6), 128.9 (C-7), 129.5
C-4a), 130.5 (C-3Ј), 133.5 (C-8a), 134.2 (C-α), 136.3 (C-4Ј), 149.9
6
]DMSO): δ ϭ 68.9 (C-1), 123.6 (C-5Ј),
1
(
(
3
3
C-6Ј), 150.0 (C-2Ј), 167.4 (dt, Jα-H,C-3 ϭ 7.3, J1-H,C-3 ϭ 5.3 Hz,
11NO (237.26): calcd. C 75.94, H 4.67, N 5.90;
found C 76.07; H 4.76, N 5.81.
C-3) ppm. C15
H
2
corporating the MOPAC97 semiempirical quantum-chemical pack-
age. The PM3 parametrization[
29]
and in vacuo conditions were
used. Geometries were optimized to a gradient norm of Ͻ 0.1
kcal/mol.
(
E)-4-[(1Ј-Methyl-1H-pyrrol-2Ј-yl)methylene]-3-isochromanone (4E)
and (Z)-4-[(1Ј-Methyl-1H-pyrrol-2Ј-yl)methylene]-3-isochromanone
4Z): These compounds were obtained as a 2:1 mixture of (E)/(Z)
diastereoisomers (based on separation) from 3-isochromanone
1.00 g, 6.75 mmol) and 1-methylpyrrole-2-carbaldehyde (0.74 g,
.75 mmol) by the above procedure (0.80 g, 50% yield). The iso-
(
General Procedure for the Synthesis of 4-(Arylmethylene)-3-isochro-
manones: A mixture of 3-isochromanone (6.75 mmol), the appro-
priate aldehyde (6.75 mmol) and five drops of piperidine was stirred
at 140 °C under argon for 1 h. The mixture was allowed to cool to
room temperature, and the oily residue was crystallized from eth-
anol. A second recrystallisation from methanol gave pure products.
In some cases the products were purified by column chromato-
graphy.
(
6
meric mixture was separated by column chromatography (silica gel)
and eluted with petroleum ether/dichloromethane (30:70). 4E: Or-
ange crystals from methanol; m.p. 127 °C (decomposition). UV
1
(
(
ethanol): λmax (log ε) ϭ 251 nm (4.56), 389 (4.79). H NMR
6 3 2
[D ]DMSO): δ ϭ 3.85 (s, NϪCH ), 5.38 (s, 1-H ), 6.19 (dd, 4Ј-H),
(
E)-4-(Phenylmethylene)-3-isochromanone (1E) and (Z)-4-(Phenyl-
6.91 (dd, 3Ј-H), 7.20 (t, 5Ј-H), 7.5Ϫ7.4 (m, 6-H, 7-H), 7.53 (m, 8-
1
3
methylene)-3-isochromanone (1Z): These compounds were obtained
from 3-isochromanone (0.56 g, 3.75 mmol) and benzaldehyde
H), 7.68 (s, α-H), 8.06 (m, 5-H) ppm. C NMR ([D
34.0 (NϪCH ), 68.4 (C-1), 108.9 (C-4Ј), 112.6 (C-3Ј), 117.7 (C-4),
125.4 (C-α), 125.7 (C-5, C-8), 127.0 (C-2Ј), 127.7 (C-6), 128.0 (C-
6
]DMSO). δ ϭ
3
(
(
0.40 g, 3.75 mmol) as a 3:2 mixture of (E)/(Z) diastereoisomers
based on separation). Recrystallization from methanol gave 1E
3
7), 128.2 (C-5Ј), 131.0 (C-4a), 132.7 (C-8a), 168.8 (dt, Jα-H,C-3
7.5, J1-H,C-3 ϭ 5.3 Hz, C-3) ppm. C15
ϭ
3
and 1Z (0.51 g, 57% yield). The isomeric mixture was separated by
2
H13NO (239.27): calcd. C
column chromatography (silica gel) with dichloromethane as elu-
ent. 1E: UV (ethanol): λmax (log ε) ϭ 230 nm (4.49), 321 (4.40). H crystals from methanol; m.p. 116 °C (decomposition). UV (eth-
75.30, H 5.48, N 5.85; found C 75.21, H 5.32, N 5.99. 4Z: Orange
1
1
NMR ([D
H), 7.46 (m, 7-H), 7.53Ϫ7.41 (m, 3Ј-H, 4Ј-H, 5Ј-H), 7.56 (d, 8-H), δ ϭ 3.75 (s, NϪCH
.61 (m, 2Ј-H, 6Ј-H), 7.84 (s, α-H) ppm. 13C NMR ([D
]DMSO): H), 7.11 (s, α-H),7.20 (d, 8-H), 7.29 (dt, 7-H), 7.39 (dt, 6-H), 7.47
3
δ ϭ 68.8 (C-1), 125.4 (C-4), 125.8 (C-8), 126.7 (C-5), 127.8 (C-6), ): δ ϭ 34.3
6
]DMSO): δ ϭ 5.53 (s, 1-H
2
), 7.30 (t, 6-H), 7.35 (d, 5- anol): λmax (log ε) ϭ 251 nm (4.30), 385 (4.75). H NMR (CDCl
3
):
3
), 5.21 (s, 1-H ), 6.27 (dd, 4Ј-H), 6.84 (t, 5Ј-
2
7
6
1
3
(d, 5-H), 7.76 (dd, 3Ј-H) ppm. C NMR (CDCl
28.6 (C-7), 128.7 (C-3Ј, C-5Ј), 129.3 (C-2Ј, C-6Ј), 129.6 (C-4Ј), (NϪCH ), 68.8 (C-1), 109.5 (C-4Ј), 116.7 (C-4), 118.2 (C-3Ј), 122.9
30.0 (C-4a), 133.2 (C-8a), 134.2 (C-1Ј), 137.7 (C-α), 167.8 (dt, (C-5), 124.1 (C-8), 126.4 (C-α),126.9 (C-7), 127.9 (C-5Ј), 128.3 (C-
1
3
1
3
α-H,C-3 ϭ 7.4, 3
3
J
J
1-H,C-3 ϭ 5.2 Hz, C-3). 1Z: UV (ethanol) λmax
2Ј), 128.9 (C-6), 131.1 (C-8a), 136.0 (C-4a), 165.8 (dt, Jα-H,C-3 ϭ
1
3
(
(
(
log ε) 229 nm (3.94), 316 (4.11). H NMR ([D
s, 1-H ), 7.54Ϫ7.45 (m, 3Ј-H, 5Ј-H, 8-H, 4Ј-H), 7.54 (m, 7-H), 7.59
m, 6-H), 7.60 (s, α-H), 7.81 (m, 2Ј-H, 6Ј-H), 7.89 (d, 5-H) ppm.
6
]DMSO): δ ϭ 5.50 12.5, J1-H,C-3 ϭ 5.1 Hz, C-3) ppm. C15
2
H13NO (239.27): calcd. C
2
75.30, H 5.48, N 5.85; found C 75.42, H 5.59, N 5.90.
1
3
(Z)-4-[(Pyrrol-2Ј-yl)methylene]-3-isochromanone (5Z): This com-
pound was obtained from 3-isochromanone (1.00 g, 6.75 mmol)
and pyrrole-2-carbaldehyde (0.64 g, 6.75 mmol). Recrystallization
from methanol gave 5Z as dark red crystals (1.13 g, 74% yield).
6
C NMR ([D ]DMSO): δ ϭ 68.9 (C-1), 124.0 (C-5), 125.0 (C-8),
1
4
1
25.4 (C-4), 128.3 (C-3Ј, C-5Ј), 128.5 (C-7), 129.3 (C-6), 129.5 (C-
Ј), 130.3 (C-2Ј, C-6Ј), 132.1 (C-8a), 134.4 (C-4a), 134.8 (C-1Ј),
39.8 (C-α), 165.9 (dt, 3
α-H,C-3 ϭ 13.1, 3
J1-H,C-3 ϭ 5.0 Hz, C-3)
J
M.p. 85Ϫ86 °C. UV (ethanol): λmax (log ε) 256 nm (4.36), 384
ppm. All the physical data for 1E and 1Z are in accordance with
1
those published by Barbier.[13]
(4.80). H NMR (CDCl
3
): δ ϭ 5.27 (s, 1-H
2
), 6.36 (m, 4Ј-H), 6.72
(
m, 3Ј-H), 7.10 (m, 5Ј-H), 7.19 (d, 8-H), 7.28 (m, 7-H), 7.30 (s, H-
1
3
4-[(E)-3-Oxoisochroman-4-ylidene]benzoic Acid (2E): This compound α),7.39 (dt, 6-H), 7.52 (d, 5-H), 12.03 (NH) ppm. C NMR
was obtained from 3-isochromanone (1.00 g, 6.75 mmol) and 4-for-
mylbenzoic acid (1.01 g, 6.75 mmol). Recrystallization from meth-
3
(CDCl ): δ ϭ 69.5 (C-1), 111.1 (C-4Ј), 113.1 (C-4), 121.5 (C-3Ј),
122.9 (C-5), 124.1 (C-8), 124.3 (C-5Ј), 126.8 (C-7), 128.7 (C-2Ј),
Eur. J. Org. Chem. 2002, 2996Ϫ3003
3000

(E)- and (Z)-4-(Arylmethylene)-3-isochromanones
FULL PAPER
1
29.0 (C-6), 129.8 (C-8a), 130.5 (C-α), 135.0 (C-4a), 169.0 (C-3)
ppm. C14
C 74.79, H 5.01, N 6.29.
Recrystallization from methanol gave 9E as faint yellow crystals
H11NO
2
(225.25): calcd. C 74.65, H 4.92, N 6.22; found (1.66 g, 83% yield). M.p. 136 °C (decomposition). UV (ethanol):
max (log ε) ϭ 250 nm, shoulder (3.66), 323 (3.63). 1H NMR
[D ]DMSO): δ ϭ 3.89 (2Ј-OCH ), 3.94 (3Ј-OCH ), 5.50 (s, 1-H ),
.90 (m, 6Ј-H), 7.04 (t, 5Ј-H), 7.13 (dd, 4Ј-H), 7.25 (m, 5-H), 7.27
λ
(
6
3
3
2
(
Z)-4-[(2Ј,6Ј-Dichlorophenyl)methylene]-3-isochromanone (6Z): This
compound was obtained from 3-isochromanone (1.00 g,
.75 mmol) and 2,6-dichlorobenzaldehyde (1.18 g, 6.75 mmol).
Recrystallization from methanol gave 6Z as faint yellow crystals
1.22 g, 59% yield). M.p. 158 °C (decomposition). UV (ethanol):
6
13
(
(
1
1
m, 6-H), 7.43 (m, 7-H), 7.52 (d, 8-H), 7.87 (s, α-H) ppm. C NMR
[D ]DMSO): δ ϭ 56.1 (3Ј-OCH ), 61.0 (2Ј-OCH ), 69.1 (C-1),
14.4 (C-4Ј), 120.9 (C-6Ј), 124.3 (C-5Ј), 125.9 (C-8), 126.2 (C-4),
6
6
3
3
(
27.0 (C-5), 128.1 (C-6), 128.6 (C-1Ј), 128.8 (C-7), 130.2 (C-4a),
33.1 (C-8a), 134.0 (C-α),147.9 (C-2Ј), 152.9 (C-3Ј), 168.1 (dt,
1
λ
H
max (log ε) ϭ 288 nm (3.98). H NMR (CDCl
3
): δ ϭ 5.35 (s, 1-
1
2
), 7.17 (s, α-H), 7.21 (m, 4Ј-H), 7.26 (d, 8-H), 7.37 (m, 3Ј-H, 5Ј-
3
3
1
J
α-H,C-3 ϭ 7.3, J1-H,C-3 ϭ 4.9 Hz, C-3). H NMR (CDCl
.88 (2Ј-OCH ), 3.89 (3Ј-OCH ), 5.32 (s, 1-H ), 6.87 (m, 5Ј-H,
Ј-H), 6.91 (m, 4Ј-H), 7.11 (m, 6-H), 7.24 (m, 8-H), 7.26 (m, 7-H),
3
): δ ϭ
13
H), 7.41 (dt, 7-H), 7.47 (dt, 6-H), 7.73 (d, 5-H) ppm. C NMR
CDCl ): δ ϭ 69.2 (C-1), 124.0 (C-5), 124.4 (C-8), 127.8 (C-5Ј, C-
Ј), 129.0 (C-7), 129.2 (C-6), 129.3 (C-4Ј), 130.0 (C-4), 131.5 (C-
a), 131.8 (C-α), 132.5 (C-4a), 133.4 (C-2Ј, C-6Ј), 133.8 (C-1Ј),
3
6
7
3
3
2
(
3
3
8
1
13
.30 (d, 5-H), 8.02 (s, α-H) ppm. C NMR (CDCl
3
): δ ϭ 55.7
(
(
(
(
3Ј-OCH
3
), 61.2 (2Ј-OCH ), 69.1 (C-1), 113.3 (C-4Ј), 121.0
3
3
3
2 2
64.5 (dt, JHα,C3 ϭ 12.7, J1H,C3 ϭ 5.0 Hz, C-3) ppm. C16H10Cl O
C-6Ј), 123.5 (C-5Ј), 124.8 (C-8), 125.6 (C-4), 127.4 (C-5), 127.8
C-6), 128.2 (C-7), 128.8 (C-1Ј), 130.6 (C-4a), 132.1 (C-8a), 134.8
(305.16): calcd. C 62.98, H 3.30; found C 62.82, H 3.44.
3
C-α), 148.3 (C-2Ј), 152.9 (C-3Ј), 168.1 (dt,
Jα-H,C-3 ϭ 7.2,
(E)-4-[(2Ј-Methoxyphenyl)methylene]-3-isochromanone (7E): This
3
J1-H,C-3 ϭ 5.2 Hz, C-3) ppm. C18
16 4
H O (296.32): calcd. C 72.96,
compound was prepared from 3-isochromanone (1.00 g,
.75 mmol) and 2-methoxybenzaldehyde (0.92 g, 6.75 mmol).
Recrystallization from methanol gave 7E as faint yellow crystals
1.41 g, 78% yield). M.p. 113 °C (decomposition). UV (ethanol):
H 5.44; found C 73.11, H 5.56.
6
(
E)-4-[(2Ј,4Ј-Dimethoxyphenyl)methylene]-3-isochromanone (10E):
This compound was prepared from 3-isochromanone (1.00 g,
.75 mmol) and 2,4-dimethoxybenzaldehyde (1.12 g, 6.75 mmol).
Recrystallization from methanol gave 10E as faint yellow crystals
1.40 g, 70% yield). M.p. 91 °C (decomposition). UV (ethanol):
(
1
λ
3
(
max (log ε) ϭ 234 nm (4.33), 341 (4.20). H NMR (CDCl
.79 (2Ј-OCH ), 5.29 (s, 1-H ), 6.77 (t, 5Ј-H), 6.91 (d, 3Ј-H), 7.10
m, 6-H), 7.22 (m, 8-H), 7.23 (m, 7-H), 7.30 (m, 4Ј-H), 7.32 (2 ϫ
3
): δ ϭ
6
3
2
(
λ
3
6
7
13
d, 5-H, 6Ј-H), 8.03 (s, α-H) ppm. C NMR (CDCl
OCH ), 69.1 (C-1), 111.0 (C-3Ј), 120.0 (C-5Ј), 123.3 (C-1Ј), 124.6
C-4), 124.8 (C-8), 127.1 (C-5), 127.7 (C-6), 127.9 (C-7), 129.4 (C-
Ј), 130.9 (C-4a, C-6Ј), 132.0 (C-8a), 135.0 (C-α),158.0 (C-2Ј), 168.4
dt, 3
1-H,C-3 ϭ 5.0 Hz, C-3) ppm. C17
266.29): calcd. C 76.68, H 5.30; found C 76.79, H 5.44.
3
): δ ϭ 55.3 (2Ј-
1
max (log ε) ϭ 244 nm (4.19), 359 (4.20). H NMR (CDCl
.76 (2Ј-OCH ), 3.78 (4Ј-OCH ), 5.24 (s, 1-H ), 6.29 (dd, 5Ј-H),
.43 (d, 3Ј-H), 7.10 (m, 6-H), 7.20 (m, 7-H, 8-H), 7.32 (d, 6Ј-H),
3
): δ ϭ
3
3
3
2
(
6
(
(
1
3
.42 (d, 5-H), 7.99 (s, α-H), ppm. C NMR (CDCl
3
): δ ϭ 55.2 (2
J
α-H,C-3 ϭ 7.3, 3
J
14 3
H O
ϫ OCH
3
), 68.9 (C-1), 98.0 (C-3Ј), 104.8 (C-5Ј), 115.7 (C-1Ј), 122.2
(
(
(
C-4), 124.8 (C-8), 126.7 (C-5), 127.6 (C-7, C-6), 130.3 (C-6Ј), 131.3
C-4a), 131.9 (C-8a), 134.5 (C-α), 159.5 (C-4Ј), 162.4 (C-2Ј), 168.8
(
E)-4-[(2Ј-Chlorophenyl)methylene]-3-isochromanone (8E) and (Z)-
-[(2Ј-Chlorophenyl)methylene]-3-isochromanone (8Z): These com-
pounds were obtained as a 7:3 mixture of (E)/(Z) diastereoisomers
based on separation) prepared from 3-isochromanone (1.00 g,
.75 mmol) and 2-chlorobenzaldehyde (0.95 g, 6.75 mmol) by the
C-3) ppm. C18
2.82, H 5.61.
16 4
H O (296.32): calcd. C 72.96, H 5.44; found C
4
7
(
6
(
E)-4-[(2Ј-Nitrophenyl)methylene]-3-isochromanone (11E) and (Z)-4-
(2Ј-(Nitrophenyl)methylene]-3-isochromanone (11Z): These com-
pounds were obtained as a 1:2 mixture of (E)/(Z) diastereoisomers
based on separation) from 3-isochromanone (1.00 g, 6.75 mmol)
[
above procedure (1.24 g, 68% yield). The isomeric mixture was sep-
arated by column chromatography (silica gel) and eluted with
dichloromethane. 8E: Faint yellow crystals from methanol; m.p.
(
and 2-nitrobenzaldehyde (1.02 g, 6.75 mmol) by the above proced-
ure (1.05 g, 55% yield). The isomeric mixture was separated by col-
umn chromatography (silica gel) and eluted with dichloromethane/
MeOH (10:0.01). 11E: Yellow crystals from methanol; m.p. 151 °C
103 °C (decomposition). UV (ethanol): λmax (log ε) ϭ 228 nm
1
(4.18), 310 (4.06). H NMR ([D
6 2
]DMSO): δ ϭ 5.57 (s, 1-H ), 7.06
(d, 5-H), 7.25 (t, 6-H), 7.36 (t, 5Ј-H), 7.44 (m, 7-H), 7.45 (d, 6Ј-H),
1
3
7
.52 (m, 4Ј-H), 7.54 (d, 8-H), 7.70 (d, 3Ј-H), 7.87 (s, α-H) ppm.
]DMSO): δ ϭ 68.9 (C-1), 125.7 (C-8), 126.6 (C-5), 127.3
C-5Ј), 127.5 (C-4), 128.0 (C-6), 128.8 (C-7), 129.4 (C-4a), 129.9
C-3Ј), 130.2 (C-6Ј), 130.9 (C-4Ј), 133.1 (C-8a, C-2Ј), 133.3 (C-1Ј),
C
(
(
(
decomposition). UV (ethanol): λmax (log ε) ϭ 224 nm (4.21), 274
NMR ([D
(
(
6
1
3.93). H NMR (CDCl
3 2
): δ ϭ 5.36 (s, 1-H ), 6.81 (d, 5-H), 7.04
m, 6-H), 7.25 (m, 8-H), 7.26 (m, 7-H), 7.32 (m, 4Ј-H), 7.54 (m, 5Ј-
1
3
3
3
H, 6Ј-H), 8.11 (s, α-H), 8.19 (m, 3Ј-H) ppm. C NMR (CDCl
3
):
1
34.2 (C-α), 167.1 (dt, JHα,C3 ϭ 7.3, J1H,C3 ϭ 5.1 Hz, C-3) ppm.
11ClO (270.72): calcd. C 70.99, H 4.10; found C 70.81, H
.33. 8Z: Faint yellow crystals from methanol; m.p. 122 °C (decom-
position). UV (ethanol): λmax (log ε) ϭ 229 nm (4.17) 304 (4.26).
δ ϭ 69.3 (C-1), 125.1 (C-8, C-3Ј), 126.9 (C-4), 127.4 (C-5), 128.1
C
4
16
H
2
(
(
C-6), 128.7 (C-7), 129.3 (C-4a), 129.7 (C-6Ј), 131.0 (C-4Ј), 131.5
C-1Ј), 132.3 (C-8a), 133.7 (C-5Ј), 135.4 (C-α), 147.7 (C-2Ј), 167.2
3
3
1
(dt, Jα-H,C-3 ϭ 7.2, J1-H,C-3 ϭ 5.1 Hz, C-3) ppm. C16H11NO
4
H NMR ([D
6 2
]DMSO): δ ϭ 5.56 (s, 1-H ) 7.47 (m, 5Ј-H), 7.48 (m,
(
281.27): calcd. C 68.32, H 3.94, N 4.98; found C 68.28, H 4.09, N
4Ј-H), 7.53 (m, 8-H), 7.57 (m, 7-H), 7.62 (m, 6-H), 7.63 (m, 3Ј-
13
4.82. 11Z: Yellow crystals from methanol; m.p. 154 °C (decomposi-
H), 7.68 (s, α-H), 7.74 (m, 6Ј-H), 7.88 (d, 5-H) ppm. C NMR
[D ]DMSO): δ ϭ 68.7 (C-1), 123.9 (C-5), 124.9 (C-8), 126.7 (C-
Ј), 127.6 (C-4), 128.8 (C-7), 129.0 (C-3Ј), 129.1 (C-6), 130.1 (C-
Ј), 131.1 (C-6Ј), 131.9 (C-8a), 132.1 (C-2Ј), 132.7 (C-4a), 134.2 (C-
tion). UV (ethanol): λmax (log ε) ϭ 226 nm, shoulder (4.09) 269
(
6
1
(
4.00). H NMR (CDCl
3
): δ ϭ 5.35 (s, 1-H
2
) 7.25 (dd, 8-H), 7.40
5
4
1
3
7
(
dt, 7-H), 7.47 (m, 6-H), 7.49 (m, 6Ј-H), 7.52 (m, 4Ј-H), 7.64 (dt,
1
3
3
3
5Ј-H), 7.74 (m, 5-H), 7.74 (s, α-H), 8.22 (dd, 3Ј-H) ppm. C NMR
CDCl ): δ ϭ 69.3 (C-1), 124.2 (C-5), 124.4 (C-8), 124.7 (C-3Ј),
26.0 (C-4), 128.8 (C-7), 129.1 (C-4Ј), 129.3 (C-6), 131.0 (C-8a),
31.3 (C-6Ј), 132.3 (C-1Ј), 132.7 (C-4a), 133.4 (C-5Ј), 136.4 (C-α),
Ј), 135.6 (C-α), 164.7 (dt, Jα-H,C-3 ϭ 12.7, J1-H,C-3 ϭ 5.0 Hz, C-
) ppm. C16 11ClO (270.72): calcd. C 70.99, H 4.10; found C
1.11, H 4.20.
(
1
1
3
H
2
3
3
(
E)-4-[(2Ј,3Ј-Dimethoxyphenyl)methylene]-3-isochromanone
This compound was prepared from 3-isochromanone (1.00 g, ppm. C16
.75 mmol) and 2,3-dimethoxybenzaldehyde (1.12 g, 6.75 mmol). C 68.21, H 4.09, N 4.87.
(9E):
147.0 (C-2Ј), 164.6 (dt, Jα-H,C-3 ϭ 12.7, J1-H,C-3 ϭ 4.7 Hz, C-3)
H
11NO (281.27): calcd. C 68.32, H 3.94, N 4.98; found
4
6
Eur. J. Org. Chem. 2002, 2996Ϫ3003
3001

ˆ
T. L o´ r a´ nd, P. Forg o´ , A. Földesi, E. Osz, L. Pr o´ kai
FULL PAPER
2
-[(2Ј-Hydroxymethyl)phenyl]-3H-naphtho[2,1b]pyran-3-one
This compound was prepared from 3-isochromanone (1.00 g,
.75 mmol) and 2-hydroxy-1-naphthaldehyde (1.16 g, 6.75 mmol),
(12):
128.4 (C-4Јa), 128.6 (C-6), 130.4 (C-8a), 131.2 (C-2Ј), 131.3 (C-α),
3
3
135.4 (C-4a), 135.6 (C-7Јa), 166.2 (dt, Jα-H,C-3 ϭ 12.7, J1-H,C-3
ϭ
6
5.0 Hz, C-3).
with addition of ten drops of piperidine. Recrystallization from
methanol gave 12 as white crystals (1.33 g, 65% yield). M.p. 141 °C
(
E)-4-[(2Ј-Bromophenyl)methylene]-3-isochromanone (15E): This
compound was prepared from 3-isochromanone (1.00 g,
6.75 mmol) and 2-bromobenzaldehyde (98%, 1.10 g, 6.75 mmol).
Recrystallization from methanol gave 15E as faint yellow crystals
(
λ
(
(
4
(
8
decomposition). UV (ethanol): λmax (log ε) ϭ (log ε) 233 nm
1
4.84), 325 (4.19), 357 (4.32). H NMR (CDCl
.58 (d, CH ), 7.39 (dt, 6Ј-H), 7.43 (dt, 5Ј-H), 7.50 (dt, 4Ј-H), 7.53
d, 5-H), 7.59 (m, 8-H), 7.61 (d, 3Ј-H), 7.68 (t, 9-H), 7.94 (d, 7-H),
3
): δ ϭ 3.00 (t, OH),
2
1.57 g, 74% yield). M.p. 133 °C (decomposition). UV (ethanol):
1
.03 (d, 6-H), 8.25 (d, 10-H), 8.57 (s, 1-H) ppm. 1 C NMR (CDCl
3
max (log ε) ϭ 310 nm (4.04). H NMR ([D
-H ), 6.99 (d, 5-H), 7.23 (t, 6-H), 7.40 (d, 5Ј-H, 6Ј-H), 7.42 (m,
Ј-H), 7.43 (m, 7-H), 7.53 (d, 8-H), 7.80 (s, α-H), 7.86 (d, 3Ј-H)
6
]DMSO): δ ϭ 5.55 (s,
3
):
), 113.5 (C-10b), 116.6 (C-5), 121.4 (C-10), 126.1 (C-
), 127.7 (C-2), 128.2 (C-5Ј), 128.3 (C-9), 129.0 (C-7, C-10a), 129.5
C-4Ј), 130.1 (C-3Ј), 130.2 (C-6Ј), 130.3 (C-6a), 133.1 (C-6), 134.2
1
4
2
δ ϭ 63.4 (CH
8
2
1
3
ppm. C NMR ([D
(C-8), 126.9 (C-5), 127.4 (C-4), 128.1 (C-5Ј), 128.3 (C-6), 129.1 (C-
7
1
5
6
]DMSO): δ ϭ 69.2 (C-1), 123.6 (C-2Ј), 126.0
(
(
9
3
C-1Ј), 138.3 (C-1), 139.6 (C-2Ј), 153.3 (C-4a), 161.8 (d, J1-H,C-3
.9 Hz, C-3) ppm. C20 (302.33): calcd. C 79.46, H 4.67; found
C 79.58, H 4.70.
ϭ
), 129.5 (C-4a), 130.6 (C-6Ј), 131.3 (C-4Ј), 133.3 (C-8a, C-3Ј),
14 3
H O
3
3
35.5 (C-1Ј), 136.8 (C-α), 167.5 (dt,
1-H,C-3
Jα-H,C-3 ϭ 7.3, J ϭ
.1 Hz, C-3) ppm. C16 11BrO (315.17): calcd. C 60.98, H 3.52;
H
2
found C 61.12, H 3.66.
(E)-4-[(2Ј-Furanyl)methylene]-3-isochromanone (13E) and (Z)-4-[(2Ј-
Furanyl)methylene]-3-isochromanone (13Z): These compounds were
obtained as a 2:1 mixture of (E)/(Z) diastereoisomers (based on
separation) from 3-isochromanone (1.00 g, 6.75 mmol) and 2-fural-
dehyde (0.65 g, 6.75 mmol) by the above procedure (1.23 g, 81%
yield). The isomeric mixture was separated by column chromato-
graphy (silica gel) and eluted with benzene/ethyl acetate (10:1). 13E:
3
-[(2Ј-Hydroxymethyl)phenyl]coumarin (16). Method A: This com-
pound was prepared from 3-isochromanone (0.50 g, 3.38 mmol)
and salicylaldehyde (0.41 g, 3.38 mmol), with addition of ten drops
of piperidine. Recrystallization from ether gave 16 as white crystals.
The product was purified by column chromatography (silica gel)
and eluted with benzene/ethyl acetate (10:1) and recrystallized from
methanol, yielding 16 (0.83 g, 97% yield). M.p. 73Ϫ74 °C. UV (eth-
anol): λmax (log ε) ϭ 290 nm (3.96), 313 (3.92). H NMR (CDCl
δ ϭ 2.84 (t, OH), 4.54 (d, CH
Yellow crystals from ether; m.p. 85 °C (decomposition). UV (eth-
1
anol): λmax (log ε) ϭ 236 nm (4.08), 346 (4.27). H NMR (CDCl
3
):
1
3
):
δ ϭ 5.25 (s, 1-H
7
5
2
), 6.51 (dd, 4Ј-H), 6.86 (d, 3Ј-H), 7.25 (m, 8-H),
.35 (m, 7-H), 7.37 (m, 6-H), 7.43 (d, 5Ј-H), 7.55 (s, α-H), 7.84 (m,
-H) ppm. 13C NMR (CDCl
): δ ϭ 69.2 (C-1), 112.4 (C-4Ј), 117.9
2
), 7.29 (dt, 6Ј-H), 7.34 (t, 6-H), 7.39
(
dt, 5Ј-H), 7.41 (d, 8-H), 7.47 (dt, 4Ј-H), 7.55 (d, 5-H), 7.58 (d, 3Ј-
3
1
3
H), 7.58 (dt, 7-H), 7.77 (s, 4-H) ppm. C NMR (CDCl
3
): δ ϭ 63.3
(C-3Ј), 120.9 (C-4), 123.7 (C-α),124.5 (C-8), 127.7 (C-6), 127.8 (C-
(
(
(
(
CH ), 116.6 (C-8), 119.2 (C-4a), 124.7 (C-6), 127.9 (C-5), 128.1
C-5Ј), 128.8 (C-3), 129.4 (C-4Ј), 129.9 (C-3Ј), 130.0 (C-6Ј), 131.7
C-7), 133.8 (C-1Ј), 139.6 (C-2Ј), 142.2 (C-4), 153.6 (C-8a), 161.7
2
5
2
), 128.3 (C-7), 130.6 (C-4a), 132.0 (C-8a), 144.7 (C-5Ј), 150.2 (C-
Ј), 169.2 (dt, 3
1-H,C-3 ϭ 5.1 Hz, C-3) ppm.
(226.23): calcd. C 74.33, H 4.46; found C 74.48, H 4.46.
3Z: Yellow crystals from ether; m.p. 51 °C (decomposition). UV
ethanol): λmax (log ε) ϭ 236 nm (3.99), 351 (4.44). 1H NMR
CDCl ): δ ϭ 5.26 (s, 1-H ), 6.56 (m, 4Ј-H), 7.19 (m, 8-H), 7.23 (s,
J
α-H,C-3 ϭ 7.5, 3
J
14 10 3
C H O
1
(
(
3
d, J4-H,C-2 ϭ 9.9 Hz, C-2) ppm. MS (APCI): m/z ϭ 253 [M ϩ
ϩ
ϩ
H] , 235 [MH Ϫ H
.79; found C 76.06, H 4.83. Method B: A modified preparation by
the general procedure was applied, yielding a product identical to
6 in every respect. Method C: In a third method, the conditions
2 12 3
O] . C16H O (252.27): calcd. C 76.18, H
4
3
2
α-H), 7.31 (dt, 7-H), 7.39 (dt, 6-H), 7.51 (d, 5-H), 7.55 (m, 5Ј-H),
1
7
4
1
1
.81 (d, 3Ј-H) ppm. 13C NMR (CDCl
Ј), 117.7 (C-3Ј), 119.5 (C-4), 123.4 (C-5), 124.2 (C-8), 127.8 (C-7),
29.0 (C-6), 129.1 (C-α), 131.1 (C-8a), 134.2 (C-4a), 144.8 (C-5Ј),
3
): δ ϭ 69.1 (C-1), 113.1 (C-
above were used, but the mixture was dissolved in ethanol (10 mL)
and the pH was adjusted to 5 with acetic acid at the end of the
reaction. The ethanolic solution was concentrated and the residue
was worked up as in Method A. The product was identical to 16
in every respect.
10 3
50.8 (C-2Ј), 165.3 (C-3) ppm. C14H O (226.23): calcd. C 74.33,
H 4.46; found C 74.25, H 4.59.
(
Z)-4-[(1H-Indol-3-yl)methylene]-3-isochromanone (14): This com-
(
E)-4-[(3Ј-Hydroxyphenyl)methylene]-3-isochromanone (17E): This
compound was prepared from 3-isochromanone (0.50 g,
.38 mmol) and 3-hydroxybenzaldehyde (0.41 g, 3.38 mmol).
Recrystallization from methanol gave 17E as faint yellow crystals
0.55 g, 65% yield). M.p. 228Ϫ230 °C. UV (ethanol): λmax (log ε) ϭ
pound was obtained as a 1:4 mixture of (E)/(Z) diastereoisomers
(
(
based on NMR spectroscopic data) from 3-isochromanone
1.00 g, 6.75 mmol) and indole-2-carbaldehyde (96%, 1.02 g,
3
6
.75 mmol). Recrystallization from methanol gave orange crystals
(
(1.27 g, 68% yield). It was not possible to separate the (E) and (Z)
1
3
4
7
6 2
21 nm (4.42). H NMR ([D ]DMSO): δ ϭ 5.51 (s, 1-H ), 6.89 (d,
Ј-H), 7.01 (s, 2Ј-H), 7.02 (d, 6Ј-H), 7.28 (t, 5Ј-H), 7.32 (t, 6-H),
1
isomers completely, due to isomerization. 14E:
[D ]DMSO): δ ϭ 5.45 (s, 1-H ), 7.07 (m, 5Ј-H), 7.16 (d, 4Ј-H),
.27 (m, 6Ј-H), 7.31 (dt, 6-H), 7.41 (dt, 7-H), 7.54 (d, 8-H), 7.59
d, 7Ј-H), 7.62 (d, 5-H), 8.14 (2 ϫ s, 2Ј-H, α-H), 12.03 (br. s, NH)
H NMR
(
7
(
6
2
.41 (d, 5-H), 7.45 (t, 7-H), 7.54 (d, 8-H), 7.75 (s, α-H), 9.68 (br. s,
13
6
OH) ppm. C NMR ([D ]DMSO): δ ϭ 68.7 (C-1), 115.5 (C-2Ј),
1
1
16.8 (C-4Ј), 120.2 (C-6Ј), 125.2 (C-4), 125.7 (C-8), 126.9 (C-5),
13
ppm. C NMR ([D
(
(
6
]DMSO): δ ϭ 68.4 (C-1), 110.3 (C-3Ј), 112.4
C-7Ј), 117.9 (C-4), 120.3 (C-5Ј), 120.5 (C-4Ј), 122.3 (C-6Ј), 125.3
C-8, C-4Јa), 126.1 (C-5), 127.8 (C-6), 128.4 (C-7), 130.6 (C-2Ј),
31.4 (C-α), 132.1 (C-4a), 132.4 (C-8a), 136.7 (C-7Јa), 168.9 (dt,
27.9 (C-6), 128.6 (C-7), 129.9 (C-5Ј), 130.0 (C-4a), 133.1 (C-8a),
3
1
35.4 (C-1Ј), 138.0 (C-α), 157.5 (C-3Ј), 167.9 (dt, Jα-H,C-3 ϭ 7.3,
3
ϩ
J
1-H,C-3 ϭ 5.4 Hz, C-3) ppm. MS (APCI): m/z ϭ 253 [M ϩ H] .
1
C
16 12 3
H O (252.27): calcd. C 76.18, H 4.79; found C 76.06, H 4.83.
3
3
1
J
3
α-H,C-3 ϭ 7.3, J1-H,C-3 ϭ 5.2 Hz, C-3). 14Z: H NMR (CDCl /
6
[D ]DMSO): δ ϭ 5.23 (s, 1-H), 7.14 (dt, 5Ј-H), 7.17 (dt, 6Ј-H), 7.24 General Method for the Examination of the Thermal Stability of 4-
(
d, 8-H), 7.26 (dt, 7-H), 7.40 (dt, 6-H), 7.44 (dd, 7Ј-H), 7.65 (d, 5-
(Arylmethylene)-3-isochromanones: A mixture of the corresponding
isochromanone (0.2 mmol) and five drops of piperidine was stirred
3
H), 7.72 (s, α-H), 7.80 (dd, 4Ј-H), 8.75 (d, J2Ј-H,N-H ϭ 2.9 Hz, 2Ј-
H), 11.43 (br. s, NH) ppm. 13C NMR (CDCl
/[D
8.3 (C-1), 110.3 (C-3Ј), 111.9 (C-7Ј), 116.1 (C-4), 117.5 (C-4Ј),
20.3 (C-5Ј), 122.0 (C-6Ј), 122.8 (C-5), 123.9 (C-8), 126.3 (C-7), the oily residue was concentrated in vacuo to remove the traces
3
6
]DMSO): δ ϭ at 140 °C under argon for 1 h. The reaction was monitored by
TLC. The mixture was allowed to cool to room temperature, and
6
1
3002
Eur. J. Org. Chem. 2002, 2996Ϫ3003

(
E)- and (Z)-4-(Arylmethylene)-3-isochromanones
FULL PAPER
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[
3]
of piperidine and was checked by NMR spectroscopic methods.
According to the results of the TLC and the NMR method neither
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5
69, 38Ϫ59.
[
[
4]
5]
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follows. Empirical formula: C14
tal system: triclinic; space group: P1; unit cell dimensions: a ϭ
7
1
1
graphy data were collected at 173 K with a Siemens SMART
PLATFORM equipped with a CCD area detector and a graphite
˚
α
monochromator with Mo-K radiation (λ ϭ 0.71073 A). The Θ
range for data collection was 2.11Ϫ27.50°, the number of
reflections collected was 7514 and the number of symmetry-inde-
pendent reflections was 4786. The absorption coefficient was 0.098
[
[
[
6]
7]
8]
H
18
O
3
¯
; formula mass: 226.22; crys-
˚
˚
˚
.3563(5) A, α ϭ 82.485(1)°, b ϭ 10.0159(6) A, β ϭ 80.082(1)°, c ϭ
˚
3
11, 35Ϫ53.
5.448(1) A, γ ϭ 75.395(1)°; V ϭ 1080.4(1) A ; Z ϭ 4; density:
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T. M. AL-Nakib, T. L o´ r a´ nd, A. Földesi, R. Varghese, Med.
Principles Pract. 2001, 10, 191Ϫ196.
3
.391 mg/m ; crystal size: 0.09 ϫ 0.16 ϫ 0.35 mm. X-ray crystallo-
[9]
[10]
[11]
Ϫ1
mm . Cell parameters for each structure were refined by use of
[12]
up to 8192 reflections and a hemisphere of data (1381 frames) was
collected by the ω-scan method (0.3° frame width). Absorption cor-
rections by integration based on measured indexed crystal faces
were applied. The maximal and minimal transmissions were be-
[
[
13]
14]
M. Barbier, Heterocycles 1987, 26, 421Ϫ425.
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[15]
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methods in SHELXTL5[
27]
and refined by full-matrix, least
[16]
squares. The non-H atoms were treated anisotropically, whereas the
hydrogen atoms were placed in calculated ideal positions on their
respective heavy atoms. CCDC-178573 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Center, 12, Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
[
[
17]
18]
K. E. Litinas, X. N. Stampelos, J. Chem. Soc., Perkin Trans. 1
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[
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[21]
[22]
Acknowledgments
The authors thank Dr. Khalil A. Abboud for providing the X-ray
crystallography data and Dr. Corine Sandström (Department of
Chemistry, Swedish University of Agricultural Sciences, Uppsala)
[23]
[24]
1
[25]
for recording 400- and 600-MHz H NMR spectra for some of the
compounds in order to remove ambiguities in the spectral assign-
ments. The authors are similarly indebted to the Optical Spectro-
scopy Group of the Chemical Research Center, Hungarian Acad-
emy of Sciences for the FT-IR studies and to Mrs. G. N e´ meth for
technical assistance.
[
[
26]
27]
S. Okamoto, A. Kasatkin, P. K. Zubaidha, F. Sato, J. Am.
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Received February 4, 2002
[O02061]
Eur. J. Org. Chem. 2002, 2996Ϫ3003
3003