Novel one-pot synthesis of polysubstituted isocoumarins from arynes and trifluoroacetylated β-diketones

Article abstract of DOI:10.1246/cl.131112

Polysubstituted isocoumarins such as thunberginol A were synthesized by the reaction of substituted 2-(trimethylsilyl)-phenyl triflate with trifluoromethylated β-diketones in the presence of CsF. The reaction proceeded via carboncarbon bond insertion of aryne followed by intramolecular cyclization and CF₃ anion extrusion. The C(..O)CF₃ unit has high potential for not only the nucleophilic moiety but also a useful leaving group of CF₃.

Full text of DOI:10.1246/cl.131112

CL-131112
Received: November 28, 2013 | Accepted: December 18, 2013 | Web Released: December 26, 2013
Novel One-pot Synthesis of Polysubstituted Isocoumarins
from Arynes and Trifluoroacetylated β-Diketones
Kentaro Okuma,* Koki Hirano, Yukiko Tanabe, Ryoichi Itoyama, Atsumi Miura,
Noriyoshi Nagahora, and Kosei Shioji
Department of Chemistry, Fukuoka University, Jonan-ku, Fukuoka 814-0180
(E-mail: kokuma@fukuoka-u.ac.jp)
Polysubstituted isocoumarins such as thunberginol A were
R
synthesized by the reaction of substituted 2-(trimethylsilyl)-
phenyl triflate with trifluoromethylated β-diketones in the
presence of CsF. The reaction proceeded via carbon-carbon
bond insertion of aryne followed by intramolecular cyclization
and CF3 anion extrusion. The -C(£O)CF3 unit has high potential
for not only the nucleophilic moiety but also a useful leaving
group of CF3.
O
O
R
O
O
R
CF3
CF3
O
O
a
+
CF3
Figure 1.
Table 1. Reaction of 4,4,4-trifluorobutane-1,3-dione 2 with
triflate 1a
Isocoumarins are valuable intermediates for the synthesis of
several natural products and important hetero- and carbocyclic
molecules, including isocarbostyrils, isoquinolines, and isochro-
menes.1 Substituted isocoumarins are attractive synthetic targets
because of their biological and pharmacological activities.2
Recent syntheses of these heterocycles include the palladium-
catalyzed coupling of 2-halobenzoate esters or 2-halobenzoni-
triles with alkenes, vinylic stannanes, or terminal alkynes and
the subsequent cyclization of π-allylnickel cross-coupling either
unsaturated phthalides or 3-substituted isocoumarins as the
major products.3 However, to our knowledge, there is no report
on the synthesis of isocoumarins from aryne precursors. The
carbon-carbon insertion reaction of arynes with β-dicarbonyl
compounds is one of the best methods for the synthesis of ortho-
substituted benzenes.4 Recently, we reported the reaction of β-
diketones with benzyne, which afforded the corresponding
4-substituted 2-naphthols in good yields.5 If trifluoromethyl-
substituted β-diketones were used as substrates, corresponding
ortho-substituted acetophenone intermediate a would be formed.
Moreover, if the trifluoroacetyl group of intermediate a was
attacked by an enolate, isocoumarin derivatives would be
synthesized in a one-pot operation (Figure 1). We applied this
method to the general synthesis of polysubstituted isocoumarins
by using trifluoromethylated β-diketones and arynes. Herein,
we describe a novel one-pot synthesis of isocoumarins from
benzyne precursors and trifluoroacetylated β-diketones.
Starting 4,4,4-trifluoro-1-p-tolylbutane-1,3-dione (2a) was
synthesized by the reaction of ethyl trifluoroacetate with
acetophenones in the presence of tert-BuOK.6 Treatment of
2-(trimethylsilyl)phenyl triflate (1a) with 2a in the presence of
CsF at rt resulted in the formation of 3-(p-tolyl)isocoumarin
(3a), 1-trifluoromethyl-3-(p-tolyl)-1H-isochromen-1-ol (4a), and
2-(trifluoroacetyl)-2¤-(p-toluoyl)diphenylmethane (5) in 36%,
8%, and 6% yields, respectively (Table 1, Entry 1). The structures
of compounds 3a, 4a, and 5 were determined by spectroscopic
analysis. The 19F NMR spectra of 4a and 5 showed characteristic
peaks at ¹75 and ¹77 ppm, respectively. When 1.7 equiv of 1a
was used, compounds 3a, 4a, and 5 were isolated in 48, 22,
and 20% yields, respectively (Entry 2). As the formation of
isocoumarin clearly showed that CF3 acted as a leaving group,
R
R
TMS
O
O
CsF
+
F3C
+
O
O
MeCN
R
OTf
HO
CF3
O
2a: R= p-Tol
2b: R= Me
3a: R= p-Tol
3b: R= Me
1a
4a: R= p-Tol
4b: R= Me
OH
F3C
O
+
+
F3C
O
p-Tol
O
5
6
Products yields/%
3a or 3b 4a or 4b 5 or 6
1a
/equiv
Entry
2
Temp.
1
2
3
4
5
6
1.2
1.7
1.1
1.7
1.7
1.7
2a
2a
2a
2a
2b
rt
rt
reflux
reflux
rt
36
48
55
71
46
68
8
22
0
0
22
0
6
20
9
12
12
6
2b reflux
we tried to conduct the reaction under refluxing conditions.
Treatment of triflate 1a (1.7 equiv) with β-diketone 2a and CsF
in refluxing acetonitrile for 6 h resulted in the formation of 3-(p-
tolyl)isocoumarine (3a), and diarylmethane 5 in 71% and 12%
yields, respectively (Entry 4). When 1,1,1-trifluoropentane-2,4-
dione (2b) was used as a starting β-diketone, 7,12-dihydro-7-
hydroxy-7-trifluoromethyldibenzo[a,d]cycloocten-5(6H)-one (6)
was isolated as a by-product in 12% yield (Entry 5).7 We have
already reported the reaction of butane-1,3-dione with triflate 1a
in the presence of CsF, which resulted in the formation of 4-
methyl-2-naphthol via intramolecular aldol condensation in
80% yield.5 Yoshida et al. have reported that the reaction of
trifluoromethyl ketones with aryne gave C-C bond insertion
products along with [2 + 2] cycloaddition and O-arylation
products.8 The result was quite different from ours except for the
formation of 5.
492 | Chem. Lett. 2014, 43, 492–494 | doi:10.1246/cl.131112
© 2014 The Chemical Society of Japan

Me
+ CsF
Table 2. Reaction of triflate 1 with trifluoromethylated 1,3-
diketones 2
Me
+ HCF3
70°C
O
O
CD3CN
O
O
R'
TMS
CsF
R
+
R
HO
CF3
F3C
R'
O
O
MeCN
3b
4b
OTf
reflux, 6 h
O
1
3
2
Scheme 1.
Entry
1
2
R′
Yield/%
70
Ph
TMS
OTf
O
a
O
1
2c
Ph
O
O
CF3
O
O
CF3
O
CF3
CF3
3c
O
1a
1a
OMe
Cl
R
R
O
R
O
p-MeOC6H4
p-ClC6H4
2
3
2d
2e
68
50
O
O
R
3
3d
3e
O
O
Minor route
O
1a
O
O
O
R
R
R
R
O
O
p-Tol
Me
Me
Me
Me
TMS
O
F3C
F3C
O
O
4
5
2a
2b
p-Tol
71
73
O
CF3
CF3
OTf
b
3f
O
1b
1b
O
O
H2
C
Me
Me
R
CH2
Me
H
O
Me
O
6
3g
O
CF3
O
TMS
OTf
MeO
MeO
Me
MeO
MeO
O
6
2a
Me
70
CF3
O
F3C
c
1c
3h
O
O
5
TMS
OTf
O
O
Me
O
O
7
8
2b
2c
Me
Ph
67
51
O
3i
Scheme 2. Reaction mechanism.
1d
1d
O
O
Ph
To confirm the leaving ability of trifluoroacetyl group under
the reaction conditions, we performed the reaction of hemiacetal
4b with CsF. Treatment of 4b with CsF in CD3CN at 70 °C for
6 h resulted in the complete formation of isocoumarin 3b and
fluoroform (Scheme 1). Without CsF, compound 4b was
recovered unchanged even after 2 days at 70 °C.
Thus, the reaction might proceed as follows: the reaction
initially produced C-C insertion product anion a, which
intramolecularly cyclized to give anion of hemiacetal 4, and 4
extruded CF3 anion to afford isocoumarin 3 (Scheme 2). At
room temperature, intermediate 4 was also isolated (major
route). Another initially formed C-C insertion product anion b
was further reacted with another benzyne to give 5. By using 2b
as a substrate, α-hydrogen of methyl ketone was further
abstracted to give enolate c, which further attacked trifluoro-
acetyl carbonyl carbon to give 6 (minor route).
Jablonski et al. reported that the reaction of trifluoroaceto-
phenone with potassium tert-butoxide gave trifluoromethyl
anion, which further reacted with benzophenones to give
trifluoromethylated diaryl alcohols.9 Trifluoroacetophenones
also reacted with alkoxide or hydroxide to give benzoates.10
Recently, Prakash et al. reported the nucleophilic trifluoro-
methylation of carbon centers, in which trifluoromethane was
used as trifluoromethyl anion source.11 However, to our knowl-
edge, there is no report on the intramolecular nucleophilic
cyclization of trifluoroacetophenone derivatives.
O
3j
O
TMS
OTf
F
F
Me
F
F
9
2b
2c
Me
Ph
61
53
O
1e
3k
O
OMe
TMS
OTf
Ph
10
O
1f
O
OMe
3l
We then applied this method to the synthesis of other
polysubstituted isocoumarins. Treatment of benzoylacetone 2c
with triflate 1a in the presence of CsF in refluxing acetonitrile
resulted in the formation of 3-phenylisocoumarin (3c) in 70%
yield. Other isocoumarins were similarly obtained in moderate
to good yields (Table 2). The yields were higher when electron-
donating groups (Me and MeO) were substituted at para-
position of aroylacetone 2 than when electron-withdrawing
group (Cl) was substituted (Entries 1-3). Generally, when
electron-donating groups, such as Me and MeO, were substituted
at aryne precursors, higher yields of isocoumarins were obtained
(Entries 4-7). When 4,5-difluoro-2-trimethylsilylphenyl triflate
(1e) was used as the substrate, 6,7-difluorinated isocoumarin 3k
Chem. Lett. 2014, 43, 492–494 | doi:10.1246/cl.131112
© 2014 The Chemical Society of Japan | 493

OMe
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TMS
OTf
O
OMe
CsF
O
1f
O
O
OMe
OMe
+
3m
OMe
OMe
F3C
BBr3
2f
3
4
OH
O
7
O
OH
OH
Thunberginol A
TMS
O
O
O
O
O
CsF
+
O
F3C
O
CH3CN
OTf
O
1d
2h
5
6
7
K. Okuma, R. Itoyama, A. Sou, N. Nagahora, K. Shioj, Chem.
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reflux, 3 h
8
Xyridine A
I. Katsuyama, S. Ogawa, Y. Yamaguchi, K. Funabiki, M.
Matsui, H. Muramatsu, K. Shibata, Synthesis 1997, 1321.
Structure of 6 was confirmed by spectroscopic and X-ray
crystallographic analysis. Crystallographic data for 6: triclinic,
Scheme 3. Synthesis of thunberginol A and xyridine A.
was obtained in 61% yield (Entry 9). When 3-methoxy-2-
trimethylsilylphenyl triflate (1f) was used as the aryne precursor,
only one regioisomer of isocoumarin 3l was formed, while the
yield was relatively low (Entry 10).
ꢀ
space group P1, a = 8.816(3), b = 11.502(4), c =
14.546(5) ¡,
¡ = 107.236(5),
¢ = 100.16(3),
£ =
93.981(4)°, Z = 4, R1 = 0.0353, wR2 (all data) = 0.0888.
CCDC 967214 contains the supplementary crystallographic
data for compound 6. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
The present method provides a general synthesis of 3,6,7,8-
substituted isocoumarins in a one-pot operation. To highlight the
utility of the developed isocoumarin chemistry we embarked on
the synthesis of naturally occurring isocoumarins, thunberginol
A (7)12 and xyridine A (8).13 The reported biological activity of
these compounds (antimicrobial, antiallergic, antidiabetic, and
anticancer) has resulted in a number of successful syntheses.2,14
Treatment of 1f with 2f in the presence of CsF at rt resulted in
the formation of 3-(3,4-dimethoxyphenyl)-8-methoxyisocou-
marin (3m) (53%), which was treated with BBr3 to afford
thunberginol A (7) (93%). Similarly, reaction of 1d with 1,1,1-
trifluoroheptane-2,4-dione (2g) in the presence of CsF gave
xyridine A 8 in 69% yield (Scheme 3).
In summary, polysubstituted isocoumarins were synthesized
by the reaction of triflate 1 with trifluoromethylated β-diketones
2 in moderate to good yields. The most interesting feature of this
reaction include intramolecular cyclization of enolate to tri-
fluoroacetyl moiety. This method provides a versatile synthesis
of polysubstituted isocoumarins in a one-pot operation.15
8
9
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2
15 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
494 | Chem. Lett. 2014, 43, 492–494 | doi:10.1246/cl.131112
© 2014 The Chemical Society of Japan