Synthesis of highly substituted isocoumarins by rhodium-catalyzed annulation of readily available benzoic acids

Article abstract of DOI:10.1016/j.tet.2012.11.092

Readily available benzoic acids possessing a number of oxygen-containing group(s) efficiently undergo oxidative coupling with alkynes through regioselective C-H bond cleavage under rhodium catalysis to form highly substituted isocoumarin derivatives. Such isocoumarins are of considerable interest due to their unique biological properties.

Full text of DOI:10.1016/j.tet.2012.11.092

Tetrahedron 69 (2013) 4454e4458
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Synthesis of highly substituted isocoumarins by rhodium-catalyzed
annulation of readily available benzoic acids
*
*
Yuto Unoh, Koji Hirano, Tetsuya Satoh , Masahiro Miura
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily available benzoic acids possessing a number of oxygen-containing group(s) efficiently undergo
oxidative coupling with alkynes through regioselective CeH bond cleavage under rhodium catalysis to
form highly substituted isocoumarin derivatives. Such isocoumarins are of considerable interest due to
their unique biological properties.
Received 8 September 2012
Received in revised form 26 November 2012
Accepted 27 November 2012
Available online 5 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Annulation
CeC coupling
CeH activation
Carboxylic acids
Rhodium
1. Introduction
substituted isocoumarin derivatives (Scheme 1). Such iso-
coumarins have been of considerable interest due to their unique
Multiply hydroxy- and methoxy-substituted benzoic acids in-
cluding gallic acid, syringic acid, and vanillic acid are widely pres-
ent in plants and are readily available from biomass.1 Especially,
they become more promising as building blocks, along with the
development of their production from abundant lignin. However,
the derivatization methods of such sustainable starting materials
have been less explored and thus their development is strongly
desired. Although few basic reactions, such as decarboxylation,2
esterification,3 and amidation4 have been performed, to our
knowledge, there is no report for their direct coupling involving
CeC bond formation, nor application to heterocycle synthesis.
On the other hand, we have continuously studied on developing
new coupling methods of aromatic carboxylic acids with un-
saturated compounds under transition-metal catalysis.5 Recently
we reported the rhodium-catalyzed oxidative coupling of simple
benzoic acid with internal alkynes5j,k involving CeH bond cleavage6
to produce isocoumarin derivatives. In the context of our work, it
has been revealed that this annulation procedure is applicable to
polysubstituted benzoic acids possessing a number of oxygen-
containing substituents, which are readily preparable from gallic,
syringic, and vanillic acids, to form the corresponding highly
biological properties.7 Compared with conventional multi-step
synthetic methods, the present direct annulation process is dra-
matically more atom- and step-economical. The results obtained
for the annulation are described herein.
O
R1
R2
CO2H
R1
R2
R5
[Cp*RhCl2]2
oxidant
O
+
R5
R4
R3
R3 R4
1a-e
2a-i
Scheme 1. Annulation of substituted benzoic acids 1.
3a-i,5-8
2. Results/discussion
In an initial attempt, the reaction of 3,4,5-trimethoxybenzoic acid
(1a) with diphenylacetylene (2a) was examined under conditions
similar to those previously employed for the reaction of unsub-
stituted benzoic acid with 2a,5j,k using [Cp*RhCl2]2 (Cp*¼
h
5-pen-
tamethylcyclopentadienyl; 1 mol %) and Cu(OAc)2$H2O (2 equiv) as
catalyst and oxidant, respectively, in o-xylene at 120 ꢀC under N2
(conditions A). As a result, their oxidative coupling product, 5,6,7-
trimethoxy-3,4-diphenylisocoumarin (3a), was obtained in 64%
yield (R1¼R2¼R3¼OMe, R4¼R5¼Ph in Scheme 1; entry 1 in Table 1).
* Corresponding authors. Tel.: þ81 66879 7361; fax: þ81 66879 7362; e-mail
addresses: satoh@chem.eng.osaka-u.ac.jp (T. Satoh), miura@chem.eng.osaka-u.ac.jp
(M. Miura).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.092

Y. Unoh et al. / Tetrahedron 69 (2013) 4454e4458
4455
Pd(OAc)2 (10 mol%)
P(1-Naph)3 (20 mol%)
PhBr (20 mol%)
Throughout thewhole study the choices of solvent and oxidant were
found to be important, depending on the solubilities and reactivities
of substrates. In this case, the use of DMF as solvent (conditions B)
brought about the improvement of the yield of 3a up to 86% yield
(entry 2). Under conditions B, methyl-, methoxy-, chloro-, and tri-
fluoromethyl substituted diphenylacetylenes 2bee also reacted
with 1a smoothly to produce the corresponding isocoumarins 3bee
(entries 2e6). The reaction of 1a with 1-phenyl-1-propyne (2f)
proceeded efficiently to afford isolable isocoumarin 3f pre-
dominantly, along with a minoramountof 3f0 (entry 7). The coupling
with 4-octyne (2g) was sluggish under conditions B (entry 8). It was
found that the reaction efficiency was improved by using Ag2CO3 as
oxidant in place of Cu(OAc)2$H2O in o-xylene (entry 9). Treatment of
1a with 2-methyl-4-phenyl-3-butyn-2-ol (2h) did not give any an-
nulation product at all under the standard conditions B (entry 10). In
this case using Cu(OAc)2$H2O, alkyne dimerization took place prior
to coupling with 1a to form 1,4-diphenyl-1,3-butadiyne (20%). For-
tunately, the use of Ag2CO3 suppressed the dimerization and effec-
tively induced the expected reaction. Thus, under the modified
conditions, isocoumarin 3h was produced in 95% yield (entry 11). It
should be noted that 3h was obtained in completely pure form: no
regioisomers being detected. The 2-hydroxyprop-2-yl substituent in
3h was found to be removable upon treatment with a palladium
catalyst system, previously developed by us (Scheme 2).8
O
O
O
MeO
MeO
MeO
MeO
Cs2CO3 (20 mol%)
O
Me
Me
Ph OH
o-xylene
170 oC, 16 h
MeO
MeO
Ph
3h (0.25 mmol)
4, 79%
Scheme 2. De(hydroxy)propylation of 3h.
As was proposed for the oxidative coupling of unsubstituted
benzoic acid with alkynes,5j,k the present reaction of 1a seems to
proceed through cyclorhodation at the ortho-position of a rhodiu-
m(III) benzoate intermediate, alkyne insertion to form a seven-
membered rhodacycle, and subsequent reductive elimination to
produce isocoumarin 3 (Scheme 3). The resulting Rh(I) species may
be reoxidized in the presence of a Cu(II) or Ag(I) salt to regenerate
a Rh(III) species. In the case using 2h, 3h was formed exclusively in
a good yield (entry 11 in Table 1). The observed high regioselectivity
in the alkyne insertion step may be due to the interaction between
hydroxy oxygen in 2h and the rhodium center.
MeO
MeO
MeO
CO2H
Table 1
O
O
Reaction of acid 1a with alkynes 2a
MeO
MeO
MeO
MeO
1a
O
RhX2
Entry
2
Time (h)
Product(s), % yieldb
O
RhX3
Rh
HX
2CuX or 2Ag
HX
X
O
MeO
R1
MeO
MeO
MeO
X
O
R2
MeO
X
2CuX2 or 2AgX
RhX
2
O
X
MeO
MeO
O
RhX
X
1c
2
3
4
5
2a: X¼H
2a: X¼H
5
4
7
6
5
6
3a: X¼H, 64 (46)
3a: X¼H, (86)
R2
R1
MeO
O
2b: X¼Me
2c: X¼OMe
2d: X¼Cl
3b: X¼Me, 83 (81)
3c: X¼OMe, (98)
3d: X¼Cl, 88 (65)
3e: X¼CF3, (79)
MeO
O
MeO
MeO
R2
6
2e: X¼CF3
R1
O
O
3
MeO
MeO
MeO
Ph
O
+
O
Scheme 3. A plausible mechanism for the reaction of 1a with 2.
Me
Ph MeO
Me
MeO
Me
MeO
Ph
7
2f
5
3fþ3f0, 85 (76) [4:1]
The reactions of variously substituted benzoic acids with 2a
were next examined. 4-Acetoxy-3,5-dimethoxybenzoic acid (1b)
coupled with 2a under conditions B to produce isocoumarin 5 in
a low yield (entry 1 in Table 2). In o-xylene, the yield of 5 somewhat
increased to 40% (entry 2). Finally, the use of Ag2CO3 as oxidant was
found to be a key to improve the reaction efficiency. Thus, 5 was
obtained in 82% yield (entry 3). Methoxymethyl protected syringic
acid 1c could also be employed for the annulation to form 6, along
with a minor amount of deprotected isocoumarin 60 (entry 4).
Treatment of syringic acid itself with 2a using Cu or Ag salt oxidant
did not give any annulated product at all. Therefore, 60 appears to be
formed via annulation/deprotection. Under similar conditions us-
ing Ag2CO3 as oxidant in DMF, the reaction of 4-acetoxy-3-
methoxybenzoic acid (1d) proceeded smoothly to produce iso-
coumarin 7, accompanied by formation of a negligible amount of 70,
arised from annulation at the sterically hindered ortho-position
(7:70¼24:1) (entry 5). 3,4-Dimethoxy- (1e) and 4-methoxybenzoic
acid (1f) underwent the coupling even under standard conditions
B to smoothly form the corresponding isocoumarins 8(þ80) and 9,
respectively (entries 6 and 7).
O
O
Pr
MeO
MeO
Pr
Pr
MeO
Pr
8
2g
2g
18
5
3g, 30
3g, 52 (46)
9c,d
O
O
MeO
MeO
Ph
Me
Me
R
MeO
Ph OH
10
2h: R¼CMe2(OH)
2h: R¼CMe2(OH)
6
9
3h, 0
3h, (95)
11d
a
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (0.005 mmol),
Cu(OAc)2$H2O (1 mmol) in DMF (2.5 mL) at 120 ꢀC for 4e7 h under N2.
b
GC yield based on the amount of 1a used. Value in parentheses indicates yield
after purification.
c
In o-xylene (2.5 mL).
Ag2CO3 (0.5 mmol) was used in place of Cu(OAc)2$H2O.
d

4456
Y. Unoh et al. / Tetrahedron 69 (2013) 4454e4458
Diarylacetylenes 2bee9 and benzoic acids 1b,10 1c,11 and 1d10
were prepared according to published procedures. Other starting
materials were commercially available.
Table 2
Reaction of acids 1 with alkyne 2aa
Entry
1
Time (h)
Product(s), % yieldb
The following experimental procedures may be regarded as
typical in methodology and scale.
O
MeO
AcO
CO2H
MeO
O
AcO
Ph
4.2. Reaction of 3,4,5-trimethoxybenzoic acid (1a) with di-
phenylacetylene (2a) (entry 2 in Table 1)
OMe
MeO
Ph
1c
2
1b
1b
1b
6
11
6
5, 25
5, 40
5, 82 (79)
A mixture of 3,4,5-trimethoxybenzoic acid (1a) (0.5 mmol,
106 mg), diphenylacetylene (2a) (0.6 mmol, 107 mg), [Cp*RhCl2]2
(0.005 mmol, 3.1 mg), Cu(OAc)2$H2O (1.0 mmol, 200 mg), and
dibenzyl (ca. 40 mg) as internal standard was stirred in DMF
(2.5 mL) under nitrogen at 120 ꢀC for 4 h. GC and GCeMS analyses
of the mixtures confirmed formation of 3a. After cooling, the re-
action mixture was extracted with dichloromethane (40 mL). The
organic layer was washed by water (40 mL, three times), and
dried over Na2SO4. After evaporation of the solvent under vac-
uum, the product 3a (166 mg, 86%) was isolated by column
chromatography on silica gel using hexaneeethyl acetate (75:25,
v/v) as eluent.
3d
O
O
MeO
CO2H
MeO
MeO
HO
O
O
MOMO
MOMO
Ph
Ph
OMe
OMe Ph
Ph
OMe
4c,d
1c
4 6, (60)
60, (14)
Ph
Ph
O
O
MeO
AcO
CO2H
MeO
AcO
MeO
AcO
O
O
O
+
Ph
Ph
O
4.3. Characterization data of products
5c,d
1d
4
7þ70, (76) [24:1]
Ph
4.3.1. 5,6,7-Trimethoxy-3,4-diphenylisocoumarin (3a). Mp 137e
Ph
140 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.12 (s, 3H), 3.90 (s, 3H), 4.00 (s,
O
MeO
MeO
CO2H
MeO
MeO
MeO
MeO
3H), 7.1e7.3 (m,10H), 7.74 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
56.3,
O
+
60.8, 61.0, 106.9, 115.1, 116.8, 126.9, 127.0, 127.5, 127.6, 128.4, 129.5,
131.0, 133.5, 136.8, 149.4, 150.1, 150.2, 153.9, 162.2; HRMS m/z (Mþ)
calcd for C24H20O5: 388.1311. Found 388.1313.
Ph
Ph
6
1e
4
5
8þ80, (93) [12:1]
O
4.3.2. 5,6,7-Trimethoxy-3,4-bis(4-methylphenyl)isocoumarin
CO2H
(3b). Mp 180e182 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.25 (s, 3H),
2.36 (s, 3H), 3.12 (s, 3H), 3.90 (s, 3H), 3.99 (s, 3H), 6.95 (m, 2H),
7.07e7.15 (m, 6H), 7.72 (s, 1H); 13C NMR (100 MHz, CDCl3):
21.25,
O
MeO
MeO
Ph
d
Ph
21.32, 56.3, 60.90, 60.94, 106.8, 114.6, 116.7, 127.3, 128.28, 128.33,
129.4, 130.7, 130.8, 133.9, 136.4, 138.3, 149.4, 150.1, 150.3, 153.6,
162.3; HRMS m/z (Mþ) calcd for C26H24O5: 416.1624. Found
416.1621.
7
1f
9, 81 (74)
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (0.005 mmol),
Cu(OAc)2$H2O (1 mmol) in o-xylene (2.5 mL) at 120 ꢀC for 4e7 h under N2.
b
GC yield based on the amount of 1 used. Value in parentheses indicates yield
after purification.
c
4.3.3. 5,6,7-Trimethoxy-3,4-bis(4-methoxyphenyl)isocoumarin
In DMF (2.5 mL).
Ag2CO3 (0.5 mmol) was used in place of Cu(OAc)2$H2O.
d
(3c). Mp 186e187 ꢀC; 1H NMR (400 MHz, CDCl3):
d 3.14 (s, 3H), 3.75
(s, 3H), 3.82 (s, 3H), 3.91 (s, 3H), 3.99 (s, 3H), 6.68 (d, J¼9.2 Hz, 2H),
6.83 (d, J¼8.7 Hz, 2H), 7.15e7.18 (m, 4H), 7.71 (s, 1H); 13C NMR
3. Conclusion
(100 MHz, CDCl3):
d 55.15, 55.21, 56.3, 60.9, 61.0, 106.9, 113.0 (2C),
113.8, 116.6, 126.1, 127.4, 129.2, 130.9, 132.1, 149.4, 150.1, 150.2, 153.5,
158.5, 159.4, 162.3; HRMS m/z (Mþ) calcd for C26H24O7: 448.1522.
Found 448.1519.
In summary, we have demonstrated that the rhodium-catalyzed
oxidative coupling of polysubstituted benzoic acids with alkynes
proceeds efficiently through ortho-CeH bond cleavage. The re-
action provides straightforward synthetic routes to the corre-
sponding isocoumarin derivatives from the readily available
starting materials.
4.3.4. 5,6,7-Trimethoxy-3,4-bis(4-chlorophenyl)isocoumarin (3d). Mp
201e202 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.16 (s, 3H), 3.91 (s, 3H),
4.00 (s, 3H), 7.1e7.2 (m, 6H), 7.26e7.28 (m, 2H), 7.71 (s, 1H); 13C NMR
(100 MHz, CDCl3): 56.3, 60.8, 61.0, 107.0, 114.3, 116.7, 126.2, 127.9,
d
4. Experimental section
4.1. General
128.0, 130.7, 131.7, 132.2, 133.1, 134.7, 135.2, 149.1, 149.4, 150.0, 154.1,
161.6; HRMS m/z (Mþ) calcd for C24H18Cl2O5: 456.0531. Found
456.0536.
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, for CDCl3 solutions. MS data were obtained by EI. GC
analysis was carried out using a silicon OV-17 column (i.d.
2.6 mmꢁ1.5 m) or a CBP-1 capillary column (i.d. 0.5 mmꢁ25 m).
GCeMS analysis was carried out using a CBP-1 capillary column (i.d.
0.25 mmꢁ25 m). The structures of all products were un-
ambiguously determined by 1H and 13C NMR with the aid of NOE,
COSY, HMQC, and HMBC experiments.
4.3.5. 5,6,7-Trimethoxy-3,4-bis(4-trifuloromethylphenyl)isocoumarin
(3e). Mp 160e162 ꢀC; 1H NMR (400 MHz, CDCl3):
d 3.13 (s, 3H),
3.92 (s, 3H), 4.17 (s, 3H), 7.31 (d, J¼8.7 Hz, 2H), 7.41 (d,
J¼8.2 Hz, 2H), 7.43 (d, J¼8.7 Hz, 2H), 7.58 (d, J¼8.2 Hz, 2H), 7.73
(s, 1H); 13C NMR (100 MHz, CDCl3):
d 56.4, 60.7, 61.0, 107.2,
115.1, 116.8, 123.7 (q, J¼271 Hz), 124.1 (q, J¼271 Hz), 124.7 (q,
J¼3.8 Hz), 124.8 (q, J¼3.8 Hz), 125.7, 129.6 (q, J¼32 Hz), 129.8,
130.6 (q, J¼32 Hz), 131.2, 136.5, 140.5, 148.6, 149.4, 150.0, 154.5,

Y. Unoh et al. / Tetrahedron 69 (2013) 4454e4458
4457
161.4; HRMS m/z (Mþ) calcd for C26H18F6O5: 524.1058. Found
524.1061.
7.15e7.35 (m, 7H), 7.39e7.46 (m, 3H), 7.78 (s, 1H); 13C NMR
(100 MHz, CDCl3): 56.0, 56.4, 106.2, 109.4, 113.8, 116.7, 127.8, 128.2,
d
128.7, 129.09, 129.13, 131.1, 133.1, 134.5, 134.6, 149.6, 150.1, 154.9,
162.2; HRMS m/z (Mþ) calcd for C23H18O4: 358.1205. Found
358.1208.
4.3.6. 5,6,7-Trimethoxy-4-methyl-3-phenylisocoumarin
115e117 ꢀC; 1H NMR (400 MHz, CDCl3):
2.43 (s, 3H), 3.92 (s, 3H),
3.99 (s, 3H), 4.00 (s, 3H), 7.4e7.5 (s, 3H), 7.55e7.60 (m, 2H), 7.69 (s,
1H); 13C NMR (100 MHz, CDCl3):
16.6, 56.3, 61.0, 61.6, 107.1, 108.8,
(3f). Mp
d
d
4.3.15. 6-Methoxy-3,4-diphenylisocoumarin (9).12 Mp 171e174 ꢀC;
117.4,127.4,128.2,129.1,129.8,133.7,149.1,149.6,150.8,153.5,162.3;
1H NMR (400 MHz, CDCl3):
d
3.75 (s, 3H), 6.58 (d, J¼2.28 Hz, 1H),
HRMS m/z (Mþ) calcd for C19H18O5: 326.1154. Found 326.1158.
7.05 (dd, J¼2.76, 8.72 Hz, 1H), 7.15e7.26 (m, 5H), 7.30e7.33 (m, 2H),
7.38e7.42 (m, 3H), 8.33 (d, J¼8.72 Hz, 1H); 13C NMR (100 MHz,
4.3.7. 5,6,7-Trimethoxy-3,4-di-n-propylisocoumarin (3g). Mp 85e
CDCl3): d 55.5, 108.5, 113.7, 115.6, 116.8, 127.8, 128.2, 128.9, 129.1,
87 ꢀC; 1H NMR (400 MHz, CDCl3):
d
0.98e1.03 (m, 6H), 1.51e1.57 (m,
129.3, 131.2, 131.9, 133.0, 134.4, 141.2, 151.2, 162.0, 164.7; HRMS m/z
2H),1.73 (qt, J¼7.8, 7.8 Hz, 2H), 2.56 (t, J¼7.8 Hz, 2H), 2.69 (t, J¼7.8 Hz,
(Mþ) calcd for C22H16O3: 328.1099. Found 328.1102.
2H), 3.91 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 7.64 (s, 1H); 13C NMR
(100 MHz, CDCl3):
d 13.8, 14.3, 21.5, 24.2, 30.0, 32.5, 56.1, 60.8, 61.5,
Acknowledgements
107.0, 111.9, 117.2, 126.3, 148.8, 149.7, 152.2, 152.8, 162.7; HRMS m/z
(Mþ) calcd for C18H24O5: 320.1624. Found 320.1624.
This work was partly supported by Grants-in-Aid from MEXT
and JSPS, Japan.
4.3.8. 3-(2-Hydroxypropan-2-yl)-5,6,7-trimethoxy-4-phenylisocoum-
arin (3h). Mp 110e111 ꢀC; 1H NMR (400 MHz, CDCl3):
d
1.43 (s, 6H),
1.74 (s, 1H), 3.09 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H), 7.32e7.42 (m, 5H),
7.66 (s, 1H); 13C NMR (100 MHz, CDCl3):
30.1, 56.2, 60.6, 60.8, 74.0,
Supplementary data
Copies of 1H and 13C NMR spectra of 3e9. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2012.11.092.
d
106.5, 112.6, 116.3, 127.0, 127.5, 127.7, 130.3, 136.7, 149.4, 150.3, 153.8,
155.2, 161.5; HRMS m/z (Mþ) calcd for C21H22O6: 370.1416. Found
370.1414.
References and notes
4.3.9. 5,6,7-Trimethoxy-4-phenylisocoumarin (4). Mp 170e171 ꢀC;
1H NMR (400 MHz, CDCl3):
d
3.19 (s, 3H), 3.92 (s, 3H), 3.99 (s, 3H),
ꢀ
ꢀ
ꢀ
1. Selectedexamples:(a)Chavez-Gonzalez,M.;Rodríguez-Duran,L. V.;Balagurusamy,
ꢀ
7.00 (s, 1H), 7.33e7.39 (m, 5H), 7.70 (s, 1H); 13C NMR (100 MHz,
N.; Prado-Barragan, A.; Rodríguez, R.; Contreras, J. C.; Aguilar, C. N. Food Bioprocess
Technol. 2012, 5, 445; (b) Moodley, B.; Mulholland, D. A.; Brookes, H. C. Water SA
2012, 38,1; (c) van Haveren, J.; Scott, E. L.; Sanders, J. Biofuels, Bioprod. Biorefin. 2008,
2, 41; (d) Xu, Y.; Hanna, M. A.; Isom, L. Open Agric. J. 2008, 2, 54; (e) Kambourakis, S.;
Draths, K. M.; Frost, J. W. J. Am. Chem. Soc. 2000, 122, 9042.
CDCl3): d 56.3, 60.9, 61.1, 107.4, 117.3, 118.6, 125.4, 127.4, 127.5, 129.7
(overlapped), 136.1, 141.6, 149.4, 153.9, 162.0; HRMS m/z (Mþ) calcd
for C18H16O5: 312.0998. Found 312.0999.
€
2. (a) Sietmann, R.; Uebe, R.; Boer, E.; Bode, R.; Kunze, G.; Schauer, F. J. Appl.
Microbiol. 2010, 108, 789; (b) Sharma, A.; Kumar, R.; Sharma, N.; Kumar, V.;
Sinha, A. K. Adv. Synth. Catal. 2008, 350, 2910.
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Cocuzza, C. E. A.; Pori, M.; Quintavalla, A.; Musumeci, R.; Giacomini, D. Chem-
MedChem 2011, 6, 1919; (c) Catel, Y.; Aladedunye, F.; Przybylski, R. J. Agric. Food
Chem. 2010, 58, 11081.
4.3.10. 6-Acetoxy-5,7-dimethoxy-3,4-diphenylisocoumarin (5). Mp
187e189 ꢀC; 1H NMR (400 MHz, CDCl3):
d
2.32 (s, 3H), 3.02 (s, 3H),
3.96 (s, 3H), 7.1e7.3 (m,10H), 7.79 (s,1H); 13C NMR (100 MHz, CDCl3):
20.5, 56.6, 61.4,107.1,114.8,119.5,126.6,127.2,127.57,127.64,128.5,
d
4. (a) Serradjia, N.; Bensaida, O.; Martinc, M.; Sallema, W.; Dereuddre-Bosquetd, N.;
Benmehdia, H.; Redeuilha, C.; Lamouria, A.; Divee, G.; Clayetted, P.; Heymansa, F.
Bioorg. Med. Chem. 2006, 14, 8109; (b) Serradji, N.; Martin, M.; Bensaid, O.;
Cisternino, S.; Rousselle, C.; Dereuddre-Bosquet, N.; Huet, J.; Redeuilh, C.;
Lamouri, A.; Dong, C.-Z.; Clayette, P.; Scherrmann, J.-M.; Dormont, D.; Heymans, F.
J. Med. Chem. 2004, 47, 6410.
5. (a) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024; (b)
Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2011, 13, 706; (c) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth.
Catal. 2011, 353, 631; (d) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2010, 12, 5776; (e) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2009, 74, 7481; (f) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J.
Org. Chem. 2009, 74, 6295; (g) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2009, 11, 2337; (h) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2009, 74, 3478; (i) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett.
2008, 10, 1159; (j) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362;
(k) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407; (l) Miura, M.; Tsuda,
T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211 See also
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129.5,131.2,133.3,136.1,140.3,149.8,150.5,152.5,161.8,167.7; HRMS
m/z (Mþ) calcd for C25H20O6: 416.1260. Found 416.1258.
4.3.11. 5,7-Dimethoxy-6-(methoxymethoxy)-3,4-diphenylisocoumarin
(6). Mp 120e122 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.09 (s, 3H), 3.55
(s, 3H), 4.00 (s, 3H), 5.17 (s, 2H), 7.11e7.26 (m, 10H), 7.75 (s, 1H); 13C
NMR (100 MHz, CDCl3): 56.3, 57.5, 60.7, 98.6, 107.0, 115.1, 117.3,
d
127.0, 127.5, 127.6, 128.4, 129.6, 131.1, 133.5, 136.7, 146.3, 150.2, 150.5,
153.9, 162.1; HRMS m/z ([MþNa]þ) calcd for C25H22NaO6: 441.1309.
Found 441.1308.
4.3.12. 5,7-Dimethoxy-6-hydroxy-3,4-diphenylisocoumarin (60). Mp
221e222 ꢀC; 1H NMR (400 MHz, CDCl3):
d
3.08 (s, 3H), 4.05 (s, 3H),
6.14 (br, 1H), 7.11e7.27 (m, 10H), 7.74 (s, 1H); 13C NMR (100 MHz,
CDCl3): 56.6, 60.8,106.4,113.3,114.9,127.1,127.2,127.5,127.6,128.5,
d
6. Selected reviews concerning CeH bond functionalization: (a) Colby, D. A.; Tsai,
A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814; (b) Engle, K. M.;
Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788; (c) Cho, S. H.; Kim, J.
Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068; (d) Wencel-Delord, J.;
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740; (e) Kuninobu, Y.;
Takai, K. Chem. Rev. 2011, 111, 1938; (f) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem.
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Miura, M. Chem.dEur. J. 2010, 16, 11212; (i) Lapointe, D.; Fagnou, K. Chem. Lett.
2010, 39, 1118; (j) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (k)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; (l) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 677; (m) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (n) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074; (o) Thansandote, P.; Lautens, M.
Chem.dEur. J. 2009, 15, 5874; (p) McGlacken, G. P.; Bateman, L. M. Chem. Soc.
Rev. 2009, 38, 2447; (q) Li, C.-J. Acc. Chem. Res. 2009, 42, 335; (r) Vasil’ev, A. V.
Russ. J. Org. Chem. 2009, 45, 1; (s) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013; (t)
Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron 2008, 64, 5987; (u) Park, Y. J.;
Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222; (v) Beccalli, E. M.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318; (w) Alberico, D.;
129.6, 131.3, 133.5, 136.4, 142.7, 146.0, 148.0, 150.6, 162.3; HRMS m/z
([MþNa]þ) calcd for C23H18NaO5: 397.1046. Found 397.1047.
4.3.13. 6-Acetoxy-7-methoxy-3,4-diphenylisocoumarin (7) and 6-
acetoxy-5-methoxy-3,4-diphenylisocoumarin (70) [24:1]. 1H NMR
(400 MHz, CDCl3): d
2.28 (s, 3H), 2.31 (s, 3H, 70), 3.01 (s, 3H, 70), 3.97
(s, 3H), 6.87 (s, 1H), 7.14e7.32 (m, 7H), 7.37e7.44 (m, 3H), 7.91 (s,
1H), 8.26 (d, J¼8.24 Hz, 1H, 70); 13C NMR (100 MHz, CDCl3):
d 20.6,
56.5, 111.3, 116.4, 119.2, 119.6, 127.9, 128.3, 128.9, 129.1, 129.2, 131.2,
132.8, 133.5, 134.2, 145.9, 150.1, 151.6, 161.8, 168.2; HRMS m/z
([MþH]þ) calcd for C24H19O5: 387.1227. Found 387.1226.
4.3.14. 6,7-Dimethoxy-3,4-diphenylisocoumarin(8). Mp 196e198 ꢀC;
1H NMR (400 MHz, CDCl3):
d 3.74 (s, 3H), 4.02 (s, 3H), 6.56 (s, 1H),

4458
Y. Unoh et al. / Tetrahedron 69 (2013) 4454e4458
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