Palladium-catalyzed synthesis of isocoumarins and phthalides via tert -butyl isocyanide insertion

Article abstract of DOI:10.1021/jo302004u

A novel and highly efficient strategy for the synthesis of isocoumarins and phthalides through a palladium(0)-catalyzed reaction incorporating tert-butyl isocyanide has been developed. This process, providing one of the simplest methods for the synthesis of this class of valuable lactones, involves two steps including cyclization reaction and simple acid hydrolysis. The methodology is tolerant of a wide range of substrates and applicable to library synthesis.

Full text of DOI:10.1021/jo302004u

Article
pubs.acs.org/joc
Palladium-Catalyzed Synthesis of Isocoumarins and Phthalides via
tert-Butyl Isocyanide Insertion
Xiang-Dong Fei,† Zhi-Yuan Ge,† Ting Tang,† Yong-Ming Zhu,*,† and Shun-Jun Ji*,‡
†College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
‡College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China
S
* Supporting Information
ABSTRACT: A novel and highly efficient strategy for the synthesis of isocoumarins and phthalides through a palladium(0)-
catalyzed reaction incorporating tert-butyl isocyanide has been developed. This process, providing one of the simplest methods
for the synthesis of this class of valuable lactones, involves two steps including cyclization reaction and simple acid hydrolysis.
The methodology is tolerant of a wide range of substrates and applicable to library synthesis.
approach. Enlightened by the above literature, we surmised that
the insertion of tert-butyl isocyanide into the substrate to
synthesize isocoumarins and phthalides might be possible
(Scheme 1). However, we considered whether isocyanide can
INTRODUCTION
■
Isocoumarins and phthalides represent an important class of
naturally occurring lactones,1 which are structural subunits in
numerous natural products exhibiting a wide range of biological
and pharmacological activities.2 For example, 3-phenylisocou-
marin (3a) could completely prevent visible growth of fungi,
including Alternaria maritime, Cochliobolus miyabeanus, Fusa-
rium splendens, etc.2a (Z)-3-(2-Chlorobenzylidene)phthalide
(6e) strongly inhibits HIV replication via acting through
inhibition interference with Tat function.2f In addition,
isocoumarins and phthalides are useful synthetic intermediates,
particularly for further elaboration to other biologically
heterocyclic3 and carbocyclic compounds.4 So far, various
methods for constructing lactones have been explored and
reported.5 Previously, we’ve reported copper-catalyzed syn-
thesis of 3-substituted isocoumarins via a cascade intra-
molecular process.6 In a continuation to our interest, we are
making an effort to investigate some more novel and efficient
methods for the synthesis of this class of lactones.
Scheme 1. Strategy to Isocoumarins and Phthalides via tert-
Butyl Isocyanide Insertion
be easily coupled with oxygen atom of enolic form by carbonyl
tautomerism. To our delight, this method, which uses
Pd(OAc)2/DPEPhos as the catalyst system, has advantages
such as simple handling, wide substrate scope and mild
conditions over carbon monoxide.14 To the best of our
Recently, small molecular insertions for the synthesis of
biologically important moieties have been reported. tert-Butyl
isocyanide,7−13 a kind of unsaturated molecule similar to
carbon monoxide, has emerged as an irreplaceable building
block in the construction of important molecules. A wide range
of organic compounds including azaindole,7 indoloquinoline,8
quinazoline,9 phthalazinone,10 isoquinolinone,11 azomethine12
and (imino)isoindolinone13 has been synthesized through this
Received: September 14, 2012
Published: October 26, 2012
© 2012 American Chemical Society
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knowledge, no example of utilizing isocyanides as a carbonyl
source to synthesize lactones have been reported. Herein, we
report this novel and practical synthesis of lactones via
palladium-catalyzed C−C and C−O coupling of substrates
with tert-butyl isocyanide, followed by acid hydrolysis in almost
theoretical yield.
rich and electron deficient aromatics both gave high yields
(Table 2, entries 1−9). Note that good yields were also
obtained when R3 was a naphthalene, heteroaryl or aliphatic
group (Table 2, entries 10−14). In addition, substrates
including disubstituents R2 and R3, such as 1o and 1p, also
generated 3o and 3p in moderate yields, respectively (Table 2,
entries 15 and 16). Substrate 1q gave product 3q only in 39%
yield because of hydrolyzation of the acetal (Table 2, entry 17).
To further evaluate this practical approach, a variety of
substrates 4a−4i were investigated, and the results are
summarized in Table 3. This method was successfully applied
to synthesize various phthalides. At the outset, we considered
probably obtaining a mixture of cis−trans isomerism, which
made the purification difficult. However, only one main spot
was observed on TLC after completion of the reaction.
Through comparing the NMR data of 6a with the reference,15
we confirmed 6a as Z-configuration. Electron-rich substitutes
afforded higher yields than electron-poor counterparts (Table
3, entries 2−7). Product 6e was formed in only 37% yield due
to side reaction during the cyclization step (Table 3, entry 5).
Note, substrates with aliphatic groups such as decyl and
cyclohexyl generated products 6h and 6i in moderate yields
(Table 3, entries 8 and 9).
On the basis of the above experimental results and related
reports,9−11 a plausible mechanism for this reaction is outlined
in Scheme 2. Oxidative addition of 1a to the Pd(0) catalyst
leads to a palladium complex 7, followed by tert-butyl
isocyanide insertion to form 8. Palladium(II) in complex 8,
which coordinates to the oxygen atom of hydroxyl group,
promotes the formation of 9. Reductive elimination of 9 leads
to the intermediate 2a, which yields product 3a by acid
hydrolysis.
In summary, we have developed a simple and efficient
method for the synthesis of isocoumarins and phthalides from
easily accessible substrates and tert-butyl isocyanide. This
process, which provides one of the easiest pathways for
accessing this class of valuable compounds, uses Pd(OAc)2/
DPEPhos as the catalyst system and THF/hydrochloric acid as
the hydrolysis condition. We obtained Z-configuration of 3-
substituted phthalides. Characterized by mild reaction con-
ditions and good to excellent yields, this protocol may be very
attractive in synthetic organic and medicinal chemistry.
RESULTS AND DISCUSSION
■
In an initial study, reaction of 1a with tert-butyl isocyanide was
examined in DMF at 120 °C in the presence of Pd(OAc)2 (5
mol %) and Xantphos (10 mol %), which was found to be
effective for the tert-butyl isocyanide insertion (Table 1, entry
Table 1. Condition Optimizations of 1a with tert-Butyl
a
Isocyanide
b
entry
ligand
base
solvent
yield (%)
1
Xantphos
DPPF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
dioxane
78
79
75
70
71
65
68
94
62
23
82
15
68
2
3
(R)-BINAP
PPh3
4
5
PCy3
6
TFP
7
P(o-tol)3
DPEPhos
−
DPEPhos
DPEPhos
DPEPhos
DPEPhos
8
9
10
11
c
12
d
13
a
Reaction conditions: All reactions were performed with 1a (0.5
mmol), tert-butyl isocyanide (0.75 mmol), Pd(OAc)2 (2.5 mol %),
ligand (5 mol %) and base (1.0 mmol) in 3.0 mL of solvent at 120 °C
for 2 h. Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxan-
thene, DPPF = 1,1′-Bis(diphenylphosphino)ferrocene, (R)-BINAP =
(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, PCy3 = tricyclohex-
ylphosphine, TFP = tri(2-furyl)phosphine, DPEPhos = bis[(2-
b
c
diphenylphosphino)phenyl]ether. Isolated yield. Reaction at 110
°C. Reaction at 100 °C
d
EXPERIMENTAL SECTION
■
General Remarks. Chemicals and reagents were purchased from
commercial suppliers and used without further purification. All
anhydrous solvents used in the reactions were dried and freshly
distilled. TLC was performed on silica HSGF254 plates. Melting
points were determined with a digital melting-point apparatus. 1H and
13C NMR spectra were obtained from a solution in CDCl3 or DMSO
with TMS as internal standard using a 400/101 MHz (1H/13C) or
300/75 MHz (1H/13C) spectrometer. Chemical shifts (δ) are given in
ppm and J in Hz. IR spectra were recorded in KBr tablets, and
wavenumbers are given in cm−1. HRMS analyses were carried out on
an electrospray ionization (ESI) apparatus using time-of-flight (TOF)
mass spectrometry.
1). The reaction of 1a took place efficiently to give product 2a
in 78% yield after 2 h. Then, several phosphorus ligands or no
ligand were tested in this reaction, and a 94% yield of the
expected product was obtained when DPEPhos was employed
as the ligand (Table 1, entries 2−9). Bases were also tested, and
in comparison use of K2CO3, Cs2CO3 resulted in diminished
yield (Table 1, entry 10). When the solvent was switched to
DMSO, toluene, or dioxane, the yield of 2a decreased (Table 1,
entries 11−13). On the basis of these considerations, the
optimal reaction condition was set as Pd(OAc)2 (5 mol %) and
DPEPhos (10 mol %) in DMF using K2CO3 (2 equiv) as a
base. Then, acid hydrolysis of 2a could make the generation of
3-phenylisocoumarin 3a in high yield.
General Procedure for the Synthesis of lactones. A sealed
tube was charged with a magnetic stir bar, 1 or 4 (0.5 mmol),16 tert-
butyl isocyanide (0.75 mmol, 85 μL), Pd(OAc)2 (2.5 mol %, 6 mg),
DPEPhos (5 mmol %, 27 mg), K2CO3 (1.0 mmol, 138 mg) and
anhydrous DMF (3 mL). The tube was purged with nitrogen gas and
stirred at 120 °C for 2 h. After reaction completion, the mixture was
filtered through a short plug of Celite, and DMF was removed by a
vacuum. The combined filtrates were refluxed in THF (15 mL) and
hydrochloric acid (1 M, 3 mL) for 2 h. Then, the mixture was
With the optimized reaction conditions in hand, we then
tested the scope and generality of the method. Various
substitutes in R3, including aryl (Table 2, entries 1−10),
heteroaryl (Table 2, entries 11 and 12), and alkyl (Table 2,
entries 13 and 14), were well tolerated. Substrates with electron
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a
Table 2. Synthesis of Isocoumarins from Substrates (1a−1r) with tert-Butyl Isocyanide
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Table 2. continued
a
All reactions were performed under N2 on a 0.5 mmol scale, using tert-butyl isocyanide (0.75 mmol), Pd(OAc)2 (2.5 mol %), DPEPhos (5 mol %),
b
and K2CO3 (1.0 mmol) in DMF (3 mL) at 120 °C for 2 h, followed by refluxing in THF/hydrochloric acid for 2 h. Isolated yield.
extracted with EtOAc, dried (Na2SO4) and evaporated. The residue
was purified on a silica gel column using petroleum ether/EtOAc as
the eluent to give the pure target product.
125.0, 120.2, 100.9, 21.3; IR (KBr) ν = 3067, 3034, 2965, 2920, 1734,
1630, 1608, 1510, 1483, 1236, 1067, 818, 753, 688 cm−1; HRMS (ESI)
m/z calcd for C16H13O2 [M + H]+, 237.0910, found 237.0904.
3-(4-Chlorophenyl)-1H-isochromen-1-one (3d).17b White solid
(Z)-(1H)-3-Phenyl-N-tert-butylisochromen-1-imine (2a).17a Yel-
1
1
low solid (130 mg, 94%); 69−71 °C; H NMR (300 MHz, CDCl3)
(110 mg, 86%); 142−144 °C; H NMR (400 MHz, CDCl3) δ 8.28
δ 8.19 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.46−7.31 (m,
4H), 7.26 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.54 (s, 1H),
1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 152.4, 146.5, 133.2,
132.8, 131.2, 129.1, 128.7, 127.7, 127.3, 125.1, 124.9, 100.7, 53.3, 29.8;
HRMS (ESI) m/z calcd for C19H20NO [M + H]+, 278.1539, found
278.1540.
(d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.72 (td, J = 7.7, 1.1 Hz,
1H), 7.53−7.46 (m, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.92 (s, 1H); 13C
NMR (101 MHz, CDCl3) δ 162.0, 152.4, 137.2, 135.9, 134.9, 130.3,
129.6, 129.0, 128.3, 126.4, 126.0, 120.4, 102.0; IR (KBr) ν = 3101,
1726, 1707, 1639, 1492, 1090, 1070, 1037, 1009, 828, 752, 685 cm−1;
HRMS (ESI) m/z calcd for C15H10ClO2 [M + H]+, 257.0364, found
257.0377.
3-Phenyl-1H-isochromen-1-one (3a).6 White solid (101 mg, 91%);
80−82 °C; H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.1 Hz, 1H),
3-(4-Fluorophenyl)-1H-isochromen-1-one (3e).6 Yellow solid (101
1
1
7.87 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.6 Hz, 1H), 7.52−7.41 (m, 5H),
6.94 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 162.3, 153.6, 137.5,
134.9, 131.9, 129.9, 129.6, 128.8, 128.1, 125.9, 125.2, 120.5, 101.8; IR
(KBr) ν = 3071, 3054, 2963, 2927, 1719, 1636, 1482, 1072, 1028,
1011, 764, 746, 685 cm−1; HRMS (ESI) m/z calcd for C15H11O2 [M +
H]+, 223.0754, found 223.0754.
mg, 84%); 129−131 °C; H NMR (400 MHz, CDCl3) δ 8.29 (d, J =
7.8 Hz, 1H), 7.92−7.81 (m, 2H), 7.72 (t, J = 7.4 Hz, 1H), 7.49 (t, J =
7.3 Hz, 2H), 7.14 (t, J = 8.2 Hz, 2H), 6.88 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 164.9, 162.4, 162.1, 152.6, 137.3, 134.9, 129.6, 128.2,
127.2, 125.9, 120.3, 116.0, 115.8, 101.5; IR (KBr) ν = 3104, 1721,
1639, 1600, 1510, 1483, 1234, 1069, 829, 747, 684 cm−1; HRMS (ESI)
m/z calcd for C15H10FO2 [M + H]+, 241.0659, found 241.0665.
3-(3-Chlorophenyl)-1H-isochromen-1-one (3f).6 White solid (114
3-(4-Methoxyphenyl)-1H-isochromen-1-one (3b).6 White solid
1
(107 mg, 85%); 113−115 °C; H NMR (400 MHz, CDCl3) δ 8.25
1
(d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.66 (t, J = 7.5 Hz, 1H),
7.46−7.38 (m, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.78 (s, 1H), 3.83 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 161.0, 153.6, 137.8,
134.8, 129.5, 127.6, 126.7, 125.6, 124.4, 120.0, 114.1, 100.2, 55.3; IR
(KBr) ν = 2999, 2846, 1738, 1634, 1604, 1514, 1264, 1066, 1023, 837,
820, 752, 687 cm−1; HRMS (ESI) m/z calcd for C16H13O3 [M + H]+,
253.0859, found 253.0859.
mg, 89%); 158−160 °C; H NMR (400 MHz, CDCl3) δ 8.26 (d, J =
7.8 Hz, 1H), 7.81 (s, 1H), 7.71 (t, J = 6.6 Hz, 2H), 7.49 (t, J = 7.4 Hz,
2H), 7.35 (d, J = 4.1 Hz, 2H), 6.91 (s, 1H); 13C NMR (101 MHz,
DMSO) δ 161.8, 151.8, 136.9, 134.9, 133.5, 130.0, 129.8, 129.6, 128.5,
126.1, 125.1, 123.1, 120.5, 102.6; IR (KBr) ν = 3111, 1720, 1639,
1606, 1483, 1419, 1238, 1070, 754, 681 cm−1; HRMS (ESI) m/z calcd
for C15H10ClO2 [M + H]+, 257.0364, found 257.0373.
3-p-Tolyl-1H-isochromen-1-one (3c).6 White solid (93 mg, 79%);
106−108 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H),
7.74 (d, J = 8.2 Hz, 2H), 7.70−7.64 (m, 1H), 7.48−7.41 (m, 2H), 7.23
(d, J = 8.4 Hz, 2H), 6.86 (s, 1H), 2.37 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.3, 153.7, 140.1, 137.6, 134.7, 129.4, 129.0, 127.8, 125.8,
3-(3-(Trifluoromethyl)phenyl)-1H-isochromen-1-one (3g). White
1
solid (110 mg, 76%); 100−102 °C; H NMR (400 MHz, CDCl3) δ
8.30 (d, J = 8.1 Hz, 1H), 8.11 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.78−
7.71 (m, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.56−
7.50 (m, 2H), 7.02 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 161.8,
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a
Table 3. Synthesis of Phthalides from Substrates (4a−4i) with tert-Butyl Isocyanide
a
All reactions were performed under N2 on a 0.5 mmol scale, using tert-butyl isocyanide (0.75 mmol), Pd(OAc)2 (2.5 mol %), DPEPhos (5 mol %),
b
and K2CO3 (1.0 mmol) in DMF (3 mL) at 120 °C for 2 h, followed by refluxing in THF/hydrochloric acid for 2 h. Isolated yield
151.9, 136.9, 135.0, 132.8, 129.7, 129.4, 128.7, 128.2, 126.4, 126.4,
126.2, 122.0, 120.7, 102.9; IR (KBr) ν = 3103, 1731, 1640, 1605, 1491,
1341, 1333, 1230, 1170, 1109, 1068, 802, 752, 690 cm−1; HRMS (ESI)
m/z calcd for C16H10F3O2 [M + H]+, 291.0627, found 291.0625.
3-(2-Chlorophenyl)-1H-isochromen-1-one (3h).17b White solid
3-(2-Fluorophenyl)-1H-isochromen-1-one (3i).17b White solid (91
mg, 76%); 111−113 °C; H NMR (400 MHz, CDCl3) δ 8.30 (d, J =
1
7.8 Hz, 1H), 7.99 (td, J = 7.9, 1.6 Hz, 1H), 7.72 (td, J = 7.7, 1.2 Hz,
1H), 7.51 (t, J = 7.6 Hz, 2H), 7.41−7.34 (m, 1H), 7.29−7.22 (m, 1H),
7.19 (s, 1H), 7.17−7.12 (m, 1H); 13C NMR (101 MHz, CDCl3) δ
161.9, 161.2, 158.7, 148.0, 137.3, 134.8, 131.1, 131.0, 129.4, 128.5,
128.4, 126.4, 124.5, 120.7, 120.1, 120.0, 116.5, 116.2, 107.2, 107.1; IR
(KBr) ν = 3080, 1733, 1629, 1605, 1487, 1459, 1230, 1069, 752, 684
cm−1; HRMS (ESI) m/z calcd for C15H10FO2 [M + H]+, 241.0659,
found 241.0671.
1
(74 mg, 58%); 114−116 °C; H NMR (400 MHz, CDCl3) δ 8.33
(d, J = 7.9 Hz, 1H), 7.80−7.66 (m, 2H), 7.59−7.44 (m, 3H), 7.40−
7.33 (m, 2H), 6.98 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 162.3,
151.3, 136.9, 134.9, 132.3, 131.5, 130.6, 129.5, 128.6, 127.0, 126.2,
120.6, 107.6; IR (KBr) ν = 3066, 1735, 1644, 1605, 1484, 1343, 1229,
1049, 1031, 839, 760, 745, 685 cm−1; HRMS (ESI) m/z calcd for
C15H10ClO2 [M + H]+, 257.0364, found 257.0369.
3-(Naphthalen-2-yl)-1H-isochromen-1-one (3j).6 White solid (117
mg, 86%); 151−153 °C; 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H),
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134.2, 132.8, 131.1, 129.4, 129.1, 129.0, 128.8, 128.0, 128.0, 127.8,
125.3, 120.3, 116.8; IR (KBr) ν = 3072, 3049, 3025, 1738, 1725, 1623,
1603, 1480, 1311, 1244, 1198, 1080, 1057, 783, 760, 712, 693 cm−1;
HRMS (ESI) m/z calcd for C21H15O2 [M + H]+, 299.1067, found
299.1065.
Scheme 2. Plausible Mechanism for the Synthesis of 3a
3,4-Dihydro-1H-benzo[c]chromen-6(2H)-one (3p).14e White solid
(89 mg, 89%); 61−63 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J =
8.0 Hz, 1H), 7.74−7.67 (m, 1H), 7.44 (t, J = 8.3 Hz, 2H), 2.61−2.52
(m, 4H), 1.89−1.81 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 162.7,
152.3, 137.9, 134.5, 129.6, 127.0, 121.3, 120.4, 109.2, 27.3, 22.6, 22.0;
IR (KBr) ν = 2936, 2918, 2868, 2842, 1724, 1653, 1603, 1489, 1455,
1186, 1063, 756, 689 cm−1; HRMS (ESI) m/z calcd for C13H13O2 [M
+ H]+, 201.0910, found 201.0917.
3,4-Dihydrospiro[benzo[c]chromene-2,2′-[1,3]dioxolan]-6(1H)-
one (3q).14e White solid (50 mg, 39%); 111−113 °C; H NMR (300
1
MHz, CDCl3) δ 8.24 (dd, J = 7.9, 0.6 Hz, 1H), 7.69 (t, J = 7.7 Hz,
1H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.07−4.00 (m,
4H), 2.82−2.74 (m, 4H), 1.98 (t, J = 6.7 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 162.3, 151.0, 137.4, 134.6, 129.7, 127.4, 121.1, 120.2,
107.2, 107.1, 64.7, 33.2, 30.5, 26.2; IR (KBr) ν = 2970, 2941, 2893,
2862, 1731, 1721, 1661, 1605, 1492, 1365, 1306, 1062, 1032, 849, 768,
693 cm−1; HRMS (ESI) m/z calcd for C15H15O4 [M + H]+, 259.0971,
found 259.0987.
7-Fluoro-3-phenyl-1H-isochromen-1-one (3r).6 White solid (68
1
mg, 57%); 152−154 °C; H NMR (400 MHz, CDCl3) δ 7.95 (d, J =
8.32 (d, J = 7.9 Hz, 1H), 7.96−7.89 (m, 1H), 7.89−7.80 (m, 3H),
7.76−7.68 (m, 1H), 7.56−7.46 (m, 4H), 7.06 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 162.4, 153.4, 137.5, 134.9, 133.8, 133.1, 129.6, 128.8,
128.6, 128.2, 127.6, 127.2, 126.8, 126.0, 125.2, 121.9, 120.5, 102.2; IR
(KBr) ν = 3106, 3053, 3030, 1717, 1636, 1607, 1560, 1508, 1485,
1373, 1192, 1074, 747, 681 cm−1; HRMS (ESI) m/z calcd for
C19H12O2Na [M + Na]+, 295.0730, found 295.0743.
8.2 Hz, 1H), 7.86 (d, J = 6.3 Hz, 2H), 7.55−7.42 (m, 5H), 6.94 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 163.4, 161.4, 160.1, 153.1, 134.0,
131.6, 130.0, 128.8, 128.2, 128.1, 123.5, 123.2, 122.1, 122.0, 115.3,
115.0, 101.0; IR (KBr) ν = 3086, 1715, 1641, 1619, 1499, 1448, 1338,
1256, 1069, 864, 758, 681 cm−1; HRMS (ESI) m/z calcd for
C15H9FO2Na [M + Na]+, 263.0479, found 263.0481.
(Z)-3-Benzylideneisobenzofuran-1(3H)-one (6a).17d White solid
(100 mg, 93%); 81−83 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J
= 7.7, 0.7 Hz, 1H), 7.85−7.79 (m, 2H), 7.76−7.66 (m, 2H), 7.54−7.48
(m, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.33−7.27 (m, 1H), 6.39 (s, 1H);
13C NMR (101 MHz, CDCl3) δ 167.0, 144.5, 140.5, 134.4, 133.0,
130.0, 129.7, 128.7, 128.3, 125.4, 123.3, 119.7, 107.0; IR (KBr) ν =
3067, 3026, 1785, 1774, 1655, 1607, 1472, 1354, 1270, 1084, 1071,
970, 763, 688 cm−1; HRMS (ESI) m/z calcd for C15H11O2 [M + H]+,
223.0754, found 223.0752.
3-(Furan-2-yl)-1H-isochromen-1-one (3k).6 White solid (75 mg,
1
71%); 116−118 °C; H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.1
Hz, 1H), 7.70−7.61 (m, 1H), 7.50−7.38 (m, 3H), 6.90 (d, J = 3.4 Hz,
1H), 6.81 (s, 1H), 6.52−6.47 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
161.5, 146.8, 145.9, 143.9, 137.2, 134.9, 129.7, 127.9, 125.9, 120.3,
112.0, 110.0, 99.9; IR (KBr) ν = 3152, 3130, 3119, 1736, 1719, 1646,
1479, 1230, 1164, 1090, 1005, 759, 748, 687 cm−1; HRMS (ESI) m/z
calcd for C13H9O3 [M + H]+, 213.0546, found 213.0556.
3-(Thiophen-2-yl)-1H-isochromen-1-one (3l).6 Yellow solid (76
1
(Z)-3-(3,5-Dimethylbenzylidene)isobenzofuran-1(3H)-one (6b).
White solid (108 mg, 86%); 142−144 °C; 1H NMR (300 MHz,
CDCl3) δ 7.92 (dd, J = 7.7, 0.9 Hz, 1H), 7.77−7.67 (m, 2H), 7.56−
7.49 (m, 1H), 7.47 (s, 2H), 6.96 (s, 1H), 6.35 (s, 1H), 2.36 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 167.0, 144.0, 140.4, 137.9, 134.1, 132.7,
130.1, 129.3, 127.7, 125.1, 123.0, 119.5, 107.2, 21.1; IR (KBr) ν =
3053, 2918, 1773, 1663, 1603, 1474, 1354, 1280, 1082, 977, 856, 762,
690, 627 cm−1; HRMS (ESI) m/z calcd for C17H15O2 [M + H]+,
251.1067, found 251.1058.
mg, 67%); 106−108 °C; H NMR (300 MHz, CDCl3) δ 8.25 (d, J =
7.9 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 3.6 Hz, 1H), 7.48−
7.35 (m, 3H), 7.12−7.04 (m, 1H), 6.75 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 161.6, 149.3, 137.4, 135.6, 134.9, 129.7, 128.1, 127.9, 127.3,
126.1, 125.7, 120.2, 100.8; IR (KBr) ν = 3103, 3082, 2927, 1733, 1719,
1629, 1559, 1231, 1070, 1059, 818, 752, 707, 686, 669 cm−1; HRMS
(ESI) m/z calcd for C13H9O2S [M + H]+, 229.0318, found 229.0327.
3-Cyclohexyl-1H-isochromen-1-one (3m).6 White solid (99 mg,
87%); 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.8 Hz,
1H), 7.66 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.36 (d, J = 7.7
Hz, 1H), 6.23 (s, 1H), 2.44 (t, J = 11.1 Hz, 1H), 2.03 (d, J = 11.6 Hz,
2H), 1.85 (d, J = 11.9 Hz, 2H), 1.74 (d, J = 13.4 Hz, 1H), 1.52−1.17
(m, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 162.3, 137.7, 134.6,
129.4, 127.4, 125.2, 120.2, 100.8, 41.8, 30.5, 25.9, 25.8; IR (KBr) ν =
2930, 2902, 2851, 1722, 1649, 1604, 1482, 1330, 1163, 1060, 1043,
1024, 829, 764 cm−1; HRMS (ESI) m/z calcd for C15H17O2 [M + H]+,
229.1223, found 229.1233.
(Z)-3-(4-Methylbenzylidene)isobenzofuran-1(3H)-one (6c).17d
White solid (98 mg, 83%); 147−148 °C; 1H NMR (300 MHz,
CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.75−7.62 (m, 4H), 7.52−7.43 (m,
1H), 7.18 (d, J = 8.0 Hz, 2H), 6.34 (s, 1H), 2.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.0, 143.8, 140.5, 138.5, 134.3, 130.2, 130.0,
129.4, 125.3, 123.1, 119.6, 107.1, 21.3; IR (KBr) ν = 3092, 3035, 3023,
1779, 1767, 1661, 1605, 1474, 1352, 1269, 1077, 971, 858, 760, 688
cm−1; HRMS (ESI) m/z calcd for C16H13O2 [M + H]+, 237.0910,
found 237.0905.
3-tert-Butyl-1H-isochromen-1-one (3n).6 Colorless oil (90 mg,
(Z)-3-(4-Fluorobenzylidene)isobenzofuran-1(3H)-one (6d).17d
White solid (85 mg, 71%); 143−145 °C; 1H NMR (300 MHz,
CDCl3) δ 7.88 (dd, J = 7.7, 0.9 Hz, 1H), 7.82−7.74 (m, 2H), 7.73−
7.64 (m, 2H), 7.54−7.47 (m, 1H), 7.05 (t, J = 8.7 Hz, 2H), 6.33 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.0, 160.7, 144.1, 140.4,
134.5, 131.9, 131.7, 129.7, 129.3, 129.2, 125.5, 123.1, 119.7, 115.9,
115.6, 105.7; IR (KBr) ν = 3085, 3036, 1794, 1664, 1599, 1508, 1272,
1231, 1078, 970, 859, 827, 756, 685 cm−1; HRMS (ESI) m/z calcd for
C15H9FO2Na [M + Na]+, 263.0479, found 263.0484.
1
89%); H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 1H), 7.60
(td, J = 7.8, 1.1 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz,
1H), 6.25 (s, 1H), 1.26 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
164.8, 162.7, 137.4, 134.4, 129.0, 127.4, 125.3, 119.8, 99.5, 35.4, 27.7;
IR (KBr) ν = 2967, 2928, 2871, 1733, 1725, 1647, 1603, 1568, 1481,
1338, 1114, 1087, 1050, 1015, 953, 828, 765, 690 cm−1; HRMS (ESI)
m/z calcd for C13H15O2 [M + H]+, 203.1067, found 203.1075.
3,4-Diphenyl-1H-isochromen-1-one (3o).17c White solid (140 mg,
1
94%); 166−168 °C; H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 7.9
Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.40 (d, J =
5.3 Hz, 3H), 7.35−7.31 (m, 2H), 7.27−7.23 (m, 2H), 7.22−7.15 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 162.1, 150.8, 138.7, 134.5,
(Z)-3-(2-Chlorobenzylidene)isobenzofuran-1(3H)-one (6e).2f
White solid (47 mg, 37%); 156−158 °C; 1H NMR (300 MHz,
CDCl3) δ 8.30 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.84 (d, J
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Article
= 7.9 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.41
(d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24−7.18 (m, 1H), 6.89
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 166.8, 145.8, 140.4, 134.6,
133.8, 131.7, 130.9, 130.2, 129.6, 129.2, 127.2, 125.6, 123.4, 120.2,
102.2; IR (KBr) ν = 3065, 2963, 1793, 1781, 1655, 1610, 1478, 1358,
1279, 1263, 1080, 966, 758, 746, 685 cm−1; HRMS (ESI) m/z calcd
for C15H10ClO2 [M + H]+, 257.0364, found 257.0372.
(Z)-7-Benzylideneisobenzofuro[5,6-d][1,3]dioxol-5(7H)-one
(6f).17e White solid (90 mg, 67%); 197−199 °C; 1H NMR (300 MHz,
DMSO) δ 7.66 (d, J = 7.6 Hz, 2H), 7.52 (s, 1H), 7.37 (t, J = 7.6 Hz,
2H), 7.26 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 6.66 (s, 1H), 6.17 (s, 2H);
13C NMR (75 MHz, DMSO) δ 165.7, 154.1, 150.1, 144.1, 137.1,
71, 1692−1695. (c) Kornsakulkarn, J.; Thongpanchang, C.; Lapanun,
S.; Srichomthong, K. J. Nat. Prod. 2009, 72, 1341−1343.
(d) Rukachaisirikul, V.; Rodglin, A.; Sukpondma, Y.; Phongpaichit,
S.; Buatong, J.; Sakayaroj, J. J. Nat. Prod. 2012, 75, 853−858.
(2) (a) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.-I.; Nakajima, S.
Chem. Pharm. Bull. 1981, 29, 2491−2495. (b) Matsuda, H.; Shimoda,
H.; Yamahara, J.; Yoshikawa, M. Bioorg. Med. Chem. Lett. 1998, 8,
215−220. (c) Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med.
Chem. 1999, 7, 1445−1450. (d) Bellina, F.; Ciucci, D.; Vergamini, P.;
Rossi, R. Tetrahedron 2000, 56, 2533−2545. (e) Hussain, M.; Hussain,
M. T.; Rama, N. H.; Hameed, S.; Malik, A.; Khan, K. M. Nat. Prod. Res.
2002, 17, 207−214. (f) Bedoya, L. M.; Del Olmo, E.; Sancho, R.;
133.3, 129.5, 128.8, 128.1, 116.7, 105.9, 103.3, 103.1, 99.9; IR (KBr) ν
= 3023, 2910, 1771, 1753, 1610, 1477, 1325, 1304, 1075, 967, 939,
849, 778, 692, 642 cm−1; HRMS (ESI) m/z calcd for C16H10O4Na [M
+ Na]+, 289.0471, found 289.0478.
Barboza, B.; Beltran
́ ́
, M.; García-Cadenas, A. E.; Sanchez-Palomino, S.;
Lopez-Perez, J. L.; Munoz, E.; San Feliciano, A.; Alcamí, J. Bioorg. Med.
́
́
̃
Chem. Lett. 2006, 16, 4075−4079. (g) Kurume, A.; Kamata, Y.;
Yamashita, M.; Wang, Q.; Matsuda, H.; Yoshikawa, M.; Kawasaki, I.;
Ohta, S. Chem. Pharm. Bull. 2008, 56, 1264−1269.
(Z)-3-Benzylidene-6-fluoroisobenzofuran-1(3H)-one (6g).17e
White solid (72 mg, 60%); 152−154 °C; 1H NMR (300 MHz,
CDCl3) δ 7.90 (dd, J = 8.5, 4.7 Hz, 1H), 7.85−7.78 (m, 2H), 7.44−
7.35 (m, 3H), 7.35−7.28 (m, 1H), 7.22 (td, J = 8.6, 2.1 Hz, 1H), 6.37
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 168.5, 165.8, 165.1, 143.5,
143.4, 143.2, 143.0, 132.6, 130.2, 128.8, 128.0, 127.9, 119.5, 118.3,
118.0, 108.2, 106.7, 106.4; IR (KBr) ν = 3067, 3025, 1771, 1619, 1599,
1480, 1445, 1288, 1195, 994, 934, 879, 774, 687 cm−1; HRMS (ESI)
m/z calcd for C15H9FO2Na [M + Na]+, 263.0479, found 263.0489.
(Z)-3-Decylideneisobenzofuran-1(3H)-one (6h). Colorless oil (76
(3) (a) Del Olmo, E.; García Armas, M.; Ybarra, M. I.; Lop
́
ez, J. L.;
Oporto, P.; Gimenez, A.; Deharoe, E.; San Felicianoa, A. Bioorg. Med.
́
Chem. Lett. 2003, 13, 2769−2772. (b) Kummerle, A. E.; Vieira, M. M.;
̈
Schmitt, M.; Miranda, A. L. P.; Fraga, C. A. M.; Bourguignon, J.-J.;
Barreiro, E. J. Bioorg. Med. Chem. Lett. 2009, 19, 4963−4966.
(c) Manivel, P.; Nawaz Khan, F.; Hatwar, V. R. Phosphorus, Sulfur
Silicon Relat. Elem. 2010, 185, 1932−1942.
(4) Ramesha, A. R.; Roy, A. K. Synth. Commun. 2001, 31, 2419−
2422.
1
mg, 56%); H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.7 Hz, 1H),
(5) (a) Napolitano, E. Org. Prep. Proced. Int. 1997, 29, 631−664.
(b) Pal, S.; Chatare, V.; Pal, M. Curr. Org. Chem. 2011, 15, 782−800.
(6) Ge, Z.-Y.; Fei, X.-D.; Tang, T.; Zhu, Y.-M.; Shen, J.-K. J. Org.
Chem. 2012, 77, 5736−5743.
7.67−7.58 (m, 2H), 7.50−7.43 (m, 1H), 5.61 (t, J = 7.8 Hz, 1H), 2.44
(dd, J = 15.1, 7.6 Hz, 2H), 1.54−1.43 (m, 2H), 1.39−1.14 (m, 12H),
0.85 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 145.5,
139.5, 134.1, 129.2, 125.1, 124.3, 119.5, 109.7, 31.8, 29.5, 29.3, 29.2,
25.8, 22.6, 14.0; IR (KBr) ν = 2955, 2926, 2854, 1853, 1783, 1686,
1468, 1272, 1258, 1065, 982, 761, 690 cm−1; HRMS (ESI) m/z calcd
for C18H25O2 [M + H]+, 273.1854, found 273.1864.
(7) Zhang, S.; Zhang, W.-X.; Xi, Z. Chem.Eur. J. 2010, 16, 8419−
8426.
(8) Wang, Y.; Zhu, Q. Adv. Synth. Catal. 2012, 354, 1902−1908.
3-Cyclohexylideneisobenzofuran-1(3H)-one (6i).17f White solid
(53 mg, 49%); 73−75 °C; 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J
= 11.5, 7.9 Hz, 2H), 7.69−7.61 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H), 2.70
(t, J = 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 1.76−1.62 (m, 7H); 13C
NMR (75 MHz, CDCl3) δ 167.1, 138.9, 138.6, 134.1, 128.3, 128.2,
125.9, 125.5, 122.8, 29.4, 28.6, 27.6, 27.2, 26.1; IR (KBr) ν = 2935,
2922, 2855, 1766, 1704, 1608, 1472, 1446, 1279, 1257, 1103, 1032,
766, 692 cm−1; HRMS (ESI) m/z calcd for C14H15O2 [M + H]+,
215.1072, found 215.1077.
́
̌
(9) Van Baelen, G.; Kuijer, S.; Rycek, L.; Sergeyev, S.; Janssen, E.; De
Kanter, F. J. J.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A. Chem.Eur.
J. 2011, 17, 15039−15044.
(10) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.; De Kanter, F. J. J.;
Maes, B. U. W.; Orru, R. V. A. Org. Lett. 2011, 13, 6496−6499.
(11) Tyagi, V.; Khan, S.; Giri, A.; Gauniyal, H. M.; Sridhar, B.;
Chauhan, P. M. S. Org. Lett. 2012, 14, 3126−3129.
(12) Soeta, T.; Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226−1229.
(13) Liu, B.; Li, Y.; Jiang, H.; Yin, M.; Huang, H. Adv. Synth. Catal.
2012, 354, 2288−2300.
(14) (a) Uozumi, Y.; Mori, E.; Mori, M.; Shibasaki, M. J. Organomet.
Chem. 1990, 399, 93−102. (b) Ciattini, P. G.; Mastropietro, G.;
Morera, E.; Ortar, G. Tetrahedron Lett. 1993, 34, 3763−3766.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra. This material is available free
́
(c) Negishi, E.; Coperet, C.; Sugihara, T.; Shimoyama, I.; Zhang, Y.;
of charge via the Internet at http://pubs.acs.org.
Wu, G.; Tour, J. M. Tetrahedron 1994, 50, 425−436. (d) Negishi, E.;
Makabe, H.; Shimoyama, I.; Wu, G.; Zhang, Y. Tetrahedron 1998, 54,
1095−1106. (e) Tadd, A. C.; Fielding, M. R.; Willis, M. C. Chem.
Commun. 2009, 6744−6746.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhuyongming@suda.edu.cn; chemjsj@suda.edu.cn.
Fax: (+86)-512-67166591; (+86)-512-65880307.
■
(15) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.;
Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517−
5520.
Notes
(16) (a) For the preparation of substrates 1a−1j, 1m, 1n, 1r and
The authors declare no competing financial interest.
4a−4i, see: Wessig, P.; Glombitza, C.; Muller, G.; Teubner, J. J. Org.
̈
Chem. 2004, 69, 7582−7591. (b) For the preparation of substrates 1k,
1l, see: Ogata, M.; Matsumoto, H.; Kida, S.; Shimizu, S.; Tawara, K.;
Kawamura, Y. J. Med. Chem. 1987, 30, 1497−1502. (c) For the
preparation of substrate 1o, see: Churruca, F.; San Martin, R.; Tellitu,
I.; Domínguez, E. Eur. J. Org. Chem. 2005, 2481−2490. (d) For the
preparation of substrates 1p and 1q, see: Willis, M. C.; Taylor, D.;
Gillmore, A. T. Org. Lett. 2004, 6, 4755−4757.
(17) For the known compounds, see: (a) Liu, G.; Zhou, Y.; Ye, D.;
Zhang, D.; Ding, X.; Jiang, H.; Liu, H. Adv. Synth. Catal. 2009, 351,
2605−2610. (b) Khan, K. M.; Ahmed, S.; Khan, Z. A.; Rani, M.;
Perveen, S.; Choudhary, M. I.; Atta-ur-Rahman. Lett. Org. Chem. 2005,
2, 532−534. (c) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407−1409. (d) Zhou, L.; Jiang, H.-F. Tetrahedron Lett. 2007, 48,
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support by PAPD (A
Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions) and NSFC
(National Nature Science Foundation of China, No.
21172162).
REFERENCES
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