Synthesis of phthalide derivatives using nickel-catalyzed cyclization of o-haloesters with aldehydes

Article abstract of DOI:10.1002/chem.200305740

The reaction of o-bromobenzoate (1b) with benzaldehyde (2a) in the presence of [NiBr₂(dppe)] (dppe = 1,2-bis(diphenylphosphino)ethane) and zinc powder in THF (24 hours, reflux temperature), afforded 3-phenyl-3H- isobenzofuran-1-one (3a) in an 86% yield. Similarly, o-iodobenzoate reacts with 2a to give 3a, but in a lower yield (50%). A series of substituted aromatic and aliphatic aldehydes (2b, 4-MeC₆H₄CHO; 2c, 4-MeOC ₆H₄CHO; 2d, 3-MeOC₆H₄-CHO 2e, 2-MeOC₆H₄-CHO; 2f, 4-CNC₆H₄CHO; 2g, 4-(Me)₃-CC₆H₄CHO; 2h, 4-C₆H ₄C₆H₄CHO; 2i, 4-ClC₆H ₄CHO; 2j, 4-CF₃C₆H₄CHO; 2k, CH ₃(CH₂)₅CHO; 21, CH₃(CH ₂)₂-CHO) also underwent cyclization with o-bromobenzoate (1b) producing the corresponding phthalide derivatives in moderate to excellent yields and with high chemoselectivity. Like 1b, methyl 2-bromo-4,5- dimethoxybenzoate (1c) reacts with tolualdehyde (2b) to give the corresponding substituted phthalide 3m in a 71% yield. The methodology can be further applied to the synthesis of six-membered lactones. The reaction of methyl 2-(2-bromophenyl)acetate (1d) with benzaldehyde under similar reaction conditions afforded six-membered lactone 3o in a 68% yield. A possible catalytic mechanism for this cyclization is also proposed.

Full text of DOI:10.1002/chem.200305740

FULL PAPER
Synthesis of Phthalide Derivatives Using Nickel-Catalyzed Cyclization
of o-Haloesters with Aldehydes
Dinesh Kumar Rayabarapu, Hong-Tai Chang, and Chien-Hong Cheng*[a]
Abstract: The reaction of o-bromoben-
zoate (1b) with benzaldehyde (2a) in
the presence of [NiBr2(dppe)] (dppe=
1,2-bis(diphenylphosphino)ethane) and
zinc powder in THF (24 hours, reflux
temperature), afforded 3-phenyl-3H-
isobenzofuran-1-one (3a) in an 86%
yield. Similarly, o-iodobenzoate reacts
with 2a to give 3a, but in a lower yield
(50%). A series of substituted aromat-
ic and aliphatic aldehydes (2b, 4-
MeC6H4CHO; 2c, 4-MeOC6H4CHO;
2d, 3-MeOC6H4CHO; 2e, 2-MeOC6H4-
CHO; 2 f, 4-CNC6H4CHO; 2g, 4-(Me)3-
CC6H4CHO; 2h, 4-C6H5C6H4CHO; 2i,
4-ClC6H4CHO; 2j, 4-CF3C6H4CHO;
2k, CH3(CH2)5CHO; 2l, CH3(CH2)2-
CHO) also underwent cyclization with
o-bromobenzoate (1b) producing the
corresponding phthalide derivatives in
moderate to excellent yields and with
high chemoselectivity. Like 1b, methyl
2-bromo-4,5-dimethoxybenzoate (1c)
reacts with tolualdehyde (2b) to give
the corresponding substituted phthalide
3m in a 71% yield. The methodology
can be further applied to the synthesis
of six-membered lactones. The reaction
of methyl 2-(2-bromophenyl)acetate
(1d) with benzaldehyde under similar
reaction conditions afforded six-mem-
bered lactone 3o in a 68% yield. A
possible catalytic mechanism for this
cyclization is also proposed.
Keywords: chemoselectivity ¥ cycli-
zation ¥ heterogeneous catalysis ¥
natural products ¥ nickel
Introduction
Phthalides (isobenzofuranones) are five-membered lactones
found in plants. These species possess several important
properties, such as fungicidal,[1,2] bactericidal,[2] herbicidal,[2]
and analgesic activities.[3] In addition, phthalide derivatives
are useful in the treatment of circulatory and heart-related
diseases.[4] In spite of their numerous valuable functions,
there are only a few efficient metal-mediated reactions
Scheme 1. Palladium-catalyzed cyclocarbonylation reaction.
ployed as a one-carbon source. Recently, the use of ortho-
halobenzenes as reagents for the synthesis of five-, six-, and
seven-membered carbocycles[11,12] or heterocycles[13] cata-
lyzed by metal complexes has attracted great attention. Our
interest in the nickel-catalyzed[14] cyclization reactions led us
to investigate the reaction of o-halobenzoates with alde-
hydes in the presence of nickel complexes. Herein, we wish
to report a novel, highly chemoselective cyclization of o-halo-
benzoates with aldehydes catalyzed by nickel complexes to
afford phthalides. This new cyclization reaction provides a
convenient method for the synthesis of various substituted
phthalides in a one-pot reaction, with good to excellent
yields from easily available starting materials.
9]
known for the synthesis of phthalides.[5
Cowell and Stille reported a cyclocarbonylation[10] of o-io-
dobenzyl alcohols catalyzed by palladium complexes,[5]
whereas Larock et al. reported a two-step process involving
an ortho-thallation of o-iodobenzyl alcohols and a palladi-
um-catalyzed cyclocarbonylation of the thallated intermedi-
ate (Scheme 1).[6] A palladium-catalyzed carbonylative cycli-
zation of o-bromobenzaldehyde in the presence of nucleo-
philes at very high CO pressure to give phthalide derivatives
was also reported.[7] In all these reactions, CO gas was em-
[a] Dr. D. K. Rayabarapu, H.-T. Chang, Prof. C.-H. Cheng
Department of Chemistry, Tsing Hua University
Hsinchu 300 (Taiwan)
Results and Discussion
Fax : (+886)3-5724698
E-mail: chcheng@mx.nthu.edu.tw
The reaction of 2-iodobenzoate (1a) with benzaldehyde
(2a) in THF in the presence of [NiBr2(dppe)] (dppe: bis(di-
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 2991 2996
DOI: 10.1002/chem.200305740
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2991

FULL PAPER
phenylphosphino)ethane) and zinc powder (24 hours, reflux
temperature), afforded substituted phthalide 3a in a 50%
yield (Scheme 2 and Table 2 later). Under similar conditions,
the reaction of 2-bromobenzoate (1b) with 2a also gave 3a,
but in a much higher yield (86%). Product 3a was fully
such as [NiBr2(dppm)], [NiBr2(dppp)], [NiBr2(dppb)],
[NiCl2(dppe)], and [NiI2(dppe)], afforded 3a in 72, 79, 58,
67, and 71% yields, respectively. [NiBr2(dppe)] appears
to be the best catalyst for this cyclization reaction, afford-
ing 3a in an 86% yield. The catalytic reaction also depends
greatly on the solvent employed: no reaction occurred in
CH2Cl2 and both diethyl ether and DMF afforded only a
trace of product, whereas, CH3CN, toluene, dioxane, and
ethyl acetate afforded 3a in moderate yields. THF was
found to be the solvent of choice when using [NiBr2(dppe)]
as the catalyst. Surprisingly, palladium complexes appear be
totally ineffective for this cylization. No product was ob-
served for the reaction of 1a/1b with 2a in the presence of
[Pd(dba)2]/Zn (dba=trans,trans-dibenzylideneacetone) or
[PdCl2(dppe)]/Zn under similar reaction conditions.
Similar to the reaction with benzaldehyde, the cyclization
of 1a with tolualdehyde (2b) and anisaldehyde (2c), gave
lactonization products 3b and 3c in low yields (48 and
~0%, respectively). The product yield improves greatly by
using bromobenzoate as the substrate. Thus, 1b reacts with
2b and 2c affording 3b and 3c in 91 and 92% yields, respec-
tively (Table 2 entries 4, 6). The lactonization of 1b was suc-
cessfully extended to other aldehydes. Treating 1b with m-
and o-anisaldehyde (2d, 2e) afforded the corresponding lac-
tones 3d and 3e in 81 and 86% yields, respectively. The re-
action of 4-(tert-butyl)benzaldehyde and 4-phenylbenzalde-
hyde with 1b produced 3g and 3h in excellent yields
(Table 2 entries 10, 11). Similarly, the reaction of 1b with 4-
cyanobenzaldehyde (2 f), 4-chlorobenzaldehyde (2i), and 4-
(trifluoromethyl)benzaldehye (2j) afforded lactones 3 f, 3i,
and 3j in 80, 61, and 88% yields, respectively, with excellent
chemoselectivity (Table 2 entries 9, 12, 13). Under similar
conditions, dialdehyde 2m reacted smoothly with 1b to give
diphthalide derivative 3n in a 52% yield (Scheme 3). Inter-
Scheme 2. Nickel-catalyzed cyclization reaction to produce phthalides.
characterized by its spectral data. A common byproduct is
(o-PhCOOMe)2, from the reductive homocoupling of 1a or
1b. The presence of this byproduct is much lower for bro-
mobenzoate 1b than for the iodo analogue 1a.
To understand the nature of the present catalytic reaction,
the effects of catalyst and solvent on the reaction of 1b with
2a were examined, and the results are summarized in
Table 1. Nickel complexes with monodentate phosphine li-
Table 1. Effects of ligands and solvent on the cyclization reaction of
o-bromobenzoate (1b) with benzaldehyde (2a).[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
THF
THF
THF
THF
THF
THF
THF
THF
THF
0
trace
trace
trace
0
72
91
79
58
67
71
0
trace
trace
43
38
70
[NiCl2(PPh3)2]
2(PPh3)2]
1
estingly, a single isomer was apparent by H and 13C NMR,
3[NiBr
4
5
6
7
8
9
10
11
12
13[NiBr
14
15
16
17
18
19
[NiBr2(PPh2Me)2]
[NiBr2(bipy)]
[NiBr2(dppm)]
[NiBr2(dppe)]
[NiBr2(dppp)]
[NiBr2(dppb)]
[NiCl2(dppe)]
[NiI2(dppe)]
[NiBr2(dppe)]
2(dppe)]
[NiBr2(dppe)]
[NiBr2(dppe)]
[NiBr2(dppe)]
[NiBr2(dppe)]
[NiBr2(dppe)]
[Pd(dba)2]
THF
THF
CH2Cl2
diethyl ether
DMF
toluene
dioxane
ethyl acetate
CH3CN
THF
Scheme 3. Synthesis of a diphthalide derivative.
42
0
and single-crystal X-ray analysis of a recrystallized sample
illustrated the meso stereochemistry. The cyclization reac-
tion can also be applied to aliphatic aldehydes, although in
lower yields (entries 14, 15). The present cyclization method
was extended to methoxy-substituted bromoester (1c),
which, when treated with 2b under standard conditions, pro-
duced phthalide 3m in a 71% yield (entry 16). Overall, the
cyclization reaction tolerates a variety of functional groups,
such as alkyl, cyano, methoxy, and chloro, on the aromatic
ring of aldehydes. The product yield is much less sensitive to
the substituent on the aldehyde for 2-bromobenzoate than
for 2-iodobenzoate.
20
[PdCl2(dppe)]
THF
0
[a] Unless stated otherwise, all reactions were carried out by using a Ni
catalyst (0.0500 mmol), Zn (2.75 mmol), 1b (1.50 mmol), and 2a
(1.00 mmol) in a solvent (2.0 mL) at reflux temperature for 24 h under
N2; [b] Yields were determined by 1H NMR analysis with mesitylene as
the internal standard.
gands, such as [NiCl2(PPh3)2], [NiBr2(PPh3)2], and
[NiBr2(PPh2Me)2], afforded a trace of 3a. No product was
observed when [NiBr2(bipy)] (bipy=2,2’-bipyridine) was
used. Complexes containing bidentate phosphine ligands,
2992
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Chem. Eur. J. 2004, 10, 2991 2996

Synthesis of Phthalide Derivatives
2991 2996
Table 2. Results of the nickel-catalyzed cyclization of o-haloesters with aldehydes.[a]
Unexpectedly, the reaction of
methyl 2-(2-bromophenyl)ace-
tate (1d) with 2a produced six-
membered lactone 3o consist-
ing of Z and E isomers in a
ratio of about 1:3.3 (Scheme 4).
The product is evidently from
two molecules of aldehyde 2a
and one molecule of 1d. Con-
densation of the a-methylene
group of 1d or the subsequent
intermediate with 2a during the
reaction explains the formation
of 3o.
On the basis of the above ob-
servations and the known or-
ganometallic chemistry of nickel,
a catalytic cycle is proposed as
shown in Scheme 5. Reduction
of nickel(ii) to nickel(0) by
using zinc powder[15] is likely to
initiate the catalytic reaction.
Oxidative addition of aryl
iodide to the nickel(0) species
yields the nickel(ii) intermedi-
ate 4. Coordination of an alde-
hyde molecule to the nickel
center, followed by insertion
into the nickel carbon bond, af-
fords nickel alkoxide inter-
mediate 6. Attack of the coor-
dinated alkoxy group at the
ester moiety of 6 gives the final
phthalide derivative 3 and nick-
el(ii). The latter is reduced by
zinc powder to regenerate the
active nickel(0) species.
1
Entry
R
CHO
Product
Yield[b]
[%]
À
R
X
R1
1
2
H
H
I
1a
1b
C6H5 (2a)
(2a)
50
86
Br
3a
3b
3c
3
4
5
H
H
H
I
1a
1b
1a
4-MeC6H4 (2b)
(2b)
48
91
0
Br
I
4-MeOC6H4 (2c)
6
7
H
H
Br
Br
1b
1b
(2c)
92
81
3-MeOC6H4 (2d)
8
9
H
H
Br
Br
1b
1b
2-MeOC6H4 (2e)
4-CNC6H4 (2 f)
86
80
10
H
Br
1b
4-(CH3)3CC6H4 (2g)
90
A possible reason for the en-
hanced catalytic activity of bi-
dentate phosphine ligands com-
pared with those that are mono-
dentate is the formation of
catalytic intermediates 4 and 5
with cis structures. The cis ar-
rangement facilitates insertion
of the coordinated aldehyde
into the nickel carbon bond in
5 to give intermediate 6. For a
nickel catalyst with monoden-
tate ligands, such as triphenyl-
phosphine, the oxidative addi-
tion of aryl halide to nickel(0)
11
12
H
H
Br
Br
1b
1b
4-C6H5C6H4 (2h)
95
61
ClC6H4 (2i)
13H
14
Br
1b
1b
4-CF3C6H4 (2j)
CH3(CH2)5 (2k)
88
36
generally
gives
trans-
[NiL(Ar)X] because of steric
repulsion of the two bulky
phosphine ligands. The substitu-
ents of the trans structure are
inappropriately positioned for
aryl migration to the carbonyl
H
Br
Chem. Eur. J. 2004, 10, 2991 2996
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C.-H. Cheng et al.
FULL PAPER
Table 2. (Continued)
palladium intermediate is much
slower than with nickel, and so
does not afford a lactonization
product.
1
Entry
R
Product
Yield[b]
[%]
À
CHO
R
X
R1
Conclusion
15
16
H
Br
1b
1c
CH3(CH2)2 (2l)
24
71
In conclusion, we have demon-
strated that nickel complexes
effectively catalyze the cycliza-
tion of o-bromobenzoate with
aldehydes to afford phthalide
derivatives in excellent yields
and with high chemoselectivity
under mild conditions. This new
reaction provides a remarkable
methodology for the construc-
OCH3
Br
(2b)
[a] Reactions were carried out using the aldehyde (1.0 mmol), organic halide (1.50 mmol), [NiBr2(dppe)]
(0.050 mmol, 5.0 mol%), and Zn (2.75 mmol) in THF (2.0 mL) at reflux temperature for 24 h under N2;
[b] Isolated yields were based on the aldehyde used.
tion of phthalide cores in a one-pot reaction. We are now
working to explore the full scope of this new catalytic reac-
tion, including an asymmetric version.
Experimental Section
Scheme 4. Synthesis of a six-membered lactone.
All reactions were conducted under a nitrogen atmosphere on a dual-
manifold Schlenk line by using purified deoxygenated solvents and stan-
dard inert-atmosphere techniques, unless stated otherwise. Reagents and
chemicals were used as purchased, without further purification.
[NiBr2(dppe)] was synthesized according to a reported procedure.[16]
General procedure for the cyclization of 2-bromobenzoates (1) with alde-
hydes (2): A round-bottomed side-arm flask (25 mL) fitted with a reflux
condenser containing [NiBr2(dppe)] (0.050 mmol, 5.0 mol%) and zinc
powder (2.75 mmol) was evacuated and purged with nitrogen gas three
times. Freshly distilled THF (2.0 mL), o-bromobenzoate (1.50 mmol),
and aldehyde (1.00 mmol) were sequentially added to the system, and
the reaction mixture was stirred under reflux conditions for 24 h. The re-
action mixture was cooled to RT, diluted with dichloromethane, and then
stirred in air for 15 min. The mixture was filtered through a short Celite
and silica-gel pad, and washed with dichloromethane several times. The
filtrate was concentrated, and the residue purified on a silica-gel column
by using hexanes/ethyl acetate as the eluent, to afford cyclization product
3.
Spectral data for all new compounds
3-Phenyl-3H-isobenzofuran-1-one (3a): 1H NMR (400 MHz, CDCl3): d=
7.96 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.55 (t, J=6.4 Hz, 1H),
7.39 7.32 (m, 6H), 6.40 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=
170.48 (s, C=O), 149.65 (s), 136.40 (s), 134.29 (d), 129.33 (d), 129.27 (d),
128.95 (d), 128.44 (s), 126.94 (d), 125.84 (d), 122.83(d), 82.68 ppm (d);
HRMS: m/z calcd for C14H10O2: 210.0681; found: 210.0683.
3-(4-Methylphenyl)-3H-isobenzofuran-1-one (3b): 1H NMR (400 MHz,
CDCl3): d=7.96 (d, J=6.4 Hz, 1H), 7.63(t, J=7.6 Hz, 1H), 7.57 (t, J=
7.2 Hz, 1H), 7.31 (d, J=6.8 Hz, 1H), 7.20 7.14 (m, 4H), 6.38 (s, 1H),
2.35 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=170.54 (s, C=O),
149.77 (s), 139.28 (s), 134.23 (d), 133.36 (s), 129.59 (d), 129.24 (d), 127.01
(d), 125.66 (s), 125.52 (d), 122.82 (d), 82.73(d), 21.18 ppm (q); HRMS:
m/z calcd for C15H12O2: 224.0837; found: 224.0831.
3-(4-Methoxyphenyl)-3H-isobenzofuran-1-one (3c): 1H NMR (400 MHz,
CDCl3): d=7.93(d, J=7.6 Hz, 1H), 7.63(t, J=7.2 Hz, 1H), 7.53(t, J=
7.2 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 6.87 (d, J=
8.8 Hz, 2H), 6.35 (s, 1H), 3.78 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=170.48 (s, C=O), 160.37 (s), 149.71 (s), 134.18 (d), 129.24 (d),
128.73(d), 128.24 (s), 125.88 (s), 125.51 (d), 122.88 (d), 114.27 (d), 82.67
(d), 55.27 ppm (q); HRMS: m/z calcd for C15H12O2: 240.0786; found:
240.0790.
Scheme 5. Possible mechanism for the nickel-catalyzed cyclization reac-
tion.
carbon of the coordinated aldehyde, thus, greatly reducing
the yield of the product.
Unlike the present nickel-catalyzed cyclization reaction,
the reaction using palladium complexes as catalysts fails to
give the desired lactone product, but instead affords only
the homocoupling product (o-(C6H4)CO2Me)2. The differ-
ence in catalytic behavior can be attributed to the fact that
nickel complexes are generally more labile than palladium
species; thus, the substitution of a halide ligand by an alde-
hyde and the subsequent insertion into the corresponding
2994
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Chem. Eur. J. 2004, 10, 2991 2996

Synthesis of Phthalide Derivatives
2991 2996
3-(3-Methoxyphenyl)-3H-isobenzofuran-1-one (3d): 1H NMR (400 MHz,
CDCl3): d=7.91 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.51 (t, J=
7.2 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.2 Hz, 1H), 6.88 6.84
(m, 2H), 6.76 (s, 1H), 6.34 (s, 1H), 3.73 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=170.42 (s, C=O), 159.91 (s), 149.51 (s), 137.85 (s),
134.26 (d), 129.98(d), 129.28 (d), 125.51 (d), 125.34 (s), 122.76 (d), 118.99
(d), 114.52 (d), 112.32 (d), 82.42 (d), 55.21 ppm (q); HRMS: m/z calcd
for C15H12O2: 240.0786; found: 240.0783.
3-(2-Methoxyphenyl)-3H-isobenzofuran-1-one (3e): 1H NMR (400 MHz,
CDCl3): d=7.93(d, J=7.2 Hz, 1H), 7.60 (t, J=6.4 Hz, 1H), 7.52 (t, J=
7.2 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.08 (d, J=
7.6 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.90 (t, J=7.6 Hz, 1H), 6.85 (s,
1H), 3.90 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=170.93(s, C =O),
156.95 (s), 150.34 (s), 134.06 (d), 130.08 (d), 128.93 (d), 126.82 (d), 125.57
(s), 125.33 (d), 124.94 (s), 122.87 (d), 120.78 (d), 110.94 (d), 78.01 (d),
55.53ppm (q); HRMS: m/z calcd for C15H12O2: 240.0786; found:
240.0781.
4-(3-Oxo-1,3-dihydro-1-isobenzofuranyl)benzonitrile (3 f): 1H NMR
(400 MHz, CDCl3): d=7.94 (d, J=7.6 Hz, 1H), 7.67 7.63(m, 3H), 7.56
(t, J=7.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H),
6.41 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=170.00 (s, C=O),
148.47 (s), 141.62 (s), 134.67 (d), 132.79 (d), 129.86 (d), 127.31 (d), 125.98
(d), 125.08 (s), 122.58 (d), 118.07 (s), 113.13 (s), 81.18 ppm (d); HRMS:
m/z calcd for C15H9O2N: 235.0633; found: 235.0633.
5,6-Dimethoxy-3-(4-methylphenyl)-3H-isobenzofuran-1-one (3m): 1H
NMR (400 MHz, CDCl3): d=7.30 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.10
(d, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.22 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H),
2.31 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=21.4 (q), 56.5 (q),
82.5 (d), 104.2 (d), 106.0 (d), 117.9 (s), 127.4 (d), 129.8 (d), 133.8 (s),
139.5 (s), 144.5 (s), 150.8 (s), 155.2 (s), 171.0 ppm (s, C=O); HRMS: m/z
calcd for C17H16O4: 284.1049; found: 284.1045.
1,2-Diphthalidylbenzene (3n): 1H NMR (400 MHz, CDCl3): d=7.69 (d,
J=7.2 Hz, 2H), 7.69 (t, J=7.6 Hz, 2H), 7.56 (t, J=8.0 Hz, 2H), 7.46 (d,
J=7.6 Hz, 2H), 7.37 (dd, J=6.0, 2.0 Hz, 2H), 7.19 (dd, J=6.0, 2.0 Hz,
2H), 6.39 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=170.00 (s, C=O),
149.21 (s), 134.87 (d), 134.66 (s), 129.89 (d), 129.68 (d), 129.76 (d), 125.46
(s), 123.05 (d), 80.08 ppm (d); HRMS: m/z calcd for C22H14O4: 342.0892;
found: 342.0882.
1-Phenyl-4-[(E)-1-phenylmethylidene]-3,4-dihydro-1H-3-isochromenone
(3o): 1H NMR (500 MHz, CDCl3): d=7.76 (s, 1H), 7.45 7.32 (m, 9H),
7.30 7.27 (m, 2H), 7.24 (t, J=7.0 Hz, 1H), 7.14 (td, J=7.5, 1.0 Hz, 1H),
7.03(d, J=8.0 Hz, 1H), 6.41 ppm (s, 1H); HRMS: m/z calcd for
C22H16O2: 312.1150; found: 312.1154.
Acknowledgements
3-[4-(tert-Butyl)phenyl]-3H-isobenzofuran-1-one
(3g):
1H
NMR
(400 MHz, CDCl3): d=7.94 (d, J=8.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H),
7.54 (t, J=6.8 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.38 (d, J=7.6 Hz, 2H),
7.35 (d, J=7.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.38 (s, 1H), 1.27 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3): d=170.51 (s, C=O), 152.41 (s),
149.67 (s), 134.17 (d), 133.25 (s), 129.20 (d), 126.78 (d), 125.85 (d), 125.69
(s), 125.51 (d), 122.91 (d), 82.63 (d), 34.61 (s), 31.16 ppm (q); HRMS:
m/z calcd for C18H18O2: 266.1307; found: 266.1312.
3-Biphenyl-4-yl-3H-isobenzofuran-1-one (3h): 1H NMR (400 MHz,
CDCl3): d=7.97 (d, J=7.2 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.59 7.54
(m, 5H), 7.42 (t, J=7.6 Hz, 2H), 7.38 7.32 (m, 4H), 6.44 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=170.70 (s, C=O), 149.85 (s), 142.56 (s),
140.51 (s), 135.56 (s), 134.59(d), 129.64 (d), 129.09 (d), 127.93 (d), 127.70
(d), 127.36 (d), 125.93 (d), 123.13 (d), 114.46 (d), 82.72 ppm (d); HRMS:
m/z calcd for C20H14O2: 286.0994; found: 286.0992.
3-(4-Chlorophenyl)-3H-isobenzofuran-1-one (3i): 1H NMR (400 MHz,
CDCl3): d=7.97 (d, J=7.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.57 (t, J=
7.2 Hz, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 7.21 (d, J=
7.6 Hz 1H), 6.37 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=170.44 (s,
C=O), 149.44 (s), 135.55 (s), 135.21 (s), 134.69 (d), 129.81 (d), 129.46 (s),
128.58 (s), 126.02 (d), 125.76 (s), 112.98 (d), 82.08 ppm (d); HRMS: m/z
calcd for C14H9ClO2: 244.0291; found: 244.0286.
3-(4-Trifluoromethylphenyl)-3H-isobenzofuran-1-one (3j): 1H NMR
(400 MHz, CDCl3): d=7.97 (d, J=7.2 Hz, 1H), 7.68 7.63(m, 2H), 7.57
(t, J=7.2 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.32 (d, J=7.6 Hz, 2H),
6.43ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=170.06 (s, C=O),
148.89 (s), 140.47 (s), 134.53 (d), 131.01 (s), 129.65(d), 127.04 (d), 125.91
(d), 125.75 (d), 125.04 (s), 122.65 (d), 81.44 ppm (d); HRMS: m/z calcd
for C15H9F3O2: 278.0555; found: 278.0564.
3-Hexyl-3H-isobenzofuran-1-one (3k): 1H NMR (400 MHz, CDCl3): d=
7.88 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H),
7.41 (d, J=7.6 Hz, 1H), 5.45 (dd, J=8.0, J=4.0 Hz, 1H), 2.04 1.95 (m,
1H), 1.69 1.72 (m, 1H), 1.49 1.40 (m, 2H), 1.38 1.30 (m, 4H), 1.29 1.23
(m, 2H), 0.85 ppm (t, J=5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
170.68 (s, C=O), 150.13 (s), 133.89 (d), 128.99 (d), 126.15 (s), 125.69 (d),
121.68 (d), 81.44 (d), 34.74 (t), 31.56 (t), 28.97 (t), 24.75 (t), 22.49 (t),
14.00 ppm (q); HRMS: m/z calcd for C14H18O2: 218.1307; found:
218.1302.
3-Propyl-3H-isobenzofuran-1-one (3l): 1H NMR (400 MHz, CDCl3): d=
7.87 (d, J=7.6 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.2 Hz, 1H),
7.41 (d, J=7.2 Hz, 1H), 5.46 (dd, J=8.0, 4.0 Hz, 1H), 2.01 1.95 (m, 1H),
1.77 1.68 (m, 1H), 1.56 1.35 (m, 2H), 0.92 ppm (t, J=7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d=170.86 (s, C=O), 150.36 (s), 133.11 (d),
129.21 (d), 126.39 (s), 125.91 (d), 121.91 (d), 81.47 (d), 34.07 (t), 18.44 (t),
13.99 ppm (q); HRMS: m/z calcd for C11H12O2: 176.0837; found:
176.0845.
We thank the National Science Council (Grant NSC 92-2113-M-007-044)
of the Republic of China for the support of this research.
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Received: November 22, 2003
Published online: April 28, 2004
2996
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 2991 2996