Synthesis of isocoumarin via PTSA-catalyzed annulation of diarylalkynes

Article abstract of DOI:10.1055/s-2008-1072575

p-Toluenesulfonic acid (PTSA) in ethanol was used as a mild acid catalyst for the annulation of various functionalized diarylalkynes under microwave irradiation. This metal-free process allowed the synthesis of a range of 3-aryl-substituted isocoumarins in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072575

PAPER
1607
Synthesis of Isocoumarin via PTSA-Catalyzed Annulation of Diarylalkynes
S
ynthesis of Isoco
a
umarin via
ë
PTSA-Cata
l
lyzed
A
l
nnulat
e
ion of
D
iarylalky
L
nes e Bras, Abdallah Hamze, Samir Messaoudi, Olivier Provot,* Pierre-Benoît Le Calvez, Jean-Daniel Brion,
Mouâd Alami*
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université Paris-Sud XI, CNRS, BioCIS, UMR 8076,
rue J. B. Clément, 92296 Châtenay-Malabry, France
Fax +33(1)46835828; E-mail: olivier.provot@u-psud.fr; E-mail: mouad.alami@u-psud.fr
Received 28 January 2008
phatic alkynes in aqueous or alcoholic media.11
Abstract: p-Toluenesulfonic acid (PTSA) in ethanol was used as a
mild acid catalyst for the annulation of various functionalized dia-
rylalkynes under microwave irradiation. This metal-free process al-
lowed the synthesis of a range of 3-aryl-substituted isocoumarins in
good yields.
Interestingly, this new, environmentally friendly, metal-
free procedure has been applied successfully to diaryla-
lkynes to regioselectively afford a series of carbonyl com-
pounds.12 Following this work, we were interested in
applying this mild and friendly procedure to diarylalkynes
bearing an ortho-alkoxycarbonyl function on the aromatic
ring in order to give the corresponding 3-arylisocou-
marins. Herein, we report the results of this study.
Key words: alkynes, annulations, isocoumarin, isochromene, mi-
crowave activation
Isocoumarin structures are important components in
many natural products that exhibit a broad range of bio-
logical activities including antiallergic and antimicrobi-
First, we studied the reaction of diarylalkyne 1a, bearing
an ortho-ethoxycarbonyl function on the aromatic ring, as
a model substrate. The results, summarized in Table 1,
showed that treatment of 1a with a catalytic amount of p-
toluenesulfonic acid (PTSA; 20 mol%) in refluxing etha-
nol afforded the corresponding isocoumarin 2a in a good
yield but only after prolonged reaction time (70%, 24 h,
entry 1). Next, in a continuation of our work on develop-
ing rapid and efficient methodologies,13 we chose to pro-
mote and accelerate this reaction using microwave
irradiation.
al,1,2
antifungal,3
antiinflammatory,4
immuno-
modulatory,5 cytotoxic,6 and antiangiogenic.7 Therefore,
a number of methods have been reported in the literature
for the synthesis of the isocoumarin ring.8 The most com-
mon route is undoubtedly the cyclization of 2-(1-alky-
nyl)benzoic acids/esters through activation of the triple
bond.9 A recent approach to the synthesis of isocoumarins
from diarylalkynes using trifluoroacetic acid (TFA)10 as a
reagent and solvent, prompted us to present our results in
this field.
In this way, we were pleased to observe that a reaction
time of 30 minutes was sufficient to reach up to 98% con-
version of starting diarylalkyne 1a into isocoumarin 2a,
which was obtained in excellent isolated yield (89%, entry
Previously, we reported a new and efficient p-toluene-
sulfonic acid-catalyzed hydration of unsymmetrical ali-
Table 1 PTSA-Promoted Annulation of ortho-Substituted Arylalkynes 1 in Ethanol
OMe
PTSA (20 mol%)
OMe
EtOH
O
R
1
2a
O
Entry
Alkyne 1
R
Conditions
Time (h)
24
Temp (°C)
78
Yield (%)a
1
2
3
4
5
6
1a
1a
1a
1b
1c
1d
CO2Et
CO2Et
CO2Et
CO2H
CONH2
CN
reflux
70
89
30
98
74b
38
microwave
sealed tube
microwave
microwave
microwave
0.5
160
0.5
160
0.5
160
0.5
160
0.5
160
a Isolated yield.
b 3-(4-Methoxyphenyl)isoquinolin-1-one (19%) was also isolated.
SYNTHESIS 2008, No. 10, pp 1607–1611
x
x.
x
x
.
2
0
0
8
Advanced online publication: 07.04.2008
DOI: 10.1055/s-2008-1072575; Art ID: Z03208SS
© Georg Thieme Verlag Stuttgart · New York

1608
G. Le Bras et al.
PAPER
2). As a control experiment, 1a was heated in ethanol in a resulting from the 6-endo-dig nitrogen-cyclization. When
sealed tube at 160 °C for 30 minutes. Comparison of the 1d (R = CN) was heated with PTSA in ethanol under mi-
results obtained using conventional or microwave heating crowave irradiation, 2a was still isolated but in a modest
indicated clearly the efficiency of the latter method [com- yield (38%, entry 6).
pare Table 1, entry 2 (89%) with entry 3 (30%)]. Other
carboxyl groups were also examined for this annulation
reaction. Interestingly, the yield of 2a was remarkably in-
creased by switching the ethoxycarbonyl ester to a car-
boxylic acid function (98%, entry 4). When the reaction
was performed on 1c, containing an amide group on the
aromatic ring, 2a was obtained in 74% isolated yield (en-
try 5), together with 19% of the 3-arylisoquinolin-1-one
Using our protocol, we were able to prepare a series of
functionalized isocoumarins from various diarylalkynes 1
in good yields (Table 2). For practical considerations, we
choose to prepare these isocoumarins 2 from diaryl-
alkynes bearing an ortho-ethoxycarbonyl group (rather
than CO2H), as they were readily available from
Sonogashira–Linstrumelle couplings.14
Table 2 One-Pot Synthesis of 3-Arylisocoumarins 2 from Diarylalkynes 1
R2
APTS, EtOH
R2
R1
O
MW, 160 °C
R1
CO2Et
O
1
2
Entry
Alkyne 1
Time (h) Isocoumarin 2
Yield (%)a
OMe
OMe
1
2
1a
1e
0.5
2a
2b
89
O
CO2Et
O
MeO
MeO
1
70
64
O
CO2Et
O
OMe
OMe
OMe
OMe
OMe
OMe
3
1f
1
2c
O
CO2Et
CO2Et
CO2Et
O
Me
Me
4
1g
1h
1i
1
2d
2e
2f
62
60
67
O
O
NH2
NH2
5
1
O
O
OMe
MeO
OMe
6
2
O
CO2Et
MeO
O
Synthesis 2008, No. 10, 1607–1611 © Thieme Stuttgart · New York

PAPER
Synthesis of Isocoumarin via PTSA-Catalyzed Annulation of Diarylalkynes
1609
Table 2 One-Pot Synthesis of 3-Arylisocoumarins 2 from Diarylalkynes 1 (continued)
R2
APTS, EtOH
R2
R1
O
MW, 160 °C
R1
CO2Et
O
1
2
Entry
Alkyne 1
Time (h) Isocoumarin 2
Yield (%)a
OMe
O2N
OMe
7
8
1j
1
2g
2h
61
85
O
CO2Et
O2N
O
1k
2
O
CO2Et
O
N
9
1l
2
2i
2j
59
N
O
CO2Et
O
nC5H11
nC5H11
88b
O
10
1m
2
CO2Et
O
a Isolated yield.
b Obtained as an inseparable 65/35 mixture with the Markovnikov ketone resulting from the triple bond hydration.
As shown in Table 2, entries 2 and 3, the presence of a could be applied successfully to a range of aliphatic aryl-
methoxy group on the ortho or the meta position did not alkynes.
significantly affect the yield of this annulation process. A
To show the high synthetic potential of this protocol, we
similar result was obtained starting from 1g–i, which pro-
have tested it with the diarylalkyne 1n bearing a nucleo-
vided the 3-arylisocoumarins 2d–f in satisfactory isolated
philic ortho-hydroxymethyl substituent in place of the
yields (entries 4–6). The presence of a nitro group on the
ethoxycarbonyl group (Scheme 1). We were pleased to
aromatic ring did not interfere with the outcome of this
observe that after stirring for 30 minutes at 120 °C under
microwave heating, the annulation proceeded effectively
process, as demonstrated with diarylalkyne 1j (entry 7,
61% yield). Similarly, the arylnaphtlyl alkyne 1k was suc-
to give the desired isochromene 2k in good yield.
cessfully transformed into the isocoumarin 2h in an excel-
In conclusion, a novel and reliable procedure for the syn-
lent 85% yield (entry 8). Finally, when replacing the
thesis of isocoumarins has been achieved via PTSA-cata-
phenyl substituent by a pyridine ring, this methodology
lyzed annulation of ortho-substituted arylalkynes in
ethanol under microwave irradiation. This metal-free pro-
cedure is characterized by the mildness of its acidic con-
was still found to be efficient, and the corresponding iso-
coumarin derivative 2i was obtained in a satisfactory iso-
lated yield within a reasonable reaction time (entry 9, 2 h,
ditions, the short reaction times and good yields. The
59%). Interestingly, we observed that our protocol was
synthesis of other heterocycles such as isoquinolines and
isothiochromenes from their corresponding ortho-substi-
still efficient with the aliphatic arylalkyne 1m. In this
case, 3-pentylisocoumarin (2j) was obtained in good yield
tuted benzylamine or thiol derivatives, respectively, is
(entry 10, 82%), suggesting that the presented protocol
OMe
PTSA, EtOH
OMe
MW, 120 °C
O
86%
CH2OH
1n
2k
Scheme 1 Isochromene 2k obtained via PTSA-catalyzed annulation of 1n
Synthesis 2008, No. 10, 1607–1611 © Thieme Stuttgart · New York

1610
G. Le Bras et al.
PAPER
3-(3,4,5-Trimethoxyphenyl)isocoumarin (2c)
Beige solid; mp 171 °C.
currently under investigation and will be presented in due
course.
IR (neat): 1716, 1635, 1580, 1501, 1416, 1240, 1170, 1119, 765,
750, 684 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.83 (s, 3 H), 3.88 (s, 6 H), 6.80
(s, 1 H), 7.00 (s, 2 H), 7.37–7.44 (m, 2 H), 7.63 (dt, J = 7.6, 1.3 Hz,
1 H), 8.22 (d, J = 4.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 56.2 (2 × CH3), 60.8 (CH3), 101.5
(CH), 102.7 (2 × CH), 120.3 (C), 125.8 (CH), 127.5 (C), 128.0
(CH), 129.7 (CH), 134.9 (CH), 137.5 (C), 139.9 (C), 153.4 (C),
153.5 (2 × C), 162.2 (C).
IR spectra were recorded on a Perkin–Elmer 841 spectrometer. 1H
and 13C NMR spectra were measured with a Bruker Avance 300
(300 MHz and 75 MHz, for 1H and 13C, respectively). 1H chemical
shifts are reported in ppm from an internal standard TMS or residual
CHCl3 (d = 7.27 ppm). 13C chemical shifts are reported from the
central peak of CDCl3 (d = 77.1 ppm). ESI mass spectra were ob-
tained with a LCT Waters Micromass spectrometer. Elemental anal-
yses were performed with a Perkin–Elmer 240 analyzer. Melting
points were recorded on a Büchi B-450 apparatus and are uncorrect-
ed. Analytical TLC were performed on Merck precoated silica gel
60F plates. Merck silica gel 60 (230–400 mesh) was used for col-
umn chromatography. All microwave experiments were performed
using an Emrys Optimizer in 2–5 mL pyrex reaction vessels. Each
vessel contained a Teflon stir bar and Teflon-coated reaction vessel
cap.
Anal. Calcd for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.15; H,
5.12.
MS (ES+): m/z = 335.0 [M + Na+].
3-(4-Methylphenyl)isocoumarin (2d)
Colorless solid; mp 108–110 °C.
IR (neat): 2920, 1776, 1729, 1629, 1607, 1562, 1510, 1482, 1455,
1343, 1277, 1197, 1187, 1065, 845, 814 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H), 6.83 (s, 1 H), 7.15–
7.23 (m, 2 H), 7.36–7.44 (m, 2 H), 7.60 (t, J = 8.3 Hz, 1 H), 7.70 (d,
J = 8.3 Hz, 2 H), 8.23 (d, J = 8.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.5 (CH3), 101.0 (CH), 120.5 (C),
125.3 (2 × CH), 125.9 (CH), 128.0 (CH), 129.3 (C), 129.7 (2 × CH),
129.8 (CH), 134.9 (CH), 137.8 (C), 140.4 (C), 154.0 (C), 162.5 (C).
Typical Procedure
To an Emrys Optimizer 2–5 mL pyrex reaction vessel were added
diarylalkyne (0.5 mmol) and PTSA (0.01 mmol) in EtOH (2.5 mL).
The reaction vessel was then placed in the Emrys Optimizer and ex-
posed to microwave irradiation for the time indicated in Table 2
(160 °C; fixed hold time; high sample absorption; pre-stirring: 60
s). After cooling to r.t., H2O (3 mL) was added and the mixture was
extracted with EtOAc (3 × 2 mL). The organic layers were washed
with aq sat. NH4Cl (3 mL), dried and concentrated. The crude mix-
ture was purified by column chromatography on silica gel (cyclo-
hexane–CH2Cl2, gradient elution).
Anal. Calcd for C16H12O2: C, 81.34; H, 5.12. Found: C, 81.25; H,
5.08.
3-(4-Aminophenyl)isocoumarin (2e)
Yellow solid; mp 158 °C.
IR (neat): 3360, 3346, 1705, 1601, 1524, 1072, 812, 748 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.78 (br s, 2 H), 6.49 (d, J = 8.7
Hz, 2 H), 6.59 (s, 1 H), 7.29–7.23 (m, 2 H), 7.51 (t, J = 7.8 Hz, 1 H),
7.56 (d, J = 8.7 Hz, 2 H), 8.11 (d, J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 98.5 (CH), 112.4 (2 × CH), 119.7
(C), 120.4 (C), 125.4 (CH), 126.7 (2 × CH), 127.0 (CH), 129.5
(CH), 134.7 (CH), 138.5 (C), 149.8 (C), 154.6 (C), 162.8 (C).
3-(4-Methoxyphenyl)isocoumarin (2a)
Colorless solid; mp 111–113 °C.
IR (neat): 2999, 2844, 1957, 1734, 1632, 1601, 1575, 1562, 1512,
1480, 1457, 1442, 1420, 1344, 1309, 1287, 1260, 1235, 1200, 1175,
1114, 1064, 1020, 925, 887, 835, 790 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H), 6.86 (s, 1 H), 7.00
(d, J = 9.0 Hz, 2 H), 7.44–7.50 (m, 2 H), 7.75 (t, J = 7.8 Hz, 1 H),
7.86 (d, J = 9.0 Hz, 2 H), 8.32 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.4 (CH3), 100.2 (CH), 114.3
(2 × CH), 120.2 (C), 124.4 (C), 125.7 (CH), 126.8 (2 × CH), 127.7
(CH), 129.6 (CH), 134.8 (CH), 137.9 (C), 153.7 (C), 161.0 (C),
162.6 (C).
Anal. Calcd for C15H11NO2: C, 75.94; N, 5.90; H, 4.67. Found: C,
75.61; N, 5.74; H, 4.47.
MS (ES+): m/z = 238.0 [M + H+].
Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found: C, 76.00; H,
4.67.
MS (ES+): m/z = 275.0 [M + Na+].
7-Methoxy-3-(4-methoxyphenyl)isocoumarin (2f)
Colorless solid; mp 144–146 °C.
IR (neat): 2964, 2839, 1717, 1632, 1602, 1573, 1562, 1510, 1496,
1454, 1440, 1419, 1352, 1290, 1256, 1178, 1163, 1119, 1067, 1024,
935, 889, 867, 850, 837, 813 cm–1.
3-(2-Methoxyphenyl)isocoumarin (2b)
Colorless solid; mp 115–117 °C.
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 3.94 (s, 3 H), 6.83
(s, 1 H), 7.00 (d, J = 8.9 Hz, 2 H), 7.32 (dd, J = 8.6, 2.6 Hz, 1 H),
7.42 (d, J = 8.6 Hz, 1 H), 7.73 (d, J = 2.6 Hz, 1 H), 7.82 (d, J = 8.9
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.5 (CH3), 55.9 (CH3), 100.2
(CH), 110.0 (CH), 114.3 (2 × CH), 121.3 (C), 124.9 (CH), 126.6
(2 × CH), 127.4 (CH), 131.5 (C), 131.8 (C), 134.2 (C), 159.4 (C),
160.9 (C).
IR (neat): 3117, 3011, 2978, 2843, 1716, 1621, 1596, 1575, 1562,
1483, 1460, 1435, 1366, 1336, 1313, 1277, 1252, 1178, 1165, 1130,
1108, 1071, 1015, 963, 944, 924, 887, 854 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.00 (s, 3 H), 7.00–7.14 (m, 2 H),
7.37–7.44 (m, 2 H), 7.52 (d, J = 7.6 Hz, 2 H), 7.70 (td, J = 7.9, 1.2
Hz, 1 H), 8.00 (d, J = 7.9 Hz, 1 H), 8.33 (d, J = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.7 (CH3), 107.1 (CH), 111.4
(CH), 120.7 (CH), 120.9 (C), 126.3 (CH), 128.0 (CH), 128.9 (CH),
129.4 (CH), 130.8 (C), 134.6 (CH), 138.1 (CH), 145.1 (C), 150.5
(C), 157.3 (C), 162.6 (C).
Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.27; H,
4.97.
Anal. Calcd for C16H12O3: C, 76.18; H, 4.79. Found: C, 76.03; H,
4.66.
3-(4-Methoxyphenyl)-7-nitroisocoumarin (2g)
Yellow solid; mp 204 °C.
IR (neat): 1729, 1599, 1481, 1336, 1178, 1093, 829 cm–1.
Synthesis 2008, No. 10, 1607–1611 © Thieme Stuttgart · New York

PAPER
Synthesis of Isocoumarin via PTSA-Catalyzed Annulation of Diarylalkynes
1611
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 6.92 (s, 1 H), 7.00
(d, J = 9.0 Hz, 2 H), 7.60 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 9.0 Hz,
2 H), 8.42 (dd, J = 8.6, 2.4 Hz, 1 H), 9.12 (d, J = 2.3 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 3.54 (s, 3 H), 5.20 (s, 2 H), 6.35
(s, 1 H), 6.91 (d, J = 8.4 Hz, 2 H), 7.08–7.26 (m, 4 H), 7.68 (d,
J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.5 (CH3), 99.0 (CH), 114.5 (2 ×
CH), 120.1 (C), 123.3 (C), 125.9 (CH), 126.8 (CH), 127.5 (2 × CH),
129.0 (CH), 143.0 (C), 146.3 (C), 157.3 (C), 160.6 (C), 162.1 (C).
13C NMR (75 MHz, CDCl3): d = 55.3 (CH3), 69.0 (CH2), 99.5 (CH),
113.7 (2 × CH), 123.5 (CH), 126.0 (CH), 126.6 (CH), 126.9 (2 ×
CH), 127.8 (C), 128.2 (C), 129.1 (CH), 132.3 (C), 154.0 (C), 160.3
(C).
Anal. Calcd for C16H11NO5: C, 64.65; N, 4.71; H, 3.73. Found: C,
64.45; N, 4.58; H, 3.68.
MS (ES+): m/z = 298.0 [M + H+].
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.51; H,
5.84.
MS (ES+): m/z = 239.0 [M + H+].
3-(Naphthalen-1-yl)isocoumarin (2h)
Colorless solid; mp 120–122 °C.
Acknowledgment
IR (neat): 3091, 3042, 1938, 1715, 1638, 1606, 1566, 1508, 1486,
1454, 1396, 1352, 1310, 1241, 1200, 1178, 1154, 1116, 1065, 1023,
992, 956, 922, 881 cm–1.
The CNRS is gratefully thanked for support of this research. We
also thank the Servier Group for a doctoral fellowship to G.L.B.
1H NMR (300 MHz, CDCl3): d = 6.80 (s, 1 H), 7.47–7.61 (m, 5 H),
7.70–7.81 (m, 2 H), 7.86–8.00 (m, 2 H), 8.21–8.30 (d, J = 9.7 Hz,
1 H), 8.40 (d, J = 7.4 Hz, 1 H).
References
13C NMR (75 MHz, CDCl3): d = 107.1 (CH), 120.6 (C), 125.0 (CH),
125.1 (CH), 125.9 (CH), 126.3 (CH), 127.1 (CH), 127.7 (CH),
128.4 (CH), 128.6 (CH), 129.7 (CH), 130.6 (CH), 130.8 (C), 133.8
(2 × C), 134.9 (CH), 137.5 (C), 154.7 (C), 162.6 (C).
(1) Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med.
Chem. 1999, 7, 1445.
(2) Yoshikawa, M.; Harada, E.; Naitoh, Y.; Inoue, K.; Matsuda,
H.; Shimoda, H.; Yamahara, J.; Murakami, N. Chem.
Pharm. Bull. 1994, 42, 2225.
(3) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima,
S. Chem. Pharm. Bull. 1981, 29, 2689.
Anal. Calcd for C19H12O2: C, 83.81; H, 4.44. Found: C, 83.60; H,
4.27.
(4) Furuta, T.; Fukuyama, Y.; Asakawa, Y. Phytochemistry
1986, 25, 517.
(5) Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M.
3-(Pyridin-2-yl)isocoumarin (2i)
Yellow solid; mp 109–111 °C.
Bioorg. Med. Chem. Lett. 1998, 8, 215.
(6) Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Mallock, D. J. Nat.
Prod. 1996, 59, 765.
IR (neat): 3059, 3011, 1963, 1737, 1641, 1600, 1582, 1568, 1472,
1453, 1431, 1346, 1316, 1282, 1232, 1183, 1153, 1075, 1012, 990,
932, 899 cm–1.
(7) Lee, J. H.; Park, Y. J.; Kim, H. S.; Hong, Y. S.; Kim, K.-W.;
1H NMR (300 MHz, CDCl3): d = 7.47–7.65 (m, 1 H), 7.72–7.88 (m,
2 H), 7.90–8.14 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.54–8.63 (m,
1 H), 8.90–8.96 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 103.8 (CH), 120.0 (CH), 124.2 (C),
126.8 (CH), 127.0 (CH), 128.7 (CH), 129.8 (CH), 132.1 (C), 135.0
(CH), 137.1 (CH), 145.5 (C), 149.7 (CH), 152.2 (C), 168.7 (C).
Lee, J. J. J. Antibiot. 2001, 54, 463.
(8) For a review, see: Napolitano, E. Org. Prep. Proced. Int.
1997, 29, 631.
(9) For some recent examples, see: (a) Cherry, K.; Parrain,
J.-L.; Thibonnet, J.; Duchêne, A.; Abarbri, M. J. Org. Chem.
2005, 70, 6669. (b) Woon, E. C.; Dhami, A.; Mahon, M. F.;
Threadgill, M. D. Tetrahedron 2006, 62, 4829.
(c) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.;
Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8,
5517. (d) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.;
van de Weghe, P. Tetrahedron 2007, 63, 9979.
(10) Hellal, M.; Bourguignon, J.-J.; Bihel, F. Tetrahedron Lett.
2008, 49, 62.
(11) Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Synlett 2004, 2175.
(12) Le Bras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion,
J.-D. Tetrahedron Lett. 2006, 47, 5497.
Anal. Calcd for C14H9NO2: C, 75.33; N, 6.27; H, 4.06. Found: C,
75.29; N, 6.21; H, 3.97.
3-(n-Pentyl)isocoumarin (2j)
Yellow oil.
IR (neat): 2927, 1729, 1657, 1342, 1287, 1108 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88–0.95 (t, J = 7.8 Hz, 3 H),
1.05–1.40 (m, 6 H), 1.51–1.70 (m, 2 H), 6.20 (s, 1 H), 7.38 (d,
J = 7.8 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H),
8.17 (d, J = 7.8 Hz, 1 H).
(13) (a) Bekaert, A.; Provot, O.; Rasolojaona, O.; Peyrat, J.-F.;
Alami, M.; Brion, J.-D. Tetrahedron Lett. 2005, 46, 4187.
(b) Le Bras, G.; Provot, O.; Bekaert, A.; Peyrat, J.-F.; Alami,
M.; Brion, J.-D. Synthesis 2006, 1537. (c) L’Hermite, N.;
Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron 2006, 62, 11994. (d) Giraud, A.; Provot, O.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron 2006, 62,
7667.
13C NMR (75 MHz, CDCl3): d = 14.3 (CH3), 22.5 (CH2), 26.6
(CH2), 31.2 (CH2), 33.5 (CH2), 102.9 (CH), 120.1 (C), 125.4 (CH),
127.8 (CH), 129.9 (CH), 134.4 (CH), 136.7 (C), 158.3 (C), 167.1
(C).
Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.48; H,
7.27.
3-(4-Methoxyphenyl)-1H-isochromene (2k)
Colorless solid; mp 126–128 °C.
IR (neat): 1602, 1501, 1443, 1250, 1170, 1114, 1025, 803, 720 cm–1.
(14) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403.
Synthesis 2008, No. 10, 1607–1611 © Thieme Stuttgart · New York